2handbook of Occupational Dermatology

Part 1
Epidemiology, Treatment, and Prognosis

L. Kanerva • P. Eisner • J. E. Wahlberg • H. I. Maibach (Eds.)
Handbook of Occupational Dermatology
Springer-Verlag Berlin Heidelberg GmbH
L. Kanerva . P. Eisner . J. E. Wahlberg . H.1. Maibach
Editors
Handbook
of Occupational
Dermatology
With 194 Figures, 70 in colour
and 350 rabIes
, Springer
Prof. Lasse Kanerva, M.D., Ph.D. Univ.-Prof. Dr.med. P. Eisner
Section of Dermatology Klinikum der FSU Jena
Finnish Institute of Occupational Health Klinik für Hautkrankheiten
Topeliuksenkatu 41 aA Erfurter Straße 35
00250 Helsinki, Finland 07740 Jena, Germany
Prof. Jan E. Wahlberg, M.D., Ph.D. Prof. Howard I. Maibach, M.D.

Department of Occupational Dermatology University of California
Karolinska Hospital School of Medicine
and the National Institute for Working Life Box 0989, Surge 100
11776 Stockholm, Sweden San Francisco, CA 94143-0989, USA
This book has been supported by the Scientific Committee of the International
Commission of Occupational Health (ICOH) and the Working Group on Occupational
Dermatoses, European Society of Contact Dermatitis (ESCD).
ISBN 978-3-662-07679-8 ISBN 978-3-662-07677-4 (eBook)

DOI 10.1007/978-3-662-07677-4
Library of Congress Catatoging in-Publication Data

Handbook of occupational dermatology / [edited by] 1. Kanerva ... [et al.]. p.; cm. Includes biblio-
graphical references and index. 1. Occupational dermati-
tis-Handbooks, manuals, etc. 2. Skin-Diseases-Handbooks, manuals, etc. 3. Dermatotoxicology-
Handbooks, manuals, etc. I. Kanerva, 1. (Lasse), 1943- . [DNLM: 1. Dermatitis, Occupational-eti-
ology-Handbooks. 2. Skin-Diseases-chemically induced-Handbooks. WR 39 H236 20000]
RL241 .H362000 616.5'I-dc21 99-053897
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© Springer-Verlag Berlin Heidelberg 2000
Originally published by Springer-Verlag Berlin Heidelberg New York in 2000.
Softcover reprint of the hardcover I st edition 2000
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Preface
The field of occupational dermatology has been weH mented by late twentieth and early twenty-first cen-
served by textbooks. The twentieth century giants in tury clinical bioassays.
this field have produced books that are universally Although the field is served by general dermatol-
accepted. These include Schwartz, Tullipan, and ogists, occupational physicians, and occupational
Birmingham, as weH as Fousseau and Adams. dermatologists, other health workers are also fre-
What then is the need in terms of the next gener- quendy involved. For this reason, we have deliberate-
ation of textbooks in this rapidly evolving and com- ly included a number of redundancies in an attempt
plex clinical research area? The varied complexity to make it easier for the reader. Whenever possible,
and inordinate detail of information makes it diffi- we have emphasized evidence-based dermatology,
cult for any one individual to cover this huge and the authors were chosen on the basis of both
expanse of knowledge. The present volume stresses their scientific approach and clinical good sense.
individual exceHence and scholarship covering the HopefuHy, a second edition will benefit by
various areas. It is not meant to be a static book. If increased controHed experimentation currently
the readership finds it as interesting as the editors under way, so that there will be even more hard data
and authors have, this should evolve over genera- included. The editors welcome YOUf comments for
tions.The information in the various chapters the proposed second edition.
includes nineteenth century approach es, such as
morphology and histology, but is amply supple- The Editors
Contents
Part 1: Epidemiology. Treatment, Oeeupational Marks ......................... 137

and Prognosis 1. Kanerva
The Epidemiology Oeeupational Dermatitis Artefacta ............. 141
of Oecupational Contaet Dermatitis 3 G.Angelini
T.1. Diepgen and P.J. Coenraads
Physieal Causes - Heat, Cold and Other
The Role of Clinieal Epidemiology in the Atmospherie Faetors ......................... 148
Study of Oeeupational Contaet Dermatitis . . . . . .. 17 W. Uter and 1. Kanerva
A. Sehnueh and W. Uter
Meehanieal Causes
Classifieation of Oeeupations . . . . . . . . . . . . . . . . .. 27 of Oecupational Skin Disease .................. 157
W. Uter 1. Kanerva
Dermatotoxieology . . . . . . . . . . . . . . . . . . . . . . . . .. 32 Raynaud's Phenomenon ("White Fingers")
P. Hewitt and H. I. Maibach in Workers Using Hand-Held Vibrating Tools
G. Gemne .................................. 162
Systemie Toxieity . . . . . . . . . . . . . . . . . . . . . . . . . . .. 43
P. Hewitt and H. I. Maibach Physieal and Cholinergic Urtiearia ............. 167
The Strueture of the Human Skin Barrier ....... 56 M.Henz
B. Forslind Biologie Causes of Oeeupational Dermatoses ..... 179
Evaluation of Barrier Funetions and Skin J.M. Laehapelle
Reaetivity in Oecupational Dermatoses ......... 64 Oeeupational Airborne Skin Diseases ........... 193
S. Seidenari J.M. Laehapelle
Hydration Injury to Human Skin: Oeeupational Contaet Urtiearia ................ 200
A View from the Horny Layer ................. 76 S.l. Ale and H. I. Maibach
A.M. Kligman
Oeeupational Contaet Urtiearia in Numbers ..... 217
Measurement of Dermal Exposure ............. 81 1. Kanerva, R. Jolanki, and T. Estlander
S. Sadhra and I.S. Foulds
Non-Immunologie Contact Urtiearia ........... 221
Occupational Dry Skin ......... . . . . . . . . . . . . .. 90 A. Lahti
M.Gon~alo
Oeeupational and Environmental Aene .......... 225
Contact Dermatitis Due to Irritation ........... 99 K. MeDonnell and J.S. Taylor
W. Wigger-Alberti and P. Eisner
Oceupational Aquatie Dermatology ............ 234
Repeated Low-Grade Frietional Trauma ......... 111 G.Angelini
S. Freeman
Oeeupational Skin Cancer and Tumors .......... 248
Skin Hardening C.P. Callahan, H.F. Merk,
in Oecupational Dermatology ................. 115 and B. Blämeke
B. Wulfhorst
Oeeupational Diseases of the Oral Mueosa ....... 254
Fiberglass Dermatitis ........................ 122 1. Kanerva
A. Sertoli, S. Franealanei, and S. Giorgini
Oeeupational Nail Disorders .................. 259
Oeeupational Skin Granulomas ................ 135 R. Baran
P. D. Pigatto and A.S. Bigardi
VIII Contents
Chemically Induced Hair Loss ................. 267 Identification and Assessment in Relation
S. Heshmati and H.1. Maibach to the Material Safety Data Sheets .............. 395
D. A. Basketter and L. Kanerva
The Psoriasis Patient and Work ................ 273
Y.-H. Leow and C. L. Goh Treatment of Irritant
and Allergic Contact Dermatitis ............... 402
Non-eczematous Occupational Contact
H. Zhai, A. Anigbogu, and H.1. Maibach
Reactions .................................. 275
C.L. Goh Prevention and Rehabilitation ................. 412
J.E. Wahlberg
Occupational Pigmentary Disorders ............ 280
P. Wattanakrai, L. Miyamoto, Protective Gloves ............................ 417
and J.S. Taylor G.A. Mellström and A. Boman
Occupational Connective Tissue Disorders ...... 295 Disadvantages of Gloves ...................... 426
u.F. Haustein and B. Haupt T. Estlander, J. Jolanki, and L. Kanerva
Occupational Phototoxicity and Photoallergy .... 314 Plant Survey and Inspection .................. 437
V. DeLeo R.J.G. Rycroft
Chemical Skin Bums ......................... 325 Workers' Education .......................... 441
M. Bruze, S. Fregert, and B. Gruvberger H.J. Schwanitz and B. Wulfhorst
Chronic Venous Insufficiency and Occupation .... 333 Prognosis
E.M. de Boer and R.M.A. Krijnen of Occupational Contact Dermatitis ............ 444
c.L. Goh
Human Immunodeficiency Virus J/ Acquired
Immunodeficiency Syndrome
Part 2: Substandes and Products
in the Workplace ............................ 338
S.-L. Valle and A. Ranki Computerized Product Database.
Registered Chemical Contact Allergens ......... 451
Operational Definition of Occupational Allergic
M.-A. Flyvholm
Contact Dermatitis .......................... 344
S. Ale and H.1. Maibach Antimicrobials and Disinfectants .............. 462
C. Timmer
Occupational and Non-occupational
Compound Allergy .......................... 351 Formaldehyde and Formaldehyde
S.J. Bashir, L. Kanerva, R. Jolanki, Releasers .................................. 474
and H.1. Maibach M.-A. Flyvholm
The Role of Atopy in Working Life ............. 356 Pharmaceutical Drug Allergens ................ 479
K. Kalimo and K. Lammintausta A.J. Bircher
Job Fitness Evaluation ........................ 360 Barrier Creams and Emollients ................ 490
M. Crippa and G. Pasolini W. Wigger-Alberti and P. Elsner
Risk Management of Occupational Hazards Fragrances ................................. 497
at the Workplace ............................ 367 A.C. de Groot
U.Funke
Colophony ................................. 509
Diagnostic Patch Testing ..................... 371 A. T. Karlberg
J.E. Wahlberg
Industrial Enzymes .......................... 517
Patch Testing With a Patient's Own L. Kanerva and M. Vanhanen
Materials Handled at Work .................... 375
Nickel ..................................... 524
R. Jolanki, T. Estlander,
C.Liden
K. Alanko, and L. Kanerva
Chromium ................................. 534
Physicochemical Methods for Detection
D.Burrows
of Occupational Contact Allergens ............. 384
B. Gruvberger, M. Bruze, and S. Fregert Hard Metals ................................ 541
T. Fischer
Sources of Information on the Occurrence
of Chemical Contact Allergens ................. 392 Gold ...................................... 544
M.-A. Flyvholm M. Isaksson and M. Bruze
Contents IX
Other Metals ............................... 551 Woods .................................... 771

J.E. Wahlberg B.M. Hausen
Cement .................................... 556 Pesticide-Related Dermatoses
C.Avnstorp in Agricultural Workers ...................... 781
W. Manuskiatti, K. Abrams,
Acrylic Resins .............................. 562
D.J. Hogan, and H.1. Maibach
B. Björkner
Epoxy Resins ............................... 570 Part 3: Job Describtions with Their Irritants
R. Jolanki, 1. Kanerva, and Allergens
and T. Estlander
Aircraft Industry ............................ 805
Phenol-Formaldehyde Resins .................. 591 M. Isaksson and M. Bruze
E. Zimerson and M. Bruze
Air Hammer Operators ....................... 808
Polyurethane Resins ......................... 597 D.J. Gawkrodger
T. Estlander, 1. Kanerva, and R. Jolanki
Aromatherapists ............................ 811
Polyester Resins ............................. 602 K.Alanko
1. Kanerva, K. Tarvainen,
Asphalt Workers (Paving) ..................... 814
T. Estlander, and R. Jolanki
R. Riala and P. Heikkilä
Other Plastics .............................. 607
Automobile Mechanics ....................... 816
B. Björkner
U.Funke
Plastic Composites .......................... 611
Bakers ..................................... 817
K. Tarvainen and 1. Kanerva
N.K.Veien
Textiles .................................... 622
Barbers and Hairdressers ..................... 821
K.1. Hatch and H.1. Maibach
A. Alomar and 1. Conde-Salazar
Leather and Shoes ........................... 637
Bartenders ................................. 824
J. Geier
1. Kanerva
Adhesives and Glues ......................... 644
Bath Attendants ............................. 826
M. Gebhardt and P. Eisner
A. Barbaud
The Electronics Industry ..................... 650
Batik Manufacturing Workers .................. 830
S.C. Tucker and J.S.C. English
R.W. Soebaryo
Paints, Lacquers and Varnishes ................ 662
Battery Makers ............................. 838
T. Estlander, R. Jolanki,
M.H.Beck
and 1. Kanerva
Beekeepers ................................. 840
Organic Solvents ............................ 679
T. Karamfilov and P. Eisner
A. Boman and J.E. Wahlberg
Biotechnical Industry Workers ................. 842
Plasticizers and Other Additives
T. Tuomi
in Synthetic Polymers ........................ 688
B. Björkner Boat Builders ............................... 845
K. Tarvainen and 1. Kanerva
Cutting Fluids .............................. 691
I.S. Foulds Brake-Lining Workers ........................ 847
M.H.Beck
Rubber .................................... 701
D.V. Belsito Butchers and Slaughterhouse Workers .......... 850
N.K. Veien
Natural Rubber Latex Allergy .................. 719
K. Turjanmaa, H. Alenius, S. Mäkinen-Kjunen, Cabinet Makers ............................. 854
T. Reunala, and T. Palosuo D. Cohen and J. Krant
Plants ..................................... 730 Candle Makers .............................. 861
J.D. Guin S.M.John
Spices ..................................... 767 Confectionery and Candy Makers .............. 863
A. Niinimäki C.C. Lyon
X Contents
Carpenters ................................. 868 Forestry Workers ............................ 938

T. Leino R.J. Schmidt
Car Industry ............................... 871 Foundry Workers ............................ 945
U. Funke R. Hayakawa and M. Sugiura
Cement Workers ............................ 875 Fur Farming and the Fur Industry ............. 947
C.Avnstorp J. Uitti
Ceramic and Pottery Workers ................. 878 Furniture Manufacture ....................... 950
J.S.C. English and J. Hobson E.E Sherertz
Cheese Makers .............................. 880 Gardeners .................................. 952

EO. Nestle and P. EIsner C.R.Lovell
Chemists .................................. 882 Glass Workers .............................. 956

R. Jolanki and 1. Kanerva S.M. Wilkinson
Child Daycare Workers ....................... 886 Grinders and Brazers of Hard Metal
E.E Sherertz and Stellite ................................. 958
P. Susitaival and M. Linnainmaa
Cigarette and Cigar Makers
and Tobacco Workers ........................ 887 Hairdressers ................................ 960
C.J. Le Coz H.B van der Walle
Construction Workers ........................ 890 Health Care Workers ......................... 969

C.Avnstorp D. V. Belsito
Cosmetologists ............................. 893 Highway Construction Workers ................ 974

P.G. Engasser, J.S. Taylor, H. Rast
and H.1. Maibach Histology Technicians ........................ 976
Dental Personnel ............................ 899 A.E Fransway
T. Rustemeyer and P.J. Frosch House Workers ............................. 978
Detergent Workers .......................... 906 T. Fischer
M. Vanhanen and 1. Kanerva Insulation Workers .......................... 980
Divers ..................................... 910 R. Riala
B. Wood and C.S. Mumo Jewellers ................................... 982
Electron Microscopy Workers ................. 912
J. Vilaplana
A.E Fransway Laboratory Technicians ...................... 989
R. Jolanki and 1. Kanerva
Electronic Workers .......................... 914
D.Koh Leather Industry ............................ 995
J. Geier
Electroplaters ............................... 917
M. Kiilunen and 1. Kanerva Locksmiths ................................. 997
1. Kanerva
Embalmers
(Induding Funeral Service Workers) ............ 920 Machinists ................................. 998
D.1. Holness U. Berndt and P. Eisner
Engravers .................................. 922 Masseurs ................................. 1001
1. Kanerva M.Isaksson
Farmers and Farm Workers ................... 924 Mechanics ................................ 1003
P. Susitaival U.Funke
Floor Layers ................................ 932 Metal Industry ............................. 1004
1. Conde-Salazar and A. Alomar D. Iliev and P. Eisner
Florists .................................... 935 Metal Polishers ............................ 1005
C.R. Lovell 1. Kanerva
Contents XI
Military Personnei .......................... 1007 Reindeer Herding .......................... 1086

A. Lazarov, A. Trattner, K. Reijula, S. Näyhä, E. Larmi,
and A. Ingber M. Hannuksela, and J. Hassi
Mining (Tunneling) ......................... 1013 Roofers ................................... 1089
H. Rast and P. Eisner D.V. Belsito
Musicians ................................. 1015 Shoe Manufacturers and Repairers ............ 1094

H.Hyry J. Geier
Office Workers ............................. 1018 Silk-Screen Workers ........................ 1096

J.E. Wahlberg A. Goossens
Oil-Rig Workers ............................ 1021 Stonemasons .............................. 1099

A.Nyfors A. Schmidt
Operating-Room Staff ....................... 1028 Sugar Artists .............................. 1102

D.L. Holness P. Eisner
Painters, Lacquerers and Varnishers ........... 1030 Swimming Pool Workers .................... 1103
T. Estlander, L. Kanerva, D.E. Cohen and E. Wolff
and R. Jolanki Tattoo Artists .............................. 1109
Paper and Pulp Workers, L. Kanerva
and Paper Dermatitis ....................... 1033 Textile Workers ............................ 1110
P. Jäppinen and L. Kanerva A.Azenha
The Pharmaceutical Veterinary Surgeons ........................ 1113
and Cosmetic Industries ..................... 1041 P. Susitaival
A. Goossens and L. Geusens
Welding .................................. 1117
Photographers M. Hindsen and M. Bruze
and Other Photo-Lab Workers ................ 1053
C. Liden Winemakers ............................... 1119
R.R. Brancaccio
Poultry Processors .......................... 1058
M.Gonyalo
Pitch Workers .............................. 1060 Part 4: Chemistry and Concentrations

R.C. Tung, J.S. Taylor, of Patch Test Allergens
and T.P. Downham II
Dictionary of Occupational Allergens:
Plumbers and Pipe Fitters ................... 1066 Chemical Structures, Sources and References ... 1125
R. Riala J.-P. Lepoittevin and C. Le Coz
Printers and Lithographers .................. 1067 List of Patch-Test Allergens .................. 1192
A. Morris and J. English B.J. Niklasson
Professional Sports: Patch-Test Concentrations and Vehicles

Skin Disorders in Athletes ................... 1072 for Testing Contact Allergens ................. 1257
A.S. Rogachefsky and J.S. Taylor A. de Groot
Railroad Shop Workers ...................... 1084 Subject Index .............................. 1281

H. Rast
List of Contributors
Kristiina Alanko, MD David A. Basketter Dr. Anders Boman, Med Sei

Seetion of Dermatology Unilever Environment Safety Laboratory Department of Occupational and
Finnish Institute of Occupational Health Colworth House, Sharnbrook Environmental Dermatology
Topeliuksenkatu 41 aA Bedford MK44 1LW, UK Karolinska Hospital
00250 Helsinki, Finland 17176 Stockholm, Sweden
Tel.: +358-9-4747239 D. Michael H. Beck, FRP Tel.: +46-8-517-744-43
FAX: +385-9-2413691 Director - Contact Dermatitis FAX: + 46-8-34-44-45
e-mail: Kristiina.Alanko@occuphealth.fi Investigation Unit e-mail: aboman@yderm.ks.se
Department of Dermatology
S.l. Ale Hope Hospital, Stott Lane Ronald R. Brancaceio, MD, PC
All. Prof., Dept. of Dermatology Salford, Lancs, M6 8 HD UK Bay Ridge Dermatology Assoeiates
University Hospital, Republic University Tel.: +44-161-787-1014 7901 Fourth Avenue
Arazati 1194, 11300, Montevideo, FAX: +44-161-787-1018 Brooklyn, NY 11209, USA
Uruguay Tel.: 001-718-491-5800
Donald V. Belsito, MD FAX: 001-718-748-2151
Augustin Atomar, MD Professor of Medieine (Dermatology)
Chairman and Professor University of Kansas Medical Center Magnus Bruze, MD
Department of Dermatology Kansas City, KS, USA Department of Occupational
Hospital de la Santa Creu i Sant Pau Tel.: 001-913-588-3840 and Environmental Dermatology
San Antonio Ma Claret 167 FAX: 001-913-588-4060 University Hospital
08025 Barcelona, Spain e-mail: dbelsito@kumc.edu 205 02 Malmö, Sweden
Tel.: +34-3-291-9013 Tel.: +46-40-336516
FAX: +34-3-291-9136 Dr. Undine Berndt FAX: +46-40-336213
e-mail: aalomar@meditex.es Department of Dermatology e-mail: magnus.bruze@derm.mas.lu.se
Friedrich Schiller University
Prof. Gianni Angelini, MD Erfurter Straße 35 Prof. Desmond Burrows, MD
Department of Dermatology 07740 Jena, Germany 11 Broomhill Park
University of Bari Belfast BT9 5JB, UK
Piazza Giulio Cesare, 11 Andrea Stefano Bigardi, MD
70124 Bari, Italy Department of Dermatology c.P. Callahan, BS, BA
Tel.: +39-80-854919 University of Milan Dept. of Dermatology, Univ. Hospital
FAX: +39-80-854954 IRCCS Ospedale Maggiore of Milan RWTH Aachen,
Milan, Italy 52074 Aachen, Germany
Christian Avnstorp, MD, PhD, Dr. med.
Dermatology Clinic Prof. Dr.med. Andreas J. Bircher P.J. Coenraads
Roskildevej 264 Allergy Unit Ziekenhuis Groningen
2610 Roedovre, Denmark Department of Dermatology 9713 GZ Groningen, The Netherlands
University Hospital
Angelo Azenha, MD Petersgraben 4 David E. Cohen, MD MPH
Quinta do Arco, Lote 1 - Tenöes 4031 Basel, Switzerland Director of Occupational and
4719 Braga, Portugal Tel.: +41-61-265-4229 Environmental Dermatology
FAX: +41-61-265-4885 Assistant Professor
Robert Baran, MD e-mail: Bircher@UBACLU.UNIBAS.CH New York University School of Medicine
Nail Disease Center The Ronald O. Perelman Department
"Le Grand Palais" Prof. Bert Björkner, MD, phD of Dermatology
42, Rue des Serbes Department of Occupational and 550 First Avenue
06400 Cannes, France Environmental Dermatology NewYork, NY 10016, USA
Tel.: +33-4-93-39-99-66 Malmö University Hospital Tel.: 001-212-263-6889
FAX.: +33-83 85 24 12 205 02 Malmö, Sweden FAX: 001-212-263-8752
Tel.: +46-4033 6516
Annick Barbaud, MD, PhD FAX: +46-4033 6213 Luis Conde-Salazar, MD
Centre Hospitalier Universitaire Chairman
Service de Dermatologie Department of Occupational Dermatology
Höpital Fournier Instituto Naeional de Medieina y
36, quai de la Bataille Seguridad dei Trabajo
54035 Nancy Cedex, France Madrid, Spain
Tel.:+33-3-83-85 24 65
FAX: +33-83 85 24 12
XIV List of Contributers
Dr. med. Michela Crippa Prof. Torkel Fischer, MD Dr. med. M. Gebhardt
Institute of Occupational Health National Institute for Working Life University Hospital
Universitiy of Brescia 17l 84 Solna, Sweden Department of Dermatology
P.le Spedali Civili 1 Tel.: +46-8-7309327 07740 Jena, Germany
25123 Brescia, Italy FAX: +46-8-7309892 Tel.: +49-3641-937-370
Tel.: ++39-30-3995660 e-mail: TorkelFischer@niwl.se FAX: +49-3641-937 315
FAX + 39- 30-3995662/394902
Mari-Ann Flyvholm Dr. med. Johannes Geier
Dr. E.M. de Boer Senior Scientist, MSc, PhD IVDK
Department of Dermatology Microbiology, Irritation and Allergy Zentrale an der Universitäts-Hautklinik
Free University Hospital National Institute of von-Siebold-Straße 3
P.O. Box 7057 Occupational Health, 37075 Göttingen, Germany
1007 MB Amsterdam, The Netherlands Lers0 Parkalle 105 Tel.: +49-551-39-8884
Tel.: + 31-20-444-2819 2100 Copenhagen, Denmark FAX: +49-551-406-6095
FAX: +31-20-444-2816 Tel.: +45-39 165200 e-mail: jgeier@med.Uni-goettingen.de
FAX: +45-39 165201
Anton C. de Groot, MD, PhD e-mail: ami@ami.dk Gösta Gemne, MD, PhD, BSc, Assoc. Prof.
Department of Dermatology Bygdöy Alle 28
Carolus-Liduina Hospital Bo Forslind, MD PhD 0262 Oslo, Norway
P.O. Box 1101 Professor e-mail: ggemne@riksnett.no
5200 BD 's-Hertogenbosch, EDRG, Medical Biophysics, MBB
The Netherlands Karolinska Institute L. Geusens
Tel.: +31-73-6486080 171-77 Stockholm, Sweden Katholieke Universiteit Leuven
FAX: +31-73-6486243 Tel.: +46-8-728-6796 University Hospital
e-mail: anton.de.groot-huidarts@wxs.nl FAX +46-8-326505 Department of Dermatology
e-mail: bosse@mango.mef.ki.se Kapucijnenvoer 33
V.DeLeo,MD 3000 Leuven, Belgium
Dept. of Physicians and Surgeons Dr. Iain S. Foulds MB, Ch B, FRCP, MFOM
of Columbia University The Birmingham Skin Center Dr. Chee Leok Goh, MBBS, M Med,
NewYork,NY City Hospital NHS Trust FRCP,MD
DudleyRoad Clinical Associate Professor
Prof. Dr. med T.L. Diepgen Birmingham B18 7QH, UK Insititute of Dermatology, Singapore
Institut für klinische Sozialmedizin National Skin Center
Berufs- und Umweltdermatologie Susanne Freeman, MD 1 Mandalay Road
Bergheimer Straße 58 30 Blenheim Street Singapore 308205, Singapore
69115 Heidelberg, Germany Randwick NSW 2031, Australia e-mail:nsc@pacific.net.sg
Tel.: +61-02-9399-3114
Thomas F. Downham II, MD FAX: +61-02-9399-3224 Margarinda Gon~alo, MD
Department of Dermatology e-mail: suron@enternet.com.au Clinica de Dermatologia
The Cleveland Clinic Foundation Hospital da Universidade
9500 Euclid Avenue Prof. Sigfrid Fregert, MD 3000 Coimbra, Portugal
Cleveland, OH 44195-5032, USA Department of Occupational Tel.: +351-39-400420 or +351-39-717885
and Environmental Dermatology FAX: +351-39-400490
Prof. Dr. med. Peter Elsner University Hospital
Department of Dermatology 205 02 Malmö, Sweden Prof. An Goossens, PhD
Friedrich Schiller University Katholieke Universiteit Leuven
Erfurter Straße 35 Prof. Dr. med. Peter J. Frosch University Hospital
07740 Jena, Germany Hautklinik der Städtischen Kliniken Department of Dermatology
Tel.: +49-3641-937370 Dortmund Kapucijnenvoer 33
FAX: +49-3641-937418 und Lehrstuhl für Dermatologie 3000 Leuven, Belgium
e-mail: elsner@derma.uni-jena.de der Universität Witten/Herdecke Tel.: +32-16-337870
Beurhausstraße 40 FAX: +32-16-337951
P.G. Engasser, MD 44137 Dortmund
34 Ashfield Road Tel.: +49-231-5021550 Birgitta Gruvberger, PhD
Atherton, CA 94027, USA FAX: +49-231-502 1554 Department of Occupational and
Environmental Dermatology
Dr. John S.c. English Dr. med. Ulrich Funke University Hospital
Dermatology Department Arzt für Arbeitsmedizin/Umweltmedizin 205 02 Malmö, Sweden
C Floor, South Block AUDIAG Tel.: +46-40-336516
Queen's Medical Centre Nottingham 85045 Ingolstadt, Germany FAX: +46-40-336213,
University Hospital Tel.: +49-841-89-4783/2466 e-mail:
Nottingham NG7 2UH, UK FAX: +49-841-89-4801 birgitta.gruvberger@derm.mas.lu.se
Tel.: + 44-115-924-9924, Ext. 43745
FAX: +44-115-970-9003 David J. Gawkrodger, MD FRCP FRCPE Prof. Jere D. Guin, MD
Consultant Dermatologist and Honorary 18 Corporate Hili, Suite 100
Tuula Estlander MD, PhD Clinical Lecturer Little Rock, AR 72205, USA
Section Dermatology Departement of Dermatology
Finnish Institute of Occupational Health Royal Hallamshire Hospital Prof. Matti Hannuksela MD, PhD
Topeliuksenkatu 41 aA University of Sheffield Oulu University Hospital
00250 Helsinki, Finland Glossop Road 90220 Oulu, Finland
Tel.: +358-9-4747292 Sheffield S10 2JF, UK
FAX: +358-9-2413691 Tel.: +44-114-271-2203
e-mail: Tuula.Estlander@occuphealth.fi FAX: +44-114-271-3763
List of Contributers XV
Prof. Juhani Hassi, MD, PhD D Linn Holness, M.D., FRCPC Theodor Karamfilov, MD
Oulu Regional Institute of Occupational Department of Occupational Department of Dermatology
Health and Environmental Health University of Jena Medieal School
90220 Oulu, Finland St Miehael's Hospital Erfurter Straße 35
and University of Toronto, 30 Bond St 07740 Jena, Germany
Kathryn L. Hateh, Professor Toronto, Ontario, Canada M5B 1W8 Tel.: +49-3641-937320
The University of Arizona Tel.: 001-416-867-7470 FAX: +49-3641-937315
Bldg. 33 FCR, PO Box 210033 FAX: 001-416-867-3673 e-mail: TKAR@derma.uni-jena.de
Tucson,AZ 85721-0033, USA e-mail: holness@smh.toronto.on.ca
e-mail: khatch@arizona.edu Prof. Ann-Therese Karlberg, PhD
Heli Hyry, MD PhD, Occupational Dermatology,
Bettina Haupt, MD Dermatologist National Institute for Working Life,
Department of Dermatology Department of Dermatology 11279 Stockholm, Sweden
Liebigstraße 21 and Allergie Diseases Tel.: +46-8-730-9323
04103 Leipzig, Germany Helsinki University Central Hospital FAX: +46-8-730-9892
P.O.Box 160 e-mail: ann-therese.Kalberg@niwl.se
Prof. Dr. med. B.M. Hausen 00029 Hyks, Finland
Dermatology Center Tel.: +358-9-4711 Dr. Mirja Kiilunen, PhD
Am Krankenhaus 1 FAX: +358-9-471-6443 Finnish Institute of Occupational Health
21614 Buxtehude, Germany e-mail: heli.hyry@huch.fi Biomonitoning Laboratory
Tel.: +49-4161-703-6905 Arinatie 3
FAX: +49-4161-703-6945 D. Iliev, MD 00370 Helsinki, Finland
Department of Dermatology
Prof. Dr. med. Uwe-Frithjof Haustein Ernst von Bergmann University Prof. Albert M. Kligman, MD, PhD
Department of Dermatology Teaching Hospital Department of Dermatology
Liebigstraße 21 Lennestr. 7a, 14471 Potsdam, Germany University of Pennsylvania
04103 Leipzig, Germany 226 Clinieal Research Building
Tel.: +49-341-9718600 Arieh Ingber, MD 415 Curie Boulevard
FAX: +49-341-97l8609 Professor and Chairman Philadelphia, PA 19104-6142, USA
Department of Dermatology Tel.: 001-215-386-4358
R. Hayakawa, M.D. Hadassah University Hospital FAX: 001-215-573-2ll6
Department of Environmental Jerusalem, Israel
Dermatology David Koh, MBBS, MSc, PhD, FFOM, FAM
Nagoya University School of Mechine Marlene Isaksson, MD Associate Professor
1-1-20 Daikominami, Higashi-ku, Department of Occupational and Department of Community, Occupational
Nagoya 461-0047, Japan Environmental Dermatology and Family Medieine, Faculty of
University Hospital Malmö Medicine National University of
Pirjo Heikkilä 205 02 Malmö, Sweden Singapore
Finnish Institute of Occupational Health Tel.: +46-40-331844 10 Kent Ridge Crescent
Topeliuksenkatu 41 aA FAX: +46-40-336213 Singapore ll9260, Republic of Singapore
00250 Helsinki, Finland e-mail: marlene.isaksson@derm.mas.lu.se Tel.: +65-874-4972
FAX: +65-779-1489
Prof. Dr. med. Beate M. Henz Swen Malte John, MD
Department of Dermatology, Charite Dermatologie, Umwelt medizin, Jessica Krant, MD
Campus Virchow Klinikum Gesundheitstheorie New York University School of Medicine
Augustenburgerplatz 1 Universität Osnabrück The Ronald O. Perelman Department of
13344 Berlin, Germany Sedanstraße ll5 (D1) Dermatology, 550 First Avenue
Tel.: +49-30.450.65001 49069 Osnabrück, Germany NewYork, NY 10016, USA
FAX: +49-30-450-65900 Tel.: +49-541-969-2357
e-mail secretary:mfuchs@ukrv.de FAX: +49-541-969-2445 R.M.A. Krijnen
e-mail private:henz@prolink.de e-mail: sjohn@rz.uni-osnabrueck.de Oepartment of Oermatology
Free University Hospital
Siamak Heshmati, MD Prof. Riitta Jolanki, D. Tech. P.O. Box 7057
University of California, Section of Dermatology 1007 MB Amsterdam, The Netherlands
School of Medicine Finnish Institute of Occupational Health
Department of Dermatology Topeliuksenkatu 41 aA Prof. J.M. Lachapelle, MD
Box 0989, Surge 100 00250 Helsinki, Finland Unit of Occupational and Environmental
San Francisco, CA 94143-0989, USA Oermatology,
e-mail: Riitta.Jolanki@occuphealth.fi
Tel.: 001-415-476-2468 Department of Oermatology,
FAX: 001-415-753-5304 Kirsti Kalimo, MD, PhD Universite Catholigue de Louvain
Docent University of Turku 30, Clos Chapelle-aux-Champs UCL 3033
Philip Hewitt
Department of Dermatology 1200 Brusse!, Belgium
University of California Kiinamyllynkatu 8
San Francisco, CA 94143-0989, USA Arto Lahti, MD, PhO
20520 Turku, Finland
Oocent Senior Lecturer
M. Hindsen, MD
Prof. Lasse Kanerva, MD, PhD Department of Dermatology
Department of Occupational and
Chief, Seetion of Dermatology Oocent University of Oulu
Environmental Dermatology
Finnish Institute of Occupational Health 90220 Oulu, Finland
Malmö University Hospital
Tope!iuksenkatu 41 aA
20502 Malmö, Sweden Kaija Lammintausta, MD, PhD
00250 Helsinki, Finland
Tel.: +358-9-4747288 University of Turku
J. Hobson
FAX: +358-9-2413691 or +358-9-2412414 Department of Dermatology
Occupational Physician
Michelin Tyre Pie e-mail: Lasse.Kanerva@occuphealth.fi Kiinamyllynkatu 8
20520 Turku, Finland
Stoke-on -Trent, ST4 4EY, UK
XVI List of Contributers
Dr. Eva Larmi, MD, PhD Woraphong Manuskiatti Giorgio Pasolini

Oulu University Hospital Fellow in Dermatology, Department Department of Dermatology
90220 Oulu, Finland of Dermatology, Civil Hospital Brescia
University of California P.le. Spedali Civili I
Aneta Lazarov, MD San Francisco, School of Medicine, 25123 Brescia, Haly
Dermatology Clinic Box 0989, Surge 110, San Francisco Tel.: ++39-30-3995300
Meir Hospital CA 04143-0989, USA
Sapir Medical Center Paolo Daniele Pigatto, MD
44281, Kfar Saba, Israel Gunh A. Mellström, PhD Department of Dermatology
Analytical and Pharmaceutical R&D, University of Milan
Christophe J. Le Coz, MD B211:3, Astra Pain Control AB IRCCS Ospedale Maggiore
Unite de Dermato-Allergie 15185 Södertälje, Sweden of Milan, Via Pace 9
Universite Louis Pasteur Tel.: +46-8-553-258-36 20122 Milan, Haly
Clinique Dermatologique, CHU Fax: +46-8-553-288-36
1, Place de I'Höpital e-mail: Prof. Annamai Ranki, MD, PhD
67091 Strasbourg, France gunh.mellstrom@pain.se.astra.com and Chairperson,
Tel.: +33-388-116-680 Helsinki University
FAX: +33-388-116-040 Dr. Andrew Morris Central Hospital
e-mail: clecoz@chimie.u-strasbg.fr Queen's Medical Centre Nottingham Department of Dermatology
University Hospital and Venereology
T.Leino,MD Nottingham NG7 2UH, UK P.O.Box 160
Finnish Institute of Occupational Health, Tel.: 0044-115-924-9924 00029 Hyks, Finland
Topeliusksenkatu 41 aA extension 42431
00250 Helsinki, Finland FAX: 0044-115-970-9196 Dr. Hans Peter Rast, MD
(e-mail: Timo.Leino@occuphealth.fi) Abt. für Arbeitsmedizin
C.S.Munro SUVA - Postfach
Yung-Hian Leow, MBBS, Mmed, FAMS Department of Dermatology 6002 Luzern,Switzerland
National Skin Centre Southern General Hospital Tel.: +41-419-5146
1 Mandaly Road Glasgow G51 4TF, UK FAX: +41-419-5669
Singapore 308205, Singapore Tel.: +44-141-2011567
FAX: +44-141-2012989 Kari Reijula, MD, PhD
Jean-Pierre Lepoittevin, DSc e-mail: c.s.munro@clinmed.gla.ac.uk Uusimaa Regional Institute
Laboratoire de Dermatochimie, of Occupational Health
UMR 7509 Simo Näyhä Arinatie 3 A
Universite Louis Pasteur Oulu Regional Institute 00370 Helsinki, Finland
Clinique Dermatologique, CHU of Occupational Health Tel.: ++358-9-474932
67091 Strasbourg Cedex, France 90220 Oulu, Finland FAX: +358-9-5061087
Tel.: +33-388-35-06-64 e-mail: kreijula@occuphealth.fi
Fax:+33-388-14-04-47 Frank O. Nestle, MD
Department of Dermatology Riitta Riala
c. Liden MD, PhD University of Zürich Medical School Finish Institute of Occupational Health,
Dept. of Occupational and Environmental Gloriastraße 31 Topeliuksenkatu 41 aA
Dermatology 8091 Zürich, Switzerland 00250 Helsinki, Finland
Stockholm Country Council Tel.: +41-4-255-2550
Norrbacka, 17176 Stockholm, Sweden FAX: +41-1-255-4403 Arlene S. Rogachefsky, MD
e-mail: nestle@derm.unizh.ch Department of Dermatology
Christopher R LovelI, MB ChB, MD, FRCP The Cleveland Clinic Foundation
Kinghorn Dermatology Unit Aila Niinimäki, MD, PhD 9500 Euclid Avenue
Royal Uni ted Hospital Docent Cleveland, OH 44195-5032, USA
Combe Park Department of Dermatology
Bath BAI 3NG, UK University Hospital of Oulu Dr. Thomas Rustemeyer, MD
Tel.: +44-1225-824524 90220 Oulu, Finland Experimental Immunology
Tel.: ++358-8-3153594 Department of Pathology
Calum C. Lyon, MA MRCP FAX: ++358-8-3153135 Free University Hospital of Amsterdam
Contact Dermatitis Investigation Unit e-mail: aila.niinimaki@ppshp.fi De Boelelaan 1117
University of Manchester School of 1981 HV Amsterdam, The Netherlands
Medicine and Dentistry Dr. Bo Niklasson
Hope Hospital, Stott Lane Chemotechnique Diagnostics AG Richard JG Rycroft, MD FRCP FFOM DIH
Salford M6 8 HD, UK P.O. Box 80 Consultant Dermatologist
Tel.: +44-161-789-7373 Edvard Ölsväg 2 St John's Institute of Dermatology
FAX: +44-161-787-1018 23042 Tygelsjö, Malmö, Sweden St Thomas' Hospital
e-mail: clyon@fsl.ho.man.uk e-mail: info@chemotechnique.se Lambeth Palace Road
London SEI 7EH, UK
Prof. Howard J. Maibach, MD Prof. Allan Nyfors, MD FAX: +44-171-922-8224
University of California, San Francisco Department of Occupational Medicine
School of Medicine Haukeland University Hospital Dr. S. Sadhra
Department of Dermatology 5021 Bergen, Norway Institute of Occupational Health
Box 0989, Surge 100 Tel.: +47-90 83 91 97 University of Birmingham
San Francisco, CA 04143-0989, USA e-mail: anyf@Haukeland.no University Road West, Edgbaston
Tel.: 001-415-666-2717 Birmingham B15 2TT, UK
Fax: 001-415-753-5304 Fax: +44-121-414-6217
(e-mail: HIMFLM@itsa.UCSEEDU) e-mail: S.Sadhra@bham.ac.uk
List of Contributers XVII
Dr. Anne Schmidt Kyllikki Tarvainen, MD, PhD Wolfgang Uter, MD

Gewerbeärztlieher Dienst Docent University of Osnabrück
Gewerbeaufsichtsamt Department of Dermatology Dermatology, Environmental Medicine
90336 Nürnberg, Germany North Karelia Central Hospital and Health Theory
e-mail: anne.schmidt.nbg@t-online.de Tikkamäentie 16 Sedanstraße 115
80210 Joensuu, Finland 49069 Osnabrück, Germany
Richard J. Schmidt Tel.: +358-13-1713201 Tel.: +49-541-4051810
Wound Care Research Group FAX: +358-13-1713206 FAX: +49-541-9692445
Johnson & Johnson Medical e-mail: Kyllikki.Tarvainen@PKSHP.Fi e-mail: wuter@rz.uni-osnabrueck.de
Airebank Mill
Gargrave BD23 3RX, UK James S. Taylor, MD Docent Sirkka-Liisa Valle, MD, PhD
Tel.: +44-(0)1756-747522 Department of Dermatology HelsinkiUniversity Central Hospital
FAX: +44-(0)1756-747497 The Cleveland Clinic Foundation Department of Dermatology
e-mail: rschmidt@medgb.jnj.com or 9500 Euclid Avenue and Venereology
schmidt@cf.ac.uk Cleveland, OH 44195-5032, USA P.O. Box 160
Tel.: 001-216-444-5723 00029 Hyks, Finland
Axel Schnuch, MD FAX: 001-216-445-6365
IVDK, Dr. Henk B. van der Walle, MD
Zentrale an der Universitäts-Hautklinik Christiaan Timmer, MD Centrum voor Huid en Arbeid
von-Siebold-Straße 3 University Hospital Groningen Wagnerlaan 55
37075 Göttingen, Germany Department of Dermatology 6815 AD Arnhem, The Netherlands
Tel.: +49-551-39-6456 PO Box 30 001 Tel.: +31-26-378-7815
FAX: +49-551-406-6095 9700 RB Groningen, The Netherlands FAX: +31-26-378-7812
e-mail: aschnuch@med.uni-goettingen.de Tel.: +31-50-361-2520
FAX: +31-50-361-2624 Markku Vanhanen, MD
Prof. Hans Joachim Schwanitz, MD, PhD e-mail: C.Timmer@derm.azg.nl Finnish Institute of Occupational Health
University of Osnabrück Topeliuksenkatu 41 aA
Dermatology, Environmental Medieine Akiva Trattner, MD 00250 Helsinki, Finland
and Health Theory Department of Dermatology Tel.: +358-9-47-471
Sedanstraße 11 5 Rabin Medical Center FAX: +358-9-24l2414
49069 Osnabrück, Germany Beilinson Campus e-mail: Markku.Vanhanen@occuphealth.fi
Tel.: +49-541-405-1810 Petah Tiqva 49100, Israel
FAX: +49-541-9692445 Tel.: 972-3-937-7377 Niels K. Veien, MD, PhD
Dermatology Clinic
Prof. Stefania Seidenari, MD Simon C. Tucker, MRCP (UK) Vesterbro 99
Department of Dermatology Specialist Registrar, Dermatology 9000 Aalborg, Denmark
University of Modena Department of Dermatology Tel.: +45-9812-5259
via dei Pozzo 71 Hope Hospital, Stott Lane FAX: +45-9812-8173
41100 Modena, Italy Eccles M6 8HD, UK e-mail: veien@inet.uni2.dk
Tel.: +39-59-422464 Tel.: +44-161-787-1025
FAX: +39-59-424271 FAX: +44-161-787-1018 Prof. Dr. Juan Vilaplana
e-mail: seidenari@unimo.it C<itedra de Dermotologia
Rebecca C. Tung, MD Escalera 0_40
Prof. Achille Sertoli, MD Department of Dermatology biso

Department of Dermatalogy The Cleveland Clinie Foundation Hospital C!lnk
Unit of Allergological, Occupational, 9500 Euclid Avenue Villaroel, 170
and Environmental Dermatologys Cleveland, OH 44195-5032, USA 08036 Barcelona, Spain
University of Florence Tel.: 001-216-444-5492
Via Alfani, 37 FAX: 001-216-445-6365 Jan E. Wahlberg, MD, PhD
5012l Florence, Italy e-mail: rctung@en.com Professor
Tel.: +39-55-27582817 Department of Occupational Dermatology
FAX: +39-55-2758373 Docent Timo Tuomi, PhD Karolinska Hospital
Finnish Institute of Occupational Health and the National Institute
Elizabeth F. Sherertz, MD Topeliuksenkatu 41 aA for Working Life
Professor 00250 Helsinki, Finnland 171-76 Stockholm, Sweden
Wake Forest University Shool e-mail: Timo.Tuomi@occuphealth.fi Tel.: +46-8-517-736-29
ofMedicine FAX: +45-8-34-44-45
Medieal Center Bouldevard Dr. Kristiina Turjanmaa, MD
Winston-Salem, NC 27l57, USA Department of Dermatology W. Wigger-Alberti, MD
Tel.: 001-336-716-6882 Tampere University Hospital Department of Dermatology
FAX: 001-336-716-5139 33520 Tampere, Finland Friedrich-Schiller-University Jena
e-mail: esherertz@bgsm.edu FAX: +358-31-247-5654 Erfurter Straße 35
07740 Jena, Germany
R.W. Soebaryo, MD Jukka Uitti, MD Tel.: +49-3641-937301
Jl. Tebet Dalam IV J No. 17 Tampere Regional Institute FAX: +49-3641-937429
Jakarta 12810 of Occupational Health e-mail: wigger@derma.uni-jena.de
Indonesia PO Box 486
Tel.: 6221-8294332 33101 Tampere, Finland Dr. S. Mark Wilkinson
FAX: 6221-83702856 Tel.: +358-3-2608655 Dermatology Department
FAX: +358-3-2608615 The General Infirmary
e-mail: Jukka.Uitti@occuphealth.fi Leeds LSI 3EX, UK
Tel.: +44-113-3923661
FAX: +44-1423-873524
e-mail: mark_wilkinson@compuserve:com
XVIII List of Contributers
Elizabeth Wolff Dr. Britta Wulfhorst, MD H. Zhai, M.D.

New York University School of Medicine Fachgebiet Dermatologie Department of Dermatology,
The Ronald o. Perelman Department Umweltmedizin und Gesundheitstheorie University of California,
of Dermatology Universität Osnabrück School of Medicine
550 First Avenue Sedanstraße 115 San Franciso
NewYork,NY 10016, USA 49069 Osnabrück, Germany CA 94143-0989, USA
Tel.: +49-541-405-1819
B.Wood FAX: +49-541-405-1812 Erik Zimerson, PhD
Department of Dermatology e-mail: bwulf@rz.uni-osnabrueck.de Department of Occupational
Auckland Public Hospital and Environmental Dermatology
Park Road Auckland, New Zealand University Hospital
205 02 Malmö, Sweden
Part 2
Substances and Products
Part 3
Job Descriptions with Their Irritants and Allergen
r
Part 4
Chemistry and Concentrations of Patch Test Allergens
CHAPTER 1
The Epidemiology of Occupational Contact Dermatitis

T.L. Diepgen and P.J. Coenraads
Work-related dermatoses, in particular hand dermati- progress to hand eczema (HE). Since 1989, dIe Finnish
tis, are still among the most prevalent occupational register of notified cases of occupational allergie
diseases. On a visit to any manufacturing plant, one is contact dermatitis (ACD) has distinguished contact
likely to encounter workers with hand dermatitis. urticaria as aseparate entity (Kanerva et al. 1996). In
There is a vast literature on work-related dermatoses, the past decade, this disease entity has gained
particularly case reports and investigative clinical increasing attention due to dIe increasing prevalence
studies; their epidemiology, however, has received of contact urticaria due to latex-proteins among health
little attention. care workers (Turjanmaa et al. 1996). This chapter will
Epidemiological studies play an important role in not be focused on contact urticaria but on studies
controlling outbreaks and disease trends, analyzing related to contact dermatitis.
risk factors, and monitoring efficacy of preventive Contact dermatitis is a pattern of inflammatory
measures. Understanding the epidemiology of occu- response of dIe skin that may occur as a result of
pational contact dermatitis (OCD) is essential to contact with extern al factors (allergens, irritants). The
determine etiologic factors of the disease and to make clinical picture is a polymorphie pattern of inflamma-
recommendations for its prevention. However, very tion of the skin characterized by a wide range of
few truly epidemiologie al studies of OCD have been clinical features such as itching, redness, scaling,
published, and most of our knowledge about OCD is erytlIema, vesiculation, and clustered papulovesicles.
derived primarily from clinical case reports, clinical In chronic cases, fissuring, hyperkeratosis, and lichen-
studies of groups of in- and out-patients, statistical ification occur. The variety of morphology and natural
compilations of patch -test reports, official occupational history makes it difficult to define a widely accepted
disease reports based on workers compensation agen- standardized definition of the disease, which is needed
eies and state labor and health departments, or from to compare epidemiological studies.
studies of small outbreaks of skin diseases at the work On etiological grounds, the two most important types
place. All these data sources have their limitations and of OCD are irritant contact dermatitis (rCD) and ACD.
must be interpreted carefully. rCD results from contact with irritant substances, while
In this chapter, methodological aspects of the ACD is a delayed-type immunologie al reaction in
available data on the distribution and determinants response to contact wiili an allergen in sensitized
of OCD will be discussed. individuals. Primary lesions of OCD are usually found
at the site of contact with the irritant or allergen; in the
case of ACD, secondary lesions may occur subsequently
What is OCD? on other sites of the body that have never been in
contact with the allergen. The majority of OCD is
The vast majority of work-related dermatoses com- localized on the hands, alone or in combination with
prises contact dermatitis (90-95%); the rest are of odIer localizations (Meneghini and Angelini 1984).
other dermatoses such as contact urticaria, oil acne,
chloracne, chemically-induced leucoderma, and infec-
Social and Economic Impact of OCD
tions (Hogan and Tanglertsampan 1992). A special
subtype of contact allergy is mediated by immuno-
globulin (Ig)E, resulting in an immediate-type contact Although contact dermatitis uncommonly leads to
reaction and presenting itself as contact urticaria. The hospitalization, and minor degrees of contact derma-
clinical picture of urticaria is different from eczema/ titis are often accepted as anormal hazard of life, dIe
dermatitis, but after repeated episodes on the hands occupational, domestic, social, and psychological im-
this contact-urticaria can eczematize, i.e., gradually plications of OCD may be considerable. It must be
L. Kanerva et al. (ed.), Handbook of Occupational Dermatology

4 T.L. Diepgen and P.J. Coenraads
assumed that the total economic impact of OCD is very distinction is often difficult because the classifications
high (Table 1). OCD interacts with numerous allergens are based upon a combination of morphological,
and irritants that are present in the daily household etiological, constitutional, and other factors (Coenra-
activities, in many hobbies and sports. Additionally, ads and Smit 1995).
contact dermatitis is often localized on the hands, a The accuracy of the diagnosis depends on the
highly visible area of the body, thus drawing attention experience, knowledge and skill level of the physician
and causing difficulties in social interaction. Jowett who makes the diagnosis, and on the difficulties to
and Ryan (1985) found that, in general, 38% of patients confirm the relationship with an exposure. Detailed
with eczema noticed interference with sociallife. patch testing or provocation tests are necessary to
In a follow-up study of 954 patients with OCD, 61% determine whether sensitization to certain agents had
reported that they had lost time from work due to their occurred, but even then it is sometimes not certain
skin disease (Wall and Gebauer 1991). About 6% of all whether the contact dermatitis is of allergic origin.
patients had been off work for longer than 12 months These patch tests or provocation tests are helpful in
continuously. ACD, but are often discouraged because of high false-
There are only a few studies that look at the costs of positive rates, irritant reactions or difficulties in
OCD. About 10 years ago, the total annual costs of interpretation. It has to be distinguished between not
OCD may have ranged from US $ 222 million to US $ 1 clinically or occupationally relevant and false-positive
billion in the US (Mathias 1985). These estimates do patch-test results. It might be often a matter of
not include costs of occupational retraining. In Ger- subjectivity to establish a positive patch-test result as
many, retraining costs about DM 100,000-200,000 per a clinically or occupationally relevant reaction.
case; during 1993, 3150 individuals attended such a Additionally, false-positive reactions are also com-
retraining program (Diepgen et al. 1995). mon. It was reported by Nethercott (1990), that the
The Netherlands government (Ministry of Social sensitivity and specificity of patch testing are approx-
Affairs and Employment 1997) published areport imately 70% with a 50% relevance for positive tests
about the cost of work-related diseases and injuries. (i.e., in only half of the cases the substance inducing a
The direct medical costs, i.e., not the costs in terms of patch test response be established as the cause of the
loss of income, loss of productivity etc, due to work patient's skin disease). In order to ascertain the validity
related skin diseases was, for the year 1995, estimated of an instrument such as patch testing, the terms
to be 92 million NL guilders. This is about 42 million "sensitivity", "specificity", and "predictive value" are
Euro for the Netherlands population of about 15 used. The sensitivity stands for the chance that cases
million inhabitants. with ACD are correctly diagnosed, the specificity that
Despite the poor clinical prognosis of OCD, there the non-ACD cases are correctly stated. From a
are no recent studies regarding the costs attributable statistical point of view, however, it will be more
to the effects on the quality of life or activities of daily essential to calculate the positive predictive value
living. (PPV), which is the proportion of those individuals
diagnosed by the used instrument, who actually have
ACD. The PPV is a function of the true prevalence of
(ase Ascertainment, Misclassification, and Bias ACD in the population, the sensitivity, and the
specificity (Diepgen and Coenraads 1999a,b). If, for
example, the prevalence of ACD to nickel were 10%
(linical Diagnosis and Patch-Test Reactions
and the specificity and sensitivity of patch testing 90%,
then a positive reaction results in 50% of cases
As mentioned above, in the pathogenesis of contact
diagnosed correctly. Therefore, individuals who do
dermatitis, irritants and allergens are simultaneously
carry an ACD are almost always missed, while others
interwoven and endogenous and environmental factors
are wrongly designated as cases of ACD. In conclusion,
are often additionally involved. This leads to overlap-
patch testing is less than the ideal gold standard. With
ping categories between ICD and ACD. In practice, the
ICD there are no additional confirmatory tests.
Table 1. The total economic impact of occupational contact (ase Definition and Bias
dermatitis is very high according to the following costs
There exist further possibilities for systematic errors in
• Direct cost of medical care, workers' compensation or sampIes of patients with OCD (Table 2). The lack of a
disability payments
• Indirect costs associated with lost workdays and loss of standard case definition of OCD leads to difficulties in
productivity obtaining accurate epidemiological data because a
• Costs of occupational retraining precise case definition is aprerequisite for the gath-
• Costs attributable to the effects on the quality of life
ering of epidemiological data. Consequently, in contact
The Epidemiology of Occupational Contact Dermatitis
Table 2. Reasons for systematic errors in sampies of patients with occupational contact dermatitis
Type of errors Reasons
Misclassification Overlap between allergie and irritant contact dermatitis

Sensitivity and specificity of patch testing is approximately 70%
Lack of standard case definition
Information bias Ascertainment of cases varied from dermatological examination to self-administered questionnaires
Instruments are not standardized nor evaluated (->over- or underestimation)
Selection bias Sampies of OCD are not selected by random
Sampies are not population based
Only less than one third of cases with work related skin complains result in medieal attention
dermatitis, the case definition can vary from one data In an epidemiological study on the prevalence of HE
source to another. in different occupational groups, it was noted that in
The case ascertainment depends largely on the population-based studies the symptoms of contact
sources of data that are used, such as morbidity dermatitis are relatively mild in the majority of cases,
statistics or observational studies. Mortality statistics judged from the proportion of cases that resulted in
are unhelpful because contact dermatitis commonly is sick leave or medical attention (Smit et al. 1993). üf all
never fatal. In morbidity statistics, case ascertainment persons with work-related hand dermatitis, only
usually involves registration of persons with dermatitis between 15% and 36% had consulted a physician for
who fulfil additional criteria for registration, such as treatment, and sick leave due to their symptoms'
hospital admission, sickness leave, or referring to a resulted in only 4-9% (Table 3).
specialist. This restriction in the definition of a case To avoid bias resulting from the method of case
will probably result in selective inclusion of the more ascertainment, it is usually not enough to restrict case
severe cases, since a large proportion of individuals ascertainment within a defined study population to
suffering from contact dermatitis do not come to reviewing the files of dermatologists or general prac-
medical attention or are seen elsewhere (Fig. 1). titioners. In general, it requires some effort to bring all
The important question "how do we know who has cases in the study population to the attention of the
the disease and who does not" can cause selection bias. investigator. Screening of the complete study popula-
Ideally, the sampie of cases would be a random sampie tion according to standardized criteria by one or more
of everyone who has the disease. Especially in case- trained dermatologists is the most reliable and there-
control studies, cases are usually sampled from fore preferred method.
patients in whom contact dermatitis has already been In observational studies on contact dermatitis, the
diagnosed, and who are available for the study. This ascertainment of cases varied from intensive efforts by
sampie is not representative of all patients with the a medical examination of the complete study popula-
disease because those who are undiagnosed, misdiag- tion (Coenraads et al. 1983; Lantinga et al. 1984; Funke
nosed, or lost to follow-up are less likely to be et al. 1995) to the relatively easy-to-apply method of
included. self-administered questionnaires (Kavli and Forde
1984; Meding and Swanbeck 1987; Smit et al. 1993) or
Cases with Occupational Contact Dermatitis by a combination of both. The advantage of observa-
tional studies is that case ascertainment can be
No medical attention Table 3. Siek-leave, medical consultation due to "work-related"

hand eczema in different occupational groups (modified accord-
ing to Smit et al. 1993)
Remission before diagnosis
Occupational Improvement Medical Siek leave
group after cessation consult (%)
of work (%) (%)
Seen elsewhere
(e.g. family doctor) Nurses 98 15 4
Surgical 100 25 8
assistants
Undiagnosed or misdiagnosed Chemieal 59 35 4
company
DGD Gases available for the study Electricity 85 36 6
company
Municipal 81 25 9
Fig. 1. Selection bias in epidemiological studies on contact public works
dermatitis
performed using uniform criteria for the definition of seems an unlikely explanation. The authors conduded
cases. However, the frequencies of cases obtained by that questionnaires may be insensitive for some
questionnaire may be quite different from those dermatological conditions and active surveillance
ascertained by dinical examination. The size of the would improve case finding and the validity of
differences in prevalence estimates that may arise as a incidence data.
result of differences in the definition and method of
diagnosing HE (information bias) has been investi-
Incidence and Prevalence
gated by Smit et al. (1992). Two types of questionnaire
diagnoses, a "symptom-based" and a "self-reported"
diagnosis were compared with the medical diagnosis Measures of disease frequencies indude "prevalence",
of HE. The prevalence of HE according to the medical which is the amount of disease that is already present
diagnosis was 18%, but according to the symptom- in a population; "incidence", which refers to the
based diagnosis 48%, and to the self-reported diagno- number of new cases of contact dermatitis during a
sis 17%. The sensitivity and specificity of the defined period in a specified population; and "inci-
symptom-based diagnosis were 100% and 64%, and dence rate" (IR), which is the number of non-diseased
of the self-reported 65% and 93%. That means that the persons who become diseased within a certain period
symptom-based diagnosis ofHE overestimated and the of time, divided by the number of person-years in the
self-reported diagnosis underestimated the prevalence population.
of HE according to the medical diagnosis. Data on the incidence and prevalence of occupa-
A diagnosis of contact dermatitis based on a self- tional dermatoses are scarce. The most important
administered questionnaire is significantly less valid sources of data are occupational disease registries, case
than the diagnosis based on examination by a derma- series of patients visiting dermatology dinics, and a
tologist. This is illustrated by experience in a study of limited number of cross-sectional studies in one or
occupational skin disease among California grape more occupational groups. There exists a huge amount
(n = 183) and tomato (n = 43) harvesters (McCurdy of data on patch-test patients in different countries
et al. 1989). The survey was prompted by reports of (Storrs et al. 1989; Frosch et al. 1993; Schnuch et al.
increased dermatitis amongst table grape growers; the 1993).
tomato harvesters were chosen as a comparison. To All measures of disease frequency consist of the
evaluate skin diseases, subjects were asked "Have you number of cases as the numerator, and the size of the
had any type of skin rash or skin irritation within the population under study as the denominator. As
last three months that has las ted two days or more?". mentioned above, in case series the sampie represented
Fifty-two percent of grape workers and 19% of tomato by the numerator is often biased. With few exceptions,
workers reported rashes lasting 2 days or more during however, the size of the denominator is unknown in
the previous 3 months; a slightly greater difference was many publications presenting the frequencies of OCD.
no ted when the period in question was 1 year. No Therefore it is not possible to calculate rates. This is
significant differences were seen between the two the reason why studies among patient populations
occupational groups, however, for prevalence of skin from dermatology dinics are not adequate for esti-
conditions on examination. One of the explanations mating prevalence or IRs.
raised by the authors was that rashes earlier in the The point prevalence indudes only subjects with
growing season were reported in the questionnaire, actual OCD. Since OCD is often a chronically relapsing
while the symptoms had disappeared by the time of disease, the point prevalence is therefore less informa-
examination. Assuming that the investigators were tive than the period prevalence. However, the accuracy
blinded to the occupation of the workers, the authors of recall will decrease with time, because persons who
also suggested the presence of information bias, in the did not have complaints recently are more likely to
sense that grape workers may have been more aware forget to report their earlier contact dermatitis.
than tomato workers of dermatitis from harvest work. The period prevalence indudes subjects with long-
The sensitivity of the questionnaire for evaluating lasting contact dermatitis as weIl as relatively recent
current skin conditions was 31%, indicating that only cases and thus possesses all interpretational difficulties
about one-third of the cases was detected by the that are inherent to aperiod prevalence. No inference
questionnaire. The low sensitivity was attributed to can be made between exposure and contact dermatitis
differences in the understanding of abnormality because the exposure may have changed over time,
between examiner and respondent. The authors stated past exposure may be over- or underestimated, and
that it might also relate to the observed skin condi- preventive measures may have been taken after symp-
tions being of less than 2 days' duration; however, toms occurred. Given these considerations, incidence
given the nature of those most common (acne and figures are preferred for analyzing risk factors for
variants, folliculitis and eczematous dermatitis), this OCD.
The Epidemiology of Occupational Contact Dermatitis 7
Frequency of HE in the Population Table 5. Reported 1-year prevalence of hand eczema in men and
women in occupations according to a population-based study in
Gothenburg (Sweden) (modified according Meding and Swan-
Data on the incidence and prevalence of contact beck 1990)
dermatitis are scarce and population-based studies
are lacking. Table 4 summarizes the results of the 1-Year prevalence (%)
prevalence of HE of some population-based studies.
Occupational group Men Women Total
Different prevalence rates are reported, while there
were differences in methodology, identification of Production 8.1 13.0 8.8
persons with contact dermatitis and disease definition. Administration 8.4 11.8 10.6
Service work 9.4 17.9 15.4
The study of Meding and Swanbeck (1987) demon- Medical and nursing 8.7 12.3 11.9
strates the difference between point and period prev- Sales 8.1 12.3 10.2
alence: in the same population, the point prevalence of Engineering 6.6 12.3 7.4
HE was 5.4% and the 1-year period prevalence 10.6%.
In all these studies, the prevalence among women was
around 0.5 to 1.9 cases per 1000 full-time workers per
higher than among men. In Table 5, the reported 1-year
year (Mathias et al. 1990; Roche 1993; Coenraads and
prevalences of HE in occupations are presented for
Smit 1995; Halkier-Sorensen 1996). The incidence in
both gender according to a population-based study in
agriculture and the construction and manufacturing
Gothenburg (Sweden). Irritant HE is more common
industries is above average in most countries. Within
than allergie HE.
the manufacturing industry, relatively high rates are
observed in the leather, metal, food, chemical, and
Incidence of OCO and Occupational Disease Registries rubber industries.
National registries are usually incomplete as a result
In many countries, OCD ranks first among all notified of underdiagnosis and underreporting of the disease
occupational diseases and constitutes up to 30% of all (Taylor 1988). It has been estimated that the incidence
occupational diseases for which compensation is of occupational skin diseases in the USA is being
payable. In some countries, this proportion has underestimated by 10-50 times (Mathias and Morrison
declined in recent years because other diseases (in 1988, BLS 1993), the milder cases of skin disease not
partieular musculo-skeletal diseases) have been recog- being registered at all. The extent of underreporting is
nized as occupational diseases. This caused an increase likely to differ between countries, because each coun-
in the total number of notified occupational diseases try has its own system of notification. The registration
and a decrease of the proportion of skin diseases, while of occupational diseases in Sweden, the former Federal
the IRs remained about the same. To follow trends in Republic of Germany, and Finland is based upon the
incidence of work-related dermatoses recent data are notification of occupational diseases for which com-
needed. pensation is payable (Vaaranen et al. 1983, Fabry 1981).
Occupational disease registries provide national data Criteria for compensation, and thus criteria for noti-
based on the notification of occupational skin diseases fication of occupational diseases, depend on the
and are available in many countries. Although the legislation on occupational diseases in each country.
comparison of national data are harn pe red by differ- In the United States, the occupational disease
ences across countries in reporting occupational dis- statistics originate from an annual survey by the
eases, the IR of registered OCD in most countries lies Bureau of Labor Statistics among a representative
Table 4. Prevalence of hand eczema in population-based studies (selection)
Country Method of case No.of Measures of Prevalence of hand eczema (%)

ascertainment responders prevalence
Males Females Total
Netherlands (Coenraads et al. 1983; E 3140 3 years 4.6 8.0 6.2*

Lantinga et al. 1984)
USA (Johnson and Roberts 1978) E 20,749 Point 0.5**
Norway (Kavli and Forde 1984) Q 14,667 1 year 4.9 13.2 8.9
Sweden (Meding and Swanbeck 1987) Q,E 16,587 1 year 8.8 14.6 10.6
Netherlands (Smit et al. 1993) Q 2185 1 year 5.2 10.6 8.2
Germany (Funke et al. 1995) E 1196 1 year 5.6 10.5 6.7
E dermatological examination; Q questionnaire

* Includes mild cases
** Cases that should be seen by physician
random sampie of employees in private industry No. of OCD per 10.000 employees / year
(Mathias and Morrison 1988, BLS 1993).
In the United Kingdom, the EPIDERM project for Hairdresser 194
Baker 64
recording occupational dermatoses requires dermatol-
Electroplaters
ogists in a number of centers to report confirmed or Florist
suspected cases of occupational skin disease, including Co nfectloner
the occupation of the patient concerned (Cherry et al. TUe selters
Plumber
1994). It is a voluntary system, and operates on the
Metal-, Surfeceworker
principle of simplicity (ensuring compliance). The Dentaltechnlclan
system can detect previously unreported hazards. Cooks
The epidemiological limitations are weil recognized, Health service
Mechaniclan
but the system corrects the virtual absence of mean-
Leather worker ~~====================::7
ingful official statistics in the UK since 1983.
In the Finnish register, which identifies contact Fig. 2. Incidence rates (per 10,000 employees/year) of occupa-
urticaria as a special entity, bakers, preparers of food, tional contact dermatitis (OCD) in North Bavaria (according to
animal handlers, and dental personnel rank highest Diepgen et al. unpublished observations)
among cases notified with this disease (Kanerva et al.
Determinants of OCD
1996).
A fairly active nation-wide notification program
operates in Denmark - the incidence is 17,700 cases on The development of OCD is determined by a combi-
a workforce of about 2.6 million, i.e., about 7 per 1000 nation of individual susceptibility (endogenous fac-
per year (Halkier-Sorensen 1996). tors) and exposure characteristics (exogenous factors).
In Germany, occupational skin diseases constitute Skin contact with irritants and/or allergens is a
34% of all registered occupational diseases. In one necessary condition of contact dermatitis and the
region of this country, a detailed population-based probability and severity of areaction depend on the
prospective study was performed to classify ail cases of type and intensity of exposure. Additionally, apart
occupational skin diseases without skin cancer (ac- from exposure to hazardous substances, there are
cording to the German code number of occupational many endogenous factors that may influence the
diseases: BK 5101) in North Bavaria (Diepgen et al. development of contact dermatitis, such as atopic
1994; Tacke et al. 1995). During the 3 years (1990- constitution, the condition of the epidermal barrier,
1993), about 3000 notified cases were reviewed and, in sensitization, psychological factors, age, and gender.
2567 cases, a work-related skin disease was established. Environmental factors may playa role in this process
In cooperation with the State Institute of Labor and by influencing the individual susceptibility and the
Occupation (Bundesanstalt für Arbeit), the numbers of characteristics of exposure. If these factors are not
all persons employed in different occupations during properly controlled for either in the design or in the
the same time period were collected. Thus, because all analysis, they may act as confounders in the study.
cases of OCD have been recorded and the number of
employees during the same time period in the same Exposure to Irritants and Allergens
referral area is known, IRs could be calculated. In
Fig. 2, the IRs for a 3-year period are given for different The most important risk factor for OCD is the
professions. The highest IRs were found in hairdress- exposure to irritants. Well-known irritants are water
ers, bakers, electroplaters, grinders, drillers, and oth- (wet work), detergents and cleansing agents, hand
ers. The median of age in hairdressers, the food cleaners, chemicals, cutting fluids, and abrasives. In a
industry, health service, and metal workers varied study of HE (Diepgen and Fartasch 1993), at least one
between 19 years and 33 years. The induction period of those irritants was always involved in ICD but also
was very short: about 2 years in hairdressers, 3 years in in 84% of ACD, and in 60% of atopic HE. Of 145
the food industry, and about 4 years in health service grouped exposure sources, the five most frequently
and in metalworkers (Fig. 3). In the food industry stated substances were detergents, water, metals,
(Tacke et al. 1995), bakers had a higher risk of foodstuff, and rubber in notified occupational skin
OCD with an IR of 191 (95%-CI 156-226) than diseases in Denmark (Halkier-Sorensen 1996). These
confectioners (IR 84, 95%-CI 55-113) and cooks (IR 34, substances caused approximately half of the eczema
95%-CI 28-40). Females had a considerably higher risk cases. The most important irritant seems to be wet
of developing OCD than men (Table 6). The IRs of work. According to a new German regulation of
contact dermatitis were highest between the ages hazardous substances at the work place (Diepgen
of 15 years and 24 years. 1997), "wet work" is defined if individuals have their
Fig. 3. Median of age and median of

induction period of occupational skin Age (median)
diseases in different professions
Hairdresser
~ - -' 19 yrs.
(according to Diepgen et al. unpublished
observations)
Food ind.
Health service
Metalworker ~~~~~~~~~~~~~~~~~~~
o 5 10 15 20 25 30 35
Induction period (median)

~ . "
2.1 yrs .
Hairdresser
Health service
Foodind.
Metalworker
j~~iiiiiiiiiiiiiiiiiiiiil;;I1~~~~~
o 2 3 4 5
skin exposed to liquids for longer than 2 h per day, use employed in the Channel Tunnel project. Of 180 patch-
occlusive gloves longer than 2 h per day, or clean the tested workers with OCD, 53% had a positive re action
hands very often (e.g., 20 times per day or less if the to chromate. Wehave analyzed the distribution of
cleaning procedure is more aggressive). type-IV sensitization against chromium and the per-
In hairdressers, there is detailed knowledge about centage of occupational relevant sensitization in
the work-related allergens. According to the study in different groups of patients with notified OCD
North Bavaria (Diepgen et al. 1994), it could be shown (Fig. 5). The highest percentages were found in tile
that glycerylmonothioglycolate (GMTG), p-phenylen- setters, bricklayers, electroplaters, and the leather
diamine, ammonium persulfate, and toluenediamin- industry. Only according to such a population-based
sulfate are the most frequent sensitizers and the most investigation can it be clearly demonstrated which
frequent occupationally relevant allergens in hairdress- occupational groups are running a mild, moderate or
ers with OCD (Fig. 4a). Sensitization to nickel is high risk of ACD due to specific allergens.
frequent, but nickel very rarely plays an occupational There are, however, limitations and problems of
relevant role in hairdressers. epidemiological studies examining the risk of sensitiz-
On the contrary, OCD in metalworkers is mostly ing or irritant agents. A high ranking agent in a case
caused by irritants. In metal workers with OCD, series is not automatically a strong sensitizer or
occupationally important allergens are rarely detect- irritant. A wide application of a weak allergen or
ed. In the North Bavarian study, the sensitization irritant is more likely to result in a high proportion of
diagnosed in this group was mostly caused by cases than the use of a particular strong but rare agent.
substances that are included in the "European stan- It should be noted, that exposure is characterized by
dard series" (a standard panel of patch tests) but only concentration and duration. Without doubt, exposure
a few of these sensitizers were occupationally relevant is the most important determinant of risk, but
(Fig. 4b). exposure quantification techniques are underdevel-
Chromium sensitization and eczema are still a oped in occupational dermatology. Exposure changes
problem in OCD and non-OCD. Irvine et al. (1994) with time, and the affected worker may continue to
have described OCD among 1138 construction workers have eczema yet no longer be exposed to the causative
Table 6. Incidence of occupational contact dermatitis in the food industry (according to Tacke et al. 1995)
Baker Confectioner Cook Total
No. of employees 5611 3691 23,252 32,554

Male 4447 2563 9063 16,073
Female 1164 1128 14,189 16,481
No. of OSD 107 31 79 217
Male 65 6 24 95
Female 42 25 55 122
Incidence rate 191 (156; 226) 84 (55; 113) 34 (28; 40) 67 (58; 76)
Male 146 (111; 181) 23 (5; 42) 26 (18; 34) 58 (48; 70)
Female 361 (254; 468) 222 (136; 307) 39 (30; 48) 74 (64; 84)
a) Hairdressers n=662
glyceryl monothioglycolate
nickel
p-phenylenediamine
ammonium persulfate
toluylendiaminsulfate
cobaltchloride
o-nitro-p-phenylenediamine .occup. relevant
pyrogallol
dlchromate . sensitization
fragrance mix ~~+==+=:::::j:==i==+==+==r'
0% 10% 20% 30% 40% 50% 60% 70%
b) Metalworkers n=448
nickel
cobaltchloride
dichromate
p-phenylenediamlne
formaldehyde " ' _ '__ •
Kathon CG .occup. relevant
colophony .sensitization
epoxy resin
paraben mix ~!::':+=====i===+==+==+===+==r
0% 10% 20% 30% 40% 50% 60% 70%
Fig. 4. Frequencies of delayed-type sensitization and work-relat- exposed to oeeupational agents that are a burden to
ed sensitization for frequent allergens in hairdressers (a) and
metal workers (b) with occupational contact dermatitis (accord- the skin (Coenraads and Diepgen 1998). In eomparing
ing to Diepgen et al. unpublished observations). The percentage the figures quoted in the literature, one is
of work-related sensitization is related to subjects with an allergie faeed with the same diffieulties of seleetion and
contact dermatitis for whieh an occupational relevant sensitiza-
tion was found to be responsible interpretation that have been mentioned before.
Additionally, the definition of atopy itself differs
agent. The evaluation of past exposure may be eonsiderably. Some authors include a family history
exeeedingly diffieult, whieh leads to reeall and infor- as weIl as a personal history of atopy, others divide
mation bias. Beeause of unique exposures, the results their group of subjeets into those with atopic eezema
of a study may not be generalizable. Cross-seetional and those with respiratory aIlergy; so me would only
studies are subjeet to survivor bias beeause subjeets aeeept positive priek-tests as evidenee for the atopie
with severe skin diseases often leave the work force diathesis.
(healthy worker effeet). Individuals with an atopie disposition ean develop
atopie eezema, allergie rhinitis, or allergie asthma.
Atopy and Atopic Skin Diathesis Presently, there is suffieient evidenee that these differ-
ent atopie manifestations are not always assoeiated
Individuals with a personal history of atopy seem to with an inereased risk for OCD. Two important issues
run a eonsiderable risk of developing HE when have to be distinguished:
Dichromate Fig. 5. Distribution of delayed-type sensitiza-

tion and occupational relevant allergy against
sensitized (%) occup. relevant (%) chromium in different occupational groups of
Florists '" 1 0.6% individuals with notified occupational contact
Chem istry VI (/J 4.8% dermatitis in North Bavaria
Plastics
Printing 4
Metalproducer
Metalwor ke r
Electroplater 40 15~,5 35
:~:~6
Solderer
Locksmilh.KFZ
Mechanic
Denlallechn.
Fitter
Le ath er
Cook
Food
Baker
Confectioner
'9 t~;t 10
Conslruction 60 54
Tile setter SB 54
Painter 9
Wood
Miscellaneous 15
Machinists
Health servo
Hairdresser
Cleaners 1--.-r--.-r--,-----'~!!!!'/'!...IoJ..,.__;_-,.__;_-.-_r--l
70 60 50 40 30 20 10 0 10 20 30 40 50 60 70
1. A personal history of atopy is a well-known factor Table 7. Score of atopic skin diathesis (ASD-score) based on chi-
square values without laboratory investigations (modified
influencing irritant but not ACD. An ACD based on according to Diepgen et al. 1991, 1992) The statistieal analysis
a type-IV contact allergy to occupational sensitizers is based on 428 atopie eczema (AE) patients and 628 non-
does not seem to be more prevalent among atopics eczematous controls.
(Rystedt 1985; Klas et al. 1996). This is supported by
Atopie feature Points X2 OR 95%-ClofOR
data from a study among hairdressers in North
Bavaria (Diepgen et al. unpublished observations) Xerosis 3 429 279 23.2-33.8
where, in a group heavily exposed to occupational Itch when sweating 3 410 254 21.1-30.1
allergens, there were no significant differences in White dermographism 3 357 193 16.2-23.2
W 001 intolerance 3 355 158 l3.4-18.5
sensitization rates between those with atopic man- Pityriasis alba 2 304 601 41.6-87.0
ifestations on the skin and non-atopics. With respect Infraorbital fold 2 292 110 9.4-12.7
to type-I (IgE-mediated) contact urticarial reactions, Hertoghe sign 2 282 448 32.1-62.6
Palmar hyperlinearity 2 242 117 9.8-l3.9
which can develop into HE, the situation is different. Ear rhaghade 2 236 192 15.2-24.4
Immediate-type contact reactions to latex (gloves Perleche 1 201 70 6.1-8.2
used by health-care personnei) or alpha-amylase (in Cradle cap 184 106 8.7-12.9
Family history of atopy 69 29 2.6-3.3
yeast used by bakers) or food proteins (in caterers) Faeial pallor/erythema 117 53 4.5-6.3
are more common among atopics (Rycroft 1995; Keratosis pilaris 103 49 4.2-5.8
Food intolerance 85 47 4.0-5.7
Lahti 1995). Allergie rhinitis 65 31 2.7-3.6
2. It has to be distinguished between mucosal atopy Allergie asthma 55 48 3.4-6.0
(asthma, hay fever) and atopic skin diathesis (ASD) Metal sensitivity 55 27 2.4-3.1
regarding the risk of developing OCD. Nowadays, Photophobia 41 26 2.3-3.1
there is sufficient evidence that mucosal atopy, OR odds ratio; 95%-CI: 95% confidence interval of OR. Atopy-
without skin manifestations, is not associated with score: X2 > 350: 3 points; 350 > X2 > 220: 2 points; X2 < 220: 1
increased risk of ICD (Rystedt 1985; Diepgen and point
Fartasch 1993, Diepgen et al. 1993, Majoie et al.
1996).
may occur in subjects with respiratory atopy and in
The term ASD (Lammintausta and Kalimo 1981; non-atopics.
Diepgen et al. 1991) is a prognostically useful definition In a prospective study among 1564 new employees of
of the skin condition, which might be involved in the an automobile manufacturing industry, on average
development of OCD. On the basis of statistical 4.4% acquired HE during the first year of employment
modeling, a diagnostic score system for ASD was (Kristensen 1992). The risk was significantly higher in
established, which is based on anamnestic and clinical individuals with previous HE (21%), atopic dermatitis
criteria (Diepgen and Fartasch 1992; Diepgen et al. (14%), wool intolerance (11%), and hay fever (9%).
1996). For practical use, every atopic feature obtained a Smit et al. (1994) followed 74 apprentice hairdress-
value between 1 and 3 points according to its statistical ers and 111 apprentice nurses from the start of first
significance (Table 7). Based on this score system, occupational exposure until the end of their appren-
patients with more than 10 points should be consid- ticeship. The average IR of hand dermatitis was 32.8
ered to have an ASD, patients with more than 6 points cases/loo person-years in hairdressers and 14.5 casesl
are suspected of having ASD. 100 person-years in nurses. The relative risk of having
In bakers, we could demonstrate that ASD is the a dry versus normal skin type was 7.3 in hairdressers
most important endogenous risk factor (Tacke et al. and 1.7 in nurses. Apprentice nurses with a history of
1995). Assuming different frequency figures of ASD in (atopic) mucosal symptoms had a 3.4-fold increased
the general population, the relative risk for atopic
subjects to develop OCD differs between 4.6 and 18.8
(Table 8). The etiologic fraction was between 42% and Table 8. Relative risk and etiologie fraction for subjects with
51 %. The attributable risk or etiologic fraction repre- atopie skin diathesis (ASD) in bakers with notified oecupational
contact dermatitis (n = 107) The frequency of ASD in diseased
sents the proportion of OCD that can be explained by bakers was 61 % (modified according to Tacke et al. 1995)
the risk factor.
Atopic eczema (AE) in childhood seems to be a risk Assumed frequencies Relative risk Etiologic
factor for HE in adults (Lammintausta and Kalimo of ASD in the general (95%-CI) fraction
population
1981; Rystedt 1985). However, theses studies also found
that a considerable number of subjects with a personal 5% 18.8 (13.0; 27.0) 51%
history of AE managed to work in risk occupations 10% 9.7 (6.7; 14.1) 49%
without developing HE. Therefore a reduced resistance 15% 6.3 (4.4; 9.2) 46%
20% 4.6 (3.1; 6.6) 42%
to irritants does not occur in all subjects with AE and
risk of hand dermatitis. The risk of mucosal atopy in exposure characteristics are for the most part respon-
apprentice hairdressers was 2.2. sible for these differences.
In a prospective cohort study, we investigated the Ethnic differences in the susceptibility of contact
risk of developing OCD in hairdressers, nurses, and dermatitis are controversially discussed. Good epide-
metalworkers (Diepgen et al. 1993; Funke et al. 1995). miological studies are lacking. The clinical implication
The design of the study comprised a first dermatolog- from experimental sensitization studies with poison
ical investigation at the start of apprenticeship and, ivy and DNCB demonstrating less susceptibility to
thereafter, regular follow-ups over a 3-year period. In contact dermatitis in blacks than whites (Andersen and
the first year of apprenticeship, 68% of the hairdressers Maibach 1979; Kligman 1966) is unknoWll, because
developed mild, moderate or severe HE. In this study, Fisher (1977) reported an approximately equal fre-
the two most important endogenous factors (ASD and quency of contact sensitization in blacks and whites in
mucosal atopy) were simultaneously analyzed with the North America. It is commonly believed that the
following risk factors: personal history of nickel darker the skin, the greater the resistance to irritation.
sensitivity, duration of daily wet work, and duration Because erythema is more difficult to perceive and to
of daily work with permanent wave. Analyzing the data quantify with increasing pigmentation, Berardesca and
using a logistic regression model, it could be demon- Maibach (1988) investigated transepidermal water 10ss
strated that ASD, wet work (more than 4 h daily) and and skin blood flow to evaluate skin irritation induced
permanent wave (more than 1 h daily) are the most by sodium lauryl sulfate on both black and white skin.
important, independent risk factors. The odds ratios Surprisingly, blacks showed higher water loss levels for
(OR) and the corresponding 95% confidence intervals irritated skin than whites. Goh and Chia (1988) found
were as follows: ORatopic skin diathesis 2.1 (1.4, 3.2), Chinese significantly more sensitive to lauryl sulfate
ORwet work 2.1 (1.4, 3.0), ORpermanent wave 1.7 (l.l,.4). In than Malays using the same technique. The key points
contrast, respiratory atopy and a history of nickel of determinants of OCD are summarized in Table 9.
sensitivity were not associated with a significantly
elevated risk for HE (ORrespiratory atopy 0.8 (0.4, 1-4),
Prognosis of OCD
ORhistory of nickel sensitivity 1.3 (0.9, 1.9). The logistic
regression model assurnes a multiplicative model,
which means in our example that the risk is 7.5-fold The prognosis of OCD is notoriously poor (Rycroft
elevated if all three risk factors are given. 1995). A review of most of the studies concerned with
Even if in epidemiological terms atopic eczema is an the pro gnosis of contact dermatitis showed that only
effect modifier, it can be argued that the observed ICD half or less than half of the patients had healed after
associated with atopy is in fact an exacerbation of several years of follow-up (Hogan et al. 1990). De-
atopic eczema, rather then ICD. pending on the severity of the symptoms, the period of
follow-up, and the intensity of exposure, recurring
Individual Susceptibility symptoms of contact dermatitis in working-popula-
tions widely varied in eczema patients (35-80%).
In general, it is believed that the irritancy and The prognosis for ACD is thought to be worse than
sensitivity of the skin decreases with age. In other for ICD (Fregert 1975, Meding and Swanbeck 1990).
studies, it could be demonstrated, however, that the Not all studies show this effect, but the greater
association between age and contact dermatitis pre- tendency for medical consultation, sick leave, and
valence disappeared when occupation was accounted permanent disability in persons with ACD is consistent
for in the analysis (Varigos and Dunt 1981; Coenraads with the observation that symptoms in these patients
et al. 1983). In conclusion, occupation and not age was are generally more persistent than in patients with
a major factor. It is likely that age- and gender-related irritant dermatitis (Fregert 1975; Menne and Bachmann
Table 9. Key points of determi-

nants of occupational contact There is ample evidence for exposure, especially wet work, being the most important
dermatitis determinant of risk
Quantification techniques of exposures and their association with disease risk are virtually
absent
Extremes in the micro-environment (dryness, humidity, occlusion) are important effect
modifiers
Atopic skin dia thesis is an important endogenous risk factor, or atopic dermatitis is activated
byexposure
Dry skin is probably a risk factor, a proxy for atopic dermatitis
Except in specific circumstances, contact allergy is not a risk factor
Within the time span of employment life, age is not a risk factor
Gender is not a risk factor, but is associated with exposure
There is no other known personal skin characteristic associated with risk
1979; Meding and Swanbeck 1990). It should be kept in Another methodological problem is that the lack of
mind, however, that information bias and selection improvement may be due to the fact that even
bias may have caused the discrepancies; contact allergy occasional contact with the allergen at horne or at
to chromate in men and to nickel in women have the work place is sufficient to maintain the condition.
probably "contaminated" the statistics. A persistent Fregert (1975) concluded that a change of occupation
and troublesome type of dermatitis is more likely to be did not result in better healing than continuing in the
subject to additional skin testing, creating a greater same job, although the rate of healing seemed to be
chance of a positive test result. The relevance of these slightly better in the group which had changed. In his
common allergies with respect to persistence is discussion, Fregert noted that most of those who
uncertain; it can be questioned whether people with changed their work had the most severe eczema, which
such an allergy have ACD, rather than a subtype of could explain the persistence of the condition. He
dermatitis that is complicated by allergy to the metals, therefore did not discourage advice to change jobs.
chromate and nickel. Moreover, for specific contact Among metal workers with soluble oil dermatitis, no
allergies, it may be relatively easy to avoid the significant beneficial effect was observed from a change
causative agent. of occupation. Pryce et al. (1989), however, noted that 11
Some recent retrospective studies found a better of the 15 individuals who had changed their occupation
prognosis: in a questionnaire study with a response healed within 3 months. Rystedt (1985b) found that 65-
rate of 68%, of 201 workers with OCD, 76% noted 70% of the patients with HE and severe or moderate
improvement and 40% reported that they were atopic dermatitis had improved substantially after a
currently free of any eruption (Nethercott and Holness change of job. Wall and Gebauer (1991) observed a clear
1994). Approximately one-third noted that their skin beneficial effect of a change to an entirely different kind
disease interfered with household, work, or recreation- of work. Over a quarter of the patients who changed
al activities. It is notable that 37% of this group still jobs because of skin problems chose occupations in
had ongoing problems with their skin at the time of which the work environment aggravated their occupa-
follow-up. In a Swiss study, of 88 construction workers tional skin disease. This should be taken into account in
with occupational dichrornate dermatitis, 72% healed studying the effect of change. A study of 896 Finnish
in the first few years after declaration of medical farmers with hand derma tos es showed that, after 12-
inability (Lips et al. 1996). These workers mostly years of follow-up, the proportion that healed was
changed industry and strictly avoided all contact with greater in those who had given up farm work during the
cement or chromium salts. The authors conclude that period of follow-up than in those who continued
strict allergen avoidance and financial support in the farming (48% vs 71%). (Susitaival and Hannuksela
case of job change, are important factors in improving 1995). Wall and Gebauer (1991) found that 11.5% of the
the prognosis of OCD. patients had persistent skin disease for which there was
In contrast to these findings Shah et al. (1996) no obvious present cause. The major allergens involved
reported that HE in metalworkers carries a poor in these cases were chromate among men and nickel
pro gnosis, with most workers remaining symptomatic among women. Although this is consistent with earlier
even if they no longer had occupational exposure to reports of the alleged bad prognosis of dermatitis from
metals or oils. Of 51 patients, 82% still had HE. both metals (Fregert et al. 1979; Christensen 1982),
Among the 1238 patients with hand dermatitis who observer bias and selection bias, as explained above,
were identified in a population-based study in Gothen- may be a more likely explanation.
burg, 22% reported five or more medical consultations
for their condition (Meding and Swanbeck 1990). Sick
Prevention of OCD
leave in relation to hand dermatitis was reported by
21%. The mean duration of sick leave was 4 weeks.
Wall and Gebauer (1991) followed 954 patients with Approaches to the prevention of work-related
occupational skin diseases diagnosed between 1980 and dermatoses are analogous to the prevention of other
1987. The period from original diagnosis until review work-related diseases. In Table 10, the principles and
varied from 6 months to 8 years. Sixty-one percent of range of prevention measures for OCD are presented.
the subjects reported that they had lost time from work The highest priority should be given to measures "at
as a result of their skin disease. About 6% had been off the source", such as elimination or replacement of
work for longer than 12 months continuously. harmful exposures to irritants and allergens. Strategies
Opinions are divided with respect to the effect of in the prevention of OCD include identifying allergens
change of occupation. It should be mentioned, how- and irritants, substituting chemicals that are less
ever, that the majority of those who changed their irritating or allergenic, establishing engineering con-
work had the most pronounced contact dermatitis, trols to reduce exposure, and organizing the work in a
which may explain the persistence of the disease. way that all employees are exposed at the same degree.
Table 10. Principles and range of prevention measures for towards a beneficial effect. The prevalence of chromate
occupational contact dermatitis allergy in cement workers had fallen from 11% to 3% in
1. Elimination or replacement of harmful substances
Denmark (Avnstorp 1989). Since the data of this study
(irritants, allergens) are mostly derived from two different populations and
2. Technical measures (e.g., encapsulation of the process, do not give incidence-based relative risks, the evidence
automation)
3. Organization (e.g., wet work distributed to all employees)
is only indirect. Zachariae et al. (1996) confirm that
4. Personal protection (e.g., gloves, barrier creams, after-work chromium eczema due to occupational cement contact
creams, soaps) is now a rare disease in a Danish region where the
5. Pre-employrnent screening chromate content in wet cement has been reduced
below a level of 2 ppm, but chromium eczema from
Personal protection, for example using gloves or other causes, particularly from leather is still a
barrier cream, has to be the last option, but is often problem in the same area. It should be kept in mind,
selected in the first place. Selection of less susceptible however, that chromate allergy also seemed to decrease
individuals has to be the last measure. in countries that did not introduce this measure or in
Epidemiological studies on the prevention of contact Sweden before the measures (Färm 1986).
dermatitis in the work environment are needed to The effectiveness of barrier creams is also contro-
prove the effectiveness of preventive measures and versial and there is a lack of epidemiological studies
interventions. Presently, epidemiological intervention dealing with the beneficial effects of these measures.
studies that evaluate the relative impact of various The misuse of soaps and detergents can directly
measures to prevent contact dermatitis, have not been provoke ICD of the hands. Therefore, additional
published. interventions are needed, which include providing
Clinical observations indicate that many personal advice on the proper use of gloves and barrier creams,
protective measures do not have the desired effect, but and educating the workforce about exposure and skin
epidemiological evidence for or against is lacking. care. To learn more about the impact of these
Protective gloves, for example, are widely recommend- measures it would be important to perform prospec-
ed, but may well contribute to increased risk of contact tive, intervention type studies.
dermatitis: inside gloves the micro-environment is
drastically changed and faulty gloves are worse than no
Needs for Further Epidemiologie Studies on OCD
gloves at all. In so me working processes (machine
operating), the use of gloves can be even harmful due
to causing accidents. Barrier creams are also widely Although there is a wealth of information based on
prescribed, although the effect in terms of reduction of clinical data and case series, the paucity of sound
incidence or prevalence of dermatitis has never been epidemiological data on work-related contact derma-
documented. Hairdressers, for example, are exposed to titis is clearly illustrated in this chapter.
a variety of allergens and irritants, and a pro gram for First of all, data on prevalence of ICD and ACD are
elimination or reduction of exposure seems timely. A missing and the few published population-based
properly designed intervention study might help in studies are difficult to compare due to the lack of
finding the most effective strategy. standardization of case definitions and methods. To be
Emollient creams and ointments used during and able to compare cross-sectional studies, it is important
after work are also supposed to be effective in that some form of standardization is reached about
preventing contact dermatitis of the irritant type, but definition of contact dermatitis in epidemiological
the epidemiological evidence is scant (Halkier-Soren- studies, as well as methods of case ascertainment.
sen and Thestrup-Pedersen 1993). Second, very little is known about the interaction of
Scandinavian countries introduced the addition of exposure (at horne and at work), individual suscepti-
ferrous sulfate to cement as mandatory to reduce the bility, and environmental conditions. Prevention
prevalence of chromate allergy in bricklayers (Fregert should be focused upon elimination, reduction and
et al. 1979). However, chromate allergy seems to have avoidance of exposure to these agents. In many
decreased in countries that did not introduce this instances, however, this is not feasible. Studies devel-
measure (Burrows and Corbett 1977) and in Sweden oping and using advanced exposure assessments, or
before the change (Färm 1986). A historical cohort, job-exposure matrices, are needed to give regulatory
studied during the transition to chromate-free cement authorities the means of enforcing a cost-effective
in Denmark, was reconstructed by Avnstorp (1989) reduction of exposure to acceptable levels.
from two cross-sectional studies in the same cement Achallenging question for epidemiologists and
factory. As the data were derived mostly from two dermatologists to solve together is: given the situation
different populations and did not give incidence-based where exposure occurs, why is it that some individuals
relative risks, the evidence was indirect, but pointed develop contact dermatitis and others do not? This
type of question requires carefully designed prospec- Diepgen TL, Fartasch M (1992) Recent epidemiological and
genetic studies in atopic dermatitis. Acta Derm Venereol
tive studies for which some considerations are given
176:13-18
above. Results of these studies will hopefully provide Diepgen TL, Fartasch M (1993) General aspects of risk factors in
further clues on effective methods to give special care hand eczema. In: Menne T, Maibach HI (eds) Hand eczema.
to susceptible individuals, job advice, pre-employment CRC Press, Boca Raton, pp 141-156
Diepgen TL, Fartasch M, Hornstein OP (1991) Criteria of atopic
screening, for situations where exposure can not be skin diathesis. Dermatosen 39:79-83
avoided or further reduced. Diepgen TL, Tepe A, Pilz B, Schmidt A, Hüner A, Huber A,
Hornstein OP, Frosch PI, Fartasch M (1993) Occupational
Third, intervention studies are needed to demon- skin diseases in hairdressers and nurses during apprentice-
strate the benefi.t of preventive measures at the ship - design of a prospective epidemiological study.
workplace. In recent years, many proposals have been Allergologie 10:396-403
Diepgen TL, Schmidt A, Schmidt M, Fartasch M (1994) Demo-
published to avoid OCD. New and more effective skin graphic and legal characteristics of occupational skin diseas-
protection and skin care products are now on the es. Allergologie 17:84-89
market. New regulations for the prevention of OCD Diepgen TL, Schmidt A, Berg A, Plinske W (1995) Medizinische
Hinweise für die berufliche Rehabilitation von hautkranken
have been developed. The awareness of the importance Beschäftigten Dtsch Ärztebl 92:A31-A40
of OCD has increased. In the near future, we should Diepgen TL, Sauerbrei W, Fartasch M (1996) Development and
perform carefully designed intervention studies to validation of diagnostic scores for atopic dermatitis incor-
po rating criteria of data quality and practical usefulness.
prove the efficacy of these prevention measures. J Clin Epidemiol 49:1031-1038
Diepgen TL, Schmidt A, Fartasch M Occupational contact
dermatitis in hairdressers - an epidemiological study. Con-
References tact Dermatitis
Diepgen TL, Schmidt A, Fartasch M Epidemiology of occupa-
tional dermatoses in North Bavaria. Contact Dermatitis
Andersen KE, Maibach HI (1979) Black and white human skin Fabry H (1981) Statistik der Berufskrankheiten der Haut-
differences. J Am Acad Dermatol 1:276-282 gefährdungskataster. Dermatosen 29:42-44
Avnstorp C (1989) Prevalence of cement eczema in Denmark Färm A (1986) Changing patterns in chromate allergy. Contact
before and since addition of ferrous sulfate to Danish cement. Dermatitis 15:298-299
Acta Derm Venereol 69:151-155 Fisher A (1977) Contact dermatitis in black patients. Cutis 20:
Berardesca E, Maibach HI (1988) Raeial differences in sodium 303-320
lauryl sulphate induced cutaneous irritation: black and white. Fregert S (1975) Occupational dermatitis in a 10-year material.
Contact Dermatitis 18:65-70 Contact Dermatitis 1:96-107
BLS: Bureau of Labor Statistics (1993) Occupational injuries and Fregert S, Gruvberger G, Sandahl E (1979) Reduction of chromate
illnesses in the United States. US Department of Labor: 1993: in cement by iron sulfate. Contact Dermatitis 5:39-42
bulletin 2424 Frosch PJ, Burrows D, Camarasa JG, Dooms-Goossens A,
Burrows D, Corbett JR (1977) Industrial dermatitis in Northern Ducombs G, Lahti A, Menne T, Rycroft RJG, Shaw S, White
Ireland. Contact Dermatitis 3=145-150 IR, Wilkinson JD (1993) Allergic reactions to a hairdressers'
Christensen OB (1982) Prognosis in nickel allergy and hand series: results from 9 European centres. Contact Dermatitis
eczema. Contact Dermatitis 8:7-15 28:180-183
Coenraads PJ, Diepgen TL (1998) Risk of hand eczema in Funke U, Diepgen TL, Fartasch M (1995) Identification of high-
employees with past or present atopic dermatitis. Int Arch risk groups for irritant contact dermatitis by occupational
Occup Environ Health 71:7-13 physieians. In: Eisner P, Maibach HI (eds) Irritant dermatitis:
Coenraads PI, Smit J (1995) Epidemiology. In: Rycroft RJG, new c1inical and experimental aspects. Karger, Basel, pp
Menne T, Frosch PJ (eds) Textbook of contact dermatitis. 64-72
Springer, Berlin Heidelberg New York, pp 133-150 Goh CL, Chia SE (1988) Skin irritability to sodium lauryl sulphate
Coenraads PJ, Nater JP, van der Lende R (1983) Prevalence of - as measured by skin vapour loss - by sex and race. Clin Exp
eczema and other derma tos es of the hands and arms in the DermatoI13:16-19
Netherlands. Association with age and occupation. Clin Exp Hallder-Sorensen L (1996) Occupational skin diseases. Contact
Dermatol 8:495-503 Dermatitis 35 [SUppl1]:1-120
Cherry NM, Beck MH, Owen-Smith V (1994) Surveillance of Halkier-Sorensen L, Thestrup-Pedersen K (1993) The efficacy of a
occupational skin disease in the United Kingdorn: the OCC- moisturizer (Locobase) among c1eaners and kitchen assis-
DERM project. In: Proceedings of the Ninth International tants during everyday exposure to water and detergents.
Symposium on Epidemiology in Occupational Health, DHHS Contact Dermatitis 29:1-6
(NIOSH) Publication no 94-112, Cineinnati, pp 608-610 Hogan DJ, Tangiertsampan C (1992) The less common occupa-
Diepgen TL (1997) Der Berufsgenossenschaftliche Grundsatz G 24 tional dermatoses. Occup Med 7:385-401
Hauterkrankungen und die TRGS Feuchtarbeit. In: Harwerth Hogan DI, Dannaker CJ, Maibach HI (1990) The prognosis of
A (ed) Tagungsbericht 1996 Verband Deutscher Betriebs- und contact dermatitis. J Am Acad Dermatol 23:300-307
Werksärzte e.V .. Gentner, Stuttgart, p 83-90 Irvine C, Pugh CE, Hansen EJ, Rycroft RJG (1994) Cement
Diepgen TL, Coenraads PJ (1995) What can we learn from dermatitis in underground workers during construction of
epidemiological studies on irritant contact dermatitis. In: the Channel Tunnel. Occup Med 44:17-23
Elsner P; Maibach HI (eds) Irritant dermatitis: new c1inical Johnson MLT, Roberts J (1978) Skin conditions and related need
and experimental aspects. Karger, Basel, pp 18 for medical care among persons 1-74 years. United States,
Diepgen TL, Coenraads PJ (1999a) The impact of sensitivity, 1971-, USA. Vital Health Stat 11:1-72
speeificity and positive predictive value of patch testing: the Jowett S, Ryan T (1985) Skin disease and handicap: an analysis of
more you test, the more you get? Contact Dermatitis (in the impact of skin conditions. Soc Sei Med 20:425-429
press) Kanerva L, Toikkanen I, Jolanki R, Estlander T (1996) Statistical
Diepgen TL, Coenraads PJ (1999b) The epidemiology of occupa- data on occupational contact urticaria. Contact Dermatitis
tional contact dermatitis. Int Arch Occup Environ Health 35:229-233
72:416-506 Kavli G, Forde OH (1984) Hand dermatoses in Tromso. Contact
Dermatitis 10:174-177
16 T.L. Diepgen and P.J. Coenraads: The Epidemiology of Occupational Contact Dermatitis
Klas PA, Corey G, Storrs FI, Chan SC, Hanifin JM (1996) Allergie Rea JN, Newhouse ML, Halil T (1976) Skin disease in Lambeth. A
and irritant patch test reactions and atopic disease. Contact community study of prevalence and use of medical care. Br J
Dermatitis 34:121-124 Prev Soc Med 30:107-114
Kligman AM (1966) The identification of contact allergens in Roche LM (1993) Use of employer illness reports for occupational
human assay. J Invest Dermatol 47:375-392 disease surveillance among public employees in New Jersey.
Kristensen 0 (1992) A prospective study of the development of J Occup Med 35:581-586
hand eczema in an automobile manufacturing industry. Rycroft RJG (1995) Occupational contact dermatitis. In: Rycroft
Contact Dermatitis 26:341-345 RJG, Menne T, Frosch PJ, Benezra C (eds) Textbook of
Lammintausta K, Kalimo K (1981) Atopy and hand dermatitis in contact dermatitis. Springer, Berlin Heidelberg New York,
hospital wet work. Contact Dermatitis 7:301-308 pp 343-400
Lantinga H, Nater JP, Coenraads PJ (1984) Prevalence, incidence Rystedt I (1985a) Hand eczema and long-term prognosis in atopic
and course of eczema on the hands and forearms in a sampie dermatitis (thesis). Acta Derm Venereol117:1-59
of the general population. Contact Dermatitis 10:135-139 Rystedt I (1985b) Work-related hand eczema in atopics. Contact
Lahti A (1995) Immediate contact reactions. In: Rycroft RJG, Dermatitis 12:167-171
Menne T, Frosch PJ, Benezra C (eds) Textbook of contact Schnuch A, Uter W, Lehmacher W, Fuchs T, Enders F, Enders F,
dermatitis. Springer, Berlin Heidelberg New York, pp Arnold R, BalImer F, Brasch J, Diepgen TL, Frosch PJ,
62-74 Henseler T, Müller St, Peters K-P, Schulze-Dirks A, Stary A,
Lips R, Rast H, Eisner P (1996) Outcome of job change in patients Zimmermann J (1993) Epikutantestung mit der Standardserie.
with occupational chromate dermatitis. Contact Dermatitis Dermatosen 41:60-70
34:268-271 Shah M, Lewis FM, Gawkrodger DJ (1996) Prognosis of occupa-
Majoie IML, von BIomberg BME, Bruynzeel DP (1996) Develop- tional hand dermatitis in metalworkers. Contact Dermatitis
ment of hand eczema in junior hairdressers: an 8-year follow- 34:27-30
up study. Contact Dermatitis 34:243-247 Smit HA, Coenraads PJ, Lavrijsen APM, Nater JP (1992)
Mathias CGT (1985) The cost of occupational skin disease. Arch Evaluation of a self-administered questionnaire on hand
Dermatol 121:332-334 dermatitis. Contact Dermatitis 26:11-16
Mathias CGT, Morrison JH (1988) Occupational skin disease, Smit HA, Burdorf A, Coenraads PJ (1993) The prevalence ofhand
United States: results from the Bureau of Labor Statistics dermatitis in different occupations. Int J Epidemiol 22:
Annual Survey of Occupational Injuries and Illnesses, 1973 288-293
through 1984. Arch DermatoI124:1519-1524 Smit HA, van Rijssen A, Vandenbroucke J, Coenraads PJ (1994)
Mathias CGT, Sinks TH, Seligman PI, Halperin WE (1990) Individual susceptibility and the incidence of hand dermatitis
Surveillance of occupational skin disease: a method utilizing in a cohort of apprentice hairdressers and nurses Scand J
worker's compensation claims. Am J Ind Med 17:363-370 Work Environ Health 20:113-121
MCCurdy SA, Wiggins P, Schenker MB, Munn S, Shelab A, Storrs FI, Rosenthai LE, Adams RM, Clendenning W, Emmet EA,
Weinbaum Z, et al. (1989) Assessing dermatitis in epidemi- Fisher AA, Larsen WG, Maibach HI, Rietschel RL, Schorr WF,
ologie studies: occupational skin disease among California Taylor JS (1989) Prevalence and relevance of allergie reactions
grape and tomate harvesters. Am J Ind Med 16:147-157 in patients patch tested in North America - 1984 to 1985.
Meding B, Swanbeck G (1987) Prevalence of hand eczema in an J Am Acad Dermatol 20:1038-1045
industrial city. Br J Dermatol 116:627-634 Susitaival P, Hannuksela M (1995) The 12-year prognosis of hand
Meding B, Swanbeck G (1990) Consequences of having hand dermatosis in 896 Finnish farmers. Contact Dermatitis
eczema. Contact Dermatitis 23:6-14 32:233-237
Meneghini CL, Angelini, G (1984) Primary and secondary sites of Tacke J, Schmidt A, Fartasch M, Diepgen TL (1995) Occupational
occupational contact dermatitis. Dermatosen 32:205-207 contact dermatitis in bakers, confectioners and cooks - a
Menne T, Bachmann E (1979) Permanent disability from skin population-based study. Contact Dermatitis 33=112-117
diseases. A study of 564 patients registered over a six year Taylor JS (1988) Occupational disease statistics in perspective
period. Dermatosen 27:37-42 (editorial). Arch DermatoI124:1557-1558
Ministry of Social Affairs and Employment, The Netherlands Turjanmaa K, Alenius H, Makinen-Kiljunen S, Reunala T,
(1997) The cost of workplace circumstances in The Nether- Palosuo T (1996) Natural rubber latex allergy. Allergy
lands (in Dutch). Vuga Uitgeverij, The Hague, NL 51:593-602
Nethercott JR (1990) Practical problem in the use of patch testing Vaaranen V, Vasama M, Alho J (1983) Occupational diseases in
in the evaluation of patients with contact dermatitis. Curr Finland in 1982. Publication office Institute of occupational
Probl Dermatol 2:4 health, Vantaa.
Nethercott JR, Holness DL (1994) Disease outcome in workers Varigos GA, Dunt DR (1981) Occupational dermatitis. An
with occupational skin disease. J Am Acad Dermatol 30: epidemiological study in the rubber and cement industries.
569-574 Contact Dermatitis 7:105-110
Pryce DW, Irvine D, English JSC, Rycroft RJG (1989) Soluble Wall LM, Gebauer KA (1991) A follow up of occupational skin
oil dermatitis: a follow-up study. Contact Dermatitis 21: disease in Western Australia. Contact Dermatitis 24:241-243
28-35 Zachariae COC, Agner T, Menne T (1996) Chromium allergy in
consecutive patients in a country where ferrous sulfate has
been added to cement since 1981. Contact Dermatitis 35:83-85
CHAPTER 2
The Role of Clinical Epidemiology

in the Study of Occupational Contact Dermatitis
A. Schnuch and W. Uter
Introduction efficient methods of monitoring the frequency of

contact allergy to environmental chemicals (Schnuch
1998). However, sensitization to the culprit agent must
The epidemiologist deals of necessity .with. ~ata ?n
be diagnosed in allergic contact dermatitis an? ~u~t be
defined populations. The most basic settmg glVlng nse
excluded in any other form of eczema, be 1t 1rntant
to epidemiological data is the evaluation of the
contact dermatitis, atopic eczema, dyshidrotic eczema,
occurrence of a disease in the presence of an exposure.
pustulosis palmaris or even psoriasis and other
The exposure may be present or absent and the disease
dermatoses (Marks and DeLeo 1992). This diagnostic
may be present or absent. Frequency measures, such as
procedure, namely patch testing, is done in patients,
prevalence or incidence of the disease, ~re used
and the analysis of aggregated data of patch test results
to estimate the impact of that disease on pubhc health;
and patient histories (including information on the
to find out, possibly, the cause(s) of the disease, i.e., to
occupational background) is the domain of clinical
identify the risk associated with a certain exposu~e
epidemiology. .
(exogenous factors) or constitutional an~ demogra?h1C
The main difference between 'traditional' epidem1-
factors (endogenous factors); to quantlfy these ns~s;
ology and clinical epidemiology is that the former is
and, finally, to use this information for pre~e~tlve
'population based', while the latter is 'patient based'
measures (Monson 1990; Diepgen 1996; W1lhams
(Grufferman and Kimm 1984; Tobacman and Wenzel
1996).
1990). Such patient data may be collected in a single
For example, the incidence of occupation~l co~tact
department of dermatology (Enders et al. 1989; Ho-
dermatitis was assessed in different occupatiOns m a
lness and Nethercott 1994; Jacobs et al. 1995) or in
population-based study (Fig. 1). The risk resulting
several departments cooperating in a multicenter study
from exposure to wet work (Lammintausta et al. 1982)
(Fregert et al. 1969; Perrenoud et al. 1994; Marks et al.
and exposure to permanent wave solutions was deter-
1998; Schnuch et al. 1997). Obviously, these two types
mined (Uter et al. 1995), atopic diatheses was proven
of epidemiology will yield different results (Ni elsen
to be an endogenous risk factor (Diepgen 1991),
and Menne 1992; Diepgen 1996), as illustrated by
and preventive actions were taken in hairdressers,
Figs. 1 and 2, and Table 1. The chara.cteristics of
known to be frequently affected by contact dermatitis
different epidemiological methods used m the study
(Schwanitz et al. 1996). Comprehensive reviews on the
of contact dermatitis have already been discussed
epidemiology of (occupational and n.on -occupa~ional)
(Menn' and Knudsen 1997; Schnuch 1997a) and can be
contact dermatitis have been pubhshed (Smtt and
summarized as folIows. Clinical data cannot be used as
Coenraads 1993; Schnuch 1994).
the basis to calculate incidence and prevalence rates.
By contrast, the definite causes of contact dermatitis,
While the problem of population-based registries (and
mainly allergenic or irritant substances, are .rarely
respective epidemiological studies) is the numerator
identified by 'traditional' epidemiological stud1es or
(due to underreporting [Hinnen et al. 1994]), the
registers, respectively (Me ding and Swanbeck 1989;
problem in clinical surveillance systems is both the
Meding 1990; Rothe and Bräunlich 1991; Kanerva et al.
denominator, Le., the number of people 'exposed', and
1994; Diepgen et al. 1994). Population studies may give
often a more or less pronounced selection (so that only
valuable information on the magnitude of the disease
a certain proportion of diseased persons are included).
problem. However, contact allergy to substances ot~er
However, these rates are not essential to meet the
than nickel occurs rarely, and only large populatiOn
objectives of a surveillance system on skin allerg~es.
studies would have the statistical power to detect
Furthermore, changes within the clinical populatiOn
significant determinants of sensitization (Schnuch
can be identified without delay using a clinical
1998). Population or cohort studies, therefore, are not
surveillance system, especially if it is an 'active'

._IiI!!I__" __
18 A. Schnuch and W. Uter
Hairdressers
.!I!ii!___ IIi'!I_l!iiiiH!!!rl~~ _ _ 580
._!HIII
191
Bakers
Electroplaters 11 3
Florists ._.103
Confectioners .1IE!I84
Tilers ~!!II!I 74
Plumbers 57
Metalworkers. welders
Dental Technicians
Cooks
Health service workers
Mechanics
Leather workers
Fig. 1. Example of "traditional" epidemiology: occupations most The earliest signal indicating an emerging (new)
often affected by occupational skin diseases. Three years allergen is a diseased person. Because this person is first
incidence in Northern Bavaria (Germany) (Diepgen 1996)
examined and identified in clinical practice, the eval-
uation and statistical analysis of such cases yields the
surveillance system [such as the Information Network most rapid information. Based on this information,
of Departments of Dermatology in Germany (IVDK) patch testing can be optimized continuously and
(Uter et al. 1998)]. Active systems collect data regularly adapted to current trends, such as the introduction of
and do not depend on the 'good will' of the reporter; new allergens in occupational patch testing or further
passive surveillance systems depend on reporting in-depth studies could be prompted, e.g., epidemiolog-
(Beck 1992). ical studies in sensu strictu.
Table 1. Traditional and clinical epidemiology. Comparison of frequencies of positive patch-test reactions in the general population
and in eczema patients at a dermatological clinic in the same area of greater Copenhagen in 1990 (from Menne and Knudsen 1997)
Test substances General population % positive of tested Dermatological clinic % positive of tested
Men Women Total Men Women Total

n = 279 n = 288 n = 567 n = 262 n = 410 n = 672
Potassium dichromate 0.7 0.3 0.5 1.9 2.7 2.4

Neomycin sulfate 0.0 0.0 0.0 3.4 3.7 3.6
Thiurarn mixture 0.7 0.3 0.5 4.6 2.7 3.4
p- Phenylenediamine 0.0 0.0 0.0 1.9 2.7 2.4
Cobalt chloride 0.7 1.4 1.1 2.3 2.7 2.5
Benzocaine NT 0.4 0.7 0.6
Caine mix 0.0 0.0 0.0 NT
Formaldehyde NT 1.9 2.2 2.1
Colophony 0.4 1.0 0.7 4.6 5.4 5.1
Quinoline mix 0.4 0.3 0.4 1.9 0.5 1.0
Balsam of Peru 0.7 1.4 1.1 3.4 5.4 4.6
PPD black rubber mix 0.4 0.0 0.2 1.2 0.0 0.5
W 001 alcohols 0.4 0.0 0.2 1.2 1.7 1.5
Mercapto mix 0.7 0.0 0.4 1.2 0.2 0.6
Epoxy resin 0.4 0.7 0.5 0.8 0.2 0.5
Paraben mix 0.4 0.3 0.4 0.8 0.2 0.5
p-tert Butylphenol formaldehyde resin 1.1 1.0 1.1 0.4 1.2 0.9
Fragrance mix 1.1 1.0 1.1 6.1 7.1 6.7
Ethylenediamine dihydrochloride 0.4 0.0 0.2 0.8 0.7 0.7
Quaternium 15 0.4 0.0 0.2 0.0 0.0 0.0
Nickel sulfate 2.2 11.1 6.7 4.2 16.1 11.0
MCI/Ml (chloro-methyl-and 0.4 1.0 0.7 0.4 0.7 0.6
methyl-isothiazolinone)
Mercaptobenzothiazole 0.4 0.0 0.2 1.2 0.2 0.6
Primin NT 0.4 1.5 1.0
Thiomersal 3.6 3.1 3.4 NT
Carbamix 0.7 0.0 0.4 NT
The Role of Clinical Epidemiology in the Study of OeD 19
Occupation percent of 4.397
-. - 10.0
Nurses - - - ~ -
--.~
--'. .
--~
Hairdressers 6.3
Cleaning personnel '~'i," __ :.- '_ - ._ 4.0
Dental technicians 2.2

Construction workers 1.9
Cooks 1.8
Dental nurses 1.8

Metal workers 1.4
Receptionists 1.3
Bakers 1.2
Pain ters 1.2
Fig. 2. Example of clinical epidemiology: occupations of patients Table 2. Clinical epidemiology as a surveillance system I:
with suspected occupation-related dermatoses (n = 4.397). Eval- chronological evolution of sensitization to the most frequent
uation of 28,957 patients patch tested from 1994 to 1996. allergens. Proportions of sensitization are standardized by sex
Unpublished data from the IVDK and age (2 age groups: <40 and >40 (from Uter et al. 1998)
Allergen 1992 1993 1994 1995 1996

There are three main applications of clinical epide-
6700 8750 10,150 10,050 9600
miology concerning contact dermatitis (Uter et al. Nickel sulfate 16.7 17.0 17.1 17.1 16.3
1998): Fragrance mix 7.4 11.2 13.2 9.7 10.3
Thiomersal 4.2 4.8 6.2 6.4 7.5
1. Surveillance system monitoring (new) allergens Balm of Peru 5.5 6.3 7.0 6.3 7.0
2. A method to analyze exposure-( occupation-)related Cobalt chloride 4.4 4.8 5.0 4.8 4.9
p-Phenylenediamine 4.8 5.0 5.4 4.6 4.3
sensitization W001 wax alcohols 2.2 2.1 2.5 2.6 3.8
3. A tool to improve patch testing techniques (quality Potassium dichrornate 5.9 4.3 4.4 4.1 3.8
control) Colophony 2.8 3.4 3.6 3.2 3.6
Thiuram mix 2.7 2.5 3.2 2.6 2.6
Hg(II)-amide-chloride 2.3 2.3 3.2 2.1 2.5
MCI/MI 3.0 2.5 2.4 2.0 2.5
Surveillance System Neomycine sulfate 2.0 2.5 2.8 2.2 2.3
Formaldehyde 2.2 2.1 2.4 1.9 1.9
Turpentine 0.5 0.5 0.3 0.5 1.7
Methyldibromoglutaro- 1.2 1.9 2.0 1.7 1.7
'Surveillance' (Schnuch 1998) has been defined as nitril/phenoxyethanol
"continuous analysis, interpretation, and feedback of Paraben mix 1.5 1.4 1.8 1.1 1.6
systematically collected data, generally using methods Benzocaine 1.3 1.6 1.6 1.6 1.5
Epoxy res in 1.2 1.3 1.1 1.1 1.1
distinguished by their practicability, uniformity, and p-tert-Butylphenol- 0.9 0.9 1.1 0.9 1.1
rapidity rather than by accuracy or completeness" FA-res in
(Last 1995). This method differs from other epidemi-
ological methods, such as cohort, case-control or
cross-sectional studies, which may provide more research projects or preventive intervention concern-
precise data on prevalence, along with partial data on ing the respective problem. In comparison with
incidence and the significance of risk factors. However, infectious diseases, for which surveillance systems
such studies are usually rather costly, cover only a are often employed, such sentinel events occur much
certain period of time and are often limited to a more slowly. A few examples shall be listed. As
relatively narrow issue, e.g., incidence of, and risk sensitization rates depend on the distribution of
factors for skin damage in hairdressers or other gender and age of the population studied, these rates
occupationally defined cohorts. should be standardized as aprerequisite of further
The observation of trends in time (Table 2), e.g., an analysis (Schnuch 1996a).
increase in the proportion of a certain sensitization, A mixture of methyldibromoglutaronitrile (synonym:
can as a 'sentinel health event' give rise to aimed dibromodicyanobutane) and phenoxyethanol (1:4) is a
preservative which is widely used now in cosmetics and and that cheaper products are used especially in non-
toiletries, but also in industrial lubricants. While, in medical and non-cosmetic applications, giving rise to
1990, less than 1% of patients tested were sensitized, a more wool-alcohol allergies.
steady increase to 2% in 1994, reaching a plateau since Further examples, induding non-occupational aller-
then (Geier et al. 1996), has been noted which can most gens, are listed in Table 3 (see Uter et al. 1998 also).
likely be attributed to increased use in cosmetics Guidelines for evaluating surveillance systems in
(Wüstermann and Siebert 1997). Nevertheless, the rate contact dermatitis have been proposed (Schnuch
in Germany is not as high as reported elsewhere 1998) (see Appendix).
(DeGroot et al. 1996). It is yet to be determined whether
the change of the test concentration in 1997 has
improved the diagnostic procedure, reflected by an A Method to Analyze
increase of the sensitization rate (Table 3) or has led to Exposure-(Occupation-)Related Sensitization
quite a number of 'false-positive' reactions.
Turpentine oil is a mixture of mono- and bicydic
The aim of clinical epidemiology in this context is to
terpenes, e.g., alpha-pinen, beta-pinen, D- and L-
identify and analyze certain subgroups within the
limned, delta-3 caren, and camphene. Formerly, it
tested population that are at a particular risk, e.g.,
was widely used as a solvent in paints. Skin sensitiza-
those working in certain occupations. These subgroups
tion is caused by oxidation products (Hellerström
have to be large enough for valid analysis. While a
et al. 1963; Piril et al. 1969; Karlberg and Dooms-
single center may need years to collect a considerable
Goossens 1997). Sensitization rates have decreased
number of cases, for instance, workers in a certain
during the last decades, and rates were so low «1%)
occupation or patients with some rare sensitization,
that its inclusion in the standard series was questioned
multicenter cooperation can constitute such subgroups
(Cronin 1979; Schnuch et al. 1997). Surprisingly, rates
relatively fast. Two main issues have evolved:
are again increasing (Tables 2 and 3), although tur-
pentine itself is rarely used (Flyvholm 1991). These 1. The spectrum of allergens of a subgroup defined by
rates may indicate an increasing exposure to terpenes, occupation, age, gender, atopy or other parameters.
such as limonene, which is used as an industrial Certain allergens that are irrelevant on the scale of the
solvent, (Ippen 1998) or the ingredients of the tea tree total population tested may be extremely important,
oil, used as an 'natural' remedy (Knight and Hausen e.g., in certain occupations or in a certain age group.
1994; Bhushan and Beck 1997; Buchbauer 1997). 2. The 'demographie profile' of a certain allergen may
Sensitization to wool alcohols is a well-known reveal similar assoClatlOns using a different
phenomenon (Mortensen 1979; Schnuch et al. 1993a), approach: for instance, medical or deaning staff is
but its increase within 2 years (Tables 2 and 3) cannot over represented in the subgroup of glutaraldehyde-
easily be explained. W001 alcohols are not only used in sensitive patients (Geier and Schnuch 1995b), and
topical medieaments and cosmetics, but also in other nurses and metal workers are over represented in
products of daily use (Hausen et al. 1979) and in formaldehyde-sensitive patients (Schnuch and Geier
industrial applications (CaInan 1979). It is probable 1997). This approach may give some hint regarding
that different processing of the raw material yields the occupational distribution of allergens and, thus,
wool alcohols of different quality and varying aller- the risk for a sensitized person in different occupa-
genicity (Clark et al. 1981; Edman and Moller 1989), tions.
Table 3. Clinical epidemiology as a surveillance system II: "sentinel health events" (i.e. striking sensitization rates urging for further
studies and preventive action)
Population Allergen Test Number % Positive

period of patients (stand.)
tested
Unselected Turpentine 1997 7.917 3.1

Patch test Wool wax ale. 1997 7.914 3.7
Population* Bufexamac 1997 4.918 1.9
MDBGN/PE* 1997 7.787 3.0
Non-occupational exposure to paints (men)** MCIIMI 1996/1997 52 11.7
Formaldehyde 1996/1997 52 4.2
Chloracetamine 1996/1997 43 4.7
Non-occupational exposure to plants/flowers (women)** MCIIMI 1996/1997 102 5.1
* MDBGNIPE methyldibromoglutonitril-phenoxyethanol after an increase of test concentration from 0.5% to 1%

**Unpublished study supported by the Umweltbundesamt (No. 11606114)
The Role of Clinical Epidemiology in the Study of OCD 21
Demographie Determinants of Sensitization Analysis of Oeeupational (auses of Sensitization
The analysis of the total study population of the IVDK Hea/th Care Workers
tested up until 1995 (Schnuch et al. 1997) revealed
strikingly different proportions of sensitization Health care workers (especially nurses) are often
between different departments, even after standardiza- affected by occupational dermatitis (Fig. 2). Arecent
tion by gen der and age (Schnuch 1996a) (Table 4). study (Schnuch et al. 1998a) analyzed sensitization
These differences could be attributed to several details patterns of health care workers tested within the IVDK
of the MOAHL (male, occupational dermatitis, atopic (Table 5). In general, this 'occupational sensitization
dermatitis, hand dermatitis, leg dermatitis) index and pattern' comprises thiurams (rubber compounds),
to geographical, e.g., east versus west Germany, differ- thiomersal (vaccine preservative) and several biocides,
ences in allergen exposure. However, further factors such as glutaraldehyde, formaldehyde, glyoxal and
were identified: the high rate of sensitization to benzalkonium chloride, which are used as surface and
fragrances in Tuebingen (21.1%) correlates with a high instrument disinfectants. The shift from formaldehyde
percentage of patients with face dermatitis (23% vs 14% (formerly by far the most important allergen in nurses)
on average). This led us to propose an extension of the to glutaraldehyde and glyoxal shows that one evil was
MOAHL index, by including 'face' and the previously cured with an even worse evil. However, our study did
acknowledged factor 'age' ('MOAHLFA'). Another not indicate an increase in substances listed commonly
example is the difference in nickel sensitization beas important allergens in the health care sector, namely
tween departments in Munich and Göttingen or Tue- drugs. Because of this limited importance, and in view
bingen, for which sociological determinants of nickel of a high risk of active sensitization, routine testing of
exposure and consecutive allergy may be responsible drugs in nurses cannot be recommended. Some other
(Edman and Janzon 1989). The possible importance of allergens seem to be characteristic for specific health
such a factor (social-class-specific exposure and sensi- care occupations, e.g., methacrylates for dental tech-
tization), though rarely considered as yet, mayaIso nicians, possibly metals for dental nurses, and fra-
account for an increased incidence of nickel hypersen- grances for nurses and, in particular, masseurs.
sitivity at the start of their apprenticeship in junior
hairdressers (26%) compared with junior nur ses (12%) Construrtion Workers
(van der Burg et al. 1986). This is further supported by
another study (Schnuch et al. 1998a) demonstrating Allergic contact dermatitis due to hexavalent chromi-
that receptionists were affected significantly more often um in cement, one of the occupational skin diseases
by nickel allergy than the average, and female physi- known for a long time, is still the most important
cians significantly less often. contact allergy in construction workers (bricklayers,
The overall (pooled) results contain a broad spec- manufacturers of concrete elements, etc.). However,
trum of different sub populations and may weIl be
regarded as being representative for central Europe.
Table s. Clinical epidemiology - sensitization in specific occupa-
tions I: the most frequent allergens in women with and without
Table 4. Geographie differences: extreme (low and high) propor- medical occupations. Number of patients tested (1), rates
tions of sensitization (standardized by age/sex) (%) of selected standardized by age (two groups, <40 and >40) (2), and rates
allergens in different dermatological departments (IVDK) in of the total test population (women; medical occupations
Germany and Austria (from Schnuch et al. 1997) excluded) (3-4). Significant differences with asterix (P < 0.05)
(from Schnuch et al. 1998a)
Low High
Substance Medical occupations Control
Nickel (women) Goettingen 14.0 Munich LMU 20.9 group
Tuebingen 12.3 Munich TU 20.6 2 3 4
Nickel (men) Goettingen 3.2 Osnabrueck 9.9
Tuebingen 1.6 Nickel sulfate 2187 23.6% 18857 23.2%
Fragrances (women) Osnabrueck 7.0 Tuebingen 21.1 Fragrance mix 2192 12.4% 18855 11.4%
Thiomersal Dresden 2.5 Graz 11.8 Balm of Peru 2197 4.9%* 18898 6.7%
(women + men) Potassium dichrornate 2212 3.2% 19029 4.0%
Potassium dichrornate Graz 3.1 Osnabrueck 8.8 Colophony 2206 2.9% 18928 3.5%
(men) Thiomersal 2174 12.6%* 18502 4.9%
Goettingen 3.4 Dortmund 8.9 Glutaraldidehyde 1194 9.9%* 3985 2.6%
Munich LMU 3.8 Dresden 10.5 Formaldehyde 2234 3.6%* 18964 2.1 %
Isothiazolinones Dresden 0.5 Tuebingen 7.2 Sothiazolinone (MI/MC!) 2110 2.5% 18470 2.4%
(MI/MCI) (men) Methyldibromo- 2148 1.9% 18361 1.7%
Berin Charite 1.0 Osnabrueck 10.9 glutaronitril/PE
Neomycine (women + Berin Charite 1.0 Munich TU 5.1 Glyoxal 774 4.2%* 1895 1.4%
men) Benzalkonium-Cl 1406 2.0% 10274 1.6%
Dresden 1.2 Tuebingen 5.7 Thiuram mix 2197 6.7%* 18928 2.6%
important occupational allergens other than chromate an interna! analysis of data from the IVDK. This
have been identified {Table 6}, e.g., cobalt, rubber observation prompted communal patch-test training
additives {such as thiurams and dithiocarbamates}, sessions, both with patients and slides, which were
epoxy resin, hexamethylendiamine and isophorondi- later discussed and analyzed, giving each participant
amine {Geier and Schnuch 1995a; Geier and Schnuch feedback as to whether individual reading differed
1998}. An exposure checklist has been developed for from the 'general opinion' {it should be noted here
use in occupational dermatology {Geier and Struppek that clear-cut allergic - papulovesicular - reactions
1995} based on data of the IVDK as weIl as expertise of were rarely a matter of debate, in contrast to weak or
specialists from the respective employers' liability equivocal reactions}.
insurance association {in Germany, Bau-Berufsgeno- - The composition of test series is an important aspect
ssenschaft}· of the quality of patch testing. The hairdressers'
series could be reduced from 16 to 9 substances after
an analysis of cross-reaction patterns {Peters et al.
A Tool to Improve Patch Testing Techniques 1994}. Two series containing ointment bases {n = 16}
(Quality Control) and preservatives {n = 31}, respectively, were re-
placed by one series {n = 22}. This omitted those
substances that rarely caused reactions in several
Quality control of patch testing is both aprerequisite
thousand patients, or which cross reacted with other
for, and an objective of, clinical epidemiology of
substances or mixes {Schnuch et al. 1993a}. Thus,
contact dermatitis. Continuous development of test
patch testing has been rationalized, i.e., made
standards concerning the composition of test series,
cheaper while remaining as sensitive as before.
test concentration, and vehicle and standardization of
However, new allergens are introduced into the
test readings is provided by the national and interna-
series, if indicated. Bufexamac, for example, was
tional research groups on contact dermatitis. Test
suspected to be an underestimated allergen {Kränke
results contributed by single partners can regularly be
et al. 1996}. The sensitization rate was clearly more
checked for missing data, formal correctness and
than 1% in a short period of patch testing and, thus,
plausibility.
its inclusion in the standard series is indicated.
Some aspects of quality control - improving 'good
clinical practice' in patch testing - can be implemented
Mixes
by respective analyses of a large multicenter database:
- Further standardization of test readings. Although Mixtures of allergens, usually chemically related, are
participants of a multicenter study read patch tests often used in patch testing, mainly in the standard
according to International Contact Dermatitis Re- series, to increase efficacy in terms of a maximum
search Group (ICDRG) criteria, considerable differ- information obtained with a minimum number of
ences were noted between the spectrum of reactions allergens applied. In case of a positive reaction to the
to certain allergens in different centers, as shown by mix, its single constituents should be tested to identify
the actual allergen. It is therefore important that the
mix detects such specific sensitization. An analysis of
Table 6. Clinical epidemiology - sensitization in specific occupa- mixes of rubber chemicals {Geier and Gefeller 1995}
tions II: important allergens in construction workers (men)
suspected to suffer from occupational dermatoses working in revealed that only the thiuram mix {sensitivity 0.84}
construction. Rates standardized for age «40; >40) (from Geier was satisfactory in this respect, while contact sensiti-
and Schnuch 1998) zation to one of the constituents of the mercapto mix
Controls
{sensitivity 0.57} was better detected using
Substance Construction
mercaptobenzothiazole alone! Similar results were
No. % No. % obtained analyzing other rubber mixes {Geier and
tested Positive tested Positive Gefeller 1995}.
Potassium dichromate 317 44.3 9109 4.1
Cobalt chloride 322 17.9 9113 2.5 Analysis of Cross Reactions and Concomitant Reactions
Thiuram mix 321 8.2 9081 2.1
Epoxy resin 321 7.8 9100 l.5
p- Phenylenediamine 322 7.2 9086 4.2 The well-known phenomenon of cross reactions, i.e.,
Diaminodiphenyl- 121 6.2 155 3.5 the fact that patients sensitized to a certain allergen
methane will more or less regularly exhibit positive test
Hexamethylendiamine 66 5.9 76 2.2
Isophorondiamine 106 4.9 121 0.4 reactions to a cluster of other allergens, may have
Mercaptobenzothiazol 171 4.2 3354 6.8 two reasons: {I} the other substance{s} are chemically
Zinc diethyldithio- 315 2.9 8330 0.4 so closely related that they may act as a specific hapten,
carbamat
even without previous contact and independent sen-
The Role of Clinical Epidemiology in the Study of OCD 23
Table 7. Allergie reaetions to different biocides in unequivoeal (++/+++) formaldehyde allergie patients (from Sehnueh and Geier
1997)
Women Men
With formaldehyde Without formaldehyde With formaldehyde Without formaldehyde
n % positive n % positive n % positive n % positive
Glutaraldehyde 46 28 4.938 4 18 22 2.532 2

Quatemium 15 81 26 11.932 <1 30 17 6.153 <1
Glyoxal 32 22 2.561 2 9 11 1.091 <1
Isothiazolinone (MI/MCI) 128 18 20.283 2 61 13 10.852 2
Thiomersal 129 13 20.214 6 60 8 10.840 5
Diazolidinylurea 76 13 11.052 1 26 8 5.725 <1
Benzalkonium-Cl 78 6 11.249 2 23 17 5.491 2
Chloraeetamid 81 5 11.630 1 34 9 6.389 <1
MDBGN/PE 126 2 20.120 2 59 7 10.811 2
sitization, e.g., aminoglycoside antibiotics (Geier and that structurally related compounds do not cross react,
Schnuch 1995c) or aldehydes (Table 7), or (2) the other i.e., that patients sensitized to one substance are not at
substance(s) occur simultaneously in the environment an increased risk of contact dermatitis from exposure
of allergens to which the patients have been exposed, to the other substance. This is the case with the
such as different biocides (Table 7). Patients sensitized industrial biocide octyl-isothiazolinone not cross re-
unequivocally to formaldehyde show a pattern of acting with (chloro-)methylisothiazolinone (Geier and
concomitant sensitization that may give hints regard- Schnuch 1996), or with the rare allergen benzoic acid
ing the formaldehyde exposure [disinfectants, but not cross reacting with parabens (para-amino-benzoic
probably not cosmetics, as the rate of met- acid esters) (Schnuch 1997b).
hyldibromoglutaronitrillphenoxyethanol (MDBGN/
PE) - often used in cosmetics - was not increasedl
(Schnuch and Geier 1997). Clinical Epidemiology as the Starting Point
Another possibility of 'cross reaction' is found with of Experimental Research
formaldehyde-releasing biocides (Tables 8 and 9),
which may cause positive test reactions (and clinical While aspects of clinieal research (clinical epidemiol-
reactions) in persons sensitized to formaldehyde to a ogy) have been the focus of attention, projects for
certain, varying extent (Geier et al. 1997). It is not yet experimental research can also be derived from the
clear whether the reaction to formaldehyde in patients data. Analysis of the structure-activity relationship, for
sensitized to a formaldehyde releaser can be interpreted example, especially if neither human nor animal data
as a cross or as a concomitant reaction (Geier et al. 1997). on the sensitization potency of a compound are
Knowledge of these aspects improves diagnosis of available. In the case of naphthalic acid anhydride,
contact dermatitis, as well as its prevention, because it neither human nor animal data were available. Anal-
aids the avoidance of sources of allergens otherwise ysis of cross reactions between different dicarbonic
overlooked. However, it may be important to know acid anhydrides led us to hypothesize that this
substance should be a sensitizer (Schnuch 1996b),
Table 8. Reaetions to formaldehyde and formaldehyde releasers
used in eosmeties (from Geier et al. 1997) whieh later was clearly confirmed in (16/20) guinea
pigs (unpublished data).
Test substanee Positive Positive reaetion A second example deals with the identification of
reaetion to the to the substanee individual, constitutional risk factors for contact sensi-
substanee and formaldehyde
tization in patients with multiple sensitization (Schnuch
n % n % and Geier 1996). To study the issue of genetic risks
further, we investigated whether patients with contact
Formaldehyde 309 2.4 309 100.0 allergy differed from non-contact-allergic, non-atopie
1% Aq.
Bronopol 160 1.2 8 5.0 controls with regard to genotype and phenotype of the
0.5% Vas. polymorphie enzyme N-acetyltransferase 2 (NAT2).
Diazolidinylurea 129 1.0 16 12.4 Within aperiod of 3 months, 55 patients allergic to
2% Vas.
Imidazolidinylurea 85 0.6 13 15.3 para-substituted aryl compounds were recruited from
2% Vas. the Information Network of Departments of Dermatol-
Quaternium 64 0.5 30 46.9 ogy. A significantly increased proportion of 'rapid
15.1% Vas.
acetylators' was found, and it was concluded that
Table 9. Reactions to formaldehyde and formaldehyde releasers used for industrial application (from Geier et al. 1997)
Test substance Positive reaction to the Positive reaction to the

substance substance and formaldehyde
n % n %
Formaldehyde 1% Aq. 39 2.8 39 100.0

N,N' Methylen-bis-5-methyl-oxazolidin 1% Vas. 46 3.3 13 28.3
Benzylhemiformal 1% Vas. 32 2.3 16 50.0
Bioban P 1487 1% Vas. 31 2.2 2 6.5
Bronopol 0.5% Vas. 27 1.9 4 14.8
Bioban CS 1135 1% Vas. 15 1.1 6 40.0
Grotan BK 1% Vas. 11 0.8 5 45.5
Bioban CS 1246 1% Vas. 9 0.6 5 55.6
N-Methylchloracetamid 0.2% Vas. 6 0.4 0 0
Tris Nitro 1% Vas. 3 0.2 1 33.3
NAT2 status may be one of possibly several markers for Buchbauer G (1997) über das Teebaum Oe! Euro Cosmetics 5:
contact sensitizability (Schnuch et al. 1998b). 21-26
Calnan CD (1979) Lanolin in protective metal coatings. Contact
Clark EW, Blondee! A, Cronin E, Oleffe JA, Wilkinson DS (1981)
Lanolin of reduced sensitizing potential. Contact Dermatitis
Practical Consequences of Clinical Epidemiology 7:80-83
Cronin E (1979) Oi! of turpentine - a disappearing allergen.
Contact Dermatitis 5:308-311
The continuous collection and analysis of data within DeGroot AC, vanGinkel qw, Weijland JW (1996) Methyl-
multicenter clinical epidemiology offers, apart from a dibromoglutaronitrile (Euxyl K 400): an important "new"
allergen in cosmeties. J Am Acad Dermat 35:743-747
purely scientific aspect, practical benefit for several Diepgen TL (1991) Die atopische Hautdiathese. Gentner Verlag,
institutions: Stuttgart
Diepgen TL (1996) Epidemiological studies on the prevention of
- The public, informed by media and various institu- occupational contact dermatitis. In: Eisner P, Lachapelle JM,
tions, can profit from in-depth, scientifically evalu- Wahlberg JE, Maibach HI (eds) Prevention of contact
dermatitis. (Current problems in dermatology, vol 25) Karger,
ated data on the health impact of various potential Basel, pp 1-9
allergens, e.g., in cosmetics, toiletries and other Diepgen TL, Schmidt A, Schmidt M, Fartasch M (1994) Be-
every-day products. This may also include the rufs ekzeme und Berufskrankheitsverfahren - epidemiol-
ogische Aspekte. Allergologie 17:84-89
information that a certain substance has not been Edman B, Janzon L (1989) Sodal and demographic aspects of
found to be a serious hazard. nickel contact allergy. In: Maibach HI, Menn' T (eds) Nickel
- Federal (or state) regulatory institutions can refer to and the skin: immunology and toxicology. CRC Press, Boca
Raton, Florida, pp 207-214
the results of clinical epidemiology, e.g., to give Edman B, Moller H (1989) Testing a purified lanolin prepara-
arguments in support of actions such as nickel tion by a randomized procedure. Contact Dermatitis 20:
exposure limits. 287-290
Enders F, Przybilla B, Ring J, Goilliausen R (1989) Patch test
- Employers' liability insurance associations or occu- results in 1987 compared to trends from the period 1977-1983.
pational physicians rely on data of the occurrence of Contact Dermatitis 20:230-232
certain allergens in the work environment, but are Flyvholm MA (1991) Contact allergens in registered chemieal
products. Contact Dermatitis 25:49-56
also interested in non-occupational allergen sourees. Fregert S, Hjorth N, Magnusson B, Bandmann H-J, Calnan CD,
- Manufacturers of cosmetic and other consumer Cronin E, et al. (1969) Epidemiology of contact dermatitis.
products can use surveillance data both for pre- Trans St. John's Hospit Dermatol Soc 55=17-35
Geier J, Gefeller 0 (1995) Sensitivity of patch tests with rubber
marketing analysis of the sensitization potential of mixes: results of the Information Network of Departments of
possible ingredients (also relevant for staff in the Dermatology from 1990 to 1993. Am J Contact Dermat 6:
manufacturing process) and for post-marketing 143-149
Geier J, Schnuch A (1995a) A comparison of contact allergies
surveillance of ingredients of products already on among construction and nonconstruction workers attending
the market. contact dermatitis dinies in Germany - results of the
Information Network of Departments of Dermatology from
November 1989 to July 1993. Am J Contact Dermat 6:86-94
Geier J, Schnuch A (1995b) Glutaraldehyd - Berufsspektrum eines
References Allergens. Dermatosen 43:30-31
Geier J, Schnuch A (1995C) Kreuzreaktionen zwischen topisch
angewandten Aminoglykosid-Antibiotika. Dermatosen
Beck MH (1992) Occupational dermatoses surveillance in the 43:266-269
United Kingdom. Br J DermatoI127:J6-17 Geier J, Schnuch A (1996) No cross-sensitization between MCII
Bhushan M, Beck MH (1997) Allergie contact dermatitis from tea MI, benzisothiazolinone and octylisothiazolinone. Contact
tree oil in a wart paint. Contact Dermatitis 36:117-118 Dermatitis 34:148-149
The Role of Clinical Epidemiology in the Study of OeD 25
Geier 1, Schnuch A (1998) Kontaktallergien im Bau- Perrenoud D, Bircher A, Hunziker T, Suter H, Bruckner-
Hauptgewerbe. Eine Auswertung der IVDK-Daten 1994- Tuderman L, Stager J, et al. (1994) Frequency of sensitization
1996. Dermatosen 46:109-114 to 13 common preservatives in Switzerland. Swiss Contact
Geier J, Struppek K (1995) Anamnese-Auxilium für die be- Dermatitis Research Group. Contact Dermatitis 30:276-279
rufsdermatologische Untersuchung von Maurern, Bet- Peters K-P, Frosch PI, Uter W, Schnuch A, Arnold R, Bahmer F,
onbauern, Fliesenlegern und Angehörigen verwandter et al. (1994) Type IV - Allergien auf Friseurberufsstoffe.
Berufe. Dermatosen 43:75-80 Dermatosen 42:50-57
Geier J, Schnuch A, Fuchs T (1996) Zunahme der Kon- Pirilä V, Kilpiö 0, Olkkonen A, Pirilä L, Siltanen E (1969) On the
taktallergien gegen Methyldibromoglutaronitril in Deutsch- chemical nature of the eczematogens in oil of turpentine. V.
land. Allergologie 19:399-402 Dermatologica 139:183-194
Geier 1, Lessmann H, Schnuch A, Fuchs T (1997) Kontaktallergien Rothe A, Bräunlich A (1991) Zur Epidemiologie der Berufsder-
durch Formaldehyd abspaltende Biozide. Allergologie 20: matosen in der ehemaligen DDR. In: Ring J (ed) Epidemi-
215-224 ologie allergischer Erkrankungen, MMV Medizin Verlag,
Grufferman S, Kimm SYS (1984) Clinical epidemiology defined. München, pp 83-97
N Engl J Med 311:541-542 Schnuch A (1994) Die Verbreitung des Kontaktekzems in der
Hellerström S, Lodin A, Rajka G, Swedin B, Widmark G (1963) Allgemeinbevölkerung und in verschiedenen Berufen. In:
Sensitization of pigs with 3-carene. Acta Derm Venereol Fuchs E, Schulz K-H (eds) Manuale allergologicum, Dustri-
Stockh 43:311-323 Verlag, München-Deisenhofen V.16.2, pp 1-42
Hinnen U, Hotz P, Gossweiler B, Gutzwiller F, Meier PJ (1994) Schnuch A (1996a) PAFS - population adjusted frequency of
Surveillance of occupational illness through anational poison sensitization (I) - influence of sex and age. Contact Derma-
control center: an approach to reach small-scale enterprises? titis 34:377-382
Int Arch Occup Environ Health 66:117-123 Schnuch A (1996b) Dikarbonsäureanhydride vom Type
Holness DL, Nethercott JR (1994) Patch testing in an occupational Phthalsäureanhydrid als (Kreuz-) Allergene? Dermatosen
health dinic. Am J Contact Dermatitis 5=150-155 44:177-178
Ippen H (1998) Limonen - Dipenten, Citrus-le und Citrus Schnuch A (1997a) Methods for epidemiological surveillance of
Terpene. Teil I: Allgemeines, Vorkommen, Verwendung, prevalence and incidence of skin allergy. In: Flyvholm A-A,
Penetration, Kinetik, Metabolismus. Dermatosen 46:18-25 Andersen KE, Baranski B, Sarlo K (eds) Criteria for dassi-
Jacobs M-C, White IR, Rycroft RJG, Taub N (1995) Patch testing fication of skin- and airway-sensitizing substances in the
with preservatives at St. John's from 1982 to 1993. Contact work and general environments. WHO Regional Office for
Dermatitis 33:247-254 Europe, Copenhagen, pp 91-100
Kanerva L, Jolanki R, Toikkanen J (1994) Frequencies of Schnuch A (1997b) Kreuzreaktionen zwischen Benzoesäure und
occupational allergie diseases and gender differences in p-Hydroxybenzoesäureestern. Dermatosen 45:288
Finland. Int Arch Occup Environ Health 66:111-116 Schnuch A (1998) Proposal for evaluating surveillance systems in
Karlberg A-Th, Dooms-Goossens A (1997) Contact allergy to contact dermatitis. In: Maibach HI, Schwindt DA (eds)
oxidized D-limonene among dermatitis patients. Contact Coetaneous biometries. Plenum, New York (in press)
Dermatitis 36:201-206 Schnuch A, Geier J (1996) Identification of patients with multiple
Knight TE, Hausen BM (1994) Melaleuca oil (tea tree oil) sensitizations to contact allergens - subgroups to be exam-
dermatitis. J Am Acad Dermatol 30:423-427 ined for genetic risks? (abstract). Jadassohn Centenary
Kränke B, Derhaschnig J, Komericki P, Aberer W (1996) Congress, London 9-12 October 1996, pp 64
Bufexamac is a frequent contact sensitizer. Contact Derma- Schnuch A, Geier J (1997) Formaldehyde-Allergie: Aktuelle
titis 34:63-64 Trends im internationalen Vergleich. Auswertungen der
Lammintausta K, Kalimo K, Havu VK (1982) Occurrence of IVDK-Daten der Jalue 1992-1995. Allergologie 20:205-214
contact allergy and hand eczemas in hospital wet work. Schnuch A, Arnold R, Bahmer F, Brasch J, Diepgen TL, Enders F,
Contact Dermatitis 8:84-90 et al. (1993a) Epikutantestung mit der Salbengrundlagenreihe
Last JM (ed) (1995) A dictionary of epidemiology, 3rd edn, Oxford - Ergebnisse des Informationsverbundes Dermatologischer
University Press, New York Kliniken (IVDK). Dermatosen 41:176-183
Marks JG, DeLeo VA (1992) Contact and occupational dermatol- Schnuch A, Uter W, Lehmacher W, Fuchs Th, Enders F, Arnold R,
ogy. Mosby Year Book, St. Louis et al. (1993b) Epikutantestung mit der Standard serie - Erste
Marks JG, Belsito DV, DeLeo VA, Fowler JF, Fransway AF, Ergebnisse des Projektes "Informationsverbund De-
Maibach HI, et al. (1998) North American Contact Dermatitis rmatologischer Kliniken" (IVDK). Dermatosen 41:60-70
Group patch test results for the detection of delayed type Schnuch A, Geier 1, Uter W, Frosch PI, Lehmacher W, Aberer W,
hypersensitivity to topical allergens. J Am Acad Dermatol et al. (1997) National rates and regional differences in sensi-
38:911-918 tization to allergens of the standard series. Population adjusted
Meding B (1990) Epidemiology of hand eczema in an industrial frequencies of sensitization (PAFS) in 40,000 patients from a
city. Acta Derm Venereol Stockh Suppl 153:2-43 multicenter study (IVDK). Contact Dermatitis 37:200-209
Meding B, Swanbeck G (1989) Epidemiology of different types of Schnuch A, Uter W, Geier 1, Frosch PJ, Rustemeyer Th (1998a)
hand eczema in an industrial city. Acta Derm Venereol Contact allergies in health care workers. Acta Derm Venereol
Stockh 69:227-33 Stockh 78:358-363
Menne T, Knudsen B (1997) Clinical data in the dassification Schnuch A, Westphal GA, Müller MM, Schulz TG, Geier 1, Brasch
of contact allergens. In: Flyvholm A-A, Andersen KE, et al. (1998b) Genotype and phenotype of N-acetyltransfer-
Baranski B, Sarlo K (eds) Criteria for dassification of skin- ase 2 (NAT2) polymorphism in patients with contact allergy.
and airway-sensitizing substances in the work and general Contact Dermatitis 38:209-211
environments. WHO Regional Office for Europe, Copenha- Schwanitz H-J, Uter W, Wulfhorst B (1996) Neue Wege zur
gen, pp 91-100 Prävention - Paradigma Friseurekzem. Osnabrück: Univ-
Monson RR (1990) Occupational epidemiology, 2nd edn. CRC ersitätsverlag Rasch
Press, Boca Raton Smit HA, Coenraads P) (1993) Epidemiology of contact derma-
Mortensen T (1979) Allergy to lanolin. Contact Dermatitis 5: titis. In: Burr ML (ed) Epidemiology of dinical allergy
137-139 (Monographs in allergy, vol 31) Karger, Basel, pp 29-48
Nielsen H (1994) Occupational exposure to isothiazolinones - a Tobacman JK, Wenzel RP (1990) Clinical epidemiology: further
study based on a product register. Contact Dermatitis 31: consideration. J C!in Epidemiol 43:633-635
18-21 Uter W, Gefeller 0, Schwanitz HJ (1995) Frühe irritative
Nielsen NH, Menne T (1992) Allergie contact sensitization in an Hautschäden bei Friseurlehrlingen. Hautarzt 46:771-778
unselected Danish population - the Glostrup allergy study, Uter W, Schnuch A, Geier J, Frosch PJ (1998) Epidemiology of
Denmark. Acta Derm Venereol (Stockh) 72:456-460 contact dermatitis: the information network of the depart-
26 A. Schnuch and W. Uter: The Role of Clinkal Epidemiology in the Study of OCD
ments of dermatology (IVDK) in Germany - a surveillance 10. If allergie contact dermatitis is addressed: is
system on contact allergies. Eur J Dermatol 8:36-40 sensitization confirmed and specified by patch
van der Burg CK, Bruynzeel DP, Vreeburg KJ, von BIomberg BM,
Scheper RJ (1986) Hand eczema in hairdressers and nurses: a testing? Are the methods of patch testing (material
prospective study. l. Evaluation of atopy and nickel hyper- used, procedure) communicated? Do they comply
sensitivity at the start of apprenticeship. Contact Dermatitis
with internationally accepted rules?
14:275-279
Williams HC (1996) Relative and attributable risk and its 11. If atopie dermatitis is addressed: which criteria are
relevance to the prevention of contact dermatitis. In: Elsner used to diagnose "atopic dermatitis" or "atopic
P, Lachapelle JM, Wahlberg JE, Maibach HI (eds) Prevention diathesis"?
of contact dermatitis. (Current problems in dermatology, vol
25) Karger, Basel, pp 10-17 12. Are possible causative exposures assessed and
Wüstermann S, Siebert J (1997) Contact allergies to Methyldib- registered? (e.g., occupation, occupational activity,
romo Glutaronitrile and methylchloroisothiazolinone/met-
hylisothiazolinone as .preservatives in cosmetics: relevance
non-occupational exposure like consumer prod-
and exposure. Seifen ale Fette Wachse 123:398-404 ucts, leisure activities)?
13. Is the relevance of a single contact allergy assessed
and registered? What is the set of criteria used for
Appendix: Proposal for the Evaluation its assessment?
of Surveillance Systems in Contact Dermatitis 14. Are basic demographie data (age, gender, geo-
(Schnuch 1998) graphie origin) registered?
15. Which methods and instruments are used for: (a)
data exchange, storage, processing, and communi-
1. What are the diseases under surveillance? Irritant cation between participants, and (b) communica-
contact dermatitis, allergie contact dermatitis, tion with institutions to be advised or informed?
atopie dermatitis. On whieh criteria is the differ- 16. Are the results partially (for age and gender) or
ential diagnosis based? extensively adjusted (standardized) by considering
2. Who "diagnoses" contact dermatitis (what is the other factors such as occupation?
diagnostic evidence of the signal to be reported): 17. Is the study population described by the MOAHL
dermatologist, occupational physician, general index or the recently extended MOAHL index
practitioner, or only the patient hirns elf (with or (MOAHLFA)? Are the results discussed with re-
without a questionnaire), or a consumer, or spect to these items?
workers, or others (pharmacists, nurses etc.)? 18. Are measures of quality control (completeness,
3. How is the population under surveillance defined: plausibility, comparison between different partic-
general population, workers from a certain occu- ipants of the system, feedback and discussion of
pation, or a certain plant, subpopulations, e.g., the results) part of the system? Are diagnostic
children, patients, consumers of certain products, materials (patch test preparations) subject to
e.g., cosmetics? quality contro!?
4. Epidemiologie system: surveillance system, regis- 19. What is the ultimate goal of the system? Simple
ter, epidemiological study (type, e.g., cross-sec- counting of the 'signal' for the purpose of publie
tional), clinical epidemiology (dermatologie al (or occupational) health statistics, or contributing
practitioner, dermatological department, multi- to prevention by analyzing data with regard to
center). causative factors. To whom are the results ad-
5. Is follow-up of cases possible? dressed? On a regular basis or sporadically? Are
6. Duration of the study/the system: limited, repeat- there confidential elements (not to be published)
ed, or continuous? and reserved for certain groups of interest (indus-
7. Measure of frequency: incidence or prevalence? try, regulatory institutions, workers' insurance
8. Data acquisition: active or passive. Further infor- companies)?
mation on the methods used (e.g., questionnaires - 20. Is extern al evaluation possible? To what degree did
evaluated for sensitivity and specificity), diagnoses the information delivered contribute to successful
by medical experts? preventive decisions/actions? Does the economie
9. Is confidentiality or anonymity of personal data benefit of the system exceed the costs of the
guaranteed? system?
CHAPTER 3
Classification of Occupations
w. Uter
workers. This can be explained by the fact that these

Introduction
classifications, such as international standard classifi-
cation of occupations (ISCO) (International Labour
Several classification problems have to be solved prior Office 1990), have been conceived for a variety of other
to establishing an epidemiological system for surveil- purposes also, for example, for social sciences, inter-
lance of the health of a population, e.g., the residents of national trade and commerce, or international statis-
a certain country or the employees of a certain tics of employment status.
industrial plant. These problems include, among A competing concept of documenting medically
others, the design and use of a standardized system (dermatologically) relevant descriptors, i.e., exposures
(1) of diagnostic entities to document health problems and their duration and intensity, would be to classify
and (2) of a list of occupational activities and not the individual occupation of the patient, but the
exposures. The first aspect represents an obvious type of industry in which he or she works. Examples of
necessity; without a set of well-defined diagnoses, it such classifications and some of their applications, e.g.,
is impossible to perform analyses of health problems employers liability insurance or governmental labor
in a population. On an international level, the Inter- statistics, are listed below. A classification system
national Classification of Diseases, presently in its 10th provided by the United Nations (UN) for this purpose
revision ("ICD-lO"), provides such a tool. is the international standard industrial classification
The second aspect does not address an outcome, but (ISIC) (United Nations 1990), as ShOWll below.
rather a potential explanatory (causal) factor for the In many instances, both types of classification will
development or aggravation of disease. A certain achieve the same result; for example, allowing either
occupation can be regarded here as a more or less the classification of a patient as "hairdresser" ("ISCO-
precise surrogate marker for a characteristic profile of 88" No. 5141) or as a person working in the "hair-
medically relevant exposures, e.g., to carcinogens or dressing trade" ("ISIC Rev. 3" No. 9302). In other
allergens (Schnitzer et al. 1995). Such profiles, if cases, the classification according to industry may be
standardized, are termed job-exposure matrix (JEM) more specific - at least when comparing "ISCO-88"
(Goldberg et al. 1993; Plato and Steineck 1993). They and "ISIC Rev. 3": while "ISCO-88" aggregates "miners
are utilized to link information on occupation with and quarry workers" (No. 7111) irrespective of the
information on exposure to specific workplace haz- minerals extracted, "ISIC Rev. 3" details the material
ards, e.g., for epidemiological risk analyses, if only data extracted on the second hierachical level ("mining of
on occupation but no individual data on exposure are coal ... " no. 10; "mining of uranium ... " no. 12; "mining
available. The precision of JEM may vary: if designed of metal ores" no. 13, etc.).
for a company or an industrial sector, JEM can be However, in some cases, particularly in large indus-
based on a more detailed classification of occupations trial plants, a whole range of different occupations (and
and better exposure information, whereas, if it is different exposures) is found in one industry, e.g., in
applied in population-based studies, it has to be more the "automobile manufacturing industry" ("ISIC Rev.
general (Goldberg et al. 1993). 3" No. 34) cutting- and non-cutting metal workers,
Gross (general) classification of occupations can be mechanics, painters, administrative personnei, clean-
due to inadequate use of the respective classification ing and kitchen staff, etc ("ISCO-88", numbers 7223,
system or an imprecise data source. Another reason 7221, 7231, 7142, 1222 and 9132 and 5122, respectively).
may be the lack of refinement of the system itself, Thus, the documentation of occupation and not of
which may, however, have a depth of classification in industry appears preferable, as it offers more precision
other parts that appears unnecessary from a medical (Table 1). A combination of both concepts may have
point of view, e.g., listing many subtypes of office advantages in some situations (Schnitzer et al. 1995).

28 W. Uter
Table 1. International standard classification of occupations "ISCO-88" occupational code numbers (different skill levels) and
international standard industrial classification "ISIC Rev. 3" industrial code numbers, as appropriate, for selected occupations and
industries. Code numbers selected on a hierarchicallevel as low as possible. Exclusions in "job tide" may not be applicable to units
determined by numbers. In case of multiple code numbers, the original classifications should be consulted as to which number (entry)
is most appropriate for the actual classification problem
ISCO-88 Job tide ISIC rev.3
611,621,8331,9211 Agricultural field work (see also farmers) 01

7232, 8281 Aircraft industry 3530
8111,931 Air hammer operators 451,455
8223 Anodizers 28,29
3241 Aromatherapists 8519
2452, 2454, 3471, 3473, 3474 Artists (except musicians) 9214,9219
9312 Asphalt workers (paving) 452
Automobile mechanics: see car industry
7412,8274 Bakers 154
5141 Barbers (see also hairdressers) 9302
5123 Bartenders 552
5141 Bath attendants 9249
7332, 7346, 8264 Batik factory workers 1810
8229 Battery makers 314
6123 Bee keepers 0122
2211, 3211 Biotechnical industry workers (food) 15
7112 Blasters cat C
3118 Blueprint makers 45
3115, 7124, 8232, 8284 Boat builders 351
Body and fender workers: see car industry 34
Brake-lining workers: see car industry 34
7411, 8271 Butchers and slaughterhouse workers 1511
7422 Cabinet makers 361
8229 Candle makers 2429
7412, 8274 Candy and confectionery industry 1543
7414 Cannery workers cat D
7124 Carpenters 2022,45
5122, 741 Catering workers (see also food preparation workers) 5122, 552
7231, 817, 8281, 8284, 8290 Car industry (see also metal industry) 34
8275 Cashew oil factory workers 1514
4211,4212 Cashiers 67
7124 Caulkers 351
8212 Cement workers (see also construction workers) 2694, 2695
7321, 7324, 813 Ceramic and pottery workers 2691-2693
74l3, 8272 Cheese makers 1520
2113,2146,3116,8151,8154, 8159, 823 Chemists, chemical industry 731,803
5131 Child day-care workers 8531
7416,8279 Cigarette and cigar makers and tobacco workers 16
712, 7l3, 833 (except 8331), 9312, 9313 Construction workers 45
5141 Cosmetologists 9302
6121,7413, 8272 Dairy workers 1520
6121 Dairy farmers 0121
3225, 5l32, 7311 Dental personnel 8512
7143, 9l32, 9142 Detergent workers (Cleaners, except textile)' 7493,90
6152, 7216 Divers (including compression divers) 7523,9309
Dry cleaners: see laundry workers
31l3, 7l37, 7241, 7244, 7245, 8282 Electricians 31,45
3139 Electron microscopy technicians 3320
2144, 3114, 7242, 7243, 8283 Electronic workers 32, 725
8223 Electroplaters 28,29
5143 Embalmers (including funeral service workers) 9303
2452, 7313, 7323, 7343 Engravers cat D
3212, 32l3, 611, 612, 6l3, 621, 9211 Farmers (except dairy farmers) Oll, 0122, 103, 014
5161 Fire fighters 7523
6151, 6152, 6153, 621, 7411, 8271, 9213 Fishing industry cat B, 1512
7132 Floor layers 454
2213,6113 Florists 0112
5122, 741, 827 Food preparation workers cat D
6141, 9212 Forestry workers 02
8122 Foundry workers (melters, casters) 27,28,29
6129 Fur farmers 0122
7434, 7441, 8265 Fur processors 1820
8240,8285 Furniture manufacture 2021, 36
Classification of Occupations 29
Table 1. (Contd.)
ISCO-88 Job title ISIC rev.3
6113 Gardeners 0112

7135 Glaziers 454
7224 Grinders of hard-metal blades 292
5141 Hairdressers 9302
222,223,3133, 3221, 3222, 3223, Health care workers (except dental) 851
3229, 323, 324
8332, 9312 Highway construction workers (except asphalt workers) 45
3211 Histology technicians (except electron microscopy) 8519
5121, 5142, 9131 House workers 95
7134 Insulation workers 453,454
7313 Jewellers 3691
6129 Laboratory animal attendants 014
3133,6129 Laboratory technicians
8264,9133 Laundry workers 9301
7332, 744, 8265, 8266, 8269 Leather industry 19
7222 Locksmiths 28,29
Machinists (metal workers): see metal industry
3226 Masseurs 8519
723,8211 Mechanics 28, 29, 502, 504
Medical personnel: see health care workers
3115,721, 722, 812, 817, 8211, Metal industry 27,28,29
8223, 8284
7224,8223 Metal polishers 28,29
o Military personnel 7522
8273 Mill workers (food) 153
117,2147,7111,811,9311 Mining (tunneling) cat C
2453, 3473 Musicians 9214
Various Office workers Various
3117,8111 Oil industry workers 11,231,232
2221,2230, 3133, 3221, 3231, 3232 Operating room staff 8511
3224 Optical technicians 33
7141,7142 Painters 34,454
8142, 8143 Paper industry, paper makers 21
3222 Pest control workers 90
2224 Pharmacists 5231
3228, 5139, 8221 Pharmaceutical and cosmetic industry 2423,2424
3131, 7344, 8224 Photographers 7494,9214
6122 Poultry processors 0122
7134 Pitch workers 45
7136 Plumbers and pipe fitters 453
345, 5162 Police officers and detectives 7492, 7523
4142 Postal workers 641
Pottery industry: see ceramics industry
7343, 8251 Printers and lithographers 222
3475 Professional sports 9241
7243 Radio and television repairers (see also electronic workers) 5260
9312 Railroad shop workers 3520,45
6121 Reindeer farming 0122
7131 Roofers 452
7213 Sheet -metal workers 28,29
7442, 8266 Shoe repairers (see also leather industry) 5260
7346 Silk-screen workers (printers) 2222
Slaughterhouse workers: see butchers
7212 Soldiers 28,29
Space industry: see aircraft industry
7113, 7122 Stonemasons 2696,45
7412 Sugar artists 1543
9132 Swimming pool service personnel (except bath attendants) 90
7441, 8265 Tannery workers 1911
3471 Tattoo artists 9214
7332, 7346, 743, 8261, 8262, 8263, 8264 Textile workers 17
7123, 7132 Tile setters and terrazzo workers 454
Tobacco industry: see cigarette makers
3227 Veterinarians 8520
7212 Welders 28,29
6112, 8278 Wine makers 0113, 1552
3133, 7243, 8224 X-ray technicians 3312,8511,8519
I Manufacture of Detergents: ISIC No. 2424

30 W. Uter
Even a seemingly precise job title may hide quite based on national classifications of eight industrialized
varying exposure patterns, as illustrated by a compar- countries. Revisions followed in 1958, 1968 and 1988, the
ison between a metal turner in a small workshop and a latter being the current version at the time this chapter
turner in a large, fully CNC (computer numeric was written. The main objective of "ISCO-88" was to
control)-equipped factory. The former will most likely facilitate international communication and research
be greatly exposed to cutting fluids, not being able to concerning occupational data. It has also been suggest-
wear protective gloves because of having to work ed that it be used as a model for the development or
continuously with turning power tools. This individual adaptation of national classifications, which may be
will probably use more aggressive hand-cleansing extended to a finer structure. This refinement could be
agents because of greater soiling and may have no necessary to represent national characteristics of the
safety or medical officers at hand. The latter turner labor market or more detailed occupational descrip-
may feed mostly crude work pieces into a completely tions, which are "of particular interest for vocational
encapsulated machine, check and pack finished work guidance and training, placement services, or analysis
pieces, while setting or repairing the CNC lathe only of occupation-specific morbidity and mortality" (In-
occasionally. Theoretically, this individual would be ternational Labour Office 1990). Thus, as judged by Hs
able to wear protective gloves at all times and have easy authors, the 10 major groups, 28 sub-major groups, 116
access to safety and medical specialists. minor groups and 390 unit groups contained in "ISCO-
Such differences may account for considerable 88" may still be too gross - in parts - to serve some
variance of exposure, i.e., the need to employ more special demands, including occupational medicine (see
general (and imprecise) JEM the more heterogeneous above). On an international level, "ISCO-88" is used by
the respective population is (see above). As such the International Labour Office, Geneva [http://www.
characteristics mayaIso vary a lot among countries - ilo.orgJ, for statistical analyses published in the current
mostly depending on the degree of industrialization "Yearbook of Labour Statistics".
and labor division - a truly international meaning of "ISCO-88" is based on both the concept of job (a
one job title, particularly referring to a uniform certain kind of work performed by one person, which
exposure, cannot always be assumed. is the statistical unit of "ISCO-88") and skill (the
These limitations have to be kept in mind when ability to carry out the tasks and duties of a given
considering any classification of occupations or in- job, partly requiring some level of formal training).
dustries. Despite this, the use of such a classification This division is not only useful from a social or
may be required by certain national regulations for economical but also from a medical point of view,
selected purposes. In addition, and beyond legal because exposure patterns may vary considerably
requirements, the use of a set of well-defined entries among, for example, a chemical plant operator
of a catalog of occupations may facilitate standardized (no. 8151, no. 8154, no. 8159), a chemical-engineering
documentation for epidemiological analyses concern- technician (no. 3116), a chemical engineer (no. 2146)
ing occupational risk factors, e.g., patterns of sensiti- and a chemical scientist (no. 2113), all working, for
zation (Uter et al. 1998), prevalence or incidence of instance, in the same plastic manufacturing plant.
dermatitis, etc. Therefore, code numbers of the current However, even within one of these unit groups - which
version of "ISCO-88" are given in Table 1, referring to often encompass several occupations - marked differ-
occupations listed in the Chapters "Job Descriptions". ences in exposure may exist. As an example, in the
These numbers may also serve as an identifier or group of hairdressers (no. 5141), exposure to wet work
common denominator of job titles for different is, at least in some countries, much heavier for
languages, as far as a national adaptation of "ISCO- apprentices - encountering a high risk of irritant hand
88" exists. Because so me of the "descriptions" refer to dermatitis - than for skilled beauticians. Approaches
industries rather than occupations, and because most to some specific problems in the classification of actual
occupations can be related to one (or few) type(s) of occupations are discussed within the "ISCO-88" (In-
industries, "ISIC Rev. 3" code numbers have been ternational Labour Office 1990), and shall not be dealt
supplemented (Table. 1). with here in detail; the principles have been applied to
the suggested code numbers (Table 1).
International Standard Classification

of Occupations (88) International Standard Industrial Classification
of all Economic Artivities
The International Labor Organisation, Geneva, pub-
lished the first edition of an international classification The ISIC was first published in 1948 by the United
of occupations in 1952, comprising 1,727 occupations, Nations Statistics Division (UNSD); the last (third)
Classification of Occupations 31
reVISIOn was issued in 1989. It provides a standard Morrison 1988). The limitations of this system with
classification of economic activities arranged so that respect to occupational dermatology have been com-
entities, e.g., persons and companies or institutions, mented on by Taylor (1988).
can be classified according to the activity that they NAICS '97 is an international system and has been
carry out. The categories of ISIC at the most detailed developed in collaboration with Statistics Canada,
level (classes) are delineated according to what is the Mexico's Instituto Nacional de Estadistica, Geografia
customary combination in most countries of activities eInformation, and the U.S. Office of Management and
described in statistical units. The groups and divisions, Budget, i.e., the NAFTA countries. NAICS '97 is also
the successively broader levels of classification, com- organized in a hierarchie al structure. The first two
bine the statistical units according to the character, digits designate major economic sectors, such as
technology, organization and financing of production. agriculture or manufacturing. On this gross two-digit
The structure is hierarchieal, consisting of 17 "tabula- level, it is relatively compatible with the "ISIC Rev. 3".
tion categories", 60 "divisions", 159 "groups" and 292 Readers from the three countries mentioned are
"classes", the latter coded in four-digit codes. Wide use referred to the U.S. National Technical Information
has been made of ISIC, both nationally and interna- Service [http://www.ntis.govl for further information
tionally, in classifying data according to the kind of and possible applications.
economic activity in the fields of population, produc-
tion, employment, gross domestic product and other
economic activities. Other uses include demographie, References
social and health analysis, e.g., ILO "Yearbook of
Labour Statistics".
EC Council (1995) Council regulation (EEC) No. 3037/90 on the
statistical classification of economic activities in the Europe-
an Community (OJ No L 293, 24.10.1990, p.l) as amended by
Statistical Classification of Economic Activities Commission Regulation (EEC) No. 761/93 of 24 March 1993
(NACE Rev. 1) of the European Community (OJ No L 83, 3.4.1993, P 1, and corrigendum OJ No L 159,
lI.7.1995, p 31)
Executive Office of the President, Office of Management and
Budget (1987) Standard industrial classification manual, 2nd
In 1970, a "GeneralIndustrial Classification of Eco- edn. N.T.I.S., Springfield
nomic Activities within the European Communities" Goldberg M, Kromhout H, Guenel P, Fleteher AC, Gerin M et al.
was published by Eurostat, Luxembourg. This was (1993) Job exposure matrices in industry. Int J Epidemiol
22[Suppl 2):SIO-S15
revised in 1990 and made generally compatible with International Labour Office (1990) International standard classi-
the "ISIC", containing some extensions, however, as an fication of occupations: ISCO-88. International Labour Office,
adaptation to European demands. In contrast to the Geneva
Mathias CGT, Morrison JH (1988) Occupational skin diseases.
previous edition, which had no legal character, it has United States: results from the Bureau of Labor Statistics
been used as a compulsory standard for Eurostat Annual Survey of occupational injuries and illnesses, 1973
economic statistics since 1993 (EC Councill995) and is through 1984. Arch DermatoI124:1519-1524
O'Malley M, Thun M, Morrison J, Mathias CGT, Halperin WE
regarded as part of the common statistical language (1988) Surveillance of occupational skin disease using the
being developed. supplementary data system. Am J Ind Med 13:291-299
Plato N, Stein eck G (1993) Methodology and utility of a job-
exposure matrix. Am J Ind Med 23:491-502
Schnitzer PG, Teschke K, Olshan AF (1995) A classification
North American Industry Classification System scheme for aggregating U.S. census occupation and industry
codes. Am J Ind Med 28:185-191
Taylor JS (1988) Occupational disease statistics: in perspective.
In January, 1997, the North American Industry Clas- Arch DermatoI124:1557-1558
sification System (NAICS) replaced the 1987 Standard United Nations (1990) United Nations: international standard
industrial classification of alI economic activities (ISIC -
Industrial Classification (SIC) system (Executive Office Rev. 3). Statistical Papers, Series M, No. 4/Rev. 3. United
1987) in the United States. The SIC has been used Nations, New York
widely for national (U.S.) statistics regarding occupa- Uter W, Schnuch A, Geier J, Frosch PJ (1998) The epidemiology
of contact dermatitis. The information network of depart-
tional accidents and diseases, including occupational ments of dermatology (IVDK) in Germany. Eur J Dermatol
skin diseases (O'Malley et al. 1988; Mathias and 8:36-40
CHAPTER 4
Dermatotoxicology
P. Hewitt and H.1. Maibach
Introduction through shunts, openings of skin appendages, and

gaps in the stratum corneum associated with these
structures have been considered (Simpson and Cramer
Adverse skin responses associated with repetitive, low-
1943). Absorption can be described as passive diffusion
dose exposure to industrial chemieals may not be
across this membrane by the equation:
accurately predicted by standard assays. The need to
market industrial chemieals with low risks of produc-
ing dermal and systemic injury has led to the i.e., [rate of absorption = (vehicle/stratum corneum
development of numerous assays to rank chemieals partition coefficient x skin surface concentration x
for their toxic ability. Although these assays are often diffusion constant of penetrant in the stratum corn-
not mandated by regulatory agencies, the frequency eum) divided by thickness of the stratum corneuml
with which they are conducted and their utility warrant (Dugard 1983). Other factors affecting thermodynamic
attention. activity of the solution at the skin surface, e.g., pH and
The field of dermatotoxicology includes measure- temperature, may vary the absorption rate (Scheuplein
ment of absorption of materials as well as assays that 1978; Scheuplein and Bronaugh 1983). Vehicle infiu-
evaluate the ability of topically applied chemieals to ence cannot be overstated; for a specific concentration
induce or promote the development of neoplasia, of chemieal, thermodynamic activity may vary 1000-
trigger an immune response in the skin (allergie fold from one vehicle to another (Scheuplein and
contact dermatitis and immunological contact urticar- Bronaugh 1983). Other factors that affect percutaneous
ia), directly destroy the skin (corrosion), irritate the absorption include skin condition (Feldman and
skin, and produce non-infiammatory, painful sensa- Maibach 1967), age, surface area to which the material
tions. The infiammatory responses of skin are the most is applied (Wester and Maibach 1983), penetrant
common chemically induced dermatoses in humans. volatility, temperature and humidity (Frosch 1982),
This chapter briefiy intro duces the subject; the Mar- substantivity, wash-and-rub resistance to removal
zulli texts provide more detail (Marzulli and Maibach from the skin, and binding to the skin (Ostrenga
1996, 1997)· et al. 1971).
Once a chemie al reaches the viable epidermallayers,
it may initiate a local effect, be absorbed into the
Dermatopharmacokinetics: Relationship circulation and produce an effect, or produce no local
to Predictive Assays or systemic effects. The viable epidermis contains
enzymes capable of metabolizing exogenous chemie als
(Noonan and Wester 1983), including a substantial
Although the skin's barrier properties are impressive,
cytochrome P-450 system, esterases, mixed-function
interest in cutaneous pharmacokinetics has increased
oxidases, and glucuronyltransferases. When the epi-
as the skin has been reconsidered as a route for
dermal surface area is taken into account, then
systemic administration of drugs and chemieals, as
enzymatic activities of the epidermis can range from
well as a route of entry for toxins. Assays, both in vivo
80% to 240% of those in liver (Hotchkiss 1992).
and in vitro, for measuring absorption through the
skin have been developed (Bartek et al. 1972; Bartek
and LaBudde 1975; Bronaugh 1985; Bronaugh and In Vivo Percutaneous Absorption Assays
Collier 1991), and many factors that govern absorption
through the skin have been determined. Percutaneous absorption can be determined by mea-
A major diffusion barrier of the skin is considered to suring levels of the chemical in the urine and/or feces.
be the stratum corneum. Absorption of chemieals Because analytical techniques to measure the chemical

Dermatotoxicology 33
are not always available and because some chemie als Allergie Contact Dermatitis
may be metabolized, radiolabeled chemieals contain-
ing 14C or 3H are often used.
Jadassohn (1896) demonstrated that, in some patients,
In vivo studies have been conducted in humans and
dermatitis was due to increased sensitivity following
other species (Bartek et al. 1972). Comparison of
repeated contact with a substance, and not the irritant
absorption rates showed that absorption rates in the
properties of the material. By 1930, a procedure for
rat and rabbit te nd to be higher than in humans and
producing this hypersensitivity to chemieals in guinea
that the skin permeabilities of monkeys and swine
pigs had been developed (Bloch and Stein er-Wourlisch
more closely resembles that of man. No significant
1930). The pioneering work of Landsteiner and associ-
mouse-human skin comparisons exist. Guinea pig-
ates demonstrated that low-molecular-weight chemi-
human comparisons offer some promise for refine-
eals conjugate with proteins to form antigens that
ment of guinea pig-human irritation and sensitization
stimulate the immune system to develop a hyperreac-
extrapolations (Anderson et al. 1986). Although these
tive state (Landsteiner and Jacobs 1936), that immuno-
differences are not predicted by any single factor, they
genicity is related to chemical structure (Landsteiner
are not unexpected in light of differences in metabo-
and Jacobs 1935), and that two types of immunological
lism and excretion routes. Therefore, the metabolie
response exist, one transferable by serum and another
capabilities of the species should be considered when
transferred by suspensions of white blood cells (Land-
selecting an animal model. Although there is no
steiner and Chase 1937). Most cases of allergie contact
question that pharmacokinetic studies of this type in
dermatitis are of the cell-mediated type, transferable by
man or animal provide the best estimate of percuta-
lymphocytes. Details of these mechanisms are provided
neous absorption, difficulty in conducting well-con-
by von BIomberg et al. (1991).
trolled studies has led to the use of other in vivo assays
Appropriate planning and execution of predictive
that are poorer predictive tools and to the development
sensitization assays is critical. The first priority is to
of in vitro models. Details may be found in the report
choose an appropriate experimental design. A com-
by Bronaugh and Maibach (1985).
mon error in choosing an animal assay is using
Freund's complete adjuvant (FCA) when setting dose-
response relationships. The adjuvant provides such
In Vitro Percutaneous Penetration Assays
sensitivity that dose-effect relationships are muted.
Choice of dose and vehicle appropriate to the assay
The excised skin of man or animal can be used to
and the study question is the second priority.
measure chemical penetration. In vitro assays using
Although the dose must be high enough to ensure
excised skin utilize specially designed diffusion cells
penetration, it must be below the threshold in
(Bartek and LaBudde 1975; Franz 1975). The skin is
question to avoid misinterpretation of irritant inflam-
stretched over the opening of a collecting receptacle,
mation as allergie. Knowing the irritation potential of
epidermal side up. The chemical is applied to the
compounds will allow the investigator to design and
epidermis and fluid from the receptacle is assayed to
execute these studies appropriately. Vehicle choice
measure penetration. In vitro assays offer some
determines, in part, the absorption of the test
advantages over in vivo assays: highly toxic com-
material and can influence sensitization rate, ability
pounds can be studied on human skin; large numbers
of sam pIes can be run simultaneously; diffusion to elicit the response in question, and the irritation
threshold.
through the membrane, eliminating other pharmaco-
kinetic factors, can be studied; and these assays may be
easier to conduct. Quantitative Structure-Activity Relationship
Comparison of penetration rates obtained from in
vitro and in vivo assays have been made (Bartek and Quantitative structure-activity relationship (QSAR)
LaBudde 1975), often with a good correlation. Differ- describes the relationship of the chemical structure
ences in the methods for some compounds could be to the biological activity - in this case, allergie contact
explained by the different solubilities in the receptacle dermatitis. A computer-assisted database describing
fluid and blood; others could not be explained. Skin the chemical structure and physicochemical parame-
of the weanling pig and miniature swine appear to be ters of a wide array of chemieals provides a facile
good in vitro models for most compounds (Bartek approach to designing appropriate in vitro, animal and
et al. 1972). On the basis of a limited number of human sensitization studies (Magee et al. 1994; Hos-
studies, the skin of monkeys also appears to be a tynek et al. 1995, 1996, 1997). In essence, analyzing the
good model (Wester and Maibach 1983). Further prior experimental data permits not only determina-
details may be found in Bronaugh and Maibach tion of relationships between structures and allergeni-
(1991). city, but provides insights useful for planning a given
34 P. Hewitt and Hol. Maibach
*
+
Guinea Pig
Maximization Test
I Y Y
Dry ice +
*
Split Adjuvant yvv y y
Test
+ + + + + + * *
Optimization Test t t + + + t + + t -:si'
I
+ + + * *
Freund's Complete
Adjuvant Test
t + i 0
I
*
Draize Test t i i t t t t + i t t
*
y(6h) y(6h) y(6h)
Buehler Test Y
* *
0000000000000000000000 0
Open Epicutaneous I I I I I
Test
I I I I I I I
Days 0 7 14 21 28 35 42
t - Intradermal injection
* - Challenge by intradermal injection

t
v - Epicutaneous application, closed
+ - Freund's complete adjuvant
o - Epicutaneous application, open
Fig. 1. Features of most commonly used assays to predict humans are most often conducted in guinea pigs. All
sensitization tests utilize young (1-3 months old), randomly bred
albino guinea pigs. Most visually evaluate the responses
experiment. For example, if a structure closely related using descriptive scales for erythema and edema. The
to the chemical of interest has been shown to be a tests differ significantly in route of exposure, use of
potent allergen, the new chemical may be examined adjuvants, induction interval, and exposure number.
with a more quantitative assay. The principal features of the most commonly used
assays and the assays acceptable to regulatory agencies
Guinea-Pig Sensitization Tests for prediction of sensitization are summarized in Fig. 1
(Environmental Protection Agency 1982; Office of the
Predictive animal tests for determination of the poten- Federal Registrar 1985).
tial of substances to induce delayed hypersensitivity in
Draize Test Buehler Test (Occlusion Only)
The Draize sensitization test (DT) (Draize et al. 1944; The Buehler test (Buehler 1964) also employs topical
Klecak 1983) was the first predictive sensitization test application of the test material. An absorbent patch
accepted by regulatory agencies. One flank of 20 or vehicle alone is placed on the shaved flanks of 10-
guinea pigs is shaved and o.os ml of a 0.1% solution of 20 guinea pigs. Test concentration varies from
test material in saline, paraffin oil, or polyethylene undiluted to usage levels. A concentration that
glycol is injected into the anterior flank on day o. produces slight erythema is optimum and is selected
Every other day through day 20, 0.1 ml of the test based on an irritancy screen conducted in other
solution is injected into a new site on the same flank. animals. This procedure is repeated 7 days and
After a 2-week rest period, the opposite untreated flank 14 days after the initial exposure. Two weeks after
is shaved and o.os ml of test solution is injected into the last induction patch, animals are challenged with
each animal (challenge). Twenty previously untreated patches saturated with a non-irritating concentration
controls are injected at the same time. The test site is of test material and with the vehicle. After 6 h, the
visually evaluated 24 hand 48 h after injection. A patch is removed and the area depilated. Test sites
larger or more intensely erythematous response than are visually evaluated 24 hand 48 h after patch
that of controls is considered a positive response. More removal. Animals developing erythematous responses
recent assays are more sensitive; however, with many are considered sensitized (if irritant control animals
modifications this assay can be robust. do not respond).
Open Epicutaneous Test

FCA Test
The open epicutaneous test (OET) (Kero and Han-
FCA test is an intra-dermal technique incorporating
nuksela 1980) simulates the conditions of human use
test material in asoIso mixture of FCA and distilled
by utilizing topical applications. The procedure
water (Klecak 1985).
determines the doses required to induce sensitization
and to elicit a response in sensitized animals. The
irritancy profile is determined by applying 0.02S ml Optimization Test
of varying concentrations to a 2-cm 2 area of the
shaved flanks of six to eight guinea pigs. Test sites The optimization test resembles the DT, but incor-
are visually evaluated 24 h after application of test porates the use of adjuvant for some induction
solutions for the presence or absence of erythema. injections and both intradermal and topical challeng-
The highest dose not causing areaction in any es (Klecak 1983). On day 1, one injection into the
animal (maximal non-irritant concentration) and the shaved flank and one into a shaved area of dorsal
lowest dose causing areaction in 2S% of the animals skin are given. One injection into a new dorsal site is
(minimal irritant concentration) are determined. given 2 days and 4 days later. The test material is
During induction, the test solution is applied to the administered in saline during the first week. During
flank skin of six to eight guinea pigs for 3 weeks, or the second and third weeks, test material is admin-
five times per week for 4 weeks. A control group is istered in FCA/saline every other day to a shaved area
treated with vehicle only. The highest dose tested is over the shoulders. Twenty test animals are treated
usually the minimal irritant concentration and lower and 20 controls are injected with vehicle alone. The
doses are based on usage concentration or a stepwise thickness of a skin fold over the injection site is
reduction. Each animal is challenged on the untreated measured with a caliper. Any animal developing a
flank 24-72 h after the last induction treatment. The reaction volume at challenge greater than the mean
minimal irritant concentration, the maximum non- plus one standard deviation during induction is
irritant concentration and five solutions of lower considered sensitized. A second challenge is conduct-
concentrations are applied. Skin reactions are read on ed 4S days after the first injection. A non-irritating
an all-or-none basis at 24, 48 and 72 h after appli- concentration of the test material in a suitable vehicle
cation. The maximum non-irritating concentration in is applied to the flank skin, away from injection sites.
the vehicle-treated group is calculated. Animals in Reactions are visually evaluated after 24 h using the
test groups that develop inflammatory responses to four-point erythema scale of the Draize primary
lower concentrations are considered sensitized. This irritancy scale. To classify materials as a strongl
method, although more work than others, provides moderate/weaklnon-sensitizer, a classification scheme
useful data on irritation, dose response and sensiti- has been devised using results of the exact Fisher test
zation. and number of positives detected.
36 P. Hewitt and H.I. Maibach
Split Adjuvant Test Human Sensitization Assays
The split adjuvant test (Klecak 1985) utilizes skin Chemicals can be tested for their ability to induce
damage and FCA as adjuvants. An area of the back skin contact hypersensitivity in panels of human volunteers
of 10-20 guinea pigs is shaved to glistening, then from whom informed consent is obtained. Allergic
treated with dry ice for 5-10 s. A layer of loose mesh contact dermatitis to materials already in commercial
gauze and stretch adhesive with a 2 x 2-cm opening use is sometimes detected by early induction patches.
over the shaved area is placed around the animal. This does not reflect the particular test material's
Approximately 0.2 ml of cream or solid test material ability to induce sensitization; it merely indicates that,
(0.1 ml if liquid) is spread over the test site and under patch conditions, the material may elicit a
occluded. The concentration tested varies by irritancy response in presensitized individuals.
potential, use conditions, etc. Two days later, the There are four basic predictive human sensitization
occlusive filter paper is removed, the test material retests in current use: (1) a single-induction/single-
applied and the covering replaced. On day 4, the filter challenge patch test; (2) repeated-insult patch test
paper cover is removed, two injections of 0.075 ml (RIPT); (J) RIPT with continuous exposure (modified
FCA are given into the edges of the test site, the test Draize); and (4) the maximization test; all of these use
material re-applied and the site is resealed. On day 7, similar customized patches (Frosch and Kligman 1979;
the test material is re-applied and, on day 9, the Kaminsky et al. 1986). Principal features of human
dressing is removed. Twenty-two days after the initial sensitization assays are summarized in Table 1, and
treatment, animals are challenged by topical applica- further details can be found in Marzulli and Maibach
tion of 0.5 ml of test material to a 2 x 2-cm area of the (1996). For assays other than maximization, 150-200
shaved mid-back. A group of naive controls, 10-20 subjects are usually tested. Henderson and Riley (1945)
animals, is treated by the same procedure at challenge. statistically showed that if no positive reactions are
The dressing is removed 24, 48 and 72 h after observed in 200 randomly selected subjects, as many
application, and the test site is visually evaluated using as 15/1000 of the general population may react (95%
a descriptive visual scale. Sensitization of individual confidence). As sampIe size is reduced, the likelihood
animals is indicated by significantly stronger reactions of unpredicted adverse reactions in the general pop-
than those of controls. ulation increases.
Guinea-Pig Maximization Test Repeated-Insult Patch Tests
The guinea pig maximization test (Klecak 1983 and Three major variations on the RIPT are in common
1985) combines FCA, irritancy, intra-dermal injection use: (1) the Draize human sensitization test (Draize
and occlusive topical application during the induction 1955); (2) the Shelanski-Shelanski test (Shelanski 1951);
period. Two identical sets of o.l-ml intradermal and (3) the Voss-Griffith test. The three assays have
injections of 50/50 FCA/water, test material in water, much in common. There are, however, some signifi-
paraffin oil, or propylene glycol, and the same dose of cant differences in the assays as originally described by
test material in FCA/vehicle are placed on a filter Draize.
paper, placed over the shaved injection site, covered In the Draize human sensitization test, an occlusive
with approximately 4 x 8-cm occlusive surgical tape, patch containing the test material is applied to the
and seeured in place. If the test material is non- upper arm or upper back of 200 volunteers for 48 h.
irritating, the test site is pretreated with 10% sodium The test site is evaluated at patch removal for
lauryl sulfate (SLS) in petrolatum on day 6 to provoke erythema and edema. This process is repeated until
an irritant re action. After 48 h, test and control a total of nine to ten patches have been applied.
(vehicle alone) animals are challenged on the shaved Subjects are challenged 10-14 days after application of
flank with the highest non-irritating concentration and the last induction patches via a patch applied to a
with the vehicle. Solutions are applied to filter paper new site for 48 h. Sites are visually evaluated at
secured in place and patches removed 24 hIater. removal of the patches and the response at challenge
Reactions are visually evaluated 24 hand 48 h after is compared with the response to patches applied
patch removal. Reactions are considered positive when early in induction.
they are more intense than the response to vehicle and
the responses to the test materials in controls. The test Modified Oraize Human Sensitization Test
material is rated as a weak-to-extreme sensitizer, based
on the incidence of positives in the test group. Details The RIPT procedure was modified to provide contin-
of these animal assays can be found in Anderson et al. uous patch exposure to the test material during a
(1986). 3-week induction period (Marzulli and Maibach 1973).
Table 1. Principal features of human sensitization assays. Table modified from Patrick and Maibach (l991)
Test Number Concentrationl Vehicle Skin Patch type Induction Duration Rest Challenge
of subjects amount of site number of
test material patches
Schwartz 200 Fabric Fabric 5 days 10 days 48-h Patch;

observe 10 days
Schwartz 200 1 inch fabric, Arm, Cellophane 72h 7-10 days 72 h; Same site;
liquid or thigh or covered with observe 3 days
powder back 2 x 2 inch
Elasto~last
"Prophetic" 200 ',4inch 2 4-ply Petrolatum Arm or 1 inch non- 24 h, 72 h 10-14 days 48 h; Observe
(Shwartz-Peck) gauze, liquid or corn oil back waterproof or 96 h 3 days: compare
saturated' cellophane new and old
covered with formulas
2 inch 2 adhesive
piaster
"Repeated 200 Proportional Mineral Occlusion; 10-15 24 h Every 2-3 weeks 48-h Patch
insult" to area of oil follows other day:
(Shelanski) ultimate use Schwartz test same site
"Repeated 100 Males, 0.5 ml or Arm or 1 inch2 10 24 h 10-14 days Repeat patch
insult" (Draize) 100 females 005 g back Alternate days on new site
Modified 200 0.5 mlor Petrolatum Arm Square 10 48 h 2 weeks Patch on new
Draize 005 g High BandAid; no site 72 h with
concentration perforations non-irrtant
concentration
"Maximization" 25 1 ml 5% Petrolatum Forearm 1.5 inch 2 5 24 h SLS 10 days 1 inch 2 patch
(Kligman) SLSh, or calf Webril occluded (Same site) followed by on lower back
followed by with Blenderm; 48-h test or forearm;
1 ml 25% held with material far 004 ml of 10%
test material perforated each of five SLS for 1 h
plastic tape inducing followed by
applications 004 ml of 10%
test material for
48 h
Modified 25 Same as Petrolatum Forearm Same as 7 24 h SLS 10 days 2% SLS far
"maximization" maximization or calf maximization followed by 005 h followed
48 h test by 48-h patch
material for with test
each of material 0
ll>
seven
inducing 3
Qj
applications 8
8
150
,..,
• Modified for solids, powders, ointment and cosmeticso Concentration, amount, area and site of application are considered important in evaluating resultso Authars recommended that 0
cosmetics be tested uncovered 0
lC
b Sodium lauryl sulfate (SLS) pretreatment is used to produce moderate inflammationo SLS is mixed with test material when compatibleo SLS is eliminated when the test material is a strong '<
irritant
"'"
38 P. Hewitt and H.1. Maibach
Patches are applied to the outer upper arm each Irritation Tests in Animals
Monday, Wednesday, and Friday until a total of nine to
ten patches have been applied. Fresh patches are Droize-Type Tests
applied to the same site unless moderate inflammation
has developed, in which case the patches should be Primary irritation and corrosion are most often
placed on adjacent non-inflamed skin. This produces a evaluated by modifications of the method described
continuous exposure of 504-552 h, compared with a by Draize et a1. (1944). The Federal Hazardous
total exposure period of 216-240 h for RIPT of Substance Act (FHSA) adopted one modification as
comparable induction periods. In addition, induction a standard procedure (Office of the Federal Registrar
concentrations are increased to levels above usage 1985). The backs of six albino rabbits are clipped.
exposure. Subjects are challenged by exposure of a new Each undiluted material is tested on two l-inch 2 sites
site to a patch for 72 h at a non-irritating concentra- on the same animal (one site is intact and one is
tion 2 weeks after induction. Test sites are evaluated at abraded in such a way that the stratum corneum is
o hand 24 h after removal. opened but no bleeding is produced). Each test site
is covered with two layers of l-inch 2 surgical gauze
and secured in place. The animal's trunk is then
Irritant Dermatitis wrapped with rubberized cloth or other occlusive
impervious material to retard evaporation of the
substances and hold the patches in position. The
HistoricaIly, skin irritation has been described, by
wrappings are removed 24 hand 48 h after applica-
exclusion, as localized inflammation not immunolog-
tion and the test sites evaluated for erythema and
ically mediated. Application of some chemicals direct-
edema. Modifications of the Draize procedure that
ly destroys tissue, producing skin necrosis at the
have been proposed include changing the species
application site, i.e., corrosive chemicals. Chemicals
tested (Motoyoshi et a1. 1979), reduction of exposure
may disrupt cell functions and/or trigger the release,
period, use of fewer animals, and testing on intact
formation, or activation of autocoids that produce
skin only (Guillot et al. 1982). Several governmental
local increases in blood flow, increase vascular per-
bodies utilized their own modification of the Draize
meability, attract white blood cells in the area, or
procedure for regulatory deeisions. The FHSA,
directly damage cells. The additive effects of these
Department of Transportation, Environmental Pro-
mediators result in local skin inflammation, i.e., acute
tection Agency, Federal Insectieide, Fungicide, Ro-
irritants. A number of as yet poorly defined pathways
dentieide Act and Organization for Economic
involving different processes of mediator generation
Cooperation and Development guidelines are con-
appear to exist. Although no agent has yet met all the
trasted to the original Draize methods. All Draize-
criteria to establish it as a mediator of skin irritation,
type tests are used to evaluate corrosion as weIl as
histamine, 5-hydroxytryptamine, prostaglandins, le-
irritation. When severe reactions that may not be
ukotrienes, kinins, complement, reactive oxygen spe-
reversible are noted, test sites are observed for a
eies, and products of white blood cells have been
Ion ger period. Delayed evaluations are usually made
strongly implicated as mediators of irritation (Prottey
on days 7 and 14, but may be as late as 35 days.
1978).
Some chemicals do not produce acute irritation
from a single exposure, but may produce inflamma-
Non-Droize Animo/ Studies
tion following repeated application to the same area of
skin (cumulative irritation) (Shelanski 1951). Studies of
Animal assays to evaluate the ability of chemicals to
skin corrosion are conducted in animals using stan-
produce cumulative irritation have been developed
dardized protocols, as it is not appropriate to conduct
(Phillips et al. 1972). Those assays used often are not as
screening studies in humans. However, acute irritation
weIl standardized as Draize-type tests, and many
is sometimes evaluated in humans after animals
variables have been introduced.
studies have been completed. Tests for cumulative
Repeat application patch tests in which diluted
irritation in both animals and humans have been
materials are applied to the same site each day for
reported.
15-21 days have been reported using several speeies
(the guinea pig or rabbit being most commonly
In Vitro Assays used) (Phillips et a1. 1972). Because the degree of
occlusion is an important determinant of percutane-
Numerous in vitro assays for irritation exist. Rougier ous penetration, the choice of covering materials
et a1. (1994) summarizes these assays and offers may determine the sensitivity of a given test (Mag-
guidelines as to their potential validation. nusson and Hersie 1965). A reference material of
similar use or one that pro duces a known effect in described by Kligman and Wooding (1967)] was used
humans is included in almost all repeat application to evaluate and compare test materials. Modifications
procedures. Test sites are evaluated for erythema and of the cumulative irritation assay have been reported
edema, either using the scales of the Draize-type tests (Mathias and Maibach 1978; Rapaport et al. 1978), and
or more descriptive scales developed by the investi- newer chamber devices have replaced Webril with
gator. occlusive tape in some laboratories. Some investiga-
tors currendy use cumulative scores to compare test
materials and do not calculate an IT 50" Many variables
Human Irritation Tests of the chosen test procedure, e.g., vehicle, type of
patch, and concentration tested, may modify the
Because only a small area of skin needs to be tested, it intensity of the response (Emery and Edwards 1940;
is possible to conduct predictive irritation assays in Maurer et al. 1975). Differences in intensity of re-
humans, provided systemic toxicity (from absorption) sponses have also been linked to differences in age,
is low. Human tests are preferred to animals tests in gender (Kligman 1983), and race (Weigand and
some cases because of the uncertainties of inter-species Gaylor 1976).
extrapolation. Many forms of a single application
patch test have been published. Custom-made appa-
ratus to hold the test material have been designed Contact Urticaria Syndrome
(Kaminsky et al. 1986; Magnusson and Hersie 1965).
Duration of patch exposure has varied between 1 hand
72 h. The single application patch procedure outlined Contact urticaria has been defined as a wheal-and-flare
by National Academy of Sciences (NAS) Publication response that develops within 30-60 min after expo-
1138 (Mathias and Maibach 1978) incorporates impor- sure of the skin to certain agents (von Krogh and
tant aspects of assays used by many investigators. For Maibach 1982). Symptoms of immediate contact reac-
new materials or volatiles, a relatively non-occlusive tions can be classified according to their morphology
tape, e.g., Micropore, Dermical, or Scanpore, should be and severity:
used. Increasing the degree of occlusion with occlusive
- Itching, tingling and burning with erythema is the
tapes, e.g., Blenderm or chamber devices, generally
weakest type of immediate contact reaction.
increases the severity of responses. A 4 hexposure
- Local wheal-and-flare with tingling and itching
period was suggested by the NAS panel. However, it is
represents the prototype reaction of contact urticaria.
desirable to test new materials and volatiles for shorter
- Generalized urticaria after local contact is rare, but
periods (30 min to 1 h), and many investigators apply
can occur from strong urticaria.
materials intended for skin contact for 24 h to 48 h
- Symptoms in other organs can appear with the skin
periods. After the period of exposure, the patches
symptoms in cases of immunologic contact urticaria
should be removed and the area cleaned with water to
syndrome.
remove any residue. Responses are evaluated at 30 min
to 1 hand at 24 h (to allow hydration and pressure The strength of the reactions may vary gready, and
effects to subside) after patch removal. Persistent often the whole range of local symptoms can be seen
reactions may be evaluated for 3-4 days. The Draize from the same substance if different concentrations
scales for erythema and edema have no provision for are used (Lahti 1980). In addition, a certain concen-
scoring papular, vesicular, or bullous responses. tration of contact urticant may produce strong
Therefore, integrated scales ranging from 4 to 16 edemic and erythemic reactions on the skin of the
points have been published. upper back and face, but only erythema on the volar
Most multiple-application patch tests were patterned surfaces of the lower arms or legs. In some cases,
after human sensitization studies with 24 hexposures, contact urticaria can be demonstrated only on
with or without a rest period between patches. damaged or previously eczematous skin, and it can
The cumulative irritation assay as described by be part of the mechanism responsible for mainte-
Lanman and coworkers (1968) was used to compare nance of chronic eczemas (Anders on and Maibach
antiperspirants, deodorants, and bath oils to provide 1983). Because of the risk of systemic reactions, e.g.,
guidance for product development. A 1 inch 2 of anaphylaxis, human diagnostic tests should only be
Webril was saturated with test compound and applied performed by experienced personnel with facilities
to the skin of the upper back. After 24 h, the patch for resuscitation on hand. Contact urticaria has been
was removed, the area evaluated, and a fresh patch divided into two main types on the basis of proposed
applied. The procedure was repeated daily for up to pathophysiological mechanisms, namely non-immu-
21 days. The time it took to produce an irritant nologic and immunologic (Maibach and Johnson
response in 50% of the test subjects [IT 50> as 1975).
Non-Immunologie Contact Urticaria solvent) is applied to one ear of the animal. Ear
thiekness is measured before applieation and then
Non-immunologie eontaet urtiearia is the most eom- every lS min for 1-2 h after applieation. The maximum
mon form of urtiearia and oeeurs without previous response is a 100% inerease in ear thiekness (within
exposure in most individuals. The reaetion remains so min after applieation).
loealized and does not eause systemie symptoms to Materials ean also be sereened for non-immunologie
spread and beeome generalized urtiearia. Typieally, the eontaet urticaria in humans. A small amount of the test
strength of this type of eontaet urtiearia reaetion varies material is applied to a marked site on the forehead,
from erythema to a generalized urtiearial response, and the vehicle is applied to a parallel site. The areas
depending on the eoneentration, skin site and sub- are evaluated at about 20-39 min after applieation for
stanee. The meehanism of non-immunologie eontaet erythema and/or edema (von Krogh and Maibach
urtiearia has not been delineated, but a direet influenee 1982).
on dermal vessel walls or a non-antibody-mediated Differentiation between non-specifie irritant reae-
release of histamine, prostaglandins, leukotrienes, tions and eontaet urticaria may be diffieult. Strong
substanee P, other inflammatory mediators, or differ- irritants, e.g., hydroehlorie acid, laetic acid, and
ent eombinations of these mediators represent possible phenol, ean eause clear-eut immediate whealing if the
meehanisms (Lahti and Maibach 1985). The most eoneentration is high enough, but the reaetions do not
potent and best-studied substanees producing non- usually fade away quiekly. Instead, they are followed by
immunologie eontaet urtiearia are benzoie acid, cin- signs of irritation (erythema, sealing, or erusting) 24 h
namie acid, cinnamie aldehyde, and nieotinie esters. later. Some substanees have only irritant properties,
Under optimal eonditions, more than half of a random e.g., benzoic acid and nieotinic acid esters, some are
sampie of individuals show loeal edemie and erythemie pure irritants, e.g., SLS, and some have both of these
reaetions within 4S min of applieation of these sub- features, e.g., dimethyl sulfoxide (DMSO) and formal-
stanees if the eoneentration is high enough. dehyde. Amin et al. (1997) provide details.
Immunologie Contact Urtiearia

Subjective Irritation and Paresthesia
Immunologie eontaet urtiearia is an immediate type-1
allergie reaetion (von Krogh and Maibach 1982). The
moleeules of a eontact urtieant reaet with specifie Cutaneous applieation of some chemieals elicits sen-
immunoglobulin E moleeules attaehed to mast eell sory discomfort, tingling and burning without visible
membranes. The eutaneous symptoms are elieited by inflammation. This non-inflammatory, painful re-
vasoaetive substanees (mainly histamine) released sponse has been termed "subjeetive irritation" (Frosch
from mast eells. Other mediators of inflammation and Kligman 1977). Materials reported to produee
may influenee the degree of response. Immunologie subjeetive irritation include DMSO, salieylie acid,
eontaet urtiearia reaetion ean extend beyond the amyl-dimethyl-p-aminobenzoie acid, and 2-ethoxy-
eontaet site, and generalized urtiearia may be aecom- ethyl-p-methoxycinnamate, which are ingredients of
panied by other symptoms, such as rhinitis, eonjune- eosmeties and over-the-eounter drugs. Pyrethroids, a
tivitis, asthma, and even anaphylaetie shoek. The term group of broad-speetrum inseetieides, produee a
"eontaet urtiearia syndrome" was therefore suggested similar eondition that may lead to temporary numb-
by Maibach and Johnson (197S). Fortunately, the ness, whieh has been ealled paresthesia (Cagen et al.
appearanee of systemic symptoms is uneommon, but 1984). Only a portion of the human population seems
it may be seen in eases of strong hypersensitivity or in to develop non-pyrethroid subjeetive irritation. For
widespread exposure and abundant percutaneous example, only 20% of subjeets exposed to S% aqueous
absorption of an allergen. laetie acid in a hot, humid environment developed a
stinging response (Frosch and Kligman 1977). Prior
skin damage, e.g., sunburn, pretreatment with surfaet-
Guinea Pig Ear Swelling Test ants, and tape stripping, inereases the intensity of
responses in those experiencing stinging (ealled
Predietive assays for evaluating the ability of materials "stingers"). Reeent data show that stingers develop
to produee non-immunologie eontaet urtiearia have stronger reaetions to materials eausing non-immuno-
been developed. No predietive assays for immunologie logie eontaet urtiearia. The meehanisms by whieh
eontaet urticaria have been published. Lahti and materials produee subjeetive irritation have not been
Maibach (1984) developed an assay in guinea pigs extensively investigated. Pyrethroids aet direetly on the
using materials known to produee urtiearia in humans. axon, interfering with the ehannel-gating meehanism
One tenth of a milliliter of the material (or eontrol and impulse firing (Vivjeberg and VandenBereken
1979). It has been suggested that agents causing Bronaugh RL, Maibach HI (eds) (1991) In vitro pereutaneous
absorption: principles, fundamentals and applieations. CRC
subjective irritation act via a similar mechanism, Press, Florida
because no visible infiammation is present. Buehler EV (1964) A new method for detecting potential
An animal model was developed to rate paresthesia sensitizers using the guinea pig. Toxieol Appl Pharmaeol
to pyrethroids and may be useful for other agents 6:341
Cagen SZ, Malloy LA, Parker CM, Gardiner TH, van Gelder CA,
(Cagen et al. 1984). Both fianks of guinea pigs (300- Jud VA (1984) Pyrethroid mediated skin sensory stimulation
450 g body weight) are shaved and 100 111 of the test eharaeterized by a new behavioral paradigm. Toxieol Appl
material (or vehicle) is spread over approximately Pharmacol 76:270-279
Draize JH (1955) Proeedures for the appraisal of the toxicity of
30 mm 2 on separate fianks. The animals' behavior is chemieals in foods, drugs, and cosmetics. VIII. Dermal
monitored by an unmanned video camera for 5 min at toxicity. Food Drug Cosmetic Law J 10:722-731
Draize JH, Woodard G, Calvery HO (1944) Methods for the study of
0.5, 1, 2, 4, and 6 h after application. Subsequently, the irritation and toxicity of substanees applied topically to the
film is analyzed for the number of fuH turns of the head skin and mueous membrane. J Pharmaeol Exp Ther 82:377-390
made, usually accompanied by attempted licking and Dugard PJ (1983) Skin permeability theory in relation to
measurements of percutaneous absorption in toxicology. In:
biting of the application sites. Using this technique, it Marzulli FN, Maibach HI (eds) Dermatotoxieology, 2nd edn.
was possible to rank pyrethroids for their ability to Hemisphere, New York, pp 91-116
produce paresthesia and corresponded to the ranking Emery BE, Edwards LD (1940) The pharmaeology of soaps. H.
The irritant action of soaps on human skin. J Am Pharm
available from human exposure. Assoe (Wash) 29:251-254
Environmental Proteetion Agency (1982) Pesticides registrations:
proposed data requirements. Sec. 158.135: toxieology data
Human Assay requirements. Federal Regulations 47:53192
Feldman RI, Maibach HI (1967) Regional variation in pereuta-
neous penetration of ['4C]eortisone in man. J Invest Dermatol
As originaHy published, the human subjective irnta- 48:181-183
tion assay required the use of a 110°F environmental Franz TJ (1975) Pereutaneous absorption. On the relevance of in
chamber with 80% relative humidity (Frosch and vitro data. J Invest Dermatol 64:190-195
Frosch PJ (1982) Irritaney of soap and detergent bars. In: Frost P,
Kligman 1977). Sweat was removed from the nasolabial Horwitz SN (eds) Principles of eosmetics for the dermatol-
fold and cheek, then a 5% aqueous solution of lactic ogist. CV Mosby, St. Louis, pp 5-12
acid was briskly rubbed over the area. Those who Frosch PJ, Kligman AM (1977) A method for appraising the
stinging capacity of topically applied substanees. J Soc
reported stinging for 3-5 min within the first 15 min Cosmetic Chemists 28:197-207
were designated as stingers and were used for subse- Frosch PI, Kligman AM (1979) The Duhring ehamber: an
quent tests. Subjects were asked to evaluate the degree improved teehnique for epicutaneous testing of irritant and
allergie reaetions. Contaet Dermatitis 5:73
of stinging as 0 = no stinging; 1 = slight stinging; Guillot JP, Gopnnet JF, Clement C, Caillard L, Truhauf R (1982)
2 = moderate stinging; or 3 = severe stinging. Evaluation of the cutaneous-irritation potential of com-
pounds. Food Chem Toxieol 20:563-572
Henderson CR, Riley EC (1945) Certain statistieal eonsiderations
in pateh testing. Invest Dermatol 6:227-230
References Hostynek J], Magee PS (1997) Fragranee allergens: classifieation
and ranking by QSAR. Toxieol In Vitro 1l:377-384
Hostynek J], Laurma AI, Magee PS, Bloom E, Maibach HI (1995)
Andersen KE, Maibach HI (1983) Multiple-application delayed- A loeal Iymph-node assay validation study of a strueture-
onset contact urtiearia: possible relation to certain unusual activity relationship model for eontact allergens. Areh
formalin and textile reactions. Contact Dermatitis 10: Dermatol Res 287:567-571
227- 2 34 Hostynek JJ, Magge PS, Maibach HI (1996) QSAR predictive of
Anderson C, Sundberg K, Groth 0 (1986) Animal model for eontact allergy: seope and limitations. In: Eisner P, LaCha-
assessment of skin irritancy. Contact Dermatitis 15:143-151 pelle JM, Wahlberg JE (eds) Prevention of eontaet dermatitis.
Bartek MJ, LaBudde JA (1975) Percutaneous absorption in vitro. Karger, Basel, pp 18-27
In: Maibach HI (ed) Animal models in dermatology. Chur- Hotchkiss SAM (1992) Skin as a xenobiotic metabolising organ.
chill-Livingstone, New York, pp 103-120 In: Gibson GG (ed) Progress in drug metabolism (vol 13).
Bartek MI, LaBudde JA, Maibach HI (1972) Skin permeability in Taylor and Francis, London, pp 217-262
vivo: comparison in rat, rabbit, pig and man. J Invest Jadassohn J (1896) Zur Kenntniss der medieamentosen Dermato-
Dermatol 58:114-123 sen. Verh Dtsch Dermatol Ges 5 Congress:103-129
Bloch B, Stein er-Wourlisch A (1930) Die Sensibilisierung des Kaminsky M, Szivos MM, Brown KR (1986) Application of the
Meerschweinchens gegen Primeln. Arch Dermatol Syphilis Hili top pateh test ehamber to dermal irritaney testing in the
162:349-378 albino rabbit. J Cutan Ocular Toxicol 5:81-87
Bronaugh RL (1985) Determination of percutaneous absorption Kero M, Hannuksela M (1980) Guinea pig maximization test,
by in vitro techniques. In: Bronaugh RL, Maibach HI (eds) open epicutaneous test and ehamber test in induction of
Percutaneous absorption: mechanisms-methodology-drug delayed contact hypersensitivity. Contact Dermatitis 6:
delivery. Marcel Dekker Inc., New York, pp 239-257 341-344
Bronaugh RL, Collier S (1991) Protocol for in vitro percutaneous Kleeak G (1983) Identifieation of eontaet allergens: predietive
absorption studies. In: Bronaugh RL, Maibach HI (eds) In tests in animals. In: Marzulli FN, Maibach HI (eds) Der-
vitro percutaneous absorption: principles, fundamentals and matotoxieology, 2nd edn. Hemisphere, New York, pp 193-236
applieations. CRC Press, Florida, pp 237-242 Kleeak G (1985) The Freund's complete adjuvant test and the
Bronaugh RL, Maibach HI (eds) (1985) Pereutaneous absorption: open epieutaneous test. In: Maibach HI, Anderson KE (eds)
meehanisms-methodology-drug delivery. Mareel Dekker Ine., Contaet allergy, predictive tests in guinea pigs. Karger, Basel,
New York pp 152- 171
42 P. Hewitt and H.1. Maibach: Dermatotoxicology
Kligman AM (1983) A biologieal brief on percutaneous absorp- perfurnes to the skin of rabbit, guinea pig, rat, miniature
tion. Drug Dev Ind Pharm 19:521-560 swine, and man. Cosmetie Toiletries 94:41-42
Kligman AM, Wooding WM (1967) A method for the measure- Noonan PK, Wester RC (1983) Cutaneous biotransformations and
ment and evaluation of irritants on human skin. J Invest some pharmacologieal and toxieological implications. In:
Dermatol 49:78-94 Marzulli FN, Maibach HI (eds) Dermatotoxicology, 2nd edn.
Lallti A (1980) Nonimmunologie contact urticaria. Acta Derm Hemisphere, New York, pp 71-90
Venereol Suppl (Stockh) 60:1-49 Office of the Federal Registrar, National Archives of Records
Lahti A, Maibach HI (1984) An animal model for non-immuno- Service (1985) Code of Federal Regulations. General Services
logie contact urtiearia. Toxicol Appl Pharmacol 76:219-224 Administration Title 16, parts 1500.50-1500.41
Lallti A, Maibach HI (1985) Speeies speeifieity of non-immuno- Ostrenga 1, Steinmetz C, Poulsen B, Yett S (1971) Significance of
logie contact urticaria: guinea pig, rat and mouse. J Am Acad vehicle composition. H. Predietion of optimal vehicle com-
Dermatol 13:66-69 position. J Pharm Sei 60:1180-1183
Landsteiner K, Chase MW (1937) Studies on the sensitization of Patrick E, Maibach HI (1991) Predietive skin irritation tests in
animals with simple chemieal compounds. IV. Anaphylaxis animals and humans. In: Marzulli FN, Maibach HI (eds)
induced by picryl chloride and 2:4 dinitrochlorbenzene. J Exp Dermatotoxicology, 3rd edn. Hemisphere Publishing, New
Med 66:337-351 York, pp 201-222
Landsteiner K, Jacobs J (1935) Studies on the sensitization of Phillips L, Steinberg M, Maibach HI, Akers W A (1972) A
animals with simple chemical compounds. J Exp Med 61: comparison of rabbit and human skin response to certain
643-648 irritants. Toxicol Appl Pharmacol 21:369-382
Landsteiner K, Jacobs J (1936) Studies on the sensitization of Prottey C (1978) The molecular basis of skin irritation. In: Breuer
animals with simple chemieal compounds. Ir. J Exp Med MM (ed) Cosmetic Seience (VOll). Academic Press, London,
64:625-629 pp 275-349
Lanman BM, Elvers WB, Howard CS (1968) The role of human Rapaport M, Anderson D, Pierce U (1978) Performance of the 21
patch testing in a product development program. In: day patch test in eivilian populations. J Toxicol Cutan Ocular
Proceedings of the Joint Conference on Cosmetie Seien ces. Toxieol 1:109-115
The Toilet Goods Assoeiation, Washington DC, pp 135-145 Rouger A, Goldberg L, Maibach H (1994) Irritation: in vitro
Magee PS, Hostynek JJ, Maibach HI (1994) A classification model approaches. In: Rouger A, Goldberg L, Maibach H (eds)
for allergie contact dermatitis. Quant Struct Activity Rela- In vitro toxicology. Academic Press, London, pp 23-185
tionships 13:22-33 Scheuplein RJ (1978) Permeability of skin: a review of major
Magnusson B, HersIe K (1965) Patch test methods. I. A concepts. Curr Probl Dermatol 7:58-68
comparative study of six different types of patch tests. Acta Scheuplein R1, Bronough RL (1983) Percutaneous absorption. In:
Derm Venereol 45:123-128 Goldsmith LA (ed) Biochemistry and physiology of the skin.
Maibach HI, Johnson HL (1975) Contact urtiearia syndrome. Oxford, New York, pp 1255-1295
Contact urtiearia to diethyltoluamide (immediate-type hy- Shelanski HA (1951) Experience with and considerations of the
persensitivity). Arch Dermatol11l:726-730 human patch test method. J Soc Cosmetic Chemists 2:324-331
Marzulli FN, Maibach HI (1973) Antimierobials: experimental Simpson WL, Cramer W (1943) Fluorescence studies: careinogens
contact sensitization in man. J Soc Cosmetic Chemists in skin. Cancer Res 3:362-369
24:399-421 Vivjeberg HP, VandenBercken J (1979) Frequency dependent
Marzulli FN, Maibach HI (eds) (1996) Dermatotoxicology, 5th effects of the pyrethroid insectieide decamethrin in frog
edn. Taylor and Franeis, Washington DC myelinated nerve fibers. Eur J Pharmacol 58:501-504
Marzulli FN, Maibach HI (eds) (1997) Handbook of dermatology. von BIomberg BME, Bruynzeel, DP, Scheper RJ (1991) Advances
Taylor and Franeis, Washington DC in mechanisms of allergie contact dermatitis: in vitro and in
Mathias CGT, Maibach HI (1978) Dermatoxicology monographs. vivo research. In: Marzulli FN, Maibach HI (eds) Dermato-
1. Cutaneous irritation: factors influeneing the response to toxicology, 4th edn. Hemisphere, New York, pp 255-362
irritants. Clin Toxieol 13:333-346 von Krogh C, Maibach HI (1982) The contact urticaria syndrome.
Maurer T, Thomann P, Weirich EG, Hess R (1975) The Semin Dermatol 1:59-66
optimization test in the guinea pig. A method for the Weigand DA, Gaylor JR (1976) Irritant reaction in negro and
predictive evaluation of the contact allergenieity of chemieals. caucasian skin. South Med J 67:548-551
Agents Actions 5=174-179 Wester RC, Maibach HI (1983) Cutaneous pharmacokinetics: 10
Motoyoshi K, Toyoshima Y, Sato M, Yoshimura M (1979) steps to percutaneous absorption. Drug Metab Rev 14:
Comparative studies on the irritancy of oils and synthetie 169-205
CHAPTER 5
Systemic Toxicity
P. Hewitt and H.l. Maibach
Introduction hydrophilicity (to aid its passage through the viable

epidermis and dermis). Other factors, such as molec-
ular weight, molecular volume and melting point, will
Human skin is exposed to a plethora of chemicals from
also be important determinants.
birth to death. Following percutaneous absorption, a
chemical and/or its metabolites may cause toxicity in Ocdusion
another organ distant from the point of entry.
Although not generally appreciated, some chemicals The penetration of some topicals may be increased by
are more toxie, at least in animals, when applied up to a factor of ten or more by the use of an occlusive
topieally rather than orally. Further, many compounds covering. This can be due to increased water retention
are absorbed to a greater degree from the skin than the in the stratum corneum, increased blood flow, in-
gastrointestinal (GI) tract, and whole-body exposure creased temperature, and increased surface area after
can produce systemic absorption of grams of material. prolonged occlusion (skin wrinkling). Occlusion also
This chapter focuses on the limited epidemiologic prevents accidental wiping off or evaporation (for
material available, depending largely on case reports. volatile compounds), hence maintaining a higher dose
Many drugs for topieal use are capable of producing on the skin surface.
systemic side effects whose occurrence and severity
depends largely on factors that affect the absorption of Vehide Containing the Drug
topically applied drugs.
The greater the affinity of a vehicle for the drug it
Factors Affecting Percutaneous Absorption contains, the less the percutaneous absorption of the
drug. Physieal properties of vehicles, especially the
degree of occlusion they produce, affect percutaneous
Integrity of the Barrier absorption, as discussed above (greases). Structural or
chemical damage to the barrier layer can be caused by
The stratum corneum layer of the epidermis is a major the vehicle used; vehicles, such as dimethyl sulfoxide,
barrier to percutaneous absorption. Anything that alters cause greatly increased percutaneous absorption. In
the structure or function of the stratum corneum will general, a higher concentration of the drug in its
affect epidermal absorption. The integrity of this barrier vehicle enhances penetration. Enhanced solubility
is reduced by any inflammatory process of the skin, pro duces greater thermodynamic activity, yielding
such as any form of dermatitis or psoriasis, which may greater flux. Extensive documentation on factors
result in increased percutaneous absorption. Similarly, affecting penetration is found in Bronaugh and
removal of the stratum corneum by stripping or damage Maibach (1990, 1991) and Smith and Maibach (1995).
by alkalis, acids, etc. will increase absorption.
Site of Application
The Physicochemical Properties of the Substance
Regional differences in permeability of skin largely
Absorption is affected by the relative water/lipid depend on the thickness of the intact stratum corneum
solubility of the drug and the relative solubility of (Wester and Maibach 1989). According to the findings
the drug in its vehicle compared with its solubility in of a study by Feldmann and Maibach (1967), the
the stratum corneum. In order for a chemical to highest total absorption of hydrocortisone is that from
penetrate through the skin into the systemic circula- the scrotum, followed (in decreasing order) by
tion, it requires both a degree of lipophilicity (to absorption from the forehead, scalp, back, forearms,
facilitate its entry into the stratum corneum) and palms and plantar surfaces.

Age type of side effeet, usually limited to the skin, is outside

the seope of this ehapter. The reader is referred to the
The greatest toxieologieal response to topieal admin- textbooks of Fisher (1986) and Ryeroft (1995) for
istration has been seen in the infant. The preterm referenees to eontaet dermatitis. Systemie side effeets
infant does not have intaet barrier funetion and henee from topieally applied ehernieals ean sometimes result
is more suseeptible to systemie toxieity from topieally from either a toxie (irritant) reaetion or a hypersen-
applied drugs (Naehman and Esterly 1971; Greaves sitivity reaetion. The latter ean be an anaphylaetie type
et al. 1975). Anormal full-term infant probably has a of reaetion, whieh is the extreme manifestation of
fully developed stratum eorneum with eomplete bar- eontaet urtiearia syndrome (Amin et al. 1996). Many
rier funetion (Rasmussen 1979). However, topieal topieal drugs and eosmeties have reportedly eaused
applieation of the same amount of a eompound to anaphylaetie reaetions. While anaphylaetie reaetions to
both adults and newborns reveals greater systemie topieal medieaments are uneommon, their potentially
availability in the newborn (Wester et al. 1977). This is serious nature warrants attention. However, reports of
beeause the ratio of surfaee area to body weight in the toxie (as distinet from allergie) reaetions to applied
newborn is three times that in the adult. Therefore, drugs and eosmeties are more numerous and include
given an equal area of applieation of a drug on to the many medieaments that have been safely used for
skins of newborns and adults, the proportion absorbed many years but whieh ean be toxie under special
per kilogram of body weight is mueh higher in the cireumstanees.
infant. Barrett and Rutter (1994) and Maibaeh and The following is a list, in alphabetieal order, of the
Boisits (1982) provide extensive doeumentation on this ehernieals to be reviewed, followed by a detailed
issue. Although counterintuitive, absorption of some diseussion of eaeh ehemieal.
eompounds deereases in the aged (Roskos et al. 1989).
Later, Roskos and Maibaeh (1992) reported that, in 1. Agroehemieals
older subjeets, absorption was deereased for steroids 2. Anti-aene ereams
but unehanged for other, more hydrophilie eom- 3. Antibioties
pounds. They suggested that this was due to the Chloromyeetin
deereased coneentration of surfaee lipids in older Clindamycin
subjeets. Gentamycin
Neomycin
Temperature 4. Antihistamines
Diphenylpyraline hydroehloride
Generally, inereased skin temperature enhanees pen- Promethazine
etration rate (Jetzer et al. 1988). This may be due to the Doxepin
inereased blood flow associated with inereased skin 5. Antimierobials
temperature or an inerease in skin hydration (Danon Borie acid
et al. 1986; Siddiqui 1989). Castellani's paint
Hexaehlorophene
Homosulfanilamide
Metabolism
Iodine; povidone-iodine
Phenol
It has been weil documented that the skin is eapable of
Resorcinol
metabolizing a wide range of xenobioties and has a full
Silver sulfadiazine
eomplement of phase-I and phase-II enzymes. The
Triehloroearbanilide
specifie aetivities found in the skin are relatively low
6. Aromatie amines
when eompared to their equivalent hepatie forms.
7. Arsenie
However, when the total volume of the skin is taken
8. Carmustine
into aeeount, then it is apparent that the skin is an
9. Camphor
efficient drug-metabolising organ. Reeent information
10. Coal tar
on skin metabolism is found in Hotehkiss (1995).
11. Cosmetie agents
12. Crude oil
13. Diethyltoluamide (DEET)
Systemic Side-Effects Caused 14. Dimethyl sulfoxide (DMSO)
by Topically Applied Drugs and Cosmetics
15. Dinitroehlorobenzene (DNCB)
16. Ethanol
Topieally applied drugs and eosmeties ean eause 17. Fumarie acid monoethyl ester
allergie or irritant eontaet dermatitis. However, this 18. Inseeticides
Systemic Toxicity 45
Lindane row aplasia with a fatal outcome after topical applica-

Malathion tion of chloramphenicol in eye ointment was described
19. Local anesthetics by Abrams et al. (1982).
Benzocaine
Lidocaine Clindamycin
20. Mercurials
21. Monobenzone Topical clindamycin is widely used in the treatment of
22. 2-Naphthol acne vulgaris. Approximately 5% clindamycin hydro-
23. Podophyllum resin chloride is absorbed systemically (Barza et al. 1982).
24. Salicylic acid (SA) The degree of absorption largely depends on the
25. Selenium sulfide vehicle, ranging from 0.13% (acetone) to 13.92%
26. Silver nitrate (DMSO) (Franz 1983). Several cases of topical-clin-
27. Steroids damycin-associated diarrhea have been reported
Corticosteroids (Becker et al. 1981). Pseudomembranous colitis is a
Sex hormones side effect of systemic administration of clindamycin.
28. Transdermal drug-delivery systems A case of pseudomembranous colitis has been reported
29. Miscellaneous after topical administration by Milstone et al. (1981).
Agrochemicals Gentamycin
It has been proposed that the most serious occupa- Ototoxicity is a well-known toxic effect of systemic
tional skin-exposure hazard is in agricultural workers, gentamycin administration. However, topical applica-
involved in pesticide application. Contaminated cloth- tion to large thermal injuries of the skin has similarly
ing, lack of adequate protection and unsafe spraying caused ototoxic effects ranging from mild to severe
procedures have caused numerous toxic responses, hearing loss, with an associated decrease of vestibular
mainly due to skin absorption (Hotchkiss 1995). function (Dayal et al. 1974). In the two patients
Systemic toxicity after topical exposure to agrochem- described, serum levels of gentamycin measured were
icals has been widely reported. A prime example is the 1.0-3·0 )lg/ml and 3-3-4.3 )lg/ml. Drake (1974) de-
insecticide Lindane, which, when absorbed into the scribed a woman who developed tinnitus each time
body, accumulates in the central nervous system (CNS) she treated her paronychia with gentamycin sulfate
and the brain and has been linked with cancer cream 0.1%. Use of gentamycin ear drops may also be
(Murphy 1986). Therefore, the use of Lindane has associated with ototoxic reactions (Mittelman 1972).
been restricted in the United States and is being
replaced by the far safer insecticide permethrin Neomycin
(Moody and Ritter 1989). Other pesticides have been
found to be genotoxic after topical exposure, including Just as ototoxicity is a well-known hazard of parenteral
aminocarb, chlordane, dichloro-diphenyl-trichloroe- neomycin administration, deafness has been reported
thane and dichlorvos (Schop et al. 1990). Agrochem- after local treatment, including skin infections and
icals, such as parathion, malathion and chlordane, burns (Bamford and Jones 1978), application as an
have been reported to persist in the skin up to 2 years aerosol for inhalation, instillation into cavities (Masur
after exposure (Wester and Maibach 1989). et al. 1976), irrigation oflarge wounds (Kelly et al. 1969)
and use of neomycin-containing eardrops (Goffinet
Anti-acne (reams 1977). Kellerhals (1978) reported 13 cases of inner-ear
damage in which the use of eardrops containing
Anti-acne creams have been shown to cause systemic neomycin and polymycin were incriminated. All cases
toxic effects. For example, retinoic acid is a known had perforated tympanie membranes, and the paper
teratogen (Steele et al. 1983) and is found in certain conc1udes that these drops (and also those containing
formulations. Other formulations contain clindamycin, chloromycetin, colistin and polymycin) should not be
which is reviewed below. used in such cases for periods longer than 10 days.
Antibiotics Antihistamines
Chloramphenicol Oiphenylpyra/ine Hydrochloride
Oral administration of chloramphenicol may lead to Diphenylpyraline hydrochloride has been used topi-
aplastic anemia (Brandwein and Keating 1990). Mar- cally in Germany for the treatment of eczematous and
other itching derma tos es. Symptomatic psychosis has Hexachloraphene

been observed in 12 patients, nine of whom were
children. The amounts of the active drug applied Hexachorophene has, since 1961, been extensively used
ranged from 225-1350 mg. The first symptoms of in hospital nurseries (Haddad 1990b), mainly for
toxicity were psychomotor restlessness in all cases, reducing the incidence of staphylococcal infections
usually within 24 h. Other symptoms included disori- among the newborn. In addition, it has been an
entation and optic and acoustic hallucinations. All ingredient of many medical preparations, cosmetics
symptoms disappeared 4 days after discontinuation of and other consumer goods. Hexachlorophene readily
the topical medication (Cammann et al. 1971). penetrates damaged skin and its absorption through
intact skin has also been demonstrated (Curley
Promethazine et al. 1971; Alder et al. 1972). In 1972 in France, as a
result of the accidental addition of 6.3% hexachloro-
Block and Beysovec (1982) reported a 16-month-old phene to baby talcum powder, 204 babies fell ill
male weighing 11.5 kg treated with 2% promethazine (convulsions, behavioural changes and CNS depres-
cream for generalized eczema. The child showed sion), and 36 died from respiratory arrest (Pines 1973).
abnormal behavior, loss of balance, inability to focus, This report was followed by animal experiments with
irritability, drowsiness and failure to recognize his hexachlorophene, confirming that the drug is neuro-
mother after 15-20 g of the cream had been applied. toxic. Consequently, in 1972, the U.S. Food and Drug
One day later, all symptoms had spontaneously Administration (FDA) banned use of hexachlorophene
disappeared. A diagnosis of promethazine toxicity to prescription use only or as a surgical scrub and
through percutaneous absorption was made. hand wash for health-care personnel. Hexachlorop-
hene has been excluded from cosmetics except as a
preservative in levels not exceeding 0.1%. Premature
Ooxepin
infants are also at risk, and the safety of hexachlorop-
hene for routine bathing of babies is still controversial.
Five percent topical doxepin has been introduced as an Marzulli and Maibach (1975) has placed in perspective
antipruritic. Percutaneous absorption frequently leads lessons to be learned from its toxicity.
to clinical sedation (package insert, Zonulong, Gen-
4-Homosulfanilamide
derm, Lincolnville).
4-Homosulfanilamide (sulfamylon) is a topical sulfon-
Antimicrobials amide used for the treatment of large burns. Sulfa-
mylon is a carbonic anhydrase inhibitor and caused
Boric Acid hyperchloremic metabolic acidosis in patients with
extensive burns treated with its topical application,
The toxicity of this mildly bacteriostatic substance is caused by percutaneous absorption of the drug
reviewed in detail by Stewart et al. (1990). The use of (Liebman et al. 1982). Reversible pulmonary compli-
borates has been abandoned because of their limited cations (Albert et al. 1982) and methemoglobinuria
therapeutic value and high toxicity, resulting in few (Ohlgisser et al. 1978) have also been reported.
new cases of borate intoxication.
Povidone-Iodine
Castellani's Solution
Povidone-iodine (Betadine) is a water-soluble iodine
Castellani's solution (or paint) is an old medicament complex which retains the broad-range microbiocidal
mainly used for the local treatment of fungal skin activity of iodine without the undesirable effects of
infections. It contains boric acid, fuchsin, resorcinol, iodine tincture. However, toxicity still occurs from
water, phenol (90%), acetone, and spirit. Lundell and povidone-iodine percutaneously absorbed, mainly
Nordman (1973) reported a case in which two appli- when it is used on large areas of burnt skin or on
cations of Castellani's solution severely poisoned a neonates. This subject is comprehensively dealt with
6-week-old boy, who became cyanotic with 41% by Postellon and Aronow (1990).
methemoglobin. Another case report (Rogers
et al. 1978) states that, hours after the application of Phenol (Carbolic Acid)
Castellani's paint to the entire body surface (except the
face) of a 6-week-old infant for severe seborrheic Phenol is no longer widely used as a skin antiseptic
dermatitis, the child became drowsy and had shallow but, in dilutions of 0.5-2.0%, it is sometimes pre-
breathing. scribed as an antipruritic in topical medicaments and
is used for phenol face peels. As much as 25% of of Pseudomonas infections, this bactericidal agent acts
phenol is absorbed from 2 ml of a solution of 2.5 g on a variety of gram-positive and gram-negative
phenollL water applied to the fore arm and left for bacteria, as weIl as on yeasts. Its relative freedom from
60 min (Baranowski-Dutkiewicz 1981). The toxic dose side effects has contributed to its popularity. There
for adults has been estimated to be 8-15 g. Phenol- have been reports of nephrotic syndrome (Owens
induced ochronosis has been reported in patients who, et al. 1974) and leukopenia (Fraser and Beaulieu 1979)
for many years, treated leg ulcers with wet dressings following topical therapy. Current evidence suggests a
containing phenol (Cullison 1983). Several case reports causal relationship of silver sulfadiazine with leuko-
document fatal reactions to percutaneously absorbed penia, although the mechanism of this re action is
phenol by accidental spillage of phenol (Johnstone unknown. The drug presumably affects the white blood
1948), due to treatment of burns with a phenol- cells peripherally, but not the erythrocyte count. The
containing preparation (Cronin 1949) or due to the sulfadiazine-induced leukopenia is at its nadir within
application of phenol to wounds (Deichmann 1949). A 2-4 days of starting therapy, with the leukocyte count
one-day-old child died after application of 2% phenol returning to normal within 2-3 days, and recovery is
to the umbilicus (Von Hinkel and Kitzel 1968). Several not affected by continuation of therapy.
cases of sudden death and intra- or post-operative
complications have been reported after phenol face Triclocarban
peels (DeI and Tanski 1980). Major cardiac arrhythm-
ias were noted in 10 out of 43 patients during phenol Triclocarban (trichlorocarbanilide, TCC) is a bacterio-
face peels (Truppman and Ellenby 1979). However, this static agent which has been used as an antimicrobial in
is rather controversial, and some authors feel that, toilet soap since 1956. The percutaneous absorption
when the procedure is done over aperiod of more has been studied by Scharpf et al. (1975), who showed
than 1 hand when the dose applied is carefully that, after a simple shower employing a whole-body
monitored, phenol face peels are not risky (Baker lather with approximately 6 g of soap containing 2%
1979). TCC, 0.23% of the applied dose was recovered in feces
after 6 days and 0.16% in the urine after 2 days. At all
sampling times, blood levels were below the detection
Resorcino/
limit of 10 ppm. There have been reports of met-
hemoglobinemia induced in neonates by topical TCC
Resorcinol is used for its keratolytic properties in the
(Fisch et al. 1985).
treatment of ac ne vulgaris. It is also a constituent of
the antifungal Castellani's solution. Formerly, leg
Aromatic Amines
ulcers were treated with external applications of
resorcinol. It has an anti-thyroid activity similar to
4,4' -Methylenedianiline and 4,4' -methylene-bis-
that of methyl thiouracil. Consequently, several cases
chloroaniline are two widely used aromatic amines
of myxedema caused by percutaneous absorption of
employed in the manufacture of polyurethane foams,
resorcinol, especially from ulcerated surfaces, have
epoxy res ins and as a curing agent in rubber manu-
been described (Thomas and Gisburn 1961). Met-
facture. These two chemicals have been shown to be
hemoglobinemia in children, caused by absorption of
carcinogenic and mutagenic in a number of animal
resorcinol applied to wounds, has also been reported
species, and they are structurally similar to the known
(Murray 1926). Cunningham (1956) reported a case in
human bladder carcinogen benzidine (McQueen
which an ointment containing 12.5% resorcinol applied
et al. 1981; Lamb et al. 1986). Both chemicals have
to the napkin area of an infant produced cyanosis,
been detected in the urine of factory workers (Cocker
hemolytic anaemia and hemoglobinemia. In the liter-
et al. 1988), and Hotchkiss et al. (1993) reported sub-
ature, the author found seven cases of acute poisoning
stantial absorption through human skin in vitro.
in babies as a consequence of topical resorcinol
application, in some instances to limited areas; five
Arsenic
fatalities were recorded. Although the use of resorcinol
in young children and for leg ulcers should be avoided,
The toxicity of ingested or inhaled arsenic is dealt with
topical resorcinol, when used for acne vulgaris, has
by Hall (1990). Fowler's solution, used orally in the
been reported to be safe (Yeung et al. 1983).
treatment of psoriasis, contains arsenic. Arsenical
keratoses and malignancies are well-recognized long-
Si/ver Su/fadiazine term reactions to this. However, Von Roemeling
et al. (1979) reported multifocal malignancies of the
Silver sulfadiazine cream is widely used for the topical bowel and bladder in a psoriatic patient treated
treatment of burns. Intended primarily for the control 20 years previously with topical Fowler's solution,
indieating percutaneous absorption can also be car- glottis, pharynx, neck and bronchi. These occur within
cinogenic. ho urs of the application of the dye-mix to the skin. The
symptoms may then progress on the second day to
Carmustine anuria and acute renal failure, with death occurring on
the third day. Dialysis has helped some patients, but
Topieal carmustine has been used for the treatment of others have died from renal tubular necrosis (D' Arcy
mycosis fungoides, lymphomatoid papulosis and pa- 1982). Whether this toxicity is due to p-phenylenedi-
rapsoriasis en plaques. Zackheim (1994) reported their amine per se (probably grossly impure) or its
experience of 172 patients with patch-plaque-stage combination with henna is unknown. Systemic admin-
mycosis fungoides treated with topical 1,3-bis(2-chlo- istration of the p-phenylenediamine leads to similar
roethyl)-l-nitrosourea solution. Complete blood symptoms, and several deaths due to ingestion with
counts were determined once each month during suicidal intent have been reported (EI et al. 1983).
treatment. Mild, reversible myelosuppression occurred Spencer and Bischoff (1987) reported that, after skin
in less than 10% of patients using 20 mg/day total- penetration, musk ambrette (mainly used as a fra-
body application and was rare in those using 10 mg/ grance) causes the breakdown of cellular elements
day. within the brain, spinal cord and peripheral nerves.
These types of effects were also reported for the
Camphor fragrance acetyl ethyl tetramethyl tetralin.
Camphor is a cydic ketone of the hydroaromatic Crude Oil

terpene group. It is an ingredient of a large number of
over-the-counter topical remedies (with a camphor Feuston et al. (1997) have reported major systemic
content of 1-20%) taken especially for symptomatic toxic effects after the dermal application of crude oils
relief of "chest congestion and musde aches" but its to rats. The major effects induded reduction in body
effectiveness is of some doubt. Camphor is readily weight gain and increases in absolute and relative liver
absorbed from all sites of administration, induding and thymus weight. Red blood cell count, hemoglobin,
topical application to the skin. The compound is hematocrit and platelet count were all affected. These
dassified as a dass-IV chemieal, Le. a very toxie effects were related to concentrations of polycydic
substance. Hundreds of cases of intoxication have been aromatic compounds found in the crude oil.
reported, usually after accidental ingestion by children
(Skoglund et al. 19m Kopelman 1990). Diethyltoluamide
Coal Tar N,N-Diethyl-m-toluamide (DEET) has been used as an

effective insect repellent since 1957. It is commercially
A case of methemoglobinemia in an infant following available in various topical forms containing between
the 5-day application of an ointment containing 2.5% 10% and 95% DEET. Although DEET has an overall
crude coal tar and 5% benzocaine to about half the low incidence of toxicity, prolonged use in children
body surface has been reported (Goluboff and Mac- has been discouraged because of reports of toxic
Fadyen 1955). encephalopathy (Edwards and Johnson 1987). In this
report, one of two children displaying signs of severe
Cosmetic Agents tonic encephalopathy died after prolonged hospital-
ization. At autopsy, edema of the brain and conges-
Henna dye is used on nails, skin and hair by married tion of the meninges was found. Although most
women in the Islamic community and, traditionally, it reports of CNS toxicity have been in children, adults
is used by the major participants in marriage ceremo- and fetus es mayaiso be at risk. Long-term occupa-
nies. Henna consists of the dried leaves of Lawsonia tional exposure led to episodes of confusion, depres-
alba, and the coloring matter, lawsone, is a hydroxy- sion, insomnia and musde cramps (Robbins and
naphthoquinone. Dyeing hair or skin with powdered Cherniack 1986). Schaefer and Peters (1992) reported a
henna is a lengthy procedure and, to speed up this 4-year-old boy with mental retardation, impaired
process, Sudanese women mix a "black powder" (p- sensorimotor co ordination and craniofacial dysmor-
phenylenediamine) with henna to accelerate the fixing. phology whose mother applied a lotion containing
The combination of henna and p-phenylenediamine is 25% DEET daily to her arms and legs throughout her
particularly toxic, and over 20 cases of such toxicity, pregnancy. Although adefinite causal relationship
some fatal, were noted in Khartoum alone over a between DEET exposure and developmental disorder
2-year period. Initial symptoms are those of angio- could not be established, the authors recommend its
neurotic edema with massive edema of the face, lips, cautious use in pregnancy.
Dimethyl Sulfoxide crying, excitability and irritability. The children were

of both sexes and ranged in age from 33 months to
The toxicology of topical DMSO has been investigated 1 year. Ethanol-soaked cloths had been applied under
by Kligman (1965). In this study, 9 ml of 90% DMSO rubber panties, and the number of applications varied
was applied twice daily to the entire trunk of 20 from one to three (40 ml/application). All 28 children
healthy volunteers for 3 weeks or 26 weeks. The showed some degree of CNS depression, 24 showed
following laboratory tests were done: complete blood miosis, 15 hypoglycemia, 5 convulsions and 5 res pi ra-
count, urinalysis, blood sedimentation rate, serum tory depression; 2 died. Eleven cases showed blood
glutamate oxaloacetate transaminase, blood urea ni- alcohollevels from 0.6 g to 1.49 g. Of the two who died,
trogen and fasting blood-sugar determinations. At the one was autopsied, and the findings were consistent
end of the study, all laboratory values had remained with ethanol toxicity. Topically applied ethanol in tar
normal. Except for the appearance of cutaneous signs, gel (Ellis et al. 1979) and beer containing shampoo
such as erythema, scaling, contact urticaria, stinging (Stoll and King 1980) has caused Antabuse effects
and burning sensations, the drug was tolerated weIl by (through percutaneous absorption) in patients on
all but two individuals, who developed systemic disulfiram for alcoholism.
symptoms. In one, a toxic reaction, which was
characterized by a diffuse erythematous and scaling Fumaric Acid Monoethyl Ester
rash accompanied by severe abdominal cramps, de-
veloped on the 12th day; the other had a similar rash The effect of systemically and/or topically adminis-
and complained of nausea, chills and chest pains. tered fumaric acid monoethyl ester (ethyl fumarate) on
These signs, however, abated in spite of continued psoriasis was studied by Dubiel and Happle (1972) in
administration of the drug. Most subjects did experi- six patients. Two patients who had been treated with
ence the weIl-known DMSO-induced disagreeable oys- locally applied ointments consisting of 3% or 5% ethyl
ter-like breath odor, to which they eventually became fumarate in petrolatum developed symptoms of renal
insensitive. One fatality due to a hypersensitivity toxicity.
reaction has been alleged (Bennett 1980).
Insecticides
Dinitrochlorobenzene
Lindane
DNCB, a potent contact allergen, has been used for the
treatment of recalcitrant alopecia areata. Today, how- Lindane, the y isomer of benzene hexachloride, is
ever, its use has been discouraged because of suspicion widely used in the treatment of scabies and pediculo-
that DNCB may be mutagenic. Another unfavourable sis, usually in a 1% lotion which is applied to the entire
response is its alleged ability to potentiate ep- body and left on for 24 h (in the case of scabies). The
icutaneous sensitization to non-related allergens (De percutaneous absorption of the drug has been widely
Groot et al. 1981). DNCB is absorbed in substantial documented (Ginsburg et al. 1977; Hosler et al. 1980),
amounts through the skin, with about 50% of an as has toxicity from excessive topical therapeutic
applied dose ultimately recoverable in the urine application of lindane (Davies et al. 1983). The issue
(Feldmann and Maibach 1970). Possible systemic of possible toxic reactions to a single therapeutic
reactions to DNCB have been reported (McDaniel application of lindane, notably CNS toxicity, has not
et al. 1982). A 25-year-old man treated with 0.1% been settled (Food and Drug Administration 1976;
DNCB (daily for 2 months) after prior sensitization Pramanik and Hansen 1979). Most authors agree that
experienced generalized urticaria, pruritus and dys- the benefits to be derived from the use of lindane as a
pepsia. Discontinuation of the drug led to cessation of scabicide and pediculicide outweigh the risks involved
all symptoms, which recurred after reintroduction of (Solomom et al. 1977).
DNCB therapy.
Ma/athion
Ethanol
The detailed toxicology of malathion is dealt with by
Gimenez et al. (1968) described 28 children with eth- Haddad (1990a). Malathion is used in the treatment of
anol toxicity from percutaneous absorption. In Argen- lice, a single application of a 0.5% solution being
tina, a popular procedure was to apply ethanol-soaked customary. Used in this way, it is generally safe. Ramu
cloths to the abdomens of babies as ahorne remedy for et al. (1973) reported four children with toxicity fol-
the treatment of disturbances of the GI tract, such as lowing hair washing with 50% malathion in xylene for
cramps, pain, vomiting and diarrhea, or because of the purpose of louse control.
Local Anaesthetics rial poisoning could be detected in 33 patients.

Nephrotic syndrome has been reported after
Benzoca;ne ammoniated-mercury-containing ointment application
(Silverberg et a1. 1967; Lyons et a1. 1975). There have
Methemoglobinemia has been reported following the been two case reports (Stanley and Frank 1971; Clark
topical application of benzocaine (ethyl aminobenzo- et al. 1982) of children who died following the treat-
ate) to both skin and mucous membranes, with most ment of an omphalocele with merbromin (an organic
cases occurring in infants (Haggerty 1962; Olson and mercurial antiseptic).
McEvoy 1981). However, toxicity is uncommon (Amer-
ican Medical Association 1977). Monobenzone
Lidoca;ne Monobenzone (monobenzyl ether of hydroquinone) is

used topically by patients with extensive vitiligo to
Lidocaine hydrochloride is widely used for topical and depigment their remaining normally pigmented skin.
local injection anesthesia. When the drug is applied to A patient who had been applying the drug for 1 year
mucous membranes, blood levels simulate those had an anterior linear deposition of pigment on both
resulting from intravenous injection (Adriani and corneas. Eleven additional patients with vitiligo using
Zepernick 1964). Serum lidocaine concentrations high- monobenzone acquired conjunctival melanosis and
er than 6 Jlg/ml are associated with toxicity (Selden pingueculae (Hedges et a1. 1983).
and Sasahara 1967), whose signs are CNS stimulation
followed by depression and later inhibition of cardio-
2-Naphthol
vascular function. Systemic toxicity from lidocaine
applied to the oral cavity in two children has been
2-Naphthol (ß-naphthol) is used in peeling pastes for
described (Giard et a1. 1983; Mofenson et a1. 1983). In
the treatment of acne, and between 5% and 10% of a
one, after applying 2% lidocaine hydrochloride solu-
cutaneous dose has been recovered from the urine of
tion to the infant's gums 5-6 times daily for a week, the
subjects (Hemels 1972). Extensive application of
child experienced two generalized seizures within an
2-naphthol ointments has been responsible for sys-
hour. Analysis revealed lidocaine, both in the urine
temic side effects, including vomiting and death (Osol
and in the blood (10 Jlg/ml). The other cbild had a
and Farrar 1947). Hemels (1972) concludes that
seizure after having received 227 mg/kg oral lidocaine
2-naphthol-containing pastes should be applied only
for stomatitis herpetica over a 24-h period. In this case,
for short periods of time and to a limited area not
however, ingestion and resorption from the GI tract
exceeding 150 cm 2 •
may have contributed to the clinical symptoms. It has
been suggested that, for pediatric patients, lidocaine
should be applied with an oral swab to individual Podophyllum
lesions, thus limiting buccal absorption by decreasing
the surface area exposed to lidocaine. The toxicity of podophyllum was reviewed by Cassidy
et a1. (1982). Although there have been a significant
Mercurials number of case reports describing serious neurologie
illness or death following the application of pod-
The toxicology of mercury is comprehensively dealt ophyllum, these are generally related to its use in
with by Aronow (1990). With few exceptions, the use of widespread lesions. Podophyllum (20%) in tincture of
mercury in medicine is considered to be outdated. benzoin is still indicated for iso la ted venereal warts
However, attention should be paid to the possibility of (Chamberlain et a1. 1972). In many countries, pod-
mercurial poisoning even nowadays, as mercury may ophyllotoxin is replacing podophyllum for efficacy and
still be present in many drugs, even in over-the- toxicity reasons (Beutner and von Krogh 1990).
counter formulations. Although there are considerable
differences between various mercurials regarding the Salicylic Acid
rate of absorption through the skin, all mercurial
preparations are a potential hazard and may cause The general toxicology and percutaneous absorption of
toxicity. Metallic mercury is readily absorbed through salicylates is reviewed by Proudfoot (1990). SA is
intact skin, as is ammoniated mercury chloride in widely used in dermatology as a topical application for
psoriatic patients (Bork et a1. 1973). Before, during and its keratolytic properties. Salicylate poisoning after
after treatment, Young (1960) examined 70 psoriatic topical use of SA has been reported. SA therapy for
patients treated with an ointment containing extensive lesions may be especially dangerous for
ammoniated mercury. Symptoms and signs of mercu- children. An unpublished review by the V.S. Depart-
ment of Health, Education and Welfare, quoted by Steroids

Rasmussen (1979), revealed 13 deaths associated with
the widespread use of SA preparations, and all but Corticosteroids
three occurred in children. In 1952, Young reported 8
fatal cases of salicylate poisoning with symptoms of Topically applied glucocorticosteroids are absorbed
vomiting, tinnitus, stupor, Cheyne-Stokes respiration through the skin (Feldmann and Maibach 1965),
and nuchal rigidity. Von Weiss and Lever (1964) resulting in sufficient quantities in the system to
reported three adults with extensive psoriasis who replace endogenous production. However, iatrogenic
were treated with 3% or 6% SA ointment 6 times daily. Cushing's syndrome resulting from the use of topical
Between the second and fourth days, symptoms of steroids is uncommon. Systemic side effects of topical
salicylism developed in all three patients. The levels of corticosteroids occur more frequently in children than
SA in the serum ranged from 46 mg/wo ml to 64 mg/ adults (Feiwel et al. 1969) and also occur in patients
100 ml. These symptoms largely disappeared within with liver disease, due to reduced metabolism of the
1 day of stopping treatment. The same authors also drug (Burton et al. 1974). The two main causes of
recorded 13 deaths and several non-fatal intoxications, systemic side effects are hypercorticism, leading to an
reported in literature up to 1964, resulting from iatrogenic Cushing's syndrome, and suppression of the
intoxication with SA following application to the skin. hypothalamic-pituitary-adrenal axis (May et al. 1976).
The 13 deaths included 3 patients with psoriasis, 5 cases
of scabies, 3 of dermatitis, 1 of lupus vulgaris and 1 of Sex Hormones
congenital ichthyosiform erythroderma. The most
dramatic account is that of two plantation workers in Topical application of estrogen-containing prepara-
the Solomon Islands who were painted twice daily with tions leads to resorption of these hormones and,
an alcoholic solution of 20% SA and who contracted therefore, to systemic estrogenic effects. Beas
tinea imbricata involving about 50% of the body. The et al. (1969) reported on seven children with pseudo-
victims were comatose after 6 hand dead within 28 h precocious puberty due to an ointment containing
(Lindsey 1968). A case of SA toxicity leading to coma in estrogens (for treatment or prevention of ammoniacal
an adult patient with psoriasis who had been treated dermatitis for aperiod of 2-18 months with two to ten
with 20% SA in petrolatum was also described by daily applications). The most important clinical signs
Treguer et al. (1980). were intense pigmentation of mammillary areola, linea
alba of the abdomen and the genitals, mammary
enlargement and the presence of pubic hair. Three
Selenium Sulfide
female patients also had vaginal dis charge and bleed-
ing. After discontinuation of the drug, all symptoms
Ransone et al. (1973) reported a case of systemic
progressively disappeared in every patient. Pseudo-
selenium toxicity in a woman who had been sham-
precocious puberty has also been observed in young
pooing her hair two or three times weekly for
girls after contact with hair lotions and other sub-
8 months with a selenium sulfide suspension.
stances containing estrogens (Bertaggia 1968). Such
contact has led to gynecomastia in young boys
Silver Nitrate (DiRaimondo et al. 1980; Edidin and Levitsky 1982).
Estrogen cream for the treatment of baldness has also
Ternberg and Luce (1968) observed fatal met- caused gynecomastia, which was persistent in the
hemoglobinemia in a 3-year-old girl suffering from reported case (Gabrilove and Luria 1978).
extensive bums who was treated with silver nitrate
solution. Due to the hypotonicity of the silver nitrate Transdermal Drug-Delivery Systems
dressings, hyponatremia, hypokalemia and hype-
rchloremia may develop, especially in children (Con- Reed and Hamburg (1986) reported a case of cloni-
nelly 1970). Also, loss of other water-soluble minerals dine-patch toxicity in a 9-month-old infant when a
and vitamins may occur. Post-mortem examinations of Catapres trans dermal therapeutic system 1 was inad-
patients treated with silver nitrate have revealed that vertently transferred to hirn while sharing a bed with
silver has been deposited in internaiorgans, showing his father. When the folded-over clonidine patch was
that absorption of silver from topical preparations discovered, less than one-tenth of the patch's surface
does occur (Bader 1966). Excessive use of silver- area was adherent to the skin. Transdermal systems
containing drugs has led to local and systemic argyria contain an excess amount of drug to maintain the
(Marshall and Schneider 1977) and to renal damage needed concentration gradient for drug delivery. Upon
involving the glomeruli with proteinuria (Zech removal, patches still retain a substantial amount of
et al. 1973). active drug (McEvoy 1989), increasing the risk of
toxicity if applied to the skin of an infant or young Alder VG, Burman D, Corner BD, Gillespie WA (1972) Absorption
child and emphasizing the need for proper use and of hexachlorophane from infants' skin. Lancet 2:384-385
American Medical Association (1977) AMA drug evaluations.
disposal of trans dermal drug-delivery systems. Publishing Sciences Group, Littleton
Amin S, Lalüi A, Maibach H (1996) Contact urticaria and the
Miscellaneous contact urticaria syndrome (immediate contact reactions). In:
Marzulli F, Maibach H (eds) Dermatoxicology, 5th edn.
Hemisphere, Washington, pp 485-504
There are many other examples of systemic toxicity Aronow R. Mercury (1990) In: Haddad L, Winchester J (eds)
Clinical management of poisoning and drug overdose.
caused by absorption through the skin. For example, Saunders, Philadelphia, pp 1002-1009
exposure to acrylamide dust in polymer factories, Bader KF (1966) Organ deposition of silver following silver
causing a chronic disease of the nervous system nitrate therapy of burns. Plast Reconstr Surg 37:550-551
(Garland and Patterson 1967). Skin exposure to ethyl- Baker T (1979) The voice of polite dissent. Plast Reconstr Surg
63:262
ene glycol dinitrate during dynamite production Bamford MF, Jones LF (1978) Deafness and biochemical imbal-
results in toxic effects after only a few minutes ance after burns treatment with topical antibiotics in young
children. Report of 6 cases. Arch Dis Child 53:326-329
(Hogstedt and Stahl 1980). Carbon tetrachloride and Baranowski-Dutkiewicz B (1981) Skin absorption of phenol from
2-chloroethanol cause hepatotoxicity and hepatocar- aqueous solutions in men. Int Arch Occup Environ Health
cinogenicity (Kronevi et al. 1979). Glycol ethers, in 49:99
Barlow SM (1987) Reproductive hazards from chemicals absorbed
particular ethylene glycol monoethylene ether, are through the skin. In: Marzulli FN, Maibach HI (eds)
teratogenic and cause menstrual dis orders in women Dermatotoxicology. Hemisphere, New York, pp 597-605
(Barlow 1987). Mint (1995) showed that repeated Barrett DA, Rutter N (1994) Transdermal delivery and the
premature neonate. Crit Rev Ther Drug Carrier Syst 11:1-30
dermal exposure of rats in vivo to dibutyl phthalate Barza M, Goldstein JA, Kane A, Feingold DS, Pochi PE (1982)
caused significant hepatic peroxisome proliferation Systemic absorption of clindamycin hydro chloride after
within 14 days. topical application. J Am Acad Dermatol 7:208-214
Beas F, Vargas L, Spada RP, Merchak N (1969) Pseudoprecocious
puberty in infants caused by adermal ointment containing
estrogens. J Pediatr 75:127-130
Comment Becker LE, Bergstresser PR, Whiting DA, et al. (1981) Topical
clindamycin therapy for acne vulgaris. A cooperative clinical
study. Arch Dermatol 117:482-485
Bennett C (1980) Dimethyl sulfoxide. JAMA 244:2768
This chapter summarizes literature citations and the Bertaggia A (1968) A case of pseudo-precocious puberty in a girl
basic aspects of percutaneous penetration to alert the following the use of an estrogen preparation on the skin.
reader to the potential for systemic toxicity from Pediatria (Napoli) 76:579-585
topical exposure. Demonstrating causality (rather than Beutner KR, von Krogh G (1990) Current status of podophyllo-
toxin for the treatment of genital warts. Semin Dermatol
association) requires careful documentation. Combin- 9:148-151
ing knowledge of the inherent molecular and animal Block R, Beysovec L (1982) Promethazine toxicity through
percutaneous absorption. Contin Pract 9:28
toxicology, cutaneous penetration and metabolism Bork K, Morsches B, Holzmann H (1973) Mercury absorption out
with the adverse-human-reaction literature permits a of ammoniated mercury ointment. Arch Dermatol Forsch
more precise determination of causality. With each 248:137-143
example presented here, the original citations com- Brandwein 1, Keating A (1990) Hematological consequences of
poisoning. In: Haddad L, Winchester J (eds) Clinical man-
bined with the further documentation noted here agement of poisoning and drug overdose. Saunders, Phila-
should permit more discriminate causality judgements. delphia, pp 296-307
The above data focuses the need for controlled studies Bronaugh R, Maibach H (eds) (1990) Percutaneous absorption.
Marcel Dekker, New York
on the toxicity of chemicals that come into contact Bronaugh R, Maibach H (eds) (1991) Percutaneous penetration in
with the skin, either accidentally or deliberately. vitro. Marcel Dekker, New York
Burton T, Cunliffe W, Holti G, Wright W (1974) Complications of
Recent texts emphasizing current approaches and topical corticosteroid therapy in patients with liver disease.
technology are Bronaugh and Maibach (1990, 1991), Br J Dermatol 9:22
Smith and Maibach (1995) and Marzulli and Maibach Cammann R, Hennecke H, Beier R (1971) Symptomatic psychoses
after application of "Kolton-Gelee". Psychiatr Neurol Med
(1996). Psychol (Leipz) 23:426-431
Cassidy DE, Drewry I, Fanning JP (1982) Podophyllum toxicity: a
report of a fatal case and a review of the literature. J Toxicol
Clin Toxicol 19:35-44
References Chamberlain MI, Reynolds AL, Yeoman WB (1972) Medical
memoranda. Toxic effect of podophyllum application in
pregnancy. BMJ 3:391-392
Abrams SM, Degnan TI, Vinciguerra V (1980) Marrow aplasia Clark JA, Kasselberg AG, Glick AD, O'Neill JJ (1982) Mercury
following topical application of chloramphenicol eye oint- poisoning from merbromin (Mercurochrome) therapy of
ment. Arch Intern Med 140:576-577 omphalocele: correlation of toxicologic, histologic, and
Adriani I, Zepernick R (1964) Clinical effectiveness of drugs used electron microscopic findings. Clin Pediatr (Phila) 21:
for topical anesthesia. JAMA 118:711 445-447
Albert T, Lewis N, Warpeha R (1982) Late pulmonary complica- Cocker I, Boobis AR, Davies DS (1988) Determination of the N-
tions with use of mafenide acetate. J Burn Care Rehabil 3 acetyl metabolites of 4,4'-methylenedianiline and 4,4'-meth-
ylene-bis(2-chloroaniline) in urine. Biomed Environ Mass Giard MJ, Uden DL, Whitlock DJ, Watson DM (1983) Seizures
Spectrom 17:161-167 induced by oral viscous lidocaine. Clin Pharm 2:110
Connelly DM. Silver nitrate (1970) Ideal burn wound therapy? N Y Gimenez ER, Vallejo NE, Izurieta EM, et al. (1968) Acute
State J Med 70:1642-1644 alcoholic intoxication by the percutaneous route. Clinical
Cronin T, Brauer R (1949) Death due to phenol contained in and experimental study. Arch Argent Pediatr 66:121-135
FoilleR. JAMA 139:777 Ginsburg CM, Lowry W, Reisch JS (1977) Absorption of lindane
Cullison D, Abele DC, O'Quinn JL (1983) Localized exogenous (y benzene hexachloride) in infants and children. J Pediatr
ochronosis. J Am Acad Dermatol 8:882-889 91:998-1000
Cunningham A (1956) Resorcine poisoning. Arch Dis Child 31:173 Goffinet M (1977) Clinically presumptive toxicity of various ear-
Curley A, Kimbrough RD, Hawk RE, Nathenson G, Finberg L drops. Acta Otorhinolaryngol Belg 31:585-590
(1971) Dermal absorption of hexochlorophane in infants. Goluboff N, MacFadyen D (1955) Methemoglobinemia in an
Lancet 2:296-297 infant. J Pediatr 47:222
Danon A, Ben-Shimon S, Ben-Zui Z (1986) Effect of exercise and Greaves SJ, Ferry DG, McQueen EG, et al. (1975) Serial hex-
heat exposure on percutaneous absorption of methyl salicy- achlorophene blood levels in the premature infant: clinical
late. Eur J Clin Pharmacol 3:49-52 pharmacology of hexachlorophene in newborn infants. N Z
D' Arcy P (1982) Fatalities with the use of a henna dye. Pharm Int Med J 81:334-336
3:217 Haddad L (1990a) Organophosphates and other insecticides In:
Davies JE, Dedhia HV, Morgade C, Barquet A, Maibach HI (1983) Haddad L, Winchester J (eds) Clinical management of
Lindane poisonings. Arch Dermatol119:142-144 poisoning and drug overdose. Saunders, Philadelphia,
Dayal VS, Smith EL, McCain WG (1974) Cochlear and vestibular pp 1076-1087
gentamicin toxicity. A clinical study of systemic and topical Haddad L (1990b) Miscellany. In: Haddad L, Winchester J (eds)
usage. Arch Otolaryngol 100:338-340 Clinical management of poisoning and drug overdose.
De Groot GA, Nater JP, Bleumink E, de JM (1981) Does DNCB Saunders, Philadelphia, pp 1474-1478
therapy potentiate epicutaneous sensitization to non-related Haggerty R (1962) Blue baby due to methemoglobinemia. N Engl
contact allergens? Clin Exp Dermatol 6:139-144 J Med 267:1303
Deichmann W (1949) Local and systemic effects following skin Hall A, Robertson W (1990) Arsenic and other heavy metals. In:
contact with phenol- a review of the literature. J Ind Hyg Haddad L, Winchester J (eds) Clinical management of
31:146 poisoning and drug overdose. Saunders, Philadelphia,
Dei PA, Tanski A (1980) Chemical face peeling-malignant pp 1024-1034
therapy for benign disease? Plast Reconstr Surg 66:121-123 Hedges TD, Kenyon KR, Hanninen LA, Mosher DB (1983)
DiRaimondo CV, Roach AC, Meador CK (1980) Gynecomastia Corneal and conjunctival effects of monobenzone in patients
from exposure to vaginal es trogen cream. N Engl J Med with vitiligo. Arch Ophthalmol 101:64-68
302:1089-1090 Hemels HG (1972) Percutaneous absorption and distribution of
Drake TE (1974) Reaction to gentamicin sulfate cream. Arch 2-naphthol in man. Br J Dermatol 87:614-622
Dermatol 110:638 Hogstedt C, Stahl R (1980) Skin absorption and protective gloves
Dubiel W, Happle R (1972) Experimental treatment with fumaric in dynamite work. Am Ind Hyg Assoc J 41:367-372
acid monoethylester in psoriasis vulgaris. Z Haut Ge- Hosler 1, Tschanz C, Hignite CE, Azarnoff DL (1980) Topical
schlechtskr 47:545-550 application of lindane cream (Kwell) and antipyrine metab-
Edidin DV, Levitsky LL (1982) Prepubertal gynecomastia associ- olism. J luvest Dermatol 74:51-53
ated with estrogen-containing hair cream. Am J Dis Child Hotchkiss SAM, Hewitt PG, Caldwell J (1993) Percutaneous
136:587-588 absorption of 4,4'-methylene-bis-2-chloroaniline and 4,4'-
Edwards DL, Johnson CE (1987) Insect-repellent-induced toxic methylenedianiline through rat and human skin in vitro. In
encephalopathy in a child. Clin Pharm 6:496-498 Vitro Toxicol 7:141-148
EI AE, Ahmed ME, Clague HW (1983) Systemic toxicity of Hotchkiss SAM (1995) Skin absorption of occupational chemicals.
p-phenylenediamine. Lancet 1:1341 In: Handbook of occupational hygiene (instaliment 46).
Ellis CN, Mitchell AJ, Beardsley GJ (1979) Tar gel interaction with Croner, Surrey, pp 1-38
disulfiram. Arch Dermatol115:1367-1368 Jetzer WE, Hou SYE, Hug AS, Duraiswamy N, Ho WFS, Flynn GL
Feiwel M, James VH, Barnett ES (1969) Effect of potent topical (1988) Temperature dependency of skin permeation of
steroids on plasma cortisollevels of infants and children with waterborne organic compounds. Pharm Acta Helv 63:197-201
eczema. Lancet 1:485-487 Johnstone R (1948) Occupational medicine and industrial
Feldmann RJ, Maibach HI (1965) Penetration of 14C hydrocorti- hygiene. Mosby, st. Louis
sone through normal skin. Arch Dermatol 91:661 Kellerhals B (1978) Risk of inner ear damage from ototoxic
Feldmann RJ, Maibach HI (1967) Regional variation in percuta- eardrops. HNO 26:46-52
neous penetration of 14C cortisol in man. J luvest Dermatol Kelly DR, Nilo ER, Berggren RB (1969) Brief recording: deafness
48:181-183 after topical neomycin wound irrigation. N Engl J Med
Feldmann RJ, Maibach HI (1970) Absorption of some organic 280:1338-1339
compounds through the skin in man. J luvest Dermatol Kligman A (1965) Dimethyl sulfoxide - part 2. JAMA 193:151
54:399-404 Kopelman R (1990) Camphor. In: Haddad L, Winchester J (eds)
Feuston MH, Mackerer CR, Schreiner CA, Hamilton CE (1997) Clinical management of poisoning and drug overdose.
Systemic toxicity of dermally applied crude oils in rats. Saunders, Philadelphia, pp 1451-1455
J Toxicol Environ Health 51:387-399 Kronevi T, Wahlberg JE, Holmberg B (1979) Histopathology of
Fisch R, Berglund E, Bridge A, Finley P, Quie P (1985) On skin, liver and kidney after epicutaneous administration of
triclocarban and methemoglobinemia. In: Marzulli F, Mai- five industrial solvents to guinea pigs. Environ Res 19:56-69
bach H (eds) Dermatoxicology. Hemisphere, Washington Lamb JC, Huff JE, Haseman JK, Murphy ASK, Lilja H (1986)
Fisher A (ed) (1986) Contact dermatitis. Lea and Febiger, Carcinogenesis studies of 4,4' -methylene-dianiline dihydro-
Philadelphia chloride given in drinking water to F344/N rats and B6C3Fl
Food and Drug Administration (1976) y Benzene hexachloride mice. J Toxicol Environ Health 18:325-337
(Kwell) and other products alert. FDA Drug Bulletin 6:28 Liebman PR, Kennelly MM, Hirsch EF (1982) Hypercarbia and
Franz TJ (1983) On the bioavailability of topical formulations of acidosis associated with carbonic anhydrase inhibition: a
clindamycin hydro chloride. J Am Acad Dermatol 9:66-73 hazard of topical mafenide acetate use in renal failure. Burns
Fraser GL, Beaulieu JT (1979) Leukopenia secondary to sulfa- Incl Therm Inj 8:395-398
diazine silver. JAMA 241:1928-1929 Lindsey CP (1968) Two cases of fatal salicylate poisoning after
Garland TO, Patterson MW (1967) Six cases of acrylamide topical application of an antifungal solution. Med JAust
poisoning. BMJ 4:134-138 1:353-354
Lundell E, Nordman R (1973) A case of infantile poisoning by Prarnanik AK, Hansen RC (1979) Transcutaneous gamma
topical application of Castellani's solution. Ann Clin Res benzene hexachloride absorption and toxicity in infants and
5:404-406 children. Arch Dermatol 115=1224-1225
Lyons TJ, Christu CN, Larsen FS (1975) Ammoniated mercury Proudfoot A. Salicylates and salicylamide (1990) In: Haddad L,
ointment and the nephrotic syndrome. Minn Med 58:383-384 Winchester J (eds) Clinical management of poisoning and
Maibach H, Boisits E (eds) (1982) Neonatal skin: structure and drug overdose. Saunders, Philadelphia, pp 909-920
function. Marcel Dekker, New York Ramu A, Slonim AE, London M, Eyal F (1973) Hyperglycemia in
Marshali JD, Schneider RP (1977) Systemic argyria secondary to acute malathion poisoning. Isr J Med Sci 9:631-634
topical silver nitrate. Arch Dermatol113:1077-1079 Ransone J, Scott N, Knoblock E (1973) Selenium sulfide intox-
Marzulli F, Maibach H (1975) Relevance of animal models: the ication. N Eng! J Med 9:631
hexachlorophene story. In: Maibach H (ed) Animal models in Rasmussen JE (1979) Percutaneous absorption in children. In:
dermatology. Churchill Livingstone, Edinburgh, pp 156-167 Dobson R (ed) Year book of dermatology. Year Book Medical,
Marzulli F, Maibach H (eds) (1996). Dermatoxicology, 5th edn. Chicago, pp 15-38
Hemisphere, Washington Rasmussen JE (1981) The problem of lindane. J Am Acad
Masur H, Whelton PK, Whelton A (1976) Neomycin toxicity Dermatol 5:507-516
revisited. Arch Surg 1ll:822-825 Reed MT, Harnburg EL (1986) Person-to-person transfer of
May P, Stein EJ, Ryter RJ, Hirsh FS, Michel B, Levy RP (1976) trans dermal drug-delivery systems: a case report. N Engl J
Cushing syndrome from percutaneous absorption of Med 314:1120-1121
triamcinolone cream. Arch Intern Med 136:612-613 Robbins PJ, Cherniack MG (1986) Review of the biodistribution
McDaniel DH, Blatchley DM, Welton W A (1982) Adverse systemic and toxicity of the insect repellent N,N-diethyl-m-toluamide
reaction to dinitrochlorobenzene. Arch Dermatol 118:371 (DEET). J Toxicol Environ Health 18:503-525
McEvoy G (1989) American hospital formulary service drug Rogers SC, Burrows D, Neill D (1978) Percutaneous absorption of
information 89. American Society of Hospital Pharmacists, phenol and methyl alcohol in Magenta Paint BPC. Br J
Bethesda Dermatol 98:559-560
McQueen CAB, Maskinsky CJ, Crescenzi SB, Williams GM (1981) Roskos KV, Maibach HI (1992) Percutaneous absorption and age:
The genotoxicity of 4A'-methylenebis(2-chloroaniline) in rat, Implications for therapy. Drugs Aging 2:432-449
mouse and hamster hepatocytes. Toxicol Appl Pharmacol Roskos KV, Maibach HI, Guy RH (1989) The effect of aging on
58:231-235 percutaneous absorption in man. J Pharmacokinet Biopharm
Milstone EB, McDonald AJ, Scholhamer CJ (1981) Pseudomem- 17:617-630
branous colitis after topical application of clindamycin. Arch Rycroft R (ed) (1995) Textbook of dermatitis. Springer, Berlin
DermatoI117:154-155 Heidelberg New York
Mint A (1995) Investigation into the topical disposition of the Schaefer C, Peters PW (1992) Intrauterine diethyltolu-
phthalic acid esters, dirnethyl phthalate, diethyl phthalate and amide exposure and fetal outcome. Reprod Toxicol
dibutyl phthalate in rat and human skin (Ph.D. thesis) 6:175-176
Imperial College, London Scharpf LG Jr, Hill ID, Maibach HI (1975) Percutaneous penetra-
Mittelman H (1972) Ototoxicity of "ototopical" antibiotics: past, tion and disposition of triclocarban in man: body showering.
present, and future. Trans Am Acad Ophthalmol Otolaryngol Arch Environ Health 30:7-14
76:1432- 1443 Schop RN, Hardy MH, Goldberg MT (1990) Comparison of the
Mofenson HC, Caraccio TR, Miller H, Greensher J (1983) activity of topically applied pesticides and the herbicide 2,4-D
Lidocaine toxicity from topical mucosal application. With a in short term in vivo assays of the genotoxicity in the mouse.
review of the clinical pharmacology of lidocaine. Clin Pediatr Fundam Appl ToxicoI15:666-675
(Phila) 22:190-192 Seiden R, Sasahara AA (1967) Central nervous system toxicity
Moody RP, Ritter L (1989) An automated in vitro dermal induced by lidocaine. Report of a case in a patient with liver
absorption procedure. II. Comparative in vivo and in vitro disease. JAMA 202:908-909
dermal absorption of the herbicide fenoxaprop-ethyl (HOE Siddiqui 0 (1989) Physicochemical, physiological and math-
33171) in rats. In Vitro Toxicol 6:53-59 amatical considerations in optimizing percutaneous absorp-
Murphy SD (1986) Toxic effects of pesticides. In: Klaasen CD, tion of drugs. Crit Rev Ther Drug Carrier Syst 6:1-39
Amdur MO, Doull J (eds) The basic science of poisons, 3rd Silverberg DS, McCall JT, Hunt JC (1967) Nephrotic syndrome
edn. Macmillan, New York, pp 519-582 with use of ammoniated mercury. Arch Intern Med 120:
Murray M (1926) An analysis of sixty cases of drug poisoning. 581-586
Arch Pediatr 43=193 Skoglund RR, Ware LL Jr, Schanberger JE (1977) Prolonged
Nachman RL, Esterly NB (1971) Increased skin permeability in seizures due to contact and inhalation exposure to camphor.
preterm infants. J Pediatr 79:628-632 A case report. Clin Pediatr (Phila) 16:901
Ohlgisser M, Adler M, Ben-Dov D, Taitelman U, Birkhan HJ, Smith E, Maibach HI (eds) (1995) Percutaneous penetration
Bursztein S (1978) Methemoglobinaemia induced by maf- enhancers. CRC, Boca Raton
enide acetate in children. Areport of two cases. Br J Anaesth Solomon LM, Fahrner L, West DP (1977) Gamma benzene
50:299-301 hexachloride toxicity: a review. Arch Dermatol 113:353-357
Olson ML, McEvoy GK (1981) Methemoglobinemia induced by Spencer PS, Bischoff MC (1987) Skin as an entry for neurotoxic
local anesthetics. Am J Hosp Pharm 38:89-93 substances. In: Marzulli FN, Maibach HI (eds) Dermatotox-
Orkin M, Maibach HI (1993) Scabies therapy - 1993. Semin icology. Hemisphere, New York, pp 625-640
Dermatol 12:22-25 Stanley BE, Frank JE (1971) Mercury poisoning from application
Osol A, Farrar GJ (1947) The dispensatory of the United States of to omphalocele. JAMA 216:2144-2145
America. Lippincott, Philadelphia Steele CE, Trasler DG, New DA (1983) An in vivo/in vitro
Owens CJ, Yarbrough Dd, Brackett NJ (1974) Nephrotic syndrome evaluation of the teratogenic action of excess vitamin A.
following topically applied sulfadiazine silver therapy. Arch Teratology 28:209-214
Intern Med 134:332-335 Stewart N, McHugh T. Borates (1990) In: Haddad L, Winchester J
Pannatier A, Jenner P, Testa B, Etter JC (1978) The skin as a drug- (eds) Clinical management of poisoning and drug overdose.
metabolizing organ. Drug Metab Rev 8:319-343 Saunders, Philadelphia, pp 1447-1451
Pines WL (1973) Hexachlorophene: why FDA concluded that Stoll D, King LJ (1980) Disulfiram-alcohol skin reaction to beer-
hexachlorophene was too potent and too dangerous to be containing shampoo. JAMA 244:2045
used as it once was. CAL 36:4-6 Ternberg J, Luce E (1968) Methemoglobinemia: a complication of
Postellon D, Aronow R (1990) Iodine. In: Haddad L, Winchester J the silver nitrate treatment of burns. Surgery 63:328
(eds) Clinical management of poisoning and drug overdose. Thomas A, Gisburn M (1961) Exogenous ochronosis and myxo-
Saunders, Philadelphia, pp 1049-1053 edema from resorcinol. Br J Dermatol 73:378
Treguer H, Le BG, Coloignier M, Le RP, Bernard JP (1980) Percutaneous absorption: mechanisms - methodology - drug
Salicylate poisoning by local application of 20% salicylic acid delivery. Marcel Dekker, New York, pp 335-342
petrolatum to a psoriatic patient. Nouv Presse Med 9:192-193 Wester RC, Noonan PK, Cole MP, Maibach HI (1977) Percuta-
Truppman ES, Ellenby JD (1979) Major electrocardiographic neous absorption of testosterone in the newborn rhesus
changes during chemical face peeling. Plast Reconstr Surg monkey: comparison to the adult. Pediatr Res 1l:737-739
63:44-48 Yeung D, Kantor S, Nacht S, Gans EH (1983) Percutaneous
Von Hinkel G, Kitzel H (1968) Phenolvergiftungen bei Neugebo- absorption, blood levels, and urinary excretion of resorcinol
renen durch kutane resorption. Dtsch Gesundheitswes 23:240 applied topically in humans. Int J Dermatol 22:321-324
Von Roemeling R, Hartwich G, Konig H (1979) Multiple Young E (1960) Ammoniated mercury poisoning. Br J Dermatol
neoplasms after arsenic therapy. Med Welt 30:1928-1929 72:449
Von Weiss J, Lever W (1964) Percutaneous salicylic acid Zackheim H (1994) Topical carmustine (BCNU) for patch/plaque
intoxication in psoriasis. Arch Dermatl 90:614 mycosis fungoides. Semin Dermatol 13:202-206
Wester RC, Maibach HI (1989a) Regional variation in percuta- Zech P, Colon S, Labeeuw R, Blanc BN, Richard P, Perol M (1973)
neous absorption. In: Bronaugh R, Maibach HI (eds) Percu- Nephrotic syndrome with silver deposits in the glomerular
taneous absorption: mechanisms - methodology - drug basement membranes during argyria. Nouv Presse Med 2:
delivery. Marcel Dekker, New York, pp 111-120 161-164
Wester RC, Maibach HI (1989b) Dermal decontamination and
percutaneous absorption. In: Bronaugh RL, Maibach HI (eds)
CHAPTER 6
The Structure of the Human Skin Barrier

B. Forslind
Occupational Hazards and Skin Barrier Function The Horny Layer - Stratum Corneum
Dermal exposure becomes a risk, eventually causing There is an intimate relationship between the archi-
injury and damage, when the stratum corneum is tecture of the corneocyte part of the horny layer and
insufficient to protect the viable epidermis, the dermis the extracellular lipid bilayers. It is conceivable that the
and the body from noxious agents. Although we may Hat corneocytes (thickness of 0.3 11m and diameter of
be prone to regard the integument as a barrier against 30 11m) provide a mechanical scaffold (Fig. 2a) for the
a ho stile environment, it must be remembered that the stacked bilayers of lipids, which occupy the inter-
most important task for human skin is to create a corneocyte spaces (Fig. 2b). Due to an internal rein-
watertight enclosure of the body to prevent water loss. forcement provided by keratin filaments that are
Body-water homeostasis is a strict requirement for oriented mainly in the plane of the very Hat cell
normal physiological function, as uncontrolled loss of (Fig. 2c,d), the corneocytes maintain a mechanieally
water will result in a drastic increase in salt concen- stable form in the plane of the skin surface. The
trations, with consequent harmful effects on the straight keratin filaments are covalently anchored in
physiology of cells and tissues. the pro tein envelope of the corneocyte and each
The actual barrier is located in the horny layer corneocyte is mechanically coupled to its neighbours
since, once this part of the skin has been removed, by special pro tein "rivets", (corneo)desmosomes. The
substances are allowed to diffuse freely into or out of organisation of this internal reinforcement allows the
the body. We may put this fact into perspective by horny layer to swell only in the vertical direction.
noting that man has a large surface area relative to the Recently, Norlen et al. (1997) showed that the hori-
volume enclosed by the integument. Almost 50% of zontal extension is only about 1-3%, whereas the
the body surface covers the limbs in man; this corneocytes may swell more than 25% in the vertical
compares unfavourably to most mammals (Fig. 1), in direction (Fig. 2e). This swelling behaviour ensures
which approximately 10% or less of the integument that the intercellular compartment, in which the lipid
covers the limbs. bilayers reside, will suffer a minimum of distortion in
the horizontal dimensions during swelling. In addition,
surface roughness, which would impair the mechanical
Perspiratio Insensibilis properties of the skin on swelling, is minimised.
The perspiratio insensibilis, i.e. the water loss through

Penetration Pathways into the Skin
the stratum corneum disregarding sweat glands,
amounts to less than 7 ml/m 2 /h, a negligible amount
- indeed, unnoticeable without the aid of sensitive There is today a consensus about penetration pathways
instruments (Nilsson 1977). Normal skin can there- through the skin barrier (Bodde et al. 1990). Under
fore be regarded as effectively watertight. However, a normal conditions, the corneocytes are permeable
loss of barrier function in an area of, e.g. 20 x 20 cm essentially only to water, which implies that the trans-
(the size of two palms), will cause a water loss port route for hydrophilic and hydrophobie substances
comparable with that of an open water surface, more is via the extracellular space of the stratum corneum.
than 100 ml/m 2 /h. Such a loss may endanger survival The lipids of this space are organised in bilayers stacked
and this is actually the main concern with burn on top of each other. The corneocyte envelopes have
injuries. long-chain ceramides covalently bound to their surfaces

The Structure of the Human Skin Barrier 57
CORNEOCrIE
a)
C~
LIPID BILAY
b)
Fig. 1. Surface area of man compared with that of mouse.
Approximately 50% of man's body surface resides over the limbs, CORNEOCYTE
CORNEOCYTE
compared with approximately 10% for the mouse, which can [TOPVlEW)
(SIOEWAY VIEWI
attain a practically spheroid form at rest, thus optimising its

surface-to-volume ratio x y
(Wertz and Downing 1991), whieh renders the eorn-

eoeyte surfaee hydrophobie in eharaeter. Between the
d) EE~!~~~5i1 x~
cl
lipid bilayers, thin water sheets provide a eontinuum,
allowing transport of hydrophilie substanees in the
SWELLED CORNEOCYTE
plane of the bilayer (Fig. 2b). In a eorresponding
manner, hydrophobie substanees are able to diffuse in
the plane of the bilayers and, thus, the intereorneoeyte
spaee enables both hydrophilie and hydrophobie sub- Fig. 2. a The organisation of the corneocytes, mutually fixed by
stanee transport (Engström et al. 1995). Transport desmosomes, provides a scaffold for (b) stacked bilayers oflipids
normal to the bilayer struetures is neeessary for in the intercellular space between corneocytes. c, d The disper-
sion of keratin fibrils in the plane of the skin surface results in an
penetration, and this will be dealt with below. internal reinforcement that stabilises the cell form in this plane.
Transmission eleetron mieroseope (TEM) studies of e This intracellular reinforcement allows expansion of the cell
the stratum eorneum have demonstrated that the only in the direction perpendicular to the skin surface
topmost part eontains eorneoeytes with varying de-
the intereellular lipids (Fartaseh 1997). Tentatively, the
grees of translueeney, i.e. these eells have suffered
stratum eorneum ean thus be divided into three layers:
different degrees of mass loss (Bodde et al. 1990).
the bottom third represents the intaet barrier; the
There is also a loss of desmosome strueture in the
top most third prepares the eorneoeytes for shedding;
stratum eorneum, and patehes of eleetron-dense ma-
and the intermediate part is a transient zone between
terial representing the remains of the extraeellular
the two extremes (Fartaseh et al' 1993; Menon and
lipids are found in the intereorneoeyte spaees. These
Ghadially 1997). The morphologie al TEM studies
findings are the result of enzymatic digestion by
suggest that the intermediate layer is expeeted to have
proteases and lipases present in the stratum eorneum
impaired barrier properties. Still, it represents a two-
(Lundström and Egelrud 1990). The integrity of the
fold lipid-water eompartment type of strueture and
eorneoeyte envelope is eompromised during this
will therefore impede the penetration of hydrophilie
proeess (Bodde et al. 1990), and the interior of the
and hydrophobie substanees via partitioning effeets.
eorneoeytes in the topmost part of the stratum
corneum eontained the metal tracer used in this
experimental penetration study. This finding was not
The Formation of the Human Skin Barrier
repeated in the lowermost layers.
TEM of the deepest part of the stratum eorneum
demonstrates an eleetron eontrast that is more or less In response to the need of ensuring an intaet barrier
homogeneous both with regard to the corneoeytes and despite an always-persisting environment al load on the
58 B. Forslind
EPIDERMIS
~E
/o~~~~e~~~;:~
Area -20 j..lm'
Str granuJosum
I
salce"s ~~
~ ~~
Str spinosum
~w;(l-l/l:<itn 0=-20 ~~aPillaryPJeXa-

Papillary dermis ~.....--; ~
(
Arterial and venous vessels
/ -----~~----
Fig. 3. Cross section of the cellular part of human skin, the (Fartasch et al. 1993). Apparently, immediately after
epidermis. The size of the epidermal cross section is approxi- this process the nucleus and the cytoplasmic nucleic
mately 120 ~m, of which the stratum corneum takes up 10 ~m.
However, the intact lipid barrier is found in the lower third of the acids are disintegrated, the cell membrane is ex-
stratum corneum. The cellular part of the skin is separated from changed for a protein envelope, and the resulting
the connective tissue part, the dermis, by a mechanical support, corneocyte contains essentially only the fibrous kera-
the basal lamina, that allows free diffusion of nutrients and waste
products from the epidermis tin. In fact, this process is so fast that it has not yet
been recorded by TEM.
integument, there is a continuous renewal of cells and
lipids from the viable epidermis, and a continuous
shedding of corneocytes from the surface to ensure a
Skin-Barrier Research of the Past in Brief
constant thickness of the horny layer (Fig. 3). The cell
division of basal cells occurs in an orderly manner
through a number of control mechanisms including, Contact allergy and irritative reactions in the skin
presumably, Ca2+ -triggered channels, so-called "gap initially focused the interest on barrier properties of
junctions" that form interconnections between the the stratum corneum. Later, an interest in understand-
basal cells. The resulting progeny will be metabolically ing how topically administered drugs penetrate the
very active in order to fill the cell with fibrous keratin skin stimulated research on the skin barrier. Pioneer-
and produce other proteins necessary for the differing work of Blank and Scheuplein (1971) suggested that
entiation process. In addition to this protein produc- lipids played an important role in barrier function.
tion, the epidermal keratinocytes synthesise Despite this, it was not until 1975 that Michaels et al.
glycosylated ceramides (Gray and White 1978), which (1975) presented the first barrier model, which has
together with long-chain fatty acids and cholesterol been called the "brick-and-mortar" model. The stra-
esters are stored in membrane-enclosed (lamellar) tum corneum was envisioned as a two-compartment
bodies in the form of bilamellar sheets (Fig. 4). structure in which the lipids represented a hydropho-
Eventually, at the border between the topmost cell bie pathway, whereas the corneocytes with their
layer of the so-called viable epidermis, the stratum content of hydrophilie keratin represented a hydro-
granulosum, and the lowermost stratum corneum cells, philie one. Using this model as his starting point, Elias
these lamellar bodies fuse with the cell membrane and and his co-workers (Elias 1983; Williams and Elias
their content is extruded into the extracellular space 1987) have carried out pioneering work on skin barrier
through the skin barrier have been performed on

DESMOSOME ~--..~~ animal models even though the lipid composition of
LLULAR
the horny layer of most animals is vastly different from
that of the human skin barrier (Hotchkiss 1994). The
only substitute for human skin to be considered thus
far in penetration studies is that of pig (Swartzend-
ruber et al. 1989). This animal is in many respects
closely related to man, e.g. it is an omnivore, has a
LAMELLAR BODY similar basic immunology, has naked skin with a lipid
a) composition that closely mirrors that of human skin,
B
GOLGIAPPARATUS
etc.
The presence or absence of fur is likely to be
responsible for the conspicuous differences in lipid
••i~ --- - __-__---

__
composition and content shown by furry mammals
when compared with humans, "the naked apes". The
isolating properties of fur achieved by effective trap-
ping of air, which has low thermal conductivity, gives
physical and mechanical protection to the skin of
b) ~~~l~ ~m~~ -- ~~~JRm)l~~~ mammals, preventing loss of water and direct access to
the skin by chemical substances.
~ -- (E.0J
cpp < 1 cpp 2 1
Properties of Lipid Bilayers
CR YSTALL1 NE DOMAIN L1QUID CRYSTALU NE
DOMAIN Anormal cell membrane contains lipid bilayers with
an average chain length of 16 or 18 carbons, including a
"
•
xaf~M~rR~ double bond. At normal physiological temperatures
(approximately 20-40 °C), these carbon chains may be
~~lg <td ~l~~ in a liquid state (Singer and Nicholson 1972). Double
A
~ layers of such lipids in the liquid crystalline state will
V & allow water to pass through the membrane more or
less freely (Alberts et al. 1989); a cell membrane is
~~--A"fII_~=~
:"'----"~~--, therefore not a barrier to water. Also, this liquid state
c) will provide the membrane with mechanically plastic
C ~VSTA.l.UNE OOMAIN LIQUID CRYSTAlLINE
OOMAIN properties, allowing a rapid change of form, e.g. endo-
and exocytotic vesicles for uptake or delivery of
Fig. 4. a The lipid-containing lamellar bodies are produced by substances, pseudopodia for movement etc. However,
the Golgi apparatus of the cell machinery. Glycosylated ceramides
dominate the content of these bodies and are organised in bilayers in the closely packed crystalline gel state will
bilayers enclosed by a bilayer membrane. In the final stage of effective1y bar the penetration of water molecules
lamellar-body production, this membrane will fuse with the (IsraelachviIi et al. 1980; Larsson 1994) and, at the
stratum granulosum cell membrane to extrude the bilayer sheaths
into the intercellular compartment. b It is plausible that these same time, form rigid (brittle) structures. It is obvious
lipid units subsequently are joined by lipids in the liquid- from the study of the stratum corneum lipids (Table 1)
crystalline state. Conceivably, the barrier lipids are organised in that the majority will form crystalline structures and
water-impermeable domains joined by interdomain areas in the
liquid-crystalline state (c), which allows water to pass (Fig. 4b hence provide a watertight enclosure.
taken from Engbiom 1996)
The Domain Mosaic Model

function, and his work has had important effects on
our present view of this topic.
It must be emphasised that the brick-and-mortar Our work has been based on the knowledge of the
model is not a structural model but a conceptual one, unique composition of the barrier lipids of the "naked
since it does not take lipid structure into account as a ape" compared with that of furry animals or geneti-
means for explaining the properties of the human skin cally manipulated naked-animal species (Forslind
barrier. This lack of a structure-function concept in 1994, 1995; Forslind et al. 1997). Chromatographic
skin-barrier research may be one reason for the fact analyses of the lipids extracted from human and
that numerous studies on the penetration of substances mammal skins have revealed that human skin is
60 B. Forslind
Table 1. Lipid composition (weight %) of human and porcine stratum corneum (SC)
Swartzendruber Wertz et al. 1987 Norlen et al. 1999 Gray et al. 1982 Wertz et al. 1992
et al. 1988
SC origin Human Human Human Porcine Porcine

Ceramides 41.1 41 47 52.4 39.7
Free fatty acids 9.1 9 (0.7 unsaturated, 11 (saturated) 22.0 11.2
8.3 saturated)
Cholesterol 27 24 20.5 28.4
Cholesterol esters 10.0 10 18 1.4 12.8
Cholesterol sulfate 1.9 1.9 2.0
Triglycerides 0 1.9 1.3
unique with regard to its high content of long-chain sions of low crystallographic order such as a liquid-
ceramides (Gray and Yardley 1975; Gray and White crystalline phase mixed wiili highly ordered crystalline
1978; Yardley and Summerly 1981). In addition to the gel domains in ilie present case. This means iliat if the
ceramides, (mostly saturated) free fatty acids and liquid-crystalline phase occupies less than 20% of the
cholesterol constitute the bulk of ilie barrier lipids. lipid part of the skin, only a very high degree of ordering
The dominance of long-chain ceramides and fatty in iliis part would appear in the diffraction patterns.
acids suggests that the bulk of barrier lipids reside in EngbIom (1996) addressed this problem in his thesis
crystalline gel bilayer domains, which are separated by and found it unlikely for changes to appear in the
an interdomain phase in the liquid-crystalline state. interdomain phase in the X-ray diffraction patterns.
Bearing in mind that TEM studies demonstrate iliat the Correspondingly, it is likely that the water adsorbed in
intercorneocyte bilayers are stacked in multiple layers the lipid compartment is confined to ilie interdomain
(Fartasch 1997; Menon and Ghadially 1997), such phase and, thus, is not detected by X-ray diffraction
mosaics of domains will constitute an essentially although present. The bulk of the water absorbed in
water-tight structure. Any water molecule escaping the stratum corneum will be found in the corneocytes
from the body will have to navigate a meandering way (Norlen et al. 1997). In this context, it is appropriate to
out of the system via the interdomain boundary emphasise iliat the morphological information provid-
regions. A random diffusion path in the interbilayer ed by TEM on stained specimens must be regarded
water sheath will occupy a comparatively long time wiili caution, since the preparation involves dehydra-
compared with a vertical passage through a liquid- ti on using organic solvents and substitution of the
crystalline area to reach the water sheaili separating water phase with plastic. The structural organisation of
the passed bilayer from the next one (Fig. 5). In fact, the barrier lipids in such preparations must therefore
Engström has estimated that if just a few percent of the be compromised to a significant degree.
interdomain areas are transformed, e.g. by a penetra- The morphology of the stratum corneum is also a
tion enhancer to form vertical channels, the overall factor hindering perceptible swelling in ilie lipid
effect on penetration may increase one or more orders compartment. The corneocytes are, as stated above,
of magnitude (Engström et al. 1995). mutually coupled to all neighbours by means of ilie
With ilie present state of art, the evidence for the rigid corneodesmosomes, and this arrangement will
domain mosaic model for the human skin barrier not allow an increased size of the intercorneocyte
remains circumstantial. However, there are several compartment. Rather, corneocyte swelling (up to >25%
reports giving evidence for the presence of a high in the vertical direction) is expected to compress the
degree of ordering of human skin barrier lipids, e.g. by lipid-bilayer stacks. An increased pressure in ilie
means of nuclear magnetic resonance spectroscopy intercorneocyte compartment may force at least some
(Thewalt et al. 1992; Fenske et al. 1994), by differential of the lipids in the liquid-crystalline state into the gel
scanning calorimetry (Guy et al. 1994; Onpipanattakul state (Cheng et al. 1994), ilius making transport
et al. 1994; Cornwell et al. 1997) by infrared spectros- through ilie lipid barrier less likely than normal. This
copy (Mantsch and McElhaney 1991; Moon et al. 1997) may be a tentative explanation for the closure of ilie
and by X-ray diffraction (Bowstra et al. 1991; Bowstra barrier when ilie body is immersed in water.
et al. 1992). The X-ray diffraction studies give no direct In this context, it is of interest to consider recent
support to the presence of a liquid-crystalline phase or a results of a quantitative high-performance liquid
swelling of the lipid phase on excessive hydration of ilie chromatography analysis of lipids from the deepest
stratum corneum. However, it should be borne in mind part of ilie stratum corneum, the stratum compactum.
iliat the X-ray diffraction method actually is insensitive This study shows that the lipid yield after stripping of
to minor perturbations in a mixed system, e.g. inclu- the skin in vivo (Table 1) results in a composition
~'1iWtJ'tl1ßJ!fllJ11IfJ/lWll[
~c""
V
.~~~~~~~~(COR:NEOCYTEENVElOPE
\
, . f!ElR'l!()lf 'I'EIooIUU
a)
n
c> ~ __ -*____________-/
b)
3.5 '1-.,---,--.---.----.--.---.-----,.-,---r----;
...1 3.5
3 -, - -. ,- 3
\. /,
,'1
2.5 2.5
/ "'
,'1
u.. 2 ,'1. 2
er
(Q
W ;/1
Cl ,'1 m
"Tl
.2 1.5 1.5
0.5 0.5
o
·4 -2 o 2
logK
c)
Fig. 5. a Bilayer organisation of the stratum corneum lipids. In domain·mosaic model (left panel). Most of the time is spent in
the corneocyte, a protein envelope has replaced the lipid cell the water tablet separating the stacked bilayers, as schematically
membrane of the cell of the viable epidermis and some lipids are demonstrated in the right panel. c When a fraction Cl of the
covalently bound to this envelope (not represented here). liquid·crystalline phase undergoes a structural transformation
Between the hydrophilie head groups of the stacked bilayers from a lamellar phase to a cubic, hexagonal or micellar phase,
resides a water tablet, within which diffusion transport may take the enhancement factor (EF) is drastically influenced. Here the
place parallel to the skin surface. b A water molecule passing enhancement factor is plotted against the logarithm for the
through the skin barrier is visualised to take a conspicuously lipid-water partition coefficient (redrawn from Forslind et al.
meandering way through the liquid·crystalline zones of the 1997)
62 B. Forslind
pattern (Norh~n et al. 1999) corresponding to that Acknowledgements. Professor Kare Larsson's generous sup-
found in epidermal cysts (Wertz et al. 1987), Le. with a port, advice, and kind interest during the development of the
very low conte nt of contaminating triglycerides (Ta- domain mosaic model should not be underestimated. I have
also enjoyed constructive discussions with Professor Sven
ble 1). Special notice should be given to the fact that
Engström, Dr Johan Engbiom, and Lars Norlen, which have
Norlim's data (Norlen et al. 1999) show a very high resulted in crucial developments of the model. A number of
content of saturated long-chain (;::>:C20) free fatty acids scientific friends, among whom I like to single out the late
(28% by weight). Harry Bodde, have helped me with penetrating discussions of
The role of cholesterol is a somewhat enigmatic one our model. For generous financial support we are indebted to
and a problem that has not been widely addressed in the Swedish Work Environmental Foundation (#94-0414,
the past. In ordinary cell membranes, the unsaturated #95-0289) the Swedish Council for Work life research (#96-
0486, #96-0110) (BF), the Edvard Welander foundation and
phospholipids are compacted by introduction of cho-
the Karolinska Institute funds (BF, LN).
lesterol. However, in lipid films consisting of saturated
lipids, cholesterol may have fiuidising properties
(Friberg, personal communication 1997). In more
References
generalised terms, cholesterol fiuidises lipid gel phases
and stabilises lamellar liquid crystals. In view of the
fact that our re cent data confirm that the free fatty acid Alberts B, Bray D, Lewis I, Raff M, Roberto K, Watson JD (1989)
The molecular biology of the cell, 2nd edn. Garland Publi-
part of human skin lipid extracts contain long-chain cations Inc. New York
saturated species (>C20), one role of cholesterol may Bodde H, van den Brink I, Koerten HK, de Haan FHN (1990)
therefore be to ensure a certain degree of fiuidity in the Visualisation of in vitro penetration of mercuric chloride;
transport through intercellular space versus cellular uptake
interdomain areas. Furthermore, Wennerström (per- through desmosomes. J Controlled Release 15:227-236
sonal communication) holds that cholesterol may act Bowstra JA, de Vries MA, Gooris GS, Bras W, Brusse I, Ponec M
as a lineactant between crystalline gel and liquid- (1991) Thermodynamic and structural aspects of the skin
barrier. J Controlled Release 15:209-220
crystalline phases (surfactant). Bowstra JA, Gooris GS, Salmons de Vries MA, van der Spek JA,
Bras W (1992) Structure of human stratum corneum as a
function of temperature and hydration: a wide angle X-ray
diffraction study. Int J Pharmacol 84:205-216
Conclusions Bowstra JA, Gooris GS, Bras W, Downing DT (1995) Lipid
organisation in pig stratum corneum. J Lipid Res 36:685-695
Cheng A, Hummel B, Mencke A, Caffrey M (1994) Kinetics and
Present-day occupational dermatology is in great need mechanism of the barotropic lamellar gel/lamellar liquid
crystal phase transition in fully hydrated dihexadecyl-
of reliable in vitro systems for analysis of substances phosphatidyl-ethanolamine: a time-resolved X-ray diffraction
that may represent a potential occupational hazard. To study using press ure jump. Science 67:293-303
be able to create model systems for the analysis of Cornwell PA, Barry BW, Bouwstra JA, Gooris GS (1996) Modes of
action of terpene penetration enhancers in human skin;
substance penetration through the human skin barrier differential scanning calorimetry, small angle X-ray diffrac-
and barrier equivalents, modelling is a necessary tion and enhancer uptake studies. Int J Pharmacol 127:9-26
complement to animal experiments. Wehave proposed Elias PM (1983) Epidermal lipids, barrier function, and desqua-
mation. J Invest Dermatol 80:44S-49S
a two-phase structure organisation for the skin barrier, Engbiom J (1996) On the phase behaviour oflipids with respect to
the domain mosaic model, based on the composition of skin barrier function (thesis). Lund University, Sweden
lipids extracted from the horny layer of human skin. Engström S, Engbiom J, Forslind B (1995) Lipid polymorphism -
a key to the understanding of skin penetration. In: Brain KR,
The model that assumes that all barrier lipids are James VI, Walters KA (eds) Proceedings of prediction of
organised in a bilayer configuration represents the percutaneous penetration, (vol 4b). STS Publishing Ltd.,
dominant part of the lipids in the crystalline gel state Cardiff, pp 163-166
Fartasch M (1997) Epidermal barrier in disorders of the skin.
envisioned as domains. Lipids in the liquid-crystalline Microsc Res Tech 38:361-372
state surround such crystalline domains. On theoretical Fartasch M, Bassuskas ID, Diepgen TL (1993) Structural rela-
grounds, our model can be shown to provide a tionship between epidermal lipid lamellae, lamellar bodies
and desmosomes in humans epidermis: an ultrastructural
watertight skin barrier, still allowing the minute leakage study. Br J Dermatol 128:1-9
of water necessary to keep the keratin of the corneocytes Fenske DB, Thewald JL, Bloom M, Kitson N (1994) Models of
hydrated to a level that ensures plasticity of the horny stratum corneum intercellular membranes: 2H NMR of
macroscopically oriented multilayers. Biophys J 67:1562-1573
layer. A lipid construct of this kind will allow penetra- Forslind B (1994) A domain mosaic model of the skin barrier.
tion only via the liquid-crystalline phase, and perturb- Acta Derm Venereol 74:1-6
ing this phase, e.g. by introduction of a penetration Forslind B (1995) The skin: upholder of physiological homeosta-
sis. A physiological and biophysical study program. Thromb
enhancer, may result in an increase in trans dermal Res 80:1-22
transport by several orders of magnitude. The model Forslind B, Engström S, Engbiom J, Norlen L (1997) A novel
also satisfies mechanical/physical requirements on a approach to the understanding of human skin barrier
function. J Dermatol Sci 14:115-125
tight barrier, allowing mechanically satisfactory re- Gray GM, White RJ (1978) Glycosphingolipids and ceramides in
sponses from the lipid structures under tensional stress. human and pig epidermis. J Invest Dermatol 70:336-341
Gray GM, Yardley HJ (1975) Lipid compositions of cells isolated corneum liped content related to physical parameters of skin
from pig, human, and rat epidermis. J Lipid Res 16:434-440 barrier function in vivo. J Invest Dermatol 112:72-77
Guy CL, Guy RH, Golden GM, Mak VHW, Francoeur ML (1994) Ongpipanattanakul B, Francoeur ML, Potts RO (1994) Polymor-
Characterisation of low-temperature (i.e. <65°C) lipid phism in stratum corneum lipids. Biochem Biophys Acta
transitions in human stratum corneum. J Invest Dermatol 1190:115-122
103:233-239 Scheuplein RJ, Blank IH (1971) Permeability of the skin. Physiol
Hotchkiss S (1994) How thin is your skin. New Scientist 1910: Rev 51:702-747
24-27 Singer SJ, Nicholson GL (1972) The fluid mosaic model of the
Iraelachvili JN, Marcelja S, Horn RG (1980) Physical principles of structure of cell membranes. Science 175:720-731
membrane organisation. Q Rev Biophys 1J;121-200 Swartzendruber DC, Wertz PW, Kitko DJ, Madison KC, Downing
Larsson K (1994) Lipids - molecular organization, physical DT (1989) Molecular models ofthe intercellular lipid lamellae
function and technical application. Oily Press, Dundee, U.K. in mammalian stratum corneum. J Invest Dermatol 92:
(Oily Press Lipid Library, vol 5) 251-257
Lundström A, Egelrud T (1990) Cell shedding from human Thewalt J, Kitson N, Araujo C, MacKay A, Bloom M (1992)
plantar skin in vitro: evidence that two different types of Models of stratum corneum intercellular membranes: the
protein structures are degraded by a chymotrypsin-like sphingolipid headgroup is a determinant of phase behaviour
enzyme. Arch Dermatol Res 282:234-237 in mixed lipid dispersions. Biochem Biophys Res Commun
Mantsch HH, McElhaney RN (1991) Phospholipid phase transi- 188:1247-1 2 52
tions in model and biological membranes as studied by Vicanova J, Boelsma E, Mommaas AM, Kempenaar J, Forslind B,
infrared spectroscopy. Chem Phys Lipids 57:213-226 Pallon J, Egelrud T, Koerten HK, Ponec M (1998) Normal-
Menon G, Ghadially R (1997) Morphology of lipid alterations in ization of epidermal calcium distribution profile in reconsti-
epidermis. A review. Microsc Res Tech 37:180-192 tuted human epidermis is related to improvement of terminal
Michaels AS, Chandrasekaran SK, Shaw JE (1975) Drug penetra- differentiation and stratum corneum barrier formation.
tion through human skin: theory and in vitro experimental J Invest Dermatol111:97-106
measurements. AIChE J 21:985-996 Wertz PW, Downing DT (1991) Epidermal lipids. In: Goldsmith
Moore DJ, Rerek ME, Mendelsohn R (1997) Lipid domains and LA (ed) Physiology, biochemistry, and molecular biology of
orthorhombic phases in model stratum corneum: evidence the skin, 2nd edn. Oxford University, Oxford, U.K.,
from Fourier transform infrared spectroscopy studies. Bio- pp 205-236
chem Biophys Res Commun 231:797-801 Wertz PW, Schwartzendruber DC, Madison KC, Downing DT
Nilsson GE (1977) On the measurement of evaporative water loss. (1987) Composition and morphology of epidermal cyst lipids.
Methods and clinical applications. Linköping University J Invest Dermatol 89:419-425
Medical Dissertations No. 48, Linköping Williams ML, Elias PM (1987) The extracellular matrix of stratum
Norlen L, Emilson A, Forslind B (1997) Stratum corneum corneum: role of lipids in normal and pathological function.
swelling. Biophysical and computer assisted quantitative Crit Rev Ther Drug Carrier Syst 3:95-122
assessments. Arch Exp Derm 289:506-513 Yardley HJ, Summerly R (1981) Lipid composition and metab-
Norh~n L, Nicander I, Lund-Rozell B, Ollmar S, Forslind B (1999) olism in normal and diseased epidermis. Pharmacol Ther
Inter- and intra-individual differences in human stratum 13:357-383
CHAPTER 7
Evaluation of Barrier Function and Skin Reactivity

in Occupational Dermatoses
S. Seidenari
Introduction skin surface are not only based on personal charac-

teristics but are also media ted by the environment,
since the skin responds to environmental aggression
A complex interplay of exogenous risk factors and the
with modifications of its barrier properties, thus
endogenous disposition is believed to be responsible
modulating the response to further stimuli. Therefore,
for the occurrence and course of irritant contact
a periodical evaluation of skin-barrier function during
dermatitis (ICD) in humans. To prevent its appear-
occupational exposure may represent a method suit-
ance, determinants of disease development, also
able not only to identify subjects at risk because of
known as risk factors, must be identified.
their intrinsic attributes, but also to evaluate the
Besides identification of job-related aspects like
impact of environmental threats on the skin.
frequent exposure to irritants, knowledge of the host-
The induction of experimental dermatitis by means
related predisposing components in risk groups rep-
of model irritants represents a method for reproducing
resents an important tool for prevention. This can be
ICD in a standardized way and can be employed both
achieved both by epidemiological observations and by
for evaluating skin reactivity in high-risk subjects and
employing experimental conditions reproducing envi-
for monitoring the response and adaptation to the
ronmental exposure to skin-damaging substances.
occupational milieu. Skin reactivity to exogenous
The major endogenous predisposing factor is atopic
substances may vary with respect to both the intensity
dermatitis (AD). The atopic constitution interacts with
and course of barrier damage and the inflammatory
allergic and irritant influences, modulating the occur-
response. Transepidermal water loss (TEWL) and
rence and course of the dermatitis localized to parts of
capacitance measurements and instrumental evalua-
the body exposed to exogenous influences, particularly
tion of skin blood flow, erythema and edema represent
the hands. However, a considerable number of subjects
the methods for the quantification of different aspects
with a personal history of AD manage to work in risk
of experimentally induced irritation.
occupations without developing hand eczema. There-
fore, a reduced resistance to irritants does not occur in
all subjects with atopic eczema and may occur in non-
Skin Lipids and the Barrier
atopics. Other constitutional factors not fully identified
so far may playa more important role than the atopic
condition. The role of quantitative and qualitative During the last decade, the essential role oflipids in the
alterations of skin lipids has been recently highlighted regulation of stratum corneum (SC) barrier function
by experimental evidence obtained in non-atopic and in the water-holding properties of the SC has been
populations. These alterations, possibly associated to thoroughly investigated (Imokawa and Hattori 1985;
other constitutional deficiencies, result in an impaired Imokawa et al. 1989; Elias and Menon 1991; Elias and
barrier function. However, one must be careful not to Feingold 1992). Removal of lipids from the SC by
be to restrictive with respect to job selection, especially solvent extraction leads to a pronounced increase in
considering the possibilities of medical guidance with TEWL (Grubauer et al. 1989). Skin repair is associated
instructions on how to minimize the risk of irritant with proliferation of basal keratinocytes and lipid
exposure. A periodical medical examination including synthesis. An increased TEWL, which expresses a
evaluation of skin barrier conditions could represent a defect in the integrity of skin function, also represents
suitable compromise for subjects belonging to high- a stimulus to barrier repair and increased synthesis of
risk groups. lipids by keratinocytes (Grubauer et al. 1989). After
Skin defense mechanisms impeding the penetration barrier recovery, lipid synthesis returns to the normal
of toxic substances and neutralizing their action on the rate (Grubauer et al. 1989). Both glycosphingolipids

Evaluation of Sarrier Function and Skin Reactivity in Occupational Dermatoses 65
and ceramides of intercellular lipids undergo some hydrolyzed to release sphingosyl phosphatidilcholine,
degradation, releasing sphingosine, which controls a proinflammatory agent and potent modulator of
proliferation of the basal cells (Wertz and Downing epidermal functions (Murata et al. 1996). On examin-
1990). Recent studies have defined the sequence of ing the skin of 47 patients with AD, we found an
metabolie and subcellular events leading to recovery inverse correlation between ceramide-3 levels and
after acute barrier perturbation (Elias and Menon 1991; barrier impairment, as measured by TEWL (Di Nardo
Feingold 1991; Elias and Feingold 1992). After a rapid et al. 1998) (Fig. 1). Patients with no active signs of
secretion of preformed lamellar bodies by stratum eczema had anormal barrier function and intermedi-
granulosum, an increase in lipid synthesis and the ate values of ceramides and cholesterol when com-
formation of new lamellar bodies lead to further pared with normal subjects and AD patients with
secretion of lamellar bodies with reconstitution of SC active lesions. These findings suggest that a decrease in
intercellular lamellar bilayers. ceramides in the SC is involved in barrier impairment
The levels of SC ceramides vary according to age, in AD.
sex, race and extern al environment and can influence
barrier function, water content and, ultimately, skin
condition. Senile xerosis is based on an age-related Exogenous Influences on Skin Lipids
decline in lipid levels (Rogers et al. 1996) due to both
reduced epidermal lipid biosynthesis and increased
Exogenous substances vary in their early effects on the
activity of ceramidase (Jin et al. 1994). In females, a
epidermis and in the endogenous substances released,
significant increase was shown in ceramide-l and -2,
although the macroscopic changes they cause may
with a corresponding decrease in ceramide-3 and -6
seem very similar. However, depletion of lipids is
from prepubertal age to adulthood (Denda et al. 1993).
considered a fundamental mechanism in barrier
Female hormones may have an influence on the
damage. Fulmer and Kramer reported that surfact-
composition of SC sphyngolipids, since age-related
ant-induced perturbation of keratinization leads to
differences in SC lipid content are reported to be
abnormal ceramide biosynthesis and that the propor-
limited to women (Denda et al. 1993). The ethnic
tion of ceramide species is significantly altered,
background was studied by Reinertson and Wheatley,
although the total amount of ceramide does not
who found a greater percentage of lipids in the SCs of
change (Fulmer and Kramer 1986).
African-American subjects than in white subjects
Fartasch investigated the ultrastructural changes of
(Reinertson and Wheatley 1959). Recently, however,
epidermal lipids resulting from the topical application
Sugino et al. reported that ceramide levels were lower
of sodium lauryl sulfate (SLS) and absolute acetone
in African Americans, compared with other racial
(Fartasch 1997). SLS caused cell damage to the
types (Sugino et al. 1993). Rogers et al. studied the
nucleated cells of the epidermis, with disturbance of
influence of the season on SC lipids. Decreases in all
lamellar body lipid extrusion and transfer into the lipid
major lipid classes on three body sites were described
bilayers. However, the upper portions of the SC
during the winter months (Rogers et al. 1996). Al-
displayed intact intercellular lipid layers. With acetone
though the levels of ceramide subtypes were un-
treatment, the lamellae showed disruption and loss of
changed, the amount of linoleate esterified to
ceramide-l was reduced. TEWL increase induced by
exposure to hard water was correlated to reduced lipid 30
content (Parish 1992). Changes in skin surface tem- 0
perature also change or modify the lipid barrier; the 25 r= - 0.31

0
lipids are in asolid or crystalline gel state at low 0
temperatures and are converted to a more fluid liquid ... 20

crystal as the temperature increases (Halkier-S0rensen ~
and Thestrup-Pedersen 1991; Halkier-S0rensen et al. "' 15
0
1995). In patients with AD, decreased levels of

'" 0
0
10
ceramides in SC and abnormalities in epidermal lipid
metabolism may be responsible for the changes in the 5
physiological parameters of the skin and barrier-
function impairment (Imokawa et al. 1991; Schäfer 0
and Kragballe 1991). Reduced levels of ceramides in 0 0.5 1.5 2.5 3 3.5
atopics have been linked to an altered expression of the CER3

enzyme sphingomyelin acylase (Murata et al. 1996).
Fig. 1. Correlation between ceramide 3 levels and transepidermal
Moreover, skin inflammation appears to be partly due water loss values in 47 subjects with atopic dermatitis. Correla-
to altered metabolism of sphingomyelin, which is tion coefficient r = -0.31
66 S. Seidenari
cohesion at all levels of the Sc. However, a 3-week 4% cluded that skin lipids, and especially ceramide levels,
glycolic acid treatment did not induce any alteration in may play a protective role with respect to irritant
the lamellar-body secretory system in the stratum substances. In fact, the finding of subpopulations
granulosum and the intercellular lipid lamellae in the reacting differently to the application of irritant
SC (Fartasch et al. 1997). The results of these studies substances is not rare and is also observable with
suggest that different irritants induce distinct and other irritant substances. Twenty-four-hour patch
characteristic alterations in skin lipids, reflecting the testing with 4% NaOH allowed a subdivision of
specific interaction with the epidermal permeability subjects into normal- and hyper-reactors (Seidenari
barrier. et al. 1995). The latter showed an enhanced inflamma-
Cold exposure after barrier abrogation inhibits the tory response and more pronounced barrier-function
normal formation and secretion of lamellar bodies, damage, as assessed clinically and instrumentally. In
with a marked decrease in the return of lipids in the SC this case, too, ceramide levels differed significantly in
and a delay in barrier recovery. In a study performed these two groups (Di Nardo et al., unpublished data).
on hairless mice, Halkier-S0rensen et al. induced a Based on the results of these studies, we can deduce
barrier disruption with topical acetone and exposed that the analysis of baseline skin lipid composition
the treated skin to ice for some hours (Halkier- may serve for the identification of subjects with a
S0rensen et al. 1995). Although TEWL values immedi- proclivity to ICD, with practical implications for
ately after cold exposure were low, TEWL increased workers engaged in at-risk occupations.
when skin temperature reverted to normal. Electron
microscopy revealed transient alterations of lamellar
bodies, whereas histochemical studies showed a de- Time Course of Barrier Impairment
layed appearance of SC intercellular lipids following in Acute and Cumulative ICD
cold exposure.
Agents, such as surfactants, play an important role in
the majority of ICD cases. SLS is frequently employed
Skin Lipids and Susceptibility to Irritation
to simulate acute irritant damage to the skin. After a
single application of SLS, a concentration-, applica-
The amount of skin lipid represents an important tion-time- and skin-site-dependent impairment of the
factor in susceptibility to irritation. Percentage of lipid barrier is observed. If patches are re-applied on the
weight is a more important prediction of barrier same site, skin reactivity may vary owing to previous
function than SC thickness or cell layers (Elias et al. exposure influencing the skin. Thus, under experi-
1981). Thune et al. studied non-atopic elderly patients mental conditions, we can expect different phases
with dry skin and evaluated local effects of cleansing whose length and course depend both on the irritant
products and emollients (Thune et al. 1988). The employed and pre-exposure barrier function, i.e. a first
authors found that high TEWL values are frequently phase where the damage is induced, a second phase
correlated with high pH, low hydration of the SC and with clinical symptoms and ongoing repair, a third
reduced skin-surface lipid content, as evaluated by subclinical phase with further repair, and a final phase
photometric measurements. Di Nardo et al. studied the with barrier restitution, where the memory of the
relationship between baseline ceramide composition preceding aggression is preserved for a certain period.
and the intensity of SLS-induced ICD, as evaluated by The major factor in skin diseases caused by exog-
TEWL and colorimetry (Di Nardo et al. 1996a). SC enous substances is the repeated and cumulative action
lipids were isolated from SC sheets obtained from the on the skin of agents in weak irritant solutions. The
volar forearm by a single stripping with cyanoacrylate repeated exposure to surfactants represents a model
resin and analyzed by thin-Iayer chromatography and for the induction of ICD (Tupker et al. 1989a). During
densitometry. A correlation between colorimetric a* the course of the exposure (patch test applied twice
values and ceramide-6I and between TEWL and daily for 3 weeks), a progressively damaging clinical
ceramide-1 levels was observed. The same authors effect accompanied by an increase in TEWL (due to a
employed a 24-h application of xylene and toluene to cumulative action of these agents on the skin) is
induce acute irritation (Di Nardo et al. 1996b) On observable.
comparing values of the different classes of lipids with
clinical irritation parameters, a negative correlation Skin Hardening
was obtained. Based on clinical observations, two
populations were selected: less reactive and hyper- Hardening describes a situation with adaptation and
reactive, which also differed in the total weight of possible recovery in spite of continuous exposure to
lipids, ceramides and triglycerides. The authors con- irritant substances. It may be ascribed both to epider-
Evaluation of Barrier Function and Skin Reactivity in Occupational Dermatoses 67
mal phenomena, such as a hyperkeratotic re action of skin, which showed detectable modifications after the
the epidermis (Widmer et al. 1994) and to down- second application of the irritant.
regulation of inflammation (Rietschel 1995). Injection In a study analyzing the influence of repeated low-
of bradykinin and histamine on accommodated skin dose irritant exposure on individual susceptibility to
sites induced less weal and flare with respect to normal develop acute non-specific skin reactions, Lam-
sites, indicating that the axon reflex-mediated events mintausta et al. showed that repeated open SLS
are blunted in accommodation (Rietschel 1995). Em- applications at one skin site induced a post-irritant
ploying SLS with a 3-week application procedure, no hyporeactive state at a different site 6 weeks later
further increase in TEWL was observed by Widmer (Lammintausta et al. 1987). Widmer et al. studied
et al. during the third week of irritation (Widmer et al. post-irritation irritant reactivity by assessing the
1994). In fact, a slight decrease was observed. Hard- response to SLS on previously irritated sites (Widmer
ening appears to be related to the irritant substance et al. 1994). Cumulative ICD was induced on fore arm
(and possibly to irritation modalities) and to consti- skin by repeated occluded application of 0.5% SLS 1 h
tutional factors. In a study by Rietschel where maleic per day over 3 weeks. Previously treated and untreated
acid 20% was applied to one forearm daily for 6 weeks, control sites were challenged with 2% SLS 3, 6 and
only five out of 50 subjects were deemed to have 9 weeks later. A significant hypo-reactivity of previ-
accommodated (with normal clinical status of treated ously irritated skin, as expressed by clinical scores,
skin). The remainder had varying degrees of inflam- TEWL and capacitance values at 6 weeks and 9 weeks,
mation or hyper-irritable skin. Reactivity to other was observed. This hypo-reactivity was in no way
irritants was lower in the accommodated than in the indicated by clinical inspection of pre-treated areas,
inflamed group. However, the accommodated forearm nor by baseline TEWL and capacitance, which showed
was not as resistant to irritation as the untreated no significant differences from untreated sites; instead,
normal skin; the number of subjects reacting with the hypo-reactivity became evident only after a re-
normal skin was lower than that of subjects reacting challenge with the irritant. Possible explanations for
with accommodated skin. persistent alterations of epidermal barrier function
after cumulative ICD are changes in the composition of
Post-Irritation Irritant Reactivity SC lipids (Proschk 1990) and/or reactive hyperkerato-
sis (Van der Valk and Maibach 1990) similar to what
Despite the frequency of ICD, very little is known about has been described after ultraviolet (UV) irradiation
the duration of barrier-function alteration and skin (Lehmann et al. 1991). Lehmann et al. observed that
memory following skin irritation. Freeman and Mai- the skin becomes more resistant to irritants after UV
bach performed 2% SLS patch tests in human volun- exposure and ascribed this kind of hypo-reactivity to
teers and evaluated the response instrumentally an increase in SC thickness and lipid level (Lehmann
(Freeman and Maibach 1988). After 1 week, patch tests et al. 1991).
were repeated on the same site. Although the skin had From a practical point of view, post-irritative hypo-
returned to normal before the second patch test, an reactivity probably represents another aspect of skin
augmented response to irritation was generally seen, as adaptation to environmental influences. Whereas
evaluated by TEWL. These results show that, following post-irritant hyper-reactivity would explain the great-
acute ICD, there is still hyper-reactivity of the skin after er irritability of eczematous skin during patch testing,
1 week of irritant avoidance in spite of a clinically a hypo-reactive state may cause false negative patch-
normal aspect of the skin and the normalization of test results for as long as 9 weeks after an irritant
water loss. The clinical implications are that, although re action.
the skin may seem healed, it may not be functionally
normal. Healed ICD may flare again after exposure to
mild irritation, such as hand washing. The repetition of Dermatitis and Skin Hyper-Irritability
the same stimulus or a combination of several different
stimuli may surpass a criticallevel and cause a clinically
detectable ICD. Tur et al. demonstrated that very low Barrier Function and Skin Reactivity
concentrations of irritants alter the skin barrier, as in Non-atopic Eczema
evaluated by bio engineering methods, making the skin
susceptible to a further insult with even lower concen- At eczematous skin sites, barrier impairment is well
trations (Tur et al. 1995). The authors employed two demonstrated by an increase in TEWL values. In non-
consecutive 24-h patch tests with different irritants at atopic eczematous patients, basal barrier function and
concentrations lower than the minimal irritant dose. skin reactivity at healthy skin sites vary according to
Whereas the effects induced by the first patch test were the activity of eczema. When skin lesions are present,
not instrumentally detectable, irritants did alter the barrier impairment is also evident at healthy skin sites.
68 S. Seidenari
TEWL values on the forearms in non-atopie niekel- et al. showed that responses to patches wiili a mar-
sensitive patients with circumscribed areas of eczema ginally irritant concentration of SLS applied elose to
in a chronic phase of the disease were significantly strongly positive allergie patch-test reactions were
higher with respect to healthy subjects (Seidenari significantly enhanced wiili respect to SLS reactions
1996). In apparently normal skin, a lowered tlueshold induced by patches applied on more distant sites
to stimuli is observed in the acute phase of eczema (Bruynzeel et al. 1983). The enhancement of a skin-test
(Bjornberg 1974; Mitchell 1975; Hamami and Marks reaction by an adjacent strong reaction is known as
1988), possibly mediated by cytokines (Pasche-Koo spillover (Mitchell1977). This observation emphasizes
and Hauser 1992). In non-atopie eczema, when the iliat ilie risk of false positive reactions in the direct
dermatitis has healed, baseline barrier function and neighbourhood of strong positive patch-test reactions
reactivity to irritants revert to normal, unlike AD. is higher. Soluble infiammatory factors iliat diffuse
When patients with inactive or healed eczema were from the strong patch-test reaction into ilie surround-
considered, baseline TEWL measured on the forearm ing skin are supposed to be involved. Therefore, a
or upper arm was not significantly different from that slight irritation in such an area may be enhanced by
in controls (Van der Valk et al. 1985; Agner 1991a). these factors (Bruynzeelet al. 1983).
Bjornberg found that a constitutional increase in skin If the excited skin syndrome phenomenon is hapten-
reactivity to primary irritants was not present in related, this has not been elucidated. However, Ander-
patients with healed hand eczema when tested on skin sen et al. employed adjacent nickel sulfate patch tests
distant from ilie hands (Bjornberg 1974). Susceptibility at different dilutions to study boili the dose-response
to SLS-induced irritant dermatitis was evaluated by the relationship for nickel sulfate among nickel-sensitive
application of a single 24-h SLS patch test to ilie upper patients and the nickel-sulfate-related angry back
arm by Agner in eczematous patients (Agner 1991a). phenomenon (Andersen et al. 1993). Strong reactions
No difference in TEWL after exposure to SLS was at high concentrations of nickel sulfate did not
found in patients with chronic or healed eczema as enhance the response to adjacent lower concentrations
compared to controls, while patients with acute eczema of nickel sulfate, and ilie spillover effect was not
showed an increased skin reactivity. significant.
Various researchers have suggested that pre-existing
Skin Reactivity in Eczematous Patients eczema could be an explanation for the findings of
and Patch-Test Responses false positive reactions. Geiger reported that, when he
applied 60% turpentine solution to eczema patients
Dermatitis localized to one skin site can have an and controls, 90% of eczema patients reacted, com-
enhancing effect on epieutaneous test reactions else- pared with only 6% of normal controls (Geiger 1929).
where. Therefore, if the dermatitis has not healed or if Grolnick demonstrated that ilie skin of the site of
at least the test area is not elear of dermatitis, the patch eczema is more reactive ilian normal skin; he re-
test should not be applied. Otherwise, it could easily challenged a healed challenge site wiili an allergen to
produce an isomorphie irritant effect, giving a false which his patients were not allergie and obtained
positive result (Bandmann and Agathos 1981). Even a positive reactions (Grolnick 1948). Kligman and Go-
strong positive patch test reaction may induce skin llhausen failed to demonstrate an enhancement of
hyper-reactivity and other false positive reactions reactions to irritants and allergens in the presence of
during the same test procedure. By performing re- strongly positive allergie reactions (Kligman and
testing on 35 patients with multiple positive responses Gollhausen 1986). In two different experiments, the
to the first patch test series, employing all positive authors applied SLS and benzalkonium chloride patch
substances simultaneously at day 7, 42% of ilie tests to the skin of ilie backs of Rhus- and din-
reactions were lost (Mitchell 1975). In contrast, in itrochlorobenzene-sensitive volunteers. No variation in
Bandmann and Agathos' series, only 8.6% of positive the intensity of skin reactions to irritants at 24 h was
reactions were lost at re-testing. The authors believed observed in the presence of very strong allergie
iliat iliese different figures could be attributed to ilie reactions. Similarly, the intensity of reactions to niekel
fact that patch testing was performed with subsequent sulfate in nickel- and Rhus-sensitive women was not
single tests when the back was completely elear of increased by concomitant testing. Moreover, no evi-
dermatitis. The term "excited skin syndrome" indi- dence of spillover was found. The authors coneluded
cates that the whole skin may be involved (Maibach that it is the pre-existing dermatitis and not one or
1981). The distance between the infiamed skin and the more strongly positive patch-test reactions that makes
test site is not important for skin hyper-reactivity, ilie skin hyper-irritable.
according to some auiliors (Bandmann and Agailios Memon and Friedman investigated wheilier the
1981), but others reported that elose proximity may angry back syndrome is a generalized state of hyper-
enhance skin reactivity (Maibach 1981). Bruynzeel reactivity of the skin or if it is localized only in elose
proximity of a strong patch-test reaction (Mernon and more pronounced at clinically uninvolved skin areas
Friedman 1996). However, their studies failed to when eczematous skin lesions are present, whereas the
demonstrate any generalized or localized change in hydration state of the epidermis and permeability to
the reactivity of the skin, and the authors concluded water show a tendency to normalization in the silent
that the angry back syndrome is a rare and individual- phase of the disease. In fact, when biophysical data
specific phenomenon. referring to the clinically uninvolved skin of children
with AD were divided into two groups according to the
presence of active dermatitis at the moment of the
Barrier Function and Skin Hyper-Reactivity
investigation, significant differences were observed
in Atopic Eczema
between patients with and without skin lesions; in the
former group, TEWL and pH values were higher and
From an operational point of view, AD can be defined capacitance values lower with respect to values in the
as "an inherited defect of skin barrier function, in latter group (Seidenari and Giusti 1995) (Fig. 2).
which there is a decreased resistance to irritants and an Increased susceptibility to irritant stimuli has been
increased susceptibility to asthma, hay fever and described in AD, owing to impairment of barrier
dermatitis" (Adams 1993). Recent studies show that function (higher pre-exposure TEWL) and possibly to
the onset in more than 20% of cases is after the age of atopic immune disregulation. Skin hyper-reactivity is
20 years (Diepgen and Fartasch 1992). Frequently, the proportional to the degree and extent of the dermatitis.
first manifestation in these persons with late-occurring In uninvolved skin in dermatitis patients, Shahidullah
atopy is hand eczema that appears a few weeks after et al. demonstrated reduced barrier function related to
they begin their first job, especially if the work involves the severity of the dermatitis on another body region
exposure to irritants (Rystedt 1985). Eczematous skin in (Shahidullah 1969). Tupker et al. employed a scoring
the atopic differs from uninvolved skin, as it features system enabling the subdivision of AD patients into
higher TEWL values and lower hydration values (Rajka four groups. A positive correlation between the der-
1974; Abe et al. 1978; Werner and Lindberg 1985). matitis severity score and epicutaneous irritant sus-
Increased pH values are also observable (Seidenari and ceptibility was demonstrated (Tupker et al. 1995). We
Giusti 1995). Ultrasound reveals an increase in skin measured TEWL and capacitance values at eight
thickness and a decrease in skin echogenicity at different skin sites in 48 children with AD and
affected skin areas (Seidenari 1998). At healthy skin evaluated, using the scoring index for AD (SCORAD)
sites, an increased TEWL (Rajka 1974; Abe et al. 1978; scoring system, the extent of the dermatitis, severity
Werner and Lindberg 1985; Van der Valk et al. 1985; and subjective symptoms. A fair correlation was
Agner 1991b; Seidenari and Giusti 1995; Conti et al. observable between TEWL and capacitance values (as
1996), associated to decreased hydration values (Be- evaluated as mean values from eight different skin sites,
rardesca et al. 1990; Seidenari and Giusti 1995) and minimum values and forearm values) on one side and
impaired water-retention capacity (Berardesca et al. extension of the dermatitis (according to the rule of
1990), is observable. Alterations ofbarrier function are nine) and SCORAD values on the other side (Table 1).
Fig. 2. Transepidermal water loss (g/m 2 h) g1m' h A.u.

and capacitance (A. U., arbitrary units) , ------------------------,-------------------------r 70
mean (±standard deviation) values in 186 14
children with atopic dermatitis (AD) and in
38 healthy age- and sex-matched control
subjects. Values referring to uninvolved 12
skin sites in children without skin lesions at
the moment of the investigation differ from 10 60
those of AD children with active dermatitis
8
6
50
4
o --'--------"------'-- 40
c::::::J healthy skin 01 control subjects ~ uninvolved skin 01 AD patienlS without skin leslons
lIlIIlIIl uninvoiVed skin 01 AD paUents wi th skin lesions

70 S. Seidenari
Table 1. Correlation coefficients (r) between clinical and instru- sites were much lower in AD patients with respect to
mental data eczematous non-atopics, indicating more profound
SCORAD % Extension
alterations of the barrier in the former group (Seiden-
ari 1996). After exposure to 5% SLS, skin barrier
Mean capacitance -0.392 -0.302 damage, as assessed by TEWL, was greater in AD with
(eight skin sites) respect to ACD patients (Fig. 3). Echographie evalua-
Capacitance on forearm skin -0.303 -0.15
Lowest capacitance value -0.372 -0.311 tion and processing of images corresponding to
Mean TEWL (eight skin sites) 0.364 0.325 SLS-exposed skin sites, showed that a significant
TEWL on forearm skin 0.225 0.057 hypo-reflectivity of the epidermis, expressing barrier-
Highest TEWL value 0.287 0.185
function damage, was present at 24 h only in atopic
SCORAD, scoring index for atopic dermatitis; TEWL, transepi- subjects (Seidenari 1994). Moreover, the intensity of
dermal water loss the inflammatory response, as evaluated by dermal
echogenicity variations, was greater in AD patients.
Lower responses to intracutaneous bioactive agents These data indicate an increased reactivity to SLS in
in more severe (Giannetti and Girolomoni 1989) and the AD group with respect to the ACD group, and a
acute (Reed et al. 1958) forms of AD were described. specific susceptibility of atopic skin to surfactants.
Tupker et al. demonstrated a negative correlation
between dermatitis severity score and reactivity to Barrier Function and Skin Hyper-Reactivity
intradermal injections of co deine, histamine, methaco- in Atopics Without Dermatitis
line and substance P, as evaluated by the intensity of
the weal and flare response in AD patients (Tupker Barrier-function abnormalities are characteristic of
et al. 1995). The authors suggested that down-regula- AD. We studied the baseline functional characterisitcs
tion of target structures due to higher skin concentra- of the skin in subjects with allergie asthma/rhinitis
tions of inflammatory media tors may lead to increased (AAR), employing evaporimetry, capacitance and pH-
resistance to stimuli (Tupker et al. 1995). A few studies metry. Compared to that of healthy subjects (HS), the
compare the skin reactivity of atopics with that of skin of patients with respiratory atopy does not show
eczematous non-atopics. Van der Valk et al. detected a alterations of biophysical parameters, as in AD (Conti
greater vulnerability of the skin to surfactants in et al. 1996). We also investigated skin reactivity to
patients with atopic eczema but not those with ICD or detergents in AAR patients by challenging volar
allergie contact dermatitis (ACD) (Van der Valk et al. forearm skin sites with a single exposure to 0.5% SLS
1985). This observation was confirmed by Tupker and compared the results with those obtained in AD
et al., who showed that a patient group with a history patients and healthy controls (Seidenari et al. 1996).
of AD had a lower pre-exposure barrier function and Skin response was evaluated instrumentally by means
higher TEWL values following irritant exposure than a of TEWL, capacitance and echogenicity measurements.
group with ACD (Tupker et al. 1990). Comparing Instrumental data confirmed an increased inflamma-
subjects with AD and contact eczema with dermatitis tory response and increased barrier damage in AD
of limited extension, capacitance values at healthy skin patients. Conversely, in patients with AAR, both
t. g/m'h Fig. 3. Transepidermal water loss (g/m 2 h)

22~--------------------,-----~----------------~-, and echogenicity (0-30 pixel) values
expressing the intensity of skin-barrier
damage and infiammation on forearm skin
20 ~
/ after a 30-min 5% sodium lauryl sulfate
/ challenge in subjects with contact dermatitis
/ (CD) and with atopic dermatitis (AD)
18 /
/
11"
16
14
12
10
8~ ____, -__________, -____L -__- ,__________- ,____- L
24 h • baseline 72 h • baseline 24 h • baseline 72 h • baseline

baseline and post-exposure TEWL, capacitance and treatment in nickel-allergic persons compared with a
echogenicity values were similar to those of HS, thus control group (Van der Valk et al. 1985). Eisner and
demonstrating that patients with respiratory atopy Burg studied the potential of the irritant response to
without AD do not show skin hyper-reactivity to SLS to predict nickel sensitization in 100 consecutive
detergents, as in AD (Fig. 4). Whereas the presence of patients undergoing standard patch testing (EIsner and
active eczema infiuences the response of the whole skin Burg 1993). They observed that patients with nickel
to irritants and allergens, cytokines and/or other sensitization had a significantly higher TEWL follow-
mediators released by the infiamed mucous mem- ing SLS exposure with respect to the control popula-
branes during the active phase of respiratory atopic tion. In a study on lO74 subjects with contact
disease do not act on the skin as infiammation dermatitis, Nethercott and Holness noted that patients
enhancers inducing the same effects. In fact, no who had positive responses to nickel reacted more
difference in skin responses to SLS exposure, as frequently to marginal irritants, such as formaldehyde
evaluated by TEWL, capacitance and echogenicity and benzoyl peroxide (Nethercott and Holness 1990).
measurements, was observed in the same subjects They speculated that the irritancy threshold might be
with AAR tested during the active phase of the disease reduced in nickel-sensitive subjects.
and in winter, when no symptoms were present (Conti How contact sensitization and susceptibility to
et al. 1997). During wintertime, post-exposure TEWL irritation interact and which one is responsible for
was even high er due to environmental infiuences on the beginning of the dermatitis is difficult to assess.
the barrier (Fig. 5), indicating that atopic skin hyper- Irritant reactivity may weIl playa role in the develop-
reactivity is organ specific and is not infiuenced by ment of contact sensitization. Increased irritant reac-
cytokines and other mediators released by mucosal tivity will result in a higher frequency of ICD, with
tissues during allergic infiammation. Based on these more frequent barrier perturbation and enhanced
results, we can assurne that respiratory atopics with no penetration of allergens infiuencing both the likelihood
signs of cutaneous atopy will behave in an occupa- to sensitization and elicitation of the dermatitis. The
tional environment as non-atopics, confirming re cent combination of irritants and sub-eliciting doses of
literature data (Funke et al. 1996). allergens can induce a dermatitis in sensitive patients.
In order to simulate simultaneous exposure to irritants
and allergens in domestic and occupational environ-
ments, pre-treatment of patch-test sites where a nickel
Barrier Impairment and Contact Sensitization
sulfate solution of low concentration was subsequently
applied was performed employing SLS in nickel-
The relationship between constitutional or irritant- sensitive atopics and non-atopics (Seidenari 1994).
mediated barrier impairment and contact sensitization With respect to non-pre-treated nickel patch-test sites,
is complex and reciprocal. Contact-sensitive subjects, consecutive applications of SLS and nickel sulfate
especially nickel-sensitive ones, are reported to have induced a higher number of skin responses and more
an increased susceptibility to irritants. Van der Valk marked allergic reactions, probably depending on
et al. showed a higher TEWL increase following SLS enhanced nickel penetration and/or summation of
Fig. 4. Transepidermal water loss (glm 2 h) ß g/m2h ß 0-30 pixels

and echogenicity (0-30 pixel) values, ex- 18 1400
pressing the intensity of skin-barrier damage --.- AD
and inflammation on forearm skin, after a --.- AAR
• •
~
16 -4--- HS
30-min 0.5% sodium lauryl sulfate challenge 1200
in subjects with atopic dermatitis (AD), all- 14
ergie asthma/ rhinitis (AAR) and in healthy
1000
controls (HS) 12
..
10 800
8 /
/ 600
/
6 /
/ 400
/
4 /
..... - - -= _-=:-~ ::! ._-,L-----
2 ..-- Ii
/ 200
o o
24 h - baseline 72 h - baseline 24 h - baseline 72 h - baseline
72 S. Seidenari
mm g1m'h Fig. 5. Skin thickness (mm) and transepider-

1.35 18 mal water loss (g/m' h) mean (±standard
16
deviation) values expressing the intensity of
1.30 inflammation and skin-barrier damage on fore-
~ arm skin after a 30-min 0.5% sodium lauryl
/ 14
1.25 / sulfate challenge in subjects with allergie asth-
---11 12 ma/rhinitis during winter and spring
1.20 10
/;
/'
1.15 .-" /
8
V 6
1.10
4
1.05
2
1.00 0
Baseline 30min 24 h 72 h Baseline 30 min 24 h 72 h
immune and non-immune mechanisms. In nickel- low molarity twice daily for 4 days, TEWL measured
sensitive subjects with AD, an earlier inflammatory after the fifth day of exposure was strongly related to
response and a more pronounced skin damage follow- baseline TEWL. This observation was confirmed by
ing challenge with SLS was observed, whereby the comparing the effects of repetitive irritation to those of
allergie response was further enhanced (Fig. 6). Thus, the application of a single 24-h SLS patch test
increased susceptibility to irritants might be respon- (Pinnagoda et al. 1989b). Thus, the baseline TEWL
sible for augmented allergie responses in sensitized level may be a reliable indicator of an individual's
patients, especially in subjects with AD. susceptibility to weak irritants (Tupker et al. 1989b). In
fact, in persons with a high pre-exposure baseline
TEWL, the barrier function of the SC is impaired from
Monitoring of Barrier Function
the start. This allows SLS to penetrate and damage the
in Workers Exposed to Irritants
skin more easily, resulting in higher TEWL values after
repeated low-dose irritation. Assessing barrier func-
TEWL measured under standardized conditions pre- tion in metal workers, Coenraads and Pinnagoda
sents low day-to-day intra-individual variations and observed that baseline TEWL was significantly higher
represents a stable personal characteristic (Pinnagoda in subjects who developed dermatitis at the end of the
et al. 1989a). Therefore, some authors suggest that study with respect to those with no dermatitis
individuals susceptible to ICD due to occupational (Coenraads and Pinnagoda 1985). These findings
exposure may be reliably characterized by utilizing indicate that a high pre-employment TEWL at selected
their baseline TEWL values for "prediction" of risk in sites may predict later development of irritant derma-
epidemiologie al field studies. After cumulative irrita- titis in risky exposure situations. A correlation between
tion induced by the application of a solution of SLS of baseline TEWL and susceptibility to SLS was con-
!'J.mm !'J. 0-30 pixels 3000 Fig. 6. Skin thickness (mm) and echogenic-
0.45 ity (0-30 pixel) values expressing the
intensity of the inflammatory response
0.40 on forearm skin at nickel patch-test sites
~ ~ after pre-treatment with 5% sodium
0.35
/ / 2500
lauryl sulfate for 30 min in nickel-sensitive
/ / subjects with contact dermatitis (CD) and
/ / with atopic dermatitis (AD)
0.30 / /
/ / 2000
0.25 ~ .'"
0.20
1500
0.15
0.10
1000
0.05
0.00 - " - - - - - , - - - - - - - - . , - - - - - ' - - - - - , - - - - - - - - - , - - - - ' - 500

24 h - baseline 72 h - baseline 24 h - baseline 72 h - baseline
firmed by Agner (Agner 1991c), whereas it was undergone many months of training. If the condition
questioned by other groups (Berardesca and Maibach is bad enough to require a job change, this represents
1988; Freeman and Maibach 1988). Assessing the skin great economic and personalloss. Therefore, recording
of subjects of different races, Reed et al. showed that at-risk subjects at the beginning of job training and
basal measurement of TEWL may not correlate with following up their skin condition during the training
the ability of the epidermal barrier to function under may lead to the diagnosis of occupational skin
stress (Reed et al. 1995). In fact, functional measure- dis orders at an earlier stage and may enable the
ments under basal conditions do not provide an occupational physician to give suitable instructions on
accurate assessment of barrier competence when it is preventive measures, such as use of appropriate
repeatedly faced with dynamic challenges and exposed barrier creams, mild deansing agents and protective
to adverse occupational or environmental situations. gloves. Besides dinical examination, pre- and period-
These authors found differences in barrier function ical post-employment instrumental evaluation of skin
based on skin type only under dynamic conditions and barrier and skin reactivity to irritants could lead to a
daimed that the assessment of barrier status can be further breakthrough for suggesting individual pre-
made only by measurement ofbarrier recovery after an ventive strategies.
appropriate previous challenge.
Only a few studies employ the assessment of skin
functions to monitor the state of the barrier during
References
occupational exposure, in order to identify at-risk
subjects. Metal workers have a high incidence of
occupational skin diseases, and the risk of hand Abe T, Ohkido M, Yamamoto K (1978) Studies on skin surface
barrier functions, skin surface lipids and transepidermal
dermatitis is dosely linked to metalworking-fluid water loss in atopic skin during childhood. J Dermatol 5:
exposure, especially to water-based fluids. Coenraads 223-229
and Pinnagoda demonstrated that a dose relationship Adams RM (1993) Hand eczema: the atopic subject and work.
Cutis 52:267-269
exists between skin conditions and barrier function Agner T (1991a) Skin susceptibility in uninvolved skin of hand
during follow-up of metal workers (Coenraads and eczema patients and healthy controls. Br J Dermatol 125:
Pinnagoda 1985). They undertook a 12-week study in 140-144
Agner T (1991b) Basal trans epidermal water loss, skin thickness,
newly recruited employees. TEWL measurements were skin blood flow and skin colour in relation to sodium lauryl
taken from the back of the right hand and the extensor sulphate-induced irritation in normal skin. Contact Derma-
and flexor surfaces of the right forearm. The workers titis 25:108-114
Agner T (1991c) Susceptibility of atopic dermatitis patients to
were subdivided into three groups according to irritant dermatitis caused by sodium lauryl sulphate. Acta
different degrees of exposure to metalworking fluids. Derm Venereol 71:296-300
At the end of the study, TEWL values had increased in Andersen KE, Liden C, Hansen I, V0lund Ä. (1993) Dose-response
testing with nickel sulphate using the TRUE test in nickel-
subjects who had developed hand dermatitis. More- sensitive individuals. Multiple nickel sulphate patch-test
over, average TEWL values were high er for workers reactions do not cause an "angry back". Br J Dermatol
belonging to the workstation where continuous expo- 129:5°-56
Bandmann HJ, Agathos M (1981) New results and some remarks
sure was unavoidable. A Swiss study showed that 10% to the "angry back syndrome". Contact Dermatitis 7:23-26
of metalworker trainees experienced minor signs of Berardesca E, Maibach HI (1988) Racial differences in sodium
irritation 8-10 months after beginning of their ap- lauryl sulphate induced cutaneous irritation: black and white.
prenticeship (Wigger-Alberti et al. 1997). TEWL in- Berardesca E, Fideli D, Borroni G, Rabbiosi G, Maibach HI (1990)
creased continuously during the first 3 months after In vivo hydration and water-retention capacity of stratum
the first examination, and the observed increase was corneum in clinically uninvolved skin in atopic and psoriatic
patients. Acta Derm Venereol 70:400-404
significantly influenced by exposure to water-soluble Bjornberg A (1974) Increased skin reactivity to primary irritants
metalworking fluids alone. provoked by hand eczema. Arch Dermatol Forsch 249:
Occupational dermatitis is a major dinical problem 389-392
Bruynzeel DP, Nieboer C, Boorsma DM, Scheper RJ, van Ketel
and a significant cause of social disability. Many cases WG (1983) Allergic reactions, "spillover" reactions and T-cell
of contact dermatitis are multifactorial in origin, which subsets. Arch Dermatol Res 275:80-85
gives rise to difficulties in both diagnosis and man- Coenraads PI, Pinnagoda (1985) J Dermatitis and vapour loss in
metal workers. Contact Dermatitis 13:347-348
agement. Exogenous factors frequently interact with Conti A, Di Nardo A, Seidenari S (1996) No alteration of
endogenous influences. For subjects with a constitu- biophysical parameters in the skin of subjects with respira-
tional barrier impairment, such as patients with AD, tory atopy. Dermatology 192:317-320
Conti A, Giusti G, Seidenari S (1997) Variations in skin reactivity
the first work experience may be responsible for to sodium lauryl sulfate in patients with respiratory atopy. In:
aggravation or activation of the disease. Hand eczema Abstracts of the 3rd International Symposium on Irritant
triggered by the occupational exposure may also Contact Dermatitis, Vatican City, October 2-4. p 266
Denda M, Koyema J, Hori I, Horii I, Takahashi M, Hara M,
represent the first manifestation of an intrinsic barrier Tagami H (1993) Age- and sex-dependent change in stratum
deficiency, often appearing after the subject has corneum sphyngolipids. Arch Dermatol Res 285:415-417
74 S. Seidenari
Diepgen TL, Fartasch M (1992) Epidemiological and genetic the stratum corneum: induction and recovery study of
studies in atopic dermatitis. Acta Derm Venereol (Stockh) surfactant dry skin. Arch Dermatol Res 281:45-51
Suppl 176:13-18 Imokawa G, Abe A, ]in K, Higaki Y, Kawashima M, Hidano A
Di Nardo A, Sugino K, Ademola 1, Wertz PW, Maibach HI (1996a) (1991) Decreased level of ceramides in stratum corneum of
Sodium lauryl sulfate induced irritant contact dermatitis: a atopic dermatitis: an etiologic factor in atopic dry skin. 1
correlation study between ceramides and in vivo parameters Invest Dermatol 96:523-526
of irritation. Contact Dermatitis 35:86-91 Iin K, Higaki Y, Tagaki Y, Higuchi K, Yada Y, Kawashima M,
Di Nardo A, Sugino K, Ademola 1, Wertz PW, Maibach HI Imokawa G (1994) Analysis of ß-glucocerebrosidase and
(1996b) Role of ceramides in proclivity to toluene and xylene- ceramidase activities in atopic and aged dry skin. Acta Derm
induced irritation in man. Derm Beruf Umwelt 44:119-125 Venereol (Stockh) 74:337-340
Di Nardo A, Wertz P, Giannetti A, Seidenari S (1998) Ceramide Kligman A, Gollhausen R (1986) The "angry back": a new concept
and cholesterol composition of the skin of patients with or old confusion? Br 1 Dermatol 115(suppl 31):93-100
atopic dermatitis. Acta Derm Venereol 78:27-30 Lammintausta K, Maibach HI, Wilson D (1987) Human cutaneous
Elias PM, Feingold KR (1992) Lipids and the epidermal water irritation: induced hyporeactivity. Contact Dermatitis 17:
barrier: metabolism, regulation and pathophysiology. Semin 193-198
Dermatol11:176-182 Lammintausta K, Maibach HI, Wilson D (1988) Susceptibility to
Elias PM, Menon GK (1991) Structural and lipid biochemical cumulative and acute irritant dermatitis. An experimental
correlates of the epidermal permeability barrier. Adv Lipid approach in human volunteers. Contact Dermatitis 19:84-90
Res 24:1-26 Lehmann P, Holze E, Melnik B, Plewig G (1991) Effects of
Elias PM, Cooper ER, Rorc A, Brown BE (1981) Percutaneous ultraviolet A and B on the skin barrier: a functional, electron
transport in relation to stratum corneum structure and lipid microscopic and lipid biochemieal study. Photodermatol
composition. 1 Invest Dermatol 75:297-301 Photoimmunol Photomed 8:129-134
Eisner P, Burg G (1993) Irritant reactivity is a better risk marker Maibach HI (1981) The E.S.S. - excited skin syndrome (alias the
for nickel sensitization than atopy. Acta Derm Venereol "angry back"). In: Ring I, Burg (eds) New trends in allergy.
(Stockh) 73:214-216 Springer, Berlin Heidelberg New York, pp 208-221
Fartasch M (1997) Ultrastructure of the epidermis barrier after Memon AA, Friedmann PS (1996) "Angry back syndrome": a
irritation. Microsc Res Tech 37:193-199 non-reproducible phenomenon. Br 1 Dermatol 135:924-930
Fartasch M, Teal 1, Menon GK (1997) Mode of action of glycolic Mitchell IC (1975) The angry back syndrome: eczema creates
acid on human stratum corneum: ultrastructural and func- eczema. Contact Dermatitis 1:193-197
tional evaluation of the epidermal barrier. Arch Dermatol Res Mitchell IC (1977) Multiple concomitant positive patch test
289:404-409 reactions. Contact Dermatitis 3:315-320
Feingold KR (1991) The regulation and role of epidermal lipid Murata Y, Ogata 1, Higaki Y, Kawashima M, Yada Y, Higuchi K,
synthesis. Adv Lipid Res 24:57-82 Tsuchiya T, Kawaminami S, Imokawa G (1996) Abnormal
Freeman S, Maibach HI (1988) Study of irritant contact dermatitis expression of sphyngomyelin acylase in atopie dermatitis: an
produced by repeat patch test with sodium lauryl sulphate etiologic factor for ceramide deficiency? 1 Invest Dermatol
and assessed by visual methods, transepidermal water loss 106:1242-1249
and laser Doppler velocimetry. 1 Am Acad Dermatol 19: Nethercott IR, Holness DL (1990) Cutaneous nickel sensitivity in
496-502 Toronto, Canada. 1 Am Acad Dermatol 22:756-761
Fulmer AW, Kramer GI (1986) Stratum corneum lipid abnor- Parish WE (1992) Chemical irritation and predisposing environ-
malities in surfactant induced dry skin. 1 Invest Dermatol mental stress (cold wind and hard water). In: Marks R, Plewig
86:377-380 G (eds) The environmental threat to the skin. Martin Dunitz,
Funke U, Diepgen T, Fartasch M (1996) Risk-group-related London, PP 185-193
prevention of hand eczema at the workplace. Curr Probl Pasche-Koo F, Hauser C (1992) How to understand the angry
Dermatol 25:123-132 back syndrome. Dermatology 184:237-240
Geiger R (1929) Unspezifische Desensibilisierungsversuche an Pinnagoda I, Tupker RA, Smit IA, Coenraads PI, Nater IP (1989a)
Ekzematikern mit Turpentinöl auf perkutanem Wege. Arch The intra and inter-individual variability and reliability of
Dermatol Syphilol 158:76-87 transepidermal water loss measurements. Contact Dermatitis
Giannetti A, Girolomoni G (1989) Skin reactivity to neuropep- 21:255-259
tides in atopic dermatitis. Br 1 DermatoI121:681-688 Pinnagoda 1, Tupker RA, Coenraads PI, Nater IP (1989b)
Grolnick M (1948) Studies in contact dermatitis. The response of Predietion of susceptibility to an irritant response by
healed specific dermatitis sites to stimulation with another trans epidermal water loss. Contact Dermatitis 20:341-346
contactant. 1 Allergy 19:298-303 Proksch E (1990) Die Epidermis als metabolisch aktives Gewebe:
Grubauer G, Elias PM, Feingold KR (1989) Transepidermal water Regelung der Lipidsynthese durch die Barrierefunktion.
loss: the signal for recovery of barrier structure and function. Z Hautkr 65:296-300
1 Lipid Res 30:323-333 Rajka G (1974) Transepidermal water loss on the hands in atopic
Halkier-S0rensen L, Thestrup-Pedersen K (1991) The relationship dermatitis. Arch Dermatol Forsch 251:111-115
between skin surface temperature, transepidermal water loss Reed IT, Ghadially R, Elias PM (1995) Skin type but neither race
and electrical capacitance among workers in the fish nor gender, influence epidermal permeability barrier func-
processing industry: comparison with other occupations. A tion. Arch DermatoI131:1134-1138
field study. Contact Dermatitis 24:345-355 Reed WB, Kierland RR, Code CF (1958) Vascular reactions in
Halkier-S0rensen L, Menon GK, Elias PM, Thestrup-Pedersen chronically inflamed skin. III: Action of histamine, the
K, Feingold KR (1995) Cutaneous barrier function after histamine releaser 48-80 and monoethanolamine nicotinate
cold exposure in hairless mice: a model to demonstrate (Nicamin). Arch Dermatol 77:263-268
how cold interferes with barrier homeostasis among Reinertson R, Wheatley V (1959) Studies on the chemieal composi-
workers in the fish-processing industry. Br 1 Dermatol tion of human epidermal lipids. 1 Invest Dermatol 32:49-58
132:391-401 Rietschel RL (1995) Physiologie response of chronieally inflamed
Hamami I, Marks R (1988) Abnormalities in clinically normal and accommodated human skin. Curr Probl Dermatol 23:
skin- a possible explanation of the "angry back syndrome". 104- 107
Clin Exp Dermatol 13:328-331 Rogers 1, Harding C, Mayo A, Banks 1, Rawlings A (1996) Stratum
Imokawa G, Hattori M (1985) A possible function of structural corneum lipids: the effect of ageing and the seasons. Arch
lipids in the water-holding properties of the stratum corn- Dermatol Res 288:765-770
eum. 1 Invest Dermatol 84:282-284 Rystedt I (1985) Hand eczema in patients with history of atopic
Imokawa G, Akasaki S, Minematsu Y, Kawai M (1989) Impor- manifestations in childhood. Acta Derm Venereol (Stockh)
tance of intercellular lipids in water-retention properties of 65:305-312
Schäfer L, Kragballe K (1991) Abnormalities in epidermal lipid skin as determined by transepidermal water loss and visual
metabolism in patients with atopic dermatitis. J Invest scoring. Contact Dermatitis 20:108-114
Dermatol 96:10-15 Tupker RA, Coenraads PJ, Pinnagoda I, Nater JP (1989b) Baseline
Seidenari S (1994) Reactivity to nickel sulfate at sodium lauryl transepidermal water loss (TEWL) as aprediction of suscep-
sulfate pretreated skin sites is higher in atopics: an echo- tibility to sodium lauryl sulphate. Contact Dermatitis 20:
graphic evaluation by means of image analysis performed on 265-269
20 MHz B-scan recordings. Acta Derm Venereol (Stockh) Tupker RA, Pinnagoda J, Coenraads PJ, Nater JP (1990)
74:245-249 Susceptibility to irritants: role of barrier function, skin
Seidenari S (1996) Skin sensitivity, interindividual factors: atopy. dryness and history of atopic dermatitis. Br I Dermatol
In: van der Valk PGM, Maibach HI (eds) The irritant contact 123:199-202
dermatitis syndrome. CRC, Boca Raton, pp 267-277 Tupker RA, Coenraads PI, Fidler V, De Jong MCJM, Van der
Seidenari S (1998) Biophysical methods for disease monitoring in Meer JB, De Monchy JGR (1995) Irritant susceptibility and
dermatology. Curr Probl Dermatol 26:108-119 weal and flare reactions to bioactive agents in atopic
Seidenari S, Giusti G (1995) Objective assessment of the skin of dermatitis. I. Influence of disease severity. Br J Dermatol
children affected by atopic dermatitis: a study of pH, 133:358-364
capacitance and TEWL in eczematous and clinically unin- Tur E, Eshkol Z, Brenner S, Maibach HI (1995) Cumulative effect
volved skin. Acta Derm Venereol (Stockh) 75:429-433 of subthreshold concentrations of irritants in humans. Am
Seidenari S, Pepe P, Di Nardo A (1995) Sodium hydroxide- I Contact Dermat 6:216-220
induced irritant dermatitis as assessed by computerized Van der Valk PGM, Maibach HI (1990) A functional study of
elaboration of 20 MHz B-scan images and by TEWL mea- the skin barrier to evaporative water loss by means of
surement: a method for investigating skin barrier function. repeated cellophane-tape stripping. Clin Exp Dermatol 15:
Acta Derm Venereol (Stockh) 75:97-101 180-182
Seidenari S, Belletti B, Schiavi ME (1996) Skin reactivity to Van der Valk PGM, Nater IP, Bleumink E (1985) Vulnerability of
sodium lauryl sulfate in patients with respiratory atopy. J Am the skin to surfactants in different groups of eczema patients
Acad Dermatol 35:47-52 and controls as measured by water vapour loss. Clin Exp
Shahidullah M, Raffle EJ, Rimmer AR, Frain-Bell W (1969) DermatoI1O:98-102
Transepidermal water loss in patients with dermatitis. Br J Werner Y, Lindberg M (1985) Transepidermal water loss in dry
Dermatol 81:722-730 and clinically normal skin in patients with atopic dermatitis.
SuginoK, Imokawa G, Maibach HI (1993) Ethnic differences of Acta Derm Venereol (Stockh) 65:102-105
skin lipids in relation to stratum corneum barrier function. Wertz PW, Downing DT (1990) Free sphingosine in human
J Invest Dermatol 100:587 epidermis. J Invest Dermatol 94:159-161
Thune P, Nilsen T, Hanstad IK, Gustavsen T, Dahl L (1988) The Widmer J, Elsner P, Burg G (1994) Skin irritant reactivity
water barrier function of the skin in relation to the water following experimental cumulative irritant contact dermatitis.
content of stratum corneum, pH and skin lipids. The effect of Contact Dermatitis 30:35-39
alkaline soap and syndet on dry skin in elderly, non-atopic Wigger-Alberti W, Hinnen U, Elsner P (1997) Predictive testing of
patients. Acta Derm Venereol (Stockh) 68:277-283 metalworking fluids: a comparison of 2 cumulative human
Tupker RA, Pinnagoda I, Coenraads PJ, Nater JP (1989a) The irritation models and correlation with epidemiological data.
influence of repeated exposure to surfactants on the human Contact Dermatitis 36:14-20
CHAPTER 8
Hydration Injury to Human Skin:

A View trom the Horny Layer
A.M. Kligman
Introduction stratum corenum has been handsomely reviewed by

Rawling et al. (Rawlings et al. 1994).
Elias and his co-workers have popularized a model
During the mid-century, textbooks of dermatology
which views the stratum corneum as a brick-and-
described the horny layer as a graveyard of disinte-
mortar structure (Elias and Menon 1991). The bricks
grated keratinocytes, covering the surface with an
are protein-rich corneocytes separated by li.pid-:ich
amorphous mass of keratin fibrils, supposedly a
intercellular domains consisting of stacks of bIlammar
product of the epidermis. This image was completely
membranes. Excellent reviews of the complex structure
false, an artifact of H- and E-stained sections. I
of the stratum corneum and the dynamics of its
subsequently showed that the horny layer ,:as a
behavior have been presented by Menon and Fartasch
cellular tissue, a fabric of cornified cells creatmg a
Menon and Ghadially 1997; Farasch et al. 1993).
tough, flexible, coherent membrane. It was then
Final1y, it is important to know that the horny layer is
learned that this stratum corneum was quite imper-
adepot of pro-inflammatory cytokines; the appropria~e
meable and constituted the rate-limiting barrier to the
insult or stimulus is released, initiating pathologlC
diffusion of substances into and out of the skin (Idson
changes in the viable tissue below! The horny layer is
1975). I proclaimed that it was the single biological
especially rich in interleukin-l (Gabring et al. 1985), as
mission of the epidermis to create the horny layer
has been amply demonstrated in scrapings from the
barrier, which I likened to saran wrap. The horny layer
glabrous skin and the soles. Injection of horny-l~yer
is an impermeable plastic film beautifully designed. to
extracts or implantation of horny-layer fragments mto
"water proof" the viable tissue below, thus preventmg
the skin provokes a sharp inflammatory response
it from drying out, and making terrestrial existence
(Dalziel et al. 1984). The potential role of normal
possible (Kligman 1964).
horny-layer constituents for inciting and maintai~ing
Systematic and comprehensive investigations cen-
inflammatory reactions has just begun to be reahzed.
tered on epidermal biology have completely revamped
Recently, HaIes and Camp have compellingly advanced
these simplistic and inaccurate conceptions (Elias and
this idea by showing that aqueous abstracts of normal
Friend 1975). The epidermis has a multitude of functions
stratum corneum can potently induce proliferation of
besides generating the horny layer and is no longer a
peripheral blood monocytes, possibly behaving as an
passive target of disease processes. Likewise, ~e stratu~
antigen [14l. It is important for the horny .layer. to
corneum is no longer an inert passive wrappmg but m
maintain its structural integrity. One can Imagme,
fact plays a highly important role in re?ulating hom~o
therefore, that any traumatic mechanical or chemical
stasis ofthe skin (Elias 1996). PerturbatIOn ofthe barner
insult that exposes the epidermis or dermis to horny-
sets off a cascade of selective pro-inflammatory cyto-
layer products may generate an inflammatory casca~e.
kines that influence the evolution and devolution of
This explains the intense inflammatory papule WhlCh
various diseases processes, such as contact dermatitis
develops when a closed acne comedone ruptures. I have
(Nickoloff and Naida 1994). Likewise, the stratum
experimentally provoked a deep-inflammation pa~u~e
corneum is very much alive, as heralded by the title of
by intradermal injection of aqueous extracts of dehpl-
arecent paper by Jais and Elias, "The living stratum
dized closed comedones. I plot thickness with every
corneum", despite being made up of anucleated dead
new study that looks at the substances deposited on the
cells (Jais and Elias 1991). From the bottom to the top of
horny layer by the process of differentiation. It has also
the horny layer, there occur striking biochemical
been found that homogenates of the horny layer can
gradients that regulate orderly differentiation, ending
activate complement by the alternative pathway (Terui
in desquamation of terminal corneocytes at the surface
et al. 1989). We can anticipate immunological functions
(Warner et al. 1995). The molecular biology of the
for the stratum corneum.

Hydration Injury to Human Skin: A View from the Horny Layer 77
In sum, the horny layer is a semlOhe membrane loss. The result is a slow build-up of water, which can
regulating cutaneous homeostasis by sending signals have injurious consequences. For example, Lindberg
to the underlying tissues. A defective horny layer can and Fosslund biopsied skin after only 6 h of exposure
prolong an underlying disease process. An illuminat- to empty chambers and found striking changes in the
ing example of this is the finding that the stratum morphology of Langerhans' cells, which showed dilat-
corneum is defective in hypertrophie scars and keloids ed endoplasmic reticulum, villiform projections of tlIe
(Suetaki et al. 1996). It functions poorly as a barrier; cell membranes associated with invading mononu-
for example, among other water holding deficiencies, clears (Lindberg and Forslund 1981). Mikulowska
transepidermal water loss is greatly increased over that showed even more striking changes in Langerhans'
in the normal nearby skin. This immediately suggests cells after 24 h of exposure to a water patch
tlIat fortifying or restoring the faulty barrier might (Mikulowska 1990). I previously showed that exposure
promote regression of the hyperplastic fibrous tissues. of volar forearm skin to water for only 48 h produced
Empirically, it had been found tlIat hypertrophie scars striking pathologie changes to virtually all the cells
respond with flattening to silicone sheets and gels and comprising the epidermis viz. Langerhans cells, mela-
occlusive dressings (Abu et al. 1995). This beautiful nocytes and keratinocytes. Prominent changes in-
clinical advance could have been predicted had we cluded intra- and intercellular edema, marked
known earlier about the homeostatic dynamics of tlIe vacuolization of keratinocytes and melanocytes and
horny layer. degenerative changes of mitochondria. In addition to
In the remainder of tlIis essay, I shall focus on only tlIese cytotoxic changes, the uppermost corneocytes
one aspect of the role played by tlIe horny layer in the became swollen and detached from each other, leading
pathogenesis of chronic inflammatory disorders: the to premature desquamation. WitlI longer occlusive
baleful effects whieh follow from prolonged hydration exposures tlIere occurred (starting with a disrupted
of the skins surface. I have explored this area stratum corneum) a downward progression of events,
experimentally in a previous work (Kligman 1996). creating a markedly pathologie picture consisting of a
My purpose now is to show tlIat physicians working in peri-venular inflammatory infiltrate, dilated vessels
occupational settings need to become more aware of witlI swollen endothelial cells, numerous degranulating
the harmful effects of water. Intuitively, it seems mast cells and hyper-plastic fibroblasts. Keeping the
paradoxieal tlIat water, a life-sustaining fluid, can skin occluded under Saran Wrap for 2-3 weeks
sometimes be antagonistic to health. resulted in severe rebound dermatitis after removing
The underpinnings for my hydration thesis derive the wrap. Occlusion is clearly hazardous to normal
from the following observations. The horny layer is skin.
extremely hygroscopie. When immersed in water, it While free water is most damaging, any form of
can pick up 500% of its dry weight in less than 1 h, occlusion that prevents diffusional water loss inelucta-
swelling vertically to 4-5 times its original width bly results in the build-up of water. We hypotlIesize
(personal observations). The outermost, oldest cells that swelling of the horny layer releases preformed
pick up more water than those deeper down. After cytokines, whieh diffuse inward to provoke inflamma-
keeping the surface wetted by water for a few hours, tion. As we have seen, the horny layer is adepot for pro-
ultrastructural analysis shows a great swelling of inflammatory cytokines, serving tlIe biologie purpose
individual corneocytes and a great increase in tlIe of promptly responding to exogenous insults. Wehave
intercellular spaces separating corneocytes (Warner found that a simple 24-h exposure to water results not
et al. 1988). Another recent novel finding is tlIe only in a weaker barrier with increased trans epidermal
occurrence, in normal stratum corneum, of isolated water loss, but also sub-clinical dermal edema, visual-
lacunar dilatations, which appear as cavities embedded ized by high frequency ultrasound and an increase in
within the intercellular lipid domains (Menon and increased blood flow by laser Doppler imaging. These
Elias 1997). After hydration, tlIese lacunae swell, revelations have been long in coming; because they are
extend, become continuous and open new channels hidden to tlIe naked eye, they lie within the domain of
for the penetration of hydrophilie and hydrophobie invisible dermatology (Kligman 1991).
substances. Such observations go a long way to Water should not be regarded as an "irritant" like
explaining tlIe ancient observation that occlusion anionie surfactants or lipid solvents, such as acetone.
drives drugs tlIrough the horny layer barrier; occlusive Unlike tlIese, it is not cytotoxic but exerts its patho-
dressings, as every clinician knows, greatly enhance logie effects indirectly by markedly altering the struc-
the efficacy of topieal corticosteroids in the treatment tural organization of tlIe horny layer, releasing
of dermatoses (Lindberg and Forslund 1981). Free pre-formed products that are stored tlIerein. With tlIis
water is not the only way to bring about hydration of background, we can briefly review the abnormal
the horny layer. Covering tlIe surface with imperme- clinical states in whieh hydration is a prominent
able tape or plastic film will block diffusion al water element in pathogenesis.
78 A.M. Kligman
Wet Work dermatitis. The children are usually quite athletic and
wear rubber sneakers, which trap sweat, leading to
superhydration of the horny layer. The etiopatho-
Clinicians have long known that excessive exposure to
genesis is suggested by the terminology, the "wet and
water in wet occupations can lead to a troublesome
dry foot" syndrome. It is the alternate swelling and
chronic dermatitis. Wet occupations are common and
drying out which provokes the syndrome. The stratum
include cannery workers, hairdressers, hospital cleans-
corneurn of the foot is ten times thicker than elsewhere
ers, bartenders, processors of fish and tradition al
and by volume alone is a reservoir for pro-infiamma-
housewives who wash laundry and dishes by hand. It
tory cytokines.
was formerly thought that it was not the water itself
I have partially reproduced this effect by having
but associated factors that caused these chronic
subjects wear an occlusive rubber cot on the middle
dermatoses, such as anionic detergents in occupations
toe for 24 h on alternate 24-h days - one day on and
requiring cleaning and was hing. Wet occupations also
one day off. It generally takes about 2 weeks for the toe
encourage the growth of microbacteria, especially
to become swollen, reddened and sore. This phenom-
gram negatives, prompting clinicians to diagnose
enon of alternate swelling and drying doubtless
bacterial infections as the cause of the dermatitis.
disrupts the structural integrity of the horny layer,
The historical ac count shows that clinical observa- probably causing sub-clinical cracks.
tions may be very misleading, encouraging clinicians Finally, it should be noted that alternately wetting
to provide glib diagnoses for problems that are not
and drying the nails also leads to degenerative
otherwise explicable. The role of water is often only structural changes in the nail plate, resulting in
contributory, a predisposing factor that makes the skin
lamellar splitting (onychoschizia) (Wallis et al. 1991).
more permeable to noxious chemicals, such as soaps,
Some cosmeticians have experienced this.
solvents and metallic allergens nickel and chromium,
in the workplace. Chronic hand dermatitis is a
convincing example of this in wet occupations, such Rubber Gloves
as hairdressers and workers in the chemical industries.
In addition, one should recall that water is an
important and traditional penetration enhancer. This Rubber-glove dermatitis is a relatively new phenom-
is well known to therapists, who use various different enon occurring in dental and medical personnel who
forms of "water" therapy for the treatment of psoriasis, wear gloves for long periods, sometimes most of the
such as psoralens ultraviolet A baths and swimming in day, mainly because they are concerned about con-
the acid sea. Occlusion can also be a confounding tracting acquired immune deficiency syndrome from
factor in other situations that involve dermatologists. non-disclosing infected patients. Glove dermatitis
For example, in routine patch testing for suspected cannot be attributed to bacterial overgrowth, since it
contact sensitization, a visible reaction may be a false occurs just as readily in the presence of bacteriostatic
positive, especially when the test allergen is dissolved chemicals. Allergy to protein in latex gloves is a quite
in water, such as metallic salts, formaldehyde, etc. different matter and has no relevance to the present
About 20% of normal adults will show an erytherna- discussion.
tous reaction to water after a 24-h exposure. By The experiments of Ramsing and Agners are
contrast, water exposure has its positive uses. A case in convincing (Ramsing and Agner 1996). Volunteers
point are negative patch tests to nickel salts in the face wore occlusive non-latex gloves 6 h per day for
of a clear-cut his tory of contact allergy to nickel. One 14 days. This uniformly resulted in deterioration of
way to overcome these false negatives is to perform a the barrier function, as exemplified by increased
24-h patch test to water before exposure to the nickel transepidermal water loss. Furthermore, 6 of 37
salto It is surprising how often this results in a positive volunteers developed a papular dermatitis. Wearing
allergic response (Seidenari et al. 1995). Thus, all is not cotton gloves under the occlusive glove completely
negative about water! prevented these changes, obviously by preventing
superhydration.
Juvenile Plantar Dermatitis

Tropical Immersion Foot (Paddy Foot)
This chronic foot eczema is especially common in
children and has baffied pediatricians for years. Some Knowledge about this disabling condition derives from
clinicians regard it as one of the varied manifestations the Vietnam War, when soldiers on patrol were
of atopic eczema. The epidemiologic evidence, how- exposed for days in water-soaked rice paddies, with
ever, suggests that it is an example of hydration no chance to remove their boots to allow drying out.
Hydration Injury to Human Skin: A View from the Horny Layer 79
An early and prominent finding was marked swelling mal systems. Incidentally, adhesive-tape reactions,
and folding of the horny layer, followed by various such as one encounters in 21-day cumulative irritancy
inflammatory lesions, which were painful and dispatch testing on the back, is another fine example of
abling. Complete accounts can be found in the reports hydration dermatitis, though clinicians usually like to
by Akers (Akers 1974) and Allen (Allen 1973). blame contact allergy, which in fact is rare.
Immersion foot is the most dramatic example of
hydration dermatitis, in which water itself has to be
viewed as the main pathogenic factor. Trauma, pres- Hearing-Aid Dermatitis
sure and abrasive particles are simply secondary
factors. The manifestations of bacterial and fungal
Hearing aids are designed to fit snugly in the ear and
affections in rice paddies are quite different and can
infrequently are associated with such an intense
easily be recognized by experienced observers. Soldiers
with severe immersion foot are rendered completely dermatitis as to require discontinuance (Lear et al.
1998). Clinicians tend to diagnose this as seborrheic
ineffective as fighting men and were cured only after
dermatitis, which it strongly resembles, or to contact
hospitalization. I also call attention to the frequency of
sensitization to methyl methacrylate, neither of which
systemic signs, such as fever and lymphadenopathy in
tropical immersion foot. These have received little are acceptable explanations.
more than passing attention in otherwise thorough Because of abundant secretions, the extern al ear
canal is normally a wet habitat, further accentuated by
accounts. Infection cannot be implicated, since a few
days of bed rest without modifications leads to rapid occlusion by the ear piece. I have encountered this
resolution as the foot dries out. My conjecture is that relatively new phenomenon in patients referred to me
cytokines released from the thickened, swollen plantar for treatment of stubborn contact dermatitis.
stratum corneum are absorbed into the circulation and
are the cause of the fever. The analogy that comes to
mind is the fever associated with severe sunburns. Diaper Dermatitis of the Elderly
Circulating interleukin-1 has been shown to mediate
the fever. Diaper dermatitis is no longer a problem restricted to
babies. Incontinence among nursing horne residents is
frequent and exceedingly disagreeable to patients and
Transdermal Systems personnel alike. Misdiagnosis is the rule, setting off a
futile search for infections due to gram negatives,
Candida, S. aureus and hemolytic streptococci, fol-
These occlusive devices are used to drive potent drugs lowed by useless application of antimicrobials. The
into the systemic circulation as an alternative to oral or treatment, of course, is elimination of excessive
parenteral administration, avoiding first-pass metabol- moisture, abetted when possible by control of urinary
ic inactivation (Hurkmans et al. 1985). Local reactions incontinence. Fortunately, adult dia pers that can
to these systems are fairly common, especially with absorb huge amounts of water so that the horny layer
nicotine and clonidine. does not become over-hydrated are now available.
The adverse effects take the form of a variable
erythematous dermatitis, resembling a contact derma-
titis. Clinicians usually attribute such reactions to
Point Counterpoint
contact sensitization, to chemical irritation or to
friction and press ure.
These may be operative in so me cases, but the more This essay denounces water is an agent ho stile to skin
likely explanation is hydration dermatitis, especially under circumstances that excessively hydrate the
when the device is left in place for 5-7 days before horny layer. However, the water discussion would be
being removed. By leaving nitroglycerin transdermal incomplete and unbalanced without mentioning clin-
systems in place for 2 weeks, I have provoked an ical situations where water is helpful rather than
eczematous re action in about 35% of normal volun- harmful.
teers, usually becoming evident 3-4 days after remov- The treatment of plaque-tape psoriasis is the best
ing the device. example. Moderate clearing occurs when tapes are left
The systems that cause the most trouble are those in in place for 2-3 weeks (Christopher et al. 1995). A
which the drug is dissolved in water, in contrast to variety of hydrocolloid dressings are better suited to
ethanolic matrices, which are uncommonly erythema- the purpose of providing prolonged occlusion without
togenic. The evidence strongly favors hydration as the maceration. At first glance, this outcome seems to
etiologic agent in most adverse reactions to transder- contradict what has been the central thesis of this
80 A.M. Kligman: Hydration Injury to Human Skin: A View from the Horny Layer
essay. The deleterious effects described above result ldson B (1975) Percutaneous absorption. J Pharm Sei 64:901
Jais H, Elias P (1991) The living stratum corneum. Cosmetics and
from super-hydration of normal skin. Hydrocolloid Toiletries 106:47
dressings and tapes exert their beneficial effects on Kligman AM (1964) The biology of the stratum corneum. In:
dermatitis-affected skin in which there are profound Montagna W, Lobitz WC Jr (eds) The epidermis. Academic,
biochemical and immunology abnormalities. How New York, pp 387-433
Kligman AM (1991) The invisible dermatoses. Arch Dermatol
occlusion reverses these disturbances is achallenging 127:1375-1382
mystery. Finally, despite the interpretations I have Kligman AM (1996) Hydration injury to human skin. In: van der
Wild PG, Maibach H (eds) The irritant contact dermatitis
proffe red, the mechanism by which occlusion damages syndrome. CRC, Boca Raton, p 187
normal skin is also a mystery! Lear JT, Sandhu G, English SC (1998) Hearing aid dermatitis: a
study of 20 consecutive patients. Contact Dermatitis 38:212
Lindberg M, Forslund B (1981) The effects of occlusion of the skin
on the Langerhans' cell and epidermal mononuclear cells.
Acta Derm Venereol 61:201
References Menon GK, Elias PM (1997) Morphology basis for a pore pathway
in mammalian stratum corneum. Skin Pharmacol 10:235
Menon GK, Ghadially R (1997) Morphology of lipid alterations in
Abu ST, Monnafo WW, Mustoz TA (1995) Topieal silicone gel: a the epidermis. A review. Microse Res Tech 37:180
new treatment for hypertrophie and keloid sc ars. Dermatol Mikulowska A (1990) Reactive changes in the Langerhans' cells of
Surg 21:947 human skin caused by occlusion with water and sodium
Akers W A (1974) Paddy foot. A warm water immersion foot lauryl sulfate. Acta Dermatol Venereol 70:468
syndrome. Milit Med 139:605 Nickoloff BJ, Naida Y (1994) Perturbation of epidermal water
Allen AA (1973) Tropical immersion foot. Lancet 197:1185-1189 function correlates wet initiation of cytokine cascade in
Christopher E, Griffiths M, Transfaglia G, Karig S (1995) human skin. J Am Acad Dermatol 30:535
Prolonged occlusion in the treatment of psoriasis. A clinical Ramsing DW, Agner T (1996) Effect of glove occlusion on human
and immunohistologic study. J Am Acad Dermatol 32:618 skin. Contact Dermatitis 34:258
Dalziel K, Dykes PJ, Marks R (1984) lnflammation due to Rawlings AU, Scott IR, Harding CR (1994) Stratum corneum
intracutaneous implantation of stratum corneum. Br J Exp moisturization of the molecular level. J luvest Dermatol
Pathol 65=107 103:731
Elias PM (1996) Stratum corneum architecture, metabolie activity Seidenari S, Manzini BM, Belletti B (1995) Pretreatment of the test
and interactivity with, subjacent cell layers. Exp Dermatol area with I-day occlusion improves the response to NaSO. 5%
5=19 1 petrolatum patch tests in subjects with a positive history of
Elias PM, Friend DS (1975) The permeability barrier in mamma- nickel allergy. Contact Dermatitis 33=152
lian epidermis. J Cell Biol 65=180 Suetaki T, Sasal S, Zhen YX, On T, Tagami H (1996) Functional
Elias PM, Menon GK (1991) Structural an lipid biochemical analysis of the stratum corneum in scars, sequential studies
correlates of the epidermal permeability barrier. Adv Lipid after injury and comparisons among keloids, hypertrophie
Res 24:1 and atrophie scars. Arch Dermatol 132:1453
Fartasch M, Baisukas ID, Diepgen TIL (1993) Structural relation- Terui T, Kato, Tagami H (1989) Stratum corneum activation of
ship between epidermal lipid lamellae, lamellar bodies and complement through the antibody-independent alternative
desmosomes in human epidermis. Br J Dermatol 128:256 pathway. J luvest Dermatol 92:593-597
Gabring LC, Buckley A, Daynes R (1985) Presence of interleukin-l Wallis MS, Bowen WR, Guin JD (1991) Pathogenesis of on-
in normal human stratum corneum. J Clin luvest 76:1585 ychoschizia (lamellar dystrophy). J Amer Acad Dermatol
HaIe JM, Camp RDR (1998) Potent T cell stimulations materials 24:44
with antigenie properties in stratum corneum of normal Warner RR, Myers MC, Taylor DA (1988) Electron probe analysis
human skin. J lnvest Dermatol 110:725 of human skin. Determination of the water concentration
Hurkmans JFGM, Bodde HE, Van Driel LMJ, Van Doosne H, profile. J luvest Dermatol 90:218
Junginger HE (1985) Skin irritation caused by transdermal Warner RR, Bush RD, Ruebusch NA (1995) Corneocytes undergo
drug delivery systems during long-term (5 days) application. systematie changes in element concentrations across the
Br J Dermatol112:461-467 human inner stratum corneum. J luvest Dermatol 104:530
CHAPTER 9
Measurement of Dermal Exposure

S. Sadhra and 1.S. Foulds
Introduction (stratum corneum) - represent the stages of matura-

tion of keratin by keratinocytes. Extensive in vitro and
in vivo studies have shown that the stratum corneum
Absorption across the skin has long been recognised as
provides the main barrier against percutaneous ab-
an important primary route of entry of toxic agents
sorption. The stratum corneum contains approximate-
into the body. However, percutaneous absorption is
ly 40% protein, 40% water and 15-20% lipids. The
complex, variable and affected by a variety of factors
lipids in the stratum corneum occur mainly in the
and still defies simple measurement. The rates of skin
form of triglycerides, fatty acids, cholesterol and
penetration are unknown for most liquids, solids and
phospholipids (Michaels et al. 1975). The stratum
gaseous substances.
corneum is replaced about every 2 weeks in adults.
This chapter describes the mechanism by which
Therefore, for substances with a slow penetration rate
chemicals are absorbed through the skin and the
but high solubility in the stratum corneum, initial
factors that affect this absorption process. Experimen-
absorption into the outermost layers may be followed
tal methods, in vivo and in vitro, for estimating dermal
by release as the cells are shed.
absorption rates are described. This is followed by a
Penetration across the stratum corneum occurs by
discussion of field techniques available for measuring
passive absorption. Polar and non-polar substances
both dermal exposure and airborne contact allergens.
appear to diffuse through the stratum corneum by
different pathways. Polar substances appear to diffuse
through the outer surface of pro tein filaments of the
Percutaneous Absorption
hydrated stratum corneum, whereas non-polar sub-
stances dissolve in and diffuse through the lipid matrix
An understanding of the percutaneous absorption is between the protein filaments. The rate of diffusion of
essential when evaluating the potential of a chemical to non-polar substances is proportional to their lipid
cause skin dis orders or systemic toxicity. This section solubility and inversely proportional to their molecular
provides abrief description of the barrier function of weight.
the skin and considers the factors affecting percuta- Although appendages such as hair follicles, seba-
neous absorption. Although this section only discusses ceous glands and sweat glands facilitate the passage of
the barrier function of the skin, it must be remembered chemicals, their area is relatively smalI. In total, they
that a chemical coming into contact with skin can also occupy less than 1% of the skin surface and, for most
evaporate from the skin surface, bind to stratum chemicals, absorption through the general skin surface
corneum or become metabolised. is the preferred route. Available evidence suggests that
such appendages can act as additional diffusion shunts
Skin as a Barrier and are important in the early stages of percutaneous
absorption.
The skin consists of three main layers: the epidermis, Beneath the stratum corneum, the dermis (or
the dermis and the subcutis. The epidermis is a corneum) is a tough supportive connective-tissue
stratified squamous epithelium, which is about O.l-mm matrix, containing specialised structures and a sub-
thick. In some parts of the body, for example the stantial vascular supply. The dermis varies in thick-
glabrous skin of the palms and soles, this layer is ness, being thin (0.6 mm) on the back of the eyelids
thicker (0-4-1.4 mm). The main cell type of the and thicker (3 mm or more) on the back, palms and
epidermis is the keratinocyte; this produces the protein soles. The dermis provides flexibility and elasticity to
keratin. The four layers of the epidermis - the basal, the skin. Its major components are collagen, reticulin,
prickle and granular cell layers and the horny layer elastin and fibres, and ground substance. The ground

82 5. 5adhra and 1.5. Foulds
substance provides a slow diffusion medium for with the solubility of the compound in stratum
constituent fluids. In addition, the dermis contains corneum and it decreases with increased thickness of
macrophages, mast cells and lymphocytes, which the skin. The permeability constant is usually expres-
contribute to dermal inflammatory, phagocytic and sed in units of cm h -1; the Kp for water is about
immune reactions. The cell layers in the dermis 10 x 10 4 cm h- 1 •
provide less of a diffusion barrier than the stratum The above expressions show that the determinants
corneum, especially for polar substances. The rate of of absorption through the stratum corneum are the
diffusion in the dermis depends on blood flow, solvent-stratum corneum partition coefficient, the
interstitial-fluid movement and perhaps interaction diffusion constant, the thickness of the stratum
with dermal constituents. corneum, and the difference between the two sides of
Passage of a chemical through the skin is as follows: the stratum corneum. The above equation, however, is
first, absorption at the surface of the stratum corneum, an oversimplification and provides an approximation
then passage through the dead horny layers of the for most in vivo exposure situations, where steady-
stratum corneum, and then movement through the state conditions are rarely attained. Fick's law is not
living layers of the epidermis. Here it may be appropriate for certain situations, for example when
biotransformed or photochemically altered. The sub- the substance is applied in high concentration or when
stance will then pass through the connective tissue of highly lipid-soluble materials are applied to the skin.
the dermis before reaching blood capillaries. When In these cases, the presence of significant amounts of
chemicals are absorbed through the skin, local toxicity these substances in the skin may increase the further
may occur within the skin, as with caustic, sensitising penetration of lipid-soluble materials. Fick's law is also
and phototoxic agents or compounds that cause skin not appropriate for substances that damage the
cancer. Some organic solvents may severely damage stratum corneum, destroying part of the barrier
the epidermis, impairing the barrier function and function.
resulting in more rapid absorption. Percutaneous
absorption is also substantially influenced by the Fartors that Influence Percutaneous Absorption
condition of the skin and the vehicle by which any
penetrant is applied to the skin. The rate and extent of percutaneous absorption of a
substance depends on both the physiologic character-
Rate of Percutaneous Absorption - Application istics of the skin and the physico-chemical nature of
of Fick's Law the substance. Developments in this area have been
largely due to in vivo and in vitro experiments.
Movement of a molecule across the stratum corneum is The concentration of the substance and the surface
characterised by a delay period of rising flux, followed area of contact are the two most important factors
by a steady state of flux if the concentration of the affecting the absorption of a chemical through skin.
substance under study is maintained at constant The polarity (solubility) and the volatility (evapora-
concentration and the penetration itself does not tion) of the substance, both governed by its chemical
damage the barrier. If the circulation on the other structure, are also important. In general, polar sub-
side of the membrane is sufficient to remove the stances, which are less soluble in lipids, are not as well
substance rapidly, then Fick's law of diffusion can be absorbed as non-polar, soluble ones. The solubility of
applied, i.e. the steady penetration rate (flux) is the substance (penetrant) is particularly important and
proportional to the concentration difference across has been expressed as a partition coefficient in
the barrier membrane. different solvent systems. The solvent used to deliver
a chemical to the skin (vehicle) will also have an effect
Js = Kp x C on the efficiency of absorption. Covering the skin with
an occlusive wrap restricts evaporation and prornotes
where Js = the steady-state flux of the substance, hydration of the skin, which results in increased
Kp = the permeability constant for the substance, and absorption of topically applied substances. The condi-
C = the concentration difference of the substance tion of the skin, such as loss of barrier function of the
across the membrane. stratum corneum through disease, chemical or phys-
When the substance is applied to skin in a solvent, ical damage, will also affect percutaneous absorption.
Furthermore, the skin thickness will also have some
bearing on absorption, since diffusion through any
where Km = the solvent-membrane partItIon coeffi- membrane is proportional to its thickness. The skin
cient for the substance, D = the diffusion coefficient contains many enzymes that catalyse the metabolism
for the substance, and 8 = the thickness of the of certain substances; thus, metabolism by the skin
membrane. Thus, the permeability constant increases could also affect absorption. In summary, a number of
Measurement of Dermal Exposure 83
factors substantially affect percutaneous absorption. of a radiolabelled compound. The amount of radio ac-
These can be grouped as follows: tivity retained in the body or excreted through lungs or
sweat can be determined by measuring the amount of
- Physico-chemical properties of the penetrant:
radioactivity excreted following an intravenous injec-
Polarity
tion (Feldmann and Maibach 1970).
Volatility
Alternatively, unlabelled parent compounds can be
Solubility (partition coefficients)
measured in blood, plasma or tissue after topical
Concentration
administration. However, because of the difficulty of
Molecular weight and particle size
detecting and quantifying low levels of many com-
- Skin factors:
pounds in plasma, this approach has only been used
Site of application of the substance
for a few substances. Wester and Maibach (1983)
Frequency of application
measured levels of nitroglycerin (NTG) in plasma after
Surface area exposed
topical administration; these investigators also moni-
Condition of skin - age, hydration, temperature
tored absorption of the radiolabelled compound.
Metabolism of substance within the skin
Another technique used to measure in vivo percu-
- Other factors:
taneous exposure involves determining the loss of
Vehicle and release rate of compound from vehicle
substance from the surface as it penetrates the skin.
Multiple- versus single-dose applications
The difference between the applied dose and the
Occlusion of exposed skin
residue on the skin is assumed to be the amount
The above factors need to be considered when absorbed. There are several limitations to this tech-
conducting dermal-exposure assessment studies, par- nique: volatile materials may evaporate from the skin
ticularly when developing sampling strategies. before penetration occurs; also, recovery of the
substance from the skin surface is difficult.
In vivo biological responses, such as vasodilation and
vasoconstriction, have also been used to estimate the
Experimental Data
rate of penetration. Laser Doppler velocimetry has been
used to monitor the vasodilatory effects of topically
The Kp and percentage absorbed values presented in applied nicotine compounds (Guy et al. 1985). Vasodi-
the literature for various substances have been gen er- lation and vasoconstriction are complicated biological
ated from both in vivo and in vitro studies using a wide responses which may vary with the tissues ability to
range of experimental techniques. Studies on human produce the response. Furthermore, the response
subjects are costly, experimental conditions are more measured is only of value if a dose-response relation-
difficult to control and ethical constraints may rule out ship has been established for the substance.
testing of toxic compounds. If percutaneous data are More recently, Rougier et al. (1987) have demon-
obtained using animal studies, this presents a number strated the use of the stripping method in the
of difficulties associated with the extrapolation of measurement of percutaneous absorption. The rela-
animal data to humans, e.g. animal species variation, tionship between percutaneous absorption and the
different sites of application, differences between amount of substance present in the stratum corneum
shaved versus unshaved skin and differences in skin was investigated in humans. The experimental design
metabolism. included a 30-minute application followed by imme-
diate washing of the application site; the upper layers
In Vivo Studies of the stratum corneum were then removed by
successive strippings using adhesive tape. The con-
In vivo studies have been conducted in humans and in centration of substances in the stripped cells was then
animals. Comparison of absorption rates of a number correlated to the total amount absorbed. Although
of substances shows that, in general, the penetration of promising, this technique has only been evaluated with
chemicals through skin in humans is similar to that in a limited number of substances of interest in the
monkeys, pigs, and guinea pigs and much slower than occupational health setting.
that in rats and rabbits (Bartek and LaBudde 1975). The Although in vivo studies are physiologically relevant,
majority of the Kp values reported in the literature they only provide an indirect measurement of the
have been obtained in studies in which the compound absorption of the substance across the skin. Further-
of interest was applied to rat skin. more, the results of in vivo studies are often reported as
The rate and extent (percentage) of absorption of a the percent of the applied dose that is absorbed, which
substance through the skin (bioavailability) in vivo are limits their use for dermal-exposure assessment if a Kp is
usually determined by measuring the total radioactiv- required. Possibilities for errors also exist in corrections
ity in blood or excreta following a topical application for incomplete excretion, particularly for lipophilic
compounds. These limitations and the potential toxicity include the choice of species, the age of the test subject,
of many substances have led to the development of in the site from which the skin is obtained, the mounting
vitro models for estimating percutaneous absorption. of the skin under experimental conditions, the method
of applying the chemical onto the surface of the skin
In Vitro Studies and the removal of the penetrating amounts on the
receptor side of the skin (Bronaugh and Maibach 1985;
In vitro studies using excised skin have provided useful Franz 1975). These variables have been addressed in
information on percutaneous absorption rates for a different ways in studies; however the major limitation
number of substances under various conditions. A of these studies is that the receptor side of the excised
model for studying skin penetration in vitro is shown in skin is exposed to an aqueous solution rather than to
Fig. 1. A piece of excised human skin is attached to a dermal tissues with a blood supply. Furthermore, use
diffusion apparatus, which has a top chamber contain- of surfactants or other lipophilic receptor fluids may
ing the applied dose of a chemical, an O-ring to hold the alter the metabolie activity of the skin.
skin in place and a temperature-controlled bottom
chamber containing saline or other solvents, plus a Skin Denotation and Dermal-Exposure Limits
sampling port to withdraw fractions for analysis.
Although human forearm skin is optimal, this is difficult In many countries, compounds that present a skin
to obtain, so it is common practice to use abdominal hazard are identified by a 'skin' denotation (or 'Sk'
skin. It is generally believed that, for most classes of notation) in the list of occupational exposure limits
chemicals, properly conducted in vitro tests using (OELs). The purpose of this is to draw attention to
human skin can be a reasonably good predictor of the substances that can penetrate intact skin and contrib-
absorption rate in humans. In studying percutaneous ute to total systemic exposure.
absorption, in vitro assays offer a number of advantages Dermal LD 50 has been used to quantify dermal
over in vivo assays (Bronaugh and Maibach 1983): penetration. This refers to the amount of the chemical
that induces 50% mortality in animals (rats or rabbits)
- Investigation of percutaneous absorption without
following skin application for aperiod of 24 h. A
the influence of other pharmacokinetic factors that
relatively low dermal LD 50 , in particular when com-
may affect cutaneous uptake
pared with LD 50 values obtained by oral or inhalation
- Simultaneous processing of a larger number of
exposure, would tend to indicate that skin absorption
assays
may be significant. The commission of the European
- Sampling directly beneath the skin
Communities has used an LD 50 of 2 g kg- l as a
- Absorption of highly toxic compounds can be
criterion for labelling of chemieals as a skin hazard.
investigated using human tissues
The American Conference of Government Industrial
Furthermore, in vivo assays may be cheaper and easier Hygienists (ACGIH) have adopted a similar practice
to conduct. Despite these advantages, the conditions for adding a skin denotation to the list of threshold-
present in vitro studies can be quite different from limit values (TLVs). In the UK, the Health and Safety
those present in the in vivo state. The main difficulties Executive (HSE) assigns substances an 'Sk' notation in
cases where the available data or experience suggests
that exposure via the dermal route may:
a. Make a substantial contribution to body burden
(when compared with the contribution attributable
to inhalation exposure at the OEL)
b. Cause systemic effects, so that conclusions about
exposure and health effects based solelyon airborne
concentration limits may be invalid (Health and
Safety Executive 1999)
So far, no limit values specially designed for control
of skin exposure have been established, although
biological-exposure limit (BEL) values (published by
the ACGIH) are used to control the total uptake of
substances, including the uptake through skin absorp-
tion. Fenske (1993) discusses the need for and feasi-
bility of developing dermal occupational exposure
limits (DOELs). He suggested that DOELs couId be
Fig. 1. Experimental cell for studying in vivo skin penetration based on the surface-sampling technique; that is,
exposure could be estimated on the basis of surface- The technique of patch sampling was originally used
residue measurements and dermal transfer coeffi- in studies of workers exposed to organophosphate
cients. This approach would be most feasible where pesticides and has been subsequently standardised
dermal exposure primarily results from surface con- (World Health Organization 1982), with its use being
tact. The basic requirements for the development of extended to other substances, such as polyaromatic
DOELs for a surface contact scenario were listed as hydrocarbons Oongeneelen et al. 1988). Two assump-
follows: tions are made when using the patch-sampling tech-
nique: (1) the exposure is uniform, i.e. the deposition
- Reproducible and representative methods for mea-
rate on the patch is representative of the deposition
suring surface residues and daily dermal exposure
over that part of the body, or (2) worst-case exposure,
- Establishment of dermal transfer coefficients across
i.e. the patch has been located at the point of highest
a range of surface residue levels and work activities
exposure potential for that part of the body.
- Validation of dermal dose estimates by biological
Patches are essentially spot or grab samples (typi-
monitoring
cally 25 cm 2 ) of the skin, whereby dermal exposure is
assessed by extrapolating the patch loading level to the
Exposure Monitoring Techniques surface of the entire body. Given that only a small area
of exposed skin is covered by the patches used, the
uncertainties in calculating true exposure are likely to
Dermal exposure can be caused by direct contact with be high. Furthermore, the exposure pattern may vary
the pollutants or by splashing, contact with contam- with time, with activities, and both within and between
inated surfaces and skin deposition by airborne agents. individuals, days and shifts. However, several field
This section discuss techniques available for measur- studies have shown that this technique is a useful tool
ing dermal exposure, approaches for measuring in the identification and evaluation of dermal expo-
airborne contact allergens and general factors which sures to a range of workplace contaminants and in the
need to be considered when designing sampling assessment of the effectiveness of personal protective
programmes. equipment (Fenske et al. 1990).
Limitations in patch sampling can be overcome by
sampling the whole body with garments. Absorbent
Monitoring Skin Exposure
cotton gloves have been used to estimate hand
exposure (Davis et al. 1983), and whole-body garments
In recent reviews on the assessment of dermal expo- have been used for assessing workers' exposure to
sure, little progress has been made with respect to pesticides (Abbott et al. 1987). Garment sampling has
methodologies used for monitoring dermal exposure. several advantages: distributional assumptions are not
Much of the developments have been carried out in the required, a standard sampling approach can be applied
assessment of pesticide exposure where the dermal to virtually all body regions, and the sampling of work
route predominates over inhalation. The developments activities with different skin exposure patterns is
in skin exposure monitoring have been reviewed comparable. Disadvantages of this technique inc1ude:
comprehensively by Fenske (1993) and summarised putting on and removing garments can be cumber-
below. Fenske grouped the various direct-sampling some, extraction of used garments requires a large
techniques into three categories: surrogate-skin tech- volume of solvents prior to chemical analysis, and
niques, where the collection medium is placed against garments are susceptible to breakthrough and may
the subject's skin; removal techniques, where sub- require changing during the work shift. Further
stances deposited on the skin are removed by washing research is also needed on the specifications of
or wiping; and fluorescent-tracer techniques, where garment materials, as well as their absorption and
measurements are made by measuring the ultraviolet retention characteristics for different chemicals.
fluorescence of materials deposited onto the skin.
These techniques essentially measure the mass of the Removal Techniques
material deposited onto the skin.
This monitoring technique relies on the rem oval of
Surrogate-Skin Techniques residual quantities of chemicals by the wiping
or washing of skin surfaces. Water-surfactant mixes
These methods involve placing a chemical collection or water-alcohol solutions are generally used to assess
medium against the skin and subsequently analysing it hand exposure, while wiping techniques can be applied
for the chemical agent. Two approach es have been to other skin surfaces.
used: patch samplers covering small skin surface areas, The rem oval techniques are only suitable when the
and garment samplers covering the whole body. substance remains on the surface for a significant
86 S. Sadhra and J.S. Foulds
period of time. Similarly, substances that penetrate stance before the worker is exposed. The substance
rapidly into the skin or adsorb strongly onto the skin used by the worker may be absorbed through the skin
surface could be not be monitored using this tech- during work, but the tracer remains on the skin
nique. Furthermore, it is important to note that the surface. At the end of the shift, the worker is examined
measurement of chemicals using this technique only under ultraviolet light, which causes any deposited
represents what can be removed from the skin at the tracer to emit blue light. The emission can then be
time of sampling and not the actual skin loading recorded with a linear-response-integrating mono-
(exposure) unless the removal efficiency of the tech- chrome video recorder camera and stored on a image
nique is 100%. Thus, laboratory-based quality-control processor (Fig. 2). By analysing the intensity of the
trials need to be performed to evaluate the efficiency of emission, an estimate may be made of the quantity of
different washing and wiping procedures at different tracer, and hence of the substance deposited on the
loading concentrations prior to their use in the field. skin.
Recently, Fenske and Lu (1994) have proposed a The dye can be photographed and quantified using
standard laboratory procedure for assessing removal various fluorescence-monitoring apparatus, e.g. the
efficiencies of hand-wash techniques. FIVES (fluorescence interactive video exposure sys-
tem) fluorescent monitor, developed at the Health and
Fluorescent-Tracer Techniques Safety Laboratories in the UK (Roff 1994), and has
been used to determine the dermal exposure of
Dermal exposure can be quantified directly and non- workers using wood-preservative fluids (Roff 1997).
invasively by measuring deposition of fluorescent As weIl as providing an estimate of the mass
materials. A fluorescent tracer is added to the sub- deposited on the skin, fluorescence tracers can indicate
Fig. 2. Dermal contamination as revealed by

fluorescence - contamination of a sheep-
dipper who wore a wollen cardigan and wollen
trousers, but no waterproofs (Roff 1997)
dermal exposure patterns and identify the mechanism present in exposed areas, particularly the face and
of skin exposure, and are also valuable for worker eyelids, when the patient denies having applied a
education and training. However, in practice this topical agent and when the symptoms subside with a
technique has a number of limitations: (1) use of change in the environment (Angelini and Vena 1992).
tracers requires the introduction of an additional Sampling methods for measuring airborne exposure
substance to the production process, (2) the relative to different airborne contaminants have been well
transfer of the substance of interest and the tracers established in the field of occupational hygiene, and
needs to be demonstrated during field investigations, the general approaches to air monitoring are discussed
(3) additional quality-assurance steps may be required briefly here. Generally, there are two approach es to air
during laboratory studies, such as range finding and sampling for determination of airborne contaminants.
potential degradation of tracers under sunlight and (4) With personal sampling, a collection device is placed
separate studies may be required to investigate the near to the breathing zone of the worker. The
relative fabric penetration of the tracer and skin losses. collection device may either be active, requiring air
In addition to the above techniques, total exposure to be drawn through it, or passive, requiring no pump
(exposure from all routes, induding dermal exposure) or other suction source. The second approach is area
can be assessed indirectly by biological monitoring. sampling; this indudes housing a fixed sampling
Biological monitoring involves quantification of the station in the work area. The main advantage of fixed
pollutant or a metabolite in the body, fluids, or excreta, monitoring stations is that a large sample volume can
usually urine, of the exposed workers. This requires an be collected with the aims of identifying the nature of
adequate and valid technique for measurement and a the contaminant, measuring emissions from sources,
means to decide on the extent of the exposure and risk measuring background concentrations or measuring
to health. The feasibility of biological monitoring is concentrations in several areas simultaneously in order
thus determined by two kinds of considerations: (1) a to evaluate the effectiveness of controls. However,
knowledge of the toxicology and kinetics of the personal sampling is usually preferred since exposures
substance, and (2) practical aspects. An overview of are measured dose to the point nearest to the actual
biological monitoring methods is presented by Baselt entry of airborne contaminant and the sampling
(1988). system moves with the worker. Thus, personal mea-
surements are more likely to represent an individual's
exposure.
Air monitoring normally involves two stages -
Measurement of Airborne Contart Allergens
sampling of the substance, followed by analysis.
Sampling and analytical techniques can be divided
A number of substances that have caused contact into several categories based on factors such as time
dermatitis from direct contact of skin with airborne and the method of collection and analysis:
agents have been reported in the literature. Review
- Instantaneous or direct reading
articles on airborne contact allergens have been
- Integrated or continuous sampling
published by Dooms-Goossens et al. (1986), Lachapelle
- Bulk sampling
(1986), Dooms-Goossens and Deleu (1991) and Angel-
ini and Vena (1992). Airborne agents may be in the The main advantage of direct-reading instruments is
form of gases (mustard gas), vapours (formaldehyde), that both the collection and analysis are provided
non-biological particles (metals, cement), biological immediately. Applications indude the detection of
partides (pollen, dust from exotic trees), fibres (glass leaks, determination of the spread of contaminants and
fibre), mists (insecticides) and fumes (plastics and the investigation of exposure variability with time and
rubbers). Airborne agents may exist in these forms as the exposure process. Integrated sampling refers to the
result of evaporation at room temperature, heating, collection of samples continuously over aperiod of
thermal degradation, agitation (grinding, cutting, time, and provides a single time-weighted average
transport) and spraying operations. Almost all air- (TW A) concentration which can be compared with
borne allergens identified are occupation-related. Gen- OELs. In some situations, the nature of the contam-
erally, the symptoms of airborne contact allergens do inant needs to be identified before making decisions on
not have any special characteristics, with dIe dinician air sampling. In such cases, bulk samples of air, liquids
basing their diagnosis of the airborne origin of the or settled particulates may need to be collected for in-
dermatitis mainly on the case his tory and the sites of depth qualitative and quantitative analysis.
the lesions. The areas commonly affected are those In evaluating a worker's exposure, a sampling
exposed to the air: face, neck, upper part of chest, technique must be used that will provide dIe necessary
hands, wrists and forearms. Airborne contact derma- sensitivity, specificity, accuracy, reproducibility and,
titis must be suspected when symmetric lesions are preferably, rapidity of results. As well as these factors,
the choice of a particular sampling instrument also Sampling Strategy

depends on:
The term "sampling strategy", as used here, means the
- Portability and ease of use assembly of aseries of decisions about how to make a
- Sampling efficiency of equipment set of measurements represent exposure for a partic-
- Reliability of equipment under various conditions of ular purpose. An optimum strategy requires selection
field use of the elements under the control of the exposure
- Type of analysis and information required assessor that most efficiently achieve the objectives,
- Availability given the physical circumstances and environmental
- Cost variability (Health and Safety Executive 1989). An
When available, standard methods of sampling and important factor in the design of any measurement
analysis should be used. The International Standard scheme is the degree of variability in the system being
Organisation (ISO), the Comite Europeen de Normal- observed. This variability affects both the number of
isation (CEN) and various national bodies have pub- sampies to be taken and the accuracy of the results that
lished several methods for determination of airborne can expected. Possible causes of variability typically
contaminants. Primary sources are the compendia of observed include:
methods recommended by the regulatory bodies, i.e. - Process factors - process type, production rate,
the UK, HSE the US National Institute for Occupational physical states and properties of materials, adjacent
Safety and Health (NIOSH) and the Occupational Safety operations, exposure-control methods
and Health Administration (OSHA). The HSE has - Environmental variables - temperature, humidity,
published Methods for the Determination ofHazardous process and plant layouts, distribution of contam-
Substances (MDHS) for over 70 specific substances inants
(Health and Safety Executive 1981-95). OSHA and - Time variables - build-up of substances with time,
NIOSH have published manuals with more than 500 work shift, season of year, cyclical process opera-
and 100 sampling and analytical methods respectively tions
(National Institute for Occupational Safety and Health - Behaviour variables - Worker job practices, move-
1994; Occupational Safety and Health Administration ment, habits, training, attitudes
1985). Secondary sources are published literature ref- - Incidental variables - Spills, equipment mainte-
eren ces in, for example, Annals of Occupational nance, machine breakdowns, leaks, accidental mix-
Hygiene, the American Industrial Hygiene Association ing of chemicals, operator errors
Journal, Applied Occupational and Environmental
Hygiene, or Analytical Chemistry. In designing a sampling strategy for dermal expo-
Having established the need for sampling (identifi- sure, the sampling must at least be representative; that
cation/quantification of airborne contaminants) and is, all skin surfaces with potential exposure need to be
the appropriate sampling and analysis techniques, a identified and monitored using a validated technique.
number of other fundamental questions need to be The sampling dura ti on should take into account the
asked before embarking on a sampling programme: exposure time and the requirements of the technique
used. Furthermore, all controls used to minimise skin
- Why are you sampling at all? exposure, such as gloves, should be identified and
- Whose exposure should be measured? evaluated with reference to their theoretical protection
- What substances should be measured? values, actual use time and frequency of use.
- Where should the sampie be collected?
- When should measurements be taken?
- How long should the sampie be taken? References
- How many measurements/readings should be per-
formed? Abbott IM, Bonsali JL, Chester G, et al. (1987) Worker exposure
- How often should sampies be taken? to herbicide applied with ground sprayers in the United
Kingdom. Am Ind Hyg Assoc J 48:167-175
- What should be done with the data? Andersen KE, Benezra C, Burrows D, et al. (1987) Contact
dermatitis: a review. Contact Dermatitis 16:55-78
The above questions require careful consideration in Angelini G, Vena GA (1992) Airborne contact dermatitis. Clin
order to make the monitoring survey worthwhile. DermatoI1O:123-131
These questions have been dealt with in detail in a Bartek MJ, Labudde JA (1975) Percutaneous absorption in vitro.
In: Maibach HI (ed) Animal models in dermatology. Chur-
number of textbooks on occupational hygiene (Sadhra chili Livingstone, New York, p 103
and Gardiner 1998). Baselt RC (1988) Biological monitoring methods for industrial
chemicals. PSG Publishing Company Inc., Littleton
Bronaugh RL, Maibaeh HI (1985) In vitro models for human Health and Safety Exeeutive (1989) Monitoring strategies for toxie
pereutaneous absorption. In: Maibaeh HI, Lowe NJ (eds) substanees. Guidanee note EH42, Health and Safety Exeeu-
Models in dermatology, vol 2. Karger, Basel, pp 178-188 tive. HMSO, London
Bronaugh RL, Maibaeh HI (1983) In vitro pereutaneous absorp- Jongeneelen FJ, Seheepers PT], Groenendijk A, et al. (1988)
tion. In: Marzulli FN, Maibaeh HI (eds) Dermatotoxieology. Airborne eoneentrations, skin eontamination, and urinary
Hemisphere, Washington, pp 117-129 metabolie exeretion of polyeyclie aromatie hydroearbons
Brouwer DH, Van Hemmen JJ (1992) Elements of a sampling among paving workers exposed to coal tar derived road tars.
strategy for dermal exposure assessment. International Am Ind Hyg Assoe J 49:600-607
Oeeupational Hygiene Association, First International Scien- Laehapelle JM (1986) Industrial airborne irritant or allergie
tifie Conferenee, 7-10 Deeember, Brussels eontaet dermatitis. Contaet Dermatitis 14:137-145
Davis JE, Stevens ER, Staff DC (1983) Potential exposure of apple Miehaels AS, Chandrasekaran SK, Shaw JE (1975) Drug perme-
thinners to azinphosmethyl and comparison of two methods ation through human skin: theory and in vitro experimental
for assessment of hand exposure. Bull Environ Contam measurement. Am Inst Chem Eng J 21:985-996
Toxieol 31:631-638 National Institute of Oeeupational Safety and Health (1994)
Dooms-Goossens AE, Debussehere KM, Gevers DM, Dupre KM, NIOSH manual of analytieal methods, 4th edn. DHEW
Degreef HJ, Loneke JP, Snauwaert JE (1986) Contaet derma- (NIOSH) Pub No. 94-113
titis eaused by airborne agents. A review and ease reports. Oeeupational Safety and Health Administration (1985). OSHA
J Am Aead Dermatol1p-10 analytical methods manual. OSHA Analytical Laboratories,
Dooms-Goossens A, Deleu H (1991) Airborne eontaet dermatitis: Salt Lake City
an update. Contaet Dermatitis 25:211-217 Roff MW (1994) A novellighting system for the measurement of
Feldmann R], Maibaeh HI (1970) Absorption of some organie dermal exposure using a fluoreseent dye and an image
eompounds through the skin in man. J Invest Dermatol proeessor. Ann Oeeup Hyg 38:903-919
54:339-404 Roff MW (1997) Dermal exposure of amateur or non-oeeupa-
Fenske RA (1990) Non-uniform dermal deposition patterns tional users to wood-preservative fluids applied by brushing
during oeeupational exposure to pestieides. Areh Environ outdoors. Ann Oeeup Hyg 41:297-311
Contam Toxieol 19:332-337 Rougier A, Lotte C, Maibaeh HI (1989) In vivo pereutaneous
Fenske RA (1993) Dermal exposure assessment teehniques. Ann penetration of some organie eompounds related to anatomie
Oeeup Hyg 37:687-706 site in man: predietive assessment by the stripping method.
Fenske RA, Lu C (1994) Determination of handwash removal J Pharm Sei 76:451-454
efficieney: incomplete removal of the pesticide ehlorpyrifof Sadhra S, Gardiner K (1999) Requirements of monitoring
from skin by standard handwash teehniques. Am Ind Hyg exposure to workplaee eontaminants. In: Sadhra S, Rampal
Assoe J 55:425-432 KG (eds) Oeeupational Health-Risk assessment and manage-
Franz TJ (1975) Pereutaneous absorption. On the relevanee of ment. Blaekwell Scienee, Oxford
in vitro data. J Invest Dermatol 64:190-195 Scott RC, Dugard PH (1986) A model for quantifying absorption
Guy RH, Tur E, Maibaeh HI (1985) Optieal teehniques for moni- through abnormal skin. J Invest Dermatol 86:208-213
toring eutaneous mierocireulation. Int J Dermatol 24:88-94 Wester RC, Maibaeh HI (1989) Skin eontamination and absorp-
Health and Safety Exeeutive (1981-94, in series) Methods for the tion of ehemieals from drinking water while bathing or
determination of hazardous substanees. HSE Oeeupational swimming. In: Bronaugh RL, Maibaeh HI (eds) Pereutaneous
Medicine and Hygiene Laboratory, Sheffield absorption: meehanisms, methodology, drug delivery, 2nd
Health and Safety Exeeutive (1999) Oeeupational exposure limits edn. Mareel Dekker, New York, pp 191-196
1999. Guidanee note EH40/99, Health and Safety Exeeutive. World Health Organization (1982) Field surveys of exposure to
HMSO, London pesticides. Standard protoeol: VBC/82.1. World Health Orga-
nization, Geneva
CHAPTER 10
Occupational Dry Skin

M. Gons:alo
Introduction amounts of water are lost to the environment, as

measured by trans epidermal water loss (TEWL), and
the skin gets "dry". In case of persistent barrier
Dry skin (xeroderma or xerosis) is a very common
disruption, besides the loss of the water-holding
skin condition which occurs when the water content of
capacity of the SC, the skin becomes less competent
the stratum corneum (SC) falls below normal, inducing
in the protection from environmental hazards, and the
morphological and functional skin changes (Spencer
manifestations of dry skin worsen and develop into dry
1988; Rudikoff 1998). There is a loss of smoothness
erythema, erythema craquele, eczema craquele or other
with fiaking, scaling and cracking of the most super-
infiammatory and eczematous reactions (Thune 1996a;
ficial epidermallayers; this is feIt as an uncomfortable
Rudikoff 1998).
sensation of tightness, roughness and pruritus often as-
Dry skin and its complications are very frequent
sociated with erythema, fissures and eczema (Spencer
problems in several occupational settings, although they
1988; Thune 1996a).
are often underestimated and seldom included in the
Water in the SC is necessary to maintain its
lists of occupational skin diseases. In order to under-
pliability, elasticity, extensibility and resistance to
stand how dry skin develops, how the main environ-
trauma (Rawlings et al. 1994; Cork 1997) and to control
mental factors induce it and how we can prevent or treat
the function of several enzymes that control desmo-
this condition, we have to understand the constitution
some degradation and the formation of natural mois-
and physiology of the permeability skin barrier.
turizing factors (NMF) (Rawlings et a1. 1994). When
water falls below 5-10 mg/lOo mg of the SC dry weight
(Schurer et a1. 1991; Thune 1996b), the SC loses sup-
Permeability Skin Barrier:
pleness and cracks easily (Rudikoff 1998), the process
of desquamation is altered and, instead of the usual
Constitution and Physiology
unicellular and invisible cell detachment, corneocytes
are shed in large visible blocks (Spencer 1988; Marks The permeability skin barrier, a highly specialized
1997; Rudikoff 1998). structure responsible for retaining skin moisture, is
Although SC water is relentlessly lost to the localized mainly at the stratum corneum (Rudikoff
environment by perspiratio insensibilis (about 1998); however, its formation begins deeper in the
2-8 ml/m 2 /h at rest) (Forslind 1994; Rudikoff 1998), epidermis and its constituents are progressively mod-
an almost constant amount ofwater is retained both in- ified during the process of keratinization until they
side the protein-rich keratinocytes (20%) and in the re ach their highest efficiency in the five layers of the
intercellular space (10%) (Imokawa et a1. 1991). A stratum compactum (Rawlings et a1. 1994). The mod-
highly specialized and dynamic permeability skin ified keratinocytes - the corneocytes - and the
barrier controls the movement of water across the SC intercellular complex lipid matrix in which they are
as weIl as the penetration of environmental chemical, embedded form this specialized structure, which Elias
physical and biological hazards (Kerscher et a1. 1991; compared to a "bricks and mortar" model, in which
Cork 1997), allowing the body to suffer little change the corneocytes are the bricks and the lipid matrix the
while encountering the different environments that are mortar (Elias 1983).
apart of daily life (Spencer 1988). The corneocytes are the main constituent of the
When disruption of the skin barrier occurs, either stratum corneum and hold tightly most of its water.
due to environmental insults, intrinsic constitutional The intercellular lipids are the main obstacle to the
defects, deficient reparative mechanisms or a combi- outward movement of water from inside our body to
nation of these factors (Thune 1996a), excessive the environment, but they still retain a smaller amount

Occupational Dry Skin 91
of less tightly bound water within their layers glucosylceramides are transformed into less polar or
(Imokawa et al. 1991). nonpolar ceramides (Kerscher et al. 1991; Abeck
et al. 1997). For the skin to adapt to a low-humidity
The Corneocytes environment, the percentage of ceramides and other
nonpolar lipids increase progressively from the inner
In the corneocytes at the upper stratum granulosum, to the outer SC layers (Bonte et al. 1997), opposing
keratin filaments are aggregated witlI filagrin. As they mucosal epithelia that face an aqueous media in whieh
move further into the surface, depending on the degree tlIe hydrophilie lipids, like glucosylceramides, are
of skin hydration, keratins and, especially, filagrin, abundant in the outer layers (Holleran et aI. 1993).
they are proteolytically cleaved into nitrogen-rieh Ceramides play a very unique role in tlIe skin
amino acids and derivatives, namely glutamine, furtlIer permeability barrier. They are a heterogeneous group
converted into 2-pyrrolidone-5 carboxylic acid (PCA), of sphingolipids with apolar sphingosine or a
histidine, converted then into urocanic acid, and urea phytosphingosine base to which a non polar long
(Rawlings et al. 1994; Rudikoff 1998). These water- non-hidroxy or et-hydroxyacid is linked (Kerscher
soluble and highly hygroscopie compounds, which et al. 1991; Abeck et al. 1997). Apart from ceramide 1,
constitute about 10% of tlIe dry weight of SC cells, are which is an O-acylceramide esterified usually with
collectively called the natural moisturizing factor linoleic acid, the other five classes of skin ceramides
(NMF) of tlIe epidermis (Rawlings et aI. 1994; Rudikoff (C2-C5, 6-1 and 6-11) have very long nonpolar tails and
1998). They retain a large amount of water (about 20%) the more polar head, corresponding to the sphingo-
that is tightly bound and difficult to extract by solvents sine-related base. Due to this structure, and especially
(Imokawa et al. 1991). For water retention within the because of the geometry of ceramide 1, ceramides
corneocytes, the plasma membrane is replaced by a arrange tlIemselves with their long intermingled tails
cornified envelope, an insoluble proteinaceous struc- forming nonpolar layers, limited on botlI sides by the
ture cross-linked irreversibly by transglutamination small polar ceramide heads (sphingosine base) tlIat
(Smack et aI. 1994), and further protected by an form a narrower polar layer (Kerscher et al. 1991;
external continuous lipid monolayer of ceramide 1 Forslind 1994). The nonpolar layers are stabilized by
that binds covalently to glutamate residues of the fatty acids and cholesterol (Martini 1995) and are
proteinaceous envelope (Chapman et aI. 1991). organized in a crystalline or gel phase (Forslind 1994)
In the outer 15 layers of tlIe SC, corneocytes adhere that is inflexible, impermeable to water and highly
to one another by rudimentary desmosomes - the resistant to heat and oxidation (Kerscher 1991). The
corneosomes - (Chapman et al. 1991) and by the alternating narrower polar layers, formed by the heads
intercellular lipid bilayers bound tightly to cer amide 1 of tlIe ceramides and fatty acids, are in a fluid state,
of the envelope, which work as tlIe scaffold for these have the capacity to handle some molecules of water
intercellular lipids (Schurer et al. 1991) and for tlIeir and are responsible for the bilayers pliability (Forslind
correct orientation along the surface of the corneocytes 1994; Martini 1995).
(Ponec et al. 1997). At the stratum disjunctum, cer- This multilamellar structure with stable alternating
amide 1 is probably hydrolyzed by ceramidases or nonpolar crystalline hydrophobie layers and polar
surfactant-like lipids (Rawlings et al. 1994) and the hydrophilie fluid layers, is the main component of tlIe
desmosomes are degraded by humidity-dependent permeability barrier of the skin that prevents excessive
proteases, allowing the normal unicellular corneocyte water loss, although it still allows some movement of
desquamation (Rawlings et aI. 1995; Rudikoff 1998). water and hydrophilie substances through tlIe fluid
phase (Forslind 1994). The moleeules of water retained
The Intercellular Lipid Matrix within this structure and the nearby resident corn-
eocytes are responsible for maintaining tlIe pliability
The corneocytes are embedded in a complex lamellar and extensibility of the SC (Forslind 1994; Cork 1997)
lipid matrix forming 20% of the volume of the SC and for coordinately regulating the activity of SC
(Forslind 1994) and 8-10.3% of its total dry weight enzymes, such as the proteases that degrade corneo-
(Schurer et al. 1991; Martini 1995). The main epidermal somes (Rawlings et al. 1995; Rudikoff 1998) and pro-
lipids are the ceramides (±49%), fatty acids (±26%) teases that cleave profilagrin and filagrin into the NMF
and cholesterol (±20%) (Forslind 1994). Within the (Rawlings et al. 1994).
deeper keratinocytes, these lipids are collected in the
epidermal lamellar bodies or Odland bodies, already Dynamics of the Skin Barrier
disposed in lamellae, and are then discharged to tlIe
extracellular space at the upper layers of the stratum To keep up its efficiency, the skin barrier has sensitive
granulosum. They are synthesized eitlIer "de novo" or sensors tlIat detect minor barrier disruptions and
from rearrangement of polar lipid precursors, as induce reparative mechanisms: loss of the extracellular
92 M. Gon~alo
Ca2+ and K+ concentration gradient in the epidermis Dry skin, which is difficult to define, has subjective
due to the outward movement of water, production of and objective clinical symptoms, and morphological
cytokines by subcorneal "less-protected" keratinocytes modifications on histology (Rudikoff 1998). It can be
[tumor necrosis factor alpha (TNF-et), interleukin (IL)- quantified by bio engineering methods such as con-
1et and ß, and granulocyte-macrophage colony-stimu- ductance and capacitance, which are directly depen-
lating factor (GM-CSF); and feedback signaling by dent on the water content of the se and, indirectly, by
modified ceramides and sphingosine (Elias et al. 1993). TEWL (Berardesca and Borroni 1995), which is the best
Reparative mechanisms are activated within minutes measure for epidermal skin barrier efficiency, espe-
after an aggression and consist of the following (Elias cially on dynamic studies (Reed et al. 1995).
et al. 1993; Mao-Quiang et al. 1993): (1) almost imme- Dry skin complaints often begin as asensation of
diate extrusion of the content of the preformed tightness and/or pruritus that develops spontaneously
lamellar bodies to the extracellular space, forming or on contact with woolen clothing, and especially at
competent bilayers as early as 2 h after an insult (Elias night. The objective signs of xerosis are a rough skin
et al. 1993); (2) sequential increase in the synthesis of with a dull grayish-white accentuation of normal skin
cholesterol, fatty acid and ceramides (Ghadially furrows, scaling and erythema with linear excoriation
et al. 1995; Abeck et al. 1997; Harris et al. 1997); or tiny superficial cracks in a retiform pattern (as
(3) formation of new lamellar bodies and their cracked porcelain or cracks in the dry mud) with
replenishment by newly synthesized lipids; and polygonal scales adherent in the center and with
(4) DNA synthesis and keratinocyte proliferation (Elias slightly elevated borders - "erythema craquelt?'
et al. 1993; Abeck et al. 1997). These processes seem to (Rudikoff 1998; Thune 1996a).
occur in two sequential phases: an acute recovery In cases of prolonged exposure to a hot, low
phase mainly dependent on cholesterol and FF A humidity ambient or to cold, dry wind in winter, dry
synthesis (first 6 h in mice), and a late recovery phase skin occurs mainly in air-exposed areas such as the
that is much slower and is dependent on ceramide and dorsa of the hands and the face, particularly the beard
DNA synthesis and epidermal proliferation (Ghadially area, where there is the extra daily insult of shaving.
et al. 1995; Harris et al. 1997). The anterior shins, lateral aspects of the thighs,
There are confiicting results concerning the time forearms, upper arms, and lower back are frequently
necessary for complete recovery: in mice it occurs involved, eventually due to the rubbing effect of
within 24-36 h (Mao-Quiang et al. 1995), whereas clothing or to over cleaning attitudes in the bath
studies conducted in man, using TEWL as a measure (Marks 1992). In the hands, it is the palms and
ofbarrier function, showed a 50% recovery by 24 h but fingertips near the lateral nail margins which are
complete recovery occurred only by day 7, indepen- mainly affected, especially when hand washing and
dently of the acute insult that induced a similar degree contact with detergents and surfactants is frequent, as
of barrier disruption (Ghadially et al. 1995). Inter- in health care workers, restaurant professionals or
study variations can be due to individual differences or hairdressers (Rudikoff 1998). This occurs because in
external infiuences that delay or even abrogate barrier the palmar SC, lipids are scarce, making it more
recovery. Nevertheless, there is a variable period of susceptible to agents that disturb lipid lamellar
transient barrier incompetence, when an environmen- arrangement (Schurer et al. 1991; Abeck et al. 1997).
tal aggression may further disrupt the fragile skin
barrier and induce skin lesions, such as dry skin or dry Environmental Insults to the Barrier
eczema.
The main environmental occupational factors that
interfere with barrier function and cause dry skin are:
Dry Skin in Occupational Settings
(1) physical factors, e.g., temperature, relative humidity
of the air and ultraviolet rays (UVRs); (2) mechanical
There are occupational settings in which dry skin factors, e.g., repeated skin rubbing and strain; and
occurs frequently, due to different types of aggression (3) chemical factors, e.g., solvents, surfactants and water.
- physical, chemical, mechanical - that separately,
concomitantly or sequentially disturb the epidermal Phys;cal Insults
skin barrier. However, dry skin does not uniformly
affect all workers; it occurs mainly in winter and only Epidermal lamellar lipids, namely ceramides, show
in more susceptible individuals, namely older ones little structural change with supra-physiologic temper-
(Ghadiallyet al. 1995; Rogers et al. 1996) or those with atures from 37 oe to 40 oe (Forslind 1994), but
intrinsic defects in the skin barrier, such as atopics sequential exposure to cold and hot temperatures
(Imokawa et al. 1991; Elias et al. 1993; Di Nardo may disturb the barrier. This occurs iIi office workers
et al. 1996; Abeck et al. 1997). who stay for prolonged periods in the warm atmo-
sphere of their office and then leave into the cold, dry the SC (Haratake et al. 1997a). This explains more
winter outdoors or, during summer months, when they frequent dry skin complaints after a sunburn, partic-
stay in the cold, dry air-conditioned atmosphere of ularly in younger individuals whose skin is more prone
their office and then leave into the humid and hot to UV -barrier disruption (Haratake et al. 1997b).
outdoor weather (Rudikoff 1998).
Exposure to very low temperatures has profound
effects on skin barrier function and is a frequent cause Chemical Insults
of occupational dry skin, namely in the fish-processing
industry. During work, while individuals manipulate Dry skin, often as the precursor lesion of an irritant
frozen fish or fish stored in ice, the skin of their hands contact dermatitis, is induced mainly by organic
has a very low temperature (20°C) and they do not solvents and surfactants that disturb the skin barrier
complain of dry skin but, as soon as they warm their either by acute or repeated smaller insults (Shmunes
skin, hands get dry with highly increased TEWL. As 1990; Rudikoff 1998). Organic solvents (aliphatic,
ShOWll by complementary animal studies, cold blocks aromatic or chlorinated hydrocarbons, alcohols, ethers
the formation of new lamellar bodies interfering with and ketones) are extensively used in industries for
barrier formation and recovery and it also abrogates chemical reactions in organic synthesis, for chemical
the signals for barrier disruption. Consequently, dur- extraction processes and as degreasing and dewaxing
ing working ho urs, no symptoms are perceived by agents. Direct contact with skin is usually avoided, as
patients; after work, when the temperature returns to cutaneous and systemic harmful effects of solvents
normal, the cold-disrupted skin barrier allows too absorbed through the skin are well known, but due to
much water loss and the skin gets dry before the their good degreasing properties, workers sometimes
reparative mechanisms become effective (Halkier- use them incorrectly as a cleaning agent for their skin
Sorensen 1996b). or their clothing (Shmunes 1990; Svendsen and Hilt
Low relative humidity of the air, namely in air- 1997). Also, volatile hydrocarbons can contaminate the
conditioned office buildings, hospitals or aircraft, occupational environment and induce dry skin in air-
facilitates the loss of the water that is less tightly exposed areas (Rycroft and Smith 1980) and, in this
bound to the SC (Rudikoff 1998). However, normal way, facilitate allergic contact dermatitis. This
skin does not modify its water content when it stays for occurred among us in a small histopathology depart-
short periods in environments with low relative ment of our faculty: after a long period of dry skin
humidity, such as commercial aircraft (7-12%) complaints attributed to environmental contamination
(Rudikoff 1998), and it can stand environments with by xylol, formol and methanol, one doctor and a
a relative humidity around 30-35% for long periods laboratory technician developed allergic contact der-
(Wahlberg and Stenberg 1991; Eberlein-Konig matitis from an epoxy res in present in the immersion
et al. 1996). However dry skin can develop in an oil for microscopy.
environment with 35% relative humidity if there are Solvents, such as acetone or chloroform, reduce the
additional insults, such as airborne fiber glass or water-holding capacity of the SC by dissolving and
degreasing trichloroethylene vapors (Rycroft and extracting intercellular lipids (Thune 1996b; Abeck
Smith 1980). et al. 1997). Lipids can be completely removed, and
UVRs, both UV A and UVB, in suberythemogenic then the corneocytes adhere tightly to one another by
doses improve barrier function (Rawlings et al. 1995). the single ceramide 1 outer layer of the involucrum,
They increase all SC lipids (Lehmann et al. 1991), which prevents corneosome destruction (Chapman
especially ceramides (Rawlings et al. 1995), and en- et al. 1991) and disturbs desquamation (Rawlings
hance lamellar body extrusion from the corneocytes to et al. 1995).
the extracellular space (Fartasch et al. 1992). However, Cutaneous application of a surfactant, such as
after exposure to higher doses ofUVR (>3 or 4 MEDs- sodium lauryl sulfate (SLS) or dodecyl sulfate, induces
Minimal Erythema Dose), there is a delayed disruption dry, scaly skin (Thune 1996b) with decreased skin
of the permeability barrier with a significant increase capacitance and a dose-dependent increase in TEWL,
both in TEWL and in the penetration of xenobiotics which is significant by 24 hand maximal by 48-72 h
(Haratake et al. 1997b). Opposing the immediate sur- (Di Nardo et al. 1996; Welzel et al. 1996). There are
factant and solvent-induced barrier disruption, which contradictory results concerning the capacity of sur-
is dependent on their effect on corneal lipids, UV- factants to remove epidermal lipids in the same way as
induced skin barrier defects occur later (>48-72 h); solvents do (Thune 1996b; Di Nardo et al. 1996), and
they are due to the UV -induced inflammatory T-cell most studies suggest that they mainly disturb the
response, epidermal proliferation and an effect on the multilamellar layered lipid structure and facilitate lipid
deeper layers of the epidermis with the delivery of UV- removal, especially after prolonged skin contact
damaged "permeability-incompetent" keratinocytes to (Thune 1996b; Kawasaki et al. 1997). Actually, sur-
94 M. Gon~alo
factants bind to the lipid membranes (Kawasaki Skin Barrier Susceptibility

et al. 1997), disturb the arrangement and the mobility
of the lipid bilayers (Thune 1996b; Kawasaki There are intra- and inter-individual differences in
et al. 1997) and increase the water-permeable fluid skin barrier susceptibility to aggression and in its
phase of the intercellular lipids, which significantly recovery capacity; these can best be documented in
reduce the SC water-holding properties (Forslind 1994; dynamic studies of barrier function, including TEWL,
Kawasaki et al. 1997). They also affect lipid-pro tein both at basal conditions and at several intervals after
interactions, disturb the corneocyte envelope and allow an aggression (Reed et al. 1995). Small differences in
the loss of intracellular water and NMF molecules the constitution of epidermal lipids may be responsible
(Rawlings et al. 1994), and interfere with epidermal for such susceptibility. Di Nardo et al. showed that a
lipid synthesis (Loden and Andersen 1996) reducing reduction of SC ceramide content is associated with
the ceramide fraction, especially ceramides 2, 3 and 4 high er TEWL after surfactant aggression, with a
(Di Nardo et al. 1996). correlation between the type of ceramide deficiency
Surfactants, present in household and industrial and the response to aggression, e.g., a reduction of
detergents and in skin hygiene products, are one ceramide 1 is associated with a higher TEWL at 24 h;
important cause of occupational dry skin, namely in ceramide 611 seems to influence later stages of barrier
hairdressers or dish washers, who contact the deter- recovery, with increase in TEWL later (72 h), whereas a
gent in their work, or in occupations where hand relative deficiency in ceramide 61 is responsible for
washing is frequent, such as hospital workers, food increased erythema after surfactant aggression (Di
handlers and typists. In these settings, dry skin Nardo et al. 1996).
develops due to repeated and cumulative insults of Besides skin diseases that affect the skin barrier and
the surfactant and often by concomitant high temper- increase susceptibility to environmental aggression
ature, e.g. skin cleaning with hot tap water, or (atopic dermatitis, psoriasis, ichthyosis, essential fatty
mechanical friction, e.g. over cleaning attitudes in acid deficiency), other barrier modifications occur with
surgeons preparing for the operating theater. age, skin type, dietary factors, seasons of the year and
skin localization (Rawlings et al. 1994). There is no
significant difference between sexes, but skin type
Mechanical Insults VlVI is more resistant to damage and recovers more
quickly from environmental aggression than skin type
Mechanical factors, such as repeated skin rubbing or IIIIII (Reed et al. 1995). In old age, skin barrier is
friction induced by clothing or other devices used at normal under basal skin conditions, even with reduced
work, can remove the outermost SC layers, as in tape TEWL, but it is more easily disturbed and repairs very
stripping, and induce dry skin or increase the effect of slowly after extern al aggression (Ghadially et al. 1995).
other aggressive factors. Prolonged use of occlusive With increasing age, the SC becomes thinner and the
clothing or occlusive protective measures, such as total amount of epidermal lipids decreases progres-
impermeable gloves, especially over a previously sively (Imokawa et al. 1991; Rogers et al. 1996) with a
damaged dry skin, may further disturb barrier func- very significant reduction in ceramides (Imokawa
tion and aggravate dry skin (Halkier-Sorensen 1996a; et al. 1991); arrangement of the lipid bilayers is defec-
Ramsing and Agner 1996). Although there are contra- tive (Ghadially et al. 1995) and, mainly after an
dictory results showing no interference on human skin aggression, lipid synthesis is slower, secretion of
(Welzel et al. 1996), most studies have shown that lamellar bodies is reduced and they have very few
impermeable occlusive dressings over barrier-disrupt- lipid layers or are almost empty of lipids (Ghadially
ed skin are harmful. Water accumulates in the SC, et al. 1995).
which inhibits the feedback signals that control barrier In contrast to summer and spring, during winter
repair (Elias et al. 1993; Harris et al. 1997) and, due to there is a significant reduction (30%) in the total
SC overhydration, the conversion of profilagrin to amount of SC lipids, although the relative percentage
filagrin and NMF does not occur at the upper stratum of the main lipid fractions is maintained (Rogers
granulosum. When the occlusive effect is removed, et al. 1996). Nevertheless, the more saturated oleate
NMF will be formed only on the innermost SC layers, fatty acid replaces the unsaturated linoleate of cer-
while the most externallayers that are deficient in NMF amide 1, which (linoleic acid) is very important for SC
lose water (Rawlings et al. 1994). Usually workers use flexibility and bilayer fluidity (Rogers et al. 1996). This
impermeable gloves or other impermeable clothing, explains predominance of dry skin complaints in
especially if they have already experienced some winter, along with winter pruritus and winter eczema
symptoms of dry skin, and this often aggravates their (Rudikoff 1998).
skin condition (Halkier-Sorensen 1996a; Ramsing and In the hands, palmar SC is more susceptible to
Agner 1996). solvents or surfactants and chapping, hyperkeratosis
and fissuration often affect the palms while sparing the by an oligoclonal T-lymphocyte proliferation by super-
dorsal hand (Abeck et al. 1997). Even though the antigens (Hauser et al. 1996).
palmar SC is thicker, it has fivefold less lipid between Also, after acute or chronic barrier disruption, the
the corneocytes (2%) (Schurer et al. 1991; Rogers skin exhibits a subtle state of continuous dermo-
et al. 1996) and the supra-basal highly flexible gly- epidermal inflammation, with altered cutaneous
cine-rich K1-10 keratin pairs, present in other skin immunoregulatory mechanisms that may lead to
areas, are replaced by the less pliable K6-16 pairs, eczema: (1) keratinocytes produce pro-inflammatory
usually associated with hyperproliferation and barrier cytokines, such as TNF-Cl, IL-1, IL-8 and GM-CSF
disruption (psoriasis) (Smack et al. 1994). (Nickoloff and Naidu 1994; Wood et al. 1992, 1994;
Among skin diseases affecting skin barrier, atopic Nishijima et al. 1997); (2) epidermal Langerhans' cell
dermatitis is associated most frequently with occupa- density increases proportionally with the degree of
tional dry skin symptoms (Seidenari 1996; Abeck barrier disruption, reaching its maximum density by
et al. 1997). Atopic dermatitis patients characteristi- 24-48 h (Proksch et al. 1996); (3) epidermal Langer-
cally have a dry skin, especially when exposed to hans' cells show activation markers, expressing a
surfactants (Seidenari 1996), hot water and exaggerated higher number of the co-stimulatory moleeules HLA-
cleaning measures, and they are the main individuals 11, CD54 and CD86 (Nishijima et al. 1997); and
to develop dry skin complaints in low-humidity (4) Langerhans' cells isolated from disrupted barrier
environments (Eberlein-Konig et al. 1996). They have skin exhibit an increasing capacity for antigen
a basal increased TEWL, reflecting a disturbed SC presentation and T-cell stimulation/sensitization
water-holding capacity (Fartasch et al. 1992), a lower (Nishijima et al. 1997).
resistance to aggression and a slower recovery phase. In atopic dermatitis, there is evidence that dry skin
They have a near 50% reduction in the SC lipid content and eczema are related; sphingomyelin is not used for
along with a very significant reduction of ceramide 1, synthesizing the ceramides due to an abnormal sph-
both in lesional and non-lesional skin (Imokawa ingomyelin acylase activity. Instead, it is metabolized
et al. 1991); sphingomyelin is not committed to cer- into the pro-inflammatory sphingosyl-phosphorylcho-
amide synthesis due to a sphingomyelin acylase line that enhances arachidonic acid or eicosanoid
deficiency (Murata et al. 1996). Also, in atopic dry release and increases membrane ICAM-1 expression in
skin, lamellar bodies are incompletely fused with the human keratinocyte cultures (Murata et al. 1996).
plasma membrane and their conte nt is not regularly Dermal cutaneous vascular response is also altered
extruded to the intercellular space, which explains by barrier disruption: after exposure to SLS for three
intercellular lipid reduction (Fartasch et al. 1992). consecutive days, the skin exhibits an increased
cutaneous blood flow after exposure to tap water
(Ramsing and Agner 1997), which probably explains
frequent patient complaints that water aggravates their
From Occupational Dry Skin To Eczema
dry skin or hand dermatitis.
Therefore, patients with dry skin continuously
When the barrier function is disturbed, besides exces- exposed to an aggressive environment are more prone
sive loss of water to the environment and consequent to develop eczematous conditions, either by non-
dryness, the skin becomes more vulnerable to exoge- immune or immediate and/or delayed immune me ch-
nous hazards: (1) there is an increased penetration of anisms. For instance, hairdressers who are exposed
irritants, namely surfactants, solvents and enzymes continuously to water and shampoos develop dry
(Haratake et al. 1997b), with a lowered threshold to hands frequently, followed by an irritant contact
induce irritant contact dermatitis (Seidenari 1996); dermatitis, then allergie contact dermatitis to occupa-
(2) most allergens have an easier access to the stratum tional allergens. Immediate-type allergie contact der-
spinosum, where they react with living keratinocytes matitis, like pro tein contact dermatitis or contact
and Langerhans' cells and induce skin sensitization urticaria also occur more frequently in patients with
or initiate allergie contact dermatitis in sensitized dry hands, namely in the catering or fish processing
individuals (Gons:alo 1996); and (3) mites and microor- industries (Halkier-Sorensen 1996b) or in surgeons
ganisms adhere more easily to the skin, as occurs with and nurses who are exposed to latex gloves after
Staphylococcus aureus in atopic dry skin, and their exaggerated hand cleaning measures.
enzymes or other secretion products, their allergens or Also, patients with dry skin, namely those with atopic
their superantigens penetrate the SC more easily and dermatitis, frequently develop face and eyelid eczema
induce cutaneous eczematous reactions. This can occur when they are exposed to polluted air and cigarette
in several ways: by a nonspecific cutaneous inflamma- smoke or simply to the dry and cold winter wind or to
tion (Murata et al. 1996), by an antigen-specific immune hot and dry air-conditioning (Eberlein-Konig
activation mast cells or sensitized T lymphocytes or et al. 1996). When they abuse hot water baths and
96 M. Gon~alo
soaps, especially antiseptie soaps, they develop "eeze- and their relative amount may be responsible for
ma craquel!?' or "aesteatotie eezema". This is present as disparate results on barrier proteetion and recovery.
very pruriginous, ill-defined erythematous patehes with For instance, the addition of 0.1% chlorhexidine to a
roughened and dry skin that cracks superficially, barrier cream delays the later phases of barrier
ereating red intereonneeted fissures that form a recovery, very probably by the aggression on deeper
geometrieal 'crazy-paving' aspect (Thune 1996a; Rudik- keratinocytes that are preparing the lipid bilayers
off 1998), or as circular erythematous plaques with a (Halkier-Sorensen 1996a).
vesicular or crusted well-limited border and a tendeney There are several topical agents, usually called
to central clearing (Wahlberg and Stenberg 1991). moisturizers or emollients, that ameliorate the mani-
festations of dry skin (turn it smoother, more pliable
and extensible and less sealy) and also restore or
Treatment Of Dry Skin
improve the protective barrier against the penetration
of environmental hazards (Marks 1997). Moisturizers
When considering the treatment of dry skin conditions work mainly via three different meehanisms. Humect-
in an oceupational setting, it is most important to ants, such as glycerin and sorbitol, urea, laetie acid and
eorreet first any environmental aspeet that may be pyrrolidone carboxylic acid [PCAJ, whieh diffuse and
responsible for the chronie barrier disruption (tem- fix themselves into the SC, attraet and retain water and,
perature, relative air humidity, cleaning products or thereby, increase SC water content. Occlusive emol-
proteetive measures) and this may be sufficient to eure lients are formed mainly by lipids from animal fats
dry skin. (lanolin and derivatives), vegetable or vegetable-based
Particular attention should be paid to the prolonged oils (olive oil, eoconut oil, primrose oil), mineral oils
use of impermeable gloves, a frequent complaint (vaseline and light paraffin oil), synthetie oils (syn-
among hospital personnel and dentists, especially if thetie silicone oils) or waxes (beeswax, paraffin wax).
the hands have been previously exposed to soaps, Physiologie lipid mixtures, eonsisting of ceramides,
detergents, disinfectants or irritants (apart from delay- cholesterol and free fatty acids mixed in physiologie
ing barrier recovery, impermeable gloves inerease the proportions, are incorporated into the naseent multi-
damaging effeet of these substances). Cotton gloves lamellar bilayers therefore helping in the reconstitu-
used under the rubber gloves prevent the harmful effect tion of the physiologie skin barrier (Mao-Quiang
of glove oeclusion on barrier recovery and ameliorate et al. 1993; Mao-Quiang et al. 1996). Petrolatum, an
cutaneous symptoms (Ramsing and Agner 1996). occlusive emollient constituted mostly by inert lipids,
Exposure to low-dose UVR may benefit other types penetrates within the intercellular spaees, takes the
of dry skin, beyond atopic dry skin and atopic eczema, plaee of the lipids in the upper SC layers and has a
as it inereases ceramides and all other SC lipids transient but very efficient occlusive effect, preventing
(Lehmann et al. 1991; Rawlings et al. 1995; Rawlings the movement of the water to the environment and
et al. 1996). However, even without sun exposure, promoting its slow accumulation in the SC (Ghadially
during summer, barrier funetion improves due to the et al. 1992; Mao-Quiang et al. 1995).
inereased lipid production (Rogers et al. 1996). Some substanees, usually included in moisturizers,
In the case of more suseeptible workers or when the have other potential beneficial effeets on dry skin:
environmental factors eannot be correeted, other (1) the L-isomer oflactic acid inereases the endogenous
measures must be used to prevent and treat dry skin synthesis of ceramides and prornotes the ineorporation
and avoid progression to eezema and increased of linoleate, instead of oleate, into ceramide 1 (Raw-
penetration of harmful xenobioties. In individuals with lings et al. 1996); (2) glycerol and other polyols prevent
predominantly wet work, who eontaet with surfactants lipid crystallinity (Rawlings et al. 1994), inerease SC
and foods, frequent application of petrolatum or a humidity and promote corneosome digestion and,
lipid-rieh emollient protects them from developing dry consequently, the unicellular invisible desquamation
skin, e.g., in experimental conditions previous appli- (Rawlings et al. 1995); (3) alpha-hydroxy acids im-
cation of a lipid-rieh emollient reduced the SLS- prove keratinization and SC hydration (Leyden
induced TEWL increase (Halkier-Sorensen 1996a; et al. 1995); and (4) silicones or silieone-based barrier
Loden 1997). Nevertheless, these eonclusions cannot ereams may have an extra proteetive effeet on external
be extended to all occupational settings and to every aggressions.
commercial emollient available; different aggressions The combined use of these substances is the rule, as
in the working place need different protective mea- they can have an additive beneficial effect: humectants
sures, whieh are not yet weIl standardized or adjusted have a very effective and almost immediate effect of
for every partieular case. In addition, for each protec- attracting water to the SC and, if we add an occlusive
tive cream studied, whose complete constitution is lipid-rich emollient that penetrates the intercellular
seldom known, a small difference in the ingredients space, it will keep the water trapped within the SC and
prevent its loss. Because this emollient effect is transient Eberlein-Konig B, Spiegel A, Przybilla B (1996) Change of skin
(4-6 h), physiologic lipid mixtures that incorporate roughness due to lowering air humidity in c1imate chamber.
Acta Derm Venereol 76:447-449
themselves within the lamellar layers will have a more Elias PM (1983) Epidermal lipids, barrier function, and desqua-
delayed but prolonged effect (Mao-Quiang et al. 1996), mation. J Invest Dermatol 80:44-49
Elias PM, Holleran WM, Menon GK, Ghadially R, Williams ML,
probably similar to the use of substances that promote Feingold KR (1993) Normal mechanisms and pathophysiol-
ceramide synthesis. Nevertheless, these substances have ogy of epidermal permeability barrier homeostasis. Curr
to be mixed in adequate proportions in order to avoid a Opin Dermatol1:231-237
deleterious effect on the skin barrier; the use of isolated Fartasch M, Bassukas ID, Diepgen TL (1992) Disturbed extruding
mechanism of lamellar bodies in dry non-eczematous skin of
ceramides or cholesterol or an unbalanced mixture of atopics. Br j DermatoI127:221-227
physiologic lipids in a previously disturbed skin Forslind B (1994) A domain mosaic model of the skin barrier.
barrier is more harmful than beneficial (Mao-Quiang Acta Derm Venereol Suppl (Stockh) 74:1-6
Ghadially R, Halkier-Sorensen L, Elias PM (1992) Effects of
et al. 1993; Mao-Quiang et al. 1996). petrolatum on stratum corneum structure and function. j Am
As knowledge increases regarding the skin barrier Acad Dermatol 26:387-396
and how to modify it, the old art of making emollients Ghadially R, Brown BE, Sequeira-Martin SM, Feingold K, Elias PM
(1995) The aged epidermal permeability barrier. Structural,
to treat dry skin, dating back to the 'cold cream' of functional, and lipid biochemical abnormalities in humans
Galien, is turning into the new, developing science of and asenescent murine model. j Clin Invest 95:2281-2290
Gon~a1o M (1996) Fisiopatologia da dermatite de contacto
making moisturizers that clear dry skin, improve
alergica. 0 papel do ceratinocito. Boletim informativo do
disrupted skin barrier, accelerate recovery and protect GPEDC 10:6-19
it from specific environmental aggressions. There are Halkier-Sorensen L (1996a) Preventive activities. General aspects
several available ingredients with additive effects that and the efficacy of emollients and moisturizers. Contact
Dermatitis 35: [SUppI1]:89-120
can be mixed in water-in-oil, oil-in-water or more Halkier-Sorensen L (1996b) Skin problems in an industry. A
complex emulsions that are more acceptable to the multidimensional approach to identify the injury causing
patient and are best adapted to each occupational factor(s). An example from the fish processing industry.
Contact Dermatitis 35[Suppl1]:45-87
setting. For the moment, studies clearly show benefits Haratake A, Uchida U, Schmuth M, Tanno 0, Yasuda R, Epstein
from correct use of adequate moisturizers in protec- JH, Elias PM, Holleran WM (1997a) UVB-induced alterations
ting against harmful occupational aggressions and in in permeability barrier function: roles for epidermal hyper-
proliferation and thymocyte-mediated response. j Invest
treating dry skin in certain occupational settings. DermatoI108:769-775
However, there is still much more to do in adapting Haratake A, Uchida U, Mimura K, Elias PM, Holleran WM
each emollient to each particular occupation, to each (1997b) Intrinsically aged epidermis displays diminished
UVB-induced alterations in barrier function associated with
particular patient and either as a preventive or a decreased proliferation. J Invest Dermatol 108:319-323
treatment for dry skin conditions. Harris IR, Farrel AM, Grunfeld C, Holleran WM, E1ias PM,
For the present, because these rules are not well Feingold KR (1997) Permeability barrier disruption coordi-
nately regulates mRNA levels for key enzymes of cholesterol,
established, emollients should be used for occupational fatty acid and ceramide synthesis in the epidermis. J Invest
dry skin, although somehow empirically, and as both a Dermatol 109:783-787
preventive and a therapeutic measure. We should try Hauser C, Prins C, Lacour M (1996) The role of infectious agents
in atopic dermatitis. In: Leung DYM (ed) Atopic dermatitis:
to adapt the emollient to each patient and to each from pathogenesis to treatment. Springer, Berlin Heidelberg
occupation, let the patient choose the emollient with New York, pp 67-112
which he feels best, and use a topical corticosteroid Holleran WM, Takagi Y, Menon GK, Legler G, Feingold KR, Elias
PM (1993) Processing of epidermal glucosylceramides is
whenever eczematous changes develop on dry skin, as required for optimal mammalian cutaneous permeability
steroids improve inflammation and do not further barrier function. J Clin Invest 91:1656-1664
disturb the skin barrier (Loden and Andersen 1996; Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A
(1991) Decreased levels of ceramides in stratum corneum of
Halkier-Sorensen 1996a). atopic dermatitis: an etiologic factor in atopic dry skin?
J Invest Dermatol 96:523-526
Kawasaki Y, Quan D, Sakamoto K, Maibach HI (1997) Electron
References resonance studies on the influence of anionic surfactants on
human skin. Dermatology 194:238-242
Kerscher M, Korting HC, Schafer-Korting M (1991) Skin cer-
Abeck D, Bleck 0, Ring J (1997) Skin barrier and eczema. In: Ring amides: structure and function. Eur J Dermatol 1:39-43
J, Behrendt H, Vielluf D (eds) New trends in a1lergy IV. Lehmann P, Holze E, Melnik B, Plewig G (1991) Effects of
Springer, Berlin Heidelberg New York, pp 213-220 ultraviolet A and B on the skin barrier: a functional, electron
Berardesca E, Borroni G (1995) Instrumental evaluation of skin microscopic and lipid biochemical study. Photodermatol
hydration. Clin Dermatol 13:323-327 Photoimmunol Photomed 8:129-134
Bonte F, Saunois A, Pinguet P, Meybeck A (1997) Existence of a Leyden J, Lavker R, Grove G, Kaidbey K (1995) Alpha hydroxy
lipid gradient in the upper stratum corneum and its possible acids are more than moisturizers. J Geriatr Dermatol [Suppl
biologic significance. Arch Dermatol Res 289:78-82 A3]:33-37
Chapman Sj, Walsh A, jackson SM, Friedmann PS (1991) Lipids, Loden M (1997) Barrier recovery and influence of irritant stimuli
pro teins and corneocyte adhesion. Arch Dermatol Res in skin treated with a moisturizing cream. Contact Dermatitis
283:167-173 36:256- 260
Cork MJ (1997) The importance of skin barrier. J Dermatol Loden M, Andersson A-C (1996) Effect of topically applied lipids
Treatment 8:S7-S13 on surfactant irritated skin. Br j Dermatol 134:215-220
98 M. Gon~alo: Occupational Dry Skin
Mao-Quiang M, Feingold KR, Elias PM (1993) Exogenous lipids Rawlings AV, Davies A, Carlomusto M, Pillai S, Zhang K,
influence permeability recovery in acetone-treated murine Kosturko R, Verdejo P, Feinberg C, Nguyen L, Chandar P
skin. Arch DermatoI129:728-738 (1996) Effect of lactic acid isomers on keratinocyte ceramide
Mao-Quiang M, Brown B, Wu-Pong S, Feingold KR, Elias PM synthesis, stratum corneum lipid levels and stratum corneum
(1995) Exogenous nonphysiologic vs physiologic lipids. barrier function. Arch Dermatol Res 288:383-390
Divergent mechanisms for correction of permeability barrier Reed JT, Ghadially R, Elias PM (1995) Skin type, but neither race
dysfunction. Arch Dermatol 131:809-816 nor gender, influence epidermal permeability barrier recov-
Mao-Quiang M, Feingold KR, Thornfeldt CR, Elias PM (1996) ery. Arch DermatoI131:1134-1138
Optimization of physiological lipid mixtures for barrier Rogers J, Harding C, Mayo A, Banks J, Rawlings A (1996) Stratum
repair. J Invest Dermatol 106:1096-1101 corneum lipids: the effect of aging and the seasons. Arch
Marks R (ed) (1992) Eczema in the elderly. In: Eczema. Martin Dermatol Res 288:765-770
Dunitz, London, pp 170-191 Rudikoff D (1998) The effect of dryness on the skin. Clinics in
Marks R (ed) (1997) Emollients. Martin Dunitz, London, pp 1-44 DermatoI18:99-107
Martini M-C (1995) Importance des lipides dans la fonction Rycroft RJG, Smith WDL (1980) Low humidity occupational
barriere epidermique. Bull Esthet Dermatol Cosmetologie derma tos es. Contact Dermatitis 6:488-492
3:273-281 Schurer NY, Plewig G, Elias PM (1991) Stratum corneum lipid
Murata Y, Ogata J, Higaki Y, Kawashima M, Yada Y, Higuchi K, function. Dermatologica 183:77-94
Tsuchiya T, Kawaminami S, Imokawa G (1996) Abnormal Seidenari S (1996) Skin sensitivity, inter-individual factors: atopy.
expression of sphingomyelin acylase in atopic dermatitis: an In: Valk P, Maibach HI (eds) The irritant contact dermatitis
etiologic factor for ceramide deficiency? J Invest Dermatol syndrome. CRC Press, Boca Raton, pp 267-277
106:1242-1249 Shmunes E (1990) Solvents and plasticizers. In: Adams RM
Di Nardo A, Sugino K, Wertz P, Ademola J, Maibach HI (1996) (ed) Occupational skin diseases. Saunders, Philadelphia, pp
Sodium lauryl sulfate (SLS) induced irritant contact derma- 439-461
titis: a correlation study between ceramides and in vivo Smack DF, Korge BP, James WD (1994) Keratin and keratinaza-
parameters of irritation. Contact Dermatitis 35:86-91 tion. J Am Acad Dermatol 30:85-102
Nickoloff BJ, Naidu Y (1994) Perturbation of epidermal barrier Spencer TS (1988) Dry skin and skin moisturizers. Clin Dermatol
function correlates with initiation of cytokine cascade in 6:24-28
human skin. J Am Acad Dermatol 30:535-546 Svendsen K, Hilt B (1997) Skin dis orders in ship's engineers
Nishijima T, Tokura Y, Imokawa G, Seo N, Furukawa F, Takigawa exposed to oils and solvents. Contact Dermatitis 36:216-220
M (1997) Altered permeability and disordered cutaneous Thune P (1996a) Special syndromes: asteatotic eczema/xerosis
immunoregulatory function in mice with acute barrier cutis. In: van der Valk P, Maibach HI (eds) The irritant
disruption. J Invest Dermatoll09:175-182 contact dermatitis syndrome. CRC Press, Boca Raton, pp
Ponec M, Weerheim A, Kempenaar J, Mulder A, Gooris GS, 251- 254
Bouwstra J, Mommaas AM (1997) The formation of compe- Thune P (1996b) The effects of detergents on hydration and skin
tent barrier lipids in reconstructed human epidermis requires surface lipids. Clin Dermatol 14:29-33
the presence of vitamin C. J Invest Dermatol 109:348-355 Wahlberg JE, Stenberg B (1991) Skin problems in the office
Proksch E, Brasch J, Sterry W (1996) Integrity of the permeability environment. In: Menne T, Maibach HI (eds) Exogenous
barrier regulates epidermal Langerhans cell density. Br J dermatoses: environmental dermatitis. CRC Press, Boca
Dermatol 134:630-638 Raton, pp 327-338
Ramsing DW, Agner T (1996) Effect of glove occlusion on human Welzel J, Wilheim KP, Wolff HH (1996) Skin permeability barrier
skin (11) long term exposure. Contact Dermatitis 34:258-262 and occlusion: no deiay of repair in irritated human skin.
Ramsing DW, Agner T (1997) Effect of water on experimentally Contact Dermatitis 35:163-168
irritated human skin. Br J Dermatol 136:364-367 Wood LC, Jackson SM, Elias PM, Grunfeid C, Feingold KR (1992)
Rawlings A, Scott I, Harding C, Bowser P (1994) Stratum corneum Cutaneous barrier perturbation stimulates cytokine produc-
moisturization at the molecular level. J Invest Dermatol tion in the epidermis of mice. J Clin Invest 90:482-487
103:731-740 Wood LC, Feingold KR, Sequeira-Martin SM, Elias PM, Grunfeid
Rawlings A, Harding C, Watkinson A, Banks J, Ackerman C, C (1994) Barrier function coordinately regulates epidermal
Sabin R (1995) The effect of glycerol and humidity on IL-I and IL-I receptor antagonist mRNA levels. Exp Dermatol
desmosome degradation in the stratum corneum. Arch 3:56-60
Dermatol Res 287:457-464
CHAPTER 11
Contact Dermatitis Due to Irritation

W. Wigger-Alberti and P. Elsner
Introduction Clinical Types of Irritant Contact Dermatitis
Irritant contact dermatitis (ICD), defined as Ha nonim- Irritants produce a wide range of elinieal features.
munologic local inflammatory re action characterised by Cutaneous responses depend on the type of irritant
erythema, oedema or corrosion following single or (Table 2), the concentration at which the irritant
repeated application of a chemieal substance to an comes into contact with the skin, the type of exposure,
identical cutaneous site" (Mathias and Maibach 1978), is and the individual response. Clinical manifestations of
a leading cause of occupational disease in dermatology ICD syndromes are also modified by external factors,
and causes economie damage to workers, companies, such as environmental factors (mechanical pressure,
and social-security systems worldwide. The perception temperature, and humidity) and predisposing charac-
of ICD as more trivial than the more intellectually teristics of the individual (age, gender, ethnic origin,
appealing problem of allergic sensitisation has recently pre-existing skin disease, atopic skin diathesis and the
changed dramatically. In Germany, skin diseases are the anatomie region exposed) (Pinnagoda et al. 1989;
second most frequent occupational disease fOllowing Emtestam and Ollmar 1993).
musculoskeletal dis orders, and most occupational For instance, elderly people are not only affected
dermatoses are cases of contact dermatitis. Among more often by contact dermatitis because of their
these, ICD is probably more frequent than allergic reduced epidermal barrier, they also show more severe
contact dermatitis (ACD), although reliable data are still symptoms of this disease (Patil and Maibach 1994;
very limited. In contrast to ACD, ICD is defined as being Ghadially et al. 1995). Environmental influences, such
the result of primarily nonspecific damage to the skin. It as cold and low ambient humidity, are important
is not a elinical entity but rather a spectrum of diseases. factors in decreasing the water conte nt of the stratum
The elinical aspect of ICD is determined by the dose- corneum (Mozzanica 1992). Cold alone may also
effect relationship (Patil and Maibach 1994). The reduce the plasticity of the horny layer, with conse-
morphology of acute ICD ineludes erythema, oedema, quent cracking of the stratum COrneum. Ocelusion
vesieles that may coalesce, bullae and oozing (Figs. 1,2). increases the water content of the stratum corneum,
Necrosis and ulceration is seen with corrosive materials with consequent enhanced percutaneous absorption of
(Fig. 3). The elinical features of chronie ICD inelude water-soluble substances. A list of factors influencing
redness, lichenification, excoriations, scaling and tlIe irritancy potential of substances are summarised in
hyperkeratosis (Figs. 4, 5). Any skin site may be Table 3.
affected. However, most frequently affected by ICD are Several different types of ICD have been described
the hands, as they are the human "tools" that interact (Lammintausta and Maibach 1990; Berardesca and
with the environment most and have intensive contact Distante 1995; Iliev and EIsner 1997):
with irritants. Spilling of fluids may irritate the forearms
or other body sites, especiallY when fluids soak through Acute
work elothes. Airborne ICD develops in irritant- Acute delayed
exposed, sensitive skin, mostly the face and especially Irritant reaction
the periorbital region (Dooms-Goossens et al. 1986; Cumulative
Lachapelle 1986). A compilation of substances that Traumiterative
cause airborne ICD is presented in Table 1. Irritant Exsiccation eczematid
dermatitis caused by dust may mimic textile dermatitis, Traumatie
with lesions most prominent in sites with elose skin- Pustular and acneiform
garment contact, such as the axilla, the gluteal region or Nonerythematous
the thighs (Hafner et al. 1995) Subjective

100 W. Wigger-Alberti and P. Eisner
characterised by the crescendo phenomenon (i.e. a

tran sie nt increase of signs and symptoms despite
removal of the allergen). The clinical appearance of
acute ICD is highly variable, and it may even be
indistinguishable from the allergie type. There are
numerous reports in the literature of experienced
dermatologists being misled into an initial assumption
of ACD that later, after a careful work up, turned out to
be "only irritation" (Frosch 1995). Furthermore, the
combination of allergie and irritant dermatitis is
frequent, e.g. "black-spot poison-ivy dermatitis"
(Hurwitz et al. 1984), as an acute ICD superimposed
upon an ACD.
Symptoms of acute ICD are: burning, stinging and
Fig. 1. Chernical burn, caused by tear gas, on a policeman
soreness of the skin. Signs include erythema, oedema,
bullae and, possibly, necrosis. These lesions are
Acute ICO restricted to the area where the irritant or toxicant
damaged the tissue. Borders are mostly sharply
Acute ICD develops when the skin is exposed to a demarcated, and the asymmetrical patterns of lesions
strong irritant or caustic chemical. Usually, this hint at an exogenous cause. The prognosis of this type
happens as an accident at work or in special emer- of dermatitis is good (Elsner 1994). The most frequent
gency situations. The irritant reaction reaches its peak potent irritants leading to acute ICD are acids and
quickly, then starts to heal; this is called the decre- alkaline solutions (Eichmann and Amgwerd 1992). A
scendo phenomenon. Because the lag time is short typical accident situation results in chemical burning
(usually minutes to hours after exposure) and the in construction workers (Skogstad and Levy 1994)
association between exposure and skin symptoms is when alkaline concrete fluid soaks through garments
usually clear, the diagnosis is easy in most cases. It or spills into work boots.
may become difficult when the patient was unaware of Chemicals burns by hydrofluoric acid are the most
an exposure. Acute ACD has to be considered as dangerous of all injuries caused by acids and need
differential diagnosis and is caused by a delayed special treatment. However, even substances thought
sensitisation reaction; 24-48 h after allergen contact, to be less toxic, such as N-methyl-2-pyrrolidone, may
symptoms appear. This type of contact dermatitis is cause acute ICD (Malten et al. 1979).
Fig. 2. A Iifeguard's reaction to a jellyfish Fig. 3. Caustic reaction caused by cernent

Contact Dermatitis Due to Irritation 101
Table 1. Irritants that cause airborne-irritant contact dermatitis

(Dooms-Goossens et a1. 1986)
Acids and alkalis

Aluminium
Ammonia
Anhydrous calcium sulphate
Arsenic
Bromoacetoxy-2-butene
Calcium silicate
Cement
Diallylglycol carbonate monomer
Diehlorvos
Domestic products (e.g. cleaning products)
Epoxy resins
Formaldehyde
Fibreglass
Hexanediol diacrylate
Industrial solvents
Metallic-oxide powders (slag)
Paper, carbonless copy paper
Phenol vapours
Phenol-formaldehyde resins
Quinine dust
Sawdust from toxie woods
Sewage sludge
Si!ver
Fig. 4. Housewives' eczema due to chronic wet work Sodium sesquiearbonate (trona)
Urea-formaldehyde insulation foam
Wool dust
matory response (Table 4). Clinically, acute delayed

ICD resembles acute ICD. The visible inflammation is
not seen until 8-24 h or more after exposure (Malten
et al. 1979). Delayed irritation may be more common
than generally thought so far. Further substances
causing acute delayed ICD include benzalkonium
chloride and tretinoin. Irritant patch-test reactions
to benzalkonium chloride may be papular and
increase in intensity with time, thus imitating ACD.
On the normal skin surrounding psoriatic plaques,
dithranol causes redness and oedema, which may
become very severe on the legs because of venous
Fig. 5. Fingertip eczema due to physieal trauma in a cellist
stasis. Irritation due to tretinoin develops after a few
days, and is characterised by mild to fiery redness
Acute Oelayed ICO followed by desquamation or large flakes of stratum
corneum. The symptoms are burning rather than
Acute delayed ICD is characteristic of certain lrn- itching. The skin becomes sensitive to touch and to
tants, such as anthralin, that elicit a retarded inflam- water (Frosch 1995).
Table 2. Common irritants and

their modes of action (Elsner Substance Mechanisms of toxicity
1994)
Detergents Solubilisation and/or organisation of barrier lipids and natural
moisturising factors in the stratum corneum; protein denaturation;
membrane toxicity
Acids Protein denaturation; cytotoxicity
Alkalis Barrier-lipid denaturation; cytotoxicity through cell swelling
Oils Disorganisation of barrier lipids
Organic solvents Solubilisation of barrier lipids; membrane toxieity
Oxidants Cytotoxicity
Reducing agents Keratolysis
Water If barrier is disrupted, cytotoxicity through swelling of viable epidermal
cells
lable 3. Factors influencing

the irritancy potential of substan- Exogenous Endogenous Cofactors
ces on human skin (Wilkinson
and Willis 1998) Chemical characteristics Individual susceptibility Mechanical
Molecular structure Atopy Thermal
pH Race/skin colour/phototype Climatic
pKa Age Hormonal
Hydrophobicity (log of the partition Barrier function
coefficient)
Inherent toxicity Repair capacity
Concentration/dose Eczema elsewhere
Penetration characteristics Other skin diseases
Vehicle Other unknown
Solubility Site of exposure
Duration of contact
Type of contact
labre 4. Chemicals inducing delayed acute chemical irritation and fingers, but irritants can also cause eczema of the
(Lammintausta and Maibach 1990) palmar sides of the fingers and the hands.
This distribution occurs in caterers and, described
Anthralin
Bis(2-chloroethyl)sulfide as dyshidrotic eczema, it has been reported in metal
Butanedioldiacrylate workers with an ICD from cooling lubricants (Cronin
Dichloro(2-chlorovinyl)arsine 1995). Frequently, this condition heals spontaneously,
Epichlorhydrin
Ethylene oxide resulting in hardening of the skin; sometimes it
Hydrofluoric acid progresses to cumulative irritant dermatitis.
Hexanedioldiacrylate
Hydroxypropylacrylate
Podophylline Cumulative ICD
Propane sulphone
According to Malten (Fig. 6), cumulative ICD is a
consequence of multiple subthreshold damages to the
skin if the time between the insults is too short for
Irritant-Reaction ICD
complete restoration of skin barrier function (Malten
1981). It may be the result of frequent repetition of one
Irritant-reaction ICD is a type of subclinical irritant
impairing factor but is more commonly the result of a
dermatitis in individuals exposed to wet work, includ-
variety of stimuli, each beginning before recovery from
ing hairdressers and metal workers, during their first
the foregoing stimuli has been competed. Clinical
months of training. This diagnosis is made if the
symptoms develop only when the damage exceeds a
clinical picture is monomorphic rather than polymor-
phie and is characterised by one or more of the
Fig. 6. Model of the pathogenesis of chronic irritant contact
following signs: scaling, redness, vesicles, pustules and dermatitis, according to Malten. a Subliminal irritants do not
erosions (Frosch 1995). lead to clinical irritant dermatitis if exposures are far enough
On the hands, it often begins under rings and then apart for restoration of skin barrier function. b When the same
irritants follow each other closely or when the manifestation
may spread over the fingers to the hands and the threshold is reduced, irritant dermatitis develops (based on
forearms. It usually affects the dorsum of the hands Malten 1981)
..... .....
~ §Y!l1ptQITIs_of S_ki!} gi~e~s~ _______ ~
1B 1ii
CU CU
0 .~
'e: .~
Ü Ü
A 8
Time Time
certain "manifestation threshold", which is individu- healing. This eczematous condition persists for a
ally determined. Persons with sensitive skin are considerable time period, with a minimum of 6 weeks
characterised by a decreased threshold or an increased (Frosch 1995).
restoration time, leading to earlier development of The most common location is the hands. In a fully
clinical irritant dermatitis. The threshold is not a fixed developed case, redness, infiltration and scaling with
value for an individual but may decrease with the fissuring are seen all over the affected areas.
progress of the disease. This explains why, in patients
with cumulative rCD, even limited irritant exposure Pustular and Acneiform ICO
may perpetuate the condition. Cumulative rCD is
linked to exposure to weak irritants rather than potent Pustular and acneiform rCD are results of exposure to
irritants. Very often, this exposure occurs not only at certain irritants, such as croton oil, mineral oils, tars,
work but also in private life. Because the link between greases and naphthalenes. This syndrome must always
exposure and disease is often not obvious to the be considered in conditions in which acneiform lesions
patient, diagnosis may be delayed considerably. This is develop outside the typical acne age. Those most
one of the reasons for the rather doubtful pro gnosis of affected are atopics and patients with seborrhoea,
this disease (Elsner and Maibach 1993). macroporous skin conditions or prior acne vulgaris.
Symptoms of chronic irritant dermatitis include The pustules are sterile and transient; however, sub-
itching and pain due to the cracking of hyperkeratotic corneal pustular eruption may also be a manifestation
skin. Signs of the disease include dryness, erythema and of allergy to trichlorethylene, which has to be consid-
vesicles, but are mainly lichenification, hyperkeratosis, ered as a differential diagnosis in patients with
and chapping. rn contrast to acute irritant dermatitis, appropriate history (Goh 1995).
the lesions are less sharply demarcated. Xerotic derma-
Nonerythematous ICO
titis is the most frequent type of cumulative toxic
dermatitis (Eichmann and Amgwerd 1992).
Many bioassays have been proposed for the purpose Nonerythematous ICD may be defined as a subclinical
of identifying sensitive skin. A 24-h patch test with form of ICD with early stages of skin irritation
sodium lauryl sulphate (SLS) and repetitive patch tests, characterised only by changes in the stratum-corneum
such as the 21-day cumulative-irritation assay, the barrier function without a c1inical correlation (van
chamber scarification test, and the soap-chamber test, der Valk et al. 1985; Berardesca and Maibach 1988;
have been used (Lee and Maibach 1994). Lammintausta et al. 1988).
Subjective ICO
Traumiterative ICO
Subjective or sensory ICD is characterised by the lack
rn contrast to cumulative rCD resulting from an early
of clinical signs; individuals complain of a subjective
repetition of exposures differing in type, traumiterative
sensation of stinging, burning or smarting after
rCD is a result of early repetition of just one type of contact with certain chemie als, such as lactic acid,
load (Malten and Arend 1985). Nevertheless, these two
which is also a model irritant for this type of nonvisible
types are very similar clinically.
cutaneous irritation. This re action may be reliably
reproduced in a double-blinded exposure test. rmpor-
Exsiccation Eczematid
tant parameters are the quality and the concentration
of the exposing agent. Also, neural pathways are
Exsiccation eczematid is a special variant of rCD that is
considered to be responsible (Lammintausta and
seen mainly in elderly individuals with a history of
Maibach 1990). Immediate-type stinging caused by
frequent showering and bathing without remoisturis-
chemie als such as chloroform and methanol (1:1) or
ing of their skin. Patients suffer from intense itching,
95% ethanol, can be differentiated from delayed-type
and their skin appears dry, with ichthyosiform scaling.
stinging, mostly caused by sunscreen agents, insect
The condition mainly occurs during the winter
repellents, several dermatological therapeutic agents
months, when humidity is low.
and vehicles that are used in cosmetics and medica-
ments (Frosch and Kligman 1977; Soschin and Kligman
Traumatic ICO
1982; Frosch 1995).
Traumatic rCD may develop after acute skin trauma,
such as burns, lacerations and acute rCD. Patients Irritation or Allergy?
should be asked whether they have cleansed their skin
with strong soaps or detergents. The syndrome is The distinction between irritant and allergie contact
characterised by eczematous lesions and delayed dermatitis has become increasingly blurred. Despite
their different pathogenes es, ACD and ICD, especially even the therapy is similar (Binnick 1981; Lauerma et al.
of the chronic type, show remarkable similarities with 1994). Additionally, the concept that irritants are
respect to clinical appearance, histology and immuno- thought to cause symptoms and signs within minutes
histology. It is apparent that so me of the same to hours, whereas allergens take days, has been
inßammatory immune mechanisms are operating both disqualified for one of the most widely studied irritants;
for ACD and ICD. The epidermal and dermal cell 24 h of occlusion with SLS resulted in clearly more signs
activity that produces the cascade of inßammation of inßammation at 48 h, a time course more character-
appears to be similar in both cases and is applicable istic of allergie reactions (RietscheI1997).
to both irritants and allergens. However, although
inßammatory and immunological mediators may be
activated, in contrast to ACD, no memory T-cell Epidemiology
function is involved. A review of all of the comparative
studies that suggest these two entities are alike has While population-based epidemiological studies on the
recently been presented (Gaspari 1997) (Table 5). frequency of ICD are rare, there is agreement that
Histologically, ICD reactions show much greater irritant dermatitis is more frequent than ACD,
pleomorphism than those elicited by allergens. Various although ACD tends to have more severe consequences
alterations of epidermal cells can be observed ac cord- for the patient. Coenraads and Smit (1995) reviewed
ing to the nature and concentration of the irritant international prevalence studies for eczema due to all
applied, the type and duration of exposure, and the causes conducted with general populations in five
individual reactivity of the skin (Table 6). Frequently, countries (England, the Netherlands, Norway, Sweden,
Table 5. Comparison of irritant and allergie eontaet dermatitis (Gaspari 1997)
Irritant Allergie
Clinieal morphology Dermatitis ean be similar to ACD Dermatitis can be similar to ICD. Kinetics
of resolution may be slower than
ICD during patch testing
Histology Spongiosis, exocytosis, dermal oedema Same as ICD; neutrophils usually
and a mononuclear infiltrate; occasionally, less prominent
neutrophil-rieh infiltrates
Immunoehemistry
Teens Predominantly CD4+ T cells; Predominantly CD4+ T cens; some
some CD8+ T eells; activated state CD8+ Teens; activated state
indicated by IL-2-receptor expression indicated by IL-2-receptor expression
Frequeney of hapten Not known Estimated to be approximately
specific T cens in infiltrate 1%
Langerhans' cens number No consistent changes Decrease, then recovery
Morphology Alterations noted but are highly Alterations noted, particularly
dependent on chemical environment with high doses of hapten
Accessory molecules
HLA-DR Increased Increased
ICAM-l Increased Increased
B7-l Increased Increased
Cytokine profiles
TNF-Cl Increased Increased
IFN-y Increased Increased
GM-CSF Increased Increased
IL-lA, B Not detected Increased
IP-lO Not detected Increased
MIP-2 Not detected Increased
IL-4 Not detected Increased at 24 h, absent by 48 h
Transgenic mice
Overexpression of:
B7-l by keratinocytes Increased Increased
ICAM-l by keratinocytes Increased Increased
Knock-out miee that laek:
TNF-Cl RI Not tested Increased
.CD4 Decreased Decreased
CD8 Decreased Decreased
CD28 Decreased Decreased
ACD, allergie contact dermatitis; ICD, irritant contaet dermatitis; IL, interleukin; HLA, human leukoeyte antigen; ICAM, intercellular
adhesion molecule; TNF, tumour-neerosis factor; IFN, interferon; GM-CSF, granulocyte-macrophage-colony-stimulating factor; IP,
IFN-induced protein; MIP, macrophage inflammatory protein
Table 6. Epidermal damage observed in relation to various irritants (from Lachapelle 1995a)
Type of irritant Epidermal lesions
Non-chlorinated organic solvents Achromasia, superficial necrosis, karyopyknosis, possibly

(i.e. alkanes, toluene, xylene, white spirit) acantholysis and superficial vesicles/bullae
Chlorinated organic solvents (i.e. trichlorethylene, Acantholysis, karyopyknosis, complete epidermal necrosis,
trichlorethanes, carbon tetrachloride ) intraepidermal vesicles/bullae
Acids, alkalis, surfactants, detergents, aldehydes Achromasia, superficial or complete epidermal necrosis,
sub epidermal vesicles/bullae
United States). They showed point prevalence rates of suspected that increased exposure to irritants at horne
1.7% to 6.3%, and 1- to 3-year-period prevalence rates ac counts for the higher prevalence in females. This is
of 6.2% to 10.6%. supported by the observation that caring for children
In a questionnaire study performed by Meding and under the age of 4 years and the lack of a dish-washing
Swanbeck on a random sampie of 20,000 individuals machine significantly increased the risk of contracting
from the population of the Swedish city of Gothenburg, hand eczema in a population of female hospital
11.8% reported having had hand eczema within the workers (Nilsson 1986). Irritant reactivity declines
previous 12 months (period prevalence), whereas 5.4% with increasing age. This is true not only for acute but
suffered from hand eczema at the time of investigation also for cumulative irritant dermatitis (Suter-Widmer
(point prevalence) (Meding 1990; Meding and Swan- and Eisner 1994). Atopy is probably the best-estab-
beck 1990). The period prevalence was twice as high in lished risk factor for irritant hand dermatitis (Lam-
women (14.6%) as in men (8.8%). The prevalence of mintausta et al. 1987; Meding and Swanbeck 1990). It
hand eczema in the population working full time must be stressed, however, that respiratory manifesta-
(10.3%) was lower than in the general population. tions of atopy seem to be less predictive of irritant
However, in the subgroup doing medical and nursing reactivity than skin manifestations. On the level of the
work, the l-year prevalence ofhand eczema was 15.9%, individual, there remains considerable uncertainty in
and in the population doing service work it was 15-4%. the prediction of irritant reactivity. As was shown in a
The occurrence of irritant dermatitis was significantly Swedish study, about 25% of the atopics in extreme-
increased in women exposed to water and detergents risk occupations, such as ladies' hairdressers and
and in men exposed to oils and solvents, whereas the nursing assistants, did not develop hand eczema
occurrence of allergie dermatitis was not significantly (Rystedt 1985).
influenced by these exposures. The incidence of ICD correlates with the irritant
The perception that irritant dermatitis is more exposure of the workers in a given profession (Goldner
frequent than ACD in the occupational setting is 1994). Some high-risk occupations are: caterers
supported by data from Singapore. Of 557 patients (Cronin 1980, 1987; Cleenewerck and Martin 1996;
with occupational dermatoses, 55,iVo (310) had ICD, Wood and Greig 1997), construction workers
38.6% (215) had ACD, and 5.7% (32) had noncontact (Avnstorp 1996), furniture-industry workers (Gan
dermatitis (Goh 1987). However, the incidence rates of et al. 1987), hospital workers (Gawkrodger et al. 1986;
selected occupations, according to the diagnosis of Wrangsjö and Meding 1997), nur ses (Kassis et al.
ICD and ACD in a population-based study in North 1984), cleaners (Singgih et al. 1986), kitchen workers,
Bavaria, showed different preferences for ICD or ACD hairdressers (van der Walle and Brunsveld 1994; Uter
in different occupational groups (Diepgen and Co- et al. 1995), chemical-industry workers (Conde-Salazar
enraads 1995). Since cases of irritant dermatitis tend et al. 1993), dry cleaners (Aoki and Kageyama 1989),
to be less severe and chronic than those of ACD, the warehouse workers (Ashworth et al. 1993) and metal
latter may outnumber the former in specialised workers (de Boer et al. 1989; Foulds and Koh 1990;
occupational-dermatology clinics (Kanerva et al. Goh and Yuen 1994; Eisner et al. 1995; Rycroft 1997;
1988). Wigger-Alberti et al. 1997). Recently three important
risk factors, apart from chemical irritants, for the
development of occupational hand dermatitis in met-
Risk Fadors al-work trainees have been examined: atopic disposi-
tion, mechanical irritation and insufficient amount of
A number of individual factors for irritant dermatitis skin-regeneration time (Berndt et al. 1999). Generally,
have been identified. Although occupational, irritant occupations involving 'wet work' are especially pro ne
hand dermatitis is more frequent in females (Meding to irritant dermatitis. More detailed lists of specific
1990), no sex difference of irritant reactivity could be occupational hazards are given in Part 3, Job Descrip-
established experimentally (Hogan et al. 1990). It is tions.
Diagnosis sulation of irritating fluids), individual skin protection

(gloves, protective suits, protective creams) and, if
ICD must be diagnosed by excluding other causes for necessary, siek leave until the epidermal barrier has
the dermatitis. Although this is easily done on the completely regenerated, which may be a lengthy
basis of signs and symptoms for acute ICD, it is process, especially in cumulative irritant dermatitis.
usually more difficult for cumulative irritant derma- The use of topical corticosteroids, used in the
titis. ACD, which tends to show spreading papules successful treatment of ACD, has been questioned as
and vesicles, is the most important diagnosis to be a treatment for irritant dermatitis (van der valk and
excluded. ACD is hard to differentiate from ICD in the Maibach 1989). They may be effective in chronic,
chronic state. Irritant dermatitis may be diagnosed if hyperkeratotic irritant dermatitis, but their prolonged
patch tests remain negative, if there is an exposure to use may lead to epidermal atrophy and, consequently,
irritants, and if the disease develops and heals increased irritant sensitivity. Other therapeutic options
depending on the frequency and intensity of this in irritant dermatitis include topical tars and photo-
exposure. However, many allergens are also good therapy (ultraviolet B or psoralen plus ultraviolet A).
irritants and may confuse the interpretation of patch In difficult cases of chronic, irritant hand dermatitis,
tests (Moshell 1997). radiation may be indicated (Goldschmidt and Pan-
Since cumulative ICD may become chronic at a later izzon 1991). Bacterial superinfection may be a compli-
stage, the relationship between exposure and disease cation of contact dermatitis; it is treated with topicalor
tends to weaken. Histologie examination of a biopsy systemic antibiotics. Potential irritants, such as irritant
cannot differentiate among chronic irritant, allergie, cleansing products, must be identified and (whenever
and atopic dermatitis. However, chronic ICD differs possible) eliminated, not only in the workplace but in
morphologically from acute ICD (Willis 1996). the home (Frosch 1989).
Immunohistologic staining has not shown any signi- Prognosis for acute ICD is good if irritant contact is
ficant differences in the inflammatory infiltrate of avoided. Cumulative irritant dermatitis, however, has a
chronic irritant and allergie dermatitis (Brasch et al. doubtful prognosis. In arecent survey, it was stressed
1992). While a biopsy may be helpful to exclude palmar that the prognoses of occupational and nonoccupa-
psoriasis, psoriasis can usually be excluded or con- tional contact dermatitis, ICD, and ACD are similar,
firmed on clinical grounds that consider sharply and that a job change does not affect the course of the
demarcated hyperkeratotic or pustular lesions in disease (Hogan et al. 1990). However, Goh summarised
contrast to the fuzzy borders of eczema while searching that most studies appear to indicate that patients with
for other features, such as nail and scalp involvement. ICD have a poorer pro gnosis than those with ACD
Visual evaluation of skin erythema and surface (Goh 1997). A reason could be that, in allergie
changes is still widely used to assess irritant reactions. dermatitis, a specific causative allergen can be identi-
However, various noninvasive techniques have been fied and avoided, but the cause of ICD is often
developed that permit more objective evaluation of skin unknown. Well-known factors that cause a poor
changes than subjective visual assessment (Wilhelm prognosis of ICD are the existence of atopic dermatitis
et al. 1989). New bio engineering techniques, such as (Hogan 1996; Seidenari 1996) or what has been termed
measuring trans epidermal water loss as an indicator of "persistent post-occupational dermatitis (PPOD)"
epidermal barrier function, are weIl suited to detect (Wall and Gebauer 1991). In our experience, metal
minute epidermal barrier impairment earlier than workers with cutting-fluid dermatitis took up to
clinical examinations and to asses the grade of several years to recover despite job change and
dermatitis quantitatively. However, they are not useful avoidance of irritants (Elsner et al. 1995). This stresses
in making a safe differential diagnosis between ACD the importance of early intervention in irritant der-
and ICD. Rather, they offer the ability to objectively matitis before it reaches the chronic stage.
evaluate and quantify inflammation parameters, such
as redness, scaling and infiltration. In Table 7, an
overview of biophysical measurements is given, which Prevention
can be used to characterise the functional and
morphologie properties of irritated skin. Considering the high incidence of ICD at the work-
place, preventive measures play an important role. In
order to increase the awareness of this health risk and
Treatment and Prognosis to achieve an optimal compliance with protective
measures, employees should be adequately instructed
Avoiding the irritant(s) remains the basis for treatment at the start of their training. It has been shown that the
of occupational ICD. This is achieved through techni- behaviour of metal-working apprentices must be
cal measures (change of working substances, encap- considered high risk, a result of the fact that they are
Table 7. Non-invasive bioengineering methods for characterisation of skin properties in occupational dermatology (Iliev et al. 1998)
Skin Possible Measured Principle Device

property significances parameters of measurement
in occupational
dermatology
Barrier function Prediction of TEWL Measurement of the air- Evaporimeter;

of the stratum eczema moisture gradient at a defined tewameter
corneum risk; detection distance from the skin
of a subclinical eczema;
therapy control
Skin Prediction of Conductivity; Measurement of the Skicon;
moisture eczema risk; capacity conductance between corneometer
detection of a two electrodes;
subclinical eczema; measurement of the
therapy control capacity between two
electrodes
Acid mantle Buffer capacitance Skin-surface pH Hydrogen-ion activity pH meter
of the skin against alkali at a pH electrode
substances
(prediction of
eczema risk);
detection of a
subclinical eczema;
therapy control
Skin blood Tolerance to Capillary Wavelength shift of Laser Doppler
flow temperature, erythrocyte flow reflected light because velocimeter
detection of a of the Doppler effect
subclinical eczema
Skin Prediction of Adhesional- and Measurement of the Frictionmeter;
roughness eczema risk; glide friction; power necessary to profilometer;
detection of a deviation of move an object on the visiometer
subclinical elevations and skin surface
eczema; therapy grooves from the mechanically; laser-
control mean controlled profilometry
of a skin-surface
replica
Stratum- Mechanical Corneocyte Measurement of the Cohesiometer
corneum resistance cohesion power
cohesion
Skin colour Objectivation of Light reflection Measurement of Tristimulus
erythema and reflection of a defined colorimeter;
pigmentations as light flash produced by spectrophotometer
proof of eczema a photo element
and light-induced
changes
Skin Quantification of Distance between Reflection of a high- A-scan or C-scan
thickness eczema-induced the skin surface frequency ultrasound ultrasound
lichenifications and corium-subcutis signal at the skin
border surface and at the
acoustic border
between the corium
and subcutis
TEWL, trans epidermal water loss
insufficiently informed about skin diseases, the poten- (Wigger-Alberti and Eisner 1997). Prevention of ICD
tial risk of hand eczema at the workplace and the requires an integrated approach that considers both
benefits of skin care (Itschner et al. 1996). Considering the exposure and tlIe exposed individual. The respon-
tlüs finding, it seems urgent that health and safety sibility for primary prevention rests mainly witlI
education be intensified. manufacturers and producers of chemicals and prod-
Several types of prevention can be distinguished. ucts, government agencies, consumer organisations,
Primary prevention tries to prevent tlIe development of industrial physicians and nurses and safety engineers
disease in the healtlIy individual. Secondary prevention (Wahlberg and Maibach 1994). A multidimensional
is targeted at tlIe diseased individual; it tries to inhibit approach with eight basic elements of prevention
a relapse of contact dermatitis. In tertiary prevention planning has been proposed by Mathias (Mathias
(rehabilitation), a chronically diseased patient is 1990): recognition of potential cutaneous irritants and
treated and reintegrated into the working environment allergens, engineering controls or chemical substitu-
tion to prevent skin exposure, personal protection with optimise working conditions. Suitable washing facili-
appropriate clothing or protective creams, personal ties should be provided. Encapsulation of irritants and
and environmental hygiene, regulation of potential exchange of toxie working substances (e.g. choosing
allergens and irritants within the workplace, educa- less irritating cutting fluids and controlling their
tional efforts to promote awareness of potential correct dilution) are particularly beneficial. Therefore,
allergens and irritants, motivational techniques to predictive tests are necessary to determine not only
promote safe work conditions and practices, and pre- whether a chemieal can behave as a skin irritant but
employment and periodic health screening (Table 8). also how potent a skin irritant is (Basketter et al. 1997).
In the prevention of exposure, the main elements are
technical measures, i.e. avoidance of the irritant Protective Gloves and Clothing
through its removal from the workplace or through
technical shielding by the use of potent irritants in Well-fitting and irritant-resistant protective gloves and
closed systems or automation, irritant replacement or clothing that are acceptable to the worker are a highly
rem oval (Lachapelle 1995b), and personal protection of effective means of decreasing irritant exposure and the
the workers (Wigger-Alberti and Eisner 1998). Screen- development of contact dermatitis. Selection of a glove
ing individuals for predisposition to irritant dermatitis appropriate for the specific working situation is of
and counselling of sensitive individuals may be utmost importance, since gloves permeable to irritants
appropriate preventive measures. such as organic solvents (Zaza et al. 1994) may even
aggravate the damage to the barrier impairment, due
Technical Measures to occlusion by the gloves (Zugerman 1990). Rubber
gloves are widely used nowadays, but they may cause
In selecting public-health approaches of prevention, problems, based on increasing incidence of immediate-
relative and attributable risks must beconsidered and delayed-type allergy to latex and rubber additives
(Williams 1996). While water-based cutting fluids are (Wigger-Alberti and Eisner 1998). The use of polyeth-
associated with a far higher relative risk of developing ylene gloves under latex gloves should be recommend-
ICD than cleaning liquids, the higher exposure to the ed in cases of allergy. Gloves consisting of ethylene
latter in the population results in a far higher vinyl alcohol copolymer sandwiched between polyeth-
attributable risk from cleaning liquids, i.e. far more ylene have been shown to be highly effective in
cases of ICD are caused by cleaning liquids than by protecting against epoxy resin (Henriksen 1982),
cutting fluids. Therefore, the removal of exposure to a methyl methacrylate (Darre et al. 1987) and many
weak but frequent irritant results in a small benefit to other organic compounds (Rycroft 1995). Very useful
the exposed individual but a large benefit to the information on this topic is given by Mellström et al.
population. Identification of irritants is based on the (Mellström et al. 1994; Mellström 1996) and Estlander
analysis of quantitative structure-activity relation- and Jolanki (Estlander and Jolanki 1988).
ships, in vitro and animal testing, and in vivo human
testing that has been considerably refined by nonin-
Protective Creams
vasive bioengineering techniques (Mize et al. 1995;
Roguet et al. 1995; Wilhelm 1995). However, it is
Since use of gloves can sometimes cause accidents, and
important to prove the correlation between human-
the substitution of noxious products by less aggressive
testing results and epidemiological data (Wigger-
substances is sometimes not possible for technieal or
Alberti et al. 1997). The improvement of working
economieal reasons, skin-care products play an im-
conditions, resulting in decreased exposure to irritants
portant role in the prevention of occupational contact
or allergens, is by far the most effective measure used
dermatitis. Preventive skin care at the workplace may
to reduce the incidence of contact dermatitis. In many
be divided into pre-exposure protection by protective
countries, workplaces are inspected by occupational
creams, removal of irritants by mild cleaning agents,
physicians or outside technical experts, if cases of
and enhancement of barrier-function generation by
contact dermatitis have been observed, in order to
emollients or moisturisers. More details are given in
Chap. 62, Barrier CreamslEmollients.
Table 8. Elements
of prevention pl- Hazard recognition
anning (Matllias Hazard contral
1990) Personal pratection References
Hygiene
Regulation
Education Aoki T, Kageyama R (1989) Three cases of dry cleaning
Motivation dermatitis. Nippon Hifuka Gakkai Zasshi 9:1035-1038
Pre-employment screening Ashworth J, Rycroft RJG, Waddy RS (1993) Irritant contact
dermatitis in warehouse employees. Occup Med 43:32-34
Avnstorp C (1996) Irritant cement eczema. In: van der Valk PGM, Frosch PJ (1995) Cutaneous irritation. In: Rycroft RJG, Menne T,
Maibach HI (eds) The irritant contact dermatitis syndrome. Frosch PJ (eds) Textbook of contact dermatitis. Springer,
CRC, New York, pp 111-119 Berlin, pp 28-61
Basketter DA, Reynolds FS, York M (1997) Predictive testing in Frosch PI, Kligman AM (1977) A method for appraising the
contact dermatitis: irritant dermatitis. Clin Dermatol 15: stinging capacity of topically applied substances. Soc Cos-
637-644 metic Chem 28:197-209
Berardesca E, Distante F (1995) Mechanisms of skin irritation. In: Gan SL, Goh CL, Lee CS (1987) Occupational dermatitis among
Elsner P, Maibach HI (eds) Irritant dermatitis: new dinical sanders in the furniture industry. Contact Dermatitis 17:
and experimental aspects. Karger, Basel, pp 1-8 237-240
Berardesca E, Maibach HI (1988) Racial differences in sodium Gaspari AA (1997) The role of keratinocytes in the pathophys-
lauryl sulphate induced cutaneous irritation: black and white. iology of contact dermatitis. Immunol Allergy Clin North Am
Contact Dermatitis 18:65-70 17:377-405
Berndt U, Hinnen U, Iliev D, Elsner P (1999) Risk factors for hand Gawkrodger DJ, Lloyd MH, Hunter JA (1986) Occupational skin
eczema in metal worker trainees (in German). Allergologie disease in hospital deaning and kitchen workers. Contact
22:195 Dermatitis 15:132-135
Binnick AN (1981) Allergic and irritant contact dermatitis. Compr Ghadially R, Brown BE, Sequeira-Martin SM, Feingold KR, Elias
Ther 1:17-21 PM (1995) The aged epidermal permeability barrier. Structur-
Brasch L, Burgard I, Sterry W (1992) Common pathogenetic al, functional, and lipid biochemical abnormalities in humans
pathways in allergic and irritant contact dermatitis. J Invest and asenescent murine model. J Clin Invest 95:2281-2290
Dermatol 98:166-170 Goh CL (1987) Occupational skin disease in Singapore: epidemi-
Cleenewerck MB, Martin P (1996) Irritants: food. In: van der Valk ology and causative agents. Ann Acad Med Singapore 16:
PGM, Maibach HI (eds) The irritant contact dermatitis 303-305
syndrome. CRC, New York, pp 157-184 Goh CL (1995) Noneczematous contact reactions. In: Rycroft RJG,
Coenraads PJ, Smit J (1995) Epidemiology. In: Rycroft RJG, Menne T, Frosch PJ (eds) Textbook of contact dermatitis.
Menne T, Frosch PJ (eds) Textbook of contact dermatitis. Springer, Berlin Heidelberg New York, pp 221-236
Springer, Berlin Heidelberg New York, pp 133-150 Goh CL (1997) Prognosis of contact and occupational dermatitis.
Conde-Salazar L, Gomez I, Meza B, Guimaraens D (1993) Clin Dermatol 15:655-659
Artefactual irritant contact dermatitis. Contact Dermatitis Goh CL, Yuen R (1994) A study of occupational skin disease in
28:246 the metal industry (1986-1990). Ann Acad Med Singapore
Cronin E (1980) Contact dermatitis. Churchill Livingston, 23:639-644
Edingburgh Goldner R (1994) Work-related irritant contact dermatitis. Occup
Cronin E (1987) Dermatitis of the hands in caterers. Contact Med 9:37-44
Dermatitis 17:265-269 Goldschmidt H, Panizzon RG (1991) Radiation therapy of benign
Cronin E (1995) Hand eczema. In: Rycroft RJG, Menne T, Frosch tumors, hyperplasias, and dermatoses. Springer, Berlin Hei-
PJ (eds) Textbook of contact dermatitis. Springer, Berlin delberg New York
Heidelberg New York, pp 207-218 Hafner J, Rüegger M, Kralicek P, Elsner P (1995) Airborne irritant
Darre E, Vedel P, Jensen JS (1987) Skin protection against contact dermatitis from metal dust adhering to semisynthetie
methylmethacrylate. Acta Orthop Scand 58:236-238 working suits. Contact Dermatitis 32:285-288
de Boer EM, van Ketel WG, Bruynzeel DP (1989) Dermatoses in Henriksen H (1982) Selection of materials for protective gloves.
metal workers I: Irritant contact dermatitis. Contact Derma- Polymer membranes for protection against contact with
titis 20:212-218 epoxy preparations. Danish Directorate of Labour Inspection
Diepgen TL, Coenraads PJ (1995) What can we learn from Services, Copenhagen
epidemiological studies on irritant contact dermatitis? In: Hogan DJ (1996) The prognosis of irritant contact dermatitis. In:
Elsner P, Maibach HI (eds) Irritant dermatitis: new dinical van der Valk PGM, Maibach HI (eds) The irritant contact
and experimental aspects. Karger, Basel, pp 18-27 dermatitis syndrome. CRC, New York, pp 9-15
Dooms-Goossens AE, Debusschere KM, Gevers DM, Dupre KM, Hogan DJ, Dannaker q, Maibach HI (1990) The prognosis of
Degreef HJ, Loncke JP, Snauwoert JE (1986) Contact derma- contact dermatitis. J Am Acad Dermatol 23:300-307
titis caused by airborne agent. A review and case reports. J Am Hurwitz RM, Rivera HP, Guin JD (1984) Black-spot poison ivy
Acad DermatoI15:1-10 dermatitis. An acute irritant contact dermatitis superimposed
Eichmann A, Amgwerd D (1992) Toxische Kontaktdermatitis. upon an allergie contact dermatitis. Am J Dermatopathol
Schweiz Rundsch Med Prax 19:615-617 6:319-322
Elsner P (1994) Irritant dermatitis in the workplace. Dermatol Iliev D, Elsner P (1997) Clinical irritant contact dermatitis
Clin 12:461-467 syndromes. Immunol Allergy Clin North Am 17:365-375
Elsner P, Maibach HI (1993) Irritant and allergie contact Iliev D, Hinnen U, Elsner P (1998) Skin bioengineering methods
dermatitis. In: Elsner P, Martius J (eds) Vulvovaginitis. in occupational dermatology. In: Elsner P, Barel AO, Berard-
Dekker, New York esca E, Gabard E, Serup J (eds) Skin bioengineering
Elsner P, Baxrnann F, Liehr HM (1995) Metal working fluid techniques and applications in dermatology and cosmetology.
dermatitis: a comparative follow-up study in patients with Karger, Basel, pp 145-150
irritant and non-irritant hand dermatitis. In: Elsner P, Itschner L, Hinnen U, Elsner P (1996) Prevention of hand eczema
Maibach HI (eds) Irritant dermatitis: new dinieal and in the metal-working industry: Risk awareness and behaviour
experimental aspects. Karger, Basel, pp 77-86 of metal worker apprentiees. Dermatology 193:226-229
Erntestarn L, Ollmar S (1993) Electrieal impedance index in Kanerva L, Estlander T, Jolanki R (1988) Occupational skin
human skin: measurements after ocdusion in 5 anatomical disease in Finland. An analysis of 10 years of statistics from
regions and in mild irritant contact dermatitis. Contact an occupational dermatology dinie. Int Arch Occup Environ
Dermatitis 28:104-108 Health 60:89-94
Estlander T, Jolanki R (1988) How to protect the hands. Dermatol Kassis V, Vedel P, Darre E (1984) Contact dermatitis to methyl
Clin 6:105-114 methacrylate. Contact Dermatitis 11:26-28
Foulds IS, Koh D (1990) Dermatitis from metalworking fluids. Lachapelle JM (1986) Industrial airborne irritant or allergie
Clin Exp DermatoI15=157-162 contact dermatitis. Contact Dermatitis 14:137-145
Frosch PJ (1989) Irritant contact dermatitis. In: Frosch PJ, Lachapelle JM (1995a) Histopathological and immunohistopath-
Dooms-Goossens A, Lachapelle JM, Rycroft RJG, Scheper RJ ological features of irritant and allergie contact dermatitis. In:
(eds) Current topics in contact dermatitis. Springer, Berlin Rycroft RJG, Menne T, Frosch PJ (eds) Textbook of contact
Heidelberg New York, pp 385-403 dermatitis. Springer, Berlin Heidelberg New York, pp 91-101
110 W. W.-Alberti and P. Elsner: Contact Dermatitis Due to Irritation
Lachapelle JM (1995b) Principles of prevention and protection in Seidenari S (1996) Skin sensitivity, interindividual factors: atopy.
contact dermatitis (with special reference tp occupational In: van der Valk PGM, Maibach HI (eds) The irritant contact
dermatology). In: Rycroft RJG, Menne T, Frosch PJ (eds) dermatitis syndrome. CRC, New York, pp 267-277
Textbook of contact dermatitis. Springer, Berlin Heidelberg Singgih SI, Lantingha H, Nater JP, Woest TE, Kruyt-Gaspersz JA
New York, pp 695-702 (1986) Occupational hand dermatoses in hospital cleaning
Lammintausta K, Maibach HI (1990) Contact dermatitis due to personnel. Contact Dermatitis 14:14-19
irritation: general principles, etiology, and histology. In: Skogstad M, Levy F (1994) Occupational irritant contact derma-
Adams RM (ed) Occupational skin disease. Saunders, Phil- titis and fungal infection in construction workers. Contact
adelphia, pp 1-15 Dermatitis 31:28-30
Lammintausta K, Maibach HI, Wilson D (1987) Irritant reactivity Soschin D, Kligman AM (1982) Adverse subjective reactions. In:
in males and females. Contact Dermatitis 17:276-280 Kligman AM, Leyden JJ (eds) Safety and efficacy of topical
Lammintausta K, Maibach HI, Wilson D (1988) Mechanisms of drugs and cosmetics. Grune and Stratton, New York, pp
subjective (sensory) irritation. Propensity to non-immuno- 377-388
logic contact urticaria and objective irritation in stingers. Suter-Widmer J, Eisner P (1994) Age and irritation. In: van der
Derm Beruf Umwelt 36:45-49 Valk PGM, Maibach HI (eds) The Irritant contact dermatitis
Lauerma AI, Stein BD, Homey B, Lee CH, Bloom E, Maibach HI syndrome. CRC, Boca Raton, pp 257-261
(1994) Topical FK506: suppression of alIergic and irritant Uter W, Gefeller 0, Schwanitz HJ (1995) Occupational dermatitis
contact dermatitis in the guinea pig. Arch Dermatol Res in hairdressing apprentices. In: Eisner P, Maibach HI (eds)
286:337-340 Irritant dermatitis. New clinical and experimental aspects.
Lee CH, Maibach HI (1994) Study of cumulative irritant contact Karger, Basel, pp 49-55
dermatitis in man utilizing open application on subclinically van der Valk PGM, Maibach HI (1989) Do topical corticosteroids
irritated skin. Contact Dermatitis 30:271-275 modulate skin irritation in human beings? Assessment by
Malten KE (1981) Thoughts on irritant contact dermatitis. Contact transepidermal water loss and visual scoring. J Am Acad
Dermatitis 7:238-247 Dermatol 21:519-522
Malten KE, den Arend JA (1985) Irritant contact dermatitis: van der Valk PGM, Nater JP, Bleumink E (1985) Vulnerability of
traumiterative and cumulative impairment by cosmetics, the skin to surfactants in different groups of eczema patients
climate, and other daily loads. Derm Beruf Umwelt 33:125-132 and controls as measured by water vapour loss. Clin Exp
Malten KE, den Arend JA, Wiggers RE (1979) Delayed irritation: DermatoI1O:98-103
hexanediol diacrylate and butanediol diacrylate. Contact van der Walle HB, Brunsveld VM (1994) Dermatitis in hairdress-
Dermatitis 3:178-184 ers. I. The experience of the past 4 years. Contact Dermatitis
Mathias CG (1990) Prevention of occupational contact dermatitis. 30:217-221
J Am Acad Dermatol 23:742-748 Wahlberg JE, Maibach HI (1994) Prevention of contact derma-
Mathias CGT, Maibach HI (1978) Dermatotoxicology mono- titis. In: Mellström GA, Wahlberg JE, Maibach HI (eds)
graphs. I. Cutaneous irritation: factors influencing the Protective gloves for occupational use. CRC, New York, pp
response to irritants. Clin Toxicol 13:333-346 7-9
Meding B (1990) Epidemiology of hand eczema in an industrial Wall L, Gebauer K (1991) A follow-up study of occupational skin
city. Acta Derm Venereol Suppl (Stockh) 153=1-43 disease in Western Australia. Contact Dermatitis 524:
Meding B, Swanbeck G (1990) Occupational hand eczema in an 241-243
industrial city. Contact Dermatitis 22:13-23 Wigger-Alberti W, Eisner P (1997) Preventive measures in contact
Mellström GA (1996) Prevention of irritant dermatitis by gloves. dermatitis. Clin Dermatol 15:661-665
In: van der Valk PGM, Maibach HI (eds) The irritant contact Wigger-Alberti W, Eisner P (1998) Do barrier creams and gloves
dermatitis syndrome. CRC, New York, pp 367-377 prevent or provoke contact dermatitis? Am J Contact Dermat
Mellström GA, Waltlberg JE, Maibach HI (1994) Protective gloves 9:100-106
for occupational use. CRC, Boca Raton Wigger-Alberti W, Hinnen U, Eisner P (1997) Predictive testing of
Mize N, Johnson J, Hansch C (1995) Quantitative structure- metalworking fluids: a comparison of 2 cumulative human
activity relationship and cytotoxicity. In: Eisner P, Maibach irritation models and correlation to epidemiological data.
HI (eds) Irritant dermatits. New clinical and experimental Contact Dermatitis 36:14-20
aspects. Karger, Basel, pp 224-229 Wilhelm KP (1995) Irritant dermatitis: Experimental aspects. In:
Moshell AN (1997) Workshop on irritant contact dermatitis. Am J Elsner P, Maibach HI (eds) Irritant dermatitis. New clinical
Contact Dermatitis 8:79-105 and experimental aspects. Karger, Basel, pp 144-151
Mozzanica N (1992) Pathogenetic aspects of allergic and irritant Wilhelm KP, Surber C, Maibach HI (1989) Quantification of
contact dermatitis. Clin DermatoI1O:115-121 sodium lauryl sulphate irritant dermatitis in man: compar-
Nilsson E (1986) Individual and environmental risk factors for ison of four techniques: skin color, reflectance, transepider-
hand eczema in hospital workers. Acta Derm Venereol Suppl mal water loss, laser Doppler flow measurement and visual
(Stockh) 128:1-63 scores. Arch Dermatol Res 281:293-295
Patil S, Maibach HI (1994) Effect of age and sex on the elicitation Wilkinson JD, Willis CM (1998) Contact dermatitis: irritant. In:
of irritant contact dermatitis. Contact Dermatitis 30:257-264 Champion RH, Burton JL, Bums DA, Breathnach SM (eds)
Pinnagoda J, Tupker RA, Smit JA, Coenraads PJ, Nater JP (1989) Textbook of dermatology, 6th edn. Blackwell, London,
The intra- and inter-individual variability and reliability of pp 709-731
trans epidermal water loss measurements. Contact Dermatitis Williams H (1996) Relative and attributable risk and its relevance
21:255-259 in the prevention of contact dermatitis. In: Eisner P,
Rietschel RL (1997) Comparison of allergic and irritant derma- Lachapelle J, Wahlberg J, Maibach H (eds) Prevention of
titis. Immunol Allergy Clin North Am 17:359-364 contact dermatitis. Karger, Basel, pp 10-17
Roguet R, Cohen C, Rougier A, Leclaire J (1995) Measurement of Willis CM (1996) The histopathology of irritant contact derma-
proinflammatory mediator production by cultured keratin- titis. In: van der Valk PGM, Maibach HI (eds) The irritant
ocytes. In: Elsner P, Maibach HI (eds) Irritant dermatitis. New contact dermatitis syndrome. CRC, New York, pp 291-303
clinical and experimental aspects. Karger, Basel, pp 230-242 Wood BP, Greig DE (1997) Catering industry. Clin Dermatol
Rycroft RJG (1995) Occupational contact dermatitis. In: Rycroft 15:567-571
RJG, Menne T, Frosch PJ (eds) Textbook of contact derma- Wrangsjö K, Meding B (1997) Hospital workers. Clin Dermatol
titis. Springer, Berlin Heidelberg New York, pp 343-400 15:573-578
Rycroft RJG (1997) Metal working industry. Clin Dermatol 15: Zaza S, Reeder JM, Charles LE, Jarvis WR (1994) Latex sensitivity
565-566 among perioperative nurses. AORN J 60:806-812
Rystedt I (1985) Work-related hand eczema in atopics. Contact Zugerman C (1990) Chloracne. Clinical manifestations and
Dermatitis 12:164-171 etiology. Dermatol Clin 8:209-213
CHAPTER 12
Repeated Low-Grade Frictional Trauma

S. Freeman
Introduction have probably not made very great strides since then in
really understanding the effects of friction on the skin,
especially low-grade friction.
Leonardo da Vinci (1452-1519) was the first to write
Since many occupations involve work that produces
perceptively about friction and the skin. He described
mild friction on the skin, the question - is dermatitis
a simple load/pulley device to measure coefficients of
attributable to such mild friction and can it therefore
friction for human skin against various materials. We
Table 1. Reported cases of irritant contact dermatitis caused by friction. All patients except for the 418 neonates proved negative on
patch testing and improved on avoidance of the source of friction
Reference Occupation Site( s) involved No.of Source of friction

cases
Ayres and Not relevant Face Rotating brush used in

Mihan (1979) treatment of acne
2 Dahlquist and Neonates Face, knees, 418 Babies nursed pro ne on sheets
Fregert (1979) dorsal toes with high coefficient of
friction. Change to textile
with lowest coefficient of
friction decreased symptoms
to 30% (dermatitis partly
due to alkaline remnants of
detergents in the sheets)
3 Menne (1983) Post -office worker Palms of hands Rough plastic table top
4 Menne and Bus driver Fingertips Bus tickets
Hjorth (1984)
5 Menne and Nurse Dorsal hands Surgical scrubber incorrectly
Hjorth (1985) used on the bristle side.
Cleared when correctly used
on sponge side
6 Menne and Office worker Hands - sites correspond Carbonless copy paper, 100-200
Hjorth (1985) to sites of contact invoices handled per day
7 Freeman and Carpenter Left thumb and both Nails and screws held in left
Rosen (1990) index fingers (Figs. la,b) thumb and index fingers and
hammer rubbed on right
index finger
8 Freeman and Teacher of Right thumb, index and Right thumb, index and middle
Rosen (1990) classical guitar middle fingers and pulps fingers used to pluck guitar
of fingers of left hand strings. Pulps of fingers of
left hand used to compress
the strings
9 Freeman and Schoolgirl Abdomen and hips Elastic and foam brace worn
Rosen (1990) (Figs. 2a,b) for correction of scoliosis
10 Freeman and Self-taught Pulps of four fingers of Contact with keyboard using
Rosen (1990) keyboard operator right hand and index four fingers of right hand and
finger of left hand only index finger of left hand
(Figs. 3a,b)
11 Freeman (unpublished Student Feet - dorsal surfaces to Angle-high "sneaker"
observations) level of ankle boot (Fig. 4)
12 Freeman (unpublished Retiree Left upper ehest (Fig. 5) Contact with metal pacemaker
observations)
13 Freeman (unpublished Retiree Amputation stump Friction from prosthesis
observations) (Figs. 6a,b)

112 S. Freema n
Figs. la,b. Carpenter with frictional irritant contact dermatitis

involving only the sites in contact with screws and nails; the rest
of the hand was spared
be classified as occupational? - can arise. This type of

irritant contact dermatitis (ICD) is seldom reported in
the dermatological literature, but is probably not
uncommon. Friction is more often acknowledged to
play an adjuvant part in producing irritant or allergie
contact dermatitis. In juvenile plantar dermatosis,
friction on the forefoot is considered to be a major
aetiological factor, if not the main cause (Verbov 1989).
The skin's usual response to repeated low-intensity
Figs. 2a,b. Thoracolumbar brace for correcting scoliosis causing
frietion is callus formation, namely hyperkeratosis and frictional irritant contact dermatitis of the abdomen
acanthosis. In some atopics, lichenification can also
result from friction. Hardening is another adaptive sites of that friction. This frictional dermatitis must be
phenomenon in which daily exposure to friction distinguished from allergie contact dermatitis and
eventually leads to thickening, toughness and resis- psoriasis. The former must be excluded by patch
tance to further irritation. The hardened skin appears testing. The latter can occur in psoriatieally predis-
coarse, thickened and somewhat lichenified (Lam- posed individuals at sites of trauma (Koebner phe-
mintausta and Maibach 1990). nomenon). There may be evidence of psoriasis
elsewhere on the body. It differs in clinical features
from ICD. Psoriasiform dermatitis (usually affecting
the hands) typically consists of thickened, coarsely
Body of Information
scaling, sharply demarcated plaques, often with a
tendency to painful fissuring rather than itching. It is
It is important to recognise that repeated low-grade recalcitrant and, usually, does not resolve on avoidance
friction can also result in dermatitis occurring at the of the trauma. Frictional ICD lacks these features and
Repeated Low-Grade Frictional Trauma 113
Fig. S. External pacemaker causing frictional irritant contact

dermatitis on left ehest
Figs. 3a,b. Keyboard operator with frictional irritant contact

dermatitis involving only those fingertips used on the keyboard
Fig. 4. Ankle-high "sneaker" causing frictional irritant contact Figs. 6a,b. Prosthesis causing frictional irritant contact dermati-
dermatitis of feet and ankles tis on below-knee amputation stump
usually res ponds well to avoidance of the frictional ical Trauma to the Skin: A Description of the Problem
trauma. in the Workplace. At this symposium, three investiga-
In 1983, the U.S. National Institute of Occupational tors (Menne and Hjorth 1985; Wilkinson 1985; Samitz
Health (NIOSH) held an international symposium in 1985) dealt with ICD caused by repeated low-grade
Cincinatti on The Chronic Effects of Repeated Mechan- friction. Yet since then, reports have been sparse in the
114 S. Freeman: Repeated Low-Grade Frietional Trauma
dermatologie al literature. Four eases were reported in References

1990 (Freeman and Rosen 1990) and three more eases
are listed in Table 1 (own unpublished results). In all
Ayres S Jm, Mihan R (1979) Facial dermatitis following friction
the eases mentioned in Table 1, allergie eontaet treatment of acne. Cutis 24:610-611
dermatitis was excluded by pateh testing (exeept in Dahlquist I, Fregert S (1979) Skin irritation in newborns. Contact
the neonates) and improvement oeeurred on avoid- Dermatitis 5:336-337
Freeman S, Rosen R (1990) Friction as a cause of irritant contact
anee of the frietional trauma. dermatitis. Am J Contact Dermatitis 1:165-170
Lammintausta K, Maibach HI (1990) Contact dermatitis due to
irritation. In: Adams RM (ed) Occupational skin disease.
Saunders, Philadelphia, pp 1-12
Conclusion Menne T (1983) Frictional dermatitis in post office workers.
Menne T, Hjorth N (1984) Mechanically-induced contact derma-
Oecupational dermatologists usually reeognise that titis and psoriasis. Z Hautkr 59:647-653
Menne T, Hjorth N (1985) Frictional contact dermatitis. Am J Ind
ICD ean be eaused by low-grade, repeated frietional Med 8:401-402
trauma. However, reports in the literature are sparse; Samitz M (1985) Repeated mechanical trauma to the skin:
henee, the eoneept may not be widely understood by occupational aspects. Am J Ind Med 8:265-271
Verbov J (1989) Juvenile plantar dermatosis. Acta Derm Venereol
all dermatologists. If dermatitis ean be shown to be due
Suppl (Stockh) 144:153-154
to frietional trauma in the workplaee, a claim for Wilkinson D (1985) Dermatitis from repeated trauma to the skin.
workers eompensation ean be substantiated. The Am J Ind Med 8:307-317
reeognition of this entity, therefore, eould have
important medieo-Iegal implieations. ICD eaused by
repeated low-grade friction is a distinet entity.
CHAPTER 13
Skin Hardening in Occupational Dermatology

B. Wulfhorst
What Is a Hardening Effert? enon, it has not been clearly defined' and no general
consensus regarding its existence has been reached, it
In experimental dermatology, the determination and is repeatedly mentioned in reports of everyday situa-
evaluation of parameters of individual skin sensitivity tions by persons who expose their skin to especially
has long been an object of research. It is noticeable, stressful activity. This is often the case with hairdress-
however, that persons who do not suffer from sensitive ers. The significance of such empirical observations for
skin have hardly been the subject of scientific research. which no sufficient explanation is currently available is
Important knowledge could also be gained from described by Kligman (1958): "In industry however,
research into parameters that require and/or lead to hardening has definite practical consequences; it may
the development of specific insensitivity, which could enable a worker to stay on his job".
be put to use for preventative and therapeutic needs. In Jadassohn (in 1897), who has exerted a great
this study into the 'hardening effect', an assessment inftuence on the defining of the hardening effect, and
will be made of factors relating to the individual's other authors (Fischer and Adams 1986; Kligman 1958)
(in)sensitivity of the skin, factors which have previ- differentiate between immunological and irritative
ously been neglected and run counter to current processes of adaptation. With regard to the division
discussion among experts. This assessment can be said of specific and non-specific hardening effects, a clear
to run counter to the current discussion for two delimitation between immunological and physical-
reasons: (1) because the investigations into how chemical hardening effects is, feasible. However, so is a
negatively defined 'non-immunological, non-specific direct connection between a chemically induced hard-
inftammation processes' originate have led a shadow of ening effect and a resultant improved mechanical
existence in comparison with the growth in knowledge barrier, which also prevents allergens from penetrating
about allergic skin reactions ever since the establish- immunologically competent skin layers. When distin-
ment of immunology as a research discipline; and (2) guishing between specific (i.e., adaptation to allergens
because medical research is, as a rule, geared towards in the case of proven sensitivities) and non-specific
pathological mechanisms which lead to the emergence hardening effects (i.e., adaptation to irritants) (Fisher
of illnesses. Research into 'self-healing processes' or and Adams 1986), it can be established that such a
'spontaneous remission' is only just starting to devel- differentiation does not delve deep enough. This is
op. The 'hardening effect' will be examined in this because the question of specification can be posed for
context, as the mechanisms of its origin have not as yet only one noxa or a group of noxas, even in the case of
been sufficiently understood. lowered reactivity to irritative stimuli. This hypo thesis
is based on the results of research into irritability,
whereby specific damage mechanisms can be attribut-
Definition of Terms and Basis for Discussion ed to individual irritants and groups of irritants
(Fartasch et al. 1992).
In general, the term "hardening effect" means the
adaptation of the skin to the cause of irritative contact 1 The existing definitions used by various authors are influenced
diseases (Frosch 1985). Some writers state that this by diverging attitudes towards induction. Several expressions are
adaptation process is preceded by an irritative inftam- used synonymously to describe hardening phenomena: "accom-
modation" (MeOsker and Beck 1967), "chemical calluses"
matory reaction which, in the second phase, lessens in (Klaschka 1985), "adaptation phenomena" (Klaschka 1985), "local
spite of continuing contact with the triggering noxa(s). hypo-reactivity" (Andersen et al. 1987) and "immunological
This results not only in the recreation of the 'normal' tolerance" (Wilkinson and Rycroft 1986). These terms show that
no real clear delimitation is available between an adaptation to
tolerance, but also in a certain insensitivity. Although substances with exclusively irritative potential and adaptation to
science has not paid much attention to this phenom- allergens in the case of proven sensitization.

116 B. Wulfhorst
Historical Aspects tensides. Klein, Grubauer and Fritsch (Klein et al.

1993) investigated the daily influence of deansing
A historical review of the experimental investigations liquid on the skin. For this purpose, the test persons
and theoretical descriptions would show that present bathed their hands in diluted washing-up liquid
knowledge regarding the hardening effect is not solution three tim es daily for 15 min over a 3-week
distinguishable from the theoretical rudiments already period. When evaluating the individual cases it was
possessed 100 years ago, even though our understand- found that, in the third week of irritation, TEWL sank
ing of the mechanisms causing it to emerge has grown slightly in those cases where an increase had initially
considerably. Moreover, the investigations started at been established. This trend was not, however, cor-
the end of the last century that started to deliver roborated by other cases, where values rose only to the
explanations pointing the way forward were discon- medium range. The authors nevertheless speak of an
tinued. The oldest primary source on the subject adaptation or hardening of the skin.
comes from the year 1890. Kreibich (1890) dealt with Widmer et al. (1994) investigated the strength of the
the local insensitivity of diseased skin (due to syphilis irritative reaction to SDS after irritative contact der-
and vitiligo, for example). Samuel utilised these matitis had been induced experimentally. During the
investigations in 1892 (Samuel 1892), and showed by first phase, the skin was irritated daily for 3 weeks.
experiments on rabbits' ears that an ear that had fully Then the model irritant was applied ocdusively three
recovered from a croton-oil inflammation does not times for 24 h; each application was separated by a
react as strongly to a repeated exposure to croton oil as space of 3 weeks. During the 3-week-Iong phase of
an ear that had no such previous exposure. irritation, a dedine in TEWL values, albeit non-
In 1897, Jadassohn was the first person to describe significant, could be distinguished toward the end of
adaptation experiments on humans (chrysarobin). the second week and in the third week. In the first post-
This and other early investigations into the hardening test after a 3-week gap, no difference in the reactivities
effect were explained by each author by either a of the previously irritated test areas and the test areas
changed reactivity of the dermal vascular plexus or by irritated for the first time could be established. This was
neural influences. In 1930, Miescher was the first to different in the second and third tests of the second
point to the mechanism of a reactive thickening of the phase. The test areas not irritated in phase 1 showed a
horny layer. A decisive moment came in McOsker's significantly higher proportional rise in TEWL values
and Beck's investigation in 1967 (McOsker and Beck than the test areas previously irritated in phase 1.
1967), which succeeded in accommodating the skin of An individual prognosis regarding the occurrence of
guinea pigs. One result of their investigation was, for a hardening effect has not been delivered to the present
example, the discovery that the skin can be made day. Whether the ability to harden is dependent on
resistant to irritation by very high concentrations of constitution is not dear. Present research is not in
substances if exposure is started at low concentrations agreement regarding whether there is a correlation
and slowly increased. In this way, animals treated with between the functioning of the horny-Iayer barrier and
slowly increased doses survived 20 exposures to 1% the induction of the hardening effect. According to
alkylbenzene sulphonate, whereas animals not previ- Frosch (1985), a missing correlation could explain why
ously treated died after three or four exposures. very sensitive individuals whose skin is exposed to
Three of the most important more recent investiga- strong pressure do not suffer from diseases; this
tions, which pointed to the possibility of inducing a apparent immunity occurs mainly because they pos-
hardening effect but were not carried out specifically sess the ability for the hardening effect. Other authors
for that purpose, will be referred to here. These presume that a hardening effect either cannot at all or
investigations have in common the repetitive use of an can only partially be induced on atopic persons
irritation model. The irritative inflammatory reaction (Schwanitz 1986). No exact details on the prevalence
was quantified by dermaphysiological methods of of the hardening effect can be found in the literature.
measuring. Tupker et al. (1990) irritated the skin of References to the hardening effect are based mainly on
33 test persons twice daily with sodium dodecyl sulfate dinical observations, which are only seldom based on
(SDS), discovering at first a rise in transepidermal theory and, similarly, are only seldom anamnestically
water loss (TEWL) which reached its dimax at the end and diagnostically evaluated (see synopsis by Wulf-
of the second week. In the third week a reverse trend horst 1996).
could be observed. The authors speak of an adaptation
effect which would first occur when a certain level of
irritative inflammatory reaction was reached. The Experimental Attempt at Induction
quicker this occurred, the quicker the adaptation
would come into effect. Therefore the effect would This investigation was carried out in an attempt to
occur especially in the case of strongly irritating answer the following questions: can a hardening effect
Skin Hardening in Occupational Dermatology 117
be generally induced by repeatedly applying irritants, on the flexor sides of the forearm for TP1 and TP2 are
or is the ability to harden limited to certain groups of shown in Table 2.
irritants? Is the ability to produce a hardening effect
dependent on the concentration of the acting noxa in Dermaphysiological Methods of Measurement
the sense of a threshold concentration? Is the ability to
produce a hardening effect dependent on the consti- The extent of the experimentally induced irritative
tution of the individual? inflammatory reaction was determined by measuring
the TEWL with the Evaporimeter EP1 (Servomed,
Method Sweden) and by measuring the peripheral skin blood
flow with a Laser-Doppler-Flowmetrie (Periflux 4001
Test Persons Master, Perimed, Sweden). The functional mechanisms
of the methods employed have been extensively
The group of test persons was made up of 20 persons described in other reports (Pinnagoda et al. 1990;
with healthy skin (14 fern ales and 7 males) with an Bircher et al. 1994). The measuring of the TEWL and
average age of 25.9 years (range 21-36 years). the blood flow (BF) proceeded according to the
relevant guidelines of the Standardization Group of
Irritation Phases the European Society of Contact Dermatitis (Pinna-
goda et al. 1990; Bircher et al. 1994).
In a first test phase (TP1), the test persons were exposed
to different concentrations of SDS and acetone (100%) Atopy Score
for 30 min daily over a 3-week period (Monday through
Friday). The test area was the right ventral fore arm. At the beginning of the study, the test persons were
Another test area was treated with H 2 0. As a control, a examined anamnestically and clinically with the help
further test area was not treated with anything. Three of the atopy score (Diepgen et al. 1991). The purpose of
weeks after the termination of TP1, the irritation was this was to determine an existing atopic skin diathesis
continued for a further 5 days (test phase 2, TP2) on the on the basis of this score in order to register
same test areas on the right forearm. In addition, constitutionally varying reactions to the irritation.
contralateral test areas were irritated on the left
forearm, which was left untreated in TP1. The exact Statistic Evaluation
course of the investigation is shown in Table 1.
As the results were not distributed normally, median
Irritants
values were used for the descriptive statistics, while
parameter-free test procedures were used for the
In accordance with a preliminary study into tolerance
analytical statistics (Wilcoxon test for paired differen-
and with concentrations described in the literature,
ces by Wilcoxon/Mann and Whitney) (Clauß and
sodium lauryl sulphate (Caesar & Lorenz GmbH
Ebner 1992).
Hilden, Ch.-B. 13594311, purity 95.2%) was used both
openly and occlusively in the following concentrations:
Results
open application - 5 ~ daily in distilled water: 2%, 5%,
7.5%; oCclusive application - 5 J.lI daily in distilled
Test Phase 1
water on the filter paper of the test pIaster: 0.5%, 1%,
2%. Acetone was tested to 100%. The application sites
In TP1, a strong initial rise dependent on concentra-
tion was observed for both measuring parameters
Table 1. Course of experiment in test phase 1 - irritation only on
right forearm and test phase 2 - irritation of test areas previously
irritated on right forearm in test phase 1 with contralateral test Table 2. Test areas and test concentration in test phases 1 and 2
areas on left forearm, steps 3-5 not carried out on day 19 test
phase 1 and day 5 test phase 2 Right volar forearm: Left volar forearm:
Phase 1 (PI) and Only Phase 2 (P2)
Time (min) Step Phase 2 (P2)
Antecubital fossa Antecubital fossa
0-40 Acclimatisation, marking of test areas Outwards inwards Outwards
41-65 Measuring of base values TEWL and BF a: H 2 0 occl. a: H 2 0 occl.
66-70 Application of irritants on test areas a-i on b: Empty control i: 2% SOS open b: Empty contral
right forearm in test phase 1 and on both c: 0.5% SOS occ!. h: 5% SOS open c: 0.5% SOS occl.
forearms in test phase 2 d: 1% SOS occ!. g: 7.5% SOS open d: 1% SOS occ!.
71-100 Phase of irritation e: 2% SOS occ!. f: Aceton occl. e: 2% SOS occl.
101 Removal of test piasters Wrist Wrist
TEWL, transepidermal water loss; BF, blood flow occl, occlusively

118 B. Wulfhorst
(TEWL and BF); the rise was continuous for TEWL in the TEWL values occurred (P < 0.01). In TP2,
until the end of the test phase, while the values for BF comparisons of the values from day 1 with days 2-5
stabilised during the second week of irritation. For the showed no statistically significant differences.
TEWL values in test area "e" (highest occlusive SDS
test concentration: 2%), the comparisons of days 1, 5 Oifferences in Constitution
and 12 with day 19 show that, after the end of the
second week of irritation (comparison 12119, Table 3), Through the use of the atopy score, the test persons
there was no further rise in the values. Although the could besplit into two groups. The non-atopic group
BF values initially rose in relation to irritation, their (n = 13) included all persons who had between 0 and 7
stabilisation by the end of the second week of points (categories "no atopic skin diathesis" and
irritation is clear from the statistical analysis. Com- "improbable atopic skin diathesis"). The atopic group
parisons of the measurements from days 5 and 12 with (n = 7) included all persons who reached a score
day 19, the last day of irritation, mainly show no more between 8 and 20 points (categories "unclear atopic
statistically significant differences (Table 3). A notice- skin diathesis" and "atopic skin diathesis") (Diepgen
able result is the significant rise of the TEWL values, et al. 1991). The results of the evaluation after the
even for the empty control test area (test area "b") splitting of the whole group into atopic and non-atopic
and for test area "a", where water was applied groups must, as a result of the small number of
occlusively (Table 3). persons, be regarded as indicators. However, these do
point to the existence of diverging reactions to
Test Phase 2 repeated irritative inflammatory stimuli among atopic
and non-atopic persons, the reason for which is the
In comparison to the first day of TP1, at the beginning individual constitution. In TP1, a rise in values for both
of TP2, significantly increased TEWL base values were parameters (TEWL and BF), both in the individual
measured at the test areas on both forearms. In this groups and for the whole group, arose due to
phase, a rise in the values over the five irritation days concentration, whereby the median values of the
also took place continually and in relation to the test non-atopic group lay slightly under the measurement
concentration. There was no difference in the strength for the group as a whole. Similarly, the median values
of reactions in the right (previously irritated) and left of the atopic group lay slightly above the measurement
(non-irritated) fore arm. It is striking, however that the for the group as a whole. In TP2, the non-atopic
TEWL values for TP2 rose proportionally less strongly group's TEWL values underwent a proportionally
in relation to those in TP1 (on days 1-5), i.e., significant smaller rise than in TP1 (just as did the whole group).
differences present at the outset disappeared over the For the atopic group, there was no difference in the
5-day irritation phase because of the increased base extent of the rise in TEWL values between the first
values in TP2. This result for test area "e" (highest 5 days of irritation in TP1 and TP2. A distinguishing
occlusive test concentration: 2% SDS) is shown in feature of the atopic group was the significantly higher
Fig. 1. The same tendency was registered for an other base value in comparison with the non-atopic group.
test areas. A reduced reactivity in TP2 for test area "f", This significance disappeared in the course of TP1 and
where acetone was applied occlusively, stands out. It is also in TP2. This means that atopic and non-atopic
apparent here that until day 5 in TP1, a significant rise values approximated one another after repeated irri-
Table 3. Median values and significance calculations (Wilcoxon test for paired sampIes) for transepidermal water loss and blood flow
in test phase 1 - comparison of day 1 with day 19, day 5 with day 19, and day 12 with day 19
Test area Transepidermal water loss Blood flow
Day 1/19 Day 5/19 Day 12/19 Day 1/19 Day 5/19 Day 12/19
a 3/6* 4/6** 5/6** 7/9.1** 8/9.1, n.s. 8.4/9.1, n.s.

b 3.5/5.5*** 3.5/5.5*** 4/5.5** 7.1/9.4** 8.4/9.4, n.s. 11/9.4, n.s.
c 3/11.5*** 4.5/11.5*** 8/11.5*** 8.5/13.4** 13.1/13.4, n.s. 14.9/13.4, n.s.
d 3/14*** 8.5/14*** 11/14** 9.4/31.5*** 16.7/31.5** 25.2/31.5**
e 3.5/16*** 12/16** 12.5/16, n.s. 9/51.5*** 24.4/51.5** 49.5/51.5, n.s.
f 4/7.5*** 6/7.5** 6/7.5** 9.3/11.6** 11.1/ 11.6, n.s. 11.9/11.6, n.S.
g 3.5/10*** 6/10*** 7.5/10*** 8.9/14.3** 9.9/14.3** 12.4/14.3, n.s.
h 3/10*** 6/10*** 7/10*** 7.9113.4** 8.9/13.4** 12.4/13.4, n.s.
3/7.5*** 5/7.5*** 6/7.5*** 8.2/13.4*** 11.4/13.4** 10.8/13.4**
n.s. = not significant; * P < 0.05

** P < 0.01
*** P < 0.001
TEWL
D.S.
14
12 12
.__ .... __ ............_...................._ .... _. __....... _.~._._._._ ...._ ..... _............. _..... _ ..._..P..S. 0.0.l ....... _..........
10
Dphase 1
o Phase 2
6
o
Day I Day2 Day3 Day4 Day5
Fig. 1. Transepidermal water loss median progress on days 1-5 in definition of irritative infiammatory reactions which,
test phases 1 and 2 . The examples shown are from test area e as opposed to allergie reactions, are characterised by
(highest occlusive concentration of sodium dodecyl sulfate at 2%)
being "non-immunological", "locally limited" and
"non-specific" (Prottey 1978; Mathias 1983). The results
tation. An example from a test area of this "approx- of this study confirm, however, the indications of other
imation" is shown in Fig. 2. authors (McKenna et al. 1989; Brand et al. 1993) that
irritative stimuli (and thereby hardening effects) are
not only limited to local areas, but are also able to
Does the Hardening Effect Exist? cause generalised reactions. The TEWL measurements
Summarising Discussion for TP2 rose proportionally more slowly than in TPI
(during days 1-5). Initial significant differences caused
Previous major attempts at explaining the induction of by the increased base values for both forearms, i.e.,
the hardening effect can be summarised as folIows: an also for the previously non-irritated left forearm,
increased permeability of adapted skin combined with disappeared in the course of the 5-day irritation period
an increase in vascular reactivity leads to a faster of TP2. A systematic effect of locally applied irritants
removal of the noxa (MeOsker and Beck 1967). A can therefore be presumed.
thickening of the horny layer, stimulated by irritants, In TP1, a significant rise in TEWL and BF was also
causes an improvement in the protective function of ascertained in the empty control test area. A rise in the
the skin (Widmer et a1. 1994). TEWL values for the control test areas was also found
by Pinnagoda et al. (Pinnagoda et al. 1989), who
1. The cumulative effect of irritants leads to a change in
named this the "spill-over irritant effect". As a conse-
the lipid composition of the stratum corneum,
quence of the higher base values recorded in TP2 and
which in turn leads to decreased permeability (often
the following slower proportional rise in TEWL, it can
in connection with item 2 below) (Widmer et al.
be presumed that systematic effects (in the sense of
1994).
excited skin syndrome) occurred, as a result of which a
2. The induction of the hardening effect is directed by
decreased irritability took hold. Studies into ultraviolet
humoral factors; active regenerative fore es are
(UV)-induced immune suppression can be conducted
mobilised through contact with irritants (Lam-
in order to address the generalised effects of local
mintausta et al. 1987).
irritative stimuli (Rosen et al. 1989). Schwarz (1988),
It is apparent that, with the exception of the last for example, has described the production of both
thesis, all approaches are based on a local induction of immune-stimulating and immune-suppressing cyto-
the hardening effect stemming exclusively from chan- kines by keratinocytes after exposure to UV rays,
ges of part-systems in the permeability barrier or in which, according to the hitherto-existing classification
the dermal vascular plexus which have come into scheme of possible skin reactions to exogenous stimuli,
direct contact with the causal noxa. There is therefore a would be classified as an irritative noxa. The "non-
correlation between the above definitions and the specific" criteria of characterising irritative infiamma-
120 B. Wulfhorst
TEWL
16 / n.s.--====i'I
............. - ... _ .............................. _... __ ......................................_ ........................... _....... ............_ ..._ ... f'"
... IS
14 14
12
,.'
, ...... _._._ .... ~_ ........ ,._ .... - ......._._. __ .. ....-..._._.-.-..........
~
12
/
10 ._...................._.... -.-.- .•...... .............
- _- .- ............. .... D ooalopics
/
":'.
............. ........ _..................._............. ~==l DAlopics
6 ......... 7
... .. p. ~ .0.9.L ........................... ..
4 4
3 .;. /;
2
- ~
0
V
Day 1 Day 5 Day 19
Fig. 2. Transepidermal water loss (TEWL) median progress in the highest occlusive concentration of SDS (2%) at the
test phase 1 on days 1, 5 and 19: comparison of atopic and non- end of the second week of irritation. In contrast to all
atopic groups. The examples shown are from test area e (1%
sodium dodecyl sulfate occlusively). Initial significant differences the other (lower) test concentrations, no further
in TEWL base values on day 1 are due to higher atopic values. significant increase in TEWL value occurred with this
There then follows a much faster increase in atopic values before concentration.
the non-atopics "catch up" with the atopics towards the end of
the test phase There seem to exist constitutionaHy.. determined
differences between atopic and non .. atopic persons
concerning their reactions to repeated irritative in ..
tory reactions must be looked at criticaHy, if only fiammatory stimuli. It was apparent from the compar ..
because of the diverging damage mechanisms of ison of TEWL values in both test phases between both
individual irritants and even of individual concentra- groups that initial significant differences between the
tions of irritants (Fartasch et al. 1992). That means that groups based on the atopic increased base values either
the classification of irritative infiammatory reactions disappeared in the course of both irritation phases or
hitherto in use must be reworked. that there was an approximation of both groups'
The dermaphysiological measuring methods chosen values. This "approximation phenomenon" raises a
proved to be a sensible combination for recording question which should form the basis of further studies
infiammatory reactions caused by irritation. By deter- into irritative reactions: is there a fixed extent of
mining BF with the Laser.. Doppler .. Flowrnetry, a stabi- variation for the rise in TEWL that is not crossed in
lisation of values could be established weH before the certain concentrations of irritants and is reached faster
end of the 3.. week ..long TP1. These had initiaHy risen as by atopics due to the higher base values? Or, do TEWL
a result of the irritation. TEWL, however, continued to values rise more slowly when base values are lower?
rise until the end of TPl. As erythematous reactions The results of this study prove that a hardening
refiect the acute phase of an infiammatory reaction, it effect is inducible and appears generalised - or at least
can be concluded that the adaptation effect started to not strictly localised. Subsequent studies should be
occur in TPl. This result correlates weH with the results dedicated to the possible functional connections of the
of earlier studies, in which a reduction in the strength induction of a hardening effect. Possible changes as a
of the reaction was described despite continued result of repetitive irritation (Widmer et al. 1994), e.g.,
irritation (Tupker et al. 1990; Klein et al. 1993; Widmer the composition of the stratum corneum, lipids or the
et al. 1994). A particular correspondence can be found thickness of the horny layer, should be recorded by gas
with Tupker et al.'s results (Tupker et al. 1990), which chromatographic determination and histological in ..
describe a hardening effect on the applied tensides vestigations. Furthermore, it is necessary to systemat..
during a 3.. week irritation phase. In that experiment, icaHy study working factors, such as cytokines, in
the tenside with the greatest irritative potential was connection with adaptation effects. In addition, in
more likely to cause a decline in the TEWL values, cases of high and low base values, the question of the
which had initiaHy risen. In this study, the highest extent of variation or the reaching of a predetermined
TEWL values also reached a maximun reaction with level of value rise via irritation must be answered
(Wulfhorst 1996). The prospects for the practical Lammintausta K, Maibach HI, Wilson D (1987) Human cutaneous
irritation: induced hyporeactivity. Contact Dermatitis 17:
re1evance of these results must remain speculative at
193-198
present, as basic research to clarify the mechanisms of Malten KE, Den AJ (1978) Topical toxicity of various concen-
how the hardening effect occurs must first be con- trations of DMSO recorded with impedance measurements
and water vapour loss measurements. Contact Dermatitis
ducted. It is conceivable, however, that the skin can be 4:80-92
hardened to forms of stress such as wet work in order Mathias T (1983) Clinical and experimental aspects of cutaneous
to prevent damage to the skin. irritation. In: Marzulli FN, Maibach HI (eds) Dermatotoxi-
cology, 2nd edn. Hemisphere, Washington, pp 167-183
McKenna K, Burrows D, Walsh M (1989) Comparison of
expression of human Iyrnphocyte dass II antigens by
References cutaneous Langerhans cells and keratinocytes between pa-
tients with allergie, irritant and atopic dermatitis. In: Frosch
Andersen KE, Maibach HI (1980) Cumulative irritancy in the P, Dooms-Goossens A, Lachapelle JM, et al. (eds) Current
guinea pig from low grade irritant vesides and the angry skin topics in contact dermatitis. Springer, Berlin Heidelberg New
syndrome. Contact Dermatitis 6:430-434 York, pp 404-411
Andersen KE, Benezra C, Burrow D, et al. (1987) Contact McOsker DE, Beck LW (1967) Characteristics of accommodated
Dermatitis (a review). Contact Dermatitis 16:55-78 (hardened) skin. J Invest Dermatol 48:372-383
Bircher A, DE Boer EM, Agner T, et al. (1994) Guidelines for Mieseher G (1930) Das Problem des Lichtschutzes und der
measurement of cutaneous blood flow by laser Doppler Lichtgewöhnung. Strahlenther Onkol 35:403-443
flowrnetry. Contact Dermatitis 30:65-72 Mitchell JC (1977) Multiple concomitant positive patch test
Brand CU, Hunziker T, Limat A, et al. (1993) Large increase of reactions. Contact Dermatitis 3:315-320
Langerhans cells in human skin Iyrnph derived from irritant Pinnagoda I, Tupker RA, Coenraads PJ (1989) Prediction of
contact dermatitis. Br J Dermatol128:184-188 susceptibility to an irritant response by transepidermal water
Clauß G, Ebner H (1992) Statistik, VOll, 7th edn, Deutsch, loss. Contact Dermatitis 20:341-346
Frankfurt Pinnagoda I, Tupker RA, Agner T (1990) Guidelines for
Diepgen TL, Fartasch M, Hornstein OP (1991) Kriterien zur transepidermal water loss (TEWL) measurement. Contact
Beurteilung der atopischen Hautdiathese. Dermatosen 39: Dermatitis 22:164-178
79-83 Prottey C (1978) The molecular basis of skin irritation. In: Breuer
Fartasch M, Diepgen TL, Kuhnert A (1992) The reaction of MM (ed) Cosmetic science (VOll). Academic, London,
human stratum corneum epidermal lipids to irritation. Clin pp 275-349
Exp Dermatol 17:288 Rosen K, Jontell M, Mobacken H, et al. (1989) Epidermal
Fisher AA, Adams RM (1986) Occupational dermatitis. In: Fisher langerhans cells in chronic eczematous dermatitis of the
AA (ed) Contact dermatitis, 3rd edn. Lea & Febiger, Phila- palms treated with PUV A and UVB. Acta Derm Venereol
delphia, pp 486-514 69:200-205
Fisher LB, Maibach HJ (1975) Effect of some irritants on human Samuel S (1892) Über eine Art Immunität nach überstandener
epidermal mitosis. Contact Dermatitis 1:273-276 Krotonentzündung. Virchows Arch 127
Frosch PJ (1985) Hautirritation und empfindliche Haut. Grosse, Schwanitz HJ (1986) Das atopische Palmoplantarekzem. Springer,
Berlin Berlin Heidelberg New York
Jarisch R, Dechant E, Zajc J, Grabner G (1986) Toxische Schwarz T (1988) Die Bedeutung epidermaler Zytokine in der
Kontaktdermatitis bei Friseurlehrlingen: Therapiestudie mit UV-induzierten Immunsuppression. Hautarzt 39:642-646
steroidfreien, pH-stabilisierten Salbengrundlagen. Wien Klin Tupker RA, Pinnagoda J, Coenraads PI, Nater P (1990) Suscep-
Wochen sehr 98:428-432 tibility to irritants: role of barrier function, skin dryness and
Klaschka F (1985) Äußere Schutzmechanismen der Haut. In: history of atopic dermatitis. Br J Dermatol 123=l99-205
Hornstein OP, Nürnberg E (eds) Externe Therapie von Widmer J, Eisner P, Burg G (1994) Skin irritant reactivity
Hautkrankheiten. Thieme, Stuttgart, pp 29-34 following experimental cumulative irritant contact dermatitis.
Klein G, Grubauer G, Fritsch P (1993) Greifen synthetische Contact Dermatitis 30:35-39
Detergentien die Haut an? Arch Dermatol Syphilis 7:13-16 Wilkinson JD, Rycroft RJG (1986) Contact dermatitis. In: Rook A
Kligman AM (1958) Hyposensitization against Rhus dermatitis. (ed) Textbook of dermatology, VOll, 4th edn. Blackwell,
Arch Dermatol 78:47-72 Oxford, pp 435-450
Kreibich C (1890) Über lokale Unterempfindlichkeit der Haut. Wulfhorst B (1996) Hardening-Effekt. Untersuchung zur In-
Arch Dermatol Syphilis 103:133-138 duktionsmöglichkeit durch Irritantien. Shaker, Aachen
CHAPTER 14
Fiberglass Dermatitis
A. Sertoli, S. Francalanci, and S. Giorgini
Introduction Production of Fiberglass
Glass fibers (man-made vitreous fibers, MMVF) rep- Glass fibers are produced exdusively from glass, while
resent a subgroup of the so-called man-made mineral mineral wool for insulation can also be obtained from
fibers (MMMF) and indude glass fibers, ceramic fibers, rocks (limestone, dolomite, wallastonite, etc.) and blast
glass wool, rock wool and slag wool (TIMA 1991; Stam- furnace slag (International Labour Office 1983; Sertoli
Westerveid 1996). The term "mineral wool" refers et al. 1992). From the technical viewpoint, glass fibers
specifically to masses of entangled fibers not showing are produced through fusion at temperatures ranging
any three-dimensional order, while real fibers are from 1000 °C to 1500 °C and subsequent filtering of
single continuous filaments, sometimes very long (like siliceous-based mixtures containing earthy-alkaline
the continuous glass filaments), which can be pro- additives to improve their workability.
cessed using the techniques typical of the textile The first techniques used to produce glass fibers
industry to produce fabrics and can be gathered were the Gossler technique, the Hager technique and
together to produce felts, or cut in pieces of shorter the Owens technique and, nowadays, among them,
length (Björnberg 1985; Konzen 1987). only the Hager method is still in use for manufacturing
As to their use - and in relationship with their rock wool (Sacchi 1989). Modern productive glass-fiber
diameter - glass fibers can be dassified into fibers for systems do not show remarkable differences; they
special purposes: glass fibers with a 0.2-/lm to 1.5-/lm differ only in the characteristics of the raw materials
diameter; insulation wool (glass wool with a diameter used, the automation of mixing systems, checks and
ranging from 4 /lm to 9 /lm, together with slag wool some technical particulars of minor importance. Dos-
and rock wool with a diameter fluctuating between ing systems and mixing of components, a continuous
4 /lm and 6 /lm); and continuous filaments (fibers with furnace - which is usually electric - a crucible
a diameter between 6 /lm and 15 /lm, sometimes up to equipped with feed channels, fibering machines, and
25 /lm. Refractory fibers (ceramic fibers), used for assembly and finishing systems are the basic common
insulating at very high temperatures, have a diameter elements of the productive cyde used in all the glass-
that ranges between 2.5 /lm and 4 /lm (Stam-Wester- fiber manufacturing methods (International Labour
veld, 1996). The greatest part of glass fibers shows an Office 1983; Sertoli et al. 1992).
amorphous structure and is prone to break transver- Glass fibers, in particular, are produced by three
sally. Asbestos fibers, however, tend to break longitu- main methods: centrifugation, blowing with hot gasses
dinally, with the result that many finer fibers with a and thinning by flame (International Labour Office
smaller diameter but the same length can be released 1983). Centrifugation takes place in special rotating
into the atmosphere, unlike glass fibers which can give drums from which the vitreous mixture, coming out of
rise to various fibers with the same diameter, but the furnace and melted at high temperatures, exits
shorter length (International Labour Office 1983). through special holes in the shape of primary filaments
During the last years, the use of MMVF has which are thinned by a high-pressure fluid flux,
registered an ever-increasing expansion in various enabling fibers with arated diameter fluctuating
fields due basically to their characteristics of acoustic, between 6 /lm and 7 /lm to be obtained. Blowing
thermal and electrical insulators and their possible use through hot gas ses is similar to the preceding tech-
as strengthening and filtering material (Lammintausta nique but, in this case, melted magma, instead
and Maibach 1990; Lachapelle et al. 1992; Sertoli et al. of exiting through a rotating drum, exits by gravity
1992). out of the special crucible while the thinning down of
filaments is carried out by a gaseous jet instead of a

Fiberglass Dermatitis 123
fluid jet. This technique enables the manufacture of and represents about 80% of the whole production of
fibers with arated diameter up to 15 11m. MMVF (Patroni 1989). The production of glass fibers
Lastly, in the technique used to thin down fibers for speeial purposes, such as aircraft insulation and
using a flame to produce microfibers, the vitreous highly effieient paper filters, was estimated at 60,000
mixture, after exiting a special crueible in the form of tons in 1989 and accounts for 1% of the whole
primary filaments, is conveyed into an inner combus- production of mineral fibers.
tion chamber where, submitted to the action of high-
speed gas jets at high temperature, thins down their Acoustic Insulators
diameter up to 1 11m or less. The maximum length of
continuous filaments that can be obtained is 10 cm. Glass wool finds application in the internal setting of
Fibers are then treated with particular substances that public buildings (offices, theatres, schools, hospitals,
have binding, protective and lubricating effects, espe- etc.) usually in the form of panels (Verbeck et al. 1981;
eially if they are to be used in the manufacture of Wang et al. 1993).
reinforced plastic. The above-mentioned substances
are: phenol-formaldehyde resins (particularly in the Thermal Insulators
case of resin glass wool), formaldehyde-urea resins,
melaminoformaldehyde resins, epoxy resins (in par- Glass wool in mattresses, felts and fiber glass tissues is
ticular for the treatment of glass fibers), polyester used to insulate steam or water pipes, stoves, under-
resins (for the use of fibers in the manufacture of roof coverings in houses with wave-form ceiling
laminated plastic), polyvinylacetate, silicon, ammo- boards and in the aircraft industry. A more recent
nium hydroxide and mineral oils (Björnberg 1985; and peculiar application is in the production of printed
Konzen 1987; Bruze and Almgren 1989; Jolanki et al. circuit boards (PRCB) (Koh et al. 1992; Marks and
1996). Glass wool is produced from a vitreous mixture DeLeo 1992; Wang et al. 1993; Koh and Khoo 1994).
which is subsequently filtered in the shape of wool They are composed of several layers, the core (fire-
(International Labour Office 1983; Stam-Westerveid proof) consisting of fiberglass fabric soaked with
1996). It is made up of fibers with arated diameter brominated epoxy res in, the outer layers consisting of
fluctuating between 4 11m and 9 11m and is used for copper sheets (Bruze and Almgren 1989).
acoustic and thermal insulation of both private houses
and industrial environments, whose maximum oper- Electrical Insulators
ating temperature is lower than 450 oe. It is always
produced with dressing agents, i.e., binding materials Glass fibers are used In the form of wool, tissues,
and, in this shape, is used to manufacture mattresses, ribbons, etc. to insulate motors, wires and electric
felts or panels. cables (Sertoli et al. 1992).
During the production of insulating mineral wool, a
given amount of material (up to 30% of the total Reinforcing Material
amount) is not changed into fibers, but into small
grains called "shots" (Stam-Westerveld et al. 1994). Tissues in glass fibers and glass wool are used with
The lower the percentage of shots in the end product, polyester, epoxy and melaminic resins to produce a
the better the insulating wool material. large number of reinforced plastic-manufactured arti-
des to strengthen their mechanical resistance; they are
mainly used in aircraft, automotive, naval and railway
Use of Fiberglass industries (doors, hulls, boards, etc.) and to produce
sportswear and printed material in general (Sertoli
Due to their ever-increasing applications, glass fibers et al. 1982, 1992; Carrino 1988; Tarvainen et al. 1995). In
are the most widespread artifieial mineral fibers the epoxy composite materials, e.g., those used to
(Meneghini 1977; Lammintausta and Maibach 1990; produce skis, plastic sheets reinforced with glass fibers
Lachapelle et al. 1992; Sertoli et al. 1992; Rietschel and are laminated one by one with sheets in epoxy res ins
Flower 1995; Stam-Westerveld 1996). They have be- (Jolanki et al. 1996). Very short glass fibers (0.8 mm),
co me more and more important because they can made up by milled fibers, are used as filling charges for
replace asbestos fibers which are particularly danger- resins and stickers.
OUS (Ruegger 1996). Furthermore, compared with
asbestos - a natural mineral - they can be produced Filtering Material
in dimensions and forms best suited to meet the widest
variety of requirements. World production of glass Very thin glass fibers are mainly used in the shape of
fibers used in various kinds of insulation, assessed in tissues for seientific purposes (chemistry laboratories,
1973 at 3,600,000 tons, reached 4,800,000 tons in 1989 food and beverage industries) such as filters for air,
124 A. Sertoli et al.
gases and liquid material (Sertoli and Farli 1991; diameter superior to 4.5 11m is commonly considered
Lachapelle et al. 1992). They are also used in the to be injurious. Nevertheless, a potentially irritant
filtering devices of private and public air circulating activity was also noticed for those fibers with an
systems. inferior rated diameter (3.2 11m) (Heisel and Hunt
1968; Hatch and Maibach 1985; Eun et al. 1991; Stam-
Westerveid et al. 1994; Adams 1995; Stam-Westerveld
Health Hazards 1996). The possible presence of "shots" in mineral
wool and the arrangement of fibers according to the
The most frequent health hazards due to glass-fiber kind of manufactured article could be responsible,
exposure are represented by skin lesions, commonly together with their diameter, for the irritant activity
known as fiberglass dermatitis, described for the first (Stam-Westerveld and Coenraads, unpublished obser-
time at the beginning of the 1940S (Sulzberger and Baer vations). Penetration of fiberglass into derma, rather
1942). We also have to remember the potential uncommon indeed, can cause the formation of foreign-
bronchopneumopathy hazard due to glass-fiber inha- body reactions (Lechner and Hartmann 1979; Lacha-
lation, which seems to be inversely proportional to pelle et al. 1992).
their diameter and length; evidence exists that only The risk of sensitization by contact is mainly due to
fibers with a length between 5 11m and 80 11m, whose professional exposure to the resins used for the
diameter is lower than 3 11m can reach peripheral areas finishing of glass fibers; allergic contact dermatitis
of the lung, in which, in any case, they are expelled was reported in those workers coming into contact
much more quickly than asbestos fibers. In rats, with resins not completely cured, in particular, epoxy
inhalation of glass fibers does not result in tumors of and formaldehyde resins (Cuypers et al. 1975a; Dahl-
the respiratory system, and the epidemiological data quist et al. 1979; Kalimo et al. 1980; Conde-Salazar
do not seem to indicate a higher meaningful occur- et al. 1985; Holness and Nethercott 1989). Epoxy (resins
rence of malignant cancers or mesothelioma in the and reactive diluents) and hardening byproducts have
respiratory airways in those professional workers been reported to be responsible for sensitization by
exposed to these fibers. In light of these considerations contact in industries that produce PRCB using glass
and relative to the current levels of exposure, it does fibers and reinforced plastics with epoxy resins (Bruze
not seem to be a clear-cut cancer risk for those workers and Almgren 1989; Jolanki et al. 1996).
handling glass fibers (Ruegger 1996).
Fiberglass Irritant Contact Dermatitis

Pathogenesis of Fiberglass Dermatitis
Fiberglass dermatitis is one of the most common
From a chemical viewpoint, fiberglass is inert and, in professional mechanic irritant contact dermatitides
itself, is not endowed with any sensitizing activity (ICD) (Heisel and Mitchell1957; Fisher and Warkentin
(International Labour Office 1983). The basic pathoge- 1969; Lachapelle 1986; Konzen 1987; Okano et al. 1987;
netic mechanism of fiberglass dermatitis (Table 1) is Adams 1990; Fleming and Bergfeld 1990; Tarvainen
represented by penetration (supported by pressure, et al. 1994; Adams 1995; Rietschel and Fowler 1995;
rub and scraping) of fine sharp particles into the skin Stam-Westerveid 1996).
causing mechanical irritation (Stam-Westerveld et al. The first paper on the Effect of Fiberglass on Animal
1994; Stam-Westerveld 1996). Fibers are usually found and Human Skin was published by Sulzberger and
in the horny layer but, occasionally, they can also Baer in 1942, followed by Skin Hazards in the
penetrate the skin more deeply. The pathogenic Manufacture of Glass Wool and Thread by Schwartz
activity of fiberglass on the skin is direcdy propor- and Botvinick (1943) and La Dermatose de la Lain de
tional to the diameter and inversely proportional to the Verre by Pellerat (1947). Generally speaking, dermatitis
length (Konzen 1987). Only fiberglass featuring arated arises in subjects exposed to glass fibers for a short
period, while those who routinely co me into contact
with it seem to develop a sort of hardening and can
Table 1. Pathogenetic meehanism of fiberglass dermatitis continue working without any difficulty (Björnberg
1985). In fact, very few workers ask to be transferred to
Direet, indireet (through clothing) or airborne (irritant eontaet another production line, also because symptoms
dermatitis, rCD) followed by: usually disappear after 1 week or 2 weeks without
Simple meehanieal trauma by sting
Fibers penetration and permanenee into derma and consequences. The hardening phenomenon seems to
subeutaneous concern, in particular, the subjective symptom of
Sensitization (allergie eontaet dermatitis, ACD) by finishing itching, which could be explained, at least in part, by
resins
a psychological component (Cuypers et al. 1975a;
Stam-Westerveld 1996). Symptomatology can reappear higher than 17% (Bruze and Almgren 1989; Koh et al.
after a few weeks; a relapse of dermatitis occurs if its 1992). This percentage is much lower in industries
source has not been eliminated by the time the worker (such as that producing skis) that use laminated
goes back to work. plastics reinforced with glass fiber (Jolanki et a1. 1996).
Diagnosis is not always easy because of the different In Finland, during the period 1975-1991, fiberglass
aspects conditioning the clinical picture with this kind dermatitis represented 1.7% of occupational de-
of dermatitis: rmatoses concerning 58 different activities (Tarvainen
et a1. 1994).
1. Individual characteristics. The presence of personal
The most widespread glass-fiber field of application,
and/or family atopy, altered dermographic reactivity
insulation and ventilation plants, used in public and
which, together with clear skin, are important
private buildings, exposes an ever-growing number of
promoting factors (Björnberg 1985)
people who are not professionally involved in the
2. Environmental conditions. High temperatures and
working activities of production and application of
humidity characterizing the microclimate in the
glass fibers (Verbeck et a1. 1981; Farkas 1983). This kind
working environment; summer season - but also
of pollution does not concern secluded areas only
winter time - during which the relative humidity
(offices), but also open spaces, above all those in the
dramatically decreases because of the heating sys-
neighborhood of factories producing glass fibers. The
tems; inadequate ventilation; concentration of fibers
presence of airborne glass fibers in secluded spaces is
also due to incorrect cleaning (Sertoli et a1. 1982;
directly connected not only with the release of fibers by
Adams 1990)
insulators and air filters in ventilation plants, but also
3. Mechanisms of contact. Direct contact of fibers with
with the external contribution which, though usually at
the skin or their indirect contact due to accumula-
minimum levels, is possible. Fiberglass pollution in
ti on on clothing, presence of fibers in the powder
secluded spaces is usually very low and more modest
from the floor and/or on working surfaces; contact
than that recorded in working areas such as factories
with airborne fibers; duration of exposure (Lacha-
and places in which they are used (at least lOo-fold to
pelle 1986; Sertoli et a1. 1992; Rietschel and Fowler
1000-fold). Of course, a natural deterioration of
1995)
materials or the use of free fibers as filling material
4. Pathogenetic mechanisms. Simple mechanical trau-
can give rise to the release of a high number of fibers.
ma by fibers on the skin or their permanence in
derma and hypodermis after penetration; sensitiza-
Clinical Picture
ti on to the resins used for the finis hing of fibers or
to manufacture reinforced plastics (Konzen 1987;
Itching (of different intensity, usually very strong) and
Tarvainen et a1. 1993; Stam-Westerveld 1996)
a tingling sensation, above all at the skin fold or where
clothing sticks more to the skin, usually represent the
Epidemiology initial symptoms characterizing fiberglass dermatitis.
Their sudden manifestation can be the cause of serious
Few data are available regarding the predominance of apprehension in affected patients (Adams 1990).
fiberglass dermatitis and they pertain solely to profes- Afterwards, a diffused eruption of small erythematous
sional exposure. In factories where fibers and glass patches together with papules featuring a small diam-
wool are produced, studies which are not updated eter can be observed - as in the case of papular
report on percentages ranging from 11% to 58% (Heisel urticaria - but not showing the typical vesicle in the
and Mitchell 1957; Björnberg et al. 1979a). Within an center. Sometimes the patch is excoriated, prevalently
establishment of the Ferrovie dello Stato (Italian with follicular localization, diffused through the ex-
Railways Company), Sertoli and his colleagues found posed areas when fibers co me into contact with the
percentages equal to 20.3% in the personnel directly ex- skin through the airborne mechanism (airborne fiber-
posed to the hazard, 19.9% in those indirectly exposed glass contact dermatitis) or on the portions of skin,
and 1.1% in the other personnel apparently not directly above all the fore arms, which came into contact with
exposed (for example, clerks), who worked in areas far surfaces contaminated by glass fibers such as, in the
from the departments where glass fibers were pro- professional environment, a work bench or, in the case
cessed (Sertoli et a1. 1982). In the building industry, of extra-professional environments, clothing. The other
where the hazard appears to be high, dermatitis main sites are legs, trunk and neck; scalp, face and
prevalence among the personnel has been reported as hands are not usually involved. Dermatitis heals as
being higher than 60% (Björnberg 1985). PRCB indus- soon as the contacts stop (Erwin 1947), rarely becom-
try is another field at risk, in which micro-epidemics ing chronic with the formation of nodular elements. It
(more exactly pseudo-epidemics) have been reported, can occur in epidemics, affecting children through
and where the percentage of afflicted personnel is fibers at school, at horne or on playgrounds and is
subjeet to differential diagnosis with other itehing by (Sertoli et al. 1982). Skin lesions were present in about
external causes. 20% of examined subjects, but also in those personnel
This dermatitis also has the following particular who worked in buildings which were far away from it
characteristics: affected subjects complain of a strong and not directly exposed to the specific hazard (for
and sudden itching through neck, cubital fossa and example, clerks). Their lesions were localized mainly
foreharms, sites in which clothing are more in contact on the lower limbs and above all on thighs, but they
with the skin - wrists, waist and feet. An excoriated also involved, though to a lesser extent, upper limbs,
folliculitis diffused through arms, face, neck and armpits and the trunk side surfaces. Only the face,
sometimes legs - beyond linear excoriations due to hands and scalp were not affected. Dermatitis was
the scraping - acute paronychia (caused by the characterized by the occurrence of different kinds of
penetration of fibers into the perionychium) and lesions; the same subject presented papules centered
nummular eczema-like lesions can also be observed by a petechia accompanied by an abrasion, small
(Camarasa and Moreno 1984; Fisher 1986; Beyer and roundish erythematous patches with clear-cut or
Vossmann 1996). Eye-burning sensations and con- blurred outlines, sometimes centered by a petechia
junctivitis can also be caused by smaller glass fibers; and eczematous lesions. Signs of pyodermization were
some individuals cannot use contact lenses (Verbeck also found. Erythematous lesions regressed spontane-
et al. 1981). Lesions secondary to the scraping are ously after few hours, while papules and eczematous
represented by bacterial infections and lichenification. lesions remained for a longer time and could change
Glass fibers can give rise to purpuric lesions; contact into brownish macules and, exceptionally, small nod-
urticaria, particularly in those subjects with altered ules. Allergie pathogenesis did not play any role in the
dermographic activity; erythema multiforme-like der- epidemics of this fiberglass dermatitis (the patch tests
matitis and granuloma anulare-like; folliculitis and carried out with the most common resins used for the
acneiform lesions with follicular pustules due to finishing of fibers did not give any positive result), the
hydrogenated vegetable oils and emulsions used for onset of which was pro mo ted by particular climatic
the finishing of glass fibers (Björnberg et al. 1979b; changes. Because the hot, damp climate, on the one
Lechner and Hartmann 1979; Fisher 1982; Camarasa hand, prevents the airborne mechanism from
and Moreno 1984; Fisher 1986; Konzen 1987; Sertoli being started up while, on the other, it supports
et al. 1992). Furthermore, teleangectatic lesions and the spontaneous elimination of fibers by gravity, the
linear erosions in the skin folds may be found in prevalent localization of this pathology through the
subjects with clear and dry skin and blue eyes lower limbs is thus justified.
(Björnberg 1985). The same author (Sertoli, personal communication)
Eby and Jetton (1972) reported on an 8-year-old girl reports on two other episodes concerning fiberglass
affected by a chronic dermatitis characterized by dermatitis epidemics. The first took place on one of the
erythema, papules, excoriations and lichenification, floors of a new building, built up for a daily newspaper;
loealized on the baek surfaee of her thighs, the cause of the floor was reserved for the administration. At the
which was identified as the irritant contact with the beginning of the summer season, the insiders began to
glass fibers used to reinforce the plastic school chairs. complain about a generalized itching thickened by
Lechner and Hartmann (1977) deseribed the case of papules and small erythematous patches. This derma-
a 6-year-old girl in whom glass fibers, with which she titis was found to be caused by a filter in a malfunc-
had come into contact while playing in a barn, had tioning air-conditioning system which caused glass
given rise to the formation of nodules due to the fibers to be released into the environment. The second
penetration of fibers into the skin of the lower limbs. episode took place in the month of September in a
Garcia-Patos and Pujol (1994) described that a visit by factory producing fabrics for interior decoration.
a 16-month-old baby girl to her father's factory, where About 50% of the insiders complained of itching. The
occasionally glass wool was used, provoked a gen er- subjects involved performed their duties in different
alized itching, together with lesions characterized by parts of the factory (offices, woven and piece-goods
erythematous micro-papules on the right antecubital storehouse, warping and knotting department, etc).
fossa. The diagnosis of dermatitis by contact with glass The doubt of dermatitis by direct contact, but, above
felt, suggested by the physical examination and by her all, by airborne glass fibers arose mainly because of:
detailed family his tory, found confirrnation, by micro-
scopic analysis, of glass fiber spicules in sampies of 1. The kind of lesions, i.e., small erythematous pomp-
cellophane-tape taken from the right antecubital flex- hoid patches and itching papules localized mainly
ure (Garcia-Patos and PujoI1994). on the trunk (Fig. 1).
Sertoli and co-workers investigated an epidemic of 2. Healing after removal from the working environ-
dermatitis by glass fibers which occurred within a ment with relapse once the subjects went back to
workshop of the Ferrovie dello Stato (ltalian Railways) work.
in the environment and fell on the looms and other

surfaces (cylinders, pieces, tables, etc.). Further-
more, during the production of mattresses, glass
fibers contaminated the outer surface of the wrap
and after adhering to PVC by electrostatic force,
because of the same vibrations, they came off. At
last, the rainproof blanket insulation covering the
roof loft was coated with a tarred glass-fiber cloth
and, in summertime, when the insiders opened the
Vasistas model skylights, glass fibers fell down from
their edges.
6. The presence of glass fibers in sampies of powder
from different areas of the factory (Fig. 3) and from
the loft cloth.
Fig. 1. Antonio T., 35 years old - airborne fiberglass dermatitis:
rash in small itching papules at the trunk and upper limbs in an The histological analysis carried out on three
office worker employed in the textile industry mentioned in the subjects revealed the compatibility of some of the
text
results with the diagnosed fiberglass dermatitis;
lymphohistoid infiltrate with some perivascular eosi-
3. Occurrence of similar symptoms in some of the nophiles, papillary edema with exudative-necrotic
members of the families whose subjects took their phlogosis with erosive tendency, teleangiectasies of
overalls horne for weekly washing. superficial capillary plexus es - spongiosys was evident
4. The failure both of the cortisone therapy - adopted in the epidermis.
either systematically or topically - and of the The adhesive tape stripping carried out on the
disinfestation suggested by other dermatologists lesions was either negative or gave results difficult to
after they diagnosed an acariasis, following the interpret. The allergological investigation carried out
report of questionable clinical importance of mites on subjects by patch testing was not thought to be
in some sampies of powder. convenient. It is worth mentioning that, as a matter of
5. The setting up, in May, of drilled boards in confusion in the etiological analysis, the factory was
phonosorbent aluminium (Fig. 2), containing mat- surrounded by pine trees, and that induced the idea
tresses 60-mm thick in glass wool treated with that some of the springtime episodes were due to the
thermohardener resins, wrapped up in polyvinyl- contact with the Processionary moth's chitinous hairs
chloride (PVC) in order to reduce the noise level in and that the environment was obviously polluted by
the weaving department. One or more wraps had fragments of yarns which were probably irritant. This
broken, maybe because of a manufacturing defect or fiberglass dermatitis epidemics by mechanical irritant
when they were inserted into the boards, and, as a contact was solved changing all the wraps in the
result, through their holes, induced by the vibra- boards; the residual glass fibers were removed from the
tions, glass wool fibers were discharged and released boards through blowing and washing; cloths were
Fig. 2. Textile department of the textile industry mentioned in Fig.3. Microphotography (X100): dust sampie coming from the
the text. Note the aluminum panels (containing glass wool in surface of a 100m of the same textile industry. Note the presence
polyvinylchloride envelope) for acoustic insulation hanging on of fiberglass spicules mixed with dust f1uff
ceiling
painted with a silver paint that, beyond refiecting the glass lamps (Grzegorczyk 1987). The X-ray controls
sunrays previously absorbed by the black paint cov- carried out 12 years later documented the presence of
ering the loft, in the hot season also produced an glass fibers that had penetrated into the hands reaching
increase in temperature and did not permit the the subcutis among the sinews and the interossei.
removal of fibers; the working environment - together
with the machines and the furniture - was repeatedly Histopathology
cleaned with a vacuum cleaner and thoroughly washed.
Familial fiberglass dermatitis micro-epidemics Histopathological lesions observed in fiberglass der-
(Table 2) requires a careful differential diagnosis with matitis are almost equal to those produced by the
scabies - above all if clothing were washed together contact eczema presenting spongiosis, sometimes dia-
with the curtains containing these kinds of fibers - stasis at the level of the basal layer, and lymphocytic
were also observed. On this subject, in 1962 Madoff perivascular and perifollicular infiltrate (Cuypers et al.
reported on two episodes characterized by itching and 1975b). These reports are consequent to a simple
erythema in three children within the same family, micro-trauma produced by the glass fiber tip on the
whose dermatitis was provoked by clothing which had skin (Heisel and Hunt 1968). In bioptic sampies, the
been washed in the washing machine previously used presence of glass fibers is not easy to ascertain; usually
to wash curtains. they are located in the corneum and under observation
Later, Abel (1966) described dermatitis affecting a with the polarized light microscope they appear to be
mother and her three children which was characterized birefringent (Björnberg 1985; Garcia-Patos and Pujol
by strong itching, excoriated papules and several 1994; Stam-Westerveid 1996). The persistence of
lesions produced by scraping and localized on the lesions, sometimes found out, and their possible
covered areas of the skin. Etiological diagnosis was evolution towards nodules, suggests the presence of a
made possible only when it was ascertained that she continuous stimulus due to the penetration, however
had unintentionally washed the curtains in the washing documented, of fibers into the skin. In this case, the
machine together with the clothing. In 1974, Lucas histopathologie al investigation puts in evidenee pat-
confirmed that fiberglass dermatitis could be due to a terns characteristic of the foreign-body granuloma
mechanical skin irritation produced by glass fibers (Siebert 1942; Cuypers et al. 1975b; Björnberg 1985).
from curtains or from other products containing them
if they are washed with the clothing causing their Diagnosis
contamination ("pseudoclothing dermatitis"). Accord-
ing to this author, epidemics could be caused even by The diagnosis of fiberglass dermatitis is fundamentally
washing the working cloths, contaminated by glass based on the clinical observation and accurate collec-
fibers, in public self-service laundries (Lucas 1974). On tion of anamnestic data. Though not pathognomonic,
the basis of these and other observations, the Depart- skin lesions, nevertheless, show the characteristic
ment of National Health and Welfare recommended distribution and evolution previously described, while
not to wash those products whose label states that they the subjective itching symptomatology has to be
have a glass-fiber content in the same washing machine considered with particular care. While collecting
together with clothing (National Institute of Occupa- anamnestic data, the possible onset of similar lesions
tional Safety and Health 1977). in other subjects of the working and/or the familial
The penetration of glass fragments into the skin of environment should be carefully investigated (epidem-
the hands of employees working in the department ics or micro-epidemics). The identification of the
wh ich produces fibers causes the so-called glass-hand's sources of exposure is relatively easy in those cases in
syndrome described by Grzegorczyk in 1982. This whieh onset took place in the working environment
syndrome is characterized by the absence of skin and can be confirmed by the inspection of the faetory
lesions and sometimes by the presence of a painful and by the knowledge of the technological cycle. The
sensation. Later, the same author provided evidence investigation is more difficult in the case of non-
using X-rays and, in some cases, computed axial professional exposure because it also involves the
tomography (CAT), the penetration of glass fibers into collection of detailed information concerning the
the skin of workers in a faetory producing fiuorescent subject's lifestyle, not excluding its possible changes.
Diagnosis can be then confirmed by the detection of
Table 2. Non-occupational hazards of fiberglass contact glass fibers on those portions of skin affected by
dermatitis that can, on its turn, be eonfirmed through
Horne environment: thermal and acoustic insulation systems,
upholstery, curtains, cloths for furniture in general, clothing, the "adhesive tape stripping" technique with a scotch
overalls tape which has to be applied repeatedly in order to be
School environment: desks directly observed under the optical microscope or by
Hobbies
maceration of the corneous sampies taken by scraping
with one or more drops of potassium hydroxide at rows - showing sometimes a centered blister, on the
20% (Deeken 1978; Cronin 1980). trunk, upper and lower limbs where insects have
As previously described, the histological investiga- bitten. These lesions appear about 12-72 h after the
tion of skin sampies from the affected areas does not bite or sting and are accompanied by a strong itching;
put in evidence any peculiar alteration; it is however they regress slowly and completely leaving a spot or a
possible, though not easy, to find spicules of glass pigmented nodule. The form occurring in adults is
fibers, above all if the observation is carried out under usually due to professional causes and hardly has an
a polarized light which makes them birefringent epidemie character; it appears in the spring-summer
(Garcia-Patos and Pujol 1994). Furthermore, when period, is mainly connected with the activities carried
the presence of glass fibers in tissues is suspected, an out in the agricultural and forest environment in which
X-ray should be carried out to confirm the results it can occur in epidemics; papules, even in the case of
obtained by means of the histological investigation. adults, prevail over any other possible lesions so that
dermatosis is less polymorphous.
Differential Diagnosis In the form typieal of scabies by Sarcoptes scabiei,
var. hominis, affected sites have a symmetrical dispo-
Due to its clinical characteristics, fiberglass dermatitis, sition and concern hands - particularly the interdigital
even if it is not an irritant contact dermatitis, can be spaces - wrists, elbows, ankles, feet, in man also penis
associated with the group of generalized acute prurigo and scrotum are involved, while in women areola
and itching by extern al causes. The greatest part of mammae, waist and umbilical area, buttocks, thighs
authors divides prurigo and itching into generalized and armpits; in adults, back and face are not involved.
and localized itching; by extern al, internal or unknown The fundamental lesion is identified with the burrow
causes; during skin diseases, by systemic causes or of dug (not always easily noticeable) by the fern ale mite in
psychological origin (Bernhard 1987; Lorette and the corneum and represented by a grayish straight line
Vaillant 1990; Greaves 1992; Braun-Falco et al. 1996). ending up, at one of the extremities, with ablister.
Fiberglass dermatitis is subject to differential diag- Erythematous papules (similar to those appearing in
nosis (Table 3) first of all if the itching symptom is the case of urticaria papulosa), both isolated and in
suspected to be expression of epizoonosis (Sertoli et al. group, can be observed. They present excoriations,
1992). Urticaria papulosa (strophulus, simplex acute sometimes with eczematization and impetiginization,
prurigo, acute prurigo, lichens urticatus by insect by scraping. Dark red nodules at elbows, armpits and
stings and bites - mosquitoes, midges, bugs, fieas, genitalia can occur mainly in man but regress spon-
etc.), typieal of children, is characterized by the taneously. Itching, whieh is the most characteristic
presence of itching papules - gathered together or in symptom, appears mostly at night. The hazard of
epidemics of scabies at a familial or collective level
requires an extensive and objective investigation and
Table 3. Most common simple itching (sine material or prurigo
in differential diagnosis with fiberglass dermatitis an accurate anamnesis in order to distinguish it from
fiberglass dermatitis. Finally, the main elements per-
By external cause mitting one to carry out a differential diagnosis are
Orticaria papulosa* represented by the sites involved by the symmetrie al
Acariasis*
Pediculosis* disposition of lesions, by the burrow - when present -
Swimmers' prurigo* by the possibility of observing the mite under the
Phytodermatitis by thorns* mieroscope in scrapings from skin lesions and also by
Prurigo by Thaumatopea pinivora hairs*
Prurigo by irritant solid airborne particles* the kind of itching. Furthermore, also the difference in
Actinic prurigo diffusion (contagion), the environment in which it
Eczema prurigo usually develops in epidemics (sanitary), the disap-
Improper or excessive use of detergents
Side effects of drugs pearance of lesions after specific therapy and the rarity
By internal cause of relapses should be taken into due consideration.
Pruritus senilis In the case of fiberglass dermatitis, relapses take
Psychosomatic pruritus
Delusions of parasitosis place if, after a quick improvement obtained without
Biliary stasis any specific therapy and a non-working period, the
Diabetes mellitus worker go es back to work and the hazard has not been
Uremia
Pregnancy eliminated. Also "Incognito" scabies, in which the
Dysthyroidisms typical lesions have been modified by the use of
Cancers various topic therapies, should be taken into ac count.
Hodgkin's disease or chronic leukemias
Myeloma More difficult is the differential diagnosis of profes-
sional acariasis by mites from animals: Sarcoptes
* Also in epidemics scabiei var. animalis (dogs, horses, cows, pigs, sheeps
etc.); Cheyletiella parasitovorax in rabbits (through the floating in the air (Sertoli 1991). Also, solid particles
cat); Dermanissus gallinae 0 D. avium. Other profes- in the environment (sawdust, small cardboard frag-
sional and environmental acariasis like those provoked ments, wood or metal filings, cement powder causing
by Pyemotes ventricosus e Tyroglyphus farinae in the so-called "cement scabies" etc.) can co me into
cereals and meals ("scabies from cereals") and Tyro- contact with the skin, irritating it and provoking
gliphus siro which develops in milk and its coagulated itchings. Hutchinson's prurigo (prurigo aestivale,
by-products ("itching from cheese") Sphoerogina hydroa aestivale), concerning mainly children, is
cerealella in barley ("brewers' prurigo"), differentiated from fiberglass dermatitis by its seasonal
Dermatophagoides pteronyssinus, Glycyphagus occurrence, by the predominant localization on the
domesticus etc. These acariases are characterized by exposed areas and by its acuteness. After initial
erythematous-papulovescicular lesions and can be exposure to the sun in summertime, papulous ele-
connected with professional activities, domestic ments, preceded and accompanied by a strong itching
life, hobbies etc. (Sertoli 1991). Trombiculosis by and an intense burning, appear on the exposed parts of
Neotrombicula autumnalis ("plane-tree lopper's sca- the body such as the face, arms and hands; sometimes
bies") more commonly known as autumnal erythema wheals can also be found in association with it and can
differentiates also by its seasonal incidence (May- follow, combine or alternate with the papulo-prurigi-
October). Among the various pediculoses, either the nous phenomena.
capitis form by Pediculus humanus var. capitis, or the Eczema-prurigo, which can be found in subjects
pubis form by Phtirius pubis must be excluded because sensitized to haptens, is characterized by the presence
of the localization of lesions, though, often, patients of diffused, often follicular, papules presenting a small
also complain of a diffuse pruritis. Differential diag- blister on top; isolated papules can also be found but in
nosis can be carried out with the rare pediculosis most cases they join in patches. Fiberglass dermatitis
corporis by Pediculus humanus var. corporis, but in differential diagnosis has to be carried out keeping in
this case, clear erythematous patches together with mind that excessive or improper igienical practices,
papules and sometimes wheals are present; petechias, such as the inefficient rinse of liquid soaps and the use
linear parallel excoriations by scraping (caused by an of bath and shower detergents, can also be responsible
intense pruritus), melanodermias in its most advanced for itching with erythematous lesions, above all in the
stages and, above all, anamnestic data together with case of atopical subjects with dry skin (Sertoli et al.
the findings of the insect or the nits contribute to its 1992). Pruritis and prurigo can also be drug side
differentiation from fiberglass dermatitis. effects.
The latter has also to be differentiated from the When faced with a possible fiberglass dermatitis, an
dermatitis by contact with plant thorns such as those accurate personal and familial anamnesis, together
of the barberry (Berberis vulgaris) or of the cactus with appropriate clinical and instrumental investiga-
(Opuntia Lingularis, Opuntia Tunia Mills or prickly tions, is necessary to eliminate systemic diseases
pear) families. Berberis dermatitis concerns farmers characterized by itching and papulous rashes (Bern-
and floriculturists with lesions similar to urticaria hard 1987; Greaves 1992). At the beginning - months
papulosa or with the presence of an isolated nodule before its onset - the Hodgkin's disease can manifest
almost always due to the permanence of the thorn - with nonspecific and polymorphous skin lesions,
responsible for a granulomatous reaction - into the characterized by itching and excoriated papules with
skin. The penetration of cactus prickles into the skin is impetiginization and secondary eczematization local-
followed by the onset of papules showing an intense ized mainly on the lower limbs. Itching is typically
erythematous-edematous halo and pustules evolving to exacerbated by spirits and is accompanied by abund-
nodules because of a possible induction of a cell- ant night sweating. We must keep in mind that a
mediated sensitivity. Sabra dermatitis by prickle pear, strong and generalized itching can also be the
described in Israeli farmers, differentiates by the nonspecific symptom of chronic leukemia (sometimes
greatest diffusion of dermatitis and by the intensity papules are also present) and myeloma and that
of pruritis. In the "swimmers' prurigo" and "bathers' nodular reactions with pseudolymphomatous hystolo-
rash" by grabs (where the papulo-pomphoid lesions gial patterns can be provoked by mites and insect
are mainly localized through the parts of the body stings (Braun-Falco et al. 1996).
covered by the swimsuit) a general symptomatology Fiberglass dermatitis, at its initial stage, can be set in
with shivers and temperature also manifests (Angelini differential diagnosis with the itchings by hepatic
and Vena 1991). cholestasis also induced by drugs (oppiaceous drugs
Urticaria papulosa-like patterns can also be caused and its derivatives, phenothiazines, oestrogens, pro-
not only by insect stings or bites, but also by contact gestagens, etc.), senile, psychosomatic and in dysthyr-
with the chitinous hairs of grubs, e.g., Processionary odisms. In the case of the third-month itching of
moth's grubs (Thaumatopea Pinivora), sometimes pregnancy, or polymorphous rash of pregnancy or
"pruritic urticarial papules and plaques of pregnancy" 3. Cutting of fiberglass-manufactured products should
(PUPP), differential diagnosis with fiberglass dermati- be carried out in the forms required for the
tis must be carried out only when in presence of a mounting before the application, so that the long
strong and acute itching. However, wheals and papules successive cutting and shaping operations which
typically localized at the level of the abdominal striae, represent the main cause of release of fibers and
periumbilical and connected areas to form patches of powders are not necessary.
various configurations represent the polymorphous 4. To cut and apply felts on the spot, suitable tools
lesions characteristic of this dermatosis and together should be used, for example, hand tools (special
with the gravidic condition make the diagnosis easier knives), instead of power-driven tools to avoid
(Lawley 1987). The psychosomatic, old age, expression release of fibers and powders.
of delusions of parasitosis itching without skin lesions 5. For insulation using the spray method, the wet
(as sometimes can be found in fiberglass dermatitis) technique should be used instead of the dry tech-
can also be, for a long period, the unique and only nique; wraps containing the fiberglass-manufactured
symptom of several systemic diseases such as diabetes products should be emptied without shaking them
mellitus, bile-duct obstruction with jaundice, chronic and should then be refolded with care to avoid fibers
renal failure particularly in hemodialyzed subjects, from being released. At the end of the work, the
dysthyroidisms and visceral tumors, adenocarcinomas spraying machine should be cleaned in the same
and squamous cell carcinoma affecting different place as the operations took place.
organs (Sertoli et al. 1992). 6. To clean the production and application depart-
ments (an operation that has to be carried out at
regular intervals), a vacuum cleaner should be used
Prevention (washing and successive drying should be avoided
since residual fibers could continue floating in the
Concentration of airborne fibers when setting up environment).
various products, generally for insulation, varies dra- 7. Both the containers used for transportation and the
matically relative to the application technique, the processing residues should be stored in suitable
finishing of products and the micro-climate in the places or in perfectly sealed plastic containers to
neighboring rooms in which these activities are carried avoid any kind of dispersion.
out. Generally speaking, the level of exposure these
Particular safety regulations should be observed
technicians must bear - that, in many cases, is the
while removing fiberglass insulations (Sertoli et al.
most frequent cause of dermatitis - is higher than that
1982). Removal of resined or starched materials is
which the workers in the fiberglass production depart-
easier and less risky but, nevertheless, the cutting
ment must cope with (Possick et al. 1970). While the
operations, which must never be carried out by a
levels of glass fibers in the working environments that
motor-driven device, should be reduced to a mini-
can penetrate the lungs (those fibers with such a
mum. Removal of non-resined materials is highly
diameter and length that cannot cause skin patholo-
risky; every single operation should be preceded by
gies) have been investigated for some time, in order to
suitable humidification of materials or by an adequate
prevent bronchopneumopathies, specific rules con-
ventilation of the rooms and localized aspiration when,
cerning the prevention of skin damage still do not exist
carried out dry, it involves the insulation of electric
(Koh and Khoo 1995).
systems. Special rooms for personal hygiene (showers,
To prevent the onset of fiberglass pathologies, a
bathrooms), secluded from those in which fibers are
good level of personal hygiene together with a high
processed, should be available.
accuracy in their production are fundamental (Sertoli
Protective clothing must always be worn during
et al. 1992; Chang et al. 1996; Stam-Westerveid 1996).
high-risk processing (such as the removal of non-
In particular, the following points have to be kept in
resined materials) and they should be changed and
mind:
washed frequently (even with two successive wash-
1. In the different stages of production, closed cycles, ings), but always in the working place and not at horne
or methods minimizing the release of fibers - and to avoid any kind of contamination. Tissues should
the consequent exposure to fibers and powders - give the guarantee of being warm enough and their
have to be adopted. weft closely woven. Barrier creams, base, emollient,
2. Storage, packaging and transportation of materials ointments and silicon sprays have not proved useful in
to the place at which they are prepared and applied preventing fiberglass dermatitis and, on the contrary,
should be carried out in particular sealed containers in some cases, they can exacerbate itching (Bensöe
and in such a way as to minimize the possible et al. 1987). Use of barrier creams can be useful in
release of fibers and powders. preventing contact dermatitis caused by the resins
used for the finishing of fibers, simply because it consequence, insufficient - considering the concentra-
reminds the worker to wash his hands before eating. In tion in time and, in many cases, the unpredictability of
this way, the rem oval of probable fibers on the skin is the causal event, fiberglass dermatitis can be seen as an
favored (Konzen 1987). industrial accident.
Therapy
Allergie Contact Dermatitis by Fiberglass
Fiberglass-dermatitis therapy is solely symptomatic so
Regarding the pathogenetic mechanism by allergic
that antihistamine drugs can be administered p.o. or
contact, we point out the following: 36 workers of 160,
corticosteroid low-power topical drugs can be applied,
that is to say, 54% of the total workers tested in a
together with antibiotics in the case of bacterial
fiberglass factory presented positive reactions, partic-
overlapping (Lachapelle et al. 1992). Removal of fibers
ularly, to the epoxy res ins used for the finishing of
from the corneum can be attempted using the adhesive
fibers (Cuypers et al. 1975a). In 1979, Dahlquist and co-
scotch tape or plumbers' duct tape (Deeken 1978).
workers reported on five fiberglass spinners sensitized
to epoxy resin containing low-molecular-weight olig-
Medicolegal Aspects omers. In 1980, Kalimo and co-workers described a
subject sensitized to p-tert-butyl-formaldheyde resin
According to the Italian legislation, industrial accident used for the finishing of glass fibers.
means dermatosis caused by unforeseeable and acci- In 1985, Conde-Salazar and co-workers announced
dental events, concentrated in time and connected to the case of a worker who had been working for 4 years
the working activity, and considered as being suffi- in a glass fiber factory and presented with eczematous
cient, if not prominent, causes. This definition is only lesions, first on the left forearm and then on hands,
partially suitable in the case of fiberglass dermatitis, trunk and lower limbs. He also presented with
meant as an ICD, and this is evident by the data sensitization to epoxy resin containing a 628-kD-
existing in literature and deriving from our experience. molecular-weight oligomer. In a group composed of
The above-mentioned data could lead to consider 130 workers, who were in contact with glass fibers
fiberglass dermatitis as a professional disease, that is to coated with epoxy resins, 6 were sensitized to epoxy
say, a disease due to foreseeable, and as such, causal resin, and 1 to the cresilglycidyl ether, a diluent used as
events, that are not concentrated in time, are connect- reagent; lesions covered mainly hands, forehands and,
ed with the professional activity and represent the to a lesser extent, face and neck (Holness and
main, though not unique, cause. In fact, the presence Nethercott 1989).
of glass fibers in the working environment is not In a PRCß factory, ßruze and Almgren (1989) found
always unforeseeable and then the accidental prereq- 6 workers of the 19 tested were sensitized to epoxy
uisite prescribed by the Law is not satisfied. For this res in. During the production of manufactured articles
reason, it is doubtful that the prejudicial event causing (made of copper sheets and rolled fiberglass soaked
the single lesions, although repeated in time because of with epoxy brominated resins), subjects were exposed
the lasting of pollution and exposure, is concentrated mainly to such nonpolymerized resins and to powders
in time. Dermatitis is then the result of all the micro- from fiberglass tissues soaked with resins.
traumas taken together, everyone of which takes place In a factory where skis were produced with fiber-
in the time defined necessary for the contact. However, glass-reinforced plastics, 6 workers of 22 presented
it is evident that the contact with glass fibers is not with sensitization to an epoxy-resin low-molecular-
only the sufficient cause, but it is also the main, if not weight oligomer, and three among them were sensi-
the unique cause, it is the prerequisite that has to be tized to diethyleneglycol diglycidyl ether, a new
specifically satisfied in the case of pathogenetic agents reactive diluent. Three subjects were sensitized to
responsible for a professional disease. The medico- other epoxy and polyamidic reactive diluents used to
legal definition as industrial accident or professional harden resins. In all the subjects, dermatitis was
disease, by which the kind of privileged or unprivi- localized on the back of the hands, but in some of
leged protection derives, is in this case, as in other them it also involved the face, trunk and lower limbs.
dermatoses, not univocal and the Law, as usual, lends Furthermore, another worker showed a positive reac-
itself to different jurisprudential interpretations. Ac- tion to the cobalt used as an accelerating agent of
cording to an accepted, though limited practice - being polyester resin binding in fiberglass-reinforced sheets,
the contention concerning this disease, which heals whose presence was demonstrated by atomic absorp-
rather quickly without any complication or permanent tion spectrophotometer (Jolanki et al. 1996).
References Fisher AA (1986) Fiberglass and rockwool dermatitis. In: Fisher

AA (ed) Contact Dermatitis. Lea & Febiger, Philadelphia,
pp 566-569 . ..
Abel RR (1966) Washing machine and fiberglass. Arch Dermatol Fisher BK, Warkentin JD (1969) FIber glass dermatitis. Arch
9):78 Dermatol 99:717-719
Adams RM (1990) Dermatitis due to fibrous glass. In: Adams RM Fleming MG, Bergfeld WF (1990) The etiology of irritant contact
(ed) Occupational skin disease. Saunders, Philadelphia, dermatitis. In: Iackson E, Goldner R (eds) Marcel Dekker,
pp 16-17 .. . New York, pp 41-66
Adams RM (1995) Occupational contact dermatitis. In: GUln JD Gareia-Patos V, Pujol RM (1994) Generalized pruritus with
(ed) Practical contact dermatitis. Me Graw-Hill, New York, flexural micropapules in a 16-month-old girl. Arch Dermatol
pp 585-5 87 .. .. 130:785-788
Angelini G, Vena GA (1991) Dermatologla acquatIca. In: Angehm Greaves MW (1992) Pruritus. In: Champion RH, Burton JL,
G, Vena GA (eds) Dermatologia acquatica. Gruppo Lepetit Ebling FJG (eds) RooklWilkinson/Ebling Textbook of der-
SpA, Milano, pp 64-65 matology. Blackwell, Oxford, pp 527-535
Bensöe N, Björnberg A, Lowhagen GB, et a1. (1987) GI~~s Grzegorczyk L (1982) lur Bedeutung physikalischer Faktoren
fibre irritation and protective creams. Contact Dermatltls fur die Entsthung von Berufsdermatosen. Dermatosen 30:
17:69-7 2 179-181
Bernhard JD (1987) Clinical aspects of pruritus. In: Fitzpatrick Grzegorczyk L (1987) "Glasshände" ein neues berufsbedingtes
TB, Eisen Al, Wolff K, et a1. (eds) Dermatology in general Syndrom. Dermatosen 35:62-64
medicine. Me Graw-Hill, New York, pp 78-90 Hatch KL, Maibach HI (1985) Textile dermatitis. Contact
Beyer AV, Vossmann D (1996) Glasfaser-induzierte chronische Dermatitis 12:1-11
Dermatitis. Dermatosen 44:225-227 Heisel EB, Hunt FE (1968) Further studies in cutaneous reactions
Björnberg A (1985) Glass fiber dermatitis. Am J Ind Med 8: to glass fibers. Arch Environ Health 17:705-711
395-400 . . Heisel EB, Mitchell JH (1957) Cutaneous reactions to fiberglass.
Björnberg A, Lowhagen GB, Tengberg JE (1979a) RelatlOnshlp Ind Med Surg 26:547-550
between intensities of skin test reactions to glass fibres and Holness DL, Nethercott JD (1989) Occupational contact derma-
chemical irritants. Contact Dermatitis 5:171-174 titis due to epoxy resin in a fiberglass binder. I Occup Med
Björnberg A, Lowhagen GB, Tengberp JE (1979b) Does occup~ 31:87-89
tional exposure to glass fiber mcrease the general skm International Labour Office (1983) Fibres, man-made glass and
reactivity to irritants? Contact Dermatitis 5:175-177 . mineral. In: Parmeggiani L (ed) Encyclopedia of occupational
Braun-Falco 0, Plewig G, Wolff HH (1996) Pruntus, health and safety. ILO, Geneva, pp 852-855
Prurigokrankheiten, Artefakte, neurologische Erkrankunge~. Jolanki R, Tarvainen K, Tatar T, et a1. (1996) Occupational
In: Braun-Falco 0, Plewig G, Wolff HH (eds) DermatologIe dermatoses from exposure to epoxy resin compounds in a ski
und Venereologie. Springer, Berlin Heidelberg New York, factory. Contact Dermatitis 34:390-396
pp 893-911 Kalimo K, Saarni K, Kytta J (1980) Immediate and delayed type
Bruze M, Almgren G (1989) Occupational dermatoses in workers reactions to formaldehyde resin in glass wool. Contact
exposed to epoxy-impregnated fiberglass fabric. Dermatosen Dermatitis 6:496
37:171-175 Koh D, Khoo NY (1994) Identification of a printed eircuit board
Camarasa JG, Moreno A (1984) Fiberglass dermatitis. Contact causing fibreglass irritation among electronics workers.
Dermatitis 10:43 Contact Dermatitis 30:46-47
Carrino L (1988) Plastiei rinforzati con fibre di vetro: tecnologie Koh D, Khoo NY (1995) Environmental glass fibre counts and
di produzione, settori di utilizzo e tendenze di sviluppo dei skin symptoms. Contact Dermatitis 32:185
processi e dei sistemi. In: Seminario Na~io?,ale "St~ategie 'p.er Koh D, Aw TC, Foulds IS (1992) Fiberglass dermatitis from
la difesa nel comparto delle vetroresme . RegglO Emlha, printed circuit boards. Am I Ind Med 21:193-198
Proceedings, pp 167-193 Konzen JL (1987) Fiberglass and the skin. In: Maibach HI (ed)
Chang CH, Wang CM, Ho CK, et a1. (1996) Fiberglass dermatitis: Occupational and industrial dermatology. Year Book Medical
a case report. Kaohsiung J Med Sei 12:491-494 Publishers, Chicago, pp 282-285
Conde-Salazar L, Guimaraens D, Romero VL, et al. (1985) Lachapelle JM (1986) Industrial airborne irritant or allergie
Occupational dermatitis from glass fiber. Contact Dermatitis contact dermatitis. Contact Dermatitis 14:137-145
13:195-196 Lachapelle JM, Frimat P, Tennestedt D, et al. (1992) Dermatoses
Cronin E (1980) Fibre glass. In: Cronin E (ed) Contact dermatitis. aeroportees. In: Lachapelle IM, Frimat P, Tennestedt D, et a1.
Churchill Livingstone, Edinburgh, pp 78-80 (eds) Dermatologie Professionelle et de l'environment. Mas-
Cuypers JMC, Bleumick E, Nater IP (1975a) Dermatologische son, Paris, pp 142-143
Aspekte der Glasfarefabrikation. Dermatosen 23:143-154 Lammintausta K, Maibach HI (1990) Contact dermatitis due to
Cuypers JMC, Hoedemaker 1, Nater ~p.' ~t a1. (~975b) The irritation. In: Adams RM (ed) Occupational skin disease.
histopathology of fiber-glass dermatitis m. r.elatlOn to von Saunders, Philadelphia, pp 1-12
Hebra's concept of eczema. Contact Dermatltls 1:88-95 Lawley TJ (1987) Skin changes and diseases in pregnancy. I~:
Dahlquist S, Fregert S, Trulsson L (1979) Allergie contact Fitzpatrick TB, Eisen Al, Wolff K et a1. (eds) Dermatology m
dermatitis from epoxy resin finished glass fiber. Contact general medicine. McGraw-Hill, New York, pp 2085-2086
Dermatitis 5:190 Lechner W, Hartmann AA (1977) Glasfaserinduzierte Fremdkor-
Deeken JH (1978) Tape treatment for fiberglass splinters. Arch pergranulome. Hautarzt 30:100-101
Dermatol 114-623 Lorette G, Vaillant L (1990) Pruritus. In: Saurat JH, Grosshans E,
Eby CS, Jetton RL (1972) School desk dermatitis. Arch Dermatol Lampier P, et a1. (eds) Dermatologie et Venereologie. Mas-
105:890-891 son, Paris, pp 809-825
Erwin JR (1947) Fiberglass plastics-Industrial medical aspects and Lucas JB (1974) Common industrial dermatoses. Cutis 13:33
experiences. Ind Med 16:439-441 Madoff MA (1962) Dermatitis assoeiated with fibrous glass
Eun HC, Lee HG, Paik NW (1991) Patch test responses to material. Tufts Folia Med 8:100-101
rockwool of different diameters evaluated by cutaneous blood Marks JG Jr, DeLeo VA (1992) Occupations commonlyassoeiated
flow measurement. Contact Dermatitis 24:270-273 with contact dermatitis. In: Marks JG Jr, DeLeo VA (eds)
Farkas I (1983) Fiberglass dermatitis in employers of project Contact and occupational dermatology. Mosby Year Book, St.
office in a new building. Contact Dermatitis 9:79 Louis, pp 276-278
Fisher AA (1982) Fiberglass vs mineral wool (rockwool) derma- Meneghini CL (1977) Fiberglass dermatitis. Contact Dermatitis
titis. Cutis 29:412, 415-416 3:218
134 A. Sertoli et al.: Fiberglass Dermatitis
National Institute of Occupational Safety and Health (1977) A Sertoli A, Giorgini S, Farli M (1992) Fiberglass dermatitis, Clin
recommended standard for occupational exposure to fibrous DermatoI1O:167-174
glass. V.S. Department of Health, Education and Welfare, Siebert WJ (1942) Fiberglass health hazards investigation. Ind
Public Health Service (ed), Cincinnati Med 11:6-7
Okano M, Kozuka T, Tanigaki, et al. (1987) Fiberglass dermatitis Stam-WesterveId EB (1996) Man-made vitreous fiber: glass fiber
in Japan: report of four cases. J DermatoI14:590-593 and rockwool dermatitis. In: van der Valk GM, Maibach HI
Patroni M (1989) Fibre di vetro in ambiente di vita. G Ital Ig Ind (eds) The irritant contact dermatitis syndrome. CRC Press,
15:59-70 Boca Raton, pp 121-126
Pellerat J (1947) La dermatose de la laine de verre. Ann Dermatol Stam-Westerveld EB, Coenraads PI, van der Valk PGM, et al.
Syphil 7:2 (1994) Rubbing test responses of the skin to man-made
Possick PA, Gellin GA, Key MM (1970) Fibrous glass dermatitis. mineral fibres of different diameters. Contact Dermatitis 31:
Am Ind Hyg Assoc 31:12-15 1-4
Rietschel RL, Fowler JF, Jr (1995) Textile and shoe dermatitis. In: Sulzberger MB, Baer RL (1942) The effects of fiber glass on animal
Rietschel Rl, Fowler JF jr (eds) Fisher's Contact Dermatitis. and human skin. Ind Med Surg 11:482-484
Williams & Wilkins, Baltimore, pp 366-367 Tarvainen K, Jolanki R, Forsman-Gronholm L, et al. (1993)
Ruegger M (1996) Are artificial mineral fibers harmful to health Exposure, skin protection and occupational skin disease in
and unsuitable for asbestos substitute. Schweiz Rundschau the glass-fibre-reinforced plastics industry. Contact Derma-
Med Prax 85:961-966 titis 29:119-127
Sacchi A (1989) Processi produttivi e corretto impiego delle fibre Tarvainen K, Estlander T, Jolanki R, et al. (1994) Occupational
di vetro. G Ital Ig Ind 15:43-48 dermatoses caused by man-made mineral fibers. Am J
Schwartz L, Botvinick I (1943) Skin hazards in the manufacture of Contact Dermat 5:22-29
glass wool and thread. Ind Med Surg 12:482-484 Tarvainen K, Kanerva L, Jolanki R, et al. (1995) Occupational
Sertoli A (1991) Dermatosi professionale da artropodi. In: Sertoli dermatoses from the manufacture of plastic composite
A (ed) Dermatologia allergologica professionale ed ambient- products. Am J Contact Dermat 6:95-104
ale. Il Pensiero Scientifico, Roma, pp 7-13 TIMA (1991) Man-made vitreous fibres: nomenclature, chemical
Sertoli A, Farli M (1991) Dermatite da fibre di vetro. In: Sertoli A and physical properties by the Nomenclature Commitee of
(ed) Dermatologia allergologica professionale ed ambientale. TIMA. TIMA, Stamford
Il Pensiero Scientifico, Roma, pp 40-41 Verbeck SJA, Bluise-Van Vnnik EMM, Malten KE (1981) Itching
Sertoli A, Spallanzani P, Cappelli V, et al. (1982) Patologia in office workers from glass fibres. Contact Dermatitis 7:354
dermatologica da fibre di vetro in una officina delle Ferrovie Wang BJ, Lee JY, Wang RC (1993) Fiberglass dermatitis: report of
dello Stato. Boll Coll Med Ital Transport 2:31-38 two cases. J Formos Med Assoc 92:755-758
CHAPTER 15
Occupational Skin Granulomas

P.D. Pigatto and A.S. Bigardi
Granuloma is a chronic proliferative inflammatory weIl known in epidemiology. Silica occupational gran-
re action surrounded and delimited by healthy tissue ulomas of the skin are described in mineworkers
(Rabinowitz 1996). The penetration into the skin of a (Mesquita-Guimaraes et al. 1987). Reports in the recent
number of insoluble, non-degradable and slowly literature of occupational skin granulomas are very
released substances may give rise to a foreign-body rare; however, one case of a granulomatous skin
granulomatous re action. These substances include re action was observed recently in a Seveso (ltaly)
wood, silk, nylon, paraffin, silicon, talcum powder, accident caused by intermediates of dioxin synthesis
starch, oils, animal and vegetable spines or bristles, resulting not from specific work but from occasional
vaccine (Jones 1996) and human hair. Histology contact with pollutants. In the case of beryllium and its
distinguishes two types of granuloma: the more salts (particularly oxide salts), occupational medicine
frequent foreign-body granuloma and a second so- recognizes a specific pathologic picture, which bears
called allergic granuloma. This type of reaction, i.e., witness to its pulmonary aggression - berylliosis.
contact allergic granulomatous reaction, has been At an industriallevel, beryllium (mainly in the form
described in subjects sensitized to zirconium, berylli- of beryllium fluoride) is used in the production of
um and some tattoo colorants. A foreign-body gran- fluorescent lamps, light copper, nickel, and iron alloys
uloma may "transform itself" into an allergic skin and, in small quantities, the production of steel. After
granuloma when the etiologic agent remains in the penetrating the skin, beryllium causes allergic rather
lesion for some time and, in the final analysis, behaves than foreign-body granulomas. Beryllium allergic
as an allergen. This possibility leads to a difference in granuloma may therefore occur not only in minework-
patient prognosis; renewed contact with the substance ers, but also in people working in the production of
present in the granulomatous lesion triggers the same metals, fluorescent lamps, and X-ray screens. Cases of
clinical manifestation. In both forms, microscopic simultaneous lung and skin beryllium granuloma have
examination reveals macrophages and giant cells with, also been described. Foreign-body occupational gran-
at the center of the lesion, lymphocytes, monocytes ulomas are also reported by beryllium from bulb
and occasionally epithelioid cells. The detection of lamps. Highly purified zirconium is used as a deoxi-
epithelioid and giant cells, as well as the presence or dant and catalyst in the construction and lining of
absence of a central necrotie zone with a caseous atomie reactors, although it is more frequently used in
appearance, are very important in making a differen- steel production. Zirconium-contact occupational skin
tial histopathologic diagnosis of allergic granuloma. granulomas, in workers who frequently handle steel or
The presence of phagocytic macrophages is considered alloys with a high steel content, have been reported as
to be a central event in the formation of foreign-body having a partieular clinical presentation: multiple,
granulomas; this macrophagie tendency is limited or rather than individuallesions with a lupoid appearance
totally absent in allergic granuloma. The main target (Palmer and Walton 1967).
organs of external aggressive granulomatous disease Cadmium is abivalent metal that is used as an
are the respiratory apparatus and the skin. anticorrosive and, in association with nickel, cop per
Occupational granuloma, both dermatological or and silver, in the production of conducting alloys. One
otherwise, is a well-known and well-defined noso- of its salts (cadmium sulfide) is used as a colorant for
graphie entity. In re cent years, occupational respira- paints and rubber; cadmium acetate is used in the
tory granulomatous disease has been studied and production of craftware. There are reports in the
monitored because it is the cause of numerous and literature of cadmium granulomas with a sarcoid-like
severe cases of occupational dis ability. An emblematic appearance. Occupational exposure to rare metals has
case is that of mineworkers, whose pulmonary picture been weIl reviewed recently (McFadden et al. 1989;
after inhalation of mineral dusts (pneumoconiosis) is Kusaka 1993). The histopathological diagnosis is

136 PD. Pigatto and A.5. Bigardi: Occupational Skin Granulomas
frequently difficult as confirmed by a reported case in symmetrical granulomatous skin lesions at the forearm
which it was not even possible to make a histological caused by the manner of taking the sheep when
distinction between sarcoidosis and foreign body coupling.
granuloma. The same type of difficulty has also been Another rare cause of occupational skin granuloma is
observed in barbers. Painless flat or raised nodules the starch found in surgical gloves (EHis 1997). Once it
appear on the hands and/or arms, and there is a penetrates the skin, the starch can give rise to a foreign-
moderate general symptomatology with locoregional body granuloma and develops when microinjuries of
lymphadenomegaly. The skin presents deep irregularly the skin are present. This condition represents a small
shaped rhagadiform fissures of variable length, partic- problem, but it is increasing more and more because of
ularly in the interdigital creases; as a result of the widespread use of latex gloves for sanitation
penetration by hair fragments during cutting, the purposes. The intradermal penetration of the oils used
direction of the fissures is always at an angle to the in high-pressure air-compressed lubrication can cause
cutaneous plane. The presence of hair fragments leads oleomas (or oleogranulomas), which appear as yeIlow-
to the onset of a granulomatous process which ish, rarely phlegmatic nodules (Macaulay 1986). A
becomes subsequently colliquative and suppurative continuous cutis solution in an environment containing
with fistulation. About 15 days need to pass from the high concentrations of carbon particles can lead to the
moment of inoculation to the development of granu- formation of brown indelible tattoos in exposed work-
loma. This form of dermatosis generally resolves itself ers, e.g., miners. Among the biotic agents reported
over 30-40 days without an aftermath. intentionally since the 1950S, important granulomas
From a clinical and etiopathogenetic point of view, include those caused by atypical mycobacteria, in
this form is very similar to that which occurs in people particular, Mycobacterium marin um. This micro-or-
working with animals, when the cutis is penetrated by ganism seems to find its ideal habitat in aquariums and
fragments of hair (particularly at the level of the manifests locally on the hands of people who, for work
interdigital creases), resulting similarly in the appear- or pleasure, come into contact with such. The increas-
ance of granulomas and fistulas. Interdigital pilonidal ingly frequent reports of occupational contact granu-
sinus or "barber's hair sinus", described historically lomas from biotic agents (particularly aquatic
(Currie et al. 1953) and recently (Zerboni et al. 1990), is microorganisms) should be kept in mind (Fischer 1988).
not the only form of occupational dermatitis associated
with these types of activities. Interdigital pilonidal
sinus is a foreign-body granuloma with a highly References
variable course. Given its asymptomatic nature, it
may be observed just by chance; however, it may Abdel-Aziz AH (1981) Pilonidal sinus caused by cutting trauma.
become supportive even at an early stage and, thus, Cutis 28:455-457
Beer WE, Wayte DM, Morgan GW (1992) Knobbly granuloma
lead to fistulation. It presents as a cutaneous inflam- annulare (GA) of tbe fingers of a milkman - a possible
matory nodule, localized generally to the second or relationship to his work. Clin Exp Dermatol 17:63-64
third interdigital space on the hand, with a black spot Currie AR, Gibson R, Goodall AL (1953) Interdigital sinuses of
barber's hands. Br J Surg 41:278-286
in the center (the points of penetration of the hair). Ellis H (1997) Hazards from surgical gloves. Ann R Coll Surg Engl
Among the hypotheses concerning the pathogenesis 79:161-163
of this condition, the most accredited is that which Fischer AA (1988) Swimming pool granulomas due to Mycobac-
terium marin um: an occupational hazard of lifeguards. Cutis
considers the interdigital space as a locus minoris 41:397-398
resistentiae, resulting from occupational contact with Jones DP (1996) Accidental self inoculation with oil based
detergents, constant steeping in water, and repeated veterinary vaccines. NZ Med J 109:363-365
Kusaka Y (1993) Occupational diseases caused by exposure to
traumas from cutting instruments. It is certain that the sensitizing metals. Jpn J Ind Healtb 35:75-87
central event is the penetration of the epidermis and Lambert D, Terrussot MC, Dalac S, Boulitrop-Morvan C (1995)
dermis by ahair, followed by a foreign-body granu- Granulome a
la laine de brebis. Ann Dermatol Venereol
122:534-535
lomatous reaction. Interdigital pilonidal sinus seems to Macaulay JC (1986) Occupational high-pressure injection injury.
affect only men's hairdressers, perhaps because of the Br J Dermatol 115:379-381
particular characteristics of men's hair or the type of McFadden N, Lyberg T, Hensten-Pettersen A (1989) Aluminum-
induced granulomas in a tattoo. J Am Acad Dermatol 20:
haircutting involved. A case of subunguial trichogran- 903-908
uloma has recently been described in a hairdresser for Mesquita-Guimaraes J, Azevedo F, Aguiar S (1987) Silica gran-
both men and women (Abdel-Aziz 1981). Work-related ulomas secondary to tbe explosion of a land mine. Cutis
40:41-43
and histological granulomas are the lesions described Palmer L, Walton W (1967) Lupus miliaris disseminata faciei:
on the hand of a milkman by Beer et al. (1992). Skin zirconium hypersensitivity as possible cause. Cutis 7:744-748
granulomas caused by sheep wool are reported and Rabinowitz LO, Zaim MT (1996) A clinicopathologic approach to
granulomatous dermatoses. J Am Acad Dermatol 35:15-33
weIl known. Lambert et al. (1995) observed recently an Zerboni R, Moroni P, Cannavo SP, et al. (1990) Sinus pilonidale
unusual case of a woman farmer who presented with interdigitale dei parrucchieri. Med Lav 81:138-141
CHAPTER 16
Occupational Marks
L. Kanerva
Occupational marks represent the effects of a partic- better protective dothing, and a shorter work week,
ular occupation on a worker's skin. They are usually occupational marks have become less frequent. They
calluses or corns that develop in locations subjected to have almost disappeared from many industries, but
repeated friction, press ure, or other trauma, and can probably still be found in less industrialized
indude discolorations, telangiectases, tattoos, odors, countries. A large number of occupationaI marks are
deformities, and other changes. In some occupations, listed in Table 1, based on Ronchese's valuable book
the marks may be quite variable, as with musicians (1948) and more recent artides by Samitz (1985),
(Harvell and Maibach 1992). Corresponding marks Harvell and Maibach (1992), Kanerva (1998, 1999) and
may be seen in athletes (Kanerva 1998). Such marks others (Chap. 157 by Hyry). Occupational marks must
were common previously among workers and served be distinguished from so-called pseudo-occupational
to identify many occupations. Today, with increasing marks, such as knuckle pads (Kanerva 1998), knuckle
automation, less frequent manual operation of tools, biting, nail biting, cutide pulling and trichotillomania.
Table 1. Occupational marks by mechanical trauma. The table is updated from the study by Ronchese (1948) and other more recent
data (Kanerva 1998, 1999)
Asbestos workers (carders, Penetration of fibers Corns, warts on palms

weavers, mattress makers)
Athletes (see also Chap. 169 by
Rogachefsky and Taylor)
Basketball Press ure and pounding Asymptomatic punctuate (but sometimes
0.5 cm or more in diameter), horizontally
arranged hemorrhages on heels ("black heel",
calcaneal petechiae); can simulate acrolentiginous
malignant melanoma; punctuate intracorneal
hemorrhages on palms ("black palm", teche
noire, talon noir, affecting the palm); trauma
to finger tips and finger pads from repeated
contact with pebbled surface of basketball
("basketball pebble fingers")
Friction Blisters
Boxing Punch Cauliflower ear
Repeated blunt trauma, friction "Knuckle pads" (on the knuckles)
and pressure
Breakdancing Friction Alopecia from repeated spinning on the head
Cyding Friction, thermal injury "Bicydist's nipple" secondary to thermal injury
rather than mechanical trauma; "saddle sores"; any
combination of chafing, skin ulceration, furundes,
folliculitis or ischial tuberosity pain in bicydists
Football Pressure and pounding; acne "Black heel" (see basketball); chronic inflammation
keloidalis nuchae of mechanical and bacterial origin
Contact with cement powder used to Cement burns
mark boundaries on football ground
Gymnastics Friction Hyperkeratosis, callosities on the hands and feet
Jazz ballet Natal deft abscess in young women in the absence of
a pilonidal etiology associated with local trauma
from jazz ballet exercises ("jazz ballet bottom")
Jogging and running Friction Erythema, separation of toenail ("jogger's toe",
subungual hematoma). May also result in nail
dystrophy and toe fracture; scaly, hyperkeratotic
patches on heel ("runner's bumps"); small
ecchymoses occurring on the superior portion of

138 L. Kanerva
Table 1. (Contd.)
the gluteal cleft in long-distance runners from

continual contact between the cheeks of the
buttocks during every stride in running ("runner's
rump"); painful, fissured (occasionally bleeding)
erosions of the nipples and areolae
("jogger's nipples")
Mechanical press ure Painful piezogenic papules, multiple small papular
projections from heel margins accentuated by
pressure of standing (herniations of fat into the
dermis at the sides of the heel)
Repeated blunt trauma, friction "Athletes' nodules" corresponding to boxers'
and press ure "knuckle pads", over the dorsal aspects of the feet
from repeatedly worn tightly laced sneakers
Frost Penile frostbite
Lacrosse Press ure and pounding "Black heel" (see basketball)
Marble player Repeated blunt trauma, friction "Knuckle pads"
and pressure
Ping-pong Ping-pong balls moving at high speeds Purpuric plaques ("ping-pong patches")
Roller-blading Friction Calluses on the lower legs
Rowing Friction; chronic and repeated A form of chronic lichen simplex caused by repeated
frictional trauma friction from the seat of a rowing machine
("rower's rump"); calluses on the hands
Running See jogging
Skiing Friction Shin abrasions, erosions and ulcers ("skier's shins"),
"skier's toe" corresponding to jogger's toe; "mogul
skier's palm", traumatic hypothenar ecchymosis
from repetitive pole planting while skiing
Soccer Pressure on toe nails Ingrowing nails. Tender, painful swollen paronychial
tissue, granulation tissue; lateral paronychia
Surfing Friction, repeated blunt trauma Subcutaneous, nontender masses on the anterior
tibial prominence of the leg, occasionally on the
middorsum of the foot ("surfer's nodules"); "surf
rider's dermatitis"; dermatitis on the front of the
body from riding in the prone position with
alternative surf board materials made of poly-
ethylene and polypropylene foam; combination
of mechanical, irritant, and allergie etiologies
but mechanical trauma is likely initiating event
Swimming Copper in swimming pool water Green hair
Tennis (and other racket Shearing; chronic and repeated Splinter hemorrhages of toenails ("tennis toe"),
sports) frictional trauma resembles acute gout; calluses on the hands
Press ure and pounding Painful erythema and swelling of the big toe ("turf
toe") associated with acute tendinitis of the flexor
and extensor tendons (athletes who play on artificial
"turf' surfaces, such as Astroturf); "black heels,"
(see basketball)
Weight lifting Mechanical pressure, stretching; chronic Striae distensae (consider also misuse of anabolie
and repeated frictional trauma steroids); striae may also develop as an effect of
endogenous corticosteroids in adolescents.
Lichenified plaques on the neck; calluses on
the hands
Bakers Pressure on kneading board Callosities on palmar and cubital surface of
little finger
Band jobbers Friction of twine dragged through rollers Excoriations and thickening on ulnar side
of the hands
Bank executives Rubbing Lichenification of the elbows
Barbers Sharp hair penetrates into the skin Inflamed interdigital papules ("barber's sinus")
Basket makers Hammering canes with clenched fist Thickening on ulnar side of the palms
Bending and intertwining hard cane Callosity and broadening on thumbs
Innumerable cuts from handling Cicatrices, rhagades on palmar surface of
materials fingers and the hands
Blacksmiths Heat and pressure Bullae on palms, fingers
Burnishers of metal Pressure of tools Multiple callosities on hands
Butchers Hot water and resin used in Hyperkeratosis on palms
depilation of hides
Carpenters, joiners Pressure of plane Thickening, hygromata on thumbs, index fingers
Carpet installers Pressure and friction Hyperkeratosis on the knuckles and dorsal
aspects of the hands and feet
Cement workers Bums from occlusion with alkaline Abraded skin, "cement knees"
cement
Occupational Marks 139
Table 1. (Contd.)
Cotton-mill workers
Winders Guiding yarn into dearer slot Thiekening on right index finger
Doffers Frietion from replacing bobbins Thiekening on web between the thumb
and the forefinger
Cutters of dothing Pressure of shears Callosities on thumb, fingers
Cutters of fustian Pressure of shears Papilloma on inner side of the thumb joint
Diamond setters Pressure Knuckle pads (on the third finger)
Electricians Friction and pressure Lichenification
Engravers Pressure of engraving tools Callosities on palmar surface of little finger
File cutters Pressure Hypertrophy on right little finger
Fishermen Handling of cables and ropes wet with Dermatitis on hands
salt water, especially if skin is abraded
Flax hacklers Pulling flax off pins Callosities on right index finger
Flax spinners Blows from the flyer Callosities on hypothenar eminence of the left hand
Foundry workers Bumping or rubbing Abrasions
Garment cutters Rubbing of the scissors Callosities on the thumb and middle finger
Glove makers Press ure on knife and scissors Callosities, deformities on hands and fingers
Grinders of lenses Frietion from abrasives Thickening on middle finger
Hairdressers Friction from teasing hair; sharp hair Inflamed interdigital papules (corresponds to
penetrates into skin barber's sinus)
Harp players Friction from strings Thiekening on finger tips
Hatters
Felt hat sizers Friction and immersion in hot and Keratosis, rhagades on palmar surface from
cold water wrist to finger tips
Plankers Rolling cylinder with hands Callosities on thenar eminen ces, fingers
Straw-hat makers Picking and plaiting straw Callosities on palms and fingers
Hod carriers Weight bearing Thickening on shoulders
Janitors Friction and press ure Lichenification
Lathe workers Press ure and friction Bullae, callus on palms
Leather buffers Press ure and friction Callosities on thumb
Leather cutters Friction from tools Callosities on right index finger
Lea ther gIazers Friction from tools Callosities on knuckles
Miners Friction from tools Callosities on hands
Coal miners Impregnation of skin with coal dust BIue-black tattooing on upper half of the body
Molders Droppings of molten metal Scars from bums on dorsum of feet
Musicians (see also Chap 157)
Brass instruments (trumpet, Press ure, friction Upper (mid) lip callus; perioral/lip dermatitis due to
trombone, French horn, mouthpiece irritation or allergy; hand dermatitis
baritone horn, tuba) from polishing compounds
Cello Press ure, friction Left-finger callus; cellist's ehest; cellist's knee; cellist's
seroturn
Clarinet Pressure, frietion Lower-lip callus; darinetist's cheilitis
Flute Pressure, frietion Flautist's chin
Guitar Pressure, friction Guitar nipple; mastitis
Harp Press ure, friction Harpist' s fingers; onycholysis; subungual
hemorrhages; paronychia
Oboe Press ure, friction Upper lip callus
Piano Press ure, friction Vasospastie white finger disease; paronychia;
loss of nails
Recorder Press ure, friction Perioral lip dermatitis due to irritation or allergy
to exotic woods
Saxophone Pressure Lower lip callus; cheilitis
Viola Pressure, frietion Left-finger callus; fiddler's neck; exacerbation of
pseudofolliculitis of the beard
Violin Press ure, friction Left-finger callus; fiddler' s neck; exacerbation of
pseudofolliculitis of the beard; Garrod's pads
Wind players (darinet, Pressure, frietion Cheilitis; perioral dermatitis
oboe, etc)
Paperhangers Frietion and pressure Liehenification
Plumbers Friction and pressure Lichenification
Porters
Alabaster blocks Weight bearing, friction Lichenification
Boxes, cases Weight bearing, friction Callosities on shoulders
Timber Carrying logs Bullae on hands
Potters Friction of revolving lathe Horny thickening, atrophy of skin on left hand
Printers, compositors Press ure of type Callosities on finger tips
Shoemakers Press ure of tools Callosities on folds of fingers, thigh above patella
Cobblers Cutting leather Scars from cuts on right thigl1
Stakers, glazers Pressure Knuckle pads on the dorsum of the hands
Stenographers Pressure of pencil Callosities on the middle finger
140 L. Kanerva: Occupational Marks
Table 1. (Contd.)
Stone workers Press ure of tools, impregnation Bullae and tattooing, pigmentation on palms and
with particles dorsa of hands
Sugar workers Manipulating machine cutting cubes Callosities between fingers
Tile, floor and linoleum layers Friction and pressure Lichenification on knees
Typists Pressure Callosities on the thumbs
Washer women Friction against edge of washtub Callosities on inner surface of forearms
References Ronchese F (1948) Occupational marks and other physical signs:

a guide to personal identification. Grune & Stratton, New
York, pp 1-181
Harvell J, Maibach HI (1992) Skin disease among musicians. Med Samitz MH (1985) Repeated mechanical trauma to the skin:
Problems Performing Artists 7:114-120 occupational aspects. Am J Ind Med 8:265-271
Kanerva L (1998) Knuckte pads from boxing. Eur J Dermatol
8:359-361
Kanerva L (1999) Physical causes of occupational skin disease. In:
Adams RM (ed) Occupational skin disease, 3rd edn. Saun-
ders, Philadelphia 35-68
CHAPTER 17
Occupational Dermatitis Artefacta

G. Angelini
Introduction Definition
The term "dermatitis artefacta" was coined in 1908 by Dermatitis artefacta is a self-infiicted complaint pro-
the writer Paul Bourget, who had been asked by a voked by the patient for various purposes and by
dermatologist to define the peculiar behaviour of one various means. Artefact diseases can in fact be
ofhis patients. This patient, aged between 30 years and provoked in almost all organs by means of exogenous
40 years, had self-infiicted gangrene of a limb using or endogenous mechanisms. In reality, the latter
potassium hydroxide and had managed to deceive solution is rarely adopted because it can be seriously
various doctors as to the nature of his complaint dangerous and is difficult to control over time,
(Dieulafoy 1908). providing inconstant and ungovernable dinical evi-
The classification of self-infiicted dermatoses is still den ce. The exogenous mechanism is much more
very vague. They come under the heading of simulated frequently resorted to, with the skin as the target
or artefactual diseases (Table 1), the best-known organ. Such simulators can choose the site to be
example of which is Munchausen's syndrome (Asher affected carefully and avoid damaging the whole
1951; O'Shea 1984; Janofski 1994). In their turn, self- organism; the self-infiiction can be suspended at the
infiicted skin conditions can be subdivided into desired moment and, above all, the disease is
various clinical forms (Table 2). Dermatitis artefacta "obvious" to all. The latter characteristic paradoxi-
is one of the most important of these pictures (Lyell cally justifies the very existence of these artefact
1979; Fabisch 1981; Van Moffaert et al. 1985; Consoli dermatoses.
1995). Disease can be simulated with illegal intent: to gain
advantage from situations of a professional nature (to
obtain prolongation of a disease or its recognition as a
Table 1. Simulated diseases
Munchausen's syndrome professional affliction, to attain a higher dass of
Self-inflicted dermatoses disability pension) or to escape various duties, e.g.
Self-mutilations military, especially in the case of compulsory military
Vulvodynia
Glossodynia service, or a prison sentence. In all these cases, the
Factitious pyrexia simulators are fully conscious of what they are doing
and why (Meneghini and Rantuccio 1962; Lyell 1979;
Meneghini and Angelini 1979; Petruzzellis et al. 1988);
Table 2. Self-inflicted derma- there are no psychic disturbances underlying these
toses Dermatitis artefacta
Pathomimic artefacts particular forms of behaviour.
Heteropathomimic artefacts In contrast, in other subjects, the simulated disease
True simulation is due to psychiatric problems such as psychoses,
True heterosimulation (Uwitch-
craft syndrome") mental retardation and personality dis orders. In these
Behavioural disorders cases, the intrinsic reason for the lesions is different, as
Neurotic excoriations the subject gene rally hopes to attract the attention of
Acne excorit!e
Trichotillomania the people he is surrounded by and of the doctor, or
Onychotillomania else he is reacting to difficult or unfavourable envi-
Factitious cheilitis ronmental conditions with involuntary somatisation at
Callosities of the hands
Dermatological pathomimicry the skin level. These unconscious simulators are
Painful bruising syndrome prevalently female.
Psychogenic purpura Artefact skin diseases for illicit purposes, aiming to
Religious stigmata
gain some advantage, are true simulations. Lesions

142 G. Angelini
provoked by subjects with psychological disturbanees, Lesions

i.e. irresponsibly and without a venal interest, are
described as pathomimic (a term which really refers to Virtually all elementary lesions can be observed,
faithful imitations of known diseases and, in derma- perhaps excluding nodules, gummata, atrophy and
tological terms, only to simulations with a psycholog- sclerosis. Erythematous lesions are usually livid or
ical basis). In this chapter, only true simulations for cyanotic with clear-cut margins; purpuric lesions,
professional purposes will be examined. usually due to suction or stricture from bandaging,
and excoriations are also frequently observed. Vesic-
ular lesions are rare, whereas irregular bullous lesions
are quite common, caused using vegetable extracts or
Diagnostic Criteria chemie al substances (Fig. 1); these lesions are some-
times rounded, having been induced by suction
The diagnosis of dermatitis artefacta does not usually (Dufton and Griffiths 1981). Pustules are often second-
present particular difficulties, despite the fact that the ary to infection of previously inflicted lesions, or due
dermatologist cannot rely on precise anamnestic data to contact with contaminated objects, or methodical
or the patient's collaboration. The diagnostic criteria scratching with infected nails. Ecchymoses with sharp
are described below. margins are often observed, procured by repeated
trauma from pinching or beating with various objects
Site
(wooden sticks, sand bags).
Subcutaneous introduction of various substances
The lesions are usually localised in areas exposed to (paraffin, milk) gives rise to infiltrating lesions, which
the possible action of occupational risks and of easy can later take on a wooden consistency (paraffinomas)
access, such as the left arm (or the right if the and may evolve into ulcers. Pigmented lesions with
simulator is left handed), the lower limbs, the anterior linear borders can be an outcome of previous erythe-
region of the ehest, the abdomen and, rarely, the face mato-exudative manifestations. Ulcerous or ulcero-
(but almost exclusively in cases of pathomimic, escharotic lesions are very commonly observed
psychologically-induced simulations) and the neck. (Fig. 2), whereas gangrenous lesions of the legs, with
The back is usually left alone, unless the simulator irregular contours, are less frequent. In the latter case,
can persuade a friend to collaborate (obviously, the normal surrounding tissue and integrity of the
provoking the same type of lesions as in the other annexes can help to exclude a vascular origin of the
sites), so as to prove the spontaneous nature of the affiiction.
clinical form.
Morphology
Unlike spontaneous lesions, those of dermatitis arte-

facta do not usually present a rounded or oval
appearance, conforming with the skin irritation cones.
They are generally irregular, occasionally even having
abizarre, decorative appearance, with clearly defined
margins, broken lines and acute angles. They are
sometimes noticeably linear, or monomorphous, with
little involvement of the surrounding skin. Often,
particularly in cases of ulcerous or ulcero-escharotic
lesions, there is a distinct pattern visible, which
reproduces the shape and size of the object used to
inflict the lesions. Ulcerative lesions can have well-
defined margins, a base infiltration of greater or lesser
extent, and are often surrounded by erythematous,
oedematous skin, a clear sign of inflammation due to
physical or chemical aggression. In oedema from
interrupted blood flow, signs of arrest at the ligature
point are often evident together with an identical, hard
consistency along the whole length of the region Fig. 1. Bullous and escharotic lesions from chromic mixture.
involved. Similar lesions were present at other sites
Occupational Dermatitis Artefacta 143
constituted by pictures associated with severe trophic

damage to the dermal-hypodermal tissues (ulcers,
gangrene, paraffinomas), which have a slower dinical
course. Unexpectedly slow improvement or healing of
alesion is a guiding element for diagnosis. For rapid
healing, it is essential that the topical medication be
applied under ocdusive bandaging and constant med-
ical and paramedical supervision. Refractory response
to treatment is typical when the medicated zone is
easily accessible or careful supervision is lacking.
Etiological Agents
The etiological agents may be physical, chemical or

biotic in nature (Table 3), although those in the first
two categories are more commonly used. Amongst
Fig. 2. Ulcerative lesion from chromic mixture at unusual site physical-type agents, fingernails should also be taken
into account. Chemical substances most commonly
Complementary Investigations belong to the dass of strong acids and alkalis. Strong
acids have a corroding action, while weak acids have
In all cases of primitive occupational dermatitis arte- an astringent effect. Rydrochloric acid provokes deep
facta, rather than secondary forms due to worsening of burns and blisters may form; sulphuric acid carbonises
the existing condition, the various laboratory tests give the skin, forming ulcers which are slow to heal; nitric
normal results, apart from inftammatory-type findings acid has a marked oxidising effect and induces deep
in acute pictures [raised erythrocyte sedimentation rate burns of an intense, yellowish colour. The other strong
(ESR), leukocytosis], and the latter values rapidly acids generally provoke ulcerating lesions with soft
normalise. Instrumental tests will also be negative in margins. Strong alkaline substances destroy wide areas
cases of artefactual arterial or venous afftictions. of skin, solubilising the tissues and causing hard
Apart from the dinical characteristics suggesting a eschars to form.
simulated dermatitis, the following tests at the level of The many different, complex mechanisms of action
the lesions may provide confirrnation. Extraneous of the numerous biotic agents can essentially be
material on the surface of suspicious lesions can be summarised under the heading 'pharmacological',
elicited by means of surface biopsy, performed by due to the freeing of proteolytic biochemical mediators
stripping with a polyethylene polyester pIaster with a and enzymes. In reality, discovering the etiological
drop of cyanoacrylate glue placed in the centre. The agent is often very difficult, owing to the obstinate
pIaster is held against the skin surface for 30-60 sand
T.a~le 3. Most common etiological agents of occupational derma-
then detached. The layer of corneum cells obtained can titis artefacta
be used for histological examination or cultures. In
cases of ulcerous lesions, brushing the base of the ulcer Physical agents Metal objects, paper knives, scissors,
can lead to an approximate identification of the foreign tweezers, pincers, forks, various
tools, fingernails, small sand-bags,
material. Determination of the pR may be helpful to haemostatic ligatures, pumice
demonstrate the use of acid or alkaline substances stone, incandescent needles, lighted
applied shortly before and not rinsed away. cigarettes
Chemical agents
In all cases, histopathological examination is dearly Acids Hydrochloric, acetic, formic,
necessary to make a definite differential diagnosis with trichloroacetic, chromic acids
respect to spontaneous dinical forms presenting the Alkalis Sodium and potassium salts, caustic
potash, chlorinated lime and
same appearance. In the case of ulcerative lesions, for calcium oxide
instance, histological examination does not show any Solvents Trementina oil, boiling oils and
specific signs, particularly at the level of the vessels and liquids, propane gas, liquid
paraffin, petrol, salt
nerves. Biological agents
Plants Nettle, cactus, agave, ferula, primula,
Clinical Course fig latex
Animals Jellyfish, sea-anemones, caterpillars,
The most common artefact lesions have a sudden acute sardin es, biological secretions
(urine, feces)
onset and rapidly resolve; exceptions to this rule are
144 G. Angelini
reticence of most simulators. In these cases, some In addition to the above-two dassical types of
general assumptions can be made: blisters are more occupational dermatitis artefacta, provoked on healthy
commonly induced by vegetable substances, ecchymo- or on damaged skin, there is another aspect to the
ses by mechanical agents and uIcers by chemical problem. This is constituted by attempts to produce
substances. Sometimes, however, it is impossible to positive results to skin tests which would otherwise
discover the exact agent unless the simulator confesses; give negative results. As these methods of diagnostic
it is hard to imagine the use of such substances as investigation have grown more common, simulators'
sardines, propane gas from a cigarette lighter and so concern has shifted from the dinical disease picture
on, which emerged in some of our cases. towards the results of such tests, knowing that
recognition of his condition as a professional com-
plaint largely depends on the latter. The phenomenon
Occupational Dermatitis Artefacta was already reported by Meneghini and Rantuccio
(1962) in two of eight cases of occupational dermatitis
The spread of state insurance has certainly increased artefacta and has since been observed by ourselves and
the number of simulations but, although many com- other authors (Meigel and Koops 1978; Lyell 1986).
mon cases of self-aggravated dermatoses have been Three cases of artefact dermatitis caused by manhan-
reported, only rarely do forms intended to reproduce a dling the patch tests have recently been described
picture of professional-type dermatitis seem to have (Maurice et al. 1987). Clearly, in suspicious cases, the
been documented. The first group indudes cases of patch tests must be applied without allowing the
voluntary aggravation of traumatic lesions secondary patient to identify the site of the individual substances
to accidents at the work site: wounds which fail to heal, and the results must be interpreted with some caution.
suppurate or eczematise; and burns which heal but
then ulcerate again and have a recurrent dinical
course. Despite ocdusive bandaging, which should Other Occupational Artefact Dermatoses
resolve such cases very rapidly, the risk of particularly
cunning simulators injecting harmful substances under Secretan's syndrome is characterised by a hard,
the bandage should be borne in mind. sometimes cyanotic, oedema (Charcot's blue oedema)
From a pathogenetic viewpoint, occupational der- on the back of one or both hands and forearms. This
matitis artefacta of the second type can be subdivided can be obtained by applying a haemostatic ligature or
into two subgroups: (1) dermatitis provoked directly bandage tightly around the forearm or by repeated
on healthy skin and (2) aggravation of a pre-existing self-inflicted trauma using hard objects (Angelini et al.
contact dermatitis the onset of which occurred 1982). This picture, first described in 1901 by Henri
spontaneously due to irritants or sensitisers. Diagno- Secretan, a Swiss doctor, and experimentally repro-
sis of the latter forms can be fairly simple when the duced in monkeys by means of repeated injuries, has
simulator intends to reproduce a picture of eczema on been observed in professional environments in simu-
healthy non-sensitised skin. In fact, it is difficult to lators with an eye to their pension. The oedema is
provoke erythemato-vesicular spongiotic lesions in likely to be of lymphatic nature and may be associated
different phases of evolution, so that self-inflicted with pain and limited flexion of the metacarpal-
lesions tend to manifest as groups of gross blisters. phalangic joints. Oedema from a haemostatic ligature
The epicutaneous test may be useful in such cases, can sometimes present with clearcut margins and a
especially if the substances of the working cyde fairly regular, horizontal, erythematous ring.
assumed to be responsible are notoriously highly Secretan's syndrome must be differentiated from
sensitising. professional traumatic complaints featuring hard,
These criteria do not apply if the patient aggravates persistent and spontaneous lymph oedema, which
a pre-existing spontaneous eczematous dermatitis. It have been described in fis hermen, due to various
should be remembered that the simulator may be causes and particularly to repeated trauma from sea-
perfectly weIl aware of what substance provokes his urchin spines and the tight cuffs of the wet-suit
dermatitis and may make use of it during convalescent (Angelini et al. 1990; Angelini and Vena 1991). In these
periods. In this event, only hospitalisation and con- spontaneous, chronic professional cases, lympho-
tinual supervision of the patient can sometimes graphy may showalterations of the lymph vessels.
provide a precise diagnosis. Although such an act Secretan's syndrome must also be differentiated from
would certainly be rare, it should be rem em bered that other types of acute or chronic oedema, such as
aggravation of a pre-existing spontaneous eczematous lymphatic aplasia, recurrent erysipelas, deep thrombo-
dermatitis could be voluntarily obtained by ingesting phlebitis, angio-oedema, filariasis, venous obstruction,
the product which originally caused the allergic skin post-surgical disturbances, carcinoma and other tu-
reaction. mours of the breast.
Oeeupational Dermatitis Artefaeta 145
A simulated oedema can, of course, involve either or exeluded Weber-Christian's disease and pancreatic
both lower limbs. Investigation of arte rial, venous and involvement. Winkelmann and Barker (1985) underline
lymphatic cireulation, urogenital and intestinal func- the diagnostic value of haemosiderin in nodular
tion and such other tests as may fit the ease should lesions in eases of dermatitis arte facta.
help to provide a diagnosis. A simulated dermatitis Bullous lesions from suction or chemical agents
mayaiso assurne an epidemie character in a profes- should be differentiated from pemphigoid. Porphyra
sional environment. Among factory workers, in fact, cutanea tarda lesions on the hands and arms may look
epidemics of simulated dermatoses can be observed, like artefacta, as may bizarre forms of skin necrosis
aiming to reinforce protest actions. These epidemics occasionally observed in polyarteritis nodosa. Some-
must be differentiated from group psychoses (mass times, even a fixed drug eruption can cause confusion.
psychogenous disease, or closed-building syndrome), Epidemie simulation in a working environment
which are not rare observations in the industrial field must be differentiated not only from group psychoses
(Adams 1989; Angelini et al. 1992). but also from the so-called "sick-building syndrome"
(US Environmental Protection Agency 1988), a term
describing situations which can arise in particular
Diagnosis, Differential Diagnosis factories whose workers complain of aseries of
and Complications subjective symptoms due to causes that may at first
go unrecognised.
Among the various assessment criteria, elinico-mor- Dermatologieal pathomimicry was described by
phological examination is undoubtedly the most im- Millard in 1984 in 13 patients who had caused
portant. The types of lesions and especially their recurrences or exacerbations of their existing skin
arrangement and configuration are all elements of disease. These patients had aggravated their condition
considerable diagnostic value. Nevertheless, this crite- by deliberate exposure to the noxae which they knew
rion must not be overemphasised because spontaneous had triggered the complaint. In fact, most of these
dermatitis can sometimes ass urne equally bizarre patients described by Millard were young women, who
shapes. A diagnosis of simulated dermatitis should were trying to gain greater sympathy from their
only be made after all the other possible extraneous families. The author considers pathomimicry to differ
causes have been diligently and impartially excluded from dermatitis artefacta, characterised rather by
on the basis of anamnestic and elinical data. The lesions differing from those of true organic skin
possible unfavourable effects of previous treatments disease. This is only partly true, since the above-
before the patient came under observation must also described behaviour can also be observed in conscious
be borne in mind. In short, a diagnosis of dermatitis simulators with a financial objective.
artefacta should not be the result of a process of Among the complications of dermatitis arte facta we
elimination but should be regarded as a possible must inelude the risk of sepsis, the possible but rare
diagnosis among others. Even when the diagnosis of thickening of a bone cortex after persistent constric-
simulation is almost certain it is always best to request tion of a limb with ties or bandages, and the equally
a neuropsychiatrie consultation to exelude concomi- rare observation of subcutaneous fibrosis after chronic
tant or prevalent psychiatrie disturbanees. lymph oedema. Naturally, deep destructive lesions
Owing to its variable aspects, differential diagnosis leave ugly scars, keloids and retractions.
of dermatitis artefacta is made in the presence of
different dermatological eonditions. In the case of
fairly superficial ulcerative lesions, extending centrif- Personal Data
ugally, pyoderma gangrenosum must be exeluded. The
histologie al results and an examination of the intesti- Over the last 30 years, we have observed 46 cases of
nal tract, together with an ocelusive dressing test under professional dermatitis artefacta. These cases are
elose medical supervision, should help to elarify the certainly true simulations beeause the suspicion,
diagnosis. suggested by the combination of work "problems",
Ulcerative lesions of the legs in a young subject, in the particular morphology of the lesions and the
the absence of vascular conditions, call for investiga- repeated negative findings of all the relative tests, was
tions aiming to exelude so me rare conditions, such as confirmed by confessions obtained from all the
haematological diseases, thrombocytaemia, lympho- patients after repeated, confidential and informal
proliferative syndromes, collagenases, Wegener's dis- discussions.
ease and cryoglobulinaemia, before thinking of Frequency of presentation was one or two cases per
dermatitis artefacta. year, with an incidence of 0.2-0.4 per thousand
Artificial panniculitis, whose incidence is probably including in- and outpatients. In recent years, how-
underestimated, should be considered after having ever, we have observed only two new cases. This
146 G. Angelini
marked drop in incidence is likely to be due to the This is supported by the fact that the simulator often
present socio-political situation in Italy, much more tries to reproduce a c1inical picture of professional
strict than in the past. contact dermatitis on healthy skin without considering
The causal agents used, reported in the table, the difficulties inherent in the lack of pre-existing
indude metal objects, incandescent ne edles, lighted sensitisation to the relevant chemical agents. Diagnosis
cigarettes, chromie mixtures, small sand-bags, acetic is more difficult if the self-inflictor aims to aggravate
acid, paraffin, caustic potash, propane gas, sardin es and prolong a pre-existing eczematous dermatitis,
and plants. üf the 46 subjects, 30 were masons, 9 when continual hospital supervision may be necessary
mechanics, 2 ho usern aids and 5 farm workers. In 38 to solve the problem.
cases, the reason for the simulation was to obtain legal
recognition of professional disease, in 2 to gain a Certainty Criteria
higher dass of dis ability pension and, in 6, to prolong
the disease (Angelini and Bonamonte 1998). The certainty criteria are constituted by the identifi-
Criteria for differential diagnosis between occupa-
cation of residues of the causal agent (chemical or
tional dermatitis artefacta and pathomimic artefacta, biological) on the damaged site or by a partial or
(apart, of course, from the psychiatrie problems complete confession.
underlying the latter), are reported in Table 4. These
criteria are based on our experience of many cases of
unconscious simulators, in addition to the above 46
cases of deliberate simulation. Measures
In cases of true simulated dermatitis, the dermatologist

Conclusions must unmask the situation and explain his/her con-
c1usions in c1ear terms to the individual involved, once
To condude, the diagnostic criteria for professional sufficient evidence has been achieved to prove that
dermatitis artefacta can be summarised as follows. diagnosis. The professional and legal consequences are
usually fairly serious and the dermatologist may be of
Presumptive Criteria considerable help to the legal doctor. It must be
remembered that, although there is no specific law
The presumptive criteria raise a suspicion of fraud and regulating this act, conscious simulation comes under
are based particularly on detailed history of the the general heading of fraudulent acts.
development of the lesions and of working conditions
(loss of job, reduced hours and hence salary, disagree-
ments with the employer).
References
Probability Criteria
Adams RM (1989) Advances and controversies in occupational
dermatology. Immunology and allergy dinics of North
The prob ability criteria serve to confirm the suspicion America. Urticaria and exogenous dermatoses. Saunders,
and are based on dinico-morphological findings, Philadelphia
observation of the lesions over time and the results Angelini G, Meneghini CL, Vena GA (1982) Secretan's syndrome:
an artefact oedema of the hand. Contact Dermatitis 8:345-346
of occ1usive bandaging. In many cases, the morphology Angelini G, Vena GA, Meneghini CL (1990) Occupational
of the lesions alone is enough to justify the diagnosis. traumatic lymphedema of the hands. Dermatol Clin 8:
205-208
Angelini G, Vena GA (1991) Dermatologia acquatica. Lepetit,
Milano
Table 4. Differential diagnosis between occupational dermatitis Angelini G, Grandolfo M, Vena GA, Foti C (1992) Dermatite da
artefacta (ODA) and pathomimic artefacta (PA) contatto professionale e fattori di rischio. Boll Dermatol
Allerg Profess 7:9-32
Criteria ODA PA Angelini G, Bonamonte D (1998) Occupational dermatitis arte-
facta. Proceedings of the 19th World Congress of Dermatol-
Gender Generally male Generally female ogy, Sydney, 15-20 June
Age Young and adult Young and adult Asher R (1951) Munchausen's syndrome. Lancet i:339-341
History Episodic affliction Chronic history of Consoli SG (1995) Dematitis artefacta: a general review. Eur J
with acute onset complaint Dermatol 5:5-11
Cutaneous sites Hands, arms, and Generally face Dieulafoy G (1908) Escarres multiples et recidivantes depuis deux
unusual sites and arms ans et demi aux deaux bras et au pied. Amputation du bras
Morphology More bizarre lesions Less bizarre lesions gauche. Discussion sur la nature de ces escarres. Pathomimie.
Causal agents Highly varied, Common mechanical La Presse Med 47:369-372
strange and objects or chemical Dufton P, Griffiths A (1981) Suction blister mimicking pemphi-
unimaginable agents goid. An unusual case of dermatitis artefacta. Clin Exp
Dermatol 6:163-166
Occupational Dermatitis Artefacta 147
Fabisch W (1981) What is dermatitis artefacta? Int J Dermatol Meneghini CL, Angelini G (1979) Occupational dermatitis arte-
20:427-428 facta. Berufsdermatosen 27:163-165
Janofsky JS (1994) The Munchausen syndrome in civil forensic Millard LG (1984) Dermatological pathomimicry: a form of
psychiatry. BuI! Am Acad Psychiatry Law 22:489-497 patient maladjustment. Lancet ii:969-971
LyeU A (1979) Cutaneous artifactual disease. A review, amplified O'Shea S (1984) The truth about Munchausen. Irish Med J 77:
by personal experience. J Am Acad Dermatol1:391-407 216-217
LyeI! A (1986) Dermatitis artefacta in relation to the syndrome of Petruzzellis V, Angelini G, Vena GA (1988) La dermatite artefatta.
contrived disease. Clin Exp DermatoI11:109-126 Boll Dermatol AUerg Profes 3:23-40
Maurice PDL, Rivers JK, Jones C, Cronin E (1987) Dermatitis Sew!tan H (1901) Oedeme dur et hyperplasie traumatique du
artefacta with artefact of patch tests. Clin Exp Dermatol metacarpe dorsal. Revue Medicale Suisse Romande 21:409-415
12:204-206 US Environmental Protection Agency (1988) Indoor Air Facts no.
Meigel WN, Koops DH (1978) Skarifikationsartefakte der 4, Sick Buildings. Washington DC
Testreaktion bei einer berufsdermatologischen Begutachtung. Van Moffaert M, Vermander F, Kint A (1985) Dermatitis artefacta.
Hautartz 27:349-351 Int J Dermatol 24:236-238
Meneghini CL, Rantuccio F (1962) Patomimie cutanee profes- Winkelmann RK, Barker SM (1985) Factitial traumatic panniculi-
sionali. Giorn It Dermatol103:143-155 tis. J Am Acad Dermatol 13:988-994
CHAPTER 18
Physical Causes - Heat, Cold and Other Atmospheric Factors

W. Uter and L. Kanerva
Heat degrees of disfigurement. Squamous ceIl carcinoma

arising from burn scars was described by Marjolin in
Thermal Burns 1828; the frequency of this complication is unknown
(Kennedy 1992). The criteria established by Ewing
Burns result from exposure to extremes of heat. The (1935) for associating a carcinoma with a previous burn
lowest temperature at which a burn can occur has been are still considered valid.
estimated to be 44°C (111°F) (Moritz and Henriques Burns may cause either hyperpigmentation or
1947). Burns may be of industrial, domestic or envi- hypopigmentation. When totalloss of pigment occurs,
ronmental origin. Industrial burns are common it denotes deeper burns with destruction of melano-
(Moritz and Henriques 1947; Cason 1981) and may cytes, and recovery of skin color is doubtful. With
have characteristic occupational patterns (Renz and more superficial burns, hyperpigmentation may result,
Sherman 1994; Woods et al. 1996). Apart from direct depending on the depth of the burn and the genetic
contact with hot objects or radiation heat [infrared background of the patient. Blacks and other pigmented
radiation (IR)], accidental exposure to laser energy persons show the greatest hyperpigmentation, which
may cause thermal destruction through absorption by on the face and other exposed areas may be greatly
skin chromophores such as melanin and haemoglobin, disfiguring. Fading occurs slowly; a final evaluation of
weIl known from the therapeutic application of differ- permanency should not be made until 18-24 months
ent lasers in dermatology. Classification of burns is after the burn has completely healed.
based on the depth of the burn as first, second, or third
degree (Table 1) (Burke and Bondoc 1993). Electrical Burns
Although in many countries dermatologists are
often not involved in the acute-phase treatment of Electrical burns occur from environmental, domestic
more severe burns, they frequently are requested to and industrial sources. üf 290 fatal factory accidents in
evaluate impairment of patients with healed burns. Great Britain, 21 were due to electric shock; a larger
Pigmentation, vascularity, pliability and sc ar height are number died from burns after contact with domestic
the main parameters (Sullivan et al. 1990) for derma- 240-V alternating current (50 Hz) (Cason 1981). The
tological evaluation. Sometimes scarring is extensive lesions are due to heat and direct injury by electricity,
enough to limit joint mobility or muscle strength the severity depending, for example, on current
(Jonsson et al. 1997) in addition to producing varying voltage, thickness and wetness of the skin, and
Table 1. Classification of bums based on the depth of the bums (Burke and Bondoc 1993)
Classification of bums Surface appearance Sensation Outcome/prognosis
First degree Dry, erythematous, no Painful, hypersensitive Complete healing within 1

blisters week; no sc ar
Second degree (superficial) Blisters, red oozing base, Painful, extremely sensitive Complete healing within 3
good capillary refill, to pinprick weeks; may be erythematous
blanching on press ure early after healing
Second degree (deep) Blisters may be present; Some insensitive areas; many Firm, thick scar with loss of
pale, indurated areas; areas anesthetic to pinprick hair follicles, sweat glands,
some areas red and skin pigmentation;
healing may take 1 month
Third degree Pearly white or brown No sensation Total skin loss includes all
opaque gray; firm appendages; heals by scar
leathery, dry formation if small

Physical Causes - Heat, Cold and Other Atmospheric Factors 149
duration of contact (Kennedy 1992). High-voltage 1992). It has also been reported as a marker of chronic
bums are severe; low-voltage bums are milder but pancreatitis (Mok and Blumgart 1984).
penetrate more deeply than is apparent by following Workers who may develop erythema ab igne inelude
nerves and vessels, and extending some distance away stokers, blacksmiths, glassblowers, bakers (especially
from the edge of the visible wound. Even 24 V may those using old-fashioned brick-lined ovens), cooks
produce deep injury (Benmeir et al. 1993). Late rupture and others working over a heat source. Schwartz et al.
of blood vessels can occur even as late as 2 weeks after (1957) described the condition in stenographers who sit
the electrical bum (Kennedy 1992). Electrothermal very elose to radiators in cold weather. According to
bums may be caused by grasping a heated electrical Kennedy (1992), it also occurs on the face of silver-
element. Bums from cardiac defibrillators have caused smiths and jewelers and on the arms of foundry men.
local skin ulcers. The depth of electric flash bums In mentally disturbed patients with thermophilia,
depends on the temperature of the agent and the bizarre areas of erythema ab igne have been encoun-
duration of contact. Recently, Campbell and coworkers tered (Kennedy 1992).
(1996) reported high-voltage electrical injury in two After an interval of up to 30 years or more, thermal
hang-glider pilots from 1l,000-V power lines. Magnetic skin injury and erythema ab igne may proceed to
resonance imaging (MRI) is a new diagnostic aid in the cancer (Kaplan 1987). Several variants, mostly depend-
care of high-voltage electrical bums (Nettelblad et al. ing on a certain geographical influence or habit, have
1996). been described (Kanerva 1999) (see also Chap. 30). IR
Bums from lightning cause a bizarre, superficial may significantly enhance aging and carcinogenic
erythema that Bartholome et al. (1975) considered effects of ultraviolet radiation (Kligman 1982; Kligman
pathognomonic. The skin shows numerous erythema- and Kligman 1984).
tous macules arranged in a streaked feather- or
femlike pattem. Blanching on diascopy does not occur Erythermalgia
and, in those persons who survive, fading occurs
within 24-48 h. The condition is probably due to the Erythermalgia is a syndrome of bilateral symmetrie
transmission of static electricity along the superficial buming and redness of the lower, or sometimes upper,
vasculature, similar to that occurring when an elec- extremities. Symptoms can be initiated by exercise or
trodessiccating current is used to destroy small angio- exposure to heat, while rest and cold offer relief (Heller
mas. Lightning injuries are an occupational risk of Page and Shear 1993; Drenth and Michiels 1994). Thus,
outdoor workers, such as railroad and highway con- occupational factors may aggravate symptoms
struction workers, surveyors, geologists, fore sters and (Table 2). Primary erythermalgia usually arises in
agricultural workers. The heat torch can cause severe
bums when operated improperly, especially when used
as a hand tool. Table 2. Workers potentially exposed to excessive heat
Erythema Ab Igne Animal rendering workers

Asphalt workers
Bakers
IR, composed of wavelengths of 800-170,000 nm, Bitumen workers
results in thermal bums at temperatures over 44°C Boiler heaters
(Zalar and Harber 1985). Chronic exposure to heat can Cannery workers
Chemical plant operators working near hot containers
result in erythema ab igne and skin cancer. It is and furnaces
characterized by a mottled, reticulate hyperemia with Cleaners
melanoderma and teleangiectases and sometimes Coke oven operators
Cooks and other kitchen workers
superficial epidermal atrophy and sub epidermal blis- Firemen
te ring. Erythema ab igne occurs after prolonged Foundry workers
exposure to heat, i.e., infra-red radiation, which is Glass manufacturing workers
Greenhouse workers
usually insufficient to produce bum. At one time, the Kiln workers
condition was common on the anterior legs and inner Miners in deep mines
thighs of women who sat for long periods before an Outdoor workers during hot weather
Sailors passing hot c1imatic zones
open fire, and on the abdomens of patients with Shipyard workers when c1eaning cargo holds
chronic abdominal pain who applied heating pads for Smelter workers
hours at a time. New cases are now being observed as Steel and metal forges
Textile manufacturing workers (weaving, dyeing)
heating with wood fires has become more common Maintenance workers in nuclear plants
again. Heater cushions still cause erythema ab igne Tight protective c10thing (all occupations), e.g., maintenance
(Dvoretzky and Silverman 1991), which may be a sign worker in nuclear plants
Tire (rubber) manufacturing workers
leading one to suspect hypothyroidism (Kennedy
150 W. Uter and L. Kanerva
childhood; secondary erythermalgia develops in adults condition is caused by widespread inactivation of

in association with or without an apparent underlying sweat glands from prolonged exposure to a hot
dis order. Aspirin has given the best results (Heller environment. It usually follows an extended period of
Page and Shear 1993), but treatment may be difficult miliaria rubra. Heat exhaustion and collapse are
and symptoms may persist throughout life. Secondary common sequelae. A condition called tropical an-
erythermalgia can arise as a side effect of drugs, but hidrotic asthenia, with acute fatigue, nausea, dizziness,
otherwise the etiology is unknown (Drenth and palpitations, tachycardia and malaise, has been ob-
Michiels 1994; Drenth et al. 1997). served among military personnel during wartime in
very hot, humid environments. Tropical anhidrotic
Miliaria asthenia is secondary to widespread miliaria profunda
in particularly adverse conditions (Cage et al. 1987).
Miliaria is caused by sweat retention. Heat causes Treatment of miliaria consists of cooling the patient
swelling of the keratin within sweat ducts, resulting in to reduce sweating. Mild, nonocelusive lotions may be
pore elosure and rupture of the ducts immediately used. In miliaria crystallina, removal of the damaged
beneath the obstruction. If the obstruction occurs area by mechanical means or by natural sloughing
within the stratum corneum, miliaria crystallina (sud- stops the process. In miliaria rubra, a week of rest from
amina) results, producing small, elear vesieles that the inciting factors allows removal of the damaged
soon rupture, resulting in desquamation. Cutaneous portion of the epidermis by natural desquamation;
bacteria, particularly staphylococci seem to playa role however, in miliaria profunda, rest in cool surround-
in the pathogenesis of miliaria (Mowad et al. 1995). ings for several weeks is needed for complete recovery.
The skin surface may or may not be faintly erythema- Systemic and topical steroids are not helpful.
tous. It is most commonly seen after mild nonspecific Occupations associated with excessive heat exposure
damage to the epidermis and/or profuse sweating. are listed in Table 2; in addition, work in the tropics
While miliaria crystallina is usually asymptomatic, may be inadvisable for very susceptible persons.
patients may become concerned when they notice,
suddenly, that the entire palm is desquamating (Lobitz
Intertrigo
1962). Widespread involvement may, in rare cases,
interfere with thermoregulation.
A macerated, erythematous eruption in body folds -
When elosure occurs somewhat deeper in the
intertrigo - can occur from excessive sweating, espe-
epidermis, in the granular layer, firm vesieles are
cially in obese persons. Friction between opposing
formed accompanied by marked pruritus. Called
surfaces in addition to sweat retention are important
miliaria rubra, or prickly heat, it is easily confused
etiologic factors. Secondary bacterial or candidal
with contact dermatitis. This condition is more trou-
infection commonly accompanies intertrigo. The
blesome than miliaria crystallina because the eruption
groin, axillae and interdigital areas are favored sites.
may be quite extensive and is accompanied by
In particular, the interdigital space between the third
paroxysms of burning and itching. The lesions are
and fourth fingers is a common site for intertrigo and
small erythematous macules and vesieles unassociated
secondary candidal infection among cannery workers,
with follicular openings; a hand lens aids in observa-
bartenders, medical and dental personnei, and others
tion. The lesions may appear a few days after exposure
performing wet work for prolonged periods. Cooks,
to a hot, humid environment, but most commonly
swimming instructors, nurses and others exposed to
appear after one to several months (Lillywhite 1992).
moisture are also disposed to this condition. An
The trunk and intertriginous areas are especially
important differential diagnosis, if finger web spaces
involved. The palms and soles are spared. When pore
are affected, is interdigital dermatitis as a common
elosure is severe, hyperpyrexia and heat exhaustion
early type of irritant contact dermatitis in wet-work
occur, causing a decrease in work efficiency. The
occupations. This will, however, show scaling and
lesions that later develop may be pustular from
probably fissuring without maceration and will re-
infiltration of inflammatory cells and may be compli-
spond well to emollient treatment.
cated by secondary bacterial infection.
If obstruction is even deeper, i.e., in the dermo-
epidermal junction zone, miliaria profunda results Miscellaneous Conditions
(Kirk et al. 1996), producing deep-seated asymptom-
atic vesieles, which appear much like gooseflesh, but Acne vulgaris and rosacea can be aggravated by
elose examination shows that they spare the follieles. prolonged chronic exposure to heat, especially intense
The lesions consist of pale white papules, 1-3 mm in heat from ovens, steam, open furnaces or heat torches.
diameter, which are most prominent on the trunk. Herpes simplex may be triggered by sudden blasts of
Erythema and pruritus are mild or absent. This serious heat. Prolonged exposure to excessive heat also
increases irritability, decreases workers' ability to Frostbite

concentrate, and results in a generally lower level of
efficiency. There are three stages of freezing cold injury: the first
is massive vasoconstriction, causing a rapid fall in skin
temperature; second, the hunting phenomenon, i.e.,
Cold transient cyclic vasodilatation by the opening of
arteriovenous anastomoses, causing a cyclic rise and
The effect of coldness is the result of a complex fall in skin temperature; and third, if cold exposure
interaction of climatic factors (air temperature, mean continues, freezing, as the skin temperature falls to
radiant temperature, humidity and wind), protection approach ambient temperature (Kulka 1965; Heller
(clothing) and metabolie heat production (activity). Page and Shear 1993).
The nature of cooling encompasses: (1) whole-body The events that ensue freezing and nonfreezing cold
cooling, (2) extremity cooling, (3) convective cooling injury are similar and include: (1) arterial and arteri-
(wind chill), (4) conductive cooling (contact), and (5) olar vasoconstriction, (2) excessive venular and capil-
airway cooling (Holmer 1993). Cooling the brain leads lary vasodilatation, (3) increased endothelial leakage,
to confusion and later to incoordination, while cooling (4) erythrostasis, (5) arteriovenous shunting, (6) seg-
the limbs results in numbness and clumsiness, making mental vascular necrosis, and (7) massive thrombosis
the performance of intricate tasks difficult. (Heller Page and Shear 1993).
Local cooling, in most cases, produces discomfort The degree of cellular injury depends on: (1) the
and harmful effects before more significant whole- minimum temperature, (2) the duration of time at that
body cooling develops. With strong wind or movement temperature, (3) the cooling rate, with rapid cooling
at very low temperature, frostbite of unprotected skin causing more destructive intracellular ice crystal
may quickly develop (see "Frostbite"). However, as formation and, hence, more destruction as is obvious
digit cooling depends largely on whole-body heat from cryotherapy, (4) rewarming rate (in slow re-
balance, it is important to control body cooling by warming, intracellular ice crystals become larger and
selection and use of appropriate protective clothing more lethai for the cell) and, finally, (5) repeated
(Holmer 1993). freeze-thaw cycles lead to greater injury. Different cell
Everybody reacts to cold, but in addition to phys- types vary in their susceptibility to cold. Melanocytes
iologie responses to cold, abnormal reactions may are very sensitive, and damage occurs at -4°C to -7°C
occur in some individuals. Chilblains may result from (25-19 °F). Accordingly, cryotherapy causes hypopig-
chronic exposure to moderate cold. Cold plays an mentation (Heller Page and Shear 1993).
important role in, for example, Raynaud's phenome- Low air temperatures and high wind speeds ("wind
non, cryoglobulinemia and cold urticaria. Cutaneous chill") are associated with an increased risk of freezing
reactions to cold can be divided into reactions to of the exposed skin. As the skin surface temperature
abnormal cold and abnormal reactions to "normal" falls from -4.8 °c to -7.8 °c, the risk of frostbite
cold. The diseases caused or aggravated by cold are increases from 5% to 95% (Danielsson 1996). Frostbite
listed in Table 3. additionally causes impairment of circulation due to
slowly progressing vasconstriction.
In its mildest form only redness and pain are
Table 3. Diseases caused or aggravated by cold present. In more severe cases, tissue destruction and
blistering occur and this may be superficial, full
1. Reactions to abnormal cold thickness or involve deep tissues analogous to the
1. Cold injury burns (see Table 1). In its most extreme form,
2. Frostbite
3. Nonfreezing cold injury gangrene and loss of limb may result. Exposed parts,
a. Immersion or trench foot Le., toes, feet, fingers, ears, nose and cheeks are most
b. Tropical immersion foot often affected.
II. Abnormal reactions to cold
1. Perniosis As tissue temperature falls, the area becomes numb,
2. Pulling boat hands and the initial redness is gradually replaced by a white,
3. Acrocyanosis waxy appearance with blistering and, later, necrosis;
4. Erythrocyanosis
5. Livedo reticularis the affected part becomes deceptively anaesthetic. In
6. Cold urticaria the early stages, it is difficult to predict the extent of
7. Cold erythema
8. Cold panniculitis
tissue loss becoming perceivable after rewarming,
9. Sclerema neonatorum especially concerning deeper structures such as muscle
10. Subcutaneous fat necrosis of the newborn and bone. Accurate estimation may not be clinically
11. Cryoglobulinemia
12. Raynaud's phenomenon
possible for several weeks (Knize et al. 1969); however,
MRI and magnetic resonance angiography (MRA)
provide for early recognition of damaged tissue Immersion Foot: Nonfreezing Cold Injury
(Barker et al. 1997). The more superficial the injury,
the better the prognosis, especially if infection is Formerly called trench foot, immersion foot results
absent. However, even without loss of tissue, long-term from exposure to cold temperatures above freezing for
effects may include telangiectasias (Huh et al. 1996), several days. In the presence of moisture and con-
vasomotor instability with Raynaud-like changes, strictive clothing, however, continuous exposure for as
paresthesia and hyperhidrosis. This is attributed to litde as 19 h may be sufficient (Rietschel and Allen
damage to the blood vessels and sympathetic nerves. 1976). Immersion foot is less severe than frostbite and
Squamous cell carcinoma may arise in the old scars develops in three stages: initial erythema, edema and
(Rossis et al. 1982). tenderness (stage I); followed within 24 h by pares-
In slow rewarming, intracellular ice crystals become thesia, marked edema, numbness and sometimes
larger and more lethal for the cells. Therefore, treat- bullae (stage II); and progressing to gangrene (stage
ment entails rapidly rewarming the part; a whirlpool or III). Gangrene does not develop unless there is
waterbath, or warm air for 20 min (until the most infection. Convalescence may be prolonged for several
distal part is fiushed) is useful for this purpose. weeks or months, during which time there is cold
A temperature no higher than blood temperature sensitivity, vasomotor instability, hyperemia and hyper-
(Daniels 1987) or 42°C (Heller Page and Shear 1993) hidrosis. Rest, analgesics and antibiotics are the
has been recommended, e.g., employing warm baths mainstays of treatment, the same as for frostbite.
for some 20 min (Champion 1992). Thereafter, the During the Korean and Vietnam Wars, thousands of
affected part is rested at usual room temperature. cases occurred and immersion foot became the major
Rewarming is painful and causes an increase in cause of disability. In industries where workers are
erythema and blistering. The pain should be relieved required to stand for long periods in cold, wet mud or
with analgesics. The damaged part should be elevated water, e.g., when excavating foundations for new
and blisters left intact. Infection must be treated construction, immersion-type injuries may be frequent
vigorously. Early application of heparin or infusion of (Schwartz et al. 1957). Street and sewer workers, as weIl
low-molecular-weight dextran may be of some addi- as golf caddies walking for hours on wet grass, are also
tional benefit (Champion 1992). The popular old idea at risk (Chow et al. 1980). For the homeless, immersion
of rubbing the affected part with snow (Ronchese 1948) foot can be a major health problem (Wrenn 1991),
has an adverse, or even disastrous effect. aggravated by lack of care. Interestingly, immersion
Historically, the persons at greatest risk of frostbite foot can also develop in warm water (Humphrey and
have been military personnel. Nearly 200,000 cold Ellyson 1997), including the tropics (tropical immer-
casualties occurred during World Wars I and II and sion foot, Table 3).
the Korean confiict (Daniels 1987). Today, many cases
are associated with alcohol consumption, homeless- Chilblains (Perniosis)
ness in urban centers and car breakdown (Miller and
Chasmar 1980). Frostbite can also occur in those taking The mildest form of cold injury, chilblains or pernio-
part in winter sports, e.g., cross country skiers or sis, occurs as an abnormal reaction to cold in the
backpackers. W orkers at risk include oil pipeline temperate humid climate of Great Britain and north-
workers in northern regions, utility maintenance western Europe, where there is a lack of central
personnel, sailors (especially those working on ice- heating (Heller Page and Shear 1993). Chilblains are
breakers), fishermen, firefighters, mail delivery per- less often seen in continental cold climates such as
sons, rescue personneI, researchers in cold laboratories Finland, where well-heated houses and warm clothing
and polar areas, and others who work outdoors in cold are essential. The lesions are reddish blue dis color-
regions (Table 4). ations that become swollen and boggy, with tense
bullae and, later, ulcerations that may result in
Table 4. Workers potentially exposed to excessive cold scarring. Often, chilblains are superimposed on a
background of acrocyanosis or erythrocyanosis.
Cooling room workers Lesions occur especially on the dorsa of the proximal
Divers phalanges of the fingers and toes, heels, lower legs,
Dry-ice workers
Firefighters thighs, no se and ears. The shiny red plaques itch and
!ce makers burn severely. Chilblains are particularly frequent in
Liquified-gas workers children, in whom they tend to start at the beginning
Outdoor workers during cold weather
Packing-house workers of winter. In adults who work outdoors, chilblains
Refrigerated-warehouse workers often seem to start in the spring months (Champion
Refrigeration workers 1992). Genetic factors are often apparent, e.g., acrocy-
Winter-sports instructors
anosis as an underlying factor. Differential diagnoses
of idiopathic perniones include chilblain lupus erythe- Low Outdoor Humidity

matosus (Millard and Rowell 1978), sarcoidosis and
several other entities that have to be considered The following two measures are most commonly used
clinically, histologically and serologically (Crowson to quantify the humidity of air: (1) absolute humidity
and Magro 1997). (AH) is the mass of water vapor present in a unit
The most important point in management is volume of the atmosphere and is mostly measured as
prophylaxis with warm housing, warm clothing and mg/I; (2) relative humidity (RH) is the ratio of the
regular exercise. Once a chilblain has appeared, quantity of water vapor present in the atmosphere to
treatment is mainly symptomatic with local application the quantity that would saturate it at the existing
of an antipruritic. Some patients may benefit from temperature (expressed as a percentage). Thus, with a
ultraviolet radiation (Champion 1992). This therapy given quantity of water per air volume (AH), RH
may relieve chronic vasospasm believed to occur in depends on the temperature: the higher the tempera-
chilblains (Heller Page and Shear 1993). Nifedipine ture, the greater the water-holding capacity of the
may be effective in the treatment of severe recurrent atmosphere and the lower the RH, and vice versa.
perniosis (Dowd et al. 1986). In seven of ten patients, AH = (RHT/100) x SVPT
clearing ranged from 8 days for lesions of the hands to
23 days for foot lesions (Dowd et al. 1986). where SVP T is the saturated vapor pressure at a certain
temperature (which is proportional to temperature).
Low humidity of the air is believed to cause
Pulling-Boat Hands
dehydration of the horny layer and impairment of
the epidermal barrier function (Agner and Serup 1989),
This dermatosis has been described from coastal New
i.e., increased irritability of the skin. Subclinical xerotic
England (Toback et al. 1985). Erythematous macules
changes may occur within hours of exposure and are
and plaques developed on the dorsa of the hands and
more pronounced in atopics (Eberlein-König et al.
fingers of instructors and students after 3-14 days
1996).
aboard a pulling boat. Later, small vesicles appeared,
Persons working and living in (sub-) polar or even
accompanied by itching, burning and tenderness.
temperate climates with a strong continental infiuence
Subjects had been exposed to high humidity, cool air
(prolonged periods of dry, frosty weather in winter)
and wind, which was considered an ideal setting for the
are regularly exposed to low atmospheric humidity,
development of this nonfreezing type dermatosis.
such as 10 mg/l or less. Clinical experience from these
Hours of vigorous rowing provided additional repet-
countries gives a strong hint at the contributing role to
itive trauma. Some of the patients also had a his tory of
irritant hand dermatitis of these meteorological con-
frostbite and Raynaud's phenomenon. This syndrome
ditions (Kavli and Förde 1984), which has recently
may be caused by a combination of nonfreezing cold
been confirmed by an epidemiological study (Uter
and the mechanical effects of rowing (Toback et al.
et al. 1998) and agrees well with some experimental
1985).
data (partially reviewed by Uter et al. 1998).
Interestingly, unexposed skin also displays an
Other Reactions to Cold impaired epidermal barrier function (Agner and Serup
1989), which may indicate that even the wearing of
Cold urticaria and Raynaud's phenomenon are dealt protective (warm, wind-tight) gloves may not be able
with later in this book. The reader interested in other to completely abolish the effect of low humidity on the
types of abnormal reactions to cold (Table 3) is skin of the hands. As the hands may additionally be
referred to major textbooks of dermatology, e.g., exposed to a variety of occupational irritants or to wet
Heller Page and Sheer (1993). work, and as (sub-) clinical irritation is often known to
be a multifactorial process (Malten 1981), this fairly
inalterable environmental condition puts extra em-
Other Atmospheric Fadors phasis on the necessity of adequate skin protection, be
it domestic or occupational.
A low water content of ambient air may cause or
contribute to occupational dermatoses, which has been Other Ambient Factors
emphasized by Rycroft and coworkers (Rycroft and
Smith 1980; White and Rycroft 1982; Rycroft 1984, Several authors of experimental studies have attributed
1985). In addition, low temperature, wind, and elec- negative effects on epidermal properties to low tem-
tromagnetic fields or electrostatic charge have been perature. However, AH is also always low with low
claimed to be ambient factors important to some skin temperature, according to the formula quoted above,
conditions. and AH has not been considered in most of these older
studies. At present, the effect of temperature concern- Table 5. Reported low-humidity risk occupations
ing irritant damage can most likely be regarded as
Office work
indirect. Soft contact lens manufacturing
Windspeed has been found to be a significant risk Silicon-chip manufacturing
factor in the occurrence of "dry fiaking" facial skin Cabin crew of long distance airplanes
Resident staff in hospitals and hotels
(Cooper et al. 1992). Parish (1992), who exposed the Travelling salesmen (from automobile heaters)
hands of volunteers to "a cold dry wind" for 3 h daily,
found visible alteration (roughness, desquamation)
and impaired lipid and enzyme composition of the (Rycroft 1985). Pruritus and burning can be the only
epidermis after a few days. sign of low humidity. Puffiness of the cheeks and
In addition to natural environmental conditions, eyelids has been observed. The skin lesions evolve
anthropogenic factors may lead to occupational (skin) through dryness of the skin to erythema and round or
disease: oval patches of eczema. Erythema has been accompa-
nied by urticarial whealing, possibly secondary to
1. During work on a television mast, exposure to high
scratching pruritic skin. In so me cases, areas covered
levels of ultrahigh frequency radiofrequency radia-
by clothing have been predominantly involved, while
tion (UHF, 785 MHz mean frequency) caused an
facial itching with diffuse superficial scaling on the
immediate sensation of intense heating and later
cheeks, forehead and neck have been the main
transient erythema, malaise, numbness and pain
anatomical areas in other instances. Patchy erythema
(Schilling 1997).
on the shaven face of male employees has been
2. Microwave radiation (1-30 GHz) has been reported
observed. Fair-skinned individuals are at higher risk.
as a cause of more or less severe burns, lesser injury
Both atopics and nonatopics have been affected.
being followed by paraesthesia (Kennedy 1992).
Differential diagnosis includes a wide variety of
possibilities that have to be considered, such as
Low Indoor Humidity inhalable and ingestible allergens, irritant or allergic
airborne contact dermatitis, psychological causes,
Below a water content of 10%, the stratum corneum menopausal hot fiashes, rosacea and seborrheic ecze-
loses its softness and pliability (Blank 1952). The water ma.
content of the horny layer remains below 10% when Treatment should include routine use of emollients
the RH is less than 50% at room temperature (Rycroft and increasing the RH indoors to about 50% during
1985). High temperature and fiowing air accentuates the whole low-humidity (winter) season.
the drying of the horny layer. An open-plan office, next
to or under the ventilation system, where warm, Visual Display Units
unhumidified air is introduced into the room, is a
typical working site in which the risk of low humidity In some countries, patients often complain of skin
dermatoses is apparent. Low-humidity dermatoses can symptoms from work with visual display units (VDU)
be accentuated by small irritant or hygroscopic (Liden and Wahlberg 1985; Berg 1989). A study from
airborne particles, such as textile particles, dust from Sweden among 353 routine office workers showed an
ceramics, small particles from paper cutting and fine increased tendency for seborrheic eczema and non-
angular, hygroscopic particles as in a soft lens factory specific erythema. Organizational conditions during
(Rycroft 1984, 1985). Domestic and general climatic VDU work, such as high work load and inability to
conditions can potentiate low-humidity occupational take rest breaks, were found to be associated with the
dermatoses. Air-conditioned buildings have a low RH reported skin symptoms. A low RH was associated
(and AH) and, in temperate areas such as Scandinavia, with a diagnosis of seborrheic eczema. However, no
the low humidity/high temperature indoor environ- associations were found between eurrent field levels of
ment is accompanied by low humidity/low tempera- electric or magnetic field and skin diseases/signs or
ture outdoor climate during the winters, which also has reported symptoms (Bergqvist and Wahlberg 1994).
a drying effect on the stratum corneum. The empirical Accordingly, a reduction of electric fields was only
threshold value of 40% RH reported by White and weakly associated with an improvement of symptoms
Rycroft (1982) corresponds well, at a temperature of attributed to VDU work (Oftedal et al. 1995). Possibly
around 20°C, with a critical value of 9-10 mg/l AH, independent from the initial cause of skin problems,
found to be a significant outdoor risk factor (Uter et al. psychological conditioning may lead to a perpetuation
1998). Some of the occupations in which low-humidity of symptoms even without exposure, as illustrated by
dermatoses have been reported are listed in Table 5. experiments with affected office workers (Swanbeck
These derma tos es are far more distressing than their and Bleeker 1989). In some cases, perceived symptoms
comparative paucity of physical signs might suggest attributed to VDU work or other indoor factors may be
part of the ill-defined "siek building syndrome" ogy in general medicine, 4th edn. McGraw-Hill, New York,
(Stenberg et a1. 1994; Rothman and Weintraub 1995). pp 1581-1592
Holmer I (1993) Work in the cold. Review of methods for
assessment of cold exposure. Int Arch Occup Environ Health
65:147-155
Huh ), Wright R, Gregory N (1996) Localized facial telangiectasias
References following frostbite injury. Cutis 57:97-98
Humphrey W, Ellyson R (1997) Warm water immersion foot: still
Agner T, Serup ) (1989) Seasonal variation of skin resistance to a threat to the soldier. Mil Med 162:61O-611
irritants. Br ) Dermatol 121:323-328 )onsson CE, Schuldt K, Linder ), Bjomhagen V, Ekholm ) (1997)
Barker )R, Haws M), Brown RE, Kucan )0, Moore WD (1997) Rehabilitative, psychiatrie, functional and aesthetic problems
Magnetic resonance imaging of severe frostbite injuries. Ann in patients treated for bum injuries-a preliminary follow-up
Plast Surg 38:275-279 study. Acta Chir Plast 39:3-8
Bartholome CW, )acoby WD, Ramchand SC (1975) Cutaneous Kanerva L (1999) Physical causes of occupational skin disease. In:
manifestations of lightning injury. Arch Dermatol lll: Adams RM (ed) Occupational skin disease, 3rd edn. Saun-
1466-1468 ders, Philadelphia (in press)
Benmeir P, Lusthaus S, Ad-EI D, Neuman A, Moor EV et al. Kaplan RP (1987) Cancer complicating chronic ulcerative and
(1993) Very deep bums of the hand due to low voltage scarifying mucocutaneous disorders. Adv Dermatol 2:19-46
electrical laboratory equipment: a potential hazard for Kavli G, Förde OH (1984) Hand derma tos es in Tromsö. Contact
scientists. Bums 19:450-451 Dermatitis 10:174-177
Berg M (1989) Facial skin complaints and work at visual display Kennedy CTC (1992) Reactions to mechanical and thermal injury.
units. Epidemiologieal, clinical and histopathological studies. In: Rook A, Wilkinson DS, Ebling F)G, et al. (eds) Textbook
Acta Derm Venereol Suppl (Stockh) 150:1-40 of dermatology, 5th edn. Blackwell, Oxford, pp 777-832
Bergqvist U, WalIlberg )E (1994) Skin symptoms during work Kirk )F, Wilson BB, Chun W, Cooper PH (1996) Miliaria
with visual display terminals. Contact Dermatitis 30:193-196 profunda. ) Am Acad Dermatol 35:854-856
Blank IR (1952) Factors which influence the water content of the Kligman LH (1982) Intensification of UV induced dermal damage
stratum corneum. ) luvest Dermatol 18:433-440 by IR radiation. Arch Dermatol Res 272:229
Burke )F, Bondoc CC (1993) Bums: the management and Kligman LH, Kligman AM (1984) Reflections on heat. Br )
evaluation of the thermally injured patient. In: Fitzpatrick Dermatol 1l0:369-375
TB, Eisen AZ, Wolff K, et al. (eds) Dermatology in general Knize DM, Weatherley-White LCA, Paton BC, et al. (1969)
medicine, 4th edn. McGraw-Hill, New York, pp 1592-1598 Prognostic factors in the management of frostbite. ) Trauma
Cage GW, Sato K, Schwachman H (1987) Eccrine glands. The 9:749-759
management and evaluation of the thermally injured patient. Kulka )P (1965) Cold injury of the skin. Arch Environ Health
In: Fitzpatrick TB, Eisen AZ, Wolff K, et al. (eds) Dermatol- 38:484
ogy in general medicine, 3rd edn. McGraw-Hill, New York, Liden C, Wahlberg )E (1985) Does visual display terminal work
pp 69 1-7 0 4 provoke rosacea? Contact Dermatitis 13:235-241
Campbell DC, Nano T, Pegg SP (1996) Pattern of bum injury in Lillywhite LP (1992) Investigation into the environmental factors
hang-glider pilots. Bums 22:328-330 associated with the incidence of skin disease following an
Cason )S (1981) Treatment of burns. Chapman & Hall, London, outbreak of Miliaria rubra at a coal mine. Occup Med (Oxf)
pp 205-220 42:183-187
Champion RH (1992) Reactions to cold. In: Rook A, Wilkinson Lobitz WC (1962) Sweat retention syndrome. In: Rees RB (ed)
DS, Ebling F)G, et al. (eds) Textbook of dermatology, 5th edn. Dermatoses due to environmental and physical factors.
Blackwell, Oxford, pp 833-847 Charles C Thomas, Springfield, pp 146-156
Chow S, Westfried M, Lynfield Y (1980) Immersion foot: an Malten KE (1981) Thoughts on irritant contact dermatitis. Contact
occupational disease. Cutis 25:662 Dermatitis 7:238-247
Co oper MD, )ardine H, Ferguson ) (1992) Seasonal influence on Millard LG, Rowell NR (1978) Chilblain lupus erythematodes
the occurrence of dry flaking facial skin. In: Marks RG, Plewig (Hutehinson). A clinical and laboratory study of 17 patients.
G (eds) The environmental threat to the skin. M. Dunitz, Br ) Dermatol 98:497-506
London, pp 159-164 Miller Bj, Chasmar LR (1980) Forstbite in Saskatoon: a review of
Crowson AN, Magro CM (1997) Idiopathic pemiosis and its 10 winters. Can ) Surg 23:423-426
mimics: a clinical and histological study of 38 cases. Hum Mok DWH, Blumgart LH (1984) Erythema ab igne in chronic
Pathol 28:478-484 pancreatic pain: a diagnostic sign. ) R Soc Med 77:299-301
Daniels F (1987) Physiologie factors in the skin's reactions to heat Moritz AR, Henriques FC )r (1947) Studies in thermal injuries. II.
and cold. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al. (eds) The relative importance of time and surface temperature in
Dermatology in general medicine, 3rd edn. McGraw-Hill, New the causation of cutaneous bums. Am ) Pathol 23:695-720
York, pp 1412-1424 Mowad CM, McGinley Kj, Foglia A, Leyden JJ (1995) The role of
Danielsson U (1996) WindehilI and the risk of tissue freezing. extracellular polysaccharide substance produced by Staphy-
) Appl Physiol 81:2666-2673 lococcus epidermidis in miliaria. ) Am Acad Dermatol 33:
Dowd PM, Rustin MHA, Lanigan S (1986) Nifedipine in the 729-733
treatment of chilblains. BM) 293:923-924 Nettelblad H, Thuomas KA, Sjöberg F (1996) Magnetic resonance
Drenth )PH, Michiels JJ (1994) Erythromelalgia and erythermal- imaging: a new diagnostic aid in the care of high-voltage
gia: diagnostic differentiation. Int ) Dermatol 33:393-397 bums. Burns 22:1q-1l9
Drenth )PH, Michiels JJ, Van )oost Th (1997) Substance P is not Oftedal G, Vistnes AI, Rygge K (1995) Skin symptoms after the
involved in primary and secondary erythermalgia. Acta Derm reduction of electric fields from visual display units. Scand )
Venereol Suppl (Stockh) 77:325-326 Work Environ Health 21:335-344
Dvoretzky I, Silverman NR (1991) Reticular erythema of the lower Parish WE (1992) Chemical irritation and predisposing environ-
back. Arch Dermatol 127:405-410 mental stress (cold wind and hard water). In: Marks RG,
Eberlein-König B, Spiegl A, Przybilla B (1996) Change of skin Plewig G (eds) The environmental threat to the skin. M.
roughness due to lowering air humidity in climate chamber. Dunitz, London, pp 185-193
Acta Dermatol Venerol 76:447-449 Renz BM, Sherman R (1994) Hot tar bums: twenty-seven
Ewing ) (1935) Modem attitude toward traumatic cancer. Arch hospitalized cases. ) Burn Care RehabilI5:341-345
PathoI19:690-728 Rietschel RL, Allen AM (1976) Immersion foot: a method for
Heller Page E, Shear NH (1993) Disorders due to physical factors. studying the effects of protracted water exposure on human
In: Fitzpatrick TB, Eisen AZ, Wolff K, et al. (eds) Dermatol- skin. Mil Med 141:778-780
156 W. Uter and L. Kanerva: Physical Causes - Heat, Cold and Other Atmospheric Factors
Ronchese F (1948) Occupational marks and other physical signs: Stenberg B, Eriksson N, Hoog J, Sundell J, Wall S (1994) The sick
a guide to personal identification. Grune & Stratton, New building syndrome (SBS) in office workers. A case-referent
York pp 1-181 study of personal, psychosocial and building-related risk
Rossis CG, Yiacoumettis AM, Elemenoglou J (1982) Squamous indicators. Int J Epidemiol 23:1190-1197
cell carcinoma of the heel developing at site of previous Sullivan T, Smith J, Kermode J, Mclver E, Courtemanche DJ
frostbite. J R Soc Med 75:715-718 (1990) Rating the burn scar. J Burn Care Rehabil11:256-260
Rothman AL, Weintraub MI (1995) The sick building syndrome Toback AC, Korson R, Krusinski PA (1985) Pulling boat hands: a
and mass hysteria. Neurol Clin 13:405-412 unique dermatosis from coastal New England. J Am Acad
Rycroft RJG (1984) Low humidity occupational dermatoses. Dermatol 12:649-655
Dermatol Clin 2:553-557 Vter W, Gefeller 0, Schwanitz HJ (1998) An epidemiological
Rycroft RJG (1985) Low humidity and microtrauma. Am J Ind study of the influence of season (cold and dry air) on the
Med 8:371-373 occurrence of irritant skin changes of the hands. Br J
Rycroft RJG, Smith WDL (1980) Low humidity occupational Dermatol 138:266-272
dermatoses. Contact Dermatitis 6:488-492 White IR, Rycroft RJG (1982) Low humidity occupational
Schilling CJ (1997) Effects of acute exposure to ultrahigh dermatosis - an epidemic. Contact Dermatitis 8:287-290
radiofrequency radiation on three antenna engineers. Occup Woods JA, Cobb AT, Drake DB, Edlich RF (1996) Steam press
Environ Med 54:281-284 hand burns: a serious burn injury. J Emerg Med 14:357-360
Schwartz L, Tulipan L, Birmingham DJ (1957) Occupational Wrenn K (1991) Immersion foot. A problem of the homeless in
diseases of the skin. Lea & Febiger, Philadelphia the 1990S. Arch Intern Med 151:785-788
Swanbeck G, Bleeker T (1989) Skin problems from visual display Zalar GL, Harber LC (1985) Reactions to physical agents. In:
units - provocation of skin symptoms under experimental Moschella SL, Hurley HJ (eds) Dermatology, 2nd edn.
conditions. Acta Derm Venereol Suppl (Stockh) 69:46-51 Saunders, Philadelphia, pp 1672-1690
CHAPTER 19
Mechanical Causes of Occupational Skin Disease

L. Kanerva
Introduction mechanical causes comprised 139 cases of a total of

4320 cases (3%) of occupational skin diseases in
The skin is we11 adapted to co pe with many types of Finland (Kanerva et a1. 1995). The actual number is
trauma, but excessive friction and microtrauma can probably much higher (Susten 1985) but a11 cases are
result in the formation of various dermatoses not reported. The present article is an updated review
(Table 1). Microtraumas include a variety of superficial of previous articles by the present author (Kanerva
skin injuries: friction, abrasions, pressure, stretching, 1990, 1996, 1999).
compressions, cuts, etc. Mechanical insults to the skin
may affect a11 levels of the skin from the cornified layer
through the subcutaneous fat. The time a110wed for Friction
adaptation determines the reaction of the skin. Slowly
increasing pressure or friction induces hyperkeratosis, A moderate degree of friction in everyday life is usua11y
lichenification and ca11uses, while sudden friction can harmless, but excessive friction causes different types
induce blisters. The effects of trauma are modified by of changes in the skin. Intermittent or repeated friction
humidity, sweating, age, gender, nutritional status, (rubbing, scratching) of low intensity induces lichen-
infection, genetic and racial factors. ification (thickening). This may be accompanied by
Mechanical insults to the skin can cause a wide hyperpigmentation [friction melanosis (Hayakawa
variety of clinical manifestations. The clinical picture is 1996)). With stronger force and pressure, corns and
then a summation of the various mechanical forces on ca110sities form. The thick horny layer of the ca11uses is
the skin. Many traumas are common and accepted as subject to painful fissures.
natural occurrences by workers who do not often seek Friction can also cause erosions, ulcers or blisters
occupational compensation. During a 7-year period (Freeman and Rosen 1996). Friction blisters are
common reactions to mechanical trauma. They seldom
Table 1. Skin manifestations from mechanical trauma
present a diagnostic problem, but can help to diagnose
Hyperkeratoses/calluses an underlying disease. The most important causative
Fissuring component is a shearing force horizontal to the
Lichenification/hyperpigmentation surface, while pressure, temperature, stretching, and
Blistering/friction injury
Pulpitis ischemia do not seem to playa direct role in friction
"Black heel" lrupture of capillaries injury (Samitz 1985). Friction blisters seldom occur on
Increased susceptibility to the effects of chemical loose skin, which stretch es easily.
irritants and allergens
Increased susceptibility to penetration of bacteria, The literature on the chronic effects of occupational
fungi, viruses, and parasites mechanical trauma, inc1uding friction, is rather scanty
Irritant and foreign body reactions to fiberglass, (Susten 1985). Menne (1983) described a post-office
non-absorbable dusts (asbestos), and metal filings (beryllium)
Tattooing from occupational exposures to metals worker with palmar dermatitis resulting from constant
Scars and keloids friction on the palm with a rough-surfaced tabletop.
Cutaneous neoplasms secondary to bums and sc ars Menne and Hjorth (1985) reported cases of frictional
Cutaneous neoplasms secondary to repeated
mechanieal trauma dermatitis in workers handling large quantities of
Käbner phenomenon (psoriasis) from friction pressure-sensitive carbonless copy paper. Storrs (1994)
Dermographie urticaria, pressure urtiearia, observed a case of frictional dermatitis associated with
vibratory angioedema
Raynaud phenomenon ("white/dead fingers") and paperwork, and we presented a case of hand dermatitis
sderodactyly from vibration caused by telefax paper (Kanerva et a1. 1992). Storrs
Post-traumatic eczema (1994) believes that frictional dermatitis seen on the
Chronie hyperkeratotic hand eczema
fingertips of secretaries is one variant of the entity of

158 L. Kanerva
hyperkeratotic hand eczema (see below). See also by glass needles have been reported to penetrate the skin
Freeman in this book. of workers in a fluorescent lamp factory (Grzegorczk
1987). See also Chap. 89, on occuptional contact
dermatitiv to plants by Guin.
Pressure The abrasive materials in occupational settings
include sharp-texture small particles, e.g., machinists
Prolonged or excessive pressure may produce ery- may develop irritant dermatitis from metal chips
thema, vesicobullae, and necrosis (Gellin 1987). Usu- (shavings, swarf) present in cutting fluids (Fischer
ally, press ure is accompanied by friction, and this and Rystedt 1985). Abrasive mineral dusts have caused
combination is mainly responsible for the callosities dermatitis in miners (Williamson 1981). W001 and
and deformities that constitute most of the so-called fiberglass textiles may cause an occupational derma-
stigmata, peculiar to certain occupations (Ronchese titis through a mechanical irritant effect (Hatch and
1948; Chap. 16). Pressure intensifies contact dermatitis Maibach 1985). Non-occupational frictional dermatitis
(Gollhausen and Kligman 1985). has also been reported from artificial fur (Paulsen and
Andersen 1991) and pantyhose (Gould 1991).
Pounding
Hyperkeratotic Hand Eczema
Pounding may result in mpture of the papillary capil- from Friction and Pressure
laries. For example, "black heel" results from pressure
and po unding in those sports where repeated jumping Chronic hyperkeratotic dermatitis is chiefly encoun-
and sudden stops or twists of the heel occur, as in tered in middle-aged or elderly men. It may be a
basketball, football, squash, lacrosse, track and field, and manifestation of psoriasis (Menne and Bachman 1979).
tennis. Different types of dermatological disorders However, a 10-year review of 32 cases by HersIe and
caused by mechanical trauma in athletes are reviewed Mobacken (1982) did not support this view. Thirteen of
in this book by Rogaschefsky and Taylor (Chap. 169) and their patients had been engaged in hard manual work.
Kanerva (Chap. 16). They proposed a clinically real entity of hyperkeratotic
hand eczema. Wilkinson (1985) suggested that friction
and pressure playa determining role in this condition.
Abrasive Materials The condition is severe and accounted for 2.5% of all
applications for permanent disability determined in a
An abrasion is major, visible damage to the epidermis Danish study (Menne and Bachman 1979). Hyper-
caused by friction. Abrasions facilitate the entry of keratotic dermatitis of the palms was reviewed recently
allergens and irritants into the skin. Friction and other by Menne (1994), and he accepted this disease as an
microtraumas may contribute to irritant and allergic own entity, independent of psoriasis and of mechanical
contact dermatitis. The chamber-scarification test of irritation.
Frosch and Kligman (1976) can be used to study the
combined effect of abrasions and mechanical irritants.
The irritation caused by abrasive materials has been Post-Traumatic Eczema
reviewed by Fleming and Bergfelt (1990).
Plants may induce mechanical irritant dermatitis It is known from clinical practice that dermatitis recurs
from delicate hairs called tri chromes or hairs with tiny at the site of prior cutaneous trauma. The interval
barbs known as glochids. Sabra dermatitis is an irritant between injury and the development of eczema was
dermatitis seen in workers who pick the fmit of prickly considered by Calnan (1968) to be about 2 weeks.
pears, which have small barbed bristles (Evans and Wilkinson (1979) had a patient who, 1 week after a
Schmidt 1980). The awns of barley and other ce real caustic-soda burn, developed a discoid eczema which
grasses may cause mechanical occupational dermatitis persisted for 15 months. Another of his patients
(Evans and Schmidt 1980). Dieffenbachia (Stoner and developed eczema 3 weeks after an accident and, a
Rasmussen 1983), daffodil (Narcissus) and hyacinth year later, the eczema spread to other sites. Zuehlke
(Hyacintus) are plants with fine, needle-shaped calci- et al. (1982) reported 13 patients with predilective
um-oxalate crystals (Evans and Schmidt 1980). The development of eczema in previously damaged skin
irritation caused by these plants is thought to be and called it "dermatitis in loco minoris resistentiae".
induced both by the mechanical action of the oxalate They adapted the term from "locus minoris resist-
crystal and subsequent penetration of a plant enzyme entiae," meaning a site of diminished resistance. The
or toxin into the skin (Epstein 1990). Irritant plants skin had been damaged mainly by surgery or burns,
have been reviewed recently by Lovell (1996). Tiny and Zuehlke et al. (1982) speculated that injury might
Mechanical Causes of Occupational Skin Disease 159
have caused permanent changes in the skin structures, ists and lathe workers, who have developed lesions
resulting in functional alterations. from gripping tools; in a pusheart peddler from the
Mathias (1988) reported 13 similar cases which he cart's hand grips; and in a pharmacist from twirling
termed post-traumatic eczema. The injuries were finger movements while handling bottle caps. Recent-
mainly of occupational origin. Eczema started within ly, we reported a dentist with occupational psoriasis
a few weeks after the trauma, and the individuallesions on the fingertips (Kanerva et al. 1998; Chap. 33 by
recurred for up to 8 years. Post-traumatic eczema has Leow and Goh). Psoriatics should be advised not to
to be differentiated from other eczematous and enter jobs in which the possibility of mechanical
non-eczematous dis orders, such as trauma-induced trauma is obvious. The differential diagnoses include
psoriasis, foreign-body reaction and recurrent herpes non-eczematous skin diseases associated with Köb-
simplex precipitated by trauma. Superimposed allergie ner's phenomenon, foreign-body reactions, bacterial
contact dermatitis from topical preparations used to infections, herpes simplex recidivans, and a second-
treat the eczematous skin must be excluded. ary allergie contact dermatitis to topical preparations
(Andersen 1994).
Compromised Skin
Oeeupational Marks
Bruynzeel and de Boer (1996) have used the term
"compromised skin". It is explained as follows: "clin- Occupational marks represent the effects of a partic-
ically healed skin needs a long period of rest before it ular occupation on a worker's skin. They have been
no longer reacts with an exacerbation of the dermatitis listed in detail in this book (Chap. 16).
after minor insults like dish washing. The skin is still
irritable and is apparently not normal because of the
previous inftammation". Oeeupational Skin Granulomas
Foreign substances penetrating the skin may induce

Pulpitis granulomas (see Chap. 15 by Pigatto).
Fingertip eczema, known as "pulpite" in the French

literature, localizes to the pulps rather than to the
backs of the fingers. Cronin (1995) describes pulpitis as Sensitization in Traumatized Skin
a dry, scaly, fissured, painful change on the pulps of
the fingers of young women. She finds it common It is believed that the majority of the cases of
although seldom reported. It may be endogenous, but occupational contact allergie sensitivity develop on a
is worsened by, for example, domestic work in preexisting dermatitis, caused by irritants, pressure,
housewives. Probably mechanical factors are also friction, sweating, and prolonged immersion in water.
involved. Burton (1992) and Wilkinson (1994) recog- Fischer and Rystedt (1983) considered that the trau-
nized two patterns: the first involves preferentially the matic frictional effect of grinding and etching was an
thumb and forefinger of the master hand, but all of the important factor in the development of cobalt allergy
fingers may be involved. The second affects the thumb in hard-metal workers. The high incidence of allergie
and first two fingers of the master hand and is usually sensitization in hospital cleaning personnel (Lam-
occupational, caused by repetitive handling of, for mintausta et al. 1982) may be due partly to the trauma
example, newspapers (Wilkinson 1994). Pulpitis re- encountered in this work. Gloves are the most impor-
sponds poorly to all forms of treatment. tant cause of occupationally induced allergie rubber
dermatitis (Estlander et al. 1986, 1994a). This might be
due to the fact that protective gloves are not used
The Isomorphie Köbner Response before a preexisting eczema develops. Cuts, wounds
and abrasions incurred on the job, while not very
The presence of certain underlying diseases may serious injuries per se, should be regarded as having
result in the replication and aggravation of that greater clinical importance insofar as they increase
disease in the area of injury. Psoriasis and lichen the likelihood of contact sensitization to allergens
planus are classical examples. The palm of the hand is (Meneghini 1985). Workers themselves may disregard
usually the area of involvement. As examples of such traumas as unimportant and unworthy of atten-
psoriatic lesions after trauma from occupation, tion, but later allergie reactions may cause consider-
Samitz (1985) mentions palmar psoriasis in seam- able distress and may even require a change of jobs
stresses working in the garment industry; in machin- (Meneghini 1985).
160 L. Kanerva
Mechanically Induced Epidermal Carcinogenesis References
Repeated mechanical injuries are capable of enhancing Alanko K, Kanerva L, Estlander T, Jolanki R, Leino T, Suhonen R
(1997) Hairdresser's koilonychia. Am J Contact Dermat 8:
papillomas and carcinomas in mouse skin (Argyris 177-178
1985). Repeated mechanical trauma at work could Andersen KE (1994) Mechanical trauma and hand eczema. In:
predispose to epidermal neoplasms, but this has not Menne T, Maibach H (eds) Hand eczema. CRC Press, Boca
Raton, pp 31-34
been proven (Argyris 1985). Malignancies occurring in Argyris TS (1985) Promotion of epidermal carcinogenesis by
burn scars have been accepted as occupational cancers repeated damage to mouse skin. Am J Ind Med 8:329-337
(Epstein et al. 1990). About 15% of Canadian farmers Baran R, Tosti A (1993) Occupational acro-osteolysis in a guitar
player. Acta Derm Venereol 73:64-65
with skin cancer reported a past history of trauma or Bruynzeel DP, de Boer EM (1996) Compromised skin. In: van der
frostbite in the involved area (Hogan and Lane 1986). Valk P, Maibach HI (eds) The irritant contact dermatitis
syndrome. CRC Press, Boca Raton, pp 283-287
Burton JL (1992) Eczema, lichenification, prurigo and erythrod-
erma. In: Champion RH, Burton, JL, Ebling FJG (eds)
Mechanically Induced Urticaria Textbook of dermatology. Blackwell Scientific Publications,
London, PP 537-588
Calnan CD (1968) Eczema for me. Trans St John's Hosp Dermatol
Urticarias resulting from non-chemical insults are Soc 54:54-64
classified as physical urticarias (see Chap. 21 by Henz). Cronin E (1995) Hand eczema. In: Rycroft RJG, Menne T, Frosch
PJ (eds) Textbook of contact dermatitis, 2nd edn. Springer,
Berlin Heidelberg New York, pp 207-218
Destouet JM, Murphy WA (1981) Guitar player acro-osteolysis.
Effects of Mechanical Trauma on Nails Skeletal Radiol 6:275-277
Epstein WL (1990) House and garden plants. In: Jackson EM,
Goldner R (eds) Irritant contact dermatitis. Marcel Dekker,
The effects of mechanical trauma on nails is discussed New York, pp 127-165
in Chap. 31. We recently reported on two hairdressers Epstein JH, Ormsby A, Adams RM (1990) Occupational skin
cancer. In: Adams RM (ed) Occupational skin disease, 2nd
with occupational koilonychia from the combined edn. Saunders, Philadelphia, pp 136-159
effect of mechanical trauma and ammonium thioglyco- Estlander T, Jolanki R, Kanerva L (1986) Dermatitis and urticaria
late present in solutions for permanent waves (Alanko from rubber and plastic gloves. Contact Dermatitis 14:
20-25
et al. 1997). Estlander T, Jolanki R, Kanerva L (1994a) Allergic contact
dermatitis from rubber and plastic gloves. In: Mellström G,
Wahlberg JE, Maibach HI (eds) Protective gloves for occu-
pational use. CRC Press, Boca Raton, pp 221-239
Mechanical Acro-Osteolysis Estlander T, Jolanki R, Kanerva L (1994b) Protective gloves. In:
Menne T, Maibach H (eds) Hand eczema. CRC Press, Boca
Among many other etiological factors, mechanical Raton, pp 311-321
Evans EJ, Schmidt RJ (1980) Plants and plant products that
traumas may cause acro-osteolysis (Joung et al. 1977; induce contact dermatitis. Planta Medica 38:289-316
Destouet and Murphy 1981; Baran and Tosti 1993). Fischer T, Rystedt I (1983) Cobalt allergy in hard metal workers.
Fischer T, Rystedt I (1985) Hand eczema among hard-metal
workers. Am J Ind Med 8:381-394
Gloves Against Mechanical Hazards Fleming MG, Bergfelt WF (1990) The etiology of irritant contact
dermatitis. In: Jackson EM, Goldner R (eds) Irritant contact
dermatitis. Marcel Dekker, New York, pp 41-66
Gloves give good protection against minor m)uries Freeman S, Rosen RH (1996) Irritant contact dermatitis resulting
(Estlander et al. 1994b). Leather and textile gloves from repeated low-grade frictional trauma. In: van der Valk
protect against abrasions, lacerations and cuts, and P, Maibach HI (eds) The irritant contact dermatitis syn-
drome. CRC Press, Boca Raton, PP 205-210
brief exposure to heat. They also minimize the effect of Frosch PI, Kligman AM (1976) The chamber-scarification test for
impacts, and protect in welding. Leather gloves can be irritancy. Contact Dermatitis 2:314-324
reinforced by steel staples or studs to improve their cut Gellin GA (1987) Physical and mechanical causes of occupational
dermatoses. In: Maibach HI, Gellin GA (eds) Occupational
resistance. Textile gloves can be improved by rubber or and industrial dermatology. Yearbook Medical Publishers,
plastic coatings, which also increase the slip-resistance 2nd edn, Chicago, pp 88-93
of the grip. Gloves with metal mesh have been Gollhausen R, Kligman AM (1985) Effects of pressure on contact
dermatitis. Am J Ind Med 8:323-328
developed for meat cutters and slaughterers. Metal Gould WM (1991) Friction dermatitis of the thumbs caused by
mesh gloves made of welded nickel-plated brass pantyhose. Arch Dermatol127:1740
or stainless steel are used in the textile industry Grzegorczk L (1987) "Glashände" - ein neues berufsbedingtes
Syndrom. Derm Beruf Umwelt 35:62
(Estlander et al. 1994b). Gloves made of polyurethane, Guignard JC (1979) Evaluation of exposure to vibration. In:
for example, may give some protection against vibra- Cralley LV, Cralley LJ (eds) Patty's industrial hygiene and
tions, thus reducing the risk of developing Raynaud's toxicology. (Theory and rationale of industrial hygiene
practice, vol 3) Wiley Interscience, New York
phenomenon and the vibration syndrome (Guignard Hatch KL, Maibach HI (1985) Textile fiber dermatitis. Contact
1979; Taylor 1985). Dermatitis 12:1-11
Mechanical Causes of Occupational Skin Disease 161
Hayakawa R (1996) Friction melanosis. In: van der Valk P, Menne T (1983) Frictional dermatitis in post office workers.
Maibach HI (eds) The irritant contact dermatitis syndrome. Contact Dermatitis 9:172-173
CRC Press, Boca Raton, pp 213-220 Menne T (1994) Hyperkeratotic dermatitis of the palms. In:
Hersie K, Mobacken H (1982) Hyperkeratotic dermatitis of the Menne T, Maibach HI (eds) Hand eczema. CRC Press, pp
palms. Br J Derrnato! 107:195-202 95-98
Hogan DJ, Lane P (1986) Dermatological disorders in agriculture. Menne T, Bachman E (1979) Permanent disability from skin
In: Occupational medicine. State of the Art Reviews 1:285-300 diseases. Dermatosen 27:37-42
Joung RS, Bry K, Ratner H (1977) Selective phalangeal tuft Menne T, Hjorth N (1985) Frictional contact dermatitis. Am J Ind
fractures in a guitar player. Br J Radiol 50:147-148 Med 8:401-402
Kanerva L (1990) Physical causes of occupational skin disease. Paulsen E, Andersen KE (1991) Irritant contact dermatitis of a
Mechanical trauma. In: Adams, RM (ed) Occupational skin gardener's hands caused by handling fur-covered plant
disease, 2nd edn. Saunders, Philadelphia, pp 41-65 ornaments. Am J Contact Dermat 2:113-116
Kanerva L (1996) Mechanical causes of occupational skin disease. Ronchese F (1948) Occupational marks and other physical signs:
In: van der Valk P, Maibach HI (eds) The irritant contact a guide to personal identification. Grune & Stratton, New
dermatitis syndrome. CRC Press, Boca Raton, pp 195-204 York, pp 1-181
Kanerva L (1999) Physical causes of occupational skin disease. In: Samitz MH (1985) Repeated mechanical trauma to the skin:
Adams RM (ed) Occupational skin disease, 3rd edn. Saun- occupational aspects. Am J Ind Med 8:265-271
ders, Philadelphia, 35-68 Stoner JG, Rasmussen JE (1983) Plant dermatitis. J Am Acad
Kanerva L, Estlander T, Jolanki R, Henriks-Eckerman M-L (1992) Dermatol 9:1-15
Contact dermatitis from telefax paper. Contact Dermatitis Storrs FJ (1994) All the things I knew were true about contact
27:12-15 dermatitis that aren't. Cutis 52:3°1-306
Kanerva L, Jolanki R, Toikkanen J, Tarvainen K, Estlander T Susten AS (1985) The chronic effects of mechanical trauma to the
(1995) Statistics on occupational dermatoses in Finland. In: skin: a review of the literature. Am J Ind Med 8:281-288
Eisner P, Maibach HI (eds) Irritant dermatitis. New clinical Taylor JS (1985) Vibration syndrome in industry: dermatological
and experimental aspects. Curr Probl Dermatol 23:28-40 viewpoint. Am J Ind Med 8:415-432
Kanerva L, Talvi A, Estlander T (1998) Occupational contact Wilkinson DS (1979) Letter to editor. Contact Dermatitis 5:118-119
psoriasis. Eur J Dermatol 8:217-218 Wilkinson DS (1985) Dermatitis from repeated trauma to the
Lammintausta K, Kalimo K, Havu VK (1982) Occurrence of skin. Am J Ind Med 8:307-317
contact allergy and hand eczema in hospital wet work. Wilkinson DS (1994) Introduction, definition and classification.
Contact Dermatitis 8:84-90 In: Menne T, Maibach H (eds) Hand eczema. CRC Press, Boca
Lovell CR (1996) Irritant plants. In: van der Valk P, Maibach HI Raton, pp 1-12
(eds) The irritant contact dermatitis syndrome. CRC Press, Williamson DM (1981) Skin hazards in mining. Br J Dermatol
Boca Raton, pp 87-94 105[Suppl 21]:41-44
Mathias CGT (1988) Post-traumatic eczema. Dermatol Clin 6:35-42 Zuehlke RL, Rapini RP, Puhl SC, Ray TL (1982) Dermatitis in loco
Meneghini CL (1985) Sensitization in traumatized skin. Am J Ind minoris resistentiae. J Am Acad Dermatol 6:1010-1013
Med 8:319-321
CHAPTER 20
Raynaud's Phenomenon ("White Fingers") in Workers

Using Hand-Held Vibrating 10015
G. Gemne
Introduction and a small excess risk of osteoarthrosis from percus-

sion to the wrist and elbow.
Terminology A disposition to feeling cold in fingers and toes,
accompanied by general pallor without topical distinc-
This chapter deals with the vascular component of the tion, is seen as a constitutional trait in many individ-
hand-arm vibration syndrome (HAVS) (Gemne and uals not exposed to any specific factor. This condition
Taylor 1983; reviews in Gemne et al. 1987; Gemne may be termed "constitutional Raynaud". In the lack
1994). It consists of the attackwise appearance of of stringent diagnostic criteria, it is often mistaken for
white-finger skin patches in response to environmental WF in vibration-exposed subjects. It is, however, not
cold and is accompanied by a secondary loss of easy for a doctor untrained in interpreting skin
sensibility caused by ischemia of the sensorineural symptoms and not a specialist in vibration-induced
structures in the affected skin area. In accordance with disorders to distinguish correctly between Raynaud's
the clinical picture, this disorder has been given the disease and VWF. The symptoms of the former are
descriptive name of "white fingers", more specifically often symmetrically distributed over both hands and
(since it occurs in persons exposed to hand-arm comprises all fingers in a strong general pallor.
vibration) "vibration-induced white fingers" (VWF). The first observations of vibration-induced disor-
The symptoms are caused by a strong net constriction ders were made by Loriga (1911) in Italian marble-
of the blood vessels in the hand and fingers, a quarry workers, and later by Cottingham (1917),
"vasospasm" of sorts, resulting from an unbalance Hamilton (1918) and Leake (1918) in sandstone cutters
between the constrictor and dilator mechanisms which in Indiana. Modern research can be said to have begun
are at play in the typical trigger situation (that of in the 1970S, and there is now an extensive bibliogra-
environmental cold). Vasospasm was also what Mau- phy of works related to research on vibration.
rice Raynaud considered to be the pathophysiological
mechanism in a small group of patients with finger
blanching, even gangrene (Raynaud 1862), a clinical Vibration-Induced White Fingers
entity later called "Raynaud's disease". In a review of
skin manifestations, Blunt and Porter (1981) suggested Symptomatology
"Raynaud's syndrome" to encompass all color changes
in the finger skin due to vasospasm. VWF, then, is a The typical symptom of VWF is the appearance of a
particular variant of that syndrome. In the literature local patch of finger skin blanching, weIl demarcated
dealing with disorders caused by hand-arm vibration, from surrounding skin. It results from an abnormally
however, "Raynaud's phenomenon" has instead been strong contraction of the smooth muscle cells in the
widely used to denote the WF skin patches. A change walls of the finger skin blood vessels, often called
of this usage seems uncalled for here, and therefore "vasospasm". This contraction stops the blood fiow,
"vibration-induced Raynaud's phenomenon" is em- and the normal skin hue disappears.
ployed interchangeably with VWF. A generally accepted feature of the symptomatology
It should be emphasized that VWF is not synony- (Gemne et al. 1987) is that the blanching appears due
mous with the HA VS, which is incorrectly stated now to attacks triggered by environmental cold. It is elicited
and then. The HA VS consists also of diffusely distrib- most easily if the cold is unpleasant, as when the whole
uted finger neuropathy caused, presumably, by direct body is cooled. The reason for the particularly strong
mechanical infiuence of vibration on peripheral recep- effect of unpleasant general body cooling is that this
tors and nerve endings, pain in the hand-arm system stimulus works as a stressor, with the physiological
caused by excess load of musculo-skeletal structures, effect of peripheral vasoconstriction, especially in the

Raynaud's Phenomenon in Workers Using Hand-Held Vibrating Tools 163
skin. The concomitant reduction of sensibility in the labre 1. The Stockholm scale for the classification of cold-
blanched area is commonly called numbness and is induced Raynaud's phenomenon in the hand-arm vibration
syndrome (from Gemne et al. 1987). The staging is done
caused by the fact that the touch receptors cannot separately for each hand. In the evaluation of the subject, the
function without blood supply. Often, the attack stops grade ofthe disorder is indicated by the stages of both hands and
the number of affected fingers on each hand; examples: "2L(2)/
only when the whole body is warmed again. In contrast lR(l)", "-/3R(4)". The first notation means that two fingers on
with the most common feature of Raynaud's disease - the left hand show Raynaud's phenomenon in stage 2, and the
the symmetrical distribution of blanching on both injury involves one finger on the right hand with severity "mild",
hands and all fingers - the patchwise blanching in Le., stage 1
VWF is seen in those finger parts that have been most Stage Grade Description
strongly exposed to vibration. The blanching does not
usually involve the thumbs, and workers seldom 0 No attacks
complain of WF attacks during ongoing work with 1 Mild Occasional attacks affecting only
the tips of one or more fingers
the vibrating tool. 2 Moderate Occasional attacks affecting distal
The symptoms usually disappear when the hand and and middle (rarely also proximal)
arm or, preferably, the whole body is warmed. The phalanges of one or more fingers
3 Severe Frequent attacks affecting all
vasospasm is succeeded by a short period of reddened phalanges of most fingers
skin, evidence of reactive hyperemia elicited by the net 4 Very severe
vasodilatory action of metabolites and other substanc-
es that have accumulated in the vasculature during the
attack. Case reports of other skin color changes have regress partly or completely. If there is only a partial
been published from time to time, but their relation- regress, it is likely that the end state is the premorbid
ship to vibration exposure is most often unsubstanti- condition (Gemne and Nilsson 1995).
ated.
Epidemiology
Diagnostics
Epidemiological data on the quantitative association
The diagnostics of HA VS involve a number of between vibration and excessive risks of WF are
difficulties. For a review covering the aspects that will incomplete (Gemne et al. 1993; Gemne 1994). Preva-
be discussed here, the reader is referred to the lence studies, mostly cross-sectional and therefore
proceedings of the recent Stockholm Workshop often liable to serious bias, have suggested a quanti-
(Gemne et al. 1995), notably those working-group tative relationship between WF symptoms and the
reports that deal with the specific diagnostics of vascular exposure dose. The observed prevalences, however,
disturbances. The question of diagnostics has also been also vary with the type of tool and the work processes
dealt with in other reviews (Gemne 1992, 1994, 1997). in which they were used. The prevalence of WF among
The symptomatic diagnosis of WF is still mainly Finnish lumberjacks (Koskimies et al. 1992) decreased
based on anamnestic information. Available laboratory during the period 1972-1990 from 40% to 5%, which is
tests are incapable of grading the severity of individual the approximate level of primary Raynaud prevalence
cases (Olsen et al. 1995). Recording the finger systolic in the general male population. The decrease was
blood press ure during cold provocation is the best ascribed to a reduction in weight and vibration
method available for a symptomatic diagnosis. acceleration of the chain saws. It seems likely, however,
The grading of the severity of WF symptoms in that other measures in the working environment, such
workers using hand-held vibrating tools was originally as reduced exposure to cold and noise, as well as
made according to the so-called Taylor-Pelmear scale exposure to physical and psychological stress factors,
(Taylor et al. 1975). The current internationally used have also contributed. In other occupations, there are
Stockholm scale resulted from arevision which still higher prevalences but, in general, the incidence of
accounts for observations of prevalence in relation to new cases is low, and the knowledge of the hazards is
various exposure factors (Gemne et al. 1987) (Table 1). more widely spread than before.
This scale has been reported to suffer from classi-
ficatory shortcomings; Palmer and Coggon (1997) Risk Prediction
concluded that it does not encompass the full range
of disease and that its grading is highly sensitive to Efforts toward international standardization have led
different interpretations of "frequent attacks". Upon to a document (ISO 5349 1986) containing guidelines
cessation of exposure, the VWF pro gnosis is good for for the proper measurement of hand-arm vibration
most patients, at least in stages 1-3; in due time - if exposure. In an informative addendum, which is not
there are no environmental factors other than vibra- part of the standard, a model is proposed for the
tion that may trigger the attacks - the symptoms will recognition of the risk of developing WF. Based on a
164 G. Gemne
relationship between two variables - the latency
lrl
BLOOD
ENDOTHELIUM SMOOTH MUSCLE
VESSEL
between the onset of symptoms and the beginning of ,---
~
vibration exposure, and the mean acceleration level of

I,
. .oo~ ...
ACh
[ (meta-
the characteristie tool used, the model has serious chollne) EDRF z
(nltrlc oxide) 0 Z
deficiencies, unfortunately (Gemne and Lundstrom guanylat. ;:: 0
1996). Predicting the risk of acquiring VWF must be jt............. eyel •••
:::;
j:
U
based on separate models for vascular and neurolog- NO ~~ ce
a:
...~~ '.."
ieal disorders and for work with different tools and (.odlum
:E I-
Z
;;
processes. A promising attempt has been made for that
nltro-
pru •• lde) HPROSTA-/.
CYCLIN
adenylat.
eyell.e
u
.... 0
U
purpose in a study of WF in forestry workers using
chain saws with or without vibration damping '- '---
(Bovenzi et al. 1995). ... = 'oclliloling ~= Inhlblling
Fig. 1. Endothelial vasodilator mechanisms (from Gemne 1992)

Pathophysiology
An abnormal, general elevation of sympathetie activity EDRF, while nitroprusside also has direct access to the
(termed either hyperactivity, hyper-reactivity or over- smooth muscle.
reactivity) as the major cause of Raynaud's phenom- The idea of a localized lesion instead of an oblig-
enon in vibration-exposed workers has been advocated atory digital artery spasm also appears to be supported
by Olsen (1990). In arecent paper, however, the same by the fact that typieal VWF occurs in well-demarcated
author (Olsen 1991) sees this as only one of several patches of the finger skin that may not always extend
possible mechanisms leading to vibration-induced over the whole width of the finger. A white patch may
Raynaud's phenomenon. The active mechanism of even be localized proximal to an unaffected skin area,
digital artery closure mediated by central sympathetic which seems to require vasospasm in smaller vessels
reflexes is seen as predominant, but other active and than the digital artery.
passive mechanisms - such as abnormal adrenergic
receptor activity of the smooth muscle cell or hyper- Etiopathologic Relationship to Cold and Smoking
trophy of vascular smooth muscle cells - are also
envisaged as possible etiologic factors. An imbalance It is natural to look for pathogenic clues in the fact that
between the parasympathetic and sympathetic parts of cold is the typieal trigger for Raynaud's phenomenon,
the autonomie nervous system has been suggested to especially since peripheral vasoregulation is inherendy
contribute to the development of VWF (Heinonen sensitive to cold. Thus, cold influences neuronal
et al. 1987; Bovenzi 1990; Färkkilä et al. 1990). activity, receptor mechanisms, smooth muscle con-
However, for a number of reasons, a "local fault" tractile elements, platelets, endothelial mechanisms,
(Lewis 1930) seems to be the decisive factor for the and rheologieal factors. Cold initiates a whole series of
development of WF in workers exposed to hand-arm events that influence the net reactivity of the system. In
vibration. This local deficiency may be caused by a the absence of epidemiological studies with successful
lesion to anatomical structures in the blood vessel control of these events, the question of cold as a
walls that are responsible for vasoregulatory mecha- pathogenic factor cannot be answered. It is suggested,
nisms. Damage to ()(-adrenoceptors has been suggested of course, that WF is not reported to occur in countries
by Ekenvall et al. (1988) and Lindblad and Ekenvall with a warm climate, but this may simply be explained
(1990). The results of experiments (Gemne et al. 1992) by the absence of cold stimuli to trigger symptoms of a
with iontophoresis of sodium nitroprusside and meta- latent, subclinical dis order.
choline into the finger skin of chain sawyers, and laser- Many persons experience cold habituaIly, with a
Doppler recording of blood flow suggest another concomitant diffuse pallor in their fingers and often
pathophysiological explanation - that vibration expo- their toes as weIl. The role of such a constitutional
sure may damage endothelial vasoregulatory mecha- disposition has not been epidemiologieally clarified,
nisms by disturbing the endothelial-derived relaxing but it is physiologically reasonable that persons with
factor (EDRF)-mediated vasodilatory function. A this trait (indicating a high sympathetic activity) are
weaker vasodilatory reaction to metacholine, but not more susceptible to harmful influence from various
to nitroprusside, was observed in the combined group vasoconstrictor stimuli. Since the exposure to different
of subjects with current and past WF than in those vasoconstrictors varies widely, this explanation would
subjects who had never experienced the syndrome. also account for the great variation always observed in
This agrees with the physiological premises illustrated the prevalence of WF within different occupational
in Fig. 1; metacholine induces relaxation only through groups as weIl as within one and the same group.
Raynaud's Phenomenon in Workers Using Hand-Held Vibrating Tools 165
The use of tobacco and snuff is another factor that Ekenvall L, Lindblad LE, Norbeck 0, Etzell B (1988) Alpha-
adrenoceptors and cold-induced vasoconstrietion in human
has been suspected to contribute to the development finger skin. Am J Physiol 255:Hl000-H1003
of VWF because it is known that nicotine, like cold, Falkenbach A, Watanabe I, Hartmann B, Agishi Y (1997)
has a constrictive effect on blood vessels. The habitual Raynaud's phenomenon in vibration syndrome: the impact
of cold feet on skin temperature and vasomotion of the hand
use of tobacco and snuff has also been shown to after immersion in cold water. Angiology 48:1037-1044
aggravate WF symptoms (Ekenvall and Lindblad Färkkilä M, Pyykkö I, Heinonen E (1990) Vibration stress and
1989). Many studies have demonstrated a high er the autonomie nervous system. Kurume Med J 37[SUppl):
VWF prevalence in smokers than in non-smokers, 53-60
Gemne G (1992) Pathophysiology and pathogenesis of dis orders
yet others have failed to do so (this is not surprising; in workers using hand-held vibrating tools. In: Pelmear P,
past smoking cannot be accurately quantified because Taylor W, Wassermann D (eds) Hand-arm vibration. A
comprehensive guide for occupational health professionals,
of, for instance, recall bias). There is also difficulty chapter 4. Van Nostrand Reinhold, New York, pp 41-76
with the estimation of exposure dose, which depends Gemne G (1994) Where is the research frontier for hand-arm
greatly on inhalation habits and the nicotine content vibration? Scand J Work Environ Health 20[special issue):
of tobacco. Thus, it remains an open question whether 90-99
Gemne G (1997) Diagnostics of hand-arm system disorders in
these results reffect only a higher rate of triggering workers who use vibrating tools. Occup Environ Med 54:
of WF in smokers or a contribution of nicotine to 90-95
Gemne G, Lundström R (1996) Evaluation of the white finger risk
the pathogenesis of the disorder, perhaps in synergy predietion model in ISO 5349 suggests need for prospective
with cold. studies. Central Eur J Occup Health 3:122-124
Gemne G, Nilsson T (1995) Note to discussion on diagnostics of
white fingers. In: Gemne G, Brammer Al, Hagberg M,
Treatment Lundström R, Nilsson T (eds) Hand-arm vibration syn-
drome: diagnostics and quantitative relationships to expo-
Since VWF is generally believed to regress (at least sure. Proc Stockholm Workshop 94, NIOH, Solna. Arbete och
from less advanced stages) some time after the Hälsa 5:184-185
Gemne G, Taylor W (eds) (1983) Hand-arm vibration and the
discontinuation of exposure, most cases require no central autonomie nervous system. Proc Int Symp London.
special therapy. The application of nitroglycerin oint- J Low Freq Noise l[special issue):u
Gemne G, Pyykkö I, Taylor W, Pelmear P (1987) The Stockholm
ment to the skin is effective in many cases, but this Workshop scale for the classification of cold-induced Ray-
method has not found widespread use because of the naud's phenomenon in the hand-arm vibration syndrome
relapse when the treatment is discontinued. Some (revision ofthe Taylor-Pelmear scale). Scand J Work Environ
substances inffuencing the neurovascular mechanisms Health 13:275-278
Gemne G, Pyykkö I, Inaba R (1992) Finger blood flow reaction to
responsible for the excess vasoconstriction or facili- iontophoresis of metacholine and nitroprussid in chain-
tating vasodilatation have also been tried in persons sawyers with and without white fingers (abstract). Sixth
International Conference on Hand-Arm Vibration, Bonn,
with VWF, but this treatment has been largely aban- Germany, p 23
doned because of unwanted side effects. In a study of Gemne G, Lundström R, Hansson J-E (1993) Disorders induced
former forestry workers who suffered VWF, Falken- by work with hand-held vibrating tools. A review of current
knowledge for criteria documentation. Arbete och Hälsa
bach et al. (1997) found that warming the hand again 6, p 83
after cooling was faster when the feet were immersed in Hamilton A (1918) A study of spastic anemia in the hands of stone
cold water rather than when the feet were immersed in cutters. (Bull 236, Industrial accidents and hygiene, series 19)
Bureau of Labor Statistics, V.S. Department of Labor,
warm water. It was therefore suggested that a delib-
Washington, pp 53-123
erate training of the systemic counterreaction may Heinonen E, Färkkilä M, Forsstrom J, Antila K, Jalonen J,
prove beneficial for patients with vibration-induced Korhonen 0, Pyykkö I (1987) Autonomie neuropathy and
vibration exposure in forestry workers. Br J Ind Med 44:
Raynaud's phenomenon. 412-416
ISO 5349 (1986) Mechanical vibration - guidelines for the
measurement and the assessment of human exposure to
hand-transmitted vibration. International Organization for
Standardization
References Koskimies K, Pyykkö I, Starck J, Inaba R (1992) Vibration
syndrome among Finnish forest workers between 1972 and
Blunt RJ, Porter JM (1981) Raynaud syndrome. Semin Arthritis 1990. Int Arch Occup Environ Health 64:251-256
Rheum 10(4):282-308 Leake JP (1918) Health hazards from the use of the air hammer in
Bovenzi M (1990) Autonomie stimulation and cardiovascular cutting Indiana limestone. Public Health Rep 3:379-393
reflex activity in the hand-arm vibration syndrome. Kurume Lewis T (1930) Observations upon the reactions of the vessels of
Med J 37[Suppl):85-94 the human skin to cold. Heart 15:177-208
Bovenzi M, Franzinelli A, Mancini R, Cannava MG, Maiorano M, Lindblad LE, Ekenvall L (1990) Alpha2-adrenoceptor inhibition
Ceccarelli F (1995) Dose-response relation for vascular in patients with vibration white fingers. Kurume Med J
disorders induced by vibration in the fingers of forestry 37[SUppl):95-99
workers. Occup Environ Med 52:722-730 Loriga G (19U) Illavoro con i martelli pneumatici. Boll Ispett Lav
Cottingham CC (1917) Report on the health situation of stone 2:35-60
cutters in Indiana. Stone Cutters' J 32:5-6 Olsen N (1988) Vibration-induced white finger. Physiological and
Ekenvall L, Lindblad LE (1989) Effect of tobacco use on vibration clinical aspects (thesis). Copenhagen, Laegeforeningens
white finger disease. J Occup Med 30:13-16 Forlag
166 G. Gemne: Raynaud's Phenomenon in Workers Using Hand-Held Vibrating Tools
Olsen N (1990) Hyperreaetivity of the eentral sympathetie Palmer KT, Coggon DN (1997) Deficiencies of the Stoekholm
nervous system in vibration indueed white finger. Kurume vascular grading seale for hand-arm vibration. Seand J Work
Med J 37[Suppl):109-116 Environ Health 23:435-439
Olsen N, et al. (1995) Clinical and laboratory diagnostics of Raynaud M (1862) L'asphyxie loeale et de gangrene symetrique
vaseular symptoms indueed by hand-arm vibration. Report des extremites. Ringoux, Paris
from diseussions in a working group. In: Gemne G, Brammer Taylor W, Pelmear P, Pearson J (1975) Vibration-indueed
AJ, Hagberg M, Lundström R, Nilsson T (eds) Hand-arm white finger epidemiology. In: Taylor W, Pelmear P (eds)
vibration syndrome: diagnosties and quantitative relation- Vibration white finger in industry. Aeademic Press, London,
ships to exposure. Proe Stoekholm Workshop 94, NIOH, pp 1-13
Solna. Arbete oeh Hälsa 5:181-186
CHAPTER 21
Physical and Cholinergic Urticaria

B.M. Henz
General Aspects antigen in the epidermis (Czarnetzki et al. 1986), and is

therefore c1assified as contact urticaria.
Definition and Classification
Physical urticaria is defined as localized or generalized Epidemiology and Occupational Aspects

urticaria or angioedema of the skin or the mucous
membranes in response to different specific physical Up to 50% of all types of chronic urticaria are due to
stimuli. In cholinergic urticaria, a reflex-type, pin- physical urticaria, with dermographie urticaria being
point size whealing re action or angioedema arises in most frequent, followed by cholinergic, delayed pres-
response to a rise in body core temperature. Reasons sure, cold and solar urticaria (Table 2). Heat contact
for the over-reaction of the skin to normally tolerated urticaria and vibratory angioedema are very rare. In
stimuli remain unexplained. In most cases, an associ- cold regions, cold urticaria becomes manifest at a
ated mast-cell degranulation has been identified, in higher frequency. Generally, young adults are more
some an underlying immunoglobulin (Ig)E-dependent frequently affected. The disease begins mostly without
sensitization and, in rare cases, a genetic predisposi- obvious reason, persists over many years (Table 2),
tion to the disease itself or to associated diseases, and disappears again spontaneously. It persists how-
inc1uding atopy. ever in the rare familial types of physical urticaria
Physieal urticaria is c1assified according to the (dermographie, delayed cold or heat and solar urti-
nature of the eliciting stimulus, i.e., mechanieal, caria, and familial vibratory angioedema) which are
thermal or e1ectromagnetic (Table 1). Rarely, urticaria mostly based on an autosomal dominant inheritance.
has also been reported in association with decompres- Physical urticarias are not known to be induced by
sion and with X-ray and argon laser treatment specific occupations, but they may become manifest in
(reviewed in Henz et al. 1997). Cholinergic urticaria this setting. This holds particularly for professions
is often c1assified as physical urticaria since an increase requiring heavy mechanical work. Increased physical
in body heat is involved. Aquagenic urticaria is elicited and sportive activities may also explain the higher
by a chemical rather than a physical stimulus to the frequency of manifest cholinergie and delayed press ure
skin surface, with the water dissolving a water-soluble urticaria in men (Table 1). Severely affected persons
Table 1. Classifieation, clinical and diagnostic aspeets of physical urticaria
Elieiting stimulus Type of urticaria Time of onset Duration (h) Diagnostic test
Meehanical
Sheering forees Dermographie urtiearia 2-5 min 1-3 Firm stroking with a
dermographometer
Sheering forees Delayed urtiearial 0.5-8 h 1-8 Same as above
dermographism
Statie pressure Delayed pressure urticaria 0.5-10 h 8-48 Loeally applied weights
Vibration Vibratory angioedema 0.5-1 min 1 Vibrating motor (vortex)
Thermie
Cold eontaet Cold urtiearia 2-5 min 1-3 Cold objeets (iee), fluid (bath),
wind or air
Heat eontaet Heat urtiearia 2-15 min 0.5-1 Warm bath
Physical exercise, stress Cholinergie urticaria 2-20 min 0.5-1 Exercise until sweating
Eleetromagnetic waves
UV-light Solar urtiearia 2-15 min 0.25-3 Tests with UV-light of different
wavelengths

168 B.M. Henz
Table 2. Epidemiologie data on physieal urtiearia and occupational activities potentia1ly affected
Urticaria* Mean age** Mean disease M/F Occupational activities affected

at start duration**
of disease
Dermographie urtiearia 25 6.5 004/1.0 Heavy manual work

Cholinergie urticaria 25 5.3 1.4/1.0 Professions ass. with sports, physical exertion
Press ure urtiearia 34 6.0 1.7/1.0 Heavy manual work
Cold urticaria 18 4.2 0.5/1.0 Outdoor work in the cold, freezing industry
Solar urticaria 28 7.1 0.9/1.0 Daytime outdoor work
Heat urtiearia 37 1.0 0.2/1.0 Work in hot environment
Vibratory angioedema nk nk nk Work on vibrating machines
M, males; F, females; nk, not known

* Listed in descending order of frequency
** In years
may be hampered in their professional activities or generalize and involve the entire body surface. In the
may be forced to modify their activities or conditions reflex types of the disease, wheals are generally only of
of work. Since most physical urticarias can be pinpoint size (Fig. 2), and they arise at sites distant
adequately treated and tend to remit spontaneously from the contact or are elicited from within the body as
(Table 2), a change of occupation is generally not in cholinergic urticaria. The tiny wheals may however
necessary. Delayed press ure urticaria is an exception become confluent.
because of its refractoriness to most therapies other In cholinergic and cold urticaria, whealing can occur
than corticosteroids. in association with angioedema, or angioedema may be
the only manifestation, as is always the case in
vibratory angioedema. In delayed pressure urticaria,
(linical Manifestations wheals always reach into the deeper dermis and thus
resemble angioedema.
Most types of physical urticaria share three common All patients with physical urticaria note itching at
characteristics: they can be repeatedly elicited by the site of whealing, although some experience stinging
specific stimuli, the symptoms usually develop rapidly, or burning instead. Deep swellings, particularly in
and the lesions also disappear in a short time, with the areas where the skin cannot expand, such as at the
skin again assuming anormal appearance. Exceptions hands and over joints, tend to be painful. In few
to these rules are the delayed types of physical urticaria
(Table 2).
Fig. 1. Lesions of dermographie urtiearia, with redness and
Lesions provoked by physical contact are restricted itching appearing 1 min after application of linear pressure with
to the area of elicitation (Fig. 1), but they can also a dermographometer (picture from Henz et al. (1997))
Physical and Cholinergic Urticaria 169
Fig. 2. Typical appearance of cholinergic urticaria, with tiny, it eoexists with aeute or chronie urticaria sinee the
itching wheals on the upper arm, 5 min after physical exercise symptomatology of the latter is generally more
(picture from Henz et al. (1997))
impressive.
patients, stimuli normally eliciting physical urticaria Therapeutic Principles

only cause itching, without recognizable skin changes
or only erythema and no whealing. As with other types of urtiearia, effeetive treatment of
While the majority of wheals in physical urticaria physieal urtiearia requires an exaet diagnosis. Under-
develop rapidly and are of short duration, reactions lying diseases must be treated in seeondary types of
can also appear with a delay of 2 h or even 4-8 h after physieal urticaria eaused by other diseases. Further-
stimulation. The most frequent representative of this more, the patient must be instrueted to avoid the
group is delayed pressure urticaria, with lesions elieiting stimuli. This is partieularly important when
persisting for up to 3 days. symptoms are intense or even life threatening.
Depending on the intensity and the extent of Since the majority of symptoms is due to histamine
stimulation, massive release of histamine and other release, antihistamines almost invariably afford relief
mast-cell mediators can cause systemic symptoms from itehing and suppress whealing. In ease of non-
that range from headaches to anaphylactic shock. responsiveness, other anti-inflammatory agents ean be
Involvement of other organs such as the lung tried. Corticosteroids should be avoided because of the
(shortness of breath) or the intestinal tract (nausea, ehronieity of the disease. In most types of physieal
epigastric pain, diarrhea) are also often observed, at urticaria, a refractory period is observed which can be
times also malaise, fever, leukocytosis and used to induce temporary tolerance.
arthralgias.
Diagnostic Principles Dermographie Urtiearia
The diagnosis of physical urticaria is rarely missed General and Occupational Aspects
because (1) the patient hirns elf generally recognizes the
e1iciting stimulus, and (2) the special shape and Dermographie urticaria, also named faeticial urticaria,
distribution of whealing allow for a correct diagnosis is a whealing reaetion that follows the lines of stroking
on inspection or by patient his tory in the contact types on the skin with moderate press ure (Breathnach et al.
of physical urticaria. The diagnosis can be confirmed 1983; Wong et al. 1984). Dermographic urticaria is the
by elicitation of the wheals, imitating the provoking most frequent type of physical urtiearia (Table 2). It is
stimuli in ordinary or professionallife. observed in all age groups, with a peak incidenee in
The methodology of testing for physical urticaria young adults and an overall incidenee of 1.5-5%. It
is outlined in Table 1 and deseribed below in more must be differentiated from urticarial dermographism,
detail for each special type of physical urticaria. The whieh lacks associated subjeetive symptoms and has a
presence of physical urticaria is easily missed when widely varying ineidenee (between 1.5-50.0%), depend-
170 B.M. Henz
labre 3. Different types of urtiear-

ial dermographism dependent on Lateney (min) Duration (min) Itehing
lateney until appearanee, duration
of the wheal and associated symp- Dermographie urtiearia 1-5 20-30 +++
toms Urtiearial dermographism 2-10 10-30
Delayed dermographie 30-240 720-2880 +1-
urtiearia/urtiearial dermographism
Cholinergie dermographie urtiearia/eholinergie 5-10 20-30 +1-
urtiearial dermographism
ing on the intensity of the eliciting pressure (Henz elicitation; delayed urticarial dermographism: same
et al. 1996). Delayed urticarial dermographism and but without symptoms
cholinergic urticarial dermographism are, in contrast, 4. Cholinergic dermographic urticaria: appearance of
very rare (Henz et al. 1997). localized erythema and multiple pin-point size
Despite its high frequency, the disease rarely repre- wheals and itching, within 5-10 min after stroking
sents an occupational problem since the symptoma- 5. Cholinergic urticarial dermographism: same but no
tology is mostly mild or can be readily treated (see symptoms
below).
Delayed urticarial dermographism can be associated
with ordinary urticarial dermographism, in which
Clinical Aspects
case the rapidly developing wheals disappear after
20-30 min, to reappear after 1-2 h at the same sites,
Patients with dermographic urticaria suffer primarily
with deeper swellings that pers ist over many ho urs.
from the intermittent, generalized pruritus and the
The initial reaction can, however, also present only as
chronic recurring whealing reactions, particularly at
an erythema, with the whealing reaction occurring only
sites of shearing forces on the skin, e.g. in the belt
1-4 hiater. These delayed reactions are easily missed
region and the groin, due to tightly fitting and rubbing
unless specifically looked for.
garments, such as belts. Linear wheals also develop
Dermographic urticaria and urticarial dermogra-
after scratching of the skin. Skin prick tests for type-I
phis m as well as delayed urticarial dermographism
allergies can be falsely positive.
must be differentiated from delayed pressure urticaria,
In some patients with dermographic urticaria,
which is elicited by resting rather than sheering forces.
penicillin and other drugs apparently initiate the
symptomatology, wh ich generally persists for many
Therapy
months after cessation of treatment. Furthermore, the
disease frequently occurs in association with parasito-
Simple urticarial dermographism generally requires no
sis, chronic, cholinergic, pressure and aquagenic
treatment, but associated diseases must be treated.
urticaria, during pregnancy and at sites of previous
Patients must be instructed to avoid eliciting stimuli,
contact dermatitis or insect stings as weIl as in tattoos.
such as tight clothes, certain drugs (penicillin, aspirin,
lidocaine, famotidine), rigorous showering or any
Diagnosis and Differential Diagnosis
stimulus that elicits or activates itching, including
stress (Schafer 1995).
There are no specific laboratory tests for dermographie
Non-sedating antiliistamines generally suffice to
urticaria. The diagnosis is made simply by applying
control the symptoms (Cap et al. 1985). At night, higher
sheering forces over the upper back, e.g. via firm linear
than usual doses of these drugs or the potent sedating
stroking with a tongue depressor, the closed end of a
H,-blocker hydroxyzine may be used in patients with
ballpoint pen, or a dermographometer (Table 2; Henz
severe pruritus (Breathnach et al. 1983). In co-operative
et al. 1997). The diagnosis is made depending on the
patients, a low-pseudoallergen diet (Henz et al. 1997)
type of re action:
can be tried for about 4-6 weeks since it occasionally
1. Dermographic urticaria: localized erythema and induces remissions (own unpublished results).
whealing extending over the area of stroking, within
seconds to minutes, with associated itching (Fig. 1)
2. Urticarial dermographism: localized erythema and Delayed Pressure Urticaria
whealing not extending over the area of stroking,
within 5-10 min, without associated itching General and Occupational Aspects
3. Delayed dermographic urticaria: development of
deep, linear, persisting whealing with mild or no Patients with this type of physical urticaria develop
erythema and burning or pain, within 1-4 h after deep wheals in skin regions exposed to high press ure,
e.g., palms and soles, the buttocks, the upper back and attention must be paid to the distribution of the
rarely also the face, after a latency period of 4-8 h lesions, their time of appearance, and the shape of the
(range 0.5-10 h). Leisons persist for 30 ± 8 h (range 8- wheals. Frequently associated other types of urticaria
48 h) (Table 1). In recent years, the existence of with a different time course and distribution of the
immediate press ure urticaria has also been considered wheals must be considered.
(wheals appearing within 5-10 min after elicitation). The typical deep whealing at the sites of predilection
The frequency of pressure urticaria among patients supports the diagnosis, but requires confirrnation by
with chronic urticaria ranges from 2-35%, depending reproduction of the lesions, preferably with a specially
on the method of evaluation (Barlow et al. 1993). Males designed press ure apparatus (Blig and Kunick 1969;
(65-80%) and persons of young to medium age are Henz et al. 1997). A simple alternative method consists
preferentially affected (Table 2). Pressure urticaria of applying weights from 3 kg to 10 kg with a broad
becomes particularly evident in patients employed in belt over the shoulder or the upper thigh, with the
jobs requiring heavy physical work, and 11% of patient in a sitting position and perhaps even a glass
patients are severely disabled during their daily sphere (marble) placed below the weighted cuff to
physical activities (Sussman et al. 1982; Czarnetzki increase and localize the press ure stimulus (Warin
et al. 1984b; Dover et al. 1988). Even the change from a 1987). The weights should remain in place for 10-
heavy manual to a secretarial position may be a 30 min, and possible changes of the skin at the site of
problem because patients develop wheals on their application should be recorded immediately after
buttocks while sitting all day. In severe cases and after removal of the weights and 4, 6, 8 and, possibly also,
all therapeutic possibilities have been explored, pa- 24 h thereafter. Concomitantly, the patient's back
tients may be forced into invalidity until their disease should be scratched with a dermographometer or a
remits spontaneously. similar device in order not to overlook the coexistence
of delayed urticarial dermographism.
Clinical Aspects In case of negative test results in a patient with a
positive his tory, testing should be repeated on different
The lesions in pressure urticaria present as erythema- skin areas at 48-h intervals since patients with proven
tous, deep, warm swellings, at times with a central press ure urticaria fail to have regularly positive test
pallor. Their size fits exactly the area of application of results. In some patients, for example, press ure tests
press ure. Due to the deep swelling, one can accentuate are only positive on the shoulder, but not on the back.
the peau d'orange appearance of the lesion by squeezing Pressure urticaria often also has a fluctuating course
the wheal between thumb and index finger. Most which coincides with the activity of a simultaneously
patients experience itching before the whealing ap- existing chronic urticaria (Estes and Young 1981).
pears, but some also report pain, burning or stinging. Laboratory findings and histological examinations
When the swellings involve joints or muscles, the can add further support to the clinical diagnosis. Most
patients often experience marked pain. About 50% of of the changes are however not disease specific. Thus,
patients with press ure urticaria complain about addi- 70% of all pressure urticaria patients have a mild to
tional extracutaneous symptoms, such as shivering, moderately raised erythrocyte sedimentation rate
fever, dizziness, arthralgias, increased perspiration, (ESR), and leukocytosis occurs in 20-53%, without
nausea, headache, shortness of breath or tiredness. correlation to disease activity. Serum enzymes, Igs,
Some patients observe a correlation between the complement levels, Cl INH, (12-macroglobulin and (1,-
intensity of symptoms and physical or emotional stress. antitrypsin are normal. On histology of lesional
Various other types of urticaria have been observed biopsies, an inflammatory infiltrate consisting of
in 25-94% of patients with pressure urticaria. More than eosinophils, neutrophils, T-lymphocytes and activated
50% have an associated delayed dermographie urticaria macrophages is particularly prominent around ap-
(Dover et al. 1988). There is also a slightly increased pendages in the deep dermis and can also extend into
frequency of atopic diseases in the patient or family the subcutis. Mast cell numbers are increased, even in
his tory. The increased incidence of positive prick tests normal skin and, in contrast to other types of urticaria,
is however mostly due to false-positive reactions caused there is no expression of the cytokine migration
by associated urticarial dermographism (Czarnetzki inhibitor factor (Czarnetzki et al. 1984b, 1989; Haas
et al. 1987). An increased incidence of aspirin intoler- et al. 1998).
ance is found by some investigators (Dover et al. 1988).
Therapy
Diagnosis
Of all types of urticaria, press ure urticaria is the most
The diagnosis of pressure urticaria can be made solely difficult to treat. Classical antihistamines are ineffec-
on the basis of a good medical history. Particular tive. Observations of an improvement on high doses of
172 B.M. Henz
cetirizine (>30 mg/day), reported to be effective in occurs more often secondarily, i.e. together with
Greek patients (Kontou-Fili et al. 1991), could not be infectious, neoplastic or immunologic diseases. In
confirmed by us or others (our own unpublished these cases, abnormal body proteins altered by cold
observations and Prof. Greaves, London, personal temperatures most likely act as antigens. Familial
communication). delayed cold urticaria is very rare and is transmitted
Corticosteroids induce a reproducible improvement by autosomal dominant inheritance.
in all patients with pressure urticaria. Because of the Cold urticaria is classified on the basis of the
chronicity of the disease and the potential adverse eliciting stimuli and the type of clinical reaction
effects, this treatment is, however, justifiable only in (Table 4). Another classification is based on the
case of serious problems in daily life and at work. A severity of symptoms (Wanderer 1995), namely a
maintenance dose below the Cushing level should be localized urticaria and angioedema (type I), systemic
aimed at, with minimal adverse events. Individuallocal reactions with hypotensive symptoms (type II), and
lesions can also be reduced in size by the application of severe systemic reactions with fainting, disorientation
potent topical steroids. Dapsone, at a dose of and shock (type III). Among physical urticarias, the
50-100 mg/day, can totally control symptoms in so me frequency of cold urticaria varies between 5.2% and
patients and is worth a trial. Sulfazalazine has similarly 33.8%, with a higher incidence in cold climates.
been reported to be successful in two patients (starting Improvement or spontaneous remission is observed
dose 500 mg/day, with weekly increments to 4 g/day, in 50% of patients within 5 years (Henquet et al.
then weaning to a maintenance dose of 2 g/day) 1992; Möller et al. 1996). In patients with secondary
(Engler et al. 1995). Oral disodiumcromoglycate, da- cold urticaria, the mean age of onset is higher
nazole, colchicine, ketotifen, cimetidine, propanolol or (49 years) than in other patients (Table 1) (Wanderer
combinations of these drugs are, in contrast, ineffec- 1995).
tive, and non-steroidal antiphlogistics (indomethacin, Although the disease is diagnosed more frequently
aspirin) have only a minor effect, although they can during the cold season and in cold climates, there are
reduce the pain in already existing lesions (Schafer also reports on its occurrence in tropical regions, since
1995). changes in temperature rather than the absolute
Elimination of specific food allergens, identified by a temperature provoke the symptoms. Occasionally, cold
positive delayed skin test, caused remission in a group urticaria is diagnosed accidentally in patients suspect-
of patients managed by Davis et al. (1986). These ed to suffer from chronic urticaria. Cold urticaria has
findings could however not be reproduced in our been reported several times in the context of profes-
patient group (Czarnetzki et al. 1987), although a low- sional activities (Björkner 1981; Shaw 1988; Fitzgerald
pseudoallergen diet has been found by us to be et al. 1995). In professions where the skin cannot be
effective in one patient (unpublished observation), protected from contact with cold and where treatment
and Rajka and M0rk (1985) have reported a strict diet is not satisfactory, a change of occupation must be
to be beneficial in two of their patients. Avoidance of considered.
provocation of the lesions remains the most important
therapeutic measure but may be difficult during work. Clinical Manifestations
Reduction of the intensity of press ure is also helpful.
Patients can be told that local pressure can be reduced Lesions of cold urticaria are provoked by direct
by distribution of weights over a larger area, for contact of the skin or the mucous membranes with
example, by choosing broad belts for their bags. cold objects, cold water or ice, cold air, cold wind or
Cushioning can also reduce pressure, for example, in cold solid food and beverages. Cold temperatures
shoes. developing because of evaporation, even after sweat-
ing, can also provoke symptoms. Lesions can be either
limited exactly to the site of contact or can be
Cold Urticaria
Table 4. Classifi-
General and Occupational Aspects cation of cold ur- Localized cold contact urticaria
ticaria Immediate cold urticaria
Delayed cold urticaria
Cold urticaria is defined as urticaria or angioedema Cold-dependent dermographie urticaria
on exposure to cold. Lesions can be provoked Localized cold urticaria
Localized reflex cold urtiearia
through contact with firm cold bodies, cold fluid, Perifollieular cold urticaria
cold air via a chilling effect and, sometimes, by Familial delayed cold urtiearia
lowering of the body core temperature. In 96% of Generalized cold urticaria
Cold wind and air urticaria
patients with cold urticaria, the disease is idiopathic. Cholinergie cold urticaria
Compared with other forms of physical urticaria, it
generalized, and they often appear with a delay of a few including dysregulation of body temperature, changed
minutes after cold exposure on re-warming. eating habits, anxiety and depression.
The initial changes on the skin present as redness, Cold urticaria can be idiopathic or the primary
followed by a rapidly developing whealing reaction, manifestation of numerous associated diseases, in-
with surrounding erythema and associated mild to cluding allergic, infectious, auto immune and malig-
moderate itching. During bathing in cold water or after nant diseases, as weIl as complement defects and
leaving the water, extensive diffuse erythema and primary cryoglobulinemia (Henz et al. 1997). Abnor-
edema, also with confluent lesions, can develop over mal serum proteins probably play a pathogenetic
large areas of the body. Often, the large edematous role in all cases.
areas are studded with small wheals, as frequently also Secondary cold urticaria may be triggered or main-
observed in heat urticaria. In severe cases, the oral tained during viral or bacterial infections. This is
mucous membran es and the tongue can be involved as supported by observations that 20-50% of patients
well. With reactions to cold air, lesions appear mostly with idiopathic cold urticaria respond to antibiotics
at the time of shivering. In general, lesions develop (Möller et al. 1996) and that significantly increased
more rapidly the lower the eliciting temperature, and antibody titers and a number of viral infections
they disappear slowly within 30 min to 1 h, maximally (measles, varicella, hepatitis, infectious mononucleo-
after 3 h (Table 1). In about 80% of patients, residual sis, HIV -infections) have been observed in patients
mild purpura can be observed at sites of most intense with cold urticaria (Doeglas 1975; Tyson and Czarny
involvement. This purpura can at times be severe and 1981; Lemanske and Bush 1982; Lin and Schwartz 1993).
extensive, with subsequent ulceration. Angioedemas Non-infectious pathomechanisms may also be in-
are observed in 73% of patients in association with volved, since cold urticaria has been observed after
whealing. insect stings or exposure to other animal venoms, in
Lesions of delayed cold urticaria (Table 4) appear association with food allergies, exercise-induced
after a latency of 3 h to maximally 24 h after cold asthma or other types of urticaria (Hertl and Merk
exposure and can persist over many hours. In cold 1994), and after treatment with drugs such as
induced dermographic urticaria, small wheals appear griseofulvin, oral contraceptives and penicillin (Wan-
in skin exposed to the cold only after additional derer 1995). An association with atopy is reported to be
mechanical irritation such as scratching or rubbing. occur in up to 46% of patients (Möller et al. 1995).
Localized cold urticaria can only be elicited in certain Cryoglobulins can be demonstrated in 20% of
skin areas. In cold reflex urticaria, small transient, but patients with cold urticaria, although the incidence of
also larger wheals develop only in the vicinity of the cold urticaria in cryoglobulinemia is very low (Houser
area of contact. Follicular cold urticaria is arare, et al. 1970). Cold urticaria can precede the diagnosis of
recently described subtype of cold urticaria, with cryoglobulinemia or myeloma by many years, and the
wheals appearing at sites of cold contact in a perifol- disease can disappear after reduction of cryoglobulin
licular distribution. In autosomal-dominant delayed levels during chemotherapy. Cutaneous manifestations
familial cold urticaria, deep red swellings appear only are observed only when titers rise above 500 mg/dl.
after 9-18 h at sites of contact, without previous early
reactions. Diagnosis
After local elicitation of cold urticaria, wheals and
swellings can also spread over the entire skin, whereas When cold urticaria is suspected by history, the
in patients who react only to cold air when sitting in diagnosis should be confirmed in two steps: (1)
cold rooms, or to cold wind, lesions are generalized. confirmatory provocation tests and (2) clinical and
Similarly, in cholinergic cold urticaria, wheals and laboratory examinations to rule out secondary cold
swellings extend over the entire body. Cholinergic cold urticaria. In the office, spraying of the skin with ethyl
urticaria develops after physical strain in the cold and chloride can be employed as a screening test. More
is characterized by small, transient wheals. reliable and specific is the ice-cube test. Pieces of ice
In all types of cold urticaria, very sensitive patients suspended in cold water are placed into a container
can develop systemic reactions even on mild to and left on the lower arm for 3-5 min, in milder cases
moderate exposure to cold temperatures. This holds even for up to 10 min or even 20 min. In 76% of
also for less sensitive patients on extensive exposure. patients, reactions occur after 10 min and in 100%
Symptoms include headaches, chills, dizziness, tachy- after 20 min (Neittanmäki 1985). The test is positive
cardia, abdominal pain, nausea, vomiting, diarrhea, when a wheal or angioedema develop on re-warming of
peptic ulcers, muscle pain, shortness of breath and the skin.
unconsciousness. Even on moderate exposure to cold, For exact quantification during clinical studies, the
increases in gastric acid have been measured. Central cold stimulation time can be measured (Henz et al.
nervous system (CNS) disturbances are also possible, 1997). In non-responsive patients, a cold water, cold air
174 B.M. Henz
or cold wind test should be performed, depending on responses have also been observed with the newer non-
the history (Henz et al. 1997). The following laboratory sedating H,-antihistamines (Villas-Martinez et al.
examinations should be done routinely in all patients 1992). Oral disodium cromoglycate is ineffective
with cold urticaria: serology for syphilis, borreliosis, (Haustein and Kirchhoff 1984), and a combination of
HIV- and Epstein-Bar-viral infections, tests to rule out H, and H2 -blockers is not superior to H,-blockers
systemic lupus erythematosus (SLE), determinations of alone.
cryoglobulins, cold agglutinins, cryofibrinogens and In patients with severe involvement who fail to
cryohemolysins. Hematologic or lymphatic diseases respond satisfactorily to H,-antihistamines, a trial with
should be excluded by clinieal and laboratory exam- sulfones, such as dapsone, may be worthwhile. Short-
inations. In case of suspected drug-induced cold time treatment with moderate doses of corticosteroids
urticaria, the particular drug should be omitted or (20-25 mg for 1-5 days) suppresses symptoms only
substituted. partially (Kobza-Black et al. 1981). Interferon rt
The differential diagnosis includes other types of (3 x 3 million units/week) caused no improvement in
urticaria, particularly dermographie and aquagenie one of our patients after a 6-week treatment (unpub-
urticaria. The disease should also be distinguished lished observations). Recently, good results have been
from abortive forms of cold urticaria such as pruritus reported with a combination of ß-sympathomimetic
or prurigo hiemalis (cold itch), cold erythema, cold and aminophylline-containing drugs (Husz et al.
pruritus and cold panniculitis (Henz et al. 1997). 1994)·
If the patient is highly motivated and cooperative,
Therapy the refractory period after cold exposure, which may
last for several days, can be put to good use by
The most important aspect of treatment is a diligent tolerance induction with cold baths (Henquet et al.
education of patients or their parents regarding 1992). This treatment is dangerous and should only be
avoidance of potentially life-threatening situations done by experienced physicians. According to our own
during ingestion of ice-cream, the intake of cold experience and as also reported in the literature
beverages or a jump into cold water (Table 5). Patients (Wanderer 1995), no patient maintains this therapy
reacting within 3 min on cold testing are particularly in over an extended period of time because it is too
danger. Highly sensitive patients should always carry a difficult to maintain in daily life.
kit with them, containing adrenaline and steroid
tablets for self-treatment.
In patients with secondary cold urticaria, the Cholinergic Urticaria
underlying disease must first be treated and, if the
diagnosis is correct, cold urtiearia should resolve soon General and Occupational Aspects
thereafter. Since up to 50% of patients res pond to a
2-week treatment with penicillin or tetracycline, this Cholinergic urticaria has a prevalence of 11.2% among
treatment should always be tried too (Möller et al. young adults (16-35 years old), with a maximum of
1996). 20% in subjects aged 26-28 years (Table 2), altltough
H,-antihistamines can be used to decrease the clinical manifestations are rarely severe and bother-
symptomatology in patients with cold urticaria. In some in daily life (11%) (Zuberbier et al. 1994).
the older literature, the treatment of choice was Since the symptoms are provoked during exercise in
cyproheptadine (Sigier et al. 1980), although this could a warm environment, the disease is particularlY
not be supported by newer studies (Haustein and problematic among sports students and young teach-
Kirchhoff 1984). In a comparative study of the very ers. Other persons in professions requiring vigorous
potent H,-blocker doxepin (30 mg/day) and hydroxy- physieal exertion up to sweating are similarly affected.
zine (40 mg/day) with cinnarizine (Jo mg/day), all Psychic stress as an eliciting stimulus is observed most
three drugs were equally effective and better than frequently with students before an examina ti on, but I
placebo (Neittanmäki et al. 1984). Moderate to good have also observed the disease in a middle-aged banker
Table 5. Therapy of cold urticaria

General measures Symptomatic treatment
Patient education HI-Type antihistamines

Treatment of underlying diseases ß2-Sympathomimetics and aminophylline
Ce.g. with antibiotics)
Omission of suspected inducing drugs Stanozolole, danazole
Avoidance of cold exposure Sulfones or dapsone
Induction and maintenance of cold tolerance Corticosteroids
under severe emotional stress. Various possibilities to therapy, or cooling effects due to evaporation. In
treat this disease satisfactorily and the almost invari- case of doubt, tests should be repeated after an
able spontaneous remissions of the disease only rarely interval of 2 days, imitating the natural setting
justify a change of occupation. The symptomatology inducing symptoms on medical history as elosely
may however be severe enough to even lead to as possible. On repeated negative testing, a full warm
attempts at suicide. tub bath (40°C, 10-15 min) is a laborious but very
reliable alternative method.
(Iinical Manifestations Differentiation between aquagenic and heat urti-
caria is easily done using the speeific tests for these
Cholinergic urticaria presents as intensely itching, types of urticaria (Henz et al. 1997), but differenti-
pinhead-size wheals on an erythematous base (Fig. 2). ation from adrenergic urticaria may be difficult.
The lesions develop during or up to 20 min after Although also induced by emotional stress, the small
provocation and pers ist for 30-60 min, rarely even for lesions are typically surrounded by pallor rather than
3 h (Table 1). They may be preceded by a prodromal erythema and respond to ß-blockers such as propa-
itching of the scalp. Wheals develop preferentially on nolol (Shelley and Shelley 1985). Exercise-induced
the arms, upper chest, upper legs, back and abdomen, anaphylaxis also arises 5-30 min after physical exer-
while palms, soles and axillae are always spared. eise, but usually only after previous intake of food,
Erythematous and edematous swellings of the face are particularly celery or crabs. The symptoms may be
noted in 18% of patients, particularly in the periorbital indistinguishable from cholinergic urticaria, but
region. After disappearance of the wheals, there is wheals are larger, and anaphylactic symptoms persist
often a refractory period lasting from 8 h to 24 h, in for up to 48 h (Casale et al. 1986; Orfan and Kolski
some individuals even for several days. This may also 1993). Patients furthermore fail to respond to a warm
explain why some patients experience remissions tub bath. Tests should be done with an empty
during the summer months and why provocation tests stornach, since angioedema can also develop after
are not always positive. food intake followed by a hot bath (Zuberbier et al.
The symptoms of cholinergic urticaria are provoked 1993). Cholinergic pruritus, cholinergic erythema and
by a rise of the body's core temperature. Frequent cholinergic dermographism may represent abortive
elieiting situations are running, bicyeling, intensive forms or variants of ordinary cholinergic urticaria
sports, such as squash or tennis, dancing, hot showers, (Henz et al. 1997).
sauna, and intake of spicy food or alcoholic beverages.
Fever, emotional stress, or even a rapid injection of Therapy
calcium can also provoke the symptomatology. Its
intensity varies among patients and depends also on Non-sedating potent H,-type antihistamines are the
the strength of the stimulus, the extent of sweating, and treatment of choice since they satisfactorily suppress
the increase of the body's core temperature. itching and whealing (Zuberbier et al. 1995). The dose
Other possibly assoeiated systemic symptoms in- may have to be increased in patients with severe
elude dizziness, nausea and headache. Rhinorrhea, symptomatology. In so me patients, prophylactic use of
bronchospasms or gastrointestinal symptoms are less the drugs before physical exertion, such as sports, may
frequent, and hypotension or anaphylactic shock are be sufficient. Some patients use their refractory period
very rare. There is an increased incidence of atopy therapeutically in that they do vigorous physical
(45.5%) (Zuberbier et al. 1994) and of bronchial exereise before going, for example, to a disco where
reactivity on provocation (Czarnetzki et al. 1984a). they want to be free of symptoms.
Other types of urticaria can coexist, although they are
not particularly frequent (Henz et al. 1997).
Heat Contact Urticaria
Diagnosis
Definition and Occupational Implications
Because of the elose temporal relationship between
provocation and the appearance of lesions, most Heat urticaria is elicited after direct contact of the skin
patients give a diagnostic description of their with warm or hot objects. The condition is extremely
disease, and the diagnosis is rarely missed. It is rare (Table 1). Since Duke's first description (1926),
verified by provocation tests (Table 2). Simple and slightly more than 20 cases have been reported in the
reliable methods are knee ben ding, elimbing stairs or literature. Accordingly, there are no data regarding the
cyeling in a warm room or with warm elothing. impact of the disease on occupational life. One must
False-negative tests may be due to temporary nevertheless assurne that the disease interferes with
refractoriness, recent antihistamine or corticosteroid occupations requiring contact with warm objects, such
176 B.M. Henz
as during cooking. Furthermore, the disease is difficult Solar Urticaria

to treat and remission seems rare. One 48-year-old
female patient has suffered, for example, from the General and Occupational Aspects
disease since late childhood (Michaelsson and Ros
1971). Solar urticaria can be elicited by ultraviolet (UV)
Hereditary delayed he at urticaria is extremely rare waves, with wavelengths ranging between 280 nm
and has mainly been reported in young adult and 760 nm, and occurs only rarely (Table 2),
women. although a recently described localized form seems
more frequent (Reinauer et al. 1993). The disease is
Clinical Manifestations classified on the basis of possible eliciting stimuli
and underlying diseases into an idiopathic type,
Wheals may be either small or large, confluent and elicited by UVB (280-320 nm), UV A (320-400 nm)
indurated; they develop either rapidly (Table 1) or after or visible light (400-760 nm), and a secondary type
a 60-min to 90-min delay, and they are associated due to underlying porphyria (erythropoetic pro-
with an intense local itch, burning or even a toporphyria or prophyria cutanea tarda), SLE, or
dysesthesia. Affected areas may be refractory for from drug reactions.
24 h up to 3 weeks. Systemic reactions such as Serum factors that act as photo allergens after UV
tiredness, headache, dizziness, nausea, diarrhea and irradiation may be involved in the pathogenesis
even unconsciousness are observed only on extensive (Hölzle and Hadshiew 1996). An association with other
involvement. diseases has been reported for cystic fibrosis, dermo-
There is an increased incidence of atopy (42%). An graphic, heat, delayed pressure and cold urticaria
association with urticarial dermographism, cold urti- (Laufer and Laufer 1983; Kojima et al. 1986; Horio and
caria, solar urticaria and aspirin intolerance has been Fujigaki 1988; Hölzle and Hadshiew 1996).
reported for one patient each (Tennenbaum and Since the disease is generally readily treated and
Lowney 1973; Wise et al. 1978; Willis and Epstein since it can go into spontaneous remission (Table 2),
1974, unpublished own patient). an impact on professionallife is only to be expected in
severely affected patients with an outdoor occupation.
One patient, however, had persistence ofhis disease for
Diagnosis
48 years (Ive et al. 1965).
Local heat should be applied to the skin for about Clinical Manifestations
3-5 min, possibly even 10 min, by, for example,
submerging an arm in a warm bath or by applying a Diffuse areas of erythema and whealing, often associ-
metal cylinder filled with warm water to the inner ated with reflex erythema and itching or burning,
part of the lower arm. The eliciting temperature is develop within 30 s to 20 min on appropriate exposure
usually 38-41 °C, although some patients respond and can persist for up to 1 h, the erythema even for 3 h
only to higher temperatures (up to 56°C). In case (Table 1). If the dose of irradiation is low, lesions may
delayed reactions are suspected by history, test sites merely present as diffuse erythema. Areas of the body
should be checked again after 2-4 h. Routine labo- constantly exposed to light, such as the face and the
ratory examinations or immunological laboratory hands, are usually refractory and clinically not in-
tests are usually negative. volved, whereas the opposite holds for polymorphous
The disease must be differentiated from solar light reactions. Lesions typically appear during the first
urticaria and cholinergic urticaria (heat reflex urticar- sunny days in spring when the skin has not yet been
ia) by appropriate testing (see above). hardened against light.
Generalized symptoms develop only when large
Therapy areas of the body are involved and include malaise,
headaches and even anaphylactic shock.
Treatment with antihistamines is worthwhile since the
disease is mast-cell dependent in about half of the Diagnosis
patients. In the other patients, the complement system
seems to play a major pathogenetic role so that As with other types of urticaria, a careful history is
treatment with anti-inflammatory drugs (chloroquine, essential. If the patient has noted lesions also after
dapsone) should be tried. Furthermore, as with cold exposure behind glass windows or in artificiallight, the
urticaria, a hardening or desensitization after increas- possible eliciting wavelength can already be guessed at.
ing exposure regarding duration, body surface and Light tests are usually done on the back in test areas
temperature can be successful. measuring 1 cm\ using UVB- and UVA-Iamps as weIl
as visible light, as describe in detail (Henz et al. 1997). Symptomatic treatment of solar urticaria with anti-
A possible problem with light testing is the marked histamines is generally disappointing (Willis and
variation (changes often within 2-3 days) of the Epstein 1974; Hasei and Ichihashi 1982). A trial with
minimal eliciting dose as weIl as the eliciting wave- H,-blockers is nevertheless worthwhile (Baart de la
length in individual patients. Changes of various Faille et al. 1975; Hudson-Peacock et al. 1993; Harris
inhibitory, enhancing and eliciting wavelengths further et al. 1997), particularly with the newer, non-sedating
complicate the situation (Leenutaphong 1993; Hölzle antihistamines. Some but not all patients res pond also
and Hadshiew 1996). Furthermore, irradiated skin to anti-malarials (Willis and Epstein 1974; Ratanen and
areas may remain refractory for several days, i.e., Sukonen 1980).
repeated whealing cannot be elicited at these sites
during that time period. Light tests should therefore
only be done on skin areas that have been protected References
from light for several days.
Heat urticaria, polymorphous light reaction, photo- Baart de la Faille H, Rottier PB, Baart de la Faille-Kuyper EH
allergic contact eczema, phototoxic contact eczema, (1975) Solar urticaria. A case with possible increase of skin
mast cells. Br J Dermatol 92:101-107
SLE and porphyria must be differentiated from solar Barlow RJ, Warburton F, Watson K, Black AK, Greaves MW
urticaria by history, appearance of the lesions, skin (1993) Diagnosis and incidence of delayed pressure urticaria
testing and laboratory examinations. Reactions on in patients with chronic urticaria. J Am Acad Dermatol
29:954-958
exposure to infrared light should be classified as heat Björkner B (1981) Occupational cold urticaria from contact spray.
urticaria. Contact Dermatitis 6:338-339
Breathnach SM, Allen R, Milford Ward A, Greaves MW (1983)
Symptomatic dermographism: natural history, clinical fea-
Therapy tures, laboratory investigations and response to therapy. Clin
Exp Dermatol 8:463-476
Induction of tolerance is the most important treatment Cap JP, Schwanitz HJ, Czarnetzki BM (1985) Die Wirkung von
Ketotifen bei der Urticaria factitia und der Urticaria choli-
modality of idiopathic solar urticaria and should be nergica im gekreuzten Doppelblindversuch. Hautarzt 36:
conducted with an appropriate UV -light source at the 509-511
office or in the hospital. Hardening by sunlight is Casale TB, Keahey TM, Kaliner M (1986) Exercise-induced
anaphylactic syndromes: insight into diagnostic and patho-
generally disappointing because of fluctuating weather physiologie features. JAMA 255:2049-2053
conditions and since results last only for a few days. Collins P, Ahamat R, Green C, Ferguson J (1996) Plasma ex-
Most patients with UV -A sensitivity profit from UV A change therapy for solar urticaria. Br J Dermatol 134:
1093-1097
and even more so from PUV A treatment (psoralens Czarnetzki BM, Galinski C, Meister R (1984a) Cutaneous and
plus UV A light), with total protection being achieved pulmonary reactivity in cholinergic urticaria. Br J Dermatol
within a few weeks. For practical purposes, total body 110:587-591
Czarnetzki BM, Meentken J, Rosenbach T, Pokropp A (1984b)
UV-A irradiation, starting below the eliciting dose, Clinical, pharmacological and immunological aspects of
with increases at hourly intervals, is most effective. delayed pressure urticaria. Br J Dermatol 111:315-323
When tolerance is reached, the change to PUV A Czarnetzki BM, Breetholdt B, Traupe H (1986) Evidence that
water acts as a carrier for an epidermal antigen in aquagenic
treatment can be done with care. This procedure urticaria. J Am Acad DermatoI15:623-627
avoids a laborious initial treatment with multiple low Czarnetzki BM, Cap H-P, Forck G (1987) Late cutaneous reactions
doses and shortens the total time of PUV A treatment to common allergens in patients with delayed pressure
urticaria. Br J DermatoI117:695-701
needed to reach protection (Hudson-Peacock et al. Czarnetzki BM, Zwadlo-Klarwasser G, Bröcker E-B, Sorg C (1989)
1993). lmmunohistochemical demonstration of migration inhibitor
Topical sun screens are a helpful adjunct. Only factor (MlF) in different types of urticaria. J luvest Dermatol
93:471-474
preparations awarding a high level of protection Davis KC, Mekori YA, Köhler PF, Schocket AL (1986) Cold
should be chosen, paying particular attention to urticaria and virus infection: a clinical and serological study
protection in the wavelength region eliciting the in 39 patients. Br J DermatoI114:311-318
Doeglas HMG (1975) Reaction to aspirin and food additives in
lesions. patients with chronic urticaria, including the physical urtic-
Since serum factors apparently elicit solar urticaria arias. Br J Dermatol 110:382-388
in some patients, trials with plasmapheresis alone or in Dover JS, Black AK, Ward AM, Greaves MW (1988) Delayed
pressure urticaria. Clinical features, laboratory investigations,
combination with PUVA have been done in a number and response to therapy of 44 patients. J Am Acad Dermatol
of patients, with extended periods of remission in 18:1289-1298
some and failure in others (Hudson-Peacock et al. Duke WW (1926) Physical allergy as a cause of dermatoses. Arch
Dermatol Syphilis 13:176-186
1993; Collins et al. 1996). This treatment can only be Engler R, Squire E, Benson P (1995) Chronic sulfasalazine therapy
done in a hospital setting and with the necessary in the treatment of delayed press ure urticaria and angioede-
equipment and expertise. In patients diagnosed as ma. Ann Allergy 74:155-159
Estes S, Young C (1981) Delayed press ure urticaria: an investi-
suffering from secondary solar urticaria, any underly- gation of some parameters of lesion induction. J Am Acad
ing disease should be treated. Dermatol 5:25-31
178 B.M. Henz: Physical and Cholinergic Urticaria
Fitzgerald DA, Heagerty AHM, English JSC (1995) Cold urticaria Möller A, Henning M, Zuberbier T, Czarnetzki BM (1996)
as an occupational dermatosis. Contact Dermatitis 32: Epidemiologie und Klinik der Kälteurtikaria. Hautarzt
240-241 47:510-514
Haas N, Toppe E, Henz BM (1998) Microscopic morphology in Neittaanmäki H (1985) Cold urticaria. Clinical findings in 220
different types of urticaria. Arch Dermatol 133:41-46 patients. J Am Acad Dermatol 13:636-643
Harris A, Burge SM, George SA (1997) Solar urticaria in an infant. Neittanmäki H, Myöhänen T, Fräki JE (1984) Comparison of
Br J DermatoI136:105-107 cinnarizine, cyproheptadine, doxepin, and hydroxyzine in
Hasei K, Ichihashi M (1982) Solar urticaria. Determinations of treatment of idiopathic cold urticaria: usefulness of doxepin.
action and inhibition spectra. Arch Dermatol 118:346-350 J Am Acad Dermatol 11:483-489
Haustein UF, Kirchhoff B (1984) Die Behandlung der erworbenen Orfan NA, Kolski GB (1993) Physical urticarias. Ann Allergy
Kälteurtikaria mit Ketotifen. Dermatol Wochensehr 170: 171:205-215
536-537 Rajka G, MfIlrk NJ (1985) Clinical observations on the mechanism
Henquet CJM, Martens BPM, Van Vloten WA (1992) Cold of delayed pressure urticaria. In: Champion RH, Greaves
urticaria: a clinico-therapeutic study in 30 patients, with MW, Kobza Black A, Pye RJ (eds) The urticarias. Churchill
special emphasis on cold desensitization. Eur J Dermatol Livingstone, Edinburgh, pp 191-193
2:75-77 Ratanen T, Suhonen R (1980) Solar urticaria. A case with increased
Henz BM, Jeep S, Ziegert FS, Niemann J, Kunkel G (1996) Dermal skin mast cells and good therapeutic response to an antihis-
and bronchial hyperreactivity in urticarial dermographism. tamine. Acta Derm Venereol Suppl (Stockh) 60:363-365
Allergy 51:171-175 Reinauer S, Leenutaphong V, Hölzle E (1993) Fixed solar
Henz BM, Zuberbier T, Grabbe J, Monroe E (eds) (1997) Urticaria urticaria. J Am Acad Dermatol 29:161-165
- clinical, diagnostic and therapeutic aspects. Springer, Berlin Schafer CM (1995) Physical urticaria. Immunol Allergy Clin N Am
Heidelberg, New York 15:679-699
Hertl M, Merk HF (1994) Occurrence of cold urticaria in insect Shaw D (1988) Cold urticaria and employment. J Soc Occup Med
venom allergie individuals. Allergoi J 3:379-381 38:89
Hölzle E, Hadshiew IM (1996) Mechanisms of solar urticaria. Shelley WB, Shelley ED (1985) Adrenergic urticaria: a new form of
Curr Opin Dermatol p85-189 stress-induced hives. Lancet 11:1031-1033
Horio T, Fujigaki K (1988) Augmentation spectrum in solar Sigler RW, Evans R, Horakova Z, Ottesen E, Kaplan AP (1980)
urticaria. J Am Acad DermatoI18:1189-1193 The role of cyproheptadine in the treatment of cold urticaria.
Houser DD, Arbesman CE, Kohi ITO, Wicher K (1970) Cold J Allergy Clin Immunol 65:309-312
urticaria (immunologie studies). Am J Med 49:23-33 Sussman GL, Harvey RP, Schocket AL (1982) Delayed pressure
Hudson-Peacock MI, Farr PM, Diffey BL, Goodship THJ (1993) urticaria. J Allergy Clin Immunol 70:337-342
Combined treatment of solar urticaria with plasmapheresis Tennenbaum JI, Lowney E (1973) Localized heat and cold
and PUV A. Br J Dermatol 128:440-442 urticaria: new phenomenon occurring in the same individual.
Husz S, Toth-Kase I Kiss M, Dobozy A (1994) Treatment of cold J Allergy Clin Immunol 51:57-59
urticaria. Int J Dermatol 33:210-213 Tyson CJ, Czarny D (1981) Cold-induced urticaria in infectious
Illig L, Kunick J (1969) Klinik und Diagnostik der physikalischen mononucleosis. Med JAust 1:33-35
Urtikaria. Hautarzt 20:167-178 Villas-Martinez F, Contreras FJ, Lopez-Cazana JM, Lopez-Serrano
Ive H, Lloyd J, Magnus IA (1965) Action spectra in idiopathic MC, Martinez-Alzamora F (1992) A comparison of new
solar urticaria. A study of 17 cases with a monochromator. Br nonsedating and classical antihistamines in the treatment of
J Dermatol 77:229-243 primary acquired cold urticaria (AUC). J Invest AllergoI Clin
Kobza-Black A, Keal!ey TM, Eady RAJ, Greaves MW (1981) Immunol 2:258-262
Dissociation of histamine release and clinical improvement Wanderer AA (1995) The spectrum of cold urticaria. Immunol
following treatment of acquired cold urticaria by prednisone. Allergy Clin N Am 15:701-723
Br J Clin Pharmacol 12:327-331 Warin RP (1987) A simple out-patient test for delayed pressure
Kojima M, Horiko T, Nakamura Y, Aoki T (1986) Solar urticaria. urticaria (letter). Br J Dermatol 116:742-743
The relationship of photoallergen and action spectrum. Arch Willis I, Epstein JH (1974) Solar vs heat-induced urticaria. Arch
Dermatol 122:550-555 Dermatol 110:389-392
Kontou-Fili K, Maniatakou G, Demaka P, Gonianakis M, Wise RD, Malkinson FD, Luskin A, Gewurs AT, Zeitz HJ (1978)
Palaiogolos G, Aroni K (1991) Therapeutic effects of cetirizine Localized heat urticaria. Arch Dermatol 114:1079-1080
2HCl in delayed press ure urticaria: clinicopathologic findings. Wong RC, Rairley JA, Ellis CN (1984) Dermographism: a review.
J Am Acad Dermatol 24:1090-1093 J Am Acad Dermatol 11:643-652
Laufer P, Laufer R (1983) Solar urticaria in cystic fibrosis. Cutis Zuberbier T, Böhm M, Czarnetzki BM (1993) Food intake in
31:665-666 combination with a rise in body temperature: a newly
Leenutaphong V (1993) Solar urticaria induced by UVA and identified cause of angioedema. J All Clin Immunol 91:
inhibited by visible light. J Am Acad Dermatol 29:337-340 1226-1227
Lemanske RF, Bush RK (1982) Cold urticaria in infectious Zuberbier T, Althaus C, Chantraine-Hess, Czarnetzki BM (1994)
mononucleosis JAMA 247=I604 Prevalence of cholinergic urticaria in young adults. J Am
Lin RY, Schwartz RA (1993) Cold urticaria and HIV infection. Br J Acad Dermatol 31:978-981
Dermatol 129:465-467 Zuberbier T, Aberer W, Burtin B, Rihoux J-p, Czarnetzki BM
Michaelsson G, Ros AM (1971) Familiallocalized heat urticaria of (1995) Efficacy of cetirizine in cholinergic urticaria. Acta
delayed type. Acta Derm Venereol 51:279-283 Derm Venereol Suppl (Stockh) 75=147-149
CHAPTER 22
Biologie Causes of Oeeupational Dermatoses

I.M. Lachapelle
Introduction Human lesions are caused by direct inoculation of

infected material. Various occupations are at risk:
Strietly speaking, the biologic agents that cause occu- shepherds, farmers and veterinarians are at greatest
pational dermatoses are comprised of infections and risk. Orf is a frequent occupational disease among
infestations. It is not always easy to define the time shearers, of considerable industrial importance in
when a natural hazard becomes an occupational Australia and New Zealand. Occasionally, butchers
hazard (Wilkinson 1987). Among infections, it is and me at porters can be affected from infected
tradition al to consider viral, microbial and mycotic carcasses. In Western countries, it is not rare among
infections. immigrants from Muslim countries, who work as sheep
slaughtermen in unofficial slaughterhouses (Lachapelle
et al. 1992).
Viral Infections The lesions of orf, occurring mainly on fingers
(Fig. 1), are rather large, painful nodules (1-2 cm in
Some viral infections are undoubtedly related to
diameter), which may be multiple, with a vesiculo-
occupational activities. The most important ones are
pustular roof; the surrounding skin is infiamed. There
described below, excluding acquired immune deficien-
may be a low fever and swelling of the draining lymph
cy syndrome, the occurrence of which in occupational
nodes. More rarely, "giant" lesions (as large as 5 cm in
life is discussed in another chapter.
diameter) may occur. Secondary infection is not un-
common (Groves et al. 1991). Spontaneous recovery
Parapoxvirus Infections
occurs in 3-6 weeks. Second attacks are quite common.
Erythema multiforme occasionally develops, typically
Three parapoxviruses of domestic animals occasion-
10-14 days after the onset of orf (Sterling and Kuntz
ally cause infections in humans: orf virus, normally
1998). Diagnosis is confirmed by examination of
causing a disease of sheep, pseudocowpox (syn-
collected material (from a vesiculo-pustule or a scab)
onyms: milker's nodule, paravaccinia) and bovine
by negative electron microscopy, which reveals the
pustular stomatitis viruses, normally causing diseases
presence of characteristic virions. Treatment is limited
of cattle. Parapoxviruses (DNA viruses) are ovoid
to prevention and/or cure of secondary infection.
particles that vary from about 260 nm long by
160 nm wide for orf virus to 300 nm by 190 nm for
pseudocowpox virus. A tubular, thread like structure
10-20 nm wide and perhaps 1000 nm long forms a Milker's Node
criss-cross pattern on the surface of negatively
stained parapoxvirus virions. Milker's node (pseudocowpox; paravaccinia) pro duces
mild infections of the teats of cows and ulcers in the
Orf mouths of calves. Man may be occasionally infected.
Lesions occur on the hands of milkers or veterinarians
The orf virus may infect sheep (more rarely goats) who examine the mouths of animals. Human infection
throughout the world. It affects mainly young lambs, is considered to be accidental, and human-to-human
who contract the infection from one another. Ewes iliat spread does not appear to have been recorded.
are suckling affected lambs may develop lesions on Clinically, the lesions, relatively painless, are hemi-
their udders. Healing occurs in about a monili, without spherical, cherry-red papules that appear 5-7 days
scarring. Orf virus remains viable for a long period in after exposure and gradually enlarge into firm, elastic,
dried scabs, and this is important in maintaining purple, smooth, hemispherical nodules (Fig. 2) varying
enzootie infection in sheep under field conditions. in size up to 2 cm in diameter and, when fully

180 J.M. Lachapelle
Fig. 1. Orf
developed, may be umbilicated. They are highly Orthopoxvirus Infections

vascular, which explains the purpie colour. The lesions
disappear after 4-6 weeks (Groves et al. 1991). Negative Two orthopoxviruses may, very occasionally, be in-
electron-microscopy examination of biopsy fragments volved as human offenders in occupational life: the
is most useful in confirming diagnosis. There is no vaccinia virus and ilie cowpox virus. Orthopoxviruses
treatment available. Milker's node is nowadays thought are DNA viruses; ilie virions have an ovoid structure,
to occur less frequently than orf. 300 x 250 nm, and are readily identified by negative
electron microscopy.
Bovine Papular Stomatitis Vaccinia
Human infections with bovine papular stomatitis virus Vaccinia rarely occurs in occupational life nowadays.
are less common than with ilie other two parapox- Vaccinia virus can potentially be used as a carrier of
virus es, probably because contact between animal genes for protective antigens of other pailiogenic
handlers and lesions of bovine papular stomatitis, micro-organisms (recombinant vaccinia viruses), and
clinically similar to milker's node, are less common it is used in some specialised laboratory research.
than those of shearers and shepherds with orf and Vaccination has ceased except for investigators at
milkers with pseudocowpox lesions. special risk (Sterling and Kuntz 1998). Buffalopox is
Fig. 2. Milker's node

Biologie Causes of Occupational Dermatoses 181
considered to be astrain of vaccinia virus. It is found

in buffalo herds in certain areas in India and may
cause bullous or crusted lesions in buffalo farmers
(Ramanan et al. 1996).
Cowpox
Cowpox is traditionally considered to be a disease of

cattle; yet, despite the name, it appears that cattle are
only infected by chance, as are cats and humans
(Sterling and Kuntz 1998). Cowpox appears to occur
only in Europe; it is uncommon and sporadic. An
occupational source is probable when professional
activities involve contact with infected animals, such as
Fig. 3. Butchers' warts
cattle or cats (in the latter case, when skin has been
broken by a scratch).
Clinical symptoms can be reported as follows: after Traditional treatments of common warts can be
an incubation period of 5-7 days, a papule appears and applied to butchers' warts; it is our experience that
rapidly becomes vesiculo-pustular, haemorrhagic and, injections of a bleomycine solution using a Dermo-Jet
later, ulcerated. Later, ulceration is covered by a hard offer better results than liquid-nitrogen applications
black crust, surrounded by a zone of erythema and (Lachapelle et al. 1992). There is no proof that wearing
oedema. Lymphangitis and lymphadenitis are usual gloves is an efficacious preventive method. Recurrence
(Baxby et al. 1994). Healing takes place in 3-4 weeks. of older lesions and outcome of new lesions is not rare
Treatment is limited to prevention and/or care of and may represent areal hindrance in terms of quality
secondary infection. of life.
Butchers' Warts Herpes Simplex
Viral warts are very common on hands and/or fingers Herpes simplex, caused by Herpes virus hominis is one
in some occupational groups, such as me at or poultry of the most common infections of humans throughout
handlers (primarily slaughtermen). Fish handlers are the world. There are two major antigenic types: type 1
another group at risk. This is not a case of transmis- (HSV 1) which is traditionally associated with facial
sion of an animal papilloma virus to man (it has never infection, and type 2 (HSV 2), which is typically
been mentioned in the literature) but of interhuman genital, although there is considerable overlap in
transmission favoured by a combination of environ- disease manifestations. In some circumstances, an
mental circumstances. Indeed, several factors acting occupational origin can be postulated.
concomitantly seem to be important for explaining
such an occurrence of the disease among selected
groups: (a) work at relatively low temperature; (b) Herpes Simplex in Health-Care Workers
constant humidity of the hands; and (c) presence of
cuts and/or repeated minor trauma to the skin (De It is well known that trauma facilitates transfer of the
Peuter et al. 1977; Jablonska et al. 1988). According to virus to fully keratinised skin. Doctors, nurses, dentists
our current knowledge, two types of human papillo- and dental assistants can be infected by contaminated
maviruses (HPV) are preferentially involved. HPV-2 saliva, pharyngeal or laryngotracheal secretions. Pri-
(the cause of common warts) is frequently found in mary infection occurs on the extremity of one finger
butchers' warts, but HPV -7 is present in up to one- (Gill et al. 1990). Inoculation of the fingertips results in
third of lesions (Keefe et al. 1994). The clinical features a "herpetic whitlaw", in which pruritic and painful,
are: (a) on the palmar aspect ofboth fingers and hands, deep vesicles coalesce to form a honeycombed appear-
butchers' warts resemble the myrmeciae of HPV-1 ance or large bulla. The condition is easily confused
infection (endophytic lesions surrounded by a small with pyogenic infection, but virological identifica-
ring of keratosis, with central black dots representing tion from collected material can be easily achieved
thrombosed capillaries); or (b) on the dorsal and/or nowadays.
lateral aspects of fingers and on the backs of hands, Recurrent herpes may occur, presenting as coales-
viral warts are either of the common type or may cent vesicles gradually transforming to pustules on a
become very exophytic, showing advanced, craggy very painful erythemato-oedematous plaque. Use of
keratosis (Fig. 3). protective gloves has dramatically decreased the
182 J.M. Lachapelle
occurrence of this occupational disease and represents countries, some skin side effects may be expected
the best preventive measure. (Grezard et al. 1995). In addition to short-lived, local
reactions, generalised granuloma annulare has been
Herpes Simplex in Sport Pradice described recently (Wolf et al. 1998).
Inoculation of herpes simplex may be favoured by the

practice of some particular sport activities. Multiple Bacterial Infections
crops of vesicles and pustules on plaques or erythema
and oedema on the face, scalp and upper trunk, Some occupational bacterial infections are distributed
simulating impetigo and lasting some 10-12 days, have worldwide, whereas others are nowadays limited to
occurred in wrestlers. On the face of the adult male, the certain countries where prevention measures have not
appearance of herpes may be deceptive; it may take the been applied.
form of a folliculitis, but satellite, umbilicated vesicles
soon suggest the correct diagnosis. Facial contact during
rugby is another recognised means of acquiring herpes- Staphylococcal and Streptococcal Infections
simplex-virus infection (White and Grant-Kels 1984).
The most common staphylococcal and/or streptococ-
Recurrent Herpes Simplex Triggered cal infections result from cuts, abrasions, burns and/or
by U1traviolet Radiation puncture wounds. ß-Hemolytic Streptococcus of group
A, Staphylococcus aureus or both are the usual bacteria
Recurrent facial herpes simplex (and, in particular, cultured from lesions (Barnham and Neilson 1987).
herpes labialis) can be triggered by sun exposure. Some occupations are at particular risk: butchers, meat
Ultraviolet B (290-320 nm) seems to playa major role, packers, fish handlers, slaughtermen, ete. The most
the mechanisms involved being related to an inhibitory common clinical picture is impetigo characterised by
effect on Langerhans' cells (Perna et al. 1987). erythematous patches covered by a yellowish crust. A
Seasonal workers suffering from recurrent herpes variant is ecthyma, mainly observed in tropical coun-
simplex are prone to present reactivation at the tri es; it consists of a slow and gradually deepening
beginning of each sun-exposure period (Fig. 4). Skiing, ulceration surmounted by a thick crust. After healing,
sailing or swimming instructors are good examples of there is a permanent scar.
professions at risk. Prevention of recurrences is Workers in contact with industrial mineral oils, e.g.
achieved by the use of aciclovir, starting treatment a in the metallurgie industry, can develop lesions of
few days before exposure. folliculitis due to Staphylococcus spp. (Fig. 5). Bacteria
that may contaminate used oil are not responsible for
Hepatitis B: Skin Complications of Vaccination the infection. In fact, occlusion of hair follicles by
cutting, lubrication and cooling mineral oils may lead
Since hepatitis-B vaccination becomes generalised to a secondary infection by staphylococci present on
among health-care personnel in many European the skin of patients. Industrial staphylococcal folliculi-
Fig. 4. Recurrent herpes simplex in a ski

instructor after sun exposure
pricks are the usual mode of incubation. More

anecdotally, it has been mentioned among dolphin-
arium attendants or, in the United States, among crab
fishermen (crab dermatitis).
The clinical symptoms are usually obvious - about
3 days after inoculation, a hot, violaceous and tender
erythema develops around the inoculation site and
extends centrifugally but irregularly, with a sharp and
sometimes gyrate border, which may be vesicular .
. Erysipeloid is, in fact, a true cellulitis. Most lesions are
on the fingers, hands and forearms. Some lesions have
a violaceous hue. Fever and mild general symptoms,
such as arthralgia, are present in only 10% of cases.
Without treatment, healing normally occurs sponta-
Fig. S. Staphylococcal folliculitis
neously in 2 weeks without desquamation or suppu-
ration (Weinberg and Swartz 1999). Diagnosis is
tis is less frequent nowadays due to an increased use of mainly clinical.
soluble oils in industry. In those conditions, conven- Recommended treatment centres on antibiotics:
tional therapy is applied, but secondary prevention of penicillin (intramuscularly), ciprofloxacin or erythro-
infection is man da tory, requiring, in many cases, a mycin. Prevention is, as far as pigs are concerned, the
change of work habits. responsibility of the veterinarian; systematic slaugh-
tering of infected animals is mandatory. Reduction of
Bacterial Athlete's Foot trauma (for instance, in fish processors) can be
achieved by constant use of protective gloves.
The most common cause of this purely bacterial Erysipeloid was rather common in Belgium 30 years
variant is a mixture of flora comprising both gram- ago, but has become an exceptional disease nowadays,
positive and -negative bacteria. The clinical presen- probably due to preventive measures, especially in
tation can be florid, with the entire interdigital web slaughterhouses. Our last erysipeloid patient was a
and neighbouring skin subject to extensive ulceration Belgian tourist fishing in the Indian Ocean during his
with raised, whitish and macerated margins. It may holidays.
be associated with small fissures in the clefts,
providing a portal of entry for erysipelas of the leg.
Athlete's foot is amisnomer, as both water sports and Anthrax
occlusive (maceration-promoting), high-ankled train-
ers also contribute to this environmental dermatosis. Anthrax is a specific infection with Bacillus anthracis, a
It is encountered in occupational life and is consid- gram-positive, encapsulated organism that can survive
ered to be a common problem in sports medicine as spores for over 20 years in soil. Herbivores are
(Lachapelle et al. 1997). Topical treatment includes primarily affected. In endemic countries (some parts of
potassium permanganate (1 part in 10,000) baths and Africa, Pakistan, India, Iran, the Middle East and parts
antibiotic creams. Systemic antibiotics are needed of Russia), human infections remain a serious prob-
when secondary erysipelas occurs. Prevention is of lem. In Western Europe or the United States, anthrax
prime importance in avoiding recurrences; the wear- often follows occupational exposure during care of
ing of shoes provoking minimal occlusion is highly livestock or the handling of products. Therefore, most
recommended. cases occur in wool, hair or bristle industries. Unster-
ilised, imported bone meal, sacks contaminated with it
Erysipeloid or even straw remain a potential hazard.
Cutaneous inoculation is favoured by minor trauma
Erysipeloid is an acute infection due to Erysipelothrix or pre-existing skin lesions. The lesion of cutaneous
rhusiopathiae, which colonises a wide variety of anthrax, called "the malignant pustule" commonly
animals worldwide, including mammals, birds, fowl, occurs on exposed skin and is usually single. One to
fish and shellfish. It is a pathogen for many of them, five days after infection, a papule develops at the site of
especially for pigs. Human infection is contracted by inoculation. A bulla on a red oedematous zone soon
direct contact, most commonly from carcasses; this is follows. The bulla ruptures and forms a haemorrhagic
the reason why the occupations mainly affected by the crust. General symptoms of great severity appear and
disease are slaughtermen, butchers, cooks, fishermen, may be life threatening. Diagnosis is confirmed by
farmers, veterinarians and housewives. Scratches or bacteriological examination.
184 J.M. Lachapelle
The treatment of choice is intravenous penicillin G. Tularaemia

Tetracycline and erythromycin are alternative drugs.
Vaccination gives some protection, but prevention Tularaemia results from systemic infection with the
should be directed primarily at control of the disease gram-negative bacteria Francisella tularensis. Wild
in animals and disinfection of animal products (Hay rodents (in particular, hares) and other smaIl-animal
and Adriaans 1998). populations are the main reservoir of infection. In
humans, most cases are sporadic, related to tick bites
Brucellosis
(Dermacentor) or direct contact with infected animals.
Hunters are at greatest risk, but the disease also affects
Some years ago, brucellosis was a common disease in butchers, farmers, foresters, laboratory workers and
farm animals, due to three Brucella organisms: B. suis veterinarians (Evans et al. 1985). The incubation period
(pigs), B. abortus (cattle) and B. melitensis (sheep and varies from 1 day to 10 days. The clinical manifestation
goats). In recent years, the incidence of the disease has is usually an ulcerated nodule at the point of inoculation,
dramatically decreased due to extensive animal pro- associated with enlargement and, later, breakdown of
phylaxis programs, including elimination of infected lymph nodes. Systemic symptoms and toxaemia may be
animals and vaccination of healthy ones; it is weIl severe. Minocycline is considered to be efficacious in
controlled in many European countries but is still most cases (100 mg twice per day for 4 weeks).
common in some parts of the world.
Farmers, shepherds, veterinarians and slaughtermen Pseudomonas aeruginosa Folliculitis
are at risk in endemie areas. Human infection is related
to handling contaminated animals or ingesting milk Epidemics of Pseudomonas aeruginosa are now com-
and cheese that is contaminated and unpasteurised. monly associated with aquatic activities, particularly
Occupational injuries are another mode of entry. The public jacuzzis (pH > 8 and only 2-3 g free chlorine,
skin manifestations are nonspecific and range from a which is inadequate at this pH) or inadequately
maculopapular eruption to petechiae, which occur in chlorinated swimming pools. P. aeruginosa is an
less than 5% of patients. A chronic ulcer may develop organism universally present in humid environments.
at the site of inoculation or injury. Systemic symptoms Sports instructors are, of course, at risk, but most cases
include chills, high fever, headache and extreme are linked with recreational activities (Lachapelle et al.
weakness. The treatment of choice is a combination 1997). The clinical manifestations consist of a papulo-
of doxycycline (100 mg twice per day) and rifampicin pustular eruption of fulminant onset on the trunk
(300 mg 3 times per day) for 6 weeks. (Fig. 6). As the lesions are perfectly symmetrical, the
"Contact brucellosis" refers to urticarial and/or differential diagnosis is a drug eruption. The diagnosis
eczematous lesions on the skin sites in contact with is confirmed by means of microbiology. The treatment
infected animals. It is considered to be a pro tein contact of first choice is oral ciprofioxacin (500 mg twice per
dermatitis to Brucella antigens (Lachapelle et al. 1992). day). Prevention of epidemics consists of the usual
Fig. 6. Pseudomonas aeruginosa folliculitis

Biologie Causes of Oeeupational Dermatoses 185
recommendations in terms of water maintenance (pR tuberculosis. Treatment is adapted to each individual
between 7.2 and 7.8, adequate chlorination). situation; when BCGitis is confirmed, the use of
isoniazid for aperiod of 6 months is traditionally
Warty Tuberculosis prescribed.
This variety of tuberculosis occurs as a result of the

inoculation of organisms into the skin of a previously Mycobacterium marinum Mycobacteriosis:
infected patient, who usually has a moderate or high Aquarium Granuloma
degree of immunity. In occupational life, the disease
occurs by accidental superinfection from extraneous Mycobacterium marin um is the agent of a cosmo-
sources: physicians, pathologists and postmortem politan, atypical mycobacteriosis, often mentioned in
attendants are traditionally at risk. This explains the the literature under the name of aquarium granu-
traditional terms used in the past: "anatomist's warts" loma. Its natural habitat is water, particularly enclo-
and "prosector's warts" (Lundgren et al. 1987). At the sures of water that are not often replenished. It is
present time, it is an extremely rare disease in Western especially prevalent in heated water in temperate
countries. climates and in the sea and natural pools in warmer
The lesion starts as a smalI, symptomless, in dura ted, regions.
warty papule with a slight inflammatory areola. By It can be isolated from diseased fish. Pathogenic
gradual extension, a verrucose plaque is formed. Its only on abraded skin, it has been called a "leis ure-time
colour is purplish, red or brown. Usual localisations pathogen"; in fact, it is mainly observed among people
are the hands and fingers. Treatment utilises antibiotic keeping tropical fish. Apart from fish fanciers, pet-
schedules used in other forms of tuberculosis. Wearing shop hel pers can also be infected (due to infested
of appropriate gloves (resistant to cutting) is highly tropical aquariums), and this represents a true occu-
recommended in terms of primary prevention. pational disease.
The portal of entry is a minor wound which may go
Bacillus (almette-Guerin: unnoticed. The lesion presents either as a light-red,
Skin (omplications of Vaccination single nodule (Fig. 7) that is mildly keratotic or as
coalescent, purplish-red plaques on the fingers or
Bacillus Calmette-Guerin (BCG) vaccination is still dorsum of the hand. A fairly common clinical variant
compulsory for some occupational groups, according is the sporotrichoid form (Fig. 8), in which one or
to the current legislation applied in each individual several satellite nodules appear at successive intervals
country. It is an occasional source of complications on the forearm along the line of lymph drainage,
that can be summarised as folIows: (a) nonspecific sometimes in association with locoregional lymph-
reactions, including urticaria and erythema multi- adenopathy. Diagnosis seems obvious when consider-
forme; (b) nonspecific abscess formation generally ing both anamnestic data and clinical symptoms and is
resulting from an injection made too deeply; and (c) confirmed, in 70% of cases, by cultures obtained from
BCGitis, which is considered an attenuated form of a skin biopsy.
Fig. 7. Aquarium granuloma due to Myco-

bacterium marinum
186 J.M. Lachapelle
Fig. 8. Sporotrichoid form of Mycobacte-

rium marinum mycobacteriosis
Treatment schedules are still debated. Combining demarcated. It remains tradition al to describe clinical
rifampicin (15 mg/kg/day) and ethambutol (25 mg/kg/ forms of dermatophytosis according to the skin sites
day) for 6 months is a traditional approach; minocyc- that are invaded; such a division is useful for epide-
line (100 mg 2 times per day) is sometimes, but not miological studies and also for treatment strategies.
always, efficacious. Excision of the nodule has also Diagnostic procedures include (a) direct microscopy of
been proposed as a reasonable approach. the squames, which shows dermatophyte filaments,
Simple preventive measures, such as the use of and (b) culture on Sabouraud's medium for the
gloves, could reduce the incidence of infections identification of the species involved.
considerably (Gray et al. 1990). Minocycline can be
added to fish-tank water to eradicate fish infection.
Tinea Corporis
Mycotic Infertions All known dermatophytes can produce lesions of the

glabrous skin. These are perfecdy circular erythe-
Many fungi are able to infect man, provoking common mato-squamous lesions usually sharply demarcated
superficial mycoses or subcutaneous and systemic with a raised edge; in some cases, the centres of the
infections. Dermatophytoses, candidosis and pityriasis lesions are the same colour as the normal skin, with
versicolor are the most common cutaneous mycoses; a few squames, which means that spontaneous
systemic mycoses such as cryptococcosis are also of regression is underway. The degree of inftammation
prime importance in some parts of the world. In the is very variable. This feature depends not only on the
following sections, we refer only to mycotic infections species of the fungus and the immune status of the
that are provoked or significandy worsened by the host but is also roughly proportional to the extent of
work environment. follicular invasion. In the latter case, ringworm
appears as a large, round, infiltrated erythemato-
Dermatophytosis squamous plaque dotted with multiple follicular pus-
tules (Fig. 9).
Dermatophytes are related fungi capable of causing The occupational origin of many cases of tinea
skin changes of the type known as ringworm or corporis is obvious and closely related to the species of
dermatophytosis (Hay and Moore 1998). Thus defined, the dermatophyte. Among others, the most common
the ringworm species are all moulds belonging to three species are Microsporum canis (major hosts: cat, dog),
asexual genera, Microsporum, Trichophyton and Trichophyton mentagrophytes (small rodents),
Epidermophyton. It is also traditional to group M. persicolor (voles), T. verrucosum (catde), and
dermatophytes according to their ecological niche: T. equinum (horses). M. praecox, living in the horse
geophilic species originating in the soil, zoophilic environment, is apathogen for human skin. Extensive
species having animalorigins and anthropophilic forms of dermatophytosis occurring mainly on the
species, which are largely restricted to human skin. trunk and/or buttocks may be due to T. rubrum, an
However, these three groups are not always sharply anthropophilic species of dermatophyte.
Biologie Causes of Oeeupational Dermatoses 187
Epidermophyton floccosum, are together responsible

for the vast majority of cases of foot ringworm
throughout the world.
It is important to say that tinea pedis is the most
common form of dermatophytosis in most countries.
The wearing of shoes and the resultant maceration of
the toe eIeft predisposes people to this condition,
usually involving the lateral toe-eIefts. About 10% of
the total population is considered to be infected; some
subjects can be almost asymptomatic. Living in an
institution, especially where washing facilities are
shared, is likely to increase the chances of infection
(English 1969). Prevalences as high as 80% have been
reported in some factories or sport institutes. How-
Fig. 9. Tinea corporis with follicular pustules ever, tinea pedis may be equally well transmitted
within the family bathroom. Reinfection from the
environment is usual (with the same or another species
Not only workers normally in contact with domestic or with combined species). Maceration of the toe eIefts
and farm animals but also explorers, surveyors, zoo plays an important role. A simultaneous increase in the
attendants and laboratory technicians are at risk. bacterial flora mayaiso play a part. Resident bacteria,
Particular examples ineIude T. verrucosum among such as large-colony coryneforms, may be acting as
farmers (or veterinarians) and their families and important copathogens. In adolescents and children,
T. mentagrophytes among laboratory workers. Pet- swimming pools are the major source of infection.
shop and kennel workers are at risk from M. canis. The most common form of tinea pedis is located in
Sportsmen and various categories of workers (e.g. the toe webs. The fourth interdigital web is preferen-
miners) may contract T. rubrum infection (Wilkinson tially infected, but the other webs can also be infected,
1987).
on one or both feet. The eIinical symptoms are
characterised by a whitish, diffuse maceration in the
eIeft marginated by a collarette of continuous desqua-
Tinea Cruris mation (Fig. 10). In some cases, there is a small,
painful fissure running along the line of the eIeft. The
Tinea cruris is due mainly to T. rubrum, T. men- entire area is ulcerative and macerated from microbial
tagrophytes variant interdigitale and Epidermophyton superinfection. Itching is usually present. In T. rubrum
floccosum. It is probably more prevalent in tropical infections, a squamous, hyperkeratotic variety that is
zones and particularly among migrants from temper- particularly chronic and resistant to treatment and that
ate countries (Hay and Moore 1998). It is also affects the soles, heels and sides of the feet ("moccasin
commoner in men than in women. The most impor- foot"), is often found (Hay and Moore 1998). The
tant feature is the fact that tinea cruris is often dorsal surfaces of the toes and feet are not often
combined with tinea pedis: this means that all profes- affected, but associated onychomycosis is common.
sional circumstances which favour the onset of tinea Tinea pedis is sometimes associated with reactive
pedis can also be of importance for tinea cruris plantar pompholyx; extremely pruritic, coalescent
(Lachapelle et al. 1992). vesicular eczema is observed. Microscopic examina-
Clinically, lesions of tinea cruris are sharply mar- tion sometimes reveals the presence of dermatophytic
ginated, infiltrated, erythemato-squamous plaques in filaments in these so-called "id" reactions.
the groin. Vesiculation is rare, but dermal nodules
forming beading along the edge are commonly found
in older lesions. Minute pustules are often present. Tinea Manuum
Tinea Pedis Infections of the dorsal aspect of the hands resemble

ringworm of the glabrous skin. Ringworm of the
Tinea pedis corresponds to an infection of the feet or palmar skin (palm and palmar aspect of the fingers)
toes with a dermatophyte. The term althlete's foot, presents a particular eIinical picture. There is dusty
used by some to imply any form of toe-eIeft intertrigo desquamation on an erythematous background, with
(see bacterial athlete's foot) is infrequently used in the pearl white accentuation of the palmar flexor folds. The
dermatologic literature. Three anthropophilic species, appearance is very similar to that of some cases of
T. rubrum, T. mentagrophytes variant interdigitale and hyperkeratotic palmar eczema but, in tinea manuum,
188 J.M. Lachapelle
Fig. 10. Tinea pedis
scraping yields a flurry of disintegrating scabs. In most Dermatophyte Onychomycosis

cases, the organisms concerned are the three ant-
hropophilic species involved in tinea pedis. ZoophHic Dermatophyte onychomycosis is a frequently occurring
dermatophytes can also be incriminated. Apart from condition which may be isolated or associated with
animal infections, there is pre-existing foot infection tinea pedis and!or tinea manuum. The role of occupa-
with or without toenaH involvement. In this respect, tional activities is therefore similar to that in tinea
the occupational origin of tinea manuum can be pedis. It affects one or more toenails; it is less common
ascertained in some cases. The "two feet-one hand on the hands. The infection begins at the distal
syndrome" is not uncommon. An extensive study of extremity of the naH bed or naH fold. Onychomycosis
this clinical entity has been carried out recently (Daniel may have different clinical characteristics: in some
et al. 1997). From the results, it can be seen that cases, leukonychia affecting part of the distal naH
patients with a high degree of hand use in their jobs extremity but also extending along a naH fold towards
are significantly more likely to develop tinea pedis! the cuticle is the major symptom. Full thickness,
onychomycosis and tinea manuum at an earlier age. including the superficial plate, ac counts for the pearly
Tinea pedis precedes, in most cases, the development mat appearance of the infected area. In other cases,
of tinea manuum. massive destruction of the naH does occur, spicules of
which are detached all along the free border (Fig. 11).
Fig. 11. Dermatophyte onychomycosis

Irregular pigmentation - whitish at some points and Each type of dermatomycosis requires an adapted
bright yellow at others - suggests mixed infection with schedule of administration. Itraconazole and terbina-
dermatophytes and opportunistic yeasts, such as Scop- fine have been more extensively studied for these
ulariopsis brevicaulis. indications than fluconazole. In tinea corporis and
tinea cruris, the scheme of treatment is: terbinafine
250 mg/day for 2 weeks, itraconazole 100 mg/day for
Kerion Celsi
2 weeks and fluconazole 150 mg/once weekly or 50 mg/
Kerion Celsi (or tinea barbae) is a particular form of day for 2-4 weeks. Tinea manuum and tinea pedis
ringworm affecting the beard and moustache areas of require a longer period of treatment: terbinafine
250 mg/day for 4 weeks, itraconazole 100 mg/day for
the face with invasion of coarse hairs. The affected men
are commonly farm workers in cases caused by the two 4 weeks and fluconazole 150 mg/once weekly or
50 mg/day for 4 weeks.
main species, T. verrucosum and T. mentagrophytes
variant mentagrophytes. Recently, the treatment of dermatophyte on-
The infection is traditionally acquired from contact ychomycosis has been studied extensively. The sched-
with cattle, mainly during winter months, when they ules proposed are as follows: terbinafine 250 mg/day for
are kept in the cattle sheds. The clinical picture is that 3-4 months according to the severity of the disease and
of a highly inflammatory, pustular folliculitis. Hairs of the response to the treatment (Goodfield et al. 1989).
the beard or moustache regions are surrounded by red, Itraconazole is more efficient when a "pulse therapy" is
inflammatory papules or pustules, usually with exuda- conducted as follows: 100 mg four times per day for
1 week followed by 3 weeks of no treatment. Three or
tion or crusting (Fig. 12). Many hairs within the
affected areas are loose and easily removed with four consecutive waves are prescribed following the
forceps without causing pain. It is noteworthy that, same schedule (Degreef et al. 1987).
without treatment, lesions tend to settle spontaneously Kerion Celsi also requires a well-defined schedule of
but may persist for months. treatment: terbinafine 250 mg/day for 6 weeks or
itraconazole 100 mg/day for the same period. Fairly
Treatment and Management of Dermatophytosis long-term follow up is recommended, and late recur-
ren ces undoubtedly occur.
Treatment of dermatophytoses is nowadays straight- In addition to treatment, some other management
forward. The topical agents, including various imidaz- measures are generally helpful. The identification of
oles (econazole, tioconazole, isoconazole, bifonazole, the causative agent is useful, particularly where treat-
etc.) are equally efficient and can be used in all forms ment of infected animals is important, in order to
of dermatophytosis except onychomycosis (due to lack prevent other infections.
of penetration). One daily application is considered
adequate for 2-4 weeks. There is a tendency to use Prevention of Tinea Pedis
simultaneously systemic antimycotics, even in tinea
corporis, when multiple lesions are present. Specific measures of prevention can be applied to tinea
pedis. They include:
Fig. 12. Kerion Celsi

190 J.M. Lachapelle
1. Frequent was hing of changing-room floors and of workers handling food, including cooks and house-
walkways; this will remove infective material from wives. Clinical symptoms are obvious. Several fingers
skin scales are usually infected, but one or all may be involved. The
2. Use of imidazole powders to reduce levels of toenail fold is red and swollen, and there is loss of the
cleft tinea pedis cuticle and detachment of the nail fold from the dorsal
3. Prompt treatment of infected people, combined with surface of the nail plate, leading to pocketing (Fig. 13).
simple hygienic measures, such as washing shower- Occasionally, thick, white pus may discharge; often,
room floors with an antiseptic solution force is needed to express it. In more advanced cases,
nail dystrophy and onycholysis occur.
Candidosis
Treatment and Management of Candidosis
Candidosis refers to various forms of infection caused
Candida intertrigo requires specific therapy. Topical
by the yeast Candida albicans or, occasionally, other
imidazoles are commonIy used for aperiod of 2 weeks,
species of Candida. A limited number of Candida
but a longer period of treatment is sometimes needed.
infections can be directly related to the work environ-
When the toe webs are involved, attention should be
ment.
given to treating concomitant bacteria; potassium
permanganate soaks (1 part in 10,000) are, therefore,
Candida Intertrigo of the Toe Webs advisable. In general, systemic treatment is not con-
sidered for this indication.
Candidosis may affect the web spaces of the toes. Candida paronychia is often difficult to treat.
Marked maceration with a thick, white horny layer is Topical treatment is insufficient; the best therapeutic
the usual clinical symptom. Gram-negative bacteria are approach is intermittent (pulsed) itraconazole or
often copathogens. Work circumstances that favour fluconazole, following the schedules indicated in the
tinea pedis can also play a role in the occurrence of treatment of dermatophyte onychomycosis. Prevention
candidosis of the toewebs. of candidosis is straightforward. It includes the avoid-
ance of maceration at work. Chronic paronychia is best
Candida Intertrigo of the Interdigital Folds prevented by the use of appropriate gloves. The
avoidance of contact with foods incriminated in the
An erythematous, glazed, "velvety" maceration area of initiating protein contact dermatitis (assessed by
one or more folds is the usual clinical picture. There is positive prick tests) is mandatory.
often a collarette of desquamation at the periphery
(Fig. 13). Similar lesions can also develop under the
rings. In those cases, it is thought that the candidosis is
triggered by a previous skin irritation, mainly due to
detergents and/or sugar; this could explain the occur-
rence of the disease in bakeries, confectioner's shops,
chocolate factories, the fruit-packing trade, etc. Minor
trauma (such as superficial abrasions) could initiate
the infection.
Candida Paronychia
Candida albicans can be isolated in the majority of cases

of chronic paronychia. The yeast has traditionally been
considered to play an etiological role in the condition,
but bacteria and irritant or allergic contact dermatitis
also playa role, although the contribution of each varies
from patient to patient. A more recent proposal is the
primary role of repeated contact with various kinds of
foods. Proteins of foods could induce a protein contact
dermatitis (Tosti et al. 1992) and, secondarily, an
infection by Candida albicans. The primary role of the
yeast is, therefore, minimised. Professions at risk, apart
from those already quoted as prone to develop Candida Fig. 13. Candida intertrigo of an interdigital fold with parony-
intertrigo of the interdigital folds, include all categories chia
Subcutaneous Mycoses the bloodstream, from the original site of infection to

different organs, including the skin (Hay and Moore
Subcutaneous mycoses, or mycoses of "implantation" 1998). We have summarised, in Table 2, some of the
are sporadically occurring infections caused by fungi features of the most important systemic mycoses,
present in the natural environment, which are directly including occupational sources of infection.
inoculated into the dermis or subcutaneous tissue
through a penetrating injury. They are not common,
even in endemic countries, and are mainly seen in the Parasitic Infections
tropics (Hay and Moore 1998). We have summarised,
in Table 1, some of the features of the most important Various parasites may cause skin disease; as with
subcutaneous mycoses, including occupational sources bacteria, any can cause occupational disease under
of infection. favourable conditions. The list of these diseases is so
long that the reader is referred to classic textbooks of
Systemic Mycoses dermatology for a complete description (Bryceson and
Hay 1998; Bums 1998). In many circumstances, the
The systemic mycoses are fungal infections that causes of parasitic infections are more environmental
involve deep structures and disseminate, usually via than occupational.
Table 1. Main subeutaneous

myeoses implying oeeupational Myeosis Fungus Endemie areas Oeeupational Workers
sourees of infeetion sourees of affeeted
infeetion
Sporotriehosis Sporothrix Cosmopolitan; Inoeulation Common among

schenkii more frequent by trauma South Afriean
in the Amerieas (thorns, miners; sporadie
and South Africa splinters, ete.) among forestry
than in Europe workers, florists
or gardeners
Myeetoma Various Tropieal and Inoeulation by Agrieultural
species of subtropieal trauma workers
fungi or eountries (thorns,
aetinomyeetes splinters, ete.)
Chromoblasto Various Various eountries Inoeulation Agricultural
myeosis species throughout by trauma workers
of fungi the world.
Rare in Europe
(imported eases
mostly)
Table 2. Main systemie myeoses

implying oeeupational sourees of Myeosis Fungus Endemie areas Oeeupational sourees Workers affeeted
infection of infection
Histoplasmosis Histoplasma Cosmopolitan, Soil eontaminated Cleaners,

capsulatum but very rare with ehieken laboratory
in Europe feathers or workers,
droppings speleologists
(oeeasionally
bat droppings);
airborne eonidia
Blastomyeosis Blastomyces North and Wood debris Agrieultural
dermatitidis Central Ameriea, and soil workers
Middle East, dose to rivers
India, Poland,
Zimbabwe
Coecidioido Coccidioides Southwestern Inhalation of Travellers in
mycosis immitis states of the airborne spores endemie areas,
USA, Central agrieultural
and South workers
America
Paraeoecidioido Paracocci- Latin American Inhalation of Agrieultural
myeosis dioides eountries airborne spores workers
brasiliensis
192 J.M. Laehapelle: Biologie Causes of Oeeupational Dermatoses
References Hay RJ, Adriaans BM (1998) Anthrax. In: Champion RH, Burton
JL, Bums DA, Breathnach SM (eds) Textbook of dermatology,
6th edn. Blackwell Science, Oxford, pp 1136-1137
Bamham M, Neilson DJ (1987) Group L beta haemolytic Hay RJ, Moore M (1998) Mycology. In: Champion RH, Burton JL,
streptococcal infection in meat handlers: another streptococ- Bums DA, Breathnach SM (eds) Textbook of dermatology,
cal zoonosisl Epidemiol Infect 99:257-264 6th edn. Blackwell Science, Oxford, pp 1277-1376
Bryceson ADM, Hay RJ (1998) Parasitic worms and protozoa. In: Jablonska S, Obalek S, Golebiowska A, Favre M, Orth G (1988)
Champion RH, Burton JL, Bums DA, Breathnach SM (eds) Epidemiology of butchers' warts. Arch Dermatol Res
Textbook of dermatology, 6th edn. Blackwell Science, Oxford, 280(Suppl):24-28
pp 1377-1422 Keefe M, al-Ghamdi A, Coggon D, Maitland NJ, Egger P, Keefe q,
Bums DA (1998) Diseases caused by arthropodes and other Carey A, Sanders CM (1994) Cutaneous warts in butchers. Br
noxious animals. In: Champion RH, Burton JL, Bums DA, J Dermatol 130:9-14
Breathnach SM (eds) Textbook of dermatology, 6th edn. Lachapelle JM, Frimat P, Tennstedt D, Ducombs G (1992) Precis
Blackwell Science, Oxford, pp 1423-1481 de Dermatologie Professionnelle et de I'Environnement.
Daniel CR III, Gupta AK, Daniel MP, Daniel CM (1997) Two feet- Masson, Paris
one hand syndrome: a retrospective multicenter survey. Int J Lachapelle JM, Tennstedt D, Marot L (1997) Atlas of environ-
Dermatol 36:658-660 mental dermatology. UCB Pharma, Braine-l' Alleud, p 166
De Peuter M, De Clercq B, Minette A, Lachapelle JM (1977) An Lundgren R, Norrman E, Asberg I (1987) Tuberculosis infection
epidemiological survey of virus warts of the hands among transmitted by autopsy. Tubercle 68:147-150
butchers. Br J Dermatol 96:427-431 Pema JJ, Mannix ML, Rooney JF, Notkins AL, Straus SE (1987)
Degreef H, Marien K, De Veylder H, Duprez K, Borghys A, Reactivation of latent herpes simplex virus infection by
Verhoeve L (1987) Itraconazole in the treatment of de- ultraviolet light: a human model. J Am Acad Dermatol 17:
rmatophytoses: a comparison of two daily dosages. Rev Infect 473-478
Dis 9(Suppl):I04-108 Ramanan C, Ghorpade A, Kalra SK, Mann S (1996) Buffalopox.
English MP (1969) Tinea pedis as a public health problem. Br J Int J Dermatol 35:128-130
Dermatol 81:705-707 Sterling JC, Kuntz JB (1998) Viral infections. In: Champion RH,
Evans ME, Gregory DW, Schaffner W, McGee ZA (1985) Burton JL, Bums DA, Breathnach SM (eds) Textbook of
Tularemia: a 30-year experience with 88 cases. Medicine dermatology, 6th edn. Blackwell Science, Oxford, pp 1001-1004
(Baltimore) 54:252-269 Tosti A, Guerra L, Morelli R, Bardazzi F, Fanti PA (1992) Role of
Gill MJ, Arlette J, Buchan KA (1990) Herpes simplex virus foods in the pathogenesis of chronic paronychia. J Am Acad
infection of the hand. J Am Acad Dermatol 22:111-u6 Dermatol 27:706-710
Goodfield MJD, Rowell NR, Forster RA, Evans EG, Raven A (1989) Weinberg AN, Swartz MN (1999) In: Freedberg IM, Eisen AZ,
Treatment of dermatophyte infection of the finger- and toe- Wolff K, et al. (eds) Fitzpatrick' s dermatology in general
nails with terbinafine in onychomycosis. Br J Dermatol medicine, 5th edn. McGraw-Hill, New York, pp 2260-2261
121:753-758 White WB, Grant-Kels JM (1984) Transmission ofherpes simplex
Gray SF, Smith RS, Reynolds NJ, Williams EW (1990) Fish tank virus type 1 infection in rugby players. JAMA 252:533-535
granuloma. BMJ 300:1069-1070 . . Wilkinson DS (1987) Biologic causes of occupational dermatoses.
Grezard P, Philippot V, Perrot H (1995) InCldents et aCCldents In: Maibach HI (ed) Occupational and industrial dermatol-
de la vaccination contre l'hepatite B. J Med Lyon 1502: ogy, 2nd edn. Year Book Medical, Chicago, pp 56-74
1133-1136 Wolf F, Grezard P, Berard F, Clavel G, Perrot H (1998)
Groves RW, Wilson-Jones E, MacDonald DM (1991) Human orf Generalized granuloma annulare and hepatitis B vaccination.
and milkers' nodule: a clinicopathological study. J Am Acad Eur J Dermatol 8:435-436
Dermatol 25:706-711
CHAPTER 23
Occupational Airborne Skin Diseases

I.M. Lachapelle
Introduction Airborne Offending Agents
Most patients consulted in occupational dermatology Airborne offending agents are present under various
are referred to as contact dermatitis cases; conceptu- forms.
ally, the term "contact dermatitis" implies a direct
contact of the skin with the offending (liquid and/or Fibres
solid) agents. It is not surprising that, in this respect,
hand dermatitis is the major complaint; this is due to Different types of fibres can be implicated (Stam-
direct manipulation - at work - of thousands of Westerveid et al. 1994). The most classical example is
different products. It is clear that other skin sites can fibreglass. Other examples include rock wool, carbon
also be affected, either direct1y or indirect1y (i.e. by the fibres and plastic materials, such as polypropylene fibres,
transfer of chemieals by hands). etc. Fibres can be chemically inert and provoke only
Outside of this "familiar landscape", the occurrence mechanical trauma to the skin. Carbon fibre dermatitis
of occupational airborne dermatoses, i.e. due to agents and most cases of fibreglass dermatitis are good exam-
carried by or through the air, has been underestimated pIes of this condition. However, some fibres, such as
in the past. Pirilä (1950) was the first to promote the epoxy-coated fibreglass, can produce allergie reactions.
concept of airborne dermatoses on clinical and exper-
imental grounds. In his extensive paper, the author Dust Particles
called attention - almost exclusively - to allergie
conditions, referring, for instance, to cases of thiokol Dust is ubiquitous in the work environment. Dust
dermatitis he had observed in Finland after World War particles are transported by air; they can agglomerate,
11. Later on, examples of occupational dermatoses visibly or invisibly, at the surface of the skin. Like
closely related to those caused by airborne skin fibres, some dust particles are chemically inert but can
offenders were occasionally reported throughout the provoke mechanical (frictional) injury to the skin,
relevant literature (Pirilä et al. 1963). whereas other particles contain chemie als that are
In the 1980s, more attention was paid to the dissolved by sweat; depending on their nature, these
problem after the publication of two review articles chemie als are responsible for several types of skin
(Dooms-Goossens et al. 1986; Lachapelle 1986); now- reactions (Lachapelle 1987).
adays, each year brings a blossom of new observa-
tions coming from various parts of the world. These Sprays
publications reftect the diversity of problems encoun-
tered as a result of new chemieals and/or modified Water or other liquid-based products moving in a mass
technical procedures. A better knowledge of occupa- of dispersed drop lets represent an important source of
tional airborne dermatoses has practical implications airborne offending agents. Any of numerous commer-
in terms of diagnosis, treatment and prevention. cial products, including paints, cosmetics and insecti-
There is a clear distinction to be made between eides that are dispensed from containers in this manner
airborne dermatoses and the "sick-building syn- are good examples. Skin reactions may be of several
drome"; the latter refers to epidemics of subjective types: irritant, eczematous, urticarial or combined.
symptoms (itching or burning sensations) without
any clinically visible signs, which occur in the work Vapours and Gases
environment. This situation can be related, for
instance, to low relative humidity but may also Vapour is defined as barely visible or cloudy, diffused
represent a mass psychogenic illness. matter, such as mist, fumes or smoke, suspended in

194 J.M. Lachapelle
the air. Gas has a more restricted meaning. Vapours Table 1. Classifications of occupational airborne contact derma-
and gasses may be, like sprays, irritant, allergenic or toses
both. Occupational airborne irritant (frictional and/or chemical)
contact dermatitis
Occupational airborne allergic c?ntact dermatitis ..
Occupational airborne phOtOtOXIC ~ontact dermahh~ .
Classification Occupational airborne photoallerglC contact dermahhs
of Occupational Airborne Skin Diseases Occupational airborne (immunological and/or
non immunological) contact urticaria
Two categories of occupational airborne skin diseases
must be considered.
Occupational Airborne Irritant (Frictional
and/or Chemical) Contact Dermatitis
"Systemic" Occupational Airborne Skin Diseases
Airborne Irritant Contact Dermatitis Due to Fibres
Some skin conditions are a result of the toxic
Subjective symptoms are always present. Itching,
effects of chemicals that have been absorbed into
stinging and burning sensations are the usual com-
the body tissues either by inhalation or trans dermal
plaints of many patients, with or without objective
penetration. Wehave coined the term "system~c"
signs. In particular, facial complaints are not often
occupational airborne skin disease by analogy wlth
accompanied by detectable lesions; they correspond to
the term "systemic contact dermatitis" (Lachapelle
the so-called "subjective irritant dermatitis". The
1999)· eyelids, cheeks, nasal folds and neck are commonly
The most classical example is chloracne, which,
involved. Subjective symptoms may occur on covered
though rare, may serve as an extremely important
parts of the body, mainly in the flexures (axillae,
indicator of internal poisoning and should be
groins, cubital and/or popliteal fossae) but also on the
recognised by physicians treating occupational skin
extensor aspects of the limbs or on the trunk.
disease. Cloracneigenic substances, such as polyha-
Objective symptoms are usually present but vary in
logenated naphthalenes are well known (Coenraads
severity from case to case. Scratch marks, tiny papules
et al. 1994); tetrachloro-2,3,7,8-dibenzo-p-dioxin was
or a maculopapular rash are the usuallesions (Fig. 1).
the agent incriminated in the Seveso catastrophe,
Severe cases could involve secondary infection (pus-
which occurred in northern Italy in 1976 (Plewig and
tules) from scratching. The most typical example
Kligman 1993). Other examples of systemic oc.cupa-
quoted in the literature is fibreglass dermatitis. Symp-
tional airborne derma tos es have been reported In the
toms include itching and prickling in areas of the skin
literature (Kanerva et al. 1991), but they are scarce
and often poorly documented.
Occupational Airborne Contact Dermatoses
This group refers to all skin symptoms directly related

to airborne contact of the skin with the accountable
agents. In fact, all varieties of contact dermato~es due
to direct contactants can also be provoked by alrborne
contactants. Furthermore, in many cases, direct con-
tact and airborne contact can occur simultaneously;
contact urticaria to latex pro teins (Lagier et al. 1990)
or allergic contact dermatitis to epoxy resins (Sommer
et al. 1998; Le Coz et al. 1999) represent two good
examples of such situations.
A system classification of occupational airborne
contact dermatoses is proposed in Table 1. Although
no specific criteria do exist for assessment of an
airborne origin, some morphological and/or topo-
graphical aspects of the disease can help in the
diagnostic procedure, as explained in the next para-
graphs.
Fig. 1. Fibreglass dermatitis: tiny papules and scratch marks
Occupational Airborne Skin Diseases 195
that come into contact with fibreglass spicules present Airborne Irritant Contact Dermatitis
in the work environment. Scratch marks, papules and Due to Dust Particles
pustules are sometimes present (Fisher 1982; Koh et al.
1992). To some extent, airborne irritant contact derma- Two different situations have to be taken into consid-
titis may resemble scabies. eration when examining airborne irritant contact
The presence of fibres encrusted in the horny layer dermatitis due to dust particles. First, the dust
of the epidermis is clearly shown by the skin surface particles are "chemically inert". Skin symptoms are
biopsy technique (Marks and Dawber 1971). The related to the mechanical (frictional) properties of
method consists of the following very simple steps: particles. It is not clear whether the shape of the
(a) a drop of cyanoacrylate glue is placed on the skin; particles (e.g. particles with sharp edges) plays an
(b) a clear glass slide is gently pressed on the drop for important role or not (Fig. 2). Many other concomi-
30 s; and (c) the slide is then removed. A slight tant factors are probably important, such as ambient
modification consists of using polyester tape instead of heat, low humidity, sweating and/or an atopic state.
glass as the holder (Lachapelle et al. 1977). Foreign The clinical symptoms are quite similar to those
material present at the surface of the skin or encrusted observed with fibres. Facial complaints are usually
in horny cells is removed with the adhesive, which prominent; the eyelids, cheeks, nasal folds, retroauric-
remains attached to the glass slide or the plastic sheet; ular folds and neck are commonly involved. Workers
the foreign material can be visualised under a micro- wearing ill-fitted masks sometimes complain of itching
scope. of the face due to the accumulation of dust under the
Other examples of fibres that cause dermatitis mask, particularly in the nasal folds. Subjective and
include glass wool, rock wool, and carbon, ceramic, objective complaints can also occur on covered parts
polypropylene and urea-formaldehyde insulating- of the body due to the accumulation of dust particles
foam fibres, etc. In all cases, the symptoms are similar under the garments. Indeed, solid particles can pass
to those observed in fibreglass dermatitis but are easily under protective clothes, most often between
usually milder. It is obvious that clinical manifesta- sleeves and gloves; dust particles can also accumulate
tions are due to a mechanical effect, either frictional or on the skin of the feet even when workers wear safety
a result of encrustment of fibres in the skin. The shoes.
diameter of the fibres seems to be crucial in explaining The second situation is that in which the dust
the severity of skin symptoms (Lachapelle 1986; Stam- particles are not chemically inert. They release irritant
Westerveid 1997). substances (acidic, alkaline or neutral) that are
In our experience, the diameter of most fibres responsible for true irritant (i.e. chemically induced)
incriminated in airborne contact dermatitis was be- contact dermatitis. When dust material is suspended
tween 6 !im and 20 !im. Atopics are undoubtedly more in distilled water, the pH of the supernatant can be
prone to develop severe symptoms than non-atopics very alkaline, as mentioned in some reports (Lacha-
(Björnberg et al. 1979). This can be clearly demon- pelle et al. 1984). Examples of dust materials produc-
strated when epidemics of fibre dermatitis occur in ing alkaline solutions include anhydrite (pH: 11.2),
factories. sewage sludge (pH: 11) and trona (pH: 10.5). Dried
Fig. 2. Dust particles with sharp edges (po-

larised light; x 100)
196 J.M. Lachapelle
industrial dyes show a wide range of pH. In these Oeeupational Airborne Allergie Contact Dermatitis
situations, eIinical symptoms are unequivocaIly typical
of irritant contact dermatitis. Eyelids are preferentiaIly Occupational airborne allergie contact dermatitis
involved due, not only to the accumulation of parti- seems to be very frequent, according to recent liter-
eIes, but also to the increased penetration of chemie als ature. Airborne "contact" allergens can be volatile
into the skin. (vapours and/or gasses), transported in the form of
sprays (minidroplets), or present in dust partieIes; all
physical forms are common in the work environment.
Airborne Irritant Contact Dermatitis A list of allergens is quoted in Table 2 (Dooms-
Due to Sprays, Vapours and Gases Goossens et al. 1986; Dooms-Goossens and Deleu 1991;
Tennstedt et al. 1994).
In contrast to fibre and/or dust-partieIe dermatitis,
which may affect covered as weIl as uncovered parts Table 2. Selected allergens responsible for occupational airborne
of the body, occupational airborne contact dermatitis allergie contact dermatitis
related to sprays, vapours and/or gas ses is almost
exeIusively limited to uncovered parts. The face and Animal feeds
Bryozoans (Dogger Bank itch)
neck are usually involved; eIinical symptoms are Chromate, i.e. from cement dust or from welding fumes
typical of irritant contact dermatitis. Itching, stinging Cobalt, i.e. from cement dust
and burning sensations are the usual complaints that Colophony (in woodcutting and soldering)
Drugs (and/or chemieals used in the synthesis of drugs in
precede the occurrence of a maculopapular rash the pharmaceutical industry)
(Fig. 3). The lesions may be limited to the eyelids or Epoxy resin, when heated
extend to the whole face and neck, sparing some Epoxy hardeners
Epoxy reaction diluents
partly protected areas, such as retroauricular folds or Formaldehyde
the margins of the scalp. Organic solvents, ammonia Fulminate
and formaldehyde are often quoted as tradition al Pesticides
Plastics, such as acrylates and phenolformaldehyde res ins
offending agents, but many others can be incriminat- (see also epoxy res ins )
ed, such as acids and alkalis, domestic products (e.g. Sesquiterpene lactones, such as those in Compositae
eIeaning products), industrial solvents, carbonless or Frullania
Sulphur compounds
copy paper or phenol vapours (Dooms-Goossens et al. Turpentine
1986). Woods (wood dust from exotic or indigenous woods)
Fig. 4. Airborne allergie contact dermatitis to propacetamol (Pro-

Fig. 3. Perchlorethylene-fume irritant dermatitis after cleaning Dafalgan) in a female nurse prior to injection into the infusion
an unventilated tanl<. Extensive, erythematous, pruritic plaques set. Erythematous, intensely pruritic lesions of the face, with
on the lateral aspect of the neck marked malar oedema
Oeeupational Airborne Skin Diseases 197
The clinical symptoms are typieal of allergie contaet high molecular weight (mainly proteins) present in
dermatitis. There is no specifie sign indicating air- house dust, pollens, moulds, etc.
borne contact. Eczematous lesions are symmetrie al in 4. Photo allergie contact dermatitis, bearing in mind
most cases (Fig. 4); they are acute or chronie, depend- that some photo allergie reactions can be initiated by
ing on the environmental eonditions (nature and/or airborne agents. In contrast to allergie airborne
eoncentration of the allergens, frequency of air borne contact dermatitis, some parts of the face are
contact, and so on). For instance, dermatitis from relatively or completely spared in non-airborne
wood dust normally starts on the eyelids (Fig. 5) or the photoallergie reactions, including the eyelids, sub-
lower half of the face, often preceded by aperiod of mental region and retroauricular folds. In most
itching. Swelling and redness spread to the neck, hands cases, lesions of allergie airborne contact dermatitis
and forearms. By the time the patient presents for are symmetrical.
treatment, a diffuse dermatitis may have developed, 5. Seborrhoeic dermatitis, sometimes worsened bywork
distinctly limited at the margins of the sleeves and conditions, such as irritant fumes or dusts, high
collar. Because of the accumulation of dust and sweat, temperature involving increased sweating and so on.
the elbow fiexures and the skin under a tight collar are
often lichenified. As already emphasised, airborne
allergie contact dermatitis has no specific clinical
Occupational Airborne Phototoxic
features. Therefore, there is no magie clue that leads to
and Photoallergie Contact Dermatitis
an unequivocal diagnosis. Anamnestic data, analysis of
symptoms and patch-test results are needed to reach a
Phototoxic and/or photo allergie chemieals can be
correct conclusion.
airborne. In practice, there is no clinical sign that
Differential diagnosis of facial allergie airborne
allows a clear-cut distinction between direct contact
contact dermatitis includes:
and airborne contact dermatitis. Both produce a
1. "True" (or direct) contact allergie contact dermati- similar type of eruption. On theoretical grounds,
tis. Asymmetry of facial lesions is a clinical sign in phototoxic reaetions are more sharply demarcated,
favour of "true" (or direct) allergie contact; this whereas photo allergie reactions display ill-defined
assertion must be cautious, due to the fact that some margins, but there are many exceptions to this general
airborne allergens can be sprayed on the face in an rule. However, it can be claimed that, in non-airborne
asymmetrical way at the workplace. phototoxic or photoallergie reactions, some parts of
2. Flare-up of the so-called "id" type, including (even- the face are relatively or completely spared whereas, in
tually) systemic contact dermatitis. airborne ones, no part is spared. Once again, the rule
3. Atopic dermatitis limited to the face. The distinction suffers many exceptions. Diagnosis is, therefore, based
between both conditions is difficult to assess in on carefully gathered anamnestic data, analysis of
many cases. The complexity of the problem has symptoms and signs, and patch-test and photopatch-
increased in recent years due to the knowledge that test results (Lachapelle et al. 1992).
facial signs of atopic dermatitis could be triggered, Occupational airborne phototoxic agents, includ-
worsened or even provoked by various allergens of ing coal tar and its derivatives, e.g. anthracene,
Fig. 5. Airborne allergie contact dermatitis

to meranti (an exotic wood) dust particles.
Extensive eczematous lesions of the eyelids
198 J.M. Lachapelle
acridine, phenanthrene, pyrene, are rarely incrimi- Jones 1998). Other offending agents responsible for
nated. Dyes and furocoumarins are quoted in most occupational airborne immunological contact urticaria
textbooks. Photoallergenic molecules include fra- are cosmetics, fruit, vegetables, animal hair, ammonium
grance ingredients (in the cosmetic industry), coal- persulphate, anhydrides (Tarvainen et al. 1995), etc.
tar derivates, olaquindox and several drugs (in the Nonimmunological airborne urticarial reactions oc-
pharmaceutical industry). Combined airborne and cur less frequently in occupational life. Processionary
photoaggravated contact allergies, as seen with caterpillars, very common in the south of France,
Compositae and lichens, present difficulties in diag- provoke airborne reactions, mainly of the urticarial
nosis (Thune 1977). type, nonimmunological or immunological (the of-
fending molecule is thaumetopoein, molecular weight
28 kDa). The disease is quite common among fore sters.
Occupational Airborne (Immunological
and/or Nonimmunological) Contact Urticaria
Diagnostic Procedures
Occupational airborne contact urticaria has been
underestimated in the past. In most cases, it is the The diagnosis of occupational airborne contact der-
clinical expression of an immunological reaction of the matitis may be extremely difficult. The approach to
immediate type and is mediated by immunoglobulin E. each individual case consists of various steps that can
Allergy to natural rubber latex has now become a major be discussed in an algorithmic way. The major issue is
health-care issue. Direct contact urticaria due to latex to determine whether or not the clinical symptoms
gloves affects both hands, but natural rubber latex indicate such a diagnosis. The classical tools available
proteins are absorbed onto the maize-starch powder of for diagnosing occupational contact dermatitis can, in
gloves; these are released into the air when the packets general, be applied to occupational airborne contact
are opened or gloves are pulled out of multipack boxes dermatitis. These include: anamnestic data, clinical
(Tennstedt and Lachapelle 1998). The particles contam- symptoms, exacerbation (or not) of symptoms during
inate the air and, in operating theatres with recirculated work activities, determination of the occurrence of all
air systems, the allergens can be spread to the whole offending agents at the workplace, knowledge of the
theatre suite and cause different clinical problems, chemical nature of these agents, etc.
including urticarial plaques on the face (Fig. 6), When an airborne contact is reasonably suspected,
conjunctivitis, rhinitis and even asthma (Handfield- the following strategy is recommended:
1. Patch testing and/or photopatch testing, which are
performed in the usual way. There are no specific
techniques that are recommended for airborne
dermatitis. The methodology also includes addition-
al procedures, such as open tests, repeated open-
application tests and, eventually, use tests.
2. Prick testing. Prick tests are needed when airborne
contact urticaria or protein contact dermatitis (i.e.
to latex or pollen proteins) is suspected.
3. Procedures useful in the diagnosis of irritant occu-
pational airborne contact dermatitis. Some proce-
dures are available that permit one to evaluate the
potential accountability of so me offending agents for
provoking airborne irritancy of the skin. This
approach cannot be achieved without the collabo-
ration of occupational physicians and/or safety
officers. It also requires laboratory equipment and
dermatological expertise in the field.
The following steps are usually recommended:
1. Visit by the dermatologist to the workplace and
analysis of the technical aspects of the work
Fig. 6. Airborne immune contact urticaria of the face caused by procedure.
the dispersion of corn-starch particles with a high latex-protein
content in a female operating-theatre nurse presensitised by latex 2. Collection of sampies (i.e. suspected fibres, dusts or
gloves liquids sprayed in the air).
Occupational Airborne Skin Diseases 199
3. Analysis of samples, induding pH, physical and Kanerva L, Estlander T, Jolanki R, Lahteenmaki MT, Keskinen H
chemical properties of chemicals, etc. (1991) Occupational urticaria from welding polyurethane.
J Am Acad Dermatol 24:825-826
4. Determination of the presence of particles (and, Koh D, Aw TC, Foulds IS (1992) Fiberglass dermatitis from
eventually, of chemicals) in the skin (i.e. using skin- printed circuit boards. Am J Ind Med 21:193-198
surface biopsy). Lachapelle JM (1986) Industrial airborne irritant or allergie
contact dermatitis. Contact Dermatitis 14:137-145
5. Evaluation of the irritant potential of collected Lachapelle JM (1987) Industrial airborne irritant contact derma-
materials on the skin of workers or volunteers by titis due to dust particles. Boll Dermatol Allergoi Profess 2:83-
means of noninvasive techniques (such as transepi- 89
Lachapelle JM (1999) Eczemas "systemiques". In: Saurat JH,
dermal water loss, erythrometry, laser-Doppler Grosshans E, Laugier P, Lachapelle JM (eds) Dermatologie et
fiowmetry and others). maladies sexuellement transmissibles. Masson, Paris, p 50
6. Evaluation of the relative rate of humidity in the air. Lachapelle JM, Gouverneur JC, Boulet M, Tennstedt D (1977) A
modified technique (using polyester tape) of skin surface
7. Use of an exposure chamber designed for experi- biopsy. Br J Dermatol 97:49-52
ments with controlled exposure to airborne parti- Lachapelle JM, Mahmoud G, Vanherle R (1984) Anhydrite
dermatitis in COai mines: an airborne irritant reaction
des, mainly skin and respiratory allergens and
assessed by laser Doppler flowmetry. Contact Dermatitis
irritants. The aims are to study skin effects and to 11:188-189
develop methods for the measurement of the depo- Lachapelle JM, Frimat P, Tennstedt D, Ducombs G (1992) Precis
de Dermatologie Professionnelle et de l'Environnement.
sition of partides on the skin (Liden et al. 1998). Masson, Paris, pp 107-111
8. Review of the relevant literature. Lagier F, Badier M, Martigny J, Charpin D, Vervloet D (1990)
Latex as aeroallergen. Lancet 336:516-517
Using such techniques does not lead - in many Le Coz CJ, Coninx D, Van Rengen A, EI Aboubi S, Ducombs G,
instances - to a final condusion, but it allows Benz MH, Boursier S, Avenel-Audran M, Verret JL, Erikstam
recommendations in terms of preventive measures U, Bruze M, Goossens A (1999) An epidemie of occupational
contact dermatitis from an immersion oil for mieroscopy in
that will be applied and evaluated by occupational laboratory personnel. Contact Dermatitis 40:77-83
physicians. Liden C, Lundgren L, Skare L, Linen G, Tornlings G, Krantz S
(1998) A new whole-body exposure chamber for human skin
and lung challenge experiments - the generation of wheat
flour aerosols. Ann occup Hyg 42:541-547
Treatment and Prevention Marks R, Dawber RPR (1971) Skin surface biopsy: an improved
technique for the examination of the horny layer. Br
J Dermatol 84:117-123
Treatment and prevention measures commonly used Pirilä V (1950) Thiokol as a frequent cause of dermatitis. Allergy
in occupational dermatology can be applied to air- 3:319-328
Pirilä V, Noro L, Laamen A (1963) Air pollution and allergy.
borne dermatoses. Allergy 18:113-130
Plewig G, Kligman AM (1993) Acne and rosacea, 2nd edn.
Springer, Berlin Heidelberg New York, pp 360-395
Sommer S, Wilkinson SM, Wilson CL (1998) Airborne contact
dermatitis caused by microscopy immersion fluid containing
epoxy resin. Contact Dermatitis 39:141-142
References Stam-Westerveld EB (1997) Man-made mineral fibres: glasvezei-
en steenwoldermatitis. Ned Tijdschr Dermatol Venereol
Björnberg A, Lowhagen G, Tengberg JE (1979) Relationship 7:196-198
between intensities of skin test reactions to glass fibers and Stam-Westerveld EB, Coenraads PJ, van der Valk PG, de Jong
chemical irritants. Contact Dermatitis 5:171-174 MC, Fidler V (1994) Rubbing test responses of tl1e skin to
Coenraads PJ, Brouwer A, ülie K, Tang N (1994) Chloracne. Some man-made mineral fibres of different diameters. Contact
recent issues. Dermatol Clin 12:569-576 Dermatitis 31:1-4
Dooms-Goossens A, Deleu H (1991) Airborne contact dermatitis: Tarvainen K, Jolanki R, Estlander T, Tupasela ü, Pfaffli P,
an update. Contact Dermatitis 25:211-217 Kanerva L (1995) Immunologie contact urticaria due to
Dooms-Goossens A, Debusschere KM, Gevers DM, Dupre KM, airborne methylhexahydrophthalic and methyltetra-
Degreef HJ, Loncke JP, Snauwaert JE (1986) Contact hydrophthalie anhydrides. Contact Dermatitis 32:204-209
dermatitis caused by airborne agents. J Am Acad Dermatol Tennstedt D, Lachapelle JM (1998) Allergy to latex. Nouv
15:1-10 Dermatol (Strasbourg) 17:397-398
Fisher AA (1982) Fiberglass vs mineral wool (rockwool) derma- Tennstedt D, Leroy B, Lachapelle JM (1994) Dermatoses de
titis. Cutis 29:415-416 contact aeroportees d' origine allergique. Ann Dermatol
Handfield-Jones SE (1998) Latex allergy in health-care workers Venereol 121:850-854
in a English district general hospital. Br J Dermatol 138: Thune P (1977) Contact allergy due to lichens in patients with a
273-276 history of photosensitivity. Contact Dermatitis 3:267-272
CHAPTER 24
Occupational Contact Urticaria

s. Iris Ale and H.l. Maibach
Introduction vesicles appearing usually on previously eczematous

skin are seen in protein contact dermatitis. Extracu-
taneous symptoms may also occur as part of a more
The contact urticaria syndrome (CUS) (immediate-
severe reaction and may include rhinoconjunctivitis,
contact rea~tions), first defined as a biologie al entity in
asthmatic attack and orolaryngeal or gastrointestinal
1975 by Ma1bach and Johnson [1], comprises a heter-
dysfunctions. Finally, anaphylaxis may occur as the
ogeneous group of inflammatory reactions that usually
most severe manifestation of CUS.
appear within minutes after cutaneous or mucosal
Contact urticaria usually clears spontaneously; re-
contact with the eliciting agent - although delayed-
peated exposure may produce dermatitis (eczema). In
onset reactions are sometimes observed [2] - and
addition, it may be associated with allergie contact
disappear within 24 h, usually within a few hours. The
der~atitis (type-IV hypersensitivity). von Krogh and
term "syndrome" clearly illustrates the biological and
Ma1bach [4] tested 67 patients for immediate and
clinical polymorphism of this entity, which may be
delayed hypersensitivity, and 22 (33%) developed a
either localized or generalized and may involve organs
positive delayed response subsequent to the initial
other than the skin, such as the respiratory or the
wheal-and-flare re action. The responsible agents were
gastrointestinal tract, as well as the vascular system,
food products, rubber latex, cinnamic aldehyde, para-
displaying a wide spectrum of clinical manifestations,
aminodiphenylamine, ethylaminobenzoate, ammo-
ranging from mild erythema and/or itching, to death
nium persulfate, teak, epoxy resin and lemon perfume.
[3-5]. Numerous cases of CUS continue to be reported
They suggested that the term "contact dermatitis of
and the list of etiologic agents constantly increases,
im~e~~ate and delayed type" be used for patients
providing evidence for the high frequency of these
exhlbltmg both types of reactions in the test situation,
entities [6-10]. A complete overview of CUS is found in
whether the initial reaction is uncharacteristic urtica-
Amin et al. [10].
rial or vesicular [4]. '
Occupational contact urtiearia (OCU) refers to those
Not only contact urticaria may produce dermatitis,
immediate contact reactions caused by exposure to
but immediate contact reactions aggravating chronie
substances in the work environment. Contact urticaria
~e~matitis have been reported [2, 4, 6, 12]. A previous
is common in occupational settings [u], and its
lrn~ant contact dermatitis produced by the working
prevalence should be expected to increase because of
enVIronment may predispose one not only to allergie
workers' increasing exposure to a variety of industrial
contact dermatitis but also to immediate contact
materials.
Table 1. The contact urticaria syndrome: staging by symptoma-
tology. Adapted from [2]
Symptoms and Nomenclature
Cutaneous reactions only
The symptoms can be classified according to mor- Stage 1 Localized urticaria

phology and severity (Table 1) [2, 4]. In the invisible Dermatitis
Nonspecific symptoms (itching, tingling,
contact urticaria, only subjective symptoms (itching, burning, etc.)
tingling or burning) without any objective change or Stage 2 Generalized urticaria
just a mild erythema occur. These reactions are often Cutaneous and extracutaneous reactions
Stage 3 Rhinoconjunctivitis
seen from cosmetics and from fruits and vegetables. Orolaryngeal symptoms
Wheal-and-flare at the contact area is the prototype of Bronchial asthma
contact urticaria, while generalized urticaria following Gastrointestinal symptoms
Stage 4 Anaphylactic symptoms
a local contact is less common. Tiny dyshidrotie

Occupational Contact Urticaria 201
reactions. A defective skin barrier function might they seem to induce nonspecific rather than specific
facilitate the penetration of macromolecules, such as IgE production in peripheral B cells. Sometimes the
protein allergens that have been proven to be respon- ICU re action extends beyond the contact area and
sible for most of the immediate-contact-type reactions generalized urticaria or even anaphylaxis may occur.
[12, 13]. Fortunately, the appearance of severe systemie reac-
tions is less common, but it may occur in highly
sensitized patients and/or after a widespread exposure
to the allergen. In addition to physically direct skin or
Etiology and Mechanisms
mucosal contact, in so me cases, contact may be
mediated through the air (airborne contact urticaria)
The mechanisms underlying immediate-contact reac- or may be indirect, through contaminated objects.
tions are divided into two main types: immunologic and Agents responsible for ICU reactions are mostly
nonimmunologic. However, there are substances that proteins, but there is increasing evidence that low-
cause immediate contact reactions whose mechanisms molecular-weight agents (haptens) may cause IgE-
(immunologic or not) remain unknown [9, 10, 14]. mediated type-I allergic reactions. The hapten binds to
a protein or another macromolecule, and the resulting
Immunologie Contact Urticaria hapten-carrier conjugate acts as the allergen. Since
allergens must be able to bridge IgE molecules on the
Immunologic contact urticaria (lCU) is a type-1 surface of mast cells to cause degranulation, they are
hypersensitivity immunologie reaction in individuals somewhat constrained in their molecular dimensions.
who have previously contacted the causative agent and Thus, these allergens - or hapten-carrier conjugates -
synthesized specific immunoglobulin E (lgE) antibod- must contain at least two IgE antibody reactive sites in
ies against that agent. IgE molecules react with IgE order to trigger mediator release. However, there are
receptors on the mast cells, basophils, eosinophils, some monovalent allergens, such as the 21-residue
Langerhans' cells and other cells [15]. Eventually, venom peptide mellitin that can still elicit histamine
allergen (urticant) penetrating through the skin or release [19].
mucosal membrane will react with two adjacent IgE Immunologic-type agents are confirmed by specific
molecules bound to the cell membrane of the mast cell. positive radioallergosorbent tests (RASTs) and by
Within minutes, histamine, exoglycosidases, neutral negative tests on control subjects, rarely by passive
proteases and proteoglycans are released from the transfer tests (Prausnitz-Küstner tests) in animals.
mast cells, resulting in an immediate skin response. In vitro tests can also be used to assess the relationship
This reaction comprises local edema (wheal) and with a possible IgE-mediated mechanism, namely,
erythema dependent on reflex neural stimulation determination of histamine release from peripher al
(flare). Massive amounts of these active substances basophils or platelet cytotoxicity test, which explores
lead to anaphylaxis. The allergen-IgE reaction also the presence on platelets of specific IgE antibodies
leads to synthesis of leukotrienes, prostaglandins and bound to the low-affinity receptor for IgE.
platelet-activating factors in the cell membranes of the
activated mast cells. These media tors acting on endo- Nonimmunologic Contact Urticaria
thelial cells increase vascular permeability. No single
mediator ac counts for all of the components of the IgE- Nonimmunologie contact urtiearia (NICU) occurs in
dependent response; many substances have similar individuals not sensitized to the contactant, Le., almost
actions resulting in additive effects. The mast cells also any normal subject. The mechanism of action is the
release chemotactie factors attracting eosinophils and result of a direct release of vasoactive substances,
T cells from the vessels into the dermis. which causes a localized response [20]. Prostaglandins
In long-Iasting antigen exposure, they may partici- are mediators in the re action to at least benzoic and
pate in the development of an eczematous re action, sorbie acids and to methyl nicotinate, and systemic or
which sometimes results in IgE-mediated allergy. In topieal inhibitors of prostagiandin synthesis inhibit the
addition, IgE molecules bind to the high-affinity re action to these substances [21-23]. Ultraviolet radi-
receptors on Langerhans' cells [15-17]. It has been ation (UVB and UV A) has also been shown to inhibit
postulated that Langerhans' cells - or other antigen- NICU reactions to some substances [24]. The NI CU
presenting cells - can present pro tein allergens to the T reaction is often redness without edema rather than a
helper 2 (Th2) cell inducing a delayed-type hypersen- real wheal-and-flare re action. The appearance of clin-
sitivity re action resulting in eczematous lesions [18]. ieal signs depends mainly on the duration of exposure,
The activated Th2 cell also produces interleukins (lL), the concentration of the contactant and other factors,
which switch B cells to produce IgE. IL-4 and IL-13 such as rubbing or scratching. The re action usually
have been shown to be potent switch factors; however, remains localized and systemic reactions are probably
202 5.1. Ale and H.1. Maibach
not evoked. Substances capable of producing NI CU are tional dermatosis only include subjects that present
usually low-molecular-weight chemicals that easily clinical symptoms or have already been diagnosed with
cross the barrier of the skin. Responsible agents occupational skin disease. Therefore, although the type
include plants, animals or chemical substances. Many of reaction can be distinguished and the etiologic agent
of the chemical substances involved are used as identified, prevalence data cannot be obtained. Highly
flavorings, fragrances and preservatives in the useful data are reported from Finland, where OCU has
cosmetic, pharmaceutical and food industries. been classified as aseparate occupational skin disease
since 1989 [11].
Uncertain Mechanism
Food Industry Workers
A third category of CUS consists of cases of uncertain
mechanism. In some instances, the reaction resembles Food industry comprises a broad spectrum of activi-
that of ICU, but no specific IgE can be demonstrated in ties, such as farming, food processing and manufac-
the patient's serum or in the tissues. It could be turing, delivering, etc. Workers in these diverse areas
possible that there are other immunologic mechanisms are exposed to a variety of food-derived and food-
in addition to the IgE-mediated ones. Specific IgG and associated materials, such as preservatives, flavorings,
IgM might activate the complement cascade through stabilizers, emulsifiers, antioxidants, etc., many of
the classical pathway [25]. which are capable of inducing contact dermatitis
A characteristic example of uncertain mechanism- [26-28], photosensitivity [29], pro tein contact derma-
mediated urticaria is provided by ammonium persul- titis (PCD) [30-32] and contact urticaria [2, 4, 10, 33-
phate. There have been several reports of both 35]. Moreover, cutaneous lesions in food workers
localized and generalized contact urticaria, as weIl as usually combine different pathogenic mechanisms,
respiratory symptoms and even anaphylactoid namely, irritancy, delayed and immediate allergy, and
reactions [2, 4, 6]. Although the clinical symptoms even infection. Food-related immediate contact reac-
correspond to an IgE-mediated re action, IgE antibod- tions with urticariallesions or flare of dermatitis at the
ies against ammonium persulphate have not been contact areas have received increasing attention over
demonstrated and passive transfers were negative. In the last 20 years and have also been described in food-
addition, some individuals reacted on the first handlers and housewives. Contact urticaria and im-
exposure as in NICU. Immediate reactions to some mediate vesicular reactions as causal factors of hand
low-molecular-weight substances, such as formalde- eczema were pointed out by Maibach [12] and Maibach
hyde, are not always mediated by IgE. In a laboratory and Johnson [1]. The terms "protein contact derma-
worker with OCU to formaldehyde and positive open titis" [30,36] and "atopic contact dermatitis" [37] were
test, IgE antibodies against formaldehyde could not be applied to these composite reactions (Table 2). Most of
demonstrated and passive transfer was negative. Con- the responsible substances for immediate-type reac-
trol tests with formaldehyde in 20 controls were tions in food industry workers are food-derived
negative [14]. Carbonless copy paper has produced protein allergens [34,38] (Table 3), but many nonfood
contact urticaria with positive tests for immediate agents may also induce sensitization of the immediate
sensitivity in three patients. However, the RASTs were type in exposed subjects, e.g., grain storage mites,
not conclusive. Ten of 59 employees in a factory fungus, antibiotics, latex, etc.
engaged in printing and cutting carbonless business Food contains a variety of different proteins; only a
forms complained of immediate-type skin and respi- few of these are known allergens. The frequency, dose
ratory symptoms. One of them was studied and an and duration of exposure to the responsible agent is
increase in plasma thromboxane B2 and prostagIandin likely to be a critical component in the induction of
PGF2 was observed. Thus, the symptoms might - at sensitivity, but the immunogenicity of the pro tein is
least partially - be mediated by prostaglandins [14]. the most important factor [34].
Many food allergens are highly stable molecules that
are resistant to food processing and cooking [38].
Prevalence and Characteristics of OCU
However, there are exceptions, such as the labile
in Different Occupations
To determine prevalence or incidence of OCU with Table 2. Protein contact dermatitis

certainty is difficult. Both employees and physicians
Mainly reported with natural products
are prone to underreport occupational health prob- 2 Contact urticaria usually present
lems, and data from epidemiological studies, with the 3 Many subjects have positive delayed sensitivity
exception of OCU caused by natural rubber latex, to the involved material
4 Mechanisms remain sub judice
remain limited. Furthermore, most studies of occupa-
allergens present in apple and other fresh fruits and a result of a work-related irritant dermatitis may playa
vegetables [35]. The primary route of exposure for food significant role in the appearance of immediate contact
allergens is through ingestion; food proteins can reactions. The relationship between sensitization by
permeate the gut mucosal membranes [34]. Skin is skin contact and symptomatology following direct
re1atively impermeable to large macromolecules such contact or ingestion of the same (or a related) antigen
as protein allergens; however, exposure through skin is puzzling. Exposure to food allergens generally
contact can produce immediate and delayed contact occurs by ingestion; thus, studying patients with
allergy in food workers. Increased skin permeability as immediate- or delayed allergie contact reactions to
food allergens may provide insights into different
aspects of the two exposure routes. Most food-related
Table 3. Foods and food additives eausing eontaet urtiearia occupational allergens do not induce symptoms fol-
lowing ingestion by workers sensitized by contact. It is
Meat(l) [12, 95, 97, 98] Mushrooms*(l) [118] possible that the antigenie structure of food allergens
Beef* Salami easing molds*(l) [117] may be modified during digestion. However, in some
Chicken* Fruits(l) [35, 68, 75, 78, 80, 82]
Lamb Apple* cases, symptoms are elicited by ingestion of the same
Pork* Apricot or a related substance after sensitization by skin
Sausage Apricot stone* [75] contact [39-43].
Turkey Banana
Liver r100, 101] Kiwi Allergy to flour dust in bakers has been known since
Calf*rI) Litehi 1700 [44,45]. Baker's asthma is a well-known occupa-
Chieken*(l) Lemon* tional disease caused by IgE-mediated sensitization to
Pork' Lemon peel*
Fish·(l)(Nl) [107-109, 119] Lime* cereal - mainly wheat, rye and barley - proteins.
Frog·(l) r179] Mango Hjorth [46] stated that most baker's dermatitis was
Seafood (I) [30] Orange associated with an immediate-type hypersensitivity.
Cod* Peaeh [82]
Crab Plum Herxheimer [47, 48] studied the development of skin
Herring* Strawberry*(P!) sensitivity in baker's apprentices for 5 years and
Lobster* Watermelon* showed that the percentage of sensitive subjects
Oysters*[111] Nuts(l)
Plaiee* Almond* increased gradually until a constant figure of 20%
Shrimp*[110] Peanuts was reached. Many different proteins were identified as
Other anima! produets(l) Peanut butter allergenie in wheat flour, especially in the water-
Cheese* [106, 116] Seeds(l)
Eggs* [39, 43, 67] Sesame seeds soluble albumin and globulin fractions [49]. There is
Honey Sunflower seeds extensive cross-reactivity between these cereals, and -
Milk* [104, 105] Grains(l) [40,44,45,47,64] to a minor extent - between them and other cereals
Vegetables(l) [26, 27, 30, Buekwheat* such as oat, corn and rice [50].
31, 35, 81, 119] Flour*
Asparagus*(!) [79] Maize* Baking additives have also proven to be important
Beans** Malt allergens. Enzymes and other flour additives are being
Cabbage*(l) Rice* increasingly used in bakeries to improve the properties
Carrots* Wheat*
Castor bean*(l) (Kanerva) Wheat bran of the baked products and accelerate the baking
Celery* (Ninimaki) Flavorings and fragrances process. Amylases (especially IX-amylase obtained from
Chives [26,81] Aspergillus oryzae) are starch-cleaving enzymes used
Coffee been (green)*(l) Balsam of Peru(Nl)(l)
[140, 141] Benzaldehyde*(Nl) worldwide in the baking industry as flour additives
Cueumber piek!e*(l?) [68] Benzoic acid [51]. Other enzymes, such as proteases, are additionally
Endive*(l) [42] Cassia (cinnamon) oi!
Garlie·(l) [84] Cinnamic acid(Nl)
used in the United States and Canada, [52] and
Lettuee*(l) [31,42, 71] Cinnamie aldehyde*(Nl) cellulase is used in Finland. Lipoxygenases are also
Mustard*(l) Menthol(Nl) added to bleach flour [51]. IX-Amylase has long been
Onion*(l) Vanillin (Nl) known to produce skin and respiratory allergie symp-
Parsley* Condiments and spiees toms [53-56](Table 4). Sandiford [57] et al. have
Parsnip* [69, 85, 87-89]
Potato* [72-74] Cayenne pepper(Nl) shown that ß-amylases are also allergenic. Many cases
Rocket Caraway of occupational asthma and rhinitis [53-58] and
Rutabaga (Swede) Coriander
Soybean*(l) [84] Curry*(U)
Stock (Matthiola ineana) Paprika
Tomato*(Nl)(l) (eapsieum annuum)*(!)
Thyme(Nl)
Table 4. Enzymes
Winged bean*(l) [70] eausing eontaet urti- rJ. Amylase*(l) [51-60]
Fungi earia Cellulase*(l) [51,56,61]
Papain*(l) [51,63]
I, immunologie contaet urtiearia; NI, non-immunologie eontaet Xylanase*(l) [51,59]
urtiearia
* Oeeupational urticaria * Oeeupationa! urtiearia
204 5.1. Ale and H.I. Maibach
dermatitis [52, 59, 60] caused by (X-amylase in bakers and a nasal provocation test was also positive. Occu-
have been reported. These are immunological reac- pational asthma and rhinitis in bakers, confectionery
tions and specific Ig-E antibodies have been found in and factory workers exposed to inhalation of egg have
patients [54]. been well described [65, 66]. According to skin test and
Baur studied 118 bakers, 35 of whom had bronchial RAST results, many different allergenic fractions may
asthma, rhinitis and/or conjunctivitis after contact with be involved, namely, ovoalbumin, ovomucoid and
flour. Twelve individuals from the symptomatic group lysozyme, etc. [43, 67].
(34%) had positive RAST to IX-amylase, but none ofthe Immediate contact reactions to fruits and vegetables
symptom-free group [54]. Morren et al. [51] studied 32 are fairly common among food industry workers
bakers with hand dermatitis; seven had a positive (kitchen personnei, sandwich makers, cooks, etc.).
immediate reaction to IX-amylase with the scratch Several cases of contact urticaria [68-83] even associ-
chamber test, and two of them also had a positive ated with anaphylaxis and PCD [26, 30-32, 42, 84-86]
delayed reaction. Four of them were then prick tested have been reported in food handlers and also house-
with a dilution series of purified IX-amylase and showed wives.
positive responses to a dilution down to 1:250.000 mgl Clinical studies have suggested that fruit and veg-
ml. All of the seven patients had hand eczema of several etable allergy is connected with birch pollen allergy.
months' evolution, extending to other areas, such as Hannuksela & Lahti l35] tested 388 atopic patients with
their arms and face in three cases. Four of the seven the scratch-chamber method and demonstrated that
patients experienced urticaria-like lesions within a short 36% of subjects with hypersensitivity to birch pollen
period - generally less than an hour - after starting had immediate positive responses to many fruits and
work. In three patients, other immediate symptoms vegetables, mainly apple, carrot, parsnip and potato.
(rhinoconjunctivitis, sneezing, etc.) were also present. A Only 7 of 158 (4%) atopic patients who were not allergic
dermatological diagnosis of PCD was made. Quirce [56] to birch pollen had positive skin-test reactions to one
reported five cases of IX-amylase sensitized bakers and or more of the fruits or vegetables tested. Not only
four were also sensitive to cellulase. allergy to fruits and vegetables, but also allergy to
In a Finnish study, l2 workers in four bakeries, three spices, seems to be associated with pollen allergy.
in one flour mill and four in a bread factory were skin- Niinimäki and Hannuksela [87] and Niinimäki et al.
prick positive to both IX-amylase and cellulase [60]. [88, 89] studied 1120 atopic and 380 nonatopic patients
Although bakers probably represent the most exposed and observed that positive skin-test reactions to spices
occupational group [51], enzymes may affect workers were more frequent in atopic patients with allergy to
in several industries, such as paper [61], textile and birch pollen and fruit and vegetables. Positive reac-
pharmaceutical industries, starch [62] and sugar pro- tions were more often seen with paprika, coriander,
duction, alcohol and wine production, enzyme pro- caraway, cayenne and mustard. Positive responses
duction [63], farming, and industries in which workers were generally reproducible with retesting [88]. These
come into contact with proteins, detergents, etc. observations should be considered when counseling
Nonoccupational exposure with skin and respiratory food handlers with atopic background. The allergen
symptoms has been reported in housewives (detergent characterization in fruits, vegetables and pollens have
enzymes) and in contact-Iens wearers (papain in conducted to identify profilins as common antigenic
cleansing solutions) [51]. When assessing allergy pre- determinants. Profilins are a group of actin-binding
sumably caused by enzymes, note that commercial proteins found in all eukaryotic cells that are thought
enzyme products must also contain traces of the to play an important role in plant cell growth and
microorganisms used for fermentation as weIl as pollen germination. Specific IgE antibodies from
preservatives, such as parabens, benzoates, sorbates, patients' serum have been found to react with profilins
etc. These substances may be the actual cause of the isolated from birch, timothy and mugwort pollens and
allergy in some cases [51]. from many fruits, vegetables and spices [90-94].
Other flour additives have been reported as cause of Food workers are also exposed to animal products
immediate contact reactions in bakers such as sorbic (Table 5). Not only raw meat (beef [95-97], chicken
acid and, in some countries, ammonium persulphate [98, 99], lamb [l2], pork [86]), but any other part of
[64]. Egg allergy with immediate contact reactions and the animal handled, such as skin (chicken [99], turkey
respiratory symptoms have been reported in two [l2]), liver (chicken [100], calf [101], pork [98]), gut
confectionery workers after handling egg white [43]. (pig [101]) and blood (cow, pig [102]), (Table 2) have
One of them complained of gastrointestinal and mouth been found to cause contact urticaria or PCD. Animal
symptoms after ingestion of eggs. Skin tests were derivatives such as milk [103, 104], cheese [105,106] or
positive for different egg components, namely, whole eggs [39, 43, 67], as weIl as fish [107-109] and other
egg, egg white, yolk, ovoalbumin and ovomucoid. seafood [30, 110, lll] have also been responsible for
Specific IgE RAST to egg white and yolk was found, immediate contact reactions. The exposed workers are
Table 5. Animals, plants and derivatives (natural products) the workers had one or more immediate type-I
causing contact urticaria
reactions in either a scratch test or patch test in a
Animals and their derivatives Plants and their derivatives
previously dermatitic area, whilst patch tests on
Ammniotic fluid* (I) Aigae (I) normal skin were usually negative. The majority of
[160-165] Aloe (Morrow) positive reactions were caused by fish and seafood, and
Blood* (I) Birch (I) (leaves, sap)
Cow* [103, 163, 164] (Lahti-Hannuksela) RAST tests were often also positive; some patients also
Pig* [103, 112] Boungainvillea (U) reacted to vegetables and cheese.
Brucella abortus, (I) Camomile* In 1978, Hjorth [112] described an itchy vesicular
Caterpillars (NI) Chrysanthemum* (I) [144]
Cephalopods Cinchona* (U)
hand eruption in workers in contact with viscera and
(Loligo vulgaris)* Coral (NI) mesenteric fats in pigs with the characteristics of PCD
Chironomus (I) Cotoneaster commonly known as "fat eczema". Since then, PCD
Cockroaches * (I) [178] Crataegus (hawthorn) (I) [113, 114] and OCU [102, 103, 115] have been reported
Corals (NI) Elm tree (U)
Dander* (I) [128-131] Eruca sativa (I) in slaughterhouse workers, and also in butchers [102]
Gut (pig)* (I) [102] Eucalyptus (I) from contact with intestines, mesenteric fat or me at
Guinea pig* (I) [176] Ficus benjamina (I) of cattle, pig and chicken. In a study by Hansen and
Hair (rat-mice)* (I) Gerbera * (I) [145]
[174, 192] Grevillea juniperina (NI)(I?) Petersen [113], 31 (22%) of 144 slaughterhouse workers
Human hair [257] [151] cutting and cleaning pigs were diagnosed as having
Jellyfish (I) (NI) Hakea suaveolens [152] PCD mostly after contact with pig gut. Prick test,
Liver (mouse)* (I?) [175] Larch
Locust* (I) Tee Lichens
patch test on "stripped" skin and scratch-patch test
Mites* (I) Lilies* (I) [143] were performed with small intestine, mesenteric fat
Moths (NI) Lime (Tilia) and blood from freshly slaughtered pigs. Positive
Placenta (cow)* (I) Limonium tartarieum
Saliva (I) (dried flowers)* (I) [147]
reactions to one or more of those materials were
Calf* Mahogany* elicited only by the scratch-patch test in 12 cases.
Cow* [135] Mulberry Nestle and Eisner [106] reported occupationally
Dog Obeche (Triplochiton
Horse scleroxylon)* (I) [157-159]
related skin diseases in four Swiss cheese makers
Rat* [177, 192] Phaseolus multiflorus (U) with hand dermatitis; three of them had immediate
Seminal fluid (I) Poppy flowers (Papaver skin-test reactions to various milk products and
Serum (amphibian)* (I) rhoeas) (I) [146] delayed positive patch-tests reactions to other occu-
[181] Sea anemona (NI)
Silk (I) Semecarpus anacardium (U) pationally related substances. A diagnosis of concur-
Spider mite* (I) Sunflower seeds (I) re nt irritant and allergic contact dermatitis and PCD
Pearl oysters* Teak (I) was made. Other than milk products, type-I reactions
Rat tail* (I) [176] Tobacco* (I)
Urine (mice, rat)* (I) Tropieal woods* (I?) [156] in cheese makers can be caused by powdered or
[167-174, 183, 185, 192, Tulips * (I) [143] liquid rennets, molds and antimicrobial agents [116].
194, 196, 198, 199] Verbena (V. hybrida & Immediate contact reactions from salami casing
Worms* (PI) e1egans)* (I)
Anisakis simplex Plants derivatives [201-210] molds [117] and edible mushrooms [118] have also
Lumbrinereis impatiens Abietic acid (U) been reported (Table 3).
Nereis diversicolor Colophony* (I) The study of a chronic hand eczema in professional
Cornstarch* (I)
Latex rubber* (I) food handlers should include immediate and delayed
Turpentine (NI) tests using foods and food extracts, especially in those
individuals whose history reveals that the handling of
I, immunologie contact urticaria; NI non-immunologie contact
urticaria; U unknown mechanism; these foods produce itching, urticarial or vesicular
* Occupational urticaria reactions or a fiare of the dermatitis. When performing
tests with some "whoie" foods, at least six control
subjects should also be tested [101]. Open immediate
butchers, slaughterhouse workers, cooks and kitchen tests may be negative on normal skin, but positive on
assistants, sandwich makers, etc. Fisher [101] reported previously eczematous or slightly damaged skin [12,
of a butcher with chronic hand dermatitis with 30]. Prick or scratch tests may be required to prove the
immediate fiare when handling calfliver. An open test cause of the dermatitis [30,112]. This is consistent with
with fresh material was negative, but the scratch test the observation that damaged skin is more readily the
showed an immediate vesicular reaction. Hjorth and site of "PCD" than is healthy skin. The scratch-
Roed-Petersen [30] studied 33 chefs and sandwich chamber test has the advantage that immediate and
makers with occupational hand eczema by means of delayed type hypersensitivity can be readily assessed
patch and scratch test with various meats, fish, [119]. When testing with fresh materials, such as meat
vegetables and spices. Many of them complained of or viscera, fish, etc., care should be taken with respect
immediate reactions after handling proteinaceous to infectious diseases. In these cases, testing in normal
materials, mostly fish and shellfish. Twenty-five of controls should be avoided [120].
Agriculture, Farming, Floriculture and Wood Industry grains and storage mites [136]. Enzymes such as
cellulases, amylase, phytase, glucanase and protease
Agriculture has consistently had the highest rates and are used for animal rations and, therefore, farmers can
numbers of occupational skin diseases reported in the contact them [51].
United States [121]. The acute toxie events related to Occupational allergies in coffee workers, especially
pesticide exposure and issues of long-term carcino- those involved in the handling of green coffee beans,
genieity have been the focus of most toxicologie have long been known. Cutaneous and respiratory
reports [122]. Delayed contact allergy commonly symptoms, such as asthma and rhinoconjunctivitis
occurs from pesticides. Fungieides are implicated as [137-139] and immediate and delayed skin allergy [138],
the causative agent much more ilian insecticides or have been described in workers from different coffee
herbicides. Zinc diethylditlliocarbamate (ZDC) is a plant-derived materials. Castor beans (a possible
fungicide and insecticide that is also utilized in the contaminant in transportation sacs) and chlorogenie
process of rubber manufacture. ZDC and chemically acid can be responsible for some of the allergie
related thiocarbamates have been reported as among reactions attributed to coffee allergy. Long-Iasting
the most frequent causes of allergie contact dermatitis urticaria to castor bean was reported by Kanerva et al.
in farmers [123]. These chemie als that have been [140, 141]. There is no evidence of cross reactions
reported as a cause of contact urticaria in rubber [124] between coffee-bean and castor-bean allergens [142].
have not yet been reported to cause contact urticaria Occupational asthma, rhinoconjunctivitis and con-
when exposure occurs as a pesticide. Chlorothalonil tact urticaria from flowers, flower pollen and plants
(tetrachloroisothalonitrile), a fungicide, has been re- have been reported in floriculturists, florists and
ported to cause OCU and anaphylactic symptoms. gardeners [143-155]. De Jong et al. [155] studied 14
Dannaker and Maibach [125, 126] reported a nursery Dutch subjects with occupationally related rhinocon-
worker who developed facial erythema and edema junctivitis (14114), asthma (10114) and contact urticaria
accompanied by respiratory symptoms. Testing on (5114) from handling flowers. Twelve were skin prick-
normal skin with 0.01% chlorothalonil resulted in an tested wiili horne-made pollen extracts from 17 differ-
anaphylactic reaction. ent flowers commonly grown in The Neilierlands, and
Cow dander has not been frequently reported as a RAST against mugwort, chrysaniliemum and solidago
cause of occupational diseases in farmers, aliliough was performed. They found that the concordance
both immediate and delayed contact allergy to cow between ilie prick test and the clinical history was 74%
dan der was described as early as 1948 by Epstein [127]. and that between priek test and RAST, 77%. Since all
In Finland, allergy to cow dander represents 25% of patients were sensitive to mugwort pollen, it was
reported occupational dermatitis in farmers and is the concluded that it could be used as a screening test for
most important cause of OCU [128]. Cow dan der is possible flower allergy.
also the most common cause of occupational rhinitis Woods can also cause immediate contact reactions
and asilima in Finland [11]. Susitaival [129] et al. prick in exposed workers. OCU and respiratory symptoms
and patch tested 104 farmers with hand dermatitis; 41 from tropical woods (Lauan, Philippine, Red Mahog-
were positive to cow dan der; one-third had an imme- any) [156] and obeche wood (Triplochiton scleroxylon)
diate positive reaction to both tests, one-third had a [157-159] have been described in wood workers and
delayed reaction on patch testing and one-third had carpenters.
boili immediate and delayed reactions. Timmer et al.
[130] and Mahler et al. [131] reported one case each Veterinarians
from Netherlands and Germany, respectively. In boili
cases, the subjects suffered dermatitis with an airborne There are several reports in the literature of cases of
pattern and with immediate itching after contact with occupational contact dermatitis and contact urticaria
cows. RAST and prick tests for cow epithelium were of animal origin in veterinary surgeons, especially
negative. Patch test and scratch-chamber tests were those who perform obstetric work with cows [160-164].
positive after 2 days. The cases were interpreted as Obstetric work is traditionally performed without
allergie contact dermatitis and PCD, respectively. rubber gloves, and direct contact with obstetrie fluids
Contact urticaria caused by cow dander is IgE-medi- and other proteinaceous materials is responsible for
ated and, recently, some 17 bovine allergens, of which many immediate contact reactions. Animal hair, blood
four have been shown to be "major" allergens for and saliva [163-166] have also been reported as
humans, were characterized by immunoassays [132, causative agents (Table 5). Hjorili et al. [161] studied
133]. Cow's milk [134] and saliva [135] have also been 36 veterinary surgeons with incapacitating hand der-
reported as producing an immediate flare of hand matitis. Sixteen of them stated that vaginal or rectal
dermatitis in farmers. Other causes of OCU in farmers examinations could cause a flare of dermatitis; scratch
are fruits and vegetables, flour and flour additives, test with obstetric fluid from cow was performed on
15 and five reacted positively. Prick test with animal sawdust and litter leading to an airborne contact [193,
hair was positive in 18 subjects, and four also had a 194]. Almost half of the workers with ALA seemed to
positive RAST to cow hair. Patch test with antibiotics be allergie to more than one species if exposed,
used in veterinary practice was positive in 32 subjects. although whether this is due to multiple sensitization
Many of these reactions were considered relevant. or to cross-reactivity between allergens from different
Immediate-type tests with antibiotics were not per- species remains a sub judice.
formed. Other positive patch test reactions were rubber The relationship between atopy and the susceptibil-
chemieals, balsams, paraphenylenediamine (PPD) and ity to ALA also represents a matter of controversy
fragranees. In a case of PCD with disseminated lesions [195]. Pre-employment atopic symptoms do not in-
reported by Degreff et al. [163], a positive RAST for crease the likelihood of developing animal allergy.
bovine blood and amniotic fluid was obtained. Veter- Even atopic subjects were more likely than non-atopic
inarians employed in meat control in slaughterhouses subjects to develop asthma from animal contact [183].
also can develop contact urticaria and PCD following The frequency and intensity of the allergie symptoms
contact with intestines or mesenteric fat. were directly related to the intensity of exposure; they
were high er in animal technicians working in elose
Laboratory Workers and Biologists contact with animals and in individuals handling
soiled litter [196].
Allergy to laboratory animals (ALA) is the most Future efforts to prevent or reduce allergy among
important occupational disease in personnel engaged animal workers apparently will depend mainly on the
in work with these animals [167-170]. Among the many adoption of effective and practical ways of reducing
people putatively affected are scientists, research and exposure, such as use of ventilated cabinets, individual
laboratory technicians, veterinarians, breeders, animal respiratory protection, non-contact absorbent litters,
caretakers, personnel involved with health and safety etc. It has been demonstrated that applying strict safety
at work, etc., in the pharmaceutical industry, univer- conditions leads to a decrease in the incidence of ALA
sities and research laboratories. Many animals used in symptoms [197, 198]. However, the prevalence of
biological research (rats, mice, guinea pigs, rabbits, sensitization was unchanged [199].
hamsters, monkeys, frogs, toads, sheep and cockroach- Other causes of immediate contact reactions in
es [171-181]) (Table 5) have been reported to cause laboratory workers are medicaments and latex gloves
symptoms such as rhinitis, conjunctivitis, asthma and [199].
contact urticaria. In rare cases, anaphylactic episodes
can follow animal bites [182]. From epidemiological Health (are Workers
studies, the prevalence of ALA has been found to vary
between 20% and 30% [173, 183-185], while asthma will Natural rubber latex (NRL) allergy has become a major
develop in 10% of exposed workers [186]. Laboratory occupational problem for health care workers [200].
animals are consistently reported by the SWORD Since the 1980s, the prevention of blood-borne infec-
(surveillance of work-related and occupational res pi- tions, such as hepatitis and acquired immunodeficiency
ratory diseases) project as one of the three most syndrome has determined a great increase in glove use
common causes of occupational asthma [187]. Almost in health care personnel. Therefore, since the first
half of those with respiratory symptoms from labora- report by Nuter in 1979 [201], a growing number of
tory animals have also had skin symptoms. Contact reports of immediate allergie reactions to NRL have
urticaria is the only symptom in about 10% of cases of dominated the medicalliterature [202-206]. Not only
ALA. In the Finnish Register of Occupational diseases an increased incidence, but also greater awareness and
from 1990 to 1994, the causes of PCD ineluded rabbit better diagnostic techniques explain the rising number
(two cases), mouse, rat and guinea pig (one case) [120]. of diagnosed cases [207]. Prevalence oflatex allergy in
Allergens have been isolated for some species. The health care personnel in different countries has been
main allergens in rat and mice are urinary proteins shown to vary between 3% and 16% [208], but
whose production is under hormonal control, being comparison of different materials is not easy because
maximal in male adult animals [188-190]. The major of dissimilar diagnostic methods and inelusion criteria.
allergens in rat's urine are glycoproteins of 17 (Rat n 1), In most studies, atopy and previous hand dermatitis
23 and 21 kDa [191], and in mice, aprealbumin are important risk factors for NRL allergy [208, 209];
(17 kDa, Mus m 1) and a protein derived from the this should be taken into consideration when estab-
hair follieles are major allergens [173]. Allergens are lishing preventive measures.
also present in saliva [192]. In guinea pigs and rabbits' Immediate allergy to NRL is a typical example of
fur, saliva and urine have been found to contain contact urticaria syndrome, in which elinical manifes-
allergens. In addition, dried material from the excreta tations vary from itching and redness at the contact
and hairs containing allergens are transported with area to generalized cutaneous and/or extracutaneous
symptoms. Severe anaphylactic reactions and even are antibiotics [218], antiseptics, psychopharmaceuti-
death have been reported [208]. These immediate cals, antineoplastic drugs, etc. Immediate reactions to
hypersensitivity reactions have been shown to be IgE antibiotics (penicillin [219], mezlocillin [220], strepto-
mediated by skin testing, basophil histamine release, mycin [221] and cefotiam [222]), antineoplastics (cis-
RAST, enzyme-linked immunosorbent assay (ELISA) platin) [223] and analgesics (methamizol) [224] have
and IgE immunoblots, and are elicited by peptides been reported in nurses. Several drugs and antiseptics
present in natural rubber [210-213]. Several approach es have caused immediate contact reactions [225-233],
have been used to identify the responsible peptides. In sometimes with anaphylaxis [234-241] (Table 6).
fresh NRL, 240 polypeptides have been demonstrated Because of the risk of anaphylactic reactions,
and at least 57 have the capability to bind IgE caution should be exerted when performing diagnostic
antibodies from NRL-allergic patients' sera. The anti- tests. An open patch test with a very diluted chemie al is
gens that are recognized may depend not only on the recommended as the first step [218].
antigen source material, but also on the patient
population from which the detecting serum is ob-
tained. Health-care workers with latex allergy produce Pharmaceutical Industry
IgE specific for a 20-kDa latex peptide (prohevein). A
17-kDa recombinant hevea antigen (Hev b 5) is The spectrum is wide, from chemists and laboratory
allergenie for over 90% of the latex allergie health- workers involved in research and development of
care workers, but just over half of the spina bifida drugs to workers in the production level to dispensing
patients allergie to latex [214, 215]. The proteins ofNRL pharmacists. Therefore, the risk of skin disease will
are emitted from gloves and other latex items into the vary depending on the specific exposure. On one hand,
air; the starch and other powders used in latex gloves advances in manufacturing technology should reduce
may act as carriers of latex pro teins. Antigen content direct chemical exposure. On the other hand, the
in gloves and other latex items may be estimated by number of putative allergens is progressively increas-
measuring total protein or by immunospecific assays ing [242].
using either human or animal antisera. The range of Many different pharmaceutical products have been
antigen content is great among brands of disposable reported to cause contact urticaria, mostly of the
gloves [216]. Turjanmaa et al. [207, 216, 217] studied immunologie type. Sometimes, oculorhinitis, respira-
the allergenicity of 20 brands of international surgical tory symptoms or even anaphylaxis can develop.
and examination gloves used in Finland using the skin Because of the powdered nature of several pharma-
prick test, RAST inhibition and ELISA inhibition, ceutical products, the causative agent may induce
concurrently, and demonstrated differences of more cutaneous symptoms by direct contact or through an
than 1000-fold in the gloves' allergenicity. Moreover, airborne mechanism. The most frequent agents caus-
contaminated glove powder may produce airborne ing contact urticaria in this occupational group are
transmission of the allergens. Therefore, in the pri- latex and medicaments, especially antibiotics [218,
mary prevention of NRL allergy, adequate glove 242-244] (Table 6).
selection is crucial. As NRL gloves have excellent
physical and protective properties and a reasonable
price, it is expected that they will remain in use. Hairdressers
However, low latex-protein-content unpowdered
gloves should be selected. Efforts should be made to Hairdressers are exposed to a great variety of hair-care
adopt a standard, reliable and simple method to products containing substances that cause both im-
estimate in vitro allergenicity of NRL products, and mediate contact reactions and contact dermatitis [245]
gloves should be labeled accordingly. (Table 6). Although data from epidemiologie al studies
In secondary prevention, when even low-allergenic are scanty, prevalence should be expected to be high,
non-powder gloves are not tolerated, totally latex free owing to the number of potential offenders. Ammo-
surgical gloves should be used. In addition, specific nium persulphate and other persulphates used in hair
written instructions should be given to the worker bleaches represent the most common cause of OCU in
together with the advice of using a medical-alert badge hairdressers. Both, localized and generalized even
stating the allergie condition. When performing diag- anaphylactoid reactions have occurred in hairdressers
nostie cutaneous tests for latex allergy it is imperative and also their clients [246-249]. The pathogenic
to follow the recommended procedure in order to mechanism for persulphate reactions remains un-
avoid potentially life-threatening situations. Health known. Other potential agents of immediate reactions
care personnel also handle pharmaceutieal agents in hair bleaches are sodium silicate (filler material),
(Table 3), many of which are potent sensitizers and ammonia and colorants such as henna [245, 250].
can penetrate protective gloves. Some of these agents Edwards et al. reported a beautician with both contact
'Table 6. Topical drugs and cosmetics causing contact urticaria
Medicaments Camphor (NI)

Acetylsalicilyc acid [3] Chloramine (I)
Aescin (I?) (saponine from dried seeds) [226] Chlorhexidine (I) [239,241]
Antibiotics (I) [218] Chlorine
Ampicilin Chlorocresol* (NI)(I?) [227]
Bacitracin [235, 237, 240] Formaldehyde* (NI)(I)
Cephalosporins* [222, 243] Gentian violet (I)
Chloramphenicol [236] Imidazolidinyl urea (NI)
Gentamycin Kathon CG (NI)
Iodochlorhydroxyquin Mercurochrome (I) [228]
Mezlocillin * [220] 0- Phenylphenate (I)
Neomycin Parabens (I?)
Penicillin* [219] Phenylmercuric acetate* (I)
Rifamycin [229, 234, 238] Phenylmercuric propionate (I)
Streptomycin * [221] Sodium benzoate* (NI)
Virginiamycin Sodium hypo chlorite (I)
Antineoplastic [233] Sorbic acid (NI)
Cisplatin* (I) [223] Cosmetics, fragrances and emulsifiers
Mechlorethamine (I) Hair care products
Antiparasitics agents Ammonium persulphate* (U) [246-249]
Pentamidine isethionate* (I) Basic blue 99 (amino ketone dye)* (I)
Benzocaine (U) [232] Henna* (I) [248,250]
Benzoyl peroxide (I) Protein hydrolysate* (I?) [252, 253]
Capsaicin (NI) Paraphenylenediamine* (I) [251]
Carboxymethylcellulose sodium (I) Emulsifiers
Chloroform (NI) Cetyl alcohol (U)
Dinitrochlorobenzene Stearyl alcohol (U)
Diphenylcyclopropenone (I) Polysorbate (I?) [231]
Dimethylsulfoxide (NI) Sorbitan monolaurate (I?)
Lindane (I) Sorbitan monostearate (I?)
Nicotinic acid esters (NI) Sorbitan sesquioleate (I?) [230]
Pentamidine (I) [225] Fragrances
Phenothiazines (I) ()(-amyl cinnamic aldehyde (NI)
Chlorpromazine [3] Anisyl alcohol (NI)
Levopromazine* Balsam of Peru * (NI) (I?)
Promethazine Cassia oil (NI)
Pilocarpine (U) Cinnamic aldehide (NI)
Pyrazolones (I) Cinnamic alcohol (NI)
Aminophenazone Cinnamic acid (NI)
Methamizole* [224] Coumarin (NI)
Prophylphenazone Eugenol (NI)
Tar extracts (NI) Fragrance mix (NI)
Tincture of benzoin (NI) Geraniol (NI)
Preservatives and disinfectants Hydroxycitronellal (NI)
Acetic acid Other substances
Alcohols (NI) (I) Allantoin (I?)
Amyl Aloe gel (I?)
Ethyl Benzophenone (NI)(I)
Butyl Chamomile extract (I?)
Isopropyl Lecithin (I?)
Benzyl (I) (NI) Melissa extract (I?)
Ammonia (I) Pyrrolidone carboxylate (NI)
Benzoic acid (NI)(I?) Propylene glycol (NI)
Bronopol (NI) Resorcinol (NI)
Butilated hydroxytoluene (I?) Wool alcohols (I)
urticaria and delayed allergy from PPD [251]. Contact making it necessary to complement the tests with a
urtiearia from pro teins and other agents in shampoos RAST and to include a control group [245]. Raw
and conditioners have been reported in workers and products, such as eggs, have caused urticaria upon
also consumers [252-255]. Natural products, such as professional contact and also anaphylactie symptoms
protein hydrolysates of animal or vegetal origin are [256]. Human hair and dandruff have also been
increasingly reported as a cause of immunologieal reported to elicit immediate and delayed allergie
OCU [245, 253, 254]. Some pro tein hydrolysates, such reactions in hairdressers [257]. Leino et al. performed
as keratine and collagen hydrolysates, may produce skin-prick tests to human dandruff and Pityrospoum
false irritative responses in prick and scratch tests, ovale yeast and demonstrated a higher degree of
response in hairdressers than nonoccupationally ex- in both patients. In the first patient, a positive test
posed controls (8.6% and 11.2% versus 0.3% and 3.5%, response and specific IgE antibodies against unsatu-
respectively) [245]. rated polyester resin were also found. Jolanki et al.
[260, 261] reported two cases of contact urticaria due
Plastics Industry and Workers Exposed to Epoxy Resins to MHHPA with positive immediate skin tests (open
test with undiluted MHHP A and scratch test with 1%
Epoxy res in compounds include many chemicals, MHHP A in ethanol). Kanerva et al. [262] reported a
including epoxy resins, reactive diluents and hardeners horizontal boring machine worker (involved in tooling
that have been known to cause skin and respiratory metals) who had been occupationally exposed to
symptoms in the exposed workers [258] (Table 7). several products including plastics chemicals for many
Phthalic anhydride (PA), methylhexahydrophthalic years and developed allergic contact dermatitis as well
anhydride (MHHP A) and methyltetrahydrophthalic as allergie rhinitis. Patch test with a dilution series
anhydride (MHTP A) are dicarboxylic anhydrides used down to 0.125% of MHHP A was positive at 3 days and
as curing and harden er agents for epoxy res ins that 6 days. Control patch tests were performed in 20
have been reported to induce IgE-mediated respiratory subjects and caused slight irritation at 2% and 1% in
aHergy. There are few reports on immediate-type skin some subjects, whilst 0.5% did not cause any irritation.
reactions to these agents [259-262]. Tarvainen et al. Prick tests with human serum albumin-conjugated
[259] reported two patients - one in the plastics acid anhydrides were positive for MHHP A, MHTP A
manufacturing industry and the other working as a and maleic anhydride. It was concluded that the
winder (insulating wires with epoxy-resin-containing patient had both immediate and delayed allergy to
tapes) in a plant manufacturing electrical devices - MHHP A. The positive skin prick tests to the other
who developed occupational airborne contact urticaria anhydrides were interpreted as cross-sensitivity reac-
from MHHP A and MHTP A. Skin prick tests with both tions. Immediate allergy to the epoxy compound, i.e.,
anhydrides conjugated with human serum albumin diglycidyl ether ofbisphenol A (DGEBA), has also been
were positive, and specific IgE antibodies were found reported [263].
Diagnosis of OCU
Table 7. Miseellaneous chemie als and metals eausing eontaet
urtiearia When assessing OCU, a comprehensive history -
considering all suspicious occupational and nonoccu-
Acetyl acetone (I) Nylon (I)
Acid anhidrides* (I) [259-262J Oleylamide pational contacts - physical examination and diagnos-
Methylhexahydrophtalie anhydride Phosphorous sesquisulfide tic skin tests should be performed. A detailed clinical
Methyltetrahydrophtalie anhydride Polypropylene* history concerning any occurrence of immediate
Phtalie anhydride Potassium ferrieyanide
Acrylic acid (I1) Sodium fluoride reaetions - whether limited to the skin or not - and
Aerylie monomers* (I) Sodium silicate their association with occupational exposure should be
Aliphatic polyamide* (I) Sodium sulfide obtained. OCU has a large heterogeneity of clinical
p-Aminodiphenylamine* (I) Sulfur (NI)
Aminothiazole Triehloroethanol (U) manifestations and, therefore, patients may disclose a
Aziridine* (I?) Vinyl pyridine* variety of symptoms. Some of them have a history of
Butylhidroxytoluol Xylene* relapsing dermatitis, which exacerbates after contact
Calcium hypochloride Zine diethyldiothio-
Carbamates* (I) earbamate*[124J with occupational materials or urticarial reactions
Carbonless eopy paper* (I) Metals related to occupational exposure. However, some
Chlorothalonil* (I) Aluminium disclose only uncharacteristic symptoms, such as
Citraconic anhydride Chromium* (I)
Denatonium benzoate* (I?) Cobalt* (I) itching, burning or tingling, that can be easily over-
Dieyanidiamide Co oper looked if the physician is not alert to the possible
Diethylfumarate Gold occurrence of contact urtiearia [4]. In addition, OCU
Diethyltoluamide (I) Iridium* (I)
Diglycidyl ether of bisphenol Mereury (I?)
has to be considered in patients developing other
A* (I) [263J Niekel* (I) immediate-type symptoms, such as work-related bron-
Formaldehyde resin* (I) Palladium chial asthma or rhinoconjuncitivitis. History should
Fumarie acid Platinum salts* (I) also investigate the presence of other skin diseases, as
Methyl ethyl ketone (I) Rhodium*
Monoamylamine (I) Ruthenium weH as personal or family atopy.
Naphta * (NI) Tin Guidelines for evaluating immediate-type responses
Naphthylaeetie acid Zine have been suggested by von Krogh and Maibach [2,4]
(Fig. 1). Tests should be first performed on healthy skin,
I, immunologie eontaet urtiearia; NI, non-immunologie eontaet
urtiearia; preferably in open application. The test substance
* Oeeupational urtiearia should be applied as is or - if necessary - diluted in an
1. Non-invasive The ability of occupational agents to produce

Open application
Non affected (nonnal skin) immediate contact reactions must be specifically
./- investigated, as has been the case for delayed-type
Negative
./- contact sensitizers. Studies on the mechanisms of
Open application immediate contact reactions, development of appro-
Slightly affected (or previously affected) skin
./- priate models and standardization of diagnostic tests
Negative --> Positive constitute achallenge for further research.
(b)
./-
Occiusive application (patch or chamber)
Non affected (nonnal skin)
./- References
Negative
./-
Occiusive application (patch or chamber) 1. Maibach HI, Johnson HL (1975) Contact urticaria syndrome.
Slightly affected (or previously affected) skin Contact urticaria to diethyltoluamide (immediate type
./- hypersensitivity). Arch Dermatol11l:726-730
Negative 2. von Krogh G, Maibach HI (1982) The cantact urticaria
2. Invasive ./- syndrome. Semin Dermatol 1:59-66
3. Odom RB, Maibach HI (1976) Contact urticaria: a different
Intraepidennal (prick, scratch, scracht chamber tests)
contact dermatitis. Cutis 18:672-675
./-
Negative
4. von Krogh G, Maibach HI (1981) The contact urticaria
./- syndrome - an update review. J Am Acad Dermatol 5:
Intradennal injection (ifneccesary) 328-342
5. von Krogh G, Maibach HI (1984) The contact urticaria
syndrome and associated disease entities. In: Moschella SL,
Fig. 1. Suggested test procedures for evaluation of immediate- Pillsbury DM, Hurley HJ (eds) Dermatology, 2nd edn.
type responses - recommended order (according to von Krogh Saunders, Philadelphia, pp 323-333
and Maibach [2]. Note that if positive reactions are obtained, 6. Burdick AE, Mathias CGT (1985) The contact urticaria
further evaluation should be discantinued syndrome. Dermatol Clin 3:71-84
7. Lahti A, Maibach HI (1987) Immediate contact reactions:
contact urticaria syndrome. Semin Dermatol 6:313-320
8. Lahti A, Maibach HI (1991) Immediate contact reactions:
excipient. If negative, the test should be repeated on a contact urticaria and cantact urticaria syndrome. In: Mar-
slightly affected (or previously affected) area. This step zulli FN, Maibach HI (eds) Dermatotoxicalogy. Hemisphere,
New York, pp 473-495
is fundamental when suspecting OCU from large mac- 9. Harvell J, Bason M, Maibach HI (1992) Contact urticaria
romolecules or PCD. Even after apparent cure of (immediate reaction syndrome). Clin Rev Allergy 10:303-323
dermatitis, previously compromised skin may remain 10. Amin S, Tangiertsampan C, Maibach HI (1997) Contact
urticaria syndrome: 1997. Am J Contact Dermatitis 8:15-19
in a status of enhanced responsiveness compared with 11. Kanerva L, Jolanki R, Toikkanen J, Estlander T (1997)
healthy skin. A defective skin barrier function facilitates Statistics on occupational contact urticaria. In: Amin S,
the penetration of the protein allergens being tested. Lahti A, Maibach HI (eds) Contact urticaria syndrome. CRC
Press, Boca Raton, pp 57-69
Sometimes, invasive skin tests, such as the prick test or 12. Maibach H (1976) Immediate hypersensitivity in hand
scratch test, are necessary to obtain a positive reaction. dermatitis, Arch Dermatol 112:1289-1291
Occlusive application, as in the scratch-chamber test, is 13. Cromwell 0 (1997) Biochemistry of tl1e allergens. In: Kay AB
(ed) Allergy and allergie diseases, vol 2. Blackwell Science
convenient when testing non-standardized materials, Ltd, Oxford, pp 797-810
such as food products, especiallywhen a delayed reading 14. Hannuksela M (1997) Mechanisms in cantact urtiearia. Clin
is mandatory (PCD). Following the recommended order Dermatol 15:619-622
15. Sutton BI. Gould HJ (1997) IgE and IgE reeeptors. In: Kay
is important for minimizing the occurrence of hazard- AB (ed) Allergy and allergie diseases, vol 2. Blaekwell
ous extracutaneal reactions. Life-threatening reactions Seienee Ltd, Oxford, pp 797-810
when performing skin tests have been documented [4, 16. Bruynzeel-Koomen C (1986) IgE on Langerhans eells: new
insights into the pathogenesis of atopie dermatitis. Der-
236, 264-266); therefore, caution is advised, especially matologiea 172:181-183
when testing some occupational materials. Skin tests 17. Barker JNWN, Alegre VA, Mac Donald DM (1988) Surface-
should be performed only if resuscitation equipment bound immunoglobulin E on antigenpresentating eells in
eutaneous tissue of atopie dermatitis. J Invest Dermatol
and trained personnel are readily available. 90:117-121
18. Najem N, Hull D (1989) Langerhans eells in delayed skin
reaetions to inhalant allergens in atopie dermatitis - an
Concluding Remarks eleetron microseopie study. Clin Exp Dermatol 14:218-222
19. King TP, Coscia MR, Koehoumian K (1993) Strueture-
immunogenicity relationship of a peptide allergen, mellitin.
In: Kraft D, Sehon A (eds) Moleeular biology and immu-
OCU represents an increasing problem in occupational nology of allergens. CRC Press, Boea Raton, pp 11-20
dermatology. Current industrial processes involving 20. Lathi A (1980) Nonimmunologie cantaet urtiearia. Acta
new chemicals and, especially, increased physicians' Derm Venereol Suppl (Stoekh) 60[Suppll]:1-50
21. Lahti A, Oikarinen A, Ylikorkala 0, et al. (1983) Prostag-
awareness contribute to the rising number of diag- landins in eontaet urtiearia indueed by benzoie acid. Acta
nosed cases. Derm Venereol 63:425-427
22. Lahti A, Väänänen A, Kokkonen E-L, et al. (1987) Acetyl- 50. Block G, Tse KS, Kijek K, et al. (1983) Baker's asthma:
salicylic acid inhibits non-immunologie contact urticaria. clinical and immunological studies. Clin Allergy 13:359-370
Contact Dermatitis 16:133-135 51. Kanerva L, Brisman J (1997) Contact urticaria, dermatitis
23. Johansson I, Lahti A (1988) Topieal non-steroidal anti- and respiratory allergy caused by enzymes. In: Amin S, Lahti
inflammatory drugs inhibit non-immunologie immediate A, Maibach HI (eds) Contact urticaria syndrome. CRC Press,
reactions. Contact Dermatitis 19:161-165 Boca Raton, pp 129-142
24. Larmi E, Lahti A, Hannuksela M (1988) Ultraviolet light 52. Morren MA, Janssen V, Dooms Goossens A, et al. (1993)
inhibits nonimmunological contact reactions to benzoie Alfa-amylase, a flour additive: an important cause of protein
acid. Arch Dermatol Res 280:420-423 contact dermatitis in bakers. J Am Acad DermatoI29:723-728
25. von Krogh G, Maibach HI (1983) Contact urticaria. In: Adam 53. Brisman J, Belin L (1991) Clinical and immunological
RM (ed) Occupational skin disease. Grune & Stratton, New responses to occupational exposure to (X-amylase in the
York, pp 58-69 baking industry. Br J Ind Med 48:604-608
26. Cronin E (1987) Dermatitis of the hands in caterers. Contact 54. Baur X, Fruhmann G, Haug B (1986) Role of aspergillus
Dermatitis 17:265-269 amylase in baker's asthma (letter). Lancet 8471:43
27. Peltonen L, Wickstrom G, Vaahtoranta M (1985) Occupation- 55. Birnbaum J, Latil F, Vervloet D, et al. (1988) Role de l'alpha-
al dermatosis in the food industry. Dermatosen 33=166-169 amylase dans l'asthma du boulanger. Rev Mal Resp 5:519-521
28. Veien N, Hattel T, Justesen 0, Norholm A (1983) Causes of 56. Quirce S, Cuevas M, Dies-Gomez ML, et al. (1992) Respira-
eczema in the food industry. Dermatosen 31:84-86 tory allergy to Aspergillus-derived enzymes in baker' s
29. Berkley SF, Hightower AW, Beier RC, et al. (1986) Derma- asthma. J Allergy Clin Immunol 90:970-978
titis in grocery workers associated with high natural 57. Sandiford CP, Tee RD, Taylor AJ (1994) The role of cereal
concentration of furocoumarins in celery. Ann Intern Med and fungal amylases in cereal flour hypersensitivity. Clin
105:351-355 Exp Allergy 24:549-557
30. Hjorth N, Roed-Petersen J (1976) Occupational protein 58. Blanco Carmona JG, Picon SI, Sotillos MG (1991) Occupa-
contact dermatitis in food handlers. Contact Dermatitis tional asthma in bakeries caused by sensitivity to (X-amylase.
2:28-42 Allergy 46:274-276
31. Alonso MD, Martin JA, Cuevas M, et al. (1993) Occupational 59. Tarvainen K, Kanerva L, Grenquist-Norden B, et al. (1991)
protein contact dermatitis from lettuce. Contact Dermatitis Berufsallergien durch Cellulase, Xylanase and Alpha-amy-
29:109-110 lase. Z Hautkr 66:964-967
32. Fisher AA (1976) Allergie "protein" contact dermatitis due 60. Vanhanen M, Tuomi T, Hokkane H, et al. (1996) Enzyme
to foods. Cutis 16:793-796 exposure and enzyme sensitization in the baking industry.
33. Rostenberg A (1970) Contact urtiearia from food. Arch Occup Environ Med 53:670-676
DermatoI101:491-493 61. Hytönen M, Vanhanen M, Keskinen H, et al. (1994)
34. Lehrer SB, Taylor SL, Hefle SL, Bush RK (1997) Food Pharyngeal edema caused by occupational exposure to
allergens. In: Kay AB (ed) Allergy and allergie diseases, vol cellulasa enzyme. Allergy 49:782-784
2. Blackwell Science Ltd, Oxford, pp 961-80 62. Kanerva L, Vanhanen M, Tupasela 0 (1998) Occupational
35. Hannuksela M, Lalüi A (1977) Immediate reactions to fruits contact urticaria from cellulase enzyme. Contact Dermatitis
and vegetables. Contact Dermatitis 3:70-84 38:176-177
36. Janssens V, Morren M, Dooms-Goossens A, Degreef H 63. Baur X, König G, Bencze K, Fruhmann G (1982) Clinical
(1995) Protein contact dermatitis: myth or reality? Br J symptoms and results of skin tests, RAST and bronchial
Dermatol 132:1-6 provocation test in thirty three papain workers: evidence for
37. Hannuksela M (1980) Atopic contact dermatitis. Contact strong immunogenic potency and clinically relevant "pro-
Dermatitis 6:30-32 teolytic effects of airborne papain". Clin Allergy 12:9-17
38. Taylor SL, Lemanski RF, Bush RK, Busse WW (1987) Food 64. Fisher AA (1982) Hand dermatitis - a "baker's dozen". Cutis
allergens: structure and immunological properties. Ann 29:214-221
Allergy 59:93-99 65. Edwards JH, McConnochie K, Trotman DM (1983) Allergy to
39. Temesvari E, Varkonyi V (1980) Contact urticaria provoked inhaled egg material. Clin Allergy l2:427-432
by egg. Contact Dermatitis 2:143-145 66. Smith AB, Bernstein DI, London M, et al. (1990) Evaluation
40. Valdivieso R, Moneo I, Pola J, et al. (1989) Occupational of occupational asthma from airborne egg protein exposure
asthma and contact urticaria caused by buckwheat flour. in multiple settings. Chest 98:398-404
Ann Allergy 63:149-152 67. Rudzki E, Grzywa Z (1977) Contact urticaria from egg.
41. Rilliet A, Hunziker N, Brun R (1980) Alcohol contact Contact Dermatitis 3=103-104
urticaria syndrome (immediate-type hypersensitivity). Der- 68. Weltfriend E, Kwangsukstith C, Maibach HI (1995) Contact
matologica 161:361-364 urticaria from cucumber pickle and strawberry. Contact
42. Krook G (1977) Occupational dermatitis from Lactuca Sativa Dermatitis 32:173-174
(lettuce) and Cichorium (Endive). Simultaneous occurrence 69. Carino M, Cassano N, et al. (1997) Occupational contact
of immediate and delayed allergy as a cause of contact urticaria from paprika. Contact Dermatitis 37:135
dermatitis. Contact Dermatitis 3:27-36 70. Lovell CR, Rycroft RJG (1984) Contact urticaria from winged
43. Valero A, Lluch M, Amat P, et al. (1996) Occupational egg bean (Psophocarus tetragonolobus). Contact Dermatitis
allergy in confectionary workers. Allergy 51:588-592 10:314-315
44. Bonnevie P (1958) Occupational allergy in bakery. In: 71. Fregert S, Sjöborg S (1982) Unexpected lettuce immediate
European Academy of Allergy (ed) Occupational allergy. allergy in a case of delayed metal allergy. Contact Dermatitis
CC Thomas, Springfield, Illinois, pp 161-168 8:265
45. Block G, Tse K, Kijek K, et al. (1983) Baker's asthma: clinical 72. Cronin E (1973) Immediate type hypersensitivity to potato.
and immunological studies. Clin Allergy 13:359-370 Contact Dermatitis Newslett 13:358
46. Hjorth N (1981) Occupational dermatitis in the catering n Larkö 0, Lindstedt G, Lundberg PA, Mobacken H (1983)
industry. Br J Dermatol 105:37 Biochemical and clinical studies in a case of contact
47. Herxheimer H (1967) Skin sensitivity to flour in baker's urticaria to potato. Contact Dermatitis 9:108-114
apprentices. Lancet 1:83-84 74. Nater JP, Swartz JA (1967) Atopic allergie reactions due to
48. Herxheimer H (1967) The skin sensitivity to flour ofbaker's raw potato. J Allergy 40:202-205
apprentices: a final report of long term investigation. Acta 75. Göransson K (1981) Contact urticaria to apricot stone.
Allergologica 28:42-49 Contact Dermatitis 7:282
49. Sutton R, Skerritt JH, Baldo BA, Wrigley CW (1984) The 76. Sanchez MC, Hernandez M, Morena V, et al. (1997) Immu-
diversity of allergens involved in bakers' asthma. Clin nologie contact urticaria caused by asparagus. Contact
Allergy 14:93-107 Dermatitis 37:181-182
77. Temesvari E, Beeker K (1993) Contaet urtiearia from 103. Göranson K (1981) Occupational eontaet urtiearia to fresh
watermelon in a patient with pollen allergy. Contaet eow and pig blood in slaughtermen. Contaet Dermatitis
Dermatitis 28:185-186 7:281-282
78. Valsecchi R, Reseghetti A, Leghisa P, et al. Immediate 104. Boso EB, Brestel EP (1987) Contaet urticaria to eow milk.
eontaet hypersensitivity to pomegranate. Contaet Dermatitis Allergy 42:151-153
38:44-45 105. Stöger P, Wüthrich B (1993) Type I allergies to eow milk
79. Sanehez MC, Hernandez M, Morena V, et al. (1997) Immu- proteins in adults. A retrospeetive study of 34 adult milk-
nologie eontaet urtiearia eaused by asparagus. Contaet and eheese allergie patients. Int Areh Allergy Immunol
Dermatitis 37:181-182 102:399-407
80. Temesvari E, Beeker K (1993) Contaet urtiearia from 106. Nestle FO, Elsner P (1997) Oeeupational dermatoses in
watermelon in a patient with pollen allergy. Contaet eheese makers: frequent assoeiation of irritant, allergie and
Dermatitis 28:185-186 protein contaet dermatitis. Dermatology 194:243-246
81. Wood BP, Greig DH (1997) Catering industry. Clin Dermatol 107. Melino M, Toni F, Rigguzzi G (1987) Immunologie eontaet
15:567-571 urtiearia to fish. Contact Dermatitis 17:182
82. Cuesta-Herranz j, Lazaro M, de las Heras M, et al. (1998) 108. Diaz Sanehez C, Laguna Martinez j, Iglesias Cadarso A,
Peaeh allergy pattern: experienee in 70 patients. Allergy Vidal Pan C (1994) Protein contaet dermatitis assoeiated
53:78-82 with food allergy to fish. Contaet Dermatitis 31:55-57
83. Muiioz D, Leanizbarrutia I, Lobera T, de Cores F (1985) 109. Göranson K (1981) Contaet urtiearia to fish. Contaet
Anaphylaxis from eontaet with earrot. Contaet Dermatitis Dermatitis 7:282-283
13:345-346 1l0. Kavli G, Gram T, Moseng D, Orpen G (1980) Oceupational
84. Gons;alo M, Chieira L, Gons;alo S (1992) Immediate and dermatitis in shrimp peelers. Contaet Dermatitis 6:27-29
delayed hypersensitivity to gar/ie and soybean. Am j 111. Nakamori M, Matsuo I, Ohkido M (J996) Coexistenee of
Contaet Dermatitis 3:102-104 eontaet urtiearia and eontaet dermatitis due to pear/ oysters
85. Hafner J, Riess CE, Wüthrieh B (1992) Protein eontaet in an atopie dermatitis patient. Contaet Dermatitis 34:438
dermatitis from paprika and curry in a cook. Contaet 112. Hjorth N (1978) Gut eezema in slaughterhouse workers.
Dermatitis 26:51-52 Contact Dermatitis 4:49-52
86. Tosti A, Guerra L (1988) Protein eontaet dermatitis in food 113. Hansen KS, Petersen HO (1989) Protein contaet dermatitis
handlers. Contaet Dermatitis 19:149-150 in slaughterhouse workers. Contaet Dermatitis 21:221-224
87. Niinimäki A, Hannuksela M (1981) Immediate skin test 114. Zenarola P, Lomuto M (1991) Protein contaet dermatitis
reaetions to spiees. Allergy 36:487-493 with positive RAST in a slaughterman. Contaet Dermatitis
88. Niinimäki A, Hannuksela M, Makinen-Kiljunen S (1995) 24:134-135
Skin priek tests and in vitro immunoassays with native 115. Kanerva L (1996) Oceupational IgE-mediated protein eon-
spiees and spiee extraets. Ann Allergy Asthma Immunol taet dermatitis from pork in a slaughterman. Contaet
75:280-286 Dermatitis 34:301-302
89. Niinimäki A, Björksten F, Puukka M, et al. (1989) Spiee 116. Niinimäki A, Sari S (1978) Dermatologieal and allergie
allergy: results of skin priek tests and RAST with spiee hazards of cheesemakers (letter). Seand j Environ Health
extraets. Allergy 44:60-65 4:262-263
90. Halmepuro L, Vuontela K, Kalimo K, et al. (J984) Cross- 117. Maibach HI (1995) Contaet urtiearia syndrome from mold
reaetivity of IgE antibodies with allergens in bireh pollen, on salami easing. Contaet Dermatitis 32:120-121
fruits and vegetables. Int Areh Allergy Appl Immunol 118. Tarvainen K, Salonen j-P, Kanerva L, et al. (1991) Allergy
74:235-240 and toxidermia from shiitake mushrooms. j Am Acad
91. Halmepuro L, L0wenstein H (1985) Immunologieal investi- Dermatol 24:64-66
gation of possible struetural similarities between pollen 119. Niinimäki A (1987) Serateh-ehamber tests in food handler
antigens and antigens in apple, earrot and eelery tuber. dermatitis. Contaet Dermatitis 16:11-20
Allergy 40:264-272 120. Susitaival P, Hannuksela M (1997) Animals and animal
92. Valenta R, Duehene M, Pettenburger K, et al. (J991) produets. In: Amin S, Lahti A, Maibach HI (eds) Contaet
Identifieation of profilin as novel pollen allergen: IgE urtiearia syndrome. CRC Press, Boea Raton, pp 95-105
autoreaetivity in sensitized individuals. Seienee 253:557-560 121. Mathias CGT, Morrison jH (1988) Oeeupational skin
93. Valenta R, Duehene M, Ebner C, et al. (1992) Profilins diseases, United States. Results from the Bureau of Labor
constitute a novel family of funetional plant pan -allergens. Statisties Annual Survey of Oecupational Injuries and
j Exp Med 175:377-385 Illnesses, 1973 through 1984. Areh DermatollO:1519-1524
94. Ebner C, Hirschwehr R, Bauer L, et al. (1995) Identification 122. Abrams K, Hogan Dj, Maibach HI (1991) Pesticide-related
of allergens in fruits and vegetables: IgE cross reaetivities dermatoses in agrieultural workers. Oeeup Med 3:463-492
with the important bireh pollen allergens Bet VI and Bet V2 123. Sharma VK, Kaur S (1990) Contaet sensitization by pesti-
(bireh profilin). j Allergy Clin Immunol 95:962-969 eides in farmers. Contact Dermatitis 2:77-80
95. Seeberg G (1952) Eezematous dermatitis from eontact with, 124. Helander I, Makela A (1983) Contaet urtiearia to zine
or ingestion ofbeef, pork, and mutton (4 case reports). Acta diethydithioearbamate (ZDC). Contact Dermatitis 4:
Derm Venereol 32[Suppl 29]:320-322 327-328
96. Fisher A (1982) Contact urtiearia from handling meats and 125. Dannaker C), Maibach HI (1990) Contaet urtiearia and
fowl. Cutis 30:726-729 anaphylaxis to Chlorothalonil (abstract). Am j Contaet
97. jovanovie M, Oliwieeki S, Beck M (1992) Oceupational Dermatitis 1:65
contact urtiearia from beef associated with hand eczema. 126. Dannaker C), Maibach HI, O'Malley M (1993) Contact
Contaet Dermatitis 27:188-189 urtiearia and anaphylaxis to the fungieide Chlorothalonil.
98. Harrington CI (1981) Chicken sensitivity. Contact Dermatitis Cutis 52:312-315
7'l26 127. Epstein S (1948) Milker's eezema. j Allergy 19:333-341
99. Aeeiai MC, Brusi S, Franealanei M, et al. (1991) Skin tests 128. Kanerva L, Susitaival P (1996) Cow dander - the most
with fresh foods. Contaet Dermatitis 24:67-68 common eause of oeeupational eontaet urticaria in Finland.
100. Beek H-I, Knudsen Nissen (1982) Type I and type IV allergy Contact Dermatitis 35:309-310
to speeifie ehicken organs. Contaet Dermatitis 3:217-218 129. Susitaival P, Husman L, Hollmen A, et al. (1995) Hand
101. Fisher AA, Stengel F (1977) Allergie oecupational hand eezema in Finnish farmers. A questionnaire-based clinieal
dermatitis due to ealfs liver. An urticarial "immediate" type study. Contaet Dermatitis 32:150-155
hypersensitivity. Cutis 19:561-565 130. Timmer C, Coenraads P-j (1996) Allergie eontact dermatitis
102. Moseng D (1982) Urtiearia from pig's gut. Contact Derma- from cow hair and dander. Contaet Dermatitis 34:
titis 8:135-136 292-302
214 S.1. Ale and H.I. Maibach
131. Mahler V, Diepgen TL, Heese A, Peters K-P (1998) Protein 158. Hinojosa M, Moneo I, Dominguez J, et al. (1984) Asthma
contact dermatitis due to cow dander. Contact Dermatitis caused by Afriean maple (Triplochiton sc/eroxylon) wood
38:47-48 dust. J Allergy Clin Immunol 74:782-786
132. Ylönen 1, Virtanen T, Horsmanheimo L, et al. (1994) Affinity 159. Tuppurainen M, Keskinen H, Tupasela 0 (1995) Occupa-
purification of the major bovine allergen by a novel tional asthma caused by obeche wood dust. Allergy 50[Suppl
monoclonal antibody. J Allergy Clin Immunol 93:851-858 26]:38-39
133. Prahl P, Bucher D, Plesner T, et al. (1982) Isolation and 160. Rudzki E, Rebandel P, Grzywa Z, et al. (1982) Occupational
characterisation of three major allergens in an extract from dermatitis in veterinarians. Contact Dermatitis 8:72-73
cow hair and dan der. Int Arch Allergy Appl Immunol 161. Hjorth N, Roed-Petersen J (1980) Allergic contact dermatitis
69:293-301 in veterinary surgeons Contact Dermatitis 6:27-29
134. Crippa M, Misquith L, Pasolini G (1990) Contact dermatitis 162. Roger A, Guspi R, Garcia-Patos V, et al. (1995) Occupational
from animal proteins in a milker. Contact Dermatitis 22:240 protein contact dermatitis in a veterinary surgeon. Contact
135. Camarasa JG (1982) Contact eczema from cow saliva. Dermatitis 32:248-249
Contact Dermatitis 15:117 163. Degreff H, Bourgeois M, Naert C, et al. (1984) Protein
136. Astarita C, Di Martino P, Scala G, et al. (1996) Contact contact dermatitis with positive RAST caused by bovine
allergy: another occupational risk to Tetranychus urticae. blood and amniotie fluid. Contact Dermatitis 11:129-130
J Allergy Clin Immunol 98:732-738 164. Fisher AA (1983) Urticaria from animals, their appendages
137. Axelsson IG (1994) Allergy to the coffee plant. Allergy and secretions. Cutis 31:142-148
49:885-887 165. Prahl P, Roed-Petersen J (1979) Type I allergy from cows in
138. Treudler R, Tebbe B, Orfanos CE (1997) Coexistence of type veterinary surgeons. Contact Dermatitis 5:33-38
I and type IV sensitization in occupational coffee allergy. 166. Schmidt H (1978) Contact urtiearia. Contact Dermatitis
Contact Dermatitis 36:lO9 4: 2 30 - 2 31
139. Osterman K, Johansson SG, Zetterstrom 0 (1985) Diagnostic 167. Agrup G, Sjostedt L (1988) Contact urtiearia in laboratory
test in allergy to green coffee. Allergy 40:336-343 technicians working with animals. Acta Derm Venereol
140. Kanerva L, Estlander T, Jolanki R (1990) Long-lasting 81:736-742
contact urticaria. Type I and type IV allergy from castor 168. Aoyama K, Ueda A, Manda F, et al. (1992) Allergy to
bean and a hypo thesis of systemie IgE-mediated allergic laboratory animals: an epidemiological study. Br J Ind Med
dermatitis. Dermatol Clin 8:181-188 49:41-47
141. Kanerva L, Estlander T, Jolanki R (1990) Long-lasting 169. De Groot AC, Messerschmidt HJB (1984) Laboratory animal
contact urticaria from castor bean. J Am Acad Dermatol allergy. Contact Dermatitis 11:120-136
23:351-355 170. Slovak AJM, Hili RN (1981) Laboratory animals allergy: a
142. Lehrer SB, Karr RM, Salvaggio JE (1978) Extraction and clinical survey of an exposed population. Br J Ind Med
analysis of coffee bean allergens. Clin Allergy 8:217-226 38:38
143. Lahti A (1986) Contact urticaria and respiratory symptoms 171. Burrows D (1979) Urticaria from rats. Contact Dermatitis
from tulips and lilies. Contact Dermatitis 14:317-319 5:122
144. Tanaka T, Moriwaki S, Horio T (1987) Occupational 172. Eggleston PA, Ansari AA, Ziemann B, et al. (1990) Occupa-
dermatitis with simultaneous immediate and delayed allergy tional challenge studies with laboratory workers allergie to
to Chrysanthemum. Contact Dermatitis 16:152-154 rats. J Allergy Clin Immunol 86:63-72
145. Estlander T, Kanerva L, Tupasela 0, Jolanki R (1998) 173. Hunskaar S, Fosse RT (1990) Allergy to laboratory miee and
Occupational contact urticaria and type I sensitization rats: a review of the pathophysiology, epidemiology and
caused by gerbera. Contact Dermatitis 38:118-120 clinical aspects. Lab Animals 24:358-374
146. Gamboa PM, Jauregui I, Urrutia I, et al. (1997) Allergic 174. Karches F, Fuchs T (1993) A strange manifestation of
contact urticaria from poppy flowers (Papaver rhoeas). occupational contact urticaria due to mouse hair. Contact
Contact Dermatitis 37:140-141 Dermatitis 28:200
147. Quirce S, Garcia-Figueroa B, Olaguibel JM, et al. (1993) 175. Kauppinen K (1980) Occupational contact urtiearia pro-
Occupational asthma and contact urticaria from dried voked by mouse liver. Contact Dermatitis 6:444-445
flowers of Limonium tartaricum. Allergy 48:285-290 176. Rudzki E, Rebandel P, Rogozinski T (1981) Contact urticaria
148. Kanerva L, Mäkinen-Kiljunen S, Kiistala R, Granlund H from rat tail, guinea pig, streptomycin and vinyl pyridine.
(1995) Occupational allergy caused by spathe flower (Spat- Contact Dermatitis 7:186-188
hiphyllum wallis). Allergy 50:174-178 177. Wong AV, Shili-Wen H, Burnett JW (1984) Hypersensitivity
149. Potter P, Mather S, Lockey P, et al. (1995) Immediate and to rat saliva. J Am Acad Dermatol 11:606-608
delayed contact hypersensitivity to verbena plants. Contact 178. Zschunke E (1978) Contact urtiearia, dermatitis and asthma
Dermatitis 33:343-346 from cockroaches (Periplaneta Americana). Contact Der-
150. Lahti A (1986) Contact urtiearia and respiratory symptoms matitis 4:313-314
from tulips and lilies. Contact Dermatitis 14:317-319 179. Armentia A, Vega JM (1997) Allergy to frogs (letter). Allergy
151. Apted J (1988) Acute contact urticaria from Grevillea 52:6 74
juniperina. Contact Dermatitis 18:126 180. Lutsky II, Neuman I (1975) Laboratory dander allergy. I An
152. Apted J (1988) Acute contact urticaria from Hakea suaveo- occupational disease. Ann Allergy 35:201-205
lens. Contact Dermatitis 18:126 181. Thomsen RJ, Honsinger RW (1987) Immediate hypersensi-
153. Lahti A (1986) Contact urticaria to plants. Dermatol Clin tivity reaction to amphibian serum manifesting as eczema.
4:127-136 Arch Dermatol 123:1436-1437
154. Paulsen E, S0gaard 1, Andersen KE (1997) Occupational 182. Teasdale EL, Davies GE, Slovak A (1983) Anaphylaxis after
dermatitis in Danish gardeners and greenhouse workers. (I) bites by rodents. BMJ 286:1480
Prevalence and possible risk factors. Contact Dermatitis 183. Cockroft A, McCarthy P, Edwards 1, Andersson N (1981)
37:263-270 Allergy in laboratory animals workers. Lancet 8224:827-830
155. de Jong NW, Vermeulen AM, Gerth van Wijk R, de Groot H 184. Taylor G, Davies GE, Altounyan REC, et al. (1976) Allergie
(1998) Occupational allergy caused by flowers. Allergy reactions to laboratory animals. Nature 260:280
53:204-209 185. Davies GE, Thompson AV, Niewola Z, et al. (1983) Allergy to
156. Göransson K (1980) Contact urticaria and rhinoconjuncti- laboratory animals: a retrospective and a prospective study.
vitis from tropieal wood (Lauan, Philippine, Red Mahoga- Br J Ind Med 40:442-449
ny). Contact Dermatitis 6:223-224 186. Gordon S, Tee RD, Newman Taylor AJ (1993) Analysis of rat
157. Kanerva L, Tuppurainen M, Keskinen H (1998) Contact urine proteins and allergens by sodium dodecyl sulfate-
urticaria caused by obeche wood (Triplochiton sc/eroxylon). polyacrylamide gel electrophoresis and immunoblotting.
Contact Dermatitis 38:170-171 J Allergy Clin Immunol 92:298-305
187. Ross DJ, Sallie BA, McDonald jC (1995) SWORD '94: 211. Alenius H, Turjanmaa K, Mäkinen-Kiljunen S, et al. (1994)
surveillance of work-related and occupational respiratory IgE immune response to rubber proteins in adult patients
disease in the UK. Occup Med 45:175-178 with latex allergy. j Allergy Clin Immunol 93:859-863
188. Schumacher MJ (1980) Characterization of allergens from 212. Fuchs T, Wahl R (1992) Immediate reactions to rubber
urine and pelts of laboratory miee. Mol Immunol 17: products. Allergy Proc 13:61-66
1087-1095 213. Turjanmaa K, Rasanen L, Letho M, et al. (1989) Basophil
189. Longbottom JL (1984) Occupational allergy due to animal histamine release and lymphocite proliferation tests in latex
allergens. Clin Immunol Allergy 4:19-36 contact urticaria. Allergy 44:181-186
190. Walls AF, Longbottom JL (1983) Quantitative immunoelec- 214. Alenius H, Palosuo T, Kelly K, et al. (1993) IgE reactivity to
trophoretic analysis of rat allergen extracts. I Antigenie 14-kD and 27-kD natural rubber proteins in latex-allergie
characterization of fur, urine, saliva and other rat-derived children with spina bifida and other congenital anomalies.
materials. Allergy 38:419-431 Int Arch Allergy ImmunoI102:61-66
191. Gordon S, Tee RD, Newman Taylor AJ (1993) Analysis of rat 215. Alenius H, Kurup V, Kelly K, et al. (1994) Latex allergy:
urine proteins and allergens by sodium dodecyl sulfate- frequent occurrence of IgE antibodies to a cluster of 11 latex
polyacrylamide gel electrophoresis and immunoblotting. pro teins in patients with spina bifida and histories of
J Allergy Clin Immunol 92:298-305 anaphylaxis. J Lab Clin Med 123:712-720
192. Walls AF, Longbottom JL (1985) Comparison of rat fur, 216. Turjanmaa K, Laurila K, Mäkinen-Kiljunen S, Reunala T
urine, salive, and other rat allergen extracts by skin testing, (1988) Rubber contact urticaria. Allergenie properties of 19
RAST and RAST inhibition. J Allergy Clin Immunol 75: brands of latex gloves. Contact Dermatitis 19:362-367
242-251 217. Turjanmaa K, Palosuo T, Alenius H, et al. (1997) Latex
193. Gordon S, Tee RD, Newman Taylor AJ (1996) Analysis ofthe allergy diagnosis: in vivo and in vitro standarization of
allergenie composition of rat dust. Clin Exp Allergy 26: natural rubber extract. Allergy 52:41-50
533-541 218. Hannuksela M (1997) Antibiotics. In: Amin S, Lahti A,
194. Hollander A, van Run P, Spithoven J, et al. (1997) Exposure Maibach HI (eds) Contact urticaria syndrome. CRC Press,
of laboratory animal workers to airborne rat and mouse Boca Raton, pp 107-110
urine allergens. Clin Exp Allergy 27:617-626 219. Boonk WR (1981) Dermatologie hazards from hidden
195. Renström A, Malmberg P, Larsson K, et al. (1994) Prospec- contact with penicillin. Dermatosen 29:131-135
tive study of laboratory animal allergy: factors predisposing 220. Keller K, Schwanitz HJ (1992) Combined immediate and
to sensitization and development of allergie symptoms. delayed hypersensitivity to mezlocillin. Contact Dermatitis
Allergy 49:548-552 27:348-349
196. Gordon S (1997) Occupational sensitization to laboratory 221. Levene GM, Withers AFD (1969) Anaphylaxis to strep-
animals. Clin Exp Allergy 27:603-605 tomicin and hyposensitization (parasensitization). Trans St
197. Edwards RG, Beeson MF, Dewdney jM (1983) Laboratory John's Hosp Dermatol Soc 55:184
animal allergy: the measurement of airborne urinary aller- 222. Miyahara H, Koga T, Imayama S, Hori Y (1993) Occupa-
gens and the effects of different environmental conditions. tional contact urticaria syndrome from cefotiam hydrochlo-
Lab Animals 17:235-239 ride. Contact Dermatitis 29:210-211
198. Eggleston PA, Ansari AA, Ziemann B, et al. (1990) Occupa- 223. Schena D, Barba A, Costa G (1996) Occupational contact
tional challenge studies with laboratory workers allergie to dermatitis due to cisplatin. Contact Dermatitis 34:2320-
rats. J Allergy Clin Immunol 86:63-72 2321
199. Botharn PA, Lamb CT, Teasdale EL, et al. (1995) Allergy to 224. Sertoli A, Marliani A, Lombardi P, Panconesi E (1980)
laboratory animals: a follow up study of incidence of atopy Immediate sensitization to methamizole verified by patch
and pre-existing sensitisation on its development. Occup tests. Contact Dermatitis 6:294
Environ Med 52:129-133 225. Belsito DV (1993) Contact urticaria from pentamidine
200. De Groot H, De Jong NW, Duijster E, et al. (1998) Prevalence isethionate. Contact Dermatitis 29:158-159
of natural rubber latex allergy (type I and type IV) in 226. Escribano MM, Muanoz-Bellido FJ, Velazquez E, et al.
laboratory workers in The Netherlands. Contact Dermatitis (1997) Contact urticaria due to aescin. Contact Dermatitis
38:159-163 37:233
201. Nuter AF (1979) Contact urticaria to rubber. Br J Dermatol 227. Freitas JP, Brandao FM (1986) Contact urticaria to
101:597-598 chlorocresol. Contact Dermatitis 15:252
202. Förström L (1980) Contact urtiearia from latex surgical 228. Galindo PA, Feo F, Garcia R, et al. (1997) Mercurochrome
gloves. Contact Dermatitis 6:33-34 allergy. Immediate and delayed hypersensitivity. Allergy
203. Beaudouin E, Pupi! P, Jacson F, et al. (1990) Allergie 52:1138-1141
professionelle au latex. Enquete prospective sur 907 sujets 229. Grob JJ, Pommier G, Robaglia A, et al. (1987) Contact
du milieu hospitalier. Rev Fr Allergoi 30:157-161 urticaria from rifamycin. Contact Dermatitis 16:284-285
204. Handfield-Jones SE (1998) Latex allergy in health care 230. Hardy MP, Maibach HI (1995) Contact urticaria syndrome
workers in an English distriet general hospital. Br J from sorbitan sesquioleate in a cortieosteroid ointment.
Dermatol 138:273-276 Contact Dermatitis 32:114
205. Hesse A, Lacher U, Koch HU, et al. (1996) Update on the 231. Maibach HI, Conant M (1977) Contact urticaria to a
latex allergy topic (in German). Hautarzt 47:817-824 corticosteroid cream: Polysorbate 60. Contact Dermatitis
206. Turjanmaa K, Cacioli P, Thompson RL, et al. (1995) 3:350-351
Frequency of natural rubber latex allergy among US 232. Ryan ME, Davis BM, Marks JG, Jr (1980) Contact urticaria
operating room nurses using skin priek testing (abstract). and allergie contact dermatitis to benzocaine gel. J Am Acad
J Allergy Clin Immunol 95:214 Dermatol 2:221-223
207. Turjanmaa K (1997) Contact urticaria from latex gloves. In: 233. Tosti A, Guerra L, Bardazzi F (1989) Contact urticaria
Amin S, Lahti A, Maibach HI (eds) Contact urticaria during topical immunotherapy. Contact Dermatitis 21:
syndrome. CRC Press, Boca Raton, pp 173-187 196-197
208. Turjanmaa K, Mäkinen-Kiljunen S, Reunala T, et al. (1995) 234. Cardot E, Tillie-Leblond I, Jeannin P, et al. (1995) Anaphy-
Natural rubber latex allergy, the European experience. lactic reaction to local administration of rifamycin SV.
Immunol Allergy Clin N Am 15:71-88 J Allergy Clin Immunol 95:1-7
209. Levy DA, Charpin D, Pecquet C, et al. (1992) Allergy to latex. 235. Knowles SR, Shear NH (1995) Anaphylaxis from bacitracin
Allergy 47:579-587 and polymyxin B (Polysporin) ointment. Int J Dermatol
210. Carillo T, Cuevas M, Hinojosa M, Moneo I (1986) Contact 8:572-573
urticaria and rhinitis from latex surgical gloves. Contact 236. Kosakova M (1977) Sub-Schock bei der Epikutanprobe mit
Dermatitis 15:69-72 Chloramphenicol. Berfsdermatosen 25:134-135
216 5.1. Ale and H.1. Maibach: Occupational Contact Urticaria
237. Lin FL, Woodmansee D, Patterson R (1998) Near-fatal 252. Freeman S, Lee M (1996) Contact urtiearia to hair condi-
anaphylaxis to topical bacitracin ointment. J Allergy Clin tioner. Contact Dermatitis 35:195-196
ImmunollOl:136-137 253. Kousa M, Strand R, Mäkinen-Keijunen S, Hannuksela M
238. Mancuso G, Masara N (1992) Contact urticaria and severe (1990) Contact urticaria from hair conditioner. Contact
anaphylaxis from rifamycin SV. Contact Dermatitis 27:124- Dermatitis 23:279
125 254. Pasche-Koo F, Cleys M, Hauser C (1996) Contact urticaria
239. Okano M, Nomura M, Hata S, et al. (1989) Anaphylactic with systemic symptoms caused by bovine collagen in a hair
symptoms due to chlorhexidine gluconate. Arch Dermatol conditioner. Am J Contact Dermatitis 7:56
125:50-52 255. Picardo M, Rovina A, Cristaudo A, et al. (1985) Contact
240. Roupe G, Strannegard 0 (1969) Anaphylactic shock elicited urticaria from Tilia (lirne). Contact Dermatitis 13:72-73
by topical administration of bacitracin. Arch Dermatol 256. Temesvari E, Varkonyi V (1980) Contact urticaria provoked
100:450-452 by egg. Contact Dermatitis 6:143-144
241. Susitaival P, Häkkinen L (1989) Anaphylactic allergy to 257. Mikkelsen F, Thomsen K (1978) Occupational contact
chlorhexidine cream. In: Frosch PJ, Dooms-Goossens A, dermatitis to human hair. Contact Dermatitis 4:165
Lachapelle J-M, et al. (eds) Current topics in contact 258. Sasseville D (1998) Contact urticaria from epoxi res in and
dermatitis. Springer, Berlin Heidelberg New York, pp 99-103 reactive diluents. Contact Dermatitis 38:57-58
242. Sherertz E (1994) Occupational skin disease in the pharma- 259. Tarvainen K, Jolanki R, Estlander T, et al. (1995) Immuno-
ceutical industry. Dermatol Clin 12:533-536 logie contact urticaria due to airborne metlIylhexa-
243. Tuft L (1975) Contact urticaria from cephalosporins. Arch hydrophtalic and methyltetrahydrophtlIalic anhydrides.
Dermatol 111:1609 Contact Dermatitis 32:204-209
244. Fisher AA (1982) Contact urticaria due to medicaments, 260. Jolanki R, Estlander T, Kanerva L (1987) Occupational
chemicals and food. Cutis 30:168-172 contact dermatitis and contact urticaria caused by epoxy
245. Leino T, Kanerva L (1997) Contact urticaria from hairdress- resins. Acta Derm Venereol Suppl (Stockh) 134:90-94
ing products. In: Amin S, Lahti A, Maibach HI (eds) Contact 261. Jolanki R, Kanerva L, Estlander T, et al. (1990) Occupational
urticaria syndrome. CRC Press, Boca Raton, pp 157-172 dermatoses from epoxy resin compounds. Contact Derma-
246. Calnan C, Shuster S (1963) Reactions to ammonium titis 23=172-183
persulphate. Arch Dermatol 88:812 262. Kanerva L, Hyry H, Jolanki R, et al. (1997) Delayed and
247. Gautier R, Gervaise P, Mellario F (1966) Two causes of immediate allergy caused by methylhexalIydrophtalic anhy-
occupational asthma and urticaria in hairdressers: persul- dride. Contact Dermatitis 36:34-38
phate salts and silk. Arch Mal Prof 27:809 263. Kanerva L, Jolanki R, Tupasela 0, et al. (1991) Immediate
248. Pepys I, Hutchcroft BI, Breslin ABX (1967) Asthma due to and delayed allergy from epoxy resins based on diglycidyl
immediate chemical agents - persulphate salts and henna in ether of bisphenol A. Scand J Work Environ Health 17:
hairdressers. Clin Allergy 6:399-404 208-215
249. Fisher AA (1985) The persulphates - a tripIe threat. Cutis 264. Haustein UF (1976) Anaphylactic shock and contact urti-
35:520-525 caria after tlIe patch test witlI professional allergens. Allergie
250. Majoie ML, Bruynzeel DP (1992) Occupational immediate- Immunol 22:349-352
type hypersensitivity to henna in a hairdresser. Am J 265. Maucher OM (1972) Anaphylaktische Reaktionen beim
Contact Dermatitis 7:38-40 Epicutantest. Hautarzt 23:139-140
251. Edwards EK, Jr, Edwards EK (1984) Contact urticaria and 266. Temesvari E, Albonczy E, Somlai B (1979) Kontakturtikaria
allergic contact dermatitis caused by paraphenylenediamine. durch Ei. Dermatosen 27:69-71
Cutis 34:87-88
CHAPTER 25
Occupational Contact Urticaria in Numbers

L. Kanerva, R. Jolanki, and T. Estlander
Introduction assistants, cleaners, physicians, kitchen assistants,

restaurant workers, laboratory assistants, assistant
nurses and hospital attendants (Table 3).
In Finland, occupational contact urticaria (including
protein contact dermatitis) has been classified as a
separate occupational skin disease since 1989 and, Prevalence of Occupational Contact Urticaria
accordingly, statistical data are available (Kanerva et al.
1995b, 1996b; Kanerva and Brisman 1997). The prevalence of occupational contact urticaria during
a 5-year period per 100,000 employed workers is given
in Table 4. Bakers, food-processing workers, dental
The Most Common Causes of Occupational
assistants, veterinary surgeons, domestic animal atten-
Contact Urticaria
dants, farmers, chefs, cooks, cold-buffet managers and
dairy workers had the highest prevalence (Table 4).
Table 1 gives a ranking list of the most common causes
of occupational contact urticaria. The tluee most The Most Common Occupational Groups
common causes are (1) cow dander, (2) natural rubber with Occupational Contact Urticaria
latex, and (3) flour, grains, feed and other foodstuffs.
These three groups (n = 985) comprised 82% of all cases
of occupational contact urticaria during a 7-year period The most common occupational groups with occupa-
(n = 1205). Contact urticaria from cow dander and tional contact urticaria per 100,000 workers are given
natural rubber latex, as weH as the total number of in Table 5. Food and beverage manufacturing work;
cases of contact urticaria, is much more common in agricultural, forestry and fishing work; accommoda-
women than in men (Kanerva et al. 1995b, 1996b). tion establishments and household work; health care
and veterinary work; and hygiene and personal care
work were the five occupational groups with tlIe
Occupational Contact Urticaria Caused highest number of occupational contact urticaria cases.
by low-Molecular-Weight Chemieals
Age-Standardized Risk Ratio
The prevalence of contact urticaria caused by low- to Develop Occupational Contact Urticaria
molecular-weight chemicals is very low, and only
occasional cases were detected during a 7-year period
Ten occupations with the highest risk of developing
(Table 2). It should be no ted , however, that more than
occupational contact urticaria and protein contact
70 low-molecular-weight chemicals have caused con-
dermatitis, and their causes, are given in Table 6.
tact urticaria (Tupasela and Kanerva 1997).
Bakers and confectioners; farmers; butchers and sausage
makers; plastic product workers, and physicians were
Occupations with the Greatest Number of Ca ses the five occupations with the highest risk (Table 6).
of Occupational Contact Urticaria
Remarks on the Most Common Causes
of Occupational Contact Urticaria
Farmers experienced the greatest number of occupa-
tional contact urticaria cases in Finland (Table 3).
Other risk occupations were: animal attendants, bak- In Finland, hand eczema is common in Finnish dairy
ers, nurses, chefs, cooks, cold-buffet managers, dental farmers, partly due to immediate and delayed aHergy

218 L. Kanerva et al.
Table 1. The causes of occupational contact urticaria and protein Table 3. Occupations with the greatest number of cases of
contact dermatitis during a seven-year period (1990-1996; 1205 occupational contact urticaria in Finland during a 5-year period
cases), according to the Finnish Register of Occupational (n = 815)
Diseases
Ranking Occupation Number
Cause Number (% )
of cases 1 Farmers, silviculturists 341
2 Domestic animal attendants 61
1. Cow dan der 531 44.0 3 ~~ ~
2. Natural rubber latex 311 25.8 4 Nurses 42
3. Flour, grains and feed 143 11.4 5 Chefs, cooks, cold buffet managers 40
4. Handling of foodstuffs 27 2.2 6 Dental assistants 28
5. Decorative plants 22 1.8 7 Cleaners, etc. 21
6. Industrial enzymes 16 1.3 8 Physicians 20
7. Roots 13 1.1 9 Kitchen assistants, restaurant workers, etc. 16
8. Spices 10 0.8 10 Laboratory assistants 15
8. Vegetables 10 0.8 11 Assistant nurses, hospital attendants 14
10. Pork 8 0.7 12 Shop assistants, shop cashiers 9
10. Storage mites 8 0.7 Laboratory technicians, radiographers 9
12. Trees (teak, abachi, etc.) 6 0.5 Waiters in cafes and snack bars, etc. 9
12. Ammonium and potassium persulfate 6 0.5 Hairdressers, beauticians, bath 9
14. 2-Ethylhexyl acrylate 5 0.4 attendants, etc.
14. Phthalic anhydrides 5 0.4 Housekeeping managers, snack bar 9
14. Egg 5 0.4 managers, etc.
14. Ethylhexyl acrylate 5 0.4 17 Packers 8
18. Onions 4 0.3 18 Butchers and sausage makers 7
18. Fish, fish meal 4 0.3 Machine and engine mechanics, etc. 7
20 Horticultural supervisors 6
Total 1205 100
21 Homemakers, horne helps (municipal) 5
Technical nursing assistants 5
Dentists 5
Dairy workers 5
Table 2. Occupational contact urticaria caused by low-molecular- Horticultural workers 5
weight chemicals during 1990-1996 26 Food processing workers 4
Industrial sewers etc. 4
Ammonium and potassium persulfate 6 28 Veterinary surgeons 3
2-Ethylhexyl acrylate 5 Assemblers of electrical and 3
Phthalic anhydrides 5 teletechnical equipment
Chlorhexidine gluconate 2
Acetic acid 1 Total 815
Furfuryl aldehyde
Ammonium persulfate
Potassium persulfate
Epoxy resin
flour (Kanerva 1998), grains, feed and foodstuffs have
Eugenol received much less attention in the dermatological
Phenol formaldehyde res in literature. Bakers and farmers, as weIl as workers in
various food industries, are at risk. 1t is emphasized
that flour contains many groups of allergens - the
to cow dan der (Susitaival et al. 1995; Kanerva and pro tein flour itself, natural enzymes and industrial
Susitaival 1996; Susitaival 1996). Finland is geograph- enzymes added to the flours (Kanerva and Brisman
ically located above the 60th degree of Northern 1997). Enzymes were the fourth most common cause of
latitude and is, thus, the most northern country with occupational contact urticaria. Contact urticaria from
dairy farming. Accordingly, cows are kept in cow- enzymes has been dealt with elsewhere in this book
houses during most of the year, generally from (Chap. 65). The relatively high number of reported
September until May or lune. Farmers are therefore cases caused by enzymes in Finland is due to the rather
strongly exposed to cow dander. extensive enzyme industry, as well as the re cent
Cow dander is also the most common cause of research interest in allergy caused by enzymes in
occupational rhinitis and asthma in Finland (Kanerva Finland.
and Vaheri 1993; Kanerva et al. 1994). Contact urticaria Decorative plants, roots, spices (Niinimäki 1995;
caused by cow dander is 19E-mediated and, recendy, Kanerva et al. 1996a), pork (Kanerva 1996), and
major bovine allergens have been characterized by vegetables (Hjorth and Roed-Petersen 1976) are well-
immunoassays (Ylönen et al. 1992, 1994). Allergy to known causes of contact urticaria, whereas storage
cow dan der is weIl known in Finland, but elsewhere mites are less weIl known, although they are well
may not be looked for or recognized (Janssens et al. recognized as respiratory allergens (Terho et al. 1985;
1995). Cuthbert 1990). We routinely prick test farmers and
Contact urticaria caused by natural rubber latex has other exposed workers with three storage mites,
been extensively reviewed in the literature, whereas namely Acarus siro, Lepidoglyphus destructor and
Occupational Contact Urticaria in Numbers 219
Table 4. Occupational contact urticaria by occupation per Table S. The most common occupational groups with occupa-
100,000 employed persons in Finland over 5 years (815 cases), tional contact urticaria in Finland during a 5-year period per
according to the Finnish Register of Occupational Diseases 100,000 workers
Occupation Number Total Type ofwork Number Total

per number per number
100,000 100,000
workers workers
1. Bakers 140.5 53 1. Food and beverage manufacturing work 67.5 72

2. Food-processing workers 101.8 4 2. Agricultural, forestry and fishing work 44.2 417
3. Dental assistants 95.5 28 3. Accommodation establishments 20.4 65
4. Veterinary surgeons 72.5 3 and household work
5. Domestic animal attendants 69.1 61 4. Health care and veterinary work 16.5 127
6. Farmers, silviculturists 7.7 341 5. Hygiene and personal care work 11.7 9
7. Chefs, cooks, cold buffet managers 38.5 40 6. Catering 7.2 10
8. Dairy workers 37.9 5 6. Service work (not classified "elsewhere") 7.2 7
9. Horticultural supervisors 37.8 6 8. Cleaning work 6.7 21
10. Laboratory technicians, radiographers 35.6 9 9. Textile, sewing, shoe and leather work 4.8 6
11. Physicians 3.0 20 10. Packing, warehousing and 3.8 8
12. Butchers and sausage makers 28.9 7 stevedoring work
13. Laboratory assistants 24.6 15 11. Wood working 2.7 4
14. Dentists 23.4 5 11. Chemical processing, pulp and 2.7 3
15. Nurses 21.2 42 paper making work
16. Waiters in cafes and snack bars, etc. 15.1 9 13. Manual work ("not classified elsewhere") 2.5 4
17. Kitchen assistants, restaurant 13.6 16 14. Social and psychological work 1.8 5
workers, etc. 15. Metal work 1.7 11
18. Hairdressers, beauticians, bath 11.8 9 16. Technical, scientific, juridical, 1.5 24
attendants, etc. humanistic and artistic work
19. Housekeeping managers, snack 11.5 9 17. Building caretaker work 1.4 2
bar managers, etc. 18. Electrical, radio and television work 1.2 3
20. Packers 11.2 8 19. Printing and photographic work 1.1 1
21. Horticultural workers 10.7 5 20. Commercial work 1.1 12
22. Assistant nurses, hospital attendants 10.2 14
23. Industrial sewers, etc. 9.1 4
24. Cleaners, etc 6.7 21
25. Assemblers of electrical and 6.6 3
teletechnical equipment
26. Homemakers, horne helps (municipal) 6.2 5
Low-molecular-weight chemicals are a rare cause of
27. Technical nursing assistants 4.2 5 contact urticaria. Wehave encountered cases caused
28. Machine and engine mechanics, etc. 3.9 7 by, e.g., methylhexahydrophthalic and met-
29. Shop assistants, shop cashiers 2.1 9
hyltetrahydrophthalic anhydride (Tarvainen et al.
Total 3.7 815 1995), diglycidyl ether of bisphenol A epoxy resin
(Kanerva et al. 1991), polyfunctional aziridines
(Kanerva et al. 1995a,c), nickel (Estlander et al. 1993)
Tyrophagus putrescentiae (ALK, Copenhagen, Den- and reactive dyes (Estlander 1988). Diagnostics and
mark). It seems evident that if prick tests or alterna- prick testing may be difficult because allergens need to
tively radioallergosorbent tests (RASTs) to storage be conjugated to human serum albumin (Kanerva et al.
mites are not performed, it is not possible to investi- 1991; Tarvainen et al. 1995).
gate storage mites as a possible cause of contact
urticaria.
Table 6. Ten occupations with

the highest risk of developing Rank and Occupation SRR (95% confidence The most common causes
occupational contact urticaria interval)
and protein contact dermatitis,
and their causes [relative risk is 1. Bakers, confectioners 14 (7.8-27) Flours
expressed as the age-standard 2. Farmers, silviculturists, etc. 10 (8.0-13) Cow dander
rate ratio (SRR)] 3. Butchers and sausage makers 6.6 (2.1-20) Meat
4. Plastic product workers 4.2 (1.3-13) Natural rubber latex
5. Physicians 4.1 (1.8-9.2) Natural rubber latex
6. Chefs, cooks, cold buffet managers, etc. 3.1 (1.5-6.7) Foodstuffs
7. Floor layers, building painters, 2.8 (1.0-7.5) Natural rubber latex,
other painters and lacquerers plastic chemicals
8. Laboratory assistants, technicians 2.7 (1.0-7.3) Natural rubber latex
9. Kitchen assistants, restaurant workers 2.1 (0.8-5.6) Foodstuffs
10. Nurses, midwives 1.8 (0.9-3.4) Natural rubber latex
220 L. Kanerva et al.: Occupational Contact Urticaria in Numbers
References Kanerva L, Jolanki R, Toikkanen J, Tarvainen K, Estlander T

(1995b) Statisties on oeeupational dermatoses in Finland.
Curr Probl Dermatol 23:28-40
Cuthbert OD (1990) Storage mite allergy. Clin Rev Allergy 8: Kanerva L, Keskinen H, Autio P, Estlander T, Tuppurainen M,
69-86 Jolanki R (1995e) Oeeupational respiratory and skin sensiti-
Estlander T (1988) Oeeupational allergie dermatoses and respi- zation eaused by polyfunetional aziridine hardener. Clin Exp
ratory diseases from reaetive dyes. Contaet Dermatitis Allergy 25:432-439
18:290-297 Kanerva L, Estlander T, Jolanki R (1996a) Oeeupational allergie
Estlander T, Kanerva L, Tupasela 0, Keskinen H, Jolanki R (1993) eontaet dermatitis from spiees. Contaet Dermatitis 35:157-162
Immediate and delayed allergy to niekel with eontaet Kanerva L, Toikkanen J, Jolanki R, Estlander T (1996b) Statistieal
urtiearia, rhinitis, asthma, and eontaet dermatitis. Clin Exp data on oeeupational eontaet urtiearia. Contaet Dermatitis
Allergy 23:306-310 35:229-233
Hjorth N, Roed-Petersen J (1976) Oeeupational protein contaet Niinimäki A (1995) Spiee allergy. Investigations on the prevalenee
dermatitis in food handlers. Contaet Dermatitis 2:28-42 of positive skin test reaetions and tlIe appearanee of clinieal
Janssens J, Morren M, Dooms-Goossens A, Degreef H (1995) symtoms (tlIesis). Aeta Univ Oul D 357, Oulun Yliopisto,
Protein eontaet dermatitis: myth or reality. Br J Dermatol Oulu, pp 1-81
132:1- 6 Susitaival P (1996) Epidemiologieal study of hand dermatoses
Kanerva L (1996) Oeeupational IgE-mediated protein eontaet and other skin diseases in a eohort of Finnish farmers
dermatitis from pork in a slaughterman. Contaet Dermatitis (thesis). (Medieal Scienees, vol 93) Kuopio University Pub-
34:301-302 lieations D, pp 1-104
Kanerva L (1998) Oeeupational fingertip protein eontaet derma- Susitaival P, Husman L, Hollmen A, Horsmanheimo M, Husman
titis eaused by grain flours and natural rubber latex. Contaet K, Hannuksela M (1995) Hand eezema in Finnish farmers. A
Dermatitis 38:295-296 questionnaire-based clinieal study. Contaet Dermatitis
Kanerva L, Brisman J (1997) Contaet urtiearia, dermatitis and 32:150-155
respiratory symptoms eaused by enzymes. In: Amin S, LalIti Tarvainen K, Jolanki R, Estlander T, Tupasela 0, Pfaffli P,
A, Maibaeh HI (eds) Contaet urtiearia syndrome. CRC Press Kanerva L (1995) Immunologie eontaet urtiearia due to
Ine, Boea Raton, FL, pp 129-142 airborne metlIylliexalIydrophthalie and methyltetralIydro-
Kanerva L, Susitaival P (1996) Cow dander - the most eommon phtlIalie anhydrides. Contaet Dermatitis 32:204-209
eause of oeeupational eontaet urtiearia in Finland. Contaet Terho EO, Husman K, Vohlonen I, Rautalahti M, Tukiainen H
Dermatitis 35:309-310 (1985) Allergy to storage mites or eow dander as a eause of
Kanerva L, Vaheri E (1993) Oeeupational rhinitis in Finland. Int rhinitis among Finnish farmers. Allergy 40:23-26
Areh Oeeup Environ HealtlI 64:565-568 Tupasela 0, Kanerva L (1997) Skin tests and speeifie IgE
Kanerva L, Jolanki R, Tupasela 0, Halmepuro L, Keskinen H, det~rm.inations in tlIe diagnosties of immunologie eontaet
Estlander T, Sysilampi M-L (1991) Immediate and delayed urtIeana eaused by low-moleeular weight ehernieals. In: Amin
alIergy from epoxy resins based on diglycidyl etlIer of S, LalIti A, Maibaeh HI (eds) Textbook ofthe eontaet urtiearia
bisphenol A. Seand J Work Environ Health 17:208-215 syndrome. CRC Press Ine, Boea Raton, FL, pp 33-44
Kanerva L, Jolanki R, Toikkanen J (1994) Frequencies of Ylönen J, ~äntyjärvi R, Taivainen A, Virtanen T (1992) IgG and
oeeupational allergie diseases and gender differenees in IgE antIbody responses to eow dander and urine in farmers
Finland. Int Areh Oeeup Environ Health 66:111-u6 witlI eow-indueed asthma. Clin Exp Allergy 22:83-90
Kanerva L, Estlander T, Jolanki R, Tarvainen K (1995a) Oeeupa- Ylönen J, Virtanen T, Horsmanheimo L, Parkkinen S, Pelkonen J,
tional allergie eontaet dermatitis and contaet urtiearia eaused Mäntyjärvi R (1994) Affinity purifieation of the major bovine
by polyfunetional aziridine hardener. Contaet Dermatitis allergen by a novel monoclonal antibody. J Allergy Clin
33:304-309 Immunol 93:851-858
CHAPTER 26
Non-Immunologie Contact Urticaria

A. Lahti
Introduction and ean be part of the meehanism responsible for the

maintenanee of ehronie eezema.
Non-immunologie contaet urtiearia (NI CU) and other The usage of the terms "immediate eontaet reaetion,
non-immunologie immediate eontaet reaetions contaet urtiearia, immediate-type irritaney, eontaet
(NIlCRs) of the skin eomprise a group of infiammatory urticaria syndrome, protein eontaet dermatitis and
reaetions that appear within minutes to an hour after atopie eontaet dermatitis" varies in the literature.
eontaet with the eliciting substanee and usually disap- Immediate eontaet reaetion is the broadest eoneept,
pear within a few hours. These reaetions ean also be eovering both immunologie (allergie) and non-immu-
ealled immediate-type irritaney. NIlCRs oeeur without nologie (irritant) reaetions, but does not relate any-
previous sensitization in most exposed individuals, thing about the appearanee of the reaetion. Contaet
and they are the most eommon type of immediate urtiearia ean be allergie or irritant. The redness of skin
eontaet reaetion (Lahti 1995). appearing within tens of minutes after eontaet with the
eliciting substanee eannot be regarded as eontaet
Definitions, Concepts and Symptoms urtiearia unless at least some persons get urtiearial
reaetions at the applieation site. Protein eontaet
Symptoms of NIlCRs are heterogeneous and the dermatitis is eaused by pro teins or proteinaeeous
intensity of the reaetion varies typieally, depending on materials and it means allergie or irritant dermatitis,
the eoneentration, the vehicle, the skin area exposed, whieh has eharaeteristie features of acute or ehronie
the mode of exposure and the substanee itself (Lahti eezema (Lahti 1995). Atopie eontaet dermatitis is a
1980). Itehing, tingling or burning aeeompanied by historieal term and means an immediate-type (IgE-
erythema are the weakest types of reaetion. Sometimes mediated) allergie eontaet reaetion in an atopie person
only loeal sensations without any visible ehange in the (Hannuksela 1980). It is included in the eoneept of
skin are reported. The redness is usually follieular at allergie protein eontaet dermatitis (Table 1).
first and then spreads to eover the whole applieation
site. A loeal weal and fiare suggest a eontaet urtiearial Mechanisms of NIlCRs
reaetion. Generalized urticaria after contaet with NI CU
agents is a rare phenomenon, but has been reported The meehanisms of NIlCRs, similarly to other irritant
more often after eontaet with agents eliciting immuno- reaetions, are not well understood. It was previously
logie IgE-mediated eontaet urtiearia. Repeated appliea-
tions of NI CU agents may eause eezematous reaetions. Table 1. Definitions and terms
Quiekly appearing mierovesicles are frequently seen
after eontaet with food produets in protein eontaet Immediate eontaet reaetion Immunologie (allergie) or
dermatitis, whieh ean be eaused by non-immunologie non-immunologie (irritant),
urtiearial or non-urtiearial
(irritant) or immunologie (allergie) meehanisms reaetions; does not define
(Hjorth and Roed-Petersen 1976; Hannuksela 1986). In the appearanee of the reaetion
NI CU reaetions, the symptoms usually appear and Contaet urtiearia Allergie and non-allergie
urtiearial reaetions
remain in the eontaet area. In addition to loeal skin Immediate-type irritaney Non-allergie urtiearial or
symptoms, other organs are oeeasionally involved non-urtiearial reaetions
eausing eonjunetivitis, rhinitis, an asthmatie attaek or Protein eontaet dermatitis Allergie or non-allergie eezematous
immediate reaetions eaused by
anaphylaetie shoek. This is ealled the eontaet urtiearia pro teins or proteinaeeous material
syndrome and it involves immunologie meehanisms Contaet urtiearia syndrome Loeal reaetions in the skin and
mostly (Maibaeh and Johnson 1975). In some eases, systemie symptoms in other
organs, usually allergie
NICU reaetions appear only on slightly affeeted skin

222 A. Lahti
assumed that substances eliciting NIl CRs result in the molecular structure of a chemical may substantially
non-specific histamine release from mast cells. How- alter its capacity to produce NIlCRs (Hannuksela et al.
ever, it has been shown that H1-antihistamines, 1989).
hydroxyzine and terfenadine, do not inhibit reactions
to benzoic acid, cinnamic acid, cinnamic aldehyde,
methyl nicotinate or dimethyl sulfoxide, though they Agents Producing NIlCRs
inhibit reactions to histamine in prick tests (Lahti
1980, 1987). These results suggest that histamine is not The best studied substances producing NIlCRs are
the main mediator in NIlCRs to these weIl-known benzoic acid, sorbic acid, cinnamic acid, and aldehyde
contact urticants. and nicotinic acid esters. Under optimal conditions,
The NIl CRs to benzoic acid, cinnamic acid, cin- most individuals react with local erythema and/or
namic aldehyde, methyl nicotinate and diethyl fuma- edema to these substances within 45 min after appli-
rate can be inhibited by peroral acetylsalicylic acid and cation. Cinnamic aldehyde at a concentration of 0.01 %
indomethacin (Lahti et al. 1983, 1987) and by a topical may elicit erythema with a burning or stinging feeling
application of diclofenac or naproxen gels (Johansson in the skin. Some mouthwashes and chewing gums
and Lahti 1988). The duration of inhibition by a single contain cinnamic aldehyde at concentrations high
dose of acetylsalicylic acid can be as long as 4 days enough to produce a pleasant tingling in the mouth
(Kujala and Lahti 1989). The mechanism by which and enhance the sale of the product. Higher concen-
non-steroidal anti-inflammatory drugs inhibit NIlCRs trations may produce lip swelling. Some agents causing
in human skin has not been defined, but it is probably immediate irritant skin reactions are listed in Table 2.
ascribable to the inhibition of prostagIandin metabo-
lism.
The role of skin nerves in NIlCRs has been studied Animal Testing Methods
using capsaicin (trans-8-methyl-N-vanillyl-6-nonen-
amide), which is known to induce arelease ofbioactive Animal test methods for determining NIlCRs are
peptides, such as substance P, from the axons of needed to screen for putative agents and to clarify
unmyelinated C-fibers of sensory nerves. Pretreatment the mechanisms. At the moment, the guinea-pig ear
of the skin with capsaicin inhibits erythema reactions swelling test is the best animal test available for
in histamine prick tests (Bernstein et al. 1981), but does studying NIl CRs (Lahti and Maibach 1984, 1985a). A
not inhibit either erythema or edema elicited by positive reaction in the guinea-pig ear lobe comprises
benzoic acid or methyl nicotinate (Larmi et al. erythema and edema. Quantification of the edema by
1989a). This suggests that NIl CRs to these model measuring the change in ear thickness is an accurate,
substances are not a type of neurogenic inflammation quick and reproducible method. Similarly to human
of the skin. Topical anesthesia inhibits erythema skin, the swelling response in the guinea-pig ear lobe
reactions to histamine, benzoic acid and methyl depends on the concentration of the eliciting sub-
nicotinate, but it is not known whether the inhibitory
effect is due to the influence on the sensory nerves only
or whether the anesthetic also affects other cell types Table 2. Agents producing immediate non-immunologie contact
or regulatory mechanisms of immediate-type skin reactions including contact urticaria
inflammation (Larmi et al. 1989a). Animals Arthropods, caterpillars, corals,
NIlCRs to benzoic acid and methyl nicotinate can be jellyfish, moths, sea anemones
inhibited by exposure to ultraviolet (UV) Band A light. Foods Cayenne pepper, fish, mustard, thyme
Fragrances and Balsam of Peru, benzaldehyde, cassis
The inhibition lasts for at least 2 weeks (Larmi et al. (cinnamon oil), cinnamic acid,
flavorings
1988). The reactions on non-irradiated skin sites also cinnamic aldehyde
decrease, suggesting the possibility that UV irradiation Medicaments Alcohols, benzocaine, camphor,
cantharides, capsaicin, chloroform,
may have "systemic effects" (Larmi 1989). While the dimethyl sulfoxide, friar's balsam,
mechanism of UV inhibition is unknown, it does not iodine, methyl salicylate, methylene
seem to be due to thickening of the stratum corneum green, myrrh, nicotinic acid esters,
resorcinol, tar extracts, tincture of
as speculated earlier (Gollhausen and Kligman 1985). benzoin, witch hazel
Molecular structure is important for the irritant Metals Cobalt
properties of a NIICR agent. Pyridine carboxaldehyde Plants Nettles, seaweed
Preservatives and Benzoie acid, chlorocresol,
(PCA) has three isomers, 2-,3-, and 4-PCA, depending disinfectants formaldehyde, sodium benzoate,
on the position of the aldehyde group on the pyridine sorbic acid
ring. It has turned out that 3-PCA is a strong irritant Miscellaneous BUtyric acid, diethyl fumarate,
histamine, pine oil, pyridine
and 2-PCA a weak irritant in both human and animal carboxaldehyde, sulfur, turpentine
skin (guinea-pig ear swelling test). A slight change in
Non-Immunologie Contact Urtiearia 223
stance. The maximal response is a roughly 100% irritant re action to a cosmetic cream has appeared on
increase in ear thickness and it appears 40-50 min the face, we may see nothing if the test is performed on
after the application, depending on the vehic1e. the back, but the reaction can be elicited by reappli-
A decrease in reactivity to NIlCR agents is noticed cation to the previously affected skin of the face.
after reapplication on the following day (Lahti and Repeated open tests on the same test site may be
Maibach 1985b). This tachyphylaxis phenomenon is needed to detect weak immediate irritant reactions
not specific to the substance that produces it, and (Hannuksela et al. 1993). In a use test, the suspected
reactivity to other agents also decreases. The length of product or substance is used in the same way as it was
the refractory period is 4 days for methyl nicotinate, used when the symptoms appeared.
8 days for diethyl fumarate and cinnamic aldehyde, The chamber test is a routine method of patch
and 16 days for benzoic acid, cinnamic acid and testing for contact allergy, but it can also be used to
dimethyl sulfoxide. study NIlCRs. The test substances are applied in small
The guinea-pig ear lobe resembles human skin in aluminum chambers (Finn Chamber, Epitest Ud,
many respects, inc1uding the morphology of the Hyrylä, Finland) and fixed to the skin with porous
reaction, the timing of the maximal response, the acrylic tape. The occ1usion time is 15 min and the test
concentrations of the eliciting substances needed to is read at 20, 40 and 60 min. Occ1usion enhances
produce the re action, the tachyphylaxis phenomenon, percutaneous penetration and may increase the sensi-
and the lack of an inhibitory effect of antihistamines tivity of the test. The advantage of the chamber test is
on the NIlCRs. that a smaller skin area is needed than in the open test
(Lahti 1980; Hannuksela 1995).
The concentration of a NIlCR agent needed in a skin
Human Testing Methods test may be difficult to define, as it is in case tests with
c1assical, delayed-type irritants. Therefore, dilution
Special tests for NIl CRs are needed because these series are recommended. They make it possible to
reactions are not seen in ordinary tests for irritancy determine the threshold irritant concentration for that
and contact allergy. The tests used most frequently are particular patient and skin area. Examples of the
the open test and the chamber test. concentrations often used in dilution se ries in alcohol
In the open test, 0.1 ml of the test substance is vehic1es are 250, l25, 62, 31 mM for benzoic acid and
spread on a 3 x 3-cm area of the skin of the upper 50, 10, 2 and 0.5 mM for methyl nicotinate (Lahti 1987,
back, on the extensor aspect of the upper arm, or on 1995).
the fore arm. There are marked differences between It is known that oral and topical non-steroidal anti-
skin sites in the reactivity to NIlCR substances. inflammatory drugs suppress NIl CRs efficiently and
The face, especially the cheek, the antecubital space, may therefore cause false-negative results in testing
the upper back, the upper arm, the volar fore arm, the (Lahti et al. 1987; Johansson and Lahti 1988). The
lower back and the leg constitute a rough order of minimum refractory period is 3 days (Kujala and Lahti
decreasing reactivity (Gollhausen and Kligman 1985; 1989). Tanned skin has decreased reactivity to NIlCR
Lahti 1995; Larmi et al. 1989b). A 10-111 dose to a1 x 1- agents (Gollhausen and Kligman 1985), and both UVB
cm area is often used if a greater number of substances and UVAirradiation suppresses these reactions for
are tested at the same time. Petrolatum and water were 2-3 weeks (Larmi et al. 1988; Larmi 1989). Skin sites
the vehic1es used most often 15 years ago (Lahti 1995), that are washed repeatedly may have a lowered
but it has been shown that the use of alcohol vehic1es threshold for immediate irritancy to NIlCR agents
and the addition of propylene glycol to the vehic1e (Lahti et al. 1995). The importance of the selection of
enhance the sensitivity of the test to detect marginal the test site and the testing method has already been
immediate irritant reactions (Lahti et al. 1993b; Ylipieti mentioned. These sources of false results should be
and Lahti 1989). The test is usually read at 20, 40 and kept in mind when tests for immediate irritancy are
60 min in order to see the maximal response. In visual performed and the results of such tests are interpreted.
grading, scores for the erythema and edema compo-
nents of the re action (+ weak, ++ moderate, +++
strong) have been used (Ylipieti and Lahti 1989), but References
objective measurement of erythema using chroma
meters and laser Doppler flow meters is strongly Bernstein JE, Swift RM, Keyoumars S, Lorinez AL (1981)
Inhibition ofaxon reflex vasodilatation by topically applied
suggested (Lahti et al. 1987, 1993a). The test is usually eapsaicin. J Invest Dermatol 76:394-395
performed on normal-Iooking skin, but it is sometimes Gollhausen R, Kligman AM (1985) Human assay for identifying
useful to test suspected irritants on slightly or previ- substanees whieh induee non-allergie eontaet urtiearia: the
NICV-test. Contaet Dermatitis 13:98-106
ously affected skin areas or on skin sites suggested by Hannuksela M (1980) Atopie eontaet dermatitis. Contact Derma-
the patient's history. For example, if an immediate titis 6:30
224 A. Lahti: Non-Immunologie Contact Urticaria
Hannuksela M (1986) Contact urticaria from foods. In: Roe DA Labti A, Oikarinen A, Viinikka L, Ylikorkala 0, Hannuksela M
(ed) Nutrition and the skin, vol 10. Alan R Liss, New York, (1983) Prostaglandins in contact urticaria induced by benzoie
pp 153-162 acid. Acta Dermatol Venereol 63:425-427
Hannuksela M (1995) Skin tests for immediate hypersensitivity. Labti A, Väänänen A, Kokkonen E-L, Hannuksela M (1987)
In: Rycroft RJG, Menne T, Frosch PJ (eds) Textbook of Acetylsalicylic acid inhibits non-immunologie contact urti-
contact dermatitis. Springer, Berlin Heidelberg New York, caria. Contact Dermatitis 16:133-135
pp 287-292 Labti A, Kopola H, Harila A, Myllylä R, Hannuksela M (1993a)
Hannuksela A, Lahti A, Hannuksela M (1989) Nonimmunologie Assessment of skin erythema by eye, laser Doppler f1owmeter,
immediate contact reactions to three isomers of pyridine spectroradiometer, two-channel erythema meter and Minolta
carboxaldehyde. In: Frosch PJ, Dooms-Goossens A, Lacha- chroma meter. Arch Dermatol Res 285:278-282
pelle J-M, Rycroft RJG, Scheper RJ (eds) Current topies in Labti A, Poutiainen A-M, Hannuksela M (1993b) Alcohol vehicles
contact dermatitis. Springer, Berlin Heidelberg New York, in tests for non-immunologieal immediate contact reactions.
pp 448-452 Contact Dermatitis 29:22-25
Hannuksela A, Niinimäki A, Hannuksela M (1993) Size ofthe test Lahti A, Pylvänen V, Hannuksela M (1995) Immediate irritant
area does not affect the result of the repeated open reactions to benzoie acid are enhanced in washed skin areas.
application test. Contact Dermatitis 28:299-300 Contact Dermatitis 33:177-182
Hjorth N, Roed-Petersen J (1976) Occupational protein contact Larmi E (1989) Systemic effect of ultraviolet irradiation on
dermatitis in food handlers. Contact Dermatitis 2:28-42 nonimmunologie immediate contact reactions to benzoie
Johansson I, Lahti A (1988) Topieal non-steroidal anti-inflam- acid and methyl nieotinate. Acta Dermatol Venereol 69:
matory drugs inhibit non-immunologie immediate contact 296-301
reactions. Contact Dermatitis 19:161-165 Larmi E, Labti A, Hannuksela M (1988) Ultraviolet light inhibits
Kujala T, Lahti A (1989) Duration of inhibition of non-immu- nonimmunologie immediate contact reactions to benzoie
nologie immediate contact reactions by acetylsalicylic acid. acid. Arch Dermatol Res 280:420-423
Contact Dermatitis 21:60-61 Larmi E, Labti A, Hannuksela M (1989a) Effects of capsaicin and
Labti A (1980) Non-immunologie contact urticaria. Acta topieal anesthesia on nonimmunologie immediate contact
Dermatol Venereol 60:1-49 reactions to benzoie acid and methyl nicotinate. In: Frosch
Lahti A (1987) Terfenadine (H1-antagonist) does not inhibit non- PI, Dooms-Goossens A, Lachapelle J-M, Rycroft RJG, Scheper
immunologie contact urticaria. Contact Dermatitis 16:220-223 RJ (eds) Current topies in contact dermatitis. Springer, Berlin
Lahti A (1995) Immediate contact reactions. In: Rycroft RJG, Heidelberg New York, pp 441-447
Menne T, Frosch PJ (eds) Textbook of contact dermatitis. Larmi E, Lahti A, Hannuksela M (1989b) Immediate contact
Springer, Berlin Heidelberg New York, pp 62-74 reactions to benzoie acid and the sodium salt of pyrrolidone
Lahti A, Maibach HI (1984) An animal model for nonimmuno- carboxylic acid. Comparison of various skin sites. Contact
logie contact urtiearia. Toxieol Appl Pharmacol 76:219-224 Dermatitis 20:38-40
Labti A, Maibach HI (1985a) Species specificity of nonimmuno- Maibach HI, Johnson HL (1975) Contact urtiearia syndrome.
logie contact urtiearia: guinea pig, rat and mouse. J Am Acad Contact urticaria to diethyltoluamide (immediate-type hy-
Dermatol 13:66 persensitivity). Arch Dermatol 111:726-730
Lahti A, Maibach HI (1985b) Long refractory period after one Ylipieti S, Labti A (1989) Effect of the vehicle on non-immuno-
application of nonimmunologie contact urticaria agents to logie immediate contact reactions. Contact Dermatitis 21:
the guinea pig ear. J Am Acad Dermatol 13:585-589 105-106
CHAPTER 27
Occupational and Environmental Acne

J.K. McDonnell and J.S. Taylor*
Introduction Prolonged oil exposure produces a reactive follicular

hyperkeratosis and results in sebum retention. This
Occupational and environmental acne is a variety of manifests clinically as multiple open comedones,
acne venenata, resulting from various chemical expo- inflammatory folliculitis and microcystic lesions
sures and from a variety of environmental, physical caused by the oil itself. Lesions are distributed
and mechanical factors, usually encountered in the primarily over exposed areas, such as the dorsal hands
workplace but occasionally seen in non-occupational and extensor forearms. Oil-soaked clothing may pro-
settings. The eruption may be mild, involving localized duce lesions on the thighs, lower abdomen and
exposure or covered areas of the body, or severe, buttocks (Kokelj 1992). The face may be involved from
explosive and dis semina ted with the involvement of wiping the brow with an oil-contaminated sleeve.
almost every follicular orifice. Additionally, chloracne Although the lesions are commonly referred to as oil
almost always represents a cutaneous sign of systemic boils, they usually do not develop from bacteria
exposure to highly toxic chemicals. Occupational and present in the oils (Taylor 1986). The inflammatory
environmental acne is separated into oil acne, coal-tar lesions are more prominent than in chloracne and may
acne, acne cosmetica, acne aestivalis, acne mechanica, mimic conglobate cystic acne.
tropical acne and chloracne. This listing is not Acquired perforating (transepidermal elimination
exhaustive but serves as a useful paradigm and disease has been reported in oil field workers exposed
includes the most common causes. to drilling fluids. The fluids contain many additives,
including calcium chloride. Histopathologic examina-
tion revealed trans epidermal elimination of calcium
Oil Acne
with minimal involvement of hair follicles (Knox et al.
1986).
Oil acne is the most common form of occupational
Oil acne is treated with the usual acne vulgaris
acne and is most commonly observed in workers
modalities, such as topical benzoyl peroxide and
employed in the machine tooling trades. Others
retinoic acid. Systemic treatment is often needed with
affected may include auto, airplane and truck mechan-
tetracycline, erythromycin or minocycline, or with
ics; petroleum refiners; and rubber workers. The
isotretinoin in severe cases. The key factor is avoiding
incidence of oil acne has declined in recent years
contact with oils and grease. Work clothes should be
because of decreased use of pure cutting oils and
changed daily and frequent cleansing of the skin with
improved industrial and personal hygiene practices
soap and water is advised.
(Kokelj 1992).
Cutting oils, especially insoluble (straight) oils, and
semi-synthetic coolants have been the most commonly
incriminated oil acnegens (Taylor 1987). In mechanics, Coal-Tar Acne
prolonged exposure to grease, lubricating oils and
kerosene may induce oil acne (Upreti et al. 1989). An Coal-tar oils, creosote and pitch can produce a
anecdotal report of acne observed in young fast-food comedonal type of acne, which shows a predilection
workers exposed to grease and fat while frying for exposed areas, particularly the malar regions
hamburgers has been termed "McDonald's acne" (Litt (Bertolini 1989). Coal-tar plant workers, roofers, road
1974), although there is no other evidence that this is a maintenance workers and construction workers are
separate entity. among those at risk. Coal-tar acne may be complicated
by phototoxic reactions affecting both the skin and the
* Modified, expanded and updated with permission from Om- eyes and resulting in hyperpigmentation known as
ohundro and Taylor (1998) coal-tar melanosis. Late complications include the

226 J.K. McDonnell and J.5. Taylor
development of pitch and tar papillomas, keratoses focally (Mills and Kligman 1975). We have also seen it
and acanthomas (Taylor 1987). as a complication of friction and sweating in chloracne.
Acne Cosmetica Tropical Acne
Acne cosmetica may develop in actors and models who Tropical acne may result from exposure to excessively
are often required to wear heavy, greasy make-up; hot or humid environments and, when such exposure
cosmetologists mayaiso be affected (Kligman and is required in the performance of the patient's job, may
Mills 1972). Acne cosmetica consists of essentially non- be considered to be a form of occupational acne.
inflammatory, small, closed comedones and a few Tropical acne has been observed most commonly in
intermittent papules and pustules. When superim- soldiers stationed in tropical climates, but variants
posed upon acne vulgaris, the clinical picture may be may result from chronic exposure to other hot and/or
obscured (Kligman and Mills 1972). humid environments as can be found in foundries
Cosmetic ingredients found experimentally to be (Mathias 1994).
comedogenic include lanolin, petrolatum, certain veg- Onset is explosive in nature and typically occurs
etable oils and pure chemicals such as butyl stearate, several months after entering the hot, humid environ-
lauryl alcohol and oleic acid. Many of these substances ment. This is a severely inflammatory condition, with
are now avoided or modified by cosmetic manufactur- the development of papules, pustules, nodules, and
ers and cosmetics are frequently advertised as non- draining sinus es as in acne conglobata. Patients often
comedogenic. feel quite ill, and acute-phase reactants may be
elevated. There is characteristic involvement of the
buttocks and upper thighs, but lesions may be
Acne Aestivalis (Mallorca Acne) extensive, with the neck, arms, and trunk being
. affected. The face is usually spared (Sperling 1994).
Acne aestivalis is arare, infrequently described, Cultures have not identified a consistent pathogen,
generally, non-occupational eruption, which can also and the role of bacterial infection is felt to be
affect performing artists. Typically, it affects women in unimportant. Antibiotic therapy is without significant
the age range of 25-40 years and involves the cheeks, benefit. The only effective therapeutic measure is to
sides of the neck, chest, shoulders and upper arms. remove the patient from the precipitating environment
Typical lesions are erythematous, round, hard, small (Sperling 1994).
papules; comedones and pustules are absent or scarce.
Lesions involute in the fall without scar formation.
Acne aestivalis responds to topical retinoic acid but Chloracne
not to antibiotics (Hjorth et al. 1972).
Chloracne is a follicular dermatosis, often refractory to
treatment, which results from environmental exposure
Acne Mechanica to certain halogenated aromatic hydrocarbons. Chlor-
acne is considered one of the most sensitive indicators
Repeated or prolonged physical insults to the skin, such of biological response to these chemicals and it occurs
as rubbing, pressure, friction, pinching or pulling, may regardless of whether chemical exposure has occurred
produce an acneiform eruption that can be strikingly via skin contact - the usual route, inhalation or
inflammatory in nature. An example is the local pressure ingestion (Crow and PuhveI1991).
and rubbing against seat covers which occurs in truck Chloracne was first reported by Von Bettman in
drivers. Other occupational causes of acne mechanica 1897. In 1899, Herxheimer used the term chloracne to
include the use of face masks (as in hospital workers or describe four cases of severe ac ne resulting from
clean-room workers in the semiconductor industry), environmental contact with electrolytically produced
belts, straps, tight-fitting work clothing, football shoul- potassium hypochlorite. Since that time, various
der pads, football heImets, hats, and telephones (Mills chloracnegenic chemicals have been identified. Chlo-
and Kligman 1975). Violinists neck is also a variant of ronapthalenes and polychlorinated biphenyls (PCBs)
acne mechanica (Omohundro and Taylor 1998). were the causative agents in the pre-World-War-11 era.
Clinically, crops of inflammatory papules and pus- Since then, trace contaminants formed during the
tules appear in affected areas of skin. Deep, inflam- manufacture of PCBs and other polyhalogenated
matory nodules may result from prolonged press ure. It compounds, especially herbicides, have been the major
has been emphasized that acne mechanica is a causes of chloracne. These include polyhalogenated
complication of ac ne vulgaris and that external phys- dibenzofurans, polychlorinated dibenzo-p-dioxins and
ical forces merely exacerbate the underlying disease chlorinated azo- and azoxy benzenes.
Occupational and Environmental Acne 227
Table 1. Chloracne-producing chemicals
Polyhalogenated naphthalenes: a
Polychloronaphthalenes
Polybromonaphthalenesb,c
Polyhalogenated biphenyls:
Polychlorobiphenyls (PCBs)
Polybromodiphenyls (PBBs)
CI Polyhalogenated dibenzofurans: a
Fig. 1. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) - a haloge- Polychlorodibenzofurans, especially tri-, tetra-, penta- and
nated aromatic compound - is highly toxic and causes chloracne hexachlorodibenzofuran
Polybromodibenzofurans, especially tetrabromodibenzofuran
Contaminants of polychlorophenol compounds, especially
Chloracnegenic compounds are structurally similar herbicides (2,4,5-T and pentachlorophenol) and herbicide
(Fig. 1), sharing relative molecular planarity and intermediates (2,4,5-trichlorophenol):
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)
containing two benzene rings with halogen atoms Hexachlorodibenzo-p-doxin
occupying at least three of the lateral ring positions. Tetrachlorodibenzofuran
The position of halogen substitution appears to be Contaminants of 3,4-dichloroaniline and related herbicides:
3,4,3',4',-Tetrachloroazoxybenzene (TCAOB)
critical, as reduced biological activity results from 3,4,3',4' -Tetrachloroazobenzene (TCAB)
substitution into positions that lead to molecular non- Other:
planarity (Kokelj 1992). Dihydrotrifluoromethylphenylbenzothiopyrazolone
1,2,3,4-Tetrachlorobenzene (experimental)
The stereospecificity necessary for biological activity Dichlobenil, a herbicide (clinical only)
suggested the interactions of specific receptors at the DDT (crude trichlorobenzene)C
cellular level. Radiolabled 2,3,7,8-tetrachlorodibenzo-p-
a The polychlorodibenzofurans and hexachloronaphthalenes may
dioxin (TCDD) was used to demonstrate the presence
occur as contaminants in so me PCBs
of a binding protein in the cytosol of mice liver and a b The polybromonaphthalenes may occur as contaminants in
relative absence of this pro tein in non-responsive some PBBs
animals (Poland 1976). The degree of affinity of various CNot confirmed as chloracnegens
chloracnegens for the binding protein designated as the
Ah receptor (for aromatic hydrocarbons), correlated Table 2. Partial list of past and present sources of chloracnegens
with their biological efficacy. It is theorized that the Ah
receptors behave similarly to steroid hormone recep- Chloracnegen Source
tors in translocating chloracnegenic ligands to the cell
Polychloronaphthalenes Electrical insulators;
nucleus where they bind to DNA and alter translation fire-resistant materials;
of genes. These molecular changes are thought to be wood preservatives; boat
responsible for the various biological effects observed huH coatings (antimagnetic
properties); high-pressure
(Greenlee and Nea1198S; Crow and PuhveI1991). additives for lubricants
A decreasing incidence of chloracne may be attrib- Polychlorobiphenyls (PCBs) Hydraulic fluids; plastics;
uted to the advent of plastics, the gradual substitu- adhesives; fire retardants in
trans formers; sealants
tion of chlorinated hydrocarbons with synthetic resins Polychlorodibenzofurans Contaminants of PCBs and
and the restriction of the use of polychlorinated (PCDFs) various chlorinated phenols
biphenyls to only closed-system formulations (Kokelj Polychlorinated phenols Wood preservatives; leather;
paper industry applications;
1992). herbicides; fungi ci des;
algicides; insecticides;
disinfectants
Chloracne-Producing Chemieals and Sources Dioxins Contaminant of agent orange,
of Exposure formed during production of
chlorinated organic solvents
(hexachlorophene and the
Table 1 classifies the chemical causes of chloracne. üf herbicide 2,4,5,-T); products
related interest, Table 2 provides a partial list of past of combustion
Azo- and azoxybenzenes Herbicide intermediates
and present sources of the various chloracnegens. The
majority of chloracne cases have resulted from occu-
pational exposure during chemical manufacturing or
rarely from end product use. Polyhalogenated Naphthalenes
Industrial use of the polyhalogenated naphthalenes

Occupational Exposure (PCNs), occupational chloracne outbreaks and exper-
imental human and animal studies have been reviewed.
Selected outbreaks will be discussed as classified by No occupational cases of PCN chloracne have been
chemical cause. reported since 1972. Trace contamination of PCBs with
hexachloronaphthalenes and of polybromodiphenyls burden shortly after the accident of 44 Ilg (range 9.7-
(PBBs) with polybromonaphthalenes are potential 124 Ilg). Thus, a body burden of 9.7 Ilg, as measured in
current, but unlikely, sources of exposure (Taylor adipose tissue, may be the lowest observable effect
1979). level for TCDD-related chloracne in humans. Thirty-
two years after exposure, the German workers still had
Polychlorinated Biphenyls detectable levels of TCDD in adipose tissue, and one
still had chloracne (Agency for Toxic Effects of
PCBs are chloracnegens as has been demonstrated in Chemical Substances 1993).
reports in capacitor workers (Taylor et al. 1977; Tindall A case of palmoplantar keratoderma, scleroderma
1985) and in other workers (Longnecker et al. 1997). and chloracne was reported in an agricultural worker
Cutaneous hyperpigmentation eye discharge and who had been a weed sprayer for 5 years. He had used
palpebral edema have also been reported (Taylor et al. 2,4,5-trichlorophenoxyacetic acid and/or 2,4 dichloro-
1977). phenoxyacetic acid, both of which may contain chlo-
rinated dibenzodioxins as impurities. He also had been
Polyhalogenated Dibenzofurans chronically exposed to multiple other, non-chloracne
associated herbicides, some of which have been
Since polyhalogenated dibenzofuans (PHDFs) contam- associated with scleroderma. Safety equipment was
inate PCBs and polyhalogenated phenols, their cuta- not utilized (Poskitt et al. 1994).
neous effects are discussed under those headings. PCP is frequently used as a wood preservative,
herbicide and fungicide. It has additional uses in the
Dioxins leather and paper industry and an estimated 17,000
workers are exposed to PCP in the United States
Dioxin, specifically TCDD, is the paradigm for chem- (O'Malley et al. 1990). A retrospective review of 648
icals causing chloracne and also for the biological medical and personnel records from individuals man-
importance of trace industrial contaminants. Dioxins ufacturing PCP between 1938 and 1978 demonstrated 47
contaminate polychlorophenols, especially the herbi- cases of chloracne occurring in a 25-year period. These
cides 2,4,5-T and pentachlorophenol (PCP) and herbi- workers were exposed only to PCP for 2 years prior to
cide intermediates (2,4,5-trichlorophenol). TCDD is their diagnosis. PCP was produced by direct chlorina-
one of the most toxic small molecules known to man. It tion of phenol, monochlorophenol, dichlorophenol
is also one of the best studied toxic chemicals, largely and/or 2,4,6-trichlorophenol in the presence of an
after intense scrutiny over its use in Vietnam. aluminum catalyst. During the commercial synthesis of
More than 20 outbreaks of dioxin chloracne, as weIl PCP, varying amounts of polychlorinated aromatic
as its other health effects, have been reviewed (Taylor by-products, including dioxins, are produced (O'Mal-
et al. 1977; Tindall 1985; Mukerjee 1998). Follow-up ley et al. 1990).
studies have shown persistence of chloracne in some Cole et al. (1986) reported an unusual case of
cases. They also concluded that there is an increased occupational chloracne that developed in a carpenter
risk of soft-tissue sarcoma in end-product use in who assembled piers for small boat marinas using
Sweden, occupational exposure in the US and envi- PCP-treated lumber. The worker, wearing only shorts
ronmental exposure in Seveso, Italy. Although these and shoes, took measurements for extended periods of
conclusions are controversial, the International Agen- time while laying atop the treated lumber. After
cy for Research on Cancer has concluded that TCDD is 9 months of this activity, he noted the onset of a
a human carcinogen (Mukerjee 1998). Occupational papular acneiform eruption. Multiple small yeIlow-
exposures to TCDD in the herbicide and chemical white papules were present involving the malar regions
plants was much greater than most other non-occu- of the face, post auricular area, trunk, buttocks, thighs
pational exposures. Exposure would sometimes begin and lower legs. Sampies of treated lumber were tested
as a caustic chemical burn when the trichlorophenol for octachlorodibenzodioxin (OCD) and contained 10-
reactors would over heat. These workers showed the 40 times the amount of OCD than untreated wood. The
earliest and most severe chloracne (Taylor 1979; yellow residue from treated wood contained 400 ppm
Tindall 1985). OCD compared with technical grade PCP which
Chloracne is the hallmark of dioxin exposure in contained 1600 ppm OCD. This case is unusual
man; however, its absence does not exclude dioxin because the only source of PCP exposure was pres-
exposure. There is no apparent dose-response model sure-treated lumber; chloracne developing from this
for chloracne in exposed human populations. It may type of exposure is unusual. In the United States, the
develop weeks or months after exposures. In Germany, Environmental Protection Agency oversees the use of
six workers who developed chloracne after an indus- wood preservatives. In 1986, the agency proposed a
trial accident had an estimated mean TCDD body level of hexachloro-p-dioxin no greater than 15 ppm,
which was to be reduced to 1 ppm within 18 months and ears. Hyperpigmentation of the face and oral
(Cole et al. 1986). cavity was also observed. Chlorobenzenes were mea-
sured in the water at a concentration of 15 ppm. All
Azo and Azoxybenzenes workers reported chronic conjunctivitis with thick
secretions from meibomian glands. Hepatic involve-
We first documented cases of chloracne from ment including elevated serum alkaline phosphatase
tetrachloroazoxybenzene (TCAOB) in 1977.and lower extremity peripheral neuropathy were also
Tetrachlorozobenzene (TCAB) was also produced evident (Vazquez et al. 1996).
during the synthesis of 3kdichloro aniline or during
its further conversion to herbicides. More than 90% of
41 workers in a small chemical plant developed Non-Occupational Exposure
chloracne. Family members of four workers, none of
whom had been in the plant, also developed chloracne, Non-occupational chloracne has resulted from indus-
probably from exposure at horne to contaminated tools trial accidents, contaminated industrial waste and
or work clothes (Taylor et al. 1977). Eight years later, poisoned food products. A weIl publicized example
three of five workers with chloracne still had some was the extensive environmental contamination with
evidence of chloracne and scarring. Two children who TCDD, which occurred on 10 July, 1976, at the ICMESA
had chloracne were clear, except for mild scarring; one chemical plant ne ar Seveso, Italy. An explosion
had acne vulgaris when seen again (Taylor and Lloyd occurred during the manufacturing of trichlorophenol
1982). Similar episodes of chloracne have been report- that resulted in the formation and ultimate dis charge
ed from the production of the pesticide-herbicide into the atmosphere of an estimated 2 kg of TCDD.
Proponil in Arkansas in 1977. We are aware of other The contaminated area encompassed more than 200
reports of TCAB and TCAOB chloracne in the United acres of land, and 135 cases of chloracne, mostly in
States and England in the 1970S and 1980s (Taylor and children, were confirmed among the 2000 area inhab-
Lloyd 1982). itants. The toxie cloud caused the death of hundreds of
An outbreak of chloracne in 17 workers from a fowl in the first days after the explosion; the develop-
British plant manufacturing dichloro-aniline-derived ment of chloracne occurred after different time peri-
herbicides was reported in 1993. TCAB and TCAOB ods. Aside from chloracne, some cases of subclinical
were the acnegens. Comedones evolved 6-12 weeks neurologie al damage were reported. No other severe
after exposure to these chloracnegenic contaminants. problems or birth abnormalities were reported in the
Cutaneous xerosis and folliculitis, on the trunk, limbs, involved population in the numerous long-term fol-
thighs and buttocks, previously uncommonly de- low-up studies (Pocchiari et al. 1979).
scribed, was present in 50% of exposed workers. Ingestion alone of PCBs and their thermally degrad-
Affected follicles were surrounded by a collarette of ed polychlorinated dibenzofurans (PCDFs) played a
scale and frequently the hair shaft was twisted or major role in two mass "oil-poisoning" episodes -
broken. The pathogenesis of these lesions is unclear Yusho in Japan in 1968 and Yu-Cheng in Taiwan in
but may involve a dis order of keratinization. A direct 1979, the largest epidemics of chloracne to date. In
toxie effect on epidermal keratinocytes or a secondary both countries, several thousand persons were affected
effect due to a perifollicular inflammatory reaction has after eating rice-based cooking oil that had been
been theorized (McDonough et al. 1993). They sug- accidentally contaminated with large amounts of
gested that folliculitis and xerosis should be included tetrachlorobiphenyl. Dermatologie manifestations in-
in the clinical spectrum of chloracne. cluded chloracne, hyperpigmentation and hypersecre-
In 1996, nine workers from a Mexiean chemie al tion of conjunctival meibomian glands. Most clinical
plant were evaluated for the effects of chronie exposure manifestations were observed in patients who had
to mono-, ortho- and paradiehlorobenzenes. They had directly ingested the oil. PCBs and PCDFs can persist
a mean exposure of 24 working years and worked in all in human tissues (similar dioxins have half-lives in
stages of chemical production. Safety equipment was humans of about 7 years) in the offspring of exposed
not used, and direct contact with the chlorobenzenes females, described as cola babies because of their dark
occurred via the skin and respiratory tract. The nine color. Generalized hyperpigmentation, meibomian
workers had a polymorphie acneiform eruption con- gland enlargement with eye discharge and nail defor-
sisting mainly of comedones and cysts. All had mities occurred in congenitally exposed individuals.
comedones on the face, predominately in the malar Severe chloracne scars were observed 11 years post-
area; lesions on the nose, axillae, ehest, shoulders, congenital exposure in some affected individuals in
arms, buttocks and thighs were also present. Yellow Taiwan (Hsu et al. 1995).
cysts (2-5 mm in diameter) were found on the malar We studied 128 children who were transplacentally
area of the face, eyelids, penis, sero turn, ehest, axilla exposed to PCBs and dibenzofurans in Taiwan, their
parents and siblings who were direct1y exposed, and 115 potential exposure, but 98% of sampIes tested had
control children. Direct exposure of the mothers values found in unexposed populations. One-third of
stopped in 1979 and the children were born as late as the fire fighters and other persons who were in the
1985. At birth, exposed children had increased rates of building for 25 h or more reported "rash" or itching.
hyperpigmentation, eyelid swelling and discharge, However, no cases of chloracne, liver disease or
deformed nails, acne, natal teeth and swollen gums neurological disorders were identified in the exposed
unlike controls. On cutaneous examination in 1985, key individuals (Fitzgerald et al. 1989).
findings were a much higher rate of dystrophie
fingernails and pigmented or dystrophie toe nails than
Mechanism
in controls. Increased rates of hyperpigmentation and
acne were also seen in the exposed groups. The
The mechanism involved in the initiation of chloracne
cutaneous findings were part of a transplacental
remains unknown. The interference of halogenated
neuroectodermal dysplasia, with dental abnormalities,
biphenyls, dibenzo-p-dioxins, dibenzofurans and azo-
a growth deficit, developmental delay, and a behavior
and azoxy-benzenes in vitamin A metabolism and
dis order. Transplacental dermatotoxins are rare (mi-
function may offer an explanation about the acnegenic
noxidil, phenytoin, carbamazepine and hexachloro-
effects of these compounds on human skin (Chen et al.
benzene). This syndrome is one of very few
1992; DenBesten et al. 1993; Coenraads et al. 1994).
documented to result from transplacental exposure
Studies have reported a marked depletion of hepatic
to pollutant chemie als (Rogan et al. 1988). On re-
vitamin-A storage and alterations in plasma retinol
examination 6 years later, nail changes were still
levels in laboratory rats after exposure to several PCB
present and suggested prenatal injury to the nail
congeners, 2,3,7,8-TCDD, or their mixtures. Chemie al-
matrix (Hsu et al. 1995). The findings in transplacen-
ly-induced vitamin-A depletion involves interaction at
tally exposed children differ from those seen in people
several different points in the homeostatic control
direct1y exposed, particularly the higher prevalence of
mechanism of vitamin A: (1) hepatic storage and
acne in the latter group (Rogan et al. 1988; Gladen
mobilization; (2) hepatic elimination; and (3) plasma
et al. 1990; Hsu et al. 1995).
transport system. The magnitude to which each is
In 1982, eight members of a Spanish family were
expressed depends on the type of congener and
poisoned by consumption of olive oil contaminated
exposure to single compounds or complex mixtures.
with PCDDs and PCDFs. The entire family had varying
TCDD or higher chlorinated PCB congeners increased
degrees of acneform lesions, including papules, pus-
hepatic mobilization and elimination, promoting vita-
tules, cysts, comedones and scars located on the face,
min-A depletion. However, interference with plasma
axilla, neck, trunk, groin and genitals. Hyperpigmen-
transport may have an essential role in hypovitami-
tation of the face was also reported. These lesions are
nosis A induced by lower chlorinated (PCBs with four
comparable in severity to those described in the Yusho
or less chlorine substitutions) and other relatively
incident. The olive oil consumed was stored in a 50-1
easily metabolized dioxin and furan congeners
plastic container, which had presumably stored hex-
(Coenraads et al. 1994). Coenraads and co-workers
achlorobenzene and pentachlorophenol prior to the
(1994) found that retinol concentrations in skin
oil. The causative agents were identified as PCDDs,
biopsies from nine PCP-exposed workers with chlor-
PCDFs and PCP, each ofwhich was recovered from the
acne were much lower in comparison with controls.
cooking oil. There were high serum levels of PCDDs
and PCDFs, which returned to normal when measured
5 years after oil consumption ceased (Rodriguez- Histology
Pichardo et al. 1991).
In 1981, an electrical transformer fire occurred in Histologie changes in the skin may begin within 5 days
Binghamton, New York. The fire began in the base- of severe exposure to chloracnegenic chemieals (Ham-
ment mechanical room of an 18-story office building. brick 1957). Lesions demonstrate squamous metaplasia
Approximately 180 gallons of Askarel, a dielectric fluid and plugging of infundibular ducts in addition to
composed of 65% PCBs (Aroclor 1254) and 35% atrophy of sebaceous glands. The specificity of these
polychlorinated benzenes leaked from a transformer. findings is unclear. A characteristic of chloracne is the
The fire originated in the switch gear of the secondary rapid transformation of sebaceous glands into comed-
electrical power distribution system. Pyrolysis of the ones. This appears to be pathognomic for chloracne
Askarel led to the formation of a fine oily soot poisoning. Biopsies from Seveso showed eccrine duct
containing PCBs, dibenzo-p-dioxins and dibenzofur- metaplasia with possible acrosyringeal cyst formation.
ans, which spread to all areas of the building through Foreign body granulomas around detached walls of
ventilation shafts. Three-year post-exposure serum eccrine gland excretory ducts may also be present
PCB concentrations increased with the degree of (Omohundro and Taylor 1998).
Diagnosis PCBs) folliculitis and xerosis (TCAB, TCAOB) and

actinic elastosis (TCDD). Erythema and edema of the
Diagnosis of chloracne entails a compatible c1inical exposed face and extremities associated with trichlo-
picture with distribution of comedones and non- rophenol production was also seen in the Seveso cases.
infiammatory cysts beyond the typical locations of These "pre-chloracne" lesions were also accompanied
acne vulgaris. Documentation of significant exposure by vesiculobullous and necrotic lesions on finger tips
to known chloracnegens and the absence of other and palms, and papulonodular lesions, all of which
external causes is also required. Based on cutaneous resolved within a few weeks. Hyperkeratotic, in-
findings alone, it may be very difficult to differentiate filtrative erythematous granuloma annulare or ery-
chloracne from early acne vulgaris (Table 3) and senile thema elevatum diutinum-like lesions were also seen in
(solar) comedones of the Favre-Racouchot syndrome. association with chloracne 2 months after the explo-
Dowling-Degos' disease also can be considered in the sion. Axillary involvement and follicular hyperkerato-
c1inical differential diagnosis (Kersevovich et al. 1992). sis are linked with inhalation or ingestion of
Differentiation of chloracne from other types of chloracnegens (Taylor 1979; Tindall 1985).
environmental acne - oil folliculitis, pitch acne and Hypertrichosis in association with chloracne has
tropical acne - is listed in Table 4. been mainly confined to the temples and may rarely be
a sign of hepatic porphyria. However, hypertrichosis
has also been described in chloracne patients with
Cutaneous Manifestations normal uroporphyrin levels (Jirasek et al. 1973 and
Crow and PuhveI1991).
Clinical features of chloracne inc1ude multiple c10sed Conjunctivitis has often been noted with severe
comedones and straw-colored cysts distributed pri- poisoning from chloracnegens. The Yusho victims
marily over the malar crescents and retroauricular demonstrated an extreme form when their meibomian
folds, typically sparing the nose. This pattern of glands were converted to squamous cysts filled with a
distribution is of significant diagnostic importance. cheesy keratinous substance; the unusual oral route of
Infiammatory lesions occur but are less frequent than entry and absorption of PCBs may have been an
in other forms of acne. As toxicity increases, the essential part of the syndrome (Tindall 1985).
posterior neck, trunk and extremities, buttocks, scro- Chloracne may occur in relatives of workers exposed
turn and penis may become involved. Dermatologic at horne to contaminated work c10thing and tools
observations associated with chloracne, which may (Taylor et al. 1977).
lead to identification of specific exposures, inc1ude
hyperpigmentation of the skin (PCBs, TCDD), mucous
membrane and nail hyperpigmentation (PCBs), follic- Non-Cutaneous Manifestations
ular hyperkeratosis (PCBs, TCDD [Seveso]), conjunc-
tivitis and meibomian gland changes (PCBs), facial Various c1inical manifestations indicative of systemic
erythema and edema (trichlorophenol, hypertrichosis poisoning have been reported in patients with chlor-
(TCDD), hyperhidrosis of the palms and soles (TCDD, acne. It is advisable that patients with chloracne have
Table 3. Clinical features of acne

vulgaris compared with chloracne Clinical features Acne vulgaris Chloracne
(after Peter Pochi) Usual age Teenage Any
Comedones Present many (if absent, not chloracne)
Straw-coloured cysts Rare Pathognomonic
Temporal comedones Rare Diagnostic
Inflammatory papules and cysts Common Uncommon
Retroauricular involvement Uncommon Common
Nose involvement Often spared Often spared
Associated systemic findings Rare Common
Table 4. Differential diagnosis of

various forms of occupational and Etiology Loeation Lesion
environmental acne Chloracne Halogenated Malar; retroauricular; Comedones;
aromatics mandibular straw-coloured cysts
(0.1-1.0 cm)
Oll follieulitis Oil Arms; thighs; buttoeks Erythematous; papules;
pustules
Piteh aene Tar/pitch Exposed facial areas, Open comedones
especially malar
Tropical aene Heat/humidity Baek; neck; buttocks; Nodules, cysts
proximal extremities
232 J.K. McDonnell and J.S. Taylor
complete physical and laboratory evaluations to ex- There are anecdotal reports of the efficacious use of
clude systemic poisoning. oral 13-cis-retinoic acid (isotretinoin) which, if insti-
Epidemiologic data suggesting that high-level dioxin tuted early, may prevent cyst formation. Isotretenoin
exposure causes liver function abnormalities and 0.3-1 mg/kg/day may be indicated in severe cases for a
chloracne are incontrovertible (Longnecker et al. course of 20 weeks. The drug should be administered
1997). In Seveso, a transient rise in values of hepatic only by those experienced in its use and in strict
enzymes that refiect hepatocellular damage, i.e., gam- accordance with current prescribing instructions. The
ma-glutamyl transferase and alanine amino transfer- hepatotoxicity and lipid abnormalities sometimes
ase, occurred. Alkaline phosphatase and serum associated with chloracne are theoretical reasons to
bilirubin levels were not found to be elevated. Jaundice avoid isotretinoin. Isotretinoin is a potent teratogen
or other signs of hepatic injury were not appreciated. with other potentially significant side effects that
Crow and Puhvel (1991) suggested that the degree of require close monitoring (Gawkrodger 1991).
hepatic injury is dependent on the specificity of the Local therapy with acne surgery and dermabrasion
toxicant involved, rather than a consistent conse- have been reported. Light cautery following topical
quence of all forms of chloracnegen exposure. anesthesia with EMLA cream has been used success-
Porphyria cutanea tarda (PCT) has been reported in fully in six patients with resistant chloracne lesions
humans following TCDD exposure (Bleiberg et al. (Yip et al. 1993).
1964). However, normal urine porphyrin levels have
been observed from individuals with severe chloracne-
gen exposure (Strik 1979). TCDD is a porphyrinogen in
References
animal models and inhibits uroporphyrinogen decar-
boxylase, the enzyme precipitating PCT in some Agency for Toxic Substances and Disease Registry (1993) Dioxin
patients (Mukerjee 1998). toxicity. Am Farn Physician 47:855-861
Other systemic dis orders reported with chloracne Bartolini R (1989) Acne. A summary of the occupational health
concern. Canadian Centre for Occupational Health and
include peripheral neuropathy, hypertriglyceridemia, Safety. Hamilton, Ontario. Report No. F89-1E:l-7
hypercholesterolemia, bronchitis, renal and pancreatic Bleiberg I, Wallen M, Brodken R et al. (1964) Industrial acquired
involvement (Taylor 1987). prophyria. Arch Dermatol 89:793-797
Caputo R, Monti M, Ermacora E, et al. (1988) Cutaneous
Populations occupationally or accidentally exposed manifestations of tetrachlorodibenzo-p-dioxin in children
to chemicals contaminated with dioxin may have an and adolescents. J Am Acad Dermatol 19:812-819
increased incidence of soft-tissue sarcomas and non- Chen LC, Berberian I, Koch B, et al. (1992) Polychlorinated and
polybrominated biphenyl congeners and retinoid levels in rat
Hodgkin's lymphoma. To date, no comprehensive tissues: structure-activity relationships. Toxicol Appl Phar-
studies have been conducted to determine any health macol 114:47-55
impact to the general population from environmental Coenraads PI, Brouwer A, Olie K, Tang N (1994) Chloracne.
Dermatol Clin 12:3
exposure to PCDDs (Mukerjee 1998). Cole GW, Stone 0, Gates D, Culver D (1986) Chloracne from
pentachlorphenol - preserved wood. Contaet Dermatitis
15:164-168
Crow KD, Puhvel MS (1991) Chloracne (halogen acne). In:
Treatment Marzulli FN, Maibach HI (eds) Dermatoxicology. Hemi-
sphere, New York, pp 647-667
Chloracne tends to resolve slowly upon cessation of DenBesten C, Bennik MHJ, Bruggeman I, et al. (1993) The role of
oxidative metabolism in hexchlorobenzene induced porphyr-
chemical exposure. Its duration correlates with the ia and thyroid hormone homeostasis: a eomparison with
severity of the disease, which usually refiects the degree pentachlorobenzene in a 13-week feeding study. Appl Phar-
and extent of exposure. The severely exposed victims macol119:181- 194
Fitzgerald EF, Weinstein AL, Youngblood LG, et al. (1989) Health
of Yusho in 1968 had characteristic chloracne lesions effects three years after potential exposure to the toxie
that continued to develop for as long as 14 years post- eontaminants of an eleetrical transformer lire. Areh Environ
exposure. Health 44:214-221
Gawkrodger DJ (1991) Chloraene: eausation, diagnosis and
Treatment has been difficult as the modalities that treatment. J Dermatol Treatment 2:73-76
are useful in acne vulgaris are often ineffective in Gladen BC, Taylor JS, Wu YC, Ragan NB, Rogan WJ, Hsu CC
chloracne. Topical application of retinoic acid (0.005- (1990) Dermatologic lindings in ehildren exposed trans-
plaeentally to heat-degraded polyehlorinated biphenyls in
0.3% concentration) or of tretinoin (Retin-A) gel or Taiwan. Br J Dermatol 122:799-808
cream is of so me benefit in controlling comedones, but Greenlee WF, Neal RA (1985) The Ah reeeptor: a bioehemieal and
other topical agents are of little use (Caputo et al. biological perspective. In: The reeeptors, vol II. Academic
Press, Orlando, pp 89-129
1988). A combination of tetracycline and short courses Hambriek GS (1957) The effeets of substituted napthalenes on the
of orally administered prednisone helped with severe pilosebacious apparatus of rabbit and man. J Invest Dermatol
infiammatory cases. A trial regimen of methotrexate, 28:29-103
Hardell L, Sandstrom A (1979) Case-eontrol study: soft tissue
25 mg every 10 days for several months was unsuc- sareoma and exposure to phenoxy-aeetie acids or chloro-
cessful (Taylor et al. 1977). phenols. Br J Cancer 39:711-717
Herxheimer K (1899) Ueber chlorakne. Munch Med Wochenschr Poland A, Glover E, Kende AS (1976) Stereo-specific high affinity
46:278 binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic
Hjorth N, Sjolin KE, Sylvest B, et al. (1972) Acne aestivalis: cytosol. J Biol Chem 251:4936-4946
Mallorca acne. Acta Derm Venereol 52:61-63 Poskitt LB, Duffill MB, Rademaker M (1994) Chloracne, palmo-
Hsu MM-L, Mak C-P, Hsu C-C (1995) Follow up of skin plantar keratoderma and localized scleroderma in a weed
manifestations in Yu-Cheng children. Br J Dermatol sprayer. Clin Exp Dermatol 19:264-267
122:799-808 Rodriguez-Pichardo A, Camacho F, Rappe C, Hansson M, Smith
Jirasek L, Kalensky I, Kubec K (1973) Acne chlorina and AG, Greig JB (1991) Chloracne caused by ingestion of olive oil
porphyria cutanea tarda during the manufacturing of herbi- contaminated with PCDDs and PCDFs. Hum Exp Toxicol
eides Part 1. Cesk Dermatol 48:306-317 10:311-322
Kersevovich J, Langenberg A, Odom RB, et al. (1992) Dowling- Rogan WJ, Gladen BC, Hung K-L, Koong S-L, Shih L-Y, Taylor JS
Degos' disease mimicking chloracne. J Am Acad Dermatol (1988) Congenital poisoning by polychlorinated biphenyls
27:345-348 and their contaminants in Taiwan. Science 241:334-336
Kligman AM, Mills OH (1972) Acne Cosmetica. Arch Dermatol Scerri L, Zaki I, Millard LG (1995) Severe halogen acne due to a
106:843-850 trifluoromethylpyrazole derivative and its resistance to
Knox JM, Dinehart SM, et al. (1986) Acquired perforating disease isotretinoin. Br J DermatoI132:144-148
in oil field workers. J Am Acad Dermatol 14:605-6u Sperling L (1994) Skin disease assoeiated with excessive heat,
Kokelj F (1992) Occupational Acne. Clin Dermatol 10:213-217 humidity, and sunlight. In: Zajtchuk R (eds) Textbook of
Litt JZ (1974) McDonald's acne. Arch Dermatoluo:956 military medicine, part III. Sergent General, Department of
Longnecker MP, Rogan WJ, Lueier G (1997) The human health the Army, Washington DC, pp 44-45
effects of DDT (dichlorodiphenyltrichloroethane) and PCBs Strik JJ (1979) Porphyrins in urine as an indicator of exposure to
(polychlorinated biphenyls) and overview of organochlorines chlorinated hydrocarbons. Ann NY Acad Sei 320:308-310
in public health. Ann Rev Public Health 18:211-44 Taylor JS (1979) Envionmental chloracne: update and overview.
Mathias CGT (1994) Occupational Dermatoses. In: Zenz C, Am NY Acad Sei 320:295-307
Dickerson OB, Horvath EP (eds) Occupational medieine, Taylor JS (1986) Occupational dermatoses. In: Conn HF (ed)
3rd edn. Mosby, St. Louis, pp 93-131 Current therapy. Saunders, Philadelphia, pp 686-688
McDonough AI, Gawkrodger DJ, Walker AE (1993) Chloracne- Taylor JS (1987) Pilosebaceous unit. In: Maibach HI (ed)
study of an outbreak with new clinical observations. Clin Exp Occupational and industrial dermatology. Year Book Medical
Dermatol 18:523-525 Publishers, Chicago, pp 105-120
Mills OH, Kligman A (1975) Acne Mechanica. Arch Dermatol Taylor JS, Lloyd KM (1982) Chloracne from 3,3',4,4'-
m:481-483 tetrachloroazoxybenzene and 3,3',4,4'-tetrachloroazobenzene:
Mukerjee D (1998) Health impact of polychlorinated dibenzo- update and review. In: Hutzinger 0 (ed) Chlorinated dioxins
p-dioxins: a critical review. J Air Waste Manag Assoc 48: and related compounds. Pergamon, Oxford, pp 535-544
157-165 Taylor JS, Wuthrich RC, Lloyd KM, Poland A (1977) Chloracne
O'Malley MS, Carpenter AV, Sweeney MH, Fingerhut MA, et al. from manufacture of a new herbieide. Arch Dermatol 113:
(1990) Chloracne associated with employment in the 616-619
production of pentachlorophenol. Am J Ind Med 17: Tindall JP (1985) Chloracne and chloracnegens. J Am Acad
411-421 Dermatol 13:539-558
Omohundro C, Taylor JS (1998) Occupational acne. In: English Upreti RK, Das M, Shanker R (1989) Dermal exposure to
JSC (ed) A colour handbook of occupational dermatology. kerosene. Vet Hum Toxicol 31:16-20
Manson, London, pp 121-134 Vazquez ER, Maeias PC, Tirado JG, Solana CG, Casanova A,
Pocchiari F, Silano V, Zampieri A (1979) Human health effects Moncada JF (1996) Chloracne in the 1990S. Int J Dermatol
from accidental release of tetrachlorodibenzo-p-dioxin 35:643-645
(TCDD) at Seveso, Italy. Ann NY Acad Sei 320:311-320 Yip J, Peppall L, Gawkrodger DJ, Cunliff WJ (1993) Light cautery
and EMLA in the treatment of chloracne lesions. Br J
Dermatol 128:313-316
CHAPTER 28
Occupational Aquatic Dermatology

G. Angelini
Introduction an amorphous gelatinous substance (mesoglea). Owing

to the symptoms they induce, coelenterates are also
The fields of aquatic medicine, followed by aquatic known as "sea nettles".
dermatology, have developed due to the ever growing The coelenterate phylum is very prevalent in tropieal
incidence of diseases and accidents relative to the and subtropical seas. Of the 1000 known species, about
aquatic environment (Fisher 1978; Angelini and Vena 100 are harmful to man. These belong to the Scyphozoa
1991, 1997; Angelini and Bonamonte 1997). (true jelly fish) , Anthozoa and Hydrozoa classes
As weIl as affiicting bathers, aquatic dermatoses are (Table 2).
very common in the professional environment (fish-
Table 1. The most common skin reactions to aquatic organisms
ermen, skin divers, sailors, boatmen, bay watchers,
workers at swimming pools, swimming instructors, Dermatitis caused by coelenterates (jelly fish, sea
workers in aquariums, saunas and Turkish baths), and anemones, hydroids)
Dermatitis caused by echinoderms (sea urchins, sea stars)
may be caused by biotic or non-biotic (physical or Eruptions caused by mollusks (clams, octopods, squids)
chemical) agents. Dermatoses caused by arthropods (crustaceans)
Dermatitis caused by sponges
Dermatitis caused by algae
Dermatoses caused by aquatic worms (cercariae,
Aquatic Dermatosis with Biotic Causes leeches, annelids )
Dermatoses caused by fish spines (sting rays, scorpion
fish, weever fish)
Oceans, rivers, lakes, pools, swimming pools and Dermatoses caused by nematodes (cutaneous larva migrans)
aquariums all contain millions of animal and vegetable Dermatoses caused by bacteria (mycobacteriosis,
erysipelotrix, other infections)
organisms of various sizes, including myriads of
mieroscopie organisms. During the course of evolu-
Table 2. Phylum of toxic coelenterates
tion, many aquatic species have developed defense and
offen ce mechanisms against their natural predators. Class Order Species
These include stings and bites, often associated with a
venomous apparatus. Obviously, these self-protective Scyphozoa Pelagia noctiluca
mechanisms are also used against man, often an (true jelly fish) Rhizostoma pulmo
Cyanea capillata
involuntary aggressor but sometimes a voluntary Aurelia aurita
predator or destroyer. Diseases from aquatic biotic Chironex fleckeri
organisms can be due to three different types of Chiropsalmus
quadrigatus
pathological event: toxie, toxo-traumatic and traum at- Anthozoa Actiniaria Anemonia sulcata
ic. This chapter concentrates particularly on the first (sea anemones) Actinia equina
two types (Table 1) because traumatic lesions, foIlow- Adamsia palliata
Calliactis parositica
ing an encounter with an electric eel or a shark, for Condylactis
instance, are not really dermatological problems. aurantiaca
Scleractinia (corals)
Sagartidae Sagartia elegans
Dermatitis from Coelenterates Hydrozoa Siphonofora Physalia physalis
Physalia uticulus
Coelenterates, or "cnidaria" (from knidi, meaning a Velella velella
Leptomedusae
nettle), are animals with a simple symmetrical radial (feather hydroids)
structure, a mouth which opens out of a single cavity Milleporina Millepora alcicornis
(coelenteron) and a body membrane consisting of two (stinging coral: not
a true coral)
layers of cells (ectoderm and endoderm) separated by

Occupational Aquatic Dermatology 235
Coelenterates have thousands of mieroseopic organie; tlley are not eonsidered poisonous, however,
elles, ealled enidoeysts, running all over the body and beeause the heat inactivates their toxins; moreover,
tentacles. These dead organoids, also known as "nettle they are digested by tlle intestinal proteolytie enzymes.
eells" or "stinging eapsules," contain a partieular Along the eoral barriers of the Pacifie (Tahiti, Hawaii)
globe-shaped body ealled the nematoeyst beeause it and the Caribbean (Jamaica), some poisonous coelen-
envelops a long, slender filament wound in a spiral. On terates belonging to the Zoantharia family and Pal-
eontaet with a foreign body, the enidoeyst ejeets these ythoa genus ean still be found, from which palytoxin,
nematoeysts violently and the latter penetrate the body the most toxic biotoxin in the animal world with the
of the vietim, opening a gap through whieh the most eomplex ehemical strueture ever identified, has
filament passes and injeets its toxins. Nematoeysts been isolated (C129 H223 N3 054) (Moore and Scheurer
eontain many different biologieally aetive toxie sub- 1971; Vemura et al. 1981).
stanees, not all of whieh are known for eaeh speeies. A highly variable range of skin reaetions is caused
In 1902, a Freneh physiologist, Riehet, studied the by contact with nematoeysts, depending on the size of
eoelenterate toxins and diseovered the anaphylaetie the area stung and the toxicity of the poison. Subjec-
phenomenon, whieh won hirn the Nobel prize in 1913. tively, the symptoms vary from a slight prieking
Using a glyeerinated extraet, first of whole tentacles of sensation to pain, itching and intense burning. Objec-
the Physalia and later of tlle Actinia, the author tive manifestations are generally of erythemato-ede-
demonstrated its toxie action on some animals, e.g., matous type with more or less bizarre shapes. Diffuse
birds and rabbits. To aseertain the lethaI dose, he urtiearial reaetions are also fairly eommon, together
injeeted the extraet into dogs, whieh died after 5- with anaphylaxis (laryngeal edema, eollapse). In highly
6 days. The animals that had reeeived an insuffieient sensitive subjects, shoek and death ean develop.
dose of the extraet and survived the experiment were
used in further experiments. This led to one of the Reodions to Jellyfish
most important diseoveries made in the medieal field.
A dog, whieh had been administered 0.1 ml of glyeer- Reactions to jellyfish stings present various clinieo-
inated extraet and had not manifested any symptom, morphologie al pictures and different pathogenetic
was re-injeeted with a seeond dose of 1.2 ml of extraet mechanisms (Table 3) (Rosco 1977; Reed et al. 1984;
after 22 days. A few seconds after this seeond injeetion, Mansson et al. 1985; Burnett et al. 1986a,b, 1987; Fisher
the animal went into a coma and died after 25 min. 1987). The most common and well-known are obvi-
Richet ealled tlüs phenomenon "anaphylaxis" or, in ously loealized, including toxie urtiearial reaetions.
other words, the reverse of protection (Portier and Instantaneous pain is followed by an immediate linear
Richet 1902; Riehet 1903a, b). Thus, it was discovered skin eruption presenting in various forms, charaeter-
that some substanees eompound, rather than reduce, ized by urtieariallesions lasting between a few minutes
the organism's sensitivity to their action. From the and several hours aeeording to the intensity of tlle
same tentacles of Anemonia sulcata, Richet also damage. The lesions mayaIso be vesicular, hemor-
isolated three different eomponents: hypnotoxin, rhagie or neerotizing.
thalaxin and congestin. The former induces somno- Urtiearial reaetions ean aggravate into angio-
lenee followed by res pi ra tory paralysis; the second has edematous lesions lasting about 10 days. They may
an urticarial action on the skin and eauses eardiae reeur onee or several times at varying intervals, even
arrest, while the third, which is the one with anaphy- some months from the first, single sting. Delayed
lactic action, causes vomiting, diarrhea and gastroin- reactions, present about 4-7 days from contaet, are
testinal hemorrhage. granulomatous in type and persist for months. The
Various other substanees have been isolated in histological examination reveals a dense dermic cellu-
coelenterates, including tetramine, histamine and 5- lar infiltrate just like that provoked by delayed
hydroxytryptamine. On the basis of these chemie al hypersensitivity reaetions. A subject stung on one site
compounds, co elen te rates are considered actively tox- may develop clinical lesions at a different site. Apart
Table 3. Cutaneous and systemic reactions to jelly fish envenomation
Loeal reaetions Toxie reaetions, angioedema, reeurrent reaetions, delayed persistent reactions,
distant site reaetions
Loeal sequelae Keloids, dysehromia, fat atrophy, sears, gangrene
Systemie reaetions Asthenia, ataxia, muscular cramps, paraesthesia, vertigo, fever, siekness, vomiting
Fatal reaetions Toxie reactions (immediate eardiae and respiratory arrest, delayed renal
failure), anaphylaxis
Reaetions from jelly fish ingestion Abdominal pain and cramps, papular urtiearia
"Indirect" eoelenterate dermatitis Nudibraneh dermatitis, antigenie venom substances in aquatie environment
236 G. Angelini
from toxic reactions, all other reactions may be allergie dermatitis was evident with an unusual configuration
in nature mediated by specific immunoglobulin (Ig)G of the lesions. These presented as an agglomerate of
or IgE; these antibodies pers ist for many years and erythematous, edematous and vesico-bullous strip es.
cross-react with one another. The erythema, which was bright red with a purpuric
The local outcome of jelly fish-provoked dermatitis imprint, had fairly distinct outlines. The stripes varied
may be constituted by keloids, dyschromia, scarring, in length between 2-7 cm and were interwoven,
subcutaneous atrophy and gangrene. creating an elegant abstract design with a central
nucleus branching out in various directions, having an
appearance similar to that of pseudopods. Identical
Readions to Sea Anemones
lesions, but with a more elementary shape, were
present on the volar surface of the right wrist. The
The most common species of sea anemones are Actinia
skin complaint provoked intense pain and burning,
equina, Condylactis aurantiaca, Adamsia palliata and,
and was associated with headache, nausea, vomiting,
above all, Anemonia sulcata. These can induce various
bronchospastic crises and muscular cramps.
skin pietures, which have only in rare cases been
The second case, of a girl aged 12 years, presented
reported in the literature (Maretec and Russel 1963;
with an extensive erythemato-edemato-bullous figured
Angelini and Vena 1991; Angelini and Bonamonte
dermatitis on the posterior face of the right thigh. The
1997). Local reactions are most commonly toxic and, in
complaint again included intense pain at the affected
our experience, present generally with many more
part, nausea, vomiting, headache, muscular cramps
marked symptoms than those due to local reactions to
and bronchospastic crises. In both cases, the dermatitis
jelly fish. The lesions are more extensive and assume
resolved in about 25-30 days.
very bizarre pathognomonic pictures, notably featur-
The approaches to treatment of reactions to coelen-
ing elegant arabesque-like stripes. Morphologieally, in
terates are reported in Table 5.
addition to the erythematous-edematous aspect, the
lesions are more often vesicular or blistering and Table s. Principles of treatment of the reactions to coelenterates
sometimes necrotizing. The edema is often serious
enough to create an angioedematous pieture. Owing to Local treatment:
this greater clinical severity of the lesions, the course of Vinegar, alcohol, ammonia, urine, meat tenderizer, salt
water heated to the limit of tolerance
the complaint lasts from 15 days to 20-30 days and is Avoid the use of fresh water because it activates nematocysts;
accompanied by very strong subjective and systemie avoid showering until the nematocyst toxin has
symptoms. The local pain and burning are sometimes been neutralized
Remove tentaeles with gloved hands; a paste of sea water
intolerable, while systemic reactions, such as malaise, and baking soda, or applications of flour or talcum powder
weakness and muscular cramps, are almost always may also be used, and the tentaeles may then be scraped
present (Table 4). Dyschromic or scarring sequelae are off easily with a knife or sharp instrument (dry sand may
be used if powders are not available)
much more common after reactions to sea anemones Wash the area frequently with salt water
than to jelly fish. In severe cases, a tourniquet may be used on exposed limbs
No cases of fatal reactions to sea anemones have Local anaesthetic and corticosteroid ointments,
creams or lotions
been reported in the literature. We observed two cases Systemic treatment:
of systemie reactions to Anemonia sulcata. The first Corticosteroids, antihistamines, epinephrine, cardiotonics,
calcium gluconate or pain-killers (aspirin, phenacetin,
occurred in a young boy, aged 9 years: on the fiexural codeine)
surface of the right thigh, an erythematous-edematous
Table 4. Differential characteristics between reactions to jelly fish and to sea anemones
Reactions to jelly fish Reactions to sea anemones
Incidence Frequent Less frequent

Type of contact Generally superficial Generally very elose
Means of contact Brushing against it During swimming; leaning on it when sitting or lying on the rocks
Sites All sites All sites, particularly posterior face of thighs, back and volar surface
of wrists because of above contact incidence
Extension Slight (contact with jelly fish) Marked (contact with various areas of dermatitis for above reasons)
Clinical picture Generally modest Generally severe
Morphology Figured, most often linear Bizarre, arabesque-like configuration of the lesions
Clinical lesions Erythema, edema, rarely blisters Erythema, serious edema, blisters and necrosis
Rounded lesions Not observed Frequent
Subjective symptoms Generally modest pain and burning Generally intolerable pain and burning
Systemic symptoms Possible, generally modest Almost invariable and severe
Clinical course A few days 15-30 days
Sequelae Not frequent Frequent
Reartions to Sagartidae Reartions to Portuguese Man-of-War
One of the most common reactions to sea anemones is The Physalia species live in the tropical regions of the
sagartia's dermatitis, also called "sponge fishermen's Pacific, Atlantic and Indian Ocean. They float along
disease" or "maladie des pecheurs d'eponges nus," as carried by the winds and superficial currents and can
it is called in some parts of the Mediterranean. The sometimes end up on the European co asts of the
Sagartia is a coelenterate that lives symbiotically at the Atlantic or in the Mediterranean. They include two
base of sponges; it is shaped like a flower about 1-4 cm species: Physalia physalis, the most representative type,
long, and has a cylindrical polypoid body with two present in the tropical Atlantic and the Mediterranean;
rows of tentacles arranged radially. and Physalia utriculus, present in the Indo-Pacific
Fishermen harvest these sponges with their bare region and South of Japan.
hands, remove stones and other encrustations from Physalia physalis, commonly called "Portuguese
their base and put them in a net slung around their man-of-war," is composed of a main floating nucleus
necks. During these maneuvers, the fishermen come filled with gas (a mixture of oxygen, nitrogen and
into contact with the sagartia's tentacles and after a few argon), whose upper surface bears the reproductive
minutes they feel burning and itching sensations, apparatus, gastrozoids, dactylozoids and slender tenta-
accompanied by erythema and blistering; the erythema cles covered with nematocysts. The tentacles may reach
is bright red at first but then turns purpie. The a length of 10 m. This characteristic, together with their
dermatitis may be associated with systemic symptoms, transparency, makes them even more dangerous be-
including headache, nausea, vomiting, fever, shivering, cause they can float very far behind the physalia.
collapse and muscular spasm. The skin complaint Physalia stings cause very violent pain, which may
takes quite a time to resolve; sometimes multiple be unbearably intense and radiates from the affected
abscesses develop, which may evolve into ulcers area accompanied by strong burning sensations. The
(Molfino and Zannini 1964; Fisher 1978). objective picture is characterized by linear erythema-
tous-edematous lesions on which vesicles and blisters
Reartions to Corals may develop. Sometimes, after a few hours, an
urticarial eruption with wide pomphoid areas, which
Two types of coral are distinguished, based on whether are particularly itchy, can be observed. A few minutes
they have hard or soft skeletons. Hard corals have a after contact, anxiety and anguish are brought on, as
solid skeleton composed of calcium carbonate, secret- weIl as lipothymia. Muscle pain, breathlessness, nausea
ed by the epidermic cells; the animal can thus create a with or without vomiting, asthenia, bradycardia and
cup-like shell (fossil coral) in which it lives during the hypothermia may also be present. In benign cases, the
day. That is why the skeleton is the visible part of the skin lesions resolve in a few hours leaving hyperpig-
coral, at least by day, and it is the skeleton which is left mented or scarred areas. General conditions improve
when the animal dies. rapidly, while dyspnea and a sharp cough, generalized
Soft corals, of the Alcyonaria subclass, secrete the urticaria and violent digestive symptoms (vomiting,
same type of skeleton composed of calcium carbonate; painful colic) may persist for several days. A late
the cohesion and extension of this skeleton determine complication, frequent in the tropical zones, is the
the consistency of the coral. These corals, called onset of coma. The linear skin lesions may turn into
gorgonia (because they have a flexible axial skeleton), deep, purulent sores.
are very abundant in the Caribbean Sea.
Skin lesions from corals may be of various types. Reartions to Other Coelenterates
Toxic contact reactions provoked by the nematocysts
are infrequent and gene rally fairly mild. Wounds from Contact dermatitis can also be induced by Hydroids
corals, however, are very common; despite their fragile and Milleporina. The former are present in tropical
appearance, hard corals have cutting surfaces. These and subtropical waters and induce urticaria or a
wounds evolve rapidly into painful ulcerations and, papulo-hemorrhagic or zoster-like eruption. Eruptions
unless they are promptly and appropriately treated, from so-called "fire corals" (not true corals), common
into cellulitis. The severity of this picture is due to a in the tropical zones of the Pacific Ocean, Indian
combination of a number of different factors: me chan- Oceans, Red Sea and Caribbean Sea, appear after
ical skin laceration; offensive action of the nemato- 1-12 h from contact and resolve within 1-3 days.
cysts; introduction of foreign bodies into the wound
(calcium carbonate, detritus, microorganisms, sludge); Dermatoses from Echinoderms
secondary bacterial infections; climatic conditions
(high temperature and humidity) favoring the devel- Echinoderms are animals with a rotate pentamerous
opment of bacteria. These wounds heal very slowly. symmetry. About 6000 species are known, 80 of which
238 G. Angelini
are toxic or venomous. Their various different shapes tous. The latter picture ("sea urchin granulomas")
have led to a subdivision into five classes: Echinoder- features hard, parenchymatous lesions of variable
mata (sea urchins), Asteroidea (starfish), Ophiuroidea dimensions ranging from 4-5 mm to 1-2 cm in diam-
(serpent stars), Holothuroidea (sea cucumbers) and eter; they are darkish or brownish-red in color. It is
Crinoidea (sea lilies or feather stars). possible to elicit a positive delayed allergie reaction by
injecting intradermally a hydro-alcoholic extract of sea
Readions to Sea Urchins urehin spines (Meneghini 1972). Histological examina-
tion of the nodular lesions may demonstrate sarcoid-
The best known and most frequent reactions induced type granulomas or more often lymphohistiocytic
by Echinoidei are those from sea urchins (Para- granulomas with giant cells due to a foreign body.
centrotus lividus), which ean eause immediate and These lesions can be treated with intralesional injee-
delayed reaetions (Burnett et al. 1986a,b; Fisher 1978; tions of eorticosteroids or liquid nitrogen.
Angelini and Vena 1991; Angelini and Bonamonte In underwater fishermen, repeated trauma due to
1997). Both types of reaetion are due to the spines of penetration of sea urchin spines, together with the
the urehins. These spines, developed variously in the constriction of the wrists caused by the wet suit and
different species, are sharp and very fragile; at contact the low temperature of the water, can induee a
they penetrate the skin easily and break off, making the different type of delayed reaction, called "chronie
fragments inside the wound difficult to extract. Pen- professional traumatic lymphedema of the hands"
etration of the spines causes immediate, sharp, burn- (Angelini et al. 1990a,b,c). This complaint manifests
ing pain, which may last a few hours, followed by with hard, persistent edema of the baek of the hands
redness, exeoriations and edema of the affected part; and sometimes also of the forearms (Fig. 1). This
there mayaiso be eopious bleeding. Torpor and scleredema persists even many years after abandon-
localized muscular pain have also been reported, and ment of this working activity and may be accompanied
secondary infeetions are not rare. by lymphographic alterations of the limb involved.
The treatment of these immediate reaetions is This picture of hard scleredema resembles closely
application of water as hot as is bearable on the Secretan's syndrome, a cutaneous artifact due to
edematous, painful lesions. Immediate and complete various repeated mechanical stimuli (hemostatic liga-
removal of the spines is obviously a priority. The tures, occlusive bandaging, traumas), self-inflicted for
dermatitis usually resolves within 1-2 weeks, provided financial gain (generally to obtain a pension) or
no spines remain inside the skin. psychiatric reasons. Spontaneous, chronic professional
Delayed reactions can onset 2-3 months after the scleredema of the hands must also be differentiated
primitive contact and may be nodular or scleroderma- from other acute or chronic lymphedemas, such as
Fig.1. Chronic professional traumatic lymph-

edema of the hands in fishermen
lymphatic aplasia, recurrent erysipelas, deep thrombo- bleeding. Severe cases may result in death from
phlebitis, angioedema, chilblains, urticaria due to the muscular and respiratory paralysis.
cold, filariasis, venous obstruction, complications of
surgical operations and radiotherapy, mammary car- Readions to Cone Shells
cinoma or other tumors.
The most toxic cone shells belong to tropical and
Readions to Starfish subtropical species: Conus aulicus, C. geographus,
C. gloria maris. Their bite can induce intense burning
Starfish, of which there are about 2000 species, have pain, ischemia and cyanosis, leading to coma and
spines made of calcium carbonate crystals mixed with death from heart paralysis. A possible preventive
organic substances. These contain glandular tissue measure is to wear gloves and pick the shells up by
which can secrete a toxin with a hemolytic, antibiotic their wide posterior extremity.
action consisting of steroid glucosides. The toxin
spreads inside the water, where many animals are Lesions from Arthropods
present, so that contact with the surrounding water can
induce a pruriginous, papulo-urticarial eruption. One Marine arthropods (crustaceans: crabs, shrimps, lob-
of the most common starfish in the Mediterranean is sters) do not contain toxins, so their harmful effects
Echinaster sepositus, which is a bright red color. The are due to mechanical causes (lacerating wounds),
resulting dermatitis can be treated with a lotion with a provoked by the claws of large examples, such as
0.5% calamine and menthol base. Some starfish, such Eriphia verrucosa and Homarus gammarus. Dermatitis
as Acanthaster planci (or "crown of thorns"), can of the hands has also been reported in lobster catchers,
infiict a painful sting which may result in granuloma- and is characterized by a pruriginous eruption with
tous lesions. hyperkeratosis and ragade-like cracks. There are
various pathogenetic factors: trauma during maneu-
vers for catching and deweeding the crustacean, the
Dermatoses from Mollusks
contact with sea water and the sensitizing action of
some seaweeds.
The phylum of mollusks includes about 4500 spedes
which differ greatly as regards habitat, shape and
Dermatitis from Sponges
function. Mollusks are present in waters all over the
globe; their biotoxins have various chemical and
Porifera, or sponges, lie stationary normally and
pharmacological structures; some are urticant and
attached to the sea bottom or sometimes the lake
others are highly toxic. There are three main classes:
bottom. There are 5000 known species of sponge,
Lamellibranchia (bivalvular), Gastropoda (muricides
which vary as to shape, size (from practically invisible
and conides) and Cephalopoda (octopus, squid, sepia).
to 2 m in length) and color. These organisms are
The best-known cephalopod is the octopus; enter-
pluricellular, composed of epithelioid-like cells and a
amine (5-hydroxytryptamine or serotonin) was isolat-
skeleton made of spongin, a scleroprotein. Sponges
ed in 1950 from Octopus vulgaris, the most common
have long been known not to be entirely innocuous
species in the Mediterranean.
and several toxins have been isolated.
Sponge fishing is carried out today in the Mediter-
Readions to Cepha/opods ranean, in Florida, Cuba and the Bahamas, and
dermatitis from sponges has been observed in all of
The most common Cephalopods are Octopus vulgaris, these areas. When they are detached or their ramifica-
o. macropus, Eledone moschata, E. aldrovandi and tions are broken off, the fisherman notices an itching or
Sepia officinalis. With their bony beaks, these mollusks stinging sensation; within a few hours, pain, edema and
can bite, leaving small, lacerated star-shaped wounds rigidity of the hands onset, together with erythema and
with edematous margins, which bleed abundantly and blisters. The dermatitis regresses after about 2 days. An
provoke burning local pain which can involve the eruption of erythema multiform type may also appear.
whole limb. Espedally during the summer, the coasts Some sponges can induce traumatic dermatitis due
of Australia are populated by a small octopus, the to contact with the spicules, which are composed of
Hapalochlaena maculosa, which is lO-cm long. It has silicone dioxide or calcium carbonate. Sponge fishers
characteristic markings featuring two blue rings on a must wear canvas gloves when handling live sponges,
brownish-yellow background, hence the name "blue- which can cause various injuries.
ringed octopus". Its bite may be fatal even for man. Fisher (1978) reports dermatitis caused by Tedania
The symptoms onset after 5-10 min, involving burning ignis, Fibula nolitangere and Macrociona prolifera.
pain running down the whole limb and copious T. ignis (the "fire sponge") is abundant in the Miami
240 G. Angelini
area and along other parts of the coast of Florida. In fishermen, dermatitis from bryozoans is quite
Contact with this sponge induces itching or stinging disabling. It was first observed in the North Sea
and after some hours, pain, erythemato-bullous le- ("Dogger Bank itch") (Bonnevie 1948) and manifests
sions, edema and immobility of the fingers. These by means of an allergie mechanism, recurring each
symptoms resolve in about 2 days. This sponge may summer. Fishermen come in contact with bryozoans
also give rise to an erythema multiform-like eruption. when they pull their nets on board the boat. The
F. nolitangere ("poison bun sponge" or "touch-me- dermatitis presents with acute or dry exudative lesions.
not sponge") owes its name to the fact that its sting The hands and forearms are first affected by direct
provokes a much more violent reaction than the one contact, followed by the face and neck by airborne
described above. This sponge colonizes the waters of contact with drops of water containing the allergizing
Central America. substance. The dermatitis may even become general-
Contact with M. prolifera, the red sponge, causes ized. The allergen responsible is 2-hydroxyethyl-
erythema and edema; later, blisters develop on the methylsulphoxonio in the case of A. gelatinosum.
affected area and have a purulent evolution. Unless Epicutaneous tests are made with fragments of live
treated adequately, this dermatitis may persist for bryozoans just harvested, with sea water containing the
several months. Patch test with a fragment of sponge allergen, and with aqueous and acetonyl extracts of sea
will confirm the diagnosis. moss.
Dermatitis trom Seaweed Dermatitis trom Sea Worms
About 30,000 different species of algae have been These organisms are classified in the phyla of Platy-
identified in sea and fresh water. Those that produce helminthes, Nemertea, Nematoda and Annellida. Some
biotoxins belong to the Cyanophyceae and Din- aquatic species in sea and fresh water contain biotox-
ophyceae classes. The latter are particularly harmful ins.
when growth bursts occur ("red tides"). A cyan-
ophycea seaweed which causes a dermatological con- Cercaria! Dermatitis
dition is Lyngbya majuscola, present in oceans, rivers,
lakes and pools. Two toxins have been isolated in this Schistosome cercarial dermatitis ("swimmer's itch")
species, which cause painful dermatitis ("swimmer's is most commonly due to Trichobilharzia ocellata,
itch"): lyngbyatoxin A and debromoaplisiatoxin. T. stagnicocolae, Gigantobilharzia huronensis and
L. majuscola caused a dermatitis epidemie among Schistosomatium douthitti. The intermediate hosts,
Hawaiians from a coastline along the island Oahu, near i.e., mollusks, belong to the Lymnaea, Physa and
Honolulu (Grauer and Arnold 1961). Only a few Planorbis species. Cercarial dermatitis is common
minutes after bathing, intense itching and burning everywhere and apart from swimmers, may affect
onset, followed by blistering leaving painful erosions, subjects working with fresh water for irrigation:
particularly at the level of the genitals and the perianal agricultural workers and rice growers.
area. The eruption affects the areas covered by the According to the target host, three forms of derma-
swimming costume and must be differentiated from titis can be distinguished. Dermatitis from fresh water
"sea bather's eruption". cercarias, whose host is a bird, has been described in
Recently, a contact allergy that developed in a Italy among female workers in the rice fields of the
fisherman was reported; it was brought on by Electra Padania Plain (Gianotti and Invoni 1958).
pilosa (a bryozoan) and Sargassum muticum, a brown Dermatitis from salt water cercarias has a sea bird as
seaweed which has been present in European seas for host and has been reported in the USA, Australia and
the last 15 years and has an explosive growth during Hawaii. In the workers in oriental rice fields (India,
March and October (Jeanmougin et al. 1987). Malaya, China) and Austral Africa, fresh water derma-
titis from cercarias whose hosts are buffaloes, sheep
Dermatitis trom Bryozoa and goats has been observed.
Skin affiictions from cercarias involve the epidermis
The bryozoans (moss animals or sea mats) responsible because cercarias seem unable to penetrate beyond the
for contact dermatitis are mainly Alcyonidium gela- derma. Initial itching is followed by an urticarial
tinosum, A. hirsutum, A. topsenti, Flustra foliacea and eruption which resolves within about 0.5 h, leaving
Electra pilosa (Bonnevie 1948; Audebert and Lam- maculae; after a few hours, these transform into very
oureux 1978; Jeanmougin et al. 1983, 1987). A. gela- itchy papules. The dermatitis resolves in 1-2 weeks.
tinosum is widespread in the Northern hemisphere Prevention is only by individual protection, wearing
and, in particular, in the Atlantic, the Baltic, the North overall wet suits, while environmental clean-up is
Sea, the Arctic and the Channel. required to solve the problem. Dermatitis from cerc-
arias must be differentiated from "sea bather's erup- (fireworm) and Aphrodite aculeata (sea rat). Their
tion" and seaweed dermatitis (Table 6). bristles induce irritant contact dermatitis featuring
itching, pain, erythema and edema. These fine bristles
Readions to Leeches can be removed with an adhesive pIaster. The me-
chanical effect of the bristles (hence the name "bristle
Leeches belonging to the phylum Annellida live in worm dermatitis") can be associated with a toxic
pools and streams, and feed on the blood of mammals. action, which affects heart and respiratory functions
With their bite, they inject an anticoagulant, hirudin, particularly, and is due to toxins which have not yet
and other unknown substances. In non-sensitized been identified.
subjects, the wound bleeds and heals slowly. In allergic
subjects, urticarial, blistering, or necrotic and even Contad Dermatitis from Bait
anaphylactic reactions may onset.
Fishermen using lines may, albeit rarely, present a
Sea Bather's Eruption peculiar contact dermatitis (Angelini et al. 1989;
Angelini and Vena 1991). This affects the fingertips,
Sea bather's eruption is due to various coelenterates, periungual area and nails of the left hand and presents
induding the jelly fish Linuche unguiculata and the sea with desquamation, ragades and onycholysis. This
anemone Edwardsiella lineata. Dermatitis may follow painful dermatitis is provoked by a sea worm used as
bathing in salt water or subaqua or surfing activities. It bait, onsets 10-24 h after contact and resolves when
presents during or after swimming with papules having contact is interrupted. Up until now, this dermatitis
a pustulous and vesicular evolution, together with has been described only on the co asts of the Mediter-
malaise, fever, nausea, headache, abdominal pain, ranean, and has been attributed to some annelids like
diarrhea. It mainly affects covered areas. Removal of Nereis diversicolor and Lumbrinereis impatiens (Mon-
the costume and showering straight after swimming tel and Gouyer 1957; Moureaux 1986; Baran 1987).
limits the entity of the dermatitis, which has a While hooking fragments of the bait, the coelomic
spontaneous evolution lasting about 2 weeks (W ong liquid impregnates the fisherman's fingers causing the
et al. 1994). above dinical picture, which may weIl be considered a
protein contact dermatitis.
Marine Annelid Dermatitis
Reactions to Fish
A variety of very common species belong to the
Polychaeta dass, induding Hermodice carunculata
There are various species of poisonous fish that
possess specialized organs (an apparatus or glandular
Table 6. Differential diagnosis between eerearial dermatitis (CD),
"sea bather's dermatitis" (SBD) and seaweed dermatitis (SD) structure) for secreting toxie substances. They belong
to two different dasses: the Condroitti (sting-rays) and
CD SBD SD Osteoitti (weever-fish, scorpion-fish, morays)
(Table 7).
Habitat Ubiquitous Atlantie eoast Hawaii,
Caribbean
The most likely contact in our seas is with sting-
Etiology Cereariae Cnidaria larvae Algae rays and weever-fishes. These fish, wh ich live on
Type of water Mainly fresh Sah Fresh and salt sandy bottoms half-hidden under the sand, sting man
Cutaneous sites Exposed Covered Covered
with their spines when they are trodden on inadver-
Table 7. Fish with toxie eharaeteristies
Class Order Family Species
Condroitti Rays (sting rays) Dasyatidae Dasyatis pastinaca

Dasyatis violacea
Dasyatis centroura
Osteoitti Traehinidae (weever fish) Trachinus araneus
Trachinus draco
Trachinus vipera
Trachinus radiatus
Seorpaenidae (seorpion fish) Scorpaena porcus
Scorpaena scrofa
Scorpaena ustulata
Scorpaena dactyloptera
Muraenidae (morays) Muraena helena
242 G. Angelini
tendy or handled wrongly. The resulting symptoms has a strong hemolytic action on other fish but is not
can be very severe (Fisher 1978; Weiller and Genolier- toxic to man.
WeiHer 1987a,b; Angelini and Vena 1991). The pain is Many fish of the Gammistidae family, known as
instantaneous, constant and extremely fierce; it irra- soapfish, produce toxic skin secretions. The toxin
diates around the limb within a few minutes and involved is gammistine. A known species found in the
persists for 24-48 h. In all cases, it is so violent as to Virgin Isles and Puerto Rico is Rypticus saponaceus,
provoke malaise, lipothymia and loss of function of contact with which produces an acute dermatitis with
the limb. The wound generally appears slight and itching and burning.
falsely reassuring. The type of wound can help to
identify the precise species: an extensive, lacerated
Sea Louse Dermatitis
wound suggests a sting-ray and is most frequent on
the legs and or arches of the feet; whereas, a po in ted,
Water skiers, skin divers and swimmers in the waters
copiously bleeding wo und, localized on the feet or
of southern California have experienced bites from
hands, is likely caused by a weever-fish. The pain will
"sea lice" and the relative "sea louse dermatitis"
be followed by an inflammatory reaction with is-
(cymothoidism) (Best and Sablan 1964). Sea lice, small
chemie necrosis, pallor, cyanosis and serohematic
marine crustaceans of the Isopoda order, Cymothoidea
blisters.
sub order, inhabit the shoal waters of tropical and
The tearing pain provokes anguish, tachycardia,
temperate estuarial shorelines. Cymothoids have a
dyspnea and hypotension; neurological symptoms can
powerful biting apparatus and attack even human
sometimes present with vertigo, parasthesia, muscular
extremities. The bite is rapid and sharp, causing
spasm, convulsions and delirium. The treatment must
punctate hemorrhagic wounds. The affected site
be immediate and expert, and carried out at the site of
should be treated with hydrogen peroxide and antibi-
the accident (Table 8).
otic ointments.
The toxic activity of morays, and particularly
Muraena helena, has not yet been established. Contact
with morays occurs generally during capture and Fish with Mechanical and Eleetric Defense Mechanisms
handling of the fish. Local pain from a moray sting is
intense and burning, and may be associated with Fish which can cause mechanical injuries to man
breathlessness and collapse. belong to the Ray, Shark and Eel orders. Shark injuries
are fairly well known; these are the only marine
Dermatoses from Other Macroscopic Organisms animals that may attack humans without any provo-
cation. It is generally held that all species longer than
Soapfish Dermatitis 1.5 m should be considered potentially harmful to man,
especially with the presence of food or blood in the
Among toxic fish, some produce toxins in the skin water.
glands to repel attack. The discovery of toxic skin The family of Torpedinidae, of the Ray order, is
secretions in fish was made during chance observa- characterized by fish with kidney-shaped electric
tions of irritations on the hands due to touching these organs arranged one on each side of the spine. These
fish, and from having seen other fish die if placed in electricity-producing organs can produce shocks up to
the same tank. Many tropical fish are toxic. From the 220 V. In emergency situations, electric-rays use an
Ostracion lentiginosus species ("boxfish"), a toxin even higher voltage and amperage; as the charges
called pahutoxin (from the Hawaiian name "pahu," continue to be emitted, their power diminishes. On the
after the fish which produces it) has been isolated; it muddy or boggy bottoms of the Mediterranean, there
are three types of rays: Torpedo torpedo, T. marmorata
and T. nobiliana, the largest species, which can attain a
Table 8. Principles of treatment of the reactions to fish spines
length of 1.80 m and a weight of about 70 kg.
Wash the area with sah water Injury occurs by means of direct or indirect contact
Debride the wound and remove spine residues during capture and handling of the animal. In fact, if a
Use a tourniquet in case of limb involvement skin diver touches his metal rod after having har-
Soak the wound in hot but not scalding water for 30-90 min
or until pain is relieved. The water should be kept as hot pooned an electric ray, he will get an electric shock
(45°C) as the patient can bear, and the treatment should more or less proportional in power to the size of the
be started as soon as possible animal. The shock is not generally such as to cause
In cases of face or body involvement, hot moist compresses
or irrigation with heated fluids can be employed (the heat direct skin or nerve lesions, apart from a slight state of
may have an attenuating effect on the heat-labile stupor induced by very large animals. The greatest
components of the venom) danger to the diver may be abnormal, incorrect
Systemic treatment at a trauma center is mandatory
emersion due to loss of awareness or panic caused
by the unexpected shock, occurring in an unfavorable Histological findings are generally aspecific, and it is
environment. very difficult to isolate the larva histologically because
they are very often situated beyond the visible lesion.
Larva Migrans Cutanea The derma shows an aspecific infiammation and the
presence of eosinophils.
In man, larva migrans cutanea ("creeping eruption"), a Cryotherapy with liquid nitrogen or carbon dioxide
dermatitis caused by the migration of parasites snow is usually efficacious in very mild infestations,
through the skin, is caused by nematoda larvae, but it must be performed for a fair depth beyond the
induding the Ancylostoma brasiliense and Uncinaria site of progression apparent at the visible lesion. Good
stenocephala species and perhaps Ancylostoma cani- results have also been obtained using topical
num. These nematodes are natural parasites of dogs thiabendazole in 10% suspension or 2% in dimethyl-
and cats. The affiiction is most commonly observed in sulfoxide. In cases characterized by diffuse lesions, oral
the tropical and subtropical areas, particularly South thiabendazole at doses of 20-50 mg/kg/day for 7-
Africa, the Par East, Central America and southern 10 days may be used (Stromberg and Christie 1976).
parts of the USA. In Europe, and generally in temper-
ate zones, autochthonous cases of creeping eruption Protothecosis
are less frequent. üf the six cases observed in our
department, only one was imported, that being in a Protothecosis is a skin or systemic infection caused by
nun who had stayed in Kenya (Loewental and Leeming the Prototheca, an achlorotic mutant of the green
1969; Angelini and Vena 1991). seaweed Chlorella. Prototheca is found in seas and in
Man can become part of the parasitic life cyde as a fresh and sewage waters. Pathogenic species for man
temporary host. The larva is not able to penetrate are Prototheca segbwema and P. wickerhamii. The
beyond the derma, probably because it lacks the affiiction has been observed in man in the U.S.A. and
necessary enzymes. Hence, in man the larvae migrate in South Africa, and in farm animals in Germany.
in the epidermis or between the derma and the The initial lesion on penetration is a pruriginous
epidermis. In these areas, progression of the larvae papule. An area of dry, atrophie and depigmented skin
varies from a few millimeters to some centimeters per later develops, borde red by well-defined papulo-nod-
day. The larvae migrate for biologie al purposes, since ular margins. Verrucous lesions similar to those
they need to reach the host intestine, where the second observed in elephantiasis can also be observed. This
phase of the life cyde terminates and the adult parasite condition is resistant to all local and systemic treat-
can take hold. Migration of a single larva is therefore ment, induding X-ray treatment, and the only possible
limited in time: most die within the space of a month, treatment is surgery before the organism disseminates
although longer survival is possible (up to 6 months). in the lymphatic system. The infestation is probably
There are also cases of "larva currens," induced by contracted by walking through marshy areas with bare
larvae of Strongyloides stercoralis, in which the speed feet, by exposure to water contaminated by sewage, or
of progression is 10 cm per day. by exposure to contaminated aquariums.
The skin sites most commonly affected by this
parasite are those which come into contact with the Reactions to Marine Bacteria
earth, i.e., feet, hands and buttocks. Localization in the
oral mucosa has also been reported. Damp and sandy Mycobaderiosis
terrain, contaminated by the feces of dogs and cats, is
the ideal environment for egg maturation and survival Mycobacterioses are most commonly infections due to
of the larvae. Those most commonly affected by this Mycobacterium marinum (M. balnei), a slow growing
disease are generally bathers, agricultural workers, (5-14 day) photochromogen belonging to group I of
gardeners and sewage-farm workers. Runyon's dassification with an optimal environmental
The incubation time varies and may last a few temperature of 25-30 °C (lower than skin temperature,
months. In most cases, 24-48 h after penetration of the which is why the bacillus only causes skin disease).
larvae, the entry site shows an erythemato-papular The M. marin um can be found in both salt and fresh
lesion with one or more tunnel-like formations radi- water, preferably temperate, and causes disease in fish
ating out from it. The linear lesion is about 2-mm to 4- and man. In the latter case, the infection manifests
mm wide, of a more or less intense reddish color, and most often in the form of "swimming pool granuloma"
only slightly more raised than the surrounding skin. or "fish tank granuloma" (Angelini et al. 1990b, 1995a,
Itching, pain and pustular lesions are sometimes also b; Angelini and Vena 1991, 1997).
present. In swimming pools it is easiest to find M. marinum
The affiiction is self-healing and the larvae stay in near the entry valve and on the pool walls. The bacillus
the skin for a time ranging from 10 days to 55 weeks. is only destroyed by high concentrations of chloride
244 G. Angelini
(1-10 mg/I). Swimming pool infections give rise to why it is most often observed in fishermen and
granulomas localized mainly on the elbows and knees. butchers. It has also been reported in housewives
Fish tank granuloma can be professional (workers in pricked by fish or chicken bones. Erysipeloid generally
charge of aquarium maintenance) or non-professional onsets in late summer when animal infections are most
(due to cleaning the horne aquarium). The sites common. About 3 days after contagion, the puncture
involved are the hands and forearms. Apart from area develops a dark, erythematous raised area with an
clinical forms with a single plaque, sporotrichoid irregular centrifugal extension and distinct, raised
forms are frequently observed with nodules having a polycyclical margins. The sites most commonly in-
"rosary-like" spread and ulcerative evolution (Fig. 2). volved are the hands and forearms but all exposed
The incubation period of the infection is 2-3 weeks. areas may be affected. In 10% of cases, fever onsets;
There are no generalized symptoms or regional pricking and itching sensations and pain may be
adenopathy. The PPD of M. marinum is always present. The area affected may reach a maximum
positive, while the PPD of M. tubereulosis may be diameter of 10 cm and will resolve spontaneously in 2-
positive or weakly positive. Culture of biopsy or 3 weeks (Burnett 1962; Barnett 1983).
aspirated material in Löwenstein-Jensen culture medi- Apart from this modest, localized form, a general-
um at 30°C gives positive results in 70-80% of cases. ized skin condition is observed in rare cases, as weIl as
Tampons of material from the lesions, stained with systemic forms with endocarditis. Differential diagno-
Ziehl-Neelsen, and the search for bacilli in the biopsy sis must be made with erysipelas, afebrile streptococ-
are almost always negative. In some cases it is only cal infection with a rapid extension. The disease does
possible to isolate the bacillus in the dead fish in the not leave any immunity and re-infection is therefore
aquarium or in the aquarium filter. The histological possible. The bacteria responsible can be cultured from
picture of the granuloma shows an aspecific inflam- bioptic cells obtained from the margins of the lesion or
matory infiltrate in the first few months, while older from the blood in systemic forms. The disease can be
lesions are usually characterized by a granulomatous treated with penicillin or tetracycline for 1 week.
structure.
Effective drugs for the treatment of the infection are Infeded Wounds
minocycline, tetracycline, rifampicyn, isoniazide and
sulfamethoxazole; polytherapy is advisable in any case. Sea water is a diluted suspension of bacteria, many of
which are harmful to man and cause various infections
(externaIotitis, gastroenteritis, pneumonia). Wounds
Erysipelothrix Dermatitis occurring in the marine environment from any cause
may therefore evolve very easily into infection. The
Also known by the name of Baker-Rosenbach's micro-organisms isolated from infected wounds in-
erysipeloid, Erysipelothrix dermatitis is an acute, clude bacteria present in sea water (vibrioni, Entero-
rarely chronic, infection induced by Erysipelothrix bacter, Eseheriehia eoli, pseudomonas, Aehromobaeter
rhusiopathiae, a non-sporigenous, non-mobile gram- xylosoxidans, Acinetobacter ealeoaeetieus) and normal
positive bacillus which usually has long filaments. It is skin flora (staphylococci, streptococci). The treatment
a frequent infection in pigs, horses, sheep, turkeys and of wounds infected by marine micro-organisms in-
other animals and in salt and fresh water fish. That is cludes debridement of necrotic tissue, removal of
Fig. 2. Sporotrichoid fish -tank granuloma in

aquarium maintenance worker
foreign bodies, drainage of abscesses and irrigation the combination of friction and the abrasive action of
with saline or antiseptic solutions. If necessary, anti- the salt (abrasion and salt are, in fact, a weH known
tetanus injections should be given and systemic method for removing tattoos). Surfers' nodules are
antibiotic treatment. tendinous cysts which occur foHowing repeated fric-
tion. External otitis is an acute bacterial infection of
the external ear favored by the macerating effect of the
Aquatic Dermatology for Chemical water and the persistent humidity inside the ear.
and Physical Causes Clinical signs are pain, exudation, itching and some-
times fever and impaired hearing. The most common
Apart from the conditions described until now, there cause is Pseudomonas aeruginosa.
are various other dermatological pictures connected in
some way with salt or fresh water contact or with Fresh-Water Dermatitis
aquatic activities (Table 9) (Hicks 1977). Affiictions
favored, induced or aggravated by exposure to the sun, Swimming pools with chlorinated water have a drying
as weH as those which may gain benefit from such effect on the skin and hair, which is particularly
exposure, are beyond the scope of this chapter, evident in atopical subjects. Depending on the con-
although exposure to the sun is certainly inevitable centration, chlorine has a bleaching effect on the hair,
in subjects carrying out aquatic activities for short- or which is most evident in blonde subjects and during
long-term periods. the summer months because of the combined action of
the sun. Greenish coloring of the hair may occur in
Contact Dermatitis blonde subjects who often swim in pools with a high
chlorine content; shampooing the hair immediately
Contact dermatitis from swimming attire, caused by after swimming is the best prophylaxis.
sensitization to the elastic (rubber additives) or dyes is Temporary chemical conjunctivitis (so-caHed "red
a rare event. Contact dermatitis from marine eyes") is observed in subjects who swim with their eyes
equipment may be due to professional or amateur open.
activities and induced by masks, goggles, snorkels, fins
and rubber wet suits. The aHergenic substances Dermatitis Associated with Subaquatic Activities
involved are mercaptobenzothiazole, thiourams,
dithiocarbamates, paraphenylenediamine, thioureas, Notoriously, professional or amateur skin divers are
formaldehyde, butylphenolformaldehyde resins, iso- exposed to an enormous variety of risks, including
propylphenyl-paraphenylenediamine. In sensitized skin problems. Staphyloccocal skin infections are
subjects, snorkels can also cause oral infiammation, relatively frequent and also difficult to treat. Local
which generally starts with a mild, intermittent feeling burns can derive from overheating inside the wet suit.
of burning when ingesting hot drinks or spicy foods. Underwater welding procedures can induce erythemas
and telangiectasia. The skin trapped in the folds of the
Salt-Water Dermatitis suit can present linear abrasions.
During decompression, the diver may notice itching,
Prolonged immersion in sea water causes electrolytic with or without an urticarial eruption, localized
alterations due to percutaneous absorption (immer- prevalently on the trunk. If remaining under water
sion syndrome). Occasionally, in the areas where the for long periods of time, the diver may develop a
swimming attire adheres most tightly, a skin peeling dermatitis of "napkin eruption" type, due to having to
effect may occur, which can evolve into ulcers due to attend to physiological needs (Malpieri 1988).
Table 9. Various skin diseases of aquatic origin
General Sunburn, aquagenic urticaria, cold urticaria, contact dermatitis (from swimming attire,
fishing equipment)
Sea water Immersion syndrome, abrasive effect, surfer's noduIes, external otitis
Fresh water Micosis, verrucas, chlorine irritations, chapping in atopical subjects
Swimming pool Green hair coloring, hair bleaching, chemical conjunctivitis, externaiotitis
Jacuzzi/hydromassage FollicuIitis from pseudomonas
Sauna Miliaria, tinea versicolor
Running water Onchocerciasis
Shower Aquagenic pruritus
Subaquatic activities Externaiotitis, intertrigo, staphylococcal infections, burns, linear abrasions from wetsuit
folds, pruritus and erythema from decompression, "napkin eruption" type dermatitis
246 G. Angelini
Aquagenic Urticaria References
This is an exceptional form of urticaria from a physical Angelini G, Bonamonte D (1997) Dermatoses aquatiques Medi-
terraneennes. Nouv Dermatol 16:280-286
agent, evoked simply by the skin contact with the water Angelini G, Vena GA (1991) Dermatologia Aequatiea. Lepetit,
at body temperature. The lesions are punctiform, 2- Milano
3 mm in diameter, in the follicular sites. They onset Angelini G, Vena GA (1997) Dermatologia Professionale e
Ambientale. ISED, Brescia
between a few minutes and 1 h after contact and Angelini G, Giglio G, Filotieo R, Vena GA (1989) Dermatite da
regress after about 0.5 h. The diagnosis can be eontatto eon Nereis diversicolor. In: Dermatologia in poster.
confirmed by applying gauze compresses soaked in Ayala F, Balato N (eds) Cilag SpA, Naples
Angelini G, Vena GA, Meneghini CL (1990a) Oeeupational
tap or distilled water at 35-36 °C for 30 min. The traumatie lymphedema of the hands. Dermatol Clin 8:205-208
re action appears to be mediated by histamine and Angelini G, Filotieo R, De Vito D, Vena GA (1990b) Infezioni
acetylcholine. Differential diagnosis is necessary with eutanee professionali da Mycobacterium marinum. Boll
Dermatol Allerg Prof 5:165-175
other clinical forms provoked directly or indirectly by Angelini G, Vena GA, Filotico R, Foti C (1990e) Linfedema
contact with water (Table 10). Antihistamine treatment traumatieo oeeupazionale delle mani. Boll Dermatol Allerg
is not very effective; the symptoms can be prevented by Prof 5:75-82
Angelini G, Vena GA, Grandolfo M (1995a) Mieobatteri e eute.
drying the skin rapidly. 1° parte. Dermotime 7:11-20
Angelini G, Vena GA, Grandolfo M (1995b) Mieobatteri e eute.
2° parte. Dermotime 7:4/5:11-19
Cold Urticaria Audebert C, Lamoureux P (1978) Eezema professionnel du marin
peeheur par contaet de Bryozoaires en Baie de Seine. Ann
Dermatol VenereoI105:187-192
Cold urticaria can present under various guises Baran R (1987) Dermatite des peeheurs-amateurs. La lettre du
(familial, acquired, immediate, delayed, localized and G.E.R.D.A. 4:27-29
systemic). The acquired form is the most common. It Barnett JH (1983) Erysipeloid. J Am Aead Dermatol 9:116-123
Best WC, Sablan RG (1964). Cymothoidism (sea louse dermatitis).
can onset at any age, particularly in young adults and
Areh Dermatol 90:177
in females. The lesions affect sites exposed to the cold, Bonnevie P (1948) Fishermen's "Dogger Bank Iteh" allergie
including cold water, within a few minutes of contact eontaet eezema due to coralIine Alcyonidium hirsutum, the
sea-ehervil. Aeta Allergoi 1:40-46
and persist for several hours. In cases with diffuse
Burnett JW (1962) Uneommon baeterial infeetions of the skin.
manifestations, after swimming for instance, breath- Areh Dermatol 86:597-607
lessness, headache, tachycardia, vertigo and even Burnett JW, Calton GI, Burnett HW (1986a) Jellyfish envenom-
ation syndromes. J Am Dermatol 14:100-106
shock may be present. The diagnosis is confirmed by
Burnett JW, Calton GI, Morgan RJ (1986b) Venomous sea
pressing an ice-cube against the flexural surface of the urehins. Cutis 38:151
forearm for 5-20 min. Burnett JW, Calton GI, Morgan RJ (1987) Venomous eoelenter-
ates. Cutis 39:191-192
Fisher AA (1978). Atlas of Aquatie Dermatology. Grune and
Stratton, New York
Aquagenic Pruritus
Fisher AA (1987) Toxie and allergie eutaneous reaetions to
jellyfish with special reference to delayed reactions. Cutis
Aquagenic pruritus is characterized by intense stinging 40:303-305
or burning and itching due to contact with water, Gianotti F, Invoni R (1958) La patologia eutanea degli addetti alla
monda e al trapianto dei riso. Studio eziopatogenetieo eon
regardless of its temperature, and without any objec- partieolare riguardo ai rilievi parassitologici deli' ambiente.
tive signs. It lasts from 10-120 min and can manifest Giorn It Derm 99:377-382
during bathing or after getting out of the water, and Grauer FH, Arnold HL (1961) Seaweed dermatitis. Areh Dermatol
84:720-732
involves mainly the limbs. The pathogenetic mecha- Hieks JM (1977) Swimming and the skin. Cutis 19:448-450
nism is not really known. Antihistamines are only Jeanmougin M, Janier M, Prigent F (1983) Eezema de contaet avee
partially effective. a
photosensibilite Alcyonidium gelatinosum. Ann Dermatol
Venereolllo:725-726
Jeanmougin M, Lemarehand-Venencie F, Hoang XD, D'Hondt JL,
Civatte J (1987) Eezema professionnel avee photosensibilite par
Table 10. Skin reaetions direetly (*) or indireetly CO) (pseudo- eontaet de Bryozoaires. Ann Dermatol VenereoI1l4:353-357
aquagenie reaetions) due to contaet with water Loewental LJA, Leeming JAL (1969) Cutaneous larva migrans.
Essay on tropical dermatology. Exeerpta Mediea Foundation,
Reaetion Causal agent Amsterdam
Malpieri M (1988) Medieina Subaequea. Leadership Mediea 4:
Aquagenie pruritus (*) Water 12-16
Aquagenie urtiearia Water Mansson T, Randle HW, Maudojana RM, Calton CJ, Burnett JW
Cholinergic urtiearia (0) Bathing or swimming in (1985) Recurrent cutaneous jellyfish eruptions without en-
warm water venomation. Aeta Derm Venereol 65:72-75
Aequired eold urtiearia (0) Cold water Maretee Z, Russel FE (1963) Stings by the sea Anemonia sulcata in
Loealized heat urtiearia (0) Hot water the Adriatie sea. J Trop Med Hyg 32:891-894
Symptomatic dermographism (0) Shower jet, towel frietion Meneghini CL (1972) Cases of sea urehin granuIoma with positive
Polyeythemia vera (*) Water intradermal test to spine extraets. Contaet Dermatitis News-
letter 12:316
Molfino F, Zannini D (1964) L'uomo ed il mondo sommerso. Rosco MD (1977) Cutaneous manifestations of marine animal
Medieina Subacquea. Minerva Mediea, Torino injuries including diagnosis and treatment. Cutis 19:
Montel RL, Gouyer E (1957) L'escavenite. BuH Soc Franc Derm 507-510
Syph 64:672 Stromberg BE, Christie AD (1976) Creeping eruption and
Moore RE, Scheurer PJ (1971) Palytoxin: a new marine toxin from thiabendazole. Int J Dermatol 15:355-358
a coelenterate. Seience 172:495 Vemura D, Ueda K, Hirata Y (1981) Further studies on palytoxin.
Moureaux P (1986) Dermatite de contact aux proteines animales 11. Structure of palytoxin. Tetrahedron Lett 22:27
(a propos de 2 cas). La Lettre du G.E.R.D.A. 3=73-74 WeiHer M, Genolier-WeiHer A (1987a) Aceidents cutanees pro-
Portier P, Riehet C (1902) Sur les effets physiologiques du poison voques par la faune sous-marine Mediterraneenne. Premiere
des filaments pecheurs et des tentacules des Coelenteres partie. Nouv Dermatol 6:331-337
(hypnotoxine). CR Acad Sei (Paris) 134:247 WeiHer M, Genolier-WeiHer A (1987b) Accidents cutanees pro-
Reed KM, Broustein BR, Baden HP (1984) Delayed and persistent voques par la faune sous-marine Mediterraneenne. Deuxieme
cutaneous reactions to coelenterates. J Am Acad Dermatol partie. Nouv Dermatol 6:354-357
10:462-466 Wong DE, Meinking TL, Rosen LB, Taplin D, Hogan DJ,
Riehet C (1903a) Des poisons contenus dans les tentacules des Burnett JW (1994) Sea bather's eruption. Clinieal, histologieal
actinies (congestine et thalassine). CR Soc Biol 55:246 and immunologie features. J Am Acad Dermatol 30:
Richet C (1903b) De la thalassine, toxine crystallisee pruritogene. 399-406
CR Soc Biol 55:707
CHAPTER 29
Occupational Skin Cancer and Tumors

C.P. Callahan, H.F. Merk, and B. Blömeke
Introduction Freedman et al. 1997; Suzuki et al. 1997; Lear et al.

1998). Although it would appear obvious that outdoor
Over the past four decades, the cases of skin cancer workers, who have a greater exposure to ultraviolet
have dramatically increased (Ko et al. 1994). This radiation, would have an increased risk of cancer,
phenomenon is most commonly attributed to a greater results of recent studies have been conflicting. Freed-
exposure to sunlight due to the depleting ozone layer man et al. (1997) reported that for outdoor (non-
and sunbathing, but may also include incidents of farming) workers in 24 states of the U.S., the risk of
occupational skin cancer. Of the three main types of occupational exposure for skin cancer was slight
skin cancer - malignant melanoma, basal cell carcino- compared with indoor workers. This finding was
ma (BCC) and squamous cell carcinoma (SCC) - SCC attributed to variations in occupations among different
has been reported in greater numbers for occupational regions. Green et al. (1996) also found a lack of
skin cancer (Letzel et al. 1992; Gallagher et al. 1996). correlation between skin cancer and outdoor work.
Until recently, it has been difficult to determine the They reasoned that those with skin types less suscep-
exact role of chemical carcinogens on those patients tible to skin cancer were more likely to choose outdoor
with SCC due to the fact that those patients with work than those with skin types at a greater risk for
occupational exposure to chemical carcinogens also skin cancer.
experience daily ultraviolet (UV) light exposure. In contrast, the study carried out by Lear et al.
However, the new field of molecular epidemiology (1997) showed that there was a significant association
may aid in this investigation. between skin cancer and outdoor occupation for
This approach is based on the discovery that patients in the West Midlands, England. Suzuki et al.
carcinogens cause specific mutations in tumors. The (1997) also reported a greater incidence of actinic
unique pattern in UV-induced skin cancers has been keratosis (AK), a precancerous form of skin cancer, in
identified in the p53-tumor-suppressor gene (Brash outdoor workers in Kasai City, Japan. Due to the
et al. 1991; Reid et al. 1992; Somers et al. 1992; Moles inconclusive nature of these reports, we will not
et al. 1993; Ziegler et al. 1993; Nakazawa et al. 1994), a consider outdoor work (with ultraviolet light as the
key gene which is mutated in more than 50% of all main carcinogen) as a form of occupational skin
tumors (Greenblatt et al. 1994; Hollstein et al. 1991, cancer.
1996). The specific mutations can then be used as a
molecular marker for UV-induced skin cancer. We
hypothesize that such an indicator can also be found Malignant Melanoma, Basal Cell Carcinoma
for tar-induced (one example of chemically-induced) and Squamous Cell Carcinoma
SCC skin tumors, which can be differentiated from the
genetic marker for UV -induced skin tumors. This Of all reported cases of skin cancer, 10% are diagnosed
proposed study will produce a clearer picture as to the as malignant melanoma, and 95% of all reported deaths
exact nature of occupational skin cancer caused by taro from skin cancer are from malignant melanoma
In addition, it will provide further evidence as to the (Armstrong and Kricker 1994). The etiology of malig-
use of molecular epidemiology in cancer risk assess- nant melanoma is still unclear. It is unlikely that
ment. chemical carcinogens are a major cause of melanoma
In this chapter, occupational skin cancer will be development, but it does show a strong association with
defined as those skin cancers induced by chemical UV exposure. A few studies have addressed occupa-
carcinogens in the workplace. Many studies have tional exposure to non-solar radiation. These investi-
considered the relationship between sunlight-induced gations showed that there is a significantly increased
skin cancer and outdoor occupation (Green et al. 1996; risk of melanoma for workers exposed to printing

Occupational Skin Cancer and Tumors 249
lights, welding-torch light (Elwood et al. 1986) and controversial. Arecent study by Pambor (1997) inves-
fluorescent lights (Beral et al. 1982; Walter et al. 1992). tigated a case of SCC due to occupational exposure of
Non-melanoma skin cancer (NMSC), the most welding torch lights. However, Bajdik et al. (1996)
common form of skin cancer, can be divided into reported that non-solar UV radiation does not produce
two groups: BCC and Scc. It is estimated that for any significant risk of Scc. Arecent study by Gallagher
countries such as the U.S. or Australia, 2% of the et al. (1996) reported a variety of chemical carcinogens
population over the age of 60 years will develop NMSC found in the workplace that increased the incidence of
(Quinn 1997). Although both BCC and SCC have a low SCC, including herbicides, insecticides, fungicides,
mortality rate (Quinn 1997), they have a great social grain or coal dust, petroleum products, grease, and
importance due to the cost of treatment and the diesel fumes. The two main sources of occupational
increased morbidity rate. BCC makes up 75-80% of chemical carcinogens are arsenic and polycyclic aro-
reported cases of NMSC (Yiannias et al. 1988) and is matic hydrocarbons (P AHs) (Emmet 1975; Everall and
the most common form of cancer among Caucasians Dowd 1978; Urbach 1980; Urbach 1982).
(Chuang et al. 1990). It is known that BCC located on
the face is critically related to UV exposure (Kricker
et al. 1993; Kripke 1994; Karagas and Greenberg 1995), Arsenic
but the exact nature of the association is not well
understood and is less clear than in the case of SCC. Arsenic, most commonly used as arsenic (III), is
The majority of truncal BCCs appear on parts exposed involved in processes associated with glass works;
to light, with 90% of tumors located on the neck and copper, zinc and lead smelters; the production of
face in Caucasians (Mora and Robins 1978). Recent pesticides and herbicides; and semiconductors
studies present some evidence that BCC may be (Hartwig et al. 1997). Although the commercial use
affected by carcinogens other than UV radiation and production of substances containing arsenic have
(Kricker et al. 1993; Karagas and Greenberg 1995; decreased over the past few decades (Hartwig et al.
Gallagher et al. 1996; Lear et al. 1997). Evidence from 1997), it is still an occupational hazard. In March of
Kricker et al. (1993) and Karagas and Greenberg (1995) 1998, the German employers' insurance company
show that BCCs are more commonly found on reported 34 total accepted cases of diseases, including
less-sun-exposed sites than SCCs. Lear et al. (1997) cancer, related to arsenic or its compounds from 1994
reported that about 20% of the patients in their study to 1996 (Arbeitsmed Sozialmed Umweltmed 1998).
with BCCs have at least one tumor on apart of the Arsenic is a puzzling carcinogen and difficult to
body less exposed to light. Lear et al. suggested that study because it does not cause tumors in laboratory
susceptibility factors such as genetic polymorphism in animals. Studies have associated arsenic (most often
metabolic enzymes may influence this disease. Recent sodium arsenite) with an induction of gene amplifica-
results indicate that BCCs on the trunk are due to a tion, an inhibition of DNA repair, an arrest of cells in
mutation in the PTCH gene, the human homologue of mitosis, and an expression of heme oxygenase, the
the Drosophila patched gene, which acts as a tumor oxidative stress protein, and the c-Jos gene (Lee et al.
suppressor (Chidambaram et al. 1996; Gailani et al. 1988; Keyse et al. 1990; Vega et al. 1995). In addition, it
1996; Unden et al. 1996). The mutation might also has been reported that arsenic works as a mutagen in
occur in the gene of the receptor of the PTCH gene combination with other substances or carcinogens,
product. Gallagher et al. (1996) found that there were such as UV radiation (Cavigelli et al. 1996; Hartwig
few significant associations between BCC and specific et al. 1997). Arecent report by Hei et al. (1998) found
chemical carcinogens, i.e., dry cleaning fluids, fiber- that arsenic is in fact a strong mutagen that causes
glass dust and luminous paint. However, since there large, chromosomal mutations.
were relatively few subjects exposed to these carcino-
gens, further studies are required.
Occupational skin cancer is most commonly associ- Polycyclic Aromatic Hydrocarbons
ated with SCC. Statistics and studies on SCC may
underestimate the incidence rate of this disease PAHs comprise a large group of chemical carcinogens
because of its long latency period. Case history must found in the workplace. This group of hydrophobic,
be assessed carefully in order not to miss the exposure non-polar compounds is formed by a pyrolitic process,
to an occupational carcinogen 20-30 years before. SCC such as the combustion of organic compounds (IARC
is particularly dangerous due to its ability to metasta- 1983). PAHs are made up of two or more benzene rings
size and spread to the lymph nodes (Headington 1978). and are exemplified by the chemical benzo[a]pyrene
Occupational SCC is mainly induced from chemical (IARC 1983). Workers are exposed to PAHs mainly
carcinogens. However, results for occupational non- from inhalation, but also from skin contact (Bofetta
solar radiation exposure for SCC are limited and 1997). The highest exposure to PAHs (where PAHs are
250 CP. Callahan et al.
the main carcinogen) is found in coal gasification, individual cancer risks. Although Letzel et al. reported
aluminum production, iron and steel foundries, coke a less-intense association between UV light and tar-
production industries and occupations involved with induced skin cancer, they were unable to distinguish
diesel engine exhaust, carbon blacks, coal tars and between the two factors. In the future, molecular
other similar substances (Bofetta 1997). The study of epidemiology will allow scientists to investigate cancer
PAHs is complicated by the fact that they are often risk factors at a more specific level. Carcinogens such
found in a mixture of materials which might contain as UV light and tar damage DNA and can cause
other carcinogens. In addition, many investigations on specific genetic mutations regarding type, frequency
the association between PAHs and skin cancer are and location in cancer-related genes. Such mutation
incomplete due to the use of mortality data (Bofetta spectrums can be used to identify specific carcinogens
1997). This data underestimates the incidence of skin and the pathway with which they damage DNA (Harris
cancer because of the low mortality rate of SCC and 1996).
BCC. Therefore, of the studies reviewed by Bofetta
et al. (1997), only a few reported an increase risk in
skin cancer. Evidence was.found for workers exposed The pS3-Tumor-Suppressor Gene
to shale oil extraction, creosote, asphalt and roofing
material and chimney soot (Miller et al. 1986; Karich- The pS3-tumor-suppressor gene is ideal for the iden-
agen et al. 1992; Evanoff et al. 1993; Partanen and tification of genetic mutations in molecular epidemi-
Bofetta 1994). ological studies because it is mutated in over 50% of
tumors (HolIstein et al. 1991, 1996; Greenblatt et al.
1994). DNA damage and mutations are critical for
Tar-Refinery Workers tumor-suppressor genes such as pS3 because these
genes control cell growth and metastasis of malignant
In 1998, the German employers' insurance company cells (Bishop 1991; Harris 1991; Weinberg 1991). The
reported 15 accepted cases in 1996 of skin cancer due to pS3 gene has been associated with several cellular
tar, soot, raw paraffin, hard coal, pitch and similar functions, including DNA repair, programmed cell
materials. This was an increase from seven accepted death, cell-cycle control, differentiation, and genomic
cases in 1994 and nine in 1995 (Arbeitsmed Sozialmed plasticity (Lane and Benchimol1990; Levine et al. 1991;
Umweltmed 1998). These numbers are most likely Greenblatt et al. 1994). Molecular epidemiologie al
underestimated due to the fact that physicians are not studies have used the pS3 gene to investigate mutation
required to ask about possible occupational exposure. spectrums for cigarette smoke in lung cancer (Take-
Arecent study reported on the risk of skin cancer for shima et al. 1993), dietary aflatoxin B, in liver cancer
tar refinery workers (Letzel et al. 1992). The main (Bressac et al. 1991; Hsu et al. 1991) and ultraviolet
carcinogens found in tar and related materials are radiation in skin cancer (Rady et al. 1992; Stephenson
PAHs. However, several authors have reported that et al. 1992; Nagano et al. 1993; Kerschmann et aI. 1994;
tar-induced skin cancer is also affected by UV expo- Bito et al. 1995; Borkowski et al. 1996). Although pS3 is
sure (Ippen 1956; Fabry 1967; Braun-Falco et al' 1984; often mutated in SCC and BCC, it is rarely mutated in
Millard 1986; Hundeiker 1990). Tar-induced skin malignant melanoma. Mutations in pS3 have been
tumors are most likely found on those parts exposed found in up to 90% of SCCs compared to only 5%
to sunlight, with the exception of a high incidence of malignant melanomas (Brash et al. 1991).
tumors on the scrotum (Korting 1979-1981; Braun-
Falco 1984; Hundeiker 1990). More recently, a 1992
study by Letzel et al. showed that UV light might not Is p53 a Possible Marker for Occupational
playas important a role in tar-induced skin cancer as Skin Carcinogens?
previously thought. Although this study also reported
the majority of tumors on sun-exposed parts, such as Recent reports have identified the pS3 genetic marker
the head, many tumors were located on the inner for UV -induced skin cancer (Piercell et al. 1991; Rady
nostril and other less-exposed parts of the face. In et al. 1992; Bums et al. 1993; Moles et al. 1993). The
addition, several tumors were located on the underarm DNA mutations induced by UV light occur when UV
and the scrotum. radiation is absorbed by the DNA and pyrimidene
photoproducts are produced. The misrepair of the
photoproducts at dipyrimidine sites causes transition
Molecular Epidemiology mutations (Mitchell et al. 1992). CC to TT transition
mutations in the pS3 gene have been identified as the
The study by Letzel et al. (1992) exemplifies the unique molecular marker for UV-light-induced skin
weaknesses of classical epidemiology in identifying cancer (Brash et al. 1996) and the resulting mutation
spectrum is completely different from those of internal Beral V, Evans S, Shaw H, Milton G (1982) Malignant melanoma
tumors (Pierceall et al. 1991; Burns et al. 1993; Moles and exposure to fluorescent lighting at work. Lancet 2:
290- 293
et al. 1993). It was reported that 90% of SCCs Bishop JM (1991) Molecular themes in oncogenesis. Cell 64:
contained the genetic marker for UV light. However, 235-248
due to the difference in biology between BCC and SCC, Bito T, Ueda M, Ahmed NU, Nagano T, Ichihashi M (1995) Cyclin
D and retinoblastoma gene product expression in actinic
the specific UV -induced pS3 mutations were only keratosis and cutaneous squamous cell careinoma in relation
found in 50% of BCC tumors (Rady et al. 1992; Ziegler to pS3 expression. J Cutan Pathol 22:427-434
Bofetta P, Jourenkova N, Gustavsson P (1997) Cancer risk from
et al. 1993). occupational and environmental exposure to polycyclic
Studies have also identified a molecular marker for aromatic hydrocarbons. Cancer Causes Control 8:444-472
PAH-induced tumors. In lung cancer, PAHs found in Borkowski A, Bennett WP, Jones RT, Borkowski P, Harris CC,
cigarette smoke cause specific DNA mutations in so Ferreira LR, Kao GF, Trump BF (1996) Quantitative image
analysis of pS3 protein accumulation in keratoacanthomas.
called "hot spots" in the pS3 gene. The resulting Am J Dermatopathol 17:335-338
mutations, if not repaired, cause a transversion from G Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP
to T (Denissenko et al. 1996). (1991) A role for sun in skin cancer: UV -induced pS3
mutations in squamous skin cancer. Proc Natl Acad Sei USA
88:10124-10128
Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffell DJ
Conclusions (1996) Sunlight and sunburn in human skin cancer: pS3,
apoptosis, and tumor promotion. J luvest Dermatol Symp
Proc 1:136-142
Molecular epidemiological techniques can be applied Braun-Falco 0, Plewig G, Wolf HH (1984) Dermatologie und
to the investigation of the association between UV light Vernerologie. Springer, Berlin Heidelberg New York
Bressac B, Kew M, Wands I, Ozturk M (1991) Selective G to T
and tar-induced skin cancer. We hypothesize that one mutations of pS3 gene in hepatocellular careinoma from
will find a specific pS3 mutation spectrum for tar- southern Africa. Nature 350:429-431
induced skin cancer which can be differentiated from Burns JE, Baird MC, Clark LI, Burns PA, Edington K, Chapman C,
Mitchell R, Robertson G, Soutar D, Parkinson EK (1993) Gene
UV -induced pS3 mutations for skin cancer. Studies mutations and increased levels of pS3 protein in human
such as the one proposed will aid in future cancer risk squamous cell careinomas and their cell lines. Br J Cancer
assessments. 67:1274-1284
Cavigelli M, Li WW, Lin A, Su B, Yushioka K, Karin M (1996) The
Although, historically, classical epidemiology has tumor promoter arsenite stimulates AP-1 activity by inhib-
been used to study cancer risk, it has recently become iting a JNK phosphatase. EMBO J 15:6269-6279
apparent that there are several weaknesses in this field Chidambaram A, Goldstein AM, Gailani MR, Gerrard B, Bale SJ,
DiGiovanna JJ, Bale AE, Dean M (1996) Mutations in the
of study. Classical epidemiological analysis of carcin- human homologue of Drosophila patched in Caucasian and
ogens and their induced tumors are conservative in African-American nevoid basal cell carcinoma syndrome
nature due to the lack of clear understanding of the patients. Cancer Res 56:4599-4601
Chuang TY, Popescu A, Su WPD, et al. (1990) Basal cell
complex mechanisms involved with carcinogenesis careinoma: a population based ineidence study. J Am Acad
(Harris 1991; Barrett and Wiseman 1992). In contrast, Dermatol 22:413-417
molecular epidemiology provides a way to study Elwood JM, Williamson C, Stapleton PJ (1986) Malignant
melanoma in relation to moles, pigmentation, and exposure
cancer risk in detail. Occupational cancer risk is an to fluorescent and other lighting sourees. Br J Cancer 53:65-74
important public health and social problem that Emmet EA (1975) Occupational skin cancer-review. J Occup Med
requires further investigation into the best method of 17:44-49
Evanoff BA, Gustavsson P, Hogstedt C (1993) Mortality and
assessment. incidence of cancer in a cohort of Swedish chimney sweeps.
Br J lnd Med 50:450-459
Everall JD, Dowd PM (1978) lnfluence of environmental factors
Acknowledgement. The support of the START program excluding ultra-violet radiation of the incidence of skin
(RWTH Aachen) is gratefully acknowledged. cancer. Bull Cancer 65:241-247
Fabry H (1967) Sogenannte Pechhaut nach Einwirkung von
Verbrennungs- und Destillationsprodukten der Kohle. Be-
rufsdermatosen 15:198-209
References Freedman DM, Zahm SH, Dosemeei M (1997) Residential and
occupational exposure to sunlight and mortality from non-
Hodgkin's lymphoma: composite (threefold) case-control
Arbeitsmed Sozialmed Umweltmed (311998) Anzeigen auf study. BMJ 314:1451-1455
Verdacht einer Berufskrankheit und neue Berufskrank- Gailani MR, Stahle-BackdalIl M, Leffell DI, Glynn M, Zaphiropou-
heitenrenten nach Krankheitsarten. ASU Arbeitsmedizinische los PG, Press man C, Unden AB, Dean M, Brash DE, Bale AE,
Tafeln: BeKV Nr.u08, 5102:125-127 Toftgard R (1996) The role of the human homologue of
Armstrong BK, Kricker A (1994) Cutaneous melanoma. Cancer Drosphila patched in sporadic basal cell careinomas. Nat
Surv 20:219-240 Genet 14:78-81
Bajdik CD, Gallagher RP, Astrakianakis G, Hili GB, Fincharn S, Gallagher RP, Bajdik CD, Fincharn S, Hili GB, Keefe AR, Coldman
McLean DI (1996) Non-solar ultraviolet radiation and the risk A, McLean DI (1996) Chemical exposures, medical history,
of basal and squamous cell skin cancer. Br J Cancer 73: and risk of squamous and basal cell carcinoma of the skin.
1612-1614 Cancer Epidemiol Biomarkers Prev 5:419-424
Barrett JC, Wiseman RW (1992) Molecular careinogenesis in Green A, Battistutta D, Hart V, Leslie D, Weedon D, Nambour
humans and rodents. Prog Clin Biol Res 376:1-30 Study Group (1996) Skin cancer in a subtropical Australian
252 c.P. Callahan et al.
population: incidence and lack of association with occupa- Lee TC, Tanaka N, Lamb PW, Gilmer TM, Barrett IC (1988)
tion. Am 1 Epidemiol 144:1034-1040 Induction of gene amplification by arsenic. Science 241:
Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) 79-81
Mutations in the pS3 tumor suppressor gene: clues to cancer Letzel S, Drexler H, Lehnert G (1992) Teer-induzierte Praekan-
etiology and molecular pathogenesis. Cancer Res 54: zerosen und Malignome der Haut bei Beschaeftigten einer
4855-4878 Teer-Raffinerie. Dermatosen 40:94-101
Harris CC (1991) Chemical and physical carcinogenesis: advances Levine AI, Momand I, Finlay CA (1991) The pS3 tumour
and perspectives. Cancer Res 51:5023S-5044S suppressor gene. Nature 351:453-456
Harris CC (1996) pS3: at the crossroads of molecular carcino- Millard LG (1986) Multiple pigmented papular basal cell carci-
genesis and molecular epidemiology. 1 Invest Dermatol Symp nomas: a new pattern of industrial tar induced skin tumours.
Proc 1:115-118 Br lInd Med 43:143-136
Hartwig A, Groeblinghoff UD, Beyersmann D, Natarajan AT, Miller BG, Cowie HA, MiddIeton WG (1986) Epidemiologie
Filon R, Mullenders LHF (1997) Interaction of arsenic (III) studies of Scottish oil shale workers: III. causes of death. Am 1
with nucleotide excision repair in UV-irradiated human Ind Med 9:433-446
fibroblasts. Carcinogenesis 18:399-405 Mitchell DL, Ien 1, Cleaver IE (1992) Sequence specificity of
Headington IT (1978) Verrucous carcinoma. Cutis 21:207-211 cyclobutane pyrimidine dimers in DNA treated with solar
Hei TK, Liu SX, Waldren C (revised 511998) Mutagenicity of (ultraviolet B) radiation. Nucleic Acids Res 20:225-229
arsenic in mammalian cells: role of reactive oxygen species. Moles I-P, Moyret C, Guillot B, Ieanteur P, Guilhou 1-1, Theillet C,
Proc Natl Acad Sci USA (in press) Basset-Seguin N (1993) pS3 gene mutations in human
Hollstein M, Sidransky D, Vogels tein B, Harris CC (1991) pS3 epithelial skin cancers. Oncogene 8:583-588
mutations in human cancers. Science 253:49-53 Mora RG, Robins P (1978) Basal-cell carcinomas in the center of
Hollstein M, Rice K, Greenblatt MS, Sous si T, Fuchs R, Sorlie T the face. Special diagnostic, prognostic, and therapeutic
(1996) pS3 data base. Nucleic Acids Res 22:3547-3551 considerations. 1 Dermatol Surg Oncol 4:315-321
Hsu IC, Metcalf RA, Sun T, Welsh IA, Wang NI, Harris CC (1991) Nagano T, Ueda M, Ichihashi M (1993) Expression ofpS3 protein
Mutational hotspot in the pS3 gene in human hepatocellular is an early event in ultraviolet light-induced cutaneous
carcinoma. Nature 350:427-428 squamous cell carcinogenesis. Arch DermatoI129:1157-1161
Hundeiker M, BK-Nr.5102 (1990) Hautkrebs oder zur Krebsbil- Nakazawa H, English D, RandeIl PL, Nakazawa K, Martel N,
dung neigende Hautveraenderungen durch Russ, Rohparaf- Armstrong BK, Yamasaki H (1994) UV and skin cancer:
fin, Teer, Anthrazen, Pech oder aehnliche Stoffe. In: Kuehl M, Specific pS3 gene mutation in normal skin as a biologically
Klaschka F (eds) Berufsdermatosen. Urban und Schwarzen- relevant exposure measurement. Proc Natl Acad Sei 91:
berg, Muenchen-Wien, pp 119-124 360-364
International Agency for Research on Cancer (1983) Polynuclear Pambor M (1997) Multiple Plattenepithelkarzinome der Haut bei
aromatic compounds, part 1. ChemieaI, environmental and einem Schweisser. Dermatosen 45:229-231
experimental data. IARC Mongr Eval Carcinog Risk Chem Partanen T, Bofetta P (1994) Cancer risk in asphalt workers and
Humans 32 roofers: review and meta-analysis of epidemiologie studies.
Ippen H (1956) Die Rolle des Lichtes bei der Entstehung von Am lInd Med 26:721-740
Berufdermatosen. Berufsdermatosen 4:235-242 Piereeall WE, Mukhopadhyay T, Goldberg LH, Ananthaswamy
Karagas MR, Greenburg ER (1995) Unresolved issues in the HA (1991) Mutations in the pS3 tumor suppressor gene in
epidemiology of basal cell and squamous cell skin cancer. In: human cutaneous squamous cell carcinoma. Mol Carcinog
Mukhtar H (ed) Skin cancer: mechanisms and human 4:445-449
relevance. CRC, Boca Raton, FL, pp 79-86 Quinn AG (1997) Ultraviolet radiation and skin carcinogenesis.
Karlehagen S, Andersen A, Ohlson CG (1992) Cancer incidence Br 1 Hosp Med 58:261-264
among creosote-exposed workers. Scan 1 Work Environ Rady P, Scinicariello F, Wagner RF Ir, Tyring SK (1992) pS3
18:26-29 mutations in basal cell carcinomas. Cancer Res 52:
Kerschmann RL, McCaimont TH, LeBoit PE (1994) pS3 Onco- 3804-3806
pro tein expression and proliferation index in keratoacantho- Reid TM, Loeb LA (1992) Mutagenic specificity of oxygen radicals
ma and squamous cell carcinoma. Arch Dermatol 130: produced by human leukemia cells. Cancer Res 52:
181-186 1082-1086
Keyse SM, Applegate LA, Tromvoukis Y, Tyrell RM (1990) Somers KD, Merrick MA, Lopez ME, Incognito LS, Schechter GL,
Oxident stress leads to transcriptional activation of the Casey G (1992) Frequent pS3 mutations in head and neck
human heme oxygenase gene in cultural skin fibroblasts. Mol cancer. Cancer Res 52:5997-6000
Cell Biol 10:4967-4972 Stephenson TI, Royds I, Silcocks PB, Bleehen SS (1992) Mutant
Ko CB, Walton S, Keezkes K, et al. (1994) The emerging epidemie pS3 oncogene expression in keratoacanthoma and squamous
of skin cancer. Br 1 Dermatol 130:269-272 cell carcinoma. Br 1 Dermatol 127:566-570
Korting GW (1979-1981) Dermatologie in Praxis und Klinik. Bd. Suzuki T, Ueda M, Kazuhiro N, Tohru N, Harada S, Imaizumi K,
I-IV, Thieme, Stuttgart Watanabe S, Ichihashi M (1997) Incidence of actinic kerato-
Kricker A, Armstrong BK, Iones ME, Burton RC (1993) Health, sis of Iapanese in Kasai City, Hyogo. 1 Dermatol Sci 16:
solar UV radiation and environmental change. International 74-78
Agency for Research on Cancer Technical Report no. 13. Takeshima Y, Seyama T, Bennett WP, Akiyama M, Tokuoka S,
Lyon, France, pp 52-61 Inai K, Mabuchi K, Land CE, Harris CC (1993) pS3 mutations
Kripke ML (1994) Ultraviolet radiation and immunology: some- in lung cancer from non-smoking atomic-bomb survivors.
thing new under the sun. Cancer Res 54:6102-6105 Lancet 342:1520-1521
Lane DP, Benchimol S (1990) pS3: oncogene or anti-oncogene. Unden AB, Holmberg E, Lundh-Rozell B, Stahle-BackdaiIl M,
Genes Dev 4:1-8 Zaphiropoulos PG, Toftgard R, Vorechovsky I (1996) Muta-
Lear IT, Smith AG, Bowers B, Heagearty AHM, Iones PW, Gilford tions in the human homologue of Drosophila patched
1, Alldersea 1, Strange RC, Fryers AA (1997) Truncal tumor (PTCH) in basal cell carcinomas and the GorIin syndrome:
site is associated with high risk of multiple basal cell different in vivo mechanisms of PTCH inactivation. Cancer
carcinoma and is influenced by glutathione S-transferase, Res 56:4562-4565
GSTT1, and cytochrome P450, CYP1A1 genotypes, and their Urbach F (1980) UV radiation and skin cancer in man. Prev Med
interaction. 1 Int Dermatol 108:519-522 9:227-230
Lear IT, Tan BB, Smith AG, Iones PW, Heagerty AH, Strange RC, Urbach F (1982) Epidemiology and etiology of skin cancer in
Fryer AA (1998) A comparison of risk factors for malignant man. Cancer Campaign, New York, pp 213-227
melanoma, squamous cell carcinoma and basal cell carcino- Vega L, Gonsebatt ME, Ostrosky-Wegman P (1995) Aneugenic
ma in the U.K. Int 1 Clin Pract 52:145-149 effect of sodium arsenite on human lymphocytes in vitro: an
individual susceptibility effect detected. Mutat Res 334: Yiannias JA, Goldberg LH, Carter-Cambell S, et al. (1988) The
365-373 ratio of basal cell careinoma to squamous cell carcinoma in
Walter SO, Marrett LD, Shannon HS, From L, Hertzman C (1992) Houston, TX. J Dermatol Surg Oncol 14:886-889
The assoeiation of cutaneous malignant melanoma and Ziegler A, Leffell DJ, Kunala S, Sharma HW, Gailani M, Simon JA,
florescent light exposure. Am J Epidemol 135:749-762 Halperin AJ, Baden HP, Shapiro PE, Bale AE, Brash OE (1993)
Weinberg RA (1991) Tumor suppressor genes. Seience 254: Mutation hotspots due to sunlight in the p53 gene of non-
1138-1146 melanoma skin cancers. Proc Natl Acad Sei USA 90:4216-4220
CHAPTER 30
Occupational Diseases of the Oral Mucosa

1. Kanerva
Introduction and farmers. Diseases such as orf, anthrax, and

brucellosis may be occupationally transmitted. In
Occupational diseases of the mucosa are relatively medical and dental personneI, occupational herpes
uncommon. They can be divided into acute and has been reported.
chronic diseases (Bork et al. 1993). The acute diseases Heavy metals used to cause chronic diseases, often
are usually accidental, e.g., chemical burns in labora- deposited along the marginal gingiva. Improved work
tory workers when they pipette strong acids or bases. safety standards have made these types of chronic
Caustic fumes or burning gases may cause more intoxication rare in the industrialized world but, in
widespread lesions, including lesions of the oral earlier times, lead, silver, bismuth, tin and cadmium
mucosa. Cooks and housewives may burn their caused oral problems. The discoloration may result
mouths when tasting hot foods. Infectious diseases from either metallic deposition within the skin itself
may affect the oral mucosa in the work of, for or stimulation of melanin synthesis (Bleehen et al.
example, veterinarians, butchers, ranchers, shepherds 1992).
Table 1. Occupational diseases of the oral mucosa
Agent Use/work Symptom Additional
Acids
Hydrochloric acid Cleansing solution, Irritates lips, oral mucosa, Decalcification of
for soldering, zinc pharynx; produces ulcers and tooth enamel
plating scars, necrosis of trachea,
shedding of mucous
membrane, edema of glottis
Hydrofluoric acid Bleaching, etching Bullae and ulcers of the nasal Decalcification of
of glass and buccal mucous tooth enamel
membranes and the skin
Sulfuric acid Ulceration and Decalcification of tooth
reddish-brown sloughs enamel and dentin
Phenol Irritates the mucous membranes;
hemorrhages from the nose
and mouth
Nitric and chromic acids Ulcers with yellow sloughs
Acrylics Dental personnel Irritation and allergy of the
conjunctiva (Estlander et al.
1996) and the mucous
membranes; pharyngitis
(Kanerva et al. 1992);
laryngitis (Sala et al. 1996)
Alcohols Irritation of the conjunctiva and
the mucous membranes
Ammonia Fumes cause salivation and a
burning sensation in the throat
Angioneurotic-edema-
causing agents (see Chap. 24)
Animal products (see Chap. 24) Immediate and delayed allergy,
bacterial infections
Arsenic Ulceration of the fingertips, Carcinogenic
gingivitis, loss of teeth,
phanryngitis

Occupational Diseases of the Oral Mucosa 255
Table 1. (Contd.)
Bacteria Veterinarians, butchers, Orf, anthrax,

ranchers, shepherds, brucellosis
farmers, medical
personnel, dental
personnei, research
workers
Basochrome Loader Contact pemphigus
(basic chromium sulfate) (Tsankov et al. 1990)
Baytan, CAS 55219-65-3 Pesticide, agricultural Contact pemphigus
workers (Dimitrowa et al. 1984)
Beta-( 4-chlorophenoxy)-
alpha-( 1, I-dimethylethyl)-
IH -1 ,2,4-triazole-l-ethanol
(see Baytan)
Bismuth Bluish-black discoloration of Teeth encircled by a
the oral mucosa in the form diffuse line of
of dots and lines; ulceration; pigmentation,
slight temperature tongue blackened
Cadmium (see Nickel-cadmium)
Carbon monoxide Poisoning produces rose-red
spots on the face and mucous
membranes
Cement dust Cement workers; see Mechanical trauma; Periodontitis
chromate inflammation of oral mucosa;
gingivitis (Schneider and
Schworer 1982)
Chromium Ulceration and perforation of Chromate salts
(see also Basochrome) the nasal septum; localized allergenic
gingivitis around the upper
front teeth
Copper Copper smelters and other Copper dust causes a
exposed workers greenish-black
discoloration of the
hair, skin and teeth
(Browning 1969)
Cyanide compounds Electro-plating baths Irritation of the oral and
pharyngeal mucosa
Decorative plants Laryngitis (Sala et al. 1996)
1,3-Dichloropropene Agriculture (pesticide) Contact pemphigus
(Vozza et al. 1996)
Dihydrodiphenyltrichlor- Agriculture (pesticide) Contact pemphigus
ethane (DDT) (Tsankov et al. 1998)
0,0- Dimethyl-
carbamoilmethyl-
dimethylphosphate
(see Phosphamide)
Effort Glass-blowers and players Physical effort in some workers
of wind instruments may cause swelling of the
cheeks due to overstretching
of the facial muscles
Enzymes Industrial enzyme Pharyngeal edema (Hytönen Daily environmental
factory worker et al. 1994) contact with airborne
proteolytic enzymes
has caused abrasion
of dental enamel
(Westergaard et al.
1993)
Flours Laryngitis (Sala et al. 1996)
Food Cooks and housewives Cheilitis, stomatitis
may burn their mouths
when tasting hot foods
Formaldehyde Laryngitis (Roto and Sala 1996)
Fumes Accidents may affect the face
and oral mucosa
Garlic Food industry Contact pemphigus (Pirogova
et al. 1970)
Gases Burning gases (accidents)
may affect the face and
oral mucosa
Gold Goldsmiths The oral mucosa is not affected Conjunctivitis
(Schmidt 1941; Burrows (Estlander et al.
and Adams 1990) 1998)
256 L. Kanerva
Table 1. (Contd.)
Granite Abrasive quartz dust increased

prevalence of gingivitis and
dental caries in Danish
granite-industry workers
(Petersen and Henmar 1988)
Hairdresser's chernicals Laryngitis (Sala et al. 1996)
Halogens (fluorine, Irritate in high concentrations
chlorine, bromine,
iodine)
Heat Glass-blowers, tea and Hot substances repeatedly
coffee tasters applied to the mucous
membranes of the mouth
produce increased
keratinization, which may
result in leukoplakia
Herpes Medical personnel, Herpetic whitlow is an Pharyngitis, sore
pediatricians and occupational hazard of throat, fever
pediatric nurses medical personnel
(Amir et al. 1997) or
dental personnel
(Hochman et al. 1989)
Industrial enzymes
(see Enzymes)
Laboratory workers Pipetting solutions of primary
irritants (acids, bases) may
result in acute stomatitis, etc.
Lead Painters, storage-battery "Lead line" is a bluish-black line Abdominal cramps,
workers on the gingival margin of all weakness of
the teeth, dark-bluish patches muscles, basophilic
may also be observed on stippling of the
the mucous membranes; lead red cells
breath (halitus saturninus)
Lime Chloride of lime may
cause gingivitis
Mercury Gingivostomatitis and salivation; Neurologie and
could cause occupational oral psychiatrie complaints
disease to dental personnei; (Mad Hatter's disease)
lichenoid drug eruption; patchy (ü'Carrol et al. 1995)
alopecia (Schrallhammer-
Benkler et al. 1992); systemic
administration of mercury has
been reported to result in
gingival hyperpigmentation
similar to that produced by
lead and bismuth (Everett
1979). It may be seen as
diffuse blue-gray or black
gingival pigmentation
(Dummett 1971)
Musicians Clarinetist's eheilitis from cane see Chap. 157
reed (Friedman and Connolly
1986); flutist's cheilitis from pao
ferro wood (Hausen 1982), ete.
Nickel Nickel-cadmium-battery Many workers in the nickel- Increased risk for renal
workers (Bar-Sela et al. cadmium battery industry had disease and cancers in
1992) gingivitis (Bar-Sela et al. 1992); nickel-cadmium-
a university student had battery workers
cheilitis from sucking and (Bar-Sela et al. 1992)
chewing pencils containing
nickel (Bruze 1994)
Nitrobenzene Used in the manufacture Greenish-blue discoloration of
of aniline dyes and the mucous membranes,
explosives; also in the bluish-black line on the gums
manufacture of
perfumes, liqueurs
and confectionery
Pharmaceutical industry Manufacturing of Workers developed leukoplakia Allergenic
sulfonamides, aspirin, and inflammation of oral compounds
psychotropic drugs mucosa (Nowicka et al. 1988)
Phosphamide Pesticide Contact pemphigus in engineers
(CAS 60-51-5) (Tsankov et al. 1987)
Occupational Diseases of the Oral Mucosa 257
Table 1. (Contd.)
Phosphorus Loss of teeth

Photocopy paper Photocopier's papillitis of
the tongue (glossitis)
(Galun and Rubinow
1989)
Phthalic anhydrides Laryngitis (Sala et a1. 1996)
Plants (see Decorative plants)
Proteolytic enzymes
(see Enzymes)
Obeche Laryngitis (Sala et a1. 1996)
Orf Reindeer herders
(Palatsi et al. 1993)
Quartz (see Granite) Granite workers Gingivitis Dental caries
Silver From various processes in Argyria; pigmentation as a violet
which silver or its salts line with metallic luster at the
are used; has been gingival margin, may spread
reported among to oral mucous membrane,
photographers and conjunctivae, sclerae and
workers who make entire skin (Granstein and
silvered beads by hand Sober 1981)
Soot, smoke, ordinary dust Leukoplakia
Sulfur dioxide, hydrogen Catarrhal stomatitis, ulcers,
sulfide, hydrogen selenide, hemorrhages
hydrogen telluride
Thallium Severe gingivostomatitis, Pain and weakness
purplish discoloration of of the extremities,
the gums, alopecia abdominal pain,
vomiting, paralysis
of the cranial
nerves, strabismus
Tobacco (smokeless) Athletes; baseball Gingival recession was more
players, etc. common in smokeless-tobacco
users than non-users among
baseball players (Cumming et a1.
1989)
Trinitrophenol (picric acid) Manufacture of explosives Catarrhal stomatitis, irritation Discoloration of
of the skin, conjunctivae, the teeth
and nasal mucosa
Ultraviolet light Fishing workers (Nicolini Actinic cheilitis
et al. 1989), farmers
Vegetables, fruits, other Gingivitis and vesicular see Chaps. 89-91
plant products dermatitis resembling herpes
labialis have been reported
in basket makers (due to
holding strips of wicker
between their lips)
Viruses (see Herpes) Many virus es may cause
occupational diseases of the
oral mucosa (medical
personnel, veterinarians,
research workers, Reif
et a1. 1987)
War gases (tear gas, Diffuse infiammation of the Tear gases are strong
mustard gas, chlorine) mucous membranes when allergens (Kanerva
inhaled in the course of et al. 1993)
manufacture
Wood Musicians may develop
contact cheilitis from
instruments made of
wood (see Chap. 157)
Zinc chloride Ulceration of the oral cavity
with dry, white sloughs
that adhere to the base
of the lesion
Oral changes in musicians have been discussed by tional cheilitis are summarized in Table 2. Further-
Hyry (Chap. 157). Both past (Schwartz and Tulipan more, any of the occupational airborne allergens
1957) and more recent causes of occupational (Chap. 23) are potential causes of cheilitis and
diseases of the oral mucosa are summarized in possibly other manifestations of disease in the oral
Table 1. Causes of occupational and non-occupa- mucosa.
258 L. Kanerva: Occupational Diseases of the Oral Mucosa
Table 2. Causes of cheilitis (modified from Burton 1993) (Pao ferro), a substitute wood for palisander (in German).
Hautarzt 33:321-328
Angular cheilitis* Hochman N, Ehrlich J, Zakay-Rones Z (1989) Oral cavity herpes
Chapping due to cold and wind* simplex virus - a risk factor to dental personnel and patients
Drug-induced cheilitis* (an overview). Isr J Dent Sei 2:2158-2161
Eczema, e.g., atopic or contact cheilitis* Hytönen M, Vanhanen M, Keskinen H, Tuomi T, Tupasela 0,
Glandular cheilitis Nordman H (1994) Pharyngeal edema caused by occupational
Granular cheilitis exposure to cellulase enzyme. Allergy 49:782-784
Exfoliative (factitious) cheilitis* Kanerva L, Estlander T, Jolanki R, Pekkarinen E (1992) Occupa-
Infective cheilitis, e.g., herpes labialis * tional pharyngitis associated with allergie patch test reactions
Nutritional cheilitis from acrylics. Allergy 47:571-573
Plasma cell cheilitis Kanerva L, Estlander T, Jolanki R, Förström L, Granlund H, Leino
Ultraviolet irradiation* T, Pinola A, Tarvainen K (1994) A single accidental exposure
Acute sunburn may result in a chemical burn, primary sensitization and
Actinic cheilitis allergie contact dermatitis. Contact Dermatitis 31:229-235
Actinic prurigo of the lip Lim JT, Ng SK, Goh CL (1992) Contact cheilitis in Singapore.
Other dermatoses, e.g., lupus erythematosus, lichen Contact Dermatitis 27:263-264
planus, pemphigus, etc. Nicolini S, Ascorra C, Guzman C, Latife AV (1989) Actinic
cheilitis in Quinta fishing workers: prevalence and assoeiated
* May be occupational or work-related histopathological aspects (in Spanish). Odontol Chil 37:
169-174
Nowicka J, Zajaczkowska-Bialowas L, Kuc B, Sibora P (1988)
Clinical picture of dentition, periodontium and mouth
mucosa in pharmaceutical industry workers (in Polish).
References Med Pr 39:130-136
O'Carroll RE, Masterton G, Dougall N, Ebmeier KP, Goodwin GM
Amir J, Nussinovitch M, Kleper R, Cohen HA, Varsano I (1997) (1995) The neuropsychiatrie sequelae of mercury poisoning.
Primary herpes simplex virus type 1 gingivostomatitis in The Mad Hatter's disease revisited. Br J Psychiatry 167:5-8
pediatric personne!. Infection 25:310-312 Palatsi R, Oksanen A, Sormunen R, Kallioinen M, Karvonen J
Bar-Sela S, Levy M, Westin JB, Laster R, Richter ED (1992) (1993) The first Orf virus epidemie diagnosed in man and
Medical findings in nickel-cadmium battery workers. Isr J reindeer in 1992-1993 in Finland (in Finnish). Duodeeim.
Med Sei 28:578-583 109:1945-1950
Bleehen SS, Ebling FJG, Champion RH (1992) Disorders of skin Petersen PE, Henmar P (1988) Oral conditions among workers in
color. In: Champion RH, Burton JL, Ebling FJG (eds) the Danish granite industry. Scand J Work Environ Health
Textbook of dermatology, 5th edn. Blackwell Seientific, 14:328-331
London, pp 1561-1622 Pirogova EP, Katyukhina ZD (1970) Artificial dermatitis caused
Browning E (1969) Toxieity of industrial metals, 2nd edn. by garlic. Vestn Dermatol Venerol 44:53-54
Butterworth, London, pp 149 ReifJS, Webb PA, Monath TP, Emerson JK, Poland JD, Kemp GE,
Bruze M (1994) Allergic contact cheilitis related to university Cholas G (1987) Epizootie vesicular stomatitis in Colorado,
studies. Contact Dermatitis 30:313 1982: infection in occupational risk groups. Am J Trop Med
Burrows D, Adams RM (1990) Metals. In: Adams RM (ed) Hyg 36:177-182
Occupational skin disease, 2nd edn. Saunders, Philadelphia, Roto P, Sala E (1996) Occupational laryngitis caused by form-
pp 349-386 aldehyde: a case report. Am J Ind Med 29:275-277
Burton JL (1993) The lips. In: Champion RH, Burton JL, Ebling Sala E, Hytönen M, Tupasela 0, Estlander T (1996) Occupational
FJG (eds) Textbook of dermatology. Blackwell, London laryngitis with immediate allergie and immediate type
pp 2761-2774 speeific chemical hypersensitivity. Clin Otolaryngol 21:42-48
Cummings KM, Michalek AM, Carl W, Wood R, Haley NJ (1989) Schmidt OEL (1941) Chrysiasis. Arch Dermatol Syphilol 44:
Use of smokeless tobacco in a group of professional baseball 446-452
players. J Behav Med 12:559-567 Schneider HG, Schworer H (1982) Effect of cement dust on
Dimitrowa J, Obreshkowa E, Tsankov N, Zaimova Z (1984) periodontal conditions (in German). Z Arzt! Fortbild (Jena)
Pemphigus Vulgaris induziert durch ultraviolette Strahlen 76:357-360
und das Pesticid Baytan. Dtsch Dermatol 32:971-976 Schrallhammer-Benkler K, Ring J, Przybilla B, Meurer M,
Dummett CO (1971) Systemic significance of oral pigmentation Landthaler M (1992) Acute mercury intoxication with
and discoloration. Postgrad Med 49:78-82 lichenoid drug eruption followed by mercury contact allergy
Estlander T, Jolanki R, Kanerva L, Kari 0, Mölsä K (1996) and development of antinuclear antibodies. Acta Derm
Occupational conjunctivitis associated with type IV allergy to Venereol 72:294-296
methacrylates. Allergy 51:56-59 Tsankov N, Dimitrowa J, Lasarowa A, Obreschkowa E (1987)
Estlander T, Jolanki R, Kanerva L, Kari 0 (1998) Occupational Induced pemphigus caused by the pestieide phosphamide (in
allergie contact dermatitis and blepharoconjunctivitis caused German). Z Hautkr 62:196-201
by gold. Contact Dermatitis 38:40-41 Tsankov N, Kostowa M, Mitrova T, Obreshkova E, Stransky L
Everett MA (1979) Metal discolorations. In: Demis DJ, et al. (eds) (1990) Induzierter Pemphigus durch beruflichen Kontakt mit
Clinical dermatology (unit 11-14). Harper & Row Inc., Basochrom. Derm Beruf Umwelt 38:91-93
Hagerstown, p 4 Tsankov N, Gantcheva M, Kazandjieva J (1998) Contact pemphi-
Friedman SJ, Connolly SM (1986) Clarinettist's cheilitis. Cutis gus induced by dihydrodiphenyltrichlorethane. Eur J Der-
38:183-184 matol 8:442-443
Galun E, Rubinow A (1989) Photocopier's papillitis. Lancet 2:929 Vozza A, Ruocco V, Brenner S, WolfR (1996) A case of"contact
Granstein RD, Sober AJ (1981) Drug and heavy metal induced pemphigus". Int J Dermatol 35:199-201
hyperpigmentation. J Am Acad Dermatol 5:1-18 Westergaard J, Moe D, Pallesen U, Holmen L (1993) Exaggerated
Hausen BM (1982) Ineidence and significance of toxic and allergic abrasion/erosion of human dental enamel surfaces: a case
contact dermatitis caused by machaerium scleroxylum Tu!. report. Scand J Dent Res 101:265-269
CHAPTER 31
Occupational Nail Disorders

R. Baran
Introduction for scraping or gripping small objects, and (3) to

provide counter-press ure for the pulp, which is essen-
Anatomy tial to the tactile sensation involving the fingers.
Fingernails grow at a rate of 0.1 mm/day; toenails
The nail plate is the product of constantly differenti- grow much more slowly.
ating ectodermal tissue. Its normal appearance and
growth depend on the integrity of: (1) the four
Definition
epidermal structures (matrix, nail bed, hyponychium
and proximal nail fold) and (2) the bony phalanx that
Occupational nail diseases are abnormalities of one or
forms part of the nail apparatus. The nail is set into
more of the structures of the nail apparatus, produced
proximal and lateral nail grooves formed by invagina-
or aggravated by the working environment.
tions in the corresponding nail folds. The periungual
In assessing a nail condition suspected of being
tissue and, above all, the distal bony phalanx deter-
occupational, one should:
mine its gross form.
Study of the local anatomy reveals four areas which 1. Rule out nail involvement produced by dermatoses,
are particularly vulnerable to trauma. The nail plate such as psoriasis, atopic dermatitis, onychomycosis
emerges from beneath the proximal nail fold, which and lichen planus, which may present with an
adheres dosely to the nail for a short distance and isolated symptom and lead to a "false-positive"
forms a transverse strip of desquamating tissue, the diagnosis (Bennet 1975) in the absence of a thorough
cutide (first area of weakness), which seals the cul-de- his tory and laboratory tests.
sac. The matrix from which the nail is derived extends 2. Determine whether it may be exacerbated, precipi-
approximately 6 mm under the proximal nail fold, but tated or revealed by occupational trauma (Baran and
its most distal part is visible as the white semicircular Levy 1992; Fisher and Baran 1992).
lunula. For most of its length, the nail plate, which has 3. Visualize what the hands do at work.
a loose attachment to the matrix, lies distally on a 4. Look for functional distribution of the lesions; for
firmly adherent nail bed of highly vascular connective example, the first three fingers of the dominant hand
tissue containing glomus organs. It is colorless but are commonly involved in occupational disease.
translucent, transmitting the pink color of the under- 5. Look for occupational stigmata on the nails (Ron-
lying nail bed. The nail bed epithelium presents with chese 1962a).
parallel longitudinal rete ridges. The subepithelial 6. Examine the whole skin surface and mucous mem-
capillaries run longitudinally at different but parallel branes.
levels. Distally adjacent to the nail bed, the hypo-
nychium, which is an extension of the epidermis under
Clinical Reaction Patterns
the nail plate, ends at the distal groove. The hypo-
nychium (second area of weakness of the nail appa-
Clinical reaction patterns mainly indude:
ratus) marks the point at which the nail plate separates
from the underlying tissue. There is very little space 1. Variations in the contour or micro-contour of the
between the nail and the bone of the distal phalanx, nail induding modification of the shape, such as
and this space is solely occupied by the non-keratini- dubbing and koilonychia, and alteration of the
zing nail epidermis and mesenchyme. There is no surface, such as longitudinal or transverse ridging,
subcutaneous tissue. brittleness, pitting.
The functions of the nail are multiple: (1) to protect 2. Modifications of the nail plate and soft tissue
the normal nail bed, (2) to act as a weapon or as a tool attachments. This may give rise to paronychia with

260 R. Baran
disappearance of the cuticle and the creation of a Table 2. Acute injuries (Baran and Dawber 1994)
pocket between the ventral aspect of the proximal May be associated with:
nail fold and the dorsum of the nail plate. Sponta- Partial or total hematoma
neous separation of the nail plate from the matrix, Lacerating wounds
Fractures of the terminal phalanx
called onychomadesis, may appear. Acute trauma Denudation of the terminal phalanx
may result in dorsal or even ventral (distal)
pterygium. Onycholysis refers to the detachment of
the nail from its bed at its distal and lateral end. Table 3. Delayed post-acute traumatic deformities (Baran and
Sometimes, epithelial hyperplasia of the subungual Dawber 1994)
tissues may result from exudative skin diseases and Onycholysis
produce subungual hyperkeratosis. Split nail deformity
3. Variations in the color of the nail or subungual Pterygium
Various nail dystrophies
tissue. Hooked nail
4. Distal bony phalanx anomalies. Some physical
hazards are mentioned in Table 1.
Table 4. Repeated micro trauma associated with koilonychia. In
time, nail changes may become irreversible
Occupational Traumatic Abnormalities Automotive workers (Dawber 1974)

Cabinet makers
Cement workers
Occupational traumatic abnormalities in the nail area Chimney sweeps
represent one of the most important chapters in this Coil winders (Smith et al. 1980)
Glass workers
field. This includes major trauma, repeated microtrau- Hairdressers (thioglycolates) (Alanko et al. 1997)
ma and foreign body injury. Homemakers
Mushroom growers (Schubert et al. 1977)
Oil burner repairers (Meyer-Hamme and Quadripur 1983)
Major Trauma Organic chemist (organic solvents) (Aneona-Alayon 1975)
Pin threaders
The impairment of the normal functional anatomy of Rickshaw puller (feet) (Bentley Philips and Bayles 1971)
Slaughterhouse workers (Forek and Kästner 1967)
the tip and perionychium will depend on the various
levels at which fingertip injuries are sustained, e.g.,
distal to the bony phalanx; distal to the lunula; Table 5. Repeated mierotrauma associated with fingernail fragi-
proximal to the distal end of the lunula. The plane of lity. This leads to a gradual destruetion of the nail plate, whieh
injury will determine the most suitable approach to the beeomes brittle and atrophie. Nail fragility may oeeur in isolation
or associated with paronyehia and/or onycholysis
reconstruction of the pedicle. The level of nail-bed
injury is the critical factor in deciding the requirement Bean shellers and potato peelers (paronychia)
for nail bed management. Nail stability requires at least Butchers
Cement workers
5 mm of healthy nail bed distal to the lunula for nail Chemists and laboratory workers (paronyehia)
adherence (Rosenthal1983) (Tables 2-9). Dentist (onycholysis, subungual hyperkeratosis, dermatitis)
Engravers (paronyehia)
Etehers (paronyehia)
Variations in Color File makers
Glaziers (paronyehia)
The term chromonychia indicates an abnormality in Hat cleaners (paronyehia)
Nurses
color of the substance and surface of the nail plate and/ Optical glass handlers
or subungual tissues. Abnormalities of color depend Packers
on the transparency of the nail, its attachment to the Painters (paronychia)
Photographers (paronyehia, discoloration)
Plasterers (eorroded nails)
Poreelain workers (serrated nails)
Table 1. Physical hazards Pottery workers
Radio workers (paronychia and nail loss)
Burns (onycholysis, pterygium) Rope workers
Cold (Beau's line, nail shedding, koilonychia) (Dolma et al. 1990) Shoe shiners
Dishwashers using heavy rubber gloves (subungual hemorrhages) Shoemakers (onyeholysis and paronyehia)
(Long 1958) Silk weavers (Ronehese 1955)
Foreign bodies Wet work (paronyehia)
Ionizing radiation (Dulanto and Camacho 1979) Woodworkers (paronyehia and stains)
Trauma Workers exposed to mierowave radiation (onyeholysis)
Vibrating power tools (discoloration, ridging, nail shedding, Workers handling small instruments
carpal tunnel syndrome and Raynaud's phenomenon, also Workers lifting repeatedly heavy plastie bags
observed in typists, violinists and pianists) (Boyle et al. 1988) (Schubert et al. 1977)
Occupational Nail Disorders 261
Table 6. Repeated microtrauma associated with toenail dystro- Table 9. Occupational paronychia
phy
Agricultural workers
Dancers (exostosis) (Sebastian 1977) Automotive workers (sulfuric acid exposure from batteries)
Rickshaw pullers (koilonychia) (Bentley-Philips and Bayles 1971) Bakers and pastry cooks
Miners (onychomycosis) (Gugnani and Oyeka 1989) Barbers and hairdressers (onycholysis)
Sportsmen (hematoma; nail shedding) Bartenders
Athletes Bean shellers
Joggers Book binders (paste)
Walkers Bricklayers (limes, cement, mortar)
Squash players Builders and carpenters (including glass fiber)
Soccer players Button makers
Tennis players Cement workers
Chemists and laboratory workers
Chicken factory workers
Cooks
Table 7. Repeated microtrauma associated with onycholysis of Cosmetic workers
mechanical origin (Ronchese 1962b; Forck and Kästner 1967; Dentists (Kanerva et al. 1997b)
Somov et al. 1976) Dyers (aniline dyes, producing stains and necrosis)
Engravers, glass etchers (brittle nail)
Chicken processing plant workers Fishermen
Cropping Fishmongers
Fur workers Florist and gardeners (onycholysis) (hyacintlI, narcissus
Milking bulbs, tulip fingers) (fungal infection)
Nut cracking Glaziers (brittle nail)
Poultry plucking Ground keepers
Separating meat from bone Hairdressers
Scraping Janitorial and domestic workers
Shell casing Meat handlers
Destalking mushrooms Mechanics
Milkers (onycholysis from bristle)
Oil-rig workers
Painters
Table 8. Repeated microtrauma associated with onycholysis Photographic developers (brittle nail, discoloration)
caused by foreign bodies. This may be associated witii an acute Pianists
trauma (metal) or repeated microtrauma (hairdressers, for Physicians, dentists' nurses
example). Occupational onycholysis is most frequently due to Potato peelers
chemical irritants or sensitizers. In addition, there are infective Radio workers (methanol, causing pigmentation and nailloss)
causes, which tend to be limited to medical personnel and Salt plant workers (ulcers)
occupations which entail prolonged soaking of the hands Shoes workers (brittle nails)
(Candida and Pseudomonas) Tanners (whitlow)
Textile workers (threads of fabric)
Animal (bristles, sea urchin, oyster shell) Violinists (nail dystrophy)
MetaI, glass, fiber glass (Rogailin et al. 1975), plastic. They Woodworkers (brittle nails, stains)
mayaiso produce paronychia Wool workers (wool thread)
Splinters of hair (Buendia-Eisman et al. 1997;
de Berker D et al. 1994) and bacterial infection
Vegetable (thorn, splinter, hyacintii and narcissus bulbs occupation, trauma or infection may be implicated.
raphide cells witii crystals of calcium oxalate) (Hjorth and Thus, his tory of the condition may, for example,
Wilkinson 1968)
confirm the traumatic origin of a hematoma. However,
the possibility of malignant melanoma following trau-
underlying tissues and the character of the latter. ma to a nail as a coincidental or causal event should be
Examination of the abnormal nails should be studied kept in mind (Roberts 1984). When the discoloration is
with the fingers completely relaxed and not pressed confined to the nail plate, neither fingertip pressure
against any surface. The fingertips should be blanched producing blanching nor the pen-torch placed against
to see whether the pigmented abnormality is grossly the pulp will alter the pigmentation.
altered; this may help to differentiate between discol- When there is nail contact with occupationally
oration of the nail plate itself and discoloration of the derived agents, or topical application of therapeutic
vascular nail bed. If the abnormality lies in the latter, it agents, the discoloration often follows the shape of the
usually disappears. Further information may be proximal nail fold, and it can be removed by scraping
gleaned by transillumination of the nail using a pen- the nail plate or cleaning it with a solvent such as
torch (light) placed against the pulp. If the discolor- acetone. To determine whether the color is within the
ation is in the subungual soft tissues, its exact position nail plate, a piece of nail should be cut off and
can more easily be identified. examined while immersed in water. When specimens
When discoloration results from abnormalities at are allowed to dry, their true color may be obscured by
the nail plate-nail bed attachment, leading to onycho- the scattering of the transmitted light. When the
lysis and/or subungual hyperkeratosis, the history of pigmentation involves all the digits, it results from the
the condition will help in diagnosis. Chemicals, wet systemic absorption of a chemical.
262 R. Baran
1. When the route of systemic absorption is oral, the bluish discoloration of the terminal digits and
discoloration is more likely to correspond to the should be looked for in an otherwise asymptom-
shape of the lunula. Transverse leukonychia might atic worker, i.e., following exposure to aromatic
occur, for example, in arsenic or thallium poisoning. nitro and amino compounds that can penetrate
2. When systemic absorption of a chemical through the all glove materials. The color disappears within
lung or the skin pro duces dyschromia, there are two 16 h of leaving work, as opposed to sultbemoglo-
possibilities: binemia, which presents with the same distal
a. Disappearance of the pigmentation on the nail- discoloration as an early warning sign of intox-
bed blanching test means that the pigment kation (Pinkus et al. 1963) but which disappears
originates from the blood vessels. Met- only with the normal life span of the red blood
hemoglobinemia, as an example, manifests as a ceIl, i.e., 4 months (Kern 1990).
Table 10. Variations in color of the nail plate
Sign Workers affected
Leuconychia Arsenic workers

Butchers
Keypunchers (Honda et al. 1976)
Salt plant workers and contact with salted intestines (Frenk and Leu 1966)
Weedkillers (paraquat) (Botella et al. 1985; Dobbelaere and Bouffioux 1974)
Workers manufacturing thallium rodenticides
Fly tyer's finger (apparent leuconychia) (MacAulay 1990)
Blue Anodisers (aluminum)
Local argyria (Bergfeld and McMahon 1987; Sarsfield et al. 1992)
Auto mechanics (oxalic acid in radiators)
Cyanosis from methemoglobinemia or sulfhemoglobinemia-
Dye makers
Electroplaters
Gold piasters
Metal cleaners, metal patina solution
Ink makers
Paints removers
Photographers
Rust removers
Silver workers (presenting generalized argyria) (Bleehen et al. 1981)
Textile workers
Brown/Black Cigar makers
Cobblers
Coffee bean workers
Cooks and bakers (burnt sugar)
Electric bulb cleaners (hydrochloric acid)
Gunsmith
Hairdressers
Photographers
Roadway pavers
Shoe-shiners
Vintners (red wine)
Walnut pickers (pecans)
Woodworkers (varnish)
Woodworkers (ebony, mahogany) (Harris and Rosen 1989)
Green (usually caused by
Pseudomonas infection) Bartenders
Dish-washers
Electricians
Fruit handlers
Laundry workers
Metallurgists
Restaurant workers
Sugar factory workers
Yellow Epoxy system handlers
Metaphenylenediamine and 4,4'-methylenedianiline (Cohen 1985)
Flower handlers
Pesticide workers : diquat (Samman 1961; Clark and Hurst 1970), paraquat
(Samman 1961; Hearn and Keir 1971), dinitro-orthocresol (Baran 1974),
dinobuton (Wahlberg 1974)
Workers handling chromium salts
Workers handling dyestuffs: dinitro-salicylic acid (Fregert and Trulson 1980),
dinitrobenzene, dinitrotoluene and trinitrotoluene
Table 11. Chemical sensitizers
Contact sensitization occurring through the nai! plate is probably rare. Usually sensitizers alter the distal sub- and periungual tissue
Flowers and plants Aistroemeria (onycholysis) (Rycroft and Calnan 1981; Marks 1988)
Hydrangea (paronychia) (Bruynzeel 1986)
Nasturtium (finger tip dermatitis) (Derrick and Darley 1997)
Tabernaemontana coronaria (finger tip dermatitis)
(Bajaj et al. 1996)
Tulip fingers (painful onycholysis and fissured keratotic eczema)
(Gette and Marks 1990)
Rhus dermatitis from poison ivy, oak and sumac (onycholysis,
yellowish discoloration of the nai!) (Fulghum 1972)
Chemieals Acrylic resins' (Kanerva et al. 1997c,d)
"Cain" (Iocal anesthetics) and propanidid (Castalain and Piriou 1980)
Cement dermatitis from dichromate content (koilonychia, fissures)
Codein (onycholysis, subungual hyperkeratosis, nai! atrophy)
(Romaguera and Grimalt 1983)
Ethyl cyanoacrylate (Shelley and Shelley 1988)
Epoxy resin (Castelain et al. 1992)
Hydroxylamine (onycholysis, paronychia) (Baran 1991)
1-methylquinoxalinium-p-toluene sulfonate
(periungual dermatitis)
Mydriatic agents containing tropicamide and
phenylephrine hydrochloride (nurses)
Nonoxynol-6 (transverse nai! dystrophy)
Quaternium 15 (subungual hyperkeratosis, onycholysis)
(Marren et al. 1991)
p- Tertiary butyl phenol formaldehyde (onycholysis subungual hyper-
keratosis, nai! atrophy, periungual dermatitis) (Rycroft et al. 1980)
Thiourea (Dooms-Goossens et al. 1988)
Turpentine (periungal dermatitis, subungual hyperkeratosis)
Protein contact dermatitis Baits (onycholysis, paronychia) (Montel and Gouyer 1957)
Food animalorigin (food handlers) (Tosti et al. 1992)
Vegetable origin
• Acrylic dermatitis usually starts from the fingertips. Fingertips paresthesia (dental nurses, orthopedic surgeons) can be seen
Kanerva L et al. 1998). Most of the analyzed acrylate products contain undeclared highly sensitizing acrylics up to 46% (Kanerva et al.
1997c). Acrylic tri-eure glass ionomer produces fingertip dermatitis (dental nurses) (Kanerva et al. 1997a)
b. If the pigmentation is not altered on the nail lase-positive staphylococci and various streptococci
blanching test, it may be obliterated by the pen- (Barnham et al. 1980; Barnham and Kerby 1984).
torch pressed against the pulp. This means that Pseudomonas infection is responsible for the green
the pigment is deposited in the nail bed, as nail syndrome. Such infected nails, in health care
observed in the blue nails of silver refinery personnei, may then be a source of nosocomial
workers (Bleehen et al. 1981) (Tables 10-12). infections, especially from nurses with artificial nails
in whom Serratia, Acinobacter and Pseudomonas have
been found.
Bacterial Infections Acute paronychia occurs frequently enough in meat
handlers (Barnham and Kerby 1984). Erysipeloid
The usual micro-organisms that may deve10p in infection is rare and can be observed in meat and fish
abrasions or lacerations of the nail area are coagu- handlers. Prosector's wart [tuberculosis verruca cutis
(Goette et al. 1978)] has its source in a tuberculous-
Table 12. Chemical irritants
infected cadaver. It may be seen in pathologists,
Alkalis morgue attendants and other hospital personnel.
Alkaline chlorine-containing compounds (Coskey 1974) In Mycobacterium marinum infection (Califano
Aminoethylethanolamine-containing soldering flux
(onycholysis, periungual dermatitis) (Goh 1985) et al. 1998), called fish-tank granuloma or swimming
Detergents (onycholysis, subungual bleeding ulcerations) pool granuloma, the association of skin infection with
(Göthe et al. 1972) aquariums and tropical fish has been noted. A prick
Formaldehyde
Gold potassium cyanide (purplish-brown discoloration, from a rose thorn might also cause the infection. This
onycholysis) in electroplaters, electronic workers (Budden is characterized by the presence of one papule, nodule
and Wilkinson 1978) or erythematous plaque with a verrucous surface on
Hydrofluoric acid (excruciating pain, onycholysis)
(Shewmake and Anderson 1979) the dorsum of the distal phalanx of the finger.
Organic solvents and motor oils (onycholysis, subungal Pasteurella tularensis is transmitted to man by direct
hyperkeratosis, nai! softening) contact with infected wildlife (rabbits are the principal
Oxalic acid (bluish discoloration, brittle nai!s)
reservoirs of tularemia in nature). Over half the
264 R. Baran
Table 13. Fungal infections
Candida fungal infection of the nail area is a common condition involving occupations that require the hands to be wet for prolonged
periods
Candida spp. (onycholysis paronychia) Dish-washers, poultry and fish handlers
Dermatophytic toenail infection
T. rubrum is the most common dermatophyte, Increased prevalence in coal miners (Tappeiner and Maler 1966)
sometimes responsible for the one hand-two-foot and others who work in hot, humid environment
tinea syndrome
T. mentagrophytes var. interdigitale Washing facilities
Molds, especially scytalidium spp. involves the toenails Miners
patients with any cutaneous ulcers, present with 3. Human Orf can assume a target-like appearance on
multiple lesions including shallow erosions into the the dorsum of the right index finger which is the
subungual tissues (Young et al. 1969). most commonly affected (Amichai et al. 1993).
4. Milker's nodule is clinically similar to human Orf
and involves mostly agricultural workers and veter-
Viral Infections inarians (Groves et al. 1991).
5. Viral warts are more common in butchers (Jab-
Viral infections involving the distal digit include lonska et al. 1987; Aloi et al. 1988; Keefe et al. 1994),
(Tables 13-15): poultry handlers (Moragon et al. 1987) and fish
handlers (Rüdlinger 1984).
1. Foot and mouth disease (pustular paronychia)
(Armstrong et al. 1967).
2. Herpes simplex infection. This is the most frequent
viral infection. It occurs in dentists (Rames et al. Final Comments
1984), nurses (Kanaar 1967), anesthesiologists
(Rosato et al. 1970) and pathologists (Haedicke et al. There are often pitfalls in diagnosis such as:
1989). In these occupations, it exhibits a particular
1. Where the presentation of cutaneous disease is
tendency to frequent recurrence.
restricted to an isolated sign involving the nail
2. Where dual pathology exists, such as fungal infec-
Table 14. Individuals at risk of fungal infections (Baran 1997)
tion combined with any of the previously mentioned
Athletes conditions
Dust men
Employees of indoor swimming pools
3. Where there is an isomorphic reaction, for example,
Excavation workers in a psoriasis which may not be evident as yet and is
Mine workers even overlooked, or might be latent
Rubber industry workers
Sewer workers The main goals when handling occupational nail
Soldiers dis orders are: (1) long-term management and (2)
Steel and furnace workers
Woodcutters prevention. Management must take into account the
Table 15. Occupational systemic conditions
Clubbing (resulting from pneumoconiotic lung diseases) Exposure to:

Asbestos (Petry 1966)
Talc
Beryllium (Kern 1990)
Silica
Cobalt (Desoille et al. 1962)
Tungsten (Desoille et al. 1962)
Pseudoclubbing (systemic sclerosis with acroosteolysis) Vinyl chloride monomer
Cutaneous hemangioendothelioma Polyvinyl chloride (Davis 1990)
Collagen diseases:
Systemic sclerosis Vinyl chloride monomer
Epoxy resin (vapors)
Trichlorethylene, trichlorethane
Silica (Rustin et al. 1989)
Sclerodactyly (nail-fold capillary changes, Raynaud's phenomenon,
acroosteolysis) (Bachurzewska and Boruka 1986; Flindt-Hansen and
Isager 1987)
Lupus eythematosus-like erythema and periungual telangiectasia Coffee plantation workers (Narahari et al. 1990)
patient's continuing occupation; for example, protec- Bentley-Philips B, Bayles MAH (1971) Occupational koilonychia
tive gloves might be effective when handling epoxy in toe nails. Br J Dermatol 85:140-144
Bergfeld WF, McMahon JT (1987) Cutaneous metalloid hyper-
resins, as these chemicals have probably caused more pigmentation. In: Callen JP, Dahl MV, Golitz LE, Stegman SJ
instances of occupational dermatitis than any other (eds) Advances in dermatology, vol 1. Yearbook, Chieago,
chemicals introduced in recent years. However, the pp 123-124
Bleehen SS, Gould DJ, Harrington CP, et al. (1981) Occupational
gloves might impair the persons manual dexterity. argyria. Br J Dermatol 104:19-26
Furthermore, rubber gloves are penetrated by acrylic Botella R, Sastre A, Castells A (1985) Contact dermatitis to
monomers and this is relevant for orthopedic sur- paraquat. Contact Dermatitis 13:123-124
Boyle JC, Smith NI, Burke FD (1988) Vibration white finger.
geons, nurses or dental personnel. The overall aims J Hand Surg Br 13:171-175
should include: Bruynzeel DP (1986) Allergic contact dermatitis to hydrangea.
Contact Dermatitis 14:128
1. Efficacy of treatment Budden MG, Wilkinson DS (1978) Skin and nail lesions from gold
2. Prevention of continuing cause potassium cyanide. Contact Dermatitis 4:172-173
Buendia-Eisman A, Serrano-Ortegas, Ortega del Olmo RM (1997)
3. Cleanliness Hair fragments as a subungual foreign body. Eur J Dermatol
4. Hand comfort 7:517-518
5. Facilitation of continued manual dexterity Califano L, Cannavo SP, Malara G, et al. (1998) Verrucous nodule
of the finger. Arch Dermatol 134:365-366
6. Above all, ease of application in the treatment and Castalain PY, Piriou A (1980) Contact dermatitis due to
the preventive measures propanidid in an anesthetist. Contact Dermatitis 6:360
Castelain PY, Com I, Castelain M (1992) Occupational dermatitis
in the aircraft industry: 35 years of progress. Contact
Acknowledgements. We would like to thank the publisher for the
Clark DG, Hurst EW (1970) The toxicity of diquat. Br J Indust
permission to reproduce some of the tables which appeared in
Med 27:51-55
Rycroft and Baran R (1994). Cohen SR (1985) Yellow staining caused by 4,4'-methylenedian-
iline exposure. Arch DermatoI121:1022-1027
Coskey RJ (1974) Onycholysis from sodium hypo chlorite. Arch
Dermatol 109:96
References Davis MFP, Curtis M, Howat JMT (1990) Cutaneous hem-
angioendothelioma: possible link with chronie exposure to
vinyl chloride. Br J Indust Med 47:65-67
Alanko K, Kanerva L, Estlander T, et al. (1997) Hairdresser's Dawber R (1974) Occupational koilonychia. Br J Dermatol
koilonychia. Am J Contact Dermat 8:177-178. . 91[SUppI1O]:11
Aloi FG, Molinero A, Passera A, et al. (1988) VIral warts m de Berker D, Dawber R, Wojnarowska F (1994) Subungual hair
butchers. Clinieal and statistieal study. G ltal Dermatol implantation in hairdressers. Br J Dermatol 130:400-401
Venereol123:341-344 Derrick E, Darley C (1997) Contact dermatitis to nasturtium. Br J
Amiehai B, Grunwald MH, Abraham A, et al. (1993) Tense Dermatol 136:287-299
bullous lesions on fingers. Arch DermatoI129:1043-1048 Desoille H, Brouet G, Assouly M, et al. (1962) Fibrose pulmonaire
Ancona-Aiayon A (1975) Occupational koilonychia from organic diffuse chez un sujet expose aux poussieres de cobalt et de
solvents. Contact Dermatitis 1:367-369 carbure de tungstene. Arch Mal Prof 23:570-578
Anerva L, Mikola H, Henriks-Eckerman ML, et al. (1998) Dobbelaere F, Bouffioux J (1974) Leuconychia en bandes due au
Fingertip paresthesia and occupational allergic contact der- paraquat. Arch Dermatol 30:283-384
matitis caused by acrylics in a dental nurse. Contact Dolma T, Norboo T, Yayha M, et al. (1990) Seasonal koilonychia
Dermatitis 38:114-116 in Ladakh. Contact Dermatitis 22:78-80
Armstrong R, Davie I, Hedger RS (1967) Foot and mouth disease Dooms-Goossens A, Dubusschere K, Morren M, et al. (1988)
in man. BMJ 4:529-530 Silver polish: another source of contact dermatitis reactions
Bachurzewska B, Boruka I (1986) Dermatosen in Beruf und to thiourea. Contact Dermatitis 19:133-135
Umwelt. Occup Environ Dermatol 34:77-79 Dulanto (De) F, Camacho F (1979) Radiodermatitis. Acta Derm
Bajaj AK, Pasricha JS, Gupta S et al. (~~96) Tabernaemont~~a Sif 70:67-94
coronaria causing fingertip dermatitis. Contact Dermatitis Fisher AA, Baran R (1992) Occupational nail disorders with a
35:104-105 reference to Koebner's phenomenon. Am J Contact Dermat
Baran R (1974) Nail damage caused by weed killers and 3:404-406
insecticides. Arch Dermatol 110:467 Flindt-Hansen H, Isager H (1987) Scleroderma after occupational
Baran R (1991) Onycholysis from hydroxylamine. Contact Der- exposure to trichlorethylen et trichloretane. Acta Derm
matitis 24:158 Venereol 67:263-264
Baran R (1997) Epidemiology and prevention of onycholysis. In: Forck G, Kästner H (1967) Charakteristische onycholysis trau-
Grob JJ, Stern RS, Mackie RM, Weinstock WA (eds) matica bei Fleissbandarbeiter in Geflügelschlachterei. Ha-
Epidemiology, causes and prevention of skin diseases. utarzt 18:85-87
Blackwell Science, Oxford. pp 276-278 Fregert S, Trulson L (1980) Yellow stained skin from dinitrosal-
Baran R, Dawber RPR (1994) Nail diseases and their manage- ieylic acid. Contact Dermatitis 6:362
ment. Blackwell Science, Oxford Frenk F, Leu F (1966) Leukonychie durch berufliehn Kontakt mit
Baran R, Levy JL (1992) Onychopathies et travail. Rev Med gesalzenen Därmen. Hautarzt 17:233-235
Travail 19:47-49 Fuighum DD (1972) Allergie contact onycholysis due to poison
Barnham M, Kerby J (1984) A profile of skin sepsis in meat ivy oleoresin. Contact Dermatitis Newslett 11:266
handlers. J Infect 9:43-50 Gette MT, Marks JE (1990) Tulip fingers. Arch Dermatol 126:
Barnham M, Kerby J, Skillin J (1980) An outbreak of streptococ- 203-205
cal infection in a chieken factory. J Hyg Camb 84:71-75 Goette DK, Jacobson KW, Doty RD (1978) Primary inoculation
Bennet JH (1975) The "false positive" diagnosis: skin disorders tuberculosis of the skin. Prosector's paronychia. Arch
that mimic an occupational dermatitis. Cutis 15:410-411 Dermatol 114:567
266 R. Baran: Occupational Nail Disorders
Goh CI (1985) Occupational dermatitis from soldering flux among contact with a fungieide - zinc ethylene bisdithiocarbamate
workers in electronic industry. Contact Dermatitis 13:85-90 in a subject with glucose-6-phosphate dehydrogenase defi-
Göthe CJ, Nilzen A, Holmgren A, et al. (1972) Medieal problems ciency and hypocatalasemia. Blood 21:484-494
in the detergent industry caused by proteolytic enzymes from Rames S, Folkrnar T, Roed-Petersen B (1984) Herpes simplex as a
bacillus subtiles. Acta Allergy 27:63 possible occupational disease in dentists of the county of
Groves RW, Wilson-Jones E, MacDonald DM (1991) Human Orf Aarhus, Denmark. Acta Derm Venereol 64:163-165
and milkers nodules: a clinieo pathologie study. J Am Acad Roberts AHN (1984) Subungual melanoma following a single
Dermatol 25:706-711 injury. J Hand Surg Br 9:328-330
Gugnani HC, Oyeka CA (1989) Foot infections due to hender- Roga VI, Selisski GD, Zakharov GA (1975) Clinieal characteristic
sonula toruloidea and scytalidium hyalinun in coal miners. of skin disease in production of glass fibre. Sovietsk Med
J Med Vet Mycol 27:169-179 9:154
Haedicke GJ, Crossman JAI, Fisher AE (1989) Herpetic whitlow of Romaguera C, Grimalt F (1983) Dermatitis de contacto profes-
the digits. J Hand Surg Br 14:443-446 sional por codeina. Bol Inform G.E.I.D.C. 5:21-23
Harris AO, Rosen T (1989) Nail discoloration due to mahogany. Ronchese F (1955) Peculiar silk weavers nails. A new type of
Cutis 43:55-56 artefacts. Arch Dermatol 71:525-526
Hearn CED, Keir W (1971) Nail damage in spray operators Ronchese F (1962a) Nails: injuries and disease in traumatic
exposed to paraquat. Br J Indust Med 28:399 medicine and surgery for the attorney, vol 6. Butterworth,
Hjorth N, Wilkinson DS (1968) Contact dermititis IV: tulip Washington, pp 626-639
fingers, hyacinth itch and lily rash. Br J Dermatol 80:696 Ronchese F (1962b) Nail defect and occupational trauma. Arch
Honda M, Hattori S, Koyama L, et al. (1976) Leukonychia striae. Dermatol 85:404
Arch Dermatol 112:1147 Rosato FE, Rosato EF, Plotkin SA (1970) Herpetic paronychia, an
Jablonska S, Obalek S, Favre M, et al. (1987). The morphology of occupational hazard of medical personnel. New Engl J Med
butcher's warts as related to papilloma-virus types. Arch 282:804-805
Dermatol Res 279:566-572 Rosenthal EA (1983) Treatment of fingertip and nail bed injuries.
Kanaar P (1967) Primary herpes simplex infection of fingers in Orthop Clin North Am 14:675-697
nurses. Dermatologica 134:346 Rüdlinger R, Bunney MH, Grab R, et al. (1984) Warts in fish
Kanerva L, Estlander T, Jolanki R (1997a) Occupational allergie handlers. Br J Dermatol 120:375-381
contact dermatitis caused by acrylic tri-cure glass ionomer. Rustin MHA, Bull HA, Ziegler V, et al. (1989) Silica exposure and
Contact Dermatitis 37:49-50 siliea-associated systemic sclerosis. Br J Dermatol 121[SUppi
Kanerva L, Henriks-Eckerman ML, Estlander T, et al. (1997b) 34]:29-30
Dentists' occupational allergic paronychia and contact der- Rycroft RJG, Baran R (1994) Occupational abnormalities and
matitis caused by acrylics. Eur J Dermatol 7:177-180 contact dermatitis. In: Baran R, Dawber RPR (eds) Diseases of
Kanerva L, Henrieks-Eckerman ML, Jolanki R, et al. (1997c) the nails and their management, 2nd edn. Blackwell Science,
Plastics/acrylics: material safety data sheets need to be Oxford, pp 263-284
improved. Clin DermatoI15:533-546 Rycroft RJG, Calnan CD (1981) Alstroemeria dermatitis. Contact
Kanerva L, Jolanki R, Estlander T (1997d) Ten years of patch Dermatitis 7:284
testing with the (meth)acrylate series. Contact Dermatitis Rycroft RJG, Wilkinson JD, Hornes R, et al. (1980) Contact
37:255-258 sensitization to p-tertiary butylphenol (PTBP) res in in plastie
Kanerva L, Mikola H, Henriks-Eckerman ML, et al. (1998) nail adhesive. Contact Dermatitis 5:441-445
Fingertip paresthesia and occupational allergic contact der- Samman PD (1961) Onychia due to synthetie nail coverings.
matitis caused by acrylics in a dental nurse. Contact Experimental studies. Trans St Johns Hosp Derm Soc 46:
Dermatitis 38:114-116 68-73
Keefe M, Ghamdi A, Coggon D, et al. (1994) Cutaneous warts in Sarsfield P, White JE, Theaker JM (1992) Silverworker's finger: an
butchers. Br J DermatoI130:9-14 unusual occupational hazard mimieking a melanocytic lesion.
Kern DG (1990) Occupational disease. In: Scher R, Daniel C (eds) Histopathology 20:73-75
Nails: therapy, diagnosis, surgery. Saunders, Philadelphia, Schubert B, Minard JJ, Baran R, et al. (1977) Onychopathie des
pp 224-243 champignonnistes. Ann Dermatol Venereoll04:627-630
Long PI (1958) Subungual hemorrhage in pan washer. JAMA Sebastian G (1977) Subungual Exostose der Grosszche, Berufs-
168:1226 stigma bei Tänzern. Derm Monatsschr 163:998-1000
MacAulay JC (1990) Fly tiers finger. Can J Dermatol 2:67 Shelley DE, Shelley WB (1988) Nail dystrophy and periungual
Marks JG (1988) Allergie contact dermatitis to alstroemeria. Arch dermatitis due to cyanoacrylate glue sensitivity. J Am Acad
Dermatol 124:914-916 DermatoI19:574-575
Marren P, de Berker D, Dawber R, et al. (1991) Occupational Shewmake SW, Anderson BG (1979) Hydrofluoric acid burns.
contact dermatitis due to quaternium 15 presenting as nail Arch Dermatol 115:593-596
dystrophy. Contact Dermatitis 25:253-255 Smith SJ, Yoder FW, Know DW (1980) Occupational koilonychia.
Meyer-Hamme S, Quadripur SA (1983) Berufsbedingte koilony- Arch Dermatol 116:861
chia. Hautarzt 34:577-579 Somov BA, Lipets ME, Ivanov VV, et al. (1976) Occupational
Montel MI, Gouyer E (1957) L'Escavenite. Bull Soc Fr Dermatol onycholysis. Vestn Derm Venereol 2:51-55
Syphil 64:672 Tappeiner J, Maler 0 (1966) Nagelveränderungen durch Schim-
Moragon M, Ibanez MD, San Juan L, et al. (1987) L'incidence des melpilze. Derm Int 5:145
verrues vulgaireschez les travailleurs d'abattoirs industriels Tosti A, Guerra L, Morelli R, et al. (1992) Role of foods in the
de volaille de la province de Valence. Arch Mal Prof 48:41-43 pathogenesis of chronie paronychia. J Am Acad Dermatol
Narahari SR, Skiniva CR, Kelkar SK (1990) L.E.-like erythema and 27:706-710
periungual telangiectesia among coffee plantations workers. Wahlberg JE (1974) Yellow staining ofhair and nails and contact
Contact Dermatitis 22:296-297 sensitivity to dinobuton. Contact Dermatitis Newslett 16:481
Petry H (1966) Uhrglasnägel und Trommelschlegelfinger bei Young IS, Bieknell DS, Archer BG, et al. (1969) Tularemia
Asbestose. Int Arch Geweberpath, Gewerberghyg 22:55-59 epidermie: Vermont 1968. Forty-seven cases linked to contact
Pinkus J, Djadetti M, Joshua H, et al. (1963) Sulfhemoglobinemia with muskrats. New Engl J Med 280:1253
and acute hemolytie anemia with Heinz bodies following
CHAPTER 32
Chemically Induced Hair Loss

S. Heshmati and H.1. Maibach
Introduction possible exception of the bone marrow. The inner

sheath and the hair move upward together, gliding over
Increased shedding of hair (effiuvium) and noticeable the relatively passive, more stationary outer sheath. The
hair thinning or baldness (alopecia) are increasingly fiattened cells of the cutide of the inner sheath and the
cited as side effects of exogenous chemicals and drugs. cells of the cutide of the hair overlap one another like
This report reviews some drugs implicated, discusses interlocking shingles, thereby ensuring that the inner
the mechanisms that may be responsible, describes sheath and the hair ascend together at the same pace.
criteria for defining the mechanism, and proposes
animal and human assay models. This background
provides the basis of similar judgment as relates to Hair Cycle
inhalation and percutaneous penetration of chemicals
at the work site. Every hair follide on the human body, whether present
on the scalp, brow, or trunk, moves through three
phases: (1) growing or anagen, (2) involution or
Hair Anatomy and Mechanism of Production catagen, and (3) resting or telogen.
A hair represents complete maturation of follicular

matrical cells and is a fully cornified structure that Anagen
emanates from a follide and extends above the surface
of the skin for varying distances, from millimeters to Anagen is the phase during which a mature hair is
feet. It has three components: an outer cutide, a cortex, produced. On the scalp and beard areas, this phase
and an inner medulla. The medulla in human hair is lasts 2-6 years, but it may last much longer in certain
discontinuous and often absent. When viewed by individuals. With hair growth occurring at a rate of
means of electron microscopy, the medulla appears approximately 0.35 mm/day (or 0.5 inch/month), this
amorphous, superior to the level of insertion of the means that human scalp hair attains a length of
hair erector musde. The loosely aggregated cells of the 12-36 inches before being shed. Those persons (mainly
medulla contain melanosomes, empty vacuoles, citrul- women) enjoying a 6-year anagen will have untrimmed
line-rich granules, and immature filaments embedded hair reaching the buttock in the manner portrayed in
in an electron-dense material. In contrast to the the rendition of Lady Godiva. On the brow, trunk, or
medulla, the cortex of hair consists of tightly packed elsewhere, the growth period does not exceed
fusiform cornified cells, aligned with their long axes 6 months, resulting in a uniform untrimmed hair
parallel to the long axis of the hair. The cells of the length of a few inches or less.
cortex contain a type of fibrous keratinous protein that
is distinct biochemically from keratin produced by (atagen
epidermal keratinocytes. These have plentiful disulfide
bonds, which give hair its great tensile strength. Anagen is followed by abrief involution al phase called
The matrix cells of the follicular bulb constitute a catagen. Here the follicular cells cease division and the
pool of undifferentiated cells that have intense meta- hair root shrivels to a small group of cells ascending
bolic activity. A complete replicative cyde of matrix toward the surface, pushing the inert hair shaft ahead
cells of follides on a human scalp is about 39 h in of it. Another characteristic feature in catagen is the
duration. This rapid rate of turnover of cells is phenomenon of cell death by apoptosis. Apoptosis is
evidenced by numerous mitotic figures in matrix cells observed in the outer sheath cells at the level of the
and is greater than that of any normal tissue, with the bulb and of the epithelial column.

268 S. Heshmati and H.1. Maibach
Telogen Anagen Versus Telogen Hair Loss
The resting telogen phase occurs with the hair shaft Chemicals or medications may either cause excessive
and attached bulb of cells lying loosely in the dormant hair shedding by precipitating telogen development,
follicle. Mild trauma, such as brushing or shampooing, directly poison the anagen root, or work in other,
dislodges these "club hairs" with their terminal white undetermined ways.
bulb. The duration of catagen and telogen is unknown
but it approximates 3 months. It is followed by the
redevelopment of an anagen follicle below the telogen
Identification of Anagen and Telogen
one, which dislodges the club hair if it still remains.
In humans these cycles occur in a relatively random
The phase of hair loss may be determined by exam-
fashion in the follicles at various sites of the body. In
ining the shed or easily plucked (abnormally loose)
certain animals, e.g., the mouse or rabbit, the hair cycle
hairs. The anagen hair will have, at its proximal end, an
is largely synchronized with regional waves of growth
elongated translucent sheath (representing layers of
and loss leading to readily discernible areas of hair
the living follicle) with a pigmented tip, unless the hair
loss. Other animals are more mosaic (like humans) in
is light in color. Generally, during anagen, the majority
their cycles. It is likely that patterns of cycling occur in
of hairs have so severe a mitotic inhibition that the hair
humans; the anterior hair line is one probable candi-
shaft breaks, leaving the bulb in the scalp. These
date. Identifying these minor areas of synchrony in
broken hairs are almost always tapered, revealing a
humans has been difficult.
diagnostic artifact of anagen effiuvium (Maibach and
In the scalp, about 85-95% of the follicles are in
Maguire 1964). The only condition mimicking this is
anagen at any given time, while 5-15% are in the
the acutely spreading phase of generalized alopecia
telogen phase of shedding. On average, 40-100 hairs
areata (alopecia totalis). The club hair of a telogen
are lost from the scalp each day. In comparison,
follicle possesses on its proximal end the familiar
anagen in the eyebrow lasts only 10 weeks, while
nonpigmented spherical bulb. Biopsy of the hair
telogen persists for 9 months so that a greater
bearing skin may be helpful in verifying the relative
percentage of eyebrow hairs are in telogen rather than
frequency of telogen versus anagen follicles, or, with
anagen. Areas with a higher percentage of anagen
severe toxicity, it may show actual necrosis of the
follicles, such as scalp or beard, will be more suscep-
follicle.
tible to agents affecting rapidly dividing cells, and the
higher telogen areas will be relatively resistant. This
accounts for the scalp-beard pattern of hair loss seen,
for example, with cytotoxic agents. Plucking: Gentle Pull Test Versus Pluck Test
The above description refers to the appearance of shed

Nonchemical-Related Hair Loss hair or that about to be shed. The sampIe is obtained
from the comb, pillow, clothing, or shampoo, or by
Few endogenous events affecting hair growth are gently pulling at several areas of the scalp (without
delineated. Extreme starvation or pro tein deprivation forceps). With minimal clinical experience and know-
may result in the formation of sparse and brittle hair ledge of when the hair was last shampooed, the
through diminished mitotic activity of the hair bulb frequency and extent of combing and brushing, and,
(Goette and Odom 1975). An unusually large percent- in general, the number of hairs in the scalp, it is
age of hair follicles may be thrown into an untimely possible to make a shrewd assessment of whether an
telogen phase by a major systemic insult, such as high abnormal amount of hair is shed. This examination,
fever, major surgery, illness, or trauma. Telogen may lasting but aminute or two and requiring only a good
also be precipitated by sudden abnormal fiuctuations, light source and several powers of magnification, is all
such as those following childbirth. The shedding that is required in most instances.
resulting from this telogen synchronization (or "telo- An alternate method of demonstrating the anagen-
gen effiuvium") occurs about 3 months after the insult, telogen ratio is more direct but, unfortunately, more
refiecting the time required for the full telogen state to cumbersome, time - and equipment - consuming, and,
be reached. This statement represents a generalization hence, less frequently performed (Crounse and Van
only. All hairs in telogen effiuvium rarely synchronize. Scott 1960). Here, one takes rubber-tipped forceps and
They gradually increase in loss frequency, reaching a gras ps 30-100 hairs (near the scalp) in its grip. A rapid,
crescendo, then gradually decrease to a normal level. forceful pluck yields all hairs - anagen and telogen.
The patient notices the loss at varying times up to its Placing these in a petri dish with a thin layer of water,
peak. for viewing with a binocular dissecting microscope at
Chemically Induced Hair Loss 269
low magnification, permits accurate enumeration of Hair growth resurnes 2 months after therapy has
the number of anagen, catagen (uncommon), and stopped. The loss affects the anagen but not telogen
telogen hairs. Cutting of the extraneous hair on the hairs; thus, eyebrow and body hair is relatively
other side of the grasping forceps simplifies manipu- spared.
lation of the bulbs in the dish. Any hair whose shaft is The effect of these drugs on the rapidly dividing
broken is considered as anagen with its bulb being too hair matrix cells is directly toxic, leading to hair loss
securely fixed in the scalp to remove it. If the hair is in two ways (Crounse and Van Scott 1960). If the
not jerked quickly, but extended gradually instead, matrix itself suffers a severe and/or prolonged insult,
discomfort is increased and bulb artifacts produced then much of the hair follide is affected, so that hairs
(Maguire and Kligman 1964). may be easily removed with the necrotic anagen
sheath adhering to them. This is a true anagen
effiuvium. If the insult is less severe or of brief
Diagnostic Criteria duration, then mitotic activity will only temporarily
decrease, which will result in continued growth of the
Proving that alopecia in an individual is caused by a hair but with a weak constricted area in the shaft.
chemical or a drug may be difficult because idiopathic When this weak point grows above the surface of the
hair shedding, which is common, may be coincident skin it will break with minor trauma and appear to the
with drug therapy or chemical exposure; other drugs observer as a type of hair shedding. This tapered hair
may be in use at the same time; or the disease for is the hallmark of anagen effiuvium (Maibach and
which the drug is being given may produce hair loss, Maguire 1964). Methotrexate is also an established and
e.g., high fever. The most condusive demonstration of highly effective systemic drug for treatment of severe
chemical or drug-related hair loss is reproduction of psoriasis. Van Dooren-Greebe et al. (1994) allege hair
hair loss with repeated administration of the putative loss in 6% of patients under treatment. Calcipotriol,
materials. Some drugs cause hair loss so uniformly that another psoriasis treatment, has theoretical hair
even a small se ries with few patients will convince the growth inhibiting potential. Although it could induce
observer of the relationship. Less convincing are hair loss, Kuijpers et al. (1995) conduded this is not
isolated cases "proved" by regrowth of hair when reflected in the in vivo hair growth pattern during
therapy is discontinued. treatment.
Medications reputed to cause hair shedding will be
discussed below, grouped, as weIl as possible, by Phenyl Glycidyl Ether (Topicai?)
probable mechanism of action on the hair follide. The
last group mentioned will be those drugs only tenu- Lee et al. (1977) report alopecia in rats exposed to a
ously culpable for this side effect. vapor of phenyl glycidyl ether, a material used in
industry to stabilize halogenated compounds. Oral
administration of this agent causes profound systemic
Anagen-Type Hair Loss symptoms and death from central nervous system
depression. Controlled exposure to various levels of
Hair loss of the anagen type refers to hair loss within vapor caused no systemic effects in rats and dogs, but
days to weeks of drug administration, which is due to there was hair loss in the rats, predominantly in
inhibition of follicular mitoses and subsequent kera- females. The hair loss was due to damage to anagen
tinization. Examination of a shed or pulled hair reveals follides, which caused abnormal keratinization of the
a tapered broken shaft, or an anagen sheath (which is hair shaft, and to increased conversion to telogen
much less common). follides. Lee et al. postulate that the effect was from
percutaneous and follicular absorption, not from
Antimitotic Agents inhalation. The reliance of this data in man requires
documentation.
Hair loss occurs following the use of cancer chemo-
therapeutic agents of all types: alkylating agents,
alkaloids, and antimetabolites. Colchicine, an antimi- Medications Precipitating Telogen
totic used in the treatment of gout, has similar
effects. Shedding of hair begins after only 1-2 weeks Medications precipitating telogen refers to hair shed-
of therapy, but, as it occurs gradually, it may be ding that occurs 2 months after drug administration.
several weeks longer before thinning of the hair is The shed hairs bear telogen bulbs and are easily teased
noticed by the patient (Falkson and Schulz 1964). It is from the scalp. There is an increased conversion of
more common and severe with combination therapy anagen to telogen follides. A partial list of these
than the use of only a single drug (Tosi et al. 1994). medications can be found in Table 1.
270 S. Heshmati and H.1. Maibach
Table 1. Drugs that may induce telogen effluvium of growth - a constriction of the shaft. Physicians
Allopurinol Indandiones should be aware of the possibility of thallium poison-
Amiodarone Indomethacin ing in patients who have a combination of alopecia and
Amphetamines Interferons psychiatrie or neurological symptoms.
Amdrogens Iodine
Bromocriptine Itraconazole
Butyrophenones Levodopa Phenyl Glycidyl Ether
Carbamazepine Maprotiline
Carbimazole Methyldopa See section above, Anagen. Hair loss is of the anagen
Cholestyramine Methysergide
Cimetidine Metoprolol and telogen types.
Clofibrate Metyrapone
Contraceptives Minoxidil Selenium Disulfide (Topical)
Coumarins Nadolol
Danazol Nicotinic acid
Desipramine Dextran Selenium disulfide is the active ingredient in several
Propranolol Dixyrazine popular antidandruff shampoos. In the United States,
Pyridostigmine Ethambutol the 2.5% strength requires a prescription, while the 1%
Retinol Etionamide
Salicyla tes Fluoxetine preparation is available over the counter. Wirth et aI.
Sulfasalazine Gentamicin (1980) induced significant telogen hair loss in guinea
Thallium Selenium pigs by applying a 2.5% solution of selenium disulfide
Terfenadine Gold salts
Thiamphenicol Heparin six times/day at 3-day intervals. The material was not
Hydantoins Trimethadione washed off and exposure was very intense; conse-
Ibuprofen Triparanol quently, even though Wirth et al. mention "isolated
Imipramine Valproic acid
observations of diffuse hair loss" after such use, it is
difficult to compare this exposure with use of the
Thallium material by humans as a shampoo. The significance of
this information for man requires further validation.
Thallium, a cumulative poison, is readily absorbed
through skin and lungs, as weIl as the gastrointestinal Occupational Exposure to Selenium
tract. This element (usually as the sulfate salt) was used
for its depilatory effect in the treatment of ringworm of The manufacture and maintenance of drums used in
the scalp. It is currently not found in any medications, photocopy machines involves use of a selenium alloy.
but is still available in the Uni ted States in rodent The external manifestations of selenium exposure in
poisons, and accidental poisoning may occur from this type of setting includes hair loss, deformity of
contaminated grains and other foods. nails, and discoloration of teeth.
Thallium interferes with the incorporation of cys- The main environmental pathway of occupational
teine into the keratin mole eule, and its toxic effect can exposure to selenium is through the air or, in some
be blocked by the administration of cysteine. In cases, by direct dermal contact. Srivastava et al. (1995)
humans, hair loss begins 10 days after ingestion of reports a worker employed in this type of job for
thallium and is complete after 1 month. Scalp hair, 6 months who presented with alopecia areata, which
eyelash, and lateral aspect of eye brows are primarily later deteriorated to alopecia universalis. This patient's
affected, with sparing of the trunk and axillary hair. blood selenium levels were 0.5 Ilg/mI. Yang et al. (1983)
A pattern of alopecia is not characteristic but hair reported mean blood selenium levels of 3.2 mg/l in a
loss is most marked on the crown (Hubler 1966). The selenium rich area in China where chronic selenosis was
hairs show an accumulation of air bubbles in the shaft, common. Mean normal blood selenium in different
through which area breakage occurs. This appears to states of the U.S. and China range from 0.082 mg/mI to
the unaided eye as a black opaque band about 1 mm in 0.206 mg/I. In spite of much work, knowledge about the
length, appearing at the root a few days after thallium health effects of occupational exposure to selenium is
intoxication (Hubler 1966). The follicles themselves far from complete (Srivastava et aI. 1995). Since alope-
show, on biopsy, dyskeratosis, necrosis, parakeratosis, cia areata is common in 1.7% of the population studied
spongioform abscess formation, and increased number Oackow et aI. 1998), this report requires follow-up
of telogen follicles. before a cause and effect relationship can be assumed.
The follicular changes are those of an incomplete
telogen (A.M. Kligman, personal communication). The
hairs are thrown into an imperfect catagen, becoming Medications Causing Hair Loss of Unknown Type
incomplete club hairs, and the follicular column
retracts only slightly. Anagen begins after 3 weeks. In this category, hair loss has reliably been noted to
About 5-10% of the hairs show a temporary inhibition occur, but the mechanisms are either unknown or have
Chemically Induced Hair Loss 271
not been studied. Among the medications causing hair effects of physical and chemical insults rather than to
loss of unknown mechanism are: antithyroid drugs, the alkalis alone (Nicholson et al. 1993).
antihyperlipemics, boric acid, some antibiotics (espe-
cially thiamphenicol), valproic acid, and even hyper
vitaminosis A. Typical Senarios in Alleged
Occupational Hair Loss
The two most typical scenarios are the appearance of

Medications Possibly Associated with Hair Loss
alopecia areata (or totalis or universalis) and patterned
A large number of drugs (Table 2) may interfere with alopecia in the work place. The workers, understand-
the hair cyde and produce hair loss. Drug-induced hair ably, on finding similarly involved coworkers, assurne
loss is usually reversible after discontinuation of causality. As both conditions are common - alopecia
treatment. Prevalence and severity of alopecia depends areata in 1.7% of the population studied (Jackow et al.
1998) and patterned alopecia, almost ubiquitous - the
on the drug as well as the individual's predisposition.
Some drugs produce hair loss in most patients opportunity for confusion is obvious. It is conceivable
receiving appropriate dosages, while other drugs are that alopecia areata and patterned alopecia could be
only occasionally responsible for hair abnormalities. related to exogenous chemicals, but this has not been
Table 2 contains a partial list of these medications. documented.
Pharmacokinetics
Chemically Induced Cosmetic Alopecia
Percutaneous penetration can be in excess of 50% of
Cosmetic causes of scarring alopecia (cicatricial) are applied dose. In theory, percutaneous penetration of
far more prevalent than previously realized and are occupational chemicals could lead to sufficient body
poorly documented. They indude traction alopecia, burden to lead to hair loss. Similar kinetics are
hot combing, and, recently, another group related to possible from inhalation. Future work in the field of
misuse of chemical hair-straightening agents (relax- occupation induced hair loss will benefit by induding
ers). These agents are either sodium hydroxide or dermatopharmecokinetic data (Bronaugh and Maibach
ammonium thioglycollate based. Affected patients are 1991).
young, female of Afro-Caribbean origin and typically
display hair loss on the vertex of the scalp. Histological
pattern found on biopsies taken from the affected areas Animal Models
is one of fibrosis and infiammation, distinguishable
from other non-cosmetic causes of scarring alopecia, The past history of toxicology warns us adequately
such as discoid lupus erythematosus or lichen plan- that, once we know the existence of a potential hazard
opilaris. These biopsies may reveal complete replace- from an animal model, we are more likely to identify
ment of follides by vertical bands of fibrosis, that phenomenon in human trials. We know of no
perifollicular scarring, chronic infiammation, and pharmaceutical or toxicological laboratory presently
abscess formation (Mehregan et al. 1992). Acanthotic induding a systematic examination of hair growth and
epidermis with hyperderatosis and focal parakeratosis loss in its profile in drug predinical evaluation. We
are also seen. Relaxers are caustic substances with their believe that it is time that such an evaluation was
pH strictly regulated; however, the abnormalities considered. It is not unreasonable to suspect that, once
observed are related to a combination or sum of this is initiated, we will identify other drugs and
chemicals that produce hair loss. Anagen effiuvium is
dramatic and not as likely to be missed by ilie patient
Table 2. Drugs or drug
classes that may produce Trimethaddione or physician; telogen effiuvium is far from obvious.
hair loss Lithium The several boron toxicity patients (Stein et al. 1973;
Cimetidine J. Herndon, personal communication) with severe hair
Pyridostigmine
Gold loss resulting in a marked alopecia did not have a sign
Salicylates on their scalp identifying the chemical or its source for
Amphetamines the patient. It took the investigators' shrewd detective
L-dopa
Allopurinol work to make the association. When we have a list of
Methysergide chemicals and drugs (and approximate potencies)
Gentamycin productive of hair loss (and mechanism), we will
Ibuprofen
know where and when to look in humans. Will each
272 S. Heshmati and H.1. Maibach: Chemically Induced Hair Loss
study show that a significant portion of "typicai" male ical or drug producing hair loss in the animal must not
pattern hair loss or diffuse alopecia of women is, in be excluded from consideration for human use without
fact, secondary to drug or other chemical dosing? careful examina ti on of the data. It is possible that
chemical and drug producing hair loss in animals will
Animal Choice not do so in humans at the dose levels used by the
latter.
Animal choice is moot at present. An inexpensive,
conveniently handled animal would be valuable for
screening, with less convenient animals, such as the References
monkey, reserved for special studies. An animal that is
a mosaic, similar to humans, may be more realistic for Bronaugh R, Maibach HI (1991) Percutaneous absorption, 3rd
edn. Marcel Dekker, New York
humans than an animal (such as the mouse) that has Crounse RG, Van Scott EJ (1960) Changes in sc alp hair roots as a
synchronous waves. At present, the guinea pig would measure of toxicity from cancer chemotherapeutic drugs.
appear suitable in terms of cost, handling and simi- J Invest Dermatol 35:83-84
Falkson G, Schulz EJ (1964) Skin changes caused by cancer
larity to humans. The experimental design should chemotherapy. Br J Dermatol 76:309-310
include control (vehicle)-treated animals, since many Goette DK, Odom RB (1975) Profuse hair loss. Arch Dermatol
factors, including season, nutrition, intercurrent dis- 111:930-932
Hubler WR (1966) Hair loss as a symptom of chronic thallotox-
ease, etc., may infiuence hair growth dynamics in icosis. South Med J 59:436-442
animals. If the animals become otherwise toxic, the Jackow C, Puffer N, Hordinsky M, Nelson J, Tarrand J, Duvic M
usual maneuvers used in toxicology must be employed (1998) Alopecia areata and cytomegalovirus infection in
twins: genes versus environment? J Am Acad Dermatol
to ascertain whether this is a drug effect or secondary 38:418-425
to the animals' general status. Dose-response studies, Kligman AM (1959) The human hair cycle. J Invest Dermatol
temporal relationships, and toxicity controls will be 33:307
Kuijpers AL, Van Baar HM, Van GasseIt MW, Van de Kerkhof PC
helpful in this regard. (1995) The hair root pattern after calcipotriol treatment for
scalp psoriasis. Acta Derm Venereol 75:388-390
Observations Lee KP, Terrill JB, Henry NW (1977) Alopecia induced by
inhalation exposure to phenyl glycidyl ether. J Toxicol
Environ Health 3:85-87
Gross hair observations include the presence or Maguire HC, Kligman AM (1964) Hair plucking as a diagnostic
absence of spotty or diffuse alopecia, and excessive tool. J Invest Dermatol 43:77-78
Maibach HI (1974) Brown AC (ed) The first human hair
shedding noted in the cage. Only potent agents might symposium. Med Com Press, New York, p 399
be expected to produce a loss significant enough for Maibach HI, Maguire HC (1964) Acute hair loss from drug-
gross observation. induced abortion. New Engl J Med 270:1112
Mehregan DA, Van HaIe HM, Muller SA (1992) Lichen planopil-
Pull tests and pluck tests should reveal more subtle aris: clinical and pathological study of 45 patients. J Am Acad
changes. This will require careful record keeping and Dermatol 27:935-942
sampling. If no one in the laboratory is experienced in Nicholson AG, Harland CC, Bull RH, Mortimer PS, Cook MG
(1993) Chemically induced cosmetic alopecia. Br J Dermatol
observations of the anagen, catagen, and telogen, they 128:537-541
can be rapidly trained to perform the pull test and Srivastava AK, Gupta BN, Bihari V, Gaur JS (1995) Generalized
pluck, placing the sampies in envelopes to forward to a hair loss and selenium exposure. Vet Hum Toxicol 37:
468-469
laboratory experienced in hair bulb morphology. It is Stein KM, Odom RB, Justice GR, Martin GC (1973) Toxic alopecia
preferable that the hair be forwarded in coded fashion; from ingestion of boric acid. Arch Dermatol 108:95-97
control animals must be included. Tosi A, Misciali C, Piraccini BM, Peluso AM, Bardazzi F (1994)
Drug-induced hair loss and hair growth. Incidence, manage-
ment and avoidance. Drug Safety 10:310-317
Van Dooren-Greebe RJ, Kuijpers AL, Mulder J, De Boo T, Van de
Human Models Kerkhof PC (1994) Methotrexate revisited: effects of long-
term treatment in psoriasis. Br J Dermatol 130:204-210
Wirth H, Dunsing W, Gloor M (1980) Telogen effluvium
The mensuration of hair growth and loss has been following application of selenium disulfide in the guinea
studied. The reader is referred to a review for details pig. Hautarzt 31:502-504
Yang GQ, Wang SZ, Zhou RH, Sun SZ (1983) Endemic selenium
(Maibach 1974). The same principles used in the intoxication of human in China. Am J Clin Nutr 37:
animal model are appropriate to humans. Any chem- 872-881
CHAPTER 33
The Psoriasis Patient and Work

Y-H. Leow and c.L. Goh
Introduction In an epidemiological study of 1253 psoriatic pa-

tients, Melski et al. (1983) found that one-third of the
Psoriasis is a chronic proliferative inßammatory skin study population had a history of Koebner response at
condition. The severity of the condition ranges from sites of physical trauma. These patients were also
mild focal involvement to generalised exfoliative found to be associated with earlier onset of psoriasis in
dermatitis. The clinical course is also unpredictable. life and a tendency to ßare despite various treatment
Clinically, psoriasis of the hands presents as kerato- options. Apart from the limitations of this study, the
tic patches on the palms and often the bony promi- authors believed that there is indeed a subset of
nences of the hands. The skin lesions on the palms do psoriatic patients, in which Koebner phenomenon may
not display the classical features of psoriatic lesions be an important marker. Thus, it is important to
elsewhere on the body. A high degree of suspicion is identify psoriatic patients and dis courage them from
necessary to recognise the condition. The presence of engaging in jobs in which they will be subject to
psoriatic lesions elsewhere, e.g., on the elbows, knees, excessive trauma.
trunk and scalp, and the associated nail changes of
psoriasis often help the physician to establish the
diagnosis. Occupational Contact Psoriasis
Palmar psoriasis is often confused with chronic
keratotic hand eczema. It is often difficult to differen- Occupationally related psoriasis, particularly psoriasis
tiate it from a chronic eczema. Skin biopsies often affecting the hands and fingers, has been reported
show non-specific changes of an eczema rather than anecdotally in different workers. The term "occupa-
that of psoriasis, and the histological findings often do tional contact psoriasis" was not used in these reports;
not help to confirm the diagnosis. however, it probably best describes these clinical
Well-recognised aggravating factors of psoriasis examples in which the Koebner phenomenon, i.e.,
include inter-current infection, certain drugs, stress trauma, pressure and friction, accounted for the
and trauma. In the work environment, skin trauma appearance of psoriasis in these patients. No specific
is common; thus, aggravation of psoriasis resulting occupation predominates, because the phenomenon
from skin trauma is not uncommon. This chapter occurs in people from different walks of life who
discusses the effects of the work environment on develop psoriasis in the course of their work, e.g., a
psoriasis. pharmacist from the pressure of opening and closing
containers with child-resistant caps; a foundry worker
who fills moulds with sand; a bus driver from the
Koebner Phenomenon and Psoriasis pressure of the steering wheel; an office worker from
po unding astapier; a dentist from the pressure of
The association between trauma and psoriasis was first handling various dental instruments; and others
described by Heinrich Koebner in the 18th century. (Fisher 1979; Ancona et al. 1986; Moroni et al. 1988;
The "Koebner response" refers to the development of Rietschel and Fowler 1995; Kanerva et al. 1998).
an overt lesion of psoriasis following an injury to
previously normal appearing skin. This new lesion of Incidence
psoriasis has morphology identical to the injury; thus,
it is also known as an "isomorphic response". Koebner Moroni et al. (1988) reported that occupational contact
phenomenon tends to occur more commonly in psoriasis probably accounted for 1.2% of all the
patients with active psoriatic disease (Eyre and occupational dermatoses in 3000 patients observed
Krueger 1991). over a 5-year period (1980-1985) in their department.

274 Y.-H. Leow and c.L. Goh: The Psoriasis Patient and Work
Diagnostic Criteria 3. Reeurrent lip lesions in winter time

4. Pitting of the nails
Ancona et al. (1986) proposed the following diagnostic 5. Thickening of the great toe nail
criteria for occupational contact psoriasis: (1) elinically 6. Hyperkeratosis of the palms in winter time
demonstrable psoriasis localised to hands, mainly 7. Hyperkeratosis with persistent fissures on heel
palms, without significant involvement elsewhere, or 8. Dry perionychium and eponyehium with rhagades
(2) psoriasis affecting other sites except the hands with
further development of lesions on this location after
engaging in a particular job. Conclusion
The importance of preventing occupational contact

The Role of Pre-Employment Evaluation psoriasis in the work environment goes beyond the
of Psoriasis Patients morbidity and cost in managing these patients. As
trauma may incite or trigger new lesions of psoriasis, it
Pre-employment evaluation of workers serves the is potentially a medico-legal issue, especially in eoun-
purpose of primary prevention against occupational tries where workman's eompensation is a major
skin disease. Screening prospective workers for an coneern (Rietschel and Fowler 1995).
increased risk of developing occupational contact Primary prevention should be practised by identi-
psoriasis, by looking for personal and familial psoriatic fying individuals with the propensity to develop
background and the physical markers of the disease, oeeupational contaet psoriasis during the course of
may be important in job placement. Workers with work. Onee identified, these individuals should be
predisposition to psoriasis should be discouraged from counselled aeeordingly before embarking on their
holding jobs that expose them to risk of skin injury eareers.
and repetitive trauma.
Pre-employment evaluation should entail a screen-
ing questionnaire and thorough physical examination. References
The screening questionnaire should inelude questions
such as (Adams 1983): Adams RM (1983) Treatment, prevention and rehabilitation. In:
Adams RM (ed) OeeupationaI skin disease. Grune and
1. Do you have psoriasis? Stratton, New York, pp 157-178
Aneona A, Fernandez-Diez J, BeIIamy C (1986) OeeupationaI
2. Have you ever had a rash on your elbows, knees or indueed psoriasis. Dermatosen 34:71-73
scalp? Eyre RW, Krueger GG (1991) The Koebner response in psoriasis.
3. Do you have severe, stubborn dandruff? In: Roegnik HH Jr, Maibaeh HI (eds) Psoriasis. Mareel
Dekker, New York, pp 135-147
4. Do any of your elose relatives have psoriasis? If yes, Fisher AA (1979) Oeeupational palmar psoriasis due to safety
which relative? preseription eaps. Contaet Dermatitis 5:56
Kanerva L, Talvi A, Estlander T (1998) Oeeupational eontact
Pre-employment physical examination should in- psoriasis. Eur J Dermatol 8:217-218
elude examination of the skin with specific emphasis Melski JW, Bernhard JD, Stern RS (1983) The Koebner (isomor-
phie) response in psoriasis. Areh DermatoI 119:655-659
on (Moroni et al 1988): Moroni P, Cazzaniga R, Pierini F, Panella V, Zerboni R (1988)
OeeupationaI eontaet psoriasis. Dermatosen 36:163-164
1. Dry scales on the sealp Rietsehel RL, FowIer JF (1995) Fisher's eontaet dermatitis, 4th
2. Reeurrent dry scales on the outer ear edn. Williams and Wilkins, Baltimore, pp 92-113
CHAPTER 34
Non-Eczematous Occupational Contact Reactions

c.L. Goh
Introduction Patch Test
Contact reactions may present as non-eczematous In all cases, a positive patch test to the contact allergen
lesions. A variety of non-eczematous occupational can be elicited. The patch-test re action is always
contact reactions has been described. The exact patho- eczematous and often severe.
mechanism of these reactions is unknown. The
following non-eczematous contact reactions have been Histology
described:
The epidermis is normal or shows mild spongiosis with
1. Erythema multiforme-like eruption [urtiearial
upper dermal edema and perivascular lymphohistiocy-
papules and plaque eruptions (UPPE)]
tic infiltrate. Vacuolar degeneration of the basal cells is
2. Purpuric eruption
occasionally present. The classieal features of
3. Lichen planus-like eruption
erythema-multiforme are absent. The morphology,
4. Papular and nodular eruption
clinical course and histology of the eruptions are not
5. Granulomatous reaction
characteristie of classieal erythema multiforme.
6. Pustular eruption
The patho-mechanism of these papular and urtica-
7. Erythema and exfoliation
rial eruptions is unknown. An immune complex
8. Pseudoscleroderma
re action may be the basis of the clinieal manifestation
here. Goh postulated that the allergen is absorbed
percutaneously and evoked an allergie contact derma-
Erythema Multiforme-like Reaction (UPPEs) titis at the primary site, while concurrently forming
immune complexes with a circulating antibody (Goh
Several contact allergens, e.g., metal, topieal medica- 1989). The immune complexes were probably depos-
ments, wood and industrial chemieals have been ited in the microvasculature and triggered by an
reported to cause "erythema multiforme-like" erupt- inflammatory process that led to the UPPE. Occupa-
ions. These allergie contact reactions can be confirmed tional allergens reported to cause UPPE include woods
by positive patch-test reactions. The morphology of and/or plants, and chemieals.
these reactions includes target-like erythemacular, and
urticarial lesions. Such eruptions have been described Woods and Plants
as UPPE to distinguish them from the erythema-
multiforme (Goh 1989). Holst et al. (1976) described three carpenters who
developed erythema multiforme-like eruption from
contact allergy to three different tropieal woods - Rio
Clinical Features rosewood (Dalbergia nigra), pao ferro (Mackerium
scleroxylon) and Euculyptus saligna. The antigen in
The characteristic presentation is usually an eczema- pao ferro was R-3, 4-dimethoxy-dalbergione. A wood-
tous lesion on the primary contact site. Within a few en bracelet (Fisher 1986) and pendant (Fisher and
days, urticarial papular and plaque lesions appear on Bikowski 1981) made from Dalbergia nigra were also
the primary contact site, spreading to adjacent skin reported to cause erythema multiforme-like eruption.
and occasionally distant sites. The urticarial eruptions The specific chemical antigen was identified as
persist longer than the primary eczematous lesions and quinone R-4-methoxy-dalbergione (Hausen 1981).
tend to persist after the disappearance of the initial Nonoccupational causes have also been reported.
dermatitis. Irvine et al. (1988) reported such re action to pao ferro

276 c.L. Goh
(Machaerium scleroxylon) in a hobbyist handling the ers in an electronic factory. The liver was involved in
wood. Plants reported to cause erythema multiforme- three workers and one died of liver faHure. Patch test
like eruption include poison ivy (Toxicodendron) to trichloroethylene on one worker was negative. The
(Schwartz and Downham 1981; Mallory et al. 1982), re action was suspected to be due to a hypersensitivity
primula (Primula obconica) (Hjorth 1966) and mug- reaction from percutaneous and/or transrespiratory
wort (Artemesia vulgaris) (Kurz and Rapaport 1979). tract absorption of trichloroethylene (Phoon et al.
Mallory et al. (1982) reported urticarial eruptions with 1984).
black deposits on the skin of four patients with Goh (1988) reported erythema multiforme-like
Toxidocendron radicans dermatitis. Urticaria, eruption in a worker with contact allergy to trinitro-
erythema multiforme-like eruptions, in a patient from toluene who was employed at an ammunitions factory.
Rhus dermatitis was reported by Schwartz and Down- The systemic absorption of trinitrotoluene appeared
ham (1981). They recommended that patients with such low as its urinary metabolite, dinitroaminotoluene, was
reactions should be screened for systemic involvement not detected. Patch test to trinitrotoluene gave a strong
as previous reports have shown that nephritis can be eczematous reaction.
an associated feature (Meneghini and Angelini 1981; Recently, contact dermatitis to natural rubber latex
Fisher 1986). was also reported to present with features of erythema
multiforme-like eruptions (Bourrain et al. 1996). Air-
Metals and Chemieals borne erythema multiforme-like eruption was also
reported in individuals exposed to pyrethrum (Garcia-
Metals and several industrial chemicals have been Bravo et al. 1995).
reported to cause UPPE in sensitized patients.
Nonoccupational UPPE from nickel was first de-
scribed by Calnan (1956). Cook also reported UPPE Pigmented Purpuric Reaction
in a 13-year-old girl due to allergic contact dermatitis
from nickel and cobalt from the metal studs in her Occupational contact allergy occasionally presents as
jeans (Cook 1982). Friedman and Perry (1985) purpuric eruption. The eruption may or may not be
described a garment worker who developed UPPE preceded by erythema or itch. The exact mechanism of
from nickel dermatitis on her hands from her the reaction is unknown. It appears to represent an
scissors. Patch test revealed allergy to nickel and immune complex disease. Percutaneous absorption of
paraphenylenediamine. During patch testing, there contact allergens appears to form immune complexes
was exacerbation of the worker's hand dermatitis with a circulating antibody that becomes deposited in
and UPPE. Similar eruption appeared when the the microvasculature, producing the vasculitic lesions.
worker was patch tested to nickel alone. However, such immune complexes cannot be identi-
fied (Cainan and Peachey 1971). Purpurie eruption
Laboratory Chemieals associated with allergie contact dermatitis to rubber
chemical N-phenyl-nisopropyl PPD (IPPD) in clothing
De Feo reported chemistry students who developed was described by Batschvarov and Minkov in 1968.
UPPE while synthesizing 9-bromofiuorene in the Allergic contact dermatitis to IPPD, whieh is used in
laboratory (De Feo 1966). Roed-Petersen reported of the manufacture of some types of rubber in rubber
a 22-year-old chemistry student who developed UPPE boots, was also reported to cause purpurie eruption
on the exposed parts from a phenyl sulfone derivative (Cainan and Peachey 1971). Fisher (1974) reported
whieh he was synthesizing. Patch test gave a strong similar eruptions in three patients caused by a rubber
positive re action to the compound (Roed-Petersen diving suit, elasticized shorts and a rubberized support
1975). bandage. Romaguera and Grimalt (1977) also reported
similar eruption from IPPD in a rubberized brassiere
Industrial Chemieals due to nonoccupational cause. Shmunes (1978) report-
ed of a woman with purpurie allergic contact derma-
Nethercott et al. (1982) reported of four men working titis to paraphenylenediamine from black hats she was
with printed circuit boards who developed erythema handling as a saleswoman.
multiforme. Liver involvement was documented in
three cases. Formaldehyde was suspected to be the
cause of the eruption since two of the workers gave a Lichen Planus-Like and Lichenoid Reaction
positive reaction to formaldehyde. However, these
workers were also exposed to other substances, Occupational allergic contact dermatitis to so me color
including triehloroethylene. Trichloroethylene was developers may manifest as lichen planus-like erupt-
suspected to cause erythema multiforme in five work- ions. Such eruptions often present as itchy, dusky or
Non-Eczematous Occupational Contact Reactions 277
violaceous papules or plaques on areas of skin exposed Granulomatous Reaction

to the allergen. The eruptions behave like any allergic
contact dermatitis and tend to clear when the allergen Contact reactions to metals and metallic salts can
is removed. The histologie al features of patients with manifest as granulomatous lesions. Skin injury from
lichen planus-like eruptions from color developer zirconium, silica, magnesium, beryllium may cause
poses an interesting feature. Buckley (1958), Canizares granulomas (Rubin 1956). Some reactions are due to
(1959) and Hyman and Berger (1959) reported the delayed-type allergie re action and some are nonallergie
histology as compatible with lichen planus in a number reactions. Clinically, the granulomatous eruptions
of instances, but some authors reported nonspecific appear as inflamed papules. Eczema is usually present
chronic dermatitis changes. Fry reported that only two but pruritus is usually minimal. The histology shows
of five patients' biopsies showed histology suggestive epithelioid cells and may be indistinguishable from
of lichen planus (Fry 1965). Histology of the lesions sarcoid.
may show nonspecial superficial perivascular derma- Contact with sheep wool has been reported to cause
titis or lichenoid infiltrate in the upper dermis. There is granulomatous eruptions. An unusual case of cutane-
controversy about the etiology of the lichen planus-like ous foreign body granulomas was provoked by sheep
eruption from color developers. Color developers are wool. The patient presented, within 1 year, two epi-
known to cause lichen planus-like eruptions. Kodak sodes of a papular eruption on her neck and limbs. She
CD2 (4-N, N-diethyl-2 methylphenylenediamine), was working as a farmer's wife and each episode
Kodak CD3 (4-N-ethyl-N-2-methanesulfonylamino- occurred after preparing the ewes for coupling. She
ethyl 2 methyl-phenylenediamine sesquisulfate mono- had to keep a tight hold on the ewes while the farmer
hydrate), Agfa TSS(4-amino-N-diethylanilinesulfate), introduced warm and moist compresses in the genitals
Ilford MI 210(N-ethyl-N[5-hydroxy-amyll paraphenyl- of the animals. Each diseased skin area was closely
enediamine hydrogen sulfate), and Kodak CD4 (2- related to the tight contact with the sheep's wool and,
amino-5-N-ethyl-N-[beta hydroxyethyll amino toluene on histologie al slides, each granuloma was centered by
sulfate) are reported allergens (Goh et al. 1984). a tiny ply of wool (Lambert et al. 1995).
Recently, lichen planus-like eruptions have been
reported from contact with methacrylic acids esters.
The patient presented with lichen planus-like lesions
on sites repeatedly exposed to methacrylic acid esters Pustular Reaction
used in the car industry. Histologically, the lesions
showed all the features of classicallichen planus. Patch Pustular re action to contactant was first observed in
testing revealed positive reactions to methacrylic acid patch-test re action. The pustules are sterile and are
esters in concentrations as low as 5 x 10-3% (Kawa- transient. Fisher et al. (1959) reported that metallic
mura et al. 1996). salts, e.g., nickel, cop per, arsenic and mercurial salts,
may produce pustular reaction. Stone and Johnson
explained that such reactions may represent an
Nodular and Papular Reactions enhanced re action of prior inflammation, rather than
an irritant or allergie reaction, because such areaction
Contact allergy to gold has been reported to cause can be elicited in non-nickel-sensitive patients on skin
papular and nodular eruptions (Shelly 1963). These sites previously injected with heat-killed Corynebacte-
occurred peculiarly on the earlobes after ear piercing rial acne organisms (Stone and Johnson 1967). Hjorth
with gold earrings. Similar eruptions have been reported that atopics are more predisposed to such
observed on the hands and forearms of gold electro- reactions (Hjorth 1977). The significance of such
platers who develop contact allergy to gold salts. The re action remains controversial. Wahlberg and Maibach
eruptions characteristically pers ist for months after the believed that such pustular reactions are usually
patients have avoided contact with metallic gold irritant in nature but may also be a manifestation of
(Petros and Macmillan 1973). In some patients, the allergie reactions (Wahlberg and Maibach 1981).
patch test also evokes an unusual reaction, the re action Conde-Salazar reported a subcorneal pustular erupt-
being infiltrative and tends to persist for months ion in a patient with trichloroethylene exposure
(Monti et al. 1983). In most of these patients, the patch (Conde-Salazar et al. 1983). The patient reacted system-
test produced strong positive and persistent delayed- ically upon cutaneous challenge test made by exposing
type hypersensitivity re action to gold compounds. The only the right leg to an environment saturated with
re action to gold in these individuals appeared to trichloroethylene (to avoid inhalation) with reappear-
provoke lymphoplasia. Histology of such eruptions or ance of erythema on the exposed area within a few
its patch test re action may show dense lympho- hours and fleeting exanthema on the trunk and in the
monocytic infiltrate in the dermis (Iwatsuki et al. 1982). flexures.
278 c.L. Goh
Erythema and Exfoliation of neutrophils. The skin lesions were believed to be

due to the direct toxic effect of methyl bromide as an
Exposure to some industrial organic chemicals, e.g., alkylating agent.
triehloroethylene, appears to cause localized or gener-
alized erythema with or without papular and/or
vesicular eruption to be followed by skin exfoliation. Scleroderma-Like Readion
The skin eruptions usually take several weeks to elear.
In most of cases, the skin reaction was believed to be a Solvents have been reported as predisposing or eliciting
toxic or allergie reaction from percutaneous or muco- factors in some patients with seleroderma-like reaction.
sal absorption of the chemicals. The reaction is suspected to result from repeated
cutaneous contact with the solvent. The pathogenic
Trichloroethylene mechanism is unknown. Walder (1983) reported six
seleroderma patients who had elose contact with
Generalized erythema followed by exfoliation after aromatic hydrocarbon solvents, such as benzene,
exposure to trichloroethylene was reported by Sch- toluene and white spirit. Unlike chlorinated hydrocar-
wartz et al. (1947). It was believed to be due to systemie bons, these aromatic hydrocarbons do not produce
sensitization to trichloroethylene. The route of entry multi system disease resembling vinyl chloride disease.
may be inhalation of the vapor or percutaneous The associated seleroderma is limited to the skin of
penetration or a combination of both. Similar eruption hands and feet where the direct contact took place.
was also documented by Bauer and Rabens (1977). Yamakage and Ishikawa (1982) also reported that
Nakayama et al. (1988) also reported a generalized various aliphatic hydrocarbons, such as naphtha,
erythema and exfoliation with mucous membrane n-hexane, and hexachloroethane, can induce a gen er-
involvement in a patient exposed to trichloroethylene. alized morphea-like selerosis either by vapor exposure
The patient gave positive patch-test reaction to or by direct contact.
trichloroethylene and trichloroethanol (its metabolite). In arecent report of an analysis of 28 men suffering
It was believed that the reaction was mediated by from systemic selerosis collated over a 25-year period,
delayed-type hypersensitivity. In their patient, the skin 21 (75%) were suspected to be associated with occu-
eruption continued to appear after cessation of expo- pational seleroderma. The exposures were revealed by
sure to trichloroethylene. This was explained by the patients' files, reports to health authorities and inter-
action of trichloroethylene and its metobolites accu- views and/or answers to questionnaires. The most
mulated in the fatty tissue and released from there. frequent chemical exposure was to organic solvents.
Trichloroethylene appears to have an affinity for This was found in 13 of the patients (46%). A
adipose tissue. significant difference was found between seleroderma
Goh and Ng (1988) reported of a patient with patients and control patients not suffering from
recurrent localized erythematous xerotic plaques, connective tissue diseases in relation to total number
which became parched and fissured on the arms and of subjects exposed to one or several of the agents in
trunk of a patient with trichloroethylene. Biopsy question (Zachariae et al. 1997).
showed superficial perivascular lymphohistiocytic
infiltrate. The epidermis shows parakeratosis. The route
of entry of trichloroethylene was from the respiratory
References
tract and it was believed to be a form of systemic
trichloroethylene toxicity in a sensitized individual. Batschvaros B, Minkow DM (1968) Dermatitis and purpura from
rubber in clothing. Trans St John's Hospit Derm Soc 54:73-78
Methyl Bromide Bauer M, Rabens SF (1977) Trichloroethylene toxicity. Int J
DermatoI16:113-116
Bourrain JL, Woodward C, Dumas V, Caperan D, Beani JC,
Exposure to methyl bromide was reported to cause Amblard P (1996) Natural rubber latex contact dermatitis
sharply demarcated erythema with vesiculation in six with features of erythema multiforme. Contact Dermatitis
workers during fumigation work by Hezemans-Boer et 35:55-56
Buckley WR (1958) Lichenoid eruptions following contact
al. (1988). Plasma bromide levels after exposure dermatitis. Arch Dermatol 78:454-457
strongly suggested percutaneous absorption of methyl Calnan CD (1956) Nickel dermatitis. Br J Dermatol 68:229-232
Calnan CD, Peachey RDG (1971) Allergie contact purpura. Clin
bromide. The lesions were especially more prominent
Allergy 1:287-290
on skin that was relatively mo ist or subject to Canizares 0 (1959) Lichen planus-like eruption caused by color
mechanical pressure, such as axillae, groin and abd- developer. Arch Dermatol 80:81-86
omen. Microscopically, early skin lesions revealed Conde-Salazar L, Guimaraens D, Romero LV, Yus ES (1983)
Subcorneal pustular eruption and erythema from occupa-
necrosis of keratinocytes, severe edema of the upper tional exposure to trichloroethylene. Contact Dermatitis
dermis, sub epidermal blistering and diffuse infiltration 9:235-237
Non-Eczematous Occupational Contact Reactions 279
Cook LJ (1982) Associated niekel and cobalt contact dermatitis Kurz G, Rapaport MJ (1979) ExternaUinternal allergy to plants
presenting as erythema multiforme. Contact Dermatitis (Artemesia). Contact Dermatitis 5:407-417
8:280-281 Lambert D, Terrussot MC, Dalac S, Boulitrop-Morvan C (1995)
De Feo CP (1966) Erythema multiforme bullosum caused by Granulome a la laine de brebis. Ann Dermatol Venereol
9-bromofluorene. Arch Dermatol 94:545-551 122:534-535
Fisher AA (1974) Allergie petechial and purpurie rubber derma- Mallory SB, Miller OF, Tyler WB (1982) Toxieodendron radicans
titis. The PPPP syndrome. Cutis 14:25-27 dermatitis with black lacquer deposit on the skin. J Am Acad
Fisher AA (1986) Erythema multiforme-like eruptions due to Dermatol 6:363-368
exotic woods and ordinary plants: part 1. Cutis 37:101-104 Meneghini CL, Angelini G (1981) Secondary polymorphie erupt-
Fisher AA (1986) Erythema multiforme-like eruptions due to ions in allergie contact dermatitis. Dermatologica 163:
topical medications: part H. Cutis 37:158-161 63-70
Fisher AA, Bikowski J (1981) Allergie contact dermatitis due to Monti M, Berti E, Cavicchini S, Sala F (1983) Unusual cutaneous
wooden cross made of Dalbergia nigra. Contact Dermatitis reaction after gold chloride patch test. Contact Dermatitis
7:45-46 9:150-151
Fisher AA, Chargrin L, Fleischmayer R, et al. (1959) Pustular Nakayama H, Bobayashi M, Takaltashi M, Ageishi Y, Takano T
patch test reactions. Arch Dermatol 80:742-752 (1988) Generalized eruption with severe liver dysfunction
Friedman SF, Perry HO (1985) Erythema multiforme associated associated with occupational exposure to trichloroethylene.
with contact dermatitis. Contact Dermatitis 12:21-23 Contact Dermatitis 19:48-51
Fry L (1965) Skin disease from color developers. Br J Dermatol Nethercott JR, Albers 1, Gurguis S, et al. (1982) Erythema
77:456-461 multiforme exudativum linked to the manufacture of printed
Garcia-Bravo B, Rodriguez-Piehardo A, de-Pierola SF, Camacho circuit boards. Contact Dermatitis 3:314-322
F(1995) Airborne erythema-multiforme-like eruption due to Petros H, Macmillan AL (1973) Allergie contact sensitivity to gold
pyrethrum. Contact Dermatitis 33:433 with unusual features. Br J Dermatol 88:505-508
Goh CL (1988) Erythema multiforme-like eruption from trinitro- Phoon WH, Chan MOY, Rajan VS, et al. (1984) Stevens-Johnson
toluene allergy. Int J Dermatol 27:650-651 syndrome associated with occupational exposure to triehlo-
Goh CL (1989) Urticarial papular and plaque eruption. A roethylene. Contact Dermatitis 10:270-276
manifestation of allergie contact dermatitis. Int J Dermatol Roed-Petersen J (1975) Erythema multiforme as an expression of
28:172-176 contact dermatitis. Contact Dermatitis 1:270-271
Goh CL, Kwok SF, Rajan VS (1984) Cross sensitivity in color Romaguera C, Grimalt F (1977) PPPP syndrome. Contact
developers. Contact Dermatitis 10:280-285 Dermatitis P03-3
Goh CL, Ng SK (1988) A cutaneous manifestation of trichloro- Rubin L (1956) Granulomas ofaxillae caused by deodorants.
ethylene toxicity. Contact Dermatitis 18:59-60 JAMA 162:953-955
Hausen BM (1981) Woods injurious to human health. Walter de Schwartz RS, Downharn TF (1981) Erythema multiforme associ-
Gruyter, Berlin, p 59 ated with Rhus contact dermatitis. Contact Dermatitis 27:
Hezemans-Boer M, Toonstra J, Meulenbelt 1, Zwaveling JH, 85-86
Sangster B, van Vloten W A (1988) Skin lesions due to Schwartz L, Tulipan L, Birmingham A (1947) Occupational
exposure to methylbromide. Arch Dermatol 124:917-921 disease of the skin, 3rd edn. Lea & Febiger, Philadelphia,
Hjorth N (1966) Primula dermatitis. Trans St John's Hospit Derm p 771
Soc 52:207-219 Shelly WB, Epstein E (1963) Contact-sensitivity to gold as a
Hjorth N (1977) Diagnostic patch testing. In: Marzulli F, Maibach chronic papular eruption. Arch Dermatol 87:388-391
HI Dermatoxicology and pharmacology. John Wiley, New Shmunes E (1978) Purpuric allergie contact dermatitis to para-
York, p 344 phenylenediamine. Contact Dermatitis 4:225-229
Holst R, Kirby 1, Magnusson B (1976) Sensitization to tropieal Stone OJ, Johnson DA (1967) Pustular patch test - experimentally
woods giving erythema multiforme-like eruptions. Contact induced. Arch Dermatol 95:618-619
Dermatitis 2:295-296 Wahlberg JE, Maibach HI (1981) Sterile cutaneous pustules - a
Hyman AB, Berger RA (1959) Lichenoid eruption due to color manifestation of primary irritancy? J Invest Dermatol 76:
developer. Arch Dermatol 80:243-244 381-383
Irvine C, Reynolds A, Finlay AY (1988) Erythema multiforme-like Walder BK (1983) Do solvents cause scleroderma? Int J Dermatol
reaction to "rosewood". Contact Dermatitis 19:224-225 22:157-158
Iwatsuki K, Tagami H, Moriguchi T, Yamada M (1982) Lympho- Yamakage A, Ishikawa H (1982) Generalized morphea-like
adenoid structure induced by gold hypersensitivity. Arch scleroderma occurring in people exposed to organie solvents.
Dermatol 118:608-611 Dermatologica 165:186-193
Kawamura T, Fukuda S, Ohtake N, Furue M, Tamaki K (1996) Zachariae H, Bjerring P, Sondergaard KH, Halkier-Sorensen L
Lichen planus-like contact dermatitis due to methacrylic acid (1997) Occupational systemic sclerosis in men. Ugeskr-Laeger
esters. Br J Dermatol 134:358-360 28:2687-2689
CHAPTER 35
Occupational Pigmentary Disorders

P. Wattanakrai, L. Miyamoto and J.S. Taylor
Occupational Hyperpigmentation greater in dark-skinned subjects. Both conditions

occurring together is termed dyschromia. Hyperpig-
Definitions mentation usually follows obvious infiammation, but
sometimes the preceding lesions may not have been
Normal skin color is an admixture of the following noticed by the patient, or may have been transitory or
chromophores: red (oxyhemoglobin); blue (deoxygen- clinically imperceptible. Characterization and recogni-
ated hemoglobin); yellow-orange (carotene); and tion of the underlying infiammatory dermatosis is
brown (melanin), the major component (Mosher et al. required to assess the occupational significance. In our
1993). Environmental exposures that disturb these experience, postinfiammatory hyperpigmentation is
color factors may result in various pigmentary chan- more common than postinfiammatory hypopigmenta-
ges. Disorders of occupational pigmentation are clas- tion.
sified as: (1) the presence or absence of melanin in
melanosomes responsible for epidermal pigmentation; Physico/ (ouses
(2) the presence of melanin in dermal melanophages,
responsible for dermal pigmentation; (3) deposits of Physical agents causing hyperpigmentation include
metallic substances or pigmented particles (tattooing) artificial or natural ultraviolet light (sun exposure),
in the skin; (4) chemical discoloration or staining of ionizing radiation, and chemical and thermal burns
the skin from extern al contact with a dye or deposition (Gellin 1990). Blunt trauma and continued friction or
of chemicals or dyes after ingestion, inhalation or scratching can also increase pigmentation in suscep-
percutaneous absorption. tible, pigmented individuals. People with occupations
Hyperpigmentation refers to increased formation of in which there is prolonged standing, such as in police,
melanin, which may be caused by increased melanin letter carriers and waitresses, are said to develop stasis
production by existing melanocytes or from increased dermatitis with pigmentation due to hemosiderin
proliferation of active melanocytes (Mosher et al. deposition (Schwartz 1947). Haemosiderosis without
1993). Occupationally induced hyperpigmentation, the clinically evident hypermelanosis is seen in chronic
most common work-related pigment change (Gellin pigmented purpura (Bleehen et al. 1992).
1987), may result from an antecedent infiammatory A case of occupationally induced chronic pigmented
dermatosis, including infections, many physical caus- purpura was reported in a dye factory worker. His
es, exposure to excessive sunlight, chemical photo sen- workplace was filled with dust from sulfonated and azo
sitivity, and other non-photosensitive chemical dyes. However, skin lesions cleared after he wore a
exposures (Bleehen et al. 1992; Hogan and TangIe- mask to stop inhalation of the dye dust (Nishioka et al.
rtsampan 1992). 1980).
Workers with prolonged exposure to heat from open
Physical and Chemical Causes of Epidermal fiames, such as welders, glass workers, foundry work-
and Dermal Hyperpigmentation ers, blast-furnace workers (Schwartz 1947); open field
cooks (Olumide et al. 1991); bakers and silversmiths
Postinflommotory Hyperme/onosis (Page and Shear 1993), may develop striking reticulate
pigmentation called erythema ab igne. After many
Hyper- and hypopigmentation may follow any acute or years, these individuals may also develop thermal
chronic infiammatory process in the skin with the keratoses which may show only cutaneous epidermal
intensity and persistence of the pigmentation being dysplasia, squamous cell carcinoma in situ, or become
invasive squamous cell carcinoma (Schwartz and Stoll
Adapted in part from Miyamoto and Taylor (2000) 1993).

Occupational Pigmentary Disorders 281
Chemica/ Photosensitivity described in occupations where phototoxic plants are

handled. Examples include chefs (Maso et al. 1991),
Cutaneous photosensitivity (Emmett 1987; Rietschel grocery-store workers (Berkley et al. 1986; Seligman
and Fowler 1995) is due to the presence of an et al. 1987). All cases reported were exposed to celery
exogenous chemical that absorbs ultraviolet radiation which naturally produces psoralen. Phytophotoderma-
and initiates photochemical events in normal tissue. A titis in celery harvesters (Birmingham and Key 1961)
number of substances used industrially or contacted resulted from exposure to celery infected with the
occupationally can cause occupational photosensitivi- psoralen-producing, pink-rot fungus (Sclerotinia
ty, but usually only phototoxic reactions cause signi- sclerotiorum). Other occupations at risk of phytopho-
ficant hyperpigmentation. todermatitis include vegetable pickers, harvesters, field
workers, farmers, carrot processors, cannery packers,
Phototoxic Readions florists and bartenders (Emmett 1990).
Coal-tar derivatives are among the most commonly
Phototoxic reactions are analogous to irritant contact encountered occupational photosensitizers; others in-
dermatitis, except for the additional requirement of clude crude petroleum, residues of petroleum distilla-
ultraviolet or visible radiation. They are non-immu- tion, and asphalt. W orkers exposed to these substances
nological and occur in most individuals upon first either in the form of dusts, vapors or fumes complain
exposure. Other factors include the amount of radia- of photosensitization. Photo dermatitis due to tar and
tion of the appropriate wavelength and the quality of pitch appears as a severe sunburn with erythema,
the photosensitizing chemicals. Phototoxicity usually swelling and an intense burning sensation referred to
manifests as an exaggerated sunburn re action followed as "flashes" and "smarts". Pigmentation subsequently
by hyperpigmentation. Chronic changes, in particular occurs on the exposed skin and is due partly to
persistent hyperpigmentation, may be found after melanin and partly to actual dyeing or discoloration of
repeated reactions. Phototoxic chemicals include the skin by the coal tar itself. After the exposure to coal
coal-tar derivatives, dyes, phototoxic oils and fra- tar ceases, the pigmentation fades and may disappear
grances, and phototoxic plant chemicals. Phototoxic in about a year, but photosensitization may persist for
drugs include phenothiazines, sulfonamides and nali- longer (Schwartz 1947). Coal-tar derivatives are used in
dixic acid (Tables I, 2 for lists of selected phototoxic many diverse industries, including drug manufacture,
plants, drugs and chemicals). dyes, perfumes, synthetic resins, explosives, insecti-
Phytophotodermatisis is a phototoxic re action cides, and disinfectants (Rietschel and Fowler 1995).
caused by the interaction of ultraviolet radiation and The principle occupational sources in which coal-tar
a photoactive substance, such as any of the furocou- and petroleum derivatives cause photosensitization
marins, deposited on the skin surface after contact and melanosis are: (1) coal-tar distillation plants;
with various species of plants (Table 1) (Pathak et al. (2) making conduits by impregnating paper tubing
1962; Pathek 1986). The dermatitis is usually vesicular
or bullous healing with characteristic residual hyper-
pigmentation. Phytophotodermatitis is a well-known Table 2. Selected phototoxic drugs and chemicals. Adapted from
Emmett (1987); Rietschel and Fowler (1995); Harber and Bickers
cause of occupational hyperpigmentation and has been (1989)
Table 1. Phototoxic plants Plant derivatives Furocoumarins

containing furocoumarins Celery Coal-tar derivatives Acridine
(psoralens). Adapted from Parsnip Anthracene
Pathek 1986; Pathak et al. Limes, lemons Phenanthrene
(1962) Figs Fluoranthene
Carrot Drugs Phenothiazines
Dill Sulfonamides
Mustard Tetracyclines
Buckwheat Nalidixic acid
Bergamot Amiodarone
Fenne! Benoxaprofen
Caraway Thiazides
Rue Furosemide
Gas plant Naproxen
Angelica Piroxicam
Buttercup Dyes Anthraquinone
Goosefoot Eosin
Scurfy pea Methylene blue
St. John's wort Rose bengal
Masterwort Halogenated xanthine dyes
Anise Ultraviolet -cured inks Amyl-o-dimethylamino
Coriander benzoic acid
282 P. Wattanakrai et al.
and roofing with coal-tar pitch or heavy coal-tar within the field of hyperpigmentation ("raindrops on
distillates; (3) using paint containing heavy coal-tar a dusty road"). The pigmented areas tend to affect the
distillates or pitch, as in rust proofing iron pipes; (4) nipple, axillae, groin, pressure points and areas around
wood-preserving industries, which use coal-tar distil- scars, similar to Addison's disease, except that in
lates to impregnate railroad ties, telegraph poles, pier arsenicism the oral mucosa is usually spared (Adams
supports, etc.; (5) on roads using pitch and asphalt; 1993; Mosher et al. 1993; Schwartz and Stoll 1993).
(6) briquette factories, which use coal-tar pitch to Pigmentation results from deposit of melanin, formed
make fuel briquettes from coal dust; (7) petroleum from arsenie-altered cell metabolism, and not from the
refineries; and (8) oil fields (Schwartz 1947). deposit of arsenie in the skin (Osorne 1925). Arsenic-
Phototoxic dermatitis with burning pain similar to ism is a systemic disease; therefore, recognition of the
that caused by coal-tar derivatives has been observed cutaneous stigmata may alert the physician to other
in workers manufacturing ultraviolet cured inks con- organ involvement, i.e., peripheral neuritis, gastroin-
taining amyl-o-dimethyl-aminobenzoie acid as a pho- testinal disturbances, hematologic involvement, and
toinitiator (Emmett 1987). A phototoxie dermatitis of myocardial injury (Stokinger 1981).
the fingers and hands has been observed in medical Hyperpigmentation from acnegenic halogenated,
and nursing personnel or pharmaceutieal workers who aromatic hydrocarbons has been reported with expo-
contaminate their hands while handling phenothi- sure to dioxin [2,3,7,8-tetrachlorodibenzo-p-dioxin or
azines or other phototoxic drugs (Cahn and Levy 1957; (TCDD)] and polychlorinated biphenyl (PCB). Expo-
Epstein and Brunsting 1958). Table 2 lists selected sure may occur in many situations - in industrial,
phototoxic drugs and chemieals. military, or accidental settings. These halogenated
aromatic compounds or their contaminants are now
Photoa/lergic Reactions only rarely found or used in products, such as in
hydraulie fluid, lubricants, plasticizers, adhesives,
Photoallergy is analogous to allergie contact dermatitis paints and varnishes, putty and sealants, fire retar-
in that it is mediated by the immune system and there dants, herbicides and carbonless paper (Brodkin and
is no reaction with first exposure. Photoallergy is less Schwartz 1984). The mechanism of hyperpigmentation
common than phototoxicity and the concentration of from the acnegenic halogenated, aromatic hydrocar-
drug needed to elicit photoallergy is much lower than bons has not been definitely determined. Color may
for phototoxicity. Photoallergic dermatitis presents as vary from brown to gray with the face, neck, and dorsal
an acute eczematous reaction which may be followed aspect of the hands being most obviously involved.
by lichenoid dermatitis or papules. Chloracne is the most common skin stigmata seen with
exposure to TCDD and, less commonly, hyperpigmen-
Non-Photosensitive Chemica/ Exposures tation and hirsutism. Cases of PCB poisoning, in Japan
and Taiwan, from ingestion of contaminated rice-bran
Exposure to some chemicals pro duces hyperpigmen- cooking oll were also associated with chloracne, and
tation without photosensitization. Examples inc1ude finger- and toe-nail and mucosal pigmentation. Similar
arsenic and certain acnegenic halogenated aromatic pigmentation of the nails and conjunctiva has only
hydrocarbons. been found in 2-3% of industrial PCB poisoning
Occupational arsenic exposure may be found in the (Gladen et al. 1990; Ruxin and Taylor 1994).
following types of work: agricultural (as a cotton
desiccant); animal husbandry (for sheep dip and Pigmented Contact Dermatitis
growth promotion of swine and poultry); rodenticide,
insecticide and fungicide; cop per and lead smelters; Pigmented contact dermatitis is another cause of
ore miners; semiconductors, glass and ceramic, print- occupational pigmentation. This term was first used
ing ink, and leather; and painters (Schwartz et al. by Osmundsen (1970), who contributed much to our
1957a,b; Dickerson and Smith 1988; Ruxin and Taylor understanding of melanosis as a feature of contact
1994). In the occupational setting, the respiratory tract dermatitis. He described an epidemic of intense and
is the most common port of entry. Skin and gastro- bizarre hyperpigmentation caused by contact allergy to
intestinal routes are also possibilities, but are less the optical whitener, Tinopal CM3566, used in washing
prevalent, unless by accident or medication. Hyper- powders. This optical whitener was a mixture of two
pigmentation from arsenic is seen as a feature of pyrazoline derivatives and is no longer used by
chronie arsenie poisoning, the most characteristic industry. Clinically, the sites of pigmentation corre-
feature being arsenical keratoses. sponded to those of textile dermatitis, with discolor-
The pigmentary changes in the skin are seen as ation varying from blue-brown to slate gray.
"bronze" hyperpigmented patches, with characteristic Pigmentation also developed at the site of application
1- to 2-mm hypopigmented raindrop-like macules of several patch tests that contained the responsible
chemicals. Biopsies showed deposits of melanin within (Zenorola et al. 1994). The clinical picture and histol-
as weIl as outside of upper dermal melanocytes. ogy was compatible with ashy dermatosis/erythema
Melanin hyperpigmentation may follow many acute dyschromicum perstans, with no clinical evidence of
and chronic inflammatory processes in the skin. The contact dermatitis. Patch testing was positive to cobalt
primary inftammatory reaction disturbs the epidermal- chloride, also leaving residual pigmentation at the
dermal junction, causing incontinence of pigment positive patch test site 1 month later. In 1991, Tanii
which gives rise to a rather persistent, slate-colored et al. reported a case of prurigo pigmentosa caused by
pigmentation; it is commonly seen in lichen planus, contact allergy to the chromium component of an
fixed drug eruption, ashy dermatosis and Riehl's acupuncture needle. Erythema with sub se quent pig-
melanosis. Riehl's melanosis is now considered to be a mentation was induced by patch testing with potassi-
pigmented contact dermatosis, mostly from sensitizing um dichromate, and resumption of acupuncture
fragrances and chemieals in cosmetics. Hyperpigmen- caused a flare-up, both at the previous patch test site
tation is not a common feature of irritant and allergie and initial dermatitis on the patient's back. Prurigo
contact dermatitis. Pigmented contact dermatitis is pigmentosa and pigmented contact dermatitis resem-
usually seen in persons with a dark complexion, who bled the patient's eruptions, subsequent reticular
have a tendency to react with hyperpigmentation and pigmentation and the histologie al finding of lichenoid
may be less likely than fair-skinned people to develop reaction. Therefore, the authors concluded that the
typical eczematous changes when exposed to certain reported conditions should be regarded as pigmented
allergens (Osrnunden 1970; Pinol-Aguade et al. 1971). contact dermatitis to chromium. Table 3 lists chemi-
Azo dyes are well-known causes of occupational eals that cause pigmented contact dermatitis.
pigmented contact dermatitis. Ancona-Alayon et al. In conclusion, when an epidemie of hyperpigmen-
(1976) reported an epidemie of pigmented contact tation occurs in the occupational setting, a diagnosis of
dermatitis occurring in a textile mill from an azo-dye- pigmented contact dermatitis should be considered.
coupling component, naphthol AS. The hyperpigmen- However, in isolated, non-occupational cases, pig-
tation was most pronounced in individuals with dark mented contact dermatitis is more likely to be missed.
complexions, whereas fair-skinned people showed
"classic" eczematous symptoms, including pruritus. Deposits of Metallic Substances
These observations confirmed the correlation between
dark complexion and absence of pruritus and typical Meta/s
eczema. Other azo dyes, Sudan land Vacanceine red,
have also been described as the cause of occupational Occupational deposits of metals in the skin that cause
pigmented contact dermatitis (Fujimoto et al. 1985). It pigmentary changes are rare (Schwartz 1947). The
is also important to note that Brillant Lake Red R was discoloration may result from either the metallic
widely used in cosmetic cheek rouges and lipsticks in deposition within the skin itself or stimulation of
Japan until1976. It was the most important cause of an melanin synthesis (Wahlberg 1987; Bleehen et al. 1992).
epidemie of pigmented contact dermatitis among
Japanese women and contained Sudan I as a major Silver
impurity (Kozuka et al. 1979). Argyria results from deposition of silver in the skin,
Several other isolated cases of occupational pigmen- causing a blue to slate-gray coloration, most intense on
ted contact dermatitis have been studied. Insoluble exposed skin, especially the face and hands, with
cutting oils have been reported to cause occupational relative sparing of skin folds. The pigmentation may
melanoderma (Fountain 1967). The clinical picture and also occur on the gingiva, oral mucous membranes,
histology seem to be compatible with melanodermati- conjunctivae, sclerae and nails (Schwartz et al. 1957a,b;
tis toxica, which is thought to be caused by contact Granstein and Sober 1981). Onset of argyria ranges
with tar or industrial oils. Paraphenylenediamine, a from several months to the more-usual several years
rubber antioxidant, was described as the cause of
reticular brownish black pigmentation in a Japanese
ferry boat captain contacting a rubber peephole of a Table 3. Chemi-
ship radarscope (Hamada and Horiguchi 1978). The cals causing pig- Optical whitener
mented contact Naphthol AS
contact region of the rubber covering over the peep- dermatitis. Based Azo dyes: Sudan I
hole of the radarscope coincided with the pigmentation on text references Vacanceine red
on his face, and there were positive reactions with the Insoluble cutting oils
rar or industrial oils (melanodermatitis
rubber peephole material and paraphenylenediamine. toxica)
A case report of "ashy dermatosis" associated with Paraphenylenediamine
cobalt allergy in a plumber should also be taken as an Cobalt chloride
Chromium
example of occupational pigmented contact dermatitis
(Gawkrodger 1998). Several cases of occupational sa. A distinctive blue-black gingival line produced by
argyria have been reported in the past by White bismuth is similar to the lead line, but may be
(1934a,b) and Gettler et al. (1927), such as during differentiated by the occupational exposure history
handling of silver metals by silversmiths or the oral and accompanying symptoms. Occupationally, bismuth
suctioning of silver nitrate solution in the preparation is employed in the preparation of metal alloys, and the
of silver beads, and in silver polishers, resilverers and sub nitrate was previously listed as an ingredient in
silver-leaf handlers. In 1981, Bleehen et al. additionally some cosmetic preparations (Schwartz 1947). Bismuth
reported argyria in furnace men industrially exposed compounds were once used parenterally in the treat-
to molten silver. ment of venereal disease. More recently, bismuth-
Localized argyria may result from exposure to containing drugs have become more popular as a
topical silver salts through either occupational or treatment of chronic gastritis, peptic ulcers, duodenal
medical sources. Specks of silver may become embed- ulcers and traveler's diarrhea. Therapy with colloidal
ded in the skin of silver workers in the silversmith or bismuth subcitrate to promote healing of peptic,
silver-plating industry causing bluish-black spots duodenal ulceration may cause temporary discoloration
(Lewin 1887). Buckiey (1963) reported localized argyria ofthe oral cavity (Dekker et al. 1986). In 1993, Zala et al.
on the hands of a duplicating machine operator from reported generalized metal-gray pigmentation of the
daily immersion in photographic developing solution skin and mucous membranes without further signs of
containing silver. chronic bismuth poisoning following long-term bis-
muth injection for pneumatosis cystoides intestinalis.
Mercury
Chrome
Mercury causes gray-brown pigmentation, which is
equally prominent in exposed and light-protected skin The skin and nails of electroplaters, leather tanners,
and often is increased in skin folds. Generally, the lithographers and others who contact bi chromate
pigmentation is most pronounced on the eyelids, in the assume a pale "ochre" yellow tint (White 1934a,b).
nasolabial folds, and in the folds of the neck (Lamar
Copper
and Bliss 1966). This pigmentation sometimes results
from repeated applications of mercury-containing Copper dust causes a greenish-black discoloration of
topical preparations and can also occur following the hair, skin and teeth of copper smelters and other
industrial exposure (Burge and Winkelmann 1970; exposed workers with no association to copper
Kennedyet al. 1977). A characteristic bluish staining of poisoning (Browning 1969).
the conjunctiva is caused by fulminate of mercury
Cadmium
(White 1934a,b). Systemic administration of mercury
has been reported to result in gingival hyperpigmen- Cadmium solution coming in contact with the skin
tation similar to that produced by lead and bismuth may turn the skin black (Prodan 1932).
(Everett 1979). It may be seen as diffuse blue-gray or
Tellurium
black gingival pigmentation (Dummett 1971).
Occupational absorption of tellurium was reported by
Gold
Blackadder and Nanderson (1975) in two research
Chrysiasis results from deposition of gold in the skin, workers who showed the typical early signs and
usually resulting from the excessive use of therapeutic symptoms of tellurium intoxication: the characteristic
gold injection. The pigmentation is slate like, bluish smell of garlic in their breath and excreta. Additional
gray or may show a purplish hue. Sun exposure is findings, which have not previously been reported,
necessary for the appearance of gold pigmentation. were bluish-black discoloration of the finger webs and
The oral mucosa is not affected (Schmidt 1941; Burrows streaks on the face and neck. No systemic involvement
and Adams 1990). Clinically, the pigmentation in or permanent damage resulted and both individuals
chrysiasis differs from argyria in that gold-induced recovered spontaneously without treatment. The na-
pigment is more prominent about the eyes and is ture and histopathology of the pigmentation in these
limited to exposed areas (Granstein and Sober 1981). two cases were not determined.
Bismuth
Tattoos
Aside from silver, mercury and gold, bismuth has also
been reported to be a cause of generalized gray Pigmented foreign particles may accidentally be intro-
pigmentation. The conjunctivae and the oral mucosa duced as contaminants of wounds or may, at high
mayaiso become pigmented (Granstein and Sober velocity, with explosive or abrasive forces penetrate
1981). Dust containing bismuth may be absorbed and previously intact skin. Carbon is the most common
produce a bluish-black discoloration of the oral muco- material, leaving black or blue blemishes, depending
on the depth of the deposit. Another common example yellow staining of the skin and sclerae. Glutaraldehyde
of accidental tattooing is seen in abrasions induced by can produce a yellow-brown stain on contact, in
road accidents with the embedding of blacktop and medical personals, nurses and hemodialysis techni-
asphalt (Agris 1976). cians. An epoxy resin hardener 4,4'-methylenedian-
"Collier strip es" are distinctive occupational marks ilene (MDA) caused yellow staining of the skin, nails
found on coal miners. They are seen as blue-black, and hair in workers engaged in a molded plastic
bluish-gray, irregularly-shaped linear or angular scars operation (Cohen 1985). MDA is a known hepatotoxin
at the site of abrasions and small scratches as the result in human, with carcinogenic properties in animal test
of tattooing coal dust into the skin. In very old reports, systems. Thus, yellow staining serves as a cutaneous
the collier, stripped down to the waist when working, marker of exposure to MDA. Aside from exogenous
soiled every wound with coal dust before healing contact with these chemicals, yellowish discoloration
became complete (White 1934a,b; Bettlen 1940). must also be differentiated from the other non-
"Pigmented scars" are also observed in iron, stone, occupational causes of yellowish staining of the skin,
silver and flour-mill employees. Cases of skin pigmen- mainly jaundice and carotenemia.
tation from the external therapeutic application of iron
salts, such as ferrous sulfate and ferric chloride, have Brown
been described. Hare (1951) reported red-brown, punc-
tate, perifollicular pigmentation from deposition of Topical anthralin (dithranol) may cause brown discol-
iron granules on the forearms of a metal worker oration in pharmacists and nurses contacting the
employed in "pickling" metal in hydrochloric acid. The medication. Brownish discoloration is also seen on the
pickling fluid contained iron salts in an acid medium. skin and nails of coffee roasters and burnt-sugar
workers (White 1934a,b).
Other Discolorations and Staining of the Skin
Red
Exposure to dyes or chemicals that have dyeing
properties will discolor the skin and hair. Workers in Red pigmentation of the hair and skin is seen in the
dye factories, especially those handling the finished operators manufacturing ferricyanide of potassium
chemical dyes, will have their hands and, less often, used in electroplating.
their face stained. The staining is superficial and can be
removed totally or partially by suitable washing Block
(Schwartz et al. 1957a,b), but persistent dye staining
of the skin has been reported (Buckley and West 1970). Black lacquer-like deposit on the skin in patients with
Toxicodendron radicans dermatitis has been described.
Yellow Histologically, the deposit material was identified in
the stratum corneum (Mallory et al. 1982). These
Yellow discoloration and staining of the skin has been "black spots" were also mentioned by McNair (1923)
caused by various chemicals. The light-yellow hue of to occur in two gardeners who let fresh sap fall on their
picric-acid workers is characteristic. They were com- hands. Table 4 contains an expanded list of chemicals
monly known as "canaries". In fair-skinned people, that cause skin discoloration and staining.
the hair may also become olive-green (White 1934a,b).
Trinitrophenylmethylnitramine (tetryl) is known for
producing yellow stains on exposed skin, as well as Occupational Leukoderma and Hypopigmentation
causing liver cirrhosis (Schwartz et al. 1957a,b). Nitric
acid or nitrates in an acid environment also result in Definitions
less intense yellowing at sites of contact. Sodium nitrite
in an electric steel etching agent was reported to stain Leukoderma is a general term for any pigmentary
the palmar skin of seven workers (Fregert et al. 1980). dilution, whether congenital or acquired, circum-
The hands, face and hair of munition workers handling scribed or generalized (Ortonne et al. 1983). Occupa-
trinitrotoluene (TNT), dinitrotoluene (DNT), dinitro- tionalleukoderma will usually present as an acquired
benzene, pentaerythryltetranitrate (PETN), trinitro- and circumscribed leukoderma.
phenol, ammonium picrate, lead styphnate and Hypopigmentation/hypomelanosis refers to a reduc-
hexanitrophenylamine are often yellowish from con- tion in melanin content relative to the individual's
tacting these chemicals (Schwartz 1947). Dinitrosali- normal skin. Depigmentation is a term implying loss of
cyclic acid also stained the palms and nails of a pre-existing melanin pigmentation (Mosher et al.
laboratory assistant yellow (Fregert and Trulson 1980). 1993). Vitiligo should be reserved for idiopathic or
Dinitrophenol, formerly used in industry, pro duces hereditary acquired leukoderma or depigmentation
Table 4. Chemicals causing occupational discoloration. Based on Non-Specific Agents

text references
Discoloration Causative agents Melanocytes are vulnerable to non-specific trauma.

Therefore, many non-specific physical, mechanical or
Yellow Chrome chemical agents, if causing enough injury, may cause
Glutaraldehyde
Picric acid, ammonium picrate loss of epidermal and follicular melanocytes, produc-
Nitric acid, sodium nitrate ing loss of pigment in skin or hair of exposed area
Trinitrophenylmethylnitramine (tetryl) (ürtonne et al. 1983).
Trinitrotoluene (TNT)
Trinitrophenol
Hexanitrophenylamine Postinflammatory Hypopigmentation
Dinitrotoluene (DNT)
Dinitrobenzene
Dinitrosalicylic acid Postinßammatory hypopigmentation may result from
Pentaerythryltetranitrate (PETN) any inßammatory dermatologie disease or process. It is
4,4' -methyl dianilene (MDA) a common problem in darkly pigmented individuals
Lead styphnate
Anthracene (Papa and Kligman 1965), but may occur in many
Fluorescein dye different skin types. Frequent causes of postinßamma-
Brown Topical anthralin (dithranol) tory hypopigmentation include eczematous dermatitis;
Arsenic
Dioxin (TCDD) either irritant or allergie contact dermatitis; atopic
Polychlorinated biphenyls (PCBs) dermatitis; discoid lupus erythematosus; chronic gut-
Coffee, burnt sugar tate parapsoriasis; lichen striatus; pityriasis alba;
P-phenylenediamine
Permanganates psoriasis; pityriasis lichenoides; and cutaneous T-cell
Phenothiazine lymphoma (ürtonne et al. 1983; Bleehen et al. 1992).
Blue, Blue Gray Silver, silver salts The cause of pigment loss is usually an obvious
Mercury
Gold antecedent inßammatory process. However, in so me
Bismuth cases, the inßammation may be clinically impercepti-
Tellurium ble and not apparent. Therefore, characterization and
Osmium trioxide
Black Toxicodendron radicans resin recognition of the underlying inßammatory skin
Cadmium solutions condition is important in establishing the occupational
Blacktop, asphalt significance.
Coal dust
Red Iron salts
Potassium ferricyanide Chemical Leukoderma
Green Copper dust
Ichthymol
Introduction
(Gellin 1990), while chemical leukoderma or toxic Chemicalleukoderma is a form of cutaneous pigment
vitiligo, although not clearly defined, describes a loss resembling vitiligo and is caused by exposure to a
depigmentation caused by the cutaneous exposure to variety of chernicals that act by selective melanocyto-
chemie als that have direct, specific melanocytotoxic toxicity (Gellin and Maibach 1985). Most cases result
effects or suppress the capacity of melanocytes to from skin contact, but ingestion or inhalation of
produce melanin (Cummings and Nordlund 1995). chemieals may also be factors. Chemie al leukoderma
Leukoderma can also be divided into (1) me- has been referred to as occupational vitiligo, but a
lanocytopenic leukoderma, in which the melanocytes number of non-occupational cases have also been
are reduced or absent, usuaily with clinically pure reported.
white macules, and (2) melanopenic leukoderma, in A number of chemieals have been proposed to
which the melanocytes are present, but there is a induce leukoderma by both human and animal in vivo
reduction of melanin due to adefeet in the melaniza- studies, and also by experimental in vitro work (Ta-
tion process causing a mild to very marked pigmentary ble 7). The largest and best-studied group of chemie als
dilution. The differential diagnosis of an acquired and are derivatives of phenol and catechol (Fig. 1).
circumscribed leukoderma, as seen in the occupational Hydroxylation of the 4-(para)-position and substitu-
setting, if melanocytopenic would include vitiligo and tion of a non-polar alkyl side group in the I-position
chemical leukoderma. In contrast, melanopenic pig- has been observed to increase effectiveness for depig-
ment loss commonly includes postinßammatory mentation (Riley 1969). Alkyl phenols are used in the
hypomelanosis and non-specific chemie al or physical industrial setting as antioxidants or rust inhibitors. In
leukoderma (ürtonne et al. 1983) (Table 5). commercial uses, they may be found in deodorants,
A classification of agents causing occupational disinfectants, germicides, insecticides, motor oils, oil
pigment loss is listed in Table 6. additives, de-emulsifiers, paints, photographie chemi-
Table 5. Differential diagnosis of acquired and localized hypopigmentation (leukoderma). Adapted from Mosher et al. (1993)
Etiologic factors Melanocytopenic Melanopenic
Heritable or developmental Vitiligo

Chemical and drug Monobenzyl ether of hydroquinone (MBEH) Hydroquinone
Alkyl phenols (phenols and catechols) Arsenicals
Sulfhydryl compounds Corticosteroids - topical, intralesional
Chloroquine diphosphate
Physical Bums (thermal, UV ionizing radiation) Postdermabrasion
Trauma
Inflammation and infection Pinta, yaws Sarcoidosis
Onchocerciasis Syphilis
Mycosis fungoides Leprosy
Pityriasis lichenoides chronica Post Kala-azar
Actinic reticuloid Tinea versicolor
Pityriasis alba
Postinflammatory eczematous dermatitis, discoid
lupus, erythematosus, psoriasis
Miscellaneous Vogt-Koyanagi-Harada syndrome Canities
Alopecia areata Idiopathic guttate hypomelanosis
cals, printing inks, varnishes, lacquers, plasticizers, Table 7. Selected chemieals associated with chemical leukoder-
adhesives, resins and rubber (Cainan 1973; Gellin and ma. Adapted from Gellin (1987), Ortonne et al. (1983), and Taylor
et al. (1993)
Maibach 1983).
Phenollcatechol derivatives
Causes Monobenzyl ether of hydroquinone (MBEH)
Monomethyl ether of hydroquinone (MMEH)
(p-methoxyphenol; p-hydroxyanisole)
Monobenzyl Ether oi Hydroquinone Monoethyl ether of hydroquinone (MEEH)
(p-ethoxyphenol)
In 1939 and 1940, respectively, Oliver et al. and Hydroquinone (HQ)
Schwartz et al. from the US Public Health Service first (1,4-dihydroxy benzene; 1,4-benzenediol; quinol;
p-hydroxyphenol)
documented an outbreak of occupational leukoderma p-tert-butylcatechol (PTBC)
in tannery workers wearing rubber gloves. Depigmen- p-tert-butylphenol (PTBP)
tation was caused by the rubber antioxidant mono- p-tert-amylphenol (PTAP)
p-phenylphenol
benzylether of hydroquinone (MBEH), also known as p-octylphenol
"Agerite Alba". Fifty-two percent of exposed workers p-isopropylcatechol
who wore heavy acid-cured rubber gloves containing p-methylcatechol
Butylated hydroxytoluene (BHT)*
0.2% MBEH were affected (Malten et al. 1971). In some, Butylated hydroxyanisol (BHA)*
the leukoderma occurred on the hands and half way up Pyrocatechol
the forearms with a uniform, sharp cut-off line (1,2-benzenediol)
p-cresol
corresponding to areas covered by the gloves. In Sulfhydryls
others, there was a patchy, guttate, confetti-like ß-mercaptoethylamine hydrochloride (MEA)
pigment loss. The face and trunk were also involved (cysteamine)
N-(2-mercaptoethyl)-dimethylamine hydro chloride (MEDA)
in some workers, probably from direct contact with the Sulfanolicacid
gloves. Depigmentation was most marked in African Cystamine dihydrochloride
Americans, less intense in Hispanics, and noticed in 3-mercaptopropylamine hydrochloride
Miscellaneous
Caucasians only during the summer. The workers wore Mercurials
Arsenic
Cinnamic aldehyde
p-phenylenediamine (PPDA)
Table 6. Occupational causes of hypopigmentation. Based on Benzyl alcohol
work by Cummings and Nordlund (1995), Gellin (1987, 1990), Azaleic acid*
and Ortonne et al. (1983) Corticosteroids
Optic Preparations
Physical agents: X-rays, ionizing radiations, ultraviolet rays, Eserine (physostigmine)
freezing, hypothermia
Diisopropyl fluorophoshate
Mechanical agents: physical trauma; blunt, repeated trauma;
Thio-tepa (N,N'N" -triethylenethiophosphoramide)
traumatic loss of tissue
Guanonitrofuracin
Bums: chemical and thermal bums
Systemic Medications
Caustic chemieals: alkali, acid
Chloroquine
Postinflammatory hypopigmentation: irritant and/or allergie Fluphenazine (Prolixin)
contact dermatitis
Specific chemicalleukoderma
* Depigmentation weak or not known
o 6 0
Fig. 1. Chemical structures of selected phenols and catechol OH OH OH
derivatives
00
phenol catechol OH
hydroquinone
o 0 o
OH OH OH
00
-9- CH eH3 -c- eH3 oI
6
CH3 3
I
CH3 eH3
p-tert-butylphenol p-tert-butylcatechol
monobenzyl ether of hydroquinone
the rubber gloves for many months before leukoderma hearing aid, which was found to contain MBEH (Bajaj
developed. et al. 1992). Bajaj also described cases of depigmenta-
Patch testing with various chemicals in the gloves tion of the breast, corresponding to the site of eontact
confirmed that MBEH was the cause of the pigment with a synthetic leather wallet, and 19 cases of depig-
loss. Leukoderma occurred at most positive patch test menta ti on of the feet, corresponding to contact with
sites within 14 days to several months; there was no footwear material (bathroom slip-ons, rain shoes); all
direct correlation between intensity of patch test incriminating objects were, on analysis, confirmed to
reactions and subsequent leukoderma. Hydroquinone contain MBEH (Bajaj et al. 1991, 1996).
(HQ) was present as an impurity at less than one
Hydroquinone
percent and was not a factor in the leukoderma.
Several months after workers discontinued wearing HQ, at concentrations of up to 40/0, is present in
the gloves, partial perifollicular repigmentation was bleaching creams that are used to lighten hyperpig-
noted. mented skin, such as in melasma. HQ is a weak
Around the same time, McNally (1939) reported depigmenter at 10/0 concentration, but is a stronger
similar cases of depigmentation in 34 tannery workers, depigmenter at higher concentrations and with differ-
initially involving the hands and arms. The leukoder- ent vehicles. Prolonged use of HQ followed by sun
ma was associated with the use of a new brand of exposure may lead to exogenous ochronosis with
rubber gauntlet gloves, which was found to contain the colloid milium production (EIder 1986). Fisher (1982)
same antioxidant, MBEH, as well as unchanged HQ. reported about four patients who developed leukoder-
Leukoderma caused by MBEH has been reported to ma following the use of bleaehing creams containing
be related to a number of rubber devices including 20/0 HQ, and Markey et al. (1989) deseribed confetti-
tape, diaphragms, condoms, finger cots, clothing, like depigmentation in the beard area of a dark-
aprons, dolls, and shoes (Ortonne et al. 1983, Fisher skinned man after application of a HQ-eontaining
1995). It has also been identified in synthetic neoprene cream. Three other separate anecdotal reports of
rubber (Ortonne et al. 1983). The US rubber industry depigmentation due to the HQ present in photographic
has not used MBEH as an antioxidant for many years developer, in concentrations ranging from 0.060/0 to
(Taylor 1986). In 1951, Botvinick reported dermatitis 70/0 have also been reported (Frenk and Loi-Zedda
and secondary leukoderma from a fabric-lined house- 1980; Kersey and Stevenson 1981; Das and Tandon
hold glove containing MBEH, and reproduced the 1988).
dermatitis and leukoderma with patch testing (Botvi- However, results of a large study, comprised of 840
nick 1951). In 1992, Bajaj et al. identified, by means of volunteers with examination of over 7000 test areas,
high-pressure liquid chromatography (HPLC) analysis, demonstrated that "concentrations of HQ of 30/0 or less
a patient in India with depigmentation at the site of a produced negligible adverse effects, irrespective of the
base or the color of the user's skin" (Bentley-Phillips because PTBP is rarely added in excess. However, 100
and Bayles 1975). The Cosmetic Ingredient Review cases of depigmentation caused by PTBP present at a
Panel pronounced HQ safe for cosmetic use at a concentration of 80% in an adhesive used to apply
concentration of 1% or less. bindi, the circular red mark worn on the forehead of
In vivo studies of black guinea pigs identified that Indian women, has been documented (Bajaj et al.
HQ may be a weak depigmenter via a mild toxic effect 1990). Arecent report from Italy described allergie
on melanocytes (Bleehen et al. 1968; Jimbow et al. contact dermatitis and depigmentation of the lip
1974). HQ rarely pro duces complete depigmentation, margins from PTBP in a lip liner. The PTBP patch
does not produce pigment loss at distant sites (as test site also depigmented and the presence of PTBP
MBEH does), and is a weaker allergen than MBEH was confirmed by gas chromatography and mass
(Ortonne et al. 1983; Fisher 1995). spectroscopy (Angelini et al. 1993).
Paratertiary Butylphenoland Paratertiary Amylphenol Paratertiary Butylcatechol and 4-Isopropyl Catechol
Cases of occupational leukoderma occurring in Rus- Gellin et al. (1970a,b) documented occupational le-
sian, Japanese, and Dutch factories producing para- ukoderma in 4 of 75 tappet assembly workers who were
tertiary butylphenol (PTBP) were summarized by exposed to paratertiary butylcatechol (PTBC) present
Malten et al. (1971). PTBP and paratertiary amylphenol in an assembly oil. Each had preceding dermatitis, and
(PTAP) are both used as phenolic germicides. PTAP patch tests demonstrated allergie contact reaction to
was more widely used as a commercial germicide than PTBC, tested at a concentration of 0.1% in acetone, in
PTBP, and was much more toxic to epidermal and three of the four cases. Depigmentation at distant sites
bacterial cells than PTBP (Kahn 1970). Kahn reported was present in three of the cases, with one showing
on 12 hospital workers who developed depigmentation extensive 75% involvement. One of the workers who
of the hands and forearms caused by phenolic deter- had a strong allergie contact re action developed
gent germicides. Leukoderma developed despite the depigmentation at the patch test site. Animal studies
fact that some employees wore gloves, and patch with black guinea pigs confirmed that PTBC- and even
testing confirmed that PTBP and PT AP were able to PTBP-induced depigmentation were reversible
produce depigmentation at the test sites. 2 months after chemical application ceased (Gellin
James et al. (1977) reported leukoderma in 54 of 198 et al. 1970a,b). Horio (1977) reported one case of
exposed workers at a PTBP manufacturing factory. The chemical leukoderma to PTBC in a worker in a
occurrence of depigmentation was related to duration polyester resin plant. Testing revealed an allergie
of PTBP exposure and even more so to the intensity of contact reaction to 0.5% PTBC, with depigmentation
exposure, which included vapor inhalation and dust at this site after 2 weeks. Cross reactivity to 0.05%
contact. In addition, 6 of the 54 workers developed PTBP was also observed, but without depigmentation.
increased aspartate aminotransferase (AST) and fatty In a comprehensive review, Bleehen et al. (1968)
changes on liver biopsy. Rodermund (1976) described tested the depigmenting capacity of 33 compounds on
similar findings in three cases from Germany and black guinea pigs and found that 4-isopropyl catechol
believed it to represent a triad of vitiligo, hepato- (4-IPC) was the most potent.
splenomegaly, and thyroid dysfunction (struma) We reported three cases of circumferential contact
caused by PTBP. leukoderma of the scalp associated with the application
PTBP had been known to cause contact dermatitis in of permanent and semi-permanent hair colors. Depig-
shoe manufacturers, and wearers, and in automobile mentation developed at the site of patch testing or
assemblymen (Kahn 1970). PTBP formaldehyde resin rechallenge with p-phenylenediamine (PPDA) and/or
(PTBPFR) is also a contact sensitizer, present in the hair color, but not at sites of positive patch test
neoprene adhesives used in the manufacture of car reactions to other chernicals. There was no other
seats, roof linings, and care interiors. Depigmentation clinical evidence of vitiligo in these patients. We also
on the hands and fore arms were observed in 11 of 99 reported a similar patient with partial scalp depig-
British automobile factory workers who were exposed mentation following the use of a benzyl-alcohol-
to a PTBFR glue without wearing protective gloves containing hair color; there was no pigment loss at
(CaInan and Cooke 1974). Malten (1984) attributed the the site of the positive patch test reaction (Taylor et al.
leukoderma to excess PTBP in the glue. 1993). Brancaccio and Cohen (1995) reported a case of
Malten (1975) also reported depigmentation as a contact leukoderma of the upper lip due to PPDA in a
consequence of contact with a PTBPFR glue in a wrist- mustache coloring solution; however, patch tests were
watch strap. He believed that depigmentation from negative for both allergie contact dermatitis and
consumer products containing PTBPFR was infrequent depigmentation.
Clinical Features and an ophthalmological examination to document

any other ocular disturbances may be indieated.
Chemicalleukoderma occurs in both dark- and light- The period of chemical exposure required for
skinned racial groups. Examination with Wood's light depigmentation to appear ranges from 2 weeks up to
may be helpful in identifying areas of leukoderma not 4-6 months (Kahn 1970; Malten et a1. 1971). Depig-
obvious on routine visual inspection of the skin, mentation appears after the reservoir of pre-existing
especially in light-skinned individuals. The appearance melanin has been metabolized, a process which may
of chemical leukoderma may be identical to vitiligo, take weeks to months (Schwartz et a1. 1940).
with a similar anatomic distribution. Depigmentation Most cases of chemicalleukoderma are preceded by
usually begins from small confetti-like, round-to-oval, infiammation of the affected skin (Gellin et a1. 1970a,b;
grouped macules. The pattern of spread may be a Horio 1977; Taylor et a1. 1993). This is not surprising
helpful clue in differentiating chemical leukoderma since many of the chemicals capable of producing
from vitiligo; "a history of gradual coalescence of small depigmentation are irritants. Additionally, the devel-
discrete macules, rather than development of large opment of allergie contact dermatitis, as demonstrated
macules with perifollicular sparing suggests chemical by patch testing, although frequent, is not a prerequi-
leukoderma" (Ortonne et a1. 1983). site (Malten et al. 1971; James et a1. 1977). The dimin-
Chemicalleukoderma, especially in the occupational ished ability of depigmented skin in vitiligo patients to
setting, initially often involves the hands and forearms, develop contact allergy to known sensitizers, such
presumably where there is contact with the inciting as dinitrochlorobenzene and MBEH, may partially
agent. Some individuals with chemical leukoderma explain the absence of preceding infiammation in some
develop depigmentation at distant sites, which is cases of chemical leukoderma (Uehara et a1. 1984;
usually symmetrical, and may, at times, become Nordlund et a1. 1985). Depigmentation at patch test
extensive (Schwartz et al. 1940; Kahn 1970; Gellin et a1. sites in reported cases of chemicalleukoderma has not
1970a,b; Malten et al. 1971; Calnan and Cooke 1974; been consistently demonstrated (Gellin et a1. 1970a,b;
Horio 1977). The mechanism for spread may involve Malten et a1. 1971; Taylor et a1. 1993).
either the transfer of the chemical by the hands to In most studies, there was some degree of sponta-
other parts of the body, or absorption of the chemieal neous follicular-based repigmentation after avoidance
through inhalation or ingestion (Malten et a1. 1971). of the presumed chemical; however, depigmentation at
The evidence to support a systemic route of entry is tim es is permanent (Kahn 1970; Malten et a1. 1971;
based on depigmentation in animals following oral or Horio 1977). This is in contrast to untreated vitiligo, in
parenteral administration of depigmenting agents and which depigmentation is usually permanent (Fisher
on observations of selected cases in man. In 1936, 1994). Malten et a1. (1971) found that the more limited
Oettel observed that feeding HQ to black-haired cats the extent of chemical leukoderma and the shorter its
resulted in their hair turning gray (Peck and Sobotka duration before avoidance, the earlier that spontane-
1941). Hara fed PTBP or p-octyl phenol to black mice ous repigmentation was apt to occur.
resulting in patchy depigmentation (Malten et a1. 1971). Host factors mayaiso be involved to explain the
Denton et a1. (1952) fed MBEH to guinea pigs whieh observation that not all workers exposed to depig-
produced depigmentation, while subcutaneous injec- menting chemicals will develop chemical leukoderma.
tion of MBEH resulted in depigmentation at the This may involve a genetic predisposition, similar to
injection site. The observations by both James et al. the case of vitiligo.
(1977) and Rodermund (1976) that some PTBP workers The effects of depigmenting agents on the skin are
developed abnormalliver enzymes also suggest sys- most likely time and dose dependent. In selected
temic absorption. human and animal studies, a higher concentration of
Scalp hair is rarely involved in chemicalleukoderma depigmenting agents, such as PTBP, MBEH, or MEDA,
except for the case reports of scalp depigmentation and resulted in increased depigmentation or more rapid
poliosis attributed to PPDA (Taylor et al. 1993); depigmentation (Denton et a1. 1952; Frenk et a1. 1968;
however, Nordlund et al. (1981) and Taylor et a1. Kahn 1970). According to Mathias (1988), at low doses,
(1993) consider premature white hair, before age 30, the chemicals inhibit melanin synthesis, but are
to be a variant of vitiligo). Eye color is unchanged in cytotoxic to melanocytes at higher doses, resulting in
chemicalleukoderma. In contrast, ocular disturbances, irreversible pigment loss.
usually involving fundal pigment disturbances, have
been described in patients with vitiligo (Cowan et a1. Differential Diagnosis
1986); also, patients with uveitis were found to have a
higher than expected incidence of vitiligo (Nordlund Other causes of depigmentation should also be con-
et a1. 1981; Wagoner et al. 1983). The presence or sidered and excluded before attributing the cause
absence of depigmentation of the iris should be noted, to chemieals. The main differential diagnoses are
idiopathic vitiligo and postinflammatory pigment loss. form phenolic or catecholic depigmenting derivatives.
Postinflammatory pigment changes usually consist of In this situation, gas chromotography or other chem-
off-white patches corresponding to the site of preced- ical analysis may be required (O'Malley et al. 1988;
ing inflammation; the opposite is also true - that the Bajaj et al. 1992).
absence of preceding dermatitis at all areas of pigment The role of patch testing is important in document-
loss excludes postinflammatory leukoderma. (Mosher ing cases of suspected chemical leukoderma. Patch
et al. 1993). The clinical courses differ in that postin- testing should be performed carefully, especially in
flammatory leukoderma begins to fade over weeks to darker-skinned individuals, to minimize the potential
months. In patients with dark skin, hyperpigmentation for depigmentation in cosmetically important anatom-
is more common than hypopigmentation as a postin- ic sites (Taylor et al. 1993). Because our patient with
flammatory event (Fisher 1986, 1995). PPDA hair dye-allergy developed adepigmentation of
Vitiligo may be indistinguishable from chemical the patch test site on the arm which expanded in size
leukoderma. Histopathologic examination is not usu- for 1 year, we now use a 48-h occlusive patch test on a
ally helpful in differentiating the two entities because covered area such as the buttocks. Peripheral and
both have decreased to absent numbers of melanocytes distant spread of pigment loss is possible. The material
(Fisher 1995). However, vitiligo may be associated with or chemical in question should be tested using a non-
ocular disturbances as well as with systemic dis orders , irritating concentration derived from standard dilution
such as thyroid disease, diabetes mellitus, Addison's techniques. The patch test sites should be evaluated for
disease, alopecia areata, and pemicious anemia (Mos- dermatitis after 2 days and again after 4-7 days and,
her et al. 1993). Vitiligo may be familial. HLA-DR4 has for pigment loss, after 4-6 weeks and, in some cases,
been associated with vitiligo in at least one report after 4-6 months. A delayed reading at 4-6 weeks is
(Foley and Lowe 1983). Additionally, the differential necessary when testing for chemicalleukoderma since
diagnosis also includes pigment loss from physical the reservoir of preformed melanin must be first shed
agents, such as bums or trauma; discoid lupus by the epidermis prior to detecting depigmentation
erythematosus, or pityriasis alba; genetic disorders, (Fisher 1994).
such as albinism and Waardenburgs; and endocrine The use of a labor-intensive, animal bioassay, such
dis orders such as hypopituitarism, Addison's disease, as the black guinea pig, to assess a chemical's
and hyperthyroidism. depigmenting potential should be reserved for cases
with inconclusive patch test results requiring addi-
Pathology tional documentation, when patch testing is declined
or impractical, or in pre-market product testing
Histopathology does not reliably distinguish between (Mansur et al. 1978; Gellin and Maibach 1983).
chemical leukoderma and vitiligo. On light microsco-
py, both demonstrate reduced numbers of melano- Treatment
cytes. Vitiligo has been associated, classically, with an
increased number of Langerhans' cells, compared with In the workplace, it is important to prevent and
anormal number in chemical leukoderma (Zelickson minimize exposure to known depigmentating agents
1985). through environmental engineering and industrial
hygiene measures. These include good work practices,
Diagnosis/Evaluation local exhaust ventilation, chemical substitution and, as
a last resort, personal protective equipment. Preven-
Diagnosis of chemicalleukoderma is more easily made tion is especially important for those with chemical
when a number of cases are clustered, typically in a leukoderma.
factory, and there is exposure to known depigmenting Spontaneous repigmentation has been reported in
agents; when pigment loss follows contact dermatitis; cases following avoidance of the causative agent (Kahn
or when the person affected is an adult with no 1970; Malten et al. 1971; Horio 1977). Repigmentation is
personal or family his tory of vitiligo or its associated perifollicular, gradual in onset and has been noted
diseases (Gellin and Maibach 1985). A detailed history variably over aperiod of weeks to months.
is especially important in isolated cases and in cases Photochemotherapy with Psoralen and ultraviolet
involving litigation to exclude other causes such as light type A (PUVA) has had limited success.
medications, trauma, and bums. A history of exposure Ehmfeld's case of depigmentation from a phenolic
to known depigmenters, either through direct contact detergent germicide responded to PUV A at weekly
or through systemic absorption should be established. intervals for 2 months with follicular repigmentation
Review of ingredients in chemical formulations may be occurring after six treatments (Ehrenfeld 1971). Kahn
inadequate to detect the presence of chemicals induc- (1970) was not able to duplicate this success. Limited
ing leukoderma, as the synthesis of by-products may therapy with systemic PUV A resulted in partial follic-
ular repigmentation in one of our patients with Browning E (1969) Toxicity of industrial metals, 2nd edn.
leukoderma from hair dye (Taylor et al. 1993). Almost Butterworth, London, pp 149
Buckley WR (1963) Localized arguria. Arch Dermatol 88:531-539
total repigmentation occurred in an unreported patient Buckley WR, West W (1970) Persistent dye staining of the skin.
of ours with chemical leukoderma of the hands from Arch DermatoI102:71-77
Burge KM, Winkelmann RK (1970) Mercury pigmentation. Arch
rubber gloves. Dermatoll02:51-61
Burrows D, Adams RM (1990) Metals. In: Adams RM (ed)
Occupational skin disease, 2nd edn, Saunders, Philadelphia,
Conclusion pp 349-386
Calm MM, Levy EJ (1957) Ultraviolet light factor in chlorprom-
azine dermatitis. Arch Dermatol 75:38
Key diagnostic criteria for chemical leukoderma Calnan C (1973) Occupational leukoderma from alkyl phenols.
include documented exposure to a known depigment- Proc R Soc Med 66:258-260
ing chemical, pigment loss consistent with such Calnan C, Cooke M (1974) Leukoderma in industry. J Soc Occup
Med 24:59-61
exposure by both his tory and examination, no evi- Cohen SR (1985) Yellow staining caused by 4,4' -methylenedi-
dence of idiopathic vitiligo, and reproduction of the aniline exposure. Arch DermatoI121:1022-1024
pigment loss by chemical rechalIenge - usually a patch Cowan C, Halder R, Grimes P, et al. (1986) Disturbances in
vitiligo. J Am Acad Dermatol 15:17-24
test - in the patient or an animal model. Cummings MP, Nordlund JJ (1995) Chemiealleukoderma: fact or
fancy. Am J Contact Dermat 6:122-127
Das M, Tandon A (1988) Occupational vitiligo (1988). Contact
References Dekker W, Dalmonte PR, Bianchi PG, et al. (1986) An interna-
tional multi-clinic study comparing the therapeutie efficacy of
Adams RM (1993) Occupational dermatoses and disorders due to colloidal bismuth subcitrate coated tab lets with chewing
chemieal agents. In: Fitzpatriek TB, Eisen AZ, Wolff K, et al. tablets in the treatment of duodenal ulceration. Scand J
(eds) Dermatology in general medicine, edn 4. McGraw-Hill, Gastroenterol Suppl 122:46-50
NewYork, pp 903-995 Denton C, Lerner A, Fitzpatrick T (1952) Inhibition of melanin
Agris J (1976) Adventitious tattooing. J Dermatol Surg 2:72-74 formation by chemical agents. J Invest DermatoI18:119-135
Ancona-Alayon A, Escobar-Marques R, Gonzalez-Mendoza A, Diekerson DB, Smith TH (1988) Antimony, arsenic and their
et al. (1976) Occupational pigmented contact dermatitis from compounds. In: Zen ZC (ed) Occupational medicine, 2nd edn.
Naphthol AS. Contact Dermatitis 2:129-134 Year Book Medieal, Chieago, pp 509-516
Angelini E, Marinaro C, Carrozzo A, et al. (1993) Allergie contact Dummett CO (1971) Systemie significance of oral pigmentation
dermatitis of the lip margins from para-tertiary-butylphenol and discoloration. Postgrad Med 49:78-82
in a lip liner. Contact Dermatitis 28:146-148 Ehrenfeld I (1971) Depigmentation due to phenolic detergent
Bajaj A, Gupta S, Chatterjee A (1990) Contact depigmentation germicide. Treated with methoxsalen and blacklite. Arch
from free para-tertiary-butylphenol in bindi adhesive. Con- Dermatol 104:216-217
tact Dermatitis 22:99-102 Eider R (1986) Final report on the safety assessment of
Bajaj A, Gupta S, Chatterjee A (1991) Contact depigmentation of hydroquinone and pyrocatechol. J Am Coll Toxicol 15:
the breast. Contact Dermatitis 24:58 123-165
Bajaj A, Gupta S, Chatterjee A (1992) Hearing aid depigmenta- Emmett EA (1987) Photobiologie effects. In: Maibach HI (ed)
tion. Contact Dermatitis 27:126 Occupational and industrial medicine, 2nd edn. Yearbook,
Bajaj A, Gupta S, Chatterjee A (1996) Footwear depigmentation. Chicago, pp 94-104
Contact Dermatitis 35:117-118 Emmett EA (1990) Phototoxieity and photosensitivity reactions.
Bentley-Phillips B, Bayles M (1975) Cutaneous reactions to topieal In: Adams RM (ed) Occupational skin disease, 2nd edn.
application of hydroquinone. Results of a 6-year investiga- Saunders, Philadelphia, pp 184-193
tion. S Afr Med J 49:1391-1395 Epstein JH, Brunsting LA (1958) Topieal application of chlor-
Bettlen FR (1940) Colliers' stripes - the coal miners' dermatosis. prornazine: its effect on the erythema response to ultraviolet
Br J Dermatol Syphilis 52:129-130 light. J Invest Dermatol 30:91
Berkley SF, Hightower AW, Beier RC, et al. (1986) Dermatitis in Everett MA (1979) Metal discolorations. In: Demis DJ, et al. (eds)
grocery workers associated with high natural concentrations Clinieal dermatology. Harper & Row Inc., Unit 11-14,
of furanocoumarins in celery. Ann Int Med 105:351-355 Hagerstown, p 4
Birmingham DJ, Key MM (1961) Photoxic bullae among celery Fisher A (1982) Leukoderma from bleaching creams containing
harvesters. Arch Dermatol 83:73-87 2% hydroquinone. Contact Dermatitis 8:272-273
Blackadder ES, Nanderson WG (1975) Occupation absorption of Fisher A (1986) Acne venenata in black skin. Cutis 37:24-26
tellurium: areport of two cases. Br J Indust Med 39:59-61 Fisher A (1994) Differential diagnosis of idiopathic vitiligo. Part
Bleehen SS, Pathak M, Hori Y, et al. (1968) Depigmentation of III: occupationalleukoderma. Cutis 53:278-280
skin with 4-isopropylcatechol, mercaptoamines, and other Fisher A (1995) Contact leukoderma (vitiligo) hyperpigmentation
compounds. J Invest Dermatol 50:103-117 and discolorations from contactants. In: Rietschel R, Fowler
Bleehen SS, Gould DJ, Harrington CI, et al. (1981) Occupational JJ (eds) Fisher's contact dermatitis, 4th edn. Williams &
argyria: light and electron microscopic studies and x-ray Wilkins, Baltimore, pp 765-777
microanalysis. Br J Dermatol 104:19-26 Foley L, Lowe N (1983) Association of HLA-DR4 with vitiligo.
Bleehen SS, Ebling FJG, Champion RH (1992) Disorders of skin J Am Acad Dermatol 4:528-536
color. In: Champion RH, Burton JL, Ebling FJG (eds) Fountain RB (1967) Occupational melanderma. Br J Dermatol
Textbook of dermatology, 5th edn. Blackwell, London, 79:59-60
pp 1561-1622 Fregert S, Trulson L (1980) Yellow stained skin from dinitro-
Botvinick I (1951) Dermatitis and secondary leukoderma due to salieylic acid. Contact Dermatitis 6:362
fabric-lined rubber gloves. Arch Dermatol Syphilis 53:334 Fregert S, Poulsen J, Trulson L (1980) Yellow stained skin from
Brancaccio R, Cohen D (1995) Contact leukoderma secondary to sodium nitrite in an etching agent. Contact Dermatitis 6:296
para-phenylenediamine. Contact Dermatitis 32:313 Frenk E, Loi-Zedda P (1980) Occupational depigmentation due to
Brodkin RH, Schwartz RA (1984) Cutaneous signs of dioxin a hydroquinone-containing photographic developer. Contact
exposure. Cutis 30:189-194 Dermatitis 6:238-239
Frenk E, Pathak M, Szabo G, Fitzpatrick T (1968) Selective action Malten K, Seutter E, Hara I, et al. (1971) Occupational vitiligo due
of mercaptoethylamines on melanocytes in mammalian skin. to paratertiary butylphenol and homologues. Trans St Johns
Arch Dermatol 97:465-477 Hosp Dermatol Soc 57:115-134
Fujimoto K, Hashimoto S, Kozuka T, et al. (1985) Occupational Mansur J, Fukuyama K, Gellin G, et al. (1978) Effects of 4-tertiary
pigmented contact dermatitis from azo dyes. Contact Der- butyl catechol on tissue cultured melanocytes. J Invest
matitis 12:15-17 Dermatol 70:275-279
Gawkrodger DJ (1998) Pigmentary changes related to occupation. Markey A, Black A, Rycroft R (1989) Confetti-like depigmentation
In: English JSC (ed) A colour handbook of occupational from hydroquinone. Contact Dermatitis 20:148-149
dermatology. Manson, London, chapter 10, pp 147-158 Maso MI, Ruszkowski AM, Bauerle J, et al. (1991) Celery
Gellin GA (1987) Pigment responses: occupational disorders of phytophotodermatitis in a chef. Arch Dermatol 127:912-913
pigmentation. In: Maibach HI (ed) Occupational and indus- Mathias C (1988) Occupational dermatoses. In: Zenz C (ed)
trial medicine, 2nd edn. Yearbook, Chicago, pp 134-141 Occupational medicine, 2nd edn. Yearbook, Chicago, pp 132-
Gellin GA (1990) Pigmentary changes. In: Adams RM (ed) 165
Occupational skin disease, 2nd edn. Saunders, Philadelphia, McNair JB (1923) Rhus dermatitis from Rhus toxicodendron
pp 21-25 radicans and diversibola (poison ivy). Its pathology
Gellin G, Maibach H (1983) Detection of environmental depig- and chemotherapy. University of Chicago Press, Chicago, pp
menting chemicals. In: Marzulli F, Maibach H (eds) Dermato- 56-71
toxicology, 2nd edn. Hemisphere, Washington DC, pp 443-459 McNally W (1939) Depigmentation of the skin by rubber gloves.
Gellin G, Maibach H (1985) Chemically induced depigmentation. Industrial medicine 8:405-410
In: Maibach H, Lowe N (eds) Models in dermatology. Karger, Miyamoto L, Taylor JS (2000) Chemical leukoderma chapter 32.
Basel In: Hann SK, Nordlund JJ (eds) A comprehensive monograph
Gellin G, Possick P, Davis I (1970a) Occupational depigmentation on its clinical and basic science. Blackwell, Oxford, pp 271-282
due to 4-tertiarybutyl catechol (TBC). J Occup Med 12: Mosher D, Fitzpatrick T, Hori Y, et al. (1993) Disorders of
386-389 pigmentation. In: Fitzpatrick T, Eisen A, Wolff K, et al. (eds)
Gellin G, Possick P, Perone V (1970b) Depigmentation from 4- Dermatology in general medicine, 4th edn. McGraw-Hill, New
tertiary butyl catechol - an experimental study. J Invest York, pp 903-995
Dermatol 55:190-197 Nishioka K, Sarachi C, Katayana I (1980) Chronic pigmented
Gladen BC, Taylor JS, Wu YC, et al. (1990) Dermatological purpura reduced by chemical substances. Clin Exp Dermatol
findings in children exposed transplacentally to heat-degrad- 5:213-218
ed polychIorinated biphenyls in Taiwan. Br J Dermatol Nordlund I, Taylor N, Albert D, et al. (1981) The prevalence of
122:799-808 vitiligo and poliosis in patients with uveitis. J Am Acad
Granstein RD, Sober AJ (1981) Drug and heavy metal induced Dermatol 4:428-536
hyperpigmentation. J Am Acad Dermatol 5:1-18 Nordlund J, Forget B, Kirkwood J, et al. (1985) Dermatitis
Hamada T, Horiguchi S (1978) Chronic melanodermatitis due to produced by applications of monobenzone in patients with
the rubber peephole of a ship radarscope. Contact Dermatitis active vitiligo. Arch Dermatol121:1141-1144
4:245-246 Oliver E, Schwartz L, Warren L (1939) Occupationalleukoderma.
Harber LC, Bickers DR (1989) Drug induced photosensitivity J Am Med Assoc 113:927-928
(phototoxic and photoallergic drug reactions). In: Photo sen- Olumide YM, Odunocuo BD, Odiase 0 (1991) Regional de-
sitivity diseases: principles of diagnosis and treatment, 2nd rmatoses in the African. Part 1 facial hypermelanosis. Int J
edn. Decker, Toronto, pp 160-202 DermatoI3:186-189
Hare PJ (1951) A case of occupational iron pigmentation of the O'Malley M, Mathias C, Priddy M, et al. (1988) Occupational
skin. Br J Dermatol 63:63-66 vitiligo due to unsuspected presence of phenolic antioxidant
Hogan DJ, Tangiertsampan C (1992) The less common occupa- byproducts in commercial bulk rubber. J Occup Med 30:
tional dermatoses. Occup Med 7:385-401 512-516
Horio T (1977) Depigmentation due to para tertiary butyl Ortonne JP, Mosher DB, Fitzpatrick TB (1983) Hypomelanosis
catechol. Int Arch Occup Environ Health 39:127-133 secondary to irradiation and physical trauma, chemical
James 0, Mayes R, Stevenson C (1977) Occupational vitiligo hypomelanosis, hypomelanosis associated with inflammation.
induced by p-tert-butylphenol, a systemic disease? Lancet In: Vitiligo and hypomelanosis of hair and skin, Plenum
2:1217-1219 Medical Book Company, New York, London, pp 475-522
Jimbow K, Obata H, Pathak M, Fitzpatrick T (1974) Mechanism of Osmundsen PE (1970) Pigmented contact dermatitis. Br J
depigmentation by hydroquinone. J Invest Dermatol 62: Dermatol 83:296-301
436-449 Page EH, Shear NH (1993) Temperature-dependent skin disor-
Kahn G (1970) Depigmentation caused by phenolic detergent ders. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al. (eds)
germicides. Arch Dermatoll02:177-187 Dermatology in general medicine, 4th edn. McGraw-Hill, New
Kennedy C, Molland EA, Henderson WJ, et al. (1997) Mercury York, pp 1581-1592
pigmentation from industrial exposure. Br J Dermatol Papa CM, Kligman AM (1965) The behavior of melanocytes in
96:367-374 inflammation. J Invest Dermatol 45:465-474
Kersey P, Stevenson C (1981) Vitiligo and occupational exposure Pathak MA (1986) Phytophotodermatitis. Clin Dermatol 4:
to hydroquinone from servicing self-photographing ma- 102-121
chines. Contact Dermatitis 7:285-287 Pathak MA, Daniels F, Fitzpatrick TB (1962) The presently known
Kozuka T, Tashiro M, Sano S, et al. (1979) Brilliant lake red R as a distribution of furocoumarins (psoralens) in plants. J Invest
cause of pigmented contact dermatitis. Contact Dermatitis Dermatol 39:225-239
5:297-304 Peck S, Sobotka H (1941) Effect of monobenzyl hydroquinone on
Lamar LM, Bliss BD (1966) Localized pigmentation of the skin oxidase systems in vivo and in vitro. J Invest Dermatol 4:
due to topical mercury. Arch Dermatol 93:450-453 325-329
Lewin G (1887) Localized argyria in workers in silver plate. Ann Pinol-Aguade J (1971) Dermatitis por blanquedores opticos. Med
Dermatol Venereol 3:9 Cutan 5:249-268
Mallory SB, Miller OF, Tyler WB (1982) Toxicodendron radicans Rietschel RL, Fowler JFJ (1995) Contact photo dermatitis. In:
dermatitis with black lacquer deposit on the skin. J Am Acad Rietschel RL, Fowler JFJ (eds) Fisher's Contact Dermatitis,
Dermatol 6:363-368 4th edn. Williams & Wilkins, Baltimore, pp 524-543
Malten K (1975) Paratertiary butylphenol depigmentation in a Riley P (1969) Hydroxyanisoledepigmentation: in-vivo studies.
"consumer". Contact Dermatitis 1:181-182 J Pathol 9n85-191
Malten K (1984) Dermatological problems with synthetic res ins Rodermund 0 (1976) Occupational vitiligo caused by paratertiary
and plastics in glues. Dermatosen 32:81 butylphenol. Arch Dermatol 112:554-555
294 P. Wattanakrai et al.: Occupational Pigmentary Disorders
Ruxin TA, Taylor JS (1994) Other occupational dermatoses: acne, Tanii T, Kono T, Katoh 1, et al. (1991) A case of prurigo
pigmentary disorders, skin cancer, infection, reactions to pigmentosa considered to be contact allergy to chromium in
temperature and humidity, scleroderma, and nail changes. In: an acupuncture needle. Acta Derm Venereol 71:66-67
Hogan DJ (ed) Occupational skin disorders. Igaku-Shoin, Taylor J (1986) Rubber. In: Fisher A (ed) Contact Dermatitis 3rd
New York, pp 89-103 edn. Lea & Febiger, Philadelphia, pp 603-643
Schmidt OEL (1941) Chrysiasis. Arch Dermatol Syphilol 44: Taylor 1, Maibach H, Fisher A, Bergfeld W (1993) Contact
446-452 leukoderma associated with the use of hair colors. Cutis
Schwartz L (1947) Occupational pigmentary changes in the skin. 52:273-280
Arch Dermatol Syphilol 56:592-600 Uehara M, Miyauchi H, Tanaka S (1984) Diminished contact
Schwartz L, Oliver E, Warren L (1940) Occupationalleukoderma. sensitivity response in vitiliginous skin. Arch Dermtol
Public Health Rep 55:1111-1130 120:195-198
Schwartz L, Tulipan L, Birmingham DJ (1957a) Dermatosis caused Wagoner M, Albert D, Lerner A, et al. (1983) New Observations
by metals. In: Occupational diseases of the skin. Lea & on vitiligo and ocular disease. Am J Ophthalmol 96:16-26
Febiger, Philadelphia, pp 260-293 WalIlberg JE (1987) Metals and skin. In: Maibach HI (ed)
Schwartz L, Tulipan L, Birmingham DJ (1957b) Occupational Occupational and industrial dermatology, 2nd edn. Yearbook,
sources of oral affections In: Occupational diseases of the Chicago, pp 348-350
skin. Lea & Febiger, Philadelphia, pp 742-748 White RP (1934a) Colored by industry. In: The dermatergoses, 4th
Schwartz RA, Stoll HL (1993) Epithelial precancerous lesions. In: edn. HK Lewis and Co. Ltd., London, pp 66-69
Fitzpatrick TB, Eisen AZ, Wolff K, et al. (eds) Dermatology White RP (1934b) Silver, arsenic, chromates. In: The de-
in general medicine, 4th edn. McGraw-Hill, New York, rmatergoses. HK Lewis and Co. Ltd., London, pp 140-154
pp 804-821 Zala L, Hunzinker T, Broathen LR (1993) Pigmentation following
Seligman PJ, Mathias T, O'Malley MA, et al. (1987) Phytophoto long-term bismuth therapy for pneumatosis cystoides intes-
dermatitis from celery among grocery store workers. Arch tinalis. Dermatology 184:288-189
Dermatol 123:1478-1482 Zelickson A (1985) The clinical use of electron microscopy in
Stokinger HE (1981) The metals. In: Clayton GD, Clayton FE (eds) dermatology, 4th edn. Bolger Publications, Minneapolis
Patty's industrial hygiene and toxicology, vol 2A, 3rd. edn. Zenorola P, Bisceglia M, Lomuto M (1994) Ashy dermatosis
Wiley, New York, pp 1493-2060 associated with cobalt allergy. Contact Dermatitis 31:53
CHAPTER 36
Occupational Connective Tissue Disorders

U.-F. Haustein and B. Haupt
Occupational Connective Tissue Disorders crystallographic methods, for example X-ray diffrac-
tometry and polarization microscopy, but it is difficult
Connective tissue disorders involving occupational to trace by chemical analysis.
factors are, first of all, systemic sclerosis (SSc),
probably also lupus erythematosus (LE) and very Epidemiological and (linical Aspects
rarely dermatomyositis, mixed connective tissue dis-
ease (MCTD), rheumatoid arthritis (RA) and Sjägren's In 1914, the Scottish physician Bramwell reported a
syndrome (Zschunke et al. 1990; Koeger et al. 1991). coincidence between "sclerodermia" and occupations
involving exposure to silica dust. Five of the nine
patients who reported diffuse SSc worked as stone
Systemic Sclerosis masons. Bramwell supposed that holding the chis el
and working under cold-weather outdoor conditions
Introduction might be work-associated causative factors.
Erasmus (1957) observed 17 cases of SSc among
SSc, characterized by fibrosis of the skin and internal 8000 underground miners in South Africa, 6 of them
organs, is a disease of unknown etiology with a with silicosis. In order to get an impression about
pathogenesis that is still vague. The prevalence in a the morbidity of SSc he examined 25,000 male and
Caucasian population is estimated at 0.3-1.9 per 27,000 female infirmary patients. He found one male
100,000 (Haustein and Albrecht 1993). Women are patient (also aminer) and nine female patients with
affected three to six times more frequently (Medsger SSc and suggested a greater incidence among miners
and Masi 1971; Sluis-Cremer et al. 1985). In recent than among non-miners. In the following years (from
years, some environmental substances have been 1960 until 1969), 29 additional cases of SSc were
reported as inducing factors in SSc and in so-called registered in miners who had been working in the
scleroderma-like diseases (SLD) (Table 1). South African gold mines. That corresponds to an
incidence of 7.7 cases per 100,000 miners per year in
Silica (Quartz)
Table 1. Factors inducing systemic sclerosis (SSc) or sclero-
Next to oxygen, silicon is the most common substance derma-like diseases (SLD), respectively
in our environment. Silicon has never been found in its
SSc SLD
elementary state. In nature it exclusively occurs in
compounds derived from silicon dioxide (silica = Mineral Chemical compounds
SiOJ. Silica is a regular constituent part in about Silica Plastics
92% of all sorts of rock. Solvents Vinyl chloride
Chlorinated hydrocarbons Epoxy resins(bis( 4-amino-3-
The three important crystalline structures of silica methylcyclohexyl) methane)
are quartz, tridymite, and cristobalite. These co m- Aromatic hydrocarbons Solvents
pounds are also called "free silica" to distinguish them Chlorinated hydrocarbons
Aromatic hydrocarbons
from the silicates, minerals containing silica bound to Aliphatic hydrocarbons
one or more metallic cations (American Thoracic Pesticides
Drugs (e.g. bleomycin,
Society 1997). pentazocine)
From the chemical point of view, quartz is an Others
extremely inert material. It cannot be destroyed by Aniline and fatty acid aniJides
water or solvents. Only hydrofluoric acid is capable of (oleylanilides)
Paraffin, silicon
dissolving quartz. It may easily be detected by

296 U.-F. Haustein and B. Haupt
contrast with an incidence of 0.33 in 100,000 in a pulmonary silicosis started before SSc in 41 of 57
control group consisting of railway and harbor (72%); the reverse was true in a minor fraction (19%).
workers. From 1955 to 1984, a total of 79 definite In 9%, both diseases were detected at the same time.
or probable cases of SSc in miners were registered. From the remaining 54 SSc patients without silicosis,
These investigations were related exclusively to 25 (46%) developed lung fibrosis within 2 years.
Caucasian individuals (Sluis-Cremer et al. 1985). Raynaud's phenomenon was observed as a preceding
Cowie (1987) analyzed the occurrence of SSc in a or concurrent symptom in 107 of the 111 silica-dust-
native South African male population. Among miners exposed SSc patients (96%). Skin involvement oc-
he found an incidence of 8.2 per 100,000 versus curred before pulmonary symptoms in 36 of III (32%),
merely 0.3 per 100,000 among inhabitants serving as at the same time in 5 of III (5%), after silicosis in 41 of
a control group. In the Republic of South Africa SSc III (37%), and in 29 of III (26%) patients no respiratory
has been acknowledged since 1974 as an occupational disorders were observed.
disease in miners that has to be compensated by law The occupations of our silica-exposed SSc patients
(Sluis-Cremer et al. 1985). are listed in Table 2. Fifty-seven of the 77 miners were
In the United States, Rodnan and colleagues (1967) exclusively exposed through uranium mining, 8
analyzed the occupations of 60 male patients with SSc. through coal mining, and 12 through both. Forty-two
They reported that 26 of them had been coal miners of the 111 patients have never worked in uranium
and 10 of them had been foundry workers exposed to mines. Twelve of these 42 suffered from silicosis. The
quartz sand. In eight of the patients, SSc was associated odds ratio of the 42 patients who never worked in
with silicosis of the lungs. This association between SSc uranium mines to develop SSc was still 3.9. Since
and silicosis has been confirmed by other groups (Beck uranium mines were shut down between 1980 and
et al. 1976; Ziegler et al. 1982). 1989, we could follow up only the sequelae of this
One report on the increased prevalence of SSc in exposure. Today, only a few patients are still alive or
workers exposed to silica dust, mainly in the mining of have been recently diagnosed.
ores in the former German Democratic Republic, was It is possible that sclerosis of the lungs, fibrosis due
published in 1976 by Zschunke, whose findings initi- to nonspecific dust impact, and genuine silicosis might
ated a study that appears to be the most extensive be confused in several cases; however, fibrosis of the
evaluation until now. A first analysis, which included lungs accompanied by SSc obviously occurs in subjects
all SSc patients of the whole country, was performed by exposed to silica dust rather than in those who have not
our group in 1981 and revealed that 77% of all male been exposed in such a way. The rate of silicosis in the
patients with SSc had been exposed to silica dust in the male patients with SSc presented by our group is higher
workplace. In addition, half of the patients showed than the number reported by Erasmus (1957) and
simultaneous silicosis of the lungs (Ziegler et al. 1981, Rodnan et al. (1967). This difference might be ex-
1982, 1986; Haustein and Ziegler 1985). Continuing this plained by regional variations in defining silicosis in
evaluation, records are currently available on 137 male the past, by differences in the composition of the rocks,
patients with SSc. Silica dust exposure was established and at least in several cases by the radioactivity of the
in 111 of these patients, and silicosis was found in 57 of uranium. Progress in the differential diagnosis has been
them (Haustein and Herrmann 1994). The comparable achieved by high-resolution computer tomography.
occupational silica exposure in the general population Sluis-Cremer et al. (1985) suggested that abrief
of an industrial area is estimated as being 10% or less. exposure to dust with high silica content causes SSc
Utilizing epidemiological tools, the following risk was without simultaneous silicosis. This would imply that
calculated. The likelihood (odds ratio) that SSc will the mode of exposure determines whether SSc with or
develop in men with silicosis who are older than without silicosis might develop. We do not share the
40 years of age is 12 times higher than in workers who opinion that SSc in these patients is not idiopathic SSc,
are the same age but not exposed to silica dust. Ten
fernale patients with SSc were also exposed to silica Table 2. Occupations of our systernic sclerosis patients with
dust in the workplace. One of them had also developed verified silica-dust exposure (n = 111)
silicosis. In contrast to the male patients, the epide-
Occupation Nurnber of patients
miologic research concerning fernales lacks evidence,
probably due to their small numbers. Miner 77
All our patients fulfilled the criteria of the American Foundry worker 10
College of Rheumatology (ACR). The average time of Quarryrnan 6
Sand-blaster 5
exposure was 13.6 years. The delay in symptomatic Dental rnechanic 4
disease (from beginning of exposure to onset of SSc) Sandstone sculptor 3
was 24.3 years on average. In some cases, the silica Glass grinder 3
Cast polisher 3
exposure las ted until the onset of SSc. The majority of
Occupational Connective Tissue Disorders 297
but rather should be labeled as SLD (Siegel 1977). The However, numerous hidden sources of silica exposure
symptomatic criteria for diagnosing SSc (compiled by exist, e.g., cleansers used in housekeeping (Mehlhorn
the ACR; Masi 1980) have been fulfilled by almost all et al. 1990; Koeger et al. 1992) and polishes used in
patients investigated (Table 3). According to our view, various jobs. Even fondant powders contained quartz
Rodnan et al. (1967), Rustin et al. (1990), and Gabay in the past and were found to be a cause of silicosis
and Kahn (1992) emphasized the lack of differences (Beck and Irmscher 1974). Silicosis was also observed
between so-called idiopathic SSc and SSc in patients in female laundry workers washing dust-contaminated
with silicosis. clothes (Evans and Posner 1971). One anecdote refers
Typical workplaces in which exposure to silica dust to a husband and his wife who both developed SSc, the
must be taken into account are listed in Table 4. husband after silica exposure and his wife probably by
inhaling dust from his clothes (Christy and Rodnan
1984). Koeger et al. (1992) reported of two patients who
Table 3. Clinical features and laboratory findings of systemic
sclerosis patients associated with silicosis (n = 37), limited:dif- developed edematous scleroderma and subluxing
fuse form = 22:15 arthropathy, respectively, after applying aerosolic sil-
icon glaze on cables over a 20-year period.
Symptoms/laboratory Number of Limited Diffuse Yamamoto et al. (1994) described a SSc patient with
findings patients form form
high levels of serum immonoglobulin E who developed
Raynaud's phenomenon 36 21 15 multiple papules in an area of non-sclerotic skin. He
Finger-tip ulcers 28 15 13 had been working on polishing watches with an
Arthralgia 28 13 12
Lung involvement 37 22 15 abrasive agent composed mainly of aluminum, chro-
Esophagus involvement 29 16 13 mium dioxide, and silica. Histological examination of a
Heart involvement 11 3 8 biopsy of the papules revealed the typical features of
Muscle involvement 9 2 7
Kidney involvement 5 0 5 scleroderma. This seems to be the first report of
Anti-nuclear antibodies 35 20 15 nodular scleroderma that occurred in the course of SSc
(ANA) being associated with chemical agents.
Anti -topoisomerase 13 12
antibodies (AT A) It is also known that dental technicians are exposed to
Anti-centromere 9 8 various particulate maUers including silica, alloys, and
antibodies (ACA) acrylic plastics which may induce pneumoconiosis and
Platelet factor 4 27 14 13
ß- Thromboglobulin 27 15 12 probably other occupational lung diseases (Choudat
Endothelin 17 7 10 1994). The prevalence of pneumoconiosis is very high
and related to the duration of exposure: three epidemi-
ological studies have reported a prevalence of
Table 4. Workplaces associated with silica-dust exposure
(according to Zschunke et al. 1990)
pneumoconiosis 1/0 or greater of about 15% in techni-
cians with 20 or more years of exposure. However, silica
Mining industry Underground workers is probably not the sole causative agent. Since
pneumoconiosis is a frequent risk among dental tech-
Extracting and processing of Quarrymen, crushers, sculptors, nicians, compensation should be paid to those suffering
stones (sands tone, granite, stone masons, workers
slate, fluor-spar, mica) producing slate pencils, from this work-related disease (Choudat 1994).
workers handling slate Yanez-Diaz et al. (1992) presented two male patients
powder, e.g. as a carrier with SSc and pulmonary silicosis after occupational
for hexachlorocyclohexane
insecticides, workers exposure to silica, and one of them to trichloroethylene
producing roof paper as a degreasing agent. The clinical and analytical
Producing and processing Grinders, mixers, stove fitters, findings could not be distinguished from those present
of chamotte blast furnace-lining
bricklayers in idiopathic SSc except the chest X-ray with intersti-
Foundry industry Moulders, coremakers, casters, tial images featuring caIcified hilar lymph nodes
cast dressers suggestive of pulmonary silicosis.
Tire industry and industries Workers handling talc that is
producing other products sometimes heavily Gabay and Kahn (1992) have analyzed 202 SSc
made from natural or contaminated by silica patients diagnosed at the Rheumatology Department,
synthetic rubber, e.g., University Bichat (Paris) since 1976. Among them were
cables
Industries producing pottery Workers handling raw material, 39 male patients (women/men = 4.211). Twenty-five
including glassware in particular sand and kaolin; men were included in a subsequent study, 14 of them
the latter also regularly with a high occupational risk and a duration of
contains considerable
quantities of silica exposure between 4 years and 33 years (mean ± SD
Dental technicallaboratories Dental technicians 14.5 ± 11.4 years). Eleven of them had been exposed to
(polishing and embedding silica dust (as miners, foundry workers, or bricklayers),
materials)
one to solvents (as a painter), and two to both. The
mean age at onset of disease was 50.4 ± 10.19 years been reported previously and merit recognition in the
(range 31-72 years) with Raynaud's phenomenon be- name of future prevention.
fore onset of disease in 24 cases (mean duration Steenland and Brown (1995) updated a study of 3328
6 months). The delay between the beginning of expo- gold miners who worked underground for at least
sure and onset of disease was 24.4 ± 12.2 years (range 1 year between 1940 and 1965 in South Dakota.
4-45 years). Clinical manifestations included lung dis- Multiple-cause analysis revealed significant excesses
eases in 18 patients, gastrointestinal tract diseases (13 of arthritis, musculoskeletal diseases, and various
patients), joint problems (5 patients), diseases of the cutaneous disorders (including SSc and systemic LE).
serosa (4 patients), myositis (4 patients), Sjögren's Evidence that occupational exposure to silica is also
syndrome C3 patients), arterial pulmonary hyperten- associated with autoimmunity was reinforced by the
sion (2 patients), cardiomyopathy (1 patient), impo- observation that workers from a factory that produced
tence (1 patient), and subcutaneous nodules (1 patient). scouring powder with an increased silica content (70-
There were no significant differences between the two 90% powdered quartz) exhibited a high prevalence of
groups (induced SSc versus "primitive" SSc) regarding clinical and biological auto immune manifestations
age at onset of disease, mortality, systemic manifesta- (Table 6). Among a group of 50 workers, Sanchez-
tions except myositis (which occurred only in the Roman et al. (1993) demonstrated symptoms of sys-
"primitive" group), therapy, anti-nuclear antibodies temic illness in 32 (64%) and ANA in 36 (72%) ofthem.
(ANAs) and anti-Scl-70 antibodies [anti-topoisomerase Wichmann et al. (1996) showed that individuals
antibodies (ATAs)]. Among the 163 female patients chronically exposed to silica, independent of whether
there was no silica-induced case. they are suffering from CTD, have antibodies to
Surprisingly, a recently performed occupational myeloperoxidase (MPO) as detected by enzyme-linked
analysis of 56 men with SSc in the United Kingdom immunosorbent assay (ELISA) in a range higher than
showed no evidence of silica exposure implicated in the normal population and in the same range as
the onset of the disease (Silman and Tones 1992). systemic diseases not induced by silica (i.e., systemic
Case reports and epidemiological studies reporting LE, SSc).
on patients suffering from SSc and silicosis are In 9 of 11 patients with silica exposure and renal
summarized in Table 5. involvement with systemic vasculitis, Chevalier et al.
(working in Angers) found various antibodies indica-
Silica and Other Autoimmune Diseases tive of autoimmunity, such as MPO-anti-neutrophil
cytoplasmic antibodies (AN CA) and ANA at low titers,
Evaluating 764 patients with connective tissue disease with anti-RO/Sjögren's syndrome-A in two patients,
(CTD) hospitalized in the clinic ofthe University Pitü~ but without anti-double-stranded DNA (dsDNA) (Con-
Salpetriere/Paris, Koeger et al. (1995) found 24 (3%) rad et al. 1997).
patients with silica-associated CTD. Eight of them had According to our data, Conrad et al. (1997) demon-
SSc, in four cases in association with Sjögren's strated that uranium miners with heavy exposure to
syndrome and in three cases in association with silica run a higher risk of developing SSc and systemic
silicosis. RA has been found in five patients (four in LE than miners with slight or no exposure, because they
association with Sjögren's syndrome), systemic LE in showed a higher frequency of SSc-specific autoantibod-
four patients (three with silicosis), discoid LE in one ies [anti-centromere antibodies (ACAs), ATAs, anti-
patient, and dermatomyositis in association with nucleolar antibodies] related to the intensity of the silica
Sjögren's syndrome in three patients. The last three exposure and to preceding symptoms ofSSc (Raynaud's
patients had erosive polyarthritis and Sjögren's syn- phenomenon, diffuse interstitiallung fibrosis).
drome, Grave disease, and inßammatory polyarthral- By summarizing various studies and case reports,
gia. Three additional cases of auto immune diseases Gregorini (working in Brescia) showed that extrapul-
after unusual exposure to silica or silicons have been monary silicotic lesions and/or autoimmune processes
reported by the same authors (Koeger et al. 1992). A may playa role in kidney diseases after silica exposure,
woman who had extensively used an abrasive cleansing more specifically MPO-ANCA-positive microscopic
powder rich in silica for 12 years developed a CTD polyangiitis and its renal-limited form of "idiopathic",
consisting of destructive inßammatory oligoarthritis, rapidly progressive glomerulonephritis (Conrad et al.
Gougerot-Sjögren's syndrome, Raynaud's syndrome, 1997).
ANA and hypocomplementemia. Another woman, who In conclusion, silica may induce systemic diseases
had sprayed silicon glaze on cables for 15 years, with various clinical and serological manifestations:
suffered from edematous SSc. A man who had applied systemic sclerosis with ACA, ATA or anti-nucIeolar
the same silicon glaze on cables over a 20-year period antibodies, systemic LE and systemic LE-like diseases
developed a subluxing arthropathy. The authors with anti-dsDNA and/or anti-RO/SS-A and anti-car-
pointed out that these means of exposure have not diolipin antibodies, and necrotizing systemic vasculitis
Table 5. Published cases of systemic sclerosis (SSc) in association with silica exposure and silicosis, respectively
Author Cases Diagnosis Occupation Exposure
1914 BramweIl 5 Diffuse scleroderma Stone masons Silica dust

1957 Erasmus 17 SSc, 6 with silicosis Underground miners Silica dust
1959 Francia et al. 6 SSc and silicosis
1967 Rodnan et al. 36 SSc, 8 with silicosis 26 Coal miners, 10 Silica dust (coal miners),
foundry workers quartz sand (foundry
workers)
1955-1984 Sluis-Cremer et al. 79 SSc Gold miners Silica dust
(including the cases
of Erasmus 1957)
1987 Cowie 10 SSc, 6 with silicosis Gold miners Silica dust
1981-1997 Haustein and Herrmann 111 SSc, 57 with silicosis Uranium mining (57), Silica dust (uranium)
(1994) (some of these coal mining (8),
patients were also both (12)
reported by Ziegler
et al. 1986, Baur 1994,
Mehlhorn 1994)
1984 Christy and Rodnan 2 SSc The husband developed Silica dust
SSc after silica
exposure and his
wife probably by
inhaling dust from
his clothes
1990 Mehlhorn et al. SSc Cleaning woman Scouring powder
containing crystalline
silica
1992 Koeger et al. Edematous Sprayed silicon-glaze Silicon-glaze
scleroderma on cables
1992 Yanez-Diaz et al. SSc, silicosis Lead mine Silica dust
1992 Yanez-Diaz et al. SSc, silicosis Lead mine Fiberglass,
(trichloroethylene)
1992 Gabay and Kahn II SSc Miner, foundry worker, Silica dust
bricklayer
1992 Gabay and Kahn 2 SSc Miner, foundry worker, Silica and solvents
bricklayer
1994 Yamamoto et al. Multiple papules in Polishing watches Abrasive agent
an area of (aluminum, chromium
non-sclerotic dioxide, silica)
skin in SSc
1995 Koeger et al. 8 SSc, 3 with silicosis Underground worker, Silica dust
sand molder, dental
prosthetist, foundry
engineer, marble
sculptor, miner,
sandblaster, mason,
sandstone cutter
1996 Wichmann et al. 12 SSc Scouring powder Silica content: 70-90%
(including the patients powdered quartz
reported by
Sanchez-Roman
et al. 1993)
Total = 287
Table 6. Autoimmune diseases in association with silica exposure (according to Sanchez-Roman et al. 1993 and Wichmann et al. 1996)
Sanchez-Roman et al. (1993), Wichmann et al. (1996),

50 workers; number (%) 52 workers, same factory; number (%)
Systemic sclerosis (SSc) 5 (10) 12 (23)

Systemic lupus erythematosus (SLE) 3 (6) 16 (31)
Polymyositis (PM) 1 (2)
Overlap syndrome (SLE/SSc) 5 (10) 7 (14) (Included in SLE, SSc, PM
and undefined collagen disease)
Secondary Sjögren's syndrome 6 (12) (Included in the three
first clinical diagnosis )
Undefined collagen disease 19 (38) (Including three cases of 15 (29)
primary Sjögren's syndrome)
Asymptomatic subjects 19 (38) 15 (29)
with renal involvement and MPO-ANCA (Conrad et al. (Haustein and Ziegler 1985; Rustin et al. 1990; Gabay
1997). and Kahn 1992).
Quartz is absorbed both via inhalation and percu-
Silicon taneously. Silicosis of the lung is caused by particles
with a diameter of less than 5 J.!m. The orifice of the
For many years, controversial discussions continued sebaceous glands in healthy individuals is approxi-
conceming whether silicon breast implants performed mately 24 times wider than the particle size relevant for
for augmentation mammoplasty are able to cause silicosis. At the extremities, there are up to 50 follicles
auto immune disease and SSc. The term "human per square centimeter (Plewig and Kligman 1978).
adjuvant disease" was introduced by Miyoshi et al. in Miners experience microinjuries of their hands and
1964, who reported two patients with CTD after direct forearms quite frequently. Therefore, it is not surpris-
injections of paraffin and silicon to augment breast ing that about 150 particles of quartz between 1 J.!m and
size. Later, implantable cushions of silicon gel or saline 20 J.!m could be traced in a single biopsy specimen
were applied. After a delay of approximately 20 years, (Ziegler et al. 1988).
50 of 85 subjects treated in this way suffered from a In several patients we determined the silica content
definite CTD, including 25 patients with SSc, 13 with in skin specimens obtained from fingers, dorsum of
RA, 8 with systemic LE, and 4 with MCTD (Hochberg the hand, and lower arms by polarization and phase-
1993). In addition, corresponding autoantibodies, contrast microscopy, and in two cases by electron
including anti-silicon antibodies, were detected. Apart spectroscopy for chemical analysis. As shown in
from leakage in the surrounding tissue followed by Table 7, silica crystals can be found in a high percent-
foreign body granuloma, connective tissue formation age of silica-exposed subjects. In the majority of
and fibrosis, the current scientific literature no longer occupations, the mechanical forces (e.g. in air or
supports the idea of systemic auto immune diseases, compressed air, drilling or hewing) are substantial and
due to a lack of convincing evidence that implants are may promote the penetration of silica crystals by
a major risk to the integrity of the immune system. microwounding. However, these data do not dis tin-
This is confirmed by a retrospective cohort study guish patients from silica-exposed miners without skin
evaluating 395,543 women via a questionnaire. The self- and lung diseases.
reported data indicated that the relative risk of any This mechanism of penetration might serve as an
CTD among the women with implants was 1.24 explanation for the observation that symptoms start at
(Hennekens et al. 1996). Similar results were reported the distal portions of extremities in the majority of
from three university-based tertiary-care scleroderma cases.
research centers with 837 women and 2507 race- Silica particles are ingested by macrophages (Fig. 1),
matched local control individuals. The adjusted odds- e.g., in the lung or skin, and can be transported to
ratio was 1.07 versus 1.11 (no significant difference) extrapulmonary sites (Holt 1981). Subsequently, acti-
(Hochberg et al. 1996). vated macrophages release enhanced amounts of
In addition, Bums et al. (1996) reported on a interleukin (IL)-lCt and ß (Oghiso and Kubota 1986).
population-based case-control study among 274 female Similarly, silica-stimulated monocytes can release
patients with SSc and 1184 controls in Michigan. They fibroblast-proliferation-inducing factors (Schmidt
found no increased risk of SSc among women with et al. 1984), leading to stimulation of collagen pro duc-
silicon breast implants, equivocal evidence of risk from tion by fibroblasts, too. The spontaneous secretion of
other silicon exposures, and no evidence of risk from IL-l from silicotic rat alveolar macrophages can be
silica exposure. inhibited by anti-la antibodies (Struhar and Harbeck
Finally, it is doubtful whether silica can be released 1989). Furthermore, silica added to antigen- or mito-
from silicon. Using electron-probe microanalysis, gen-stimulated lymphocyte cultures increases the
however, it has been shown that silicon or even silica number of immunoglobulin-secreting cells (Moseley
may escape from breast implants (even without frank et al. 1988). IL-lct and ß also affect T-helper lympho-
rupture) and may migrate beyond the capsule to cytes promoting production and release of 1L-2. IL-2
regional lymph nodes and distant sites where infiam-
matory and fibrotic processes can take place, triggered
by vacuolated, silica-incorporating macrophages Table 7. Silica in exposed skin areas
(Varga et al. 1989; Silver et al. 1993).
Subjects Positive/total
Pathogenesis Silica-induced SSc 24/26

Silicosis 4/5
Silica-associated SSc is clinically, serologically, and Silica-exposed miners (without SSc/silicosis) 3/5
Non-exposed controls 1/6
immunologically indistinguishable from idiopathic SSc
IL-1, IL-6
-----1.~ Vessels
Macrophages
Skin Jng .. MAF • I TH-Cells t I
~--------------~
IL-1 ! IL-2
IL-6
Fibroblasts B-cells t
Co/lAgenase + Autoantibodies
IEndothelial cellsl
TGF-ß
con active force +
GF IL FIBROSIS
disturbed balance of collagen
synthesis and degradation
occlusion Silicosis
Lung Fibrosis
SYSTEMIC SCLEROSIS
Fig. 1. Silica can activate various cell types involved in the Obviously, the endothelial eell damage oeeurs early,
pathophysiology of systemic sclerasis (SSc). Macrophages acti- before systemie symptoms appear. This is suggested by
vated by silica in vitro liberate the same cytokines and growth
factors known to be active in the pathophysiology of idiopathic the observation that Raynaud's phenomenon often
SSc. Micravascular endothelium is involved in silica-induced as preeedes SSe and by elevated levels of von Willebrand
weil as idiopathic SSc with similar activation patterns in vitra and faetor and eireulating immune eomplexes not only in
in vivo. Dermal fibroblasts are affected by silica in vitro, and
fibrablasts are the cells producing large amounts of extracellular siliea-indueed SSe, but also in healthy siliea-exposed
matrix in vivo. In vitra, the synthesizing capacity of fibroblasts miners.
depends greatly on culture conditions. All these effects are based Coneerning the involvement of blood vessels, Dowd
on our in vitra experiments with silica shown in italic. These
effects are similar to pathophysiological events known fram and Ziegler (1987) demonstrated deereased formation
idiopathic SSc of prostaeydin, a vasodilating lipid mediator originat-
ing from endothelial eells. The laek of prostaeydin
formation was shown in patients with Raynaud's
may stimulate B lymphoeytes synthesizing immuno- phenomenon as weil in patients with SSe who had
globulins and (auto)antibodies. Aetivated T lympho- been exposed to siliea. Furthermore, there are eertain
eytes also produee other lymphokines (e.g., patterns of ultrastruetural ehanges of the endothelial
maerophage-aetivating faetors) whieh are eapable of layer whieh seem to be eharaeteristie of SSe (Haustein
stimulating macrophages and fibroblasts. and Klug 1975; Haustein et a1. 1986). Accordingly,
These mechanisms are eontinuously triggered by subintimal fibrosis of small arteries has been deseribed
siliea, whieh is not ehemieally reaetive and remains in by Fleisehmajer et al. (1983).
the tissue over an extended period. Nevertheless, it has Siliea seems to be a potent aetivator of endothelial
toxie effeets on maerophages in a dose-dependent eells in vitro, too. Incubation of human dermal
manner. After phagoeytosis and destruetion of these mierovaseular endothelial eells (HDMEC) with siliea
eells, siliea is set free in the tissue, and the proeess of at non-toxie eoneentrations inereased the steady-state
ingestion through phagoeytosis might start again. In levels of the messenger RNA (mRNA) for intereellular
this way, a vieious eyde of a dysfunetional inflamma- adhesion moleeule 1 (ICAM-l), and also inereased the
tory response is established (Haustein and Herrmann eorresponding levels of this eell-surfaee pro tein as
1994). shown by fluoreseenee-aetivated eell-sorter (FACS)
However, Adamson et al. (1989) have shown that analysis; the ineubation also inereased the level of
siliea and irradiation are eaeh able to enhanee the soluble protein in the eulture fluid, as shown by means
number of interstitial eells in the lung. In addition, the of ELISA, in a dose- and time-dependent manner.
eontent of eells, protein, and hydroxyproline is Additionally, inereased levels of IL-6 in the eulture
inereased in bronehoalveolar lavage fluids. Taken supernatants have been found. In addition, a signifi-
together, irradiation plus siliea exposure might lead eant inerease in eollagenase I mRNA in HDMEC has
to a synergistie enhaneement of their effeets. been demonstrated (Anderegg et al. 1997).
The intratracheal instillation of silica crystals (Blair et al. 1974). However, it is extremely unlikely
(Cl quartz) into the lungs of C57BII6 mice resulted in that so me of the patients, such as sandblasters, glass
a significant increase in levels of ICAM-1 in lung tissue grinders, cast polishers, and stove fitters, have ever
and bronchoalveolar lavage fluids (Nario and Hubbard worked with pneumatic tools. Increased incidences of
1996). Raynaud's phenomenon, sclerodactyly and edema of
In patients with SSc, Frank et al. (1993) found a the hands were observed in chain-saw workers and in
slight decrease of IL-1 basal secretion from monocytes individuals operating jack-hammers (Nagata et al.
in comparison with healthy volunteers, and no changes 1993).
in IL-6 and tumor necrosis factor Cl (TNFCl) produc-
tion. In monocyte-enriched cultures from healthy
donors, a dose-dependent modulation of the cytokine Human Lymphocyte Antigen Association
pattern (IL-1 Cl, IL-1ß, IL-6, TNFCl) could be demon-
strated after silica phagocytosis. Using titanium diox- The association of immunological disorders to certain
ide for phagocytosis, no comparable effects were human lymphocyte antigen (HLA) alleles emphasizes
observed. The impact of silica on cytokine secretion the role of genetic factors determining susceptibility to
of monocytes might explain inflammatory tissue reac- environmental factors (Table 8). Rihs et al. (1994)
tions and increased collagen synthesis in silica-associ- analyzed the association of circulating autoantibodies
ated SSc. and HLA alleles in 71 uranium miners and 1 cleaning
The incubation of fibroblasts in culture with silica woman. They could show a positive correlation of anti-
demonstrated the induction of interstitial collagenase I Scl-70 to DR3 (1*0300) and DQ2 (1*0201) as well as of
mRNA and protein in the monolayer and a decreased ACA to DR1 (1*0101-1*0103), DR8 (1*0801-1*0804),
ability to contract collagen fibers in a three-dimen- and DQ4 (1*0400). Significant differences between
sional gel. Unexpectedly, we could not find an increase affected and unaffected miners have not been observed.
in the expression of collagen I or III mRNA (Anderegg In addition, Rihs et al. (1996) studied the genetic
et al. 1996). association of HLA-DPB1 alleles in 54 patients with
Taken together, the enhanced expression of ICAM-1 idiopathic SSc, 26 uranium miners with SSc, and 70
by endothelial cells might cause enhanced adhesion of unrelated, healthy control subjects. SSc patients with
activated (and activating) mononuclear cells to the and without former employment in mines were
microvascular wall. Together with increased collagen- assigned to two subgroups according to their sclerod-
ase activities originated from endothelial cells and the erma-specific autoantibody pattern - anti-Scl-70 pos-
neighboring dermal fibroblasts, the extravasation of itive and ACA positive - and a third subgroup
monocytes into the surrounding tissue could be comprising the rest. Statistical analysis revealed a
realized. The resulting perivascular infiltrate may take significantly increased frequency of DPB1 *1301,
part again in the activation of fibroblasts to produce DPB1 *0601, and DPB1 *1701 (P = 0.0001, corrected
more collagen and matrix proteins in skin or lung P = 0.011) in idiopathic anti-Scl-70-Positive SSc cases
tissue. The mechanism of SSc due to silica is summa- when compared with unexposed controls. Since these
rized in Fig. 1. three alleles contain the genetic information encoding
a glutamic acid residue in position 69 of DPB1, a strong
Vibration association of this residue with anti-Scl-70 expression
was observed in idiopathic SSc patients when com-
Vibrations caused by pneumatic tools are known to pared with anti-Scl-70-negative idiopathic SSc patients
induce Raynaud's phenomenon, which regresses after (P = 0.0009) or unrelated controls (P = 0.0007). ACA
cessation of the exposure. To what extent vibration expression was not associated with the presence of any
hammers, which are often used in mining and treating DPB1 allele tested. The data show that anti-Scl-70
stones, take part in promotion of SSc is still vague expression in idiopathic SSc patients is linked with
Table 8. Association between human lymphocyte antigen (HLA) alleles and several subgroups of systemic sclerosis (SSe) patients
aceording to Rihs et al. (1994, 1996), Baur et al. (1996) and Conrad et al. (1997)
Circulating autoantibody SSc patient subgroup HLA alleles
Anti-Scl-70/anti-topoisomerase antibodies Uranium miner DR 3 (DRB 1*0300), DQ2 (DQB 1*0201)

Silica-associated SSe DRB 1*0301, DQB 1*0201
Idiopathic SSc DPB 1 (1 *1301, *0601, *1701)
Anti-centromere Uranium miners DR 1 (1 *0100, *0101-*0103),
DR 8 (1 *0800, *0801-*0804), DQ (1 *0400)
Silica-associated SSc DRB 1*0800, DQB 1*0402
DPB1 *1301, whereas anti-Scl-70-Positive miners do not - Type of skin manifestation, in particular acroscle-
exhibit such a DPB1 association. Furthermore, the data rosis, circumscribed and generalized morphea, fi-
indicate that glutamate at position 69 of DPB1 might be brotic nodules, or joint contractures
involved in the susceptibility to idiopathic anti-Scl-70 - Visceral involvement due to toxic damage of liver,
expression. kidney, nervous system and muscles, or angiosar-
Additionally, DRB1 *0301 and DQB1 *0201 were sig- coma of the liver
nificantly increased in ATA-positive, silica-associated - Laboratory findings, discrete thrombocytopenia,
SSc patients, and DRB1 *0800 and DQB1 *0402 were and absence of autoantibodies
elevated in ACA-positive, silica-associated SSc patients - Cessation or reversal of the disease process after
compared with unrelated controls and the idiopathic early discontinuation of exposure
SSc group studied (Conrad et al. 1997). - Female preponderance for idiopathic SSc is often
One TNF(J(2 allele (associated with an increased TNF not observed in occupationally induced SLD
production capacity) was only increased in silica-
associated SSc, independently of any DRB alleles. The Vinyl Chloride
prevalence of TNF(J(2 in ATA responders was signifi-
cantly different between idiopathic SSc (decreased Individuals cleaning or inspecting auto claves for
compared with controls) and silica-associated SSc polymerization of vinyl chloride (VC) to polyvinyl
patients (increased). A similar result was found with chloride (PVC) are in danger of developing SLD with
TNF(J(-308A. The results of this study reinforce the idea high incidence (Leibach and Marsteller 1981; Ostlere
that not only structural conditions of antigen binding et al. 1992). Cleaning is usually performed by scraping
encoded by major histocompatibility class-ll genes, and water splashing. In this way, workers are exposed
but also an association to a certain TNF region, may be to the remnants of the monomer.
important for the generation of an immune response The first large study was conducted in Rumania in
through regulation of TNF production, which is 1963, where 168 PVC workers had been observed over
modified in silica-associated SSc patients due to 4 years (Suciu et al. 1963). The symptoms included
continuous ingestion of silica by macrophages (Conrad pruritus of the arms and face, and scleroderma-like
et al. 1997). lesions which mostly disappeared after rem oval from
the workplace. Later on, the disease was described in
detail and labeled as occupational acro-osteolysis
Conclusion (OAOL) in England, France, and the USA (Cordier
et al. 1966; Harris and Adams 1967; Wilson et al. 1967;
As silica cannot be removed from the body once it is Dinman et al. 1971; Markowitz et al. 1972). The disease
incorporated, its deleterious precipitating effect is is characterized by Raynaud's phenomenon, papular-
unavoidable. This indicates that the clinical course of fibrotic skin lesions on the wrist and dorsa of the
silica-induced dis orders is quite similar to classical hands, and osteolysis in the middle of the distal
auto immune diseases or SSc, characterized by pro- phalanges (bullet holes), mainly of the first three
gressions and remissions. The subsequent therapy fingers, which became shortened and shapeless. OAOL
should take these findings into ac count and has to be occurred only in those workers who had been exposed
adjusted according to the criteria for the extent, organ to the VC monomer and was most common in reactor
involvement, and clinical activity of the disease. The cleaners (Leibach and Marsteller 1981).
best way to prevent this type of SSc is to minimize the Histopathological examination of scleroderma-like
exposure to silica. lesions showed distended collagen fibers, shrinkage of
However, continuous efforts are still required to elastic fibers, interstitial edema, sometimes perivascu-
encourage acknowledgment of SSc as an occupational lar lymphocytic infiltrates, swollen endothelial cells of
disease after long-term silica exposure. Individual the enlarged capillaries, and marked acanthosis in the
decisions by clinical experts should provide the basis epidermallayer (Czernielewski et al. 1979).
enabling social and financial support to reduce the In 1974, Lange et al. reported of a systemic form of
harm caused by silica-induced SSc. VC disease. Changes included skin sclerosis, pulmo-
nary fibrosis, fibrosis of the liver and spleen, and
disturbances in the capillary vascular system, joints,
Scleroderma-Like Diseases and musculature. Further manifestations are pares-
thesia, thrombocytopenia, leukopenia, and splenomeg-
In contrast to silica and several solvents, a whole aly (Bachner et al. 1974). Capillary microscopy reveals
variety of substances is reported to induce SLD, which that abnormalities of the nail-fold in VC workers are
can be distinguished from SSc using the following similar but less pronounced than those found in SSc
criteria: (Maricq et al. 1976). Distal pitting scars, esophageal
labre 9. Relationship between vinyl chloride (VC) disease and exposure, skin lesions, capillary abnormalities and
systemic sclerosis (SSc) (according to Veltman 1980, Haustein
and Ziegler 1985)
acro-osteolytic lesions will revert to an almost normal
status (Veltman 1980). VC is a volatile gas. It is not
Features of VC disease resembling SSc Percentage quite clear to what extent inhalation of VC might
Raynaud's phenomenon 33-74 induce skin lesions; however, remnants of the gaseous
Fibrotic skin, sclerodactyly 10
Resorption of bone at the distal phalanges 11
monomer VC have been demonstrated in the polymer
Pulmonary fibrosis 13 PVC. VC is stored and metabolized by the organism.
Esophageal variation 23 One of its metabolites, thiodiglycolic acid, can easily be
Skin capillary abnormalities 23
Arthralgia 82 detected in urine sampies, even when levels of VC in
Myalgia 16 the atmosphere are considerably lower (Mueller et al.
Features of VC disease different from SSc Percentage 1978). So-called activated metabolites of VC (Fig. 2)
Paresthesia 80
Thrombocytopenia 76 may participate in the pathogenesis. Other mechanisms
Splenomegaly 48 might affect the individual's cellular immune response,
Reticulocytosis 35 especially in workers exposed to the small molecules of
Central nervous system symptoms 17
Leukopenia 8
VC (Kohanka 1982). Circulating immune complexes
Angiosarcoma of the liver 6 were found to be increased (Milford 1976). However,
No calcinosis autoantibodies - particularly ANA, ATA, and ACA -
could not be traced (Black et al. 1983). HLAs of the
pattern HLA DR5, HLA DR3, HLA Al, HLA B8, and
dysmotility, renal disease, and cardiac disease are HLA B3 prevail in patients with VC disease. The genetic
generally absent. background, together with the impairment of cellular
Leukopenia, as well as angiosarcoma of the liver, immune functions, might lead to an increased suscep-
drew attention to the carcinogenic and mutagenic tibility to the dis order (Black et al. 1983). One of the
properties of Vc. Wh ether other kinds of malignancies main targets of VC-inducible effects seems to be
are caused by VC was questioned by Fox and Collier microvascular tissues. Fibrosis of the vessel wall results
(1977) based on an extensive epidemiological study. in fibrosis of other organ systems. Patients with VC
The relationship between VC disease and SSc is shown disease have fewer capillary abnormalities of their
in Table 9. fingers than patients with SSc, but they have more than
Finally, common symptoms of VC-related diseases healthy controls (Maricq 1981).
such as fatigue, cold, burning pain, emotional instabil- In rats fed for 2 years with 30 mg VC per kilogram
ity, loss of libido, and impotence should be mentioned of body weight, thickening of the skin with collagen
(Penin et al. 1975; Veltman 1980). After discontinued deposition as well as an increase in glycosylated lysine
H H H 0 H H 0 H 0 Fig. 2. Metabolism of chlorinated

\ / \/\/ I // I /j ethylenes (according to Bolt et al.
C=C C-C - CI-C-C Cl-C -C 1982)
/ \ / \ I \ I \
H CI H CI H H H OH
vinyl chloride epoxide monochloroacetic acid
CI Cl Cl 0 CI Cl 0 Cl H
\ / \/\/ I // I I
C=C C-C - Cl-C-C CI-C -C-OH
/ \ / \ I \ I I
Cl H Cl H Cl H Cl H
trichloroethylene epoxide trichloroacetaldehyde trichloroethanol
Cl
\ /
C=C
Cl CIOCI
\/\/
C-C - Cl-C-C
CI~~
I I;
CI-C-C
Cl
I I;
0
/ \ / \ I \ I \
Cl Cl Cl CI CI Cl Cl OH
perchloroethylene epoxide trichloroacetic acid
and hydroxylysine have been described, indicating an H

increased collagen synthesis (Knight and Gibbons I
1987). H2N c
Reducing maximum concentrations in the work I
place from 500 ppm to negligible levels «5 ppm) by H
automation and contact-free technology will subse-
quently decrease the number of reported cases.
Fig. 3. Bis(4-amino-3-methylcyclohexyl)methane
PVC Dust
Recently, a case of MCTD in a male patient occupations of one compound produced skin sclerosis in a
tionally exposed to PVC and other toxic agents was murine model (Yamakage et al. 1980).
presented. Clinical symptoms consisted of typical signs A 33-year-old man developed SSc without sclerod-
of systemic LE, rheumatoid arthritis, and lupoid erma while working and being exposed from age
hepatitis. MCTD diagnosis was confirmed serologically 20 years to 30 years to epoxy resin polymerization
by the presence of u l-ribonucleoprotein-autoantibo- during surfboard manufacturing (Inachi et al. 1996).
dies. Prednisone, 60 mg daily, produced remission The symptoms included a shortening of the frenulum
(Panaszek et al. 1993). Studnicka et al. (1995) presented linguae, diffuse hyperpigmentation and facial telean-
a 58-year-old patient exposed to thermoplastic dusts, giectasia, positive ANA, and pulmonary dysfunction,
mainly PVC, for 10 years. He developed pneumoconio- but no acrosclerosis or sclerodactylia. Modest dermal
sis and secondary SSc. collagen proliferation in the forearm skin confirmed
SSc without scleroderma.
Bis(4-Amino-3-Methylcyciohexyl)Methane
(Polymerization of Epoxy Resins) Chlorinated Hydrocarbons, Aliphatic Hydrocarbons
Two male patients (of 233 workers) with a newly The chlorinated hydrocarbons trichloroethylene and
diagnosed SLD induced by epoxy res ins were reported perchloroethylene (Fig. 2) are widely used as solvents
from Japan in 1980 (Yamakage et al. 1980). Ishikawa and cleaners. They may be considered closely related
et al. (1995) described the clinical and laboratory to VC because of the clinical similarity of the dis orders
findings of these patients after a 17-year follow-up caused by these compounds to VC disease. Trichloro-
from 1976 to 1993. Both patients have been employed ethylene is more volatile (boiling point 87.2 °C) and
by a chemical factory since May 1975, and were much more toxic than perchloroethylene (boiling
continuously exposed to a polymerization process of point 121.1 °C). It penetrates the skin and, in its
epoxy resins. First symptoms appeared after 1 month vaporous state, is also absorbed by the alveolar
(patient 1) and 1.5 months (patient 2). After this brief capillaries. Prolonged contact with the skin will induce
exposure, the patients developed erythema and edema, irritative dermatitis (Schirren 1971; Bauer and Rabens
which evolved to generalized dermal sclerosis and 1977). Besides the well-described toxic effects in the
alopecia, weakness, and muscle atrophy, but no nervous system, liver, kidney, and bone marrow,
Raynaud's phenomenon or ANA. Treatment was several reports on SLD resembling VC disease have
started with a small dose of prednisolone and discon- been published (Reinl 1957; Saihan et al. 1978). Spar-
tinued in 1980. The hair loss recovered in 1977, the row (1977) observed a SLD similar to VC disease,
sclerotic skin changes disappeared by 1980, and the probably caused by perchloroethylene.
sclerodactyly recovered in 1993. Bis(4-amino-3-met- Recently, Flindt-Hansen and Isager (1987) reported
hylcyclohexyl)methane (BAMM), a new type of plas- three cases of SSc after occupational, prolonged (4-
ticizer belonging to the cyclohexamines (Fig. 3), was 12 years), and intensive exposure to trichloroethane
suspected as the causative agent from the list of and/or trichloroethylene during metal-cleaning proce-
chemical substances used. dures. According to the ACR-criteria, all three cases
BAMM may interfere with the amine metabolism could be classified as definite SSc.
which has been suggested to be disturbed in SSc Another case of SSc after working with trichloro-
patients (Stachow et al. 1979). In addition, oligomers of ethylene (Czirjcik et al. 1993) was observed in a female
epoxy resins, being strong sensitizers, might induce patient after inhalation for 2 years (beginning at the
dysfunctional immune responses (Thorgeirsson et al. age of 40 years). At the age of 43 years, she developed
1978). Using SSc-inducing glycosaminoglycans in lym- Raynaud's phenomenon, acrosclerosis, and joint
phocyte transformation tests, splenocytes of mice symptoms. A serious involvement of the lower esoph-
experimentally treated with BAMM showed a positive agus was found from the age of 47 years. Thirteen
response (Ishikawa et al. 1982). Intraperitoneal injec- years later, congestive heart failure, thrombocytopenia
and renal involvement was detected. Two years later, contact with the liquid substance. Further features of
the patient died suddenly due to cardiac arrest. the induced dis order are sclerodactyly, Raynaud's
Indirect immunofluorescence showed a speckled phenomenon, esophageal dysfunction, and fibrosis of
ANA pattern on Hep-2 cell monolayers. the lung. The disease could be reproduced by chronic
Lockey et al. (1987) described a 47-year-old woman intraperitoneal injection of these organic compounds
with previously excellent health who developed fatal in animal experiments.
SSc after a single 2.5-h predominantly dermal exposure A 41-year-old male foundry worker with exposure to
to trichloroethylene. During aperiod of 10 months, the trichloroethane, xylene, trimethylbenzene, and naph-
patient developed proximal scleroderma, reflux eso- thalene for 15 years developed following symptoms:
phagitis, microangiopathic hemolytic anemia, restric- sclerodactyly, digital pitting scars, Raynaud's phenom-
tive pulmonary disease, pericarditis with effusion, and enon, impotence, reflux esophagitis and ANA titers of
renal insufficiency with severe hypertension. Renal 1:320 (Brasington and Thorpe-Swenson 1991).
and skin biopsies were consistent with SSc. An Trichloroethylene elicits acute pulmonary cytotox-
additional case of SSc in a 51-year-old female worker icity in mice, which involves Clara cells of bronchioles.
has been presented, who developed SSc after 15 years Forkert and Forkert (1994) examined the effects of a
of exposure to perchloroethylene (Szeimies et al. single dose of trichloroethylene in lungs of mice and
1992). showed that structural and functional abnormalities
A 26-year-old woman with localized scleroderma progress for at least 3 months. Pulmonary fibrosis was
after 1 year of exposure to various organic solvents, first detected at 15 days and was ongoing and diffuse in
including trichloroethylene, tetrachloroethylene, ace- the alveolar zone, resulting in thickening of alveolar
tone, benzene, isopropyl alcohol, dimethyl phthalate, septa and destruction of lung structure. The fibrosis
methoxyethanol, polyethylene glycol, polyvinyl alco- was most pronounced at 90 days. Levels of total lung
hol, polyvinyl acetate, xylene and phenol, has been hydroxyproline content were not significantly different
presented by Czirjak et al. (1994). Disseminated cir- in control and treated mice at days 30 and 60, but were
cumscribed scleroderma (morphea) has been de- significantly increased at day 90, while the proline
scribed in a painter exposed to perchloroethylene content remained unchanged. The increase in collagen
(Hinnen et al. 1995). deposition at 90 days coincided with a significant
Recently, two cases of fasciitis (no scleroderma) with increase in lung elastic recoil (Forkert and Forkert
eosinophilia associated with prolonged exposure to 1994).
trichloroethylene were reported: the first case (a 63- As shown in Fig. 2, chlorinated hydrocarbons such
year-old woman) by drinking contaminated water as VC, perchloroethylene and trichloroethylene are
from a residential weIl, and the second (a 65-year-old metabolized in similar pathways (Lockey et al. 1987).
man) through occupational exposure (Waller et al. However, the significance of the P 450 system for
1994). metabolization and in the detoxification of putative
Czirjcik et al. (1987) analyzed 21 female patients with SSc-inducing environmental toxins has not been
SSc. In eight of them, occupationally hazardous agents studied so far.
were considered: trichloroethylene in one, organic
solvents in six, and polyethylene and possibly its
derivatives in the last. Another patient had been Aromatic Hydrocarbons
heavily exposed to trichloromethane during 13 years
of work renovating carburetors in Israel (Tibon-Fisher In 1983, Walder reported of six patients with limited
et al. 1992). scleroderma who were exposed to aromatic hydrocar-
The analysis of 61 patients with SSc (Czirjcik et al. bon solvents, such as benzene, toluene, xylene, white
1989) revealed a female-to-male ratioof 60:1. Prior spirit, and diesel oil. Unlike chlorinated hydrocarbons,
occupational exposure to chemicals (mainly organic these aromatic hydrocarbons do not cause systemic
solvents) was found in 17 (28%) of the patients, with a dis orders. The scleroderma-like lesions were limited to
mean age of 49 ± 8 years. The exposure preceded the hands and feet, body parts directly exposed.
onset of disease by 9 ± 7 years. The mode of exposure Recently, however, a sclerodermatous syndrome
was mainly through inhalation, with a duration of with unusual features and visceral involvement has
6.3 ± 6.5 years. Features from patients with exposure been reported following prolonged occupational expo-
to organic solvents were clinically indistinguishable sure (32 years) to a wide variety of organic solvents
from the other cases studied. (including benzene in various forms, toluenes, tolui-
As mentioned by Yamakage and Ishikawa (1982), dines, xylenes, xylidenes, aniline compounds, and
various aliphatic hydrocarbons, such as naphtha and ethanolamine and its derivatives) (Bottomley et al.
n-hexane, are able to induce generalized morphea-like 1993). Associated functional changes include cold
sclerosis, either by exposure to vapor or by direct skin sensitivity, restrictive pulmonary disease, peripheral
neuropathy, esophageal dysfunction, labile hyperten- In a recently performed occupational analysis of 56

sion, and a monoclonal paraproteinemia. men with SSc in the United Kingdom showing no
Garcia-Zamalloa et al. (1994) described a 56-year- evidence of silica exposure implicated in the onset of
old patient who developed SSc with skin, lung, and the disease, only exposure to organic solvents were
pericardial affections after he had worked in a rubber reported to any extent. No significant increase in
transformation section of a tire factory for 23 years. He exposure to organic solvents was found in a case
had been exposed to toluene (an aromatic hydrocar- control analysis (Silman and Jones 1992).
bon), heptane (an aliphatic hydrocarbon), dimethyl- Table 10 summarizes data on patients with SSc or
buthylphenyldiamine (an aromatic amine), and SLD in association with exposure to organic solvents.
octhyphenol formaldehyde (a formaldehyde deriva-
tive), cutaneously and by inhalation. Exposure to Pesticides/Herbicides
nonchlorinated hydrocarbon and sulfated substances
was also assessed. Two male patients developed SLD Dunnill and Black (1994) reported a case of generalized
after occupational exposure to various chemicals cutaneous sclerosis associated with prominent myosi-
(respectively, meta-phenylenediamine, VC, and silicon tis and esophageal involvement in a patient exposed to
tetrachloride) in the same building. One patient had herbicides containing bromocil, diuron, and aminotri-
been exposed to VC, a known cause of SLD. Because of azole. There was no evidence of lung involvement, and
the prolonged delay between the VC exposure and the antibody titers were in the normal range. Treatment
onset of scleroderma, the authors excluded this agent with oral prednisolone resulted in modest improve-
as the causative one. In addition, both patients were ment of the cutaneous changes, particularly of the face,
intermittently exposed to silicon tetrachloride, which trunk, and proximallimbs. The considerable exposure
yields hydrochloric acid and free silica upon chemical to chemicals, time course, and unusual pattern of
breakdown. It might be speculated that the disease organ involvement were suggestive for the diagnosis of
described therein was precipitated by an unusual occupational scleroderma.
indirect exposure to silica, which seems unlikely. The Another case of sclerodermiform lesions after use of
most attractive candidate for a potential causative various herbicides has been described by Poskitt et al.
agent in this SLD is meta-phenylenediamine (Owens (1994). A 53-year-old man developed chloracne, paIrno-
and Medsger 1988). plantar keratoderma and scleroderma after many years
In our own clinical practice, we examined a 58-year- of exposure to a variety of chloracnegens. Chloracne is
old painter who had been exposed to a wide variety of a rare but important acneiform eruption associated
organic solvents for 30 years. He developed a SLD of with exposure to halogenated aromatic compounds
the skin, esophagus and lung, with polyneuropathy used primarily in agriculture. However, to the authors'
and chronic hepatosis and elevated titers of ANA and knowledge, the association of palmoplantar kerato-
Scl-70-antibodies. The second patient was a 49-year- derma and scleroderma with exposure to chloracne-
old woman who had sewn leather in an oil bath gens has not been previously reported.
containing various oils and organic solvents for Dermatohistopathological changes, selected as an
12 years. She suffered from an acrosclerosis of the example of highly organized connective tissue, were
hands, lung fibrosis and kidney involvement, chronic studied by eight different staining and histochemical
hepatitis, and peripheral neuropathy including posi- techniques in 896 biopsies of macroscopically unin-
tive ANA and ACA titers (Haustein and Albrecht volved skin from the gluteal region of 56 patients with
1996). acute phospho-organic pesticide intoxication between
Bovenzi et al. (1995) examined 21 patients (16 days 2 and 15 after intoxication (Tashev and Tsonev
women, 5 men) with SSc or localized variants of 1990). Two hundred and seventy-two biopsies from 17
scleroderma. A significant association was found healthy individuals and published data served as
between exposure to organic solvents (aromatic hydro- controls. Nonspecific changes affecting mainly the
carbons) and SSc (3 men, 1 woman). Among the male elastic and collagen components were found, in some
subjects, an increased odds ratio for SSc was observed cases paralleled with the severity of intoxication. The
for exposure to organic solvents, silica dust, and hand- reticular net, vessels, matrix and cell elements were far
transmitted vibration. Exposure to solvents and other less affected, indicating their relative stability to the
chemicals was associated, albeit not significantly, with pesticides' toxicity.
SSc among the women.
Finally, SLD has also been reported in a 53-year-old
man after exposure to LOC, a domestic detergent Mixed Connective Tissue Disease
widely used in Japan. Its constituents are polyoxy-
ethylene alkyl ether and fatty acid alkanol amide Vincent et al. (1996) reported a 25-year-old woman
(Tanaka et al. 1993). who developed Sharp's syndrome 5 years after diag-
Table 10. Cases of systemic sclerosis (SSc) and scleroderma-like diseases (SLD) in association with exposure to solvents
Author Number Clinical Exposure

symptoms
Sparrow 1977 1 SLD Perchloroethylene

Walder 1983 6 SLD Benzene, toluene, xylene, white spirits, diesel oil
Czirjak et al. 1987 8 SSc Trichloroethylene (1), organic solvents (6),
polyethylene (1)
Lockey et al. 1987 1 SSc Trichloroethylene
Flindt-Hansen and Isager 1987 3 SSc Trichloroethylene, trichloroethane
Owens and Medsger 1988 2 SLD Meta-phenylenediamine, silicon tetrachloride
(hydrochloric acid and free silica),
meta-phenylenediamine,
vinyl chloride and silicon tetrachloride
Czirjak et al. 1989 17 SSc Benzene and petroleum-derived crude solvents (3),
organic solvents (isopropyl alcohol, terpene
derivatives) (4), ethyl acetate and other solvents (3),
organic solvents (not weIl defined) (4), silica dust,
paints and solvents (1), ethylene derivatives (1),
trichloroethylene (1)
Szeimies et al. 1990 SSc Perchloroethylene
Brasington and SSc Trichloroethane, xylene, naphthalene, trimethylbenzene
Thorpe-Swenson 1991
Yanez-Diaz et al. 1992 1 SSc, silicosis Trichloroethylene, fibergiass
Tibon-Fisher et al. 1992 1 SSc Trichloromethane
Gabay and Kahn 1992 3 SSc Solvents (1), solvents and silica dust (2)
Czirjak et al. 1993 1 SSc Trichloroethylene
Tanaka et al. 1993 1 SLD LOC (domestic detergent, constituents: polyoxyethylene
alkyl ether, fatty acid alkanol amide)
Bottomley et al. 1993 SLD Organic solvents (including benzene in various forms,
toluenes, toluidines, xylenes, xylidenes, aniline
compounds, and ethanolamine and its derivatives)
Waller et al. 1994 2 Fasciitis, Trichloroethylene
eosinophilia
Czirjak et al. 1994 Localized Trichloroethylene, tetrachloroethylene, acetone, benzene,
scleroderma isopropyl alcohol, dimethyl phthalate,
methoxyethanol, polyethylene glycol, polyvinyl
alcohol, polyvinyl acetate, xylene, phenol
Garcia-Zamalloa et al. 1994 SSc Toluene, heptane, dimethylbutylphenyldiamine and
octyphenol formaldehyde, exposure to nonchlorinated
hydrocarbon and sulphated substances was also
assessed
Hinnen et al. 1995 Disseminated Perchloroethylene
morphea
Bovenzi et al. 1995 4 Scleroderma Organic solvents (aromatic hydrocarbons)
Haustein and Albrecht 1996 2 SLD Wide variety of organic solvents (for 30 years), various
oils and organic solvents (for 12 years)
nosis of acute silicosis due to inhalation of the patient, who also had anti-SS-A (RO) and anti-SS-B
scouring powder Ajax (Colgate Palmolive Co.), con- (LA) antibodies. Although the prevalence of SSc, RA,
taining 95% silica, 2% alkylbenzosulphonate, and 3% and probably systemic LE is significantly higher after
trichlorocyanuric acid. MCTD due to PVC dust is long-standing occupational exposure to silica, so far no
mentioned above (Panaszek et al. 1993). case of Sjögren's syndrome has been described in the
course of pulmonary silicosis.
Sjögren's Syndrome
Lupus Erythematosus
Three cases of primary Sjögren's syndrome were
described by Puisieux et al. (1994) in silicotic coal Silica-induced LE is a chronic multiorgan system
miners. All patients fulfilled the diagnostic criteria for autoimmune disease with frequent exacerbations and
Sjögren's syndrome recently established by the Euro- remissions similar to the natural course of mixed
pean Community study group. One patient had connective tissue disease. The pathomechanism of LE
cryoglobulinemia and polyneuritis. Another had Ray- is not yet completely understood. Based on a genetic
naud's phenomenon, arthralgia, purpura and polyneu- background, a major role seems to be played by
ritis. Capillary microscopy revealed normal findings in disturbances of immune regulation, such as T-cell
all three patients. ANA were detected only in one abnormalities, including T-cell cytokine network,
polyclonal B-cell stimulation, immune complex for- Wich mann et al. published a study of 16 systemic LE
mation, defects in the clearance of immune complexes, patients among a group of 52 workers occupationally
and dysregulation of apoptosis. Various environmental exposed to silica.
factors have been discussed, such as drugs, solvents, Siebeis et al. (1993) presented case histories of five
and silica. patients with silicosis who had developed systemic LE
There is only scant knowledge with reference to and microscopic polyarteritis in two cases each, and
occupational infiuences on LE. Exposure to heat, cold, rapidly progressive glomerulonephritis (limited We-
and wind were cited in the past (Warde 1903). Sunlight gener's granulomatosis) in one case. Recently, a male
was frequently considered an eliciting factor for the patient who had worked as a stone cutter and had
primary manifestations, and the exacerbations as well developed silicosis and systemic LE was also reported
(Baer and Harber 1965; Epstein et al. 1965; Diezel et al. by Siebeis et al. (1995).
1977). However, among 236 patients examined, only six Koeger et al. (1995) observed four patients with
showed an improvement after the patients moved from systemic LE (three with silicosis) and one with discoid
an outdoor job to an indoor workplace. In this study, LE among 24 cases of silica-associated CTD.
no relationship between occupation and LE could be Conrad et al. (1996) described 28 definite and 15
confirmed (Nebe and Lenz 1971). In terms of associ- likely systemic LE patients among 15,000 heavily
ation with silicosis of the lung in the former German silica-exposed miners, probably part of the same
Democratic Republic, 193 male infirmary patients were group analyzed by Mehlhorn and Gerlach (1990).
examined, with three cases of coincidental silicosis Therefore, the prevalence of systemic LE in the
among them (Ziegler et al. 1987). population of highly quartz-dust-exposed uranium
Further reports exist about the association of LE miners may be estimated as up to 93 of 100,000. ANA
with silicosis (Hatron et al. 1982) or with occupational could be detected in all definite and in 72.9% of
silica exposure (Ebihara and Kawami 1985). In addi- probable patients having systemic LE. Middle-to-high-
tion, Mehlhorn and Gerlach (1990) and our group titred ANA were present in 94.4% of definite and in
(Ziegler et al. 1991) demonstrated several cases in the 54.7% of probable patients having systemic LE. In
uranium-mining industry in East Germany. The for- patients exhibiting definite systemic LE, clear positive
mer author observed 37 patients with LE exposed to results were obtained for anti-dsDNA in 38.9%, anti-
quartz over many years (Mehlhorn and Gerlach 1990). RO/SSA in 38.9%, and anti-LA/SSB in 11.1%. In
Thirty of them suffered from silicosis. In a survey of uranium miners without systemic LE, the prevalence
877 male LE patients (592 systemic LE, 279 discoid LE), of ANA was significantly higher than the age- and
we only found seven patients with silicosis out of 428 gender-related control group. Furthermore, an in-
systemic LE patients over 40 years of age (Ziegler et al. crease in ANA titers in heavily rather than slightly
1991). Recently, we reported of four additional male exposed uranium miners could be detected. Table 11
systemic LE patients with long-term silica exposure comprises data of patients with LE in association with
(12-23 years) and silicosis (Haustein 1998). In 1996, silica exposure.
Table 11. Lupus erythematosus (LE) in association with silica exposure
Author Cases Diagnosis Exposure (occupation)
Ziegler et al. 1987 3 Systemic LE and silicosis Silica

Mehlhorn and Gerlach 1990 37 25 systemic LE and silicosis, Silica (36 ore miners, 1 foundry worker)
5 discoid LE and silicosis,
4 systemic LE, 3 discoid LE
Ziegler et al. 1991 30 LE, 5 with silicosis Silica (16 ore miners, 3 foundry workers,
2 underground workers, 2 enamellers,
1 sandblaster, quarry worker, stove
bricklayer, grindstone maker, weil driller,
glass industry worker)
Siebels et al. 1993 2 Systemic LE and silicosis Silica
Siebeis et al. 1995 1 Systemic LE and silicosis Silica (stone cutter)
Koeger et al. 1995 5 4 systemic LE (3 with silicosis), Silica (mason, miner, dental prothetist,
1 discoid LE scouring and tooth powder worker)
Wichmann et al. 1996 16 Systemic LE Silica (scouring powder factory)
Haustein and Albrecht 1996 1 Systemic LE and silicosis Silica (uranium hewer)
Conrad et al. 1996 43 28 systemic LE, 15 probable Silica (uranium miners)
(partially the same group systemic LE
as analyzed by Mehlhorn
and Gerlach 1990)
Haustein 1998 4 Systemic LE and silicosis Silica (uranium hewer, cast polisher,
stone mason, uranium driller)
An ANA profile suggestive of Sjögren's syndrome or and tuberculosis, but without lung cancer (Steenland
systemic LE without symptoms of either disease and Brown 1995). The study of Koeger et al. (1995)
occurred in a patient with chronic obstructive pulmo- presented five patients with RA (four in association
nary disease. He worked for less than 5 years as a with Sjögren's syndrome).
maintenance mechanic in a plant in South Carolina
manufacturing silica flour and industrial sand (John-
son and Busnardo 1993). Excessive occupational expo- Conclusion
sure to free silica by inhalation was documented. An
open-Iung biopsy revealed an early stage of silicosis Connective tissue dis orders such as SSc, LE, Sjögren's
characterized by perivascular and peribronchial ac cu- syndrome, dermatomyositis and RA can be induced by
mulation of macrophages, as weIl as early granuloma occupational exposure to silica, solvents, and other
formation. chemical offenders. An enhanced genetic susceptibility
Certain chemical contaminants in weIl water have seems to favor these disorders. SSc is the most frequent
been implicated in the etiology of rheumatic disorders. and best-studied disease. While silica precipitates SSc,
Kilburn and Warshaw (1992) found an association the other offenders induce sderoderma-like diseases
between the prevalence of symptoms of systemic LE with different dinical and laboratory findings than
and ANA with chronic exposure to trichloroethylene with SSc. Taking a careful case history of patients with
and other chemicals in weIl water in the Tucson, SSc will help to identify the occupational causes. The
Arizona area. Beer et al. (1994) presented two patients best way to prevent this type of connective tissue
with insecticide-induced LE after use of two "bug- disease is to minimize the exposure to occupational
bombs" containing 1,1,1-trichloroethane, propane, substances. However, efforts in the form of individual
S-methoprene, and permethrin in the patients' trailer expert decisions have to be made in order to
horne. acknowledge these dis orders as occupational diseases
and provide so me social and financial support to
Dermatomyositis patients and reduce the harm caused by these disor-
ders.
Few reports are available on dermatomyositis after
occupational exposure. Koeger et al. (1991) described Acknowledgment. We gratefully acknowledge Ulf Anderegg
dermatopolymyositis in two men and one woman after (PhD) for helpful discussion and Jörg Kleine-Tebbe (MD) for
editorial assistance.
5, 16 and 21 years of occupational exposure to silica.
Pulmonary involvement was present as diffuse inter-
stitial fibrosis in two patients whose lung biopsies
revealed high particulate silica contents. Another References
patient with polymyositis among 52 workers from a
factory producing scouring powder with an increased Adamson IYR, Letourneau HL, Bowden DH (1989) Enhanced
silica content (70-90% powdered quartz) was de- macrophage fibroblast interactions in the pulmonary inter-
stitium increases fibrosis after siJica injection to monocyte-
scribed by Wichmann et al. (1996). Among 24 patients depleted mice. Am J PathoI134:411-418
with silica-associated CTD, three patients have been American Thoracic Society (1997) Adverse effects of crystalline
diagnosed with dermatomyositis and Sjögren's syn- siJica exposure. Am J Respir Crit Care Med 155:761-765
Anderegg U, Vorberg S, Herrmann K, Haustein UF (1996)
drome (Koeger et al. 1995). lncreased expression of interstitial collagenase in silica-
treated fibroblasts. Eur J Dermatol 6:51-55
Rheumatoid Arthritis Anderegg U, Vorberg S, Herrmann K, Haustein UF (1997) Silica
directly induces intercellular adhesion molecule 1 (ICAM-l)
expression in cultured endothelial cells. Eur J Dermatol
Rosenman and Zhu (1995) found an assoClatlOn 7:27-31
between silicosis and RA using hospital discharge Bachner U, Etzel F, Lange CE, Marsteller HJ, Veltman G (1974)
Haemostaseologische Aspekte bei der Vinylchlorid-Kran-
data from Michigan between the years 1990 and kheit. Dtsch Med Wochenschr 99:2409-2410
1991, exammmg potential assoClatlOns between Baer RL, Harber LC (1965) Photobiology of lupus erythematosus.
pneumoconiosis and pulmonary hypertension, lung Arch Dermatol 92:124-128
Bauer M, Rabens SF (1977) Trichloroethylene toxicity. Int J
cancer, obstructive lung disease, and connective tissue DermatoI16:113-116
disease among both male and female patients. In an Baur X (1994) Systemische Sklerodermie im Uranerzbergbau der
updated multivariate analysis of 3328 gold miners who ehemaligen SDAG Wismut. Arbeitsmed Sozialmed Umwelt-
med Sonderheft 22:5-7
worked underground for at least 1 year in South Baur X, Rihs HP, Altmeyer P, Degens P, Conrad K, Mehlhorn 1,
Dakota between 1940 and 1965, an extended foIlow- Weber K, Wiebe V (1996) Systemic sclerosis in German
up from 1977 to 1990 revealed significant excesses of uranium miners under special consideration of autoantibody
subsets and HLA dass II alleles. Respiration 63:368-375
arthritis, musculoskeletal diseases, and skin conditions Beck B, Irmscher G (1974) Silikosen durch weniger bekannte
induding systemic LE and SSc, in addition to silicosis Expositionsarten. Z Erkr Atmungsorgane 140:282-293
Beck B, Irmscher G, Zschunke E (1976) Sklerodermie und Silikose Dunnill MG, Black MM (1994) Sclerodermatous syndrome after
- Versuch einer Synopsis. Z Gesamte Inn Med 31: occupational exposure to herbicides-response to systemic
493-496 steroids. Clin Exp DermatoI19:518-52o
Beer KR, Lorincz AL, Medenica MM, Albertini I, Baron J, Ebihara I, Kawami M (1985) Health hazards of mineral dust with
Drinkard L, Swartz T (1994) Insecticide-induced lupus special reference to the causation of immuno-pathologic
erythematosus. Int J Dermatol 33:860-862 systemic diseases. J Sci Labour 61:1-31
Black CM, Welsh KI, Walker AE, Bernstein RM, Catoggio LJ, Epstein IH, Tuffanelli DL, Dubois EL (1965) Light sensitivity and
McGregor AR, Jones JK (1983) Genetic susceptibility to lupus erythematosus. Arch Dermatol 91:483-485
scleroderma-like syndrome induced by vinyl chloride. Lancet Erasmus LD (1957) Scleroderma in gold-miners on the Witwa-
1:53-55 tersrand with particular reference to pulmonary manifesta-
Blair HM, Headington JT, Lynch PJ (1974) Occupational trauma, tions. South Afr Lab Clin Med 3:209-231
Raynaud's phenomenon and sclerodactylia. Arch Environ Evans DJ, Posner E (1971) Pneumoconiosis in laundry workers.
Health 28:80-81 Environ Res 4:127-l28
Bolt HM, Laib RJ, Filser JG (1982) Reactive metabolites and Fleischmajer R, Perlish IS, Duncan M (1983) Scleroderma: a
carcinogenicity of halogenated ethylenes. Biochem Pharmacol model for fibrosis. Arch Dermatol 119:957-962
31:1-4 Flindt-Hansen H, Isager H (1987) Scleroderma after occupational
Bottomley WW, Sheehan-Dare RA, Hughes P, Cuncliffe WJ (1993) exposure to trichlorethylene and trichlorethane. Acta Derm
A sclerodermatous syndrome with unusual features following Venereol 67:263-264
prolonged occupational exposure to organic solvents. Br J Forkert PG, Forkert L (1994) Trichloroethylene induces pulmo-
Dermatol l28:203-206 nary fibrosis in mice. Can J Physiol Pharmacol 72:205-10
Bovenzi M, Barbone F, Betta A, Tommasini M, Versini W (1995) Fox AJ, Collier PF (1977) Mortality experience ofworkers exposed
Scleroderma and occupational exposure. Scand J Work to vinyl chloride monomer in the manufacture of polyvinyl
Environ Health 21:289-292 chloride in Great Britain. Br J Ind Med 34:1-10
Bramwell B (1914) Diffuse sclerodermia: its frequency; its Francia A, Monarca A, Cavallot A (1959) Osservazioni clinico-
occurrence in stone-masons; its treatment by fibrolysin roentgenologiche sollassociazione silicosi-sclerodermia. Med
injections - elevations of temperature due to fibrolysin. Lav 50:523
Edinburgh J Med 12:387-401 Frank R, Giese T, Dummer R, Walther T, Rytter M, Ziegler V,
Brasington RD, Thorpe-Swenson AJ (1991) Systemic sclerosis Haustein UF (1993) Silica-induced cytokine release in human
associated with cutaneous exposure to solvent: case report monocyte cultures and its possible involvement in the
and review of the literature. Arthritis Rheum 34:631-633 pathophysiology of silica-associated scleroderma. Eur J
Burns CI, Laing TI, Gillespie BW, Heeringa SG, Alcser KH, Mayes Dermatol 3:304-309
MD, Wasko MCM, Cooper BC, Garabrant DH, Schottenfeld D Gabay C, Kahn MF (1992) Les sclerodermies masculines; role de
(1996) The epidemiology of scleroderma among women: I' exposition professionelle. Schweiz Med Wochenschr
Assessment of risk from exposure to silicone and silica. 122:1746-1752
J Rheumatol 23:1904-1911 Garcia-Zamalloa AM, Ojeda E, Gonzalez-Beneitez C, Goni I,
Choudat D (1994) Occupational lung diseases among dental Garrido A (1994) Systemic sclerosis and organic solvents:
technicians. Tuber Lung Dis 75:99-104 early diagnosis in industry. Ann Rheum Dis 53:618
Christy WC, Rodnan GP (1984) Conjugal progressive systemic Harris DK, Adams WGF (1967) Acroosteolysis occurring in men
sclerosis (scleroderma): report of the disease in husband and engaged in the polymerisation of vinyl chloride. BMJ 3:
wife. Arthritis Rheum 27:1180-1182 712-714
Conrad K, Mehlhorn J, Lüthke K, Dörner T, Frank KH (1996) Hatron PY, Plouvier B, Francois M (1982) Assoziation von
Systemic lupus erythematosus after heavy exposure to quartz systemischem Lupus erythematodes und Silikose. Kasuistik
dust in uranium mines: clinical and serological characteris- (5 Pat.). Rev Med Intern 3:245-246
tics. Lupus 5:62-69 Haustein UF (1998) Silica-induced Lupus erythematosus. Acta
Conrad K, Humbel RL, Tan EM, Shoenfeld Y (1997) Autoanti- Derm Venereol 78:73-74
bodies - diagnostic, pathogenetic and prognostic relevance. Haustein UF, Albrecht M (1993) Zur Epidemiologie und Klinik
Clin Exp Rheumatol 15:457-465 der systemischen Sklerodermie. Z Hautkr Geschlechtskr
Cordier JH, Fieviez C, Lefevre MI, Sevrin A (1966) Acroosteolyse 68:651-658
et lesions cutanees chez deux ouvriers affectees au nettoyage Haustein UF, Albrecht M (1996) Berufsbedingte progressive
d'autoclaves. Can Med Travail 4:3 Sklerodermie, Pseudosklerodermie und systemischer Lupus
Cowie RL (1987) Silica-dust-exposed mine workers with sclerod- erythematodes. Derm Beruf Umwelt 44:77-80
erma (systemic sclerosis). Chest 92:260-262 Haustein UF, Herrmann K (1994) Environmental scleroderma.
Czernielewski A, Swierczynska-Kiec M, Gluszcz M (1979) Der- Clin Dermatol l2:467-473
matological aspects of so called vinyl chloride monomer Haustein UF, Klug H (1975) Zur Ultrastruktur der Hautkapillaren
disease. Derm Beruf Umwelt 27:108-112 bei Lupus eythematodes, Dermatomyositis und progressiver
Czirjak L, Dank6 K, Schlammadinger J, Suranyi P, Tamasi L, Sklerodermie. Dermatol Monatsschr 161:353-363
Szegedi GY (1987) Progressive systemic sclerosis occurring in Haustein UF, Ziegler V (1985) Environmentally induced systemic
patients expos~d to chemicals. Int J Dermatol 26:374-378 sclerosis-like disorders. Int J Dermatol 24:147-151
Czirjak L, Bokk A, Csontos G, Lörincz G, Szegedi G (1989) Haustein UF, Herrmann K, Boehme HJ (1986) Pathogenesis of
Clinical findings in 61 patients with progressive systemic progressive systemic sclerosis. Int J Derm 25:286-293
sclerosis. Acta Derm Venereol 69:533-536 Hennekens CH, Lee IM, Cook NR, Hebert PR, Karlson EW,
Czirjak L, Schlammadinger I, Szegedi G (1993) Systemic sclerosis LaMotte F, Manson JE, Buring JE (1996) Self-reported breast
and exposure to trichloroethylene. Dermatology 186:236-7 implants and connective-tissue diseases in female health
Czirjak L, Pocs E, Szegedi G (1994) Localized scleroderma after professionals. JAMA 275:616-621
exposure to organic solvents. Dermatology 189:399-401 Hinnen U, Schmid-Grendelmeier P, Muller E, Elsner P (1995)
Diezel W, Meffert H, Günther W, Huse K, Sönnichsen N (1977) Exposure to solvents in scleroderma: disseminated circum-
Exazerbation des Lupus erythematodes visceralis infolge UV- scribed scleroderma (morphea) in a painter exposed to
Bestrahlung. Dermatol Monatsschr 163:290-295 perchloroethylene (in German). Schweiz Med Wochenschr
Dinman BD, Cook WA, Whitehouse WM, Magnuson HJ, l25:2433-2437
Ditcheck T (1971) Occupational acroosteolysis: an epidemio- Hochberg MC (1993) Cosmetic surgical procedures and connec-
logical study. Arch Environ Health 22:61-65 tive tissue disease: the Cleopatra syndrome revisited. Ann
Dowd PM, Ziegler V (1987) Endothelial cell cultures in silica Intern Med 118:981-983
induced systemic sclerosis. Abstr Sympos Aktuel Probl Hochberg MC, Perlmutter DL, Medsger TA, Nguyen K, Steen V,
Arbeitsderm Leipzig, p 51 Weisman MH, White B, Wigley FM (1996) Lack of association
between augmentation mammoplasty and systemic sclerosis Miyoshi K, Miyaoka T, Kobayashi Y, Itahura T, Nishijo K,
(scleroderma). Arthritis Rheum 39:1125-1131 Hagashitara M, Shiragami H, Ohno F (1964) Hype-
Holt PF (1981) Transport of inhaled dust to extrapulmonary sites. rgammaglobulinemia by prolonged adjuvanticity in man:
J Pathol 133:123-129 disorders developed after augmentation mammoplasty. Ijish-
Inachi S, Mizutani H, Ando Y, Shimizu M (1996) Progressive impo 2122:9-14
systemic sclerosis sine scleroderma which developed after Moseley PL, Monick M, Hunninghake GW (1988) Divergent
exposure to epoxy resin polymerization. J Dermatol 23: effects of silica on lymphocyte proliferation and immuno-
344-346 globulin production. 1 Appl Physiol 65:350-357
Ishikawa H, Yamakage A, Tamura T, et al. (1982) Scleroderma Mueller G, Norpoth K, Kusters E (1978) Determination of
induced by epoxy res ins with special reference to experi- thiodiglycolic acid in urine specimens of vinyl chloride
mental scleroderma with Bis(4-amino-3-methylcyclohexyl)- exposed workers. Int Arch Occup Environ Health 41:199-205
methane as the probable causative agent. J UOEH 4: Nagata C, Yoshida H, Mirbod SM, Komura Y, Fujita S, Inaba R,
225-235 Iwata H, Maeda M, Shikano Y, Ichiki Y, et al. (1993)
Ishikawa 0, Warita S, Tamura A, Miyachi Y (1995) Occupational Cutaneous signs (Raynaud's phenomenon, sclerodactylia
scleroderma. A 17-year follow-up study. Br J Dermatol and edema of the hands) and hand-arm vibration exposure.
133:786-789 Int Arch Occup Environ Health 64:587-591
Johnson WM, Busnardo MS (1993) Silicosis following employ- Nario RC, Hubbard AK (1996) Silica exposure increases expres-
ment in the manufacture of silica flour and industrial sand. sion of pulmonary intercellular adhesion molecule-l (ICAM-
J Occup Med 35:716-719 1) in C57BI/6 mice. 1 Toxicol Environ Health 49:599-617
Kilburn KH, Warshaw RH (1992) Prevalence of symptoms of Nebe H, Lenz U (1971) Untersuchungen ueber berufliche Noxen
systemic lupus erythematosus (SLE) and of fluorescent beim Lupus erythematodes. Dermatol Monatsschr 157:
antinuclear antibodies associated with chronic exposure to 500-504
trichloroethylene and other chemicals in weil water. Environ Oghiso Y, Kubota Y (1986) Enhanced interleukin 1 production by
Res 57:1-9 alveolar macrophages and increase in la-positive lung cells in
Knight KR, Gibbons R (1987) Increased collagen synthesis and silica-exposed rats. Microbiol Immunol 30:1189-1198
cross-link formation in the skin of rats exposed to vinyl Ost!ere LS, Harris D, Buckley C, Black C, Rustin MH (1992)
chloride monomer. Clin Sci (CoIch) 72:673-678 Atypical systemic sclerosis following exposure to vinyl
Koeger AC, Alcaix D, Rozenberg S, Bourgeois P (1991) Occupa- chloride monomer. A case report and review of the cutaneous
tional exposure to silicon and dermatopolymyositis. 3 cases aspects of vinyl chloride disease. Clin Exp Dermatol 17:
(in French). Ann Med Interne 142:409-413 208-210
Koeger AC, Marre JP, Rozenberg S, Gutmann L, Bourgeois P Owens GR, Medsger TA (1988) Systemic sclerosis secondary to
(1992) Autoimmune diseases after unusual exposure to silica occupational exposure. Am 1 Med 85=114-116
or silicones. 3 cases. (in French). Ann Med Interne 143=165-70 Panaszek B, Malolepszy 1, Wrzyszcz M, Iutel M, Machaj Z (1993)
Koeger AC, Lang T, Alcaix D, Milleron B, Rozenberg S, Chaibi P, Mixed connective tissue disease in a male patient chronically
Arnaud J, Mayaud C, Camus JP, Bourgeois P (1995) Silica- exposed to toxic chemicals (in Polish). Pol Tyg Lek 48:
associated connective tissue disease. A study of 24 cases. 430-432
Medicine (Baltimore) 74:221-237 Penin H, Sager G, Lange GE, et al. (1975) Neurologisch-
Kohanka V (1982) Epidemiologic studies of the delayed-type psychiatrische und elektroenzephalographische Befunde bei
immunity in workers exposed to vinyl chloride monomers (in Patienten mit Vinylchlorid-Krankheit. Proc. 15. Jahrestagung
German). Boerg Vener Szemle 58:145-149 Dt Gesellschaft Arb Med, Gentner, Stuttgart, pp 299-304
Lange GE, Juehe S, Veltman G (1974) Ueber das Auftreten von Plewig G, Kligman A (1978) Acne. Springer, Berlin Heidelberg
Angiosarkomen der Leber bei zwei Arbeitern der PVC- New York
herstellenden Industrie. Dtsch Med Wochenschr 99:1598-1599 Poskitt LB, Duffi1l MB, Rademaker M (1994) Chloracne, palmo-
LeIbach WK, Marsteller HJ (1981) Vinyl chloride-associated plantar keratoderma and localized scleroderma in a weed
disease. Ergeb Inn Med Kinderheilkd 47:1-110 sprayer. Clin Exp Dermatol 19:264-267
Lockey JE, Kelly CR, Cannon GW, Colby TV, Aldrich V, Puisieux F, Hachulla E, Brouillard M, Hatron PY, Devulder B
Livingston GK (1987) Progressive systemic sclerosis associ- (1994) Silicosis and primary Gougerot-Sjogren syndrome (in
ated with exposure to trichloroethylene. J Occup Med 29: French). Rev Med Intern 15:575-579
493-496 Reinl W (1957) Sklerodermie durch Trichloraethyleneinwirkung?
Maricq HR (1981) Vinyl chloride disease. International Confer- Zentralbl Arbeitsmed 7:58-60
ence on Progressive Systemic Sclerosis. Austin, 9 October Rihs HP, Conrad K, Mehlhorn 1, May-Taube K, Welticke B, Frank
1981 KH, Baur X (1994) Association between HLA-D alleles and
Maricq HR, Johnson MN, Whetstone CL, LeRoy EC (1976) scleroderma-specific autoantibodies in quartz dust exposed
Capillary abnormalities in polyvinyl chloride production persons (in German). Z Arzt! Fortbild (Jena) 88:513-518
workers. Examination by in vivo microscopy. lAMA Rihs HP, Conrad K, Mehlhorn J, May-Taube K, Welticke B, Frank
236:1368-1371 KH, Baur X (1996) Molecular analysis of HLA-DPBl alleles in
Markowitz SS, McDonald q, Fethiere W (1972) Occupational idiopathic systemic sclerosis patients and uranium miners
acroosteolysis. Arch Dermatol 106:219-233 with systemic sclerosis. Int Arch Allergy Immunol 109:
Masi AT (1980) Preliminary criteria for the classification of 216-222
systemic sclerosis. Arthritis Rheum 23:581-590 Rodnan GP, Benedek TG, Medsger TA, Cammarata RI (1967) The
Medsger TA, Masi AT (1971) Epidemiology of systemic sclerosis. association of progressive systemic sclerosis (scleroderma)
Ann Intern Med 74:714-721 with coal miners pneumoconiosis and other forms of
Mehlhorn J (1994) "Qarzinduzierte" Progressive Systemische silicosis. Ann Intern Med 66:323-334
Sklerodermie Exposition, Klinische Beobachtungen, Rosenman KD, Zhu Z (1995) Pneumoconiosis and associated
Lungenfunktion. Arbeitsmed Sozialmed Umweltmed Sonder- medical conditions. Am 1 Ind Med 27:107-113
heft 22:8-11 Rustin MHA, Bull HA, Ziegler V, Mehlliorn J, Haustein UF,
Mehlhorn 1, Gerlach C (1990) Gemeinsames Auftreten von Maddison PJ, James J, Dowd PM (1990) Silica-associated
Silikose und Lupus erythematodes. Z Erkr Atmungsorgane systemic sclerosis is clinically, serologically indistinguishable
175:38-41 from idiopathic systemic sclerosis. Br 1 Dermatol 123:725-34
Mehlhorn 1, Gerlach C, Ziegler V (1990) Berufsbedingte progres- Saihan EM, Burton IL, Heaton KW (1978) A new syndrome with
sive systemische Sklerodermie durch ein quarzhaltiges pigmentation scleroderma, gynaecomastia, Raynaud's phe-
Scheuermittel. Derm Beruf Umwelt 38:180-184 nomenon and neuropathy. Br 1 Dermatol 99:437-441
Milford W A (1976) Evidence of an immune complex disorder in Sanchez-Roman J, Wichmann I, Salaberri J, Varela 1M, Nunez-
vinyl chloride workers. Proc R Soc Med 69:289-291 Roldan A (1993) Multiple clinical and biological autoimmune
manifestations in 50 workers after occupational exposure to Veltman G (1980) Klinische Befunde und arbeitsmedizinische
silica. Ann Rheum Dis 52:534-538 Aspekte der Vinylchlorid-Krankheit. Dermatol Monatsschr
Schirren SM (1971) Skin lesions caused by trichloroethylene in a 166:705-712
metal working plant. Berufsdermatosen 19:240-245 Vincent M, Pouchelle C, Martinon S, Gerard F, Arthaud Y (1996)
Schmidt JA, Oliver CN, Lepe-Zuniga JL, Green I, Gery I (1984) Connective tissue disease due to intentional inhalation of
Silica-stimulated monocytes release fibroblast proliferation scouring powder. Eur Respir J 9:2688-2690
factors identical to interleukin 1. J Clin Invest 73=1462-1472 Walder WB (1983) Do solvents cause scleroderma? Int J Dermatol
Siebeis M, Schulz V, Andrassy K (1993) Silicosis and systemic 22:157-158
diseases (in German). Immun Infekt 21:53-54 Waller PA, Clauw D, Cupps T, Metcalf JS, Silver RM, Leroy EC
Siebeis M, Schulz V, Andrassy K (1995) Systemic lupus (1994) Fasciitis (not scleroderma) following prolonged expo-
erythematosus and silicosis (in German). Dtsch Med sure to an organic solvent. J Rheumatol 21:1567-1570
Wochenschr 120:214-218 Warde WB (1903) Lupus erythematosus: some illustrative cases.
Siegel RC (1977) Scleroderma. Med Clin North Am 61:283-296 Br J DermatoI15:161-168
Silman AI, Jones S (1992) What is the contribution of occupa- Wichmann I, Sanchez-Roman J, Morales J, Castillo MJ, Ocana C,
tional environmental factors to the occurrence of scleroderma Nunez-Roldan A (1996) Antimyeloperoxidase antibodies in
in men? Ann Rheum Dis 51:1322-1324 individuals with occupational exposure to silica. Ann Rheum
Silver RM, Sahn EE, Allen JA, Sahn S, Greene W, Maize JC, Garen Dis 55:205-207
PD (1993) Demonstration of silicon in sites of connective Wilson RH, McCormick WE, Tatum CF, Greech JL (1967)
tissue disease in patients with silicone-gel breast implants. Occupational acroosteolysis: report of 31 cases. JAMA
Arch Dermatol 129:63-68 201:577-580
Sluis-Cremer GK, Hessel PA, Hnizdo E, Churchill AR, Zeiss EA Yamakage A, Ishikawa H (1982) Generalized morphea-like
(1985) Silica, silicosis and progressive systemic sclerosis. Br J scleroderma occurring in people exposed to organic solvents.
Ind Med 42:838-843 Dermatologica 165=186-193
Sparrow GP (1977) A connective tissue disorder similar to vinyl Yamakage A, Ishikawa H, Saito Y, Hattori A (1980) Occupational
chloride disease in a patient exposed to perchloroethylene. scleroderma-like disorder in men engaged in the polyrner-
Clin Dermatol 2:17-22 ization of epoxy res ins. Dermatologica 161:33-44
Stach6w A, Jablonska S, Skiendzielewska A (1979) Biogenic Yamamoto T, Furuse Y, Katayama I, Nishioka K (1994) Nodular
amines derived from tryptophan in systemic and cutaneous scleroderma in a worker using a silica-containing abrasive.
scleroderma. Acta Derm Venereol 59:1-5 J Dermatol 21:751-754
Steenland K, Brown D (1995) Mortality study of gold miners Yanez-Diaz S, Moran M, Unamuno P, Armijo M (1992) Silica and
exposed to silica and nonasbestiform amphibole minerals: an trichloroethylene-induced progressive systemic sclerosis.
update with 14 more years of follow-up. Am J Ind Med 27: Dermatology 184:98-102
217-229 Yoshida S, Gershwin ME (1993) Autoimmunity and selected
Struhar D, Harbeck RJ (1989) Anti-la antibodies inhibit the environmental factors of disease induction. Semin Arthritis
spontaneous secretion of IL-1 from silicotic rat alveolar Rheum 22:399-419
macrophages. Immunol Lett 23:31-33 Ziegler V, Koepping H, Münzberger H, Haustein UF, Löschke K
Studnicka MJ, Menzinger G, Drlicek M, Maruna H, Neumann MG (1981) Arbeitsmedizinische Aspekte der progressiven Skler-
(1995) Pneumoconiosis and systemic sclerosis following 10 odermie. Wiss Z Karl-Marx-Univ Leipzig 30:478-482
years of exposure to polyvinyl chloride dust. Thorax 50: Ziegler V, Pampel W, Zschunke E, Münzberger H, Mährlein W,
583-5 Koepping H (1982) Kristalliner Quarz - (eine) Ursache der
Suciu I, Drejman I, Valaskai M (1963) Contributii la studiul progressiven Sklerodermie? Dermatol Monatsschr 168:
imbolnavirilor produse de clorina de vinil. Med Int 15: 398-401
967-978 Ziegler V, Haustein UF, Mehlhorn J, Münzberger H, Rennau H
Szeimies RM, Lissner A, Meurer M (1992) Perchlorethylen- (1986) Quarzinduzierte Sklerodermie, sklerodermie-aehn-
induzierte systemische Sklerodermie. Derm Beruf Umwelt liches Syndrom oder echte Sklerodermie? Dermatol Mona-
40:66-69 tsschr 172:86-90
Tanaka M, Niizeki H, Shimizu S, Miyakawa S (1993) Scleroderma Ziegler V, Kipping D, Herrmann K, Haustein UF, Löschke K
after exposure to domestic detergent LOe. J Rheumatol (1987) Quarz - seine Relevanz für die Dermatologie. Derm
20:1993-1994 Beruf Umwelt 35=199-204
Tashev TS, Tsonev I (1990) The connective tissue changes in Ziegler V, Keyn I, Mehlliorn J, Kipping D, Haustein UF (1988)
patients with acute poisonings by organophosphate pesticides Qarznachweis in Sklerodermiehaut. Dermatol Monatsschr
(in Bulgarian). Vutr Boles 29:83-87 174:688-689
Thorgeirsson A, Fregert S, Ramnaes 0 (1978) Sensitization Ziegler V, Pfeil B, Haustein UF (1991) Berufliche Quarzstaubex-
capacity of epoxy resin oligomers in the guinea pig. Acta position - Progressive Sklerodermie und Lupus erythemat-
Derm Venereol 58:17-21 odes. Z Hautkr Geschlechtskr 66:968-970
Tibon-Fisher 0, Heller E, Ribak J (1992) Occupational sclerod- Zschunke E (1976) Dermatologische Probleme in der Ar-
erma due to organic solvent exposure. Harefuai1122:530-532, beitsmedizin. Dermatol Monatsschr 162:454-458
55 1 Zschunke E, Ziegler V, Haustein UF (1990) Occupationally
Varga J, Schumacher R, Jimenez SA (1989) Systemic sclerosis induced connective tissue disorders. In: Adams RM (ed)
after augmentation mammoplasty with silicone implants. Occupational skin disease. Saunders, Philadelphia
Ann Intern Med 111:377-383
CHAPTER 37
Occupational Phototoxicity and Photoallergy

V. DeLeo
Introduction erythema, edema, and bullous lesions on clinieal

examination and neerosis of keratinoeytes on histo-
Chemical photosensitivity is a term that is used to logie study. The dose of both ehemieal and radiation
deseribe skin disease eaused by the interaction of light neeessary to induee the response is more eritieal in the
and an exogenously aequired ehemieal agent. In all produetion of PICD than PACD [1-4].
such reaetions, both the chemie al and radiation are The differenees between phototoxieity and photoal-
neeessary for the response to be produeed. Exposure to lergy to systemie agents are less clear, and such
the ehemieal photosensitizer ean be either through the distinetions are usually based on animal and in vitro
systemie or the topieal route. The meehanism of the studies, not on a clinieal basis. When the distinetion
response ean be either irritant (toxie) or allergie has been made, almost all photosensitivity to systemie
(Table 1). Chemieal photosensitivity classified into agents is thought to be toxie in meehanism. In
four clinieal entities: photoirritant eontaet dermatitis addition, most offending chemie als are therapeutie
(PICD), photoallergie eontaet dermatitis (PACD), agents (Table 3). For tlIese reasons, it is eonvenient to
photoallergy to a systematie agent, and phototoxieity refer to all such reaetions as photosensitivity to a
to a systematie agent. systemie agent (PSA) or as photodrug reactions.
The meehanism of action (allergie versus toxie) is The diagnosis of a photodrug re action is made
fairly easy to diseern on the basis of clinieal features in primarily if there is a history of ingestion of a
the ease of topieally applied chemieals. By definition, photosensitizing agent and tlIe presentation of a skin
photopateh testing to a chemie al indueing PACD reaetion in a photodistribution. Exposure of unin-
reveals positive responses only in sensitized individ- volved skin to etiologie radiation while the patient is
uals and negative responses in unsensitized individuals taking the drug may reproduee the eruption. Simi-
or the population in general. By eontrast, all or at least larly, PICD is a diagnosis made by eareful history
the vast majority of the population develop positive taking to reveal skin exposure to the photoirritant.
reaetions on photopateh testing with phototoxie agents Photo-pateh testing in such patients is contraindicat-
(PICD). Other differenees are outlined in Table 2. They ed, since a positive response might be severe, would
include areaction oeeurring on first exposure to tlIe be expeeted to oeeur in the general population and,
ehemieal agent and light in PICD, with a sensitization thus, would not be helpful in making the diagnosis
delay neeessary for PACD. The timing of the response (Table 4).
to testing is delayed in PACD, as it is in allergie eontaet The pathophysiologie mechanisms involved in
dermatitis. In PICD, the timing of the response varies, PACD have been extensively studied. These studies
depending on the chemie al involved; for instanee, tars routinely revealed that the immunologie proeess
induee an immediate positive re action in skin on involved in this reaetion is analogous to the proeess
exposure to radiation, whereas psoralens produee a oeeurring in plain allergie eontaet dermatitis to a
response in skin 48-72 h after exposure to light. On nonphotosensitized antigen. The meehanism involved
clinieal and histologie examination, PACD is evident as in the production of the photoantigen is less clearly
an eezematous response, whereas PICD results in defined.
Table 1. Types of exogenous

photoehemieal-sensitivity patho- Route of exposure Toxie effeet Allergie effeet
physiology
Topical Photoirritant eontaet dermatitis Photoallergie eontaet dermatitis
Systemic Phototoxicity to a systemic agent Photoallergy to a systemic agent
a* Photosensitivity to a systemie agent or a photodrug reaetion

Occupational Phototoxicity and Photoallergy 315
Table 2. Differences between pho-

toallergic and phototoxic chemical Feature Photo allergie Phototoxic
reactions
Incidence Low High
Occurrence on first exposure No Yes
Onset after ultraviolet exposure 24-28 h Minutes to days
Dose dependence
Chemical Not crucial Important
Radiation Not crucial Important
Clinical morphologie Eczematous, bullous, Erythema and urticarial,
appearance (erythroderma) eczematous pigmentation; papular, pseudoporphyric
lichenoid pigmentation
Route of exposure
Topical Common Common
Systemic Unusual Common
Since most systemic sensitizers are drugs, it would The agents that induce the response are listed in
be unlikely that photosensitivity to systemic agents Table 4 above. As one might expect, most individuals
would occur in the workplace as a function of chemical who experience occupationally related PICD are likely
exposure on the job. üf course, many patients with to be workers in outdoor occupations, but this is not
outdoor occupations would be liable for occupationally always the case. Any individual with an eruption in a
related reactions due to drugs they take for personal photo distribution should be suspected of having
medical problems. Many of the systemic photos- PICD, and a careful history of exposure to photos-
ensitizers listed in Table 4 can cause photo-contact ensitizers in the workplace should be taken. The
reactions in health-care workers who have topical diagnosis is also suggested by the classic morphology
exposure to these medications while delivering them to of the eruption. lt is usually erythematous and
their patients and in farmers who administer drugs to edematous, with bullae in severe cases. lt is not
animals. Therefore, the vast majority of occupationally eczematous in most individuals. Frequently, the le-
related photosensitivity reactions are due to PACD and sions of PI CD heal with pigmentation, especially when
PICD. due to furocoumarin sensitizers. In fact, many patients
Many occupationally related cases of photo sensitiv- present with only hyperpigmentation, without a histo-
ity have been reported in workers in outdoor occupa- ry of preceding inflammation.
tions [4]. However, this is not always the case, since the
quantity of radiation necessary to induce areaction
Tar Products
can be quite small, as little and 20-30 min of natural
sun exposure [3]. In addition, it must be remembered
Coal tar and related products produce a very distinc-
that almost all chemical photosensitization has its
tive photosensitive reaction known as "tar smarts" or
action spectrum in the long wave ultraviolet (UV) A
"pitch smarts" [6, 7]. The patient experiences burning
(320-400 nm) and visible (400-800 nm) ranges [3]. As
and stinging while in the sun. This occurs with as little
such, window glass will not protect an individual
as 15 min of exposure. Roofers with exposure to pitch
whose skin is harboring a photosensitizer. Patients
and coal tar are most susceptible and direct skin
might easily develop areaction while riding in an
contact is not necessary, since aerosolized contact is
automobile to and from work.
sufficient to produce the re action. Associated ophthal-
mologic involvement may occur [8]. Kochevar and
colleagues reported that the sensitizers in coal tar
Photoirritant Contact Dermatitis
included acridine, anthracene, benzopyrene and flu-
orabthene [9]. Reactions to creosote in roof paper and
The incidence of PICD in the general population is
creosote-soaked wood products, inc1uding saw dust
unknown. A review of large studies of patients being
and boxes, have been reported in over 400 workers [10,
evaluated for photosensitivity reveals a fairly low
11].
incidence of this diagnosis [5]. This may be because
the diagnosis is made clinically, since photo testing
and photo-patch testing is nondiscriminating. For this Furocoumarins
reason, patients with PICD would not undergo testing
and not appear in statistics. lt is probably at least as Furocoumarins are photosynthesizing chemicals that
common as PACD in the general population and occur naturally in the plant kingdom and have been
probably more common in a population of individuals synthesized for many uses, including as fragrance
with occupationally related skin disease. materials and as therapeutic agents. In fact, the latter
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Table 3. Common drugs inducing photosensitivity to a systemic agent or photodrug reaction [33]
Anticancer drugs Antidepressants Antihistamines Antimicrobials Antiparasitic Antipsychotic drugs Diuretics Hypoglycemics NSAIDs Others
drugs
Actinomycin Amitriptyline Carbinoxamine Ciprofloxacin Bithionola * Chlordiazepoxide Acetazolamide Acetohexamide Ketoprofen Amiodaronea *
D (Elavil and (Cipro) (Bitin) hydrochloride (Diamox and (Dymelor) (Orudis) (Cordarone)
others) (Librium) others)
Dacarbazinea * Amoxapine Cyproheptadine Demeclocycline a * Chloroquine Chlorpromazine Amiloride Chlorpropamide Carprofen Captopril
(DTIC-Dome) (Asendin) (Periactin and (Declomycin (Aralen) (Thorazine (Midamor) (Diabinese (Captoen)
others) and others) and others) and others)
Doxorubicin Desipramine Diphenhydramine Doxycycline Pyrvinium Chlorprothixene Bendroflumethiazide Glipizide Naproxen Carbamazepine
hydrochloride (Norpramin; (Benadryl (Vibramycin pamoate (Taractan) (Naturetin (Glucotrol) (Naprosyn) (Tegretol)
(Adriamycin) Pertofrane) and others) and others) (Povan) and others)
Fluorocytosin Doxepin Enoxacin Quinine (many Fluphenazine Cyclothiazide Glyburide Piroxicam Clofibrate
(Adapin; manufacturers) (PermitiI; Prolixin) (Anhydron) (Dia Beta) (Feldene) (Atromide-S)
Sinequan)
Fluorouracil Imipramine Flerofloxacin Haloperidol (Haidol) Chlorthiazide Tolazamide Phenylbutazone Disopyramide
(Fluoroplex (Tofranil (Diuril and (Tolinase (Butazolidine (Norpace
and others) and others) others) and others) and others) and others)
Hydroxyurea Isocarboxazid Griseofulvin Perphenazine Furosemide Tolbutamide Sulindac Etretinate
(Hydrea) (Marplan) (Fulvicin-U/F (Trilafon) (Lasix and (Orinase (Clinoril) (Tegison)
and others) others) and others)
Methotrexate Nortriptyline Methacycline Piperacetazine Hydrochlorothiazide Fenofibrate
(Mexate and (Aventyl; (Rondomycin) (Quide) (Hydrodiuril
others) Pamelor) and others)
Procarbazine Protriptyline Minocycline Prochlorperazine Hydroflumethiazide Gold salts
(Matulane) (Vivactil) (Minocin) (Compazine (Diucardin (Myochrysine;
and others) and others) Solganol)
Vinblastine Trimipramine Nalidixic acid a * Thioridazine Maprotiline Hematopor-
(Velban) (Surmontil) (NegGram) (Mellaril) (Ludiomil) phyrin
Norfloxacin Thiothixene (Navan) Methyclothiazide Isotretinoin
(Aquatensen (Accutane)
and others)
Oxytetracycline Tricyclic Metolazone Oral
(Terramycin antidepressants (Diulo; Zaroxolyn) contraceptives
and others) (Protriptyline
and others)
Sulfasalazine Trifluoperazine Polythiazide Promethazine
(Azulfidine (Stelazine (Renese) (Phenergan)
and others) and others)
SulfadOldne + Quinethazone Psoralen
pyrimethamine (Hydromox) derivatives
(Fansidar)
Sulfamethizole Trichlormethiazide Quinidine
(Thiosulfil and (Metahydrin) sulphate
others) and gluconate
Sulfamethoxazole Triacetyldiphe-
(Gantanol and no-lisatin (TDI)
others)
Sulfamethoxazolel Trimeprazine
trimethoprim (Temaril)
(Bactrim)
Sulfasoxazole
(Gantrisin
and others)
Tetracycline
hydrochloride
a* Reactions occur frequently. NSAID, non-steroidal anti-inflammatory drugs; DTIC, 5-dimethyltriazenoimidazole-4-carboxamide o

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Table 4. Agents commonly inducing photoirritant contact der- dumosum, a native bush in the chaparral vegetation
matitis zone in California and Mexico, has been reported in
field worker-students [12]. Unlike the reaction to tar-
Tar-related products
Tars related products, the reaction to furocoumarins is
Pitch delayed, occurring 1-2 days after the plant and light
Acridine exposure. Healing is frequently accompanied by
Coal Tar
Anthracene hyperpigmentation.
Creosote The plant most often reported to induce phytop-
Dyes hotdermatitis in the workplace is celery. Initially, it
Methylene blue
Eosin was believed that only celery infected with pink-rot, a
Disperse blue 35 fungal parasite, was capable of inducing this response.
Amino-benzoic-acid derivative The infection induced increased productions of fur-
Amyl-o-dimethylarninobenzoic acid
Furocoumarins ocoumarins in the celery and, therefore, led to the
Therapeutic agents reaction [13,14]. This is now known not to be the case.
8-Methoxypsoralen Reactions have been reported in cannery workers,
4,5,8-Trimethylpsoralen
5-Methoxypsoralen (Bergapten) grocery-store cashiers, baggers, produce clerks, and
Fragrance materials a * chefs [15]. Limes contain large amounts of furocou-
Plantsb ** marins in the exocarp, or colored part of the skin, and
Rutacease
Lime handling these and other citrus fruits may lead to
Lemon phytophotodermatitis in bartenders. The lime is the
Bergamot most common cause of phytophotodermatitis in non-
Burning bush
Bitter orange occupational settings [3]. Farmers and other outdoor
Gas plant workers are also at risk for developing phytophotod-
Common rue ermatits from exposure to the food products and other
Umbelliferae
Carrots plants listed in Table 4. Many such reactions will
Cow parsley present with linear lesions, as for poison-ivy contact
Wild chervii dermatitis.
Fennel
Dill
Parsnip
Celery Other Agents
Moraceae
Fig
Cruciferae Amyl-o-dimethylaminobenzoic acid induced an imme-
Mustard diate photosensitivity response followed by a second,
Ranunculceae
Buttercup delayed erythema in workers formulating UV -cured
inks [16]. On sun exposure, disperse blue dye 35
a* Berloque dermatitis produced a transient erythema and burning in workers
b** Phytophotodermatitis (not all-inclusive)
when leaving work [17].
usage is dependent on the photosensitizing potential

of these agents in the photochemotherapy of skin Photoallergie Contact Dermatitis
disease. The most common agents used therapeuti-
cally are also the ones present in plant extracts that The incidence of PACD in the general population is
are potent photosensitizers - 8-methoxypsoralen and unknown. The available incidence data are based on
5-methoxypsoralen. Trisoralen is also used therapeu- positive photo-patch test results in groups of patients
tically. with presumed photosensitivity who were referred to
When an individual develops PICD to a fragrance tertiary-care facilities for diagnostic photo-patch test-
product, it usually appears as a hyperpigmented ing. In Canada, 6% of such patients who were
macule at the site of application of the perfume or phototested were found to have PACD, in a study
cologne. This is the so-called "berloque dermatitis" published in 1975. In England, 25% of tested patients
[2]. were found to have positive photo-patch test responses
The most common occupationally related reactions in each year of the 1970S [1]. In 1988, the Scandinavian
are those that occur to plants and plant products, and Multicenter Photo-patch Study recently found 274
are referred to as "phytophotodermatitides". Although positive photo-patch test results and 369 positive plain
there have been reports of plants other than those patch-test responses in 1993 patients who were tested
containing furocoumarins causing phytophotdermati- between 1980 and 1985. Of these, 217 patients (11%)
tis, they are exceedingly rare. For example, Cneoridium were thought to have clinically relevant positive test
responses resulting in a diagnosis of PACD [5, 18]. In the UVA range is between 20 I/em 2 and 60 I/cm" any
the United States, 70 patients were tested at the Mayo dose that ean be eonveniently delivered below this level
Clinic during the same 5-year period. Of those tested, ean be used, and 10 I/em 2 has been selected more or
38.5% and 31% had positive photo-patch-test and less arbitrarily to fulfil these two criteria.
plain-patch-test responses, respectively. Only 14 In addition to photo-patch testing, it is reeommend-
(20%) of the patients tested had clinically relevant ed that the patient being tested also be given graded
photo-patch test reactions [19]. In a study from New doses of radiation in the UVB range for determination
York, 187 patients were phototested; positive photo- of the MED. Such testing assists in distinguishing
patch test responses resulted in a diagnosis of PACD in transient and persistent light reaetivity. This neeessi-
20 patients (11%) [20]. When these data are taken tates a UVB-light souree (Table 5). A suggested list of
together, it would appear that the incidence of PACD, photoallergens is given in Table 6.
in individuals with a his tory of a photosensitivity
eruption, would be approximately 10% to 20%.
Unlike PICD, the only way to confirm a diagnosis of Protocol for Patch Testing
P ACD is with photo-patch testing. That technique is
outlined in the next section. A reeommended protocol for photo-patch testing is
outlined below. This protocol should reliably diagnose
Photo-patch Testing Techniques

Table 5. Light soure es for photo-pateh testing
Photopatch testing, simply stated, is patch testing with Ultraviolet B speetrum

Ultraviolet A speetrum
the addition of radiation to induce formation of the Fluoreseent blaek lights Fluoreseent sunlamp
photo antigen. Application of antigens and seoring Fluoreseent PUV A lights Mereury halide lamp without
criteria are the same as those described for plain pateh a filter
Mereury halide lamp with Sunlight
testing [3]. The only additional equipment that is a filter
neeessary is an appropriate light souree and light Hot quartz lamp with a filter Hot quartz lamp without a filter
opaque shielding for the period after removal of the Sunlight with a filter
Finn chambers before readings. "* Diseontinuous speetrum: less desirable. PUVA, psoralen-
With very few exceptions, the most notable being ultraviolet A radiation
diphenhydramine hydroehloride, the radiation respon-
sible for formation of the photo antigens and clinieal
Table 6. Photo allergen test panel - North Ameriean Contaet
PACD falls within the UV A speetrum (320-4000 nm). Dermatitis Group
The ideal light source should produce UVA radiation
in a continuous speetrum (fairly uniform radiation Oetyl-methoxycinnamate, 7.5% in pet
from 320 nm to 400 nm) of sufficient irradianee and Sulisobenzone (BZP-4), 10% in pet
Cinoxate, 1% in pet
field size to allow irradiation of 20-25 antigen sites Thiourea (thioearbamide), 0.1% in pet
with a dose of 5-10 I/ern within a reasonable time Diehlorophen, 1% in pet
(about 30 min). The source should also produce little Triclosan, 2% in pet
Hexaehlorophene, 1% in pet
UVB radiation or should be equipped with a filter to Chlorhexidine diaeetate, 0.5% in H2 0
remove most sueh radiation. Between 3 mm and 5 mm Sandalwood oil, 2% in pet
of window glass is adequate to block UVB radiation. Chlorpromazine hydrochloride, 0.1 in pet
Musk ambrette, 1% in pet
Table 5 lists the most eommonly available of sueh p-aminobenzoie acid, 5% alcohol
sources. A photometer-radiometer matched to the Petrolatum control
source is also required for proper dosimetry. Sueh Tribromosalieylanilide, 1% in pet
Oetyl-dimethyl PABA, 5% in aleohol
source-radiometer matching is most easily accom- Oxybenzone (BZP-3), 3% in pet
plished by purchasing the two units from the same Promethazine, 1% in pet
manufaeturer. By far the most readily available souree Oetyl-dimethyl PABA, 5% in pet
Bithionol (thiobis-ehlorophenol), 1% in pet
in the dermatologist's office is the unit used for p-Aminobenzoie acid, 5% in pet
delivery of photoehemotherapy [psoralen UV A Musk ambrette, 1% in alcohol
(PUVA)]. Fenticlor (thiobis-ehlorophenol), 1% in pet
Oetyl salieylate, 5% in pet
The dose of radiation used in photo-pateh testing Butyl methoxydibenzoylmethane, 5% in pet
varies between 1 I/em 2 and 10 I/em 2 in most studies. Homosalate, 5% in pet
Theoretically, the largest dose that does not alone Menthylanthranilate, 5% in pet
6- Methylcoumarin, 1% aleohol
induee erythema in skin would be most likely to yield
produetion of the photo antigen and a positive test pet, petrolatum; BZP, benzodiazepine; PABA, p-aminobenzoic
response. Sinee the minimal erythema dose (MED) in acid
320 V. DeLeo
PACD and also aids in the differential diagnoses of between these two different testing schedules. As
other common types of photosensitivity. before, two readings should be taken.
On day 1, two sets of photo antigens are applied, one One antigen, 6-methylcoumarin, is not applied on
set to either side of the upper portion of the back. The day 1 with the other antigens. This agent's ability to
antigens are applied in Finn chambers, as described form a photoantigen disappears rapidly after appli-
previously. Graded doses (8-10 doses) of UVB radia- cation to skin. For this reason, the antigen is applied
tion are applied to previously unexposed skin sites on the day of patch irradiation (usually day 2). It is
(approximately 1 cm across in each area) on one applied in duplicate in Finn chambers for a 30-min
buttock. These doses should include the dose of period before irradiation.
radiation that would normally correspond to the The photopatch test result is read as for plain patch
patient's MED. For a light-complexioned individual, tests. An area of significant controversy exists,
10, 20, 30, 40, 50, 60, 70, and 80 mJ/cm 2 would be however, in distinguishing photocontact allergy from
appropriate. These dos es, however, depend on the light plain contact allergy. The system used by the North
source and photometer used. UVA radiation at a dose American Contact Dermatitis Group is shown in
to be used for photo-patch testing (usually 10 J/cm 2 ) is Table 7.
then delivered to a single site on the opposite buttock It is agreed that a positive response in the irradiated
(about I-cm across). site and a negative one in the covered site is diagnostic
On day 2, the patient returns, and the photo test sites of photoallergy. Likewise, equal positive responses in
are evaluated for erythema. The MED in the UVB range both irradiated and covered sites are diagnostic of
is determined as the site with minimal perceptible plain contact allergy. The North American system
erythema. Whether such an MED is "normal" or allows for the diagnosis of both allergy and
"lowered" is determined by experience with the photoallergy when both sites are positive, but only
particular light source used. Erythema resulting from when the resuIt in the irradiated patch is significantly
UVA is required to determine the proper UV A photo- more positive than in the covered site. In the system
patch test dose. This is done in a fashion analogous to used by the Scandinavian and Mayo Clinic groups [5,
UVB MED testing, by using doses of 1, 2, 3, 4, 5, 6, 7, 8, 18, 19], any reaction in the covered site resuIts in a
9 and 10 J/cm 2 of UVA on day 3 and reading the diagnosis of plain contact allergy.
resuIts. Occasionally, irradiation appears to inhibit a
Assuming that a UV A radiation dose of 10 J/cm 2 did positive patch-test reaction. In such cases, the nonir-
not elicit a response, the photo-patch test continues on radiated site will be reactive, whereas the irradiated site
day 2. Both sets of antigens are removed and marked, will be negative. The pathophysiology of such an
and readings are done at all sites for contact allergy or occurrence is not understood; neither are its clinical
irritancy. One set of patches (dark control) is covered ramifications. Such a response, if clinically relevant,
with light-opaque material, and the other set is may be significant.
exposed to a UVA-radiation dose of 10 J/cm 2 • Next, As with plain-patch testing, false-positive and false-
the irradiated set is also covered with light-opaque negative resuIts can occur in photopatch testing. One
material. Gauze pads covered with aluminum foil or particularly common false-positive or photoirritant
black feIt are suitable light-opaque materials. The response is to the phenothiazine agents in the tray
patient returns for readings, preferably on day 4 (48 h (chlorpromazine and promethazine), which is
after irradiation) and at one later point up to a week discussed in detail in the antigen sections of this
after irradiation. Two readings are recommended and chapter.
might be scheduled at 48 hand 72 h, 48 hand 96 h, or Some antigens produce an immediate photoirritant
48 hand 1 week. If scheduling a 48-h reading is response. Erythema is noted at the completion of the
impossible, two readings could be done at 24 hand irradiation period. This is not usually clinically
72 h or at 24 hand 96 h. If 10 J/cm 2 of UVA radiation relevant and may be disregarded.
alone produced erythema, a lower dose must be used In addition to the photo allergens in the tray,
for photo-patch testing. That dose is determined by patients can be tested to their own products, partic-
reading the MED testing (on day 3) to graded doses of
the UV A radiation that were applied on day 2. Half of Table 7. Reading the photo-patch test reading
the MED should be used, but any dose that alone will
not produce erythema can be used. The use of too low Diagnosis Irradiated site Nonirradiated site
a dose may result in false-negative photo-patch test
No sensitivity
results. With a lowered MED in the UV A range, the Photocontact allergy +
irradiation of patches will be on day 3. Therefore, the Contact allergy + +
Photocontact and ++ +
patches are in place for 48 h rather than 24 h. There is
contact allergy
no evidence to suggest that major differences occur
ularly to sunscreens and fragrance-containing cosmet- of the clinical eruption without antigen. This type of
ics. Industrial cleansers and the like, as well as response is more difficult to explain pathophysiolog-
personal-care cleansers that may be the source for ically than the localized persistent light reactions. Not
antibacterial agents, must be diluted appropriately. only has skin not previously exposed to light or
antigen developed sensitivity, but the speetrum has
also shifted from the UVA to the UVB range. It has
Chronic Acting Dermatitis: been suggested that the original photo allergie reaction
Persistent Light Reactions (UV A radiation plus allergen) has resulted in the
development of an endogenous photo allergen, proba-
As with plain contact dermatitis, avoidance of contact bly an altered carrier protein, with absorption and
with the photo allergen in a patient with PACD usually activation in the UVB range. Only certain photo aller-
results in clearing of the dermatitis and the photo sen- gens are, apparently, capable of indueing such sensi-
sitivity. Occasionally, however, the patient continues to tivity. This includes a number of the antibacterial
be photo sensitive; that is, he or she continues to react halogenated phenols, phenothiazines, and musk am-
to light, with the development of dermatitis. Such brette.
patients were first observed with antibacterial photo- Although the severity of photosensitivity in patients
allergens and were referred to as persistent light with persistent light reaction varies greatly, many
reactors. In contrast, patients whose conditions cleared patients have been severely debilitated. Such individ-
once the photo allergen was removed were called uals reaeted adversely to minimal sun exposure (less
transient light reactors. than 1 min of natural exposure) and were even
Occasionally, persistent photosensitivity remained believed to be reacting to indoor ßuorescent lighting.
localized to the distribution of the original photo aller- The eczematous eruption beeame chronic and spread
gen exposure. This was called a localized persistent to involve non-sun-exposed areas, sometimes eventu-
light reaction and was seen with the antibacterial agent ating in generalized erythroderma. Histologie study
bithionol. In such patients, it was postulated that the occasionally revealed an atypical infiltrate, leading to
sensitivity was related to persistence of allergen at the the misdiagnosis of mycosis fungoides. Such patients
sites of initial exposure. In these individuals, exposure were referred to as having actinic reticuloid. Most such
of previously uninvolved skin to UV radiation pro- patients were older men. Patients of similar age and
duced normal reactions (normal MED in the UVB and sex with a similar disseminated, photosensitive, ecze-
UVA ranges). Photopatch testing (UVA and allergen), matous response have also been reported under the
of course, produced a positive response. terms photosensitive eczema, eczematous, polymor-
Other patients, however, developed a generalized phous light eruption, and photosensitivity dermatitis.
photosensitivity in the absence of continued antigen The photobiologie criteria for diagnosis of these
exposure. Most notable were patients who were various conditions are listed in Table 8. All of these
photoallergie to the antibacterials tetrachlorosalicylan- patients have in eommon a persistent eczematous
ilide (TCSA) and tribromosalicylanilide (TBS) and, clinical eruption of sun-exposed skin, with possible
more recently, to the fragrance musk ambrette. In extension to non-sun-exposed areas, sensitivity to
these individuals, exposure of previously uninvolved UVB radiation (with possible sensitivity to UV A and
skin to irradiation without allergen resulted in abnor- visible radiation), and ehronie eezematous ehanges on
mal reactivity. This resulted in a lowered MED in the skin biopsy with or without atypical infiltrate. It has
UVB range (possibly in the UVA and visible ranges). been no ted that patients may develop and/or lose
These responses were different both quantitatively and criteria for differentiating these various diagnoses.
qualitatively from sunburn or MED erythema. On Therefore, it has been suggested that all such patients
clinical and histologie examination, the reactions were represent variations of a single proeess and that they
eczematous. The responses represented a reproduction all be grouped under the diagnosis chronic aetinic
Table 8. Chronic actinic dermatitis

Original terminology Abnormal Photo-patch test Atypical
reactivity histology
UVB UVA Visible
Actinic reticuloid + + +/- +/- +

Photo sensitive dermatitis + +/- +/-
Photosensitive eczema +
Persistent light reaction + +/- +
Eczematous PMLE +/- +/-
322 V. DeLeo
dermatitis (CAD). Patients with CAD may have pos- "deodorant" -type bar soaps marketed in the United
itive photo-patch test responses. They mayaIso have States today contain this agent. It appears to be a very
multiple positive plain patch-test reactions to airborne low-Ievel photosensitizer, and few cases have been
or industrially relevant antigens, such as chrysanthe- reported despite its widespread use.
mum and dichromates. Chronic actinic dermatitis is Dichlorophene (G-4) is widely used in this country
also reported to occur without other apparent cause in and in Europe in shampoos, dentifrices, antiperspi-
human-immunodeficiency-virus-positive patients. rants, and "athlete's foot" powder. Dichlorophene is
Photobiologie testing in these individuals reveals a also used in the treatment of fabrics. It is rarely
lowered MED to UVB radiation. The test site is reported as a photosensitizer.
eczematous on clinical and histologie examination. Bithionol is a chlorinated phenol that was used in
the 1960s in the United States and, more extensively,
Japan. It caused an epidemie of PACD in Japan, where
Occupational Photoallergens it was present in bar soaps. It is banned in that country
and is no longer used in bar soaps in the United States.
Most of the agents listed in Table 4 are agents used in It may still be used in industrial cleaners and agricul-
consumer products. As such, outdoor workers would tural and veterinary products marketed in the United
be at risk when using such products. There are other States.
agents, however, that have been reported to cause Fenticlor is a chlorinated phenol used as an
photoallergy in the workplace. antibacterial and antiseborrheic agent in hair-care
products made primarily in Canada, the British Isles,
Sunscreens and Australia. It was never used extensively in the
United States. It appears to be a moderately potent
In the 1970S and 1980s, people in the United States, photo allergen. It may produce false-positive responses
Europe, and Australia began to increase their usage of in photopatch tests. Such responses have the features
sunscreens as they were educated to the dangers of sun of true photoallergy; they appear eczematous and
exposure. This is particularly true of outdoor workers. occur in a delayed fashion, with an increase in severity
This has led to increased exposure to active ingredients of response at the second reading.
in these products. Therefore, it is not surprising that Hexachlorophene was a widely used antibacterial in
such agents induce contact allergy and, since such over-the-counter skin cleansers in the United States.
ingredients by definition absorb UV radiation, it is not Reports of neurotoxicity resulted in a change of status
surprising that they also induce PACD. The incidence to prescription-only by the Food and Drug Adminis-
of these reactions in the sunscreen-using population is tration.
unknown, but it is probably very low. Sunscreen Phisohex is still used in the United States today, but
components were the most common group of agents with much lower frequency. It is rarely reported as a
producing relevant photo-patch-test reactions in a photo allergen.
New York [20] photo-patch-test series but were less Chlorhexidine is used as an antibacterial in hospital
frequent than antimicrobials and fragrances in the cleansers for both skin and mucosa. It is also used as a
Mayo Clinic and Scandinavian studies [5, 18, 19]. The dental rinse. It is a rare photo allergen.
most common agents to induce this response are the
benzophenones, oxybenzone and slisobenzone, octyl- Fragrances
dimethyl PABA, and the dibenzoylmethanes.
A number of fragrance ingredients have been associ-
Antibacterials ated with photo allergie contact dermatitis. The three
most common include musk ambrette, 6-methylcou-
Tetrachlorosalicylanilide (TCSA) and tetrabromosal- marin, and sandalwood oil.
icylanilide (TBS), the most potent of the photos- Musk ambrette is a synthetic fragrance fixative used
ensitizers, caused an epidemie of PACD in many areas primarily in men's cosmetics because of its potent
of the world. The former caused an outbreak in factory floral odor. Related chemicals extracted from the scent
workers in Great Britain in 1960 [21,22]. These agents glands of animals and some plants have been used for
were responsible for producing a large number of cases years as fixatives and enhancers in perfumes. In the
of debilitating CAD. While these agents are no longer 1970S and 1980s, huge quantities were used in the
used in consumer cleaners (that is, bar soaps and United States in various cosmetics, primarily men's
shampoos), in the United States they may still be used after-shave lotions and colognes. Concentrations of
in industrial cleansers. musk ambrette as high as 15% were used in such
Triclosan (Irgasan DP 300) is a widely used products. In the late 1970S, reports of photoallergy
antibacterial agent in bar soaps and deodorants. Most began to appear in the literature. By the 1980s, this
agent was the most frequently reported cause of PACD. ized. In addition, some individuals with airborne
Many of the men sensitized to musk ambrette devel- contact dermatitis have gone on to develop an
oped persistent reactions (CAD). The International idiopathic photosensitivity - CAD - described above.
Fragrance Association has recommended that musk The major allergens in this group include occupation-
ambrette not be used in products that will have contact ally acquired agents, such as chrornates [27, 28],
with skin. In other products, a concentration of 4% or and plants of the Compositae [29, 30] and Lichen
less is recommended. [31] families. An extensive review of this area, as
6-Methycoumarin is a synthetic fragrance that related to the Compositae experience, has revealed that
caused an epidemie of PACD when it was used in a this is not truly a PACD, but conversion to photosen-
"sun-tanning" lotion in the late 1970S. The reactions sitivity from contact dermatitis by an unknown
were particularly severe ones, requiring hospitalization mechanism.
in many cases. The morphology of many of the
reactions suggested phototoxicity, but photoallergy
was probably the underlying mechanism. The agent
was removed from sun-related lotions, and it is no References
longer recommended for use as a fragrance compo-
nent. An early problem with the identification of this 1. Cronin E (1980) Contact dermatitis. Churchill Livingstone,
agent as etiologic occurred because of its apparent London
2. DeLeo VA, Harber LC (1986) Contact photodermatitis. In:
instability as a photo allergen once applied to skin. In Fisher AA (ed) Contact dermatitis, 3rd edn. Lea and Febiger,
routine photopatch testing, antigens are applied to Philadelphia
skin 24-28 h before UV A exposure. Such testing 3. Marks Jr JG, DeLeo VA (1992) Contact and occupational
dermatology, 2nd edn. Mosby-Yearbook, St. Louis
yielded negative results. When the antigen was applied 4. Emmett EA (1990) Phototoxicity and photosensitivity reac-
shortly (30-60 min) before exposure, positive reactions. In: Adams RM (ed) Occupational skin disease, 2nd edn.
tions were found in sensitized individuals. Testing with Saunders, Philadelphia
5. Thune P, Jansen C, Wennersten G et aI. (1988) The Scandi-
this agent is, therefore, done differently from the other navian multicenter photopatch study: 1980 to 1985-final
routinely tested photo allergens. report. Photodermatol Photoimmunol Photomed 5:261-269
Sandalwood oil is a "woodsy" -smelling fragrance 6. Crow KD, Alexander E, Buck WHL, Johnson BE, Magnus IA,
Porter AD (1961) Photosensitivity due to pitch. Br J Dermatol
ingredient. It is rarely reported as a photosensitizer. 73:220-232
7. Emmett EA (1986) Cutaneous and ocular hazards of roofers.
Therapeutic Agents Occup Med 1:307-322
8. Emmett EA, Stetzer W, Taphorn B (1977) Phototoxic kerato-
conjunctivitis from coal-tar pitch volatiles. Science 198:
A number of systemic drugs that produce photo sen- 841-842
sitivity have been reported to cause PACD when 9. Kochevar JE, Armstrong RB, Einbinder J, Walther RR, Harber
LC (1982) Coal tar phototoxicity: active compounds and
contacted topically. Theoretically, this might occur action spectra. Photochem Photobiol 38:65-69
with many such agents. The two most frequently 10. Jonas AD (1943) Creosote burns. J Ind Hyg Toxicol 25:
reported are the phenothiozines, chlorpromazine hy- 418-420
11. Heyl T, Mellett WA (1982) Creosote dermatitis in an
drochloride (Thorazine) and promethazine (Phener- ammunition depot. S Afr Med J 62:66-67
gan). The PACD reported for the former has been 12. Tunget CL, Turchen SG, Manoguerra AS, Clark RF, Pudoff
found in health-care workers who have frequent skin DE. Sunlight and the plant: a toxic combination: severe
phytophotodermatitis from Cneoridium dumosum
contact with the agents. 13. Klaber R (1942) Phytophotodermatitis. Br J Dermatol 54:
Quindoxin is a growth-promoting agent used in 193-211
animal foodstuffs. It has been reported to cause PACD 14. Birmingham DJ, Key MM, Tubich GE, Perone VB (1961)
Phototoxic bullae among celery harvesters. Arch Dermatol
in farm workers handling the feed [23, 24]. It is no 8):73-87
longer used. Olaquindox, similarly used in animal feed, 15. Morbidity and Mortality Weekly Report (1985) Leads from
caused an outbreak of PACD in pig farmers [25]. the MMWR: phytophotodermatitis among grocery workers.
JAMA 253:753
16. Emmett EA, Taphorn BR, Kominsky JR (1977) Phototoxicity
Pesticides and Insecticides occurring during the manufacture of ultraviolet cured ink.
Arch Dermatol 113:770-775
17. Gardiner JS, Dickson A, Macleod TM, Frain-Bell W (1972)
Folpet and capan, used by farmers and groundskeep- The investigation of photocontact dermatitis in a dye
ers, have been recently reported to induce PACD [26]. manufacturing process. Br J Dermatol 86:264
18. Thune P (1984) Contact and photocontact aIlergy to sun-
screens. Photodermatol Photoimmunol Photomed 1:5-9
Air-borne Contact Dermatitis 19. Menz MB, Sigfrid AM, Connolly SM (1988) Photopatch
and Chronic Actinic Dermatitis testing: a six-year experience. J Am Acad Dermatol 18:
1044-1047
20. DeLeo VA, Suarez SM, Maso MJ (1992) Photoallergic contact
Photosensitivity can be mimicked by contact derma- dermatitis: results of photopatch testing in New York - 1985
titis in skin exposed to allergens that can be aerosol- to 1990. Arch Dermatol128:1513-1518
324 V. Deleo: Occupational Phototoxicity and Photoallergy
21. Wilkinson DS (1961) Photodermatitis due to tetrachlorosal- 27. Tronnier H (1970) Zur Lichtempfindlichkeit von Ekzemati-
icylanilide. Br J Dermatol 73:213-219 kern (unter besonderer Berucksiehtigung des Chromat-Ekz-
22. Calnan CD, Harman RRM, Wells GC (1961) Photodermatitis ems). Arch Klin Exp Dermatol 237:494-506
from soaps. BMJ 2:1266 28. Feuerman EJ (1971) Chromates as the cause of contact
23. Frain-Bell W, Gardiner J (1976) Photocontact dermatitis due dermatitis in housewives. Dermatologiea 143:292-297
to quindoxin. Contact Dermatitis 1:256-257 29. Burry JM, Kuchel R, Reid JG, Kirk J (1973) Australian bush
24. Scott KW, Dawson TAJ (1974) Photocontact dermatitis dermatitis: Compositae dermatitis in South Australia. Med J
arising from the presence of quindoxin in annual feeding Aust 1:110-116
stuffs. Br J Dermatol 90:543-546 30. Epstein S (1960) Role of dermal sensitivity in ragweed contact
25. Schauder S, Schroder W, Geier J (1996) Olaquindox-induced dermatitis. Arch Dermatol 82:48-55
airborne photoallergie contact dermatitis followed by tran- 31. Thune PO, Solberg YJ (1980) Photosensitivity and allergy to
sient or persistent light reactions in 15 pig breeders. Contact aromatic lichen acids, Compositae oleoresins and other plant
Dermatitis 35:344-354 substances. Contact Dermatitis 6:81-87
26. Mark KA, Brancaccio RR, Soter NA, Cohen DE (1999) Allergie 32. (1986) Drugs that cause photosensitivity. Med Lett Drugs
and photoallergie contact dermatitis to plant and pesticide Ther 28:51-52
allergens. Arch Dermatol 135:67-70
CHAPTER 38
Chemical Skin Burns*

M. Bruze, S. Fregert, and B. Gruvberger
Introduction and metabolism. The corrosive action of chemieals

depends on their chemie al properties, concentration,
Chemie al skin bums are particularly common in pH, alkalinity, acidity, temperature, lipid/water solu-
industry, but they also occur in non-work-related bility, interaction with other substances, and duration
environments. Occupationally induced chemical bums and type (for example, occlusion) of skin contact.
are frequently noticed when visiting and examining It also depends on the body region, previous skin
workers at their work sites. Corrosive chemicals used in damage, and possibly on individual resistance capacity.
hobbies are an increasing cause of skin bums. Disin- Many substances cause chemical bums only when
fectants and cleansers are examples of household they are applied under occlusion from, for example,
products which can cause chemie al bums. However, gloves, boots, shoes, clothes, caps, face masks, adhesive
in most cases, the cause of a chemie al bum is obvious to pIasters, and rings. Skin folds may be formed and act
the affected persons and damage is minimal and heals occlusively in certain body regions, e.g., under breasts
without medical care, so medical attention is not sought. and in the axillae. Many products, which under ordinary
Sometimes the chemical bums are severe and extensive, skin exposure conditions cause weak irritant reactions
with the risk of complications and long-term dis ability. or irritant contact dermatitis, can under occlusion cause
In the acute stage, there is a varying risk of systemic chemie al bums, e.g., detergents, emulsifiers, solvents,
effects, including a fatal outcome, depending on expo- plants, woods, topical medicaments, toiletries, insecti-
sure conditions and the incriminating agent. For these eides, pesticides, preservatives, cleansers, polishes,
reasons it is important for the physician to have plastic monomers, and Portland cement. Wet cement
knowledge of corrosive chemieals as weIl as of chemical can usually be handled without causing a chemical bum,
bums with regard to their clinical manifestations, but when present under occluding clothes for some
specific medical treatments, and preventive measures. hours, it can cause severe skin damage, e.g., on knees.
White spirit causes only slight dryness at open appli-
cation, but causes blisters under occlusion.
Definition There are different mechanisms for reactions be-
tween skin components and agents causing chemical
A caustic bum (chemical bum) is an acute, severe and thermal bums. Chemical agents cause progressive
irritant re action by which the cells have been damaged damage until either no more chemical remains unre-
to a point where there is no retum to viability; in other acted in the tissue or the agent is inactivated by
words, a necrosis develops (Stewart 1985; Sykes et al. treatment, while thermal damaging effects cease shortly
1986; Cartotto et al. 1996). One single skin exposure to after removal of the heat source.
certain chemieals can result in a chemical bum. These The most commonly reported chernicals that can
chemieals react with intra- and intercellular compo- cause chemie al bums are listed in Table 1. Acids and
nents in the skin. However, the action of toxic (irritant) alkalis have been grouped separately, as the corrosive
chemieals varies, causing partly different irritant reac- effect within the respective group is exerted through
tions morphologicaIly. They can damage the homy the same mechanism. These groups contain both
layer, cell membran es, lysosomes, mast ceIls, leuko- strong and weak acids and alkalis, respectively. The
cytes, DNA synthesis, blood vessels, enzyme systems, other compounds are listed together although their
corrosive effects are mediated through different me ch-
anisms. Most of these compounds are neutral. How-
ever, some are weak acids or alkalis but are considered
* This chapter is based on the chapter Chemical Skin Bums,
written by M. Bruze and S. Fregert. In: T. Menne and H.1. to be corrosive due to properties other than acidity or
Maibach (Eds.) Hand Eczema. alkalinity, respectively.

326 M. Bruze et al.
Table 1. Agents causing chemical bums. The chemicals listed are the most common reported to cause chemical bums in industries,
hobbies, and households. The list features strong corrosive substances and also less irritating compounds that require special
conditions, for example occlusion, to cause chemical bums
Acids Alkalis Miscellaneous
Acetic acid Amines Acethyl chloride

Acrylic acid Ammonia Acrolein
Benzoic acid Barium hydroxide Acrylonitrile
Boric acid Calcium carbonate Alkali ethoxides
Bromoacetic acid Calcium hydroxide Alkali methoxides
Chloroacetic acids Calcium oxide Allyl diiodine
Chlorosulfuric acid Hydrazine Aluminum bromide
Fluorophosphoric acid Lithium hydroxide Aluminum chloride
Fluorosilicic acid Potassium hydroxide Aluminum trichloride
Fluorosulfonic acid Sodium carbonate Ammonium difiuoride
Formic acid Sodium hydroxide Ammonium persulfate
Fumaric acid Sodium metasilicate Ammonium sulfide
Hydrobromic acid Antimony trioxide
Hydrochloric acid Aromatic hydrocarbons
Hydrofiuoric acid Arsenic oxides
Lactic acid Benzene
Nitric acid Benzoyl chloride
Perchloric acid Benzoyl chlorodimethylhydantoin
Peroxyacetic acid Benzoyl chloroformate
Phosphonic acids Borax
Phosphoric acids Boron tribromide
Phthalic acids Bromine
Picric acid Bromotrifiuoride
Propionic acid Calcium carbide
Salicylic acid Cantharides
Sulfonic acids Carbon disulfide
Sulfuric acid Carbon tetrachloride
Tartaric acid Chlorobenzene
Toluenesulfonic acid Chlorinated acetophenones (tear gas)
Chlorinated solvents
Chloroform
Chlorocresols
Chlorophenols
Chromates
Chromium oxychloride
Chromium trioxide
Creosote
Cresolic compounds
Croton aldehyde
Dichloroacetyl chloride
Dichromates
Dimethyl acetamide
Dimethyl form amide
Dimethyl sulfoxide (DMSO)
Dioxane
Dipentene
Dithranol
Epichlorohydrine
Epoxy reactive diluents
Ethylene oxide
Ferric chloride hexahydrate
Fluorides
Fluorine
Fluorosilicate
Formaldehyde
Gasoline
Gentian violet
Glutaraldehyde
Halogenated solvents
Hexylresorcinol
Iodine
Isocyanates
Kerosene fuel
Limonene
Lithium
Lithium chloride
Mercury compounds
Methylchloroisothiazolinone
Chemical Skin Burns 327
Table 1. (Contd.)
Acids Alkalis Miscellaneous
Methylenedichloride
Methylisothiazolinone
Morpholine
Perchloroethylene
Peroxides
Benzoyl
Cumene
Cyciohexanone
Hydrogen
Methylethylketone
Potassium
Sodium
Phenolic compounds
Phosphorus
Phosphorus bromides
Phosphorus chlorides
Phosphorus oxychloride
Phosphorus oxides
Piperazine
Potassium
Potassium cyanide
Potassium difluoride
Potassium hypo chlorite
Potassium permanganate
Povidone iodine
Propionic oxide
Propylene oxide
Quaternary ammonium compounds
Reactive diluents
Sodium
Sodium borohydride
Sodium difluoride
Sodium hypochlorite
Sodium sulfite
Sodium thiosulfate
Styrene
Sulfur dichloride
Sulfur dioxide
Sulfur mustard
Thioglycollates
Thionyl chloride
Tributyltin oxide
Trichloroethylene
Turpentine
Vinyl pyridine
White spirit
Zinc chloride
Diagnosis Clinical Features
It is usually easy to arrive at a diagnosis of chemical Not only the skin but also the eyes, lips, mouth,
skin burn, as the symptoms are easily recognized and esophagus, nose septum, glottis, and lungs can be
the exposure to a corrosive agent obvious. However, directly affected. As a result of resorption, toxie
sometimes the exposure is concealed, at least initially. chemicals can damage the blood, bone marrow, liver,
For example, hospital personnel may be exposed to kidneys, nerves, brain, and other organs. The most
ethylene oxide, which may remain in gowns and straps common locations of chemical burns on the skin are
after sterilization (Biro et al. 1974), and cleaners may the hands and face/neck, but the whole body can be
occasionally be exposed to a corrosive agent contam- affected. The exposure usually occurs by accident.
inating non-hazardous objects in a laboratory. Corro- However, occasionally, a chemical burn is the result of
sive substances under occlusion mayaiso, at least malingering. The major symptoms are burning and
initially, confuse and delay the diagnosis. Occasionally, smarting. Morphologically, chemical burns are char-
a chemical burn can mimic other dermatoses, e.g., acterized by erythema, blisters, erosions, ulcers, and
ethylene oxide can mimic bullous impetigo. necrosis with surrounding erythema. Usually, the
328 M. Bruze et al.
symptoms develop immediately or in elose connection resulting in insensibility. Sometimes, peripheral nerves
to exposure, but certain chemicals, such as phenols, can be affected without visible damage to the skin.
weak hydrofluoric acid, and sulfur mustard gas, can After exposure to phenolic compounds, the local blood
give delayed reactions which first appear several hours, vessels become constricted, which can contribute to
or even a day, after the exposure. the development of the necrosis. Shock and renal
Strong acids coagulate skin proteins, and further damage can appear after absorption of phenolic
penetration is decreased by the barrier formed. Some compounds (Lin and Yang 1992; Horch et al. 1994;
common toxic chemicals affect the skin in a special Shibata et al. 1994).
way (Kuniyuki and Oonish 1997). Principally, all Sulfur mustard, 2,2' -dichlorodiethyl sulfide, is a
strong acids give the same symptoms and major chemical warfare agent (Newman-Taylor and Morris
features, including erythema, blisters, and necrosis. 1991; Smith and Dunn 1991; Ruhl et al. 1994). It has
Some acids dis color the skin, e.g., producing a yellow been dumped into the sea, and fishermen have been
color from nitric acid. The action of hydrofluoric acid injured when leaking containers get in their nets. The
in the skin differs from other strong acids (Vance 1990; chemical is a viscous liquid below and agas above
Kirkpatrick et al. 1995). It causes liquefaction necrosis, 14 oe. On the skin, the liquid causes blisters and
and the penetration may continue for days. When an necrosis 10-12 h after skin exposure. The gas attacks
area above 1% of the total body surface is affected, mainly the eyes and the respiratory organs. Sometimes
systemic effects can arise. In the skin, this acid causes the skin is also affected by direct contact with the gas,
much stronger pains than other acids. Diluted hydro- and the chemical burn then clinically appears 3-6 h
fluoric acid can cause pain starting several hours or after exposure; initial redness is foilowed by blisters
even a day after the exposure. For example, when and ulcers. Tear gas can give a bullous dermatitis
bricklayers use this acid at a concentration of 10-30% (Zekri et al. 1995).
for rinsing brick walls, it may penetrate into their nail Ethylene oxide gas used for sterilization of surgical
beds and, there, cause severe pain after several hours. instruments, textile, and plastic material can remain in
The strong pain is due to the capacity of fluorine ions these objects for several days if not ventilated weil
to bind calcium in the tissue, which affects the nervous enough (Biro et al. 1974; Fisher 1990). Thus, when
system. Hydrofluoric acid can penetrate to the bone hospital personnel handle such objects, there is a
and cause decalcification there. Also, fluorides and possible exposure to ethylene oxide, which is not
fluorosilicic acid can give the same types of symptoms. obvious, and the symptoms, including erythema,
Alkalis often cause more severe damage than acids, edema and large bullae, may therefore be misdiag-
except hydrofluoric acid (Gelmetti and Cecca 1992; nosed as another skin disease. Accidental skin expo-
Winemaker et al. 1992; Beausang and Herbert 1994). sure to chemicals under high press ure, for example
The necrotic skin first appears dark brown, then hydraulic oil, can result in deep penetration into the
changes to black. Later, skin becomes hard, dry, and skin, where a chemical burn with necrosis can develop.
cracked. Generally, no blisters appear in the skin.
Alkalis split proteins and lipids, and there is a
saponification of the released fatty acids. The emulsi- Treatment
fying effect of the soap formed facilitates further
penetration of the alkali into deeper layer of the skin. Rinsing with water is the first-aid treatment; prefera-
Chemical burns from alkaline chemicals are more bly, tepid running tap water should be used. Irrigation
painful than from acids, except from hydrofluoric acid. should not be done at high press ure, as the corrosive
Because of its alkalinity, cement mixed with water can agent may be splashed onto other parts of the body or
cause acute ulcerative damage (Stoermer and Wolz on the persons treating the burn. It is important that
1983; McGeown 1984; Lane and Hogan 1985; Fisher the treatment starts immediately after exposure and
1986; Unuba and Essiet 1986; Tosti et al. 1989; Adams that copious volumes of water be supplied, sometimes
1990; Morley et al. 1996). Severe skin damage has for hours. Occasionally, chemical burns are caused by
involved the lower limbs, often after kneeling on wet corrosive substances insoluble in water; therefore, a
concrete or when it gets inside boots or shoes. solution of water and soap should frequently be used
Sometimes, necrotic skin appears 8-12 h after expo- instead. However, sometimes specific antidotes for
sure. Rarely, hands can also be affected, particularly certain types of chemical burns are required. Clothes,
when the insides of gloves have been contaminated. watches, rings, shoes, etc., can be contaminated with
The alkalinity can also vary considerably between the corrosive agent, so they should be removed.
batches from the same cement factory. Theoretically, neutralizing solutions should be an
Phenolic compounds such as phenol, cresol, alternative treatment to water after exposure to acids
chlorocresol, and unhardened phenolic res ins pene- and alkalis (Dunn et al. 1992; Yano et al. 1994; Erdm-
trate the skin easily and can damage peripheral nerves, ann et al. 1996). However, neutralization of the corro-
Chemical Skin Burns 329
sive agent with weak acids/bases is not recommended copious volumes of water is necessary. Thereafter,
for two reasons: (1) irrigation should not be delayed and within 2 h after the exposure, all burnt tissue must
while waiting for a specific antidote - immediate be excised. To remove circulating chromium, perito-
irrigation provides the best removal of the agent, and neal dialysis has to be carried out during the first 24 h.
(2) neutralization of the corrosive agent may produce Solid particles of lime, cement, and phosphorus, for
an exothermic reaction, and the heat can cause further example, tend to fix to the skin and should be
damage (Sawhney and Kaushish 1989). mechanically removed before or during irrigation.
Heat is generated when strong sulfuric and phos- Phosphorus, above all white phosphorus, is oxidized
phoric acids are exposed to water; hence, a thermal by air and can ignite spontaneously, thus causing
burn can add to the chemical burn. To prevent this, it thermal burns (Kaufamn et al. 1988; Eldad and Simon
is important that copious volumes of running water be 1991; Eldad et al. 1992; Eldad et al. 1995). In water,
applied. However, water is contraindicated in extin- oxidized phosphorus is transformed into phosphoric
guishing burning metal fragments of sodium, potassi- acid, which can cause a chemical burn; therefore, it is
um, and lithium, because a chemical burn can be important to remove particles mechanically before
caused by hydroxides formed when water is added to washing with soap and water. The skin is then washed
hot metals. These metals spontaneously ignite when with 1% copper(II) sulfate in water, which reacts with
exposed to water. To extinguish the burning metal, phosphorus to form black copper phosphite, which
sand can be used. The burn should then be covered makes any remaining phosphorous visible and thus
with cooking or mineral oil to isolate the metal from easily removable. Wet dressings of copper sulfate
water. Metal pieces should be mechanically removed. should never be applied to wounds because of the risk
Embedded pieces should be removed surgically. First, of systemic copper poisoning. To minimize the copper
though, the area should be irrigated with water to absorption, a water solution of S% sodium bicarbonate
prevent an alkali burn from the hydroxides already and 3% copper sulfate suspended in 1% hydroxyethyl
formed from the metal and water naturally present in cellulose can be used for irrigation instead of the 1%
the skin. copper sulfate solution. However, it should be stressed
Skin exposed to hydrofluoric acid should be that copper is a potentially toxic substance, which can
carefully irrigated with copious volumes of running cause systemic effects. Cop per sulfate must therefore
tap water, then treated with calcium gluconate gel be used only for a few minutes in order to visualize
(2.S%) by massaging into the burned skin for at least phosphorous and, after mechanical removal of the
30 min. ("K-Y Jelly", Johnson and Johnson Products, phosphide, it is important to irrigate the skin with
Inc., New Brunswick, NJ, USA.) (Anderson and water.
Anderson 1988; Chick and Borah 1990; Seyb et al. Skin contaminated with bromine or iodine should
1995; Dunn et al. 1996). The calcium gluconate gel can be washed frequently with soap and water and treated
also be made by mixing 3.S g calcium gluconate with with S% sodium thiosulfate, which reacts with bromine
ISO g of a water-soluble lubricant. A variation of this and iodine, forming ions less hazardous to the skin
treatment is suggested - ten lO-g tablets of calcium (White and Joseet 1990; Corazza et al. 1997).
carbonate (648 mg) are crushed to a fine powder. The Skin contaminated with phenolic compounds can
powder is mixed with 20 ml of a water-soluble initially be washed with soap and water, and as early as
lubricant to create a slurry. This calcium preparation possible treated with undiluted polyethylene glycol 300
is applied repeatedly to the skin until the pain has or 400, or with 10% ethanol, which all dissolve
disappeared. Necrotic tissue should be excised, blis- phenolic compounds (Lin and Yang 1992; Horch et al.
ters debrided, and the underlying tissue treated with 1994; Shibata et al. 1994). Tissues with deep damage
the calcium preparation. Nails should be removed if from phenolic compounds should be excised immedi-
the acid penetrates to the nail bed and matrix and ately, as the compounds easily penetrate further with
causes severe pain there. If there is no effect of the subsequent damage of, for example, nerves.
topical treatment within 2 h, 10% calcium gluconate Skin contaminated with sulfur mustard liquid
(o.S mllcm') should be injected into and under the should be treated with a mixture of 7S% calcium
lesions. No anesthetics should be given, since the hypochlorite and 2S% magnesium sulfate for so me
disappearance of pain is a sign of successful treat- minutes before washing with soap and water. Contam-
ment. Without treatment, the burn can increase in inated objects should also be treated with this mixture
depth for several weeks. (Newman-Taylor and Morris 1991; Smith and Dunn
Superficial chemical burns from chromic acid with 1991; Ruhl et al. 1994).
an area greater than 1% of the total body surface imply Hot tar, pitch, and asphalt cause burns mainly due
a high risk of systemic damage to many organs, to the heat. They stick to the skin and should not be
induding erythrocytes (Terrill and Gowar 1990). removed mechanically, as the skin can be further
Therefore, immediate irrigation of the burn with damaged and thus increase the risk of secondary
330 M. Bruze et al.
infection. The material will fall off spontaneously in Many contact sensitizers also have irritant proper-
due time. ties. Patch testing with such sensitizers at high
Generally, an antibacterial cream should be given to concentrations can cause an irritant re action or a
chemical skin burns to protect the surface and to chemical burn, which seems to facilitate active sensi-
prevent secondary infection. If there is a significant tization. However, only a few sensitizers can cause
element of inflammation in non-necrotic areas, a mild chemical burns without occlusion, e.g., formaldehyde,
topical corticosteroid preparation can be used. Fre- chromic acid, amines, chloroacetophenone, some
quent examinations of primarily superficial and lim- plastic monomers, and methylisothiazolinones. Even
ited burns are also advisable, as they can become one single contact with these chemicals can both cause
deeper in a few days. a chemical burn and induce sensitization, with a
Surgical treatments, such as excision, debridation of subsequent possible development of an allergic contact
blisters, transplantation, and removal of nails can be of dermatitis (Bruze et al. 1990; Kanerva 1994). Therefore,
great value. When a limb is affected circumferentially, when a potential sensitizer has caused a chemical burn,
there is a risk of blood-vessel compression. The best the patient should be patch tested with the sensitizer
method for treating the black, adherent necrotic tissue after healing of the burn, independent of any sub se-
caused by cement and other toxic compounds is quent development of an eczema.
excision. For example, the healing time of cement Another type of eczematous dermatitis that can
burns on knees can be diminished from 8-10 weeks to follow after a chemical burn is "post-traumatic ecze-
3 weeks if the necrotic tissue is excised. ma" (Mathias 1988). It can present as discoid eczema
Several chemicals can also produce systemic effects and is a poody understood complication of skin
without severe skin injury, e.g., phenolic compounds, injuries (Wilkinson 1979). It can appear after either
hydrofluoric acid, chromic acid, sulfur mustard, and physical or chemical skin injuries, including chemical
gasoline (Andersen 1990; Chan et al. 1995). When the burns, and is always unrelated to infection and topical
chemical burn is not minimal, there is a risk of treatment.
systemic damage, and an analysis including hemato-
logical screening and liver and kidney function
should be made both at the first examination and Prevention
then later in the course of treatment, depending on
the intensity and extension of the chemical burn as Employees should be informed of the risks of exposure
well as on the results of laboratory investigations. to corrosive agents and be well trained to handle the
These analyses are performed mainly to enable chemicals as well as to act when they have been
precautions and measures necessary to prevent and exposed. Showers for rapid irrigation with water
diminish damage on internaIorgans, but also partly should be easily accessible. A 1% copper sulfate solu-
for legal reasons. tion, polyethylene glycol 300 or 400, 5% sodium
Patients with severe and extensive skin damage and/ thiosulfate solution, and a proper calcium preparation
or with systemic symptoms after exposure to corrosive should be present in the first-aid kit. A calcium
agents should be treated in intensive care units. It preparation for topical treatment should also be
should be noted that hydrofluoric acid or chromic acid present ne ar any employees' work site where hydro-
exposure affecting only 1% of the total body surface of fluoric acid or fluorides are used. Workers at risk
a person means risk of severe systemic effects. should wear proper protective equipment, which may
Hospitalization is also recommended for persons include eye glasses, face masks, gloves, boots, and
who have concurrent illnesses, implying that they are safety dresses.
high-risk patients, as well as for persons with chemical In industries in which corrosive chemicals are
burns on the hands, feet, and perineum (Andersen handled, certain procedures frequently lead to acci-
1990; Chan et al. 1995). dents, resulting in exposure to the chemicals. Such
procedures include the repairing as well as charging
and discharging of procedure vessels, during which
Complications chemicals can be spilt and splashed. Accidents can be
caused by breakage of hoses or connections with snap
Chemical skin burns can cause hyper- or hypopig- couplings. A non-accidental but unintended exposure
mentation. Chemical burns involving deeper parts of may occur due to material sterilized with ethylene
the skin heal with scarring. Tumors of both malignant oxide; thus, the material should be well ventilated and
and benign types may rarely develop in scars. In the not used until a week after the sterilization procedure.
acute stage of chemical burns from, for example, For these reasons, it is important to prevent chemical
phenolic compounds and hydrofluoric acid/fluorides, burns via careful planning and supervision of the
the sensory nerve system is frequently affected. working environment.
Chemical Skin Bums 331
Table 2. Treatment for chemie al skin bums caused by some Andersen KE (1990) Systemic toxicity from percutaneous
specific chemie als absorption of industrial chemieals. In: Adams RM (ed)
Occupational skin disease, 2nd edn. Saunders, Philadelphia,
Chemical Treatment pp 73-88
Anderson WJ, Anderson JR (1988) Hydrotluoric acid bums ofthe
Hydrotluoric acid Calcium gluconate gel (2.5%) hand: mechanism of injury and treatment. J Hand Surg [Am]
Phosphorous Cop per (II) sulfate in water (1 %) 13:52-57
Bromine, iodine Sodium thiosulfate in water (5%) Beausang E, Herbert K (1994) Bums from a dust explosion. Bums
Phenolic compounds Polyethylene glycol 300 or 400; 20:551-552
ethanol in water (10%) Biro L, Fisher AA, Price E (1974) Ethylene oxide bums. Arch
Sulfur mustard liquid Mixture of 75% calcium hypochlorite Dermatol 110:924-925
and 25% magnesium sulfate Bruze M, Dahlquist I, Gruvberger B (1990) Chemieal bums and
allergie contact dermatitis due to Kathon WT. Am J Contact
Dermat 1:91-93
Cartotto RC, Peters WJ, Neligan PC, et al. (1996) Chemical bums.
Summary Can J Surg 39:205-211
Chan TC, Williams SR, Clark RF (1995) Formie acid skin bums
resulting in systemie toxicity. Ann Emerg Med 26:383-386
Thousands of chemicals and products can cause Chick LR, Borah G (1990) Calcium carbonate gel therapy for
chemical skin bums, some only under special circum- hydrofluorie acid bums of the hand. Plast Reconstr Surg
86:935-940
stances, for example occlusion. Most chemical bums Corazza M, Bulciolu G, Spisani L, et al. (1997) Chemie al bums
are due to accidents and the majority are occupation- following irritant contact with povidone-iodine. Contact
ally induced, but chemical bums also frequently occur Dermatitis 36:115-116
Dunn BJ, MacKinnon MA, Knowlden NF, et al. (1992) Hydroflu-
in households and while engaged in hobbies. Clinically, oric acid dermal bums. An assessment of treatment efficacy
a chemical bum is characterized by erythema, blisters, using an experimental pig model. J Occup Environ Med 34:
and necrotic skin. Some corrosive chemicals, such as 902-909
Dunn BI, MacKinnon MA, Knowlden NF, et al. (1996) Topieal
phenolic compounds, sulfur mustard, chromic acid, treatment for hydrotluorie acid dermal bums. Further
hydrofiuoric acid, and gasoline, may cause systemic assessment of efficacy using an experimental pig model
effects that require hospitalization. Other chemical J Occup Environ Med 38:507-514
Eldad A, Chaouat M, Weinberg A, et al. (1992) Phosphorous
bums, particularly those affecting hands, feet, and pentachloride chemical bum - a slowly healing injury. Bums
perineum, mayaiso require hospitalization. To prevent 18:340-341
and diminish the damage after exposure to corrosive Eldad A, Simon GA (1991) The phosphorous bum - a preliminary
comparative experimental study of various forms of treat-
agents, it is important to administer immediate treatment. Bums 17:198-200
ment. Irrigation with copious volumes of water is a Eldad A, Wisoki M, Cohen H, et al. (1995) Phosphorous bums:
universal remedy, except for treatment of buming evaluation of various modalities for primary treatment.
J Bum Care Rehabil 16:49-55
metal fragments of sodium, potassium, and lithium. Erdmann D, Hussmann I, Kucan JO (1996) Treatment of a severe
First-aid treatment after exposure to water-insoluble alkali bum. Bums 22:41-146
corrosive agents consists of washing with soap and Fisher AA (1986) Chromate dermatitis and cement bums. In:
Fisher AA (ed) Contact dermatitis, 3rd edn. Lea and Febiger,
water. Sometimes specific antidotes are needed, as for Philadelphia, pp 762-772
chemical bums from hydrofiuoric acid, phenolic Fisher AA (1990) Ethylene oxide (EO) bums. In: Adams RM (ed)
compounds, phosphorous, iodine, bromine, and sulfur Occupational skin disease, 2nd edn. Saunders, Philadelphia,
pp 17-18
mustard (Table 2). Surgical intervention may be Gelmetti C, Cecca E (1992) Caustie ulcers caused by calcium
required for certain chemical bums. A few corrosive hydroxide in 2 adolescent football players. Contact Dermatitis
compounds are potential sensitizers, and one single 27:265-266
Horch R, Spilker G, Stark GB (1994) Phenol bums and intoxi-
exposure to such a compound may both cause a cations. Bums 20:45-50
chemical bum and induce sensitization with subse- Kanerva L, Tarvainen K, Pinola A, et al. (1994) A single accidental
quent allergic contact dermatitis. To prevent chemical exposure may result in a chemieal bum, primary sensitiza-
tion and allergie contact dermatitis. Contact Dermatitis
bums, it is important to use as few corrosive agents as 31:229-235
possible and, when unavoidable, to use the weakest Kaufman T, Ullmann Y, Har-Shai Y (1988) Phosphorus bums: a
ones possible, particularly in households and while practical approach to local treatment. J Bum Care Rehabil
engaged in hobbies. In the working environment, well- 9:474-475
Kirkpatriek JJ, Enion DS, Burd DA (1995) Hydrotluoric acid
informed workers, access to first-aid treatment, careful bums: a review. Bums 21:483-493
planning, and supervision are required to prevent Kuniyuki S, Oonishi H (1997) Chemical bum from acetic acid
with deep ulceration. Contact Dermatitis 36:169-170
chemical bums. Lane PR, Hogan DJ (1985) Chronic pain and scarring from
cement bums. Arch Dermatol 121:368-369
Lin CH, Yang JY (1992) Chemical bum with cresol intoxieation
and multiple organ failure. Bums 18:162-166
References Mathias CGT (1988) Post-traumatic eczema. Dermatol Clin 6:
35-42
Adams RM (1990) Cement bums. In: Adams RM (ed) Occupa- McGeown G (1984) Cement bums of the hands. Contact
tional skin disease, 2nd edn. Saunders, Philadelphia, pp 15-16 Dermatitis 10:246
332 M. Bruze et al.: Chemical Skin Burns
Morley SE, Humzah D, McGregor JC, et al. (1996) Cement-related Sykes RA, Mani MM, Hiebert JM (1986) Chemical bums:
bums. Bums 22:646-647 retrospective review. J Bum Care Rehabil 7:343-347
Newrnan-Taylor AI, Morris AJR (1991) Experience with mustard Terrill PI, Gowar JP (1990) Chromic acid bums; beware, be
gas casualties. Lancet 337:242 aggressive, be watchful. Br J Plast Surg 43:699-701
Onuba 0, Essiet A (1986) Cement bums of the heels. Contact Tosti A, Peluso AM, Varotti C (1989) Skin bums due to transit-
Dermatitis 14:325-326 mixed Portland cement. Contact Dermatitis 21:58
Ruhl CM, Park SI, Danisa 0, et al. (1994) A serious skin sulfur Vance MV (1990) Hydrofluoric acid (HF) bums. In: Adams RM
mustard bum from an artillery shell. J Emerg Med 12:159-166 (ed) Occupational skin disease, 2nd edn. Saunders, Philadel-
Sawhney CP, Kaushish R (1989) Acid and alkali bums: consid- phia, pp 18-21
erations in management. Bums 15:132-134 White A, Joseet M (1990) Bums from iodine. Anaesthesia 45:75
Seyb ST, Noordhoek L, Botens S, et al. (1995) A study to Wilkinson DS (1979) Discoid eczema as a consequence of contact
determine the efficacy of treatments for hydrofluoric acid with irritants. Contact Dermatitis 5:118-199
bums. J Bum Care Rehabil 16:253-257 Winemaker M, Douglas L, Peters W (1992) Combination alkali/
Shibata K, Yoshita Y, Matsumoto H (1994) Extensive chemical thermal bums caused by "black liquor" in the pulp and paper
bums from toluene. Am J Emerg Med 12:353-355 industry. Bums 18:68-70
Smith WJ, Dunn MA (1991) Medical defense against blistering Yano K, Hata Y, Matsuka K, et al. (1994) Effects ofwashing with a
chemical warfare agents. Arch Dermatol127:1207-1213 neutralizing agent on alkaline skin injuries in an experimen-
Stewart CE (1985) Chemical skin bums. Am Farn Physician tal model. Bums 20:36-39
31:149-157 Zekri AMB, King WWK, Yeung R, et al. (1995) Acute mass bums
Stoermer D, Wolz G (1983) Cement bums. Contact Dermatitis caused by o-chlorobenzylidene malononitrile (CS) tear gas.
9:421-422 Bums 21:586-589
CHAPTER 39
Chronic Venous Insufficiency and Occupation

E.M. de Boer and R.M.A. Krijnen
Introduction tion, lipodermatosclerosis, white atrophy, eczema,

phlebitis, thrombosis or ulcers may develop.
Chronic venous disorders are one of the most common Small intracutaneous or reticular veins are present
ailments affecting mankind in the world today (Callam in over half of the world's Westernized population
1994). In the Netherlands, government authorities do (Krijnen et al. 1998). Even without treatment, only a
not record the instance of venous disorders, with the minority of these individuals develop clinically rele-
exception of patients admitted to hospitals for venous vant varicosis. Clinically relevant varicose veins which
surgery or for complications such as venous ulcer- give rise to complaints and complications are present
ation. In other countries the situation is similar, in approximately 10% of the Western population
meaning that exact numerical data are not available. (Madar et al. 1986). Approximately 1% of the popula-
In contrast to other chronic conditions, patients and tion suffers from leg ulceration at some point in their
physicians alike often trivialize the presence and lives (Callam 1992). There is evidence of venous disease
severity of venous dis orders (Krijnen et al. 1997a). in 60% to over 90% of leg ulcers (Callam 1992).
This can be attributed to the fact that varicose veins are Epidemiological reviews have cited a number of risk
common and that progression takes place slowly. factors for CVI; age is a major risk factor. Varicose
Many workers with venous disorders, even with veins may develop before puberty (Schultz Ehrenburg
progressed forms, never consult a doctor. Literature et al. 1989). By the age of 20 years, the prevalence is
shows evidence that venous dis orders lead to incapac- estimated to be approximately 10% (Schweiger and
ity to work in approximately 2% of the occupational Rudofsky 1981). From the age of 40 years, the in ci-
population (Fischer et al. 1980; Callam 1994; Krijnen dence of varicose veins is the same for every age group
et al. 1997a). Persons with a standing position at work (Brand et al. 1988). This means that the prevalence of
are especially at risk. this chronic disease increases linearly with age. By the
In arecent study, we found that 7% of male workers age of 80 years, the prevalence of varicose veins is
with a standing profession had been temporarily unfit estimated to be about 65%.
for work due to phlebological dis orders (Krijnen et al. Another important risk factor is inactivity of the calf
1997a). muscle pump, which may be due to prolonged
standing or sitting. In several studies, the prevalence
of varicose veins was higher for workers with a
Chronic Venous Insufficiency: standing profession than for those with physically
Symptoms and Risk Factors active professions (Lorenzi et al. 1985; Maffei et al.
1986). A direct relationship between the severity of CVI
In the pathogenesis of venous disorders, the elevated and the numbers of years of standing was also
venous pressure due to hampered venous return is demonstrated (Krijnen et al. 1997a).
crucial. The term chronic venous insufficiency (CVI) Gender is another risk factor which is often men-
refers to an array of symptoms resulting from venous tioned. However, though clinically less important side-
hypertension. Subjective complaints of varicose veins branch varicosis occurs more often in females, severe
and CVI often include a feeling of heaviness and pain, cases of trunk varicosis and CVI have about the same
asensation of swelling of the legs, nighttime calf prevalence in males and females (Da Silva et al. 1974).
cramps, and restless legs. Complaints increase during During pregnancy, hormonal changes cause relaxation
the course of the day, especially after prolonged of smooth muscle and increased venous distensibility.
standing. Edema, ankle flare, and corona paraplantaris Parity is often discussed, but after correcting for age,
phlebectatica and varices in all sizes are the first an association with CVI in later life has never been
objective signs of CVI. Subsequently, hyperpigmenta- demonstrated conclusively (Krijnen et al. 1998). He-

334 E.M. de Boer and R.M.A. Krijnen
redity is a risk factor that is often cited, but family venous pressure and venous refill time with compres-
history is not very reliable. Controlled family studies sion stockings, but this could not be verified by others
are rare. Racial or geographical differences are difficult (Horner et al. 1980; Noyes et al. 1987; Ohlert and
to evaluate. People born and raised in Africa have a Wienert 1988; Partsch 1988; Mayberry et al. 1991; Sarin
lower incidence of CVI than white people in western et al. 1992). Furthermore, it was argued that compres-
countries (Abramson et al. 1981). Obesity is generally sion therapy causes restoration of venous wall elastic-
accepted as a risk factor for CVI (Fischer et al. 1980; ity, but this mainly benefits patients with early venous
Brand et al. 1988); there may be a threshold effect incompetence (Szendro et al. 1992). Nowadays, there is
(Krijnen et al. 1997a). a tendency to attribute the beneficial effects of com-
In most studies of the epidemiology of CVI, only pression mainly to microcirculatory changes in the
dinical data, which are not well described, are used. skin (Kuiper and Brakkee 1988; Gaylarde et al. 1993;
Unfortunately, consensus has not been reached on Abu-Own et al. 1995). As a result of a sustained high
defining or diagnosing CVI. Several proposals have press ure in the venous capillary end, the filtration
been made and sometimes accepted, such as Widmer's pressure is raised, causing edema of the surrounding
(Widmer et al. 1967) and the American Venous Forum tissues (Fagrell 1982). External compression restores
(Beebe et al. 1995) dassifications. this disturbed pressure gradient by increasing the
In daily patient-related practice, a physical exami- pressure in the surrounding tissues (Kuiper and
nation of the patient standing erect is performed in Brakkee 1988). Furthermore, it was demonstrated that
most dinics, supplemented with continuous-wave compression enhances the microcirculatory fiow ve-
Doppler examination to determine the fiow in the locity and restores the transcutaneous oxygen press ure
superficial veins and the junction with the deep-venous in areas affected by CVI (Gaylarde et al. 1993; Abu-
system. Additionally, Duplex scanning has become Own et al. 1995). As an alternative to compression, oral
important. This newer non-invasive technique based treatment with rutosides (triterpene glycoside mixture,
on echo-Doppler provides a visualization of the vessels i.e., Aescin) is mentioned. According to some authors,
on a monitor in combination with blood-fiow mea- the positive effect on edema is equal to that achieved
surements. Duplex scanning is replacing ascending by elastic stockings (Pohlmann 1995).
phlebography more and more, becoming the standard
diagnostic tool. Other tests such as venous-pressure
measurements, light refiection rheography (LRR), Risk Inventarisation
plethysmography and volumetry sometimes have
additional value. A standing profession, and to a lesser extent a sitting
There are several treatments available for venous profession, is associated with an increased risk of the
disorders. The main objective is to normalize venous development of venous disorders (Guberan et al. 1973;
physiology. Superficial venous insufficiency of the Brand et al. 1988; Stvrtinova et al. 1991; Krijnen et al.
stern veins (the vena saphena magna or parva) is 1997a). Although questioned by some, the relative risk
usually treated by stripping of the vein or crossectomy of contracting CVI as a result of having a standing
and, subsequently, sderotherapy. Side-branch varico- occupation is estimated to be up to twice as high as in
sis is usually treated by sderotherapy combined with workers who walk or have varied jobs. The number of
compression over several weeks. Ambulatory phlebec- years of having a standing profession is also positively
tomy using mini-incisions is another possibility for the associated with the severity of CVI.
larger side branches. Insufficient perforating veins are Risk inventarisation may focus on general and
either treated by surgery or sderotherapy or are left individual aspects. The occupational physician has
untreated. In case of deep venous insufficiency, the access to the workplace of a given worker. By
only available treatment is external compression ther- observing the physical activity of the workers, he is
apy. This therapy can be realized by either bandages provided with information on the use of the calf
or, of course preferably, medical compression stock- musde pump. Workers with static standing or sitting
ings. The wearing of medical compression stockings duties don't use their musde pump, making them
has a significant reducing effect on the development prone to increased venous pressure.
of post-thrombotic syndrome (Brandjes et al. 1997; Furthermore, individuals should be examined in
Hanley et al. 1997). terms of their own personal risk factors, focusing on
The literature shows evidence that compression CVI and restrictions of the locomotor system. There is
stockings infiuence the development of edema and no general agreement as to how to identify individuals
slow down the progression of CVI. The mechanism by with CVI or those prone to CVI.
which compression acts on venous hemodynamics has In arecent study of males with a standing profes-
never been condusively demonstrated (Mayberry et al. sion, several screening methods were compared and
1991). Some authors found improvement in ambulatory evaluated (Krijnen et al. 1997b). The sensitivity and
Chronic Venous Insufficiency and Occupation 335
specificity of a short and an extended questionnaire, is most pronounced in mats with high resilience, such
physical examination, LRR and optical leg-volume as rubber mats. To the best of our knowledge, the
measurements were computed. Continuous-wave action that rubber mats have on venous function has
Doppler examination was selected as the means of only been described once. In a laboratory study of four
diagnosis. Risk factors for CVI were analyzed. healthy subjects, the venous pressure was decreased by
It appeared that a short questionnaire in combina- approximately 10 mmHg, measured at the ankle with
tion with physical examination (inspection and palpa- an intravenous catheter in a standing position (Brant-
tion of the legs) had a predictive value of 8iYo ingham et al. 1970). As the venous pressure in the
(sensitivity 85%, specificity 88%). The short question- standing position can be reduced 80 mmHg by walk-
naire consisted of only four items: age, weight, his tory ing, this effect is minimal.
of treatment for phlebological disorders and ti red In arecent study of 13 male workers with CVI having
feeling in the legs. With a more extended questionnaire a standing position at work, the use of a mat resulted
in combination with a physical examination, the in some decrease in leg complaints, although only a
predictive value for having CVI increased to 89%. In statistical trend. During the same time, diurnal volume
this way, an alert physician can adequately screen for changes were recorded using optoelectronic volume
CVI and select individuals for preventive measures and measurements. The mean diurnal volume increase was
referral to a specialist, using simple means and without not significantly influenced by standing on a rubber
any special equipment. mat (Krijnen et al. 1997c).
In the same study, in terms of the risk factors for the Individual protection is also possible. Workers who
presence of CVI, age and weight were determined to be require medical treatment should be selected and
the most important, with age as the dominant factor. referred to a dermatologist or a (vascular) surgeon for
These findings are in accordance with those of other further investigation and treatment. In milder cases,
studies (Abramson et al. 1981; Madar et al. 1986; Brand and as aftercare for severe cases, medical compression
et al. 1988). Worth mentioning is that subjective stockings are the method of first choice. Because
complaints also occur regularly among individuals during early pregnancy venous distensibility increases,
who do not have proven CVI (Table 1), making these stockings may help females with a standing/sitting
unsuitable for screening purposes. profession to decrease the development of varicosis.
Medical compression stockings can be obtained in
several press ure dasses, seamless or flat knitted, below
Preventive Measures the knee or thigh high, ready to wear or custom made.
Generally, in cases of prevention and mild CVI, dass 11
The first means of prevention is eliminating the reason (25-35 mmHg at the ankle) , below-the-knee, custom-
for calf-musde pump inactivity by avoiding prolonged made stockings are preferable. It is essential that
standing and sitting while working. If this is not compression stockings fit perfectly for reasons of
possible, a second option is to adapt the workplace adequate compression, comfort to the wearer and
itself, for instance by installing specially designed therapy compliance.
resilient floor mats. In case of previous deep-venous thrombosis, in
It is not known exactly what effect floor surfaces, more severe cases of CVI and after the occurrence of
e.g., mats, have on the legs. Nonetheless, these semi- ulceration, dass III (35-45 mmHg at the ankle) below-
bouncy, uneven mats cause slight changes in the the-knee, custom-made, flat-knitted stockings will
position of the angle of the foot, resulting in lower- usually be the most effective.
leg-musde contractions. Theoretically, the venous
calf-musde pump is stimulated in this way. The effect
Evaluation of Intervention
Table 1. Recommended questionnaire in screening for chronic Individuals with mild cases of CVI particularly need to
venous insufficiency be motivated, as they do not always realize the need for
treatment or prevention. People do have to get
1. Are you malelfemale? accustomed to wearing compression stockings, so it
2. Are you pregnant?
3. What is your age? is advisable to check that they are indeed being worn.
4. Males: do you weigh more than 90 kg? Sometimes stockings do not fit properly and are
Females: are you more than 10 kg overweight? therefore not tolerated. Sometimes irritation occurs,
5. Have you ever been treated for varicose veins, phlebitis
or thrombosis? causing folliculitis, especially in individuals with hairy
6. Do you have an occupation that requires you to stand or legs working in a warm environment. In rare cases, a
sit for extended periods of time? contact allergy to one or more of the rubber compo-
7. Do you (sometimes) have a tired or heavy feeling in the legs?
nents of elastic stockings occurs. Alternatives contain-
336 E.M. de Boer and R.M.A. Krijnen
ing lycra instead of rubber are available. Carefully practical reasons. On the questionnaire, we expected a
evaluating the reason for not wearing elastic stockings question on the presence of pain in the legs to be
helps to differentiate between stocking-related prob- relevant. However, using logistic regression analysis
lems and any work-related restrictions of these mea- with the presence of CVI as an dependent variable, the
sures. presence of pain did not add to the predictive value of
Evaluation of the effect of preventive measures is the questionnaire. This needs to be further investi-
difficult as CVI is a disease that progresses slowly. gated. While the physical examination requires so me
Effects on the prevalence of ulcera ti on, dermatitis, special training, equipment is not necessary. After
(recurrent) thrombosis and sick leave only become identifying an individual with (mild) CVI, tertiary
evident years after the initial intervention. Therefore, prevention or treatment can be started in order to slow
evaluation of the effect of intervention on CVI should the progression of CVI due to both natural progression
consider, for instance, subjective complaints and the and further standing. Tertiary preventive measures
presence of leg edema, as these symptoms react include elastic compression stockings and floor mats.
immediately to therapy. Elastic stockings are weIl tolerated in almost all
In arecent study, the effects of stockings on leg workplaces (Krijnen et al. 1997C). The application of
complaints and edema was evaluated (Krijnen et al. floor mats, however, entails numerous restrictions.
1997C). In the group wearing stockings, a significant Standing supports used for positive effect on lumbar
decrease in having a tired feeling and pain was noted spinal structures result in a significantly greater lower-
relative to the control group. It is striking that some of leg swelling than standing (Oude Vrielink et al. 1994).
the workers, who had no complaints at the first visit, Therefore, especially in cases of CVI, the use of these
experienced a decrease in complaints upon wearing devices is not recommended.
stockings. At first they had not realized that they had The cost of elastic stockings is moderate. For ready-
leg complaints. After wearing stockings, the workers made below-the-knee stockings, the price is about US
with CVI showed a significant decrease in leg edema, $ 60 per pair. For custom-made stockings the price is
as verified by optoelectronic volume measurements, doubled. A pair of stockings lasts about 6 months,
relative to pre-treatment values. No long-term inves- depending on how they are used. In the Netherlands,
tigation on the effect of stockings on sick-Ieave or on medical insurance companies almost fully refund two
the subjective and objective weIl-being of workers has pairs of stockings per year. Clearly this applies to
been completed as of yet. The longest foIlow-up study treatment as opposed to prevention, as prevention is
is 3 months and shows that weIl-fitting stockings are not covered. Thus, large-scale supplies of stockings
usually appreciated and useful (Krijnen et al. 1997C). should be paid for by the company concerned, the
same way protective gloves, clothing and shoes are
paid for. In our opinion, in terms of cost-effectiveness,
Practical Implications these measures are justified. Our study shows that 7%
of all workers have had some period of siek leave due
While work-related risk inventarisation is easy, risk to CVI (Krijnen et al. 1997a). Furthermore, it is easy to
imagine that a worker suffering from a feeling of
elimination is often impossible. Using simple means,
heaviness and pain in the legs has lower productivity.
individuals suffering from CVI can be detected rather
We therefore recommend that physicians be alert to
adequately (almost 90%). A short questionnaire (Ta-
ble 1) and a physical examination (Table 2) are suffi- potential CVI in workers. The time invested to take
cient. For males, a threshold weight of about 90 kg was simple measures to select high-risk individuals and the
low cost required to keep workers free from CVI-
found to be a risk factor (Krijnen et al. 1997a). In
related ailments is time and money weIl spent.
fern ales, this threshold is not demonstrated clearly, but
adipositas is a risk factor in many studies. In the
proposed questionnaire, we defined "overweight" as
References
being 10 kg or more over the ideal body weight, for
Abramson JH, Hopp C, Estein LM (1981) The epidemiology of
varicose veins. A survey in western Jerusalem. J Epidemiol
Table 2. Recommended symptoms of chronic venous insuffi- Community Health 35:213-217
ciency (CVI), which should be checked for at the physical Abu-Own A, Scurr JH, Coleridge Smith PD (1995) Effect of
examination when screening for CVI compression stockings on the microcirculation in chronic
venous insufficiency. Phlebology 10:5-11
Ankle flare, corona paraplantaris Beebe HG, Bergan JJ, Bergquist D, et al. (1995) Classification and
Edema, lipodermatosclerosis grading of chronic venous disease in the lower limbs: a
Hyperpigmentation consensus statement. Phlebology 10:42-45
Varices of all sizes Brand FN, Dannenberg AL, Abbot RD, et al. (1988) The epide-
Dermatitis, ulceration miology of varicose veins: the Framingham study. Am J Prev
Med 4:96-101
Chronic Venous Insufficiency and Occupation 337
Brandjes DPM, Büller HR, Heyboer H, Huisman MV, de Rijk M, Lorenzi G, Constantini A, Domanin M (1985) General and
Jagt H, ten Cate JW (1997) Randomised trial of effect of occupational risk factors in the etiology of varicose veins.
compression stockings in patients with symptomatic proxi- Phlt~bologie 38:174-175
mal-vein thrombosis. Lancet 349:759-762 Madar G, Widmer LK, Zemp E, et al. (1986) Varicose veins and
Brantingham CR, Beekman BE, Moss CN, Gordon RB (1970) chronic venous insufficiency. Disorder or disease? A critical
Enhanced venous pump activity as a result of standing on a epidemiological review. Vasa 15=126-134
varied terrain floor surface. J Occup Med 12:164-169 Maffei FHA, Magaldi C, Pinho SZ, Lastoria S, Pinho W, Yoshida
Callam MJ (1992) Prevalence of chronic leg ulceration and severe WB, Rollo HA (1986) Varicose veins and chronic venous
chronic venous disease in western countries. Phlebology insufficiency in Brasil: prevalence among 1755 inhabitants of a
SUppI1:6-12 country town. Int J Epidemiol 15:210-217
Callam MJ (1994) Epidemiology of varicose veins. Br J Surg Mayberry JC, Moneta GL, De Frang RH, Porter JM (1991) The
81:167-173 influence of elastic compression stockings on deep venous
Da Silva A, Widmer LK, Martin H, et al. (1974) Varicose veins hemodynamics. J Vasc Surg 13:91-100
and chronic venous insufficiency. Vasa 2:118-125 Noyes LD, Rice JC, Kernstein MD (1987) Hemodynamic assess-
Fagrell B (1982) Microcirculatory disturbances - the final cause ment of high-compression hosiery in chronic venous disease.
for leg ulcers? Vasa 11:101-103 Surgery 102:813-815
Fischer H, Widmer LK, Biland K (1980) Sozioepidemiologische Ohlert P, Wienert V (1988) Der Einfluss des kompression-
Studie über die Venenleiden bei einer erwachsenen sstrumpfes auf die venöse Kapazität und den venösen
Wohnbevölkerung in der Bundesrepublik Deutschland. Ausstrom des Unterschenkels. Swiss Med 10:33-37
Phlebologie Proktologie 9:147-152 Oude Vrielink HHE, Cloosterman SGM, van der Bunt JA, Krijnen
Gaylarde PM, Sarkany I, Dodd HJ (1993) The effect of compres- RMA, van Drieen JH (1994) Is a sit-stand seat an appropriate
sion on venous stasis. Br J Dermatol 128:225-228 alternative in standing work situations? In: Arghazadeh F (ed)
Guberan E, Widmer LK, Glaus L, Muller R, Rougeman A, Da Advances in industrial ergonomics and safety VI. Taylor and
Silva, et a1. (1973) Causative factors of varicose veins: my- Francis Ltd, London, pp 223-228
ethsanafacts. An epidemiological study of 610 women. Vasa Partsch H (1988) Verbesserung der venösen Beinpumpe durch
2:115-120 Kompressionsstrümpfe. Swiss Med 1O:4a
Hanley TP, Kiev J, Rice JC, Kerstein MD (1997) Long-term Pohlmann BK (1995) Integratives therapie prinzip bei chronisher
prevention of sequelae of chronic venous disease with Veneninsuffizienz. Systemische Arzneimittel therapie gehört
graduated-compression stockings. J Vasc Surg 31:451-455 dazu. BDA konsensuspapier. Therapiewoche 22:1309-1310
Horner J, Fernandez JFE, Nicolaides AN (1980) Value of Sarin S, Scurr JH, Coleridge Smith PD (1992) Mechanism of
graduated compression in deep venous insufficiency. BMJ action of external compression on venous function. Br J Surg
75:820-821 79:499-502
Krijnen RMA, De Boer EM, Ader HJ, Bruynzeel DP (1997a) Schultz Ehrenburg U, Weindorf N, von Uslar D, et al. (1989)
Venous insufficiency in male workers with a standing Prospective Epidemiologische Studie über die Entsteh-
profession. Part I. Epidemiology. Dermatology 194:111-120 ungsweise der Krampfadern bei Kindern und Jugendlichen
Krijnen RMA, De Boer EM, Ader HJ, Bruynzeel DP (1997b) (Bochumer Studie I und 11). Phlebol ProktoI18:3-11
Venous insufficiency in male workers with a standing Schweiger H, Rudofsky G (1981) Die Primäre Varikosis bei jungen
profession. Part II. Diurnal volume changes of the lower Männern. Ergebnisse einer Reihenuntersuchung bei We-
legs. Dermatology 194:121-126 hrpflichtigen. Vasa 10:41-45
Krijnen RMA, De Boer EM, Ader HJ, Osinga DSC, Bruynzeel DP Stvrtinova V, Kolesr J, Wimmer G (1991) Prevalence of varicose
(1997C) Compression stockings and rubber floor mats: do veins of the lower Iimbs in the women working at a
they benefit workers with CVI and a standing profession? department store. Int Angiol 2:5
J Occup Environ Med 39:889-894 Szendro G, Veller M, Fischer C, Christopoulos D, Belcaro G,
Krijnen RMA, De Boer EM, Bruynzeel DP (1997) Epidemiology of Clarke H, et al. (1992) The effect of elastic compression on the
venous disorders in the general and occupational population. venous tone in patients with varicose veins. Vasa 21:198-202
Epidemiol Rev 19:294-309 Widmer LK, PIechi SCh, Leu HJ, et al. (1967) Venenerkrankungen
Kuiper LP, Brakkee AJM (1988) Über die hemodynamische bei 1800 Berufstätigen. Basle Studie II. Schweiz Med
auswirkungen von kompressions-strümpfen. Phlebologie Wochenschr 97:107-110
Proktologie 17:202-207
CHAPTER 40
Human Immunodeficiency Virus/Acquired Immunodeficiency

Syndrome in the Workplace
S.-L. Valle and A. Ranki
Introduction world, where 75,000 new cases of HIV infection were

estimated to have occurred during 1998 only.
Along with the increasing prevalence of human In the western countries, prevalence of HIV infec-
immunodeficiency virus (HIV) infection worldwide, tion among patients attending health-care settings
the number of HIV -infected individuals in the work- varies widely, but is generally highest in the inner cities
place is also increasing. As HIV is not transmitted by of big urban centers. In addition to genitourinary and
casual contacts, the only way for occupational expo- infectious disease dinics, accident and emergency
sure is through a contact with contaminated blood or departments [2, 3) as weIl as maternity units [4) have
body fluids. In order to infect, the virus must penetrate witnessed a rising prevalence of HIV infection among
the skin barrier. Thus, exposures with sticks or cuts their dienteIe during the last decade. The Center for
with HIV -contaminated material offer a risk of trans- Disease Control (CDC) study by Janssen et al. [2)
mission. Also, mucous membranes and non-intact skin found a seroprevalence ranging from 0.2% to 14.2% in
provide a potential route of transmission. In addition 20 acute-care hospitals in the United States. Poznansky
to health-care personnel, the at-risk occupations reports a HIV prevalence of 2.4% from one accident
comprise, for example, policemen and deaning per- and emergency department in London [3). In the
sonnel. The HIV -related problems in health-care future, an increasing number of HIV -infected dients is
settings are complex, ranging from prevention of to be anticipated in health-care settings induding
occupational exposures to minimizing discrimination dermatologists' offices.
of HIV -infected health-care workers.
Frequency and Type of Exposures
Occupational Risk of HIV Infection Percutaneous Injuries

for the Health-Care Worker
Accidental exposures to potentially infective blood and
The risk of HIV transmission from patient to health- body fluids are common in health care despite risk
care worker (HCW) depends on (1) the prevalence of reduction policies [5, 6). The greatest risk of blood-
HIV infection in the patient population, (2) the borne infections is posed by percutaneous injuries
number of exposures during the time practiced, (3) the either by sticking with a needle or cutting with a sharp
type of exposure and the volume of contaminated object. This may happen during the medical procedure
blood and (4) the transmissibility of HIV per acciden- performed to the patient or by handling used instru-
tal exposure. ments afterwards.
In the Uni ted States, approximately 4.4 million HCWs
Prevalence of HIV Infection receive an estimated number of 800,000 needle-sticks
and other injuries from sharp objects annually [7). Of
The Joint United Nations Programme on AIDS these objects, about 16,000 are contaminated with HIV.
(UNAIDS) and the World Health Organization Such percutaneous injuries occur in as many as 1 in 40
(WHO) recently estimated that a total of 33.4 million emergency room physicians or nurses annually at
people were living with HIV/acquired immunodefi- hospitals serving areas with high HIV seroprevalence
ciency syndrome (AIDS) at the end of 1998 b). Of [8). The medical activities with the highest risk ofblood
them, the overwhelming majority lives unaware of the contacts or percutaneous injury are surgical and
infection in the developing world, where HIV is obstetric procedures, dental care, phlebotomy or plac-
spreading rapidly. However, more than 1.5 million ing infusion catheters. For example, at least one blood
HIV -infected people are currently living in the western contact in 30% of surgical operations and at least one

Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in the Workplace 339
percutaneous injury during 6.9% of operations have being capable of carrying viable HIV [20]. No cases of
been reported in surgical personnel [9,10]. aerosol-mediated infections have been reported, how-
Seventy-five percent of percutaneous injuries are ever, and the risk is likely to be minuscule.
from suture ne edles [u], needle-sticks being most
common during gynecologic surgery. Although the risk Risk of Occupational Transmission of HIV
of transmission is much less for suture needles than for
hollow-bore ones, development of new technology is Percutaneous Exposure
essential [10]. Whereas the perforation rate of gloves in
orthopaedic and general surgery may be as high as 50% Based on prospective studies, the average risk of HIV
[l2], the risk of exposure even in minor surgery during infection after a single percutaneous exposure is 0.32%
local anesthesia is considerable [13]. (95% confidence interval 0.18-0.45%) [14, 21]. The risk
As ofDecember 1997, 95 definite and 191 possible HIV is considerably lower than the risk associated with an
infections were reported globally to have been occupa- exposure to hepatitis B virus (HBV). Approximately 5-
tionally acquired [14]. Nurses and clinical laboratory 30% of HBV needle-stick accidents produce infection
workers together accounted for 71% of the definite and in non-immune parenterally exposed HCWs, depend-
43% of the possible cases. Surgeons and dental workers ing on the stage of infection [22]. However, according
accounted for l2% of the possible cases but less than 1% to an international case-control study reported by the
ofthe definite ones. Nearly all (91%) definite transmis- CDC, the risk of HIV transmission exceeds 0.3% for
sions resulted from exposure to blood [14]. exposures involving (1) a deep injury to the HCW, (2)
visible blood on the device causing the injury, (3) a
Exposure of Mucous Membranes or Non-intad Skin device previously placed in the vein or artery of the
source patient or (4) a source-patient who died of AIDS
Compared with injuries resulting from sharp objects, within 60 days post-exposure and therefore was pre-
exposures of the mucous membranes and non-intact sumed to have had a high titer of HIV [23].
skin carry far less risk of HIV transmission, but may
outnumber the percutaneous injuries. Chapped or Mucous-Membrane Exposure
eczematous skin offers a portal of entry to HIV and
other blood-borne pathogens. HIV has also been The estimated HIV transmission rate after mucocuta-
detected in blister fluid of the skin, which should be neous exposure is 0.03% (0.006-0.19%, 95% confi-
added to the list of infectious body fluids [15]. It dence interval) [14]. The CDC states that the previously
follows that oozing eczematous lesions and bullous suggested average risks after a mucous-membrane
eruptions in HIV -infected individuals should be exposure and a skin exposure may be even higher, if
promptly treated, and exclusion from work is recom- the contact is prolonged, extensive or involves a high
mended until the skin has healed. HIV titer [23-25].
Exposure of Intad Skin Environmental Exposure
Soiling of clothes and subsequent exposure of intact Unlike HBV, which may remain viable in a dried state
skin is common [16], especially so during obstetric for up to 1 week, HIV viral amounts are reduced by
procedures, which was demonstrated in the United 99% within a few ho urs if left to dry. There are no
Kingdom by Kabukoba et al. [17]. They found that reported cases of HIV infections due to transmission of
contamination of clothes with body fluids was 42%, the virus from an environmental surface. HIV is not
and that 23% of the staff had broken skin on hands and able to replicate outside the human body.
arms. However, none of the 2712 HCWs enrolled in a
National Institute of Health (NIH) study, who reported
skin contact with HIV -infected blood, have serocon- Exposure Prevention
verted thus far [18]. Similarly, in an Italian study of 466
mucocutaneous occupational exposures, no serocon- Background
versions were reported following contamination of
intact skin [19]. Recognition of the newly discovered AIDS as a
potential health hazard for HCWs in the United States
Other Types of Exposures prompted first precautions for clinical and laboratory
staffs in November 1982 [26]. Based on these detailed,
Cool aerosols have been suspected of being able to still pertinent precautions, which were designed before
transmit HIV via respiratory or mucosal surfaces in the causative agent was identified, national guidelines
operating rooms and were, in fact, demonstrated as were issued worldwide.
340 S.-L. Valle and A. Ranki
Reassuringly, early prospective studies of HCWs Management of Occupational HIV Exposure

exposed to infectious material in the workplace
showed that the risk of contracting HIV infection The CDC recommendations for PEP following occu-
occupationally was very low. However, the first report pational exposures to HIV [25] were prompted by a
of nosocomial infection from patient to provider was reduction of HIV transmission by 79% after 3-4 weeks
published in 1984 [27]. It described an acute febrile of post-exposure zidovudine treatment [23]. An up-
illness in a HCW who had experienced a percutaneous dated and revised version of the report was published
needle-stick injury with blood derived from an AIDS in May 1998 [34]. Data on PEP in preventing HIV
patient. In 1986, HIV seroconversion was reported infection is, however, stilllimited and there are reports
following a superficial needle-stick injury of a finger on HIV seroconversion despite adequately adminis-
[28]. tered PEP [14].
In 1987, the CDC reported on three non-needle-stick Occupational exposures to HIV should be considered
exposures on chapped, eczematous skin and oral urgent medical concerns to ensure prompt administra-
mucous membranes resulting in HIV infection, and tion ofPEP. After an accidental exposure to blood that is
strongly re-emphasized the need to adhere to the thought to be HIV-contaminated, the HCW should be
prevailing infection-control policies [29]. At the time, tested for HIV antibodies at baseline, 6 weeks, 12 weeks
alarming prevalence of unsuspected HIV infection was and 6 months following the exposure, and at any other
detected in critically ill emergency patients in United occasion if symptoms or signs associated with acute
States' hospitals, further stressing the risk of occupa- seroconversion illness occur. Ninety-five percent of
tional HIV transmission [30, 31]. infections will be detectable at 6 months post-exposurej
As it became evident that identifying HIV -seropos- later seroconversion is rare [14].
itive clients in health-care settings was not always The HCW should also receive hepatitis B vaccine
possible in spite of adequately performed diagnostic and be evaluated for hepatitis C. The HIV status of the
examinations and medical history interviews, the source patient should be determined according to the
concept of universal precautions was introduced by recommendations and legislation of each country.
the CDC as the corners tone of prevention against HIV Expert counseling of both the exposed HCW and the
and other blood-borne pathogens [32]. This CDC source patient is needed. The type and occasion of
report of August 1987, in summarizing all previous exposure as weIl as eventual PEP should be reported
recommendations, aims at the prevention of all immediately to the local occupational health physi-
parenteral, mucous membrane, and non-intact skin cians or other medical authorities as indicated in each
exposures by infected blood or bodily fluids in both country.
HCWs and the patient. Universal precautions are
based on the assumption that all blood is potentially Post-exposure Prophylaxis
infectious, regardless of whether it is from a patient or
a HCW, and, regardless of whether an HIV test is According to the current CDC guidelines (Fig. 1) [34],
positive, negative or not done at all (Table 1). The need HAART should be started within 1-2 h of exposure.
for strict guidelines was further stressed after the first However, there is no outside time limit for initiating
recognition of HIV transmission from provider to the therapy. For the currently recommended doses of
patient during an invasive dental procedure [33]. anti-retrovirals, see Table 2 and Fig. 1.
Recently, preventive measures were efficiently sup- All persons receiving PEP should be informed about
plemented by the use of highly active anti-retroviral the potential toxicity associated with these drugs.
treatment (HAART) as post-exposure prophylaxis
(PEP) [25, 34]. Although PEP may prevent accidental
HIV infection in some individuals, avoiding blood The HIV-Infected HCW
exposures remains the mainstay of prevention. Data on
PEP is stilllimited, and recommendations on PEP will The first report on the risks to patients from exposure
be updated upon accumulating experience. to blood of an HIV -seropositive surgeon appeared in
1985 [35]. After the death of the surgeon in 1983, a total
Table 1. Components of universal precautions of 400 patients were identified who had undergone
endoscopies or surgical procedures with a risk of
1. Hand washing exposure. No attempt to trace the patients was made at
2. Careful handling of sharp objects the time. Strict adherence to infection control policies
3. Sterilization, disinfection and disposal of instruments
as appropriate was advocated by the CDC in order to avoid no-
4. Appropriate use of personal protective equipment, e.g., socomial HIV transmission.
gloves, masks, gowns or aprons and protective eyewear, as After the recognition of actual HIV transmission
indicated by the nature of the specific procedure
from a dentist to five patients [33], the CDC estimated
I Determine exposure category (EC):
Wbat type of exposure bas occurred?

Mueous membrane or
skin integrity I Intaet skin only
I I
Pereutaneous
exposure
eompromised
J 1
L I No PEP needed
I I Severity
I
1
Volume
I
1 ! More Severe
Small Large Less Severe
(e.g.,few drops, (e.g.,solid needle, (e.g.,large-bore hollow
(e.g., several drops, major needle, deep puncturc,
short duration) blood splash andlor duration superfieial scratch)
visible blood on device, or
of several minutes or more) needle used in source -
j I
patient's artery or vein)
ECI EC2 EC4
11. Determine tbe HIV status code (JIIV SC):
Wbat is tbe HIV status of the exposure sonrce?
1
HIV-negative
1 1
Status
1
Source
j
unknown unknown
~
o PEP needed
Lower titer Higher titer exposure

exposure (e,g. , advanced AIDS , primary HIV infection,
(e .g ., asymptomat ic high or increasing viral load or low CD4
and high CD4 count) count)
!
HIV SC 1 HIV SC 2 HIV SC Unknown
III Determine tbe PEP Recommendation

EC HIVSC PEP recommendation
1 I PEP may not be warranted. Whether the risk for drug toxieity outweighs the benefit of
PEP should be decided by the exposed HCW and treatmg elinieian.
I 2 Consider basic regimen. Whether the risk for drug toxieity outweighs the benefit of PEP
should be deeided by the exposed HCV and treating clinician
2 1 Recommend basic regimen. Most HIV exposures are in this eategory; no inereased risk
for HIV transmission has been observed but use ofPEP is appropriate
2 2 Recommend expanded regimen.
3 1 or 2 Recommend expanded regimen.
Unknown If the SOUIce or, in the case of an unknown source, the setting where the exposure oeeurred
suggest a possible risk for HIV exposure and the EC is 2 or 3, consider PEP basic regimen.
Fig. 1. Determining the need for HIV postexposure prophylaxis (PEP) after an occupational exposure. Modified from [34]
342 S.-L. Valle and A. Ranki
Table 2. Currently recommended doses of antiretrovirals 6. Henderson DK, FalIey BJ, Willy M, et al. (1990) Risk for
occupational transmission of human immunodeficiency virus
Basic regimen 4 Weeks of zidovudine (ZDV, AZT) type 1 (HIV-1) associated with clinical exposures. A prospec-
600 mg/day and lamivudine (3TC) tive evaluation. Ann Intern Med 113:740-746
300 mg/day 7. Department of Labor (1991) Occupational safety and health
Expanded regimen The basic regimen plus either indinavir administration. Occupational exposure to bloodborne patho-
(2400 mg/day) or nelfinavir gens; final rule, 29 CFR Part 1910. 1030. Fed Reg 56:64004-
(2250 mg/day) 64182
8. Marcus R, Culver D, Bell D, et al. (1993) Risks of human
immunodeficiency virus infection among emergency depart-
ment workers. Am J Med 94:363-370
9. Panlilio A, Foy DR, Edwards JR, et al. (1991) Blood contacts
in 1991 that the prob ability of sporadic transmission during surgical procedures. JAMA 26P533-1537
from an infected surgeon to a patient during an 10. Tokars J, Bell D, Culver DH, et al. (1991) Percutaneous injuries
invasive procedure lies between 1 in 42,000 and 1 in during surgical procedures (abstract). Proceedings of VII
International Conference on AIDS. Florence, June 1991, p C603
420,000 [36]. The low risk notwithstanding, revised 11. Bell DM (1997) Prevention of occupational H1V transmission
guidelines were issued to prevent both nosocomial (abstract). Proceedings of 4th Conference of Retroviruses and
transmissions during invasive procedures [37, 38] and Opportunistic Infections, Washington D.e., 22-26 January,
p S17
public anxiety. 12. Lafferty K, Wyatt AP (1987) After safe sex, safe surgery? BMJ
Subsequently, only one more incident of HIV 295:392
transmission from a HIV-infected HCW to the patient 13. Richmond PW, McCabe M, Davies JP, et al. (1992) Perfora-
tion of gloves in an accident and emergency department. BMJ
was recently recognized [39] despite several thousand 304:879-880
patient exposures to HIV-seropositive HCWs [14]. 14. PHLS AIDS & STD Centre, United Kingdom (1997) Occupa-
The case of HIV-infected HCWs has been widely tional transmission of HIV. Summary of published reports.
Dec edition, London. (website: www.open.gov.uk!CDSC/
debated. The challenge of protecting patients and at CDSCHOME.HTM)
the same time minimizing discrimination and in- 15. Correia 0, Delgado L, Santos C, et al. (1994) H1V-l in btister
fringements of privacy of the HCW puts the onus on fluid of a patient with toxic epidermal necrolysis and AIDS.
Lancet 344:1432-1433
health-care professionals. Guidelines are under con- 16. Littlechild P, Macmillan A, White MM, et al. (1992) Contam-
stant development because of changes in the attitude in ination of skin and clothing of accident and emergency
the society. personnel. BMJ 30P25-127
17. Kabukoba J, Young P (1992) Midwifery and body fluid
contamination. BMJ 305:226
18. Ippolito G, DeCarli G, Puro V, et al. (1996) Risk of occupa-
Nosocomial Outbreaks of HIV Infection tional HIV and HCV infection after occupational exposure
(abstract). Proceedings ofXIth International Conference, 7-12
July, Vancouver B.e., TU.e.123
Several outbreaks of nosocomial HIV transmission 19. Ippolito G, Puro V, DeCarli G, et al. (1993) The risk of
have been recorded [14]. The means of transmission occupational human immunodeficiency virus infection in
include injections from multi-dose vials and multi-use health care workers. Arch Intern Med 155:1451-1458
20. Johnson G, Robinson WS (1991) Human immunodeficiency
needles and syringes, inadequate sterilization tech- viruS-1 (HIV-1) in the vapors of surgical power instruments.
niques of medical equipment during plasma donations J Med Virol 33:47-50
and dialysis centers. Strict adherence to infection- 21. Bell DM (1997) Occupational risk of human immunodefi-
ciency virus infection in healthcare workers: an overview. Am
control policies is needed in order to avoid HIV J Med 102[Suppl 5B]:9-15
transmission in health-care settings. 22. Werner BG, Grady GF (1982) Accidental hepatitis-B-surface-
antigen-positive inoculations: use of e antigen to estimate
infectivity. Ann Intern Med 97:367-369
23. CDC (1995) Case-control study of HIV seroconversion in
References health-care workers after percutaneous exposure to HIV-
infected blood. Morbidity Mortality Weekly Rep 44:929-933
1. UNAIDS/WHO (1998) AIDS epidemie update: December 1998 24. Gerberding JL (1995) Management of occupational exposures
2. Janssen RS, St Louis ME, Satten GA, et al. (1992) HIV to blood-borne viruses. N Engl J Med 332:444-451
infection among patients in US acute care hospitals. Strate- 25. CDC (1996) Update: provisional public health service recom-
gies for the counseling and testing ofhospital patients. N Engl mendations for chemoprophylaxis after occupational expo-
J Med 327:445-452 sure to H1V. MMWR 45:468-472
3. Poznansky MC, Torkington J, Turner G, et al. (1994) Prev- 26. CDC (1982) Acquired immune deficiency syndrome (AIDS):
alence of HIV infection in patients attending an inner city precautions for clinical and laboratory staffs. MMWR 31:
accident and emergency department. BMJ 308:636 578-580
4. Nieoll A, McGarrigle C, Brady AR, et al. (1998) Epidemiology 27. Anonymous (1984) Needlestick transmission of HTLV-III
and detection ofHIV-l among pregnant women in the United from a patient infected in Africa. Lancet ii:1376-1377
Kingdom: results from national surveillance 1988-1996. BMJ 28. Oksenhendler E, et al. (1986) HIV infection with seroconver-
316:253-258 sion after a superficial needlestick injury to the finger. N Eng!
5. Gerberding JL, Littell C, Tarkington A, et al. (1990) Risk of J Med 315:582
exposure of surgical personnel to patients' blood during 29. CDC (1987) Update: human immunodeficiency virus infec-
surgery at San Francisco General Hospital. N Engl J Med tions in health-care workers exposed to blood of infected
322:1788-1793 patients. MMWR 36:285-289
30. Baker JL, Kelen GD, Sivertson KT, et al. (1987) Unsuspected 35. Sachs JJ (1985) AIDS in a surgeon. N Engl J Med 313:1017-1018
human immunodeficiency virus in critically ill emergency 36. Bernard L, Steinbrook R (1992) Health care workers infected
patients. JAMA 257:2609-2611 with the human immunodeficiency virus. JAMA 267:
31. Kelen GD, Fritz S, Oagish B, et al. (1988) Unrecognized 1100-1105
human deficiency virus infection in emergency department 37. CDC (1991) Recommendations for preventing transmission of
patients. N Engl J Med 318:1645-1650 human immunodeficiency virus and Hepatitis B virus to
32. CDC (1987) Recommendations for prevention of HIV trans- patients during exposure-prone invasive procedurtes. Mor-
mission in health-care settings. MMWR 36[SUppl 2S]:3S-18S bidity Mortality Weekly Rep 40:1-9
33. CDC (1990) Possible transmission of HIV to a patient during 38. UK Departments of Health (1993) AIDS-HIV infected health
an invasive dental procedure. MMWR 39:489-493 care workers: guidance on the management of infected health
34. CDC (1998) Public health service guidelines for the manage- care workers. Scottish Office Horne and Health Department,
ment of health-care worker exposures to HIV and recom- Edinburgh
mendations for postexposure prophylaxis. Morbidity 39. Dorozynki A (1997) French patient contracts AIDS from
Mortality Weekly Rep 47:RR-7 surgeon. BMJ 314:250
CHAPTER 41
Operational Definition
of Occupational Allergie Contact Dermatitis
S.1. Ale and H.1. Maibach
Introduction immediate contact reactions, such as contact urticaria,

leading to or coexistent with dermatitis [u-18], or
Despite its capacity to withstand the environmental composite reactions such as protein contact dermatitis
offenses, the skin represents the most commonly [19-24], should also be considered as OCD. Disagree-
injured organ in industry nowadays. In many coun- ment in reaching a precise and undeniable definition of
tries, skin disorders comprise 20-70% of all occupa- occupational dermatosis leads to differences in what
tional diseases, while contact dermatitis ac counts for an OCD standard case should be considered to be and,
the vast majority of occupational skin dis orders [1-6]. consequently, to an inadequate estimation of disease
In a multicenter European study of consecutive clinic prevalence.
patients with dermatitis, 30% of the men and 12% of
the women had occupational dermatitis [1].
Contact dermatitis is the greatest cause of disability Diagnosis
in occupational settings [7]. Occupational contact
dermatitis (OCD) usually affects the hands and, thus, The correct diagnosis and characterization of the
may not only impair a worker's dexterity to perform causative agent(s) of dermatitis are indispensable
his or her work, but also determines disturbances in prerequisites for establishing appropriate therapeutic
common quotidian activities [7-9]. Persistent der- and preventive measures. Yet, misdiagnosis or inter-
matitis will develop in as many as 25% of affected vention at a late stage may result in a chronic disabling
workers, despite job modification or appropriate condition. Criteria for assessing the eventual occupa-
medical treatment [4]. Given this poor prognosis, tional cause of a contact dermatitis have been
adequate preventive measures have to be established. proposed (Table 1) [5, 10, 25, 26]. Establishing the
These measures, including enclosing potential aller- diagnosis of OCD involves two fundamental steps: (1)
gens, chemical substitution and personal protection, recognizing the existence of an occupational exposure;
are based on effective recognition of occupational and (2) assessing whether that exposure represents a
sensitizers and irritants as weH as early identification cause or substantial aggravating factor in the patient's
of those workers at higher risk. dermatitis. To accomplish this task, the physician
relies on a comprehensive his tory, complete physical
examination and skin testing. A visit to the workplace
Definition mayaiso provide essential information in the investi-
gation of suspected occupational dermatitis.
In 1939, the Committee on Industrial Dermatoses of the
American Medical Association elaborated a medical Exposure Assessment in OCO
definition of occupational dermatosis as follows: "An
occupational dermatosis is a pathological condition of Identifying all probable hazardous agents in the
the skin for which occupational exposure can be shown worker's environment is an indispensable step in the
to be a major causal or contributory factor" [10]. diagnostic workout. The offensive agent may be either
However, the legal definition of occupational dermato- chemical, physical or biological, depending on the
sis can differ from the medical definition and also nature of the dermatitis. Chemical agents may produce
varies according to regulatory legislation in different allergic or irritant contact dermatitis, photosensitivity
countries. Sometimes, definitions may not include and also immediate contact reactions [27-30]. Physical
recently recognized occupational dermatosis. OCD has factors, such as heat, cold, high- and low humidity,
traditionally been considered as being either irritant or occlusion, vibration, radiation and mechanical trauma
allergic (delayed hypersensitivity) in nature. However, not only may produce direct skin damage [31-33], but

Operational Definition of Occupational Allergie Contact Dermatitis 345
Table 1. Diagnostic criteria for occupational contact dermatitis. Numerous modifications to this method have been
Adapted from [5] proposed and adopted to improve its relevance to
Onset of the eruption after the patient began work
human experience [48-50]. In humans, the 21-day
Precise cause identified cumulative irritancy assay has been developed to rank
Patient primarily exposed to the etiologic agent at work the cumulative irritant potential of a chemie al or a
Site of onset exposed to the causative agent at work
Distribution of lesions conforms with occupational exposure
product compared with a standard reference com-
Appropriate time between exposure to the causative agent and pound [51]. Complete revision of predietive assays
the development of lesions methodology can be found elsewhere [52]. Extrapola-
Biological plausibility
Non-occupational dermatitis excluded tion of results from predictive toxicological assays to
Severity of dermatitis varies with exposure human experience is always a difficult task and
Other workers similarly affected requires critical interpretation. Besides data procure-
Process change before the onset of the dermatitis
True positive patch-test reaction(s) in cases of allergie ment from predietive assays, the physicochemical
contact dermatitis properties of the substance, i.e., pH, solvent properties,
oxidizing capacity, hygroscopicity, volatility, morpho-
logie characteristics (such as sharp angulations or
mayaiso influence the harmful effect of chemieals [34, spikes), substantivity, binding capacity and wash-and-
35]. Photoallergie and phototoxic dermatitis are the rub resistance to removal, should always be considered
result of the combined effect of exposure to a chemical when assessing its hazardous potential.
and a physical agent. Biological agents are increasingly
recognized as a cause of OCD and may induce Routes of Exposure
immediate reactions [36, 37], and allergie or irritant
contact dermatitis [38, 39]. Skin contact with hazard- Albeit individuals can be exposed to toxic chemie als in
ous agents is a sine qua non condition, but whether or many ways, industrial exposures usually occur via the
not this contact will result in the development of OCD dermal and/or the respiratory routes. Theoretically,
depends on a combination of exposure characteristics gastrointestinal absorption of chemieals may result
and individual susceptibility. When assessing expo- from contaminated hands or handling of foods [53].
sure, many quantitative and qualitative parameters Direct skin contact with the hazardous substance
have to be considered (Table 1). undoubtedly represents the most important and com-
mon route of exposure for occupational skin disorders.
Assessment of the Hazardous Potential Cutaneous site and total area of exposure are signifi-
of the Substance or Produd cant factors in skin penetration of substances [54, 55]
and, consequently, in determining the degree of loeal -
Considering the hazardous potential of the substance, and also systemic - toxicity of chemical agents.
abasie concept in toxicology, states that any substance
may be harmful in sufficiently large doses; however, Intensity of Exposure and Additional Exposure Fadors
some chemie als are more capable of inducing allergie
or toxic reactions than others. Before new substances The intensity of exposure, i.e., dose, duration, fre-
are introduced into the market and the workplace, quency and total area of exposure, is crucial not only
reliable data concerning their hazardous potential for irritant but also for allergie eontact dermatitis.
should be procured. Predictive tests used to determine Delayed hypersensitivity is a dose-related phenome-
the potential of substances to induce delayed hyper- non. There is a threshold surface eoncentration of the
sensitivity include: (1) mathematical models, used to allergen required to induce sensitization and/or elic-
predict the sensitizing behavior of substances ac cord- itation of the response [56, 57]. Besides the intrinsic
ing to their chemical strueture (quantitative structure- hazardous potential of the substanees and intensity of
aetivity relationship) [40-42]; (2) in vitro-in vivo exposure, we have to consider simultaneous exposure
methods, such as the murine local lymph-node assay factors that might enhance the penetration of the
[43]; (3) in vivo methods in animals - guinea-pig hazardous substance and are unique to the workplace
sensitization tests [44], mouse ear swelling test [45]; or task, i.e., wet work, occlusion, temperature, humid-
and (4) in vivo methods in humans, such as the human ity and mechanical trauma.
repeat-insult patch test (HRIPT), which is often used
after a negative guinea-pig sensitization test to confirm Difficulties in Assessing Exposure
the safety of the substance [46].
Tests for irritancy in vitro and in vivo, in both Sometimes, even when a meticulous clinical his tory is
animals and humans, have also been developed. taken, the source of exposure remains unidentified.
Primary irritation is most often evaluated by modifi- This can be due to multiple causes; the exposure can be
cations of the method described by Draize et al. [47]. indirect (produced through a contaminated item),
infrequent or occasional. Not infrequently, an allergie diphenylcarbazide test for chromium [61], the lutidine
contact dermatitis can be elicited from this type of test for formaldehyde [62] and the filter-paper test for
exposure provided that the patient's hypersensitivity is epoxy resin [63]. Quantitative microanalysis of aller-
strong enough [58]. When assessing exposure, we have gens and physicochemical techniques for the isolation
to also consider substances of personal hygiene, of allergens can be performed in specialized laborato-
measures of skin protection (such as gloves, glasses, ries. Close collaboration between chemists and derma-
barrier creams, etc.) and medicaments used for the tologists is essential for an optimum approach.
patient. All other potential causes of contact dermatitis
from non-occupational exposures should be excluded Relationship Between Exposure and (linical Dermatitis
by a thorough history and by comprehensive patch
testing. To ascertain whether the exposure is relevant to the
patient's dermatitis, the following factors should be
Information on Exposure taken into account: (1) existence of a temporal
relationship between the exposure and the evolution
Identifying the responsible allergen is crucial in of the dermatitis and (2) appropriate morphology
patients with allergie contact dermatitis in which the (correspondence between the exposure and the clinical
outcome may depend on eliminating or reducing pattern of the dermatitis).
further contact with the offen ding allergen. Elimina-
tion of the allergen concerns also the occurrence of Time Relationship Between Dermatitis and Exposure
non-occupational allergens.
Information on exposure is not only essential for Time relationship between the occupational exposure
adopting appropriate preventive measures in individ- and the clinieal course of the dermatitis varies
ual cases and, therefore, improving the prognosis of depending on many different factors related to the
dermatitis patients, but also for implementing appro- exposure, individual susceptibility and type of the
priate techniques of primary prevention and preclud- dermatitis. Irritant dermatitis often appears within
ing new cases of sensitization. There are many sources weeks or months after the contact. The onset in allergie
and data systems available that can provide both contact dermatitis is variable depending on the expo-
workers and physicians with the necessary information sure. Fregert [64] found that 40% of allergie contact
to identify sources of exposure not only in occupa- dermatitis and 53% of irritant contact dermatitis in
tional environments but also in products for house- women start within the first few years of occupation. In
hold or personal use (Table 2). Due to the continuous men, 23% of allergie and 34% of irritant contact
introduction of new industrial chemie als, lists of dermatitis appear within the first year of occupational
substances must be permanently updated. exposure. Usually, OCD improves when the patient is
off work for more than a week and relapses when work
Chemical Analysis of the Produrt is resumed. Allergie contact dermatitis improves more
slowly than irritant contact dermatitis when exposure
Chemical analysis of the suspected involved product( s) is discontinued and recurs faster (in a few days) after
represents a fundamental step in the assessment of returning to work. In contrast, cumulative irritant
relevance in occupational allergie contact dermatitis contact dermatitis usually recurs gradually (days or
(OACD). Preliminary studies performed by the der- weeks) when exposure is resumed. Occupational con-
matologist may direct the laboratory work [59]. There tact urtiearia appears within minutes to hours after
are available simple qualitative chemical spot tests that contact and improves shortly after stopping work
can be performed with little equipment; these tests activities. Nevertheless, interpreting the above-men-
include the dimethylglyoxime test for nickel [60], the tioned facts should always be judicious due to
concurrence of several confounding factors. Some-
times, exposure may continue even when the patient is
Table 2. Parameters of exposure off work; therefore, failure to improve does not
necessarily invalidate a causal relationship. Chronic
Hazardous potential of the substance/product dermatitis may require 3-4 weeks away from work
Other intrinsic (physicochemical) properties of the substance
Concentration of the substance before apparent improvement occurs. In addition, a
Duration of exposure substantial number of patients may not improve
Frequency (periodicity) of exposure regardless of changing work. The majority of studies
Route of exposure
Skin site and total area of exposure assessing the role of job changes for patients with
Specific exposure mechanisms chronic hand dermatitis of occupational origin do not
Simultaneous exposure factors (occlusion, temperature, conclude that a job change improves the prognosis
humidity, mechanical trauma, etc.)
[64-68].
Operational Definition of Oeeupational Allergie Contaet Dermatitis 347
C/inica/ Morph%gy of the Dermatitis the real situation at the working milieu and, then,
many details gain clinical significance. It also allows
The anatomical distribution of the dermatitis should the identification of putative sources of exposure, that
be consistent with the exposure, correlating with the is, irritants or allergens that come into contact with the
occupational gestures and activities. The clinical skin, as well as the actual degree of skin contact.
appearance of contact dermatitis is habitually charac- Moreover, it is possible to reconstruct the occupational
terized by eczematous infiammation. A wheal-and- gestures, to appreciate the working conditions (space,
fiare re action is the prototype of immediate contact temperature, ventilation) and the existence of adequate
urticaria. However, it is impossible to make a distinc- protective measures. Similar skin complaints in em-
tion based exclusively in morphological criteria. ployees other than the patient, may substantiate the
Neither allergie nor irritant OCD has definite clinieal probable occupational cause for the dermatitis. Visit-
or histological features that can lead to the diagnosis, ing the workplace also enables the detection of
and immediate contact reactions are most consistently allergens missed from patch testing and the assessment
characterized by a broad spectrum of clinieal mani- of relevance of previously unexplained positive reac-
festations. tions, as well. Last, but not least, it will help to recognize
Eczematous contact dermatitis is more easily recog- related social or psychological problems [69].
nized in its acute phase from other forms of dermatitis
by the presence of vesicles. Sub-acute and chronic Patch Testing in 0(0
stages are mostly characterized by scaling, hyperke-
ratosis and lichenification; hence differential diagnosis Patch testing constitutes the most important tool for
can be difficult to establish. No pathognomonic clinical the study of allergic contact sensitivity. In the diag-
features can allow unambiguous differentiation nostic study of OCD, extensive testing including the
between irritant and allergic contact dermatitis, screening standard tray, se ries of allergens for specific
although vesiculation and pruritus are more likely to occupations and substances used by the patient in the
be found in the latter. Irritant contact dermatitis is workplace is often required. Patch testing constitutes
generally confined to the area in contact with the the essential procedure for studying delayed hyper-
irritant, whereas allergic contact dermatitis - though sensitivity. However, as contact urticaria represents an
more severe in the area in direct contact - may present increasing problem in occupational dermatology, and
widespread lesions. The physical form of the agent frequently it can be associated with dermatitis, per-
determines the areas of maximal exposure. Contact forming tests for immediate-type sensitivity may be
dermatitis from solid agents predominantly affects necessary [70].
areas in direct contact and can be sharply demarcated Four particular substantial aspects have to be
and confined to that area, thus providing diagnostic considered when performing patch tests in the assess-
clues. Dermatitis from fumes, gases and vapors usually ment of OCD: (1) interpreting results, especially
affect the exposed areas of face and eyelids. Dusts and evaluating false-positive and false-negative reactions;
airborne partieIes also produce dermatitis in exposed (2) deciding when to retest; (3) deciding when to
areas, though they usually become trapped and con- perform special tests; and (4) assessing clinical rele-
centrated in skin folds and beneath the clothing vance of positive responses. The most significant
affecting covered areas. Liquids particularly affect the aspect in evaluating a positive patch test is ascertaining
dorsal aspects of the hands and fingers, the finger webs whether the response represents a true-positive allergic
and the forearms. Sometimes, clinical examination or a false-positive reaction. Irritant reactions are the
reveals a distinct occupational "mark" that points out principal cause of false-positive responses and are
the causative agent. However, most of the time the frequently observed when testing industrial chemicals.
clinieal situation is intricate and the diagnostic The best solution to the problem of irritant reactions is
approach needs to be systematie and critical. Derma- to prevent them; thus, the following aspects should be
titis is often the joint outcome of endogenous, irritant taken into account when testing with putatively irritant
and allergic factors. Previous irritant dermatitis chemieals: (1) consult reliable sources to determine the
produced by an irritative working environment may exact concentrations of non-standard materials; (2) if
predispose to allergic contact dermatitis and also to no information is available concerning concentrations
immediate contact reactions. and vehicles to use in patch testing, perform an open
test; (3) if the substance likely produces irritant
Visiting the Workplace reactions when undiluted, perform serial dilutions;
and (4) when a new compound gives a positive
The accurate diagnosis of OCD often requires a reaction, testing in control subjects is required.
workplace visit. This activity - although time consum- Besides causing false-positive reactions, the uncrit-
ing - enables the physician to obtain a whole picture of ical use of undiluted industrial chemieals in patch
testing increases the risk of active sensitization. Careful responsible allergen represents the primary cause or
interpretation of positive reactions from standard aggravating factor of the patient's dermatitis. An
allergens that are marginally irritant is also necessary. allergen is elinically relevant if: (1) we can establish
Such reactions can be shown to be false positive the existence of an exposure, and (2) the patient's
irritant reactions by applying serial dilutions of the dermatitis is explainable (cause or aggravating factor)
chemical to demonstrate an abrupt loss of the reaction. with regard to that exposure [71]. When the positive
Skin hyper-reactivity ("excited skin syndrome", patch-test reaction can explain the patient's dermatitis,
"angry back") [71, 72] has to be considered when we consider the reaction as being of "present" or
concomitant multiple positive patch-test reactions "current" relevance. However, when the positive patch
occur. It may be the result of strongly positive test explains a past dermatitis, we refer to it as of "past
responses that induce reactions in contiguous sites. relevance". In contrast, if the source of the positive
In addition, many weak or doubtful reactions may patch-test response is not traced, we consider the
appear in patients who had active dermatitis at the response as being of "unknown relevance".
time of testing. These reactions can be demonstrated to A relevance scoring system for positive patch-test
be false-positive reactions on re-testing. Distinction reactions has been proposed [75], establishing the
between true-positive allergic responses and false- scores for current or past relevance as follows: 0 = not
positive reactions induced by excited skin syndrome traced, 1 = doubtful, 2 = possible and 3 = likely. An
(ESS) requires individual, sequential testing of the assessment of "unknown relevance" does not neces-
involved allergens. sarily mean the allergen is not relevant. It may rather
False-negative reactions represent a further compli- refiect inadequate knowledge to explain the result. A
cation of patch testing. They present a special problem reaction of unknown relevance may afterward assume
because the test will not be repeated; thus, the cause of primary significance if new information is forthcoming
the dermatitis may be missed. Many causes of false- and, consequently, should always be recorded. Rele-
negative reactions exist, such as failure to perform vance scores and accuracy of the assessment are
delayed readings, concurrent corticosteroid treatment, significantly improved by a comprehensive knowledge
technical problems, etc. However, in occupational of the patient's chemical environment. This can be - at
dermatology the most significant causes of false- least partially - achieved through a complete elinical
negative reactions are: (1) failure of the patch test to history, a workplace visit searching for the involved
reproduce the conditions of exposure, for example, allergen or cross-reacting substances, chemical exam-
sweating and friction experienced at work may not be ination of the suspected products and further skin
adequately reproduced in patch testing; (2) inadequate testing (Table 3).
penetration of the allergen; the allergens are applied to
normal skin in patch testing, but allergic dermatitis
may result from an allergen contacting the more Operational Definition of OACD
permeable dermatitis skin; and (3) insufficient COll-
centration of allergen in the sampIes acquired from the Nine steps in the assessment of OACD can be
workplace; the concentration of the allergen in the considered as follows [26]:
product may be too low to elicit a positive patch-test
1. History of occupational exposure
re action, but enough to produce a dermatitis through
2. Existence of time relationship between occupational
multiple exposures. When patch testing results are
exposure and onset of dermatitis
negative, but strong suspicion of contact allergy from
an occupational substance persists, performing some
additional tests can be helpful: (a) patch test with the Table 3. Suggested guidelines for the assessment of relevanee.
product's extracts, (b) patch test on a previous Modified from [74]
dermatitic site, or elose to a dermatitis area (in this
case, careful interpretation is needed); and (c) special Re-interrogate the patient in light of the test results
Look for all probable sourees of allergen exposure
tests, i.e., provocative use test (PUT.), repeated open- (induding indireet, infrequent and eoneealed)
application test (ROAT) [73], etc. Seek eross-reaeting substanees
Obtain information from "lists" of allergens, databases,
produet's manufaeturers, ete
Assessment of Clinical Relevance Perform ehemical analysis of produets
Perform a workplaee visit
After interpreting a patch-test reaction as being a true Perform additional testing proeedures with the suspeeted
allergenes), produets brought by the patient presumably
positive allergic response, there is still one more task to eontaining the suspeeted allergen and produet's extraets:
fulfill: assessing its relevance to the elinical dermatitis Perform pateh test with serial dilution
[74]. In assessing the elinical relevance of a positive Perform provoeative use test
Perform repeated open -applieation test
patch-test reaction, we must ascertain whether the
Operational Definition of Oeeupational Allergie Contaet Dermatitis 349
3. Morphology of the dermatitis consistent with occu- 15. Amin S, Maibach HI (1997) Contact urtiearia syndrome: 1997.
pational exposure Environ Dermatol 4:87-94
16. Krook G (1997) Occupational dermatitis from Lactuca sativa
4. Positive diagnostic test with appropriate vehicle and (lettuce) and Cichorium (endive). Simultaneous occurrence of
concentration immediate and delayed allergy as a cause of contact
5. Repeat patch test when excited skin syndrome is dermatitis. Contact Dermatitis 3:27-36
17. Maibach HI (1976) Immediate hypersensitivity in hand
suspected dermatitis. Arch DermatoI112:1289-1291
6. Positive PUT or ROAT to define clinical relevance 18. Kanerva L, Estlander T, Jolanski R (1990) Long-lasting
7. Serial dilutions of the chemie als tested, when contact urtiearia from castor bean. J Am Acad Dermatol
23:351-355
necessary 19. Hjorth N, Roed-Petersen J (1976) Occupational protein
8. Reviewing controls for non-irritating concentrations contact dermatitis in food handlers. Contact Dermatitis
2:28-42
and performing a special test for not commonly
20. Nestle FO, Elsner P (1997) Occupational dermatoses in cheese
utilized allergens makers: frequent association of irritant, allergie and pro tein
9. Clearing of dermatitis when allergen is removed, or contact dermatitis. Dermatology 194:243-246
21. Hansen KS, Petersen HO (1989) Protein contact dermatitis in
exposure is significantly decreased
slaughterhouse workers. Contact Dermatitis 21:221-224
No single criterion provides sufficient evidence for 22. Mahler V, Diepgen TL, Heese A, Peters K-P (998) Protein
contact dermatitis due to cow dander. Contact Dermatitis
probable occupational origin of allergie contact der- 38:47-48
matitis. The above guidelines can provide a simplified 23. Kanerva L (1996) Occupational IgE-mediated protein contact
rational approach for an operational definition of dermatitis from pork in a slaughterman. Contact Dermatitis
34:301-302
OACD until more information is forthcoming. 24. Cronin E (1987) Dermatitis of the hands in caterers. Contact
25. Mathias CGT (1989) Contact dermatitis and worker's com-
pensation: criteria for establishing occupational causation
and aggravation. J Am Acad Dermatol 20:842-848
References 26. Marrakchi S, Maibach HI (1994) What is occupational contact
dermatitis? Dermatol Clin 3:477-484
1. Malten KE, Fregert S, Bandmann H-J, et al. (1963) Occupa- 27. Kanerva L, Estlander T, Jolanski R, Tarvainen K (1995)
tional dermatitis in five European dermatology departments. Occupational allergic contact dermatitis and contact urticaria
Berufsdermatosen 11:181 caused by polyfunctional aziridine hardener. Contact Der-
2. Mathias CGT, Morrison JH (1988) Occupational skin diseases, matitis 33:304
US results from the Bureau of Labor Statistics annual survey 28. Kanerva L, Hyry H, Jolanki R, et al. (1997) Delayed and
of occupational injuries and illnesses, 1973 through 1984. Arch immediate allergy caused by methylhexahydrophthalic anhy-
DermatoI124:1519-1524 dride. Contact Dermatitis 36:34-38
3. National Institute for Occupational Safety and Health (1990) 29. Kanerva L, Jolanski R, Tupasela 0, et al. (991) Immediate
Prevention of occupational skin disorders: a proposed and delayed allergy from epoxi resins based on diglycidyl
national strategy for the prevention of dermatological con- ether of bisphenol A. Scand J Work Environ Health 17:208-
ditions. Am J Contact Dermatitis 1:56-59 21 5
4. Mathias CGT (990) Prevention of occupational contact 30. Galindo PA, Feo F, Garcia R, et al. (1997) Mercurochrome
dermatitis. J Am Acad Dermatol 23:742-748 allergy. Immediate and delayed hypersensitivity. Allergy
5. Hogan DJ, Dannaker CJ, Maibach HI (1990) The prognosis of 52:1138-1141
contact dermatitis. J Am Acad Dermatol 23:300-307 31. Mathias CGT (1988) Post-traumatic eczema. Dermatol Clin
6. Diepgen TL (1996) Epidemiologieal studies on the prevention 6:35-42
of occupational contact dermatitis. In: Elsner P, Lachapelle 32. Andersen KE (1994) Mechanieal trauma and hand eczema. In:
J-M, WalIlberg JE, Maibach HI (eds) Prevention of contact Menne T, Maibach HI (eds) Hand eczema. CRC Press, Boca
dermatitis. (Current problems in dermatology, vol 25. Series Raton, PP 31-34
Ed: G Burg) Karger, Basel, pp 1-9 33. Menne T, Hjorth N (1985) Frictional contact dermatitis. Am J
7. Skog E, Tottie M (961) Occupational eczema causing Ind Med 8:401-402
disablement. Acta Derm Venereol 41:205-212 34. Meneghini CL (1985) Sensitization in traumatized skin. Am J
8. O'Ouinn SE, Cole J, Many H (1972) Problems of disability and Ind Med 8:319-321
rehabilitation in patients with chronic diseases. Arch De- 35. Shmunes E (1988) Predisposing factors in occupational skin
rmatol 105:35-41 diseases. Dermatol Clin 6:7-13
9. Meding B (1990) Epidemiology of hand eczema in an 36. Göranson K Ü98J) Contact urticaria to fish. Contact Derma-
industrial city. Acta Derm Venereol Suppl (Stockh) 153:1-43 titis 7:282-283
10. Lane G, Dennie CG, Downing JG, et al. (942) Industrial 37. Prahl P, Roed-Petersen J (1979) Type I allergy from cows in
dermatoses. JAMA 118:613-615 veterinary surgeons. Contact Dermatitis 5:33-38
11. Maibach HI, Johnson HL (1975) Contact urticaria syndrome. 38. Lutsky II, Neuman I (1975) Laboratory dander allergy. 1. An
Contact urticaria to diethyltoluamide (immediate type hy- occupational disease. Ann Allergy 35:201-205
persensitivity). Arch Dermatol11I:726-730 39. Thestrup-Pedersen K, Halkier-S0rensen L (1991) Skin prob-
12. Lahti A, Maibach HI (1991) Immediate contact reactions: lems in the fish processing industry. In: Menne T, Maibach HI
contact urticaria and contact urticaria syndrome. In: Marzulli (eds) Exogenous dermatoses: environmental dermatitis. CRC
FN, Maibach HI (eds) Dermatotoxicology. Hemisphere, New Press, Boca Raton, PP 267-282
York, pp 473-495 40. Benezra C, Sigman CC, Perry LR (1985) A systematie search
13. Lahti A, Maibach HI (1987) Immediate contact reactions for structure-activity relationships of skin contact sensitizers:
(contact urticaria syndrome). In: Maibach HI (ed) Occupa- methodology. J Invest Dermatol 85:351-356
tional and industrial dermatology, 2nd edn. Year Book Inc, 41. Roberts DW, Basketter DA (1990) A quantitative structure
Chicago, pp 32-44 activity/dose response relationship for contact allergic po-
14. Von Krogh G, Maibach HI (1982) The contact urticaria tential of alkyl group transfer agents. Contact Dermatitis
syndrome. Semin Dermatol 1:59-66 23:331-335
350 5.1. Ale and H.1. Maibach: Operational Denition of Occupational Allergie Contact Dermatitis
42. HostYnek JJ (1998) Structure-activity relationship in contact Experimental contact sensitization in humans. Contact Der-
sensitization: classification and ranking of allergens. In: matitis 2:325-329
Marzulli FN, Maibach HI (eds) Dermatotoxicology methods: 57. Upadhye MR, Maibach HI (1992) Influence of area of
the laboratory worker's vade mecum. Taylor and Francis, application of allergen on sensitization in contact dermatitis.
Washington DC, pp 115-120 Contact Dermatitis 27:281-286
43. Kimber I, Weisenberger C (1989) A murine local lymph node 58. Bruze M (1993) Principles of occupational hand eczema. In:
assay for the identification of contact allergens. Assay Menne T, Maibach HI (eds) Hand eczema. CRC Press, Boca
development and results for an initial validation study. Arch Raton FL, pp 165-178
Toxicol 63:274-282 59. Bruze M (1985) Contact sensitizers in resins based on phenol
44. Andersen KE, Maibach HI (1985) Guinea pig sensitization and formaldehyde. Acta Derm Venereol Suppl (Stockh) 119:
assays: an overview. In: Andersen KE, Maibach HI (eds) 1-83
Contact allergy, predictive tests in guinea pigs. (Current 60. Menne T, Andersen KE, Kaaber K, et al. (1987) Evaluation of
problems in dermatology, V0114) Karger, Basel, pp 263-290 the dimethylglyoxime stick test for the detection of nickel.
45. Gad SC, Dunn BI, Dobbs DW, et al. (1986) Development and Derm Beruf Umwelt 35=128-130
validation of an alternative dermal sensitization test: the 61. Fregert S (1988) Physicochemical methods far detection of
mouse ear swelling test (MEST). Toxicol Appl Pharmacol contact allergens. Dermatol Clin 6:97-104
84:93-114 62. Fregert S, Dahlquist I, Gruvberger B (1984) A simple method
46. Rietschel RL, Fowler JF Jr (1995) Predictive testing for human for the detection of formaldehyde. Contact Dermatitis 10:
contact dermatitis. In: Rietschel RL, Fowler JF Jr (eds) 132-134
Fischer's contact dermatitis, 4th edn. Williams and Wilkins, 63. Fregert S, Trulsson L (1978) Simple methods for demonstra-
Baltimare, pp 33-37 tion of epoxy res ins of bisphenol A type. Contact Dermatitis
47. Draize JH, Woodard G, Calvery HO (1944) Methods far the 4:69-72
study of irritation and toxicity of substances applied topically 64. Fregert S (1975) Occupational dermatitis in a 10 years
to the skin and mucous membrane. J Pharmacol Exp Ther material. Contact Dermatitis 1:96-107
82:377-390 65. Dannaker q, White IR, Rycroft RJG (1989) Long-term
48. Edwards CC (1972) Hazardous substances. Proposed revision prognosis in occupational chromate allergy: an attempted
of test for primary skin irritants. Fed Reg 37:635-636 (see also 18 years follow-up study. Contact Dermatitis 21:59-64
p 27) 66. Hellier FF (1958) The prognosis in industrial dermatitis. BMJ
49. Marzulli FN, Maibach HI (1975) The rabbit as a model for 1:196-198
evaluating skin irritants: a comparison of results obtained on 67. Keczes K, Bhate SM, Wyatt EH (1983) The outcome of
animals and man using repeated skin exposure. Food primary hand dermatitis. Br J Dermatol 109:665-668
Cosmetic Toxicol 13:533-540 68. Williamson KS (1967) A prognostic study of occupational
50. Nixon GA, Tyson CA, Wertz WC (1975) Interspecies com- dermatitis cases in chemical works. Br J Ind Med 24:
parison of skin irritancy. Toxicol Appl Pharmacol 31:81-90 103-113
51. Lanman BM, Elvers WB, Howard CS (1968) The role of 69. Maguire A (1978) Pyschic pos session among industrial
human patch testing in a product development program. In: workers. Lancet 1:376
Proceedings of the Joint Conference on Cosmetic Sciences. 70. Kanerva L, Estlander T, Jolanski R (1990) Skin testing for
Toilet Goods Association, Washington, DC, pp 135-145 immediate hypersensitivity in occupational dermatology. In:
52. Pati! SM, Patrick E, Maibach HI (1998) Animal, human and in Menne T, Maibach HI (eds) Exogenous dermatoses: environ-
vitro test methods for predicting skin irritation. In: Marzulli mental dermatitis. CRC Press, Boca Raton, pp 103-126
FN, Maibach HI (eds) Dermatotoxicology methods: the 71. Maibach HI (1981) The ESS - excited skin syndrome (alias the
laboratory worker's vade mecum. Taylor and Francis, Wash- "angry back"). In: Ring I, Burg G (eds) New trends in allergy.
ington DC, pp 89-114 Springer, Berlin Heidelerg New York, pp 208-221
53. Haley TJ (1984) Toxicology. In: Sax NI (ed) Dangerous 72. Mitchell J, Maibach HI (1997) Managing the excited skin
properties of industrial materials, 6th edn. Van Nostrand syndrome: pateh testing hyperirritable skin. Contaet Derma-
Reinhold Inc, New York, pp 1-8 titis 37:193-199
54. Wester RC, Maibach HI (1983) Cutaneous pharmacology: 10 73. Hannuksela M (1986) The repeated open application test
steps to percutaneous absorption. Drug Metab Rev 14:169-205 (ROAT). Contact Dermatitis 14:221-227
55. Wester RC, Maibach HI (1985) Interrelationships in the dose- 74. Ale SI, Maibaeh HI (1995) Clinical relevance in allergie
response of percutaneous absorption. In: Bronaugh RL, contact dermatitis. An algarithmic approach. Dermatosen
Maibach HI (eds) Percutaneous absorption. Marcel Dekker 43:119-121
Inc. New York, pp 347-357 75. Lachapelle J-M (1997) A proposed relevance scoring system
56. Marzulli FN, Maibach HI (1976) Effects of vehicles and for positive allergic patch test reactions: practical implica-
elicitation concentration in contact dermatitis testing. I. tions and limitations. Contact Dermatitis 36:39-43
CHAPTER 42
Occupational and Non-Occupational Compound Allergy

S.]. Bashir, L. Kanerva, R. ]olanki, and H.I. Maibaeh
Definition Diagnosis
The present article is based on a reeent review by The clinieal features of a eompound allergy are those of
Bashir and Maibaeh (1997). They defined eompound allergie eontaet dermatitis. Diagnosis of a eompound
allergy as an allergie eontaet dermatitis in whieh a allergy requires the fulfillment of eertain eriteria:
preparation is believed to be allergenie on pateh
1. The reaetion must be allergie and not irritant
testing, whilst its individual ingredients show a neg-
2. The pateh tests for the eonstituents of the prepara-
ative pateh-test result. Some or all of those ingredients
tion must be negative
must have interaeted to form a new allergen (Table 1).
3. The whole preparation must give a positive reaetion
on pateh testing
Introduction 4. All the ingredients must be known and tested
5. Vehicle-dependent eontaet allergy (Rietsehel 1992)
Compound allergies, first suggested by Calnan (1975) in must be excluded (the eorreet vehicle must be used
an allergy to a eosmetie, are usually identified in allergie and the individual ingredients must be present in
reaetions to eosmeties or pharmaeeutieal preparations. sufficient coneentrations to produee a reaetion)
The ingredients of these allergenie eompounds are often
supplied by the manufaeturers for pateh testing. In eases
Can an Interaction Produce an Allergen?
of eonventional allergie eontaet dermatitis, the ingredi-
ents of a produet known to be allergenie are pateh tested
Several papers provide strong evidenee that the
individually to identify the allergen(s). In the ease of
ingredients of apreparation must interaet with eaeh
eompound allergy, however, no ingredient is found to
other for that preparation to beeome allergenic.
be an allergen on pateh testing. The dermatologist ean
Possible eompound allergens (some eonsidered pro-
only eonclude, after earefully pateh testing the ingredi-
yen) have been summarized in Table 2. Aldridge and
ents, that there must be a new produet formed within the
Main (1984) demonstrated the neeessity for partieular
preparation that is eausing the allergy.
ingredients of Daktaeort (2% mieonazole nitrate!
Evidenee that the eonstituents of apreparation ean
1% hydroeortisone) eream to be present together for
interaet to form a new allergen is diseussed here.
an allergie response to take plaee. They report two
Several researehers provide strong evidenee that a
patients in whom a eompound allergy to Daktacort was
eombination of ingredients is required to produee an
diagnosed on the basis of the faet that pateh testing the
allergen, and three teams have isolated allergenic
individual eonstituents of the drug showed negative
reaetion produets. In addition, the debate regarding
results, while the full preparation was allergenic.
the validity of the entire eoneept of eompound allergy
Having identified that Daktarin (2% mieonazole ni-
is addressed and theories regarding possible meeha-
trate) differs from Daktaeort only by two ingredients,
nisms are presented.
hydroeortisone and ethylene diamine tetra-aeetate
(EDT A), they tested the patients with Daktarin alone
Table 1. Definition of compound allergy and obtained a negative pateh-test result. However,
when hydroeortisone and EDTA were added to Dakt-
Patch test Result
arin, an allergie response was seen. Neither hydroeor-
Entire product + tisone nor EDTA, alone or in eombination together,
Irritant controls (at least 20) produeed a positive reaetion. This demonstrates that
Individual ingredients the eombination of the three ingredients, i.e., micona-
New chemical formed in mixture +
zole nitrate, hydroeortisone and EDT A, are required

352 S.J. Bashir et al.
Table 2. Compound allergens dation products of THT and thymol. A positive

reaction was found when both the degradation prod-
Proven compound allergens*
Cutting oil (Shrank 1985)
ucts (formaldehyde and ethanolamine) were present
Daktarin cream (Aldridge and Main 1984) together with thymol. Using NMR and IR spectrosco-
Elics eyedrops (Yamashita and Kawashima 1991) py, the reaction product was identified (a benzoxazine
Hirudoid cream (Smeenk 1985; Kellett et al. 1986)
Tetrahydro-epoxy-ethylanthraquinone
derivative) and was found to be allergenie when the
(Wilkinson et al. 1994) patients were patch tested. In nonallergie control
Possible compound allergens** subjects, the result was negative.
Aureomycin cream (Kellett et al. 1986)
Budesonide (Corazza et al. 1994)
Boots E45 (Kellett et al. 1986)
Calcipotriol cream (Garcia-Bravo and Camacho 1996) Occupational Compound Allergy
Colgate toothpaste (Kellett et al. 1986)
Cosmetic foundation cream (Calnan 1975) Very few cases of occupational compound allergy have
Haelan cream (Kellett et al. 1986)
Medi-swab (Freeman 1996) been reported (Table 3). Shrank (1985) describes a
Patch-testing marker (Cox et al. 1989) patient with an occupationally related allergie contact
Sepso (Heine and Zschunke 1976) dermatitis. The allergenie preparation was an indus-
Spectraban 15 lotion (Kellett et al. 1986; Goh 1990)
Steret swab (Tan and King 1996)
trial cutting oil, but, by patch testing using an
Steri-Iette (van Ketel 1979) appropriate vehicle, the ingredients supplied by the
Ultracool (Kellett et al. 1986) manufacturer were not found to be allergenic. A
Zovirax cream (Goh 1990)
diagnosis of compound allergy was made. As the
* Products contain identifiable new allergens or known allergenie cutting oil was manufactured in five stages, it was
combinations of ingredients possible to determine that the allergen was formed in
** New allergens not identified or sought the first stage, which consisted only of mixing trieth-
anolamine and caprylic acid. This resulted in the
to produce a compound allergy. As they are non- formation of triethanolamine caprylate, which is a
allergenie alone, there must be an interaction between water-soluble amine soap believed to be allergenic.
these substances that makes them allergenic. This case of compound allergy demonstrates direct
Logically, the next step would be to elucidate the evidence of the formation of an allergenie re action
putative reaction product and demonstrate its aller- product when nonallergenie ingredients are combined.
genicity. Three authors have been able to demonstrate High-performance liquid chromatography can be
the existence of an allergenie re action product (Shrank used to extract allergenie derivatives from industrial
1985; Smeenk et al. 1987; Wilkinson et al. 1994). working solutions (Wilkinson et al. 1994). Two pa-
Smeenk et al. (1987) used a sophisticated process of tients who patch tested negatively to the ingredients
nuclear magnetic resonance (NMR) and infrared (IR) were found to be allergie to tetrahydro-epoxy-ethyl-
spectroscopy to isolate areaction product and prove anthraquinone (TEEQ), a derivative of ethylanthraqui-
its allergenicity when investigating contact allergy to none, which had formed in the solution. Of the 30
Hirudoid cream. This preparation had been previously control subjects who patch tested negatively, one
shown to contain a contact allergen, which has been developed late reactions at 3 weeks (active sensitiza-
removed by the manufacturers (Prins and Smeenk tion), suggesting that TEEQ is strongly allergenic.
1971). Despite this, patients continued to present with At the Finnish Institute of Occupational Health, one
allergie reactions, which Smeenk et al. (1987) diag- patient was shown to be allergie to an oxidation
nosed as a compound allergy. Two ingredients, 1,3,5- product of phenyl-ct-naphthylamine (PAN), used as an
triliydroxyethyl-hexahydrotriazine (THT) and thymol, antioxidant in an industrial grease. Patch tests to the
had to be present simultaneously for a positive grease were strongly positive, but freshly made PAN
re action to occur. As a chemical reaction between test substances at concentrations of up to 10% in
THT and thymol was thought to be unlikely, patients petrolatum, acetone and water gave negative results.
were patch tested with the combination of the degra- However, during 2-month storage of a petrolatum-
Table 3. Occupational compound allergy
Product Putative allergen Reference
Industrial cutting oil Triethanolamine caprylate, which forms Shrank 1985

by mixing triethanolamine and caprylic acid
Industrial working solution TEEQ, which had formed in the solution Wilkinson et al. 1994
Industrial grease Oxidation product of phenyl-IX-naphthylamine Alanko et al. 1999
TEEQ, tetrahydro-epoxy-ethylanthraquinone
Occupational and Non-Occupational Compound Allergy 353
based patch-test substance at a concentration of 1%, For example, patch testing with neomycin is usually
and PAN oxidized by hydrogen peroxide at a concen- performed at a concentration of 20% in petrolatum,
tration of 10% in acetone, caused positive reactions in whereas the concentration in many preparations is
the patients (Alanko et al. 1999). 0.5%. Patch testing at the lower dose will lead to a false
The above studies demonstrate strong evidence that negative result (MaeDonald and Beck 1983).
an allergy-inducing reaction product can be found in However, despite these arguments, there is evidence
cases of compound allergy. It has been clearly shown to demonstrate the presence of a new allergen in some
that specific products must be simultaneously present cases. The studies reviewed above show the formation
for an allergy to occur. However, Cox et al. (1989), of a new reaetion product as the compound allergen.
despite a comprehensive study of a compound allergy Cox et al. (1989) refute the suggestion that the com-
to a skin marker used in patch testing, failed to identify pound allergies they report could be the result of a
areaction product by thin layer chromatography or greater absorption of an allergen in their patch-test
gas-liquid chromatography. Despite this, the authors model. They used a dose 12-fold greater than that in
are confident of their diagnosis of compound allergy. the original preparation and obtained negative patch-
One must question where the site of the interaction test results. They believe that it is unlikely that
between the products iso Rather than a chemical enhanced absorption would result in the delivery of
reaction in the preparation, it may be within the skin such a high dose, and thus reaffirm the result as
itself, perhaps a result of protein binding, or the negative. Kellett et al. (1986) reported seven cases of
re action may be at the cellular level, perhaps a result of eompound allergy, despite determining the best vehicle
altered antigen processing or T-cell responses. and eoneentration for patch testing. They employed
standard references and used their judgment, based on
the solubility of the ingredient and its concentration in
Compound Allergy and Patch Testing the medieament. Corrazza et al. (1994) report a com-
pound allergy to budenoside, in which case they patch
Current debate on this topic centers on whether there tested at concentrations of 0.026%, 1% and 2% in
is an interaction within apreparation to form a new petrolatum. This was on the basis of the fact that a
allergen, or whether there is merely a deficiency in the concentration of 0.005% had previously shown to be
patch test. Rietschel (1992) argues that the appearance sufficient to produce a positive result (Noda et al.
of a compound allergy is due to the vehicle employed 1993). Therefore, their first test dose should have been
in the patch test failing to deliver an adequate sufficient to produce areaction, yet low enough to
concentration of a proposed allergen to the stratum avoid immunosuppression of an allergy. However, the
corneum in the lipid phase. As a result, a negative patch tests were negative, even at the high er doses.
result is obtained. For example, dimethylsulphoxide Petroleum had been previously demonstrated to be a
(DMSO) has been reported to increase the penetration good vehicle for budenoside (Dooms-Goossens and
of allergens; patch testing without DMSO may produce Mooren 1992), so it appears that this compound allergy
erroneously negative results (Roeleveld et al. 1975). was diagnosed on solid pateh-testing data.
Should the original preparation itself be a better In summary, several authors who have been mindful
vehicle for the adsorption of the unaltered allergenie of the problems of pateh testing have documented
moleeule than the patch-test vehicle, a negative test eases of eompound allergy. It is unlikely that eom-
would falsely imply that the substance was nonaller- pound allergy ean be explained by erroneous patch
genie. This could be taken to indicate that there had testing in all these studies.
been an interaction where there had, in fact, been
none. Rietschel terms this pharmacodynamic phenom-
enon "vehicle-dependent contact allergy". Details of Confusion in Diagnosis
vehicle effects on the elicitation of allergie contact
dermatitis are provided by Tanglertsampan and Mai- Irritant or Allergie Dermatitis?
bach (1993). Bashir and Maibach (1997) have proposed
an alternative term - pseudocompound allergy - to In the correet diagnosis of eompound allergy, an
cover this and other mechanisms of false-negative irritant contact dermatitis must be excluded. As it is
patch tests. occasionally diffieult to distinguish between an irritant
Similarly, a sufficient concentration of the allergen and allergie reaction, it is possible to argue that a
must be used in the patch test, enabling a sufficient compound allergy may be a misdiagnosed irritant
dose to penetrate the skin to cause an allergy. If the dermatitis. However, some studies have excluded this
concentration used is incorrect, then a false negative explanation either by careful clinical diagnosis or by
result will be obtained, resulting in the misdiagnosis of exposing control subjects to the proposed allergen and
a compound allergy (i.e., pseudocompound allergy). looking for an irritant reaction. For example, Cox et al.
354 S.J. Bashir et al.
(1989) ruled out the possibility of irritant dermatitis to Theories

gentian violet dye used in patch testing as a skin
marker. Thousands of their patch-test patients, as The authors above have shown the need for particular
unwitting controls, had been exposed to the combined ingredients to be simultaneously present, demonstrat-
dye containing the gentian violet. None of them had ed the formation of allergenic re action products, ruled
ever shown an irritant reaction. Kellett et al. (1986), out accidental contamination and reproduced the
testing each of the preparations involved on at least 25 allergie re action with their own pharmacy's prepara-
controls, report seven cases of compound allergy. They tions. It seems that these are, indeed, cases of
only found one product, a toothpaste, to be irritant in compound allergy, the mechanisms of which must
the control group. However, the patient undertook a now be considered.
daily usage test for 1 week, and the result was a marked
perioral allergic reaction, suggesting that, in this case, Site of the Reaction
the toothpaste was allergenic rather than irritant.
The first matter to consider is the site of the allergen
Excited-Skin Syndrome or Angry Back producing the reaction (allergenic reaction). In the two
studies above, in which the compound allergen has
It may be argued that the patch tests are pOSItive been identified, the site of the reaction has been within
because the skin is in astate ofhyper-reactivity termed the preparation. Therefore, a chemical allergenic reac-
excited-skin syndrome or "angry back" (Bruynzeel tion has occurred, which is distinct from a biological
and Maibach 1995). This may lead to strong positive allergenic reaction. That is to say that, in the former,
reactions to patch tests of minor irritants or subclinical there is no biologieal involvement from the patient
or weak allergens. Authors who report compound whilst, in the latter, there may be.
allergies, such as Cox et al. (1989) or Kellett et al.
(1986), have eliminated this as far as possible by Chemical Allergenic Readions
repeating the patch tests 2 months later and obtaining
another positive result. Chemical allergenic reactions may be subdivided into
two broad categories. First, we will consider reactions
in which the formation of an allergen is the inevitable
Chemical Contaminants and Unknown Ingredients result of the formation of essential allergens by
ingredients included in the mixture. This is distinct
Another point of contention is whether all the ingredi- from a second scenario, in which environmental
ents of apreparation are patch tested. Although almost conditions dictate whether or not the allergen is
all the studies obtained from manufacturers' sampies of formed. For example, a cosmetie may be left lying in
the ingredients used in patch testing, one can argue the direct sunlight for a long period of time. This avoidable
possibility that the manufacturers themselves do not event may have catalyzed the formation of an inciden-
know the exact ingredients. To take this matter into tal allergen. If a partieular environmental situation
consideration, Cox et al. (1989), Smeenk et al. (1987) resulted in the formation of an incidental allergen, it
and Aldridge and Main (1984) made up mixtures of the may be possible for a patient to continue to use that
allergenie preparation in their own pharmacies to product, while observing reasonable storage instruc-
compare the responses of these mixtures to that of the tions. For example, products may need to be refriger-
original. All found positive results using the preparation ated or may have a finite shelf life. In an occupational
they had made. Therefore, in these cases, the allergen setting, changing the way certain chemicals are stored
cannot be an unknown contaminant or ingredient that or handled may allow a patient to keep his or her job.
was not supplied in the manufacturers' data. In any
instance, irritant controls (at least 20) are mandatory. Biological Allergenic Readions
It may be that the allergen is produced metabolically

Barterial Contamination rather than as the result of an external chemieal
reaction. In this scenario, human metabolic processes
Cox et al. (1989) ruled out the possibility of bacterial theoretically combine the ingredients of apreparation
contamination causing a false-positive result. They to form a molecule that stimulates T-lymphocytie
performed microbiological investigations to detect activity. A variety of mechanisms may act, singularly
bacterial and fungal infections of the original marker or in combination, to bring this process about. For
solution and were able to produce an allergenic example, the ingredients of a product may undergo a
response to a mixture they had freshly made. conformational change if bound to proteins or inor-
Occupational and Non-Occupational Compound Allergy 355
ganic molecules, such as phosphates or calcium ions. Bashir SJ, Maibaeh HI (1997) Compound allergy. An overview.
This conformational change may serve to catalyze an Contaet Dermatitis 36:179-183
Bruynzeel DP, Maibaeh HI (1995) "Angry back" or the excited
allergen-producing re action between the necessary skin syndrome. In: Guin JD (ed) Practical contact dermatitis.
molecules. Alternatively, enzymes may catalyze a reac- A handbook for the practitioner. McGraw-Hill, New York,
tion by cleaving the molecules, allowing them to bind pp 75-82
Calnan CD (1975) Compound allergy to a cosmetic. Contact
more favorably with each other than their parent Dermatitis 1:123
molecules. Corazza M, Mantovani L, Romani I, Bettoli V, Virgili A (1994)
Compound allergy to topieal budesonide. Contact Dermatitis
Cellular processes mayaiso be implicated in the
30:246
formation of an allergen. Within the antigen-present- Cox NH, Moss C, Hannon MF (1989) Compound allergy to a skin
ing cells themselves, there may be interaction between marker for patch testing: a chromatographie analysis. Contact
Dermatitis 21:12-15
molecules, either before they are expressed on the cell Dooms-Goossens A, Morren M (1992) Results of routine patch
surface or even at the cell surface. Whatever the testing with corticosteroid series in 2073 patients. Contact
process may be, the compound allergen is presented to Dermatitis 26:182-191
a T-lymphocyte, which is stimulated to differentiate, Freeman S (1996) Compound allergy to skin swabs. Contact
Dermatitis 35:66
resulting in an allergie response. Garcia-Bravo B, Camacho F (1996) Two cases of contact
dermatitis caused by calcipotriol cream. Am J Contact
Dermat 7:118-119
Goh CL (1990) Compound allergy to Spectroban 15 and Zovirax
Conclusion cream. Contact Dermatitis 22:61-62
Heine A, Zschunke E (1976) Contact dermatitis to Sepso. Contact
Previous work has shown patients to be allergie to a new Dermatitis 2:60
Kellett JK, King CM, Beck MH (1986) Compound allergy to
re action product formed within apreparation to which medieaments. Contact Dermatitis 14:45-48
they are allergie. Meanwhile, other studies have dem- MacDonald RH, Beck MH (1983) Neomycin: a review with
onstrated the need for reaction ingredients to be present particular reference to dermatologieal usage. Clin Exp
Dermatol 8:249-258
together before the preparation can be allergenic. Noda H, Matsunaga K, Noda T, Abe M, Ohtani T, Shimizu Y,
However, difficulties in diagnosing a compound allergy Asahi K, Iida Y, Takigami N, Masutani M, Ueda H (1993)
exist. In each individual case presenting as a compound Contact sensitivity and cross-reactivity of budesonide. Con-
tact Dermatitis 28:212-215
allergen, the issue of dosing and vehicle selection Prins FJ, Smeenk G (1971) Contacteczeem door Hirudoid zalf. Ned
remains a gray area that researchers must overcome. Tijdschr Geneeskd 115:1935
Each individual constituent must be patch tested in all Rietsehel RL (1992) The patch test as an exercise in cutaneous
pharmacokinetics. Does compound allergy exist? Arch Der-
possible combinations in order to determine which matol 128:678-679
ingredients are reacting together. Further, the reaction Roeleveld CG, van Ketel WG (1975) Allergic reactions to a hair
product should be identified, if possible. If it cannot be dye elicited by an ointment containing DMSO. Contact
Dermatitis 1:331
found, a compound allergy may still be diagnosed, as the Shrank AB (1985) Allergy to cutting oil. Contact Dermatitis 12:229
allergen may be made within the skin itself. Smeenk G, Kerckhoffs HPM, Schreurs PHM (1987) Contact
allergy to areaction product in Hirudoid cream: an example
of compound allergy. Br J Dermatol 116:223-231
Tan BB, King CM (1996) Allergie contact dermatitis from Steret
swab. Contact Dermatitis 34:62-63
TangIertsampan C, Maibach HI (1993) The role of vehicles in
References diagnostic patch testing. A reappraisal. Contact Dermatitis
29:169-174
Alanko K, Jolanki R, Estlander T, Kanerva L (1999) Oeeupational Van Ketel WG (1979) Reaction to a wetting agent (Steri-lette)
eompound allergy from an industrial grease eaused by an used for soft contact lenses. Contact Dermatitis 5:192
oxidation produet of phenyl-alpha-naphtylamine. J Eur Aead Wilkinson SM, Brittain J, Beck MH (1994) Allergic contact
Derm Venereol12: Suppl 2: 186-187 dermatitis from an anthraquinone derivative in a chemieal
Aldridge RD, Main RA (1984) Contaet dermatitis due to a plant. Contact Dermatitis 30:241-242
eombined mieonazole nitrate/hydroeortisone eream. Contaet Yamashita H, Kawashima M (1991) Contact dermatitis from
Dermatitis 10:58-60 amlexanox eyedrops. Contact Dermatitis 25:255-256
CHAPTER 43
The Role of Atopy in Working Life

K. Kalimo and K. Lammintausta
Atopy located in the hands in about 40% of patients (Rystedt

1985c; Lammintausta et al. 1991); thus, the prevalence
The definition of atopy includes atopic dermatitis of atopic hand eczema follows the prevalence of atopic
(AD), established by Hanifin and Rajka (1980), with the eczema, both with increasing figures.
suggested major and minor criteria, including other In the studies that analyse those features of atopy
atopic diseases such as allergic rhinitis, conjunctivitis that are significant in the development ofhand eczema,
or asthma. Atopic skin diathesis (ASD), first proposed the atopic criteria show differences since the spectrum
by Lamnintausta and Kalimo (1981), and later by of atopic symptoms is extensive. However, certain
Diepgen et al. (1991) and Diepgen and Fartasch (1992), prognostic associations can be established (Lam-
includes as the main criteria dry skin, his tory of low mintausta and Kalimo 1981; Lamnintausta 1982; Nils-
threshold for pruritus in contact with sweating, dust or son et al. 1985; Rystedt 1985a,b, 1986; Meding and
rough materials and white dermographism. Swanbeck 1990a; Diepgen et al. 1991; Diepgen and
In recent epidemiological studies, the occurrence of Fartasch 1992; Funke et al. 1995).
AD has shown variable although, in the majority, One of the major risk factors is a his tory of AD. The
increasing frequencies among different populations. possibility of hand eczema occurring later in life
The prevalence figures have varied from 10% to 16% of increases significantly if the AD was severe during
the general population (Varjonen et al. 1992; Williams childhood and was localised in the hands (60-90% of
1992; Schultz-Larsen et al. 1996). This change has been these patients and 40% of patients with moderate AD
interpreted to depend on environmental and other develop hand eczema later in working life). The risk of
external factors as well as racial, social and endogenous hand dermatitis decreases if the AD was mild. The risk
factors in common with methodological variables. of developing hand dermatitis has been estimated to be
threefold in atopic relative to non-atopic workers if
there is exposure to skin-irritating factors. Episodes of
hand eczema can occur in patients predisposed to AD,
Hand Eaema and AD even if they are not in working life or are just in clean,
dry office work.
According to epidemiological studies, the frequency of A significant association between atopy and hand
hand eczema has shown increasing prevalence in the dermatitis has also been found in patients who may
general population. In two studies carried out over a not have had manifest AD, but present with ASD
20-year period in Southern Sweden, the point preva- especially if these workers are exposed to skin irrita-
lence increased from roughly 2% to 5.4% (Agrup 1969; tion. According to several studies, no increased risk of
Meding and Swanbeck 1989). Other estimates of the hand eczema has been reported in those atopic
prevalence of hand eczema have varied from 4% to subjects who only have or have had atopic rhinitis,
about 22% (Peltonen 1979; Lantinga et al. 1984; Menne conjunctivitis or asthma, when their skin is normal,
et al. 1992; Susitaival et al. 1994). without any signs of ASD (Lammintausta and Kalimo
A previous history of AD, or ASD, during childhood 1981; Rystedt 1986; Diepgen and Fartasch 1992). How-
has been reported in 20-90% of hand eczema patients ever, in a questionnaire-based epidemiological study,
(Lammintausta and Kalimo 1981; Shmunes and Keil Meding and Swanbeck (1990a) suggested that a history
1984; Baurle et al. 1985; Nilsson et al. 1985; Rystedt of asthma or hay fever could also suggest increased
1985a,b, 1986; Meding and Swanbeck 1990a; Funke risk of hand eczema. It is typical that the frequency of
et al. 1995) and the number of these atopic hand hand dermatitis is highest among the younger workers;
eczema patients has shown a tendency to increase with age, all atopic symptoms show a tendency to
(Meding and Swanbeck 1989). Simultaneously, AD is decline. Concerning gender differences, women are

The Role of Atopy in Working Life 357
likely to suffer almost twice as often from hand contradictory (Gallacher and Maibach 1998). To eval-
dermatitis as men (Meding and Swanbeck 1990a). This uate skin irritation, visual scoring and measurement of
can partly depend on different duties at work and at transepidermal water loss (TEWL) have been em-
horne and working manners, as weil as on constitu- ployed. Increased TEWL has been reported in atopic
tional factors. persons in some studies (Hannuksela and Hannuksela
1995; Goh 1997). Experimental studies with multiple
irritants, and different application and quantitation
methods suggest that irritability of atopic skin is
Allergy and AD
increased, but the variation is extensive. Epidemiologie
data, however, strongly suggest that AD is an apparent
According to the definition, atopic patients have an
risk factor that is dose dependent since, for example,
increased risk of developing immunoglobulin E (IgE)
90% of atopic patients developed hand dermatitis if
antibodies against common allergens. Thus, they often
the heavy wet-work exposure las ted for 2 h compared
suffer from allergy to pollens, epithelia and different
with 50% hand eczema cases in non-exposed workers
foods. This can lead to manifestation of symptoms in a
(Lammintausta and Kalimo 1993).
working life which puts one in contact with food, e.g.,
in a bakery or in kitchen work or when working with
animals (Kanerva and Susitaival 1996). In such posi-
tions, it is common to also suffer from rhinitis, asthma
and conjunctivitis. Natural rubber latex allergy has
Occupational Hand Eczema and AD
become a significant health problem, causing symp-
toms from local reactions to severe anaphylactic shock.
According to long-term follow-up studies, it appears
AD patients possessing the risk of developing IgE
that young atopic subjects who belong to the risk
antibodies are also at risk of developing latex allergy
groups often develop skin problems when they enter
(Turjanmaa 1994).
working life (Lammintausta and Kalimo 1981; Shmunes
Several allergens that are able to give rise to IgE
and Keil 1984; Baude et al. 1985; Nilsson et al. 1985;
production mayaiso lead to the development of local
Rystedt 1985a,b,c, 1986; Meding and Swanbeck 1989,
contact eczema (protein contact dermatitis), if contin-
1990a; Lammintausta et al. 1991; Funke et al. 1995).
uous exposure to the skin takes place (Hjort and Roed-
Increased exposure to wet work, foods and chemieals,
Petersen 1976). It seems evident that both animal
dirt and mechanical friction seems to be especially
epithelia and food products may give rise to contact
hazardous for them. Some of the workers cannot
sensitisation, although many of these substances are
manage to continue in their chosen occupation and
simultaneously strong irritants. Sensitisation and hand
have to plan job changes, whereas others are able to
eczema have been found frequently in exposed AD
continue even in the same position in which the
patients (Kanerva and SusitaivaI1996).
eczema started. In some cases "hardening" mayaiso
With regard to contact allergy, it has been disputed
develop. Apparently, the principal reason behind the
whether patients with AD have the same potential to
better pro gnosis may be the improved protection and
become sensitised to contact allergens as non-atopic
skin care and adequate rationalisation of working
persons. According to the literature, it seems that AD
methods. Although the individual prognosis is highly
patients develop contact allergy, but the positive
variable, the hand eczema in atopic workers is
reactions include topical treatments they have used.
generally more persistent (Meding and Swanbeck
The most common contact allergens among atopics
1990a,b; Lammintausta and Kalimo 1993).
include nickel, fragranees, neomycin, balsam of Peru,
The distinction between endogenous AD and der-
cobalt, colophony, chromate, propyleneglycol, formal-
matitis caused by external factors is often difficult.
dehyde and wool alcohols (Rystedt 1985d, 1986; Lam-
When the diagnosis of an "occupational hand eczema"
mintausta et al. 1992).
is made, the diagnosis indicates that occupational
exposure has been the major cause of dermatitis. In the
case of an AD patient, the diagnosis of an occupational
Skin Irritation hand eczema requires that AD has been symptom free
and hand eczema is seen to develop or deteriorate
An irritant contact eczema is frequently seen to significantly in the working environment. Sometimes
develop in AD patients and in workers with ASD. the dermatitis fiares up so that the association is
The decreased capacity of atopic skin to resist external evident and the diagnosis of an occupational skin
irritation is poody understood. Depending on the disease may be made. However, the practice of
different methods used, reports from experimental compensatory principles in this kind of case is variable
studies on the irritability of the atopic skin are in different countries (Bruze 1994).
358 K. Kalimo and K. Lammintausta
Risk Occupations 1990b; Lammintausta and Kalimo 1993). It is evident

that good motivation and thorough understanding of
The increased risk of hand eczema seems to depend on the risks will result in a better prognosis in working
multiple factors. Exposure to common irritating fac- life. This has been proven in practice since, according
tors, wet work, detergents, chemicals, dirt and me- to Lammintausta and Kalimo (1993), several AD
chanical friction are the most common causes for the patients have managed to continue working as hair-
development of hand eczema at work. Exposure to dressers despite their condition. It is also evident that
airborne allergens or irritants can also lead to derma- not all of the AD patients are willing or able to proceed
titis. In addition, working at jobs in which there are in those positions in which the exposure to skin
changes in temperature and humidity or working in irritation can be eliminated. There may also be other
ways that lead to extensive sweating increase risk of factors behind these differences since approximately
dermatitis. 10% of patients with severe AD did not develop hand
According to long-term follow-up studies of AD dermatitis during wet-work exposure (Lammintausta
patients from Sweden and Finland (Rystedt 1985C; et al. 1991; Diepgen and Fartasch 1992).
Lammintausta et al. 1991; Meding 1996), the occupa- Therefore, it is important that the AD patients get
tions with high hand eczema prevalences are presented information as early as at school age regarding the
in the Table 1, as are the types of occupation with the risks and treatment alternatives associated with atopy.
most frequent changes. When the frequency of occu- Later, when they enter working life, profound infor-
pational changes was compared between atopics and mation concerning skin care, protection and working
non-atopics, no significant differences were found. In manners should be provided (Diepgen 1996).
addition, the frequency of working days missed due to
sick leave in atopic patients was comparable with that
in non-atopics, although some of the sick-leave periods Summary
had longer durations.
The prevalence of atopic patients is remarkable. Both
AD and ASD patients have an increased risk of hand
Councelling dermatitis in working life, especially if the AD was
severe early in childhood and if there is involvement of
W orking life will never be risk free and, therefore, it is the hands. This risk increases in women and in
important that AD patients are aware of the specific occupations with exposure to skin-irritating factors,
character of their skin to be able to treat and protect wet work, detergents, other chemicals, friction, food
themselves and to choose the correct working condi- and animals. However, many workers are able to work
tions. These conditions may develop and change successfully when they are provided with information
continuously, and risks can be decreased by, for concerning the risks and how to treat and protect. If
example, automatisation. The prognosis in AD is they are well motivated to perform the work, their
highly variable (Rystedt 1985C; Meding and Swanbeck ability to manage in working life is good. Thus, no
absolute restrictions for atopic subjects should be
given.
Table 1. Change of occupation among atopic dermatitis patients
according to Lammintausta et al. (1993). The initial and new
occupations of 111 individuals are indicated. The reported
prevalence of hand eczema (HE) in 955 atopic dermatitis patients References
with the same occupations is also shown (Rystedt 1986a)
Agrup G (1969) Hand eczema and other hand dermatoses in
Occupation Number in Number Prevalence South Sweden (thesis). Acta Derm Venereol Suppl (Stockh)
initial in new of HE (%) 61:49
occupation occupation Baurle Von G, Hornstein OP, Diepgen T (1985) Professionelle
Handekzeme und Atopie. Dermatosen 5:161-165
Food handling 24 18 81 Bruze M (1994) Principles of occupational hand eczema. In:
Cleaning 20 5 66 Menne T, Maibach HI (eds) Hand eczema. CRC Press, Boca
Nursing work 15 15 71-76 Raton, pp 166-178
Office work 15 15 52 Diepgen T (1996) Epidemiological studies on the prevention of
Metal work 13 57 occupational contact dermatitis. Curr Probl Dermatol 25:1-9
Textile work 7 5 Diepgen TL, Fartasch M (1992) Recent epidemiological and
Building work 7 57 genetic studies in atopic dermatitis. Acta Derm Venereol
Transport and 7 16 49 Suppl (Stockh) 176:13-18
motormechanic Diepgen TL, Fartasch M, Hornstein OP (1991) Criteria of atopic
Education 14 skin diathesis. Dermatosen 39:79
Others 34 13 Funke U, Diepgen T, Fartasch M (1995) Identification of high risk
Domestic work 10 68 groups for irritant contact dermatitis by occupational phy-
sicians. Curr Probl Dermatol 23:64-72
The Role of Atopy in Working Life 359
Gallacher G, Maibach HI (1998) Is atopic dermatitis a predis- Meding B, Swanbeck G (1990b) Consequences of having hand
posing factor for experimental acute irritant contact derma- eczema. Contact Dermatitis 23:6-14
titis? Contact Dermatitis 38:1-4 Menne T, Borgen 0, Green A (1992) Nickel allergy and hand
Goh CL (1997) Comparing skin irritancy in atopics and dermatitis in a stratified sampIe of the Danish female
nonatopics to sodium lauryl sulphate and bezalkonium population; an epidemiological study including a statistic
chloride using TEWL measurements. Environ Dermatol appendix. Acta Derm Venereol Suppl (Stockh) 62:35-41
4:30-32 Nilsson E, Mikaelsson B, Andersson S (1985) Atopy, occupation
Hanifin IM, Rajka G (1980) Diagnostic features of atopic and domestic work as risk factors for hand eczema in hospital
dermatitis. Acta Derm Venereol Suppl (Stockh) 92:44-47 workers. Contact Dermatitis 13:216-223
Hannuksela A, Hannuksela M (1995) Irritant effects of a detergent Peltonen L (1979) Nickel sensitivity in the general population.
in a wash and chamber tests. Contact Dermatitis 32:163-166 Contact Dermatitis 5:27-32
Hjort N, Roed-Petersen I (1976) Occupational protein contact Rystedt I (1985a) Atopic background in patients with occupa-
dermatitis in food handlers. Contact Dermatitis 2:28-42 tional hand eczema. Contact Dermatitis 12:247-254
Kanerva L, Susitaival P (1996) Cow dander, the most common Rystedt I (1985b) Factors influencing the occurrence of hand
cause of occupational contact urticaria in Finland. Contact eczema in adults with a history of atopic dermatitis in
Dermatitis 35:309-310 childhood. Contact Dermatitis 12:185-191
Lammintausta K, Kalimo K (1981) Atopy and hand dermatitis in Rystedt I (1985c) Hand eczema and long term prognosis in atopic
hospital wet work. Contact Dermatitis 7:301-308 dermatitis. Acta Derm Venereol Suppl (Stockh) 117:1-59
Lammintausta K, Kalimo K (1993) Does a patient's occupation Rystedt I (1985d) Contact sensitivity in adults with atopic
influence the course of atopic dermatitis? Acta Derm dermatitis in childhood. Contact Dermatitis 12:185-191
Venereol 73:124-128 Rystedt I (1986) Atopy, hand eczema, and contact dermatitis:
Lammintausta K, Kalimo K, Raitala K, Forsten Y (1991) Prognosis summary of recent large scale studies. Semin Dermatol 5:
of atopic dermatitis. A prospective study in early adulthood. 290-300
Int I Dermatol 30:563-568 Schultz-Larsen F, Diepgen T, Svensson A (1996) The occurrence
Lammintausta K, Kalimo K, Fagerlund V-L (1992) Patch test of atopic dermatitis in north Europe: an international
reactions in atopic patients. Contact Dermatitis 26:234-240 questionnaire study. I Am Acad Dermatol 34:760-764
Lantinga H, Nater IP, Coenraads PI (1984) Prevalence, incidence Shmunes E, Keil I (1984) The role of atopy in occupational
and course of eczema on the hands and forearms in a sampIe dermatoses in South Carolina. Contact Dermatitis 11:174-178
of general population. Contact Dermatitis 10:135-139 Susitaival P, Husman L, Horsmanheimo M, Notkola V, Husman
Meding B (1987) Prevalence of hand eczema in an industrial city. K (1994) Prevalence of hand dermatoses among Finnish
Br I Dermatol 116:627-634 farmers. Scand I Environ Health 20:206-212
Meding B (1996) Prevention of hand eczema in atopics. Curr Turjanmaa K (1994) Update on occupational natural rubber latex
Probl Dermatol 25:116-122 allergy. Dermatol C!in 12:561-567
Meding B, Swanbeck G (1989) Epidemiology of different types of Varjonen E, Kalimo K, Lammintausta K, Terho P (1992)
hand eczema in an industrial city. Acta Derm Venereol Suppl Prevalence of atopic disorders among adolescents in Turku,
(Stockh) 69:227-233 Finland. Allergy 47:243-248
Meding B, Swanbeck G (1990a) Predictive factors for hand Williams HC (1992) Is the prevalence of atopic dermatitis
eczema. Contact Dermatitis 23:154 increasing? Clin Exp Dermatol 17:385-391
CHAPTER 44
Job-Fitness Evaluation
M. Crippa and G. Pasolini
Fitness for Employment: General Considerations whether a worker is fit for employment or not, he may
consult other health professionals, in particular indus-
Assessment of fitness for employment represents an trial hygienists and other specialists (dermatologists in
essential feature of any preventive measure designed to the event of occupational skin diseases or other
protect workers' health. The International Labour Office dermatologie diseases). Assessment of fitness for
(ILO), in Recommendation 171 (International Labour employment entails a deep knowledge of the occupa-
Office 1985), has discussed the health surveillance of tional environmental conditions, individual job fea-
workers and the assessment of fitness for employment. tures and the worker's health situation.
In particular, it has been pointed out that the assessment
of workers is necessary in the following cases:
Job-Fitness Evaluation and Dermatoses
- Before their assignment to specific tasks that may
involve a danger to their health When a worker develops a skin disease, the occupa-
- At periodic intervals during any type of employment tional physician must verify whether it is a professional
that involves exposure to a particular hazard to disease or not, and, in this respect, he must acquire
health some information - in particular:
- On resumption of work after a prolonged absence
for health reasons for the purposes of (1) determin- A. Regarding the working environment
ing the possible occupational causes of the health - Characteristics of the manufacturing cyde
problems, (2) recommending appropriate action to - Substances/products in the workplace known as
protect the workers and (3) determining the work- allergie or irritant risk factors
er's suitability for the job and the need for - How these substances have been used and the
reassignment and rehabilitation length of usage
On and after the termination of assignments involv- - Amounts used
ing hazards that might cause or contribute to future B. Any individual and preventive measures adopted up
health impairment to that moment
C. Presence of any factors favouring the occurrence of
Moreover, the ethical code of the International
the skin diseases, e.g. inappropriate detergents,
Commission on Occupational Health (International
microdimate, wet work, ete.
Commission on Occupational Health 1992) shows that
D. The positivity of the on/off test
the " ... aim of occupational health practice is to protect
worker's health and to promote the establishment and These procedures make it possible to formulate an
maintenance of a safe and healthy working environ- etiologieal diagnosis, necessary to express a fitness
ment as well as to promote the adaptation of work to evaluation, which should take into account the de-
capabilities of workers, taking into ac count their state mands of the job and the abilities of the person to do
ofhealth. A dear priority should be given to vulnerable the job without health impairments or a worsening of
groups ... ". In this respect, the ILO states that, where pre-existing diseases. Thus, it is dear that the co-
the continued employment of a worker in a particular operation of the dermatologist is necessary.
job is contraindicated for health reasons, the occupa- It must be pointed out that the vast majority of
tional health service in the workplace should find occupational dermatoses is represented by contact
alternative employment for the worker or another dermatitis [irritant contact dermatitis (ICD), allergie
appropriate solution. contact dermatitis (ACD), immunoglobulin E (IgE)-
Therefore, job-fitness evaluation falls within occu- mediated reactionsJ; rarely, infectious dermatitis or
pational physicians' competence. In order to decide other forms of dermatitis are encountered.

Job-Fitness Evaluation 361
The job-fitness evaluation must take into account among those who did not develop occupational de-
that the ICD are characterised by graded effects, i.e. rmatoses. The percentage might depend either on a self-
they are dose related, and their prevention in the selection of atopic subjects in jobs at high risk for
workplace appears easier with respect to the allergic dermatoses or on the criteria chosen to define the atopic
diseases (ACD and IgE-mediated) whose clinical man- subject (De Groot 1990; Cronin and McFadden 1993).
ifestations, in already sensitised subjects, are not On the basis of our experience among health care
related to the degree of exposure. workers, hairdressers, metal workers, food handlers
It is difficult to set up criteria for job-fitness and agricultural workers, we think that:
evaluations. A few suggestions can be made that can
- The atopic subject and, in particular, the subject
vary according to the different situations:
with past or active atopic eczema must be consid-
- Workers in pre-employment stage or already em- ered hypersusceptible to occupational allergens or
ployed irritant factors
- Atopic subjects - Atopic dermatitis itself can be worsened by occupa-
- Subjects with occupational dermatoses (ICD, ACD, tional factors
IgE-mediated reactions)
Should atopics thus be excluded from those jobs in
- Subjects afflicted with non-occupational dermatoses
which allergic or irritant risks prevail? Scientific and
that could be worsened by occupational factors
practical considerations (20% of the population in
Italy are atopics) induce us to reject a rigid selection
Pre-Employment Job-Fitness Evaluation but to attempt a guided placing of these subjects in the
workplace. Hence, during the pre-employment stage,
There are several unsolved problems associated with after an analysis of possible occupational risk factors,
pre-employment medical examination; however, it we deemed that, for atopic subjects, the following
should not be a tool to discriminate against those choices should be made:
subjects who have a health problem or disease but
1. They should be assigned to tasks that do not expose
should be used to:
them to allergens or irritant substances
- Inform the worker about the occupational risks 2. If this is not possible, it is necessary to check the
- Avoid a worsening of pre-existing diseases possibility of substituting allergenic or irritant
- Reduce the occurrence of diseases in hypersuscepti- substances with other less-dangerous substances
bile subjects 3. If this is also not possible, it is important to:
- Ensure that all environmental preventive mea-
To date, the effectiveness of pre-employment med-
sures/devices have been adopted to minimise
ical examination is still under discussion, since there
exposure as far as technically feasible
are no follow-up studies or cost/benefit assessments.
- Inform the worker about the occupational risks
Moreover, some studies have revealed how, even in
and the possibility of their prevention
similar situations, the job-fitness evaluations can differ
- Provide the workers with effective personal pro-
considerably according to the criteria used by the
tective devices
physicians (De Kort et al. 1991, 1992). This lack of
- Perform a periodic surveillance of the worker's
homogeneity might depend on the lack of standardised
health condition
protocols. For this reason, we think it might be useful,
within so me limits, to give a few suggestions on these There are nevertheless some work activities that are
problems. generally considered to put the worker particularly at
risk for the development of contact dermatitis, e.g.
Atopic Subjeds hairdressing, food handling/kitchen working, nursing
and cleaning (Adams 1993). Atopics, in particular those
Although complete agreement on the definition of who have developed an atopic eczema, should be
atopy does not exist, we assumed that a subject can be advised against undertaking any of these activities,
defined as atopic when afflicted with atopic dermatitis especially if the worker is over school age.
and/or allergic rhinitis, conjunctivitis or asthma. There With regard to subjects with atopic diathesis (xero-
is no agreement regarding the role of atopy as a sis and/or itching on sweating, white dermographism,
predisposing factor for developing allergic and/or wool intolerance, family history for atopy, etc.), it is
irritant skin diseases (Blondel et al. 1987; Meding and advisable to perform:
Swanbeck 1990; Lammintausta et al. 1992; Klas et al.
1996). In some studies, the percentage of atopic - An informative programme on the occupational
subjects among those who developed occupational allergological or irritant risk factors and the way to
diseases did not appear to be significantiy greater than defend the skin against them
362 M. Crippa and G. Pasolini
- A periodic follow-up to assess the appearance of Dermatologie examination during the job-fitness
early signs/symptoms of allergic/irritant diseases or evaluation is especially useful in the event of chronic
atopic dermatitis that might be worsened by occu- or recurrent non-occupational dermatoses. We will
pational factors describe only the most frequent chronic or recurrent
dermatoses and mainly those that, due to their
Pre-Employment Exom;not;on of Subjeds w;th Post location, can cause functional limitations or alter
or Ad;ve ACD social relationships. In addition, we will deal with
those dermatoses that might be worsened by occupa-
It is necessary to assign tasks that do not require tional factors or might favour the development of
exposure to those substances to which the subject allergie diseases (Fisher et al. 1986; Fitzpatrick et al.
became sensitised. If this is not possible, we must 1993; Rook et al. 1993).
ensure safe protection from contact; in fact, as Keratinisation Disorders
previously specified, the allergie reactions are not dose
related in sensitised subjects. Keratinisation diseases can involve "critical" sites such
as the palmar/plantar areas, causing evident functional
Pre-Employment Exom;not;on of Subjeds w;th Prev;ous limits. In this context, psoriasis is the most frequent
or Ad;ve ICD disease. The extent and localisation of the lesions can
often affect not only the working capacity but also the
patient's sociallife. Lesions on the hands and feet are
1. A previous, completely recovered ICD should not be typically erythemato-desquamatous and/or hyperke-
considered as a hypersusceptible condition. For ratotic with fissures, and they can cause problems in
these subjects, in case of exposure to irritant or differential diagnosis with eczematous dermatitis
allergenie sustances, the common preventive mea- (which, however, can be favoured or can coexist).
sures (environmental prevention, information, ef- Moreover, variants of pustular psoriasis, localised at
fective personal protective devices) are sufficient the hands and feet, are the most disabling. We also
2. An active ICD must be appropriately treated; once have to emphasise that traumatic damage to the skin
the lesions have been recovered, the previous may result in lesions of psoriasis, the so-called
common preventive measures are sufficient Koebner phenomenon. In fact, there are intervals in
the course of psoriasis when skin injuries result in
disease. Many types of cutaneous injuries have been
Pre-Employment Exom;not;on of Subjeds reported to induce psoriasis, and the incidence of
w;th Other Dermotoses Koebner phenomenon is increased when the disease is
active. It is thus clear that several working activities
Dermatologie diseases can represent an important that cause microtraumas, abrasions, contact with
problem in the assessment of job fitness. The skin is in irritant substances, chemical burns, etc., can worsen
fact a "barrier" between the human body and the the clinical picture, with development of typicallesions
external environment; consequently, it is exposed to at the sites where trauma or contact occurs. Among the
risks deriving from irritant or traumatic factors which other keratinisation diseases, we note the ichthyosi-
might thus induce skin diseases or worsen pre-existing form dermatoses, and particularly ichthyosis vulgaris
lesions. Some dermatologie diseases can reduce the (the incidence is about 1 per 300 persons), with typical
working capacity of a patient if it occurs in areas such cutaneous xerosis, hyperkeratosis and deep' skin
as hands, which are necessarily involved in the job markings of the palms and soles. The dis order can
task. (Lisi 1991; Sertoli 1991). elose collaboration be exacerbated by cold, dry weather. Finally, it is
between the dermatologist and the occupational phy- important to remember, among the other causes of
sician is thus necessary, not only for an accurate palmar-plantar keratoderma, pityriasis rubra pilaris is
diagnosis and treatment but also to formulate a often worsened by some working factors such as low
prognosis in relation to the specific task. Many pre- temperature, humidity, traumas, etc.
existing skin diseases can in fact be diagnosed and
treated before the start of a working activity. For
Bullous Diseases
instance, in their various clinical pictures different
infectious diseases, such as viral diseases (warts), Bullous diseases are rare diseases, occurring infre-
mycologic infections (onychomycosis or palmo-plan- quently in young people and, today, effectively con-
tar mycosis) and bacterial diseases, might be consid- trolled by specific treatments (pemphigus, pemphigoid
ered partial contraindications in the performance of and dermatitis herpetiformis). Some types of
some tasks, but, as a matter of fact, they can be rapidly epidermolysis bullosa, congenital (especially the sim-
and completely recovered by a specific treatment. plex form) and acquired, must be mentioned since they
are characterised by the appearance of vesides and - Cold urticaria (acquired and inherited) is charac-
bullae at sites of even mild traumas. terised by the appearance of cutaneous and mucosal
pomphoid and angio-oedematous lesions which, in
Neoplastic Diseases
the acquired form, appear a few minutes after
The carcinogenic action of ultraviolet radiation (UVR) exposure to cold objects or water and low environ-
is well known. Most of the non-melanoma skin cancers mental temperatures, e.g. by working in cold stores.
in the Caucasian population are thought to result from Cold urticaria could also be associated with different
chronic exposure to solar UVR. The risk deriving from systemic diseases, in particular, cryoglobulinaemia
occupational exposure to UVR is thus dear in photo- and cryofibrinogenaemia, and calls for appropriate
type-I and -11 subjects with scanty or no pigmentation investigation.
following solar exposure. In fact, pigmentation that is - Cholinergic urticaria is a skin eruption characterised
protective against sun burning is also protective against by small wheals induced by emotional stress or
skin cancer. However, the role played by UVR in the increase in body temperature. Even low environmen-
induction and pathogenesis of melanoma is not yet tal temperatures can trigger the symptoms (choliner-
fuHy dear. Exposure to UVR of subjects with precan- gic urticaria due to cold), although the typical tests for
cerous lesions or previous epitheliomas is obviously cold urticaria are always negative (exduding cases
contraindicated. Careful health surveillance must also resulting from an association of the two forms).
be performed, even after cessation of exposure, for - Solar urticaria is an idiopathic photo dermatitis
those subjects who have been occupationally exposed characterised by the appearance of wheals following
to UVR or underwent UVR for personal or therapeutic exposure to sun or artificial sources of light.
reasons for long-Iasting periods. Moreover, the typi- - Vibratory angio-oedema, heat urticaria and aqua-
caUy Mediterranean, non-human immunodeficiency genie urticaria are some rare forms which can be
(HIV)-related Kaposi's sarcoma, generally not present exacerbated by occupational physical factors.
in young people and occurring with angiomatoid
nodules and sometimes oedema of the lower limbs, Since neither the severity and extension of symptoms
can be a contraindication to some working activities, nor the entity of the stimulus needed to trigger the
e.g. jobs requiring prolonged orthostasis. dinical picture are predictable, careful attention must be
paid to preventive measures in order to avoid relapses.
Inj1ammatory Diseases Dermatosis Due to Cold
There are many skin infiammatory diseases with These diseases worsen following exposure to cold,
known and unknown etiologies. We will deal briefiy induding in the workplace, and they can be considered
with the most frequent, characterised by chronic andl as abnormal reactions to cold itself (but not reactions
or relapsing courses that can infiuence job-fitness to abnormal cold).
evaluation.
- Chilblains, frequent especially in young women,
Lichen planus. Koebner phenomenon may be present in the occur generally on the dorsal surface of the fingers.
disease Lichen planus, especially during the acute stage. - Acrocyanosis is characterised by cyanosis and
Several types of trauma may induee isomorphie phenomena, hypothermia of the hands and feet.
and typical papules will oeeur in the injured areas.
Physical urticaria. Physieal urticarias are eharaeterised by the
- Erythrocyanosis is charaeterised by mild oedema
appearanee of wheals or angio-oedematous manifestations and red cyanotic colour on the skin of the legs.
after physieal stimulation. Frequently, different forms of - Livedo reticularis is characterised by cyanotic lines
physieal urtiearia may eoexist in the same subjeet, and they and erythema which indude vasoconstriction areas,
often spontaneously recover (especially from the aequired giving the lesion a reticular aspect.
forms). Oecupational physical faetors, e.g. low or high
temperatures, etc., ean thus trigger recurrenee of the symp- - Raynaud's phenomenon is associated with different
toms. diseases and, in particular, is present in different
rheumatic diseases.
- Dermographie urticaria is the most frequent form of
physical urticaria, and it is characterised by the
Dermatosis Induced or Worsened by UVR
development of wheals in those sites exposed to
even mild traumas (scratching, rubbing, etc.). Many skin diseases can be induced or worsened by
Moreover, a typical dermographie re action is pres- UVR. Among the idiopathic photodermatoses, poly-
ent in the case of mastocytosis, even in the absence morphie light eruption with delayed reactions to sun
of apparent skin lesions. exposure (which it is nevertheless correlated to) is the
- Pressure urticaria is characterised by erythematous most frequent. Phototoxic or photoallergic dermatitis
and oedematous lesions, which usually appear 4-6 h is more frequent and is due to contact with substances
after apressure stimulus. that, by an irritant or immunological mechanism, can
364 M. Crippa and G. Pasolini
induce a skin infiammatory response. Conversely, Examination of Subjects with Previous or Active
photodermatitis can also be caused by systemic ACD" are sufficient
administration of photosensitising substances. In this - Subjects with occupational ICD; it is necessary to:
respect, we note several drugs, among them sulfon- - Prescribe a specific treatment and remove the
amides, sulfonylureas, tetracyclines, thiazides, etc. worker from his job until recovery of the clinical
Several types of porphyria can be worsened by picture
circulating metabolites following exposure to UVR. In - Verify which occupational factors could have
particular, congenital and acquired porphyria cutanea caused the dermatitis, e.g. personal protective
tarda are typically characterised by skin lesions, in devices not fit for the job or not correctly used,
particular on the hands, with increased skin fragility substances improperly diluted, ete.
and vesicular, bullous and ulcerative lesions on light - Remove the abnormal conditions of exposure to
exposed skin. Similar lesions can also be induced by irritant substances
simultaneous exposure to UVR and contact/adminis- - Perform a periodical health surveillance of the
tration with porphyrinogenic substances, e.g. hex- subject after resumption of work
achlorobenzene, tetrachlorodibenzo-p-dioxin, etc. - Subjects with occupational IgE-mediated allergies
UVR can also worsen auto immune diseases such as
These diseases may be characterised by skin and/or
chronic discoid lupus erythematosus and subacute and
respiratorylsystemic manifestations, which sometimes
systemic lupus erythematosus, as weIl as mixed
can be very serious if the worker is not promptly
connective tissue diseases and dermatomyositis or
removed from exposure. It must be pointed out that
other derma tos es, such as rosacea, etc.
the clinical picture can occur following either contact
To sum up, it is clear how several dermatologic
or inhalation. Therefore, the measures adopted to
diseases, often characterised by a complex pathogene-
avoid exposure must be as drastic as warranted by the
sis, can infiuence the job-fitness evaluation, which must
seriousness of the clinical manifestations, and the
take into account occupational factors able to worsen or
preventive measures can be extended to colleagues or
trigger exacerbations of these diseases. Close co-oper-
departments of the factory.
ation between the dermatologist and the occupational
By way of example, the criteria for job-fitness
physician is thus very important for the correct
evaluation of health care workers affiicted with glove-
diagnosis of all skin diseases occurring in a worker
related diseases are reported in the following para-
and possibly correlated or worsened by job tasks.
graph. In the context of this example, the procedures
to be followed in the case of IgE-mediated sensitisat-
Job-Fitness Evaluation for Employed Subjects ions have been described.
Since contact dermatitides represent the most frequent

occupational dermatoses, in this paragraph we will An Example of Job-Fitness Evaluation Criteria:
discuss them. The job-fitness evaluation for employed Glove-Induced Dermatitis in Health (are Workers
workers who develop an occupational dermatosis,
must take into consideration general and specific The examples of job-fitness evaluation criteria are
preventive measures. General measures include: practical suggestions (not definitive ones, because of
the evolving nature of the topic) to be adapted to the
- Identification/localisation and quantification of risk
different possible work situations. They have been taken
factors present in the workplace
from a consensus document prepared by the Italian
- Removal or reduction of risk factors
Society of Preventive Medicine for Health Care Workers
- Provision of information to the worker on risk factors
on "Allergic and irritant glove-related diseases in health
and ways of preventing the correlated diseases
care workers and their prevention" (Alessio et al. 1997).
- Adoption of effective and specific personal protec-
tive devices A. Allergie contact dermatitis. The worker must use
- Reduction or removal of possible predisposing gloves devoid of the allergens to which he is
factors sensitised.
B. Irritant contact dermatitis. Powder-free, cotton or
Every possible effort should be made to maintain the
polyethylene gloves should be worn, and the
worker's job, although the risk of possible relapses or
removal of irritant factors apart from gloves may
chronic or severe reactions should not be underesti-
be useful, e.g. improper use of strong disinfectants,
mated. When specific preventive measures must be
alkaline detergents, unnecessary brushing, etc.
adopted, we can distinguish:
C. IgE-mediated reactions (mainly due to latex) and in
- Subjects with occupational ACD; suggestions pro- particular urticaria localised only in the contact
vided in the section entitled "Pre-Employment sites. The following choices are possible:
- Latex-free gloves Glove-related adverse reactions (allergic and irri-

- Powder-free latex gloves with an inner coating, tant)
with or without other gloves beneath, e.g. - Possible predisposing factors
polyethylene gloves) - The correct way to use gloves
An aspecific bronchial provocation test must be - Skin care and cleansing
performed. If negative, the above-mentioned - Cessation of inappropriate habits/behaviours
measures are sufficient; if positive, the precau-
These topics have been discussed during meetings
tions shown in the next paragraph are necessary.
and they have been reported in booklets subsequently
D. Other IgE reactions associated with or without
distributed to the workers. An evaluation of knowledge
urticaria. The measures to be adopted are based on
on these specific topics has been carried out after
the fact that it is necessary to avoid atmospheric
12 months by administering multiple-choice question-
dispersion and contact with the allergen (generally
naires. The questionnaires were scored. If gaps in
latex), and these measures vary on the basis of the
learning have been pointed out, further informative
severity of the symptoms and working conditions.
meetings have been organised.
Three steps can be identified:
On the basis of our experience, the health-educa-
1. In the event of conjunctivitis and/or rhinitis, the
tional programmes have shown their effectiveness in
patient must use latex-free gloves and avoid
reducing work-related diseases, pointing out the im-
contact with other latex objects. He does not
portance of prevention and removing inappropriate
have to change his work site. Powder-free gloves
behaviours which might facilitate the onset of occu-
should be adopted by the other colleagues.
pational diseases; the programmes yield these benefits
2. In the event of mild asthma, in addition to the
with low costs.
above measures, latex-free gloves must also be
Recently, a study of the effectiveness of a specific
used by the other workers in the department.
skin-care education programme has been published. It
3. In the event of severe asthma or anaphylactic
was carried out at a fine-chemical manufacturing site
reactions, the subject must work in a latex-free
(Heron 1997), and it has pointed out a significant
department or he must change the type of job.
decrease in the incidence of new cases of dermatitis
The former measure is particularly important
after health education, the effectiveness and usefulness
when a high degree of professionalism must be
of training materials, such as video and posters, and
maintained.
the need of periodical reinforcement of retention of
knowledge.
Information: Necessary Tool for the Application
of Job-Fitness Evaluation
References
Informative programmes on occupational risk factors
are important in preventing occupational injuries and Adams RM (1993) Hand eczema: the atopic subject at work. Cutis
52:267-269
illnesses, and they are a necessary tool for the Alessio L, Baruffini A, Biscaldi G, et al. (1997) Allergic and irritant
application of job-fitness evaluations. This information glove-related diseases in health care workers and their
should be systematically provided by the occupational prevention. Consensus document of the Italian Society of
Preventive Medicine for Health Care Workers. Int J Occup
physician to the worker during the pre-employment Environ Health 3:300-303
examination, by means of the use of audiovisual Blondeel A, Achten G, Dooms-Goossens A, Buekens P, Broeckx
devices and the distribution of informative booklets. In W, Oleffe J (1987) Atopic et allergie de contact. Acta Dermatol
Venereol 114:2033-209
addition, periodic evaluations and updates of the Cronin E, McFadden JP (1993) Patients with atopic eczema do
worker's information levels are necessary. In this become sensitized to contact allergens. Contact Dermatitis
respect, our Institute has already carried out health- 28:225-228
De Groot AC (1990) The frequency of contact allergy in atopic
education programmes for workers exposed to lead patients with dermatitis. Contact Dermatitis 22:273-277
and for health care workers using gloves and exposed De Kort WL, Fransman LG, van Dijk FJ (1991) Preemployment
to anaesthetic gases and antineoplastic dmgs (Porm medical examinations in a large occupational health service.
Scand J Work Environ Health 17:392-397
et al. 1993; Lucchini et al. 1995). De Kort WL, Uiterweer HW, van Dijk FJ (1992) Agreement on
For instance, the aim of the educational programme medical fitness for a job. Scand J Work Environ Health
on glove-related diseases in health care workers was to 18:246-251
Fisher AA (1986) Contact Dermatitis, 3rd edn. Lea and Fabiger,
inform the workers about: Philadelphia
Fitzpatrick TB, Eisen AZ, Wolff K, et al. (1993) Dermatology in
- The frequency of these diseases general medicine, 4th edn. McGraw Hill Inc., New York
- The types of gloves used by health care workers Heron RJL (1997) Worker education in the primary prevention of
- The composition and use of the gloves occupational dermatoses. Occup Med 47:407-410
366 M. Crippa and G. Pasolini: Job-Fitness Evaluation
International Commission on Occupational Health (1992) Inter- gases and nurse handling antineoplastic drugs. In: Hagberg
national code of ethics for occupational health professionals. M, Hofmann F, Stobel U, Westlander G (eds) Occupational
International Commission on Occupational Health, Singa- health for health care workers. Ecomed Publisher, Landsberg,
pore pp 235-238
International Labour Office (1985) Recommendation 171 concern- Meding B, Swanbeck G (1990) Predictive factors for hand eczema.
ing occupational health services. International Labour Office, Contact Dermatitis 23:154-161
Geneva Porru S, Donato F, Apostoli P, Coniglio L, Duca P, Alessio L
Klas PA, Corey G, Storrs FJ, Chan SC, Hanifin JM (1996) Allergie (1993) The utility of health education among lead workers: the
and irritant patch test reactions and atopic disease. Contact experience of one program. Am J Ind Med 22:473-481
Dermatitis 34:121-124 Rook A, Wilkinson DS, Ebling FJG, et al. (1993) Textbook of
Lammintausta K, Kalimo K, FagerIund VL (1992) Patch test dermatology, 4th edn. Blackwell Scientific Publications,
reactions in atopic patients. Contact Dermatitis 26:234-240 Oxford
Lisi P (1991) L'ambiente di lavoro e le dermopatie non profes- Rystedt I (1985) Work-related hand eczema in atopics. Contact
sionali. Ann It Derm Clin Sperim 45:9-14 Dermatitis 12:164-171
Lucchini R, Porru S, Apostoli P, Alessio L (1995) A health Sertoli A (1991) Dermatologia alIergologica professionale ed
education pro gram for personnel exposed to anaesthetic ambientale. n Pensiero Scientifico Editore, Rome
CHAPTER 45
Risk Management of Occupational Hazards at the Workplace

U. Funke
Introduction risk is defined by a history of hand eczema, clinically-

and (proven) job-relevant allergy and atopic skin
Risk management of occupational skin diseases at the diathesis. The assessment of individual risk can be
workplace includes identification of risk groups, achieved by special medical examinations, or with
design of workplaces, special occupational medical some limitations, also by self assessment.
care by periodical medical examinations, risk-group-
related measures at the workplace, and their contin-
uous evaluation. A reasonable risk management Design of Workplaces
focuses on the job-related attributive risk (Williams
1996) of dermatoses in a given company or industry The reduction of the amount of wet work is the most
and, i.e., not on the elimination of any substance that important measure in prevention of occupational skin
can rarely cause allergies. The chances of risk man- diseases, not only because wet work itself is irritant,
agement depend on the risks themselves, the organi- but because many relevant allergens contact the skin
zation of the work, the size of the business, and the during wet work. Furthermore, the concept of wet
quality of management and occupational medical care. work is easily understood, and it is often not difficult
In contrast with many other occupational diseases, to convince the management to reduce wet work by
occupational skin diseases are not hidden at first. showing its effects on the frequency of hand eczema
Because they are visible to the subject and his (Fig. 1).
colleagues, with signs on the hands/forearms and/or In Germany, a special technical guideline Wet Work
face, success or failure of preventive measures is also (Bundesministerium für Arbeit und Sozialordnung
obvious to all participants. The most important part of 1996) provides substantial preventive advice concern-
risk management is to te ach company management ing how to minimize wet work. It must be considered
and the workers about existing dermatological risks at that, in the education of engineers, the hand appears
the workplace and their consequences, and to convince primarily as a grasping tool, and education in
both groups that there are good ways of avoiding them. ergonomics does not often include dermatological
The context of open communication offers extraordi- risks. The elimination of hazardous substances is
nary chan ces for prevention by qualified occupational another strategy of prevention. In the field of occupa-
medical care. tional derma tos es, it is important to focus on potent
sens1tlzers, i.e., glycerylmonothioglycolate, epoxy
resins, natural rubber latex, etc., or irritants. The
Identification of Risk Groups exchange of substances will be successful if technical
alternatives are given. Elimination or exchange of all
The identification of risk groups for occupational skin substances with only moderate sensitizing potential,
diseases depends on skin exposures at the workplace, for example, would not be a practicable and accepted
the individual's specific and nonspecific skin suscep- strategy. The organization of work offers additional
tibility, and the quality and use of protective equip- options for prevention of occupational skin diseases.
ment and barrier creams. The daily duration of wet Preventive measurements, such as the wearing of
work, working with dry irritants (grinding dusts) or protective gloves, will be not accepted by the workers
the wearing of occlusive protective gloves for 2 hand if, in the pro gram of work, jobs with exposition to
more, the necessity and frequent cleaning of the hands allergens/irritants change frequently with jobs de-
(more than 20 times) or the unavoidable direct skin manding precision mechanical tasks or others where
contact to potent sensitizers represent the most gloves make the job more difficult, i.e., manual
relevant burden-associated risk marker. Individual measurement processes in metal working. Unavoidable

368 U. Funke
% Hand eczema(3-year incidence) Fig. 1. Hand eczema and wet work

at the workplace
30
Total N = 1 ,186 25.0
25 ~ .=~
20
15.9
r""""""'''':'
15
~2 1- ~
10
5
o '-- ~
o >0-1 >1-2 >2-3 >3-4 >4 hours/day

N = 550 N =395 N = 79 N = 54 N =40 N =68
RR: > 3h vs <= 3h wet work: 1.8 (95% CI: 1.3-2.6)
wet work should not be concentrated on a single Group 3 (moderate risk). Wool intolerance, itch when
person if it is possible to share it within the working sweating, xerosis, etc.
group, i.e., hair washing done by apprentices in
To minimize the requirement of exclusion from jobs
hairdresser's). Finally, workers must be provided with
with exposures to irritants, which remains relevant for
adequate protective gloves, skin-cleaning equipment,
group 1 (with very high risk for occupational skin
adjusted skin cleaners and barrier creams.
diseases), all other subjects were included in periodical
examinations. Intervals of examinations were then
Special Occupational Medical (are adjusted for risk group and degree of exposure.
by Periodical Medical Examinations Subjects of group 2 who experience intense exposure
to irritants, such as hairdressers, will then be examined
A central component of risk management of occupa- every 3 months within the first year; subjects without
tional skin diseases at the workplace is special period- predisposing factors and only a less intense exposure
ical medical examinations for all subjects at risk. These to irritants at the workplace may be seen again by a
examinations contain identification of high-risk doctor after 2 years (Fig. 2). Even the high-risk groups
groups, advice concerning the selection of jobs or the for occupational skin diseases do not use barrier
choice of career according to individual risk, early creams sufficiently (Funke et a1. 1995). This indicates
diagnosis of beginning occupational skin diseases, that the risk groups do not have sufficient knowledge
individual advice to minimize skin contact with about their higher risk of developing hand eczema and
irritants/a11ergens, and appropriate use of protection so they probably will not perform other measures of
equipment and barrier creams. skin protection, such as using protective gloves or
The German Berufsgenossenschaften (professional avoiding skin-contact with irritants in general when-
associations having the liability for industrial safety ever possible. In this situation, the concept of special
and insurance) has just revised and updated its periodical medical examinations is an effective tool for
instructions for special periodical medical examinations prevention, because it is based on a valid description
for prevention of occupational skin diseases (Hauptver- of risk groups and concentrates a11 preventive activities
band der gewerblichen Berufsgenossenschaften 1997). on the groups with the highest risks. Job selection
All subjects with relevant exposures to irritants at the according to individual risk of occupational skin
workplace (for example, 2 h or more wet work per day), diseases remains necessary only for a minority of
with unavoidable skin contact to potent sensitizers, or subjects, those with extreme susceptibility of the skin
in industries with high dermatological risks, ought to in relation to jobs with long-term unavoidable expo-
be included in special periodical medical examina- sures to irritants or those subjects with clinically
tions. In these new instructions, risk groups for relevant and actual job-relevant allergies.
occupational skin diseases are defined as follows:
Group 1 (very high risk). Atopic eczema (severe) + Risk-Group-Related Measures at the Workplace
hand eczema (long-lasting or recurring), hand
eczema (severe + chronical or recurring) Special periodical medical examinations will trigger
Group 2 (high risk). Atopic eczema (without hand and enforce proper behavior in avoiding exposure to
eczema), dyshidrosis and similar irritants, as weIl as proper use of protective equipment
Risk Management of Occupational Hazards at the Workplace 369
.•
Group 2 + inlense exposure 10 irritants
u::.ilL.-....Il!:.~,----l~~'L '----Il<lIWl!!!l.'
- _wlDliI..--_----llififfi~'-,---.J~IIWill-,· _ _ ~ • l1li
o 3 6 9 12 16 24
.•
Group 3 + inlense exposure 10 irrilanls
-_ ... - next medical

o 6 12 24 8xamination
after 5 years
No risk group but inlense exposure 10 irritants
•
(at the latest)
B .. --
o g
No risk 9 roup + less inlense exposure 10 irrilants

• ß _ _E
o 24
Monlhs
Fig. 2. Risk group and exposure·related intervals of periodieal sen 1992; Funke 1995). The frequency of hand eczema
medieal examinations (examples) (26.5%) was plausible too, because a lifelong history of
hand eczema was requested and the median of age was
and barrier creams. But, for the continuous stabiliza- 34 years in that sampie. Meanwhile, the reliability of
tion of risk-appropriate behavior, on the one hand, self-assessment of hand eczema-risk was able to be
individual awareness of risk is imperative, while on the proven in another collective of about 1500 workers,
other, communication and behavior patterns within and there was only a minimal variation in frequency of
the production teams are equally necessary (Funke parameters.
et aI. 1996). To enforce awareness of risk, the self- For the sustaining stabilization of risk-adjusted
assessment of hand eczema-risk is a simple but behavior patterns, communication within the produc-
effective tooI. During a skin-protection campaign in a tion teams has to be inftuenced. Therefore, team
motor and chassis parts manufacturing department in leaders can play a central role in the prevention of
the car industry, four questions for the self-assessment occupational skin diseases if they are instructed
of hand eczema-risk were answered by 2102 workers adequately. In the example cited here, the leaders of
(Table 1). In Table 2, relative risks and their 95% 237 production teams were used as disseminators for a
confidence intervals of ever occurring hand eczema for brochure containing a self-assessment of hand eczema
the three other parameters of the questionnaire were risk, information concerning the use of barrier creams
calculated. The results were nearly the same as in the at the workplace and at horne, and advice on skin
3-year incidence analysis in a cohort study (Funke protection and medical care relating to some risk
et aI. 1996) and the confidence intervals were, as a groups and exposure to irritants. Additionally, a small
result of the large sampie, rather small. competition was included. All team leaders were
Furthermore, the frequencies of ftexural eczema, hay trained about aims, objectives and the organization
fever and itch when sweating accorded quite weIl with of the campaign. Then, each team leader distributed
the results of other population-based studies (Kristen- the brochures in his production team, and the ques-
tions were discussed and answered during regular
team meetings. The return of the questionnaire portion
of the brochure was again organized by the team
Table 1. Self-assessment of hand eezema-risk. Questions an-
swered by 2102 workers in the ear industry leaders and a participation of 94% (2102/2236) was
reached. During the next step, the team leaders were
Hand or forearm eczema (history) 26.5% responsible for the feedback of the campaign results to
Flexural eezema (history) 07.9% the workers. Within the team meetings, the topics of
Hay fever, allergie asthma or allergie 14.2%
eonjunetivitis (history) subjects with susceptible skin, the hazards at the
Iteh when sweating 14.6% workplace, adequate behavior and skin care were
discussed. A central issue in this discussion was that
only 48.2% of the workers with and 30.9% without a
Table 2. Relative risks (and their 95% eonfidenee intervals) of history of hand eczema used the free barrier creams
ever oeeurring hand eezema for the three other parameters of the available twice per day and more (once per day and
questionnaire more: 72.0%/56.5%). Experience of hand eczema was
the most important factor for the frequent use of
Flexural eezema (history) 3.4 (3.0-3.8)
Hay fever, allergie asthma or allergie 1.9 (1.6-2.2) barrier creams, yet there were 23.2% of the workers
conjunetivitis (history) with a history of hand eczema who did not use barrier
Iteh when sweating 1.7 (1.4-2.0)
creams at the workplace or at horne.
370 U. Funke: Risk Management of Occupational Hazards at the Workplace
mI/month/worker additional barrier cream

60
50
40
30
20
10
skin protection campaign additional skin proteetion brochure
Fig. 3. Use of barrier creams and preventive measures management, the consumption of barrier creams is a
well-accepted tool in risk management. The preventive
effects may result from the barrier creams themselves,
It is essential to analyze the success of this proce-
although this use also indicates that workers are aware
dure and to give basic information for management- of risks and will avoid skin hazards by appropriate
evaluation processes. The decreasing frequency of behavior.
worker contact with the company's occupational
physician for hand eczema does not indicate the
success of such measurements. There are a large References
number of unrecorded cases of hand eczema in a plant
population and, with the intensifying awareness, these Bundesministerium für Arbeit und Sozialordnung (ed) (1996)
individuals go to see the doctor; therefore, it is better TRGS 531 Gefährdung der Haut durch Arbeiten im feuchten
Milieu (Feuchtarbeit). Bundesarbeitsblatt 9/96:65-67
to evaluate the amount of distributed barrier creams Funke U (1995) Risikogruppenbezogene Prävention von Ha-
regularly. After the skin-protection campaign and the utkrankheiten im Betrieb. Arbeitsmed Sozialmed Umweltmed
following team meetings in the autumn of 1994, the 30:257-264
Funke U, Diepgen TL, Fartasch M (1995) Identification of high-
consumption of barrier creams was elevated to a risk groups for irritant contact dermatitis. Curr Probl
higher level than before (Fig. 3). Dermatol 23:64-72
However, 1 year later, the use of barrier creams Funke U, Diepgen TL, Fartasch M (1996) Risk-group related
prevention of hand eczema at the workplace. Curr Probl
decreased again. By the distribution of an additional Dermatol 25:123-132
brochure (content: general information about skin Hauptverband der gewerblichen Berufsgenossenschaften (ed)
hazards and preventive measures) and a well-accepted (1998) Berufsgenossenschaftliche Grundsätze für ar-
beitsmedizinische Vorsorgeuntersuchungen, G24. In: Haute-
additional barrier cream, it then was possible to rkrankungen (mit Ausnahme von Hautkrebs). Gentner
stabilize the individual skin protection on a signifi- Verlag, Stuttgart, pp 317-325
cantly higher level than before the first skin care Kristensen 0 (1992) A prospective study of the development of
hand eczema in an automobile manufacturing industry.
campaign. The monitoring of the use of barrier creams Contact Dermatitis 26:341-345
was also differentiated by sub-departments and was Williams HC (1996) Relative and attributable risk and its
shown to the management regularly. If a commitment relevance for prevention of contact dermatitis. Curr Probl
Dermatol 25=l0-17
to prevention of hand eczema is established in the
CHAPTER 46
Diagnostic Patch Testing

J.E. Wahlberg
Purpose Test Systems
Patch testing is a well-established method of diagnos- One can distinguish two test systems - the original, in
ing contact allergy and allergie contact dermatitis, a which the allergens, patches and tapes are supplied
delayed type of hypersensitivity (type-IV reaction). separately (Finn chamber, Al-test, van der Bend square
Patients with a his tory and clinical picture of contact chambers and others) and the modern ready-to-use
dermatitis are exposed to the suspected allergens, system, in which only a covering material has to be
materials or products under controlled conditions to removed before the test is applied (True test system).
verify the diagnosis. Besides testing patients with hand, At present, the latter test system is available for 23
arm, face or leg eczema, testing of other types of standard allergens. Testing with screening series and
eczema (atopic, seborrhoie dermatitis, nummular ec- with materials brought by the patient is therefore
zema) is sometimes indicated, especially when the carried out according to the original system.
dermatologist suspects contact allergy to prescribed
topieal medieaments and their vehicles. The procedure
can also be used before recommending alternative Allergens
protective gloves, skin care products, corticosteroids,
etc. to a particular patient. If the patient does not react The standard patch test allergens sold by Chemotech-
to the alternatives tested, it is very unlikely that the nique Diagnostics (1998) and Hermal (1997) can,
same individual will react to the products in ordinary according to these suppliers' product catalogues, be
use. considered chemically defined and pure. The cata-
Patch testing is usually required in medicolegal cases logues contain lists of approximately 300 allergens in
of compensation. The first patch tests according to alphabetical order, allergens in the European standard
present principles were carried out in 1895. Much effort series, as weil as tables of mixes and lists of screening
has been put into standardization of allergens, vehi- series (Table 1). They also contain information on the
cles, concentrations, patch test materials, tapes and the occurrence of allergens, cross-reactivity patterns and
scoring of test reactions; the procedure is today additional practical advice on the patch-test proce-
considered accurate and reliable. Standardization has dure.
facilitated comparisons of contact allergy frequency in
selected industrial populations and between clinics and
geographical areas. Standard Se ries
Patch testing with standard allergens can be carried
out by any dermatologist after adequate training, while The present European standard series contains 23 items,
testing with materials and products brought by the but six of them are mixes; so in fact, at least 24 additional
patient requires special resources and facilities allergens are applied. The basic idea of using mixes
(Chaps. 183-185). Testing in vitro [compare radio- instead of single allergens is to save time and space, and
allergosorbent test (RAST)] has been carried out with the screening capacity is thereby greatly increased.
some selected and chemieally defined allergens, such
as nickel, but the methodology is not fully standard-
ized and cannot yet be recommended for routine use Screening Se ries
(McMillan and Burrows 1995).
To evaluate the significance of special exposures,
mainly occupational, a number of screening series
are available (Table 1). They are compiled from the

372 J.E. Wahlberg
Table 1. Commercially available screening series and number of allergens in each series
Chemotechnique (1998) Number Hermal (1997) Number
Bakery 19 Antimicrobials, preservatives, antioxidants 31

Corticosteroid 08 Cosmetics 13
Cosmetics 44 Dental materials 20
Dental 30 Hairdressing 06
Epoxy 08 Medicaments 34
Fragrance 24 Metal compounds 05
Hairdressing 26 Metal working/technieal oils 25
Isocyanate 06 Miscellaneous 23
Medieament 12 Perfumes, f1avors 14
(Meth) acrylate: adhesives, dental and other 14 Photoallergens 22
Nails (-artificial) 13 Photographic chemicals 10
Printing 24 Plants 07
Oil and cooling fluid 33 Plastic, glues 28
Photographie chemieals 16 Rubber chemieals 09
Plant 13 Sunscreen agents 09
Plastie and glues 25 Textile and leather dyes 14
Rubber additives 24 Vehicles, emulsifiers 07
Scandinavian photopatch 20
Shoe 22
Sunscreen 10
Textile colors and finish 21
Various allergens 53
experience gathered at departments of occupational that impurities or contaminants have caused the
dermatology and from the literature. Newly defined dermatitis, this can only be discovered through sam-
allergens are added regularly and these series can be pIes of the ingredient from the manufacturer. It is
considered to cover the present exposure situation in essential to use sampies from the actual batch to which
the occupational setting. However, the allergens are the patient has been exposed; but, when testing cutting
pure chemicals and, if the original offen ding agent was fluids, for example, unused products must be tested for
an impurity, adegradation product, etc., the cause will comparison.
be missed. A supplementary test with the patient's own
working material is therefore highly recommended.
Identification of New Contact Allergens
Tests With Substances or Products Brought When testing with products and materials brought by
by the Patient patients, previously unknown allergens are sometimes
discovered. A scheme for identification of new aller-
When patients bring suspected products or materials gens is presented in Table 2. If the test is positive in a
from their work environment, it is recommended that particular patient, one has to demonstrate in at least
material safety data sheets, lists of ingredients and 10-20 unexposed controls that the actual test prepa-
other such information be requested from the manu- ration is nonirritant; otherwise the observed reaction
facturer so that a general impression of the product, in the patient does not prove allergenicity.
ingredients, concentrations, intended use, etc. can be
formed. There are usually one or two ingredients that
are of interest as suspected allergens, while the rest are Table 2. Scheme for identification of new contact allergens
well-known substances of proven innocousness, for
Clinical
which detailed information is available. For substances
Positive patch-test reaction to a product
or products where skin contact is unintentional and Test with ingredients of the product
the dermatitis is a result of misuse or accident, detailed Serial dilution test to define a threshold of sensitivity
Control test for irritancy
information from the manufacturer is required before
Cross reactivity - equimolar concentrations
any tests can be initiated. A word of warning: totally ROAT (repeated open application test)
unknown substances or products should never be Experimental
Structural formula
applied to human skin.
Chemical analysis
Based on the list of ingredients, the next step is to Purity
look for suspected allergens. If these are available from Animal testing
Allergenic potential
suppliers of patch-test allergens, one can rely on the
Cross-reactivity pattern
choice of vehicle and concentration. If one suspects
Diagnostic Patch Testing 373
Vehicles the patches (day 2) and the second 2-5 days later. If
practical or geographical circumstances permit only
White petrolatum is the most widely used vehicle and one reading, an accepted compromise is at day 3 or
the majority of commercial test preparations are day 4, Le., 1-2 days after removal of the patches.
delivered in this vehicle. However, each allergen almost
certainly has its own optimal vehicle, and it is improb- Recording of Test Reactions
able that just one vehicle, e.g., petrolatum, could be
optimal for all allergens. Liquid vehicles, such as water Recording of test reactions is carried out according to
and solvents (acetone, ethanol, methyl ethyl ketone), an international agreement and based on presence of
are recommended since they facilitate penetration into erythema, edema, papules and vesicles.
the skin; but they also have some drawbacks. Solvents
may evaporate, which does not favor exact dosing, and Artifacts
most test solutions must be freshly prepared. Liquid
vehicles are used mainly when testing products and Sometimes strong necrotic reactions are seen and an
materials brought by the patients. In cases of unex- artifact is suspected. In medicolegal cases, it is
pected test reactions, a vehicle control is recommended. recommended that control patches (empty or contain-
ing water or petrolatum) should be applied simulta-
neously and in random order.
Practical Information
Effect of Medicaments and Irradiation
Concentrations
Testing patients on oral corticosteroids, antihistamines
In the suppliers' catalogues, the concentration of an or immunomodulators always creates uncertainty. It
allergen is normally given as a percentage, and has been shown that irradiation with UVB reduces the
sometimes also in molality. intensity of patch-test reactions in man and testing
after heavy sun exposure should therefore be avoided.
Tapes
Excited-Skin Syndrome
Modern acrylate-based adhesive tapes are recommend-
ed. The presence of a strong positive patch-test re action
will, according to some authors, infiuence the reactiv-
Test Sites ity at adjacent sites. Retesting of the items one at a time
is recommended in those cases, as weIl as in patients
Tests sites should be the upper back or sometimes the with current eczema and those in which multiple
upper arm. reactions have been observed.
Application of Test Preparations to Patches Compound Allergy
Commercial test preparations in petrolatum - kept in Compound allergy is used to describe the condition in
syringes - are applied directly into Finn chambers or patients who are patch-test positive to formulated
onto the filter paper discs of other patches. When products, but are negative to all the ingredients tested
testing liquids in Finn chambers, filter papers are individually. This phenomenon can sometimes be
recommended. explained by irritancy of the original formulation,
but, in some cases, it has been demonstrated that
Exposure Time reactivity was due to combination of the ingredients to
form re action products (Bashir and Maibach 1997).
An exposure time of 48 h (2 days) is recommended.
During this time period, the patients should avoid Cross Sensitivity
showers, wetting of test sites, heavy work, excessive
exercise and ultraviolet (UV) irradiation. In cross sensitivity, contact allergy caused by a primary
allergen is combined with allergy to other chemically
Reading When? related substances. In patients who have become
sensitized to one substance, an allergie contact der-
Wherever possible, it is strongly recommended that matitis can be provoked or worsened by several other
two readings are carried out, the first after removal of related substances.
374 J.E. Wahlberg: Diagnostic Patch Testing
For additional aspects of patch testing, such as false- Use Tests

positive and false-negative test reactions, patch-test
sensitization and other complications, standard text- Use tests and open tests are sometimes used as
books are recommended (Wahlberg 1995; Rietschel synonyms. The original (provocative) use (or usage)
and Fowler 1995). tests were intended to mimic the actual use situation
(repeated open applications) of a formulated product,
such as an oil, shampoo or a topical medicament. A
Relevance positive result supported the suspicion that the prod-
uct had caused the patient's dermatitis. Nowadays,
Evaluating the relevance of areaction is the most these tests are increasingly used to evaluate the clinical
difficult and intricate part of the patch-test procedure, significance of one or more ingredients of a formulated
and it is achallenge to both dermatologist and patient. product previously found reactive by ordinary patch
The dermatologist's skill, experience and curiosity are testing. The concentration of the particular ingredient
crucial factors. can be so low that one may wonder whether the
For standard allergens, detailed lists are available positive patch-test reaction can explain the patient's
that present the occurrence of each in the environ- dermatitis.
ment. The patient and the dermatologist should study Details of the performance of the repeated open-
the lists together in order to judge the relevance of a application test (ROAT) and its relevance are given in
positive patch-test reaction in relation to the expo- textbooks (Rietschel and Fowler 1995; Wahlberg 1995).
sure, site, course and relapse of the patient's current
dermatitis. A positive test re action can also be
explained by a previous, unrelated episode of contact Recommendations
dermatitis (past relevance). Sometimes, the relevance
of a positive reaction remains unexplained until the In occupational dermatology, patch testing is of great
patient brings a package or bottle with the allergen in importance in order to obtain an accurate diagnosis. If
question named on the label. In other cases, chemical the offending allergen(s) can be found at comprehen-
analyses demonstrate the presence of the allergen, or sive patch testing (standard allergens plus own mate-
the manufacturer finally, after many inquiries, admits rials) it is of outmost value for the possibility of
that the offending substance is present in the avoiding relapses (secondary prevention). The tests
product. should be carried out by dermatologists with interest
In paints, cutting fluids, glues, skin care products, in the field and with sufficient experience of patch
detergents, etc., it is common that new ingredients are testing, and using materials and products from the
added or replace previous ones, but the product keeps patient's work environment. This knowledge is crucial
its original trade name. Alternatively, well-known in medicolegal cases of compensation. As stated, the
allergens are included in new products, but with other evaluation of the relevance of a positive test reaction is
fie1ds of application than the original. To discover the the most intricate part of the patch-test procedure.
cause of the patient's dermatitis, the dermatologist
must sometimes be obstinately determined!
References
Open Tests
Bashir SI, Maibach HI (1997) Compound allergy: an overview.
Open testing usually means that a product, "as is" or Contact Dermatitis 36:179-183
Chemotechnique Diagnostics (1998) Patch test products, cata-
dissolved in water or some solvent, e.g., ethanol, logue, Malmö, Sweden
acetone or ether, is dropped onto the skin and allowed Hermal (1997) Patch test allergen. Trolab, Reinbeck, Germany
to spread freely. No occlusion is used. An open test is McMillan C, Burrows D (1995) In vitro testing in contact
hypersensitivity. In: Rycroft RJG, Menne T, Frosch PJ (eds)
recommended as the first step when testing poody Textbook of contact dermatitis, 2nd edn. Springer, Berlin
defined substances or products, such as those brought Heidelberg New York, pp 306-322
by a patient (paints, glues, oils, detergents, cleansing Rietschel RL, Fowler JF Jr (1995) Fisher's contact dermatitis, 4th
edn. Williams & Williams, Baltimore, pp 11-32
agents based on solvents, etc.). The test site should be Wahlberg JE (1995) Patch testing. In: Rycroft RJG, Menne T,
checked at regular intervals during the first 30-60 min Frosch PJ (eds) Textbook of contact dermatitis, 2nd edn.
after application, especially when the history indicates Springer, Berlin Heidelberg New York, pp 239-268
immediate reactions or contact urticaria. A second
reading should be done after 3-4 days.
CHAPTER 47
Patch Testing With a Patient's Own Materials Handled at Work

R. Jolanki, T. Estlander, K. Alanko, and L. Kanerva
Introduction patch-tested patients are also tested against their own

materials, which mostly include workplace materials,
Almost 20 million individual chemical substances have such as industrial chemicals, cleansing agents, food-
been identified according to the Registry of the stuffs, fodder, plant materials, protective gloves, and
Chemical Abstract Service (CAS) numbers and, annu- hand cleansers and creams. Infrequently, also non-
ally, 1 million substances enter the registry. Most of the occupationally exposing materials, such as cosmetics
registered substances are not significant in practice. and chemicals used at horne, are patch tested. On
The number, type and quantities of chemicals used average, each patient is tested using eight different own
vary, depending on the national economy, level of materials; some materials are tested using several
industrialization, and the extent of agriculture in the different vehicles and test concentrations. In many
country. The European Inventory of Existing Com- cases, patch testing with the patient's own materials
mercial Chemical Substances (EINECS), established in has been the main clue in revealing the causative agent
the beginning of the 1980s, contains about 100,000 for allergic contact dermatitis, and many such cases
chemicals supplied by their importers or manufactur- have also been reported (Table 1).
ers. Workers are constantly exposed to new chemicals Patch testing the patients' own materials is impor-
as, every year, thousands of new molecules are tant, but it entails many problems. Most materials are
synthesized and hundreds of chemicals and formula- not suitable for testing as such, but have to be properly
tions come on the market, older ones being replaced by diluted, using an appropriate vehicle. The evaluation of
better new alternatives. Also the variety of chemical a test re action may be difficult. To avoid false-positive
substances hazardous to the skin is enormous; for or false-negative reactions, it may be necessary to test
example, De Groot (1994) listed about 3700 contact control persons with the adopted test substance.
allergens. The number of potentially skin-sensitizing Separate testing of the ingredients, and even chemical
industrial chemicals (pure chemicals or chemical analyses, may be needed. Active sensitization is rare,
mixtures) is much greater. In Finland, data on around but must be taken into consideration when the
90,000 chemical preparations are listed in the product patients' own materials are tested.
register, which includes data on chemicals hazardous
to health or the environment (Forss 1998). Of the
chemicals on which complete information is available, Reasons for Testing a Patient's Own Materials
around 13% are classified as sensitizing by skin contact
- most often due to their content of epoxy resins, Annually, several hundreds of chemicals and formu-
formaldehyde or colophony (unpublished data). lations co me on the market. The new human contact
Patch testing with commercially available test kits allergens may be identified by predictive testing, and
often leads to detection of the majority of the relevant particularly by performing patch tests to patients with
allergens (Fisher and Maibach 1986; Menne et al. 1992). contact dermatitis from the new products and their
However, an analysis of patients tested using com- ingredients. Commercially available test substances
mercial patch-test kits and patient-supplied products can never include all possible allergens. Furthermore,
showed that 44% of the relevant allergens could only all commercial test substances corresponding to the
be found by testing the patient's own substances ingredients of the product in question may not be
(Daecke et al. 1994). available in the clinic.
At the Finnish Institute of Occupational Health The exact composition of products with which the
(FlOH), all patients suspected of having occupational patient has come into contact at the workplace is not
contact dermatitis are tested using a standard series. If known, or is not known before patch testing. In
the clinical and anamnestic data indicate, tests will also general, all ingredients occurring in the industrial
be performed using other test series. About 70% of the chemicals are not listed in material safety data sheets

376 R. Jolanki et al.
Table 1. Examples of cases diagnosed at the Finnish Institute of Occupational Health in which patch testing with the patient's own
industrial chemical has been the main clue in revealing the causative agent for allergie contact dermatitis
Causative chemical Reference
Dibutylthiourea in a paint remover Kanerva et al. 1984

2,3-Epoxypropyl trimethyl ammonium chloride in the manufacture of cationic starch Estlander et al. 1986
1,4-Butanediol diglycidyl ether in an epoxy glue . Jolanki et al. 1987
Cycloaliphatic epoxy res ins in the manufacture of electrical insulators Jolanki et al. 1989
Phenyl-alpha-naphthylamine in industrial greases Kalimo et al. 1989
Reactive dyes in textile industry Estlander et al. 1990
2,4,6-tris-(Dimethylaminomethyl)phenol in epoxy paints Kanerva et al. 1991a
Industrial enzymes Tarvainen et al. 1991
Diethyleneglycol maleate in polyester cements Tarvainen et al. 1993
Triglycidyl isocyanurate in silk-screen printing coatings Jolanki et al. 1994
Polyfunctional aziridine hardener Kanerva et al. 1995
N-N' -Tetraglycidyl-4,4' -methylene dianiline and ortho-diglycidyl phthalate in prepreg-laminates Tarvainen et al. 1995
Diethyleneglycol diglycidyl ether used as epoxy reactive diluent Jolanki et al. 1996
Cobalt-2-ethylhexoate in offset printing inks Kanerva et al. 1996b
5-Chloro-1-methyl-4-nitroimidazole in pharmaceutical industry Jolanki et al. 1997
Dipropylene glycol diacrylate from ultraviolet-cured lacquer Estlander et al. 1998
(MSDS). Even major allergens may not be mentioned made of a product may include some other allergenic
(Kanerva et al. 1997). Hence, the individual constitu- ingredients, such as preservatives and fragrances, in
ents are not known and cannot be patch tested. too low concentrations or rarely in an inadequate
Sensitization to a product is not always detected vehicle to induce an allergic test reaction.
when the ingredients are tested separately. The contact If a patient sensitized to a specific industrial chemical
allergen may be a contaminant or an intermediate begins to handle an alternative chemical, it may be
product. Also some substances, such as emulsifiers and reasonable to patch test it predictively, especially if the
keratolytic agents, can enhance penetration and thus exact composition of the chemical is not known.
influence the bioavailability of the allergens. Finally, a
new allergen might be formed during storage (Dooms-
Goossens 1995). Patient-Supplied Materials
Patch testing with the patient's workplace materials
is a screening test similar to testing with, for example, Specimens
rubber mixes. In subsequent testing, it is reasonable to
confirm the previous reactions by repeating the The selection of patient-supplied materials for patch
investigation and by testing individual constituents of testing should be based on careful exposure anamne-
strongly suspected materials. Individual chemicals, sis. The clinic must have a list of the chemicals handled
that according to the anamnesis are highly suspected at the workplace and sampIes of each chemical
as causes of allergic contact dermatitis, must so me- corresponding to the situation during the skin expo-
times be tested even in higher test concentrations than sure believed to be the cause of the patient's skin
the published concentrations (Kanerva et al. 1999). problems. Hand creams (moisturizers and barriers)
A positive test result to a patient's own material and and cleansers, and protective gloves should also be
a simultaneous negative result to the corresponding included in the patient's own materials. Special atten-
commercial test substance may reveal that there is tion should be paid to materials that are strongly
something wrong with the commercial test substance suspected to cause allergic contact dermatitis. Some-
(Leisvaara et al. 1998). Testing with the patient's own times a visit to the patient's workplace is necessary,
materials often helps to confirm the causative product, because the patient and health care personnel at the
even in cases where the potential individual allergens workplace are not always able to evaluate all the
have been tested separately. An allergic reaction possible causative agents. If industrial chemicals are
produced by an own material mayaIso help to used diluted, such as metal-working fluids and emul-
convince the patient and the insurance companies of sions, undiluted products must also be supplied to the
the causative substances of allergic contact dermatitis. clinic. If the patient handles chemical mixtures or two-
Unfortunately, a positive test result to separate ingre- component products in mixture form, the individual
dients and a negative one to the whole product may chemicals or components should be packed separately.
also be possible. The test substances made of individ- Even solid materials, such as parts of plants should
ual chemicals often have the allergen in an optimal also be packed separately in plastic bags to avoid their
concentration and vehicle, whereas the test substance contaminating each other.
Patch Testing With a Patient's Own Materials Handled at Work 377
Liquid chemicals should be packed separately in the product is not labeled properly. Sometimes even a
tightly closed containers made of some inert material, chemical analysis is necessary.
e.g., polypropylene or glass, that does not interfere
with the chemical product or influence its properties.
Evaporation or hardening of the chemical is not Determination of Patch-Test Substances
allowed during storage, because the chemical may be
needed later for repeated or control tests, or for Some materials such as cosmetic preparations and
chemical analyses. The wrapping of the patient's own topical medicaments can easily be tested reliably in the
industrial chemicals should be provided with a label form in which they are normally used by the patient,
including at least the trade name of the chemical. It is i.e., as iso Patch testing with industrial chemicals is
important to confirm that the container really contains much more complicated and entails many problems.
the product as labeled. Thus, the results must be interpreted with great care.
Most industrial chemicals are not suitable for testing as
Information Regarding the Products such, but have to be diluted prior to patch testing. Too
low a test concentration may lead to a false-negative or
In the clinic performing patch tests with patient- too-weak doubtful reactions. Too high a test concen-
supplied products, information regarding the products tration may lead to a false test reaction that is difficult
must be available to those who conduct the tests. When to interpret, such as a false-positive or irritant reaction,
patients bring materials for patch testing from their active sensitization, a chemical burn or an extremely
work environment, it is recommended that the MSDS, strong bullous allergic reaction, which may be greatly
other product information, lists of ingredients, etc., are inconvenient or even harmful to the patient. Testing
referred to the clinics with the chemical specimens so should, if possible, be performed only at specialized
that a general impression of the product, ingredients, c1inics, where substances brought in by the patients are
concentrations, intended use, etc., can be formed. The routinely used for patch testing, and clinicians who are
above instructions must be supplemented with a familiar with the patient's specific problems should
written request for the chemical specimens from the perform the readings personally (Beck 1995). Each
patient's workplace. For substances or products where antigen has to be in the correct concentration and be
skin contact is unintentional and the dermatitis is a matched to the vehicle.
result of misuse or accident, detailed information from
the manufacturer is required before any tests are Concentration
initiated. Chemical handbooks that give general as well
as toxicological information for various compounds The proper test concentration and the best vehic1e for
will be a valuable source in the evaluation preceding all the chemical substances should be estimated
the preparation of patch test substances (Gosselin et al. carefully on the basis of the information on toxicity
1984; Budavari et al. 1996; Hawley and Lewis 1997). The and the composition of the material available. In
use of on-line databases, such as MEDLINE, and, addition, one should check which of the individual
increasingly, the use of other internet services will give chemical components are available from the suppliers
valuable information for patch testing, e.g., the exact as patch-test substances, because one may rely on their
chemical names, previous case reports and test con- choke of vehicle and concentration and these sub-
centrations used (Niklasson 1995). stances, if available, should be included in the test
A review of the MSDS of the industrial chemicals is battery of the patient. It is helpful to use selected test
important because this often reveals enough informa- series related to a specific type of product aimed to be
tion for patch testing with the chemical. If the MSDS or tested, e.g., metal-working series for metal-working
product dec1aration is not available, the name and fluids. Several reports provide useful information on
address of the manufacturer or the supplier is neces- the concentrations and vehic1es to be used (Fregert
sary for further contacts. The MSDS often does not give 1981; De Groot 1994; Guin 1995; Niklasson 1995;
detailed information regarding the exact chemicals Rietschel and Fowler 1995). The test concentration
present, and most chemicals present in a concentration for the chemical substance should not exceed the
under 1%, such as preservatives, are not required to be previously recommended test concentration for any of
listed (Adams 1995). More detailed information on the the components. This may, however, lead to the risk of
composition may therefore be needed from the man- the over dilution of potential allergens, especially when
ufacturer or the importer, especially for the evaluation the responsible ingredient is present in a low concen-
of the positive patch-test reaction produced by the tration or appears as a contaminant in the product.
chemical. It is also important to determine the degree Sometimes the reported concentrations or a suppli-
of acidity or alkalinity in a product in order to avoid er's test concentrations are not appropriate. We have
false-positive, i.e., irritant, test reactions, especially if noted that the recommended test concentration of
0.5% for isophoronediamine (unpublished data) and Vehicles

1% for eugenol (Kanerva et al. 1998) in some cases may
be too low. The selection of the most appropriate vehicle depends
To avoid complications, patch testing should never on the solubility and other characteristics of the
be performed with materials whose composition or product. White or yellow petrolatum or distilled water
inftuence on the skin are not known, or they are known are the most recommended vehicles, but also acetone
to be extremely hazardous, such as strong acids or and ethanol of pharmaceutical quality, even olive oil or
alkalis, or highly toxic chemicals. If the exact nature of other vegetable oils and methyl ethyl ketone (MEK)
the substance is not known, but the group to which it can be used for chemie als that are not water soluble.
belongs or the purpose for which it is used can be For a water-soluble product, the appropriate vehicle
determined, one may proceed with the testing as is determined on the basis of pH. Water or other
recommended for that particular group of chemicals vehicles for neutral products, acid buffer for alkaline
(Table 2). products (pH above 9), and alkaline buffer for acid
Acrylics are difficult compounds to use in patch products (pH below 4) can be used. One should be
testing. Too high a test concentration may sensitize the especially careful with products that may contain
patient, whereas too low a concentration may cause hydroftuoric acid, which can cause chemical bums and
false-negative patch-test results (Kanerva et al. 1996a). should not be tested at all (see Buffering).
Therefore, during the first patch-test session, patch Non-irritant solid materials or powders may be
testing should be performed with the commercially tested with a drop of water in a test chamber. Organic
available (meth)acrylates, and the patient's own acrylics solvent vehicles, e.g., acetone, ethanol or methyl ethyl
at a low concentration, i.e., 1-2% for methacrylate- ketone, may be used instead of water, depending on
based products such as dental acrylics and 0.1% for the material or powder to be tested. The use of water or
acrylate-based products used in ultraviolet-cured inks, organic solvent improves the extraction of chemieals
lacquers and adhesives (Table 2). If these are negative and their penetration into the skin. Moisturizing also
and further patch testing is needed, the final patch-test helps the application of a test chamber containing
concentration of individual (meth)acrylate ingredients powder or solid material. Water is recommended for
in the patient-supplied acrylics should match those in textiles and paper, but organic solvents for plastic or
the (meth)acrylate series (Kanerva et al. 1996a). rubber materials (Niklasson 1995).
Other highly reactive chemie als such as those used
as intermediates in chemical syntheses should also be
patch tested (including control tests) with extreme Buffering
precaution due to the risk of active sensitization
(Foussereau et al. 1972; Dooms-Goossens et al. 1986; The method of using buffers greatly widens the range
Sonnex and Rycroft 1986; Rothe 1988; Sasseville 1996). of the possible products that can be used for testing. It
Patch-test preparations should match published con- also allows detection of allergy to ingredients (per-
centrations and should not exceed 0.1% in concentra- fumes and preservatives) that otherwise would be
tion of the reactive component. missed if the products were diluted to the extent that
When asolid non-irritant product is suspected the pH is within an acceptable range. Using buffer
(rubber, wood, paper, etc.), these can usually be solutions for the dilution of acid or alkaline chemicals,
supplied as is with a drop of vehicle in the test the test concentration may be increased 10-fold or even
chamber or using extracts. In particular, many plants a 1000-fold, and the problem of too low a test
are highly irritant (Hausen 1988; Lamminpää et al. concentration can thus be overcome (Bruze 1984). At
1996), and are preferred to be tested in diluted form the FlOH, buffering is used, for example, in testing
after an ultrasonic bath extraction (see Extraction). washing agents, preservatives, ethanol amines, even
In order to find the most suitable test concentration, phenol formaldehyde resins.
it is a good idea to use a few different concentrations. The product should be diluted gradually with buffer
Testing using a dilution series helps in the reading and (acid buffer for alkaline chemicals and alkaline buffer
interpretation of the test results; this is especially for acidic chemicals), monitoring with pH paper or
valuable when one has no previous experience of the other pH measurement device until a pH range of 4-9
products to be tested. It is suitable to use a dilution is reached. At pH 4-9, very few irritant reactions are
series, in which the two consecutive test concentrations caused due to acidity or alkalinity (Bruze 1984). The
have a ratio of the square root of 10 (about 3.2), e.g., 10 buffering does not reduce the irritancy of products by
- 3.2 - 1%, or a ratio of 2, e.g., 10 - 5 - 2.5% (Fregert mechanisms other than changes in pH. Dilution with
1985). A similar number of test dilutions in the first buffer solution alone is not sufficient to reduce the
series with a ratio of 3.2 covers a much wider irritancy of the product by mechanisms other than
concentration range than dilutions using a ratio of 2. changes in pH. For example, products containing
Table 2. Recommended vehicles and concentrations in dilution series for patch testing industrial chemicals
Chemical Patch test concentration and vehicle
Acrylics
Epoxy diacrylates 0.5% pet.
Epoxy dimethacrylates, e.g., dental composite materials 1-2% pet.
Instant glues (cyanoacrylate-based) 1-10% pet. or allow to dry
Methacrylates (prosthesis materials, floor coatings) 2% pet.
Ultraviolet-curable inks and lacquers (acrylate-based) 0.01-0.1% pet.
Adhesive tapes As such
Alkyd resins 1-10% pet.
Brake fluids 1-5% pet.
Detergents and soaps (without solvents)
pH <2 1-10% alkaline buffer (make sure that the pH is 4-9)
pH 2-4 1-10% pet. or aq.
pH 4-9 10-100% pet. or aq.
pH 9-10 1-10% pet. or aq.
pH >10 1-10% acid buffer (make sure that the pH is 4-9)
Epoxy products
Adduct hardeners 1-10% pet.
DGEBA epoxy res ins, liquid 1-2% pet.
DGEBA epoxy resins, solid 10% pet.
Non-DGEBA epoxy resins 0.5% pet.
Paints, lacquers, glues etc., solvent-based 1-10% pet. or ac.
Paints, lacquers, glues etc., without solvent 1-2% pet. or ac.
Polyamine hardeners 0.1-1% pet.
Powder paints 5-10 pet or ac.
Formaldehyde res in products
Resins, glues, lacquers etc. 1-10% pet. or acid buffer (make sure that the pH is 4-9)
Glues (excluding epoxy, formaldehyde resin and acrylic)
Dispersion glues 10-100% pet. or aq.
Solvent-based contact glues 1-10% pet. or allow to dry
Industrial greases 10-100% pet.
Metal-worldng oils and fluids
Fluid concentrates 1-10% pet.
Fluid emulsions As such
Cutting oils 10-100% pet.
Mineraloils
High-viscosity 10-100% pet.
Low-viscosity 1-10% pet.
Organic solvents
Aliphatic, cycloaliphatic 1-10% pet.
Aromatic 1-5% pet.
Chlorinated 0.1-1% pet.
Esters 1-10% pet.
Paints (excluding epoxy, polyester and acrylic)
Di-isocyanate hardeners of polyurethane paints or lacquers 2-5% pet.
One component, water-based 10-100% pet. or aq.
One component, solvent- or oil-based, e.g., alkyds 1-10% pet.
Powder paints (plastisols) 10-100% pet.
Photographic chemicals
Developers 0.1-1 % alkaline or acid buffer (make sure that the pH is 4-9)
Fixations fluids 0.1-1 % aq.
Polyester product
Cobalt accelerators 0.1-1 % pet.
Hardeners of two-component cements 0.1-1% pet.
Lamination res ins 1-10% pet.
Powder paints 1-10% pet.
Resins of two-component cements 1-10% pet.
Printing inks (excluding ultraviolet-curable) 1-10% pet.
Reactive intermediates in chemical syntheses 0.01-0.1 % pet.
Textile dyes 0.1-1 % pet.
Water additives used in offset printing 1-10% aq.
pet. petrolatum; aq. aqua; ac. acetone; DGEBA diglycidyl ether of bisphenol A
Table 3. Composition of
acid buffer solution, Compound Concentration Percentage
pH 4.7, and alkaline of total volume (0/0)
buffer solution, pH 9.9
(Bruze 1984) Acid buffer solution, pH 4.7
Sodium acetate 0.1 N (8.2 g CH 3COONa/L aqua) 50
Acetic acid 0.1 N (6.0 g CH 3COOH/L aqua) 50
Alkaline buffer solution, pH 9.9
Sodium carbonate, anhydrous 0.1 M (10.6 g Na2C03/L aqua) 50
Sodium bicarbonate 0.1 M (8.4 g NaHC0 3/L aqua) 50
hydrofiuoric acid (stain removers in the graphie The test substance should be mixed thoroughly. If
industry, cleaners for metals, etc.) should not be used the preparation is used to patch test other patients
for testing, even if the pH is adjusted to above 4, as the later, it should be protected from heat and light, and
toxicity of hydrofiuoric acid is not media ted only preferably be refrigerated. The vehicle should not be
through its acidity. Also, washing agents used for allowed to evaporate.
cleaning metal surfaces or the hands in dirty work may
contain organic solvents. These products may cause Extraction
severe irritant reactions if diluted only slightly with
acidic buffer solution. The composition of acid and Solid materials can be tested as such, placing scrapings
alkaline buffers is detailed in Table 3. or cut pieces in the test chamber. Nevertheless, tests
with such materials often turn out to be falsely
Recommended Concentrations and Vehicles tor Patch negative, because the concentration of the sensitizer
Testing the Patients' Own Industrial Chemicals in the product is too low or the sensitizer is not
released. To overcome this problem, the sensitizer can
Table 2 gives some guidelines for recommended test be extracted with water or organic solvents (Table 4)
concentrations using dilution series and vehicles for (Niklasson 1995).
common industrial chemieals. The table is based on The extraction of various types of materials, such as
recommendations found in textbooks on contact paper, textile, plastic products, plant materials and
dermatitis (Fregert 1981; De Groot 1994; Niklasson rubber products, can be done by placing the material
1995; Rietschel and Fowler 1995) supplemented with in water or organic solvent, and heating it to 40-50 oe.
our own experience. It is not possible to give precise The use of an ultrasonic bath makes the extraction
recommendations for each patient-supplied material. process more efficient (Bruze et al. 1992).
Preparation of the Patch-Test Substances

Sem i-Open Tests in Testing Patient-Supplied
Because instruments and tools, etc., contaminated by Materials
the patients' industrial chemicals are difficult to clean
perfectly, it is handy to use disposable containers, Dooms-Goossens (1995) has suggested the use of a
syringes, stirrers or sticks to prepare test substances or semi-open test for testing patient-supplied products.
dose them onto test chambers. Polypropylene is Minute amounts (about 1-2 )1L) of the liquid product
chemically inert and contains very few additional are applied with a cotton swab on an area (1 cm 2 ) of
chemie als besides the polymer. If a liquid raw material the skin, allowed to dry completely, then covered with
dissolves plastic materials, glass containers should be acrylate tape. The tape is removed after 2 days and
used. Wooden stirrers and sticks mayaIso be used. If read as ordinary patch tests. Dooms-Goossens has
the product is solid (in crystal or powder form), it can rarely seen very strong reactions using this technique.
be pulverized using a mortar.
The dilutions can be made using disposable syringes
Table 4. Materials suitable for extraction and recommended
for volumetrie determination and electronic scales for (Niklasson 1995)
the determination of weights. At the Section of
Dermatology of FlOH, we use ascale with aprecision Material Solvent
of 0.001 g. Petrolatum is mostly used as the diluting
Paper Ethanol
vehicle. If ascale is used, the test concentration is Plants and wood dusts Acetone, ether, ethanol, or water
given as a percentage by weight (weight/weight) but, if Plastics, e.g., gloves Acetone
a pipette is used, the concentration is given as a Rubber, e.g., gloves Acetone, or water
Textiles Ethanol
percentage by volume (volume/volume).
Even an "unknown" product with solvents or emulsi- patient. In general, the actual allergen produces a test
fiers, such as paints, resins, varnishes, glues, waxes, re action at a concentration as low as 0.01%. Accord-
cooling oils, and thinners, can be tested. Products with ingly, it is possible to consider whether the allergenic
a pH below 3 or above 10 should not be tested as such. component is the main product or an additive. When
Although the semi-open test is an easy way to test highly sensitizing chemicals (such as acrylates, inter-
industrial chemicals, it is not yet commonly accepted. mediates in pharmaceutical syntheses and epoxy
All reactions must be verified by means of normal compounds) are control tested the tenfold concentra-
patch testing. One must keep in mind that even a single tion may be too high, and the proper test concentra-
exposure to a strong allergen may sensitize (Kanerva tion for control tests is usually the same one that gave a
et al. 1991b, 1994; Kanerva and Lauerma 1998). clear (2+) re action in the patient (Jolanki 1991),
otherwise there may be risk of active sensitization.
Even when these precautions are taken, weak irritant
Evaluation of Test Reactions reactions are still possible. They may be preferable to
false-negative reactions that usually are not referred
What to do when a patient develops a test re action to for further examination, and the allergen remains
his/her own industrial material. An industrial material unrecognized.
is usually a mixture of two or more chemicals. To be
able to treat the patient's dermatitis and to prevent Problems
further cases of sensitization, it is important to find the
chemical which was responsible for the positive There are so me patient-supplied chemicals that are
reaction. It is often possible to discover the allergenic very difficult to test because of the low level of allergen
ingredient by comparing concomitant positive reac- available in the chemical. The allergen release from
tions to individual test substances in the standard or in some solid materials is quite low. Furthermore, chem-
additional test series. If this is not possible, even icals having the potential allergens in high concentra-
weakly positive (?+) reactions caused by a patient's tions have to be tested in the proper vehicle and at the
own substances should be confirmed by repeating the right concentration to avoid active sensitization and
test and performing control patch tests (usually to 20 too strong allergic reactions.
persons). Repeated tests should be performed using The precise composition of chemical preparations is
the same test concentration supplemented with a often unknown (Dooms-Goossens 1995). If there is a
dilution series; in case of a weak reaction, test clear his tory of a product inducing a contact allergy
substances of higher and lower concentrations than reaction, it may be necessary to ask the manufacturer
that producing the weak re action should be used. The for the ingredients and test them individually at
determination of the particular component to which appropriate concentrations in order to detect the
the patient has been sensitized is sometimes crucial in allergy.
cases of occupational dermatoses. The sensitizer can be
identified by testing separately the ingredients of the fa/se-Negative Resu/t
product. Manufacturers or importers are usually
willing to supply individual ingredients as such or as The concentration of the allergen in the product may
ready-made test substances for additional patch test- be too low to cause a positive response. Moreover, the
ing. The pure components can also be purchased from allergen may not be liberated in sufficient quantity, or
chemical suppliers. Sometimes the allergen is an the occlusion may be insufficient, so that other testing
impurity or a product of a chemical reaction. methods might be required. In certain cases, repeated
open-application tests (ROAT) (Hannuksela and Salo
Control Tests 1986) can be useful. With the semi-open test method
(Dooms-Goossens 1995), it is possible to use undiluted
To avoid both false-positive and false-negative reac- chemicals, but the penetration may be too low to
tions, it may be necessary to test a suitable number of induce test reactions. If a product is under serious
control persons with the adopted test substance. suspicion, the different ingredients should be tested
The irritancy of a chemical can be shown by testing individually.
at least 20 non-sensitized individuals with a higher test
concentration than that to which the patient reacted. fa/se-Positive Resu/t
Using the laser Doppler technique, the number of
controls can possibly be reduced (Wahlberg 1998). One of the problems in the testing of non-commer-
Fregert (1985) has suggested that the test concentration cially available antigens, such as those made from the
for the control test should be ten times high er than the patient-supplied materials, is the possibility of an
lowest concentration that gave areaction to the irritant reaction causing a false-positive test. The
irritant reaction can sometimes be recognized as such, for all ingredients, especially if individual ingredients
but this requires considerable experience. Serial dilu- could not be tested separately.
tions are helpful in distinguishing between irritant and
allergie reactions. Negative control tests on at least 20
normal individuals would make it unlikely that the test Health Hazards in the Testing Unit
substance is a primary irritant (Dooms-Goossens 1995;
Niklasson 1995). Personnel of the testing unit may have a risk of skin
sensitization against the patient's own industrial
Adive Sensitizotion chemieals. When making the test preparations, pro-
tective gloves are preferred, and disposable plastic
Active sensitization is rare, but is more common when (polyvinylchloride or polyethylene) or synthetic rub-
reactive chemieals such as intermediates in chemical ber (nitrile) are the most suitable materials. The use of
syntheses (Foussereau et al. 1972; Dooms-Goossens disposable containers and stirrers, etc. also diminishes
et al. 1986; Sonnex and Rycroft 1986; Rothe 1988; exposure to the potential allergenie chemieals. A place
Sasseville et al. 1996) or (meth)acrylates (Kanerva for washing the hands and rinsing the eyes should be
et al. 1992) are tested. The sensitization risk correlates very near the place where the handling of industrial
with the concentration of the test substance chemie als takes place, and adequate local exhaust
(Friedmann 1991); therefore, the concentration of the ventilation should be available.
patch-test substance should be as low as possible, but
high enough to confirm contact allergy. This must be
kept in mind especially when performing patch tests Conclusion
with patients' own substances. Reactive chemieals and
acrylics should be patch tested with extreme precau- The importance of making a correct diagnosis, espe-
tion. Though the patient may handle the chemieals as cially when patients with a suspected occupational
such, tests with the chemie al are not recommended dermatitis are being investigated, is obvious. The
when using undiluted chemie als (Kanerva et al. 1991b). outcome has such a great impact on the patient's life
Active sensitization should also be taken into consid- that complicated cases with, for example, extensive
eration when control tests are performed. Patch-test exposure to several chemieals should be referred to
preparations should match published concentrations clinics specialized in occupational dermatology, if
and should not exceed 0.1% in concentration in the possible (Niklasson 1995).
case of testing very reactive components, such as Supplementing testing to the standard tray, with
intermediates of some chemie al syntheses (Sonnex and selected series, and the patient's own products - plus
Rycroft 1986; Niklasson 1995). the suspicious ingredients in those products - gives the
best chance of revealing the cause or causes of allergie
Compound AI/ergy contact dermatitis. Quality-controlled skin tests with
the materials handled by the patient may be the only
Compound allergy has been reviewed by Bashir et al. way to detect contact allergy, especially to those
elsewhere in this book (see Chap. 42). chemical ingredients that are not included in about
500 commercially available patch-test substances. The
Need for Chemical Analyses importance of identifying all contact allergens cannot
be overemphasized.
Contact sensitizers from a patient's own materials,
such as formaldehyde, isothiazolinones, nickel, chro-
mium, cobalt, colophony (in the form of resin acids), References
epoxy resin oligomers, reactive diluents, acrylates,
Adams RM (1995) Additional sources of information that can be
methacrylates, polyamines and di-isocyanates, can be caused in patch testing. Am J Contact Dermatitis 6:40-41
analyzed. In fact, any product can be analyzed, but it is Beck MH (1995) The patient with negative patch tests - what now?
not a routine task for laboratories and may be very In: Guin JD (ed) Practical contact dermatitis. A handbook for
the practitioner. McGraw-Hill, USA, pp 659-672
expensive. There are two main reasons for chemical Bruze M (1984) Use ofbuffer solutions for patch testing. Contact
analyses. First, on patch testing, the patient is found to Dermatitis 10:267-269
be allergie to a specific chemie al, and the causative Bruze M, Trulson L, Bendsöe N (1992) Patch testing with
ultrasonic bath extracts. Am J Contact Dermatitis 3=133-137
product(s) are analyzed for the chemieal. Second, the Budavari S, O'Neil MJ, Smith A, E HeckeIman PE, Kinneary JF
patient's own material has caused an allergie test (1996) The Merck index: an encyclopedia of chemicals, drugs
re action, but MSDS or other information from the and biologicals, 12th edn. Merck & Co. New Jersey
Daecke CM, Schaller 1, Goos M (1994) Der Stellenwert patient-
manufacturer did not reveal the causative chemie al. In eneigener Testsubstanzen bei der Epikutantestung. Hautarzt
this case, it may be reasonable to analyze the material 45:292-298
Oe Groot AC (1994) Pateh testing, 2nd edn. Elsevier, Amsterdam. struetural observations of epieutaneous testing with
Dooms-Goossens A (1995) Pateh testing without a kit. In: Guin JD dibutylthiourea. Contaet Dermatitis 10:158-162
(ed) Praetieal contaet dermatitis. A handbook for the Kanerva L, Jolanki R, Estlander T (1991a) Allergie eontaet
praetitioner. MeGraw-Hill, USA, pp 63-74 dermatitis from epoxy resin hardeners. Am J Contaet
Dooms-Goossens A, de Boulle K, Snauwaert 1, Degreef H (1986). Dermatitis 2:89-97
Sensitization to 3,4,6-triehloropyridazine. Contaet Dermatitis Kanerva L, Turjanmaa K, Jolanki R, Estlander T (1991b)
14:64-65 Oeeupational allergie eontaet dermatitis from iatrogenic
Estlander T, Jolanki R, Kanerva L (1986) Oeeupational dermatitis sensitization be a new aerylate dentin adhesive. Eur J
to 2,3-epoxypropyl trimethyl ammonium chloride. Contaet Dermatol 1:25-28
Dermatitis 14:49-52 Kanerva L, Estlander T, Jolanki R (1992) Aetive sensitization
Estlander T, Kanerva L, Jolanki R (1990) Oeeupational allergie eaused by 2-hydroxyethyl methaerylate, 2-hydroxypropyl
dermatoses from textile, leather, and fur dyes. Am J Contaet methaerylate, ethyleneglyeol dimethaerylate and N,N-di-
Dermatitis 1:13-20 methylaminoethyl methaerylate. J Eur Aead Derm Venereol
Estlander T, Jolanki R, Kanerva L (1998) Oeeupational allergie 1:165-169
eontaet dermatitis from UV -eured laequer eontaining dipro- Kanerva L, Tarvainen K, Pinola A, Leino T, Granlund H,
pylene glyeol diaerylate. Contaet Dermatitis 39:36 Estlander T, Jolanki R, Förström L (1994) A single aecidental
Fisher T, Maibach HI (1986) Antigen presentation for the pateh exposure may result in a chemieal burn, primary sensitiza-
test. Oeeup Med 1:343-348 tion and allergie eontaet dermatitis. Contaet Dermatitis
Forss P (1998) Handbook of the advisory eommittee on chemieals 31:229-235
(in Finnish). Kemikaalineuvottelukunta, Helsinki Kanerva L, Estlander T, Jolanki R, Tarvainen K (1995) Oeeupa-
Foussereau 1, Lantz JP, Grosshans E (1972) Allergie eezema from tional allergie eontaet dermatitis and eontaet urtiearia eaused
vinyl-4-pyridine. Contaet Dermatitis Newslett 11:261 by polyfunetional aziridine hardener. Contaet Dermatits
Fregert S (1981) Manual of eontaet dermatitis. Munsgaard, 33:304-309
Copenhagen Kanerva L, Estlander T, Jolanki R (1996a) False negative pateh
Fregert S (1985) Publieation of allergens. Contaet Dermatitis test reaetion eaused by testing with dental eomposite aerylie
12:123-124 resin. Int J DermatoI35:189-192
Friedmann PS (1991) Graded eontinuity, or all or none - studies Kanerva L, Jolanki R, Estlander T (1996b) Offset printer's
of the human immune response. Clin Exp Dermatol 16:80-84 oeeupational allergie eontaet dermatitis eaused by eobalt-2-
Gosselin R, Hodge M, Smith R, Gleason M (1984) Clinieal toxieity etilylhexoate. Contact Dermatitis 34:67-68
of eommercially available produets. Williams & Wilkins, Kanerva L, Henriks-Eekerman M-L, Jolanki R, Estlander T (1997)
Baltimore Plasties/aerylies: material safety data sheets need to be
Guin JD (1995) Praetieal eontaet dermatitis. A handbook for the improved. Clin Dermatol 15:533-546
praetitioner. MeGraw-Hill, USA Kanerva L, Estlander T, Jolanki R (1998) Dental nurse's oeeupa-
Hannuksela M, Salo H (1986) The repeated open applieation test tional allergie eontaet dermatitis from eugenol used as a
(ROAT). Contaet Dermatitis 14:221-227 restorative dental material with polymethylmetilaerylate.
Hausen BM (1988) Allergiepflanzen - Pflanzenallergene. Kontak- Contaet Dermatitis 38:339-340
tallergene. Eeomed, Munieh Lamminpää A, Kanerva L, Estlander T, Jolanki R (1996)
Hawley GG, Lewis RJ (Sr) (1997) Hawley's condensed ehemieal Oeeupational allergie eontaet dermatitis eaused by deeorative
dietionary, 13th edn. John Wiley & Sons, New York plants. Contaet Dermatitis 34:330-335
Jolanki R (1991) Oeeupational skin diseases from epoxy Leisvaara K, Estlander T, Jolanki R (1998) Allergie eontaet eezema
eompounds. Epoxy res in eompounds, epoxy aerylates and eaused by MOl isocyanate in insulation work (in Finnish). In:
2,3-epoxypropyl trimethyl ammonium chloride (doetoral Kanerva L, Jolanki R, Keskinen H, Savela A, Karjalainen A
dissertation). Acta Derm Venereol SuppI159:1-80 (eds) Työperäiset allergiat v. 1995-96. Työterveyslaitos,
Jolanki R, Estlander T, Kanerva L (1987) Contaet allergy to an Helsinki, pp 237-240
epoxy reaetive diluent: 1,4-butanediol diglycidyl ether. Con- Menne T, Dooms-Goossens A, Wahlberg JE (1992) How large a
taet Dermatitis 16:87-92 proportion of eontaet sensitivity are diagnosed with tile
Jolanki R, Sysilampi M-L, Kanerva L, Estlander T (1989) Contaet European Standard Series? Contaet Dermatitis 26:201-202
allergy to eycloaliphatie epoxy res ins. In: Frosch PJ, Dooms- Niklasson B (1995) Mixing your own antigens. In: Guin JD (ed)
Goossens A, Laehapelle J-M, Ryeroft RJG, Scheper RJ (eds) Praetieal eontaet dermatitis. A handbook for the praetitioner.
Current topies in eontaet dermatitis. Springer, Berlin Heidel- MeGraw-Hill, USA, pp 687-695
berg New York, pp 360-367 Rietsehel RL, Fowler JJ (Jr) (1995) Fisher's eontaet dermatitis, 4th
Jolanki R, Kanerva L, Estlander T, Tarvainen K (1994) Concom- edn. Williams & Wilkins, Philadelphia
itant sensitization to triglycidyl isocyanurate, diaminodiphe- Rothe A (1988) Contact dermatitis from N-(a-ehlorlbenzy-
nyl methane and 2-hydroxyethyl methaerylate from lidene}phenylhydrazine. Contaet Dermatitis 18:16-19
silk-sereen printing eoatings in the manufaeture of cireuit Sasseville D, Balbul A, Kwong P, Yu K (1996) Contaet sensitiza-
boards. Contaet Dermatitis 30:12-15 tion to pyridine derivatives. Contaet Dermatitis 35:100-101
Jolanki R, Tarvainen K, Tatar T, Estlander T, Henriks-Eekerman Sonnex TS, Rycroft RJG (1986) Allergie contaet dermatitis from
M-L, Mustakallio KK, Kanerva L (1996) Oecupational de- chloromethyl heteroeyclie intermediates in the synthesis of a
rmatoses from exposure to epoxy resin eompounds in a ski histamine antagonist. Contaet Dermatitis 14:265-267
faetory. Contaet Dermatitis 34:390-396 Tarvainen K, Kanerva L, Tupasela 0, Grenquist-Norden B,
Jolanki R, Alanko K, Pfäffli P, Estlander T, Kanerva L (1997) Jolanki R, Estlander T, Keskinen H (1991) Allergy from
Oecupational allergie eontaet dermatitis from 5-ehloro- eellulase and xylanase enzymes. Clin Exp Allergy 21:609-615
1-methyl-4-nitroimidazole. Contact Dermatitis 36:53-54 Tarvainen K, Jolanki R, Estlander T (1993) Oceupational eontaet
Kalimo K, Jolanki R, Estlander T, Kanerva L (1989) Contaet allergy from unsaturated polyester resin eements. Contact
allergy to antioxidants in industrial greases. Contaet Derma- Dermatitis 28:220-224
titis 20:151-152 Tarvainen K, Kanerva K, Jolanki R, Estlander T (1995) Oeeupa-
Kanerva L, Lauerma A (1998) Iatrogenie aerylate allergy eompli- tional dermatoses from the manufaeture of plastie composite
eating amalgam allergy. Contaet Dermatitis 38:58-59 produets. Am J Contact Dermatoses 6:95-104
Kanerva L, Jolanki R, Plosila M, Estlander T (1984) Contaet Wahlberg JE (1998) Identifieation of new allergens and non-
dermatitis from dibutylthiourea. Report of a ca se with fine irritant pateh test preparations. Contaet Dermatitis 39:155-156
CHAPTER 48
Physicochemical Methods for Detection

of Occupational Contact Allergens
B. Gruvberger, M. Bruze, and S. Fregert
Introduction solution on the object. For accurate determination of

the pH in a solution, it is necessary to use a pH meter.
Many allergens are widely used in both environmental
and occupational products. In many cases, it is difficult
to know all the ingredients of a product since most Spot Tests
products are not sufficiently labeled. To diagnose and
prevent allergic contact dermatitis, the demonstration Spot tests can be used to demonstrate both inorganic
of allergens in products from the patient's environ- and organic compounds [2,3]. A specific re agent may
ment is important. Chemical analysis of a product can react with a specific substance giving a specific color
make it possible to demonstrate the presence or and, thus, indicate the occurrence of the specific
absence of known allergens. Simple spot tests or substance. However, other substances can disturb the
documented analytical methods, such as thin-Iayer chemical reaction and the specific color can be difficult
chromatography (TLC), high-performance liquid chro- to identify. A discolored sampIe can contain the
matography (HPLC), gas chromatography (GC), and investigated substance. To confirm the presence and
atomic absorption spectrophotometry (AAS), can be quantify the substance, more sophisticated methods
used. Moreover, with chemical methods, the purity of a are required.
substance can be checked and new allergens can be To demonstrate nickel ions released from metal
isolated and identified. Advanced methods such as objects, a spot test is commonly used.
mass spectrometry (MS), nuclear magnetic resonance
spectroscopy (NMR) and infrared spectrophotometry
(IR) are often required to identify isolated allergens. Thin-Layer Chromatography
In this chapter, some principal chemical methods
and some examples of chemical methods for derma- Chromatography is a general term applied to a variety
tological applications are described. of separation techniques based on the sampIe parti-
tioning between a moving phase, which can be agas or
a liquid, and a stationary phase, which may be either
Measurement of pH liquid or solid.
In TLC, the stationary phase consists of an inert
Acid and, particularly, alkaline products playa signi- absorbent, e.g., silica gel. The stationary phase covers
ficant role in the development of irritant contact the surface of a glass plate. The moving phase
dermatitis and in chemical skin bums [1]. It is constitutes an eluting solvent. The sampIe to be
important to determine the degree of acidity or analyzed is dissolved in a low-boiling solvent and a
alkalinity in a product suspected of causing skin small amount is applied near the bottom of the plate.
problems in order to avoid false-positive diagnoses of The plate is placed in a closed vessel containing a small
contact dermatitis. amount of the eluting solvent. The eluent is drawn up
Determinations of pH are relevant only in water- to the top of the plate owing to the capillary forces.
based products/solutions. A universal pH paper is Substances with high affinity to the stationary phase
usually satisfactory for clinical work. A few drops of will move slower than those substances with a low
the solution/emulsion to be investigated are applied on affinity. When the eluent has reached almost to the top
the pH paper, and the resulting color is compared with of the plate, the plate is removed from the glass vessel
the color scale on the package of the pH paper. and dried. To detect the spots on the plate, they must
Moistened with water, pH paper can be applied to solid be visible. Ultraviolet (UV) absorbing substances can
subjects to demonstrate residual acid or alkaline be detected by radiating the plate with a UV lamp.

Physicochemical Methods for Detection of Occupational Contact Allergens 385
Some substances may react with various reagents to detect components that do not absorb UV radiation.
applied to the plates giving visible compounds. The Rp- In some cases, derivatization can be used by adding a
value for a substance is the ratio between the distance UV -absorbing substance that will react with the
traveled by the substance and the distance traveled by component, making a new component detectable in
the eluent. To investigate whether a sampie contains a the UV detector. The signals from the detector are
specific substance (reference), the reference is applied registered as a chromatogram. A variety of columns of
beside the sampie on the plate. If the sampie contains a both nonpolar and polar types are available on the
substance with the same Rp-value as the reference, it market. Columns containing polar groups are used in
will indicate that the substance and the reference may straight-phase HPLC, and columns with nonpolar
be identical. However, to confirm this, more chro- groups are used in reversed-phase HPLC.
matographic methods are required. HPLC technique can be used for both analytical and
preparative purposes. In preparative HPLC, larger
amounts of a sampie can be injected, and fractions
Gas Chromatography containing various components can be separated and
collected for further analyses and/or patch testing.
A GC consists of an injector, a column and a detector.
In GC, the mobile phase constitutes a carrier gas, e.g.,
nitrogen or helium, and the stationary phase is a
Atomic Absorption Spedrophotometry
nonvolatile liquid on a solid support or on the walls of
the column. The most common supports are inert
AAS is one of the most common methods used to
porous materials. The sampie, dissolved in an organic
identify and quantify small amounts of metals in both
solvent, is injected into the column and heated.
organic and inorganic materials. The method reHes on
The components evaporate and the gas will carry the
the absorption oflight by atoms. The atoms can absorb
components through the column. Depending on the
light, but only at certain wavelengths corresponding to
molecular weight of the components and the polar
the energy requirements of the particular atoms. A
interactions between them and the stationary phase,
successful operation of an atomic absorption spectro-
they will be retarded. Detectors with different sens i-
photometer lies in generating a supply of free,
tivity for specific compounds are available on the
uncombined atoms in the ground state and exposing
market. Flame ionization detector (FID) is a common
this atom population to light at the characteristic
detector that detects most organic components passing
absorption wavelength. The atomization process con-
through the column. The organic compounds are
sists of heating a solution of the analyte to a
readily pyrolyzed when introduced into a hydrogen-air
temperature that is sufficient to dissociate the com-
flame and ions are produced in the process. The
pound. The thermal energy required can be supplied
signals are recorded as peaks in a chromatogram.
by a flame (air-acetylene) or by a flameless technique
To identify substances in a sampie, it is often
(graphite furnace). For quantitative measurements the
necessary to use several columns with different
sampie must be compared with standard solutions of
stationary phases that give the substances different
known concentrations.
retention times. When GC is combined with a mass
spectrometer, it is often possible to identify unknown
substances.
Ultraviolet-Visible Spedrophotometry
High-Performance Liquid Chromatography With a UV -VIS spectrophotometer, substances that

absorb light in the ultraviolet and visible regions can
In HPLC, the eluent is pumped through the column be detected. The substance is dissolved in a solvent
under high pressure in a closed system. In an isocratic with a low UV absorption and placed in the light beam
system the composition of the mobile phase is the in the spectrophotometer. The absorbance is plotted as
same throughout the analysis. In a gradient system at a function of the wavelengths. An absorption curve
least two pumps are used delivering varying amounts often includes both maximum/maxima and minimum/
of different eluents. In this manner the composition of minima.
the mobile phase can be changed during the analysis. Many substances have characteristic absorption
The sampie, dissolved in the mobile phase, is injected curves in the UV -VIS region and this information
into the HPLC. The components of the sampie are can be useful when identification of substances shall be
passing through the column to the detector with performed.
different speed. The most common detector is a UV A UV detector is the most commonly used detector
detector. A refractive index (RI) detector can be used in HPLC.
386 B. Gruvberger et al.
Infrared Spectrophotometry ions formed. Fragmentation of a substance into smaller

ions is very common. This fragmentation pattern is
IR spectrophotometry is used especially to identify unique for each compound and gives invaluable
organic substances. Nearly all molecules containing information about the chemical structure.
covalent bonds will show some degree of selective
absorption in the infrared region. Various functional
groups in a molecule give specific patterns of peaks in Nudear Magnetic Resonance Spectroscopy
an IR spectrum which can be used to identify, e.g.,
amino groups, carbonyl groups, and nitro groups. Using NMR spectroscopy together with MS and/or IR
Transparent samples, such as plastic films, can be analysis, it is often possible to elucidate the molecular
analyzed without processing. Other samples can structures of unknown substances.
be mixed with potassium bromide and pressed to a The NMR technique is based on absorption of
tablet. The IR spectra can be compared with reference energy by the sample to be analyzed. The sample is
spectra. placed in a strong magnetic field that will affect atoms
in the sample. The nucleus can absorb energy from an
additionally applied radio pulse when the frequency of
Mass Spectrometry the pulse matches that of the oscillating nucleus. The
absorption is recorded by the instrument.
MS is especially used to determine the molecular The most commonly studied atom is hydrogen
weights and structures of organic substances. Pure CH-NMR). Other atoms that can be studied are
substances can be analyzed directly, while components 13carbon, 19f1uorine and 3'phosphorus. A NMR spec-
in products have to be separated before analyzing. trum consists of absorption peaks from which infor-
Often, GC is combined with MS (GC-MS). The gas flow mation on functional groups and relative number of
containing separated components is introduced di- hydrogen atoms can be retrieved.
rectly into the mass spectrometer, where ions are Many reports concerning chemical methods to
generated by collision of rapidly moving electrons with detect various allergens have been published. In
the molecules of the gas. The ions are separated in an Table 1, methods applying to allergens in the European
electromagnetic field according to their mass-to-charge standard test series are shown. Chemical methods to
ratio. The result of the analysis is demonstrated in a identify and/or quantify miscellaneous sensitizers are
mass spectrum showing the relative intensities of the shown in Table 2.
Table 1. Literature references of chemical methods for allergens in the European standard test series
Spot test TLC HPLC GC AAS UV-VIS
Potassium dichromate 9-18 19

4-phenylenediamine base
Thiuram mix 20
Neomycin sulfate
Cobalt chloride 11, 13,21, 16-18
Benzocaine 22-24 23,24
Nickel sulfate 4, 5 11, 17, 18, 25-28
Quinoline mix
Colophony 29-31 29, 31-34
Parabens 35,36
N-isopropyl-N-phenyl-4- 37 37
phenylenediamine
W001 alcohols
Mercapto mix 38 38,39 38,39
Epoxy resin 6,40,41 40,42
Balsam of Peru 43
4-tert-Butylphenol 39
formaldehyde resin
Mercaptobenzothiazole 38,39 38,39 38,39
Formaldehyde 7, 8, 44-47 45,48-51 8
Fragrance mix 52,53
Sesquiterpene lactone mix
Quaternium 15 54,55
Methylchloroisothiazolinonel 56,57
methylisothiazolinone
TLC thin-Iayer chromatography; HPLC high-performance liquid chromatography; GC gas chromatography; AAS atomic absorption
spectrophotometry; UV- VIS ultraviolet-visible spectrophotometry
Table 2. Literature references of chemical methods for miscellaneous sensitizers
Spot test TLC HPLC GC AAS
Acrylates BUDA 58
BUDMA 58
DEGDA 58
EGDMA 58
OTA480 58
PETA-3 58
TEGDMA 58
TMPTA 58
TRPGDA 58
Allyl glycidyl ether 59
p-Aminobenzoic acid 22,23 23,24
Amyl p-dimethylaminobenzoate 23,24
Atranorin 60 60
Bithionol 22
Bronopol (2-Bromo-2-nitropropane-1 ,3-diol) 54,61
Buclosamide 22
Cadmium chloride 62
Chlorhexidine acetate 22
Chlorhexidine gluconate 22
Chlorpromazine hydro chloride 22
Diazolidinyl urea 54
Dichlorophene 22
Diethylthiourea 64 67
Dimethyloldimethylhydantoin 54,65
Diphenhydramine chloride 22
Diphenylthiourea 66 66,67
Ethyl-4-bis(hydroxypropyl)aminobenzoate 23 23,24
Ethylene thiourea 66,68 66
2-Ethylhexyl p-dimethylaminobenzoate 23 23,24
Fentichlor 22
Glyceryl p-aminobenzoate 23 23,24
Hexachlorophene 22
Imidazolidinyl urea 54
D-Limonene 69,70
6-methylcoumarine 22
Methyldibromoglutaronitril 54,63
Moskene 71 71
Musk ambrette 71 71,72
Musk ketone 71 71
Musk tibetine 71 71
Musk xylene 71 71
Phenol formaldehyde res in 73
Phenylisothiocyanate 67
Promethazine hydrochloride 22
Tetrachlorosalicylanilide 22
Thiourea 22
Tinuvin P 74-76 74
Tribromosalicylanilide 22
Trichlorocarbanilide 22
Triclosan 22
Zinc dibutyldithiocarbamate 77 77
Zinc dimethyldithiocarbamate 77 77
Zinc ethylphenyldithiocarbamate 77 77
TLC thin layer chromatography; HPLC high-performance liquid chromatography; GC gas chromatography; AAS atomic absorption
spectrophotometry; UV- VIS ultraviolet-visible spectrophotometry
Common Chemical Methods Used respectively, are applied to a cotton-tipped applicator,

by Dermatologists which is rubbed against the metal object to be
investigated. Dimethylglyoxime reacts with nickel ions
Detection of Nickel Ions Released from Metal Objects in the presence of ammonia, giving a red-colored salto
Coins known to contain nickel can be used to test the
Nickel is most commonly detected using the dimethyl- reagent and to observe the color.
glyoxime test [4]. A few drops of dimethylglyoxime in The sensitivity of the test can be enhanced by
ethanol 1% and ammonium hydroxide 10% in water, pretreatment of the surface of the object with a
solution of synthetic sweat and by heating. This test Demonstration of Epoxy Resin of the Bisphenol A Type
has been proposed by the European Committee for
Standardization [5]. 1. Material: TLC plates (Silica gel 60, F 254)
The method is very simple and can be used, for 2. Eluent: chloroform/acetonitrile 90/10 (v/v)
example, by dermatologists and nickel-allergic indi- 3. Spray reagents: sulfuric acid 1 molll - anisaldehyde
viduals, to detect nickel release from various metal in methanol 2.5% (v/v)
objects. 4. Standard: 1% (w/v) epoxy resin ofbisphenol A type
in acetone containing low-molecular-weight oligo-
mers (MW 340, 624, 908 g/mol, etc.)
Detection of Hexavalent Chromium (Chromate) 5. Extraction solution: acetone/methanol (90/10 v/v) or
ethanol
The chromium spot test is valid only for hexavalent
chromium. Sym-dipheny1carbazide reacts with chro- Proeedure
mate and dichrornate ions in the presence of sulfuric
acid, giving a red-violet color. The sampie to be investigated is dissolved in the
extraction solution. Solid sampies are extracted at
Reagents: room temperature or in an ultrasonic bath. The
required extraction time is dependent on the amount
1. Sym-dipheny1carbazide 1% w/v in ethanol (must be oflow molecular epoxy resin in the sampie. The extract
prepared immediately before the investigation) is evaporated to a volume of a few ml before being
II. Sulfuric acid 1 molll applied to the plate. The standard solution, 2-5 fil (20-
50 fig), is deposited with a capillary pipette on a TLC
Investigative Proeedures plate. A similar volume of the sampie is applied beside
the standard. Since the concentration of the epoxy
Chromate on the Surface of aSolid Object resin in the sampie is often unknown, it is advisable to
apply double and tripie amounts of the sampie on the
A few drops of reagents land II are applied on a cotton
same plate. The plate is eluted in a tank lined with filter
swab. The cotton swab is thereafter rubbed against the
paper saturated with the eluent. The plate is air-dried
surface of the object for 1 min. If chromate is present a
and sprayed with sulfuric acid until just moist and then
red-violet color appears.
sprayed lightly with anisaldehyde. After heating in an
Chromate in Solutions oven at 110°C for 10 min, the oligomers are visible as
violet spots with oligomer 340 at the top, followed by
To a sampie of approximately 10 ml, a few drops of
624. If the sampie contains unhardened low molecular
reagents land II are added. If chromate is present a
epoxy resin, the oligomers 340, 624 and 908 shall be
red-violet color appears.
identified with the same Rp values as the oligomers in
Chromate in Powders Insoluble in Water (e.g., Cement) the standard.
Fillers and pigments in the sampie can disturb the
A measured 5 g of cement is mixed with 10 ml water
analysis. In such cases special treatment of the sampie
for so me minutes. The mixture is then filtered and the
may be required.
filtrate is handled according to Chromate in Solutions.
lron ions can interfere with the reagent and give
discolored solutions. Detection of Formaldehyde
Formaldehyde is agas which dissolves easily in water-

Detection of Epoxy Resin Based on Bisphenol A based products. Small amounts may be released from
many preservatives and many water-based products
The most common epoxy resin of the bisphenol A type may thus contain formaldehyde. Two simple methods
[6] is diglycidyl ether of bisphenol A (DGEBA). This are frequently used to identify formaldehyde in various
epoxy resin contains oligomers of various molecular types of products.
weights (340, 624, 908, 1024 g/mol). Since the oligomer
with a molecular weight of 340 is a strong sensitizer, a Chromotropie Acid Method
chemical method to detect the sensitizer in various
types of products is important. There is a simple TLC Reagent: 40 mg of chromotropic acid is dissolved in
method to demonstrate the oligomers. 10 ml of concentrated sulfuric acid (freshly prepared)
[7]. Standard solutions: a concentrated water solution Summary

of formaldehyde (35%) is diluted to 100 Ilg/ml and
refrigerated (stock solution). Standard solutions con- To diagnose and prevent allergie contact dermatitis,
taining 2.5, 10, 20 and 40 Ilg formaldehyde/mi are the demonstration of allergens in products from the
prepared. The standard solutions should be refriger- patient's environment is important. With various
ated and freshly prepared every week. chemical methods it can be possible to demonstrate
Approximately 0.5 g of the sampie is placed in a the presence or absence of known allergens in
25-ml glass jar with a ground glass stopper. One ml of products, and to isolate and identify new allergens.
each standard solution and 1 ml water (blank) are However, chemical methods have limitations, and
placed in separate glass jars. The reagent (0.5 ml) is false-positive as weIl as false-negative results can be
added to small glass tubes and then placed individually obtained, especially when simple methods are used.
in the glass jars containing the sampie, the standards
and the blank, respectively. The jars are kept in the
dark and observed after 2 days. A violet color of the References
reagents indicates the presence of formaldehyde.
This method is based on a chemie al re action of 1. Bruze M, Fregert S (1993) Chemical skin burns. In: Menne T,
chromotropic acid and free formaldehyde evaporated Maibach HI (eds) Hand eczema book. Boca Raton, Florida,
from the sample/standards. However, other aldehydes pp 21-30
2. Feigl F, Anger V (1972) Spot tests in inorganic analysis, 6th
and ketones can also react with chromotropic acid edn. Elsevier, Amsterdam
giving colors that can interfere with the violet color. 3. Feigl F, Anger V (1966) Spot tests in organic analysis, 7th edn.
Elsevier, Amsterdam
With the chromotropic acid method, a rough
4. Rietschel RL, Fowler JF Jr (eds) (1995) Fisher's Contact
estimation of the concentration of formaldehyde can Dermatitis, 4th edn. Williams and Wilkins, Baltimore,
be obtained by comparing the intensity of the color of pp 857
the sampie with the colors of the standards. 5. European Committee for Standardization (CEN) (1997)
Reference test method for release of nickel from products
intended to come into direct and prolonged contact with the
skin
6. Fregert S, Trulsson L (1978) Simple methods for demonstra-
tion of epoxy resin of bisphenol A type. Contact Dermatitis
Acetylacetone Method 4:69-72
7. Dahlquist I, Fregert S, Gruvberger B (1980) Reliability of the
chromotropic acid method for qualitative formaldehyde
Reagent: 15 g ammonium acetate, 0.2 ml acetylacetone, determination. Contact Dermatitis 6:357-358
0.3 ml glacial acetic acid are dissolved in water to 8. Fregert S, Dahlquist I, Gruvberger B (1984a) A simple method
100 ml [8]. The solution should be refrigerated and for detection of formaldehyde. Contact Dermatitis 10:132-134
freshly prepared every week. Standard solutions: from 9. Adams RM, Fregert S, Gruvberger B, Maibach HI (1976)
Water solubility of zinc chromate primer paints used as
the stock solution of formaldehyde (100 Ilg/ml), stan- antirust agents. Contact Dermatitis 6:357-358
dards containing 2.5, 10, 20 and 40 Ilg formaldehyde/ 10. Bruze M, Gruvberger B, Hradil E (1990) Chromate sensitiza-
tion and elicitation from cement with iron sulfate. Acta Derm
ml are prepared. The standard solutions should be VenereoI70:160-162
refrigerated and freshly prepared every week. 11. Fregert S, Gruvberger B (1972) Chemical properties of
Approximately 0.5 g of the sampie is placed in a cement. Berufsdermatosen 20:238-248
12. Fregert S, Gruvberger B (1973) Factors decreasing the content
glass jar with a ground glass stopper. Ointments and of water-soluble chromate in cement. Acta Derm Venereol
other fat products should be emulsified with a few 53:267-270
drops of formaldehyde-free emulsifier such as Triton 13. Fregert S, Gruvberger B, Heijer A (1972) Sensitization to
X-100. Added to separate jars is 1 ml of each standard chromium and cobalt in processing of sulphate pulp. Acta
Derm Venereol 52:221-224
solution and 1 ml water (blank). To each glass jar 14. Ingber A, Gammelgaard B, David M (1998) Detergents and
2.5 ml of the re agent solution is added and the jar is bleaches are sources of chromium contact dermatitis in
thereafter shaken. The jars are heated at 60 oe for Israel. Contact Dermatitis 38:101-104
15. Lachapelle JM, Lauwerys R, Tennstedt D, Andanson J,
10 min. A yellow color of the mixture indicates the Benezra C, Chabeau G, Ducombs G, Foussereau J, Lacroix
presence of formaldehyde. If the concentration of M, Martin P (1980) Eau de Javel and prevention of chromate
allergy in France. Contact Dermatitis 6:107-110
formaldehyde is high, the yellow color will appear 16. Spruit D, Malten KE (1975) Occupational cobalt and chromi-
already before heating. The intensity of the yellow um dermatitis in an offset printing factory. Dermatologica
color can be compared with the standards to estimate 151:34-42
the content of formaldehyde in the sampie. 17. Tandon R, Aarts B (1993) Chromium, nickel and cobalt
contents of some Australian cements. Contact Dermatitis
If the sampie to be analyzed is colored, an extraction 28:201-205
procedure with I-butanol as described by Fregert et al. 18. Wahlberg JE, Lindstedt G, Einarsson Ö (1977) Chromium,
[8] can be performed. Quantification of the content of cobalt and nickel in Swedish cement, detergents, mould and
cutting oils. Berufsdermatosen 25:220-228
formaldehyde can be performed by using a UV -VIS 19. Wass U, Wahlberg JE (1991) Chromated steel and contact
spectrophotometer [8]. allergy. Recommendation concerning a "threshold limit
value" for the release of hexavalent chromium. Contact 42. Hansson C (1994) Determination of monomers in epoxy res in
Dermatitis 24:114-118 hardened at elevated temperature. Contact Dermatitis 31:
20. Knudsen BB, Larsen E, Egsgaard H, Menne T (1993) Release 333-334
of thiurams and carbamates from rubber gloves. Contact 43. Oxholm A, Heidenheim M, Larsen E, Batsberg W, Menne T
Dermatitis 28:63-69 (1990) Extraction and patch testing of methylcinnamate, a
21. Fregert S, Gruvberger B (1978) Solubility of cobalt in cement. newly recognized fraction of balsam of Peru. Am J Contact
Contact Dermatitis 4:14-18 Dermat 1:43-46
22. Bruze M, Fregert S (1983) Studies on purity and stability of 44. Biom G (1959) Formaldehyde contact dermatitis. Acta Derm
photopatch test substances. Contact Dermatitis 9:33-39 Venereol 39:450-453
23. Bruze M, Fregert S, Gruvberger B (1984) Occurrence of para- 45. Gryllaki-Berger M, Mugny Ch, Perrenoud D, Pannatier A,
aminobenzoic acid and benzocaine as contaminants in Frenk E (1992) A comparative study of formaldehyde
sunscreen agents of para-aminobenzoic acid type. Photo- detection using chromotropic acid, acetylacetone and HPLC
dermatol Photoimmunol Photomed 1:277-285 in cosmetics and household cleaning products. Contact
24. Bruze M, Gruvberger B, Thulin I (1990) PABA, benzocaine, Dermatitis 26:149-154
and other PABA esters in sunscreens and after-sun products. 46. Sheretz EF (1992) Clothing dermatitis: Practical aspects for
Photodermatol Photoimmunol Photomed 7:106-108 the clinician. Am J Contact Dermat 3:55-64
25. Andersen KE, Nielsen GD, Flyvholm M-A, Fregert S, Gruv- 47. Stonecipher MR, Sherertz EF (1993) Office detection of
berger B (1983) Nickel in tap water. Contact Dermatitis 9: formaldehyde in fabric: Assessment of methods and update
140-143 on frequency. Am J Contact Dermat 4:172-174
26. Bang Pedersen N, Fregert S, Brodelius P, Gruvberger B (1974) 48. Benassi CA, Semenzato A, Bettero A (1989) High-Perfor-
Release of nickel from silver coins. Acta Derm Venereol mance Liquid Chromatographic determination of free form-
54:231-234 aldehyde in cosmetics. J Chromatogr 464:387-393
27. Fischer T, Fregert S, Gruvberger B, Rystedt I (1984a) Contact 49. Bergendorff 0, Ezzelarab M, Wallengren J, Hansson C (1994)
sensitivity to nickel in white gold. Contact Dermatitis 10: Airborne contact dermatitis from formaldehyde released
23-24 from heated plastic polymers. Am J Contact Dermat 5:223-225
28. Fischer T, Fregert S, Gruvberger B, Rystedt I (1984b) Nickel 50. Flyvholm M-A, Hall BM, Agner T, Tiedemann E, GreenhilI P,
release from ear piercing kits and earrings. Contact Derma- Vander Veken W, Freeberg FE, Menne T (1997) Threshold for
titis 10:39-41 occluded formaldehyde patch test in formaldehyde-sensitive
29. BergiI M, Menne T, Karlberg A-T (1994) Colophony in paper- patients. Contact Dermatitis 36:26-33
based surgical clothing. Contact Dermatitis 31:332-333 51. Karlberg A-T, Skare L, Lindberg I, Nyhammar E (1998) A
30. Ehrin E, Karlberg A-T (1990) Detection ofrosin (colophony) method for quantification of formaldehyde in the presence of
components in technical products using an HPLC technique. formaldehyde donors in skin-care products. Contact Derma-
Contact Dermatitis 23:359-366 titis 38:20-28
31. Karlberg A-T, Gäfvert E, Meding B, Stenberg B (1996) 52. Rastogi SC (1995) Analysis of fragrances in cosmetics by gas
Airborne contact dermatitis from unexpected exposure to chromatography-mass spectrometry. J High Resol Chroma-
rosin (colophony). Contact Dermatitis 35:272-278 togr 18:653-658
32. Karlberg A-T, Magnusson K (1996) Rosin components 53. Rastogi SC, Johansen JD, Menne T (1996) Natural ingredients
identified in diapers. Contact Dermatitis 34:176-180 based cosmetics. Content of selected fragrance sensitizers.
33. Karlberg A-T, Gäfvert E, Liden C (1995) Environmentally Contact Dermatitis 34:423-426
friendly paper may increase risk of hand eczema in rosin- 54. Gruvberger B, Bruze M, Tammela M (1998) Preservatives in
sensitive pe~sons. J Am Acad Dermatol 33:427-432 moisturizers on the Swedish market. Acta Derm Venereol
34. Meding B, Ahman M, Karlberg A-T (1996) Skin symptoms 78:52-56
and contact allergy in woodwork teachers. Contact Dermatitis 55. Kreilgard B (1996) Pharmacia Research Hilleröd Denmark,
34:185-190 personal communication
35. Rastogi SC, Schouten A, de Kruijf N, Weijland JW (1995) 56. Gruvberger B, Persson K, Björkner B, Bruze M, DalIlquist I,
Contents of methyl-, ethyl-, propyl-, butyl-, and benzylpara- Fregert S (1986) Demonstration of Kathon CG in some
ben in cosmetic products. Contact Dermatitis 32:28-3° commercial products. Contact Dermatitis 15:24-27
36. Seventh Commission Directive 96/45/EC of 2 July 1996 57. Rastogi SC (1990) Kathon CG and cosmetic products. Contact
relating to methods of analysis necessary for checking the Dermatitis 22:155-160
composition of cosmetics products (1996) Identification and 58. Henriks-Eckerman M-L, Kanerva L (1997) Gas chromato-
determination of 2-phenoxyethanol, I-phenoxypropan-201, graphie and mass spectrometric purity analysis of acrylates
methyl, ethyl, propyl, butyl and benzyl 4-hydroxybenzoate in and methacrylates used as patch test substances. Am J
cosmetic products. Official J Eur Cummunities L213:9-15 Contact Dermat 8:20-23
37. Kaniwa M-A, Isama K, Nakamura A, Kantoh H, !toh M, 59. Dooms-Goossens A, Bruze M, Buysse L, Fregert S, Gruvberger
Ichikawa M, Hayakawa R (1994) Identification of causative B, Stals H (1995) Contact allergy to allyl glycidyl ether present
chemicals of allergic contact dermatitis using a combination as an impurity in 3-glycidyloxypropyltrimethoxysilane, a
of patch testing in patients and chemical analysis. Application fixing additive in silicone and polyurethane resins. Contact
to cases from industrial rubber products. Contact Dermatitis Dermatitis 33:17-19
30:20-25 60. Dahlquist I, Fregert S (1980) Contact allergy to atranorin in
38. Kaniwa M-A, Momma J, Ikarashi Y, Kojima S, Nakamura A, lichens and perfumes. Contact Dermatitis 6:111-119
Nakaji Y, Kurokawa Y, Kantoh H, !toh M (1992) A method for 61. Guthrie WG (1984) Analysis of bronopol in water-based
identifying causative chemicals of allergic contact dermatitis lotion. Provisional HPLC method. The Boots Company PLC,
using a combination of chemical analysis and patch testing in Nottingham
patients and animal groups: application to a case of rubber 62. Wahlberg JE (1977) Routine patch testing with cadmium
boot dermatitis. Contact Dermatitis 27:166-173 chloride. Contact Dermatitis 3:293-296
39. Kaniwa M-A, Isama K, Nakamura A, Kantoh H, !toh M, 63. Rastogi SC, Johansen SS (1995) Comparison of high-perfor-
Miyoshi K, Saito S, Shono M (1994) Identification of causative mance liquid chromatographie methods for the determina-
chemicals of allergic contact dermatitis using a combination tion of 1,2-dibromo-2,4-dicyanobutane in cosmetic products.
of patch testing in patients and chemical analysis. Application J Chromatogr A 692:53-57
to cases from rubber footwear. Contact Dermatitis 30:26-34 64. Kerre S, Devos L, Verhoeve L, Bruze M, Gruvberger B,
40. Fregert S, Meding B, Trulsson L (1984b) Demonstration of Dooms-Goossens A (1996) Contact allergy to diethylthiourea
epoxy resin in stoma pouch plastic. Contact Dermatitis 10:106 in a wet suit. Contact Dermatitis 35:176-178
41. Jenkinson HA, Burrows D (1987) Pitfalls in the demonstration
of epoxy resins. Contact Dermatitis 16:226-227
65. Sehouten A, Vermeulen M (1994) The determination of 72. Bruze M, Gruvberger B (1985) Contact allergy to photo
dimethyloldimethylhydantoin (DMDMH) in eosmetie prod- products of musk ambrette. Photodermatol Photoimmunol
uets. TNO Nutrition and Food Research report V 94:608 Photomed 2:310-314
66. Meding B, Baum H, Bruze M, Roupe G, Trulsson L (1990) 73. Bruze M, Persson L, Trulsson L, Zimerson E (1986) Demon-
Allergie eontaet dermatitis from diphenylthiourea in Vulkan stration of contact sensitizers in resins and products based on
heat retainers. Contaet Dermatitis 22:8-12 phenol-formaldehyde. Contact Dermatitis 14:146-154
67. Fregert S, Trulsson L, Zimerson E (1982) Contaet allergie 74. Arisu K, Hayakawa R, Ogino Y, Matsunaga K, Kaniwa M-A
reaetions to diphenylthiourea and phenylisothioeyanate in (1992) Tinuvin P in a spandex tape as a cause of clothing
PVC adhesive tape. Contaet Dermatitis 8:38-42 dermatitis. Contact Dermatitis 26:311-3161
68. Bruze M, Fregert S (1983) Allergie eontaet dermatitis from 75. Björkner B, Niklasson B (1997) Contact allergy to the UV
ethylene thiourea. Contact Dermatitis 9:208-212 absorber Tinuvin P in a dental restorative material. Am J
69. Karlberg A-T, Dooms-Goossens A (1997) Contact allergy to Contact Dermat 8:6-7
oxidized d-limonene among dermatitis patients. Contact 76. Niklasson B, Björkner B (1989) Contact allergy to the UV-
Dermatitis 36:201-206 absorber Tinuvin P in plastics. Contact Dermatitis 21:330-334
70. Karlberg A-T, Magnusson K, Nilsson U (1992) Air oxidation 77. Kaniwa M-A, Isama K, Nakamura A, Kantoh H, Hosono K,
of d-limonene (the citrus solvent) creates potent allergens. Itoh M, Shibata K, Usuda T, Asahi K, Osada T, Matsunaga K,
Contact Dermatitis 26:332-340 Ueda H (1994) Identification of causative chemicals of allergie
71. Bruze M, Edman B, Niklasson B, Möller H (1985) Thin-layer contact dermatitis using a combination of patch testing in
chromatography and high press ure liquid chromatography of patients and chemical analysis. Application to cases from
musk ambrette and other nitro musk compounds including rubber gloves. Contact Dermatitis 31:65-71
photopatch studies. Photodermatol Photoimmunol Photo-
med 2:295-302
CHAPTER 49
Sources of Information on the Occurrence

of Chemical Contact Allergens
M.-A. Flyvholm
Introduction 3. Material safety data sheets

4. Inquiries to manufacturers or suppliers
Information on the occurrence of chemie al contact 5. Chemieal analysis
allergens is necessary for the prevention and treatment 6. Product databases
of allergie contact dermatitis. The ideal situation is
The different sources of information each have their
access to a reliable, easy and quick detection and
advantages and limitations, and are thus more or less
identification of contact allergens in the environment.
adequate in different situations (Flyvholm et al. 1995;
Each different method used to obtain this information
Flyvholm 1996). This chapter gives a presentation of
has its own advantages and drawbacks depending on
the different methods used to obtain information on
the nature or the origin of the allergen(s) and
the occurrence of chemie al contact allergens with a
product(s) in question and the context in which the
short discussion on each method followed by a general
information will be used. For example, in the clinical
discussion.
elucidation of the cause of allergie contact dermatitis, a
throughout chemie al separation and identification of
constituents in a complex product is the ideal for
Literature
revealing the offending allergen. For governmental
agencies planning regulation of population expos~re to
Textbooks on contact dermatitis frequently include
allergens, overviews on exposure, based on nahonal
overviews on occurrence of contact allergens in
databases of chemical products and including infor-
product categories or occupations based. on, for
mation on product composition for the relevant
example, published papers, author expenence or
product categories, will be much more useful. Ideally,
product databases. These overviews will always be
all products should be labelled with ingredient listings
restricted to existing knowledge and the background of
including all contact allergens. For cosmetics, this
the data must be considered when using and evaluating
situation is partly realised through the 6th Amendment
such information. For some substances and product
of the European Union (EU) Cosmetics Directives,
categories, textbook information will be quickly out-
although fragrances are not included in the decla:a-
dated due to changes in technology and lifestyle, but
tion. For chemieal products, the value of the labelhng
for others it can be expected to last longer. If textbooks
is reduced by the threshold of 1% given in the
are available, they are easy and inexpensive to use.
Dangerous Preparations Directive for labelling of
Scientific journals often publish case reports on new
products containing skin sensitisers (R43 "may cause
or unrecognised sources of exposure to specific
contact sensitisation by skin contact").
allergens. Due to developments in the field of easy
Several studies have shown that careful investigation
access on-line literature databases, this source of
and information on exposure to contact allergens is
exposure information will become more useful in the
important for the prognosis of patients with allergie
future than in the past when searches on literature
contact eczema (Cronin 1991; Edman 1988; Flyvholm
were rather expensive and time consuming.
and Menne 1992). Furthermore, early elimination of
the exposure to the allergens seems to ~revent
chronicity of the eczema (Flyvholm and Menne 1992).
Product Labelling and Declarations
Exposure information can be obtained from differ-
ent sourees, such as:
Product labelling and declarations are the most
1. Literature obvious ways to obtain and provide information on
2. Product labelling and declarations the content of contact allergens in chemical products

Sources of Information on the Occurrence of Chemical Contact Allergens 393
but, unfortunately, not all product categories are practice, this is often very time consuming and
covered by labelling requirements. This kind of sometimes the detailed information may not even be
information on exposure has an advantage in that it available from a supplier. However, some manufactur-
is accessible immediately for both patients and ers are able to provide detailed information on a
doctors, provided that the product package is still specific batch of a product quickly.
existing. The only requirement is that the user must
have some knowledge of how to read and understand
chemical names. The labelling or declaration is Chemical Analysis
restricted to the information that the manufacturer,
importer or supplier has to or is willing to provide. Chemical analysis is very suitable for well-defined and
Furthermore, labelling or declaration is influenced by known substances if reliable analytical methods are
legislation and regulations concerning what type of available for the specific allergens. Simple and quick
product categories to cover, what kind of information test methods make it possible for clinical departments
to include and how to provide the information. In to analyse products brought in by the patients.
some cases, compounds added to raw materials may be Analytical methods requiring specialised laboratory
missing in the declaration. As regards cosmetic prod- equipment or expertise must be carried out in
ucts, the fragrances do not have to be included in the specialised laboratories, and this may cause time delay
declaration, according to the EU rules. For chemical or incredibly high expenses for the clinical routine
products containing contact allergens, the EU rules work. For example, nickel and formaldehyde can be
require labelling of products (preparations) with Xi detected by simple tests methods, but chromate and
(irritating) and Risk Phrase (R43 "may cause contact epoxy demand methods requiring specialised labora-
sensitization by skin contact"), but the default thresh- tory equipment and expertise.
old value for labelling the conte nt of contact allergens Usually, it is necessary to know for which allergens
is 1% (10,000 ppm). Another problem in the use of to search before doing chemical analyses, because a
product labelling and declarations is that the names for thorough chemical identification of all components in
the allergens are not always easy to read and interpret complex products is seldom practicable. As only a
(De Groot and Weijland 1997). minor part of the known contact allergens can be
Product labelling and declarations with sufficient detected by routine analytical methods, it is thus only
information on specific ingredients, including infor- possible to obtain information on exposure to contact
mation on components less than 1%, is the ideal as allergens by analysing the products in a limited
regards contact eczema. number of cases.
Material Safety Data Sheets Product Databases
Material safety data sheets can, like product declara- Product databases can, if they are easily accessible and
tions, be accessible immediately, provided that they are include the relevant product categories, be a quick and
available and that the user is able to read and easy way to obtain information on contact allergens in
understand chemical names. The value of the data is chemical products. It will normally be possible to make
also restricted to the information which the manufac- lists of product categories or single products with
turer, importer or supplier has to or is willing to content of specific allergens or lists of allergens
provide, and again, information on components less occurring in a product category. Depending on the
than 1% is needed. Material safety data sheets make it data sources and the degree of specificity, so me
possible to include additional information on safe use databases may have restricted access, whereas those
and precautions in case of accidents. The practical use with nonconfidential data can be used without limita-
is dependent on the local management and adminis- tions. Databases of relevance in dermatology are
tration of a workplace system ensuring easy access to reviewed in the Textbook of Contact Dermatitis
the relevant material safety data sheets. (Dooms-Goossens et al. 1995). The Danish Product
Register Database (PROBAS) is an example of a
national database established on legal demands and
Inquiries to Manufacturers or Suppliers notification rules. This database includes information
and evaluations on substances, materials and products
Inquiries to manufacturers or suppliers in order to used in Denmark; the registered data is focused on use,
obtain information on ingredients in chemical prod- chemical composition of products, quantities used in
ucts can, in principle, provide information on ingre- Denmark and the adverse effects on health and
dients in products used by eczema patients. In environment. For further description of PROBAS, see
394 M.-A. Flyvholm: Sources of Information on the Occurrence of Chemical Contact Allergens
Chap. 58 (Computerised Product Database. Registered pIe, updated and adequate information on formalde-
Chemical Contact Allergens) and Flyvholm et al. (1992). hyde content in the specific products used
Product databases can be used on the single patient independently of the origin of formaldehyde, if the
level by doctors and patients. On a more general level, products are analysed, or the information obtained
the authorities can use databases to survey the use of may include only added components and eventual
chemical products and to plan preventive measures. content from raw materials. Chemical analysis can
Particularly in the use of administrative databases, the provide information on the content of formaldehyde
background of the registered data and the product independently of the origin, if analytical methods
categories included should be considered. suitable for the product type are available. Product
databases cannot provide data better than the input
data, so databases compiling product labelling and
Discussion declarations will equal these and so on, which stresses
once again the need to be aware of the background of
As indicated in this chapter, different sources of the product databases.
information on the occurrence of contact allergens are In conclusion, the best strategy for a dermatological
suitable for different exposure situations and allergens. department seems to be a solid background knowledge
Depending on the local facilities and demands, differ- from the literature combined with routine examination
ent methods may be preferred, but access to a variety of product labelling, declarations and material safety
of sources is usually necessary. data sheets for products used by the eczema patients.
Formaldehyde is an example of a contact allergen This may be combined with chemical analysis for
which can occur in products from various origins, each detection of allergens originating from raw materials,
of which requires different sources of information to residues, formation in the products or contamination.
be detected (Flyvholm 1997). Thus, formaldehyde is For regulatory purposes and prevention of sensitisa-
used below to illustrate advantages and limitations of tion, overviews based on product databases can be of
the different sources of information on occurrence of great benefit in the supplying of information which,
chemical contact allergens. under other circumstances, could take years to compile
Formaldehyde can occur in chemical products as a from product labelling, declarations, material safety
component added directly in the manufacturing pro- data sheets, inquiries to manufacturers and suppliers,
cess or as a component added in raw materials. Some or chemical analysis.
components can release formaldehyde as part of their
function in the products, i.e., formaldehyde releasing
preservatives (Flyvholm and Andersen 1993). Besides References
these intentional occurrences of formaldehyde, it can
Cronin E (1991) Formaldehyde is a significant allergen in women
occur as residues from synthesis of other product with hand eczema. Contact Dermatitis 25:276-282
components and from formation during storage and De Groot AC, Weijland JW (1997) Conversion of common names
handling of raw materials or end products. Contam- of cosmetie allergens to the INCI nomenclature. Contact
ination from packages coated with formaldehyde Dooms-Goossens A, Dooms M, Drieghe J (1995) Computers and
resins has also been reported. patient information systems. In: Rycroft RJG, Menne T,
Textbooks and scientific journals can provide a Frosch PJ (eds) Textbook of contact dermatitis, 2nd edn.
Springer, Berlin Heildelberg New York, pp 771-784
tremendous amount of data on the occurrence of Edman B (1988) The usefulness of detailed information to
formaldehyde in chemical products from various patients with contact allergy. Contact Dermatitis 19:43-47
sources, which can provide a solid background on Flyvholm M-A (1996) Prevention by exposure assessment. Curr
Probl Dermatol 25:97-105
potential exposure to formaldehyde. Nevertheless, Flyvholm M-A (1997) Formaldehyde exposure at the workplace
eczema patients with contact aIlergy to formaldehyde and in the environment. Allergologie 5:225-231
have until recently been able to receive only scanty Flyvholm M-A, Andersen P (1993) Identification of formaldehyde
releasers and occurrence of formaldehyde and formaldehyde
information on exposure to formaldehyde (Cronin releasers in registered chemieal products. Am J Ind Med
1991; Flyvholm and Menne 1992). Product labelling 24:533-552
and declarations normally give information on com- Flyvholm M-A, Menne T (1992) Allergie contact dermatitis from
formaldehyde. A case study focussing on sources of formal-
ponents added by the manufacturer. Content derived dehyde exposure. Contact Dermatitis 27:27-36
from raw materials may be missing and content Flyvholm M-A, Andersen P, Beck ID, Brandorff NP (1992)
coming from residues, formation in the products or PROBAS: The Danish Product Register Data Base - anational
register of chemieal substances and products. J Hazardous
contamination cannot be expected to be covered by Materials 30:59-69
labelling and declarations. Material safety data sheets Flyvholm M-A, Menne T, Maibach HI (1995) Skin allergy:
will more or less cover the same formaldehyde exposures and dose-response relationships. In: VOS JG,
Younes M, Smith E (eds) Allergie hypersensitivities induced
sources as labelling and declarations. Inquiries to by chemieals. Recommendations for prevention. CRC Press,
manufacturers or suppliers could provide, in princi- Boca Raton, pp 261-285
CHAPTER 50
Identification and Assessment in Relation

to the Material Safety Data Sheets
D.A. Basketter and L. Kanerva
Introduction System for Hazardous Chemicals (286/78) made MSDS

mandatory in Finland (Kanerva et al. 1996) in 1978.
The manufacturer's material safety data sheet (MSDS) Even though current MSDSs are of great help, they
represents the primary piece of information on the may not be exact enough from a dermato-allergist's
safety issues related to the material or product to point of view (Table 1). We feel that efforts should be
which it is related. It is thus a first point of call for the taken to achieve more complete MSDSs, and the
dermatologist trying to judge whether a particular dermato-allergist also needs to know the components
product or substance might be responsible for any case with a lower concentration than the abitrary 1% cut-off
of occupational skin disease under consideration. Even limit; currently, chemicals with a concentration below
though current MSDSs are of great help, they may not 1% are usually not declared, even when they are
be exact enough from a dermato-allergist's point of allergenic.
view (Kanerva et al. 1997).
In this chapter, we review how skin irritationl
sensitisation information is generated/collated for the Irritation/Sen5iti5ation Hazard Identification
MSDS, what it does tell the physician, what it does not and the MSDS
tell the physician and how the information given might
be refined/improved. We also present recently pub- In this book, we are largely concerned with the threat
lished data on the quality of currently used MSDS by posed to normal skin by contact with irritant and
comparing gas-chromatographic (GC) analyses of sensitising substances; it is worth noting that whilst
acrylate chemicals with MSDS and product declarations both substances and/or mixtures thereof can be
(Kanerva et al. 1997). From that study, we conclude that irritating, for skin sensitisation it is the substances
better MSDS and product declarations should be themselves that must be allergens (haptens). In this
required from industries before the products are sold; section, approaches to the identification of skin
otherwise, many patients/customers will be sensitised irritants are described briefty, together with a descrip-
before any preventive measures have taken place. tion of how the data may be interpreted in terms of a
MSDS. Subsequently, a similar succinct account for
skin sensitisers is presented.
What 15 a MSDS?
Skin Irritation
An example of a MSDS is given in Fig. 1. The MSDS is
simply a means for a manufacturer to present basic For many years, the standard approach to the deter-
safety information on his product, whether that mination of skin-irritation potential has been the
product is a single substance, a mixture of substances Draize rabbit test (Draize 1944, 1959). This simple, 4-h,
or even a fully finished product. It should contain semi-occluded patch testing, typically using three
details of all the known safety hazards presented by the rabbits, is still the one recommended in regulatory
product, both physical and biological, together with guidelines (Food and Drug Administration 1972;
details of how these hazards should be managed. European Community 1988, 1992, 1993; United Nations
Previously, manufacturers were often unwilling to 1993; Organisation for Economic Cooperation and
reveal the chemicals in their products (Kanerva et al. Development 1993). Generally, the information gener-
1996). Examples in Finland were printing plates ated is interpreted against standard criteria, such as
containing acrylics in the 1970S: hardly any informa- those in Europe (European Community 1993), which
tion on the hazardous chemicals was available to the then serve to convert the continuous erythema/oede-
physician. The Finnish Identification and Labelling ma/scaling reaction of skin irritancy into a "yes/no"

396 D.A. Basketter and L. Kanerva
Table 1. Possible reasons for material safety data sheets being

inaccurate
u. Wondercle80 SU
Low concentrations of chemieals may not be declared
Raw materials may contain hidden impurities
_...
Final product may contain starting materials
Decomposition of components
-,.
Contamination of residues
Hf" SODuM SAll InlUnl
Manufacturing processes may be poorly controlled
-""
.....
Im....
c.m.on
Undeclared components may be added intentionally
principle of crude hazard identification using this type

111~ _1_1_
_"_- ..... _T.--..... ..'_ __ · __ of approach is usually followed. It is noteworthy that
this test only evaluates the ability of the material in
GIIIJ,._UOE_""~ "_""'l'1o.o-o,,,~._~ "_I_·.~
3. HAlAAtIS 1OEN'1lACA 110M: 1Irrif...,. 10 tk'ItI ".,...
question to give rise to an acute irritant response.

-
W..lllmmHi.,efywrtrlc.-lIr!OCU!tS!14 ...w"'-"~~
w.-" '&hell.....,...,. -W
~ ".,...... tr_ -.eh. Dr\nII. I
...".,... conuo-\Jt'd_'*'O
0It 2: p a l of WlU., Iar mItJ KM!

Whilst the test described above is a common way in
which an attempt is made at predictive identification of
obtUIlIIMIc.II.ncn!lcn.
those substances or products with significant skin-
~"(Itft ..... oe",.,,",,",Ir'\CIOIDI,,",,~.\!"""*
E"_P.oft-ttfwIOl~ irritation potential, other information can also be used.

1 f«(...f1c;HT1NO M EASURU
H..Al.t!J.AAlTY. Consideration is given to structure-activity relation-
________
_~
_.
SU'TAk" (X1INGUtSHER$.. ships, although it must be said that this subject is in its
~~~_~.~Wd~~~~ -1'-~
(lCllNGu1$HUtS NOT m BI: USiD! infancy for skin irritants (Whittle et al. 1996; Barratt
~AL NOUCllVl! fOuAilUfT HoI.ZANXIVS Ccm8U$T1OH fIROOuCT$ 1996). Data may also come from non-standard animal
tests, predictive human tests and from human expe-
.t'ldWIt~IIIaWI~WIIIIIW_UdJirWaIir~ TmkMClllot\lllrtll~"",.,.IMI~O'II"""'hN·liHI!o
~Uldprldxf ~_
"'DOUClNAMll Ql,lllIIInSUl21 I ""NO; fItli" rience. These may cover either acute and/or cumula-
tive irritant responses in skin. It is also possible for
manufacturers to use data from in vitro studies. Lastly,
......._.w,..... ..
Atl.orbllo .... .,..q,.. ......,.. .............. IJ.-..no...twlKt
SI'R.l.AGI!ClEAHUf' ~-....aa.c.IIoJOtjta*
_o~_
•• ~,., tOOMItl ..... ......,..; .. ~ 'NulI ....... -.a,.....
~~_.w
where the product is a mixture of two or more
7. Hok,NOllN(I MD S'T0IU00l!
HN<OU"" "'I/IMI~"'~c.anraa: "'CYRflC8nYn.lontIrßon.

substances [a "preparation" in European Union (EU)
STOfU,Gf St_In.".......,.dIMtf~""*"'..,~ ..
""~.~001
terminology], the manufacturer may elect to calculate
the likely irritancy on the basis of the knowledge of the
skin irritancy of the component substances and the
concentration at which they occur in the product. For
certain types of product, this process has been
formalised in the EU as the "conventional method"
, I. TO)[JCOl.OQICAL IN rOIRMAllOtII
~ c-tlttrtttion.
(European Community 1988).
SIel.. c......w.lnitMlon.
Whilst the formal classification of skin-irritation
IMJ,ESOON c...sn Itrbdon-
c..- ........ potential in the EU for both substances and prepara-
.-
~1lOt. 1
,2.. ECOlQCllCAl,l\IfQlUU.nQH ".1IAId ...... _ ...

w.
~~11t1lw..-uc-WDMWlllwl'lNvl
tions should lead to a harmonisation of the informa-
---
~ n. ~ c.ampanml be 11fd.ndy NmI'\'td In •• nt .....ttI'
---
, 3. OISIOUl. CONS«IUt, nClHS
tion applied to the MSDS, this does not in fact occur.
COWTIJrI,TS: The standard rabbit test is highly variable (Weil and
0.tPTV COHT.t.I~
14.. TMKUOfn" .f(IIIMA1l(JN
Scala 1971). A key problem is that even well-defined
UNt...,... eo; ....'\O'",t,CJtAGIr.'GGftOI..P' ~QoA~ criteria are still open to differences of interpretation.
For most of the types/sources of information men-
tioned above, there are no criteria for their interpr-
etation. How much human clinical data and of what
fIiIecII.IQ_Inmua _ _ . . ._ . . . . .'tw~". .... 4IfICI.,..",..,.
type should be sufficient to categorise a product as an
.v..oroduct\iVIIHIMm.~
iIIIId"'"
Iftt,a-.-.It"'_'.~on.
HMcIt OoVy",tC~.
irritant? How might in vitro data be interpreted in a
Fig. 1. Material safety data sheet of the product "wonderclean meaningful way? In practice, the manufacturer has to
SU" make an independent judgement on whether the data
are sufficient to cause concern about skin irritancy.
decision. Thus, in the European Community (EC), and
expressed in layman's terms, if a substance in duces an Skin Sensitisation
average of mild to moderate irritancy in at least two of
the rabbits, it is classified as a skin irritant. If it fails to The generation and interpretation of skin sensitisation
achieve the arbitrary threshold, it is not classified as a data suffers from many of the problems associated
skin irritant. Whilst some countries have a slightly with skin irritation data, but has, in addition, special
different threshold (if they have any at all), the general characteristics of its own. As with skin irritation, the
Identification and Assessment in Relation to the Material Safety Data Sheets 397
protocols commonly used for the predictive identifi- Similar inconsistencies exist for skin sensitisation. One
cation of skin-sensitising chemicals use a small num- real difficulty can be manufacturers who err wholly on
ber of animals to detect the hazard. The most common the side of caution and thus label a great many
method employed is the Magnusson and Kligman products as irritants; there is a tendency to be less
guinea-pig maximisation test (GPMT) (Magnusson cavalier about the use of the term "sensitising".
and Kligman 1970), which is very effective at identi- Being cautious is not by itself bad. However, it does
fying even weak skin sensitisers. The interpretation of highlight a further limitation of the MSDS information
the results in terms of classification of a chemical as a - that it is binomial, a product is either irritatingl
skin sensitiser follows a similar process to that for skin sensitising or it is not. This is so far from the truth as
irritation, i.e. the continuously variable biological data to be laughable. The only action that can ensue on the
is converted into a binomial result. Using EU criteria, basis of such limited information is to "avoid skin
if at least 30% of the animals are positive in the GPMT, contact". Risk assessment and management activities
then the chemical is described as a skin sensitiser need to be much more sophisticated to be of real
(European Community 1996). No account is taken of benefit, not least since total avoidance of skin contact
the test concentrations, the intensity of individual is rarely possible.
reactions or indeed the number of reactions, except to Most commonly, skin irritation to chemicals occurs
ensure that the latter is above the threshold. Manu- clinically as cumulative irritant dermatitis. MSDS data
facturers use this or similar criteria in an ad hoc way to is most often based on evidence of the acute skin-
judge whether their product is a skin sensitiser. Also, irritation potential of the product. Such data may not
in a similar mann er to irritancy, it is possible to make always be fully predictive of cumulative irritation
use of structure-activity considerations (Barratt et al. potential (Hannuksela and Hannuksela 1995). Further-
1997). Furthermore, data mayaIso be derived from more, if the product is apreparation rather than a
other animal tests, predictive human tests and from single substance, MSDS information may be based on
human clinical experience. the conventional calculation method, in which labeling
Although there appears to be considerable stan- is only applied if the sum of classified irritants is at
dardisation of test protocols for the predictive identi- least 20% (European Community 1988). To put this in
fication of skin sensitisers (Organisation for Economic simple terms, it means that 20% aqueous sodium
Cooperation and Development 1993), both the use and lauryl sulphate would be described as irritant, whilst
the interpretation of test data is subject to wide 19.9% would not be so labeled.
variations (Robinson et al. 1990; Frankild et al. 1996). Skin sensitisation can often arise from highly
It is almost impossible to overestimate the variability allergenic substances that are present either as impu-
of the results which can be obtained by different rities or are deliberately added, but at a very low level.
laboratories testing the same substance and using the TypicaIly, these may not be identified on a MSDS; the
same protocol. manufacturer may not even be aware of their presence.
Following EC rules (European Community 1988), a
preparation is not normally labeled as skin sensitising
MSDS Information - if the offending agent is present at a concentration
What Does it Tell Me/Not Tell Me? below 1.0%. Yet it is quite obvious that such a the
judgement of whether apreparation is likely to be
"Something, but not a lot" is the short answer. What sensitising depends not only on the concentration, but
the MSDS does say is that the manufacturer of the also is heavily dependent on the potency of the skin
product has made a judgement (hopefully on the basis sensitiser as weIl as on a number of other factors. Skin
of all the available data) as to whether that product sensitisation mayaIso arise by oxidation of specific
possesses either skin irritating and/or sensitising chemicals (Karlberg et al. 1997); a MSDS does not
properties to a "significant" extent. What is significant normally address such matters.
is generally left to the judgement of the manufacturer
although, at least for certain products in the EU, the
standard criteria may be applied (European Commu- MSDS - Comparison of Data in MSDS
nity 1988, 1993). to Chromatographic/Mass Spectrometric Analysis
However, the information contained on a MSDS is
limited in a variety of ways. First, both the derivation Identification of allergens can be performed with
of data and its interpretation vary to a considerable chromatographic/mass spectrometric (GC/MS) analy-
degree. For example, lactic acid has been described as sis. Here, we review recent data in which GC/MS
corrosive to skin by some manufacturers, yet left analysis was compared with data given in MSDSs
unlabeled (i.e. not regarded as significantly irritant) by (Kanerva et al. 1997). The chemicals identified in the
another (David Basketter, personal communication). various plastics are given in Tables 2-7.
398 DA Basketter and L. Kanerva
Table 2. Identified chemieals in dental plastics according to gas Table 3. Identified chemieals in dental prostheses according to
chromatographie analysis. The data have been compared with the gas chromatographie analysis. The data have been compared with
information given in the material safety data sheets (MSDS) the information given in the material safety data sheets (MSDS)
Dental composite res ins Concentration MSDS Dental prostheses Concentration (%) MSDS (%)
and bonding materials (%) (%)
Product 31 (powder for the manufacturing of prostheses)
Product 21 (adhesive of dental composite resin) Methyl methacrylate 3.0 NG
BIS-GMA 7.6 NG n-Butyl methacrylate 0.5 NG
Triethylene glycol dimethacrylate 24 NG Product 32 (liquid for the manufacturing of prostheses)
2-Hydroxyethyl methacrylate 6.8 5-9 Methyl methacrylate 94 99.95
Decamethylene dimethacrylate 1.5 NG Ethylene glycol 4.6 NG
Diethylene glycol dimethacrylate 0.5 NG dimethacrylate
Ethylene glycol dimethacrylate 0.3 NG N,N-dimethyltoluidine 0.7 NG
Ethyl ester of dimethylaminobenzoic 0.3 NG Tinuvin P (Le. 2(2-Hydroxy- 0.4 NG
acid 5-methylphenyl)
Product 22 (dental filling material) benzotriazol)
Tricyclodecanediyl-dimethyl-bis- 18 11-17
acrylate, two isomers NG not given
Methyl methacrylate 0.3 NG
Product 23 (light-cured microfiller composite resin)
BIS-GMA 7.9 15-20
Triethylene glycol dimethacrylate 8.3 15-20 Table 4. Identified chemieals in reinforced composite resin
Diethylene glycol dimethacrylate 0.15 NG according to gas chromatographie analysis. The data have been
Methyl methacrylate 0.1 NG compared with the information given in the material safety data
Tinuvin P (i.e. 2(2-Hydroxy-5- 0.1 NG sheets (MSDS)
methylphenyl)benzotriazol)
Product 24 (light cured dental filling material) Reinforced composite resin Concentration (%) MSDS (%)
BIS-GMA 5.1 5-10
Triethylene glycol dimethacrylate 5.5 5-10 Product 41 (composite resin based on vinyl ester)
Diethylene glycol dimethacrylate 0.07 NG 2-Hydroxypropyl 8.1 NG
Methyl methacrylate 0.07 NG methacrylate Styrene 50 45-50
Dimethylaminophenethyl alcohol 0.05 NG
Product 25 (light -cured adhesive) NG not given
BIS-GMA 32 50-60
2-Hydroxyethyl methacrylate 29 40-50
Ethylene glycol dimethacrylate 13 NG
Di- and triethylene glycol 0.06 NG hydroXY-3-methacryloxypropoxy)phenylpropane (BIS-
dimethacrylate
Dimethylaminophenethyl alcohol 0.2 <1
GMA) was present (at 7.6%) in an adhesive (Prod-
Product 26 (light-cured adhesive) uct 31, Table 2). Many other undeclared methacrylates
BIS-GMA 57 55-65 were present in a concentration greater than 1%,
Triethylene glycol dimethacrylate 37 NG
Diethylene glycol dimethacrylate 1.5 NG
namely ethylene glycol dimethacrylate (EGDMA; 13%,
Ethylene glycol dimethacrylate 0.13 NG Product 25), decamethylene dimethacrylate (5.9%,
Product 27 (radio-opaque filling) Product 27) and diethylene glycol dimethacrylate
BIS-GMA 14 22?
Decamethylene dimethacrylate 5.9 NG
(DEGDMA; 1.5%, Product 26). A great number of
2-Hydroxyethyl methacrylate 0.8 NG acrylics was present in lower concentrations than 1%
Urethane dimethacrylate 35? (Table 2).
Product 28 (adhesive)
Product 29a (dentin primer) Dental Prostheses
2-Hydroxyethyl methacrylate 48 30-65
Methacrylic acid 9 <18
Ethylene glycol dimethacrylate 0.8 NG
The prosthesis powder contained 3% methyl methac-
Methyl methacrylate 0.2 NG rylate (MMA) and 0.5% n-butyl methacrylate, al-
Product 29b (bonding agent for composite resin) though the MSDS did not declare any acrylics
N-methacryloxyethyl-N- 20 20-30
methylformamide
(Table 3). Acrylic denture-base liquids may contain
BIS-GMA 5.5 5-10 cross-linking dimethacrylates, and the analysis showed
Methacrylic compound 0.4 NG 4.6% EGDMA although it had not been declared in the
MSDS.
NG not given, BIS-GMA 2,2-bis-4-(2-hydroxy-3-methacryloxy-
propoxy)phenylpropane
Reinforced Composite Resin
Dental Acrylic Resins The analysis of an epoxy acrylate and styrene-based

reinforced plastic showed that only styrene was
Dental acrylics contained up to 37% of undeclared declared as a hazardous compound, although 8.1% of
acrylics (triethylene glycol dimethacrylate (TREGD- sensitising 2-hydroxypropyl methacrylate (2-HPMA)
MA) in Product 26, Table 2). Undeclared 2,2-bis-4-(2- was present in the plastic (Table 4).
Table 5. Identified chemicals in glues according to chromato- Table 5. (Contd.)

graphie analysis. The data have been compared with the
information given in the material safety data sheets (MSDS) Oligomethacrylate based on 10.0 NG/NG
ethylene glycol
Glue Concentration (%) MSDS (%) Polyurethane resin NA 20-40/NG
Acrylic acid 0.5-4/4-5
Product 51 (contact glue based on neoprene) Maleic acid NA NG/2-3
Acrylates, methacrylates <0.01 NG
Product 52 (jointing compound) NG not given, NA not analysed, MDI 4,4'-diphenylmethane
Acrylates, methacrylates <0.005 NG diisocyanate
Product 53 (water soluble dispersion glue) *Two MSDS
Dibutylphthalate ~2 NG
Acrylates, methacrylates <0.005 NG
Product 54 (anaerobic glue) Acrylic Glues
Oligoethylene glycol 58 NG
dimethacrylates
Triethylene glycol 13 <70 Acrylic glues used in the construction industry did not
dimethacrylate contain acrylics (detection limit 0.005%) (Table 5).
Diethylene glycol 2.7 NG The main component of the an aerobic glues was
dimethacrylate
Ethylene glycol 0.5 NG TREGDMA. DEGDMA or 2-HPMA were used as
dimethacrylate reactive diluents. Undeclared 2-HPMA was present
Acetophenone + cumyl ~1 NG (at 7.6%) in one glue (Product 55).
alcohol
Derivatives of toluidine ~1 <1 Tetrahydrofurfural methacrylate and isobornyl
Product 55 (anaerobic adhesive paste) acrylate were the main components in the analysed
Triethylene glycol 69 <60 two-component glues. Ethylhexyl methacrylate and 2-
dimethacrylate
Dibutylphthalate ~20 NG hydroxyethyl methacrylate (2-HEMA) were present as
2-Hydroxypropyl 7.6 NG reactive diluents. High concentrations of two sen-
methacrylate sitisers, HEMA (26%) and isobornyl acrylate (24%),
Mono- and diethylene glycol 0.3 NG
dimethacrylate were present, although undeclared. Undeclared epoxy
Methyl methacrylate 0.15 <1 resin (6%) had been added to two glues.
Acetophenone + cumyl ~0.5 NG
alcohol
N,N-dimethyltoluene amine ~0.1 NG Paints, Lacquers and (oatings
Hydroquinone <0.1
Product 56 (acrylic adhesive)
2-Hydroxyethyl methacrylate 26 NG
The UV lacquers contained several types of diacrylates,
Isobornyl acrylate 24 NG triacrylates and epoxy diacrylates. Up to 46% unde-
Ethylene glycol 1.0 NG clared diacrylates (tripropylene glycol diacrylates in
dimethacrylate
Methacrylic acid 0.3 NG
Product 64) were analysed. MMA was the main
Acetophenone + cumyl ~0.1 NG component in two concrete paints. These contained
alcohol up to 7.3% undeclared butanediol dimethacrylate
MDI-prepolymer 30
Product 57 (acrylie adhesive)
(Product 65). UV -light-cured coatings contained up
Tetrahydrofurfuryl 67 75-85 to 13% of undeclared oligotriacrylates and 7.6%
methacrylate undeclared hexanediol diacrylate.
2-Ethylhexyl methacrylate 15 NG
Methacrylic acid ~6 10
Ethylene glycol 1.4 NG
dimethacrylate MSDS - Opportunities for Improvement
Epoxy resin ~5 NG
Di-tert-butylcresol (BHT) 1.4 NG
Acetophenone + cumyl ~0.4 NG It must be accepted that there are real practical
alcohol difficulties in making substantive improvements in
Product 58 (adhesive)
Tetrahydrofurfuryl 80 55-65 the MSDS. That does not mean that they should not be
methacrylate attempted. It is our view that a much greater
Epoxy res in ~6 NG harmonisation of the current information contained
Epoxy diacrylate 0.32 NG in the MSDS would be helpful. Standardisation of the
n-Butyl methacrylate 0.05 NG predictive test methods employed, preferably by
Product 59 (acrylic glue) MSDSl/ adoption of more reliable protocols and the use of
MSDS2*
2-Hydroxyethyl methacrylate 24.6 30-60/ suitable benchmarks, would considerably enhance the
40-50 quality of the information in a MSDS. However, of
Ethylene glycol 0.4 NGING even greater value would be information on the
dimethacrylate
Isobornyl acrylate 61.9 NG/NG potency of the sensitisation or irritation hazard
present, even if this was seen to be a low risk due to,
400 D.A. Basketter and L. Kanerva
Table 6. Identified chemicals in paints and lacquers according to Table 7. Identified chemicals in ultraviolet (UV)-light-cured
gas chromatograpie analysis. The data have been compared with coatings according to chromatographie analysis. The data have
the information given in the material safety data sheets (MSDS) been compared with the information given in the material safety
data sheets (MSDS)
Paints and lacquers Concentration MSDS
(%) (%) UV -light-cured coating Concentration (%) MSDS (%)
Product 61 (UV -lacquer) Product 71 (offset coating)

Epoxy diacrylate 12 10-20 Oligotriacrylates (based on 14 NG
Oligotriacrylates (based on 13 20-25 propylene glycol)
propylene glycol) Benzyldimethylketal 2 NG
Tripropylene glycol diacrylates 7.6 NG Ester of dimethylamino- 2 NG
Hexanediol diacrylate 5.9 3-7 benzoie acid
Benzoyl hexanol ~2 NG Epoxy diacrylate 0.5 NG
Product 62 (UV -lacquer) Vinyl ester resin 35-45
Epoxy diacrylate 20 25-35 Product 72 (offset coating)
Tripropylene glycol diacrylates 27 17-20 Oligotriacrylates (based on 13 NG
Oligotriacrylates (based on 4.3 3-4 propylene glycol)
propylene glycol) Hexanediol diacrylate 7.6 NG
Hexanediol diacrylate 2.9 NG Tripropylene glycol 1.3 NG
Benzophenone ~I I diacrylates
Benzyldimethylketal ~1.5 1-2 Methylamino-bis-ethanol 7 NG
Ethylene glycol diacrylate 0.2 NG acrylate
Product 63 (UV-lacquer) Methylamino-bis-ethanol 4 NG
Epoxy diacrylate 14 20-25 Benzophenone 8 NG
Tripropylene glycol diacrylates 15 10-15 Vinyl-2-pyrrolidinone 2 NG
Oligotriacrylates (based on 3.0 NG Product 73 (gloss lacquer used in printing inks)
propylene glycol) Hexanediol diacrylate 31 30
Hexanediol diacrylate 14 10 Trimethylolpropane 16 9
Benzophenone ~I 1-2 triacrylate
Benzyldimethylketal ~1.5 NG Benzophenone 3 NG
Ethylene glycol diacrylate 0.3 NG Benzoylhexanol 0.5 NG
Product 64 (UV-lacquer) Ethylene glycol diacrylate 0.5 NG
Epoxy diacrylate 8.2 15-20 Polyester urethane acrylate * 61
Tripropylene glycol diacrylates 46 NG
Oligotriacrylates (based on 2.4 NG NG not given
propylene glycol) * Could not be analysed with the methods used
Hexanediol diacrylate 2.4 NG
Benzophenone ~2 NG
Trimethylolpropane triacrylate 0.2 35-45
Benzoylhexanol ~I NG for example, the presence of a strong sensitiser at a
Urethane acrylate prepolymer 10-20
very low concentration. Such information would be of
Product 65 (shop primer for concrete floors)
Methyl methacrylate 91 73 immense practical value in risk assessment/manage-
Butanediol dimethacrylate 7.3 NG ment. In addition, proper attention should be paid to
2-Ethylhexyl acrylate 0.06 NG the risk of oxidation of certain materials. Limonene
n-Butyl acrylate 0.05 NG
Toluidine ~I I and colophony are not sensitisers, but their oxidation
Product 66 (primer for concrete floors) products are (Karlberg et al. 1988). Such knowledge
Methyl methacrylate 55 45
should be encapsulated in the MSDS. Other suscepti-
2-ethylhexyl acrylate 35 24
Butanediol dimethacrylate 1.7 NG bilities of the product or other potential impurities
Toluidine ~I I should be included.
Tinuvin P (Le. 2(2-hydroxy-5- ~0.5 NG
methylphenyl)benzotriazol)
Product 67 (raw material for lacquer)
Epoxy diacrylate 34 NG Conclusion
Hexanediol diacrylate 26 20
Diglycidyl ether of bis-phenol A 0.2 NG
(DGEBA) In summary, the MSDS usually provides only the most
Product 68 (raw material for lacquer) basic information on significant intrinsic skin irrita-
Trimethylolpropane triacrylates 2.9 2
tion and sensitisation hazards. The quality of any
Ethylene glycol diacrylate 4.0 <3.5
Triethylene glycol diacrylates 4.5 NG information is highly variable and generally will say
Hydroxyethyl acrylate 0.4 <I nothing about the strength of the hazard presented.
Product 69 (cross-linker for parquet lacquer)
Information on sensitising impurities or the risk of
Reaction products of >80 NG
propyleneimine their formation, e.g. through oxidation, is normally
and trimethylolpropane triacrylate absent.
Trimethylolpropane triacrylate 0.6 NG
Accurate MSDSs are very important when trying to
NG not given reveal the cause of occupational contact dermatoses.
However, most of the analysed acrylate products packaging and labeling of dangerous preparations. Off J Eur
contained undeclared sensitising acrylics: (meth)acry- Communities L18:14
European Community (1992) Annex to Commission Directive 921
lates were not declared in 17 of 28 (61%) of the analysed 69/EEC Ohl July 1992 adapting to technieal progress for the
products, and up to 46% of the materials present were seventeenth time Council Directive 67/548/EEC on the
undeclared, sensitising acrylics (Kanerva et al. 1997). approximation of laws, regulations and administrative pro-
visions relating to the classification, packaging and labelling
Thus, the user of the MSDS has in effect three of dangerous substances. Off J Eur Communities L383A:35
options: take the information at face value, ignore the European Community (1993) Council regulation EEC No 793/93
information or treat the information as a stimulus to of 23 March 1993 on the evaluation and control of the risks of
existing substances. Off T Eur Communities L18:14 ..
undertake a more detailed search followed by an European Community (1996) Annex V. Off J Eur CommumtIes
analysis of the information in the context of the L2481226
known/expected skin exposure. This last course of Food and Drug Administration (1972) Uni ted States - Food and
Drug Administration. Hazardous substances. Proposed revi-
action is the one that is recommended if the need for a sions of test for primary skin irritants. Fed Reg 37:27635
clinical or safety evaluation is of importance. Infor- Frankild S, Basketter DA, Andersen KE (1996) The value and
mation on product ingredients should also be given for limitations of rechallenge in the guinea pig maximisation test.
sensitising substances present at concentrations lower Hannuksela A, Hannuksela M (1995) Irritant effects of a detergent
than 1%. Therefore, better MSDSs and product decla- in wash and chamber tests. Contact Dermatitis 32:163-166
rations should be required from industries before their Kanerva L, Estlander T, Jolanki R (1996) Allergy caused by
acrylics - past, present and prevention. In: Elsner P,
products are put on the market. Lachapelle T-M, WaiIlberg J, Maibach HI (eds) Prevention
of contact dermatitis. (Curr Probl Dermatol vol 25). Karger,
Basel, pp 86-96
Kanerva L, Henriks-Eckerman M-L, Tolanki R, Estlander T (1997)
Plastics/acrylics: material safety data sheets need to be
References improved. Clin DermatoI15:533-546
Karlberg A-T, Bohlinder K, Boman A, HackseIl U, Hermansson J,
Tacobsson S, Nilsson TLG (1988) Identification of 15-hydro-
Barratt MD (1996) Quantitative structure activity relationships peroxyabietie acid as a contact allergen in Portugese
for skin irritation and corrosivity of neutral and electrophilic colophony. J Pharm Pharmacol 40:42-47
organie chemie als. Toxicol In Vitro 10:247-256 Karlberg A-T, Goossens A (1997) Contact allergy to oxidized D-
Barratt MD, Basketter DA, Roberts DW (1997) Quantitative limonene among contact dermatitis patients. Contact Der-
structure activity relationships. In: LePoittevin J-p, Basketter
matitis 37:308-309
DA, Dooms-Goossens A, Karlberg A-T (eds) The molecular Organisation for Economie Cooperation and Development (1993)
basis of allergie contact dermatitis. Springer, Berlin Heidel- Skin sensitisation test guideline 406
berg New York, pp 129-154 Robinson MK, Nusair TL, Fletcher ER, Ritz HL (1990) A review of
Consumer Product Safety Commission (1979) Federal Hazardous the Buehler guinea pig skin sensitisation test and its use in a
Substances Act, Code of Federal Regulations. Title 16, part risk assessment process for human skin sensitization. Tox-
1500.42. Federal Register icology 61:91-107
Draize JH, Woodard G, Calvery HO (1944) Methods far the study United Nations (1993) Recommendations in the transport of
of imitation and toxicity of substances applied topically to the
dangerous goods, 8th edn. United Nations. ST/SG.AC.I0/REv.
skin and mucous membranes. T Pharmacol Exp Ther 82: 8:185
377-390 Weil CS, Scala A (1971) Study of intra- and inter-laboratory
Draize JH (1959) Dermal toxieity. In: Appraisal of the safety of variability in the results of rabbit eye and skin irritation tests.
chemicals in foods, drugs and cosmeties. Association of Toxieol Appl Pharmacol 19:276-360
Foods and Drugs Officials of the United States, Littleton, Whittle E, Barratt MD, Carter TA, Basketter DA, Chamberlain M
pp 46-59 (1996) Use of QSAR and an in vitro skin corrosivity test to
European Community (1988) Council Directive of 7 June 1988 on investigate the corrosion/irritation potential of organic acids.
the approximation of the laws, regulations and administrative Toxicol In Vitro 10:95-100
provisions of the Member States relating to the classification,
CHAPTER 51
Treatment of Irritant and Allergie Contact Dermatitis

H. Zhai, A. Anigbogu, and H.l. Maibach
Introduction single application of a moisturizer did not cause long-

lasting effects expressed as skin capacitance and
It is not always practical for persons, whose occupation conductance [8, 55], whereas repeated applications of
or activities mandate the use of irritants or allergens, a moisturizer twice daily for 1 week produced a
to avoid their use. In order to reduce the risk of significant increase in the skin conductance for at
developing irritant contact dermatitis (ICD) and aller- least 1 week post-treatment [79].
gic contact dermatitis (ACD) in industry, prophylactic Urea, a physiological non-allergic substance [77,84],
measures are indicated. Application of moisturizers as has long been used in dermatological therapy. Urea
weIl as barrier creams (BCs) before or during work and can decrease reversibly the turnover of epidermal cells
wearing appropriate gloves and clothing may be [41] and may also enhance the penetration of other
protective. Oral and, to a lesser extent, topical substances into the skin [24, 77, 96]. Other effects
corticoids have demonstrated significant efficacy in include binding water in the horny layer, antipruritic,
the treatment of ACD. Additional therapies include and reducing contact dermatitis from irritant stimuli
UVB/UVA treatment, other immunosuppressives, and [53, 77, 78, 84].
Grenz ray. Hannuksela and Kinnunen [42] developed a washing
test method to determine the effect of moisturizers in
preventing irritant dermatitis. The participants washed
Avoidance the outer aspects of their upper arms with a liquid
dishwashing detergent for 1 min twice daily for 1 week.
Moisturizers Eight commercial moisturizers were applied onto the
left upper arm just after each washing, while the other
Moisturizers are frequently used to improve "dry" skin arm was untreated. During the second week, the left
signs and symptoms, as weH as chapped hands and heels, upper arm only was treated with the moisturizers twice
ichthyosis, asteatosis, atopic dermatitis, and atopic dry daily. Transepidermal water loss (TEWL) increased
skin, etc. Application of moisturizers daily may modify during the washing period by 13 g/m 2 /h in the
the skin surface's physical and chemical nature, so as to untreated arm, while the increase in the treated areas
smooth, soften and make more pliable [100]. was only 3 g/m 2 /h. Visible dermatitis appeared on the
Moisturizers often contain humectants of low mole- untreated arm, while the treated areas remained
cular weight and lipids. Humectants, such as urea, objectively and subjectively symptom and sign free.
glycerin, lactic acid, pyrrolidone carboxylic acid Blood fiow also increased significantly in the washed,
(PCA), and salts, are absorbed into the stratum untreated arm, but not in the arm treated with
corneum and there, by attracting water, increase moisturizers. During the second week, the dermatitis
hydration [54]. Lipids, for instance petrolatum, beeson the washed, untreated arm disappeared and the
wax, lanolin, and various oils in moisturizers, have laser Doppler values normalized. The TEWL values
traditionally been considered to exert their effects on also decreased to near normal. The mean decrease was
the skin solely by forming an inert, epicutaneous, more pronounced when moisturizers with a high fat
occlusive membrane. They are incorporated into content were used but, due to inter-individual varia-
formulations on the basis of their technical and tion, the differences among the results for the eight
sensory properties rather than on their possible moisturizers were not statistically significant. When
epidermal impact [52, 54]. However, topically applied the effect of a moisturizer was compared with no
lipids may also penetrate to the living cells of normal treatment after the 1-week wash-out period, the use of
epidermis, be metabolized and significantly modify the moisturizers was found to enhance the healing
endogenous epidermal lipids [92]. In normal skin, a process significantly.

Treatment of Irritant and Allergie Contact Dermatitis 403
Halkier-S0rensen and Thestrup-Pedersen [40] uti- Barrier Creams

lized a cross-over study to evaluate the efficacy of a
moisturizer (Locobase, Yamanouchi Europe B. V. BCs are designed to prevent or reduce the penetration
Research Laboratories, Leiderdrop, The Netherlands) and absorption of various hazardous materials into
among cleaners and kitchen assistants during daily skin, preventing skin lesions and/or other toxic effects
work. The population was divided into two groups: 56 from dermal exposure [27, 28, 47, 70, 98, 99]. BCs are
workers used the test moisturizer only on their hands often used to prevent and treat contact dermatitis (CD)
for the first 2 weeks and no emollient during the in industry and in the horne. Their efficacies have been
subsequent 2 weeks, and vice versa (n =55). The investigated by means of in vitro and in vivo studies
moisturizer prevented the development of skin dry- [27, 47, 94, 99]. However, their actual benefit remains
ness. Electrical capacitance (epidermal hydration) sub judice in clinical trials [27-30,35-37,47,86,87,94].
decreased significantly when the study subjects were Inappropriate BC application may exacerbate rather
not using the moisturizer but, unexpectedly, there was than ameliorate [27-30,35,36,98]. In practice, BCs are
no increase in the TEWL rates or in skin temperature. usually recommended only for low-grade irritants
Loden [53] showed that repeated applications of (water, detergents, organic solvents, cutting oils) [30,
urea-containing moisturizers infiuenced both TEWL 94,98]. They are also used to protect the face and neck
and the apparent susceptibility to sodium lauryl sulfate against chemical and resinous dust and vapors [6].
(SLS)-induced irritation. Three applications of 5% urea Minimal information on the mechanisms of BC's
increased TEWL, whereas treatment with 10% urea for action exists. The frequently quoted theory is that
10 days and 20 days decreased TEWL. It is possible water in oil (W/O) emulsions are effective against
that a greater amount of urea alters the binding aqueous solutions of irritants, and oil in water (O/W)
capacities of the stratum corneum, retarding SLS emulsions are effective against lipophilic materials [14,
penetration. 27,47,61]. Some studies have demonstrated exceptions
Gammal et al. [33] assessed the efficacy of moistur- to this rule [26,29]. BC may contain active ingredients
izers using a soap-induced xerosis human model. The that are presumed to work by trapping or transforming
lower legs of 22 women were washed daily for 10 days allergens or irritants [26, 47]. Most believe they
with soap to induce chemical xerosis. After washing, interfere with absorption and penetration of the
one side received a moisturizer, the other served as an allergen or irritants by physical blocking - forming a
untreated control. The values of clinical scaling, thin film that protects the skin [26, 47, 60, 70].
electrical conductance, and D-Squames were compared To avoid frequent interruptions for reapplication,
on each evaluation day. On the moisturizer-treated BCs are expected to remain effective for 3-4 h. Most
legs, there was a significant decrease in dryness grades manufacturers claim that their products last approx-
and scaling at all time points. Conductance was imately 4 h. Others suggest to use "as often as
significantly increased on day 8 and day 11. necessary" [14]. Several studies document duration of
Olivarius et al. [69] evaluated the effect of moistur- action with varying results [10,74, 102, 98].
izing creams against water in an vivo human model, Application methods may infiuence the effectiveness
based on the color intensities when an aqueous of the BCs [71]. By means of a fiuorescence technique
solution of crystal violet was applied to the dorsal in the workplace, Wigger-Alberti et al. [95] determined
and volar ofhand skin in 12 subjects whose hands were areas of tlIe hands likely to be skipped on self-
pretreated with test creams. The test moisturizer application of Be. Results showed the application of
showed some protective effect (dorsal 57%, volar BC was incomplete, especially on the dorsal aspects of
34%) against water. the hands. Most manufacturers suggest rubbing tho-
Recently, Held et al. [44] determined the affect of roughly into skin; to pay special attention to cuticles
long-term use of a moisturizer on normal skin on 20 and skin under nails; to let it dry for approximately
healthy volunteers. One forearm was treated with a 5 mini and to apply a thin layer of BC to all appropriate
moisturizer three times daily, while the other forearm skin surfaces three to four times daily.
served as an untreated control. Four weeks later, both Various in vivo and in vitro methods have been
forearms were challenged with SLS patches. Electrical developed to evaluate the efficacy of BCs. Table 1
capacitance was significantly increased on the treated summarizes the efficacy from recent experiments.
arm. After the challenge with SLS, the TEWL was
significantly higher on the moisturizer-treated arm. Protective Gloves and Clothing
They suggested that long-term application with mois-
turizer on normal skin may increase skin susceptibility Gloves may provide certain protective effects against
to irritants. corrosive agents (acids, alkalis, etc.) [10,62,64,65,94].
A wealth of data on the physiology, pharmacology, Protective clothing as well as other personal devices
and toxicology of moisturizers is found in Loden [56]. also play a critical role as an important measure in
404 H. Zhai et al.
Table 1. Summary of the efficacy of barrier cream (BC) from recent experiments
Models Irritants or allergens BCs Efficacy Authors and reference

In vitro/In vivo
Animals or humans
Guinea pigs n-Hexane, 3 Water-miscible Limited protective Lachapelle et al. [48]

trichlorethylene, creams effects
and toluene
Guinea pigs Cutting oil 2 BCs Exacerbating the irritation Goh [35,36]
Humans who had a Epoxy resin, glyceryl One BC Minimizing the McClain and Storrs [62]
his tory of allergic monothioglycolate, development of allergic
to test allergens frullania, and tansy contact dermatitis
Humans who had a Toxicodendron Various barrier Most ofthem Grevelink et al. [38]
positive patch test extract preparations provided good
to Toxicodendron protective effects.
extract
Guinea pigs and SLS, sodium Several BCs Some of them suppressed Frosch et al. [26, 28-30]
humans hydroxide, toluene, irritation, some failed,
and lactic acid and some even aggressive
irritation
Human skin Dyes (eosin, 16 BCs Various % protection Treffe! et al. [87]
methylviolet, effects
oil red 0)
Machinists Castroloil One BC and one They did not appear any Goh and Gan [37]
afterwork significant effect against
emollient cutting fluid dermatitis
Humans who had a Urushiol Quaternium-18 Q-18B lotion Marks et al. [60]
his tory of allergic bentonite (Q18B) significantly reduced
to poison ivy/oak lotion reactions to the urushiol
Human skin Nicke! disc Ethylenediamine- Significantly reduced the Fullerton and Menne [31]
Nickel-sensitive etraacetate (EDT A) amount of nickel in the
patients gels epidermis in vitro, and
significantly reduced
positive reactions in vivo
Humans Dyes (methylene blue 3 BCs Two of them exhibited Zhai and Maibach [98]
and oil red 0) effectiveness, one
enhanced cumulative
amount of dye
Humans Water 2 BCs and a Various % protection Olivarius et al. [69]
moisturizer effects
Humans 10% SLS, 1% NaOH, 4 BCs and white Very different protective Schlater-Wigger and
30% lactic acid, petrolatum effects were detectable. Eisner [75]
and undiluted All products were very
toluene effective against SLS
irritation
Humans Toluene Several BCs All tested BCs markedly Grunewald et al. [39]
reduced the irritating
effect of repetitive
toluene contact
Humans Toluene and NaOH Several BCs None of them were able Treffel and Gabard [86]
to prevent the skin
erythema induced by
toluene. One BC as weil
as petrolatum and a
fatty cream protected
the skin significantly
when against NaOH
Guinea pigs Sulfur mustard Povidone iodine (PI) PI ointment showed the Wormser et al. [97]
ointment powerful protective
effect
Humans Self-application An oil in water Self-application of BC Wigger-Alberti et al. [95]
ofBC emulsion was incomplete
Human skin [35S]-SLS 3 Quaternium-18 % protection effect Zhai et al. [102]
bentonite (Q18B) was 88%, 81% and
gels 65%, respectively
Humans SLS, ammonium Several protectants Most of them suppressed Zhai et al. [101]
hydroxide (NH 4OH) the SLS irritation and
and urea, Rhus Rhus allergic reaction,
failed to NH 40H and
urea irritation
industries [14, 61]. Note that protective clothing may Mechonism of Action
trap moisture and occlude potentially damaging sub-
stances next to the skin for prolonged periods and Corticoids being lipophilic in nature permeate the skin
increase the likelihood that dermatitis will develop [14, by passive diffusion, the rate of which is directly
61]. The first line of defense against hand dermatitis is related to the extracellular concentration. The extra-
to wear gloves but, in many professions, it is impos- cellular concentration is determined by many factors,
sible to wear gloves because of the loss of dexterity. In which include the concentration of the applied steroid,
some instances, an alternative would be to utilize BCs. percutaneous penetration, metabolie inactivation, and
Note that many gloves do not res ist the penetration of removal into the systemic circulation. Even though the
low-molecular-weight chemieals. Some allergens are precise sequence of cellular and subcellular events
soluble in rubber gloves and may penetrate the glove leading to the observed effects of topical steroids are
and produce severe dermatitis [18, 19, 61, 64, 94]. still unclear; these compounds are known to act in four
Recently, allergy to rubber latex has become a growing ways: anti-inflammatory, immunosupprossive, anti-
problem [18, 19, 64, 94], and workers can develop mitotic and vasoconstrictive.
serious symptoms [3] (i.e., contact urticaria syn- Following the penetration of the cell membrane,
drome), including generalized urticaria, conjunctivitis, corticoids bind with specific cytoplasmic receptors.
rhinitis, and asthma, etc [3, 94]. Estlander et al. [18] These receptors have been demonstrated in all target
have introduced the role and details of protective tissues including the skin [4, 17]. After modification,
gloves in preventing ICD and ACD in their chapter. the steroid-receptor complex enters the nucleus, where
Mellström et al. [64] documents this area in detail. it interacts with DNA to alter the production of mRNA
induced locally by RNA polymerase. This mRNA
moves into the cytoplasm, where it attaches to
Treatment ribosomes and acts as a template for protein synthesis.
Since inflammation is the endpoint of the immune
Corticoids response, the anti-inflammatory and immunosuppres-
sive effects of corticoids may overlap. Corticoids
Soon after the introduction of glucocorticoids, it was effectively suppress inflammation caused by infectious,
apparent to dermatologists that this group of com- mechanical, radiant, immunologieal, or chemie al
pounds had a wide ranging application to human agents. They inhibit many aspects of the inflammatory
diseases, particularly in conditions involving inflam- response, a major focus being the reduction of
mation. Corticoids are used in three ways: orally and neutrophil and monocyte recruitment into the in-
parenterally, intralesionally and topically. These drugs, volved areas [72]. Corticoids also affect leucocytes and
whether administered orally or topically, are effective macrophages by reducing adherence, migration, and
in many inflammatory conditions. Topical application phagocytosis [85, 90]. Corticoids also inhibit the later
is, however, preferred with a view to minimizing their manifestations of inflammation: capillary proliferation,
systemic side effects. This seetion reviews topical fibroblast proliferation, deposition of collagen, and
corticoids and their use in the treatment of irritant cicatrization [43]. There is also evidence that corticoids
and allergie contact dermatitis. induce the synthesis of a protein that inhibits phos-
Hydrocortisone, which became available in the 1950S, pholipase A2, thus diminishing the release of arachi-
was shown to be efficacious in eczematous dermatoses donic acid from phospholipids. This in turn decreases
[83]. The success associated with hydrocortisone led to the formation of prostaglandins, leukotrienes, and
the design and development of other more potent related compounds that play a key role in the
analogues. The fluoro derivatives of hydrocortisone inflammation process [7, 45].
and prednisolone were also active topically but had The vasoconstrictive property of corticoids may
strong mineralocorticoid activity. The next major contribute to their anti-inflammatory effects. The
advance in topical corticoid therapy came with the mechanisms by which topical corticoids cause vaso-
introduction of triamcinolone acetonide, followed constriction remains unclear but is thought to be
shortly after by flucinonolone acetonide. Bethamethas- related to their inhibition of natural vasodilators,
one-17-valerate was found to be more active than histamine, bradykinins, and prostaglandins [2, 46].
triamcinolone acetonide and flucinonolone acetonide. Some have suggested that corticosteroids potentiate
The early 1970S saw the introduction of the 21-acetate norepinephrine [34], while others suggest that co-
derivative of fluocinolone acetonide, with more bio- rticoids cause the release of norepinephrine [81].
logical activity than the others. Since the late 1970S, Corticoids are thought to also have a direct effect on
many more-potent topically active glucocorticoids have vascular endothelial cells.
been introduced including desoximetasone, clobetasol The effect of topical application of corticoids on
propionate, and betamethasone-17-dipropionate. human mast cells have been examined [50]. Two
406 H. Zhai et al.
potent corticoids, clobetasol-17-propionate and flu- C/inica/ Formu/ations and Potency of Corticoids
ocinonide, produced a greater than 85% decrease in
histamine content over 6 weeks of treatment. Exami- Corticoids form a vast range of compounds and
nation of biopsies taken after the treatment by electron formulations with varying effects. Table 2 is a grouping
microscopy revealed marked mast-cell depletion. His- of topical corticoids according to their relative potency.
tamine levels did not decline until after 3 weeks of The relative potencies are based on the vasoconstrictor
treatment. This therefore suggests that corticoids are assay [82]. The formulations in each group are only
not immediately harmful to mast cells. The first signs roughly equipotent. Note that the relative potency
of cells containing sparse amounts of mast-cell gran- should be considered carefully when choosing the
ules were apparent 14 days post-steroid treatment. By formulations for an individual patient. While the least
3 months, histamine levels returned to normal. This potent corticoids, such as hydrocortisone, may be
work suggested a possible treatment for one human sufficient in certain conditions, and for long-term
mast cell disease, urticaria pigmentosa, and a possible maintenance therapy, it may be ineffective in other
additional mechanism of action of corticoids. Maibach conditions and in certain sites such as palms and soles,
and Surber [58] and Korting and Maibach [57] provide where the skin is thickened. Furthermore, it is to be
additional details. noted that the greater the potency of the corticoid, the
Percutaneous Penetration Table 2. A partial list of topical corticoids available in the United
States, ranked according to their potencies
Theoretically, an ideal corticoid should permeate the Drug Potency (%)

stratum corneum and reach an adequate concentration
Lowest potency
in the epidermis without crossing the dermis to reach Hydrocortisone 0.25-2.5
the systemic circulation. This may be achieved by Methylprednisolone acetate 0.25
increasing the lipophilicity of the topically active Dexamethasonea 0.04
Dexamethasonea 0.1
steroids resulting in an alteration of the partition Methylprednisolone acetate 1.0
coefficient. Prednisolone 0.5
In reality, following topical application, corticoids Betamethasonea 0.2
Low potency
penetrate the stratum corneum and are absorbed into Fluocinolone acetonidea 0.01
the epidermis. The efficacy and toxicity are directly Betamethasone valeratea 0.01
related to corticoid penetration. Corticoids may act on Flurometholonea 0.025
Aclometasone dipropionate 0.05
the epidermis, the dermis or both. In each case, it is Triamcinolone acetonidea 0.025
therefore unlikely that molecules residing only in the Clocortolone pivalatea 0.1
stratum corneum contribute to their therapeutic Flumethasone pivalate a 0.03
Intermediate potency
effects. Hydrocortisone valerate 0.2
The rate of absorption is influenced by the status of Mometasone furoate 0.1
the skin, chemical structure of the steroid and such Hydrocortisone butyrate 0.1
Betamethasone benzoatea 0.025
other factors as formulation and formulation vehicle. Flurandrenolidea 0.025
Topical corticoids applied to diseased skin will be Betamethasone valerate a 0.1
absorbed to some degree into the systemic circulation. Desonide 0.05
Halcinonidea 0.025
When administration is chronic or when large areas of Desoximetasone a 0.05
skin are involved, the absorption may be sufficient to Flurandrenolidea 0.05
cause systemic effects including cushinoid changes and Triamcinolone acetonide a 0.1
Fluocinolone acetonidea 0.025
adrenocortical suppression. High potency
Topical corticoids are minimally absorbed from Betamethasone dipropionate a 0.05
healthy skin. On the forearm, approximately 1% of the Amcinonidea 0.1
Desoximetasonea 0.25
applied dose of hydrocortisone penetrates [21, 59]. Triamcinolone acetonide a 0.5
Other corticoids for which data exist are not neces- Fluocinolone acetonidea 0.2
sarily absorbed to a greater degree than hydrocorti- Diftorasone diacetate a 0.05
Halcinonidea 0.1
sone [23], suggesting that they may owe their increased Fluocinonidea 0.05
efficacy to their potency rather than enhanced pene- Highest potency
tration. To put this in perspective, only 1% of Betamethasone dipropionatea in optimized 0.05
vehicle
corticoids applied to healthy skin is therapeutically Diftorasone diacetatea in optimized vehicle 0.05
active, with approximately 99% being wasted either by Clobetasol propionatea 0.05
being rubbed off, washed off, or exfoliating with the
stratum corneum. a Fluorinated steroids
greater the therapeutic efficacy and likelihood, there- Adverse Effeds

fore, of more adverse effects. When reading relative
vasoconstriction data, verify whether the experiment All absorbable corticoids possess the ability to produce
refers to the use of occlusion, to a simple solvent vehicle adrenal suppression [11,76]. The degree of suppression
like alcohol, rather than the final formulation, or to is related to potency. Comparative quantitative studies
open testing, with or without a guard to protect wipe- employ the Food and Drug Association's (FDA)
off, for variable times. The relative rankings can be diseased-skin protocol. As little as 14 g per week of
varied significantly by altering these factors. clobetasol has induced suppression. Optimized beta-
Superpotent formulations include clobetasol propi- methasone diproprionate is somewhat less suppres-
onate, optimized betamethasone diproprionate, and sive, requiring over 49 g per week to significantly
difluorosone. These corticoids are grouped together reduce plasma cortisol. Incomplete data with difluo-
since they are unique in being a class of compounds rosone suggests that it may be less suppressive.
that are not only superpotent, but must be used with Fortunately, plasma cortisol usually returns to normal
caution; they have the potential for significant topical within 3 days when the superpotents are discontinued,
and systemic side effects far in excess of other at least in short-time application studies.
currently utilized formulations. Certain factors increase the penetration and there-
Because of the increased risk of systemic and local fore the tendency to suppression - application to large
toxicity from the super-potents, considerable clinical surface areas, occlusion, inflamed skin and higher
investigation is underway to define application sched- concentrations. Of concern in children is growth
ules that maximize efficacy and minimize adverse retardation associated with excessive and prolonged
effects. This research depends on clinical observations, use of topical corticoids [9, 68, 89, 93]. A summary of
i.e., ascertaining the least frequency of application that adverse effects caused by corticoids is in Table 3.
will maintain a disease (usually psoriasis) under
control. Too few studies have been completed to Dosage and Administration
prudently generalize; nevertheless, we suspect that
each superpotent corticoid and specific vehicle may Physicians rarely prescribe oral or parenteral prepara-
not be the same as the other. Furthermore, none of the tions without due consideration to dosage; yet most
studies utilized fundamental studies of dermatophar- physicians prescribe topical corticoids with little or no
macokinetics to separate drug delivery from biologie thought as to number of milligrams of material per
result. We hope that meticulous experimental design surface area of skin. There is a dose-response relation-
will lead to dermatopharmacokinetics and biologie ship, with increasing efficacy closely following in-
(efficacy) intermittent studies maximizing efficacy and creased dose. Several-fold differences in dose can
minimizing toxicity, so that intermittent dosing will override differences in potency among halogenated
permit greater use of the superpotents. analogues. It is therefore important to make an estimate
Ascertaining the optimal intermittent schedule has of the quantity a patient would require in any given
yet to be achieved; this golden grail might be attained condition. Remember that with a given corticoid,
more efficiently by combining knowledge of the basic increasing the concentration will often produce in-
dermatopharmacokinetics with the classical approach- creased efficacy. Fortunately, most manufacturers pro-
es of clinical studies. Until the appropriate kinetic data vide a standard or regular concentration yielding the
become available with these potent agents, we cannot desired therapeutic result for most patients. For
be certain how much less systemic exposure occurs instance, triamcinolone acetonide is available in
with the intermittent exposures than with daily or 0.025%, 0.1% and 0.5% formulations. The bulk of
twice-daily dosing. patients with corticoid-responsive dermatoses need
only the 0.025% formulations; by increasing this to
0.1%, all but a few percentages of probable responders
Vehic/es will respond. For the patient with more resistant
lesions, however, the 0.5% formulations may provide
The potency of topical corticoids can be further the difference between therapeutic success and failure.
enhanced by enhancing percutaneous absorption. One For certain uncommon instances, such as psoriasis of
such way of optimizing absorption is by altering the the palms and soles, even higher concentrations, 1%
formulation vehicle. It is now very clear, however, that triamcinolone acetonide, may be compounded.
some vehicles enhance the penetration and biologie The standard trade concentrations suffice for most
activity of therapeutic agents [82]. It is important for patients. In the more resistant diseases, higher con-
vehicles to be free of the three S's, namely, sting, stench, centrations should be considered. For instance, ap-
and stain. Ointment bases tend to give better activity to proximately 1% of a 0.25% hydrocortisone solution is
the corticoid than do cream or lotion vehicles [82]. absorbed from the forearm. Increasing the amount
408 H. Zhai et al.
Table 3. Adverse effeets associated with topieal eortieosteroid associated with occlusion therapy - the plastics are
therapy sometimes uncomfortable, warm, and troublesome to
Loeal use. Side effects encountered with occlusion include
Atrophy miliaria, and bacterial and candidal infections. The
Striae
Ulcerations
incidence of side effects correlates directly with the
Eetasia duration of occlusion and, for this reason, the plastic
Purpura should generally be worn for no more than 12 h per day.
Stellate pseudosears
Nonhealing wounds
Occlusion has the added advantage of keeping the
Infeetions drug on the skin by preventing rubbing off onto
Granuloma gluteal infantum clothing. Occlusion is also particularly useful in
Tinea ineognito
Seabies ineognito
pruritic skin diseases, as it limits access to the skin
Ophthalmie and therefore scratching, which may worsen the
Oeular hypertension condition. We do not have data delineating the effect
Glaueoma
Cataraets
of duration of occlusion on percutaneous penetration
Pharmaeologie with topical corticoids.
Cortieoid addietion
Corticoid rebound
Taehyphylaxis
Frequency of Application
Dermatologie
Cortieoid aene Previously, patients applied topical corticoids three to
Cortieal rosaeea
Allergie eontaet dermatitis
four times daily. Studies on the percutaneous absorp-
Perioral dermatitis tion of hydrocortisone failed to reveal a significant
Hypopigmentation increase in absorption applied on a repetitive basis
Masking underlying eutaneous diseases
Generalized
compared with a single dose [49]. Clinical trials of
Weight gain various corticoids suggest that less-frequent applica-
Cushing's syndrome tions are equally effective [25]. In view of the relatively
Eleetrolyte imbalanee
Hypertension
slow process of corticoid absorption, a phenomenon
Diabetes referred to as the "reservoir effect" [91], there may not
Pseudo-primary aldosteronism be any advantage in frequent applications.
Growth retardation
Acute tolerance (tachyphylaxis) to vasoconstriction
and antimitotic effects of and suppression of epidermal
applied per unit area of skin tenfold increases the DNA synthesis by topical corticoids have been dem-
amount absorbed four times. Other methods of onstrated [15, 16]. This suggests that the resistance
increasing effectiveness are described under Occlusion clinically observed after prolonged use might be
and previously under Vehicles. Increased efficacy, prevented by less intensive therapy, such as daily
however, must be balanced against increased risk of application with short resting periods between treat-
adverse effect (see discussion of adverse effects). ment courses [5, 67]. Another study examining co-
Regional differences in response are partially based rticoid tachyphylaxis used fluocinolone acetonide
mainly on the differences in penetration of skin in under occlusion to the forearm and induced wheal
various areas. Thus, areas with increased permeability, and flare to histamine with the prick technique [80].
such as the scrotum, eyelids, ears, scalp, and face By the eighth day, the wheal was nonexistent, adding
respond far better to topical corticoids than such areas now a third tachyphylaxis phenomena.
as the dorsa of the hands, extensor surfaces of knees
and elbows, and the palms and soles [63]. Anatomic Variation
Occlusion Large regional variations in percutaneous absorption

of compounds are determined by factors including
Ninety-minute and six-hour occlusions with an imper- hair follicle density, thickness of the stratum corneum,
meable film, such as plastic wrap, constitute a most and vasculature of the region [13]. There is a distinct
effective method of enhancing penetration, yielding difference in the penetration of hydrocortisone in
approximatelya tenfold increase [20]. Specifically, with different anatomic sites. This suggests that for areas of
occlusion, penetration of hydrocortisone on the fore- higher penetrability, such as the face, scalp, scrotum,
arm increases from 1% of applied dose to 10%. This axilla, and the groin, smaller doses are required and
tenfold increase constitutes an important clinical occlusion is not needed [22].
advantage; even with the more potent analogues, In flexural areas, in which hydration may occur,
occlusion in the resistant case will often produce a absorption may be increased. Absorption through
successful result. There are, however, obvious problems diseased skin with an increased blood supply may
Treatment of Irritant and Allergie Contaet Dermatitis 409
also increase. Little quantitative information is, how- References

ever, available on how much penetration is increased
in diseased skin [1]. In initial studies, it was noted that 1. Aalto-Korte K, Turpeinen M (1995) Pharmacokinetics of
skin with only minimally involved atopic dermatitis topical hydrocortisone at plasma level after applications once
or twice daily in patients with widespread dermatitis. Br J
allowed for a several-fold increase in penetration; Dermatol 133:259-263
psoriatic plaques showed no significant increase, 2. Altura BM (1966) Role of glucocorticoids in local regulation
whereas exfoliative psoriatic skin had little barrier to of blood flow. Am J Physiol 211:1393-1397
3. Amin S, Maibach HI (1997) Immunologic contact urticaria
penetration. This important subject needs additional definition. In: Contact urticaria syndrome. Amin S, Lahti A,
investigation, which should be of practical value in Maibach HI (eds), CRC Press, Boca Raton, pp 11-26
dermatopharmacology. 4. Ballard PL, Baxter JD, Higgins SJ, Rousseau GC, Tomkins GM
(1974) General presence of glucocorticoid receptors in
mammalian tissues. Endocrin 94:998-1002
5. Barry BW, Woodford R (1977) Vasoconstrictor activities and
bioavailabilities of seven proprietary corticosteroid creams
Controlled Topical Efficacy Studies - assessed using a non-occluded multiple dosage regimen:
ICD and ACD clinical considerations. Br J Dermatol 97:555-560
6. Birmingham D (1969) Prevention of occupational skin
disease. Cutis 5:153-156
Irritant Dermatitis 7. Blackwell GJ, Carnuccio R, DiRosa M, Flower RJ, Parente L,
Persico P (1980) Macrocortin: a polypeptide causing the anti-
phospholipase effect of glucocorticoids. Nature 287:147-149
Although most physicians employ topical corticoids in 8. Blichmann CW, Serup J, Winther A (1989) Effects of single
irritant dermatitis, the two controlled studies in application of a moisturizer: evaporation of emulsion water,
experimental irritant dermatitis to SLS show either skin surface temperature, electrical conductance, electrical
capacitance, and skin surface (emulsion) lipids. Acta Derm
no, or a negative [88] or a minimal effect [73]. Venereol 69:327-330
9. Bode HH (1980) Dwarfism following long-term topical
corticosteroid therapy. J Am Med Assoc 244:813-814
Allergie Contact Dermatitis 10. Boman A, Walliberg JE, Johansson G (1982) A method far the
study of the effect of barrier creams and protective gloves on
the percutaneous absorption of solvents. Dermatologica
Several studies document some degree of efficacy when 164:157-160
high potency corticoids are applied after the acute 11. Carr RD, Tarnowski WM (1968) Percutaneous absorption of
corticosteroids: adrenocortical suppression with total body
phase [32]. Considering the massive amounts pre-
inunction. Acta Derm Venereol 48:417-428
scribed, the data is limited - presumably because this 12. Christensen OB (1994) UV -light treatment of hand eczema.
has long been the standard of care. In: Menne T, Maibach HI (eds) Hand eczema. CRC Press,
Boca Raton, pp 293-301
13. Cronin E, Stoughton RB (1962) Percutaneous absorption:
Immunosuppressives regional variations and the effect of hydration and epidermal
stripping. Br J Dermatol 74:265-272
Cyclosporin, tacrolimus, and azathioprine are used in 14. Davidson CL (1994) Occupational contact dermatitis of the
upper extremity. Occup Med 9:59-74
unusual instances. See the book of Menne and Maibach 15. Du Vivier A, Stoughton RB (1976) Acute tolerance to effects
[66] for details. of topical glucocorticoids. Br J Dermatol 94[Suppl12]:25-32
16. Du Vivier A, Phillips H, Hehir M (1982) Applications of
glucocorticosteroids: the effects of twice-daily vs once-every-
UV Light other-day applications on mouse epidermal cell DNA syn-
thesis. Arch Dermatol 118:305-308
Most patients with ICD and ACD may be controlled by 17. Epstein EH, Bonifas JM (1982) Glucocorticoid receptors of the
human epidermis. J Invest Dermatol 78:144-146
topical therapy and protective measures. But, some 18. Estlander T, Jolanki R, Kanerva L (1994) Protective gloves. In:
cases cannot be controlled either topically or by Menne T, Maibach HI (eds) Hand eczema. CRC Press, Boca
acceptable doses of systemic corticosteriods. In these Raton, pp 311-321
19. Estlander T, Jolanki R, Kanerva L (1996) Rubber glove
situations, UV treatment should be considered. Chris- dermatitis: a significant occupational hazard-prevention. In:
tensen [12] and Menne and Maibach [66] provide the Eisner P, Lachapelle JM, Wahlberg JE, Maibach HI (eds)
details for UV treatment regime. Prevention of contact dermatitis. (Curr Probl Dermato!)
Karger, Basel, pp 170-176
20. Feldmann RJ, Maibach HI (1965) Penetration of 14C_hydro_
Grenz Ray cortisone through normal human skin: the effect of stripping
and occlusion. Arch Dermatol 91:661-666
21. Feldmann RJ, Maibach HI (1966) Percutaneous penetration of
Grenz ray may act as an adjunct topical therapy in hydrocortisone in man. H. Effect of certain bases and
so me chronic cases. In addition, it is extremely suitable pretreatments. Arch Dermatol 94:649-651
if one considers the sparing effect of grenz radiation on 22. Feldmann RJ, Maibach HI (1967) Regional variation in
percutaneous penetration of 14C cortisol in man. J Invest
hair roots, sebaceous and sweat glands, etc. More Dermatol 48:181-183
details are provided by Lindelöf [51] and Menne and 23. Feldmann RJ, Maibach HI (1968) Percutaneous penetration of
Maibach [66]. steroids in man. J Invest Dermatol 52:89-94
410 H. Zhai et al.
24. Feldmann RJ, Maibach HI (1974) Percutaneous penetration of 44. Held E, Sveinsd6ttir S, Agner T (1999) Effect oflong-term use
hydrocortisone with urea. Arch Dermatol 109:58-59 of moisturizer on skin hydration, barrier function and
25. Fredrickson T, Lassus A, Bleeker J (1980) Treatment of susceptibility to irritants. Acta Derm Venereol 79:49-51
psoriasis and atopic dermatitis with haleinonide cream 45. Hirata F, Schiffmann E, Venkatasubamanian K, Salomon D,
applied once, two-three times daily. Br J Dermatol 102: Axelrod J (1980) A phospholipase A2 inhibitory protein in
575-577 rabbit neutrophils induced by glucocorticoids. Proc Natl
26. Frosch PI, Kurte A (1994) Efficacy of skin barrier creams. Acad Sei USA 77:2533-2536
(IV). The repetitive irritation test (RIT) with a set of 4 46. Juhlin L, Miehaelsson G (1969) Cutaneous vascular reactions
standard irritants. Contact Dermatitis 31:161-168 to prostaglandins in healthy subjects and in patients with
27. Frosch PJ, Kurte A, Pilz B (1993) Biophysical techniques for urticaria and atopic dermatitis. Acta Derm Venereol 49:
the evaluation of skin protective creams. In: Frosch PJ, 251-261
Kligman AM (eds) Noninvasive methods for the quantifica- 47. Lachapelle JM (1996) Efficacy of protective creams and/or
tion of skin functions. Springer, Berlin Heidelberg N ew York, gels. In: Elsner P, Lachapelle JM, Wahlberg JE, Maibach HI
pp 214-222 (eds) Prevention of contact dermatitis. (Curr Probl Derrnato!)
28. Frosch PJ, Kurte A, Pilz B (1993) Efficacy of skin barrier Karger, Basel, pp 182-192
creams.. (III). The repetitive irritation test (RIT) in humans. 48. Lachapelle JM, Nouaigui H, Marot L (1990) Experimental
Contact Dermatitis 29:113-118 study of the effects of a new protective cream against skin
29. Frosch PI, Schulze-Dirks A, Hoffmann M, Axthelm I (1993) irritation provoked by the organic solvents n-hexane,
Efficacy of skin barrier creams. (II). Ineffectiveness of a trichlorethylene and toluene. Dermatosen 38:19-23
popular "skin protector" against various irritants in the 49. Lagos BR, Maibach HI (1998) Frequency of application of
repetitive irritation test in the guinea pig. Contact Dermatitis topieal corticosteroids: an overview. Br J Dermatol 139:
29:74-77 763-766
30. Frosch PJ, Schulze-Dirks A, Hoffmann M, Axthelm I, Kurte A 50. Lavker R, Scheckter N (1985) Cutaneous mast cell depletion
(1993) Efficacy of skin barrier creams. (I). The repetitive results from topieal corticosteroid usgae. J ImmunoI135:2368-
irritation test (RIT) in the guinea pig. Contact Dermatitis 2373
28:94-100 51. LindelöfB (1994) X-raytreatment ofhand eczema. In: Menne
31. Fullerton A, Menne T (1995) In vitro and in vivo evaluation of T, Maibach HI (eds) Hand eczema. CRC Press, Boca Raton,
the effect of barrier gels in nickel contact allergy. Contact pp 303-309
Dermatitis 32:100-106 52. Loden M (1995) Biophysieal properties of dry atopie and
32. Funk JO, Maibach HI (1994) Horizons in pharmacologic normal skin with special reference to effects of skin care
intervention in allergic contact dermatitis. J Am Acad products. Acta Derm Venereol Suppl (Stockh) 192:1-48
Dermatol 31:999-1014 53. Loden M (1996) Urea-containing moisturizers influence
33. Gammal CE, Pagnoni A, Kligman AM, Gammal SE (1996) A barrier properties of normal skin. Arch Dermatol Res
model to assess the efficacy of moisturizers - the quantifi- 288:103-107
cation of soap-induced xerosis by image analysis of adhesive- 54. Loden M (1997) Barrier recovery and influence of irritant
coated discs (D-Squames). Clin Exp Dermatol 21:338-343 stimuli in skin treated with a moisturizing cream. Contact
34. Ginsburg I, Duff RS (1958) Influence of intra-arterial hydro- Dermatitis 36:256-260
cortisone on adrenergic responses in the hand. BMJ 2:424- 55. Loden M, Lindberg M (1991) The influence of a single
428 application of different moisturizers on the skin capacitance.
35. Goh CL (1991) Cutting oil dermatitis on guinea pig skin. (I). Acta Derm Venereol 71:79-82
Cutting oil dermatitis and barrier cream. Contact Dermatitis 56. Loden M, Maibach HI (1999) Skin moisturizers: development
24:16-21 and clinical use. CRC Press, Boca Raton (in press)
36. Goh CL (1991) Cutting oil dermatitis on guinea pig skin. (II). 57. Maibach HI, Korting HC (1993) Topieal glucocortieoids with
Emollient creams and cutting oil dermatitis. Contact Derma- increased benefitlrisk ratio. Karger, Basel
titis 24:81-85 58. Maibach HI, Surber C (1992) Topical corticorsteroids. Karger,
37. Goh CL, Gan SL (1994) Efficaeies of a barrier cream and an Basel
afterwork emollient cream against cutting fluid dermatitis in 59. Malkinson FD, Ferguson EH (1955) Percutaneous absorption
metalworkers: a prospective study. Contact Dermatitis 31:176- of hydrocortisone-l-C'4 in two human subjects. J Invest
180 Dermatol 25:281-283
38. Grevelink SA, Murrell DF, Olsen EA (1992) Effectiveness of 60. Marks JG Jr, Fowler JF Jr, Sherertz EF, Rietschel RL (1995)
various barrier preparations in preventing and/or ameliorat- Prevention of poison ivy and poison oak allergie contact
ing experimentally produced Toxicodendron dermatitis. J dermatitis by quaternium-18 bentonite. J Am Acad Dermatol
Am Acad Dermatol 27:182-188 33:212-216
39. Grunewald AM, Lorenz I, Gloor M, Gehring W, Kleesz P 61. Mathias CGT (1990) Prevention of occupational contact
(1996) Lipophilic irritants: protective value of urea- and of dermatitis. J Am Acad Dermatol 23:742-748
glycerol-containing oil in water emulsions. Dermatosen 62. McClain DC, Storrs F (1992) Protective effect of both a barrier
44:81-86 cream and a polyethylene laminate glove against epoxy res in,
40. Halkier-S0rensen L, Thestrup-Pedersen K (1993) The efficacy glyceryl monothioglycolate, frullania, and tansy. Am J Con-
of a moisturizer (Locobase) among cleaners and kitchen tact Dermat 13:201-205
assistants during everyday exposure to water and detergents. 63. Mckenzie AW, Stoughton RB (1962) Method for comparing
Contact Dermatitis 29:266-271 percutaneous absorption of steroids. Arch Dermatol 86:603-
41. Hannuksela A (1996) Moisturizers in the prevention of 610
contact dermatitis. In: Elsner P, Lachapelle JM, WalIlberg JE, 64. Mellström GA, WalIlberg JM, Maibach HI (1994) Protective
Maibach HI (eds) Prevention of contact dermatitis. (Curr gloves for occupational use. CRC Press, Boca Raton
Probl Derrnato!) Karger, Basel, pp 214-220 65. Mellström GA, Johansson S, Nyhammar E (1996) Barrier
42. Hannuksela A, Kinnunen T (1992) Moisturizers prevent effect of gloves against cytostatic drugs. In: Elsner P,
irritant dermatitis Acta Derm Venereol 72:42-44 Lachapelle JM, Wahlberg JE, Maibach HI (eds) Prevention
43. Haynes RC, Muraud F (1985) Adrenocortieotropic hormone; of contact dermatitis. (Curr Probl Derrnato!) Karger, Basel,
adrenocortical steroids and their synthetie analogs; inhibitors pp 163-169
of adrenocortical steroid biosynthesis. In: Gilman AG, 66. Menne T, Maibach HI (1999) Hand eczema, 2nd edn, CRC
Goodman LS, Rall TW, Murad F (eds) The pharmacological Press, Boca Raton
basies of therapeuties. Macmillan Publishing company, New 67. Miller JA, Munro DD (1980) Topieal cortieosteroids: clinieal
York, pp 1459-1489 pharmacology and therapeutie use. Drugs 19:119-134
68. Munro DD (1976) The effect of percutaneously absorbed 86. Treffel P, Gabard B (1996) Bioengineering measurements of
steroids on hypothalamic-pituitary-adrenal function after barrier creams efficacy against toluene and NaOH in an
intensive use in patients. Br J Dermatol 94[SUppl12]:67-76 in vivo single irritation test. Skin Res Technol 2:83-87
69. Olivarius FDF, Hansen AB, Karlsmark T, Wulf HC (1996) 87. Treffel P, Gabard B, Juch R (1994) Evaluation of barrier
Water protective effect of barrier creams and moisturizing creams: an in vitro technique on human skin. Acta Derm
creams: a new in vive test method. Contact Dermatitis VenereoI74:7-11
35:219-225 88. Van der Valk PGM, Maibach HI (1996) The irritant contact
70. Orchard S (1984) Barrier creams. Dermatol Clin 2:619-629 dermatitis syndrome. CRC Press, Boca Raton
71. Packham CL (1994) Evaluation ofbarrier creams: an in vitro 89. Verrneer BJ, Heremans GFP (1974) A case of growth
technique on human skin (letter). Acta Derm Venereol retardation and Cushing's syndrome due to excessive
74:405 application of betamethasone-17-valerate ointment. Der-
72. Parrillo JE, Fauci AS (1979) Mechanisms of glucocorticoid matologica 149:299-304
action on immune processes. Ann Rev Pharmacol Toxicol 90. Vernon-Roberts B (1969) The effects of steroid hormones on
19:179-201 macrophage activity. Int Rev Cytol 25:131-159
n. Ramsing DW, Agner T (1995) Efficacy of topical corticoste- 91. Vickers CFH (1963) Existence of reservoir in the stratum
roids on irritant skin reactions. Contact Dermatitis 32:293- corneum. Arch Dermatol 88:20-23
297 92. Wertz PW, Downing DT (1990) Metabolism of topically
74. Reiner R, Roßmann K, Hooidonk CV, Ceulen BI, Bock J applied fatty acid methyl esters in BALB/C mouse epider-
(1982) Ointments for the protection against organophos- mis. J Dermatol Sci 1:33-37
phate poisoning. Arzneimittelforschung 32:630-633 93. Weston WL, Sams WM, Morris HG (1980) Morning plasma
75. Schläter-Wigger W, Elsner P (1996) Efficacy of 4 commer- cortisol levels in infants treated with topical fluorinated
cially available protective creams in the repetitive irritation glucocorticosteroids. Paediatrics 65:103-106
test (RIT), Contact Dermatitis 34:278-283 94. Wigger-Alberti W, Eisner P (1998) Do barrier creams and
76. Scoggins RB, Kliman B (1965) Relative potency of percuta- gloves prevent or provoke contact dermatitis? Am J Contact
neously absorbed corticosteroids in the suppression of Dermat 9:100-106
pituitary-adrenal function. J Invest Dermatol 45:347-355 95. Wigger-Alberti W, Maraffio B, Wernli M, Eisner P (1997)
77. Serup J (1992) A double-blind comparison of two creams Self-application of a protective cream. Pitfalls of occupa-
containing urea as the active ingredient, Assessment of tional skin protection. Arch DermatoI133:861-864
efficacy and side-effects by non-invasive techniques and a 96. Wohlrab W (1990) Effect of urea on penetration kinetics of
clinical scoring scheme. Acta Derm Venereol Suppl (Stockh) vitamin A acid in human skin. Z Hautkr 65:803-805
177:34-43 97. Wormser U, Brodsky B, Green BS, Arad-Yellin R, Nyska A
78. Serup J (1992) A three-hour test for rapid comparison of (1997) Protective effect of povidone-iodine ointment against
effects of moisturizers and active constituents (urea), skin lesions induced by sulphur and nitrogen mustards and
measurement of hydration, scaling and skin surface lipid- by non-mustard vesicants. Arch Toxicol 71:165-170
ization by noninvasive techniques. Acta Derm Venereol 98. Zhai H, Maibach HI (1996) Effect ofbarrier creams: human
Suppl (Stockh) 177:29-33 skin in vivo. Contact Dermatitis 35:92-96
79. Serup J, Winther A, Blichmann CW (1989) Effects of 99. Zhai H, Maibach HI (1996) Percutaneous penetration
repeated application of a moisturizer. Acta Derm Venereol (Dermatopharmacokinetics) in evaluating barrier creams.
69:457-459 In: Eisner P, Lachapelle JM, Walliberg JE, Maibach HI (eds)
80. Singh G, Singh P (1986) Tachyphylaxis to topical steroid Prevention of contact dermatitis. (Curr Probl Dermatol)
measured by histamine-induced wheal response. Int J Karger, Basel, pp 193-205
Dermatol 25:324-326 100. Zhai H, Maibach HI (1998) Moisturizers in preventing
81. Solomon LM, Wentzel HE, Greenberg MS (1965) Studies in irritant contact dermatitis: an overview. Contact Dermatitis
the mechanism of steroid vasoconstriction. J Invest De- 38:241-244
rmatol 44:129-131 101. Zhai H, Willard P, Maibach HI (1998) Evaluating skin-
82. Stoughton RB (1972) Bioassay systems for topically applied protective materials against contact irritants and allergens:
glucocorticoids. Arch Dermatol 106:825-827 an in vivo screening human model. Contact Dermatitis
83. Sulzberger MB, Witten VH (1957) The effect of topically 38:155-158
applied compound F in selected dermatoses. J Invest 102. Zhai H, Buddrus D1, Schulz AA, Wester RC, Hartway T,
DermatoI19:101-102 Serranzana S, Maibach HI (1999) In vitro percutaneous
84. Swanbeck G (1992) Urea in the treatment of dry skin. Acta absorption of sodium lauryl sulfate (SLS) in human skin
Derm Venereol Suppl (Stockh) 177:7-8 decreased by quaternium-18 bentonite gels. In Vitro Mol
85. Thompson 1, van Furth R (1970) The effect of glucocortic- Toxicol (in press)
oidsteroids on the kinetics of mononuclear phagocytes. J
Exp Med 131:429-442
CHAPTER 52
Prevention and Rehabilitation

J.E. Wahlberg
Introduction All of the items listed in Table 1 should be consid-

ered, and the best results are usually achieved when
A distinction is usually made between primary pre- several of the prophylactic means are combined
vention, i.e. inhibition of the induction and onset of a judiciously. To rely on just one of these recommenda-
disease, and secondary prevention, i.e. inhibition of tions - sometimes to reduce costs - is definitely less
relapses. Tertiary prevention aims at inhibition of effective. However, it is up to the persons involved in
worsening ("quality of life"). The value of disease preventive dermatology to demonstrate that the sug-
prevention is evident to individuals, the community gested methods and measures are efficacious and cost
and the medical profession. For human, social, and effective.
economic reasons, it would be of great benefit if people
exposed to harmful chemicals and products, physical
factors, and biological agents could be protected from
Prevention of Occupational Dermatoses Caused
developing occupational skin diseases.
by Chemieals and Products
When facing the current or imminent skin problems
of a single patient, all of the prophylactic means listed
On some items involved in prevention of occupational
in Table 1 should be considered. However, the respon-
dermatoses caused by chemicals and products (Ta-
sibility for primary prevention rests mainly with
ble 2) additional comments are presented.
manufacturers and producers of chemicals and prod-
ucts, governmental agencies, consumer organisations,
industrial physicians and nurses, and safety engineers. Identification of Allergens and lrritants
Speaking of secondary and tertiary prevention, a
greater responsibility is placed on physicians treating Allergens
the cases (dermatologists, industrial physicians and
others) and on nurses and safety engineers. In this In order to give a patient meaningful advice as to what
chapter, more general aspects of prevention of occu- chemicals and products to avoid for prevention of
pational dermatoses will be reviewed (Table 1). The recurrence, the allergen responsible should be identi-
majority of these are caused by exposure to chemicals fied. Otherwise the advice will be too general and
and products and will be especially addressed here, sometimes erroneous, and will make the patient's
while prevention concerning physical factors is mainly mode of life unnecessarily difficult.
discussed in Chaps. 6 and 7. Biological causes are In the examination of patients with contact eczema
discussed in Chap. 9. Atopy is reviewed in more detail from environmental agents, tests are made with
in Chap. 24, barrier creams and emollients in Chap. 62, standard series and with formulated products and
material safety data sheets in Chap. 50 and gloves in
Chaps. 53 and 54. The prognosis (Chap. 57) is related to
the efficacy of the prevention measures.
Table 2. Prevention of occupational dermatoses caused by
chemieals and products
Table 1. Preven-
Chemicals and products (Table 2) Identification of allergens and irritants
tion of occupa-
tional dermatoses Physical causes (Chaps. 12, 18-20) üccurrence, concentration of allergens in the environment
- an outline Biological causes (Chap. 22) (Chap.49)
Individuals (Table 3) Allergen removal or replacement
Avoidance of contact (Table 4) Modification or inactivation of the allergen
Skin care program (Table 5) Predictive testing: skin irritating potential
Miscellaneous (Table 6) Predictive testing: sensitising potential

Prevention and Rehabilitation 413
their ingredients (Chaps. 46, 47) to identify the Modification or Inactivation of the Allergen
allergen. The examinations should be supplemented
by chemical analysis to demonstrate the degree of Chromium by Iron Sulfate
purity of the test compound and ensure that impurities
are not the cause of an allergie reaction. Examples are It was demonstrated that iron sulfate added to cement
chromium in cement (Chap. 71), epoxy and phenol- reduced the chromate completely and trivalent chro-
formaldehyde resins, acrylics and other plastics mium was precipitated (Fregert et al. 1979). An
(Chaps. 72-76), colophony (Chap. 64) and sultones amount of 0.35% iron sulfate is enough to reduce
(Lindup and Nowell1978). 20 ).1g Cr+ 6 /g cement. In Denmark, the incidence of
On the basis of these examples, it can be conc1uded chromium allergy among cement workers, after addi-
that, when patch-test reactions to a formulated product tion of iron sulfate to the cement, has decreased. For
occur, it is extremely important to also test with the details see Chap. 71.
ingredients in order, if possible, to see where the
allergenie potential exists. It is the manufacturer's Inartivation of Chromium and Nickel by Ingredients
responsibility to elucidate through chemie al analysis in Barrier Creams
whether it is the ingredient or some impurity that
possesses the allergenie potential. Mainly to prevent relapses in sensitised individuals
(secondary prevention), protective creams containing
various "inactivating" agents have been introduced.
Irritants Dimethylglyoxime, diethylthiocarbamate and ethylene
diamine tetraacetate (EDTA), among other substances,
There is no analogous procedure for irritants. Irritant have been used as chelating agents for chromium
contact dermatitis is a diagnosis of exc1usion and is absorbic acid and anionic exchangers and for nickel.
based on a negative patch test involving all the For details see Chap. 62.
substances with which the patient comes into contact.
The irritant potential of a chemical is based on
predictive testing in experimental animals or man
Inhibition of Sensitisation Reartions (Quenching)
(see Predictive Testing: Skin Irritating Potential).
Quenching is a process used in the perfume industry to
suppress contact sensitisation from cinnamic alde-
Allergen Removal or Replacement hyde, citral, and phenylacetaldehyde by the addition of
another agent, usually an alcohol or terpene (Opdyke
When a new allergen has been identified, the manu- 1976). More re cent studies, however, have not been
facturer and the governmental agencies have to decide able to confirm the initial promising findings (Basket-
whether the chemical should be banned or whether it ter and Allenby 1991).
can be used when specified precautions are taken. If
the new chemie al or drug has great advantages over Predirtive Testing: Skin Irritating Potential
those used previously, this must be balanced against
the allergy risk (risk assessment). If a chemicalor drug Skin irritation testing is performed to help identify
is available that lacks allergenic potential but has equal chemieals, products and material that may be potential
technicalor therapeutic effects, this alternative should, human skin irritants before their introduction into the
of course, be chosen ("substitution"). Under special environment. The tests may give varying results due to
circumstances, potent allergens are used but precau- variation in a number of test-related factors, such as
tions, such as c10sed processes, automation, gloves, host, test dose, patch size, degree of occ1usion, length
heImets, impermeable overalls etc, are taken to avoid of exposure, vehic1e, time for reading and quality of
any skin contact. reading. Therefore, in skin irritation tests, it is
For example, preservatives and biocides (Chaps. 59, important to inc1ude a well-known positive and
60) are well-known sensitisers, and the frequency of negative control material to compare the test results
contact allergy is rather high in workers exposed to with those of the control materials, thereby making the
cutting fluids (Chap. 86) and to paints (Chap. 83). results relative.
Several alternatives are available but, nevertheless, skin Decades of experience have been obtained using
contact is hard to avoid entirely since the workplace is the Draize dermal irritation test on albino rabbits,
so contaminated. In the case of a sensitised worker, the described in OECD guideline 404. However, the use of
management has to decide whether to make a costly laboratory animals for skin irritation testing is de-
change to an alternative bio eide or to transfer the creasing due to the development of in vitro models
worker in question to another job. (Ponec 1996) and more frequent use of human
414 J.E. Wahlberg
volunteers (Marzulli and Maibach 1975; Frosch and Individuals Identified at Pre-Employment
Kligman 1977; Simion 1996; OECD guideline 1997). In Examination or Periodic Health Screening
the latter case, predictive testing of allergenic potential
must be carried out and exduded before the chemical Examination Before Exposure ("Pre-Employment")
or material can be applied to humans. In the future,
analysis of structure-activity relationships might be a To identify in advance individuals who have a consti-
fruitful area. tutional susceptibility to development of contact ecze-
ma is no easy task. Why some individuals are affiicted
with contact eczema while others are unaffected by
Predirtive Testing: Sensitising (Allergenie) Potential exactly the same exposure is still undear; explanations
advanced have been hereditary, constitutional factors
The tests are used to identify potential allergenic and the development of tolerance (Table 3).
chemicals (hazard identification). They can be carried
out in experimental animals (guinea pigs, mice) and in Those with Increased Susceptibility or Predisposition,
human volunteers. Approximately 15 guinea-pig meth- i.e. Atopics
ods have been described; the most widely used are the
guinea-pig maximisation test (GPMT) and the Buehler The general view is that individuals with current, or a
topical dosed-patch technique (Andersen and Maibach history of, atopic dermatitis have an inferior quality of
1985). In mice, two methods have been introduced (the skin with impaired barrier function. Therefore, they
local node assay - LLNA, and the mouse ear swelling are more readily affiicted with irritant contact derma-
test - MEST). An intra- and inter-laboratorial evalu- titis (Chap. 43) and wet work, exposure to oils and
ation of the LLNA has demonstrated reproducible solvents, etc. should be minimised. Regular check-ups
dose-response relationships within and between the of these individuals are recommended. The relative
laboratories (Kimber et al. 1995; Loveless et al. 1996). significance of endogenous and exogenous factors
The LLNA has furthermore been able to identify shows variation from individual to individual. Some
proven important contact allergens previously identi- studies have demonstrated that by means of modern,
fied with the human maximisation test (Basketter et al. non-invasive bio engineering techniques, such as trans-
1994)· epidermal water loss (Serup and Jemec 1995), one can
For humans, the most widely known methods are identify these susceptible individuals, while other
the human maximisation test (HMT) and the modified studies have not confirmed this. Besides an atopic
Draize repeated-insult patch test (Kligman 1966; Mar- dermatitis, the industrial physicians must also consid-
zulli and Maibach 1973). GPMT and HMT were er other manifestations of atopy (asthma, rhinitis)
developed in parallel and the results were in dose when discussing employment on a particular job. The
conformity, which has been adduced as support for physician must have detailed information on expected
extrapolating guinea pig findings to man. exposure conditions before any recommendation on
Lanolin is a known sensitiser in humans (mainly employment can be made.
patients with leg ulcers and stasis eczema), but is a
grade-I allergen in the guinea pig. This is a known
exception, but may have been due to batch-to-batch Patients with a History of Contact Dermatitis
variation and to varying composition of the lanolins
studied. The risk of a contact allergen being missed in Allergie Contart Dermatitis
a correctly performed GPMT (hazard identification)
must be considered minimal. The reverse is far more It is generally believed that individuals with demon-
common, i.e. that a substance is allergenic to guinea strated contact allergy to allergens commonly occur-
pigs, but no dinical case of allergic contact eczema has ring in the environment, such as nickel, chromium,
been reported. Wh ether contact allergy will occur in an and paraphenylene diamine, retain their sensitivity
individual, however, does not depend solelyon the throughout their lives and must therefore entirely
substance's inherent allergenic potential, but also on avoid the eliciting allergens to prevent relapse. The risk
exposure conditions: whether the chemical is present
in high concentrations, penetrates into the skin, comes Table 3. Individuals identified at pre-employment examination
into contact with irritated or damaged skin, or whether and periodic health screening
the exposure is intermittent, continuous, or the size of
Those with increased susceptibility or predisposition, i.e. atopics
the exposed area, etc. Patients with a his tory of contact dermatitis
In vitro methods for predictive skin sensitisation Patients with a history of other types of eczema, psoriasis, acne
testing are not presently available for routine use (De and others
Specific and non-specific hardening
Silva et al. 1996).
Prevention and Rehabilitation 415
of recurrence is related to exposure conditions, such as Specific Hardening

dose, intermittent or continuous exposure, and barrier
function at exposed skin sites. Specific hardening is defined as a condition in which
allergic contact dermatitis in sensitised persons has
Irritant Contact Dermatitis disappeared or failed to reappear on repeated exposure
to the sensitising chemical. Change from a positive to a
For patients diagnosed with irritant (non-allergic) negative patch-test reaction has been adduced as
contact dermatitis, the prognosis is assumed to be evidence that this treatment strategy was effective.
better, but an impaired barrier function of the skin With our present knowledge of patch-test methods and
appears to exist long after it looks normal to the naked their pitfalls, one may suspect that many of the
eye. This necessitates regulations governing exposure, reactions observed at the first test were expressions
use of protective gloves, skin care programs, etc. of irritancy or the excited-skin syndrome. To prove the
(Table 4). Normal barrier function is considered to be value of hardening today, repeated serial dilution tests
restored after several months, but the period is difficult would be needed to define thresholds of sensitivity to
to state on a scientifically acceptable basis. Modern, the allergen, and in vitro determination of the sensi-
non-invasive bio engineering techniques seem to give tivity would be needed (Wahlberg 1992).
assistance in this respect.
Non-Specific Hardening
Patients with a History of Other Types Non-specific hardening refers to instances in which a
of Eczema, Psoriasis, Acne and Others patient acquires a dermatitis from an irritant and,
subsequently, can handle it without developing an
Detailed patch testing of patients with other types of eruption. This can take place due to continued use of
eczema, (seborrhoeic, discoid, stasis, etc.) has demon- mild or moderate irritants with gradual thickening and
strated that they frequently have contact allergies to pigmentation of the skin. The hardened skin may
topical medicaments, preservatives or perfumes, but withstand irritants, while adjacent unhardened skin
the relevance is usually uncertain. Whether the remains susceptible.
frequency is higher than that in the "normal" popu-
lation has not been settled. It is possible that a contact
dermatitis is superimposed on the original eczema, Avoidance of Direct (ontact with Products
and change of topical remedies can result in clearance. and Materials
Psoriasis is dealt with in Chap. 33. Hand psoriasis
can be provoked by repeated trauma, which should be Protective gloves are reviewed in Chap. 53 and barrier
taken in consideration. Patients with severe acne (protective) creams in Chap. 62. The effects of the
should avoid contact with straight oils (Chap. 27). In other preventive measures suggested in Table 4 are
case of more severe chronic skin diseases, such as evident and need no further comment. The table can
scleroderma, Raynaud's phenomenon, systemic lupus be used as a checklist.
erythematosus, and light sensitivity, the patient's
ordinary dermatologist should be consulted before
employment. Skin (are Program
Soaps, detergents and other cleansing agents are

Table 4. Avoidance of direct contact with products and materials known irritants. Recent studies have demonstrated
that allergens are formed in detergents due to air
Protective gloves (Chap. 53) oxidation (Bergh et al. 1997). The clinical relevance of
Aprons, sleeves, boots, glas ses, masks
Barrier (protective) creams (Chap. 62) the observation is not yet settled but may have great
Dishwasher, washing machine, long-handled brushes impact on producers of detergents.
Automation, closed systems The effects of the other preventive measures sug-
Efficient ventilation
gested in Table 5 are evident and need no further
comments. The table can be used as a checklist.
Table S. Skin care program
Soaps, detergents and cleansing agents, without allergens and

with low irritant potential Miscellaneous
Hot water, shower, sauna
Soft towels The effects of the preventive measures suggested in
Emollient and moisturising creams (Chap. 62)
Table 6 are evident and need no further comments.
416 J.E. Wahlberg: Prevention and Rehabilitation
Table 6. Miscellaneous depend largely on the legislation in a particular country.

Legislation, regulation
Many social and personal factors are often more
Labelling of products and chemicals, material safety data sheets decisive for change of work than is the skin disease.
(Chap.50) Physicians can give advice based on examinations,
Information to patients, consumers, workers, supervisors, i.e.
through videos, pamphlets
tests, etc. and knowledge of exposure conditions, but
Training of industrial physicians and nurses, safety engineers they cannot ultimately decide on a patient's future.
Training of workers in special industrial processes
Good housekeeping
Research on prevention; dissemination of results obtained
References
Rehabilitation
Andersen KE, Maibach HI (1985) Contact allergy. Predictive tests
in guinea pigs. Curr Probl Dermatol vol 14. Karger, Basel
Legislation concerning rehabilitation varies from coun- Anonyrnous (1988) Dorland's illustrated medical dictionary.
try to country; only more general principles can be Saunders, Philadelphia
reviewed. Rehabilitation is defined in Dorland's Basketter DA, Allenby CF (1991) Studies on the quenching
phenomenon in delayed contact hypersensitivity reactions.
Illustrated Medical Dictionary as "the restoration of Contact Dermatitis 25:160-171
an ill or injured patient to self-sufficiency or to gainful Basketter DA, Scholes EW, Kimber I (1994) The performance of
employment at his highest attainable skill in the the local Iyrnph node assay with chemicals identified as
contact allergens in the human maximization test. Food
shortest possible time" (Anonymous 1988). This in- Chem Toxicol 32:543-547
cludes medical as well as social goals. Bergh M, Magnusson K, Nilsson JLG, et al. (1997) Contact
In the case of occupational dermatoses, there is an allergenic activity of Tween 80 before and after air exposure.
imperative for the cause of the skin disease to be De Silva 0, Basketter DA, Barratt MD, et al. (1996) Alternative
investigated in detail, including both workplace and methods for skin sensitisation testing. Report and recom-
leisure time exposures, in order to obtain a correct mendations of ECV AM workshop 19. Altern Lab Anim
24:683-705
diagnosis. The eliciting factors - physical, biological, Fregert S, Gruvberger B, Sandahl E (1979) Reduction of chromate
chemicals, products, materials, etc. (Table 1) - should in cement by iron sulfate. Contact Dermatitis 5:39-42
be considered according to the principles for preven- Frosch PJ, Kligman AM (1977) The chamber scarification test for
assessing irritancy of topically applied substances. In: Drill
tion reviewed in this chapter. As pointed out, the best VA, Lazar P (eds) Cutaneous toxicity. Academic Press,
results are achieved when the prophylactic means are Orlando, pp 127-154
combined. Kimber I, Hilton J, Dearman RJ, et al. (1995) An international
evaluation of the murine local Iymph node assay and
A serious attempt should be made to bring the comparison of modified procedures. Toxicology 103:63-73
patient back to his old place of work. If it fails and the Kligman AM (1966) The identification of contact allergens by
patient has a relapse, the exposure conditions must be human assay III. The maximization test. A procedure for
screening and rating contact sensitizers. J Invest Dermatol
re-analysed. Has the offen ding allergen been removed 47:393-409
entirely or was it met in other products or materials? Lindup WE, Nowell PT (1978) Role of sultone contaminants in an
Has the patient followed the instructions on avoidance outbreak of allergie contact dermatitis caused by alkyl
ethoxysulphates. Food Cosmetic Toxicol 16:59-62
of contact (Table 4) and followed the skin care Loveless SE, Ladics GS, Gerberick GF, et al. (1996) Further
program (Table s)? The next attempt should be carried evaluation of the locallymph node assay in the final phase of
out after a more extended period of sick leave to an international collaborative trial. Toxicology 108:141-152
Marzulli FN, Maibach HI (1973) Antimicrobials: Experimental
guarantee that the barrier function of the skin has been contact sensitization in man. J Soc Cosmetic Chem 24:399-421
restored. When contact allergens are present as dusts Marzulli FN, Maibach HI (1975) The rabbit as a model for
or vapours that cannot be controlled by ventilation or evaluating skin irritants: a comparison of results obtained on
animals and man using repeated skin exposures. Food
otherwise removed, it is usually impossible to continue Cosmetic Toxicol 13:533-540
in the same job. OECD guideline (1997) for the testing of chemicals. Acute dermal
After several relapses and periods of sick leave, one irritation study in human volunteers
Opdyke DLJ (1976) Inhibition of sensitisation reactions induced
has to look for alternatives. The extent of the problem by certain aldehydes. Food Cosmetic ToxicoI14:197-198
varies with the worker's degree of disability, motiva- Ponec M (1996) In vitro models to predict skin irritation. In: van
tion, age, intelligence, and how long the individual has der Valk PGM, Maibach HI (eds) The irritant contact
dermatitis syndrome. CRC Press, Boca Raton, pp 335-341
worked in the particular job. Proper rehabilitation Serup J, Jemec GBE (1995) Handbook of non-invasive methods
involves not only medical but also social activities, e.g. and the skin. CRC Press, Boca Raton
by employer, welfare officer, insurance companies Simion FA (1996) In vivo models to predict skin irritation. In: van
der Valk PGM, Maibach HI (eds) The irritant contact
involved with compensation, social institutions, labour dermatitis syndrome. CRC Press, Boca Raton, pp 329-334
inspectors and trade unions. Their contributions Wahlberg JE (1992) Hardening. Contact Dermatitis 26:359
CHAPTER 53
Protective Gloves
G.A. Mellström and A. Boman
Introduction 1970S. A survey of the United States rules, regulations

and standards concerning protective and medical
There has been both an increased occupational use of gloves use has been presented by N. Henry III (1994).
protective gloves and an increased interest in their
protective capacity against harmful chemicals as well Protective Gloves
as blood-borne infections, e.g. hepatitis and human
immunodeficiency virus (HIV). This interest paralleis The European Economic Community (EEC) Directive
new directives and regulations that have come into gives general requirements for aII personal protective
force in Europe concerning the use of and safety equipment; requirements dependent on types of gloves
requirements for protective gloves. have been described (Mellström and Carlsson 1994).
In order to select, purehase or use protective gloves, Protective gloves are cIassified into three categories
it is necessary to obtain information concerning based on intended use and attestation procedures:
current standards, quality requirements, nature of
Category 1. Gloves of simple design - for minimal-
hazards, performance data, acceptable level of expo-
risk application
sure to hazards, and the nature of adverse dermato-
Category II. Gloves of intermediate design (neither
logical effects caused by protective gloves of rubber
simple nor complex design) - for inter-
and plastics.
mediate risk
The information on the performance of protective
Category 1II. Gloves of complex design - for irrevers-
gloves and other protective clothing is found in an
ible/mortal risks
increasing number of reports in the literature. Gener-
ally, the choice of protective material may obtained by The requirements for European Community (EC)-
reviewing the literature and deciding on the best type certification are declaration of conformity and
suitable material. technical documentation files for all categories of
gloves. For categories II and III, there are additional
requirements: EC-type examination testing by ap-
Field of Application - Rules and Regulations proved laboratories, certified by approved notified
bodies and manufacturing under a formal EC quality
Gloves intended for protection of the user are referred assurance system.
to in Europe as personal protective equipment and European Standard EN 420, for protective gloves,
covered by the Personal Protective Equipment Direc- defines general requirements for most kinds of pro-
tive 89/686/EEC. However, gloves intended for use in tective gloves. Key points are suitability of purpose,
the medical field to protect patients and user from innocuousness, sound construction, storage, sizing,
cross-contamination are referred to as medical devices measure of glove hand dexterity, product information
and are covered by Council Directive 93/42/EEC and labelling.
concerning medical devices (MeIIström and Carlsson Examples of EN and ASTM standards for protective
1994). gloves against chemicals are given in Table 1.
In the United States, a committee within the ASTM
(American Society of Testing and Materials), F-23 on Medical Gloves
Protective Clothing, has been working during the last
15 years with the development of standards for items of Medical gloves for single use are those intended for use
protective clothing, such as gloves. Another ASTM in the medical field to protect patients and users from
committee, D-ll on Rubber, has been working with cross-contamination. They are cIassified in categories:
medical glove standard-setting activity since the mid- surgical gloves, examination and/or procedure gloves

418 GA Mellström and A. Soman
(sterile or non-sterile) and foil-film gloves. Examples textile fibres, leather and several polymerie materials
of EN and ASTM standards and specifications for (Table 3). A detailed description of the materials used
medical gloves for single use are given in Table 2. for glove manufacturing as weil as the different
manufacturing methods and glove types was presented
by Mellström and Boman (1994). The protective effect
of different glove materials against hazardous chem-
Glove Materials and Manufacturing icals is dependent of the following factors:
Today, the materials used for manufacturing of pro- Thickness. The break-through time increases as the
tective gloves are natural rubber, synthetic rubber, thickness of the glove material increases but in a
nonlinear fashion (Schwope et al. 1988; Jencen and
Hardy 1989).
Table 1. Examples of American Society of Testing and Materials
(ASTM) and European Standard, European Committee for Material composition. The same generic material but
Standardisation (EN) standards for protective gloves against from different manufacturers has different chemical
chemicals resistance capacity due to variation in polymer
formulation. The barrier effect of different generic
Document number Title
materials is quite variable. Each combination of
ASTM F 739 Standard test methods for resistance of chemical and protective glove material has to be
protective clothing materials to considered (Sansone and Tewari 1980; Mickelsen
permeation by liquids and gases
under conditions of continuous contact and Hall 1987). The quality and protective effect of
ASTM F 1383 Standard test method for resistance of gloves of the same material can differ due to
protective clothing materials to manufacturing processes, additives and quality
permeation by liquids and gases under
conditions of intermittent contact control (Mellström and Boman 1994; Perkins and
ASTM F 1407 Standard test method for resistance of Pool 1997).
protective clothing materials to liquid
permeation - permeation cup method
ASTM F 903 Standard test metiIod for resistance of
protective clothing materials to
penetration by liquids Testing of the Protective Glove Barrier
EN 420 General requirements for gloves
EN 374 Protective gloves against chemieals and
micro-organisms To ensure that protective gloves and medical gloves
Part 1 Terminology and performance requirements for single use give an adequate level of protection,
Part 2 Determination of resistance to penetration the different properties had to be tested and
Part 3 Determination of resistance to permeation
by chemicals evaluated.
Table 2. Examples of American Society of Testing and Materials

(ASTM) and European Standard, European Committee for Table 3. Survey of glove materials used for protective (PG) and
Standardisation (EN) standards for medical gloves medical (MG) gloves
Document number Title Material name/trade names Intended use
ASTM D 3577 Standard specification for rubber Natural rubber (Latex) PG and MG
surgical gloves SyntiIetie rubber materials
ASTM D 3578 Standard specification for rubber Butyl rubber PG
examination gloves Chloroprene/N eoprene PG and MG
ASTM D 5151 Standard test method for detection Fluor rubberlViton PG
of holes in medical gloves Nitrile rubber/Nitrilite, N-Dex PG
ASTM D 5250 Standard specification for polyvinyl Styrene-butadiene/Elastyren MG
chloride gloves for medical Styrene-ethylene-butadienel MG
application Tactylon
ASTM D 5712 Standard test metiIod for analysis Plastic polymerie materials
of protein in natural rubber and EMA (ethylene-metiIylacrylate) PG and MG
its products PolyetiIylene, polytiJene (PE) PG and MG
EN 455 Medical gloves for single use Polyvinyl chloride (PVC) PG and MG
Part 1 Requirements and testing for PE/EVALlPE, laminate/4H-glove PG
freedom from holes Leather PG
Part 2 Requirements and testing for Textile PG
physical properties Cotton, nylon, jersey PG, inner gloves
prEN 455 Part 3 (in Medical gloves for single use - Fiber materials/Kevlar, Lycra Used in jersey surgical
formal vote process) Requirements and testing for and Spectra fibre inner gloves, cut resis-
biologieal evaluation tant
prEN draft European Standard

Protective Gloves 419
Standard Test Methods discussed. The tests used for evaluation of the barrier
integrity fall into two categories:
Physica/ Properties
- Those intended to assure quality during and after
manufacturing
In the EN and ASTM standard specifications, require-
- Those tests that imply challenging the barrier with
ments and test methods are given. These include
viral or chemical agents
sampling and selection of test pieces, physical dimen-
sions with length, strength and thickness, and load for They concluded that viral challenges to gloves indicated
break before and after accelerating ageing. The barrier that latex gloves provided significant barrier protection
effect is also affected by the storage conditions, and against very small viruses. They also concluded that
this is most important for medical gloves made of apparent barrier integrity cannot assure safety, al-
natural rubber latex. though current quality control protocols do assure that
In the British Standard (BS 3574:1989), the following medical gloves provide significant protection. Changes
guidelines and requirements for storage are given: of tensile strength and barrier integrity of medical
gloves during hospital use have been evaluated by
- The gloves should be kept in the original transpor-
Douglas et al. (1997).
tation or ward package and the storage temperature
should be below 25°C.
Permeation
- The relative humidity of the air may not be so high
that there is condensation.
The permeation is usually described as the process by
- The gloves should be stored in darkness, protected
which a chemical migrates through the protective
from the sun and the light from fiuorescent tubes,
clothing material on a molecular level, including
and not be stored near any source yielding ionized
sorption, diffusion and desorption processes. The
radiation, e.g. X-ray apparatus.
principle of permeation standard testing is a fiow-
through system in which a two-compartment perme-
Permeation (Leakage) ation cell of standard dimensions is used. The test
specimen act as an barrier between the first compart-
The penetration of chemicals and/or micro-organisms ment of the cell, which contains the test chemical, and
is a process which can be defined as the fiow through the second compartment through which a stream of
closures, porous materials, seams and pinholes or the collecting medium (gas or liquid) is passed for
other imperfections in a protective or medical glove collection of diffused molecules of the test chemical, or
material and on a non-molecular level. Leakage can collection of its component chemicals for analysis. The
lead to uncontrolled contact to hazardous chemicals or key parameters measured are usually:
infectious materials, especially in the health care field.
Breakthrough time (BT). In both the ASTM and EN
Penetration test methods for protective gloves and
standard test methods, the BT is defined as the time
leakage testing for medical gloves have been described
(in minutes) taken for a specified permeation rate to
by Mellström et al. (1994). Leakage tests, as a rule,
be reached.
include a random sampling procedure in which a
Permeation rate (PR). The mass of test chemical
certain number of gloves are filled with a specified
permeating the material per unit time per unit area
volume of water or air. These are pass/fail tests, and
(Ilg/min cm 2 ).
the number of gloves allowed to fail/number of gloves
Steady-state permeation (SP). Astate that is reached
tested is dependent of the batch or lot size. A sampling
when the permeation rate becomes virtually constant.
procedure for inspection by attributes is defined by the
International Organisation for Standardisation (ISO In the European Standard for protective gloves
2859). Examples of some ASTM and EN standard test against chemicals and micro-organisms, one of the
methods for penetration/leakage testing are presented requirements is that the protective effect for a certain
in Tables 1 and 2. combination of protective glove/test chemical should
There are several standardised leakage test methods be presented as protection index. Protection index is
designed for medical gloves which have been evaluat- based on breakthrough time measured at constant
ed, and all test methods had inherent limitations contact with the test chemical (European Standard EN
(Carey et al. 1989; Douglas et al. 1992). Standard 374-1, 1994) (Table 4).
quality control and virus penetration testing have been
presented in an overview by Lytle et al. (1994). The Biocompatibility
standard tests for glove integrity and the virus
penetration testing in used and intact gloves, as well Over the last years, there have been increased prob-
as penetration through punctures in gloves, are lems with severe adverse reactions in health care
420 G.A. Mellström and A. Boman
Table 4. Index based on breakthrough times determined during Work-Related Testing

constant contact with the test chemical described in European
Standard EN 374-3
In this kind of investigation, the effect of exposure to
Protection index Measured breakthrough potentially hazardous chemicals used in the workplace
time (min) is studied. The concentration of the chemical or its
metabolites is measured in blood, urine or other body
Class 1 >10
Class 2 >30 fluids after exposure in the actual working situation
Class 3 >60 with and without protective gloves (Brooks et al. 1980;
Class 4 >120 Hogstedt and Stahl 1980; Lauwerys et al. 1980; Sessink
Class 5 >240
Class 6 >480 et al. 1994).
Clinical Testing with the Glove Material

workers caused by latex products, e.g. latex proteins in
gloves. Also, adverse reactions due to rubber chemi- The protective effect and side effects of gloves can be
cals, powder, lubricants, endotoxins and pyrogens are studied by patch-testing of contact allergic individuals
well known and more frequent than reactions to with the specific allergen together with pieces of glove.
proteins. Today, there is still no complete agreement A piece of the glove is placed between the skin and the
regarding methods of measurements and control of test chemical under occlusion. The results are read as
these allergens. However, in a draft to European the difference in reactivity between protected and
standards, the requirements and test methods for unprotected skin. The patch-test method may be used
biological evaluation for medical gloves use have been when no data on permeation are available (Liden and
prepared, and "prEN 455: Medical Gloves for Single Wrangsjö 1994).
Use, Part 3: Requirements and Testing for Biological
Evaluation", is now in the formal voting and imple-
mentation procedure. In this draft standard, there is a Protective Effect
requirement that the manufacturer shall monitor the
amount of leachable protein in the finished natural Protection Against Micro-Organisms
latex glove by the method given (modified Lowry
method). The result of the test and applied test method A number of glove barrier studies, concerning protec-
shall be made available on re quest. No limit for the tion against micro-organisms, that used different test
amount of leachable protein is set. There is also a methods during the period 1976-1993, has been reviewed
requirement for the manufacturer to monitor the by Hamann and Nelson (1993). They also compared the
endotoxin contamination of sterile gloves if the gloves protective barriers provided by latex and thermoplastic
are labelled with "low endotoxin content". elastomer (TPE) sterile surgical gloves against penetra-
In the ASTM, there is also current work to develop tion of the baceteriophage phi X174 as surrogate for
requirements and standardised test methods for those blood-borne pathogens. They found that the TPE gloves
chemicals that are clearly associated with allergic had a mechanical barrier effect that was equal to or
reactions, as well as for determination of allergenic better than that offered by the latex gloves tested. Their
relevant natural rubber latex proteins (Table 2). conclusions from the review of investigations of glove
barrier properties and their own results, were that the
barrier effect of the gloves is dependent on a complex
In Vivo Testing
interaction of several factors, such as:
Additional information on protective efficacy of gloves - Type and brand of glove (latex or plastic materials)
can be derived from "in vivo" testing in man or in - Condition of use (unused, stimulated use or use in
experimental animals. For screening and to reduce the actual clinical situations)
need for human experiments, an animal model can be - Sensitivity of the assay (water-, air-, dye-Ieak tests,
used for comparative investigation of the protective bacterial or viral penetration)
effect of gloves. A skin area on the back of a guinea pig
They also concluded that some trends could be seen
is exposed to the test chemical in a depot on top of a
from the data, such as:
glove membrane. The capacity of the membrane to
reduce the percutaneous absorption of the test chemical - The material is an important determinant of the
in comparison with an unprotected site is determined glove barrier.
by measuring the concentration in regularly taken - The brand of glove influences the outcome of
blood sampies (Boman and Mellström 1989, 1994). barrier testing.
- Quality of a glove is more closely related to the by personnel handling these drugs is still not com-
manufacturer than to the glove material. pletely known and, therefore, it is necessary to
- Leakage rates are related to the level of use that a minimise the exposure. In order to minimise the
glove receives. exposure when preparing, dispensing and administer-
- The efficacy of the glove barrier varies with the ing these drugs, standard procedures and appropriate
sensitivity of the testing procedure. techniques, together with personal protective equip-
ment, e.g. gloves, should be used. However, there are
no requirements or criteria for evaluating medieal
Protection Against Some Chemical Agents Hazardous
glove suitability for this use.
to the Skin
In an overview, the permeability of gloves to several
cytostatic drugs was presented by MeHström et al.
Disinfedants
(1996). However, the procedures used were not stan-
dardised methods and the analytical methods, equip-
Disinfectants are generally used to clean surfaces and
ment and sensitivity vary tremendously; therefore, the
objects and to sterilise instruments. At skin disinfec-
test results are difficult to evaluate and compare.
tion and in working situations where there is a risk of
Three factors seem to have a crucial infiuence on the
acquiring blood-borne infections, the use of different
permeation through the lipophilic natural latex glove
kinds of disinfectants is frequent. In these circum-
membrane - the pH value (ionisation), lipophilicity
stances it is important to use gloves, both to protect
and the molecular size. Both mitoxantrone and
the skin against infections and to prevent contact with
carmustine (BCNU), the two drugs that permeated in
disinfectants harmful to the skin. Some of these agents
less than 15 min, have low molecular weight and high
are known to cause allergie and/or irritant reactions
lipophilicity (Mader et al. 1991). The need for require-
after contact with the skin, e.g. ethanol (V an Ketle and
ments of barrier effect against hazardous drugs for
Tan-Lim 1975), isopropyl alcohol (Jensen 1981),
medical gloves has been shown by Sessink et al. (1994).
chlorocresol (Freitas and Brandäo 1986; Gon~alo et al.
They studied occupational exposure to cyclophospha-
1987) and glutaraldehyde (Nethercott et al. 1988).
mide, 5-fiuorouracil and methotrexate in technicians
The infiuence of four disinfectants on six different
involved in drug preparation. Contamination and
brands of medical gloves by measuring the permeation
permeation through latex gloves were found for each
and scanning electron microscopy (SEM) studies of the
of the three compounds. Today, there are some
exposed glove material surfaces has been described by
medical gloves intended for use in handling cytostatic
MeHström et al. (1992). They found that gloves oflatex,
drugs (protective gloves by definition), and these
polyvinyl chloride (PVC) and polyethylene gave
should then fulfil the requirements regarding perme-
acceptable protection from contact with p-chloro-m-
ation for protective gloves and not just requirements
cresol (Blifacid) and glutaraldehyde (Cidex), contain-
on leakage for medical gloves. This means that they
ing these products for at least 60 min, but did not give
should have a protection index for the specific drugs
acceptable protection from contact with isopropanol
against which they are intended to give protection
and ethanol.
(Table 4).
At risk of splashes or very short contact time (lO-
30 min) and at occasional but intentional exposure
(30-60 min), thin gloves made of natural rubber,
Composite Materials (Bone Cement
ethylene methylmethacrylate (EMA), polyethylene (PE)
and Dental Fitting Materials)
and PVC can be useful. At intentional exposure during
extended periods (>60 min), domestic gloves of nat-
The increased use of acrylic compounds as a substitute
ural rubber or PVC or double gloving, or natural
for amalgam by dentists, dental nurses and dental
rubber with EMA, PE or PVC as inner gloves should be
technieians has caused an increasing frequency of
used.
hand eczema in these groups. This is a serious and
increasing problem since there are no gloves available
Pharmaceuticals today that have the dexterity required and, at the same
time, give sufficient protection to the skin. Standard
Pharmaceutical preparations of drugs, e.g. cytostatic procedures, appropriate technique and packaging
agents, have a very heterogeneous mechanism of design, together with adjusted personal protective
action, they have potent pharmacological properties gloves, are highly needed.
and it is weH known that they can cause acute skin Acrylic compounds used in orthopaedic and dental
injuries in cases of accidental exposure (Knowles and surgery are weH known to cause skin problems (Pegum
Virden 1980). The extent of health hazard due to and Medhurst 1971; Kassis et al. 1984; Kanerva et al.
chronic exposure to small amounts of cytostatic drugs 1989). These compounds can also affect the barrier
422 GA Mellsträm and A. Boman
capacity of the glove material after only a short time of with small amounts but during short repeated expo-
exposure. sure or extended exposure, cause severe irritation to
One brand of latex examination glove was exposed the skin. Glove materials suitable for work with and at
for 15 min to some dental materials, methylmethacry- risk for exposure to these types of hazardous chemicals
late composite resin bonding adhesive among others, at very short contact time (10-30 min) are natural
and then tested for virus (HSV-1) penetration by rubber, PE and PVA. At occasional but intentional
Richards et al. (1993). A significant virus leakage was exposure (30-60 min) gloves made of neoprene, nat-
discovered for the gloves treated with the acrylic ural or nitrile rubber, can be useful. At intentional
monomer. They also studied and evaluated the effect of exposure during extended periods (>60 min), gloves
dental materials on the glove material surface, using such as butyl rubber, Viton or the 4H-glove can be
SEM. The acrylic monomer and chloroform showed useful.
the most dramatic changes to the glove material
surface both when inspected with the naked eye and Detergents, Surfadants, Cleansers
in the SEM evaluation. The penetration of acrylic bone
cement through surgical gloves has also been investi- Washing-up liquids, cleaning agents and soaps are
gated by Jensen et al. (1991). They used extracts from usually water based and, when used in recommended
methylmethacrylate monomer (MMA) and the ingre- concentrations, there are only mild effects on the skin;
dients of a new bone cement consisting of a mixture of however, used in too high a concentration, they can
MMAln-decyl-methacrylate (DMA)/isobornyl methac- cause skin injuries. Sometimes organic solvents, such
rylate(IBMA). Latex gloves were not impervious but as white spirit or isopropanol, are added.
more resistant than the polystyrene/butadiene gloves, At risk for splashes or very short contact time (10-
which even dissolved in MMA monomer. In another 30 min), gloves made of EMA, PE or PVC can be
study of the permeability of protective gloves to useful; at occasional but intentional exposure (30-
(di)methacrylates in resinous dental material, almost 60 min), gloves made of natural rubber, neoprene or
the same results were received (Munksgaard 1992). The PVC, can be useful; and at intentional exposure during
latex gloves tested (AnselI, Neutralon, Mediglove, extended periods (>60 min), gloves made of natural
Biogel D) provide protection against BISGMA (1,6- rubber, neoprene or PVC should be used. If organic
hexanediol dimethacrylate, 2,2-bis[ 4-( -hydroXY-3-met- solvent is an ingredient, then use gloves made of nitrile
hacryloyl-oxypropoxy)phenyl]propane) and UEDMA rubber as an alternative.
(1,6-bis- (methacryloyloxy-2-ethoxycarbonylamino )-
2, 4>4-trimethylhexane) for 80 min and against HEMA Oils, Cutting Fluids, Lubricant Oi/s
(2-hydoxyethyl methacrylate) and TEGDMA (tri ethyl-
ene glycol dimethacrylate) for at least 5 min. The These agents often contain anti-corrosive agents,
combined use of latex gloves with the 4H-gloves as bactericides and antioxidants. Used oils can contain
an inner glove can be useful in some working small amounts of chromium, nickel and cobalt. At risk
situations. for splashes or very short contact time (10-30 min),
gloves made of natural rubber or PVC gloves can be
useful; at occasional but intentional exposure (30-
Solvents 60 min), industrial gloves made of nitrile rubber,
natural rubber or neoprene can be useful; and at
Alcohols and other aliphatic and aromatic organic intentional exposure during extended periods
solvents have a degreasing and irritating effect on the (>60 min), gloves such as nitrile rubber gloves or the
skin and can be absorbed through the skin into the 4H-glove should be used.
blood circulation. At risk for splashes or very short Warning! When working at machinery with rotating
contact time (10-30 min) gloves made of natural parts, gloves can imply a risk for tear injury.
rubber, PE or PVC can be useful. At occasional but
intentional exposure (30-60 min), gloves made of
nitrile rubber, natural or neoprene rubber can be Limitation of Use Due to Side Effects
useful, and at exposure on purpose during extended
periods (>60 min), gloves such as butyl rubber, Viton Allergic reactions to gloves can be caused by, for
or the 4H-glove should be used. example, rubber chemicals, organic pigments, latex
proteins and glove powder. Irritant reactions to gloves
Corrosive Agents can occur, e.g. by mechanical stress, endotoxins and
ethylene dioxide. There is also the possibility of side
Corrosive substances, oxidising/reducing agents, acids, effects due to glove powder, e.g. starch-induced
bases and concentrated salt solutions can, after contact adhesions and granulomas following surgery. The risk
of side effects from glove use will be described in detail or micro-organism has been suggested by Burman and
in another chapter in this book. Fryklund (1994).
1. Protection of personnel from hepatitis (A, B, C),
Glove Selection and Therapeutic Alternatives HIV, human T-lymphotropic virus (HTLV)
- Surgical glove: surgery
Selection Procedure for Gloves Against Chemieals - Examination gloves, non sterile: dentistry, risk of
contact with blood
Several factors need to be taken into account when - Protective gloves (e.g. domestic gloves): risk of
selecting a glove for a particular application. One of the contact with blood
first guidelines for the selection of protective clothing, 2. Protection of personnel and patients from various
gloves included, was presented by Schwope et al. viruses and bacteria
(1985). - Protective gloves: handling of faeces, urine,
The selection and use of gloves for protection vomit, etc.
against chemicals have been described by Leinster 3. Protection of patients from hepatitis, HIV, other
(1994) in a matrix model based on working activity and viruses and bacteria
chemical classification. The selection procedure adapt- - Surgical glove: surgery
ed to the new EN standards for protective gloves is - Examination gloves, sterile: other invasive proce-
condensed as detailed below. dures
- Examination gloves, non-sterile: dentistry, isola-
Chemical Classification - Risk of Skin Injury tion, barrier nursing
- Protective gloves: isolation, barrier nursing, han-
A. Mainly contact with chemicals less harmful and not dling of faeces, urine, vomit, etc.
classified as hazardous substances or requiring
labelling. Minimal risk for only slight injuries. A similar schedule with clinical selection criteria for
B. Mainly contact with chemicals classified as toxic, the gloves in health care treatment has been presented
harmful or irritant. Intermediate risk for moderate, by Fay (1994).
reversible injuries.
C. Mainly contact with chemicals classified as highly
toxic, highly corrosive, corrosive and agents causing Therapeutic Alternatives
cancer, sensitisation or those absorbed through
the skin. High risk for severe or irreversible injuries. The occupational groups that are most frequently
affected by contact dermatitis and contact urticaria
Working Activity - Degree of Exposure due to rubber (latex) gloves are cleaning personnel,
food industry workers (manufacturing, cooking) and
1. Risk of exposure, possible splashing all types of health care employees (Estlander 1990;
2. Occasional, repeated and expected exposure Maso and Goldberg 1990; Estlander et al. 1994). The
3. Continuous exposure during certain times, expected risk of side effects when using natural rubber latex
or by accident gloves can be reduced by utilising other alternatives.
Glove Selection - Requirements Gloves of Synthetic Materials
Al: Gloves are not essential. Gloves of polymer materials are necessary for use in
A2, BI, Cl: No testing of the protective effect the treatment of patients and by those employees with
required (Category I). known allergy to latex proteins. Such gloves reduce the
A3, B2, B3, C2: BT and/or PR are required (Catego- risk of contact dermatitis caused by rubber additives
ry II). and contact urticaria caused by latex proteins. Gloves
C3: BT and/or PR are required; also test of polymer materials are also necessary for use by
results based on the glove task (Cate- those employees with a known allergy to chromate in
gory III). leather gloves.
Selection Procedure for Gloves Against Micro-Organisms Double Gloving
A scheme for the selection and use of gloves by health - Natural rubber latex gloves plus inner gloves of
care personnel in different situations based on pur- plastic, nylon or cotton material reduce the risk of
pose, working procedure, type of glove(medical gloves contact dermatitis and urticaria caused by latex
or protective gloves) and risk of exposure to infection rubber gloves.
424 G.A. Mellström and A. Boman
Natural rubber latex gloves plus synthetic fibre McBriarty JP, Henry N (eds) Performance of protective
gloves reduce the risk of cut and puncture injuries. clothing (ASTM STP 1133, vol4) American Society for Testing
and Materials, Philadelphia, pp 99-113
- Natural rubber latex gloves plus latex or plastic Estlander T (1990) Occupational skin diseases in Finland, 1974-
gloves reduce the risk of blood-borne infections 1988 (academic dissertation). Acta Derm Venereol Suppl
and/or chemical permeation. (Stockh) 155
Estlander T, Jolanki R, Kanerva L (1994) Allergie contact
dermatitis from rubber and plastic gloves. In: Mellström
Non-Powder Gloves GA, Wahlberg JE, Maibach HI (eds) Protective gloves for
occupational use. CRC Press Inc, Boca Raton, pp 221-239
Fay MF (1994) Risk analysis as the base for surgical glove
Powder-free gloves should be used to reduce the risk of selection. In: Edlich RF (eds) Joumal oflong - term effects of
symptoms such as rhinitis, conjunctivitis and asthma medical implants (vol 4, issues 2 and 3). pp 141-155
Freitas JP, Brandäo FM (1986) Contact urtiearia to chlorocresol.
caused by glove powder contaminated by latex pro- Contact Dermatitis 15:252
teins. Gons;alo M, Gons;alo S, Moreno A (1987) Immediate and delayed
sensitivity to chlorocresol. Contact Dermatitis 17:46-47
Hamann CP, Nelson JR (1993) Permeability of latex and
thermoplastic elastomer gloves to the baceteriophage Phi X
Conclusions 174. Am J Infect Control 21:289-296
Henry III NW (1994) Protective gloves for occupational use - US
Factors of importance that have to be considered in the rules, regulations and standards. In: Mellström GA, Walliberg
JE, Maibach HI (eds) Protective gloves for occupational use.
selection procedure are: CRC Press Inc, Boca Raton, pp 45-49
Hogstedt C, Stähl R (1980) Skin absorption and protective gloves
1. Mechanical quality of the glove material (tensile in dynamite work. Am Ind Hyg Assoc J, pp 236
strength; dexterity; cut, tear and puncture resis- Jencen DA, Hardy JK (1989) Effect of glove material thickness on
tance). permeation characteristics. Am Ind Hyg Assoc J 50:623-626
Jensen JS, Trap B, Skydsgaard K (1991) Delayed contact hyper-
2. The resistance to penetration and permeation of sensitivity and surgical glove penetration with acrylic bone
hazardous chemie als and micro-organisms. cements. Acta Orthop Scand 62:24-28
3. Risk of adverse effects when using a specific glove Jensen 0 (1981) Contact allergy to propylene oxide and isopropyl
alcohol. Contact Dermatitis 7:148-150
(allergie contact dermatitis, contact urticaria, irri- Kanerva L, Estlander T, Jolanki R (1989) Allergic contact
tation, itching, etc.). dermatitis from dental composite resins due to aromatic
4. Function - the gloves must not imply another risk epoxy acrylate and aliphatic acrylates. Contact Dermatitis
20:201-211
or be a hindrance. Kassis V, Vedel P, Darre E (1984) Contact dermatitis to methyl
5. Comfort - the right size, pie asant to wear. methacrylate. Contact Dermatitis 11:26-28
6. Quality - uniformity, a moderate price. Knowles RS, Virden JE (1980) Occasional review. Handling of
injectable antineoplastic agents. BMJ 30:589-591
All of these factors show that the selection procedure Lauwerys RR, Kivits A, Lhoir M, Rigolet P, Houbeau D, Buchet
J-p, Roels H (1980) A biological surveillance of workers
can be complicated indeed. exposed to methylformamide and influence of skin protection
on its percutaneous absorption. Int Arch Occup Environ
Health 45:189
Leinster P (1994) The selection and use of gloves against
References chemicals. In: Mellström GA, Wahlberg JE, Maibach HI
(eds) Protective gloves for occupational use. CRC Press Inc,
Boman AS, Mellström GA (1989) Percutaneous absorption of Boca Raton FL, pp 269-281
three organic solvents in the guinea pig. IV. Effect of Liden C, Wrangsjö K (1994) Protective effect of gloves illustrated
protective gloves. Contact Dermatitis 21:260 by patch test testing - practical aspects. In: Mellström GA,
Boman AS, Mellström GA (1994) Percutaneous absorption Wahlberg JE, Maibach HI (eds) Protective gloves for occu-
studies in animals. In: Mellström GA, Wahlberg JE, Maibach pational use. CRC Press Inc, Boca Raton, pp 207-212
HI (eds) Protective gloves for occupational use. CRC Press Lytle CD, Cyr WH, Carey RF, Shombert DG, Herman BA, Dillon
Inc, Boca Raton, pp 91-107 JG, Schroeder LW, Bushar HF, Kotilainen HJR (1994)
British Standard (BS 3574:1989) Storage conditions for medical Standard quality testing and virus penetration. In: Mellström
gloves. Her Majesty's Stationery Office, London GA, Wahlberg JE, Maibach HI (eds) Protective gloves for
Brooks SM, Anderson L, Emmet E, Carson A, Tsay JY, Elia V, occupational use. CRC Press Inc, Boca Raton, pp 109-127
Buncher R, Karbowsky R (1980) The effects of protective Mader RM, Rizovski B, Steger GG, Moser K, Rainer H, Dittrich C
equipment on styrene exposure in workers in the reinforced (1991) Permeability of latex membranes to anti-cancer drugs.
plastics industry. Arch Environ Health 35:287 Int J Pharmacol 68:151-156
Burman LG, Fryklund B (1994) The selection and use of gloves by Maso MI, Goldberg DJ (1990) Contact dermatitis from disposable
health care professionals. In: Mellström GA, Wahlberg JE, gloves. A review. J Am Acad Dermatol 23:733
Maibach HI (eds) Protective gloves for occupational use. CRC Mellström GA, Boman AS (1994) Gloves: types, materials, and
Press Inc, Boca Raton, pp 283-292 manufacturing. In: Mellström GA, Wahlberg JE, Maibach HI
Carey R, Herman W, Herman B, Casamento J (1989) A laboratory (eds) Protective gloves for occupational use. CRC Press Inc,
evaluation of standard leakage tests for surgical and exam- Boca Raton, pp 21-35
ination gloves. J Clin Eng 14:133-143 Mellström GA, Carlsson B (1994) European standards on
Douglas A, Simon TR, Goddard M (1997) Barrier durability of protective gloves. In: Mellström GA, Walliberg JE, Maibach
latex and vinyl medieal gloves in clinical settings. Am Ind HI (eds) Protective gloves for occupational use. CRC Press
Hyg Assoc J 58:672-676 Inc, Boca Raton, pp 39-43
Douglas AA, Neufeld PD, Wong RKW (1992) An interlaboratory Mellström GA, Carlsson B, Boman AS (1994) Testing of protective
comparison of standard test methods for medical gloves. In: effect against liquid chemicals. In: Mellström GA, Wahlberg
JE, Maibach HI (eds) Protective gloves for occupational use. Richards JM, Sydiskis RJ, Davidson WM, Josell SD, Lavine DS
CRC Press Inc, Boca Raton, PP 53-77 (1993) Permeability of latex gloves after contact with dental
Mellström GA, Lindberg M, Boman A (1992) Permeation and materials. Am J Orthod Dentofacial Orthop 104:224-229
destructive effects of disinfectants on protective gloves. Sansone EB, Tewari YB (1980) Differences in the extent of solvent
Contact Dermatitis 26:163-170 penetration througlI natural rubber and nitrile gloves from
Mellström GA, Wrangsjö K, Wahlberg JE, Fryklund B (1996) The various manufacturers. Am Ind Hyg Assoc J 41:527-528
value and limitation on gloves in medical health service: part Schwope AD, Costas PP, Jackson JO, Weitzman JO (1985)
11, dermatology nursing, vol 8. 4:287-295 Guidelines for the selection of protective clothing. American
Mickelsen RL, Hall RC (1987) A breakthrough time comparison of Conference of Governmental Industrial Hygienists, Inc, 2nd
nitrile and neoprene glove materials produced by different edn. Cincinnati
glove manufacturers. Am Ind Hyg Assoc J 48:941-947 Schwope AD, Costas PP, Mond CR, Nolen RL, Conoley M, Garcia
Munksgaard EC (1992) Permeability of protective gloves to (di) DB, Walters DB, Prokopetz AT (1988) Gloves for protection
methacrylates in resinous dental materials. Scand J Dent Res from aqueous formaldehyde: permeation resistance and
100:189-192 human factors analysis. Appl Ind Hyg 3:167-176
Nethercott JR, Holness DL, Page E (1988) Occupational contact Sessink PJM, van de Kerkhof, MC A, Anzion RB, Bos RP (1994)
dermatitis due to glutaraldehyde in health care workers. Environmental contamination and assessment of exposure to
Contact Dermatitis 18:93-197 antineoplastic agents by determination of Cyclophosphamide
Pegum JS, Medhurst FA (1971) Contact dermatitis from perme- in urine of exposed pharmacy technicians: ls skin absorption
ation of rubber gloves by acrylic monomer. BMJ 2:141-143 an important exposure route? Arch Environ Health 4:165-169
Perkins JL, Pool B (1997) Batch lot variability in permeation Van Ketle WG, Tan-Lim HN (1975) Contact dermatitis from
trough nitrile gloves. Am Ind Hyg Assoc J 58:474-479 ethanol. Contact Dermatitis 1:7-10
CHAPTER 54
Disadvantages of Gloves
T. Estlander, J. Jolanki, and 1. Kanerva
Introduction Gloves fully impregnated with harmful chemical

substances do not protect the hands. Noxious agents in
Protective gloves are important, although only sec- the glove material come into direct contact with the
ondary, safeguards against factors hazardous to hands. skin and can cause allergic or irritant dermatitis.
They can be manufactured from polymers such as Sometimes harmful chemicals or agents are absorbed
rubber and plastic, leather, fabric or combinations of and retained in glove materials, e.g., nitroglycerin in
these materials. There is no glove material ideal for the gloves of dynamite workers (Hogstedt and Stahl
every type of work. 1980); lubricant powders such as bacterial endotoxin in
Each material has its advantages and disadvantages. gammasterilized gloves (Shmunes and Darby 1984); or
The quality of the work and materials to be handled ethylene oxide (ETO), ethylene chlorhydrin, or ethyl-
determines what type of gloves should be chosen. ene glycol residues as invisible dirt that has a general
Rubber and plastic gloves are mainly used to protect or local injurious effect on health. In ETO-sterilized
hands from chemical and biologic agents, but they are gloves ETO residues in both industrial and medical
also important for protecting products from workers' gloves that are not sufficiently aerated before their use
dirty hands. They can also be used to protect against can cause, in addition to irritant dermatitis, chemical
physical and mechanical hazards, although leather and bums (reviewed by Taylor 1994). Allergens mayaiso
textile gloves are mainly used for protection against contaminate gloves in invisible amounts sufficient to
these hazards. provoke dermatitis in sensitized persons (Rycroft 1986;
Hand protection must not increase the risk of Estlander et al. 1992, 1997).
dermatitis, the risk of universal adverse effects to
health, or the risk of hand accidents. Even when gloves
are chosen to give the best possible protection against Irritation and Maceration of the Skin
hazards, their use entails many problems, the most
important are: Irritation
- Dirt
Although irritation caused by polymeric gloves is
- Irritation and maceration of the skin
possibly more common than allergy, there is scant data
- Allergy to glove materials and donning powders
available on the subject (Taylor 1994; Brehler et al.
- Getting caught in moving parts of machinery
1998). Com starch, club moss (Lycopodium) powder
(in some cases), tale, lactose and silicone can be used
as glove-donning powders (Taylor 1994). Glove powder
Dirt crystals have been suggested to be a cause of irritation
in powdered gloves (Heese et al. 1991). Skin replica
Chemicals may contaminate polymeric protective techniques have demonstrated that skin roughness was
gloves by permeation (Sumwalt 1967; Moursiden and significantly increased after wearing powdered Peha
Faber 1973; Pegum 1979; Wall 1980; Kassis et al. 1984; taft gloves or powder-free Biogel gloves on prepow-
Storrs 1984; Jolanki et al. 1987a) through intact gloves. dered hands for 2 h, but no change was found after
Although gloves do not have visible cracks or dirt, they wearing powdered Manex neoderm gloves (Brehler
may be heavily soiled on the inside by chemicals. et al. 1998). Mechanical rubbing of the skin caused by
Chemicals may also be accidentally spilled through the powders was suggested to cause the roughness of the
mouth of gloves, thereby causing skin damage, or the hands.
chemicals may touch the skin when soiled gloves are In a Japanese study (Aoyama et al. 1982) 31 (51%) of
being pulled on or off. 61 women who had developed contact eczema from

Disadvantages of Gloves 427
using household gloves connected their symptoms tlün skin between the fingers and on the palmar side of
with the use of vinyl gloves, and 26 (43%) with rubber the wrist is very sensitive to irritants.
gloves. In four cases, the type of glove used was not Water and other liquids make leather slippery and
identified. Irritation was suggested as the cause of vinyl cause it to deteriorate. Wet gloves are uncomfortable
glove dermatitis, rather than allergy to the material to wear and they mayaiso cause skin irritation or even
itself. Discomfort caused by polyvinylchloride (PVC) irritant contact dermatitis (Estlander and Jolanki
gloves is possibly better known in Japan than else- 1988).
where because PVC gloves are commonly used there. A
fraction, probably an irritant, thought to be responsi- Maceration
ble for this discomfort has been found in vinyl gloves
sold in Japan by doing animal tests (Naruse and Iwama When watertight polymerie gloves are worn for long
1992). periods without breaks, profuse sweating of the hands
Nonimmunologie contact urticaria (NICU) has not can cause softening or maceration and irritation of the
been reported from the use of rubber or plastic gloves, skin. Macerated, softened skin gives poor protection
but some glove powders may contain sorbic acid against microbes and chemical injuries. In re cent
(Heese et al. 1991) whieh is a known NICU agent and years, 1% of the cases reported as irritant contact
could explain some of the immediate itching and dermatitis to the Finnish Register of Occupational
redness reactions attributed to gloves. Pressure urti- Diseases (ROD) have been caused by maceration,
caria or cholinergic urticaria associated with glove use mainly due to polymerie gloves (Jolanki et al. 1998a).
mayaiso be a cause of irritation (Taylor 1994). Tight or
poorly fitting gloves can also cause hand fatigue, which
increases the risk of hand accidents (Sumwalt 1967). Allergy to Glove Material and Donning Powder
Such gloves also cause skin irritation, especially in
persons with considerable dermographism (Estlander Rubber Gloves
and Jolanki 1988).
Occlusion caused by gloves, especially when the Rubber gloves are an important cause of occupational
gloves are used without interruption for long periods and non-occupational hand dermatitis (Estlander et al.
or when double gloving is used, as well as friction from 1994a,b, 1996; Wigger-Alberti and Eisner 1998). Rubber
gloves rubbing against the skin, are other important glove dermatitis may involve delayed (type-IV) allergy,
causes of glove irritation (Taylor 1994). The effect of leading to contact eczema, or immediate (type-I)
occlusion has been shown experimentally (Ramsing allergy appearing as contact urticaria and pro tein
and Agner 1996a,b). contact dermatitis. Simultaneous type-I and type-IV
Frequent hand washing using soaps, detergents and allergy to rubber gloves mayaiso occur (Turjanmaa
other cleaning agents can also increase the irritant 1994, 1997). When occupationally related glove der-
effect of gloves. Some workers may not have enough matoses are considered, allergie contact dermatitis
time to let their hands dry after using hand washes (type-IV allergy) is probably more common than type-
containing ethyl alcohol and other disinfectants before I allergie contact urticaria (Estlander et al. 1996). In
donning their gloves, thus increasing the irritant effect certain occupations, however, in which natural rubber
of the gloves on skin. The ingredients of glove (NRL) gloves are used daily for long periods, e.g., in
materials can also cause irritation. The materials may hospitals (Turjanmaa 1994), dental care (Field 1998,
contain residua of chemieals used in the manufactur- Jolanki et al. 1998a,b), and laboratory work (de Groot
ing process such as organic solvents and tanning et al. 1998), contact dermatoses due to type-I allergy
agents (Figard 1980). The variation in glove pH and can be more important. Most of the reported cases of
glove chemie als may be highly responsible factors in type-IV allergy to rubber gloves are due to gloves made
the irritation caused by gloves (Brehler et al. 1998). of NRL (Heese et al. 1991; Estlander et al. 1994a, 1996).
Brehler et al. (1998) found extreme differences in the Reports on cases due to synthetic materials are few and
surface pH of the gloves they tested. Powdered gloves usually describe allergy to neoprene gloves (Estland er
were highly alkaline. In addition, glove materials may et al. 1994a, 1996; Kanerva et al. 1994), but sensitiza-
contain detergent residues after washing (Mellström tion to other materials, e.g., nitrile rubber is also
et al. 1992). In some workplaces with striet sterility possible (Estlander et al. 1995a). NRL gloves have long
requirements, glove users mayaiso wipe the gloves on been the only source of type-I allergy due to rubber
their hands with disinfectant solutions that may gloves, but also latex-free nitrile gloves (Brehler 1996)
permeate the glove material and cause skin irritation. and gloves made of mixtures of synthetic rubber and
Rough leather or textile may cause friction on the NRL have been reported to cause type-I sensitization
skin and irritative dermatitis. Rough glove seams are and contact urticaria (Heese et al. 1992; Kwangsuktith
especially harmful to fingers and wrists because the and Maibach 1995). NRL gloves are also the major
428 T. Estlander et al.
contributor to latex aeroallergens in operating rooms et al. 1996; Wilkinson and Beck 1996; Wilkinson and
(Heilman et al. 1996; Palosuo et al. 1998). Burd 1998).
Thiurams and carbamates have most commonly
Symptoms of Rubber-Glove Allergy been responsible for the type-IV reactions due to
rubber gloves. Mercaptobenzothiazole was the first
Rubber-glove allergy typically appears as a skin benzothiazole accelerator used in gloves, but other
infiammation on the dorsal aspects of hands and derivatives can also be used. The reports on sensiti-
wrists or lower arms. Contact urticaria with whealing is zation to thiourea compounds from rubber gloves are
a characteristic symptom of type-I allergy to NRL few and, for the most part, involve gloves made of
gloves, but the symptoms can consist of itching and neoprene rubber which may also contain diphenyl-
redness only or aggravation of pre-existing dermatitis. guanidine (Estlander et al. 1994a, 1995; Kanerva et al.
The symptoms can also include generalized urtiearia, 1994). Antioxidants are less frequent sensitizers.
conjunctivitis, rhinitis, asthma, or even serious ana- Allergy from gloves to N-isopropyl-N-phenyl-PPDA
phylactie reactions. Delayed allergie reactions are (paraphenylenediamine) has been published (Fousser-
generally confined to the skin. Eczematous lesions eau et al. 1990; Conde-Salazar et al. 1993; Estlander
are located on areas covered by the gloves, but larger et al. 1994a, 1996; Fuchs 1995), although PPDA deriv-
areas including the face can also be involved. Glove atives are seldom used in rubber gloves except in black
allergy usually involves one of two types of reactions, or dark-colored industrial gloves. Phenol derivatives
though occasionally both coincide (Estlander et al. are rare sensitizers in rubber gloves (Estlander et al.
1994a, 1996; Turjanmaa 1994, 1997; Fuchs 1995; Heese 1994a; Fuchs 1995). However, the number of rubber
1995)· additives used in the manufacture of rubber products
is much greater than the list of known rubber chemie al
sensitizers.
Sensitizers in Rubber Gloves Proteins in NRL polymers (Turjanmaa 1994, 1997;
Mäkinen-Kiljunen and Turjanmaa 1995; Palosuo 1997;
The primary ingredient in rubber gloves is rubber Hoffmann-Sommergruber et al. 1998) are the chief
polymer, which is blended with various additives cause of type-I allergy, whereas casein (Mäkinen-
including vulcanizing agents, accelerators, antioxi- Kiljunen et al. 1993) and terpenes (Seaton et al. 1988)
dants, pigments, fillers and oils. Rubber polymer can mayaiso be possible allergens. Since the 1980s
be a natural product made from the milky liquid additives of rubber mixtures, both in natural (Helander
(natural latex) of the rubber tree or it can be and Mäkilä 1983; Geier and Fuchs 1989; Belsito 1990;
manufactured synthetieally. Neoprene and nitrile rub- Brehler and Sedlmayer 1997), and synthetic (Brehler
bers are examples of synthetic polymers used in the 1996) rubbers, have been increasingly reported as
production of gloves. Blending NRL with neoprene or causes of type-I allergy to gloves. Glove powder
nitrile rubbers is also common in order to combine the ingredients, possibly protein remnants, are other
favorable properties of both materials. potential causes of glove contact urticaria (Fisher
Additives, usually accelerators such as thiurams, 1986b, 1987; Meeren van der and Erp van 1986; Heese
carbamates and benzothiazoles and antioxidants are et al. 1994; Crippa and Pasolini 1997). In arecent study
usually responsible for type-IV allergy due to gloves of workers at the Department of Immunology, Erasmus
(Estlander et al. 1986, 1994a; Heese et al. 1991, 1995; University, Rotterdam, none of the 66 skin-tested
Fuchs 1995). Other potential type-IV sensitizers participants was patch or prick-test positive to glove
include thiourea and phenol derivatives, diphenylgua- powder extract; nor did they test positive to a non-
nidine, mercaptobenzimidazole, quinoline derivatives, latex glove extract (Elastyren) used in the study (de
preservatives, antistatic agents, glove powder ingredi- Groot et al. 1998). Certain polyurethane-coated surgi-
ents and fragrances (Cronin 1980; Milkovie-Kraus cal NRL gloves have also been reported as a possible
1992; Estlander et al. 1994a, 1996; Fuchs 1995; Heese new cause of glove contact urtiearia, probably from
et al. 1995). Organic pigments used in both rubber and NRL in the glove material (Kwangsuktith and Maibach
plastie materials may also be leachable and induce 1995). A life-threatening anaphylactic reaction has also
sensitization (Jolanki et al. 1987b). A quaternary been reported in an NRL allergie worker from the use
ammonium compound, cetylpyridinium chloride has of polychloroprene (neoprene) gloves, possibly caused
also been reported to be the cause of sensitization to by small amounts of NRL in the inside coating of the
surgical rubber gloves (Castelain and Castelain 1993; glove not declared by the manufacturer (Heese et al.
Steinkjer 1998). Rubber polymer itself has increasingly 1992).
been listed among the possible causes of delayed Proteins with molecular weight (MW) ranging from
allergy to rubber (Lezaun et al. 1992; Wyss et al. 1993; 14 kDa to 75 kDa are usually responsible for allergy to
Estlander et al. 1994a; Häffner et al. 1996; Placucci NRL, but allergenie proteins mayaiso have lower or
higher MW. More than 12 individual latex allergens Meding 1994). At least previously, the figures for gloves
have been identified, nine of which have been desig- as causes of occupational rubber allergy have been
nated with international names: Hev bl, rubber elon- even higher when housewives were included in the
gation factor; Hev b6 prohevein and Hev b6.1 mature occupational groups (Romaguera and Grimalt 1980;
hevein; Hev b2, endo-l,3-beta glucosidase (endoglu- Themido and Menezes-Brandao 1984). Allergy to
canase) and Hev b3, hydrophobic rubber particle gloves seems to be common among women, but it is
protein of 23-27 kDa. Enzymes, e.g., chitinases and also frequent among men who regularly use rubber
glucanases, are possibly responsible for the latex-fruit gloves (Tarvainen et al. 1993; Estlander et al. 1994a;
syndrome as a result of cross-allergy between NRL Fuchs 1995; Heese et al. 1995). Long-standing use of
and avocado, banana, kiwi and chestnut (Mäkinen- rubber gloves and simultaneous exposure of hands to
Kiljunen and Turjanmaa 1995; Alenius et al. 1996b; chemical or mechanical irritation or wet work seem to
Palosuo et al. 1996, 1998; Hoffmann-Sommergruber be the most important risk factors in the development
et al. 1998). of type-IV allergy to gloves. Work in medical and
Relatively little is known about the exact molecular dental health services; laboratory work; cleaning, hair
specificities and forms of allergens eluting from NRL dressing, kitchen work; work in the food industry; and
gloves or other NRL products (Palosuo 1997). Alenius agricultural and industrial work are high-risk occupa-
et al. (1996a) nevertheless showed that hevein (Hev b tions (Estlander et al. 1994a, 1996; Fuchs 1995; Heese
6.1) constituted up to 70% of the total allergen activity et al. 1995).
of a high-allergen glove, suggesting, in line with the Although rubber gloves are an important cause of
results of other investigations, that hevein can be the NRL allergy, there are also many other sources of NRL
most important NRL allergen eluting from at least contact (Hamann 1993; Turjanmaa 1994; Fuchs 1995;
high-allergen medical gloves. Many studies conducted Heese et al. 1995; Palosuo 1997; Warshaw 1998).
in the past few years also indicate that there may be Besides frequent use of NRL gloves, atopic constitution
considerable differences between the allergen contents and hand dermatitis have often been connected with
of the gloves of different manufacturers, between allergy to NRL (Turjanmaa 1994, 1997; Heese et al.
different glove brands, and between gloves from 1994, 1995; Fuchs 1995; de Groot et al. 1998; Warshaw
different batches of the same manufacturer (Turjanmaa 1998). Allergy to NRL gloves is most frequent among
et al. 1988; Leynadier and Dry 1991; Alenius et al. 1994; hospital and dental care personnei, ranging from 2.8%
Yunginger et al. 1994; Beezhold et al. 1996; Palosuo to 16.9%, but it is common also in other occupations
et al. 1996, 1998). In most cases, powdered gloves have where NRL gloves are worn daily for long periods
been shown to contain higher contents of allergens (Turjanmaa 1987, 1994; Tarvainen et al. 1993; Yassin
than powder-free gloves (Yunginger et al. 1994). et al. 1994; Fuchs 1995; Heese et al. 1995; Mäkinen-
Hamann (1993) has reviewed factors affecting antige- Kiljunen and Turjanmaa 1995; Sussman et al. 1995; van
nicity and the concentration of NRL proteins. der Walle and Brunsveld 1995; Safadi et al. 1996).
In addition, the manufacturing process of the gloves Since 1985, a worldwide increase has been reported
may cause some of the proteins to become even more in the cases of type-I allergy to NRL gloves (Hamann
allergenic (Alenius et al. 1991). Some sensitized per- 1993; Heese et al. 1995; Estlander et al. 1996). In
sons may, however, be able to use NRL gloves with low Finland, 111 cases of rubber-glove derma tos es were
allergenicity (Cormio et al. 1993), whereas others, diagnosed from 1974 to 1991 at the Finnish Institute of
especially atopic persons sensitive to NRL, seem to Occupational Health (FlOH) (Estlander et al. 1996);
be more susceptible and can develop skin symptoms 88% of these cases were allergic contact eczema and
when wearing even these gloves. Therefore, it has been 12% were contact urticaria. Since then, the information
stated that NRL gloves with low allergenicity cannot from the ROD through 1997 indicated a clear increase
always be recommended as an alternative for atopics in the proportion of type-I sensitization to NRL gloves.
sensitized to natural rubber (de Groot et al. 1998). During the period 1990-1994, 814 new cases of contact
urticaria and protein contact dermatitis were reported
Rubber Gloves as Causes of Occupational Allergy to ROD. Natural rubber (193 cases) was the second
most common cause of these dermatoses, being
Rubber gloves have long been the main source of responsible for 23% of the cases. Gloves made of NRL
occupational allergy to rubber (Estlander et al. 1986, were responsible for almost all these cases (Estlander
1994a,b, 1996; Estlander and Jolanki 1988; Conde- et al. 1996). During 1995-1996, 118 cases of contact
Salazar et al. 1993; Fuchs 1995; Heese et al. 1995; de urticaria or protein contact dermatitis were reported to
Groot et al. 1998). Of all occupationally induced type- the ROD, explaining 30% of the cases (Kanerva et al.
IV rubber allergy cases, 41-66% have been reported to 1998). In 1997, 41 cases of type-I NRL allergy were
be caused by rubber gloves (Estlander 1990; Estlander reported to the ROD, and they were responsible for
et al. 1994a, 1996; Heese et al. 1991; Wrangsjö and 21% of the cases (Karjalainen et al. 1998).
During 1990-1994, rubber chemieals were the most tant reason why the speeific allergen has only been
important cause of allergie contact eczema, explaining detected in exceptional cases.
26% of the cases. Rubber gloves were considered to be Sensitization to epoxy resin used as a plasticizer has
the most common source of type-IV allergy to rubber been reported by Fregert and Rorsman (1964). Epoxy
chemicals. When all occupations were concerned, resins can be used as plastieizers and stabilizers in
roughly 60% of the rubber-glove allergy cases were PVC (gloves), PVAC plastics, and neoprene (Fregert
due to a delayed-type re action and 40% to an and Rorsman 1964; Kanerva et al. 1985). Arecent, new
immediate-type reaction. NRL gloves can be consid- patient at the FlOH having allergic contact dermatitis
ered the most problematic cause of rubber allergy; they from the use of certain household-type PVC gloves
are a common cause of both type-I and -IV aliergies repeatedly reacted to her gloves and bisphenol A
(Estlander et al. 1996). during patch testing. Chemical analyses of the glove
material and a code ink she had handled, revealed
Plastic Gloves bisphenol A, which was probably the cause ofher glove
reaction (Estlander et al. 1998). Interestingly, one of
Completely cured plastic materials are not generally our previous patients who was allergic to her plastic
considered to be sensitizers. PVC, polyethylene (PE), gloves had been sensitized from the use of PVC gloves
polyvinylacetate (PVAC), polyvinylakohol and other of the same brand but was not allergic to bisphenol A
materials used in plastic gloves rarely cause allergic (Estlander et al. 1986).
contact dermatitis (Fisher 1986a). The use of plastic Plasticizers were possibly the cause of one patient's
materials for personal protective equipment has dermatitis when five patients were sensitized to their
become common since the 1950S but, in most coun- PVC gloves. The patient reacted to tricresyl phosphate
tries, plastic gloves are possibly less used than rubber and triphenyl phosphate, known to be used as plastic-
gloves. One reason for this may be that users still find izers in PVC (Estlander 1990; Estlander et al. 1998).
plastic gloves less comfortable because they are not Other potential plasticizer sensitizers include phtha-
always as soft and pliable as rubber gloves and do not lates, e.g., dibutyl and dioctyl phthalate (Cronin 1980).
completely follow the contours of the hands. Accord- In addition, colorants may be the cause of PVC-glove
ingly, most of the reports on allergic contact eczema dermatitis. The colorant Irgalite Orange F2G (CI
from plastic gloves are based on only one case or a few Pigment Orange 34) was the actual sensitizer in one
cases. In a German study, 31 patients investigated in of the five above-mentioned patients (Kanerva et al.
1969-1984 were sensitized from the use of rubber or 1985; Estlander et al. 1986, 1999b; Estlander 1990). In
vinyl gloves; 10% of them were allergic to vinyl gloves addition, there may still be other potential sensitizers
(Frosch et al. 1987). Similar results were obtained in a in plastic gloves. The distinction between the terms
Finnish study: 5 (7%) of 68 patients were sensitized synthetic rubber and plastic polymers is somewhat
from the use of PVC gloves (Estlander et al. 1986). artificial. Therefore, the manufacturers and distribu-
Since then, only one definite case of vinyl glove allergy tors of gloves may sometimes call a certain material a
has been diagnosed at the FlOH (Estlander et al. 1998, plastic, whereas others may designate the same mate-
1999b). rial as synthetic rubber. For instance, in Finland a
Most allergy problems are connected with the use of certain brand of gloves made of nitrile rubber or of
PVC gloves. A vinyl glove material may, for example, mixed material has been sold as plastic gloves
contain about 50% PVC and 50% additives. These (Estlander et al. 1987). However, some of the same
include plasticizers, stabilizers, UV absorbers, fungi- chemicals can be used in both plastics and rubbers,
eides, bactericides, flame retardants, and colorants e.g., certain thiourea derivatives (Cronin 1980; Taylor
(Cronin 1980). Although plastic materials are generally 1986; Kanerva et al. 1994).
considered to be non-sensitizers, some additives may
be leachable and cause contact sensitization (Jolanki Leather Gloves
et al. 1987b; Estlander 1990). PVC itself is probably not
a sensitizer (Kanerva et al. 1985). In most of the Chrome-tanned leather gloves can induce allergy to
reported cases of allergy to plastic gloves, the actual chromium, thereby causing dermatitis. On rare occa-
sensitizer in the material has remained undetermined sions dyed leather gloves can also be the cause of glove
(Templeton 1950; Morris 1953; Estlander et al. 1986; dermatitis (Estlander et al. 1995b). The leather used for
Frosch et al. 1987; Guillet et al. 1991; Krasteva et al. protective gloves is usually tanned by water-soluble
1992; Taylor and Praditsuwan 1996). The commonly chrome salts. Experiments have ShOWll that synthetic
used patch tests series of plastics and glues contains and human sweat can release chromium from leather
some potential allergens in PVC materials, and the in amounts sufficient to induce the development of
ingredients of the suspected glove materials are seldom contact allergy (Fregert and Gruvberger 1979; Estlander
available for testing. This is possibly the most impor- et al. 1995b). However, allergy to leather gloves is rare
compared with that caused by polymeric gloves, three components of the mix, zinc diethyldithiocarba-
especially rubber gloves. mate, zinc dibutyldithiocarbamate and diphenylguani-
dine, have therefore been recommended to be tested
Investigations when Allergy to Gloves Is Suspected from the beginning (Geier and Gefeller 1995). Testing
MBT instead of mercapto mix increases the sensitivity
The possibility of glove allergy should be suspected in of the test because, in addition to detecting allergy to
cases in which even the careful wearing of rubber or MBT, it reveals allergies to N-cyclohexylbenzothiazyl
plastic (PVC) gloves with or without separate inner sulfenamide (CBS), dibenzothiazyl disulfide (MBTS) or
gloves seems to be of no use. The wearing of thin morpholinylmercapto benzothiazole (MOR) with the
cotton gloves does not always prevent the development same sensitivity as mercapto mix. In the living epider-
of allergy, as the additives released from the gloves mis CBS, MBTS, and MOR are converted into MBT
may easily penetrate the fabric and reach the skin. The (Hansson and Agrup 1993).
possibility of glove dermatitis should also be kept in The standard series contains no thiourea com-
mind in cases where skin problems from contact with pounds, but some are included in a specific rubber
other rubber objects have been encountered (Cronin series, e.g., Chemotechnique Diagnostics Ab. Cross-
1980). Also, occasional use of gloves made of polymeric reactivity occurs between thiourea compounds, but not
materials, although not considered important by the constantly (Roberts and Hanifin 1980; Kanerva et al.
patient, should be borne in mind, especially in the 1994), therefore, each thiourea compound needs to be
cases of dermatoses other than contact eczema. tested separately. Patch testing with a rubber additive
Sensitization to chromium should be considered in series, e.g., Chemotechnique which contains 24 chem-
cases of hand dermatitis appearing in jobs in which icals, may increase the accuracy of patch testing and
leather gloves may often become totally wet, e.g., in help to find alternative materials for patients having a
many construction or forestry jobs or where there is specific rubber-additive allergy.
profuse sweating of the hands in work involving high Possible sensitization to rubber polymers them-
temperatures such as in welding. selves, as well as glove powders, should also be
Investigations should include patch testing with excluded (Heese et al. 1991; Wilkinson and Burd
pieces of rubber and plastic glove materials, using the 1998). The fragrances used to deodorize the materials
48-h occlusion time. A longer occlusion time has been mayaiso be the cause of glove allergy. Arecent study
considered necessary, especially when thin gloves like among patients attending a contact dermatitis inves-
examination or surgical gloves are tested (Taylor 1986). tigation unit showed that of 117 consecutive patients
However, a longer occlusion time also increases the tested, 6% (20% of those with a positive reaction)
risk of false-positive reactions. Testing with solid demonstrated type-IV allergy to NRL, indicating that
materials always includes a risk of false-positive irritant NRL is a relatively common cause of allergic contact
reactions, but re-testing and control tests on non- eczema in the absence of contact urticaria from NRL
exposed persons, as well as experience in reading tests (Wilkinson and Burd 1998). The authors also recom-
(Nurse 1979), may help to distinguish irritant reactions mend that NRL (preserved solely with ammonia)
from allergic ones. Tests with ultrasonic bath extracts should be included in a rubber series for screening
of glove materials may also help detect the sensitizer in patients with hand dermatitis who are glove users.
the materials (Bruze et al. 1992). Further testing with a Aseries of plastics and glues containing tricresyl-
standard se ries, e.g., the European series (Chemotech- phosphate and bisphenol A may help in cases where
nique Diagnostics Ab, Malmö, Sweden) is necessary to PVC gloves are suspected. Patch testing with all actual
confirm an allergy to rubber. The series contains three components of polymer gloves would give the best and
rubber mixes; a thiuram mix, black rubber mix, and the most reliable results (Kanerva et al. 1985; Estlander
carba mix; and mercaptobenzothiazole (MBT) which et al. 1997) and would also give more information on
detects most cases of rubber glove allergy (Estlander allergenic compounds found in gloves.
et al. 1994a; Holness and Nethercott 1997). The thiuram In cases where leather gloves are suspected of
mix has been shown to be a good detector of glove causing allergic dermatitis, tests with pieces of gloves
allergy (Cronin 1980; Lammintausta and Kalimo 1985; usually give negative results. The chromium salts used
Holness and Nethercott 1997). It has also been in the tanning of leather most commonly cause
suggested that, in cases of rubber glove allergy, it is sensitization. The patch test should include, in addi-
not important to know which specific thiuram com- tion to potassium dichromate in the standard series, a
pound is the sensitizer because all thiuram-containing dilution series of potassium dichromate and chromium
gloves must be avoided (Hollness and Nethercott 1997). chloride to confirm sensitization to chromium. When
However, carba mix does not seem to be a reliable the leather gloves are colored, sensitization to leather
diagnostic tool except for patients who are not allergic dye should also be kept in mind (Estlander et al.
to its components (Geier and Gefeller 1995). The single 1995b).
Investigations should also include tests to detect EEC concerning medical devices. The European Com-
type-I allergy to polymeric glove materials and glove mittee for Standardization (CEN) is responsible for
powders (prick tests, determinations of latex-specific establishing the necessary new standards for Europe. A
IgE antibodies in serum, e.g., radioallergosorbent test survey of US rules, regulations and standards con-
(RAST), and challenges with suspected gloves). See cerning protective gloves for occupational use has been
also Chap. 88, by Turjanmaa. completed by Henry (Henry 1994; Mellström and
Boman 1997).
Chemicals coming into contact with rubber-glove
Getting Caught in Moving or Revolving Parts materials may have many adverse effects on the
of Machinery materials. They may even promote the development
of allergy to the glove ingredients; for example, organic
The use of protective gloves must not increase the risk solvents can extract allergenic compounds from the
of injuries to the hands. There is considerable accident gloves and carry them inside the gloves (Williams 1979,
risk when the work involves wearing gloves near Estlander et al. 1980), and some chemicals, e.g.,
revolving machinery. Machines should always be hypochlorite, can transform a non-allergenic chemical
tagged and locked during repair, adjustment, or in a rubber material into an allergenic chemical
mounting. The use of gloves may sometimes be (Jordan and Bourlas 1975). Surgeons may treat the
necessary even though there is some risk that they thumb, index, and middle fingers of their surgical
might get caught in moving parts of machinery. To gloves with sodium hypochlorite to produce good
prevent accidents in such cases, the gloves should fit traction of the material (Guin 1992), at the same time
closely and be made of smooth materials with a low possibly increasing the risk of sensitization to the
tear strength (Sumwalt 1967), such as neoprene or material. The allergenicity of gloves mayaiso depend
nitrile. Alternatives for gloves may be pads and cuffs on other environmental factors, such as whether the
that provide partial protection for the vulnerable parts glove is used in an oxidizing or a reducing milieu
of hands (Estlander and Jolanki 1988). (Hansson and Agrup 1993).
Protective gloves are classified into three categories
according to their intended use. Category III includes
Prevention of the Problems of Glove Usage gloves of complex design, intended for use against
irreversible or life-threatening risks. Protective gloves
All efforts to minimize the role of gloves as causes of meant to protect against chemieals belong to category
occupational and non-occupational dermatoses, as III and, in Europe, they are covered by standard
contributing factors in occupationally induced acci- EN-420 (general requirements for gloves) and EN 374-1,
dents to hands, and in the worsening of dermatoses EN 374-2 and EN 374-3 (Mellström and Boman 1997).
from other causes are necessary. It is also important to Glove usage should begin at the same time handling
prevent the long-Iasting occupational and social con- of hazardous materials begins, but gloves made of
sequences of the allergy (Wrangsjö and Meding 1994). polymerie materials should not, however, be used
Preventive aspects should be considered carefully needlessly, e.g., during cleaning jobs in which no
(Estlander and Jolanki 1988; Estlander et al. 1994a, liquids are handled. One person should use each pair
1996, 1999a). A detailed job analysis should be carried of gloves, and the condition of the gloves should be the
out; all materials to be handled with gloves should user's responsibility. Every worker with long-Iasting
always be checked to see whether the materials are dermatitis should be referred for a dermatological
suitable for the job in question. Also, the demands of examination including appropriate skin testings.
the user should be taken into account before the gloves Only gloves with CE markings should be used at
are selected. work, at least in the countries of the European Union.
New directives and regulations covering the use and Since July 1, 1995, only PPE with CE (Euro pe an
safety requirements of protective gloves have come Community conformity) markings can be distributed
into force in Europe. Obtaining information on quality inside the European Economic Area. This mark
requirements and performance data, as well as an guarantees that the product fulfills the essential
acceptable level of exposure to hazards and problems requirements of directive 89/686/EEC. It also implies
in glove usage is necessary before gloves are selected, that all PPE (categories II-III), except those which are
purchased or used (Mellström and Boman 1997). meant against minimal risk only (category I) must be
In Europe, gloves intended to protect the user are type examined by a notified body before the CE mark
considered personal protective equipment (PPE) and can be affixed on the PPE. The Department of Physics
covered by the personal protective Equipment Direc- at the FlOH is such a notified body. The user of the
tive 89/686/EEC. Gloves that are intended for medical PPE is also entitled to receive information about the
purposes are covered by the Council Directive 93/42/ PPE, its classification as a PPE, and about the tests it
has passed from the distributor of the PPE. This is collected in disposable plastic bags so that other
especially important because packages of gloves no workers or family members do not come into contact
longer need to contain information on the glove with hazardous substances (Estlander and Jolanki 1988;
material. Directive 89/6S6/EEC, however, obligates Estlander et al. 1999a).
employers to make risk assessments and define the
suitability of gloves for each job, as weil as to organize
a system of glove maintenance and training for glove Summary
users (Estlander et al. 1996, 1999a).
There should be a specific place at every work site The European directives on PPE (89/686/EEC and 89/
where gloves can be left without any risk of becoming 6S6/EEC) are important guidelines in improving the
soiled or mechanically damaged (Rycroft 1986). Per- manufacture, selection and use of protective gloves.
sons allergie to rubber should use gloves made of Despite the risk of allergy, NRL and other rubber
plastic materials unless the sensitizers, and the chem- gloves still retain their place as effective means of
ieals used in the manufacture of the alternative rubber protection, provided that they are used correctly and
material, are known. Rubber gloves free from thiuram gloves manufactured of suitable materials are chosen
accelerators are available on the market (Heese et al. for each job. Apart from the glove material, many
1991). NRL gloves are best suited for occasional use. other factors affect the successful use of gloves,
Inner cotton or inner disposable PVC or PE gloves are including differences in skin types among various
recommended to be used with rubber gloves because groups of people, the great variety of chemicals and
the inner gloves increase the protection of gloves and working methods used at work places, differences in
decrease the risk of sensitization (Estlander and the degree of experience and education among differ-
Jolanki 1988; Estlander et al. 1994a; Mäkelä et al. ent groups of workers, thus in their ability to under-
1999). In addition, the material of NRL gloves should stand the importance of instructions on safe working
be of low protein content (Palosuo et al. 1997). methods and in their motivation to use PPE.
Manufacturers and shops specified to distribute PPE,
including gloves, can help sensitized persons select
suitable gloves. In some cases of rubber allergy, gloves References
made of synthetic rubber can be used with separate
inner textile gloves when exact information about the Alenius H, Turjanmaa K, Palosuo T, Mäkinen-Kiljunen S,
glove material is not known. Reunala T (1991) Surgieallatex glove allergy: characterization
of rubber latex protein sensitivity by immunoblotting. Int
Separate textile gloves should also be worn under Arch Allergy Immunol 96:376-380
unlined gloves made of polymers, especially when Alenius H, Mäkinen-Kiljunen S, Turjanmaa K, Palosuo T,
there are symptoms of skin irritation or dermatitis of Reunala T (1994) Allergen and protein content of latex
gloves. Ann Allergy 73:315-320
the hands, or the hands sweat profusely. Inner gloves Alenius H, Kalkkinen N, Reunala T, Turjanmaa K, Palosuo T
should be made of soft materials, like cotton, viscose, (1996a) The main IgE binding epitope of a major latex
polyamide, or wool. Barrier creams should not be used allergen, prohevein, is present in its N-terminal43 amino acid
fragment hevein. J ImmunoI156:1618-1625
under NRL gloves. Skin protection creams may pro- Alenius H, Kalkkinen N, Turjanmaa K, Mäkinen-Kiljunen S,
mote the uptake of allergens from the gloves, thus Reunala T, Palosuo T (1996b) Significance of rubber elonga-
increasing allergic reactions (Baur et al. 1998). tion factor as a latex allergen. Int Arch Allergy Immunol
109:362-368
Better protection is ensured if at least two pairs of Anon (1998a) 4 H An overview about chemicals and skin
gloves are available for every worker during every protection (in Danish). Plum Hudsikkerhet, DK-Assens,
work shift. The thicker the glove material, the better Denmark
Anon (1998b) New Barrier™ chemieal resistant gloves. AnseIl
protection it gives. Thickness, nevertheless, re duces Edmont, AnseIl Protective Products Europe N.V., B-9300
both fiexibility and dexterity. One alternative to thiek Aalst, Belgium
gloves would be the simultaneous use of two pairs of Aoyama M, Sugiura K, Fujise H, Naruse M (1982) On use of
gloves in the horne and their infiuence upon skin irritation.
thin gloves made of different materials (e.g., a dispos- Nagoya Med J 27:65-74
able pair of PE gloves and another pair of natural Baur X, Ammon J, Chen Z, Beckmann U, Czuppon AB (1993)
rubber to be worn outermost) (Mäkelä et al. 1999). Health risk in hospitals through air borne allergens for
patients presensitized to latex. Lancet 342:1148-1149
Special gloves made of lamina ted plastic materials, Baur X, Chen Z, Allmers H, Raulf-Heimsoth M (1998) Results of
such as the 4H Glove (Anon 1998a) or Barrier (Anon wearing test with two different latex gloves with and without
1998b), can also be used as inner gloves (Estlander skin protection cream. Allergy 53:441-443
Beezhold D, Pugh B, Liss G, Sussman G (1996) Correlation of
et al. 1992; Tarvainen 1996). pro tein levels with skin prick test reaction in patients allergie
Gloves, permeated by chemicals and thereby hard- to latex. J Allergy Clin Immunol 98:1097-1102
ened or cracked, should be discarded, as should gloves Belsito DV (1990) Contact urticaria caused by rubber. Dermatol
Clin 8:61-66
entirely impregnated with chemicals known to be Brehler R (1996) Contact urticaria caused by latex-free nitrile
hazardous to the skin. Discarded gloves should be gloves. Contact Dermatitis 34:296
Brehler R, Sedlmayer S (1997) Contact urticaria due to rubber Fisher AA (1986a) Contact dermatitis, 3rd edn. Lea & Febiger,
chemieals? Contact Dermatitis 17:125-127 Philadelphia, pp 546-565
Brehler R, Woss W, Müller S (1998) Glove powder affects skin Fisher AA (1986b) Contact urticaria due to corn starch surgical
roughness, one parameter of skin irritation. Contact Derma- glove powder. Cutis 38:307-308
titis 39:227-230 Fisher AA (1987) Contact urtiearia and anaphylactoid reaction
Bruze M, Trulsson L, Bendsöe N (1992) Patch testing with due to corn starch surgieal powder. Contact Dermatitis
ultrasonie bath extracts. Am J Contact Dermat 3:133-137 16:224-235
Castelain M, Castelain P-Y (1993) Allergie contact dermatitis from Foussereau J, Tomb R, Cavelier C (1990) Allergic dermatitis from
cetyl pyridinium chloride in latex gloves. Contact Dermatitis safety clothes and individual protective deviees. Dermatol
28:118 Clin 8:127-132
Conde-Salazar L, dei Rio E, Guimaraens D, Gonzalez D (1993) Fregert S, Gruvberger B (1979) Chromium in industrial leather
Type IV allergy to rubber additives. A 10-year study of 686 gloves. Contact Dermatitis 5:189
cases. J Am Acad Dermatol 29:176-180 Fregert S, Rorsman H (1964) Allergens in epoxy resins. Acta
Cormio L, Turjanmaa K, Talja M, Andersson LC, Ruutu M (1993) Allergoi 19:296-299
Toxicity and immediate allergenity of latex gloves. Clin Exp Frosch PJ, Born CM, Schütz R (1987) Kontaktallergien auf
Allergy 23:618-623 Gummi-, Operations- und Vinylliandschuhe. Hautarzt
Crippa M, Pasolini G (1997) Allergic reactions due to glove- 38:210-217
lubrieant powder in health-care workers. Int Arch Occup Fuchs T (1995) Gummi und Allergie. Dustri, München-Deisenho-
Environ Health 70:399-402 fen, pp 1-247
Cronin E (1980) Contact dermatitis. Churchill Livingstone, Geier 1, Fuchs Th (1989) Kontakturtikaria durch Gummihandsc-
Edinburgh, pp 1-915 huhe. Z Hautkr 65:267-272
Estlander T (1990) Occupational skin disease in Finland. Obser- Geier 1, Gefeller 0 (1995) Sensitivity of patch tests with rubber
vations made during 1974-1988 at the Institute of Occupa- mixes: results of the information network of departments of
tional Health, Helsinki (thesis). Acta Derm Venereol Suppl dermatology from 1990 to 1993. Am J Contact Dermat 6:
(Stockh) 155:1-85 143-149
Estlander T, Jolanki R (1988) How to protect the hands. Dermatol de Groot H, de Jong NW, Duisjter E, van Wijk RG, Vermeulen A,
Clin 6:105-114 van Toorenenbergen AW, Geursen L, van Joost T (1998)
Estlander T, Kilpikari I, Eskolin E (1980) Permeability of polymer Prevalence of natural rubber latex allergy (type I and type IV)
gloves and chemicals used in the manufacture of gloves (in in laboratory workers in the Netherlands. Contact Dermatitis
Finnish). Suomen Lääkärilehti (Finnish Med J) 35:800-803 38:159-163
Estlander T, Jolanki R, Kanerva L (1986) Dermatitis and urticaria Guillet MH, Menard G, Guillet G (1991) Sensibilisation de contact
from rubber and plastic gloves. Contact Dermatitis 14:20-25 aux gants en vinyl. Ann Dermatol VenereoI1l8:723-724
Estlander T, Jolanki R, Kanerva L (1987) Contact urticaria from Guin JD (1992) The doctor's surgical/examination gloves -
rubber gloves: a detailed description of four cases. Acta problems with and without them. Int J Dermatol 31:853-855
Dermatol Venereol Suppl (Stockh) 134:98-102 Häffner AC, Zepter K, Eisner P, Burg G (1996) Isolated delayed-
Estlander T, Keskinen H, Jolanki R, Kanerva L (1992) Occupa- type hypersensitivity to latex rubber. Contact Dermatitis
tional dermatitis from exposure to polyurethane chemieals. 35:247-248
Contact Dermatitis 27:161-165 Hamann CP (1993) Natural rubber latex protein sensitivity in
Estlander T, Jolanki R, Kanerva L (1994a) Allergie contact review. Am J Contact Dermat 4:4-21
dermatitis from rubber and plastie gloves. In: Mellström GA, Hansson C, Agrup G (1993) Stability of 2-mercaptopbenzothiaz-
Wahlberg JE, Maibach HI (eds) Protective gloves for occu- oie (MBT). Contact Dermatitis 28:29-34
pational use. CRC Press Inc, Boca Raton, pp 221-239 Heese A, von Hintzenstern J, Peters K-P, Koch HU, Hornstein OP
Estlander T, Jolanki R, Kanerva L (1994b) Protective gloves. In: (1991) Allergic and irritant reactions to rubber gloves in
Menne T, Maibach HI (eds) Hand eczema. CRC Press Inc, medical health serviees. J Am Acad Dermatol 25:831-839
Boca Raton, pp 311-321 Heese A, Peters K-P, Hornstein OP (1992) Anaphylactic reaction
Estlander T, Kanerva L, Jolanki R (1995a) Rubber additive to unexpected latex in polychloroprene gloves. Contact
sensitization from synthetic rubber gloves and boots. All- Dermatitis 27:336-337
ergologie 18:470 Heese A, Peters K-P, Koch HU, Hornstein OP (1994) Allergologic
Estlander T, Jolanki R, Kanerva L (1995b) Clothing. In: Guin JD evaluation and data on 173 glove-allergic patients. In:
(ed) Practieal contact dermatitis. McGraw-Hili Inc, New York, Mellström GA, Wahlberg JE, Maibach HI (eds) Protective
pp 297-323 gloves for occupational use. CRC Press Inc, Boca Raton,
Estlander T, Jolanki R, Kanerva L (1996) Rubber glove dermatitis: pp 185-205
a significant occupational hazard - prevention. In: Elsner P, Heese A, Peters K-P, Koch HU (1995) Allergien gegen Latex-
Lachapelle JM, WalIlberg JE, Maibach HI (eds) Prevention of handschuhe. Allergologie 18:358-365
contact dermatitis. (Current problems in dermatology, V0125) Heilman DK, Jones RT, Swanson MC, Yunginger JW (1996) A
Karger, Basel, pp 170-181 prospective, controlled study showing that rubber gloves are
Estlander T, Jolanki R, Kanerva L (1997) Occupational allergie the major contributor to latex aeroallergen levels in the
contact dermatitis from 2,3-epoxypropyl trimethyl ammo- operating room. J Allergy Clin Immunol 98:325-330
nium chloride (EPTMAC) and Kathon LX in starch modifi- Helander I, Mäkilä A (1983) Contact urtiearia to zinc diethyl-
cation factory. Contact Dermatitis 36:191-194 dithiocarbamate (ZDC). Contact Dermatitis 9:327-328
Estlander T, Jolanki R, Kanerva L (1998) Occupational allergy to Henry NW III (1994) Protective gloves for occupational use.
bisphenol A from non-epoxy products. J Eur Acad Dermatol Mellström GA, Wahlberg JE, Maibach HI (eds) CRC Press Inc,
Venerol II [Suppl 2] :207 Boca Raton, pp 45-50
Estlander T, Jolanki R, Kanerva L (1999a) Protective gloves. In: Hoffmann-Sommergruber K, Breiteneder H, Scheiner 0 (1998)
Menne T, Maibach HI (eds) Hand eczema book, 2nd edn. Neue Ergebnisse zur molekularen und allergologischen
CRC Press Inc, Boca Raton (in press) Characterisierung von Hevea-brasiliensis-Latexallergnen. All-
Estlander T, Jolanki R, Henriks-Eckerman ML, Kanerva L (1999b) ergol J 7:324-331
Occupational allergy to bisphenol A. Contact Dermatitis Hogstedt C, Stahl R (1980) Skin penetration and protective gloves
40:52-53 in dynamite work. Am Ind Hyg Assoc J 41:367-372
Field EA (1998) Atopy and other risk factors for UK dentists Holness DL, Nethercott JR (1997) Results of patch testing with a
reporting an adverse reaction to latex gloves. Contact special series of rubber allergens. ContactDermatitis 36:207-211
Dermatitis 38:132-136 Jolanki R, Estlander T, Kanerva L (1987a) Contact allergy to an
Figard WH (1980) Intensifying the efforts of proper glove epoxy reactive diluent: lA-butanediol diglycidyl ether. Con-
selection. Occup Health Saf 7:30-43 tact Dermatitis 16:87-92
Jolanki R, Kanerva L, Estlander T (1987b) Organic pigments in Naruse M, Iwama M (1992) Dermatitis from household vinyl
plastics can cause allergic contact eczema. Acta Dermatol gloves. Bull Environ Contam Toxicol 48:843-849
Venereol Suppl (Stockh) 134:95-97 Nurse DS (1979) Rubber sensitivity. Australas J Derm 20:31-33
Jolanki R, Savela A, Estlander T, Kanerva L (1998a) Causes of Palosuo T (1997) Latex allergens. Rev Fr Allergoi 37:1184-1187
occupational skin diseases in Finland 1990-96 (in Finnish). Palosuo T, Turjanmaa K, Reunala T, Mäkinen-Kiljunen S, Alenius
Suomen Lääkärilehti (Finnish Med J) 53:409-415 H (1996) Allergen content oflatex gloves used in 1994-1996 in
Jolanki R, Estlander T, Alanko K, Savela A, Kanerva L (1998b) health care in Finland. Results of renewed market survey in
Occupational contact urticaria or protein contact dermatitis 1995. Publications National Agency for Medieines 2:1-7
from natural rubber latex by occupation. J Eur Acad Palosuo T, Mäkinen-Kiljunen S, Alenius H, Reunala T, Yip E,
Dermatol Venereol11[Suppl 2]:207 Turjanmaa K (1998) Measurement of natural rubber latex
Jordan WP, Bourlas MC (1975) Allergic contact dermatitis to allergen levels in medical gloves by allergen specific IgE-
underwear elastic, chemically transformed by alaundry ELISA inhibition, RAST inhibition, and skin prick test.
bleach. Arch Dermatol 1ll:593-595 Allergy 53:59-67
Kanerva L, Jolanki R, Estlander T (1985) Organic pigment as a Pegum JS (1979) Penetration of protective gloves by epoxy resin.
cause of plastic glove dermatitis. Contact Dermatitis 13:41-42 Contact Dermatitis 5:281-283
Kanerva L, Estlander T, Jolanki R (1994) Occupational allergic Placucei F, Vincenzi C, Chedini G, Plana G, Tosti A (1996)
contact dermatitis caused by thiourea compounds. Contact Coexistence of type I and type IV allergy to rubber latex.
Dermatitis 31:242-248 Contact Dermatitis 34:76
Kanerva L, Jolanki R, Toikkanen J, Keskinen H, Savela A, Ramsing DW, Agner T (1996a) Effect of glove occlusion on
Karjalainen A (1998) Occupationally induced allergies in human skin (I). Short-term experimental exposure. Contact
1995-96 (in Finnish). Työterveyslaitos, Finnish Institute of Dermatitis 34:1-5
Occupational Health, Allergia ja työ-ohjelma (Allergy and Ramsing DW, Agner T (1996b) Effect of glove occlusion on
work program), Helsinki, pp 9-161 human skin (II). Long-term experimental exposure. Contact
Karjalainen A, Aalto L, Jolanki R, Keskinen H, Savela A (1998) Dermatitis 34:258-262
Ammattitaudit 1997. Occupational Diseases 1997. New cases Roberts JL, Hanifin JM (1980) Contact allergy and cross reactivity
reported to the Finnish Register of Occupational Diseases. to substituted thiourea compounds. Contact Dermatitis
Työterveyslaitos, Finnish Institute of Occupational Health, 6:138- 139
Helsinki, pp 88 Romaguera C, Grimalt F (1980) Statistical and comparative study
Kassis V, Vedel P, Darre E (1984) Contact dermatitis to methyl of 4600 patients tested in Barcelona (1973-1977). Contact
methacrylate. Contact Dermatitis 11:26-28 Dermatitis 6:309-315
Krasteva M, Chefai M, Dupoy M, Chabeau G (1992) Vinyl glove Rycroft RJG (1986) Environmental factors of occupational
intolerance. In: Book of abstracts, 1st Congress of the dermatology. Dermatosen 34:157-159
European Soeiety of Contact Dermatitis, Brussels, 8-10 Safadi G, Safadi TI, Terezhalmy GT, Taylor JS, Battisto JR, Melton
October, P 73 AL (1996) Latex hypersensitivity: its prevalence among dental
Kwangsuktith CH, Maibach HI (1995) Contact urticaria from professionals. J Am Dent Assoc 127:83-87
polyurethane-membrane hypoallergenic gloves. Contact Der- Seaton A, Cherrie B, Turnbull J (1988) Rubber glove asthma. BMJ
matitis 33:200-201 296:531-532
Lammintausta K, Kalimo K (1985) Sensitivity to rubber. A study Shmunes E, Darby T (1984) Contact dermatitis due to endotoxin
with rubber mixes and individual rubber chemicals. Der- in irradiated latex gloves. Contact Dermatitis 10:240-244
matosen 33:204-208 Steinkjer B (1998) Contact dermatitis from cetyl pyridinium
Lezaun A, Marcos C, Martin JA, Quirce S, Gomez MLD (1992) chloride in latex surgical gloves. Contact Dermatitis 39:29-30
Contact dermatitis from natural latex. Contact Dermatitis Storrs FJ (1984) Permanent wave contact dermatitis: contact
27:334-335 allergy to glyceryl monothioglycolate. J Am Acad Dermatol
Leynadir F, Dry J (1991) Allergy to latex. Clin Rev Allergy 11:74-85
Immunol 9:371-377 Sumwalt CN Jr (1967) Gloves for industry. Natl Safety News
Mäkelä E, Väänänen V, Alanko K, Jolanki R, Estlander T, Kanerva 95:43-49
L (1999) Resistance of disposable gloves to permeation by 2- Sussman GL, Lern D, Liss G, Beezhold D (1995) Latex allergy in
hydroxyethyl methacrylate and triethyleneglycol dimethacry- housekeeping personnel. Ann Allergy Asthma Immunol
late. J Occup Hyg (in press) 74:415-418
Mäkinen-Kiljunen S, Turjanmaa K (1995) Latexallergene in Tarvainen K (1996) Occupational dermatoses from plastic
verschiedenen Arten von Latex-Handschuhen und Sen- composites based on polyester resins, epoxy resins and vinyl
sibilisierung von Krankenhauspersonal und Patienten. All- ester resins (thesis). People and Work Research Reports ll,
ergologie 18:366-368 Finnish Institute of Occupational Health, Helsinki, pp 1-66
Mäkinen-Kiljunen S, Reunala T, Turjanmaa K, Caeioli P (1993) Is Tarvainen K, Jolanki R, Forsman-Grönholm L, Estlander T, Pfaffli
cow's milk casein an allergen in latex-rubber gloves? Lancet P, Juntunen J, Kanerva L (1993) Exposure, skin protection
342:863-864 and occupational skin disease among in the glass fibre-
Mellström GA, Boman AS (1997) Protective gloves: test results reinforced plastics industry. Contact Dermatitis 29:119-127
compiled in a qatabase. In: Brune D, Gerhardsson G, Taylor JS (1986) Rubber. In: Fisher AA (ed) Contact dermatitis
Crockford GW, DAuria D (eds) The work place, vol 1. 3rd edn. Lea & Febiger, Philadelphia, pp 603-643
Fundamentals of health, safety and welfare. International Taylor JS (1994) Other reactions from gloves In: Mellström GA,
Occupational Safety and Health Information Centre (CIS), Wahlberg JE, Maibach HI (eds) Protective gloves for occu-
International Labour Office, Geneva and Scandinavian Sei- pational use. CRC Press Inc, Boca Raton, pp 255-265
ence Publisher, Oslo, pp 716-730 Taylor JS, Praditsuwan P (1996) Latex allergy. Review of 44 cases
Mellström G, Lindberg M, Boman A (1992) Permeation and including outcome of frequent association with allergic hand
destructive effect of disinfectants on protective gloves. eczema. Arch Dermatol 132:265-271
Contact Dermatitis 26:163-170 Templeton HJ (1950) Contact dermatitis from plastic mittens.
Meeren van der HLM, Erp van PEJ (1986) Life-threatening Arch Dermatol Syph 61: 854
urticaria from glove powder. Contact Dermatitis 14:190-191 Themido R, Menezes-Brandao F (1984) Contact allergy to
Milcovic-Kraus S (1992) Glove powder as a contact allergen. thiurams. Contact Dermatitis 10:251
Contact Dermatitis 26:198 Turjanmaa K (1987) Incidence of immediate allergy to latex
Morris GE (1953) Vinyl plastics. Arch Ind Hyg Occup Med 8:535-539 gloves in hospital personnel. Contact Dermatitis 17:270-275
Moursiden HT, Faber 0 (1973) Penetration of protective gloves by Turjanmaa K (1988) Latex glove contact urticaria (thesis) Acta
allergens and irritants. Trans St John' s Hosp Derm Soc Universitatis Tamperensis, Ser A, vol 254, University of
59:230-234 Tampere, Finland, pp 1-86
436 T. Estlander et al.: Disadvantages of Gloves
Turjanmaa K (1994) Contact urticaria from latex gloves. In: Wilkinson SM, Burd R (1998) Latex: a cause of allergie contact
Mellström GA, Wahlberg JE, Maibach HI (eds) Protective eczema in users of natural rubber gloves. J Am Acad
gloves for occupational use. CRC Press Inc, Boca Raton, Dermatol 38:36-42
pp 241-254 Williams JR (1979) Permeation of glove materials by physiolog-
Turjanmaa K (1997) Contact urtiearia from latex gloves In: Amin ieally harmful chemicals. Am Ind Hyg Assoc J 40:877-882
S, Lahti A, Maibach HI (eds) Contact urticaria syndrome. Wrangsjö K, Meding B (1994) Occupational allergy to rubber
CRC Press Inc, Boca Raton, pp 173-187 chemieals. A follow-up study. Dermatosen 42:184-189
Van der Walle HB, Brunsveld VM (1995) Latex allergy among Wyss M, Elsner P, Wütrich B, Burg G (1993) Allergie contact
hairdressers. Contact Dermatitis 32:177-178 dermatitis from natural latex without contact urticaria.
Wall LM (1980) Nickel penetration through rubber gloves. Contact Dermatitis 28:154-156
Contact Dermatitis 6:461-463 Yassin MS, Lied MB, Fischer TJ, O'Brien K, Cross J, Steinmetz C
Warshaw EM (1998) Latex allergy. J Am Acad Dermatol 39:1-24 (1994) Latex allergy in hospital employees. Ann Allergy
Wigger-Alberti W, Elsner P (1998) Do barrier creams and gloves 72:245-249
prevent or provoke contact dermatitis. Am J Contact Dermat Yunginger JW, Jones RT, Fransway AF, Kelso JM, Warner MA,
9:100-106 Hunt LW (1994) Extractable latex allergens and proteins in
Wilkinson SM, Beck MH (1996) Allergie dermatitis from latex disposable medieal gloves and other rubber products. J Aller-
rubber Br J Dermatol 134:910-914 gy Clin Immunol 93:836-842
CHAPTER 55
Plant Survey and Inspection

R.J.G. Rycroft
Introduction names and tides of its representatives can also be

helpfullater on. Such reports can usefully be consult-
For the dermatologist, the purpose of a visit to the ed, for example, when another patient from the same
workplace will generally be for assistance in diagnosis, plant is subsequendy referred. There is nothing more
though secondary prevention is also likely to be an encouraging to a patient as to the ultimate outcome of
aim. Similar principles apply, however, to surveys and their consultation than the feeling that their derma-
inspections by occupational-health professionals, who tologist already has some familiarity with their place of
are likely to be more concerned with primary preven- work.
tion or regulation.
Although there is some published guidance available
(Carmichael and Foulds 1993), it is the accumulated Technological Notes
experience of actually making such visits that is the best
teacher. The first essential is that a plant be looked at What must be gained next, and eventually concisely
when work is going on. This may read like a truism, but expressed, is an overall appreciation of the entire
work breaks can easily arrive at just the wrong moment. production process, from the arrival of raw materials
The second requirement is that sufficient time be to the departure of the finished product. Some plants
allowed at the plant. Even the most straightforward have a wall plan or even ascale model to assist in this;
inspection usually takes at least one-and-a-half hours. others are so small that a few brief remarks are enough.
Third, it is helpful to have a firm idea about what This is not just an academic exercise, since you may be
information you require, combined with a flexible much better able to advise on redeployment of
approach as to how, precisely, you are going to acquire employees with dermatitis and identify previously
it - not unlike obtaining a good dinical history from a unsuspected irritants and allergens if you have such
patient in a busy outpatient dinic. Lastly, any recom- a total conception of the plant. Clearly, it mayaiso be
mendations need to be communicated dearly and of considerable general interest simply to know how
persuasively. It follows that you will need both to take products are made; indeed, if tlIat interest is not there,
informal notes as you go along and to write up a formal you may not be in quite the right line of work.
report of your findings on your return. In order to yield its full dermatological information,
any such scheme needs to be augmented with a bird's-
eye view of tlIe facilities in which the process is
Notes on Organisation conducted. Detailed information about the relevant
work area(s) will follow later, but it may first be
It can save time at a future date to record at the outset informative to record some more general approxima-
the full postal address (induding postal code) and the tions as to floor space, ceiling height, lighting, heating
telephone/faxle-mail numbers of the plant. Beneath and ventilation. Indoor microdimates are known to be
those notes in your report, the names and titles of all capable in themselves of causing occupational
personnel you met witlI during your visit, as well as the dermatoses, parameters such as low relative humidity
total number of employees, are useful. Medical or occasionally being the key to an endemie pruritus or
nursing staff will dearly be of particular importance, as dermatitis (Rycroft 1984).
well as the occupational-health facilities available. In Concentrating on the work area or areas of partic-
larger plants, approximations of the subdivisions of ular dermatological interest is called for next. Try to
staff into male/female, administration/production and arrange matters such that you are able simply to stand
day shift/night shift mayaiso be relevant. A note of the still and watch the whole working cyde for a while
union(s) representing the employees as well as the (Fig. 1). Resist invitations for you to watch specially

438 R.J.G. Rycroft
example, to be loaded with raw materials, unloaded of

their products and, most importantly of all, worked on
by service engineers when they malfunction. The skin
exposure that such interventions may entail is fre-
quently underestimated or, when it is accurately
foreseen, deliberately delegated to contractors who
may themselves underestimate the risk.
Much attention will usually inevitably devolve onto
the provision of gloves, 'barrier' creams, skin deans-
ers and after-work creams. Interest should be expres-
sed during the visit in the methods of selection of
such products and their resulting suitability for the
job(s) in question. It may be worthwhile, on occasion,
to ask to meet the individual(s) at the plant respon-
sible for such decisions. You will find that such
personnel often betray the fact, or know only too weIl
themselves, that they do not have adequate knowledge
on which to base their purchasing strategy. Your visit
may then act as a catalyst for an employer to acquire
more expertise in the area of prevention, as weIl as in
the initial prediction of risk from contact irritants and
allergens.
Fig. 1. Accurate information regarding skin contact is acquired Meanwhile, it is informative to try to estimate what
by dose observation the compliance is with the protective measures
supplied; gloves may be worn all the time, some of
the time or not at all; creams may be applied regularly,
arranged demonstrations, but endeavour to see the irregularly or not at aH. It is important in acquiring
work as it is usually carried out. The person dosest to such impressions from inspections that a deliberately
doing the job is usually the best guide to it. At this non-judgmental stance is maintained at the time. An
time, make notes of the names and addresses of increasingly critical tone as the visit proceeds is likely
suppliers of products needing further identification. Be only to result in a decreasing fiow of information.
sceptical of assurances that all this can be supplied to Criticisms, if justified, can best be offered later after
you later. By all means put in early requests for the due refiection upon one's whole findings.
retrieval of relevant material safety data sheets This studiously neutral attitude be comes even more
(MSDSs) from elsewhere in the factory (Adams 1995). important when obtaining a feel for psychological,
Look at the work primarily from the viewpoint of sociological and economic pressures that may be
precisely how much skin contact with potential con- present in the plant. These may be expressed to you
tactants in fact occurs. Examining gloves and overall as chance comments rather than direct information,
sleeves can help you to assess this, which will lead to but factors such as an impending redundancy pro-
the second stage of your detailed assessment, a review gramme may do much to explain arecent surge in skin
of the skin protection provided. complaints. Such asides have to be earned by instilling
confidence in your hosts as to your professionalism
and lack of bias.
Preventive Measures
When considering skin protection, it is helpful to have Clinical Evaluation

a framework in mind of a protective 'hierarchy':
substitution, automation, mechanisation, endosure, Although you may, if you are a dermatologist, already
segregation, systems of work, handling procedures, have examined at least one patient in connection with
personal protective equipment and skin-care products. the plant, examination of working colleagues may
The earlier in the list, the more reliable is that often by prompted by your findings. Flexibility is again
preventive strategy likely to be. essential here, but it is almost always possible, even in
The most important exception to the above gen er- the smallest plant, to find somewhere to examine the
alisation is the aphorism that there is no such thing as skin, though not necessarily completely, while fuHy
an automatie process (Fregert 1980). In other words, respecting the individuals' privacy and confidentiality.
even 'fully automated' processes usually still need, for Good lighting may sometimes be hard to find, but one
Plant Survey and Inspection 439
can get used to less-than-optimal examination condi- to what is to be required of them. The small risk of
tions, and sometimes even skin scrapings can be taken active sensitisation by patch testing, for example, may
for mycological investigation on such occasions. Brief not be balanced by diagnostic benefit in a control
histories and additional enquiry, particularly as to group as it generally would be in a population with
atopic background, from even a few others with rashes dermatitis.
can do much to put the original patient's dermatosis in At all times - before, during and after such surveys -
better perspective (Rycroft 1980). communication between the investigators and the
When conducting such clinical assessments, the investigated is vital to the success of the project. Small
patient's epidemiological background must not be groups are often more successful in achieving this,
forgotten. The frequency of skin complaints as a even if the message then has to be repeated more than
proportion of the total exposure is central to the once or communicated from a core group to their
eventual diagnosis. The better your background know- colleagues. The ethics of voluntarily leaving the study
ledge of the process, the more accurately you are likely as well as of joining it should be made quite clear to all
to estimate this crucial denominator. At the same time, participants, whose co-operation should never be
it should not be forgotten that at least some of those taken for granted, even when it seems self-evident to
with dermatitis may already have left the plant, giving the investigators that the study is in the best interests
rise to the so-called healthy-worker effect. of all concerned.
Aetiological Evaluation Evaluation of Chemical Risk
Your judgement as to the occupational cause (or lack On other occasions, a plant survey may uncover the
thereof) of the cases that you assess may well have to need to acquire more information as to the chemical
remain provisional pending further investigations. constituents of products and their irritant and allergic
This should freely be admitted to all interested parties potential. MSDSs are usually little more than a starting
at a briefing before you leave. Any opinions of their point in such enquiries, which may demand consider-
own should be recorded, with attributions, as well as able persistence as well as critical intelligence. A
your own initial opinion. Do not feel inadequate if this balanced approach is required for the often difficult
is inconclusive. A formal written report of your visit, extrapolation from the hazard of a substance (i.e. the
having considered your findings, may be required inherent potential to cause dermatitis) to its risk (i.e.
before a coherent view can be gained. its likelihood of actually causing dermatitis). Other-
wise, errors of judgement can easily be made in
advising against the use of a product unnecessarily, as
Epidemiological Evaluation well as in overlooking a product that is areal threat to
the skin. Sometimes your inspection may eventually
On occasion, such a survey may indicate the need for a prompt further laboratory investigation of a sub-
more formal epidemiological study. Skin complaints stance's irritant or allergic potential. The accepted tests
may, for example, be widespread but unusually hard to available for such investigations should therefore be
explain. Such investigations should never be under- known to dermatologists and occupational-health
taken by clinicians without previous epidemiological professionals.
and statistical consultation. Coenraads and Nater
(1987) have published a useful introduction to the
problems that may arise, including true prevalence Writing aReport
estimation, bias, confounding variables and sample
size. Questions of disease definition and inter-observer If the format of your report of a workplace survey or
variability are not necessarily familiar to clinicians, inspection remains your choice, it should be well
who may therefore need to seek epidemiological advice considered, under headings such as those suggested by
at the earliest opportunity. Questionnaires are fre- this chapter. The report should end with a concise
quently designed that ask for far more detail than can summary of findings, clear recommendations for
possibly be usefully analysed statistically, and they actions to be taken or further investigations, and any
should always be piloted first in order to achieve proposals for follow-up. The confidentiality of infor-
validity. mation about individual cases mentioned in the report
Perhaps the greatest stumbling block of all is the should be respected at all times. Dispatch of the report
question of control groups. These can be very difficult may need to be followed by a further meeting between
to identify in an industrial setting, and when a you and interested parties. Your copy should be filed
suitable population is found, care should be taken as securely but retrievably.
440 R.J.G. Rycroft: Plant Survey and Inspection
Adherence to the principles outlined above should References

enable dermatologists and occupational-health profes-
sionals to make plant surveys and inspections both Adams RM (1995) Additional sources of information that can be
useful and professionally enjoyable. Fregert (1963) was used in patch testing. Am J Contact Dermat 6:40-41
Carmichael AJ, Foulds IS (1993) Performing a factory visit. Clin
among the first dermatologists to find that 'the Exp Dermatol 18:208-210
opportunity of visiting work places and factories was Coenraads p-J, Nater JP (1987) Some general epidemiological and
a requisite for adequate solving of problems of statistical considerations in the design of studies on derma-
titis in selected occupational populations. Boll Dermatol
occupational dermatology'. His sentiments are sure Allergoi Prof 2:105-116
to be echoed by anyone who undertakes to visit the Fregert S (1963) The organization of occupational dermatology in
plants where patients with dermatitis work. Like many Lund. Acta Derm Venereol 43:203-205
Fregert S (1980) Possibilities of skin contact in automatic
investigations in medicine, you cannot appreciate what processes. Contact Dermatitis 6:23
you might be missing until you carry out site visits. Rycroft RJG (1980) Occupational dermatoses in perspective.
I willleave the last word to one of my most inspiring Lancet 2:24-26
Rycroft RJG (1984) Low-humidity occupational dermatoses.
teachers, the late Professor Richard Schilling (1998): Dermatol Clin 2:553-559
'Effective factory inspection depends on the art of Schilling R (1998) Achallenging life. Sixty years in occupational
persuasion, which requires finesse and plenty of time'. health. Canning Press, London
CHAPTER 56
Workers' Education
H.J. Schwanitz and B. Wulfhorst
Introduction skin on the hands is associated with aspects such as

cleanliness and neatness. In a group of 46 patients with
The education of employees toward a health-conscious atopic palmar eczema, the extent of emotional and
attitude is necessary in areas of the occupational social impairment was assessed independently. Using a
environment entailing a respective risk. Of these, the four-point ordinal scale ("none", "little", "moderate",
most common type of occupational dermatosis is hand "severe") a moderate-to-severe emotional impairment
dermatitis (Rycroft 1992; Van der Walle and Brunsveld was noted in three quarters of patients; only one of the
1994). For occupational dermatology, the most impor- 46 was not affected by his skin disease. Social
tant target of preventive efforts is the hands; thus, their impairment was rated just slightly less (Table 1).
psychosocial significance will be illustrated first. In Hand dermatitis is considered a psychosomatic
addition, the respective concepts of the occupational disease by some because "it always starts with itching".
physician and the patient as to the cause of skin Patients suffer from the impaired capability caused by
problems have to be considered and aligned with each hand dermatitis; their sociallife is affected; one-third
other. The results of an empirical study will illustrate avoids shaking hands with other persons; and they try
this issue. In a third section, the importance of to hide their hands. Personal relationships are dis-
pedagogic aspects in the fields of primary, secondary turbed; one patient reported that his wife also "with-
and tertiary prevention, respectively, will be outlined draws her hand" (Schwanitz 1988).
by discussing aspects of "classical" one-to-one con- It seems quite understandable that patients with
sultations, as well as group seminars and workplace hand dermatitis hide their hands, that they avoid social
visits. contact and that they suffer from isolation in their
private life. One explanation for this is that non-
dermatologists often think that skin diseases in general
The Psychosocial Function of the Hand are contagious.
For humans, the hands have two functions. First, they

ar~elementary tools. This function is impaired in The Understanding of Health and Disease
patients with hand dermatitis, because contact with in Workers
solid objects is painful, contact with irritating sub-
stances is barely possible and the sensitivity necessary The fact that the understanding of health and disease
for intricate manual tasks is impaired and further differs between occupational dermatologists and work-
reduced if protective gloves are worn. Mobility of ers will be illustrated by the results obtained in a
finger joints is also limited and, as a consequence research project on secondary prevention involving 215
of long-standing, recurrent infiammation, extension of hairdressers suffering from occupation-related hand
the finger(s) may be permanently impaired. dermatitis. Figure 1 depicts the personal explanations
Second, the hands are a social tool because they given by participants of this project when interviewed
serve to make and maintain contact. In addition to the
face, the hands are apart of the body which are visible Table 1. Exten t
in sociallife. The hands tell about race, age, occupation of psychic and Sca!e Psychic stress Social
(e.g., intellectual vs manual work [calluses]), and they socia! stress stress
(n = 46)
underline other forms of communication (for example, 0 1 5
speech). The act of shaking hands with someone is 1 11 9
fundamental communication itself. Skin changes are 2 24 23
3 10 8
viewed in a social context. Usually, the condition of the

442 H.J. Schwanitz and B. Wulfhorst
other personal
As aprerequisite for secondary prevention, the
11 ,2'10 acceptance of skin damage as a "normal" effect of
explanatlons
stress 10,7'10
work has to be counteracted. Early irritant skin
damage, e.g., interdigital eczema, is an ideal prompt
badluck 8,8
% for efficient secondary prevention because, at this
stage, allergie contact sensitization has usually not yet
wet work 7,2'10
occurred (Schwanitz et al. 1996; Schwanitz and Uter
genetlc 39'10 1998) (Figs. 2 and 3).
disposition As a means of both secondary and tertiary preven-
no explanation 32,1 Y. tion, a combination of one-to-one consultation (inter-
view and advice), followed by a group seminar with
o 20 40 60 80 100 practical training, a repetitive seminar and a workplace
Fig. 1. Subjective explanation of hand eczema (n = 215) visit has proven to be effective. During the initial
consultation, the individual health and disease con-
cept, respectively, are assessed, and the degree of
concerning their hand dermatitis. They were asked, for motivation for improvement of protective behavior is
instance, why they suffered from hand dermatitis and
not their colleagues. In response, 33% had no expla- fable 2. Problems in prevention from the view of employers and
nation at all, 40% attributed hand dermatitis to a trait employees
in the family and only 17% to wet work and other
occupational factors. Various other personal explana- Employers Employees
tions included psychological factors, "bad luck" or Costs Costs
"the environment". Nearly every second participant Erroneous concept of hand eczema Acceptance by clients
(93 of 215) had sought or intended to seek advice Inadequate example
beyond medicine, e.g., consultation with a healer.
Furthermore, many (99 of 215, i.e., 46%) considered
contact dermatitis anormal condition for hairdressers
(Wulfhorst and Schwanitz 1996). This phenomenon
may explain the fact that so many persons with
occupational hand dermatitis do not seek dermatolog-
ical treatment at all, or do it too late. Only those who
noted a direct causal relationship between their
working conditions and hand dermatitis sought direct
interventive efforts. Consequently, it is necessary to
give some insight first into this relationship, because
most patients are not familiar with the pathogenesis of
hand dermatitis (Pilz and Frosch 1994).
Instruments of Health Education Fig. 2. The beginning of an interdigital web space eczema
Primary prevention is part of general health education

and should thus emphasize general aims given in the
Ottawa Charta, such as advocate, enable or mediate
(World Health Organization 1986). Health promoting
activities could use both the setting of vocational
training schools and of the individual workplace.
Occupational health promotion is relatively easy in
large factories. However, in small workshops or salons,
the employer has a direct, dominating role. His
protective behavior or lack thereof sets a standard
and, furthermore, the communal aim of obtaining
profit makes employees accept a "low-budget" (i.e.,
poor) standard of protection. Prevention such as using
protective gloves is hampered by this attitude (Table 2)
(Wulfhorst and Schwanitz 1996). Fig. 3. Moderate interdigital web space eczema
Workers' Education 443
vidual allergens, exploring all possibilities of avoid-

Qult ance, e.g., technieal, personal and organizational.
Continue with
Facing the high prevalence of resignation concerning
proteetIon or qult the prognosis of their chronic hand dermatitis,
Continue wlthout
patients should be adequately and intense1y encour-
protectlon or quit aged in single and group sessions, including partici-
Conlinue wilhout pation in professional self-help associations.
protectlon
Contlnue w~h
protectlon
Health Promotion by Workers' Education
o 20 40 60 80 100 120
A complex quality of prevention, as outlined previ-
Fig. 4. Expectations of participants (n = 215)
ously, that may empower affected persons to seek
treatment and future prevention is applied health
checked. As part of the project mentioned above, the promotion. Positive experience - being able to work
motivation of participants to work actively for the with healthy hands in a hazardous occupational
chance to remain on the job was assessed. It turned out environment - may enable people to take an active,
that only one-half of the patients (52.5%) were willing health-promoting role in other settings too. Thus,
to use protective equipment uncompromisingly in the dermatologists may contribute to making the WHO
future; 27% expected to be able to work again without project, "Health for all in the year 2000", real in a very
skin protection and 9% stated that they would give up small but efficient manner. A means of prevention that
their jobs if this was not possible. Twenty patients teaches persons in an exemplary fashion to deal with
(13%) were already willing to give up hairdressing occupational health hazards in a self-determined,
(Fig. 4). democratic and rational way is concrete health pro-
The seminar offers an opportunity for persons motion.
suffering from the same problem to find out about a
rational way of dealing with it together. The objectives
of the seminar are (1) adequate information, (2) a References
critical review of skin protection as employed previ-
ously and (3) a motivation for improved protection. Pilz B, Frosch PJ (1994) Hairdresser's eczema. In: Menne T,
Another seminar is offered some weeks or months Maibach HI (eds) Hand eczema. CRC Press, Boca Raton,
pp 179-188
after the initial seminar as a forum to discuss new Rycroft RJG (1992) OccupationaI contact dermatitis. In: Rycroft
experience in the same, familiar group. RJG, Menne T, Frosch PJ, Benezra C (eds) Textbook of
Workplace visits include a presentation on types of contact dermatitis. Springer, Berlin Heidelberg New York,
pp 343-412
occupational skin damage and ways of protection. Schwanitz HJ (1988) Atopic palmoplantar eczema. Springer,
They are particularly effective because they include not Berlin Heidelberg New York
only the diseased person but also other workers, who Schwanitz HJ, Vter W (1998) InterdigitaIraumekzem in
Feuchtberufen - Früherkennung und Therapie kumulativ-
are probably not affected, and the employer. Thus, subtoxischer Handekzeme. In: Garbe C, Rassner G (eds)
prevention is addressed not only in the context of Dermatologie - Leitlinien und Qualitätssicherung für Diag-
individual behavior but also in the context of (occu- nostik und Therapie. Springer, Berlin Heidelberg New York,
pp 449-450
pational) setting. During such a visit, the cost and Schwanitz HJ, Vter W, Wulfhorst B (1996) Neue Wege zur
benefit of skin protective measures can be discussed. Prävention - Paradigma Friseurekzem. Rasch, Osnabrück
Tertiary prevention of occupational skin disease Van der Walle HB, Brunsveld VM (1994) Dermatitis in hair-
dressers (1). The experience of tlIe past 4 years. Contact
addresses mainly chronic irritant hand dermatitis or Dermatitis 30:217-221
allergie contact dermatitis. Apart from clearing the World Health Organization (WHO) (1986) Ottawa Charta for
current skin disease, efforts should be directed toward Health Promotion. WHO, Geneva
Wulfhorst B, Schwanitz HJ (1996) Angewandte Gesundheits-
a marked improvement of working conditions, e.g., pädagogik in der Dermatologie. Zeitschrift für Haut und
completely eliminating skin contact with known indi- Geschlechtskrankheiten 9:680-684
CHAPTER 57
Prognosis of Occupational Contact Dermatitis

C.L. Goh
Introduction who develop occupational contact dermatitis (Skog

and Tottie 1961; Agrup 1969; Burrows 1972; Fregert
Prognosis of occupational contact dermatitis refers to 1975; Christensen 1982; Coenraads 1983; Schubert et al.
the course of dermatitis over aperiod of time with and 1987; Pryce et al. 1989). Recent reports appear to
without medical intervention. Because of lack of indicate that the prognosis is better than previously
standardisation in assessing clinical response of occu- thought (Chia and Goh 1991; Rosen and Freeman 1993;
pational contact dermatitis and the duration of follow- Nethercott and Holness 1994). The improvement in the
up, it is difficult to compare reports on the prognosis prognosis can be attributed to improvement in diag-
of occupational contact dermatitis in the literature. nostic test procedures, the ability of the physicians to
Long-term follow-up studies on prognosis of occupa- identify causative contact irritants and allergens, and
tional contact dermatitis are often difficult because of the improvement in health education and effective
difficulty in recalling patients for review and follow-up preventive measures against occupational contact
and difficulty in finding control groups for compari- dermatitis.
son. Most reports on the prognosis rely on retrospec- Complete clearance of occupational contact derma-
tive studies. Such data tend to be biased, as they tend titis has been reported to range from 8% to 77% over
to include patients with persistent or more severe follow-up periods ranging from 1 year to more than
occupational contact dermatitis. 10 years (Skog and Tottie 1961; Agrup 1969; Burrows
Understanding the prognosis of occupational con- 1972; Fregert 1975; Christensen 1982; Coenraads 1983;
tact dermatitis is important because it enables derma- Schubert et al. 1987; Pryce et al. 1989; Chia and Goh
tologists and occupational physicians to (a) predict the 1991; Rosen and Freeman 1993; Nethercott and Holness
course of the dermatitis in his patients; (b) implement 1994). Studies done between 1961 and 1989 indicated
risk management of patients who are exposed to that total clearance of occupational contact dermatitis
contact irritants and allergens; (c) plan preventive occurred in only 8-33% of patients. In contrast, studies
measures against contact and occupational dermatitis; conducted after 1990 appear to indicate that the total
and (d) help the relevant authorities to prioritise clearance rate is about 70%.
implementation of preventive measures. Long-term While Burrows, in 1972, reported that 79% of
outcome of occupational contact dermatitis has im- patients with occupational contact dermatitis fol-
portant medico-legal implications; it helps dermatol- lowed-up over 10-13 years still require treatment for
ogists and occupational physicians to determine the their dermatitis (Burrows 1972), areport from Singa-
amount of medico-legal compensation for patients pore showed total clearance of dermatitis in 72% of
with such skin disorders. their patients after a 1-year follow-up. In Sydney,
This chapter reviews reports on the pro gnosis of Rosen et al. reported that improvement of occupa-
occupational contact dermatitis. Factors that may tional contact dermatitis occurred in 74% and 68% of
affect the prognosis of occupational contact dermatitis patients with occupational irritant and allergie contact
include atopy, job change, the age of the patient, the dermatitis followed up over 2-10 years, respectively
nature of irritants and allergens, and the nature of the (Rosen and Freeman 1993). In the United States,
occupation. Nethercott et al. reported that 63% of workers had
clearance of their occupational contact dermatitis
when followed-up over a 4-year period, and when
Prognosis of Occupational Contact Dermatitis patients with mild eczema were included, the improve-
ment rate was 81%. In arecent report form Switzer-
Epidemiology studies in the 1970S and 1980s generally land, where the medical records of 88 construction
reported the persistence of dermatitis among patients workers who had occupational dichromate dermatitis

Prognosis of Occupational Contact Dermatitis 445
between 1986 and 1989 were reviewed and the workers cutting fluids - are more likely to lead to chronicity
interviewed, 63 patients (72%) were healed in the first than others.
few years after changing jobs (Lips et al. 1996). In Singapore, occupational irritant dermatitis from
cutting fluids and solvents was reported to be associ-
ated with a poor prognosis. About 40% of workers
Influenee of Gender and Age on Prognosis with cutting-fluid dermatitis had persistent dermatitis
of Oeeupational Dermatitis after a l-year follow-up, even after the workers had
ceased working with the cutting fluids (Chia and Goh
Most studies indicated that there is no significant sex 1991). Similarly, Shah et al. from the UK reported that
difference in the prognosis of occupational contact hand dermatitis from cutting fluids confers poor
dermatitis. Chia et al., however, reported a significantly prognosis. A questionnaire survey conducted on 51
more favourable prognosis in males with occupational workers seen between 1 year and 5 years previously
allergic contact dermatitis (with a complete clearance revealed that 82% still had hand dermatitis. There was
rate of 90%) than in females (with a complete no difference in outcome between those who continued
clearance rate of 50%). The tendency of persistent to work with the occupational irritant and those who
dermatitis in fern ales could be due to concomitant had changed their occupations (Shah et al. 1996).
irritant contact dermatitis in females carrying out Chia et al. observed that occupational irritant der-
domestic chores. The authors did not find any matitis from cement and acids/alkali tends to have a
significant difference in the clearance rate of irritant relatively better prognosis than other irritants, with all
contact dermatitis between males (73%) and females workers experiencing complete clearance of their
(69%) after a l-year follow-up (Chia and Goh 1991). dermatitis when they ceased contact with the irritant
Similarly, Nethercott reported no significant gender (Chia and Goh 1991).
difference in the prognosis of occupational contact Workers who continued with exposure to occupa-
dermatitis when followed-up over a 2-year period in tional irritants tend to have a poorer prognosis than
the United States (with a clearance rate of 60% for those who cease exposure. For example, Chia et al.
males vs 75% for females) (Nethercott and Holness reported that about 60% of patients with occupational
1994). irritant dermatitis from solvents had persistent der-
The age of onset of contact dermatitis does not matitis when they continued to work with the solvents
appear to influence its pro gnosis. Burrows reported no (Chia and Goh 1991). Some occupational irritants
significant difference in the prognosis of patients who appear to cause less chronicity, e.g. irritant contact
were less than 40 years old (complete clearance rate of dermatitis from acids/alkali and cement appear to clear
15%) and those who were older than 40 years (com- when proper preventive measures are introduced (Chia
plete clearance rate of 16%) when these patients were and Goh 1991). The report from Singapore showed that
followed-up over a 10- to 13-year period (Burrows all workers with irritant contact dermatitis from
1972). Similarly, Pryce et al. (1989) reported no signi- cement had complete clearance of their dermatitis
ficant difference in the clearance of occupational despite continuing to work with the irritant. Similarly,
contact dermatitis from cutting fluids between workers in Denmark, occupational irritant dermatitis from
who were less than 50 years and those older than cement cleared in 80% of their workers despite the fact
50 years. In contrast, Chia et al. reported a slightly that they continued working at the same job (Avnstorp
better prognosis in workers with occupational derma- 1989).
titis who were older than 39 years (clearance rate of Rosen and Freeman (1993), in Sydney, reported that
85%) than in workers who less than 40 years old 30% of their workers with irritant contact dermatitis
(clearance rate of 65%), although the difference was had total clearance of dermatitis following a 2- to
not statistically significant (Chia and Goh 1991). lO-year follow-up. Allergic contact dermatitis was
Nethercott and Holness (1994) also reported no reported to confer a slightly better pro gnosis, with a
significant difference in the prognosis of contact complete clearance rate of 38%. Similarly, Nethercott
dermatitis among patients of different age groups in and Holness (1994), in the United States, also reported
the United States. better prognosis among patients with allergic contact
dermatitis (with a complete clearance rate of 70%)
compared with patients with irritant contact dermatitis
Prognosis of Oeeupational Irritant Versus Allergie (with a clearance rate of 58%) after a 4-year follow-up.
Contact Dermatitis Chia et al. from Singapore reported that 77% of
patients with occupational allergic dermatitis had
Most reports indicate that irritant contact dermatitis complete clearance of their dermatitis after a l-year
tends to have a poorer prognosis than allergie contact follow-up. Among the occupational contact allergens,
dermatitis. Some occupational irritants - for example, metals, e.g. nickel and cobalt, appeared to confer poor
446 c.L. Goh
prognosis. Despite "avoidance" of metals, 75% of health education and the reduction of the chromate
patients with metal allergy had persistent dermatitis. content of cement as a result of changes in the
Similarly, rubber-chemical allergies appeared to be manufacturing process of cement (Goh and Gan 1996).
associated with poor pro gnosis, with a chronieity rate
of 50% (Chia and Goh 1991). One reason for the
chronicity in contact allergy to these allergens could be Occupation and Prognosis
due to their ubiquity. Pro gnosis of allergie dermatitis of Occupational Contact Dermatitis
from other allergens which are found in specific
workplaces, e.g. epoxy resins, tend to be associated Construction workers with allergie contact dermatitis
with better prognosis (Chia and Goh 1991). were reported to suffer the poorest pro gnosis relative
Occupational allergie contact dermatitis to chro- to workers in other occupations (Burrows 1972; Fregert
mates in cement has been reported to persist even 1975; Rosen and Freeman 1993; Avnstorp 1989). The
upon avoidance of cement. Burrows reported that only complete clearance rate of occupational dermatitis
8% of his patients with cement dermatitis had clear- among construction workers in Sydney, Australia was
ance of their dermatitis after a 10- to 13-year follow-up reported to be 20% when these workers were followed-
(Burrows 1972). In Sydney, the prognosis from occu- up over a 2- to 9-year period, compared with a
pational allergie contact dermatitis from chromate was clearance rate of 40% among medical workers and 35%
worse than those caused by other occupational aller- among hairdressers and food handlers (Rosen and
gens; only less than 20% of such patients had clearance Freeman 1993). When "improvement" was defined as
of their dermatitis over a 2- to 10-year follow-up period good prognosis in all occupational groups, the im-
(Rosen and Freeman 1993). Another study from Perth, provement/clearance rate for construction workers
Australia, also reported poor prognosis from cement remained low - a total of 40% compared with a
dermatitis, where 89% of cement workers with chro- corresponding rate of 80% for medical workers,
mate allergy had persistent dermatitis when followed hairdressers and food handlers (Rosen and Freeman
up over aperiod between 6 months and 9 years 1993). Recent reports, however, indicate that workers
(Halbert et al. 1992). avoiding contact with cement do have better progno-
In Denmark, follow-up of patients with chromate sis, with 100% clearance in Singapore (Chia and Goh
allergy after the introduction of ferrous sulphate in 1991) and 72% clearance in Switzerland (Lips et al.
Danish cement to reduce hexavalent chromate con- 1996).
centration in cement continued to show poor progno- Pryce et al. (1989) reported poor prognosis among
sis. Only 30% of workers who remained on the job had metal workers suffering from cutting-fluid dermatitis,
total clearance of their dermatitis (Avnstorp 1989). reporting a clearance rate of about 20% during a 2-year
In contrast to the reports mentioned above, Chia follow-up. Similarly, Shah et al. (1996) from the UK
et al. from Singapore reported good prognosis among reported that hand dermatitis from cutting fluids
construction workers with chromate dermatitis from confers poor prognosis where 82% still have hand
cement if contact with cement can be avoided or dermatitis after a 1- to 5-year follow-up.
reduced. In their report, all five patients with chromate Hairdressers with irritant contact dermatitis ap-
allergy had clearance of dermatitis upon avoidance of peared to have good prognosis when they changed
contact with cement (Chia and Goh 1991). Better jobs. Matsunaga reported a 70% clearance rate for
prognosis from chromate dermatitis was also observed workers who ceased working as hairdressers (Matsu-
in Switzerland recently, where 63 (72%) of 88 workers naga et al. 1998).
were healed during the first few years after changing
jobs. These patients mostly changed industries and
strictly avoided all contact with cement or chromium Job Change and Prognosis
salts. The authors concluded that strict allergen of Occupational Contact Dermatitis
avoidance, enforced by authorities, and financial
support in case of job change are important factors Most patients with occupational contact dermatitis
in improving the prognosis in occupational dichro- who change jobs do so for reasons other then their
rnate dermatitis (Lips et al. 1996). dermatitis (Agrup 1969; Christensen 1982; Rystedt
Therefore, although previous reports appear to 1985). Most previous reports indicated that job change
suggest that occupational allergie contact dermatitis is not associated with significant improvement in the
from chromate in cement is associated with poor prognosis of occupational contact dermatitis (Agrup
prognosis, re cent reports have indicated otherwise. 1969; Fregert 1975; Christensen 1982; Rystedt 1985;
This change could be attributed to reduction in Hellier 1958; Keczkes et al. 1983; Williamson 1967).
exposure to chrornates in cement among those affected However, workers who change their job tend to have
through mechanisation of construction processes, better outcomes than those who do not change jobs.
Prognosis of Occupational Contact Dermatitis 447
There was a significant difference in prognosis between rate of patients with a personal history of atopy (30%)
patients who changed jobs, Le. those who "ceased was significantly poorer than for those without atopy
exposure" to the contactants, and those who continued (41%) (Rosen and Freeman 1993). However, Halbert
to be exposed to the contactants. et al. did not find any significant difference between
Many patients preferred to continue to work despite atopic and non-atopic workers who had chromate
their dermatitis. Burrows reported that only 20% of dermatitis (Shah et al. 1996). Similarly, Nethercott and
workers with occupational dermatitis stopped working Holness (1994) also did not observe any significant
because of their dermatitis (in a 10- to 13-year follow- difference in prognosis between atopic and non-atopic
up study). Among those who continued to work, only workers with occupational dermatitis (the clearance
about 18% of workers had clearance of their dermatitis rate was 59% for atopics and 65% non-atopics,
(Burrows 1972). Pryce reported the clearance rate of respectively).
cutting-fluid dermatitis after a 2-year follow-up to be More epidemiological studies are required to con-
12% for those who continued to be exposed to cutting firm whether a presence of atopy plays a role in the
fluid and 30% for those who ceased to be exposed to chronicity of occupational contact dermatitis.
cutting fluid (Pryce et al. 1989). Similarly, Shah et al.
(1996) from the UK reported no difference in the
outcome of the poor prognosis of workers with Conclusions
cutting-fluid dermatitis on the hands between those
who remained in the same job and those who changed The causes of chronicity from occupational contact
their occupation. dermatitis are usually multifactorial. Most studies
Among hairdressers with occupational dermatitis, indicated that allergie contact dermatitis is less likely
job change appears to confer good prognosis. Matsu- to lead to chronicity than irritant contact dermatitis.
naga from Japan reported clearance of occupational The risk factor for chronicity of dermatitis in patients
dermatitis in 70% of hairdressers who ceased work, with contact dermatitis appears to be determined by
compared with 20% who cleared when they continued the type or causes of contact dermatitis, the presence
to work as hairdressers (Matsunaga et al. 1998). of atopy, and job change. The prognosis of contact
In Singapore, the prognosis of occupational allergie dermatitis appears to be better in recent years. This
and irritant contact dermatitis for patients who ceased improvement could be due to better understanding of
to be exposed was better then those who continued the nature and causes of occupational contact derma-
exposure to the contactants. The overall clearance rates titis, availability of better diagnostic procedures and
for patients who ceased exposure and continued better health education, and preventive measures
exposure were 73% and 69%, respectively. The clear- against occupational contact dermatitis.
ance rates for allergie contact dermatitis were 71%
(ceased exposure) and 74% (continued exposure),
respectively, and for irritant contact dermatitis were
References
74% and 68%, respectively (Chia and Goh 1991).
In Sydney, Australia, the prognosis of occupational Agrup G (1969) Hand eczema and other hand dermatoses in
dermatitis was significantly poorer among patients South Sweden. Acta Derm Venereol Suppl (Stockh) 49:61
who continued in the same job (clearance rate was Avnstorp C (1989) Follow-up of workers from the prefabricated
concrete industry after the addition of ferrous sulphate to
28%) than those who changed jobs (clearance rate was Danish cement. Contact Dermatitis 20:365-371
43%) (Rosen and Freeman 1993). In Perth, Australia, Burrows D (1972) Prognosis in industrial dermatitis. Br J
among the 48% of construction workers with allergie Dermatol 87:145-148
Chia SE, Goh CL (1991) Prognosis of occupational dermatitis in
contact dermatitis to chromate who changed jobs, only Singapore Worker. Am J Contact Dermat 2:105-109
31% had complete clearance of their dermatitis after a Christensen OB (1982) Prognosis in nickel allergy and hand
6-month to 9-year follow-up (Halbert et al. 1992). This eczema. Contact Dermatitis 8:7-15
Coenraads PJ (1983) Prevalence of hand eczema. Association with
contrasted with the report from Switzerland, where occupational exposure, especially in construction workers
72% of their construction workers had clearance of (M.D. thesis). University of Groningen, Groningen
their chromate dermatitis when they changed their job. Fregert S (1975) Occupational dermatitis in a lO-year material.
Goh CL, Gan SL (1996) Change in cement manufacturing process,
a cause for decline in chromate allergy? Contact Dermatitis
Association of Atopy and Prognosis 34:51-54
Halbert AR, Gebauer KA, Wall LM (1992) Prognosis of
of Occupational Contact Dermatitis occupational chromate dermatitis. Contact Dermatitis 27:
214-219
A personal history of atopy appears to significantly Hellier FF (1958) The prognosis in industrial dermatitis. BMJ
1:196-198
affect the prognosis of patients with occupational Keczkes K, Bhate SM, Wyatt EH (1983) The outcome of primary
contact dermatitis. Rosen reported that the clearance irritant hand dermatitis. Br J Dermatol 109:665-668
448 c.L. Goh: Prognosis of Occupational Contact Dermatitis
Lips R, Rast H, Elsner P (1996) Outcome of job change in patients Rystedt I (1985) Hand eczema and long-term prognosis in atopic
with occupational chromate dermatitis. Contact-Dermatitis dermatitis. Acta Derm Venereol Suppl (Stockh) 117:1-59
34:268-271 Schubert H, Berova N, Czernielewski A, et al. (1987) Epidemiol-
Matsunaga K, Hosokawa K, Suzuki M, Arima Y, Hayakawa R ogy of nickel allergy. Contact Dermatitis 16:122-128
(1998) Occupational allergic contact dermatitis in beautician. Shall M, Lewis FM, Gawkrodger DJ (1996) Prognosis of occupa-
Contact Dermatitis 18:94-96 tional hand dermatitis in metalworkers. Contact Dermatitis
Nethercott J, Holness L (1994) Disease outcome in workers with 34:27-30
occupational skin disease. J Am Acad Dermatol 30:569-574 Skog E, Tottie M (1961) Occupational eczema causing disable-
Pryce DW, Irvine D, English JSC, et al. (1989) Soluble oi! ment. Acta Derm Venereol 41:205-212
dermatitis: a follow-up study. Contact Dermatitis 21:28-35 Williamson KS (1967) A prognostic study of occupational
Rosen RH, Freeman S (1993) Prognosis of occupational contact dermatitis cases in a chemical works. Br J Ind Med 24:103-113
dermatitis in New South Wales, Australia. Contact Dermatitis
29:88-93
CHAPTER 58
Computerised Product Database.

Registered Chemical Contact Allergens
M.-A. Flyvholm
Introduction were included as a consequence of the new European

to the Danish Product Register Database Union (EU) rules for the declaration of cosmetic
products. Anational survey on the use ~f chemical~ in
a stratified sampie of about 1500 Dalllsh enterpnses
A product database is one way to organise product
provided data on both hazardous and non-hazardous
information which, compared with, for example,
products used (Brandorff et al. 1994, 1995). Thus, the
labelling and data sheets, has some obvious advan-
data sources are notifications, surveys, research, and
tages when it comes to cross-sectional overviews on
other relevant sources, and all input is done by the
the distribution of contact allergens on product
Product Registration Department. In general, the
categories. This chapter is an introduction to the
notification rules require complete information on an
Danish Product Register Database (PROBAS) and a
of the product's components, and the notifiers have to
presentation of a study on selected contact allergens
update changes.
and their occurrence in product categories covered
PROBAS is a governmental database with no public
by this database.
access due to confidential data which requires special
PROBAS is the short name for the Danish Product
regulations for its use. The relevant authorities have
Register Database. It is a common register for both
on-line connections. The technical configuration of
external environmental and work environment author-
PROBAS is a local-area VAX-duster using Micro-VAX
ities, and it is located at the Danish Working
machines from Digital. The database management
Environment Service. PROBAS was established in
system is ADABAS with application programs written
1980 by the Ministry of Environment and the Ministry
in NATURAL. Transfer of PROBAS to a PC-based
of Labour. Objectives, administration and the use of
system is planned. Aggregated data not disdosi~g
the Product Register, including security regulations for
information about individual products or compames
storing, transmission and access to data, are laid d?w~
can be published (Flyvholm 1991, 1993, 1997; Flyvholm
in "Order on the Register of Substances and Materials
and Andersen 1993; Nielsen 1994). The data and file
(Danish Ministry of Labour 1984a). The objectives are
structures in PROBAS make it possible to connect
to collect information and evaluations on substances,
almost an information and generate the output wanted,
materials and products used in Denmark - primarily
for example: an product categories registered with a
toxic chemicals and their use, the chemical composi-
substance; an components in a product category; and
tion of products, quantities used in Denmark and the
an products/substances used in an industrial area. The
adverse effects on health and the environment.
registered information on products indudes ingred~
Registration in PROBAS is based on obligatory
ents, industrial area of use, product category, quantl-
notification rules, product data submitted to the
ties used or marketed, physical properties, labelling
authorities for various reasons and surveys and
etc., and administrative information. For further
research projects on chemical products (Flyvholm
description see Flyvholm et al. (1992). Figure 1 shows
et al. 1992). The notification rules have mostly focused
the most frequently registered product categories for
on hazardous products for occupational use (Danish
the general product registration in PROBAS for
Ministry of Labour 1984b) or products containing
January 1998.
specific types of ingredients, e.g. epoxy- and isocyan-
Background information on the basis of the regis-
ate-containing products (Danish National Labour In-
tered data and the degree of coverage is important in
spection 1985) and substances considered to. be
the use of administrative product databases (Decker
carcinogenic (Danish National Labour InspectlOn
and Wenninger 1987; Flyvholm et al. 1992) or special
1990). More recently, product categories such as
dermatological databases (Nava et al. 1987; Edman
cosmetics and products for personal care (toiletries)
1989; Goossens and Drieghe 1998) with information on

l!!!!!!!!!!!!!riii---i
452 M.-A. Flyvholm
Fig. 1. The most frequently registered

product categories for the general prod-
PainUlacquers
Cleaning agents uct registration in PROBAS. Based on
82,900 products computerised in janu-
Toiletries/cosmetics ary 1998
Binders/polymers
1555!5F
Colouring agents
Hardeners
Printing inks
Surfactants
Solvents/thiners
Adhesives/glues
o 2000 4000 6000 8000 10000
product ingredients. Some important questions in Selection of Contact Allergens for Investigation
assessing to what extent the database can provide the
information requested are:
The 1990 study included contact allergens selected
- What product categories are included in the data- from the European standard patch-test series (Anon-
base? ymous 1988), substances classified "may cause contact
- Is the information on product ingredients sufficient- sensitization by skin contact" (risk phrase R43) in lists
ly detailed? of dangerous substances in Scandinavian countries
- Is the information updated regularly? and substances reported in textbooks on contact
- Is the information representative or comprehensive? dermatitis. Substances registered in fewer than 30
products were excluded (Flyvholm 1991). The present
investigation, made in January 1998, included as a
Background Data for the Investigations starting point the same contact allergens as in the 1990
study. Furthermore, substances from the European
standard patch-test series (Anonymous 1988; Bruynz-
The data presented in this chapter update a study eel et a1. 1995) not included in the 1990 study because
made in 1990 in which the general product population of the exclusion limit (Jo products) were included. The
of PROBAS (Flyvholm 1991) was used to generate an exclusion limit in the 1998 study was 50 or more
overview of the occurrence of contact allergens. The products registered for each substance, as the total
comparison of these two sets of data gives the number of products registered doubled from 1990 to
possibility of evaluating trends in the occurrence of 1998, and the number of fully computerised products
contact allergens in the registered chemical products. was raised from 27,800 to 82,900 during that period.
The investigations were based on the general All substances were identified by CAS RN (Chemical
product registration in PROBAS (Flyvholm et a1. Abstract Service registry number).
1992; Flyvholm 1991). In January 1998, PROBAS had
information on a total of about 105,000 chemical
products. All information received was computerised
Registered Chemical Contact Allergens
for 82,900 of these products. All products containing
the selected substances either as a component or as
raw materials were included. Products no longer Table 1 shows the number of different products
existing on the Danish market and obsolete compo- registered, with the contents of each substance in
nents in products were excluded, i.e. products were 1990 and 1998 divided into product categories. In order
excluded only if the Product Registry Department had to preserve confidentiality, data on substances regis-
received the information. At the time of the 1990 tered in fewer than four products within a product
study (June 1990), PROBAS had information on a category cannot be shown.
total of 47,400 products, of which 27,800 were fully Formaldehyde was the most frequently registered
computerised. In the study period from 1990 to 1998, substance (3308 products), followed by epoxy
the total number of registered products increased by compounds (2935 and 2058 products) and some
a factor of 2.2 and the number of fully computerised preservatives, i.e. butylated hydroxytoluene (BHT,
products by a factor of 3. 2100 products) and 5-chloro-2-methyl-4-isothiazolin-
Computerised Product Database 453
3-one and 2-methyl-4-isothiazolin-3-one (CMIIMI, 1545 and metal-working fluids increased compared with the
and 1481 products). The highest increase in registration total registration.
of individual substances was observed for the three
isothiazolinones included in the study. This reflects the Chromates
increased use of water-based products in workplaces.
Chromium(VI} oxide was only registered in metal
coatings, and zinc chromate mainly in paints/lacquers.
Substances from the European Standard The registration decreased for both chrornates during
Patch-Test Series the study period; chromium(VI) oxide decreased
compared with the total registration, and for zinc
The current European standard patch-test series from chromate a numerical decrease was observed.
1994 included 22 substances (Bruynzeel et al. 1995).
Not more than seven ofthese substances were included
Epoxy
in the 1998 study (nine different CAS RNs). The
remaining substances from the European standard
Bisphenol A diglycidyl ether monomer and epi-
patch-test series were either not relevant to chemical
chlorohydrin were mainly registered in paints/lac-
products (i.e. medicaments, pharmaceuticals, perfum-
quers, binding agents and product categories
ery, rubber, metals, plants) or were registered in fewer
containing binding agents, such as adhesives/glues,
than 50 products (i.e. potassium dichromate, para-
filling agents, printing inks and flooring agents.
phenylenediamine, parabens). Two substances from
The registration of the epoxy compounds increased
the European standard patch-test se ries not included
less than the total registration during the study period,
in the 1990 study were above the exclusion limit in
and their distribution in product categories was
1998 (para-tert-butylphenol, formaldehyde resin and
generally unchanged.
Quaternium 15). The 1990 study included six substanc-
es from the European standard patch-test series
Fatty-Acid Derivatives
(ethylenediamine has since been deleted).
The fatty-acid derivatives included in the study (coc-
Aldehydes amide diethanolamine and cocamidopropyl betaine)
were mainly registered in toiletries/cosmetics and
Formaldehyde was registered most frequently in cleaning agents. Only one was included in the 1990
paints/lacquers and bin ding agents, followed by print- study, and no marked changes were observed.
ing inks and colouring agents. Glutaraldehyde was
registered in cleaning agents and photo graphie devel- Isocyanates
opers. The increase in the number of products
registered with formaldehyde and glutaraldehyde from Isocyanates were mainly registered in hardeners and
1990 to 1998 was equal to the increase in the total printing inks. 4,4' -methylene-bis(phenylisocyanate}
product registration. The registration of formaldehyde (MD!) was the most frequently registered and occurred
in colouring agents and filling agents increased also in filling agents and adhesives/glues. Hexameth-
remarkably from 1990 to 1998. The same tendency ylene-l,6-diisocyanate was also registered in paintsl
was seen for flooring agents and polishes. lacquers.
The registration of 2,4-diisocyanatotoluene (TD!)
increased more than the total registration. The changes
Amines
in the registration of the other isocyanates increased
less than the total product registration. The registra-
Amines were mainly registered in hardeners, paintsl
tion of isocyanates in printing inks increased markedly
lacquers and other product categories containing
in 1998 compared with 1990.
bin ding agents (resins, polymers, etc.). Triethanol-
amine was the most frequently registered amine and
occurred mainly in cleaning agents and toiletriesl Preservatives
cosmetics and metal-working fluids.
The registration of ethylenediamine increased more Preservatives were registered in most of the product
than the total product registration during the study categories included in the study. Paints/lacquers,
period. For about half of the amines, the relative toiletries/cosmetics, cleaning agents and printing inks
number of registered products was lower in 1998 than were the most frequent. Benzyl alcohol also occurred
in 1990. The registration of ethylenediamine in paintsl in hardeners. The most frequently registered preser-
lacquers and triethanolamine in toiletries/cosmetics vatives were BHT, CMIIMI and benzyl alcohol.
454 M.-A. Flyvholm
Table 1. Products registered, with allergens divided into selected product categories, based on 82,900 products computerised in January 1998
and 27,800 products computerised in June 1990. Products can be registered in more than one product category, and products can contain more
than one of the allergens. Data on product categories with less than four products for each substance are not shown
Product Adhesivesl Binding Cleaning Colouring Construction Corrosion Filling

categories glues agents agents agents materials inhibitors agents
(resins, (stopping,
etc.) putty, etc.)
Number of June 1990 1039 1874 3470 1165 250 478 740
products study
for each
product January 1998 2374 4917 7916 3787 758 1289 2049
category: study
Ratio of 1998 2.3 2.6 2.3 3.3 3.0 2.7 2.8
studyl1990
study
Substances CASRN Study
Aldehydes
Formaldehyde 50-00-0 1990 62 171 98 33 17 13 13
(ST) 1998 153 457 220 204 52 38 126
Glutaraldehyde 111-30-8 1990 21
1998 54
Amines
Diaminodiphe- 101-77-9 1990 4
nylmethane 1998 4 5
Diethylenetri- 111-40-0 1990 5 11 7 11
amine 1998 5 7 4
Ethylenedi - 107-15-3 1990 10
amine 1998 5 23 9 7 7
Isophoronedi- 2855-13-2 1990 6 4 8 14
amine 1998 10 9 4 5
Tetraethylene- 112-57-2 1990 5 6 9
pentamine 1998 5 10
Triethanol- 102-71-6 1990 6 105 10 8
amine 1998 11 26 222 17 52 30 63
Triethylenedi - 280-57-9 1990 26 5
amine 1998 13 53 6 12
Triethylene- 112-24-3 1990 8 13 13
tetramine 1998 4 15 9
Chromates
Chromium(VI) 1333-82-0 1990
oxide 1998
Zinc chromate 13530-65-9 1990 12 7
1998 7 6
Epoxy
Bisphenol A 1675-54-3 1990 96 217 5 31 11 94
diglycidyl 1998 177 449 11 44 13 165
ether
monomer
(ST)
Epichlorohydrin 106-89-8 1990 103 262 7 32 9 106
(ST) 1998 228 693 11 61 18 224
Fatty-acid derivates
Cocamide 68603-42-9 1990 82
diethanolamine 1998 157
Cocamidopropyl 61789-40-0 1990
betaine 1998 24
Isocyanates
2,4-diisocyanato- 584-84-9 1990 4 7 7
toluene [TDI] 1998 13 21 30 8 9
Hexamethylene- 822-06-0 1990 4 4
l,6-diisocyanate 1998 16 15 6
Isophorone 4098-71-9 1990 6 23 21
diisocyanate 1998 9 31 15
4,4' -methylene- 101-68-8 1990 79 30 6 99
bis(phenyliso- 1998 138 55 15 171
cyanate) [MDI]
Table 1. (Contd.)
Flooring Hardeners Impreg- Metal Metal- Moulding Paintsl Photo- Polish Printing Toiletries Total Ratio of
agents (for paintsl nating coatings working materials lacquers graphie inks and products 1998
lacquers, agents (not and developers cosmeties for studyl
plastics) paints) cutting substances 1990
fluids study
135 1462 219 356 391 280 2713 491 255 692 1219 27800
345 3473 535 860 724 689 6512 623 839 3466 6423 82900
2.6 2.4 2.4 2.4 1.9 2.5 2.4 1.3 3.3 5.0 5.3 3.0
5 46 12 12 8 16 361 4 5 45 30 1118
44 104 41 12 15 30 1006 4 38 219 78 3308 3.0
5 30
14 99 3.3
44 4 9 64
96 4 10 123 1.9
10 169 4 11 33 5 244
9 307 4 4 33 10 405 1.7
13 9 50
52 4 5 61 226 4.5
21 113 6 28 180
48 369 7 6 57 508 2.8
101 6 27 145
243 22 21 316 2.2
5 84 8 7 14 284
14 7 9 114 5 29 12 49 21 151 1010 3.6
4 12 61
13 17 45 200 3.3
5 187 4 6 39 5 277
4 377 13 48 503 1.8
4 31 65
38 81 1.2
10 86 110
4 49 68 0.6
49 104 17 69 563 35 1214

116 138 10 16 75 809 127 2058 1.7
49 108 14 77 592 50 1349

137 211 16 25 104 1003 227 2935 2.2
8 91 185
19 5 280 495 2.7
<30
120 160
41 4 18 82
51 5 5 82 153 378 4.6
4 145 13 45 228
6 331 8 4 107 24 532 2.3
38 16 6 123
66 40 136 336 2.7
16 150 23 52 446
16 267 28 70 279 1093 2.5
456 M.-A. Flyvholm
Table 1. (Contd.)

(resins, (stopping,
etc.) putty, etc.)
Preservatives
Benzalkonium 8001-54-5 1990 73
chloride 1998 95
1,2-benzisothia- 2634-33-5 1990 15 4
zolin-3-one 1998 13 29 51 29 6
Benzoic acid 65-85-0 1990 41 122 17 20
1998 10 67 6 8 12
Benzyl alcohol 100-51-6 1990 8 15 5 11 36
1998 20 82 35 5 13 15 45
2-bromo-2-nitro- 52-51-7 1990 37
1,3-propanediol 1998 7 12 84
[Bronopol]
Butylated 128-37-0 1990 32 30 10 11
hydroxytoluene 1998 49 128 41 32 17 19 98
[BHT]
Chloroallylhexa- 4080-31-3 1990
minium 1998 6 4
chloride
[Quaternium
15] (ST)
5-chloro-2- 26172-55-4 1990 36
methyl-4-
isothiazolin-
3-one [CMI]
(ST)
The CMI part of 1998 41 60 106 83 5 8 20
CMI/MI
[Kathon CG]
2-methyl-4- 2682-20-4 1990 32
isothiazolin -3-
one [MI] (ST)
The MI part of 1998 41 59 107 74 4 8 19
CMI/MI
[Kathon CG]
Cresol 1319-77-3 1990 7 5 5
1998 9 19 4 7
Mercaptobenzo- 149-30-4 1990 15 5
thiazole 1998 7 8
[MBT] (ST)
Para-chloro- 59-50-7 1990 5
meta-cresol 1998 4 6
Resins
Colophony (ST) 8050-09-7 1990 24 10 4 6 6
1998 49 43 4 7 7 9
Para-tert-butyl- 25085-50-1 1990
phenol formal- 1998 16 19 9 5
dehyde resin
(ST)
Phenol-formal- 9003-35-4 1990 21 23 8 4
dehyde res in 1998 31 58 9 12
Urea-formal- 9011-05-6 1990 19 25 4
dehyde resin 1998 20 28
Miscellaneous
Benzoyl peroxide 94-36-0 1990 4 5
1998 23 17 9 25
2-butanone oxime 96-29-7 1990 15 15
[Methyl ethyl 1998 14 18 29 13
ketone]
Para-tert-butyl- 98-54-4 1990
phenol 1998 20 24 18 7
Cobalt 61789-51-3 1990 5
naphthenate 1998
Table 1. (Contd.)
agents (for paintsl nating eoatings working materials laequers graphie inks and produets 1998
laequers, agents (not and developers eosmeties for studyl
plastics) paints) eutting substanees 1990
fluids study
106
5 142 1.3
19 58
9 10 6 287 53 70 692 11.9
15 4 12 153 408
6 9 4 4 318 14 549 1.3
33 116 9 11 63 23 9 16 339
73 449 6 16 24 218 13 13 118 59 1276 3.8
4 29 85
10 61 13 64 309 3.6
5 85 9 13 127 30 400
31 127 12 12 21 39 752 8 259 184 2100 5.3
<30
4 23 53
55 11 51 182
8 20 11 413 68 126 310 1545 8.5
55 9 52 176
8 20 11 410 66 100 309 1481 8.4
5 6 44
4 23 97 2.2
6 32
5 6 8 53 1.7
6 51 79
4 187 5 10 238 3.0
26 13 118
19 112 4 82 6 440 3.7
<30
15 82
6 4 4 35 125
7 4 7 71 10 249 2.0
120 186
5 82 160 0.9
21 11 5 63
91 27 11 237 3.8
10 5 167 256
23 6 650 50 922 3.6
<30
25 4 64 32 219
5 32 4 52
58 88 1.7
458 M.-A. Flyvholm
fable 1. (Contd.)

(resins, (stopping,
etc.) putty, etc.)
Sodium borate 1303-96-4 1990 10

[Borax] 1998 21 12
Stearic acid 57-11-4 1990 38 121 10 18 6 21
1998 9 11 22 27 12 10
Tri(dimethyl- 90-72-2 1990 6 5 17
aminomethyl) 1998 14 6 10 19
phenol
Turpentine oil 8006-64-2 1990 4
1998 18
sr substances included in the current European Standard Series
The most marked change was observed for 1,2- Product Categories
benzisothiazolin-3-one, which increased by a factor 12
compared with a factor 3 for the total product
Registration of the investigated contact allergens in
registration. CMI/MI increased by a factor 8.5 and
selected product categories is shown in Table 1. Prod-
BHT by a factor 5.3. In the 1998 study, both CMI/MI and
uct categories registered with few of the investigated
BHT were registered in several new product categories
allergens or registered with less than four products for
compared with the 1990 study, e.g. printing inks,
each substance were excluded. Among the 18 product
binding agents, adhesives/glues and colouring agents.
categories included, cleaning agents, paints/lacquers,
The registration of benzalkonium chloride and benzyl
toiletries/cosmetics and bin ding agents were the most
alcohol decreased compared with the total registration.
frequently registered, followed by colouring agents,
Resins hardeners, printing inks, adhesives/glues, filling agents
and corrosion inhibitors. Two product categories,
The resins included in the study were colophony and toiletries/cosmetics and printing inks, increased more
three formaldehyde res ins. They were mainly regis- than the total registration from 1990 to 1998; toiletriesl
tered in paints/lacquers, binding agents and adhesivesl cosmetics increased due to the new EU rules (for
glues. cosmetics) and printing inks increased due to an
The registration of colophony increased relative to investigation involving registration of products used in
the total registration, and phenol-formaldehyde resin the printing industry. The registration of photographic
decreased relatively. The registration of urea-formal- developers and metal-working fluids decreased during
dehyde res in decreased numerically from 1990 to 1998. the study period. For the remaining product catego-
ries, changes in the registration were in the same range
Miscellaneous as for the total product registration.
2-Butanone oxime and cobalt naphthenate were mainly Adhesives

registered in paints/lacquers, benzoyl peroxide mainly
in hardeners and other product categories containing Among the allergens included in this investigation,
binding agents, sodium borate in cleaning agents, epoxy compounds, formaldehyde and MDI were the
corrosion inhibitors and photographic developers, most frequently registered in the group of adhesivesl
stearic acid mainly in paints/lacquers and toiletriesl glues. The registration of CMI/MI in adhesives/glues
cosmetics, tri( dimethylaminomethyl)phenol mainly in was new compared with the 1990 study.
hardeners and to a minor degree in paints/lacquers,
and turpentine oil mainly in paints/lacquers and Binding Agents
cleaning agents. The registration of para-tert-butyl-
phenol increased markedly from less than 30 products Epoxy compounds and formaldehyde were the most
in 1990 to more than 200 products in 1998. The frequently registered allergens in binding agents. The
registration ofbenzoyl peroxide and 2-butanone oxime registration of benzoic acid and stearic acid decreased
increased a Hule compared with the total registration, markedly and the registration of CMI/MI in binding
and the other substances gene rally decreased. agents was new compared with the 1990 study.
agents (for paintsl nating coatings working materials lacquers graphie inks and products 1998
lacquers, agents (not and developers cosmetics for studyl
plastics) paints) cutting substances 1990
fluids study
7 10 71
4 6 5 10 4 192 2.7
15 6 6 10 134 4 40 448
37 7 6 191 10 5 111 549 1.2
7 110 7 30 185
12 317 7 13 52 5 482 2.6
17 10 63
5 4 27 6 118 1.9
(Ieaning Agents Flooring Agents
The most frequently registered allergens were trietha- Epoxy compounds, benzyl alcohol, isophoronediamine
nolamine, formaldehyde, cocamide diethanolamine, and formaldehyde were the most frequently registered
CMI/MI and benzalkonium chloride. No marked allergens in flooring agents. An increase in the share of
changes in the registration were observed during the products registered with content of formaldehyde was
study period. observed during the study period.
(olouring Agents Hardeners
The most frequently registered allergens were formal- The most frequently registered allergens in hardeners
dehyde, which increased considerably in colouring were benzyl alcohol, tri( dimethylaminomethyl)phenol
agents during the study period, and CMI/MI, which and several amines (triethylenetetramine, isophorone-
were new compared with the 1990 study. diamine, diethylenetriamine, tetraethylenepentamine).
No specific changes in the registration were observed.
(onstruction Materials
Impregnating Agents
Epoxy compounds, formaldehyde and triethanolamine
were the most frequently registered allergens in
The most frequently registered allergens in impreg-
construction materials. The registration of triethanol-
nating agents were formaldehyde, 2-butanone oxime
amine in construction materials was new compared
and CMI/MI. The registration of CMI/MI in impreg-
with the 1990 study.
nating agents was new compared with the 1990 study.
(orrosion Inhibitors
Metal (oatings
The studied allergens were only registered in a few
corrosion inhibitors compared with the total number Only few metal coatings were registered with content
of products for this product category. The most of the studied allergens. The most frequently registered
frequently registered allergens in corrosion inhibitors were epoxy compounds and benzyl alcohol.
were formaldehyde, triethanolamine and 2-butanone
oxime. Metal-Working and (utting Fluids
Filling Agents The only allergen registered in metal-working and

cutting fluids in a considerable number was trietha-
The most frequently registered allergens in filling nolamine. The number of products registered in this
agents were epoxy compounds, MD! and formalde- product category decreased between 1990 and 1998,
hyde. The registration of formaldehyde, BHT and which may be due to a change to products based on
triethanolamine in filling agents increased markedly soap and other non-hazardous substances (i.e. prod-
from 1990 to 1998. ucts not covered by the notification rules).
460 M.-A. Flyvholm
Moulding Materials Discussion
The most frequently registered allergens in moulding

It is important to bear in mind that the occurrence of
materials were epoxy compounds, although a relative
allergens in product categories in a study such as iliis
decrease was observed during the study period.
is highly influenced by ilie selection of allergens for
investigation. Thus, product categories only registered
Paints/Lacquers as containing a few of ilie studied allergens may
contain oilier allergens.
The most frequently registered allergens in paintsl One way to use ilie information presented here is
lacquers were formaldehyde and epoxy compounds, eiilier to search for allergens to patch test in a patient
followed by BHT, 2-butanone oxime, CMI/MI, benzoic exposed to a specific product category or to look for
acid, l,2-benzisothiazolin-3-one and benzyl alcohol. oilier sources of exposure to a certain allergen. The
The registration of l,2-benzisotlliazolin-3-one in registration may include some products no longer
paints/lacquers was new, and that of CMI/MI increased marketed, as only some of the registered products are
compared with the 1990 study. covered by notification rules demanding obligatory
updating of the information submitted to ilie Product
Photographie Developers Register. Thus, ilie registration of so me allergens may
be "contaminated" by "old products", but this infor-
Only few photographic developers were registered as mation can be relevant for determining previous
containing any of the studied allergens, and ilie exposure, which may be the source of sensitisation.
number of products registered for this product cate- For advising individual patients, it is always impor-
gory decreased between 1990 and 1998. The most tant to consult the data sheets and labelling for ilie
frequently registered allergens were glutaraldehyde, specific products used at ilieir workplaces, although
which increased, and benzyl alcohol, which decreased the labelling of chemical products is impaired by the
during the study period. default 1% threshold for allergens, which is typically
too high for sensitisers of normal potency. Further-
more, the limited number of allergens classified with
Polish R43 ("may cause contact sensitization by skin con-
tact") adds to the limitations of data sheets and
The most frequently registered allergens in polishes labelling compared with databases wiili registration of
were CMI/MI, l,2-benzisothiazolin-3-one, triethanol- complete product composition.
amine and formaldehyde. Except for l,2-benz-
isoiliiazolin-3-one, an increase in the registration of
these allergens in polishes was observed during ilie References
study period.
Anonymous (1988) Revised European standard series from 1
January 1989 (notice). Contact Dermatitis 19:391
Printing Inks Brandorff NP, Beck ID, Skov T, Flyvholm M-A (1994) Use of
chemicals and potential chemical exposures in Danish
Isocyanates, epoxy compounds, formaldehyde and enterprises 1989. Anational survey. AMI-report No. 43/1994
(in Danish; summary in English). National Institute of
BHT, followed by CMI/MI and benzyl alcohol, were Occupational Health, Copenhagen
the most frequently registered allergens in printing Brandorff NP, Flyvholm M-A, Beck ID, Skov T, Bach E (1995)
inks. The registration of MDI, TDI, BHT and CMI/MI National survey on the use of chemicals in the working
environment: estimated exposure events. Occup Environ Med
in printing inks was new compared with the 1990
52:454-463
study. Bruynzeel DP, Andersen KE, Camarasa JG, Lachapelle J-M,
Menne T, White IR (1995) The European standard series.
Toiletries and Cosmetics Danish Ministry of Labour (1984a) Order No. 466 of 14th
September 1981 on the register of substances and materials.
Danish Ministry of Labour, Copenhagen
Among the allergens included in iliis investigation, Danish Ministry of Labour (1984b) Order No. 540 of 2nd
CMI/MI, cocamide diethanolamine, BHT and trieilia- September 1982 on substances and materials. Danish Ministry
nolamine were ilie most frequently registered in of Labour, Copenhagen
Danish National Labour Inspection (1985) Order No 199 of 26
toiletrieslcosmetics. The selection of allergens for the March 1985 on epoxy resins and isocyanates etc. Danish
present study may cause a distorted picture of the National Labour Inspection, Copenhagen
occurrence of allergens in toiletrieslcosmetics, but it Danish National Labour Inspection (1990) Order No. 535 of 12
July 1990 on registration of substances and materials
can show which allergens relevant in chemical prod- considered to be carcinogenic. Danish National Labour
ucts also can be found in this product category. Inspection, Copenhagen
Decker RL, Wenninger JA (1987) Frequencyofpreservative use in Flyvholm M-A, Andersen P, Beck ID, Brandorff NP (1992)
cosmetic formulas as disclosed to FDA - 1987. Cosmetics PROBAS: the Danish Product Register Data Base - anational
Toiletries 102:21-24 register of chemical substances and products. J Hazardous
Edman B (1989) DALUK: the Swedish computer system for Materials 30:59-69
contact dermatitis. Semin Dermatol 8:97-98 Goossens A, Drieghe J (1998) Computer applications in contact
Flyvholm M-A (1991) Contact allergens in registered chemical allergy. Contact Dermatitis 38:51-52
products. Contact Dermatitis 25:49-56 Nava C, Venturi A, Meregalli E, Bon E, Beretta E (1987)
Flyvholm M-A (1993) Contact allergens in registered cleaning Information system in assessment of occupational allergy.
agents for industrial and household use. Br J Ind Med The model of the institute of occupational health of Milan. In:
50:1043-1050 Parmeggiani L, Roi R, Aresini G, Bino G (eds) Proceedings of
Flyvholm M-A (1997) Formaldehyde exposure at the workplace the 1st international workshop on data banks in occupational
and in the environment. Allergologie 5:225-231 health. Villa Ponti, Varese, Italy October 30/31, 1986. Euro-
Flyvholm M-A, Andersen P (1993) Identification of formaldehyde pean edn. Ispra, pp 192-203
releasers and occurrence of formaldehyde and formaldehyde Nielsen H (1994) Occupational exposure to isothiazolinones. A
releasers in registered chemical products. Am J Ind Med study based on a product register. Contact Dermatitis 31:18-21
24:533-552
CHAPTER 59
Antimicrobials and Disinfectants

C. Timmer
Introdurtion Alcohols can delipidize and dehydrate the upper part

of the stratum corneum, thereby impairing the barrier
function of the epidermis. Irritant contact dermatitis
Preservatives combine both antimicrobials and anti-
from alcohol is most often of the cumulative irritant
oxidants and are often added to water-containing
contact type and, in rare cases, of the acute irritant type
products such as skin care ointments. In general,
(Adams 1986; Tupker et al. 1997). Alcohol dermatitis
contact allergy to preservatives is considered rare.
may take the form of an eczematous eruption, or, more
Sensitization to preservatives is often due to the use of
rarely, a contact urticarial at the exposed site (Martin
products on damaged skin, e.g., eczema or leg ulcers.
Scott 1960; Fregert et al. 1963). Allergie contact derma-
Patients often present with symptoms of dermatitis of
titis to ethanol and isopropanol is considered rare
the hands or face. The most frequently used preserva-
(Pecquet and Pradalier 1992), but was reported as a
tives in cosmetics and topical drugs are parabens,
constituent of a transdermal patchsystem (Okazawa
imidazolinidyl urea, quaternium-15, dimethylol-di-
et al. 1998). The patch test concentrations for these
methyl (DMDM) hydantoin, phenoxyethanol, met-
substances are either "as is" or in 10% aqua.
hylchloroisothiazolinone/methylisothiazolinone, dia-
N-Propanol (l-propanol, Optal, CAS no. 71-23-8) and
zolinidyl urea, 2-bromo-2-nitropropane-1,3-diol and
isopropanol (2-propanol, isopropyl alcohol, CAS no.
sorbic acid (Schnuch et al. 1998). Preservatives and
67-63-0) are more likely than ethanol to cause a
antimicrobials are also used in industrial products
burning sensation along with erythema (isopropanol is
(called bioeides), such as metalwork fluids.
also processed by alcoholdehydrogenase in the epider-
Disinfectants are designed to destroy pathogens in
mis). Apart from their use as disinfectants, both are
the environment (e.g., on working surfaces, operating
constituents in many products used for antiseptic
materials). Antiseptics kill pathogenic organisms - or
wiping and prepping, stain and spot removal, cleaning
at least prevent growth in living tissue (pre-operative
glass, rugs, upholstery and windshields, and as liquid
skin cleansing). Allergie reactions to preservatives are
soaps (Adams 1990).
ranked as: (1) rare, (2) uncommon, (3) do occur and
In premature infants, chemieal skin burns were
(4) common.
reported after the use of isopropanol for conduction of
If not specifically mentioned, patch-test concentra-
electrocardiography (Schick and Milstein 1981) and
tions (Andersen and Rycrof 1991) and vehicles are
preparation of the umbilical stump for arterial cath-
derived from De Groot et al. (1994).
eterization (Bonacci and Haddow 1970). The patch-test
concentrations for both are "as is" or in 10% aqua.
Alcohols
Benzylalcohol (Benzenemethanol, Phenylcarbenol,
Ethanol (Ethyl Alcohol, CAS no. 64-17-5) Phenymethanol, A-Hydroxytoluene, CAS no. 100-51-6)
Probably the most widely used antiseptics are the Benzylalcohol is weH known for its use as a preserva-
lower aliphatic alcohols, ethanol and isopropanol. Less tive in injectable preparations (0.5%-2%), e.g., hor-
frequently used is N-propanol (l-propanol), although a mones, steroids, anti-hypertensives, vitamin
combination with isopropanol is well known (Sterili- preparations, anti-histamines, antibiotics, heparin,
um). The bactericidal activity of the aliphatic alcohols tranquilizers and sclerosing agents. Injection as a
increases with their molecular weight. Alcohols are single dose is generally well tolerated. At a concentra-
considered less irritating than aldehydes. The irritancy tion of 0.9%, it is used to flush intravascular catheters.
of an alcohol compound decreases as the molecular Allergie contact dermatitis was described when it was
size of the compound increases (Adams 1986). present as a preservative in a sclerosing agent (Shumes

Antimicrobials and Disinfectants 463
1984) and in topieal preparations (Vereeken et al. Dehydroacetic Acid (DHA, Methylaceto Pyronone,
1998). It is capable of indueing immunologieal eontaet (AS no. 520-45-6)
reaetions, is a solvent in eelluloses, shellae, flavors and
perfumes, is a eonstituent of jasmine, hyaeinth, ylang- DHA it is mostly knoWll as an antifungal agent in foot
ylang oils, Peru and Tolu balsams, and is used as eosmeties and topieal preparations. The pateh-test
embedding material in mieroseopy. Pateh-test eoneen- eoneentration is 0.1% and 1.0% pet. Although allergie
trations are 5-10% petrolatum (pet.) (Corazza et al. eontaet reaetions are reported, they are eonsidered
1996). Allergie reaetions are eonsidered rare; however, rare (Dejobert and Martin 1991).
irritant reaetions in pateh testing are seen.
Undecylenamide Diethanolamine (DEA, Steinazid DU 185)
Phenoxyethanol (Phenoxethol, Phenoxetol,
Phenyl (ellosolve, (AS no. 122-99-6) This eompound is a preservative (antimyeotie) found
predominantly in foot eosmeties and liquid soaps
Together with dibromodieyanobutane (methyldibro- (Christersson and Wrangsjo 1992). The pateh-test
moglutaronitril), phenoxyethanol forms the eoneentration is 1% aqua. Allergie reaetions are
well-known (eosmetie) preservative, Euxyl K-400. eonsidered rare.
Phenoxyethanol is often eombined with another anti-
mierobial, sueh as parabens, beeause of its synergistie Parabens
properties. It is also used as a preservative in some
vaeeines (Lowe and Souther 1994). The pateh-test The parabens include: butyl-(N-butyl p-hydroxyben-
eoneentration is 1% pet. (0.3-0.5% pet.) (de Groot et al. zoate, Butoben, Butyl Chemosept, Butyl Parasept,
1996). Although widely used, allergie reaetions are Tegosept B, CAS no. 94-26-8); ethyl-(ethyl p-hydroxy-
eonsidered rare. benzoate, Nipagin A, Ethyl Parasept, Solbrol A, CAS
no. 120-47-8); methyl-(methyl p-hydroxybenzoate,
Nipagin M, Tegosept M, Methyl Chemosept, Methyl
Antimicrobial Acids and Esters Parasept, CAS no. 99-76-3); and propyl-(propyl
p-hydroxybenzoate, Nipasol M, Solbrol P, Propyl
Parasept, CAS no. 94-13-3) paraben. These are esters
Benzoic Acid (Benzenecarboxylic Acid, Phenylformic Acid, of p-hydroxybenzoie aeid and probably the most
Dracylic Acid, (AS no. 65-85-0) frequently used preservatives in foods, topieal drugs
and eosmeties (including photoproteeting ointments)
Benzoie acid is used as a typieal preservative in (Perrenoud et al. 1994; De Groot et al. 1996). They are
eosmeties and other topieal preparations (eoneentra- usually used as a mix beeause of a beneficial synergistie
tion 0.1-0.2%). It is a eonstituent of Balsam of Peru effeet. They are aetive against fungi and gram-positive
and Balsam of Tolu. Allergie eontaet dermatitis baeteria but not against all gram-negative speeies
(eheilitis) was reported from a toothpaste (Aguirre (especially Pseudomonas). Therefore, they are usually
and Izu 1993). eombined with other preservatives. Individuals sensi-
As a eonstituent of the oils of some flowers, spiees tized to parabens may nevertheless tolerate produets
and eranberries, benzoie aeid also oeeurs naturally. It that eontaining them, a phenomenon ealled the para-
has some antimyeotie (6% in Whitfeld ointment) and ben paradox.
antibiotie properties and is eapable of producing Cieatrization of the eonjunetiva was reported after
immediate eontaet reaetions (immunologieal and use of a topieal eye preparation (Ostler et al. 1983).
non-immunologieal) in the same eoneentrations (Bas- Cross reaetions between parabens and benzoeaine,
ketter and Wilhelm 1996; Coverly et al. 1998). The para-phenylene diamine, proeaine and sulfonamide
pateh-test eoneentration is 5% pet. Allergie reaetions are also mentioned. Parabens are eapable of inducing
are eonsidered uneommon. immunologie al and non-immunologieal eontaet reae-
tions. The pateh-test eoneentration is 3% pet (paraben
mix 15% pet). Although the use of parabens is
P-Hydroxybenzoic Acid (CAS no. 99-96-7) widespread, the sensitizing potential for non-diseased
skin is eonsidered low. Therefore, allergie reaetions are
p-Hydroxybenzoie aeid is a preservative in eosmeties uneommon (Verhaeghe and Dooms Goossens 1997).
and foods. It is eapable of producing immediate
eontaet reaetions, probably both immunologieal and Potass 11m Sorbate (BB Powder, (AS no. 24634-61-5)
non-immunologie al. The esters are the well-knoWll
parabens (Eberlein-Konig et al. 1993). The pateh-test Potassium sorbate is a (rare) preservative in dry-
eoneentration is 5% pet. powder eosmeties, and a well-known food preservative
464 C. Timmer
(inhibitor of molds and yeasts). Cross-reaction with Undecylenic Acid (CAS no. 112-38-9)
sorbic acid was reported by Fisher (1980). The patch-
test concentration is 5% pet. Allergie reactions do Undecylenic acid is known as an antimycotic agent.
occur. Cross-reactions were reported to occur with zinc
undecylenate (another antimycotic drug) (Gelfarb
Salicylic Acid (Keralyt, Occlusal, Verrugon, and Leiden 1960). Patch-test concentrations are 2-5%
CAS no. 69-72-7) pet. Allergie reactions are considered rare.
Its topieal use lies mainly in the treatment of psoriasis, Usnic acid (Usninic Acid, Usnein, Usniacin,
as a keratolytic agent to descale plaques (1-20% CAS no. 125-46-2)
ointment). Salicylism is the term used to describe the
toxieological state that occurs following percutaneous Usnic acid is found in oak moss and used in perfumes.
absorption of salicylic acid (Von Weis and Lever 1964). Usnea barbata is a lichen species that occurs in oak
Intoxieation depends largely on the total body area moss. Cross-reactions between structurally related
over whieh the salicylic acid is applied (Brubacher and lichen compounds are unclear, but must be considered
Hoffman 1996). Formerly, salicylic acid also had a (Mitchell 1965; Hausen et al. 1993). Contact dermatitis
reputation as an anti-mycotic (3% in Whitfield oint- in vaginal ovules and contact allergy in deodorant
ment). Contact allergy was reported (Goh and Ng spray has been reported (Hein and Tarnick 1987;
1986). Rafanelli et al. 1995). The patch-test concentration is
The patch-test concentration is 2% pet. Although 0.1% pet. Allergie reactions are rare or uncommon.
allergie reactions are rare, irritant patch tests are
common. Salicylic acid is considered a common
(moderate) irritant whieh can cause occupational Cationic Surfactants
dermatitis. A 5% ethanol solution gives a slight and/
or delayed-type stinging, even without visible altera-
tions to the skin (Frosch 1995). Quaternary Ammonium Compounds
Quaternary ammonium compounds are cationic de-

Sodium Benzoate (CAS no. S32-32-1) tergents. They are used as preservatives in cosmetic
and medical topieal products and also as a disinfectant
Sodium benzoate is used as a preservative in cosmetics for the skin (for instance, preoperative skin cleaning).
and foods. It is also used in pharmaceuticals (concen- It is also known as an algaecide (wood preservative,
tration, 0.1%). some marine paints). Patch-test concentrations range
In concentrations of 0.1-0.2%, sodium benzoate is from 0.01% to 0.1% aqua. Patch testing with 0.1% aqua
capable of producing immediate non-immunologieal easily provokes irritant reactions; true allergie re-
(airborne) contact reactions (Lahti 1980; Nethercott sponses are also obtained with 0.01% aqua. Cross-
and Lawrence 1984). Contact allergy has also been reactions between the quaternary ammonium com-
reported (Meynadier et al. 1982). The patch-test con- pounds are frequently seen.
centration is 5% pet. Allergie reactions are uncommon. Benzalkonium chloride (Benirol, BTC, Capitol,
Cross-reactions with benzoie acid are mentioned. Cequartyl, Drapolene, Drapolex, Enuclen, Germinol,
Germitol, Osvan, Paralkan, Roccal, Rodalon, Zephiran,
Zephirol, no CAS no.) is a composition of alkyl-
Sorbic Acid (2-Propenylacrylic Acid, CAS no. 110-44-1) dimethylbenzylammonium chlorides, in whieh the
hydrophobie alkyl residues are paraffinie chains with
The 5% sorbic acid aqua solution is a weak acid that 8-18 carbon atoms. The bactericidal activity is limited
can produce a burning and stinging sensation in the to gram-positive and some gram-negative bacteria. In
skin (Frosch 1995). It can also produce an immediate partieular, Pseudomonas species are resistant and have
non-immunologieal contact re action (Clemmensen caused many problems with contaminated disinfec-
and Hjorth 1982; Safford et al. 1990). Some cases of tants (Kaslow 1976).
burning mouth syndrome are likely attributable to Benzalkonium chloride is used mainly as a disin-
sorbic acid. Sorbic acid is a frequently used preserva- fectant for pre-operative skin cleansing and, surgieal
tive found in foods and cosmetics. The patch-test instruments but has sometimes been used in the
concentration is 2% pet. Allergie reactions do occur treatment of ulcers, wounds and infected dermatoses.
(the primary sensitization that occurs in some cases is It is also present as a preservative in many cosmetic
probably due to potassium sorbate) (Ramsing and products and ophthalmie preparations. Irritation is
Menne 1993; Giordano et al. 1996). strongly related to the concentration of the solution.
Benzalkonium chloride dermatitis is of the acute Labosept, Optipect, Phylletten, Polycidine, Sorot,
irritant contact dermatitis type. Delayed irritation is a ingredient of Efisol, Gargilon, Gramipan, Hexalyse,
subtype of acute irritant contact dermatitis and seems Micrin, CAS no. 522-51-0). It has been reported to
to be a characteristic of benzalkonium chloride cause necrotic ukers on the penis, vagina and body
irritancy: macules, papules and vesicles appear one folds (Coles and Wilkinson 1965; Tilseley and
after another over the course of days, rather than at the Wilkinson 1965). It is a rare sensitizer. The patch-
same time (Björnberg 1968). Other authors describe test concentration is 0.01% aqua. Allergie reactions
erythema, pustules and papules (Frosch 1995). Patch- are rare.
test concentrations range from 0.05% to 0.1% aqua. 6. Domiphen bromide «b-phenoxyethyl)-dimethyl
Irritant patch-test reactions are frequently seen. Aller- dodecylammonium bromide, PDDB, phenododeci-
gie contact dermatitis from benzalkonium chloride was nium bromide, NSC-39415, Bradosol Bromide,
described in medical personnel following exposure to Oradol, Modicare, Neo Bradoral, CAS no. 538-71-
instruments soaked in it (Garcie-Perez and Moran 6). It is found in antibacterial mouthwashes direct-
1975) and from its use in wound-healing management ed against Candida species. The patch-test concen-
(Wahlberg 1962); nevertheless, it is considered a rare tration is 0.1% aqua. Allergie reactions are rare.
sensitizer (Gall1979; Schnuch et al. 1998).
Benzethonium chloride (Hyamine 1622, Phemerol
Chloride, Phemeride, Phemithyn, Quatrachlor, Sol-
amin, CAS no. 121-54-0) and methylbenzethonium Other Surfactants
chloride (Diaparene Chloride, Hyamine lOX, CAS no.
25155-18-4) are used as topical antiseptics and are safe in Hexamidine isethionate (Hexomidine, Desomedine,
concentrations of 0.5% on the skin and 0.05% around Ophtamedine, CAS no. 659-40-5) is a preservative
the eyes (Anonymous 1985). They produce a mild skin used in pharmaceutical products and cosmetics (Brand
irritation at 5%, but probably not at lower concentra- and Balmer Weber 1995). The patch-test concentration
tions. Patch-test concentrations are 0.1% aqua. is 0.15% aqua. Allergie reactions do occur (Dooms
The following quaternary ammonium compounds Goossens et al. 1989). Photoallergic reactions were
are possible constituents of most commercially avail- reported (Boulitrop Morvan et al. 1993; Michel et al.
able disinfectants: 1994).
Hexetidine (5-amino-1,3-bis(2-ethylhexyl) hexa-
1. Benzoxonium chloride (D-301, ZY 15021, Absonal V, hydro-5-methylpyrimidine, Glypesin, Hexigel, Hexocil,
Biakol, Bradophen, Orofar, CAS no. 19379-90-9). Hexoral, Hextril, Oraldene, Sterisil, Steri/Sol, CAS no.
The patch-test concentration is 0.05% aqua. Allergie 141-94-6) is advertised as an oral-cavity antiseptic
reactions are rare. (1 mg/mI). It is effective against gram-positive bacteria
2. Cetyl-pyridinium chloride (Ceepryn, Cepacol, and Candidia species, but not against gram-negatives.
Cetamium, Dobendan, Medilave, Merocet, Prista- The patch-test concentration is 0.1% pet (Merk et al.
ein, Pyrisept, CAS no. 123-03-5). The patch-test 1982). Allergie reactions are rare.
concentration is 0.05% aqua. Allergie reactions do
occur.
3. Cetalkonium chloride (hexadecyldimethylammo-
niumbromide, Banicol, Acetoquat CDAC, Acquat Dyes
CDAC, Ammonyx G, Zettyn, Ammonyx T, Cetol,
CAS no. 122-18-9). The patch-test concentration is
Triphenylmethane Dyes
0.1% aqua. Allergie reactions are rare.
4. Cetrimonium bromide (cetrimide, Bromat, Cetab,
Triphenylmethane dyes were used widely in the
Cetavlon, Cetylamine, C.T.A.B., Lissolamine V,
treatment of stasis ukers and occasionally in the
Micol, Quamonium, CAS no. 57-09-0). It is easily
treatment of weeping eczema, combining antiseptic
soluble in water, in concentrations of 1-40%.
and drying properties. They were all used extensively
Concentrations greater than 1% in quaternary
. as topical antiseptics; however, currently, only gentian
ammonium compounds are very irritant under
violet is of practieal importance. All dyes belonging to
occlusion (Polano 1984). Savlon is a mixture of
this group are capable of produeing phototoxic
cetrimide 15% w/v and chlorhexidine 1.5% w/v aqua.
dermatitis (White 1995). Patch-test concentrations for
Patch-test concentrations are 0.01 and 0.1% aqua.
all dyes are 2% aqua. Cross-reactions are seen among
Allergie reactions are uncommon.
all triphenylmethane dyes:
5. Dequalinium chloride (BAQD 10, decamine, de-
kamin, Dekadin, Dequadin Chloride, Dequafungan, 1. Gentian violet (hexamethyl-pararosaniline chloride,
Dequavet, Dequavagyn, Eriosept, Evazol, Groereme, hexamethyl-p-rosaniline chlorine, aniline violet,
466 C. Timmer
crystal violet, methylrosaniline chloride, C.1. 42555, against hyperhidrosis and in the treatment of verrucae
Adergon, Axuris, Badil, Gentiaverm, Meroxylan, (3-10% aqua). Formaldehyde is used mainly in a 2-8%
Meroxyl, Pyoktanin, Vianin, Viocid, CAS no. 548- aqueous solution to disinfect inanimate objects and
62-9). This is capable of producing an immediate scrub, and in an air concentration of 1-2% to fumigate.
immunological contact re action and contact der- In cosmetics, the concentration of formaldehyde
matitis (Schopperlrey et al. 1997; Whitehead 1988) aqua is usually 0.05-2%. The patch-test concentration
2. Brilliant green (C.1. Basic Green 1, c.1. 42040, is 1% aqua. Allergie contact dermatitis in response to
Malachite Green G, Ethyl Green, Emerald Green, formaldehyde is common. Immediate non-immuno-
Diamond Green G, Fast Green J, Solid Green, CAS logie contact reactions are reported.
no. 633-03-4)
3. Methyl blue (sodium triphenyl-p-rosanilinetrisul- Formaldehyde Releasers
fate, brilliant cotton blue, Helvetia blue, c.1. Acid
Blue 93, c.1. 42780, CAS no. 28938-56-4065 Cosmetic preparations that contain formaldehyde
donor compounds release formaldehyde in the pres-
Other Dyes ence of water. Very often, these are water-based
preparations, such as shampoos. The presence of
Other dyes include: released formaldehyde is not required for the antimi-
crobial action of the compound and is therefore
1. Acriflavine (CAS no. 8 048-52-0) and proflavine regarded as an nuisance; however, this depends on
dihydrochloride (CAS no. 92-62-6). These are rarely the chemie al formula as a whole. In the end, increasing
used at present, but are reported to have caused use of formaldehyde-releasing compounds may lead to
allergie dermatitis (MitchellI972; Ng and Goh 1989). an increase in the incidence of contact allergy (Kranke
They are acridine dyes. Patch-test concentrations et al. 1996). Formaldehyde-releasing agents include:
are 0.1-1% pet.
2. Aminacrine (5-aminoacridine, 9-aminoacridine, 1. 2-Bromo-2-nitropropane-l,3-diol (Bronopol, Brono-
CAS no. 90-45-9). This is also an acridine dye. sol, CAS no. 51-52-7). This is one of the most
The patch-test concentration is 0.1% pet. frequently used preservatives in cosmetics (mostly
3. Eosine (CAS no. 548-24-3). Eosine was used as a soaps) and is considered to be broad spectrum but
preservative in topieal preparations (Rushton 1977; most effective against bacteria. The concentration
Tomb 1991; Koch et al. 1995). Patch-test concentra- found in products is 0.01-0.1% (Jacobs et al. 1995).
tions are 50% pet. or 1-2% aqua. Allergie reactions The patch-test concentration is 0.5% pet. Allergie
are rare. reactions are not uncommon.
4. Ethadicrine (6,9-diamino-2-ethoxyacridine, acrinol, 2. Diazolidinylurea (Germall II). This is used widely as
akridin, Rimaon, Rivanol, Vucine, Acrolactine, a preservative in liquid soaps, and is often com-
Ethodin, Metifex, CAS no. 442-16-0). This is used bined with parabens (or other antifungal formula-
(rarely) in leg ulcer treatment. It is also an acridine tions). Allergie reactions occur - especially when
dye. Patch-test concentrations are 1-2% pet. Aller- stay-on products are used. Cross-reactions to and
gie reactions are rare. from imidazolidinyl urea occur (Ford and Beck
5. Potassium permanganate (CAS no. 7722-64-7). Di- 1986). Patch-test concentrations are 2% aqua or 2%
lute solutions (0.1% aqua) are mildly irritating and pet. Allergie reactions are uncommon.
used as wet dressings on weeping dermatitis and 3. Imidazolidinyl urea (115). This releases relatively
ulcers. No reports on contact allergy were found. small amounts of formaldehyde. Cross-reactions to
and from diazolidinyl urea occur. Patch-test con-
centrations are 1% aqua or 1% pet (Ford and Beck
1986; Hectorne and Fransway 1994).
Formaldehydes and Aldehydes/-Releasers 4. Trihydroxyethyl hexahydrotriazine (Grotan BK).
This is a preservative used in metal-cutting fluids
Formaldehyde Aqua (Formalin, Formol, Morbicid, (Alomar et al. 1985). The patch-test concentration is
Veracur, CAS no. 50-00-0) 1% pet
5. Dimethylol-dimethyl hydantoine (DMDM hydan-
Formaldehyde aqua contains 37-40% formaldehyde toin, Glydant). This is a cosmetic preservative and
gas by weight, usually with 10-15% methanol added to formaldehyde releaser. The patch-test concentra-
prevent polymerization. It is a well-known sensitizer, tion 1% aqua (Perrenoud et al. 1994).
but also a local irritant in low concentrations (Glass 6. Quaternium-15 (chloroallylliexaminium chloride,
1961). Employed chiefly as a disinfectant, it has also chloroallyl methamine chloride, 1-(3-chloroallyl)-
been used as a topieal antimycotic, as a treatment 3,5,7, -triaza -1-azonioadamantane chloride, Dowicil
200, Dowicil 100, Dowicil 75, Dowicide Q, CAS no. likely still appear in many over-the-counter products
4080-31-3). This is a quaternary ammonium com- (Fisher 1986).
pound and a formaldehyde releaser. It is used Merbromin (mercurochrome, no. 220 sol., Mercuro-
mainly in water-based cosmeties, as a preservative chrome-220 Soluble, Chromargyre, Plano chrome,
Oacobs et al. 1995; Boffa and Beck 1996; Prue et al. Flavurol, D.O.M.F., Mercurophage, Mercurocol, Gallo-
1998). The patch-test concentration is 2% pet. chrome, Gynochrome, Mercurome, Aseptichrome,
7. Glutaraldehyde (pentanedial, 7-ethylbicyclooxazoli- Mercuranine, CAS no. 7789-47-1) is the oldest known
dine glutaral, Cidex, Glutaral, Verucasep, CAS no. mercurial antiseptic. Patch-test concentrations are 0.1-
111-30-8). This is an aliphatic di-aldehyde, soluble in 2% aqua (Bardazzi et al. 1990). Allergie reactions are
water, alcohol, ether and similar organic solvents. It rare.
is commonly used as a cold sterilizer, in a 2% All phenylmercuric compounds are capable of
aqueous solution, to disinfect vulnerable instru- producing immediate immunological contact reac-
ments that cannot be heat sterilized (e.g., endo- tions. Phenylmercuric acetate (phenylmercury acetate,
scopes, anesthetic gas machines, respirators, dental PMA, PMAC, PMAS, Ceresan Slaked Lime, Gallotox,
equipment, renal dialysis machines). The major Liquiphene, Phix, Mersolite, Tag Fungicide, Tag HL-
occupational complaints among health care workers 331, CAS no. 62-38-4) is a fungicide (pesticide) and
(endoscopy unit) were eye irritation (49% of used as a seed treatment product. Phenylmercuric
reported symptoms), skin discoloration or irrita- borate (phenylmercuric borate, Famosept, Gyne-Mer-
tion (41%) and cough or shortness of breath (34%) fen, Merfen, CAS no. 102-98-7) and phenylmercuric
(Calder et al. 1992). nitrate (merphenyl nitrate, Phermenite, Phenmerzyl
Cidex is 2% acidic glutaraldehyde, a stable solution, nitrate, CAS no. 8003-05-2) were both once used as
but when activated (by means of buffering the pre-operative skin disinfectants.
solution with sodium bicarbonate to a pH of 7.5- Patch-test concentrations for all three compounds
8.0), it has a relatively strong irritant effect on the are greater than 0.01% aqua (phenylmercuric acetate is
skin. When used as a hospital disinfectant, it is also patch tested at 0.05% aqua). Allergie reactions are
considered an occupational hazard (Hasen 1983). uncommon, but contact urticatia was reported (Torre-
The patch-test concentration is 1% pet. Allergie sani et al. 1993) In antimicrobial concentrations
reactions are uncommon (Nethercott et al. 1988). (0.1-2%) they are considered irritant.
Cross-reaction with formaldehyde is possible. Phenylmercuric benzoate, phenylmercuric chloride,
8. Hexamethylenetetramine (methenamine, hexamine, and phenylmercuric propionate still are used as preser-
Aminof, Ammoform, Cystamin, Cystogen, Formin, vatives in cosmetics and phenylmercuric borate was
Uritone, Urotropin, CAS no. 100-97-0). This liber- once used as apreoperative skin disinfectant. Phenyl-
ates formaldehyde. Sometimes the product is used mercury salts are also widely used in agricultural
in foot powders - both as a preservative and as an industries as fungieides, herbicides or pesticides.
antiperspirant (Hectorne and Fransway 1994). The Apart from obligate skin irritation when used in too
patch-test concentration is 2% pet. high concentrations, all inorganic mercury salts have a
9. Hexamidine (CAS no. 3811-75-4). In addition to its reputation for sensitization (van KeteI1980).
use as an amoebicidal agent, hexamidine is used in Thimerosal (thiomersal, thiomersalate, mercuro-
topical creams. The patch-test concentration is thiolate, Merthiolate, Merzonin, Mertorgan, Merfamin,
0.15% aqua (Brand and Ballmer Weber 1995). CAS no. 54-64-8) is used widely as a preservative in
Photo allergie reactions were mentioned. cosmetic products and medical topical agents (e.g.,
creams, lotions, solutions for contact lenses). Among
various products considered, thiomerosal was impli-
Mercuric Compounds
cated as the most likely to cause chemical burns during
preoperative skin procedures (Hodgskinson et al.
Cross-reactions may occur between metal, organic and 1978). People are likely to also be sensitized by
inorganic mercurials. thiomersal-preserved vaccines (Aberer et al. 1991).
The patch-test concentration is 0.1% pet. Allergie
Organic Mercury Compounds reactions do occur. When patch-tested, thimerosal can
easily produce irritant test results.
Organic mercury compounds were once very popular
as skin disinfectants, but because they carry the risk of Inorganic Mercuric Compounds
sensitization, local irritation and the danger of sys-
temic toxicological disturbanees, they have fallen into Mercuric salts were once used as tattooing pigments
disuse. In addition, cross-reactions between organic and are capable of inducing allergie contact dermatitis
mercury compounds are common. These compounds (mercurie sulfide-red pigment). They were also the
468 C. Timmer
cause of granulomatous allergic reactions (Levy et al. 6. Captan (N-trichloromethylmercapto-delta4-tetra-

1979)· anhydrophthalimide, Merpan, Orthocide-406, Ent-
Ammoniated mercury (CAS no. 33445-15-7) was 26538, SR-406, Vancide 89RE, CAS no. 133-06-2).
formerly used in the treatment of psoriasis. The This product was used as an anti-dandruff agent but
patch-test concentration is 1% pet. Allergic reactions was prohibited in the EC, because it showed some
do occur. carcinogenic effects in a mouse model (De Groot
Mercury chloride (mercuric chloride, CAS no. 7487- et al. 1986). It is also used as a fungieide on fruits,
94-7) was once a classical disinfectant, but has fallen seeds and ornamental plants. Patch-test concentra-
into disuse because of its high toxicity and sensitizations are 0.1-0.25% pet. Allergic reactions do occur
tion index. It is a caustic compound and therefore also (Fregert 1967). Contact urtiearia is possible.
a potent skin irritant (erythema, follicular pustules and 7. Sodium hypochlorite (modified DAKIN's solution,
papules). The patch-test concentration is 1% pet. CAS no. 7681-52-9). This is used as a wound
Allergic reactions do occur. disinfectant, usually at concentrations of 0.02-
Mercurous chloride (CAS no. 10112-91-1) was for- 0.1% w/v aqueous solution. It is an oxidizing agent
merly used in the treatment of syphilis. The patch-test and considered a primary irritant (Frosch 1995;
concentration is "as is". Allergic reactions are uncom- Tupker et al. 1997).
mon. Chlorines act through protein denaturation, by deami-
nating or chlorinating amino acids and proteins
(Wright 1926). Low concentrations of free chlorine
Phenol-{Organo-)Halogen Compounds (0.001) are microbiocidal, and most of the chlorine
compounds are used for large areas, such as floors, and
for contaminated commodities, such as toilets. The
Phenol-( organo-)halogen compounds include:
patch-test concentration is 0.5% aqua. Allergie reac-
1. Phenol (hydroxybenzene, carbolic acid, CAS no. tions are uncommon.
108-95-2). This has bactericidal effects in 0.5-1% 8. EUSOL (Edinburgh SOlution of Lime). This con-
aqueous solution, although it is seldom used this tains chlorinated lime at 1.25% concentration (30%
way and is considered obsolete as an antiseptic of available chlorine) and boric acid at 1.25% in
(Adams 1990). In low concentrations, phenols are aqueous solution. Wh ether in a pure state or in
also fungicidal (1.3%) and antipruritic (1-2%). In up combination with liquid paraffin, EUSOL is em-
to 10% solution, phenols are used for chemical deep- ployed in ulcer treatment; however, because of its
peeling of the face. If not applied in proper doses, cytotoxicity, it is used only in the black and yellow
this can give very serious necrotie burn wounds and phases of wound healing. Both forms are often used
systemic reactions (cardiac arrhythmias) (Gross in chronic ulcer treatment.
1984). Phenols are capable of inducing non-immu- In combination with acids, toxic chloride gas arises; in
nologie contact urticaria and can produce a stinging combination with formaldehyde, carcinogenic reac-
sensation in the skin (Bjorkner 1968). tion-products will be formed. Cutaneous intolerance to
Phenol in a 1% ethanol solution can produce a hypochlorite may become manifest through immedi-
delayed-type (slight) stinging which occurs minutes ate-type and delayed-type responses, and could lead to
after application (Frosch 1995). Cross-reaction of systemic reactions in patients previously sensitized by
phenol is possible with resorcinol, cresols and hydro- cutaneous contact (Hostynek 1989).
quinone. Patch test concentrations are 0.5-1% aqua.
9. Povidone-iodine (PVP-I, polyvinyl pyrrolidon-
Allergie reactions are rare. Irritant patch-test reactions
iodine complex, Betadine, Betaisodona, Braunol,
are frequent.
Braunosan H, Disadine D.P., Disphex, Efo-Dine,
2. Bithionol (CAS no. 97-18-7). Bithionol is usually
Inadine, Isodine, Proviodine, Traumasept, Videne,
associated with photoallergy and/or phototoxicity.
CAS no. 25655-41-8). This is the most widely used
Persistent light reactions were reported. Prohibited
iodophor and does not have the irritant properties
in the European Community (EC). The patch-test
associated with iodine solutions. At a strength of
concentration is 1% pet. Allergic reactions are not
7.5% in a surfactant base, povidone-iodine is
uncommon.
applied as a surgieal scrub, and at 4% is used as a
3. Bromochlorophene (p-chlorophenol). The patch-
shampoo or skin cleanser. Because of the small
test concentration is 2% pet. Allergic reactions are
amounts of free iodine (less then 1 ppm in a 10%
rare.
solution), antimierobial effects are moderate in
4. 5-Bromo-5-nitro-1,3-dioxane (Bronidrox). The
comparison with iodine solutions.
patch-test concentration is 0.5% pet.
5. 2-Bromo-2-nitropropane-1,3-diol (Bronopol-). The The relationship between free iodide and strength of
patch-test concentration is 0.5% pet. PVP-I solution is paradoxical: the amount of free
iodine in PVP-I solutions with concentrations ranging test eoneentrations are 0.5 and 1% aqua. Allergie
from 10-0.1% increases 20-fold. Irritancy depends on reaetions are not uncommon and immunological
the amount of free iodine; therefore, tinctures and immediate eontact reaetions and irritant contaet der-
solutions are far more irritable than PVP-1. PVP-I is a matitis may oeeur. Photoallergy was reported.
primary irritant and a lesser-known sensitizer (Kunze
14. Chlorobutanol (chlorbutanol, triehlorbutanol,
et al. 1983).
ehlorbutol, aeetone chloroform, Chloretone, Coli-
PVP-I was reported to inhibit leucocyte migration
quifilm, Methaform, Sedaform, CAS no. 57-15-8).
and fibroblast aggregation in surgical wounds (Viljanto
This is an antimierobial used in pharmaeeutical
1980). The use of PVP-I should therefore be avoided in
preparations. It is also a mild sedative. The patch-
the so-called red (granulomatous) phase of wound-
test coneentration is 5% pet (Hannuksela et al.
healing.
1979).
It is recommended that PVP-I not be used on young
15. Lysol. This is a eompound of saponated eresol
children (neonates and babies) (Wissenschaftlicher
(mixture of 0-, m- and p-eresol) solution, usually
1980). Iodide, whieh is spoiled per operationem
50% in saponified linseed oil), and was onee used
between skin and electrocoagulation electrodes, could
extensively as a disinfectant for floors and operat-
result in serious burning wounds. Patch-test concen-
ing theaters in hospitals. p-ehloro-m-eresol is the
trations are "as is" and 10% pet. Allergie reactions are
suspeeted allergen. It is reported to produce
considered rare.
immediate immunologieal eontaet reaetions (Sing-
10. Iodoform (tri-iodomethane, CAS no. 75-47-8). This gih et al. 1986; Kiec-Swierezynska 1995). The pateh-
releases iodine under the influence of light and test coneentration is 1% pet. Allergie reaetions are
(especially) temperature. It is mostly available as a not uncommon. Cross-reaetions between p-ehloro-
bismuth-iodoform paste. The patch-test concen- m-eresol and p-ehloro-m-xylenol (ehloroxylenol)
tration is 5% pet. Allergie reactions do occur. are common.
11. Iodine tincture (a1coholic preparation). The pateh- 16. Chloroxylenol (4-ehloro-3,5-dimethylphenol,
test eoneentration is 0.5% aqua, open test (Mar- PCMX, parachlorometaxylenol, p-ehloro-m-xyle-
cussen 1963). Allergie reaetions are not uneommon. nol, Benzytol, Dettol, Emericide, Ottasept, CAS
12. Chloroacetamide (CAS no. 79-07-2). This is a well- no. 88-04-0). This is widely used as a topical
known eosmetie bioeide, but sensitization is less disinfectant with low irritant potential. It has been
common than with parabens. An allergie reaction a substitute for hexaehlorophene in a large number
was reported to deodorant (Taran and Delaney of products. It is also used as a preservative in
1997). The patch-test concentration is 0.2% pet. many over-the-counter products (baby powders,
Allergie reaetions do oecur. shampoos, contraeeptive douehes, ete.) (Adams
13. Chlorhexidine diacetate (Arlaeide A, Chlorasept 1990). Sensitization and intoxieation have been
2000, Nolvasan, Sterilon, CAS no. 55-56-0), ehlor- reported, but very little irritation is notieed (Myatt
hexidine diglueonate (Bactilens, Corsodyl, Hibi- and Beek 1985; Ranchoff et al. 1986). The pateh-test
lens, Hibidil, Hibiscrub, Hibitane, Orahexal, concentration is 1% pet. Irritant pateh tests are
Peridex, pHisoMed, Plae Out, Plurexid, Rotersept, eommon.
Steroxin, Uni sept, CAS no. 18472-51-0) and ehlor- 17. Dibromopropamidine diisethionate (Dibromopro-
hexidine dihydroehloride (Arlacide H). Chlorhexi- pamidine isethionate, Brolene ointment, Brulidine,
dine, in combination with cetrimide, is called CAS no. 614-87-9) (Lützow-Holm and Rönnevig
Savlon. Chlorhexidine has been used extensively 1988). Pateh-test eoncentrations are 1-5% pet.
over the years as a topical antiseptic (e.g., pre- 18. Hexaehlorophene (HCP, G-11, AT-7, Bilevon, Bu-
operative) and for disinfecting materials. Long- rdeo, Dermadex, Exofene, Gamophen, Hexosan,
term experience has yielded a low ineidence of pHisohex, Surgi-Cen, Surofene, CAS no. 70-30-4).
(photo-) sensitization and skin irritation (Rushton This is a chlorinated biphenol, an antiseptic that
1977). has the advantage of not being inactivated by soap.
If used extensively or applied in high eoneentra-
Patients with a long-term history of u1cer treatment
tions on intact human skin, excoriations will
are partieularly at risk of developing eontact sensiti-
eventually develop (e.g., surgeons' pre-operative
zation ( Knudsen and Avnstorp 1991). Some authors
serubs). It is prohibited in the EC and US, after
propose that ehlorhexidine should not be used on
reports of neurotoxieity (Anonymous 1982). The
mueous membran es and lips, beeause of the risk -
pateh-test eoneentration is 1% pet. It has eaused
although eonsidered very rare - of anaphylaetic
photo allergie and phototoxie reaetions (Praditsu-
reactions (Okano et al. 1989). This is considered an
wan et al. 1995). Cross-reaetions with bithionol,
immunologie al immediate eontaet reaetion. The pateh-
470 C. Timmer
diehlorophene and halogenated salieylanilides are and is also eapable of indueing asthma and rhinitis
possible. Allergie reaetions are rare. Irritant test (Moseato et al. 1997). The pateh-test eoneentration
reaetions are eommon. is 0.1% pet (0.4% aqua). Irritant pateh test
19. Diehlorophene (Anthiphen, Dieestal, Didroxane, reaetions are reported (Chew and Maibaeh 1997).
Di-phenthane-70, G-4, Hyosan, Parabis, Plath-Iyse, Allergie reaetions do oeeur.
Preventol G-D, Teniathane, Teniatol, Wespuril, 25. ChloramineT (tosylchloramide-sodium, ehlor-
CAS no. 97-23-4). This is a biocide in many soaps, amine, Aktiven, Chloraseptine, Chlorazene,
shampoos, hair tonies, liquid make-up produets, Chlorazone, Clorina, Euclorina, Gansil, Gyneclor-
ete. As a preservative in many dentifriees, it has ina, Halamid, Mianine, Toehlorine, Tolamine, CAS
eaused dermatitis of the mouth, mostly allergie, no. 127-65-1). This is used to disinfeet toilets,
with eheilitis and stomatitis (Andersen and Ham- bathtubs, floors, working areas in hospitals, eater-
ann 1984). The pateh-test eoneentration is 1% pet. ing industries ete. Also used as a sterilizer (water)
Irritant pateh tests are eommon. Photo allergie and reagent. Chloramine diluted to 0.001% (aque-
reaetions are reported (Menz et al. 1982). Cross- ous solution) is employed as a dermatologieal
reaetions with bithionol, hexaehlorophene and antiseptie on wet dressings that are applied for leg
halogenated salieylanilides are possible. ulcer treatment. It ean produee a immediate
20. Diehlorobenzylaleohol (2,4-diehlorobenzylalcohol, immunologie al eontaet reaetions (Lahti 1995) and
Dybenal, Myaeide SP, CAS no. 1777-82-8). This is is a lesser-known sensitizer (Dooms-Goossens
used as an antiseptie. The pateh-test eoneentration et al. 1983; Lombardi et al. 1984; Kanerva et al.
is 2% pet. 1997). Espeeially in high temperature aeute skin
21. Hexantriol. This is a preservative and eonstituent and mueosa, irritaney eould develop and, in ease of
of vehicle of topieal drugs. It was reported to high dosage, even blistering eould oeeur (Hostynek
produee immediate immunologie al eontaet reae- 1989). Also, ehloramine was reported to eause
tions. The pateh-test eoneentration is 5% aqua. immediate eontaet urtiearia in the faee (and airway
22. Methylchloroisothiazolinone (Kathon CG, is- symptoms) following eontaet. The pateh-test eon-
othiazolinones, 5-ehloro-2-methyl-4-isothiazolin- eentration is 0.5% aqua. Allergie reaetions do oecur.
3-one and 2-methyl-4-isothiazolin-3-one (3:1 wl 26. 1,3-Diiodo-2-hydroxypropane (iothion, CAS no.
w), Cl + Me Isothiazolinone; Kathon 886 MW, 534-08-7). This was onee used as an antiseptic. It
Kathon LX, Kathon WT, Aetieide, Algueid CH 50, ean produee immediate immunologie al eontaet
Amerstat, Euxyl KHostynek 1989, Fennosan IT 21, reaetions. The pateh-test eoneentration is 0.05%
GR 856 Izolin, Grotan TK2, Mergal K7, Metatin GT, (alcohol).
Miteo CC 31 L, Miteo CC 32 L, Special Mx 323, 27. o-phenylphenol (o-phenylphenate, Dowicide 1,
Parmetol DF 35, Parmetol DF 12, Parmetol A 23, CAS no. 90-43-7). This is a preservative in foun-
Parmetol K 50, Parmetol K 40, Parmetol DF 18, P3 dation eream (Cronin 1980). and is also used in the
Multan D, Piror PI09). These eompounds are used rubber industry and employed as an industrial
extensively as preservatives in (aquatie) rinse-off disinfeetive agent. The pateh-test eoneentration is
eosmeties, toileteries, metal-working fluids, latex 1% pet. (Adams 1981).
emulsions, eooling tower water, ete. (Madden et al. 28. Tribromsalan (TBS, halogenated salieylanilide,
1994). The pateh-test eoneentration is 100 ppm Temasept IV, Tuasol Hostynek 1989, CAS no. 87-
aqua. Allergie reaetions are eommon (Gruvberger 10-5). This is an antiseptie that is now prohibited
et al. 1998). in the EC. Photoallergie and phototoxie reaetions
23. Methyldibromoglutaronitrile (1,2-dibromo-2,4- were reported (Miyauehi and Horio 1992). Cross
dieyanobutane, Euxyl K400, Tektamer, CAS no. reaetion oeeurs with other halogenated salieylan-
35691-65-7). In eombination with phenoxyethanol, ilides. The pateh-test eoneentration is 1% pet
this produet is ealled Euxyl K 400. In reeent years (Osmundsen 1970).
it has often replaeed Kathon CG as an antimiero- 29. Tricloearban (TCC, triehloroearbanilide, Cutis an,
bial in eosmeties and toileteries. Allergie reaetions Nobaeter, Solubaeter, CAS no. 101-20-2). This is an
are expeeted to beeome more frequent in the antiseptie and baeteriostatie used in antimierobial
population (De Groot et al. 1996). The pateh-test soap bars, deodorants, antiperspirants. Photo aller-
coneentration is 1% (0.05%) pet (De Groot et al. gie and phototoxie reaetions were reported (Hasan
1996). Allergie reaetions are uneommon. and Jansen 1996). Cross reaetion oeeurs with other
24. 1,2-Benzisothiazolin-3-one (BIT, 1,2-BIT, Proxel halogenated salieylanilides. Caustie reaetion on
GXL, no CAS no.). This eompound is a popular skin and mueosa was reported (Barriere 1973).
preservative used in water-based solutions sueh as Allergie reaetions are not uneommon, and ean
detergents, pastes, paints and eutting oils (Damstra result in pigmentation afterwards. The pateh-test
et al. 1993). It is eonsidered a sensitizer and irritant eoneentration is 2% pet.
30. Triclosan (Irgasan DP300, Gamophen, Aquasept, Christersson S, Wrangsjo K (1992) Contact allergy to undecylen-
amide diethanolamide in a liquid soap. Contact Dermatitis
CH-3635, Sapoderm, Ster Zac, CAS no. 3380-34-5).
27:191- 192
This is an antimicrobial used in soap bars, Clemmensen 0, Hjorth N (1982) Perioral contact urticaria from
deodorants, antiperspirants and as an anti-acne sorbie acid and benzoic acid in a salad dressing. Contact
agent in over-the-counter products. Allergie reac- Dermatitis 8:1-6
Coles RB, Wilkinson DS (1965) Necrosis and dequalinium I:
tions are not uncommon (Perrenoud et al. 1994). balanitis. Trans St Iohn's Hosp Derm Soc 51:46
The patch-test concentration is 2% pet (De Groot Corazza M, Mantovani L, Maranini C, Virgili A (1996) Allergie
contact dermatitis from benzyl alcohol. Contact Dermatitis
et al. 1985; Steinkjer and Braathen 1988).
34:74-75
Coverly 1, Peters L, Whittle E, Basketter DA (1998) Susceptibility
to skin stinging, non-immunologic contact urtiearia and
References acute skin irritation; is there a relationship? Contact Derma-
titis 38:90-95
Cronin E (1980) Contact dermatitis. Churchill Livingstone,
Aberer W, Reiter E, Ziegler V, et al. (1991) The importance of Edinburgh, pp 93-170
including thiomersal in standard screening series for allergic Damstra RI, van Vloten WA, van Ginkel (1993) Cl Allergic
contact dermatitis. Am 1 Contact Dermat 2:110-112 contact dermatitis from the preservative 1,2-benzisothiazolin-
Adams RM (1981) Allergic contact dermatitis due to o-phenyl- 3-one (1,2-BIT, Proxel): a case report, its prevalence in those
phenol. Contact Dermatitis 7=332 occupationally at risk and in the general population, and its
Adams RM (1986) Occupational skin disease. WB Saunders, relationship to allergy to its analogue Kathon Ge. Contact
Philadelphia, p 448 Dermatitis 27:105-109
Adams RM (1990) Occupational skin disease. WB Saunders, De Groot AC, Bos ID, Iagtman BA, et al. (1986) Contact allergy to
Philadelphia, p 449 preservatives. Contact Dermatitis 15:218-222
Aguirre A, Izu R (1993) Edematous allergic contact cheilitis from Methyldibromoglutaronitrile is an important contact allergen in
a toothpaste. Contact Dermatitis 28:42 the Netherlands. Contact Dermatitis 34:118-120
Alomar A, Conde-Salazar L, Romaguera C (1985) Occupational De Groot AC, Liem DH, Nater IP, van Ketel WG (1985) Patch tests
dermatoses from cutting oils. Contact Dermatitis. 12:129-138 with fragrance materials and preservatives. Contact Derma-
Andersen KE, Hamann K (1984) The sensitizing potential of titis 12:87-92
metalworking fluid biocides (phenolic and thiazole com- De Groot AC, van Ginkel Cl, Weijland IW (1996) Met-
pounds) in the guinea-pig maximization test in relation to hyldibromoglutaronitril (Euxyl K-400): an important new
patch-test reactivity in eczema patients. Food Chem Toxicol allergen in cosmetics. 1 Am Acad Dermatol 35:743-747
22:655-660 Dejobert Y, Martin P (1991) Contact dermatitis from topiealleech
Andersen KE, Rycroft RI (1991) Recommended patch test extract. Contact Dermatitis 24:366-367
concentrations for preservatives, biocides and antimierobials. Dooms-Goossens A, Gevers D, Merstens A, et al. (1983) Allergic
Contact Dermatitis 25=1-18 contact urticaria to chloramine. Contact Dermatitis 9:319
Anonymous (1985) Final report on the safety assessment of Dooms-Goossens A, Vandaele M, et al. (1989) Hexamidine
benzethonium chloride and methylbenzethonium chloride. isethionate: a sensitizer in topieal pharmaceutieal products
1 Am Coll Toxieol 4:65 and cosmetics. Contact Dermatitis 21:270
Anonymous (1982) Hexachlorophene today (editorial). Lancet Eberlein-Konig B, Bergner T, Diemer S, Przybilla B (1993)
1:87 Evaluation of phototoxic properties of some food additives:
Bardazzi F, Vassilopoulou A, Valenti R, et al. (1990) Mercuro- sulfites exhibit prominent phototoxicity. Acta Derm Venereol
chrome-induced allergic contact dermatitis. Contact Derma- 73:362-364
titis 23:381-382 Fisher AA (1980) Cutaneous reactions to sorbie acid and
Barriere H (1973) La dermite cutaneomuceuse caustique du potassium sorbate. Cutis 25:50-423
trichlorocarbanilide. Therapeutique 49:685 Fisher AA (1986) Contact dermatitis. Lea and Febiger, Philadel-
Basketter DA, Wilhelm KP (1996) Studies on non-immune phia
immediate contact reactions in an unselected population. Ford GP, Beck MH (1986) Reactions to Quaternium-15, Bronopol
Contact Dermatitis 35:237-240 and Germali II in a standard series. Contact Dermatitis
Bjorkner A (1968) Skin reactions to primary irritants in patients 14:322-324
with hand eczema. 0 Isacson Tryckeri, Gothenburg Fregert S (1967) Allergic contact dermatitis from pesticides
Björnberg A (1968) Skin reactions to primary irritants in patients captan and phaltan. Contact Dermatitis 2:28
with hand eczema. Thesis Isacsons, Göteborg Fregert S, Groth 0, Hjorth N, et al. (1963) Dermatitis from
Boffa MI, Beck MH (1996) Allergie contact dermatitis from alcohol. 1 Allergy 34:904
quaternium 15 in oilatum cream. Contact Dermatitis 35: Frosch PI (1995) Cutaneous irritation. In: Rycroft RIG, Menne T,
45-46 Frosch PI (eds) Textbook of contact dermatitis. Springer,
Bonacci A, Haddow 1 (1970) Hazards in the nursery. N Eng 1 Med Berlin Heidelberg New York, pp 54-55
282:633 Gall H (1979) Toxisches kontaktekzem auf die quaternäre
Boulitrop Morvan C, Collet E, et al. (1993) Photoallergy to ammoniumverbindung benzalkoniumchlorid. Derm Beruf
hexemidine. Photodermatol Photoimmunol Photomed 9: Umwelt 27:139
154-155 Garcie-Perez A, Moran M (1975) Dermatitis from quaternary
Brand CU, Balmer Weber BK (1995) Contact sensitivity to 5 ammonium compounds. Contact Dermatitis 1:316
different ingredients of a topieal medieament (imacort Gelfarb M, Leiden M (1960) Contact eczematous contact derma-
dream). Contact Dermatitis 33=137 titis. Arch Dermatol 82:642
Brubacher IR, Hoffman RS (1996) Salicylism from topieal Giordano, Labadie F, Pech Ormieres C (1996) Systemie contact
salieylates: review of the literature. 1 Toxieol Clin Toxicol dermatitis from sorbic acid. Contact Dermatitis 34:61-62
34:431-436 Glass WI (1961) An outbreak of formaldehyde dermatitis. NZ Med
Calder IM, Weight LP, Grienstone D (1992) Glutaraldehyde I 60:423
allergy in endoscope units. Lancet 338:433 Goh CG, Ng SK (1986) Contact sensitivity to salicylic acid.
Chew AL, Maibach HI (1997) 1,2-benzisothiazolin-3-one (Proxel): Contact Dermatitis 14:114
irritant or allergen? A clinical study and literature review. Gross BC (1984) Cardiac arrhythmias during phenol face peeling.
Contact Dermatitis 36:131-136 Plast Reconstr Surg 73:590-594
472 C. Timmer
Gruvberger B, Bruze M, Ahngren G (1998) Occupational de- Miehel M, Dompmartin A, Moreau A, et al. (1994) Contact
rmatoses in a plant producing binders for paints and glues. photosensitivity to nonoxynol used in antiseptic prepara-
Contact Dermatitis 38:71-77 tions. Photodermatol Photoimmunol Photomed 10:198-201
Hannuksela M, Kousa M, Pirill V (1976) Allergy ingredients of Mitchell JC (1965) Allergy to lichens. Arch Dermatol 92:142-146
vehicles. Contact Dermatitis 2:105 Mitchell JC (1972) Contact dermatitis from proflavine dihydro-
Hasan T, Jansen CT (1996) Photopatch test reactivity: effect of chloride. Arch Dermatol 106:294
photoallergen concentration and UVA dosaging. Contact Miyauchi H, Horio T (1992) A new animal model for contact
Dermatitis 34:383-386 dermatitis: the hairless guinea pig. J DermatoI19:140-145
Hasen KS (1983) Glutaraldehyde occupational dermatitis. Contact Moscato G, Omodeo P, et al. (1997) Occupational asthma and
Dermatitis 9:81 rhinitis caused by 1,2-benzisothiazolin-3-one in a chemical
Hausen BM, Emde L, Marks V (1993) An investigation of the worker. Occup Med (Oxf) 47:249-251
allergenie constituents of Cladonia stellaris. Contact Derma- Myatt AE, Beck MH (1985) Contact sensitivity to para-
titis 28:70-76 chlorometaxylenol (PCMX). Clin Exp Dermatol 10:491
Hectorne KJ, Fransway AF (1994) Diazolidinyl urea: incidence of Nethercott JR, Lawrence MJ (1984) Airborne contact urtiearia due
sensitivity, patterns of cross-reactivity and clinical relevance. to sodium benzoate in a pharmaceutical manufacturing plant.
Contact Dermatitis 30:16-19 J Occup Med 26:734-736
Heine A, Tarnick M (1987) Allergisches kontaktekzem durch Nethercott JR, Holness DL, Page E (1988) Occupational contact
Usninsaure in Deodorantsprays. Dermatol Monatsschr dermatitis due to glutaraldehyde in health care workers.
173:221-225 Contact Dermatitis 18:193-196
Hodgskinson DJ, Ivens GB, et al. (1978) Chemical burns and skin Ng SK, Goh CL (1989) Contact allergy to sodium hypochlorite in
preparation solutions. Surg Gynecol Obstet 147:534 Eusol. Contact Dermatitis 21:281
Hostynek JJ (1989) Hypochlorite sensitivity in man. Contact Okano M, Nomura M, Hata S, et al. (1989) Anaphylactic symp-
Dermatitis 20:32 toms due to chlorhexidine digluconate. Arch Dermatol
Jacobs MC, White IR, Rycroft RJ, Taub N (1995) Patch testing 125:50
with preservatives at St John's from 1982 to 1993. Contact Okazawa H, Aihara M, Nagatani T, et al. (1998) Allergic contact
Dermatitis 33:247-254 dermatitis due to ethyl alcohol. Contact Dermatitis 38:233
Kanerva L, Alanko K, Estlander T, Sihvonen T, Jolanki R (1997) Osmundsen PE (1970) Contact photodermatitis to tribromsal-
Occupational allergie contact urticaria from chloramine-T icylanilide (cross reaction pattern). Dermatologiea 140:65
solution. Contact Dermatitis 37:180-181 Ostler HB, Okumoto M, Daniels T (1983) Drug induced cicatri-
Kaslow RA (1976) Nosocomial pseudobacteremia: positive blood- sation of the conjunctiva. Contact Dermatitis 9:155
cultures due to contaminated benzalkonium antiseptie. JAMA Pecquet C, Pradalier A (1992) Allergic contact dermatitis from
236:2407 ethanol in a transdermal estradiol patch. Contact Dermatitis
Kiec-Swierczynska M (1995) Preliminary assessment of the effect 27:275-276
of disinfectants on skin changes in health serviee workers. Perrenoud D, Bircher A, Hunziker T, et al. (1994) Frequency of
Med Pr 46:149-154 sensitization to 13 common preservatives in Switzerland. swiss
Knudsen BB, Avnstorp C (1991) Chlorhexidine gluconate an contact dermatitis group. Contact Dermatitis 30:276-279
acetate in patch testing. Contact Dermatitis 24:45-49 Polano MK (1984) Topieal skin therapeuties. Churchill Living-
Koch P, Baltmer FA, Hausen BM (1995) Allergic contact stone, Edinburgh
dermatitis from purified eosin. Contact Dermatitis 32: Praditsuwan P, Taylor JS, Roenigk HH Jr (1995) Allergy to Unna
92-95 boots in four patients. J Am Acad Dermatol 33:906-908
Kranke B, Szolar Platzer C, Aberer W (1996) Reactions to Prue C, Martinson ME, McAnally PM, Stagner WC (1998)
formaldehyde and formaldehyde releasers in a standard Postmarketing survey results of T.R.U.E. TEST, a new
series. Contact Dermatitis 35:192-193 allergen patch test. Am J Contact Dermat 9:6-10
Kunze J, Kaiser HJ, Petres J (1983) Relevenz einer Jodallergie beri Rafanelli S, Bacchilega R, et al. (1995) Contact dermatitis from
handelsublichen Polyvidon-Jod-Zubereitungen. Z Hautkr usnic acid in vaginal ovules. Contact Dermatitis 33:271-272
58:2 55 Ramsing DW, Menne T (1993) Contact sensitivity to sorbic acid.
Lahti A (1980) Non-immunologie eontaet urtieara. Aeta Derm Contact Dermatitis 28:124-125
Venereol 60[Suppl 91]:1-49 Ranchoff RE, Steck WD, Taylor JS, Evey P (1986) Electrocardi-
Lahti A (1995) Immediate contact reactions. In: Rycroft RJG, ography eleetrode and hand dermatitis from para-
Menne T, Frosch PJ (eds) Textbook of contact dermatitis. chlorometaxylenol. J Am Acad Dermatol 15:348-350
Springer, Berlin Heidelberg New York, p 67 Rushton A (1977) Safety of Hibitane: II human experience. J Clin
Levy J, Sewell M, Goldstein N (1979) A short history of tattooing. Periodontol 4:73
J Derm Surg Oncol 5:851-853 Safford RJ, Basketter DA, Allenby CF, et al. (1990) Immediate
Lombardi P, et al. (1984) Unusual occupational allergie contact contact reactions to chemieals in the fragrance mix and a
dermatitis in a nurse. Contact Dermatitis 20:302 study of the quenching action of eugenol. Br J Dermatol
Lowe I, Southern J (1994) The antimierobial activity of phenoy- 123:595-606
ethanol in vaccines. Lett Appl MicrobioI18:1l5-1l6 Schiek JB, Milstein MM (1981) Burn hazard of isopropyl alcohol
Lützow-Holm, C Rönnevig JR (1988) Allergie contact dermatitis in neonates. Pediatrics 68:587
from dibrompropamidine cream. Contact Dermatitis 18: Schnuch A, Geier J, Uter W, Frosch PJ (1998) Patch testing with
100-101 preservatives, antimicrobials and industrial biocides. Results
Madden SD, Thiboutot DM, Marks JG Jr (1994) Occupationally from a multieentre study. Br J Dermatol 138:467-476
induced allergic contact dermatitis to methylchloro- Schoppelrey HP, Mily H, Agathos M, et al. (1997) Allergie contact
isothiazolinone/methylisothiazolinone among machinists. dermatitis from pyoctanin. Contact Dermatitis 36:221-224
J Am Acad Dermatol 30:272-274 Shehade SA, Foulds IS (1986) Allergic contact dermatitis to
Marcussen PV (1963) Variations in the incidence of contact brilliant green. Contact Dermatitis 14:186-187
hypersensitivities. Trans St Johns Hosp Dermatol Soc 48:40 Shumes E (1984) Allergie dermatitis to benzyl alcohol in a
Martin Scott I (1960) Contact dermatitis from alcohol. J Dermatol injectable solution. Arch Dermatol 120:1200
72:372 Singgih SI, Lantinga H, Nater JP, Woest TE, Kruyt-Gaspersz JA
Menz J, Muller SA, Connolly SM (1982) Photopatch testing: a six- (1986) Occupational hand dermatoses in hospital cleaning
year experience. J Am Acad DermatoI18:1044-1047 personnel. Contact Dermatitis 14:14-19
Merk H, Ebert L, Goerz G (1982) Allergie contact dermatitis due Steinkjer B, Braathen LR (1988) Contact dermatitis [rom triclosan
to the fungieide hexetidine. Contact Dermatitis 8:216 (Irgasan DP300). Contact Dermatitis 18:243-244
Meynadier JM, Meynadier J, Colmas A, et al. (1982) Allergie aux Taran JM, Delaney TA (1997) Contact allergy to chloroacetamide.
conservateur. Ann Derm VenereOll09:1017-1027 Australas J Dermatol 38:95-96
Tilseley DA, Wilkinson DS (1965) Necrosis and dequalinium II: Viljanto J (1980) Disinfection of surgical wounds inhibitive of
vulval and extragenital ulceration. Trans St John's Hosp normal wound healing. Arch Surg 115:253
Dermatol Soc 51:49 Von Weis JF, Lever WF (1964) Percutaneous salicylic acid
Tomb RR (1991) Allergic contact dermatitis from eosin. Contact intoxication in psoriasis. Arch Dermatol 90:614
Dermatitis 24:27-29 Wahlberg JE (1962) Two cases of hypersensitivity to quaternary
Torresani C, Caprari E, Manar GC (1993) Contact urticaria ammonium compounds. Acta Derm Venereol 42:239
syndrome due to phenylmercuric acetate. Contact Dermatitis White IR (1995) Phototoxic and Photoallergic reactions. In:
29:282-283 Rycroft RJG, Menne T, Frosch PJ (eds) Textbook of contact
Tupker RA, Schuur J, Coenraads PJ (1997) Irritancy of antiseptics dermatitis. Springer, Berlin Heidelberg New York, p 84
tested by repeated open exposures on the human skin, Whitehead PN (1988) Dermatitis from crystal violet. Contact
evaluated by non-invasive methods. Contact Dermatitis Dermatitis 19:141-142
37:213-217 Wissenschaftlicher Berat der Bundes@rztekammer (1980) Zur
van Ketel WG (1980) Sensitization to mercury from mercuro- anwendung von polyvinylpyrrolidon-jod-komplexen (polyvi-
chrome. Contact Dermatitis 6:499 donjod: pvp-jod). Deutsch Arztebi: 82:1434
Verecken P, Birringer C, Knitelius AC, Herbaut D, Germaux MA Wright NC (1926) The action of hypochlorates on amino-acids
(1998) Sensitization to benzyl alcohol: a possible cause of and proteins. Biochem J 20:524
"corticosteroid allergy". Contact Dermatitis 38:106
Verhaeghe I, Dooms Goossens A (1997) Multiple sources of
allergic contact dermatitis from parabens. Contact Dermatitis
36:269-270
CHAPTER 60
Formaldehyde and Formaldehyde Releasers

M.-A. Flyvholm
Introduction with a corresponding investigation from February 1992

that was based on a total of 62,000 products, 30,900 of
which had available information fully computerised.
Formaldehyde is a commonly occurring chemical sub-
Thus, the number of registered products nearly doubled.
stance and a frequent contact allergen in many countries
Table 1 shows the total number of products regis-
(Flyvholm 1997). Allergic reactions to formaldehyde can
tered for each substance in January 1998 and February
be provoked by exposure to formaldehyde that is added
1992. The number of products registered with the
to chemical products or derived from preservatives that
investigated formaldehyde releasers varied from less
release formaldehyde into the products, i.e. formalde-
than four (the lower exclusion limit) to more than 300.
hyde releasers. Thus, eczema patients with formalde-
Formaldehyde alone was registered in 3308 products.
hyde contact allergy will often benefit from knowledge
The most frequently registered formaldehyde releas-
of exposure to compounds that can release formalde-
ers, registered in more than 100 products, were
hyde (Cronin 1991; Flyvholm and Menne 1992; Kang
bromonitropropanediol, N-methylolchloracetamide,
et al. 1995). Furthermore, some formaldehyde releasers
N-methylolethanolamine, trihydroxyethylhexahydro
can act as sensitisers themselves.
s-triazine, imidazolidinyl urea and dimethylol urea.
This chapter presents an investigation into the
Only three of these substances were among the
occurrence of formaldehyde and formaldehyde releas-
most frequently registered in 1992, i.e. bromonitro-
ers in chemical products registered in the Danish
propanediol, N-methylolchloracetamide and trihy-
Product Register Database (PROBAS). For a further
droxyethylhexahydro s-triazine. The most marked
description of the database and the use of PROBAS, see
increases were seen for imidazolidinyl urea and
Chap. 58 and Flyvholm et al. (1992).
N-methylolchloracetamide, which were both registered
more than 10 times as frequently in 1998 as in 1992.
Four of the 22 identified formaldehyde releasers
Identification of Formaldehyde Releasers were not registered in PROBAS and one was registered
in only a few products, with no changes observed from
In an earlier study, we identified preservatives reported 1992 until 1998. These substances seem to be less
to release formaldehyde. The systematic chemical relevant to chemical products covered by PROBAS.
name and synonyms, structural formula and references
to the formaldehyde-releasing ability were given for
Occurrence of Formaldehyde Releasers
each substance (Flyvholm and Andersen 1993). All
in Registered Chemical Products
studied formaldehyde releasers were identified by
means of their CAS RN (Chemical Abstract Service
Registry Number) (Table 1). The investigation is based Data on the registration of formaldehyde and formal-
on the general registration in PROBAS and includes all dehyde releasers are divided into product categories
products registered with content of formaldehyde or and shown in Table 2. Product categories registered
formaldehyde-releasing preservatives either directly as with fewer than four products for each substance are
a component or as part of raw materials. Products that not shown in the table to maintain confidentiality.
were obsolete or no longer marketed were excluded (if Only product categories with formaldehyde releasers
the Product Register had received this information). are included.
The total number of products registered in PROBAS, The number of products registered for categories
January 1998, was 105,000; available information was such as cosmetics, soap and other skin-care products
fully computerised for 82,900 of these. The number of and shampoo and other hair care products increased
products registered for each substance was compared more than the total product registration from 1992 to

Formaldehyde and Formaldehyde Releasers 475
Table 1. Formaldehyde and formaldehyde-releasing preservatives registered in the Danish Product Register Database (PROBAS)
January 1998 and February 1992 identified with CAS RN, systematic chemical names and synonyms
CAS RN Systematic chemical Synonyms Number of products registered in PROBAS

names
Feb. 1992 Jan. 1998
30,900 82,900
14548-60-8 (Phenylmethoxy)methanol Benzylhemiformal, *benzyl- 10 19

oxymethanol, phenyl-
methoxymethanol,
Preventol D2
7747-35-5 7a-Ethyldihydro-lH,3H,5H- Bioban CS-1246, *ethyl- 10 31
oxazolo [3,4-c] oxazole dihydrooxazolo [3,4-c]-
oxazole, 5-ethyl-l-aza-
3,7 -dioxa-bicydo-
[3.3.0]octane
37304-88-4 mixture Mixture of: 4-(2-nitrobutyl)- Bioban P-1487, *Mixture 15 and 6 19 and 16
of: 2224-44-4 and morpholine, and 4,4'-(2- of: nitrobutylmorpholine
1854-23-5 ethyl-2-nitro-l,3-pro- and ethylnitrotri-
panediyl)bismorpholine methylenedimorpholine
30007-47-7 5-Bromo-5-nitro-l ,3-dioxane *Bromonitrodioxane, 97 165
Bronidox
52-51-7 2-Bromo-2-nitro-l ,3- *Bromonitropropanediol, 171 309
propanediol Bronopol
4080-31-3 N-(3-chloroallyl) hexa- *Chloroallylhexaminium 42 53
methylenetetraminium - chloride, 3-chloroallyl
chloride, hexaminium chloride,
(51229-78-8) (the cis-isomer Dowicil 75, Dowicil 200,
of this substance) Quaternium 15
78491-02-8 N-(1,3-bis(hydroxymethyl)- Diazolidinyl urea, *tetra- 4 10
2,5-dioxo-4-imidiazoli- methylol hydantoin urea,
dinyl)-N,N' -bis(hydroxy- Germaben II, Germall II
methyl)urea
109-87-5 *Dimethoxymethane Formal, methylal 8 34
9065-13-8 Formaldehyde, polymer *Dimethylhydantoin
with dimethyl-2,4-imida- formaldehyde resin,
zolidinedione DMHF
140-95-4 N,N' -bis(hydroxymethyl)- *Dimethylol urea, 17 103
urea dihydroxymethylurea,
dimethylurea, urea
formaldehyde
6440-58-0 1,3-Bis(hydroxymethyl)- DMDM hydantoin, 12 22
5,5-dimethyl-2,4-imida- *dimethyloldimethylhy-
zolidinedione dantoin, 1,3-dimethylol-
5,5-dimethylhydantoin,
DMDMH, Glydant
91925-30-3 mixture Mixture of: 1,3,5-triethyl- Forcide 78, *Mixture of: 4 and 54 <4 and 213
of: 7779-27-3 and hexahydro-l ,3,5-triazine triethylhexahydro
4719-04-4 and 1,3,5-triazine- s-triazine and trihydroxy-
1,3,5(2H,4H,6H)- ethylhexahydro
triethanol s-triazine,
(4719-04-4 see below)
50-00-0 *Formaldehyde Formalin, methanal 1781 3308
100-97-0 1,3,5,7-Tetraazatri- *Hexamethylenetetramine, 29 50
cydo(3.3.l.l 3 . 7 )decane hexamine, methenamine,
Urotropine
461-72-3 2,4-lmidazolidinedione *Hydantoin, glycolylurea
39236-46-9 N,N" -Methylenebis(N'-(3- Imidazolidinyl urea, 14 187
(hydroxymethyl)-2,5- *bis(methylolhydantoin
dioxo-4-imidazolidinyl)urea) urea) methane, Euxyl
K 200, Germall 115
27636-82-4 Hydroxymethyl-5,5-di- *MDM hydantoin, mono-
methyl-2,4-imidazo- methyloldimethylhy-
lidinedione Dantoin, Dantoin 685,
MDMH
476 M.-A. Flyvholm
Table 1. (Contd.)
116-25-6 I-Hydroxymethyl-5,5-
dimethyl-2,4-imidazo-
lidinedione
16228-00-5 3-Hydroxymethyl-5,5-
dimethyl-2,4-imidazo-
lidinedione
66204-44-2 3,3'-Methylenebis- *N,N -Methylenebis(5- <4 5
(5-methyloxazolidine) methyloxazolidine),
Grotan OX
2832-19-1 2-Chloro-N-(hydroxymethyl)- *N-methylokhloracetamide, 21 226
acetamide Grotan HD, Parmetol K50,
Preventol D3, Preventol D5
34375-28-5 2-(Hydroxymethylamino)- *N-methylolethanolamine 110 225
ethanol
30525-89-4 *Paraformaldehyde Polyoxymethylene 25 74
4719-04-4 1,3,5-Triazine-l,3,5(2H,4H,6H)- *Trihydroxyethylhexahydro 54 213
triethanol s-triazine, Grotan BK, KM 200
126-11-4 2-(Hydroxymethyl)-2-nitro- *Tris(hydroxymethyl- 6 20
1,3-propanediol nitromethane,
trimethylolnitromethane
Names written in boldface are the most commonly used names. Names marked with an asterisk are preferred short-names. Adapted
from Flyvholm and Andersen (1993)
1998. This was probably a consequence of the new expected to occur in both in occupational products
European Union (EU) rules for cosmetic products. For and cosmetics (and personal care products).
single substances, the most marked increases were Among the investigated formaldehyde releasers,
seen for paints/lacquers (N-methylolchloracetamide, only imidazolidinyl urea was registered in cosmetics.
dimethylol urea and bromonitropropanediol) and for According to an earlier registration of cosmetics, i.e.
cosmetics (imidazolidinyl urea). the voluntary registration of cosmetics administered
by the U.S. Food and Drug Administration (FDA),
several formaldehyde releasers were registered in
Cleaning Agents
cosmetics, but imidazolidinyl urea was by far the most
frequent (Decker and Wenninger 1987).
Formaldehyde was registered in cleaning agents more
frequently than formaldehyde releasers were. Bromo-
nitropropanediol was the most frequently registered Hardeners
formaldehyde releaser, followed by bromonitrodioxane
and trihydroxyethylliexahydro s-triazine. More than Among the allergens included in this investigation,
half of the formaldehyde releasers were registered in only formaldehyde and paraformaldehyde were regis-
cleaning agents, but most of them occurred in tered in hardeners.
relatively few products.
Metal Working and Cutting Fluids
Colouring Agents
The formaldehyde releaser trihydroxyethylhexahydro
Formaldehyde was frequently registered in colouring s-triazine was the most frequently registered in metal
agents and the three formaldehyde releasers found working and cutting fluids, followed by formaldehyde
were registered in only a few products. and three other formaldehyde releasers.
Cosmetics Paints/Lacquers
Registration of cosmetics was recently included in Formaldehyde was frequently registered in paints/
PROBAS as a consequence of the new EU rules for lacquers. Several formaldehyde releasers were regis-
cosmetic products. The registration of cosmetics in tered in paints/lacquers, i.e. N-methylolethanolamine,
PROBAS is not complete at the present time, but there N-methylolchloracetamide, bromonitropropanediol
are some trends that indicate which allergens can be and dimethylol urea. Two of these formaldehyde
Table 2. Products registered with formaldehyde and formaldehyde releasers divided into product categories. Based on 82,900 products registered in the Danish Product Register Database
(PROBAS) with information on product composition January 1998. Products can be registered in more than one product category and products can contain more than one of the substances.
Data on product categories with fewer than four products for each substance are not shown
Product Cleaning Colouring Cosmetics Hardeners Metal Paintsl Polishes Shampoo Soap and Surface- Total
categories agents agents for paintsl working lacquers and other other skin active products
(industrial lacquers and hair care care agents for
and etc cutting products products substances
household) fluids
Total products 7916 3787 l393 3473 724 6512 839 2255 2775 3166 Total
for categories
CAS RN Substances
14548-60-8 Benzylhemiformal 5 5 19
7747-35-5 Bioban CS-1246 15 31
2224-44-4 Nitrobutylmorfoline 9 19
(part of Bioban
P-1487)
1854-23-5 Ethylnitrotri- 7 16
methylene
dimorpholine
(part of Bioban
P-1487)
30007-47-7 Bromonitrodioxane 32 l3 75 48 165
52-51-7 Bromonitro- 84 61 l3 30 34 14 309
propanediol
4080-31-3 Chloroallylhexa- 6 4 4 5 18 53
minium chloride -n
0
78491-02-8 Diazolidinyl urea 5 10 3
Q>
109-87-5 Dimethoxymethane 15 4 34 c::

<D
;;;-
140-95-4 Dimethylol urea 17 48 7 103 '<
0..
<D
6440-58-0 DMDM hydantoin 6 13 22 Q>
0..
'"
50-00-0 Formaldehyde 220 204 104 15 1006 38 44 33 90 3308 -n
0
100-97-0 Hexamethylen- 9 50
tetramine
3
Q>
c::
<D
39236-46-9 Imidazolidinyl urea 118 23 40 187 ;;;-
'<
226 0..
2832-19-1 N-Methylolchlor- 12 4 76 10 <D
acetamide :rJ
<D
34375-28-5 N-Methylolethanol- 191 5 8 225 iD
Q>
V>
amine <D
V1
30525-89-4 Paraformaldehyde 11 14 74
4719-04-4 Trihydroxyethyl- 26 10 44 213
hexahydro
s-triazine I~
478 M.-A. Flyvholm: Formaldehyde and Formaldehyde Releasers
releasers (N-methylolchloracetamide and dimethylol Surface Active Agents

urea) were new to paints/lacquers in the 1998 regis-
tration. Thus, the increased use of water-based paints/ Formaldehyde was frequently registered in surface
lacquers for occupational use were reftected in the active agents. Only three formaldehyde releasers were
increased number of registrations and in the registra- registered in surface active agents, i.e. bromonitropro-
tion of new formaldehyde releasers. panediol, N-methylolchloracetamide and N-methylol-
ethanolamine.
Polishes
Formaldehyde and several formaldehyde releasers References

were registered in polishes, but all in a moderate
number of products. Cronin E (1991) Formaldehyde is a significant allergen in women
with hand eczema. Contact Dermatitis 25:276-282
Shampoo and Other Hair (are Products Decker RL, Wenninger JA (1987) Frequency ofpreservative use in
cosmetic formulas as disclosed to FDA - 1987. Cosmetic
Toiletries 102:21-24
The most frequently registered formaldehyde releaser Flyvholm M-A (1997) Formaldehyde exposure at the workplace
in shampoo and other hair care products was bromo- and in the environment. Allergologie 5:225-231
Flyvholm M-A, Andersen P (1993) ldentification of formaldehyde
nitrodioxane followed by bromonitropropanediol and releasers and occurrence of formaldehyde and formaldehyde
imidazolidinyl urea. Formaldehyde was registered in a releasers in registered chemieal products. Am J lnd Med
moderate number of products. 24:533-552
Flyvholm M-A, Menne T (1992) Allergie contact dermatitis from
formaldehyde. A case study focusing on sources of formal-
Soap and Other Skin (are Products dehyde exposure. Contact Dermatitis 27:27-36
Flyvholm M-A, Andersen P, Beck ID, Brandorff NP (1992)
PROBAS: the Danish product register data base - anational
Bromonitrodioxane, imidazolidinyl urea and bromo- register of chemieal substances and products. J Hazardous
nitropropanediol were the most frequently registered Materials 30:59-69
formaldehyde releasers in soap and other skin care Kang KM, Corey G, Storrs FJ (1995) Follow-up study of patients
allergic to formaldehyde and formaldehyde releasers: reten-
products. Formaldehyde was registered in a moderate tion of information, compliance, course, and persistence of
number of products. allergy. Am J Contact Dermat 6:209-215
CHAPTER 61
Pharmaceutical Drug Allergens

A.J. Bircher
Introduction involves direct or airborne contact with the skin or the

mucosal surfaces or takes place by inhalation or,
rarely, b~ in~estion. Typical situations involving dust
With few exceptions, such as peptides and hormones,
or nebuhzatlOn exposure occur during the manufac-
drugs and their precursors are typically low-molecular-
turing of hand-compounded medications by pharma-
weight compounds and, therefore, haptens. To build a
cists, during the preparation of animal feed in farmers
complete antigen, they must bind to macromolecules
or in nurses crushing tablets or preparing lyophilized
e.g. human tissue or serum proteins. Some drugs are
drugs for injection. Some health professionals, such as
primarily reactive while, in others, reactive metabolites
dentists, physiotherapists or masseurs, may directly
are only generated in vivo. Oral administration is
apply .the. drug to the patient by hand, thus facilitating
usually better tolerated and may even induce tolerance.
sensltlzatlOn by repeated skin contact. Sometimes, a
However, intermittent exposure by epi- or intradermal
member of such an occupation needs pharmacother-
application or by inhalation, as it typically occurs in
apy hirnself and suffers from an adverse drug reaction,
occupational settings, carries the highest risk of
e.g. to carbamazepine, which, however, is not neces-
sensitization (Bircher 1996).
sarily linked to his occupation (Altomare et al. 1992);
Occupational allergic reactions to drugs occur
he or she mayaiso be exposed by connubial contact
mainly in two exposed groups. The first group involves
(Newton and White 1987).
employees of pharmaceutical and chemical companies
Typical clinical patterns include allergic and irritant
occupied in the production of drugs; the second group
contact dermatitis, airborne dermatoses, photoinduced
conslsts of professionals using the final drugs in a
reactions (Bjorkner 1994), immunologic and non-
therapeutic setting. The former includes chemists and
immunologic contact urticaria, rhinoconjunctivitis,
laboratory technicians involved in the development of
asthma and, rarely, anaphylaxis (Bause and Kugelman
new agents, workers exposed during the manufactur-
1990) or severe skin dis orders, such as toxic epidermal
ing and synthetization processes, technicians or clean-
necrolysis (Valsecchi et al. 1987). Irritant agents are
ing staff employed in the maintenance of equipment
numerous, and may cause symptoms on the skin or the
and employees involved in handling and packing the
mucos.al surfaces (Testud et al. 1994). Examples are
final products. This group may be exposed - directly
potassmm salts, chloroquine phosphate, ethylene oxide
or by airborne contact - to precursor substances,
and, particularly, the cytostatic drugs. Usually, these
highly reactive intermediates and the final drugs, as
sub.stances are known to the exposed workers, and
weIl as to other agents used in the synthesis, such as
aCCldental contact causes rapidly irritant or toxic skin
accelerators, catalysts, enzymes etc., which mayaiso
damage. The causal relationship is easily recognized,
act as allergens (Altomare et al. 1992; Sherertz 1994).
and an extensive diagnostic work-up is often not
The second group encompasses health-care workers,
~ecessa:r; therefore, such cases may be under-reported
such as nurses, physiotherapists, physicians, dentists,
m the hterature. However, patients with sensitization
pharmacists, masseurs, herbai therapists, veterinari-
to a particular compound are often published as single
ans, animal care takers and farmers preparing or
case reports.
applying medicaments for animals. These particular
As a practical consequence, an allergic individual
occupations are discussed in depth in the respective
mus.t meticulously avoid contact with the allergen
chapters.
or, m a more severe case, change the workplace or
Apart from drugs for topical use, where contact is
even his profession. In cases of drug allergens, a
possible during treatment of a patient, exposure to
~ur~~r problem may arise. Occupationally sensitized
systemically applied agents, e.g. powdered substances
mdlVlduals. may encounter their allergen in drug
from vials, may happen by negligence or accident and
therapy (Blrcher 1996). Topical treatment with the

480 A.J. Bircher
allergen or cross-reacting substances, e.g. the "-caine Contact Allergens

group", may elicit contact dermatitis. Systemic
exposure to an allergen (antibiotics) to which the
Additives
patient has been sensitized by epidermal contact
may result in a flare-up in formerly affected sites; it
Some examples of common additives are given which
mayaiso result in systemic (hematogenous) contact
may be used as drugs themselves (such as benzoyl
dermatitis or the so-called Baboon syndrome (Menne
peroxide for acne), in the synthesis of drugs (dicyclo-
et al. 1989). Therefore, the exact identification of a
hexyl carbodiimide) or as antioxidants in final
presumed occupational allergy and the offending
products. Ethylene diamine is present in topical
allergens has implications beyond the scope of
drugs and in aminophylline and is the allergen in
occupational safety. In this chapter, an overview
the latter compound. Several cases of occupational
on drugs reported as occupational allergens is given
contact dermatitis have been reported (Corazza et al.
(Tables 1, 2).
1994).
Analgesics and Nonsteroidal Anti-Inflammatory Drugs

Immediate-Type Reactions
With the exception of photoallergy, nonsteroidal anti-
These types of reaction include rhinoconjunctivitis, inflammatory drugs rarely induce immunologically
asthma, contact urticaria and, rarely, anaphylaxis media ted adverse reactions; more commonly, a
(Belsito 1993). In some patients, urticaria and later pseudoallergic pathogenesis is involved, reflected by
eczema may be present, in analogy to protein contact non-immunologic urticaria, asthma or anaphylactoid
dermatitis (Keller and Schwanitz 1992); patients may reactions. Nurses have been reported who have devel-
also have concomitant skin and respiratory symptoms oped contact dermatitis and, in one case, an airborne
(Stejskal et al. 1986; Moscato et al. 1995). Pharmaceu- contact dermatitis (Mathelier-Fusade et al. 1997) to
tical workers and farmers exposed to airborne dust, propacetamol (Barbaud et al. 1995), an injectable
nurses and veterinarians crushing tab lets or preparing prodrug which is rapidly hydrolyzed (by esterases) to
vials for injection, farmers exposed to animal feed and paracetamol and diethylglycine. Paracetamol and die-
individuals exposed to the dust of medicines derived thylglycine were patch-test negative, and oral admin-
from plants are typically affected. Common allergens istration was tolerated (Szczurko et al. 1996), indicating
include particularly penicillins and cephalosporins. that only the complete paracetamol-diethylglycine
Chloramine T is known to induce immunoglobulin E compound is allergenic.
(IgE) antibodies. A list of selected allergens having However, a patient sensitized to another prodrug,
elicited urticaria or anaphylaxis by contact, with or pyrazinobutazone, a piperazine salt of phenylbutazone,
without respiratory symptoms, are shown in Table 1. reacted with a flare-up to oral provocation (Dorado
In such patients, suspected allergens should be first Bris et al. 1992). Benzydamine, a topical and systemic
tested in high dilutions on intact skin and only later by nonsteroidal anti-inflammatory drug has caused two
prick and, if necessary, intracutaneous tests. The cases of occupational sensitization (Foti et al. 1992).
patients should be carefully monitored during these An unusual case of a multilocular fixed drug eruption
diagnostic procedures, since severe anaphylactic reac- upon inhalation of pyrazolones with positive oral
tions may be elicited by skin tests alone (Bause and provocation has also been described (Vanuytrecht-
Kugelman 1990; Tadokoro et al 1994). Henderickx et al. 1986).
Table 1. Selected drug

allergens eliciting im- Allergen Symptom Reference
mediate-type skin symp-
toms on contact Benzalkonium chloride Urticaria, asthma Bernstein et al. 1994
Cefotiam Anaphylaxis Miyahara et al. 1993; Tadokoro et al. 1994
Chloramine T Urticaria Dooms-Goossens et al. 1983; Kanerva et al.
1997
Cisplatin Urticaria Schena et al. 1996
Labetalol Anaphylaxis Bause and Kugelman 1990
Levomepromazine Urticaria Johansson 1988
Mezlocillin Urticaria Keller and Schwanitz 1992
Penicillin Urticaria Rudzki and Rebandel 1985; Stejskal et al.
1986
Pentamidine isethionate Urticaria Belsito 1993
Piperacillin sodium Urticaria, asthma Moscato et al. 1995
Pharmaceutical Drug Allergens 481
Table 2. Drug allergens eliciting contact dermatitis
Allergen Reference
Additives
Benzoyl peroxide Quirce et al. 1993
Ethoxyquin (CAS 91-53-2), 0.5% pet Savini et al. 1989; Mancuso et al. 1990
Ethylene diamine Rudzki et al. 1989b; Rudzki 1990; Corazza et al. 1994
Dicyclohexyl carbodiimide (CAS 538-75-0), 0.1 % acet Davies 1983; Poesen et al. 1995
Tosyl chloride, 1% eth (3 controls neg) Watsky et al. 1993
Analgesics and nonsteroidal anti-inflammatory drugs
Benzydamine hydrochloride (CAS l32-69-4), 0.5% aq Foti et al. 1992; Rademaker 1994
(15 controls neg)
Piroxicam, 1% pet (5 controls neg) Arevalo et al. 1995
Propacetamol, 50% aq (10 controls neg) Szczurko et al. 1996; Mathelier-Fusade et al. 1997
Pyrazinobutazone, 5% pet Dorado Bris et al. 1992
Pyrazolone Vanuytrecht-Henderickx et al. 1986
Anesthetics
Pantocaine Rudzki 1990
Procaine Rudzki et al. 1989a, 1989b
Propanidid Castelain and Piriou 1980
Tetracaine (amethocaine) Conde-Salazar et al. 1988, 1989; Rudzki et al. 1989a; Rudzki 1990
Antiacids
Famotidine Monteseirin and Conde 1990
Omeprazole, 0.25% pet Meding 1986; Altomare et al. 1992
Ranitidine, 1% pet (25 controls neg) Alomar et al. 1987; Romaguera et al. 1988, 1990
Antiasthmatic drugs
Aminophylline Tas and Weissberg 1958; Rudzki et al. 1989a; Rudzki 1990
Metaproterenol, 2.5% aq (50 controls neg) Fung et al. 1996
Antibiotics and tuberculostatics
Aminopenicillins Moller et al. 1986, 1990; Stejskal et al. 1986; Moller and
Jeppesen 1987; Rudzki et al. 1989b; Rudzki and Rebandel 1991;
Moller and Von Wiirden 1992; Gamboa et al. 1995
Cefradine Rudzki et al. 1989b
Ceftiofur, 1% aq Garcia-Bravo et al. 1995
Cephalosporins Conde-Salazar et al. 1986; Foti et al. 1994, 1997; Filipe et al. 1996
Chloramphenicol Schwank and Jirdsek 1963; Rudzki et al. 1989b; Rudzki 1990
Colistin Rudzki et al. 1989b
Doxycyline Rudzki et al. 1989b
Ethambutol Holdiness 1986a
Gentamycin Altomare et al. 1992
Isoniazid Holdiness 1986b; Rudzki et al. 1989a
Kitasamycin (leucomycin) Dooms-Goossens et al. 1990
Mezlocillin Keller and Schwanitz 1992
Midecamycin Dooms-Goossens et al. 1990
Oxytetracycline Rudzki 1990
Penicillin Stejskal et al. 1986; Rudzki et al. 1989a, 1989b; Pecegueirio 1990
Streptomycin Holdiness 1986b; Rudzki et al. 1989b; Altomare et al. 1992
Sulfathiazol Rudzki et al. 1989a; Rudzki 1990
Tetracyclines Rudzki et al. 1989a, 1989b
Vibramycin Rudzki 1990
Anti-infectious agents
Albendazol, 5% pet (l3 controls neg) Macedo et al. 1991
Chloramine T (CAS 127-65-1) 0.05% pet Lombardi et al. 1989
Chloroquine Kellett and Beck 1984
Fentichlora Norris et al. 1989
Foscarnet Testud et al. 1994
Griseofulvin Testud et al. 1994
N-benzyl-N,N-dihydroxyethyl-N-cocosalkyl-ammonium Placucci et al. 1996
chloride, 0.01 % aq (20 controls neg)
Piperazine Calnan 1975; Rudzki and Grzywa 1977; Rudzki et al. 1989b
Quinine a Hardie et al. 1978
Quinidine a Wahlberg and Boman 1981
Cardiovascular and vasoactive drugs
Alprenolol Ekenvall and Forsbeck 1978; Stejskal et al. 1986
Captopril, 10% pet (9 controls neg) Dziuk et al. 1994
Carbocromen Huriez and Martin 1974; Rudzki et al. 1989b
Homatropine Marcos et al. 1997
Nicergoline (CAS 27848-84-6), 7% eth (10 controls neg) Fumagalli et al. 1992
Oxprenolol Rebandel and Rudzki 1990
Phenoxybenzamine hydrochloride (x-adrenergic drug) Mitchell and Maibach 1975
Phenylephrine Marcos et al. 1997
Propanolol Rebandel and Rudzki 1990; Rudzki 1990
482 A.J. Bircher
Table 2. (Contd.)
Allergen Reference
Quinidine sulfate a Wahlberg and Boman 1981; Stejskal et al. 1986

Spironolactone, 1% eth Klijn 1984
Central nervous system drugs
Apomorphine, 0.01 % aq Dahlquist 1977
Chlorpromazinea Foussereau and Benezra 1982; Rudzki 1990; Bjorkner 1994
Chlorprothixen Schwenck et al. 1994
Codeine, 1% eth Romaguera and Grimalt 1983; Conde-Salazar et al. 1991;
Waclawski and Aldridge 1995
Cyanamide (CAS 420-04-2), 1% aq (30 controls neg) Goday Bujdn et al. 1994
Meclofenoxate Foussereau and Benezra 1982
Morphine, 1% eth Conde-Salazar et al. 1991
Oxolamine (CAS 959-14-8), 0.1 % aq (20 controls neg) Conde-Salazar et al. 1989
Perazine Rudzki et al. 1989a
Pyritinol, 2% aq (10 controls neg) Dooms-Goossens et al. 1986b; Wigger-Alberti and Elsner 1997
Tetrazepam, 1% pet (15 controls neg) Ortiz-Frutos and Alonso 1995
Thebaine, 5% eth Waclawski and Aldridge 1995
Herbai drugs and plant derivatives
Arnica Hausen 1980
Essential oils Selvaag et al. 1995; Cockayne and Gawkrodger 1997
Eugenol Rudzki et al. 1989a; Kanerva et al. 1994
Lavender Rademaker 1994
Pyrethrum Schmidt 1986
Vincamine tartrate, 1% aq (5 controls neg) Van Hecke 1981
Immunomodulating drugs
Azathioprine, 0.1% pet (5 controls neg) Burden and Beck 1992; Soni and Sherertz 1996
Dinitrochlorobenzene Garcia-Perez 1978; Lubbe 1993
Dinitrofluorobenzene Garcia -Perez 1978
Diphencyprone Sansom et al. 1995
Squaric acid dibutyl ester Noster et al. 1976; Frattasio et al. 1997
Intermediate and precursor products
2,6- Dichloropurine Rycroft 1981
Allopurinol (ethyl ethoxyrnethylene cyanoacetate), 0.01 % pet Hsu et al. 1992
Azathioprine (5-chloro-I-methyl-4-nitroimidazole), 0.01 % pet Jolanki et al. 1997
Bumetanide (sulfonyl benzoic acids), 1% pet Moller and Kromann 1989
Chlorodiazepoxide (2-chloromethyl-4-phenyl-6- Rebandel and Rudzki 1986a, 1986b
chlorquinazoline-3-oxide), 1% pet (44 controls neg)
Chloroquine (4,7-dichloroquinoline), 5% pet Pickering and Ive 1982
Clenbuterol (4-amino-(x -bromo-3,5-dichloroacetophenone), Romaguera et al. 1990
0.5% pet
Cytosine arabinoside (quarternary cis salt), 0.5% aq Conde-Salazar et al. 1984
(20 controls neg)
Diethyl-p-chloroethylamine Deschamps et al. 1988
Dichlorobenzoyl chloride De Boer and Van Joost 1988
Famotidine (uranium, FPI), 1% aq Guimaraens et al. 1994
H2 antagonist (2-( 4(5)-methyl-5( 4)-imidazolyl-methyl-thio)- Camarasa and Alomar 1980
Cl3), 0.1 % aq (20 controls neg)
Histamine antagonist (heterocyclic chloromethyl compounds), Sonnex and Rycroft 1986
I % pet (20 controls neg)
Methotrexate (2,4-di-amino-6-6-chloromethylpteridine), Lah ti et al. 1990
0.1 % pet (10 controls neg)
Nitrosourea (3-taurinyl-I-(2-chloroethyl)-I-nitrosourea, Niklasson et al. 1990
carbamates), 0.001 aq
Oxprenolol (epichlorhydrin) Rebandel and Rudzki 1990
Procaine (p-nitrobenzoyl chloride) Foussereau 1989
Propanolol (epichlorhydrin) Rebandel and Rudzki 1990
Pyridoxine (2-methyl-3-nitro-4-methoxyrnethyl-5-cyano-6- Wigger-Alberti and Elsner 1997
chloropyridine), 2% aq (10 controls neg)
Radiocontrast medium (3,4-dicarbethoxyhexane-2,5-dione) Niklasson and Bjorkner 1990
Ranitidine (cistoran) Valsecchi et al. 1989
Cistofur Romaguera et al. 1990
2- [( ([ I-Dimethylaminomethyl)]
furan-5-lmethyl)thio] ß amino ethane
I-(Methylamine )-l-(methylthio)-2-nitroethylene Romaguera et al. 1990
5-1-(2-Aminoethyl)-thiomethyl-N,N-dimethyl-2- Rycroft 1983; Goh and Ng 1984
furanmethanamine
Tetramisol (3'd intermediate) Valsecchi et al. 1987
Virustatic 6-aza-uracil (3,4,6-trichloropyridazine) Dooms-Goossens et al. 1986a
Veterinary drugs
Avoparcin, 1% aq (50 controls neg) Barriga et al. 1991
Bacitracin Mancuso et al. 1990
Furaltadone Vilaplana et al. 1990
Furazolidone De Groot and Conemans 1990
Table 2. (Contd.)
Lincomycin Vilaplana et al. 1991

Methylchlorpindol Mancuso et al. 1990
Monensin (CAS 17090-79-8) Mancuso et al. 1990
Morantel tartrate (CAS 26155-31-7), 1% (10 controls neg) Newton and White 1987
Neomycin Mancuso et al. 1990
Nitrofurazone Ancona 1985; Lo et al. 1990
Olaquindox' Francalanci et al. 1986; Schauder et al. 1996
Oxytetracycline Guerra et al. 1991
Penethamate Hjorth and Weisman 1973
Penicillin Hjorth and Weisman 1973; Guerra et al. 1991
Phenothiazines Schauder et al. 1996
Spectinomycin Vilaplana et al. 1991; Dal Monte et al. 1994
Spiramycin Veien et al. 1980; Guerra et al. 1991
Streptomycin Gauchia et al. 1996
Thiabendazole Mancuso et al. 1990
Tylosin Veien at al. 1980; Barberd and De la Cuadra 1989; Guerra et al.
1991; Caraffini et al. 1994; Tuomi and Rasanen 1995
Virginiamycin Tennstedt et al. 1978
Vitamins
Cyanocobalamine (vitamin B'2) Rudzki et al. 1989b; Rodriguez et al. 1994
Menadione sodium bisulfite (vitamin K3 ) Romaguera et al. 1980; Camarasa and Barnadas 1982;
Dinis et al. 1988
Retinyl acetate (vitamin A acetate) Heidenheim and Jemec 1995
Thiamine (vitamin B,) Ingemann-Larsen et al. 1989
Miscellaneous
Carbimazole' (CAS 22232-54-8), 10% pet Goh and Ng 1985
Disulfiram (CAS 97-77-8) Rudzki et al. 1989b; Mathelier-Fusade and Leynadier 1994
Ethylene oxide (CAS 75-21-8) Haddar et al. 1993; Lerman et al. 1995
Meglumine diatrizoate (CAS 131-49-7) Verschaeve et al. 1984
Mesna (CAS 19767-45-4), 1% aq Benyoussef et al. 1996
Minoxidil, 2% aq Veraldi et al. 1992
Mitomycine C Fisher 1991
Thiomersal De Groot et al. 1990
Tubocurarine Rudzki 1990
acet, acetone; aq, aqueous; eth, ethanol; neg, negative; pet, petrolatum
• Photosensitivity
Anesthetics H2 antagonists (famotidine, ranitidine) have been

described. Typically, the patients are not only sensi-
Occupational problems with topically applied local tized to the final products but also to intermediate
anesthetics, particularly ester derivatives, have been products from the synthesis process (see the section
known for many years (Altomare et al. 1992). Contact entitled "Intermediates").
allergy to procaine used to be a typical professional
disease of dentists due to direct handling (Kanerva et al. Anti-Asthmatic Drugs
1994). Other affected professions include ophthalmol-
ogists and veterinary surgeons. There is an extensive Compared to the widespread and long-term use of
cross-reactivity between all p-amino benzoic acid ß-mimetic drugs, typically by nebulization, the few
derivatives, such as procaine, benzocaine and tetra- reports involving anti-asthmatic drugs indicate that
caine, but not to amide derivatives, such as lidocaine. they are weak allergens (Fung et al. 1996). Aminophyl-
Since the less allergenic amide local anesthetics are used line is of importance, since it consists of ethylene
today, the number of occupational cases has declined. diamine and theophylline; therefore, positive patch
The intravenous anesthetic propanidid, a derivative of tests to ethylendiamine are present in patients sensi-
eugenol (Castelain and Piriou 1980), has caused sensitized to aminophylline (see the section entitled "Ad-
tization in anesthesists by direct and probably also ditives") (Rudzki et al. 1989; Rudzki 1990).
airborne contact (Altomare et al. 1992).
Antibiotics and Tuberculostatics
Antiacids
By far the largest number of affected workers have
Two pharmaceutical employees with contact allergy to symptoms due to antimicrobials for human or animal
the proton-pump inhibitor omeprazole have been use (see the section entitled "Veterinarian Drugs").
reported (Meding 1986). More often, pharmaceutical Among the antibiotics, the natural and the semisyn-
workers with skin problems from the production of the thetic penicillins are the most common drug allergens
484 A.J. Bircher
causing symptoms, particularly in pharmaceutical sulfate, another chemically closely related antimalarial,
workers, followed by cephalosporins and tuberculo- has been observed in a maintenance apprentice in a
static agents in pharmaceutical industry workers and drug-packing firm; cross-reactivity to quinine was not
medical employees. Contact urticaria and anaphylaxis present. Quinidine was not tested (Kellett and Beck
has also been reported (see the section entitled 1984). Also, cases of sensitization to aprecursor of
"Immediate-Type Symptoms"). In the penicillin group, chloroquine (4,7-dichloroquinoline) have been pub-
aminopenicillins have elicited occupational skin prob- lished (Pickering and Ive 1982).
lems; cross-reactivity to natural penicillins (penicillin Chloramine T, which is not identical to chloramine
G and V) was not always present, indicating an (NH 2 CI), is a recognized IgE-antibody-inducing im-
antigenie determinant on the side-chain and not on mediate-type allergen, which causes contact urticaria
the ß-Iactam ring (Rudzki and Rebandel 1991; Moller and asthma (Kanerva et al. 1997). However, allergie
and von Würden 1992; Gamboa et al. 1995). Contact contact dermatitis to chloramine T was identified in a
allergy to cephalosporins has been particularly ob- nurse who was also sensitized to quaternary ammo-
served in nurses. The problem of cross-reactivity is nium compounds and mercury derivatives (Lombardi
more complex, since the antigenie determinants for et al. 1989). Another quaternary ammonium com-
cephalosporins in IgE and T-cell-mediated reactions pound caused contact dermatitis in a dental nurse
are not known. Cases of contact allergy to ceftiofur (Placucci et al. 1996). Other anti-infectious drugs
(Garcfa-Bravo et al. 1995) and several structurally include albendazole (which induced contact urticaria
different cephalosporins have been described. Occu- and dermatitis), fentichlor (eliciting a photo allergie
pational contact allergy to tuberculostatics and tetra- reaction with positive patch and photopatch tests)
cyclines is of minor relevance today; however, in some (Norris et al. 1988), piperazine (another antihelmintic),
countries it was a common problem. foscarnet (an antiviral) and griseofulvin (an antifungal
drug) (Testud et al. 1994).
Anti-infectious Agents
(ardiovascular and Vasoactive Drugs
Common occupational allergens are quinine (an anti-
malarial) and its D-stereoisomer, quinidine (Fig. 1) Antihypertensive drugs, which have elicited occupa-
sulfate salt, used as an anti-arrhythmie drug. Both tional dermatitis in pharmaceutical workers, include
substances have elicited contact allergy without cross- the ß-blocking agents e.g. alprenolol, propanolol and
reactivity between the two compounds (Wahlberg and oxprenolol and their precursors (Rebandei and Rudzki
Boman 1981; Stejskal et al. 1986), indicating stereo se- 1990). Cross-reactivity between alprenolol and met-
lectivity for contact allergy (Isaaksson et al. 1994). oprolol was present (Ekenvall and Forsbeck 1978). In a
However, photocontact allergy cross-reactivity be- patient with contact sensitization to the ()(-blocker
tween the two isomerie substances is present (Ljungg- phenoxybenzamine, cross-reactivity to chemically re-
ren et al. 1992), due to practically identical lated haloalkylamines was demonstrated (Mitchell and
photoproducts after ultraviolet irradiation (Isaaksson Maibach 1975). Contact dermatitis has been observed
et al. 1994). An outbreak of an irritant quinine to nicergoline and spironolactone in pharmaceutical
dermatitis has been observed in a factory (Hardie employees and to carbocromene (a vasodilator) cap-
et al. 1978), whereas allergie reactions to quinine have topril (an angiotensin-converting enzyme inhibitor)
declined in recent years. Contact allergy to chloroquine and the ophtalmologic agents homatropine and phe-
Fig. ,. Chemical structures of quinine and

quinidine. The chiral C atom is indicated
with an arrow (modified from Bircher 1996)
auinine auinidine
(L-isomer) (D-isomer)
nylephrine in nurses. Quinidine sulfate has elicited induced occupational contact allergy (Wigger-Alberti
contact allergy in production workers, patch tests with and Eisner 1997). There have also been cases of
quinine were negative (Wahlberg and Boman 1981) (see occupational contact dermatitis to other centrally
the section entitled "Anti-Infectious Drugs"). active compounds, such as tetrazepam and cyanamide.
Central Nervous System Drugs Herbai Drugs and Plant Derivatives
Among the drugs acting on the central nervous system, Plant derivatives are used as fragrances and as drugs in
the opium alkaloids and the phenothiazine derivatives aromatherapy and phytotherapy. Contact allergy and
have caused most occupation-related cases. Apart from exanthematous reactions to herbal remedies have been
contact dermatitis in pharmaceutical employees and observed (Bircher 1996); airborne contact dermatitis
nurses, the opiates have also caused respiratory symp- and photosensitivity are weIl known reactions to
toms. In an IgE-mediated re action to papaveretum, the members of the Asteraceae (Compositae) family.
allergenic determinant has been located at the N-methyl- Occupational allergies have been observed to Arnica
cyclohexenyl ring in combination with a hydroxyl group montana (Hausen 1980), to essential oils in aroma- and
on the C atom in position 6 (Hade et al. 1989). For phytotherapists, to pyrethrum, which is still used as
contact allergy, the antigenic determinant is not clear, acarizide, in factory workers and to the alkaloid
since cross-reactivity between the opiates is present; vincamine tartrate from Vinca minor L. (used for
thebaine has an -OCH 3 group and hydromorphone an cerebral perfusion problems) (Van Hecke 1981).
oxygen at this position (Fig. 2) (Waclawski and Aldrige Eugenol, the essential constituent of clove oil, which
1995). It also remains unexplained why most of the is present in impression pastes and cements, may be an
patients allergic to opioids were also sensitized to p- allergen for dentists (Kanerva et al. 1994).
group substances, since there are no apparent cross-
reacting structures (Conde-Salazar et al. 1991). Immunomodulaters
The phenothiazines may elicit contact dermatitis,
airborne dermatitis (Schwenck et al. 1994) and photo- Highly reactive chemicals (and, therefore, potent
allergic dermatitis. In particular, chlorpromazine was a contact sensitizers) include dinitrofluorobenzene, din-
potent contact and photocontact allergen on direct itrochlorobenzene (DNCB), diphenylcyprone and squ-
skin contact (Rudzki 1990; Bjorkner 1994). Few cases aric acid dibutyl ester. These sensitize practically all
of occupational contact dermatitis have been reported exposed individuals and, therefore, probably only
to pyritinol, a compound of two pyridoxine (vitamin unusual cases are published. The three latter agents
B6) molecules; an intermediate of the latter also have been used in the treatment of alopecia areata, but
Fig. 2. Chemical structures of opiates. HO

The antigenie determinant for immuno-
globulin E antibodies is the N-methyl-
cyclohexenyl ring in combination with a
hydroxyl group on C6 (modified from
Bircher 1996)
Morphine Codeine
Hydromorphone Thebaine
486 A.J. Bircher
DNCB has become obsolete due to its mutagenic min B6) (Wigger-Alberti and Eisner 1997) are typical
potential (Happle et al. 1980). The main exposed occupational sensitizers, whereas others from the B
professions are accidentally exposed chemical workers, group, such as cyanocobalamine, have rarely caused
dermatologists and pharmacy employees [Birchner occupational problems. In some patients, oral admin-
et al. 1999]. istration of thiamine resulted in a flare of contact
Azathioprine, an immunosuppressant, is widely dermatitis. The retinols (vitamin A) elicit irritant
used in transplantation and autoimmune diseases; reactions in higher concentrations more often; a case
cutaneous reactions to it are rare (Soni and Sherertz of allergy to vitamin A acetate has been reported.
1996). Two pharmaceutical workers have been de- However, occupational contact allergy (in several
scribed who had a contact allergy to azathioprine; the pharmaceutical workers and a pig feeder) to the
role of impurities, such as mercatopurine and chloro- synthetic, water-soluble form of vitamin K3 (menadi-
methylnitroimidazole, could not be elucidated (Burden one sodium bisulfite) has been observed, with cross-
and Beck 1992). reactivity to vitamin K4 (menadiol sodium diphos-
phate) (Dinis et al. 1988).
Intermediates and Precursors
Miscellaneous Drugs
Intermediate products are often highly reactive chem-
icals and bind readily to proteins, aprerequisite for Several drugs have caused single cases of occupational
sensitization. Contact allergy to intermediates is not contact dermatitis. Carbimazole, a thiourea used as an
uncommon and occurs practically exclusively in indi- anti-thyroid drug, has induced photoallergic reactions
viduals involved in the development and production of in a pharmaceutical laboratory worker. Disulfiram
drugs or in maintenance employees in chemical or (tetraethylthiuram disulfide) used for adjunctive ther-
pharmaceutical plants. Allergic reactions to interme- apy in alcoholism has elicited contact dermatitis in a
diates of H2 -antagonists are well established, e.g. for nurse handling tablets. A clinically relevant cross-
ranitidine (Romaguera et al. 1990), famotidine and reactivity to other thiurams (eczema under rubber
others. Also, synthesis of cytostatic drugs apparently gloves) has been reported (Mathelier-Fusade and
pro duces allergenic intermediates, as demonstrated for Leynadier 1994). A nurse was affected with contact
cytosine arabinoside, methotrexate, nitrosoureas and dermatitis from meglumine diatrizoate, an ionic radio-
the immunosuppressant azathioprine. The intermedi- contrast medium; another nurse had areaction to
ates of a number of other drugs have been reported as mesna, a mucolytic also used to prevent cyclophospha-
contact allergens (Table 2). An unusual case of toxic mide urotoxicity. A third nurse had areaction to
epidermal necrolysis upon skin contact with an mitomycin C, a cytostatic drug, and a fourth had a
intermediate of tetramisole, an antihelmintic and reaction to tubocurarin, a myorelaxant. Finally, a
immunstimulatory agent, has been described. Patch hairdresser became sensitized to minoxidil he applied
tests were not performed (Valsecchi et al. 1987). to a customer, and an ophtalmologic assistant became
sensitized to thiomersal from contact lens fluids while
Veterinary Drugs instructing customers. Ethylene oxide a sterilizing agent
known to elicit immediate-type hypersensitivity, has
Farmers, animal caretakers and veterinarians are caused an epidemic of irritant contact dermatitis due to
particularly at risk. The majority of the eliciting agents ethylene oxide-sterilized overalls (Lerman et al. 1995).
are anti-infectious and antibiotic drugs, which are used
as growth promoters or for therapy.
Contact takes place by skin contact while treating or
Summary
vaccinating (Vilaplana et al. 1991) animals or through
dust during feeding or the production of feed. Impor-
tant allergens are tylosin, a macrolide antibiotic (Veien A considerable number of drugs have been reported as
et al. 1980) which sometimes induced airborne contact occupational allergens. Drugs are not the most com-
dermatitis, and olaquindox, a growth promoter for mon occupational allergens but, for several reasons,
pigs which induced severe photoallergic contact der- they may be of considerable importance. Cutaneous
matitis and, in some patients, a persistent light and/or respiratory symptoms (and, rarely, systemic
reaction (Schauder et al. 1996). reactions) may be elicited. Of particular importance is
the possibility of re-exposure to a particular drug for
Vitamins medical purposes in an occupationally sensitized
individual. Diagnosis of an occupational allergy and
Thiamine (vitamin BI) (Ingemann-Larsen et al. 1989) allergen recognition can lead to appropriate control
and intermediates in the synthesis of pyridoxin (vita- and prevention in many situations (Sherertz 1994).
References Davies MG (1983) Contaet allergy to dieyclohexyl-earbodiimide.

Contaet Dermatitis 9:318
De Boer J, Van Joost T (1988) Sensitisation to diehlorobenzoyl
Alomar A, Puig L, Vilaltella I (1987) Allergie eontaet dermatitis ehloride. Contaet Dermatitis 18:116-117
due to ranitidine. Contaet Dermatitis 17:54-55 De Groot AC, Conemans JMH (1990) Contaet allergy to furazoli-
Altomare GF, Capella GL, Veraldi S (1992) Oeeupational drug done. Contaet dermatitis 22:202-205
dermatitis. Clin Dermatoll0:141-147 De Groot AC, Van Wijnen WG, Van Wijnen-Vos M (1990)
Aneona A (1985) Allergie contaet dermatitis to nitrofurazone. Oeeupational eontaet dermatitis of the eyelids, without oeular
Contaet Dermatitis 13:35 involvement, from thimerosal in eontaet lens fluid. Contaet
Arevalo A, Blaneas R, Ancona A (1995) Oeeupational eontaet Dermatitis 23:195
dermatitis from piroxieam. Am J Contaet Dermat 6:113-114 Desehamps D, Gamier R, Savoye 1, Chabaux C, Efthymiou ML,
Barbaud A, Treehot P, Bertrand 0, Sehmutz JL (1995) Oeeupa- Fournier E (1988) Allergie and irritant eontaet dermatitis
tional allergy to propaeetamol. Laneet 346:902 from diethyl-b-ehloroethylamine. Contaet Dermatitis 18:
Barberda E, De la Cuadra J (1989) Oeeupational airborne allergie 103-105
eontaet dermatitis from tylosin. Contaet Dermatitis 20:308 Dinis A, Branddo M, Faria A (1988) Oeeupational eontaet
Barriga A, Romaguera C, Vilaplana J (1992) Contaet dermatitis dermatitis from vitamin K3 sodium bisulphite. Contaet
from avoparcin. Contaet Dermatitis 27:115 Dermatitis 18:170-171
Bause GS, Kugelman LC (1990) Contaet anaphylaetoid response Dooms-Goossens A, Gevers D, Mertens A, Vanderheyden D
to labetalol. Contaet Dermatitis 23:51 (1983) Allergie eontaet urtiearia due to ehloramine. Contaet
Belsito DV (1993) Contaet urtiearia from pentamidine isethionate. Dermatitis 9:319-320
Contaet Dermatitis 29:158 Dooms-Goossens A, De Boulle K, Snauwaert J, Degreef H (1986a)
Benyoussef K, Bottlaender A, Pfister HR, Caussade P, Heid E, Sensitization to 3,4,6-triehloropyridazine. Contaet Dermatitis
Grosshans E (1996) Allergie eontaet dermatitis from mesna. 14:64-65
Contaet Dermatitis 34:228-229 Dooms-Goossens AE, Debussehere KM, Gevers DM, Dupre KM,
Bernstein JA, Stauder T, Bernstein DI, Bernstein IL (1994) A Degreef HJ, Loneke JP, Snauwaert JE (1986b) Contaet
eombined respiratory and eutaneous hypersensitivity syn- dermatitis eaused by airborne agents. A review and ease
drome indueed by work exposure to quaternary amines. reports. J Am Aead DermatoI15:1-1O
J Allergy Clin Immunol 94:257-259 Dooms-Goossens A, Bedert R, Degreef H, Vandaele M (1990)
Bireher AJ (1996) Arzneimittelallergie und Haut. Georg Thieme, Airborne allergie contaet dermatitis from kitasamycin and
Stuttgart mideeamyein. Contaet Dermatitis 23:118-119
Bireher AI, Bigliardi P, Langaver Messmer S, Surber C (1999) Dorado Bris JM, Aragues Montailes M, Sols Candela M, Garcia
Oecupational airborne contaet dermatitis from dipheney- Diez A (1992) Contaet sensitivity to pyrazinobutazone
prone in a pharmaey employee. Contaet Dermatitis 41:52 (Carudol) with positive oral provoeation test. Contaet Der-
Bjorkner BE (1994) Industrial airborne dermatoses. Dermatol matitis 26:355-356
Clin 12:501-509 Dziuk M, Gall H, Sterry W (1994) Contaet dermatitis from the
Burden AD, Beek MH (1992) Contaet hypersensitivity to azathi- ACE-inhibitor eaptopril. Dermatosen Beruf Umwelt 42:
oprine. Contaet Dermatitis 27:329-330 159-161
Calnan CD (1975) Oeeupational piperazine dermatitis. Contaet Ekenvall L, Forsbeek M (1978) Contaet eezema produeed by a
Dermatitis 1:126 ß-adrenergie bloeking agent (alprenolol). Contaet Dermatitis
Camarasa G, Alomar A (1980) Contaet dermatitis to an H2 4:190- 194
antagonist. Contaet Dermatitis 6:152-153 Filipe P, So ares Almeida RSL, Guerra Rodrigo FG (1996)
Camarasa JG, Barnadas M (1982) Oeeupational dermatosis by Oeeupational allergie eontaet dermatitis from eephalosporins.
vitamin K3 sodium bisulphite. Contaet Dermatitis 8:268 Contaet Dermatitis 34:226
Caraffini S, Assalve D, Stingeni L, Lisi P (1994) Tylosin, an Fisher AA (1991) Allergie eontaet dermatitis to mitomycine C.
airborne eontaet allergen in veterinarians. Contaet Dermatitis Cutis 47:225-227
31:327-328 Foti C, Vena GA, Angelini G (1992) Oeeupational eontaet allergy
Castelain PY, Piriou A (1980) Contaet dermatitis due to to benzydamine hydroehloride. Contaet Dermatitis 27:
propanidid in an anesthesist. Contaet Dermatitis 6:360 328-329
Coekayne SE, Gawkrodger W (1997) Oeeupational eontaet Foti C, Vena GA, Cueuraehi MR, Angelini G (1994) Oeeupational
dermatitis in an aromatherapist. Contaet Dermatitis 37: eontaet allergy from eephalosporins. Contaet Dermatitis
306-307 31:129-130
Conde-Salazar L, Guimaraens D, Romero L (1984) Oecupational Foti C, Bonamonte D, Trenti R, Vena GA, Angelini G (1997)
eontaet dermatitis from eytosine arabinoside syntltesis. Oeeupational eontaet allergy to eephalosporins. Contaet
Contaet Dermatitis 10:44-45 Dermatitis 36:104-105
Conde-Salazar L, Guimaraens D, Romero LV, Gonzalez MA Foussereau J (1989) Aecidental oeeupational sensitization to
(1986) Oeeupational dermatitis from eephalosporins. Contaet p-nitr?benzoyl ehloride in a ehemistry student synthesizing
Dermatitis 14:70-71 proeame. Contaet Dermatitis 20:397-398
Conde-Salazar L, Llinas MG, Guimaraens D, Romero L (1988) Foussereau J, Benezra C, Maibaeh HI (1982) Oeeupational eontaet
Oeeupational allergie eontaet dermatitis from amethoeaine. dermatitis. Munksgaard Kopenhagen.
Contaet Dermatitis 19:69-70 Franealanci S, Gola M, Giorgini S, Muecinelli A, Sertoli A (1986)
Conde-Salazar L, Guimaraens D, Llinas G, Romero L, Gonzalez Oeeupational photoeontaet dermatitis from olaquindox.
MA (1989) Oeeupational allergie eontaet dermatitis from Contaet Dermatitis 15:112-114
oxolamine. Contaet Dermatitis 21:206 Frattasio A, Germino M, Cargnello S, Patrone P (1997) Side-
Conde-Salazar L, Guimaraens D, GonzdIez M, Fuente C (1991) effeets during treatment with SADBE. Contaet Dermatitis
Oeeupational allergie eontaet dermatitis from opium alka- 36:118-119
loids. Contaet Dermatitis 25:202-203 Fum~galli M, Bigardi AS, Legori A, Pigatto PD (1992) Oeeupa-
Corazza M, Mantovani L, Trimurti S, Virgili A (1994) Oeeupa- t!Qnal eontaet dermatitis from airborne nieergoline. Contaet
tional eontaet sensitization to ethylenediamine in a nurse. Dermatitis 27:256
Contaet Dermatitis 31:328-329 Fung MA, Geisse JK, Maibaeh HI (1996) Airborne eontaet
Dahlquist I (1977) Allergie reaetions to apomorphine. Contaet dermatitis from metaproterenol in arespiratory therapist.
Dermatitis 3:349-350 Contaet Dermatitis 35:317-318
Dal Monte A, Laffi G, Maneini G (1994) Oeeupational eontaet Gamboa P, Muregui I, Urrutia I (1995) Oeeupational sensitization
dermatitis due to speetinomycin. Contaet Dermatitis 31: to aminopenieillins with oral toleranee to penieillin V.
204-205 Contaet Dermatitis 32:48-49
488 A.J. Bircher
Garcia-Bravo B, Gines E, Russo F (1995) Occupational contact Lerman Y, Ribak I, Skulsky M, Ingber A (1995) An outbreak of
dermatitis from ceftiofur sodium. Contact Dermatitis 33: irritant contaet dermatitis from ethylene oxide among
62-63 pharmaeeutieal workers. Contaet Dermatitis 33:280-281
Garcia-Perez A (1978) Occupational dermatitis from DNFB with Ljunggren B, Hindsen M, Isaaksson M (1992) Systemie quinine
cross sensitivity to DWB. Contact Dermatitis 4:125-127 photosensitivity with photoepieutaneous eross-reaetivity to
Gauchia R, Rodriguez-Serna M, Silvestre JF, Linana JJ, Aliaga A quinidine. Contaet Dermatitis 26:14
(1996) Allergie contact dermatitis from streptomycin in a Lo JS, Taylor JS, Oriba H (1990) Occupational allergie contaet
cattle breed. Contact Dermatitis 35:374-375 dermatitis to airborne nitrofurazone. Dermatol Clin 8: 165-168
Goday-Bujan JJ, Yanguas-Bayona I, Soloeta-Arechavala R (1994) Lombardi P, Gola M, Acciai MC, Sertoli A (1989) Unusual
Allergie contact dermatitis from cyanamide: report of 3 cases. oceupational allergie eontaet dermatitis in a nurse. Contaet
Contact Dermatitis 31:331-332 Dermatitis 20:302-303
Goh CL, Ng SK (1984) Allergie contact dermatitis to ranitidine. Lubbe D (1993) Professional dinitroehlorobenzene contaet der-
Contact Dermatitis 11:252 matitis. Eleven eases in the nitration facility of a ehemieal
Goh CL, Ng SK (1985) Photoallergie contact dermatitis to plant. Derm Beruf Umwelt 41:19-24
carbimazole. Contact Dermatitis 12:58-59 Macedo NA, Pineyro I, Carmona C (1991) Contact urtiearia and
Guerra L, Venturo N, Tardio M, Tosti A (1991) Airborne contact contact dermatitis from albendazole. Contact Dermatitis
dermatitis from animal feed antibiotics. Contact Dermatitis 25:73-75
25:333-334 Mancuso G, Staffa M, Errani A, Berdondini RM, Fabbri P (1990)
Guimaraens D, Gonzales MA, Conde-Salazar L (1994) Occupa- Oceupational dermatitis in animal feed mill workers. Contaet
tional allergie contact dermatitis from intermediate products Dermatitis 22:37-41
in famotidine synthesis. Contact Dermatitis 31:259-260 Mareos NIL, Garces MM, Alonso L, Juste S, Carretero P, Blaneo I,
Haddar M, Araibia A, Laibldder C, Mekki R, Benmami F (1993) Garcia F, Perez R, Herrero D (1997) Oceupational allergie
Contact dermatitis due to ethylene oxide. Arch Mal Prof Med eontact dermatitis from homatropine and phenylephrine
Trav Secur Soc 54:358-359 eyedrops. Contaet Dermatitis 37:189
Happle R, Kalveram KJ, Buchner U, Echtemacht-Happle K, Mathelier-Fusade P, Leynadier F (1994) Oecupational allergie
Goggelmann W, Summer KH (1980) Contact allergy as a eontaet reaetion to disuIfiram. Contaet Dermatitis 31:121-122
therapeutic tool for alopecia areata: application of squarie Mathelier-Fusade P, Mansouri S, Aissaoui M, Chabane MH,
acid dibutylester. Dermatologica 161:289-297 Araetingi S, Leynadier F (1997) Airborne contact dermatitis
Hardie RA, Savin JA, White DA, Pumford S (1978) Quinine from propaeetamol. Contaet Dermatitis 36:267-268
dermatitis: investigation of a factory outbreak. Contact Meding B (1986) Contact allergy to omeprazole. Contact Derma-
Dermatitis 4:121-124 titis 15:36
Harle DG, Baldo BA, Coroneos NI, Fisher MM (1989) Anaphylaxis Menne T, Veien NK, Maibach HI (1989) Systemic contact-type
following administration of papaveretum. Case report: im- dermatitis to drugs. Semin Dermatol 8:144-148
plication of IgE antibodies that react with morphine and Mitchell JC, Maibach HI (1975) Allergie contact dermatitis from
co deine, and identification of an allergenie determinant. phenoxybenzamine hydro chloride. Contact Dermatitis 1:
Anesthesiology 71:489-494 363-366
Hausen BM (1980) Arnikaallergie. Hautarzt 31:10-17 MiyaIrara H, Koga T, Imayama S, Hori Y (1993) Occupational
Heidenheim M, Jemec GBE (1995) Occupational allergie contact contact urticaria syndrome from cefotiam hydrochloride.
dermatitis from vitamin A acetate. Contact Dermatitis 33:439 Contact Dermatitis 29:210-211
Hjorth N, Weis man K (1973) Occupational dermatitis among Moller NE, Jeppesen K (1987) Patch testing with semisynthetic
veterinary surgeons caused by spiramycin, tylosin and penieillins. Contact Dermatitis 16:227-228
penethamate. Contact Dermatitis 53:229-232 Moller NE, Kromann N (1989) Bumetanide allergy in factory
Holdiness MR (1986a) Contact dermatitis to ethambutol. Contact workers. Contact Dermatitis 20:393-394
Dermatitis 15:96-97 Moller NE, Von Wiirden K (1992) Hypersensitivity to semisyn-
Holdiness MR (1986b) Contact dermatitis to antituberculosis thetic penicillins and crossreactivity with penicillin. Contact
drugs. Contact Dermatitis 15:282 Dermatitis 26:351-352
Hsu CK, Sun CC, Su MS, Kuo EF, Wu YC (1992) Systemic contact Moller NE, Nielsen B, Von Wiirden K (1986) Contact dermatitis
allergy from occupational contact with ethyl ethoxymethylene to semisynthetic penicillins in factory workers. Contact
cyanoacetate. Contact Dermatitis 27:58-59 Dermatitis 14:307-311
Ingemann-Larsen A, Jepsen JR, Thulin H (1989) Allergie contact Moller NE, Nielsen B, Von Wiirden K (1990) Changes in
dermatitis from thiamine. Contact Dermatitis 20:387-388 penicillin contamination and allergy in factory workers.
Isaaksson M, Bruze M, Gruvberger B, Ljunggren B (1994) Quinine Contact Dermatitis 22:106-107
and quinidine photoproducts can be identical. Acta Derm Monteseirin I, Conde J (1990) Contact eczema from famotidine.
VenereoI74:286-288 Contact Dermatitis 22:290
Johansson G (1988) Contact urtiearia from levomepromazine. Moscato G, Galdi E, Scibilia I, Dellabianca A, Omodeo P,
Contact Dermatitis 19:304 Vittadini G, Biscaldi GP (1995) Occupational asthma, rhinitis
Jolanki R, Alanko K, Pfaffii P, Estlander T, Kanerva L (1997) and urticaria due to piperacillin sodium in a pharmaceutical
Occupational allergie contact dermatitis from 5-chloro-1- worker. Eur Respir J 8:467-469
methyl-4-nitroimidazole. Contact Dermatitis 36:53-54 Newton JA, White I (1987) Connubial dermatitis from morantel.
Kanerva L, Estlander T, Jolanki R (1994) Occupational skin Contact Dermatitis 16:38-39
allergy in the dental profession. Dermatol Clin 12:517-532 Niklasson B, Bjorkner B (1990) Contact allergy to 3,4-
Kanerva L, Alanko K, Estlander T, Sihvonen T, Jolanki R (1997) dicarbethoxyhexane-2,5-dione. Contact Dermatitis 23:46-47
Oeeupational allergie eontaet urtiearia from ehloramine-T Niklasson B, Bjorkner B, Hansen L (1990) Occupational contact
solution. Contaet Dermatitis 37:180-181 dermatitis from anti tumor agent intermediates. Contact
Keller K, Sehwanitz HJ (1992) Combined immediate and delayed Dermatitis 22:233-235
hypersensitivity to mezloeillin. Contaet Dermatitis 27:348-349 Norris PG, Hawk JL, White IR (1988) Photo allergie contact
Kellett JK, Beek MH (1984) Contaet sensitivity to chloroquine dermatitis from fentichlor. Contact Dermatitis 18:318-320
sulphate. Contaet Dermatitis 11:47 Noster U, Hausen BM, Krisehe B, SchuIz KH (1976) Squaric acid
Klijn J (1984) Contact dermatitis from spironolaetone. Contact diethylester - a strong sensitizer. Contact Dermatitis 2:99-104
Dermatitis 10:105 Ortiz-Frutos FJ, Alonso J, Hergueta JP, Quintana I, Iglesias L
Lahti A, Puurunen J, Hannuksela M (1990) Occupational contaet (1995) Tetrazepam an allergen with several clinical expres-
allergy to 2,4-di-amino-6-ehloromethylpteridine hydrochlo- sions. Contact Dermatitis 33:63-65
ride: an intermediate in methotrexate synthesis. Contaet Pecegueiro M (1990) Occupational contact dermatitis from
Dermatitis 22:294 penicillin. Contact Dermatitis 23:190-191
Piekering FC, Ive FA (1982) Allergie eontaet dermatitis from 4,7- Schwenck K, Gall H, Sterry W (1994) Aerogene Kontaktdermatitis
diehloroquinoline. Contaet Dermatitis 8:269-270 auf das Neuroleptikum Chlorprothixen. Allergologie 17:
Plaeueci F, Benini A, Guerra L, Tosti A (1996) Oeeupational 467-469
allergie eontaet dermatitis from disinfeetant wipes used in Selvaag E, Holm JO, Thune P (1995) Allergic contaet dermatitis in
dentistry. Contaet Dermatitis 35:306 an aroma therapist with multiple sensitizations to essential
Poesen N, De Moor A, Bussehots A, Dooms-Goossens A (1995) oils. Contact Dermatitis 33:354-355
Contaet allergy to dieyclohexyl earbodiimide and diisopropyl Sherertz EF (1994) Occupational skin disease in the pharmaceu-
earbodiimide. Contaet Dermatitis 32:368-369 tieal industry. Dermatol Clin 12:533-536
Quiree S, Olaguibel JM, Gareia BE, Tabar AI (1993) Oeeupational Soni BP, Sherertz EF (1996) Allergie contact dermatitis from
airbome eontaet dermatitis due to benzoyl peroxide. Contaet azathioprine. Am J Contact Dermatitis 7:116-117
Dermatitis 29:165-166 Sonnex TS, Rycroft RJ (1986) Allergie contact dermatitis from
Rademaker M (1994) Allergie eontaet dermatitis from lavender chloromethyl heterocyclie intermediates in the synthesis of a
fragranee in Difflam gel. Contaet Dermatitis 31:58-59 histamine antagonist. Contact Dermatitis 14:265-267
Rebandel P, Rudzki E (1986a) Dermatitis from quinazoline oxide. Stejskal VDM, Olin RG, Forsbeck M (1986) The lymphocyte
Contaet Dermatitis 15:63-5 transformation test for diagnosis of drug-induced occupa-
Rebandel P, Rudzki E (1986b) Oeeupational eontaet sensitivity in tional allergy. J Allergy Clin Immunol 77:411-426
oeulists. Contaet Dermatitis 15:92 Szczurko C, Dompmartin A, Michel M, Castel B, Leroy D (1996)
Rebandel P, Rudzki E (1990) Dermatitis eaused by epie- Occupational contact dermatitis from propacetamol. Contact
hlorohydrin, oxprenolol hydroehloride and propranolol hy- Dermatitis 35:299-301
droehloride. Contaet Dermatitis 23:199 Tadokoro K, Niimi N, Ohtoshi T, Nakajima, K, Takafuji S,
Rodriguez A, Eeheehipia S, Alvarez M, Muro MD (1994) Onodera K, Suzuki S, Murunaka M (1994) Cefotiam-induced
Oeeupational eontaet dermatitis from vitamin B12. Contaet IgE-mediated occupational contact anaphylaxis of nurses;
Dermatitis 31:271 case reports, RAST analysis, and a review of the literature.
Romaguera C, Grimalt F (1983) Oeeupational dermatitis from Clin Exp Allergy 24:127-133
eodeine. Contaet Dermatitis 9:170 Tas 1, Weissberg D (1958) Allergy to aminophylline. Allergy 12:
Romaguera C, Grimalt F, Conde-Salazar L (1980) Oeeupational 39-42
dermatitis from vitamin K3 sodium bisulfite. Contaet Der- Tennstedt D, Dumont-Fruytier M, Lachapelle JM (1978) Occupa-
matitis 6:355-356 tional allergic contact dermatitis to virginiamycin, an antibi-
Romaguera C, Grimalt F, Vilaplana J (1988) Epidemie of otie used as a food additive for pigs and poultry. Contact
oeeupational eontaet dermatitis from ranitidine. Contact Dermatitis 4:133-134
Dermatitis 18:177-178 Testud F, Descotes J, Evreux JC (1994) Pathologie professionnelle
Romaguera C, Grimalt F, Vilaplana F (1990) Contact dermatitis due aux medicaments. Arch Mal Prof 55:279-286
caused by intermediate products in the manufacture of Tuomi ML, Rasanen L (1995) Contact allergy to tylosin and cobalt
clenbutol, ranitidine base, and ranitidine hydrochloride. in a pig-farmer. Contact Dermatitis 33:285
Dermatol Clin 8:115-117 Valsecchi R, Cassina P, Cainelli T (1987) Contact toxic epidermal
Rudzki E (1990) Contact sensitivity to systemieally administered necrolysis. Contact Dermatitis 16:277
drugs. Dermatol Clin 8:177 Valsecchi R, Rohrich 0, Cainelli T (1989) Contact allergy to
Rudzki E, Grzywa Z (1977) Occupational piperazine dermatitis. cistoran, an intermediate in ranitidine synthesis. Contact
Contact Dermatitis 3:216 Dermatitis 20:396-397
Rudzki E, Rebandel P (1985) Occupational contact urticaria from Van Hecke E (1981) Contact sensitivity to vincamine tartrate.
penicillin. Contact Dermatitis 13:192 Contact Dermatitis 7:53
Rudzki E, Rebandel P (1991) Hypersensitivity to semisynthetic Vanuytrecht-Henderickx D, Bourgeois M, Marien K, Dooms-
penicillins but not to natural penicillin. Contact Dermatitis Goossens A (1986) Occupational fixed eruption by inhalation
2sa92 of pyrazolones. Contact Dermatitis 14:115
Rudzki E, Rebandel P, Grzywa Z (1989a) Patch tests with Veien NK, Hattel T, Justesen 0, Norholm A (1980) Occupational
occupational contactants in nurses, doctors and dentists. contact dermatitis due to spiramycin and/or tylosin among
Contact Dermatitis 20:247-250 farmers. Contact Dermatitis 6:410-413
Rudzki E, Rebandel P, Grzywa Z (1989b) Contact allergy in the Veraldi S, Benelli C, Pigatto PD (1992) Occupational allergie
pharmaceutieal industry. Contact Dermatitis 21:121-122 contact dermatitis from minoxidil. Contact Dermatitis 26:
Rycroft RJG (1981) Occupational contact sensitization to 2,6- 211-212
dichloropurine. Contact Dermatitis 7:349-350 Verschaeve A, Loncke J, Dooms-Goossens A (1984) Occupational
Rycroft RJG (1983) Allergic contaet dermatitis from a novel contrast media dermatitis: meglumine diatrizoate. Contact
diamino intermediate, 5-[(2-aminoethyl)-thiomethyl]-N,N-di- Dermatitis 11:318-319
methyl-2-furanmethanamine, in laboratory synthesis. Con- Vilaplana J, Grimalt F, Romaguera C (1990) Contact dermatitis
tact Dermatitis 9:456-458 from furaltadone in animal feed. Contact Dermatitis 22:232-
Sansom JE, Molloy KC, Lovell CR (1995) Occupational sensiti- 233
zation to diphencyprone in a chemist. Contact Dermatitis Vilaplana 1, Romaguera C, Grimalt F (1991) Contact dermatitis
32:363 from lincomycin and spectinomycin in chicken vaccinators.
Savini C, Morelli R, Piancastelli E, Restani S (1989) Contact Contact Dermatitis 24:225-226
dermatitis due to ethoxyquin. Contact Dermatitis 21:342-343 Waclawski ER, Aldridge R (1995) Occupational dermatitis from
Schauder S, Schrbder W, Geier J (1996) Olaquindox-induced thebaine and codeine. Contact Dermatitis 33:51
airbome photoallergic contact dermatitis followed by tran- Wahlberg JE, Boman A (1981) Contact sensitivity to quinidine
sient or persistent light reactions in 15 pig breeders. Contact sulfate from occupational exposure. Contact Dermatitis 7:27-31
Dermatitis 35:344-354 Watsky KL, Reynolds K, Berube D, Bayer FJ (1993) Occupational
Schena D, Barba A, Costa G (1996) Occupational contact urtiearia contact dermatitis from tosyl chloride in a chemist. Contact
due to cisplatin. Contact Dermatitis 34:220-221 Dermatitis 29:211-212
Schmidt RJ (1986) Compositae. Clin Dermatol 4:46 Wigger-Alberti W, Elsner P (1997) Occupational contact derma-
Schwank R, Jirdsek L (1963) Kontaktallergie gegen Chlor- titis due to pyritinol. Contact Dermatitis 37:91-92
amphenieol mit besonderer Ber Ucksichtigung der
Gruppensensibilisierung. Hautarzt 14:24-30
CHAPTER 62
Barrier Creams and Emollients

W. Wigger-Alberti and P. Eisner
Introduction to combine the different effect of hydrophilie ingredi-

ents, such as propylene glycol, glycerol and sorbitol,
and lipophilic ingredients, such as stearic acid and
Contact dermatitis is the most frequent manifestation
dimethylpolysilicane. However, a foamy skin protector
of occupational skin disease. Since the course may be
("invisible glove"), claimed to form a two-dimensional
chronic leading to dis ability, and since treatment is
network of crystalline stearic acid (impermeable to
frequently of limited efficacy, prevention should be
hydrophilie agents), failed in a repetitive irritation test
emphasized to reduce the incidence and prevalence of
against the anionic detergent sodium lauryl sulfate
irritant contact dermatitis (ICD) and allergie contact
(SLS) and against the solvent toluene (TOL) (Frosch
dermatitis (ACD). Apart from total elimination of
et al. 1993a). Other preparations include a fatty amine
cutaneous exposure to hazardous substances and the
amide acetate that binds to negatively charged car-
use of gloves or protective clothing, barrier creams
boxyl groups of keratin and the positive fatty
(protective creams) (BCs) are targeted as one of the
ammonium ion of these substances that binds firmly
classieal means of skin protection against noxious
to the negative charge of the epidermis. This is
chemieals from the environment (Lachapelle 1995).
supposed to build up a firm second layer on the skin,
Skin protection in the workplace consists of pre-
which prevents penetration of various agents in a steric
exposure BCs, mild skin cleansers and post-exposure
manner (Frosch and Kurte 1994).
skin-care products such as emollients or moisturizers
Some ingredients, such as natural or synthetic
(Table 1). While BCs are designed to prevent skin
tannery substances, zinc oxide, tale um, perfluorpoly-
damage due to irritant contact, skin cleaning should
ethers, chelating agents and other substances that can
remove aggressive substances from the skin, and skin
bind metal ions or reduce the penetration through the
care is intended to enhance epidermal barrier regen-
skin, are claimed to have special protective properties.
eration (Wigger-Alberti and Elsner 1997a).
Zinc oxide has a covering effect. Tannin is supposed to
harden the skin in order to increase the mechanical
resistance of the skin surface against microtraumatas.
Barrier Creams
Tannery agents cause a local decrease of perspiration
which seems to be helpful while wearing gloves (Jepsen
Chemistry and Mode of Action 1985). The decrease of swelling is caused by direct
bin ding of the tanning substance to keratin. Some
Even in recent years, the prevailing opinion has been chelating agents are claimed to protect against sens i-
that BCs are effective in a pure physical way because tizing substances. Tartaric acid and glycine chelate
their composition creates a barrier which can hardly be chromate can reduce chrome VI to chrome III, which
penetrated. In agreement with this common dogma, is less allergenie (Romaguera et al. 1985).
lipophilic ointments should provide benefit against
hydrophilie irritants and lipophobic ointments against Efficacy of Barrier (reams
hydrophobie irritants. Water-in-oil emulsions are
recommended against water-soluble irritants such as Though use of BCs is one of the common measures to
detergents, acids, alkalis, metal-work fluids and even prevent ICD, their actual benefit at the workplace is
plain water. Oil-in-water emulsions are offered for use still regarded with skepticism (Hogan et al. 1990) and
against lipophilic irritants such as oils, varnishes and debated in recent reviews (Lachapelle 1996; Wigger-
organic solvents. Alberti and EIsner 1998). Because BCs are claimed not
Special investigations have been undertaken to to be drugs but cosmetics, valid methods to show their
develop preparations with a dualistic mode of action efficacy have not been necessary for legal reasons.

Barrier Creams and Emollients 491
Table 1. Conception of
dermatological skin pro- Pre-exposure skin care (barrier creams, Oil-water emulsions, water-oi! emulsions, tannery
tection at the workplace protective creams) substances, zinc oxide, talcum, perfluorpolyethers,
chelating agents, ultra-violet protectors
Cleansing products Detergents, solvents, natural and synthetic grits
Post -exposure skin care Emollients, moisturizers, humectants, lipids
However, new European Union (EU) laws for cosmetic Marks et a1. 1989; Frosch et a1. 1993a-c; Fine Olivarius
standards force manufacturers now to ensure a better et a1. 1996; Schlüter-Wigger and Eisner 1996). Cumu-
claim support. In addition, European Community (EC) lative patch tests, repetitive washing procedures with
regulations require the employer to provide BCs to SLS or cyanoacrylate strips of protected skin sampies
workers at exposed workplaces for prevention of ICD. to measure the effectiveness of BCs against dye
It is in the employers' interest that this investment is indicators have been presented and summarized
not based on unfounded claims, but on scientific data. recently (Grunewald et a1. 1995; Zhai and Maibach
Double-blinded, placebo-controlled, randomized clin- 1996b; Wigger-Alberti and Eisner 1998; Zhai et a1.
ical tests of BCs are still missing for reasons of 1998). As chronic ICD is a major clinical problem, a
methodological difficulties, ethical doubts and the test model with repeated exposure to subclinical doses
enormous expenditure for tests regarding the preven- of irritants might be helpful in predicting the efficacy
tive benefit of BCs in practice. Therefore, in vivo and in of pre-applied BCs.
vitro tests are used for the evaluation of BC efficacy Frosch and Kurte (1994) introduced the repetitive
though they are considered not to be close to real irritation test (RIT) with a cumulative irritation over a
working place situations. 2-week period by standard irritants such as SLS,
Since Suskind (1955) introduced the 'slide test' to sodium hydroxide, lactic acid and toluene. This model
evaluate BCs in the 1950S, much effort has been has been shown to be suitable for comparing BCs
undertaken to develop valid methods to evaluate the simultaneously to a non-pretreated contral site. A
benefit of BCs. Besides various in vitro methods specific profile of efficacy could be demonstrated by
(Boman et a1. 1982; Loden 1986; Tronnier 1993; Treffel quantifying irritant cutaneous reactions by non-
et a1. 1994; Zhai and Maibach 1996a), non-invasive invasive measurements and it has been used recently
biophysical measurements have achieved great impor- in modified studies (Fig. 1) (Schlüter-Wigger and
tance, especially for clinically weak reactions (Ma- Eisner 1996; Eisner et a1. 1998; Wigger-Alberti et a1.
hmoud et a1. 1984; Mahmoud and Lachapelle 1985; 1998). However, manufacturers of skin care products
prefer easy study protocols that provide valid data in
short time with less restrictions for the volunteers;
Fig. 1. The effect of three barrier creams (A, B, C) and petrolatum therefore, short duration and easy application given in
on the irritation induced by 10% sodium lauryl sulfate after a 1-week test using the forearm of healthy volunteers is
2 weeks, measured by the daily visual score (0-5). Results are highly desirable (Wigger-Alberti et a1. 1999). As pet-
given as means. The results show a significant suppression of
erythema during each week for all products compared with the rolatum is effective against water-soluble and water-
untreated control (Wigger-Alberti et al. 1998a) insoluble irritants, it was recommended as a standard
5
SLS 10%
4_5
3_5 ... cream A
3
• cream B
2_5
--)1(-- cream C
2
1_5 - - 0 - - petrolatum
• control
0_5
o -.~-~~--+-----+-----+-----+-----+-----+-----+----~
2 3 4 5 8 9 10 11 12 days
substance against which BCs may be compared (Wig- seeming protection that causes workers at risk to be
ger-Alberti and Eisner 1997b). careless of contact to irritants.
Although BCs have been shown to reduce ACD in
sensitized individuals under experimental conditions
(Schuppli and Ziegler 1967; Blanken et al. 1987a), their Emollients
use in the prevention of ACD has been disappointing
under practical conditions. However, recent p~bl~ca~
Chemistry and Mode of Action
tions indicate a benefit for so me BCs used as actlve
creams in the prevention of ACD-like nickel derma-
Post-exposure skin care products that are designed to
titis or poison ivy/oak ACD (Romaguera et al. 1985;
counteract the damaging effects of irritants on skin
Grevelinck et al. 1992; Fullerton and Menne 1995;
barrier function are mostly water-in-oil or oil-in-water
Gawkrodger et al. 1995; Marks et al. 1995; Menne
varieties, which belong to the moisturizers or emol-
1995).
lients. Moisturizers are designed to actively increase
the water content of the skin. Emollients are designed
Adverse Effects and Contraindications
to smooth the skin and to increase the water content
indirectly by creating an occlusive film on the skin
While some authors reported a satisfactory protective
surface, thereby trapping the water in the upper layers
action of BCs, others found no protection from or even
of the stratum corneum (Gabard 1994). Humectants
aggravation of rCD. A foamy 'skin pr?tector' was n.ot
are substances belonging to the moisturizers and
convincing in a guinea-pig model and 1mpressed b~ 1tS
natural moisturizing factors (NMFs), such as urea,
aggravating effect on the irritation due to sodmm
lactic acid, glycerine, sorbitol or modern substances
hydroxide (Frosch et al. 1993a). Also usin~ a guinea-
such as hyaloronic acid and mucopolysaccharides.
pig model, it was shown that treatment Wlth BCs can
They increase hydration, binding water at the skin
increase skin irritation by cutting oil fluids (Goh 1991).
surface by retaining large amounts of water relative to
Boman and Mellström (1989) showed that absorption
their weight. Some of these products contain anti-
of butanol through stripped skin treated with BC was
inflammatory or epithelial growth-promoting sub-
higher than absorption through untreated skin.
stances such as alpha-bisabolol, allantoin or
Recently, a BC was shown to cause an amplification
dexpanthenol. While efficacy in wound healing has
of inflammation by TOL (Wigger-Alberti et al. 1998a)
been demonstrated for some of these substances, their
(Fig. 2) and the protective properties against systemic
absorption of solvents were less than adequate
(Lauwerys et al. 1978; Bomann et al. 1982). .
Besides less efficacy against irritants or even amph-
Fig. 2. The effect of three barrier creams (A, B, C) and petrolatum
fication of barrier damage, the creams themselves may on the irritation induced by toluene after 2 weeks, measured by
induce rCD or ACD (Gupta et al. 1987; Pinola et al. the daily visual score (0-5). Results are given as n;tea?s.
1993). Preservatives, cream bases such as wool alco- Regarding erythema, cream A and petrolatum showed a slgmfi-
cant protective effect, while cream C had no b~n~fit and cr~am B
hols, emulsifiers and fragrances are potential aller?ens. even showed a significant amplification of the lrntant reactlOn to
Preparations marketed as 'invisible glove' may felgn a toluene (Wigger-Alberti et al. 1998a)
3
TOl undiluted
2.5
'" cream A
2
• cream B
1.5
--)1(- creamC
~ petrolatum
0.5 • control
o
days
benefit in the regeneration of epidermal barrier slower for untreated skin than for skin with an
function still remains open. emollient (Hannuksela and Kinnunen 1992).
The exact mechanism of action of moisturizers and In addition to their regeneration effects, emollients
emollients is still unknown. Theoretically, the im- have also been shown not only to treat but also to
provement in the barrier function could be due to prevent ICD. A recently performed study showed on
absorption of the moisturizer into the delipidized experimentally irritated skin both a significant pre-
stratum corneum, acting as an effective barrier, as ventive effect and a therapeutic effect of a moisturizer
suggested in a study on the effect of petrolatum (Ramsing and Agner 1997). The product tested pre-
(Ghadially et al. 1992). Due to a better knowledge of vented irritant skin reaction due to SLS and it
the structural organization of the horny layer with acce1erated regeneration of skin barrier function of
corneocytes embedded in between lipid bilayers SLS-irritated skin of the hands judged by measure-
(ceramides, cholesterol and free fatty acids in approx- ments of TEWL and electrical capacitance.
imately equal quantities), new emollients could be
developed to supply the missing elements in the Adverse Effects and Contra-indications
bilayer structure after acute or chronic irritant con-
tact. However, applications of ceramides, linoleic acid Though theoretically it would make sense to apply
and a variety of other fatty acids alone have been after-work emollients after contact with irritants, with
reported to actually delay barrier recovery in acetone- the aim of restoring the skin lipids and the hydration
treated murine skin, despite the fact that these lipids state of the horny layer, the emollients tested did not
are required for barrier homeostasis. The only treat- enhance regeneration of irritated skin in a study
ments that allowed normal barrier recovery were performed by Blanken et al. (1987b). In a study
applications of complete mixtures of ceramide, fatty performed with machinists exposed to cutting fluid,
acid and cholesterol, or pure cholesterol (Man et al. an after-work emollient cream did not appear to have
1993)· any significant effect against either cutting fluid
dermatitis or TEWL changes (Goh and Gan 1994).
Efficacy of Emollients Some ingredients may worsen ICD. For example, the
use of urea in moisturizers may increase skin perme-
Data on moisturizers preventing irritant contact der- ability, and it was also found to be an efficient
matitis is increasing (Zhai and Maibach 1998). In enhancer for the penetration of several substances,
addition to previous studies that documented the e.g., hazardous substances at the workplace (W ohlrab
efficacy of moisturizers using non-invasive bioengi- 1984, 1990). Additionally, similar to BCs, emollients
neering methods in healthy volunteers with normal themselves may induce ICD and ACD due to ingredi-
skin (Blichmann et al. 1989; Serup et al. 1989; Grove ents such as preservatives, cream bases and fragrances.
1991; Korstanje et al. 1992), studies with more clinically
relevant settings have been performed. These focused
on the efficacy in the epidermis after various types of
Application
acute and chronic skin damage or during everyday
exposure to irritants (Hannuksela and Kinnunen 1992;
Halkier-Soerensen and Thestrup-Pederson 1993; While emollients are designed to he al irritated skin,
Treffe1 and Gabard 1995; Gabard et al. 1996; Gammal BCs are not intended to be used on diseased skin
et al. 1996; Loden and Andersson 1996; Loden 1997; because of the irritant properties of many formulations
Mortz et al. 1997). Theoretically, after-work emollients (Hogan 1993; Fowler 1994; Lachapelle 1996). Therefore,
may be helpful in repairing skin barrier disruption it is of utmost importance to apply BCs on intact skin
after repetitive irritation, and it was demonstrated that only. They should be applied before contact to
these products could reduce trans epidermal water loss irritants, which includes an application after every
(TEWL) increases in skin that had been exposed break. So, repeated application during the work day is
to irritants (Blanken et al. 1989). A regularly used suggested. It is clear that for both BCs and after-work
moisturizer was demonstrated to improve the skin emollients to be effective, they must be applied
hydration state (capacitance) in cleansers and kitchen frequently enough in adequate amounts and to all
workers (Halkier-Soerensen et al. 1993), and Gammal skin areas that need protection. Particularly, proper
et al. (1996) demonstrated a significant decrease in application with attention to the interdigital spaces
dryness grades and scaling for apreparation tested in a should be performed.
soap-induced xerosis human model. Different types of A simple method to determine and quantify how
emollients that were used regularly prevented irritant exactly self-application of a BC was performed at the
dermatitis from a detergent measured by TEWL and workplace was presented recently (Wigger-Alberti
laser Doppler flowrnetry. The rate of healing was et al. 1997a). Using a fluorescence technique, it was
shown that the application was mostly incomplete in reliable studies. Results of animal experiments may not
different professional groups and patients with hand be valid for humans, particularly when dealing with
eczema (Wigger-Alberti et al. 1997b), especially in the irritants, because of the complex action mechanisms
dorsal aspects of the hands and wrists (Fig 3). These and the high inter-individual variability in suscepti-
findings indieated that many people miss certain areas bility of human skin (Zhai and Maibach 1996b).
when washing their hands. Even with the application of Regarding the various models used to investigate the
BCs, these mistakes are frequent. Individuals should efficacy of skin-care products, the validation of a
apply the cream systematically by anatomie regions, sensitive, standardized and widely accepted model
ensuring that each region is adequately covered. It was proved by inter-Iaboratory standardization or con-
shown that the fiuorescence technique is also a useful trolled clinical studies at the workplace seems to be
tool in the educational demonstration of the most necessary. Clearly, studies are needed, both under
common mistakes compared with the use of an experimental conditions and in the workplace, before a
instructive videotape (Wigger-Alberti et al. 1997C). rational recommendation can be made whether a
product is safe and effective for skin protection. In
analogy to the sun protection factor, a standardized
Conclusion testing method should be envisioned to determine a
(irritant-specific) "skin protection factor" for BCs and
a "skin regeneration factor" for post-exposure skin
BCs and emollients are still not perfect. Much effort is
care.
necessary to develop products that will give more
It might be debated whether a strict distinction
protection and fewer side effects. Efficacy and cosmetic
between skin-care products used before and after work
acceptance are both important qualities of skin-care
is justified because their various properties as emol-
products for protection at the workplace, but the
lients have been shown to treat and prevent ICD. The
knowledge of how to use them correctly is a basic
benefit of an integrated skin protection based on
condition. It goes without saying that their benefit in
different products still has to be validated. However, a
the prevention of ICD and ACD has to be evaluated in
strict and easily understandable separation into pre-
Fig. 3. Application of a barrier cream by 150 volunteers with
exposure BCs, mild skin cleansers and post-exposure
occupational contact to irritants evaluated using a fluorescence skin care products might be necessary to increase the
technique. Results are given as average percentage of sufficient acceptance and appreciation of skin care at the
application for all volunteers, indicating skipped areas at the
dorsal aspects of the fingers, the interdigital spaces and the wrist
workplace. Most manufacturers offer special plans to
(Wigger-Alberti et al. 1997a) pursue this aim.
right palm right dorsal aspect

The benefit of various skin-care products cannot be Gammal CE, Pagnoni A, Kligman AM, Gammal SE (1996) A
extensive and complete in all cases, but rather, only model to asses the efficacy of moisturizers - the quantifica-
tion of soap-induced xerosis by image analysis of adhesive-
against individual irritants. The data of in vitro and in coated discs (D-Squames®). Clin Exp Dermatol 21:338-343
vivo tests underline the importance of careful selection Gawkrodger DI, Healy J, Howe AM (t995)The prevention of
nickel contact dermatitis. A review of the use of binding
of BCs for specific workplaces. Choosing the wrong agents and barrier creams. Contact Dermatitis 32:257-265
preparation may weH worsen the effect of an irritant. Ghadially R, Halkier-S0rensen L, Elias PM (1992) Effects of
Based on the validated data, BCs and emollients should petrolatum on stratum corneum structure and function. J Am
be used more critically in relation to the noxious Acad Dermatol 26:387-396
Goh CL (1991) Cutting oil dermatitis on guinea pig skin (I).
substances used at the workplace. Cutting oil dermatitis and barrier cream. Contact Dermatitis
24:16-21
Goh CL, Gan SL (1994) Efficacies of a barrier cream and an
afterwork emollient cream against cutting fluid dermatitis in
References metalworkers: a prospective study. Contact Dermatitis 31:
176-180
Grevelinck SA, Murrell DF, Olsen EA (1992) Effectiveness of
Blanken R, Nater JP, Veenhoff E (1987a) Protective effect of various barrier preparations in preventing and/or ameliorat-
barrier creams and spray coatings against epoxy resins. ing experimentally produced toxicodendron dermatitis. J Am
Contact Dermatitis 16:79-83 Acad Dermatol 27:182-188
Blanken R, van der Valk PGM, Nater JP, Dijkstra H (1987b) After- Grove GL (1991) The effect of moisturizers on skin surface
work emollient creams: effects on irritant skin reactions. hydration as measured in vivo be electrical conductivity. Curr
Derm Beruf Umwelt 35:95-98 Ther Res 50:712-719
Blanken R, Van Vilsteren MJZ, Tupker RA, Coenraads PJ (1989) Grunewald A, Gloor M, Gehring W, Kleesz P (1995) Efficacy of
Effect of mineral oil and linoleic-acid-containing emulsions skin barrier creams. In: Elsner P, Maibach HI (eds) Irritant
on the skin vapour loss of sodium-lauryl-sulphate-induced dermatitis: new clinical and experimental aspects. Karger,
irritant skin reactions. Contact Dermatitis 20:93-97 Basel, pp 187-197
Blichmann CW, Serup 1, Winther A (1989) Effects of single Gupta BN, Shanker R, Viswanathan PN, et al. (1987) Safety
application of a moisturizer: evaporation of emulsion water, evaluation of a barrier cream. Contact Dermatitis 17:10-12
skin surface temperature, electrical conductance, electrical Halkier-S0rensen L, Thestrup-Pedersen K (1993) The efficacy of a
capacitance and skin surface (emulsion) lipids. Acta Derm moisturizer (Locobase) among cleaners and kitchen assis-
Venereol 69:327-330 tants during everyday exposure to water and detergents.
Boman A, Mellström GA (1989) Percutaneous absorption of 3 Contact Dermatitis 29:266-271
organic solvents in the guinea pig (IlI). Effect of barrier Hannuksela A, Kinnunen T (1992) Moisturizers prevent irritant
creams. Contact Dermatitis 21:134-140 dermatitis. Acta Derm Venereol 72:42-44
Boman A, Wahlberg JE, Johansson G (1982) A method for the Hogan DJ (1993) The prognosis of hand eczema. In: Menne T,
study of the effect of barrier creams and protective gloves on Maibach HI (eds) Hand eczema. CRC Press, Boca Raton,
the percutaneous absorption of solvents. Dermatologica pp 285-292
164:157-160 Hogan D1, Dannaker q, LaI S, Maibach HI (1990) An interna-
Elsner P, Wigger-Alberti W, Pantini G (1998) Perfluoropolyethers tional survey on the prognosis of occupational contact
in the prevention of irritant contact dermatitis. Dermatology dermatitis of the hands. Derm Beruf Umwelt 38:143-147
197:141-145 Jepsen JR, Sparre-Jorgensen A, Kyst A (1985) Hand protection for
Fine Olivarius F, Brinch Hansen A, Karlsmark T, Wulf HC (1996) car-painters. Contact Dermatitis 13:317-320
Water protective effect of barrier creams and moisturizing Korstanje C, Ligtvoet FPT, Van Hemert KHF (1992) Differential
creams: a new in vivo test method. Contact Dermatitis 35: effects of dermatological cream bases with respect to skin
219-225 surface moisturizing capacity: a study design in volunteers.
Fowler JF (1994) Treatment of occupational dermatitis. In: Hogan J Dermatol Treatment 2:137-139
DJ (ed) Occupational skin disorders. Igaka-Shoin, New York, Lachapelle JM (1995) Principles of prevention and protection in
pp 104-111 contact dermatitis with special reference to occupational
Frosch pI, Kurte A (1994) Efficacy of skin barrier creams (IV). dermatology. In: Rycroft RJG, Menne T, Frosch PJ (eds)
The repetitive irritation test (RIT) with a set of 4 standard Textbook of contact dermatitis. Springer, Berlin Heidelberg
irritants. Contact Dermatitis 31:161-168 New York, pp 695-702
Frosch P, Schulze-Dirks A, Hoffmann M, Axthelm I (t993a) Lachapelle JM (1996) Efficacy of protective creams and/or gels.
Efficacy of skin barrier creams (II). Ineffectiveness of a In: Elsner P, Lachapelle JM, Wahlberg J, Maibach HI (eds)
popular "skin protector" against various irritants in the Prevention of contact dermatitis. (Curr Probl Dermato!)
repetitive irritation test in the guinea pig. Contact Dermatitis Karger, pp 182-192
29:74-77 Lauwerys RR, Dath T, Lachapelle JM, Buchet JP, Roels H (1978)
Frosch P, Schulze D, Hoffmann M, Axthelm I, Kurte A (1993b) The influence of two barrier creams on the percutaneous
Efficacy of skin barrier creams (I). The repetitive irritation absorption of m-xylene in man. J Occup Med 20:17-20
test (RIT) in the guinea pig. Contact Dermatitis 28:94-100 Loden M (1986) The effect of 4 barrier creams on the absorption
Frosch PJ, Kurte A, Pilz B (1993c) Efficacy of skin barrier creams of water, benzene, and formaldehyde into excised human
(II!). The repetitive irritation test (RIT) in humans. Contact skin. Contact Dermatitis 14:292-296
Dermatitis 29:113-118 Loden M (1997) Barrier recovery and influence of irritant stimuli
Fullerton A, Menne T (1995) In vitro and in vivo evaluation of the in skin treated with a moisturizing cream. Contact Dermatitis
effect of barrier gels in nickel contact allergy. Contact 36:256-260
Dermatitis 32:100-106 Loden M, Andersson AC (1996) Effect of topically applied lipids
Gabard B (1994) Testing the efficacy of moisturizers. In: Elsner P, on surfactant-irritated skin. Br J DermatoI134:215-220
Berardesca W, Maibach HI (eds) Bioengineering and the skin: Mahmoud G, Lachapelle JM (1985) Evaluation of the protective
water and the stratum corneum. CRC Press, Boca Raton, value of an antisolvent gel by laser Doppler flowrnetry and
pp 147-167 histology. Contact Dermatitis 13:14-19
Gabard B, Elsner P, Treffel P (1996) Barrier function ofthe skin in Mahmoud G, Lachapelle JM, Van Neste D (1984) Histological
a repetitive irritation model and influence of 2 different assessment of skin damage by irritants: its possible use in the
treatments. Skin Res Technol 2:78-82 evaluation of a 'barrier cream'. Contact Dermatitis 11:179-185
496 W. Wigger-Alberti and P. Eisner: Barrier Creams and Emollients
Man MQ, Feingold KR, Elias PM (1993) Exogenous lipids Wigger-Alberti W, Eisner P (1997b) Petrolatum prevents irrita-
inftuence permeability barrier recovery in acetone-treated tion in a human cumulative exposure model in vivo.
murine skin. Arch Dermatol 129:728-738 Dermatology 194:247-250
Marks jG jr, Fowler jF jr, Sheretz EF, Rietschel RL (1995) Wigger-Alberti W, Eisner P (1998) Do barrier creams and g10ves
Prevention of poison ivy and poison oak allergie contact prevent or provoke contact dermatitis? Am J Contact Dermat
dermatitis by quaternium-18 bentonite. j Am Acad Dermatol 9:100-106
33:212-216 Wigger-Alberti W, Maraffio B, Wernli M, Elsner P (1997a) Self-
Marks R, Dykes Pj, Hamami I (1989) Two novel techniques for application of a protective cream: pitfalls of occupational skin
the evaluation of barrier creams. Br J Dermatol 120:655-660 protection. Arch DermatoI133:861-864
Menne T (1995) Prevention of nickel dermatitis. Allergologie Wigger-Alberti W, Maraffio B, Eisner P (1997b) Anwendung von
18:447 Hautschutpräparaten durch Patienten mit Berufsdermatosen:
Mortz CG, Andersen KE, Halkier-S0rensen L (1997) The efficacy Notwendigkeit einer verbesserten Verhaltensprävention.
of different moisturizers on barrier recovery in hairless mice Schweiz Med Wochensehr 127:899-904
evaluated by non-invasive bio engineering methods. Contact Wigger-Alberti W, Maraffio B, Elsner P (1997C) Training workers
Dermatitis 36:297-301 at risk for occupational contact dermatitis in the applieation
Pinola A, Estlander T, jolanki R, Tarvainen K, Kanerva L (1993) of protective creams: efficacy of a fluorescence technique.
Occupational allergic contact dermatitis due to coconut Dermatology 195:129-133
diethanolamide (cocamide DEA). Contact Dermatitis 29: Wigger-Alberti W, Rougier A, Richard A, Eisner P (1998) Efficacy
262-265 of protective creams in a modified repeated irritation test
Ramsing DW, Agner T (1997) Preventive and therapeutic effects (RIT): methodological aspects. Acta Derm Venereol 78:
of a moisturizer. An experimental study of human skin. Acta 270- 273
Derm Venereol 77:335-337 Wigger-Alberti W, Caduff L, Burg G, Elsner P (1999) Experi-
Romaguera C, Grimalt F, Vilaplana J, et al. (1985) Formulation of a mentally-induced chronic irritant contact dermatitis to eval-
barrier cream against chromate. Contact Dermatitis 12:49-52 uate the efficacy of protective creams in vivo. J Am Acad
Schlüter-Wigger W, Eisner P (1996) Efficacy of 4 commercially Dermatol 40:590-596
available protective creams in the repetitive irritation test Wohlrab W (1984) The inftuence of urea on the penetration
(RIT). Contact Dermatitis 34:278-283 kinetics of topically applied corticosteroids. Acta Derm
Schuppli R, Ziegler G (1967) Neue Möglichkeiten des Ha- Venereol 64:233-238
utschutzes gegen Metalle. Z Haut Geschlechtskrankh 42: Wohlrab W (1990) The influence of urea on the penetration
345-348 kinetics of vitamin-A-acid into human skin. Z Hautkr 65:
Serup j, Winther A, Blichmann CW (1989) Effect of repeated 803-805
application of a moisturizer. Acta Derm Venereol 69:457-459 Zhai H, Maibach HI (1996a) Percutaneous penetration (dermato-
Suskind RR (1955) The present status of silicone protective pharmacokinetics) in evaluating barrier creams. In: Elsner P,
creams. Ind Med Surg 24:413-416 Lachapelle JM, Walrlberg J, Maibach HI (eds) Prevention of
Treffel P, Gabard B (1995) Stratum corneum dynamic function contact dermatitis. (Curr Probl Dermatol). Karger, Basel,
measurements after moisturizer or irritant application. Arch pp 193-205
Dermatol Res 287:474-479 Zhai H, Maibach HI (1996b) Effect ofbarrier creams: human skin
Treffe! P, Gabard B, Juch R (1994) Evaluation of barrier creams: in vivo. Contact Dermatitis 35:92-96
an in vitro technique on human skin. Acta Derm Venereol Zhai H, Maibach HI (1998) Moisturizers in preventing irritant
74:7- 11 contact dermatitis: an overview. Contact Dermatitis 38:
Tronnier H (1993) Methodische Ansätze zur Prüfung von 241- 244
Hautschutzmitteln. Dermatosen 41:100-107 Zhai H, Willard P, Maibach HI (1998) Evaluating skin-protective
Wigger-Alberti W, Eisner P (1997a) Preventive measures in materials against contact irritants and allergens. Contact
contact dermatitis. Clin Dermatol 15:661-665 Dermatitis 38:155-158
CHAPTER 63
Fragrances
A.C. de Groot
Introduction household products, and soap. Fenn (1989) examined

the "aroma chemical usage trends in modern perfum-
Perfumes are so much apart of our culture that we ery" by analysing the "TOP-25" materials in 400
take them for gran ted, but if they were suddenly taken cosmetic products: fine fragrances (perfumes, toilet
from us, our culture would suffer immeasurably. We water, some creams), household products (fabric
do pay a price for their service, and part of that is softeners, cleansers), and soaps (bar, tablet). In each
dermatologic and other medical reactions. This chap- group were commonly purchased products in the
ter discusses side effects of fragrance materials present United States of America. The most frequently iden-
in cosmetic products. For a fuH review of this subject, tified fragrances were linalool (present in 90% of
including adverse reactions to balsam of Peru (which is products), phenylethyl alcohol (82%), linalyl acetate
used as a marker for fragrance sensitivity, Fisher 1990), (78%), benzyl acetate (74%), and benzyl salicylate
to fragrances from non-cosmetic sources (e.g. fiavours (74%) (Table 2). Weyland (cited by De Groot et al.
in food) and to essential oils the reader is referred to 1994) analysed 300 cosmetic products sold on the
De Groot and Frosch (1997). Arecent book on Dutch market, and also found linalool and phenylethyl
beneficial and adverse effects of fragrances also pro- alcohol to be the most frequently incorporated fra-
vides valuable information (Frosch et a1. 1998). The gran ce materials (Table 2). Seventeen of the American
history of fragrances has been weH described by Guin "ToP-25" were also on the Dutch list and vice versa. Six
(1982) and Scheinman (1996). chemicals (linalool, phenylethyl alcohol, linalyl acetate,
benzyl acetate, terpineol and y-methylionone) were in
the top ten of identified fragrance materials for both
The Composition of Perfumes lists. Of the eight fragrances present in the fragrance
mix (vide infra), four belonged to the top 25: geraniol
(43% and 50%), eugenol (26% and 36%) I)(-amylcin-
Perfumery is the art of making individuals and
products attractive to the olfactory sense. Of the namic aldehyde (21% and 35%), and hydroxycitroneHal
thousands of chemical substances that have an odour, (21% and 49%) (Table 2).
about 3000 (of which 300-400 are of natural origin),
are used in the fragrance industry. A perfume is a Table 1. Concentrations of perfume in various products (Schein-
creative composition of a few to over 300 fragrance man 1996; De Groot et al. 1994)
materials. "Proper" perfumes contain approximately
Aerosol freshener 0.5-2%
l2-20% of the perfume compound. They are expensive Bathroom cleaners :;:;5%
and too concentrated. The more diluted products Colognes 2-5%
(perfume lotion, perfume de toilette, eau de toilette, Compressed powder 0.5%
Dishwashing liquid 0.1-0.5%
colognes) are therefore much more popular. Approx- Facial make-up 1.0%
imate concentrations of fragrance materials in cosmet- Hair pomade 0.5%
ics and other products are given in Table 1 (Larsen Hair spray 0.1-0.3%
Laundry powder 0.1-0.3%
1985; De Groot et a1. 1994; Scheinman 1996). Lipstick 1.0%
Details of the composition of a particular fragrance Liquid detergents 0.1-1%
are closely guarded by industry, which maintains that Masking perfume :;:;0.1 %
Perfume 12-20% (or higher)
secrecy of the formulae is fuHy commensurate with Perfume lotion 5-8%
investment in the development and marketing of a Shower and bath formulations 0.5-4%
product. Two studies have examined the nature of Skin care products (emulsions) 0.3-0.5%
Soap 0.5-2%
fragrance materials used in perfumes, cosmetics, roilet water 5-8% (or higher)

498 A.C. de Groot
Table 2. Most commonly found fragrances in cosmetics and toiletries
Rank order Fragrances found Percentagea Fragrances found in 300 products Percentage a
in 400 products in the USAb,c in the Netherlands d
1 Linalool 90 Linalool 91
2 Phenylethyl alcohol 82 Phenylethyl alcohol 79
3 Linalyl acetate 78 Benzyl acetate 78
4 Benzyl acetate 74 Limonene 71
5 Benzyl salicylate 74 Citronellol 71
6 Coumarin 68 Linalyl acetate 67
7 Terpineol 66 y-Methylionone 63
8 Hedione 56 Terpineol 52
9 Hexylcinnamic aldehyde 51 ß-Pinene 51
10 y-Methylionone 51 Geraniol 50
11 Terpinyl acetate 50 Hydroxycitronellal 49
12 Lilial 49 Benzyl benzoate 49
13 Lyral 46 Hexylcinnamic aldehyde 48
14 Geraniol 43 Lilial 48
15 Heliotropin 43 Coumarin 44
16 Galaxolide 41 Benzyl salicylate 43
17 Acetyl cedrene (Vertofix) 41 Benzyl alcohol 42
18 Musk ketone 38 Eugenol 36
19 Citronellol 38 Ct-Pinene 35
20 Amyl salicylate 32 Geranyl acetate 35
21 Eugenol 26 Ct-Amylcinnamic aldehyde 35
22 Vertenex 25 Musk ketone 34
23 Isobornyl acetate 23 Caryophyllene 33
24 Ct-Amylcinnamic aldehyde 21 Lyral 33
25 Hydroxycitronellal 21 Camphor 31
a Percentage of products containing the fragrances listed

b These fragrances may be present at a concentration of >1% in "fine perfumes"
cFrom Fenn (1989)
d From De Groot et al. (1994)
Contact with Fragrances and Fragranced Products and flavours. Natural fragrances like cinnamon, clove,
vanilla and cardamon are added to foods, soft drinks,
The use of fragrances is ubiquitous and not li mi ted to lozenges, chewing gum, candies, ice cream and tobacco.
those cosmetic products that are used primarily for Thus, it can be stated that virtually everyone is in daily
their scent (such as perfumes, eaux de cologne, eaux de contact with fragrance materials.
toilette, deodorant and aftershave). Virtually all cos- Contact with fragrances may be from direct product
metics and toiletries contain fragrance materials; even application to the skin or mucous membranes [tooth-
"unscented" or "fragrance-free" products may contain paste, mouth fresheners, feminine hygiene sprays,
a masking perfume. Flavours used in oral hygiene perfumed eyedrops (Meynadier et al. 1986)], by occa-
products - toothpaste, mouthwash, and dental floss - sional contact with an allergen-contaminated product
are fragrance chemicals. Scented household products such as towels and pillows, contact with products used
include detergents (Rothenborg and Hjorth 1968), by partners, friends or co-workers (consort or connu-
cleaners, softeners, deodorising sprays, polishes, sol- bial contact dermatitis) (Morren et al. 1992; Fisher
vents and waxes. In industry, cutting fluids (Panconesi 1995), airborne contact (Dooms-Goossens and Deleu
et al. 1980), electroplating fluids, paints, rubber, plas- 1991; Dooms-Goossens 1993), and systemic exposure
tics, insecticides, herbicides and additives used in air by inhalation and ingestion (fragrances, flavours and
conditioning water may all be scented. Eugenol is spices in foods and drinks, cough syrup).
occasionally used by dentists. Paper and paper prod- Any part of the body may be in contact with
ucts - including diapers, facial tissues, mo ist toilet fragranced cosmetics - scalp: shampoo, hair lacquer,
paper (De Groot et al. 1991) and sanitary napkins - hair gel; face: skin care products, aftershave, perfumed
may cause areaction. Fabrics and clothes may contain tissue handkerchiefs, airborne from perfumes on
fragrance materials, especially after they are laundered clothing; the eyelids: eye cosmetics; the lips: lipstick,
or treated with a fabric softener. Topical drugs often toothpaste; the neck: aftershave, perfume; the trunk:
contain perfumes (Garioch et al. 1989), and ventilating body lotion; the axillae: deodorant and antiperspirant;
systems may spread fragrances (Larsen 1989). The the arms and legs: body lotion; the perianal area:
distinction between fragrances and spices is often fragranced (moistened) toilet tissue; the vulvar area:
indistinct. Many synthetic fragrances are used as spices feminine hygiene sprays, sanitary napkins, topical
Fragrances 499
drugs; the hands: moisturising creams, soap; and the 1993). Micro-traumata from shaving facilitates (photo)
feet: seen ted antiperspirants. contact allergy to aftershave fragrances (Edman 1994).
Most reactions are erythematous, and some cases
may resemble nummular eczema, seborrhoeie derma-
Adverse Reactions titis, sycosis barbae, or lupus erythematosus (Meyna-
dier et al. 1986). More acute lesions with papules,
Adverse reactions to fragrances/fragranced cosmetics vesic1es and oozing may sometimes be observed.
appear to be far from rare. Guin and Berry (1980) Lesions in the skin folds may be mi staken for atopic
conducted a questionnaire study of 90 student nurses; dermatitis. Dermatitis due to perfumes or toilet water
29 (32%) gave a history of cutaneous fragrance tends to be "streaky" (Fisher 1980). Facial psoriasis
intolerance. When tested with the fragrance mix may be induced/aggravated by allergie contact derma-
(8 x 2%), 15 (18%) showed a positive reaction. Of titis from fragrances (De Groot and Liem 1983a).
these 15, 12 (80%) had a positive history of fragrance Hand eczema is common in fragrance-sensitive
sensitivity. Of the nurses with a negative patch test patients (Malten et al. 1984; Santucci et al. 1987;
reaction, only 21% considered themselves to be Christophersen et al. 1989; Johansen et al. 1996). Usu-
fragrance sensitive (Guin and Berry 1980). ally, patients first have irritant dermatitis or atopic
De Groot et al. (1987) interviewed 1609 adult dermatitis, which is later complicated by contact
subjects and 196 (12%) reported reactions to various allergy to products used for treatment (fragranced
kinds of cosmetics and toiletries in the preceding topieal drugs) or prevention (hand creams and lotions)
5 years. Sixty-nine of these (35% of the reactors and of hand dermatitis, or to other perfumed products in
4.3% of the total population) attributed their reactions the household, hobby, or work environment.
to products used primarily for their smell (45, Dyshidrotic eruptions are ascribed to ingestion of
deodorants; 16, aftershave; 8, perfumes). In Denmark, spie es (Meynadier et al. 1986). Atopic dermatitis
567 unselected individuals aged 15-69 years were tested located at other body sites, perianal dermatitis (De
with the fragrance mix, and 6 (1.1%) had a positive Groot et al. 1991), and vulvar dermatitis (Lewis et al.
re action (Nielsen and Menne 1992). The frequency of 1997) mayaiso be complicated by fragrance allergy.
reactivity in men (1.1%) was identieal to that in women
(1.0%).
The adverse reaction seen most frequently by Detecting Allergie Contact Dermatitis
dermatologists in response to fragrances is allergie from Fragranees with the Fragranee Mix
contact dermatitis. In most countries, the fragrance
mix is positive in 6-11% of patients patch tested A perfume may contain as many as 200 or more
for suspected allergie contact dermatitis. Perfurnes individual ingredients. This makes the diagnosis of
account for 4-18% of all reactions, and deodorants/ perfume allergy by patch test procedures complicated.
antiperspirants account for 5-17% of all cases of Screening agents such as the fragrance mix, balsam of
allergie cosmetic dermatitis (Adams and Maibach Peru and, to some extent, colophony have been
1985; De Groot 1987, 1988; De Groot et al. 1988; De incorporated into the standard se ries to overcome
Groot et al. 1994). the problem. The fragrance mix, or perfume mix, was
introduced as a screening tool for fragrance sensitivity
in the late 1970s, following the important work of
Larsen (1979). It contains eight fragrance materials:
Clinieal Picture of Allergie Contact Dermatitis eugenol, isoeugenol, oak moss, geraniol, hydroxy-
from Fragranees citrolellal, et-amylcinnamie aldehyde, cinnamic alde-
hyde and cinnamic alcohol. It is estimated that this
Literature on the c1inical picture of perfume dermatitis mix detects 70-80% of fragrance sensitivity cases
is rather scant and a good description is lacking. It can (Larsen 1985).
be expected, however, that the neck, skin behind the The response rate in dermatologie al patients to the
ear and axillae (Edman 1985) are often implicated, fragrance mix and its ingredients ranges worldwide
given that they are exposed to products with high from 6% to 11%, and the fragrance mix is usually the
concentrations of fragrances (perfume, deodorant). second most frequent allergen after niekel sulphate (De
Also, the sensitive skin of the face (Larsen et al. 1996) Groot and Frosch 1997).
and the eyelids should be particularly susceptible to Several studies have investigated the frequency of
developing allergie contact dermatitis to fragrances in allergie reactions to the ingredients of the fragrance
skin care products, decorative cosmetics and c1eansing mix (Santucci et al. 1987; Enders et al. 1989; De Groot
preparations, and from airborne contact dermatitis et al. 1993; Becker et al. 1994; Frosch et al. 1995a,b;
(Dooms-Goossens and Deleu 1991; Dooms-Goossens Johansen and Menne 1995). Although the results have
500 A.C. de Graot
varied widely, most reactions appear to be caused by Groot et al. 1985; Frosch et al. 1995a), and the constit-
oak moss, isoeugenol and cinnamic aldehyde (Johan- uents of the fragrance mix have remained the same for
sen et al. 1996), whereas geraniol, ex-amylcinnamic over 15 years. Testing additional fragrances may result
aldehyde and hydroxycitronellal usually yield lower in identification of more fragrance-sensitive individu-
positive reaction scores. als (Larsen et al. 1996).
Sensitivity to oak moss (Gons:alo et al. 1988) is
frequently induced by tlIe use of aftershave lotions,
because the integrity of the epidermis is lost during Clinical Relevance of a Positive Reaction
shaving, facilitating sensitisation. Lichen acids (present to the Fragrance Mix
in oak moss) tlIat cause reactions in allergie patients
include atranorin, usnic acid, evernic acid, fumarpro- As with any contact allergen, the finding of a positive
tocetraric acid, stitic acid, physodes/physodalic acid reaction to the fragrance mix should be followed by a
and diffractaic acid (Swinyer 1980; Thune et al. 1982; search for its relevance. Often, however, correlation
Fregert and Dahlquist 1983). Contact allergy to lichen with the clinical picture is lacking and many patients
acids mayaiso be acquired from woods and plants can tolerate perfumes and fragranced products witlIout
(Stinchi et al. 1997). problems. This may sometimes be explained by irritant
The fragrance mix that is used currently (8 x 1% patch test reactions to the mix. Alternative explana-
with 5% sorbitan sesquioleate) is very useful, but not tions include the absence of relevant allergens in tlIose
ideal. It causes irritant reactions (Frosch et al. 1995a,b), products or a concentration too low to elicit clinically
irrelevant positive reactions (Enders et al. 1989; visible allergie contact reactions. In addition, in the
Malanin and Ohela 1989; Frosch et al. 1995b; Johansen ageing process of a perfume, tlIe allergen may be
and Menne 1995), false-negative reactions (De Groot inactivated (Fisher and Dooms-Goossens 1976). It is
et al. 1985; De Groot et al. 1993), and leaves 20-30% of uncertain whetlIer the phenomenon of quenching, by
fragrance sensitivities undetected (Larsen 1985; Johan- which the allergenicity of a fragrance compound is
sen et al. 1997). In addition, it is not uncommon for inhibited by tlIe addition of a quencher fragrance, may
patients with clearly positive reactions to the fragrance playa role (Opdyke 1976; Basketter and Allenby 1991).
mix to have a negative break-down, i.e. no positive In various studies, tlIe relevance of positive patch-
reactions to one or more of its ingredients. This test reactions to the mix has been investigated (San-
phenomenon (assuming that the re action to the mix tue ci et al. 1987; Frosch et al. 1995b; Marks et al. 1995;
was not false positive) remains unexplained. Johansen et al. 1996). However, criteria were often not
The reverse situation - a negative re action to the provided. In cases witlI concomitant positive reactions
mix witlI a positive re action to one or more ingredi- to perfumes or fragranced products used by the
ents, i.e. a false-negative reaction to tlIe mix - mayaiso patient, interpretation of tlIe reaction as relevant may
occur. This may be overcome by testing the ingredients be quite easy. Often, however, relevance may (correctly
in a high er than currentlY recommended concentration or incorrectly) only be assumed, as tlIe role of
(all except cinnamic aldehyde 3% in petrolatum) (De fragrances likely cannot be excluded because of the
Groot et al. 1985; De Groot et al. 1993). ubiquitous occurrence of fragrances and multiple
Sorbitan sesquioleate present in the mix may possible exposure moments from indirect contact,
occasionally induce an allergie response (Frosch et al. airborne exposure, inhalation or ingestion (flavors,
1995b). Therefore, this emulsifier should always be spices).
routinely tested to avoid misinterpreting a positlve Clinical relevance of a positive patch-test reaction
reaction to sorbitan sesquioleate in tlIe mix as may exist for at least 55-65% of positive results.
fragrance allergy. Strongly positive patch test reactions (2+ or 3+) are
Future research should be directed both at optimis- more likely to be associated witlI a positive fragrance
ing the test concentration of the mix and its ingredi- his tory tlIan a weak or doubtful reaction (Frosch et al.
ents and at finding more suitable allergens for a 1995b). A positive ROAT (repeated open application
screening fragrance mix (De Groot et al. 1993). Ge- test, twice daily application on tlIe antecubital fossa for
raniol and ex-amylcinnamic aldehyde would be the first a maximum of two weeks) (Johansen et al. 1996) with
candidates to be replaced, as tlIey yield relatively few fragrance ingredients makes relevance of the reaction
reactions (De Groot et al. 1993; Frosch et al. 1995a; more likely.
Johansen and Menne 1995). Several studies have indeed
aimed at identifying fragrances that would be, by their
frequency of sensitisation, more suitable for inclusion Less Common Fragrance Allergens
in a fragrance mix. WitlI tlIe possible exception of
citral and dihydrocoumarin (Wilkinson et al. 1989), all Several investigators have routinely tested one or more
these efforts have yielded no suitable candidates (De fragrance materials in patients suspected of contact
Fragrances 501
dermatitis (Rudner 1977; Mitchell et al. 1982; Santucci reactions to the fragrance mix in hairdressers, but the
et al. 1987; Sugawara et al. 1990; Utsumi et al. 1992; frequency in controls was as high. Reactions to
Paulsen et al. 1993; Sugai 1994a; Frosch et al. 1995a). cinnamie alcohol and cinnamic aldehyde occurred less
Prevalence rates of greater than 1% have been observed frequently in hairdressers than in referents (Holness
with benzyl salieylate (Rudner 1977; Sugai 1994a), and Nethercott 1990). In Italy, Guerra et al. (1992)
carvone (possibly irritant reactions, Paulsen et al. considered nine reactions to fragrance mix to be
1993), citral (Mitchell et al. 1982), coumarin (Rudner relevant in 184 hairdressers with allergic occupational
1977), farnesol (Utsumi et al. 1992), isobornyl cydo- contact dermatitis). In the Netherlands, Van der Walle
hexanol (synthetic sandalwood oil) (Utsumi et al. and Brunsveld (1994) reported eight positive reactions
1992), jasmine absolute (Rudner 1977; Santucci et al. in 103 hairdressers, but did not comment on the
1987; Sugai 1994a), jasmine synthetic (Rudner 1977), relevance of these reactions.
methyl salicylate (Mitchell et al. 1982), musk ambrette In Italy, Gola et al. (1992) found the fragrance mix to
(Rudner 1977), oil of bergamot, rose oil (Sugai 1994a), be the second most frequent allergen in non-occupa-
sandalwood oil (Utsumi et al. 1992; Sugai 1994a), tional contact dermatitis, even though it was not one of
santalol (Utsumi et al. 1992), and ylang-ylang oil the top 10 allergens in occupational contact dermatitis.
(Sugawara et al. 1990; Sugai 1994a). In other studies, In their occupational contact dermatitis dinie, Holness
various fragrances were tested in patients suspected to and Nethercott (1994) tested 601 and found almost 20%
have cosmetic or fragrance allergies (Malten et al. 1984; positive reactions to the fragrance mix. However, in
De Groot et al. 1985; Larsen et al. 1996). In the more only 3% of the positive reactors was the allergy feIt to be
re cent international study (Larsen et al. 1996), most work-related. In Australia, perfume fragrances were
reactions were to ylang-ylang oil (17%), narcissus oil listed as allergens in 3 of 103 women with occupational
(7%), sandela (7%), sandalwood oil (7%), majantol allergic contact dermatitis (Wall and Gebauer 1991);
(5%), benzyl salicylate (5%) and galbanum res in (5%). fragrances were not implicated in any of the 265 men. In
A list of documented fragrance allergens is provided in Taiwan, Sun et al. (1995) found six reactions (8.8%) to
Table 3, with their test concentrations and relevant the fragrance mix to be relevant in 68 patients with
reference(s). occupational allergic contact dermatitis: four in hair-
dressers, one in construction and one in medical work.
Goodfield and Saihan (1988) found a 44% prevalence
Occupational Allergie Contad Dermatitis of sensitivity to one or more fragrances in 35 coal
to Fragrances miners, compared with 22% in male and 17% in female
non-miner controls. The high frequency was attributed
It may be expected that fragrances will cause derma- to the use of a highly perfumed body lotion provided at
tological problems for workers in the cosmetics the pit-head bath, and to the facilitation of contact
industry (cosmetic chemists, workers handling the sensitisation due to the frequent occurrence of irritant
raw materials and the final products, salespeople), dermatitis from working in the coal-mines (Goodfield
beauticians, hairdressers, and aroma therapists. and Saihan 1988).
Housewives, health personnel and deaning personnel On the basis of these data, it is conduded that
mayaiso be endangered by frequent contact with soap, fragrances may playa role in some cases of occupa-
deansers, dishwashing liquids and other fragranced tional contact dermatitis, but in no single profession
products. In spite of this, surprisingly litde informa- are they a major cause of occupational allergie contact
tion on occupational allergie contact dermatitis from dermatitis, and rarely are they the sole aetiological
fragrances can be found in the literature [aIthough in factor. However, fragrances may play an important role
an early study all workers in a factory became in aggravating hand eczema of other origin (atopic
sensitised to cinnamic aldehyde, (Bonnevie 1948)]. hand eczema, irritant dermatitis, allergic contact der-
This may be because in the majority of people at risk, a matitis) by contact with hand deansers, barrier creams,
definitive relationship between dermatitis and fra- moisturising preparations, etc. In addition, fiavours
grances is hard to prove. In many occupations and spices may be involved in occupational contact
(hairdressers, beauticians, housewives, heaIth person- dermatitis in bakers, cooks, caterers, and others
nei, deaning personnel) irritant factors mayaiso be working in the food industry. For documented case
relevant in the aetiology of dermatitis, and sometimes reports of occupational allergic contact dermatitis from
other allergens are also considered of paramount fragrances see Gutman and Somov (1968), Calnan
importance. In addition, non-occupational exposure (1969), Dahlquist and Fregert (1981), Nethercott et al.
to fragrances occurs in virtually everybody. (1983), Zacher and Ippen (1984), Brandäo (1986),
Most of the pertinent information comes from English and Rycroft (1988), Freeman (1990), Rudzki
studies of hairdressers. Holness and Nethercott et al. (1993), Rademaker (1994) and, Kanerva et al.
(1990) found a very high frequency (18%) of allergic (1995).
502 A.C. de Groot
Table 3. Fragrances reported as allergens in cosmetics and toiletries'
Name of fragrance Test Reference

concentration/vehiclee
Acetylcedrene (Vertofix) 1%-5% pet Handley and Burrows 1994; Frosch et al. 1995a
5-Acetyl-l,1 ,2,3,3,6-hexamethylindan 3% pet Meynadier et al. 1986
(Phantolide)
Amyl cinnamate 8% pet Malten 1979
rx-Amylcinnamic alcohol 5% pet Larsen 1979; Guin and Haffley 1983;
Oe Groot et al. 1985
rx-Amylcinnamic aldehyded 3%-5% pet Guin and Haffley 1983; Frosch et al. 1995a
Amyl salicylate 5% pet Larsen 1977; Frosch et al. 1995a
Anethole 5% pet Larsen 1977
Anisyl alcohol d 5% pet28 Larsen 1977
Anisylidene acetone 2% pet Malten et al. 1984
Atranorin (in oak moss)C 0.5% pet Thune et al. 1982; Gon~alo et al. 1988;
Lorenzi et al. 1995
Benzyl acetate 5% pet Larsen 1977
Benzyl alcohold,b 5% pet Larsen 1977; Malten et al. 1984;
Sugai 1994a; Larsen et al. 1996
Benzyl benzoated 5% pet Larsen 1977; Mitchell et al. 1982
Benzyl cinnamate 5% pet Malten et al. 1984
Benzylidene acetone 0.5% pet Malten 1979; Meneghini 1970;
Meynadier et al. 1986
Benzyl salicylateb 1% pet Rothenborg and Hjorth 1968;
Larsen 1977; Sousa Basto and
Azenha 1991; Sugai 1994a; Larsen et al. 1996
Carvacrol (isothymol) 5% pet Oe Groot et al. 1985; Meynadier et al. 1986
Cashmeran (6,7-dihydro-l,I,2,3, 5% pet Larsen et al. 1996
3-pentamethyl-4(5H)-indanone)
Cedramber (cedrol methyl ether) 5% pet Larsen et al. 1996
Cinnamic alcohold,b 3%-5% pet Frosch et al. 1995a; Nakayama 1995
Cinnamic aldehyded,C 1% pet Frosch et al. 1995a
Cinnamyl benzoate 5% pet Malten 1979
Cinnamyl cinnamated 5% pet Malten 1979
Citral 2% pet Malten 1979; Malten et al. 1984;
Mitchell et al. 1982; Wilkinson et al. 1989
Citronellol 5% pet Keil 1947; Larsen 1977; Oe Groot 1987;
Frosch et al. 1995a
Coumarind 5% pet Keil 1947; Larsen 1977; Malten et al. 1984;
Adams and Maibach 1985; Johansen et al. 1994;
Larsen et al. 1996
Cuminaldehyde 5% pet Oe Groot et al. 1985
Dehydro-isoeugenol ylang-ylang oil Toyoda et al. 1989
Diethyl maleate 2% pet Malten et al. 1984
Oiffractaic acid (in oak moss) 1% pet Thune et al. 1982
Dihydrocoumarin 5% pet Malten 1979; Malten et al. 1984;
Wilkinson et al. 1989
Oimethyl citraconate 10% pet Malten et al. 1984
OMBCA (dimethylbenzyl carbinyl acetate) 3% pet Frosch et al. 1995a
Ethyl acrylate 0.1 % Malten et al. 1984
Ethyl anisate 4% pet Malten 1977
Eucalyptol (l,8-cineole, cajeputol) 5% pet Oe Groot and Weyland 1992
Eugenold,c 3%-5% pet Frosch et al. 1995a
Evernic acid (in oak moss)C 0.1 % pet Thune et al. 1982; Gon~alo et al. 1988
Farnesol 5% pet Malten et al. 1984; Sugai 1994a;
Goossens and Merckx 1997
Fixolide 3% pet Meynadier et al. 1986
Floropal (acetaldehyde 2-phenyl-2, 5% pet Larsen et al. 1996
4-pentane-diol acetal)
Fumarprotecetraric acid (in oak moss) 0.1 % pet Gon~alo et al. 1988
Galbanum res in 2% pet Larsen et al. 1996
Geranial 1%-5% pet Nakayama et al. 1974
Geraniold,b 3%-5% pet Frosch et al. 1995a
Helional (rx-methyl-3,4-methylene 5% pet Larsen et al. 1996
dioxyhydrocinnamic aldehyde)
Heliotropin 5% pet Larsen 1977
1,3,4,6,7,8-Hexahydro-4,6,6,7,8, 15% pet De Groot et al. 1985
8-hexamethyl-cyclopenta-y-2-benzopyran (Galaxolide)
cis-3-Hexenyl salicylate 3% pet Van Ketel 1983
rx-Hexylcinnamic aldehyde 10% pet Oe Groot et al. 1985; Larsen 1977
Hexyl salicylate 12% pet
Fragrances 503
Table 3. (Contd.)
Hydroabietyl alcohol (Abitol) 10% pet Malten et al. 1984

Hydroxycitronellal b.c 3%-5% pet Frosch et al. 1995a
Ionone 8% pet De Groot et al. 1985; Bernaola et al. 1989
Isobornyl cyclohexanol (synthetic sandalwood)b 2% pet Utsumi et al. 1992; Sugai 1994a; Nakayama 1995
Isoeugenol 3%-5% pet Frosch et al. 1995a
IsopulegoI 5% pet Larsen 1977
Jasmine (absolute, synthetic)b 5%-10% pet Larsen 1977; Santucci et al. 1987; Sugai 1994a
Ligustral «methyl-(2,4(3, 5)-dimethyl-3-cyclo- 5% pet Larsen et al. 1996
hexen-l-yl)-methylene anthranilate)
Lilial (lily aldehyde, p-tert-butyl-Il- 5% pet Larsen 1983; De Groot et al. 1985; Santucci et al.
methylhydro-cinnnamic aldehyde 1987; Sugai 1994a; Larsen et al. 1996;
d-Limonene 2% pet De Groot et al. 1985; Karlberg et al. 1992
Linalool 2%-30% pet De Groot and Liem 1983a; De Groot 1987;
Schaller and Korting 1995
Lyral (4-4-hydroxy-4-methylpentyl)3-cyclo- 5% pet Benke and Larsen 1984; De Groot 1987;
hexenel-l-carboxaldehyde De Groot 1988; Handley and Burrows 1994;
Frosch et al. 1995a
Majantol (2,2-dimethyl-3-(3-methylphenyl)- 5% pet Larsen et al. 1996
propanol
0-Methoxycinnamic aldehyde 4% pet Malten 1979
Methoxycitronellalb 10% pet Nakayama et al. 1984
Methyl anisate 4% pet Malten 1977; Malten et al. 1984
Methyl heptine carbonate 0.5% pet/l % MEK Van Kete11978; Malten 1979; Mitchell et al. 1982;
Malten et al. 1984; English and Rycroft 1988
Methylionantheme 0.04% alc Bernaola et al. 1989
y-Methylionone 10% pet De Groot et al. 1985; De Groot 1987;
Bernaola et al. 1989
Methyl octine carbonate 1% MEK English and Rycroft 1988
Methyl salicylate 2% pet Mitchell et al. 1982; Romaguera et al. 1983
Musk ambrettec.b 5% pet Cronin 1984; Santucci et al. 1987; Sugai 1994a;
Nakayama 1995
Musk moskenec 5% pet Cronin 1984; Parry and Beck 1997
Musk xylenec 5% pet Cronin 1984
Narcissus oil 2% pet Larsen et al. 1996
Neral 2% pet Malten et al. 1984
Nopyl acetate 10% pet De Groot et al. 1985
Oak mossc 3%-5% pet Gonc;:alo et al. 1988; Frosch et al. 1995a
Patchouli oil b 2% pet Hausen and Kunze 1991; Larsen et al. 1996
Phellandrene ? Dooms-Goossens et al. 1977
Phenylacetaldehyde (hyacinthin) 0.5% pet Malten 1979; Malten et al. 1984
Phenylethyl alcohol 5% pet Larsen 1977; De Groot et al. 1985
Physodes/physodalic acid (in oak moss) 0.1 % pet Thune et al. 1982
ß-Pinene 15% pet Santucci et al. 1987
Propylidene phthalide 2% pet Malten et al. 1984
Rhodinol (mixture of l-citronellol and geraniol) 3% pet Hausen and Kunze 1991
Rose oil (Bulgarian) 2% pet Vilaplana et al. 1991; Schauder and Ippen 1997
Sandalore (5-( -2,2,3-trimethyl-3- 5% pet Larsen et al. 1996
cyclopentenyl)-3-methylpentan-2-01)
Sandalwood oil 2% pet Adams and Maibach 1985; Larsen et al. 1996
Sandela (isobornyl cyclohexanol + 5% pet Larsen et al. 1996
3-trans-isocamphyl cyclohexanol)
Santalolb 2% pet Utsumi et al. 1992; Sugai 1994a,b
Stitic acid (in oak moss) 0.1 % pet Gonc;:alo et al. 1988
Il-Terpineol 5% pet Larsen 1977; Santucci et al. 1987
1,1,6,7 -Tetramethyl-6-acetyl decalene 1%-5% pet Frosch et al. 1995a
(isomers) (Iso E Super)
Thymol 1% pet Larsen 1977
Tree moss absolute 5% pet Larsen 1977
Tricyclodecen-4-yl 8-acetate (Cyclacet) 5% pet Frosch et al. 1995a
Usnic acid (in oak moss) 0.1 % pet Thune et al. 1982; Heine 1987; Lim et al. 1992
Violet leaves absolute 2% pet Larsen et al. 1996
Ylang-ylang oilb 5% pet Sugawara et al. 1990; Kanerva et al. 1995;
Larsen et al. 1996
Pet petrolatum
a Presence in cosmetics not always proven; contact allergy sometimes established by routine testing
b Has caused pigmented cosmetic/contact dermatitis
c Has caused phototoxicity/photoallergy
d Has caused immediate contact reactions (contact urticaria)
e From De Groot (1994)
504 A.C. de Groot
Irritant Dermatitis (tentatively) interpreted as phototoxic rather than

photo allergie (Addo et al. 1982).
Few well-doeumented eases of irritant dermatitis from
fragranee materials ean be found in the literature
(Rothenborg et al. 1977). A large number of people Immediate Contact Reactions (Contact Urticaria)
broke out after the introduetion of a lemon-seented
detergent in a hospital. The temperature-dependent, Contaet urtiearia to fragrances is usually non-allergie
primary irritant reaetion from the lemon perfume was (non-immune immediate eontaet reaetions) (Safford
due to the chemieal, eitral (Rothenborg et al. 1977). et al. 1990), eaused by a non-allergie histamine-liber-
Although some authors state that irritant reaetions ating effeet. Well-known eauses are balsam of Peru,
oeeur frequently and are eaused especially by produets cinnamie aldehyde (Safford et al. 1990), einnamie acid,
with high eoneentrations of perfurne (notably deodor- cinnamyl einnamate, benzyl benzoate and benzyl
ants and antiperspirants) no clinieal data or literature alcohol. Immediate eontaet reaetions ean also affeet
referenees are provided to substantiate these state- the respiratory traet, as some individuals suffering
ments (Meynadier et al. 1986). Of course, deodorants from ehronie respiratory problems experienee wors-
and antiperspirants are an important eause of irrita- ening or preeipitation of their symptoms upon expo-
tion, due to the humidity and anatomieal oeclusion of sure to some fragranee materials (Guin and Berry
the axillae (De Groot et al. 1987). However, this may 1980). Several investigators reported immediate eon-
well be eaused by the aleohol or other ingredients taet reaetions to fragrances that were routinely tested
rather than by the fragranee materials. (Emmons and Marks 1985; Beeker et al. 1994, Abifadel
et al. 1992). However, many reaetions were only
maeular and erythematous and relevanee was not
Photocontact Dermatitis established (Emmons and Marks 1985).
A patient with contaet urtiearia to rouge was found
Compared with eontaet allergie reaetions, photoeon- to be eontaet allergie to y-methylionone eontained
taet dermatitis from fragrances is unusual. Only musk within it (De Groot and Liem 1983b) and terpinyl
ambrette, a fragranee fixative used in both the food acetate in spray stareh eaused eontaet urtiearia
and eosmeties industry, has eaused a eonsiderable (MeDaniel and Marks 1979). Several eases of immedi-
number of photoeontaet allergie reaetions (Raugi et al. ate eontaet reaetions to eommereial deodorants
1979; Cronin 1984; Wennersten et al. 1984). Pigmented (Temesvari et al. 1978) and perfumes (Rudzki and
photoallergie eontaet dermatitis (Gons:alo et al. 1991), Grzywa 1976; Rothenborg et al. 1977; Temesvari et al.
airborne pigmented eontaet dermatitis (Hayakawa 1978) have been reported. Non-immune immediate
et al. 1987a) and lichenoid photoeontaet dermatitis eontaet reaetions to einnamie aldehyde ean be dimin-
have all been deseribed (Parodi et al. 1987). Persistent ished (quenehed) by eugenol. The meehanism is
light reaetions are not rare (Megahed et al. 1991; Lan unclear (Safford et al. 1990).
et al. 1994), and sometimes lead to erythroderma (Lan
et al. 1994). Photocross reaetions have been observed
to musk mo skene and musk xylene (Cronin 1984). Other Adverse Reactions
Photodermatitis may be aequired by eonnubial or
eonsort exposure (Leroy and Dompmartin 1989). Pigmented cosmetie dermatitis used to be frequent in
Oeeasionally, positive photopateh tests are observed Japan (Nakayama et al. 1974; Nakayama et al. 1976;
to the fragranee mix (Wennersten et al. 1984; Leonard Nakayama et al. 1984; De Groot and Frosch 1997).
et al. 1994; Szezurko et al. 1994), and some phototoxie Other eutaneous reaetions aseribed to fragranees
reaetions have been noted (Leonard et al. 1994). include depigmented airborne eontaet dermatitis
Reaetions to oak moss and its ingredients (lichen (Hayakawa et al. 1987b), a pemphigoid-like allergie
acids) are usually of the eontaet allergie type, but reaetion (Goh and Ng 1988), and erythema multiforme-
photosensitivity may oeeur to oak moss (Leonard et al. like eontaet dermatitis (Thompson and Wansker 1981;
1994), atranorin and evernie acid (Fernandez de Corres Alomar et al. 1990; Seidenari et al. 1990). Possibly,
et al. 1983). In patients with persistent light reaetions fragrances ean induee or worsen respiratory problems,
in ehronie aetinie dermatitis, a higher ineidenee of such as rhinitis, sneezing, shortness of breath and
eontaet sensitivity reaetions to eertain fragranee ma- asthma (Sehleuter 1978; Zuskin et al. 1978; Guin and
terials was found (Addo et al. 1982; Menage et al. 1995). Berry 1980; De Groot et al. 1987). This is thought to be
Immediate and delayed photopateh test reaetions were due to a direet release of histamine - rather than to an
also observed, notably to oak moss, musk ambrette, allergie meehanism - eaused by fragranee ingredients
eugenol, einnamie aldehyde, 6-methylcoumarin, eostus known to produee non-immunologie immediate eon-
root oil and hydroxyeitronellal. These reaetions were taet reaetions (Guin and Berry 1980).
Fragrances 505
Conclusions and Recommendations studies: on the basis of literature data - benzyl

salicylate, citral, coumarin, dihydrocoumarin, hydro-
Virtually everyone is exposed continuously to fra- abietyl alcohol, jasmine absolutelsynthetic, lilial, meth-
grane es through contact with perfumes, cosmetics, yl salicylate, and ylang-ylang oil; on the basis of their
toiletries, oral hygiene products, household products, widespread presence in perfumes (Fenn 1989; De Groot
paper products, topical drugs, industrial contact ma- et al. 1994) - benzyl acetate, linalool, linalyl acetate,
terials and through contact with flavours and spices in lyral, hexylcinnamic aldehyde, y-methylionone, phe-
foods and beverages. Cutaneous adverse reactions to nylethyl alcohol, and terpineol.
fragrances include allergie contact dermatitis, imme-
diate contact reactions (contact urticaria), and photo-
sensitivity. Considering the ubiquitous occurrence of References
fragrance materials, the risk of such side effects is
relatively small. In absolute numbers, however, fra- Abifadel R, Mortureux P, Perromat M, Ducombs G, Taieb A
grance allergy is common. Approximately 1% of the (1992) Contact sensitivity to f1avourings and perfumes in
atopic dermatitis. Contact Dermatitis 27:43-46
unselected population is sensitised to fragrance mate- Adams RM, Maibach HI (1985) A five-year study of cosmetic
rials. Indeed, fragrances are the most common causes reactions. J Am Acad DermatoI13:1062-1069
of allergie contact dermatitis from cosmetics. Any part Addo HA, Ferguson J, Johnson BE, Frain-Bell W (1982) The
relationship between exposure to fragrance materials and
of the body may be affected. Classic localisations are persistent light reactions in the photosensitivity dermatitis.
the face, behind the ears, the neck, and the axillae. Brit J Dermatol107:261-274
Hand dermatitis is also frequent in fragrance-sensitive Alomar A, Pujol RM, Esquius J (1990) Erythema multiforme-like
contact dermatitis. Am J Contact Dermatitis 1:177-179
subjects. Fragrances are probably rarely the sole cause Basketter DA, Allenby CF (1991) Studies of the quenching
of hand eczema. These patients usually have irritant or phenomenon in delayed contact hypersensitivity reactions.
atopic hand dermatitis first, which is later complicated Contact Dermatitis 25:160-171
Becker K, Temesvari E, Nemeth I (1994) Patch testing with
by fragrance contact allergy to products used for fragrance mix and its constituents in a Hungarian population.
treatment or prevention, or to other perfumed prod- Contact Dermatitis 30:185-186
ucts in the household, hobby or work environment. Benke GM, Larsen WG (1984) Safety evaluation of perfumed
shampoos: dose/response relationships for product use
Occupational contact dermatitis from fragrances seems testing by presensitized subjects. J Toxicol Cutan Ocular
to be relatively uncommon. Toxicol 3:65-67
The currently used fragrance mix (eugenol, isoeuge- Bernaola G, Escayol P, Fernandez E, Fernandez de Corres L (1989)
Contact dermatitis from methylionone fragrance. Contact
nol, oak moss, geraniol, hydroxycitronellal, cr-amylcin- Dermatitis 20:71-72
namic aldehyde, cinnamic aldehyde, cinnamic alcohol, Bonnevie P (1948) Some experiences of war-time industrial
each 1% with 5% sorbitan sesquioleate) is valuable for dermatoses. Acta Derm Venereol 28:231-237
Brandäo FM (1986) Occupational allergy to lavender oil. Contact
diagnosing fragrance sensitisation. Between 6% and Dermatitis 15:249-250
11% of patients routinely tested because of suspected Calnan CD (1969) Lovage sensitivity. Contact Dermatitis Newslett
allergie contact dermatitis react to the fragrance mix, 5:99
Christophersen J, Menne T, Tangh0j P, et al. (1989) Clinical patch
and in most centres the mix is among the top 5 frequent test data evaluated by multivariate analysis. Contact Derma-
allergens, usually ranking second after nickel sulphate. titis 21:291-299
However, false-positive reactions are not rare, and a Cronin E (1984) Photosensitivity to musk ambrette. Contact
Dermatitis 11:88-92
single weak (?+ or +) reaction to the mix should not be Dahlquist I, Fregert S (1981) Atranorin and oak moss contact
taken as evidence for fragrance contact allergy, but allergy. Contact Dermatitis 7:168-169
should be substantiated with other tests (ROAT, use De Groot AC (1987) Contact allergy to cosmetics: causative
ingredients. Contact Dermatitis 17:26-34
tests, patch testing with the ingredients of the mix or De Groot AC (1988) Adverse reactions to cosmetics. Thesis, State
other fragrances and personal fragranced products). University of Groningen
Relevance is established in 50-65% of all cases, but De Groot AC (1994) Patch testing, 2nd edn. Elsevier, Amsterdam
De Groot AC, Frosch PJ (1997) Adverse reactions to fragrances. A
more strict criteria should probably be applied, and clinical review. Contact Dermatitis 36:57-86
there is a need to further investigate the profile of the De Groot AC, Liem DH (1983a) Facial psoriasis caused by contact
fragrance-sensitive patient. allergy to linalool and hydroxycitronellal in an aftershave.
False-negative reactions to the mix also occur, and De Groot AC, Liem DH (1983b) Contact urticaria to rouge.
because as many as 30% of patients allergie to Contact Dermatitis 9:322
fragrances are not detected, future research should be De Groot AC, Weyland JW (1992) Systemic contact dermatitis
from tea tree oil. Contact Dermatitis 27:279-280
aimed at increasing the sensitivity of the mix. To date, De Groot AC, Liem DH, Nater JP, van Ketel WG (1985) Patch tests
no other fragrances have been identified that would, on with fragrance materials and preservatives. Contact Derma-
the basis of frequency of allergie reactions to them, be titis 12:87-92
De Groot AC, Nater JP, van der Lende R, Rijcken B (1987)
suitable candidates for inclusion in the mix. The Adverse effects of cosmetics: a retrospective study in the
following fragrances may be investigated in large-scale general population. Int J Cosmetic Sci 9:255-259
506 A.c. de Groot
De Groot AC, Bruynzeel DP, Bos JD, et al. (1988) The allergens in Goodfield MJD, Saihan EM (1988) Fragrance sensitivity in coal
cosmetics. Arch DermatoI124:1525-1529 miners. Contact Dermatitis 18:81-83
De Groot AC, Baar AJM, Terpstra H, Weyland JW (1991) Contact Goossens A, Merckx L (1997) Allergie contact dermatitis from
allergy to moist toilet paper. Contact Dermatitis 24:135-136 farnesol in a deodorant. Contact Dermatitis 37:179-180
De Groot AC, Van der Kley AMI, Bruynzeel DP, et al. (1993) Guerra L, Tosti A, Bardazzi F, et al. (1992) Contact dermatitis in
Frequency of false-negative reactions to the fragrance mix. hairdressers: the Italian experience. Contact Dermatitis
De Groot AC, Weyland JW, Nater JP (1994) Unwanted effects of Guin JD (1982) History, manufacture, and cutaneous reactions to
cosmetics and drugs used in dermatology, 3rd edn. Elsevier , perfumes. In: Frost P, Horwitz SW (eds) Principles of
Amsterdam cosmetics for the dermatologist. The CV Mosby Company,
Dooms-Goossens A (1993) Cosmetics as causes of allergie contact St Louis, pp 111-129
dermatitis. Cutis 52:316-320 Guin JD, Berry VK (1980) Perfurne sensitivity in adults females. A
Dooms-Goossens A, Deleu H (1991) Airborne contact dermatitis: study of contact sensitivity to a perfume mix in two groups of
an update. Contact Dermatitis 25:211-217 student nurses. J Am Acad Dermatol 3:299-302
Dooms-Goossens A, Degreef H, Holvoet C, Maertens M (1977) Guin JD, Haffley P (1983) Sensitization to alpha amyl cinnamic
Turpentine-induced hyper-sensitivity to peppermint oil. aldehyde and alpha amyl cinnamic alcohol. J Am Acad
Contact Dermatitis 3:304-308 Dermatol 8:76-80
Edman B (1985) Sites of contact dermatitis in relationship to Gutman SG, Somov BA (1968) Allergie reactions caused by
particular allergens. Contact Dermatitis 13:129-135 components of perfumery preparations. Vestn Dermatol
Edman B (1994) The influence of shaving method on perfurne Venereol 12:62-66
allergy. Contact Dermatitis 31:291-292 Handley J, Burrows D (1994) Allergie contact dermatitis from the
Emmons WW, Marks JG Jr (1985) Immediate and delayed synthetic fragrances Lyral and acetyl cedrene in separate
reactions to cosmetic ingredients. Contact Dermatitis 13: underarm deodorant preparations. Contact Dermatitis
258-265 31:2 88- 2 90
Enders F, Przybilla B, Ring J (1989) Patch testing with fragrance Hausen BM, Kunze B (1991) Kontaktallergie auf Patchouli-ÖI.
mix at 16% and 8%, and its individual constituents. Contact Aktuel Dermatol 17:199-202
Dermatitis 20:237-238 Hayakawa R, Matsunaga K, Arima Y (1987a) Airborne pigmented
English JSC, Rycroft RJG (1988) Allergie contact dermatitis from contact dermatitis due to musk ambrette in incense. Contact
methyl heptine and methyl octine carbonate. Contact Der- Dermatitis 16:96-98
matitis 18:174-175 Hayakawa R, Matsunaga K, Arima Y (1987b) Depigmented
Fenn RS (1989) Aroma chemieal usage trends in modern contact dermatitis due to incense. Contact Dermatitis
perfumery. Perfumer and Flavorist 14:3-10 16:272-274
Fernandez de Corres L, Muiioz D, Leaniz-Barrutia I, Corrales JL Heine A (1987) Allergisches Kontaktekzem durch Usninsäure in
(1983) Photocontact dermatitis from oak moss. Contact Deodorant Sprays. Dermatol Monatssehr 173:221-225
Dermatitis 9:528-529 Holness DL, Nethercott JR (1990) Epieutaneous testing results in
Fisher AA, Dooms-Goossens A (1976) The effect of perfume hairdressers. Am J Contact Dermat 2:224-234
"ageing" on the allergenicity of individual perfurne ingredi- Holness DL, Nethercott JR (1994) Patch testing in an occupational
ents. Contact Dermatitis 2:155-159 health dinie. Am J Contact Dermat 5:150-155
Fisher AA (1980) Perfume dermatitis. Part 1. General consider- Johansen JD, Menne T (1995) The fragrance mix and its
ations and testing procedures. Cutis 26:458-463,477 constituents: a 14-year material. Contact Dermatitis 32:18-23
Fisher AA (1990) Perfume dermatitis in children sensitized to Johansen JD, Rastogi SC, Jemec GBE (1994) Dipropylene glycol
balsam of Peru in topieal agents. Cutis 45:21-23 allergy: a hidden cause of perfurne contact dermatitis. Am J
Fisher AA (1995) Consort contact dermatitis due to musk Contact Dermat 5:98-101
ambrette. Cutis 55=199-200 Johansen JD, Andersen KE, Rastogi SC, Menne T (1996)
Fischer T (1995) Perfumed products. In: Guin JD (ed) Practical Threshold responses in cinnamic aldehyde-sensitive subjects.
contact dermatitis. McGraw-Hill, New York, pp 355-371 Results and methodological aspects. Contact Dermatitis
Freeman S (1990) Fragrance and nickel: old allergens in new 34:165- 171
guises. Am J Contact Dermat 1:47-52 Johansen JD, Rastogi SC, Menne T (1996) Exposure to selected
Fregert S, Dahlquist I (1983) Patch testing with oak moss extract. fragrance materials. A case study of fragrance-mix-positive
Contact Dermatitis 9:227 eczema patients. Contact Dermatitis 34:106-110
Frosch PI, Johansen JD, White IR (eds) (1988) Fragranees. Johansen JD, Rastogi SC, Andersen KE, Menne T (1997) Content
Beneficial and adverse effects. Springer, Berlin Heidelberg and reactivity to product perfumes in fragrance mix positive
New York and negative eczema patients. Contact Dermatitis 36:291-296
Frosch PJ, Pilz B, Andersen KE, et al. (1995a) Patch testing with Kanerva L, Estlander T, Jolanki R (1995) Occupational allergie
fragranees: results of a multicenter study of the European contact dermatitis caused by ylang-ylang oil. Contact Der-
Environmental and Contact Dermatitis Research Group with matitis 33:198-199
48 frequently used constituents of perfumes. Contact Der- Karlberg A-T, Magnusson K, Ni!sson U (1992) Air oxidation of d-
matitis 33:333-342 limonene (the citrus solvent) creates potent allergens. Contact
Frosch PJ, Pilz B, Burrows D, et al. (1995b) Testing with the Dermatitis 26:332-340
fragrance mix - is the addition of sorbitan sesquioleate to the Keil H (1947) Contact dermatitis due to oi! of citronellal. J Invest
constituents useful? Contact Dermatitis 32:266-272 Dermatol 8:327
Garioch JJ, Forsyth A, Chapman RS (1989) Allergie contact Lan LR, Lee JYY, Kao HF, Wang BJ, Chen HC (1994) Persistent
dermatitis from the perfume in Locan cream. Contact light reaction with erythroderma caused by musk ambrette. A
Dermatitis 20:61-62 case report. Cutis 54:167-170
Goh CL, Ng SK (1988) Bullous contact allergy from cinnamon. Larsen WG (1977) Perfume dermatitis. A study of 20 patients.
Dermatosen 36:186-187 Arch Dermatol 113:623-626
Gola M, Sertoli A, Angelini G, et al. (1992) GIRDCA data bank for Larsen WG (1979) Allergie contact dermatitis to the perfume in
occupational and environmental contact dermatitis. Am J Mycolog cream. J Am Acad Dermatol1:131-133
Contact Dermat 3:179-188 Larsen WG (1983) Allergie contact dermatitis to the fragrance
Gons:alo S, Cabral F, Gons:alo M (1988) Contact sensitivity to oak materiallilial. Contact Dermatitis 9:158-159
moss. Contact Dermatitis 19:355-357 Larsen WG (1985) Perfume dermatitis. J Am Acad Dermatol 12:
Gons:alo S, Gi! I, Gons:alo M, Baptista AP (1991) Pigmented 1-9
photoallergie contact dermatitis from musk ambrette. Con- Larsen WG (1989) How to instruct patients sensitive to
tact Dermatitis 24:229-230 fragranees. J Am Acad Dermatol 4:880-884
Fragrances 507
Larsen W, Nakayama H, Lindberg M, et al. (1996) Fragrance Parry EI, Beck MH (1997) Contact allergy to musk moskene in a
contact dermatitis. A worldwide multicenter investigation perfumed moisturizing cream. Contact Dermatitis 37:236
(Part I). Am J Contact Dermat 7:77-83 Paulsen E, Andersen KE, Carlsen L, Egsgaard H (1993) Carvone:
Leonard F, Kalis B, Journe F (1994) The standard battery for an overlooked contact allergen cross-reacting with sesquiter-
photopatch tests in France. Prospective study by the French pene lactones? Contact Dermatitis 29:138-143
Society for Photodermatology. Nouv Dermatol 13:305-314 Rademaker M (1994) Allergie contact dermatitis from lavender
Leroy D, Dompmartin A (1989) Connubial photosensitivity to fragrance in Difflam gel. Contact Dermatitis 31:58-59
musk ambrette. Photodermatology 6:137-139 Raugi GJ, Storrs FI, Larsen WG (1979) Photoaliergic contact
Lewis FM, Shah M, Gawkrodger DJ (1997) Contact sensitivity in dermatitis to men's perfumes. Contact Dermatitis 5:251-260
pruritus vulvae: patch test results and dinieal outcome. Am J Romaguera C, Camarasa JMG, Alomar A, Grimalt F (1983) Patch
Contact Dermat 8:137-140 tests with allergens related to cosmetics. Contact Dermatitis
Lim JTE, Goh CL, Ng SK, Wong WK (1992) Changing trends in 9:167-168
the epidemiology of contact dermatitis in Singapore. Contact Rothenborg HW, Hjorth N (1968) Allergy to perfumes from toilet
Dermatitis 26:321-326 soaps and detergents in patients with dermatitis. Arch
Lorenzi S, Guerra L, Vezzani C, Vincenzi C (1995) Airborne Dermatol 97:417-421
contact dermatitis from atranorin. Contact Dermatitis 32: Rothenborg HW, Menne T, Sj0lin K-E (1977) Temperature
315-316 dependent primary irritant dermatitis from lemon perfurne.
Malanin G, Ohela K (1989) Allergic reactions to fragrance mix Contact Dermatitis 3:37-48
and its components. Contact Dermatitis 21:62-63 Rudner EA (1977) North American Group results. Contact
Malten KE (1977) Sensitization to solcoseryl and methylanisate Dermatitis 3:208-209
(fragrance ingredient). Contact Dermatitis 3:219 Rudzki E, Grzywa Z (1976) Immediate reactions to balsam of
Malten KE (1979) Four bakers showing positive patch-tests to a Peru, cassia oil and ethyl vanillin. Contact Dermatitis 2:360
number of fragrance materials, whieh can also be used as Rudzki E, Rebandel P, Grzywa Z (1993) Occupational dermatitis
flavors. Acta Derm Venereol Suppl (Stockh) 85:117-121 from cosmetic creams. Contact Dermatitis 29:210
Malten KE, van Ketel WG, Nater JP, Liem DH (1984) Reactions in Safford RJ, Basketter DA, Allenby CF, Goodwin BFJ (1990)
selected patients to 22 fragrance materials. Contact Dermatitis Immediate contact reactions to chemicals in the fragrance
11:1-10 mix and a study of the quenching action of eugenol. Br J
Marks JG, Belsito DV, DeLeo VA, et al. (1995) North Ameriean Dermatol 123:595-606
Contact Dermatitis Group standard tray patch test results Santucci B, Cristaudo A, Cannistraci C, Picardo M (1987) Contact
(1992 to 1994). Am J Contact Dermat 6:160-165 dermatitis to fragrances. Contact Dermatitis 16:93-95
McDaniei WR, Marks JG (1979) Contact urticaria due to Schaller M, Korting HC (1995) Allergie airborne contact derma-
sensitivity to spray starch. Arch Dermatol 115:628 titis from essential oils used in aromatherapy. Clin Exp
Megahed M, Holzle E, Plewig G (1991) Persistent light reaction Dermatol 20:143-145
associated with photoallergic contact dermatitis to musk Schauder S, Ippen H (1997) Contact and photocontact sensitivity
ambrette and allergic contact dermatitis to fragrance mix. to sunscreens. Contact Dermatitis 37:221-232
Dermatologica 182:199-202 Schein man PL (1996) Allergic contact dermatitis to fragrance: a
Menage H du P, Ross JS, Norris PG, Hawk JLM, White IR (1995) review. Am J Contact Dermat 7:65-76
Contact and photocontact sensitization in chronic actinic Schleuter DP (1978) Airway reponse to hair spray in normal
dermatitis; sesquiterpene lactone mix is an important aller- subjects and subjects with hyper-reactive airways. Chest
gen. Br J Dermatol 132:543-547 75:544-547
Meneghini CL (1970) Cosmetic constituents. Contact Dermatitis Seidenari S, Di Nardo A, Motolese A, Pincelli C (1990) Erythema
Newsletter 8:182 multiforme associated with contact sensitization. Report of 6
Meynadier J-M, Meynadier I, Peyron J-L, Peyron L (1986) Formes cases. G Ital Dermatol Venereol 125:35-40
diniques des manifestations cutanees d'allergie aux parfums. Sousa Basto A, Azenha A (1991) Contact dermatitis due to
Ann Dermatol Venereol113:31-39 incense. Contact Dermatitis 24:312-313
Mitchell JC, Adams RM, Glendenning WE, et al. (1982) Results of Stinchi C, Guerrini V, Ghetti E, Tosti A (1997) Contact dermatitis
standard patch tests with substances abandoned. Contact from lichens. Contact Dermatitis 36:309-310
Dermatitis 8:336-337 Sugai T (1994a) Group Study IV - farnesol and lily aldehyde.
Morren M-A, Rodrigues R, Dooms-Goossens A, et al. (1992) Environ Dermatol 1:213-214
Connubial contact dermatitis: a review. Eur J Dermatol 2: Sugai T (1994b) Historical data of the JSCD. Group study III -
219-223 Fragrance materials. Environ Dermatol 1:209-212
Nakayama H (1995) Pigmented contact dermatitis and chemical Sugawara M, Nakayama H, Watanabe S (1990) Contact hyper-
depigmentation. In: Rycroft RJG, Menne T, Frosch PJ (eds) sensitivity to ylang-ylang oil. Contact Dermatitis 23:248-249
Textbook of contact dermatitis, 2nd edn. Springer, Berlin Sun C-C, Guo Y-L, Lin R-S (1995) Occupational hand dermatitis
Heidelberg New York, pp 637-659 in a tertiary referral dermatology dinic in Taipei. Contact
Nakayama H, Hanaoka H, Oshiro A (1974) Allergen controlled Dermatitis 33:414-418
system (ACS). Kanehara Shuppan Co, Tokyo Swinyer LJ (1980) Connubial contact dermatitis to atranorin in
Nakayama H, Harada R, Toda M (1976) Pigmented cosmetic lichens. Contact Dermatitis 6:226
dermatitis. Int J Dermatol 15:673-675 Szczurko C, Dompmartin A, Michel M, Moreau A, Leroy D (1994)
Nakayama H, Matsuo S, Hayakawa K, et al. (1984) Pigmented Photocontact allergy to oxybenzone: ten years of experience.
cosmetic dermatitis. Int J Dermatol 23:299-305 Photodermatol Photoimmunol Photomed 10:144-147
Nethercott JR, Pilger C, O'Blenis L, Roy A-M (1983) Contact Temesvari E, Soos G, Podanyi, Kovacs I, Nemeth I (1978) Contact
dermatitis due to cinnamic aldehyde induced in a deodorant urticaria provoked by balsam of Peru. Contact Dermatitis
manufacturing process. Contact Dermatitis 9:241-242 4:65-68
Nielsen NH, Menne T (1992) Allergic contact sensitization in an Thompson JA Jr, Wansker BA (1981) A case of contact dermatitis,
unselected Danish population. Acta Derm Venereol 72: erythema multiforme, and toxic epidermal necrolysis. J Am
456-460 Acad Dermatol 5:666-669
Opdyke DLJ (1976) Inhibition of sensitization reactions induced Thune P, Salberg Y, McFadden N, Staerfelt F, Sandberg M (1982)
by certain aldehydes. Fd Cosmet ToxicoI14:197-198 Perfurne allergy due to oak moss and other lichens. Contact
Panconesi E, Sertoli A, Spallanzani P, Giorgini S (1980) Balsam of Dermatitis 8:396-400
Peru sensitivity from a perfumed cutting fluid in a laser Toyoda T, Watanabe S, Kawasaki M, Nakayama H, Sugawara M
factory. Contact Dermatitis 6:297-298 (1989) Dehydro-eugenol found in ylang-ylang oil. Skin Res
Parodi G, Guerrera M, Rebora A (1987) Lichenoid photocontact 31[SuPpI 7]:35-43
dermatitis to musk ambrette. Contact Dermatitis 16:136-138
508 A.C. de Groot: Fragrances
Utsumi M, Sugai T, Shoji A, Watanabe K, Asoh S, Hashimoto Y Wall LM, Gebauer KA (1991) Occupational skin disease in
(1992) Incidence of positive reactions to sandalwood oil and Western Australia. Contact Dermatitis 24:101-109
its related fragrance materials in patch tests and a case of Wennersten G, Thune P, Brodthagen H, Jansen C, Rystedt I
contact allergy to natural and synthetic sandalwood oil in a (1984) The Scandinavian Multicenter photopatch study.
museum worker. Skin Res 34[SUppI14]:209-213 Preliminary results. Contact Dermatitis 10:305-309
Van der Walle HB, Brunsveld VM (1994) Dermatitis in hair- Wilkinson JD, Andersen KE, Camarasa JG, et al. (1989) Prelim-
dressers. (I). The experience of the past 4 years. Contact inary results of effectiveness of two forms of fragrance mix as
Dermatitis 30:217-221 screening agents for fragrance sensitivity. In: Frosch PJ, et al.
Van Ketel WG (1978) Dermatitis from an aftershave. Contact (eds) Current topics in contact dermatitis. Springer, Berlin
Dermatitis 4:117 Heidelberg New York, pp 127-131
Van Ketel WG (1983) Sensitization to cis-3-hexenyl salicylate. Zacher KD, Ippen H (1984) Kontaktekzem durch Bergamottöl.
Contact Dermatitis 9:154-155 Derm Beruf Umwelt 32:95-97
Vilaplana J, Romaguera C, Grimalt F (1991) Contact dermatitis Zuskin E, Bouhuys A, Beck G (1978) Hair sprays and lung
from geraniol in Bulgarian rose oil. Contact Dermatitis 24:301 function. Lancet 2:1203
CHAPTER 64
Colophony
A.-T. Karlberg
Production dehydration of abietane-type acids in the pine chips

during pulping and tall-oil processing and to the high
Colophony (rosin) is a resin obtained from different production temperature. The production process also
species of coniferous trees. There are three types of results in some artifacts with diterpenoid structures,
colophony, depending on the method of recovery: gum which are not found in the other types of colophony
rosin, wood rosin and tall-oil rosin. Gum rosin is (Lawrence 1962; Holmborn et al. 1974; Soltes and
obtained from various species of living pine trees. The ZinkeI1989).
trees are tapped for oleoresin, which is then distilled to Due to air exposure, oxidized material is also
obtain turpentine as the distillate and gum rosin as the present in colophony. The oxidation of colophony
distillation residue. Wood rosin is produced from old and res in acids has been studied by several authors
pine stumps. Tall-oil rosin is obtained as a by-product (Karlberg 1988, 1991; Hausen et al. 1993; Gäfvert 1994;
in the sulphate pulping of coniferous wood. The supply Shao et al. 1995). The abietane-type resin acids with
of pine stumps for the production of wood rosin is conjugated double bonds are more susceptible to
decreasing and, today, the major types produced are oxidation than dehydroabietic acid and the pimarane-
gum rosin and tall-oil rosin. In technicalliterature, the type acids. Oxidized resin acids with allergenic activity
term "colophony" corresponds to gum rosin. In are shown in Fig. 2.
dermatologicalliterature, tall-oil rosin and wood rosin
are also included in the term "colophony", since the
resins contain the same major chemical components Chemical Modifications of Colophony
and allergens and are used in various technical
products, regardless of the source. In American Certain desirable technical properties can be achieved
literature, the term "rosin" is more frequently used. by modification with suitable chemicals to various
China, Latin American countries and Portugal are colophony derivatives. The modifications are usually
great producers of gum rosin. USA, Finland, Sweden interrupted when the desired technical properties have
and the countries of the former USSR are great been obtained, leaving so me unmodified colophony in
producers of tall-oil rosin. Approximately 1.1 million the product (Soltes and Zinkel 1989). Different mod-
tons of colophony are produced annually, and the ifications are often combined.
absolute majority is chemically modified to various Esterification of the carboxylic acid group is per-
derivatives. formed using polyhydric alcohols, such as glycerol,
pentaerythritol, ethylene glycol and diethylene glycol.
Different esters can be formed in the reaction between
Chemical Composition of Colophony polyalcohols and resin acids in colophony. This is
shown in studies of esterification of abietic acid with
Colophony is a complex mixture of resin acids (about glycerol, which resulted in mono-, di- and tri-abietates.
90%) and neutral substances, i.e. diterpene alcohols, Of these, glyceryl monoabietate (Fig. 3) has been
aldehydes and hydrocarbons (about 10%). Its compo- identified as a contact allergen (Shao et al. 1993;
sition varies with the species from which it is obtained Gäfvert et al. 1994a).
and also depends on the recovery processes and In some applications, it is desirable to enhance the
storage conditions. The acids are diterpenoid acids, hydrophilic portion of colophony. This is achieved by
of which the abietane- and pimarane-type structures re action of colophony with maleic acid, maleic anhy-
are the most abundant (Fig. 1). Tall-oil rosin contains dride or fumaric acid in a so-called Diels-Alder
less abietane-type acids and more dehydroabietic acid addition. Maleopimaric acid is formed in reactions
than gum rosin does. This is due to oxidation- with maleic anhydride, while both fumaropimaric acid

510 A.-T. Karlberg
a b c
Fig. 1. Chemical structures of (a) abietic acid, (b) dehydroabietic Use of Colophony in Modified
acid and (c) pimaric acid. Abietic acid and dehydroabietic acid
are the two major resin acids in colophony
and Unmodified Forms
Colophony has three main technical properties: it has

and maleopimaric acid are formed in reactions with good tackifying qualities, it can be used as an emulsifier
fumaric acid. Maleopimaric acid (Fig. 3) is a potent and it has acid properties without causing corrosion.
contact allergen (Karlberg et al. 1990; Gäfvert et al. Using chemical reactions, the technical properties are
1995). further modified. Unmodified colophony and colopho-
Oxidation of colophony and the res in acids are often ny derivatives are used in a vast number of technical
undesirable from a technical point of view. To prevent products. The amount of unmodified colophony in
this, the double bonds, which are susceptible to different products varies from 20% or more in some
oxidation, can be saturated by hydrogenation. Hydro- adhesives, paints and soldering fluxes for electronic
genated colophony has a very low allergenic activity assemblies to small traces in products containing
(Karlberg et al. 1988c). This was also indicated in mainly modified colophony (Ehrin and Karlberg
studies by Hausen et al. (1989). 1990). The amounts are seldom declared on the package
Disproportionationldehydrogenation of rosin is also a and, if modified colophony is used, it can be difficult to
process that decreases the ability of colophony to recognize the name as a colophony derivative. Coloph-
oxidize, since the amount of resin acids with conjugated ony is classified as a skin sensitiser within the European
double bonds is diminished in favour of dehydroabietic Union (EC). According to the legislation the classified
acid. Polymerizationldimerization of colophony de- allergen and preparations containing ~ 1% of the
creases its tendency to crystallize. Major products allergen must be labelled with a warning for skin
formed are dimers of resin acids, but the degree of sensitisation. The main areas of use for unmodified and
polymerisation varies with the conditions (time, tem- modified colophony are listed in Table 1. The markets
perature) under which the modification is performed. for the colophony derivatives are shown in Fig. 4.
Formaldehyde modification of colophony includes sev-
eral different reactions performed under various con-
ditions where formaldehyde reacts with resin acids. Analytical Methods tor Detecting Colophony
Colophony can also be modified by reacting metal salts, Components in Technical Products
e.g. sodium, potassium, or barium, calcium, cobalt
and zinc, with resin acids to form salts (resinates) Colophony consists of hundreds of different compo-
(McSweeneyet al. 1987; Soltes and ZinkeI1989). nents, and no chemical analytical method for identi-
Table 1. Areas of use for unmodified and modified colophony
Colophony type Areas of use
Unmodified Soldering /luxes, paper, depilatory waxes, cosmetics, dan cers'

and string players' rosin, wood and gum from pine trees
Modified (modification types)
Esterification with polyalcohols Adhesive tackifiers, printing inks, bubble gum
Diels-Alder addition of maleic acid Paper size, printing inks
Maleic anhydride or fumaric acid Printing inks, soldering /luxes, polymerization
Hydrogenation Emulsifiers in the production of synthetic rubber,
adhesive tackifiers
Polymerization/dimerization Adhesives, printing inks, varnishes
Disproportionation/dehydrogenation Polymerization, emulsifiers in the production of synthetic rubber,
paper size, adhesive tackifiers, printing inks, insulating material
in electronics industry
Formaldehyde modification Paper size, printing inks
Salt formation Soap, detergents, paper size, drier formulations, printing inks
Colophony 511
a b c
d e f
9 h
k
Fig. 2. Chemical structures of identified oxidation products in et al. 1974). When using such a method, the resin acids
colophony. a 15-hydroperoxyabietic acid. b 13,14( a)-epoxyabietic must be esterified, most often with diazomethane,
acid. C 13,14(ß)-epoxyabietic acid. d di(dehydroabietic acid 15-yl)
peroxide. e 15-hydroperoxydehydroabietic acid. f 7-oxodehydro- which is highly explosive and carcinogenic. Further-
abietic acid. g 15-hydroxydehydroabietic acid. h 15-hydroXY-7- more, labile compounds, such as the peroxides and the
oxodehydroabietic acid. i 13(ß), 14(ß)-dihydroxyabietic acid. hydroperoxides, decompose due to the heat required
; 12-hydroxyabietic acid. k 8,12-peroxo-7,8-dihydroabietic acid
to evaporate the compounds in the GC and, thus, will
not be detected. When using high performance liquid
fication of all colophony components is available. chromatography, the resin acids can be analysed
Traditionally, the major colophony components are without methylation. In the method developed by
quantified with gas chromatography (GC) (Holmbom Ehrin and Karlberg (1990), abietic acid and de-
512 A.-T. Karlberg
'-'
~O-CH -C H-CH OH
o 2 I 2
OH COOH
a b
Fig. 3. Structures of res in-acid derivatives with allergenic activ- phony reacted with either maleic anhydride or fumaric acid in
ity, from modified colophony. a Glycerylmonoabietate from Diels-Alder additions
glycerol-esterified colophony. b Maleopimaric acid from colo-
hydroabietic acid were quantified in various technical be of minor importance, since the neutral fraction is
products. However, analyses based only on the non- only 10% of the colophony.
oxidized acids do not tell us anything about the The allergenic activity is changed by chemical
amount of oxidized acids. A small amount of abietic modifications. It can be diminished by e.g. hydrogena-
acid detected might be due to a small amount of tion (Karlberg et al. 1988c), but some modifications
colophony present in the product or to an extensive increase the allergenicity of the product. New allergens
oxidation. Since the oxidation products are the major can be formed that do not cross-react with the allergens
allergens, it is desirable to be able to quantify some of in unmodified colophony, e.g. maleopimaric acid and
those when analysing technical products suspected to glyceryl monoabietate (Karlberg et al. 1990; Gäfvert
cause allergic contact dermatitis. et al. 1994a). Since the modifications are most often
interrupted when the desired technical properties are
obtained, unmodified material that contain allergens is
Allergenie Activity also present in the modified colophony products.
Unmodified colophony is known to cause contact

allergy. The main allergenic components are oxidized Contact Allergy and Allergie Contact Dermatitis
resin acids formed on air exposure (Fig. 2). 15-Hydro-
peroxyabietic acid was the first oxidation product Unmodified colophony is included in the standard
identified as a contact allergen in unmodified colo- se ries of patch tests for contact allergy. In general, it is
phony (Karlberg et al. 1988a). Later, several articles among the five most common causes of contact allergy
regarding isolation and identification of oxidized resin in the dermatitis patients tested, with a prevalence of
acids as contact allergens were published (Karlberg positive test reactions varying from 2% to 6% (Chris-
et al. 1988b; Hausen and Hessling 1990; Hausen et al. tophersen et al. 1989; Freeman 1990; Schehade et al.
1990, 1993; Gäfvert et al. 1992, 1994b; Khan and Saeed 1991; Veien et al. 1992; Marks et al. 1995; Brasch et al.
1994; Shao et al. 1995; Sahdra et al. 1996). Correspond- 1996). A female dominance is seen. Patients with
ing oxidation of the neutral substances might also yield positive reactions to colophony usually also react to
allergenic components. However, these allergens will balsam of Peru and fragrance mix (Karlberg and Liden
12% Fig. 4. The markets for colophony derivatives
[]
.. Adhe ive
lnk
E3 Paper ize
~ Emulsifiers
0 Mise. re in
0 Other
Colophony 513
1985; Bruze 1986; Holness et al. 1995). Studies of the (Faria, personal communication). Addition of zinc
prevalence in general populations are very sparse. A oxide was stated to diminish the allergenie effect of
Danish study (Ni elsen and Menne 1992) shows that colophony (Söderberg et al. 1990), but this could not
0.7% of a population of 576 individuals reacted to be confirmed (Gäfvert and Färm 1995). In attempts to
colophony at patch testing. minimize the allergenie effect, esterified colophony is
In patch-test studies and experimental sensitisation used in the bandages but, since the esterification is
studies, tall-oil rosin has a somewhat lower allergenie performed only until the desired properties are
activity than gum rosin (Karlberg and Liden 1985; obtained, residual allergenie oxidation products can
Hausen and Loll 1993). A slightly lower allergenie be present together with new allergens formed by
activity of tall-oil rosin could be due to a difference in modification (Shao et al. 1993; Gäfvert et al. 1994a;
the composition but, since the allergenie activity is Mallon and Powell1994).
mainly due to oxidation products, the handling and Colophony can also be present in cosmetics. There
storage times always affect the allergenie properties are reports of eye shadows, rouge, lip preparations and
(Karlberg 1991). Various types of colophony are used mascara causing colophony contact dermatitis (Cainan
interchangeably; it is mainly the price that is decisive. 1971; Foussereau 1975; Dooms-Goossens et al. 1979;
Thus, people can be sensitised to various allergens Rademaker et al. 1986; Karlberg et al. 1991; Sainio et al.
found in products depending on which allergen is the 1996; Batta et al. 1997). The adhesive of bindi, applied
most potent or most frequent in the technical products by Indian women on their forehead, has been reported
handled in the individual case. In Sweden, tall-oil rosin to cause allergie contact dermatitis due to colophony
is the type of colophony most commonly used. Thus, derivatives (Koh et al. 1995). Performing artists are
due to the widespread exposure, this type of colophony often extensively exposed to cosmetics in their occu-
could cause more cases of colophony allergy than gum pation. Theatrical cosmetics do not differ essentially
rosin among Swedes, even though the allergenie from corresponding products for everyday use, apart
activity was found to be lower. Since colophony, in from a high er pigment content. The frequency of
modified and unmodified forms, is present in such a cosmetics intolerance and contact allergy to colophony
variety of products used both at work and during was investigated among the artists in an opera house.
leisure time (Table 1), it can be difficult to trace the The prevalence of contact allergy to colophony was 2%,
source and avoid exposure. but contact allergy to colophony was not a frequent
In one study, 83 patients in whom contact allergy to problem regarding cosmetics (Färm et al. 1995).
colophony had been diagnosed at an occupational Pharmaceutical uses of oils and pitch from pines were
dermatologie al dinic were followed up after 9-13 years. noted by physicians 2000 years ago (Zinkel 1975), but
At least 30% had current hand eczema on follow-up nowadays it is mainly used in folk medicine. However,
examination. Among those in whom the dermatitis had some dental materials that contain colophony have
started on the hands, there were proportionally more been reported to cause stomatitis and lichen planus in
individuals with current hand eczema than among the mouth (Fisher 1986; Gars;ia-Bravo et al. 1992).
those in whom the onset had been on other parts of the
body. At the time of the investigation, 72% of the Occupational Exposure
participants were still patch-test positive to colophony,
and more than halfhad additional positive reactions to Individuals exposed to colophony in pine wood,
other allergens (Färm 1996). sawdust and wood wool may develop hand dermatitis
and dermatitis due to airborne exposure (Burry 1976;
Daly and Stevenson 1984; Meding et al. 1996; Watsky
Exposure from Products in ((ose Contact with the Skin 1997). The prevalence of contact allergy to colophony
among the employees in a factory for production of
Several case reports deal with the dinical problems tall-oil rosin was found to be in accordance with that of
caused by colophony in products that are in dose dermatitis patients and, thus, was higher than in the
contact with the skin. Intolerance to adhesive piasters general population. However, the dinical symptoms
has been discussed since the beginning of the 1920S were rare. A healthy-worker effect can not be exduded
(Grolnick 1936; Karlberg 1988). Efforts have been made (Färm et al. 1994).
over the years to make adhesives non-allergenic using Colophony in solde ring fluxes for electronic assem-
acrylate polymers, but colophony is needed to get a blies is a well-known cause of allergie contact derma-
maximum of adhesion effect and, therefore, is still titis. Since the allergens can be airborne, facial
used e.g. in adhesive bandages for treatment of leg dermatitis is not uncommon, in addition to hand
ulcers. In leg-ulcer patients, a high incidence of contact eczema (Widström 1983; Liden 1984; Goh and Ng 1987;
allergy has been observed. In one study, 11 of 50 Koh et al. 1990). Paint, lacquers and glues can contain
patients reacted to colophony in the standard series colophony, but reports of contact allergy to these
514 A.-T. Karlberg
products are sparse (Moura et al. 1994). Cooling fluids based on linseed oil hardened by air oxidation, but also
may contain colophony, causing dermatitis among the contains, among other things, 5-10% colophony and
employees in the manufacturing industry (Fregert 30-35% coniferous wood flour. The flooring is hung for
1979; Matos et al. 1988; Grattan et al. 1989). Colophony about 2-3 weeks at 60-80°C to harden, which oxidizes
in insulating tapes may cause dermatitis (Calnan 1972). not only the linseed oil but also the colophony
The content of colophony in paper and paper components, which increases the allergenic activity.
products has been investigated. It was found that so- Floor material containing wood flour and colophony
called environmentally friendly paper of mechanical can be released in the air, causing dermatitis in
pulp from coniferous wood contains more colophony colophony-allergic subjects.
components than paper based on chemical pulp
(Karlberg et al. 1995). In colophony-sensitive subjects,
a higher response was seen to unprinted paper of Patch Testing
mechanical pulps than to paper based on chemical
pulps, since the extractive material containing the Colophony (gum rosin from China and/or Portugal) is
colophony components is not separated from the normally tested at concentrations of 20% in petrol-
mechanical pulp. This raises the yield and lowers atum (Karlberg and Liden 1988). In the True Test, gum
the pollution of the water but is in conflict with the rosin is applied in a gel at a concentration of 1.5 mg/
allergy effects. When patch testing patients who cm 2 • When patch testing with various gum rosins and
suspected that their dermatitis was caused by contact with tall-oil rosin, fewer positive reactions were found
with paper, only those with positive patch-test reac- to the tall-oil rosin, but most persons reacted to both
tions to colophony or maleopimaric acid reacted to the gum rosin and tall-oil rosin (Karlberg and Liden 1985;
paper extracts (maleopimaric acid is the main com- Karlberg et al. 1986; Karlberg and Gäfvert 1996). In
ponent in modified colophony used for paper sizing). recent years, different colophony compounds, frac-
Colophony in paper may contribute to hand dermatitis tions and products have been suggested for more
in sensitised subjects, and the use of cotton gloves effective patch-test diagnosis. However, the problems
when in contact with paper might alleviate the with colophony allergens have not been taken into
dermatitis (Karlberg and Liden 1992). In a study on consideration (Hausen et al. 1993; Sadhra and Foulds
the prevalence of hand dermatitis and contact allergy 1995). Patch testing with the isolated oxidation prod-
in Sweden, it was found that contact allergy to ucts will not detect as many cases as testing with
colophony was over-represented among women in colophony itself. Simultaneous testing with 15-hydro-
administrative work (Meding and Swanbeck 1990). peroxyabietic acid and colophony showed that 60-70%
However, this group showed a low prevalence of hand of the patients reacting to colophony reacted to the
eczema. Cases of colophony allergy among workers in isolated allergen (Karlberg and Gäfvert 1996). Colo-
paper mills are rare (Meding et al. 1993). The handling phony contains so many allergens that it is impossible
of paper in paper mills is not as intensive as in office to isolate them all for patch testing. Furthermore, so me
work, since very little work is performed manually. allergens cross-react and might, therefore, potentiate
Dancers and musicians are exposed to colophony each other. In colophony, primary allergens are
(Angelini and Vena 1986; Rimmer et al. 1990; Helm continuously formed due to air exposure and are
et al. 1993). Fiddler's rosin consists of unmodified further oxidized to secondary oxidation products that
colophony. The dancers use colophony on the floor, on are also allergenic. Pure, isolated, unstable allergens
their shoes and even on female cloth es, as an antislip- are decomposed and, thus, the concentration can be
ping agent. Among the dancers in an opera house, only too low in a test preparation. Therefore, it is recom-
one subject had an allergic contact dermatitis caused mended to patch test with apreparation of gum rosin,
by colophony (Färm et al. 1995). To become a which should be as well defined as possible. It is
professional dancer, one has to start practising at important that the content of oxidation products is
young ages and reactions to colophony may determine kept at a constant and rather high level, since they are
which individuals become professional dancers; those the main allergens. When the history indicates that
who develop skin disease or colophony allergy during contact allergy to colophony is a possible cause of the
training might stop early. However, colophony allergy dermatitis and the standard preparation is negative, it
among those who give the dan cers massages is is advisable to test with other types of colophony and
observed (Aberer 1987; Färm et al. 1995). with products in the patient's environment. Chemical
Exposure to colophony components at the work- analysis is valuable to detect the offending agent. Since
place can come from unexpected sources. Facial most colophony is modified chemically, this is an area
dermatitis caused by colophony components in lino- that should be of more concern and should be further
leum flooring and from polish on floors has been investigated. By modification of colophony, the aller-
reported (Karlberg et al. 1996). Linoleum flooring is genic activity can be reduced; however, the activity
Colophony 515
might also be changed, so that testing with modified Foussereau J (1975) A case of allergy to colophony in a facial
colophony products and identified allergens from them cosmetic. Contact Dermatitis 1:259
Freeman S (1990) Fragrance and nickel: old allergens in new
will detect new cases of contact allergy (Hausen and guises. Am J Contact Dermat 1:47-52
Mohnert 1989; Gäfvert et al. 1996). At present, no such Fregert S (1979) Colophony in cutting oil and in soap water used
identified allergens are available for standard testing. as cutting fluid. Contact Dermatitis 5:52
Gäfvert E (1994) Allergenie components in modified and
unmodified rosin. Chemical characterization and studies of
allergenie activity. Acta Derm Venereol (Stockh) Suppl 184:
Other Health Effects of Colophony 1-36
Gäfvert E, Färm G (1995) Rosin (colophony) and zinc oxide in
adhesive bandages. An appropriate combination for rosin-
Occupational asthma due to colophony compounds in sensitive patients? Contact Dermatitis 33:396-400
the fumes from soldering ftux has been reported. Gäfvert E, Nilsson U, Karlberg A-T, et al. (1992) Rosin allergy:
Whether this is due to type-! allergy or to irritation has identification of dehydroabietic acid peroxide with allergenie
properties. Arch Dermatol Res 284:409-413
not been fully investigated (Burge 1984; Cullen et al. Gäfvert E, Shao LP, Karlberg A-T, et al. (1994a) Allergenicity of
1992). rosin (colophony esters). Ir. Glyceryl monoabietate identified
as contact allergen. Contact Dermatitis 31:11-17
Gäfvert E, Shao LP, Karlberg A-T, et. al. (1994b) Contact allergy
to resin acid hydroperoxides. Hapten binding via free radicals
References and epoxides. Chem Res Toxicol 7:260-266
Gäfvert E, Shao LP, Karlberg A-T, et al. (1995) Maleopimaric acid
Aberer W (1987) Allergy to colophony acquired backstage. - a contact allergen in fumaric acid-modified rosin used for
Contact Dermatitis 16:34-36 paper size. Nord Pulp Pap Res J 10:139-144
Angelini G, Vena GA (1986) Allergie contact dermatitis to Gäfvert E, Bordalo 0, Karlberg A-T (1996) Patch testing with
colophony in a violoncellist. Contact Dermatitis 15:108 allergens from modified rosin (colophony) discloses addi-
Batta K, Bourke JF, Foulds IS (1997) Allergie contact dermatitis tional cases of contact allergy. Contact Dermatitis 35:290-298
from colophony in lipstick. Contact Dermatitis 36:171 Gar~ia-Bravo B, Pons A, Rodriguez-Pichardo A (1992) Oral lichen
Brasch J, Geier J, Gefeller 0 (1996) Dynamic patterns of allergie planus from colophony. Contact Dermatitis 26:279
patch test reactions to 10 European standard allergens. An Goh CL, Ng SK (1987) Airborne contact dermatitis to colophony
analysis of data recorded by the Information Network of in soldering flux. Contact Dermatitis 17:89-91
Departments of Dermatology (IVDK). Contact Dermatitis Grattan CEH, English JSC, Foulds IS, et al. (1989) Cutting fluid
35:12- 22 dermatitis. Contact Dermatitis 20:372-376
Bruze M (1986) Simultaneous reactions to phenol-formaldehyde Grolnick M (1936) Studies in contact dermatitis. J Allergy Clin
res ins colophony/hydroabietyl alcohol and balsam of Peru/ Immunol 7:556-572
perfume mixture. Contact Dermatitis 14:119 Hausen BM, Hessling C (1990) Contact allergy due to colophony
Burge PS (1984) Occupational asthma, rhinitis and alveolitis due (VI). The sensitizing capacity of minor resin acids and 7
to colophony. In: Pepys J (ed) Clinics in immunology and commercial modified-colophony products. Contact Dermati-
allergy. Saunders, Philadelphia, pp 55-81 tis 23:90-95
Burry JN (1976) Contact dermatitis from radiata pine. Contact Hausen BM, Loll M (1993) Contact allergy due to colophony
Dermatitis 2:262-263 (VIII). The sensitizing potency of commercial products: an
Calnan CD (1971) Colophony in eye-shadow. Contact Dermatitis investigation of French and German modified-colophony
Newslett 10:235 derivatives. Contact Dermatitis 29:189-191
Calnan CD (1972) Colophony dermatitis from insulated tools. Hausen BN, Mohnert J (1989) Contact allergy due to colophony
Contact Dermatitis Newslett 11:281 (V). Patch test results with different types of colophony
Christophersen J, Menne T, Tangh0j P, et al. (1989) Clinical patch and modified-colophony products. Contact Dermatitis 20:
test data evaluated by multivariate analysis. Contact Derma- 295-301
titis 21:291-299 Hausen BM, Jensen S, Mohnert J (1989) Contact allergy to
Cullen RT, Cherrie B, Soutar CA (1992) Immune responses to colophony (IV). The sensitizing potency of commercial
colophony, an agent causing occupational asthma. Thorax products. An investigation of French and American modified
47:1050-1055 colophony derivatives. Contact Dermatitis 20:133-143
Daly BM, Stevenson er (1984) Contact dermatitis to wood wool. Hausen BM, Krohn K, Budianto E (1990) Contact allergy due to
Contact Dermatitis 11:123 colophony (VII). Sensitizing studies with oxidation products
Dooms-Goossens A, Degreef H, Luytens E (1979) Dihydroabietyl of abietic and related acids. Contact Dermatitis 23:352-358
alcohol (Abitol) A sensitizer in mascara. Contact Dermatitis Hausen BM, Börries M, Budianto E, et al. (1993) Contact allergy
5:350-353 due to colophony (IX). Sensitizing studies with further
Ehrin E, Karlberg A-T (1990) Detection of rosin (colophony) products isolated after oxidative degradation of resin acids
components in technical products using an HPLC technique. and colophony. Contact Dermatitis 29:234-240
Contact Dermatitis 23:359-366 Helm TN, Taylor JS, Adams RM, et al. (1993) Skin problems in
European Communities (1996) Annex to Commission Directive performing artists. Am J Contact Dermat 4:27-32
96/54/EC. Official Journal of the European Communities L Holmborn B, Avela E, Pekkala S (1974) Capillary gas chromatog-
248:1-230 EC Annex 1 raphy-mass spectrometry of resin acids in tall oil rosin. J Am
Färm G (1996) Contact allergy to colophony and hand eczema. A Oil Chem Soc 51:397-400
follow-up study of patients with previously diagnosed allergy Holness DL, Nethercott JR, Adams RM, et al. (1995) Concomitant
to colophony. Contact Dermatitis 34:93-100 positive patch test results with standard screening tray in
Färm G, Liden C, Karlberg A-T (1994) A clinical and patch test North America 1985-1989. Contact Dermatitis 32:289-292
study in a tall-oil rosin factory. Contact Dermatitis 31:102-107 Karlberg A-T (1988) Contact allergy to colophony. Chemical
Färm G, Karlberg A-T, Liden C (1995) Are opera-house artistes identifications of allergens, sensitization experiments and
afflicted with contact allergy to colophony and cosmetics? clinical experiences. Acta Derm Venereol (Stockh) Suppl
Fisher AA (1986) Contact stomatitis and cheilitis. In: Fisher AA Karlberg A-T (1991) Air oxidation increases the allergenie
(ed) Contact dermatitis, 3rd edn. Lea and Febiger, Philadel- potential of tall-oil rosin. Colophony contact allergens also
phia, pp 784-785 identified in tall-oil rosin. Am J Contact Dermat 2:43-49
516 A.-T. Karlberg: Colophony
Karlberg A-T, Gäfvert E (1996) Isolated colophony allergens as McSweeney EE, Arlt HG Ir, Russel 1 (eds) (1987) Tall oil and its
screening substances for contact allergy. Contact Dermatitis uses, vol Il. Pulp Chemicals Association, New York
35:201-207 Meding B, Swanbeck G (1990) Occupational hand eczema in an
Karlberg A-T, Liden C (1985) Clinical experience and patch industrial city. Contact Dermatitis 22:13-23
testing using colophony (rosin) from different sources. Br 1 Meding B, Toren K, Karlberg A-T, et al. (1993) Evaluation of skin
Dermatol 113:475-481 symptoms among workers at a Swedish paper mill. Am 1 Ind
Karlberg A-T, Liden C (1988) Comparison of colophony patch Med 23:Z21-728
test preparations. Contact Dermatitis 18:158-165 Meding B, Äman M, Karlberg A-T (1996) Skin symptoms and
Karlberg A-T, Liden C (1992) Colophony (rosin) in newspa- contact allergy in woodwork teachers. Contact Dermatitis
pers may contribute to hand eczema. Br 1 Dermatol 126: 34:185-190
161-165 Moura C, Dias M, Vale T (1994) Contact dermatitis in painters,
Karlberg A-T, Boman A, Holmborn B, et al. (1986) Contact allergy polishers and varnishers. Contact Dermatitis 31:51
to acid and neutral fractions of rosin. Derm Beruf Umwelt Nie!sen NH, Menne T (1992) Allergenic contact sensitization in
34:31-36 an unselected Danish population. The Glostrup allergy study,
Karlberg A-T, Bohlinder K, Boman A, et al. (1988a) Identification Denmark. Acta Derm Venereol 72:456-460
of 15-hydroperoxyabietic acid as a contact allergen in Rademaker M, Kirby ID, White IR (1986) Contact cheilitis to
Portuguese colophony. 1 Pharm Pharmacol 40:42-47 shellac, Lanopol 5 and colophony. Contact Dermatitis 15:307
Karlberg A-T, Boman A, Hacksell U, et al. (1988b) Contact allergy Rimmer S, Spielvoge! RL (1990) Dermatologie problems of
to dehydroabietie acid derivatives isolated from Portuguese musicians. 1 Am Acad Dermatol 22:657-663
colophony. Contact Dermatitis 19:166-174 Sadhra S, Foulds IS (1995) Allergic potential of neutrals in
Karlberg A-T, Boman A, Nilsson ILG (1988c) Hydrogenation unmodified colophony, and a method for their separation
reduces the allergenicity of colophony (rosin). Contact from resin acids. Br 1 DermatoI132:69-73
Dermatitis 19:22-29 Sadhra S, Foulds IS, Gray CN (1996) Identification of contact
Karlberg A-T, Gäfvert E, Hagelthorn G, et al. (1990) Maleopim- allergens in unmodified rosin using a combination of patch
aric acid - a potent sensitizer in modified rosin. Contact testing and analytical chemistry techniques. Br 1 Dermatol
Dermatitis 22:193-201 134:662-668
Karlberg A-T, Liden C, Ehrin E (1991) Colophony in mascara as a Sainio EL, Henriks-Eckerman M-L, Kanerva L (1996) Colophony,
cause of eye!id dermatitis. Chemical analyses and patch formaldehyde and mercury in mascaras. Contact Dermatitis
testing. Acta Derm Venerol 71:445-447 34:364
Karlberg A-T, Gäfvert E, Liden C (1995) Environmentally friendly Schehade SA, Beck MH, Hillier VF (1991) Epidemiological survey
paper may increase the risk ofhand eczema in rosin-sensitive of standard series patch test results and observations on day 2
persons. 1 Am Acad Dermatol 33:427-432 and day 4 readings. Contact Dermatitis 24:119-122
Karlberg A-T, Gäfvert E, Meding B, et al. (1996) Airborne contact Shao LP, Gäfvert E, Karlberg A-T, et al. (1993) The allergenicity of
dermatitis from unexpected exposure to rosin (colophony). glycerol esters and other esters of rosin (colophony). Contact
Khan L Saeed MA (1994) 13ß,14ß-dihydroXY-13ct-isopropylabietic Shao LP, Gäfvert E, Nilsson U, et al. (1995) 15-Hydroperoxy
acid, an elicitor of contact allergy. 1 Pharm Sci 83:909-910 dehydroabietie acid - a contact allergen in colophony from
Koh D, Foulds IS, Aw TC (1990) Dermatological hazards in pinus species. Phytochemistry 38:853-857
electronies industry. Contact Dermatitis 22:1-7 Söderberg T, Elmros T, Gref R, et al. (1990) Inhibitory effect of
Koh D, Lee BL, Ong HY, et al. (1995) Colophony in bindi zinc oxide on contact allergy due to colophony. Contact
adhesive. Contact Dermatitis 32:186 Dermatitis 23:346-351
Lawrence RV (1962) Composition studies on gum and tall oil Soltes EI, Zinkel DF (1989) Chemistry of rosin. In: Zinke! DF,
rosin. Tappi 45:654-656 RusselI (eds) Naval stores. Production-chemistry-utilization,
Liden C (1984) Patch testing with soldering flux. Contact 1st edn. Pulp Chemicals Association, New York, pp 261-345
Dermatitis 10:119 Veien NK, Hattel T, Laurberg G (1992) Patch test results from a
Mallon E, Powell SM (1994) Allergie contact dermatitis from private dermatologic practiee for two periods of 5 years with
Granuflex hydrocolloid dressing. Contact Dermatitis 30:110 a lO-year interval. Am J Contact Dermat 3:189-192
Marks IG Ir, Belsito DV, DeLeo VA, et al. (1995) North Ameriean Watsky KL (1997) Airborne allergic contact dermatitis from pine
Contact Dermatitis group standard tray patch test results dust. Am 1 Contact Dermat 8:118-120
(1992-1994). Am 1 Contact Dermat 6:160-165 Widström L (1983) Contact allergy to colophony in soldering flux.
Matos 1, Mariano A, Gons:alo S, et al. (1988) Occupational Contact Dermatitis 9:205-207
dermatitis from colophony. Contact Dermatitis 18:53 Zinkel DF (1975) Chemicals from tree. Chem Technol 4:235-241
CHAPTER 65
Industrial Enzymes
L. Kanerva and M. Vanhanen
Introduction could be fermented in large tanks, thus permitting

mass production without dependence on animal
organs (Gerhartz 1990).
Many chemical reactions in biological systems occur in
Meanwhile the Danish firm Novo Industry AIS
the presence of enzymes. Enzymes are pro teins or
developed a subtilisin preparation, stable under the
glycoproteins, and accelerate biological reactions by
conditions of heat and alkalinity existing in normal
factors of a million or more. The progress in biotech-
laundering. The breakthrough for enzyme-containing
nology has resulted in the expanding field of microbial
washing powders came when Novo, in collaboration
enzyme production and applications, and increased
with Swiss and Dutch firms, put its products on
numbers of industrial enzymes have been taken into use.
the European market in 1965 and in America during
This report is based on recent documents by
the following years. By the end of the 1960s, half of the
Brisman (1994) and Kanerva and Brisman (1997). It
European and North American textile detergents
is focused on immunologically media ted adverse
contained enzymes (Gerbartz 1990).
effects of enzymes on the skin. General aspects of
The market for enzymes has an estimated yearly
enzymes, such as occurrence, production and use, are
turnover of V.S. billion with an annual increase of 8-
included.
12%. By the year 2000, the market may be V.S.
The available documentation reflects the way in
1.5 billion (Gerhartz 1990; Jokinen 1993). In Scandina-
which the toxic effects of environmental factors are
via there is enzyme production in Denmark and
described: first, case reports; then cross-sectional
Finland. This production is mainly based on fermen-
studies. Vnfortunately, studies on enzymes with a
tation in tanks with Bacillus, Aspergillus, Streptomyces
longitudinal epidemiological design are rare (Brisman
or Trichoderma micro-organisms (Gerhartz 1990;
1994).
Brisman 1994; Vanhanen et al. 1994). With the use of
modern molecular biotechnology, purified and effec-
tive enzymes can be produced in large quantities. The
Occurrence, Production and Use industrial enzymes used currently and their applica-
tions are given in Table 1.
Enzymes have been used since prehistoric times, when
it was discovered that juice extracted from grapes
could be turned into wine. Similar observations, such Occupational Exposure
as how to leaven bread and brew beer, were made
during the later centuries. In the 19th century, scien-
Enzymes can be found today in a wide range of
tists studying the process of fermentation discovered
occupational settings. Bakers are probably the most
the existence of enzymes and, in 1876, William Kühne
exposed occupational group, since an enzyme, mainly
proposed the word "enzyme", which comes from the
alfa-amylase, is routinely added to flour in many
Greek words "en" meaning "in", and "zyme", meaning
countries (Poutanen 1997). The major enzyme appli-
"yeast", i.e., in the yeast (Gerhartz 1990).
cations are listed in Table 2.
The first commercial enzyme-containing washing
powder, Burnus, was marke ted in 1913. This t~sin
containing powder was not a success because 1t was
Toxicokinetics and Mechanisms of Toxicity
unstable. In 1959, the Swiss Ferment Company mar-
keted a washing powder containing a protease enzyme
from one of the species of Bacillus subtilis. This was a Enzyme exposure occurs from dust or liquid aerosols
major advance in enzyme technology since the bacteria (Brisman 1994). The partides are deposited on the skin

518 L. Kanerva and M. Vanhanen
Table 1. Industrial enzymes and their major applications (see Table 2. Major enzyme applications and used enzymes or enzyme
Gerhartz 1990; Kanerva and Brisman 1997) groups (see Gerhartz 1990; Kanerva and Brisman 1997)
Acylase Pharmaceuticals Alcohol production Amylase, cellulase, glucoamylase,

Amylase Alcohol production, animal glucosidase, protease
feeds, baking, brewing, Animal feeds Amylase, cellulase, glucanase,
detergents, pulp and paper, hemicellulase, phytase, protease
starch and sugar production, Baking Amylase, amyloglucosidase,
textile industry, wine and cellulase, glucose oxidase,
fruit juice hemicellulase, protease
Amyloglucosidase Baking, brewing Brewing Amylase, amyloglucosidase,
Cellulase (cellobiohydrolases, Alcohol production, animal carbohydrase, cellulase,
endoglucanes, feeds, brewing, protein glucanase, glucoamylase,
beta-glucosidases) industry, pulp and paper, papain, peptidase, protease
textile industry, baking Cheese manufacturing Pepsin, rennin (chymosin)
Chymotrypsine Pharmaceuticals Composting Cellulase
Glucanase Animal feeds, brewing, wine Contact lens detergent Catalase, lipase, mucinase,
and fruit juice papain, protease
Glucosidase Alcohol production Cosmetology Papain
Glucose isomerase Starch and sugar production Dairy Lactase, lipase
Glucose oxidase Baking Detergents Amylase, cellulase, lipase, protease
Lactase Dairy Leather production Lipase, protease
Lipase Dairy, detergent industry, Meat portioning Protease
leather production, oils and Oils and fats Lipase
fats, starch and sugar Pharmaceuticals Acylase, alkaline phosphatase,
production, wine and bromelin, chymotrypsine, glucose
fruit juice oxidase, papain, penicillinase,
Pectinase Wine and fruit juice peroxidase, protease,
Protease Alcohol production, animal streptokinase, trypsine, urokinase
feeds, baking, brewing, Protein industry Cellulase, protease
detergents, leather Pulp and paper Amylase, hemicellulase, cellulase,
production, meat industry lipase, pectinase, xylanase
portioning, pro tein industry Starch and sugar Amylase, cellulase, glucanase, glu-
Pullulase Starch and sugar production production coamylase, glucose isomerase,
Streptokinase Pharmaceuticals lipase, pullulase
Trypsine Pharmaceuticals Textile industry Amylase, cellulase
Urokinase Pharmaceuticals Wine and fruit juice Amylase, glucanase, lipase,
Xylanase (hemicellulase) Pulp and paper pectinase
or on the mucous membranes of the airways. When an 1970; Smith et al. 1989) or a combination of enzymatic
enzyme comes into contact with the skin or the and detergent action (Wütrich et al. 1971).
respiratory traet, antibodies to this enzyme may be In 1970, Ducksbury and Dave reported a cross-
formed, resulting in immunoglobulin (Ig) E-mediated seetional questionnaire study among home-helps. The
sensitization. Other isotypes may be formed, mainly prevalence of detergent-associated dermatitis was 5%.
IgG, but they seem to be markers of exposure rather Patch tests with enzyme-eontaining detergents were
than mediating symptoms. Direct enzymatic action negative. Bolam et al. eoncluded in 1970, after a study
may cause irritant effects in enzyme-exposed tissue. among housewives, that enzymatically aetive washing
Allergie contaet dermatitis has also been reported powders were not more irritant than conventional
(Brisman 1994). ones. In 1972, Göthe et al., 1972a) reported on 50
workers exposed to enzymes during detergent produc-
tion. Of these, 47% reported work-related skin symp-
toms, and the reactions were regarded as irritative.
Skin Generalized urticaria upon enzyme contact, probably
refiecting the contact urticaria syndrome, was reported
Irritant Dermatitis in one case. Irritant dermatitis was also reported in
Switzerland, Finland, Japan and Denmark (Wütrich
Irritant dermatitis from pineapples, apparently from et al. 1971; Okamoto et al. 1972; Stubb 1972; Zachariae
bromelain, was reported more than four decades ago et al. 1973; Niinimaki and Swari 1978). In 1973,
(Polunin 1951). After the introduction of enzyme- Zachariae et al. reported 79 workers with skin symp-
eontaining washing powders, there was much concern toms and exposure in enzyme produetion, and 12
about possible dermatological effects among users. unexposed controls. Patch tests with subtilisin were
These effects were regarded as irritative, caused by negative. A high enzyme coneentration was considered
non-enzymatic ingredients (Jensen 1970; McMurrain to cause irritant dermatitis.
Industrial Enzymes 519
Allergie Reactions Cellulase and Xylanase
Arecent study from Finland confirmed that the Four cases of contact urticaria developing after 0.5-
currently used industrial enzymes are strong sensi- 4 years of exposure to the enzymes cellulase and
tizers (Vanhanen et al. 1997). Sensitization may follow xylanase were reported by Kanerva and Tarvainen
minute exposure; even office personnel in factories (1990). All patients later developed rhinitis and asili-
may become sensitized. Proper control of exposure is ma, and two of them developed allergic contact
mandatory (Vanhanen et al. 1997). High prevalence of dermatitis (Tarvainen et al. 1991b). Skin-prick tests of
sensitization was also reported from the Danish all patients were positive to cellulase and xylanase
enzyme industry (Johnsen et al. 1997). (Table 3). The patch test of one patient was positive to
cellulase, and of the oilier to xylanase.
Alpha-Amylase Another typical case was reported by us in 1998
(Kanerva et al. 1998) involving a 38-year-old process
Allergies due to enzymes in bakeries have been man who had worked in ilie same factory for 14 years,
reported since 1986 when Baur and coworkers (1986) mainly in the distillation of ethanol. He had some
demonstrated the role of Aspergillus ((-amylase in atopic and work-related rhinitis but, when he started
baker's asthma. Since ilien, several reports have con- to work in the production of starch from barley, within
firmed the role of ((-amylase as arespiratory allergen some months he developed more severe rhinitis,
(Brisman 1994; Houba et al. 1996; Vanhanen et al. 1996). pruritus and mild whealing on his upper arms when
((-Amylase has also caused contact urticaria and exposed to dust at work. Occupationally, he was
pro tein contact dermatitis in bakers (Morren et al. exposed to both barley and oat dust. Furthermore,
1993; Schirmer et al. 1987; Tarvainen et al. 1991a). cellulase enzymes were used in ilie production of
Schirmer et al. (1987) described one baker with starch. Previously, he had no atopic or other skin
dermatitis. He had positive skin-prick tests to symptoms. Prick testing (Table 4) and RAST showed
((-amylase and various bread improvers. The immedi- that he had been sensitized to cellulase (Kanerva et al.
ate test reaction to ((-amylase persisted for 48 h. A 1998).
patch test with ((-amylase was also positive, as weIl as Twenty-five cases of occupational allergy were
radioallergosorbent test (RAST) to ((-amylase, malt detected at the Institute of Occupational Health,
and bread improvers. We had a patient with occupa- Helsinki, Finland: 19 had asilima and allergic rhini-
tional allergic contact urticaria from fungal but not tis, and 6 had allergic rhinitis (Vanhanen et al. 1994).
bacterial ((-amylase (Kanerva et al. 1997). Accordingly, During chamber provocation tests, 5 developed
enzymes with the same function and the same name symptoms of contact urticaria, although this was
may have different antigenic characteristics. When probably much more frequent, as many patients
reporting about enzyme allergy, it is important to complained of such symptoms at work. Several
reveal details of the causative enzymes. patients also had pharyngitis or laryngitis related
In a cross-sectional study, Brisman and Belin to enzyme exposure (Hytönen et al. 1994). Most of
reported in 1991 on 20 amylase-exposed workers who the 25 cases with occupational allergy (Vanhanen
had significantly more skin symptoms than the con- et al. 1994) had been exposed to enzymes in the
trols. In 1993, Morren et al. reported on 32 consecutive enzyme production industry, where the total number
bakers patch-tested wiili ((-amylase. Seven had an of exposed workers was only 300-400, indicating the
immediate reaction, and two had a positive delayed great potential of enzymes to sensitize (Vanhanen
skin test. Four of ilie seven were skin-prick tested to et al. 1994).
((-amylase and they were all positive.
Papain Clinical Symptoms
Contact urticaria from papain has been reported by Contact urticaria may present as whealing on the
Baur et al. (1982) in papain workers, and from contact- contact sites but mayaiso present as generalized
lens deansing solutions by Bernstein et al. (1984), symptoms. Apparently the mild form, i.e., "non-
Santucci et al. (1985) and Podmore and Storrs (1989). visible" contact urticaria (Kligman 1990), is only
Papain persists in ilie soft lens matrix despite careful seldom diagnosed, but may be much more common.
rinsing (Fichman et al. 1978). In a factory manufac- Type-l allergic reactions mayaiso present as dermatitis
turing papain, Baur et al. (1982) reported that 17 of 33 and is called protein contact dermatitis (Hjorth and
workers developed type-l reactions such as periorbital Roed-Petersen 1976; Tarvainen et al. 1991a; Morren
edema, conjunctival irritation or allergic asthma. et al. 1993; Kanerva 1998).
Table 3. Characteristics and test results of four patients allergie to enzymes (from Tarvainen et al. 1991a, with permission)
2 3 4
Age (Years)/Gender 49/F 38/F 25/M 29/F

Occupation Laboratory assistant Laboratory assistant Process Worker Laboratory assistant
Enzymes exposed to: Xylanase, cellulase, Cellulase Cellulase Xylanase, cellulase
amylase
Duration of exposure (Y) 4 2 2 0.5
Causative enzyme Xylanase Cellulase Cellulase Xylanase
Symptoms Asthma, rhinitis, Rhinitis, urticaria, Asthma, urticaria Asthma, urticaria,
urticaria dermatitis dermatitis
Prick tests
Cellulase 0.01%; Neg 0.001%; 3+ 0.01%; 3+ 0.001%; 2+
Xylanase 0.01%; 3+ 0.001%; 3+ ND 0.001%; 3+
Own/Family atopy -/+ +/+ +/+ -/+
Total 19E
(kU/L) 72 4500 1000 110
Patch tests
Cellulase ND 3.3%; 3+ ND Neg
1%; 3+
0.33%; 3+
Xylanase ND Neg ND 3.3%; 3+
1%; 3+
0.33%; 3+
Standard series Neg Neg Neg Neg
Specific 19E (normal below
0.35 PRU/ml)
Cellulase (PRU/rnl) 6.2 1200 175 3.6
Xylanase (PRU/ml) 6.5 490 68 1.4
ND, not done; Neg, negative; PRU, Phadebas RAST units
Prick and Patch Testing with Industrial Enzymes based on the RAST reference serum (Pharmacia &
Upjohn, Sweden). Values greater than 0.3 kUlI were
Preparing Industrial Enzymes for Prick Testing. defined as positive (elevated).
Commercial enzyme or noncommercial enzyme prep-
In another study, we used the same methods to
arations can be used for prick testing (Vanhanen et al.
prepare prick test substances for cellulase and other
1996, 1997). For example, to reveal contact urticaria to
enzymes, and we also used the same methods for IgE
ex-amylases, two bacterial ex-amylases (BAN 1000 S,
measurements (Kanerva et al. 1998). The prick-test
Novo Nordisk AIS, Denmark, and an ex-amylase
series used by us is given in Table 4, showing a patient
supplied by Genencor International, Finland), and
with an allergie prick-test reaction to cellulase but not
two fungal ex-amylases (Fungamyl, Novo Nordisk AIS,
to other industrial enzymes (Kanerva et al. 1998).
Denmark, and Sal Conc, Shin Nihhon, Japan) were used
(Kanerva et al. 1998). Dry enzyme preparations were
extracted in 0.1 M potassium phosphate buffer, pH 7.4, Table 4. Prick test results with aseries of industrial enzymes
(0 = no wheal) in a patient with occupational contact urticaria
and diluted to the Coca solution (0.5% sodium chloride, caused by cellulase (Kanerva et al. 1998)
0.3% sodium hydrogen carbonate, 0.4% phenol) to
achieve a pro tein concentration of 200 Ilg/ml. Apart of Prick test substances; Origin of prick Wheal diameter
this solution (2.5 ml) was passed through a Millex-GV enzymes and controls test substance (mm)
filter containing a 0.22-llm membrane (Millipore Ud)
Histamine HCI (10 mg/mi) 7 mm (=3+)
into a sterile vial containing 2.5 ml glycerol, yielding a Negative control 0
final protein concentration of 100 Ilg/ml. The Coca- Coca-glycerol control 0
glycerol solution served as a negative control. Cellulase Fungal 5 mm (2+)
Xylanase Fungal 0
Glucose-oxidase Fungal 0
IgE Measurements. Specific IgE antibodies to enzymes
Pectinase Fungal 0
can be measured by a RAST. Proteins of the above Protease Bacterial 0
commercial ex-amylase enzyme preparations were Protease Fungal 0
IX-Amylase Bacterial 0
conjugated to cyanogen bromide-activated paper discs IX-Amylase Fungal 0
in our study (Kanerva et al. 1998) by the method of IX-Amylase Bacterial 0
Ceska et al. (1972). Other reagents for RAST were Phytase Fungal 0
obtained from the Phadebas RAST kits (Pharmacia & Protease Bacterial 0
Lipase Fungal 0
Upjohn, Sweden). The results, expressed as kUlI, were
Preparing /ndustria/ Enzymes for Patch Testing Table 5. Prevalence of positive skin tests to enzymes according to
atopic status
We had two patients with allergie pateh-test reaetions Number of Number with Author
to eellulase and xylanese (Tarvainen et a1. 1991b, tested positive test
Table 3). Cellulase and xylanase were tested in a workers (%)
dilution series (3.3%, 1%, 0.33%) in petrolatum and
Atopics Non-atopics
aqua. As a eontrol, 20 non-exposed subjeets (10
atopies) were pateh tested with a eoneentration of 121 64 33 Greenberg et al. (1970)
3.3% w/v in petrolatum, with negative results. Cur- 640 43 l3 Flood et al. (1985)
459 26 18 Flood et al. (1985)
rently, seanty data are available on how to pateh test 1614 24 l3 Flood et al. (1985)
with industrial enzymes. Optimal pateh test eoneen- 56 28 11 Göthe et al. (1972b)
trations need to be established for eaeh enzyme, and 1642 37 15 Juniper et al. (1977)
155 77 45 Mitchell and
eontrols are neeessary. Gandevia (1971)
103 82 37 Newhouse et al. (1970)
Systemic Allergie Reactions and Food Allergy 65 83 23 Pepys et al. (1973)
173 29 7 Vanhanen et al. (1997)
Mansfield and Bowers (1983) reported a man who

developed periorbital edema on ingestion of papain- enzymes, but atopy inereases the risk for sensitization.
treated meat. Anaphylaxis has also followed the use of However, many researehers eonsider it unjustified to
ehymotrypsin for the treatment of epididymitis (Lie- exclude atopies from work with proteins, e.g., enzymes.
bowitz and Ritter 1960), and the use of ehymopapain Exclusion does not solve the problem as non-atopies
for tlIe treatment of herniated lumb ar dises (Bruno also beeome sensitized (Johnsen et a1. 1997).
et a1. 1984). Papain and bromelain have provoked
hypersensitivity reaetions when ingested (Baur 1979).
Respiratory Tract
DeI Pozo and eoworkers (1995) deseribed a patient
who developed generalized dermatitis after taking
digestive tablets eontaining amylase, protease, and The first adverse effeets from handling detergent
eellulase enzymes. Type-IV hypersensitivity was be- enzymes were reported in 1969 by Flindt (1969, 1996).
lieved to be involved. However, only some people who He observed an epidemie among the workers in a
have allergie eontaet dermatitis develop systemie detergent powder faetory in 1967: 28 patients had
reaetions after ingesting the allergen (Menne and symptoms of the respiratory traet. Positive skin-priek
Hjorth 1982). Therefore, patients with type-IV hyper- tests and precipitating antibodies with detergent en-
sensitivity may be able to eat produets eontaining the zyme extraet indieated an immediate allergy (1969).
allergen. Sinee 1989, it has been permissible in Finland Pepys and eo-workers reported immunologieal findings
to add eellulase, for example, to white bread dough to in three seleeted patients referred from Flindt (Pepys
break up roughage. Four patients, allergie to eellulase, et a1. 1969). Apart from reproducing the skin priek tests,
could eat white bread witlIout any symptoms (Tar- they found immediate and late asthmatie reaetions to
vainen et a1. 1991b). It has been reported reeently, inhalation tests with enzyme powder (Pepys et al. 1969).
however, that allergens of enzymes may be preserved Occupational asthma was also reported in tlIe same year
in bread and eause symptoms in sensitized individuals in the German literature (Wütrieh and Ott 1969). Sinee
(Baur et a1. 1994; Baur and Czuppon 1995; Kanny and then numerous studies dealing with respiratory allergy
Moneret-Vautrin 1995). have been published. Detergent enzymes are eurrently
unusual eauses of oeeupational allergies (Kanerva et a1.
1995, 1996). Respiratory allergy is probably mueh more
Atopics and Enzyme Allergy
eommon than skin allergy. Detergent enzymes are
eurrently unusual eauses of oeeupational allergies
Atopy, defined as a person's history of atopy (ehild- (Kanerva et a1. 1995, 1996). A reeent study, however,
hood eezema, asthma, hay fever) and/or a positive priek indicated that they may be more eommon than reported
test to one or more eommon allergens, usually is a risk (Vanhanen et a1. in press). The interested reader is
for developing IgE-mediated allergy to proteins. Studies referred to tlIe review of Brisman (1994).
in whieh tlIe sensitization rate to enzymes is given in
relation to atopie status are listed in Table 5 (Greenberg
ConcJuding Remarks
et a1. 1970; Newhouse et a1. 1970; Mitehell and Gandevia
1971; Göthe et a1. 1972; Pepys et a1. 1973; Juniper et a1.
1977; Flood et a1. 1985; Vanhanen et a1. 1997), indieating Skin irritation has been demonstrated for proteolytie
that both atopies and non-atopies are sensitized by enzymes, but pateh tests in the 1960s and 1970S were
negative. Recent case reports show positive patch tests Baur X, Fruhmann G, Haug B, Rasche B, Reiher W, Weiss W
to non-proteolytic enzymes, i.e., cellulase, amylase, (1986) Role of aspergillus amylase in baker's asthma. Lancet
1:43
and xylanase. It is worth noting that these persons also Baur X, Sander I, Jansen A, Czuppon AB (1994) Sind Amylasen
have positive prick tests to the same enzymes. This von Backmitteln und Backmehl relevante Nailrungs-
may indicate that the observed patch-test reactions in mittelallergene? Schweiz Med Wochenschr 124:846-851
Bernstein DI, Gallagher JS, Grad M, Bernstein IL (1984) Local
fact are IgE-mediated allergie reactions and not ocular anaphylaxis to papain enzyme contained in a contact
necessarily the classical type-IV reactions, at least in lens solution. J Allergy Clin Immunol 74:258-260
so me cases. This may also indicate that these enzymes Bolam RM (1970) Severe dermatitis and "biological" detergents
(letter). BMJ 1:817-818
are causative agents in developing contact urticaria, Brisman J (1994) The Nordic Expert Group for Criteria
and that this urticaria may proceed to an allergie Documentation of Health Risks from Chemicals. lll. Indus-
contact dermatitis. trial enzymes. Arbete och Hälsa, Arbetsmiljöinstitutet, Na-
tional Institute of Occupational Health, Solna, Sweden 28:1-26
When evaluating allergy caused by enzymes, it Brisman J, Belin L (1991) Clinical and immunologieal responses to
should be remembered that commercial enzymes are occupational exposure to alfa-amylase in the baking industry.
emde products whieh may contain remnants of the Br J Ind Med 48:604-608
Bruno L, Smith D, Bloom M, Domino K, Bagshaw R, Star A,
growth material and the micro-organism used for Cohen A, Lupo S (1984) Sudden hypotension with a test dose
fermentation. They mayaIso contain preservatives, of chymopapain. Anesth Analg 63:533-535
e.g., benzoates, sorbates and parabens, in addition to Ceska M, Eriksson R, Varga JM (1972) Radioimmunosorbent
assay of allergens. J Allergy Clin Immunol 49:1-9
the main enzyme (Pariza and Foster 1983; Tiikkainen Chabane MH, Abuaf A, Leynadier F (1994) Porquoi certains
et al. 1996), and other enzymes produced by the allergenes sont-ils des enzymes. Ann Biol Clin 52:425-431
microbes (Vanhanen et al. 1994). These additional Dei Pozo MD, Navarro JA, Gastaminza G, Munoz D, Fernandez E,
de Corres LF (1995) Delayed systemie dermatitis from
compounds may in some cases be the cause of amylase, cellulase, and protease. Am J Contact Dermat 6:9-12
enzyme allergy (Tarvainen et al. 1991b; Tiikkainen Ducksbury CFJ, Dave VK (1970) Contact dermatitis in horne
et al. 1996). helps following the use of enzyme detergents. BMJ 1:537-539
Fiehman S, Baker VV, Horton HR (1978) Iatrogenie red eyes in
Enzymes may be more prone to cause sensitization soft contact lens wearers. Int Contact Lens Clin 5:202-206
than other proteins because of their enzymatic capac- Flindt MLH (1969) Pulmonary disease due to inhalation of
ity. Several common allergens, e.g., house dust mites, derivatives of Bacillus subtilis containing proteolytie enzyme.
Lancet i:1177-1181
storage mites, ragweed, pollens, Alternaria, cat, and Flindt MLH (1996) Biologieal miracles and misadventures:
bee venoms, are in fact enzymes (Chabane et al. 1994). identification of sensitization and asthma in enzyme deter-
Enzymes modify skin antigens (Kumar et al. 1983) gent workers. Am J Ind Med 29:99-110
Flood DFS, Blofeld RE, Bruce CF, Hewitt JI, Juniper CP, Roberts
and very little is known about the combined effects of DM (1985) Lung function, atopy, specific hypersensitivity,
enzymes and other antigens. Interestingly, Sarlo et al. and smoking of workers in the enzyme detergent industry
(1997) concluded from an animal study that proteolytic over 11 years. Br J Ind Med 42:43-50
Gerhartz W (ed) (1990) Enzymes in industry. VCH Verlagsge-
enzymes may enhance the allergie antibody responses sellschaft, Weinheim
to nonproteolytic detergent enzymes. When perform- Göthe C-1, Nilzen Ä, Holmgren A, Szamosi A, Werner M, Wide L
ing skin tests, it is important to use test extracts at an (1972a) Medieal problems in the detergent industry caused by
proteolytic enzymes from bacillus subtilis. Acta Allergoi
appropriate concentration in order not to induce false- 27:63-86
positive reactions. Unfortunately, commercial test Göthe C-1, Westlin A, Sundquist S (1972b) Air-borne B. subtilis
substances are not available, and tests must also be enzymes in the detergent industry. Int Arch Arbeitsmed
29:201-208
performed in non-exposed controls. Open tests on Greenberg M, Milne JF, Watt A (1970) Survey of workers exposed
intact skin may give false negative results, and not to dusts containing derivatives of bacillus subtilis. BMJ 2:
necessarily reflect t11e situation in situ, where coexis- 629-633
Hjorth N, Roed-Petersen J (1976) Occupational protein contact
ting exogenous factors may impair the function of the dermatitis in food handlers. Contact Dermatitis 2:28-42
skin barrier. Houba R, Heederik DJJ, Doekes G, van Run PEM (1996)
Exposure-sensitization relationship for amylase allergens in
the baking industry. Am J Respir Crit Care Med 154:130-136
Hytönen M, Vanhanen M, Nordman H, Keskinen H, Tuomi T,
Tupasela 0 (1994) Pharyngeal edema caused by occupational
References exposure to cellulase enzyme. Allergy 49:782-784
Jensen NE (1970) Severe dermatitis and "biological" detergents.
BMJ i:299
Baur X (1979) Studies on the specificity of human IgE-antibodies Johnsen CR, Sorensen TB, Ingemann-Larsen A, Bertelsen-Secher
to the plant proteases papain and bromelain. Clin Allergy A, Andreasen E, Kofoed GS, Fredslund-Nielsen L, Gyntelberg
9:451-457 F (1997) Allergy risk in an enzyme producing plant: a
Baur X, Czuppon AB (1995) Allergie reaction after eating alfa- retrospective follow up study. Occup Environ Med 54:671-675
amylase (Asp 0 2)-containing bread. Allergy 50:85-87 Jokinen 0 (1993) Prospects of enzyme applications in cellulose
Baur X, König G, Bencze K, Fruhmann G (1982) Clinical and paper industry (in Finnish). Kemia-Kemi 3=180-181
symptoms and results of skin test, RAST and bronchial Juniper CP, How MJ, Goodwin BFJ, Kinshott AK (1977) Bacillus
provocation test in thirty three papain workers: evidence for subtilis enzymes: a 7-year clinical, epidemiological and
strong immunogenie potency and clinically relevant "pro te- immunologieal study of an industrial allergen. J Soc Occup
olytie effects of airborne papain". Clin Allergy 12:9-17 Med 27:3-12
Kanerva L (1998) Occupational fingertip protein contact derma- Pepys J, Longbottom JL, Hargreave FE, Faux J (1969) Allergie
titis caused by grain flours and natural rubber latex. Contact reactions of the lungs to enzymes of bacillus subtilis. Lancet
Dermatitis 38:295-296 i:1181-1184
Kanerva L, Brisman J (1997) Contact urticaria, dermatitis and Pepys J, Wells ID, D'Souza MF, Greenberg M (1973) Clinieal and
respiratory symptoms caused by enzymes. In: Amin S, LalIti immunological responses to enzymes of bacillus subtilis in
A, Maibach HI (eds) Contact urtiearia syndrome. CRC Press factory workers and consumers. Clin Allergy P43-160
LLC, New York, USA, pp 129-142 Podmore P, Storrs FJ (1989) Contact lens intolerance; allergie
Kanerva L, Tarvainen K (1990) Allergie contact dermatitis and conjunctivitis? Contact Dermatitis 20:98-103
contact urticaria from cellulolytic enzymes. Am J Contact Polunin I (1951) Pineapple dermatosis. Br J Dermatol 63:441-445
Dermat 1:244-245 Poutanen K (1997) Enzymes: an important tool in tiIe improve-
Kanerva L, Jolanki R, Toikkanen J, Tarvainen K, Estlander T ment of tiIe quality of cereal foods. Trends in Food Science &
(1995) Statistics on occupational dermatoses in Finland. In: Technology 8:300-306
Eisner P, Maibach HI (eds) Irritant dermatitis. New clinieal Santucci B, Cristando A, Picardo M (1985) Contact urtiearia from
and experimental aspects. (Curr Probl Dermatol) Basel, papain in a soft lens solution. Contact Dermatitis 12:233
Karger 23:28-40 Sarlo K, Ritz HL, Fleteher ER, Schrotel KR, Clark ED (1997)
Kanerva L, Jolanki R, Toikkanen J, Keskinen H (1996) New cases Proteolytic detergent enzymes enhance the allergie antibody
reported to tiIe Register of Occupational Diseases in 1990- responses of guinea pigs to nonproteolytie detergent enzymes
1994 (in Finnish). In: Kanerva L, Jolanki R, Toikkanen J, in a mixture: implications for occupational exposure. J Allergy
Keskinen H (eds) Työterveyslaitos, pp 13-156 Clin Immunol 100:480-487
Kanerva L, Vanhanen M, Tupasela 0 (1997) Occupational allergie Schirmer RH, Kalveram K-J, Kalveram C-M, Siebert J, Kunze J
contact urtiearia from fungal but not bacterial alfa-amylase. (1987) Chronisch lichenoide Dermatitis bei Sensibilisierung
Contact Dermatitis 36:306-307 gegen Alpha-Amylase bei einem Bäcker. Z Hautkr 62:792-797
Kanerva L, Vanhanen M, Tupasela 0 (1998) Occupational contact Smith DJ, MatiIias CGT, Greenwald DI (1989) Contact dermatitis
urtiearia from cellulase enzyme. Contact Dermatitis 38:176-177 from B. subtilis-derived protease enzymes. Contact Derma-
Kanny G, Moneret-Vautrin DA (1995) Alfa-amylase contained in titis 20:58-59
bread can induce food allergy. J Allergy Clin Immunol 95: Stubb S (1972) Enzymes in detergents as cause of respiratory and
132-133 skin symptoms (in Finnish). Duodecim 88:721-724
Kligman A (1990) The spectrum of contact urticaria: wheals, Tarvainen K, Kanerva L, Grenquist-Norden B, Estlander T (1991a)
erythema, and pruritus. Dermatol Clin 8:57-60 Berufsallergien durch Cellulase, Xylanase und Alpha-Amy-
Kumar V, Rogozinski T, Beutner EH, Jablonska S (1983) Studies lase. Z Hautkr 66:964-967
in immunodermatology. IX. Effect of organic solvents and Tarvainen K, Kanerva L, Tupasela B, Grenquist-Norden B, Jolanki
enzymes on the reactivity of stratum corneum antigens. Int R, Estlander T, Keskinen H (1991b) Allergy from cellulase and
Arch Allergy Appl Immunol 71:112-116 xylanase enzymes. Clin Exp Allergy 21:609-615
Liebowitz R, Ritter JR (1960) Anaphylactic reaction to chymo- Tiikkainen U, Louhelainen K, Nordman H (1996) Flour dust.
trypsin. JAMA 172:139-140 Arbete och Hälsa 27
Mansfield LE, Bowers CH (1983) Systemic reaction to papain in a Vanhanen M, Nordman H, Tuomi T, Tupasela 0, Leisola M,
nonoccupational setting. J Allergy Clin Immunol 71:371-374 Harkki A, Holmberg PC, Hokkanen H (1994) The use of
McMurrain KD (1970) Dermatologie and pulmonary responses in industrial enzymes and allergy to enzymes in Finland (in
the manufacturing of detergent enzyme products. J Occup Finnish). Työsuojelurahaston loppuraportti, Helsinki pp 1-57
Med 12:416-420 Vanhanen M, Tuomi T, Hokkanen H, Tupasela 0, Tuomainen A,
Menne T, Hjorth N (1982) Reactions from systemic exposure to Holmberg PC, Leisola M, Nordman H (1996) Enzyme
contact allergens. Semin Dermatol 1:15-24 exposure and enzyme sensitisation in the baking industry.
Mitchell C, Gandevia B (1971) Respiratory symptoms and skin Occup Environ Med 53:670-676
reactivity in workers exposed to proteolytic enzymes in tiIe Vanhanen M, Tuomi T, Nordman H, Tupasela 0, Holmberg PC,
detergent industry. Am Rev Respir Dis 104:1-12 Miettinen M, Mutanen P, Leisola M (1997) Sensitization to
Morren MA, Janssens V, Dooms-Goossens A, Van Hoeyveld E, industrial enzymes in enzyme research and production.
Cornelis A, De Wolf, Peeters C, Heremans A (1993) Alfa- Scand J Work Environ Health 23:385-391
amylase, a flour additive: an important cause of protein Vanhanen M, Tuomi T, Tiikkainen U, Tupasela 0, Voutilainen R,
contact dermatitis in bakers. J Am Acad Dermatol 29: Nordman H. The risk of enzyme allergy in the detergent
723-728 industry. Occup Environ Med (in press).
Newhouse ML, Tagg B, Pocock SJ (1970) An epidemiologie al Wütrich B, Ott F (1969) Berufsasthma durch Proteases in der
study of workers producing enzyme washing powders. Lancet Waschmittel industrie. Schweiz Med Wochensehr 99:
i:689-693 1584-1586
Niinimäki A, Saari S (1978) Dermatologie and allergie hazards of Wütrieh B, Schwarz K, Eichenbergern-De Beer H (1971) Zur
cheesemakers. Scand J Work Environ Health 4:262-263 Pathogenese von Hautschäden durch biologisch aktive,
Okamoto K, Futami T, Kanda Y (1972) Skin irritation and allergy proteasenhaltige Waschmittel. Dermatologiea 142:265-268
inductivity due to alkaline proteinases. Eisei Kagaku 8: Zachariae H, Thomsen K, Gowertz Rasmussen 0 (1973) Occupa-
304-308 tional enzyme dematitis. Acta Derm Venereol Suppl (Stockh)
Pariza MW, Foster EM (1983) Determining the safety of enzymes 5P- 14
used in food processing. J Food Protect 46:453-468
CHAPTER 66
Nickel
C. Liden
Introduction Plating, Alloys and (orrosion
Metallurgical aspects of nickel and the corrosion of

Nickel allergy is the most frequent contact allergy in
nickel-containing materials in contact with sweat have
the industrialised world and an important cause of
been reviewed (Morgan and Flint 1989; Flint 1998), and
hand eczema. Nickel allergy predominantly affects
some of the most relevant information is summarised
young girls and women sensitised by jewellery and
below.
other personal items. A hundred years ago, however,
Skin contact with homogeneous nickel, other than
nickel dermatitis was an occupational disease that
with some coins, is not common, but many items that
affected men. Occupational exposure to this metal is
are electroplated with nickel co me into contact with
still a major factor in eliciting and maintaining hand
skin. Bright nickel plate contains sulfur, which facil-
eczema.
itates the release of nickel ions. Nickel plate is often
covered with a topcoat of chromium, silver, gold, tinl
nickel, or different lacquers which, although they
Prevalence, Use and Properties
reduce formation of nickel ions, may not be adequate
to prevent contact dermatitis. Topcoats often have
In Nature and Production pores or cracks and they are subject to wear. Nickel
used as an inter-liner under a plating of gold, silver or
Nickel is present in the earth's crust, occurs natu- chromium causes dermatitis (Liden et al. 1996).
rally in drinking water and in food, and is possibly Alloys are compounds or solid solutions of more
an essential nutrient for humans. Nickel-related than one element in metallic form, but cannot be
health problems are, however, not caused primarily considered as mixtures of the metals. A broad spec-
by nickel in the environment but are related to trum of nickel-containing alloys are produced. Com-
industrial activity. Nickel is a transitional metal with mon examples are stainless steels (iron/nickel!
the atomic number 28. Ni(o) in metal nickel and its chromium), copperlnickel and nickel-silver (nickel!
alloys, and Ni(II) in nickel salts and stable inorganic copper/zinc). Brass (copper/zinc) and red gold (goldl
compounds are the most prevalent oxidation states. silver/copper) are examples of nickel-free alloys. Re-
Numerous nickel salts and sulfides with different sistance to corrosion on skin contact varies widely
properties and uses are known. For example, nickel among different nickel-containing alloys depending on
ions are formed when metallic nickel is in contact their composition.
with sweat. Nickel-containing alloys may be placed, regarding
Today nickel is the fourth most-used metal after their behaviour when in contact with sweat, in three
iron, chromium and lead. During the 19th century, categories reflecting their probability of causing con-
white-nickel-containing alloys were produced in Eu- tact allergy (Flint 1998). Examples are shown in
rope as substitutes for silver and, around 1870, nickel Table 1. Many stainless steels are unlikely to cause
began to be used in steels and platings. Nickel allergic contact dermatitis. Sulfur-rich stainless steels,
production has increased considerably since 1940, however, may react with sweat, possibly causing
and today half the nickel produced is used in stainless contact dermatitis (Haudrechy et al. 1994, 1997). There
steels. Nickel is used in numerous alloys and coatings, is no relationship between the content of nickel in an
and in chemical compounds. It is also found in alloy and its ability to cause an allergic reaction, while
products for occupational and private use, many of there is a elose relationship between the rate at which
which may co me into contact with the skin (Grandjean ions form from nickel in contact with sweat and the
et al. 1989; Sunderman 1989). potential to cause areaction. This fact may be difficult

Nickel 525
Table 1. Some major nickel alloys, their applications, content and prob ability of causing contact allergy (based on personal
communication from GN Flint, Nickel Development Institute 1998, and Flint 1998)
Alloy and applications Typical Nickel content Other elements Prob ability of causing
(0/0) (0/0) contact allergy
Cu-Ni Marine uses, coinage 10-30 Cu 70-90 A

Magnet alloys 14 Co 25, Fe, Al A
Nickel-silver Architecture, domestic goods 15 Cu 65, Zn 20 A
Ni-Cr Heating elements, jet engines 79 Cr 20 C
Ni-Cr-Mo Chloride resistant alloy 54 Cr 16, Mo 15, Fe C
Ni-Fe Low expansion alloy 36 Fe 63 A
Ni-Si Corrosion-resistant alloy 85 Si 10 B
Ni-Sn Corrosion-resistant coating 35 Sn 65 B
Ni-Zn Corrosion-resistant coating 12 Zn 88 B
Stainless steels 9 Cr 18, Fe 72 C
Low alloy steels/cast iron 0.5-18 Fe 80-97 A
White gold Jewellery 2-12 Au 37-75 B
A, Alloys that behave similarly to nickel; B, Alloys that react very slowly with sweat and are unlikely to cause contact allergy; C, Alloys
that only in exceptional circumstances will react with sweat and are most unlikely to cause contact allergy
to understand and has caused demands for "nickel- Sensitisation and Prevalence of Allergy
free" items instead of the generally more relevant
demand for "low nickel release". Sensitisation to nickel is caused by direct and pro-
longed skin contact with items that release nickel ions.
The causes of primary sensitisation vary depending on
Health Effects fashion and other factors which influence exposure.
Suspenders and jeans buttons have previously been
frequent sensitisers. Today, cheap jewellery and ear
Toxicology
piercing are often major sensitisers. Ear piercing
is over-represented in people with nickel allergy
The major health effect of nickel and its compounds is
(Larsson-Stymne and Widström 1985; Nielsen and
contact allergy and allergic contact dermatitis as a
Menne 1993), but nickel allergy is also common among
result of skin exposure to nickel ions, Ni(II). Inhalation
people with unpierced ears. Precious-metal jewellery,
exposure to soluble nickel and nickel oxides/sulfides
watches, spectacle frames, buckets, zippers, etc. are
has caused nasal and pulmonary cancer in workers in
other important causes of sensitisation and elicitation
nickel refineries although there are no convincing data
of dermatitis. The role of occupational exposure in
on carcinogenicity for metallic nickel dust in humans.
sensitisation and elicitation of nickel dermatitis is
Exposure to nickel or nickel compounds via routes
discussed below.
other than inhalation has not been shown to increase
The prevalence of nickel allergy in the general
the cancer risk in humans (Aitio 1995). Inhalation of
population has been shown in epidemiological studies
nickel compounds may induce asthma; however,
to be 8-15% in women and 1-3% in men (Table 2). The
nickel-induced asthma is rare.
prevalence among young females is even high er, 17%
(Nielsen and Menne 1992; Department of Environmen-
Sensitising Capacity and Cross-Reactivity in the Guinea Pig
tal Health 1998).
Nickel allergy in patch-tested dermatitis patients
Nickel sulfate is moderate1y allergenic according to
varies greatly, depending on the selection of patient
predictive studies in guinea pigs (Wahlberg 1989;
groups. Publications listed in Table 2 show figures of
Nielsen et al. 1992). To better understand the simulta-
10-30% in fern ale patients and 2-8% in male patients -
neous patch-test reactivity and possible cross-reactiv-
the highest figures for occupational dermatology
ity often recorded in humans (to nickel sulfate-cobalt
patients from our department.
chloride; to nickel sulfate-potassium dichrornate, and
to nickel sulfate-palladium chloride), series of cross-
challenge experiments have been carried out in guinea Hand Eczema
pigs (Wahlberg and Boman 1992; Liden and Wahlberg
1994; Liden et al. 1995). It appears that the reactivity to Nickel-sensitive people run a considerably increased
nickel sulfate-palladium chloride is due to cross- risk of developing hand eczema. As shown by popu-
reactivity, while cross-reactivity is not probable for lation studies 30-43% of nickel-sensitive persons
nickel sulfate-cobalt chloride and nickel sulfate- report that they have experienced hand eczema
potassium dichromate. (cumulated prevalence) (Menne 1978; Peltonen 1979;
526 C. Liden
Table 2. Prevalence of nickel allergy in the general population and in dermatitis patients
Study population Nickel allergy Reference
Men (%) Women (%)
General population, Finland (n = 980) 0.8 8.0 Peltonen 1979

Healthy volunteers, California (n = 1158) 0.9 9.0 Prystowsky et al. 1979
Women of general population, Denmark (n = 1976)" 14.5a Menne et al. 1982
Schoolgirls, Sweden (n = 960) 9.0 Larsson-Stymne and Widström 1985
Young men, military service, Italy (n = 593) 0.7 Seidenari et al. 1990
General population, Denmark (n = 567) 2.2 11.1 Nielsen and Menne 1992
Young men, military service, Sweden (n = 520) 3.3 Meijer et al. 1995
General population, Sweden (n = 11,000)a 3.4" 14.9a Department of Environmental Health 1998
Dermatitis patients, Europe (n = 4825) 1.8 10.2 Fregert et al. 1969
Dermatitis patients, Germany (n = 36,720) 4.8 18.3 Schnuch et al. 1997
Dermatitis patients, schoolchildren, Germany (n = 383) 5.6 22.0 Brasch and Geier 1997
Occupational dermatology patients, Sweden (n = 1140) 8 30 Liden 1994a
aQuestionnaire study
Menne et al. 1982; Department of Environmental then, improved industrial hygiene and technical de-
Health 1998), compared with only 15-19% among velopment have decreased the risk. Today much of the
non-nickel-sensitive controls (Menne et al. 1982; work involving exposure to nickel may be automated,
Department of Environmental Health 1998). Figures but handling of hot nickel salt solutions and heavy
from dermatology departments on hand eczema in contamination of the work environment, skin, work
nickel-sensitive patients vary between 20% and 60%, clothes and protective gloves are still prevalent (Aitio
depending on selection of patients and presentation of 1995, and personal experience). While this constitutes a
data (Cainan 1956; Cronin 1972; Christensen and Möller significant risk of sensitisation, reports of nickel
1975a; Gawkrodger et al. 1986). The relationship be- sensitivity in the electroplating industry since 1960
tween nickel allergy, hand eczema and atopic derma- have been sparse (Fischer 1989).
titis has been extensively reviewed (Wilkinson and An outbreak of occupational dermatitis in an
Wilkinson 1989). electroforming plant in the UK was due to heavy
Most people, in daily life and in many jobs, have nickel exposure (Wall and Calnan 1980). Thirteen of
repeat contact with handles, keys, coins, scissors, tools the 27 exposed male workers were allergic to nickel
and other items that may release nickel. Wet work and (Table 3). Improvement in industrial hygiene led to an
other irritant factors impair the skin barrier function immediate decrease in the incidence of dermatitis.
and facilitate the penetration of allergens into the skin. A work-site survey was carried out in all 38 Finnish
These factors contribute to the development of hand electroplating plants (Kanerva et al. 1997). All 163
eczema. Dietary intake of nickel has been proposed to platers were interviewed and a random selection of
be of greater importance for hand eczema than skin workers was patch tested. Nickel allergy was found
exposure (Möller 1990), but this issue is controversial. among 15% of the female workers and 4% of the male
workers, which was the same frequency as recorded in
Finnish dermatitis patients (Table 3). Seventy percent
Occupational Exposure of those with nickel allergy reported past or present
hand eczema. The study also indicated that sensitised
Some of the most important jobs and exposures with workers often, but not always, were able to continue
risk of occupational contact dermatitis due to nickel, their work in the electroplating industry.
and probably primary sensitisation, are described
below and in Table 3. Recent publications on occupa- Electronics Industry
tional nickel dermatitis are added to the extensive
review by Fischer (1989) and by Cavelier and Fousser- Workers in the electronics industry are exposed to skin
eau (1995). irritants and contact allergens, among them nickel,
colophony (rosin) in soldering flux, rubber chemicals,
Platers epoxy and acrylates (Koh et al. 1990; Rycroft 1995). In
Singapore the electronics industry has grown to major
Dermatitis due to nickel exposure was reported among importance. During a 5-year period 24% of occupa-
platers in 1889 and, untill930, nickel dermatitis was a tional dermatology patients were from the electronics
frequent male occupational disease in the plating industry (Tan et al. 1997). More than half were under
industry (Blaschko 1889; Schwarz et al. 1957). Since 30 years of age. Patch testing showed that 32.8% of the
Nickel 527
Table 3. Prevalence of nickel allergy in selected occupational groups according to epidemiological studies and among dermatitis
patients
Study population Nickel allergy Reference
Men Women Total

(%) (%) (%)
Electroforming plant workers, UK (n = 27) 48 Wall and Calnan 1980

Electroplaters, Finland (n = 103) 4 15 Kanerva et a1. 1997
Electronics industry workers, patients, Singapore (n = 149, 57% male) 32.8 Tan et al. 1997
Hairdressers, patients, Sweden (n = 35) 40 Wahlberg 1975
Hairdressers, patients, Canada (n = 53, 87% female) 17 Holness and Nethercott 1990
Hairdressers, patients, Spain (n = 379, 92% female) 41.4 Conde-Salazar et a1. 1995a
Hairdressers, patients, Greece (n = 106, 96% female) 42.4 Katsarou et al. 1995
Hairdressers, patients, Finland (n = 62) 35.5 Leino et al. 1998a
Junior hairdressers, the Netherlands (n = 86) 27 van der Burg et a1. 1986
Hairdressers, Finland (n = 54 cases of hand eczema of 355) 35 Leino et a1. 1998b
Car mechanics, Sweden (n = 801) 8 Meding et al. 1994
Construction workers, patients, Germany (n = 322) 7.5 Geier and Schnuch 1998
Construction workers, patients, Spain (n = 408) 10 Conde-Salazar et a1. 1995b
Hospital wet workers, Finland (n = 536) 9.1 Lammintausta et al. 1982
Hospital wet workers, Sweden (n = 1857) 26.3 Nilsson and Bäck 1986
patients were positive to nickel (Table 3). Sources of nickel has varied considerably, and figures from 17%
contact included nickel-plated earthing straps, nickel- to 42% have been published. The prevalence of nickel
plated tools and coolants. allergy among hairdresser patients has often been
interpreted as higher than among other dermatitis
Metalworkers patients, but not always.
Hand eczema and nickel allergy often affect hair-
Metalworkers are often heavily exposed to cutting dressers early in their careers and often during their
fluids and cutting oils, and they are at high risk of apprenticeship (Wahlberg 1975; Lindemayr 1984). This
developing irritant and allergic contact dermatitis due propensity to allergies among hairdressers will affect
to additives in fluids (biocides, antioxidants, fragranc- their careers and their tendency to leave the occupa-
es, tall-oil rosin) (Rycroft 1995). The role of contami- tion, and it also affects the results of epidemiological
nation of re-circulating fluids by metals has been and clinical studies concerning hairdressers.
discussed and may be of some importance. Skin disease Several epidemiological studies have been carried
in hard-metal manufacturing is described in Chap. 68 out (Table 3). In a study of 86 junior hairdressers, the
(Fischer). incidence of nickel sensitivity was high at the start of
their apprenticeship (27%) (van der Burg et al. 1986). It
Hairdressers was suggested that the high figure was related to ear
piercing and frequent use of jewellery. In an epidemi-
Hairdressers are exposed to several factors that may ological study of occupational skin and respiratory
cause and contribute to hand eczema: wet work, nickel, disease among 355 hairdressers, 54 patients with
fragrances, preservatives and specific occupational suspected occupational eczema were patch tested and
allergens such as permanent-wave liquids, p-phenyl- 35% were positive to nickel (Leino et al. 1998b). It was,
enediamine and other hair-dye and bleaching agents. however, questioned whether the reactions were rele-
These factors are responsible for the high prevalence of vant for hairdressing.
hand eczema among hairdressers. They are exposed to Some authors have doubted that the high prevalence
nickel through handling scissors, combs, clips, pins and of nickel allergy is due to occupational exposure.
other nickel-containing tools and equipment. Nickel Current epidemiological studies will hopefully help to
release from nickel-plated objects is enhanced by settle the question. In an individual case it must,
ammonium thioglycolate in permanent-wave liquids however, be recognised that occupational nickel expo-
(Dahlquist et al. 1979). sure might be an important factor contributing to or
Wahlberg (1975), who reported 40% nickel allergy causing the hairdressers' hand eczema.
among hairdresser patients with hand eczema, focused
nickel allergy among hairdressers. Results from clinical (ar Mechanics
patch testing of hairdressers referred to dermatology
departments have been published from several coun- Car mechanics have a high prevalence of hand eczema,
tries (Table 3). The frequency of positive reactions to often related to irritants such as organic solvents and
528 C. Liden
oils. In an epidemiological study of hand eczema (oins

among car mechanics, a high prevalence of nickel
allergy was found (Me ding et al. 1994). Among 801 car Cashiers handle coins throughout the workday. Most
mechanics, 8% were patch-test positive to nickel, European coins are made of alloys that give high nickel
which is high for males (Table 3). Handling of nickel- release when stored in artificial sweat, and copper/
plated tools was suggested as a contributing factor, as nickel is one of the most frequently used alloys
some of the tools were positive with the dimethyl- (Morgan and Flint 1989; Flint 1998). Coins may cause
glyoxime test (see section The Dimethylglyoxime Test), or aggravate hand eczema among cashiers with nickel
and no ear piercing or relation to jewellery was found. allergy, but handling of co ins among nickel-allergic
consumers is considered to be a minor problem. It is
(onstruction Workers also believed that handling co ins rarely induces nickel
allergy. Co ins in the pocket may cause dermatitis on
Construction workers risk occupational contact der- the thigh, especially in nickel-sensitive men. Hand
matitis from exposure to irritants, chromate, cobalt, eczema in nickel sensitive cashiers is a problem in
rubber and epoxy. Nickel allergy, however, is not often clinical occupational dermatology. The magnitude of
discussed in relation to construction work (Coenraads the problem is, however, not known, as there are few
et al. 1984). In construction workers it is often found publications on the role of coins in nickel allergy and
together with allergy to chromate and/or cobalt, and hand eczema (Husain 1977; Gollhausen and Ring 1991;
nickel in cement has been proposed as a cause. Kanerva et al. 1998).
However, nickel in cement exists mainly as insoluble In a provocation study 11 patients with nickel allergy
salts (Wahlberg et al. 1977; Goh et al. 1986). and pompholyx exposed their hands to coins and
The frequency of nickel allergy among patch-tested other nickel-containing objects for 6 min, and no
construction-worker dermatitis patients has in some aggravation of the dermatitis was recorded 24 h later
re cent publications been 7.5% and 10%, which is above (Christensen and Möller 1975b). The duration of the
the prevalence among many other male dermatitis provocation was, however, too short to be relevant for
patients (Tables 2,3). In our occupational dermatology occupational exposure to coins. In a pilot study with
department, we have frequently identified important 40 patients with nickel allergy and hand eczema, half
sources of nickel exposure in plumbers, carpenters, handled nickel-free coins and half copper/nickel coins
locksmiths and electricians, shown by a positive for 4 h (Liden 1997). Follow-up of dermatitis was done
dimethylglyoxime test, involving tools, pipes, locks blindly 4 h, 24 hand 48 h after the provocation.
and other items (Liden 1994a; Liden et al. 1998). Nickel Ongoing hand eczema became worse after handling
exposure mayaIso occur as a result of handling both types of coins, and the dermatitis had deterio-
architectural aluminium such as doors and window- rated more in the group handling copper/nickel coins.
frames since a new method for anodising aluminium Nickel sulfate is present on the surface of used coins,
leaves easily-available nickel sulfate on the surface and nickel ions are rinsed off by contact for only 1 min
(Liden 1994b). with artificial sweat. Copper/nickel coins stored in
artificial sweat for 7 days give high release of nickel
Tools ions (up to 45 ).1g/cm 2 per week) (Consumer Safety
Group 1997). Hands become contaminated by nickel
Hand-held tools are used in many male and in some when handling coins and can also become contami-
fern ale occupations and metal parts may co me into nated from handling contaminated non-nickel co ins
repeated contact with the skin often under friction and and bank notes (Bang Pedersen et al. 1974).
wet conditions. The Swedish tool market was surveyed Today the majority of European coins are made of
to study the prevalence of tools that release nickel copper/nickel, but there are some nickel-free co ins.
(Liden et al. 1998). Twenty-seven percent of 565 hand- Few coins are made of pure nickel. It was decided in
held tools with metal parts that come into contact with 1997 that the Euro coinage shall consist of eight
the skin were dimethylglyoxime-test positive. It was co ins - six nickel free and two made of nickel-
concluded that these tools might elicit allergic contact containing alloys (copper/nickel combined with nickel!
dermatitis in already nickel-sensitive people and brass).
present a risk factor for induction of nickel allergy.
No relevant information concerning nickel release or (Ieaning, Domestic and Hospital Wet Work
composition of the materials is available for workers,
consumers or retailers. It was suggested that tool Hand eczema is common among people, especially
producers should consider nickel allergy and avoid among nickel-sensitive individuals, doing "wet work"
nickel-releasing materials in parts in contact with the in hospitals, cleaning and house work. Water and
skin, which may be other parts than the handle. detergents are important skin irritants, and nickel
Nickel 529
release from frequently handled equipment, tools, Table 4. Some examples of nickel dermatitis caused by exposure
handles, and keys may contribute to hand eczema. in miscellaneous occupations - to display the broad variation in
exposure
The majority of Western European women work
outside as well as inside the horne, and domestic work Occupation Causative nickel exposure Reference
has changed its character. It is, however, still true that
women more than men carry out wet household work, Bank clerk Coins Kanerva et al. 1998
Bartender Measuring cups Kanerva et al. 1993
especially when taking care of young children. Butchers Metal clasps in protective Heber 1986
Hand eczema and contact allergy was studied in gloves
hospital employees in Finland (Lammintausta et a1. Engraver Cold-impregnated aluminium Liden 1994b
Musicians Parts of string instruments Cavelier and
1982). Nickel allergy was found in 9.1% of the 536 and wind-instruments Foussereau 1995
workers tested and 60% of all nickel-sensitive persons Offset Ink-repellant solution Cronin 1980
had a history of hand eczema (Table 3). The 20-month printers
Pottery Clay Pirilä and
prevalence of hand eczema was 41% among 1857 workers Förström 1966
women employed in "wet hospital work" in Sweden Tailors Needles Fisher 1986
(Table 3), and the most important risk factors were a Teacher Blackboard chalk Raith and Jaeger
1986
history of earlier hand eczema, followed by a history of Technician Optical instrument Liden 1994a
metal dermatitis (Nilsson and Bäck 1986). (black nickel)
Miscellaneous Occupations
However, the role of dietary nickel in provoking and
There are numerous reports on occupational nickel maintaining hand eczema (vesicular dermatitis, pomp-
dermatitis among workers in different occupations holyx, dyshidrosis) in nickel-sensitive individuals
(examples are given by Cronin 1980; Fisher 1986; remains controversia1.
Fischer 1989; Rycroft 1995). In individual cases, there
has often been a convincing relationship between Implants and Dental Materials
occupational nickel exposure and dermatitis, and
sometimes also between the exposure and primary Nickel is used in surgical implants (joint prostheses,
sensitisation. The list of examples may be extensive, screws, wires, prosthetic cardiac valves). The clinical
but a selection is given in Table 4 to display the broad significance of nickel release from surgical implants is
spectrum of potential hazards which may not be shown controversia1. Both local and systemic reactions have
by epidemiological studies. been reported. The majority of patients, however, both
nickel-sensitive and non-sensitive, seem to tolerate the
levels of nickel from surgical implants without adverse
Systemic Exposure effect (Wilkinson 1989).
Many materials used in dentistry contain nickel,
such as orthodontic wires, dental prostheses and
Diet
dental casting alloys. In most instances this does not
seem to cause adverse effects in nickel-sensitive
The normal dietary intake of nickel varies between
individuals (Hensten-Pettersen 1989). The possibility
100 j..lg/day and 900 j..lg/day, 200 j..lg/day being an
of induction of tolerance in non-sensitised individuals
average (Grandjean et a1. 1989). Vegetables, cereals
by oral nickel exposure, as in orthodontic treatment,
and bread contribute the most nickel to human diets.
has been proposed (van Hoogstraten et a1. 1991, 1992).
Foods rich in nickel are cocoa, soy beans and nuts.
The clinical significance of this possibility is, however,
Nickel in drinking water varies considerably, and
not known.
leaching from taps and from electric kettles may
Little information is available concerning metal
contribute nickel to drinking water. Acid-containing
release from surgical implants and dental alloys.
food may cause the release of nickel from stainless
Manufacturers of these types of products should be
steel cookware.
required to present data on metal release as well as on
Some oral provocation tests with high doses of
composition.
nickel (0.6-5.6 mg, as nickel sulfate) have resulted in
aggravation of hand eczema (Christensen and Möller
1975b; Cronin et a1. 1980; Veien 1989). Flare-ups of
patch-test reactions have been provoked by oral
Diagnosis
challenge (Hindsen et a1. 1999). In hand eczema,
benefit from a low-nickel diet has been reported in a Nickel sulfate 5% in petrolatum is the standard test
few open studies (Kaaber et a1. 1978; Veien et a1. 1993). material in Europe, and it is commercially available
530 C. Liden
(Hermal 1997; Chemotechnique Diagnostics 1998). artificial sweat and heat. The dimethylglyoxime test is
Nickel sulfate 2.5% is used as the standard test material a useful tool for screening purposes, but sometimes
in the USo discoloration or false-negative results may occur.
Patch testing with serial dilution of nickel sulfate is
sometimes used to gain more information on the Nickel Release in Artificial Sweat
degree of sensitivity and to discriminate between
allergic reactions and irritant ones (Andersen et al. Nickel release may be analysed by a quantitative but
1993; Wahlberg 1995). Open tests to study the concen- complicated method (Menne and Solgaard 1979; Mor-
tration threshold have been carried out with nickel gan and Flint 1989; European Committee for Stan-
sulfate or chloride as single or repeated applications dardization (CEN) 1998b; Flint 1998). Items are stored
(Menne and Calvin 1993; Allenby and Basketter 1994). in artificial sweat at 30°C for 1 week. Analysis of nickel
Intracutaneous testing with nickel sulfate is used at in the solution at the end of the period may be carried
some centres (Möller 1989). out with atomic absorption spectrometry or with
Patch testing with metal discs of different nickel- inductively coupled plasma detection (ICP). Nickel
containing materials may be used as a supplement to release of 0.5 Ilglcm2 per week is the limit of the Nickel
the analysis of metal release in artificial sweat. This will Directive (Table 5). The majority of nickel-sensitive
give information about the ability of the materials to persons do not react during patch testing to materials
cause allergic contact dermatitis (Menne et al. 1987; with nickel release below this limit (Liden et al. 1996).
Liden et al. 1996).
Prevention
Detertion of Soluble Nickel
The Nickel Directive
The Dimethylglyoxime Test
Primary prevention of sensitisation to nickel through
The dimethylglyoxime test (Fisher's test) is a simple contact with jewellery and other items in direct and
test for nickel release, and it may be used for jewellery prolonged contact with the skin would be the most
and for other objects that co me in direct contact with important contribution to the prevention of nickel-
the skin (Feigl 1972; Fisher 1986). In many countries related hand eczema. The European Union has decided
the dimethylglyoxime test is now commercially avail- on a regulation aiming at the prevention of nickel
able in pharmacies or chemist's shops. allergy, The Nickel Directive, that will enter into force
The test is based on dimethylglyoxime (0.8-1% in in 2000. It restricts the use of nickel in products
alcohol) and ammonia (10%). A cotton-wool-tipped intended for direct and prolonged contact with the
stick with 1-2 drops of each solution is rubbed for up skin and for use during epithelialisation after piercing
to 30 s against the surface to be tested. A pink-red (European Parliament and Council Directive 1994;
colour indicates presence of nickel ions. A modified Liden et al. 1996) (Table 5). Hopefully, The Nickel
dimethylglyoxime test with increased sensitivity has Directive will be an effective tool for primary preven-
been developed to correspond to the limit of the Nickel tion of nickel allergy by reducing the risk of sensiti-
Directive (see below and Table 5) (European Commit- sation and for secondary prevention through reduced
tee for Standardization (CEN) 1998d). The modifica- exposure in people already sensitised, and also through
tion inc1udes pre-treatment of the surface with increased public awareness of nickel allergy. Since 1989,
Table 5. The EU Nickel Directive and analytical methods (European Parliament and Council Directive 94/27/EC (Nickel) 1994,
European Committee for Standardization (CEN) 1998a-d)
Part Nickel may not be used CEN standard for control of the limit
In post assemblies used during epithelialisation, unless they are EN 1810 (nickel co.ntent by atomic absorption
homogeneous and the concentration of nickel is less than spectrometry)
0.05%
2 In products intended to co me into direct and prolonged contact EN 1811 (nickel release in artificial sweat); prEN 12471
with the skin, such as earrings, necklaces, wristwatch cases, (screening test by dimethylglyoxime)
watch straps, buttons, tighteners and zips, if nickel release is
greater than 0.5 ~g nickellcm 2 per week
3 In coated products in part 2, unless the coating is sufficient to EN 12472 (wear and corrosion test)
ensure that the nickel release will not exceed 0.5 ~g nickellcm 2
per week after 2 years of normal use
Nickel 531
legislation similar to point 1 of The Nickel Directive has for occupational skin disease. Nickel-related hand
been in force in Sweden and similar to point 2 in eczema was the dermatological disease most common-
Denmark. ly causing permanent dis ability from 1970 to 1976 in
Denmark (Menne and Bachmann 1979a,b).
Elimination In a follow-up study of 91 nickel-sensitive patients,
the prognosis was more favourable concerning der-
The dimethylglyoxime test presents a powerful tool for matitis, hand eczema and concomitant allergies in
secondary prevention. People with contact dermatitis patients who strictly avoided metal contact in clothing
due to nickel allergy should limit exposure to nickel, and jewellery (Kalimo et al. 1997).
including exposure to nickel-containing personal
items, in the workplace and during leis ure. In the
workplace, nickel-sensitive people with hand eczema
and occupational hygienists, etc. may identify objects References
with which skin contact should be avoided and which
should possibly be exchanged for the same object
Aitio A (1995) Nickel and nickel compounds. Arbete och Hälsa
made with other materials. 26:1-61
Allenby CF, Basketter DA (1994) The effect of repeated open
exposure to low levels of nickel on compromised hand skin of
Protection nickel-allergic subjects. Contact Dermatitis 30:135-138
Andersen KE, Liden C, Hansen 1, V0lund Ä (1993) Dose-response
Soluble nickel salts, which are especially used by testing with nickel sulphate using the TRUE test in nickel-
sensitive individuals. Multiple nickel sulphate patch-test
platers and battery workers, may heavily contaminate reactions do not cause an "angry back". Br J Dermatol
protective gloves and clothing. Good occupational 129:50-56
hygiene is of great importance in these kinds of jobs, as Bang Pedersen N, Fregert S, Brodelius P, Gruvberger B (1974)
Release of nickel from silver coins. Acta Derm Venereol
shown by the history of nickel dermatitis. Workers (Stockh) 54:231-234
handling metallic items may use protective gloves of Blaschko A (J889) Berufsdermatosen der Arbeiter. Ein Beitrag zur
fabric, leather, rubber or plastic, but contamination as Gewerbehygiene (I). Das Galvaniseur-Ekzem. Dtsch Med
Wochenschr 15:925-927
weIl as possible penetration by nickel ions must not be Brasch 1, Geier J (1997) Patch test results in schoolchildren.
forgotten. Results from the Information Network of Departments of
Barrier creams have until now been of limited value Dermatology (IVDK) and the German Contact Dermatitis
Research Group (DKG). Contact Dermatitis 37:286-293
in preventing nickel contact dermatitis. Possibly useful Calnan CD (1956) Nickel dermatitis. Br J Dermatol 68:229-236
preparations, with a specific protective effect against Cavelier C, Foussereau J (1995) Kontaktallergie gegen Metalle und
nickel, will be presented in the future. Metal-chelating deren Salze. Teil II: Nickel, Kobalt, Quecksilber und Palladi-
um. Dermatosen 43:152-162
agents, mainly ethylenediaminetetraacetic acid (EDTA) Chemotechnique Diagnostics (1998) Patch test products. Cata-
compounds in creams, have been investigated in vitro logue, Malmö, Sweden
and with in vivo patch testing (Fullerton and Menne Christen sen OB (1982) Prognosis in nickel allergy and hand
eczema. Contact Dermatitis 8:7-15
1995; Gawkrodger et al. 1995). Skin penetration of Christensen OB, Möller H (1975a) Nickel allergy and hand
nickel ions may be reduced by topical application of eczema. Contact Dermatitis 1:129-135
EDT A, but simultaneous nickel release from alloys Christensen OB, Möller H (1975b) External and internal exposure
to the antigen in the hand eczema of nickel allergy. Contact
may be enhanced. Some chelating agents are toxic. Dermatitis 1:136-141
Some creams enhance patch-test reactivity to nickel Coenraads PI, Nater JP, Jansen HA, Latinga H (1984) Prevalence
and others reduce the reactivity (Fischer and Rystedt of eezema and other dermatoses of the hands and forearms in
construction workers in the Netherlands. Clin Exp Dermatol
1990 ). 9:149-158
Conde-Salazar L, Baz M, Guimaraens D, Cannavo A (1995a)
Contact dermatitis in hairdressers: pateh test results in 379
hairdressers (1980-1993). Am J Contact Dermatitis 6:19-23
Prognosis Conde-Salazar L, Guimaraens D, Villegas C, et al. (1995b)
Occupational allergie eontact dermatitis in construction
workers. Contact Dermatitis 33:226-230
Many mild cases of nickel dermatitis will clear when Consumer Safety Group (1997) Report on nickel content and
release from coins. For the Royal Swedish Bank. Consumer
exposure to the causative object(s) is avoided and a Safety Group, Laboratory of the Government Chemist,
topical treatment is applied. Hand eczema in nickel- Teddington, UK
sensitive patients is, however, considered to have a Cronin E (1972) Clinical prediction of patch test results. Trans St
John's Hosp Derm Soc 58:153-162
poor pro gnosis and may in some cases be resistant to Cronin E (ed) (1980) Metals, nickel. In: Contact dermatitis.
treatment and persist for years (Fregert 1975; Chris- Churchill Livingstone, Edinburgh, pp 338-367
tensen 1982). Nickel dermatitis in Denmark is the Cronin E, Michiel AD, Brown SS (1980) Oral challenge in nickel-
sensitive women with hand eczema. In: Brown SS, Sunderman
second most common dermatological disease, after FW Jr (eds) Nickel toxicology. Academic Press, London,
irritant contact dermatitis, giving rise to compensation pp 149-152
532 C. Liden
Dahlquist I, Fregert S, Gruvberger B (1979) Release of nickel from Hindsen M, Bruze M, Christensen OB (1999) Flare-up reactions
plated utensils in permanent wave liquids. Contact Dermatitis after oral challenge with nickel in relation to challenge dose,
5:52-53 intensity and time of previous patch test reactions. J Am Acad
Department of Environmental Health (1998) Environmental Dermatol (in press)
Health Report, Department of Environmental Health, Stock- Holness DL, Nethercott JR (1990) Epicutaneous testing results in
holm County Council, Stockholm, Sweden (in Swedish) hairdressers. Am J Contact Dermatitis 1:224-234
European Committee for Standardization (CEN) (1998a) Body- Husain SL (1977) Nickel coin dermatitis. BMJ 2:998
piercing post assemblies. Reference test method for determi- Kaaber K, Veien NK, Tjell JC (1978) Low nickel diet in the
nation of nickel content by flame atomic absorption treatment of patients with chronic nickel dermatitis. Br J
spectrometry. EN 1810 Dermatol 98:197-201
European Committee for Standardization (CEN) (1998b) Refer- Kalimo K, Lammintausta K, Jalava J, Niskanen T (1997) Is it
ence test method for release of nickel from products intended possible to improve the prognosis in nickel contact derma-
to come into direct and prolonged contact with the skin. EN titis? Contact Dermatitis 37:121-124
1811 Kanerva L, Estlander T, Jolanki R (1993) Occupational allergic
European Committee for Standardization (CEN) (1998c) Method contact dermatitis from nickel in bartender's metallic mea-
for the simulation of wear and corrosion for the detection of suring cup. Am J Contact Dermatitis 4:39-41
nickel release from coated items. EN 12472 Kanerva L, Kiilunen M, Jolanki R, et al. (1997) Hand dermatitis
European Committee for Standardization (CEN) (1998d) Screen- and allergic patch test reactions caused by nickel in electro-
ing tests for nickel release from alloys and coatings in items platers. Contact Dermatitis 36:137-140
that come into direct and prolonged contact with the skin. Kanerva L, Estlander T, Jolanki R (1998) Bank clerk's occupa-
prEN 12471 tional allergic nickel and cobalt contact dermatitis from
European Parliament and Couneil Directive 94127/EC (Nickel) coins. Contact Dermatitis 38:217-218
(1994) Offieial Journal of the European Communities 22.7.94, Katsarou A, Koufou K, Takou T, et al. (1995) Patch test results in
No. L 188/1-2 hairdressers with contact dermatitis in Greece (1985-1994).
Feigl F (1972) Spot tests in inorganic analysis, 6th edn. Elsevier, Contact Dermatitis 33:347-361
Amsterdam, pp 325-331 Koh D, Foulds IS, Aw TC (1990) Dermatological hazards in the
Fischer T (1989) Occupational nickel dermatitis. In: Maibach HI, electronics industry. Contact Dermatitis 22:1-7
Menne T (eds) Nickel and the skin: immunology and Lammintausta K, Kalimo K, Havu VK (1982) Occurrence of
toxicology. CRC Press, Boca Raton, pp 117-132 contact allergy and hand eczemas in hospital wet work.
Fischer T, Rystedt I (1990) Influence of topical metal binding Contact Dermatitis 8:84-90
substances, vehicles, and corticosteroid creams on the allergic Larsson-Stymne B, Widström L (1985) Ear piereing - a cause
patch test reactions in metal-sensitive patients. Dermatol Clin of nickel allergy in schoolgirls? Contact Dermatitis 13:
8:27-31 289-293
Fisher AA (1986) Contact Dermatitis, 3rd edn. Lea & Febiger, Leino T, Estlander T, Kanerva L (1998a) Occupational allergic
Philadelphia, pp 745-761 dermatoses in hairdressers. Contact Dermatitis 38:166-167
Flint GN (1998) A metallurgical approach to metal contact Leino T, Tammilehto L, Hytönen M, et al. (1998b) Occupational
dermatitis. Contact Dermatitis 39:213-221 skin and respiratory disease among hairdressers. Scand J
Fregert S (1975) Occupational dermatitis in a lO-year material. Work Environ Health 24:398-406
Contact Dermatitis 1:96-107 Liden C (1994a) Occupational contact dermatitis due to nickel
Fregert S, Hjorth N, Magnusson B, et al. (1969) Epidemiology of allergy. Sei Total Environ 148:283-285
contact dermatitis. Trans St Johns Hosp Dermatol Soc 55=17 Liden C (1994b) Cold-impregnated aluminum. A new source of
Fullerton A, Menne T (1995) In vitro and in vivo evaluation of the nickel exposure. Contact Dermatitis 31:22-24
effect of barrier gels in nickel contact allergy. Contact Liden C (1997) Report to the Royal Swedish Mint. Nickel allergy
Dermatitis 32:100-106 and coins. A European provocation study, Karolinska
Gawkrodger DJ, Vestey JP, Wong W-K, Buxton PK (1986) Contact Hospital, Stockholm, Sweden
dinic survey of nickel-sensitive subjects. Contact Dermatitis Liden C, WalIlberg JE (1994) Cross-reactivity to metal com-
14:165-169 pounds studied in guinea pigs induced with chromate or
Gawkrodger DJ, Healy J, Howe AM (1995) The prevention of cobalt. Acta Derm Venereol (Stockh) 74:341-343
nickel contact dermatitis. A review of the use of binding Liden C, WalIlberg JE, Maibach HI (1995) Skin. In: Goyer RA,
agents and barrier creams. Contact Dermatitis 32:257-265 Klaassen CD, Waalkes MP (eds) Metal toxicology. Academic
Geier J, Schnuch A (1998) Kontaktallergien im Bau-Hauptge- Press, San Diego, pp 447-463
werbe. Eine Auswertung der Daten des Informationsverbunds Liden C, Menne T, Burrows D (1996) Nickel-containing alloys
Dermatologischer Kliniken (IVDK) 1994-1996. Dermatosen and platings and their ability to cause dermatitis. Br J
46:109-114 Dermatol 134:193-198
Goh CL, Kwok SF, Gan SL (1986) Cobalt and nickel content of Liden C, Röndell E, Skare L, Nalbanti A (1998) Nickel release from
Asian cements. Contact Dermatitis 15:169-172 tools on the Swedish market. Contact Dermatitis 39:127-131
Gollhausen R, Ring J (1991) Allergy to coined money. J Am Acad Lindemayr H (1984) Hairdresser eczema and nickel allergy.
Dermatol 25:365-369 Hautarzt 35:292-297
Grandjean P, Nielsen GD, Andersen 0 (1989) Human nickel Meding B, Barregard L, Marcus K (1994) Hand eczema in car
exposure and chemobiokinetics. In: Maibach HI, Menne T mechanics. Contact Dermatitis 30:129-134
(eds) Nickel and the skin: immunology and toxicology. CRC Meijer C, Bredberg M, Fischer T, Widström L (1995) Ear piereing,
Press, Boca Raton, pp 9-34 and nickel and cobalt sensitization, in 520 young Swedish
Haudrechy P, Foussereau J, Mantout B, Baroux B (1994) Nickel men doing compulsory military service. Contact Dermatitis
release from nickel-plated metals and stainless steels. Contact 32:147-149
Dermatitis 31:249-255 Menne T (1978) The prevalence of nickel allergy among women.
Haudrechy P, Mantout B, Frappaz A, et al. (1997) Nickel release Dermatosen 26:123-125
from stainless steels. Contact Dermatitis 37:113-117 Menne T, Bachmann E (1979a) Permanent disability from skin
Heber W (1986) Nickel allergy in butchers. Berufsgenossenschaft disease. A study of 564 patients registered over a six-year
8:452 period. Dermatosen 27:37-42
Hensten-Pettersen A (1989) Nickel allergy and dental treatment Menne T, Bachmann E (1979b) Permanent disability from hand
procedures. In: Maibach HI, Menne T (eds) Nickel and the dermatitis in females sensitive to nickel, chromium and
skin: immunology and toxicology. CRC Press, Boca Raton, cobalt. Dermatosen 27:129-135
pp 195-205 Menne T, Calvin G (1993) Concentration threshold of non-
Hermal (1997) Patch test allergens. Trolab, Germany occluded nickel exposure in nickel-sensitive individuals and
Nickel 533
controls with and without surfactant. Contact Dermatitis Schwarz L, Tulipan L, Birmingham DJ (1957) Occupational skin
29:180-184 diseases of the skin, 3rd edn. Lea & Febiger, Philadelphia,
Menne T, Solgaard P (1979) Temperature-dependent nickel p 274
release from nickel alloys. Contact Dermatitis 5:82-84 Seidenari S, Manzini BM, Danese P, Motolese A (1990) Patch and
Menne T, Borgan 0, Green A (1982) Nickel allergy and hand prick test study of 593 healthy subjects. Contact Dermatitis
dermatitis in a stratified sampIe of the Danish female 23:162-167
population: an epidemiological study including a statistic Sunderman FW Jr (1989) Chemistry, analysis, and monitoring. In:
appendix. Acta Derm Venereol (Stockh) 62:35-41 Maibach HI, Menne T (eds) Nickel and the skin: immunology
Menne T, Bandrup F, Thestrup-Pedersen K, et al. (1987) Patch and toxicology. CRC Press, Boca Raton, pp 1-8
test reactivity to nickel alloys. Contact Dermatitis 16:255-159 Tan H-H, Chan MT-L, Goh C-L (1997) Occupational skin disease
Morgan LG, Flint GN (1989) Nickel alloys and coatings: release of in workers from the electronics industry in Singapore. Am J
nickel. In: Maibach HI, Menne T (eds) Nickel and the skin: Contact Dermatitis 8:210-214
immunology and toxicology. CRC Press, Boca Raton, pp 45- Wahlberg JE (1975) Nickel allergy and atopy in hairdressers.
54 Contact Dermatitis 1:161-165
Möller H (1989) Intradermal testing in doubtful cases of contact Wahlberg JE (1989) Nickel: animal sensitization assays. In:
allergy to metals. Contact Dermatitis 20:120-123 Maibach HI, Menne T (eds) Nickel and the skin: immunology
Möller H (1990) Nickel dermatitis: problems solved and un- and toxicology. CRC Press, Boca Raton, pp 65-73
solved. Contact Dermatitis 23:217-220 Wahlberg JE (1995) Patch testing. In: Rycroft RJG, Menne T,
Nielsen NH, Menne T (1992) Allergic contact sensitization in an Frosch PJ (eds) Textbook of contact dermatitis, 2nd edn.
unselected Danish population. The Glostrup allergy study, Springer, Berlin Heidelberg New York, pp 241-268
Denmark. Acta Derm Venereol (Stockh) 72:456-460 Wahlberg JE, Boman AS (1992) Cross-reactivity to palladium and
Nielsen NH, Menne T (1993) Nickel sensitization and ear piercing nickel studied in the guinea pig. Acta Derm Venereol
in an unselected Danish population. The Glostrup Allergy (Stockh) 72:95-97
Study, Denmark. Contact Dermatitis 29:16-21 Wahlberg JE, Lindstedt G, Einarsson Ö (1977) Chromium, cobalt
Nielsen GD, Rohold, AE, Andersen KE (1992) Nickel contact and nickel in Swedish cement, detergents and cutting oils.
sensitivity in the guinea pig: an efficient open application test Dermatosen 25:220-228
method. Acta Derm Venereol (Stockh) 72:45-48 Wall LM, Calnan CD (1980) Occupational nickel dermatitis in the
Nilsson E, Bäck 0 (1986) The importance of anamnestic electroforming industry. Contact Dermatitis 6:414-420
information of atopy, metal dermatitis and earlier hand van der Burg CKH, Bruynzeel DP, Vreeburg KJJ, et al. (1986)
eczema for the development of hand dermatitis in women in Hand eczema in hair-dressers and nurses; a prospective
wet hospital work. Acta Derm Venereol (Stockh) 66: study. Contact Dermatitis 14:275-279
45-50 van Hoogstraten IM, Andersen KE, von BIomberg BM, et al.
Peltonen L (1979) Nickel sensitivity in the general population. (1991) Reduced frequency of nickel allergy upon oral nickel
Contact Dermatitis 5:27-32 contact at an early age. Clin Exp Immunol 85:441-445
Pirilä V, Förström L (1966) Pseudo-cross-sensitivity between van Hoogstraten IM, Boden D, von Blomberg ME, Kraal G,
cobalt and nickel. Acta Derm Venereol (Stockh) 46: Scheper RJ (1992) Persistent immune tolerance to nickel and
40-45 chromium by oral administration prior to cutaneous sensi-
Prystowsky SD, Allen AM, Smith RW, et al. (1979) Allergic tization. J Invest Dermatol 99:608-616
contact hypersensitivity to nickel, neomycin, ethylenedi- Veien NK (1989) Nickel dermatitis: its relationship to food and
amine and benzocaine. Arch Dermatol 115:959-962 experimental oral challenge. In: Maibach HI, Menne T (eds)
Raith L, Jaeger K (1986) The nickel content of chalk - cause of Nickel and the skin: immunology and toxicology. CRC Press,
contact dermatitis? Contact Dermatitis 14:61 Boca Raton, pp 165-178
Rycroft RJG (1995) Occupational contact dermatitis. In: Rycroft Veien NK, Hattel T, Laurberg G (1993) Low nickel diet: an open,
RJG, Menne T, Frosch PJ (eds) Textbook of contact derma- prospective trial. J Am Acad Dermatol 29:1002-1007
titis, 2nd edn. Springer, Berlin Heidelberg New York, pp 341- Wilkinson DS, Wilkinson JD (1989) Nickel allergy and hand
400 eczema. In: Maibach HI, Menne T (eds) Nickel and the skin:
Schnuch A, Geier J, Uter W, et al. (1997) National rates and immunology and toxicology. CRC Press, Boca Raton, pp
regional differences in sensitization to allergens of the 133-163
standard series. Population-adjusted frequencies of sensiti- Wilkinson JD (1989) Nickel allergy and orthopedic prostheses. In:
zation (PAFS) in 40,000 patients from a multicenter study Maibach HI, Menne T (eds) Nickel and the skin: immunology
(IVDK). Contact Dermatitis 37:200-209 and toxicology. CRC Press, Boca Raton, pp 187-193
CHAPTER 67
Chromium
D. Burrows
Chromium United Kingdom (Burrows 1978). An active pro-

gramme of reducing contamination of the workplace
with chromate will significantly reduce the incidence of
Chromium is so called because of the brightness of
chrome ulcers (Dornan 1981). In view of this, it is
many of its salts, hence the use of the Greek word for
disappointing that, in arecent survey of 71 platers in
colour. Chromium can occur in every one of the
the West Midlands of Britain, 22% were found to have
oxidation states from -2 to +6, but the ground states 0,
permanent nasal damage, 34% had evidence of healed
+2, +3, and +6 are common (Love 1983). Chromium
chrome ulcers, and 13% had evidence of new and
metal itself does not act as an allergen and must do so
healing ulcers. Of the 20 companies studied, 10% had
in combination with a protein. Only the trivalent and
at least one plater with a new ulcer (Williams 1996).
hexavalent salts are able to act as haptens; that is, they
Most ulcers will heal if the patient is removed from
form potentially antigenic bonds with proteins. The
the source. Necrosis of cartilage, but not bone, can
metal is highly resistant to corrosion in the atmosphere
occur; malignant change does not occur, and there is
and many aqueous solutions and is an unlikely cause
no increased incidence of chrome allergy in those with
of contact allergy.
chrome ulcers.
Toxicity Allergie Contact Dermatitis
Trivalent chromate is not considered toxic, but hex- Dermatitis occurs more commonly with hexavalent
avalent chromate has considerable toxic effects. In than trivalent chromate. Trivalent chromate binds very
sufficient concentrations, it (1) causes cancer, partic- readily to protein and, thus, penetrates the skin poorly;
ularly lung cancer (Bidstrup 1983), (2) causes respira- litde trivalent chromate gets past the stratum corneum,
tory symptoms ofbronchitis (Langard 1983), (3) affects whereas hexavalent chromate penetrates easily and
the immune system [Snyder et al. (1986) found a lower deeply into the dermis and is then transformed to
level of interleukin 6 produced by pokeweed nitrogen- trivalent chromate, whereupon it readily forms the
stimulated mononuclear cells isolated from patients hapten with the pro tein and is processed as an
exposed to chromate in the soil], and (4) causes allergen. Polak (1983) demonstrated that it is difficult
irritant dermatitis and chrome ulcers of the skin and to sensitize guinea pigs with trivalent chromate but,
mucous membranes. once sensitized, they react on patch testing in the same
way as those sensitized to hexavalent chromate.
Dermatitis
Pateh Testing
Irritant dermatitis is uncommon except for those in
contact with high concentrations; for instance, workers Potassium dichromate (0.5% in petrolatum) is the
whose duties include chrome plating. standard test material in Europe; in the United States,
0.25% is used. The concentration needed for eliciting
Chrome Uleers allergy is very near that which pro duces irritant
reactions (Burrows 1987). Patch testing with 0.5%
The commonest symptom associated with the irritant and 0.375% potassium dichrornate will produce a
effect of chromates are chrome ulcers occurring either number of irritant reactions, whereas patch testing
in the skin or nasal septum. In 1978, there were about with lower percentages, while producing fewer irritant
100 reported cases of chrome ulcers occurring in the reactions, will miss some allergic reactions (Burrows

Chromium 535
et al. 1989). The consequence of this is that 0.25% is Explosives

probably a safer percentage to use for those without Fire retardant
much experience in patch testing. Galvanised sheeting
Hardeners and res ins in the aircraft industry
Incidence of Chromate Allergy Leather
Magnetic tapes
The incidence of positive patch tests to chromate Metallic chromium
depends on which population is studied. In normal, Milk preservatives
healthy volunteers without apparent contact with Paints and varnishes
chromate, Peltonen and Fraki (1983) found only 0.5% Paper
were positive, whereas healthy volunteers in contact "Chrome cake" (containing sodium sulphate and small
with chromate had an incidence of 1.8%. Decaestecker amounts of sodium dichromate)
et al. (1990) found a similar incidence (1.7%) in Photography
chromate-pigment workers, and Goh et al. (1986b) Roofing
found 2.9% in prefabrication-construction factory Stainless steel
workers with normal skin. Nethercott (1982), in a Sutures
review of the world literature, found an incidence of Tanning leather
7.9% positive chromate sensitivity in routine testing in Textile mordants and dyes
a patch-test dinic. Peltonen and Fraki (1983) found Television screens
that, in their routine patch testing, 6.8% of 1159 men Welding
and 2.8% of 1823 women reacted to dichromate. üf Wood preservatives
these, 16.1% of the men and 18.1% of the women had a
Chromium is used in industry as folIows.
present or past history of atopic dermatitis but, of 390
patients with atopic dermatitis as a primary diagnosis, 1. Metallergical industries (85%), primarily stainless
only 1.3% showed a positive re action to dichrornate. steel. It is added to harden the metal and provide
These high figures of apparent allergy to dichromate high-temperature strength and corrosion resistance.
must be accepted with a certain amount of reserve, It is also used in combination with aluminium,
bearing in mind the potentially irritant nature of 0.5% zirconium, and zinc alloys.
potassium dichromate, which could give irritant reac- 2. Chemical applications (8%). Leather tanning is the
tions in those with active skin disease. Indeed, Fischer largest chemical use, followed by timber preserva-
and Rystedt (1985) found that only 40% of their tion and in paints, inks, textiles, and as pigments in
positive chromium patch tests were relevant. The plastics. Zinc and strontium chromates are used as
incidence of positive patch tests in routine testing in a corrosion inhibitors in priming paints. Chromium
skin dinic probably runs nearer to 1-2% and, if the can be used as a catalyst in drilling muds. It can also
figures are higher, then some special reason should be be used in water treatment, electroplating, passi-
sought. vation treatments of metal, and as a preservative in
milk testing.
3. Refractory bricks (7%). It is useful in refractory
Exposure to Chromium linings for furnaces and the kilns of the cement
industry and in moulding sands in foundries
because of its high melting point and relatively
Exposure to chromium is possible in contact with the
low cost.
following compounds (Burrows and Adams 1990):
Metals
Analytic standardsIreagents Cement
Anticorrosion agents
Batteries Cement, of course, is by far the most common and
Catalysts (for hydrogeneration, oxidation, best-recognised cause of chromate allergy. Cement
polymerization) contains varying amounts of chromate; for instance,
Ceramics Ellis and Freeman (1986) found water-soluble cement
Cement in Australia to vary from less than 1 ppm to 124 ppm,
Drilling muds with the majority tested showing less than 10 ppm.
Chromium lignosulphonates (from sodium dichromate Cement, on the addition of water, becomes alkaline
using lignosulphate waste) and is probably a factor in facilitating sensitization to
Electroplating and anodizing agents the chromate in cement. This may be the reason why
Engraving cases of contact dermatitis due to allergy to chromate
536 D. Burrows
in cement are seldom seen in cement-manufacturing because of contact with other irritants and wetness in
workers or in those handling dry, powdered cement. the process of tanning.
The percentage of patients with cement dermatitis
who have positive patch tests to chromate is probably Chrome Plating
about 80-85%, but some (Conde-Salazar et al. 1995)
have found lower levels (42%; 20% had positive patch Chrome plating, in which chromic acid and sulphuric
tests to cobalt). Chromate in cement derives from the acid are used, provides a significant opportunity for
ingredients (clinker), from the machinery used in contact with chromate (Lee and Goh 1988).
processing (grinders, etc.), and from refractory bricks.
Most of the chromate that go es into the cement is Galvanising
trivalent, but a varying proportion of this is changed to
hexavalent chromate during manufacture. This is Iron sheeting is protected from rusting by galvanising
important, because it is likely that the amount of with zinc applied either by electroplating or dipping in
chromate in ce me nt will decrease because of two molten zinc. This is coated with chromate to give
factors: (1) a number of magnesium chrome refracto- protection. This has been recognised as a cause of
ries are currently beginning to use magnesium alumi- dermatitis to chromate (Rycroft and Calnan 1977).
nate (spinal refractories) (Tandon and Aarts 1993), and
(2) slag from iron blast furnaces, which contains little Pigments
or no chromate (Goh and Gan 1996), is likely to be
increasingly used as a clinker substance. Furthermore, Chromates are used as:
with increased mechanisation, cement is decreasingly
1. Dye substances; for example, lead chromate. They
handled, and this has led to a reduction in cement
are usually in an insoluble hexavalent form and,
dermatitis (Chap. 43).
thus, not relevant as a skin hazard. Chromium
oxide, a trivalent form, is used in artists' paints and
Anticorrosion Agents ceramics.
2. Soluble sodium dichromate is used as a chelating
Chromates are still used as anticorrosion agents in agent in the presence of acid to yield an insoluble
water-cooling systems and paints. Their use persists in dyestuff. This is particularly used in wool processing.
spite of their toxicity, because they are very effective, 3. Occasionally, it is added to dyestuffs to prevent
persistent, relatively inexpensive agents and do not wool reducing the dye.
form insoluble complexes as some other anticorrosion
agents do.
Printing
Welding Printing was a relatively common source of allergy to

chromate (Burrows 1983); however, with the use of
Chromium may be present in electrorods used in acrylates, this has become infrequent.
electric arc welding, together with the metals which are
being welded. During welding, chromium is oxidised Stainless Steel
to the hexavalent chrome, is present in fumes, and has
caused dermatitis (Fregert and Ovrum 1963, Shelley Most stainless steels will contain about 18% chromate,
1964). but this can be up to 30%. A thin layer of chromium
oxide is formed under conditions of acidity and high
Leather chloride content. The oxide film may break down and
permit corrosion to occur. Corrosion products are
The incidence of chromate allergy in footwear derma- trivalent but, with an oxidising agent present, hexava-
titis varies in different studies. Trivalent chromate is lent chromium could be produced. In synthetic sweat
used; hence, the sensitization potential is low. Never- and in saline solution, only trivalent chromium was
theless, chromate allergy should always be considered formed, and the presence of hexavalent chromium
in shoe dermatitis and possibly even as a factor in could not be detected (Carter, personal communica-
hand dermatitis due to wearing leather gloves. Chro- tion). Kanerva (1997) has reviewed the literature on
mate is used in leather for other purposes than leaching of chromium from various cooking utensils.
tanning, e.g. water-repellent trivalent chromium stea- His conclusions were that chromium is leached only in
rate chloride or stain-repellent trivalent chromium and small amounts from stainless steels in contact with
fluorinated carboxylic acids, or as a dye. In those marked acidity and high temperature. It is unlikely,
carrying out tanning, the sensitization risk is increased however, that the amount leached from stainless steel
Chromium 537
utensils - even with acidic food - would exceed 50 Ilg Spot Test for Detection of Hexavalent Chromium
per day, the amount considered to be beneficial to (Chromate)
health.
Reagents
Reagent I: l,5-diphenylcarbazide (1% weight/volume
Bleaches and Detergents
in ethanol)
Concentrated sulfuric acid
On routine patch testing, a large percentage of female
Investigative procedures
patients have a positive patch test to chromate, without
Chromate on the surface of asolid object: a few drops
any obvious cause. Allenby and Goodwin (1983) found
of each reagent is applied on a cotton swab. The
one patient who reacted to as little as 1 ppm, and
cotton swab is thereafter rubbed against the surface
Nethercott et al. (1996) reported a person previously
of the object for 1 min. If chromate is present, a red-
sensitized to dichrornate developed inflammation of
violet colour appears.
the sweat ducts by dipping their forearm in a solution
Chromate in solutions: to a sampie of approximately
containing 25 Ilg/ml of chromate for 30 min. Basketter
10 ml a few drops or each re agent is added. If
et al. (1993) showed that chromium content was less
chromate is present, a red-violet colour appears.
than 5 ppm in detergents and would be likely to be less
Chromate in powders insoluble in water (cement): G
than 0.3 ppm when diluted with water, but Nethercott,
cement is mixed with 10 ml water for some minutes.
Allenby, and Goodwin's findings could not rule out
The mixture is then filtered and the filtrate is
detergents as a factor in chromate dermatitis, espe-
handled in the same way as described for chromate
cially if someone was already sensitized.
in solutions.
Clemmensen et al. (1981) suggested that contact with
ashes in cigarette trays could be an explanation of Reagent I must be prepared immediately before the
some cases of chromate allergy in females. The ashes investigation. Spot testing is not so accurate or easily
contain a relatively high amount of chromate, and the carried out as the dimethylglyoxime test for nickel.
cloths used to wipe these by cleaners would contain
an increasing concentration of chromate as the day
went on. Photosensitivity and Chrome Allergy
Other Sources of Contact Dermatitis Photosensitivity has been suggested as a factor in

chrome allergy, if only because many patients have
Magnetic tapes (Krook et al. 1997) their dermatitis on the exposed areas. This might be
Paper pulp manufacture (Pirila and Kilpi 1954; Conner expected in a substance that is a potential airborne
1972; Fregert et al. 1972) allergen (EI Sayed and Bazex 1994). Goh (1986a),
Cutting fluids (Cainan 1978a) however, found little chromate in the atmosphere of a
Tire fitters (Burrows 1981) Singapore cement construction factory and a busy city
Milk testers (Huriez et al. 1975; Rogers and Burrows center.
1975) Wahlberg and Wennersten (1977) found that pa-
Food laboratories (Pedersen 1977) tients showed a more intense re action when sites were
Machine oils (Oleffe et al. 1971; Einarsson et al. 1975; irradiated with short-wavelength ultraviolet light and,
Calnan 1978b) recently, Manciet et al. (1995) were able to demonstrate
Pigment in soap (Mathias 1982) that patch tests - when subsequently irradiated with
Resin hardeners containing high amounts of chromate ultraviolet light - showed both immediate and delayed
(this is especially seen in aircraft workers) (Handley reactions. However, White and Rycroft (personal
and Burrows 1994) communication) were unable to find an increased
Antifreeze (Freeman 1995). incidence of chromate sensitivity in patients with
photosensitivity. It seems that, while in very rare cases
one can find a certain element of photosensitivity, this
is unusual and rare.
Detection of Chromate
Effect of Systemic Chromium

Chromate is often a hidden allergen, and in any
situation where a patient has a positive patch test to
chromate and has contact dermatitis, one should Chromium is an essential element, particularly for
always suspect that they are in contact with chromate, glucose metabolism; indeed, addition of 200 Ilg chro-
and spot testing for chromate can be helpful. mium per day to the diet improved metabolism of
538 D. Burrows
glucose in diabetic patients. There have been several try and allergen replacement - for instance, change to
open studies on systemic chromate in patients with trivalent chromate for plating - produce a significant
chromate dermatitis (Schleiff 1968) which suggested a improvement (Burrows and Cooke 1980). A survey in
connection. Joensen et al. (1979) found that 11 out of 31 the chrome plant industry showed that there is
patients experienced a flare with 2.5 mg potassium considerable room for improvement, and Dornan
dichrornate. Veien et al. (1994), in a piacebo-controlled (1981) showed that efforts in improving hygiene were
oral challenge of 2.5 mg, found a significant number of quite worthwhile. Changing trivalent chromate into
flares. McMillen (1990), however, found no connection. hexavalent chromate in cement is taking place in four
The daily human chromium intake varies in differ- countries (Norway, Sweden, Finland, and Denmark),
ent geographical areas and is usually between 20 Ilg and there has been a reduction in chromate dermatitis
and 85 Ilg per day, although "values up to 130 Ilg per in the cement industry in these countries. There are
day have been reported" (Kanerva 1997). The doses three main reasons why this has not been universally
used in these trials of oral aggravation of chromate adopted:
dermatitis, therefore, bear no resemblance to anything
one might meet in everyday life, even in exceptional 1. Chromate allergy in the cement industry is dimin-
circumstances, and do not offer any evidence that ishing throughout the world whether ferrous sul-
chromate dermatitis is aggravated by oral intake. phate is added or not.
While it is weIl recognised that nickel and cobalt 2. The cost of this preventative measure may be
implants can aggravate dermatitis, particularly over considered prohibitive by some. The cost of ferrous
the implant, this is not a problem with chromium. sulphate is f 150 per ton per works for bag material;
taking into ac count transport costs and possible
Prognosis price reduction for bulk orders, one could ass urne a
delivered price of f 150. The maximum effective
It is weIl documented that prognosis in chromium level is likely to be 0.5% and, in some circumstanc-
dermatitis is probably worse than in any other form of es, would need to be 1%. For an annual cement
dermatitis. Burrows (1972) found that a very small production of 14 million tons in Britain, the
percentage were clear after 10-15 years. Halbert et al. additional cost would thus be between fio.5 million
(1992) confirmed this, and Hogan et al. (1990), in a and f 21 million. There would also be a capital cost
review of the prognosis of occupational contact of approximately f 150,000 for each works. In the
dermatitis of the hands, again confirmed the poor UK, there are 19 works, with a capital cost of three
prognosis in chromate dermatitis. million pounds.
3. With the change in refractory materials used
Change of Occupation (Tandon and Aarts 1993) and the change in raw
materials (Coh and Gan 1996), there is going to be a
There is very little clear data on the beneficial effect of decrease in the amount of chromate in cement
a change of occupation, but common sense and clinical anyway. Cement dermatitis is also reviewed in
experience would suggest that it would be beneficial. Chap.43.
Halbert et al. (1992), in a review of 122 patients with
chromate allergy followed up for 6-9 years found 62
(52%) were in the same occupation and, of these, 55 Barrier Creams
(89%) had ongoing dermatitis, 7 (11%) had completely
cleared despite continuing chromate exposure, 58 It is doubtful that ordinary barrier creams have any
(48%) had completely changed their type of work protective effect. Specific barrier creams that change
since initial presentation and, despite this, changing hexavalent chrome into trivalent chrome have been
dermatitis persisted in 40 (69%). A significant factor in suggested, including ascorbic acid (Valsecchi and
improvement appeared to be the length of time the Cainelli 1994), ascorbic acid with ethylenediamine
person had continued in employment with their tetraacetic acid (Romaguera et al. 1985), dithionate
dermatitis prior to changing work. (Wall 1982), tartaric acid plus glycine (Romaguera
et al. 1985), and sodium metabisulphite (Burrows and
Calnan 1965). Romaguera has also found apreparation
Treatment
containing silicone, glyceryl lactate, glycine, and tar-
taric acid to be effective in a clinical trial. Niklasson
Prevention et al. (1996) reported a polymer resin with a che1ating
agent that was effective in depressing nickel patch
Reduction of exposure is clearly the best method of tests. This is also effective in chelating chromate
prevention. Mechanisation in the construction indus- (Niklasson, personal communication).
Chromium 539
Treatment Decaestecker AM, Marez T, Jdaini J, et al. (1990) Hypersensitivity

to dichrornate among asyrnptomatic workers in achromate
pigment factory. Contact Dermatitis 23:52-53
One of the most important steps in improving prog- Dornan JD (1981) Occupational derrnatoses amongst chrome
nosis is to remove the patient from the source of the platers in the Sheffield area 1977-80. Contact Dermatitis
chromate as soon as possible (Halbert et al. 1992). A 7:354-355
Einarsson 0, Kylin B, Lindstedt G, et al. (1975) Chromium and
discussion must take place with the patient, because cobalt in nickel in using cutting fluids. Contact Dermatitis
improvement of their dermatitis cannot be guaranteed, 1:182-183
and many patients will continue to experience dis- EI Sayed F, Bazex J (1994) Airborne contact dermatitis from
chromate in cement with recall dermatitis on patch testing.
comfort even though they have no obvious further Contact Dermatitis 30:58
contact with chromate. There has never really been any Ellis V, Freeman S (1986) Dermatitis due to chromate in cement.
satisfactory explanation for this; it may be that Part I. Chromate conte nt in cement in Australia. Aust J
Dermatol 27:86-90
chromate remains a long time in the skin or that it Fischer T, Rystedt I (1985) False positive follicular and irritant
only requires minute quantities of chromate, such as patch test reactions to metal salts. Contact Dermatitis 12:
are found in soil, paper, etc., to keep the dermatitis 93-98
Freeman S (1995) Chromate allergy from 'antifreeze-antiboil'.
going. Nevertheless, it is ideal for the patient to be Australas J Dermatol 36:168
moved to another area of the company where they do Fregert S, Ovrum P (1963) Chromate in welding fumes with
not have contact with chromate-containing com- special reference to contact dermatitis. Acta Derm Venereol
43: 11 9-124
pounds. Otherwise, the treatment is the same as that Fregert S, Gruvberger B, Heijer A (1972) Sensitization to
for any eczematous condition: emollients and use of chromium and cobalt in processing of sulfate pulp. Acta
local steroids, when necessary. Derm Venereol 52:221-224
Goh CL, Gan SL (1996) Changes in cement manufacturing
process, a cause for decline in chromate allergy? Contact
Dermatitis 34:51-54
Goh CL, Gan SL, Ngui SJ (1986a) Occupational dermatitis in a
prefabrication construction factory. Contact Dermatitis
References 15:235-240
Goh CL, Wong PH, Kwok SF, et al. (1986b) Chromate allergy:
total chromium and hexavalent chromium in the air. Derm
Allenby CF, Goodwin BFS (1983) Influence of detergent washing Beruf Umwelt 34:132-134
powders on minimal eliciting patch test concentration of Halbert AR, Gebaver KA, Wall LM (1992) Prognosis of occupa-
nickel and chromium. Contact Dermatitis 9:491-499 tional chromate dermatitis. Contact Dermatitis 27:214-219
Basketter DA, Bratico-Vangosa G, Kaestner W, et al. (1993) Handley J, Burrows D (1994) Dermatitis from hexavalent
Nickel, cobalt and chromium in consumer products: a role in chromate in the accelerator of an epoxy sealant (PT 1422)
allergic contact dermatitis? Contact Dermatitis 28:15-25 used in the aircraft industry. Contact Dermatitis 30:193-196
Bidstrup PL (1983) Effects of chrome compounds on the Hogan DJ, Dannaker W, Lai S, et al. (1990) An international
respiratory system. In: Burrows D (ed) Chromium: metabo- survey of the prognosis of occupational contact dermatitis of
lism and toxicity. CRC Press, Boca Raton, pp 31-51 the hands. Derm Beruf Umwelt 38:143-147
Burrows D (1972) Prognosis in industrial dermatitis. Br J Huriez C, Martin P, Lefebvre M (1975) Sensitivity dichrornate in a
Dermatol 87:145-148 milk analysis laboratory. Contact Dermatitis 1:247-248
Burrows D (1978) Chromium and the skin. Br J Dermatol 99: Joensen HD, Thormann J, Jespersen NP, et al. (1979) Kromallergi
587-595 medicinsice og sociale aspekter. Ugeskr Laeger 141:1405-1407
Burrows D (1981) Chromium dermatitis in a tyre fitter. Contact Kanerva L (1997) Dermatotoxicological aspects of metallic
Dermatitis 7:55-56 chromium. Eur J Dermatol 7:79-84
Burrows D (ed) (1983) Chromium: metabolism and toxicity. CRC Krook G, Fregert S, Gruvberger B (1977) Chromate and cobalt
Press, Boca Raton eczema due to magnetic tapes. Contact Dermatitis 3:60-61
Burrows D ('987) Comparison of 0.25 and 0.5% potassium Langard S (1983) The carcinogenicity of chrome compounds in
dichromate in patch testing. Bull Dermatol Allerg Profes- man and animals. In: Burrows D (ed) Chromium: metabolism
sionale 2:117-120 and toxicity. CRC, Boca Raton, pp 13-31
Burrows D, Calnan CD (1965) Cement dermatitis. Trans St Johns Lee HS, Goh CL (1988) Occupational dermatitis among chrome
Hosp Dermatol Soc 51:27-39 platers. Contact Dermatitis 18:89-93
Burrows D, Cooke MD (1980) Trivalent chrome plating. Contact Love G (1983) Chromium - biological and analytical consider-
Dermatitis 6:222 ations. In: Burrows D (ed) Chromium: metabolism and
Burrows D, Andersen KE, Camaras JG, et al. (1989) Trial of 0.5% toxicity. CRC, Boca Raton, pp 1-12
versus 0.375% potassium dichrornate. Contact Dermatitis Manciet JR, Barrade A, Janssen F, Morel P (1995) Contact allergy
21:351 with immediate and delayed photoaggravation to chromate
Calnan CD (1978a) Chromate dermatitis from soluble oil. Contact and cobalt. Contact Dermatitis 33:282-284
Dermatitis 4:378 Mathias CGT (1982) Pigmented cosmetic dermatitis from contact
Calnan CD (1978b) Chromate in coolant water of gramophone allergy to a toilet soap containing chromium. Contact
record presses. Contact Dermatitis 4:246-247 Dermatitis 8:29-31
Clemmensen 01, Jorgensen J, Jons 0, et al. (1981) Exposure to Nethercott JR (1982) Results of routine patch testing of 200
chromium from hospital cleaning. Derm Beruf Umwelt 3: patients in Toronto, Canada. Contact Dermatitis 8:389-395
31-54 Nethercott I, Fowler J, Kauffman L, et al. (1996) Human response
Conde-Salazar L, Guimaraens D, Villegas C, et al. (1995) Occu- to repetitive hexavalent chromium challenge at 25 Ilglml in
pational allergic contact dermatitis in construction workers. water. Jadassohn Centenary Congress, London
Contact Dermatitis 33:226-230 Niklasson B, Bjorkner B, et al. (1996) In vivo evaluation of an
Conner B (1972) Chromate dermatitis and paper manufacture. active barrier cream in nickel contact allergy. Jadassohn
Contact Dermatitis Newslett 11:265 Centenary Congress, London
540 D. Burrows: Chromium
Oleffe J, Roosels D, Vanderkell 1, et aJ. (1971) Presence due Shelley WB (1964) Chromium in welding fumes as cause of
chrome dans I-environment de travaiJ. Derm Beruf Umwelt eczematous hand eruption. JAMA 189:772-773
19:57 Snyder CA, Udasin I, Waterman SJ, Taioli E, Gochfield M (1996)
Pedersen NB (1977) Chromate in a food laboratory. Contact Reduced IL-6 levels among individuals in Hudson County,
Dermatitis P05 New Jersey, an area contaminated with chromium. Arch
Peltonen L, Fraki J (1983) Prevalence of diehromate sensitivity. Environ Health 51:26-28
Contact Dermatitis 9:190-194 Tandon R, Aarts B (1993) Chromium, niekel and cobalt contents
Pirila V, Kilpi 0 (1954) On occupational dermatoses in Finland: a of some Australian cements. Contact Dermatitis 28:201-205
report of 1752 cases. Acta Derm Venereol 34:395-402 Valsecchi R, Cainella T (1984) Chromium dermatitis and ascorbic
Polak L (1983) Immunology of chromium. In: Burrows D (ed) acid. Contact Dermatitis 10:252-253
Chromium: metabolism and toxicity. CRC, Boca Raton, Veien NK, Hattel T, Laurberg G (1994) Chromate-allergie patients
pp 51-136 challenged orally with potassium diehromate. Contact Der-
Rogers S, Burrows D (1975) Contact dermatitis in milk testers. matitis 31:137-139
Contact Dermatitis 1:387-388 Wahlberg JE, Wennersten G (1977) Light sensitivity and chromi-
Romaguera C, Grimalt F, Vilaplana J, Carreras E (1985) Formu- um dermatitis. Br J Dermatol 97:411-416
lation of a barrier cream against chromate. Contact Derma- Wall LM (1982) Chromate dermatitis and sodium dithionate.
titis 13:49-52 Contact Dermatitis 8:291-293
Rycroft UG, Calnan CD (1977) Relapse of chromate dermatitis Williams N (1996) A survey of respiratory and dermatological
from sheet meta!. Contact Dermatitis P77-180 diseases in the chrome plating industry in West Midlands,
Schleiffp (1968) Provokation des Chromatekzems zu Testwecken UK. Occup Med 46:432-434
durch interne Chromzufuhr. Hautarzt 19:209-210
CHAPTER 68
Hard Metal
T. Fischer
Introduction ical and chemical tearing, and exposure to sensitizers,

primarily cobalt (Fischer and Rystedt 1984a,b).
In an investigation of 776 of 800 hard-metal
Hard metal is almost as hard as diamond. Hard metal
workers, the point prevalence of hand eczema was
has wide use in the mechanical industry for metal work
about 10%, and another 15% had dry, slightly
- drilling, cutting and milling. Hard metal is manu-
erythematous skin, which normalized after a 2-day
factured in a complex industrial process. A fine powder
weekend rest (irritant reactions). Of 1006 workers who
including approximately 90% tungsten carbide and
had left the industry during the previous 10 years, the
10% cobalt plus small amounts of titanium, niob,
incidence of hand eczema was estimated to be 17%.
tantal, molybdenum, sometimes 2-3% nickel and
Fifty-two percent of the hand eczemas and 67% of the
polyethylene glycol is pressed in a form. T~is results
irritant reactions started during the first year of work.
in a brittle black piece of a desired shape, WhlCh can be
The majority of both the hand eczemas and the irritant
broken by hand force and which is easily finished or
reactions appeared first in grinding activities. Wet
formed by grinding.
grinding and oil grinding entailed the highest risks of
The pieces are charged on a heat-resistant disc,
hand eczema. Hand eczema was significantly more
inserted in an oven and heated slowly in a hydrogen
common in individuals with an atopic background.
atmosphere until the power sinters, which means that
Eighteen percent of the individuals with present or
the cobalt metal melts and forms a glue between the
previous hand eczema had positive patch-test reac-
heat-resistant, extremely hard tungsten-carbide parti-
tions. Positive patch tests were equally common among
cles. The pieces shrink a little with this process but
individuals with irritant reactions and those with
keep their form and are transformed into hard metal.
normal skin (Fischer and Rystedt 1985a).
Different grinding procedures follow when diamond
powder or borium-carbide powder is used as a
Irritant Contact Dermatitis
grinding material to sharpen and polish the edges.
To smooth the edges and to give a fine finish, the
The dominant skin disease among hard-metal workers
pieces are then either thumbled with borium carbide,
is irritant contact dermatitis and irritant reactions. In a
detergent and saw dust, or diamond brushed and
detailed mapping of work places, the contamination of
cleaned.
the skin was analyzed - the flux of harmful material,
In a final step, a "golden" cheramic including
such as hard-metal powder, and cutting fluids into the
aluminum and titanium compounds is deposed on
process, shielding of the processes, and cleanliness of
the surface of the pieces to increase their mechanical
working area, hands and clothes. How machines were
resistance. The pieces are marked either by etching
served was also very important. Using epidemiological
with acid and cobalt salts or printed with dye before
methods, it was possible to prove that irritant factors
they are packed or included in tools.
caused most of the hand eczema cases, and it was
possible to indicate traumatizing factors in order of
importance.
Hand Eczema
Allergie Contact Dermatitis
Hand eczema is common among hard-metal workers.
The manufacturing process seems clean at a first A total of 853 workers presently or previously em-
glance, but a closer look reveals that the workers are ployed in hard-metal work were examined and patch
subject to heavy contamination of the hands, mechan- tested using the standard series plus tungsten, titani-

542 T. Fischer
um, niob, tantal, molybdenum, cutting fluids and other In the nickel-sensitized group, 40% had contacted
materials from the industrial environment. severe hand eczema, which generally appeared 6-12
A history of hand eczema was found in 36 of 39 months after the start of employment. In nickel
individuals with reproducible patch tests to cobalt, sensitive individuals, 25% developed cobalt allergy
while 21 of 23 individuals with a positive initial patch compared with 5% in the total population investigated.
test, but negative retest using the serial dilution Most facts indicate that nickel sensitivity and irritant
technique, had never had any skin problems. Patch hand eczema precede cobalt sensitization. Hard-metal
testing with cobalt chloride and nickel sulfate often workers with simultaneous nickel and cobalt sensitiv-
resulted in follicular erythematous reactions some- ity had a more severe hand eczema than those with
tim es reproducible with serial dilution retests, but not isolated cobalt or nickel sensitivity or only irritant
reproducible as morphologically positive reactions. dermatitis and had to leave the industry. Many of those
They were evaluated as irritant and were rarely with solitary cobalt allergy also had severe or moder-
associated with relevant hand eczema (Fischer and ately severe hand eczema. Some of them healed after
Rystedt 1985b). changing to other metal work or to dry hard-metal
Twenty-four individuals had isolated cobalt allergy. work, such as charging or inspection. It is interesting
Epidemiological investigation of different work activ- that eczema can heal, despite prolonged contact with
ities at the industry and relating them to cobalt- hard meta!. A small group of cobalt-positive workers
sensitive individuals revealed that hand grinding and had discrete or no dermatitis and cobalt allergy was
etching were areas that posed the greatest risk of cobalt not expected by history. Some of them remembered
sensitization. Few people worked at these activities. that they had experienced an earlier period of hand
Hand grinding was severely traumatizing to the eczema at the start of hard-metal work (Rystedt and
fingertips, and etching exposed the finger to a high Fischer 1983).
concentration of cobalt ions at a low pH value. A Neither sodium tungstate nor any of the additional
traumatic occupation that causes irritant contact metals patch tested, including molybdenum, gave any
dermatitis and/or a previous contact allergy or atopy positive reactions. In 2% of the patch tests with
is obviously an important prerequisite for the devel- tungstate, irritant pustular reactions appeared, often
opment of cobalt allergy. reproducible in retests but evaluated as irritant (Ryst-
Nickel sensitivity was found in two men and 38 edt et a!. 1983; Fischer and Rystedt 1985a). In GPM-tests
women. Eight women had a combined cobalt/nickel tungstate is a poor sensitizer (Boman et a!. 1982). One
allergy. Two-thirds of the female population had positive and relevant reaction to a cutting fluid and its
pierced ear lobes. Among the nickel-allergic women, ingredients has been found. Used cutting fluid con-
95% had pierced ear lobes. The use of earrings taminated with cobalt gave weak reactions in the most
containing nickel after piercing was strongly suspected sensitive of the cobalt allergic individuals.
to be the major cause of nickel sensitivity. Piercing at A few hard-metal workers had positive reactions to
an early age seems to increase the risk of incurring rubber chemicals. Most of these were evaluated as
nickel sensitivity. The majority of the nickel-sensitive relevant because exposure to rubber is common in the
women had developed a metal dermatitis prior to industrial environment.
employment in the hard-metal industry and before the
appearance of hand eczema. Those with simultaneous
nickel and cobalt allergies had probably been sensi-
Measures and Prevention
tized to nickel before their employment and then
became sensitized to cobalt by hard-metal work
(Rystedt and Fischer 1983; Fischer et a!. 1984). Irritant Contact Dermatitis and Irritant Reactions
Table 1. Materials inclu- There is strong evidence that irritant dermatitis and
ded in hard-metal manu- Cobalt metal irritant skin reactions clear the way for allergic
facturing Nickel metal
Tungsten carbide sensitization to cobalt. To institute preventive mea-
Borium carbide sures against irritant factors has high priority. The aim
Titanium metal of these measures is to reduce wearing of the skin by
Tantal metal
Niob metal improved occupational hygiene. Careful analysis of
Molybdenum each working site for physical and chemical damage to
Aluminum the skin should form the basis for suggestions of
Cutting fluids
Rubber materials measures: pay attention to the design of the tools,
Diamond machines and the ergonomics of the working site;
Polyethylene glycol analyze physical and chemical properties of the
Detergents
materials involved in the process; look for contamina-
Hard Metal 543
tion of machines, surroundings, clothes and skin; people at risk of hand dermatitis. Important risk
analyze how the contamination takes place - the route factors are previous hand eczema, a his tory of metal
by which the material enters and leaves the process, sensitivity or a history of atopic dermatitis. Individuals
encapsulation, exhaust, and skin protection; analyze with a history of metal dermatitis should be subject to
working routines for the normal work and special a pre-employment patch test to exclude nicke1lcobalt
work activities, such as loading and cleaning the sensitivity.
machines; control the hygiene routines, e.g., skin
cleaning and skin care, clothes changing and cleaning Information and Edueation
routines, and hygiene facilities.
The most important preventive measure is education
Allergie (ontact Dermatitis concerning how to work with minimal contamination
of the skin. Regular courses and/or an education
Cobalt allergy is the only important work-related package should be given to the employees with
contact allergy among hard-metal workers. As a rule, information about hand eczema, work hygiene, how
cobalt allergy is the background of severe hand eczema to protect the hands, skin cleaning, skin care and how
and, therefore, forceful preventive measures should be eczema should be handled. These measures reduce not
instituted. The epidemiological analysis will indicate only the frequency of hand eczema but improve the
work areas of high risk, usuallY those traumatizing the production and decrease the discard of hard metal
skin, such as hand grinding, or those in which high (Fischer and Rystedt 1984a,b).
concentrations of ionized cobalt come into contact
with the skin, such as etching. Try to eliminate,
auto mate or at least encapsulate such processes.
Cutting fluids vary in their properties to dissolve References
cobalt. Recommend cutting fluids that dissolve only
minimal concentrations of ionized cobalt. The cleaning Boman A, Fischer T, et al. (1982) Guinea pig maximization test
of cutting fluids from particles must also be efficient. with tungstate. Contact Dermatitis 8:344
Fischer T, Rystedt I (1983) Skin protection against ionized cobalt
and sodium lauryl sulfate with barrier creams. Contact
Protection and Skin (are Dermatitis 9:125-30
Fischer T, Rystedt I (1984a) (in Swedish). Arbete och Hälsa,
Arbetarskyddsverket, Solna, Sweden, Volume I
Skin-protective gloves can only rarely be used because Fischer T, Rystedt I (1984b) (in Swedish). Arbete och Hälsa,
they interfere with the work. Barrier creams have little Arbetarskyddsverket, Solna, Sweden Volume II
value and may even facilitate penetration of cobalt into Fischer T, Rystedt I (1985a) False-positive, follicuIar and irritant
patch test reactions to metal salts. Contact Dermatitis 12:
the skin (Fischer and Rystedt 1983, 1990). An emollient 93-98
cream after hand cleaning is recommended. Fischer T, Rystedt I (1985b) Hand eczema among hard-metal
The skin of hard-metal workers should be subject to workers. Am J Ind Med 8:381-394
Fischer T, Rystedt I (1990) Influence of topical metal binding
regular medical control and early reports of skin substances, vehicles, and corticosteroid creams on the allergic
disease should be encouraged by the employer. patch test reaction in metal-sensitive patients. Dermatol Clin
8:27-31
Fischer T, Fregert S, et al. (1984) Nickel release from ear piercing
kits and earrings. Contact Dermatitis 10:39-41
Pre-Employment Investigation Rystedt I, Fischer T (1983) Relationship between nickel and cobalt
sensitization in hard metal workers. Contact Dermatitis
9:195-200
Hard-metal work means a significant risk of getting Rystedt I, Fischer T, et al. (1983) Patch testing with sodium
hand eczema. Therefore, it is important not to employ tungstate. Contact Dermatitis 9:69-73
CHAPTER 69
Gold
M. Isaksson and M. Bruze
Introduction for heat refiectors. Thin gold foils that refiect heat
radiation and yet are able to let visible light through
can be used in windowpanes of trains and airplanes. If
Gold, Aurum in Latin, is the only metal except copper
these panes are electrically heated, mist and rime can
that is markedly colored. It is abundant in low
be avoided (Cavelier and Foussereau 1995).
concentrations almost all over the earth's crust, in
seawater, above all in metallic form and also as
goldtellurid. Gold is found as grains in the bottom of
rivers in California, Australia, Alaska, and Russia, Chemical Properties
while in South Africa gold ore is won from mines with
auriferous leaders. Gold is also won as a by-product Gold is resistant to corrosion as it does not combine
from the production of copper, nickel, and lead. The with oxygen or other substances in the atmosphere,
world's yearly production of gold is 1000 tons, of even at elevated temperatures. Gold occurs in oxida-
which 150 tons are used in the electronics industry. tion states 0, +1 and +111, the latter being most stable,
and the equilibrium between these states can be altered
easily (Brown et al. 1982). All halogens attack gold, and
Physical Properties so do halogen acids mixed with nitric acid or other
oxidizers. Aqua regia (kingly water), a mixture of
The purity of gold is measured in carat, one carat being hydrochloric and nitric acids, and cyanide solutions
a 24th part and where the carat number indicates the attack gold. Gold can also dissolve in water solutions
proportion of gold in an alloy. Hence, 24 carat is that contain thiol-substituted amino acids (cysteine,
absolute pure gold. High carat gold easily produces glutathione) and can be absorbed through animal skin
black dermografism, which is the most common cause (Brown et al. 1982).
of skin discoloration from metal jewelry. It refers to
thin deposits of metallic powder, which is always black
because these fine partic1es do not refiect light, and Applications
they are produced by friction of a metallic object on
skin that is contaminated by powders or abrasives.
Gold is found in a variety of applications:
Dusty environments or fabrics may contaminate the
skin with abrasive partic1es (Rapson 1985). 1. In jewelry, either as an alloy, as gold plating, or as
Pure gold is very soft but malleable and ductile. To rolled gold (Cronin 1980). In alloys of 18-carat and
increase its strength, alloys with other metals, such as 22-carat gold, copper and silver are added; in 14-
silver, copper, nickel, palladium, and zinc, are com- carat gold, copper, nickel, and zinc are added.
mon. The color of gold is infiuenced by the alloy White gold is hardened by the addition of palla-
addition, where silver gives a greenish-yellow, copper a dium and nickel and can also contain copper and
red and nickel a light-yellow cast to white gold. zinc. In plating, a base metal such as copper is
As pure gold is malleable, it can be rolled or beaten electrolytically covered with nickel, and then gold
to a thickness of less than 111m. From 1 g of gold, a of varying thickness is added. Rolled gold can be
thread of 2-3 km in length can be made. Gold has good applied to a metal base by mechanical press ure.
electrical conductivity and, through its durability, a 2. As gold leaf, used for lettering, decoration of books
low and stabile contact resistance is achieved. It has a and the like.
high refiective power, especially within the infrared 3. In dentistry, as alloys with silver, cop per, palladium,
spectrum, which makes surfaces covered by gold good platinum, and zinc to make crowns, bridges, etc.

Gold 545
4. As a colloidal solution of a gold salt in stannic acid 8. As a topical golds alt (Auranofin) in the treatment
(purpie of Cassius), to make ruby glass and to of psoriasis (Helm et al. 1995; Marks et al. 1995).
color enamel and porcelain. Gold hydroxide, gold 9. As a deposit of wealth (gold bars).
oxide, potassium and sodium gold tri chloride are 10. In the medical profession, as Hulka clips for the
also used in this decorative application. The gold ligation of the Fallopian tube in sterilization
salt is painted on the object and, when heated, the procedures (Trathen and Stanley 1985), as a gold
gold salt is reduced to metallic gold. ball inserted into the capsule after enucleation of
5. As gold salts, such as gold trichloride, and complex an eye (Forster and Dickey 1949), as a radioactive
gold salts, such as sodium tetrachloroaurate dihy- isotope in the form of colloidal gold or seeds used
drate (Cronin 1980), for toning and stabilizing either therapeutically or diagnostically (Merck
silver images in photography. Gold chloride in Index 1983).
neutron-activated form has been used in the 11. In alcoholic beverages (Russei et al. 1997).
intensifying of very weak images formed in some 12. As metallic gold in make-up, such as lipstick,
modern photographic applications. mascara, eye shadow (Fisher 1967) and in some
6. In gilding, where two techniques principally occur: leave-on products.
methods free of water and wet methods. The
former is when gold leaf is placed on objects that
are covered with varnish or when gold is applied
Contact Allergy to Gold
on glass through vacuum methods by means of a
pigmented lacquer or a solution of a gold salto The
object is then heated to a temperature near the A fewyears ago, contact allergy to metallic gold andgold
glass-softening level. Wet methods imply electro- salts was considered rare (Cronin 1980), but, in the past
lytic gilding, and this method has been in use since few years, several reports of a high frequency of contact
the middle of the 19th century. Pre-treatment of allergy among dermatitis patients being patch tested
the base metal (if made of copper alloys) with with gold sodium thiosulfate (GSTS) [Na3 AU(S203U
electrolytically won nickel to stop the copper and have been published. Figures ranging from 0.78% to
other alloy metals from diffusing into the gold 13.0% are presented (Björkner et al. 1994; Mc Kenna
surface is aprerequisite. Sometimes the nickel et al. 1995; Sabroe et al. 1996; Fleming et al. 1997b; Silva
surface needs to be activated in an acid bath to et al. 1997; Leow et al. 1998). Gold allergy is more
increase the attachment of the gold. In electrolytic frequent in women (Fowler Jr 1988). This predominance
gilding, different baths are used: acid cyanide probably reflects increased contact with jewelry rather
baths are used for decorative purposes as weIl as than increased susceptibility (Elgart and Higdon 1971).
within the industry; neutral baths were formerly Hypersensitivity to gold may be seen together with
used as alloy baths, but, nowadays, to get very pure contact allergy to other metals such as mercury, nickel,
coatings in the electronics industry, alkaline baths and palladium (Koch and Bahmer 1995; Heise et al.
are used for decorative purposes to get different 1997). Other investigators found no positive statistical
colors; gold baths free of cyanide are used for correlation with other allergens in a standard series
decorative purposes and when thick coatings are (Björkner et al. 1994; Sabroe et al. 1996). Also, patch
wanted; and current-free gold baths are used in the testing dental patients has revealed a high contact
manufacture of electronics. Gold potassium cya- allergy rate, 12.4% to GSTS (Räsänen et al. 1996).
nide (potassium dicyanoaurate) (KAu(CN)2) is
used in the acid, neutral, alkaline, and current-
Patch-Test Materials
free baths; whereas gold sodium sulfite (NaAuS0 3)
and gold chloride (AuCI3) are used in the cyanide-
free baths (Asthner 1990). Gilding through elec- Formerly, several gold salts as weIl as elemental gold in
troplating is common in the manufacture of alloys the form of gold leaf have been utilized in patch testing
for electrical contacts, when bonding transistors for gold allergy but, as many gold salts are acidic
and diodes to wires is needed, and in printed (Cronin 1980), irritant reactions have followed. Gold
circuit boards in the manufacture of electronics trichloride often causes irritant, false-positive and
(Adams 1990). persistent reactions (Fowler Jr 1990). The test solution,
7. As an anti-rheumatic drug since the 1920s (chryso- which is HAuCI3, is a solution of gold chloride in
therapy) (Forestier 1929). Myocrisin [gold sodium hydrochloric acid since it is insoluble in water. Hence,
(I)thiomalate][GSTM], intended for intramuscular it is a strong primary irritant that causes damage to the
injections, and Auranofin [2,3,4,6-tetra-O-acetyl-1- horny layer and can elicit a lympho-monocytic reac-
thio- ß- D-glucopyranosato-5-triethylphosphine gold tion with pseudo-Iymphomatous features (Monti et al.
(I)], to be given orally, are used. 1983). This has been noted by others (Bowyer 1967;
546 M. Isaksson and M. Bruze
Comaish 1969) and, elinically, it consists of a papular, intracutaneous testing might lead to persistent nodules
non-eczematous reaction sometimes persisting for (Bruze et al. 1995).
weeks to months (Fowler Jr 1987). Gold chloride was
shown to be a potent sensitizer in the human
maximization test (Kligman 1966). Also, gold sodium In Vitro Testing
thiomalate (GSTM) has been used in concentrations
from 0.5% to 2.0% in petrolatum (Fox et al. 1961;
A lymphocyte blast transformation test was positive in
Bowyer 1967; Elgart 1972; Fowler Jr 1987). There are no
a patient patch test allergie to GSTS (Silvennoinen-
reports of persistent or severe reactions to this salt
Kassihen and Niinimäki 1984; Aro et al. 1993) and
(Fowler Jr 1987). Sometimes these low concentrations
GSTM (Kobayashi et al. 1992). In vitro blast transfor-
may give false-negative reactions and, when a high
mation test was suggested to be of significant value in
concentration (11.5% aqueous) was tested on 12 gold-
the diagnosis of gold contact dermatitis (Silvennoinen-
allergie individuals, all reacted to GSTM. No irritant
Kassinen and Niinimäki 1984) and gold allergy (Aro
patch-test reactions were noted, and controls reacted
et al. 1993) and might be useful in the diagnosis of
to the salt neither epicutaneously nor intracutaneously
drug reactions due to systemic gold therapy used
(Bruze et al. 1995a).
in rheumatic diseases (Silvennoinen-Kassinen and
Several studies have shown that potassium
Niinimäki 1984).
dicyanoaurate often has caused false-negative reac-
tions. The patch-test concentrations have then been
low and probably too low to elicit a positive re action.
Allergie Contact Dermatitis from Gold
In one study, this salt gave concordant positive
reactions compared with GSTS when the same
volumes of solutions of GSTS and potassium dicya- There are several sporadie cases of allergie contact
noaurate at equimolar concentrations were used dermatitis from both metallic gold and gold salts
(Björkner et al. 1994). Gold leaf is unsatisfactory due reported in the literature. Elemental gold found in
to the often negative patch-test result (Fox et al. 1961; jewelry, such as earrings, rings, and necklaces, seems
Bowyer 1967; Comaish 1969), and it is presumed to be to make up the majority of causes (Fowler Jr 1987;
due to the insolubility of metallic gold (Fowler Jr Wiesner and Pambor 1998). It was shown that gold (0)
1987). Rarely have gold leaf (Forster and Diekey 1949; dissolved in various aqueous amino acid solutions
Cowan 1960), gold rings (Cowan 1960), gold earrings exposed to dioxygen, suggesting that gold jewelry in
(Cowan 1960), or a gold ball (Forster and Dickey elose skin contact could slowly solubilize to gold
1949) given positive patch-test responses when tested complexes in sweat and be absorbed through the skin
as iso GSTS at 0.5% petrolatum has been recommend- (Brown et al. 1982), thus leading to an allergie contact
ed as a reliable patch-test allergen for gold allergy dermatitis from gold. The dermatitis under rings is
(Fowler Jr 1987; Koch et al. 1997), and positive often more severe in summer due to warm (Gaul 1954),
reactions to this salt represent true contact allergy humid (Elgart and Higdon 1971) weather, or if the ring
rather than an irritant contact reaction (Björkner is broad and tight (Comaish 1969). One patient stated
et al. 1994). This gold salt has been used when high that in cold weather he could wear gold jewelry for
prevalence figures of contact allergy have been 4 days without problems, but in warm weather it took
reported. Epieutaneous and intracutaneous test reac- only 2 days for the dermatitis to appear (Fox et al.
tions to GSTS are long-Iasting (Bruze et al. 1995b) and 1961). An orbital implant - a 14-carat gold ball - gave
may pers ist for several months. Intracutaneous pos- an eczematous re action on the eyelids of a patient
itive tests to this salt have a tendency to change from 4 years after its insertion (Forster and Dickey 1949).
thin infiltrates to deep nodules (Bruze et al. 1995). Gold rings, but also earrings, are believed to
sensitize, and several cases are reported where the
piercing of ears (Comaish 1969; Fisher 1974a; Arm-
strong et al. 1997), followed by wearing of gold
Pateh-Test Readings
earrings, often studs, has resulted in an eczema on
the earlobes not long after (Elgart and Higdon 1971;
Delayed readings after 72 h or longer are essential Petros and MacMillan 1973; Iwatsuki et al. 1982), and,
when patch testing with GSTS epicutaneously. Even at patch testing, allergie reactions to various gold salts
readings after 1 week are insufficient and should be were noted (Elgart and Higdon 1971; Petros and
supplemented by a reading after 3 weeks (Bruze et al. MacMillan 1973; Iwatsuki et al. 1982; Nakada et al.
1995b). If intracutaneously injected GSTS was used, all 1997). Subsequent development of persistent papular
test reactions appeared within the first week after elements on earlobes but without superficial eczema-
testing, making only a D7 reading useful, albeit tous changes have been seen, where the microscopic
Gold 547
specimen showed dense dermal infiltration of lympho- Oeeupational Exposure

cytes and plasma cells (Petros and MacMillan 1973; and Allergie Contact Dermatitis
Fisher 1974C; Iwatsuki et al. 1982; Kobayashi et al. 1992;
Fleming et al. 1997a). A lymphomatoid contact reac-
Sporadic cases of occupational contact dermatitis to
tion to gold earrings due to persistent gold exposure
gold salts in gold electroplaters have been reported
has been suspected, and gold has actually been
(Somov and Khaimovskii 1964; Schmollack 1971;
identified in a skin specimen taken from a dermatitic
Cronin 1980; Adams 1983; Goh 1988; Larsen et al.
earlobe in a gold allergic woman that had not used gold
1992); nevertheless, gold salts should be considered as
studs for 4 months (Suzuki 1998) and also beneath
significant sensitizers in electroplaters. The reason
gold rings (Brown et al. 1982). Histological examina-
sensitization seems uncommon is claimed to be due to
tion of earlobe nodules in another such patient with
the infrequent contact with the salts by workers, as
persistent nodules demonstrated a sarcoidal-type
factory supervisors only are allowed to handle and
granulomatous reaction (Armstrong et al. 1997). After
prepare the salts. These salts are usually locked away
ear piercing and after the channel is epithelialized, any
due to their toxicity (Goh 1988). Potassium dieyanoau-
earrings may be inserted (Fisher 1974a, 1987).
rate sensitized a Chinese electroplater leading to a
subacute dermatitis on exposed skin, beginning
2 weeks after starting work (Goh 1988). Gold cyanide
Allergie Contact Stomatitis and Glossitis
sensitized Russian workers gilding watches, and patch
testing was performed using 1.0% gold cyanide (Somov
Dental applications, such as crowns (Wiesenfeld et al. and Khaimovskii 1964 In Germany, gold plating with
1984), bridges and dentures (Fregert et al. 1979), have potassium dicyanoaurate led to a hand and face
also been implicated in allergie contact stomatitis and contact dermatitis in three of ten workers. The
glossitis. The first case of allergic contact stomatitis to eruptions came after 3 weeks to 3 months of starting
metallic gold was reported in 1971, when a patient got work. The patients were positive to 1.0% gold trichlo-
irritation and superficial ulceration of the gingival ride at patch testing and two of these also to 0.01%
mucosa adjacent to a gold crown and where there potassium dicyanoaurate aqueous (Schmollack 1971).
already was a history of sensitivity to gold jewelry, A man accidentally rested his bare right forearm on
such as earrings, rings, and a wristwatch. Patch testing a laboratory bench where crystals of gold trichloride
with GSTM and gold trichloride (0.5% aqueous) were present, and irritation and subsequent sensitiza-
confirmed the contact allergy to gold (Elgart and tion to gold followed, presenting as pigmented papules
Higdon 1971). After that, several cases were published and with no eczematous change. A pathological
in which gold crowns have given soreness and specimen of a papule showed lymphoma-like features,
erosions of the tongue (Fisher 1974b), mucosal and a patch test to gold trichloride 1.0% appeared as a
erosions (Klaschka 1975; Wiesenfeld et al. 1984), oral local, delayed, papular, noneczematous reaction,
burning or stinging sensations (Young 1974; Fregert whereas a patch test to gold potassium chloride 1.0%
et al. 1979; Aro et al. 1993) and where gold sensitizing resulted in an eczematous picture clinically (Shelley
was considered to be due to earrings (Fisher 1974b) and Epstein 1963).
and a signet ring (Wiesenfeld et al. 1984). After Gold chloride is said to cause dermatitis among
removal of the incriminating gold, the patient has photographers who use it in their work (Schwartz et al.
usually recovered fully (Elgart and Higdon 1971; Fisher 1947). After working 10 years, a fern ale sales clerk in
1974b; Wiesenfeld et al. 1984). Primarily gold stomati- jewelry had dyshidrotic eczema of the fingers and
tis seems rare, and only a few cases have been intolerance to wearing gold jewelry, such as necklaces
reported (Schöpf et al. 1970; Young 1974; Fregert et al. and earrings. She reacted positively to a patch test to
1979; Aro et al. 1993), in which gold applications, such GSTS. Cotton gloves improved her hand dermatitis
as crowns, bridges, and dentures, soon after insertion markedly (Felix and Ducombs 1993). Another woman
gave problems in the oral mucosa, and in which tests worked in gilding of fountain pens and prepared the
were positive for gold salts and no history of gold gold salt bath. Hand eczema and asthmatic dyspnea
jewelry intolerance was found prior to this event. Oral soon followed, and patch testing showed her to be
mucosal reactions ascribed to gold allergy are rare, allergic to the gold bath (Sidi and Hincky 1965). A
and the reason for this is thought to be due to the low machinist in a gold jewelry manufacturing plant had a
solubility of metallic gold. Still, the moist oral hand eczema that went away when he was off work and
environment with bacteria, enzymes and other sub- relapsed when at work. Patch testing to GSTS 0.5% was
stances in the saliva may dissolve gold and thus form positive (Collet et al. 1994). A merchant jeweler had
allergenic gold compounds (Aro et al. 1993; Björkman fingertip dermatitis and experienced great difficulty in
et al. 1998). handling jewelry. A positive reaction to gold leaf
showing as a bright erythema was noted. A generalized 1992), such as pruritus, lichen planus and pityriasis
purpuric eruption resembling allergie vaseulitis flared rosea-like eruptions, erythema no dos um, pemphigus
on three patch-test occasions utilizing gold leaf. The flares, exfoliative dermatitis and toxic epidermal
authors state, that the cutaneous vaseulitis was pro- necrolysis, which is sometimes fatal. Loss of taste,
duced through prolonged cutaneous exposure to metallic taste and glossitis are also reported (Thomas
elemental gold, although they do not rule out a toxic 1987). Side effects may prompt up to 45% of patients to
reaction due to topical absorption from the patient's discontinue therapy (van Gestel et al. 1994). It was
hands or the gold dental fillings the patient had had for suggested that some of the frequent cutaneous side
several years (Roenick and Handel 1974). effects of systemic gold therapy were due to a previous,
In a study from Italy, the incidence of allergie contact but unrecognized, contact allergy to gold (Möller et al.
dermatitis due to gold in 60 jewelers (13 men, 47 women) 1996). Speaking against this theory is a study involving
was evaluated. Eighteen percent (two men and nine 55 rheumatoid arthritis (RA) patients, 35 of whom had
women, 82%) of the individuals had a contact allergy to received gold therapy and 20 who had not; these
gold as ShOWll with a positive patch test to gold chloride individuals were patch tested with GSTS 0.5% and
0.1% aqueous (Vassilopoulou and Bertazzoni 1997). 0.05% petrolatum. All but one, who had never received
gold, were negative (Fleming et al. 1998). Skin testing
for contact allergy to gold was also carried out in 77
Occupational Exposure and Irritancy
patients with RA; 10.4% positive skin tests to gold were
found. When dividing the 77 into a retrospective
When refining and extracting gold from other metals group, i.e., treatment with gold previously, and a
sometimes present in ores, workers are exposed to skin, prospective group (intended for gold therapy), gold
eye, and mucous membrane-irritating chemie als, such allergy was observed in 1 of 57 (1.8%) and in 7 of 20
as hydrocyanic acid and sulfur mono chloride (Adams (35.0%) patients, respectively. The almost non-existing
1990). In the gold electroplating industry, irritating gold gold allergy in the rheumatic patients after long-term
salts such as gold potassium cyanide and gold sodium administration of gold salts was hypothesized to be
cyanide are used and they bare a high level of irritancy due to a hyposensitization phenomenon. The authors
because of their acidity (Cronin 1980). A man worked condude that RA patients intended for chrysotherapy
with deaning gold electrode contacts and in the mixture should probably first be investigated for gold allergy,
where these were placed, gold potassium cyanide was but that a positive skin test to gold does not necessarily
formed. After 2 years without mishap, he suddenly contraindicate further treatment with gold. Starting
developed scattered sterile pustules on the backs of the with a low dose of gold and gradually increasing it
fingers of the right hand and erosions of the lower lip. seems to work in selected cases (Möller et al. 1997).
When he was off work for 2 weeks, both sets of lesions
healed, but a purplish-brown discoloration and partial
onycholysis of the free ends of most ofhis fingernails on Treatment and Prevention
the right hand developed. A month later, the nails had
returned to normal (Budden and Wilkinson 1978). A
woman made up solutions of potassium gold cyanide for Dermatitis caused by metallic gold and gold salts
1 year, when she then presented with eczema on the
occurring on the skin is treated as other cases of
volar surfaces and sides ofher fingers. Patch testing with contact dermatitis are treated. As gold salts are strong
different gold salts gave irritant responses (Cronin sensitizers and irritants, the latter mainly due to their
1980). A man deaning gold dock faces at work acidity, care should be taken to prevent direct skin
presented with an erythematous pruritic dermatitis contact with these chemicals. Proper protective equip-
with papules on the trunk and forearms, where patch ment, such as gloves and other protective garments, is
testing showed a positive re action only to gold chloride sufficient.
0.1%. Eight months later, he was seen with an
erythematous circular plaque at the site of the former
patch test. The patch test was repeated but with a
negative result. The former test was interpreted as false References
positive (Monti et al. 1983).
Adams R (1983) Occupational skin disease. Grune and Stratton,
Chrysotherapy New York, pp 221-222
Adams R (1990) Occupational skin disease, 2nd edn. Saunders,
Philadelphia, pp 367-368
Armstrong DKB, Walsh MY, Dawson JF (1997) Granulomatous
The most common side effects of gold therapy are contact dermatitis due to gold earrings. Br J Dermatol
mucocutaneous reactions (Svensson and Theander 136:776-778
Gold 549
Aro T, Kanerva L, Häyrinen-Immonen R, Silvennoinen-Kassinen Fregert S, Kollander M, Poulsen J (1979) Allergie contact
S, Konttinen YT, Jolanki R, Estlander T (1993) Long-Iasting stomatitis from gold dentures. Contact Dermatitis 5:63-64
allergic patch test reaction caused by gold. Contact Dermatitis Gaul LE (1954) Incidence of sensitivity to chromium, nickel, gold,
28:276-281 silver, and copper compared to reactions to their aqueous
Asthner B (1990) Textbook of electrolytic and chemie al finishing salts including cobalt sulfate. Ann Allergy 12:429-444
(in Swedish). Ytforum Förlags AB, Linköping, pp 41-72 Goh CL (1988) Occupational dermatitis from gold plating.
Björkman L, Ekstrand 1, Lind B (1998) Determination of gold Contact Dermatitis 18:122-123
released from dental alloys in saliva (abstract). J Dent Res Heise H, Beyer H, Rauschenbach D (1997) Ergebnisse der
77:765 Epikutantestung auf Goldsalze versus Amalgam. Z Dermatol
Björkner B, Bruze M, Möller H (1994) High frequency of contact 183:68-72
allergy to gold sodium thiosulfate. An indication of gold Helm KF, Marks JG Jr, Leyden JJ, Guzzo C, Krueger GG, Griffiths
allergy? Contact Dermatitis 30:144-151 TW, Griffiths CEM (1995) Topical auranofin ointment for the
Bowyer A (1967) Epidermal reactions and prolonged dermal treatment of plaque psoriasis. J Am Acad DermatoI33:517-519
reactions to patch testing with gold salts. Acta Derm Venereol Iwatsuki K, Tagami H, Moriguchi T, Yamada M (1982) Lymph-
47:9-14 adenoid structure induced by gold hypersensitivity. Arch
Brown DH, Smith WE, Fox P, Sturrock RD (1982) The reactions of Dermatol 118:608-611
gold (0) with amino acids and the significance of these Klaschka F (1975) Contact allergy to gold. Contact Dermatitis
reactions in the biochemistry of gold. Inorg Chim Acta 67:27-30 1:264-265
Bruze M, Björkner B, Möller H (1995a) Skin testing with gold Kligman AM (1966) The identification of contact allergens by
sodium thiomalate and gold sodium thiosulfate. Contact human assay. III. The maximization test, a procedure for
Dermatitis 32:5-8 screening and rating contact sensitizers. J luvest Dermatol
Bruze M, Hedman H, Björkner B, Möller H (1995b) The 47:393-409
development and course of test reactions to gold sodium Kobayashi Y, Nanko H, Nakamura 1, Mizoguchi M (1992)
thiosulfate. Contact Dermatitis 33:386-391 Lymphocytoma cutis induced by gold pierced earrings.
Budden MG, Wilkinson DS (1978) Skin and naillesions from gold J Am Acad Dermatol 27:457-458
potassium cyanide. Contact Dermatitis 4:172-173 Koch P, Bahmer FA (1995) Oral lichenoid lesions, mercury
Cavelier C, Foussereau J (1995) Kontaktallergie gegen Metalle und hypersensitivity and combined hypersensitivity to mercury
deren Salze. Dermatosen Occup Environ 43:100-112 and other metals: histologically-proven reproduction of the
Collet E, Lacroix M, Dalac S (1994) Allergie de contact aI'or metal reaction by patch testing with metal salts. Contact Dermatitis
a
et ses alliages. Ann Derm Syph 121:21-24 33:323-328
Comaish S (1969) A case of contact hypersensitivity to metallic Koch P, Kiehn M, Frosch PJ (1997) Epikutane Testung mit
gold. Arch Dermatol 99:720-723 Goldsalzen. Hautarzt 48:812-816
Cowan MA (1960) Contact dermatitis due to gold. Br J Dermatol Larsen W, Adams RM, Maibach HI (1992) Color text of contact
72:348-349 dermatitis. Saunders, Philadelphia, pp 812-816
Cronin E (1980) Contact Dermatitis. Churchill Livingstone, Leow Y-H, Ng S-K, Goh C-L (1998) A preliminary study of gold
Edinburgh sensitization in Singapore. Contact Dermatitis 38:69-170
Elgart M (1972) Allergie contact dermatitis to gold. Arch Marks JG Jr, Helm KF, Kreuger GG, Griffiths CEM, Guzzo CA,
Dermatol 106:254 Leyden JJ (1995) Contact dermatitis from topieal auranofin.
Elgart ML, Higdon RS (1971) Allergic contact dermatitis to gold. J Am Acad Dermatol 32:813-814
Arch Dermatol 103:649-653 Mc Kenna KE, Dolan 0, Walsh MY, Burrows D (1995) Contact
a
Felix B, Ducombs G (1993) Allergie professionelle I'or. Lettre du allergy to gold sodium thiosulfate. Contact Dermatitis 32:
G.E.R.D.A. 10:44-45 143-146
Fisher AA (1967) Contact Dermatitis. Lea & Febiger, Philadelphia, Merck Index (1983) Merck index, 10th edn. Windholz M (ed)
p 168 Merck & Co Inc, RalJway
Fisher AA (1974a) Ear piercing hazard of nickel-gold sensitization Monti M, Berti E, Caviechini S, Sala F (1983) Unusual cutaneous
(letter). JAMA 228:1226 reaction after a gold chloride patch test. Contact Dermatitis
Fisher AA (1974b) Allergic reactions due to metals used in 9:150-151
dentistry. Cutis 14:797-800 Möller H, Björkner B, Bruze M (1996) Clinieal reactions to
Fisher AA (1974c) Metallic gold: the cause of a persistent allergic systemic provocation with gold sodium thiomalate in patients
'dermal' contact dermatitis. Cutis 14:177-180 with contact allergyo to gold. Br J Dermatol 135:423-427
Fisher AA (1987) Ear piercing and sensitivity to nickel and gold Möller H, Svensson A, Björkner B, Bruze B, Lindroth Y,
(letter). J Am Acad Dermatol 17:853 Manthorpe R, Theander J (1997) Contact allergy to gold and
Fleming C, Burden D, Fallowfield M, Lever R (1997a) Lympho- gold therapy in patients with rheumatoid arthritis. Acta Derm
matoid contact reaction to gold earrings. Contact Dermatitis Venereol 77:370-373
37:298 Nakada T, Iijima M, Nakayama H, Maibach HI (1997) Role of ear
Fleming C, Forsyth A, MacKie R (1997b) Prevalence of gold piercing in metal allergic contact dermatitis. Contact Derma-
contact hypersensitivity in the West of Scotland. Contact titis 36:233-236
Dermatitis 36:302-304 Petros H, Macmillan AL (1973) Allergic contact sensitivity to gold
Fleming C, Porter D, MacKie R (1998) Absence of gold sodium with unusual features. Br J Dermatol 88:505-508
thiosulfate contact hypersensitivity in rheumatoid arthritis. Rapson WS (1985) Skin contact with gold and gold alloys. Contact
Forestier JM (1929) LilUrotherapie dans les rheumatismes chroni- Räsänen LR, Kalimo K, Laine 1, et al. (1996) Contact allergy to
ques. Bull Soc Med Hop Paris 53:323-327 gold in dental patients. Br J Dermatol 134:673-677
Forster HW Jr, Dickey RF (1949) A case of sensitivity to gold-ball Roenigk HR Jr, Handel D (1974) Gold vasculitis. Arch Dermatol
orbital implant. Eczematous contact-type dermatitis due to 109:253-255
14-karat gold. Am J Ophthalmol 32:659-662 Russel MA, Langley M, Truett AP III, King LE, Boyd AS (1997)
Fowler JF Jr (1987) Selection of patch test materials for gold Lichenoid dermatitis after consumption of gold-containing
allergy. Contact Dermatitis 17:23-25 liquor. J Am Acad Dermatol 36:841-844
Fowler JF Jr (1988) Allergie contact dermatitis to gold. Arch Sabroe RA, Sharp LA, Peachey RDG (1996) Contact allergy to
Dermatol124:181-182 gold sodium thiosulfate. Contact Dermatitis 34:345-348
Fowler JF Jr (1990) Allergic contact dermatitis to metals. Am J Schmollack E (1971) Berufliche Kontaktekzeme durch Kalium-
Contact Dermat 1:212-223 goldzyanid. Dermatol Monatsschr 157:821-824
Fox JM, Kennedy R, Rostenberg A Jr (1961) Eczematous contact- Schwartz L, Tulipan L, Peck S (1947) Occupational diseases of the
sensitivity to gold. Arch Dermatol 83:956-959 skin, 2nd edn. Lea & Febiger, Philadelphia
550 M. Isaksson and M. Bruze: Gold
SchöpfE, Wex 0, Sehulz KH (1970) Allergische Kontaktstomatitis Svensson Ä, Theander J (1992) Skin rashes and stomatitis due to
mit spezifischer Lymphocytenstimulation durch Gold. Ha- parenteral treatment of rheumatoid arthritis with sodium
utarzt 21:422-424 aurothiomalate. Ann Rheum Dis 51:326-329
Shelley WB, Epstein E (1963) Contaet sensitivity to gold as a Thomas I (1987) Gold therapy and its indieations in dermatology.
ehronie papular eruption. Arch Dermatol 87:388-391 J Am Aead Dermatol 16:845-854
Sidi E, Hineky M (1965) Problemes dactualite coneernant les Trathen WT, Stanley RJ (1985) Allergie reaction to Hulka clips.
dermatoses professionelles. Rev Fr AllergoI 5:198-209 Obstet Gyneeol 66:743-744
Silva R, Pereira F, Bordalo 0, Silva E, Barros A, Gon<;:alo M, van Gestel A, Koopman R, Wijnands M, van de Putte L, van Riel P
Correia T, Pessoa G, Baptista A, Peeegueiro M (1997) Contaet (1994) Mucocutaneous reactions to gold: a prospective study
allergy to gold sodium thiosulfate. A eomparative study. of 74 patients with rheumatoid arthritis. J Rheum 21:1814-1819
Contaet Dermatitis 37:78-81 Vassilopoulou A, Bertazzoni M (1997) Dermatite da contatto negli
Silvennoinen-Kassinen S, Niinimäki A (1984) Gold sensitivity orafi. Bollettino di Dermatologia Allergologiea e Professionale
blast transformation. Contaet Dermatitis 11:156-158 12:9-14
Somov BA, Khaimovskii GD (1964) Allergie dermatitis caused by Wiesenfeld D, Ferguson MM, Forsyth A, MacDonald DG (1984)
aurum eompounds in watch industry. Vestnik Dermatologii i Allergy to dental gold. Oral Surg 57:158-160
Venerologii 10:33 Wiesner M, Pambor M (1998) Allergie eontaet dermatitis from
Suzuki H (1998) Nickel and gold in skin lesions of piereed gold. Contaet Dermatitis 38:52-53
earlobes with eontaet dermatitis. A study using scanning Young E (1974) Contaet hypersensitivity to metallie gold.
eleetron mieroscopy and X-ray mieroanalysis. Arch Dermatol DermatoJogiea 149:294-298
Res 290:523-527
CHAPTER 70
Other Metals
J.E. Wahlberg
Introduction tion) has been studied using the guinea-pig maximi-

zation test method (Wahlberg and Boman 1985).
Chromium, nickel, cobalt, mercury, beryllium, molyb-
Contact with metals and metal compounds can cause
den um, or their compounds were identified as sens i-
various types of side effects on and in the skin as
tizers, while aluminum, arsenic, cop per, cadmium, and
specified below.
tungstate were classified as grade-I allergens according
to the original classification system (Magnusson and
Kligman 1970). In the human maximization test,
Contact Sensitivity beryllium, chromium, gold, nickel, and mercury com-
pounds did induce contact allergy, whereas aluminum
It is essential to understand that bioavailability varies did not (Kligman 1966).
between different elemental forms of metals and their
salts. That is why some precious metals are weil
tolerated, whereas their salts are identified as contact Irritancy
allergens. There is a discrepancy between test results
obtained with metal salts (in petrolatum) and tests Skin irritancy can be caused by dust of metal
with metal discs, e.g., palladium and tin. compounds and by contact with metals in solution.
Three common contact allergens diagnosed by The dust can go into solution in contact with sweat and
standard patch testing - chromium, cobalt, and moisture, but there is great variation, i.e., relating to
nickel - head every list of metal contact sensitivity the resulting concentration and pH. Some metal salts
(Chaps. 66-68). Conceming some of the metals are almost insoluble in water. Intertriginous areas
reviewed below, cases of occupational contact derma- (axillae, groin) are especially affected. In the second
titis are rarely seen today or are at least not reported. case, the metal compounds are already dissolved, and
The reason is probably due to extensive preventive the pH of the solution is of great importance. Severe
measures, including reduced exposure and automa- reactions manifest as bulla formation, necrosis, chem-
tion (Chap. 52). However, even if a contact allergy is ical bums, or corrosion (Chap. 38). Accidental contact
acquired non-occupationally, there is always a risk of with a solution that has a pH less than 1 will cause
relapses at renewed exposure in an occupational strong irritation. The milder reactions consist of
setting. erythema, edema, papules, vesicles and scaling, and
Results from patch tests performed with impure are rarely seen by physicians or nurses. Metal skin
preparations and with an insufficient number of irritants include aluminum, antimony, beryllium, cop-
controls for irritancy imply that so me anecdotal per, mercury, palladium, platinum, silver, tin, and zinc
reports on contact allergy to metals, such as antimony, ("zinc pox") compounds.
iron, lead, silver, manganese, and zinc, may be
questioned. Scientifically, as weil as from a clinical
point of view, it is somewhat challenging that nickel,
Photo Contact Dermatitis
chromium, and cobalt are so dominant, while the other
metals in the periodic table of elements play such a
minor role. Photo contact dermatitis resulting from occupational
For some metals, testing in guinea pigs has demon- exposure to metals and ultraviolet (UV) light is rarely
strated allergenic potential but, so far, no clinical case reported and may be overlooked. Chromium derma-
of allergic contact dermatitis has been reported. The titis and light are sometimes related (Wahlberg and
potential to cause contact allergy (hazard identifica- Wennersten 1977).

552 J.E. Wahlberg
Contad Urticaria Occupational nail dis orders are reviewed in Chap. 31

and hair loss in Chap. 32.
Reported cases of occupational contact urticaria from
metal compounds are few, except for some platinum Percutaneous Absorption and Toxicity
compounds, iridium, and cobalt chlorides.
Percutaneous absorption is defined as the penetration

Pigmentation - Discoloration of substances from the outside into the skin and,
thereafter, through the skin and into blood and
lymph vessels. Percutaneous toxicity is defined as
The incidence of pigmentation or discoloration from systemic poisoning following penetration of toxic
accidental contact with metal compounds in industry materials through the cutaneous barriers (Chap. 74).
is unknown. Cases are rarely seen at outpatient dinics.
The toxic effect depends both on the action of a
The pigmentation is mainly a cosmetic problem, but substance on receptors ("inherent toxicity") and on
late sensitivity reactions, such as in tattoos, may the amount and rate at which it is absorbed from the
appear. Reported agents are bismuth, copper, gold, application site.
iron (sideros), mercury, and silver (argyria) com-
It is difficult to evaluate case reports in the literature
pounds. Topical contact, accidental deposition of on putative percutaneous intoxication of metal and
metal particles in the skin, and oral administration metal compounds, since inhalation and peroral con-
can cause the pigmentation. tamination via food, cigarettes and such are not
exduded. The relative importance of the percutaneous
route for the outcome is therefore hard to state.
Granuloma Examples from the literature are mercury and lead
compounds. In a study of the percutaneous absorption
Beryllium can cause occupational granulomas; zirco- rates of some metal compounds in the guinea pig, a
nium and aluminum can cause non-occupational dose-response relationship was observed for sodium
granulomas (Chap. 15). Accidental deposition of metal chloride, while other metals, e.g., chromium and
particles (chromium, cobalt, mercury) or compounds mercury compounds, did not follow this pattern
on the skin, or injection into the skin is supposed to be (Wahlberg 1973). It was suggested that new skin
essential, together with the host response. barriers were created by protein precipitation at higher
concentrations of these compounds. A comparison of
the percutaneous toxicity of nine metal compounds in
Skin Cancer the guinea pig demonstrated great variation. There was
no mortality after cutaneous application of silver and
zinc compounds, while mortality was high (90%) after
Condusive evidence of skin cancer from topical application of some mercury compounds (Wahlberg
exposure to metal compounds alone is not available 1965).
(Chap. 29). Arsenic exposure has caused skin cancer,
but the route has mainly been oral.
Metals might function as initiators of cancer; trauma Aluminum
and continuous irritation are promoters. As chromi-
um, nickel, and cadmium have caused occupational Itching due to aluminum exposure during production
cancers of the respiratory system and the prostate, it is (Johannessen and Bergan-Skar 1980) and occupational
possible that occupational skin cancer from topical contact dermatitis in aircraft manufacture have been
exposure to metal compounds might appear. reported (Hall 1944). Two percent of the cases were
due to exposure to aluminum.
Water-soluble aluminum salts in antiperspirants
may cause axillary dermatitis, and aluminum-adsorbed
Nails and Hair vaccines may induce contact allergy; these were often
detected when patch testing with Finn chambers based
Alopecia from thallium is no longer an occupational on aluminum.
problem. Cases of accidental discoloration of hair Aluminum was a grade-I sensitizer at animal testing
(copper, cobalt, and silver) and nails (mercury, lead, (Magnusson and Kligman 1970). It is commercially
silver and chromium) by occupational exposure are available "as is" and as aluminum chloride hexahy-
nowadays rarely seen at outpatient dinics. Green hair drate for patch testing (Chemotechnique Diagnostics
from copper exposure is mainly non-occupational. 1998).
Other Metals 553
Beryllium was found not to be relevant (Karlberg et a1. 1983).

Reviewing the literature up until 1982 (Karlberg et a1.
Some beryllium compounds are strong irritants, and 1983), 4 relevant and 20 probably relevant cases were
insoluble salts can give rise to granulomas. Occupa- found. More than 90 cases were classified as uncertain
tional beryllium dermatitis was first reported in 1951 or not relevant. Many of the cases patch-test positive to
(Curtis). Since then, the few reported cases of contact copper are concomitantly positive to nickel sulfate, and
allergy have been caused by non-occupational exposure the question of cross-reactivity has repeatedly been
- dental prostheses and implants (Habermann et a1. raised. Exposure to copper via intrauterine devices,
1993). Beryllium is a potent sensitizer in the guinea pig jewelry, and coins has been discussed as causes of non-
(Wahlberg and Boman 1985) and a grade-IV allergen in occupational cop per dermatitis. In guinea-pig studies,
the human maximization test (Kligman 1966). copper sulfate was classified as a grade-I allergen
No commercial test preparation is available, but 1% (Wahlberg and Boman 1985).
beryllium sulfate in petrolatum has been used and with a Cop per oxide and copper sulfate for patch testing
sufficient number of controls (Habermann et a1. 1993). are commercially available (Hermal 1997; Chemotech-
nique Diagnostics 1998).
Cadmium
Mercury
There are some case reports on posItive patch-test
reactions to cadmium among metal workers (Borelli Occupational allergic contact dermatitis to metallic
and Dungemann 1964; Dungemann et a1. 1972; Raith mercury is rare and is mainly seen among dental
et a1. 1982). When cadmium chloride was included in personnel (Goh and Ng 1988; Ancona et al. 1982;
the standard series, 25 of 1502 individuals reacted at Kanerva et a1. 1993). The majority of positive patch-test
2%, but serial dilution tests could not verify any reactions to mercury and to mercury compounds are
relevant cases (Wahlberg 1977). The standard patch related to non-occupational exposure, e.g., dental
concentration was probably irritant, a conclusion amalgam, mercury from broken thermometers, thio-
supported by testing denture wearers (Kaaber et a1. mersal in vaccines, and contact lens cleaning solutions.
1982). In the guinea-pig mercuric chloride is a grade-III
In animal testing, cadmium chloride was classified allergen and, in the human maximization test, a grade-
as a grade-I allergen (Wahlberg and Boman 1985). V allergen (Magnusson and Kligman 1970). For patch
Cadmium chloride for patch testing is commercially testing, several mercuric compounds (mercury, thio-
available (Chemotechnique Diagnostics 1998). mersal, phenylmercuric acetate and nitrate, mercuric
chloride and mercury ammonium chloride) are com-
Cobalt mercially available (Hermal 1997; Chemotechnique
Diagnostics 1998).
Contact allergy to cobalt is common and is often Great care must be used in interpreting patch-test
associated with concomitant allergy to nickel or reactions to mercury compounds, several of which are
chromate (Chaps. 66, 67). This is interpreted as irritants. Some compounds may react with aluminum
simultaneous sensitization due to combined exposure, in the Finn chambers used for testing, which contrib-
because nickel is often contaminated with cobalt, and utes to the irritancy seen at the readings.
cement contains chromium as well as cobalt. Solitary
cobalt allergy is seen mainly among hard-metal Palladium
workers (Chap. 68) and in the glass and pottery
industries. Palladium is used in the electronics and chemical
Cobalt chloride is a potent sensitizer in the guinea pig industries, but there are no convincing case reports on
(Wahlberg and Boman 1985). Animals induced with work-related allergic contact dermatitis. Instead, the
cobalt chloride do not react to nickel, chromate, or exposure has mainly been from jewelry and dental alloys
rhodium at cross challenge testing (Liden et al. 1995). (Aberer et a1. 1993). The majority of patch-test positive
Cobalt chloride for patch testing is commercially avail- patients show concomitant reactivity to nickel; this has
able (Chemotechnique Diagnostics 1998; HermalI997). been interpreted as a sign of cross-reactivity. Patients
who patch-test positive to palladium chloride rarely
Copper react when tested with palladium discs (Todd and
Burrows 1992; de Fine Olivarius and Menne 1992).
A convincing case of contact allergy to copper in a Palladium chloride is a potent sensitizer in the guinea
welder has been published (Förström et a1. 1977). When pig, and animals induced with palladium chloride also
copper sulfate (2%) was included in the standard series, react to nickel at patch testing (Wahlberg and Boman
13 of 1190 dermatitis patients reacted, but the reactivity 1992).
554 J.E. Wahlberg
Palladium chloride for patch testing is commercially patch testing is commercially available (Chemotech-
available (Hermal 1997; Chemotechnique Diagnostics nique Diagnostics 1998).
1998).
Platinum
References
Exposure to chloropalatinates can give rise to immu-
nologie contact urticaria, accompanied by asthma and
rhinitis ("platinosis"). Cases of allergie contact der- Aberer W, Holub H, Strohal R, et al. (1993) Palladium in dental
alloys - the dermatologists' responsibility to warn? Contact
matitis due to occupational exposure to platinum or Dermatitis 28:163-165
platinum compounds were first reported in the 1950S Ancona A, Ramos M, Suarez R, et al. (1982) Mercury sensitivity
(Levene 1971). In a more re cent study (Baker et al. in a dentist. Contact Dermatitis 8:218
Baker DB, Gann PH, Brooks SM, et al. (1990) Cross-sectional
1990), 28% of former employees had a positive prick study of platinum salts sensitization among precious metals
test to platinum salts. They were not patch tested and refinery workers. Am J Ind Med 18:653-664
the "dermatitis" reported could, in fact, have been an Bedello PG, Goitre M, Roncarolo G, et al. (1987) Contact
dermatitis to rhodium. Contact Dermatitis 17:111-112
expression of contact urticaria. Borelli S, Dungemann H (1964) Aktuelle Kontakteksem -
Ammonium tetrachloropalatinate and hexachloro- Ursachen in der Metallindustrie. Berufsdermatosen 12:1-36
palatinate are commercially available (Hermal 1997; Chemotechnique Diagnosties (1998) Patch test products. Cata-
logue, Malmö, Sweden
Chemotechnique Diagnostics 1998). de la Cuadra J, Grau-Massanes M (1991) Occupational contact
dermatitis from rhodium and cobalt. Contact Dermatitis
Rhodium 25:182-184
Curtis G (1951) Cutaneous hypersensitivity due to beryllium. Arch
Dermatol 64:470-482
Cases of contact allergy to rhodium salts among Dungemann H, Borelli S, Wittmann J (1972) Über Kupfer und
workers in the precious-metal industry and among Kadmium - Kontaktekzeme bei Schweissern, Schleifern,
Galvaniseuren und ähnlichen Berufsgruppen. Arbeitsmed
goldsmiths have been reported (Bedello et al. 1987; de Socialmed Arbeitshyg 7:85-93
la Cuadra and Massanes 1991). The patients were also de Fine Olivarius F, Menne T (1992) Contact dermatitis from
patch-test positive to cobalt and cross-reactivity may metallic palladium in patients reacting to palladium chloride.
exist. In a guinea-pig model, rhodium chloride was a de Fine Olivarius F, Balslev E, Menne T (1993) Skin reactivity to
potent sensitizer and, at cross-challenge, the animals tin chloride and metallic tin. Contact Dermatitis 29:110-111
also reacted to cobalt but not to nickel or palladium Förström L, Kiistala R, Tarvainen K (1977) Hypersensitivity to
copper verified by test with 0.1% CuSO 4' Contact Dermatitis
(Liden et al. 1995). 3:280-281
Goh CL, Ng SK (1988) Occupational allergie contact dermatitis
Silver from metallic mercury. Contact Dermatitis 19:232-233
Habermann AL, Pratt M, Storrs FJ (1993) Contact dermatitis from
beryllium in dental alloys. Contact Dermatitis 28:157-162
Silver salts in solution are skin irritants. Silver nitrate Hall AF (1944) Occupational contact dermatitis among aircraft
can cause discoloration (argyria). Occupational con- workers. JAMA 125:179-185
Hermal (1997) Patch test allergens. Trolab, Reinbek, Germany
tact allergy to silver is rarely reported (Marks 1966). Johannessen H, Bergan-Skar B (1980) Itching problems among
Silver nitrate for patch testing is commercially avail- potroom workers in factories using recycled alumina. Contact
able (Chemotechnique Diagnostics 1998). Dermatitis 6:42-43
Kaaber S, Cramers M, Jepsen FL (1982) The role of cadmium as a
skin sensitizing agent in denture and non-denture wearers.
Tin Contact Dermatitis 8:308-313
Kanerva L, Komulainen M, Estlander T, et al. (1993) Occupational
allergie contact dermatitis from mercury. Contact Dermatitis
Some organotin compounds are strong irritants when 28:26-28
used as biocides. In patients allergie to nickel, 6 of 73 Karlberg A-T, Boman A, Wahlberg JE (1983) Copper - a rare
also reacted when tested with metallic tin (Menne et al. sensitizer. Contact Dermatitis 9:134-139
Kligman AM (1966) The identification of contact allergens by
1987), while 5 of 2206 patients reacted to tin chloride at human assay. UI. The maximization test: A procedure for
patch testing but were not sensitive to nickel (de Fine screening and rating contact sensitizers. J luvest Derm
Olivarius et al. 1993). The clinical relevance of the 47:393-409
Levene GM (1971) Platinum sensitivity. Br J Dermatol 85:590-593
findings has not been settled. Tin for patch testing is Liden C, Walliberg JE, Maibach HI (1995) Skin. In: Goyer RA,
commercially available and is included in the dental Klaassen CD, Waalkes MP (eds) Metal toxicology. Academic
screening series (Chemotechnique Diagnostics 1998). Press, New York, pp 447-463
Magnusson B, Kligman AM (1970) Allergic contact dermatitis in
the guinea pig. Identification of contact allergens. Charles C
Zinc Thomas, Springfield
Marks R (1966) Contact dermatitis due to silver. Br J Dermatol
78:606-607
Zinc salts in solution are skin irritants. Occupational Menne T, Andersen KE, Kaaber K, et al. (1987) Tin: an
contact allergy to zinc has not been reported. Zinc for overlooked contact sensitizer? Contact Dermatitis 16:9-10
Other Metals 555
Raith L, Schubert H, Göring H-D (1982) Contact dermatitis from Wahlberg JE (1977) Routine patch testing with cadmium chloride.
cadmium chloride? Contact Dermatitis 8:267 Contact Dermatitis 3:293-296
Todd DJ, Burrows D (1992) Patch testing with pure palladium Wahlberg JE, Boman A (1985) Guinea pig maximization test. In:
metal in patients with sensitivity to palladium chloride. Andersen KE, Maibach HI (eds) Contact allergy. Predictive
Contact Dermatitis 26:327-331 tests in guinea pigs. Current problems in dermatology, V0114.
Wahlberg JE (1965) Percutaneous toxicity of metal compounds. Karger, Basel, pp 59-106
Arch Environ Health 1l:201-204 Wahlberg JE, Boman A (1992) Cross-reactivity to palladium and
Wahlberg JE (1973) Percutaneous absorption. In: Mali JWH (ed) nickel studied in the guinea pig. Acta Derm VenereoI72:95-97
Current problems in dermatology. Karger, Basel, pp 1-36 Wahlberg JE, Wennersten G (1977) Light sensitivity and chromi-
um dermatitis. Br J Dermatol 97:411-416
CHAPTER 71
Cement
C. Avnstorp
Introduction Latin word "cementum" means crushed stone. In 1824

Joseph Aspdin, a British builder, patented a cement
produced by firing a mixture of limestone and day
Irritant dermatitis caused by cement was described as
(Bogue 1949). He called his product Portland cement
early as 1700 (Calnan 1960). In 1908, the first cases of
because it was similar in appearance to a building
cement eczema since the introduction of modern
stone quarried on tlIe island of Portland of the south
Portland cement were seen among workers building
co ast of England. In 1845, the first Portland cement, in
the Metro in Paris and were described as "la gale du
tlIe modern sense of the term, was produced by firing
ciment" (Martial 1908). In 1950, Jäeger and Pelloni
such a mixture to temperatures from 1200 °C to
brought to light tlIe importance of the chromium
1400 °C (Wexham Springs 1977).
content of cement as tlIe cause of chromium allergy
Portland cement is a hydraulic cement. Hydraulic
amo~g workers with cement eczema. In 1970, H0vding
cements are defined as cements that not only harden
pubhshed an epidemiological study in which 20 (5.5%)
by reacting with water but also form a water-resistant
from a group of 366 bricklayers and bricklayers'
p~oduct. Port~a~d cement is produced by pulverising
assistants had cement eczema. Seventeen of these
dmkers conslstmg essentially of hydraulic calcium
workers with cement eczema (85%) reacted positively
silicates, usually containing one or more of tlIe forms
to patch tests with chromate (H0vding 1970).
of calcium sulfate as an interground addition. Clinkers
Since tlIen, cement eczema has been found to be one
are 5-25 mm-diameter nodules of a sintered material
of tlIe most serious occupational health problems in
which is produced when a raw mixture of limestone
building trades and industries. This is illustrated
and day is heated to high temperatures (Mehta 1986).
currently by tlIe high frequency of cement dermatitis
The chemical reactions taking place in tlIe cement kiln
in underground workers during construction of the
system can be approximately represented as shown in
English Channel tunnel between England and France
Fig. l.
(Irvine et al. 1994), among workers from the construc-
The concrete used today is a mixture of Portland
tion industry in Taiwan (Sun et al. 1995) and con-
cement, sand, stones and water. Mortar consists of a
struction workers in Spain (Conde-Salazar et al. 1995).
mixture of Portland cement, sand, water and often also
In the United States, tlIe Occupational HealtlI Foun-
hydrated lime. The exact composition depends on the
~ation has recently focused on the problem (Occupa-
purpose for which tlIe product is to be used.
tlOnal Health Foundation 1996).
By adding ferrous sulfate to tlIe cement, it is possible
to prevent the development of allergic cement eczema. Chromate in Cement
This was illustrated in an epidemiological intervention
study from Denmark (Avnstorp 1992) and in reports
from Finland and Sweden (Roto et al. 1996). The Origin of Chromate
Further information about those being affected by
cement eczema is detailed in Chap. 114 (Cement The potential source of water-soluble hexavalent
Workers) and Chap. 120 (Construction Workers). chromate [Cr(VI)] in cement is the trivalent [Cr(III)]
compound (Cr 2 0 3 ) in the raw materials from which it
is produced. Cr(III) compounds are oxidised to Cr(VI)
compounds (CrO~-) when heated in tlIe kilns to
The Evolution of Cement
temperatures of approximately 1400 °C. The content of
chromium in cement is determined by the presence of
Cement is a material which binds togetlIer solid bodies chromium compounds in tlIe raw materials, by the kiln
(aggregate) by hardening from a plastic state. The lining and by chromium steel abrasion during tlIe

Cement 557
Clay(Si0 2, Ahü3' Fe2Ü3,), Limestone (CaCÜ3), Cr(III), ~ 1983). Since then, both Finland (in 1987) and Sweden
3CaÜ . SiÜ 2,3Caü . A12ü3,4Caü . Ahü 3 . Fe2ü3, Cr(VI). (in 1989) have established the same regulation.
The chromate in both bagged cement and bulk
Fig. 1. Basic chemical reactions taking place in the cement kiln
system
cement will remain in a reduced state, as Cr(III)
compounds, for 8 weeks. The type of storage condi-
tions used may be essential, especially if bagged
grinding processes (Skomorowski 1985). The Cr(VI) cement is stored in open sacks or exposed to moisture
content of cement varies from country to country because the Cr(VI) will not be reduced when the
according to variations in the amount of chromium in cement is subsequently mixed with water (Bruze et al.
the raw materials (Fregert and Gruvberger 1972). 1990b).
Reduction and Solubility

(linical Patterns of (ement Eczema
Ferrous sulfate reduces Cr(VI) in cement to Cr(III)
(Fig. 2). Burckhardt et al. (1971) reported that 62/78 Cement eczema may be of an irritant nature, allergic or
chromium allergic patients did not react to a solution both.
of 40% cement in water to which 0.3% ferrous sulfate
had been added. In a study including eight chromium Irritant (ement Eczema
hypersensitive individuals, negative reactions were
obtained after patch testing with 1.76 ppm of potassi- Depending on exposure, concentration and time, and
um dichrornate in water solution. Furthermore, no individual factors, different clinical manifestations of
reactions were found from patch testing with buffered irritant cement eczema are seen (Avnstorp 1995).
cement after ferrous sulfate was added (Bruze et al.
1990a). Acute Readions
Chromate is highly water soluble (Gammelgaard
et al. 1992). In ordinary Danish Portland cement, the Cement eczema may initially develop as a result of
chromium conte nt is 40.5 ppm and, of this, 9.6 ppm is daily irritation of the skin by contact with cement. The
water-soluble chromate (Lund 1977). Cr(III) com- skin of those who have daily contact with wet cement
pounds have lower solubility with increasing pH becomes irritated by the hygroscopic and alkaline
(Gammelgaard et al. 1992). The addition of 0.35% constitution of the cement. Erythema and dry skin on
(w/w) ferrous sulfate to cement reduces a Cr(VI) the dorsal aspects of the hands and fingers are the most
content of 20 ppm to very low concentrations (Fregert frequent findings. Itching of the hand and fingers is the
et al. 1979). In vitro studies on human skin showed no most important symptom (Avnstorp 1983). Acute
statistically significant difference in chromium content reactions may develop within weeks. Cement bums
of skin layers between skin exposed to cement are mostly seen in "amateurs", who are not familiar
suspensions with the conte nt of 2.1 ppm Cr(VI) and with the handling of cement products. These caustic
unexposed skin. The content in the dry cement was reactions develop on the lower legs after prolonged
3.3 ppm (Fullerton et al. 1993). These findings support contact with wet cement (Vickers and Edwards 1976).
the theory that dry cement should not contain more
than approximately 2 ppm ofwater-soluble chromium.
Chronic Readions
In 1981, Aalborg Portland AIS (Ud), the only
manufacturer of cement in Denmark, patented a
By repetition of the same stimulus or by combinations
method whereby the amount of chromate in the
of varying stimuli, the degree of impairment surpasses
cement could be reduced using this method, thus
a critical level (Malten 1981). Repeated and continual
reducing the content of water-soluble chromate in
contact with wet cement products in combination with
cement to not more than 2 ppm at a cost of about 1%
other physical traumas due to the work processes may
of the total value of the cement. Legislation stating that
lead to the development of chronic irritant cement
the content of water-soluble chromate in dry cement
eczema. This may take months or years. The efflores-
must not exceed 2 mg/kg (2 ppm) was passed in
cences may vary with time. These are erythema,
Denmark in 1983 (Arbejdstilsynets Bekendtg0relse
lichenification and hyperkeratoses on the dorsal and
volar aspects of the hands, fingers and fingertips, and
also on the wrists. The eczema may be nummular in
Fig. 2. The chemical reaction in the reduction of water-soluble
chromate by the addition of ferrous sulfate morphology (Fig. 3) or include the whole skin on the
affected area. Vesicles are seldom found (Cainan 1960;
H0vding 1970; Avnstorp 1983).
558 C. Avnstorp
In general, irritant ce me nt eczema cannot be differ- Spanish building industry, 82 (47.6%) were sensitised
entiated from allergie cement eczema clinically. This to rubber chemieals. It was suggested that chromium
differentiation should be made after patch testing. If allergy facilitated the rubber sensitisation, partieularly
the test reveals a positive reaction to chromate, the when gloves were worn in an almost occlusive way for
eczema must be classified as allergie cement eczema many hours over eczematous skin (Conde-Salazar
(Avnstorp 1992). The severity of irritant cement et al. 1995). A similar correlation has been described
eczema with respect to extension has been found to among workers from a factory in Singapore manufac-
be mild to moderate, whereas allergie cement eczema turing pre-cast concrete building components (Goh
has tended to be more severe (Avnstorp 1991). and Gan 1987).
Noneaematous Skin (hanges
Minor skin complaints are accepted as normal among

workers who have daily contact with wet cement
products (Avnstorp 1983). Mechanical traumas from
the handling of bricks, tools and machines cause
occupational stigmata in the form of hyperkeratoses,
with fissures on the palmar aspects of the hands and
fingers. This phenomenon is particularly seen among
individuals working outdoors in cold weather (Av-
nstorp 1992). In a field study among bricklayers and
bricklayers' assistants in Norway, the prevalence of
such skin changes was found to be 10% (H0vding 1970).
Allergie Cement Eaema

Fig.3. Nummular eement eezema
Allergie cement eczema is primarily located on the
hands, fingers and wrists (Burrows and Calnan 1965;
H0vding 1970; Avnstorp 1983). Eczema on the dorsal
aspect of the right hand, in particular, has been shown
to be associated with chromium hypersensitivity
(Avnstorp 1983). Furthermore, allergie cement eczema
has been found to have a greater extent of involvement
than irritant cement eczema (Avnstorp 1991). Allergie
cement eczema mayaiso spread to the forearms, the
feet and sometimes the face and parts of the trunk
(Fig. 4).
Heat and high humidity exacerbated allergie cement
eczema among workers in Kuwait. This phenomenon
was explained by the fact that excessive hydration of
the skin could lead to increased leaking of chromium
through the skin (Kanan 1972). In Singapore, where the
climate is hot and humid year round, the number of
heat-related dermatoses was, nevertheless, lower than
expected, possibly due to the use of air conditioning
and good factory ventilation (Goh and Soh 1984).
Concomitant Sensitisations
Concomitant sensitivities to cobalt and rubber chem-

ieals have been found significantly more often among
chromium-hypersensitive workers than among those
not hypersensitive to chromium (Fregert and Rorsman
1966; H0vding 1970 ; Fregert 1975; Avnstorp 1983). Fig.4. Allergie eement eezema on the leg of a eonstruetion
Among 172 chromium-allergic workers from the worker
Cement 559
Cobalt occurs in cement as water-insoluble oxides, General Prophylaxis

but forms complexes with amino acids in eczematous
skin, thereby possibly forming haptens (Fregert and Irritant cement eczema should, in part, be prevented
Gruvberger 1978). In cement eczema, cobalt sensitivity by automation of work processes whenever possible.
is therefore probably secondary to the chromium The risk of developing allergic cement eczema could be
hypersensitivity. brought to a very low level by the addition of ferrous
Nickel is a contaminant of cement in the form of sulfate to the cement (Avnstorp 1992). Ferrous sulfate
insoluble NiO which, in contrast to the cobalt oxides, is reduces the allergenic Cr(VI) to Cr(III) in the cement
not allergenic (Wahlberg et al. 1977). In a study using (see section on Reduction and Solubi/ity). In Scandi-
multivariate regression analysis, no statistically signi- navian countries, tlüs intervention has shown to be a
ficant association between nickel allergy and cement significantly effective method in the prevention of
eczema was found (Avnstorp 1983, 1989). allergic cement eczema (Avnstorp 1992; Roto et al.
Epoxy sensitivity has been observed with relatively 1996; Zachariae et al. 1996).
high frequency. Bricklayers and workers engaged in Changes in the cement manufacturing process by
pre-cast concrete building component factories are using slag as a substitute for clinker, proportionally
exposed to products containing epoxy resins (van decreases the Cr(VI) concentration of cement. This
Putten et al. 1984; Avnstorp 1992; Conde-Salazar et al. phenomenon is considered to be one of the reasons for
1994). the decline in the prevalence of cement dermatitis
among construction workers in recent years in Singa-
pore (Goh and Gan 1996).
Hereditary Factors Reduced numbers of statements and approved
claims of cement eczema have been found following
Combined influences of endogenous and exogenous the addition of ferrous sulfate to cement in Denmark
factors may lead to the development or to aggravation and Finland (Avnstorp 1992; Roto et al. 1996). This
of hand eczema (Nilsson 1985). Atopic eczema in economic benefit should be included in the calculation
childhood has been found to be a more important together with spared costs for medical support, lost
predictive factor for hand eczema than occupational working days and personal suffering of the workers
exposure (Meding and Swanbeck 1990). In a popula- developing allergic cement eczema.
tion of individuals with atopic dermatitis in childhood,
57% developed sporadic or continuous hand eczema Individual Prophylaxis
during concrete work (Rystedt 1985). When compared
with other occupations, such as the metal industry, The dynamics of the development of occupational
cleaning, and even office work, equal prevalences were hand eczema are not fully understood, but irritation
found. and contact sensitivity, together with individual con-
In a prevalence study among concrete workers stitutional factors, influence its development. Theoret-
from the building industry, up to 13% of the workers ically, at least one of the triggering factors could be
reported previous episodes of eczema other than eliminated if the workers used individual preventive
hand eczema; among those, approximately 50% measures. Use of gloves, protective hand creams and
developed hand eczema (Avnstorp 1983). The validity hand washing were not found to influence the
of the information about previous eczema and, propensity for developing irritant cement eczema
therefore, also about atopic heredity may be signif- (Avnstorp 1991). Furthermore, no additional effect
icantly influenced by the accuracy of recall. It will was found from individual preventive measures. The
decrease with time, since those persons who did not absence of influence from individual preventive mea-
have symptoms recently more often will forget their sures could be explained by the possibility that the
previous eczema episodes (Coenraads and Smit work processes are so hazardous that they overwhelm
1991). the protective effect. It could also be that the preven-
Age may influence the development of irritant tive initiatives were not conducted systematically or
cement eczema. Workers in the age group of 26-30 carefully enough.
years are more affected by the irritant properties of In workers with chromium allergy, the use of leather
cement (Geiser and Girard 1965). The reason may be gloves may deteriorate the dermatitis because of the
that younger, inexperienced workers tend to be more chromium tanning (Fregert and Gruvberger 1979). The
careless and, thereby, are more frequently exposed use of rubber gloves can cause secondary sensitisation
(Goh et al. 1986). to rubber chemicals (Conde-Salazar et al. 1995). Often
Psoriasis may be triggered by repeated mechanical gloves also contain the remains of cement spills and
traumas from handling bricks, tools and machines, may be soaked with mould oil. The moderate use of
and from daily contact with wet cement products. gloves may be advisable to protect against trauma from
560 C. Avnstorp
specific work processes, but prolonged occlusion of the Fregert S, Gruvberger B (1978) Solubility of cobalt in cement.
skin with gloves should be avoided. Contact Dermatitis 4:14-18
Fregert S, Gruvberger B (1979) Chromium in industrial leather
Barrier creams and ointments containing chemicals gloves. Contact Dermatitis 5:189
such as ethylendiaminetetraacetate (EDT A), ascorbic Fregert S, Rorsman H (1966) Allergy to chromium, nickel and
acid and combinations of sodium pyrosulfite, tartaric cobalt. Acta Derm Venereol 46:114-118
Fregert S, Gruvberger B, Sandahl E (1979) Reduction of chromate
acid and glycerine have been used in an attempt to in cement by iron sulfate. Contact Dermatitis 5:39-42
reduce Cr(VI) to Cr(III) and to chelate Cr(III) on the Fullerton A, Gammelgaard B, Avnstorp C, Menne T (1993)
skin (Samitz and Pomeranz 1958; Samitz and Gross Chromium content in human skin after in vitro application of
ordinary cement and ferrous-sulfate-reduced cement. Contact
1962; Samitz 1970; Shuppli 1970; Amphoux et al. 1975; Dermatitis 29:133-137
Romaguera et al. 1985). The effect of these measures Gammelgaard B, Fullerton A, Avnstorp C, Menne T (1992)
under actual working conditions is, however, doubtful. Permeation of chromium salts through human skin in vitro.
A thin layer of cream can easily be rubbed and washed Geiser JD, Girard A (1965) Remarques sur les cas deczema au
off, and it can hardly be thought of as an effective ciment observes a la clinique de dermato-venereologie de
barrier for those carrying out manual work. The Lausanne de 1947-1961. Dermatologica 131:93-102
Goh CL, Gan SL (1987) Rubber allergy among construction
creams themselves do not inhibit the absorption of workers in a prefabrication construction factory. Clin Exp
chromium (Wahlberg 1971). Dermatol 12:332-334
Goh CL, Gan SL (1996) Change in cement manufacturing process,
a cause for decline in chromate allergy? Contact Dermatitis
34:51-54
Goh CL, Soh SD (1984) Occupational dermatoses in Singapore.
References Contact Dermatitis 11:288-293
Goh CL, Gan SL, Ngui SJ (1986) Occupational dermatitis in a
prefabrication construction factory. Contact Dermatitis
Amphoux M, Woerth P, Grimonnet 1, Ha-Hau-Cam J (1975) 15:235-240
Doppelblind Versuch mit einer Schutzsalbe (Ivosin) an den H0vding G (1970) Cement eczema and chromium allergy, an
Händen von Cementarbeitern. Dermatosen 23:214-226 epidemiologic investigation (thesis). University of Bergen,
Danish Working Environment Service (1983) Order on water- Norway
soluble chromate in cement. Order no. 661 (in Danish) Irvine C, Pugh CE, Hansen EJ, Rycroft RJG (1994) Cement
Avnstorp ~ (.1983) Cement eczema in Danish workers engaged in dermatitis in underground workers during construction of
the bmldmg trades and industries (PhD thesis). University of the channel tunnel. Occup Med 44:17-23
Copenhagen, Denmark (In Danish with English summary) Jäeger H, Pelloni E (1950) Test epicutanes aux bichromates,
Avnstorp C (1989) Prevalence of cement eczema in Denmark positifs dans leczema au ciment. Dermatologica 100:207-215
before and since addition of ferrous sulfate to Danish cement. Kanan MW (1972) Cement dermatitis and atmospheric param-
Acta Derm Venereol 69:151-155 eters in Kuwait. Br J Dermatol 86:155-159
Avnstorp C (1991) Risk factors for cement eczema. Contact Lund MH (1977) Chrom i cement. Nordisk betong 6:28-30
Dermatitis 25:81-88 Malten KE (1981) Thoughts on irritant contact dermatitis. Contact
Avnstorp C (1992) Cement eczema. An epidemiological interven- Dermatitis 7:238-247
tion study. Acta Derm Venereol Suppl (Stockh) 179:14-17 Martial R (1908) La "Gate" du ciment. Presse Med 64:507-508
Avnstorp C (1995) Irritant cement eczema. In: van der Valk PGM, Meding B, Swanbeck G (1990) Occupational hand eczema in an
Maibach HI (eds) The irritant contact dermatitis syndrome. industrial city. Contact Dermatitis 22:13-23
CRC Press, Inc. Boca Raton, pp 111-119 Mehta PK (1986) Concrete. Strueture, properties and materials.
Bogue RH (1949) Portland cement. In: Finle GJ (ed) Encyclopedia Prentice-Hall, Inc., Englewood Cliffs
of Chemical Technology, vol 3, pp 411-431 Nilsson E (1985) Contact sensitivity and urticaria in "wet" work.
Bruze M, Fregert S, Gruvberger B (1990a) Patch testing with Contact Dermatitis 13:321-328
cement containing iron sulfate. Dermatol Clin 8:173-176 Occupational Health Foundation (1996) How to save your
Bruze M, Gruvberger B, Hradil E (1990b) Chromate sensitization skin: preventing skin problems in the construetion indus-
and elicitation from cement with iron sulfate. Acta Derm try. Symposium findings and reeommendations. Washington
Venereol Suppl (Stockh) 70:160-162 DC
Burckhardt W, Frenk E, de Sepidus D, Paschoud JM, Szadurski J, Romaguera C, Grimalt F, Vilaplana J, Carreras E (1985) Formu-
Schwartz K (1971) Abwächung der Ekzematogenen Wirkung lation of a barrier cream against chromate. Contact Derma-
des Zementes durch Ferrosulfat. Dermatologica 142:271-273 titis 13:49-52
Burrows D, Calnan CD (1965) Cement dermatitis, 2. clinical Roto P, Sainio H, Reunala T, Laippala P (1996) Addition of
aspects. Trans St John's Hosp Derm Soc 51:27-39 ferrous sulfate to eement and risk of ehromium dermatitis
Calnan CD (1960) Cement dermatitis. J Occup Med 2:15-22 among construction workers. Contact Dermatitis 43:43-50
Cement and Concrete Association Publication 98.001 (1977) Rystedt I (1985) Work-related hand eczema in atopics. Contaet
Portland cement in the making. Wexham Springs, Slough Dermatitis 12:164-171
Coenraads PJ, Smit J (1991) Epidemiology. In: Rycroft RJG, Samitz MH (1970) Ascorbic acid in the prevention and treatment
Menne T, Frosch PJ, Benezra C (eds) Textbook of contact of toxie effeets from chromates. Acta Derm VenereoI50:59-64
dermatitis. Springer, Berlin Heidelberg New York, pp 133-150 Samitz MH, Gross S (1962) Inactivation of ehromium ion in
Conde-Salazar L, Gonzalez MA, Guimaraens D (1994) Sensitiza- allergie eczematous dermatitis. J Invest Dermatol 38:5-12
tion to epoxy resin systems in special flooring makers. Samitz MH, Pomeranz H (1958) Studies on tlIe effect on the skin
Contact Dermatitis 31:157-160 of ~iekel and ch~~mium salts. Arch Ind Health 18:473-479
Conde-Salazar L, Guimaraens D, Villegas C, Romero A, Gonzalez Shupph RF (1970) Uber eine neuen Typus von Schutzsalben
MA (1995) Occupational allergic contact dermatitis in con- gegen Chromatekzeme. Dermatosen 18:350-355
struction workers. Contact Dermatitis 33:226-230 Skomorowski E (1985) Chromium in Portland eement. Cement
Fregert S (1975) Occupational dermatitis in a 1O-year material. Wapno-Gips 1:1-16
Contact Dermatitis 1:96-107 Sun CC, Guo YL, Lin RS (1995) Occupational hand dermatitis in a
Fregert S, Gruvberger B (1972) Chemical properties of cement. tertiary referral dermatology clinic in Taipei. Contact Der-
Dermatosen 20:238-248 matitis 33:414-418
Cement 561
van Putten PB, Coenraads PI, Nater JP (1984) Hand dermatoses Wexham Springs (1977) Portland cement in the making. Cement
and contact allergie reactions in construction workers and concrete association publication 98.001. Wexham
exposed to epoxy resins. Contact Dermatitis 10:146-150 Springs, Slough
Vickers HR, Edwards DH (1976) Cement bums. Contact Derma- Zachariae COC, Agner T, Menne T (1996) Chromium allergy
titis 2:73-78 in consecutive patients in a country where ferrous sulfate
Wahlberg JE (1971) Absorption-inhibiting effect of barrier has been added to cement since 1981. Contact Dermatitis
creams. Dermatosen 19:197-207 35:83-85
Wahlberg JE, Lindsted G, Einarsson Ö (1977) Chromium, cobalt
and nickel in Swedish cement, mould and cutting oils.
Dermatosen 25:220-228
CHAPTER 72
Acrylic Resins
B. Björkner
Introduction
windscreens. A two-component system is used in the
manufacture of dentures, hearing aids, noise protec-
Acrylic res ins are a thermoplastic type of res ins formed tors and "bone cement" in orthopedic surgery. The
by derivatives of acrylic acid (CH 2 =CH-COOH). The first component is aprepolymer powder of polymethyl
acrylic group is a vinyl group (CH 2 =CH-) (Fig. 1). The methacrylate, with benzoyl peroxide as an initiator.
monomers in acrylic resins are acrylic acids and The second component is a monomeric liquid of
methacrylic acids and their esters, cyanoacrylic acid methyl methacrylate containing an accelerator, e.g.,
and its esters, and acrylamides and acrylonitrile. N,N-dimethyl-p-toluidine.
Numerous different acrylic monomers therefore exist Other polymers of the mono(meth)acrylate type are
and, as a result, a multitude of different polymers and mostly used in industry. Leather finishes, adhesives,
res ins are produced. paints, printing inks and coatings are examples of
The polymerization of acrylic monomers is an practical applications. Butyl acrylate is sometimes used
addition-type reaction and is obtained either at room in spectade frames. Often, 2-ethylhexyl acrylate is used
temperature or by heating. The process is usually in the manufacture of press ure-sensitive adhesives, but
speeded up by adding initiators, accelerators and a wide range of other acrylates are also used in this field.
catalysts. Polymerization or curing can also be The acrylic monomers preferred in the preparation
achieved by ultraviolet (UV) light, visible light or of UV curable inks and coatings or in the photopre-
electron beams, in which initiators are not necessary polymer printing plate procedure are 2-hydroxyethyl
(Björkner 1995). acrylate (2-HEA), 2-hydroxypropyl acrylate (2-HPA),
2-hydroxypropyl methacrylate (2-HPMA), 2-hydroxy-
ethyl methacrylate (2-HEMA) and 2-ethylhexyl acrylate
Monoacrylates and Monomethacrylates (2-EHA). Also, 2-HPMA is used in light-sensitive
compositions for fissure sealant adhesives or bonding
Mono(meth)acrylates (monoacrylates and monometh- preparations in dentistry and in Napp printing plates.
acrylates) are used in the production of a great variety Various mono(meth)acrylates can be used in water-
of polymers (Fig. 2). Polymethyl methacrylate is the based acrylic latex paints. Plastics dispersions of
most important plastic in the group of acrylics with the acrylic polymers are used as binders or thickeners in
following repeating unit: [CH 2 -CH(CH3 )COOCH31n . paints as well as in cosmetic creams. The monomer
This plastic has an excellent transparency and is content is usually less than 0.3% (Björkner 1995).
therefore used in products such as roof windows,
house wares, watch glasses, bags, lamp housings and Methacrylate
CH 3
Acrylate 1
H2C=C-C-O-R
H2C=CH-C-O-R 11
11
o
o R=H metacrylic acid
R= H acrylic acid R=H methyl methacrylate
R = CH 3 methyl acrylate R = (CH2)2CH3 propyl methacrylate
R = CH 2CH 3 ethyl acrylate R = CH(CH 3)-CH 3 isopropyl methacrylate
Fig. 1. Derivatives of acrylic acid, where the structure of the side Fig. 2. Derivatives of methacrylic acid where the structure of the
chain (R) defines the different acrylic monomers side chain (R) defines the different methacrylic monomers

Acrylic Resins 563
Multifunctional Acrylates "new" for dermatologists but others are weH-known

sensitizers (Kanerva et al. 1989; Kanerva et al. 1994;
Björkner 1995). For example, 1,6-hexanediol diacrylate
Acrylates with at least two reactive acrylic groups are (HDDA), a known sensitizer in the printing ink and
called multifunctional acrylates. These are, for exam-
coating areas, is also used as a dental acrylate.
pIe, di(meth)acrylate esters of dialcohols or tri- and
The simplest UV -curable ink or coating formula-
tetra-acrylate esters of polyalcohols. Multifunctional
tions may consist of only three components. In
acrylates are used in formulations for UV -curable inks
practice, however, a typical industrial formulation
and coatings, in which they act as cross-linking agents
contains a much greater number of ingredients. The
and reactive diluents, and become apart of the final
three essential components are: (1) a UV -reactive
coating on UV -exposure. The multifunctional acrylates
prepolymer which provides the bulk of the desired
are also important acrylic compounds in photopoly- properties, (2) a diluent system composed of multi-
mers, flexographic printing plates and photoresists (an
functional acrylate esters (and at times monofunction-
etchresist for printed circuit boards). The multifunc-
al acrylic esters) and (3) a photo initiator system. The
tional acrylate esters are useful in acrylic glues,
most commonly used multifunctional acrylate in an
adhesives and anaerobic sealants as weH as in artificial
UV -curable ink or coating formulation is an acrylic
nail preparations. Some of the more commonly used
acid ester of either pentaerythritol (PETA), trimethyl-
multifunctional acrylates for artificial nail preparations
olpropane (TMPTA) or hexanediol (HDDA).
are ethylene glycol dimethacrylate (EGDMA), diethyl-
ene glycol dimethacrylate (DEGDMA) and trimethylol
Table 1. Acrylates used in
propane trimethacrylate (TMPTMA). The various acrylic-nail preparations Methyl rnethacrylate
acrylates used in acrylic nail preparations are seen in Ethyl rnethacrylate
Table 1, (Freeman et al. 1995; Koppula et al. 1995; Ethyl acrylate
2-Hydroxyethyl acrylate
Fischer 1996; Henmer et al. 1996; Kanerva et al. 1996). Butyl rnethacrylate
Most of the dental composite resin materials and Isobutyl rnethacrylate
denture-base polymers are "diluted" with the less Methacrylic acid
Tetrahydrofurfuryl rnethacrylate
viscous "difunctional" acrylates. These are the met- Ethylene glycol dirnethacrylate
hacrylic monomers of which EGDMA, DEGDMA, Diethylene glycol dirnethacrylate
triethylene glycol dimethacrylate (TREGDMA) Triethylene glycol dirnethacrylate
Trirnethylol propane
(Fig. 3) and 1kbutanediol dimethacrylate (BUDMA) trirnethacrylate
(Fig. 4) are the most widely used (Table 2). The use of Urethane rnethacrylate
acrylates in dentistry is an expanding field. Some are Tripropylene glycol acrylate
Fig. 3. Chernical forrnulae of n-ethyl- CH 3 CH 3

eneglycol di(rneth)acrylates
I I
H2 C =C-C-(O-CH
11
-CH ) -O-C-C
2 11
2n
=CH 2
o 0
n=1: ETHYLENEGLYCOL DIMETHACRYLATE (EGDMA)

n=2: DlETHYLENEGLYCOL DIMETHACRYLATE (DEGDMA)
n=3: TRIETHYLENEGLYCOL DIMETHACRYLATE (TREGDMA)
Fig. 4. Chernical forrnulae of 1,6-hex-

anediol diacrylate and l,4-butanediol o l?
dirnethacrylate CH
2
=C-~-O-(CH2)
I n
-O-C-C=CH 2
I
R R
R =H & n =6: 1,6-Hexanediol dlacrylate (HODA)
=
R CH 3 & n =4: 1,4-8utanediol dlmethacrylate (8UDMA)
564 B. Björkner
Table 2. Acrylic com- Epoxy Acrylates

pounds used in dental Methyl methacrylate
materials Triethyleneglycol dimethacrylate
Urethane dimethacrylate Epoxy acrylates is another name for the ß-hydroxyes-
Ethyleneglycol dimethacrylate ter acrylates because they are usually obtained by
bis-GMA
bis-MA reacting epoxy resins or glycidyl derivatives with
bis-EMA acrylic acid (Fig. 5). Both aromatic and aliphatic epoxy
bis-PMA acrylates are available, as weIl as acrylated epoxydized
2-(Dimethylamino )ethyl methacrylate
Butyl methacrylate oils. Epoxy acrylates have found a wide range of useful
2-Hydroxyethyl methacrylate applications in UV - or electron beam (EB)-curing.
1,6-Hexanediol diacrylatae The addition-reaction product of bisphenol A
1,10-Decanediol dimethacrylate
1,4-Butanediol dimethacrylate and glycidyl methacrylate or an epoxy resin and
1,12-Dodecanediol dimethacrylate methacrylic acid is bis-GMA; 2,2-bis{4-(2-hydroxy-
Trimethylolpropane trimethacrylate 3-methacryloxypropoxy)phenyl}propane (Fig. 5). Bis-
Phenylsalicylate glycidylmethacrylate
Tetrahydrofurfuryl methacrylate GMA can therefore be classified as a dimethacrylated
Benzaldehyde glycol methacrylate epoxy, although it does not contain a reactive epoxy
N- Tolylglycine-glycidylmethacrylate group. Bis-GMA is the most commonly used prepoly-
1,3-Butyleneglycol diacrylate
3,6-Dioxaoctamethylene mer in dental composite restorative materials. Several
dimethacrylate similar compounds have also appeared as substitutes
Biphenyl dimethacrylate for Bis-GMA or in addition to it in dental resins.
Glycerolphosphate dimethacrylate
Such dimethacrylates based on bisphenol A with
various chain lengths are bis-MA; 2,2-bis(4-(metha-
cryloxy)phenyl)-propane, bis-EMA; 2,2-bis(4-(2-met-
During the past 15-20 years, the use of UV-curable hacryloxyethoxy)phenyl)-propane and bis-PMA; 2,2-
acrylates in inks and coatings has increased tremen- bis(4-Ö-methacryloxypropoxy)phenyl)-propane.
dously. In the can-coating industry, UV -printing inks The industrial applications of bis-GMA res ins and
are used on beverage and beer cans as weIl as on crown the other similar derivatives are extensive. Acrylates
caps and aerosol containers. UV -curable acrylate based on bisphenol A or epoxy res in can not only be
coatings are used as wood finishes, mat varnishes, polymerized by exposure to EB, UV -light or even
parquet varnishes and sealers, and as varnishes and visible light, but can also be chemically activated by the
coatings in the manufacture of furniture (Björkner use of various peroxides.
1995).
Urethane Acrylates
TMPT A and PET A can both be used in the
production of polyfunctional aziridine added to paint
There are many types of acrylated urethanes on the
primer and floor top coatings as a self-curing cross-
linker or hardener (Dahlquist et al. 1983; Cofield et al. market. While some are based on aromatic isocyan-
ates, others are of the aliphatic type. Acrylated
1985; Kanerva et al. 1995).
In the absence of oxygen and in the presence of urethanes are used not only in prepolymers in UV-
metals, an aerobic acrylic sealants, e.g., Loctite, Tree- curable inks or coatings, for example vinyl floorings,
bond and Sta-Lok, polymerize rapidly. Dimethacrylates but also as resins with dental applications. The
are their principal components (Dempsey 1962; Ranch- acrylated urethanes used in dentistry are of the
methacrylated type.
off and Taylor 1985; Conde-Salazar et al. 1988; Kanerva
et al. 1989). Diethylene glycol dimethacrylate oligomer
Polyester Acrylates
is most commonly used for screw-thread locking,
whereas urethane dimethacrylate is used for retaining
There are various types of polyester acrylates on the
and locking flat metal surfaces (Björkner 1995).
market and they are mostly used in UV -curable
lacquers and printing inks for wood and paper
coatings (Björkner 1995).
Prepolymers
The Effects of Acrylate Esters on the Skin

Acrylate res ins, based on the conventional thermoplas-
tic resins, into which two or more reactive acrylate or
methacrylate groups have been introduced, are called The skin-irritating potential of various acrylic mono-
prepolymers. The most commonly used prepolymers mers has shown that the diacrylates are strong
are acrylated epoxy resins, acrylated polyurethanes, irritants, monoacrylates are weak to moderate irri-
acrylated polyesters and acrylated polyethers. tants, and monomethacrylates and dimethacrylates are
Acrylic Resins 565
~
?H:Cl
OH
"" C
6H
""
I I OH
H 2 C=CH-C-OCH 2 c!:;H CH 2 0 - O - 3 OCH 6HCH O-C-CH=CH
11 2211 2
o 0
EPOXY DIACRYLATE
CH 3
I
H 2 C=C-C-O-(CH 2 )3 0
11
o
jJ U
I "CrH 3I "
/.-
CH 3
I
/.-
O(CH ) -
23
o-c-c
TI
0
CH
I 3
=CH
2
BIS-PMA
U3 ?H
I "C I "
CH 3
I
H 2 C=C-C-O-(CH 2 )2 0
o
11
jJ I
CH 3 /.-
O(CH )
2 2
- o-c-c
0
11
CH
I
~CH
3
2
BIS-EMA
I I
~CH
?H:Cl
CH 3 OH "" C
Cl H "" OH CH 3
I I 3 I I
H 2 C=C-C-OCH 2 CH CH 2 0 - O - hOCH CHCH O-C-C
11 2 2 11 2
o 0
BIS-GMA
CH 3
I
H 2 C=C-C-O
11
o
jIJ U
"CrH 3I "
/.-
CIH
3 /.-
CH 3
I
O-C-C =CH
11
0
2
BIS-MA
Fig. 5. Chemical formulae of di(meth)acrylates based on bisphe- cutaneous irritant reactions as well as allergic contact
nol A and epoxy resin dermatitis (Nethercott et a1. 1984). The irritant effect of
various acrylate compounds has been reviewed by
non-irritant or weak lrntants to guinea-pig skin Kanerva et a1. (Kanerva et a1. 1996; Finnish Advisory
(Björkner 1981; Cavelier et a1. 1981; Björkner 1982; Board of Chemicals 1992).
van der Walle 1982; Parker and Turk 1983; Björkner The sensitizing potential of many mono(meth)acry-
1984a,b; Björkner et a1. 1984; Waegemaekers 1985). lates, multifunctional (meth)acrylates and acrylated
Multifunctional acrylates and acrylated prepolymers resins in guinea pigs has been thoroughly studied by
seem to be more skin irritating than the corresponding numerous authors (Björkner 1981; Cavelier et al. 1981;
methacrylates. These effects have been seen when Björkner 1982; van der Walle 1982; Parker and Turk
patch testing both humans and guinea pigs (Björkner 1983; Björkner 1984a,b; Björkner et al. 1984; Wa-
1984b). Bullous irritant skin reactions in workers egemaekers 1985). Tests have shown that monoacry-
exposed to tetramethylene glycol diacrylate have been lates are strong sensitizers while mono(meth)acrylates
reported (Beurey et a1. 1976). A peculiar delayed have a weak to moderate sensitizing potential (Cavelier
irritation from butanediol diacrylate and hexanediol et al. 1981; van der Walle 1982; Parker and Turk 1983;
diacrylate has been observed by Malten et a1. (1979). Björkner 1984b). Thus, the introduction of a methyl
Tetraethylene glycol diacrylate can cause delayed group reduces the sensitizing potential of monoacry-
566 B. Björkner
lates. Of the multifunctional acrylates, the di- and In recent decades, many reports about contact
triacrylic compounds should be regarded as potent allergy caused by various multifunctional acrylic
sensitizers (Björkner 1981; Björkner 1984b; Björkner compounds have been published (Kanerva et al.
et al. 1984). The methacrylated multifunctional acrylic 1994a, 1989; Björkner 1995). At risk of developing
compounds are weak sensitizers (Björkner 1984b; contact allergy to multifunctional tri- and diacrylates
Björkner et al. 1984). are those working with UV -curable inks or coatings;
Among the various di(meth)acrylates based on contact allergy to dimethacrylates is more commonly
bisphenol A or epoxy res in, the allergenicity seems to seen in dentistry in those working with anaerobic
diminish if the acrylates have three or more methylene acrylic sealants and in those exposed to acrylic nails
groups in the molecular chain (Björkner 1981; Cavelier (Björkner 1984b; Kanerva et al. 1989a,b, 1994a,b,c,
et al. 1981; Björkner 1982, 1984a,b; Björkner et al. 1984). 1995). There are some reports of allergic contact
It is more difficult to predict the sensitizing capacity of dermatitis to dimethacrylates based on bisphenol A
the various prepolymers. Epoxy acrylates are strong or epoxy resin in dental composite materials. At risk of
sensitizers and their sensitizing capacity is due to the developing contact dermatitis are dentists and dental
entire molecule, thereby excluding the epoxide group technicians, as well as dental patients (Kanerva et al.
as the sole sensitizing part of the compound (Björkner 1989a,b, 1994a,b,c, 1995). Patients allergic to bis-GMA
1984b). Free epoxy res in may be present in epoxy mayaiso react to epoxy resin MW 340 (Björkner et al.
acrylates, which may sensitize separately or simulta- 1984; Kanerva et al. 1989c). It is uncertain whether any
neously (Björkner 1984a). residual epoxy resin monomer is left unreacted or
The whole molecular structure of polyester acrylate whether it is formed in the synthesis of the bis-GMA
probably acts as an allergen as well. However, the monomer (Björkner et al. 1984).
reactive terminal acrylate and methacrylate groups Methyl methacrylate and 2-HEMA can cause pares-
seem to be of great importance for antigen formation thesia of the fingertips for months after discontinua-
and sentization (Björkner 1982). The carboxy ethylside tion of contact with the monomer (Bohling et al. 1977;
group seems to be of importance for antigenicity Matthias et al. 1979; Kanerva and Verkkala 1986). An
(Koppula et al. 1995). effect on the peripheral nervous system has also been
The aliphatic urethane acrylates are more potent described for acrylamide (Edvards 1975).
sensitizers than the aromatic ones, while the aliphatic
urethane methacrylates commonly used in dental
resins are weak sensitizers (Nethercott et al. 1982; Acrylonitrile
Björkner 1984a).
There are many reports about contact allergy to
Acrylonitrile (H 2 C=CH-CN) is used as a co-polymer in
mono(meth)acrylates in humans. Contact dermatitis
approximately 25% of all synthetic fibers. It is further
due to 2-HPMA in printers exposed to printing plates,
used for synthetic rubbers and for the production of
as well as to UV -curing inks, has been reported (Bang
acrylonitrile-butadiene-styrene plastics and styrene-
Pedersen et al. 1983; Björkner 1984c). Contact allergy to
acrylonitrile plastics. These ter- and co-polymers are
2-HEMA, one of the ingredients in a photo prepolymer
used in the automobile industry and in the production
mixture, has been described (Malten and Bende 1976).
of house wares, electrical appliances, suitcases, food
2-HEMA is a water-soluble form of methacrylate resin
packaging and disposable dishes. Acrylonitrile can also
and therefore it is commonly used as a dentine bonding
be a constituent in fabrics and paints (Björkner 1995).
compound. The bonding systems used contain a
primer and an adhesive. The dentine is first handled
Skin Problems from Acrylonitrile
by the primer, then by the adhesive. This is polymer-
ized with a visible-light-curing unit and then a dental
There are only a few reports of contact allergy to the
composite resin is applied to the tooth and cured either
acrylonitrile monomer (Balda 1971, 1975; Romaquera
chemically or with light. 2-HEMA is a common allergen
et al. 1985; Bakker et al. 1991). In the guinea-pig
in dental personnel. Fingertip dermatitis is common in
maximization test, however, acrylonitrile has showed
dentists and dental nurses allergic to dentine bonding
strong allergenic potential (Bakker et al. 1991).
acrylates (Kanerva et al. 1989, 1994a,b,c, 1995).
Contact dermatitis from 2-EHA in an acrylic based
adhesive tape has been reported (Whittington 1981).
Acrylamide and Derivatives
Orthopedic surgeons, surgical technicians, nurses and
dental technicians are exposed to methyl methacrylate
monomer when preparing bone cement and dentures. Acrylamide (H 2 C=CH-CO-NH,) is an odorless, white,
Contact allergy to methyl methacrylate monomer is crystalline solid used as a monomer or as a raw material
rare in patients undergoing hip surgery (Fregert 1983). in the production of polyacrylamides and other
Acrylic Resins 567
compounds. Most of the acrylamide monomer is defines the different alkyl 2-cyanoacrylates and is
produced and used as an aqueous solution. The reactive dependent on the alcohol that has been used (Fig. 6).
acrylamide monomer is used in the production of other For instance, methanol gives methyl 2-cyanoacrylate,
compounds, mostly polymers of acrylamide, and as a ethanol gives ethyl 2-cyanoacrylate, etc. Methyl
grouting agent in the construction or rehabilitation of 2-cyanoacrylate is mainly instant glue for household
dams, buildings, sewers, tunnels and other structures. use. Ethyl 2-cyanoacrylate is most commonly used in
Acrylamide grouts are used predominantly as barriers industry, and most of the different adhesive products
against ground-water seepage into sewers. About 95% on the market are manufactured by Loctite. n-Butyl
of the acrylamide produced is consumed in the 2-cyanoacrylate and isobutyl 2-cyanoacrylate are com-
production of other compounds and polyacrylamide monly used as medical adhesives.
products, which are widely used as flocculents in Glues based on cyanoacrylates are widely used as
potable water and waste-water treatment, mineral ore contact adhesives for metal, glass, rubber, plastics and
processing, sugar refining, water flow control agents in textiles as well for biological materials, which inc1udes
oil-well operations, and adhesives in paper making and binding tissues and sealing wounds in surgery. The
construction. The remaining 5% is used as a monomer. bonding action of cyanoacrylates is generally believed
Acrylamide and its derivatives are also used in the to be a result of an anionic polymerization that is
production of photopolymer printing plates. Because highly exothermic and rapid, occurring within sec-
acrylamide is produced by catalytic or sulfuric acid onds or minutes even at room temperature. Catalysts
hydration of acrylonitrile, acrylamide production are not required for this reaction to occur since weak
workers mayaiso be exposed to acrylonitrile. bases, such as water and alcohols or nuc1eophilic
groups on proteins, e.g., amine or hydroxyl groups,
Health Effects from Acrylamide and Derivatives already present on the adherent surfaces initiate the
polymerization. Vaporized cyanoacrylates are known
Polyacrylamide products are generally considered non- to irritate the eyes and respiratory tracts. Irritation
hazardous. The monomer can be irritating and cause and discomfort of the face and eyes may occur in
contact allergy. Skin problems are seen among printers workers due to associated low humidity (Cainan 1979;
exposed to photopolymerizing printing plates. Acryl- Malten 1982).
amide and their acrylamide compounds N,N' -methyl- Contact sensitization to cyanoacrylates is considered
ene-bis-acrylamide and N-methylol acrylamide have extremely rare because of the immediate bonding of
been described as allergens (Pye and Peachey 1976; the cyanoacrylate to the surface keratin (Calnan 1979).
Malten 1978; Pedersen et al. 1982; Lambert et al. 1987; The adhesive was therefore believed never to come into
Malten 1987; Dooms-Goossens et al. 1991). N-methylol contact with immunocompetent ceils further down in
acrylamide sensitization has also been observed in the epidermis. For instance, Parker and Turk (1983)
workers making PVA-acrylic co-polymers for paints. were unable to sensitize guinea pigs with methyl or
Acrylamide, N-hydroxymethyl acrylamide and N,N'- butyl 2-cyanoacrylate. However, in the last decade,
methylene-bis-acrylamide were moderate sensitizers some case reports have been published which strongly
when tested in guinea pigs (Waegemaekers 1985). indicate that cyanoacrylates are able to induce contact
The acrylamide monomer may be neurotoxic, car- allergy (Shelley and Shelley 1984; Fischer 1985; Pigatto
cinogenic, genotoxic and hazardous to reproduction. et al. 1986; Belsito 1987; Tomb et al. 1993; Bruze et al.
Recent studies confirm that acrylamide exposures cause 1995; Fitgerald et al. 1995; Jacobs and Rycroft 1995).
cancer and reproductive effects in animals, but epide- Patch testing with cyanoacrylate glue might give
miological studies have not demonstrated these effects false-negative reactions when dissolved in acetone
in humans. The neurotoxic effects from acrylamide
exposure inc1ude peripheral nerve damage and central-
nervous-system effects (Edvards 1975; Pye and Peachey
1976; Lambert et al. 1987; Dooms-Goossens et al. 1991). Cyanoacrylate
Allergic contact dermatitis from piperazine diacryl- CN
amide used as areagent and as a cross-linker for 1
acrylamide gels in electrophoreses and column chro- H,C=C-C-Q-R
matography has been described by Wang et al (1997). 11
Q
R= H cyanoacrylic acid
Cyanoacrylates R= CH, methyl cyanoacrylate
Fig. 6. The molecular structure of cyanoacrylates where the

Cyanoacrylates (H 2 C=C(CN)-COOR) are also called structure of the side chain (R) defines the different alkyl
"super glues". The structure of the side chain (R) 2-cyanoacrylates
568 B. Björkner
using the Finn chamber (aluminum) technique. Patch References

testing with petrolatum as the vehicle in a plastic
chamber is recommended (Bruze et al. 1995).
Bakker RJG, Jongen SM, van-Neer FC, et al. (1991) Occupational
Cyanoacrylates, besides causing skin sensitization contact dermatitis due to acrylonitrile. Contact Dermatitis
and irritation, have also been shown to cause occupa- 1:50
tional asthma and to be mutagenic. Furthermore, Balda BR (1971) Allergie contact dermatitis due to acrylonitrile.
Contact Dermatitis Newslett 9:219
cyanoacrylates are suspected to be carcinogenic and to Balda BR (1975) Akrylonitril als Kontaktallergen. Hautarzt 26:
induce peripheral neuropathy. 599
Bang Pedersen N, Senning A, Otkjaer Nielsen A (1983) Different
sensitizing acrylic monomers in NAPP printing plate. Contact
Dermatitis 9:459
(are in the Handling of Acrylic Resins Belsito D (1987) Contact dermatitis to ethyl cyanoacrylate
containing glue. Contact Dermatitis 17:234
Beurey 1, Mougeolle J-M, Weber M (1976) Accidents cutanes des
Use of gloves is recommended to protect the hands resines acryliques dans l'imprimerie. Ann Dermatol Venereol
103:423
against the various acrylic compounds. However, Björkner B (1981) Sensitization capacity of acrylated prepolymers
methyl ethacrylate, as weH as other acrylic monomers, in ultraviolet curing inks tested in the guinea pig. Acta Derm
such as butylacrylate and acrylamide, easily penetrates Venereol 61:7
Björkner B (1982) Sensitization capacity of polyester methacrylate
natural rubber latex gloves (Pegum and Medhurst 1971; in ultraviolet curing inks tested in the guinea pig. Acta Derm
Waegemaekers 1985). Vinyl gloves are even inferior in Venereol 62:153
this regard (Rietschel et al. 1984; Munksgaard 1992). Björkner B (1984a) Sensitizing potential of urethane (meth)acry-
lates in the guinea pig. Contact Dermatitis 11:115
Polyethylene gloves give the best protection against Björkner B (1984b) Sensitizing capacity of ultraviolet curable
methyl methacrylate diffusion (Waegemaekers 1985). acrylic compounds (thesis). University of Lund, Sweden
Nitrile gloves give better protection then neoprene Björkner B (1984C) Contact allergy to 2-hydroxypropyl methac-
rylate (2-HPMA) in an ultraviolet curable ink. Acta Derm
gloves against UV -curable acrylate res ins (Rietschel Venereol 64:264
et al. 1984; Björkner 1995). New multilayer glove Björkner B (1995) Plastic materials. In: Rycroft RJG, Menne T,
material of the folio type, with ethylene-vinyl-alcohol Frosch PJ (eds) Textbook of contact dermatitis. Springer,
Berlin Heidelberg New York,p 539-572
co-polymer laminated with polyethylene on both sides, Björkner B, Niklasson B, Persson K (1984) The sensitizing
has an especiaHy good chemical resistance (Roed- potential of di(meth)acrylates based on bisphenol A or epoxy
Petersen 1989). Because acrylics used in dentine resin in the guinea pig. Contact Dermatitis 10:286
Bohling HG, Borchard U, Drouin H (1977) Monomerie methyl-
bonding systems are strong sensitizers and quickly methacrylate acts on desheathed myelinated nerve and on
penetrate most gloves, dentists and dental personnel node of Ranvier. Arch Toxicol 38:307
should use the no-touch techniques. (Kanerva et al. Bruze M, Björkner B, Lepoittevin J-p (1995) Occupational allergie
contact dermatitis from ethyl-cyanoacrylate. Contact Derma-
1994a; Estlander and Jolanki 1988). titis 32:156
As most of the acrylic compounds used in UV- Calnan CD (1979) Cyanoacrylate dermatitis. Contact Dermatitis
curable acrylic res ins should be regarded as irritants 5=165
Cavelier C, Jelen G, Herve-Bazin B, et al. (1981) Irritation et
and relatively potent sensitizers, care should thus be allergie aux acrylates et methacrylates. Premiere partie,
taken to minimize their contact with the skin. monoacrylates et monomethacrylates simples. Ann Dermatol
Measures that seem effective in preventing the occur- Venereol 108:549
Cofield BG, Storrs FJ, Strawn CB (1985) Contact allergy to
rence of dermatitis include the use of impervious aziridine paint hardener. Arch Dermatol 121:373-6
protective gloves and protective clothing. Face shields Conde-Salazar L, Guimaraens D, Romero LV (1988) Occupational
and goggles are recommended whenever there is risk allergie contact dermatitis from anaerobie acrylic sealants.
of splattering. The contaminated skin should be Dahlquist I, Fregert S, Trulsson L (1983) Contact allergy to
washed with soap and water, and contaminated trimethylolpropane triacrylate (TMPTA) in an aziridine
clothing should be removed promptly. It is necessary plastie hardener. Contact Dermatitis 9:122
Dempsey KJ (1962) Hypersensitivity to Sta-Lok® and Loctite®
to keep the clean and the contaminated clothing anaerobie sealants. J Am Acad Dermatol 7:779
separate. Thorough education of employees regarding Dooms-Goossens A, Garmyn M, Degreff H (1991) Contact allergy
skin hazards is also recommended (Björkner 1995). to acrylamide. Contact Dermatitis 24:71
Edvards PM (1975) Neurotoxicity of acrylamide and its analogues
and effects of these analogues and other agents on acryl-
amides neuropathy. Occup Environ Med 31
Patch Testing with Acrylic (ompounds Estlander T, Jolanki R (1988) How to protect the hands. In:
Taylor, JS (ed) Occupational dermatoses. Dermatologieal
dinies, vol 6. Saunders, Philadelphia, pp 105-14
Finnish Advisory Board of Chemieals (1992) Acrylate com-
In general, a patch test concentration of 2% in pounds, uses and evaluation of health effects. Government
petrolatum is recommended for the methacrylated Printing Office, Helsinki, voll
monomers, and 0.1% in petrolatum for the acrylated Fischer AA (1985) Reactions to cyanoacrylate adhesives: "instant
glue". Cutis 35:18
monomers to avoid patch-test sensitization (Kanerva Fischer AA (1990) Adverse nail reactions and paresthesia from
et al. 1988). "photobonded acrylate 'sculptured' nails". Cutis 45:293
Acrylic Resins 569
Fitgerald DA, Bhaggoe R, English JS (1995) Contaet sensitivity to Malten KE (1987) Printing plate manufaeturing proeesses. In:
cyanoaerylate nail adhesive with dermatitis at remote sites. Maibaeh, HI (ed) Oceupational and industrial dermatology,
Contaet Dermatitis 32:175 2nd edn. Year Book Medieal Publishers Ine, Chieago, pp
Freeman S, Lee M-S, Gudmundsen K (1995) Adverse eontaet 351-66
reaetions to seulptured aerylie nails: 4 ease reports and a Malten KE, Bende WM (1976) 2-Hydroxy-ethyl methaerylate and
literature review. Contaet Dermatitis 33:381-5 di- and tetraethylene glyeol dimethaerylate: eontaet sensi-
Fregert S (1983) Oecupational hazards of acrylate bone cement in tizers in photoprepolymer printing plate proeedure. Contaet
orthopedic surgery. Acta Orthop Scand 54:787 Dermatitis 5:214
Henmer W, Focke M, Wantke F, et al. (1996) Allergie contaet Malten KE, van der Meer-Roosen CH, Seutter E (1978) Nyloprint-
dermatitis to artificial fingernails prepared from UV light- sensitive patients reaet to NN' -methylene-bis-aerylamide.
cured acrylates. J Am Acad Dermatol 35:377 Contaet Dermatitis 4:214
Jacobs MC, Rycroft RJ (1995) Allergie contact dermatitis from Malten KE, den Arend JACJ, Wiggers RE (1979) Delayed
cyanoacrylate? Contact Dermatitis 33:71 irritation: hexanediol diaerylate and butanediol diaerylate.
Kanerva L, Verkkala E (1986) Electron microscopy and immuno- Contaet Dermatitis 5:178
histochemistry of toxie and allergic effects of methylmethac- Matthias CGT, Turner MC, Maibach HI (1979) Contact Dermatitis
rylate on the skin. Arch Toxicol 9 [Suppl]:456 and gastrointestinal symptoms from hydroxyethyl methaery-
Kanerva L, Estlander T, Jolanki R (1988) Sensitization to patch late. Br J Dermatol 1l0:447
test acrylates. Contact Dermatitis 8:10-15 Munksgaard EC (1992) Permeability of proteetive gloves to
Kanerva L, Estlander T, Jolanki R (1989) Allergic contact derma- (di)methaerylates in resinous dental materials. Seand j Dent
titis from dental eomposite resins due to aromatie epoxy Res 100:189
acrylates and aliphatie aerylates. Contact Dermatitis 20:201 Nethereott IR, jakubovie HR, Pilger C, et al (1982) Allergie
Kanerva L, Estlander T, Jolanki R (1989b) Occupational allergie contaet dermatitis due to urethane acrylate in ultraviolet
contact dermatitis from aerylates: observations concerning eured inks. Br j Ind Med 40:241
anaerobie acrylie sealants and dental eomposite resins. In: Nethereott IR, Gupta S, Rosen C, et al. (1984) Tetraethylene glyeol
Frosch PI, Dooms-Goossens A, Lachapelle J-M, Ryeroft RJG, diaerylate. A eause of delayed eutaneous irritant reaetion and
Scheper RJ (eds) Current topies in contact dermatitis. allergie eontaet dermatitis. J Oecup Environ Med 26:513
Springer, Berlin Heidelberg New York, pp 352-59 Parker D, Turk jL (1983) Contaet sensitivity to aerylate eom-
Kanerva L, Estlander T, Jolanki R (1989C) Allergie contact pounds in guinea pigs. Contaet Dermatitis 9:55
dermatitis from dental composite resins due to aromatie epoxy Pedersen NB, Chevallier M-A, Senning A (1982) Seeondary
acrylates and aliphatie aerylates. Contact Dermatitis 20:201 acrylamides in Nyloprint printing plate as a souree of eontaet
Kanerva L, Estlander T, Jolanki R (1994a) Oeeupational skin dermatitis. Contaet Dermatitis 8:256
allergy in dental profession. In: Taylor S (ed) Dermatologie Pegum jC, Medhurst FA (1971) Contaet dermatitis from penetra-
dinies, vol 12. Saunders, Philadelphia, pp 517-32 tion of rubber gloves by aerylie monomer. BMJ 2:141
Kanerva L, Estlander T, Jolanki R, Tarvainen K (1994b) Derma- Pigatto PD, Giacehetta A, Altornare GF (1986) Unusual sensiti-
titis from aerylates in dental personnel. In: Menne T, Maibaeh zation to eyanoacrylate ester. Contaet Dermatitis 14:193
HI (eds) Hand eezema. CRC Press, Boea Raton, pp 231-54 Pye RJ, Peaehey RD (1976) Contaet dermatitis due to Nyloprint.
Kanerva L, Henriks-Eekerman M-L, Estlander T, et al. (1994e) Contaet Dermatitis 2:44
Oeeupational allergie eontaet dermatitis and composition of Ranehoff RE, Taylor JS (1985) Contaet dermatitis to anaerobie
acrylates in dental bon ding systems. J Eur Aead Derm sealants. j Am Aead Dermatol 1P015
Venereol 3:157 Rietsehel RL, Huggins R, Levy N, Pruitt PM (1984) In vivo and in
Kanerva L, Estlander T, Jolanki R (1995a) Dental problems. In: vitro testing of gloves for proteetion against UV -eurable
Guin JD (ed) Praetieal eontaet dermatitis. MeGraw-Hili Ine., aerylate resin systems. Contaet Dermatitis 1l:279
New York, pp 397 Roed-Petersen j (1989) A new glove material proteetive against
Kanerva L, Estlander T, Jolanki R, et al. (1995b) Oeeupational epoxy and aerylate monomer. In: Froseh Pj, Dooms-Goossens
allergic contaet dermatitis and eontaet urticaria eaused by A, Lachapelle j-M, Ryeroft RjG, Seheper RJ (eds) Current
polyfunetional aziridine hardener. Contaet Dermatitis 33:304- topies in contaet dermatitis. Springer, Berlin Heidelberg New
309 York, pp 603
Kanerva L, Björkner B, Estlander T, et al. (1996) Plastie materials: Romaquera C, Grimalt F, Vilaplana J (1985) Methyl methaerylate
oeeupational exposure, skin irritaney and its prevention. In: prosthesis dermatitis. Contaet Dermatitis 12:172
van der Valk PGM, Maibaeh HI (eds) The irritant eontaet Shelley ED, Shelley WB (1984) Chronie dermatitis simulating
dermatitis syndrome. CRC Press, Boea Raton, pp 127-55 small-plaque parapsoriasis due to eyanoaerylate adhesive
Kanerva L, Lauerma A, Estlander T, et al. (1996b) Oeeupational used on finger nails. JAMA 252:2455
allergie contaet dermatitis eaused by photobonded seulptured Tomb RR, Lepoittevin j-P, Durepaire F, et al. (1993) Eetopie
nails and a review of (meth)aerylates in nail eosmeties. Am J contaet dermatitis from ethyl-eyanoaerylate instant adhe-
Contaet Dermat 7:109 sives. Contaet Dermatitis 28:206
Koppula SV, Feldman JH, Storms FJ (1995) Sereening allergens van der Walle HB (1982) Sensitizing potential of aerylie mono-
for aerylate dermatitis associated with artificial nails. Am J mers in guinea pig (thesis). Katholieke Universiteit te
Contact Dermat 6:78-87 Nijmegen, Kripps Repro Meppel, Holland
Lambert I, Matthieu L, Doekx P (1987) Contaet dermatitis from Waegemaekers T (1985) Some toxieologieal aspeets of aerylie
aerylamide. Contaet Dermatitis 17:234 monomers, notably with referenee to the skin (thesis).
Malten KE (1982) Old and new, mainly oeeupational dermato- Katholieke Universiteit te Nijmegen, Holland
logieal problems in the production and proeessing of plastics. Wang M-T, Wenger K, Maibaeh HI (1997) Piperazine diaeryl-
In: Maibaeh HI, Gellin GA (eds) Oceupational and industrial amide allergie eontaet dermatitis. Contact Dermatitis 37:300
dermatology. Year Book Medieal Publishers Ine, Chieago, Whittington CW (1981) Dermatitis from UV aerylate in adhesive.
pp 237 Contaet Dermatitis 7:203
CHAPTER 73
Epoxy Resins
R. Jolanki, 1. Kanerva, and T. Estlander
Introduction
(MW) of 340 Da, and oligomers with a higher MW.
The DGEBA epoxy resins account for about 75% of
The first product created that contained epoxy resin the epoxy resins used world-wide. The average
was an adhesive that was introduced in 1946 (Potter number of repetitive parts in the oligomers ranges
1975). Large-scale production of epoxy resins began in from essentially 0 to approximately 25 (Fig. 1) (Bauer
1952 (HärteI1980). By the end of the 1960s, at least 25 1985).
distinct types of epoxy res ins were commercially DGEBA epoxy resins with an average MW as high as
available (Lee and Neville 1967). The first cases of 8000 Da are available (Guin and Work 1995). When
epoxy dermatitis were observed in the 1950S, shortly DGEBA epoxy res ins are prepared, apart from DGEBA
after epoxy resins were introduced (CaInan 1958; and higher oligomers, side reactions result in the
Jolanki 1991). formation of low levels of impurities that both
decrease the epoxide content from the theoretical
amount of two per molecule and affect the resin
Epoxy Compounds properties, both before and after curing. DGEBA epoxy
resins with a low average MW of 350-400 Da are
liquids with a relatively high viscosity, and they
Chemistry and Properties contain monomeric DGEBA up to more than 90%.
Resins with an average MW of over than 900 Da are
Epoxy resins are normally used in what is called an solids (Muskopf and McCollister 1987), but may
epoxy-resin system. This system consists of the epoxy contain even more than 15% DGEBA (Henriks-Ecker-
resin and a hardener, and reactive diluent or other man and Laijoki 1986b).
additives, such as fillers, modifiers, pigments and DGEBA epoxy resins are relatively expensive, but
reinforcements. they have a unique combination of properties, such as
easy cure, low shrinkage, high adhesive strength, high
Epoxy Resins electrical insulation, good chemical and mechanical
resistance, and versatility. Non-DGEBA epoxy res ins
Epoxy resins contain at least two cyclic three-mem- possess special properties that have made them
bered-ring structures containing oxygen, called epoxy competitive with less expensive DGEBA resins for
groups, oxirane or epoxide groups, in their molecules. certain applications. A list of chemical names and
The term "epoxy res in" may refer to the resins in both CAS numbers of available epoxy resins is given in
the uncured thermoplastic and cured thermoset state Table 1. The chemical structures of some dermatolog-
(Lee and Neville 1967). The uncured resins can be cross ically interesting non-DGEBA epoxy res ins are pre-
linked through the use of a variety of curing agents or sented in Fig. 2. The resin or mixture of resins chosen
hardeners to form cured plastics with insoluble three- for a particular application depends on the desired
dimensional structures. balance of properties. For example, brominated epoxy
Epoxy res ins are generally prepared by the coupling res ins are semisolids and resistant to ignition, and
of epichlorohydrin [CAS 106-89-8] with compounds epoxy novolacs exhibit better high-temperature per-
that possess at least two reactive hydrogen atoms formance and chemical resistance than DGEBA epoxy
(Muskopf and McCollister 1987). The reaction prod- resins. Triglycidyl isocyanurate (TGIC) is one of the
ucts of epichlorohydrin and bisphenol A [CAS 80-05-7] non-DGEBA epoxy resins (Table 1), but is mainly
resulted in the first commercial epoxy resins, which used in thermo setting one-component powder poly-
are generally mixtures of monomeric diglycidyl ether ester paints as a harden er (Muskopf and McCollister
of bis phenol A (DGEBA), with a molecular weight 1987).

Epoxy Resins 571
bisphenolA epichlorohydrin
o
/~
CH2-CH-CH2
~0 - Q- - C -<;:HI- Q -- c r - C H2-CH-CH
I
OH
JH
2
3
3
t n
0-
DGEBA epoxy resin
Fig. 1. Diglycidyl ether ofbisphenol A (DGEBA) epoxy res in When epoxy resins are used in two-component
products, the hardeners are added to the resins
Readive Oiluents immediately before the application, and the subse-
quent cross linking occurs at either an ambient or an
Reactive diluents are used principally to reduce the elevated temperature. Aliphatic and cycloaliphatic
viscosity of the resin. The reactive diluents are polyamines are low-viscosity liquids which react
generally glycidyl ethers and sometimes glycidyl esters; readily with epoxy resins at ambient temperatures;
structurally, they are aliphatic or aromatic, and they less reactive aromatic polyamines require an elevated
also contain epoxy groups in their molecules. Reactive curing temperature (Muskopf and McCollister 1987).
diluents participate in the curing process by the epoxy 3-Dimethylaminopropylamine (DMAPA) is an alipha-
groups and become chemically linked to cured epoxy tic alkyl polyamine harden er (Fig. 4), but it is better
res ins (Bolger 1983; Muskopf and McColiister 1987). A known as an impurity of cocamidopropyl betaines
list of chemical names and CAS numbers of represen- used in cosmetics (Angelini et al. 1995). Polyamines are
tative examples of available reactive diluents is given in often troublesome to work with because of their
Table 2. The chemical structures of some compounds reactivity and volatility, and also because of their
are also shown in Fig. 3. Reactive diluents based on irritating and sensitising properties to the skin and
diols, such as 1kbutanediol diglycidyl ether (BDDGE) respiratory tract. To overcome these problems, less
and 1,6-hexanediol diglycidyl ether (HDDGE), may volatile, less reactive, and less irritating and sensitising
also be used as low MW epoxy resins (Muskopf polyamides and amine-epoxy adducts have been
McColiister 1987). It has been estimated that more than developed. Polyamides are prepared by combining
half of the epoxy-resin products studied contained aliphatic polyamines, e.g. diethylenetriamine (DETA)
varying (0.1-20%) amounts of reactive diluents (Hen- or triethylenetetramine (TETA), with fatty acids.
riks-Eckerman and Laijoki 1986b; Jolanki et al. 1987a). Amine-epoxy adducts are formed in areaction be-
tween epoxy resin and an excess of polyamine, mostly
Hardeners DETA, TE TA or isophoronediamine (IPDA) (Bauer
1985). The content of free amine is about 5% in the
A wide variety of curing agents is currently available. amine-epoxy adduct hardeners used in metal paints,
Tables 3-6 list representative examples of available but for those used in floor and concrete coatings the
curing agents with their CAS numbers. The chemical corresponding figure is about 20% (Bäck and Saarinen
structures of some amine hardeners are also presented 1986). Free DGEBA is not found in amine-epoxy
in Fig. 4. adducts (Henriks-Eckerman and Laijoki 1986b).
Table 1. Epoxy res ins (Muskopf and McCollister 1987; Guin and cal industry when good electrical properties are
Work 1995)
required. Other examples of one-component epoxy
Diglycidyl ether of bisphenol A based epoxy res ins
products are powder epoxy or epoxy-polyester paints,
Diglycidyl ether ofbisphenol A (DGEBA) [CAS 1675-54-3] polyester paints (Peltonen 1986), one-pack glues
Brominated bis phenol A based epoxy resins (Dahlquist et al. 1979a) and prepreg-Iaminates (Math-
Diglycidyl ether of tetrabromo bisphenol A [68928-70-1,
26265-08-7, 40039-93-8]
ias 1987). With the anhydrides, the cross-linking
Phenol and cresol epoxy novolacs re action is achieved using tertiary amines (Table 6)
Cresol epoxy novolacs [37382-79-9] as catalysts and an elevated curing temperature (50-
Diglycidyl ether of bisphenol F [54208-63-8]
2,2',2",2"'-[ 1,2-ethanediylidenetetrabis( 4,
200°C). The anhydrides used as epoxy hardeners
I-phenyleneoxymethylene) ]tetrabisoxiran [7328-97-4] include, for example, phthalic anhydride (PA) and PA
Phenol epoxy novolacs [9003-36-5] derivatives (Muskopf and McCollister 1987; Jolanki
Resorcinol diglycidyl ether [101-90-6]
Trisphenol novolac epoxy resin [66072-38-6]
et al. 1997b). The typicallatent curing agents in powder
Glycidyl ethers of phenol-aldehyde adducts epoxy paints are composed of about 4% hardeners,
1,1 ,2,2-tetrakis [4- [(2,3-epoxypropyl)phenyl] ethane such as dicyandiamide or pyromellitic anhydride.
[27043-37-4]
Tris[ 4-(2,3-epoxypropoxy)phenyl] methane [66072-39-7]
Triglycidyl iso cyan urate is used to cure powder
Glycidyl ethers of phenol-hydrocarbon novolacs polyester paints. The polymerisation of the powder
2,5-bis [(2,3 -epoxypropoxy )phenyl] octahydro-4, 7-methano- paints occurs in a curing oven at about 200°C
5H-indene [13446-85-0]
Glycidyl ethers of aliphatic diols
(Peltonen 1986). Blocked isocyanates are latent curing
Ethylene glycol diglycidyl ether[2224-15-9] agents used in water-borne coatings (Muskopf and
Diglycidyl and triglycidyl ether of glycerol McCollister 1987). Polysulfides and hexavalent chro-
Diglycidyl ether of polypropyleneglycol [16096-30-3]
Diglycidyl ether of hydrogenated bisphenol A [30583-72-3]
mate are constituents found especially in the curing
Sorbitol polyglycidyl ether [68412-01-1] agents of epoxy sealants used in the aircraft industry
Aromatic glycidyl amines (Handley and Burrows 1994; Bruze et al. 1996).
4-glycidyloxy-N,N-diglycidylaniline
N,N' -tetraglycidyl-4,4' -methylenedianiline (TGMDA)
Polyamine and organic acid anhydride hardeners
[28768-32-3] serve as co-reactive hardeners, which become incor-
Triglycidyl-p-aminophenol (TGPAP) [5026-74-7] porated into the epoxy res in, whereas tertiary amines,
Heterocyclic glycidyl imides
1,3-bis(2,3-epoxypropyl)-5,5-dimethylhydantoin; dimethyl
such as 2,4,6-tris-(dimethylaminomethyl)phenol (tris-
hydantoin epoxy resin [15336-81-9] DMP) and N,N-dimethylbenzylamine, imidazoles,
3-(2-glycidyloxypropyl) -1-glycidyl-5,5 -dimetylhydan toin and boron trihalide amine complexes are catalyst-
[32568-89-1]
Triglycidyl isocyanurate (TGIC) [2451-62-9]
type curing agents, which may not be chemically bound
Glycidyl esters to the resin molecules during epoxy curing reactions
Diglycidyl ester of hexahydrophthalic acid [5493-45-8] (Guin and Work 1995; Muskopf and McCollister 1987).
Diglycidyl ester of phthalic acid [7195-45-1]
Glycidyl ester of dimerized linoleic acid and epiclorohydrin
Fluorinated epoxy res ins Epoxy Di(meth)acrylates
Epoxidized cycloaliphatic olefins
3',4' -epoxycyclohexylmethyl-3,4-epoxycyclohexanecarboxy-
late (cycloaliphatic epoxy resin) [2386-87-0]
Epoxy di(meth)acrylates (also called vinyl esters) are
4-epoxyethyl-l,2-epoxycyclohexane (vinyl cyclohexene another name for the ß-hydroxyester acrylates, be-
diepoxide) [25550-49-6] cause they are usually obtained by reacting epoxy
resins of glycidyl derivatives with (meth)acrylic acid.
They can also be manufactured from bisphenol A and
When DGEBA epoxy resins are cured by polyamine- glycidyl (meth)acrylates. Although prepared from
bearing hardeners at room temperature, the amounts compounds containing reactive epoxy groups, com-
of unreacted DGEBA and polyamine diminish rapidly pleted epoxy di(meth)acrylate molecules do not con-
within 1-2 days, but thereafter the decrease is slow. tain these groups. Both aromatic and aliphatic epoxy
Nevertheless, after 1 week's cure, 0.02-12% of free di(meth)acrylates are available, as well as acrylated
DGEBA and 0.01-1% of free DETA were found when epoxydised oils (Jolanki 1991; Jolanki et al. 1995).
six different epoxy resin products were experimentally The first epoxy dimethacrylate, known as bis-GMA
cured by DETA (Henriks-Eckerman and Laijoki (2,2-bis(4-(2-hydroXY-3-methacryloxypropoxy)phenyl)-
1986a). The use of an elevated curing temperature is propane) [CAS 1565-94-2] (Fig. 6), was developed
more effective in reducing the DGEBA concentration by Bowen in 1956. bis-GMA is manufactured from
than simply waiting until the next day (Hansson 1994). DGEBA and methacrylic acid or bisphenol A and
One-component products contain curing agents glycidyl methacrylate (Bowen 1962; Jolanki et al. 1995).
which are inactive at storage temperatures, but which Analyses have shown that epoxy di(methacrylate)
initiate a curing process when heated. Typical latent products may contain DGEBA as an impurity (Kanerva
curing agents include organic acid anhydrides et al. 1989; Henriks-Eckerman and Kanerva 1997). bis-
(Table 4, Fig. 5), which are used mainly in the electri- GA (2,2-bis[ 4-(2-hydroXY-3-acryloxypropoxy)phenyl]-
Epoxy Resins 573
/'" o
CHz-CH-CHz-O -o-'~
\ /;
JH
I
yH3
CHz-CH-CHz-O-
C~
3
v
OH
Br OH yH3
CHz-CH-CHz-O I -0-'-0
\ /; C \ /;
Br
lH 3
diglycidyl ether of bisphenol A / diglycidyl ether of tetrabromo bisphenol A
~--------CHZ~~r--H-
phenol epoxy novoJacs
o H3C \,H3 k Ü 0
/ '" 11
H2C-CH--CH2-NyN-CHz-CH-CHz / '"
Ü
dimethyl hydantoin epoxy resin diglycidyl ester ofhexahydrophthalic acid
C~27H--CH"N/tN/CH2-C~--;9H2
o I I 0
~C"N/~
0 0
1
CHz--C~~Hz
o
triglycidyl isocyanurate (TGIC)
Fig. 2. Non-diglycidyl ether of bisphenol A (DGEBA) epoxy light or even visible light, but also chemically activated
resins by the use of various peroxides and tertiary amines.
Chemically cured dental restorative composite material
propane) is an example of epoxy diacrylates based on is usually available in two bis-GMA-based components.
bis phenol A (Fig. 6). The tooth-coloured base paste contains a tertiary
Epoxy di(meth)acrylates can be polymerised not amine (1-2%), and the catalyst paste contains diben-
only by exposure to an electron beam, ultraviolet (UV) zoyl peroxide (1-1.5%). The light-cured composite
Table 2. Reactive diluents (Muskopf and McCollister 1987; abrasion, and to form tough, high-strength adhesive
Angelini et al. 1996; Jolanki 1996) bonds on metal and many other surfaces (plastics,
Aliphatic glycidyl ethers
rubber, wood, glass and ceramies). Epoxy resins are
Allyl glycidyl ether (AGE) [106-92-3] also used to insulate or encapsulate and they are used
1,4-butanediol diglycidyl ether (BDDGE) [2425-79-8] in the assembly of a wide variety of electrical and
n-butyl glycidyl ether (n-BGE) [2426-08-6]
t-butyl glycidyl ether (t-BGE) [7665-72-7]
electronic devices, in the manufacture of glass fibres as
Diethyleneglycol diglycidyl ether (DEGDGE) sizing agents (Toffoletto et al. 1994; Heino et al. 1996)
Diglycidyl ether of pentaerythritol and in the manufacture of sporting goods or other
2-ethyl hexyl glycidyl ether plastic items. They can also be used as injection res ins
Glycidyl ether of aliphatic alcohols (epoxide 8) [68609-97-2]
Glycidyl ether of polypropyleneglycol [9072-62-2] to repair cracks in concrete, and in flooring materials
1,6-hexanediol diglycidyl ether (HDDGE) [16096-31-4] (Conde-Salazar et al. 1994) and stone work (Angelini
Neopentyl glycol diglycidyl ether (NPGDGE) [17557-23-2]
Cycloaliphatic glycidyl ethers
et al. 1996). Powder paints (Peltonen 1986), microsco-
Cyclohexanedimethanol diglycidyl ether py immersion oils (Sommer et al. 1997; Le Coz et al.
Aromatic glycidyl ethers 1998) and even nail polishes (Jolanki et al. 1996a) may
tert-Butylphenyl glycidyl ether [3101-60-8]
Cresyl glycidyl ether (CGE) [26447-14-3]
contain epoxy-resin compounds. For special applica-
p-Fluorphenyl glycidyl ether tions, epoxy resins are used as lamination res ins and in
Alpha-naphthyl glycidyl ether prepreg laminates (Tarvainen et al. 1995a). üf the
Phenyl glycidyl ether (PGE) [122-60-1]
Glycidyl esters
substances classified as sensitising by skin contact,
Castor oil glycidyl ether [74398-71-3] epoxy resin is one of the most commonly used in
Glycidyl ester of neodecanoic acids (Cardura E 10) [26761-45-5] chemie al products (Flyvholm 1991).
Glycidyl methacrylate [106-91-2]
Glycidyl neodecanoate [26761-45-5]
Most epoxy surface coatings are based on DGEBA
epoxy resins, but epoxy novolac resins have also been
used increasingly. Liquid epoxy resins are used in two-
component solvent-Iess coatings. Waterborne epoxy
material consists of only one component (Anders on
coatings are prepared by the dispersion of epoxy res ins
and Messick 1985; Janda 1987).
modified with water-soluble functional groups or by
Epoxy di(meth)acrylates have the desirable proper-
the emulsification of DGEBA epoxy resins with
ties of both epoxy res ins and poly(meth)acrylates, for
surfactants. Both solvent-Iess and solvent-borne epoxy
example, relatively low volumetrie shrinkage during
coatings have been employed mainly as anticorrosion
the curing process, as in epoxy resins, and an adequate
protection for metals (marine and maintenance co at-
polymerization rate (2-5 min at 37°C), as in methacry-
ings), as waterproof protection for concrete, and as
lates of low MW (Vanherle and Smith 1985; Janda
chemical-resistant protection for floors and walls
1987). (Bauer 1985; Muskopf and McCollister 1987). Two-
component coatings can be cured at ambient temper-
Other Epoxy Compounds atures with polyamines, polyamides and amine-epoxy
adducts. Tertiary amines, e.g. tris-DMP, are frequently
Apart from epoxy res ins, reactive diluents and epi- used to accelerate the curing rates (Lee and Neville
chlorohydrin, other compounds containing at least one 1967).
epoxy group in their moleeules are also potential Epoxy adhesives range from those used as two-
causes of contact allergy. Examples of these epoxy package, ambient-cure, general adhesives in domestic
compounds include glycidyl methacrylate (Matura applications to high-performance one-component
et al. 1995; Fig. 6), epoxy propane [CAS 75-56-9] sheet adhesives for aircraft assembly (Gardiner et al.
(Steinkraus and Hausen 1994; Morris et al. 1998), 2,3- 1992). Araldite is a well-known, old trademark of Ciba
epoxypropyl trimethyl ammonium chloride (EPTMAC) Geigy for consumer epoxy adhesives. Liquid DGEBA
[CAS 3033-77-0] (Estlander et al. 1997) and trans-3- epoxy resins are used in most of the one- and two-
(4-methoxyphenyl)glycidate (Buisson et al. 1991). component epoxy adhesives. The curing agent gen er-
ally consists of polyamides or aliphatic polyamines,
Use e.g. DETA and TETA. Epoxy adhesives can be formu-
lated with reactive diluents to give mixtures a low
Epoxy-Resin Compounds viscosity with improved wetting, spreading and pen-
etrating action (Savla 1977).
The scope of epoxy-resin application is broad. Epoxy In the manufacture of epoxy composite products, for
resins are used mostly in two-component paints and example by lamination, glass fibres, woven cloth, and
other protective coatings, and two-component adhe- roving and chopped mat are impregnated with an
sives. Epoxy resins are used to provide good resistance epoxy resin/curing agent matrix. Glass fibres usually
against water, most chemieals, corrosion, heat and form composites with a DGEBA epoxy resin/diamine
Epoxy Resins 575
Fig. 3. Reactive diluents

/0",
CH2-CH-CH2 -0-CH2-CH CH2
allyl glycidyl ether (AGE)
/0", /0",
CH2-CH -CH2-o-(CH2)4-o-CH2-----cH-CH2
l,4-butanediol diglycidyl ether (BDDGE)
/0",
CH2-CH-CH2-0-CH2-CH2-CH2-CH3
n-butyl glycidyl ether (n-BGE)
/0", r 1 /0",
CH2- CH-CH2-o-rCH2-CH2-Oj;CH2-CH-CH2
diethyleneglycol diglycidyl ether (DEGDGE)
/0",
CH2-CH -CH2-O-R
glycidyl ether of aliphatic alcohols (Epoxide 8) (R is predorninantly a C12 or C14 alkyl chain)
/0", /0",
CH2-CH -CH 2-o-(CH2)6-o-CH2--CH-CH2
1,6-hexanediol diglycidyl ether (HDDGE)
/'"
° I /'"
CH3 °
CH2-CH -CH2-o-CH2-C-CH2-o-CH2--CH-CH2
I
CH3
neopentyl glycol diglycidyl ether (NPGDGE)
°
/"-
CH2-CH-CH2 - 0
--b \
o-cresyl glycidyl ether (CGE)

3-
/;
phenyl glycidyl ether (PGE)
glycidyl ester ofneodecanoic acids (Cardura E 10) (R I, R2 and R3 are aikanes)
matrix. Epoxy composites are used in the manufacture tions in articles such as electronic circuit boards
of pipes and vessels; in sporting goods, such as tennis (Fregert 1981b; Kowalska 1982; Burrows et al. 1984;
racquets, skis, ski poles and fishing rods; in automo- Muskopf and McCollister 1987; Tarvainen et al. 1995b).
tive, boat-building and aircraft industries; in military Casting resins are liquid and solvent-Iess mixtures of
and aerospace applications; and in electrical applica- low-MW epoxy res in, a curing agent, and additives, e.g.
Table 3. Polyamine hardeners (Muskopf and McCollister 1987; Table 5. Miscellaneous curing agents (Muskopf and McCollister
Guin and Work 1995; Kanerva et al. 1996a) 1987; Guin and Work 1995; Kanerva et al. 1996a)
Aliphatic polyamines N-Aminoethylpiperazine [140-31-8]

N'-(3-aminopropyl)-N,N-dimethyl-l ,3-propanediamine Cyanoethyl modified aliphatic amine
[10563-29-8] 2,4-Diamino-6-(2' -alkylimidazol-l-yl)ethyl-s-triazine
Diethylenetriamine (DETA) [111-40-0] Dicyandiamide [461-58-5]
Diethylamino propylamine (DEAPA) [104-78-9] Di- and polyisocyanates
3-dimethylaminopropylamine (DMAPA) [109-55-7] Diethylene glycol diaminopropyl ether
Dipropylene triamine (DPTA) [56-18-8] Hexavalent chromate
Ethylene diamine (EDA) [107-15-3] Melamineformaldehyde res ins [9003-08-1]
p-Menthane-l,8-diamine [80-52-4] Phenolformaldehyde resins [9003-35-4]
Poly( oxypropylene diamine ) [9046-10-0] Polycarboxylic acid polyesters
Poly( oxypropylene-triamine) [39423-51-3] Ureaformaldehyde resins [9011-05-6]
Tetraethylene pentamine (TEPA) [112-57-2]
Triethylenetetramine (TETA) [112-24-3]
2,2,4-Trimethylhexamethylene 1,6-diamine [3236-53-1]
2,4,4-Trimethylhexamethylene 1,6-diamine [3236-53-2]
Cycloaliphatic polyamines Table 6. Catalyst -curing agents (Guin and Work 1995; Kanerva
1,2-Cyclohexanediamin [694-83-7] et al. 1996a)
3-Cyclohexylaminopropylamine [3312-60-5]
1,4-Diaminocyclohexane [3114-70-3] Aliphatic thioester
Isophoronediamine (IPDA) [2855-13-2] Boron trichloride-amine complex
2,2'-Dimethyl-4,4' -methylenebis( cyclohexylamine) [6864-37-5] Boron trifluoride-benzylamine complex [696-99-1]
Aromatic polyamines Boron trifluoride:monomethylamine
4,4'-Diaminodiphenylmethane (DDM) [101-77-9] l-Cyanoethyl-2-(alkyl or phenyl)imidazoles
4,4' -Diaminodiphenyl sulfone (DDS) [80-08-0] l-Cyanoethyl-2-(alkyl or phenyl)imidazole-trimellitates
Diethyltoluenediamine [75389-89-8] l-Cyanoethyl-2-phenyl-4,5-di (cyanoethoxymethyl )imidazole
m-Phenylenediamine (MPDA) [108-45-2] Dimethylaminomethylphenol [25338-55-0]
0- Tolyl biguanide [93-69-6] 2,4,6-Tris-(dimethylaminomethyl)phenol (tris-DMP)
m-Xylene diamine [1477-55-0] [CAS 90-72-2]
Polyamide diamines Tris( dimethylaminomethyl) phenol-tri (2-ethylhexoate)
Polymerie amido-amine alkoxylated trietylene tetramine N,N- Dimethylbenzylamine [CAS-l 03-83-3]
Adducts of aliphatic amines with mono- and diepoxides and Imidazolinealkyl imidazoles
ketones (i.e. amine-epoxy adducts) Ketimine [P-83-0735]
Diethylenetriamine-ethylene oxide adduct 2-(Methyl or phenyl)imidazole-isocyanuric acid adduct
Ethylene diamine adduct to solid epoxy 4,4'-Methylene- bise 2-ethyl-5-methylimidazole)
Triethylenetetramine-propylene oxide adduct Morpholine salt of p-toluenesulfonic acid
2-Phenylimidazole [670-96-2]
Thioether
Trifunctional mercaptan terminated polymer
Table 4. Organic acid anhydride hardeners (Guin and Work

1995; Jolanki et al. 1997b)
Chlorendie anhydride [115-27-5] durability particularly to changes in weather, e.g. in

cis-Cyclohexane-l,2-dicarboxylic anhydride [13149-00-3] outdoor electrical insulators (Muskopf and McCollister
Dodecenylsuccinic anhydride (DDS) [25377-73-5] 1987; Jolanki et al. 1989).
Hexahydrophthalic anhydride (HHPA) [85-42-7]
Maleie anhydride (MA) [108-31-6] Epoxy moulding compounds are solid mixtures of
Methyl endo-methylene-tetrahydrophthalic anhydride epoxy res in (epoxy novolac), a curing agent and
Methylhexahydrophthalic anhydride (MHHPA) [19438-60-9] catalyst, mould-release compounds, fillers and other
Methyl nadic anhydride [25134-21-8]
Methyltetrahydrophthalic anhydride (MTHPA) [26590-20-5]
additives. The moulding compounds become liquid at
Phthalic anhydride (PA) [85-44-9] relatively low temperatures (150-200 0c) (Adams
Polyazelaic polyanhydride 1983; Muskopf and McCollister 1987). Epoxy mould-
Polysebacic polyanhydride [26776-29-4]
Pyromellitic dianhydride (PMDA) [89-32-7]
ing compounds are used, for example, in the
Succinic anhydride [108-30-5] manufacture of models and engine covers and in
Tetrahydrophthalic anhydride (THPA) [85-43-8] the encapsulation of electrical components (Fregert
Trimellitic anhydride (TMA) [552-30-7]
1981b).
Epoxy res ins were introduced in 1956 in the
preparation of sampies for electron microscopy
fillers, reinforcements and catalysts. The mixture is (Göransson 1977; Jolanki et al. 1988) and they are still
poured into moulds and cured to solid structures. The widely used. Three types of epoxy resin are used: the
casting resins are used mainly as electrical insulating DGEBA epoxy resins, the diglycidyl and triglycidyl
material in the manufacture of transformers, switching ethers of diols and polyols, and vinyl cyclohexene
gear, circuit breakers, conductors and insulators. diepoxide res in. The epoxy resins are generally
Anhydride-cured cycloaliphatic epoxy res ins are com- hardened by anhydrides (dodecenyl succinic an-
monly used to improve arc-track resistance and hydride), using amines (tris-DMP) as accelerators
Epoxy Resins 577
HzN- CHz-CHz- NHz

ethylene diamine (EDA)
H2N-CH2-CH2-NH -CH2-CH2-NH2
diethylenetriamine (DETA)
triethylenetetramine (TETA)
tetraethylenepentamine (TEPA)
CH3 CH3
I I
HzN -CHz-C-CH2-CH-CHz-CH2 - NHz
I
CH3
2,2,4-trimethyl hexamethylene diamine (2,2,4-TMD)
CH3
I
HzN -CHz-CH-CHz-C-CHz-CHz- NHz
I I
CH3 CH3
2,2,4-trimethyl hexamethylene diamine (2,2,4-TMD)
H3C
yy NHz
H3 C Y HZN-o-CH2 ( }--NHz
H 3C CHz-NHz
&NH'
isophorone diamine (IPDA) 4,4' -diaminodiphenyl methane
H3C~ <CH3
/N-CH~CHZ-
H3C CH3
CHz-NH z
OH
m-xylylene diamine
CHz
/ CH 3
H2N-CH2-CH2-CH2-CH2-N
I
N
"-
CH3 /~
H3C CH3
3-dimethylaminopropylamine (DMAP A)
2,4,6-tris-( dimethylammomethyl)phenol (tris-DMP
Fig. 4. Polyamine hardeners and catalyst -curing agents also when fissures in posterior teeth are sealed to
protect them from caries (Vanherle and Smith 1985;
(Göransson 1977; Dannaker 1988; Jolanki et al. 1988; Janda 1987). Several similar epoxy dimethacrylate
Glauert 1991). compounds have also appeared as substitutes for bis-
GMA or in addition to bis-GMA in dental resins.
Epoxy (Meth)acrylates Epoxy di(meth)acrylates also have many industrial
applications. They are used in UV -curable printing
bis-GMA is used in dental restoration work, in dental processes (Emmett and Kominsky 1977; Björkner 1984;
filling and coating materials, in dentin primers, and Gossens et al. 1998), in corrosion-resistant equipment,
Fig. 5. Organic acid an-
~o
hydride hardeners
~o
cqo
phthalic anhydride (PA) methylhexahydrophthalic anhydride (MHHP A)
HO
o o
trimellitic anhydride (TMA) tetrahydrophthalic anhydride (THP A)
maleie anhydride (MA) methyltetrahydrophthalic anhydride (MTHP A)
oYo
~ o 0
cqo
pyromellitic dianhydride (PMDA) succinic anhydride
o
hexahydrophthalic anhydride (HHPA) dodecenylsuccinic anhydride (DDS)
body and structural parts for land transportation Other Epoxy Compounds
equipment, electrical insulation for heavy electrical
equipment and in marine applications. In the manu- EPTMAC is used, for example, in the manufacture of
facture of composite plastic products, the epoxy cationic starch as a cationising chemieal, in the
di(meth)acrylates are used after being dissolved in manufacture of ion-exchange res ins and in many other
styrene (Anders on and Messick 1985; Janda 1987). applications (Bergquist-Karlsson 1985; Estlander et al.
Solventless epoxy acrylate coatings are cured by 1997). Other epoxy compounds are used, for example,
initiation with UV light (Bauer 1985). Glycidyl meth- in drug syntheses (Rudzki and Rebandel1990; Buisson
acrylate, which contains an epoxy group in its mole- et al. 1991) or they can be found among the oxidation
cules (Fig. 6), is used in emulsions for impregnating products of abietic and related acids (Hausen et al.
paper and textile materials (Matura et al. 1995). 1990).
Epoxy Resins 579
2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]-propane (BIS-GMA)
2,2-bis[4-(2-methacryloxyethoxy)phenyl]-propane (BIS-EMA)
C~ ?~ ~~
H2C=~-C-o-~ j C~-C -C=CH2
A J~ ~
2,2-bis[ 4-(methacryloxy)phenyl]-propane (BIS-MA)
f~
H2C=C-C-O-(CH2)30-o-C-o-0(CH2)3-0-C -C=CH2
- ?~ - f~
A J~ ~
2,2-bis [4-(3-methacryloxypropoxy)phenyl]-propane (BIS- P MA)
/; C
I
o-?-o-H3
HzC=CH-C-OCH2CHCH20 - \ \
H
/;
H
OCH2CHCH20-C -CH
I CH2
A JH 3 ~
2,2-bis[ 4-(2-hydrox y-3 -acry loxypropoxy )pheny l]-propane (BIS-GA)
/0", ~
CH2-CH-CH2- O - C - C - CHZ
I
CH3
glycidyl methacrylate
Fig. 6. Methacrylated epoxy compounds

Epoxy Dermatitis system to exhibit a positive response to DGEBA epoxy

resin. Even higher risks of eontaet allergy from
exposure to epoxy res in compounds are found for
Delayed Allergie Epoxy Dermatitis
individual groups of workers eonstantly exposed to
epoxy resin compounds, e.g. 56% in aireraft manufae-
Epoxy-Resin Compounds
turing workers (Burrows et al. 1984), 45% in marble
workers (Angelini et al. 1996), 27% in ski-faetory
The first reports of sensitisation to epoxy eompounds
workers (Jolanki et al. 1996b), and 21% in paint-
were published in the 1950S in Switzerland, the
faetory workers (Omer and AI-Tawil1994).
Netherlands, the United States and Great Britain,
Epoxy-resin eompounds have been found to be
where most of the epoxy-resin development had taken
allergens, espeeially in painting and paint proeessing,
plaee (Cainan 1958; Jolanki 1991). eleetrieal insulation, gluing and the manufaeture of
In Finland, the most eommon eauses of allergie
epoxy objeets. In addition to the amount of epoxy-
eontaet dermatitis in 1990-1995 were rubber ehernieals
res in eompounds used, other important aspeets for the
(26.2%), plastie ehernieals (20.2%) and metals (15.6%)
development of dermatitis from epoxy-resin com-
(Jolanki 1997). Plastie ehernieals have been eommon pounds include the frequeney of skin eontaets with
eauses of allergie eontaet dermatitis in Finland sinee
the eausative agent, the eoneentration of the epoxy
the 1960s and 1970S. At first, most of the eases were due eompound used, the size of the contaminated skin area
to formaldehyde-based resins, sueh as phenol-formal-
and possibilities to use proteetive gloves (Jolanki 1991).
dehyde resins. However, by the beginning of the 1970S, In some instanees, the latent period before onset of
epoxy-resin eompounds began to eause inereasing
eontaet allergy to epoxy-resin eompounds may be
numbers of oeeupational dermatoses. During 1990- quite short, ranging from less than 1 month to several
1995, the epoxy-resin eompounds were clearly more years (Laehapelle et al. 1978; Dahlquist et al. 1979b;
frequent eauses than other plastie ehernieals. They Niinimäki and Hassi 1983; Suhonen 1983; Prens et al.
have indueed 11.7-12.5% of the eases of oeeupational 1986; Holness 1992; Angelini et al. 1996). Even a single
allergie contaet dermatitis (Jolanki 1991; Holness and
aeeidental exposure may induee primary sensitisation
Nethereott 1992), and roughly 1% of the exposed
to epoxy res in (Kanerva et al. 1994). Most of the
workers, annually, developed an oecupational der- patients eontraeting epoxy-eompound dermatosis are
matosis due to epoxy-resin eompounds (Jolanki 1991).
men (Fregert 1975; Wilkinson et al. 1980; Lynde et al.
The eomponent eausing sensitivity, while most often
1982; Jolanki 1991; Holness and Nethereott 1994;
the DGEBA epoxy res in, is probably determined more
Nethereott et al. 1994). The differenee in the frequeney
by the opportunity for exposure. The 22-year statisties of dermatosis between the two genders probably
on patients diagnosed in 1974-1995 at the Finnish represents differenees in exposure.
Institute of Oeeupational Health showed that most of Epoxy eompounds ean induee direet or airbome
the 182 patients who had oeeupational allergie eontaet contaet dermatitis, but the skin symptoms are located
dermatitis from epoxy-resin eompounds were sensi- mainly on the patients' hands or arms. The fingers and
tised to DGEBA epoxy res ins. DGEBA resin allergy was interdigital spaees, forearms and wrists, and the eyelids
found in about 80% of the eases. Contaet allergy from are the most typiealloeations of the skin dis orders due
non-bisphenol A type epoxy resins was found in about to epoxy eompounds (Jolanki et al. 1990). Reaetive
9% of the patients, eontaet allergy from polyamine diluents and hardeners have been eonsidered the most
hardeners in 23% and from reaetive diluents in 16%. Of
probable eauses of airbome epoxy-resin eompou~d
the 182 patients, 95 (52%) had an isolated eontaet dermatitis beeause the substanees are more volatlle
allergy to DGEBA epoxy resins, 16 (9%) to non-DGEBA than DGEBA epoxy resins (Dahlquist and Fregert
epoxy resins, 6 to hardeners and 6 to reaetive diluents.
1979). In another study, faeial dermatitis was found in
Six patients had allergie eontaet dermatitis from 60% of the patients, but it was not espeeially eommon
triglyeidyl isoeyanurate. Simultaneous eontaet allergy among patients allergie to reaetive diluents or hard-
to different epoxy-resin eompound groups was found eners (Jolanki et al. 1990).
for 29% of the patients (Jolanki 1997; Kanerva et al.
1998). In 1993, Tosti et al. reported 39 eases of Diglycidyl Ether of Bisphenol A (DGEBAJ Epoxy Resins
oeeupational allergie eontaet dermatitis to epoxy-resin
system substanees; of these 30 showed positive pateh- The highly alkaline amine hardeners were first eon-
test reaetions to the DGEBA epoxy resin, whereas 9 sidered to be responsible for most eases of dermatitis
showed isolated sensitisation to reaetive diluents or and sensitisation observed during the handling of
hardeners. eomponents of the epoxy system (Birmingham 1959;
Holness and Nethereott (1993) found 18% of patients Boume et al. 1959), but later, Thorgeirsson and Fregert
with a history of potential exposure to the epoxy-resin (1977) finally eonfirmed that the main sensitiser was
Epoxy Resins 581
DGEBA, with a MW of 340 Da. In the guinea-pig infusion sets of an insulin pump, nasal cannulae,
maximisation test, the oligomer with a MW of 624 Da pacemaker, and amputation prosthesis (Brandao and
was also a sensitiser, but it had minor sensitising Pinto 1980; Romaguera and Grimalt 1981; Mann et al.
capacity, whereas oligomers with a MW of more than 1983; Beck et al. 1985; Boom and van Driel 1985;
900 Da did not induce sensitivity (Thorgeirsson et al. O'Brien 1986; Requena et al. 1986; Geldof et al. 1989;
1978). Toome 1989; Ancona et al. 1990; Ng et al. 1998).
Until 1964, 1.6% of 1690 patients who were not Furthermore, numerous case reports present epoxy
employed in the epoxy-resin industry developed aller- sensitisation due to hidden sources of epoxy resin,
gic patch test reactions to DGEBA epoxy resin at the such as a one-pack epoxy glue (Dahlquist et al. 1979a),
Department of Dermatology, University of Lund oil painting (Conde-Salazar et al. 1982), lamination of
(Fregert and Rorsman 1964). Thus, the DGEBA epoxy glass products (HeskeI1988), adhesive pIaster (Dooms-
resin, because it is one of the top 20 contact allergens, Goossens et al. 1993), bowls polish (Lyon et al. 1998), a
was induded in the European standard patch-test billiard cue (Gon~alo et al. 1992), and microscopy
series in 1966 (Jolanki 1991). In the 1970S and 1980s, the immersion oils (Sommer et al. 1997; Le Coz et al.
North American Contact Dermatitis Group (NACDG) 1998). Solid, completely polymerised resins rarely
patch tested approximately 9000 patients for allergic cause dermatitis, but traces of unhardened monomeric
contact dermatitis and found that 2-3% were allergic to DGEBA epoxy res in have been identified on sign
the standard epoxy resin (Rudner 1977; Lynde et al. boards, bottle caps, film cassettes, metal packages and
1982; Storrs et al. 1989); in the beginning of the 1990S, brass doorknobs (Fregert 1981a). Tooling, e.g. sawing
the positive response was 1.8% among 3500 patients and drilling, of epoxy resin in cured state, especially,
studied (Marks et al. 1995). Edman (1988) found a prornotes the release of epoxy allergens (Hansson
lower frequency, namely 1%, among 3562 patients 1994). Allergic contact dermatitis has also been
patch tested during 1982-1987 at the Malmö General induced by unhardened epoxy res in in several finished
Hospital, Sweden. Similarly, in Denmark, 0.8% of products (Herzberg 1973; Adams 1983; Taylor et al.
10,423 patients (Veien et al. 1992) and, in China, 0.7% 1983; Fregert and Orsmark 1984; Malanin and Kalimo
of 1135 patients were found to be patch-test positive to 1985; Fischer et al. 1987; Goulden and Wikinson 1996).
epoxy resin (Liu et al. 1997). The results vary with the In addition, a few cases of allergic contact dermatitis
type of dinic. In general, in the patch-test series due to DGEBA epoxy res ins with a high average MW
performed, the frequency of positive responses to have been reported (Dahlquist et al. 1979b; Jolanki
epoxy resin range from 0.4% (Enders et al. 1989) to et al. 1987b; Suhonen 1983), even though the amount of
about 3%. The percentage positives from occupational DGEBA has been as low as 0.2% in the causative
dermatology dinics in Toronto and Helsinki were as products (Jolanki et al. 1987b). Epoxy resins used as
high as 3.?'Yo, corresponding to the selectivity of the stabilisers and plasticisers for polyvinyl chloride have
patients in the dinics (Jolanki 1991; Holness and also been shown to be sensitisers (Ancona-Alayon
Nethercott 1992). et al. 1976; Adams 1983; Toome 1989).
Paints, varnishes and other surface coatings as well as
exposure in the electronics industry are common causes Non-Diglycidyl Ether of Bisphenol A
of DGEBA epoxy-resin sensitisation (Jolanki 1991;
Ortiz-Frutos et al. 1993; Tosti et al. 1993). Epoxy sensi- Most of those who have contact allergy to epoxy resins
tisation is also often due to exposure to two-component have been sensitised to DGEBA epoxy resins (Adams
glues and bon ding agents (Conde-Salazar et al. 1993; 1983; Fregert 1987; Jolanki 1991). Since the 1980s,
Lodi et al. 1993; Jolanki et al. 1994b; Leow et al. 1995). allergic contact dermatitis has also been reported from
Several reports describe workers sensitised to epoxy non-DGEBA epoxy resins, such as N-N'-tetraglycidyl-
resins used as binders in carbon- or glass-fibre- 4,4' -methylene dianiline and ortho-diglycidyl phthalate
reinforced plastic products (Dahlquist et al. 1979b; (Burrows et al. 1984; Ayala et al. 1990; Tarvainen et al.
Suhonen 1983; Burrows et al. 1984; Conde-Salazar et al. 1995b), 4-glycidyloxy-N,N-diglycidylaniline (Burrows
1985; Mathias 1987; Bruze and Almgren 1989; Holness et al. 1984; Mathias 1987), vinyl cydohexene dioxide
and Nethercott 1989; Tarvainen et al. 1995b). Epoxy (Dannaker 1988) and a triglycidyl derivative of para-
resin used as a sizing agent in glass fibres has also aminophenol (Ayala et al. 1990; Tarvainen et al. 1995b;
induced contact allergy during the production (Toffo- Bruze et al. 1996). In addition, cydoaliphatic epoxy
letto et al. 1994; Heino et al. 1996) or the use of resins based on diglycidyl ester of hexahydrophthalic
composite products (Jolanki et al. 1992), as well as epoxy acid, heterocydic dimethyl hydantoin epoxy resins,
resin used in electron microscopy (Dannaker 1988). phenol novolac epoxy res ins, and brominated epoxy
Non-occupationally induced contact sensitivity has resins have been found to be causes of allergic contact
been reported from epoxy resin in medical devices, dermatitis (Jolanki et al. 1987b; Jolanki et al. 1989;
such as hemodialysis needles, polyvinyl ostomy bags, Kanerva et al. 1991b; Bruze et al. 1996; Erikstam and
Bruze 1998). Many of the patients sensitised to non- diaminodiphenyl methane (DDM), DETA and TETA
DGEBA epoxy resins do not have contact allergy to (Jolanki 1991; Tosti et al. 1992). In addition, cases of
DGEBA epoxy resin. contact allergy to IPDA (Lachapelle et al. 1978; Kanerva
TGIC is a known skin irritant (Nishioka et al. 1988), et al. 1991a; Guerra et al. 1992; Patussi et al. 1995, Rothe
but has also been shown to be an allergen. W orkers 1995; Kanerva et al. 1998; Tarvainen et al. 1998),
may become sensitised to TGIC from short-term trimethyl hexamethylene diamine (Kanerva et al.
exposure to the chemical during its production, in 1991a, 1998), tetraethylenepentamine (TEPA) (Kanerva
the manufacture and use of TGIC-containing powder et al. 1998), xylylene diamine (Richter and Kadner
polyester paints, and from silk-screen printing coat- 1990; Kanerva et al. 1991a, 1998), or other cyclohexyl-
ings in the manufacture of circuit boards (Nishioka amines (Gordon and McLelland 1998) have been
et al. 1988; Munro and Lawrence 1992; Jolanki et al. reported. Polyamides and amine-epoxy adducts in-
1994a; Wigger-Alberti et al. 1997). duced sensitisation probably only due to the polyamine
remnants (Thorgeirsson 1978b; Kanerva et al. 1991a).
Readive Oiluents Cross-reactivity between polyamine hardeners is pos-
sible (Rudzki and Krajewska 1976; Balato et al. 1986).
An investigation of Fregert and Rorsman emphasised, Isolated contact allergy to epoxy hardeners is
in 1964, the occurrence of contact allergy to reactive unusual, but possible (Tosti et al. 1992; Kanerva et al.
diluents in patients allergie to epoxy resins. Epoxy 1991a, 1996a). tris-DMP has been reported to be
reactive diluents have been revealed to be strong probably a more common allergen than expected
sensitisers in guinea pigs (Thorgeirsson 1978a) and, in (Kanerva et al. 1991a, 1996a; Brooke and Beck 1998).
humans, reactive diluents have been shown to be Allergie patch-test reactions to DDM or ethylene
common contact allergens among exposed patients diamine (EDA) are not necessarily an indication of
(Jolanki 1991; Tosti et al. 1992; Angelini et al. 1996). sensitivity from exposure to epoxy-resin hardeners.
Contact allergy to reactive diluents without contact The relevance of DDM allergy is sometimes difficult to
allergy to epoxy resins is also possible (Jolanki et al. detect. For example, a positive patch-test reaction to
1987a; Jolanki 1991; Nakagawa et al. 1991; Chieregato DDM may represent allergy to para-amino com-
et al. 1994; Angelini et al. 1996). These materials are pounds, e.g. para-phenylene diamine (Gailliofer and
more volatile than DGEBA epoxy res in, and may cause Ludvan 1989), or exposure to diphenyl methane
an airborne dermatitis pattern (Dahlquist and Fregert diisocyanate (Jolanki et al. 1990). EDA allergy may be
1979; Tosti et al. 1988; Angelini et al. 1996). Most due to exposure, for example, to rubber, synthetic
patients sensitised to reactive diluents are allergie to coolants or topical creams (Rietschel and Fowler 1995).
phenyl glycidyl ether (PGE), cresyl glycidyl ether, Another aliphatic amine harden er, DMAP A, is an
hexanediol diglycidyl ether, butanediol diglycidyl ether impurity responsible for cocamidopropylbetaine aller-
or butyl glycidyl ether, and cross-sensitisation between gy from cosmetics (Speight et al. 1993; Angelini et al.
reactive diluents is common (Jolanki et al. 1987a; 1995; Pigatto et al. 1995; Kanerva et al. 1996a).
Jolanki 1991, 1997; Tosti et al. 1992; Chieregato et al. A few reports of contact allergy to non-amine
1994; Conde-Salazar et al. 1994; Angelini et al. 1996). hardeners have been published in the case of dicy-
Rare reactive diluent contact allergens are allyl glycidyl andiamide (Senff et al. 1988), dodecenyl succinic
ether (Jolanki 1991; Angelini et al. 1996), cyclohexa- anhydride (Göransson 1977), methylliexahydrophthalic
nedimethanol glycidyl ether (Angelini et al. 1996), anhydride (Kanerva et al. 1997), hexavalent chromate,
neopentyl glycol diglycidyl ether (Jolanki 1991), Card- an accelerator additive (Handley and Burrows 1994;
ura ElO (Lovell et al. 1984), Epoxide 8 (Björkner et al. Bruze et al. 1996) and polysulfides (Bruze et al. 1996).
1980), diethyleneglycol diglycidyl ether (Jolanki et al.
1996b) and alpha-naphthyl glycidyl ether and p-fluor- Bisphenol A and Epichlorohydrin
phenyl glycidyl ether (De Groot 1994). Allyl glycidyl
ether has also caused allergie contact dermatitis in the Occupational contact dermatitis due to epichloro-
plastics industry from the use of epoxy silane in a hydrin and bisphenol A is uncommon (Jolanki 1991).
single-component sealant (Dooms-Goossens et al. In the finished DGEBA epoxy resin, the proportion of
1995). free epichlorohydrin is less than 0.001%. The propor-
tion of bisphenol A is even smaller because, in the
Hardeners manufacturing process, epichlorohydrin is always
present in excess to ensure that the moleeules terminate
In the guinea-pig maximisation test, polyamine hard- in epoxy groups. In epoxy-resin plants, despite closed
eners with a low MW were found to be strong manufacturing systems, workers may have a rather
sensitisers (Thorgeirsson 1978b). Most of the patients high risk of becoming sensitised to epichlorohydrin,
with contact allergy to epoxy hardeners react to 4,4'- but they do not generally become sensitised to bisphe-
Epoxy Resins 583
nol A (van Joost et al. 1990). Allergy to epichlorohydrin et al. 1998; Kanerva and Alanko 1998). It has been
has also been reported from a solvent cement (Beck and shown that bis-GMA-borne dental materials may
King 1983) and from drug synthesis of propranolol contain minute amounts of DGEBA, enough to induce
hydrochloride and oxprenolol hydro chloride (Reban- sensitisation (Niinimäki et al. 1983; Kanerva et al.
dei and Rudzki 1990). One patient with allergic contact 1989). Contact allergy to epoxy di(meth)acrylates has
dermatitis from exposure to epoxy propane reacted also been found in patients who had been exposed to
also to epichlorohydrin and to diglycidyl ester of DGEBA epoxy resins, but who had no known exposure
hexahydrophthalic acid (Morris et al. 1998). to the epoxy di(meth)acrylates (Jolanki et al. 1990;
Reports of bisphenol A sensitisation have been Kanerva et al. 1991C). Matura et al. reported in 1995 on
rather controversial (van Joost et al. 1990). Krajewska a chemist who had developed contact allergy to
and Rudzki (1976) described positive patch tests to glycidyl methacrylate from compounding emulsions
bisphenol A in 13 of 17 Polish workers sensitised to used to impregnate paper and textile materials to make
epoxy resin by patch testing bisphenol A at a concen- them oil- and water-resistant. The role of glycidyl
tration of 2% in aqua, but they did not mention how methacrylates in bis-GMA contact allergy is unknown.
the positive reactions were scored. Additional data on Patients with allergie contact dermatitis due to prod-
high incidence of bisphenol A allergy among those ucts containing epoxy dimethacrylate may also have
sensitised to epoxy resin are lacking. The group of van contact allergy to bis phenol A from handling products
Joost (Prens et al. 1986; van Joost 1988; van Joost et al. containing dental composite resin (Jolanki et al. 1995).
1990) found very few cases of bisphenol A allergy in
workers at epoxy-resin plants, although several pa- Other Epoxy Compounds
tients had been sensitised to epichlorohydrin. Cases of
allergy to bisphenol A have been reported from EPTMAC has been shown to be a moderate sensitiser
fibreglass made of epoxy resin (Gaul 1960), bis-GMA- in guinea pigs and to cause allergic contact dermatitis
based dental composite resins containing 0.014- in humans (Bergquist-Karlsson 1985; Estlander et al.
0.Q15% bisphenol A (Jolanki et al. 1995), semi-synthetic 1986; Estlander et al. 1997). An intermediate product
waxes (Freeman and Warin 1984) and plastie footwear in the synthesis of the drug, diltiazem hydrochloride,
(Srinivas et al. 1989). The contact allergy to bisphenol 2,3-epoXY-3-(4-methoxyphenyl)propionate, has in-
A may also be a cross re action with compounds duced contact allergy in two cases (Rudzki and
responsible for phenol-formaldehyde res in allergy, Rebandel 1990; Buisson et al. 1991). Another epoxy
such as dihydroxydiphenyl methanes (bisphenol F) compound, 13,14(ß)-epoxyabietic acid, is an isolated
(Bruze and Zimerson 1985; Jolanki 1991). allergen of unmodified colophony (Hausen et al. 1989;
Karlberg and Gäfvert 1996). Epoxy propane (propylene
Epoxy (Meth)ocrylotes oxide) used, for example, as a solvent in histology, has
also been shown to be a contact allergen (Sreinkraus
The guinea-pig maximisation test has shown that and Hausen 1994; Morris et al. 1998).
epoxy di(meth)acrylates are weak to extreme sen-
sitisers (Björkner 1984). Despite the increasing use of Contact Urticaria
epoxy di(meth)acrylates in dental care and in industry,
relatively few reports of contact allergy due to these Only a few cases of immediate-type contact urticaria
compounds have been published (Emmett and caused by epoxy-resin compounds have been reported.
Kominsky 1977; Nethercott 1981; Björkner 1984; In particular, epoxy res ins (Jolanki et al. 1997a) and
Kanerva et al. 1989; Jolanki et al. 1995; Goossens et al. organic acid anhydride hardeners (Jolanki et al. 1997b)
1998; Kanerva and Alanko 1998). The sensitised should be regarded as potential causes of the contact-
subjects have mainly been workers in the UV -light urticaria syndrome. In Finland during 1990-1994, five
printing industry (Emmett and Kominsky 1977; Neth- cases of contact urticaria from phthalic anydrides and
ercott 1981; Björkner 1984) or in dental nursing two from epoxy resins or epoxy paints were reported
(Kanerva et al. 1989). Also, work in the manufacture to the Finnish Register of Occupational Diseases
of UV -curable epoxy diacrylate paints (J olanki et al. (Kanerva et al. 1996b).
1995) and exposure to UV-curable coating varnish In 1974, a patch test with an epoxy resin was
containing epoxy acrylate oligomers (Guimaraens reported to induce generalised urticaria and an asth-
et al. 1994) can induce contact allergy. matic re action (Woyton et al. 1974). In 1983, Suhonen
Patients who acquire their epoxy dimethacrylate reported on two patients who, in a patch test, showed
allergy from products that contain bis-GMA as the immediate urticarial reactions, probably due to an
main monomer are, in general, concomitantly allergic impure DGEBA epoxy resin used in a ski-pole factory.
to both bis-GMA and the standard epoxy resin Kanerva et al. (1991C) described two patients with both
(Kanerva et al. 1989; Carmichael et al. 1997; Goossens immediate and delayed allergy to DGEBA epoxy res in.
In these patients, the specific immunoglobulin E (IgE)- drides are hydrated to the corresponding acids and can
media ted immediate sensitisation from DGEBA with a cause caustic dermatitis and bums (Menschnik 1955;
MW of 340 Da was revealed. Recently, Sasseville (1998) Malten and Zielhuis 1964). Four patients developed
reported on a patient who presented with contact irritant epoxy contact dermatitis from paints or paint
urticaria while working in an aircraft factory. On patch raw materials containing DGEBA epoxy res ins with a
testing, at the 30-min reading, he suffered urticarial high average MW, and one patient from a mixture of a
reactions to epoxy resin (1% pet), phenylglycidyl ether DGEBA epoxy resin with a low average MW and its
(0.25% pet) and cresylglycidyl ether (0.25% pet). No anhydride harden er, used in electrical insulation
delayed reactions were seen. Similarly, Miyamoto and (Jolanki et al. 1987b; Jolanki et al. 1990).
Okumura (1998) reported on contact urticaria con-
firmed by a 15-min open test and a 15-min closed patch Active Sensitisation
test for epoxy res in at 1% in petrolatum.
Menschick (1955) and Baader (1955) reported on Patch testing has occasionally produced sensitisation
urticarial reactions in workers in the manufacture of to patch-test allergens (active sensitisation). Active
phthalic anhydride. The other case reports describe sensitisation is especially common when acrylics are
patients who developed contact urticaria from met- tested (Kanerva et al. 1992), but it has also complicated
hylhexahydrophthalic anhydride or methyltetrahydro- testing with epoxy resin compounds (Fregert and
phthalic anhydride epoxy hardeners from the Rorsman 1964; Calnan 1967; Calnan 1975; Lachapelle
manufacture of condensers (Jolanki et al. 1987b; et al. 1978; Jolanki 1991; Kanerva and Estlander 1998).
Jolanki et al. 1990), electrical machines (Tarvainen At the Finnish Institute of Occupational Health, the
et al. 1995a; Kanerva et al. 1997), or ski poles (Tar- test concentration of epichlorohydrin was lowered
vainen et al. 1995a). Acid anhydrides have the ability to twice because of active sensitisation and tlIe frequent
induce specific IgE-mediated sensitisation (Jolanki irritant reactions; tlIe first time at the beginning of
et al. 1990; Tarvainen et al. 1995a; Kanerva et al. 1984, from 1% to 0.3% and, subsequently, in September
1997), resulting in contact urticaria, and respiratory 1985, from 0.3% to 0.1%. No active sensitisation and
and conjunctival allergy symptoms. only rarely irritant reactions (Kanerva et al. 1999) have
In addition, contact urticaria can be caused by been observed with epichlorohydrin at 0.1% in petrol-
aliphatic polyamine hardeners (Rietschel and Fowler atum. It has not been established whether false-
1995) and possibly by other amines (Savonius et al. negative tests occur. Recently, phenylglycidyl etlIer at
1994). 0.25% in petrolatum has also been reported to cause
active sensitisation (Kanerva and Estlander 1998).
Irritant Epoxy Dermatitis
Other Skin Disorders Caused by Epoxy Compounds
Irritative, low-MW degradation products may be
produced in tlIe tooling of epoxy products and in Purpurie allergie contact dermatitis, scleroderma-like
heating processes (Engström and Henriks-Eckerman dis orders, atypical psoriasis and erythema multiforme
1988). Amine and anhydride hardeners and epi- have been described to be caused by exposure to epoxy
chlorohydrin irritate the skin and conjunctivae. In compounds (Holness and Nethercott 1989); Bach-
addition to causing irritant contact dermatitis, epi- urzewska and Borucka (1986) reported Raynaud's-
chlorohydrin, as a highly reactive compound, and disease-type ailments. Rycroft (1980) reported on a
aliphatic polyamines, as highly alkaline compounds patient whose epoxy-resin sensitisation was followed
(pH 13-14), can cause corrosive bums on the skin by atypical psoriasis, while Lichter et al. (1992)
(Ippen and Mathies 1970; Adams 1983). Ippen and described a patient whose sensitisation to epoxy resin
Mathies (1970) described protracted chemical bums and hardener was followed by lichenoid contact
minutes or several hours after the exposure of five dermatitis. Photosensitivity has been reported in
patients to epichlorohydrin. relation to the heating of DGEBA epoxy resin and the
DGEBA epoxy res ins are not strong irritants and tlIe use of epoxy powder paints (Göransson et al. 1984).
irritability decreases with the increasing MW of the Photosensitivity is considered probably to be due to
oligomer (Hine et al. 1958). Lea et al. (1958) found tlIat bisphenol A contained in the resin (Maguire 1988).
an epoxy reactive diluent, butyl glycidyl ether, also
irritated human volunteers. Curing agents in powder
paints, such as dicyandiamide and organic acid
Skin Testing and Chemical Investigations
anhydrides, are potentially irritant (Peltonen 1986;
Jolanki et al. 1997b). Acid anhydrides, when cold, are
not very harmful to dry skin, but hot compounds may No single chemical can be used alone to screen for
cause severe chemical bums. On sweating skin, anhy- sensitisation to several different contact allergens of
Epoxy Resins 585
epoxy compounds. The study of Holness and Nether- amine hardeners is suspected. All but tris-DMP are
cott (1993) suggests that there is only a marginal available from the test substance suppliers. The
benefit of testing with anything other than standard recommended test concentration for tris-DMP is 0.5-
epoxy res in. However, 30% of the patients who have 1% in petrolatum (Kanerva et al. 1996a; Brooke and
developed contact allergy to epoxy-resin compounds Beck 1998). Because of the vast variety of hardeners
have been found to be sensitive to more than one of the used, it is highly recommendable to test patients also
three main epoxy-resin compound groups, i.e. resins, with the hardeners that they have been exposed to;
hardeners and reactive diluents. In addition, individual then, test concentrations of up to 10% should be used
contact allergies to hardeners, reactive diluents and for the amine-epoxy adducts. A test concentration of
non-DGEBA epoxy res ins without simultaneous con- about 1% is the most suitable for polyamine-type
tact allergy to the standard epoxy resin are rather hardeners (Jolanki 1991).
common among workers exposed to epoxy-resin bis-GMA and bis-GA can be recommended for
compounds (Jolanki 1991; Tosti et al. 1992). Thus, it the detection of contact allergy due to epoxy
might be recommendable that patients suspected of di(meth)acrylates. An allergie reaction induced by the
contracting contact dermatitis from epoxy-resin com- standard epoxy resin may indicate contact allergy to
pounds be also tested with the individual allergenie epoxy di(meth)acrylates, and this possibility should be
compounds, hardeners, reactive diluents and non- clarified by additional patch tests (Kanerva et al. 1989;
DGEBA epoxy res ins, according to the contents of the Jolanki 1991).
epoxy-resin compounds used by the patients. The In general, petrolatum seems to be a good vehicle for
patients should also be tested with their own specific epoxy-resin compounds. For solid materials contain-
materials, to which they have been exposed, especially ing uncured epoxy resins, it is preferable to use
if there is no response to the standard epoxy res in acetone instead of water for ultrasonic cleaning bath
(Holness and Nethercott 1993). It should be borne in extractions or to soften the material in the patch test
mi nd that testing only with the patients' own materials chamber (Jolanki et al. 1990; Bruze et al. 1992).
is not always completely reliable, because the allergens It is necessary to combine chemical and dermato-
may become too diluted and thus give negative patch- logical experience for the optimal investigation of
test results (Jolanki 1991). occupational skin diseases induced by epoxy
A patch-test concentration of 0.5% in petrolatum for compounds. The methods include patch testing,
non-DGEBA epoxy res ins is probably preferable to 1% clarification of the causative agents and planning of
when low viscosity res ins are being tested, because 1% preventive measures for both the patient and, espe-
non-DGEBA may irritate (Jolanki et al. 1989). Patch cially, the still-healthy fellow workers. In problematic
testing with the resinous part alone does not exclude cases, skin-prick testing with epoxy compounds,
contact allergy to reactive diluents if the patient is also consultations with industrial hygienists, visits to the
sensitive to the resin. The test concentration of 0.25% patients' work sites and analyses of the materials
in petrolatum was found to be suitable for testing handled by the patients are important (Estlander 1990;
reactive diluents (Jolanki 1991; Jolanki et al. 1996b). Jolanki 1991). It is also important to note that material
On patch testing, cross allergy has been found safety data sheets are occasionally incorrect, and
between compounds that are chemically closely relat- epoxy-resin compounds are not listed on the sheets
ed, especially between reactive diluents. Reactive (Nixon 1997). Thin-layer chromatography and other
diluents do not produce cross allergy with DGEBA chromatographie methods (gas chromatography and
epoxy resins, and contact allergy to reactive diluents is high-performance liquid chromatography) can be used
not revealed by testing with the standard epoxy res in. to demonstrate the presence or absence of particular
Patients who are allergie to cycloaliphatic epoxy resins allergens (Fregert 1988; Jolanki et al. 1988; Ayala et al.
often react to reactive diluents, and vice versa (Jolanki 1990; Kanerva et al. 1991a).
1991).
Aromatic compounds, especially PGE, have been
no ted to give an allergie patch-test re action in most of
Prevention of Epoxy Dermatitis
the patients who were allergie to reactive diluents.
BDDGE was found to screen contact allergy to aliphatic
reactive diluents. Thus, PGE and BDDGE are probably Complete avoidance of contact with the causative
enough to also screen contact allergy to other related allergens is always necessary. In a patient highly
compounds (Jolanki 1991). Only cresyl glycidyl ether sensitive to epoxy compounds, even a minimal amount
and PGE ether are available from the test substance of an allergen may be enough to evoke the symptoms
suppliers. on the exposed skin. Most patients who have acquired
Patch testing with DETA, TETA, DDM, IPDA and occupational epoxy dermatitis have to quit their work.
tris-DMP should be performed when allergy to poly- Quitting may also be beneficial for the prevention of
possible respiratory allergy following by the skin Ayala F, Lembo G, Balato N, et al. (1990) The use of laboratory
sensitisation (Kanerva et al. 1991c). Allergie epoxy methods in contact dermatitis induced by composite mate-
rials. Contact Dermatitis 22:262-266 (erratum 23:384)
dermatitis nevertheless has a good prognosis. Skin Baader EW (1955) Erkrankungen durch Phthalsäure und ihre
problems generally dear up shortly after exposure has Verbindungen. Arch Gewerbepathol Gewerbehyg 13:419-453
ended. It is easier to avoid contact with the less Bachurzewska B, Borucka I (1986) Gefassläsionen bei Eisenbal!-
narbeiterinnen, die mit Epoxidharzen in Berillirung kommen.
commonly used allergens, such as uncured or reactive Dermatosen 34:77-79
epoxy compounds, than to avoid contact with a Bäck B, Saarinen L (1986) Free amines in epoxy hardeners and in
workplace air (in Finnish with English summary).
widespread allergen, such as nickel or chromate Työterveyslaitoksen tutkimuksia 1:31-36
(Rosen and Freeman 1993). Balato N, Cusano F, Lembo G, et al. (1986) Ethylenediamine
Those working with epoxy compounds should be dermatitis. Contact Dermatitis 15:263-265
aware of the risk of sensitisation. Gloves made of Bauer RS (1985) Epoxy resins. In: Tess RW, Poehlein GW (eds)
Applied polymer science, 2nd edn. American Chemieal
laminated, multilayered plastic (4H-glove), containing Society, Washington, pp 931-961
ethylene-vinyl alcohol copolymer, developed especially Beck MH, King CM (1983) Allergie contact dermatitis to
epiehlorhydrin in a solvent cement. Contact Dermatitis 9:315
for the handling of epoxy compounds give the best
Beck MH, Burrows D, Fregert S (1985) Allergie contact dermatitis
protection against them (Henriksen and Petersen 1986; to epoxy resin in ostomy bags. Br J Surg 72:202-203
Roed-Petersen 1989; McClain and Storrs 1992). The use Bergquist-Karlsson A (1985) Contact allergy to glycidyl trimethyl
ammonium chloride. Contact Dermatitis 12:61-62
of any type of gloves, however, seems to reduce the
Birmingham DJ (1959) Clinical observations on the cutaneous
exposure to epoxy res in compounds and helps to effects associated with curing epoxy res ins. Arch Ind Health
protect against the risk of sensitisation, although the 19:365-367
use of protective gloves may, in some individual cases, Björkner B (1984) Sensitizing capacity of ultraviolet curable
acrylic compounds (doctoral dissertation). University of
even promote contact allergens to come into contact Lund, Sweden
with the skin (Jolanki et al. 1990). Unhealthy skin, Björkner B, Dahlquist I, Fregert S, Magnusson B (1980) Contact
induding even small wounds and abrasions, should be allergy to Epoxide 8, an epoxy reactive diluent. Contact
Dermatitis 6:156
protected from epoxy-compound exposure because of Bolger JC (1983) Structural adhesives: today's state of the art. In:
increased skin penetration. The use of less-sensitising Schneberger GL(ed) Adhesives in manufacturing. Marcel
products may reduce the possibility of developing Dekker Inc, New York, pp 133-194
Boom BW, van Driel LMJ (1985) Allergie contact dermatitis to
allergy to epoxy, as high-MW epoxies do not sensitise epoxy resin in infusion sets of an insulin pump. Contact
readily. The use of one-bag epoxies, which mix in the Dermatitis 12:280
Boume LB, Milner FJM, Alberman KB (1959) Health problems of
package (Van Putten et al. 1984), may reduce the epoxy resins and amine-curing agents. Br J Ind Med 16:81-97
possibility of skin contact. The airways should also be Bowen RL (1962) Dental filling material comprising vinyl silane
protected from exposure to the epoxy compounds, treated fused silica and a binder consisting of the reaction
product of bis phenol and glycidyl acrylate. US Patent No.
because the compounds can be considered potential 3,066,112
causes of asthma. An automatic process, as such, does Brandao FM, Pinto J (1980) Allergie contact dermatitis to epoxy
not guarantee protection against skin contact and resin in hemodialysis needles. Contact Dermatitis 6:218-219
Brooke R, Beck MH (1998) Contact allergy to 2,4,6-tris(dimethyl-
exposure of the respiratory tract to the compounds aminomethyl)phenol. Contact Dermatitis 38:284-285
because, for example, of exposure during maintenance, Bruze M, Almgren G (1989) Occupational dermatoses in workers
re pair or sampling (Jolanki 1991). exposed to epoxy-impregnated fiberglass fabrie. Dermatosen
37:171-176
Bruze M, Zimerson E (1985) Contact allergy to dillydroxydiphenyl
methanes (bisphenol F). Dermatosen 33:216-220
Bruze M, Trulson L, Bendsöe N (1992) Patch testing with
ultrasonie bath extracts. Am J Contact Dermatitis 3:133-137
References Bruze M, Edenholm M, Engström K, Svensson G (1996) Occu-
pational dermatoses in a Swedish aircraft plant. Contact
dermatitis 34:336-340
Adams RM (1983) Occupational skin disease. Grune & Stratton Buisson H, Vaillant L, Lasfargues G, Muller C, Lorette G (1991)
Inc, New York, pp 238-266 Occupational contact dermatitis from trans-methyl-3(4-
Ancona-Alayon A, Jimenez-Castilla JL, Gomez-Alvarez EM (1976) methoxyphenyl)glycidate. Contact Dermatitis 25:262-263
Dermatitis from epoxy resin and formaldehyde in shampoo Burrows D, Fregert S, Campbell H, Trulsson L (1984) Contact
packers. Contact Dermatitis 2:356 dermatitis from the epoxy resins tetraglycidyl-4,4' -methylene
Ancona A, Arevalo A, Macotela E (1990) Contact dermatitis in dianiline and o-diglycidyl phthalate in composite material.
hospital patients. Dermatol Clin 8:95-105 Contact Dermatitis 11:80-82
Anderson TF, Messick VB (1985) Vinyl ester resins. In: Pritchard Calnan CD (1958) Studies in contact dermatitis. Trans St John's
G (ed) Developments in reinforced plastics, vol 1. Elsevier, Hosp Dermatol Soc 40:12-19
London, pp 29-58 Calnan CD (1967) Studies in contact dermatitis xx. Active
Angelini G, Foti C, Rigano L, Vena GA (1995) 3-Dimethylami- sensitization. Trans St John's Hosp Dermatol Soc 53=128-134
nopropylamine: a key substance in contact allergy to coca- Calnan CD (1975) Epoxy resin dermatitis. J Soc Occup Med
midopropylbetaine? Contact Dermatitis 32:96-99 25=123-126
Ange1ini G, Rigano L, Foti C, Grandolfo M, Veiia GA, Bonamonte Carmiehael AI, Gibson JJ, Walls AWG (1997) Allergie contact
D, Soleo L, Scorpinitti AA (1996) Occupational sensitization dermatitis to bisphenol-A-glycidyldimethacrylate (BIS-GMA)
to epoxy resin and reactive diluents in marble workers. dental resin associated with sensitivity to epoxy resin. Br
Contact Dermatitis 35=11-16 Dental J 183:297-298
Epoxy Resins 587
Chieregato C, Vencenzi C, Guerra L, Farina P (1994) Occupational Fregert S (1987) Contact dermatitis from epoxy resin systems. In:
allergie contact dermatitis due to ethylenediamine dihydro- Maibach HI (ed) Occupational and industrial dermatology, 2nd
chloride and cresyl glycidyl ether in epoxy resin system. edn. Year Book Medical Publishers Inc, Chieago, pp 341-345
Contact Dermatitis 30:120 Fregert S (1988) Physicochemical methods for detection of
Conde-Salazar L, Romero L, Guimaraens D, Harto A (1982) contact allergens. Dermatol Clin 6:97-104
Contact dermatitis in an oil painter. Contact Dermatitis Fregert S, Orsmark K (1984) Allergic contact dermatitis due to
8:209-210 epoxy resin in textile labels. Contact Dermatitis 11:131-132
Conde-Salazar L, Guimaraens D, Romero LV, Harto A, Gonzalez Fregert S, Rorsman H (1964) Allergens in epoxy resins. Acta
M (1985) Occupational dermatitis from gIass fiber. Contact Allergoi 19:296-299
Dermatitis 13:195-196 Gailhofer G, Ludvan M (1989) Zur Wertigkeit positiver
Conde-Salazar L, Gorospe M, Guimaraens D (1993) A new source Epikutantestreaktionen auf 4,4'-Diamino-diphenylmethan.
of sensitivity to epoxy resin. Contact Dermatitis 28:292 Dermatosen 37:17-22
Conde-Salazar L, Conzalez de Domingo MA, Guimaraens D Gardiner TH, Waechter Jr JM, Wiedow MH, Solomon WA (1992)
(1994) Sensitization to epoxy resin system in special flooring Glycidyloxy compounds used in epoxy resin systems: a
workers. Contact Dermatitis 31:157-160 toxicology review. Regul Toxieol Pharmacol 15:S1
Dahlquist I, Fregert S (1979) Allergic contact dermatitis from Gaul LE (1960) Sensitivity to bisphenol A. Arch Dermatol 82:1003
volatile epoxy hardeners and reactive diluents. Contact Geldof BA, Oranje AP, van Joost T (1989) Hand eczema
Dermatitis 5:406-407 associated with continuous subcutaneous insulin infusion.
Dahlquist I, Fregert S, Persson K, Trulsson L (1979a) Epoxy resin Contact Dermatitis 20:384-385
in a one-pack glue. Contact Dermatitis 5:189-190 Glauert AM (1991) Epoxy resins: an update on their selection and
Dahlquist I, Fregert S, Trulsson L (1979b) Allergic contact use. Eur Mierosc Analysis September:13-18
dermatitis from epoxy resin finished glass fiber. Contact Gon~alo S, Gon~alo M, Matos J, Mar~ues C (1992) Contact
Dermatitis 5=190 dermatitis from a billiard cue. Contact Dermatitis 26:263
Dannaker CI (1988) Allergie sensitization to a non-bisphenol A Goossens A, Coninx D, Rommens K, Verhamme B (1998)
epoxy of the cydoaliphatic dass. J Occup Med 30:641-643 Occupational dermatitis in a silk-screen maker. Contact
De Groot AC (1994) Occupational contact allergy to alpha- Dermatitis 39:40-42
naphthyl glycidyl ether. Contact Dermatitis 30:253-254 Göransson K (1977) Allergic contact dermatitis to an epoxy
Dooms-Goossens A, Boden G, Auoaix F, Bruze M (1993) Allergie hardener: dodecenyl-succinie anhydride. Contact Dermatitis
contact dermatitis from adhesive piaster due to colophony 3:277-278
and epoxy res in. Contact Dermatitis 28:120-121 Göransson K, Andersson R, Andersson G, MarkIund S, Anderson
Dooms-Goossens A, Bruze M, Buysse L, Fregert S, Gruvberger B, K, Östbye P, Zingmark P-A (1984) An outbreak of occupa-
Stals H (1995) Contact allergy to allyl glycidyl ether present as tional photodermatosis of the face in a factory in northern
an impurity in 3-glycidyloxypropoxyltrimethoxysilane, a Sweden. In: Berglund B, Lindvall T, Sundell J (eds) Indoor air,
fixing additive in silicone and polyurethane res ins. Contact vol 3. Swedish Council for Building Research, Stockholm,
Dermatitis 33:17-19 pp 367-375
Edman B (1988) Computerized patch data in contact allergy Gordon PM, McLelland J (1998) Contact sensitivity to Anc-
(doctoral dissertation). Lund University, Sweden amine® 2280 (p-aminocydohexylamine) following a change
Emmett EA, Kominsky JR (1977) Allergic contact dermatitis from in work practiee. Contact Dermatitis 38:54
ultraviolet cured ink. J Occup Med 19:113-115 Goulden V, Wilkinson SM (1996) Occupational allergic contact
Enders F, PrzybilIa B, Ring J, Burg G, Braun-Fako 0 (1989) Patch dermatitis from epoxy resin on dipboard. Contact Dermatitis
test results in 1987 compared to trends from the period 1977- 35:262-263
1983. Contact Dermatitis 20:230-232 Guerra L, Vincenzi C, Bardazzi F, Tosti A (1992) Contact
Engström B, Henriks-Eckerman M-L (1988) We!ding and paint sensitization due to isophoronediamine. Contact Dermatitis
(in Finnish). Työterveyslaitos (Työolot 68.), Helsinki 27:52-53
Erikstam U, Bruze M (1998) Contact allergy to an epoxy resin Guimaraens D, Gonzalez MA, Dei Rio E, Conde-Salazar L (1994)
based on bisphenol F. In: Kanerva L, Lauerma A, Björksten F, Occupational airborne allergic contact dermatitis in the
EstIander T, Jolanki R (eds) Proceedings of the Fourth national mint and fiscal-stamp factory. Contact Dermatitis
Congress of the European Society of Contact Dermatitis. 30:172-173
People and Work (Research Reports) no 18. Finnish Institute Guin JD, Work WJ (1995) Plasties: Epoxy resins. In: Guin JD (ed)
of Occupational Health, Finland, pp 92 Practieal contact dermatitis. A handbook for the practitioner.
EstIander T (1990) Occupational skin disease in Finland: obser- McGraw-HilI, Inc., USA, pp 433-446
vations made during 1974-88 at the Institute of Occupational Handley J, Burrows D (1994) Dermatitis from hexavalent
Health, Helsinki (doctoral dissertation). Acta Derm Venerol chromate in the accelerator of an epoxy sealant (PRI422)
Suppl 155 used in the aircraft industry. Contact Dermatitis 30:193-196
Estiander T, Jolanki R, Kanerva L (1986) Occupational dermatitis Hansson C (1994) Determination of monomers in epoxy resin
to 2,3-epoxypropyl trimethyl ammonium chloride. Contact hardened at elevated temperature. Contact Dermatitis 31:
Dermatitis 14:49-52 333-334
Estiander T, Jolanki R, Kanerva L (1997) Occupational allergic Härte! G (1980) Epoxidharze auf der Basis kondensierter
contact dermatitis from 2,3-epoxypropyl trimethyl ammo- Heterocyden (doctoral dissertation). Beriin University of
nium chloride (EPTMAC) and Kathon® LX in a starch Technology, Germany
modification factory. Contact Dermatitis 36:191-194 Hausen BM, Krohn K, Budianto E (1990) Contact allergy due to
Fischer T, Fregert S, Thulin I, Trulsson L (1987) Unhardened colophony. VII. Sensitizing studies with oxidation products
epoxy resin in tool handles. Contact Dermatitis 16:45 of abietic and related acids. Contact Dermatitis 23:352-358
Flyvholm M-A (1991) Contact allergens in registered chemical Heino T, Haapa K, Mane!ius F (1996) Contact sensitization to
products. Contact Dermatitis 25:49-56 organosilane solution in glass filament production. Contact
Freeman K, Warin AP (1984) Contact dermatitis due to bisphenol Dermatitis 34:294
A in semi-synthetie waxes. Contact Dermatitis 11:259-260 Henriks-Eckerman M-L, Kanerva L (1997) Product analysis of
Fregert S (1975) Occupational dermatitis in a lO-year material. acrylic res ins compared to information given in material
Contact Dermatitis 1:96-107 safety data sheets. Contact Dermatitis 36:164-165
Fregert S (1981a) Epoxy dermatitis from the non-working Henriks-Eckerman M-L, Laijoki T (1986a) Aliphatie polyamines
environment. Br J Dermatol 105[SUppl 21]:63-64 and epoxy oligomers in cold cured epoxy products (in
Fregert S (1981b) Manual of contact dermatitis, 2nd edn. Finnish with English summary). Työterveyslaitoksen tut-
Munksgaard, Copenhagen kimuksia 4:37-40 (summary p 69)
Henriks-Eckerman M-L, Laijoki T (1986b) Glycidyl ethers in from silk-screen prmtmg coatings in the manufacture of
epoxy resin products (in Finnish with English summary). circuit boards. Contact Dermatitis 30:12-15
Työterveyslaitoksen tutkimuksia 4:41-46 (summary p 70) Jolanki R, Kanerva L, Estlander T, Tarvainen K (1994b) Epoxy
Henriksen HR, Petersen HJS (1986) Better gloves against epoxy dermatitis. In: Nethercott JR (ed), Occupational skin disease,
products and other chemicals: protective dothing against occupational medicine: state of the art reviews, vol 9, part 1.
chemicals (In Danish with English summary). Ar- Hanley & Belfus, Inc., Medieal Publishers, Philadelphia,
bejdsmiljöfondet (Arbejdsmiljöfondets forskningsrapporter), pp 97-112
Copenhagen Jolanki R, Kanerva L, Estlander T (1995) Occupational allergic
Herzberg J (1973) Untersuchungen über einen neuen contact dermatitis caused by epoxy diacrylate in ultraviolet-
Epoxidkunststoff, "Optyl", zur Herstellung von Brillenfas- light-cured paint, and bispheol A in dental composite resin.
sungen. Berufsdermatosen 21:1-6 Contact Dermatitis 33:94-99
Heskel NS (1988) Epoxy resin dermatitis in a stained glass Jolanki R, Kanerva L, Estlander T (1996a) Allergic patch test
window maker. Contact Dermatitis 18:182-183 reactions to diglycidyl ether of bisphenol A in hardened nail
Hine CH, Kodama JK, Anderson HH, Simonson DW, Wellington base and top coat. Contact Dermatitis 35:246-247
JS (1958) The toxicology of epoxy resins. Arch Ind Health Jolanki R, Tarvainen K, Tatar T, Estlander T, Henriks-Eckerman
17:129-144 M-L, Mustakallio KK, Kanerva L (1996b) Occupational
Holness DL (1992) Outbreak of allergic contact dermatitis caused dermatoses from exposure to epoxy resin compounds in a
by epoxy res in in a gluing and swaging operation. Am J ski factory. Contact Dermatitis 34:390-396
Contact Dermat 3:150-154 Jolanki R, Kanerva L, Estlander T (l997a) Contact urtiearia from
Holness DL, Nethercott JR (1989) Occupational contact derma- epoxy res ins. In: Amin S, Laliti A, Maibach HI (eds) Contact
titis due to epoxy resin in a fiberglass binder. J Occup Med urticaria syndrome. CRC Press LLC, Boca Raton, FL, pp 143-
31:87-89 147
Holness DL, Nethercott JR (1992) Results of testing with epoxy Jolanki R, Kanerva L, Estlander T, Tarvainen K (1997b) Skin
resin in an occupational health dinie population. Am J allergy caused by organie acid anhydrides. In: Amin S, Lahti
Contact Dermat p69-174 A, Maibach HI (eds) Contact urticaria syndrome. CRC Press
Holness DL, Nethercott JR (1993) The performance of specialized LLC, Boca Raton, FL, pp 217-224
collections of bisphenol A epoxy system components in the Kanerva L, Alanko K (1998) Stomatitis and perioral dermatitis
evaluation of workers in an occupational health dinie caused by epoxy diacrylete in dental composite resins. J Am
population. Contact Dermatitis 28:216-219 Acad Dermatol 38:116-120
Holness DL, Nethercott JR (1994) Patch testing in an occupational Kanerva L, Estlander T (1998) Simultaneous active sensitization
Health dinie. Am J Contact Dermat 5:150-155 to multiple chemicals. Contact Dermatitis 38:174-175
Ippen H, Mathies V (1970) Die "protrahierte Verätzung" (unter Kanerva L, Estlander T, Jolanki R (1989) Allergic contact
besonderer Berücksichtigung der Hautschäden durch Epox- dermatitis from dental composite resins due to aromatic
ide und Propansulton). Berufsdermatosen 18:144-165 epoxy acrylates and aliphatic acrylates. Contact Dermatitis
Janda R (1987) Synthetic resins. In: Gerhartz W, Yamamoto YS, 20:201-211
Kaudy L, Pfefferkorn R, Rounsaville JF (eds) Ullmann's Kanerva L, Jolanki R, Estlander T (1991a) Allergic contact
encydopedia of industrial chemistry, vol A8. 5th Completely dermatitis from epoxy resin hardeners. Am J Contact
revised edition. VCH Verlagsgesellschaft, Weinheim, pp Dermatitis 2:88-97
277-2 84 Kanerva L, Jolanki R, Estlander T (1991b) Allergie contact
Jolanki R (1991) Occupational skin diseases from epoxy com- dermatitis from non-diglycidyl ether of bisphenol A epoxy
pounds. Epoxy res in compounds, epoxy acrylates and resins. Contact Dermatitis 24:293-300
2,3-epoxypropyl trimethyl ammonium chloride (doctoral Kanerva L, Jolanki R, Tupasela 0, Halmepuro L, Keskinen H,
dissertation). Acta Derm Venerol SUppI159:1-80 Estlander T, Sysilampi M-L (1991C) Immediate and delayed
Jolanki R (1997) Epoxy dermatitis. In: Proceedings of the Fifth allergy from epoxy res ins based on diglycidyl ether of
International Course of Occupational Dermatoses. Apr 8-13, bisphenol A. Scand J Work Environ Health 17:208-215
Ivalo, Finland, pp 16-19 Kanerva L, Estlander T, Jolanki R (1992) Active sensitization caused
Jolanki R, Estlander T, Kanerva L (1987a) Contact allergy to an by 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacry-
epoxy reactive diluent: l,4-butanediol diglycidyl etlIer. Con- late, ethyleneglycol dimethacrylate and N,N-dimethylamino-
tact Dermatitis 16:87-92 ethyl methacrylate. J Eur Acad Derm Venereoll:165-169
Jolanki R, Estlander T, Kanerva L (1987b) Occupational contact Kanerva L, Tarvainen K, Pinola A, Leino T, Granlund H,
dermatitis and contact urticaria caused by epoxy resins. Acta Estlander T, Jolanki R, Förström L (1994) A single accidental
Derm Venereol Suppl (Stockh) 134:90-94 exposure may result in a chemieal burn, primary sensitiza-
Jolanki R, Estlander T, Henriks-Eckerman M-L, Kanerva L, tion and allergic contact sensitization. Contact Dermatits
Stjernvall T (1988) Skin protection and sensitizing epoxy 31:229-235
compounds in electron mieroscopy laboratories. In: Mans- Kanerva L, Estlander T, Jolanki R (1996a) Occupational allergie
dorf SZ, Sager R, Nielsen AP (eds) Performance of protective contact dermatitis caused by 2,4,6-tris-(dimethylamino-
dothing: second symposium. American Society for Testing methyl)phenol, and a review of sensitizing epoxy resin
and Materials (ASTM STP 989), Philadelphia, pp 389-395 hardeners. Int J Dermatol 35:852-856
Jolanki R, Sysilampi M-L, Kanerva L, Estlander T (1989) Contact Kanerva L, Toikkanen J, Jolanki R, Estlander T (1996b) Statistieal
allergy to cydoaliphatie epoxy resins. In: Frosch PI, Dooms- data on occupational contact urticaria. Contact Dermatitis
Goossens A, Lachapelle J-M, Rycroft RJG, Scheper RJ (eds) 35:229-233
Current topics in contact dermatitis. Springer, Berlin Heidel- Kanerva L, Hyry H, Jolanki R, Hytönen M, Estlander T (1997)
berg New York, pp 360-367 Delayed and immediate allergy caused by methylliexa-
Jolanki R, Kanerva L, Estlander T, Tarvainen K, Keskinen H, hydrophthalic anhydride. Contact Dermatitis 36:34-38
Henriks-Eckerman M-L (1990) Occupational dermatoses Kanerva L, Jolanki R, Estlander T (1998) Occupational epoxy
from epoxy res in compounds. Contact Dermatitis 2P72-83 dermatitis with patch test reactions to multiple hardeners
Jolanki R, Estlander T, Kanerva L, Tarvainen K (1992) Occupa- induding tetraethylenepentamine. Contact Dermatitis
tional allergic contact dermatitis caused by a finished 38:299-301
reinforced polyester plastic product (abstract). In: Proceed- Kanerva L, Jolanki R, Alanko K, Estlander T (1999) Patch test
ings of the 18th World Congress of Dermatology. New York reactions with plastic and glue allergens at an occupational
City, June 12-18, pp 105A dermatology dinic. Acta Derm-Venereol (Stoch) 79:296-300
Jolanki R, Kanerva L, Estlander T, Tarvainen K (l994a) Karlberg A-T, Gäfvert E (1996) Isolated colophony allergens as
Concomitact sensitization to triglycidyl isocyanurate, di- screening substance for contact allergy. Contact Dermatitis
aminodiphenylmethane and 2-hydroxyethyl methacrylate 35:201-207
Epoxy Resins 589
Kowalska M (1982) Carbon fibre reinforced epoxy prepregs and Munro CS, Lawrence CM (1992) Occupational contact dermatitis
composites health risks aspects. Soc Advancement Material from triglycidyl isocyanurate in a powder paint factory.
Process Eng Q 13 Contact Dermatitis 26:59
Krajewska D, Rudzki E (1976) Sensitivity to epoxy resins and Muskopf JW, McCollister SB (1987) Epoxy resins. In: Gerhartz W,
triethylenetetramine. Contact Dermatitis 2:135-138 Yamamoto YS, Kaudy L, Rounsaville JF, Schulx G (eds)
Lachapelle JM, Tennstedt D, Dumont-Fruytier M (1978) Occupa- Ullmann's encyclopedia of industrial chemistry, vol A9.
tional allergie contact dermatitis to isophorone diamine 5th Completely revised edition. VCH Verlagsgesellschaft,
(IPD) used as an epoxy resin hardener. Contact Dermatitis Weinheim, pp 547-563
4:109-112 Nakagawa M, Kawai K, Kawai K (1991) Three cases of allergie
Le Coz C, Coninx D, Van Rengen A, EI Aboubi S, EI Bakali A, contact dermatitis from phenylglycidylether (in Japanese with
Goossens A (1998) An epidemie among laboratory techni- English summary). Skin Res 33[SUppl1O]:88-95
cians of occupational contact dermatitis from a reformulated NetlIercott JR (1981) Allergie contact dermatitis due to an epoxy
immersion oil for microscopy. In: Kanerva L, Lauerma A, acrylate. Br J Dermatol104:697-703
Björkner F, Estlander T, Jolanki R, Hannuksela M (eds) Nethercott JR, Holness 01, Adams RM, et al. (1994) Multivariate
Proceedings of tlIe FourtlI Congress of European Society of analysis of the effect of selected factors on the elicitation of
Contact Dermatitis: People and Work, Research Reports 18, patch test response to 28 common environmental contactants
p 86 in NortlI America. Am J Contact Dermatol 5=13-18
Lea W A, Block WD, Cornish HH (1958) The irritating and Ng PPL, Leow YH, Ng SK, Goh CL (1998) Allergie contact
sensitizing capacity of epoxy resins. Arch DermatoI78:304-308 dermatitis to epoxy res in in a hemodialysis cannula. Am J
Lee H, Neville K (1967) Handbook of epoxy resins. McGraw-Hill Contact Dermat 9:55-56
Inc, New York Niinimäki A, Hassi J (1983) An outbreak of epoxy dermatitis in
Leow YH, Ng SK, Wong WK, Goh CL (1995) Allergie contact insulation workers at an electrie power station. Dermatosen
dermatitis from epoxy resin in Singapore. Contact Dermatitis 31:23-25
33:355-356 Niinimäki A, Rosberg I, Saari S (1983) Traces of epoxy resin in
Lichter M, Drury D, Remlinger K (1992) Lichenoid dermatitis acrylic dental materials. Contact Dermatitis 9:532
caused by epoxy res in. Contact Dermatitis 26:275 Nishioka K, Ogasawara M, Asagami C (1988) Occupational
Liu YQ, Zhao B, Zhuang LH, Fan WX (1997) Patch test reactions contact allergy to triglycidyl isocyanurate (TGIC, TepicR).
to the Chinese standard screening allergens in 1,135 patients Contact Dermatitis 19:379-380
investigated for allergie contact dermatitis. Am J Contact Nixon RL (1997) Material safety data sheets and contact
Dermat 8:141-143 dermatitis: a misleading case. Aust J Dermatol 38:165
Lodi A, Mancini LL, Pozzi M, Chiarelli G, Crosti C (1993) O'Brien TJ (1986) Contact dermatitis to epoxy resin in ileostomy
Occupational airborne allergie contact dermatitis in parquet bag. Aust J Dermatol 27:94-95
layers. Contact Dermatitis 29:281-282 Omer SA, AI-Tawil NG (1994) Contact senstitivity among workers
Lovell CR, Rycroft RJG, Matood J (1984) Isolated Cardura E10 in a paint factory. Contact Dermatitis 30:55-57
sensitivity in an epoxy resin chemical process. Contact Ortiz-Frutos FJ, Borrego L, Romero G, Iglesias L (1993) Occupa-
Dermatitis 11:190-191 tional allergie contact dermatitis from epoxy varnishes.
Lynde CW, Warshawski L, Mitchell JC (1982) Screening patch Contact Dermatitis 28:297-298
tests in 4190 eczema patients 1972-81. Contact Dermatitis Patussi V, Kokelj F, Buttazzi P (1995) Occupational airborne
8:417-421 allergie contact dermatitis due to 3-amino-metlIyl-3,5,5-
Lyon CC, O'Driscoll I, Erikstam U, Bruze M, Beck MH (1998) trimethylcyclo-hexylamine. Contact Dermatitis 32:239
Bowlers' grip. Contact Dermatitis 38:223 Peltonen K (1986) Thermal degradation of epoxy powder paints
Maguire HC (1988) Experimental photoallergie contact dermatitis (Doctoral dissertation). UniversityofKuopio, Kuopio, Finland
to bisphenol A. Acta Derm Venerol 68:408-412 Pigatto PD, Bigardi AS, Cusano F (1995) Contact dermatitis to
Malanin G, Kalimo K (1985) Facial dermatitis from epoxy resin in cocamidopropylbetaine is caused by residual amines: rele-
a heimet. Contact Dermatits 12:221 vance, clinieal characteristics, and review of the literature.
Malten K, Zielhuis R (1964) Polyester res ins. In: Industrial Am J Contact Dermatitis 6:13-16
toxicology and dermatology in the production and processing Potter WG (1975) Uses of epoxy resins. Newnes-ButterwortlIs,
of plastics. Elsevier, Amterdam, pp 71-84 London
Mann RJ, Stewart E, Peachey RDG (1983) Sensitivity to urostomy Prens EP, de Jong G, van Joost T (1986) Sensitization to
pouch plastic. Contact Dermatitis 9:80-81 epiehlorohydrin and epoxy system components. Contact
Marks JG, Belsito DV, DeLeo VA, Fowler JF, Fransway AF, Dermatitis 15:85-90
Maibach HI, MatlIias CGT, Nethercott JR, Rietschel RL, Rebandel P, Rudzki E (1990) Dermatitis caused by epiehloro-
Rosenthai LE, Sherertz EF, Storrs FJ, Taylor JS (1995) NortlI hydrin, oxprenolol hydrochloride and propranolol hydro-
American Contact Dermatitis Group standard tray patch test chloride. Contact Dermatitis 23:199-200
results (1992 to 1994). Am J Contact Dermat 6:160-165 Requena L, Vazquez C, Requena C, Aguilar A, Guerra P (1986)
MatlIias CGT (1987) Allergie contact dermatitis from a nonbis- Epoxy dermatitis of an amputation stump. Contact Derma-
phenol A epoxy in a graphite fiber reinforced epoxy laminate. titis 14:320
J Occup Med 29:754-755 Richter G, Kadner H (1990) Allergische Kontaktekzeme durch
Matura M, Poesen N, de Moor A, Kerre S, Dooms-Goossens A m-Xylylen-diamin in der Poly-urethanseidenproduktion.
(1995) Glycidyl metlIacrylate and ethoxyethyl acrylate: new Dermatosen 38:117-120
allergens in emulsions used to impregnate paper and textile Rietschel RL, Fowler JF, Jr (1995) Fisher's Contact Dermatitis, 4tlI
materials. Contact Dermatitis 33:123-134 edn, Williams & Wilkins, Philadelphia
McClain DC, Storrs FJ (1992) Protective effect of both a barrier Romaguera C, Grimalt F (1981) Pacemaker dermatitis. Contact
cream and a polyethylene lamintate glove against epoxy resin, Dermatitis 7:333
glyceryl monothioglycolate, frullania, and tancy. Am J Roed-Petersen J (1989) A new glove material protective against
Contact Dermat 3:201-205 epoxy and acrylate monomer. In: Frosch PI, Dooms-Goossens
Menschnik H (1955) Gesundheitliche Gefahren bei der Herstel- A, Lachapelle JM (eds) Current topics in contact dermatitis.
lung von Phthalsäureanhydrid. Arch Gewerbepathol Ge- Springer, Berlin Heidelberg New York, pp 603-606
werbehyg 183:454-475 Rosen RH, Freeman S (1993) Prognosis of occupational contact
Miyamoto T, Okumura M (1998) Occupational contact urtiearia dermatitis in New South Wales, Australia. Contact Dermatitis
due to epoxy resin. Environ Dermatol 5:53-57 29:88-93
Morris AD, Ratcliffe I, Dalziel KL, English JSC (1998) Allergie Rothe A (1995) Contact dermatitis due to 3-amino-methyl-3,5,5-
contact dermatitis from epoxy propane. Contact Dermatitis trimethylcyclo-hexylamine (isophoronediamine; IPD) (letter
38:57 to the editor). Contact Dermatitis 33:451
590 R. Jolanki et al.: Epoxy Resins
Rudner EJ (1977) North Ameriean group results. Contact Thorgeirsson A (1978a) Sensitization capacity of epoxy reactive
Dermatitis 3:208-209 diluents in the guinea pig. Acta Derm Venerol 58:329-331
Rudzki E, Krajewska D (1976) Cross-reactivity between ethylene- Thorgeirsson A (1978b) Sensitization capacity of epoxy resin
diamine, diethylenetriamine and triethylenetetramine. Con- hardeners in the guinea pig. Acta Derm Venerol 58:332-336
tact Dermatitis 2:311-313 Thorgeirsson A, Fregert S (1977) Allergenicity of epoxy resins in
Rudzki E, Rebandel P (1990) Dermatitis from methyl 2,3 epoXY-3- the guinea pig. Acta Derm Venerol 57:253-256
(4-methoxyphenyl)propionate. Contact Dermatitis 23:382 Thorgeirsson A, Fregert S, Ramnäs 0 (1978) Sensitization
Rycroft RJG (1980) Atypical psoriasis following epoxy resin capacity of epoxy resin oligomers in the guinea pig. Acta
sensitization. J Soc Occup Med 30:132-134 Derm Venerol 58:17-21
Sasseville D (1998) Contact urticaria from epoxy resin and Toffoletto F, Cortona G, Feltrin G, Baj A, Goggi E, Cecchetti R
reactive diluents. Contact Dermatitis 38:57-58 (1994) Occupational contact dermatitis from amine-
Savla M (1977) Epoxy resin adhesives. In: Skeist I (ed) Handbook functional methoxysilane in continuous-glass-filament
of adhesives, 2nd edn. Van Nostrand Reinhold Co, New York, production. Contact Dermatitis 31:320-321
pp 434-464 Toome BK (1989) Allergic contact dermatitis to a nasal cannula.
Savonius B, Keskinen H, Tuppurainen M, Kanerva L (1994) Arch Dermatol 125:571
Occupational asthma caused by ethanolamines. Allergy Tosti A, Guerra L, Toni F (1988) Occupational airborne contact
49:877-881 dermatitis due to epoxy resin. Contact Dermatitis 19:
Senff H, Kuhlwein A, Hausen BM (1988) Allergisches Kontaktek- 220-222
zem auf Dicyandiamid. Dermatosen 36:99-101 Tosti A, Guerra L, Bardazzi F (1992) Occupational contact
Sommer S, Wilkinson SM, Wilson CL (1997) Airborne contact dermatitis from exposure to epoxy resins and acrylates. Clin
dermatitis caused by microscopy immersion fluid containing Dermatol10:133-140
epoxy resin. Contact Dermatitis 39:141-142 Tosti A, Guerra L, Vincenzi C, Peluso AM (1993) Occupational
Speight EL, Beck MH, Lawrence CM (1993) Occupational allergie skin hazards from synthetic plastics. Toxicol Ind Health
contact dermatitis due to 3-dimethylaminopropylamine. 9:493-502
Contact dermatitis 28:49-50 Vanherle G, Smith DC (eds) (1985) Posterior composite res in
Srinivas CR, Devadiga R, Aroor AR (1989) Footwear dermatitis dental restorative materials. Minnesota Mining & Mfg Co, St.
due to bisphenol A. Contact Dermatitis 20:150-151 Paul, Minnesota
Steinkraus V, Hausen BM (1994) Contact allergy to propylene Van Joost T (1988) Occupational sensitization to epichlorohydrin
oxide. Contact Dermatitis 31:120 and epoxy resin. Contact Dermatitis 19:278-280
Storrs FJ, Rosenthal LE, Adams RM, Clendenning W, Emmett EA, Van Joost T, Roesyanto ID, Satyawan I (1990) Occupational
Fisher AA, Larsen WG, Maibach HI, Rietschel RL, Schorr WF, sensitization to epiehlorohydrin (ECH) and bisphenol-A
Taylor JS (1989) Prevalence and relevance of allergie reactions during the manufacture of epoxy res in. Contact Dermatitis
in patients patch tested in North America - 1984 to 1985. J Am 22:125-126
Acad Dermatol 20:1038-1045 Van Putten PB, Coenraads PJ, Nater JP (1984) Hand dermatoses
Suhonen R (1983) Epoxy-dermatitis in a ski-stiek factory. Contact and contact allergie reactions in construction workers
Dermatitis 9:131-133 exposed to epoxy resins. Contact Dermatitis 10:146-150
Tarvainen K, Jolanki R, Estlander T, Tupasela 0, Pfäffli P, Veien NK, Hattel T, Laurberg G (1992) Patch test results from a
Kanerva L (1995a) Immunologie contact urtiearia due to private dermatologie practice for two periods of 5 years with a
airborne methylhexallydrophthalie and methyltetrallydro- 10-year interval. Am J Contact Dermatol 3:189-192
phthalic anhydride. Contact Dermatitis 32:204-209 Wigger-Alberti W, Hofmann M, Elsner P (1997) Contact derma-
Tarvainen K, Kanerva L, Jolanki R, Estlander T (1995b) Occupa- titis caused by triglycidyl isocyanurate. Am J Contact Dermat
tional dermatoses from the manufacture of plastie composite 8:106-107
products. Am J Contact Dermatoses 6:95-104 Wilkinson DS, Budden MG, Hambly EM (1980) A 10-year review
Tarvainen K, Jolanki R, Henriks-Eckerman M-L, Estlander T of an industrial dermatitis clinic. Contact Dermatitis 6:
(1998) Occupational allergie contact dermatitis from isophor- 11-17
onediamine (IPDA) in operative-clothing manufacture. Con- Woyton A, Wasik F, Blitanowska A (1974) An uncommon
tact Dermatitis 39:46-47 anaphylactic and eczematous reaction after contact with
Taylor JS, Bergfeld WF, Guin JD (1983) Contact dermatitis to knee epoxide resins (in Polish). Przegl Dermatol 61:303-308
patch adhesive in boy' s jeans: a nonoccupational cause of
epoxy res in sensitivity. Cleveland Clin Q 50:123-127
CHAPTER 74
Contact Allergy to Phenol-Formaldehyde Resins

E. Zimerson and M. Bruze
Introduction Resol res ins are produced by the reaction of phenols

with a molecular excess of formaldehyde under alka-
line conditions. The constituents of the resin become
In 1872, Baker found that the re action between phenol
rich in reactive methylol groups. In resols made from
and formaldehyde yielded a resinous product. The
phenol, the aromatic rings are joined together by
res in could be formed and cured and thus used for the
methylene groups while, in resols produced from
production of a variety of moulded and cast plastic
p-tert-butylphenol, the connecting groups are mainly
products. Baekland made the first successful commer-
of the methylene-ether type. The methylol-substituted
cial exploitation and the product entered the market in
molecules in resol res ins are reactive and this makes it
1909 under the name of Bakelite. This was the first
possible to cure the res in by applying pressure and/or
wholly synthetic polymer. Fillers and other additives
heat. Curing transforms resins based on phenol into a
were used to improve the product. From these first
rigid-network polymer, while cured resins based on
resins, other varieties have been developed so that
p-tert-butylphenol have more thermoplastic properties.
phenol-formaldehyde res ins now designate a group of
Novolac res ins are produced when formaldehyde
resins with varying properties made from different
reacts with a molecular excess of phenol under acidic
phenols and aldehydes.
conditions. As there are few or no methylol groups in
the molecules, these res ins show very low reactivity
and more aldehyde must be added in the process
Chemistry before curing. This is often done by the addition of a
formaldehyde releaser, such as paraformaldehyde or
The most used phenol-formaldehyde resins are based hexamethylenetetraamine.
on phenol or p-tert-butylphenol and formaldehyde. Phenol-formaldehyde resins are produced with
However, other phenols can be used, such as different degrees of condensation (curing). In this
resorcinol, cresols, guayachol (2-methoxy phenol), way, resins with different viscosities or tackiness can
p-phenylphenol, xylenols, amylphenol, octylphenol, be achieved. Resins with a low degree of condensation
nonylphenol and bis phenol A. In some resins, a are rieh in low-molecular-weight compounds as
mixture of phenols is used. Aldehydes other than monomers and dimers. The resins consist of hundreds
formaldehyde are occasionally used, for example, or thousands of substances, of which the vast majority
furfural. is not chemically defined. However, efforts to identify
Modified phenol-formaldehyde resins are, for ex- the main sensitisers in resins based on phenol and
ample, used for surface coatings and impregnation. In p-tert-butylphenol have been made.
these cases, the phenol-formaldehyde resin can be
mixed with colophony, terpenes, fatty acids, amines or
Use
epoxy resins.
Formaldehyde reacts with phenols giving methylol
(hydroxymethyl)-substituted phenols, which are the Previously, phenol-formaldehyde resins were often
monomers in the resin. Formaldehyde also creates used as casting compounds for products such as
chemical bonds between monomers. This bond can be knobs, electrical switches, ash trays and many others.
either of the methylene type (-CH 2 -) or of the This use has diminished and, nowadays, the res ins are
methylene-ether type (-CH 2 -O-CH 2 -), thus forming mainly used as binders in different products. Large
dimers, trimers, tetramers and so on. Phenol-formal- quantities are used, for example, in building, con-
dehyde resin can be produced in two principal ways, struction, car, leather, shoe, moulding and electric
either as resol or novolac resins. industries.

592 E. Zimerson and M. Bruze
Resins based on phenol and formaldehyde or a res ins (Hjort and Fregert 1967; Bruze et al. 1985). Free
combination of phenol, resorcinol and formaldehyde phenols also seem to be of little or no significance
are used in many glues and adhesives. The resins are concerning allergie reactions to the resins (Fregert and
used for decorative boards, laminated boards for Hjort 1969; Bruze et al. 1985), although p-tert-butyl-
floors, plywood, water-resistant boards, glass and phenol once was considered the main sensitiser in
mineral fibres for insulating, brake and clutch linings, resins based on this phenol (Malten 1958).
abrasive cloth and paper, grinding wheels and moulds There are relatively few reports on contact allergy to
for casting metal and plastic. resins based on phenol. In some investigations of
p-tert-Butylphenol-formaldehyde resin is used in workers in laminate productions, high frequencies of
adhesives when flexibility of the joint or extra water allergies have been reported (Bruze and Almgren
resistance is needed. The resin is frequently used in 1988). Reports of occupational sensitisation have also
glues for shoes and other leather products, such as concerned a secretary handling typewriter correction
watch straps. Other uses include glues for automobile paper (Jordan and Bourlas 1975), a newspaper dealer
upholstery, furniture, hobbies, artificial fingernails and (Castelain et al. 1980), painters (Hjort and Fregert
adhesive labels. Other products reported to contain the 1967), a worker in a rubber factory (van der Willingen
resin include athletic tapes, glue in hearing aids, and 1987), bricklayers (Sonneck 1964), workers producing
ink in marking pens. abrasive paper (Bompart and Smagghe 1959), a worker
Modified resins or resins based on p-tert-butylphe- manufacturing gasoline filters (Gaul 1967), and work-
nol or other alkyl-substituted phenols are used for ers sawing masonite or using grinding wheels (Fregert
surface coatings as protective and isolating varnishes and Tegner 1972). One factor that can contribute to the
for packing due to their water-repellent properties. few reported cases is that resins of this type are not
Modified res ins can be used as a binders in inks, usually used in standard patch-test series.
typewriter correction papers and different laminates. It has been shown that resol res ins of this type
contain highly sensitising substances. From this type of
resin, 14 sensitisers have been isolated and described
(Fig. 1). Both monomers and dimers were shown to be
Contact Dermatitis and Allergy
sensitisers, and 2-methylol phenol (A in Fig. 1) and
4,4' -dihydroXY-3,3'-dimethylol-diphenyl methane (M
Phenol-formaldehyde resins can cause several types of in Fig. 1) were shown to be strong sensitisers. Patch
damage to the skin. The most frequendy reported testing with serial dilutions showed that some of the
effects are different types of contact dermatitis such as sensitisers, for example 4,4' -dihydroXY-3,3' -dimethylol-
irritant contact dermatitis and allergie contact derma- diphenyl methane, could elicit an allergie reaction
titis. Depigmentation and contact urticaria have also down to a concentration of about 0.01 ppm in patients
been described. Reaction products, such as monomers with a high sensitivity. The presence of these sen-
and dimers, or remaining raw materials, such as sitisers in res ins and products based on phenol and
phenols and aldehydes, are causative agents. formaldehyde has been investigated. Concentrations of
Phenol-formaldehyde res ins can cause irritant con- allergens in products was reduced by a factor of 100-
tact dermatitis (Fregert 1980) and chemical burns 1000 when compared with the contents of the resins.
(Fisher 1973). Many phenols are known to be irritating (Bruze 1985; Bruze et al. 1986).
and can cause chemical burns and the level of p-tert-Butylphenol-formaldehyde resin is the most
remaining or free phenol can vary in the resins. The frequently reported sensitiser among the phenol-
reaction products, methylol phenols, generally seem to formaldehyde resins. As this resin is used both in
be less irritating to the skin than the phenols. Low or industries and in personal products, sensitisation can
high pH of the resin can contribute to irritant contact be of occupational origin or caused by contact with the
dermatitis. The pH of a resin mainly depends on resin in ordinary daily life. In 1958, contact allergy was
remaining or added catalyst which can be an acid or described among cobblers (Malten 1958). Since then,
a base. more patients working in shoe manufacturing or shoe
Depigmentation can be caused by certain res ins and repairing have been reported (Malten et al. 1983;
is likely due to remaining phenols such as p-tert- Mancuso et al. 1996) as well as patients with shoe
butylphenol (Malten et al. 1971; Stevenson 1981). dermatitis (Freeman 1997); a major problem that
Contact urtiearia has been ascribed to phenol-formal- sensitised persons face is finding shoes that they can
dehyde resins (Kalimo et al. 1980). Most reports about tolerate. Also, among workers in a car factory (Engel
adverse effects from phenol-formaldehyde resins and Calnan 1966), painters (Högberg and Wahlberg
describe allergie contact dermatitis. Although free 1980), and glue users (Moran and Martin-PascualI978;
formaldehyde can be found in many phenol-formal- Cronin 1980), contact allergy has been reported. Other
dehyde resins, it is not a major sensitiser in these causes of mainly non-occupational sensitisation and/or
B
Contact Allergy to Phenol-Formaldehyde Resins 593
H OH OH
I
~
A
~ -.. ; : B
I ~ OH
trF
OH OH OH
OH
~
'/"
I I
::-.... ::-....
HO H OH HO
HO~'/"
I I
::-.... ::-....
HO K OH
OH
OH
OH
HO
Fig. lA-O. Chemical structures of identified sensitisers in resins allergie eontaet dermatitis ean be leather wateh straps
based on phenol and formaldehyde. A 2-methylol phenol. B (Foussereau et al. 1968; Mobaeken and Hersle 1976),
3-methylol phenol. C 4-methylol phenol. D o-cresol. E 2,4-
dimethylol phenol. F 2,6-dimethylol phenol. G 2,4,6-trimethylol use of eertain plastie finger-nail adhesives (Ryeroft
phenol. H 4,4'-dihydroxy diphenyl methane. I 2,4'-dihydroxy et al. 1980), athletie tape (Shono et al. 1991), hearing
diphenyl methane. J 2,2'-dihydroxy diphenyl methane. K 4,4'- aids (Matrolonardo et al. 1993), lip liners (Angelini
dihydroXY-3-hydroxymethyl-diphenyl methane. L 4,4'-dihy-
droXY-3,5-dihydroxymethyl-diphenyl methane. M 4,4'-dihydroxy- et al. 1993), knee guards (Vineenzi et al. 1992), dero-
3,3'-dihydroxymethyl-diphenyl methane. N 2,4'-dihydroXY-3',5'- tation braees used after orthopaedie operations and
dihydroxymethyl-diphenyl methane. 0 2,4' -dihydroXY-3,3' -dihy- rain eoats (Hayakawa et al. 1994), a waist support for
droxymethyl-diphenyl methane
594 E. Zimerson and M. Bruze
treatment of scoliosis and leather glues (Tarvainen 1994). However, patch testing with this resin is not
1995), marking pens (Hagdrup et al. 1994) and pros- sufficient to detect allergies to phenol-formaldehyde
theses (Romaguera et al. 1985). resins based on other phenols and patch testing with
The first allergen reported in this resin was p-tert- the patients' own resin/material can therefore be
butylphenol (Malten 1958). Formaldehyde is another indicated (Bruze 1988, 1985).
allergen present in the resin. However, most individ-
uals sensitised to p-tert-butylphenol-formaldehyde
resin are not sensitive to p-tert-butylphenol or Connections to Other Sensitisers
formaldehyde (Malten 1987). The two monomers,
2-hydroxymethyl-p-tert-butylphenol and 2,6-dimethyl-
In 1967, a possible relationship between contact allergy
ol-p-tert-butylphenol, have been shown to be allergens
to phenol-formaldehyde resin and coal tar was noted
in the resin, the latter being the stronger sensitiser of
(Hjort and Fregert 1967). Some simple phenols have
the two (unpublished observations). Some theoretical
been shown to be probable cross-reacting substances
constituents and theoretical degradation products have
in patients hypersensitive to phenol-formaldehyde
been synthesised and, among these, a linear tetramer
resin, for example o-cresol (Bruze and Zimerson
has been reported as an allergen (Agatha and Schubert
1997). o-Cresol is also a known component in coal
1979; Schubert and Agatha 1979). Present investiga-
and wood tar (Snell and Ettre 1973; Richardson 1993)
tions in our department regarding isolation of aller-
and it has been identified as an allergen in phenol-
gens directly from the resin indicate the presence of
formaldehyde resin (Bruze and Zimerson 1998). This
many other allergens, some of which have a potency
could explain the connection to coal taro It also
comparable with the strongest allergens in resins based
indicates a possible connection to other sources of
on phenol (unpublished data). Chemical structures of
o-cresol, for example, tobacco smoke Oeanty et al. 1984).
identified sensitizers in res ins based on p-tert-butyl-
In patients hypersensitive to phenol-formaldehyde
phenol and formaldehyde are shown in Fig. 2.
resin (resol), simultaneous patch-test reactions to
p-tert-Butylphenol-formaldehyde resin is included
formaldehyde, colophony, hydroabietyl alcohol, bal-
in the International Contact Dermatitis Reseacrh
sam of Peru, perfume mixture and p-tert-butylphenol-
Group (ICDRG) standard patch-test series. Positive
formaldehyde resin have been reported. In patients
patch-test reactions have varied between 0.3% and
hypersensitive to p-tert-butylphenol-formaldehyde
2.6% among dermatological patients (Handley et al.
res in (resol), simultaneous patch-test reactions to
1993; Tarvainen 1995). In Portugal, positive reactions
hydroabietyl alcohol, balsam of Peru and phenol-
varied between 1.4% (1984) and 3.8% (1992), with an
formaldehyde resin have been reported (Bruze 1986).
increasing tendency mainly in woman (Marques et al.
Simultaneous patch-test reactions to p-tert-butyl-
phenol-formaldehyde resin and p-tert-butylcatechol
have been reported (Estlander et al. 1998), and p-tert-
butylcatechol has been shown to be a component in at
least some res ins based on p-tert-butylphenol-formal-
dehyde (Zimerson and Bruze 1998). This can indicate a
connection to other sources of p-tert-butylcatechol,
which is used as an antioxidant (Gellin et al. 1970) and
A as a stabiliser in different plastic monomers (Macfar-
lane et al. 1990).
Treatment and Prevention

H OH
Dermatitis caused by phenol-formaldehyde resins is

treated in the same way as other types of contact
dermatitis. Irritant dermatitis can usually be success-
fully treated if it is possible to reduce exposure to the
irritating res in. In many cases of occupationally related
allergic dermatitis caused by phenol-formaldehyde
resin, the person cannot continue the job. However,
Fig. 2A-D. Chemical structures of identified sensitisers in resins the prognosis is usually good if they can change jobs.
based on p-tert-butylphenol and formaldehyde. A p-tert-butyl-
phenol. B 2-methylol p-tert-butylphenol. C 2,6-dimethylol p-tert- Work including handling of cured products can be
butylphenol. D p-tert-butylcatechol (PTBC) tolerated if the sensitivity is not too high.
Contact Allergy to Phenol-Formaldehyde Resins 595
For patients hypersensitive to p-tert-butylphenol- Freeman S (1997) Shoe dermatitis. Contact Dermatitis 36:247-251
formaldehyde resin, for whom no clinically relevant Fregert S (1980) Irritant dermatitis from phenol-formaldehyde
resin powder. Contact Dermatitis 6:493
contact to this resin can be found, patch testing with Fregert S, Hjort N (1969) Results of standard patch tests with
p-tert-butyl catechol can be indicated. Patch testing substances abandoned. Contact Dermatitis Newslett 5:85-86
with p-tert-butylphenol-formaldehyde resin is not Fregert S, Tegner E (1972) Allergic contact dermatitis due to
phenolic resin in ready products. Contact Dermatitis Newslett
sufficient to detect hypersensivity to phenol-formal- 12:328
dehyde res ins based on other phenols. A more Foussereau MJ, Petitjean J, Barre JG (1968) Eczema aux bracelets-
complete patch testing for allergies to this group of montres par allergie ades resines formol-p.t.butylphenol des
colles pour cuir (resines du type c.k.r. 1634) Bull Soc Fr
resins should include testing with phenol-formalde- Dermatol Syphiligr 75:630-633
hyde resin and the patients' own resinslmaterials. Gaul LE (1967) Absence of formaldehyde sensitivity in phenol
Extracts of finished products can be useful for patch formaldehyde dermatitis. J Invert Dermatol 48:485-486
Gellin GA, Possiek PA, Perone VB (1970) Depigmentation from
testing. Resins based on phenol and p-tert-butylphenol 4-tertiary butyl catechol: an experimental study. J Invest
can be tested as a mix. (Bruze 1985, 1988) Dermatol 55:190-197
Phenol-formaldehyde resin included in standard or Hagdrup H, Egsgaard H, Carlsen L, Andersen KE (1994) Contact
allergy to 2-hydroXY-5-tert-butyl benzylalcohol and 2,6-
supplementary test series should be of the resol type, bis(hydroxymethyl)-4-tert-butylphenol, components of a
as this type of resin contains higher levels of potent phenolic resin used in marking pens. Contact Dermatitis
allergens than novolac resins. 31:154-156
Handley J, Todd D, Bingham A, Corbett R, Burrows D (1993)
Allergic contact dermatitis from para-tertiary-butylphenol-
formaldehyde resin (PTBP-F-R) in Northern Ireland. Contact
References Hayakawa R, Ogino Y, Suzuki M, Kaniwa M (1994) Allergic
contact dermatitis from para-tertiary-butylphenol-formalde-
hyde res in (PTBP-F-R). Contact Dermatitis 30:187-188
Agatha G, Schubert H (1979) Untersuchungen zur Allergen- Hjort N, Fregert S (1967) Sensitivity to formaldehyde and
Identifizierung bei der p-tertiären Butylphenol-Formal- formaldehyde resins. Contact Dermatitis Newslett 2:18-19
dehydharz-Allergie. Dermatol Monatsschr 165:337-345 Högberg M, Wahlberg JE (1980) Health screening for occupa-
Angelini E, Marinaro C, Carrozzo AM, Bianchi L, Delogu A, tional derrnatoses in house painters. Contact Dermatitis
Gianello G, Nini G (1993) Allergic contact dermatitis of the lip 6:100-106
margins from para-tertiary-butylphenol in a lip liner. Contact Jeanty G, Masse J, Bercot P, Coq F (1984) Quantitative analysis of
Dermatitis 28:146-148 cigarette smoke condensate monophenols by reverse-phase
Bornpart PV, Smagge G (1959) Quelques remarques d'ardre high-performance liquid chromatography. Beitr Tabakforsc-
pratique apropos d'une application industrielle des resines hung Int 12:245-250
formo-phenolique. Arch Mal Prof 20:64-67 Jordan WP, Bourlas M (1975) Contact dermatitis from typewriter
Bruze M (1985) Contact sensitizers in resins based on phenol and correction paper. Cutis 15:594-595
formaldehyde. Acta Dermatol Venereol Suppl (Stockh) 119: Kalimo K, Saarni H, Kytta J (1980) Immediate and delayed type
1-83 reactions to formaldehyde resin in glass wool. Contact
Bruze M (1986) Simultaneous reactions to phenol-formaldehyde Dermatitis 6:496
res ins colophony!hydroabietyl alcohol and balsam of Peru! Macfarlane AW, Yu RC, King CM (1990) Contact sensitivity to
perfume mixture. Contact Dermatitis 14:119-120 para-tertiary-butylcatechol in an artificial limb. Contact
Bruze M (1988) Patch testing with a mixture of 2 phenol- Dermatitis 22:56-57
formaldehyde resins. Contact Dermatitis 19:116-119 Malten KE (1958) Occupational eczema due to para-tertiary
Bruze M, Almgren G (1988) Occupational derrnatoses in workers butylphenol in a shoe adhesive. Dermatologica 117:103-109
exposed to resins based on phenol and formaldehyde. Malten KE (1987) Old and new, mainly occupational derma-
Contact Dermatitis 19:272-277 tological problems in the production and processing of
Bruze M, Zimerson E (1997) Cross-reaction patterns in patients plastics. In: Maibach HI (ed) Occupational and industrial
with contact allergy to simple methylol phenols. Contact dermatology. Year Book Medical Publishers, [ne, Chicago,
Dermatitis 37:82-86 pp 290-340
Bruze M, Zimerson E (1998) Contact allergy to o-cresol - a Malten KE, Seutter E, Hara I, et al (1971) Oecupational vitiligo
sensitizer in phenol-formaldehyde resin. Clin Exp Dermatol due to p-tert-butylphenol and homologues. Trans St John's
(in press) Hosp Derm Soc 57:115-134
Bruze M, Fregert S, Zimerson E (1985) Contact allergy to phenol- Malten KE, Rath R, Pastors PMH (1983) p-tert-Butylphenol
formaldehyde resins. Contact Dermatitis 12:81-86 formaldehyde and other causes of shoe dermatitis. Derm
Bruze M, Persson L, Trulsson L, Zimerson E (1986) Demonstra- Beruf Umwelt 31:149-153
tion of contact sensitizers in resins and products based on Mancuso G, Reggiani M, Berdondini RM (1996) Oceupational
phenol and formaldehyde. Contact Dermatitis 14:146-154 dermatitis in shoemakers. Contact Dermatitis 34:17-22
Castelain PY, Pirious A, Raulot-Lapointe H, Rabaglia JL (1980) Marques C, Gonealo M, Goncalo S (1994) Sensitivity to para-
Sensitization to abieto-formo-phenolic resin in printing ink. tertiary-butylphenol-formaldehyde resin in Portugal. Contact
Contact Dermatitis 6:145 Dermatitis 30:300-301
Cronin E (1980) Contact dermatitis. Churchill Livingstone, Matrolonardo M, Loconsole F, Conte A, Rantuecio F (1993)
Edinburgh, pp 617-619 Allergic contaet dermatitis due to para-tertiary-butylphenol-
Engel HO, Calnan CD (1966) Resin dermatitis in a car factory. Br formaldehyde res in in a hearing aid. Contact Dermatitis
J Ind Med 23:62-66 28:179
Estlander T, Kostiainen M, Jolanki R, Kanerva L (1998) Active Mobacken H, Hersie K (1976) Allergie contact dermatitis caused
sensitization and occupational allergie contact dermatitis by paratertiary butylphenol-formaldehyde res in in watch
caused by para-tertiary-butylcatechol. Contact Dermatitis straps. Contact Dermatitis 2:59
38:96-100 Moran M, Martin-Paseual A (1978) Contaet dermatitis to para-
Fisher AA (1973) Contact dermatitis, 2nd edn. Lea and Febiger, tertiary-butylphenol formaldehyde. Contact Dermatitis 4:
Philadelphia, pp 16-18 372-373
596 E. Zimerson and M. Bruze: Contact Allergy to Phenol-Formaldehyde Resins
Riehardson ML (ed) (1993) The dietionary of substances and their Sonneck HJ (1964) Hautschäden durch Kunstharzäurekitte.
effects. Cambridge Royal Society of Chemistry, Cambridge, Berufsdermatosen 12:42-48
pp 675-678 Stevenson CJ (1981) Occupational vitiligo: clinieal and epidemi-
Romaguera C, Grimalt F, Vilaplana J (1985) Paratertiary butyl- ological aspects. Br J Dermatollo5 [Suppl 21]:51-56
phenol formaldehyde resin in prosthesis. Contact Dermatitis Tarvainen K (1995) Analysis of patients with allergie patch test
12:174 reaction to a plasties and glue series. Contact Dermatitis
Rycroft RJG, Wilkinson JD, Holmes R, Hay RJ (1980) Contact 32:346-351
sensitization to p-tertiary-butylphenol (PTBP) resin in plastic Vincenzi C, Guerra L, Peluso AM, Zucchelli V (1992) Allergie
nail adhesive. Clin Exp Dermatol 5:411-445 contact dermatitis due to phenol-formaldehyde res in in a
Schubert H, Agatha G (1979) Zur Aliergennatur der para-tert. knee-guard. Contact Dermatitis 27:54
Butylphenol-formaldhydharze. Dermatosen 27:49-52 van der Willingen AH, Stolz E, van Joost T (1987) Sensitization to
Shono M, Ezoe K, Kaniwa M-A, Ikarashi Y, Kojima S, Nakamura phenol formaldehyde in rubber glue. Contact Dermati-
A (1991) Allergie contact dermatitis from para-tertiary- tisI6:291-292
butylphenol-formaldehyde resin (PTBP-FR) in athletic tape Zimerson E, Bruze M (1999) Demonstration of the contact
and leather adhesive. Contact Dermatitis 24:281-288 sensitizer p-tert-butylphenol-formaldehyde resin. Am J Con-
Snell FD, Ettre LS (1973) Encyclopedia of industrial chemical tact Dermat 10:2-6
analysis, vol17. Interscience Publishers, USA, pp 9-10
CHAPTER 75
Polyurethane Resins
T. Estlander, 1. Kanerva, and R. Jolanki
Introduction lists the isocyanates used in the production of PU

plastics.
The most commonly used difunctional isocyanates
The occupational hazards of polyurethane (PU) chem-
are TOl, MOl and 1,6-hexamethylene diisocyanate or
icals affect mainly the airways and eyes, and can cause
1,6-diisocyanatohexane (HOl). TDI often contains
rhinitis, asthma, hypersensitive pneumonitis or alveo-
mixtures of the isomers 2,4-TDI and 2,6-TDI.
litis, conjunctivitis, and chronic obstructive lung
MOl is industrially used as a mixture of 4,4' -MOl
disease (Mowe 1980; Zeiss et al. 1980; Baur 1991; Park
with 2,4'-MDI and 2,2'-MD which is also called poly-
et al. 1992). Isocyanates are toxic and poisonous
methylene polyphenyl isocyanate (P API or PMPPI).
chemieals, e.g., an ace iden tal massive exposure to
Phenyl iso cyanate is usually a trace constituent in
toluene diisocyanate (TOl) has been reported to cause
commercial MOl products. Examples of other
acute intoxication, inc1uding severe pulmonary, gastric
diisocyanates inc1ude isophorone diisocyanate
and neurological symptoms (Cronin 1980; Adams
(IPOl), trimethylhexamethylene diisocyanate
1983). Milder symptoms of intoxication in the workers
(TMOl), naphthalene diisocyanate (NOl), triphenyl-
of a glass-bottle factory were reported on exposure to
methane triisocyanate (TPMTI), and DMOl (Malten
dicyc10hexylmethane diisocyanate (DMOl) (Israeli
1977, 1982, 1984a,b, 1987a,b; Björkner 1992; Elvers
et al. 1981) and on inhalation of fumes emitted during
et al. 1991: Estlander et al. 1992; Karol and Kramarik
pyrolysis of PU driving belts welded by a special
1996).
process (Lob 1972). Analysis of the fumes revealed
When used as activators or hardeners, diisocyanates
diphenylmethane-4,4' -diisocyanate (MOl). Pyrolysis
are often dissolved in aliphatic or aromatic hydrocar-
products of PU have also been reported to cause fever
bon solvents or mixtures of different organic solvents,
(Seidel and Pohle 1960; Kanerva et al. 1991; Littorin
e.g., aliphatic hydrocarbon solvents, petroleum and
et al. 1994).
butylacetate. Adhesives, varnishes and paints mayaiso
Exposure to isocyanates and auxiliary chemieals
contain solvents.
mayaiso result in both allergie and irritant contact
Isocyanates are increasingly used in the manufac-
dermatitis, as weIl as urticaria (Malten 1964, 1982;
ture of various PU products, such as elastic and rigid
Rothe 1976; Israeli et al. 1981; Fisher 1986; Kanerva
foams, paints, lacquers, varnishes, other surface
et al. 1989, 1991; Estlander et al. 1992).
coatings, adhesives (one- or two-component glues),
binding and impregnation agents, joint sealants,
insulation materials, textile finishes, synthetic rub-
Composition
bers, and elastomeric fibers. Elastic foams are used
for mattresses, car seats, cushions, dashboards and
PUs are formed as a result of a condensation or an packages (Adams 1983; White et al. 1983; Johnson
adduction reaction between isocyanates and polyols et al. 1985; Wytch et al. 1988; Cvitanovic et al. 1989;
[polyesters or polyethers with terminal hydroxyl Wilkinson et al. 1991; Björkner 1992; Estlander et al.
(OH) groups, castor oil or tall oil]. If both compo- 1992; Bruynzeel and van der Wegen-Keijser 1993;
nents are more than difunctional, thermosetting end Abdallah et al. 1994; Kwangsukstith and Maibach
products are produced. Many auxiliary substances 1995). They can also be used in the preparation of
are also used in the manufacture of PU products. orthopedic casts (Vaichere et al. 1986), in the
The hardening process can be modified by heat or consolidation of the brittle ground of underground
with a catalyst [diamino diphenylmethane or meth- mining operations (Bertrand et al. 1984) and in the
ylenedianiline (MDA), triethylenediamine, tri ethyl- sealants injected into cracks in concrete buildings
amine, cobalt naphthenate or nickel salts]. Figure 1 (Rothe 1995).

Skin Problems Caused by PU Chemieals 1987; Kanerva et al. 1989; Huang et al. 1991; Estlander
et al. 1992).
W orkers exposed to PU chemicals and prepolymers
The reports on allergic contact eczema are few in
in laboratories (Rothe 1976; Kanerva et al. 1989;
number despite the extensive use of PU chemicals in
Estlander et al. 1992) and in the manufacture of PUs,
manufacturing pro ces ses and other applications. The
e.g., car spray painters, adhesive workers - such as
rigorous rules that workers have to follow when
those exposed to two-part glues used by floor layers
working with PUs to minimize the hazardous effects
(Lodi and Mancini 1993) - as weIl as lacquer workers
of isocyanates on the respiratory tract have probably and insulation installers, and those accidentally ex-
decreased the amount of all kinds of skin hazards
posed to pyrolysis products are at risk of developing
(Björkner 1992). dermatitis (Björkner 1992). Consolidation of brittle
ground (Bertrand et al. 1984) and sealants used to
Allergie Contact Dermatitis repair cracks in concrete buildings (Rothe 1995), and
the making of PU casts (Vaiehere et al. 1986) are other
Polyols are not considered to be sensitizers. However,
examples of products and tasks or manufacturing
Verdich and Skoven (1979) reported that a man, whose processes which have caused sensitization and allergie
job was to mix polyols and different catalysts in open eczema to PU chemicals. Rare sources of sensitization
barrels, was patch-test positive to the polyol 6510
to PU chemicals include a plastic watch strap (Alomar
(Desmophen) but not to any other chemicals used in
1986) a PU covering (Synthaderm) used to treat leg
the production. ulcers (HeIland et al. 1983), spectacle frames (Vilaplana
Allergy caused by PU chemicals has been reported
et al. 1987) and a pacemaker lining (Abdallah et al.
mainly from occupational exposure to the various
1994
diisocyanates, although cases caused by accelerators
have also been reported (Wodniansky 1967; Emmett
1976). Contact allergy is most often reported to be Allergie Contact Dermatitis and Urtiearia
caused by various MDI and DMDI, as summarized by at the Finnish Institute of Occupational Health
Malten 1987a,b. Cases due to TDI, IPDI, NDI, and HDI
have also been reported, as weIl as cases due to MDA AI/ergie Contact Dermatitis
used as an accelerator, and from exposure to MDI
(Malten 1977, 1982, 1984a,b; Lubach 1978; Cronin 1980; During 1974-1997, nine cases of allergic contact
King 1980; Liden 1980; White et al. 1983; Tanaka et al. dermatitis and one case of urticaria due to PU
chemicals (Kanerva et al. 1991) were diagnosed at the
Fig. 1. Chemical structure of isocyanates used in the production Finnish Institute of Occupational Health (FlOH). Six of
of polyurethane plastics the cases of allergic contact dermatitis have previously
OCN--O--CH2--O--NCO G!NCO
4,4-- diphenylmethane diisocyanate
Neo
toluene diisocyanate
H,N--O--CH,--O--NH,
diamino diphenylmethane 1,6-hexamethylene diisocyanate
Polyurethane Resins 599
been reported in detail (Kanerva et al. 1989; Estlander Insufficient hand protection is also an important
et al. 1992). factor in the development of sensitization to diisocy-
The first three patients with allergic contact derma- anates (Estlander et al. 1992; Dooms-Goossens et al.
titis were exposed for 2-8 months to PU chemicals 1995). Some of our patients did not use protective
containing different diisocyanates - in paint laboratory gloves at all, or glove contamination and penetration
work (IPD!), in PU foam spraying (MD!) and car spray had even increased allergen contact with their skin. For
painting (HD!) - before they developed dermatitis. On example, one of the patients had used thin cotton
patch testing, they reacted to IPD!, TMD!, TD!, HD! gloves unsuitable for gluing work and the other had
and MDA. Two of the patients also had diisocyanate- re-used neoprene rubber gloves, even though some
induced asthma confirmed by bronchial challenge, in diisocyanates, e.g., TDI, may degrade neoprene mate-
one case with MD! and in the other with HD! (Kanerva rial (Forsberg and Olsson 1985).
et al. 1989).
The next three patients - a foreman in a metal Urticaria
foundry, an industrial worker handling a two-compo-
nent PU adhesive, and a laboratory technician - had Other skin symptoms, except contact dermatitis, have
been exposed to MD! or a mixture of MD! and PAPI seldom been reported to be caused by isocyanates.
during periods ranging from 2 weeks to 19 years Urticaria has been described by Schürmann (1955) and
before they acquired dermatitis. On patch testing, all Israeli et al. (1981). Our patient was a welder who had
but the foundry foreman reacted to MDI. All three been welding mild steel profiles for 10 years and,
individuals, however, reacted to MDA, and one also occasionally, Forster Therm steel-PU profiles. The
reacted to TD! (Estlander et al. 1992). inside of the steel profile was made of PU, which was
One of the last three patients (unpublished) was an synthesized from MD!, polyol, and trichlorofiuoro-
industrial worker who developed dermatitis after methane as a blowing agent according to the informa-
1 week of mixing a PU hardener containing MD! and tion from the manufacturer, although it was evident
traces of TD! and a polyol. The second was a car that other substances had also been used.
electrician who acquired dermatitis on his face after After welding the profiles for 2 weeks, he developed
4 years of having occasionally handled two adhesivesl a generalized urticaria associated with edema of the
insulating materials containing MD! and TDI. The last lids and face, and fever up to 40 oe. He had no
one was a worker finishing circuit boards with a lacquer respiratory symptoms. The symptoms disappeared
containing, according to an analysis, TD!, MDI and 2 days after he stopped welding the profiles. One year
MDA. On patch testing, the industrial worker reacted to later, he again developed similar symptoms after
the PU harden er containing 100% MD!, and to MDA, having welded PU profiles. All skin tests to show
but this individual's reaction to TD! was weak. The car type-I or -IV allergy to isocyanates were negative.
electrician was patch-test positive only to TD!, and the Welding the profile for 30 min in the provocation
circuit-board worker to MD! and MDA but not to TDI. chamber, however, provoked a symmetrical urticarial
A structural similarity or cross allergy between MD! reaction on the hands and knees, and on the following
and MDA has been considered as an explanation for night his temperature rose to 38.5 °C.
simultaneous reactions to MD! and MDA (Fregert The lung-function tests were normal. Provocation
1967; Rothe 1976). MDA may also have formed as a tests with pure MDI and MDA were negative. The
result of hydrolysis of MD! (Buist and Gudgeon 1970). identification of etiologic factors for urticaria induced
The positive TD! reactions in patients exposed to MD! by airborne chemicals is difficult. It was not possible to
can be explained by cross reactions between MDI and determine whether the urticaria was media ted by
TDI, which has been confirmed by mouse-ear-swelling immunoglobulin E (IgE) , other immunoglobulins or
tests (Tanaka et al. 1987), although the reactions may a complement, or whether it was nonimmunological.
also be due to concomitant sensitization to the Possibly the re action was caused by product(s) formed
chemicals. Commercial MD! and PAPI may contain and inhaled while welding PU, although contact
as much as 21% TD! (Lubach 1978). urticaria from airborne chemicals was not excluded
All nine patients displayed the typicallocalization of (Kanerva et al. 1991).
dermatitis caused by isocyanates. They had dermatitis
on their hands, face or both. In line with earlier reports
(Peschel 1970; Emmett 1976; Rothe 1976; Malten 1977;
Irritant Contact Dermatitis
Wilkinson et al. 1991), heavy exposure to diisocyanates
resulted in rapid sensitization in 1 week to 2 months,
indicating that diisocyanates are strong skin sensiti- Isocyanates are described as mild to strong skin
zers, in accordance with the results of animal studies irritants and listed in industrial safety data sheets as
(Tanaka et al. 1987). skin-irritating substances. Liquid monomer coming
into contact with the skin has been reported to cause tests with the suspected products and the chemieal
edema and redness if it is not immediately washed analyses of the products are often necessary.
away (Fisher 1986). Irritant contact dermatitis seems to An analysis of the products is needed because the
be more common than allergic contact dermatitis, and information given in the material data sheets is often
small epidemics have occurred in certain plants using insufficient for diagnostic purposes. An impurity, not
isocyanates. the monomers or additives themselves, mayaiso be the
Itchy rash-like eruptions on exposed skin areas in actual cause of allergie dermatitis, e.g., allyl glycidyl
the factory workers who coat car badges with the resin ether in PU resins used in single-component se alants
have been reported within 1 week to 6 months of for metal and glass (Dooms-Goossens et al. 1995). In
exposure to DMDI (White et al. 1983). The same was the case of urticaria, prick tests with MDI, TDI and
reported in workers of a glass-bottle factory, where HDI human serum albumin conjugates and the deter-
DMDI was used to co at the bottles (Israeli et al. 1981), minations of the same diisocyanate IgE-specific anti-
as well as in .the workers of a PU-molding plant bodies in the serum should be included in the
(Emmett 1976). Irritant dermatitis appearing in a examinations. An IgE-mediated reaction mayaiso be
laboratory technician within a few ho urs of contact the cause of diisocyanate-induced urticaria. It is one of
with TDI and in arepair man have also been described the mechanisms of sensitization in occupationally
(Rothe 1976). derived asthma, and explained less than half of the
After heavy exposure to TDI, pulmonary symptoms immediate reactions in the bronchial provocation test
followed by thrombocytopenia and purpura have been in 35 cases of occupational asthma caused by MDI, TDI
reported (Jennings and Rower 1963). Pruritus and and HDI (Keskinen et al. 1988). However, achallenge
exanthema without proven contact sensitization have test in an exposure chamber (Kanerva et al. 1991) is
also been reported in workers exposed to MDI (Mowe probably the most reliable method of confirming the
1980). HDI is toxic to the eyes and skin (Cronin 1980). diagnosis of diisocyanate-induced urticaria.
Irritant dermatitis, in addition to allergic dermatitis In the prevention of dermatoses induced by PU
from HDI occurred in the workers of two clothing chemicals, it is important to inform an exposed
mills handling cloths previously coated with an anti- workers about all the health hazards of PU chemicals
pill finish containing HDI. The eruption was located and to give detailed instructions on how the chemicals
typically on the hands and face (Wilkinson et al. 1991). or products should be handled correctly. This means
Skin irritation can also be caused by amine accel- using appropriate personal protective equipment, such
erators, e.g., MDA (van Joost et al. 1987), triethylene- as EC conformity-marked chemical protective gloves,
diamine (Adams 1983) and triethylamine (Malten masks, eye and face protectors and other protective
1964). Concentrated liquids may even be corrosive. clothing. In countries belonging to the European
The irritant effect of diisocyanates in the hardeners, Union, all gloves used for chemical protection must
glues and paints mayaiso be attributed to the solvents be certified to fulfill the requirements of Directive 89/
used in these products. Completely hardened PU 686/EEC, category III, and supplied with CE markings.
products usually do not cause skin problems. However, Good ventilation, local exhausts and general cleanli-
some unreacted isocyanate monomer may remain in ness are also essential. During patient examination it is
surplus inside the PU foam, even after curing. During heard much too often that no information had been
machining and cutting, PU dust containing isocyanate given about the health hazards of PU chemicals or
is produced. When heated to above 250°C, PU products such as paints, adhesives, sealants and
polymers decompose into isocyanates and nitrogen lacquers.
oxides, and may then cause dermatitis (Björkner 1992).
Examination of Dermatoses Caused References

by PU Chemicals and Their Prevention
Abdallah HI, Balsara RK, O'Riordan AC (1994) Pacemaker
contact sensitivity: clinical recognition and management.
Examinations should include clinical follow-up of the Ann Thorac Surg 57:1017-1018
symptoms and exploration of the exposing chemicals, Adams RM (1983) Plastics. In: Occupational skin disease. Grune
as well as patch testing. Patch testing is necessary to and Stratton, New York, pp 238-266
Alomar A (1986) Contact dermatitis from a fashion watch.
distinguish between sensitization and irritation caused Contact Dermatitis 15:44-45
by PU chemie als. Patch tests should include at least Baur X (1991) Isocyanates. Clin Exp Allergy 21[SUppll]:241-246
MDI, TDI, HDI and MDA, in addition to actual Bertrand JP, Wantz JM, Heintz P, Zitter M (1984) Pathologie liee a
l'utilisation des isocyanates dans les mines de charbon.
chemicals to which the workers have been exposed Archives des Maladies Professionnelles de Mededne du
(Estlander et al. 1992). Besides the chemieals, patch Travail et de Securite Sodale 45:3-9
Polyurethane Resins 601
Björkner B (1992) Plastic materials. In: Rycroft RJG, Menne T, Lodi A, Maneini L (1993) Occupational airborne allergie contact
Frosch PI, Benezra C (eds) Textbook of contact dermatitis, dermatitis in parquet layers. Contact Dermatitis 29:281-282
Springer, Berlin Heidelberg New York, pp 557-559 Lubach D (1978) Erkrankung durch Diisocyanate, Teil 1: Schäden
Bruynzeel DP, van der Wegen-Keijser MH (1993) Contact der Atemvege und der Haut. Derm Beruf Umwelt 26:184-187
dermatitis in a cast technieian. Contact Dermatitis 28:193-194 Malten KE (1964) Occupational dermatoses in the processing of
Buist JM, Gudgeon H (eds) (1970) Advances in polymer plastics. Trans St John's Hosp Dermatol Soc 59:78-113
technology. Elsevier, London, pp 311-385 Malten KE (1977) 4,4' Diisocyanato dieyclohexyl methane (Hylene
Cronin E (1980) Contact dermatitis. Churchill Livingstone, W): a strong contact sensitizer. Contact Dermatitis 3:344-346
Edinburgh, pp 637-642 Malten KE (1982) Old and new, mainly occupational dermato-
Cvitanovie S, Zekan LI, Marusie M (1989) Occurrence and logieal problems in the production and processing of plasties.
speeifieity of IgE antibodies to isocyanates in occupationally In: Maibach HI, Gellin GA (eds) Occupational and industrial
exposed workers. Int Arch Occup Environ Health 61: dermatology. Year Book Medical Publishers Inc, Chicago,
483-486 pp 237-283
Dooms-Goossens A, Bruze M, Buysse L, Fregert S, Gruvberger B, Malten KE (1984a) Dermatological problems with synthetic resins
Stals H (1995) Contact allergy to allyl glyeidyl ether present as and plastics in glues, part I. Derm Beruf Umwelt 32:81-86
an impurity in 3-glyeidyloxypropyltrimethoxysilane, a fixing Malten KE (1984b) Dermatological problems with synthetic resins
additive in silicone and polyurethane resins. Contact Derma- and plastics in glues, part II. Derm Beruf Umwelt 32:118-125
titis 33:17-19 Malten KE (1987a) Printing plate manufacturing processes. In:
Elvers B, Hawkins S, Schulz G (eds) (1991) Ullmans's encyclope- Maibach HI (ed) Occupational and industrial dermatology,
dia of industrial chemistry, 5th edn, vol A 19. VCH 2nd edn. Year Book Medieal Publishers Inc, Chicago, pp
Verlagsgesellschaft GmbH, Weinheim, Basel, pp 371-385 351-366
Emmett EA (1976) Allergic contact dermatitis in polyurethane Malten KE (1987b) Old and new, mainly occupational dermato-
plastic moulders. J Occup Med 18:802-804 logieal problems in the production and processing of plastics.
Estlander T, Keskinen H, Jolanki R, Kanerva L (1992) Occupa- In: Maibach HI (ed) Occupational and industrial dermatol-
tional dermatitis from exposure to polyurethane chemicals. ogy, 2nd edn. Year Book Medical Publishers Inc, Chicago,
Contact Dermatitis 27:161-165 pp 290
Fisher AA (1986) Contact dermatitis, 3rd edn. Lea and Febiger, Mowe G (1980) Health risks from isocyanates. Contact Dermatitis
Philadelphia, pp 562-565 (extra issue) 8:44-45
Fregert S (1967) Allergie contact reaction to diphenyl-4.4'- Park HS, Park JN, Kim JW, Kim SK (1992) Clinieal and
diisocyanate. Contact Dermatitis Newslett 2:17 immunologieal evaluation of isocyanate exposed workers.
Forsberg K, Olsson KG (1985) Selection of chemieal protective J Korean Med Sei 7:122-127
gloves (in Swedish) Förening Teknisk Företagshälsovard, FTF Peschel H (1970) Hautvärenderung durch Isozyanate (De-
Stockholm smodur). Derm Mschr 156:691-697
Heliand S, Nyfors A, Utne L (1983) Contact dermatitis to Rothe A (1976) Zur Frage arbeitsbedingter Hautschädigungen
Synthaderm. Contact Dermatitis 9:504-506 durch Polyurethanchemikalien. Derm Beruf Umwelt 24:7-24
Huang 1, Wang XP, Chen BM, Ueda A, Aoyma K, Matsushita T Rothe A (1995) Gefahren bei der Injektion von Rissen in
(1991) Allergologie evaluation for workers exposed to toluene Betonbauwerken. Bau 2:72-75
diisocyanate. Ind Health 29:85-92 Schürmann D (1955) Gesundheitsschäden durch neuartige Lacke
Israeli R, Smirnov V, Sculsky M (1981) Vergiftungscheinungen bei und Schaumstoffe. Die DD (Desmodur/Desmophen) Lacke
Dicyclo-methan-4-4'-Diisocyanat-Exposition. Int Arch Oc- und Schaumstoffe als Ursache beruflieher Gesund-
cup Environ Health 48:179-184 heitsschädigungen. Dtsch Med Wochenschr 45=1661-1663
Jennings GH, Rower ND (1963) Thrompocytopenic purpura in Seidel H, Pohle H (1960) Zur Schädigung der Atmungsorgane
toluene di-isocyanate workers. Lancet 1:406-408 durch Desmodur. Tuberkuloseartz 14:675-686
Johnson A, Moira CY, Maclean L, Atkins E, Dybuneio A, Cheng F, Tanaka K-I, Takeoka A, Nishimura F, Hanada S (1987) Contact
Enarson D (1985) Respiratory abnormalities among workers sensitivity induced in mice by methylene bisphenyl diisocy-
in an iron steel foundry. B J Ind Med 42:94-100 anate. Contact Dermatitis 17:199-204
Kanerva L, Lähteenmäki M-T, Estlander T, Jolanki R, Keskinen H Vaichere E, Lefevre A, Choudat D, Mousel ML, Garnier R, Conso F
(1989) Allergie contact dermatitis from isocyanates. In: (1986) Allergies cutanees et respiratoires liees a la confection
Frosch PI, Dooms-Goossens A, Lachapelle J-M, Rycroft de "platres" orthopediques a base de resines synthetique.
RJG, Scheper RJ (eds) Current topics in contact dermatitis. Archives des Maladies Professionnelles de Medieine du
Springer, Berlin Heidelberg New York, pp 368-373 Travail et de Securite Soeiale 47=35-36
Kanerva L, Estlander T, Jolanki R, Lähteenmäki M-T, Keskinen H van Joost Th, Heule F, De Boer J (1987) Sensitization to
(1991) Occupational urticaria from welding polyurethane. methylenedianiline and para-structures. Contact Dermatitis
J Am Acad Dermatol 24:825-826 16:246-248
Karol MH, Kramarik JA (1996) Phenyl isocyanate is a potent Verdieh 1, Skoven I (1979) Allergie dermatitis from Desmophen, a
chemieal sensitizer. Toxicol Lett 89:139-146 polyether alcohol. Contact Dermatitis 5:120
Keskinen H, Tupasela 0, Tiikkainen U, Nordman H (1988) Vilaplana 1, Romaguera C, Grimalt F (1987) Allergie contact
Experience of speeific IgE in asthma due to isocyanates. Clin dermatitis from aliphatie isocyanate on spectacle frames.
Allergy 18:597-604 Contact Dermatitis 16:113
King CM (1980) Contact sensitivity to Hylene W. Contact White IR, Stewart JR, Rycroft AJ (1983) Allergic contact derma-
Dermatitis 6:353-35 titis from an organic di-isocyanate. Contact Dermatitis 9:
Kwangsukstith C, Maibach HI (1995) Contact urticaria from 300-303
polyurethane membrane hypoallergenic gloves. Contact Der- Wilkinson SM, Cartwright PH, Armitage 1, English JSC (1991)
matitis 33:200-201 Allergic contact dermatitis from 1,6-diisocyanatohexane in an
Liden C (1980) Allergie contact dermatitis from 4.4' -diisocyanate- anti-pill finish. Contact Dermatitis 25:94-96
diphenyl methane (MD!) in a molder. Contact Dermatitis Wodiansky P (1967) Hautschäden beider Erzeugung von Polyure-
6:301-302 than-Kunstoffen. Berufsdermatosen 15:81-92
Littorin M, Truedsson L, Welinder H, Skarping G, Martensson U, Wytch R, Ritchie IK, Clayton R (1988) Potential hazards of
Sjöholm AG (1994) Acute respiratory disorder, rhinocon- modern splinting materials. Occupational Health 40:492-494
junctivitis and fever assoeiated with the pyrolysis of poly- Zeiss CR, Kanellakes TM, Bellone JD, Levitz D, Pruzansky JJ,
urethane derived from diphenylmethane diisocyanate. Scand Patterson R (1980) Immunoglobulin E-mediated asthma and
Work Environ Health 20:216-222 hypersensitive pneumonitis with preeipitating anti-hapten
Lob M (1972) Fievre au diphenylmethane-diisocyanate (MDI). antibodies to diphenylmethane diisocyanate (MDI exposure).
Schweiz Med Wochenschr 102:647-649 J Allergy Clin Immunol 60:346-352
CHAPTER 76
Polyester Resins
L. Kanerva, K. Tarvainen, T. Estlander, and R. Jolanki
General (Björkner 1992, Kanerva et al. 1996a,b, Tarvainen

1996).
Polyester resins are polycondensates prepared in two
different forms: saturated and unsaturated. Saturated
Skin Problems from Polyester Resins
polyesters, alkyd resins, are produced from dicarbox-
ylic acids and polyalcohols. Dicarboxylic acids, chiefly
phthalic acid or maleie acid, are mainly used in their Saturated polyester resins are generally not considered
anhydride forms. Glycerol, pentaerythriol or trimeth- sensitizing. Allergie contact dermatitis has, however,
ylolpropane are the most-used polyalcohols. The been caused by an epoxy compound, triglycidyl
saturated polyesters synthesized in this way are also isocyanurate (TGIC), used as cross-linker in polyester
named unmodified alkyd resins, which are macromol- paints (Mathias 1988; Jolanki et al. 1993). Phthalic
ecules commonly used as plasticizers for other plastic anhydrides have been reported to cause irritation
materials. Alkyd resins can be modified by oil- (Malten and Zielliuis 1964; Tarvainen 1996) and
containing fatty acids to be used in water-based paints immediate IgE-mediated hypersensitivity, asthma, al-
and surface coatings (Björkner 1992; Kanerva et al. lergie rhinitis, urticaria (Howe et al. 1983; Jolanki et al.
1996a,b; Tarvainen 1996). 1987, 1997; Tarvainen et al. 1995a) and, in rare cases,
Unsaturated polyesters are produced through ester- allergie contact dermatitis (Kanerva et al. 1997). Due to
ification of organic acids or their anhydrides, e.g., automation of the manufacturing processes, exposure
maleie anhydride, phthalic anhydride or fumaric acid, to compounds of alkyd resins is only occasional,
and diols, e.g., diethylene glycol or 1,2-propylene glycol through accidents or in maintenance work. Phthalic
(Fig. 1). Unsaturated monomers, e.g., styrene, are used anhydride used in the manufacturing of alkyd res ins
as solvents and for copolymerization with unsaturated can cause irritation, and even caustic blisters on skin
groups along the polyester chain. Vinyl toluene and (Menschik 1955; Malten and Zielliuis 1964), especially
methyl methacrylate may be also used for cross- on moist skin, where anhydride is changed into the
linking. An initiator or catalyst is required to start the corresponding acid.
cross-linking process. The catalyst is usually a perox-
ide, such as benzoyl peroxide or methyl ethyl ketone Irritant Contact Dermatitis
peroxide. Accelerators, e.g., cobalt naphtenate, or
tertiary amines such as dimethyl aniline, diethyl Irritant properties ofUP resins are due to cross-linking
aniline and dimethyl-p-toluidine, are necessary for styrene (Fisher 1986) or, in earlier times, diallylphtha-
the curing of plastics at room temperature. The late (Fregert 1971). Styrene is classified as a mild
ultraviolet light (UV)-curable polyester system is used irritant, but repeated skin contact to styrene causes
in the fumiture industry as top coating and for drying of the skin and may give rise to primary
orthopedic casts. The UV -curable polyester system irritation (Schmunes 1990). Skin resorption experi-
contains vinyl toluene as the cross-linking agent and a ments of liquid (Berode et al. 1985) or gaseous styrene
benzoin-ether moleeule as photoinitiator (Björkner (Riihimäki and Pfäffli 1978) have not caused skin
1992; Kanerva et al. 1996a,b; Tarvainen 1996). symptoms on human volunteers, although styrene has
Unsaturated polyesters (UPs) have been used exten- been reported to cause blisters (Boume and Milner
sively in the reinforced plastics industry in the 1963) and even chemical bums (Bruze and Fregert
manufacture of products for transportation, construc- 1994). Prolonged exposure to styrene has caused a case
tion and marine applications. They are also used of skin atrophy, neurogenie muscular atrophy and
for coatings, finish es, lacquers, cements and glues anxiety reaction (Araki et al. 1971). Levels of styrene

Polyester Resins 603
vapor exceeding 300 ppm (1260 mg/m3 ) have been after prolonged exposure (Götell et al. 1972). Since
reported to induce erythema of the skin (Stewart et al. 1987, the hygienic limit for styrene in Finland has been
1968). Even at levels of 50 ppm (215 mg/m 3), styrene 20 ppm (85 mg/m3 ) for an 8-h time-weighted average.
vapor may irritate conjunctival and nasal mucous Organic peroxides, used as 3-10% solutions to
membranes (Götell et al. 1972). The irritancy to catalyze the hardening reactions of UP, are weak
mucous membranes is suggested to be due to the sensitizers but strong irritants (Haustein et al. 1985). In
vinyl group in styrene (Alarie 1973). Workers may the plastic-composite industry, organic peroxides have
develop a tolerance to mucous-membrane irritation caused irritant dermatitis and blisters (Boume and
Milner 1963). Reactive organic peroxide molecules in
Fig. 1. Unsaturated polyester resin is made by condensing 1,2- unhardened res in dust may cause stinging on uncov-
propanediol, maleie anhdyride and phthalic anhydrides. Styrene
is used as a cross-linking monomer ered areas of the skin during spray lamination
o
CI-1~O
11
©()
CH3
1
HO -CH -CH2-0H + 11>
CH-C~
o
+
?io
1,2-propanediol maleie anhydride phthalic anhydride
I-
+OJ:'-
H20
CH2-0-%-CH=CH -E-O-&~CH2-0-~oft.
unsaturated polyester resin
I styrene
cured polyester resin

604 L. Kanerva et al.
(Schmunes 1990). Hydrogen peroxide is very rarely an allergens have been reviewed in detail in this book
allergen (Aguirre et al. 1994; Kanerva et al. 1998). (Chap. 78), and have been summarized in Table l.
In addition to chemicals included in the resin We recently reported eight patients allergic to UP
system, mould-releasing chemicals have also induced res ins (Tarvainen et al. 1993a; Kanerva et al. 1999). Six
irritant contact dermatitis (Boume and Milner 1963). of them were employed in car-repair painting and two
Acetone is used to clean equipment in UP-resin in mould manufacturing. In order to clarify which
industries. Acetone has a low irritant and sensitizing components of the UP res in gave allergic and which
potential (Fisher 1986), but on repeated contact, gave negative patch-test reactions, our patch-test
acetone defats the skin. Acetone's irritant potential is procedures have been summarized in Table 2. All
due to its ability to disrupt the epidermal barrier patients reacted on patch testing to the UP-resin
(Fartasch 1997). It has been reported to be a contrib- component of a cement they had used in their work.
uting factor for irritant dermatitis (Boume and Milner Five patients also reacted to hardened UP-resin
1963; Tarvainen et al. 1993b; Tarvainen 1994). Chlori- cements, indicating that the hardened UP res in con-
nated hydrocarbon solvents such as methylene chlo- tains reactive monomers. Grinding the res in can give
ride and trichloroethane are used for cleaning airbome allergic reactions many years after it has been
purposes and are skin irritants (Midtgard and Knud- hardened (Kanerva et al. 1999). None of our patients
sen 1994). reacted to UP res ins used for lamination, to the
auxiliary substances, to filling materials or to catalysts
tested (Tarvainen et al. 1993a; Kanerva et al. 1999).
Allergie Contact Dermatitis The causative chemical in UP resin in our patients
was diethylene glycol maleate (DEGM; Tarvainen et al.
Allergic contact derma tos es attributed to working with 1993a; Kanerva et al. 1999). DEGM is not commercially
plastic composites were first reported from UP res ins available as a patch-test substance, and we have used
in 1955 (Lieber 1955). In 1956, Malten described five an extract of UP resin because we have not been able to
patients with contact eczema and positive patch tests synthesize DEGM due to its strong reactivity. Our own
to UP resins in a group of 30 workers in an airplane
factory (Malten 1956). Most cases of allergic contact
dermatitis have been due to UP-resin contact in Table 1. Allergens in unsaturated polyester (UP) resins
lamination work (Boume and Milner 1963; Malten
1956; Wehle 1966; Liden et al. 1984; Jinisek 1962), in Actual allergen in UP resin
painting (Kadlec et al. 1974) or in the use of UV light- Maleie acid Malten and Ziehlhuis 1964
Fumaric acid Malten and Ziehlhuis 1964
cured inks (Björkner 1982). UP dust from reinforced- Adipic acid Malten and Ziehlhuis 1964
plastic products (Boume and Milner 1963; Tarvainen Phthalic anhydride Malten and Ziehlhuis 1964;
Liden et al. 1984
1993b; Tarvainen 1995b) or UP automobile-repair putty Maleie anhydride Jinisek 1962
(Tarvainen et al. 1993a; Dooms-Goossens and De Jong Maleic esters Jinisek 1962; Malten 1984
1985; Kanerva et al. 1999) have also caused allergic Polyester methacrylate Björkner 1982
contact dermatitis. Non-occupational allergies from Methyl methacrylate Wehle 1966
Diethylene glycol maleate Tarvainen et al. 1993a; Kanerva
UP res in are infrequent, but have been reported from et al. 1999
'hypoallergenic' nail vamish (Shaw 1989), UP glue Cross-linking monomers
Styrene Key et al. 1961; Bourne and
(Sjöborg et al. 1982) and limb prostheses (Mac Farlane Milner 1963; Meneghini et al.
et al. 1986; Freeman 1986; Vincenzi et al. 1991; Haddad 1963; Sjöborg et al. 1982;
et al. 1996). Conde-Salazar et al. 1989
The allergens in UP resin are often the auxiliary Vinyltoluene (cross-reacting Sjöborg et al. 1982
with styrene)
chemicals in the resin, such as cobalt naphthenate (Key p- tert -Butyl catechol (used in Freeman 1986; Estlander
et al. 1961; Boume and Milner 1963; Malten and the manufacture of styrene) et al. 1998
Hardening catalysts
Ziehlhuis 1964; Kadlec et al. 1974), dibutyl phthalate, Benzoyl peroxide Bourne and Milner 1963;
dimethyl phthalate, dioctyl phthalate (Malten and Vincenzi et al. 1991
Ziehlhuis 1964), tricresyl phosphate (Key et al. 1961) Cyclohexanone Malten 1964
or a cross-linking monomer, such as styrene (Key et al. hydroxyperoxide
Methyl ethyl ketone peroxide Bourne and Milner 1963; Malten
1961; Boume and Milner 1963; Meneghini et al. 1963; and Ziehlhuis 1964
Sjöborg et al. 1982; Conde-Salazar et al. 1989) or a Inhibitor
Hydroquinone Torres et al. 1993
hardening catalyst such as benzoyl peroxide (Boume Artificiallimbs (made of
and Milner 1963; Malten and Ziehlhuis 1964; Vincenzi UP res in)
et al. 1991), cyclohexanone hydroperoxide (Malten p-tert-Butyl catechol MacFarlane 1986; Freeman 1986
Benzoyl peroxide Vincenzi et al. 1991
1964) or methyl ethyl ketone hydroperoxide (Boume Haddad et al. 1996
Dimethyl-p-toluidine
and Milner 1963; Malten and Ziehlhuis 1964). The
Polyester Resins 605
Table 2. Allergie and non-allergie (negative) patch-test reactions Conde-Salazar L, Gonzales M, Guimaraens D, Romero L (1989)
to the components of polyester res in (Tarvainen et al. 1993a; Occupational allergie contact dermatitis from styrene. Con-
Kanerva et al. 1999) tact Dermatitis 21:112
Dooms-Goosens A, De Jong G (1985) Letter to the editor. Contact
Allergie patch-test reaction to: Negative patch-test reaction to: Dermatitis 12:238
Estlander T, Kostiainen M, Jolanki R, Kanerva L (1998) Active
Hardener compound (1 %) sensitization and occupational allergie contact dermatitis
Two-component polyester
caused by para-tertiary-butylcatechol. Contact Dermatitis
cement (sanding dust)
38:96-100
JJ- Fartasch M (1997) Ultrastructure of the epidermal barrier after
Resin compound (including Filling materials (100%);
polyester resin and filling styrene (1 %) irritation. Mierose Res Tech 37:193-199
Fisher AA (1986) Contact dermatitis, 3rd edn. Lea and Febiger,
material)
Philadelphia
JJ- Freeman S (1986) Contact dermatitis of a limb stump caused by
Polyester resin (including Auxiliary substances (1 %)
p-tertiary butyl catechol in the artificial limb. Contact
auxiliary substances and
styrene) (1-5%) Dermatitis 14:68-69
Fregert S (1971) Outbreak of irritant contact dermatitis from
JJ- diallylphthalate in polyester resin. Contact Dermatitis News-
Pure polyester res in (1-5%) Ingredients of polyester
resin (10%) lett 10:234
Götell P, Axelson 0, Lindelöf B (1972) Field studies on human
JJ- styrene exposure. Work Environ Health 9:76-83
Purification:
Haddad FS, Cobb AG, Bentley G, Levell NJ, Dowd PM (1996)
TLC bands found at Rf-value
of 0.240.03 (n = 6) (100%) Hypersensitivity in aseptic loosening of total hip replace-
ments. The role of constituents of bone cement. J Bone Joint
JJ- Surg Br 78:546-549
Identification:
Diethyleneglycol maleate Haustein U-F, Tegetmeyer L, Ziegler V (1985) Allergie and irritant
(MW 204) (0.1-0.01 %) potential of benzoyl peroxide. Contact Dermatitis 13:252-257
Horio T, Tanaka K, Komura J (1977) Depigmentation due to para-
tertiary butylcatechol. Int Arch Occup Environ Health 39:
TLC thin-layer chromatography, MW molecular weight (in 127-133
kilodaltons) Howe W, Venables KM, Topping MD, Dally MB, Hawking R,
Laws JS, Newman Taylor AJ (1983) Tetrachlorophthalic
anhydride asthma: evidence for specific IgE antibody.
UP resins have given allergie pateh-test reaetions at J Allergy Clin Immunol 71:5-11
Jirasek L (1962) Polyesterove pryskyrice a skelne laminaty. Prac
pateh-test eoneentrations of 0.5-10% (Tarvainen et al. Lek 3:120-124
1993a; Kanerva et al. 1999). In one patient, 1% gave a Jolanki R, Estlander T, Kanerva L (1987) Occupational contact
weak allergie reaetion (Tarvainen et al. 1993a) and may dermatitis and contact urticaria caused by epoxy resins. Acta
Derm Venereol Suppl (Stockh) 134:90-94
therefore give false-negative pateh-test reaetions, and Jolanki R, Kanerva L, Estlander T, Tarvainen K, Leino T,
the test eoneentration may need to be as highs as 5% Komulainen M (1993) Occupational allergie contact derma-
(Kanerva et al. 1999). However, it is not clear at what titis caused by triglycidyl isocyanurate. In: Proceedings of the
Nordic Dermatology and Venereology Society XXVI Con-
eoneentration aetive sensitization may oeeur. gress, 12-15 June 1993, Rejkjavik, Iceland. Nordic Dermatol-
ogy and Venereology Society, Rejkjavik, pp 120
Jolanki R, Kanerva L, Estlander T, Tarvainen K (1997) Skin
allergy caused by organie acid anhydrides. In: Amin S, Lahti
A, Maibach HI (eds) Contact urticaria syndrome. CRC, Boca
References Raton, pp 217-224
Kadlec K, Hanslian L, Forprechtova (1974) Occurence of skin
disease as a result of work with polyester varnishes (in
Adams RM (1983) Occupational skin disease. Grune and Stratton, Czech). Cesk Dermatol 49:281-289
New York, pp 254-257 Kanerva L, Björkner B, Estlander T, Jolanki R, Tarvainen K
Aguirre A, Zabala R, Sanz de Galdeano C, Landa N, Diaz-Perez JL (1996a). Plastic materials: occupational exposure, skin
(1994) Positive patch tests to hydrogen peroxide in 2 cases. irritancy and its prevention. In: van der Valk P, Maibach
Contact Dermatitis 30:113 HI (eds) The irritant contact dermatitis syndrome. CRC, Boca
Alarie Y (1973) Sensory irritation of the upper airways by Raton, pp 127-155
airborne chemieals. Toxicol Appl Pharmacol 24:279-297 Kanerva L, Estlander T, Jolanki R, Tarvainen K, Björkner B
Araki S, Abe A, Ushio K, Fujino M (1971) A case of skin atrophy, (1996b) Kunststoffe ausser Epoxidharzen und Acrylaten als
neurogenie muscular atrophy and anxiety reaction following Ursache allergischer und irritativer Hautkrankheiten. Teil I.
long exposure to styrene. Jpn J Ind Health 13:427-431 Derm Beruf Umwelt 44:57-61
Berode M, Droz P-O, Guillemin M (1985) Human exposure to Kanerva L, Jolanki R, EstIander T (1996c) Offset printer's
styrene. VI. Percutaneous absorption in human volunteers. occupational allergie contact dermatitis caused by cobalt-
Int Arch Occup Environ Health 55:331-336 2-ethylliexoate. Contact Dermatitis 34:67-68
Björkner B (1982) Sensitizing capacity of polyester methacrylate Kanerva L, Hyry H, Jolanki R, Hytönen M, Estlander T (1997)
in ultraviolet curing inks tested in the Guinea pig. Acta Derm Delayed and immediate occupational allergy caused by
Venereol 62:153-182 methylhexaltydrophthalie anhydride. Contact Dermatitis
Björkner B (1992) Plastic materials. In: Rycroft RJG, Menne T, 36:34-38
Frosch PI, Benezra C (eds) Textbook of contact dermatitis. Kanerva L, Jolanki R, Riihimäki V, Kalimo K (1998) Patch test
Springer, Berlin Heidelberg New York, pp 539-572 reactions and occupational dermatoses caused by hydrogen
Bourne L, Milner F (1963) Polyester res in hazards. Br J Ind Med peroxide. Contact Dermatitis 39:146
20:100-109 Kanerva L, Estlander T, Alanko K, Pfäffli P, Jolanki R (1999)
Bruze M, Fregert S (1994) Chemical skin burn. In: Menne T, Occupational allergie contact dermatitis from unsaturated
Maibach HI (eds) Hand eczema. CRC, Boca Raton, pp 21-30 polyester resin an a car repair putty. Int J DermatoI38:447-452
606 L. Kanerva et al.: Polyester Resins
Key MM, Perone VB, Birmingham DJ (1961) Patch testing in Schmunes E (1990) Solvents and plasticizers. In: Adams RM (ed)
dermatitis from the newer resins. J Occup Med 3:361-364 Occupational skin disease, 2nd edn. Saunders, Philadelphia,
Liden C, Löfström A, Storgards-Hatam K (1984) Contact allergy pp 439-461
to unsaturated polyester in a boat builder. Contact Dermatitis Shaw S (1989) A case of contact dermatitis from 'hypoallergenie'
1l:262-264 nail varnish. Contact Dermatitis 20:385
Lieber EE (1955) Dermatitis - an industrial problem. Br Plastics 5jöborg S, Dalliquist I, Fregert 5, Trulson L (1982) Contact allergy
28:428-429 to styrene with cross reaction to vinyltoluene. Contact
MacFariane AW, Curley RK, King CM (1986) Contact sensitivity Dermatitis 8:207-208
to unsaturated polyester resin in a limb prosthesis. Contact Stewart RD, Dodd HC, Baretta ED, Schaffer AW (1968) Human
Dermatitis 15:301-303 exposure to styrene vapor. Arch Environ Health 16:656-662
Malten KE (1956) Occupational eczema in processing plastics Tarvainen K (1996) Occupational dermatoses from plastic
(doctoral dissertation in Dutch with English summary). composites based on polyester resins, epoxy res ins and vinyl
University of Amsterdam, Amsterdam ester res ins. People and Work 1l:1-66
Malten KE (1964) Einige Bemerkungen zur Hautsensibilisierung Tarvainen K, Jolanki R, Estlander T (1993a) Occupational contact
durch Aethoxylin (Epoxyd)-Kunstharze und deren Prophyl- allergy to unsaturated polyester res in cements. Contact
axe. Derm Beruf Umwelt 2:78-85 Dermatitis 28:220-224
Malten KE (1984) Dermatological problems with synthetic res ins Tarvainen K, Jolanki R, Forsman-Grönholm L, Estlander T, Pfäffli
and plastics in glues. Part I. Derm Beruf Umwelt 32:81-86 P, Juntunen J, Kanerva L (1993b) Exposure, skin proteetion
Malten KE, Zielhuis R (1964) Polyester resins. In: Malten KE, and occupational skin diseases in the glass-fibre reinforced
Zielhuis R (eds) Industrial toxicology and dermatology in the plastics industry. Contact Dermatitis 29:119-127
production and processing of plastics. Elsevier, Amsterdam, Tarvainen K, Estlander T, Jolanki R, Kanerva L (1994) Occupa-
pp 71-84 tional dermatoses caused by man-made mineral fibers. Am J
Mathias CGT (1988) Allergie contact dermatitis from triglycidyl Contact Dermat 5:22-29
iso cyan urate in polyester paint pigments. Contact Dermatitis Tarvainen K, Jolanki R, Estlander T, Tupasela 0, Pfäffli P,
19:67-68 Kanerva L (1995a) Immunologie contact urtiearia due to
Meneghini CL, Rantuccio F, Riboldi A (1963) Klinisch-all- airborne methylhexallydrophthalic and methyl tetrallydro-
ergologische Beobactungen bei beruflichen ekzematösen phthalic anhydrides. Contact Dermatitis 32:204-209
Kontakt-Dermatosen. Derm Beruf Umwelt ll:l81-244 Tarvainen K, Kanerva L, Jolanki R, Estlander T (1995b) Occupa-
Menschik H (1955) Gesundheitliche Gefahren bei der Herstellung tional dermatoses from the manufacture of plastic composite
von Phthalsäureanhydrid. Arch Gewerbepathol Gewerbehyg products. Am J Contact Dermat 6:95-104
183:454-475 Torres V, Mano-Azul AC, Correia T, 50ares AP (1993) Allergie
Midtgard U, Knudsen LE (1994) Fibre-reinforced plastics and contact cheilitis and stomatitis from hydroquinone in an
advanced polymer composites. Occupational hazards and acrylic dental prosthesis. Contact Dermatitis 29:102-193
toxicity of selected compounds. Nordic Council of Ministers Vincenzi C, Cameli N, Vassilopoulou A, Tosti A (1991) Allergie
and National Institute of Occupational Health, Denmark, contact dermatitis due to benzoyl peroxide in an arm
Copenhagen, pp 1-73 prosthesis. Contact Dermatitis 24:66-67
Riihimäki V, Pfäffli P (1978) Percutaneous absorption of solvent Wehle U (1966) Arbeitsbedingte Ekzeme durch Polyester. Allerg
vapours in man. Scand J Work Environ Health 4:73-85 Asthma (Leipz) 12:184-186
CHAPTER 77
Other Plastics
B. Björkner
Amino Plastics Skin Problems from Amino Plastics
Usually the finished product does not cause primary

Amino plastics is the common name for plastics
sensitization, but occasionally the uncured substance
formed by the reaction between an aldehyde and a
does. Textile dermatitis caused by urea- and mela-
compound with one or more amino groups. The
mine-formaldehyde resins is rare. Contact allergy to
most common aldehyde is formaldehyde but some-
amino resins is often combined with formaldehyde
times hexamethylenetetramine, which is a formalde-
allergy (Fregert 1981; Belsito 1993).
hyde releaser, can be used. Amino plastics always
Urea and melamine do not cause contact allergy.
contain an excess of formaldehyde. The most
Sensitization to amino plastics has developed from
common amino-containing compounds are urea
urea-formaldehyde resin used as textile finish (Belsito
(carbamide), H2 N-CO-NH 2 , and melamine, 2,4,6-
1993) and melamine-formaldehyde resin in orthopedic
triamino-1,3,5-triazine. The reaction with formalde-
casts (Ross et al. 1992), gypsum molds (Fregert 1981) or
hyde produces thermosetting urea-formaldehyde and
in the coating of plastic tubes intended for cosmetics.
melamine-formaldehyde resins by a polycondensa-
The irritancy of amino plastic is mainly due to
tion-type reaction. The amino resins are cured by
formaldehyde, which can be released from plastics.
heat, commonly with an inorganic acid as catalyst.
Nowadays, resins used in textiles release lower levels of
Although both resins are quite similar in appear-
free formaldehyde than previously (Belsito 1993).
ance, the melamine-formaldehyde resins have supe-
Occupational irritant contact dermatitis from fiber
rior water resistance to cured urea-formaldehyde
board containing urea-formaldehyde resin has been
resins. Both amino plastics are relatively unaffected
reported (Vale and Rycroft 1988). Dust from urea-
by common organic solvents, oils and greases and
formaldehyde insulating foam has caused airborne
are widely used as laminating and bonding mate-
irritancy (Dooms-Goossens et al. 1986).
rials in the wood and furniture industries. They are
used as wood glues and surface coatings. They are
also utilized to improve the wet strength of paper
Polystyrene Resins
and the crease-resistance of textiles. Powders from
urea-formaldehyde resins can be molded and used
as containers of cosmetics products, electric fittings Polystyrene (PS) is a hard and transparent plastic. It is
and bottle caps. Urea-formaldehyde foams have manufactured by polyaddition polymerization of sty-
found application as insulation in refrigerators and rene, CH 2 =CH-C 6 H5, using peroxide as an initiator. PS
within the walls of houses. Other typical uses of resin is one of the thermoplastics. As a foam, PS plastic
urea-formaldehyde res ins are clock cases, lavatory is an important packaging and insulation material.
seats and buttons. Melamine-formaldehyde resin Modified PS plastics with a co- or ter-polymer struc-
powders filled with cellulose are used for tableware, ture, e.g., styrene-butadiene (SB), styrene-acrylonitrile
e.g., plates and cups. High-quality decorative lam- (SAN), acrylonitrile-butadiene-styrene (ABS), are used
inates are made of melamine-formaldehyde resins. in household utensils, toys, electric appliances, han-
Amino plastics are often used in conjunction with dIes, bags and pipes. PS products are also widely used
fillers and reinforcements such as glass mat and in food packaging and disposable tableware. PS
cloth, silica, cotton fabrics and certain synthetic products can usually be identified by the metallic
fibers. sound they produce when dropped on a hard surface.

608 B. Björkner
To increase the light stability of styrene-based barium and zinc. Plasticizers, mainly phthalates, are
plastics, stabilizers such as benzophenones, benzotri- added to PVC to impart flexibility to the finished
azoles and organic nickel compounds are usually products and to improve processibility of the melt.
added. Plasticizers are added to almost all PVC. Hard PVC
contains approximately 10% and soft PVC up to
Skin Problems from PS Resins 60-70% plasticizers. The plasticizers are mostly in
the form of phthalic acid esters, most commonly
Contact allergy to styrene is extremely rare. One patient, di-ethylhexyl phthalate (DEHP), often termed dioctyl
sensitive to styrene, cross-reacted on patch testing to 2-, phthalate (DOP). However, more than one plasticizer
3- and 4-vinyltoluene (2-, 3- and 4-methylstyrene) and is usually used when properties other than flexibility
to the metabolites styrene epoxide and 4-vinylphenol are also required in the end product. Sometimes
(4-hydroxy-styrene). It is assumed that styrene is a pro- uncured epoxy resin is added as a plasticizer and
hapten metabolized in the skin by aurylhydrocarbon stabilizer to PVC. Soft or plasticized PVC is very
hydroxylase to styrene epoxide, which acts as a true popular in applications such as artificial skin, wall-
hapten. Styrene occurs both in nature and as a synthetic papers, laminated tablecloths, carpets, toys, garden
product, and vinyltoluenes (methylstyrenes) occur as hoses, wire coatings for electric cables, shower
synthetic products in plastics (Sjöborg et al. 1984). curtains, adhesive pIasters, foils, bandages, casts and
Cases of immediate allergy to styrene have been protective gloves.
reported (Bourne and Miller 1963; Conde-Salazar et al. PVC is one of the most inexpensive thermoplastics
1989; Moscato et al. 1987; Sjöborg et al. 1984). and is the most-used plastic after the polyethylene. The
Styrene defats the skin, and may give rise to primary toughness and rigidity of hard PVC give rise to its
irritation, but it is nevertheless classified as a mild application in sewage systems, agricultural products,
irritant (Kanerva et al. 1996; Schmunes 1990). Styrene drinking-water pipes, furniture, window frames, dishes
has been reported to cause chemical burns (Bruze and and packages of various shapes.
Fregert 1994).
Skin Problems from Polyvinyl Resins

Polyvinyl Resins
Workers processing PVC plastics can develop contact
dermatitis (Schulsinger and Möllegaard 1980; Vidovic
The chemie al structure of a vinyl compound is and Kansky 1985). The vinyl chloride polymer (PVC)
CH 2=CH-R, where CH 2=CH- is the vinyl group and does not sensitize, and its additives seldom do. In the
R is the symbol for different chemieal groups used to final PVC product there are always molecules of the
synthesize various polyvinyl resins. Some examples of monomer as well as a number of additives which may
vinyl compounds are vinyl chloride (R: Cl-), vinyl cause contact dermatitis (Hills and Ive 1993; Vidovic
acetate (R: CH 3COOH-), vinyl acetal (R: CH 3 (CH2}n-O-, and Kansky 1985), irritant dermatitis (Di Lernia et al.
n = 0, 1, 2 ... ) vinyl alcohol (R: OH-) and vinylidene 1989; Schulsinger and Möllegaard 1980) and contact
chloride (R: CH 2=CCI,). The polyvinyl resins are urticaria (Osmundsen 1980). Allergie contact reaction
polymerized through a polyaddition reaction and to epoxy resin in PVC plastic film and to the
belong to the group of thermoplastics. Vinyl chloride phenylthiourea and phenylisothiocyanate in PVC ad-
(CH 2=CH-Cl) is a gaseous monomer, polymerized by hesive tape has been reported (Fregert and Rorsman
suspension, emulsion, solution and bulk processes. 1963; Fregert et al. 1982; Fregert et al. 1984). Dip-
The repeating unit of polyvinyl chloride (PVC) is henylthiourea is a heat stabilizer in PCV and is partly
-CH 2-CHCI-. decomposed to phenyl isothiocyanate.
There are various additives in PVC plastics, such The irritancy of polyvinyl resins is due to the
as antioxidants, light stabilizers, initiators, plasti- plasticizers and stabilizers, dibutyl thiomaleate, dibutyl
ci zers, flame retardants, pigments and others. As sebacate or dioctyl phthalate (Di Lernia et al. 1989;
initiators, potassium persulfate, benzoyl peroxide, Kanerva et al. 1996). PVC powder may irritate in a
lauryl peroxide, percarbonate and some azo-com- special environment. An outbreak of acneform erup-
pounds can be used. The presence of chlorine in the tions occurring in a PVC-manufacturing factory has
hydrocarbon backbone gives rigidity and toughness been reported (Goh and Ho 1988). The cause was
to the polymer, but PVC liberates hydrogen chloride probably the combination of heat, high humidity and
when exposed to high temperatures. To prevent this, the irritation caused by the PVC powder. Toxic
stabilizers are added to the polymer. There are polyvinyl chloride disease from the manufacturing of
several kinds of stabilizers on the market. The most PVC, consisting of Raynaud's phenomenon, lytic
important contain lead, tin, calcium and zinc and disease of bone, and scleroderma, has been reported.
Other Plastics 609
Polyolefins Polyamides
Polyolefins belong to a group of thermoplastics poly- The polyamides are thermoplastics manufactured by
merized through polyaddition reactions of olefins condensation polymerization of adipic acid, HOOC-
(unsaturated hydrocarbons). The most important (CH2)4-COOH, and hexamethylene diamine, H 2N-
polyolefins are ethylene (ethene), CH 2=CH" which (CH2)6-NH2' The resulting polymer has a linear
gives polyethylene, and propylene (propene), structure with a repeating unit of -OC-(CH2)4CONH-
CH 2=CHCH 3, which gives polypropylene when poly- (CH2)6-NH-. Other polyamides can be polymerized
merized. from caprolactam and water.
Among the plastics already known more than half a The polyamides are made into fibers known as
century ago, polyethylene is the most important in nylons. The transparency of polyamide films makes
volume. The repeating unit of polyethylene is -CH 2- them very useful for packaging purposes. Hospital
CH 2-. The polymerization is produced at high or low wares made of polyamide plastics have a good stability
press ures, aided by catalysts and initiators. According at sterilization temperatures, and combined films of
to their density, polyethylenes are grouped into three laminates are used, for example, in vacuum packaging
main categories: low-density polyethylenes, linear low- of meat.
density polyethylenes and high-density polyethylenes.
All of these types are lighter than water and belong
Skin Problems from Polyamides
to the most inexpensive group of plastics. Films and
sheets for packaging uses are the most widespread
Irritant and allergie contact dermatitides from poly-
forms of polyethylene plastics. Because low-density
amides are rare (Bruze et al. 1988).
polyethylene is soft and flexible, transparent and
nontoxic due to the absence of plasticizers, it is used
for food packaging. In addition, shopping bags and
Polycarbonates
sacks are the most popular applications of low-density
polyethylenes. Due to its better mechanical strength,
linear low-density polyethylene is the main plastic used A polycarbonate plastic is characterized by the
in the film-manufacturing industry. Because low-den- -O-Co-o- group. It can be made from phosgene
sity polyethylene has an outstanding chemical and (COCI2) and bisphenol A (4,4'-dihydroxydiphenyl-2,2-
frost resistance, its main applications are for hoses, propane) and has the structure -O-(C6H4)-C(CH3 )2-
coatings of electric cables and wires, and many kinds (C 6H4)-O-CO-. Other bisphenols than bisphenol A
of household utensils such as jars, containers, deep- can also be used. Polycarbonate plastic is a very
freeze boxes and cases. High-density polyethylenes are transparent, tough and inert material, which is
used mainly for bottles and containers, and also for extremely resistant to sunlight and weather. It is
shopping bags and pipes. used in safety heImets, bullet-proof windows, shields,
Polypropylene has the repeating unit: -CH 2- doors, bottles and lamp globes, among other things.
CH(CH3)-. Polypropylene is similar to high-density However, the plastic is relatively expensive and
polyethylene, but is slightly harder and tougher. In therefore has limited applications.
addition to filament applications such as horne
furnishings, non-woven products and carpets, poly- Skin Problems from Polycarbonates
propylene is also used in pipes and films.
Irritant and allergie contact dermatitides from poly-
Skin Problems from Polyolefins carbonates are rare (Bruze et al. 1988).
Irritant and allergie contact dermatitides from polyeth-

ylene and polypropylene are rare. Incompletely cured
Other Rare Plastic Materials
res ins may cause contact dermatitis. It is most likely to
be caused by added ingredients, such as catalysts and
initiators. When sawing and grinding polyolefins, the Plastics of less dermatological importance are: cou-
heat may cause depolymerization and release chemi- marone-indene polymers, cellulose polymers and
eals, e.g., aldehydes, ketones, and acids, which might cyclohexanone resins. It is not entirely known if the
cause airborne contact dermatitis. Itching caused by the monomers, additives or impurities are the cause of
irritancy ofheat-decomposed polyethylene plastics has dermatitis in the reported cases (Bruze et al. 1988;
been reported (Thestrup-Pedersen et al. 1989). Heine and Laubstein 1990).
610 B. Björkner: Other Plastics
References Hills RJ, Ive FA (1993) Allergie contact dermatitis from di-
isodecyl phthalate in a polyvinyl chloride identy band.
Belsito DV (1993) Textile dermatitis. Am J Contact Dermat 4:249 Kanerva L, Björkner B, Estlander T, et al. (1996) Plastic materials:
Boume L, Milner F (1963) Polyester resin hazards. Br J Ind Med occupational exposure, skin irritancy and its prevention. In:
20:100 van der Valk PGM, Maibach HI (eds) The irritant contact
Bruze M, Fregert S (1994) Chemical skin bums. In: Menne T, dermatitis syndrome. CRC, Boca Raton, p 127
Maibach HI (eds) Hand eczema. CRC, Boca Raton, p 21 Moscato G, Biscaldi G, Cottica D, et al. (1987) Occupational
Bruze M, Boman A, Bergqvist-Karlsson A, et al. (1988) Contact asthma due to styrene: two case reports. J Occup Med 29:957
allergy to cyclohexanone resin in humans and guinea pigs. Osmun~~en PE (1980) Contact urticaria from nickel and plastic
Contact Dermatitis 18:46 addItives, butylhydroxytoluene, oleylamide. Contact Derma-
Conde-Salazar L, Gonzales M, Guimaraens D, et al. (1989) titis 6:452
Occupational contact dermatitis from styrene. Contact Der- Ross JS, Rycroft RJG, Cronin E (1992) Melamine-formaldehyde
matitis 21:112 contact dermatitis in orthopaedic practice. Contact Derma-
Di Lemia V, Cameli N, Patrizi A (1989) Irritant dermatitis in a titis 26:203
child by the plastic tube of an infusion system. Contact Schmunes E (1990) Solvents and plasticizers. In: Adams RM (ed)
Dermatitis 21:339 Occupational skin diseases, 2nd edn. Philadelphia, WB
Dooms-Goossens AE, Debusschere KM, Gevers DM, et al. (1986) Saunders, Philadelphia
Contact dermatitis caused by airborne agents. J Am Acad Schulsinger C, Möllegaard K (1980) Polyvinyl chloride dermatitis
Dermatol 15:1 not caused by phthalates. Contact Dermatitis 6:477
Fregert S (1981) Formaldehyde dermatitis from a gypsum- Sjöborg S, Fregert S, Trulsson L (1984) Contact alIergy to styrene
melamine resin mixture. Contact Dermatitis 7:56 and related chemicals. Contact Dermatitis 10:94
Fregert S, Rorsman H (1963) Hypersensitivity to epoxy resins Thestrup-Pedersen K, Madsen JB, Rasmussen K (1989) CumuIa-
used as plasticizers and stabilizers in polyvinyl chloride t~ve skin irritance from heat-decomposed polyethylene plas-
resins. Acta Derm Venereol 43:10 tlc. In: Frosch PJ, Dooms-Goossens A, Lachapelle J-M,
Fregert S, Trulsson L, Zimerson E (1982) Contact allergie reaction Rycroft RJG, Scheper RJ (eds) Current topics in contact
to diphenylthiourea and phenylisothiocyanate in PVC adhe- dermatitis. Springer, Berlin Heidelberg New York, p 412
sive tape. Contact Dermatitis 8:38 Vale PT, Rycroft RJG (1988) Occupational irritant contact
Fregert S, Meding B, Trulsson L (1984) Demonstration of epoxy dermatitis from fibreboard containing urea formaldehyde
resin in stoma pouch plastic. Contact Dermatitis 10:106 resin. Contact Dermatitis 19:62
Goh CL, Ho SF (1988) An outbreak of acneiform eruption in a Vidovic R, Kansky A (1985) Contact dermatitis in workers
polyvinyl chloride manufacturing factory. Derm Beruf processing polyvinyl chloride plastics. Derm Beruf Umwelt
Umwelt 36:53 33:104
Heine A, Laubstein B (1990) Contact dermatitis from cyclohexa-
none-formaldehyde res in (L2 resin) in a hair lacquer spray.
CHAPTER 78
Plastic Composites
K. Tarvainen and L. Kanerva
Introduction electrical, marine, aircraft and aerospace industries, for

construction, corrosion equipment, and transport
facilities, and for a wide range of consumer goods
Composites are combinations of two or more materia~s
(Midtgard and Knudsen 1994; Tarvainen and Kanerva
that are not dissolved or melted together. Plastlc
1999). Boats, car bodies, pipes, bath tubes, roof panels,
composites (PC) are manufactured by c?mbi~i~g
skis, racquets and many other kinds of sports equip-
materials at least one of which is of plastlc ongm.
ment are all examples of products in which PCs can be
Today a PC product usually has a sandwich ~truct~re
encountered in everyday life. During the 50 years or so
that consists of several variable layers of remforcmg
that PCs have been in use, the annual growth in the use
manmade mineral fibres (MMMF) and matrix polymer
of composite technology has been 10-150/0 on average
materials. MMMFs increase the strength of the final
(Kelly 1994). The European market volume for rein-
product. The matrix binds reinforcing fibres and
forced plastics was 860,000 tons in 1986, 210/0 be~ng
protects fine filaments from corrosion, oxidation or
used in transport applications, 190/0 in the electncal
other forms of environmental degradation (Kelly 1994;
industry and 200/0 in industrial equipment and agricul-
Tarvainen and Kanerva 1999). Newer PC products can
tural machines (Kelly 1994). The total European usage
contain a nonplastic part, e.g. steel, stone, cement or
of plastics was 24 million tons in 1990. üf this amount, 1
wood. In dental composites, inorganic materials, e.g.
million tons were plastic composites. By 1995, their use
glass partic1es, are embedded in acrylic plastic (Kaner-
had increased by 400/0, i.e. to 1.4 million tons.
va et al. 1989). The most common PCs are reinforced
Workers in the manufacture of PC are exposed to
plastics, in which thermo setting resins, e.g. unsaturated
reinforcing materials, matrix resins, resinous plastic
polyester resins, epoxy resins and vinyl ester resins, are
precursors and chemicals used for assembling or
the most frequently used matrix resins (Table 1).
finishing the product as weIl as for c1eaning purposes.
However, the use of thermoplastics, e.g. polypropylene
Many of these chemicals have skin-sensitising or
and polyamides, as the matrix resin is on the increase
irritating potential (Midtgard and Knudsen 1994,
(Kelly 1994; Tarvainen and Kanerva 1999). The term
Tarvainen and Kanerva 1999). Dermatoses from the
"composite" also inc1udes half-finished products called
manufacture of PC have been reported since the
prepregs, which are preimpregnated MMMF-reinforced
beginning of the industry (Malten 1956; Bourne and
materials based predominantly on epoxy or unsaturat-
Milner 1963; Malten and Zielhuis 1964; Wehle 1966;
ed polyester resins. They are used especially f~r the
Bord and Castellain 1967).
manufacturing of advanced PCs, such as those m the
aircraft industry (Roiston 1980; Burrows et al. 1984;
Mathias 1987; Lembo et al. 1989). Plastic Composite Product Industry
The PC industry began with radar plates and glass-
fibre plastic boats in the 1940s. Since then, these
products have been increasingly manufactured for the Manufacture of Plastic Composites
Table 1. Polymers used in the reinforced plastics composites The principal manufacturing process inc1udes the
moulding of reinforcements and the resin mix into
Thermosetting res ins Thermoplastic resins the desired shape. In addition to manual processes,
Polyester res ins Polyphenylene sulfides (PPS) there are many partly or totally c10sed procedures in
Epoxy resins Polyetheretherketones (PEEK)
Vinyl ester resins Polyether sulfones (PES) which the workers' exposure to matrix or reinforcing
Polyimides Polyvinyl chlorides (PVC) material is of short duration. Before the moulding,
Phenol formaldehyde resins Polypropylene resins are formulated by mixing the basic resin with
Polyurethanes Polyamide
solvents, curing agents, accelerators, fillers, mould

612 K. Tarvainen and L. Kanerva
releasers, dyes, fire retardants and other additives that 50% styrene is added in order to reduce the viscosity.
are essential for the end product of the manufacturing Styrene serves as a reactive monomer in cross-linking
process (Roiston 1980; Midtgard and Knudsen 1994; the linear polyester chains. Instead of styrene, vinyl
Tarvainen et al. 1993b; Tarvainen and Kanerva 1999). toluene, methyl methacrylate or diallyl phthalate may
The cured composite pieces or ready products usually be used (Bourne and Milner 1963; Malten and Zielhuis
require finishing by sawing, drilling, sanding or cutting 1964; Björkner 1992; Kelly 1994). Accelerators, e.g.
with diamond-coated tools, lasers or abrasive water cobalt naphthenate, or tertiary amines such as di-
jets (Bourne and Milner 1963; Bruze and Almgren 1989; methyl aniline, diethyl aniline or dimethyl-p-toluidine,
Tarvainen et al. 1993b; Mittgard and Knudsen 1994). are necessary for the curing of plastics at room
Contact moulding, also called laminating, is the most temperature. Hydroquinone is usually added to pre-
commonly used processing method. Reinforcements vent premature cross-linking. In addition, various
and res ins are laid down manually using a roller or auxiliary compounds are used to manufacture UP
sprayed over a mould in successive layers. Boats, res ins for different purposes: pigments, fillers, inhib-
caravan bodies and many small articles are usually itors, accelerators, UV -protecting agents, stabilisers
manufactured using the contact-moulding method. In and flame retardants. Polymerisation occurs after
the filament -winding method, the reinforcement, wetted adding a catalyst, such as benzoyl peroxide or methyl
by the res in, is wound around a rotating mandrei by a ethyl ketone (MEK) peroxide (Malten and Zielliuis
winding machine, by robots or manually. The filament- 1964; Björkner 1992).
winding process originates from the aerospace industry Vinyl ester resins (epoxy diacrylates) are used by the
but is nowadays also used to manufacture pipes, tanks glass-fibre-reinforcement industry for products that
and various poles (Kelly 1994). Pultrusion, centrifugal are resistant to chemicals and corrosion. They are
casting res in transfer, and compression moulding or epoxy di(meth)acrylates (ß-hydroxyester acrylates)
vacuum-bag moulding and the use of prepregs are all that are usually obtained by reacting epoxy resins of
partly or totally automated working methods used in the glycidyl derivatives with (meth)acrylic acid. They can
PC industry (Kelly 1994; Tarvainen and Kanerva 1999). also be manufactured from bisphenol A and glycidyl
However, even in the highly automated industries, (meth)acrylates (Kanerva et al. 1986; Kanerva et al.
workers may perform manual lay-up or spray-up 1989; Jolanki 1991). Acrylates based on bis phenol A or
operations during assembly or repair work. epoxy resin can be polymerised by electron beams,
ultraviolet light, and also by the addition of various
Plastics peroxides (Jolanki et al. 1995). The same cross-linker
(styrene), hardeners (organic peroxides) and acceler-
Epoxy resins are used in the composites; these are the ators (cobalt) as for unsaturated polyester resin are
diglycidyl ether ofbisphenol A (DGEBA), tetraglycidyl- used in composite epoxy acrylates (Roiston 1980).
4-4'-methylenedianiline (TGMDA), triglycidyl-p-ami- Dental composite resins (DCRs) based on bisphenol
nophenol (TGP AP) and the epoxies derived from A and (meth)acrylates, e.g. BIS-GMA, have been used
novolacs. The most important epoxy res in curing since 1962 (Bowen 1962). In addition to acrylics, DCRs
agents are the aromatic amines (p-phenylenediamine, contain additives that trigger polymerisation at an
4,4' -methylene dianiline, 4,4'-diaminodiphenyl sulf- appropriate time. These additives include initiators,
one), aliphatic amines such as triethylenetetramine e.g. benzoyl peroxide, activators, e.g. tertiary aromatic
(TETA) and diethylenetriamine (DETA), and acid amine, and inhibitors, e.g. hydroquinone; they are all
anhydrides, such as hexahydrophthalic anhydride, sensitizers (Kanerva et al. 1989). Sensitisation from
tetrahydrophthalic anhydride and pyromellitic dian- epoxy acrylates has been reported in dental personnel
hydride (Adams 1990; Kanerva et al. 1996). Composites (Kanerva et al. 1989) and in the ultraviolet (UV) or
based on epoxy resin compounds are used for sporting light-printing industry (Nethercott et al. 1983; Björkner
goods, automobile and aircraft industries, and for 1984). Acrylated urethanes are allergens. They are used
military and aerospace applications. in dental composite and sealant applications and have
Unsaturated polyester (UP) resins are used to form the same role as BIS-GMA (Nethercott et al. 1983;
composites with glass fibres, as weIl as for coatings, Björkner 1984).
finishes, cements (putties) (Tarvainen et al. 1993a) and
glues (Boennig 1994). Polyesters are formed by ester Reinforcements
linkage between dibasic acids, such as maleic, fumaric
and phthalic acids or their anhydrides, and glycols. Glass fibres, carbon fibres, graphite fibres and aramid
Propylene glycol and ethylene glycol are the commonly fibres account for most of the reinforcements found in
used alcohols. The term "unsaturated" means that plastic composites. In the large-scale production of
there is uncompleted residual chemical activity present consumer-orientated composite products, hybrid com-
in the compound. When UP res in is manufactured, 30- posites are used in which glass fibres are mixed with
Plastic Composites 613
carbon fibres (KeHy 1994; Mittgard and Knudsen 1994). During finishing operations, workers in the PC
The concentration of reinforcements in the composites industry are exposed to paints, coatings, glues and
ranges from less than 10% to above 80% by weight various solvents such as trichloroethylene, turpentine,
(Roiston 1980). methylene chloride, MEK, acetone and toluene (Bord
Glass fibres belong to a group of synthetic, organic and CasteHain 1967; Brigham and Landrigan 1985;
and amorphie MMMFs, which also includes rock wool Tarvainen and Kanerva 1999) as weH as to various
and slag wooL The main component in glass fibre is woods, wood preservatives (Brigham and Landrigan
silicon dioxide. Glass fibres are supplied in the form of 1985) and dust from machining of the hardened
continuous fibres used in the plastic composite indus- product (Brigham and Landrigan 1985; Antonson and
try and as wool used for acoustic or thermal insulation Runmark 1987; Tarvainen et aL 1993b).
(Bender et al. 1991; Tarvainen et aL 1994). Carbon fibres
and graphite fibres are made of fibrous carbonaceous
material that is subjected to controlled pyrolysis. The
Dermatoses trom PCs
precursor in the production of carbon fibres is either
polyacrylonitrile, polymer fibres such as rayon, or
petroleum pitch. The precursor can be spun into rows, A finished composite product only occasionally causes
pyrolysed and prepared for impregnation with resins an allergy. Allergie contact dermatitis (ACD) has been
for prepregs (Mittgard and Knudsen 1994). reported from limb prostheses made from UP res in
Continuous glass fibres are sized by different chem- (Mac Farlane et aL 1986; Freeman 1986; Vincenzi et al.
icals to facilitate binding of fibres to roving, or their use 1991). ACD has also been caused by unpolymerized
as reinforcements. Filaments are coated with polyvinyl epoxy resin in a billiard cue (Gonyalo et aL 1992), a
polyacetate, chromium chloride, polyvinyl acetate, screwdriver handle (Fischer et aL 1987) and a mop
silane, polyester silane or epoxy silanes (Roiston 1980; handle (Jolanki et aL 1992). Glass fibres in a school
Konzen 1987). Organic chromium compounds and desk and in printed circuit boards have caused irritant
silane are used for coupling, and solid or liquid epoxies, contact dermatitis (ICD) (Koh et aL 1992; Eby and
polyesters, and polyvinyl acetate are useful for film Jetton 1972).
forming. Lubricants and emulsifiers, used in glass- Most of the reported dermatoses due to the manu-
fibres, are usually water-soluble oils or detergent-type facture of PCs have been case reports (Bourne and
compounds (Roiston 1980). Milner 1963; Malten and Ziellmis 1964; Wehle 1966;
Fregert 1971; LachapeHe et aL 1978; Burrows et aL 1984;
Other Chemieals Liden et aL 1984; Brigham and Landrigan 1985; Konzen
1987; Mathias 1987; Lembo et aL 1989; Doyle 1989; Koh
Mould releasers are used to facilitate removal of the et aL 1992; Handley and Burrows 1994). Epidemiolog-
cured product from its mould. Internal mould releas- ical studies have been conducted in the aircraft
ers, such as lecithin, zinc, calcium or other stearates, (Malten 1956; Bord and Castellain 1967; Bruze et aL
and organic phosphate compounds, are mixed in the 1996) and boat-building (Tarvainen et aL 1993b)
res ins (Roiston 1980; Tarvainen et aL 1995a). External industries and the manufacture of hat racks (Malten
mould releasers laid on the moulds include fluorocar- and Zielhuis 1964), ski poles (Suhonen 1983), skis
bons (a dispersion of asolid fluorocarbon in a volatile (Jolanki et al. 1996) and printed circuit boards (Bruze
solvent), silicone oils, and waxes (Roiston 1980). and Almgren 1989) (Table 2).
Table 2. Prevalence of occupa-

tional dermatoses in the plastic Product Methods Number Prevalence (%) Reference
composite industry, %* ofworkers of dermatoses
Aircraft Clinical 30 6 Malten 1956

Hat rack Clinical 50 25 Malten and Ziehlhuis
1964
Aircraft Clinical 2137 5 Bord and Castellain 1967
Ski poles Questionnaire 293 34 Suhonen 1983
Ski poles Clinical 101 15 Suhonen 1983
Printed Questionnaire 159 50 Bruze and Almgren 1989
circuit boards
Printed Clinical 79 22 Bruze and Almgren 1989
circuit boards
Boats, pipes Clinical 89 26 Tarvainen et al. 1993b
Skis Clinical 22 55 Jolanki et al. 1996
Aircraft Questionnaire 341 28 Bruze et al. 1996
Aircraft Clinical 92 16 Bruze et al. 1996
* Calculated from figures in the publications

Allergie Contact Dermatitis Unsoturoted Polyester Resin
Epoxy Resin ACDs attributed to working with PCs were first

reported from UP res ins in 1955 (Lieber) followed by
Currently, epoxy resin compounds are the most Malten, who described five patients with contact
common cause of ACD from PCs. The cause of eczema and positive patch tests to UP resins in a
dermatitis has been the epoxy resin used in lamination group of 30 workers in an aeroplane factory (Malten
work (Malten 1956; Wehle 1966), in prepregs (Burrows 1956). Most cases of ACD have been due to UP-resin
et al. 1984; Doyle 1989; Tarvainen et al. 1995b) or in contact in lamination work (Malten 1956; Jinisek 1962;
se alants (Handley and Burrows 1994). Epoxy resin has Bourne and Milner 1963; Wehle 1966; Liden et al. 1984)
been reported to cause allergy more frequently than or in the use of UV-light-cured inks (Björkner 1982).
UP res in during simultaneous exposure to both resins UP dust from reinforced plastic products (Bourne and
(Malten and Zielhuis 1964; Wehle 1966; Tarvainen et al. Milner 1963; Tarvainen et al. 1993b; Tarvainen et al.
1995b). Epoxy resin is also suspected to be a concom- 1995a) or UP automobile-repair putty (Dooms-Goo-
itant factor in UP allergy (Wehle 1966). sens and de Jong 1985; Tarvainen et al. 1993a) have also
Most cases of ACD due to epoxy resin compounds caused ACD. The low number of cases of ACD in the
have been reported from DGEBA-epoxy resins (Bourne reinforced-plastics industry (Tarvainen et al. 1993b;
and Milner 1963; Malten and Zielliuis 1964; Bord and Tarvainen et al. 1995a) is probably due to the low
Castellain 1967; Suhonen 1983; Burrows et al. 1984; sensitising capacity of the lamination UP resin, its
Doyle 1989). Plüss first reported dermatitis due to a hardeners and styrene.
volatile epoxy resin hardener in 1954. A letter carrier The allergens in UP resin are often the auxiliary
working in a factory became sensitised to the hardener chemieals in the resin, such as cobalt naphthenate
without having actually touched any resin material (Bourne and Milner 1963; Malten and Zielhuis 1964),
(Malten and Zielliuis 1964). Thereafter, ACD due to dibutyl phthalate, dimethyl phthalate, dioctyl phthalate
epoxy res in hardeners (Suhonen 1983) such as DETA (Malten and Zielliuis 1964), tricresyl phosphate (Key
and TETA (Malten and Zielhuis 1964; Jolanki et al. et al. 1961), a cross-linking monomer such as styrene
1996), ethylenediamine (Jolanki et al. 1996), isophor- (Bourne and Milner 1963; Meneghini et al. 1963;
onediamine (IPDA) (Lachapelle et al. 1978), or hex- Sjöborg et al. 1982; Conde-Salazar et al. 1989) or a
avalent chromate in epoxy resin harden er (Handley hardening catalyst such as benzoyl peroxide (Bourne
and Burrows 1994) has been reported. In the manu- and Milner 1963; Malten and Zielhuis 1964; Vincenzi
facture of carbon-fibre-reinforced composites, workers et al. 1991), cyclohexanone hydroperoxide (Malten
have been sensitised to non-DGEBA epoxy resins and 1964) or MEK hydroperoxide (Bourne and Milner 1963;
their hardeners, such as TGMDA (Burrows et al. 1984; Malten and Zielhuis 1964). Para-tertiary-butyl catechol
Lembo et al. 1989; Tarvainen et al. 1995b), o-dig- used in the manufacture of styrene has caused contact
lycidylphthalate (Burrows et al. 1984; Lembo et al. allergy followed by vitiligo in workers in the rein-
1989), TGPAP (Lembo et al. 1989; Tarvainen et al. forced-plastics industry (Horio et al. 1977). Artificial
1995b) and 4-glycidyloxy-N,N-diglycidylaniline (Math- limbs, made from UP res in, have caused ACDs
ias 1987). Not only workers manufacturing PC prod- (MacFarlane et al. 1986; Freeman 1986; Vincenzi et al.
ucts but also cleaners had a delayed allergie re action to 1991). In two cases, the cause has been verified by patch
a DGEBA epoxy res in used in ski-pole manufacturing testing to be sensitisation to para-tertiary-butyl cat-
(Tarvainen et al. 1995b). echol (Freeman 1986) or benzoyl peroxide (Vincenzi
Six epoxy-resin-exposed workers from a ski factory et al. 1991).
showed allergie reactions to the standard DGEBA The actual allergen in UP resin has been thought
epoxy resin with the TRUE-Test and Finn Chamber to be one of the starting substances in the produc-
techniques as weIl as to the epoxy resin used in the tion, such as free or terminal maleie acid (Malten
factory (Jolanki et al. 1996). Three of the workers and Zielhuis 1964), fumaric acid or adipie acid
reacted to reactive diluents (diethylene glycol dig- (Malten and Zielhuis 1964), ortho-phthalic anhydride
lycidyl ether (DEGDGE) (Fig. 1), phenyl glycidyl ether (Liden et al. 1984), maleie anhydride (Jinisek 1962)
(PGE) and 1,4-butanediol diglycidyl ether (BDDGE). or maleie esters (Jinisek 1962). One of the first five
reported UP-sensitive patients (Malten 1956) reacted
in patch testing to phthalic anhydride. The cause of
UP allergies has also been suggested to be a
macromolecule containing maleie ester (Jinisek
1962), polyester methacrylate (Björkner 1982) or
Fig. 1. Ethylene glycol diglycidyl ether (Quetol 651, n = 1) and diethylene glycol maleate (DGM) (Fig. 2) (Tarvainen
diethyleneglycol diglycidyl ether (DEGDGE, n = 2) et al. 1993a).
H~H2-CH2--O-IT-CH=CH-rr-Q-CH2-CH2--oH The irritant properties of UP resins and vinyl ester

o 0 resins are due to cross-linking styrene (Fisher 1986), or
in earlier times, to diallylphthalate (Fregert 1971).
Fig. 2. Diethyleneglycol maleate (DGM) Styrene is classified as a mild irritant, but repeated skin
contact to styrene causes drying of the skin and may
give rise to primary irritation (Schmunes 1990),
Vinyl Esters blisters (Bourne and Milner 1963) or even chemical
burns (Bruze and Fregert 1994). However, skin resorp-
No cases of ACD or ICD or contact urticaria due to tion experiments of liquid styrene (Berode et al. 1985)
vinyl ester resins have been reported in the reinforced- have not caused skin symptoms on human volunteers.
plastics industry. There are relatively few published Even at levels of 50 ppm (215 mg/m3 ), styrene vapour
reports on contact allergy due to these compounds, may irritate conjunctivae and nasal mucous mem-
despite their wide use in ultraviolet curable acrylic branes (Götell et al. 1972). Workers may develop a
compounds, UV curing inks (Nethercott et al. 1983) tolerance to mucous-membrane irritation after pro-
and in DCRs (Kanerva et al. 1986; Kanerva et al. 1989). longed exposure (Götell et al. 1972). A case of
leukoderma after ICD induced by glass fibres and
Reinforcements, Manmade Mineral Fibres polyester resins has been reported (Moroni and
Tomasini 1992).
ACD from glass fibres has been caused by slzmg Organic peroxides, used as a 3-10% solution to
chemicals in MMMF production, such as epoxy resin catalyse the hardening reactions of UP, vinyl ester
(Possik et al. 1970; Hollness and Nethercott 1989) or and acrylic resins, have caused irritant dermatitis and
amine-functional methoxysilane (Toffoletto et al. 1994; blisters in workers in the PC industry (Bourne and
Heino et al. 1996) or in finished products (Fregert et al. Milner 1963). Reactive organic peroxide molecules in
1980; Jolanki et al. 1992). unhardened resin dust may cause stinging on uncov-
ered skin areas during spray lamination (Schmunes
1990). In addition to the chemicals included in the
Irritant Contact Dermatitis resin system, mould-releasing chemicals and solvents
have also been reported to induce ICD (Bourne and
MMMF is the main cause of ICD in the manufacture of Milner 1963). Acetone is used to clean equipment in
PC products (Bord and Castellain 1967; Brigham and UP- and vinyl-ester-resin industries. On repeated
Landrigan 1985; Bruze and Almgren 1989; Tarvainen contact, acetone defats the skin and has been reported
et al. 1993b; Tarvainen and Kanerva 1999). Workers to be a contributing factor for irritant dermatitis in the
exposed to MMMF complain most frequently of PC industry (Bourne and Milner 1963; Tarvainen et al.
itching without dermatitis, or rapidly healing papules, 1993b). A mould-releasing agent, alkylorthophosphate
vesicles, pustules, and folliculitis (Konzen 1987). Sec- mix, diluted in the res in, has been reported to cause
ondary lesions from scratching include bacterial ICD in a worker while packing composite parts for
infections and lichenification (Possick et al. 1970). knitting machines (Tarvainen et al. 1995a).
Most workers will develop a tolerance to MMMF itch
within a few weeks of continual exposure (Possick et al. Contact Urticaria
1970). Not all workers become tolerant, however, and
iliey may be forced to change jobs because of skin Most cases of contact urticaria in PC manufacture
distress from MMMFs (Björnberg 1985). Among the 28 have been caused by natural rubber latex (NRL) from
patients who had changed their job after ilie diagnosis protective rubber gloves (Tarvainen et al. 1993b).
of occupational dermatitis was made, 21 had ICD There are few reports on contact urticaria from resin
caused by MMMFs (Tarvainen et al. 1995a). compounds used for PC, including DGEBA epoxy
Although DGEBA epoxy resins are not strong resin (Suhonen 1983), epoxy resin amine hardener
irritants, ICD has been reported from DGEBA epoxy (Suhonen 1983), dicarboxylic anhydride hardeners,
res ins (Jolanki et al. 1996). Irritation of the skin due to MTHP A and methylhexahydrophthalic anhydride
the epoxy resin harden er phthalic anhydride is aggra- (MHHPA) (Jolanki et al. 1987; Tarvainen et al. 1995b)
vated by moisture, e.g. sweat, which causes rapid and UP resin (Tarvainen et al. 1995b). Suhonen
hydrolysis of the anhydrides to their acids, and this described two patients who had immediate patch-test
can even result in caustic burns (Malten and Zielhuis reactions to DGEBA epoxy resin and an amine
1964; Bernstein and Bernstein 1984). Another hardener, hardener (Suhonen 1983). Immediate allergy to
methyltetrahydrophthalic anhydride (MTHP A) has MHHP A has been verified by an open test with 100%
been reported to induce redness and hives on the skin MHHPA (Jolanki et al. 1987) and with positive scratch
(Kalimo et al. 1990). tests and radioallergosorbent tests (RASTs) using a
'"
'"
?'
t;;I
~
s·
fl)
::J
OJ
::J
c..
r
Table 3. Overview of the most important health hazards associated with some resin systems and solvents used in the fibre-reinforced plastics industry. • data indicating effect; - data indicating ~
::J
no effect; 0 uncommon or poorly documented effects. Blank spaces (except in the last column) indicate that no or very little data are available in the literature fl)
~
Resin or
Compound Irritation Sensitization Cancer a Reproductive Other effects
solvent group
toxicitl
Skin Respiratory tract Skin Respiratory tract
Polyester Polyester dust 0 0

Unsaturated polyester cements
Styrene 2B lL Neurotoxic
Vinyl toluene •• • 0 CNS effects
••
Methyl methacrylate 3 2M Neurotoxic
••
Organic peroxides • Tumour promotors?
Epoxy and Epoxy dust
••• ••
bismaleimides Diglycidyl ether of bisphenol A 3
•••
Epichlorohydrin • 2A lL Systemic effects
Diethylenetriamine
••
Triethylenetetramine
•••
m- Phenylenediamine 3 Methemoglobinemia
••• •• •• •
4,4-Methylenedianiline 2B 0 Toxic hepatitis
••
4,4-Diaminodiphenylsulfone •• 3
Pyromellitic dianhydride
Tetrahydrophthalic anhydride 0 •
Hexahydrophthalic anhydride (HHPA)
•• ••
Methylhexahydrophthalic
anhydride (MHHPA) •
•• •• ••
Methyltetrahydrophthalic
anhydride (MTHPA) • • • •
Polyurethanes Polyurethane dust 3
Toluene diisocyanate 2B 3
Hexamethylene diisocyanate
4,4-Diphenylmethane diisocyanate 0 0
•• •• •• ••
Polymethylene polyphenyl 0 • 0
•
isocyanate
Phenolics Phenolic resin dust Pulmonary
Formaldehyde 2A 3
Phenol 3 2H Systemic effects
•• ••
0 •
o-Cresol 0
p-tert-butylphenol
•• •••
• •
Thermoplastics PVC dust <> 3 Pulmonary
Vinyl chloride monomer 1 lL Systemic effects
Polyphenylene sulfide(PPS)
Polyetheretherketone(PEEK) Pulmonary
Polyether sulfone(PES)
Ketones Acetone CNS effects
Methyl ethyl ketone 2M Potentiates
neurotoxicity of
•• •• other solvents
Methyl isobutyl ketone <> CNS effects
Chlorinated Methylene chloride •<> 2B 2M CNS effects
hydrocarbons 1,1,1-Trichloroethane 3 2H CNS effects
Trichloroethylene 3 1H CNS effects
Glycol ethers 2-Methoxyethanol lL Bone-marrow toxicity
••• ••
2-Ethoxyethanol 1M Bone-marrow toxicity
Other Dimethylformamide 2B 2M Liver effects
solvents N-Methylpyrrolidone •• 2M
arARC classification: 1, carcinogenic to humans; 2A, probably carcinogenic to humans; 2B, possibly carcinogenic to humans; 3, not classifiable (see Appendix 1 for further explanation)
bClassification according to Hass et al. (1991): lL1M/H, reproductive toxicant at low (L), medium (M) or high (H) dose; 2L1M/H, suspected reproductive toxicant at low (L), medium (M), or
high (H) dose; 3, cannot be evaIuated
[",,0
n
o
3
-c
~
;::+
l1l
V>
0--
.:::;
human serum albumin (HSA)-conjugated test sub- Skin-Prick Tests and Determination
stance as the allergen Oolanki et al. 1987). Two patients of Specific IgE Antibodies
(Tarvainen et al. 1995b) with airborne contact urticaria
and upper-respiratory symptoms were positive in Immediate allergies can be examined by skin-prick
skin-prick tests with phthalic anhydride-HSA, tests, scratch tests, or use tests, and by determination
MHHPA-HSA, and MTHPA-HSA; one of the patients of specific IgE antibodies in the patient's serum
was also positive to UP res in HSA. Both patients had (Kanerva et al. 1991; Tarvainen and Kanerva 1999).
high levels of specific immunoglobulin E (IgE) anti- Low-molecular-weight chemicals can be conjugated
bodies to these acid anhydride conjugates in their sera. with HSA (Howe et al. 1983) before they are used in
RAST -inhibition studies showed high inhibition of skin-prick tests or RAST examinations (Ceska and
MHHPA (96%) and MTHPA (99%) supporting the Lundkvist 1972).
specificity of RAST reactions. RAST -inhibition by UP
was lower (76%). A cross-reaction between the chem- Other Methods
icals was verified by high percentage inhibitions
(Tarvainen et al. 1995b). Chemical analyses are used for both identification of
new allergens and to find the allergens responsible for
Other Skin Hazards the patients' allergie dermatoses due to PC (Ayala et al.
1990; Jolanki et al. 1991; Tarvainen et al. 1995b; Jolanki
The use of machining equipment is associated with a et al. 1996). These analyses include high-performance
risk of mechanical injuries, such as cuts or abrasions. liquid chromatography and gas chromatography for
Some processes operate at high temperatures and epoxy compounds, and thin-Iayer chromatography
involve a danger of severe burns. The risk of fire and and infrared spectrophotometry to reveal rubber
explosion is inherent in the nature of the raw chemicals in gloves Oolanki et al. 1991; Jolanki et al.
materials used in industry (Bourne and Milner 1963; 1996). The components of the epoxy res in diluent have
Brigham and Landrigan 1985). Styrene, acetone and been determined by mass spectrometry Oolanki et al.
peroxides form fiammable and explosive vapour 1996). Thin-Iayer chromatography and mass spectro-
concentrations at normal room temperatures. Certain metric and Fourier-transform infrared-spectrometric
chemieal combinations are particularly hazardous, methods have been used to identify allergens in a UP
such as a mixture of organic peroxides (catalysts) and resin and UP cements (Tarvainen et al. 1993a) and a
cobalt salts (accelerators) (Brigham and Landrigan capillary gas-chromatography method to detect phtha-
1985). lic anhydride in polyester resin (Tarvainen et al.
1995b).
Methods Used in the Diagnosis

Other Health Hazards
of Allergie Dermatitis Due to PCs
An overview of the most-important health hazards

Patch Tests
associated with some res in systems and solvents used
in the fibre-reinforced-plastics industry have been
The cause of allergic PC contact dermatitis should be
summarised in Table 3.
verified by patch tests. In the reported cases, standard
patch-test trays have been used with special epoxy-
resin test substances (Burrows et al. 1984; Matthias
Prevention of Occupational Dermatoses
1987; Lembo et al. 1989; Tarvainen et al. 1995a; Jolanki
from PCs
et al. 1996) and chemicals from workplaces (Malten
and Ziehuis 1964; Suhonen 1983; Liden et al. 1984;
Lembo et al. 1989; Jolanki et al. 1991; Tarvainen et al. Irritant dermatitis and skin traumas predispose indi-
1995a; Tarvainen and Kanerva 1999). The substances viduals to ACD (Malten and Ziellmis 1964; Tarvainen
from the workplaces can be patch tested either as and Kanerva 1999). In PC work, skin-irritating
such (shavings or dust from the cured product) or solvents, resins and glass fibres predispose individuals
mixed in petrolatum or acetone following recom- to sensitisation to epoxy resin. Exposure of some
mended test concentrations of known or hypothetical workers to epoxy resins, such as cleaners or gluers,
allergens (De Groot 1994). Care should be taken to may be low and of short duration before the
prevent active sensitisation through patch testing with appearance of dermatitis (Tarvainen et al. 1995a).
test concentrations that are too strong (Estlander et al. Uncured chemicals on the surface of prepregs can
1998). cause sensitisation. Workers feeling only a slight
tackiness of resin may not protect themselves suffi- References

ciently compared to the protection they would take
during the handling of epoxy resin in its liquid state Adams RM (ed) (1990) Occupational skin diseases, 2nd edn. Grun
(Mathias 1987; Lembo et al. 1989; Tarvainen et al. & Stratton Inc., New York
199sa). Antonson A-B, Runmark S (1987) Airborne fibrous glass and dust
originating from worked reinforced plastics. Am Ind Hyg
Even small amounts of allergen can evoke dermatitis
Assoc J 48:684-687
in previously sensitised subjects. This is especially true Ayala F, Lembo G, Balato N, Patruno C, Scognamiglio G,
in cases of ACD due to epoxy resin compounds and Strazzullo G, De Stefano S (1990) The use of laboratory
methods in contact dermatitis induced by composite mate-
polyester cements Oolanki et al. 1991; Tarvainen et al. rials. Contact Dermatitis 22:262-266
1993a; Tarvainen et al. 199sa). The allergen in dust or in Bender JR, Konzen JL, Devit GF (1991) Occupational exposure,
a finished product maintains dermatitis, and the toxie properties and work practiee guideline for fiberglass.
American Industrial Hygiene Association (AIHA), Akron
sensitised patients may have to change jobs. Discon- Bernstein IL, Bernstein DI (1984) Respiratory allergy to synthetie
tinuing work involving epoxy-resin-compound expo- res ins. Clin Immunol Allergy 4:83-101
sure immediately after the diagnosis of ACD may be Berode M, Droz P-O, Guillemin M (1985) Human exposure to
styrene, VI. Percutaneous absorption in human volunteers.
beneficial in preventing respiratory allergy (Kanerva et Int Arch Occup Environ Health 55:331-336
al. 1991). ACD due to epoxy-resin compounds is more Björkner B (1982) Sensitizing capacity of polyester methacrylate
severe if the exposure time to the causative agent is in ultraviolet curing inks tested in the Guinea pig. Acta Derm
VenereoI62:153-182
long Oolanki et al. 1996). Björkner B (1984) Sensitizing capacity of ultraviolet curable
The use of protective gloves reduces the frequency acrylic compounds. MD thesis. University of Lund, pp 1-78
of hand derma tos es and relieves symptoms. Protec- Björkner B (1992) Plastic materials. In: Rycroft RJG, Menne T,
Frosch PJ, Benezra C (eds) Textbook of contact dermatitis.
tive gloves are helpful in the prevention of both
Springer, Berlin Heidelberg New York, pp 539-572
ACD and ICD due to chemieals and glass fibres as Björnberg A (1985) Glass-fiber dermatitis. Am J Ind Med 8:
well as mechanical, thermal or chemical injuries or 395-400
bums. Furthermore, workers who use gloves wash Boenig H (1964) Unsaturated polyesters: structure and properties.
Elsevier, Amsterdam, pp 6-13
their hands less frequently, thus avoiding the drying Bord A, Castellain P-Y (1967) Les dermatoses professionnelles
effect of frequent hand washing (Tarvainen et al. dans !'industrie aeronautique. Rev Fr Allergoi 7:85-91
Bourne L, Milner F (1963) Polyester res in hazards. Br J Ind Med
1993b). 20:100-109
Rubber gloves do not offer enough protection Bowen RL (1962) Dental filling material comprising vilnyl silane
against the solvents used in the PC industry (Forsberg treated fused silica and a binder consisting of reaction
product of bisphenol and glycidyl acrylate, US Pat. 3,066,112
1992) and may cause sensitisation to NRL or to rubber Brigham CR, Landrigan PJ (1985) Safety and health in boatbuild-
chemicals. General recommendations for the use of ing and repair. Am J Ind Med 8:169-182
appropriate gloves are available (Estlander and Jolanki Bruze M, Almgren G (1989) Occupational dermatoses in workers
exposed to epoxy-impregnated fiberglass fabric. Derm Beruf
1988). Viton gloves and 4-H gloves protect against
Umwelt 37:171-175
res ins for at least 4 h (Forsberg 1992). Cotton under- Bruze M, Fregert S (1994) Chemical skin burn. In: Menne T,
gloves will prevent sensitisation to NRL or to the Maibach HI (eds) Hand eczema. CRC, Boca Raton, pp 21-30
Bruze M, Edenholm M, Engtröm K, Svensson G (1996) Occupa-
rubber chemie als present in protective gloves. tional dermatoses in a Swedish aircraft plant. Contact
Incomplete protection has frequently been the Dermatitis 34:336-340
cause of occupational PC dermatitis. Workers have Burrows D, Fregert S, Cambell H, Trulsson L (1984) Contact
been sensitised through epoxy-resin splashes, uncured dermatitis from the epoxy resins tetraglycidyl-4A'-methylene
dianiline and o-diglycidyl phthalate in composite material.
resin compounds in composite waste materials or Contact Dermatitis 11:80-82
through vapours, even though they used protective Ceska M, Lundkvist U (1972) A new and simple radioimmuno-
gloves (Tarvainen et al. 199sa; Tarvainen et al. 1995b; assay method for determination of IgE. Immunochemistry
9:1021-1030
Jolanki et al. 1996). Occupational skin diseases in PC Conde-Salazar L, GonzaIes M, Guimaraens D, Romero L (1989)
work can be prevented by complete avoidance of skin Occupational allergie contact dermatitis from styrene. Con-
contact with res ins and other known allergens, such tact Dermatitis 21:112
De Groot AC (1994) Patch testing. Test concentrations and
as cobalt accelerators. Common industrial hygienic vehicles for 3700 chemicals, 2nd edn. Elsevier, Amsterdam
measures together with local ventilation and auto- Dooms-Goosens A, De Jong G (1985) Letter to editor. Contact
Dermatitis 12:238
matie or closed processes should be used whenever
Doyle EJ (1989) Suggested strategies in screening for health
possible. These measures are important in the effects in personnel who work with composites. Appl Ind Hyg
prevention of occupational dermatoses as well as 12:64-67
respiratory and central-nervous-system symptoms. Eby CS, Jetton RL (1972) School desk dermatitis. Primary irritant
contact dermatitis to fiberglass. Arch Dermatol 105:890-891
The workers should be aware of the best working Estlander T, Jolanki R (1988) How to protect the hands. Dermatol
technique and the risks associated with the chemie als Clin 6:105-114
being handled. Good skin care with emollients as well Estlander T, Kostiainen M, Jolanki R, Kanerva L (1998) Active
sensitization and occupational allergic contact dermatitis
as rapid treatment of skin injuries reduces the risk of caused by paratertiary butyhlcatechol. Contact Dermatitis
allergie dermatitis. (in press)
Fischer T, Fregert S, Thulin I, Trulsson (1987) Unhardened epoxy yl)phenol, and a review of sensitizing epoxy resin hardeners.
resin in tool handles. Contact Dermatitis 16:45 Int J Dermatol 35:852-856
Fisher AA (1986) Contact dermatitis, 3rd edn. Lea & Febiger, Kelly E (1994) Applications of composites. In: Kelly E (ed)
Philadelphia Concise encyclopedia of composite material. Pergamon,
Forsberg K (1991) Guide für val av kemskyddsmaterial. Ord & Oxford, pp 7-9
Form AB, Uppsala Key MM, Perone VB, BirminglIam DJ (1961) Patch testing in
Freeman S (1986) Contact dermatitis of a limb stump caused by dermatitis from the newer resins. J Occup Med 3:361-364
p-tertiary butyl catechol in the artificial limb. Contact Koh D, Aw TC, Foulds IS (1992) Fiberglass dermatitis from
Dermatitis 14:68-69 printed circuit boards. Am J Ind Med 21:193-198
Fregert S (1971) Outbreak of irritant contact dermatitis from Konzen JL (1987) Fiberglass and the skin. In: Maibach HI (ed)
diallylphthalate in polyester resin. Contact Dermatitis News- Occupational and industrial dermatology, 2nd edn. Year
lett 10:234 Book Medical, Chicago, pp 282-285
Fregert S, Persson K, Trulsson L (1980) Hidden sources of Lachapelle JM, Tennstedt D, Dumont-Fruytier M (1978) Occupa-
unhardened epoxy resin of Bisphenol A type. Contact tional allergie contact dermatitis to isophoronediamine
Dermatitis 6:446-447 (IPD) used as an epoxy resin harden er. Contact Dermatitis
Gon~alo S, Gon~alo M, Matos J, Mar~ues C (1992) Contact 4:109-112
dermatitis from a billiard cue. Contact Dermatitis 26:263-283 Lembo G, Balato N, Cusano, Baldo A, Ayala F (1989) Contact
Götell P, Axelson 0, Lindelöf B (1972) Field studies on human dermatitis to epoxy resins in composite material. In: Frosch
styrene exposure. Work Environ Health 9:76-83 PI, Dooms-Goossens A, Lachapelle J-M, Rycroft RJG, Scheper
Handley 1, Burrows D (1994) Dermatitis from hexavalent RJ (eds) Current topies in contact dermatitis. Springer, Berlin
chromate in the accelerator of an epoxy sealant (PRI422) Heidelberg New York, pp 377-380
used in the aircraft industry. Contact Dermatitis 30:193-196 Liden C, Löfström A, Storgärds-Hatam K (1984) Contact allergy
Hass U, Jacobsen BM, Brandorff NP, et al. (1991) Reproductive to unsaturated polyester in a boat builder. Contact Dermatitis
toxieants in the working environment (in Danish with 11:262-264
English summary). AMI-report nO.35!I99!. National Institute Lieber EE (1955) Dermatitis-an industrial problem. Br Plastics
of Occupational Health, Copenhagen 28:428-429
Heino T, Haapa K, Manelius F (1996) Contact sensitization to MacFarlane AW, Curley RK, King CM (1986) Contact sensitivity
organosilane solution in glass filament production. Contact to unsaturated polyester resin in a limb prosthesis. Contact
Dermatitis 34:294 Dermatitis 15:301-303
Holness L, Nethercott JR (1989) Occupational contact dermatitis Malten KE (1956) Beroepsekseem, bij het verwerken van kunstof-
due to epoxy resin in a fiberglass binder. J Occup Med 31:87-89 fen in het biezonder van onverzadigde polyester harsen en
Horio T, Tanaka K, Komura J (1977) Depigmentation due to para- aethoxyline harsen Doctoral dissertation (English summary).
tertiary butylcatechol. Int Arch Occup Environ Health 39: University of Amsterdam, Amsterdam
127- 133 Malten KE (1964) Einige Bemerkungen zur Hautsensibilisierung
Howe W, Venables KM, Topping MD, Dally MB, Hawking R, durch Aethoxylin (Epoxyd)-Kunstharze und deren Prophyl-
Laws JS, Newman Taylor AJ (1983) Tetrachlorophthalic axe. Berufsdermatosen 2:78-85
anhydride asthma: evidence for specific IgE antibody. Malten KE, Zielhuis R (1964) Polyester resins. In: Malten KE,
J Allergy Clin Immunol 71:5-11 Zielhuis R (eds) Industrial toxieology and dermatology in the
Jinisek L (1962) Polyesterove pryskyrice a skelne laminaty. Prac production and processing of plastics. Elsevier, Amsterdam,
Lek 3=I20-124 pp 71-84
Jolanki R (1991) Occupational skin diseases from epoxy com- Mathias CGT (1987) Allergie contact dermatitis from a nonbis-
pounds. Epoxy resin compounds, epoxy acrylates and 2,3- phenol A epoxy in a graphite fiber reinforced epoxy laminate.
epoxypropyl trimethyl ammonium chloride. Acta Derm J Occup Med 29:754-755
Venereol Suppl (Stockh) 159:1-80 Meneghini CL, Rantuccio F, Riboldi A (1963) Klinisch-all-
Jolanki R, Estlander T, Kanerva L (1987) Occupational contact ergologischen Beobactungen bei beruflichen ekzematösen
dermatitis and contact urticaria caused by epoxy resins. Acta Kontakt-Dermatosen. Derm Beruf Umwelt 11:181-244
Derm Venereol Suppl (Stockh) 134:90-94 Midtgärd U, Knudsen LE (1994) Fibre-reinforced plastics and
Jolanki R, Estlander R, Kanerva L, Tarvainen K (1992) Occupational advanced polymer composites. Occupational hazards and
allergie contact dermatitis caused by a finished reinforced toxity of selected compounds. Nordic Council of Ministers
polyester plastie product. In: Proceedings of the 18th World and National Institute of Occupational Health, Copenhagen,
Congress ofDermatology. New York City, June 12-18 pp 1-73
Jolanki R, Kanerva L, Estlander T (1995) Occupational allergie Moroni P, Tomasini M (1992) Contact leukoderma induced by
contact dermatitis caused by epoxy diacrylate in ultraviolet- occupational contact with fibre-glass and polyester resins
light-cured paint, and bisphenol A in dental composite resin. with quinones and tertiary butylcatechol. Dermatosen 40:
Contact Dermatitis 33:94-99 195-197
Jolanki R, Tarvainen K, Tatar T, Estlander T, Henriks-Eckerman Nethercott JR, Jacubovic HR, Pilger C, Smith JW (1983) Allergie
M-L, Mustakallio KK, Kanerva L (1996) Occupational de- contact dermatitis due to urethane acrylate in ultraviolet
rmatoses from exposure to epoxy resin compounds in a ski cured inks. Br J Ind Med 40:241-250
factory. Contact Dermatitis 34:390-396 Possiek PA, Gellin GA, Key MM (1970) Fibrous glass dermatitis.
Kalimo K, Liira J, Nordman H, Engström B, Halmepuro L, Kaila T Am Ind Hyg Assoc J 31:12-15
(1990) IgE-mediated allergy to methyltetralIydrophthalic Rolston JA (1980) Fiberglass composite materials and fabrieation
anhydride among workers producing electrical components. processes. Chem Eng 87:96-100
Contact Dermatitis 23:280 Schmunes E (1990) Solvents and plasticizers. In: Adams RM (ed)
Kanerva L, Jolanki R, Estlander T (1986) Occupational dermatitis Occupational skin disease, 2nd edn. Saunders, Philadelphia
due to an epoxy acrylate. Contact Dermatitis 14:80-84 Sjöborg S, Dahlquist I, Fregert S, Trulson L (1982) Contact allergy
Kanerva L, Estlander T, Jolanki R (1989) Allergie contact dermatitis to styrene with cross reaction to vinyltoluene. Contact
from dental composite res ins due to aromatic epoxy acrylates Dermatitis 8:207-208
and aliphatic acrylates. Contact Dermatitis 20:201-211 Suhonen R (1983) Epoxy-dermatitis in a ski-stiek factory. Contact
Kanerva L, Jolanki R, Tupasela 0, Halmepuro L, Keskinen H, Dermatitis 9:131-133
Estlander T, Sysilampi M-L (1991) Immediate and delayed Tarvainen K, Jolanki R, Estlander T (1993a) Occupational contact
allergy from epoxy res ins based on diglycidyl ether of allergy to unsaturated polyester resin cements. Contact
bisphenol A. Scand J Work Environ Health 17:208-215 Dermatitis 28:220-224
Kanerva L, Estlander T, Jolanki R (1996) Occupational allergie Tarvainen K, Jolanki R, Forsman-Grönholm L, Estlander T,
contact dermatitis caused by 2,4,6-tris-( dimethylaminometh- Pfaffii P, Juntunen J, Kanerva L (1993b) Exposure, skin
proteetion and occupational skin diseases in the glass-fibre Tarvainen K, Kanerva L (1999) Oeeupational dermatoses from
reinforced plastics industry. Contact Dermatitis 29:119-127 plastic composites. J Environ Med 1:3-17
Tarvainen K, Estlander T, Jolanki R, Kanerva L (1994) Oceupa- Toffoletto F, Cortona G, Feltrin G, Baj A, Goggi E, Ceeehetti R
tional dermatoses eaused by man-made mineral fibers. Am J (1994) Oceupational contact dermatitis from amine-func-
Contaet Dermat 5:22-29 tional metoxysilane in continuous-glass-filament produetion.
Tarvainen K, Kanerva L, Jolanki R, Estlander T (1995a) Oecupa- Contact Dermatitis 31:320-321
tional dermatoses from the manufaeture of plastic composite Wehle U (1966) Arbeitsbedingte Ekzeme dureh Polyester. Allerg
products. Am J Contact Dermat 6:95-104 Asthma (Leipz) 12:184-186
Tarvainen K, Jolanki R, Estlander T, Tupasela 0, Pfäffli P, Vineenzi C, Cameli N, Vassilopoulou A, Tosti A (1991) Allergie
Kanerva L (1995b) Immunologie contaet urtiearia due to contaet dermatitis due to benzoyl peroxide in an arm
airborne methylhexIDydrophthalic and methyl tetrahydro- pros thesis. Contact Dermatitis 24:66-67
phthalic anhydrides. Contact Dermatitis 32:204-209
CHAPTER 79
Textiles
K.L. Hatch and H.l. Maibach
Introduction origin is the cause of a patient's skin problem and, if

so, the chemistry of that compound. Toward this end
we (a) provide a list of those textile chemicals that have
Textile dermatitis is a general term to cover allergic
been reported to cause textile dermatitis, (b) discuss
contact dermatitis (ACD), contact urticaria, and pho-
the types of fabrics on which these chemicals are most
toallergies, which result from exposure to chemicals
likely to be present, (c) describe dinical aspects of
that comprise fabrics. These chemicals might be dyes,
textile dermatitis, and (d) provide a guide to methods
finishing compounds, fiber additives, fiber polymers,
available to identify the specific chemical causing a
or residues that contaminate the fabric as a result of
patient's problem. To achieve this end, we have drawn
use. The term textile dermatitis also covers cumulative
from several reviews (Cavelier et al. 1988; Cronin 1980;
irritant dermatitis, a condition usually arising due to
Storrs 1986; Foussereau 1992; Hatch 1984a, 1984b, 1988,
the stiffness of fibers in fabrics. Phrases such as dye
1995; Hatch and Maibach 1985a, 1985b, 1986, 1994).
dermatitis and formaldehyde dermatitis are often used
to convey the chemical cause, and phrases such as
dress, trouser, and nylon-stocking dermatitis to convey
Dye Allergens
the name of the offen ding garment.
The prevalence of textile dermatitis is not known.
Estimates are available only for textile dyes, durable Textile dyes are large, conjugated, organic molecules
press res ins, and formaldehyde - the three chemicals having the ability to selectively absorb light. Informa-
believed to cause the greatest number of cases of textile tion about the thousands of dyes that can be chosen to
dermatitis. For textile dyes, estimates have ranged colour fabrics is complied in the Colour Index (CI)
from 15.9% among patients suspected to be sensitive to (Society of Dyers and Colourists 1997). Each dye in the
textile chemicals (Balato et al. 1990b) to 0.05% among Index has a CI name, and those whose structures are in
10,191 Portuguese children (Goncalo et al. 1992), with the public domain also have a CI number. The CI name
most estimates being between 5.8 to 1.1% of an is composed of an application-dass designation (such
eczematous population of people (Dooms-Goosens as disperse, acid, solvent, or direct), the color emitted
1992; Seidenari et al. 1991, 1995; Manzini et al. 1991, by the dye (such as red, blue, orange, yellow, brown,
1996a). For durable press res ins, estimates have been etc.) and a number which indicates the order of
reported to be about 1.2% to 2.3% of eczematous discovery of dyes within an application dass and color
patients (Sherertz 1992; Fowler et al. 1992). group. Typical names therefore indude Disperse BIue 3
Whether incidence or prevalence of textile derma- and Acid Yellow 23. The CI number for Disperse Blue 3
titis has risen or fallen during the approximately five- is CI 61505 and for Acid Yellow 26 is CI 13065. Acid
year period since the last studies were undertaken is Yellow 23 is the twenty-third yellow dye entered into
debatable. The fact that the incidence or prevalence the CI. In select instances, the CI name does not
rate for textile dermatitis is relatively low compared indicate a singular chemical compound (one dye) but
with numerous other sources of dermatitis presents a rather a mixture of dyes.
unique challenge to the practicing dermatologist, as The CI also provides the commercial and scientific
(s)he may not think of fabric as being a source of a names of dyes, chemical formulas, preparation/syn-
patient's skin problem. Once a textile is suspected, the thesis directions, literature or patent references, prop-
remaining challenge is to identify which dye, res in, or erties of the dyes, and their mode of application.
other chemical is the causative agent. Another important reference of textile dyes in current
This chapter provides information that will be manufacture is the July issue of Textile Chemist and
helpful in discovering whether a chemical of fabric Colorist (American Association of Textile Chemists

Textiles 623
and Colorists 1997), as this reference indicates the not for people wearing garments on which reactive
companies currently manufacturing textile dyes, and dyes have been used. In fact, our list contains no cases
the specific dyes they manufacture. Dyes are listed in in which reactive dyes transferred from fabric to skin.
this reference using the CI naming system. Such a transfer would be unlikely, as reactive dyes are
Table 1 is a list of all disperse dyes reported to be covalently bonded to the cellulose polymers in the
contact allergens and Table 2 lists by application dass fibers they color - usually cotton, flax/linen, or rayon.
all other textile dyes reported in the past 15 years as Estlander (1988) was the first to study the reactive-dye
being contact allergens.' An application dass contains allergens, and reported eight to be allergens when she
those dyes that are commonly used to dye the same patch tested using patches to which dye solutions had
fiber and therefore have a common dyeing procedure. been applied. Other ACD-reactive dyes were discov-
Wehave provided the chemical dass of each dye. The ered by Manzini et al. (1996a, 1996b) and Wilkinson
70 dyes listed in Tables 1 and 2 were reported as and McGechaen (1996).
causes of ACD. To our knowledge, only Hjorth and Acid dyes are used primarily to dye fabrics com-
Möller (1976) and Brandao (1988) have reported a posed of wool fibers or nylon fibers. Nylon fabrics are
phototoxic reaction to dye. They thought the irritant often worn next to the body, as they are commonly used
dye was Disperse Blue 35. in the manufacture of nylon sheer hosiery and men's
Table 3 provides a list of dyes used in patch tests dress socks. Wool is usually used in outerwear, for
that yielded no positive patch-test results. It is jackets, coats, and suits. The dye forms an ionic bond
unfortunate that we do not know the CI names and with polymers ofwool (protein) or nylon (polyamide),
numbers of many of these dyes. so the dyes are fairly weIl bonded. The degree of
wetfastness exhibited when the fabric is damped and
rubbed, however, depends on the specific dye. In
Application (lasses
Table 2, three of the acid dyes - Yellow 23, Yellow 36,
and Violet 17 - were discovered when dermatologists
Dye allergens are found in the disperse, acid, azoic,
traced a patient's skin problem to its origin. The
basic, direct, pigment, reactive, solvent, and vat
remaining four were reported as allergens by Manzini
application dasses. No dye allergens belong to the
et al. (1991), Seidenari et al. (1995) or Balato et al.
mordant and sulfur application dasses. Almost 50% of
(1990b) when they patch tested using patches to which
the 70 reported dye allergens are disperse, about 20%
dye solutions had been applied. The transfer of the dye
are reactive, and 10% are acid.
to the skin would in this testing be easier than the
Many dye allergens are disperse dyes because dyes
transfer of the same dye applied commercially to
within this dass are used to dye fibers that often
fabrics to be sold for making garments.
compose garment fabrics, are available for transfer to
The basic dyes are used primarily to color acrylic
the skin, and are of a molecular size that places them
within the ACD-allergen size range. Polyester fiber, the (polyacrylonitrile) fibers and polyester and nylon
fibers when these fibers have been suitably modified
second most-used fiber in the manufacture of dothing,
to accept basic dyes. The dye-polymer bonding is
can only be colored using disperse dyes unless the fiber
ionic, so a relatively strong bond is formed. Basic dyes
is modified to accept other types of dyes, a modifica-
as a group are given an excellent rating in terms of
tion that is uncommon. Nylon fiber, often used to
make underwear fabrics, is also often dyed with wetfastness and fastness to rubbing.
disperse dyes, although it is more frequently dyed
with acid dyes. Polyester fiber is difficult to dye, and at (hemical (lasses
best the disperse dye lies on the fiber surface or is
embedded ne ar the fiber surface. These dyes can be In terms of chemical dasses, dye allergens belong to
removed by rubbing and exposure to water (they are seven of the twenty-four chemical dassses of dyes. 2
said to have "low crock" and "wetfastness"). In The seven groups are azo, azoic, anthraquinone, azine,
addition, the disperse dyes tend to be among the diphenylmethane, quinoline, and triarylmethane.
smallest of the dye molecules. The two most important chemistries are azo and
The reason for the number of reactive dye allergens anthraquinone. Azo, particularly monoazo, and an-
differs dramatically from the reasons for the number of thraquinone are the two most important dass es of dyes
disperse dye allergens. First, the reactive dyes have used today. Over 50% of the world dyestuff production
been found to be contact allergens for workers in dye is azo dye. These chemistries appear in most of the dye
houses who handle the dye powders and solutions, and
2The other dye classes are nitroso, carotene, xanthene, acridine,
'We have not gone back further than 15 years, as prior to that methine and polymethine, thiazole, indamine and indophenol,
time analytical methods for identifying specific dyes were not azine, oxazine, thiazine, sulfur, lactone, aminoketone, hydroxy-
available. Early case reports are provided in Hatch (1984a). ketone, and natural organic coloring matters.
624 K.L. Hatch and H.1. Maibach
Table 1. Disperse dye allergens
Color index name Chemical dass References in chronological order

and number
Red 1 1l1l0 Monoazo Calnan and Wilson 1956; Cronin 1968b; Cronin 1968a; Sim-Davies 1972;
Imbeau and Reed 1979; Cronin 1980; Hausen and Schulz 1984;
Apted 1985; Foussereau 1986; Gasperini et al. 1986; Hausen 1987;
Brown 1990; Balato et al. 1990b; Patrizi et al. 1990;
Shehade and Beck 1990; Massone et al. 1991; Seidenari et al. 1991;
Dooms-Goossens 1992; Goncalo et al. 1993;
Hausen 1993; Lisboa et al. 1994; Maurer et al. 1995; Dejobert et al. 1995
Red II 62015 Anthraquinone Sim -Davies 1972; Cronin 1980
Red 15 60710 Anthraquinone Sim-Davies 1972
Red 17 11210 Monoazo Suter 1965; Cronin 1980; Hausen and Schulz 1984; Gasperini et al. 1986;
Balato et al. 1990b; Shehade and Beck 1990; Patrizi 1990; De Frutos
et al. 1991; Morren et al. 1991; Seidenari et al. 1991; Dooms-Goossens
1992; Hernando et al. 1992; Lisboa et al. 1994; Maurer et al. 1995;
Dejobert 1995
Red 19 11130 Monoazo Hausen and Schulz 1984
Red 137 Monoazo Brandao 1980
Red 153 Mixture of 2 dyes, Nakagawa et al. 1996
both benzothaizol-
azoyl-PPD derivatives
Orange 1 II 080 Monoazo Sim-Davies 1972; Shehade and Beck 1990; Balato et al. 1990b;
DeFrutos et al. 1991; Seidenari et al. 1991; Dooms-Goossens 1992;
Hernando et al. 1992; Maurer et al. 1995; Dejobert et al. 1995;
Orange 3 11005 Monoazo Hjorth/Rothenborg 1967; Cronin 1980; Kouse and Soini 1980; Foussereau
1986; Hausen and Schulz 1984; Gasperini et al. 1986; van der Veen 1988;
Hausen et al. 1991; Kojima and Momma 1989; Balato et al. 1990b;
Shehade and Beck 1990; Manzini et al. 1991; Massone et al. 1991;
Seidenari et al. 1991; Dooms-Goossens 1992; Hernando et al. 1992;
Sherertz 1992; Goncalo et al. 1993; Lisboa et al. 1994; Maurer et al. 1995
Orange 13 Disazo De Frutos et al. 1991; Dooms-Goossens 1992; Hernando et al. 1992;
Maurer et al. 1995
Orange 76 Monoazo Cronin 1980; Gasperini et al. 1986; Patrizi et al. 1990; Balato et al. 1990b;
Bajaj et al. 1991; Morren 1991; Seidenari et al. 1991
Yellow 1 10345 Nitrophenylamine Sim-Davies 1972
Yellow 3 11855 Monoazo (heterocydic) Dobkevitch and Baer 1947; Calnan and Wilson 1956; Cronin 1968b and
1968a; Foussereau et al. 1972; Sim-Davies 1972; Imbeau and Reed 1979;
Cronin 1980; Kousa and Soini 1980; Hausen and Schulz 1984; Apted
1985; Hausen 1987; van der Veen 1988; Patrizi et al. 1990; Shehade and
Beck 1990; Morren et al. 1991; Farli et al. 1991; Bajaj et al. 1991;
Dooms-Goossens 1992; Hernando et al. 1992; Hausen et al. 1993;
Lisboa et al. 1994; Maurer et al. 1995; Dejobert et al. 1995
Yellow 4 12770 Monoazo (heterocydic) Cronin 1968a
Yellow 9 10375 Nitrophenylamine Sim-Davies 1972; Cronin 1980; Brown 1990; Massone et al. 1991; DeFrutos
et al. 1991; Seidenari et al. 1991; Dooms-Goossens 1992; Hernando et al.
1992; Maurer et al. 1995;
Yellow 39 Indigole Cronin 1968a; Sim-Davies 1972; Cronin 1980
Yellow 49 Indigole Sim-Davies 1972
Yellow 54 Quinophthalone Gasperini et al. 1986; Seidenari et al. 1991
Yellow 64 47023 Quinophthalone Calnan 1977
Blue 1 64500 Anthraquinone Sim-Davies 1972; Hausen 1987; Maurer et al. 1995
Blue 3 61505 Anthraquinone Cronin 1968a, 1968b; Sim-Davies 1972; Cronin 1980; Hausen and Schulz
1984; Seidenari et al. 1991; Maurer et al. 1995
Blue 7 62500 Anthraquinone Cronin 1968a; Sim-Davies 1972; Cronin 1980
Blue 26 63305 Anthraquinone Sim-Davies 1972
Blue 35 Anthraquinone Cronin 1968a; Sim-Davies 1972; Cronin 1980; Hausen and Schulz 1984;
Gasperini et al. 1986; Kojima and Momma 1989; Balato et al. 1990b;
Patrizi et al. 1990; De Frutos et al. 1991; Morren et al. 1991; Seidenari
et al. 1991; Dooms-Goossens 1992; Hernando et al. 1992; Lisboa et al.
1994; Maurer et al. 1995
Blue 85 Monoazo van der Veen 1988; Brown 1990; Massone et al. 1991; De Frutos et al.
1991; Dooms-Goossens 1992; Hernando et al. 1992
Blue 102 -* Monoazo (heterocydic) Cronin 1968a
Blue 106 -* Monoazo (heterocydic) Brandao et al. 1985; Foussereau 1986; Gasperini et al. 1986;
Hausen and Brandao 1986; Hausen 1987; Brandao and Hausen 1987;
Hausen et al. 1991; Farli et al. 1991; Morren et al. 1991;
De Fritos et al. 1991; Hausen et al. 1991; Dooms-Goossens 1992;
Sherertz 1992; Hernando et al. 1992; Hausen 1993; Lisboa et al. 1994;
Dejobert et al. 1995; Maurer et al. 1995
Blue 124 -* Monoazo (heterocydic) Cronin 1980; Hausen and Schulz 1984; Gasperini et al. 1986; Hausen 1987;
Kojima and Momma 1989; Balato et al. 1990b; Patrizi et al. 1990;
Hausen et al. 1991; Bajaj et al. 1991; Massone et al. 1991;
Seidenari et al. 1991; Dooms-Goossens 1992; Hernando et al. 1992;
Sherertz 1992; Hausen et al. 1993; Maurer et al. 1995; Dejobert et al. 1995
Textiles 625
Table 1. (Contd.)
Blue 153 Anthraquinone De Frutos et al. 1991; Dooms-Goossens 1992

Brown I 11152 Monoazo Brown 1990; De Frutos 1991; Balato et al. 1990b; Massone et al. 1991;
Dooms-Goossens 1992; Hernando et al. 1992; Lisboa et al. 1994;
Maurer et al. 1995
Black 1 11365 Monoazo (heterocydic) Cronin 1968a and 1980; Gasperini et al. 1986; Kojima and Momma 1989;
Shehade and Beck 1990; Manzini et al. 1991; Seidenari et al. 1991;
Hernando et al. 1992; Lisboa et al. 1994
Black 2 11255 Monoazo Cronin 1968a and 1980; Lisboa et al. 1994
Four blue and thiazol-azoyl- Nakagawa et al. 1996
I violet dye paraphenylendiamine
with structures chemistry
similar to Blue
106 and 124
One orange and Simple azo Nakagawa et al. 1996
I blue dye
with chemistry
similar to Red I
and 17, Orange 3,
Brown I
Table 2. Other dye allergens
Color index name and Chemical dass References, in chronological order

number and/or trade name a
Acid
Red 118 - Supramine Red GW Monoazo (heterocydic) Manzini et al. 1991; Seidenari et al. 1995
Red 359 - Neutrichrome Red, Monoazo (1:2 metal complex) Manzini et al. 1991; Seidenari et al. 1995
Neutrichrome Red SGN
Yellow 23 19140, Azo tartrazine Monoazo (heterocydic) Roeleveld and van Ketel 1976
Yellow 36 13065, Metanil Yellow Monoazo Ancona et al. 1982; Hausen 1994
Yellow 61 18968, Supramine Yellow GW Monoazo (heterocydic) Manzini et al. 1991; Seidenari et al. 1995
Violet 17 42650 Triarylmethane Cronin 1968a
Black 48 65005 Anthraquinone Gasperini et al. 1986; Patrizi et al. 1990;
Morren et al. 1991; Bajaj et al. 1991;
Balato et al. 1990b; Manzini et al. 1991;
Seidenari et al. 1991
Azoic components
Naphthol AS, coupling agent 2-hydroxy-3-naphtholic acid analide Hayakawa et al. 1985
Coupling agent 2,4,5-trichloroaniline Sano et al. 1994
Coupling agent 4-benzmide-2,5-diethoxyaniline Sano et al. 1994
Basic
Red 22 - Synacril Red 3B Monoazo Sadhra et al. 1989
Red 46 Monoazo Foussereau 1986; Maurer et al. 1995;
Dooms-Goossens 1992; Manzini et al.
1996a
Brown 1 21000 Disazo dye mixture Gasperini et al. 1986; Balato et al. 1990b;
Goncalo et al. 1992; Manzini et al.1996a
Black I 50431 Azine dye mixture Seidenari et al. 1991; Manzini et al. 1996a
Direct
Orange 34 40215, 40220, Stilbene Seidenari et al. 1995
Arancio Diazol Luce 7 JL
Black 38 30235 Triazo Norferi et al. 1966
Pigment
Yellow 16b 20040 Disazo (pigment) Kojima and Momma 1989
Reactive
Red 123 - Scarlet Drimaren K2G Monozo with unknown reactive Estlander 1988; Manzini et al. 1996a
system
Red 238 - Red Cibacron CR Unknown Manzini et al. 1996a
Red 244 - Red Cibacron C4G Unknown Manzini et al. 1996a
Orange 107 - Gold Yellow Remazol RNL Unknown Estlander 1988; Manzini et al. 1996a
Yellow 17 18852, Gold Yellow Remazol G Monoazo with vinylsulfonyl Estlander 1988; Manzini et al. 1996a
reactive system
Yellow 56 - Cibacron Pront Yellow 4R Monozo with a chlorotriazinyl Estlander 1988
reactive system
Blue 21 - Turquoise Blue Remazol GI33 Phthalocyanine with vinylsulfonyl Estlander 1988; Manzini et al. 1996a
reactive group
Blue 74 - Cibacron Pront Blue 3R Anthraquinone with chlorotriazinyl Estlander 1988
reactive system
Table 2. (Contd.)
Color index name and Chemical dass References, in chronological order

number and/or trade name"
Blue 75 - Cibacron Pront Turquoise G Anthraquinone with chlorotriazinyl Estlander 1988

reactive system
Blue 122 - Printing Blue Remazol RR Azo (metal complex) Manzini et al. 1996a
Blue 225 Azo Wilkinson and McGechaen 1996
Blue 238 - Marine Cibacron CB Unknown Manzini et al. 1996a
Violet 5 18097, Violet Remazol BR 5R Monoazo with vinylsulfonyl reactive Estlander 1988; Manzini et al. 1996a
system
Turquoise Reactive, 42035, 42036, 42037 Unknown Manzini et al. 1991; Manzini et al. 1996a
Remazol DR Brown RR Azo with unknown reactive group Estlander 1988
Black 5 20505, Black Remazol B Gran Disazo with vinylsulfonyl reactive Estlander 1988; Wilkinson and
system McGechaen 1996; Manzini et al. 1996a
Solvent
Red 1 Monoazo Sailstadt et al. 1994
Red 3 Monoazo Golhausen et al. 1986
Orange 8 12175 Monoazo Fujimoto et al. 1985
Yellow 14 12055 Monoazo Fujimoto et al. 1985
Yellow 1 11 000 Monoazo Kouse and Soini 1980
Vat
Green 1 59825-6 Anthraquinone Wilson and Cronin 1971
Unknown application dass
Wool Red B
Unknown p-Amino-acetanilide-p-cresol Maibach 1975
Unknown Methylamino-4-(2-hydroxy- Maibach 1975
methylamino ) anthraquinone
Brilliant Green Unknown Manzini et al. 1996a
Diazol Orange Unknown Manzini et al. 1991
Foron Blue Unknown Cronin 1980
Compounds used in the dye process
Tinofix S suspected, dye fixing agent A cationic condensation DeGroot and Gerkens 1989
product of dicyandiamide,
formaldehyde, and
ethylenediamine
Chromium Davies and Barker 1944; Peterkin 1948;
Bockendahl 1954; Ebner 1967; Fregert
et al. 1978
"Manufacturers of trademarked dyes are as follows: Supramine (Bayer), Neutrichrome and Diazol OC!), Synacril (Synthron Inc.),
Drimaren (Sandoz), Cibacron and Tinofix (Ciba), Remazol (Hoechst)
b The allergen was phosgene (2, 5 - dichlorophenyl) hydrazone - a product formed as a result of hypo chlorite bleaching of Pigment
Yellow 16
application dass es and notably in the disperse, reac- with cell-surface proteins. Hatch and Magee (1998)
tive, and acid dasses. The structures of most of the explored how anthraquinone dyes might initiate an
textile-dye allergens can be found in Hatch (1995) andl ACD immune response. Nine of the reported anthra-
or in the CI (Society of Dyers and Colourists 1997). quinone ACD allergens and ten anthraquinone dyes
Azo dyes are characterized by the presence of at with no history of causing ACD were studied to
least one azo group (-N=N-) as the chromophore. Azo determine how they differed in terms of dassical and
dyes may be derived from aminoazobenzene or from a quantum-chemical descriptors. The results suggest an
variety of heterocydic structures. They may be non- electron-transfer reaction followed by a nudeophilic-
ionic with no solubilizing constituents, therefore radical attack on the cell surface proteins of the
belonging to the disperse application dass; they may epidermal Langerhans' cells as marking the beginning
be sulfonated, therefore belonging to the acid applica- of the ACD immune response.
tion dass; or they may contain constituents that
covalently bond with fiber polymers, therefore belong- Validation
ing to the reactive application dass.
Anthraquinone dyes have anthraquinone as their When compiling the dyes for Tables 1 and 2, we
base and the carbonyl group (>C=O) as the chromo- induded every dye that was identified in the literature
phore. Anthraquinone itself is not a contact allergen. as being a textile allergen, keeping track of how many
In fact, the anthraquinone ACD dyes have no obvious independent reports and how many patients were
protein reactive group or substructure for reaction patch-test positive in each report. Note that there are
Textiles 627
Table 3. Dyes used in patch testing that were found not be allergens
Color index name and Chemistry Reference

number and/or tradenamea
Class not known

Yorkshire Joracril Yellow Unknown Manzini et al. 1991
Yorkshire Red Unknown Manzini et al. 1991
Yorkshire Joracril Blue Unknown Manzini et al. 1991
Sandolan Yellow Unknown Manzini et al. 1991
Sandolan Blue Unknown Manzini et al. 1991
Diazol Black Unknown Manzini et al. 1991
Brilliant Red Unknown Manzini et al. 1991
Marine Foron Blue Unknown Manzini et al. 1991
Supramine Blue Unknown Manzini et al. 1991
Astrazon MS Green Unknown Manzini et al. 1991
Astrazon M Green Unknown Manzini et al. 1991
Reactive
Green 12 - Green Drimaren X3G Unknown Manzini et al. 1996a
Blue 18 - Turquoise Drimaren X2G Unknown Manzini et al. 1996a
Red 198 - Red Remazol RB 133 Azo Manzini et al. 1996b
Red 180 - Remazol F3B Azo Manzini et al. 1996b
Orange 16 -Brilliant Orange, Remazol 3R Azo Manzini et al. 1996b
Orange 96 17757Gold Yellow, Remazol 3R Azo Manzini et al. 1996b
Blue 220 - Formazan Brilliant Blue, Remazol BB Unknown Manzini et al. 1996b
Direct
Yellow 169 - Solophenil Yellow AGL Azo Seidenari et al. 1995
a Remazol, Cibacron and Solophenil, and Drimaren are tradenames of Hoechst, Ciba, and Sandoz, respectively
fourteen dyes for which there is but one case report Problems with mislabeling of dyes have been
describing one patient. Those 14 dyes are Disperse Red highlighted by Bide and McConnell (1996). Using
19 and 137, Disperse Yellow 4 and 64, Disperse Blue thin-Iayer chromatography (TLC), they found that a
102, Acid Yellow 23, Acid Violet 17, Reactive Red 123, dye product sold by one manufacturer as "Disperse
238, and 244, Reactive Yellow 17, Reactive Blue 21 and Violet 1" was not Disperse Violet 1 but rather Disperse
255, and Vat Green 1. Note that there are seven dyes for Violet 27. They found variations in the compositions of
which there is but one case report, but that the report twelve dye products labeled as Disperse Blue 3. Their
included many patch-test-positive individuals. Those article includes the chromatograms of five Disperse
seven dyes are Disperse Red 15, Disperse Yellow 1, Blue 3 dye products in order to show the differences in
Disperse Yellow 49, Disperse Blue 26, Direct Black 38, the compositions. They also found that two sampies of
Solvent Yellow 1, and Pigment Yellow 16. a disperse black dye mixture which were supposed to
We are unsure about the allergenicity of these 21 contain the same components actually contained very
dyes, as the evidence is not particularly strong. Sources different components.
of error lie in the administration of the patch test and/ In general, the allergenicity of dyes has not been
or with the interpretation of the results, the purity of validated by various assay techniques. Sailstad et al.
the dye used in the patch test, and mislabeling of dyes. (1994) raises a question about the allergenicity of
Questions have been raised about the purity of dyes Disperse Blue 3 and Disperse Red 11. Disperse Blue 3
used in patch testing. The presence of contaminants in has been reported to be an allergen by Cronin (1968a,
the dye product raises the question of whether the dye 1968b, 1980), Sim-Davis (1972), Hausen and Schulz
or the contaminant is the allergen. Brandle et al. (1984) (1984), Maurer et al. (1995), and Seidenari (1991). The
analyzed the purity of Disperse Yellow 3, Disperse total number of positive patch tests was 45. Sim-Davies
Orange 3, and p-aminophenol from one commercially (1972) and Cronin (1980) have reported 22 positive
available patch-test series and found that Disperse patch tests to Disperse Red 11. While considerable
Orange 3 was not pure. Foussereau and Dallara (1986) evidence indicates that Disperse Blue 3 and Disperse
analyzed twelve dyes and concluded that only Disperse Red 11 are contact sensitizers, Sailstadt et al. concluded
Yellow 3, Disperse Orange 1, and Disperse Orange 13 that they were not after conducting a locallymph node
seemed pure. Until sampies ofhigh purity are available assay (LLNA) and a modified mouse ear swelling test
for patch testing, we will remain uncertain if the (MEST). Hausen and Sawall (1989) undertook dye
sensitizer is the dye or a contaminant. The latter has sensitization experiments with guinea pigs. For a
been the case with some cosmetic dyes (Kgzuki et al. discussion of the strengths and weaknesses of these
1989), leading to a practical solution in avoiding future assays, refer to Marzulli and Maibach (1977) and
ACD cases. Patrick and Maibach (1995).
Other Textile Allergens The only case of textile dermatitis reported to be

caused by fiber polymers during the 1990S was that
described by Tanaka et al. (1993). In this case, the
Types of chemicals other than the colorants on fabrics
specific nylon polymer was epsilon-aminocaprioic acid
indude fiber additives, fiber polymers, and finishing (EACA). This is not one of the usual polymers used to
compounds. Additionally, fabrics may contain chem-
form nylon; those polymers being polyhexamethylene
icals acquired during storage and use. In this section,
adipamide for nylon 66 fibers and polycaproamide for
only chemicals found to cause skin reactions during nylon 6 fibers.
the 1990S are reported. The interested reader is
Polymers may degrade during use of the fabric.
referred to Hatch (1984a, 1984b, 1988) and Hatch and There are no instances of which we are aware in which
Maibach (1985a, 1986) for earlier reports of textile a polymer degraded to form an allergen.
chemicals causing skin reactions. These reports are
now mainly of historical interest, because textile Finishing Compounds
chemistry has advanced tremendously in the last
decade. Many compounds previously used are no A chemical finish is "a chemical material other than
longer used, and if the same compounds continue to be
colorants and residual processing chemicals added to
used they are applied in processes in which the fastness textiles to impart desired functional or aesthetic
of the chemical to the fiber/fabric has been vastly properties to the textile product" (American Associa-
improved. tion of Textile Chemists and Colorists, 1997a). Lists of
compounds used to finish fabrics are provided by Flick
Fiber Additives (1990) and in two buyers' guides (Intertec, Inc. 1997;
American Association of Textile Chemists and Color-
Fiber additives are chemicals such as flame retardants, ists 1997b). Another excellent reference is Textile
delustrants, ultraviolet (UV)-radiation absorbers, and Processing and Properties (Vigo 1997).
optical brighteners which are incorporated into man- Chemical finishing compounds may be topical,
ufactured fibers to provide properties such as en- essentially forming a thin coating on fibers. Others are
hanced flame resistance, dullness, decreased rate of absorbed into the fibers, where are they (a) entrapped or
degradation from incident UV radiation, or enhanced (b) covalently bonded to the fiber polymers. Finishing
whiteness and brightness. The chemicals are added to compounds may degrade or decompose during use.
the polymer solution or melt so that they become
embedded and locked between the fiber's polymers as Durable-Press Resins
the solution coagulates or the melt solidifies. Lists of
specific additive chemicals are available from manu- While we are aware of only three reports in the 1990S
facturers such as ICI Corporation (1987). There have (Sherertz 1992; Fowler et al. 1992; Bracamonte et al.
been few reports of fiber additives causing skin 1995) about the allergenicity of durable-press treated
reactions, a situation that would be expected because fabrics, these reports reflect continuing concern about
these compounds are not readily available for transfer the use of these resins to impart wrinkle resistance to
to the skin. 100% cotton and, more typically, to cotton/polyester-
In the 1990S, only Tinuvin P, 2-(2-hydroXY-5-meth- blend fabrics. Nine major res ins are used, which differ
ylphenyl)benzotriazole, was reported to cause ACD in formaldehyde-releasing potential (Hatch and Mai-
(Kaniwa 1991; Arisu et al. 1992). Tinuvin P, a UV bach 1994).
absorber, is added to spandex fiber to slow the rate of Both Sherertz (1992) and Fowler et al. (1992) exam-
degradation of the polyurethane polymers of wh ich the ined the records of patients referred to their respective
fiber is composed. United States dinics to determine how many patients
were formaldehyde sensitive. Sherertz found 63 pa-
Fiber Polymers tients who were patch-test positive to formaldehyde or
formaldehyde-releasing preservatives. She also found
Many different polymers are used to manufacture 13 re cords of patients referred because they had a
fibers, and these differ from the cellulose and protein suspected dothing dermatitis. All 13 had been patch
polymers of the natural fibers, which indude cotton, tested with the American Academy screening se ries
wool, and silk. Hatch (1992) provides a listing of the and had been evaluated as not being atopic before they
polymers in fibers. Polymers in fibers are long-chain arrived at the referral service. Fowler et al. found 678
molecules of far higher molecular weight than could records of patients referred in a two-year period
possibly cause ACD and are not readily available for because they had dermatitis of unknown origin.
transfer to the skin, as strong forces of attraction exist Sherertz subsequently tested each of the sixty-three
between polymers. individuals with formaldehyde allergy with the six
Textiles 629
textile resins included in the Chemotechnique Diag- known allergen. They did not report any occurrences
nostic series (Malmö, Sweden) using Finn Chambers of ACD.
and Scanpor tape (Table 3). She removed the patches
at 2 days and read them at 2 days and 3 days. Forty- Degradation Products
five of the sixty-three individuals were patch-test
positive to one or more of the resins. Details were Dyes, finis hing compounds, fiber additives, and fiber
not provided. When the re cords of the thirteen polymers are all subject to degradation. Degradation
individuals with suspected clothing dermatitis were can occur due to exposure to UV radiation and to
studied, it was discovered that eleven people had patch chlorine bleach and other oxidizing compounds, and
tested positive to one or more of the textile resins in to reducing compounds. Additionally, degradation
the Chemotechnique series, and that two individuals may occur in the skin. The degradation product may
were patch-test positive only to dyes in that se ries. be the allergen.
Fowler et al. retrospectively tested the identified Jordan and Bourlas (1975) found that the degrada-
patients with the Chemotechnique Diagnostic patch- tion product of a fiber additive was an allergen. Six of
test series or the Hermal textile series, the North their patients were allergie to certain items of under-
American Contact Dermatitis Group standard screen- wear only after it was washed with hypochlorite bleach.
ing tray, and other selected allergens. They used Finn The zinc dibenzyl dithiocarbamate (ZDC) which was
Chambers, removed the patches at two days, and read used to stabilize the rubber fiber in the elastic banding
them at 4 days or 7 days. Of the 678 patients, 16 were was degraded into N,N-dibenzyl carbamate chloride.
patch-test positive to textile formaldehyde resins. Likewise, Kojima and Momma (1989) and Kojima et al.
Formaldehyde-releasing preservatives as weIl as to (1990) discovered that the allergen in garments dyed
textile formaldehyde res ins caused allergie reactions in with Pigment Yellow 16 was actually phosgene (2,5-
12 patients. dichlorophenyl) hydrazone, the degradation product.
Certain azo dyes are metabolized to form quinonedii-
Textile Formaldehyde mine, a known allergen (Hatch 1984b). Formaldehyde
may be adegradation product of durable-press resins
The data indicate that, in many cases, the causal agent used to treat coUon and cotton/polyester-blended
was probably formaldehyde released from the resin. In fabrics.
both studies, most patients were patch-test positive to
both formaldehyde and to a textile formaldehyde resin.
More patch tests were positive when resins releasing Contaminants
high amounts of formaldehyde were applied than when
resins releasing medium- or low amounts of formal- Fabrics are highly likely to be contaminated with
dehyde were applied. chemie als such as those in ballpoint pen ink, poison
The data also indicate that, in some cases, the causal ivy plants, household cleaning products, fabric clean-
agent is probably the res in itself (not the formaldehyde ing products, and pesticide sprays. Gronemeyer (1953)
that it may release). A significant number of patients - was able to determine the allergen on a leather hat
3 of 11 in the Sherertz study (1992) and 4 of 16 in the band once he realized that the offending hats had been
Fowler et al. study (1992) - were patch-test positive to stacked. He identified Laurus nobilis, a compound
textile formaldehyde resin without being patch-test used to gloss the feIt from which the hats were made.
positive to formaldehyde. Similarly, Cadot (1974) discovered that it was poison
ivy contaminating a pair of pants that caused a woman
great suffering. She had worn the pants on an outing
Other Compounds
and did some mending on the trousers before cleaning
In the 1990s, Wilkinson et al. (1991) reported five cases them. While no cases of formaldehyde dermatitis have
been reported due to transfer of formaldehyde from
of ACD caused by 1,6-diisocyanatohexane, a compo-
durable-press-treated items to untreated items, such
nent of a finish used to slow the rate of pill3 formation,
transfer is known to üccur (Trask-Mürrell et al. 1995).
Guinnepain and Bombaron (1990) reported one case
due to a flame retardant of unknown chemistry, and
Moreau et al. (1994) reported 91 cases of ACD due to Clinical
Flammentin ASN, a flame retardant. Karlsberg and
Magnusson (1996) raise a question about the presence
of rosin in disposable diapers, as this compound is a Often, textile dermatitis presents as classical eczema-
tüus dermatitis; the skin has areas üf redness due tü
3Pills are the small fuzz balls formed on a fabric surface due to dilation of the capillaries in the superficial dermis and
the entanglement of tibers protruding above the fabric surface. swelling due to buildup of fluid in damaged vessels.
Such lesions are observed in the photographs provided The characteristic distribution of lesions when a
by Foussereau (1992). dress, blouse, or shirt contains the offending chemical is
at the axillae, especially at the outer borders, on the neck
when the garment has a collar, on the forearms when the
Characteristics garment has sleeves, and on the wrists when the
garment is long-sleeved. The axillae are generally
Sometimes, the eruption is occult, i.e., a baffiing spared. The wearing of a slip under a dress containing
chronic dermatitis, and may be misdiagnosed for the offending chemical is believed responsible for
months or years. The differential diagnosis may sparing of the back and chest. Because the custom of
include ringworm infections and malignancies such wearing a slip under a dress has subsided, it is likely that
as reticuloses. The reddened and swollen areas may be lesions will also be distributed on the back and ehest.
surmounted by small superficial elevations containing The characteristic distribution of nylon-stocking
fluid from which serum may exude, leading to forma- dermatitis lesions is on the upper sides of the feet and
tion of crusts. If not treated, the eruption may become toes, the backs of the knees, and the inner parts of the
chronic. Thickening of the epidermis with deepening upper thighs. The eruption may involve the heels,
of the normal skin lines accompanied by small soles, and bottom surfaces of the toes. The character-
superficial solid elevations (many containing fluid) istic distribution of lesions on patients with pant/
and mild redness may occur. The skin may darken in trouser dermatitis is on the thighs. Lesions are also
color and become leathery and cracked. likely on the patient's hands, if the patient frequently
Pigmented purpuric skin eruptions also occur. For tends to put his/her hands into the pockets of the
example, Van der Veen (1988) describes a sailor who pants.
experienced a pigmented purpuric skin eruption as a
result of wearing a blue uniform containing Disperse
Essential Queries
Blue 95, an azo dye.
Urticaria is observed even less frequently. Pauluzzi
Determining which garment or garments are the cause
et al. (1995), for example, examined a 36-year-old
of a patient's skin problem requires careful question-
dressmaker who had chronic urticaria for two years.
ing. The following inquiries are essential:
This condition developed a few months after the
patient began making garments from polyester fabrics. 1. Patients should be queried about the occurrence of
Clinical features, challenge tests, and the patient's dermatitis following the wearing of 'long-time'
answers to the dermatologist's questions were consis- favorite garments, as well as the wearing of new
tent with a diagnosis of contact urticaria due to dyes of garments. When patients have been sensitized by a
textile fibers. The specific allergen was not identified. weak allergen in a garment they have worn repeat-
Amin et al. (1997) review contact urticaria. edly, the diagnosis can be baffling because the
The distribution of lesions on the body is often a favorite garment is not even suspected; it has been
clue to whether a textile chemical might be the cause of worn repeatedly with no problems. However, when
a patient's skin problem, because only those skin areas patients may have been presensitized to an allergen
where the offen ding fabric actually contacted the body through exposure from another consumer product,
will have lesions. That is not to say, however, that the the initial wearing of a new garment containing that
entire area of skin contacted by the offending fabric allergen, even a weak allergen, will result in derma-
has lesions. In fact, the entire area is rarely affected. titis. The difference is that the source of the allergen
The areas might be limited to where friction is highest is more readily identified in the latter case than the
between skin and garment and/or the greatest amount former.
of moisture is present. Both friction and moisture 2. Patients suspected to have a textile dermatitis
ass ist in the transfer of the offending chemical to the should be queried about laundering practices,
skin. particularly about use of bleach and other practices
A dramatic illustration of this patterning of lesions which might lead to degradation of a chemical
was reported by Balzer and Gauchery (1899). Their component of the fabric.
patient presented with lesions on his feet which 3. Patients should be queried about possible contam-
appeared in regularly spaced parallel bands. On ination of the fabrics they wear, as a chemical
questioning the patient, it was discovered that the transferred to the fabric during storage or use might
patient owned a pair of socks with transverse black, be the allergen.
red, green, and yellow stripes. The bands of lesions 4. Experts should be queried about the possibility that
corresponded to where the black and green stripes the textile chemical applied to the fabric or a
rested on the foot, and the clear skin bands to where contaminant might be metabolized in the skin,
the red and yellow strip es rested on the foot. forming an allergenie compound.
Textiles 631
Screening for Textile-Dye Allergies Screening for Durable-Press-Resin Allergies
Because there are many dyes that are potential It is not dear what agent/allergen is best for screening
contact allergens, the ability to use one or two for durable-press-resin contact dermatitis. Fowler
compounds to indicate a possible textile dye allergy et al. (1992) state that ethylene urea mixed with
would be extremely helpful. The most commonly used melamine formaldehyde resins was their best screen-
compound has been para-phenylenediamine (PPD), ing agent because using it dearly identified 14 of the 17
but it is not as useful as many would prefer (Amold patients. Sherertz (1992) notes that urea formaldehyde,
et al. 1995). Disperse Blue 106 was found to be a the agent identifying the greatest number of her res in-
useful screening compound by Dooms-Goossens sensitive patients, is probably not the best indicator for
(1992), as it detected 57% of her cases of textile-dye fabric-finish dermatitis in the United States, because it
dermatitis. Other para-group compounds studied as is being mixed with or replaced by other formalde-
potential screening compounds have been benzocaine, hyde-based finishing agents with lower free-formalde-
PPD mixtures, diaminodiphenylmethane, Disperse hyde release.
Orange 3, p-aminoazophenol, p-aminoazobenzene,
p-dimethylaminoazobenzene, and Disperse Yellow 9. Patch Testing
After compiling the results of the six studies in which
these compounds and PPD were used, we (I985b) The most widely used procedure for establishing textile
conduded that no compound would serve as a dye and textile-resin contact allergy is to use commer-
reliable indicator of textile-dye allergy. Other studies cially available screening series. Suppliers of textile
of cross-sensitizations between azo dyes and para- allergens indude HermalIKurt Hermann located in
compounds (Hansson 1997; Seidenari et al. 1997) have ReinbeklHamburg, Germany (Trolab); Chemotech-
not led to the identification of a reliable screening nique located in Malmö, Sweden (Chemotechnique
compound. Diagnostic Series); and Firma located in Florence, Italy
Sousa-Basto and Azenha (1994) and Sertoli et al. (FIRMA). The dyes and finishing chemicals which are
(1994) have demonstrated that certain mixtures would currently members of each series are listed in Table 4.
be potentially useful. Their dye mixtures were well- The Chemotechnique series is the most extensive, with
tolerated and did not elicit false-positive reactions. The 14 dyes, 13 of which belong to the disperse dye dass
components did not interact and the mixture remained and one which belongs to the basic dye dass. The
stable for at least 1 year. number of dye allergens in aseries is a fraction of the
fable 4. Dyes and resins in textile

screening series. The concentration Chemical Chemotechnique Trolab FIRMA
is 1% in petrolatum (pet) except as
noted Disperse Red 1 X X X
Disperse Red 17 X X X
Disperse Orange 3 X X X
Disperse Orange 1 X
Disperse Orange 13 X
Disperse Yellow 3 X X X
Disperse Yellow 9 X X
Disperse Blue 3 X X X
Disperse Blue 35 X
Disperse Blue 106 X
Disperse Blue 85 X
Disperse Blue 124 X X
Disperse Brown 1 X
Disperse Black 1 X
Basic Red 46 X
Acid Black 48 X
Basic Brown 1 X
Disperse Black 1 X
Urea formaldehyde resin X (10% pet) X (10% pet) X (10% pet)
Melamine formaldehyde resin X (7% pet) X (10% pet) X (10% pet)
Dimethyloldihydroxyethylene urea X (4.5% aq) X (10% pet)
Dimethylol propyleneurea X (5.0% aq) X (10% pet)
Tetramethylol acetylenediurea X (5.0% aq)
Ethylene urea, melamine formaldehyde X (5.0% pet)
aq aqueous, pet petrolatum

known allergens, but the included allergens are those resin has been used. Such labels found on some 100%
thought to be the most useful for detecting a textile- cotton or cotton/polyester garments read "no" or
dye allergy. Likewise, Hermal includes more finishing "zero formaldehyde". It is advisable for patients to
compounds, all of which are used in durable-press launder new garments and sheets before use in order
finishing, than other suppliers. to wash away excess chemicals that might be present,
Patients mayaiso be patch tested with a swatch of whether present due to application by the manufac-
the suspected fabric, applied dry and/or wet. If the turer or due to transfer from other fabrics or sources.
patient is patch-test positive, this identifies the fabric
that contains the offending chemical. However, a
negative does not rule out the possibility that the Identification
fabric does contain the allergen. The conditions may
not permit the transfer of the offending substance or
may not permit transfer at sufficient concentrations to In certain cases, identifying the specific garment or
elicit a response, and without that essential transfer textile product and the allergen it contains will be an
step, a positive will not occur. At one time, it was important undertaking. The fiber content of the fabric
recommended that the fabric should be steamed prior will narrow the possible dyes, as certain dyes are used
to application, but that recommendation has been to color certain fibers. Cotton, rayon, and linen fabrics
withdrawn (Foussereau 1992). are dyed with direct, fiber-reactive, mordant, azoic,
Patients mayaiso be patch tested using an absorbent sulfur, and vat dyes. Wool fabrics are dyed with acid,
disk such as a Finn Chamber (Epitest, Finland) to mordant, and fiber-reactive dyes. Polyester fabrics are
which (a) an extract obtained from the suspected fabric dyed with disperse dyes unless the polyester is
has been added or (b) a dye powder taken from a TLC modified to accept basic dyes. Nylon fabrics are
plate has been added. A positive reaction in this case colored with acid and disperse dyes unless modified
must be carefully studied, as the reaction might be to accept basic dyes. Acrylic fabrics are dyed with basic
irritant rather than allergic contact because there is no and disperse dyes. Acetate fabrics are dyed with
control over the concentration of the suspected com- disperse dyes. Other synthetic fibers are dyed with
pound. The advantage is that the chemical comes from disperse dyes.
the fabric. Formaldehyde must not be tested at a Fiber content will also narrow the chemical finish
concentration exceeding 1% in petrolatum, as a false applied. For example, cotton and cotton/polyester
positive is likely. blends are those that might be durable-press resin
finished. Fabrics with other fiber contents would not be
Management finished in this way.
Knowledge about the dyes used to color certain
Management of textile dermatitis usually involves the products can be helpful. For example, the dyes used to
patient avoiding contact with fabrics that contain the color sheer nylon hosiery are known to include
allergen. This often proves difficult because dyes, fiber Disperse Yellow 3, Disperse Red 1, Disperse Red 13,
additives, and finishing compounds are not named on Disperse Red 17, Disperse Orange 3, Disperse Blue 3,
garments or other textile products. Disperse Blue 14, and Disperse Blue 124 (Balato et al.
Patients with a textile-dye allergy can be advised to 1990a; Berger 1984). Because the dyes used differ from
wear white garments, but if they have an allergy to country to country and change over time due to fiber
optical whiteners which are used to make whites whiter and dyestuff development, an inquiry to a trade asso-
and brighter, they might not avoid an episode of ciation servicing the industry would prove useful. The
dermatitis. These patients might be directed to wear US trade industry for hosiery is the National Associ-
100% cotton garments or 100% wool garments, as the ation of Hosiery Manufacturers (www.nahm.com;
dyes used to color these fibers are rarely allergens. nahminc@aol.com).
Another option is selecting fabrics made from natu-
rally pigmented cotton fiber, such as Foxfiber Dye Identification
(www.thnaturals.com). The labels in these garments
clearly identify the fiber as Foxfiber. Colors are Goetz (1985) presents aseparation and identification
currently limited to the earth colors of tan and dusty scheme for dyes. He wams that information provided
green. in the CI (Society of Dyers and Colourists 1997) under
Patients with formaldehyde dermatitis of any origin Properties, while intended to lead to the identification
or with formaldehyde durable-press-resin dermatitis of dyes, is not adequate for making a positive
need to avoid fabrics with a formaldehyde durable- identification. He recommends separation on the basis
press res in. Such patients may shop for garments with of differential solubility, with specific identification of
a label indicating that a non-formaldehyde durable dyes by spectrophotometry. The shape of the curve
Textiles 633
genera ted in spectrophotometry is unique for each dye. ical means for determining the amount of formalde-
The New York Customs Office maintains a complete hyde released under conditions of accelerated storage.
file of approximately 3,000 different dye curves. Naruse et al. (1995) describe a diffusive-sampling
Bibe and McConnell (1996) recommend TLC, an vial method. A sheet of filter paper is moistened with
analytical tool in which components of a mixture are distilled water. The diffusive-sampling vial, which has
separated by their differing rates of elution within a a 14-ml capacity, is transferred to a 12.7-1 airtight box.
thin layer of absorbent, typically silica, by a solvent The fabrics are put in the box with the vial. The box is
(eluent). Once separated, components can be identified then placed in a thermoregulated chamber. Acetyace-
by Rf value (the ratio of the distance a component tone (7 ml) is added to the vial. Water is added to give
elutes on/in the thin layer to the distance that the a total volume of 14 ml. The vial is placed for 30 min in
solvent front moves), color reactions, or they can be a water bath maintained at 40 oe. The absorbance of
recovered for analysis by other means, such as the above solution is measured by spectrophotometry
spectrophotometric tests. at 414 nm. The concentration of formaldehyde in the
fabric is calculated by a calibration curve. This
Finishing Compound Identification diffusive sampIer does not require the fabric/garment
to be cut, which makes it different from the diffusive
American Assoeiation of Textile Chemists and Color- sampIer used in Japanese legislation entitled "Toxic
ists (AATCC) test method 94-1992, "Identification of Substances in Home-Use Items", Ministry of Health
Finishes in Textiles", provides guidelines for qualita- and Welfare 1977.
tive identification of various finish components pres-
ent on textile fabrics, yarns, or fibers (American Fiber-Additive Identification
Assoeiation of Textile Chemists and Colorists 1997a).
Included are sequential solvent extractions, followed The procedure used by Kaniwa et al. (1991) to deter-
by identification of extracts by infrared spectroscopy mine that the allergen in their fabric was Tinuvin
(IR), gas chromatography (GC), high-performance P followed this general procedure: extraction was
liquid chromatography (HPLC), TLC, nuclear magnet- accomplished by shaking the fabric with a mixture of
ic resonance spectroscopy (NMR), or other instru- acetone:chloroform (1:1) at room temperature; frac-
mental or wet-chemical methods. Direct measurement tionation was done by column chromatography on
of elemental or chemical species on fabrics is done by silica gel using hexane, dichloromethane ethyl acetate,
X-ray ftuorescence spectroscopy, furnace atomic- and methanol as eluting solvents; qualitative and
absorption spectroscopy, and other instrumental or quantitative analysis work was performed using GC,
wet-chemical analysis methods. Identification of spe- GC-mass spectroscopy, and HPLe.
eific finishing components can be accomplished using
chemical spot tests on the textile or on textile extracts.
Summary
Formaldehyde Detection
Tests often eited in the medical literature for the Dyes used to color fabrics are the most likely textile
detection of formaldehyde in various products are the chemicals to cause skin problems, and among the dyes
chromotropic acid and acetylacetone tests. Flyvholm it is the disperse dyes with azo and anthraquinone
et al. (1996 and 1997) describe both tests and present chemistries used to color polyester and other synthetic
the results of a study in which both of these tests were fibers that are the most troublesome. The pattern of
used to detect formaldehyde. The majority (63%) of the distribution of lesions on the patient's body may serve
1134 products tested with the methods were cosmetics as a clue that dyes are involved. The distribution of
and toiletries and another 18% were household prod- lesions willlie where the garment directly contacts the
ucts. Some resin-finished fabrics were included. For skin and at points were friction and moisture add to
81 % of the products, the two tests gave the same the transfer of the dyes from the fabric to the skin.
results. There is no compound or single mixture of com-
Several methods are available for detection of pounds that is a reliable indicator of textile-dye allergy.
formaldehyde in textiles. The main one is AATCC Test However, PPD and other para-containing compounds
Method 112-1990, "Formaldehyde Release from Fabric, are used to indicate azo-dye sensitivity.
Sealed Jar Method" (American Assoeiation of Textile Durable-press resin-treated fabrics and other finish-
Chemists and Colorists, 1997; Pasad et al. 1989). This ing compounds are known to cause contact allergies.
method is applicable to fabrics which may have been The ineidence or prevalence is not thought to be
given a finish with a formaldehyde-containing resin. It significant. Tracing the cause of durable-press-resin
provides accelerated storage conditions and an analyt- dermatitis involves using patch testing with the various
resins used in the industry. Tracing the cause of other Brandao FM, Altermatt C, Pecegueiro M, Pecegueiro M, Bordalo
0, Foussereau J (1985) Contact dermatitis to Disperse Blue
finishing compounds requires extraction and identifi- 106. Contact Dermatitis 13:80-84
cation of compounds from the offending fabric or Brandao MF, Hausen BM (1987) Cross reaction between Disperse
obtaining of the suspected compounds from fabric Blue Dyes 106 and 125. Contact Dermatitis 16:289-290
Brandle I, Stampf JL, Foussereau J (1984) Thin-Iayer chromatog-
manufacturers. raphy study of organie dye allergens. Contact Dermatitis
In addition to dyes and finishing compounds, it is 10:254-255
known that fiber additives and polymers may be the Brown R (1990) Allergy to dyes in permanent-press bed linen.
reason for a patient's skin re action. This rarely Cadot M, Robin J, Hewitt J (1974) Apparition du poison ivy en
happens, but the origin of the problem deserves France. BuH Soc Fr Dermatol Syphil 81:33-34
careful investigation. Only those who have access to Calnan CD (1977) Textile dye Disperse Yellow 64. Contact
laboratory facilities will be successful in identifying Calnan CD, Wilson HTH (1956) Nylon stocking dermatitis. BMJ
these allergens and other textile allergens. Dermatol- 1:147-149
ogists are encouraged to report cases which reveal new Cavelier C, Foussereau J, Tomb R (1988) Allergie de contact et
colorants. Institut National de Recherche ed de Se' curite,
textile allergens and which will assist in building Paris
evidence about the allergenicity of compounds for Cronin E (1968a) Studies in contact dermatitis. XVIII. Dyes in
which evidence is not yet substantive. clothing. Trans St Johns Hosp Dermatol Soc 54:156-164
Cronin E (1968b) Studies in contact dermatitis. XIX. Nylon
stocking dermatitis. Trans St Johns Hosp Dermatol Soc
54:165-169
References Croni~ E (1980) Contact dermatitis. Churchill Livingstone,
Edmburgh
Davies JHT, Barker AN (1944) Textile dermatitis. Br J Dermatol
American Association of Textile Chemists and Colorists (1997a) Syphilol 56:33-43
1997 technieal manual. American Association of Textile DeFrutos FJO, Martin PD, Hernando LB, Romero PLO, Rodriquez
Chemists and Colorists, Research Triangle Park RR, Amoros JI (1991) Eczema alergieo de contacto por
American Association of Textile Chemists and Colorists (1997b) multiples colorantes textiles disperse. Acta Derm Syphil
Textile chemist and colorist buyer's guide. Textile Chem 10:671-674
Colorist 29:1-80 DeGroot AC, Gerkens F (1989) Contact urtiearia from a chemical
Amin S, Lahti H, Maibach HI (1997) Contact urticaria syndrome. textile finish. Contact Dermatitis 20:63-64
CRC, Boca Raton Dejobert Y, Martin P, Thomas P, Bergoend H (1995) Multiple azo
Ancona A (1982) Dermatitis from an azo-dye in industrialleather dye sensitization by the wearing of a black "velvet" body.
protective shoes. Contact Dermatitis 8:220-221 Contact Dermatitis 33:276
Apted JH (1985) Case report: trouser dermatitis. Australas J Dobkevitch S, Baer R (1947) Eczematous cross-hypersensitivity to
Dermatol 26:80 azodyes in nylon stocking and to paraphenylenediamine.
Arisu K, Hayakawa R, Ogino Y, Matsunaga K, Kaniwa M-A (1992) J Invest Dermatol 9:203-211
Tinuvin P in a spandex tape as a cause of clothing dermatitis. Dooms-Goossens A (1992) Textile dye dermatitis. Contact
Arnold WP, van Joost T, van der Valk M (1995) Adding p- Ebner H (1975) Chromat kontaktallergie als urasche von be-
aminoazobenzene may increase the sensitivity of the Euro- kleidungsekzem. Dermatologiea 135:355-361
pean standard series in detection of contact allergy to dyes, Estlander T (1988) Allergie derrnatoses and respiratory diseases
but carries the risk of active sensitization. Contact Dermatitis from reactive dyes. Contact Dermatitis 18:290-297
Farli M, Gasperini M, Giorgini S, Sertoli A (1991) Clothing
33:444
Bajaj AK, Gupta SC, Chatterjee AK (1991) Contact depigmentation dermatitis. Contact Dermatitis 14:316-317
of the breast. Contact Dermatitis 24:58 Flick EW (1990) Textile finishing chemieals: an industrial guide.
Balato N, Lembo G, de Stefano S, Patruno C, deStepfano R, Ayala Noyes, Park Ridge
R (1990a) Identification of textile dyes by laboratory meth- Flyvholm M-A, Tidedmann E, Menne T (1996) Comparison of 2
ods. Contact Dermatitis 23:266 Tests for clinieal assessment of formaldehyde exposure.
Balato N, Lembo G, Patruno C, Ayala F (1990b) Prevalence of Contact Dermatitis 34:35-38
textile dye contact sensitization. Contact Dermatitis 23=111-126 Flyvholm M-A, Hall BM, Agner T, Tiedemann E, GreenhilI P,
Balzer F, Gauchery P (1899) Dermite eczematiforme des pieds Vanderveken W, Freeberg FE, Menne T (1997) Threshold for
provoquee par lateinture des chaussettes. Ann Dermatol Syph occluded formaldehyde patch test in formaldehyde-sensitive
10:683-685 patients. Contact Dermatitis 36:26-33
Berger C, Muslmani M, Brandao FM, Foussereau J (1984) Thin- Foussereau J (1986) Contact dermatitis to Basie Red 46. Contact
layer chromatography search for Disperse Yellow 3 and Dermatitis 15:106
Disperse Orange 3 in 52 stockings and pantyhose. Contact Foussereau J (1992) Clothing. In Rycroft, RJG, Menne T, Frosch
Dermatitis 10:154-157 PJ (eds), Textbook of contact dermatitis, 2nd edn. Springer,
Bide MJ, McConnell BL (1996) In-house testing of dyes. Textile Berlin Heidelberg New York, pp 503-514
Chem Colorist 28:11-15 Foussereau J, Dallara JM (1986) Purity of standardized textile dye
Bockendahl H (1954) Chromnachweis und chromgehalt gefarbte allergens: a thin-Iayer chromatography study. Contact Der-
kleinderstoffe. ein beitrag zur bedeutung gefarbter kleiderst - matitis 14:303-306
offe fur die haufigkeit der chrom allergie. Dermatol Foussereau J, Tanahaski Y, Grosshans E, Khoschevis A (1972)
Wochenschr 130:987-991 Allergic eczema from Disperse Yellow 3 in nylon stockings
Bracamonte BG, Ortiz-Frutos FJ, Diez LI (1995) Occupational and socks. Trans St Johns Hosp Dermatol Soc 58:75-80
allergie contact dermatitis due to formaldehyde and textile Fowler JF, Skinner S, Belsito DV (1992) Allergie contact derma-
finish res ins. Contact Dermatitis 33:139-140 titis from ~ormaldehyde resins in permanent press clothing:
Brandao FM (1980) Personal communication an underd1agnosed cause of generalized dermatitis. J Am
Brandao FM (1988) Photodermatitis from anthraquinone. Con- Acad Dermatol 27:962-968
tact Dermatitis 3=171-172
Textiles 635
Fregert S, Gruberger B, Goransson K, Normark S (1978) Allergie sensibilizaeion por colorantes disperse. Actas Dermo-Sif
contaet dermatitis from chromate in military textiles. Contaet 83:191-196
Dermatitis 4:223-224 Hjorth N, Möller H (1976) Phototoxie textile dermatitis ("bikini
Fujimoto K, Hashimoto S, Kozuka T, Tashiro M, Sano S (1985) dermatitis"). Arch Dermatol112:1445-1447
Oeeupational pigmented eontaet dermatitis from azo-dyes. Hjorth N, Rothenborg HW (1967) Zur Haufigkeit der nylons-
Contaet Dermatitis 12:15-17 trumpfekzeme. Z Haut Gesehleehtskr 42:717-722
Gasperini M, Giotgini S, Farli M, Sertoli A (1986) Dermatiti da ICI Corporation (1987) ICI polymer additives teehnieal bulletin
contatto eon i tuessuts [Contaet dermatitis from fabries]. G 56-0758-015. ICI Corporation, Wilmington
!tal Dermatol VenereoI121:215-218 Imbeau SA, Reed C (1979) Nylon stocking dermatitis. Contact
Goetz A (1985) Proeedures for identifying dyes and pigments. Dermatitis 5:163-164
Textile Chem Colorist 17:171-176 Intertec Publishing Corporation (1997) Textile world buyer's
Golhausen R, Przybilla B, Ring) (1986) Contaet allergy to CI guide. Textile World 147:11-52
Solvent Red 3. Contaet Dermatitis 14:123-125 Jordan WP )r, Bourlas MC (1975) Allergic contact dermatitis to
Gonealo S, Figueiredo A, Freitas )D, Aguiar M, Neves MTC, underwear elastie ehemically transformed by laundry bleach.
Martins RM (1986) Eezema de eontaeto pelo vestua'rio. Trab Arch Dermatol 111:593-595
Soe Port Dermatol Venereol 44:111-133 Kaniwa M-A, Isama K, Kojima S, Nakamura A, Arisu K,
Gonealo S, Gonealo M, Azenha MA, Barros A, Bastos AS, Brandao Hayakawa R (1991) Chemical approach to contact dermatitis
FM, Faria A, Marques MS), Peeegueiro M, Rodriques )B, caused by household products. VIII. UV absorber Tinuvin P
Salgueiro E, Torres V (1992) Allergie eontaet dermatitis in in polyurethane elastomers for fabric products. )ap ) Toxicol
ehildren. Contaet Dermatitis 26:112-115 Environ Health 37:218-228
Gronemeyer W (1953) Hutbanddermatitis. Dtseh Med Wo- Karlberg A-T, Magnuson K (1996) Rosin components identified
ehensehr 78:232-234 in diapers. Contaet Dermatitis 34:176-180
Guinnepain MT, Bombaron M (1990) Eezema professionel a un Kgzuka T, Tashiro M, Sano S, Fujimoto K, Nakamura Y,
ignifuge. Lett GERDA 7=74-76 Hashimoto S, Nakaminami G (1989) Pigmented contact
Hansson C, Ahlfors S, Bergendorff 0 (1997) Coneomitant eontaet dermatitis from azo dyes. Contact Dermatitis 6:330-336
dermatitis due to textile dyes and to eolour film developers Kojima S, Momma ) (1989) Phosgene (2,5-dichlorophenyl)
ean be explained by the formation of the same hapten. hydrozone, a new strong sensitizer. Contact Dermatitis
Contaet Dermatitis. 37:27-31 20:235-236
Hateh KL (1984a) Chemieals and textiles, part I: dermatologieal Kojima S, Monmma J, Kaniwa M-A, Ikarashi Y, Sato M, Nakaji Y,
problems related to fiber eontent and dyes. Textile Res ) Kurokawa Y, Nakamura A (1990) Phosgene (chlorophenyl)
54:664-682 hydrozones, strong sensitizers found in yellow sweaters
Hateh KL (1984b) Chemieals and textiles, part 11: dermatologieal bleached with sodium hypochlorite, defined as causative
problems related to finishes. Textile Res) 54:721-732 allergens for contact dermatitis by an experimental screening
Hateh KL (1988) Textile dermatitis from formaldehyde. In: method in animals. Contact Dermatitis 23:129-141 (Errata.
Feinman, SE (ed) Formaldehyde sensitivity and toxicity. 23:383)
CRC, Boea Raton Kousa M, Soini M (1980) Contact allergy to a stoeking dye.
Hateh KL (1992) Textile seience. West Edueational, St. Paul Contact Dermatitis 6:472-476
Hateh KL (1995) Textile dye contaet allergens. Curr Probl Lisboa C, Barros MA, Azenha A (1994) Contact dermatitis from
DermatoI22:8-16 textile dyes. Contact Dermatitis 31:9-10
Hateh KL, Magee PS (1998) A diseriminant model for allergie Maibach, H (1975) Panty hose dermatitis resembling and com-
eontaet dermatitis in anthraquinone disperse dyes. Quant plicating tinea pedis. Contact Dermatitis 1:329-330
Struet-Aet Relat Manzini BM, Seidenari S, Danese P, Motolese A (1991) Contact
Hateh KL, Maibach HI (1985a) Textile fiber dermatitis. Contaet sensitization to newly patch tested non-disperse textile dyes.
Hateh KL, Maibach HI (1985b) Textile dye dermatitis. ) Am Aead Manzini BM, Motolese A, Conti A, Ferdani G, Seidenari S (1996a)
DermatoI12:1079-1092 Sensitization to reactive textile dyes in patients with contact
Hateh KL, Maibach HI (1986) Textile ehemieal finish dermatitis. dermatitis. Contact Dermatitis 34:172-175
Contaet Dermatitis 14:1-13 Manzini BM, Donini M, Motolese A, Seidenari S (1996b) A study
Hateh KL, Maibach HI (1994) Textile dermatitis: an update (I). of 5 newly patch-tested reactive textile dyes. Contact Derma-
Resins, additives, and fibers. Contaet Dermatitis 32:1-8 titis 35:313
Hausen BM (1987) Reaktionen auf duftstoffe und textilien Marzulli FN, Maibach HI (1977) Dermatoxicity. Washington
[Allergie reaetions to fragrances and textiles]. Z Hautkr Hemisphere, New York
62:1649-1656 Massone L, Anonide A, Isola V, Borghi S (1991) 2 eases of
Hausen BM (1993) Contaet allergy to Disperse Blue 106 and Blue multiple azo dye sensitization. Contact Dermatitis 24:60-62
124 in blaek "velvet" clothes. Contaet Dermatitis 28:169-173 Maurer VS, Seubert A, Seubert S, Fuchs T (1995) Kontaktallergie
Hausen BM (1994) A ease of allergie eontaet dermatitis due to auf textilien. Dermatosen 43:63-67
Metanil Yellow. Contaet Dermatitis 31:117-118 Moreau A, Dompmartin A, Castel B, Remond B, Miehel M, Leroy
Hausen BM, Brandao MF (1986) Disperse Blue 106, a strong D (1994) Contaet dermatitis from a textile flame retardant.
sensitizer. Contaet Dermatitis 15=102-103 Contact Dermatitis 31:86-88
Hausen BM, Sawall EM (1989) Sensitization experiments with Morren M, Dooms-Goossens M, Heidbuehel M, Sente F, Damas
textile dyes in guinea pigs. Contaet Dermatitis 20:27-31 MC (1991) Contact allergy to dihydroxyacetone. Contact
Hausen BM, Sehulz, KH (1984) Strumpffarben-allergie. Dtseh Dermatitis 25:326-327
Med Woehenschr 109:1469-1475 Nakagawa M, Kawai K, Kawai K (1996) Multiple azo disperse dye
Hausen BM, Kulenkamp D, Borries M (1991) Kontaktallergie auf sensitization mainly due to group sensitizations to azo dyes.
blaue dispersionfarbstoffe in schwarzen "samt-leggins". Ak- Contact Dermatitis 34:6-11
tuel Dermatol 17:337-340 Naruse M, Naruse H, Aoyama M (1995) Determination of
Hausen BM, Kleinheinz A, Mensing H (1993) Kontaktekzem formaldehyde in textiles using a diffusive sampier. BuH
durch textilfarbstoffe (Samt-"Ieggings"). Allergoi ) 2:13-16 Environ Contam Toxicol 55:810-816
Hayakawa R, Matsunaga K, Kojima S (1985) Pigmented contact Noferi A, Ferranti E, Testa A (1966) Dermatosi alergiche da nero
dermatitis due to cotton flannel nightdress (in )apanese). diretto (Coloranti azoieo Soluble). Folia Allergoi (Roma)
Nippon Hifuka Gakkai Zasshi 95=1441-1446 13:443-449
Hernando LB, De Frutos )0, Martin PD, Aguilera GR, Rodriguex Ortiz-Frutos J, De Pablo Martin P, Hernando BL, Rodriguez RR,
RR, Diez LI (1992) Eccema alergico de contacto vestimentaria, Amoros YI (1991) Eccem alergieo de contacto por
636 K.L. Hatch and H.1. Maibach: Textiles
mUltiples colorantes textiles "disperse". Acta Derm Syphil Sertoli A, Francalanci S, Giorgini S (1994) Sensitization to textile
82:671-674 disperse dyes: validity of reduced-concentration patch tests
Pasad DM, Cochran CL (1989) Optimization ofthe AATCC sealed and a new mix. Contact Dermatitis 31:47-48
jar and HPLC methods for measurement of low levels of Shehade SA, Beck MH (1990) Contact dermatitis from disperse
formaldehyde. Textile Chem Colorist 21:13-18 dyes in synthetic wigs. Contact Dermatitis 23:124-125
Patrick E, Maibach HI (1995) Predictive assays: animal and man, Sherertz EF (1994) Clothing dermatitis: practical aspects for the
and in vitro and in vivo. In: Rycroft RJG, Menne T, Frosch, PJ clinician. Am J Contact Dermat 3:55-64
(eds) Textbook of contact dermatitis, 2nd edn. Springler, Sim-Davies D (1972) Studies in contact dermatitis. 24. Dyes in
Berlin Heidelberg New York trousers. Trans St Johns Hosp Dermatol Soc 58:251-260
Patrizi A, Lanzarini M, Tosti A (1990) Persistent patch test Society of Dyers and Colorists and American Association of
reactions to textile dyes. Contact Dermatitis 23:60-61 Textile Chemists and Colorists (1997) Colour index, 3rd edn.
PauIuzzi P, Antonini E, Rizzi GM (1995) Urticaria due to dyes of H. Charlesworth, Huddersfield
textile fibers. JEADV 5:S156 Sousa-Basto A, Azenha A (1994) Textile dye mixes: useful
Peterkin, GAG (1948) Textile dermatitis in man. Arch Dermatol screening tests for textile dye allergy. Contact Dermatitis
Syphil 58:249-264 30:189-190
Roeleveld CG, van Ketel WG (1976) Positive patch test to the azo- Storrs FJ (1986) Dermatitis from clothing and shoes. In Fisher
dye tartrazine. Contact Dermatitis 2:180 AA, (ed) Contact dermatitis, 3rd edn. Lea and Febiger,
Sadhra S, Duhra P, Foulds IS (1989) Occupational dermatitis from Philadelphia, pp 283-337
Synacril Red 3B Liquid (CI Basic Red 22). Contact Dermatitis Suter VH (1965) Untersuchungen über das polyamidstrumpfek-
21:316-320 zem. Dermatologica 130:411-424
Sailstad DM, Teper JS, Doerfler DL, Qasim M, Selgrade MK (1994) Tanaka M, Kobayashi S, Miyakawa S (1993) Contact dermatitis
Evaluation of an azo and two anthraquinone dyes for allergie from nylon 6 in Japan. Contact Dermatitis 28:250
potential. Fundam Appl Toxicol 23:569-577 Trask-Morrell BJ, Andrews KBA, Pakarinen DR (1995) Measure-
Sailstad DM, Krishnan SD, Teper JS, Doerfler DL, Selgrade MK ment of formaldehyde transport using the dynamic chamber
(1995) Dietary vitamin A enhances sensitivity of the local test. Textile Chem Colorist 27:25-29
lymph node assay. Toxicology 96:157-163 Van Der Veen JPW, Neering H, De Hann P, Bruynzeel DP (1988)
Sano S, Kume A, Nishitani N, Higaski N (1994) Occupational Pigmented purpuric clothing dermatitis dye to Disperse Blue
pigmented dermatitis from raw materials of azo dyes, 2,4,5- 85. Contact Dermatitis 19:222-223
trichloroaniline and 4-benzamide-2,5-diethoxyaniline. Envi- Vigo TL (1997) Textile processing and properties. Elsevier
ron DermatoI1:195-198 Science, New York
Seidenari S, Manzini BM, Danese P (1991) Contact sensitization to Waillberg JE (1995) Patch testing. In: Rycroft RJG, Menne T,
textile dyes: description of 100 subjects. Contact Dermatitis Frosch PJ (eds) Textbook of contact dermatitis, 2nd edn.
24:253-258 Springer, Berlin Heidelberg New York
Seidenari S, Manzini M, Schiavi ME, Motolese A (1995) Preva- Wilkinson SM, McGechaen K (1996) Occupational allergie contact
lence of contact allergy to non-disperse azo dyes for natural dermatitis from reactive dyes. Contact Dermatitis 35:376
fibers: a study in 1814 consecutive patients. Contact Derma- Wilkinson SM, Cartwright PH, Armitage J, English JSC (1991)
titis 33=118-122 Allergie contact dermatitis from 1,6-diisocyanatohexane in an
Seidenari S, Mantovani L, Manzini M, Pignatti M (1997) Cross- anti-pill finish. Contact Dermatitis 25:94-96
sensitizations between azo dyes and para-amino compound. Wilson HTH, Cronin E (1971) Dermatitis from dyed uniforms.
Contact Dermatitis 36:91-96 Br J Dermatol 85:67-69
CHAPTER 80
Leather and Shoes

J. Geier
Manufacture of Leather done by machines with rotating knives. For dehairing,

the hides are then treated for 4-12 h with sodium
sulfide (Na2S or NaSH) and lime [Ca(OH)2]' Under
Leather is made from the dermis of animal hides. The
these alkaline conditions (pH 12), the disulfide bridges
subcutaneous tissue and the epidermis and hair are
in the keratin proteins of the hair and epidermis are
removed during the production process. Generally
broken, the hair fiber structure is destroyed, and the
speaking, the production of leather includes three
hair can easily be removed mechanically together with
broad steps: (1) removal of all parts of the hide which
the epidermis. Other methods of dehairing, such as the
are not needed, (2) improving physical resistance of
use of proteolytic enzymes, acids or oxidizing agents,
the hide, stabilization of the collagen and protection
are not frequently applied (Heidemann 1990; Thors-
against bio degradation by tanning, and (3) processing
tensen 1995).
of the tanned material in accordance with the desired
After dehairing, the hides are again floated with
qualities of the final product.
lime, but without sulfide. This makes them swell, so
Pre-Tanning Process opening of the structure for the following tanning step
takes place. In this state, the hide can be split into
Bacterial degradation starts immediately after the sheets of desired thickness.
removal of the hide from the animal corpse, so As tanning requires acid conditions, the hides have
temporary conservation is necessary. One simple to be "delimed" before further processing. By addition
possibility is air drying, but this is not applicable for of ammonium salts and acids, a neutral pH is achieved.
thick hides (>2 mm) because the surface may be sealed Proteolytic enzymes are added to eliminate undesir-
by drying, thus preventing water in deeper layers from able byproducts from the connective tissue and to
evaporation, which results in bacterial growth in the break down elastin in the hide (so-called bating),
center of the hide. Only thin hides like sheep or go at because elastin may make the leather too firm and stiff.
skins can be air dried. Usually, the hides are protected After removal of the degradation products, the bated
with insecticides du ring this process. Salt curing by hides are pickled, i.e., brought to acid conditions for
spreading sodium chloride between the piled hides is tanning, which are reached by treating the hides again
the most frequently applied curing method in modern with acids and salts. Pickled hides can be stored for a
commercial cattle-hide production. This curing proce- long time. However, usually a continuous process of
dure takes about 20 days, and the required amount of subsequent bating, pickling and tanning is preferred,
salt is about 50% of the hide weight. Alternatively, the during which the hides remain in the same processing
hides may be cured using saturated brine, usually with drum (Heidemann 1990; Thorstensen 1995).
addition of bactericides. Further methods of curing
have been established, e.g., radiation sterilization, Tanning
refrigeration, or application of disinfectants like qua-
ternary amines, but these are less frequently used. The The most widely used tanning system is chrome
cured hides are shipped from the slaughterhouse to the tanning. Chrome tanning is usually done using basic
tannery (Heidemann 1990; Thorstensen 1995). chromium sulfate (2Cr(OH)S04' Na 2S0 4), in which
On arrival at the tannery, the hides are soaked in chromium is trivalent and forms a complex which
water, thus removing the salt, dirt, and manure. penetrates the hide at pH < 3. In the beginning of the
Bactericides and proteolytic enzymes are added to process, the pH of the tanning solution usually is
the soaking water. This procedure takes about 6 h. adjusted to 2.5. After the penetration of Cr(III) into the
Afterwards, the hides are trimmed and freed of flesh hide, the pH is raised to 3.5-4. Now the chromium
and subcutaneous tissue (fleshing), which is usually complex is bound firmly to the collagen protein

638 J. Geier
forming cross-links. The pH is raised further by adding sold and shipped semi-finished as so-called "wet blue".
sodium bicarbonate, thus transforming the chromium- This is unsplit chrome-tanned leather which is pro-
pro tein complexes into stable structures (Heidemann tected against mould by biocides, stacked in piles and
1990; Thorstensen 1995). covered with plastic foil to prevent drying. The
Vegetable tanning has a far longer history than biocides used are mercury salts, mercaptobenzothia-
chrome tanning. Although it is more time consuming zole, DDT (dichloro diphenyl trichloroethane), HCH
than chrome tanning, it is still done for special (hexachloro cydohexane) (Foussereau et al. 1982),
purposes, especially in heavy leathers like those in chloroacetamide Oelen et al. 1989), octylisothiazoli-
shoe soles, saddles, belts etc. Vegetable tannins are none, quaternary ammonium salts, chlorinated cresols
polyphenolic compounds and can be dassified into and derivatives of benzothiazole (Koch et al. 1996).
two groups; hydrolyzable tannins can be regarded as The use of the latter substances is said to be increasing
derivatives of pyrogallol, condensed ones as deriva- due to the prohibition of pentachlorophenol, e.g., in
tives of (pyro )catechol. The water molecules within the Germany (Koch et al. 1996). However, "wet blue" is
hide protein structures are replaced by the phenolic often produced in developing countries and sold to
groups of the tannins. Subsequently, hydrogen bonds European or other tanneries for further processing,
with the proteins are established (Heidemann 1990; and the preservatives used in the production countries
Thorstensen 1995). Vegetable tanning agents coming are usually not known to the importing companies
from various sources (Table 1), are brown and cause (Koch et al. 1996).
the typical odor of leather. Solutions of vegetable Usually, the leather is retanned using vegetable and/
tanning agents contain residues from the plants, like or synthetic tannins. This increases softness and makes
sugar, salt and proteins. Thus, growth of mould is the leather look more like vegetable-tanned leather
promoted. (a "natural look"). Furthermore, retanning improves
Synthetic tanning agents are sulfonated condensa- the structure of those sites in the hide where chrome
tion products of formaldehyde and phenols. They have tanning has accidentally not fastened the fiber struc-
fungistatic properties and are therefore used in com- ture sufficiently. Retanning with amino resins, i.e.,
bination with vegetable tannins. oligomers constructed from urea, dicyanoamide or
Other less frequently used tanning agents are salts of melamine, results in a smooth leather. These resins,
aluminum, iron, titanium, and zirconium. These tan- cationic under acidic conditions, improve the fixation
ning methods are often combined with chrome or of other anionic compounds such as dyes. Polyacry-
vegetable tanning (Heidemann 1990; Thorstensen 1995). lates and polymethacrylates are used for similar
Chrome-tanned leather has a light blue color and purposes (Heidemann 1990; Podmore 1995; Thorsten-
tends to become stiff when dried. A lot of leather is sen 1995).
Formaldehyde and glutaraldehyde (synonyms: glu-
Table 1. Vegetable tanning materials (selection, modified from taral, glutaric dialdehyde) are also used as cross-
Haslam 1989, Hausen 1981) linking agents in tanneries. While glutaraldehyde
performs tanning properties under acidic conditions,
Barks formaldehyde requires a pH above 7. Glutaraldehyde is
Golden and black wattle (Acacia spp.)
Oak (Quercus spp.) widely used in the production of upper shoe leather
Spruce (Picea spp.) and formaldehyde in the production of white leathers
Hemlock (Tsuga spp.) (Rietschel and Fowler 1995). Both aldehydes are used
Chestnut (Castanea spp.)
Larch (Larix spp.) for pretanning to accelerate vegetable tanning. Glutar-
Birch (Betula spp.) aldehyde is also used for retanning after chrome
Yellow pine (Pinus ponderosa) tanning (Heidemann 1990; Rietschel and Fowler 1995;
Beech (Fagus sylvatica)
Woods Thorstensen 1995). Glutaraldehyde or mixtures of
Quebracho (Schinopsis lorentzii) glutaraldehyde and formaldehyde are used to improve
Redwood (Sequoia sempervirens) colorfastness and washability of the final product
Oak (Quercus spp.)
Chestnut (Castanea spp.) (Koch et al. 1996).
Red cedar (Thuja plicata)
Leaves Post-Tanning Process
American sumach (Rhus spp.)
Gambier (Uncaria gambier)
Fruits, fruitpods Almost every leather is dyed, mostly with synthetic
Myrobalans (Terminalia chebula) organic colors. The majority of the dyes used are
Valonea (Quercus aegilopsis)
Plant galls anionic azo dyes which bind to the cationic surfaces of
Oak (Quercus spp.) the leather. For completion of the dyeing process,
Tamarisk (Tamarix articulata) formic, acetic or lactic acid is added. Afterwards, basic
Aleppo (Quercus infectoria)
dyes can be applied which give the leather a brilliant
Leather and Shoes 639
shade. Metal-complex dyes are also widely used in the the leather industry are infrequently reported. This
leather industry (Heidemann 1990; Thorstensen 1995). may be due to two facts: the increasing automation and
The manufacturers regard dyeing of leather as an art the shift of hazardous work to developing countries
rather than as a technique. Therefore, combinations of where less attention is given to occupational der-
dyes used are kept secret (Koch et al. 1996). matoses than in industrialized countries (Cavelier and
According to the final product, leather requires a Foussereau 1995; Foussereau et al. 1982; Koch et al.
certain softness, which is achieved by application of 1996; Wardenbach et al. 1989). The case his tory
fat. A fat content of 5% is essential; gloves, garments, reported by Das et al. (1989) from India may serve as
and upholstery may contain up to 15%. Therefore, after an example: a 35-year-old tanner suffered from chronic
dyeing, the leather is oiled. In this process, called systemic chromium intoxication affecting his liver,
fatliquoring, oily fat is emulsified and applied to the kidneys and central nervous system, and a contact
leather in a warm bath. The emulsion breaks on dermatitis due to chromate solution that spilled onto
contact with the chrome-tanned fibers of the leather, his lower legs during the working process.
and the fat remains on the leather. The oils used are Some decades ago, dichromate allergy was more
sulfated or sulfonated plant, animal or fish oils or frequently observed in the leather industry in Europe,
synthetic products, usually biocide preserved (He- too. Wagner and Wezel (1966) analyzed expert opin-
idemann 1990; Podmore 1995; Thorstensen 1995). ions on occupational derma tos es in the department of
As the leather has only little water resistance after all dermatology of the University of Kiel, Germany, from
these processes, a hydrophobic treatment is necessary. 1952 to 1962. Of the 598 patients, 36 worked in the
For this purpose, silicones, organic chlorofluoropoly- leather industry. Among these, the most frequent
mers or water-in-oil-emulsions are used (Heidemann contact allergens were: dichrornate (19 patients),
1990). formaldehyde (8 patients), leather dyes (8 patients),
The colored and fatliquored leather is dried, staked, and tanning agents (2 patients). Until approximately
and buffered. Staking and buffering are mechanical 1970, chromate sensitizations among tanners were
treatments to increase flexibility and softness and to "occasionally" observed in France (Cavelier and
achieve special surface aspects. Foussereau 1995). Among 280 Swedish male patients
The last step is finis hing, i.e., application of a with occupational contact allergy to chromate ob-
protective and decorative coat. According to the served by Fregert (1975) from 1960 to 1969, 12% were
purpose for which the leather will be used, the finishes tannery workers.
should protect, e.g., against abrasion or water. Surfaces In contrast, an analysis of approved occupational
defects and irregularities in colour should be leveled diseases from 1978 to 1984 in Germany revealed that
out. Usually, several layers of finishing are applied. none of the 941 cases of allergie contact dermatitis due
Water-based latex finish es containing dyes or pigments to chromium salts occurred in the leather industry
may be applied first (Thorstensen 1995). Other base (Wardenbach et al. 1989). A similar development in
coats are polyacrylate dispersions, which are often France was stated by Cavelier and Foussereau (1995).
padded or brushed onto the leather surface. After As written above, tanning is done with trivalent
application, the leather is ironed so thermoplastificat- chromium salts. Although it is known that trivalent
ion and adhesion of the polymer to the leather fibers chromium compounds penetrate the skin far less easily
can take place. The second coating, often polyacrylate, than hexavalent chromium compounds (Spruit and
polybutadiene or polyurethane dispersions, usually van Neer 1964), it has been shown by analysis of
containing pigments as well, is most important for chromium in the urine that tanners have a substantial
the appearance of the leather. It is applied by spraying chromium uptake via absorption through the skin
several times. After this, the leather is ironed again. The (Bulikowski and Tyras 1976). Under alkaline condi-
third layer is important for the feel and the rub tions which may occur during the finishing process,
resistance of the leather. Usually, a solvent-based trivalent chromium (Cr(III» in leather can be oxidized
nitrocellulose solution or water-based polyurethane or to the hexavalent state (Cr(VI)) (Fregert 1981; Koch
nitrocellulose emulsions are used (Heidemann 1990, et al. 1996). In the tanning process, it happens that
Podmore 1995; Thorstensen 1995). Biocides are added either trivalent chromium salts are not completely
to the finishing chemicals, if necessary (Podmore 1995). bound to the collagen fibers or that excessive chromi-
um is not washed out sufficiently. This can lead to a
certain amount of free Cr(III) in the leather, which
under the a.m. circumstances is oxidized to the
Occupational Dermatoses in the Leather Industry
hexavalent state easily (Geier et al. 1995). In the epider-
mis, Cr(VI) is reduced to Cr(III) by methionine, cysteine
Considering the variety of potentially sensitizing or or glutathione, and subsequently Cr(III) binds to
irritating substances used, occupational dermatoses in proteins, forming the allergen (Cavelier and Foussereau
640 J. Geier
1995; Samitz and Katz 1964; Stein 1992). For diagnostic Koch et al. (1996) analyzed data of the Information
purposes, Le., for patch testing, potassium dichromate, Network of Departments of Dermatology in Germany
in which chromium is hexavalent, is generally recom- (IVDK) on contact allergies in patients working in the
mended (Cavelier and Foussereau 1995; Fuchs et al. leather and shoe industry. Of the 30,678 patients
1996; Rietschel and Fowler 1995). registered in the IVDK in the years 1990 to 1994, only
Vegetable tannins have not been reported as a cause 85 (0.3%) had an actual or former profession in this
of occupational contact dermatitis yet. Calnan and field. Compared with all other patients, increased rates
Cronin (1978) have seen a man suffering from allergic of sensitizations to the following possible occupational
contact dermatitis due to a leather watch strap. In the allergens of the standard series were noted: potassium
patch test, he reacted to dichromate, myrobalan- dichromate, p-phenylenediamine, formaldehyde,
extract powder, and quebracho-extract powder. p-tert-butylphenol formaldehyde resin (PTBP-F-R),
Furthermore, so me case reports on patients with mercaptobenzothiazole and nickel sulfate. On patch
dermatitis of the feet caused by contact allergy to testing with the leather-industry series, allergic reac-
vegetable-tanned shoe leather exist (Cronin 1966; tions were no ted to glutaraldehyde, p-aminoazobenzol,
Minkin et al. 1971). The allergens in the vegetable Bismarck brown, octylisothiazolinone, disperse orange
tannins, however, have not been identified. Also, 3, 1,3-diphenylguanidine and chloroacetamide. An
occupational contact allergies to synthetic tannins in additional analysis of contact allergies and their
the leather industry have not been reported yet. occupational relevance in the expert opinions from
However, Müller and Hausen (1994) described a patient the department of dermatology at Homburg/Saar
with contact allergy to a synthetic tannin present in a included in this study revealed a similar allergen
tincture for topical dermatological therapy. spectrum. Although nickel is mentioned as an allergen
Azo dyes like those used in the leather industry have in shoes (buckles, trims) (Cronin 1980; Podmore 1995),
a certain sensitizing capacity. p-Phenylenediamine the origin of the increased rate of allergies to nickel in
(PPD) is probably an intermediate or final product of the patients of this study remained unknown.
the decomposition of azo dyes in the skin. This might As far as clinical findings are concerned, there is no
explain the high rate of concomitant patch-test reac- characteristic aspect, localization or clinical course of
tions to azo dyes and PPD (Hausen 1997). According to occupational contact dermatitis in tanners (Foussereau
Hausen (1997), cross reactions to azo dyes occur in 50- et al. 1982). Adams (1990) mentioned callosities as
80% of patients allergic to PPD. Although PPD cannot occupational marks caused by mechanical trauma on
be regarded as a perfectly reliable indicator of a the thumbs of leather buffers, on the right index
contact allergy to azo dyes, it is often needed in this fingers of cutters and on the knuckles of glazers.
function because the incriminated dyes are unknown
(Estlander et al. 1990).
Occasionally, metanil yellow (acid yellow 36) has
Production and Repairing of Shoes
been reported as a cause of contact allergy due to
leather products. A young man suffered from a foot
eczema after wearing industrial leather protective Shoes are not only made of leather, but of a broad
shoes. On patch testing he reacted to metanil yellow, variety of materials. As shoes are subject to fashion,
which was present in the leather of the inners and their design and the materials used change more or
stiffeners. He also reacted to the leather itself, less rapidly. Shoes are produced in many countries of
p-aminonazobenzene, PPD and its derivatives (Ancona the world in different ways, which makes it impossible
et al. 1982). A woman working in a leather shop to give a complete description of the occupational
developed a contact allergy to metanil yellow, probably exposure of those working in the shoe industry. "It
by contact with a brown leather portfolio. She also must be remembered that a modern shoe is so complex
reacted to p-aminoazobenzene and p-aminodiphenyl- that the final assembler may not be aware of all of the
amine in the patch test (Hausen 1994). chemicals that have been used to prepare each of the
A certain pattern of contact allergens in the leather shoe's parts, because they may have come from all over
industry may be expected from analyses of occupa- the world to finally come together in a finished piece of
tional derma tos es in this branch. Foussereau et al. footwear" (Rietschel and Fowler 1995).
(1982) mention potassium dichromate, dyes and Shoe uppers can be made of leather, rubber or
formaldehyde as the most frequent contact allergens polyurethane. Outer and inner soles are made of
in tanners. The authors cite a manual from 1947 in rubber, polyurethane, polyvinylchloride or Evaftex, a
which nigrosine, chrysoidine and dimethylaminoazo- combination of ethyl vinyl acetate and rubber poly-
benzene are listed as sensitizing dyes, but they state mers (Podmore 1995). For insoles, fibreboard is also
that these substances are no longer or only rarely in used. Fibreboard is made of wood or leather fibers,
use. suspended in a mixture of rubber resins or acrylic
resins, which are preserved with biocides, often with biocides, e.g., phenol, formaldehyde or p-chloro-
copper-8-quinolinolate or sodium-o-phenylphenate m-eresol. They may contain triethanolamine (Pod-
(Podmore 1995). In wooden shoes, an insoie may be more 1995). Occasionally, colophony is used as a
present which has a cardboard-like appearance. This tackifier in shoe production (Fisher 1991; Podmore
material is made from wood pulp, and tetramethylthiu- 1995)·
ram disulfide is added as an antimicrobial agent (Fogh In shoe faetories, the different parts of the shoes are
and Pock-Steen 1992). Other parts, like the reinforce- prepared and assembled. Uppers, toe-caps, quarters,
ments above the toes and around the he eIs, are made of linings and insoies are cut and edged, which includes
plastics or textile materials hardened with plastics, e.g., folding, gluing and sewing. The insoies and heels are
a nylon cloth to which rubber or polyurethane foam is also cut and glued. After assembly, the shoe is finished
fiame-bonded or cotton material impregnated with and trimmed. Possible occupational exposure covers a
various resins such as formaldehyde resins (Cronin broad spectrum of allergens: preservatives, dyes,
1980; Grimalt and Romaguera 1975; Podmore 1995). tanning agents, neoprene and neoprene glues, poly-
The protective toe caps of industrial protective shoes urethane and polyurethane glues, epoxy resins, dilu-
are made of stainless steel, which may be coated with ents and epoxy resin glues, rubber and rubber glues,
epoxy resin to increase the resistance of the metal to and acrylic resins (Mancuso et al. 1996). Podmore
corrosion. The metal toe cap is protected by a synthetic (1995) mentions occupational exposure to the preser-
foam padding (Foussereau et al. 1986). Linings can be vatives benzisothiazolinone, octylisothiazolinone, di-
made of polyvinyl chloride or polyurethane. iodomethyl-p-tolylsulfone, 2-thiocyanomethyl benzo-
Rubber boots may contain N-isopropyl-N'-phenyl- thiazole, sodium-o-phenylphenate, copper-8-quinoli-
p-phenylenediamine (IPPD), chemically related eom- nolate, N-trichloromethylthiophthalimide, and in some
pounds and mercury compounds which are used for East-Asian eountries trichlorophenol and pentaehloro-
preservation of plasticizers (Cronin 1980; Koch and phenol.
Nickolaus 1996; Nishioka et al. 1996). Occupational
sensitizations to phthalates and coal tar were observed
in a factory producing shoes from polyvinyl chloride
Occupational Dermatoses in the Shoe Industry
granulate in former Yugoslavia. Both substanees were
and in Shoe Repairers
present in the granulate (Vidovic and Kansky 1985).
In shoe produetion, urethane, neoprene, natural
rubber and hot-melt adhesives are used. The latter "Shoes are manufactured from a vast range of poten-
ones are inert high-molecular-weight polymers which tially sensitizing chemicals" (Podmore 1995). The most
are melted and applied to heated material surfaces. frequent allergen in shoe makers is PTBP-F-R in
They are used, for example, for gluing of sole or heels, neoprene-based glues (Foussereau et al. 1976; Fousser-
and are not known as a eause of contaet allergy eau et al. 1982; Mancuso et al. 1996). A sensitization to
(Podmore 1995). Urethane adhesives are modified PTBP-F-R is probably due to intermediate products,
polyurethane solutions. Additives, e.g., isocyanates, but not to the resin itself or to the two basie chemicals,
epoxy resins, acrylic or phenol formaldehyde resins, formaldehyde and p-tert-butylphenol (PTBP) (Bruze
depend on the material to be glued (Podmore 1995). 1986; Geldof et al. 1989; Malten and Seutter 1985;
Further chemieals (eatalysts, hardeners, plasticizers, Maneuso et al. 1996, Schubert and Agatha 1979).
etc.) such as triethylenediamine, 4,4'-diaminodiphe- Allergic contact dermatitis caused by PTBP-F-R often
nylmethane or dibutyl tin which are used in the appears as hyperkeratotie eczema of the fingers and
production of polyurethanes have not been reported palms, with fissures (Foussereau et al. 1982). Malten
as a problem in the shoe industry. However, Rietschel (1958) and Malten and van Aerssen (1962) describe
and Fowler (1995) emphasize that contact allergies to allergie contact eczemas due to PTBP-F-R containing
these substances may be underreported, and therefore neoprene glue in right-handed shoe repairers prefer-
reeommend that these substances be kept in mind in ably being localized at the tips and sides of the fingers
unclear cases of contact allergy. Neoprene glues may, of the left hand because the parts to be glued are held
in addition to neoprene itself, eontain isocyanates, with the left hand while the glue is brushed on with the
phenolic resins like PTBP-F-R, ethylene thiourea, right hand. Additionally, the face may be affected.
dioctyl-p-phenylenediamine, tetramethylthiuram di- Sometimes eczematie lesions are also seen on the
sulfide, di-o-tolyl guanidine, sodium dibutyldithio- thighs when the shoe repairer holds the shoe between
carbamate, zine oxide, magnesium oxide and silicates his knees (Foussereau et al. 1982).
(Podmore 1995). Dodecylmercaptan is used to arrest Mancuso et al. (1996) have studied occupational
polymerization in neopren es and neoprene glues dermatoses in 246 shoe-factory workers in Italy from
(Grimalt and Romaguera 1975). Natural rubber glues 1992 to 1994; 20 suffered from irritant contact derma-
are water-based solutions of natural rubber, preserved titis, 16 from allergie eontaet dermatitis. Occupational
642 J. Geier
contact dermatitis occurred most frequently in the leukodermie lesions on the backs of the hands. The
assembly department (20 out of 70 employees). Irritant depigmenting activity of PTBP has been described
occupational dermatitis was mostly caused by organic previously (Gellin 1990). Some years ago, methyl ethyl
solvents (toluene, xylene, n-hexane) in adhesives and ketone in glues was accused of being the cause of
varnishes. Among those patients with occupational polyneuropathy in shoe-factory workers (Dyro 1978).
allergie contact dermatitis, five were sensitized to
p-tert.-butylphenol formaldehyde resin, three to mer-
captobenzothiazole, two each to diphenylmethane-4,4'-
diisocyanate, epoxy resin, potassium dichromate, References
tetramethylthiuram disulfide, and thiuram mix, and
single patients to Bismarck brown, carba mix, chloro- Adams RM (1990) Occupational skin disease. 2nd edn. Saunders,
acetamide, colophony, 4,4'-diaminodiphenylmethane, Philadelphia, pp 45, 662-663, 667-669
Ancona A, Serviere L, Trejo A, Monroy F (1982) Dermatitis from
1,3-diphenylguanidine, dodecylmercaptan, ethylenedi- an azo-dye in industrial leather protective shoes. Contact
aminedihydrochloride, mercapto mix, nickel sulfate, Dermatitis 8:220-221
p-phenylenediamine, phenylglycidyl ether, phenylmer- Angelini G, Vena GA, Meneghini CL (1980) Shoe contact
dermatitis. Contact Dermatitis 6:279-283
curie nitrate and triethylenediamine. The authors give Bajaj AK, Gupta SC, Chatterjee AK, Singh KG (1991) Shoe
an extensive, detailed list of possible occupational dermatitis in India: further observations. Contact Dermatitis
allergens in this branch, which is partly incorporated 24:149-151
Bruze M (1986) Sensitizers in PTBP-formaldehyde res ins. Contact
in the tables shown in the chapter entitled "Shoe Dermatitis 14:132-133
Manufacturers and Repairers". Bruze M, Björkner B, Lepoittevin JP (1995) Occupational aIlergic
Recently, the case his tory of an apprentice cobbler contact dermatitis from ethyl cyanoacrylate. Contact Derma-
titis 32:156-159
was reported. He was occupationally exposed to Bulikowski W, Tyras H (1976) Dermatological evaluation of
leather, rubber, plastic items and several glues, and occupational exposure of tanners to chromium compounds.
acquired a contact allergy to the major monomer of an Berufsdermatosen 24:132-137
Calnan CD, Cronin E (1978) Vegetable tans in leather. Contact
ethykyanoacrylate glue (Bruze et al. 1995). Dermatitis 4:295-296
Although under quite different local conditions Cavelier C, Foussereau J (1995) Kontaktallergie gegen Metalle und
(ocdusion, sweat), patients with allergie contact der- deren Salze. Teil I: Chrom und Chromate. Dermatosen Occup
Environ 4POO-112
matitis of the feet due to shoes have an exposure Correia S, Menezes Brandao F (1986) Contact dermatitis of the
similar to those working in shoe production or feet. Derm Beruf Umwelt 34:102-106
repairing. These patients show a similar pattern of Cronin E (1966) Shoe dermatitis. Br J Dermatol 78:617-625
Cronin E (1980) Contact dermatitis. Churchill Livingstone,
contact allergens induding mercaptobenzothiazole and Edinburgh, pp 68-76
derivatives, IPPD and other p-phenylenediamine de- Das M, Misra MP, Kumar A, Kumar P, Ahmed S, Chandra SV
rivatives, thiurams, p-phenylendiamine, azo dyes, (1989) Chronic chromium poisoning with dermatitis in the
leather industry. Contact Dermatitis 20:221-222
PTBP-F-R, dodecylmercaptane, colophony, potassium Dyro FM (1978) Methyl ethyl ketone polyneuropathy in shoe
dichromate and formaldehyde (Angelini et al. 1980; factory workers. Clin Toxicol 13:371-376
Bajaj et al. 1991; Correia and Menezes Brandao 1986; Estlander T, Kanerva L, Jolanki R (1990) Occupational allergie
dermatoses from textile, leather, and fur dyes. Am J Contact
Cronin 1980; Foussereau et al. 1986; Freeman 1997; Dermat 1:13-20
Jung et al. 1988; Lynde et al. 1982; Oumeish and Fisher AA (1991) Shoe dermatitis in a rosin-(colophony) sensitive
Rushaidat 1980; Romaguera 1987; Scutt 1966; Suur- individual. Am J Contact Dermat 2:209-210
Fogh A, Pock-Steen B (1992) Contact sensitivity to thiram in
mond and Verspijck Mijnssen 1967). Ethylbutylthio- wooden shoes. Contact Dermatitis 27:348
urea is mentioned as an allergen in a rubber adhesive Foussereau J, Cavelier C, Selig D (1976) Occupational eczema
(for neoprene/polychloroprene) used in athletic shoes from para-tertiary-butylphenol formaldehyde resins: a review
of the sensitizing resins. Contact Dermatitis 2:254-258
(Roberts and Hanifin 1979). Cronin (1966) gives a very Foussereau J, Benezra C, Maibach HI (1982) Occupational contact
good synopsis of the historical development of diag- dermatitis. Clinical and chemical aspects. Munksgaard,
nostics in this field. Kopenhagen, pp 256-259, 342-345
Foussereau J, Brändle I, Boujnall Khouadja A (1984) Allergisches
Non-allergie occupational dermatoses in the shoe Kontaktekzem durch Isothiazolin-3-on-Derivate. Derm Beruf
industry were also observed by Mancuso et al. (1996). Umwelt 32:208-211
Fifteen workers in the upper and sole-cutting depart- Foussereau 1, Muslmani M, Cavelier C, Herve Bazin B (1986)
Contact allergy to safety shoes. Contact Dermatitis 14:233-236
ments presented with hyperkeratosis and scaling of the Freeman S (1997) Shoe dermatitis. Contact Dermatitis 36:247-251
fingertips, mechanically provoked by continuous trau- Fregert S (1975) Occupational dermatitis in a lO-year material.
ma of the leather. A work-dependent localized itching Contact Dermatitis 1:96-107
Fregert S (1981) Chromium valencies and cement dermatitis. Br J
of uncovered areas was reported by eight workers Dermatol105[suppl 21]:7-9
employed in the sole cutting and scraping depart- Fuchs T, Geier J, Nickolaus G (1996) Ungewöhnliche Manifesta-
ments. This pruritus sine materia was probably caused tion einer Chromatallergie. Allergoi J 5[Sonderausgabe 1] :33
Geier J, Nickolaus G, Fuchs T (1995) Durch Lederschuhe
by dust in the work place. Two workers who had been provozierte Psoriasis pustulosa plantaris bei Chromatallergie.
exposed to PTBP-based glues for a long time showed Allergologie 18:433-435
Geldof BA, Roesyanto ID, van Joost T (1989) Clinieal aspects of Minkin W, Cohen HJ, Frank SB (1971) Contact dermatitis to east
para-tertiary-butylphenolformaldehyde resin (PTBP-FR) indian leather. Arch Dermatol 103:522-523
allergy. Contact Dermatitis 21:312-315 Müller C, Hausen BM (1994) Contact allergy to a synthetic tannin
Gellin GA (1990) Pigmentary changes. In: Adams RM (ed) in Tannosynt liquid. Contact Dermatitis 31:185
Occupational skin disease, 2nd edn. Saunders, Philadelphia, Nishioka K, Murata M, Ishikawa T, Kaniwa M (1996) Contact
pp 21-25 dermatitis due to rubber boots worn by Japanese farmers,
Grimalt F, Romaguera C (1975) New resin allergens in shoe with special attention to 6-ethoXY-2,2,4-trimethyl-1,2-dihydro-
contact dermatitis. Contact Dermatitis 1:169-174 quinoline (ETMDQ) sensitivity. Contact Dermatitis 35:241-245
Haslam E (1989) Plant polyphenols. Vegetable tannins revisited. Oleaga JM, Aguirre A, Landa N, Gonzalez M, Diaz-Perez JL (1992)
Cambridge University, Cambridge Allergie contact dermatitis from Kathon 893. Contact Der-
Hausen B (1981) Woods injurious to human health. de Gruyter, matitis 27:345-346
Berlin Oumeish OY, Rushaidat QM (1980) Contact dermatitis to military
Hausen BM (1994) A case of allergie contact dermatitis due to boots in Jordan. Contact Dermatitis 6:498
metanil yellow. Contact Dermatitis 31:117-118 Podmore P (1995) Shoes. In: Rycroft RJG, Menne T, Frosch PJ
Hausen BM (1997) Lexikon der Kontaktallergene. 4. Ergänzungs- (eds) Textbook of contact dermatitis, 2nd edn. Springer,
lieferung. Ecomed Verlag, LandsbergILech Berlin Heidelberg New York, pp 516-526
Heidemann E (1990) Leather. In: Elvers B, Hawkins S, Schulz G Rietschel RL, Fowler JF (1995) Fisher's contact dermatitis, 4th
(eds) Ullmann's encyclopedia ofindustrial chemistry, vol A15, edn. Williams and Wilkins, Baltimore, pp 392-413
5th edn. VCH, Weinheim, pp 259-282 Roberts JL, Hanifin JM (1979) Athletic shoe dermatitis. JAMA
Jelen G, Cavelier C, Protois JP, Foussereau J (1989) A new allergen 241:275-278
responsible for shoe allergy: chloroacetamide. Contact Der- Romaguera C (1987) Shoe contact dermatitis. Int J Dermatol
matitis 21:110-111 26:S32-535
Jung JH, McLaughlin JL, Stannard J, Guin JD (1988) Isolation, via Samitz MH, Katz SA (1964) A study of the chemieal reactions
activity-directed fractionation, of mercaptobenzothiazole and between chromium and skin. J Invest Dermatol 43:3S-42
dibenzothiazyl disulfide as 2 allergens responsible for tennis Schubert H, Agatha G (1979) Zur Allergennatur der para-
shoe dermatitis. Contact Dermatitis 19:254-259 tert. Butylphenolformaldehydharze. Derm Beruf Umwelt 27:
Koch P, Nickolaus G (1996) Allergie contact dermatitis and 49-S2
mercury exanthem due to mercury chloride in plastic boots. Scutt RWB (1966) Chrome sensitivity associated with tropical
Contact Dermatitis 34:405-409 footwear in the royal navy. Br J Dermatol 78:337-343
Koch P, Nickolaus G, Geier J (1996) Kontaktallergien bei Spruit D, van Neer FCJ (1966) Penetration rate of Cr(III) and
Lederherstellern, Lederverarbeitern und in der Schuindustrie. Cr(VI). Dermatologiea 132:179-182
Fünf-Jahres-Analyse auf der Grundlage von Daten des Stein G (1992) Chromatsensibilisierung durch Leder. Derm Beruf
Informationsverbundes Dermatologischer Kliniken. Der- Umwelt 40:110-112
matosen Occup Environ 44:257-262 Suurmond D, Verspijck Mijnssen GAW (1967) Allergie dermatitis
Lynde CW, Warshawski L, Mitchell JC (1982) Patch test results due to shoes and a leather prothese. Dermatologiea 134:
with a shoewear screening tray in 119 patients, 1977-80. 371-378
Contact Dermatitis 8:423-425 Thorstensen TC (199S) Leather. In: Kroschwitz TI (ed) Kirk-
Malten KE (1958) Occupational eczema due to para-tertiary Othmer encyclopedia of chemical technology, VOl1S, 4th edn.
butylphenol in a shoe adhesive. Dermatologica 117:103-109 John Wiley, New York, pp lS9-177
Malten KE, van Aerssen RGL (1962) Kontaktekzeme durch Leime Vidovie R, Kansky A (1985) Contact dermatitis in workers
bei Schuhmachern und Schuhträgern. Berufsdermatosen processing polyvinyl chloride plastics. Derm Beruf Umwelt
10:264-268 3P04-105
Malten KE, Seutter E (1985) Allergenic degradation products of Wagner G, Wezel G (1966) Art und Häufigkeit hautschädigender
para-tertiary butylphenolformaldehyde plastic. Contact Der- Berufsnoxen in Schleswig-Holstein. Berufsdermatosen 14:
matitis 12:222-224 1-40
Malten KE, Rath R, Pastors PHM (1983) p-tert.-Butylphenol Wardenbach P, Henter A, Kollmeier H (1989) Kontaktekzeme
formaldehyde and other causes of shoe dermatitis. Derm und Krebserkrankungen durch Chrom, Niekel und deren
Beruf Umwelt 31:149-153 Verbindungen. Eine Auswertung der BK-DOK 1978 bis 1984.
Mancuso G, Reggiani M, Berdondini RM (1996) Occupational Zentralbl Arbeitsmed 39:186-190
dermatitis in shoemakers. Contact Dermatitis 34:17-22
CHAPTER 81
Adhesives and Glues

M. Gebhardt and P. Eisner
Introduction them, para-tertiary butylphenol formaldehyde resin

(PTBP-FR) is a well-known allergen with particular use
as neoprene-based leather glue. Therefore it has
Exposure to adhesives and glues is common in
occupational relevance for shoemakers. An Italian
occupation, leis ure time and household activities.
survey revealed PTBP-FR-containing neoprene adhe-
Several types of glues and adhesives are in use,
sives to be the major allergens in a shoe factory
depending on the materials to be joined. Whereas a
(Manusco et al. 1996). Apart from PTBP-FR, me-
century ago only paper, wood, leather and textiles
rcaptobenzothiazole (MBT), two-component-polyure-
could be glued, today almost any type of materials can
thane- and epoxy resin-based glues were also found
be fixed to each other.
in the same study as relevant glue allergens with
In the majority of glues, the action is simply due to
special applications each in shoe manufacture. PTBP-
removal of solvents, cooling or crystallization. In
FR-based glues have also been reported for their use in
theses cases, it is not the action of the macromolecular
car manufacture (Schubert and Agatha 1979).
molecules but rather the preservatives, detergents and
Non-occupational relevance is given in foot derma-
other additives added to the adhesive preparation that
titis elicited by shoes, in wrist dermatitis by watch
may cause dermatological problems, although this is
straps and in other leather artieies (Freeman 1997).
rare. There is, however, a constantly growing second
Nine of 839 Finnish patients patch tested with a glue
group of glues in which the adhesive is a polymeriza-
series reacted to PTBP-FR, which turned out to be the
tion product formed by a complex chemie al re action
most common relevant glue allergen (Tarvainen 1995).
between the macromolecules. This second group may
Despite the similar chemical nature, there is no
cause many more irritant and allergic reactions on the
evidence for cross-reactivity between phenol-formal-
skin (Malten 1984).
dehyde res in and PTBP-FR (Geldof et al. 1989). Some
In this instance, two component systems are com-
authors have attributed test reactions to PTBP-FR to
mon that react only after being mixed. Other ways to
free formaldehyde; however, most patients are actually
start the reaction include heating, UV irradiation,
not allergie to formaldehyde. Schubert and Agatha
oxygen and air exposure, pressure-induced rupture of
(1979) performed patch-test studies with the chroma-
catalyst reservoirs, etc. We want to focus mainly on
tographically extracted ingredients of commercially
this second group of adhesive chemicals and their
available PTBP-FR. They found two linear condensates
occupational use.
named 2-hydroxy-s-tert.-butylbenzylalcohol and 2,2'-
dihydroXY-3,3-di-(2-hydroxy-s-tertiary butyl)-benzyl-
S,s-ditertiary butyl-diphenylmethan to be the real
Formaldehyde Resins
allergens.
PTBP is used in the production of PTBP-FR.
Phenol-formaldehyde resins resemble a group of Formerly, PTBP has been added in excess, which
chemieals that contain the formaldehyde structure might have caused concomitant reactions, whereas
but are not necessarily associated with formaldehyde nowadays this is no longer relevant. PTBP and para-
allergy. Resols and novolacs are distinguished within tertiary butylcatechol, both antioxidants in plastics,
that group. While the chemie al curing of novolacs might cross-react. As PTBP-FR, they are also known
requires the presence of formaldehyde to react with the for their toxic effects on skin. Toxic exposure to PTBP-
phenol terminate group, re sols do not. Resols are FR may cause chemical burn and even toxic leukod-
intermediates, which, in turn, need heat to cure erma. Vitiligo-like leukoderma on the hands of
(Malten 1984). Para-substituted phenol resins do not PTBP-FR-exposed shoe-manufacturing workers has
crosslink but adhere readily under press ure. Among been found in the above cited Italian study. For

Adhesives and Glues 645
patch-test purposes, PTBP-FR is available 1% in booster a preexlstmg sensitisation. Both penetrate

petrolatum by all well-known suppliers, either in a regular gloves, which makes skin protection areal
special plastic and glue or in the shoe series. problem, especially for sensitised people.
Urea-formaldehyde resin and melamine-formalde- Epoxy res ins are usually based on bisphenol A and
hyde resin are used as glues in the wood industries to epichlorhydrin, a highly reactive epoxy group which is
make furniture press plates. Despite a low constant responsible for the allergenicity of the compound.
release of formaldehyde from these plates into the Many different chemicals may be added to improve or
indoor air, the health effect for individuals living or adapt the material to the required condition. Harden-
working in the room is way overestimated in our ers of the amine or acid anhydride type are crosslink-
opinion. Construction workers are also exposed to ing agents for the resin (White 1990). They are usually
formaldehyde res ins in modern building materials. dissolved in organic solvents. Some of those additional
Textile finishes are another use for these formaldehyde chemicals, such as glycidyl ether, benzol and toluol, are
resins, but this does not fit into our discussion in this skin irritants, which may enhance the skin damage and
chapter (Fowler et al. 1992). Even cosmetics may thereby booster the induction or elicitation of an
contain PTBP-FR as Angelini and others have shown allergic reaction.
previously (Angelini et al. 1993). Both res ins are Workers in the electronics, optical, paint and glue
currently available from Chemotechnique, Sweden, industries are most likely to acquire occupational
urea-FR as a 10% petrolatum and melamine-FR as a allergy to epoxy res ins (Richter 1974; Tosti et al. 1993).
iYo preparation in the textile colour and finishes series. A Dutch survey among employees of several compa-
If nail varnishes are considered to be adhesives, then nies that specialise in epoxy resin-related work in the
toluene-sulfonamide-formaldehyde resin (TS-FR) construction industry revealed hand eczema in 23 of
should be included in this chapter. A very common 135 persons. Of these, 61% of the eczema population
ingredient of naillacquers and hardeners, it may be an and l2% of the healthy skin group had positive patch-
occupational allergen for cosmetologists, beauticians test reactions. Almost all positive patch-test reactions
and, in a wider sense, those who use these products were due to epoxy resin! This shows the tremendous
and who are in public service, such as bank clerks, relevance of epoxy resin as occupational allergen (van
office employees and salespersons. Among patients Putten et al. 1984). Epoxy res in coated fiberglass fibres
with cosmetic-related contact dermatitis, TS-FR was have been reported as a cause of dermatitis in this
found to be relevant in l2.6% of the cases, second only particular field of industry (Holness and Nethercott
to skin care products (De Groot et al. 1988). Typically, 1989).
TS-FR allergy involves the eyelids, lateral aspects of the There are frequent reports about non-occupational
neck and, more seldom, the truly exposed periungual cases of epoxy-resin sensitivity too. Contact dermatitis
area. Because traces of the allergen are easily trans- due to the epoxy resin in textile label patches has been
ferred to the eyelids, it has been included in the topical attributed to the epoxy containing adhesive (Fregert
eye preparation series of several allergen providers. and Orsmark 1984). We recommend limiting patch
Almost all brands of nail polishes contain TS-FR tests with epoxy chemicals to the standardised test
(Hausen et al. 1995; Sainio et al. 1997). TS-FR has series because of the danger of active sensitisation.
recently been included in most cosmetic patch-test Once proven, epoxy resins should not be re-tested, in
trays. In addition to TS-FR, acrylates are gaining more our opinion. When testing epoxy-exposed individuals,
and more importance in nail varnishes and lacquers. never forget to include chemical additives such as the
Chemotechnique provides aseparate acrylic nail test broad range of hardeners.
series for this purpose.
Acrylates
Epoxy Resins
Apart from their use in plastics, colours, lacquers,
When used for industrial adhesive purposes, epoxy coatings, dental materials, orthopaedic appliances etc.,
res ins occur mostly in the construction industry, the acrylates are now increasingly used in adhesives
assembly of cars, ships, and aeroplanes, the manufac- (Kanerva and Alanko 1999; Table 1) because of their
turing of sports equipment, as weIl as in the optical excellent properties, such as strong adhesion - even to
and electronic industries. Much is similar between the metals, ceramics, glass and other building materials -
chemistry of epoxy res ins and acrylates. Both are fast curing and easy handling. Stickers, tapes and office
(often) two-component systems. They are not sensiti- material mayaiso be based on acrylic adhesives. An
sing when fully cured but frequently contain an extensive list of ingredients in pressure-sensitive tapes
amount of remaining monomer, which is enough to was published in Fisher's Contact Dermatitis. The most
646 M. Gebhardt and P. Eisner
Table 1. Adhesives glue used to fix artificial nails. Ethyl cyanoacrylate and
based on acrylates, Anaerobic sealants
Cyanoacrylates methyl methacrylate were seen as allergens in these
methacrylates
and epoxy diacry- Ultraviolet-cured sealants patients (Belsito 1987; Guin et al. 1998). Aluminium test
lates according to Methyl methacrylate chambers should be avoided when testing cyanoacry-
Kanerva and Alanko Metal and glass glues
Epoxy diacrylates (vinyl res ins ) lates, because they may contain catalysts for the
(1999)
Acrylic dental bonding agents polymerisation process. The vehicle acetone further
enhances the tendency to polymerise spontaneously
(Bruze et al. 1995). Due to its excellent adhesive
properties with various materials, cyanoacrylate glues
common allergenic ingredient of those tapes is may occur in many different occupations. When
2-ethylhexyl acrylate. Occupational problems can arise sticking something to glass, ceramics or metal surfaces,
from workplaces where stickers and labels are put on 2-hydroxy ethyl methacrylate (2-HEMA), 2-hydroxy
the final products or, theoretically, in medicine. propyl methacrylate (2-HPMA) and (tri)ethylene glycol
However, compared with epoxy and colophony rosin, dimethacrylate (TEGDMA or EGDMA) are common
which have been preferred in the past, acrylate-based ingredients of industrial adhesives (Kanerva et al.
tape adhesives are less sensitising and reports are 1995).
based. on single cases. There are one- and two- For patch-test purposes, a test screening with several
component acrylic adhesive systems. Other macromo- acrylates should therefore be carried out when sus-
lecular substances can be included into acrylates, such pecting acrylate allergy. Chemotechnique has the most
as epoxy res ins, to form epoxy acrylates. diverse patch-test tray on methacrylates; however, the
Hazardous health effects on the skin are allergic other companies also provide a suitable screening
sensitisations and irritation to several acrylates. Glue- composition. It was as early as 1975 when Jordan
induced adherence of contaminated skin (finger, recommended that MMA alone is not a good screening
eyelids) may be very difficult to separate. If possible, for acrylate allergy (Jordan 1975). Accelerators, inhib-
wait for spontaneous resolution; gentle teasing with itors and catalysts, which may be added to the
repeated moistening of the skin may be applied in acrylates, can also sensitise. We recommend reading
this otherwise harmless condition. Asthma and the chapters that deal with that problem.
rhinitis have also been reported when handling acrylics
(Savonius et al. 1993; Kopferschmidt-Kubler et al.
1996).
As known from other fields of (meth)acrylate use
Colophony
(dental prostheses, daily plastic wear), allergy can only
be initiated and elicited by uncured monomers. In
contrast to plastic wear, monomers are always avail- Colophony rosin, a naturally occurring rosin from
able when using glues. So the rate of sensitisation trees, is another natural base of glues and adhesives.
could be rather high and similar to that of momomeric Abietic acid, also available as test allergen, and its
acrylate use in other occupational fields, such as oxidative derivatives are the causative allergens (Guin
dentistry. There is, however, only scanty data about et al. 1995). It ranks high on hit lists of contact
real incidence of acrylate sensitivity caused by acrylic allergens because of widespread exposure reaching
adhesives or glues in occupationally exposed individ- from occupational use in wood, paper, paint, electron-
uals or even those within the normal population. ics and cosmetics industries to household contacts to
Obviously there is (still) no major problem evolving natural exposure (Sadhra et al. 1994). Some tackifiers
from non-occupational temporary use of these sub- for heel and toe stiffeners in shoes are based on
stances, although several reports on sensitisation from colophony and may therefore be relevant allergens in
an adhesive in an electrosurgical grounding plate were shoe manufacturers (Freeman 1997).
reported recently (Kanerva and Alanko 1999). In Medical use of rosin derivatives on tapes, bandages,
occupational medicine, acrylates are important sen- surgical and dental dressings, wart paints (Lachapelle
sitisers to keep in mind. Sometimes it may be hard to and Leroy 1990) and hydrocolloid dressings has been
find suitable personal protective equipment for sensi- reported (Sasseville et al. 1997). For several hydrocol-
tised people because most acrylates do penetrate gloves loid dressings, the allergen is a modified ester of
easily. colophony, the pentaerythrite ester (Hausen and
Cyanoacrylates are among the most common ingre- Kulenkamp 1998). Most patients with a sensitisation
dients of acrylate glues (Loctite is a well-known brand to colophony report intolerance of brown coloured
example). Eyelid eczema, nummular eczema on the tapes. However, we have not found any report of
hands and periungual dermatitis are typical features of occupational contact dermatitis to medical colophony
allergic contact dermatitis caused by cyanoacrylate resin adhesives.
Table 2. Plastics and glue series as recommended by several distributors
Miscellaneous % Chemotechnique Brial Trolab Hermal
1. Abitol 10 A002 E 0915

2. Abietic acid 5 0328
3. Benzoyl Peroxide 1 B007 0101 E 0201
4. Turpentine Oil 10 E 2322
5. o-Cresyl glycidyl ether 0.25 0335
6. 2,6-Ditert-butyl-4-cresol (BHT) 2 D006
7. 2-tert-Butyl-4-methoxyphenol (BHA) 2 B022
8. Diphenyl thiourea D025
9. Cyclohexanone resin 1 C027
10. 2-n-Octyl-4-isothiazolin-3-one 0.1 0004
11. N,N-Dimethyl-p-toluidine 2 0326 E 0963
Formaldehyde resins
1. Phenol-formaldehyde resin 5 P005 (1%) 0315 E 0901/0911
2. Toluene-sulfonamide-formaldehyde resin 10 TOlO 0331
3. p-tert-Butylphenol-formaldehyde resin 1 B024
4. Resorcinol-formaldehyde resin 5 0314
5. Paratertiary butylphenol 1 B023 0318 E 0920
6. 2-Monomethylol phenol MOlS
Epoxies
1. Triethylenetetramine 0.5 0316 E 0905
2. Triethylenediamine 0.5 0301
3. 4-4'-Diaminodiphenyl methane 0.5 0313 E 0906
4. Diethylenetriamine 0.5 E 0913
5. Diethylenetetramine 0.5 0317
6. Isophoronediamine 0.5 0332 E 0914
? Hexamethylenetetramine 1 E 2318
8. Cresylglycidylether 0.25 E 091?
9. Epichlorhydrin 0.1 0325
10. Triglycidyl isocyanurate 0.5 T028
11. Bisphenol A BOB E 0965
Plasticiser
1. Diethylphthalate 5 0320
2. Di-n-butylphthalate 5 D007 0916 E 0903
3. Tricresyl phosphate 5 T015 0329 E 2511
4. Triphenyl phosphate 5 T022 0323 E 0959
5. Dimethylphthalate 5 0311 E 0954
6. Di-2-ethylhexyl-phthalate 5 D018 (2%) 0324 E 0960
Plastic stabilisers
1. 2-Phenylindole 2 P007
Plastic inhibitors
1. Azodiisobutyrodinitrile A018
2. Hydroquinone HOO? E 0800
3. 4-tert.Butyicatechol (PTBC) B030 (0.5%) 0338
UV adsorbers in plastics
1. 2(2-Hydroxy-5-methylphenyl)benzotriazol H016
2. Resorcinol monobenzoate R002
3. Phenyl salicylate POIl
Isocyanates
1. Diphenylmethane 4,4-diisocyanate 0.1 0336 E 2513 (1%)
2. Phenylisocyanate 0.1 0322
3. Toluenediisocyanate 1 E 2514
Acrylates
1. (2-Hydroxyethyl) methacrylate (2-HEMA) 1 HOIO (2%) E 2477
2. (2-Hydroxypropyl) methacrylate (2-HPMA) 2 H018
3. 2-Hydroxyethylacrylate 0.1 H009
4. 1,6-Hexanediol diacrylate 0.1 H004
5. Tetrahydrofurfuryl methacrylate 2 T02?
6. Tetraethyleneglycol dimethacrylate 2 T029
7. N,N-Dimethylaminoethyl methacrylate 0.2 D045
8. Methyl methacrylate 2 MOB E 1800
9. Ethyleneglycol dimethacrylate 2 EOO? E 1850
10. Triethyleneglycol dimethacrylate 2 T018 E 1851
11. Triethyleneglycol diacrylate 0.1 T01?
12. BIS-GMA 2 HOB E 1852
13. BIS-MA 2 MOO?
14. Butylacrylate 0.1 B018 0205
15. n-Butyl methacrylate 2 B021
648 M. Gebhardt and P. Eisner
Table 2. (Contd.)
16. 2-ethylhexyl acrylate 0.1 E009 0206

17. Ethyl acrylate 0.1 E004
18. Ethyl methacrylate 2 EOl2
19. Diurethane dimethacrylate 2 E 2475
20. Urethandimethacrylat 2 U004
The plastie and glue series as provided by several suppliers is a mixture of glue and plastie ingredients as weil as substances involved in
the synthesis of these products. Substances relevant for glues and adhesives are marked in bold. Many of the above-mentioned
substances are provided by all of the companies, but the ordering number is not mentioned. That is because the substance is not
included in the glue and plastic series of this company. As an exception to this rule, Chemotechnique methacrylates have been included
in Table 2 because, in addition to the glue and adhesive series, they provide an extensive list of acrylic adhesives and acrylics for
artificial nails whieh are therefore considered to be adhesives/glues. For more ordering information call the companies
Others Brial. We combined their adhesive and glue series in

order to get an overview about available glue contact
allergens. Wehave to mention that not all substances
A very special kind of biological adhesives are so- in these trays are glue allergens; many are plastic
called fibrin tissue glues. They are two-component
allergens such as phthalates, accelerators and inhibi-
systems consisting of fibrinogen and factor XIII in one
tors or UV adsorbers. To make it easier we enhanced
syringe and thrombin in the second syringe. By adding the real glue allergens listed in the table by marking
thrombin to the fibrinogen/factor-XIII mixture, there
them in boldface. We propose screening with the
is a coagulation reaction. Tissue adhesives are used to chemical subgroups after getting information about
re-combine skin and organ cuts (liver, spleen, etc.), to
the basic glue composition, e.g. epoxy, acrylic, form-
seal wounds in surgically opened body cavities or aldehyde resin, etc.?
vascular prostheses and to stop bleeding. We are not Under special circumstances we also recommend
aware of any report of either occupational contact testing the glue itself. When the complete composition
dermatitis or immediate-type contact reactions to this is known and the single allergenic ingredients are
product because skin contact to the medical person is
available, testing the native glue is avoidable. We warn
always prevented by gloves worn for reasons of
against testing unknown epoxy resin based glues
hygeine. because of possible active sensitisation. Active sens i-
Allergic reactions of the recipients are not the focus tisation is also weIl known for acrylics and has been
of this chapter but it may be mentioned that Ockenfels
reported even after a single exposure. However, by
et al. (1995) reported of a patient who developed leaving the glue exposed to air and letting it dry on the
urticaria and shortness of breath 1 h after dental patch-test chamber, the risk of strong patch-test
examination and tooth extraction. The extraction reactions is minimised.
socket of the patient had been filled with fibrin tissue The easiest way to patch test a patient's own
(Hemofibrine, Septodont, France) to stop bleeding. products is using tapes and medical self-adhesive
The causative agent was believed to be the above fibrin dressings. Simply cut a small piece and stick it to the
tissue (bovine protein). A similar case was reported by skin for 24-48 h. For further information, refer to the
Wütrich and coworkers (1996). other chapters in this book that deal with acrylates and
epoxy resins.
Patch Testing with Adhesives and Glues
References
The most important part of allergological diagnosis is
to think about possible exposure to glues and adhe- Angelini E, Marinaro C, Carrozzo AM, et al. (1993) Allergie
sives. Optimally, one should only consider patch tests contact dermatitis of the lip margins from para-tertiary-
with possible allergenic glue ingredients when the butylphenol in a lip liner. Contact Dermatitis 28:146-148
Belsito DV (1987) Contact dermatitis to ethyl-cyanoacrylate-
chemical composition of the glue or adhesive is containing glue. Contact Dermatitis 17:234-236
known. This can be determined by asking the manu- Bruze M, Björkner B, Lepoittevin JP (1995) Occupational allergie
facturer or, to a lesser extent, by looking at the material contact dermatitis from ethyl cyanoacrylate. Contact Derma-
titis 32:156-159
data safety sheets. In daily practice, however, this very De Groot AC, Bruynzeel DP, Bos JD, et al. (1988) The allergens in
often fails. Therefore, a glue-screening series makes cosmetics. Arch DermatoI124:1525-1529
good practical sense. Table 2 includes information Fowler JF, Skinner SM, Belsito DV (1992) Allergic contact
dermatitis from formaldehyde resins in permanent press
from three major European patch-test provider com- clothing: an under diagnosed cause of generalized dermatitis.
panies, namely Chemotechnique, Trolab-Hermal and J Am Acad Dermatol 27:962-968
Freeman S (1997) Shoe dermatitis. Contact Dermatitis 36:247-251 Malten KE (1984) Dermatological problems with synthetic res ins
Fregert S, Orsmark K (1984) Allergie contact dermatitis due to and plastics in glues, part 1. Dermatosen 32:81-86
epoxy res in in textile labels. Contact Dermatitis 11:131-132 Manusco G, Reggiani M, Berdondini RM (1996) Occupational
Geldof BA, Roesyanto ID, van Joost T (1989) Clinieal aspects of dermatitis in shoemakers. Contact Dermatitis 34:17-22
para-tertiary butylphenol formaldehyde resin (PTBP-FR) Ockenfels HM, Seemann U, Goos M (1995) Allergy to fibrin tissue
aIIergy. Contact Dermatitis 21:312-315 in dental medicine. Contact Dermatitis 32: 363-364
Guin JD, Baas K, Nelson-Adesokan P (1998) Contact sensitization Richter G (1974) Zur Epidemiologie des Epoxidharzekzems. Derm
to cyanoacrylate adhesive as a cause of severe onychodys- Monatssehr 160:785-789
trophy. Int J Dermatol 37:31-36 Sadhra S, Foulds IS, Gray CN, et al. (1997) Colophony uses, health
Guin JD (1995) Colophony (rosin) In: Guin JD (ed) Practical effects, airborne measurement and analysis. Ann Occup Hyg
contact dermatitis. McGraw-Hill Inc, New York, pp 115-124 38:385-396
Hausen BM, Kulenkamp D (1998) Allergische Kontaktdermatitis Sainio E-L, Engström K, Henriks-Eckerman M-L, Kanerva L
auf einem Hydrokolloidverband bei Kolophoniumallergikern. (1997) Allergenic ingredients in nail po!ishes. Contact Der-
Aktuel Dermatol 24:174-177 matitis 37:155-162
Hausen BM, Milbrodt M, König W A (1995) The allergens of nail Sasseville D, Tennstedt D, Lachapelle JM (1997) Allergie contact
polish. Contact Dermatitis 33:157-164 dermatitis from hydrocolloid dressings. Am J Contact Dermat
Holness DL, Nethercott JR (1989) Occupational contact derma- 8:236- 238
titis due to epoxy resin in a fiberglass binder. J Occup Med Savonius B, Keskinen H, Tuppurainen M, Kanerva L (1993)
31:87-89 Occupational respiratory disease caused by acrylics. Clin Exp
Jordan WP (1975) Cross-sensitization patterns in acrylate aller- Allergy 23:416-424
gies. Contact Dermatitis 1:13-15 Schubert H, Agatha G (1979) Zur Allergennatur der para-tert.
Kanerva L, Alanko K (1999) Allergie contact dermatitis from Butylphenolformaldehydharze. Dermatosen 27:49-52
2-hydroxy methacrylate in an adhesive of an electrosurgical Tarvainen K (1995) Analysis of patients with allergie patch test
grounding plate. Eur J Dermatol (in press) reactions to a plastics and glue series. Contact Dermatitis
Kanerva L, Jolanki R, Leino T, Estlander T (1995) Occupational 32:346-351
allergie contact dermatitis from 2-hydroxyethyl methacrylate Tosti A, Guerra L, Vincenzi C, Peluso AM (1993) Occupational
and ethylene glycol dimethacrylate in a modified acrylic skin hazards from synthetic plastics. Toxieol Ind Health
structural adhesive. Contact Dermatitis 33:84-89 9:493-502
Kopferschmidt-Kubler MC, Stenger R, Blaumeiser M, et al. (1996) van Putten PB, Coenraads PT, Nater J (1984) Hand dermatoses
Rev Mal Respir 13:305-307 and contact allergie reactions in construction workers
Lachapelle JM, Leroy B (1990) Allergie contact dermatitis to exposed to epoxy resins. Contact Dermatitis 10:146-150
colophony included in the formulation of flexible collodion Wütrich B, Bianchi Kusch E, Johansson SG (1996) Allergie
BP, the vehicle of a sa!icylie and lactic acid wart paint. urticaria and angioedema caused by a hemostatic sponge of
Dermatol C!in 8:143-146 bovine fibrin used in tooth extraction. Allergy 51:49-51
CHAPTER 82
The Electronics Industry

S.c. Tucker and ].S.C. English
Introduction ture of many electronic products, including computers,

communication equipment, audio and video consumer
products, semiconductors, compact discs and tapes,
The electronics industry today is a major worldwide
electronic office machinery, military electronic equip-
industry with a workforce numbering millions. Fifty-
ment, some larger electrical goods - such as washing-
years old this year, this complex scientific industry is
up machines, whose technology is semiconductor
constantly subject to changes in working practices
based - and a large number of other, miscellaneous
occurring as a consequence of evolving scientific
electronic products and components.
knowledge. What has always been a complicated
The first part of this chapter will concentrate in
industry is now even more so as technological
some detail on the manufacturing processes involved
advances substitute older materials with newer, poten-
in the production of semiconductors and printed
tially advantageous ones at various stages in the
circuit boards (PCBs). It is hoped that this will be of
manufacturing processes. This fact, along with the
scientific interest to the reader, but more importantly
inherent intricate and convoluted nature of many of
that it will give an outline of the diverse chemicals and
the methods involved, means that the numbers of
materials used. The information contained in this
materials used in the industry are large and so,
section comes from a variety of sour ces [4-6]. The
consequently, is the potential for employee exposure
second part of the chapter will concern the range of
to the various chemicals involved. Owing to the vast
dermatoses and cutaneous hazards encountered in the
size of the workforce, one might expect employees of
industry.
this industry to contribute significant numbers of
cutaneous problems to the dermatologist.
The industry is diverse and differing definitions of
what occupations may be c1assified as being within the
Semiconductor Fabrication
'electronics industry' means that it can be difficult to
determine the precise number of workers involved in Central to all other processes in the electronics industry
the industry. In the U.S.A. in 1984, the electronics is the manufacture of semiconductors, whose diverse
industry was the largest employer in the manufactur- uses as transistors, resistors, capacitors and amplifiers
ing sector, providing 2.6 million jobs, with sales of US me ans that they are used in electronic products of
$ 25 billion [1]. Developing countries in particular are a virtually every description. A significant portion of the
favourite site for larger multinational companies to chapter will therefore focus on their manufacture. The
locate to, since the comparatively low labour costs fundamental device of the digital world is the integrated
found in these countries are well-suited to this labour- circuit, or chip, which is a small (millimetre size)
intensive industry [2]. square of semiconducting substance, usually silicon,
Microelectronic devices are found in appliances of containing millions of transistors. Integrated circuit
almost every description, and projections unsurpris- boards (ICBs) are three-dimensional structures made
ingly show an industry that is likely to continue to by painstakingly building up on the silicon base several
grow in the future [3]. For the purposes of this chapter, microscopically thin layers of materials that either
the electronics industry will be taken to encompass (1) insulate or conduct electricity. Assembled according to
the manufacture of computer chips and other elec- a pre-determined pattern, these layers form transistors
tronic components, (2) the manufacture of printed that function as switches controlling the flow of
circuit boards and (3) the assembly and packaging electricity through the circuit. "On" and "off' switches
processes that bring the two together. Clearly, there- manipulate the binary code that is at the core of what a
fore, this arbitrary definition embraces the manufac- computer, for example, does.

The Electronics Industry 651
The first transistor was developed in 1947 by Walter must also take into account the intended purpose of
Brattain, John Bardeen, and William Shockley, and this the chip; for example, a processor chip carries out
replaced the cumbersome vacuum tube. Bridging the instructions in a computer and a memory chip stores
gap between the transistor and the integrated circuit data. The two types of chips differ somewhat in
was the 'planar' process, devised in 1957 by Jean structure. This design work is today usually computer
Hourni and developed in 1958 by Robert N. Noyce, aided, although engineers often print out an enlarged
which provided a means of creating a layered structure diagram of a chip's structure to examine it in detail.
on the silicon base of a chip.
The average mid-range personal computer generally
contains between 50 ICs and 75 ICs (chips). A chip
Crystal Purification and Growth
combines the functions of discrete electronic devices,
such as vacuum tubes, resistors and capacitors, and
performs complicated electronic functions in a fraction By far the most common base material for building an
of a second [7]. The most complex chip is the integrated circuit is still silicon. Silicon is a natural
microprocessor, which executes a stream of instruc- semiconductor; it can be altered to be either an
tions that operate on data. The microprocessor has electrical insulator or a conductor. These differing
direct access to an array of dynamic random access electrical properties are conferred upon the silicon by
memory (DRAM) chips, where instructions and data the introduction of precisely controlled amounts of
are temporarily stored for execution. Astate of the art dopant chemicals. It is this ability to conduct electric-
PC might have 8 DRAM chips, each capable of storing ity that forms the basis of the function of the chip.
8,388,608 bytes (64 megabits) of data. In addition to Silicon is produced in ingots, which are large (up to
the microprocessor and DRAMs, there are many other several feet long) cylindrical structures which are
kinds of chips that perform such tasks as amplification, sliced into circular wafers about 0.725-mm thick and
synchronisation and communication. 100 mm or 200 mm in diameter, although the state of
The hundreds of different steps involved in chip the art companies are moving toward standardised use
manufacture can be grouped into a few basic opera- of wafers of 300-mm (12") diameter by 1999. This is
tions. These are: chip design, crystal purification and because a single wafer yields hundreds of chips, and
growth, wafer preparation, epitaxy and oxidation, bigger wafers therefore mean that more chips can be
photolithography, doping and type conversion, me- made at one time and so the costs are cheaper. These
tallisation, and interconnection formation. Semicon- wafers are the substrate for all subsequent steps in the
ductors are then assembled, involving the processes of semiconductor manufacturing process.
die (chip) separation, die attach bonding, wire bond- The silicon required for these wafers must be
ing, encapsulation, housing and marking, and testing. extremely pure. A detailed analysis of the process of
These processes and their hazards have been described production of semiconductor-grade silicon is available
in detail before [7-11], and although these are still the elsewhere [11, 12]. Quartzite (silica sand) is reduced
same today, though with some notable changes in the with coke in an electric arc furnace and then blown
materials being used, it is nevertheless worthwhile with oxygen or an oxygen-chloride mixture to remove
repeating a summary of the different steps here. The impurities such as calcium, manganese, and alumin-
text will attempt to concentrate on those areas of the ium. In the presence of a copper catalyst, it is then
manufacturing process where there may be greater reacted with hydrochloric acid to form trichlorosilane,
personnel exposure to cutaneous hazards and will not which is then reacted with hydrogen to produce
attempt to deliver all the minutiae of every material or polycrystalline silicon (polysilicon) at 1100-1160 °C
chemical reaction involved. by chemical vapour deposition onto starter silicon seed
rods. These polysilicon rods are used to manufacture
single-crystal silicon ingots using one of two technol-
ogies: Czochralski (the more popular) or Roat zone. In
Chip Design
the former, polysilicon is placed in a quartz crucible in
a pressurised chamber and heated to 1200 °C in an
Chip design is the first operation. When tens of inert argon atmosphere. The ingot of single-crystal
millions of transistors are to be built on a square of silicon is produced by being pulled from the melt using
silicon roughly the size of a child's fingernail, the a seed crystal attached to the end of a puller. Precisely
placing and interconnections of the transistors must controlled amounts of impurities may be added to the
be meticulously worked out. Each transistor must be silicon during this stage to give desired electrical
designed for its intended function, and groups of properties.
transistors are combined to create circuit elements, Newly made ingots are ground to a uniform
such as inverters, adders and decoders. The designer diameter, have their crystal structure verified by
652 S.c. Tucker and J.5.c. English
X-ray diffraction, and are epoxy bonded to a graphite been described elsewhere [9], but clearly the potential
carrier in preparation for wafer slicing. consequences of mishandling or accidents involving
elemental arsenic cannot be overstated.
It should be understood that silicon and GaAs are
Wafer Preparation not the only semiconductor materials available today.
The microelectronics industry is an evolving one, and
research is constantly being undertaken into other
Ingots are sliced into wafers with diamond-bladed
semiconducting materials, some of which are already
saws and then washed. They are then rounded by
in use. Some of the more important substances in use
automatic machines, which rotate the wafers at high
are indium phosphide, aluminium indium gallium
speed and at the same time grind them. Surface
phosphide, and mercury cadmium telluride, and there
irregularities from sawing are etched away in an acid
is also a great deal of interest in gallium-on-silicon
bath containing usually either nitric, hydrofluoric or
technology. It should be stressed that the discovery
acetic acid. Finally, the wafer surfaces are automati-
and use of these exotic materials in most cases is
cally polished using a mixture of colloidal silica and
outstripping the ability to produce reliable toxicolog-
sodium hydroxide, cleaned with hydrofluoric acid and
ical data on either the parent compounds themselves
surfactants, inspected and packaged in shrink-wrapped
or their constituent elements and on other compounds
cellophane for contamination control. Most semicon-
released during their manufacture. It is likely to be
ductor manufacturers purchase wafers from fi.rms
so me time therefore before the true hazards involved
specialising in wafer production.
will be fully documented.
Gallium Arsenide
Epitaxy, Oxidation and Photolithography
Gallium arsenide (GaAs) is assuming increasing im-
portance as a semiconductor substrate used in the It is perhaps during these stages of semiconductor
microelectronics industry. In the mid 1980s, it ac- fabrication that there exists the greatest potential for
counted for 5% of semiconductor manufacturing [13], exposure to cutaneous hazards because the numbers of
and is likely today to ac count for more. GaAs has chemieals involved are vast. With the wafer prepared,
certain advantages over silicon. It can produce light the process of building the chip's circuitry begins.
and therefore is extremely useful in the manufacture of Making the transistors and their interconnections
light-emitting diodes (LED), lasers, solar cells and entails several different basic steps that are repeated
photodetectors. This property also makes GaAs suit- many times. The most complex chips made today
able for use in compact-disc players as the laser 'stylus' consist of 20 or more layers and may require several
that bounces off the CD's microcode of pits and spaces hundred different processing steps to build them up
before shining onto semiconductor photodetectors for one by one.
eventual conversion into sound. The heart of this laser The first layer is silicon dioxide which does not
is an exquisitely thin strip of GaAs sandwiched conduct electricity and therefore serves as an insulator.
between sliees of gallium aluminium arsenide, which This layer is applied in a diffusion furnace in an
is more electrically insulating. The infra-red light oxidising atmosphere at high temperature (Fig. 1).
emitted from this sandwich is produced when elec- The wafer is now ready for its first patterning, or
trons and positively charged electron deficiencies photolithographic, step A coating of a viscous poly-
(holes) recombine, annihilating one another and merie liquid, a photoresist, whose physical properties
releasing photons [14]. alter on exposure to energy either in the form of
GaAs integrated circuits are also of higher speed ultraviolet (UV) light, X-ray irradiation, or as electron-
than their silicon counterparts and are radiation beam radiation, is applied to the surface of the wafer.
resistant, making them more useful for military There are two types of photoresist, positive and
applications. Set against these advantages is the negative. Positive photoresists weaken (become more
increased cost of production of GaAs wafers, currently soluble) when exposed to energy; negative resists
several times that for silicon, whieh is due to the rather strengthen. Some photoresists require the addition of
high melting and boiling points of arsenic and gallium, other compounds, which act as photo initiators or
respectively, requiring resistance furnaces to produce photostabilisers, before they will respond in the
the appropriate temperature zones. The technology desired manner to incident energy. Further, since the
used, however, in producing GaAs ICs is similar to that dimensional stability of finished (fully developed)
for silicon-based ICs. The methodology and hazards resists is of vital importance (they must, for instance,
involved in the production of single-crystal GaAs has neither shrink nor swell during later steps in process-
Fig. 1. Silicon wafers on a quartz tray about to

enter a furnace for deposition of epitaxial
layers on the wafer' s surface
ing because their straight walls and sides are essential a process known as etching. During etching, insoluble
to subsequent etching) the addition of still further photoresist remaining on the surface protects the parts
ingredients is required to achieve these particular of the underlying layer from being removed by the
dimensional properties. acids or reactive gases (wet and dry etching, respec-
A spigot deposits a precise amount of photo res ist on tively) used to etch the circuit pattern on the surface of
the wafer surface. The wafer is then spun so that the wafer. After etching is complete, the protective
centrifugal force spreads the liquid over the surface at layer of the photoresist is removed, using solvents, to
an even thickness. This operation takes place on every reveal electrically conducting or electrically insulating
layer that is modified by a photolithographic proce- segments in the pattern determined by the mask. Each
dure called masking. additional layer put on the chip has a distinctive
In short, photolithography transfers the circuit pattern of this kind. Solvent-based systems for the
patterns of photomasks (masks) on to the surface of rem oval of photoresists are being gradually replaced
the silicon dioxide coated silicon substrate. Masks are by plasma processing, removing some of the likelihood
usually purchased from other specialist companies for worker exposure to solvents. Plasma processes use
who manufacture them to correspond to the desired chemicals in gaseous form and take place in sealed
computer-aided designed circuit as mentioned earlier. chambers. As a result, the use within the industry of
A mask is the device through which UV light shines compressed gases such as chlorine and hydrochloric
to define the circuit pattern on each layer of a chip. acid has increased.
Because the pattern is intricate and must be positioned Further masking and etching steps deposit patterns
precisely on the chip, the arrangement of opaque and of additional materials on the chip. These materials
transparent spaces on a mask must be done carefully include polysilicon as weil as various oxides and metal
during a chip's design stage. conductors, such as aluminium and tungsten. On each
The mask image is transferred to the wafer using a layer of material, masking and etching create a unique
computer-controlled machine known as astepper. It pattern of conducting and non-conducting areas.
has a sophisticated lens system to reduce the pattern Together these patterns aligned on top of one another
on the mask (millimetres-centimetres diameter) to form the chip's circuitry in a three-dimensional
the microscopic dimensions of the chips circuitry. The structure. The circuit is now ready for doping. Table 1
wafer is held in place on a positioning table below the lists the commonly used photoresists, photo initiators
lens system. UV light from an arc lamp or a laser (or and stabilisers, etchants and solvents used in the
X-ray irradiation or electron beam radiation) shines photolithographic process. As can be seen, many of the
through the clear spaces of the mask's intricate pattern chemicals are plastics and therefore known skin
on to the photoresist layer of a single chip. The stepper irritants and sensitisers. Toxicological data may not
table then moves the wafer the precise distance be available for some of the more exotic compounds,
required to position another chip under the light. whose presence may not even be indicated on the
On each chip, the parts of the photoresist layer that product label.
were struck by the light become either soluble or It should again be pointed out, however, that as in
insoluble and can be developed using organic solvents, many other industries these processes are almost
Table 1. Common photoresists, photo initiators and stabilisers, which stage in chip manufacture the patient works and
etchants and solvents used in photolithography
what chemicals that patient's particular company uses.
Positive photoresists
Novolak resin (phenol and formaldehyde)
Polymethylmethacrylate
Polybutene-l-sulfone Doping
Polymethylcrylamide
Polymethylmethacrylaye-coacrylonitrile
Negative photoresists Doping deliberately adds chemical impurities to parts
Polyglycidylmethacrylate-coethylacrylate
Epoxidised polybutadiene
of the silicon wafer to alter the way the silicon in each
Bisarylazide doped area conducts electricity. In electrical terms,
Polyvinyl alcohol silicon can either be n-type or p-type, depending on
Polyvinyl cinnamate
Vinyl benzene
the impurity added. The atoms in the doping material
Vinyl acetate in n-type silicon have an extra electron that is free to
Cyclised natural and synthetic rubbers move. Some of the doping atoms in p-type silicon are
Photoinitiators!stabilisers!preservatives
Quinones
short of an electron and so constitute an electron
Anthrones 'hole'. Where the two types adjoin, the extra electrons
Diphenyls can flow from the n-type region to the p-type region to
Thiophenylmethane dyes
Thiazolines
611 the holes.
Trichloroacetophenone The material at the base of the chip is p-type silicon.
Triarylselenium compounds One of the etching steps removes parts of the
Triarylarsenic compounds
Etchants
polysilicon and/or silicon dioxide masking layers
Acids previously put on the silicon base (see chemical
H2 S04 vapour deposition), thus laying bare two strips of
HF
HCl
p-type silicon. Separating them is a strip that still bears
H 3 P0 4 its layer of conducting polysilicon; it is the transistor's
CH 3 COOH "gate". The doping material now applied to the two
HN0 3
strips of p-type silicon transforms them in to n-type
Cr03
Solvents silicon. A positive charge applied to the gate attracts
Xylene electrons below the gate in the transistor's silicon base.
Cellosolve acetate
n-butyl acetate
These electrons create a channel between one n-type
Deodorised kerosene strip (the source) and the other (the drain). If a
Stoddard solvent positive voltage is applied to the drain, current will
Aqueous NaOH
Aqueous KOH
fiow from source to drain. In this mode, the transistor
Tetramethylammonium hydroxide is 'on'. A negative charge at the gate depletes the
Methylethylketone channel of electrons, thereby preventing the fiow of
Isopropanol current between source and drain. The transistor is
Glycol ethers
l,l,l-trichloroethane now 'off'. It is by this means of switching on and off
Acetone that a transistor represents the arrays of 1 and 0,
Naphthalene commands that constitute the binary code, the basis of
o-dichlorobenzene
Tetrachloroethylene function of all semiconductor devices, and the lan-
Phenol guage of the computer.
Freons
The dopant materials in most common use are
arsenic, boron, antimony and phosphorus. Today these
materials are most usually added to the wafer by the
entirely automated and occur in closed systems so that process of ion implantation, but in the past this was
worker exposure to the chemicals involved is likely to done by diffusion.
be minimal, except during the processes of cleaning Ion implantation [15] forces ions of dopant into the
and charging the machines. Owing to understandable silicon using a stream of high energy ions produced in
secrecy within the industry and to the vast numbers of a machine similar to a mass spectrophotometer.
different companies in the electronics industry, to Sources of dopants for this process are elemental
produce an exhaustive list of all the chemicals used in arsenic and phosphorus, arsine, phosphine, diborane,
this and other steps in semiconductor manufacture and some boron halides. A more detailed description
here would be impossible. The practising dermatolo- of doping procedures is beyond the scope of this text
gist investigating a possible case of occupationally and can be found elsewhere [8].
related dermatosis will need to closely investigate each Diffusion involves physical contact between dopant
individual separately, taking into account at precisely source, usually the oxide of the elemental dopant,
combined with organic solvent, and the wafer. The then packaged to make the finished electrical product.
dopants are forced in by heating in a furnace. The process of assembly of components on to PCBs
may be manual or automated as may the subsequent
soldering. Far more workers are involved in this
Metallisation and Interconnections branch of the industry than in semiconductor manu-
facture, and the jobs undertaken tend to be rather
more manual, particularly so in final product assembly
This last step begins with further masking and etching operations, increasing the potential for skin contact
sequences that open a layer of electrical contacts with various hazardous materials.
between layers of the chip. A conducting metal, most The manufacture of PCBs is less complicated than
usually aluminium, is deposited and patterned using that of ICBs. There are basically two types of PCB [16],
photolithography to create a system of wiring that the cheaper phenol-formaldehyde impregnated paper
links all the chip's transistors and allows the flow of boards and the better quality epoxy resin and hard-
electrical current through the circuit. Other common ener/fibreglass PCBs. In these latter types, the fibre-
metals used for metallisation are nickel, chromium, glass acts as a reinforcement filler, and they are
ni chrome, gold, germanium, copper, silver, titanium, manufactured as described in the following sections
tungsten, platinum and tantalum [15]. A variety of [16,17]·
methods is available to effect metallisation; filament Initially, the plain epoxy/fibreglass boards tend to be
evaporation, electron beam evaporation, flash evapo- bought in by electronics industries who modify them
ration, induction evaporation and sputtering [15]. further. The procedures involved are mostly automat-
Again, these methods all take place in enclosed ed, and again worker exposure is most likely to occur
systems. during cleaning operations and refilling of the ma-
The metallised individual chips are now tested to chines.
ensure that all their electrical connections work using The desired circuit pattern is printed on to the board
tiny electrical probes. Next, a dicing machine cuts up using photolithographic methods, as described earlier.
the wafer into individual chips, and the good chips are Acrylate resins, sensitive to UV light, are used for the
separated from the bad. Prior to dicing, the wafers are process and are spread on to the board. The desired
often coated on either side in an adhesive plastic to circuit is imaged onto the board using a mask and
facilitate the process. Wire bonders then attach metal incident UVL will then cure exposed parts of the
leads to the chips. The electrical contacts between the resins. Uncured res ins are removed with solvents, and
chip's surface and the leads are made with tiny gold or the framework of the electrical circuit has been
aluminium wires. This wire bonding process gives an imprinted on the board. In the past, and probably still
opportunity for worker exposure to gold dust during in so me lower-budget outfits today, epoxy resin-based
opening and re-charging of the bonding machines. inks were used in the place of acrylates, and these were
heat rather than UVL cured.
Other stages in manufacture include electroplating
Packaging/Encapsulation with a thin coating of copper, and holes are later
drilled at desired sites. Copper debris is removed and
Packaging ofthe chip portion ofthe chip/lead combined the board cleaned with aqueous acid solutions. Drilled
unit into a plastic or ceramic container is a semi- sites are metallised and then a polyvinyl resin coat is
automated process involving the use of epoxy resins, applied to the etched circuit pattern, which then allows
usually epoxy novolak resin formations [15]. These for copper plating on to these areas, done in an
should be fully cured prior to use, but unreacted electrolytic bath. Unwanted vinyl coating is removed
monomers may be present, which can sensitise, as by dipping the board into a bath of appropriate
may other diluent and flame retardant materials, such solvent. There then follows lead plating, using elec-
as halogenated derivatives of bisphenol A, which are trolysis, and etching away of excess copper coating to
added to the resin prior to use. The completed devices give the completed PCB.
are then laser marked in an enclosed system and tested,
again in an automated process, prior to delivery for sale.
Cutaneous Hazards and Skin Disorders
in the Electronics Industry
Printed Circuit Board Fabrication and Assembly
Despite the vast size of the electronics industry
Completed chips and other electrical components are workforce, there is little information available in the
assembled onto the printed circuits on PCBs, which are medical literature on precisely how common occupa-
tionally related skin dis orders in this industry are. In commonest irritants and allergens encountered. Again,
1984, in California, only 260 occupational illnesses this cannot be directly compared with previous figures,
were reported from a semiconductor workforce of but the data does suggest that the figure of 14.6% from
70,000, of which 30 (11%) were skin disorders [1]. Singapore in 1984 is on the increase. This study also
These 260 illnesses compare with a calculated 637 showed a skewed dermatosis incidence distribution
expected illnesses for the same number of workers with age, suggesting that the young and inexperienced
employed in manufacturing as a whole, based on the appear to constitute a risk group. The authors state
known occupational illness rates for that area. In that these workers may have experienced more occu-
addition, traditionally, 40-50% of all occupational pational exposure because of their ignorance about
illness cases are skin disease, which would give a total hazards of occupational chemicals.
expected number of 104 cases of dermatitis compared There is evidence that the appropriate authorities
with the actual figure oho [1]. are responding to the scale of the problem of skin
These figures would suggest that the incidence of disease in the electronics industry. One study [21]
occupational skin diseases in the electronics industry showed that in the United States in 1991, the computer,
is significantly lower than in other manufacturing electronics and scientific equipment manufacturing
industries despite the heavy daily use of hazardous industries employed the largest number of occupa-
chemicals. This has been assumed to be due to the near tional physicians per capita relative to occupational
complete degree of automation in this industry, which illness/injury/lost work days per capita.
makes skin contact with hazardous substances less It should be understood that in plants, particularly
likely to occur [1], although it is acknowledged that manufacturing plants, in which state-of-the-art equip-
there is likely to be a significant degree of under- ment is used, the hazards to production workers are
reporting of skin disease [16], and the situation is likely to be minimal, but cleaning, repair, and main-
complicated by misclassification of what processes tenance staff remain at special risk [1]. Production staff
exactly fall into the category of the 'electronics involved with chip manufacture work in remarkably
industry'. clean environments which have to be virtually dust-
Contrary evidence from Singapore [18], where the free to prevent chip malfunction. This is achieved both
electronics industry workforce is relatively large, by efficient air-filtering mechanisms and by the
would suggest that skin disease in this industry is requirement that all workers wear special suits with
more of a problem than is suggested by the above boots and head coverings and wear gloves and surgical
figures. In this study, 55 of 377 (14.6%) cases of masks at all times (Fig. 2). Primarily intended to
occupational contact dermatitis identified in an occu- protect the product and not the worker, there can be
pational dermatoses clinic in 1983 were among workers no doubt that the latter function is also, to some
in the electronics industry, putting it third in impor- degree, served. It should be remembered also that if
tance after the construction and engineering indus- the incidence of skin disease in the electronics industry
tries. Absolute numbers of workers involved in each is truly lower than that in other industries as a whole,
industry are not given and so the data cannot be this may be due to the fact that the industry is top
compared with that from California, but these results heavy, with professional staff involved in design and
do suggest that the sheer size of this industry in some product innovation who work in an office environ-
countries will mean that it is likely to contribute a large ment. Production and maintenance workers constitute
number of cases of occupational skin disease to the only 31% and 2.5% respectively of the workforce, but
dermatologist, both now and in the future. contribute nearly 60% of reported injury and illness
In a study from Taipei [19], further evidence of the [11, 22, 23].
relative importance of the electronics industry as a Clearly, poorly maintained plants and lackadaisical
cause of occupational skin disease is presented. Of a working practices are likely to contribute to increased
total of 164 patients seen at a tertiary referral centre risk of preventable skin disease [11]. Improperly
over a 7-year period with occupational hand dermatitis maintained filter and ventilation systems and ill-fitting
(OHD), 25 (15.2%) cases occurred among workers from furnace exhaust pipes may increase the risk of
the electronics industry. This put the electronics exposure to many chemical and radiation hazards,
industry top of their list of occupations associated and the standard clean room ventilation systems will
with OHD. re-circulate solvent vapours if these are not properly
More recent data from Singapore [20] shows that of expelled [11, 24]. Such situations may arise in devel-
all the 633 cases of occupational dermatosis seen at an oping countries where there is often an absence of
occupational dermatoses clinic over a 5-year period regulations regarding health and environmental stan-
from 1990 to 1995, 149 (23.5%) were from the dards [25].
electronics industry. Of these, 137 (91.9%) were due EPI-DERM is an organisation in the United King-
to contact dermatitis, and data is given listing the dom (UK) which has been in operation for 8 years, and
Fig. 2. The working environment in the clean

rooms is extremely clean, and protective cloth-
ing must be worn at all times. Here, a worker is
dipping a tray of wafers into an aqueous acid
bath for pre-furnace cleaning of the wafers. Note
the wall-mounted exhaust system and that the
fluid level of the acid baths is considerably lower
than the workbench itself
whose purpose is the monitoring of occupational skin vapours can lead to facial dermatitis. The additives and
disease. Hs data comes from clinical dermatologists other contaminants sometimes found in solvents can
and occupational physicians throughout the country, also cause ACD. Trichloroethylene (TCE) has largely
who are asked to record and report all the details of replaced freon as a degreaser because it does not
any patients they investigate with suspected occupa- deplete the ozone layer [20]. TCE may affect the skin in
tionally related skin disease. The labour force survey several ways. Hs vapour has been reported as causing a
gives the numbers of workers in the electronics bullous eruption [27]. Inhalation of even small
industry in the UK as 230,783. Table 2 lists the cases amounts of TCE followed within an hour or two by
of skin disease in the industry reported to EPI-DERM consumption of alcohol has been reported as resulting
between February 1993 and April 1997 [22] and gives
the most common culprit irritants and allergens. It
gives a useful idea of the main cutaneous hazards in Table 2. Skin allergens, irritants, and physical hazards reported
in the electronics industry in the UK, February 1993 to April 1997
the electronics industry, and is in broad agreement (EPI-DERM [22])
with recent figures available from Singapore [20],
except that irritant contact dermatitis (ICD) appears to Number %
be considerably less prevalent than allergic contact
Allergen
dermatitis (ACD) in the UK than in Singapore (18.iVo Epoxy resins 33 36.3
of all cases of contact dermatitis in this industry in the Nickel 18 19.8
UK compared with 55.50/0 in Singapore). A more Acrylate resins 13 14.3
Colophony/solder resin 10 10.9
detailed discussion of the main cutaneous hazards in Rubber(gloves)/carba mix 6 6.6
the electronics industry will now follow. There are two Formaldehyde res in 2 2.2
recent excellent publications which also deal with this Kathon 2
Chromate 2
subject in some detail [2,20]. Formaldehyde 1 1.1
Cobalt 1
Unspecified metals 1
Specific Hazards Oils 1
Cloth tape 1
Total 91 100
Irritant
Solvents Soldering flux 5 23.8
Solvents 5 23.8
These multi-purpose chemicals are used in many Grease 4 19
Fiberglass 3 14.3
processes in the electronics industry. Many different Oils 2 9.5
solvents are used and Table 1 lists some of the more Dust 1 4.8
common ones. Solvents primarily cause ICD [2,20,23, Lanthanum oxide (grinding
of TV tube face)
26] and it is suggested that they may be overtaking Total 21 100
soldering fiux as the most common cause of ICD in the Others
industry [20]. Solvents defat the skin, and affected Burn (not specified)
Friction (not specified)
areas not surprisingly tend to be the hands, but solvent
in a pronounced facial and neck erythema called dermatitis. Several studies [20, 44-46] have highlight-
"degreaser's ßush" [28]. Stevens-Johnson syndrome ed this problem. Clinical signs may be few, but itch can
resulting in the death of one in five reported cases [29] be a prominent symptom. Causation in one study [46]
and toxic epidermal necrolysis also resulting in death was demonstrated by the finding of fibreglass spicules
[20] has also been reported and felt by the authors to in the skin of workers that were of a similar size to
be due to exposure to TCE. In addition, scleroderma those found free in large quantities at the edge of the
and a scleroderma-like multisystem disease have been particular PCB.
reported after exposure to various solvents, especially Free fibreglass in the workplace environment,
TCE [30, 31]. released during the sawing of PCBs, has caused
generalised itching in exposed workers [1].
Soldering Flux
Acids and Alkalis
Soldering is frequently carried out in the electronics
industry, particularly in assembly processes. Solder Various acids and alkalis are used at many stages of
metals (usually tin/lead alloys) will not function manufacture in several different areas within the
properly unless oxide layers nearly always present on electronics industry. They are chießy used for cleaning
the surface to be soldered are first removed [32]. This purposes. Hydroßuoric acid (HF) is a well-known
is achieved with soldering ßux. ICD resulting from offender and is reputed to be the most common cause
exposure to liquid ßux is probably roughly as common of burns in the semiconductor industry [47]. Hydro-
as ICD resulting from solvent exposure [20]. ICD ßuoric acid, unlike other acids, often produces no
occurs because ßuxes contain aqueous solutions of immediate burning sensation and so remains in
acids. Fluxes mayaiso contain colophony. The ßux is prolonged contact with the skin, eventually producing
either in liquid form where it would be squirted by the horrific injuries. This effect may be enhanced by the
worker onto the metal surface, or it comes as a number sweaty condition of the hands and fingers underneath
of cores incorporated in to the solder wire [33]. the gloves often worn by workers, which allows for
Colophony in the ßux has been reported to cause easier penetration of the acid.
ACD, and through its fumes, airborne contact derma- In recent years, the frequency of serious HF burns
titis [34-37], and allergic contact urticaria [38]. Ami- has diminished due both to increased automation and
noethylethanolamine and hydrazine, which may be to the introduction of plasma processes for wafer
present in ßuxes, have been reported as causing ACD stripping and etching, which do not require the use of
[39,40]. HF [23].
Flux dermatitis typically involves finger pulps and Many other acids and alkalis are used in the
periungual areas, and from contamination of work- industry, particularly in etching and megasonic pre-
benches, the ulnar borders of the forearms [41]. It is furnace cleaning of wafers, and constitute potential
important to patch test to the patient's own colophony exposure risks, although again, automation and work-
in addition to that in commercially available batteries place design greatly minimises this risk.
[35, 36]. Water and detergents have recently also been
demonstrated as causes of ICD in the industry [20].
Oils and Coolants
Metals
Oils and coolants have recently been reported as
common irritants in the electronics industry [20]. This Metals are emerging alongside epoxy res ins as the chief
problem has not been previously highlighted. In the cause of ACD in the electronics industry [20, 22, 48].
paper quoted, however, the precise chemical culprits Common sources of metal allergens include nickel-
are not given. Historically, exposure to oil-based plated earthing straps worn by assembly workers to
cutting ßuids have been considered to be associated prevent damage to electronic components, which are
with cutaneous squamous cell carcinomata [42, 43], extremely sensitive to static electricity, and nickel-
although no reports of this have as yet emerged among plated tools and coolants [20]. Cobalt and platinum
workers in the electronics industry. mayaiso sensitise [1]. Gold is also used in some
processes, and although only a rare sensitiser, may
Fibreglass cause black dermographism and gold smudge [49].
Dichromate solutions used in etching and slicing of
Fibreglass is often found as the reinforcement filling wafers are highly irritating and may cause perforation
material of PCBs. Direct penetration of fibreglass of the nasal septum and "chrome holes" [23].
spicules into the skin may cause irritation [2], and There have also been reports [50,51] on the problem
larger diameter fibres (>4.5 11m) are likely to cause a of chromate dermatitis in the manufacture of television
tubes. Ammonium dichromate is used for the adhesion Acrylates and Anaerobic Sealants
of phosphorescent pigments to colour television
screens in a flow coating process. Contact with the These chemicals harden between metal parts in the
skin occurs during manual weighing of ammonium absence of air. They are resistant to shock and
dichromate powder prior to mixing with distilled water vibration, and are used for making locking threads
from aburette. The authors also point out the of screws and as sealants, structural adhesives, and as
importance of late reaction on patch testing; three of photoresists in photolithography. They are a fairly
the nine positive patch-test resuIts were not seen until common cause of sensitisation in the electronics
day seven. All nine also showed positive patch-test industry. Polyethylene glycol dimethacrylate is the
reactions to potassium dichromate although an opin- most frequently reported sensitiser [59-62]. The
ion is not given as to whether these were feIt to acrylate se alants mayaIso contain stabilisers, acceler-
represent cross-reaction. ators, and other additives which can also cause ACD
It has been demonstrated that arsenic can be [62].
released from wafers during implantation [52], and There are a variety of other chemical and physical
so potential for exposure exists aIthough all such hazards, either potential problems or already reported,
reactions should take place in dosed chambers. Again which may be encountered in the electronics industry.
those at most risk will be personnel involved in reactor With the exception of rubber chemicals these only
and furnace maintenance and deaning. To date there rarely cause problems. These, their specific cutaneous
are no reports of carcinogenesis or arsenical dermatitis consequences, and other miscellany are listed in
having occurred in the electronics industry, but there Table 3.
is a long latent period of 30-35 years following
exposure before the emergence of the lesions.
Conclusions
Epoxy Resins
Epoxy res ins are frequent irritants and sensitisers in In the recent past, the electronics industry has been
the electronics industry [20, 53, 54]. Their reactive considered, owing to an enormous degree of automa-
diluents and hardeners mayaIso cause problems. tion within it, to be a relatively safe industry as regards
Epoxies are used or may be found in the electronics cutaneous risks to its workforce [23]. Evidence is
industry in various situations induding die attaching, emerging as the industry grows in size that, despite
chip encapsulation, ingot mounting prior to slicing in this high degree of automation, cutaneous disease is
to wafers, tool handles, electrical insulation material, nevertheless a reality among electronics industry
resin moulding systems, laminated sheetings and PCBs personneI, and that this is occurring from a diverse
[2, 23]. Various reports of allergy, induding airborne array of sources. Incidence rates of skin disease in this
contact dermatitis, have occurred [55-58]. industry are lower than in most other manufacturing
Table 3. Other skin hazards, allergens and irritants in the electronics industry
Hazard Skin problem Reference
Physical hazards
Low humidity Itch, burning sensation of face, scaling of 63
face and neck
Facial itch, redness, and urticaria 64
Unpolymerised cyanoacrylate glue in concert with rrritant contact dermatitis (ICD) 65
low humidity
Heat (near furnaces) Rashes 66
Mechanical press ure (screwdrivers) Palmar callosities 67
Chemical Hazards
Formaldehyde Erythema multiforme exudativum 17
(PCB fabrication) Solvent-containing contact sprays Cold urticaria 68
Diphenylamine (additive in grease) Allergie contact dermatitis (ACD) 69
Polypropylene (capacitors) Contact urticaria 70
Bishydroxyethyltallowamine (BHETA); an oily rCD 71
antistatic agent
Rubber/ rubber additives (gloves, finger cots) ACD, Contact urticaria 1,72
Safety spectacles, safety shoes ACD 73,74
Perchloroethylene (garment cleaner) rCD 75
Risk of melanoma 76,77
X-ray, UV, microwave, and radiofrequency radiation Known potential effects 78,79, 80
industries, but in certain countries that have a very 21. Ducatman AM, et al. (1991) Occupational physician staffing
large number of people working in electronics, signi- in large US corporations. J Occup Med 33(5):613-618
22. Cherry N (1998) EPI-DERM. Personal communication, Centre
ficant numbers of cases of work-related dermatitis are for Occupational Health, University of Manchester
likely to present to the physician. 23. Adams RM (1990) The semiconductor industry. In: Adams
Both rCD and ACD appear to be important, and the RM (ed) Occupational skin disease, 2nd edn. Saunders,
major hazards are solvents, metals, soldering fiux, 24. Cone JE (1986) Health hazards of solvents in the microelec-
epoxy and acrylate res ins, oils and coolants, fibreglass, tronics industry. In: LaDou J (ed) State of the art reviews:
and rubber chemicals. occupational medicine. Hanley and Belfus, Philadelphia,
pp 69-88
25. Geiser K (1986) Health hazards in the microelectronics
industry. Int J Health Services 16(1):105-120
26. Koh D, et al. (1990) Dermatologieal hazards in the electronics
industry. Contact Dermatitis 22:1-7
References 27. McBirney RS (1954) Trichloroethylene and dichloroethylene
poisoning. Arch Ind Hygiene 10:130-133
28. Stewart Rd, et al. (1974) Degreaser's flush. Arch Environ
1. Adams RM (1986) Dermatitis in the microelectronics indus- Health 29:1-5
try. In: LaDou J (ed) State of the art reviews: occupational 29. Phoon WH, et al. (1984) Stevens-Johnson syndrome associ-
medicine. Hanley and Belfus, Philadelphia, pp 155-165 ated with occupational exposure to trichloroethylene. Contact
2. Koh D (1997) Electronics industry. Clin Dermatol 15(4): Dermatitis 10:270-276
579-586 30. Walder BK (1983) Do solvents cause scleroderma? Int J
3. US Dept. of Health and Human Services (1985) Dermatol 22:157-158
DHHS(NIOSH) Publication No. 85-100, Hazard assessment 31. Yamakage A, Ishikawa H (1982) Generalised morphoea-like
of the electronic component manufacturing industry scleroderma occurring in people exposed to organic solvents.
4. Barrett CR (1997) From sand to silicon: manufacturing an Dermatologica 165:186-193
integrated circuit. Sci Am (Special issue: The solid state 32. Rubin W, Allen BM (1972) The chemistry and behaviour of
century):s6-61 fluxes. Trans Inst Metal Finishing 50:133-137
5. Morgan DV, Board K (1985) An introduction to semiconduc- 33. Courtney D (1983) Health and safety in soft soldering. Circuit
tor microtechnology. John Wiley & Sons, Chi chester world 9:2-5
6. Beasley RWR (1988) An OH guide to the semiconductor 34. Widstrom L (1983) Contact allergy to colophony in soldering
industry. Occupational Health Sept:640-650 flux. Contact Dermatitis 9:205-207
7. Rohm T, et al. (1986) The chemical nature of the microelec- 35. Liden C (1984) Patch testing with solderimg fluxes. Contact
tronics industry. In: LaDou J (ed) State of the art reviews: Dermatitis 10:119-120
occupational medicine. Hanley and Belfus, Philadelphia, 36. Mathias CGT, Adams RM (1984) Allergie contact dermatitis
pp 13-34 from rosin used as a solde ring flux. J Am Acad Dermatol
8. Lewis DR (1986) Dopant materials used in the microelec- 10:454-456
tronics industry. In: LaDou J (ed) State of the art reviews: 37. Goh CL, Ng SK (1987) Airborne contact dermatitis to
occupational medicine. Hanley and Belfus, Philadelphia, colophony on soldering flux. Contact Dermatitis 17:89-91
pp 35-48 38. Rivers RJK, Rycroft RJG (1987) Occupational contact urticaria
9. Harrison RJ (1986) Gallium arsenide. In: LaDou J (ed) State of from colophony. Contact Dermatitis 17:181
the art reviews: Occupational reviews: occupational medicine. 39. Wheeler CE, et al. (1965) Dermatitis from hydrazine hydro-
Hanley and Belfus, Philadelphia, pp 49-58 bromide solder flux. Arch Dermatol 91:235-239
10. Teitelbaum DT (1986) Photoactive chemicals used in photo- 40. Crow D, et al. (1968) Amine flux sensitization dermatitis in
resist systems. In: LaDou J (ed) State of the art reviews: electricity cable joiners. Br J Derm 80:701-710
occupational medicine. Hanley and Belfus, Philadelphia, 41. Goh CL (1985) Occupational dermatitis from soldering /lux
pp 59-68 among workers in the electronics industry. Contact Derma-
11. Wald PH, Jones JR (1987) Semiconductor manufacturing: An titis 13:85-90
introduction to processes and hazards. Am J Ind Med 11: 42. Mastromatteo E (1971) Cutting oils and squamous cell
203-221 carcinoma. Part I: Incidence in a plant with areport of six
12. Oldham WG (1977) The fabrication of mieroelectronic cases. Br J Ind Med 12:240-243
circuits. Sci Am 237(3):110-128 43. Waterhouse JAH (1971) Cutting oils and cancer. Ann Occup
13. Robinson AL (1983) GaAs readied for high speed microcir- Hygiene 14:171-180
cuits. Science 219:275-277 44. Koh D (1993) A study of occupational derma tos es in the
14. Amato I (1997) The semiconducting menagerie. Sci Am electronics industry. J Occup Med Singapore 5:1-7
(Special issue: The solid state century):82-83 45. Koh D, et al. (1992) Fibreglass dermatitis from printed circuit
15. Rohm T (1990) The semiconductor industry. In: Adams RM boards. Am J Intern Med 21(2):193-198
(ed) Occupational skin disease, 2nd edn. Saunders, Philadel- 46. Koh D, Khoo NY (1994) Identification of a printed circuit
phia, pp 408-425 board causing fibreglass skin irritation among electronics
16. Goh CL (1994) Common industrial processes and occupa- workers. Contact Dermatitis 30(1):46-47
tional irritants and allergens-an update. Ann Acad Med 47. Edelman P (1986) Hydrofluoric acid bums. In: LaDou J (ed)
Singapore 23(5):690-698 State of the art reviews: occupational medicine. Hanley and
17. Nethercott JR, et al. (1982) Erythema multiforme exudativum Belfus, Philadelphia, pp 89-104
linked to the manufacture of printed circuit boards. Contact 48. Kiec-Swierczynska M (1988) The role of metals in the
Dermatitis 8:314-322 development of allergy in workers in the electrotechnical
18. Goh CL, Soh SD (1984) Occupational dermatosis in Singa- industry. Przegl Dermatol 75(4):272-276
pore. Contact Dermatitis 11:288-293 49. Rapson WS (1985) Skin contact with gold and gold alloys.
19. Sun CC, et al. (1995) Occupational hand dermatitis in a Contact Dermatitis 13:56-65
tertiary referral dermatology clinic in Taipei. Contact Der- 50. Stevenson CJ, Morgan PR (1983) Investigation and prevention
matitis 33:414-418 of chromate dermatitis in television manufacture. J Soc
20. Tan HH, et al. (1997) Occupational skin disease in workers Occup Med 33:19-20
from the electronics industry in Singapore. Am J Contact 51. Ali SA (1997) Occupational dermatitis in the manufacture of
Derm 8(4):210-214 color television tubes. Am J Contact Dermatitis 8(4):222-224
52. Ungers LI, et al. (1985) Release of arsenic from semieonduc- 68. Bjorkner B (1981) Occupational cold urticaria from contact
tor wafers. Am Ind Hyg Assoc J 46:416-420 spray. Contact Dermatitis 7:338-339
53. Tosti A, et al. (1993) OccupationaI skin hazards from 69. Bazin BH, et aI. (1986) Allergy to diphenylamine from an
synthetie plasties. Toxicol Ind Health 9(3):493-502 industriaI grease. Contact Dermatitis 14:116
54. Leow YH, et al. (1995) Allergie contact dermatitis from epoxy 70. Tosti A, et aI. (1986) Contact urtiearia from poly propylene.
res in in Singapore. Contact Dermatitis 33:355-356 Contact Dermatitis 15:51
55. Tosti A, et aI. (1998) Occupational airborne contact derma- 71. Bennett, et al. (1988) Dermatitis from plastic tote boxes
titis to epoxy res in. Contact Dermatitis 19:220-222 impregnated with an antistatie agent. J Occup Med 30:252-255
56. Fischer T, et al. (1987) Unhardened epoxy resin in tool 72. Estlander T, et al. (1986) Dermatitis and urtiearia from
handles. Contact Dermatitis 16:45 rubber and plastie gloves. Contact Dermatitis 14:20-25
57. Nishioka K, et al. (1988) Occupational contact allergy to 73- Sonnex TS, Rycroft RJG (1986) Dermatitis from phenylsali-
triglycidyl isocyanurate (TGIC, Tepic). Contact Dermatitis cylate in safety spectacle frames. Contact Dermatitis 14:
19:379-380 268-270
58. Jolanki R, et al. (1994) Concomitant sensitization to trig- 74. Foussereau I, Muslmani M, Cavelier C, Herve-Bazin B (1986)
lycidyl isocyanurate, diaminodiphenylmethane and 2-hy- Contact aIlergy to safety shoes Contact Dermatitis 14:233-236
droxymethacrylate from silk screen printing coatings in the 75. Redmond SF, Schappert KR (1987) Occupational dermatitis
manufacture of circuit boards. Contact Dermatitis 30(1):12-15 associated with garments. J Occup Med 29:243-244
59. Mathias CGT, Maibach HI (1984) Allergie contact dermatitis 76. Nelemans PI, et aI. (1993) Melanoma and occupation: results
from anaerobic acrylic seaIants. Arch DermatoI120:1202-1205 of a case-control study in the Netherlands. Br J Ind Med
60. RanchoffRE, Taylor JS (1985) Contact dermatitis to anaerobie 50(7):642-646
sealants. J Am Acad DermatoI13:1015-102 77. Vagero D, Olin R (1983) Incidence of cancer in the electronics
61. Patussi V, et al. (1986) Dermatitie da contatto alla Loctite industry: using the new Swedish Cancer Environment Reg-
serie 200. Ital Derm Ven 121:117-119 istry as a screening instrument. Br J Ind Med 40:188-192
62. Conde-Salazar L, et al. (1988) OccupationaI aIlergic contact 78. Garabrant DH, Olin R (1986) Carcinogens and cancer risks in
dermatitis from anaerobie acrylic seaIants. Contact Derma- the microelectronies industry. In: LaDou J (ed) State of the art
titis 18:129-132 reviews: occupational medicine. Hanley and Belfus, Philadel-
63. Rycroft RJG, Smith WDL (1980) Low humidity occupationaI phia, pp 119-134
dermatoses. Contact Dermatitis 6:488-492 79. Cohen R (1986) Radiofrequency and mierowave radiation in
64. Guest R (1991) Clean room and itchy faces. J Soc Occup Med the mieroelectronics industry. In: LaDou J (ed) State of the art
41:37-40 reviews: occupational medicine. Hanley and Belfus, Philadel-
65. Calnan CD (1995) Cyanoacrylate dermatitis. Contact Derma- phia, pp 145-154
titis 5:165-167 80. Rudolph L, Swan SA (1986) Reproductive hazards in the
66. Koh D (1995) An outbreak of occupational dermatosis in an mieroelectronies industry. In: LaDou J (ed) State of the art
electronics store. Contact Dermatitis 32( 6):327-330 reviews: occupationaI medicine. Hanley and Belfus, Philadel-
67. Koh D, et aI. (1995) An occupational mark of screwdriver phia, pp 135-144
operators. Contact Dermatitis 32(1):46
CHAPTER 83
Paints, Lacquers and Varnishes

T. Estlander, R. Jolanki, and 1. Kanerva
Introduction have other properties, including alteration of paint

flow and provision of corrosion resistance. Limited
solubility in water and in solvents, as weIl as good
The manufacture and chemistry of paints have under-
color fastness are characteristics of pigments. They
go~e profound changes since the 1940S. Nowadays
must also be dispersed in a paint formulation con-
pamts, lacquers and varnishes are complex mixtures of
taining a res in binder to bind the pigment to the
several components. Many experts, including those of
painted surface. Depending on the concentration of
organic and polymer chemistry, catalysis, pigments and
pigments and their particle sizes, paints can be
the color industry, are needed in the development and
classified as glosses (15-20% pigments), flats (40-45%
manufacture of the products. The detailed composition
pigments), and semiglosses (20-40%). Pigments also
of a paint, lacquer or varnish is planned to meet the
need to be opaque; if they are not, they can be used as
special requirements of its use as weIl as the expectations
extenders which may, for example, help to prevent
concerning health and safety requirements. Such re-
pigment setting in the can and act as a matting aid
quirements include, for example, rem oval of lead and
(Mathias 1984; Rose and Vance 1997).
chrome from decorative paints and the lowering of
Examples of inorganic pigments found in paints and
volatile-organic-compound (VOC) emissions from ve-
coatings are shown in Table 1. The most commonly
hicle paints and their total removal from decorative
used white pigment is titanium dioxide, which can be
paints (Fischer and Adams 1990; Rose and Vance 1997).
used in combination with zinc oxide (Hansen et al.
1987; Ulfvarson et al. 1992; Rose and Vance 1997).
Composition Other white pigments include white lead, lithopone
(which is a mixture of zinc sulfide and barium sulfate)
The paints can be liquids or powders that are applied and antimony trioxide. Red pigments include inor-
to surfaces to make a dry coating for protective or ganic compounds such as synthetic iron oxides, red
decorative purposes. The protective functions include, lead oxide and cadmium red. Yellow pigments include
for example, prevention of corrosion, resistance to fire chrome yellow (having varying proportions of lead
chromate, lead sulfate and lead monoxide), strontium
and protection against fungi, marine growth and
yeIlow, nickel titanate yeIlow, zinc yeIlow, zinc chro-
radiation. Reduction of friction, control of illumination
mate and earthen iron oxide (ochre). Chrome orange,
and electrical insulation are other functions of paints.
The decoration of hornes and public buildings has molybdate orange, lead molybdate and cadmium
mercurate orange are examples of orange pigments.
become more common than previously and has thus
increased the need for high-quality paints that do not Chrome green and chromium oxide are examples of
cause health problems. (Fischer and Adams 1990; Rose green pigments. Blue color is obtained with a certain
iron oxide, and violet color with manganese. Carbon
and Vance 1997).
black is the most commonly used black pigment, but
The basic constituents of modern paints include
mineral black, bone black, graphite and black iron
pigments, film formers, solvents and additives. Var-
oxide can also be used as black pigments (Mathias
nishes and lacquers have the same composition as
1984; Fischer and Adams 1990).
paints, but lack pigments (Mathias 1984; Rose and
Organic pigments are used for special purposes.
Vance 1997).
They are generally purer, but more expensive. Exam-
Pigments pIes include Hansa yeIlow, Irgazin orange and violet,
copper phthalocyanine green and blue, toluidine red,
Pigments are fine powders which give the paints their para red, Lithol red and rhodamine red (Mathias 1984;
color. They also cover and hide surfaces. They can also Fischer and Adams 1990).

Paints, Lacquers and Varnishes 663
Table 1. Examples of inorganic pigments found in paints and Water-based paints are dispersions based on syn-
coatings (Mathias 1984; Fischer and Adams 1990) thetic polymers. Dispersions of polyacrylates are the
Color Pigment
most common. Examples of these paints include
acrylic latex paint, heavy-bodied latex wall paint, latex
White Titanium dioxide, zinc oxide, white lead, enamel, latex primer, latex wall paint and sealing
lithopone, antimony trioxide water-borne paint. Water-based paints can also con-
Black Carbon black, mineral black, black iron oxide
Red Synthetic iron oxide, red lead oxide, cadmium red tain water-soluble alkyd res in and a mixture of
Yellow Chrome yellow, strontium yellow, zinc yellow, polyacrylate and polyurethane. Although water is the
nickel titanate yellow, zinc chromate, earthen main solvent in these types of paints, comprising about
iron oxide (ochre)
Orange Chrome orange, molybdate orange, lead 30-85% weight-to-weight ratio (w/w) of the raw
molybdate, cadmium mercurate orange materials, about 10% organic solvents are added to
Green Chrome green, chromium oxide improve the film forming properties of the paint.
Blue Iron blue (Prussian Blue), Ultramarine Blue
Violet Mineral violet (manganese) (Hansen et al. 1987; van Faassen and Borm 1991;
Wieslander et al. 1997). The differences between SBP
and WBP can be seen in Table 2.
Nowadays, coatings that are free from organic or
Nowadays, paint manufacturers usually supply only
other solvents are also increasingly used. Powder
some oil-based or emulsion-type basement paints,
paints are composed of pigments, binders and addi-
from which thousands of shades of color can be
tives which are melted together, cool set and ground
produced by adding a combination of pigment pastes
into a powder which is applied by electrostatic spray.
according to a special shading chart (Fischer and
The film on the coated object is cured by heating.
Adams 1990).
Powder paints can be used for the coating of new metal
goods and small metal components (Rose and Vance
Solvents 1997).
Solvent-based paints (SBPs) dominated the market for Film Formers

construction paints until the 1970S (Hansen et al. 1987;
Faassen and Borm 1991; Wieslander et al. 1997). The Resins or binders are the film-forming agents in paints.
first water-based latex-type paint was not introduced The resin hardens and keeps the pigments bound and
until1957 as an exterior paint (Rose and Vance 1997). permanently dispersed on the painted surface. The
Because of the health hazards to the peripheral and the binder dictates the most important properties of the
central nervous system (Rose and Vance 1997; Wie- paint, such as hardness, flexibility and speed of drying.
slander et al. 1994) connected with SBPs, they have Examples of res ins used in paints and coatings are
gradually been replaced by water-based paints (WBP) given in Table 2. (Mathias 1984; Rose and Vance 1997).
whenever possible (van Faassen and Borm 1991; Dias
et al. 1994; Moura et al. 1994; Rietschell and Fowler Natura/ly Orying Oils
1995; Rose and Vance 1997; Wieslander et al. 1997).
This has not been possible, for example, in a humid Naturally drying oils, including dammar, Japanese
atmosphere because of the slow evaporation of water lacquer and shellac, are suitable for lacquers and
(Rose and Vance 1997). During the past 10 years, varnishes because they dry quickly, although the film
WBPs have constituted more than 90% of the con-
Table 2. Differences between solvent-based (alkyd paint) and
struction paints in Scandinavia (Faassen and Borm water-based paints (acrylic dispersion paint) (Van Faassen and
1991; Wieslander et al. 1997). In 1992, the use of SBPs Borm 1991)
among house painters was only 4% of the total paint
consumption in Sweden (Wieslander et al. 1994). Component Acrylic dispersion Alkyd paint
SBPs contain about 50% organic solvents. Solvent is
Binder Yes (polyacrylate) Yes (alkyd resin)
the volatile component of a paint and is used to make Pigment Yes Yes
the consistency suitable for application in different Filler Yes Yes
ways (brushing, rolling, spraying, etc.). Until the 1970S, Organic solvent Yes (0-15%) Yes (about 50%)
Ammonia Yes No
turpentine was the most important solvent used in Amine Yes No
many countries in construction paints but was later Preservative Yes No
replaced by aliphatic hydrocarbon solvents. Solvents Surfactant Yes No
Corrosion inhibitor Yes No
are chosen for their solvency, evaporation and suit- Thickener Yes Yes
ability for the use of the product (Piper 1965; Mathias Drier Yes Yes
1984; van Faassen and Borm 1991; Wieslander et al. Anti -skinning agent Yes Yes
Ultraviolet-absorber Yes No
1994; Rose and Vance 1997).
Table 3. Examples of film formerslbinders and other plastic unsaturated fatty acids in drying oils. The coatings
chemieals found in paints
do not need a harden er (Mathias 1984). They will
Naturally drying oils harden by their re action with oxygen in the air. See the
Alkyds chapter on epoxy res ins in this book.
Epoxy-resin compounds
Formaldehyde resins
Vinyl resins Formaldehyde Resins
Acrylic resins
Urethane res ins Urea, melamine, phenol or substituted phenols can be
Other synthetic res ins
Polyester resins modified with formaldehyde to produce corresponding
Cyclohexanone resin resins. An excess of free formaldehyde must be
Other compounds (polyfunctional azidine hardeners, removed in order to prevent interference with the
dipropylene giycol diacrylate, para-tertiary-butyicatechol)
film-forming properties of the paint. These res ins can
also be used to cross-link alkyd resins. The curing
formed is brittle. Cop al is a fossile resin which can be takes place by heating. Phenol-formaldehyde resins
used in varnishes. Other natural oils such as fiaxseed are stable to variations of temperature and have a good
or linseed, perilla, tung oils, pine oil or tall oil, soybean resistance to moisture, acids and solvents (Piper 1965;
and ricinus oils have been used in oil-based paints. Mathias 1984; Fischer and Adams 1990).
Since the 1980s, synthetic alkyd res ins have widely
replaced naturally drying oils (Mathias 1984; Fischer Vinyl Resins
and Adams 1990).
Vinyl resins consist of polymers, copolymers or
Alkyds derivative products of vinyl acetate and vinyl chloride.
Polyvinyl acetate resins are used in latex paints. Resins
Alkyds are condensation products of polyalcohols, e.g., derived from polyvinyl chloride (PVC) can be dis-
glycerol, trimethylol propane pentaerythritol and poly- solved or dispersed in organic solvents. They require
carboxylic acids such as phthalic acid or its anhydride, the presence of heat and light stabilizers (Mathias
and adipic and maleic acids. Alkyd resins are formed 1984). PVC copolymers dry by the evaporation of
by modifications with oils containing unsaturated fatty solvents.
acids. These include linseed, soybean, sunfiower,
cottonseed and tall or pine oil. Linseed oil and similar Acrylic Resins
drying oils can be combined with colophony (rosin) to
produce a paint resistant to climatic conditions while Acrylic resins are used in latex paints. The latex binders
also having good color retention. Synthetic polyester are copolymers of two to five monomers, e.g., butyl
alkyds contain no modifying oils. Styrene and vinyl acrylate, acrylic acid and styrene. Lattices are made by
toluene are used as cross-linking agents for these emulsion polymerization of the monomers dispersed in
polyesters. Epoxidized alkyd resins are alkyds modi- water as drop lets. Polymerization takes place in these
fied with epoxidized oils which are formed by reacting drop lets and is initiated by, for example, benzoyl
double bonds in unsaturated fatty drying oils with peroxide. The lattices may contain small amounts of
oxygen to form an epoxide ring. The paints based on ammonia (0.3% w/w), formaldehyde (0.06% w/w) or
these types of alkyd resins need no hardener (Mathias other biocides (e.g., a mixture of isothiazolinones),
1984; Fischer and Adams 1990). They are hardened by surfactants and polymerization inhibitors (e.g., p-
the evaporation of organic solvents or water followed methoxy phenol or hydroquinone). (Mathias 1984;
by the reaction of the binder with oxygen in the air. Hansen et al. 1987; Fischer and Adams 1990).
Industrial acrylate paints and coatings may contain
Epoxy-Resin Compounds polyfunctional acrylics e.g. trimethylolpropane tri-
acrylate (TMPTA), pentaerythritol acrylate (PETA),
Paints, varnishes and lacquers based on epoxy resins hexanediol acrylate and photo initiators, e.g., benzop-
are used in various industrial applications because of henones. Polyfunctional acrylates can also be combined
their strength and durability. Two-component epoxy with aziridine cross-linking agents (Mathias 1984).
paints that cure at room temperature need a hardener Aziridine compounds, such as ethyleneimine, propyl-
added before their use. One-component epoxy paints eneimine and polyfunctional azidine (PFA), are three-
that are heat-cured contain a hardener which can be membered ring compounds which contain a single
activated only by heating. Polyfunctional aliphatic nitrogen in their ring. The PFA hardeners that are
amines, aromatic amines, solid polyamides and anhy- commercially available are synthesized from, for ex-
drides can be used as curing agents. Epoxy-ester-resin ample, ethyleneimine or propyleneimine and TMPTA
paints are formed by reacting epoxy res in with or PETA. Before use, a PFA hardener or cross-linker is
added to the aqueous acrylic- or water-based urethane Table 4. Examples

of additives in paints Hardeners
polymers. The cross-linking reaction is self-curing, but Extenders
heat and ultraviolet (UV) radiation may be used to Driers
enhance the re action, resulting in the more rapid Emulsifiers
Antifoaming agents
drying of the products. PFA is used to cross-link a Thixotropie agents
number of products, including water-based acrylic Plastieisers
emulsions, paint primers, inks, lacquers, topcoats, and Stabilizers
Biocides
other protective coatings (Reinhardt and Britteli 1981; Corrosion inhibitors
Dahlquist et al. 1983; Cofield et al. 1985; Garabrant 1985; Photo initiators
Roark and McKusic 1985; Autio et al. 1993; Kanerva
et al. 1995).
and magnesium carbonates, kaolin, pumice and mica
Urethane Resins (Rose and Vance 1997). Driers can feature one or more
metal salts, including cobalt, manganese, iron, lead,
Urethane resins are formed by the reaction of isocy- zinc and tin naphthenates, oleates, octoates and
anate groups with hydroxyl groups of polyalcohols. In resinates (Mathias 1984; Fischer and Adams 1990;
the reaction, diisocyanates, e.g., toluene diisocyanate, Rose and Vance 1997). Emulsifiers or surfaetants
are used. The resins can be modified with natural include, for example, sodium pyrophosphates, dioctyl
drying oils, resulting in coatings which dry in air and sodium sulfosuccinate, sodium lauryl sulfate and
are polymerizable like alkyd resins. Unmodified poly- nonionic detergents. They help to maintain pigment-
urethane res ins can be formulated in one- or two- particle dispersion in water-based latex emulsions
component systems. Two-component systems harden (Mathias 1984). Antifoaming agents prevent the
when a diisocyanate curing agent, e.g., an amine, is formation of foam during the manufacture and appli-
added to prepolymerized polyurethane (PU) resin cation of water-based latex paints (Fischer and Adams
before application. PU resins have good strength, heat 1990). Thixotropie agents (thickeners) such as poly-
resistance and fiexibility (Mathias 1984; Fischer and amides are added to oil-based paints, whereas cellulose
Adams 1990). derivatives are used for the same purpose in water-
based latex paints (Fischer and Adams 1990). Plastie-
isers are added to paints to increase the fiexibility of
Other Synthetic Resins the resinous film. They include dibutyl and dioctyl
phthalates, adipic and sebacic acids and their esters,
Polystyrene resins are made from polymerized styrene polyester res ins and castor oil. Coalescing agents
and have good insulating power. Synthetic rubber, include pine oil, butyl cellosolve and tributyl phos-
known as styrene-butadiene rubber or chlorinated phate. They are volatile substances that temporarily
rubber latex, can be used in paints for fioor coverings plasticize a liquid coating (Mathias 1984; Fischer and
or tank linings (Fischer and Adams 1990). Adams 1990). Stabilizers have an effect on the heat and
Cyclohexanone resin (C-R) can be added to increase light resistance of a paint. Examples are benzophen-
the hardness and water resistance of any paint but is ones in nonpigemented coatings and epoxy resin in
most often used in floor paints (Bruze et al. 1988a). A paints based on vinyl chloride polymers or copoly-
paint can contain 5% C-R. There are several C-Rs from mers. Antioxidants prevent coatings from drying too
various manufacturers. early and are also called antiskinnning agents. They
include oximes, e.g., butyraldoxime, methyl ethyl
Additives ketone oxime and cyclohexanone oxime, hydroqui-
none and substituted phenols used in so me specialized
Several additives can be used in paints in small industrial paints (Mathias 1984; Fischer and Adams
percentages, e.g., to ensure the stability, quality and 1990). Photoinitiators are needed in UV -curable
desired application properties of a paint (Mathias 1984; products to initiate the polymerization process, e.g.,
Fischer and Adams 1990; van Faassen and Borm 1991; benzophenones (Fischer and Adams 1990).
Rose and Vance 1997). A list of additives is given in Biocides are used to prevent the growth of microbes
Table 4. The most important of these, in terms of their (bacteria, fungi) mainly in water-based latex paints.
effects on the skin, are biocides and hardeners. They are used for conservation of the binder and the
Hardeners are used to cure a paint system and paint during production and storage. These products
include amines, peroxides and polyamides (Mathias also contain bacteria-degradable compounds like
1984). Extenders are noncovering pigments which surfactants in an aqueous vehicle. Ammonia and
improve thickness, adhesion, durability and gloss. volatile amines are used to stabilize the paint at a pH
Examples are barium and calcium sulfates, calcium of 8-9. The water-soluble alkyd resin is solubilized
with triethylamine. Biocides are effective even after the refinishing a surface. They can contain volatile sol-
paint has dried, and thus prolong the life of the paint. vents, caustic agents and special chemicals (Kanerva
Oil-based paints do not usually contain antimicrobials, et al. 1984; Fischer and Adams 1990; Vincent et al.
but some exterior paints can contain an antimildew 1994).
agent. A great number of bioeides are available for use
in paints (Table 4). Most of them can also be used in
other products such as cutting fluids, adhesives, and
Prevalence of Dermatitis Caused
other industrial water-based products (Fischer and
by Paints, Lacquers and Varnishes
Adams 1990; Hansen et al. 1987; Geier et al. 1996).
Antifouling agents are used in marine paints and should
be toxic to underwater organisms. These include, for There are only a few reports on the prevalence of
example, copper, organic tin, tetramethylthiuram di- dermatitis among professionals exposed to paints.
sulfide and zinc carbamates (Piper 1965; Goh 1985; Lewis Pirilä (1947) was the first to investigate paint-factory
et al. 1987; Fischer and Adams 1990). workers, painters, polishers and varnishers in the mid-
Corrosion inhibitors in paints protect metallic sur- 1940S. The study population consisted of 1142 Finnish
faces from oxidation. Coating primers are used when workers, of whom 103 had an occupational dermatosis.
there is continuous exposure to corrosive elements, Within aperiod of 1 year, 10.iJlo of the paint workers
e.g., in marine applications. Examples are coal-tar and 3.iJlo of the painters had had contact dermatitis. In
derivatives, epoxy res ins and coal-tar modified epox- the 1950S Schwartz et al. (1957) estimated that derma-
ies. Primers that inhibit corrosion by anodic or titis among painters constitutes about 3% of all
cathodic polarization contain inorganic metallic pig- compensated cases of occupational dermatoses, and
ments such as chrornates or leads or both. Composite is most frequent among painters in the building trade.
pigments containing calcium oxide, zinc, silica, and Between 1976 and 1977, Högberg and WahIberg
oxides of phosphorus and boron can also be used (1980) conducted a survey of 2239 Swedish house
(Mathias 1984). Nowadays, powder paints such as painters using a questionnaire and clinical examina-
polyester and epoxy powder paints can also be used for tions, with patch testing of those who reported derma-
corrosion inhibition (Rose and Vance 1997). titis. They found 87 cases of occupational contact
dermatitis. A prevalence of 3.9% contact dermatitis was
Methods of Application suggested, representing a minimum figure. Irritant
dermatitis was more common than allergic dermatitis.
Manual brushing using a brush made of synthetic or The solvents used for hand cleaning were found to be
animal hair is used for small coating tasks, e.g., in important causes of irritant dermatitis.
interior decoration. Roller brushing with a roller made Despite major changes in the contents of paints,
of lamb's wool or synthetic material is used to speed lacquers and varnishes, as weIl as changes in the
the application on large, Hat surfaces. Roller coating is methods of application and the use of hand protection,
an automated process in which the flat surfaces of an the professionals using these products still belong to
object are coated with a film of paint with by brushing occupations with increased risk of occupational dis-
the roller in a line across the object. Dipping involves eases. According to a Finnish study based on skin and
immersion of small objects in the paint. In spray other occupational diseases reported to the Finnish
painting, pressurized air is forced to produce a mist of Register of Occupational Diseases between 1986 and
air and paint. Electrostatic spraying is carried out by 1991, and concerning workers and farmers who were
applying electrostatic charges to spray guns. The 25-64 years old at the end of 1985, painters and
sprayed paint is attracted as droplets to the object, lacquerers had the greatest variety of occupational
which carries an opposite charge. Electrodeposition diseases. The reported diseases varied from hearing
systems are easily automated processes used with loss and stress diseases of the upper extremities to
water-based paints. A metal object to be painted is contact dermatoses and respiratory diseases.
immersed in a tank of a water-based primer. It acts as The painters and lacquerers were eleventh in order
an anode, and charged resin particles are attracted to among 25 occupations with an elevated risk of
the metallic surface to be painted (Piper 1965; Mathias contracting an occupational skin disease (standardized
1984; Fischer and Adams 1990). rate ratio (SRR) more than 1). The risk of contracting
allergic dermatitis was 3.5 times as common as in all
occupations (SRR 3.52) and the risk of contracting
Paint and Varnish Removers irritant dermatitis was fourfold compared with that in
all occupations. The number of irritant dermatoses (59
Paint and varnish removers can be in the form of cases) was greater than that of allergie dermatoses (46
liquids or pastes used to remove old coatings before cases).
However, in certain groups of painters exposed Biocides

mainly to less irritating and sensitizing products, hand
eczema is not more common than in the average Tri-N-butyl tin oxide (TBTO) can be used as a biocide
population. In 1989, in central Sweden, a study among (antifouling agent) in marine paints and other paints
house painters using mainly water-based paints was (Goh 1985; Lewis and Emmett 1987). It is known to be a
performed in 8 companies with more than 20 employ- strong skin irritant and has been shown to be corrosive
ees (Fischer et al. 1995). The study was restricted to to the skin in a 0.1% aqueous solution (Lewis and
include housepainters aged 16-65 years. Out of 299 Emmett 1987). An outbreak of irritant dermatitis was
painters, 202 (200 men and 2 women) participated in a caused by acrylic resin-based undercoat and top co at
dermatologie investigation including patch testing with paints containing 0.6% TBTO in two painters. Non-
the thin-Iayer rapid-use epicutaneous (TRUE) test marine paints usually contain up to 0.06% TBTO, and
standard series. Of the test subjects, 32 painters had it was concluded that TBTO was most likely the
current eczema and 16 had a history of previous responsible irritant in the paints. Two further cases
eczema. An observed point prevalence of 8% hand were also seen in painters exposed to marine paints
eczema was found and did not differ from what was containing TBTO (Goh 1985). In the case of Lewis and
generally expected for a group with this age and gender Emmett (1987), a shipwright developed pruritus, ery-
distribution. thema and vesiculation on both of his wrists and
forearms and lesions on the abdomen after using an
antifouling paint containing iYo TBTO. The use of
Clinical Aspects of Dermatitis organic tin compounds is, however, decreasing be-
cause of the toxicity of the compound to marine life
(Fischer and Adams 1990).
The site and location of dermatitis can be variable.
Most other bioeides also have skin-irritating prop-
Irritant dermatitis is usually located on the dorsal sides
erties (Fischer and Adams 1990; Fischer et al. 1995;
of the hands and arms, and in the beginning often
Geier et al. 1996).
appears as mild dryness and chapping of the skin, later
progressing to various degrees of infiammation.
Dusts and Mechanical Irritation of the Skin
Wounds and abrasions in the skin may promote the
development of both irritant and allergie dermatitis. A
Dust that irritates the skin and airways is created by
period of irritant dermatitis often precedes sensitiza-
the rem oval of old wallpapers, manual filling and
tion to paint ingredients. The appearance of an allergie
sanding of walls using sandpaper and steel wool, and
contact dermatitis can be more variable and may occur
the hanging of fiberglass fabrics used as coverings in
on the skin contact areas of accidental splashes
bathrooms and other wet spaces, especially during
(Mathias 1984).
renovation of old buildings (Mathias 1984; Fischer and
The dermatitis may also spread to other areas of the
Adams 1990; Valsecchi et al. 1992; Wieslander et al.
body via hands and contaminated tools, masks, gloves
1994; Moura et al. 1994; Fischer et al. 1995). Epoxy or
and clothes or shoes. Especially in spray painting, the
polyester powder paints can also irritate the skin. Four
face and other skin areas of airborne contact are
cases of irritant dermatitis were detected in a Finnish
affected. In modern paint factories where the manu-
plant producing epoxy powder paints (Jolanki 1991).
facturing processes are automated, only a few workers
Mechanical irritation of the skin associated with the
are at risk of contracting dermatitis, e.g., workers in
last-mentioned operations mayaiso promote the
laboratories and chemical stores, workers who take
development of skin irritation. Workers mayaiso use
sampies and perform canning, as well as the repair and
blow torches and sandblasting equipment, blueprints,
maintenance personnel of the process.
inks and stencils (Fischer and Adams 1990).
Organic Solvents
Causes of Irritant Dermatitis
Organic solvents induce dermatitis mostly by skin
Skin irritation and irritant dermatitis are usually irritation, except in some cases caused by exposure to
caused by repeated or prolonged contact with agents turpentine, glycols and citrus solvent (Pirilä 1947;
noxious to the skin. Both chemical and physical factors Cronin 1980; Alomar and Vilatella 1985; Kinnunen
are involved. Important causes include soaps, deter- et al. 1989; KarIberg et al. 1992; Matsunaga et al. 1997).
gents, acids, organic solvents, remnants of monomers Glycols or glycol ethers used in water-based paints are
and biocides as well as putties, pIasters and cement rare sensitizers, but a few cases of allergy to hexylene
(Mathias 1984; Fischer and Adams 1990; Valsecchi et al. glycol have been reported (Alomar et al. 1985; Kin-
1992; Moura et al. 1994). nunen and Hannuksela 1989; Matsunaga et al. 1997).
Solvents used as thinners or to remove grease and dirt Paint and Varnish Removers
from products to be spray painted (Fischer and Adams
1990), or to clean hands, brushes, spray guns and other Paint and varnish removers are especially noxious to
tools are more important causes of irritant contact the skin because they may contain, in addition to
dermatitis than the solvents contained in paints. irritating solvents, many caustic chemicals, such as
Clothing soaked by spills or splashes of solvents and sodium phosphate, sodium silicate and caustic soda, as
paints and allowed to stay in contact with the skin is well as special chemieals such as dibutylthiourea.
also a common cause of skin irritation (Fischer and Solvents include, e.g., methylene chloride, methyl
Adams 1990). alcohol, ethyl alcohol and toluene (Kanerva et al.
Nowadays, the most commonly used solvents are 1984; Fischer and Adams 1990; Vincent et al. 1994).
mineral or white spirits. Aromatic hydrocarbon sol-
vents, such as xylene and toluene, are used in certain
specialized industrial paints. Other solvents include a Causes of Allergie Contact Dermatitis
wide variety of alcohols (isobutanol, I-butanol), esters
(ethyl acetate, butyl or isobutylacetate) and ketones
Allergie contact dermatitis is the most important
(acetone, methyl ethyl ketone). Often, a mixture of
occupational skin disease among painters. The conse-
different solvents is used to ensure the desired
quences can be serious: the sensitized workers may, for
outcome, e.g., in thinners (Mathias 1984; Valsecchi
instance, have been obliged to change their occupation
et al. 1992; Rose and Vance 1997; Leira 1997). In
(Mathias 1984; Holmes 1993). Since the 1970S, synthetic
Scandinavia, there has been a tendency for more than a
res ins have replaced turpentine as the most important
decade to reduce the use of the more toxic solvents,
causes of sensitization caused by paints (Mathias 1984;
including benzene, n-hexane and the chlorinated
Jolanki 1991; Holmes et al. 1993; Kanerva 1995). Other
solvents, particularly carbon tetrachloride, chloroform,
causes include biocides necessary in water-based
dichloroethane and trichloroethylene (Leira 1997).
paints, and other additives such as hardeners or
accelerators and inhibitors of polymerization (Mathias
Other Solvents and Irritants
1984; Fischer 1990, 1995). There are also several other
potential causes, including plasticizers, dryers and
Water-based paints contain, in addition to solvents,
chromates (Mathias 1984; Fischer et al. 1990). Form-
other skin irritants including monomers from binders,
aldehyde and rubber chemieals, as well as turpentine
preservatives and surfaee-active agents (poly-
and other natural products, can also be included in the
phosphates), and triethylamine and ammonia. Mono-
list of potential allergens.
mers include, for example, butyl acrylate and various
At the Finnish Institute of Occupational Health
other acrylates (see also acrylic res ins in the chapter in
(FlOH) between 1974 and 1997, a total of 85 cases of
this book on Causes of Allergie Contact Dermatitis).
allergie contact dermatitis were diagnosed in different
The solvents used in these products are also called
kinds of painters, lacquerers, parquet installers and
coalescing solvents or cosolvents. They include hydro-
paint-factory workers. Synthetic resins caused 68 of
carbon mixtures (turpentine, white spirits, xylene),
the cases, 54 of them in paints, lacquers or raw
alcohols, esters, glycols and glycol ethers/esters, e.g.,
materials of paints, 5 in floor coverings, 5 in car
ethylene glycol ethyl ether, ethylene glycol butyl ether,
painters' filling cements, 4 in parquet lacquers and one
diethytelene glycol ether, ethylene glycol amyl ether
in a glue. The other agents included chromium,
and 2,2,4-trimethyl-l,3-pentanediol monoisobutyrate
formaldehyde, cobalt, colophony, a mixture of isothi-
(Texanol) (Mathias 1984; Hansen et al. 1987; Fischer
azolinones, and rubber chemicals. No cases of type 1
and Adams 1990; Rose and Vance 1997). The amounts
sensitization to natural rubber latex were found.
of glycols and glycol ethers can, however, vary in
concentrations ofI-30% in water-based paints (Fischer
and Adams 1990). According to the reports of Hansen Film Formers/Synthetic Resins
et al. (1987) and van Faassen and Borm (1992), none of
these chemieals occurred in high enough concentra- Epoxy-Resin Compounds
tions to alone cause irritation of the skin, but the
possibility of irritation due to a mixture of the Most cases of allergic contact dermatitis are caused by
ingredients cannot be excluded, especially in the case epoxy compounds contained in solvent-based and
of frequent skin contact combined, e.g., with unfavor- water-based paints (Jolanki 1991), but powder paints
able climatic conditions. Occupationally related con- have also been responsible for contact sensitization
tact dermatitis is not, however, common among due to epoxy compounds (Bokelund et al. 1980;
painters using mainly these types of paints (Fischer Dooms-Goossens 1989; Jolanki 1991; Munro et al.
et al. 1995; Wieslander et al. 1997). 1992; Foulds et al. 1992). Of the above-mentioned 68
cases of allergie contact dermatitis caused by synthetic et al. 1998). In the study of Swedish construction
resins detected in painters, lacquerers, parquet layers painters (Fischer et al. 1995) n-butyl acrylate was
and paint factory workers, 56 cases were caused by considered to be the most common residual monomer
epoxy compounds. Bisphenol A diglycidyl ether epoxy in water-based latex paints, but none of the workers in
res ins were most often the responsible compounds the study re ac ted to the chemieal. Sensitization to
(Jolanki 1991). Epoxy isocyanurate (triglycidyl isocy- acrylies was found neither in an Italian study (Valsecchi
anurate, TGIC) compounds caused five of the cases, all et al. 1992) where 16 of 324 cases of contact dermatitis
detected in spray painters. TGIC can also cause asthma were caused by paint products, nor in a Portuguese
(Piirilä et al. 1998). Epoxy-reactive diluents and hard- study (Moura et al. 1994) on 37 painters from different
eners are also important sensitizers (Mathias 1984; areas of painting. However, cases of sensitization to n-
Jolanki 1991). Phthalic anhydride and its derivatives butyl acrylate have been reported (Calnan and Steven-
used in heat-cured paints may cause urtiearia, even son 1963; van der Walle 1982; Kanerva et al. 1988). Butyl
airborne contact urticaria, rhinitis and asthma, though acrylate has also been determined in the air of
type IV allergy is rare (Jolanki 1991; Tarvainen et al. workplaces where water-based latex paints have been
1993; Tarvainen et al. 1995; Kanerva et al. 1997). See the used (Hansen et al. 1987). Asthma, rhinitis and other
chapter on epoxy res ins in this book. mucosal symptoms have also been reported to be
associated with exposure to acrylates (Kanerva et al.
Formaldehyde Res;ns 1992; Sala et al. 1996; Estlander et al. 1996b; Savonius
et al. 1993; Piirilä et al. 1998).
Formaldehyde res ins are also potential sensitizers.
Sensitization has most commonly developed from PFA Hardeners and Polyfunctional Acrylates
exposure to phenolformaldehyde resin (PFR), which
contains more than ten different components capable Allergie contact dermatitis from PF A hardeners
of sensitizing the skin (Bruze 1985). At least some (cross-linkers) and residual polyfunctional acrylates
previous cases of sensititization to PFR have been has been reported from various exposure to solvent-
reported from varnish coatings (Pirilä 1947; Cronin free products (Dahlquist et al. 1983; Cofield et al. 1985;
1980). In these cases the resin itself, rather than Kanerva et al. 1995). Four patients examined by
formaldehyde, was considered to be the sensitizer. Dahlquist et al. developed allergie hand and face
Bruze's investigations later confirmed that formalde- dermatitis from exposure to residual TMPT A in a
hyde is not one of the main sensitizers in PFR (Bruze PFA harden er used in a polyurethane floor top co at-
1985). At the FlOH, one parquet lacquerer developed ing. The PFA contained 3-5% TM PA by weight. One
work-related allergie contact dermatitis, and in patch of the patients reacted even to hardened flooring
testing he reacted to formaldehyde and PFR as well as material that had been stored at room temperature
to melamine formaldehyde resin probably encountered for one month. The patient of Cofield et al. contract-
from contact with different types of formaldehyde ed an extensive dermatitis when exposed to a paint
res ins contained in the lacquers and glues he had used primer (undercoating) used to protect wood siding.
in his work. In addition, a painter was sensitized to His job was to operate a paint line in which large
p-tertiary butylphenol formaldehyde resin from a panels of fiberboard moved via conveyors through
contact glue that he used in his work. automatie paint sprayers. The PFA cross-linker was
made by reacting propyleneimine with TMPT A. On
Acrylic Res;ns patch testing, the patient reacted to the cross-linker
and TMPT A, as well as PET A because of the cross-
Acrylic polymers and copolymers in water-based latex re action between the last-mentioned chemieals. In
paints can contain free monomers. The content of addition to allergie contact dermatitis, PF A hardeners
monomers in lattices is usually less than 0.3%, and can also cause asthma, allergie rhinitis and contact
they may consist of, e.g., butyl acrylate, methyl urticaria (Autio et al. 1993; Kanerva et al. 1995). In the
acrylate, ethyl acrylate, butyl methacrylate, 2-ethyl- FlOH, 11 patients have been detected to have been
hexyl acrylate and methyl methacrylate. All are skin sensitized to a PFA hardener, and seven of them have
irritants and sensitizers (van der Walle 1982; Björkner had allergie contact dermatitis. Six of the patients
1984; Gruvberger et al. 1998). In a Swedish factory were parquet lacquerers who used two-component
manufacturing binders for use in, e.g., water-based solvent-free lacquers. No one reacted to acrylates,
latex paints, three out of 16 occupationally sensitized although gas chromatography/mass spectrometry re-
production workers were allergie to various vealed 0.3% TMPTA in the PFA harden er. According
methacrylates, including 2-hydroxyethyl methacrylate, to the material safety data sheet, the hardener
2-(acetoacetoxy)ethyl methacrylate, N-isobutoxymeth- contained 0.3% dimethylaminoethanol and signifi-
ylacrylamide and glycidyl methacrylate (Gruvberger cantly less than 0.1% free propyleneimine, but the
patients had negative skin tests to the chemie als test substances of 115 flooring installers, of whom four
(Autio et al. 1993; Kanerva et al. 1995). (3.5%) were positive (Bruze et al. 1988a).
Dipropylene Glycol Diacrylate Para-Tertiary-Butylcatechol

Dipropylene glycol diacrylate (DPGDA) is a new
Para-tertiary-butylcatechol (PTBC) is a potential sen-
acrylate sensitizer in UV -curable wood coatings. A
sitizer in the paint industry. It can be considered a
male worker was sensitized to DPGDA by canning a
strong skin sensitizer capable of inducing active
paint containing the chemical. During the canning
sensitization. It is also a skin irritant and a depig-
process, droplets of the paint splashed onto his clothes
menting agent. It is used as a stabilizing agent in
and also contaminated his skin (Estlander et al. 1998).
monomerie styrene, butadiene and vinyl toluene. It
prevents the polymerization of polyester res in, but-
Urethane Resins adiene and PVC. Sensitization and allergie dermatitis
have been reported from various exposures (Estlander
Urethane resins may contain free diisocyanates, whieh et al. 1998).
are usually respiratory irritants and sensitizers that
have caused rhinitis and asthma (Estlander et al. 1992). Unsaturated Polyester Resins
2,4-toluene diisocyanate (TDI) and hexamethylene
diisocyanate (HDI) are important respiratory sensi- Unsaturated polyester (UP) resins are made by
tizers, whereas 4,4' -diphenylmethane diisocyanate condensation of a di- or polyhydric alcohol with a
(MDI) is the most important skin sensitizing diisocy- di- or polybasic acid or anhydride. Propylene, dieth-
anate (Estlander et al. 1992). Two-component systems ylene or ethylene glycol are the most common alcohols
in which addition of a diisocyanate to the polyhydroxyl and phthalic, maleie or fumaric acid the most common
compound immediately before use carry the greatest acids used in the manufacture of UP resins. The curing
risk of skin sensitization. Partial polymerization of re action occurs when an unsaturated cross-linking
diisocyanates to increase molecular weight and reduce monomer such as styrene or methyl methacrylate, and
volatility are used to decrease the risk of sensititization an oxidizing catalyst, most often benzoyl peroxide, are
(Mathias 1984). See also the chapter on polyurethane mixed together. In addition, many potentially sensi-
resins in this book. tizing auxiliary compounds, including pigments, fill-
ers, inhibitors, accelerators, UV -protecting agents,
Other Synthetic Resins stabilizers and flame retardants, are used to manufac-
ture UP resin for different purposes. UP resins have
No cases of sensitization have been reported from been extensively used for coatings, finishes, cements
alkyd resins. Cyclohexanone resin (C-R) has caused and glues, as well as in the reinforced-plastics industry.
allergie contact dermatitis in painters and floor Allergie dermatitis has been reported e.g., from paints
installers (Högberg and Wahlberg 1980; Bruze et al. and cements, and the causative agents have been the
1988a). C-R is not a chemically defined compound but auxiliary ingredients and cross-linking agents of UP
consists of cyclohexanone and several other substances resins. Between 1974 and 1990, four men investigated
formed when the resin is manufactured. The sensi- at the FIOH contracted allergie dermatitis from car-
tizer(s) responsible for contact allergy to C-R have not repair painting where they were exposed to UP-resin
been identified, but they are probably to be found cements (Tarvainen et al. 1993). Later, two more cases
among the monomers and dimers formed when were detected from similar exposures (Kanerva et al.
cyclohexanone is condensed in the production of 1999). Allergie reactions were found to UP-resin
C-R. Four of the five C-R-sensitive patients of Bruze chemie als of the cements. None were positive to
et al. (1988a) also reacted to perfume mixtures and auxiliary or cross-linking chemieals of the cements.
colophony. However, colophony and other natural Diethylene glycol maleate (DGM) was purified and
res ins were not the ingredients of the relevant paints, identified as an allergen from the UP resin of a cement.
suggesting that the simultaneous reactions to C-R, DGM was detected in both uncured and cured UP resin
colophony and perfume mixtures possibly indieated (Tarvainen et al. 1993).
the presence of the same or similar sensitizers or cross-
reactants in the test substances. One paint (Pansar), Turpentine and Other Natural Products
probablyalso containing C-R, was already included in
a painter's standard series used to patch test 189 Until the 1980s, turpentine was the principal solvent
painters at the end of the 1970S, and four of them and thinner in paints and the main cause of irritant
(2.1%) were positive to the paint (Högberg and and allergie dermatitis among painters. It is an extract
Wahlberg 1980). C-R was also included in the patch- of pine trees, and its chief components are terpene
hydrocarbons. Alpha-pinene and beta-pinene are the considered to be a rare and weak contact sensitizer
main ingredients, but some products contain also (Piper 1965). Sensitivities to shellac, dammar and tung
delta-carene and camphene (Vente and Fuchs 1997). oil mayaiso occur (Pirilä 1947; Schwartz et al. 1957).
The sensitizing potential of turpentine depends on its Colophony (rosin, pine rosin, wood rosin) is ob-
geographical source, method of extraction and the tained from various species of pine tree. It has a
presence of oxidation products (Mathias 1984). Tur- complex chemical composition, of which about 90% is
pentine peroxides, especiaily delta-carene, have been resin acids and the rest is corresponding esters,
considered to be the main sensitizers in turpentine aldehydes and alcohols. Two main types of acids
(Pirilä 1947; Pirilä et al. 1969; Cronin 1980). The occur: abietic acid with conjugated double bonds and
content of turpentine oxides is high, e.g., in the pimaric acid with non-conjugated double bonds.
turpentine from Finland, Sweden, Russia, India and Colophony is not used alone as a drying res in but is
Indonesia, whereas oil of turpentine from Portugal, used to modify other resins, such as alkyds. Colophony
Spain and southern France contains less delta-carene, is an important contact sensitizer, but the esterification
and the gum turpentine from the USA contains of organic acids in colophony with alcohol groups in
practically no delta-carene (Mathias 1984; Vente and alkyd resins reduces its allergenieity. Rosin esters can
Fuchs 1997; Ippen 1998). be used in paints and varnishes (Mathias 1984; Fischer
At the FlOH, between 1974 and 1997, 11 cases of and Adams 1990; Sadhra et al. 1994). See the chapter
allergic contact dermatitis primarily caused by turpen- on colophony in this book.
tine have been detected, but none of these were among About 10 years ago, citrus solvent (D-limonene) and
painters. Turpentine is still used in some countries, the racemic form of dipentene in concentrations of
e.g., in Portugal; its main sensitizers are dipentene and 20-100% found new applications because they are able
alpha-pinene (Moura et al. 1994; Cachao et al. 1986; to replace chlorinated hydrocarbons, chlorofluorocar-
Romaguera et al. 1983). In the 1990S, dipentene, which bons and other organic solvents as less toxic substanc-
is a racemic mixture of D-limonene and L-( - )limonene es. D-limone has usually been used as a perfume and
has been offered for sale as solvent for the paint perfume additive in concentrations of 0.005-1%.
industry (Karlberg et al. 1992; Karlberg et al. 1997; Products containing up to 95% D-limonene can be
Ippen 1998). Allergie contact dermatitis due to dipen- used in factories for degreasing metal surfaces before
tene in a paint thinner, honing oil and car polish have painting. D-limonene is the main ingredient of the oil
been reported (Cainan 1979; Rycroft 1980; Martins from several citrus fruits and it also occurs in caraway,
et al. 1995). dill and celery. It is obtained as a by-product from the
Artists and craftsmen mayaiso use turpentine or citrus-juice industry. The distillate, peel oil, usuaily
related terpenes (Mathias 1984; Pürchel et al. 1995). A contains more than 95% D-limonene (Karlberg and
male artist developed widespread allergic contact Dooms-Goossens 1995; Ippen 1998). The contaminants
dermatitis from sensitization to turpentine and epoxy reported are other terpenes such as alpha- and beta-
resin in an oil paint (Conde-Salazar et al. 1982). In pinene, sabinene, myrcene, delta-carene, camphene,
addition to the perfume industry, oil of turpentine is and gamma-terpinene. The oxidation products of
also used in the manual coloring of pottery and D-limonene, e.g., limonene oxide, L-carvone and
porcelain crafting. A porcelain painter with hand limonene hydroperoxides, found after prolonged air
dermatitis had used oil of turpentine and lavender or exposure of D-limonene, are potent sensitizers (Karl-
anise oils for mixing of pigments. On patch testing, she berg et al. 1992; Karlberg et al. 1994), whereas the
reacted to turpentine, fragrance mixtures, colophony, sensitizing potential of D-limonene itself has been
lavender and anise oil. The reactions to lavender and shown to be low (KarIberg et al. 1991). In the study of
anise oils as weil as to fragrance mixtures and KarIberg et al. (1992), five main oxidation products -
colophony were considered to be due to a group carvone, the cis and trans isomers of limonene oxide-
reaction to the terpene hydrocarbons which can be (1,2) and of carveol, were identified. Of these, (R)-
found in lavender and anise oils, as weIl as in many ( + )carvone and a mixture of cis and trans isomers of
essential oils (Bauer et al. 1988; Lear et al. 1996; Vente limonene oxide-(1,2) were found to be potent sensi-
and Fuchs 1997). tizers. Carvone is the main constituent of spearmint
Naturally drying oils are regarded as products with used in toothpastes. It has caused positive patch-test
low sensitizing capacity. Linseed oil was previously reactions in patients, who experience sore mouth,
commonly used for enamels and interior paints. Some stomatitis and dermatitis on perioral region (Andersen
new natural paints may contain linseed oil. According 1978). In a two-center study where 1318 dermatitis
to the information obtained from the material data patients in Stockholm and 1482 patients in Leuven
sheets of two Finnish manufacturers, such paints can (Belgium) were tested with D-limonene hydroperox-
be composed of linseed oil varnish, colored pigments ides, positive reactions were obtained in 2-4% and 1.1%,
and turpentine or white spirits. Linseed oil has been respectively. The number of positive reactions was
comparable with the number of reactions with, for who were patch tested during a study performed in a
example, epoxy res in, formaldehyde and p-phenylene- Swedish factory manufacturing such binders were
diamine (Karlberg and Dooms-Goossens 1995). Ac- allergic to the chemical. Four of the workers had
cording to Karlberg and Dooms-Goossen (1995), the spilled the preservative containing chloromethyl is-
increased domestic and industrial use of high concen- othiazolinone on their skin, resulting in chemical
trations of D-limonene-containing allergenic oxidation bums and allergic contact dermatitis (Gruvberger et al.
products might result in contact sensitization and 1998). In the FlOH, one worker had allergic contact
dermatitis. dermatitis from chloromethyl isothiazolinone used as a
slimicide in a vamish (unpublished). Airbome allergic
Additives contact dermatitis has also been reported in a chloro-
methyl isothiazolinone-allergic patient from exposure
Biocides to the chemical used as a preservative in ahorne
decoration paint (Finkbeiner and Kleinhans 1994).
Biocides are the second most common cause of allergic Chloromethyl isothiazolinone is a potent allergen
contact dermatitis after synthetic resins. The problem which has caused sensitization in concentrations as
of sensitization to biocides has become more common low as 7 ppm in stay-on cosmetics, especially when,
because of the increased use of water-based latex e.g., moisturizing creams are applied to damaged skin
paints. Table 5 gives a list of the biocides used in (Groot and Weyland 1988). The active ingredients
paints. Similar biocides are also used in the glues are a mixture of two isothiazolinones: methylchloro-
needed by wall paper hangers. isothiazolinone and methylisothiazolinone. The desig-
nation ofKathons and the recommended concentration
Isothiazolinones of the active ingredients varies according to their
intended use (Cronin et al. 1988). The isothiazolinone
Isothiazolinones are commonly used preservatives in
derivatives have more than 30 trade names, including
water-based paints (Fischer et al. 1995; Geier et al.
Kathon CG, Kathon 886 MW, Kathon LX, Acticide,
1996). Of 202 construction painters in Sweden (Fischer
Euxyl K 100, GR856 lzolin, Parmetol K50, Fennosan
et al. 1995), 13 had positive patch-test reactions to these
IT21, Bactrachem IB, Mergal V640 and Metatin K520
biocides; five reacted to chloromethyl isothiazolinone,
(Cronin et al. 1988; Hunziker 1992; Gruvberger et al.
seven to benzisothiazolinone (BIT) and one to 2-n-
1998).
octylisothiazolinone. In six of these 13 patients, an
In Sweden, benzisothiazolinone has been leading
isothiazolinone was the responsible allergen for their
preservative which has been incorporated in most
hand eczema. Chloromethyl isothiazolinone is used as
Swedish water-based paints and putties at concentra-
a preservative in binders used in latex paints. Three of
tions of up to 0.025%. Many cases of sensitization from
the former 11 workers and 12 of the present 76 workers
various exposures to the chemical have been reported.
1,2-benzisothiazolin-3-one (1,2-BIT, Proxel) has caused
Table 5. Examples of biocides used in paints and glues (Fischer
and Adams 1990; Geier et al. 1996)
sensitization to workers in an industry manufacturing
plastic emulsions (Pedersen 1976), in the paper indus-
Biocide Paint Glue try (Cronin 1980), in a rubber factory (Foussereau
et al. 1984), a paint factory (Sanz-Gallen et al. 1992)
Bronopol Yes Yes and the pottery industry (Roberts et al. 1981), as well as
Chlorocresol Yes No
Chloroacetamide Yes No to workers using a fine-art paint (Greig 1992), a
1,2-Benzisothiazolinon-3-one Yes Yes wallpaper hanger (Damstra et al. 1992) and cutting oils
2-Chlor-N-hydroxymethyl acetamide Yes Yes (Brown 1979; Alomar et al. 1985; Foulds and Koh 1990;
Zineb Yes No
2-n-Octyl-4-isothiazolin-3-one Yes No Damstra et al. 1992).
5-Chloro-2-methyl-4-isothiazolin-3-one Yes Yes N-octyl-isothiazolinone (Skane M-8) has been used
Biopan P 1487 Yes Yes mainly as a mildewcide in latex paints and sometimes
Biopan CS 1246 Yes Yes
Biopan CS 1135 Yes Yes also in oil-base paints. It is stabilized by the addition of
1,2-Dibromo-2,4-dicyanobutane Yes Yes either zinc oxide or formaldehyde in slightly alkaline
o-Phenylphenol Yes Yes formulation. Skane M-8 is supplied as 50% concentrate
Benzylhemiformal Yes Yes
Propylene glycol hemiformal Yes Yes in propylene glycol which contains about 45% active
Hexahydro-l ,3,5-triethyl-s-triazine Yes ingredients and 5% impurities for use as a paint
2-(4-Thiazolyl)benzimidazole Yes mildewcide. n-Octyl-isothiazoline is also marketed as
Tributyltin oxide Yes No
N-{Trichloromethylthio )phthalimide (Folpet) Yes Kathon 4200 and Kathon LM, and is supplied as 25%
N-(Trichloromethylthio )-4-cyciohexane-l ,2- Yes and 5% concentrates for use as a mildewcide for
dicarboximide (Captan) fabrics. The same active ingredient is also marketed as
Formaldehyde in raw materials Yes Yes
Kathon 893 and recommended as an industrial mul-
tipurpose bioeide and mildeweide, e.g., in adhesives, Airborne allergic contact dermatitis has also been
wood preservatives, metal-working fluids, paints and reported in a chloracetamide-sensitive patient from
stains (Mathias et al. 1983; Emmett et al. 1989). exposure to a home-decorating paint containing the
Allergic contact dermatitis caused by n-octyl-iso- chemical as a preservative (Finkbeiner and Kleinhans
thiazolinone has been reported in paint-factory work- 1994).
ers who had been exposed to the chemical as dye
Euxyl K400
mixers (Thormann 1982; Mathias et al. 1983). It is
chemically related to 1,2-benzisothiazolin-3-one. One Euxyl K400 is a rather new preservative which has in
of the seven Swedish construction painters who were many cases replaced chloromethyl isothiazolinone as a
patch-test positive to 1,2-benzisothiazolin-3-one also less sensitizing alternative, e.g., in toiletries, cosmetics
reacted to n-octyl-isothiazolinone (Fischer et al. 1995). and detergents (Bruze et al. 1988a; Aalto-Korte et al.
Cross-allergy between n-octyl-isothiazolinone and 1996). It consists of two active ingredients, 2-phen-
chloromethyl-isothiazolinone has not been demon- oxyethanol (PE) and 1,2-dibromo-2,4-dicyanobutan
strated (Emmett et al. 1989). (BCB) of which the last one is the main sensitizer in
the product (Fuchs et al. 1991; Aalto-Korte et al. 1996).
Formaldehyde and Formaldehyde Releasers
Allergic dermatitis has been reported from masseur
Formaldehyde was previously used as a biocide. ointments and cleansing agents (Fuchs et al. 1991;
Nowadays, small amounts of formaldehyde can be Aalto-Korte et al. 1996). As a product with the trade
present in many water-based products, either as a name Tektamer 38, it has caused allergic dermatitis
contaminant from the raw material or from the from exposure to a paste glue. Tektamer 38 can also be
formaldehyde-liberating compounds contained in the used in latex paints, metal-working fluids, joint
paints (Dahlquist and Fregert 1978). Bronopol and cements and other adhesives (Mathias 1983).
Preventol ON are formaldehyde releasers used to Chlorocresol
preserve, for example, binders intended for use in
water-based latex paints (Gruvberger et al. 1998). Chlorocresol, or p-chloro-m-cresol, e.g., Preventol
Benzylhemiformal, propylene glycol hemiformal, Bio- CMK, is a rare sensitizer which can be used in
pan P 1487, Biopan CS 1246, Biopan CS 1135 and adhesives, glues, inks, paints and varnishes, in addition
methylen-bis-5-methyl-oxazolinone are other exam- to packaging materials, textile finishes, leather and
pIes of such biocides used in paints (Geier et al. 1996). tanning agents, industrial oils and emulsions, cosmet-
A painter has been reported to be allergic to formal- ics and medications (Dooms-Goossens et al. 1981).
dehyde and benzyl alcohol mono(poly)hemiformal,
Chlorothalonil
but he had no hand eczema (Würbach et al. 1993). Two
other formaldehyde releasers, chloromethoxy propyl- Tetrachloroisophthalonitrile (chlorothalonil), a fungi-
mercuric acetate and 2-( (hydroxymethyl)amino )etha- eide for agricultural and hortieultural purposes, can
nol have caused allergic contact dermatitis in also be used for other purposes. It is a skin irritant and
wallpaper hangers from exposure to a wa1lpaper paste asensitizer. It has caused various skin affections,
containing the chemicals (Tanaka and Lucas 1984). In including contact dermatitis to workers in the pro-
the FlOH, three painters and one parquet installer had duction of the fungieide. Allergic dermatitis has been
been sensitized to formaldehyde (unpublished). reported from exposure to the chemieal used as a wood
preservative (Bach and Pederson 1980; Spindeldreir
Chloracetamides
et al. 1980; Johnsson et al. 1983) and as a pestieide in
Chloracetamide and N-methylol-chloracetamide have paints (Meding 1986; Liden 1990).
caused occasional cases of sensitization from cosmeties, N-( trichloromethylthio )phthalimide (Folpet, Fungi-
metal-working fluids, glues and a spin finish (Klascha trol, Cosan P, Phaltal) is a pesticide sensitizer (Lisi
1975; Suhonen 1983; Hjorth 1979; Dooms-Goossens et al. et al. 1986). Solitary cases of sensitization in painters
1981; Pedersen and Fregert 1976; Savage 1978). Chlor- have also been reported (Fischer et al. 1995).
acetamide was also the main contact allergen in Swedish
Butylated Hydroxytoluene
house painters in 1978 from exposure to water-based
glues (Wahlberg et al. 1978). It has also caused allergic Butylated hydroxytoluene (BHT), 2,6-di-(tert-butyl)-
dermatitis in a paint factory to a forklift driver who also p-cresol is a commonly used antioxidant. The Danish
re ac ted to Mergal K6N containing N-methylol-chlor- Product Register (PROBAS) had registered BHT in 400
acetamide. The patient was also allergie to Skane M-8 products by March 1990. The main categories were
and Algon 100, containing a chemical possibly similar to one- and two-component paints and lacquers
chloracetamide (Jones and Kennedy 1988). Cross-reac- «25 ppm), hardeners for two-component paints,
tions between the two chloracetamides are also possible glues, fillers, etc. (>10 ppm) and binders for paints,
(Jones and Kennedy 1988; Hjorth 1979; Farli et al. 1987). glues and fillers, etc. (0-2000 ppm) (Flyvholm and
Menne 1990). Allergie contact dermatitis due to BHT Paint and Varnish Removers
has been reported only in solitary cases (White et al.
1984; Bardazzi et al. 1988; Dissanauke and Powell Dibutyl thiourea (DBTU) is a chemie al used in paint
1989). BHT is extensively used in both industrial and and glue removers. Two workers were sensitized to the
consumer products. No positive patch-test reactions to chemical when using a paint remover, namely Stripper
BHT were seen in 1336 consecutive eczema patients in a 100. Both had dermatitis on their faces, and one also
Danish investigation. The risk of allergie contact on his hands and lower arms. One of the patients
dermatitis can be regarded as low when products removed polyurethane from a metal coil and the other
contain BHT in normally used concentrations (Flyv- a paint from metal pieces. Both were patch-test
holm and Menne 1990). negative to other allergens including MD!, epoxy
resins, methacrylates and other chemieals in the
Other Additives plastics and glues series (Kanerva et al. 1984; Kanerva
et al. 1998). DBTU is also a rubber allergen and has
Hardeners such as amines and anhydrides include caused allergie contact dermatitis from exposure to
many sensitizers. See the sections on epoxy, acrylate various rubber articles, including divers' foot gear
and and urethane resins. Triethylamine may irritate (Foussereau et al. 1982), swimmimg goggles (Alomar
and sensitize (Bittersohl and Heberer 1978). Benzoyl and Vilatella 1985), rubber elastic knee guards (Rom-
peroxide, p-methoxy phenol and hydroquinone are aguera et al. 1988), protective plastie glasses (Romagu-
used as accelerators and inhibitors of polymerization era et al. 1988) and the thermocoating layer of phone
(see the chapters on epoxy resin compounds and cards (Schmid-Grendhelmeir and Elsner 1995).
acrylics in this book). Of the other additives, dioctyl
sodium sulfosuccinate, a surfactant, is a potential, rare Miscellaneous
sensitizer (Fischer 1986), as are dibutyl phthalate and
triphenyl phosphate, used as plasticisers (Hjorth 1964). Protective gloves, especially rubber gloves made of
natural rubber latex or synthetic rubber (e.g., neoprene
Metals and Metal Salts rubber), as well as rubber parts of respiratory masks
used with certain industrial solvent-based paints
Chromate corrosion inhibitors such as zinc chromate should also be remembered as potential causes of
in primer paints have caused allergie contact derma- sensitization in painters. Preservatives in barrier
titis in painters (Engel and Calnan 1963; Piper 1965). creams, hand ointments and hand cleansers are other
Cobalt in paint dryers is a potential sensitizer (Pirilä potential causes of dermatitis (Mathias 1984; Estlander
1947; Piper 1965; Wehle 1966). et al. 1994, 1996a,b).
In the FlOH between 1974 and 1990, three painters
and a tinter in a paint factory were primarily sensitized
to chromates and two to cobalt (unpublished). Since
Investigations
then, no new cases have been found.
Nickel has caused sensitization, e.g., from contact
with nickel-plated tool handles (Fischer et al. 1995). The investigations should include a detailed work
Allergie contact dermatitis has also been reported from history and exploring of exposing chemieals, exami-
exposure to a powder paint containing niekel (Bannar- nation of the site and course of dermatitis, and patch
Martin and Rycroft 1990). A female nickel-allergie testing, keeping in mind the worker's individual
decoration painter, investigated at the FlOH, noted exposure. In addition to the test substances contained
worsening of her sentitization from exposure to nickel in the European standard series (e.g., Hermal, Kurt
in the paint she used (unpublished). Herrmann, Rhinebeck, Germany; TRUE test, Pharma-
Phenyl mercuric derivatives have previously caused cia Research center AS, Denmark; Chemotechnique
some skin damage to painters (Piper 1965). Mercury Diagnosties AB, Malmö, Sweden), aseries of epoxy
has also caused sensitization from exposure to an chemicals (see also the chapter on epoxy resins in this
interior latex paint (Agoes et al. 1990). book), plastics and glues also containing MD!, TD! and
HD! (Estlander et al. 1992), aseries of antimicrobials
Pigments containing active ingredients of Euxyl K 400 and an
extensive rubber-chemieal series also containing thio-
Because the pigments in paints and coatings occur as urea compounds (Kanerva et al. 1994a). Patch testing
insoluble particles, they very seldom sensitize, with the should be supplemented with test substances made of
exception of chrornates (see the section on metals). actual paints the patient has been exposed to and with
Organic pigments, especially azo derivatives, should be the ingredients of the paint according to the exposure
considered as potential skin sensitizers (Mathias 1984). history. Patch tests should also include materials of all
polymer gloves used at work and rubber parts of Careful working techniques, especially in the pre-
masks or tools, hand creams and cleansers used at vention of paint splashes from coming into contact
work. Material data sheets are useful in clearing the with skin, are essential. Paint splashes should be
exposure, but often the information given is too scarce removed as soon as possible, using paper or fabric
(Kanerva et al. 1997). Contact with manufacturers or tissues, and the skin should be washed with appropri-
distributors will probably give more detailed informa- ate skin cleansers. Organic solvents should be used
tion on the ingredients, but sometimes chemical only temporarily. Skin moisturizers should be used
analysis of a suspected product is necessary to daily to prevent drying of the skin. White petrolatum is
determine the actual sensitizer (Tarvainen et al. 1993; a rather effective barrier and greatly facilitates skin
Kanerva et al. 1997). cleansing (Mathias 1984).
In addition, depending on the type of chemicals and
type of exposure, the respiratory tract should also be
Prevention
protected against inhalation of airborne contaminants,
which can be in the form of particles, vapors or gases.
Personal protective equipment (PPE) is important in Also, hearing protectors should not be forgotten. The
the prevention of hazards caused by handling paints, need to use hearing protectors starts when the noise
lacquers and varnishes. In order to ensure the best level, in spite of engineering control measures, exceeds
possible protection, the selection and use of equipment the national limit value, which is 90 or 85 dB in many
should be carefully planned. If the use of PPE is countries (Korhonen 1997).
neglected, it can impair work and have harmful effects
on the worker. PPE includes safety heImets, eye and
face protectors, hearing protectors, respiratory protec-
tive equipment, protective gloves, safety footwear and References
other protective clothing, as well as fall-arresting
systems. The workers' own cloth es should be appro- Aalto-Korte K, Jolanki R, Estlander T, Alanko K, Kanerva L
priately protected. Overalls or separate long-sleeved (1996) Occupational allergie contact dermatitis caused by
Euxyl K 400. Contact Dermatitis 35:193-194
shirts or coats or long pants made of cotton fabrics or Adams RM, Fregert S, Gruvberger B, Maibach HI (1976) Water
blends of cotton and synthetic tibers should be used, as solubility of zinc chromate primer paints used as antirust
well as caps or safety heImets to protect the head. Hand agents. Contact Dermatitis 2:357-358
Agocs MM, Etze! R, Gibson-Parrish R, Paschal C, Campagna PR,
protection with appropriate gloves is essential. Long- Cohen S, Kilbourne EM, Hesse JL (1990) Mercury exposure
sleeved protective gloves made of PVC or rubber from interior latex paint. N Engl J Med 323:1096-1101
materials (natural or synthetic) or combinations of Alomar A, Vilatella I (1985) Contact dermatitis to dibutylthiourea
in swimming goggles. Contact Dermatitis 12:348-349
leather and cotton, or disposable cotton gloves, Alomar A, Conde-Salazar L, Romaguera C (1985) Occupational
depending on the type of paints handled, should be dermatoses from cutting oils. Contact Dermatitis 12:129-138
used (Estlander and Jolanki 1988; Estlander et al. Andersen K (1978) Contact allergy to toothpaste flavors. Contact
1996b; Mellström and Boman 1997). Depending on Autio P, Estlander T, Jolanki R, Keskinen H, Kanerva L (1993)
the type of work and the work site, protective footwear Allergy caused by aziridine hardeners (in Finnish). Duodecim
mayaiso be necessary. Protection of eyes using 109:125-130
Bach B, Pedersen NB (1980) Contact dermatitis from a wood
spectacles, goggles, visors, or hoods, e.g., against preservative containing tetrachloroisophtl1alnitrile. Contact
mechanical impacts, dust and gaseous materials, Dermatitis 6:142
should also be used when necessary (Korhonen 1997). Bannar-Martin BR, Rycroft RJG (1990) Nickel dermatitis from a
powder paint. Contact Dermatitis 22:50
When highly sensitizing epoxy paints or UV -radia- Bardazzi F, Misciali C, Borrello P, Capobianco C (1988) Contact
tion-curable acrylate coatings are used, special protec- dermatitis due to antioxidants. Contact Dermatitis 19:385-386
tive gloves and disposable overalls should be used. Bittersohl G, Heberer H (1978) Zur Toxicität von aliphatischen
Aminen. Z Gesamte Hyg 24:529-534
Separate areas for work clothes and private clothes and Björkner B (1984) Sensitizing capacity of ultraviolet curable
footwear are necessary. Control of the UV -radiation acrylic compounds (thesis). University of Lund, Lund, pp
curing process is also necessary, as well as regular 1-77
Boke!und F, Fregert S, Trulsson L (1980) Sensitization from
industrial hygiene assessment to prevent chemicals in epoxy powder of high molecular weight. Contact Dermatitis
aerosols or vapors from coming into contact with the 6:144
airways and the skin. Special preventive measures Brown R (1979) Concomitant sensitization to additives in a
coolant fluid. Contact Dermatitis 5:340-341
must also be taken when paints containing low- Bruze M (1985) Contact sensitizers in resins based on phenol and
molecular-weight epoxy compounds are handled formaldehyde (thesis). University of Lund, Lund, pp 1-200
(Holmes et al. 1993). A single exposure, e.g., a paint Bruze M, Gruvberger B, Agrup G (1988a) Sensitization studies in
tl1e guinea pig witl1 active ingredients of Euxyl K® 400.
splash onto the skin or absorbed in a worker's clothes Contact Dermatitis 18:37-39
next to the skin, may lead to primary sensitization and Bruze M, Boman A, Bergqvist-Karlsson A, Björkner B, Wahl-
allergic eczema (Kanerva et al. 1994b). berg JE, Voog E (1988b) Contact allergy to a cyclohexanone
resin in humans and guinea pigs. Contact Dermatitis 18: Fischer T, Adams RM (1990) Paints, varnishes, and laquers. In:
46-49 Adams RM (ed). Occupational skin disease, 2nd edn.
Cachao P, Menezes Brandao P, Carmo M, Frazao S, Silva M (1986) Saunders, Philadelphia, pp 426-438
Allergy to oil of turpentine in Portugal. Contact Dermatitis Fischer T, Bohlin S, Edling C, Rystedt I, Wieslander G (1995)
14:205-208 Skin disease and contact sensitivity in house painters using
Calnan CD (1979) Allergy to dipentene in paint thinner. Contact water-based paints, glues and putties. Contact Dermatitis
Dermatitis 5:123-124 32:39-45
Calnan CD, Stevenson q (1963) Studies in contact dermatitis Flyvholm M-A, Menne T (1990) Sensitizing risk of butylated
(XV). Dental materials. Trans St Johns Hosp Dermatol Soc hydroxytoluene based on exposure and effect data. Contact
49:9-26 Dermatitis 23:341-345
Cofield BG, Storrs FJ, Strawn CB (1985) Contact allergy to Foulds IS, Koh D (1990) Dermatitis from metal working fluids.
aziridine paint hardener. Arch Dermatol 121:373-376 Clin Exp DermatoI15:157-162
Conde-Salazar L, Romero L, Guimaraens D, Harto A (1982) Foulds IS, Koh D (1992) Allergic contact dermatitis from resin
Contact dermatitis in an oil painter. Contact Dermatitis hardeners during manufacture of thermosetting coating
8:209-210 paints. Contact Dermatitis 26:87-90
Cronin E (1979) Oil of turpentine - a disappearing allergen. Foussereau J, Herve-Bazin B, Cavelier C, Certin JF (1982) Ein Fall
Contact Dermatitis 5:308-311 einer Allergie gegenüber Dibutylthioharnstoff in Taucher-
Cronin E (1980) Contact dermatitis. Churchill Livingstone, Fusslingen. Derm Beruf Umwelt 30:58-59
Edinburgh, pp 614-621 Foussereau J, Brändle I, Boujnah-Khouadja A (1984) Allergisches
Cronin E, Hannuksela M, Lachapelle J-M, Maibach HI, Malten K, Kontaktekzem durch Isothiazolin-3-on-Derivative. Derm Be-
Meneghini CL (1988) Frequency of sensitization to the ruf Umwelt 32:208-211
preservative Kathon® CG. Contact Dermatitis 18:274-279 Fuchs T, Enders F, Przybilla B, Ippen H, Aberer W, Bauer R,
Dahlquist I, Fregert S (1978) Formaldehyde releasers. Contact Böhm I, Schulze-Dirks A, Frosch PJ, Peters K-P, Steffan
Dermatitis 4:173 M-A, Wassilew SW, Hensel 0, Gehring W, Lischka G,
Dahlquist I, Fregert S, Trulson L (1983) Contact allergy to Agathos M, Breit R, Bahmer F, Stary A, Brasch J (1991)
trimethylolpropane triacrylate (TMPTA). Contact Dermatitis Contact allergy to Euxyl K 400, results of a multi-center
9:122-124 study of the German Contact Allergy Group (DKG). Derm
Damstra RJ, van Vlotten W A, van Ginkel qw (1992) Allergie Beruf Umwelt 39:151-153
contact dermatitis from the preservative 1,2-benzisothiazolin- Garabrant DH (1985) Dermatitis from aziride hardener in
3-one (1,2-BIT; Proxel®): a case report, its prevalence in those printing ink. Contact Dermatitis 12:209-212
occupationally at risk and in general dermatological popu- Geier J, Kleinhans D, Peters K-P (1996) Kontaktallergien durch
lation, and its relationship to allergy to its analogue Kathon® industriell verwendete Biozide. Egebnisse des Informations-
CG. Contact Dermatitis 27:105-109 verbunds Dermatologicher Kliniken (IVDK) und der Deutsc-
De Groot AC, Weyland JW (1988) Kathon CG: a review. J Am hen Kontaktallergiegruppe. Derm Beruf Umwelt 44:154-159
Acad Dermatol 18:350-358 Goh CL (1985) Irritant dermatitis from tri-N-butyl tin oxide in
Dissanayake M, Powell SM (1989) Allergie contact dermatitis paint. Contact Dermatitis 12:161-163
from BHT in leg ulcer patients. Contact Dermatitis 21:195 Greig DE (1991) Another isothiazolinone source. Contact Der-
Dooms-Goossens A, Degreef H, Vanhee J, Klerkhofs I, Chrispeels matitis 25:201-202
MT (1981) Chlorocresol and chloracetamide: allergens in Gruvberger B, Bruze M, Almgren G (1998) Occupational
medications, glues, and cosmetics. Contact Dermatitis 1:51-52 dermatoses in a plant producing binders for paints and
Dooms-Goossens A, Bedert R, Vandaele M, Degreef H (1989) glues. Contact Dermatitis 38:71-77
Airborne contact dermatitis due to triglycidylisocyanurate. Hansen MK, Larsen M, Cohr K-H (1987) Waterborne paints, a
Contact Dermatitis 21:202-203 review of their chemistry and toxieology and the results of
Emmett EA, Ng SK, Levy MA, Moss JN, Morici IJ (1989) The determinations made during their use. Scand J Work Environ
irritancy and allergenity of 2-n-octyl-4-isothiazolin-3-one Health 13:473-485
(Skane M-8®), with recommendations for patch test con- Hjorth N (1964) Contact dermatitis from cellulose acetate film.
centration. Contact Dermatitis 20:21-26 Berufsdermatosen 12:86-100
Engel HO, Calnan CD (1963) Chromate dermatitis from paint. Br J Hjorth N (1979) N-methylol-chloracetamide, a sensitizer in
Ind Med 20:192-198 coolant oils and cosmeties. Contact Dermatitis 5:330-331
Estlander T, Jolanki R (1988) How to protect the hands. Dermatol Högberg M, WaiJlberg JE (1980) Health screening for occupa-
Clin 6:105-114 tional dermatoses in house painters. Contact Dermatitis
Estlander T, Keskinen H, Jolanki R, Kanerva L (1992) Occupa- 6:100-106
tional dermatitis from exposure to polyurethane chemicals. Holmes N, Pearce P, Simpson G (1993) Prevention of epoxy resin
Contact Dermatitis 27:161-165 dermatitis: failure of manufacturers to use available research
Estlander T, Jolanki R, Kanerva L (1994) Protective gloves. In: information. Am J Ind Med 24:605-617
Menne T, Maibach HI (eds) Hand eczema. CRC, Boca Raton, Hunziker N (1992) The 'isothiazolinone story'. Dermatology
pp 311-321 184:85-86
Estlander T, Jolanki R, Kanerva L (1996a) Rubber glove derma- Ippen H (1998) Limonen - Dipenten, Citrus-Öle und Citrus-
titis: a significant occupational hazard - prevention. Curr Terpene. Teil I: Allgemeines, Vorkommen, Verwendung,
Probl Dermatol 2s:I70-181 Penetration, Kinetik, Metabolismus. Derm Beruf Umwelt
Estlander T, Kanerva L, Kari 0, Jolanki R, Mölsä K (1996b) 46:18-25
Occupational conjunctivitis associated with type IV allergy to Johnsson M, Buhagen M, Leira HL, Solvang S (1983) Fungicide-
methacrylates. Allergy 51:56-59 induced contact dermatitis. Contact Dermatitis 9:285-288
Estlander T, Kostiainen M, Jolanki R, Kanerva L (1998) Active Jolanki R (1991) Occupational skin diseases from epoxy com-
sensitization and occupational allergic contact dermatitis pounds, epoxy resin compounds, epoxy acrylates and 2,3-
caused by para-tertiary-butylcatechol. Contact Dermatitis epoxypropyl trimethyl ammonium chloride (thesis). Acta
38:96-100 Derm Venereol Suppl (Stockh) 159:1-80
Farli M, Ginanneschi M, Francalanci S, Martinelli C, Sertoli A Jones SK, Kennedy CTC (1988) Chloracetamide as an allergen in
(1987) Occupational contact dermatitis to N-methylol-chlor- the paint industry. Contact Dermatitis 18:304-305
acetamide. Contact Dermatitis 17:182-184 Kanerva L, Jolanki R, Plosila M, Estlander T (1984) Contact
Finkbeiner H, Kleinhans D (1994) Airborne allergic contact dermatitis from dibutylthiourea. Report of a case with fine
dermatitis caused by preservatives in home-decorating structural observations of epicutaneous testing with
paints. Contact Dermatitis 31:275-276 dibutylthiourea. Contact Dermatitis 10:158-162
Kanerva L, Estlander T, Jolanki R (1988) Sensitization to patch Martins C, Concalo M, Concalo S (1995) Allergie contact
test acrylates. Contact Dermatitis 18:10-15 dermatitis from dipentene in wax polish. Contact Dermatitis
Kanerva L, Estlander T, Jolanki R, Pekkarinen E (1992) Occupa- 33:126-127
tional pharyngitis associated with allergie patch test reactions Mathias CGT (1~83) Contact dermatitis to a new biocide
from acrylics. Allergy 47:571-573 (Tektamer 38 ) used in a paste glue formulation. Contact
Kanerva L, Estlander T, Jolanki R (1994a) Occupational allergie Dermatitis 9:418
contact dermatitis caused by thiourea compounds. Contact Mathias CGT (1984) Dermatitis from paints and coatings.
Dermatitis 31:242-248 Dermatol Clin 2:585-602
Kanerva L, Tarvainen K, Pinola A, Granlund H, Estlander T, Mathias CGT (1988) Allergic contact dermatitis from triglycidyl
Jolanki R, Förström L (1994b) A single accidental exposure isocyanurate in polyester paint pigments. Contact Dermatitis
may result in chemieal burn, primary sensitization and 19:67-68
allergic contact dermatitis. Contact Dermatitis 31:229-235 Mathias CGT, Andersen KE, Hamann K (1983) Allergie contact
Kanerva L, Estlander T, Jolanki R, Tarvainen K (1995) Occupa- dermatitis from 2-n-octyl-4-isothiazolin-3-one, a paint mil-
tional allergic contact dermatitis and contact urticaria caused dewcide. Contact Dermatitis 9:507-509
by polyfunctional aziridine hardener. Contact Dermatitis Matsunaga K, Sugai T, Katoh J, Hayakawa R, Kozuka T, ltoh
33:304-309 M, Tsuyuki S, Honoso K (1997) Group study on contact
Kanerva L, Hyry H, Jolanki R, Hytönen M, Estlander T (1997) sensitivity of 1,3-butylene glycol. Environ Dermatol 4:
Delayed and immediate allergy caused by met- 195-201
hylhexahydropthalic anhydride. Contact Dermatitis 36:34-38 McFadden JP, Rycroft RJG (1993) Occupational contact dermatitis
Kanerva L, Estlander T, Alanko K, Jolanki R (1998a) Occupational from triglycidyl isocyanurate in a powder paint sprayer.
airborne allergie contact dermatitis from dibutylthiourea. Contact Dermatitis 28:251
Contact Dermatitis 38:347-348 Meding B (1986) Contact dermatitis from tetrachloroisophtalo-
Kanerva L, Estlander T, Alanko K, Pfäffli P, Jolanki R (1999) nitrile in paint. Contact Dermatitis 15:187
Occupational dermatitis from unsaturated polyester res in in a Mellström G, Boman A (1997) Protective gloves: test results
car repair putty. Int J Dermatol 38:447-452 compiled in a database. In: Brune D, Gerhardsson G,
Karjalainen A, Toikkanen J (eds) (1997) From baker's asthma to Crockford GW, D'Auria D (eds) Fundamentals of health,
cement dermatitis. Occupational disease risks in various safety and welfare. (The workplace, voll) International
occupations (in Finnish). Finnish Institute of Occupational Occupational Safety and Health Information Centre (CIS)
Health, Helsinki, pp 1-92 International Labour Office, Geneva and Scandinavian Sci-
Karlberg A-T (1988) Contact allergy to colophony, chemie al ence Publishers, Oslo, pp 716-730
identification of allergens, sensitization experiments and Moura C, Dias M, Vale T (1994) Contact dermatitis in painters,
clinieal experiences (thesis). National Institute of Occupa- polishers and varnishers. Contact Dermatitis 31:51-53
tional Health, Stockholm, pp 1-43 Munro CS, Lawrence CM (1992) Occupational contact dermatitis
Karlberg A-T, Dooms-Goossens A (1997) Contact allergy to from triglycidyl isocyanurate in a powder paint factory.
oxidized D-limonene among dermatitis patients. Contact Contact Dermatitis 26:59
Dermatitis 36:201-206 Pedersen NB (1976) Occupational allergy from 1,2-ben-
Karlberg A-T, Boman A, Melin B (1991) Animal experiments on zisothiazolin-3-one and other preservatives in plastie emul-
the allergenity of D-limonene - the citrus solvent. Ann Occup sions. Contact Dermatitis 2:340-342
Hyg 35:419-425 Pedersen NB, Fregert S (1976) Occupational allergic contact
Karlberg A-T, Magnusson K, Nilsson U (1992) Air oxidation of D- dermatitis from chloracetamide in glue. Contact Dermatitis
limonene (the citrus solvent) creates potent allergens. Contact 2:122-123
Dermatitis 26:332-340 Piirilä P, Kanerva L, Keskinen H, Hytönen M, Tuppurainen M,
Karlberg A-T, Shao LP, Nilsson U (1994) Hydroperoxides in Estlander T, Nordman H (1998) Occupational respiratory
oxidized D-limonene identified as potent contact allergens. hypersensitivity caused by acrylates in dental personnel. Clin
Arch Dermatol Res 286:97-103 Exp Allergy 28:1404-1411
Kinnunen T, Hannuksela M (1989) Skin reactions to hexylene Piper R (1965) The hazards of painting and varnishing. Br J Ind
glycol. Contact Dermatitis 21:154-158 Med 22:247-260
Klaschka F (1975) Contact allergy to chloracetamide. Contact Pirilä V (1947) On occupational disease of the skin among
Dermatitis 1:265 paint factory workers, painters, polishers, and varnishers
Korhonen E (1997) Personal protective equipment. In: Brune D, in Finland (thesis). Acta Derm Venereol 27[Suppl 26]:
Gerhardsson G, Crockford GW, D'Auria D (eds) Fundamen- 1-163
tals of health, safety and welfare. (The workplace, voll) Pirilä V, Kilpiö 0, Olkkonen A, Pirilä L, Siltanen E (1969) On the
International Occupational Safety and Health Information chemical nature of the eczematogens in oil of turpentine V.
Centre (CIS) International Labour Office, Geneva and Scan- Pattern of sensitivity to different terpenes. Dermatologica
dinavian Science Publishers, Oslo, pp 685-715 139:183-194
Lama L, Vanni D, Barone M, Patrone P, Antonelli C (1985) Pürschel W, Odia SG, Rakoski J (1995) Berufliehe Kontaktstoffe
Occupational dermatitis to chloroacetamide. Contact Derma- bei Kunstmalern. Derm Beruf Umwelt 43:219-222
titis 15:243 Reinhardt CF, Britteli MR (1981) Patty's industrial hygiene and
Lear JT, Heagerty M, Tan BB, Smith AG, English JSC (1996) toxicology, vol2A. John Wiley and Sons, New York, pp 2672-
Transient re-emergence of oil of turpentien allergy in the 2678
pottery industry. Contact Dermatitis 35:169-172 Rietschel RL, Fowler JF Jr (1995) Fisher's contact dermatitis, 4th
Leira HL (1997) Organic solvents. In: Brune D, Gerhardsson G, edn. Williams & WiIkins, Baltimore, pp 563-565
Crockford GW, Norbäck D (eds) Major industries and Roark DN, Mckusick BC (1985) Aziridines. In: Gerhartz W,
occupations. (The workplace, voll) International Occupa- Yamamoto YS, Campbell FT, Pfefferkorn R, Rounsaville JF
tional Safety and Health Information Centre (CIS) Interna- (eds) Ullman' s encyclopedia of industrial chemistry, 5th edn.
tional Labour Office, Geneva and Scandinavian Science (vol A3) VCH, Weinheim, pp 239-244
Publishers, Oslo, pp 650-660 Roberts DL, Messenger AG, Summerly R (1981) Occupational
Lewis PG, Emmett EA (1987) Irritant dermatitis from tri-butyl tin dermatitis due to 1,2 benzisothiazolin-3-one in the pottery
oxide and contact allergy from chlorocresol. Contact Derma- industry. Contact Dermatitis 7:145-147
titis 17:129-132 Romaguera C, Camarasa J, Grimalt F, Alomar A (1983) Turpen-
Liden C (1990) Facial dermatitis caused by chlorothalonil in a tine: an attempt to explain sensitization to this allergen in
paint. Contact Dermatitis 22:206-211 Spain. Contact Dermatitis 9:384-386
Lisi P, Caraffani S, Assalve D (1987) Irritation and sensitization Romaguera C, Grimalt F, Vilaplana 1, Castel T (1988) Contact
potential of pesticides. Contact Dermatitis 17:212-218 Dermatitis to thioureas. Contact Dermatitis 18:175-176
678 T. Estlander et al.: Paints, Lacquers and Varnishes
Rose FG, Vance CI (1997) The paint industry. In: Brune D, tetralIydrophtalic anhydride. Contact Dermatitis 32:
Gerhardsson G, Crockford GW, Norbäck D (eds) Major 204-209
industries and occupations. (The workplace, vol 2) Interna- Thormann J (1982) Contact dermatitis to a new fungicide, 2-n-
tional Occupational Safety and Health Information Centre OCtyl-4-isothiazolin-3-one. Contact Dermatitis 8:204
(CIS) International Labour Office, Geneva and Scandinavian Ulfvarson U, Alexandersson R, Dahlqvist M, Ekholm U, Bergs-
Science Publishers, Oslo, pp 350-360 tröm B, Scullman J (1992) Temporary effects from exposure
Rycroft RJG (1980) Allergie contact dermatitis from dipentene in to water-borne paints. Scand J Work Environ Health 18:
honing oils. Contact Dermatitis 6:325-329 376-387
Sadhra S, Foulds IS, Cray CN, Koh D, Gardiner K (1994) Valsecchi R, Leghissa P, Piazzolla S (1992) Occupational contact
Colophony - uses, health effects, airborne measurement and dermatitis from paints. (ed) Clin Dermatoll0:185-188
analysis. Ann Occup Hyg 38:385-396 Van der Walle HB (1982) Sensitizing potential of acrylic
Sala E, Hytönen M, Tupasela 0, Estlander T (1996) Occupational monomers in guinea pigs (thesis). Krips Repro, Meppel,
laryngitis with specific immediate allergie or immediate type pp 1-111
specific hypersensitivity. Clin Otolaryngol 21:42-48 Van Faassen A, Borm PJA (1991) Composition and health hazards
Sanz-Gallen P, Planas J, Di Fanso M, Venuti A (1992) Allergie of water-based construction paints: results from a survey in
contact dermatitis due to 1,2-benzisothiazolin-3-one in paint the Netherlands. Environ Health Perspect 92:147-154
manufacture. Contact Dermatitis 27:271-272 Vente C, Fuchs T (1997) Contact dermatitis due to oil of
Savage J (1978) Chloracetamide in nylon spin finish. Contact turpentine in a porcelain painter. Contact Dermatitis 37:187
Dermatitis 4:179 Vincent R, Poirot P, Subra I, Rieger P, Cicolella A (1994)
Savonius B, Keskinen H, Tuppurainen M, Kanerva L (1993) Occupational exposure to organic solvents during paint
Occupational respiratory disease caused by acrylates. Clin stripping and painting operations in the aeronautical indus-
Exp Allergy 23:416-423 try. Int Arch Occup Environ Health 65:377-380
Schmid-Grendelmeier P, Eisner P (1995) Contact dermatitis due Wahlberg JE, Högberg M, Skare I (1978) Chloracetamide allergy
to occupational dibutylthiourea exposure: a case of phone- in house painters. Contact Dermatitis 2:116-117
card dermatitis. Contact Dermatitis 32:308-309 Wehle U (1966) Arbeitsbedingte Ekzeme durch Polyester. Allerg
Schwartz L, Tulipan L, Birmingham DJ (1957) Dermatoses caused Asthma (Leipz) 12:184-196
by paints, varnishes and lacquers. In: Occupational diseases White IR, Lovell CR, Cronin E (1984) Antioxidants in cosmetics.
of the skin, 3rd edn. Lea & Febiger, Philadelphia, pp 527-534 Contact Dermatitis 1l:265-267
Spindeldreier A, Deichmann B (1980) Kontaktdermatitis auf ein Wieslander G, Norbäck D (1997) Water-based paints in the
Holzschutzmittel mit neuer fungizider Wirksubstanz. Derm construction industry. In: Brune D, Gerhardsson G, Crock-
Beruf Umwelt 28:88-90 ford GW, Norbäck D (eds) Major industries and occupations.
Suhonen R (1983) Chloracetamide: a hidden contact allergen. (The workplace, vol 2) International Occupational Safety and
Contact Dermatitis 9:161 Health Information Centre (CIS) International Labour Office,
Tanaka S, Lucas JB (1984) Dermatitis in paperhangers. Contact Geneva and Scandinavian Science Publishers, Oslo, pp 690-
Dermatitis 10:54-55 696
Tarvainen K, Jolanki R, Estlander T (1993) Occupational contact Wieslander G, Norbäck D, Edling C (1994) Occupational exposure
allergy to unsaturated polyester resin cements. Contact to water-based paints and symptoms from the skin and eyes.
Dermatitis 28:220-224 Occup Environ Med 51:181-186
Tarvainen K, Jolanki R, Estlander T, Tupasela 0, Keskinen H, Würbach G, Schubert H, Philip I (1993) Contact allergy to benzyl
Pfäffii P, Kanerva L (1995) Immunologie contact urticaria due alcohol and benzylparaben. Contact Dermatitis 28:187-188
to airborne metylhexalIydrophthalic anhydride and metyl-
CHAPTER 84
Organic Solvents
A. Boman and J.E. Wahlberg
Introduction octanol and water (log Po/w), where a high value

represents a high lipid solubility. Over the years,
steadily increasing knowledge of the various adverse
Industrial solvents are volatile organic liquids com-
effects seen in man and experimental animals has
monly used to dissolve other organic materials such as
resulted in a gradual decrease in TL Vs, e.g. methylene
oils, fats, resins, rubber, lacquers, waxes, perfumes and
chloride. It has been claimed that the relative impor-
plastic. They have a very wide variety of uses,
tance of the percutaneous route of absorption of
including:
solvents has increased as result of these regulatory
• Painting activities concerning inhalation of solvents. Awareness
• Paint manufacturing of environmental and human effects has also led to a
• Floor laying change from chlorinated solvents to biologically
• Production of glass-fibre-reinforced polyester degradable solvents with altered risk spectra.
• Surface coating The systemic adverse effects of solvents (carcino-
• Graphic industries, rotogravure printing genicity, teratogenicity, miscarriage, nephrotoxicity,
• Dyeing of paper, plastics, fabrics hepatotoxicity, neurotoxic and neuropsychiatric dis-
• Metal degreasing orders, haematological, cardiovascular, respiratory and
• Dry cleaning gastrointestinal effects) are reviewed in textbooks and
• Cleansing are beyond the scope of this chapter on skin effects
• Spotting agents resulting from solvent exposure.
• Carriers and intermediates in organic synthesis
• Media for extraction processes
• Analytical chemistry
Adverse Effects Resulting from Skin Exposure
Technical-grade organic solvents are reasonably
inexpensive; considerable volumes are used yearly
and numerous workers are exposed daily. Although The various signs, disorders, diseases and other effects
mainly treated as a group due to their general seen as a result of skin exposure to solvents are
properties, solvents are chemically diverse (Fig. 1) summarised in Table 2. Regarding systemic effects, it
and can be classified into different categories ac cord- has been demonstrated that some solvents have
ing to their physico-chemical characteristics; examples specific target organs, e.g. the liver by dimethylform-
are given in Table 1, in which threshold limit values amide (DMF) and the bone marrow by benzene.
(TLVs) for Sweden (Swedish National Board of Occu- Adverse effects are sometimes caused by the solvent
pational Safety and Health 1996) are also presented. itself, sometimes by its metabolite(s). Solvents may be
Such values, inter alia, are proposed by the American transformed into reactive metabolites that are more
Conference of Governmental Industrial Hygienists toxic than the parent compound. That metabolites
(ACGIH) and various national government agencies might be the principal offending agents causing skin
and have had great infiuence in many industrialised effects is at present just a hypo thesis.
countries when reviewing health hazards from solvents In addition to irritancy, various other adverse
and implementing preventive measures. Information effects (Table 2) can often be linked to a particular
on volatility, and water and lipid solubility, is also of solvent. However, the main side effect in the skin -
great value when discussing potential risks from different degrees of defatting - is uniform and, in
solvent exposure. The latter is expressed as the general, toxicology is related to concentration, dose
logarithm of the partitioning coefficient between and duration of exposure. It has been demonstrated

680 A. Boman and J.E. Wahlberg
Organic solvents
AliDhatic Aromatic Alcohols
CH 3(CH 2)4 CH3
n-Hexane 0
Benzene
6
Toluene
CH 3CHOHCH 3
6
iso-Propanol
Halo2enated
aliDhatics
CH2CI2
(-) ~ CH3
cH
'
CH 3CH 2CH 2CH 20H
n-Butanol
Methylenechloride Xylene Styrene
CHCI 3
Chloroform
Ketones Ethers
CCI4
CH 3COCH 3 CH 3CH 20CH 2CH 3
Carbon tetrachloride
Acetone Diethyl ether
CHCI=CCI 2
Trichloro ethylene CH 3COCH 2CH 3
Methylethyl ketone Esters
CCI 2=CCI2
Tetrachloro ethylene CH3COCH2CH2CH2CH3 CH 3COOCH 2CH 3
Methyl-n-butyl ketone Ethyl acetat
CCI 3CH 3
Methyl chloroform
Miscellaneous Glycol ethers Petroleum

solyents distillates
CS 2 Gasoline
Ethoxyethanol
Carbon disulphide White Spirit
HCON(CH 3h
Dimethyl formamide
Fig. 1. Structural formulas for selected solvents just to one solvent; more often he/she is exposed to
mixtures of several solvents with a varying degree of
(Klauder and Brill 1947) that the low-boiling-range purity. Mineral spirits, kerosene, gasoline and thin-
«250 Oe) petroleum solvents have the greatest ners are examples of widely used mixtures. From a
defatting action and dermatitis potential. Irritant clinical point of view, it is hard to demonstrate the
action such as defatting action decreases as the relative importance of one ingredient in a mixture of
boiling range increases. A worker is rarely exposed solvents.
Organic Solvents 681
Table 1. Some commonly used solvents arranged by chemical group
Examples Vapor pressure Threshold-limit value Water solubility Log po/wa Skin
(25.0 °C, kPa) (TLV) (ppm) (Swedish (mg/100 ml water) notation
National Board of
Occupational Safety
and Health 1996)
Aliphatic
n-Hexane 16 25 Insoluble 3.6
Aromatic
Benzene 10 0.5 180 2.13 H
Toluene 2.9 50 82 2.6 H
Xylenes 0.6-1.1 50 16-18 2.77-3.68 H
Styrene 0.6 20 Insoluble 2.95 H
Halogenated aliphatic
Methylene chloride 45 35 1320 1.25 H
Chloroform 21 2 820 1.97
Carbon tetrachloride 12 2 50 2.83 H
Trichloroethylene 8 10 100 2.29
Tetrachloroethylene 1.9 10 40 2.60
Methyl chloroform 13 50 50 2.49
Esters
Ethyl acetate 10 150 9000 0.73
Ketones
Acetone 25 250 -0.24
Methyl ethyl ketone 9 50 80,600 0.29
Methyl-n-butyl ketone 0.4 1 1400 0.29 H
Alcohols
Ethanol 6 500 -0.31
Isopropanol 4 150 0.05
n-Butanol 0.6 15 7800 0.88 H
Glycol ethers
2-Ethoxyethanol 0.5 5 -0.54 H
Miscellaneous
Carbon disulphide 40 5 230 2.16 H
Dimethylformamide 0.4 10 -1.01 H
Petroleum distillates
White spirit <0.7 Insoluble
a Logarithm of the partitioning coefficient between octanol and water
With the exception of generalised dermatitis and Table 2. Adverse effects of solvents on skin exposure
Steven-Johnson syndrome from trichloroethylene (see
below), the dermatoses caused by solvent exposure are Subjective irritation
Irritancy
considered to be comparatively benign and rarely a Contact urticaria
cause for job change or pension. In a Danish publi- Flushing, generalised dermatitis and Steven-Johnson
cation of notified occupational eczematous diseases syndrome - from trichloroethylene
Whitening
1984-1991 (Halkier-S0rensen 1996), exposure to sol- Irritant contact dermatitis
vents was the cause in 991 cases (3.6%) and was placed Chemieal bums
fifth in the ranking list. Higher frequencies were found Allergie contact dermatitis
Scleroderma
for water (13.9%), detergents (11.6%), nickel (5.4%) and Dermatoses from higher-boiling petroleum distillates
hand cleansers and soaps (3.9%). Percutaneous absorption - systemic toxicity
Enhancing absorption of other toxic chemicals
Subjective Irritation
Irritancy
The affected workers report a stinging, tingling and/or
burning sensation from a skin area exposed to a solvent Solvents that quickly evaporate from the skin if not
or to a mixture of solvents. The site looks normal to the occluded are not as likely to damage the skin as solvents
naked eye. This phenomenon is not restricted to that do not evaporate, i.e. they will act for a longer period
solvents only; it has been reported, for example, from of time. Erythema, oedema and drying are the most
skin exposure to lactic acid ("the stinging test") and by common side effects seen from single or repeated
workers exposed to visual display units (VDUs). exposures to solvents. These signs are sometimes
labre 3. Increase in skin blood flow from exposure to solvents (neat) as an expression of irritancy - objectively recorded by laser
Doppler flowrnetry (Wahlberg 1984a)
Solvent 0.1 ml pipetted Whitening after rubbing Duration in min required

onto the skin with cotton (exposure in to get an increase
excess of 1.5 mll3.1 cm2 )
Dimethylsulfoxide Increase No 1
Trichloroethane No increase Yes 1
n-Hexane No increase Yes 5
Carbon tetrachloride No increase Yes 5
Toluene No increase Yes 5
1,1,1-Trichloroethane No increase Yes 5
1,1,2-Trichloroethane No increase Yes 5
Dodecane No increase Yes 15
Methyl ethyl ketone No increase Yes No increase
Propylene glycol No increase No No increase
Ethanol No increase Yes No increase
Water No increase No No increase
transient or may develop into irritant contact dermatitis However, daily open treatments with solvents (neat)
(see below). The course is related to the type of solvent for 10-18 days on human volar forearms did not cause
(Table 1), concentration, dose, and exposure time. any increase in skin-fold thickness (Wahlberg 1993). A
transient erythema immediately after the administra-
Erythema tion of toluene was observed in a few cases. The
absence of oedema-inducing effects in man compared
In attempts to study and differentiate the erythema- with rabbits and guinea pigs is probably due to
inducing capacity of solvents in man, the objective evaporation of solvents immediately after administra-
laser-Doppler technique was used to measure skin tion to man, while solvents pardy adhered to the
blood ßow (Wahlberg 1984b). This technique is three animals' fur.
or four times more sensitive than the naked eye
(Wahlberg 1989). Histopathology
In the first series of experiments, 0.1 ml of the neat
solvents were applied with a pipette to the forearm The histopathological picture after epicutaneous ad-
skin of healthy subjects and were allowed to spread ministration of solvents to guinea pigs also demon-
freely. As can be seen from Table 3, only one solvent strated great variation in potency (Kronevi et al. 1977,
(dimethylsulfoxide) caused an increase in skin blood 1979, 1981).
ßow. The sites looked normal to the naked eye. In the
second series of experiments, the neat solvents were Contact Urticaria
applied in excess (1.5 m1!3.1 cm 2 ) using a glass ring as a
reservoir and attached with rubber bands to the Some solvents, e.g. alcohols, have been shown to cause
fore arm. Three different exposure times were used (1, immunological as weH as non-immunological contact
5, and 15 min) and, as can be seen from Table 3, the urticaria (Rilliet et al. 1980; Ophaswongse and Maibach
solvents varied gready in their effects on skin blood 1994). In the latter case, a racial predisposition (Wilkin
ßow. The most potent solvents were dimethylsulfoxide and Fortner 1985) is suggested. There are also case
and trichloroethylene, while 15 min of exposure in
excess to methyl ethyl ketone, propylene glycol,
lable 4. Ranking of oedema-inducing capacity of solvents (neat)
ethanol and water did not inßuence skin blood ßow. on skin exposure in experimental animals. Method: skin-fold-
thickness measurements (Wahlberg 1984b)
Oedema
Solvent Guinea pig Rabbit
Oedema caused by repeated skin exposure to solvents
Trichloroethylene 1 1
can be quantified with a rather unsophisticated device: Toluene 2 1
the caliper (Wahlberg 1984a). Results of measurements 1,1,2-Trichloroethane 3 1
of skin-fold thickness of experimental animals treated Carbon tetrachloride 4 2
1,1,1-Trichloroethane 4 2
once daily with neat solvents are summarised in Dimethylsulfoxide 5 Not tested
Table 4. Trichloroethylene and dimethylsulfoxide n-Hexane 6 4
seem to be potent oedema-inducing solvents as weH Methyl ethyl ketone 7 3
Ethanol 7 5
as inßuencing skin blood ßow in man (Table 3).
reports on, inter alia, methyl ethyl ketone (Varigos and sulfoxide, propylene glycol and water) did not cause
Nurse 1986), naphtha (Goodfield and Saihan 1988), whitening and the did not extract lipids either.
dimethyl sulfoxide, polyethylene glycol (Fisher 1978)
and xylene. However, there is some confusion in the Irritant Contact Dermatitis
literature - is a macular erythema sufficient for the
diagnosis of contact urticaria (Gollhausen and Klig- There is a general agreement that solvents are important
man 1985)? skin irritants and that repeated exposure may develop
From a clinical point of view, it is important to know into irritant contact dermatitis. As previously men-
that oral provocation with alcohol can elicit anaphyl- tioned, there is a great variation in the degree of
axis (Ophaswongse and Maibach 1994). irritancy produced (Tables 3, 4); in addition, concen-
tration, aromatic content, duration of exposure, occlu-
Testing sion, temperature, humidity and individual factors,
such as atopic diathesis, history of contact dermatitis
To diagnose immunological contact urticaria, open and barrier function, are thought to interact and
tests with gas-chromatographically pure ethanol ("as contribute to irritant contact dermatitis. Examples of
is") is recommended (Ophaswongse and Maibach predisposition and individual susceptibility to irritant
1994). With other solvents, for which data is lacking, contact dermatitis are presented in Table 5. Individuals
it is recommended to use graded concentrations as well with past or current atopic dermatitis are more suscep-
as a great number of controls to verify the specificity. tible to irritants; among those irritants, solvents and wet
work are considered to be of greatest importance in
Generalized Dermatitis, Steven-Johnson Syndrome causing relapses and deterioration. Pre-employment
and Flushing from Trichloroethylene examination and vocational guidance are recommended
for individuals in these categories (Table 6).
Exposure to trichloroethylene has been associated with A commonly affected site is the hands and especially
cases of generalised dermatitis (Bauer and Rabens the back of the hands and the finger webs, but any skin
1974) and of Steven-Johnson syndrome (Phoon et al. site contaminated by solvents can develop an irritant
1984). Several of the patients had signs of liver contact dermatitis. When the face is affected, vapours
dysfunction (toxic hepatitis) and one fatal case was are suspected as well as contamination by the hands.
reported (Nakayama et al. 1988). From the case Erythema, dryness, scaling, fissures and oedema are
reports, however, it is somewhat hard to judge what the most common features, but oozing can also be seen
route of absorption - inhalation or percutaneous (for chemical burns, see below). The clinical picture is
absorption - had domina ted. the same as for other causes of irritant contact
dermatitis and is of no help when differentiating from
Flushing other irritants or when evaluating the relative contri-
bution of the solvent exposure.
There are so me case studies in which exposure to
trichloroethylene and to DMF followed by ingestion of
Table 5. Individual susceptibility on skin exposure to organic
alcohol resulted in generalized flushing of the skin solvents
("degreasers flush") and nausea (Stewart et al. 1974).
Based on findings from an experimental study, it was History of atopic dermatitis Predisposition/increased
suggested that the underlying mechanism is interfer- susceptibility
History of asthma/rhinitis Not settied
ence of trichloroethylene with the metabolism of History of contact dermatitis Dry or senile skin; considerable
alcohol in the liver. variation, even in non -atopics
Recommendation Pre-employment examination,
vocational guidance
Whitening
When some solvents are applied to human skin Table 6. Adverse effects of skin exposure to solvents and some
followed by gende rubbing with, for example, cotton, preventive measures
the site will turn white ("whitening"). In a comparative
Reduce exposure
study, this phenomenon was observed for nine sol- Select appropriate solvents; solvents exhibit great variations in
vents (Goldsmith et al. 1988) (Table 3). No decrease in potency (irritancy, percutaneous absorption, systemic toxicity)
skin blood flow - evaluated by laser-Doppler flowme- Gloves provide some protection, as do sleeves
Barrier creams provide questionable protection; tlIeir usefulness
try - was found, indicating that the whitening was not is still a matter for debate
due to vasoconstriction. The solvents that caused Consider the individual' s susceptibility
whitening were also able to extract lipids from human Skin-care programs, cleansing, moisturisers etc.
Legislation, labelling, information, education
stratum corneum. However, three solvents (dimethyl-
Scleroderma cause of allergie contact dermatosis among painters in

Scandinavian countries, but after its replacement with
There are some case reports on scleroderma related to petroleum-derived alternatives (white spirit, "mineral
exposure to various solvents (Yamakage and Ishikawa turpentine") the frequency is nowadays low. A fre-
1982; Walder 1983; Bottomley et al. 1993; Czirjak et al. quency of positive reactions of 1.6/1.80/0 was found
1994). It is not clear from the reports whether the main when turpentine was included in the standard series in
route of exposure is percutaneous or by inhalation, southeastern Europe (Rudzki et al. 1991). The allergen
and it can be assumed that both routes contribute. A can be obtained from suppliers of patch-test allergens.
well-controlled epidemiological study to evaluate the
D-Limonene
observations is highly desirable.
D-Limonene-containing products were launched to
Dermatoses trom Higher-Boiling Petroleum Distillates replace environmentally persistent chlorinated hydro-
carbons and chlorofiuorocarbons as solvents. The main
Petroleum distillates obtained at temperatures above allergens are oxidation products created when D-
315°C are mainly oils (lubricating, spindle, trans- limonene is air exposed, e.g. limonenoxide, L-carvone
former, machine and cutting oils) and have less and limonene hydroperoxides (Karlberg et al. 1991,
defatting but more keratogenic action. They can cause 1992). The oxidation can be prevented by the addition
comedones, acne, photosensitivity, melanosis, kera- of butylated hydroxytoluene (BHT) (Karlberg et al.
toses and epitheliomas. 1994). Limonene has many other uses (Karlberg and
Dooms-Goossens 1997), and there is then a possibility
Chemical Burns of cross reactions. The worker has been sensitised via
other D-limonene-containing products and can have a
Extensive and prolonged skin exposure to solvents - relapse due to contact at work when limonene is used as
especially under occlusion - may cause severe skin a solvent. A test preparation (dipentene) is available
damage including blisters, bullae, oozing or necrosis. from suppliers of patch-test allergens.
Solvent-soaked clothing in direct and prolonged con-
Dioxane
tact with the skin is an often-mentioned cause of these
burns. Solvents that have been implieated are, ac cord- A worker who used dioxane for degreasing metal parts
ing to the literature, tetrachloroethane, trichloroethyl- developed hand eczema (Fregert 1974). He was patch-
ene, methylene chloride, carbon disulphide, Stoddard test positive to 0.50/0 dioxane in water.
solvent, gasoline, kerosene, benzene and toluene, but
Alcohols
probably many more have this potential if the expo-
sure conditions (concentration, duration, occlusion) Case reports of allergic contact dermatitis from alco-
are unfavourable for the worker. hols were recently reviewed (Ophaswongse and Mai-
Perchloroethylene used in dry cleaning may, to some bach 1994). In addition, cross reactivity and oral
extent, remain in clothing and cause skin irritation, provocation were addressed. An individual with a
especially on the legs, wrists and neck. It has been type-IV allergy may cross react to other alcohols on
suspected that this residue may cause or contribute to patch testing. In a few cases, oral provocation with
chemical burns. alcoholic beverages was positive, but it is unclear
whether there was a coexistence of type I and type IV
Allergie Contact Dermatitis in some patients. There are presumably metabolic
dose-response relationships and individual suscepti-
Solvents os Contoct Allergens bility factors that operate as risk factors in predicting
one's propensity to develop systemic contact derma-
There are rather few case reports on allergic contact titis due to oral provocation.
dermatitis to solvents, considering their extensive use
Styrene
and the size of the exposed population. This may be
due partly to the inherent problems encountered when Styrene is a skin irritant. At least one case of contact
patch testing with solvents (see below), but also to allergy has been reported (Sjöborg et al. 1982).
ignorance or lack of suspicion by the examining
physician and partly due to the solvents' relative
chemical inertness. Potch Testing with Solvents - Feosibility
Turpentine
The irritant properties and volatility of some solvents
The principal contact allergen in turpentine is ß-3- make patch testing highly problematic. For example, in
carene (Hellerström et al. 1955, 1957). It was a frequent a comparative study with tetrachloroethylene, it was
found that a positive re action was obtained when it (Swedish National Board of Occupational Safety and
was applied as a 1% solution in olive oil using ordinary Health 1996), the solvents given this notation are
patch-test techniques, while open application (neat) marked with "H" (hud or skin) (Table 1), indicating
produced negative test results (Vail 1974). In these that they are readily absorbed through the skin.
cases, it was therefore recommended to medicate the A defective skin barrier is considered to facilitate
patch immediately before the test is applied on the percutaneous penetration. In an experimental study in
patient to minimise evaporation, and to use filter guinea pigs (Boman and Wahlberg 1989), however, it
papers. Since several solvents are potent skin irritants was demonstrated that induced skin damage (strip-
even after short exposure times (Table 3), it is thus ping, needle and sand paper abrasion, delipidisation)
probably impossible to demonstrate allergenicity by caused a considerable increase in the absorption rate
the conventional patch-test technique. of n-butanol (a water-soluble solvent), while the
Information regarding test concentrations and ve- absorption of toluene and 1,1,I-trichloroethane (lipo-
hicles are rarely available - for the examining derma- philic solvents) decreased. Thus, skin damage does not
tologist, the testing is a question of trial and error. If a automatically lead to increased percutaneous absorp-
"positive" re action is obtained, it is crucial to carry out tion; instead, the lipophilic and hydrophilie properties
serial dilution tests and to test a sufficient number of of a particular solvent seem to be crucial.
controls (>25). So far, provocative use tests, such as the
repeated open application test (ROAT), do not seem to Penetration-Enhancing Action
have been used to clarify the relevance of a "positive"
patch-test re action to a solvent. Alcohols and propylene glycol are used in many topical
Ethanol, methyl ethyl ketone and acetone are medicaments and are supposed to have several func-
recommended vehicles for patch tests of materials tions, including facilitating penetration of other ingre-
and products brought to the physician by patients, dients. Irritancy is occasionally reported by patients
indicating that vast experience has demonstrated these using corticosteroid preparations containing these
solvents to be only marginal irritants (Wahlberg solvents. Solvents are often blamed, but other ingre-
1995b). Propylene glycol has irritant properties under dients should also be considered. Certain solvents,
occlusion, and the optimal test concentration and such as DMF, dimethylsulphoxide and pyrrolidones,
vehicles are not yet settled (Wahlberg 1994). have a profound absorption-enhancing effect and may
facilitate the absorption of toxic substances at con-
comitant exposure.
Percutaneous Absorption - Systemic Toxicity
As a consequence of observed risks for systemic Prevention

toxicity, carcinogenicity, etc. from inhalation of sol-
vents, a gradual decrease in TL Vs has taken place and,
therefore, the percutaneous route of uptake has The preventive measures are summarised in Table 6.
become more prominent. Skin absorption from expo- They were recently reviewed (Wahlberg and Boman
sure to solvent vapours is negligible for most common 1996).
solvents. However, those that contain a lipophilic and a
hydrophilie part (glycol ethers and DMF) are readily
absorbed, and skin exposure to solvent vapours may Reduced Exposure
contribute to the total uptake. Glycol ethers have low
volatility and high boiling points compared with other Reduced exposure is of great importance due to the
organic solvents. considerable systemic toxicity of so me solvents. As a
2-Chloroethanol, 2-butoxyethanol, carbon tetrachlo- result of increasing awareness of their adverse effects,
ride, 1,1,2-trichloroethane, DMF and dimethylsulfoxide skin exposure will also hopefully be reduced due, inter
gave rise to mortality in guinea pigs exposed percu- alia, to automation, enclosed manufacturing systems
taneously (Wahlberg and Boman 1979). Fatalities in and avoidance of direct contact.
man have also been reported. An important aspect is
thus that percutaneous absorption contributes to the Appropriate Selection
total body burden, and there are strong motives to
reduce percutaneous uptake as weIl as inhalation of Quantitative data on skin-irritant properties (Table 3),
solvents. percutaneous absorption and systemic toxicity must be
In the national occupational hygiene standards, balanced against the technical requirements of a
several of the industrial solvents have notations for solvent. It is self-evident that those with the most
skin absorption. In the recent Swedish standard favourable toxicity profile should be chosen.
Protective Gloves to irritants occurs. Solvents should not be used for skin
deansing. However, if this is the only way to remove
Gloves, if selected according to recommendations, may dirt, paint, oil, or adhesives, the use of moisturisers
provide protection which allows for direct contact with afterwards is highly recommended.
solvents for several hours. The basis for these recom-
mendation is data gathered in technical testing or in Legislation, Labelling, Information, Education
vitro studies (Mellström et al. 1994; see also Chap. 53
by Mellström and Boman). The varying efficacy of Legislation, labelling, information and education are
gloves and barrier creams and the importance of using applicable to all kinds of exposure to chemicals and
proper skin protection when working with a solvent products at the workplace. TL Vsand notations on skin
with low vapour pressure and high skin absorption absorption (Table 1) are basic knowledge supplement-
conditions was dearly demonstrated for DMF. During ed with information on the irritant properties of
the first week, gloves were used as skin protection, and solvents on skin exposure (Tables 3, 4).
some absorption of DMF was found. During the
second week, a glycerol-based barrier cream was used
instead and this was obviously less protective than the
Treatment
gloves (Lauwerys et al. 1980).
In another study, the efficacy of various protective
equipment in protecting the skin from exposure to Aside from future avoidance of direct skin contact with
styrene, a solvent with physico-chemical properties the offen ding solvents, irritant and allergic contact
different from those of DMF, was investigated (Brooks dermatitis and chemical bums are treated according to
et al. 1980). For this solvent, absorption takes place general dermatological principles. Due to the risk of
mainly via inhalation. Respiratory protection (a mask) anaphylaxis, patients with verified immunological
was crucial, and the additional protection provided by contact urticaria should avoid further contact. The
gloves was minimal. extent to which antihistamines are beneficial in cases
of contact urticaria to solvents is not known.
Barrier (reams
Barrier creams are generally considered to be less

References
protective than gloves in reducing the penetration of
solvents. In a human study using bioengineering
techniques to assess skin reactions, it was found that Bauer M, Rabens S (1974) Cutaneous manifestations of trichlo-
roethylene toxicity. Arch Dermatol 110:886-890
the barrier creams studied did not affect the irritant Boman A, Wahlberg JE (1989) Percutaneous absorption of 3
properties of toluene (Frosch and Kurte 1994). General organie solvents in the guinea pig. I. Effect of physieal and
aspects of barrier creams were recently reviewed and chemical injuries to the skin. Contact Dermatitis 21:36-45
Bottomley WW, Sheehan-Dare RA, Hughes P, Cunliffe WJ (1993)
are also discussed elsewhere in this volume (Lachapelle A sclerodermatous syndrome with unusual features following
1996; see also Chap. 62 by Wigger-Alberti and Eisner). prolonged occupational exposure to organic solvents. Br J
Brooks SM, Anderson L, Emmett E, Carson A, Tsay JY, Elia V,
Individual Susceptibility Buncher R, Karbowsky R (1980) The effects of protective
equipment on styrene exposure in workers in the reinforced
plastics industry. Arch Environ Health 35:287-294
Individual susceptibility was discussed above, and the Czirjak L, Pocs E, Szegedi G (1994) Localized scleroderma after
categories that need special attention are presented in exposure to organie solvents. Dermatology 189:399-401
Fisher A (1978) Immediate and delayed allergie contact reactions
Table 5. to polyethylene glycol. Contact Dermatitis 4:135-138
Fregert S (1974) Allergie contact dermatitis from dioxane in a
solvent for cleaning meta! parts. Contact Dermatitis Newslett
Skin-(are Programs 15:438
Frosch PJ, Kurte A (1994) Efficacy of skin barrier creams. The
repetitive irritations test (RIT) with a set of 4 standard
The use of moisturisers is crucial in all professions in irritants. Contact Dermatitis 31:161-168
which workers are exposed to irritants, induding Goldsmith LB, Friberg SE, Wahlberg JE (1988) The effect of
solvents. According to some recent findings, moistu- solvent extraction on the lipids of the stratum corneum in
relation to observed immediate whitening of the skin. Contact
risers seem to be more efficacious than barrier creams Dermatitis 19:348-350
in preventing the irritation and appearance of irritant Gollhausen R, Kligman AM (1985) Human assay for identifying
contact dermatitis. Personal hygiene, proper agents for substances which induce non-allergie contact urticaria: the
NICV-test. Contact Dermatitis 13:98-106
deansing, soft towels, etc. are general recommenda- Goodfield MJD, Saihan EM (1988) Contact urticaria to naphtha
tions applicable to every workplace in which exposure present in a solvent. Contact Dermatitis 18:187
Halkier-S0rensen L (1996) Occupational skin diseases. Contact Rudzki E, Czernielewski A, Grzywa Z, Hegyi E, Jirasek J, Kalensky
Dermatitis 35 Suppl 1 I, Michailov P, Nebenfuhrer L, Rothe A, Schubert H, Stransky
Hellerström S, Thyresson N, Blohm S-G, et al. (1955) On the L, Szarmach H, Temesvari E, Ziegler V (1991) Contact allergy
nature of the eczematogenic component of oxidized 1\.3- to oil of turpentine: a lO-year retrospective view. Contact
carene. J Invest Dermatol 24:217 Dermatitis 24:317-318
Hellerström S, Thyresson N, Widmark G (1957) Chemical aspects Sjöborg S, Dahlqvist I, Fregert S, Trulson L (1982) Contact allergy
on turpentine eczema. Dermatologica 115:277 to styrene with cross reaction to vinyltoluene. Contact
Karlberg A-T, Dooms-Goossens A (1997) Contact allergy to Dermatitis 8:207-208
oxidized d-limonene among dermatitis patients. Contact Stewart RD, Hake CL, Peterson JE (1974) "Degreasers' flush"
Dermatitis 36:201-206 dermal response to trichloroethylene and ethanol. Arch
Karlberg A-T, Boman A, Melin B (1991) Animal experiments on Environ Health 29:1-5
the allergenicity of d-limonene - the citrus solvent. Ann Swedish National Board of Occupational Safety and Health (1996)
Occup Hyg 35:419-426 Occupational exposure limit values. Statute book of the
Karlberg A-T, Magnusson K, Nilsson U (1992) Air oxidation of d- Swedish National Board of Occupational safety and Health.
limonene (the citrus solvent) creates potent allergens. Contact Ordinance 2
Dermatitis 26:332-340 Vail JT (1974) False-negative reaction to patch testing with
Karlberg A-T, Magnusson K, Nilsson U (1994) Influence of an volatile compounds. Arch Dermatol 110:130
anti-oxidant on the formation of allergenic compounds Varigos GA, Nurse DS (1986) Contact urticaria from methyl ethyl
during auto-oxidation of d-limonene. Ann Occup Hyg ketone. Contact Dermatitis 15:259-260
38:199-207 Wahlberg JE (1984a) Erythema-inducing effects ·of solvents
Klauder JV, Brill FA (1947) Correlation of boiling ranges of some following epicutaneous administration to man studied by
petroleum solvents with irritant action on skin. Arch laser Doppler flowmetry. Scand J Work Environ Health
Dermatol 56:197-215 10:159-162
Kronevi T, Wahlberg JE, Holmberg B (1977) Morphological Wahlberg JE (1984b) Edema-inducing effects of solvents follow-
lesions in guinea pigs during skin exposure to 1,1,2-trichlo- ing topical administration. Derm Beruf Umwelt 32:91-94
roethane. Acta Pharmacol Toxicol (Copenh) 41:298-305 Wahlberg JE (1989) Assessment of erythema: a comparison
Kronevi T, Wahlberg JE, Holmberg B (1979) Histopathology of between the naked eye and laser Doppler flowmetry. In:
skin, liver, and kidney after epicutaneous administration of Frosch PI, Dooms-Goossens A, Lachapelle JM, Rycroft RJG,
five industrial solvents to guinea pigs. Environ Res 19:56-69 Scheper RJ (eds) Current topics in contact dermatitis.
Kronevi T, Wahlberg JE, Holmberg B (1981) Skin pathology Springer, Berlin Heidelberg New York, p 549
following epicutaneous exposure to seven organic solvents. WalIlberg JE (1993) Measurement of skin-fold thickness in the
Int J Tissue React 3:21-30 guinea pig. Contact Dermatitis 28:141-145
Lachapelle J-M (1996) Efficacy of protective creams and/or gels. Wahlberg JE (1994) Propylene glycol: search for a proper and
Curr Probl Dermatol 25=182-192 nonirritant patch test preparation. Am J Contact Dermat
Lauwerys RR, Kivits A, Lhoir M, Rigolet P, Houbeau D, Buchet 5=156- 159
J-p, Roels H (1980) Biological surveillance ofworkers exposed Wahlberg JE (1995a) 'Green diesel' - skin irritant properties of
to dimethylformamide and the influence of skin protection diesel oils compared to common solvents. Contact Dermatitis
on its percutaneous absorption. Int Arch Occup Environ 33:359-360
Health 45:189-203 Wahlberg JE (1995b) Patch testing. In: Rycroft RJG, Menne T,
Mellström G, Wahlberg JE, Maibach HI (1994) Protective gloves Frosch PJ (eds) Textbook of contact dermatitis, 2nd edn.
for occupational use. CRC, Boca Raton Springer, Berlin Heidelberg New York, p 243
Nakayama H, Kobayashi M, Takahashi M, Ageishi Y, Takano T Wahlberg JE, Boman A (1979) Comparative percutaneous toxicity
(1988) Generalized eruption with severe liver dysfunction of ten industrial solvents in the guinea pig. Scand J Work
associated with occupational exposure to trichloroethylene. Environ Health 5:345-351
Contact Dermatitis 19:48-51 Wahlberg JE, Boman A (1996) Prevention of contact dermatitis
Ophaswongse S, Maibach HI (1994) Alcohol dermatitis: allergic from solvents. Curr Probl Dermatol 25:57-66
contact dermatitis and contact urticaria syndrome. Contact Walder BK (1983) Do solvents cause scleroderma? Int J Dermatol
Dermatitis 30:1-6 22:157-158
Phoon WH, Chan MO, Rajan VS, Tan KJ, Thirumoorthy T, Goh Wilkin JK, Fortner G (1985) Ethnic contact urticaria to alcohol.
CL (1984) Stevens-Johnson syndrome associated with occu- Contact Dermatitis 12:118-120
pational exposure to trichloroethylene. Contact Dermatitis Yamakage A, Ishikawa H (1982) Generalized morphea-like
10:270-276 scleroderma occurring in people exposed to organic solvents.
Rilliet A, Hunziker N, Brun R (1980) Alcohol contact urticaria Dermatologica 165=186-193
syndrome (immediate-type hypersensitivity). Dermatologica
161:361-364
CHAPTER 85
Plasticizers and Other Additives in Synthetic Polymers

B. Björkner
Introduction and butyl phthalate, dialkyl (C 6 Cl l ) phthalate and

diethylhexyl adipate. Adipates and other aliphatic
diesters are used in low-temperature applications,
Additives are used to modify the properties of plastic
while trimellitates are used for high-temperature
material. The major classes of additives for plastics are
applications. Methyl-, ethyl-, and butyl phthalates are
plasticizers, fillers and reinforcements, biocides, flame
more often used as solvents than as plasticizers in the
retardants, heat stabilizers, antioxidants, ultraviolet
plastics industry.
(UV)-light absorbers, blowing agents, initiators, lubri-
cants and flow-control agents, antistatic agents, curing
agents, colorants, solvents and optical brighteners.
There are nearly 2500 individual chemicals or mixtures Flame Retardants
that are utilized in the above major classes of additives.
In the plastic industry, the word "compound" de- Flame retardants are required for high-performance
scribes a chemical product composed of the plastic thermoplastic res ins because of the use of the resins in
resin mixed with additives. Compounds are delivered electrical and high-temperature applications. Numer-
to the plastic industry as powders or pellets. Master- ous chemicals are used as flame retardants. Chlorine-
batch is a concentrated mixture of additives and and bromine-containing aliphatic, cycloaliphatic and
plastics. aromatic compounds are the most widely used. Others
are antimony trioxide, aluminum hydrate and chlor-
paraffins. A more fire-resistant epoxy resin can be
Plasticizers produced by bromating bisphenol A in epoxy res ins to
tetrabromobisphenol A.
Plasticizers, which are added to improve the flexibility,
softness and processibility of plastics, constitute a
broad range of chemically and thermally stable prod- Heat Stabilizers
ucts of a variety of chemical classes. Their principal
use is in thermoplastic resins, and 80-85% of the Plastics, particularly chlorine-containing polymers, are
world's production of plasticizers are used in polyvinyl susceptible to thermal decomposition when exposed to
chloride (PVC) manufacturing. Approximately 450 high temperatures or prolonged heating. There are
plasticizers are commercially available. Many are esters several kinds of stabilizers on the market. The most
of carboxylic acids (e.g. phthalic, isophthalic, adipic, important contain lead, tin, calcium and zinc or
benzoic, abietic, trimellitic, oleic, sebacic acids) or barium and zinc. Epoxidized oils and esters are also
phosphoric acid. Other plasticizers are chlorinated used. Diphenylthiourea is used as a heat stabilizer in
paraffins, epoxidized vegetable oils and adipate poly- PVC.
mers.
Although there are about 100 phthalates that have
been employed as plasticizers, around 14-15 phthalates
Antioxidants
account for over 90% of commercial phthalate
production. The most commonly used phthalate is
diethylhexyl phthalate (DEHP), which is often called Oxidative degradation of polymers during the manu-
dioctyl phthalate (DOP). Other plasticizers used are facturing process or during their useful lifetimes are
butyl benzyl phthalate (BBP), diisononyl phthalate major industrial concerns. Examples of antioxidants
(DINP), diisodecyl phthalate (DIDP), methyl-, ethyl- are alkylated phenols and polyphenols [e.g. butylated

Plasticizers and Other Additives in Synthetic Polymers 689
hydroxytoluenes (BHT) and 4-tertiary-butylcatechol], also cause cracks in the plastic materials. Biocides are
epoxidized soybean oil, propylphenolphosphite, thi- usually added to plastie products used in environments
obisphenol, organic phosphates, bisphenol A, benzo- with high temperatures and dampness, e.g., saunas,
phenone, hydroquinones and triazoles. showers, pools and boats. The most-used biocides are
methyl- and octyl isothiazolinones and oxybisphe-
noxarsine (OBPA).
Ultraviolet-Light Absorbers
Radiation from the sun or fluorescent light is respon- Colorants (Dyes and Pigments)
sible for the rapid degradation of most plastics. The
most widely used UV absorbers belong to seven Pigments are inert and, unlike dyes, insoluble in the
distinct chemieal classes: medium in which they are incorporated. Both inor-
1. Benzophenones ganic and organic pigments are used in plastics. Most
2. Benzotriazoles colorants are inorganic pigments, with titanium diox-
3. Salicylates ide being the most commonly used and iron oxides the
4. Acrylates second most common.
5. Organo-nickel derivatives
6. Hindered amines
7. Metal complexes with dialkyldithiocarbamate Metals and Metal Salts
The most widely used UV absorbers are 2-hydroxy-
benzophenones, 2-hydroxy-phenyl-benzotriazoles and Many metals, metal salts and metallic compounds are
2-cyanodiphenylacrylate. used as additives in plastics. They are used as
stabilizers, pigments, fillers, flame retardants and
antistatics. The most commonly used metals are
Initiators aluminum, titanium, lead, zinc, antimony, tin, chro-
mium, and molybdenum. Nickel, copper and zirconi-
um compounds are used to a lesser degree.
Most commercial synthetic polymers are produced by
a chain-reaction polymerization process. Some of the
many initiators used are various peroxides (e.g.
Skin Problems from Plastic Additives
benzoyl peroxide, di-tertiary-butyl peroxide, cyclo-
hexanone peroxide and methyl ethyl ketone peroxide).
There are more than 65 commercially available organic Allergic and irritant contact dermatitis to various
peroxides in over 100 formulations. additives are briefly mentioned in connection with
various plastics by other authors. In spite of the fact
that phthalates are the most widely used additives,
Curing Agents there are only a few reports in the literature of contact
dermatitis caused by phthalates. Allergie contact
dermatitis from dibutyl phthalate has been reported
The usefulness of a number of plastics, such as
when used in a plastic watch strap, an anti-perspirant
unsaturated polyester, epoxy and phenolic resins, is
spray and asteroid cream [1-4]. Contact dermatitis
limited unless their linear polymer chains are cross-
from diethyl phthalate has been reported from
linked or cured. The various curing agents and
spectacle frames, and a hearing aid was reported to
compounds used as initiators (accelerators or cata-
cause contact dermatitis from cellulose-ester plastics
lysts) are discussed under the various plastics.
[5, 6]. Two cases of contact allergy to the dimethyl
phthalate in computer mice have been reported by
Capon et al. [7].
Biocides
An outbreak of dermatitis that occurred in an
aircraft factory was caused by o-diglycidyl phthalate,
Biostabilizers will prevent the growth of micro-organ- among other chemicals [8]. Burrows and Rycroft have
isms on plastic surfaces and in the pores of some reported contact allergy to tricresyl ethylphthalate in a
plastics. Plastic materials easily attacked by micro- plastic-nail adhesive [9]. Phthalates can also appear in
organisms are PVC, polyurethane, silicon products and deodorant formulations, perfumes, emollients and
fiber products based on polypropylene and polyamide. insect repellents [10]. Triphenylphosphate allergy from
Miero-organisms usually cause discoloration but can spectacle frames has been reported [11, 12].
690 B. Björkner: Plasticizers and Other Additives in Synthetic Polymers
In 1976, the International Contact Dermatitis 5. Smith EL, Calnan CD (1966) Studies in contact dermatitis
Research Group (ICDRG) examined an incidence of XVII. Spectacle frames. Trans St Johns Hosp Derm Soc 52:10
6. Oliwiecki S, Beck MH, Chalmers RJG (1991) Contact derma-
sensitization to the flame retardant tris(2,3-dibromop- titis from spectacle frames and hearing aid containing diethyl
ropyl)phosphate and found two positives among 1103 phthalate. Contact Dermatitis 25:264
patients. One of these two cases has been reported in 7. Capon F, Cambie MP, Clinard F, et al. (1996) Occupational
contact dermatitis caused by computer mice. Contact Der-
detail by Andersen [13]. matitis 35:57
Contact allergies to UV -light absorbers like 8. Burrows D, Fregert S, Campbell H, Trulsson L (1984) Contact
2-hydroxybenzophenone, resorcinol monobenzoate, dermatitis from the epoxy res ins tetraglycidyl-4,4' -methylene
dianiline and o-diglycidyl phthalate in composite material.
2-(2-hydroxy-s-methylphenyl)benzotriazole (Tinuvin P) Contact Dermatitis 11:80
and bis-(2,2,6,6)-tetramethyl-4-piperidyl-sebacate have 9. Burrows D, Rycroft RJG (1981) Contact dermatitis from PTBP
been encountered [14-16]. Organic pigments, mostly of resin and tricresylethylphthalate in a plastic nail adhesive.
the azo types, are potentially sensitizing additives in 10. Hamanaka S, Hamanaka I, Otsuka F (1992) Phthalic acid
plastics [17, 18]. dermatitis caused by an organostanic compound, tributyl-
Other additives of dermatological importance are tinphthalate. Dermatology 184:210
11. Carlsen L, Andersen KE, Egsgaard H (1986) Triphenylphos-
hydroquinone, p-tertiary-butyl-catechol, cobalt naph- phate allergy from spectacle frames. Contact Dermatitis 15:274
tenate, benzoyl peroxide, dimethylaniline, methyl- 12. Camarasa JG, Serra-Baldrich E (1992) Allergic contact
4-toluene sulphonate, p-tolyldiethanolamine, and dermatitis from triphenylphosphate. Contact Dermatitis
26:264
dimethyl-, diethyl- and diphenylthiourea. These agents 13. Andersen KE (1977) Sensitivity to a flame retardant, tris(2,3-
may cause both allergie and irritant contact dermatitis dibromopropyl)phosphate (Firemaster L V T 23 Pi. Contact
[19]. Dermatitis 3:297
14. Niklasson B, Björkner B (1989) Contact allergy to the UV-
absorber Tinuvin P in plastics. Contact Dermatitis 21:330
15. Ikarashi Y, Tsuchiya T, Nakamura A (1994) Contact sens i-
tivity to Tinuvin P in mice. Contact Dermatitis 30:225
References 16. Björkner B, Niklasson B (1997) Contact allergy to the UV
absorber Tinuvin P in a dental restorative material. Am J
Contact Dermat 8:6
1. Husain SL (1975) Dibutylphthalate sensitivity. Contact Der- 17. Kanerva L, Jolanki R, Estlander T (1985) Organic pigment as a
matitis 1:395 cause of plastic glove dermatitis. Contact Dermatitis 13:41
2. Calnan CD (1975) Dibutylphthalate. Contact Dermatitis 1:388 18. Jolanki R, Kanerva L, Estlander T (1987) Organic pigments in
3. Sneddon IB (1972) Dermatitis from dibutylphthalate in an plastics can cause allergic contact dermatitis. Acta Derm
aerosol anti-perspirant and deodorant. Contact Dermatitis Venereol Suppl (Stockh) 134:95
Newslett 12:308 19. Kanerva L, Björkner B, Estlander T, et al. (1996) Plastic
4. Wilkinson SM, Beck MH (1992) Allergie contact dermatitis materials: occupational exposure, skin irritancy and its
from dibutyl phthalate, propylgallate and hydrocortisone in prevention. In: van der Valk PGM, Maibach HI (eds) The
Timodine. Contact Dermatitis 27:197 irritant contact dermatitis syndrome. CRC, Boca Raton, p 127
CHAPTER 86
Cutting Fluids
l.S. Foulds
Introduction The advantages of cutting fluids have been known

for hundreds of years. Originally, water was used as a
coolant for processes such as reaming out of gun
Most metal-cutting operations require the use of
barrels, but had the disadvantage of corroding the
cutting fluids, and even those operations that can be
workpiece and provided little in the way of lubrication.
performed dry can often be carried out more efficiently
Over the years, cutting fluids were gradually developed
by the use of a cutting fluid. Cutting fluids are often
to improve efficiency.
referred to as metalworking fluids, but can also be
known as lubrication fluids, cooling emulsions or oils,
and drilling fluids.
Classification of (utting Fluids
Cutting fluids are liquids that flow or are sprayed
over metal that is altered in some physical way. This
may be by direct cutting through the metal, drilling, Cutting fluids may be classified as insoluble (neat or
reaming, boring, grinding, milling, tapping, drawing or straight) oils and soluble oils (Table 2). The soluble oils
rolling. Cutting fluids have several functions. As the are soluble in water and divided into synthetic, semi-
machine tool cuts into the metal (the workpiece), the synthetic and so-called soluble or emulsifiable oils.
pressure between the newly formed chip and the tool
head pro duces frictional heat (Fig. 1). This heat is Neat Oils
transferred to the workpiece, resulting in thermal
expansion of the metal. As a result, the workpiece may Neat oils are usually based on mineral oils which are
lose its dimensional accuracy on cooling, resulting in a formed by the decomposition of animal and vegetable
technically unacceptable product. Temperatures in matter over aperiod of millions of years within the
excess of 1300 °C may be generated at the tool head Earth's crust. Traditionally, the most commonly used
without cooling fluids, and the chips of metal removed oils are the so-called spindie oils produced by the
from the workpiece may then weId to the tool head, solvent refining of paraffin oils or from solvent
resulting in deformation, cracking and a reduced tool extraction of naphthenic oils which are distillates of
life. Therefore, cutting fluids are aimed primarily at the crude oil. However, with increasing requirements for
point of contact between the tool head and the environmentally friendly oils to aid disposal, more oils
workpiece to achieve maximum cooling effect. By of animal or vegetable origin are now being used.
providing lubrication in addition to cooling at the tool These include oils such as lard oil, tallow, skin grease
head, cutting fluids will reduce frictional forces, or fish oils. Most neat oils now being developed, such
allowing the tool to pass more cleanly through the as rape-seed oil or castor oil, are of vegetable origin.
metal and resulting in a smoother finish. This also has One of the advantages of neat oils is that they have
the advantage of reducing power consumption. The less tendency to become rancid and therefore germi-
chips of metal (often referred to as swarf) are removed cidal agents may not be required. Their main disad-
by the constant flow of cutting fluids over the vantage is their flamm ability. They are used principally
workpiece. Depending upon the metal being machined, as lubricants for moderate-to-heavy-duty machining
the size of the metal chips may vary in size from a fine and therefore do not tend to be very efficient coolants.
dust to large spiky pieces of metal. The metal chips In heavy machining operations, pressures generated
may cause physical damage to the skin, making it more between the tool head and metal workpiece may be
susceptible to the potential irritant effects of the very large, which tends to force out the film of
cutting fluid. These functions are summarised in lubricating oil. This can be overcome by the addition
Table 1. of extreme-pressure additives, and a clue to this may

692 1.5. Foulds
grounds, new classes of EP additives based on highly

overbased sulphonates are being introduced; these
WORKPIECE additives also have the benefit of reducing corrosion of
the workpiece. In fact, corrosion of the metal being
machined can be an unacceptable problem, and
corrosion inhibitors which may cause skin sensitisa-
tion problems are not infrequently added to neat oils.
Epoxy compounds mayaiso be added to scavenge any
CHIP
free radicals, and these mayaiso cause sensitisation
reactions.
1 Neat oils are usually easy to recognise, as they look

and smell like an oil and usually have a brown
translucent colour. If mixed with water, they fioat on
TOOL the surface as insoluble globules.
Soluble ails
Synthetic Oil5
Fig. 1. Schematic diagram of machining operation
Synthetic oils have the advantage that they contain no
Table 1. Functions of cut- mineral oil and are mainly solutions of wetting agents
ting fluids Cool the workpiece and corrosion inhibitors in water. They tend to be
Reduce frictional heat between
tool and chip based on soaps and are therefore potentially irritant.
Remove swarf They may contain germicidal and anti-foaming agents.
Increase the surface finish of the They are usually supplied neat and used at dilutions of
workpiece
Prolong the tool life 1-2%. They tend to have adear, watery appearance
Reduce power consumption and may be referred to by the workforce as "water".
Dyes such as fiuorescein may be added, resulting in a
dear green or yellow liquid. Although they are
Table 2. Classification of cutting fluids excellent coolants, they lack the oiliness necessary to
provide sufficient lubrication required for many pro-
Type of oil Appearance Use Dilution
ces ses. Where cooling is a primary function, such as in
Neat/straight Oily, waterless Heavy-duty No lubrication grinding, they are frequently used.
oils material,
corrosion Semi-Synthetic Oil5
inhibition
Soluble/ Milky colour, Coolant/ Yes,2-3%
emuIsifiable aqueous lubrication, Semi-synthetic oils contain mineral oils of concentra-
oils corrosion tions varying between 10% and 50%. They therefore
inhibition
Semisynthetic Translucent Coolant/less Yes,1-3% provide more lubrication than synthetic oils. To enable
oils, soluble lubrication the mineral oil to blend with water and remain in a
than for finely dispersed state requires the addition of emulsi-
aqueous oils
Synthetic oils Transparent, Excellent Yes,1-5% fiers (20-40%). These are often based on petroleum
aqueous coolant, sulphonates, which are produced by the sulphuric-acid
minimal treatment of spindie oils to produce white oils and
lubrication
carboxylic acids.
Soluble (Emul5ifiable) Oil5

be in the name of the oil, e.g. Castrol EP 501, where the
EP refers to the indusion of extreme-pressure addi- Soluble (emulsifiable) oils are composed mainly of
tives. Traditionally, these additives have been based on mineral oils (concentration 60-80%), which also
sulphur, chlorine and phosphorous which, at the high require emulsifiers (20-40%) to enable the oil to
local temperatures generated between the metal sur- blend. Supplied neat, they have an oily appearance but,
faces, form metal sulphide, chloride and phosphate on dilution with water, they take on a characteristic
bonds which then act as asolid lubricant preventing milky colour and may be referred to by the workforce
direct metal-to-metal contact. However, with current as "suds". If petroleum sulphonates are used alone as
press ures to eliminate chlorine on environmental emulsifiers, then the pH of the soluble oil tends to lie
Cutting Fluids 693
between 7 and 8 which, although more acceptable to Table 3. Composition of a

soluble (emulsifiable) Lubricants (mineral oil)
the skin, tends to favour the growth of microorgan- cutting fluid Emulsifiers/surfactants
isms. In practice, therefore, a mixture of petroleum Corrosion/anti-stain inhibitors
sulphonates and carboxylic acids are used, with the Extreme-pressure additives
Coupling agents
possible addition of caustic soda to raise the pH to a Biocides
preferred level of 9-10.5, which reduces bacterial Antifoaming agents
growth. This more alkaline pH, although more irritant Reodorants
to the skin, re duces corrosion to the workpiece.
Corrosion is further reduced by the addition of Aerobic.
corrosion inhibitors, which allows the oils to be used Pseudomonas aeruginosa, Nocardia
at a greater dilution. Sodium nitrite is still a popular Anaerobic.
corrosion inhibitor, as are aliphatic amines such as Coliforms, Desulphovibrio
triethanolamine. Older corrosion inhibitors such as
sodium mercaptobenzthiazole and benztriazole have After a short period of usage, most oil emulsions are
largely been removed because of their sensitisation at risk of contamination from machine tools, compo-
capacity. nents or operators' hands. Sumps with little movement
Soluble (emulsifiable) oils, like neat oils, also of oil may become contaminated if other waste
contain extreme-pressure additives. They may also materials (e.g. food waste, cigarette ends, etc.) finds
contain dyes. In addition, to improve their worker their way in, particularly if there is poor hygiene or
appeal, soluble (emulsifiable) oils may also contain housekeeping. Within the sump, conditions exist for
reodorants (fragrances), as an oil left unused may the growth of both aerobic and an aerobic organisms
become stagnant (often referred to as a "Monday (Fig. 2). Swarf may settle on the bottom of the sump,
morning smell" following a weekend shutdown). If the providing stagnant conditions, or tramp oil may float
oils contain carboxylic-acid soaps as emulsifiers they on the surface, allowing an aerobic growth. Tramp oil is
have a tendency to foam, and therefore anti-foaming lubricating or hydraulic oil required for the moving
agents such as silicone or waxes may be added to parts of a machine, this oil may leak into the sump or
reduce foaming. A fully formulated oil contains a contaminate the cutting fluids.
multitude of additives, some of which are oil soluble The presence of bacteria, apart from causing a nasty
(e.g. EP additives) and so me water soluble (e.g. smell, will lead to a breakdown of an emulsion, leading
corrosion inhibitors). Therefore, a coupling agent to a technically unacceptable oil and a poorly ma-
may also be added to act as a solvent between the chined end product. Although bacterial contamination
water and oil phases to produce a single stable can be minimised in a variety of ways (see the section
emulsion. These may be based on phenolics (e.g. entitled Prevention of Cutting Fluid Dermatitis), one
p-chloro-m-xylenol), which impart a disinfectant way that always is required is the addition of germi-
odour to the oil. cidal agents known as biocides. Unfortunately, it is
One of the main problems with soluble (emulsifi- these agents which tend to cause skin sensitisation.
able) oils is that they provide an excellent medium for Biocides within cutting fluids are classified into two
the growth of microorganisms, requiring the addition groups: formaldehyde-releasing biocides and non-
of germicidal agents. It can therefore be seen that a formaldehyde-releasing biocides (Table 4). Formal-
fully formulated soluble (emulsifiable) oil is a highly dehyde-releasing biocides release formaldehyde
complex mixture (Table 3). depending upon the pH of the cutting oil (Rossmoore
1981). Although the operating pH of cutting fluids may
Preservation of Cutting Fluids
TRAMP 011----14110'
Most machines that use cutting fluids have a reservoir
of oil (called the sump), with the oil being continually
recycled around the machine until it is replaced. AEROBIC
Bacteria, yeast and fungi can all potentially grow in a .-_+-_ EMULSION _+-_.
poorly preserved cutting fluid. Yeasts that may grow ANAEROBIC
include Aspergillus niger and Candida albicans (Each-

us et al. 1978). Most bacteria that grow are non- METALCHIPS
~~~~~~Z2t"-- (SWARF)
pathogenic and may originate from the water supply
used to dilute the oil (Rycroft 1980). Those found Fig. 2. Schematic diagram of a machine sump and potential for
include: the existence of anaerobic/aerobic conditions
694 1.5. Foulds
not favour this, it is thought that the pR at cell odour, a change of pR towards an acidic level, slime
boundary of potential bacteria is more favourable for accumulation, microbiological culture or loss of emul-
formaldehyde release (Roltzman and Rossmoore 1977). sion with oil droplets appearing.
Formaldehyde releasers are usually water soluble and
oil insoluble, showing efficacy against bacteria but
having less of an effect on moulds and fungi (Zuger-
man 1986). Most of this dass of biocides are relatively
Skin Problems Associated with (utting Fluids
non-toxic and inexpensive.
Non-formaldehyde-releasing biocides are relatively The problems potentially caused by cutting fluids are
more effective against fungi and moulds as weIl as listed in Table 5. With solvent refining of oils, acne and
being effective against bacteria. The phenolic members folliculitis is now seen rarely. Primary irritant and
of the group are oil soluble, whereas the morphine allergie contact dermatitis are the most frequently
derivatives are partially oil and partially water soluble. encountered dinical problems.
Alterations of pR appear to have little impact on their The most common pattern of cutting-fluid derma-
effectiveness. Although some of the bioeides used are titis is that of a patchy eczema involving the backs of
similar to those used in cosmetics and topical prep- the hands, the forearms, the backs and sides of fingers
arations, some widely used preservatives are not and web spaces. The appearance may be confused with
suitable for use in cutting fluids. For example, constitutional discoid eczema, particularly in middle-
quaternium ammonium compounds may cause foam- aged men. Although patchy patterns are most com-
ing and are readily absorbed onto the surfaces of mon, other patterns of eczema mayaiso be found,
metals. Other potential preservatives may cause envi- induding fine follicular eczema, continuous confluent
ronmental problems on disposal. Although most areas and dry, scaly finger webs.
biocides are added at the time of oil manufacture, Although it is commonly stated that dermatitis
they may also be added at the time of use, particularly involving the backs of the hands and finger web spaces
if there is suspected bacterial contamination. Bacterial is irritant whereas dermatitis affecting the palms is
contamination may be suspected if there is a foul allergie, this does not appear to hold true for cutting-
Table 4. Potential biocides within cutting fluids
Trade name Chemical type
Bakzid 2 Oxazalidine + sodium omadine

Bioban CS1l35 4,4-Dimethyl oxazalidine + 3,4,4-triethyloxazalidine
Bioban CS1246 Ethyldihydro-oxazalidine
Bioban P1487 4-(2-Nitrooctyl) morpholine + 4,4-(2-ethyl-2-nitrotrimetylene) dimorpholine
Bodoxin l-Amino propan-2-01 + 5-chloro-2-methyl-4-isothiazolin-3-one + 2 methyl isothiazolinone
Bronopol 2-Bromo-2-nitropropane-1 ,3-diol
Cinon A triazine
Dowicide 1 Orthophenylphenol
Dowicil75 Chloroallyl triaza azoniadamantane chloride
Emulcid, Glokill 77 Triazine (1,3,5 tris(hydroxyethyl) hexahydrotriazine)
Glokill 80 An isothiazolinone mix
Grotan BK Triazine (1,3,5 tris(hydroxyethyl) hexahydrotriazine)
Grotan OD Oxazalidine + sodium omadine
Kathon 886 5-Chloro-2-methyl-4-isothiazolin-3-one + 2-methyl isothiazolinone-3-one
Kathon 893 2-0ctyl-4-isothiazolin-3-one
Keytrol T S-Triazine (1,3,5 tris(hydroxyethyl) hexahydrotriazine
Panacide Diehlorophen
Proxel CRL 1,2-Benzisothiazolinone-3-one
Sodium omadine Sodium 2-pyridinethol-1-oxide
Sodium pyrion Sodium 2-pyridinethol-1-oxide
Tribaktolan Methylol compounds + isothiazolinone
Table 5. Skin problems associated with cutting fluids
Type of oil Effects on the skin Site of involvement
Neat insoluble oils Folliculitis/oil-induced acne, furunculosis (boils), injury from metal chips, Forearms, thighs, hands, face
rarely allergie contact dermatitis to additives
Water-soluble oils Irritant contact dermatitis, allergie contact dermatitis, injury from metal Hands, forearms, face
chips, rarely bacterial infection
Cutting Fluids 695
oil dermatitis. In aseries of 174 people with cutting-oil oil flows onto the forearms, then this site is also
dermatitis, 55% had involvement of the dorsa of the commonly affected. Protective gloves may not be
hands and web spaces which was shown to be allergie. practical because of moving machine parts resulting
Involvement at sites other than the dorsa of the hands in gloved hands being drawn into the machine. In
occurred in 54% of the patients with irritant contact addition, the task of changing tool heads is delicate,
dermatitis (Grattan et al. 1989). making glove-wearing difficult. If quality control
requires frequent microscopic measuring (gauging),
Irritant Contact Dermatitis then frequent removal of gloves to enhance manual
dexterity may result in contaminated hands going back
Irritant contact dermatitis is the most frequendy inside the occlusive waterproof glove, contributing to
encountered clinical problem, varying between 50% skin irritation.
(Alomar et al. 1985; Fisher 1979) and 80% (Key 1966) in
reported series. Irritant contact dermatitis is influ- Allergie Contact Dermatitis
enced by the nature of the cutting fluid. Those that
have a high level of soap, e.g. synthetic oils, are Allergie contact dermatitis always has to be considered
potentially more irritant to the skin. However, water in any outbreak of oil-related dermatitis, accounting
itself may lead to maceration and reduced barrier for more than 50% of some series investigated (Grattan
function with increased irritant contact dermatitis risk. 1989; Alomar 1985). Alomar described four different
Not only do the ingredients contribute toward irrita- patterns with varying incidences of sensitisation:
tion, but the concentration of these ingredients and the
a. Erythematous papules mainly on the forearms and
length of exposure are also relevant. Host factors are
dorsa of the hands accounted for 24% of the series,
also important. Factors which increase the risk of
with a 47% incidence of positive patch tests
irritant contact dermatitis include increasing age,
b. Papulovesicles on the hands and fingers accounted
cumulative working exposure, skin type, presence of
for 38% of the series, with a 57% incidence of
active skin disease, a previous his tory of atopic eczema
positive patch tests
(particularly if this affected the hands) and personal
c. Lichenified and fissured palmar eczema accounted
hygiene. As a result of high alkaline pH of an oil,
for only 12.6% of the series, with a 55% incidence of
buffering by the skin is impaired, resulting in reduced
positive patch tests
barrier function. Emulsifiers and soaps contained
d. Discoid eczema accounted for 25.4% of the series,
within the oils may degrease the skin, denaturing
with a 68% incidence of positive patch tests
keratin and lowering its hydration. This then results in
dryness, flaking, fissures and eventually clinical ecze- Therefore, it can be seen that allergie contact factors
ma. Additional contributions to the onset of irritant are common, and appropriate, skilled patch-testing
contact dermatitis result from poor hand care and investigations can determine relevant causes.
hygiene of the individual, particularly with respect to Allergens found include biocides such as formalde-
additional employment undertaken and hobbies pur- hyde and formaldehyde releasers, isothiazolinones,
sued. Fine metal particles machined from the work- phenols, morpholines, ethylenediamine and biostatic
piece will add additional abrasion to the skin, agents such as alkanolamines; borate complexes are
contributing to the onset of irritant contact dermatitis. amongst the most common allergens found within
Most irritant contact dermatitis occurs on the skin cutting oils (DeBoer et al. 1989). The widespread use of
of the hands, which is exposed to the flow of oil. This bio eides in industrial and cosmetic products means
may affect the machine-tool setters who have to change that sensitisation may result from domestic or personal
the tool heads, requiring their hands to go right into a exposure to cosmetics and toiletries. For example,
machine. If the flow of oil is not stopped during this biocides in the Kathon range (chlormethylizothiazoli-
procedure, then their exposure is significant. A setter none) may not only be found in cutting oils, but also in
may be responsible for 20 to 50 machines in a large shampoos, cleansing agents, skin care products and
factory and have exposure to many different types of barrier and after-work creams.
cutting fluids. The machine operators, however, may It can be seen from Table 6 that when 174 patients
only operate a few machines in their area, and their (157 male, 17 female) with cutting-oil dermatitis were
exposure to oil can be vary considerably. If they have investigated (Grattan et al. 1989), many positives were
to place parts into and remove them from a machine, found on the standard series that were relevant.
they may experience constant exposure to the oil and Metals such as nickel, chromate and cobalt are
be at increased risk of irritant contact dermatitis. Most liberated into the cutting fluids from the metal being
oil flow is over the backs of the hands and finger web machined. Although levels found are lower than one
spaces, and it is these areas that tend to first be would normally expect for sensitisation to occur, the
clinically involved with irritant contact dermatitis. If fact that 9.6% of males in the series were nickel
696 1.5. Foulds
Table 6. Positive patch-test results obtained in 174 patients Ethylenediamine may be added to an oil as a
corrosion inhibitor and was originally described by
Standard series Frequency Percentage
(%) of total
Crow (1978). Other allergens found on the standard
series include fragrance mixtures and balsam of Peru,
Nickel sulphate 20 11.5 which may be relevant to reodorants contained within
Colophony 16 9 the oil, and formaldehyde releasers such as Qua-
Formaldehyde 13 7.5
Quaternium 15 10 5.7 ternium 15.
Neomycin 9 5.2 Epoxy resin (standard digycidyl ether of Bisphenol
Potassium dichromate 9 5.2 A) may also test positive and can be relevant, as epoxy
Thiuram-mix 8 4.6
Fragrance-mix 8 4.6 compounds may be used to stabilise chlorinated
Epoxy resin 7 4.0 paraffins, particularly in neat oils (Scerri and Dalziel
Ethylenediamine 3 1.7 1996). However, cross-reactions to standard epoxy
Mercapto-mix 2 1.1
Balsam of Peru 2 1.1 resin do not always occur. Epoxide 7 may be present as
Cutting-fluid series a corrosion inhibitor and cause sensitisation (Rycroft
Formaldehyde-releasing biocides 45 25.9 1980), and cases of sensitisation to the glycidyl ester of
Non -formaldehyde- 32 18.4
releasing biocides hexahydrophthalic acid (an epoxy compound) have
Corrosion inhibitors 17 9.8 been found (English et al. 1986).
Coupling agents 7 4 Although many causes of allergy can be identified
Emulsifiers 2 1.1
from the standard series, many other cases will be
missed unless the specific allergen is tested for. There
sensitive was significant (P = 0.004) compared with is often debate as to what is an appropriate strength at
2395 males with non-occupational eczema (Grattan which to test cutting oils. Fisher (1979) suggested that
et al. 1989). This would suggest that the irritant effect both the original clean oil and the dirty oil be used to
of the cutting fluids not only damages the skin, test patients at a dilution of 1:25. However, at this
resulting in irritant contact dermatitis, but that this dilution, allergie sensitisation to an additive may be
then allows for easier penetration of potential aller- missed if the additive is only contained at a low
gens into the skin, with sensitisation subsequendy concentration in the original oil. Dilution may reduce
occurring. the additive to such an extent that not enough is
This also applies to cases of sensitisation to sodium available to elicit areaction on patch testing; in
mercaptobenzthiazole (a corrosion inhibitor), where practice, however, patch tests at this dilution may elicit
sensitisation occurs in spite of working levels between an allergie dermatitis through damaged skin in indi-
0.01% and 0.05%. The fact that this can occur suggests viduals experiencing repeated exposure to low levels of
that there are particular factors related to cutting-fluid irritant. Therefore, over the last 20 years my practice
sensitisation that are not found in other situations. has been to patch test with unused oil at 100%, 50%
Apart from the irritancy of oils, particularly if and 10%, with the water-soluble oils diluted in water
inappropriate strengths are used, the warmth of the and the neat oils diluted in methyl ethyl ketone.
oils, the wetness of the situation, the abrasion from Allergie reactions tend to have a graduated lessening of
metal fragments and occlusion from protective gloves reaction with increasing dilution, whereas irritant
may all contribute to the high level of sensitisation reactions tend to have a sharp cut-off below a certain
found. concentration. Many (particularly the oil suppliers)
In addition, sensitisation to formaldehyde occurs in would argue that the strengths tested will produce a
spite of low concentrations found, with 8.3% of males false positive irritant reaction. Although this is more
being found positive compared with 2.2% of controls common with synthetic oils due to their high soap
(P = 0.00001). Many of the bio eides added to cutting content, it rarely seems to be the case with other oils.
fluids may release formaldehyde, resulting in sensiti- With any new oil tested, however, it is vital to check
sation. that the results are not false positive irritant, which can
Colophony (rosin) may be present as an emulsifier be established by control testing. Also, in practice, I
(Tall oll) in some oils and may cause sensitisation have never found testing with used oil to be of any
(Matos et al. 1988). Sensitisation occurred in 9.6% of additional benefit. False positives may occur with used
males compared with 5.7% of controls (P = 0.046) oil if metal ions are responsible for the reaction, but
(Grattan et al. 1989). It mayaiso be found as soap this is always detected by screening with the standard
water in some oils (Fregert 1979). Non-occupational series.
causes of colophony exposure may also contribute to If a positive reaction to an oil is found with negative
the onset of dermatitis, as it is not unusual for controls, then screening with a cutting-oil series of
individuals to wrap fissured fingers with colophony- potential allergens may help to elicit the cause.
containing pIasters. However, it may be necessary to obtain both full
(utting Fluids 697
ingredient information from the suppliers and fresh a. Dipentine as an extreme press ure additive (Rycroft
sampies if new allergens are not to be missed. 1980).
The following are some of the specific chemicals that b. Alkanolamine borates have become widely used in
may be encountered in a case of allergie contact cutting fluids as corrosion inhibitors, and they also
sensitisation. have some biostatic potential. Although difficult to
patch test because of their alkalinity, when tested at
Formaldehyde-Releasing Biocides 1% buffered they have been shown to be sensitisers
(Bruze et al. 1995). However, no one individual
Some biocides are formaldehyde-releasing agents, and sensitiser has been identified (Jarvholm et al. 1995),
this may sometimes be the basis of their biocidal and therefore patch testing with the relevant
properties. Those described as sensitisers include: alkanolamine borate is essential.
c. Coconut diethanolamide (a surfactant) may sensi-
a. 5-Ethyl-l-aza-3,7-dioxabicyclo-3,3,o-octane (Bioban tise metalworkers, although the exposure to this was
CS-1246) (Dalquist 1984). mainly from barrier creams and hand-washing
b. 2-Hydroxymethyl-amino-ethanol tri-N-ethyl-hydroxy- liquids (Pinola et al. 1993).
2-amino-methylene (Forcide 78) (Hamann 1980). d. Fatty-acid ester EM-sso as an emulsifier may cause
c. Hexahydro-l,3,s-tris(2-hydroxyethyl)-s-triazine (in sensitisation (Niklasson et al. 1993).
Grotan BK) (Keczkes and Brown 1976; Rycroft e. Oleyl alcohol (octadecanol) as a surfactant found
1978). also in printing inks, textile-finishing products,
d. N-methylol-chloracetamide (in Parmetol Kso or antifoaming agents and plasticisers may sensitise
Grotan HD), which is also found in cosmetics, (Koch 1995).
topieal drugs and glues (Lama et al. 1986). N- f. Tertiary-butyl hydroquinone, present as an antiox-
methylol-chloracetamide may produce reactions in idant in cosmetics, has been found to sensitise in a
formaldehyde-sensitive individuals, and mayaiso vegetable-oil-based cutting fluid (Meding 1996).
cause sensitisation by its chloracetamide compo-
nent (Hjorth 1979).
e. Bioban P1487 is a water-based preservative that has Epidemiology of Cutting-Fluid Dermatitis
been in use for more than 10 years. It has two active
ingredients: 4-(2-nitrobutyl)-morpholine (M) and
4>4'-(2-ethyl-2-nitro-l,3-propanediyl)-bis morpho- Only a few epidemiological studies of the prevalence of
line (DM). Arecent guinea-pig study has shown cutting-fluid dermatitis have been published. In Sin-
DM to be a strong sensitiser compared to M, and as gapore, 6.6% of 751 workers in 21 small-scale factories
a result the concentration of DM has been reduced had a skin disorder of their hands and fore arms
from 20% to S% (Gruvberger et al. 1996). (Coenraads et al. 1985).
In Holland, 14% of 286 metalworkers exposed to oil
were found to have frank eczema and another 31% had
Non-Formaldehyde-Releasing Biocides minor skin changes such as dry skin or slight
erythema. Atopics did not have a higher rate of irritant
Non-formaldehyde-releasing-biocide reactions occur contact dermatitis compared to non-atopies (DeBoer
slightly less frequently than reactions to formaldehyde et al. 1989).
releasers but are still potentially significant. They Many patients with cutting-fluid dermatitis appear
include: to have chronic problems. In the UK, 30 of 174 patients
a. 5-Chloro-2-methyl-4-isothiazolin-3-one (Pilger et al. with dermatitis had it for 5 years before referral to a
1986) in the Kathon range contact clinic (Grattan et al. 1989).
b. 2-(Hydroxymethyl)-2-nitro-l,3-propanediol, which In a cross-sectional study, dermatitis occurred more
may cross-react with 2-bromo-2-nitropropane-l,3- frequently in 158 machinists than in 51 non-oil-exposed
diol (Bronopol), found in many topieal preparations assemblers (27.2% and 13.7%, P = 0.05). Risk factors
(Robertson and Storrs 1982) for the machinists included exposure to semi-synthetic
c. p-Chloro-m-xylenol, a phenolic germicide also used (as opposed to soluble) oils, current cigarette smoking
as a coupling agent, may sensitise (Adams 1981) and increasing worker age (Sprince et al. 1996).
Other Sensitising Oil Additives Investigation of Cutting-Fluid Dermatitis
Other sensitising oil additives requiring consideration

An investigative approach to a case of cutting-fluid
and specific investigation include:
dermatitis involves, firstly, the establishment of the
698 1.5. Foulds
diagnosis (Rycroft 1981). The main objective is to develop. Arm bands can help to keep oil off the
determine the roles of irritancy, allergy, endogenous forearms, and with heavy exposure, aprons and
factors or a combination of these in its aetiology. Wellington boots may also be required.
Most workers are exposed to several metalworking If gloves are not practical, then barrier creams may
fluids that may have undergone replacement since the offer some limited protection although the emulsifier
onset of dermatitis. The names, batch numbers and content of some oils will te nd to dissolve them away. A
manufacturers' addresses must be obtained and en- water-repellent barrier cream may offer some protec-
quiry made as to whether any other additives are tion. These may then allow less harsh cleansers to be
added when the cutting fluid is in use. Other relevant used when cleansing is required. During breaks and at
factors to consider include machine-cleaning chemi- the ends of shifts, cleansers which are the mildest for
cals, protective metal coatings (Cainan 1978), solvents the task required should be used, and any drying
for removing oil from finished pieces, barrier creams, effects induced should be counteracted with an
skin cleansers, protective equipment and domestic appropriate emollient after-work cream. The regular
contact factors. application of moisturising emollients is often difficult
Patch testing with a standard series of allergens, oil to achieve if no problems with dermatitis exist, as their
batteries (Foulds and Koh 1989) and ingredients of the use is often considered to be effeminate by a male
oil at appropriate dilutions as well as other potential workforce.
contact factors have to be performed. Facilities for If productivity payments are in place, these should
control testing are vital in order to exclude false not be offset by causing workers to take short-cuts in
positive irritant reactions. production-reducing skin care and protection. Allow-
If an allergen is identified, avoidance or substitution ing a clean-up time at the end of the shift can
is required. However, all the factors described below encourage good working practice and provide a more
under Prevention also need to be given credence. psychologically favourable working environment.
Adequate training of the employee in correct usage
of machines is important, particularly if oil flow can be
Prevention of Cutting-Fluid Dermatitis stopped when bare hands are placed within the
machine. Education of the workforce to prevent
contamination of the oil is vital. Unfortunately, any
When large numbers of people work with cutting
system that relies on the worker alone for prevention
fluids, it is impossible to prevent all cases of dermatitis,
will always fail.
as skin contact cannot be avoided. However, more
serious severe outbreaks of dermatitis are preventable.
Three aspects need to be considered: the machinist, the The Machine
machine and the oil itself.
Machinery should be built in such a way as to
The Machinist minimise the exposure of workers to the cutting fluids.
Manual feeding of workpieces, oil contact when
Pre-employment screening of individuals should try to machines are shut off and hands are placed into the
exclude those that have a personal history of long- machines, and the need to hold workpieces under the
standing atopic dermatitis, particularly if this has flow of oil when it is being machined are machine-
affected the hands. Those individuals with a previous design problems which will increase the risk of
his tory of hand dermatitis from other irritant causes development of dermatitis. Increasing automation with
are also at increased risk of recurrence. If they are computer-controlled machines which are enclosed to
allowed to work in a cutting-fluid environment, then prevent oil contact will reduce the incidence of
every effort needs to be made to enable them to dermatitis.
maintain meticulous hand care. Processes should be designed so as to minimise the
Gloves may not be practical because of the risk of need for frequent tool-head changes. Quality-control
being caught in the moving machines, but so me measurements should be designed so that gloves can
automatic machines will be compatible with glove still be worn.
usage. Gloves need to be impervious to the oil, but Effective filtration methods need to be in place to
contamination of the hands with oil may arise from remove the metal fragments from the machine, to
lacerations to the gloves from metal fragments, oil prevent anaerobic conditions encouraging bacterial
entry under the cuffs if the gloves are too short and growth and to lower the potential for metal ions to go
removal of gloves for more delicate operations. These into solution. Tramp oil should be prevented from
factors will lead to occlusion under the glove fabric, entering the cutting fluid and removed if it does. Regular
which may increase the risk that dermatitis will cleaning of the tool heads should be encouraged.
Cutting Fluids 699
If machines can be built with smooth internal pipe- in excess of 20% may occur. Depending on the type of
work and sumps made of stainless steel, then cleaning machine, measuring oil concentration and taking
of the machine becomes easier. Machines should be appropriate action may be required several times a
designed to operate at the lowest possible temperature, day. Keeping arecord of oil concentration beside
as this reduces evaporation of the water-based fluids. each machine is always a way of ensuring good
Low temperatures as well as low concentrations of housekeeping.
cutting fluid will also dis courage bacterial growth and The pH of the oil should be regularly monitored, as a
maintain cutting-fluid stability. change may be a sign of bacterial contamination.
Addition of caustic soda to increase the pH to a more
The Oil alkaline level should be discouraged, as this is poten-
tially irritating to the skin, and the reason for the
Oil formulators should be encouraged to develop oils bacterial contamination should be identified. The
that are potentially less irritating to the skin. This adding of additional biocides on-site potentially
could be achieved by reducing levels of anionic increases sensitisation risk because of higher biocide
compounds and increasing those of non-ionic com- working concentrations. If oil is recycled, then mon-
pounds, although this would have to balanced against itoring of potential concentrations of sensitising addi-
the technical requirements of the oil. Additives that are tives within the recycled oil is required.
known sensitisers should be excluded or used at low
levels which are less likely to sensitise in the first place.
If sensitisation to an additive has been identified in a
Prognosis of Cutting-Fluid Dermatitis
dermatitis outbreak, substitution of the additive will be
required to resolve the problem. The development of
additives to chelate metal ions that may be taken up by Very few studies document the natural history and
the oil solution from the metal swarf fragments should prognosis of cutting-oil dermatitis. In one study
be encouraged. Oohnson and Wilson 1971), 87 of 100 workers contact-
Predictive testing of cutting fluids for irritant (and ed 6-13 years after developing oil dermatitis responded
sensitising) potential is largely unsatisfactory (Itschner to a questionnaire; 60% were clear, 23% were better
et al. 1996). Useful information can be gained from and 17% remained unchanged - 82% of the workers,
human study by the application of oil under occlusion however, had changed their jobs. Those with a
for 24 h, followed by reapplication for a further 2 days personal history of constitutional eczema appeared to
at the same site; reactions appear to correlate well with fare as well as those without. Those with mild disease
the potential of a water-based cutting oil to cause with little time lost from work had the best prognosis.
irritation (Wigger-Alberti et al. 1997). Measurement of Another study (Grattan and Foulds 1989) with 40
transepidermal water loss following application of oil respondents of the 56 queried 8-31 months after
to the skin mayaiso help to predict irritant potential investigation showed that 45% were clear of dermatitis
(Huner et al. 1994) and appears to correlate better as a and, of the remainder, 75% had had an improvement in
predictor of irritancy than repeated sellotape-stripping their symptoms. Only one patient had to give up their
of the skin followed by measuring irritancy by laser work as a result of dermatitis.
Doppler flowmetry (DeBoer et al. 1990). Another study produced a less favourable outlook,
The working concentration of oils that require where 78% of 121 people who remained at work
dilution is one of the most important factors to continued to experience skin problems (Pryce et al.
monitor in order to prevent dermatitis occurring in the 1989). Of those who had changed jobs, 70% were still
first place. All too often, dilution of oils is left to a experiencing skin problems up to 2 years after the job
poorly informed labourer or dilutions are guessed at or change, with no relationship to an atopic tendency.
determined by the feel of the diluted oil. Concentration The poor pro gnosis in some studies may be due to
is easy to check using a refractometer giving an instant various factors. If the original clinical problem was
read-out. If oils are pre-diluted or diluted by using predominantly an irritant one due to inappropriate
premixing taps, the concentration should still be concentrations of oil being used, the cumulative
checked with a refractometer, as errors can occur. damage incurred may be difficult to reverse even if
Once the oil is within the machine, any heat genera ted the oils are subsequently used at correct working
will evaporate the water content of the oil, resulting in concentrations. If the problem is allergy based with
increased concentrations within the machine. There- minimal irritation present, then substitution of the
fore, if more diluted oil is added without checking the allergen will result in complete clearance with no
concentration within the machine, gradually there will ongoing skin disease (Foulds 1998). In practice, many
be a build-up of concentrated oil within the machine, causes of cutting-fluid dermatitis are multi-factorial,
and rather than oil being used at 1-2%, concentrations and the eventual outcome may be related to how far
700 1.5. Foulds: (utting Fluids
the individual physician is prepared to investigate, diethanolamide (Cocamide DEA). Contact Dermatitis 29:
advise and treat each case. 262-265
Itschner I, Hinnen H, Eisner P (1996) Skin risk assessment of
metal working fluids: a survey among Swiss suppliers.
Dermatology 193:33-35
References Jarvholm B, Ljungkvist G, Lavenius B (1995) Acetie aldehyde and
formaldehyde in cutting fluids and their relation to irritant
symptoms. Ann Occup Hyg 39:591-601
Adams RM (1981) P-chloro-m-xylenol in cutting fluids: two cases Johnson ML, Wilson HTH (1971) Oil dermatitis: an enquiry into
of allergie contact dermatitis in machinists. Contact Derma- its prognosis. Br J Ind Med 28:122-125
titis 7:341-343 Keczkes K, Brown PM (1976) Hexaltydro-l,3,5-tris(2-hydroxyeth-
Alomar A, Conde-Salazar L, Romaguera C (1985) Occupational yl)-5-triazine, a new bacteriocidal agent as a cause of allergie
dermatoses from cutting oils. Contact Dermatitis 12:129-138 contact dermatitis. Contact Dermatitis 2:92-98
Bruze M, Hradil E, Eicksohn IL, Gruvberger B, Widstrom L(1995) Key MM, Ritter EJ, Arndt KA (1966) Cutting and grinding fluids
Occupational allergie contact dermatitis from alkanolamine and their effects on the skin. Am Ind Hyg Assoc J 27:
borates in metal working fluids. Contact Dermatitis 32:24-27 423-427
Calnan CD (1978) Chromate dermatitis from soluble oils. Contact Koch P (1995) Occupational allergie contact dermatitis from oleyl
Dermatitis 4:378 alcohol and monoethanolamine in a metal working fluid.
Coenraads PI, Foo SC, Phoon WO, Lun KC (1985) Dermatitis in Contact Dermatitis 33:273
small scale metal industries. Contact Dermatitis 12:155-160 Lama L, Vanni D, Barone M, Patrone P, Antonelli C (1986)
Crow KD, Peachey BDG, Adams JE (1978) Coolant oil dermatitis Occupational dermatitis to chloroacetamide. Contact Derma-
due to ethylenediamine. Contact Dermatitis 4:359-361 titis 15:243
Dalquist I (1984) Contact allergy to cutting oil preservatives Matos J, Mariano A, Goncalo S, Freitas JD, Olivera J (1988)
Bioban CS-1246 and P-1487. Contact Dermatitis 10:46 Occupational dermatitis from colophony. Contact Dermatitis
De Boer EM, Van Ketel WG, Bruynzeel DP (1989) Dermatoses in 18:53-54
metal workers - (I) Irritant contact dermatitis. Contact Meding B (1996) Occupational contact dermatitis from tertiary
Dermatitis 20:212-218 butyl hydroquinone (TBHQ) in a cutting fluid. Contact
De Boer EM, Van Ketel WG, Bruynzeel DP (1989) Dermatoses in Dermatitis 34:224
metal workers - (Il) Allergie contact dermatitis. Contact Niklasson B, Bjorkner B, Sunberg K (1993) Contact allergy to a
Dermatitis 20:280-286 fatty acid ester component of cutting fluids. Contact Derma-
De Boer EM, Scholten RJ, Van Ketel WG, Bruynzeel DP (1990) titis 28:265-267
The irritancy of metal working fluids: a laser Doppler Pilger C, Nethercott JR, Weksberg F (1986) Allergie contact
flowmetry study. Contact Dermatitis 22:86-94 dermatitis to 5-chloro-2-methyl-4-isothiazolin-3-one. Contact
Eachus AC, Selleck JR and Hunsucker JH (1978) Antimierobial Dermatitis 14:201-204
aspects of metal working fluids. Chemieal Times Trends Pryce DW, Irvine D, English JSC, Rycroft RJG (1989) What
English JSC, Foulds IS, White IR, Rycroft RJG (1986) Allergie happens to patients with soluble oil dermatitis.
sensitisation to the glycidyl ester of hexahydrophthalic acid Robertson MH, Storrs FJ (1982) Allergie contact dermatitis in two
in a cutting oil. Contact Dermatitis 15: 66-68 machinists. Arch DermatoI118:997-1002
Fisher AA (1979) Allergie contact dermatitis of the hands due to Rossmoore HW (1981) Antimicrobial agents for water based
industrial oils and fluids. Cutis 13:131-134 metal working fluids. Occup Med 23:247-251
Foulds IS (1998) Follow-up of patients with cutting oil dermatitis Rycroft RJG (1978) Is Grotan BK a contact sensitiser? Br J
following substitution of an allergen. Personal communication Dermatol 99:346-348
Foulds IS, Koh D (1990) Dermatitis from metal working fluids. Rycroft RJG (1979) Bacteria and soluble oil dermatitis. Contact
Clin Exp DermatoI15:157-162 Dermatitis 6:7-9
Fregert S (1979) Colophony in cutting oil and in soap water used Rycroft RJG (1980a) Allergie contact dermatitis from dipentine in
as cutting fluid. Contact Dermatitis 5:52 honing oil. Contact Dermatitis 6:325-329
Grattan CEH, Foulds IS (1989) Outcome of investigation of Rycro~ RJG (1?80b) Allergie contact sensitisation to Epoxide 7 in
cutting fluid dermatitis. Contact Dermatitis 230:377-378 grmdmg oil. Contact Dermatitis 6:316-320
Grattan CEH, English JSC, Foulds IS, Rycroft RJG (1989) Cutting Rycroft RJG (1981) Soluble oil dermatitis. Clin Exp Dermatol
fluid dermatitis. Contact Dermatitis 20:372-376 6:229-234
Gruvberger B, Bruze M, Zimerson E (1996) Contact allergy to the Scerri L, Dalziel KL (1996) Occupational contact sensitisations to
active ingredients of Bioban P1487. Contact Dermatitis 35: the stabilised chlorinated paraffin fraction in neat cutting oil.
141-145 Am J Contact Dermat 7:35-37
Hamann K (1980) Forcide 78 - another formaldehyde releaser in Sprince NL, Palmer JA, Popendorf W, Thorne PS, Selim MI,
a coolant oil. Contact Dermatitis 6:446 Zwerling C, Miller ER (1996) Dermatitis among automobile
Holtzman GH, Rossmoore HW (1977) Evaluation of the action of production machine operators exposed to metal-working
a formaldehyde condensate germicide. Dev Ind Microbiol fluids. Am J Ind Med 30:421-429
18:753-758 Wigger-Alberti W, Hinnen U, Eisner P (1997) Predietive testing of
Hjorth N (1979) N-methylol-chloracetamide a sensitiser in metal working fluids: a comparison of two cumulative human
coolant oils and cosmeties. Contact Dermatitis 5:330-331 irritation models and correlation to epidemiologieal data.
Huner A, Fartasch M, Hornstein OP (1994) The irritant effect of Contact Dermatitis 36:14-20
different working fluids. Contact Dermatitis 31:220-225 Zugerman C (1986) Cutting fluids, their use and effects on the
Inola A, Estlander T, Jolanki R, Tarvainen K, Kanerva L (1993) skin. Occup Med 1:245-258
Occupational allergie contact dermatitis due to Coconut
CHAPTER 87
Rubber
D.V. Belsito
Introduction Rubber-Related Chemieals
Rubber-based products permeate our lives, forming Natural Rubber

part of the many materials used for personal,
domestic and industrial purposes. Rubber may be Natural rubber is based on isoprene monomers derived
natural, synthetic or a mixture of the two. Since the from various plants. The principal source is latex
vast majority of rubberized materials are unlabeled, it obtained from Hevea brasiliensis, whieh belongs to the
is difficult to determine whether a product contains Euphorbiaceae family. Other commercial sources of
natural or synthetic rubber. The overlap between natural rubber include Parthenium argentatum (gua-
"rubber" and "plastic" further complieates the mat- yule rubber) and plants ofthe Sapotaceae family (gutta-
ter, especially since plastics contain many of the percha). These plants produce a viscous substance that
same catalysts, stabilizers, antioxidants and pig- contains about 30% isoprenes with the remainder
ments/dyes that are present in rubber products. consisting ofwater, pro teins, res ins and sugars (Rogers
Fregert (1981) listed a number of naphthylamines, 1974). The lkpolyisoprenes occur chemieally in two
substituted para-phenylenediamines, alkylphenols different isomerie forms: the cis form is found in latex
and hydroquinone derivatives, which are utilized in and guayule rubber; gutta percha and balata, which
the manufacturing of both rubber and plastic. have slightly different properties and are much less
Although completely cured plastics are rare sensi- frequently used, contain the trans form (Adams 1983b).
tizers, fully cured rubber products produce allergie The polyisoprene chains within rubber are disorga-
reactions as the sensitizers in rubber can leach out or nized to a great extent, but not totally. When rubber is
"bloom" over time. stretched, the polymers ass urne a parallel arrangement
Natural rubber is based on the polymer lA- producing frictional heat and enhanced intermolecular
polyisoprene, a substance extracted from several attraction (van der Waals), which add to the resistance
plant sourees, especially Hevea brasiliensis. Before of rubber to stretch-induced deformation (Conde-
the 1940s, natural rubber supplied 100% of the Salazar 1990a). The total reversibility of transforma-
market demand; now, it supplies only about 35%. tions induced by stretching represents elasticity, while
Spurred by World War II, the production of artificial persistent deformation following stretching is indicative
rubber dominates the market. Although as a percent- of plasticity. Natural rubber is both elastic and plastic;
age of all rubber goods, those made of natural rubber the degree to which elasticity or plasticity dominates
are declining, the absolute use of natural rubber depends primarily upon the ambient temperature.
continues to increase due to the expanding use of Natural rubber is elastic only between 15°C and 30 oe.
rubber worldwide. Below 15°C, rubber gets hard and rigid; above 30°C, it
About 60% of all natural and synthetic rubber gets soft and plastic. To alter these characteristics,
production is utilized in the tire industry. The chemie al additives (described below) are needed.
remaining 40% is processed into thousands of differ- Delayed-type hypersensitivity reactions to natural
ent products. A variety of synthetic rubbers exists, latex were once considered rare. Sidi and Hincky (1954)
each based on different polymers (Table 1). The suggested that latex may be a delayed-type allergen
widespread use of rubber has been facilitated by the based on their study of patients with allergie reactions
development of new rubber polymers with varying to latex gloves, but without evident allergy to the
properties of industrial value (Tables 1-3). accelerators or anti-oxidants likely to be present in the

702 D.v. Belsito
Table 1. Commonly encountered synthetic rubbers'
Common name Polymer Usage
Polyurethane Isocyanates + polyesters Elasticized clothing, shoes, sealants/caulkings, adhesives,

(i.e., Spandex®) industrial products resistant to abrasion
Neoprene Chloroprene Clothinglgloves, latex foams, industrial products
Nitrile Acrylonitrile + butadiene Shoes/gloves, waterproof clothing, adhesives, artificialleathers,
industrial products designed to resist solvents and oils
Styrene-Butadiene Styrene + butadiene Widely used in industrial rubber products, especially tires
Butyl Isobutylene + isoprene or Gas impermeable products (inner tubes, hoses,
butadiene electrical insulation, etc.)
Polysulfide polysulfide + organic sealants, adhesives, protective clothing and other oil-resistant
(i.e., Thiokol®) dichlorides materials
Ethylene-propylene- ethylene-propylene-diene automobile ho ses, gaskets, belts and industrial rubber
diene terpolymer monomer (EPDM) resistant to weathering
Silicon elastomer dirn ethyl siloxane gaskets, seals, hoses and insulating tapes
designed to resist high temperature
• Abstracted from Rubber World Magazine's Blue Book (1997)
Table 2. Other specialty synthetic rubbers' It is unknown whether the polyisoprene containing
sap from Parthenium and Sapotacea spp. contains the
Acrylic elastomers Polyisobutylene chemical responsible for inducing ACU and/or ACD to
Chlorinated polyethylene Polyisoprene
elastomers latex. However, it has been reported that the sap from
Chlorosulfonated polyethylenes Polynorbornene Parthenium argentatum, a member of the Compositae
Epichlorohydrin elastomers Reclaims and regrinds family, contains a cinnamic acid ester of sesquiterpene,
Ethylene/acrylic elastomers Reprocessed synthetic
Ethylene-propylene co polymers Styrene-isoprene rubbers which is a potent sensitizer for delayed-type hypersen-
Fluoroelastomers Thermoplastic elastomers sitivity in the guinea pig (Rodriguez et al. 1981).
Isobutylene-paramethylstyrene Transoctenamer Perhaps for this reason, guayule rubber has not become
elastomers
Isoprene-acrylonitrile elastomers Vinyl acetate/ethylene a significant source of rubber worldwide. Although the
copolymers sap of Sapotaceae spp. is apparently free of sensitizers,
Polybutadiene elastomers it is highly irritating (Mitchell and Rook 1979).
Artificial Rubber
Table 3. Natural and synthetic rubber blends: emulsions, latexes At the beginning of the 20th century, the world powers,
and dispersions'
fearful that the supply of latex from the Far East could
Acrylic latex Polychloroprene latex be interrupted, began their attempts to manufacture
Natural latex Styrene-butadiene latex synthetic rubber. In 1909, Hoffman reported the
Nitrile latex Vinyl pyridine latex synthesis of dimethylbutadiene, a molecule similar to
the isoprene monomer, from acetone. Called Hoff-
man's rubber, this product was used during World
War I but was of poor quality. Throughout the 1930S,
gloves. Subsequently, Wilson (1960) had similar expe- the Germans continued production ofbutadiene-based
riences in two of 42 patients, all of whom tested positive or Buna rubbers, which were improved by co-poly-
to gloves. Substantiated reports of isoprene allergy merizing methylbutadiene with styrene (Buna S) or
include those of Wyss et al. (1993) and Wilkinson and acrylonitriles (Buna N). In the United States, Dupont
Beck (1996). In this latter study of 822 patients, ten synthesized polychloroprene-based rubber (Neoprene)
(1.2%) exhibited positive patch-test reactions to latex. in 1931. However, it was during World War 11 and the
Despite the increasingly more frequent reports of Korean War that, with little supply of natural latex, the
allergie contact dermatitis (ACD) to natural latex, the greatest advances in synthetie rubbers occurred.
exact chemical nature of the allergen(s) remains Today, one can synthesize isoprene itself from petro-
unknown. In contrast, proteins present in latex leum derivatives. Thus, multiple types of synthetic
obtained from the Hevea brasiliensis tree are the cause rubbers with specific properties can be manufactured
of the immunoglobulin (lg)E-mediated hypersensiti- (Tables 1-3).
vity/allergic contact urticaria (ACU) to natural latex Despite the proliferation of these synthetie rubbers,
rubber. Since Hevea brasiliensis accounts for more allergic reactions to the synthetic monomers/polymers
than 99% of natural rubber used worldwide, ACU to are quite rare. To date, there have only been case
latex is a significant problem. reports of possible ACD to isocyanates present in
Rubber 703
synthetic plasticlrubber wound dressings (HelIand of principal in te rest to occupational dermatologists

et al. 1983; Kilpikari and Halme 1983) and to polysul- include certain accelerators (thiazoles, thiurams,
fides in sealants (Wilkinson and Beck 1993). thiocarbamates and thioureas) and anti-oxidants (de-
rivatives of p-phenylenediamine). In addition, natural
Vulcanization and Rubber Additives rubber latex is of increasing importance. In contrast,
allergic reactions to the other components of rubber,
The monomers of both artificial and natural rubber except for reactions to the phenol formaldehyde resins
must be polymerized into a three-dimensional network (used as tackifiers/reinforcing agents) and epoxy resins
to obtain the finished product. Different processes are (used as stabilizers), are rare (Conde-Salazar et al.
used, although they are all quite similar. The process of 1993). Therefore, this chapter deals primarily with
polymerization (called vulcanization) involves the those problems related to the accelerators and anti-
reaction between rubber isomers and sulfur to produce oxidants.
a polymer with enhanced elasticity and reduced
plasticity (Table 4). The reaction between the mono- Accelerators
mers and sulfur is enhanced by the addition of
accelerators and activators. Other chemicals that can Vulcanization of rubber consists of heating the mol-
be added to both natural and synthetic rubber include: ecules of polyisoprene so that they polymerize into a
retardants, anti-oxidants, curing agents, reinforcers, product that maintains its elasticity over a range of
fillers, ultraviolet inhibitors, softeners/extenders, sta- temperatures. The process was discovered by Good-
bilizers, blowing agents and colorants. Readers are year in 1839 and involves heating rubber with sulfur
referred to Rubber World Magazine's "Blue Book" and lead. However, vulcanization is slow. Tempera-
(1997), which extensively surveys the various additives tures greater than 300°C could be used to accelerate
to both natural and synthetic rubbers. Those additives the process, but these temperature extremes would
Table 4. Vulcanization materi-

als and other rubber additives' Auxiliary and surfaee materials Proeessing materials
Adhesives and bondinglsealing agents Homogenizing agents
Blowing agents and blow promoters Peptizers
Dusting, dipping and washing materials Plasticizers and softeners
Finishes Proeessing aids and dispersing agents
Lubrieants Tackifiers
Odorants and antistaining agents Proteetive materials
Polymerization materials Antioxidants, antiozonants and inhibitors
Redaiming materials Chemieal and heat stabilizers
Solvents Vulcanization materials
Extenders, fillers and reinforeers Aecelerators
Carbon blaeks Aetivators
Other blaek materials Retarders
Non-blaek materials Vulcanizers
Fiber reinforeed materials
• Data abstracted from Rubber World Magazine's Blue Book (1997)
Table S. Aeeeierators in natural

and synthetie rubbers likely to Chemieal dass Allergen(s) present in standard pateh-test series
eause allergie eontaet dermatitis'
Thiazoles 2-mereaptobenzothiazole; mereapto mix =
N-cydohexyl-2-benzothiazyl sulfenamide,
2,2' -dibenzothiazyl disulfide and
morpholinylmereaptobenzothiazole
Thiurams Thiuram mix =
tetramethylthiuram disulfide,
tetramethylthiuram monosulfide,
tetraethylthiuram disulfide and
dipentamethylenethiuram disulfide
Dithioearbamates Carba mix =
zine diethyldithiocarmate and
zine dibutyldithioearbamate
Guanadines Carba mix =
1,3-diphenylguanadine
Thioureas No
Amine aldehydes No
• For a more complete listing of the many available aeeeierators, see Rubber World Magazine's
Blue Book (1997)
704 D.V. Belsito
destroy the isoprene chains. For this reason, chemical Table 7. Mercaptobenzothiazole: potential exposures
accelerators are added to speed vulcanization at lower
Adhesives (neoprene-based) Germicides
temperatures. The original accelerators were metallic Anti-freeze Paints
oxides. In the 1920S, 2-mercaptobenzothiazole (2- Caustie cleansers Photographic film emulsion
MBT) was introduced and revolutionized the process. (automotive eooling systems)
Cutting oils/greases Refrigerants
Subsequently, numerous other accelerators have been Detergents (granulated Rubber produets, especially
identified, including thiazoles, thiurams, dithiocarba- and tablets ) tires or other industrial
mates, guanadines, thioureas and amine aldehydes rubber items and
bootslshoes
(Table 5). Many of these contain a sulfur moiety and, Fungicides Veterinarian medicaments
depending on their action, are classified as slow Waterproof cements/glues
(amines and thioureas), medium (thiazoles) and fast
(thiurams and dithiocarbamates) accelerators of vul-
canization. While some synthetie rubbers, e.g., butyl zation to thiazoles among consumers is less frequent
and nitrile, can be polymerized with organie peroxides than it is to thiurams. In this author's experience, most
without the addition of sulfur, others, e.g., styrene- consumers sensitized to thiazoles are exposed to the
butadiene, require much greater amounts of sulfur chemical in shoes.
donors (2-MBT and thiuram) than natural rubber The dithiocarbamates include zinc dibutyldi-
(Feinman 1987). thiocarbamate (ZDBC), zinc diethyldithiocarbamate
The principal thiurams used industrially are: (ZDEC) and zinc dimethyldithiocarbamate (ZDMC).
tetramethylthiuram mono sulfide (TMTM), tetrame- In the rubber industry, the carbamates are principally
thylthiuram disulfide (TMTD), tetraethylthiuram used in gloves, condoms and elastic bands. Due to
disulfide (TETD) and dipentamethylenethiuram disul- their chemical similarity with thiurams, the potential
fide (PTD). These thiurams are frequently used as for cross-reactivity between these groups exists (Con-
mixes, whose exact composition varies with the de-Salazar 1990a; Knudsen and Menne 1996). The
particular rubber product, as weIl as with the country greatest use of carbamates is not in rubber but in
of origin. Worldwide, TMTM and TMTD are most pesticides and fungicides (Table 8).
used. Thiurams are among the more frequently used Thioureas include dibutylthiourea (DBTU), diethyl-
rubber accelerators, especially in the manufacturing of thiourea (DETU), diphenylthiourea (DPTU) and eth-
gloves. Numerous other consumer products also con- ylene thiourea (ETU). These chemicals are frequently
tain thiurams (Table 6). used, especially in the manufacture of neoprene and
Thiazoles are derivatives of benzothiazole com- foam rubbers. In addition to being accelerators,
pounded with sulfenamides. The benzothiazoles include thioureas have other uses including as anti-corrosives
2-MBT, dibenzothiazyl disulfide (MBTS) and the zinc and anti-oxidants (Table 9). Important sources of
salt of 2-mercaptobenzothiazole (ZMBT). The sulfen- sensitization to thioureas have been the foam and
amides are principally N-tert-butyl-2-benzothiazyl impermeable rubbers used in sporting equipment
sulfenamide (TBBS), N-cyclohexyl-2-benzothiazyl sul- (sport shoes, diving masks, swimming goggles, wet
fenamide (CBS) and morpholinylmercaptobenzo- suits, etc.).
thiazole (MOR). MBT, MBTS and CBS are the more
widely used. Because of their strong capacity to sensitize, Anti-Oxidants
thiazoles are less frequently used in gloves than are the
thiurams. Nonetheless, they are widely used in the Although the various rubber accelerators ac count for
rubber industry, as weIl as others (Table 7). Indeed, the vast majority of allergie reactions to rubber among
MBT remains the most widely used accelerator for
industrial rubber (Feinman 1987). Nonetheless, sensiti- Table 8. Carbamates:
potential exposures Anti-oxidants Pesticides
Fungicides Rubber produets
Table 6. Thiurams: potential exposures
Adhesives Medications (anti-alcohol, seabicide, Table 9. Thioureas: poten-

fungicides, sunsereens, surgieal wraps) tial exposures Adhesives Fungicides
Animal repellents Anti-corrosives Impermeable
Crepe soles Pesticides rubbers
(neoprene) Anti-oxidants Neoprene and
Disinfeetants Polyolefin plastics (anti-oxidant) foam rubbers
Food wrappings Preservatives (woods, paints, lubricating Cleaning Paint/glue
oils, greases, ete.) produets remover
Fungicides Putty Detergents Photocopy paper
Germicides Rubber products, especially gloves (acidic)
Insecticides Veterinary soaps and shampoos Diazo paper Textile elastic
Rubber 705
Table 10. Anti-oxidants in natural and synthetic rubber likely to sole (Rieh et al. 1991) and 4,4'-thiobis(6-tert-butyl-m-
cause allergie contact hypersensitivity eresol) (Rieh et al. 1991) have a mueh redueed capacity
Chemical dass Allergen(s) present in standard
to sensitize. Although the naphthylamines also appear
patch test series to have low rates of sensitization, they are rarely used
in eonsumer goods beeause they may eontain traee
Amines amounts of the carcinogen ß-naphthylamine (Feinman
Phenylenediamines Black rubber mix =
N-phenyl-N' -cydohexyl-p-phenylene- 1987).
diamine,
N-isopropyl-N' -phenyl-p-phenylene-
diamine and
N ,N'-diphenyl-p-phenylenediamine Incidence
Quinolines No
Phenols
Hydroquinones No
BHT No The ineidenee of ACD to rubber in the general
Phosphites No population is diffieult to evaluate. Of 274 non-der-
matologie patients undergoing hip arthroplasty at a
Swedish general hospital, 1.1% had allergie reaetions to
Table 11. Amine antioxidants: potential exposures
thiuram mix and earba mix (both aeeeierators), and
Acrylates Industrial and automotive 0.4% had reaetions to blaek rubber mix (anti-oxidants)
rubbers and mereapto mix (aeeeierators) upon routine pateh
Black rubbers Orthopedic bandages testing (Magnusson and Möller 1979). Sinee these
Cutting oils/fluids Rubber cements
Gasoline (inhibitor/antiozonant) patients were randomly seleeted as opposed to those
referred for pateh testing, the ineidenee rates of allergie
reaetions to rubber additives in this study are more
eonsumers, anti-oxidants are by no means rare eauses representative of those in the Swedish population. In
of sensitivity, especially oecupationally aequired sen- the United States, no eomparable study has been done.
sitization (Feinman 1987). Also referred to as anti- Due to genetie variations in a given population,
degradants or anti-ozonants, anti-oxidants are of great differing exposure patterns within a population or
importanee in the manufaeture of rubber produets, other demographie faetors, the ineidenee of allergie
sinee they retard the deterioration of rubber by ozone. reaetions to the various chemie als within rubber will
Thus, anti-oxidants prolong the usefulness of a rubber likely vary among countries. Overall, as delineated
produet by stabilizing the polymer, inhibiting tears below, the reported ineidenee of sensitization to
and preventing brittleness. Although there are over 100 rubber has steadily inereased worldwide. This inerease
existing anti-oxidants, the most eommon are deriva- is due both to the greater use of rubberized proteetive
tives of amines (alkylamines and quinolines), phenols gear (gloves, boots, masks) and to the use of these
(hydroquinones), and phosphites (Table 10). The most same chemieals in the manufaeture of such diverse and
important, from the aspeet of sensitization, are the widely used produets as animal repellants, inseetieides,
following phenylenediamine derivatives: N'-isopropyl- and medicaments.
N'-phenyl-p-phenylenediamine (IPPD), N-phenyl-N'- Beeause of automation and other preventive mea-
cyclohexyl-p-phenylenediamine (CPPD), N,N'-diphe- sures, eases of sensitization to rubber among workers
nyl-p-phenylenediamine (DPPD), and N-(1,3-dimethyl- manufaeturing it are rare and ae count for no more than
butyl)-N'-phenyl-p-phenylenediamine (DMPPD). Of 20% of all rubber allergies (Fregert 1975). Individuals
these, CPPD and DPPD are more strongly sensitizing most likely to be sensitized are those in other industries
than IPPD (Herve-Bazin et al. 1977). that use rubber, sinee rubberized produets ean release
These phenylenediamine derivatives are found prin- allergens over time. This release or "blooming" of
cipally in industrial rubbers (Table 11) and in almost ehemicals is partieularly likely with direet skin contaet,
any rubber ofblaek color. Their capacity to sensitize is sinee sweat and humidity are liberating faetors.
very high and they easily bloom from the surfaee of Most available data on incidenee rates of rubber
rubber with heat or frietion. Another highly sensitizing allergy are generated from patients referred for eval-
anti-oxidant, monobenzyl ether of hydroquinone, also uation of suspeeted eontaet dermatitis; thus, the rates
eauses eontaet leukoderma (Oliver et al. 1939) and is as they pertain to the general population are overstat-
now rarely used in the manufaeture of rubber (Fein- ed. In studies of the North Ameriean Contaet Derma-
man 1987). In eontrast, other anti-oxidants, such as the titis Group (Rudner et al. 1975; Storrs et al. 1989;
hydroquinones (Norris and Storrs 1990), styrenated Nethereott et al. 1991; Marks et al. 1995, 1998), a
phenol (Kaniwa et al. 1994a), dialkylamines (Kaniwa signifieant pereentage of North Ameriean patients
et al. 1994b), piperidines (Kaniwa et al. 1994b), referred for pateh testing had allergie reaetions to
dihydroquinolines (Hansson 1994), butylhydroxyani- one or more rubber additives tested (Table 12). Of note
706 D.v. Belsito
Table 12. Incidence of positive reactions to rubber-related chemieals in North Ameriea: 1972-1996"
Test substance 1972-1974b 1984-1985 c 1985-1989d 1992-1994e 1994-1996f

(n) (n) (n) (n) (n)
Thiuram mix 4.2%g (1200) 3.9% (1137) 5.5% (3986) 7.7% (3522) 6.8% (3115)
Carba mix NT 3.3% (1135) 3.1 % (3988) 4.8% (3524) 5.7% (3115)
Mercapto mix NT 2.6% (1132) 2.5% (3979) 2.6% (3497) 2.2% (3115)
2-MBT 4.8% (1200) 2.9% (1141) 2.1 % (3968) 1.8% (3525) 2.1% (3115)
Black rubber mix NT 1.4% (1140) 2.1% (3985) 2.1 % (3492) 2.3% (3113)
NT not tested; 2MBT 2-mercaptobenzothiazole

"Percentages given are for patients referred for patch testing with eczematous dermatitides and presumed allergie contact dermatitis
b Data abstracted from Rudner et al. (1975)
c Data abstracted from Storrs et al. (1989)
d Data abstracted from Nethercott et al. (1991)
e Data abstracted from Marks et al. (1995)
f Data abstracted from Marks et al. (1998)
g 2% thiram and not thiuram mix tested
is the fact that the percentage of patients reacting to occupational ACD seen in Finland - only metals
the thiazoles (mercaptobenzothiazole and mercapto (28.4%) and plastic materials (27.?'Yo) were more
mix) has been relatively constant over time. In frequent offenders (Estlander 1990). Similar results
contrast, the percentage reacting to p-phenylenedi- have been reported from other countries throughout
amine derivatives (black rubber mix) and thiurams Europe (Budden et al. 1973; Fregert 1975; Lachapele and
(thiuram mix) seems to be increasing. Tennstedt 1979; von Hintzenstern et al. 1991). In
It has been suggested that reactivity rates for black studies performed outside the rubber/tire industry,
rubber mix are indicative of the rate of sensitization the principal source of exposure to rubber-related
from industrial exposure, while those for thiuram are chemieals is gloves: in the Finnish study, gloves
indicative of the rate of sensitization from non- accounted for 58.3% of rubber-related eczema (Est-
industrial exposures, especially from gloves (Cronin lander et al. 1986). Similar results were seen in
1980). Thus, the data delineated in Table 12 suggest Germany where, of 3851 patients evaluated between
that both industrial production of rubber-related 1985 and 1990, allergie reactions to rubber additives
materials and usage of latex gloves has increased were seen in 145 individuals (J.8%); in 80 of 145 (55%),
significantly in North America during the past several the source of exposure was occupational (von Hint-
decades. A similar increase in the rate of ACD to zenstern et al. 1991). üf the occupational cases, 84% of
rubber chemie als, especially thiurams, has been re- workers (67/80) acquired the dermatitis from use of
ported worldwide (Nurse 1979; Themido and Brandäo rubber gloves. Workers most likely to develop glove
1984; Lammintausta and Kalimo 1985; Estlander et al. dermatitis were those engaged in health/laboratory
1986; Conde-Salazar et al. 1993). services or homemaking activities (von Hintzenstern
In a review of 7000 Spanish patients seen over a 10- et al. 1991). However, non-occupational exposure to
year period, a total of 2526 (54%) of the 4680 patch- items such as condoms, shoes, boots, elasticized
tested patients had one or more positive reactions on garments, belts and watchbands are also important
the standard series. Among those patients with a sources for tlIe development of ACD to rubber (Wilson
positive patch test, 686 (27%) demonstrated at least 1960; Conde-Salazar 1990a, b).
one positive reaction to a rubber additive (Conde- Because of the association between rubber-related
Salazar et al. 1993). As observed by others (Nurse 1979; allergy and "wet work", it is instructive to evaluate the
Themido and Brandäo 1984; Lammintausta and incidence of dermatitis among such workers. In a
Kalimo 1985; Estlander et al. 1986; Knudsen and Menne Danish study of 541 hospital personneI, 52 patients had
1996), Conde-Salazar et al. (1993) noted that reactions active, occupationally-related, dermatitis at the time of
to thiuram mix accounted for the majority of rubber study. üf these 52 patients, 75.0% were thought to have
allergies (83%), followed by carba mix (22.3%), black primarily irritant, and 21.2% primarily allergie, contact
rubber mix (17.8%), mercapto mix (16.0%) and naph- dermatitis. ACD to rubber accelerators accounted for
thyl mix (2.4%). 36.4% of the cases of allergie dermatitis (Hansen 1983).
Among individuals with ACD to rubber additives, a Similar results were found in a Swedish study (Nilsson
significant proportion acquired the dermatitis occupa- 1985). Thus, although irritant contact dermatitis (ICD)
tionally, although not from working in the basic rubber is the most likely cause of hand dermatitis in "wet
industry. From 1974 to 1983, allergie reactions to workers", a significant percentage of these individuals
rubber-related chemieals accounted for 19.9% of all will have ACD to chemie als found in rubber. Indeed,
Rubber 707
patients will often be allergie to two or more rubber- Skin Disease In Rubber-Industry Workers
related chemieals. In general, thiuram derivatives have
the highest incidence of sensitization; however, the
responsible thiuram varies with the product and Dermatitis among rubber plantation workers who
country of origin (Gimenez-Camarasa 1968; Song et al. harvest latex has been little studied. These workers
collect the latex sap from the trees, which is stored in
1979; Estlander et al. 1986; Conde-Salazar 1987, 1990a,
collection vats containing ammonia and is then
b; Nethercott et al. 1991; Conde-Salazar et al. 1993).
strained to remove foreign matter. Some of the res in
. Construction workers represent another occupa-
tlOnal group with a high incidence of rubber-related is subsequently centrifuged and preserved in a liquid
form for production of such rubber goods as gloves,
dermatoses. In their study of 408 construction work-
condoms and medical devices. This liquid latex is
ers, Conde-Salazar et al. (1995) found that 104 (25.4%)
treated with various chemieals which, with the excep-
of the workers were sensitized to one or more of the
tion of the preservatives, rarely cause ACD (Table 13).
rubber mixes on their standard screening series. Of
In contrast, ICD can occur following repeated exposure
note, 97 workers (23.7%) were allergie to thiuram mix,
which ranked second to chromate as a cause of ACD in to many of these latex compounding materials, espe-
cially the emulsifiers.
these workers. Additionally, 10% of workers (41/408)
The majority of latex sap is weighed, concentrated
were allergie to carba mix, 2.9% (12/408) to mercapto
approximately 70% and coagulated by the addition of
mix and 2.2% (u/408) to black rubber mix. In all
workers, the source of sensitization was either gloves formic acid, acetie acid or sodium silieofiuoride. The
coagulated mass is then pressed between rollers to
and/or boots used for personal protection (Conde-
form slabs or sheets, which are smoked for 1-2 weeks.
Salazar et al. 1995). When the results of this study were
contras ted with previous studies by the same authors, These slabs are bundled into bales which contain
the incidence of rubber allergies among construction approximately 90% rubber hydrocarbons. Given their
workers was noted to have decreased dramatically: exposure, workers processing baled rubber are more
likely to suffer ICD.
from 58% in 1976 (Conde-Salazar et al. 1976) and 47%
in the 1978-1988 period (Conde-Salazar et al. 1993) to Occupational ACD occurs more frequently in the
manufacturing of finished rubber goods, since the
25.4% in the 1989-1993 period. The authors ascribed
this decrease to better working practiees in the major delayed-type allergens are found among the
construction industry and to better manufacturing chemieals subsequently added to natural and synthetic
rubbers. Nonetheless, ACD is rare in the rubber
standards in the rubber industry.
Workers in the basic rubber industries are another industry due to automation in most aspects of
obvious high-risk group for rubber-related dermatoses. manufacturing. Among rubber workers, those who
The annual risk of allergie plus irritant dermatitis weigh the various ingredients which are added to pre-
among these workers ranges from 0.31% in Britain cu.t chunks of natural or synthetie rubber in large
(Cainan 1978) to 0.56% in Finland (Kilpikari 1982). The mIXers (Banbury mixers) and skilled laborers involved
only available data from the United States state a risk of in the fabrieation of tires (which require that layers be
0.7% for Californian workers, but this number also gradually built from the inner liner to the outer tread)
includes individuals in the plasties industry (Baginsky are most likely to develop allergie sensitization (Fig. 1).
1979). The apparently lower risk of developing ACD Other workers (Fig. 2), such as those operating the
among workers in basic rubber industries relates in part Banbury mixers, the calenders (two or more steel
to the reporting of risk as an annual rate rather than as drums used to produce sheets of rubber or to ply
the total percentage of workers with occupationally rubber to other materials), the extruders (devices
related dermatitis. In addition, increasing automation which produce lengths of rubber with specific cross-
within the rubber industry minimizes direct physical sectional characteristics), and the molding machines
contact with the allergens and, hence, reduces sensiti- are also at some risk, as are those workers involved in
zation rates. Again, an important difference between packing and shipping the final product.
ACD in rubber workers and that among other workers
is the high er percentage of ACD due to amine anti- Table 13. Latex compounding materials'
oxidants, e.g., p-phenylenediamine derivatives, in the
rubber-industry workers (Alfonzo 1979; Kilpikari 1982). Anti-blocking agents Gelling agents
Anti-foaming agents Preservatives
In a 5-year Finnish study, 15 of 21 rubber-industry Anti-webbing agents Stabilizers and emulsifiers
workers (71.4%) with occupationally-related ACD were Coagulants S~abili.zers and reducers: thickening/
allergie to a component of black rubber mix (Kilpikari VlSCOSlty
1982). In addition, 2-MBT and carbamates also have Creaming agents

Dispersing agents
Wetting agents
relatively high sensitization rates in this industry

(Nethercott 1982; Vestey et al. 1986). • Abstracted from Rubber World Magazine's Blue Book (1997)
708 D.V. Belsito
Fig. 1. Despite widespread automation in the rubber

industry, certain workers are at an increased risk of
becoming sensitized to rubber additives. Chief
among these are the workers who weigh the various
ingredients (A) and skilled laborers involved in the
fahrication of tires (B). Photographs are courtesy of
Dr. Rohert Adams, San Mateo, CA (A) and Dr.
Armando Ancona, Department of Dermatology,
National Medical Center, Mexico City, Mexico (B)
and published with their permission
Fregert (1975) studied 289 workers (92 wornen, 197 (dialkyl phthalates), the peptizers (tricresyl phos-
men) who presented with occupational contact der- phate), the blowing agents (N, N' -pentamethylenetetr-
matitis over a 10-year period. Nineteen percent of the amine and other amines that release nitrogen gas when
women and 21% of the men worked in the rubber heated) and the retarders (cyclohexyl thiophthali-
industry. Among these individuals, allergie dermatitis mide). Finally, ACD can arise from contaminants; for
was more frequent than irritant, but the allergens were example, dinitrochlorobenzene (DNCB) contamination
not specified. Schwartz et al. (1957) reported that, of MBT caused an epidemie in an Italian factory where,
among 28,000 rubber workers, 1% had severe ACD of 204 exposed workers, 42 had positive reactions to
necessitating discontinuing work and 10% had milder the DNCB (Zina et al. 1987).
involvement not affecting their work. The principal Irritant dermatitides are also common among
allergens noted were the anti-oxidants, especially rubber workers (Varigos and Dunt 1981; Kilpikari
hexamethylenetetramine, which had the highest inci- 1982; White 1988). The most common irritants are the
dence rate of ACD. However, hexamethylenetetramine, alkalis, solvents, activators (stearic acid and other fatty
which decomposes to formaldehyde in acid sweat, is acids), soaps and the various dusting/dipping/washing
now rarely used in the manufacture of rubber, materials (calcium carbonate, calcium stearate, etc.)
although it is still frequently used in phenolic plastic encountered in the workplace (Fig. 3). Mechanical
resins. Thus, derivatives of PPD, which are extensively friction is another important source of irritation. In a
used in Europe and the United States, are the main study of 1000 workers in an Australian tire factory,
sensitizers among rubber workers today (Alfonzo 1979; Varigos and Dunt (1981) identified 37 workers (3.7%)
Cronin 1980; Ancona et al. 1982; Kilpikari 1982). Other with dermatitis, of whom 34% had irritant dermatitis.
causes of ACD in the rubber industry (Brandäo 1990; Curious reactions can occasionally be seen among
Kanerva et al. 1996) have included the plasticizers rubber workers. Plotnick and Birmingham (1993)
Rubber 709
Fig.2. Workers involved in mixing (A),

ealendering (B) and extruding (C)
rubber are also at risk of aequiring allergie
and/or irritant oeeupational eontaet dermatitis.
Photographs are eourtesy of Dr. Robert Adams,
San Mateo, CA and published with his
permission
reported an epidemic of pronounced facial ftushing,

typically appearing after lunch, among 10 of 20
Banbury mixers. Patch testing to an expanded rubber
tray was completely negative. The cause was
tetramethylthiuram disulfide, used as the accelerator,
together with alcohol consumed at lunch. It was
surmised that when sweat tainted with alcohol con-
tacted the airborne accelerator, a localized disulfiram-
like reaction occurred.
The presence of carcinogenic compounds within the
rubber industry has been a controversial issue in the
field of occupational medicine (Conde-Salazar 1987,
1990a). Both 1,3-butadiene and styrene, which are used
extensively in synthetic rubber, are known carcinogens
(reviewed in Fishbein 1992). Significant levels of
butadiene (0.06-39 ppm [National Institute for Occu-
pational Safety and Health 1984; International Agency
Fig. 3. The hands of a typical rubber worker are frequently
eontaminated with the various ehemicals eneountered in the for Research on Cancer 1986; de Meester 1988]) and
workplaee. The solvents and cleansing agents used to remove the styrene (2.4 ppm [World Health Organization 1983])
aeeumulated grime are a frequent eause of irritant eontaet can be found in factories where these synthetic rubbers
dermatitis. Reprodueed with the permission of Donald V. Belsito,
M.D., Division of Dermatology, University of Kansas Medieal are produced; however, due to automation and safety
Center, Kansas City, KS precautions, workers are not routinely exposed to
710 D.v. Belsito
significant levels (International Agency for Research fable 14. Rubber additive series a
on Cancer 1979; Fajen et al. 1990). In contrast,
Allergen Conel
substances such as ß-naphthylamine, which was pre-
veh
viously used in significant amounts as an anti-oxidant,
have been prohibited for many years because of their Tetramethylthiuram disulfide (TMTD) 1.0% pet
carcinogenie activity. Other carcinogens in the rubber Tetramethylthiuram monosulfide (TMTM) 1.0% pet
Tetraethylthiuram disulfide (TETD) 1.0% pet
industry may be present in minimal concentrations as Dipentamethylenethiuram disulfide (PTD) 1.0% pet
either contaminants of the raw materials or as newly N-eyciohexyl·N-phenyl-4-phenylenediamine (CPPD) 1.0% pet
formed compounds due to uncontralled reactions N,N' -diphenyl-4-phenylenediamine (DPPD) 1.0% pet
N-isopropyl-N-phenyl-4-phenylenediamine (IPPD) 0.1 % pet
during manufacturing; e.g., n-nitrosoamines can be 2-mereaptobenzothiazole (MBT) 2.0% pet
found in parts per billion (ppb) quantities in some N-eyclohexyl-2-benzothiazylsulfenamide (CBS) 1.0% pet
accelerators of vulcanization. Disulfiram, a thiuram, is Dibenzothiazyl disulfide (MBTS) 1.0% pet
4-morpholinylmereaptobenzothiazole (MOR) 1.0% pet
much more controversial since, in experimental stud- Diphenylguanidine (DPG) 1.0% pet
ies, it has been identified as a potentiator of carcino- Zine diethyldithioearbamate (ZDEC) 1.0% pet
genesis. Rats exposed simultaneously to ethylene Zine dibutyldithioearbamate (ZDBC) 1.0% pet
N,N' -di-ß-naphthyl-4-phenylenediamine 1.0% pet
dibromide and to disulfiram in the diet had a tenfold N-phenyl·2-naphthylamine (PBN) 1.0% pet
increase in the incidence of hepatocellular carcinoma Hexamethylenetetramine 2.0% pet
compared with animals exposed only to ethylene Diaminodiphenylmethane 0.5% pet
Diphenylthiourea (DPTU) 1.0% pet
dibromide (Plotnick 1978). Zine dimethyldithioearbamate (ZDMC) 1.0% pet
2,2',4-Trimethyl-1 ,2-dihydroquinoline 1.0% pet
Diethylthiourea (DETU) 1.0% pet
Occupational Skin Disease Outside Dibutylthiourea (DBTU) 1.0% pet
the Rubber Industry Dodeeylmereaptan 0.1 % pet
aAvailable from Chemoteehnique Diagnosties AB, Malmö,

Sweden
Allergie Contact Dermatitis Cone eoneentration; veh vehicle; pet petrolatum
In some workers outside the rubber industry, the

sources of sensitization are the same raw ingredients to
which workers in the rubber industry are exposed; for
example, the carbamate-based pesticides among agri-
cultural workers. However, for most workers, the
sources of sensitization to rubber are the protective
barriers (such as gloves, boots and masks) used to
avoid other sensitizers and irritants. As a result,
sensitization to components of rubber cannot only be
the direct cause of acute dermatitis, but can also
aggravate an existing allergic or non-allergie eczema.
When it coexists with another type of dermatitis, ACD
to rubber can be difficult to diagnose and may be
suspected only after patch testing. The components of
a typieal patch-testing tray for detecting rubber
allergies are detailed in Table 14. Other allergens, such Fig. 4. Subaeute allergie eontaet dermatitis of the dorsal foot in
as the vulcanizing retardant cydohexyl thiophthali- an athletie direetor allergie to several thioureas and to 2-
mide (1% in petrolatum) or the anti-oxidants mono- mereaptobenzothiazole. Although the manufaeturer declined to
verify the eomponents of these shoes, pateh tests to rubber
benzyl ether of hydroquinone (1% in petrolatum) and portions of the "box" of the shoe were positive. Thioureas, whieh
piperazine (1% in petrolatum), can also be purchased are frequently present in rubber manufaetured for use in sporting
commercially (Trolab, Hermal Kurt Herrmann, Rein- equipment and clothes, were probably the more relevant aller-
gens. Reprodueed with the permission of Donald V. Belsito, M.D.,
beckJHamburg, Germany). It should be noted that use Division of Dermatology, University of Kansas Medieal Center,
of the dye PPD, present on most standard screening Kansas City, KS
trays, is not an adequate screen for allergy to the
"black rubber" anti-oxidants. In one study, all IPPD- oxidants, especially IPPD, are strang sensitizers and
sensitive patients reacted to CPPD, but only 37% cross- cause acute, severe eczemas. In contrast, dermatitis
reacted with PPD (Herve-Bazin et al. 1977). caused by the accelerators tends to be a more
The appearance of ACD to rubber depends on the subacute-to-chronic appearing eczema (Fig. 4). In
chronicity and the area affected. The most frequently addition to an eczematous dermatitis, ACD to rubber
encountered dinical picture is eczema. The amine anti- can present as hyperkeratosis, purpura, achromia,
Rubber 711
Fig. 5. Allergie contact dermatitis to a rubber glove. A middle- Fig. 6. Pulpitis induced by an allergy to 2-mercaptobenzothiazole
aged woman presented with dyshidrotic eczema of the fingers present in rubber finger cots utilized by this 43-year-old bank
and was advised to wear rubber gloves for household work. teller. Reproduced with permission of the Ronald O. Perelman
Several months later, she developed this erythematous, scaling Department of Dermatology, New York University School of
dermatitis of the dorsal hands. Note the demarcation at the wrists Medicine, New York, NY
with patches of dermatitis about the mid-forearm. Patch testing
revealed allergie reactions to both thiuram and carba mixes. Her
dermatitis c1eared with the use of cotton liners and vinyl gloves. implicates its allergic cause, all standard patch tests
Reproduced with the permission of the Ronald O. Perelman are negative. Patch testing with a piece of the elastici-
Department of Dermatology, New York University School of
Medieine, New York, NY zed rubber from the offending bleached garment will,
however, yield a positive reaction. The allergen is
N,N'-dibenzylcarbamyl chloride which is produced by
urticaria or other, less frequently observed, clinical the effect of chlorine bleach on zinc dibenzyldithio-
manifestations. The primary reason for such differing carbamate (Jordan and Bourlas 1975).
forms of cutaneous disease is the multitude of different "Pompholyx" or dyshidrotic-like eczema due to
allergens typically present in rubber compounds. rubber allergies is found in bank employees and other
ACD to rubber may be sharply demarcated, giving a workers with frequent exposure to rubber bands. The
clear indication of the object or garment causing the dermatitis principally affects the dorsolateral aspects of
dermatitis (Figs. 5 and 6). Allergic reactions to rubber the digits of the dominant hand. The chief sensitizers
can also appear scattered over the body including the are thiurams and thiazoles (Conde-Salazar 1990b).
eyebrows, genitalia, face and/or flexual areas of the arms Hyperkeratotic lesions due to rubber appear mainly
and legs, and thus can simulate atopy. Such disease over the palmar and plantar surfaces and initially start
patterns may result from indirect manual transfer of as dryness with minimal scaling. With continued
the allergen or from multiple different sources of cutaneous contact to the allergen, the process inten-
exposure to the allergen. In addition, the possibility of sifies and hyperkeratotic fissures, simulating psoriasis
airborne contact dermatitis (Dooms-Goossens et al. and/or mycotic disease, develop (Fig. 7). At times, it
1986) or systemic contact dermatitis due to ingestion can be difficult to differentiate between these diseases
of rubber accelerators that have migrated into food and patch tests can be diagnostic. An important
substances stored in rubber containers (Stankevich characteristic of allergic reactions is the relatively
et al. 1980) should also be considered. rapid improvement when the patient stops using the
"Bleached rubber syndrome" is an interesting aller- offending object. Although palmoplantar hyperkerato-
gic reaction to rubber accelerators. Although the sis could be attributable to the effects of any allergen
eczematous appearance of the eruption strongly on the thick, horny layer of the palms and/or soles, it is
712 D.V. Belsito
Fig. 7. Allergie eontaet dermatitis to blaek rubber in a work boot.

Note the hyperkeratotie sealing dermatitis most pronouneed over
the meta tarsal area and tips of the toes. This pattern, together
with sparing of the interdigital webs, the toe ereases and the areh
of the foot should suggest the diagnosis. Pateh tests were positive
to N-isopropyl-N'-phenylparaphenylenediamine (IPPD) and
blaek rubber mix. Reprodueed with the permission of Donald
V. Belsito, M.D., Division of Dermatology, University of Kansas
Medieal Center, Kansas City, KS
Fig. 8. Hypopigmentation of the dorsal hand be\ieved to be due
to an allergie reaetion to hydroquinone. Note the patehy
more frequently seen in people allergie to the amine involvement whieh, in some areas, is almost eonfetti like. The
patient was found to be allergie to the offending glove and to only
anti-oxidants, where it has been termed "blaek rubber hydroquinone on an expanded rubber tray. The manufaeturer
hands/feet" (Conde-Salazar 1990b). would not verify the glove's eomponents. Reprodueed with the
Leukoderma from rubber produets is largely due to permission of Donald V. Belsito, M.D., Division of Dermatology,
University of Kansas Medieal Center, Kansas City, KS
hydroquinone and its derivatives. These ehernieals
were previously used in the rubber industry as anti-
oxidants and stabilizers. The first eases of oeeupational derivatives have also been reported to induee purpurie
leukoderma were eaused by monobenzylether of ACD (Burrows 1972).
hydroquinone and were described by Oliver et al. Other clinical forms of allergie reaetions to rubber
(1939). Monobenzylether of hydroquinone not only have also been deseribed, albeit rarely. Calnan (1971)
eaused leukoderma but also an intense allergy. Now- and Aneona et al. (1982) have deseribed lichenoid
adays, sueh reaetions are rare, sinee derivatives of eontaet dermatitis produeed by IPPD. Peeegueiro and
hydroquinone are seldom used as anti-oxidants in Brandäo (1984) have reported plantar pustulosis due to
rubber, although they are still extensively used in the MBT and its derivatives. Dooms-Goossens et al. (1985)
photo graphie industry. Nonetheless, one occasionally deseribed a pustular reaetion from hexaftuorosilieate, a
sees a eonfetti-like hypopigmentation over the dorsal eomponent used in the manufaeture of foam rubber.
hands and forearms in individuals with glove allergies Eun et al. (1985) deseribed an epidemie of pitted
(Fig. 8). Whether this is due to ehemieal leukoderma keratolysis in building workers using rubber boots.
or post-inftammatory hypopigmentation following the Cases of erythema multiforme eaused by allergy to
allergy is often unclear. Sueh may have been the ease IPPD present in a blaek rubber watehband (Foussereau
for periocular leukoderma which developed following et al. 1988) and to natural rubber latex in gloves
exposure to rubber goggles (Goette 1984). (Bourrain et al. 1996) have been deseribed. Finally,
Fisher (1974) first deseribed purpurie reaetions to pyoderma gangrenosum has been linked to an allergic
rubber. He ealled the syndrome PPPP sinee it was reaetion to anti-oxidants and aeeelerants in a stomal
eharaeterized by the appearanee of purpura, peteehiae bag (Lenane et al. 1998).
and pruritus (Fig. 9). Lesions loealize to the area in
eontaet with the rubber objeet. The eausative faetor is Irritant (ontad Dermatitis
the amine anti-oxidant IPPD, as demonstrated by a
positive pateh test whieh, in so me eases, mayaiso be ICD is eommon among rubber workers, in whom it is
purpurie (Romaguera and Grimalt 1977). Thiuram usually eaused by irritant solvents and cleansers
Rubber 713
allergie to rubber-related chernicals, five of these

allergens are rubber related. In fact, four of five are
mixes; hence, on the American standard screening
series, 14 rubber additives are tested. In addition, para-
tertiary-butylphenol formaldehyde res in (PTBFR) and
epoxy res in, plasticizers which can be added to
specialty rubber items, are also included.
Given the vast number of additives in a particular
rubber product, dermatologists interested in fully
evaluating at least so me patients with ACD to rubber
must be prepared to perform tests with the patient's
own materials. In so doing, pieces of the suspected
materials should be cut out to conform to the size of
the patch; it is frequently helpful to soak the material
in water for 15 min prior to testing. Furthermore, when
testing for a rubber material as is, it may be necessary
to leave the patch in place for longer than 48 h,
perhaps up to 1 week. Alternatively, one may elect to
use ultrasonic bath extracts of the suspected rubber
product to improve the yield of patch testing (Bruze
et al. 1992). Patients who do not react to the rubber
allergens on the standard tray but who do react to their
own product will often require testing to an expanded
rubber series either obtained commercially (Table 14)
Fig. 9. Purpuric allergie contact dermatitis in a worker who used or privately. For physicians compounding their own
an abdominal waistband lined with black rubber for treatment of allergens, texts detailing appropriate concentrations
an abdominal hernia. Note the purpuric maculopapular eruption and vehicles are available (deGroot 1986).
of the lower back which was extremely pruritie. Patch testing with
black rubber mix induced an eczematous, non-purpuric reaction.
Reproduced with the permission of Donald Belsito, M.D.,
Division of Dermatology, University of Kansas Medical Center,
Kansas City, KS Treatment and Prevention
unrelated to rubber (Varigos and Dunt 1981; Kilpikari The treatment of ACD lies in correctly identifying its
1982). In contrast, ACD is the norm among users of cause and in properly instructing the patient in
rubber products. Nonetheless, powder in gloves, as avoidance of the responsible allergen(s). However, it
well as the trapping of sweat within gloves, are not can be difficult to offer adequate advice for avoiding a
unusual causes of irritant hand dermatitis from gloves product like rubber, which is widely used in many
(Heese et al. 1991). different substances and which is rarely labeled as to
its chemical composition. The problem is more serious
Allergie Contact Urticaria since the chemical composition of a given rubber
product can change from lot to lot. Thus, the same
ACU is increasingly being observed from use of natural brand of rubber gloves can contain different chemical
latex products. Nutter (1979) first called attention to constituents. Furthermore, patients must be warned
ACU induced by rubber. Since then, hundreds of that the term "hypoallergenie" when applied to a latex
additional cases have been reported. For a more article is meaningless unless they know the actual
complete discussion of ACU to latex, the reader is ingredients. Most hypoallergenie latex products con-
referred to Chap. 88 by K. Turjanmaa. tain carbamates, which have been regarded as less
sensitizing than thiurams or thiazole derivatives
(Fisher 1975). These materials would be very allergenie
Diagnosis
for the individual with ACD to carbamates or ACU to
latex. Nonetheless, the long-term prognosis for indi-
The only useful and reliable method for the diagnosis of viduals with occupational ACD to rubber is signifi-
ACD remains the patch test. At the present time, only 23 cantly better than that for those with ACD to
Food and Drug Administration (FDA)-approved aller- chromium or nickel (Fregert 1975).
gens are readily available in the United States. However, For many of the patient's needs, a variety of
in recognition of the significant number of individuals substitute plastic materials are available. When in
714 D.v. Belsito
Table 1S. A partial listing of available gloves and their ingredients a
Components
Brand name Polymer MBT TH CAR TU Powder
Sterile surgical
Dermaguard plUSb Latex + +CS
Pristinec Latex + +
Safeskin 2000 d Latex +
Dermapreneb Neoprene + +
Neolon e Neoprene + +LAC
Tactyl-Litef Thermoplastic elastomer +CS
Non-sterile exam:
Safeskinf Latex + ±i
Tru-Touchg Polyvinyl chloride +CS
Sensicareg Polyvinyl chloride/plastic hybrid +CS
Tactyl-Litef Thermoplastic elastomer +CS
Household
Bluetteh Neoprene +
Allerderm vinyli Polyvinyl chloride
Industrial
N-Dexi Nitrile + ±CSi
Nitrile Gloveh Nitrile + +
4-H Glovesk Polyethylene
MBT 2-mercaptobenzothiazole and related thiazoles; TH tetramethylthiurams and related thiurams; CAR carbamates; TU thioureas; CS
corn starch; LAC lactose
aThe accuracy of components was verified in January 1999. The components of individual brands may have changed since then
b Ansell-Perry. Telephone: 800-321-9752. Dermaguard Plus has a polyurethane inner lining
C World Medical Supply. Telephone: 800-545-5475
d Safeskin Corp. Telephone: 800-462-9993

e Maxxim Medical. Telephone: 800-346-8849
f MAPA Professional. Telephone: 800-652-2002. To order Bluette Gloves, Tel.: 800-442-3855
g Allerderm. Tel.: 800-365-6868
h Best Co. Tel.: 800-241-0323
i Safety 4, Inc. Tel.: 9l3-492-0860 [U.S.A.] or +49-454-5936383 [Denmark]
J Available in both powdered (corn starch) and non-powdered models
Table 16. Manufacturers of specialty shoes
Company Shoe types
The Cordwainer Shop, P.O. Box llO, Deerfieid, NH 03037 Men's and women's dress shoes and sandals
Tel.: +1-603-4637742
P.W. Minor & Son, Inc., P.O. Box 678, Limited men's and women's dress shoes; men's work boots;
Batavia, NY 14021-0678 Limited men's and women's athletic shoes
Tel. +1-7l6-3431500; +1-800-8288157
Loveless Orthopedic Appliance, 2434 SW 29 St., Men's dress shoes and women's dress fiats (no heels);
OklallOma City, OK 73119 Men's and women's Western-style and hunting boots
Tel.: +1-800-637-9731; +1-405-6319731
Fontana's Shoe Sales and Repair, 401 Eddy St., Women's sandal-style shoes in plastic
Ithaca, NY 14850
Tel.: +1-607-2727463 Sandal-style shoe in leather with cork inner sole.
Birkenstock sandals No rubber products. Bard glues
http://www.birkenstock.com/1.htm
LaCrosse Footwear, Inc., P.O. Box l328, LaCrosse, PVC workboot with steei toe
WI54602
Tel.: +1-800-4511806
doubt, the patient can contact the manufacturer who - Shoes present a particular problem since tracking
may be able to supply information. Guidance is the individual ingredients of commercially available
generally needed in selecting the following: shoes is rarely successful. Fortunately, specialty
shoe manufacturers can customize shoes (Table 16).
- Gloves are available for individuals reacting to the
Expensive, custom-made shoes are the easiest way
various allergens in latex. Table 15 is a partial list,
to avoid relevant allergens. Alternatively, one can
which should be sufficient for most patients. A more
patch test to all components of a patient's existing
detailed listing can be found elsewhere (Heese et al.
shoes and, if negative, have the patient "use test"
1991; Rich et al. 1991).
Rubber 715
Table 17. Contraceptive devices for rubber-sensitive individuals·
Device Comments
Condoms
Naturallamb-skin brands Made from processed sheep intestines; no rubber-related allergens; not completely effective in
blocking transmission of HIV
Avanti condom Thermoplastic elastomer free oflatex and rubber additives. Adequately prevents transmission of HIV
Latex condom Natural latex and must be avoided by patient with ACU; Trojan brands contain carbamates but
no mercaptobenzothiazole, thiurams, or anti-oxidants. Adequately prevents transmission of HIV
Reality female condom Vaginal condom made of polyurethane. No latex, MBT, thiurams, carbamates or thioureas.
Adequately prevents transmission of HIV
Diaphragms:
Koromex or Koro-Flex Latex diaphragm supposedly containing dithiocarbamate accelerators and phenolic anti-oxidants
but no mercaptobenzothiazole or thiurams b
Wide Seal Silicone diaphragm free of natural latex rubber. Manufacturer (Tel.: +1-773-7365500) declined to
specify accelerants, hardeners, etc
Sponges:
Today vaginal sponge Polyurethane foam without mercaptobenzothiazole, thiurams, carbamates or thioureas.
• The accuracy of components was verified in January 1999. The components of individual brands may have changed since then
binformation obtained from Taylor (1986). The manufacturer refused to confirm the components for proprietary reasons and
therefore the reliability of this information cannot be assured
only this pair for aperiod of several weeks. used in the production of rubber. Adams (1975)
Assuming the "use test" is negative, then the shoe proposed that 2-MBT be replaced with ethylene
is presumptively free of relevant allergens. Although thiourea (ETU or mercaptobenzimidazole), since the
not guaranteed, by purchasing the same make and latter had a lower incidence of sensitization when used
model of shoe in the future, the patient may be able in the vulcanization of neoprene. However, animal
to avoid recurrent dermatitis. Patients with persis- experiments suggested that ETU may be both a
tent dermatitis, despite avoidance of allergen in teratogen and a carcinogen in humans (Smith 1976).
their shoes, should be advised to purchase new For these reasons, if 2-MBT is indispensable to
socks since at least one investigator has found that, manufacturing a particular rubber, attempts to reduce
even when thoroughly washed, socks can harbor the its required concentration seem more reasonable.
allergens (RietscheI1984). Furthermore, avoiding the use of the more highly
- Medical devices pose a particular problem for sensitizing chemicals in gloves, boots, and other items
rubber-allergic individuals. Guidance in choosing in elose contact with the skin would be prudent;
contraceptive devices is especially needed; Table 17 however, the higher price of these "hypoallergenic"
lists some alternatives for these patients. These products could make avoidance economically impos-
individuals must also warn physicians/dentists sible, at least for some workers and their employers. A
against performing examinations with gloves to less costly alternative is to use plastic, especially for
which they might react. Finally, there are a vast gloves and shoes.
number of other medical devices containing rubber, Non-rubber materials containing rubber-related al-
which patients, especially those with ACU to latex, lergens must also be avoided. 2-MBT and related
need to avoid. More complete listings of these thiazoles (Table 7) can be found in fungicides and
devices can be found elsewhere (Fisher 1992; algicides, cutting oils, antifreeze, photographic emul-
Hamann 1993). The Spina Bifida Association of sions and veterinarian products (Fregert and Skog
America (4950 MacArthur Blvd., N.W., Suite 250, 1962; Adams 1974; Rudzki et al. 1981). Thiurams
Washington, D.C. 20007-4226; Tel.: 800-621-3141; (Table 6) are extensively used as animal repellents
ud: http://www.sbaa.org/Latex.htm) has a brochure and fungicides (Shelley 1964) and are also the active
which lists many of the potential exposures to latex ingredient in Antabuse. The carbamates (Table 8) are
in hospital and horne environments and also offers widely used as lawn and garden fungicides (Nater et al.
acceptable non-latex alternatives. Fortunately, the 1979), as well as in the plastic industry (Rietschel and
United States has recently enacted a federal regu- Fowler 1995). p-Phenylenediamine derivatives may
lation that requires all medical devices/products cross react with PPD in hair dyes and can be used in
containing natural rubber latex to be labeled as to acrylic products. Finally, the thioureas (Table 9) are
conte nt. found in detergents (Anderson 1983), plastic-based
adhesives (Fregert et al. 1982), photocopy paper (van
To lessen sensitization to rubber and its additives,
der Leun et al. 1977) and paint/glue removers (Kanerva
attempts have been made to substitute or lower the
et al. 1984).
concentration of some of the more allergenic chemicals
716 D.V. Belsito
Summary and Highlights Bourrain JL, Woodward C, Dumas V, et al. (1996) Natural rubber
latex contaet dermatitis with features of erythema muIti-
forme. Contaet Dermatitis 35:55-56
Brandäo FM (1990) Rubber. In: Adams RM (ed) Oeeupational
Sensitization to rubber eomponents often aeeompanies Skin Disease. Saunders, Philadelphia, pp 462-485
allergie or non-allergie hand eezemas. However, with- Bruze M, TruIsson L, Bendsöe N (1992) Pateh testing with
out pateh testing, the diagnosis can be missed. ultrasonie bath extraets. Am J Contaet Dermat 3:133-137
Budden MG, Kirton V, Wilkinson DS (1973) An industrial
Furthermore, since sensitizing rubber products con- dermatitis dinic. Results of a five-year pilot study. Trans St
tain multiple allergenie constituents, individuals are John's Hosp Dermatol Soe 59:261-268
often allergie to several rubber allergens. In addition, Burrows D (1972) Thiuram dermatitis and purpura. Contaet
Dermatitis Newslett 12:333
the existence of multiple sensitivities can be due to Calnan CD (1971) Lichenoid dermatitis from isopropylaminodi-
cross-reactivity (thiurams with carbamates). phenylamine. Contaet Dermatitis Newslett 10:237
The allergens in rubber vary greatly, depending on Calnan CD (1978) Dermatology and industry. Prosser White
Oration 1977. Clin Exp Dermatol 3:1-16
the product and the country of origin. The composition Conde-Salazar L (1987) Dermatosis por gomas y derivados. In:
of the same rubber product may change from lot to lot Garcia Perez A, Conde-Salazar L, Camarasa JM (eds) Tratado
without the consumer being aware of any differences in de Dermatosis Profesionales. Eudema, Madrid, pp 157-181
Conde-Salazar L (1990a) Sensibilidad profesional a eomponentes
the final product. In general, the rubber accelerators, de las gomas. Doetoral thesis, University of Madrid
especially the thiurams, cause the greatest amount of Conde-Salazar L (1990b) Rubber dermatitis: dinieal forms.
sensitivity among users of rubber products. In contrast, Dermatol Clin 8:49-55
Conde-Salazar L, Gomez Ureuyo JF (1976) Sensibilidad a los
workers involved in the manufacture of rubber are eomponentes de la goma en obreros de la eonstruecion. Aetas
more likely allergie to the amine anti-oxidants. Dermosifiliografieas 56:297-310
The amine anti-oxidants, especially IPPD, are highly Conde-Salazar L, dei Rio E, Guimaraens D, et al. (1993) Type IV
allergy to rubber additives. A 10-year study of 686 eases. J Am
sensitizing and positive patch tests are typically Aead Dermatol 29:176-180
intense. Allergie reactions to the amine anti-oxidants Conde-Salazar L, Guimaraens D, Villegas C, et al. (1995) Oeeu-
over the palms and soles often present with a pational allergie eontaet dermatitis in eonstruetion workers.
Contaet Dermatitis 33:226-230
hyperkeratotic dermatitis simulating psoriasis. The Cronin E (1980) Rubber. In: Cronin E (ed) Contaet dermatitis.
dermatitis clears quickly when contact is avoided. Churehill Livingstone, Edinburgh, pp 714-770
Fortunately, the majority of rubber products contain- de Groot AC (1986) Pateh testing: test eoneentrations and vehides
for 2800 allergens. Elsevier, Amsterdam
ing IPPD and its derivatives are black, which helps the de Meester C (1988) Genotoxie properties of 1,3-butadiene. Mutat
individual to identify them. Res 195:273-281
An individual sensitized to components of rubber Dooms-Goossens A, Loneke S, Michiels SL, et al. (1985) Pustular
reaetions to hexafluorosilieate in foam rubber. Contaet
must take precautions not only with rubberized Dermatitis 12:42-47
products used at work (gloves, masks, rubber bands, Dooms-Goossens A, Debussehere KM, Gevers DM, et al. (1986)
etc.), but also with personal products (elasticized Contaet dermatitis eaused by airborne agents: a review and
ease reports. J Am Aead Dermatollp-1O
garments, condoms, shoes, sporting equipment, etc.) EstIander T (1990) Oeeupational skin disease in Finland. Obser-
and with non-rubber sources of the allergen(s), such as vations made during 1974-1988 at the Institute ofOeeupational
insecticides, fungieides, and medicaments. For many Health, Helsinki. Acta Derm Venereol Suppl (Stockh) 155'1-85
EstIander T, Jolanki R, Kanerva L (1986) Dermatitis and urtiearia
workers, it is particularly important to identify specific from rubber and plastie gloves. Contaet Dermatitis 14:20-25
gloves and shoes that are free of their allergens. Tables Eun HC, Park HB, Chun YH (1985) Oeeupational pitted kerato-
15 and 16 are helpful in this regard. lysis. Contaet Dermatitis 12:122
Fajen JM, Roberts DR, Ungers LJ, et al. (1990) Oeeupational
exposure of workers to 1,3-butadiene. Environ Health Per-
speet 86:11-18
References Feinman SE (1987) Sensitivity to rubber ehernieals. J Toxieol
Cutan OeuIar Toxieol 6:117-153
Fishbein L (1992) Exposure from oeeupational versus other
Adams RM (1974) Mereaptobenzothiazole in veterinary medica- sourees. Seand J Work Environ Health 18[Suppl1]:5-16
tions. Contaet Dermatitis Newslett 16:514 Fisher AA (1974) Allergie peteehial and purpuric rubber derma-
Adams RM (1975) Possible substitution for mereaptobenzothiaz- titis: the PPPP syndrome. Cutis 14:25-27
oie in rubber. Contaet Dermatitis 1:246 Fisher AA (1975) "Hypoallergenie" surgieal gloves and gloves for
Adams RM (1983a) Oeeupational skin disease. Grune-Stratton, special situations. Cutis 15:797-811
New York, pp 1-26 Fisher AA (1992) Iatrogenic allergie rubber reaetions in medieal
Adams RM (1983b) Oeeupational skin disease. Grune-Stratton, and dental patients. Cutis 49:81-82
New York, pp 289-312 Foussereau J, Cavelier C, Protois JC, et al. (1988) A ease of
Alfonzo C (1979) Allergic eontaet dermatitis to isopropylami- erythema multiforme with allergy to isopropyl-p-phenylene-
nodiphenylamine (IPPD). Contaet Dermatitis P45-147 diamine of rubber. Contaet Dermatitis 18:183
Aneona A, Monroy F, Fernandez-Diez J (1982) Oeeupational Fregert S (1975) Oeeupational dermatitis in a ten-year material.
dermatitis from IPPD in tyres. Contaet Dermatitis 8:91-94 Contaet Dermatitis 1:96-107
Andersen KE (1983) Diethylthiourea eontaet dermatitis from an Fregert S (1981) Manual of eontaet dermatitis, 2nd edn.
acidic detergent. Contaet Dermatitis 9:146 Munksgaard, Copenhagen, pp 46-48
Baginsky E (1979) Surveillanee and reporting. A paper presented Fregert S, Skog E (1962) Allergie eontaet dermatitis from
at Oeeupational, Industrial and Plant Dermatology Confer- mereaptobenzothiazole in eutting oil. Aeta Derm Venereol
enee, Mareh 26-29, San Franciseo, CA, USA 42:235-238
Rubber 717
Fregert S, Trulsson L, Zimerson E (1982) Contact allergic Mitchell JM, Rook A (1979) Botanieal dermatology. Greengrass,
reactions to diphenylthiourea and phenylisothiocyanate in Vancouver, p 286
PVC adhesive tape. Contact Dermatitis 8:38-42 Nater JP, Verpstra H, Bleuminke F (1979) Allergie contact
Gimenez-Camarasa JM (1968) Dermatitis por goma. Med Cutan sensitization to the fungicide Maneb. Contact Dermatitis
Int Latin Am 3:281-286 5:24-26
Goette DK (1984) Raccoon-like periorbital leukoderma from National Institute for Occupational Safety and Health (NIOSH)
contact with swim goggles. Contact Dermatitis 10:129-131 (1984) 1,3-Butadiene. In: Current intelligence bulletin; no 41,
Hamann CP (1993) Natural rubber latex protein sensitivity in publication no. 84-105. US Department ofHealth and Human
review. Am J Contact Dermat 4:4-21 Services, NIOSH, Cincinnati, OH
Hansen KS (1983) Occupational dermatoses in hospital cleaning Nethercott JR (1982) Results of routine patch testing of 200
women. Contact Dermatitis 9:343-351 patients in Toronto. Contact Dermatitis 8:389-395
Hansson C (1994) Allergie contact dermatitis from N-(1,3- Nethercott JR, Holness DL, Adams RM, et al. (1991) Patch testing
dimethylbutyl)-N' -phenyl-p-phenlenediamine and from com- with a routine screening tray in North America, 1985 through
pounds in polymerized 2,2,4-trimethyl-l,2-dihydroquinoline. 1989: I. frequency of response. Am J Contact Dermat 2:122-129
Contact Dermatitis 30:114-115 Nilsson E (1985) Contact sensitivity and urtiearia in "wet" work.
Heese A, van Hintzenstern J, Peters KP, et al. (1991) Allergic and Contact Dermatitis 13:321-328
irritant reactions to rubber gloves in medical health services. Norris P, Storrs FJ (1990) Allergie contact dermatitis to adhesive
J Am Acad Dermatol 25:831-839 bandages. Dermatol Clin 8:147-152
Heliand S, Nyfors A, Utne L (1983) Contact dermatitis to Nurse DS (1979) Rubber sensitivity. Austr J Dermatol 20:31-33
synthaderm. Contact Dermatitis 9:504-506 Nutter AF (1979) Contact urticaria to rubber. Br J Dermatol
Herve-Bazin B Gradiski D, Duprat P, et al. (1977) Occupational 101:597-598
eczema from N-isopropyl-N' -phenylparaphenylenediamine Oliver EA, Schwartz L, Warren LN (1939) Occupationalleukod-
(IPPD) and N-dimethY-l, 3 butyl-N' -phenylparaphenylenedi- erma: preliminary report. JAMA 113:927-928
amine (DMPPD) in tyres. Contact Dermatitis 3:1-15 Pecegueiro S, Brandäo F (1984) Contact plantar pustulosis.
International Agency for Research on Cancer (IARC) (1979) Some Contact Dermatitis 11:126-127
monomers, plasties and synthetic elastomers, and acrolein. Plotnick HB (1978) Carcinogenesis in rats of combined ethylene
In: IARC monographs on the evaluation of carcinogenie risk dibromide and disulfiram. JAMA 239:1609
of chemieals to humans, vol 19, pp 231 Plotnick H, Birmingham DJ (1993) Disulfiram alcohol facial flush
International Agency for Research on Cancer (IARC) (1986) Some in rubber industry (abstract). Proceedings of the American
chemieals used in plasties and elastomers. In: IARC mono- Contact Dermatitis Society Annual Meeting, Washington,
graphs on the evaluation of carcinogenie risk of chemieals to D.C. p 11
humans, vol 39, pp 155 Rich P, Belozer ML, Norris P, et al. (1991) Allergic contact
Jordan WP Jr, Bourlas MC (1975) Allergic contact dermatitis to dermatitis to two antioxidants in latex gloves: 4,4'-thiobis( 6-
underwear elastic. Arch Dermatol 111:593-595 tert-butyl-meta-cresol) (Lowinox 44S36) and butyl-
Kanerva L, Jolanki R, Plosila M, et al. (1984) Contact dermatitis hydroxyanisole: allergic alternatives for glove-allergie pa-
from dibutylthiourea. Contact Dermatitis 10:158-162 tients. J Am Acad Dermatol 24:37-43
Kanerva L, Estlander T, Jolanki R, et al. (1996) Allergic patch test Rietschel RL (1984) Role of socks in shoe dermatitis. Arch
reactions caused by the rubber chemieal cyclohexyl thiopht- Dermatol 120:398
halimide. Contact Dermatitis 34:23-26 Rietschel RL, Fowler JF Jr (1995) Fisher's Contact Dermatitis, 4th
Kaniwa MA, Isama K, Nakamura A, et al. (1994a) Identification edn. William & Wilkins, Baltimore
of causative chemieals of allergic contact dermatitis using a Rodriguez E, Reynolds GW, Thompson JA (1981) Potent contact
combination of patch testing in patients and chemieal allergen in the rubber plant guayule (Parthenium argent-
analysis: application to cases from rubber footwear. Contact atum). Science 21:1444-1445
Dermatitis 30:26-34 Rogers TH Jr (1974) Natural rubber. In: Considine DM (ed)
Kaniwa MA, Isama K, Nakamura A, et al. (1994b) Identifica- Chemieal and process technology encyclopedia. McGraw-Hili,
tion of causative chemieals of allergie contact dermatitis New York, p 984
using a combination of patch testing in patients and Romaguera C, Grimalt F (1977) PPPP syndrome. Contact
chemieal analysis: application to cases from rubber gloves. Dermatitis P02-103
Contact Dermatitis 31:65-71 Rubber world magazine's blue book (1997) Lippincott and Peto,
Kilpikari I (1982) Occupational contact dermatitis among rubber Philadelphia
workers. Contact Dermatitis 8:359-362 Rudner EJ, Clendenning WE, Epstein E, et al. (1975) The
Kilpikari I, Halme H (1983) Contact allergy to Hypalon rubber. frequency of contact sensitivity in North America 1972-
Contact Dermatitis 9:529 1974. Contact Dermatitis 1:277-280
Knudsen BB, Menne T (1996) Contact allergy and exposure Rudzki E, Napiorkowska T, Czerwinskadihm I (1981) Dermatitis
patterns to thiurams and carbamates in consecutive patients. from 2-mercaptobenzothiazole in photographie films. Con-
Contact Dermatitis 35:97-99 tact Dermatitis 7:43
Lachapelle JM, Tennstedt D (1979) Epidemiological survey of Schwartz L, Tulipan L, Birmingham DJ (1957) Occupational
occupational contact dermatitis of the hands in Belgium. diseases of the skin, 3rd edn. Lea & Febiger, Philadelphia,
Contact Dermatitis 5:244-248 p 575
Lammintausta K, Kalimo K (1985) Sensitivity to rubber. Study Shelley WB (1964) Golf-course dermatitis due to thiram fungi-
with rubber mixes and individual rubber chemicals. Der- eide. JAMA 188:415-417
matosen 33:204-208 Sidi E, Hincky M (1954) Les eczemas aux gants de caout. Presse
Lenane P, McKenna D, Murphy GM, et al. (1998) Pyoderma Med 62:1305-1307
gangrenosum secondary to allergic contact dermatitis from Smith D (1976) Ethylene thiourea - a study of possible
rubber. Contact Dermatitis 38:238 teratogenicity and thyroid careinogenieity. J Soc Occup Med
Magnusson B, Möller H (1979) Contact allergy without skin 26:92-94
disease. Acta Derm Venereol Suppl (Stockh) 59:113-115 Song M, Degreef H, DeMaubeuge J, et al. (1979) Contact
Marks JG, Belsito DV, DeLeo VA, et al. (1995) North American sensitivity to rubber additives in Belgium. Dermatologica
Contact Dermatitis Group standard tray patch test results 158:163-167
(1992 to 1994). Am J Contact Dermat 6:160-165 Stankevieh VV, Vlasiuk MG, Prokofeva LG et al. (1980) Hygienic
Marks JG, Belsito, DV, DeLeo VA, et al. (1998) North American assessment of organosulfur accelerators for vulcanization of
Contact Dermatitis Group patch test results for the detection rubbers for the food industry. Gig Sanit 10:88-89
of delayed-type hypersensitivity to topieal allergens. J Am Storrs FJ, Rosenthai LE, Adams RM, et al. (1989) Prevalence and
Acad Dermatol 38:911-918 relevance of allergic reactions in patients patch tested in
718 D.V. Belsito: Rubber
North Ameriea - 1984 to 1985. J Am Aead Dermatol 20:1038- White IR (1988) Dermatitis in rubber manufaeturing industries.
10 45 Dermatologie Clinies 6:53-59
Taylor JS (1986) Rubber. In: Fisher AA (ed) Contaet dermatitis. Wilkinson SM, Beek MH (1993) Allergie eontaet dermatitis from
Lea & Febiger, Philadelphia, pp 603-643 sealants eontaining polysulphide polymers (Thiokol®). Con-
Themido R, Brandäo FM (1984) Contaet allergy to thiurams. taet Dermatitis 29:273-274
Contaet Dermatitis 10:251 Wilkinson SM, Beek MH (1996) Allergie eontaet dermatitis from
van der Leun JC, de Kreek EI, Deenstra-van LeeuwenM, et al. (1977) latex rubber. Br J Dermatol 134:910-914
Photosensitivity owing to thiourea. Areh DermatoI113:1611 Wilson HT (1960) Rubber-glove dermatitis. BMJ 2:21-23
Varigos GA, Dunt DR (1981) Oeeupational dermatitis. An World Health Organization (WHO) (1983). Styrene. In: Environ-
epidemiologieal study in the rubber and eement industries. mental health eriteria, no 26, WHO, Geneva
Contaet Dermatitis 7:105-110 Wyss M, Elsner P, Wuthrieh B, et al. (1993) Allergie contaet
Vestey JP, Gawkrodger DJ, Wong WK, et al. (1986) An analysis of dermatitis from natural latex without contaet urtiearia.
501 eonseeutive eontaet dinie eonsultations. Contaet Derma- Contaet Dermatitis 28:154-156
titis 15:119-125 Zina AM, Bedello PG, Cane D, et al. (1987) Dermatitis in a rubber
von Hintzenstern I, Heese A, Koeh HU, et al. (1991) Frequeney, tyre faetory. Contaet Dermatitis 17:17-20
speetrum and oeeupational relevanee of type IV allergies to
rubber ehernieals. Contaet Dermatitis 24:244-252
CHAPTER 88
Natural-Rubber-Latex Allergy
K. Turjanmaa, H. Alenius, S. Mäkinen-Kiljunen, T. Reunala, and T. Palosuo
Introduction NRL allergens have been characterized at the molec-

ular level (Czuppon et al. 1993; Alenius et al. 1994a;
Alenius et al. 1995; Lu et al. 1995; Alenius et al. 1996a;
The history of natural-rubber-latex (NRL) allergy is
Akasawa et al. 1996; Slater et al. 1996). In the near
relatively short; the first case reports appeared in 1979-
future, this progress will bring better diagnostic tests
1980 in the European (Nutter 1979; Förström 1980) and
and perhaps tools for immunotherapy to clinicians.
in 1989 in the North American (Slater 1989; Spaner
This information will also enable rubber manufactur-
et al. 1989; Taylor et al. 1989) literature. During the last
ers and governmental regulatory authorities to make
10 years, NRL allergy has become acknowledged as a
efforts to ensure that potentially harmful NRL gloves,
major occupational problem among glove-using
medical devices and consumer products are withheld
health-care workers. In addition, several authors have
from the market.
paid attention to the fact that NRL allergy also
frequently occurs outside the health-care environment.
Populations at increased risk include not only glove-
Epidemiology and Risk Factors
using kitchen workers and housekeeping personnel
(Turjanmaa 1988; Sussman and Beezhold 1995; Taylor
and Praditsuwan 1996) but also children, who may At present, the incidence of NRL allergy is still
exhibit allergic reactions when blowing balloons unknown, but several prevalence studies have been
(Axelsson et al. 1988; Sorva et al. 1995). Even patients published. In European health-care workers screened
allergic to various fruits, such as banana and avocado, with SPT, the prevalence of NRL allergy has ranged
may experience allergic reactions to NRL and vice from 2.8% to 1O.iYo (Table 1). High prevalences have
versa (M'Raihi et al. 1991; Blanco et al. 1994a; also been found in physicians (9.9%) and operating-
Mäkinen-Kiljunen 1994; Lavaud et al. 1995). The wide room nurses, dentists and dental hygienists and
spectrum of symptoms of NRL allergy range from mild assistants examined in Canada and the USA (Arellano
contact urticaria to asthma and anaphylactic reactions et al. 1992; Turjanmaa et al. 1995b; Liss et al. 1997;
(Axelsson et al. 1987; Turjanmaa 1987; Leynadier et al. Hamann et al. 1998). In agreement with SPT screening,
1989; Slater 1989). Severe allergie reactions are fre- arecent serologie al study based on RAST found a 5.5%
quently reported to occur intraoperatively in children prevalence of NRL allergy among 381 hospital workers
with spina bifida (Slater 1991; Kelly et al. 1994). It has in the USA (Kaczmarek et al. 1996). Children with
recently been emphasized that NRL allergens become spina bifida have ShOWll the highest prevalence of NRL
easily airborne with glove powder and that persons allergy (Table 1). The frequency has ranged from 32%
sensitized to NRL may also suffer from occupational to 51% in SPT screenings (Kelly et al. 1993; Moneret-
asthma (Jäger et al. 1992; Swanson et al. 1994; Tarlo Vautrin et al. 1993; Slater 1994) and from 34% to 47%
et al. 1994; Vandenplas et al. 1995). in serological IgE measurements (Tosi et al. 1993; Kelly
The presence of specific immonoglobulin E (IgE) in et al. 1994; Pittman et al. 1995). In contrast to these
NRL-allergic patients can be verified with skin-prick studies, a low 4.3% prevalence rate was reported for
tests (SPT) or by serological methods such as the Venezuelan children with spina bifida (Capriles-Hulet
radioallergosorbent test (RAST) (Turjanmaa et al. et al. 1995). The occurrence of NRL allergy has not
1988b; Wrangsjö et al. 1988; Slater et al. 1991; Hamilton been systematically searched among the general pop-
et al. 1994). The limited knowledge of the relevant NRL ulation but the prevalence seems to be clearly less than
allergens has formed a major hindrance for developing 1% (Table 1). NRL allergy was found in only one
optimal tests for diagnostic and rubber-product-mon- (0.12%) of 804 unselected adult Finns prick-tested
itoring purposes. Recently, however, several major before surgery (Turjanmaa et al. 1995c). A low, 0.4%

720 K. Turjanmaa et al.
Table 1. Prevalence of natural

rubber latex allergy in different Population Subjects Prevalence Country Reference
populations studied* (n) (0/0)
Healthcare workers
Hospital employees 512 2.8 Finland Turjanmaa et al. 1987
Hospital employees 272 4.7 Belgium Vandenplas et al. 1995
Hospital and dental care 202 3.5 Sweden W rangsjö et al. 1994
employees
Hospital physicians 101 9.9 Canada Arellano et al. 1992
Operating room nurses 197 10.7 France Lagier et al. 1992
Operating room nurses 547 8.2 USA Turjanmaa et al. 1995
Multioperated patients
Spina bifida children 25 32.0 France Moneret-Vautrin
et al. 1993
Spina bifida children 83 50.6 USA Kelly et al. 1993
Spina bifida children 93 37.6 USA Slater 1994
General population
Adult surgical patients 804 0.12 Finland Turjanmaa et al. 1995
Non-atopics in 272 0.4 France Monetret -Vautrin
allergy dinic et al. 1993
Atopics in allergy dinic 100 3.0 Canada Arellano et al. 1992
* Diagnosed by skin-prick testing
prevalence rate was also found in French non-atopic Moneret-Vautrin et al. 1993; Tosi et al. 1993; Kelly et al.
subjects prick-tested in an allergology dinic (Moneret- 1994; Pittman et al. 1995). There are also children
Vautrin et al. 1993). In atopic populations, the fre- without any history of major operations who may
quency of NRL allergy seems to be higher. The exhibit NRL allergy symptoms from balloons, rubber
prevalence was 0.85% in 4708 Finnish patients prick- toys and pacifiers (Axelsson et al. 1988; Sorva et al.
tested due to suspicion of atopic symptoms (Turjan- 1995). Many of these NRL-allergic children have had
maa et al. 1995C) and 3% in 100 atopic patients studied associated food allergies from cereals, bananas and
in Canada (Arellano et al. 1992). A serological screen- other fruits (Sorva et al. 1995; Ylitalo et al. 1997). These
ing study has been performed with the AlaST AT findings suggest that a pre-existing food allergy could
method (Diagnostic Products Corporation, Los Ange- be an additional risk factor of NRL allergy in children.
les) in blood donors (Ownby et al. 1996). The preva-
lence of latex-specific IgE antibodies was as high as
6%, but the dinical relevance of this finding should be
Clinical Manifestations of NRL Allergy
evaluated in further studies.
In addition to repeated exposure to gloves and other
NRL products, atopy seems to be the principal The dinical symptoms of NRL allergy usually arise
determinant of the development of NRL sensitization. from direct contact with a NRL product but mayaiso
In agreement with this, the NRL-allergic health-care result from inhalation of airborne allergens bound to
workers are atopics 2.2-4.2 times more often than their e.g. glove powder. The most frequently reported
co-workers without NRL allergy (Turjanmaa 1987; manifestation is contact urticaria, followed by rhino-
Arellano et al. 1992; Moneret-Vautrin et al. 1993; Yas- conjunctivitis (Table 2). Mucosal swelling is a typical
sin et al. 1994; Vandenplas et al. 1995). Hand eczema symptom after oral, vaginal or rectal exposure to NRL
disrupts the skin barrier, and together with personal products, such as balloons, gloves and condoms. The
atopy this condition is one of the main predisposing systemic reactions consist of generalized urticaria,
factors for NRL allergy (Turjanmaa 1988; Wrangsjö
et al. 1988; Jäger et al. 1992; Charous et al. 1994; Taylor
and Praditsuwan 1996). The prevalence of hand Table 2. Frequency of symptoms (as a percentage) of natural
rubber latex allergy in two European patient series
dermatitis has been as high as 67-82% in NRL-allergic
patients (Turjanmaa 1988; Taylor and Praditsuwan Finnish series* German series**
1996). In addition to contact with gloves, the patients (n = 124) (0/0) (n = 70) (0/0)
mayaiso react to airborne NRL in their working
Contact urticaria 75 100
environment (Tarlo et al. 1990; Vandenplas et al. Conjunctivitis 22 44
1995). At present, it is not known whether pre-existing Rhinitis 15 51
asthma could be a risk factor for NRL allergy (Van- Asthma or dyspnea 3 31
Severe systemic reactions 8 6
denplas 1995).
Children with spina bifida form a well-known and * Turjanmaa et al. 1995
prominent risk group for NRL allergy (Slater 1989; ** Jäger et al. 1992
Natural-Rubber-Latex Allergy 721
asthma and anaphylactic shock (Sussman et al. 1991; Table 3. Diagnosis of natural rubber latex allergy
Levy et al. 1992). While serious reactions may occur
Method Comment
under a variety of conditions, the great majority have
occurred within the health-care system, and especially Clinieal history Will not identify all allergie patients
intraoperatively (Levy et al. 1992; Slater 1994). Ana- Skin priek testing Rapid and safe, eommercial allergens
phylaxis can, however, also be induced outside the available, sensitivity not 100%
Glove use or ehallenge Highly allergenie glove brand
health-care system, e.g., in NRL-allergic children when tests (skin, lungs) required, potentially dangerous,
blowing toy balloons (Axelsson et al. 1988). emergeney treatment facilities
NRL allergens have caused occupational asthma in a needed
In vitro tests (RAST, Commercial tests available,
surgical-glove manufacturing plant (Tarlo et al. 1990). AlaSTAT, ete.) sensitivities and speeificities
Positive inhalation challenge tests have been shown to variable
occur in NRL-allergic patients {Jäger et al. 1992) and,
recently, Vandenplas and his coworkers (Vandenplas
et al. 1995) focused attention on the frequent occur- skin irritation and itching caused by glove powder or
rence of NRL-induced asthma among health-care the occlusion effect of the glove, especially in atopic
workers. After specific NRL inhalation challenges, they persons who frequently have dry skin. However,
found a 2.5% prevalence of occupational asthma several screening studies have shown that as many as
among 273 hospital employees. This and other recent 30-60% of the SPT -positive NRL-allergic health-care
studies (Swanson et al. 1994; Tarlo et al. 1994; Tomazic workers report no symptoms at primary examination.
et al. 1994) suggest that the widespread use of In children with spina bifida, a detailed history seems
powdered gloves and the airborne spread of NRL to be the most sensitive means of detecting NRL-
allergens should be considered a significant health allergic individuals at risk for anaphylaxis (Tosi et al.
problem among hospital personnel. 1993). In contrast to this patient group, the clinical
In addition to immediate cutaneous symptoms, i.e., history remains negative in about one-third of NRL-
contact urtiearia, the glove-using NRL-allergic pa- allergie children who have associated food allergies
tients can also present with persistent hand eczema (Sorva et al. 1995; Ylitalo et al. 1997).
(Turjanmaa 1988; Arellano et al. 1992; Charous et al. The diagnosis of NRL allergy should be confirmed
1994; Taylor and Praditsuwan 1996). Turjanmaa by in vivo or in vitro tests (Turjanmaa 1988; Levy et al.
(Turjanmaa 1988) found hand eczema in 67% of 1992; Ownby and McCullough 1993). In 1984, we started
NRL-allergic hospital employees. Interestingly, the to use SPT with aqueous NRL-glove extracts, and this
eczema disappeared in several patients after with- method has yielded satisfactory results when screening
drawal of NRL gloves, although the patients did not several thousand patients for NRL allergy (Turjanmaa
have type-IV contact allergy to rubber chemie als. et al. 1995c). During recent years, we have used the
This finding suggests that a chronic hand eczema same highly allergenic glove brand (1:5 weight:volume,
could be one manifestation of NRL allergy and, if this Triflex, Baxter, lot 06 92L12DPGN) and a speciallancet
is the case, the pathogenetic mechanism could be (ALK AIS, H0rsholm, Denmark) in the testing. Al-
similar to protein contact dermatitis, a well-known though anaphylactic events have been reported after
occupational problem among food handlers allergic, SPT with NRL and multipeaked lancets (Kelly et al.
for example, to fish or vegetables (Maibach and 1993), most investigators agree that SPT is the method
Johnson 1975). of choiee for screening and diagnosing NRL allergy
(Hadjiliadis et al. 1995; Turjanmaa et al. 1995c). Lack of
standardized NRL allergens has been the major short-
coming of the SPT method. A standardized commer-
Diagnosis of NRL Allergy
cial NRL allergen has now become available in Europe
(Stallergenes, SA, Fresnes, France). In addition, a few
The diagnosis of NRL allergy is based on clinical non-standardized SPT preparations are on the market
his tory and laboratory tests (Table 3). Careful history in Europe and Canada. Recently, we evaluated three
is important when diagnosing NRL allergy, but even a preparations in 110 previously diagnosed NRL-allergic
thorough history will not necessarily identify all NRL- patients and compared the results to those obtained
allergie persons (Sussman and Beezhold 1995); the with our standard glove extract. The sensitivities were
patient may or may not belong to the known risk 88% for Stallergenes, 54% for ALK, 92% for Bencard
groups, and the symptoms can be typieal of NRL SPT allergens and 92% for the reference glove extract
allergy or totally absent. In health-care workers and (Turjanmaa et al. 1995a). ALK (Denmark) brought a
other glove-using people, NRL allergy can easily new SPT allergen onto the market in 1998, the
remain unrecognized (Turjanmaa 1988). The cutane- sensitivity and specificity of which still remain to be
ous symptoms of NRL allergy are easily masked by evaluated.
In addition to skin-prick testing, Wilkinson and NRL Allergens

Beck used ammoniated latex for diagnosing delayed-
type allergy to NRL. Of 822 patients, 16 (1.9%)
Numerous studies based on immunoblotting and other
demonstrated positive cutaneous reactions to latex.
immunoelectrophoretic methods have described a
Six were SPT -positive, five were both SPT and patch-
test positive and five were only patch-test positive. large variety of NRL pro teins that bind IgE from the
sera of NRL-allergic patients, but hitherto little
Patch testing with latex will be an important method-
consensus has existed on which of these pro teins
ology in the future in diagnosing delayed-type
should be considered as major or clinically significant
eczematous reactions to NRL, but proper test materials
allergens. However, substantial progress has recently
not containing rubber chemicals are first needed
been made in the purification and molecular charac-
(Wilkinson and Beck 1996).
terization of several NRL allergens, which has facili-
Use tests with latex gloves or pulmonary inhalation
tated the assessment of their significance and given
tests have been suggested as decisive steps in judging
grounds for proper comparison of the results obtained
whether a relevant clinical allergy to NRL really exists
by different researchers.
(Turjanmaa et al. 1995C; Vandenplas 1995). Glove-use
tests frequently produce contact urticaria if perform-
ed with highly allergenic gloves. The use test has IgE-Binding Proteins in NRL Characterized
caused anaphylactic reactions in a patient with severe by Immunoblotting
hand eczema and, for safety reasons, the use test
should be started with a finger piece of a glove A 14-kDa protein has been identified in several
(Wrangsjö et al. 1994; Turjanmaa et al. 1995c). In immunoblotting studies as one of the major NRL
order to avoid false-positive results in milk-allergic allergens (Morales et al. 1989; Alenius et al. 1991;
subjects, the use test should be performed with a Chambeyron et al. 1992; Jäger et al. 1992; Slater and
glove brand which does not contain casein (Mäkinen- Chhabra 1992; Alenius et al. 1993) and, in particular,
Kiljunen et al. 1993). Recent studies have shown that almost all NRL-allergic patients with spina bifida had
a bronchial challenge test, in which subjects handle IgE antibodies combining with a pro tein of this size
either NRL gloves or aqueous extracts, can identify (Slater and Chhabra 1992; Alenius et al. 1993). How-
health-care workers with NLR-induced occupational ever, in two-dimensional electrophoresis, as many as
asthma (Jäger et al. 1992; Pisati et al. 1994; Vandenp- 26 IgE-binding polypeptides with molecular weights of
las et al. 1995). about 14 kDa and isoelectric points ranging from pH
At present, in vitro measurement of NRL-specific 4.2 to 6.5 could be detected in NRL, indicating that the
IgE can be performed using RAST, AlaSTAT and 14-kDa band is composed of a multitude of polypep-
various enzyme-linked immunosorbent assay (ELISA) tides with various isoelectric points (Alenius et al.
methods and other IgE-binding assays, such as 1994b). In addition to the 14-kDa band, most NRL-
immunoelectrophoresis, immunospot and immuno- allergic patients with spina bifida also had IgE
blotting. The sensitivities and specificities of these tests antibodies against a NRL pro tein with an apparent
are not yet optimal, possibly due to deficiencies in molecular weight of 27 kDa. Interestingly, other
NRL-allergen source materials and their cross-reactiv- NRL-allergic patients did not recognize this allergen
ity with other IgE antibodies (Turjanmaa et al. 1988b; (Alenius et al. 1993; Alenius et al. 1994b).
Kelly et al. 1993; Hamilton et al. 1994; Mäkinen- Alenius et al. (Alenius et al. 1994d) showed that the
Kiljunen 1994). The commercial latex allergy test most frequently recognized NRL allergen among adult
CAP-RAST (Pharmacia, Uppsala, Sweden) has proven patients presenting primarily cutaneous symptoms was
rather sensitive (80-90%), but the specificity may not a 20-kDa protein. IgE antibodies to this protein were
be adequate, at least in children (Wrangsjö et al. 1994; found in sera from 17 of 22 (77%) of the patients in this
Ylitalo et al. 1997). Latex RAST seems to detect highly particular patient group, whereas only 36% of the same
allergie patients well, although there is one study patients had antibodies to the 14-kDa protein (Alenius
reporting anaphylactic reactions in NRL-allergic pa- et al. 1994d). Akasawa et al. recently reported that the
tients with negative RAST (Leynadier and Dry 1991). majority of their NRL-allergic patients' sera showed
IgE antibodies to purified NRL allergens, such as IgE antibodies to an 18-kDa protein (Akasawa et al.
hevein, have also been measured by ELISA methods 1995), which could be the same as the 20-kDa NRL
that show 100% specificity (Alenius et al. 1996a; allergen described above (Alenius et al. 1994d). Also,
Alenius et al. 1996b). Their use is currently restricted several other NRL proteins, including proteins with
to scientific purposes but, when appropriate mixtures apparent molecular weights (MWs) of 25.6, 30, 46, 54
of purified allergens are available, such reagents can and 75 kDa, can be important allergens (Alenius et al.
provide exquisitely specific and sensitive means for in 1993; Alenius et al. 1994d; Beezhold et al. 1994; Aka-
vitro diagnosis of NRL allergy. sawa et al. 1995).
Molecular Characterization of NRL Allergens antibodies against the highly purified REF preparation
(Alenius et al. 1996b). Likewise, in ELISA tests, only 8
A number of NRL pro teins have been characterized at of 45 (18%) of NRL-allergic patients had IgE antibodies
the primary-structure level, and some of them have to purified REF (Table 5). Essentially similar results
recently been shown to represent significant allergens were reported by Akasawa et al. (Akasawa et al. 1995),
(Table 4). Hevein is a chitin-binding protein suggested who found that 23% of their NRL-allergic patients' sera
to be involved in the coagulation of latex and to playa reacted on immunoblotting with a 14.6-kDa NRL
role in the protection of rubber-tree wounds by protein band identified as REF by amino-acid analysis.
inhibiting the growth of several chitin-containing These data suggest that REF is one - but not the most
fungi (Broekaert et al. 1990; Gidrol et al. 1994). Hevein significant - allergen among the NRL proteins.
is synthesized as preproprotein (also known as
prohevein) that is post-translationally processed into Prohevein (20 kDa) and Hevein (4.7 kDa)
aminoterminal hevein (43 amino acids) and the
carboxyterminal 138-amino-acid C domain (Fig. 1) A 20-kDa NRL protein, previously shown to be the
(Lee et al. 1991). Hevamine, another major NRL most important allergen for adult NRL-allergic patients
protein, has been shown to exhibit chitin ase and (Alenius et al. 1993; Alenius et al. 1994d), was identi-
lysozyme activity, and it mayaiso be antifungal (Jekel fied by amino-acid sequencing as prohevein (hev b 6)
et al. 1991). Another two rubber pro teins are suggested (Alenius et al. 1995). On immunoblotting, purified
to playa role in the elongation of polyisoprene chains: prohevein bound IgE from 24 of 29 (83%) and in ELISA
rubber elongation factor (REF), which is tightly bound from 36 of 52 (69%) of the sera of NRL-allergic patients
to the surfaces of rubber particles, and prenyltrans- (Table 5) (Alenius et al. 1995; Alenius et al. 1996b).
ferase, which is found both free in the cytosol and in Purified prohevein also elicited positive SPT reactions
association with rubber particles (Dennis et al. 1989; in 6/7 of NRL-allergic patients and was concluded to
Light and Dennis 1989). represent a major NRL allergen (Alenius et al. 1995). In
line with these findings, Beezhold et al. (Beezhold et al.
Rubber Elongation Factor (14.6 kDa) 1994) showed that the amino-acid sequences of two
NRL protein bands excised at the 14-kDa and 18-kDa
REF has been suggested to be the major allergen in regions were homologous to prohevein. However, the
NRL (Hev b 1) and the only allergen present in one authors did not assess the IgE reactivity of patient sera
latex surgical glove brand analyzed (Czuppon et al. against purified proteins.
1993). In this study, REF was reported to induce Attempts have also been made to localize IgE-
symptoms in NRL-allergic patients and to completely binding epitopes of prohevein. Alenius et al. (Alenius
block NRL-specific IgE antibodies in all 13 of the et al. 1996a) recently reported that around 70-80% of
patients' sera tested using ELISA. However, these NRL-allergic patients had IgE antibodies to purified
findings have not been confirmed by other authors. prohevein, whereas a minority (15-20%) of these
When REF was purified by electroelution from rubber patients had IgE against the purified prohevein C
particles and analyzed for its IgE-binding ability by domain in ELISA and immunoblot assays (Table 5).
immunoblotting, 4 of 6 sera from NRL-allergic chil- Moreover, the IgE-binding peptides purified from a
dren with congenital anomalies but only 1 of 30 of the brand of highly allergenic NRL gloves were shown to
sera of other NRL-allergic patients showed IgE be hevein molecules, since they showed amino-acid
Table 4. Basic properties of molecularly characterized natural rubber latex allergens
Allergen Molecular Information on Functions, sequence homologies

weight (kDa) primary structure
Hevein (Hev b 6.02) 4.72 C Chitin-binding, homology to

wheat-germ agglutinin
Hevein C-domain (Hev b 6.03) 14 C Homology to wim in potato
REF (Hev b 1) 14,6 C Elongation of polyisoprene chains
Prohevein (Hev b 6.01) 20 C Hevein preproprotein
23/27 -kDa protein (Hev b 3) 23/27* P Function unknown, homology to REF
Hevamine 29.6 C Chitinase, lysozyme
36-kDa protein (Hev b 2) 36 P Endoglucosidase of rubber tree
Acidic 16-kDa protein (Hev b 5) 16-24 C Function unknown
Patatin-like protein (Hev b 7) 46 C Function unknown, homology to patatin
* Apparent molecular weight based on electrophoretic mobility. C complete amino acid sequence known; P partial sequence known;
REF rubber elongation factor
Table 5. Occurrence of immunoglobulin E antibodies to molecu- showed significant (though only partial) homology
larly characterized and purified natural rubber latex (NRL)
proteins in enzyme-linked immunosorbent assays (Alenius et al.
with REF. Since the amino-acid sequences of the
1995, 1996) tryptic peptides derived from the 27-kDa and 23-kDa
proteins were in essence identical in the studies of
Purified NRL protein Positive/patient Alenius et al. (Alenius et al. 1994a) and Lu et al. (Lu
sera studied
et al. 1995) and since the IgE reactivity against both
Hevein 24/43 (56%) proteins seemed to be restricted to NRL-allergic
Prohevein C-domain 11/52 (21%) patients with spina bifida, it could be assumed that
Rubber elongation factor 8*/45 (18%) these pro teins are the same or they represent different
Prohevein 36/52 (69%)
isomers or modifications of the same protein (Alenius,
* Includes 4 children with spina bifida unpublished observations). Differences in the estimat-
ed MW of the pro teins are probably due to differences
in the laboratory methods used. The exact MW s of the
sequences identical to those of the prohevein N-ter- proteins need to be established by mass-spectrometric
minus and had a MW corresponding to that of hevein analysis or by calculations based on their complete
(4719.1 Da), a 43-amino-acid N-terminal fragment of amino-acid sequences.
prohevein. In ELISA, 56% of 45 NRL-allergic patients'
sera showed IgE antibodies to purified hevein, and Acidic 16-kDa NRL Protein (Hev b 5)
hevein elicited positive SPT reactions in patients
showing IgE to the N-terminus of prohevein. The Using the cDNA library from Hevea brasiliensis latex
same study also showed that purified hevein inhibited and IgE from the serum of a latex-allergie health-care
72% of IgE bin ding from pooled sera of NRL-allergic worker, Slater et al. (Slater et al. 1996) identified,
patients to solid-phase glove extract in ELISA inhibi- doned and sequenced a novel NRL allergen, designated
tion assays. The authors conduded that the main hev b 5, against which 92% of health-care workers and
allergenie epitope of prohevein is located in its N 50% of spina-bifida patients with NRL allergy had IgE
terminus, and the immunologically active fragments antibodies. At the same time, Akasawa et al. (Akasawa
carrying this epitope, known as hevein, are found in a et al. 1996) reported molecular identification and
highly allergenie latex glove. Arecent study by another mass-spectrometric data of an identical protein. The
group (ehen et al. 1996) has confirmed the role of latter authors also isolated and doned the cDNA
hevein as a major NRL allergen. coding for this pro tein from a latex cDNA library and
showed that the deduced amino-acid sequence from
23/27-kDa NRL Protein (Hev b 3) the cDNA was nearly identical to that obtained by
amino-acid sequencing of enzymatically digested in-
Alenius et al. reported primary structure data on a 27- ternal peptides.
kDa protein (Alenius et al. 1994a) recognized charac-
teristically by IgE in sera from NRL-allergic patients Patatin-Like NRL Protein
with spina bifida (Alenius et al. 1993; Alenius et al.
1994b; Yeang et al. 1996). The majority of the purified Beezhold et al. (Beezhold et al. 1994; Beezhold et al.
tryptic peptides obtained from the 27-kDa protein 1996) showed that 23% of latex-allergie patients
revealed no significant homology to any of the recognize a 46-kDa latex protein that has sequence
published protein sequences, indicating that this homology to a broad dass of plant proteins known as
protein has not previously been described at the patatins. In the current allergen nomendature system,
primary-structure level. However, partial homology to this pro tein has been assigned as hev b 7.
REF was observed. Interestingly, the IgE reactivity
against the 27-kDa allergen among patients with spina Hevamine (29.6 kDa) and a 36-kDa Glucanase
bifida was very similar to its reactivity against REF. It
is possible that this co-occurrence of IgE antibodies is A 30-kDa NRL pro tein , purified and identified as
partially explained by the homology between REF and hevamine (Table 4) (Alenius et al. 1995), showed IgE
the 27-kDa protein. binding in 1 of 29 (3%) NRL-allergic patients' sera.
Lu et al. (Lu et al. 1995) recently characterized a Beezhold et al. (Beezhold et al. 1994) had also reported
23-kDa NRL protein which reacted with the IgE from 13 that the N-terminal amino-acid sequence of an excised
of 17 (76%) NRL-allergic spina-bifida patients. The NRL pro tein band at 29 kDa was homologous to
purified 23-kDa protein also induced significant pro- hevamine, but none of their 40 patients showed IgE
liferation of lymphocytes from spina-bifida patients, binding to proteins of this size on immunoblotting.
but not from health-care workers. The amino-acid These results suggest that hevamine is not an impor-
sequences of tryptic peptides from the 23-kDa protein tant NRL allergen. Alenius et al. (Alenius et al. 1995)
described a 36-kDa NRL protein which showed high than tlIe other rubber products tested. In 1994, tlIe
homology to several plant endo-1,3-ß-glucosidases. Finnish National Research and Development Centre
This 36-kDa protein bound IgE from 6 of 29 (21%) for Welfare and Health conducted a study of 20 brands
NRL-allergic patients' sera and was therefore consid- of internationally sold surgical and examination
ered to be a significant NRL allergen. The 36-kDa gloves, covering over 90% of the Finnish medical
pro tein has recently been assigned as hev b 2 glove market. The allergenicity of glove extracts was
(Sunderasan et al. 1995). assessed by three metlIods: SPT, RAST inhibition and
ELISA inhibition. Highly significant correlations
(r = 0.94-0.96) between the methods were observed,
indicating that the ELISA method can also be used for
Allergens in NRL Products
reliable NRL-allergen quantification (Turjanmaa et al.
1996; Palosuo et al. 1998). On the basis of these results,
Immunoblot assays have been used to analyze IgE- NRL gloves could be divided into three groups based
binding proteins in NRL products. In a study of eight on the NRL-allergen content: low «10 arbitrary units
different glove brands, a total of 14 protein bands, (AU) per ml; 9 gloves), moderate (10-100 AU/mI; 3
ranging from 11 kDa to 200 kDa, could be identified gloves) and high (>100 AU/mI, 8 gloves). BotlI pow-
(Alenius et al. 1994C). Five brands showed positive dered and non-powdered brands were found among
immunoblot reactions when tested with IgE antibodies gloves witlI low allergen content. It is well established
from the sera of NRL-allergic patients. The strongest that cornstarch glove powder can absorb NRL aller-
reactions were with 14-kDa and 30-kDa allergens. gens from gloves (Beezhold and Beck 1992; Tomazic
However, the authors speculated that, due to limita- et al. 1994; Turjanmaa 1994), and air sampling studies
tions of tlIe immunoblot assay, it is possible that the have shown that NRL aeroallergen concentrations are
glove extracts contained IgE-binding, low-molecular- high in areas where powdered "highly allergenic"
weight «10 kDa) peptides that may have escaped gloves are frequently used (Swanson et al. 1994; Tarlo
detection. It is possible that new allergenic epitopes are et al. 1994). At present, however, it is not known which
formed during glove manufacture. Evidence of this of the main NRL allergens contaminate the glove
was provided by Mäkinen-Kiljunen et al. (Mäkinen- powder.
Kiljunen et al. 1992b), who demonstrated by immuno-
electrophoresis that one allergen was present in the
glove extract but not in NRL. In general, allergen
Latex-Allergen Cross-Reactivity
patterns are notably simpler in glove extracts than in
NRL, but it should be kept in mind that IgE-binding
proteins detected in immunoblotting after sodium Since tlIe first report suggesting allergen cross-reactiv-
dodecyl sulfate polyacrylamide gel electrophoresis may ity between NRL and banana (M'Raihi et al. 1991), a
also be fragmentary products of larger stern molecules. number of studies dealing with possible cross-reactiv-
Information on molecularly characterized NRL aller- ity between NRL and various food allergens have been
gens that have been demonstrated in gloves is published (Ross et al. 1992; De Corres et al. 1993;
currently still very limited. In arecent study (Alenius Rodriguez et al. 1993; Blanco et al. 1994b; Mäkinen-
et al. 1996a), tlIe majority of tlIe IgE-binding capacity Kiljunen 1994; Ahlroth et al. 1995; Baur et al. 1995;
of one highly allergenic glove was attributable to Lavaud et al. 1995; Alenius et al. 1996c). RAST inhibi-
hevein, and both REF and the 23127-kDa protein, as tion, immunospot and immunoblot inhibition have
well as the 16-kDa acidic protein (hev b 5), have been been used to verify cross-reacting IgE antibodies to
identified in certain glove brands (Czuppon et al. 1993; latex and banana (Mäkinen-Kiljunen 1994; Alenius
Lu et al. 1995; Akasawa et al. 1996). et al. 1996c), but a 100% inhibition has not been
An attempt can be made to measure the "total" observed in any experiment, indicating that only a few
allergenicity of manufactured NRL products in vivo by of the NRL and banana allergens are cross-reactive.
SPT or in vitro by specific IgE inhibition assays. In The presence of at least one common allergen in NRL
1988, Turjanmaa et al. (Turjanmaa et al. 1988a) used and banana has been verified by immunoelectro-
SPT to study tlIe allergenicity of 19 surgical and phoresis (Mäkinen-Kiljunen 1994). In addition, tlIere
household NRL gloves and found great variation is evidence that sensitization to banana may result in
among them. Later, Yunginger et al. (Yunginger et al. the production of IgE antibodies which cross-react
1994) studied 71 glove brands by RAST inhibition, and with allergens in native NRL but not with allergens in
similarly demonstrated great variation (more than gloves (Mäkinen-Kiljunen 1994). Allergens in native
3000-fold differences) in their allergen contents. NRL may denature during the storage of NRL in
Overall, tlIe NRL gloves, and especially the powdered ammonia, or be otlIerwise modified during glove
ones, contained high er levels of extractable allergens manufacture.
Immunoblot inhibition has demonstrated the cross- are major allergens for health-care workers, whereas
reactivity of IgE antibodies to several proteins in NRL REF and a 27-kDa NRL protein are important
and banana (Alenius et al. 1996c). Lavaud et al. allergens for multioperated children (Alenius et al.
(Lavaud et al. 1995) and Vallier et al. (Vallier et al. 1994a; Alenius et al. 1995; Lu et al. 1995; Alenius et al.
1995) have suggested that 15-kDa and 30-kDa pro teins 1996a; Alenius et al. 1996b). The knowledge of the
are important cross-reacting allergens in NRL and whole spectrum of NRL allergens will help the
banana. One 15-kDa protein is profilin, an actin- researchers to develop more specific in vivo and in
regulating protein shown to be an important cross- vitro tests for diagnostic purposes. Furthermore, the
reacting allergen in several plants such as tree, grass production of purified NRL allergens could provide
and weed pollens, fresh fruits and vegetables (Valenta tools for immunotherapy. The mechanisms behind the
et al. 1992). Profilin has been demonstrated in NRL frequently observed cross-allergies will be better
and banana, but not in NRL-glove extracts (Vallier understood once the relevant allergenic epitopes have
et al. 1995). Latex RAST positivity has not correlated been identified. In particular, it would be helpful to
with birch, mugwort or timothy pollen RAST (Mäki- know whether sensitization to food allergens, such as
nen-Kiljunen 1994), but cross reactivity has been banana, could facilitate the development of NRL
reported between NRL, ragweed and bluegrass aller- allergy in childhood.
gens (Appleyard et al. 1994). The prevention of NRL allergy is the ultimate goal
About half of NRL-allergic patients have experi- for researchers, clinicians and regulatory authorities.
enced symptoms after eating bananas and 35% have The Food and Drug Administration (FDA) in the
had positive skin-test results to fresh banana (Blanco USA and the European Committee for Standardisa-
et al. 1994b; Mäkinen-Kiljunen 1994). Among 47 NRL- tion (CEN) have acknowledged the measurement of
allergic patients, 26 (55%) also had IgE antibodies to total protein as a simple option to enable glove
banana, and of the 31 latex-RAST -positive patients, 25 manufacturers to monitor their products. Recent
(81%) also had positive banana RAST (Mäkinen- research has brought specific methods for measuring
Kiljunen 1994). Besides banana, other foods, such as NRL allergen levels in gloves, and this progress has
avocado, chestnut, tomato, kiwi, melon, pineapple, already led authorities, for example, in Finland, to
peach and papaya, have also been suggested to cross- inform consumers of highly allergenic glove brands
react with NRL. Follow-up studies are needed to in the market (Palosuo et al. 1997; Palosuo et al.
evaluate the clinical importance of the frequent 1998). The international rubber manufacturers could
occurrence of NRL IgE antibodies in food-allergic also benefit from these new methods for developing
patients. Furthermore, the role of fruits and an early less allergenic gloves and other NRL products.
contact to, for example, NRL pacifiers (Mäkinen- Advances in this field will inevitably lead to safer
Kiljunen 1992a) as possible primary sensitizers in environments for glove-using health-care workers and
infancy should be elucidated. their patients.
Future Prospects References
Ahlroth M, Alenius H, Turjanmaa K, Mäkinen-Kiljunen S,

NRL gloves and other products are and will be Reunala T, Palosuo T (1995) Cross-reacting allergens in
ubiquitous in medical and non-medical environments. natural rubber latex and avocado. J Allergy Clin Immunol
Several crucial questions have to be answered in order 96:167-173
Akasawa A, Hsieh LS, Lin Y (1995) Serum reactivities to latex
to reduce the current problem of NRL allergy. The risk proteins (Hevea brasiliensis). J Allergy Clin Immunol 95:
groups and various symptoms have been identified 1196-1205
rather well, but asymptomatic NRL-allergic subjects Akasawa A, Hsieh S-H, Martin BM, Liu T, Lin Y (1996) A novel
acidic allergen, Hev b 5, in latex. J Biol Chem 271:25389-25393
form a diagnostic challenge for every physician. In Alenius H, Turjanmaa K, Palosuo T, Mäkinen-Kiljunen S,
addition, the mechanisms of NRL sensitization are still Reunala T (1991) Surgicallatex glove allergy: characterization
poorly understood. It would be especially useful to of rubber protein allergens by immunoblotting. Int Arch
Allergy Immunol 96:376-380
elucidate the significance of airborne NRL exposure in Alenius H, Palosuo T, Kelly K, Kurup V, Reunala T, Mäkinen-
health-care workers (Vandenplas 1995). More research Kiljunen S, Turjanmaa K, Fink J (1993) IgE reactivity to 14-kD
is also needed to assess the consequences of co existent and 27-kD natural rubber proteins in latex-allergie children
with spina bifida and other congenital anomalies. Int Arch
food and NRL allergies reported to occur frequently Allergy Immunoll02:61-66
both in children and adults. Alenius H, Kalkkinen N, Lukka M, Turjanmaa K, Reunala T,
Considerable progress has recently been made in Mäkinen-Kiljunen S, Palosuo T (1994a) Purification and
partial amino acid sequencing of a 27 kD natural rubber
identifying and characterizing several important NRL allergen recognized by latex allergie children with spina
allergens at the molecular level. Prohevein and hevein bifida. Int Arch Allergy Immunol 106:258-262
Alenius H, Kurup V, Kelly K, Palosuo T, Turjanmaa K, Fink J (Hevea brasiliensis) is the major allergen in latex. J Allergy
(1994b) Latex allergy: frequent occurrence of IgE antibod- Clin Immunol 92:690-697
ies to a cluster of 11 latex proteins in patients with spina De Corres L, Moneo I, Munoz D, Bernaola G, Fernandez E,
bifida and histories of anaphylaxis. J Lab Clin Med Audicana M, Urrutia I (1993) Sensitization from chestnuts
123:712-720 and bananas in patients with urtiearia and anaphylaxis from
Alenius H, Mäkinen-Kiljunen S, Turjanmaa K, Palosuo T, contact with latex. Ann Allergy 70:35-39
Reunala T (1994c) Allergen and protein content of latex Dennis M, Henzel W, Bell J, Kohr W, Light D (1989) Amino acid
gloves. Ann Allergy 73:315-320 sequence of rubber elongation factor protein associated
Alenius H, Turjanmaa K, Mäkinen-Kiljunen S, Reunala T, Palosuo rubber partieies in Hevea latex. J Biol Chem 264:18618-18626
T (1994d) IgE immune response to rubber proteins in adult Förström L (1980) Contact urticaria from latex surgical gloves.
patients with latex allergy. J Allergy Clin Immunol 93:859-863 Contact Dermatitis 6:33-34
Alenius H, Kalkkinen N, Lukka M, Reunala T, Turjanmaa K, Gidrol X, Chrestin H, Tan H, Kush A (1994) Hevein, a lectin-like
Mäkinen-Kiljunen S, Yip E, Palosuo T (1995) Prohevein from protein from Hevea brasiliensis (rubber tree) is involved in
the rubber tree (Hevea brasiliensis) is a major latex allergen. the coagulation of latex. J Biol Chem 269:9278-9283
Clin Exp Allergy 25:659-665 Hadjiliadis D, Khan K, Tarlo S (1995) Skin test responses to latex
Alenius H, Kalkkinen N, Reunala T, Turjanmaa K, Palosuo T in an allergy and asthma clinie. J Allergy Clin Immunol
(1996a) The main IgE-binding epitope of a major latex 96:431-432
allergen, prohevein, is present in it's n-terminal43 amino acid Hamann CP, Turjanmaa K, Rietschel R, Siew C, Owensby D,
fragment, hevein. J Immunol 156:1618-1625 Gruninger SE, Sullivan KM (1998) Natural rubber latex
Alenius H, Kalkkinen N, Turjanmaa K, Mäkinen-Kiljunen S, hypersensitivity: Incidence and prevalence of type I allergy in
Reunala T, Palosuo T (1996b) Significance of the rubber the dental professional. J Am Dent Assoc 129:43-54
elongation factor as a latex allergen. Int Arch Allergy Hamilton R, Charous B, Adkinson N, Yunginger J (1994)
Immunol 109:362-368 Serologic methods in the laboratory diagnosis of latex rubber
Alenius H, Mäkinen-Kiljunen S, Ahlroth M, Turjanmaa K, allergy: study of nonammoniated, ammoniated latex, and
Reunala T, Palosuo T (1996c) Cross-reactivity between glove (end-product) extracts as allergen reagent sources.
allergens in natural rubber latex and banana studied by J Lab Clin Med 123:594-604
immun ob lot and immunoblot inhibition methods. Clin Exp Jäger D, Kleinhans D, Czuppon A, Baur X (1992) Latex-specific
Allergy 26:341-348 proteins causing immediate-type cutaneous, nasal, bronchi-
Appleyard J, Mccullough J, Ownby D (1994) Cross-reactivity al, and systemie reactions. J Allergy Clin Immunol 89:
between latex, ragweed, and blue grass allergens (abstract). 759-768
J Allergy Clin Immunol 93=182 Jekel P, Hartmann B, Beintema J (1991) The primary structure of
Arellano R, Bradley J, Sussman G (1992) Prevalence of latex hevamine, an enzyme with lysozyme/chitinase activity from
sensitization among hospital physicians occupationally ex- Hevea brasiliensis latex. Eur J Biochem 200:123-130
posed to latex gloves. Anesthesiology 77:905-908 Kaczmarek R, Silverman B, Gross T, Hamilton R, Kessler E,
Axelsson J, Johansson S, Wrangsjö K (1987) IgE-mediated Arrowsmith-Lowe T, Moore R (1996) Prevalence of latex-
anaphylactoid reactions to rubber. Allergy 42:46-50 specific IgE antibodies in hospital personnel. Ann Allergy
Axelsson I, Eriksson M, Wrangsjö K (1988) Anaphylaxis and Asthma Immunol 76:51-56
angioedema due to rubber allergy in children. Acta Paediatr Kelly K, Kurup V, Zacharisen M, Resnick A, Fink J (1993) Skin
Scand 77:314-316 and serologie testing in the diagnosis of latex allergy.
Baur X, Chen Z, Rozynek P, Duser M, Raulf-Heimsoth M (1995) J Allergy Clin Immunol 91:1140-1145
Cross-reacting IgE antibodies recognizing latex allergens, Kelly K, Pearson M, Kurup V, Havens P, Byrd R, Setlock M,
including Hev b 1, as weil as papain. Allergy 50:604-609 Butler J, Slater J, Grammer L, Resnick A, Fink J (1994) A
Beezhold D, Beck W (1992) Surgieal glove powders bind latex cluster of anaphylactic reactions in children with spina bifida
antigens. Arch Surg 127:1354-1357 during general anesthesia: epidemiologic features, risk fac-
Beezhold D, Sussman G, Kostyal D, Chang N (1994) Identification tors, and latex hypersensitivity. J Allergy Clin Immunol
of a 46-kd latex protein allergen in health care workers. Clin 94:53-61
Exp Immunol 98:408-413 Lavaud F, Prevost A, Cossart C, Guerin L, Bernard J, Kochman S
Beezhold DH, Sussman GL, Liss GM, Chang NS (1996) Latex (1995) Allergy to latex, avocado pear, and banana - evidence
allergy can induce clinieal reactions to specific foods. Clin for a 30 kd antigen in immunoblotting. J Allergy Clin
Exp Allergy 26:416-422 Immunol 95:557-564
Blanco C, Carrillo T, Castillo R, Quiralte J, Cuevas M (1994a) Lee H, Broekaert W, Raikhel N, Lee H (1991) Co- and post-
Avocado hypersensitivity. Allergy 49:454-459 translational processing of the hevein preproprotein of latex
Blanco C, Carrillo T, Castillo R, Quiralte J, Cuevas M (1994b) of the rubber tree (Hevea brasiliensis). J Biol Chem 266:
Latex-allergy: clinical features and cross-reactivity with fruits. 15944-15948
Ann Allergy 73:309-314 Levy D, Charpin D, Pecquet C, Leynadier F, Vervloet D (1992)
Broekaert I, Lee H, Kush A, Chua N, Raikhel N (1990) Wound- Allergy to latex. Allergy 47:579-587
induced accumulation of mRNA containing a hevein se- Leynadier F, Dry J (1991) Allergy to latex. Clin Rev Allergy 9:
quence in laticifers of rubber tree (Hevea brasiliensis). Proc 371-377
Natl Acad Sci USA 87:7633-7637 Leynadier F, Pecquet C, Dry J (1989) Anaphylaxis to latex during
Capriles-Hulet A, Sanchez-Borges M, von Scazoni C, Medina J surgery. Anaesthesia 44:547-550
(1995) Very low frequency of latex and fruit allergy in patients Light D, Dennis M (1989) Purification of a prenyl transferase that
with spina bifida from Venezuela: Influence of socioeconomic elongates cis isoprene rubber from latex of Hevea brasiliensis.
factors. Ann Allergy Asthma Immunol 75:62-64 J Biol Chem 269:9278-9283
Chambeyron C, Dry J, Leynadier F, Pecquet C, Tran X (1992) Liss GM, Sussman GI, Deal K, Brown S, Cividino M, Siu S,
Study of the allergenic fractions of latex. Allergy 47:92-97 Beezhold DH, Smith G, Swanson MC, Yunginger J, Douglas A,
Charous B, Hamilton R, Yunginger J (1994) Occupational latex Holness DL, Lebert P, Keith P, Wasserman S, Turjanmaa K
exposure: characteristics of contact and systemic reactions in (1997) Latex allergy: epidemiological study of 1351 hospital
47 workers. J Allergy Clin Immunol 94:12-18 workers. Occup Environ Med 54:335-342
Chen Z, Posch A, Raulf-Heimsoth M, Baur X (1996) Isolation and Lu L, Kurup V, Hoffman D, Kelly K, Murali P, Fink J (1995)
identification of hevein as a major IgE-binding polypeptide in Characterization of a major latex allergen associated with
latex from Hevea brasiliensis (abstract). J Allergy Clin hypersensitivity in spina bifida patients. J Immunol 155:
Immunol 97:428 2721-2728
Czuppon AB, Chen Z, Rennert S, Engelke T, Meyer HE, Heber M, Maibach H, Johnson H (1975) Contact urticaria syndrome. Arch
Baur X (1993) The rubber elongation factor of rubber trees Dermatol 111:726-730
M'Raihi L, Charpin D, Pons A, Bongrand P, Vervloet D (1991) Sussman G, Beezhold D (1995) Allergy to latex rubber. Ann Intern
Cross-reactivity between latex and banana. J Allergy Clin Med 122:43-46
Immunol 87:129-130 Sussman G, Tarlo S, Dolovich J (1991) The spectrum of IgE-
Mäkinen-Kiljunen S (1994) Banana allergy in patients with mediated responses to latex. JAMA 265:2844-2847
immediate-type hypersensitivity to natural rubber latex: Swanson M, Bubak M, Hunt L, Yunginger J, Warner M, Reed C
characterization of cross-reacting antibodies and allergens. (1994) Quantification of occupationallatex aeroallergens in a
J Allergy Clin Immunol 93:990-996 medieal center. J Allergy Clin Immunol 94:445-451
Mäkinen-Kiljunen S, Sorva R, Juntunen-Backman K (1992a) Latex Tarlo S, Wong L, Roos J, Booth N (1990) Occupational asthma
dummies as allergens. Lancet 339:1608-1609 caused by latex in a surgieal glove manufacturing plant.
Mäkinen-Kiljunen S, Turjanmaa K, Palosuo T, Reunala T (1992b) J Allergy Clin Immunol 85:626-631
Characterization of latex antigens and allergens in surgieal Tarlo S, Sussman G, Contala A, Swanson M (1994) Control of
gloves and natural rubber by immunoelectrophoretic meth- airborne latex by use of powder-free latex gloves. J Allergy
ods. J Allergy Clin Immunol 90:230-235 Clin Immunol 93:985-989
Mäkinen-Kiljunen S, Reunala T, Turjanmaa K, Cacioli P (1993) Is Taylor J, Praditsuwan P (1996) Latex allergy. Review of 44 cases
cows milk casein an allergen in latex-rubber gloves? Lancet including outcome and frequent association with allergie
342:863 hand eczema. Arch Dermatol 132:265-271
Moneret-Vautrin DA, Beaudouin E, Widmer S, Mouton C, Kanny Taylor J, Cassettari J, Wagner W, Helm T (1989) Contact urticaria
G, Prestat F, Kohler C, Feldmann L (1993) Prospective study and anaphylaxis to latex. J Am Acad Dermatol 21:874-877
of risk factors in natural rubber latex hypersensitivity. Tomazic V, Shampaine E, Lamanna A, Withrow T, Adkinson N,
J Allergy Clin Immunol 92:668-677 Hamilton R (1994) Cornstarch powder on latex products is an
Morales C, Basomba A, Carreira J, Sastre A (1989) Anaphylaxis allergen carrier. J Allergy Clin Immunol 93:751-758
produced by rubber glove contact: case reports and immu- Tosi L, Slater J, Shaer C, Mostello L (1993) Latex allergy in spina
nologieal identification of the antigens involved. Clin Exp bifida patients: prevalence and surgical implications. J Pediatr
Allergy 19:425-430 Orthop 13:709-712
Nutter A (1979) Contact urtiearia to rubber. Br J Dermatol Turjanmaa K (1987) Incidence of immediate allergy to latex
101:597-598 gloves in hospital personnel. Contact Dermatitis 17:
Ownby D, McCuliough J (1993) Testing for latex allergy. J Clin 270-275
Immunoassay 16:109-113 Turjanmaa K (1988) Latex glove contact urticaria. Thesis,
Ownby D, Ownby H, McCuliough J, Shafer A (1996) The University of Tampere, Acta Univ Tamperensis A 254:1-86
prevalence of anti-latex IgE antibodies in 1000 volunteer Turjanmaa K (1994) Update on occupational natural rubber latex
blood donors. J Allergy Clin Immunol 97:1188-1192 allergy. Dermatol Clin 12:561-567
Palosuo T, Turjanmaa K, Reinikka-Railo H (1997) Allergen Turjanmaa K, Laurila K, Mäkinen-Kiljunen S, Reunala T (1988a)
content of latex gloves. A market surveillance study of Rubber contact urtiearia. Allergenic properties of 19 brands
medieal gloves used in Finland in 1997. National Agency for of latex gloves. Contact Dermatitis 19:362-367
Medicines, Helsinki Turjanmaa K, Reunala T, Räsänen L (1988b) Comparison of
Palosuo T, Mäkinen-Kiljunen S, Alenius H, Reunala T, Yip E, diagnostic methods in latex surgieal glove contact urtiearia.
Turjanmaa K (1998) Measurement of natural rubber latex Contact Dermatitis 19:241-247
allergen levels in medieal gloves by allergen -specific IgE- Turjanmaa K, Alenius H, Mäkinen-Kiljunen S, Palosuo T,
ELISA inhibition, RAST inhibition, and skin prick test. Reunala T (1995a) Commercial skin prick test preparations
Allergy 53:59-67 in the diagnosis of rubber latex allergy (abstract). J Allergy
Pisati G, Baruffini F, Bernabeo F, Stanizzi R (1994) Bronchial Clin Immunol 93:299
provocation testing in the diagnosis of occupational asthma Turjanmaa K, Cacioli P, Thompson R, Simlote P, Lopez M
due to latex surgieal gloves. Eur Respir J 7:332-336 (1995b) Frequency of natural rubber latex allergy among US
Pittman T, Kiburz J, Gabriel K, Steinhardt G, Williams D, Slater J operating room nurses using skin prick testing (abstract).
(1995) Latex allergy in children with spina bifida. Pediatr J Allergy Clin Immunol 95:214
Neurosurg 22:96-100 Turjanmaa K, Mäkinen-Kiljunen S, Reunala T, Alenius H,
Rodriguez M, Vega F, Garcia MT, Panizo C, Laffond E, Montalvo A, Palosuo T (1995C) Natural rubber latex allergy - the European
Cuevas M (1993) Hypersensitivity to latex, chestnut, and experience. In: Fink J (ed) Latex allergy. (Immunology and
banana. Ann Allergy 70:31-34 allergy clinies of North Ameriea, vol 15) WB Saunders,
Ross B, Mccullougil J, Ownby D (1992) Partial cross-reactivity Philadelphia, pp 71-88
between latex and banana allergens. J Allergy Clin Immunol Turjanmaa K, Mäkinen-Kiljunen S, Alenius H, Reunala T,
90:409-410 Palosuo T (1996) In vivo and in vitro evaluation of
Slater J (1989) Rubber anaphylaxis. N Engl J Med 320:626-631 allergenicity of natural rubber latex (NRL) gloves used in
Slater J (1991) Medical rubber anaphylaxis. Lancet 337:187 health care: a nation-wide study (abstract). J Allergy Clin
Slater J (1994) Latex allergy. J Allergy Clin Immunol 94:139-149 Immunol 97:325
Slater J, Chhabra S (1992) Latex antigens. J Allergy Clin Immunol Valenta R, Duchene M, Ebner C, Valent P, Sillaber C, Deviller P,
89:673-678 Ferreira F, Tejkl M, Edelmann H, Kraft D, Scheiner 0 (1992)
Slater J, Mostello L, Shaer C (1991) Rubber specific IgE in children Profilins constitute a novel family of function plant pan-
with spina bifida. J Urol 146:578-579 allergens. J Exp Med 175:377-385
Slater JE, Vedvick T, Arthur-Smith A, Trybul DE, Keckwiek RGO Vallier P, Balland S, Harf R, Valenta R, Deviller P (1995)
(1996) Identification, cloning, and sequence of a major Identification of profilin as an IgE-binding component in
allergen (Hev b 5) from natural rubber latex (Hevea brasi- latex from Hevea brasiliensis: clinical implications. Clin Exp
liensis). J Biol Chem 271:25394-25399 Allergy 25:332-339
Sorva R, Mäkinen-Kiljunen S, Suvilehto K, Juntunen-Backman K, Vandenplas 0 (1995) Occupational asthma caused by natural
Haahtela T (1995) Latex allergy in children with no known rubber latex. Eur Respir J 8:1957-1965
risk factor for latex sensitization. Pediatr Allergy Immunol Vandenplas 0, Delwiche JP, Evrard G, Aimont P, Vanderbrempt X,
6:36-38 Jamart J, Delaunois L (1995) Prevalence of occupational
Spaner D, Dolovieh J, Tarlo S, Sussman G, Buttoo K (1989) asthma due to latex among hospital personnel. Am J Respir
Hypersensitivity to natural latex. J Allergy Clin Immunol Crit Care Med 151:54-60
83:1135-1137 Wilkinson SM, Beck MH (1996) Allergie contact dermatitis from
Sunderasan E, Hamzah S, Hamid S, Ward MA, Yeang HY, latex rubber. Br J Dermatol 134:910-914
Cardosa MJ (1995) Latex B-serum ß-l,3-glucanase (Hev b II) Wrangsjö K, Wal1lberg J, Axelsson I (1988) IgE-mediated allergy
and a component of the microhelix (Hev b IV) are major latex to natural rubber in 30 patients with contact urticaria.
allergens. J Nat Rubber Res 10:82-99 Contact Dermatitis 19:264-271
Wrangsjö K, Osterman K, van Hage-Hamsten M (1994) Glove- recognized by IgE from spina bifida patients with latex
related skin symptoms among operating theatre and dental aIlergy. J Allergy Clin Immunol 98:628-639
care unit personnel (I1). Clinical examination, tests and Ylitalo L, Turjanmaa K, Palosuo T, Reunala T (1997) Natural
laboratory findings indicating latex allergy. Contact Derma- rubber latex allergy in children who had not undergone
titis 30:139-143 surgery and chiIdren who had undergone multiple opera-
Yassin M, Lierl M, Fischer T, O'Brien K, Cross J, Steinmetz C tions. J Allergy Clin Immunol 100:606-612
(1994) Latex allergy in hospital employees. Ann Allergy Yunginger J, Jones R, Fransway A, Kelso J, Warner M, Hunt L,
72:245-249 Reed C (1994) Extractable latex allergens and proteins in
Yeang HY, Cheoung KF, Sunderasan E, Hamzah S, Chew NP, disposable medical gloves and other rubber products.
Hamid S, Hamilton RG, Cardosa MJ (1996) The 14.6 kD (REF, J Allergy Clin Immunol 93:836
Hev b 1) and 24 kD (Hev b 3) rubber particle proteins are
CHAPTER 89
Occupational Contact Dermatitis to Plants

J.D. Guin
Introduction ablistering or blinding dermatitis, e.g., that from

manchineel (Hippomane mancinella). Such reactions
are common only locally and would be more easily
Plants are either a less common source of occupational
suspected where these plants are likely to be contacted.
contact dermatitis or a less commonly reported source,
Occupations at risk are likely a function of the
according to the data presented by Halkier-Sorens?n.
opportunity for exposure to irritant and sensitizing
In data from reports to the National Labour InspectlOn
plants. Some of the more obvious include b?tanists,
Service in Denmark, only about 1.0% of cases of
the wholesale and retail fiower industries, agnculture,
occupational skin disease were due to plants. A~~ro~
forestry and the lumber industry, but other, less
imately 14.3% of occupational contact dermatitis m
obvious occupations including pharmaceutical manu-
South Carolina was reportedly due to plants b].
facturing, the food-service industry and food handlers,
However, if one looks at industries where one might
have made many lists [10].
be more likely to see plant dermatitis, the incidence
Unless the data comes from an industry-wide study,
may be higher. For example, workers in the foodstuff
prevalence in many occupations is difficult to. deter-
industry constituted so me 5.3% of cases of occupa-
mine. Many persons, such as farmers, fionsts or
tional eczematous reactions, and agriculture and
nursery workers, recognize the plants and do not seek
forestry another 2.8% [2]. Some occupations have. a
medical attention or report the incident. In an Occu-
higher risk, as more than half of the fiower selle:s m
pational Safety and Health Administration study of
one German study had experienced occupatlOnal
fiower shops, one in three shops had at least one
dermatitis [3]. Of course, poison-ivy dermatitis, which
employee with a problem [11]. In a questionnaire study
is not present in statistics from Europe, is exceedingly
of Danish greenhouse workers and gardeners, there
common in the United States, although it is likely that
was a 19.6% prevalence [12]. Follow-up patch testing of
it is underreported, as few self-employed farmers
a random sampling showed only one of 53 persons in
would have occasion to report the problem.
the negative group answering the questionnaire had
Contact dermatitis to plants can mimic alm ost any
occupational plant dermatitis. However, 10% of those
other form of contact dermatitis, but in the United
tested were Compositae allergie, and 44 of 250 had
States most cases are easily recognized because poison
some type of re action to plants, irritant or allergic.
ivy and its relatives are the leading cause of plant
There also were· several who reacted to agricultural
dermatitis. With experience, one can perhaps at least
chemie als. Examination of the data suggested that data
suspect the cause in those eruptions caused by the
from self-employed workers was more reliable. When
Compositae and other plants containing sesquiterpene
these patients were examined, there was a diversity of
lactones. Eruptions from sesquiterpene lactones are
clinical diagnoses, which emphasizes the problem of
reported in woodcutters in the Pacific North",:est [4~,
interpretation of questionnaire data. There is also a
in farmers in most of the Uni ted States [5], and m retatl
geographieal difference, as Toxicodendron dermatitis,
[6] and wholesale [7] fiorists and fiower seIlers [3].
an enormous problem in North Ameriea, is not a
Primula, a houseplant becoming more commonly
problem in Europe, and reactions to Parthenium
grown, causes severe contact dermatitis, especially on
hysterophorus are more prevalent in India than in the
exposed areas. However, while such eruptions may ~e
United States, the plant's putative original source [13].
occupational [8], one more often expects to see t~IS
Even studies done in an industry are usually done
allergy in older housewives who do not work outsIde
nationally at best, so the plants at risk are limited to
the horne [9].
those encountered. Even the data for industries that
Irritant reactions range from a mild to severe
have been studied will change when the plants used in
urtiearia, e.g., the rash from nettles (Urtica spp.), to
that industry are changed, so one must evaluate the

Occupational Contact Dermatitis to Plants 731
potential for each situation. For retail and wholesale

florists it is usually possible to have them bring in
samples of every variety of plant sold or grown where
they work, but the problem becomes more difficult for
those who work outdoors, where not only domesticat-
ed species but also where the entire local flora may be
possible sourees.
The severity of plant-induced contact dermatitis
depends not only on the plant's irritant or allergie
potential, but also on the degree of exposure and the
sensitivity of the individual. Even plants that rarely
cause contact dermatitis may induce severe responses
in highly allergie patients. One can sometimes suspect
clinically the causative plant, but all too often identi-
Fig. 1. Typical acute eczematous streak of poison-ivy dermatitis
fication (other than for Toxicodendrons) must await a caused by hand transfer of the antigen. Note the separation
thorough investigation. Poison-ivy dermatitis is so caused by the pattern of the fingers that transferred the antigen
characteristic that the diagnosis is usually made from
the clinical picture combined with an opportunity for additional exposure. The face may be the first area
exposure, although a very similar presentation may involved [20] and, if so, is usually the first area to clear
occur from several other strong allergens and plants. spontaneously. This is probably based as much on the
Irritant reactions can also resemble allergie contact propensity of facial skin to absorb the antigen as on
dermatitis. Recognition depends on one's degree of the opportunity for exposure.
suspicion as well as so me knowledge of the patterns There are regional differences in the rate of absorp-
usually seen. Almost any plant could, on rare occa- tion [20, 21], with the face involved early, while the
sions, be the cause of some type of re action, so we shall fore arms may take several days to break out; absorption
cover only the more prominent causes. A number of takes longer in areas where the skin is thicker [20].
comprehensive publications are available [14, 15, 16, Many patients feel that the reason for this is re-exposure
17], so emphasis will be placed on the more practical or a failure on the part of their treatment. Again, it is
and prominent occupational reactions to plants that probably based on exposure and the rate of absorption
one might expect to see clinically in North America, through the skin in different parts of the body. A typical
along with many recently reported reactions. picture is a flare in new areas after completion of
treatment over a 6-day course with a "Dose-Pak". This
Toxicodendron Dermatitis allows the immune response to return while antigen is
still present in the skin, and areas not seemingly
involved when treatment was started often appear when
The typical pattern in most patients with poison-ivy steroids are withdrawn too early.
(-oak) dermatitis is caused by a transfer of the antigen In areas where the plant grows [22], poison-ivy
[pentadec(en)yl or heptadec(en)yl catechols] [18] from dermatitis should be suspected in any individual
the hands or fingers to the affected area [19]. Conse-
quently, one sees streaks from finger transfer (Fig. 1), Table 1. Sesquiterpene lactone dermatitis
broader localized involvement from rubbing and
sometimes even handprints in a mitten pattern. The Older males are typically affected
eruption may be an alm ost flat erythema, but usually it Exposed sites in five patterns
Pseudo-photodermatitis involving the eyelids, submental and
is prominently raised and often vesicular, perhaps with postauricular sites
weeping, oozing and crusting when acute. It is severely Atopic eczema-like: unlike atopic eczema, onset is in later life,
pruritic. The most prominent areas of involvement are the rash is better in winter and the feet are likely to be spared
Hand eczema: may be picked up on routine patch-test
usually exposed sites where the hands can re ach. Areas screening with sesquiterpene-lactone mix
that are hard to reach, such as the midline of the back, Exfoliative erythroderma: often appears later and mimics a
are usually spared. The scalp also is not involved in photoallergie dermatitis (persistent light reaction) or actinic
reticuloid
most cases. The palms (which may spread the antigen) Localized pattern
and soles are usually not involved but can be, Acute: localized patch{es) of an acute often weeping, eczema
especially if the skin is broken. Poison-ivy dermatitis Chronic: lichen simplex chronicus
Outdoor exposure typical
of the hands may typically occur in the finger webs or Occupation and hobbies likely factors. Farmers, florists,
as streaks on the dorsa of the hands or fingers. gardeners, woodcutters and hunters are especially at risk
The eruption may seem to spread after its initial Summer aggravation typical
Minimum erythema dose often reduced on phototesting
appearance, and this is apparently true without any
732 J.D. Guin
exhibiting sudden onset of a severe allergie contact oleoresin is released. Brushing against the plant
dermatitis. When sudden in onset in the summer seldom causes a problem. Exposure to the injured
months, this diagnosis is presumptive until it is plant when pulling weeds, trimming hedges or cleaning
disproved if the eruption is characterized by streaks, grass clippings from a lawnmower bag is a powerful
finger marks or hand prints. However, persons treating source of the allergenie oleoresin. Occupationally, one
warts with immunotherapy using 2,4-dinitrochloro- typically might see the eruption in firefighters during
benzene or squaric acid dibutyl ester can develop a forest fires and in farmers clearing fence rows.
similar eruption on hand transfer. One can see similar
streaks with English ivy (Hedera he/ix) [23), Primula Antigen Transfer
obconica [24), Phacelia [25) and phytophotodermatitis.
Phacelia dermatitis seems to occur in botanists, who The allergen may also be transferred from the fur of
know the source. Primula reactions often include the animals (who usually don't break out), from fomites
fingertips and occur in older housewives. This is likely [29) such as clothing or garden tools, or from one
a result of the fact that this population is most likely to member of the family to another (connubial contact
grow it as a houseplant. Phytophotodermatitis is often dermatitis or filial contact dermatitis) [31). Poison-ivy
due to furocoumarins in the plant, in which case the oleoresin also can be carried on the fur of livestock.
initial rash is commonly followed by hyperpigmenta- A family member may transfer the antigen not only
tion, confirming the earlier presumptive diagnosis. to hirnself but also to other family members. Poison
While psoralens can cause photoallergy [26, 27), the ivy may also be transferred as particles in smoke, as
reaction is most often phototoxic, so photopatch the antigen seems to be relatively heat tolerant, but this
testing is not done unless a photoallergy is suspected. is largely limited to individuals who are especially
To confirm the diagnosis of Toxicodendron derma- allergie, as the levels of antigen are relatively low.
titis, one should look at the pattern of the eruption and Exposure of forest rangers and firefighters during a
place the patient's hand over this to see if it might have forest fire can be extreme and would not have to be
been transferred from the hand [28). Then, by taking a from smoke.
history, one can usually uncover an opportunity for The eruption does not occur through pollen (air)
exposure. For an acute eruption of the face, this may transfer. In fact, one often sees honey bees gathering
have taken place the same day as the eruption. For nectar from the flowers of poison ivy, and I have
other parts of the body, it may require 1-2 days, personally never seen anyone break out to poison ivy
sometimes much longer [29). Rarely, it may take from exposure to honey. Another common myth is the
2 weeks or more, even in a person who is already putative spread from the blister fluid [32). This simply
allergie [20). One should inquire about outdoor does not happen. The antigen is not located within
activity including recreation and, in particular, expo- blister fluid, and even highly sensitive individuals will
sure in the woods or when working in the yard, garden not break out when exposed to blister fluid. The notion
or farm. If this is negative, one should look for that scratching the lesion tends to spread the eruption
exposure to animals that have been outdoors, clothing apparently comes from the tendency for poison ivy
worn outdoors by others, exposure to top soil or dermatitis to erupt in new areas for several days after it
potting soil, and a his tory of handling firewood. first appears. This is apparently due to the irregular
Persons who have had severe episodes of poison-ivy absorption of the antigen through uneven exposure
(or poison oak in California) dermatitis in the past are and the differences in the rate of absorption by
perhaps more at risk, as persons who are unusually different anatomieal surfaces of the skin. Under
sensitive require much less exposure [29). experimental control, one also does not see transfer
from the exposed area of the skin to new sites for much
Sources of the Antigens longer than 3 days. Naturally, the time that it takes to
dissipate the oleoresin from the contaminated surface
The antigenie component of poison ivy, poison oak is probably much shorter than this because the
and poison sumac, called urushiol, is found within possibility of antigen exposure is reduced by washing,
secretory canals located in the plant's leaves, roots and and water used as first-aid seems to be helpful in
phloem, whieh is just below the bark [30). The active reducing severity [29). However, the urushiol is also
ingredient in poison ivy mostly comprises penta- rapidly absorbed, so by the time one sees the eruption,
dec(en)yl catechols (18), and for poison oak it is mostly it is not likely to be a problem for others.
comprises heptadec( en)yl catechols. In the case of T.
radicans, exposure may occur to the tiny brown Plant Recognition
rootlets that attach the vine to the tree or post on
which it climbs, but usually it occurs when the leaf Poison ivy, poison oak and poison sumac are members
surface is broken so that the sap containing the of the genus Toxicodendron [22, 30, 33) (formerly
classed as Rhus, a benign genus). The United States has through the snow during the winter months. This plant
two species of poison ivy, two of poison oak and one of is much smaller than T. radicans, but it can still be a
poison sumac. There are also plants in tropical areas very real problem for susceptible persons. This species
that may cross-react, causing a similar or even more of poison ivy can also be found in Canada, the Rocky
severe eruption. Poison ivy and poison oak have many Mountains, and the states of Washington and Oregon.
common features, which should warn those working In the eastern United States, poison oak, T. toxicar-
around them. Both of these plants have three leaflets ium (Fig. 4) is a small shrub that grows in sandy soi!
per leaf, but their leaflets vary greatly in shape, so it along with pine, scrub oak, sassafras and bunch
can be relatively easy to overlook these plants. Other grasses. It is found especially in the coastal sands
key features may help, and with practice almost
anyone can become proficient.
One helpful characteristic of T. radicans (Fig. 2) is
the enlargement of the structure holding the leaf as it is
attached to the branch. This is seen in Fig. 3 (no. 2).
This structure is also grooved on one side of the
enlarged portion. The groove provides space for the
flowers and fruit to grow out between the leaf and
branch (Fig. 3, no. 2). Where the leaf falls off in winter,
the grooved circular attachment leaves a scar which is
"V" or "u" shaped, rather than circular (Fig. 3, no. 3).
This feature is prominent during summer and winter
in poison sumac and oak as weIl as poison ivy.
On mature female plants one may see empty fruit
stalks (Fig. 3, no. 8), even in winter. Sometimes the
fruit is also present, but if not, the empty "sterns"
(which resemble empty grape sterns) will be attached
even when birds have eaten the fruits. The fruits
(labeled as no. 6 and no. 7 in Fig. 3) are green in
summer and an off-white or ivory color in fall and
early winter. In winter, the off-white outer layer
(exocarp) peels away (Fig. 3, no. 6), exposing the
chalk-white layer beneath. In the chalk-white layer
(mesocarp), there are black lines resembling the
longitudinallines on aglobe. These are the tiny canals
containing the poisonous oleoresin (Fig. 3, no. 7). This
feature is typically present in winter in mature female
clones.
The wood on the stern of Toxicodendrons has many
tiny holes that impart a characteristic texture to the
surface of the woody part of the plant (Fig. 3, no. 9).
These can help with recognition in all seasons. In the
growing part of the branch, when the plant is still
green, these are often a bright-orange color, but they
turn to a permanent grey-brown color during early
winter.
One species of poison ivy, T. radicans, tends to
climb trees, but poison ivy in much of the northern
and western United States (T. rydbergii) is a small non-
climbing shrub that is so small it is often mi staken for
eastern poison oak. This plant grows along the ground
in waste areas, and it shares many of the characteristic
Fig. 2a,b. Toxieodendronradieans ssp. Radieans. This climbing
features of T. radicans, the climbing taxon of poison species has at least eight subspecies with some distinguishing
ivy mentioned above. Leaflets of T. rydbergii tend to be morphologie features. This subspeeies, found along the eastern
cup-shaped, and the petioles holding the leaves tend to coast of the United States, is eommonly used to illustrate poison
ivy in textbooks. More mature specimens have entire (unlobed)
be quite long. Branches divide usually within a foot or leaflets (2b), glabrous fmit, and tufts of hair in vein axils (not
so off the ground and can often be seen protruding shown)
734 J.D. Guin
Fig. 4. Eastern poison oak, T. toxicarium. The small size,

rounded lobes on leaflets and its nonclimbing nature help
distinguish this plant from T. radicans
they can fool even an experienced botanist if he does

not look closely when grabbing a "white oak" sapling.
Eastern poison oak does not climb trees and does not
have aerial rootlets.
Western poison oak, T. diversilobum (Fig. 5), unlike
its eastern counterpart, is often a very large plant. It
can grow as a standing shrub or a climbing vine and it
) can be found in abundance in canyons and valleys with
enough moisture to support its growth. Unlike eastern
Fig. 3. Distinguishing characteristics of Toxicodendrons useful poison oak, it is not nearly so particular about its soil
for field identification [33]. (1) Buds are not terminal, causing new requirements. Leaflets of western poison-oak also tend
directions of growth each season. (2) The petiole is enlarged at
the point of attachment. (3) U- or V-shaped leaf scars. (4) to have rounded lobes, often appearing dainty in their
Flowers, fruit on panicles in axillary position. (5) Trichomes on appearance. The branches of T. diversilobum tend to
fruit of poison oak and some ssp. of poison ivy. (6) Exocarp be much straighter and more reddish-brown in color
which peels away in the winter. (7) After losing exocarp, fruits are
smaller and chalk white with tiny black lines like longitudinal than those of eastern poison oak. The fruit on female
lines on aglobe. (8) Empty fruit stalk. (9) Lenticels give a plants of T. diversilobum is larger, so it tends to hang
characteristic text ure to the wood down rather than being borne erect on a stiff "stern",
and the average leaflet size is smaller. Poison sumac,
T. vernix, (Fig. 6) is a large shrub or small tree with
region of the southeast and in the valley-and-ridge pinnately compound leaves of 7-13 leaflets (usually 9).
areas, where sands tone outcroppings occur along with It prefers peat bogs, swamps and places with a high
the plants mentioned. This plant is not nearly as water table.
widespread as poison ivy, as it is much more
demanding in its soil requirements so that it is not Other Toxie Anacardiaceae
found everywhere, although it can be dense in specific
geographie areas. Although eastern poison oak may be Toxic Anacardiaceae in other countries include
relatively small, it can produce a prominent reaction Comoc/adia and Metopium (34) in Central America
with adequate exposure. Leaves of poison oak are often and the Caribbean, Mauria (35), Lithraea [36, 37) and
more stiff or leather-like (coriaceous); they mayaiso T. striata (38) in South America, Smodingium argutum
resemble those of poison ivy, but with rounded lobes. [39, 40, 41) in Africa, the Japanese wax tree (T. Succe-
The leaves of Toxicodendron toxicarium can so daneum) (42) and T. vernicifluum, the source of
resemble the leaves of white oak (Quercus alba) that Japanese lacquer (43).
T. radicans ssp. hispidum. There are some differences

in morphology, but these Asian subspeeies of T. radi-
cans have mueh in eommon with North American
poison ivy, while the differences are subtle. Beaman
[44] divided toxic Asian Anaeardiaeeae into those that
were well known and allergenic (Toxicodendron, Ana-
cardium, Gluta, Mangifera and Semecarpus), those less
well known and probably allergenic (Campnosperma,
Drimycarpus, Holigarna, Melanochyla, Nothopegia,
Pentaspadon, and Swintonia) and those that are
questionably allergenie (Buchanania, Lannea, Parishia
and Spondias), because the current literature is
ambiguous. Unfortunately, there is no single charac-
teristie that one eould plaee on these exeept, perhaps,
Fig.5. Western poison oak, T. diversilobum is found mostly on the results of a blaek-spot test. However most are
the west co ast of the U nited States, and adjacent regions of
Mexico and Canada. It is a much larger plant than eastern poison woody, they are often trees and they often have
oak, and it may climb trees alternate leaves. Included are four tribes, all of which
include at least some toxie species. Allergenie members
of the tribe Semeearpae include Semecarpus, Drimy-
carpus, Melanochyla and Nothopegia. Allergenic taxons
in the tribe Anaeardieae are Anacardium, Buchanania,
Gluta, Holigarna, Mangifera and Swintonia. The tribe
Rhoideae contains Campnosperma, Parishia, Penta-
spadon, and Toxicodendron. These are likely problems
for workers where these genera are found. Beaman
gives taxonomie sources for Asia that one ean consult,
as the information is far too eomplex to present in a
clinical review. There is one unifying characteristie,
however, as all toxie species should, if done properly,
produce a positive black-spot test [45].
The Black Spot

Fig. 6. Poison sumac, T. vernix, is a small tree or a large shrub
found in peat bogs, in swamps or along backwater ponds in
Sometimes a black deposit resembling black enamel
standing water or where the water table is high
paint can be seen at the sites of injury of poison ivy,
poison oak and poison sumae. This is a hardened form
of the allergenic sap on the surface of the plant. The
black material is not as irritating as the clear liquid
sap, but it is still very allergenic. After prominent
exposure to the plant, one occasionally finds black
spots on the skin in the areas of the dermatitis (Fig. 7).
This is ealled blaek-spot poison-ivy dermatitis [46].
The tendeney for the sap to turn black ean help to
confirm the identifieation of poison ivy, poison oak
and poison sumac in the field [45]. The direetions for
doing this are found in Table 2.
Pathophysiology
Fig.7. Black-spot poison-ivy dermatitis Toxicodendrons contain varying amounts of alk(en)yl

eateehols which are highly antigenic [18]. Poison-ivy
urushiol has mostly pentadec(en)yl eatechols, while
In Asia there are many genera that are potentially poison oak urushiol has mostly heptadec(en)yl eat-
toxie. Poison ivy is found in Japan and Russia as echols. The two-carbon differenee in the two side
T. radicans spp. orientale, and in China and Taiwan as chains is of relatively minor importanee. However, the
736 J.D. Guin
Table 2. How to recognize poison ivy and poison oak
1. Poison ivy and poison oak have three leaflets per leaf. Poison surnac has 7-13 leaflets, usually 9
2. The petiole (a structure holding the three leaflets) is grooved and enlarged where it is attached to the branch (no. 2, Fig. 3)
3. Leaf scars are "U" - or "V" -shaped (no. 3, Figs. 3, 4)
4. Tiny holes in the bark give a characteristic texture to the surface (no. 9, Fig. 4)
s. Flowers and (on female plants) fruit (no. 4, Figs. 3, 4) are supported on branched stalks in clusters. The stalks are often bare in
winter, resernbling ernpty grape sterns (no. 8, Fig. 4)
6. Fruits (on larger female plants) are green in summer (no. 5, Fig. 3), turning off-white in the fall. The outer layer peels in winter,
leaving a chalk-white surface with dark or black lines (no. 7, Fig. 4)
7. Poison-ivy branches are often gnarled because growth buds are not centered (no. 1, Fig. 3), so the branch grows in a slightly
different direction each season. This gives poison ivy on fence posts the silhouette of a Medusa head
The black -spot test
The black-spot test is used to confirm that a suspected plant is poison ivy/oak/sumac. lt is usually used when one has a plant with
rnany features of poison ivy/oak but whose identity is still unknown
1. Using a vinyl glove or multiple folded sheets of white paper, grasp severalleaves where they are attached to the branch and rernove
thern, keeping thern safely inside the paper. There is usually a slight bulge in the "stern" of the leaf there
2. Gather the bulges of the "sterns" together and, with the paper folded, crush the "sterns" so that a wet spot is left. The test does not
work if there is not enough sap released to wet the paper
3. Taking care to avoid contact, dispose of the leaves in a safe place
4. The clear, wet sap turns brown in less than ten minutes. lt takes about 24 h to turn the spot on the paper black, but the test
can be read in ten rninutes or less
number of double bonds in the side chain may be more ing is recommended, as the eruption is usually found
important, as molecules with two and three double in exposed areas. Vinyl (polyvinyl chloride) gloves
bonds in this side chain seem to cause a much higher tend to be protective, but rubber gloves are said to
percentage of positive patch-test reactions in individ- allow penetration of the antigen. Exposed clothing can
uals allergic to poison ivy and poison oak [47]. The be laundered or, in severe cases, dry cleaned to remove
lipophilic alk(en)yl component of this molecule prob- any remaining antigen.
ably binds to the cell membrane, while the hydroxyl Spread of the eruption from contaminated fomites
groups in the one and two positions are said to oxidize can occur with animal fur, garden tools and even
to quinones [48] and bind with nucleophiles (e.g., S-H, clothing. In most cases, one only has to wash clothing
NH 2 ) on the surfaces of Langerhans' cells [49], with soap and water. Bathing with a contaminated
although this mechanism cannot explain the same hand can cause spread of the antigen, so some measure
process seen with alk(en)yl resorcinols found in many of common sense must be employed.
other toxic Anacardiaceae. The mechanism has been Another method of preventing poison-ivy dermatitis
given in more detail by Kalish [50]. This extremely is to use a barrier substance such as Ivy Block,
potent antigen is oil soluble and has a strong affinity quaternium-18 bentonite cream [56, 57, 58] or Stoko-
for protein. The former characteristic allows it to be gard cream [59]. Stokogard contains multiple amino
rapidly absorbed and the latter characteristic causes it groups, ostensibly to bind the antigen on the surface,
to bind avidly to MHC proteins in Langerhans' cells. preventing absorption [59]. This preparation is applied
before exposure and washed off within a few hours. Ivy
Prophylaxis Block, an over-the-counter preparation approved by
the US Food and Drug Administration, causes surface
The most effective way to prevent contact dermatitis to binding and reduces experimental patch-test reactions.
poison ivy is avoidance of the plant. This requires Some other products marketed for this purpose are
plant recognition in all four seasons. The method used said to be less potent [60].
for identification of poison ivy, poison oak and poison
sumac is given in several published reviews [22, 28,33, Hyposensitization
51, 52, 53, 54].
The allergenic component of the plant is readily In past years, extremely sensitive individuals who
absorbed through the skin, so highly sensitive people could not avoid exposure could achieve a temporary
must remove the antigen within a few minutes of form of partial tolerance by oral administration of
exposure. Usually this is done with soap and water, but progressively increasing doses of the causative antigen
any organic solvent would be beneficial if used over aperiod of many months [61,62]. The reduction
immediately. Moderately sensitive people are said to in sensitivity in modern times was typically mild, but it
have 30 min or so to try to remove the antigen with could be useful. In the older literature, when more
soap and water or one of the organic solvents [29]. As aggressive treatment programs were used and side
an emergency treatment, when none of these is effects were seemingly less important, more prominent
available, water is beneficial [29, 55]. Protective cloth- reductions in sensitivity were achieved [63]. Interest-
ingly, individuals who work with these antigens every exposed. Short ragweed (Ambrosia artemisiifolia)
day tend to develop a form of tolerance called in the eastern United States, bitterweed (Helenium
"hardening." This phenomenon is seen in Oriental amarum) in the Southeastern US, chrysanthemum
woodworkers or in individuals who have been delib- (Dendranthema .X Cultivar) or the fiorist's chrysan-
erately, repeatedly exposed through patch testing or themum wherever it is grown, Cocklebur (Xanthium
other means. This same phenomenon tends to occur spp.), feverfew (Tanaeetum parthenium) - which is
after prolonged treatment with other strong allergens often grown as an herb. and which has been used to
in persons with alopecia areata [64]. screen for sensitivity, narrow-Ieafmarsh eIder (Iva
angustifolia) in westeru.I'.:rexas andwhere it is local,
Treatment of Toxicodendron Dermatitis sagebrush (Artemisia tridentata) in western states,
sunfiower (Helianthus annuus) where it is grown,
Oral corticosteroid therapy is usually effective, but it tansy (Tanaeetum vuZgare) in western states and wild
must be given in adequate dosage, usually beginning feverfew (Parthenium hysterophorus) in much of India
with 30-60 mg prednisone per day over 14-21 days. and in the United States, Texas and along the Gulf
Normally, treatment is maintained until at least Coast. Causative vegetation from Australia include
14 days after the initial exposure. Injectable (TM) shasta daisy (Chrysanthemum maximum), perennial
corticosteroids can be used, but they probably have no ragweed (Ambrosia Röllgstaehia), capewe~ (Are-
advantage. For milder cases, moderately potent topical totheea spp.), stinkwort (Dittriehia (InuZa) graveoZens),
corticosteroids can be used with 24-h occlusion. fieabane (Conyza spp.) [74], Gaillardia spp. [75],
Category lI-V topical steroids should be applied under Chrysanthemum parthenium [76], Dendranthema euZt"
occlusion for at least two 24-h applications. The ivars, dandelion, yarrow, and Cynara spp. [77]. These
absorption curve is better for a I-day to 3-day represent the potentially allergenic plants where the
application than for aperiod less than 24 h [65]. Use patients have an opportunity to be exposed. In addi-
of more simple topical agents may help reduce tion, Frullania, laurel and magnolia also contain SQTL.
broadening of the allergic base (extended allergen There are five known patterns of eczema from
syndrome). Hyposensitization is now an anachronism, sesquiterpene lactone-containing plants.
as oral kits for hyposensitization are no Ion ger
available and the injectable preparations are too low Pattern I. Pseudo Photodermatitis
in concentration to permit effectiveness at the recom-
mended dosages [66]. The typical presentation is an older white male,
commonly a farmer,with a prominent eruption in
exposed sites (Fig. 8), often previously misdiagnosed
as photosensitivity; here, however, the upper and lower
Compositae Dermatitis
eyelids are often involved. The submental and postau-
ricular areas are also usually involved. However,
Reactions to Compositae are called many things, such photosensitivity and Compositae allergy are commonly
as sesquiterpene-Iactone (SQTL) dermatitis [67] (be- seen together [78], and about 45.6% of photosensitive
cause of the causative chemicals within the plants), or persons also have sensitivity to SQTL-containing
weed dermatitis in the United States because of the plants [79], although photopatch tests do not confirm
association with ragweed, bitterweed, etc [5]. It is photosensitivity to the plant allergens. Therefore, those
called "bush dermatitis" in Australia because it suspected of having either Compositae allergy or
occurred in bush workers who broke out due to photosensitivity should be both patch tested for
vegetation in rural arid areas, cleared when in the city Compositae allergy and phototested for the minimum
and fiared again on returning to "the bush [68, 69]". erythema dose (MED) for both ultraviolet (UV)-B
SQTL dermatitis sometimes can present with a severe, and UV-A radiation [79]. Frain-Bell [80] has described
dramatic clinical picture. The problem is easily con- increased sensitivity with preirradiation in a few
fused with other conditions, such as light sensitivity patients, and there is areport of one patient who had
[70], atopic eczema [71], hand eczema [71, 72] or even an extremely persistent patch-test re action to Part-
poison-ivy dermatitis [67]. In Europe, about 1.5% of henium hysterophorus when he was on psoralen-UV-A
those tested are positive to the screening SQTL (PUVA) therapy [81]. The reason remains an enigma.
mixture, and many would have been missed had the Photopatch testing is also done to rule out photocon-
screening test not been included. This mixture is not tact dermatitis, especially to atranorin and other light
foolproof, however, as it detected only 6 of 17 absorbing chemicals in lichens.
Compositae-allergic patients in one study [73]. Plant Often there is severe eczema of the face, hands and
genera associated with this type of eruption will arms, with prominent involvement of the eyelids and
depend upon the vegetation to which the patient is thickening of the facial skin, which may even result
738 J.D. Guin
plant has now spread over much of the country,

sparing the desert areas and levels above 2000 m [84] .
The principal allergen in P. hysterophorus is parthenin,
a water-soluble SQTL [85].
Pattern 4. Hand Eczema
Patch-test screening with SQTL mixtures has uncov-

ered patients not suspected to have SQTL sensitivity,
including a number with hand eczema [72]. I have seen
hand involvement with ragweed allergy [71] and
especially with bitterweed dermatitis, and these likely
depend on an opportunity for direct exposure. This
pattern is also found in Europe [22], where those plants
are absent, so multiple species can cause this pattern.
Pattern S. Localized Dermatitis
A fifth pattern is a strong acute eczematous eruption in

one or more localized areas [86]. Cocklebur dermatitis
Fig. 8. Compositae (ragweed) dermatitis resembling photosen- tends to be more localized and spotty [14, 15, 16] and less
sitivity chronic. It may even resemble poison-ivy dermatitis.
The cause of (allergie) weed dermatitis is delayed
in leonine facies. There is a sharp cut-off at the hypersensitivity to one or more sesquiterpene lactones
margins of clothing such as the (short) sleeves, often [87]. The same SQTL may occur in more than one
plant, and there are cross-reactions to SQTLs with a
sparing the inner arms as one might expect with light
similar chemical structure, so a positive reaction,
allergy. A typical cause where I live in the southern
United States would be bitterweed allergy, but the although proving allergy, does not necessarily mean
causative plant will depend upon the flora of that that the plant is the cause of the patient's problem. In
Compositae, SQTLs are found in small glands in
locality as weIl as occupational exposure to exotic
trichomes, ti ny hair-like structures on the plant's
species.
surface [88]. While the pollen in a few of these plants
may contain SQTL, this does not seem to be the case
Pattern 2. The Atopic Eczema-Like Pattern for most [67] . Weed dermatitis typically begins as a
summertime eczema in exposed sites, extending to
Some persons with ragweed dermatitis present with an later in the fall in sub se quent years until it becomes
eruption that closely mimics atopic eczema [71]. SQTL "perennial", being present throughout the year. It
(weed) dermatitis, however, unlike most cases of atopic tends to clear on removal from the environment, and
eczema, begins in adult life, tends to spare the feet and farmers who move to the city tend to clear in spite of
is worse during the summer. This form has even been high pollen content in the air [89, 90, 91]. Dust from
reported in prepubertals [71, 82]. However, SQTL hay may, however, contain the antigen [92], and in
dermatitis is reported less commonly in women and such cases the antigen could easily be airborne. Most
is rarely reported in children. In adults, the prevalence cases are probably due to hand transfer.
is said to be 20 times greater in males [83], although the Plants from some other plant families, e.g., Frulla-
ratio in my practice is much lower than that. nia, Magnolia, and Laurus contain SQTLs and may
cause sensitization or cross-react with other SQTL-
Pattern 3. Exfoliative Dermatitis containing plants [67, 86] . Cross-reactions to carvone
in spearmint [93] may occur as weIl. Patients mayaiso
In prolonged and severe cases, patients may develop react to Compositae plants to which they have never
exfoliative erythroderma, especially when the cause is been exposed, as the same SQTL is sometimes found in
Parthenium hysterophorus [13]. This plant arrived in multiple species [87].
India in contaminated seed wheat, where it has
produced weed dermatitis in epidemie numbers. More Patch Testing
than half the adult male workers hired to pull this weed
became allergie to it, and many persons became Benezra et al. developed a SQTL mix, a mixture of
incapacitated by the magnitude of the eruptions. The three antigens, alantolactone (a synthetic that is found
naturally in elecasmpane and Frullania), denies. It is tested in a 0.1% concentration in petrolatum
hydrocostuslactone and costunolide, each in 0.33% [99]. It has been used to screen for allergy (to
concentration in petrolatum. The use of this mixture in Frullania, a liverwort) in woodcutters of the Pacific
screening has uncovered many patients who might northwest. It is less regularly positive in Compositae
have been missed before it was used, but it does not dermatitis [100]. For plants for which there are
detect many others [73, 94]. One European group no available commercial antigens, Mitchell suggests
compared a SQTL mix with a mixture of plant extracts: applying a leaf, fiower head, stalk and petal, using
arnica (Arnica montana), o.S%; yarrow (Achillea controls to rule out irritancy [101]. Laurel is readily
millifolium), 1.0%; tansy (Tanacetum vulgare), 1.0%; available as bay leaves in the spice racks at grocery
German chamomile (Chamomilla recutita), 2.S% in stores. However, it may not produce a positive
petrolatum; and feverfew (Tanacetum parthenium), response, even in some sensitive persons [102]. In
1.0%. The two mixes detected an equal number of warmer latitudes of the US, one can gather magnolia
responders, but they were not the same people [96]. leaves for patch testing even during winter, as that tree
To test for specific plants, one can collect causative is an evergreen. Testing is simple; a small square is cut
(local) plants and preserve them in a labeled plastic from the leaf and scratched to release sap on the side
bag in the freezer. A small piece can be cut from the applied to the skin. Positive responses may parallel the
leaf, fiower petal and stern when needed for patch location of the scratches [86].
testing. Shelmire cautioned against leaving such test
patches on longer than 1-2 h because of irritancy, but
Treatment
I have not seen patch-test irritancy from magnolia,
ragweed or bitterweed. However, if they are left on
Treatment of chronic SQTL dermatitis is difficult.
longer to elicit a positive test, one should run controls
Several approaches are possible. First, one should
to be safe. A S% a1coholic extract has been used for
educate the patient on avoidance and how to minimize
chrysanthemum (Dendranthema cultivar) [97]. Sug-
exposure. An occupational change, e.g., a move to town
gested plants one might collect for use in the United
for a farmer, is often followed by significant improve-
States are:
ment. PUV A therapy can be beneficially administered
- *Bitterweed (Helenium amarum) in the Southeast- in much the same way one treats photocontact derma-
ern US titis [81]. For resistant cases, oral azathioprine has been
- *Chrysanthemum (Dendranthema X cultivar) or the recommended [103, 104]. This affords considerable
fiorist's chrysanthemum (one should always test to relief from the pruritus and causes marked improve-
the actual plants the patient contacts if the history is ments in about half of such patients. The others are
positive) usually better but have some residual dermatitis.
- *Cocklebur (Xanthium spinosum) Kits for oral hyposensitization to Compositae ivy are
- Feverfew (Tanacetum parthenium) - often grown as no longer available. Because biological agents are
an herb difficult to standardize, trying this without a commer-
- *Narrow-leaf marsh eIder (Iva angustifolia) where it cial product is not recommended. Some oral hyposen-
is local sitization methods have been somewhat effective,
- Sagebrush in western states (Artemisia tridentata) perhaps because of the development of anti-idiotypie
- *Short ragweed (Ambrosia artemisiifolia) antibodies [103].
- Sunfiower (Helianthus annuus)
- Tansy in western states (Tanacetum vulgare)
- *Wild feverfew (Parthenium hysterophorus) in Texas Aistroemeria and Tulip
and other areas where it grows
Items marked with a * comprise the screening series Retail and wholesale fioristry workers are at risk of
Shelmire used to challenge Texas patients suspected of becoming allergie to Alstroemeria spp. (Peruvian lily
having some form of Compositae dermatitis, according or Inca lily) [lOS, 106, 107] and Tulipa (tulip) [108]. The
to J.B. Richardson. acute eruption typically occurs in the grip area of the
Chrysanthemum (or Dendranthema X cultivar) is a fingers of retail fiorists, especially the thumb, index
special case, as one must test the patient for reactions and middle fingers. Fissures are commonly present
to the plants to which the patient is exposed. I have within a hyperkeratotic eczema starting at the free
seen one color of a variety produce a prominent edge of the nail and progressing to the finger tips and
reaction, while other colors of what is ostensibly the proximally to the periungual area [109]. Tulip sensi-
same variety are negative. Alantalactone is available as tivity is caused by allergy to alpha-methylene gamma-
"helenin" (a mixture of alantolactone and isoalanto- butyrolactione or tulipalin A [110, m], which is
lactone) [98] from Sigma and other chemical compa- derived from the glycoside tuliposide A. Both tulipo-
740 J.D. Guin
side A and its hydroxy derivative, tuliposide B, have impossible without a job change. Persons affected
fungistatic and bacteriostatic properties. Contact sen- often try to avoid the plant by taking shortcuts. What
sitivity to tulip often occurs after long periods of could be more simple than avoiding it yourself and
exposure while handling the bulbs, but it can also giving the job to someone else? This practice caused
occur from contact with other parts as well [109]. The multiple sensitivities in one floral shop [113], which
allergen in Alstroemeria is especially concentrated in might have been prevented by instituting proper
the petals [m]. The allergenic chemical is found in preventive measures with the first person affected.
several of the Lilyflorae, including not only Al-
stroemeria (Peruvian or Inca lily), but also tulip,
Erythronium dens canis (dog's tooth violet), E. amer-
Bulb and Daffodil Dermatitis
icanum (trout lily, adder's tongue), [109] Bomarea,
Gagea and at least one species of onion (A/lium
triquetrum). Minor amounts can be found in a few Bulbous plants may be true bulbs (onions and daffo-
other genera. Tuliposides A and B have antifungal dils), corms (crocus and gladiolus), rhizomes (iris), or
properties, but only the former produces the allergen, tubers (dahlia). Most daffodils belong to Narcissus
alpha-methylene gamma-butyrolactone, by hydrolysis. pseudonarcissus, Amaryllidaceae [114]. In the winter,
In tulip, the allergen is found in greatest concentration these plants are grown in greenhouses for cut flowers,
in the bulb, with decreasing concentrations in the stern, and the oil derived from N. jonquil is used in the
leaf and petal. In one series, nine of ten varieties of tulip fragrance industry [114]. Flowers are collected in
were equally potent, with the Red Emperor variety bunches for commercial purposes and the pickers
slightly less allergenic. The scale of the bulb contains a come into contact with calcium oxalate in the sap and
high concentration of allergen, which can cause "mucus" from injured plants. The rash, comprising
airborne contact dermatitis. Persons who work with erythema, papules, vesicles and eczema, is found where
tulip bulbs regularly have a very high prevalence of sap comes into contact with the skin either directly or
sensitivity. Exposure to cut flowers seems to be by hand transfer. It is usually mild but has been known
associated with sensitization less often, but it occurs. to become chronic and generalized [115]. Eczema ofthe
finger tips with rhagades has also been described [116].
According to Bruynzeel, about 50% of growers claim to
Patch Testing break out to some extent, but contact with already-
irritated skin is especially likely to cause a problem.
The allergen, alpha-methylene-gamma-butyrolactone, The pathogenesis is probably a combination of phys-
can be obtained in patch-test concentration from ical injury from crystals of calcium oxalate followed by
Chemotechnique as a "various allergen". Testing has penetration of several alkaloids. Sensitization is un-
also been done both with Alstroemeria and Tulipa. usual but possible from two weak sensitizers, homo-
However, because of the high concentration, especially lycorin and masonin. There is evidence that there may
in the petals of Alstroemeria, there is some risk of both be multiple possible allergens due to species differen-
false positive irritant reactions and active sensitization. ces [114].
Patch testing can also be done with an extract of Hyacinth, Hyacinthus orientalis, causes an irritant
tulip bulb (the Apeldoorn variety is suitable). This is reaction that has been compared with scabies. The
done by shaking fresh bulb material in 80% acetone (in bulb has a thick outer membrane, or tecta, that tends
water) for 90 min, evaporating it dry and resuspending to be irritant. Injury releases calcium oxalate crystals.
it in a 1% concentration in alcohol [109]. The bulb Handling of the bulbs releases small particles that
surface is also satisfactory after the brown outside become mixed with dust and are carried in the air and
layer is removed. Controls are recommended. One by the hands. The dry plant combined with skin wet
patient developed depigmentation from testing with from sweat allows airborne material to stick to the
Alstroemeria [112]. skin. Clinically, there is itching with urticarial wheals,
papules and vesicles found especially on the volar
Prevention fore arms, face, thighs, and inguinal and anogenital
regions [114]. Removal of the crystals with dilute acid is
The allergen in Alstroemeria penetrates ordinary latex recommended, as the material is not water soluble.
and vinyl gloves, so a nitrile glove is recommended Prevention by good ventilation, vacuuming of the
[Solvex; 15 mils, catalogue number 37-155 or 37-175 premises and avoidance of contact with the face, arms
(flock-lined); Edmond-Becton Dickinson 1300 Walnut and neck are recommended [114].
Street Coshocton, OH 43812] [105, 107]. Adams et al. Garlic, onion and chives are all found in the same
warn that incidental contact caused by antigen transfer genus, A/lium. There are at least three sensitizers in
from the counter and fomites may make avoidance garlic: diallyldisulfide, allylpropyldisulfide and allicin.
Table 3. Information for Patients on Poison ivy/oak dermatitis
What causes poison-ivy The rash caused by poison ivy/oak exposure is an allergie reaction to a chemieal in the plant's
dermatitis? sap. It is carried in tiny canals beneath the skin of the leaf or just below the bark.
Just brushing against the leaves does not cause the rash, because the sap is not released unless
the leaf surface is broken
How long does it take to On first exposure, we are not allergie. It takes from at least 5-7 days or, more likely, 10-14 days
become allergie? to become allergie. If enough of the toxie agent stays in the skin when sensitization occurs,
the rash will appear. Otherwise, it is not seen until the next exposure
How do I know it is poison The rash from poison ivy/oak characteristieally occurs in streaks, because the poisonous sap is
ivy/oak dermatitis? deposited in hand-prints and finger marks. It may appear as earlyas 5.5 h to as long as 15 days
after exposure, but it usually occurs after 24-36 h. Sometimes, when a large quantity of the
poison is left on the skin, it turns black, resembling black enamel paint. This is called black-
spot poison-ivy/oak dermatitis
Can one spread poison ivy No. This has been tried many tim es. The rash that appears later is caused by slow absorption or
from blister fluid? re-exposure and not from the blister fluid
Is it contagious? No. It does not spread from the rash. However, when it is still on the hands, one can spread it
over oneself or to others touched
How can I safely and Herbicides are effective. If the plant is growing in your lawn, use repeated applieations of a
effectively kill the plant? 2-40 herbicide, as this kills broad-leaf weeds but not the grass. Round Up, properly applied,
will kill poison ivy with one application. It has the added advantage of becoming inactive when
it contacts the earth, so it does not run onto and kill nearby plants. The concentration is
important, so read the directions
What is the best way to The best protection results from recognizing the plant and avoiding it. On ce you are exposed,
prevent the rash? soap and water are he1pful if applied within a few minutes to a half hour. Even applying plain
water immediately tends to reduce the severity. Exposed clothing can be treated by washing or,
after severe exposure, dry cleaning. Dark black spots left on a garment are indelible and retain
the capacity to cause allergie reactions. Several commercial products, applied before exposure,
may delay or reduce absorption. There are "Stokogard" cream, "Ivy Block" (not yet available
in early 1992), and to a lesser degree "Ivy Shield". These are applied to high-risk areas before
exposure and washed off later. Vinyl (but not rubber) gloves provide excellent protection for
the hands, and covering an area with dothing he1ps prevent exposure
How is the rash best treated? Treatment usually means a visit to the doctor, as the more effective remedies require a
prescription. For most ca ses, oral cortisone-like medieations are taken after breakfast in a
single daily dose. Treatment should continue until at least two weeks after the exposure. For
persons who cannot take systemic cortisone, one can apply a thick layer of a moderately potent
cortisone salve, cover it with plastie (like Saran) and snugly wrap the site with an elastic
bandage. This is left in place (or reapplied) for 24 h. Two 24-h applications, one day apart, are
usually necessary
Garlic fingers are produced in chefs when the plant is shorter "hairs" on the plant's surface (and is more
held (to cut it). For patch testing, diallyldisulfide (1% in concentrated in smaller leaves), so contact is extremely
petrolatum) is available as a commercial antigen. easy [122]. Primin is such a strong antigen and is in
such variable concentration in the plant that it is wise
to patch test to the commercial antigen available at
Primula Dermatitis 0.01% concentration in petrolatum. Delayed readings
up to 7 days are important [9, 122].
Primula dermatitis can be occupational [U7], but

usually one sees an older housewife with a dermatitis
of the fingertips and streaks and patchy eczema on the
hands, face [u8] (especially the eyelids) [U9] and arms
[9,120]. Primula obconica (Fig. 9) is such a common
contact allergen in Europe that about 1.0-1.8% of
persons routinely patch tested react to the causative
allergen, primin (0.01% in petrolatum) as part of the
European screening series [u8]. The eruption may not
be suspected until the positive patch test appears [u8],
and the nondescript pattern may suggest an endoge-
nous cause [u8]. Rarely, one sees areaction to the
plant when the patch test to primin is negative [121].
The allergy apparently develops when one growing
the houseplant pinches off dying blooms to encourage
the plant to bloom again. The allergen is present in Fig. 9. Primula obconica
742 J.D. Guin
Table 4. Patch testing to plants [101,437]
1. The antigen in Primula, primin, is available in 0.01 % concentration in the ICDRG series from Chemotechnique and Trolab
2. a-Methylene-g-butyrolactone, the antigen in tulip and Alstroemeria is sold by Chemotechnique
3. Helenin, 0.1% in petrolaturn, is available from Chemotechnique and Trolab, and detects most Frullania reactors
4. Lichen acids and fumaric acid are available from Chemotechnique, and usnic acid and Atranorin from Trolab and Chemo-
technique; these can be used to screen fo rlichen allergy. Oak-moss absolute, one of eight components of the perfume mix in the
standard series, is also derived from a lichen
5. Sensitivity to colophony (standard series) and turpentine peroxides can uncover allergies to several conifers. Wood tars are sold by
Trolab and Chemotechnique. Balsams of pine and spruce can be obtained from Trolab. Pi ne wood, pine tar and beech tar are sold
y Chemotechnique
6. Compositae plants can usually be patch-tested using untreated leaves, sterns and fiower heads. A section of magnolia leaf is
excoriated before application. Bay leaf is tested as oil of laurel, if available
7. Sesquiterpene-Iactone mix is available from both Chemotechnique and Trolab and is part of the European standard series; it will
detect many reactions to Compositae and Frullania, but will also miss some
8. Plants to which the patient is exposed can be tested (without prior treatment) if not irritating, but controls are in order
a. One specimen should be used to identify the species botanically
b. One specimen is marked and stored in a plastic bag in the freezer
c. The leaf, stern and fiower ofthe plant specimen are applied, using controls Shelmire recommended one-hour applications, and for
24-48-h application, use controls. Irritancy should be excluded by checking standard references before application
9. Woods can usually be tested as sawdust
a. Sawdust should be taken from a single species and placed in a labeled plastic bag
b. Sawdust (10% in petrolatum) is tested first
c. If the 10% concentration is negative, dry sawdust can be applied
d. Wet sawdust may be tried if dry sawdust is negative, but controls are in order
10. Bulbs known or shown to be nonirritant can be applied without prior treatment after removing the outer layer On ion and garlic
are tested as a 25% concentration in petrolatum, using controls
One may see this plant growing outdoors in warmer tent, but the content of a number of varieties may be
climates, e.g., frost-free areas in California, and it adequate when the subject is exposed to large quan-
seems to be regularly available in nurseries, at least intities of UV -A by sunbathing or exposure in a tanning
San Francisco [n8]. There are approximately 400 other salon. Grocery workers have developed photo derma-
species of Primula grown outdoors or indoors [123], titis from the cut surfaces of uninfected celery if
but only one contains primin [124] and only a few followed by intense sunbathing or a visit to a tanning
produce dermatitis, usually irritant in nature. Primula salon. The cut surface of one variety of celery
dermatitis is almost always caused by Primula obcon- contained as much as 25 J,.lg/cm 2 of cut surface [128].
ica [122]. Avoidance is easy once the problem is When one grocery cashier in Ohio reported a discreet
identified and a primin-free strain of Primula obconica bullous eruption of the forearm, a National Institute
is now available as seeds from Thompson and Morgan, for Occupational Safety and Health investigation found
although, in my experience, this genus can be difficult a similar problem in 27% of workers, largely those with
to germinate unless one lives in an ideal climate. contact with fresh vegetables [129, 130].
Plants known to cause phytophotodermatitis include
Persian limes (Citrus aurantium), fig trees (Ficus carica),
Phytophotodermatitis gas plant (Dictamnus albus), giant hogweed (Heracleum
mantegazzianum), common rue (Ruta graveolens) [131,
Poison-ivy-like streaks of vesicles and bullae in light- 132], Ruta montana [133], Ruta chalepensis [134, 135],
exposed sites can be caused by photocontact derma- Ruta corsica [136], bishop's weed (Ammi majus), wild
titis, and w~en prod~ced by psoralens, the acute' parsnip (Pastinica sativa), angelica (Angelica archan-
eruption is typically 'followed by pigmentation: There gelica) and the scurfpea (Psoralea corylifolia) [126].
are multiple mechanisms of phytophotodermatitis, but Light-absorbing chemie als in lichens or oak moss
most such reactions are caused by plants containin.g (from a lichen) are said to cause photoallergie derma-
furanocoumarins or psoralens, including certain mem- titis [137, 138], although this is not experimentally
bers of the Umbelliferae and Rutaceae (citrus) [125]. reproducible, at least not with atranorin and lichen
The sensitizer can be spread with the hands or even mixtures [139]. Table 5 lists a number of putative
thrown onto the skin from astring trimmer [126]. Of causes of phytophotodermatitis, but omits those
course, it is necessary to have adequate UV -A exposure' caused by ingestion and those reported but doubted
in addition to contact with the plant. from available evidence by Mitchell and others.
There are reports of photodermatitis ,in celery The subject has been reviewed by Pathak [125] and
harvesters caused by plants infected with '.' th1 piI]k- others. There are also photosensitizing plants that do
rot fungus, Sclerotinia sclerotiorum [127]. The, variety not contain psoralens, e.g., St. John's wort (Hypericum
seems to be important in determining psoralen con- perforatum).
Occupational (ontact Dermatitis to Plants 743
As stated before, photosensitive persons are more

likely to be allergie to Compositae as weIl, so testing for
such sensitivity is often done routinely with photo-
testing.
Irritant Reactions
An "irritant" is a nonallergie response which can have

any one or more of many causes. Irritant reactions
tend to occur rapidly, often within a few minutes, and
they are more likely to burn rather than itch. They can
also occur on first exposure, and they tend to be dose
related. Allergie reactions should not occur on first
exposure, and prominent reactions can sometimes
result from very small amounts of antigen, especially in
highly sensitive subjects. The mechanism for nonal-
lergie reactions can vary greatly, ranging from me-
chanical injury from cactus to urticaria from stinging
nettles (Fig. 10), and from painful inflammation from Fig. 10. Urtica pro cera, tall nettle [403]
bull nettles (Fig. 11) to strong vesiculation from
Euphorbiaceae such as manchineel (Fig. 12).
Physical injury can be seen from splinters, glochids
of certain cacti, awns of certain grasses, burrs of
many shrubs, the bark of some trees, woody spines
and almost any plant component sharp and firm
enough to penetrate the skin. Thorns of plants from
roses and blackberry to locust and from Hawthorn
trees to Euphorbia spp. may cause mechanical injury
[140, 141]. Some grains, e.g., barley, have prominent
awns, which can be irritating. Many of the Cactaceae
also produce mechanical injury. The list of such
plants is long, but normally one can easily make the
diagnosis.
Sabra dermatitis from Opuntia ficus-indica can
sometimes resemble scabies [142]. The bunny's-ears
cactus (Opuntia microdasys), a commonly grown
ornamental, also has collections of tiny spines called
glochids, which are the source of immediate irritation,
and sometimes lead to granuloma formation [143].
Calcium oxalate is a common source of plant
irritation found in a number of irritant plants,
including dumbcane (Dieffenbachia), daffodils, hya- Fig. 11. Cnidoscolus stimulosus, bull nettle [403]
cinth, Arisaema, lily, pineapple and other species. The
chemical is contained in intracellular crystals called
raphides, and is ejected from the cell on contact with Many but not all members of the Euphorbiaceae are
water. When leaves of dumbcame are chewed, a burn- irritant and some (e.g., snow on the mountain) are
ing sensation develops almost immediately, followed grown for use as decorative plants [144]. Some spurges
by salivation and perhaps dermatitis [16]. Mustards, (Euphorbiaceae) contain phorbol esters in the latex,
including radish, horseradish, etc., contain sinigrins, which are not only strong vesicants, but contain co-
which become irritating when they are enzymatically carcinogens as weIl. Many are tropical plants, such as
converted into isocyanates. Buttercup (Ranunculus the infamous manchineel tree, but equally irritant latex
spp.) contains protoanemonin as does columbine may be found in some related houseplants, such as the
(Aquilegia), marsh marigold (Caltha), Clematis, candelabra cactus. Croton oil is obtained from Croton
Delphinium and Anemone [140]. tiglium a member of the Euphorbiaceae [141].
744 J.D. Guin
Table S. Putative causes of phytophotodermatitis
Plant dass, species, or subspecies Plant common name Comment
Brassicaceae (Cruciferae)
Brassica spp. [125] Unknown [14]
Eruca spp. Irritant reactions + sunburn [14]
Eruca sativa [14] Rocket salad Reaction when used to treat vitiligo
Sinapsis spp. [125] Unknown [14]
Compositae
Achillea millefolium [125] Yarrow
Anthemis cotula [125] Mayweed Irritant
Parthenium hysterophorus Congress weed Photoallergic reactions [438]
Wild feverfew Photoaggravated reactions [81, 439]
Tagetes spp. [440] Marigold Phototoxic agents
Chenopodiaceae
Atriplex serrata [14]
Chenopodium spp. [14, 125] Goosefoot
Convolvulaceae
Convolvulus arvensis [125] Bindweed
Cyperaceae
Scirpus holoschaenus [14] Cult bulrush Irritant causing meadow-grass dermatitis
Hyperacaceae
Hypericum crispum [125] Red quebracho
Hypericum perforatum [125] St. John's wort Hypericin
Leguminosae
Psoralea corylifolia Scurf-pea Psoralens
Moraceae
Brosimum gaudichaudii [14] Mamica de cadela Psoralens
Ficus carica [125] Fig Psoralens; also irritant reactions
Rosaceae
Agrimonia eupatoria [125] Agrimony
Rutaceae
Citrus aurantium [14] Seville orange
Bitter orange
C. aurantium bergamia [125] Bergamot
c. aurantifolia (Persian) Persian lime Bartenders [259]
C. aurantifolia [125] Lime Food-service workers
C. limon [125] Lemon
C. medica [125] Citron
C. sinensis [125]
Dictamnus albus Gas plant Psoralens
Esenbeckia leicarp? [14] Xanthotoxin
Euxylophora paraensis? [14] Xanthotoxin
Fagara jlava [14] West Indian satinwood Irritant encountered by laborers
Ptelea spp. Hop tree Psoralens
Ruta grave~lens [14] Rue Psoralens
Zanthoxylum jlava
Santalaceae
Santalum album? [14] Sandalwood
Umbelliferae
Ammi majus [125] Bishop weed Psoralens
Anethum graveolens [125] Dill Psoralens
Ange/ica archange/ica [125] Angelica Psoralens
Ange/ica sylvestris [125] Psoralens
Anthriscus spp. [125] Psoralens
Anthriscus sylvestris [125] Wild chervil
Apium graveolens [125] Celery Psoralens
Cachrys libanotis [404]
Cuminum cyminum? [14] Cumin Psoralens
Daucus carota [125] Queen Anne's lace Psoralens
Foeniculum vulgare [125] Fennel
Heracleum laciniatum [125] Tromsi palm Psoralens
H. giganteum [125]
H. mantegazzianum [125] Giant hogweed Psoralens
H. maximum (var. dulce) [125]
Heracleum spp. [14] Many other names Psoralens
Pastinaca sativa [14] Wild parsnip Psoralens
P. sylvestris [14] Psoralens; irritant causing meadow-grass
dermatitis in France
P. urens [14] Psoralens; irritant causing meadow-grass
dermatitis in France
Peucedanum oreoselinum [14] Moutain parsley Psoralens
P. ostruthium [125] Masterwort
States. Compositae dermatitis has been discussed

already, and the reader is referred to the previous
section. Some reactions to Compositae are irritant and
some are allergie. Very likely some are both.
An epidemie of bullous irritant dermatitis (and one
with erythema multiforme) was seen in 14 farm
workers whose work included pulling weeds (chiefly
Anthemis cotula) in a field of sugar beets [146]. The
eruption began the second day in which they worked
in the specific field and manifested as erythematous
macules to blisters on the lower legs, wrists, forearms
and abdomen. One patient experienced erythema
multiforme. This paralleis the report of a single case
in 1921 [147]. The weed gets its name from its tendency
to bloom in May in many geographie locations.
Various explanations have been given for the irritant
factor, but at present it is still in doubt. Similar
eruptions have been seen in workers harvesting wheat
and other grains [148]. The same plant can produce
contact urticaria [89] and allergie contact dermatitis
Fig. 12. Hippomane mancine/la, the infamous manchineel tree, a [149]. At one time, this antigen was included in the
native of the Caribbean whose latex is exceedingly irritant. The series developed by Shelmire and eventually marketed
name means little apple that drives horses crazy
by Hollister-Stier and was occaasionally reported in
persons reacting to SQTLs from other plants.
Occupations Allergie contact dermatitis to the various Comp-
ositae causing SQTL dermatitis is most often seen in
persons engaged in some form of agriculture. SQTL
Occupational plant dermatitis obviously tends to occur dermatitis can be seen as areaction to one or more of
more often in certain occupations, the prevalence many genera. In Texas, Shelmire used a screen to test
depending upon the opportunity for exposure, the for the group, which included ragweed, bitterweed,
population at risk and the sensitizing capacity of the narrow-Ieaf marsh eider, cocklebur, chrysanthemum
plant. Reactions to plants and plant products might and wild feverfew or Parthenium hysterophorus. This
occur in any occupation with exposure to sensitizing does not include all of the sensitizing Compositae, but
plants or plant products, but there are several clinical it provides enough coverage of the group to represent a
pictures within specific occupational groups of which relatively good screening test for East Texas (and
one should be aware. The following discussion is Arkansas). Allergy to P. hysterophorus, while seen in
intended to supplement the classic pictures presented the United States, has been far more common in India
in the preceding section. A totally complete list is both since the 19SoS [ISO]. This eruption typieally involves
impractical and impossible, so I have included some older males engaged in outdoor work, and about 4%
more tradition al presentations, along with some of the will become sensitive in 3-12 months [ISI]. The erupt-
more recently reported reactions. ion goes through stages with progressive severity and
more and more widespread distribution. The presen-
Agricultural Workers, Farmers, Etc. tation, pathogenesis and management of SQTL der-
matitis has been discussed in more detail previously.
Contact reactions to plants in farm workers cover a Sunflower (Helianthus annuus) causes allergie con-
wide spectrum. Reactions occur to poison ivy, oak and tact dermatitis in agricultural workers engaged in
sumac [14S] which are often not reported. Exposure growing the plant for commercial purposes [IS2, IS3,
can occur when clearing fence rows and sometimes IS4]. This sensitivity may produce a cross-reaction to
when handling domestic animals. These plants are not Arnica [ISS]. The eruption commonly involves exposed
usually found with the crops, where herbicides are sites and the hands. The SQTL antigen is located in
used for weed control, but are more often seen on fragile multicellular, capitated glandular trichomes
fence rows. Sometimes contaminated hair of farm [IS6].
animals is the source. The details of Toxicodendron Sunflower sensitivity can also occur from exposure
dermatitis were given in the previous section. to fodder [IS4]. This seems to be a common source of
SQTL (Compositae) dermatitis is perhaps seen more Compositae exposure in farmers engaged in animal
often in this occupation, especially in the United husbandry. Allergie contact dermatitis mayaiso be
746 J.D. Guin
seen in persons harvesting Arnica spp. [157]. At least shell. One worker developed allergie contact dermatitis
one patient with (nonoccupational) contact urticaria to to coconut leaf and bark [181].
sunflower tolerated ingestion of the oil, so sensitivity Contact also occurs from grains and other grasses.
to the oil does not necessarily accompany allergy to the Benini et al. reported contact dermatitis caused by
plant [158]. Lagurus ovatus (hare's-tail grass) [161], and Cronin
Malten described the occupational exposure of a described a farm worker with hand dermatitis whose
patient with chicory dermatitis who was raising the symptoms cleared on changing jobs but which flared on
plants in the open field from April until September, returning to the farm where he fed cattle and cleaned
when they are harvested. The top of the plant is stalls. Patch tests were positive to "barley dust" [182].
trimmed and used for compost, while the root is Frullania sensitivity was reported in fruit pickers in
refrigerated in the dark. Plugs of the root are planted in Portugal [183], and lichens caused contact dermatitis in
watered boxes in the dark. After a time, white leaves rural agricultural workers [184], including one who cut
(witlof) appear and are cut off alongwith a small piece trees to make posts for a vineyard. Patch testing showed
of root which serves to hold them together. The root is hirn to be allergic to Frullania as weIl as lichens [185].
replaced wit11 anot11er one from the refrigerator and, Several different species were identified as causative in
after 3-4 weeks, t11at one is harvested. Malten's patient a man who broke out after cutting wood in his orchard
tried unsucessfully to protect herself with latex gloves [186], including Hypogymnia physodes, Parmelia sul-
[159]. cata, P. exasperatula, Physcia tenella and Candelariella,
Pyrethrum, derived from Chrysanthemum cinerar- cf. reflexa. There were also reactions to SQTLs, so there
iifolium and used as a pesticide, can induce contact may have been exposure to Frullania as weil.
dermatitis in farmers [160], and Anthriscus cerefolium A mushroom gatherer developed hand eczema that
[161] has been reported several times to induce contact later spread to involve the extremities, face and trunk
allergy. [187]. Mushrooms may cause a problem in growers, as
Tobacco, Nicotiana tabacum, may induce either weIl as workers in other occupations associated with
contact urticaria [162] or contact dermatitis [163, 164, foods.
165, 166]. This plant can also cause airborne contact Opium poppy, Papa ver somniferum, reportedly
dermatitis [167]. caused allergic contact dermatitis to codeine in pro-
Coffee workers have experienced contact dermatitis ducers [188]. A vineyard worker and a gardener
to the leaf of the coffee plant [168] and to the unroasted developed contact dermatitis of the hands by pulling
coffee bean [169]. Those handling coffee beans also wild madder (Rubia sp.), a plant which at one time was
experience urticaria [170], which may sometimes be the source of alizarin [189]. One agricultural student
due to castor beans included in the harvested material ostensibly reacted to Ailanthus altissima, the tree of
[171, 172]. heaven, but this was not proven [190].
Contact dermatitis has been reported in grape Persons gathering lavage (Levisticum officinale),
workers [173, 174, 175], and grape workers in California fennel (Symphytum officinale) [191] or parsnip (Past-
were more likely to develop contact dermatitis and inica sativa) [192] may develop phytophotodermatitis
lichenified hand eczema than tomato and citrus because of the ps oralen content of these plants.
workers [176]. An orchard operator had positive patch Sunscreens with activity in the UV-A range have been
tests to the bark and wood (sap) of the vine of a kiwi recommended for workers who must handle psoralen-
plant, Actinidia chinensis [177], and a farmer reacted to containing plants [193]. Photosensitivity may occur
salicyl alcohol in aspen [178]. from figs, certain plants of the Umbilleriferae, and
Okra (Hibiscus esculentus) may cause either irritant Rutaceae [125], but the best known example in
or allergic contact dermatitis [179]. The irritant com- agricultural workers is perhaps the reaction to celery
ponent may be due to proteolytic activity [180]. Field (Apium graveolens) affected with pink rot caused by
workers harvesting okra develop a pruritic eruption the fungus organism Sclerotinia sclerotiorum [127,194].
shortly after starting to pick okra, and continued However, several epidemics of phytophotodermatitis
exposure leads to fissures and flattening of the finger have been reported from celery that was not infected
ridges. The presentation has been compared with that [128, 195, 196]. Reportedly, several factors influence the
of pineapple workers exposed to the proteolytic level of psoralens, such as the geographic area, the
enzyme bromelain. occurrence of an unusually warm season and other risk
Some mechanical irritation occurs with some crops, factors such as absence of skin pigmentation, lack of
and the specifics depend upon the crop. Harvesting protective clothing, the number of clear days during
coconuts caused lichenoid changes in frictional areas, the harvest and the presence of moisture on the hands
with scaling on the dorsal aspect of the hands and feet. [197]. Photosensitivity secondary to furanocoumarins
The problem was probably caused by the use of a tends to leave areas of hyperpigmentation following
rough rope made of coir, a product of the coconut the initial eruption.
In evaluating agricultural workers and florists pre- eczematous reactions [210], some pro tein contact
senting with putative phytodermatitis, one must always dermatitis [211] and some more than one of these.
consider the possibility of allergy to agricultural Bakers with dermatitis from grain sensitivity seem to
chemicals, including pesticides, herbicides, etc. demonstrate reactivity towards antigens with mole cu-
lar weights higher than So kDa [212]. Grains include
wheat, bran, oats, rye, barley, rice and corno Bakers
Automobile Mechanics with immediate sensitivities have an increased chance
of having respiratory allergy to whole wheat [213].
Contact urticaria to latex (a plant product), usually Contact dermatitis can occur from endive, Cichor-
seen in the health professions, can occur wherever ium endivum [214, 21S], chicory, parsley [216],
rubber gloves are worn. It was reported in an Cichorium intybus [214, 21S, 217], chervil, Anthriscus
automobile mechanic [198]. cerefolium, and lettuce, Lactuca sativa [214, 21S, 218,
219, 220, 221, 222].
Bakers, Chefs and Sandwich Makers, Food-Service Workers Reactions may be seen to Cynara scolymus in market
gardeners [224], food handlers, vegetable sellers [22S],
The risk of developing occupational skin disease is and workers cleaning artichokes [223], and to parsley
higher in bakers than confectioners, and higher in and parsnip in kitchen workers [201, 204, 20S]. In
women than men [199]. The prevalence in one study Japan, persons who wrap leaves of the beefsteak plant,
was highest in the 15-year to 24-year age group, and Perilla frutescens (shiso) are prone to develop allergic
irritant reactions were more common in this group. contact dermatitis, apparently from L-perillaldehyde
However, several types of skin reactions are seen in [226]. Mustard caused contact dermatitis in a salad
food-service workers. Pro tein contact dermatitis is maker [227]. Patch testing can be done with synthetic
seen in chefs [200] and persons handling meats, such oil of mustard [228] (0.1% allylisothiocyanate).
as sandwich makers [201]. Persons so affected may or Contact urticarial reactions have been reported from
may not have contact urticaria and persons with endive (Cichorium endivum) [229], lettuce [230],
contact urticaria may or may not have an eczematous chicory, paprika (Capsicum annuum) [231] asparagus
component. The onset of protein contact dermatitis is (Asparagus officinalis) [232], sunflower seed (Helian-
often more rapid that one expects to see with an thus annuus) [IS8], tomato, carrot [200, 201], fruits,
allergic eczematous reaction. It can occur as early as mustard [233], pickle, strawberry [234] and apricot
30 min [200], and there is usually a positive scratch, [23S], as well as many spices of plant origin. See also
prick, rub or RAST test and a usually (but not always) Table 6.
negative patch test. Sometimes a scratch chamber is Irritant reactions occur to garlic, onion, citrus fruits
used to confirm the diagnosis, and sometimes a rub and potatoes [236]. Chan and Mowad [237] list a
test will reproduce it. Veien [201] obtained positive number of potential contact allergens in foods and
patch tests to onion, lettuce, potato and carrot. spices, but spices, foods and flavoring are all impor-
Janssens et al. [202, 203] summarized the (usually tant, and many of these are from plant materials.
occupational) reported cases in 1995, with the follow- Spices of plant origin known to cause sensitivity
ing plants included: almond, banana, bean, caraway, include cinnamon, nutmeg (Myristica fragrans), cloves
carrot, castor bean, cauliflower, celery, chicory, chry- (Syzgium aromaticum), vanilla (Vanilla planifolia) and
santhemum, cress, cucumber, dill, eggplant, endive, bay leaves (Laurus nobilis).
fig, garlic, hazelnut, horseradish, kiwi, lemon, lettuce, Contact dermatitis to spices [220] often accompa-
mushroom, onion, paprika, parsley, parsnip, peanuts, nies sensitivity to fragrances. Dooms-Goossens [238]
pineapple, potato and tomato. found reactions to nutmeg and mace (from Myristica
Protein contact dermatitis also can occur from apple fragrans Myristaceae), cardamom (from Elettaria
[204, 20S], and butternut squash caused what sounds cardamomum Zingiberaceae), tumeric (from Curcuma
like pro tein contact dermatitis with an immediate longa Zingiberaceae), coriander (from Coriandrum
response [206]. While it is not the subject here, protein sativum Umbelliferae), curry (from a mixture of
contact dermatitis also occurs from animal pro tein several spices including pepper, cloves, cinnamon,
[200, 202]. Testing for pro tein contact dermatitis is cardamom, coriander, nutmeg, mace and tumeric),
done by both prick testing for urticaria and either patch cinnamon (from Cinnamomum zeylanicum Laura-
testing [200] or scratch chamber methodologies [207]. ceae) and bay leaves (Laurus nobilis Lauraceae).
The contact sensitivity to grains in atopic bakers is Spices, including vanilla [240], tumeric [241, 242],
associated with immunoglobulin-E-laden dendritic cardamom [243], nutmeg, paprika and cloves, may
cells, suggesting a similar process [208]. Some grain- produce sensitivity [239]. Colophony, balsam of Peru,
sensitive patients experience aggravation of atopic fragrance mix and wood tars are used as screens for
eczema, some contact urticaria [209], some contact such reactions [244].
748 J.D. Guin
Table 6. Contact urticaria from plants
Abietic acid [441] Lemon (Citrus limon) [482,483]

Actinidia chinensis [442] Lettuce (Lactuca sativa) [229]
Agave americana L. [443] Lichens [444, 467]
Alfalfa (Medicago sativa) [403] Lilies [400]
Algae [444, 467] Limba [467]
Aloe [445] Lime [454]
Apple (Malus sp.) [204, 446, 447] Limonium tataricum [401]
Apricot and apricot stone [235] Litchi chinensis [SOl]
Arborvitae [403] Lupin [502]
Asparagus [232] Mahogany (Shorea sp.) [503]
Aspergillus (alpha-amylase) [448, 449] Maize (see corn)
Balsam of Peru [450,451,452] Malt [262]
Banana [453,454] Mango [504]
Barley [262] Melon (Cucumis melo) [50S]
Beans [454] Monstera deliciosa [403]
Beer [262] Mukali wood dust [506]
Birch (Betula verrucosa) [455, 456] Mulberry [507]
Blumea gariepina [403] Mustard (Sinapis) [232]
Bougainvillaea [457] Myrrh [467]
Brassica oleracea var. capitata [458] Nettles [508,509, 510]
Brazil nut (Bertholletia excelsa) [403] Obeche wood [511]
Buckwheat (flour) [459] Onion (Allium cepe) [200]
Bull nettle (Cnidoscolus spp.) [141] Orange (sweet) (Citrus sinensis) [482,483]
Cabbage (Brassica oleracea var. capitata) [458] Papain [512]
Camomile [460] Paprika [231]
Caraway (Carum carvi) [461] Parsley (Petroselinum sativum) [204]
Carrot (Daucus carota) [204] Parsnip (Pastinaca sativa) [204]
Castor bean (Ricinus communis) [462] Peach (Prunus persica) [455, 493]
Cauliflower (Brassica oleracea var. botrytis) [250] Peanut or peanut butter [513,514]
Cayenne pepper (Capsicum annuum) [454] Peanut, soy, wheat [515]
Celery (Apium graveolens var. dulce) [463] Pear (Pyrus commuis) [516]
Cereals [464] Perfumes [460]
Chives (Allium Schoenoprasum) [200] Phaseolus multiflorus [517]
Chrysanthemum (Chrysanthemum X morifolium, Pickles [518]
Dendranthema X cultivar) [402] Pine products (pine oil, turpentine, colophony) [467,472]
Cinchona [286] Plum (Prunus domestica) [455]
Cinnamon (cinnamic aldehyde, cassia, etc., and the synthetic Pollens [519]
equivalents of the plant products) [465, 466, 467, 468] Poppy [520]
Clover (Trifolium pratense) [403] Potato [521, 522]
Coffee (Coffee arabica) and cola (caffeine) [403,469,470,471] Rice [209, 523, 524]
Colophony [454,472] Rose [460]
Coriander (Coriandrum sativum) [207] Rosewood (Dalbergia latifolia) [525]
Corn and cornstarch (Zea mays) [308,309,403,473,474,475,476] Rouge [460]
Cotoneaster (Cotoneaster dammeri) [477], Rubber (see latex)
Cotoneaster microphyla) [403 J Runner bean [577]
Cowhage (Mucuna pruriens) [403] Rutabaga (Swede) [467]
Cucumber (Cucumis sativus) [200,234] Sarcostemna viminale [403]
Dalechampia [141] Seaweed (Lyngbya majuscula) [526]
Dogwood, bloodtwig (Cornus sanguinea) [478] Semecarpus anacardium [527]
Elm tree [399] Sesame [454]
Emetine [460] Shiitaki mushroom [258]
Endive [467] Snow in summer (Cerastium tomentosum) [341]
Eruca sativa [479] Soybean [467]
Eucalyptus pollen [480] Spices [207]
Fennel [460] Stock [528]
Ficus benjamina [467] Strawberry [234, 529]
Flax (Linum usitatissimum) [481] Sunflower [158]
Garlic (Allium sativum) [200] Teak [530]
Globe artichoke [307] Thistle (Cirsium) [403]
Golden crownbeard (Verbesina encelioides) [89] Thyme [454]
Grapefruit (Citrus paradisi) [482,483] Tilia (time) [531]
Grass (Gramineae): hay [484], straw [485] Tobacco [162]
Green bean [486] Tomato (Lycopersicon lycopersicum) [200, 467, 516]
Grevillea juniperina [487] Tragia spp. [141]
Hakea suaveolens [488] Triplochiton scleroxylon [454]
Hawthorn (Crataegus monogyna) [489] Tulips [400]
Henna (Lawsonia inermis) [490,491,492] Tumbleweed (Salsola kali) (irritant) [532]
Honey [493] Urera sp. [496]
Hop (Humulus lupulus) [494] Vanilla [467]
Iris (Iris spp.) [403] Watermelon [533]
Kiwi [495] Wheat [262]
Laportea (Laportea spp.) [496,497] Wheat bran (Triticum aestivum) [200, 534]
Larch (Larix decidua) [403,467] Winged bean (Psophocarpus tetragonolobus) [535]
Latex (Hevea brasiliensis) [498, 499, 500] Xanthium punKens [403]
An investigation of workers in a spiee factory found cally, one sees spongiosis with dermal edema and a
both irritancy and allergy, but cinnamic aldehyde perivascular lymphocytic infiltrate. This does not
seemed to be the leading problem [245]. Fragrance occur from cooked mushrooms. This may have mul-
materials mayaiso cause reactions to citrus materials tiple underlying mechanisms, as both patch tests for
in persons working with food preparation [246]. delayed hypersensitivity and prick tests for immediate
Persons reacting to a screen composed of a fragrance hypersensitivity are positive. Sometimes a generalized
mixture, balsam of Peru, wood tars and colophony toxic erythema is seen [258]. Symptomatology is not
were more than three times as likely to be sensitive to limited to cutaneous problems, as respiratory symp-
spices as those who were negative to this screen. toms sometimes occur in persons who work in
Two workers in a cake factory making Seville cakes commercial production.
were found to be allergie to anethole [247], a fiavoring
ingredient found in anise, star anise and fennel oils. Bartenders
A herbal tea maker reacted to Mesonia chinensis on
the hands and fore arms a week after he was first Bartenders can be exposed to plants in a limited
exposed to the plant, a Chinese herb used in making number of ways. Citrus peels (lemon, lime, and
jelly. In his work, he crumbled dry leaves and twigs orange) contain potential allergens [259], and psora-
with his hands and soaked them in warm water. Soda lens in lime may produce photosensitivity [259]. Other
ash, starch and sugar were added, and the mixture was decorations are possibilities, such as mint, Menthus
cooked under pressure. He then filtered, sterilized and citrata (aquatica) [260]. There are also reports of
bottled the extract [248]. Patch tests were positive to allergy to plant materials in stirring instruments. One
the wetted leaves, and the patient cleared on avoidance patient proved to be allergie to astirrer made of
and topical treatment. coconut [261]. Contact urticaria to beer was reported
Food-service workers and cooks may have reactions in a waitress who was most sensitive to malt on RAST
to lettuce [219, 221, 222, 229], potato [249], protein test [262].
contact [200-201, 204-5], citrus, tomato and carrot
[220], caulifiower [250], kiwi, onion [251], chicory and
parsnip [200-201, 204]. Basketmakers
Of all forms of contact dermatitis in chefs, sensitivity
to garlic [252, 253] is perhaps best known and An irritant dermatitis was reported in basketmakers
recognizable, and while it is usually thought of as from the plant used, osler (Salix viminalis) [263].
causing delayed hypersensitivity reactions, immediate
sensitivity is also reported [254]. In so me countries, Beekeepers
hand dermatitis in housewives (if one considers this
occupational) which seems nonspecific may actually be Beekeepers may be exposed to allergens found in
caused by garlic dermatitis in 12.9% of housewives propolis. Occupational dermatitis from balsam of Peru,
tested [252]. However, most such reactions are seen as propolis and poplar extract was reported in a bee-
occupational dermatitis, especially in caterers and keeper [264]. Persons sensitive to propolis are fre-
other food-service occupations. Caterers and chefs quently sensitive to balsam of Peru, and there is an
are also at risk for sensitization to flavors, for which overlap of reactivity with poplar buds [265].
balsam of Peru is one marker [255]. Honeybees use wax from eight wax pockets located
Photosensitivity can occur to plants containing on the ventral abdomen to build combs. The wax is
psoralens, especially where there is opportunity for pressed forward between the abdominal rings as small
intense light exposure, such as in the tropics or in fiakes, shifted forward by the legs and masticated by
those who frequent tanning salons. Members of the the jaws. Finally, it is laid down as small mounds for
Rutaceae (persian lime, and Umbelliferae (celery [256], the worker bees to use in building the combs. Propolis
parsnip, dill, etc.) are frequent sourees. is a strongly adhesive resinous material collected from
Mushroom dermatitis can be seen in those exposed trees such as poplar, alder, birch, willow and horse
occupationally [187], as the allergy seems to be limited chestnut. This is carried back to the hive on the
to the uncooked material. In Japan and certain other bristles of the bees' hind legs, where it is mixed with
countries, a characteristic eruption follows consump- varying quantities of wax to varnish combs, stop holes
tion of an edible mushroom, Lentinus edodes [257], if it and seal cells of the combo Rothenborg described a
is uncooked. This begins with an erythematous, beekeeper allergie to poplar leaves and resins as well
papular rash in lines suggestive of finger marks some as raw beeswax from his hives, but who had a
1-2 days after the mushrooms are consumed. Exter- negative test to purified beeswax. Routine testing
nally, it fits a hand-transfer pattern, but it is best showed positive responses to balsams of Peru and
known as an eruption following ingestion. Histologi- Tolu [266].
750 J.D. Guin
Botanist tenance workers mowing and repairing where vegeta-

tion is present. One Highway Department employee in
Although botanists working in both the field and my practice had actinic retieuloid with Compositae
herbaria are at risk to develop or elieit plant-induced sensitivity as an important component. Persons who
contact dermatitis, there are relatively few reports. work on roads and bridges often encounter irritant
Perhaps this is because this occupation is uniquely plants as well, such as nettles, thorns, etc.
equipped to know the cause of the eruption and to
avoid contact through recognition. I have heard Cosmetics workers, Cosmetologists, Aroma Therapists
botanists discuss personal problems from Urticaceae
(Urtica, Laportea), Phacelia [25], exotic Anacardiaceae Natural plant materials have been used in perfumery
[37, 40, 267, 268] Umbelliferae (where phototoxicity is for many years. The use of natural products in
likely) and almost any other plant is known to cause cosmetic manufacture has exploded, but reactions to
irritant or allergie contact dermatitis. While Laportea these ingredients have only begun to be reported [270].
canadensis (Urticaceae) causes quite an urtiearial The use of natural materials in cosmeties especially
reaction, the only persons I have encountered who includes many plant materials, which are often used in
either knew about it or had experienced the problem the United States for their putative pharmacologic
were botanists working with wetland plants. The properties, as natural materials are exempted from the
reason is that most people would avoid the muddy regulatory scrutiny of the U.S. Food and Drug
soil in which the plant grows, but the botanist must Administration. Many are listed in the International
examine plants growing there, and is consequently at Cosmetie Ingredient Handbook [271], and the subject
risk. Phacelia caused contact dermatitis in six individ- has been reviewed in a number of industry publica-
uals who participated in cultivation trials [269]. tions [272, 273], some of the known problems have
Many years ago William T. Gillis, a noted authority been covered by Nater and DeGroot [274]. However,
on the genus Toxicodendron, died when we were the use has so increased recently that any publication
preparing an exhibit, and Dr. John Beaman and I were on the subject is likely already out of date, and the next
going through his materials. Dr. Beaman introduced edition of the International Cosmetic Ingredient
me to a famous botanist who warmly shook my hand, Handbook is said to be much larger than the current
until Dr. Beaman mentioned that I had been working one because of the content of botanicals.
with Dr. Gillis, whereupon I felt my hand flung toward An aroma therapist with hand eczema on patch
the ground. It seems that Dr. Gillis, who was not testing was sensitive to Tagetes (marigold), causing a
sensitive to poison ivy or its relatives, had handled flare in her hand eczema [275]. Sensitivity to natural
herbarium specimens with impunity and had managed plant materials such as fragrances may cause occu-
to transfer the antigen by shaking hands with this pational contact sensitivity, not only in that occupa-
particular botanist, who was very allergic. Many field tion [276] but in any work where such products are
botanists seem to avoid collecting toxicodendrons used or made, including manufacturing, sales and
because of the problems associated with them. Bota- applieation. Cananga odorata (ylang-ylang) [277],
nists collect specimens in a "press", where the Abelmoschatus moschatus (hibiscus, musk mallow)
botanical material is placed between layers of blotters, [278], Citrus aurantium (bergamot) [279] Levisticum
cardboard and often newspaper. The blotters and officinale (Angelica levisticum, lovage) [280], Lev-
paper between Toxicodendron specimens in the plant andula officinalis (lavender) [281, 282] and Cinnamo-
press show typical black spots where the sap has mum zeylanicum (cinnamic aldehyde in deodorant)
contaminated the paper. This black mark is, of course, [283], would be examples. Fragrance mixes are a
allergenie, and it shows that the person collecting the useful screen for many patients sensitive to fragrance
specimen is at risk unless special precautions are materials [284] and may detect many allergies to
taken, such as wearing vinyl gloves and avoiding hand natural products as well. A helpful screening series
transfer. A number of persons have developed derma- might include a fragrance mix, balsam of Peru,
titis from toxic Anacardiaceae examined as herbarium turpentine oxides, wood tars and one of the Comp-
specimens, but such cases seldom present to physi- ositae antigens.
cians for treatment and are not generally reported.
Dock Workers
Construction
Dock workers handling coffee beans may be exposed to
Construction workers building Disney World experi- castor-bean antigens at the same time, as the latter
enced an epidemie of contact dermatitis from poison species is often a contaminant [171]. Malten described a
sumac [145]. Compositae dermatitis can also be seen in dock worker who reacted to barley in cattle fodder and
highway workers in this country, especially in main- flared when handling the plant [285].
An airport warehouseman developed contact urti- Forestry and Forest-Fire Fighters

caria from airborne exposure to Cinchona from a
water-soluble component of dust from burlap bags of
Persons who must encounter forest vegetation when
the dried bark [286].
fighting forest fires are exposed to the same antigenic
materials as forestrty workers, but they are usually not
Farm Workers in a position to take time to identify the plants and
avoid them. Reactions to poison ivy, oak and sumac
See the section entitled Agricultural Workers. are discussed by Epstein [145], and prevention meth-
ods are mentioned by Oltman [57].
Food Processing According to Mitchell [99], woodcutter's eczema
was defined in France and has been reported from
See also the section entitled Bakers, Chefs and Salad Italy, Spain, Czechoslovakia and the Pacific Northwest
Makers. [183]. One can add Portugal to that list [185]. Wood-
Workers handling nuts may break out on contact cutters working in the forests of the Pacific northwest
with to macadamia nuts [287] and it is well known that are prone to develop sensitivity to SQT As because of
cashew dermatitis may occur in workers due to exposure to Frullania nisquallensis [299] (a liverwort)
contaminants from the shell [288, 289, 290]. Allergies living on decaying timber [4, 183, 99]. The time
in coffee workers may be either immediate or delayed. between starting work and developing sensitivity
Contact urticaria and contact dermatitis have been ranges from a few months to 15 years. In sensitive
reported in coffee workers [291], and this is sometimes persons, the eruption appears on the face and forearms
[172] (but not always) [292] caused by sensitivity to above the wrists within a few days after working in the
contaminant castor beans. A stockroom worker in a forest. Since these workers wear gloves, the hands are
coffee-roasting plant developed long-Iasting urticaria. commonly spared until the hands become wet inside
The main source of the immediate reactions is said to the gloves. Patients may develop the eruption in new
be green coffee beans. Coffee plantation workers in areas such as the lower extremities when the skin
India have been reported to develop lupus erythema- be comes wet from rain. Fallers (who fell trees) and
tosus-like periungual telangiectasia [293]. hookers (who encircle the tree with chains) are more
Of the Cruciferae, mustards are known irritants, and prone to become allergic. However, Mitchell has seen
contact urticaria and/or protein contact dermatitis dermatitis in buckers, top pers, choker-setters and
may occur to mustard (Brassica nigra) and caulifiower scalers, though less frequently. The condition is more
(Brassica oleracea) [201] in chefs, salad makers and common where humidity is high near the coast and
others preparing and handling food [233]. Celery less prominent in the drier and colder interior forests.
dermatitis occurred in a food-processing worker Some workers who can not work on the coast can work
[294]. Radish (Raphanus sativus) contains allyl and in the interior. Fallers are said to be more highly paid,
benzyl isothiocyanates that caused allergic contact so many of those sensitized have had to move to
dermatitis in a waitress mixing salads [295]. different jobs at lower wages [99].
Many spices are plant derived and may cause Frullania also is present in other parts of the United
allergic contact dermatitis. A worker in a food- States, but generally the plant does not grow in such
processing plant reacted to carnosol extracted from high quantities. However, I have seen persons exposed
rosemary (Rosmarinus officinalis) [296]. Sensitivity to in Arkansas to logs and firewood who reacted to
spices is covered in more detail in the section entitled alantolactone and other SQTLs (Fig. 13). Alantolactone
Bakers, Chefs and Salad Makers. Sixty spice grinders has been used by Mitchell as a marker for Frullania
studied had no allergic skin problems [297], and while sensitivity [99], but it may not be as helpful in
I have seen food-processing workers who were detecting sensitivity to Compositae [300]. Of seven
allergic to spices, the problem is probably not patients sensitive to Frullania dilatata, Quirce et al.
common. had three whose exposures were likely occupational;
Workers in corn-processing plants commonly de- alantolactone detected only two of seven of the
velop an irritant prurigo-like eruption, mostly of the sensitivities, while the SQTL mix found six of seven
hands and forearms mostly but sometimes on the legs [301]. About three in four will react to 1% D-usnic acid
and foot if there is no protection of these areas. in petrolatum [302], perhaps because of concomitant
Moisture seems to be aggravating and gloves worn may lichen exposure, with a broadening of the allergic base
protect the skin, but the "milk" that gets under the (extended allergen syndrome).
gloves often becomes a problem. This seems to be a Lichen sensitivity to "reindeer moss" (Cladonia
low-grade irritant from continuous exposure with stellaris) is sometimes called woodcutter's disease in
marginal protection under wet conditions [298]. Europe and "cedar poisoning" or "pine poisoning" in
752 J.D. Guin
the stern but were negative to the leaf [307]. An

employee of a garden and pet shop reacted to bran and
oats, contained in animal feed [210].
Healthcare Workers
In recent years, an epidemie of latex allergy has

occurred in healthcare workers. While this may not be
considered an allergy to plants, in most cases it is an
allergy to the latex of Hevea brasiliensis and sometimes
to cornstarch [308, 309], the principal ingredient of
glove powder. Hamann et al. [310] have recently
studied the prevalence of latex allergy in dental
Fig. 13. Contact dermatitis to Frullania from exposure to hard- workers and have found that up to 9% of dental
wood cut for firewood
assistants have immediate contact allergy to latex.
Cross-reactions are said to occur from banana, avoca-
the United States. The risk of sensitization to this plant do, peach [311], kiwi and pineapple. Taylor's list of
is considered low, but there are probably more cases foods possibly cross-reacting with latex also includes
among "lichen pickers". Sensitizing components in- kiwi, chestnut, hazel nut, peanut, celery, melon, potato,
clude atranorin, fumarprotocetraric acid, evernic acid, papaya, figs, passion fruit, tomato, grapes, cherries,
(-) and (+) usnic acid and stictic acid [303]. Lichens apricot, nectarines and pI ums [312]. Nurses have
and oakrnoss [137, 304] are also potentially photosen- become sensitized to lichens by applying scented
sitizing [138, 305]. The specific lichens to which materials to patients [313].
woodcutters are exposed will depend upon the location
Lawn (are
[186]. Forestry workers mayaIso become allergie to
moss along with Frullania and lichens [306].
In the United States the greatest risk in lawn-care
workers is probably Toxicodendron dermatitis. A
Grain Workers and Elevator Operators unique form of contact dermatitis may be seen in
persons cutting weeds with apower string trimmer
Questionnaire data from operators of grain elevators [126,314]. This instrument, often called a "weed eater,"
revealed that more than half had complaints of itching is capable of throwing the allergen out of the cut plant
after exposure to dust from badey and oat dust, but by centrifugal force so it can cause both phytoderma-
this was of a relatively short duration. About 13% titis and phytophotodermatitis.
complained of a rash after exposure, and younger Lawn-care workers are also at risk of developing
workers were more at risk. Compositae dermatitis, including reactions to dande-
lion and other weeds [315]. Groundskeepers constitut-
Grocery Workers ed the occupational cases of dandelion dermatitis in
one series [316]. Gardeners (or perhaps more accu-
An epidemie of phytophotodermatitis in grocery rately, groundskeepers) represented the occupational
workers was widely reported [128-9] [195-6]. Grocery cases of dandelion dermatitis in another series [316].
clerks exposed to cut stalks of celery developed Dandelion cross-reacts with laurel and Frullania [317].
phytophotodermatitis after being exposed to high Yarrow (Achillea spp., especially A. millefolium) tends
levels of sunshine or visiting a tanning salon. The to increase the concentration of the principal sens i-
variety of celery investigated had levels of psoralen tizer, alpha-peroxyachifolid and other SQTLs during
adequate to produce phototoxicity without ring-rot withering, so that particles in the air may be a problem.
infection, which had caused phytophotodermatitis in Testing for yarrow detected about 50% of German
farm workers harvesting infected celery. The study by patients allergic to Compositae [318].
Seligman et al. suggested that one couId see this at low
but adequate levels provided there was enough expo- Massage Therapy
sure to the proper wavelengths of light.
A grocer developed allergie contact dermatitis from Ointments used in massage therapy may sensitize the
an artichoke, Cynara scolymus. Patch tests were therapist or customer. Natural fragrance materials are
positive to the stern as weIl as an alcoholic extract of among the causes [319].
Metalworkers stroemeriaceae (Alstroemeria), Lilaceae (tulip and

hyacinth), Amaryllidaceae (narcissus), and Caryophyl-
A metalworker with occupational hand eczema from laceae (carnation) [7,338].
cleansing parts broke out in response to chamomile
tea, used to treat the rash [320]. Irritant Readions
Musicians Irritant reactions take many forms. Mechanical irrita-

tion is common, as most retail florists are exposed to
A saxophonist [321] and a clarinetist [322] were thorns on roses on a regular basis. However, most
reported to be allergie to cane reed (Arundo donax). never report the injury. Irritant reactions also may be
A flautist was allergie to geranium oil in a herbaI seen to Cactaceae, which can produce puncture
extract contained in a lip balm [323]. Musicians have wounds, irritant papules and granulomas [142-3].
reacted to colophony [324, 325, 326, 327] and propolis Fremontodendron (a more-or-Iess evergreen shrub)
[328] (in the varnish on the instrument). Musicians produced irritant dermatitis in horne gardeners who
mayaIso break out in response to woods; this topic is handled the plant [339]. An Australian study found
covered in another chapter. that Apalochlamys spectabilis, Wisteria sinensis and
some Grevillea species were irritant, causing "plant-
Nursery Workers, Florists, Flower Seilers hair dermatitis", and called attention to penetrating
and Horticulturists and irritating pod spines of Brachychiton spp. (ku-
rrajongs and relatives) and Lagunaria patersonii
Florists are exposed to almost every allergenie plant (Norfolk Island hibiscus or pyramid tree), often
sold or used in the shop or raised in the nursery. plan ted as ornamental street trees [340].
Paulsen et al. [329] consider floristry to be a rather Dieffenbachia, or dumbcane, available in many
risky occupation, as the lifetime occurrence of sensi- shops, can cause irritant reactions because of calcium
tivity of those so employed is almost 20%. They found oxalate crystals. Hyacinth also causes an irritant
that those with mucosal symptoms, those with a dermatitis from calcium oxalate crystals [109, 115].
previous history of plant dermatitis and those exposed Reactions to the Euphorbeaceae [341], or spurges,
to Compositae were at increased risk. Studies of sometimes sold as ornamentals are more often irritant,
national and regional occupational disease and ques- although allergie reactions to some have been reported.
tionnaire data seem to confirm the risk for floristry A review of this genus was presented by Webster, who
and agriculture workers [330-334]. In a large study of is a specialist on the taxon [}42]. Some species sold as
German retail flower seIlers, half had allergie contact houseplants and ornamentals can be highly irritating,
dermatitis [3]. Of 151 florists in Portugal, about three in including Euphorbia splendens (crown of thorns),
ten had hand dermatitis, but the prevalence was only E. lactea (candelabra cactus) and E. tirucalli (monkey
about one in eight in a like number of shop assistants pencil tree). Spurges contain phorbol and diterpene
[335]. In an American study of 462 florist shops, about esters [343] which in some species can be incredibly
one-third had at least one employee with a rash. irritating.
However, perhaps not all of these are allergie. Of the Daffodils induce an irritant dermatitis in persons
25% found in another study, 25% were irritant and harvesting them [344], and in nursery workers [345] and
some reacted to pesticides, but only 5% were found to retail florists [3] as weIl. The eruption occurs chiefly
have allergie contact dermatitis [10]. where the hand and forearm are exposed to sap from the
The prevalence of allergie contact dermatitis among broken sterns. The workers are paid by the bunch of ten,
retail florists and flower seIlers depends upon the and they hold the bunches while reaching down to snap
source and the country where the study was done. off the next flower stern. The finger webs catch on the
In the United States, Alstroemeria is a common cause sharp leaves when sliding down the stern, and granu-
[106], in Finland, Compositae and Alstroemeria [336] lomas may develop there. Paronychias are seen, and the
and in Germany, Compositae, followed by Al- irritant rash on the hand and fore arm is characteristic
stroemeria and tulip [3]. In Manchester, UK, a study [344]. Trumpet daffodils are more like to be a problem
of retail florists suggested irritant dermatitis from than the highly scented, multiflowered varieties. Aller-
daffodil was the most common cause of plant derma- gie reactions occur [3], but seem to be rare.
titis, followed by Primula, Christmas trees and Cup-
ressus used to make wreaths [334]. Lammintausta et al. Pseudophytodermatitis
[334] found 12 occupational cases, mostly in gardeners
or florists, of allergy to decorative plants, especially Pseudophytodermatitis occurs from pesticides and
Compositae (chrysanthemum, elecampane, Gerbera otlIer chemie als as weIl as parasites. While ferns can
and Tanacetum parthenium [feverfew] [337]), AI- cause sensitivity [8, 346], in one shop, where persons
754 J.D. Guin
making wreaths from fern (Polypodium) developed first on sites of contact and later spreading to the face
symptoms, the source proved to be a mite infestation and neck [359]. This patient also reacted to chamomile,
[347]. A nursery worker growing begonia was actually sunflower, magnolia and laurel, all of which contain
allergie to benomyl [348]. SQTLs. A male florist who became allergie to chrysan-
themum changed the flowers he grew commercially to
Allergie Contact Dermatitis Trachelium caeruleum (Campanulaceae), only to be-
co me allergie to that plant as weIl [360]. The presenting
Some Philodendron spp. may contain enough alk(en)yl eruption was an eczema of the hands and flexural
resorcinols (similar to certain of the Anacardiaceae) to forearms.
cause contact dermatitis in nursery workers, and in A breeder and grower broke out to feverfew crossed
so me parts of the US such as Hawaii where the plants with chrysanthemums, aster, Gaillardia, Arnica and
grow outdoors they may cause an occupational prob- true chamomile. Sensitivity to chamomile (Anthemis
lem in those who cut or remove them [349]. So me nobilis) is said to sometimes cross-react with nettles
other exotie plants cross-react with Toxicodendrons. [361]. Gaillardia, as with sunflower, can cross react
The seed of Ginkgo bilobia can be a problem, although with Arnica [362].
female plants are seldom sold commercially because of An inspector at a flower auction was found to be
their odor and other unpleasant qualities seen in the allergie to saffiower, Carthamus tinctorius (Comp-
seed of that species. This is technically a pulpy seed ositae). She was also allergie to iris (Iridaceae). Two
and not a fruit, as Ginkgo bilobia is a gymnosperm. In Compositae-sensitive florists reacted to blazing star,
tropical areas, the cashew (Anacardium occidentale), Liatris spicata (Compositae, Eupatorium family) [363].
mango (Mangiferica indica) and other species can van Ketel described two persons working with flowers
cross-react although the toxic component is more who were sensitized to chamomile (Matricaria cha-
localized within the fruit or plant. Certain Proteaceae momilla) [364, 365]. A hobby garden er was allergie to
sold as ornamentals, e.g., Grevillea robusta and both Anthemis nobilis and Sisymbrium officinale
Grevillea robyn gordon, also cross-react with the (Brassicaceae), with a positive test response [366,367].
Toxicodendrons [350, 351]. Three presentations are seen of dahlia dermatitis
Members of the Araceae are commonly sold for [368, 369]: hand eczema, facial eruptions and an
ornamental use in the horne and office [351a]. So me airborne pattern. Patients were tested with 1:10 dilu-
species of Philodendron contain alkenyl resorcinols tions of an alcohol extract of the flowers, leaves, sterns
[349] which are, rarely, reported to cause allergie and whole plant [370].
reactions [352]. (Schindapsus aureus) [353] (devil's ivy) Elecampane (Inula helenium) contains SQTLs and is
has also been reported to cause dermatitis [353]. Rothe a source of alantolactone. Testing to this plant can
reported one gardener who reacted to Hoya carnosa result in sensitization from short ether extracts [371].
(Asclepiadaceae) but was also allergie to Philodendron The configuration (-/+) does not cross-react in that
spp., pothos, Epipremnum aureum, Scindapsus aureus allergen l372]. Liatris may cross react with chrysan-
[353] and Monstera deliciosa, all Araceae. However, this themum [363].
patient was also allergie to Pelargonium (Geraniaceae). Reactions to magnolia are rare, but a nursery
Sensitivity to Araliaceae, e.g., Hedera helix, can occur worker had a severe sensitivity associated with severe
in gardeners [354] and can mimie the rash from poison liehen simplex chronicus of the face. He was cured by
ivy [23]. Other members of the Araliaceae include wearing disposable vinyl gloves, which allowed hirn to
Hedera canariensis [355], Schefflera, Fatsia and Tetrap- avoid contact with the plant and continue working
anax [356]. [86].
When presented with an obvious contact dermatitis
Compositae in a retail florist, it is wise to test the patient to all
plants and all nonirritant varieties that are sold in the
Compositae dermatitis was covered in more detail in the shop. One may see contact dermatitis to carnation
first section. Farmers are perhaps more likely to become (Dianthus caryophyllus, Caryophyllaceae) [338], Afri-
allergie to weeds, while florists often break out to can violet [373], many genera of Araceae, tulip and
chrysanthemum [357,358] and other flowering species. others. Often sensitivities are multiple, so finding one
Many such patients experience multiple sensitivities, allergy may not solve the problem. There are many
either as a concomitant or cross-reaction [157], and plants known better to growers and gardeners than to
sensitivity can be severe [6]. Gardeners (or perhaps the public to which florists, horticulturists, nursery
more accurately, groundskeepers [315]) represented the workers and others have a greater-than-usual oppor-
occupational cases of dandelion dermatitis in one series. tunity for exposure. This might include Cotoneaster
Chrysanthemum dermatitis in a 66-year-old female spp. (Rosaceae) [374], Coleus spp. (Labiatae, flame
hortieulturist caused a dermatitis on exposed sites, nettle) [375], Trachelium caeruleum (Campanulaceae),
Wedelia trilobata (376), Cynara cardunculus (wild Urticaria

artichoke) and Ixodia achillaeoides (firebush) [377].
In nursery workers and florists, Hydrangea [378,379, A hobby garden er developed delayed urticaria from
380] can cause contact dermatitis, especially of the elm, Ulmus spp., with inhibition by aluminum sulphate
hands [381], often starting on the fingers [382] and [399]. Other plants causing contact urticaria in this
sometimes starting around a cut on the finger. group include Lily longifolium and tulip [400],
Hydrangenol, (J,4-dihydro-8-hydroXY-3-(4-hydroxy- Limonium tartaricum (from dried flowers) [401], and
phenyl)-isocoumarin) has been reported as a likely chrysanthemum [402]. For a more complete listing of
sensitizer [383, 384]. This is a strong sensitizer, contact urticaria to plants see Lahti [403] and Table 6.
producing positive reactions in sensitized laboratory
animals to open application of 0.05 ml of hydrangenol Laboratory Workers
(0.01% in acetone).
Reactions to tulip occur in field workers exposed to Cachrys libanotis (Umbelliferae) caused a phytopho-
the bulbs, in whom presentation of tulip finger is todermatitis in a laboratory worker gathering the
characteristic [108]. It can also be seen in retail florists plant. The plant contains furocoumarins (psoralens)
exposed to the cut flower with the same general [404]. Cannabis sativa caused urticaria in a forensic
presentation, with the thumb and adjacent fingers laboratory worker [405].
showing a prominent contact dermatitis in a grip
distribution. Where the bulbs are handled in quantity, Office Workers
the dust from the outer layers may cause airborne
contact dermatitis [385]. Allergenic plants kept around the office are a risk
Alstroemeria f386] dermatitis is well known in mainly to those caring for them. Ayres and Ayres [352]
florists, where the clinical picture resembles tulip described a building inspector who broke out to
finger. In one floricultural center, it took about 3 years Philodendron, however. Members of the Araceae
on the job to begin to see allergy [367]. The clinical (Diffenbachia, Philodendron, etc.), Araliaceae (Hedera
presentation resembles tulip finger. Environmental helix and H. canariensis [406, 407, 408), Schefflera
contamination may also occur from Alstroemeria in arboricola [409, 410), Brassasia actinophyla [411],
workers, causing fomite transfer [107]. Polyscias fruticosa), Gesneriaceae (Saintpaulia) and
Codiaeum variegatum is commonly called croton, Cactaceae (Opuntia microdasys) would be examples.
although it does not have the irritant properties of
"croton oil", a derivative of Croton tiglium. However, Pharmaceutical Industry
it can be allergenic in nursery workers [388, 389] and
others commonly exposed to the plant, where the Pharmaceutical workers are sometimes exposed to
allergen seems to be in the sap [390]. Poinsettia latex plant materials. Plants reported to have been a problem
elicited positive reactions in 4 of 31 floral workers include Arnica longifolia [157] and A. montana (412),
tested, and 3 of 4 were positive to an aqueous extract of atropine (Duboisia spp.) [413] psyllium (Plantago
the leaves [391]. Two positive reactions to Aeschynan- spp.), [414] Vinca alkaloids [415, 416], co deine [188],
tus pulcher (family Gesneriaceae) were found in and Cinchona. The last occurred in warehousemen
nursery workers [390]. with urticaria in an airborne distribution.
Field workers may be exposed to allergenic plants
such as jasmine f392], leatherleaf fern (8), carnation Servicemen
[338] and Paeonia (Paeoniaceae) [393]. A mushroom
picker in nursery developed hand eczema from Of 23 military personnel tested to only one species of
allergic contact dermatitis to Agaricus bisporus, while grass, two were positive on prick testing, and both were
controls were negative [394]. A hobby garden er broke relevant. Three had positive patch tests, none of which
out to Verbena (Verbenaceae), which she applied as a were relevant [427]. However, four military personnel
poultice [395]. Orchid sensitivity is uncommon [396] reported by the same group in 1997 had reactions to
but can occur in persons chronically exposed [397, nonpolar fractions ofAxonopus compressus, one to the
398]. volatile fraction, one to the non polar fraction of
Primula dermatitis is usually seen outside the Imperata cylindrica as well as the polar and nonpolar
occupational setting. However, those raising the plant fractions of Panicum maximum and Pennisetum
are at some risk. Primula dermatitis takes several purpureum, and one to all fractions of Ischaemum
forms, especially on the hands and face, but it may also muticum [428].
be widespread. Patch-test reading of tests to pnmm Perhaps the best-known cases of military contact
ostensibly are most likely to be positive on day 4, dermatitis to plants were presented by Livingood in a
according to some [117]. report in 1943, after he investigated cases of Allied
756 J.D. Guin
servicemen in India who developed contact dermatitis Tree Surgeons

from alaundry mark made from Semecarpus ana-
cardium. The persons laudering their cloth es were Propolis allergy may weIl be sensitivity to poplar buds,
called Dhobis, and the condition was named by as this tree is a principal source of propolis for bees
Livingood et al. Dhobi mark dermatitis [429]. (see the section entitled Beekeepers). One such patient,
In 1943, an army unit was given the task of who frequently climbed poplar trees, developed a
establishing a beach defense at night, and in the dermatitis of his headband and earplugs, which cleared
process encountered the manchineel tree, Hippomane while he was away from the job. When exposed,
maneineIla, in the dark. In half of the servicemen, however, he developed eczema of the face, neck,
conjunctivitis with severe pain and edema occurred fingerwebs, antecubital fossae, perineum and waist.
when the sap was transferred to the eyes. Many others His allergy was apparently to poplar buds, but patch
broke out after waking up on the sandy beach after testing showed responses to balsams of Peru and Tolu,
removing their shirts and trousers and sleeping on fragrance mixes, wood tars, eugenol and isoeugenol.
them. About 60 soldiers on maneuvers were so He later was shown to be allergic to 3-methyl-2-butenyl
severely affected that they were considered unfit for caffeate (0.1% in petrolatum) as well as a mixture of
duty [430]. Of course, one may see reactions to poison caffeic acid pentenyl esters [431]. Benzyl isoferulate,
ivy and any other allergenic or irritant plant that is also found in balsam of Peru, is another strong
present where the military has to operate. sensitizer. Tree surgeons in the United States are also
at risk of being exposed to poison ivy and, on the west
Textile and Flax Workers co ast, to western poison oak. Eastern poison oak does
not climb trees. Poison sumac (Toxicodendron vernix)
Textile workers are exposed to a number of irritants can be a problem in limited areas, such as around
and allergens. Plant materials are commonly used, but Mobile, Alabama and Pensacola, Florida, where poison
irritant dermatitis is perhaps more common with wool, sumac grows as a mature tree.
which is of animalorigin, than with most plant In Hawaii, poison ivy is not a problem, but tree
materials. However, irritant dermatitis has been re- trimming there may cause areaction to Philodendron,
ported from persons working with linseed oil and flax which contains an alk(en)yl resorcinol [349, 432].
[417,418,419, 420, 421, 422]. Exposure to textile fibers
can cause irritant reactions, usually on the hands [423]. Woodcutters
Reactions to other additives are published occasional-
ly, e.g., a textile worker who reacted to tamarind flour See the section entitled Forest Workers.
[424].
Woodworkers
Tobacco Workers
Allergy to woods is covered in another chapter.
Rycroft described eruptions in tobacco workers who Japanese woodworkers who work with a natural
handle the leaf much of the day. Hand dermatitis is lacquer from Toxicodendron vernicifluum are often
more common in cigar workers than cigarette workers known to demonstrate allergy when first coming to
because the latter work is more automated. Allergic work, then develop hardening on continuing work
contact dermatitis occurs but is rare, and it tends to [43]. The lacquer is used in places that may put others
occur in factory workers (and agricultural workers; see at risk of exposure, although heat treatment of the
section above) rather than consumers. A number of lacquer seems to render the substance less allergenic
persons patch tested have produced mild reactions that [433].
have mostly been interpreted as irritant, and both false Treatment of occupational illness may cause sensi-
positive and false negative reactions are problems tization. With the use of botanical material for its
[165]. As with most cases of industrial hand eczema, pharmacologic properties, one may see patients who
secondary irritation and contact sensitivity tends to break out to plants in occupations where there should
complicate the picture and requires evaluation of each not be an opportunity for exposure. For example,
patient [425]. A study of the industry by Samitz in 1949 reactions to Arnica montana, Matricaria chamomilla,
found most cases to be mild, but a few were severe. He Echinacea angustifolia, Hamamelis spp., Calendula
concluded that the greatest majority of the thousands officinalis [434] and Melaleuca alternifolia are reported
of cases were caused by moisture from the paste and/or in "alternative treatments". The latter is said to cross-
the alkalinity of tobacco [426]. For those allergies, the react with colophony and contains eucalyptol, which
causative allergen has not been identified, but it is not caused systemic contact dermatitis in one patient [435,
nicotine. 436].
References 28. Guin JD (1995) Plant dermatitis. In Guin JD (ed) Practical

contact dermatitis: a handbook for the practitioner. Mc-
Graw-Hill, New York, pp 497-517
1. Shmunes E, Keil JE (1983) Occupational dermatoses in South 29. Kligman AM (1958) Poison ivy (Rhus) dermatitis. Arch
Carolina: a descriptive analysis of cost variables. J Am Acad Dermatol 77:149-180
Dermatol 9:861-866 30. Guin JD (1978) Poison ivy (Rhus) dermatitis. J Indiana State
2. Halkier-Sorensen L (1996) Occupational skin diseases. Med Assoc 72:774-775
Contact Dermatitis 35[suppll]:1-120 31. Guin JD (1983) Poison ivy dermatitis in winter with an
3. Hausen BM, Oestmann G (1988) Untersuchungen uber die example of filial contact dermatitis. J Indiana State Med
Haufigkeit berufsbedingter allergischer Hauterkrankungen Assoc 76:184
auf einem Blumengrossmarkt. [The incidence of occupa- 32. Sulzberger MB, Katz JH (1943) The absence of skin irritants
tionally-induced allergie skin diseases in a large flower in the contents of vesides. US Naval Med Bull 41:1258
market]. Derm Beruf Umwelt 36:117-124 33. Guin JD, Beaman JH (1986) Toxicodendrons of tl1e United
4. Mitchell JC, Schofield WB, Singh B, Towers GH (1969) States. Clin Dermatol 4:137-148
Allergy to Frullania. Allergie contact dermatitis occurring in 34. Wahlberg JE, Lovell CR (1996) Poison wood dermatitis in a
forest workers caused by exposure to Frullania nisquallen- future prime minister: Contact Dermatitis 34:363
sis. Arch Dermatol 100:46-49 35. Hurtado I, Medina JD, Dao L, Urbina C (1982) Studies on the
5. Shelmire B (1939) Contact dermatitis from weeds, patch skin -sensitizing properties of tl1e "pepeo" tree, Mauria
testing with their oleoresins. JAMA 113:1085-1090 puberuIa (Anacardiaceae). J Am Acad Dermatol 7:341-345
6. Schmiedekampf G, Schauder S, Berger H (1978) Aktinisches 36. Ale SI, Ferreira F, Gonzalez G, Epstein W (1997) Allergie
Retikuloid bei einem Blumenhandler [Actinie reticuloid in a contact dermatitis caused by Litl1raea molleoides and
florist]. Derm Beruf Umwelt 26:95-96 Litl1raea brasiliensis: identification and characterization of
7. Lamminpaa A, Estlander T, Jolanki R, Kanerva L (1996) the responsible allergens. Am J Contact Dermat 8:144-9
Occupational allergie contact dermatitis caused by decora- 37. Hurtado I (1986) Poisonous Anacardiaceae of South Amer-
tive plants. Contact Dermatitis 34:330-335 iea. Clin Dermatol 4:183-190
8. Hausen BM, Schulz KH (1978) Polyvalente Kontaktallergie 38. De Hurtado I (1970) Studies on the biologieal activity of
bei einer Floristin SO [Polyvalent contact allergy in a florist] Rhus striata. 3. Toxicity vs. hypersensitivity of dermal
Derm Beruf Umwelt 26:175-176 reactions in guinea pigs to Rhus striata ("manzanillo")
9. Ingber A, Menne T (1990) Primin standard patch testing: extracts. J Invest Dermatol 55:94-100
5 years experience. Contact Dermatitis 2j:l5-19 39. Heyl T, Gorst-Allman CP, Wells MJ, Fourie DM, Sevoir K,
10. Santucci B, Picardo M (1992) Occupational contact derma- Keene AR, Steyn PS (1987) Smodingium dermatitis. S Afr
titis to plants. Clin Dermatoll0:157-165 Med J 71:440-441
11. Kuach DL (1987) Field focus: handle witl1 care. Greenhouse 40. Whiting DA (1986) Smodingium. Allergenie Anacardiaceae
Grower 5:86-90 in South Africa. Clin Dermatol 4:204-207
12. Paulsen E (1998) Occupational dermatitis in Danish gar- 41. Findlay GH, Whiting DA, Eggers SH, Ellis RP (1974)
deners and greenhouse workers (II). Etiological factors. Smodingi~m (African "Roison ivy") dermatitis. History,
Contact Dermatitis 38:14-19 comparatlve plant chemlstry and anatomy, dinical and
13. Mitchell JC, Calnan CD (1978) Scourge of India: Parthenium histological features. Br J Dermatol 90:535-541
dermatitis. Int J Dermatol 17:303-304 42. Rademaker M, Duffill MB (1995) Toxicodendron succeda-
14. Mitchell J, Rook A (1979) Botanical dermatology: plants and neum (Rhus tree), New Zealand's poison ivy. Contact
plant products injurious to the skin. Greengrass, Vancouver Dermatitis 33:357-358
15. Kingsbury JM (1964) Poisonous plants of the United States 43. Kawai K, Nakagawa M, Kawai K, Liew FM, Yasuno H (1991)
and Canada. Prentice-Hall, Englewood Cliffs Hyposensitization to urushiol among Japanese lacquer
16. Lampe KF, McCann MA (1985) AMA handbook of poison- craftsmen: results of patch tests on students learning tl1e
ous and injurious plants. American Medieal Association, art of lacquerware. Contact Dermatitis 25:290-295
Chicago 44. Beaman JH (1986) Asian Anacardiaceae. Clin Dermatol
17. Guin JD, Beaman JH (1986) Plant dermatitis. Clin Dermatol 2:191- 203
4:1-226 45. Guin JD (1980) The black spot test for recognizing poison
18. Baer H (1986) Chemistry and immunochemistry of poison- ivy and related species. J Am Acad Dermatol 2:332-333
ous Anacardiaceae. Clin Dermatol 4:152-159 46. Mallory SB, Hurwitz RM (1986) Black-spot poison-ivy
19. Resniek SD (1986) Poison-ivy and poison-oak dermatitis. dermatitis. Clin Dermatol 4:149-151
Clin Dermatol 4:208-212 47. !ohnson RA, Baer H, Kirkpatrick CH, et al. (1972) Compar-
20. Guin JD (1980) Reaction time in experimental poison ivy Ison of the contact allergenicity of the four pentadecyl
dermatitis. Contact Dermatitis 6:289-290 catechols derived from poison ivy urushiol in human
21. Feldmann RJ, Maibach HI (1967) Regional variation in subjects. J Allergy Clin Immunol 49:27-35
percutaneous penetration of 14 C cortisol in man. J Invest 48. Hausen BM (1981) Woods injurious to human health - a
Dermatol 48:181 manual. Walter de Gruyter, Berlin
22. Guin JD, Gillis WT, Beaman JH (1981) Recognizing the 49. Breathnach SM (1986) Immunologie aspects of contact
Toxicodendrons (poison ivy, poison oak, and poison dermatitis. Clin Dermatol 4:5-17
sumac). J Am Acad Dermatol 4:99-114 50. Kalish RS (1990) The use ofhuman T-lymphocyte dines to
23. Guin JD (1993) When is "poison ivy dermatitis" not poison study T-cell function in allergie contact dermatitis to
ivy dermatitis? Am J Contact Dermat 4:133-135 urushiol. J Invest Dermatol 94:108
24. Benezra C, Ducombs G, Seil Y, Foussereau C (1985) Plant 51. Guin JD (1980) Recognizing poison ivy and related plants in
contact dermatitis. B.C. Decker, Toronto, pp 200-203 Indiana. J Indiana State Med Assoc 73:306-308
25. Reynolds G, Epstein W, Terry D, et al. (1980) A potent 52. Guin JD, Beaman JH (1980) Recognition of poison ivy
contact allergen Phacelia (Hydrophyllaceae). Contact Der- during winter with emphasis on midwestern plants. Int J
matitis 6:272-274 Dermatol 9:500-503
26. TakashimaA, Yamamoto K, Kimura S, Takakuwa Y, Mizuno N 53. Guin JD, Kral R, Lelong M (1981) Field recognition of
(1991) Allergie contact and photocontact dermatitis due to eastern poison-oak with emphasis on plants in Alabama.
psoralens in patients with psoriasis treated with topieal Soutl1 Med J 74:435-7, 443
PUV A. Br J Dermatol 124:37-42 54. Guin JD, Beaman JH (1981) Toxicodendrons and Toxicod-
27. Ljunggren B (1977) Psoralen photoallergy caused by plant en~ron dermatitis. Continuing Educ Farn Physician 14:23-32
contact. Contact Dermatitis 3:85-90 55. ~um JD, R.eynolds R (1980) Je~elweed treatment of poison
IVY dermatitis. Contact Dermatitis 6:287-288
758 J.D. Guin
56. Marks JG Jr, Fowler JF Jr, Sheretz EF, Rietschel RL (1995) 84. Nandakishore T, Pasricha JS (1994) Pattern of eross-
Prevention of poison ivy and poison oak allergie contact sensitivity between 4 Compositae plants, Parthenium
dermatitis by quaternium-18 bentonite. J Am Acad Dermatol hysterophorus, Xanthium strumarium, Helianthus annuus
33:212-216 and Chrysanthemum coronarium, in Indian patients. Con-
57. Oltman J, Hensler R (1986) Poison oakJivy and forestry tact Dermatitis 30:162-167
workers. Clin Dermatol 4:213-216 85. Lonkar A, Mitchell JC, Calnan CD (1974) Contact dermatitis
58. Epstein WL (1989) Topieal prevention of poison ivy/oak from Parthenium hysterophorus. Trans St Johns Hosp
dermatitis. Arch Dermatol 125:499 Dermatol Soc 60:43-53
59. Orchard S, Fellman JH, Storrs FJ (1986) Poison ivy/oak 86. Guin JD, Schosser RH, Rosenberg EW (1990) Magnolia
dermatitis. Arch Dermatol 122:783 grandiflora dermatitis. Dermatol Clin 8:81
60. MurreIl D (1992) Advances in the prevention of poison ivy. 87. Mitchell JC, Dupuis G (1971) Allergie contact dermatitis
Sixteenth Hawaii Dermatology Seminar, Maui from Sesquiterpenoids of the Compositae family of plants.
61. Epstein WL, Byers VS, Frankart W (1982) Induction of Br J Dermatol 84:139-150
antigen specific hyposensitization to poison oak in sensi- 88. Rodrigues E, Dillon MO, Mabry TJ, et al. (1976) Dermato-
tized adults. Arch Dermatol n8:630-633 logically active sesquiterpene lactones in trichomes of
62. Watson ES (1986) Toxicodendron hyposensitization pro- Parthenium hysterophorus L. Experientia 32:236-238
grams. Clin Dermatol 4:160-170 89. Shelmire B (1940) Contact dermatitis from vegetation. South
63. Shelmire B (1941) Hyposensitization to poison ivy. Arch Med J 33:337-346
Dermatol Syphilol 44:983-998 90. Howell JB (1971) Sensitivity to eommon weeds. Contact
64. Van der Steen PHM, Van Baar HMJ, Perret CM, Happle R Dermatitis Newslett 10:230-231
(1991) Treatment of alopecia areata with diphenylcyclop- 91. Howell JB (1978) Contact dermatitis from weeds: facts and
ropenone. J Am Acad Dermatol 24:253-257 fallacies. Contact Dermatitis 4:365-369
65. Webster RC, Noonan PK, Maibach HI (1980). Percutaneous 92. Epstein S (1972) Sensitivity to eommon weeds. Contact
absorption of hydrocortisone increases with long-term Dermatitis Newslett n:305
administration. Arch Dermatol n6:186-188 93. Paulsen E, Andersen KE, Carlsen L, Egsgaard H (1993)
66. Guin JD, Lehman P, Gage D, Franz T (1990) MS analysis Carvone: an overlooked contact allergen cross-reacting with
of commercial Toxicodendron hyposensitization antigens sesquiterpene lactones? Contact Dermatitis 29:138-143
(abstract). Contact Dermatitis 23:293 94. Green C, Ferguson J (1994) Sesquiterpene lactone mix is not
67. Guin JD (1989) Sesquiterpene-lactone dermatitis. Immunol an adequate screen for Compositae allergy. Contact Derma-
Allergoi Clin N Am 9:447-461 titis 31:151-153
68. Burry JN, Reid JG, Kirk J (1975) Australian bush dermatitis. 95. Reference deleted in press
Contact Dermatitis 1:263-264 96. Paulsen E, Andersen KE (1993) Compositae dermatitis in a
69. Burry JN, Kuchel R, Reid JG, Kirk J (1973) Australian bush Danish dermatology department in 1 year (Il). Clinical
dermatitis: Compositae dermatitis in South Australia. Med J features in patients with Compositae contact allergy. Con-
Aust l:no-n6 tact Dermatitis 29:195-201
70. Schmidt RJ (1986) Compositae. Clin Dermatol 4:46-61 97. Sugai T, Takaliashi Y, Okuno F (1980) Chrysanthemum
71. Guin JD, Skidmore G (1987) Compositae dermatitis in dermatitis in Japan. Contaet Dermatitis 6:155
childhood. Areh Dermatol 123:500-502 98. Stampf J, Benezra C, Klecak G, et al. (1982) The sensitizing
72. Ducombs G, Benezra C, Talaga P, et al. (1990) Pateh testing capacity of helenin and of two of its main constituents, the
with the "sesquiterpene lactone mix": a marker for contact sesquiterpene lactones alantolactone and isoalantolactone: a
allergy to Compositae and other sesquiterpene-lactone- comparison of epicutaneous and intradermal sensitizing
containing plants. Contact Dermatitis 22:249-252 methods in different strains of guinea pig. Contact Derma-
J3. Green C, Ferguson J (1995) Sesquiterpene lactone mix is not titis 8:16-24
an adequate screen for Compositae allergy. Contact Derma- 99. Mitchell JC (1986) Frullania (Liverwort) phytodermatitis
titis 32:254 (woodcutter's eczema). Clin Dermatol 4:62-64
74. Burry JN (1979) Dermatitis from fleabane: Compositae 100. De Corres LF (1984) Contact dermatitis from frullania,
dermatitis in South Australia. Contaet Dermatitis 5:51- Compositae and other plants. Contaet Dermatitis 11:74-79
64 101. Mitchell JC (1986) Patch testing to plants. Clin Dermatol
75. Burry JN (1980) Dermatitis from Gaillardia aristata: Comp- 4:77-82
ositae dermatitis in South Australia. Contact Dermatitis 102. Farkas J (1981) Perioral dermatitis from marjoram, bay leaf
6:157 and cinnamon. Contact Dermatitis 7:121
76. Burry JN (1980) Compositae dermatitis in South Australia: 103. StampfJ, Castagnoli N, Epstein W, et al. (1990) Suppression
contact dermatitis from Chrysanthemum parthenium. Con- of urushiol-indueed delayed-type hypersensitivity responses
tact Dermatitis 6:445 in miee with serum IgG immunoglobuiin from human
77. Burry JN, Kloot PM (1982) The spread of Composite hyposensitized donors. J Invest Dermatol 95:363-365
(Compositae) weeds in Australia. Contact Dermatitis 8: 104. Baadsgaard 0 (1986) Cireulating and in situ lymphoeyte
410-413 subsets and Langerhans eells in patients with Compositae
78. Frain-Bell W (1986) Photosensitivity and Compositae der- oleoresin dermatitis and inereased uitraviolet A sensitivity
matitis. Clin Dermatol 4:122-126 during treatment with azathioprine. J Am Aead Derrnato!
79. Wrangsjo K, Ros AM, Wahlberg JE (1990) Contact alIergy to 14:577-581
Compositae plants in patients with summer-exacerbated 105. Marks JG Jr (1988) Allergie eontaet dermatitis to Al-
dermatitis. Contact Dermatitis 22:148-154 stroemeria. Areh Derrnato! 124:914-916
80. Frain-Bell W, Hetherington A, Johnson BE (1979) Contact 106. Thiboutot DM, Hamory BH, Marks JG (1990) Dermatoses
allergic sensitivity to chrysanthemum and the photosensi- among floral workers. J Am Aead Derrnato! 22:54-58
tivity dermatitis and actinic reticuloid syndrome. Br J 107. Adams RM, Daily AD, Braneaecio R, Dhillon IP, Gendler EC
Dermatol 101:491-501 (1990) A!stroemeria. A new and potent allergen for florists.
81. Guin JD, Baker GF, Mitchell JC (1988) Persistent open patch Derrnato! Clin 8:73-76
test reaction. Contact Dermatitis 18:181-182 108. Gette MT, Marks JE (1990) Tulip fingers. Areh Derrnato!
82. Wakelin SH, Marren P, Young E, Shaw S (1997) Compositae 126:203-205
sensitivity and chronic hand dermatitis in a seven-year-old 109. Hjorth N, Wilkinson DS (1968) Contaet Dermatitis IV. Tulip
boy. Br J Dermatol 137:289-291 fingers, hyacinth iteh and !i!y rash. Br J Dermatol 80:
83. Mitchell JC, Fisher AA (1986) Dermatitis due to plants and 696-698
spices. In: Fisher AA (ed) Contact dermatitis. Philadelphia, no. Verspyek-Mijnssen GA W (1969) Pathogenesis and eausative
Lea & Febiger agent of "tuiip finger". Br J Derrnato! 81:737-745
111. Hausen BM, Prater E, Schubert H (1983) The sensitizing 140. Stoner JG (1986) Miscellaneous dermatitis-inducing plants.
capacity of Alstroemeria cultivars in man and guinea pig. Clin Dermatol 4:94-101
Contact Dermatitis 9:46-54 141. Webster G (1986) Irritant plants in the spurge family
112. Bjorkner BE (1982) Contact allergy and depigmentation (Euphorbiaceae). Clin Dermatol 4:36-45
from alstroemeria. Contact Dermatitis 8:178-184 142. Shannon J, Sagher F (1956) Sabra dermatitis: an occupa-
113. Scales JW, Sherertz EF (1997) Occupational dermatitis tional dermatitis due to prickly pear handling simulating
transferred with job duties. Am J Contact Dermat 8:179-180 scabies. Arch Dermatol 74:269-275
114. Bruynzeel DP (1997) Bulb dermatitis. Dermatological prob- 143. Snyder RA, Schwartz RA (1983) Cactus bristle implantation.
lems in the flower bulb industries. Contact Dermatitis 37: Arch Dermatol119:152-154
70-77 144. Urushibata 0, Kase K (1991) Irritant contact dermatitis from
115. Van der Werff PJ (1959) Occupational diseases among Euphorbia marginata. Contact Dermatitis 24:155-156
workers in the bulb industries. Allergy 14:338-355 145. Epstein WL (1994) Occupational poison ivy and oak
116. Lsders G (1977) Die Narzissenkrankeit der Gartner. Hautarzt dermatitis. Dermatol Clin 12:511-516
1977 28(Supp. 2):49-50 146. O'Malley MA, Barba R (1990) Bullous dermatitis in field
117. Tabar AI, Quirce S, Garcia BE, Rodriguez A, Olaguibel JM workers associated with exposure to mayweed. Am J
(1994) Primula dermatitis: versatility in its clinieal presen- Contact Dermat 1:34-42
tation and the advantages of patch tests with synthetic 147. Sequeira JH (1921) A case of bullous eruption caused by
primin. Contact Dermatitis 30:47-48 may-weed. Lancet 2:560
118. Epstein E (1990) Primula contact dermatitis, an easily 148. Krantz W (1938) Bullous dermatitis in harvest workers.
overlooked diagnosis. Cutis 45:411-416 Munch Med Wchnschr 85=1057-1060
119. Fernandez de Corres L, Leanizbarrutia I, Munoz D (1987) 149. Menz J, Winkelman RK (1987) Sensitivity to wild vegetation.
Contact dermatitis from Primula obconica Hance. Contact Contact Dermatitis 16:169-173
Dermatitis 16:195-197 150. Mahajan VK, Sharma VK, Kaur I, Chakrabarti A (1996)
120. Logan RA, White IR (1988) Primula dermatitis: prevalence, Contact dermatitis in agricultural workers: role of common
detection and outcome. Contact Dermatitis 19:68-69 crops, fodder and weeds. Contact Dermatitis 35:373-374
121. Dooms-Goossens A, Biesemans G, Vandaele M, Degreef H 151. Rao PV, Mangala A, Rao BS, Prakash KM (1977) Clinieal and
(1989) Primula dermatitis: more than one allergen? Contact immunologie al studies on persons exposed to Parthenium
Dermatitis 21:122-124 hysterophorus L. Experientia 33=1387-1388
122. Hjorth N (1979) Primula dermatitis. In: Mitchell JC, Rook 152. Szegö L (1965) Sensitization durch landwirtschaftliche
AR (eds) Botanical dermatology. Greengrass, Vancouver, Pflantzen und Pflantzenschutzmittel. Acta Med Hung
pp 554-565 21:19-24
123. Bailey LH, Bailey EZ (1976) Hortus third. MacMillan, New 153. Ravnay T, Garazsi M (1955) Napraforgo (Helianthus annuus)
York, pp 907-912 levelevel szembeni tulerzekenysegre vonatkozovizgiUatok
124. Hausen BM (1978) On the occurrence of the contact allergen borgyogy. Szemle 9:50-54
primin and other quinoid compounds in species of the 154. Gomez E, Garcia R, Galindo PA, Feo F, Fernandez FJ (1996)
family of Primulaceae. Arch Dermatol Res 261:311-321 Occupational allergie contact dermatitis from sunflower.
125. Pathak MA (1990) Phytophotodermatitis. Clin Derm 8:73-76 Contact Dermatitis 35:189-190
126. Freeman K, Hubbard HC, Warin AP (1984) Strimmer rash. 155. Machet L, Vaillant L, Callens A, Demasure M, Barruet K,
Contact Dermatitis 10:117-118 Lorette G (1993) Allergie contact dermatitis from sunflower
127. Birmingham DJ, Key MM, Tublieh GE, et al. (1961) Photo- (Helianthus annuus) with cross-sensitivity to arnica. Con-
toxic bullae among celery harvesters. Arch Dermatol 83: tact Dermatitis 28:184-185
73-87 156. Hausen BM, Spring 0 (1989) Sunflower allergy. On the
128. Seligman PJ, Mathias CG, O'Malley MA, et al. (1987) constituents of the trichomes of Helianthus annuus L.
Phytophotodermatitis from celery among grocery store (Compositae). Contact Dermatitis 20:326-334
workers. Arch Dermatol 123:1478-1482 157. Hausen BM, Herrmann HD, Willuhn G (1978) The sensitiz-
129. Morbidity and Mortality Weekly Report (1985) Leads from ing capacity of Compositae plants. 1. Occupational contact
the MMWR. Phytophotodermatitis among grocery workers. dermatitis from Arnica longifolia Eaton. Contact Dermatitis
JAMA 253=753 4:3-10
130. Morbidity and Mortality Weekly Report (1985) Phytopho- 158. Duran S, Delgado J, Gamez R, Velazquez E, Gonzalez-Pol J,
todermatitis among grocery workers - Ohio. MMWR Morb Serrano P, Lopez-Crespo R, Guardia P, Conde J (1997)
Mortal Wkly Rep 34:11-13 Contact urticaria from sunflower seeds. Contact Dermatitis
131. Heskel NS, Amon RB, Storrs FJ, White eR Jr (1983) 37=184
Phytophotodermatitis due to Ruta graveolens. Contact 159. Malten KE (1983) Chieory dermatitis from September to
Dermatitis 9:278-280 April. Contact Dermatitis 9:232
132. Gawkrodger DJ, Savin JA (1983) Phytophotodermatitis due 160. Garcia-Bravo B, Rodriguez-Piehardo A, De Pierola SF,
to common rue (Ruta graveolens). Contact Dermatitis Camacho F (1995) Airborne erythema-multiforme-like
9:224 eruption due to pyrethrum. Contact Dermatitis 33:433
133. Ortiz-Frutos FJ, Sanchez B, Garcia B, Iglesias L, Sanchez- 161. Benini F, Sivieri G, Cervi G (1970) Un caso di fitodermatosi
Mata D (1995) Photocontact dermatitis from rue professionale da lagurus ovatus e antriscus cerefolium [A
(Ruta montana L.). Contact Dermatitis 33:284 case of occupational phytodermatosis caused by lagurus
134. Brener S, Friedman J (1985) Phytophotodermatitis induced ovatus and antriscus cerefoliuml. Arcisp S Anna Ferrara
by Ruta chalepensis. Contact Dermatitis 12:230-232 23:427-436
135. Goncalo S, Correia C, Couto JS, Goncalo M (1989) Contact 162. Tosti A, Melino M, Veronesi S (1987) Contact urtiearia to
and photocontact dermatitis from Ruta chalepensis. Contact tobacco. Contact Dermatitis 16:225-226
Dermatitis 21:200-201 163. McKnight RH, Rodgers GC Jr (1995) Occupational tobacco
136. Ena P, Camarda I (1990) Phytophotodermatitis from Ruta dermatitis reported to a regional poison center. Contact
corsica. Contact Dermatitis 22:63 Dermatitis 32:122
137. Guin JD, Jackson DB (1988) Oakmoss photosensitivity in a 164. Nakamura T (1984) Tobacco dermatitis in Japanese har-
ragweed-allergic patient. Contact Dermatitis 18:240-242 vesters. Contact Dermatitis 10:310
138. Thune PO, Solberg YJ (1980) Photosensitivity and allergy to 165· Rycroft RJ (1980) Tobacco dermatitis. Br J Dermatol
aromatic lichen acids, Compositae oleoresins and other 103:225-229
plant substances. Contact Dermatitis 6:81-87 166. Goncalo M, Couto J, Goncalo S (1990) Allergie contact
139. Sandberg M, Thune P (1984) The sensitizing capacity of dermatitis from Nieotiana tabacum. Contact Dermatitis
atranorin. Contact Dermatitis 11:168-173 22:188-189
760 J.D. Guin
167. Pecegueiro M (1987) Airborne contact dermatitis to tobacco. 193. Vale PT (1993) Prevention of phytophotodermatitis from
Contact Dermatitis 17:50-51 celery. Contact Dermatitis 29:108
168. Axelsson IG (1994) Allergy to the coffee plant. Allergy 194. Austad J, Kavli G (1983) Phototoxic dermatitis caused by
49:885-887 celery infected by Sclerotinia sclerotiorum. Contact Derma-
169. Treudler R, Tebbe B, Krengel S, Orfanos CE (1997) Allergie titis 9:448-451
contact dermatitis from black tattoo. Contact Dermatitis 195. Fleming D (1990) Dermatitis in grocery workers associated
37: 2 95 with high natural concentrations of furanocoumarins in
170. Osterman K, Zetterstrom 0, Johansson SG (1982) Coffee celery. Allergy Asthma Proc 11:125-127
workers allergy. Allergy 37:315-322 196. Berkley SF, Hightower AW, Beier RC, Fleming DW, Brokopp
171. Patussi V, De Zotti R, Riva G, Fiorito A, Larese F (1990) CD, Ivie GW, Broome CV (1986) Dermatitis in grocery
Allergie manifestations due to castor beans: an undue risk workers associated with high natural concentrations of
for the dock workers handling green coffee beans. Med Lav furanocoumarins in celery. Ann Intern Med 105:351-355
81:301-307 197. Finke1stein E, Afek U, Gross E, Aharoni N, Rosenberg L,
172. Kanerva L, Estlander T, Jolanki R (1990) Long lasting Halevy S (1994) An outbreak of phytophotodermatitis due to
contact urticaria. Type I and type IV allergy from castor celery. Int J Dermatol 33:116-118
bean and a hypothesis of systemic IgE mediated allergie 198. Tan BB, Lear JT, English JS (1997) Latex contact urticaria
dermatitis. Dermatol Clin 8:181-188 presenting as facial swelling in a motor mechanic. Contact
173. Yamasaki R, Dekio S, Jidoi J (1985) Contact dermatitis from Dermatitis 36:229-230
grape budo Contact Dermatitis 12:226-227 199. Tacke J, Schmidt A, Fartasch M, Diepgen TL (1995)
174. Winter CK, Kurtz PH (1985) Factors influencing grape Occupational contact dermatitis in bakers, confectioners
worker susceptibility to skin rashes. Bull Environ Contam and cooks. A population based study. Contact Dermatitis
Toxicol 35:418-426 33:112- 117
175. MCCurdy SA, Wiggins P, Schenker MB, Munn S, Shaieb AM, 200. Hjorth N, Roed-Petersen J (1976) Occupational protein
Weinbaum Z, Goldsmith D, McGillis ST, Berman B, Samuels contact dermatitis in food handlers. Contact Dermatitis
S (1989) Assessing dermatitis in epidemiologie studies: 2:28-42
occupational skin disease among California grape and 201. Veien NK, Hattel T, Justesen 0, Norholm A (1983) Causes of
tomato harvesters. Am J Ind Med 16:147-157 eczema in the food industry. Derm Beruf Umwelt 31:84-86
176. Gamsky TE, McCurdy SA, Wiggins P, Samue1s SI, Berman B, 202. Janssens V, Morren M, Dooms-Goossens A, Degreef H
Shenker MB (1992) Epidemiology of dermatitis among (1995) Protein contact dermatitis: myth or reality? Br J
California farm workers. J Occup Med 34:304-310 DermatoI132:1-6
177. Rademaker M (1996) Allergie contact dermatitis from kiwi 203. Janssens V, Morren M, Dooms-Goossens A, Degreef H
fruit vine (actinidia chinensis). Contact Dermatitis 34: (1996) Comment. Br J DermatoI135:332-333
221-222 204. Hannuksela M, Lahti A (1977) Immediate reactions to fruits
178. Jolanki R, Suhonen R, Henriks Eckerman ML, Estlander T, and vegetables. Contact Dermatitis 3:79-84
Kanerva L (1997) Contact allergy to salicyl alcohol in aspen 205. Kaupinnen K, Kousa M, Reunala T (1980) Aromatic plants-a
bark. Contact Dermatitis 37:304-305 cause of attacks of severe angio edema and urticaria.
179. Matsushita T, Aoyama K, Manda F, Ueda A, Yoshida M, Contact dermatitis 6:251-254
Okamura J (1989) Occupational dermatoses in farmers 206. Potter TS, Hashimoto K (1994) Butternut squash (Cucurbita
growing okra (Hibiscus esculentus L.). Contact Dermatitis moschata) dermatitis. Contact Dermatitis 30:123
21:321-325 207. Niinimaki A (1987) Scratch chamber tests in food handler
180. Manda F, Tadera K, Aoyama K (1992) Skin lesions due to dermatitis. Contact Dermatitis 16:11-20
okra (Hibiscus esculentus L.): proteolytic activity and 208. Pigatto PD, Polenghi MM, Altomare GF (1987) Occupational
allergenicity of okra. Contact Dermatitis 26:95-100 dermatitis in bakers: a clue for atopic contact dermatitis.
181. Balachandran C, Srinivas CR, Shenoy SD, Edison KP (1992) Contact Dermatitis 16:263-271
Occupational dermatosis in coconut palm climbers. Contact 209. Lezaun A, Igea JM, Quirce S, Cuevas M, Parra F, Alonso MD,
Dermatitis 26:143 Martin JA, Cano MS (1994) Asthma and contact urticaria
182. Cronin E (1979) Contact dermatitis from barley dust. caused by rice in a housewife. Allergy 49:92-95
Contact Dermatitis 5:196 210. Dempster JG (1981) Contact dermatitis from bran and oats.
183. Goncalo S (1984) Occupational contact dermatitis to Contact Dermatitis 7:122
Frullania. Contact Dermatitis 11:54-55 211. Calzavara-Pinton PG, Tosoni C, Carlino A, Cattaneo R
184. Stinchi C, Guerrini V, Ghetti E, Tosti A (1997) (1989) Dermatite eczematosa da contatto a grano ed avena.
Contact dermatitis from lichens. Contact Dermatitis G !tal Dermatol VenereoI124:289-291
36:309-310 212. Schonenberger P, Savolainen H (1995) Proteinantigene in
185. Quirino AP, Barros MA (1995) Occupational contact der- Fallen von Asthma, Rhinitis und Dermatitis bei beruflich
matitis from lichens and Frullania. Contact Dermatitis mehlexponierten Personen [Protein antigens in case of
33:68- 69 asthma, rhinitis and dermatitis in patients occupationally
186. Hahn M, Lischka G, Pfeifle I, Wirth V (1995) A case of exposed to flour]. Schweiz Med Wochensehr 125:1046-1051
contact dermatitis from lichens in southern Germany. 213. Prichard MG, Ryan G, Walsh BJ, Musk AW (1985) Skin test
Contact Dermatitis 32:55-56 and RAST responses to wheat and common allergens and
187. Rosina P, Chieregato C, Schena D (1995) Allergie contact respiratory disease in bakers. Clin Allergy 15:203-210
dermatitis from Pleurotus mushroom. Contact Dermatitis 214. Friis B, Hjorth N, Vail JT Jr, Mitchell JC (1975) Occupational
33: 2 77- 2 78 contact dermatitis from Cichorium (chicory, endive) and
188. Romaguera C, Grimalt F (1983) Occupational dermatitis Lactuca (lettuce). Contact Dermatitis 1:311-313
from codeine. Contact Dermatitis 9:170 215. Vail JT, Mitchell JC (1973) Occupational dermatitis from
189. Castelain M, Ducombs G (1988) Contact dermatitis from Cichorium intybus, C. endivia, and Lactuca sativa, var.
madder. Contact Dermatitis 19:228-229 longifolia. Contact Dermatitis Newslett 14:413
190. Derrick EK, Darley CR (1994) Contact reaction to the tree of 216. Smith DM (1985) Occupational photodermatitis from pars-
heaven. Contact Dermatitis 30:178 ley. Practitioner 229:673-675
191. Ashwood-Smith MJ, Ceska 0, Yeoman A, Kenny PG (1992) 217. Friis B (1973) Occupational dermatitis from chicory salad.
Photosensitivity from harvesting lovage (Levisticum officin- Contact Dermatitis Newslett 13:349
ale). Contact Dermatitis 26:356-357 218. Krook C (1973) Contact dermatitis due to lettuce (Lactuca
192. Aberer W (1992) Occupational dermatitis from organically sativa) Contact Dermatitis Newslett 13:346
grown parsnip (Pastinaca sativa L.). Contact Dermatitis 219. Helander I (1984) Contact dermatitis to lettuce. Contact
26:62 Dermatitis 11:249
220. Kanerva L, Estlander T, Jolanki R (1996) Oeeupational 250. Van Ketel WG (1975) A eauliflower allergy. Contaet Derma-
allergie eontaet dermatitis from spiees. Contaet Dermatitis titis 1:324-325
35:157-162 251. Van Ketel WG, De Haan P (1978) Oeeupational eezema from
221. Mitehell D, Beek MH, Hausen BM (1989) Contaet sensitivity garlie and onion. Contaet Dermatitis 4:53-54
to lettuee in a ehef. Contaet Dermatitis 20:398-399 252. Lembo G, Balato N, Patruno C, Aurieehio L, Ayala F (1991)
222. Hausen BM, Andersen KE, Helander I, Genseh KH (1986) Allergie eontaet dermatitis due to garlie (Allium sativum).
Lettuee allergy: sensitizing poteney of allergens. Contaet Contaet Dermatitis 25:330-331
Dermatitis 15:246-249 253. MeFadden JP, White IR, Ryeroft RJ (1992) Allergie eontaet
223. Gougerot H, Seringe (1936) Eeze'ma professionnel par dermatitis from garlie. Contaet Dermatitis 27:333-334
l'artiehaut. Bull Soe Fr Dermatol Syphilol 43=1463 254. Campolmi P, Lombardi P, Lotti T, Sertoli A (1982) Imme-
224. Vallet G (1964) Allergy to eertain market garden plants - diate and delayed sensitization to garlie. Contaet Dermatitis
artiehokes eelery and parsley. Coneours Med 86:3603 8:352-353
225. White RP (1934) Oeeupational affeetions of the skin, 4tl1 255. Aeciai MC, Brusi C, Franealanci S, Giorgini S, Sertoli A
edn. HK Lewis & Co. (1993) Allergie contaet dermatitis in eaterers. Contaet
226. Kanzaki T, Kimura S (1992) Oeeupational allergie eontaet Dermatitis 29:48
dermatitis from Perilla fruteseens (shiso). Contaet Derma- 256. Maso MI, Ruszkowski AM, Bauerle I, DeLeo VA, Gasparro
titis 26:55-56 FP (1991) Celery phytophotodermatitis in a chef. Areh
227. Dannaker q, White IR (1987) Cutaneous allergy to mustard Dermatol 127:912-913
in a salad maker. Contaet Dermatitis 16:212-214 257. Nakamura T (1992) Shiitake (Lentinus edodes) dermatitis.
228. Gaul LE (1964) Contaet dermatitis from synthetie oil of Contaet Dermatitis 27:65-70
mustard. Areh Dermatol 90:158 258. Tarvainen K, Salonen JP, Kanerva L, Estlander T, Keskinen H,
229. Krook G (1977) Oeeupational dermatitis from Laetuea sativa Rantanen T (1991) Allergy and toxieodermia from shiitake
(lettuee) and Ciehorium (endive). Simultaneous oeeurrenee mushrooms. J Am Aead Dermatol 24:64-66
of immediate and delayed allergy as a eause of eontaet 259. Cardullo AC, Ruszkowski AM, DeLeo VA (1989) Allergie
dermatitis. Contaet Dermatitis 3:27-36 eontaet dermatitis resulting from sensitivity to citrus peel,
231. Foti C, Carino M, Cassano N, Panebianeo R, Vena GA, geraniol, and citral. J Am Aead Dermatol 21:395-397
Ambrosi L (1997) Oeeupational eontaet urtiearia from 260. Sams WM (1940) Oeeupational dermatitis due to mint:
paprika. Contaet Dermatitis 37:135 report of two eases. Areh Dermatol Syphilol 41:503-505
232. Sanehez MC, Hernandez M, Morena V, Guardia P, Gonzalez 261. Srinivas CR, Balaehandran C, Singh KK (1987) Oeeupational
J, Monteiserin J, Garcia Bravo BB, Conde J (1997) Immu- dermatosis and allergie eontaet dermatitis in a toddy tapper.
nologie eontaet urtiearia eaused by asparagus. Contaet Contaet Dermatitis 16:294-295
Dermatitis 37:181-182 262. Gutgesell C, Fuchs T (1995) Contaet urtiearia from beer.
233. Kavli G, Moseng D (1987) Contaet urtiearia from mustard in Contaet Dermatitis 33:436-437
fish stiek produetion. Contaet Dermatitis 17:153-155 263. Gonealo S, Sousa L, Moreno A, et al. (1986) Oeeupational
234. Weltfriend S, Kwangsukstitl1 C, Maibach HI (1995) Contaet dermatitis from Salix viminalis. Contaet Dermatitis 14:
urtiearia from eueumber piekle and strawberry. Contaet 188-189
Dermatitis 32:173-174 264. Melli MC, Giorgini S, Sertoli A (1983) Oeeupational derma-
235. Goransson K (1981) Contaet urtiearia to apricot stone. titis in a bee keeper. Contaet Dermatitis 9:427-428
Contaet Dermatitis 7:282 265. Hausen BM, Evers P, Stuwe HT, Konig WA, Wollenweber E
236. Camarasa JG (1995) Foods. In: Guin JD (ed) Praetieal eontaet (1992) Propolis allergy (IV). Studies witl1 further sensitizers
dermatitis: a handbook for tl1e praetitioner. MeGraw-Hill, from propolis and eonstituents eommon to propolis, poplar
New York, pp 519-537 buds and balsam of Peru. Contaet Dermatitis 26:34-44
237. Chan EF, Mowad C (1998) Contaet dermatitis to foods and 266. Rothenborg HW (1967) Oeeupational dermatitis in bee-
spiees. Am J Contaet Dermat 9:71-79 keeper due to poplar res ins in beeswax. Areh Dermatol
238. Dooms-Goossens A, Dubelloy R, Degreef H (1990) Contaet 95:381-384
and systemie contaet type dermatitis to spiees. Dermatol 267. Lampe KF (1986) Dermatitis-producing Anaeardiaeeae of
Clin 8:89-93 the Caribbean area. Clin Dermatol 4:171-182
239. Bruynzeel DP, Prevoo RL (1989) Pateh tests with some 268. Lampe KF (1986) Dermatitis-produeing plants of South
spiees. Dermatol Clin 8:85-87 Florida and Hawaii. Clin Dermatol 4:83-93
240. Mitehell JC (1975) Pateh testing with some eompounds of 269. Ippen H (1990) Contaet allergy to Phacelia spp. (Hydro-
balsam of Peru. Contaet Dermatitis 1:329-331 phyllaeeae). Dermatol Clin 8:67-71
241. Goh CL, Ng SK (1987) Allergie eontaet dermatitis to 270. Wantke F, Hemmer W, Gotz M, Jariseh R (1996) Contaet
Cureuma longa (turmerie). Contaet Dermatitis 17:186 dermatitis from jojoba oil and myristyl laetate/maleated
242. Hata M, Sasaki E, Ota M, Fujimoto K, Yajima J, Shiehida T, soybean oil. Contaet Dermatitis 34:71-72
Honda M (1997) Allergie eontaet dermatitis from eureumin 271. Wenninger JA, MeEwen GN (1995) International eosmetie
(turmerie). Contaet Dermatitis 36:107-108 ingredient handbook, 3rd edn. The Cosmetie Toiletries and
243. Mobaeken H, Fregert S (1975) Allergie contaet dermatitis Fragranee Association, Washington
from eardamom. Contaet Dermatitis 1:175-176 272. Houghton PJ (1994) Botanieally aetive eompounds. Cosmet-
244. Van den Akker TW, Roesyanto Mahadi ID, Van Toorenen- ies Toiletries 109:39-48
bergen AW, Van Joost T (1990) Contaet allergy to spiees. 273. Dorato S (1987) Water soluble plant extraets in eosmeties.
Contaet Dermatitis 22:267-272 Cosmeties Toiletries 102:70a-73
245. Meding B (1993) Skin symptoms among workers in a spiee 274. Nater JP, De Groot AC, Liem DH (1985) Plant produets in
faetory. Contaet Dermatitis 29:202-205 eosmeties. In: De Groot AC, Nater JP, Weyland JW (eds)
246. Audieana M, Bernaola G (1994) Oeeupational contaet Unwanted effeets of eosmeties and drugs used in dermatol-
dermatitis from citrus fruits: lemon essential oils. Contaet ogy. Elselvier, Amsterdam, pp 377-387
Dermatitis 31:183-185 275. Bilsland D, Strong A (1990) Allergie eontaet dermatitis from
247. Garcia-Bravo B, Perez-Bernal A, Garcia-Hernandez MI, the essential oil of Freneh marigold (Tagetes patula) in an
Camaeho F (1997) Oeeupational eontaet dermatitis from aromatherapist. Contaet Dermatitis 23:55-56
anethole in food handlers. Contaet Dermatitis 37:38 276. Selvaag E, Holm JO, Thune P (1995) Allergie eontaet
248. Goh CL (1988) Oeeupational dermatitis from Mesonia dermatitis in an aroma therapist with multiple sensitizations
ehinensis. Contaet Dermatitis 18:113 to essential oils. Contaet Dermatitis 33:354-355
249. Carmiehael AJ, Foulds IS, Tan CY (1989) Allergie 277. Kanerva L, Estlander T, Jolanki R (1995) Oeeupational
eontaet dermatitis from potato flesh. Contaet Dermatitis allergie contaet dermatitis eaused by ylang ylang oil. Contaet
20:64-65 Dermatitis 33=198-199
762 J.D. Guin
278. Dugue P, Bel 1, Gomez-Figueredo M (1990) Allergie profes- 305. Thune P (1977) Contact allergy due to liehens in patients
sionelle a'l'ambrette. Cinq observations dans l'industriede la witl1 a history of photosensitivity. Contact Dermatitis 3:
parfumerie. Rev Fr Allergoi 30:29-31 267-272
279. Zacher KD, Ippen H (1984) Kontaktekzem dsrch bergamot- 306. Mota AV, Barros MA, Mesquita Guimaraes J (1997) Contact
to:l. Derm Beruf Umwelt 32:35-37 dermatitis from moss in a forestry worker. Contact Derma-
280. Calnan CD (1969) Lovage sensitivity. Contact Dermatitis titis 37:240-241
Newslett 5:99 307. Quirce S, Tabar AI, Olaguibel JM, Cuevas M (1996)
281. Rademaker M (1994) Allergie contact dermatitis from Occupational contact urticaria syndrome caused by globe
lavender fragrance in Difflam gel. Contact Dermatitis artiehoke (Cynara scolyrnus). J Allergy Clin Immunol
31:58-59 97:710-711
282. Brandao FM (1986) Occupational allergy to lavender oil. 308. Fisher AA (1987) Contact urtiearia due to cornstarch
Contact Dermatitis 15:249-250 powder. J Dermatol Surg Oncol 13:224
283. Nethercott JR, Pilger C, O'Blenis L, Roy AM (1983) Contact 309. Assalve D, Cicioni C, Perno P, Lisi P (1988) Contact urtiearia
dermatitis due to cinnamic aldehyde induced in a and anaphylactoid reaction from cornstarch surgieal glove
deodorant manufacturing process. Contact Dermatitis powder. Contact Dermatitis 19:61
9:241-242 310. Harnman CP, Turjanmaa K, Rietschel R, Siew C, et al. (1998)
284. Johansen JD, Rastogi SC, Menne T (1996) Exposure to Natural rubber latex hypersensitivity: incidence and prev-
selected fragrance materials. A case study of fragrance mix alence of type I allergy in the dental profession. J Am Dent
positive eczema patients. Contact Dermatitis 34:106-110 Assoc 129:43-54
285. Malten KE (1970) Allergie contact dermatitis due to cattle 311. Crisi G, Belsito DV (1993) Contact urticaria from latex in a
fodder products. Contact Dermatitis Newslett 7:159 patient with immediate hypersensitivity to banana, avocado
286. Dooms-Goossens A, Deveylder H, Duron C, et al. (1986) and peach. Contact Dermatitis 28:247-248
Airborne contact urticaria due to Cinchona. Contact Der- 312. Taylor JS (1998) Latex allergy update: four vignettes. Am J
matitis 15:258 Contact Dermatitis 9:45-48
287. Knight TE, Hausen BM (1996) Dermatitis in a nutshell: 313. Dahlquist I, Fregert S (1981) Atranorin and oakrnoss contact
occupational exposure to Macadarnia integrifolia. J Am allergy. Contact Dermatitis 7:168-169
Acad Dermatol 35:482-484 314. Oakley AM, Ive FA, Harrison MA (1986) String trimmer's
288. Srinivas CR, Pasrieha JS (1990) Dermatologieal problems of dermatitis. J Soc Occup Med 36:143-144
workers employed in cashew nut factories. Contact Derma- 315. Davies MG, Kersey PJ (1986) Contact allergy to yarrow and
titis 22:192 dandelion. Contact Dermatitis 14:256-257
289. Bedi BM (1971) Cashewnut dermatitis. (Report of two cases). 316. Lovell CR, Rowan M (1991) Dandelion dermatitis. Contact
Indian J Dermatol 16:63-64 Dermatitis 25:185-188
290. Diogenes MI, De Morais SM, Carvallio FF (1996) Contact 317. Larregue M, Rat JP, Gallet P, Bressieux JM, Pousset JL (1978)
dermatitis among cashew nut workers. Contact Dermatitis Eczema de contact au pissenlit, a l'huile de laurier noble et
35=114-115 au frullania par allergie croisee. Ann Dermatol Venereol
291. TreudIer R, Tebbe B, Orfanos CE (1997) Coexistence of type 105:547-548
I and type IV sensitization in occupational coffee allergy. 318. Hausen BM, Breuer J, Weglewski J, Rucker G (1991) alpha
Contact Dermatitis 36:109 Peroxyachifolid and otl1er new sensitizing sesquiterpene
292. Lehrer SB, Karr RM, Salvaggio JE (1978) Extraction and lactones from yarrow (Achillea millefolium 1.., Compositae).
analysis of coffee bean allergens. Clin Allergy 8:217-226 Contact Dermatitis 24:274-280
293. Narahari SR, Srinivas CR, Kelkar SK (1990) LE like erythema 319. Pazzaglia M, Venturo N, Borda G, Tosti A (1995) Contact
and periungual telangiectasia among coffee plantation dermatitis due to a massage liniment containing Inula
workers. Contact Dermatitis 22:296-297 heleniurn extract. Contact Dermatitis 33:267
294. Agatl10s M (1980) Occupational dermatitis from celeriac. 320. Pereira F, Santos R, Pereira A (1997) Contact dermatitis
Contact Dermatitis 6:225 from chamomile tea. Contact Dermatitis 36:307
295. Mitchell JC, Jordan WP (1974) Allergie contact dermatitis 321. Van der Wegen-Keijser MH, Bruynzeel DP (1991) Allergy to
from the radish, Raphanus sativus. Br J DermatoI91:183-189 cane reed in a saxophonist. Contact Dermatitis 25:268-269
296. Hjortl1er AB, Christophersen C, Hausen BM, Menne T (1997) 322. McFadden JP, Ingram MI, Rycroft RJ (1992) Contact allergy
Occupational allergie contact dermatitis from carnosol, a to cane reed in a clarinettist. Contact Dermatitis 27:117
naturally occurring compound present in rosemary. Contact 323. Chang YC, Maibach HI (1997) Pseudo tlautist's lip: allergie
Dermatitis 37:99-100 contact cheilitis from geraniol. Contact Dermatitis 37:39
297. Chan OY, Lee CS, Tan KT, Thirumoortl1y T (1990) Healtl1 324. Farm G, Karlberg AT, Liden C (1995) Are opera house
problems among spiee grinders. J Soc Occup Med 40:111-115 artistes afflicted with contact allergy to colophony and
298. Seligman EJ, Key MM (1968) Corn dermatitis. Arch cosmetics? Contact Dermatitis 32:273-280
Dermatol 97:664-666 325. Lewis FM, Gawkrodger DJ, Harrington CI (1994) Colophony:
299. Mitchell JC, Chan-Yeung M (1974) Contact allergy from an unusual factor in pruritus vulvae. Contact Dermatitis
Frullania and respiratory allergy from Thuja. Can Med 31:119
Assoc J 110:653-654 326. Angelini G, Vena GA (1986) Allergie contact dermatitis to
300. Fernandez de Corres L (1984) Contact dermatitis from colophony in a violoncellist. Contact Dermatitis 15:108
Frullania. Contact Dermatitis 11:749 327. Fisher AA (1981) Allergie contact dermatitis in a violinist.
301. Quirce S, Tabar AI, Muro MD, Olaguibel JM (1994) Airborne The role of abietic acid - a sensitizer in rosin (colophony) -
contact dermatitis from Frullania. Contact Dermatitis 30:73- as tl1e causative agent. Cutis 27:466, 468, 473
76 328. Monti M, Berti E, Carminati G, Cusini M (1983) Occupa-
302. Mitchell JC (1981) Industrial aspects of 112 cases of tional and cosmetie dermatitis from propolis. Contact
allergie contact dermatitis from Frullania in British Dermatitis 9:163
Columbia during a 10-year period. Contact Dermatitis 329. Paulsen E, Solgaard J, Andersen KE (1997) Occupational
7:268-269 dermatitis in Danish gardeners and greenhouse workers.
303. Hausen BM, Emde L, Marks V (1993) An investigation of tl1e Contact Dermatitis 37:263-270
allergenie constituents of Cladonia stellaris (Opiz) Pous & 330. O'Malley MA, Mathias CGT (1988) Distribution oflost work
Vezda ('silver moss', 'reindeer moss' or 'reindeer liehen'). time claims for skin disease in California agrieulture. Am J
Contact Dermatitis 28:70-76 Ind Med 14:715-720
304. Thune P, Solberg Y, McFadden N, Staerfelt F, Sandberg M 331. Diepgen TL, Schmidt A, Schmidt M, Fartasch M (1994)
(1982) Perfurne allergy due to oak moss and otl1er lichens. Berufsekzeme und Berufskrankeitverfahren - epidemiol-
Contact Dermatitis 8:396-400 ogische. Allergologie 17:84-89
332. Halkier-Sorensen L, Thestrup-Petersen K, Haugaard-Pe- 358. Hausen BM, Schulz KH (1975) Experimental studies on tlIe
tersen B (1994) Anmeldte og anerkendte arbejdsbe- identification of chrysanthemum allergens. Contact Derma-
tingede hudsygdomme i Danmark. Industries Forlag, titis 1:244-245
Copenhagen 359. Goncalo S, Goncalo M, Sequeira j (1996) Contact dermatitis
333. Bethea LK, Schuman SH, Smith Phillips SE, Kelly JW (1988) to Dendranthema morifolium (Ramat). Contact Dermatitis
South Carolina florists dermatitis. Case report and survey 35:310-311
results. J S C Med Assoc 84:446-448 360. Van Baar HM, Van der Valk PG (1994) Contact allergy due
334. Merriek C, Fenney I, Clarke EC, Hodnett T, Fleteher G (1991) to Trachelium caeruleum. Contact Dermatitis 31:118-119
A survey of skin problems in floristry. Contact Dermatitis 361. Bossuyt L, Dooms-Goossens A (1994) Contact sensitivity to
24:306 nettles and camomile in 'alternative' remedies. Contact
335. Pereira F (1996) Hand dermatitis in florists. Contact Dermatitis 31:131-132
Dermatitis 34:144-145 362. Hausen BM (1985) Kokardenblumen Allergie [Gaillardia
336. Kanerva L, Estlander T, Jolanki R (1994) Occupational allergy]. Derm Beruf Umwelt 33:62-65
allergie contact dermatitis caused by tlIiourea compounds. 363. Goerz G, Wirth G, Maas B, Willuhn G (1985) Allergische
Contact Dermatitis 31:242-248 Kontaktdermatitis auf Asteraceae (Kompositen).
337. Hausen BM (1981) [Occupational contact allergy to feverfew Kreuzreaktion mit Liatris spicata. [Allergie contact derma-
Tanacetum parthenium (L.) Schultz Bip., Asteraceae] Be- titis due to Asteraceae (Compositae). Cross reaction with
rufsbedingte Kontaktallergie auf Mutterkraut (Tanacetum Liatris spieata]. Derm Beruf Umwelt 33:95-98
partiienium (L.) Schultz Bip., Asteraceae). Derm Beruf 364. Van Ketel WG (1987) Allergy to Matricaria chamomilla.
Umwelt 29:18-21 Contact Dermatitis 16:50-51
338. Van Grutten M (1980) Carnation dermatitis in a flower 365. Van Ketel WG (1982) Allergy to Matriearia chamomilla.
seiler. Contact Dermatitis 6:289 Contact Dermatitis 8:143
339. Wilkinson SM, Beck MH, English JS, Lovell CR (1994) 366. Manzano D, Aguirre A, Gardeazabal J, Oleaga JM, Izu R,
Contact dermatitis from Fremontodendron. Contact Der- Zabala R, Diaz-Perez JL (1994) Airborne allergie contact
matitis 31:192-193 dermatitis due to wild plants. Contact Dermatitis 31:188-189
340. Southcott RV, Haegi LA (1992) Plant hair dermatitis. Med J 367. Contact Dermatitis (1995) Erratum. Contact Dermatitis
Aust 156:623-4, 627-32 32 :3 18
341. Lear JT, Tan BB, Lovell CR, English JS (1996) Irritant contact 368. Calnan CD (1978) Sensitivity to dalIiia flowers. Contact
dermatitis from Cerastium tomentosum (snow in summer). Dermatitis 4:168
Contact Dermatitis 35:182 369. Vryman LH (1933) Dahlienwurzelrinden dermatitis. Arch
342. Webster GL (1986) Irritant plants in the spurge family Dermatol Syphilol 168:233
(Euphorbiaceae). Clin Dermatol 4:36-45 370. Sharma SC, Kaur S (1990) Contact dermatitis from Dahlia
343. Stoner JG, Rasmussen JE (1983) Plant dermatitis. J Am Acad pinnata. Contact Dermatitis 23:204-205
Dermatol 9:1-15 371. Aberer W, Hausen BM (1990) Active sensitization to
344. Julian CG, Bowers PW (1997) The nature and distribution of elecampane by patch testing to a crude plant extract.
daffodil pickers' rash. Contact Dermatitis 37:259-262 Contact Dermatitis 22:53-55
345. Bruze M, Bjorkner B, Hellstrom AC (1996) Occupational 372. Schaeffer M, Talaga P, Stampf JL, Benezra C (1990) Cross
dermatoses in nursery workers. Am J Contact Dermat 7: reaction in allergie contact dermatitis from alpha methylene
100-103 gamma butyrolactones: importance of the cis and trans ring
346. Stoof TI, Bruynzeel DP (1989) Contact allergy to Nephrol- junction. Contact Dermatitis 22:32-36
epsis ferns. Contact Dermatitis 20:234-235 373. Temesvari E (1982) Occupational contact sensitivity from
347. Shelley WB, Shelley ED, Welbourn WC (1985) Polypodium sainpaulia ionantlIa. Contact Dermatitis 8:426
fern wreaths (hagnaya): a new source of mite infestation. 374. Weller R, Ormerod A (1996) Contact dermatitis from
JAMA 253:3137-3158 cotoneaster. Contact Dermatitis 34:433-434
348. Van Ketel WG (1976) Sensitivity to the pesticide benomyl. 375. Saihan EM, Harman RR (1978) Coleus sensitivity in a
Contact Dermatitis 2:290 gardener. Contact Dermatitis 4:234-235
349. Knight TE (1991) Philodendron induced dermatitis: report 376. Goh CL (1986) Contact sensitivity to Wedelia trilobata.
of cases and review of the literature. Cutis 48:375-378 Contact Dermatitis 14:126
350. Menz j, Rossi ER, Taylor WC, Wall L (1986) Contact 377. Turner T (1980) Compositae dermatitis in South Australia:
dermatitis from Grevillea 'Robyn Gordon'. Contact Derma- contact dermatitis from Ixodia achillaeoides and Cynara
titis 15:126-131 cardunculus or the tribulations of a dry flower arranger.
351 a. Hammershoy 0, Verdich J (1980) Allergie contact Contact Dermatitis 6:444
dermatitis from Philodendron scandens Koch et Sello subsp 378. Meijer P, Coenraads Pj, Hausen BM (1990) Allergie contact
oxycardium (Schott) Bunting "Philodendron scandens cor- dermatitis from hydrangea. Contact Dermatitis 23:59-60
datum. Contact Dermatitis 6:95-99 379. Bruynzeel DP (1991) Contact dermatitis from hydrangea
351. Lothian N (1989) Grevillea species and hybrids causing [letter, comment]. Contact Dermatitis 24:78
contact dermatitis. Australas J Dermatol 30:1l1-113 380. Bruynzeel DP (1986) Allergie contact dermatitis to hydran-
352. Ayres S Jr, Ayres S III (1958) Philodendron as a cause of gea. Contact Dermatitis 14:128
contact dermatitis. Arch Dermatol 78:330-333 381. Kuligowski ME, Chang A, Leemreize JH (1992) Allergie
353. Mobacken H (1975) Allergie plant dermatitis from Scindap- contact hand dermatitis from hydrangea: report of a 10th
sus aureus. Contact Dermatitis 1:60-61 case. Contact Dermatitis 26:269-270
354. Dooms-Goossens A, Matura M, Drieghe I, Degreef H (1995) 382. Apted jH (1973) Phytodermatitis from hydrangeas. Arch
Contact allergy to imidazoles used as antimycotie agents. Dermatol 108:427
Contact Dermatitis 33:73-77 384. Bruynzeel DP, Hausen BM (1987) Allergie contact dermatitis
355. Calnan CD (1981) Dermatitis from ivy (Hedera canariensis to hydrangea. Contact Dermatitis 16:181
variegata). Contact Dermatitis 7:124-125 385. Hausen BM (1982) Airborne contact dermatitis caused by
356. Giannattasio M, Pizzolongo P, Cristaudo A, Cannistraci C, tulip bulbs. J Am Acad Dermatol 7:500-503
Salvatore G, Santucci B (1996) Contact dermatitis from 386. Apted jH (1990) Contact dermatitis due to Alstroemeria
Tetrapanax papyriferum trichomes. Contact Dermatitis (Peruvian lily). Australas J Dermatol 31:1l1-113
35:106-107 387. Santucci B, Picardo M, Iavarone C, Trogolo C (1985) Contact
357. Campolmi P, Sertoli A, Fabbri P, Panconesi E (1978) dermatitis to Alstroemeria. Contact Dermatitis 12:215-219
Alantolactone sensitivity in chrysanthemum contact derma- 388. Hausen BM, Schulz KH (1977) Occupational contact derma-
titis. Contact Dermatitis 4:93-102 titis due to croton (Codiaeum variegatum (L.) A. juss var.
764 J.D. Guin
pictum (Lodd.) Muell. Arg.). Sensitization by plants of the tional skin diseases in workers engaged in the wet spinning
Euphorbiaceae. Contact Dermatitis 3:289-292 of flax]. Vestn Dermatol Venerol 3:51-52
389. Tafelkruyer J, Van Ketel WG (1976) Sensitivity to Codiaeum 419. Makushkina VK (1983) Kliniko morfologieheskie izmeneniia
variegatum. Contact Dermatitis 2:288 kozhi u rabotnits tekstil'nogo proizvodstva po pererabotke
390. Van Ketel WG (1979) Occupational contact dermatitis due to l'na [Clinico morphological changes in the skin of female
Codiaeum variegatum and possibly to Aeschynantus puk- textile industry workers processing flax]. Vestn Dermatol
her. Derm Beruf Umwelt 27:141-142 Venerol 5:57-60
391. Santucci B, Pieardo M, Cristaudo A (1985) Contact derma- 420. Makushkina VK (1980) Osobennosti kliniki i techeniia
titis from Euphorbia pukherrima. Contact Dermatitis professional'nykh dermatozov u rabochikh l'nokombinata
12:285-286 [Characteristics of the clinical pieture and course of
392. Bedi BM (1971) Jasmine flower contact dermatitis. (Report of occupational dermatoses in flax plant workers]. Vestn
a case). Indian J DermatoI16:61-62 Dermatol Venerol 11:46-49
393. Bruynzeel DP (1989) Contact dermatitis due to Paeonia 421. Tsyrkunov LP (1981) Zabolevaniia kozhi u rabochikh
(peony). Contact Dermatitis 20:152-153 l'nopererabatyvaiushchikh zavodov [Skin diseases in flax
394. Korstanje MJ, Van de Staak WJ (1990) A case of hand processing plant workers]. Vestn Dermatol VeneroI7:60-62
eczema due to mushrooms. Contact Dermatitis 22:115-116 422. Tsirkunov LP (1965) 0 zabolevaniiakh kozhi sel'skokho-
395. Dei Pozo MD, Gastaminza G, Navarro JA, Munoz D, ziaistvennykh rabochikh l'novodcheskogo i sveklovodches-
Fernandez E, Fernandez de Corres L (1994) Allergie contact koge raionov [Skin diseases among agricultural workers in
dermatitis from Verbena officinalis 1. Contact Dermatitis flax and sugar beet of areas]. Vrach Delo 5:110-111
31:200-201 423. Soni BP, Sherertz EF (1996) Contact dermatitis in the textile
396. Hardie RA, Rajan VS (1981) A survey of orchid growers. industry: a review of 72 patients. Am J Contact Dermat
397. MacAulay JC (1987) Orchid allergy. Contact Dermatitis 424. Cirla AM, Nava C, Limonta A (1970) A case of occupational
17:112-113 allergy to tamarind flour (in Italian). Med Lav 61:447-451
398. Hausen BM, Shoji A, Jarchow 0 (1984) Orchid allergy. Arch 425. Rycroft RJ, Smith NP, Stok ET, Middleton K (1981)
Dermatol 120:1206-1208 Investigation of suspected contact sensitivity to tobacco in
399. Czarnecki D, Nixon R, Bekhor P, Mason G (1993) Delayed cigarette and cigar factory employees. Contact Dermatitis
prolonged contact urticaria from the elm tree. Contact 7:32-38
Dermatitis 28:196-197 426. Samitz MH, Mori P, Long CF (1949) Dermatologieal hazards
400. Lahti A (1986) Contact urticaria and respiratory symptoms in the cigar industry. Ind Med Surg 18:434-439
from tulips and lily. Contact Dermatitis 14:317-319 427. Wong WK, Ng SK, Goh CL (1994) Grass allergy among
401. Quirce S, Garcia Figueroa B, Olaguibel JM, Muro MD, Tabar national servieemen in Singapore. A preliminary report.
AI (1993) Occupational asthma and contact urtiearia from Contact Dermatitis 30:108-109
dried flowers of Limonium tataricum. Allergy 48:285-290 428. Koh D, Goh CL, Tan HT, Ng SK, Wong WK (1997) Allergie
402. Tanaka T, Moriwaki SI, Horio T (1987) Occupational contact dermatitis from grasses. Contact Dermatitis 37:32-34
dermatitis with simultaneous immediate and delayed allergy 429. Livingood CS, Rogers AM, FitzHugh T Jr (1943) Dhobi mark
to chrysanthemum. Contact Dermatitis 16:152-154 dermatitis. JAMA 123:23-26
403. Laiiti A (1986) Contact urtiearia to plants. Clin Dermatol 430. Satulsky EM, Wirts CA (1943) Dermatitis venenata caused
4:127-136 by the manzanillo tree. Arch Dermatol Syphilol 47:797-798
404. Ena P, Cerri R, Dessi G, Manconi PM, Atzei AD (1991) 431. Oliwiecki S, Beck MH, Hausen BM (1992) Occupational
Phototoxicity due to Cachrys libanotis. Contact Dermatitis allergic contact dermatitis from caffeates in poplar bud resin
24: 1-5 in a tree surgeon. Contact Dermatitis 27:127-128
405. Lindemayr H, Jager S (1980) Beruflich erworbene Typ I 432. Knight TE, Boll P, Epstein WL, Prasad AK (1996) Resorcin-
Allergie durch Hanfpollen und Haschisch [Occupational ols and catechols: a clinical study of cross sensitivity. Am J
immediate type allergy to hemp pollen and hashish]. Derm Contact Dermat 7:138-145
Beruf Umwelt 28:17-19 433. Kawai K, Nakagawa M, Kawai K, Miyakoshi T, Miyashita K,
406. Dorsey CS (1957) Contact dermatitis from Algerian ivy. Arch Asami T (1992) Heat treatment of Japanese lacquerware
Dermatol 75:671-675 renders it hypoallergenic. Contact Dermatitis 27:244-249
407. Hausen BM, Brohan J, Konig WA, et al. (1987) Allergie and 434. Bruynzeel DP, van Ketel WG, Young E, van JoostT, Smeenk G
irritant contact dermatitis from fakarinol and did- (1992) Contact sensitization by alternative topieal mediea-
ehydrofakarinol in common ivy (Hedera helix, 1.). Contact ments containing plant extracts. The Dutch Contact De-
Dermatitis 17:1-9 rmatoses Group. Contact Dermatitis 27:278-279
408. Roed-Petersen J (1975) Allergie contact hypersensitivity to 435. De Groot AC, Weyland JW (1992) Systemie contact derma-
ivy (Hedera helix). Contact Dermatitis 1:57 titis from tea tree oil. Contact Dermatitis 27:279-280
409. Hansen L, Hammershoy 0, Boll PM (1986) Allergie contact 436. Selvaag E, Eriksen B, Thune P (1994) Contact allergy due to
dermatitis from fakarinol isolated from Schefflera arbori- tea tree oil and cross sensitization to colophony. Contact
cola. Contact Dermatitis 14:91-93 Dermatitis 31:124-125
410. Hammershoy 0 (1981) Allergic contact dermatitis from 437. Guin JD (1995) Patch testing to plants: some practical
Schefflera. Contact Dermatitis 7:57-58 aspects of what has become an esoterie area of contact
411. Mitchell JC (1981) Allergic contact dermatitis from Hedera dermatitis. Am J Contact Dermat 6:232-235
helix and Brassaia actinophyla. Contact Dermatitis 7:158 438. Bhutani LK, Rao DS (1978) Photocontact dermatitis caused
412. Hausen BM (1980) Arnikaallergie. Hautarzt 31:10-17 by Parthenium hysterophorus. Dermatologiea 157:206-209
413. Trautner EM (1949) A contribution to the causation of 439. Jeanmougin M, Taieb M, Manciet JR, Moulin JP, Civatte J
atropine allergy. Med JAust 12:17 (1988) Photo aggravation d'un eczema de contact a Part-
414. Gauss WF, Alarie JP, Karol MH (1985) Workplace allergeni- henium hysterophorus [Photo aggravated Parthenium
city of a Psyllium containing bulk laxative. Allergy 40:73-76 hysterophorus contact eczema]. Ann Dermatol Venereol
415. Valer M (1965) Die bei Erzeugung von Devincan auftreten- 115=1238-1240
den Hautlasionen. Berufsdermatosen 13:96-110 440. Rampone WM, McCullough JL, Weinstein GD, Towers GH,
416. Van Hecke E (1981) Sensitivity to vincamine tartrate. Berns MW, Abeysekera B (1986) Characterization of cuta-
Contact Dermatitis 7:53 neous phototoxicity induced by topieal alpha terthienyl and
417. Barnes MH (1931) Linseed dermatitis. J Ind Hygeine 13:49-55 ultraviolet A radiation. J luvest Dermatol 87:354-357
418. Makushkina VK, Levin MM, Tsygankova EP (1988) Prof- 441. EI Sayed F, Manzur F, Bayle P, Marguery MS, Bazex J (1995)
ilaktika professional'nykh zabolevanii kozhi u rabochikh, Contact urticaria from abietic acid. Contact Dermatitis
zaniatykh mokrym priadeniem l'na [Prevention of occupa- 32:361-362
442. Zina AM, Bundino S (1983) Contact urticaria to Actinidia 468. Kirton V (1978) Contact urticaria and cinnamic aldehyde.
chinensis. Contact Dermatitis 9:85 Contact Dermatitis 4:374-375
443. Kerner J, Mitchell J, Maibach HI (1973) Irritant contact 469. Caballero T, Garcia Ara C, Pascual C, Diaz Pena JM, Ojeda A
dermatitis from Agave americana L. Incorrect use of sap as (1993) Urticaria induced by caffeine. J Investig AllergoI Clin
"hair restorer". Arch DermatoI108:102-103 Immunol 3:160-162
444. Champion RH (1971) Atopic sensitivity to algae and lichens. 470. Pola 1, Subiza J, Armentia A, Zapata C, Hinojosa M, Losada E,
Br J Dermatol 85:551-557 Valdivieso R (1988) Urtiearia caused by caffeine. Ann Allergy
445. Morrow DM, Rapaport MI, Strick RA (1980) Hypersensitiv- 60:207-208
ity to aloe. Arch Dermatol 116:1064-1065 471. Przybilla B, Ring J, Burg G (1983) Anaphylaxis following
446. Pigatto PD, Riva F, Altomare GF, Parotelli R (1983) Short- ingestion of coffee, chronic urticaria and analgesics id-
term anaphylactic antibodies in contact urtiearia and iosyncrasy (in German). Hautarzt 34:73-76
generalized anaphylaxis to apple. Contact Dermatitis 9:511 472. Rivers JK, Rycroft RJ (1987) Occupational alIergic contact
447. Kremser M, Lindemayr W (1983) Zur Haufigkeit so- urticaria from colophony. Contact Dermatitis 17:181
genannter "Apfelallergie" ("Apfelkontakt Urticariasynd- 473. Van der Meeren HL (1988) Levenbedreigende contacturti-
rom")bei Patienten mit Birkenpollenallergie [Frequency of caria door handschoenpoeder [Life threatening contact
the so called "apple allergy" ("apple contact urtiearia urtiearia due to glove powder]. Ned Tijdschr Geneeskd
syndrome") in patients with birch pollinosis]. Z Hautkr 132:968-970
58:543-552 474. Fisher AA (1987) Contact urticaria and anaphylactoid
448. Kanerva L, Vanhanen M, Tupasela 0 (1997) Occupational reaction due to corn starch surgical glove powder. Contact
allergie contact urtiearia from fungal but not bacterial alpha Dermatitis 16:224-225
amylase. Contact Dermatitis 36:306-307 475. Van der Meeren HL, Van Erp PE (1986) Life threatening
449. Maibach HI (1995) Contact urticaria syndrome from mold contact urticaria from glove powder. Contact Dermatitis
on salami casing. Contact Dermatitis 32:120-121 14:190-191
450. Temesvari E, So os G, Podanyi E, Kovacs I, Nemeth I (1978) 476. Fisher AA (1986) Contact urticaria due to cornstarch
Kontakturtikaria durch Perubalsam [Contact urticaria surgical glove powder. Cutis 38:307-308
caused by Peru balsam]. Derm Beruf Umwelt 26:81-82 477. Van Ketel WG (1982) Contact urticaria from Cotoneaster.
451. Forsbeck M, Skog E (1977) Immediate reactions to patch Contact Dermatitis 8:139
tests with balsam of Peru. Contact Dermatitis 3:201-205 478. Nestler A (1913) Die Hautreizende Wirkung des roten
452. Temesvari E, Soos G, Podanyi B, Kovacs I, Nemeth I (1977) Hartriegels und der Kornelkirsche. Die Umschau 17:860
Perubalzsam contact urticaria [Peru balsam contact urti- 479. Pigatto PD, Bigardi A, Fumagalli M, Legori A, Altomare GF
caria]. Orv Hetil118:1767-1768 (1991) IgE-mediated contact and generalized urtiearia from
453. Meynadier J, Meynadier JM, Guilhou JJ (1982) L'urticaire de Eruca sativa. Contact Dermatitis 25:191-192
contact chez l'atopique. Apropos de deux observations 480. Vidal C, Cabeza N (1992) Contact urticaria due to eucalyptus
[Contact urticaria in atopic patients. Apropos of 2 cases]. pollen. Contact Dermatitis 26:265
Ann Dermatol VenereoI109:871-874 481. Derbes VJ, Coleman WP (1972) Urtiearia due to inhalants.
454. Amin S, TangIertsampan C, Maibach HI (1997) Contact Cutis 9:847
urticaria syndrome: 1997. Am J Contact Dermat 8:15-19 482. Urbach E (1931) Citronendermatitis. Zentralbl Haut Ge-
455. White IR, Calnan CD (1983) Contact urticaria to fruit and schlechtskr 37:787
birch sensitivity. Contact Dermatitis 9:164-165 483. Urbach E, Gottlieb PM (1949) Allergy. Grune and Stratton,
456. Lahti A, Hannuksela M (1980) Immediate contact allergy to New York
birch leaves and sap. Contact Dermatitis 6:464-465 484. Bonnivie P (1935) Urticaria following contact with hay.
457. Fischer T (1991) Bougainvillaea contact urticaria. Contact Vereinigung Dusseldorfer Dermatologen
Dermatitis 24:376 485. Marcussen PV (1935) Vereinigung Dusseldorfer Dermato-
458. Calnan CD (1981) Contact urticaria from cabbage (Brassiea). logen
Contact Dermatitis 7:279 486. Igea JM, Fernandez M, Quirce S, De la Hoz B, Diez-Gomez
459. Valdivieso R, Moneo I, Pola J, Munoz T, Zapata C, Hinojosa M, ML (1994) Green bean hypersensitivity: an occupational
Losada E (1989) Occupational asthma and contact urticaria allergy in a homemaker. J Allergy Clin Immunol 94:33-35
caused by buckwheat flour. Ann Allergy 63:149-152 487. Apted J (1988) Acute contact urtiearia from Grevillea
460. Lahti A (1995) Immediate contact reactions. In: Rycroft RJG, juniperina. Contact Dermatitis 18:126
Menne T, Frosch PJ (eds) Textbook of contact dermatitis. 488. Apted J (1988) Acute contact urticaria from Hakea suaveo-
Springer, Berlin Heidelberg New York, pp 62-74 lens. Contact Dermatitis 18:126
461. Niinimaki A, Hannuksela M (1983) Immediate skin reactions 489. Steinman HK, Lovell CR, Cronin E (1984) Immediate type
to spiees. Allergy 51:269-272 hypersensitivity to Crataegus monogyna (hawthorn). Con-
462. Kanerva L, Estlander T, Jolanki R (1990) Long-lasting tact Dermatitis 11:321
contact urtiearia from castor bean. J Am Acad Dermatol 490. Cronin E (1979) Immediate type hypersensitivity to henna.
463. Kremser M, Lindemayr W (1983) Sellerieallergie (Seller- 491. Majoie IM, Bruynzeel DP (1996) Occupational immediate
iekontakturtikariasyndrom) und Zusammenhange mit All- type hypersensitivity to henna in a hairdresser. Am J
ergien gegen andere Pflanzenantigene [Celery allergy Contact Dermat 7:38-40
(celery contact urticaria syndrome) and relation to aller- 492. Sir-Hashim M, Hamza YO, Yahia B, Khogali FM, Sulieman
gies to other plant antigens]. Wien Klin Wochenschr GI (1992) Poisoning from henna dye and para phenylene-
95:838-843 diamine mixtures in children in Khartoum. Ann Trop
464. Valsecchi R, Tribbia G, Foiadelli L, Rossi A, Cainelli T (1987) Paediatr 12:3-6
L'orticaria da contatto. Descrizione di un caso [Contact 493. Lombardi P, Campolmi P, Giorgini S, Spallanzani P, Sertoli A
urticaria. Description of a case]. G !tal Dermatol Venereol (1983) Contact urticaria from fish, honey and peach skin.
465. Allenby CF, Goodwin BF, Safford RJ (1984) Diminution of 494. Raith L, Jager K (1984) Hop allergy. Contact Dermatitis 11:53
immediate reactions to cinnamic aldehyde by eugenol. 495. Veraldi S, Schianchi Veraldi R (1990) Contact urticaria from
Contact Dermatitis 11:322-323 kiwi fruit. Contact Dermatitis 22:244
466. Guin JD, Meyer BN, Drake RD, Haffley P (1984) The effect of 496. MacFarlane WV (1963) The stinging properties of Laportea.
quenching agents on contact urticaria caused by cinnamic Econ Bot 17:303
aldehyde. J Am Acad Dermatol 10:45-51 497. Urchida C, Norikane S (1958) The pathology of dermatitis
467. Warner MR, Taylor JS, Leow YH (1997) Agents causing caused by "Iranoki" (Laportea pterostidua weed): indigi-
contact urticaria. Clin Dermatol 15:623-635 nous plant of Formosa. J Med Assoc Formosa 35
766 J.D. Guin: Occupational Contact Dermatitis to Plants
498. Nutter AF (1979) Contact urtiearia to rubber. Br J Dermatol witb constitutional eczema]. Ned Tijdschr Geneeskd 136:
101:597-598 1347-1351
499. Taylor JS, Praditsuwan P (1996) Latex allergy. Review of 44 516. Van Ketel WG (1982) Skin eruptions caused by vegetables
cases including outcome and frequent association witb and fruit including pears. Contact Dermatitis 8:352
allergie hand eczema. Arch Dermatol 132:265-271 517. Marshman G, Lovell CR (1991) Contact urtiearia from
500. Lahti A, Turjanmaa K (1992) Prick and use tests witb 6 glove runner bean (Phaseolus multiflorus). Contact Dermatitis
brands in patients with immediate allergy to rubber 24:76
proteins. Contact Dermatitis 26:259-262 518. Edwards EK Jr, Edwards EK (1984) Contact urticaria
501. Giannattasio M, Serafini M, Guarrera P, Cannistraci C, provoked by pickies. Cutis 33:230
Cristaudo A, Santucci B (1995) Contact urticaria from litchi 519. Panaszek B, Malolepszy J, Kuryszko J, Litwa M (1994)
fruit (Litchi chinensis Sonn.). Contact Dermatitis 33:67 Specific pollen allergen activates eosinophils of the patient
502. Gutierrez D, Conde A, Duran S, Delgado J, Guardia P, with chronie allergie contact urticaria. Arch Immunol Ther
Martinez R, Garcia-Cubillana A, Gonzalez J, Conde J (1997) Exp (Warsz) 42:253-258
Contact urticaria from lupin. Contact Dermatitis 36:311 520. Gamboa PM, Jauregui I, Urrutia I, Gonzalez G, Barturen P,
503. Goransson K (1980) Contact urtiearia and rhinoconjuncti- Antepara I (1997) Allergie contact urticaria from poppy
vitis from tropical wood (Lauan, Philippine red mahogany). flowers (Papaver rhoeas). Contact Dermatitis 37:140-141
Contact Dermatitis 6:223-224 521. Delgado J, Castillo R, Quiralte J, Blanco C, Carrillo T (1996)
504. Calvert ML, Robertson I, Samaratunga H (1996) Mango Contact urticaria in a child from raw potato. Contact
dermatitis: allergic contact dermatitis to Mangifera indiea. Dermatitis 35:179-180
Australas J Dermatol 37:59-60 522. Larko 0, Lindstedt G, Lundberg PA, Mobacken H (1983)
505. Vaughn WT (1933) Food allergy as a common problem. J Lab Biochemieal and clinical studies in a case of contact
Clin Med 19:53-63 urticaria to potato. Contact Dermatitis 9:108-114
506. Garces-Sotillos MM, Blanco-Carmona JG, Juste-Pieon S 523. Sasai S, Takallashi K, Takallashi K, Tagami H (1995) Contact
(1995) Occupational astbma and contact urtiearia caused urtiearia to rice. Br J DermatoI132:836-837
by mukali wood dust (Aningeria robusta). J Investig Allergoi 524. Di Lernia V, Albertini G, Bisighini G (1992) Immunologie
Clin Immunol 5:113-114 contact urtiearia syndrome from raw riee. Contact Derma-
507. Munoz FJ, Delgado J, Palma JL, Gimenez MJ, Monteseirin titis 27:196
FJ, Conde J (1995) Airborne contact urticaria due to 525. Stenberg M (1908) Aus dem gebiete der Berufskrankheiten.
mulberry (Morus alba) pollen. Contact Dermatitis 32:61 Med Klin 14:479
508. Oliver F, Amon EU, Breatbnach A, Francis DM, Sara- 526. Grauer FH, Arnold HL (1961) Seaweed dermatitis: first
tbchandra P, Black AK, Greaves MW (1991) Contact report of a dermatitis producing marine alga. Arch De-
urticaria due to the common stinging nettle (Urtica dioica) rmatol 84:720-732
- histological, ultrastructural and pharmacological studies. 527. Shankar DS (1992) Contact urticaria induced by Semecarpus
Clin Exp DermatoI16:1-7 anacardium. Contact Dermatitis 26:200
509. Kulze A, Greaves M (1988) Contact urtiearia caused by 528. Galindo PA, Feo F, Garcia R, Gomez E, Melero R, Martin-
stinging nettles Br J Dermatol 119:269-270 Esteban M, Ojeda JA (1996) Contact urtiearia from stock, a
510. Thurston EL, Lersten NL (1969) The morphology and cruciferae plant. Allergy 51:363-364
toxieology of plant stinging hairs. Bot Rev 35:393 529. Grattan CE, Harman RR (1985) Contact urticaria to straw-
511. Hinojosa M, Subiza J, Moneo I, Puyana J, Diez ML, berry. Contact Dermatitis 1):191-192
Fernandez-Rivas M (1990) Contact urtiearia caused by 530. Schmidt H (1978) Contact urtiearia to teak witb systemie
Obeche wood (Triplochiton scleroxylon). Report of eight effects. Contact Dermatitis 4:176-177
patients. Ann Allergy 64:476-479 531. Picardo M, Rovina R, Cristaudo A, Cannistraci C, Santucci B
512. Santucci B, Cristaudo A, Picardo M (1985) Contact urticaria (1988) Contact urtiearia from Tilia (lirne). Contact Derma-
from papain in a soft lens solution. Contact Dermatitis titis 19:72-73
12:233 532. Powell RF, Smith EB (1978) Tumbleweed dermatitis. Arch
513. Cantani A (1997) Allergic reaction to inadvertent peanut DermatoI114:751-754
contact in a child. Allergy Asthma Proc 18:323-326 533. Temesvari E, Becker K (1993) Contact urtiearia from
514. Matbias CG (1983) Contact urticaria from peanut butter. watermelon in a patient witb pollen allergy. Contact
515. Oranje AP, Van Toorenenbergen AW, Mulder PG, Aarsen 534. Langeland T, Nyrud M (1982) Contact urticaria to wheat
RS, Liefaard G, Vermeulen AM (1992) Immunologisch bran batb: a case report. Acta Derm Venereol 62:82-83
bepaalde contacturticaria door voeding bij jonge kinderen 535. Lovell CR, Rycroft RJ (1984) Contact urticaria from winged
met constitutioneel eczeem [Immunologically mediated bean the (Psophocarpus tetragonolobus). Contact Dermati-
contact urticaria caused by foods in young children tis 10:314-315
CHAPTER 90
Spices
A. Niinimäki
Introduction spiee), einnamon, nutmeg, paprika and ginger elieited

positive reaetions most frequently (Niinimäki 1984;
van den Akker et al. 1990; Bruynzeel and Prevoo 1990;
For more than a eentury, spiees have been known to
Futrell and Rietsehel 1993). Vanilla has also been
eause eontaet dermatitis. In the first half of this
reported to be a signifieant eontaet allergen (Hjorth
eentury, spiees were reported as signifieant eauses of
1961). All these studies have revealed a eorrelation
allergie eontaet dermatitis, especially in bakers and
between allergies to perfumes and spices, obviously
eonfeetioners. In addition to delayed-type eontaet
due to their identieal or related substanees. Contaet
allergies, spiees may also eause immediate allergies
dermatitis has also been reported from bay (laurel) leaf
(Niinimäki et al. 1981; Thiel and Fuchs 1981). Although
(Foussereau et al. 1967), eardamom (Mobacken and
spiees are relatively rare eauses of oeeupational
Fregert 1975), turmerie (Goh and Ng 1987) and mustard
dermatitis today (Kanerva et al. 1996), they should be
(Dannaker and White 1987). Garlie is a well-known
taken into eonsideration when assessing the hand
contaet allergen in food handlers (Hjorth and Roed-
dermatitis of workers exposed to spices.
Petersen 1976).
Origin and Sensitizing Constituents of Spices

Immediate Allergy to Spices
Spiees are aromatie parts of plants, ineluding seeds,
fruits, roots, buds, flowers and barks. A synonymous
In routine serateh or priek tests with native spices,
term, herb, is used for aromatie plants whose dried or
paprika, mustard, eoriander, earaway, eayenne, anise,
fresh leaves or shoots are used. The boundary between
dill, fennei, eelery seed and parsley elieited positive
spiees and some aromatie plants may be vague. For
reaetions most frequently (Niinimäki et al. 1981; Thiel
example, garlie, eayenne and paprika might be
et al. 1984). In an investigation performed on workers
regarded as either vegetables or spices. The flavoring
preparing fish fingers, three out of 122 reaeted to
eonstituents of spiees are usually found in their
mustard in skin-prick tests (Kavli and Moseng 1987).
ethereal oils, the main eomponents of which are
Positive serateh/priek test reaetions to spie es and
mostly known (Merek and Co., Ine. 1989). Spiee oils
elevated spiee-speeifie serum immunoglobulin E (IgE)
and their eonstituents are also used in perfumery.
values have been seen, espeeially in subjeets with bireh
Spiee oils eontain substanees whieh may irritate the
or mugwort-pollen allergy (Niinimäki et al. 1981; Thiel
skin and eause type IV allergies (Table 1). Spiees also
and Fuchs 1981; Thiel et al. 1984). These subjeets also
eontain pro teins whieh may eause immediate allergies.
frequently reaet to fresh fruits and vegetables, and
The two major type-I allergens of mustards (Sinapis
therefore a term "eelery-earrot-mugwort-spiee syn-
alba and Brassica juncea) have been eharaeterized in
drome" has been proposed (Wüthrieh and Hofer 1984;
detail. Both are albumins with moleeular weights of
Wüthrieh and Dietsehi 1985). Test reaetions to
14 kDa (Menendez-Arias et al. 1988; Gonzatez de la
lyophilized spiee extraets (Fig. 1) and elevated serum
Pena et al. 1991).
spiee-speeifie IgE suggest that the priek-test reaetions
to native spiees are true allergie reaetions (Niinimäki
et al. ~989; Niinimäki et al. 1995; van Toorenenbergen
Delayed Allergy to Spices
and Dleges 1985; van Toorenenbergen and Dieges 1987).
!he eorrelation between pollens, vegetables and spiees
In routine pateh tests with native spiees performed on IS probably due to eross-allergies (van Toorenenbergen
dermatologie al patients, elove, Jamaiea pepper (all- et al. 1988; Stäger et al. 1991; Helbling et al. 1993).

768 A. Niinimäki
Table 1. Patch-test materials for some ordinary spices
Native (powdered) spices' Ethereal oils of spices d; Merck Known allergens of spice oi!se
Index numbers in the parentheses
Basilica Oi! ofbasil4% (6695) Linalool (1%, 2%, 20%, 30%)

Bay (laurel) leaf Oi! of sweet bay 4% (6771) Costunolidef , eugenolf , pinene
(1 %, 12%, 15%)
Caraway Oi! of caraway 4% (6703) Dipentene (limonene )f,
carvone (2%, 5%)
Cardamom Oi! of cardamom (6704) 4% Dipentene f
Cayenne (Capsicum Jrutescens)b
Clove Oi! of clove (6718) 2% Eugenolf , vanillin f
Cassia (Chinese cinnamon); Oi! of cassia (6715) 4%; Cinnamic aldehyde f , eugenolf
cinnamon of Ceylon oi! of cinnamon, Ceylon (6716) 8%
Coriander Oi! of coriander (6720) 6% Linalool (1%, 2%, 20%, 30%)
Garlicb Diallyldisulphidef
Ginger Oil of ginger (6734) 4% Phellandrene (5%), citral (1 %, 2%)
Jamaica pepper (allspiee, pimenta) Oi! of pimenta (6760) 8% Eugenol f
Marjoram Oil of marjoram (6744) 6%
Mustard (seeds of white and black mustard)b Allyl isothiocyanate (293) 0.1 %
Nutmeg Oi! of nutmeg (6749) 8% Eugenol f , dipentene f, geraniolf ,
pinene (1 %, 12%, 15%)
Oregano Oi! of origanum (6752) 2%
Paprika (Capsicum annuum)b
Spearmint Oil of spearmint (6768) 2% Dipentene f, carvone (2%, 5%),
pinene (1 %, 12%, 15%)
Vanillac Vanillinf
• All may irritate when tested as such. In doubtful cases, 25% and 10% di!utions in petrolatum may be used (Futrell and Rietschel1993)
bNot suitable to be tested as such. Dilutions (in petrolatum) may be used: cayenne as 0.5% (de Groot 1994), paprika as 25% (Futrell
and Rietschel 1993), garlic and mustard as 10% (Kanerva et al. 1996)
C Today, synthetic vanillin is almost always used instead of native vanilla
dThe presented concentrations do not irritate, i.e., they are safe for patch testing (de Groot 1994)
e The test concentrations of the allergens which are not avai!able as ready test materials from patch-test-allergen suppliers are
presented in parentheses. These concentrations were collected from the literature by de Groot and are cited in his monograph (de
Groot 1994)
f The allergens available as ready test materials from allergen suppliers
Clinical Picture of Contact Dermatitis from Spices faetors in multietiologieal ehronie hand dermatitis.
Garlie dermatitis has a typieal distribution on the finger
tips.
In addition to spice-processing plants, spices are
handled in almost all places where food is prepared
or meals are served. Of the five patients with
occupational spice allergy reported by Kanerva and
his coworkers, two were chefs, one a kitchen assistant,
one a coffee-room assistant and one a self-employed
restaurant worker (Kanerva et al. 1996). Spices may be
handled directly, but workers may also be exposed
indirectly to spiced foodstuffs, contaminated spice
containers and contaminated work surfaces. The
exposure may be aerogenic when bare and wet hands
are used to add powdered spices to foods.
Delayed (type-IV) allergy to spices manifests as
"classie" allergie eontaet dermatitis. Immediate (type-I)
allergy manifests as eontaet urticaria or protein eontaet
dermatitis. The primary urticarial reactions may be
weak and fade rapidly, and may even go unnotieed by
the worker her/himself. Instead, protein eontaet der-
matitis develops (Hjorth and Roed-Petersen 1976; Fig. 1. Positive prick-test reactions from various dilutions of
Janssens et al. 1995). The dermatitis eaused by spiees Iyophilized mustard extract (cut-offs of 3.5 kDa and 8 kDa). The
is situated mostly on the palmar sides of the fingers and prick-test reaction from corresponding native mustard (a
mixture of seeds of white mustard, Sinapis alba, and black
hands (Niinimäki et al. 1981; Kanerva et al. 1996). In mustard, Brassica nigra) performed 0.5-1 h earlier is dimly
most eases, spiees are one among the many aggravating visible above
Spices 769
Skin Tests with Spices sie" contact dermatitis on their hands. Consequently,
both prick tests and patch tests with spie es are needed
if contact dermatitis from spices is suspected. Delayed
Both patch and prick tests can be performed with
allergy to spices is mostly seen in subjects previously
native spices as such. Patch tests can also be done with sensitized to perfumes. Immediate allergies are almost
ethereal oils of spices. In addition, some pure allergens
exclusively seen in atopics, especially those with
of spiee oils are available from patch-test allergen
allergies to birch or mugwort pollens. Patients with
suppliers (Table 1). The selection of spices used in tests
immediate allergies to spices frequently also react to
is dependent on the worker's exposure his tory. In most fresh fruits or vegetables. Allergies to spices are hardly
cases, cinnamon, clove, cardamom, allspiee, vanilla,
ever the only causes of dermatitis. Avoidance of all
ginger and nutmeg should be tested with patch tests,
aggravating factors, including spices, is essential to the
and mustard, coriander, caraway, celery seed and
recovery of the mostly multi-etiological hand derma-
parsley with prick tests. Paprika and garlic should be
titis of food handlers.
tested with both patch and prick tests.
In patch tests, dry powdered spices are put in Finn
chambers on a moistened filter paper. The tests are
read and interpreted according to the recommenda-
tions of the International Contact Dermatitis Research References
Group. Garlic, mustard, paprika and cayenne are too
irritative to be tested as such (Table 1). Patch tests with Bruynzeel DP, Prevoo RL (1990) Pateh tests with some spie es.
other native spices may also elicit irritant reactions Dermatol Clin 8:85-87
Dannaker CJ, White IR (1987) Cutaneous allergy to mustard in
(Meding 1993; Niinimäki 1987), and dilution tests may salad maker. Contaet Dermatitis 6:212-214
be needed. Patch tests with ethereal oils and pure de Groot AC (1994) Pateh testing. Elsevier, Amsterdam
allergens of spie es may also be used (Table 1). Dreborg S, Foueard T (1983) Allergy to apple, earrot and potato in
ehildren with bireh pollen allergy. Allergy 38:167-172
Prick tests are performed with native spie es as European Aeademy of Allergology and Clinieal Immunology
follows: a small amount (2-5 mg) of powdered spiee Subeommittee on Skin Tests (1993) Position paper: allergen
and a drop of saline are first mixed on the skin and standardization and skin tests. Allergy 48 [suppl 14l :48-62
Foussereau J, Benezra CL, Ourisson G (1967) Contaet Dermatitis
then pricked into the skin. The reactions are read after from laure!. I. Clinieal aspeets. Trans St Johns Hosp Dermatol
15 min. Reactions with a diameter of at least 3 mm Soe 53=141-146
larger than the negative control (saline) are regarded as Futrell JM, Rietsehel RL (1993) Spiee allergy evaluated by results
of pateh tests. Cutis 52:288-290
positive (European Academy of Allergology and Goh CL, Ng SK (1987) Allergie eontaet dermatitis to Curcuma
Clinical Immunology Subcommittee on Skin Tests longa (turmerie). Contaet Dermatitis 17:186
1993). In cases of fresh materials, prick-prick tests Gonzalez de la Peiia MA, Menendez-Arias L, Monsalve RI,
Rodriguez R (1991) Isolation and eharaeterization of a major
(Dreborg and Foucard 1983) or scratch-chamber allergen from oriental mustard seeds, BrajI. Int Areh Allergy
tests (Hannuksela and Lahti 1977) can be used. In a Appl Immunol 96:263-270
prick-prick test, the tested material (for example Hannuksela M, Lahti A (1977) Immediate reaetions to fruits and
vegetables. Contaet Dermatitis 3:79-84
garlic) is first pricked with the prick lancet and then Helbling A, Lopez M, Sehwartz HJ, Lehrer SB (1993) Reaetivity of
the skin is pricked with the same lancet. In a scratch- earrot-specifie IgE antibodies with eelery, apiaeeous spiees
chamber test, the test material (for example parsley) is and bireh pollen. Ann Allergy 70:495-499
Hjorth N (1961) Eezematous allergy to balsams, allied perfumes
first put in Finn chambers and the chambers are then and fiavouring agents with special referenee to balsam of
fixed onto 5-mm scratches of the skin. After 20 min, Peru. Acta Derm Venereol Suppl (Stoekh) 41:46
the chambers are opened and the reactions are read Hjorth N, Roed-Petersen J (1976) Oeeupational protein eontaet
dermatitis in food handlers. Contaet Dermatitis 2:28-42
like the prick tests. Determination of spice-specific IgE Janssens J, Morren M, Dooms-Goosssens A, Degreef H (1995)
of serum (radioallergosorbent test; RAST) may also be Protein eontaet dermatitis: myth or reality. Br J Dermatol
used when evaluating the clinical significance of the 132:1-6
Kanerva L, Estlander T, Jolanki R (1996) Oeeupational allergie
reactions. RAST may be negative in prick-test-positive eontaet dermatitis from spices. Contaet Dermatitis 35:
cases (Niinimäki et al. 1995). 157-162
Kavli G, Moseng D (1987) Contaet urtiearia from mustard in fish-
stick produetion. Contaet Dermatitis 17:153-155
Meding B (1993) Skin symptoms among workers in a spiee
faetory. Contaet Dermatitis 29:202-205
Conclusions Menendez-Arias L, Moneo I, Dominguez J, Rodriguez R (1988)
Primary strueture of tlle major allergen of yellow mustard
(Sinapis alba L) seed, SinaI. Eur J Bioehern 177:159-166
Workers may be exposed to spices in various Merek and Co., Ine. (1989) The Merek index, an eneyc10pedia of
occupations where food is handled. Spices may cause chemie als, drugs, and biologieals, 11th edn (1989) Merek and
Co., Rahway
both immediate and delayed allergies manifesting as Mobaeken H, Fregert S (1975) Allergie eontaet dermatitis from
contact urticaria, pro tein contact dermatitis or "clas- eardamom. Contaet Dermatitis 1:175-176
770 A. Niinimäki: Spices
Niinimäki A (1984) Delayed-type allergy to spiees. Contact Mitteilung. In: 4. Kölner RAST -Symposium, Pharmacia,
Dermatitis 11:34-40 Sweden, pp 118-127
Niinimäki A (1987) Scratch-chamber tests in food handler van den Akker TW, Roesyanto-Mahadi ID, van Toorenenbergen
dermatitis. Contact Dermatitis 16:11-20 AW, van Joost T (1990) Contact allergy to spices. Contact
Niinimäki A, Hannuksela M (1981) Immediate skin test reactions Dermatitis 22:267-272
to spie es. Allergy 36:487-493 van Toorenenbergen AW, Dieges PH (1985) Immunoglobulin E
Niinimäki A, Björksten F, Puukka M, Tolonen K, Hannuksela M antibodies against coriander and other spices. J Allergy Clin
(1989) Spiee allergy: results of skin prick tests and RAST with Immunol 76:477-481
spiee extracts. Allergy 44:60-65 van Toorenenbergen AW, Dieges PH (1987) Demonstration of
Niinimäki A, Hannuksela M, Mäkinen-Kiljunen S (1995) Skin spice-specific IgE in patients with suspected food allergies.
prick tests and in vitro immunoassays with native spices and J Allergy Clin Immunol 79:108-113
spiee extracts. Ann Allergy 74:280-286 van Toorenenbergen AW, Huijskes-Heins MIE, Leijnse B, Dieges
Stäger J, Wüthrich B, Johansson SGO (1991) Spiee allergy in PH (1988) Immunoblot analysis of IgE-binding antigens in
celery-sensitive patients. Allergy 46:475-478 spices. Int Arch Allergy Appl Immunol 86:117-120
Thiel C, Fuchs E (1981) Über korrelative Beziehungen bei Wüthrieh B, Dietschi R (1985) Das "Sellerie-Karotten-Beifuss-
Kräuterpollen und Gewürzallergenen. In: RAST 3 Berichts- Gewürz-Syndrom": Hauttest- und RAST-Ergebnisse. Schweiz
band, Grosse Verlag, Berlin, pp 178-185 Med Wochensehr 115:358-364
Thiel C, Fuchs E, Kalveram K-J, Forck G (1984) Über korrelative Wüthrich B, Hofer T (1984) Nahrungsmittelallergie: das "Sellerie-
Beziehungen bei Kräuterpollen und Gewürzallergenen. Zweite Beifuss-Gewurz-Syndrom". Assoziation mit einer Mango-
frucht-Allergie? Dtsch Med Wochensehr 109:981-986
CHAPTER 91
Woods
B.M. Hausen
Introduction timbers contain strong allergens in very high concen-

trations, e.g. Pao ferro.
Contact urticaria has been observed from several
Besides providing lumber, furniture, plywood and
woods, such as Ash, Larch, Limba, Oak, Obeche, Pine,
veneer, wood is the source of pulp board and paper
Ramin, Spruce and Teak (Schmidt 1978; Beck et al.
and of hundreds of chemicals derived from cellulose,
1984). Trees may become infected with caterpillars or
lignin and certain resins. Wood is also a major source
bear lichens on their bark, which may cause occupa-
of the world's fuel. The global consumption of wood
tional dermatitis in workers trimming and debarking
reached a maximum in the 1980s; since then, this level
trees or thinning branches ("wood cutter's disease")
of use has been maintained or may even be decreasing.
(Katzenellenbogen 1955; Storrs et al. 1976). Photosen-
However, the number of species offered has dimin-
sitising furocoumarins are present in wood species of
ished remarkably. The largest timber resources are in
the Rutaceae and Flindersiaceae (Mitchell and Rook
the Amazon basin, Central Africa and Southeast Asia.
1979). Cases of photocontact dermatitis are extremely
In most cases, occupational dermatitis caused by
rare.
wood occurs in individuals working with raw wood,
Generally, allergie sensitisation comes from the
such as cabinetmakers, carpenters, sawmill workers
hear~ood. The sapwood seldom contains sensitising
and lumberjacks. A special risk arises, however, when
constltuents. The chemical substances responsible for
fine sanding is done. Allergie dermatitis resulting from
allergie reactions are mostly benzo-, naphtho-, furano-
contact with finished wood items is seen rarely. It may
and phenanthrene quinones, but stilbenes, phenolic
develop after contact with wooden jewellery, wo oden
compounds and terpenes mayaiso induce specific
footwear and especially parts of musical instruments,
hypersensitivity. A list of genuine wood constituents
e.g. mouthpieces and chin rests. For the individual
known to cause allergie contact dermatitis is found in
earning a living by playing an instrument, such an
Table 1. The compounds responsible for the majority
allergy may gain remarkable importance. The actual
of non-allergie reactions are alkaloids, glycosides,
in~idence of wood dermatitis is quite small, although it
anthraquinones, saponins, phenols, flavonoids and
mlght be greater in countries, from which no reports
coumarins.
reach th.e public. Commonly, the literature only
Allergie contact dermatitis from wood dust often
records smgle cases or observations from local regions.
resembles airborne contact dermatitis (Fig. 1). Besides,
Irritation of the skin may arise from bristles, hair,
the fine dust, created during the various working
thorns, or leaves (bamboo, palm), or from constituents
processes, may collect in the clothing at the neckline,
of the sap (latex) as weIl as resins of species belonging
at the trouser's ends and in the tops of the socks. The
to the Anacardiaceae, Apocynaceae, Euphorbiaceae,
shoes or boots may become heavily impregnated with
Moraceae and Coniferae. Some timbers stain the skin
dust and are a source of perpetual exposure. Initially,
when contact occurs with freshly cut wood, e.g. old
the dermatitis appears on exposed areas of the skin,
fustic. Powders from the bark or heartwood, e.g. of
e.g. the dorsa of hands, the forearms and the eyelids.
Araroba, Brigalow and Tagayasan, may evoke rashes,
~he first s~mptom is itching. Often these first erup-
stain the skin and colour the hair. Lesions from
tlO~S are l?nored and improve or even disappear
splinters of Afrormosia, Douglas fir, Green heart,
dunng penods away from work. With continued
Limba, Mansonia and Redwood are notoriously slow
exposure, the dermatitis gradually becomes worse;
to heal and commonly become infected. The symptoms
larger areas of the skin become involved and the
are caused by toxic alkaloids, glycosides, saponins,
periods of freedom from symptoms become shorter.
anthraquinones and other poisonous constituents.
Finally, the dermatitis becomes widespread and res em-
Some irritant reactions are obligatory, as certain
bles other generalised dermatoses, such as chromate

772 B.M. Hausen
<=I
o
.~
i::.,'"
u
<=I
o
u
Fig 1. Airborne contact dermatitis due to teak wood dust
and poison ivy dermatitis, mycosis fungoides, actinic

reticuloid and exfoliative dermatitis.
Diagnosis is made by evaluation of the patient's
occupational history, the clinical appearance of the
dermatitis, the botanical nature of the wood and patch
testing. Patch testing with sawdust, mixed 10% by
weight in petrolatum, is usually reliable (Mitchell and
Rook 1979); the sawdust should be freshly ground.
Irritant reactions may occur, especially with Teak and
Pao ferro. In case of an irritant nature, controls are
necessary. An appropriate number to use is 20
persons; however, some recommend 50 to be more
reliable. The sensitising constituents named in Table 1
are not commercially available.
Botanical identification of the suspected wood is
essential, otherwise a description of the case is useless.
Trade names, especially those of tropical and subtrop-
ical species, are often confusing, insufficient and
., misleading. For example, a common name, such as
S rosewood or satinwood, refers to several different and
.,'"<=I completely unrelated species. Few workers know with
'"E-<'"'" any degree of certainty the species they are working
with. Almost always, the help of a wood taxonomist is
required. In such a case, asolid wood sample, not wood
dust, should be available for botanical identification.
'"
.~ Prevention of contact dermatitis caused by woods is
.,u difficult. Dust control with proper ventilation is very
~
important. Protective clothing should be worn and
'"
0
0
must cover the exposed areas. Only seldom, can a
~
.5 strong sensitising species be substituted by a less
.,'"<=I sensitising one.
.,'"
OI)
In case a worker has to change his job, retraining
-'"
:::I
should not include occupations that bear the risk of
u
Zl recurrent allergic contact dermatitis. Cross reactions
<=I
0
u might occur in wood workers sensitive to quinonoid
., wood constituents. After changing job to that of a
~ S
'"<=I
0
<=I gardener, florist, nursery worker or even pharmacy
~
<d assistant, relapses may occur resulting from related
,.: .~
cu
:ii
<=I
Zl quinones in ornamental plants or extracts handled
....'" 0
c:Q occupationally.
Woods 773
The following description concerns the most com- It gains some interest for turned artides and as a
mon wood species that may cause dermatitis. For more veneer for inlays in high-dass furniture. Cases of
extensive information, the reader is referred to the occupational contact dermatitis have been described
books by Mitchell and Rook (1979), Hausen (1981), the by Freise (1932), Dantin-Galego et al. (1952), Heyl
treatise by Woods and Calnan (1976), the chapter on (1966) and Gons:alo (1992) in joiners and flooring
wood by Cronin (1980) and the literature survey of the manufacturers. The heartwood contains at least five
National Institutes for Occupational Safety and Health quinonoid constituents, of which two could be iden-
(NIOSH) (Anonymous 1987). tified: 2,6-dimethoxy-p-benzoquinone and bowdichi-
one (Hausen et al. 1972; Brown et al. 1974). A third, still
unknown, quinone seems to be related to the dalbergi-
Acacia melanoxylon R. Br. (Leg.-Mimosaceae) ones, as cross reactivities have been observed in a
Australian Blackwood sucupira-sensitive patient (Hausen 1981).
Australian blackwood (Acacia melanoxylon) is the H3CO

;;/ ° Bowdichione
most important timber for almost every purpose in /-
°
1
Australia. Even fences and musical instruments are 11
manufactured from it. Cases of allergie contact der- ° OCHa

11
matitis in joiners, furniture makers, and house and °
boat-builders have been reported since 1925. Besides
acamelin and 2,6-dimethoXY-l,4-benzoquinone func-
tioning as minor allergens, the main sensitiser is a new Brya ebenus BENTH. (Leg.-Papilionaceae). COCUS
hydroxyflavan named melacacidin (Hausen et al.
1990a). In Australia, even the wife of a joiner who
was making cabinets in his house suffered from Cocus is a small tree from the West Indies used for
allergie contact dermatitis, although the working room making musical instruments, particularly flutes, re-
was in the basement (Tilsley 1990). Occasionally the corders and darinets. It also serves for making interior
wood is exported to Europe (Correira et al. 1992). turnery, cutlery handles, fancy artides, sawn veneers
Melacacidin is also responsible for occupational der- and wooden breakfast platters. Although of small
matitis seen in the workers handling koa wood (Acacia diameter, it has been imported from Jamaica and Cuba
koa) (Knight and Hausen 1992). for more than a century as one of the most valuable
woods.
2,6-DimethoxY-l,4-benzoquinone Occupational contact dermatitis has been observed
not only in flute makers who saw and sandpaper the
wood, but also in flutists playing instruments manu-
factured with this wood. Typically, the allergie lesions
of the latter are swollen lips and mouths (Crocker 1903;
White 1903; Meister 1934).
° Acamelin A re-investigation of the wood was prompted by the
H,C0Y\--0,»- recurrent lesions (swollen lips) developing in a young
~ CH, girl studying the flute. Two hydroxyisoflavans were
identified eliciting ++ to +++ reactions at a 1% test
° Melacacidin concentration (Hausen et al. 1991).
HO~OH CF"
(2,3-cis 3,4-cis 3,3',4,4',7,8- HO Cocus I =
hexahydroxyflavan) HO 7,8-dihydroXY-2',4',5-
:/ I ° .'. . trimethoxy isoflavan
~ . "''OH
OH
OCH3
Cocus 11 =
7,8,3'-trihydroXY-2,4' -
Bowdichia nitida BENTH. (Leg.-Papilionaceae)
dimethoxy isoflavan
Sucupira
Sucupira from Brazil is best suited for structural

purposes and is mostly used in Europe for flooring. OCH 3
774 B.M. Hausen
C%cedrus decurrens (TORR.) Florin they are used mainly for interior work, furniture and
(Cupressaceae). Incense Cedar joinery. Only the Brazilian species are also suitable for
boat building and exterior constructions.
Although used abundantly, only two published
The incense cedar tree, native to California and
reports of occupational contact dermatitis are known
Oregon, is used for the manufacture of pencils, fence
(Schwartz 1931; Rackett and Zug 1997). However, the
posts, boarding, venetian blinds, chests and toys. Cases
author has also seen four cases, which remain unpub-
of contact dermatitis have been described by Calnan
lished. In these cases, a typical airborne contact
(1972). Positive reactions were obtained with thymo-
dermatitis developed due to bad air exhaust conditions
quinone; ß-thujaplicin remained negative. Incense in workers who manufactured balcony breastwork and
cedar contains up to 4% of thymoquinone (for
mouldings. Cordiachrome A and E, both 0.1% in
structure, see Thuja plicata).
petrolatum, were positive.
Cordiachromes
Ch/orophoro exce/so BENTH. and HOOK.

(Moraceae). Iroko, Kambala
The West African timber, Iroko, Kambala, is used

frequently as a substitute for teak because it possesses
Q:6:
o o
many of the desirable features of Tectona grandis. For CH
'~
decades it has been in demand due to its strength and
durability for construction work, especially in making
windows and door frames, and in shipbuilding.
o F (R=OeH,) CH,
Occupational contact dermatitis has been described
since 1910 (Schulz 1957; Jung 1967; Beer 1970; Pereira
Marques 1989; Hinnen et al. 1995). In 1949, King and
Grundon isolated a hydroxy stilbene, named chlor-
ophorin, which was revealed to be a moderate Do/bergio /otifolio ROXB. East Indian rosewood
sensitiser (Schmidt 1963; Hausen 1981). Its structure,
first elucidated by King and Grundon (1950), was Do/bergio me/onoxy/on GUILL. & PERR.
corroborated in 1986 by Krohn et al. Grenadil
Chlorophorin
OH
Do/bergio nigro ALL. Brazilian Rosewood
Do/bergio retuso HEMSL. (D. obtuso LEC.)

OH
Cocobolo (Leg.-Papilionaceae)
The different Dalbergia species provide most valuable

woods used for high-dass furniture, cabinet work,
Cordio millenii BAKER. Cordia
inlay work and parts of musical instruments.
Cordio gerosconthus R. BR. (Boraginaceae).

Canalete Cocobolo
Cocobolo derives from Central America; it is strong,

Cordio goe/diono HUBER. Freijo
hard, compact, fairly heavy, easy to work with and of
extreme durability. It holds a supreme position in the
Cordia goeldiana from Brazil, also often called Brazil- cutlery trade, especially in knife handles, but also
ian walnut, and Cordia gerascanthus derived from serves for brush backs, chessmen, scientific instru-
Venezuela form together with Cordia millenii and ments, bulbs of billard cues, wooden bracelets, wooden
Cordia platythyrsa BAKER from tropical Africa a jewellery and interior turnery. Cocobolo is especially
group of valuable timbers with moderate durability. used for musical instruments; 90% of all recorders
Due to their light weight, softness and low strength, manufactured before World War II were made from
Woods 775
Cocobolo. Descriptions of occupational dermatitis

occurring in workers manufacturing hairbrushes, knife
handles and recorders have been published just as
often as allergic reactions of the lips and fingertips in
those playing the instruments (Neisser 1907; MacKee
1913; Modlmayer 1931; Steinbrink 1950; Schulz and
Dietrichs 1962; Hausen and Münster 1983; Rackett and
Zug 1997). The responsible allergens belong to the dass
of neo-flavonoids, named dalbergiones. In Cocobolo,
obtusaquinone and (R)-4-methoxydalbergion play a
major role, while (S)-4'-hydroXY-4-methoxydalbergion
plays only a minor role (Hausen 1997).
Grenadil Fig. 2. "Fiddler's neck": allergie reaction due to contact with a

wooden chin rest (Rosewood)
As a hard and heavy blue-black coloured wood,

Grenadil or African blackwood is mainly imported 0
from Mozambique, Zimbabwe, Togo and Senegal. Hs H3 CO (S)-4- Methoxydalbergion
use comprises knife handles, brush backs, chessmen, (R = H)
truncheons, flutes, darinets, oboes, chanters of bag- (S)-4,4'-Dimethoxydal
pipes and some types of recorders. bergion (R = OCH3)
Cases of dermatitis have been described since 1934 (S)-4'-HydroxY-4-methox-
and have been observed in darinet makers and in dalbergion (R = OH)
knife-handle turners (Meister 1934; Woods and Calnan R
1976; Hausen et al. 1984). The responsible allergens are
(S)-4-methoxydalbergion, (S)-4'-hydroXY-4-methoxy-
dalbergion and (S)-3'-hydroXY-4,4'-dimethoxydalber- H 3CO
0
gione (Schulz et al. 1979).
East Indian and Brazilian Rosewood
Although of different origins, both rosewoods are used

for similar purposes and contain the same main OH
sensitisers. The timbers are of attractive appearance Obtusaquinone
when cut from old sterns. Imports are few but steady.
This wood is used for high-dass furniture and cabinet
work, handles, decorative veneers, wooden jewellery
(bracelets, necklaces), inlay work and especially mu-
o
sical instruments, such as flutes, recorders, piano
cases, pegs, bridges of violins and chin rests (Fig. 2).
Occupational contact dermatitis has been observed in Diospyros celebica BAKH. Macassar
cabinet makers, knife grinders, as weH as by use of
knifes, e.g. in butchers, and chin rests by professional
violinists (Gougerot and Blamoutier 1929; Pontes de
Diospyros crassifolia HIERN. African Ebony
Carvalho 1956; Findlay 1972; Cronin and Calnan 1975;
Holst et al. 1976; Woods and Calnan 1976; Martin et al. Diospyros ebenum KOENIG. Ceylon Ebony
1980; Haustein 1982; Hausen 1985; Gallo et al. 1996).
The responsible sensitisers (R)- and (S)-4-methoxy-
Diospyros melanoxylon ROXB. Coromandel
dalbergion, (S)-4,4' -dimethoxydalbergion and (S)-4'-
(Ebenaceae)
hydroXY-4-methoxdalbergion do not only occur in the
species named above, but also in Dalbergia stevensonii
STANDLEY, which has been found also to cause Ebony is the name for wood species belonging to the
occupational contact dermatitis (Woods and Calnan genus Diospyros. Most prized are those with a deep
1976; Bottenbruch et al. 1988).H3 black heartwood, extreme hardness and durability.
776 B.M. Hausen
Ebony species are used for cabinet and inlay work, lops from the sap contracting the skin during sawing
piano and organ keys, organ stops, violin fingerboards (May 1960; Adams and Gimenezarnau 1991; Knight and
and pegs, parts of string bows ("frogs") and bagpipes. WhiteselI 1992). Bracelets made from Grevillea wood
Macassar has been long in use for expensive rulers. grown in India and shipped to the United States and
Occupational dermatitis may occur, but reports are other countries were shown to be the source of allergic
found rarely in the literature. Buschke and Joseph contact dermatitis (Hoffman et al. 1985; Larsen et al.
(1927) observed hand eczema in a cabinet maker due to 1992). The responsible allergen is grevillol, a phenolic
Macassar ebony, while Bleumink and Nater (1974) compound with a long side chain, which very much
obtained positive patch tests to an ethanol extract of resembles the sensitising urushiols from poison ivy.
Dalbergia melanoxylon in 4 of 20 patients suffering
from airborne contact dermatitis due to tropical woods. Grevillol
In Macassar, aprecursor of a sensitising naphtho-
ortho-quinone (Macassar quinone) is found as the
main constituent. Besides, more than 17 different
naphthoquinone derivates (diospyrin derivates) have
been isolated, which possess possibly allergy-inducing
properties (Zakaria et al. 1984; Zhong et al. 1984).
Khaya grandiflora De. African Mahogany
Macassar quinone
Khaya ivorensis A. eHEV. Kahya Mahogany
Khaya anthotheca e. De. Krala
Distemonanthus benthamianus BAILL. Khaya senega/ensis A. JUSS.

Ayan (Leg.-eaesalpinaceae) Dry Zone Mahogany (Meliaceae)
All four Khaya species are timbers of West Africa.

Movingui or Ayan is used for domestic flooring,
They serve as a substitute for South American
frames, windows and cabinet making. It is also
mahogany, especially for cabinets, furniture, boat-
imported from West Africa to England, where it is
building, moulding and other purposes for which a
mainly used for coffins. In four carpenters, strong
good-quality wood is required.
patch-test reactions were seen with 2 of the 12 known
Outbreaks of contact dermatitis caused by these
flavonoids: oxyayanin A and B (Morgan and Thomson
woods have been described by Morgan (Morgan and
1967). These flavonoid constituents were not tested in
Wilkinson 1965; Morgan and Thompson 1967; Morgan
13 other patients mentioned by Orsler (1969) or by
et al. 1968), Wilkinson and colleagues (Wilkinson 1968,
Woods and Calnan (1976).
1971; Wilkinson et al. 1980), Shevljakov (1974), Orsler
(1969) and Hjorth (1961). Recently, the author also
Oxyayanin A observed two cases in which airborne contact derma-
(R = R,= H, R 2 = OH) titis developed to the sawdust of African mahogany.
Oxyayanin B Patch tests with a 10% ethanol extract were positive.
(R, = OH, R 2 = H) The responsible sensitisers are not yet known. One
of the allergenic constituents seems to be anthothecol,
found in K. anthotheca up to 0.03% (Morgan and
Orsler 1967). In addition, K. anthotheca and K. ivorensis
contain the weak sensitiser 2,6-dimeth0XY-l,4-benzo-
Grevillea robusta A. eUNN. quinone (see Acacia melanoxylon).
Australian Silky Oak (Proteaceae)
Anthothecol
Australian silky oak is native to the fifth continent, but
it is also grown in Africa, Sri Lanka, India, and the
United States. Flooring, furniture, and plywood are the
main uses, but the tree is also required for telegraph
poles and as a shade tree. Grevillea poisoning is a
common term for occupational dermatitis that deve- OH
Woods 777
o
Machaerium scleroxylon TUL. Pao Ferro 11
(R )-3.4-Dimethoxydalber-
(Leg.-Papilionaceae). "Santos"-Palisander. gion (R = OCH 3)
Caviuna Vermelha
R
The wood of Pao ferro dosely resembles true Brazilian

rosewood in appearance and physical properties and,
thus, is frequently used as a substitute or often simply
mistaken for real rosewood. In Europe, Pao ferro is
used for furniture, veneers (Fig. 3), television sets,
knife handles, recorders and multiple other purposes.
Occupational contact dermatitis has been reported not Mansonia altissima A. CHEV. Mansonia,
only from its native country Brazil, but also from Bete (Sterculiaceae)
Denmark, Great Britain, Germany, Italy and Spain. All
together, more than one hundred cases have been The attractive durable wood of the Mansonia tree is
described in the literature (Miranda Bastos and Matos imported from Nigeria and the Gold Co ast, and is used
Filho 1962; Morgan et al. 1968; Conde-Salazar et al. as a substitute for walnut. Outbreaks of occupational
1980; Hausen 1982; Sak et al. 1983; Beck et al. 1984; contact dermatitis have been described since 1936 in
Roed-Petersen et al. 1987; Rackett and Zug 1997). hundreds of cases, of which only some can be cited
Active sensitisation occurred in two nurses who had (Horner and Wigley 1936; Bourne 1956; Sandermann
been used as controls and patch tested with the pure and Dietrichs 1959; Hanslian and Kadlec 1965; Nava
wood dust. The responsible contact allergen is (R)-3.4- et al. 1975).
dimethoxydalbergion. This constituent is the strongest The responsible allergens belong to the dass of
sensitiser within the group of dalbergiones (Schulz sesquiterpenoid mansonones, of which mansonone A,
et al. 1979). Its safe patch test concentration is 0.01%! a red ortho-quinone is the main (strong) sensitiser
In some Pao ferro sam pies collected from different (Schulz et al. 1979). Interestingly, some of these
woodworking factories, up to 4.9% were detected in quinones, e.g. mansonone E and F, occur in the elm
the heartwood (Hausen 1983). Thus, a patch test with species (Ulmus hollandica), making the tree resistant
the sawdust itself should strictly be avoided. Pao ferro to the Dutch elm disease.
is the most hazardous commercial timber in the
woodworking industry. (R)-3.4-dimethoxydalbergion Mansonone A
does not occur in the related Dalbergia species.
Pinus spp. Pi ne
Picea spp. Fir, Spruce (Pinaceae)
Pine and Spruce are the common names used for

hundreds of species of conifers belonging to the genus
Pinus and Picea, members of the Pinaceae family.
Principally, most of these timbers are found in the
northern hemisphere. Pine and Spruce species are the
source of wood balsam which, after separation of the
volatile part (turpentine), yields rosin (colophony).
Rosin consists of 90% res in acids an 10% neutral
components.
Resin acids such as abietic and dehydroabietic acid
oxidise easily under common conditions, e.g. oxygen,
daylight, room temperature, to give (auto) oxidative
Fig. 3. Haemorrhagic contact dermatitis caused by Pao ferro degradation products, which are more or less strong
778 B.M. Hausen
sensitisers. From more than 30 constituents detected in The primary sensitiser is a simple naphthoquinone,
degraded tall oil resin (by-product in the paper and named deoxylapachol (Sandermann and Simatupang
pulp industry) and colophony of different origins, 8,12- 1962). Compared with other plant allergens, de-
peroxy-.1' 3(1 4 )-dihydroabietic acid and 12 ex-hydroxy- oxylapachol is one of the strongest sensitisers found in
abietic acid contribute a great deal to colophony nature (Schulz 1967). Patch testing with sawdust may
allergy by means of both their sensitising capacity and produce false-positive reactions due to its highly irritant
their determined concentration in the mixture of properties. Deoxylapachol may actively sensitise when
degradation products (Hausen et al. 1990b). not patch tested in its safe concentration of 0.01%.
Occupational contact dermatitis has been seen in Another major constituent of teak is lapachol, equipped
numerous cases and may occur, for example, in with a blocking hydroxy group at the quinonoid ring
joiners, woodworkers, clerks handling paper and which may be tested 1% in petrolatum. Cross reactions
newspapers, females using epilation wax (O'Reilly between deoxylapachol and lapachol are obligatory.
and Murphy 1996), handball players using adhesive
wax (Hausen and Kuhlwein 1983) and in many other o Deoxylapachol (R = H)
IIII~
~
situations (Hinnen et al. 1995; Karlberg et al. 1996). Lapachol (R = OH)
The importance of occupational contact dermatitis due
to colophony is demonstrated by its rank in the hit list ~ R
I
of the most common contact allergens where it reached o
the fifth or sixth place in recent years (Brasch et al.
1996). For further details, see Chap. 64 by Karlberg.
8,12_Peroxy_.1'3(4) -dihydroa- Thespesia populnea (L.) SOL. Milowood

bietic acid (Malvaceae)
Milowood is a small tropical tree distributed widely

throughout the tropics and in many areas of the United
States, including California, Florida and Hawaii. Pri-
marily, it is used for making bowls, bracelets, carved
OH 12 ex-Hydroxyabietic acid tikis and furniture. Among the different mansonones
that are known sensitisers from Mansononia altissima,
Milowood contains a new sesquiterpenoidal quinone,
named mansonone X (Milbrodt et al. 1997).
Persistent occupational contact dermatitis has been
observed in a Hawaiian bowl turner who was shown to
be allergic to the mentioned constituent, mansonone X.
W
This compound showed a moderate sensitising capacity
in experiments with guinea pigs (Hausen et al. 1997).
Tedona grandis L. Teak (Verbenaceae) H
Mansonone X
~ 0
Teak wood is one of the most valuable timbers of the
world. While native to Burma, India, Thailand and
Malaysia, it also has been plan ted in South Africa and
o ~:
the West Indies. Due to its strong durability, it is used
in furniture, exterior joinery, fiooring, fittings, door
and window frames, rails, shipbuilding, bridges and
wharves. Teak is resistant to termites and chemicals
Thuja plicata DONN. ex D. DON
and, therefore, can be used outdoors and for labora-
Western Red Cedar (Cupressaceae)
tories too.
Occupational contact hypersensitivity has been ob-
served as early as in Ancient Egypt, where ships were The western red cedar tree is native to the west coast of
built with teak from India. More recent descriptions the United States, but exported all over the world,
dated back to the last century and continue until the especially to Australia, Japan and Europe. It is a timber
1970S, when it became one of the most common of good stability useful for constructions, venetian
sensitisers in the wood industry (Woods and Calnan blinds, boat building, planking, panelling and framing.
1976). Besides many cases of bronchial asthma due to the
Woods 779
sawdust, observations of oeeupational allergie eontaet Cronin E (1980) Contact dermatitis. Churchill Livingstone,
Edinburgh
dermatitis have also been reported (Orsler 1969; Cronin E, Calnan CD (1975) Rosewood knife handle. Contact
Bleumink et al. 1973; Burry et al. 1973). Suskind Dermatitis 1:121
(1967) sueeeeded in sensitising guinea pigs with Dantin-Gallego I, Armayor AF, Riesco J (1952) Some new toxic
woods. Some new manifestations of toxicity. Ind Med Surg
different extraets of the wood. Thymoquinone must 21:41-46
be eonsidered as the main eontaet sensitiser, showing a Findlay LJ (1972) An unusual case of rosewood dermatitis of the
high sensitising eapaeity in guinea-pig experiments genus Dalbergia (East Indian rosewood). Br J Ind Med
(Hausen 1981). The safe pateh test eoneentration is 29:343-344
Freise FW (1932) Gesundheitsschädigungen durch Arbeiten mit
0.1% in petrolatum. giftigen Hölzern. Beobachtungen aus brasilianischen Ge-
werbebetrieben. Arch Gewerbepathol Hyg 3:1-14
Gallo R, Guarrera M, Hausen BM (1996) Airborne contact
Thymoquinone
~
dermatitis from East Indian rosewood (Dalbergia latifolia
Roxb.). Contact Dermatitis 35:60-61
Gon~alo S (1992) Allergic contact dermatitis from Bowdichia
nitida (Sucupira) wood. Contact Dermatitis 26:205
Gougerot H, Blamoutier J (1929) Dermite eczemateuse profes-
o sionelle due a la poudre de palissandre. Bull Soc Med Hop
15:739-743
Hanslian L, Kadlec K (1965) A contribution to the problem of
eczematogenie effect of Mansonia-wood. Pracovni Lekarstvi
17:392-395
References Hausen BM (1981) Woods injurious to human health. W de
Gruyter, Berlin
Hausen BM (1982) Häufigkeit und Bedeutung toxischer und
Adams RM, Gimenezarnau JM (1991) Allergie contact dermatitis allergischer Kontaktdermatitiden durch Machaerium sc/erox-
caused by the sawdust of Grevillea robusta A. CUNN. Am J ylon TUL. (Pao ferro), einem Ersatzholz für Palisander
Contact Dermatitis 3:192-193 (Dalbergia nigra). Hautarzt 33:321-328
Anonymous (1987) Health effects of exposure to wood dust: a Hausen BM (1983) Aktuelle Kontaktallergene. Allergologie 6:
summary report of the literature. US Department of Health 194-197
and Human services, Public Health service centers of disease Hausen BM (1985) Chin rest allergy in a violinist. Contact
control, National Institutes for Occupational Safety and Dermatitis 12:178-179
Health. Cincinnati, Ohio Hausen BM (1997) Allergie contact dermatitis from a wooden
Beck MH, Hausen BM, Dave VK (1984) Allergic contact derma- necklace. Am J Contact Dermat 8:185-187
titis from Machaerium sc/eroxylon TUL. (Pao ferro) in a Hausen BM, Kuhlwein A (1983) Allergisches Kontaktekzem bei
joinery shop. Clin Exp Dermatol 9:159-166 einer Handballspielerin. Aktuel Dermatol 9:126-130
Beer WE (1970) Sensitizing to Iroko wood in a wood machinist. Hausen BM, Münster G (1983) Cocobolo-Holz, ein vergessenes
Contact Dermatitis Newslett 7:159 Ekzematogen? Dermatosen 31:110-117
Bleumink E, Nater JP (1974) Allergic reaction to (tropical) woods. Hausen BM, Simatu'pang MH, Kingreen JC (1972) Un-
Contact Dermatitis Newslett 16:436 tersuchungen zur Uberempfindlichkeit gegen Sucipura- und
Bleumink E, Mitchell JC, Nater JP (1973) Allergie contact Palisanderholz. Berufsdermatosen 20:1-7
dermatitis from cedar wood (Thuja plicata). Br J Dermatol Hausen BM, Kuhlwein A, Schmalle HW (1984) Kontaktallergie
88:499-504 auf ein "afrikanisches Ebenholz", Grenadil- Dalbergia me-
Bottenbruch S, Hausen BM, Plewig G (1988) Allergische Kontakt- lanoxylon. Aktuel Dermatollo:221-223
dermatitis durch Honduras-Palisander (Dalbergia stevensonii Hausen BM, Bruhn G, Tilsley AD (1990a) Contact allergy to
STANDLEY). Aktuel DermatoI14:164-166 Australian blackwood (Acacia melanoxylon R. Br.): isolation
Bourne LB (1956) Dermatitis from Mansonia wood. Br J Ind Med and identification of new hydroxyflavan sensitizers. Contact
13:55-58 Dermatitis 23:33-39
Brasch J, Geier J, Gefeller 0 (1996) Dynamic patterns of allergie Hausen BM, Krohn K, Budianto E (1990b) Contact allergy due to
patch test reactions in 10 European standard allergens. colophony. VII - Sensitizing studies with oxidation products
Contact Dermatitis 35:17-22 of abietic and related acids. Contact Dermatitis 23:352-358
Brown PM, Thomson RH, Hausen BM (1974) Über die Inhalt- Hausen BM, Bruhn G, König WA (1991) New hydroxyisofiavans
stoffe von Bowdichia nitida BENTH. Liebigs Ann Chem: as contact sensitizers in Cocus wood Brya ebenus DC.
1295-1300 (Fabaceae). Contact Dermatitis 25:149-155
Burry JN, Kirk J, Reid GI, Turner T (1973) Environmental Hausen BM, Knight TE, Milbrodt M (1997) Thespesia populnea
dermatitis: patch test in 1000 cases of allergic contact dermatitis. Am J Contact Dermat 8:225-228
dermatitis. Med J Austr 2:681-685 Haustein UF (1982) Violin chin rest eczema due to East Indian
Buschke A, Joseph A (1927) Über Hautentzündung, hervorgeru- rosewood (Dalbergia latifolia ROXB). Contact Dermatitis
fen durch Makassarholz, mit Berücksichtigung gewerbe- 8:77-78
hygienischer Fragen. Dtsch Med Wochenschr 53:1641-1642 Heyl U (1966) Kontaktekzem bei Überempfindliehkeit gegen
Calnan CD (1972) Dermatitis from cedar wood pencils. Trans St Sucupira- und Pailsanderholz. Berufsdermatosen 14:239-244
John's Hosp Dermatol Soc 58:43-47 Hinnen U, Willa-Craps C, Elsner P (1995) Allergie contact
Conde-Salazar L, Garcia Diez A, Rafeensperger F, Hausen BM dermatitis from Iroko and Pine wood dust. Contact Derma-
(1980) Contact allergy to the Brazilian rosewood substitute titis 33:428
Machaerium sc/eroxylon TUL. (Pao ferro). Contact Dermatitis Hjorth N (1961) Contact sensitivity to plants and balsams. Acta
6:246-250 Derm Venereol 41[Suppl 46]:65-79
Correira 0, Antonio Barros M, Mesquita Guimares J (1992) Hoffman TE, Hausen BM, Adams RM (1985) Allergic contact
Airborne contact dermatitis from the woods Acacia me- dermatitis to "silver oak" wooden arm bracelet. J Am Acad
lanoxylon and Entandophragma cylindricum. Contact Der- Dermatol 13:778-779
matitis 27:343-344 Holst R, Kirby I, Magnusson B (1976) Sensitization to tropieal
Crocker HR (1903) Diseases of the skin, 3rd edn. Lewis, London, woods giving erythema multiforme like eruptions. Contact
p 418 Dermatitis 2:295-296
780 B.M. Hausen: Woods
Horner S, Wigley JEM (1936) A case of dermatitis venenata due to Pereira Marques MSJ (1989) Dermite de contacto a Cambala. Bol
Mansonia wood (Sterculia altissima). Br J Dermatol 48:26-28 Inf Gruppo Portugues E Dermatite Contato No 3:23-24
Jung HD (1967) Berufliche Kontaktekzeme durch Kambala-Teak- Pontes de Carvalho L (1956) Dos allergenos de contato nas
Holz. Dtsch Gesundheitswes 22:2141-2143 profissöes. Brazil Med 70:77-88
Karlberg AT, Gäfvert E, Meding B, Stenberg B (1996) Airborne Rackett SC, Zug KA (1997) Contact dermatitis to multiple exotic
contact dermatitis from unexpected exposure to rosin (colo- woods. Am J Contact Dermat 8:114-117
phony). Contact Dermatitis 35:272-278 Roed-Petersen J, Menne T, Mann Nielsen K, Hjorth N (1987) Is it
Katzenellenbogen I (1955) Caterpillar dermatitis as an occupa- possible to work with Pao ferro (Machaerium scleroxylon
tional disease. Dermatologica 111:99-106 TUL.)? Arch Dermatol Res 279:108-110
King FE, Grundon MF (1949) The constitution of chlorophorin, a Sak M, Uhrik J, Fabian J, Stracenska H, Hermanova E (1983)
constituent of Iroko, the timber of ehlorophora excelsa. Dermatozy vyvolane drevinon Machaerium sc/eroxylon.
Part 1. J Chem Soc 699:3348-3352 Ceskoslovenska Dermatol 58:89-91
King FE, Grundon MF (1950) The constitution of chlorophorin. Sandermann W, Dietrichs HH (1959) Über die Inhaltstoffe von
Part H. Further oxidation experiments and the completion of Mansonia altissima und ihre gesundheitsschädigende Wir-
the structural problem. J Chem Soc 702:3547-3552 kung. Holz als Roh + Wstoff 17:88-97
Knight TE, Hausen BM (1992) Koa wood (Acacia koa) dermatitis. Sandermann W, Simatupang MH (1962) Ein toxisches Chinon aus
Am J Contact Dermat 3:30-32 Teakholz. Angew Chem 74:782-783
Knight TE, Whitesell CD (1992) Grevillea robusta (Silver oak) Schmidt H (1978) Contact urticaria to teak with systemic effects.
dermatitis. Am J Contact Dermat 3=145-149 Contact Dermatitis 4:176-177
Krohn K, Müller H, Adiwidjaja G, Jarchow OH, Schmalle HW, Schmidt P (1963) Experimentelle Untersuchungen über die
Hausen BM, Schulz KH (1986) The structure of the tetra- Sensibilisierungsfahigkeit von akzessorischen Inhaltstoffen
acetate of the allergen chlorophorin. Z Kristall 174:283-290 tropischer Hölzer (Medical thesis). University of Hamburg,
Larsen WG, Adams RM, Maibach HI (1992) Color text of contact Germany
dermatitis. Saunders, Philadelphia Schulz KH (1957) Allergische Kontaktdermatitis durch exotische
MacKee GM (1913) Dermatitis venenata from Cocobolo-wood. Hölzer insbesondere durch Kambala-Teakholz. Berufsder-
J Cutan Dis 31:582-583 matosen 5:3-9
Martin P, Bergoend H, Piette F (1980) Erythema multiforme -like Schulz KH (1967) Berufsdermatosen - ausgewählte Kapitel.
eruption from Brazilian rosewood. Proceedings of the 5th Z Haut Geschlechtskrankheiten 42:449-509
International Symposium on Contact Dermatitis Barcelona, Schulz KH, Dietrichs HH (1962) Chinone als sensibilisierende
p 42 Bestandteile von Rio Palisander (Dalbergia nigra) und
May SB (1960) Dermatitis due to Grevillea robusta (Australian Cocobolo (Dalbergia retusa) Holz. Allergie Asthma 8:125-131
silky oak). Ar~.h Dermatol 82:~~lO6 Schulz KH, Garbe I, Hausen BM, Simatupang MH (1979) The
Meister H (1934) Uber eine neue Athiologie für Gesichtsekzeme. sensitizing capacity of naturally occurring quinones. Part H.
Schweiz Med Wochenschr 43:993 Benzoquinones. Arch Dermatol Res 264:275-286
Milbrodt M, König WA, Hausen BM (1997) 7-hydroXY-2,3,5,6- Schwartz L (1931) Dermatitis venenata due to contact with
tetrahydro-3,6,9-trimethylnaphtho[I,8bc]pcyran-4,8-dione Brazilian walnut wood. Public Health Rep 46:1938-1943
from Thespesia populnea (L.) Sol. Phytochem 45:1523-1525 Shevljakov LV (1974) Occupational skin diseases in the wood
Miranda Bastos AD, de Matos Filho A (1962) A "Jacaranda" industry abroad and in the USSR. Gigiena Truda i Profes-
timber causing dermatitis. Proceedings of the 5th World sionalnye Zabolevanija 18:33-36
Forest Congress, Seattle. 29 AUg-l0 Sept 1960 3:1414-1416 Steinbrink W (1950) Besondere Beobachtungen an allergischen
Mitchell JC, Rook A (1979) Botanical dermatology. Greengrass, Krankheiten. Z Gesamte Inn Med 5:311-314
Vancouver Storrs FJ, Mitchell JC, Rasmussen JE (1976) Contact hypersensi-
Modlmayer H (1931) Palisander-bzw. Cocoboloholz-Dermatitis. tivity to liverwort in the Compositae family of plants. Cutis
Zentralbl Haut Geschlechtskrankheiten 36:728 18:681-686
Morgan JWW, Orsler RJ (1967) A simle test to destinguish Khaya Suskind RR (1967) Dermatitis in the forest product industries.
anthotheca from Khaya ivorensis and Khaya grandifolia. J Inst Arch Environ Health 15:322-326
Wood Sei 18:61-64 Tilsley DA (1990) Australian blackwood dermatitis. Contact
Morgan JWW, Thomson J (1967) Miscellanea (Ayan dermatitis). Dermatitis 23:40-41
Br J Ind Med 24:156-158 Wilkinson DS (1968) Khaya woods. Contact Dermatitis Newslett
Morgan JWW, Wilkinson DS (1965) Sensitization to Khaya 3:44
anthotheca. Nature 207:1101 Wilkinson DS (1971) (Patch)tests with different speeies of Khaya
Morgan JWW, Orsler RJ, Wilkinson DS (1968) Dermatitis due to woods. Contact Dermatitis Newslett 9:216
the wood dust of Khaya anthotheca and Machaerium Wilkinson DS, Buddan MG, Hambly EM (1980) A 1O-year review
scleroxylon. Br J Ind Med 25:119-125 of an industrial dermatitis dinic. Contact Dermatitis 6:11-17
Nava C, Mardisio M, Priatino Vangova G, Arbosti G (1975) White JC (1903) Dermatitis venenata - a supplement list. J Cutan
Aspetti della malattia di Mansonia altissima. Med Lav 66: Dis 21:441-455
574-576 Woods B, Calnan CD (1976) Toxic woods. Br J Dermatol
Neisser EJ (1907) Internationale Übersicht über Gewerbehygiene 95[Suppl]I3=1-97
nach den Berichten der Gewerbeinspektionen der Kul- Zakaria MB, Jeffreys JAD, Waterman PG, Zhong SM (1984)
turländer. Bibliothek fuer Soziale Medezin no. 1, Gutenberg, Naphthoquinones and triterpenes from Asian Diospyros
Berlin, p 225 species. Phytochem 23:1481-1484
O'Reilly FM, Murphy GM (1996) Occupational contact dermatitis Zhong SM, Watermann PG, Jeffreys JAD (1984) Naphthoquinones
in a beautician. Contact Dermatitis 35:47-48 and triterpenes from African Diospyros species. Phytochem
Orsler RJ (1969) The effect of irritant timbers. Woodworking Ind 23=1067-1072
26:28-29
CHAPTER 92
Pesticide-Related Dermatoses in Agricultural Workers

W. Manuskiatti, K. Abrams, D.J. Hogan, and H.l. Maibach
Agricultural Chemieals Pesticides
Besides the many infectious diseases and traumatic A pesticide is defined as any chemical used to control
injuries farmers risk on a regular basis, pesticide unwanted insects, fungi, viruses, weeds, and rodents.
exposure often daily and in concentrated form Insecticides, herbicides, fungicides, fumigants, and
presents a unique hazard [1]. It can lead to problems rodenticides are all pesticides. Their names denote
ranging from acute illness, such acute toxicity, irritant the type of pest to which the chemicals are directed.
contact dermatitis, or bronchitis, to carcinogenesis and More than 13,000 pesticide products are registered for
immune-system dis orders [2]. Approximately 60% of use in California alone. It is one of the few states with
all pesticides used in the United States are applied in reasonable statistics of pesticide use and resultant
the agricultural industry. illness. These products contain more than 800 active
In 1988, the average employment for the agriculture, ingredients and more than 1000 inert ingredients. They
forestry, and fishing industry reported by the U.S. are formulated in different ways, such as liquids,
Department of Labor Statistics was over US 18 billion. wettable powders, dusts, and fumigants. Approxi-
Hired workers on the farm are not counted with mately 100 million pounds of active ingredients in
accuracy. Between 100,000 and 300,000 hired hands over 550 million pounds of pesticide products pur-
work on farms in California, the largest agriculture chased in California alone were used in 1989 [3, 4].
state. However, they usually work for less than 25 days
a year, with different exposures and different inherent
health risks. Besides mixing, diluting, and spraying the
crops with pesticides, farmers and their workers Pesticide Usage
fertilize and harvest them. They contact numerous
other chemical irritants and potential allergens doing
other farm-related activities, such as mixing animal Assessing the extent and consequences of pesticide
feed, grooming and tending to animals, and using exposure is difficult and sterns from the complexity of
building materials such as cement and petroleum the subject. Nationally, pesticide use by the agriculture
products. industry is monitored by the Department of Agricul-
Farmers are not the only people exposed to ture, the Environmental Protection Agency (EPA), and
agrochemicals. Forty percent of these chemicals are the Department of Health and Human Services. Several
used outside the agricultural industry. Horne gardeners state organizations and labor unions also monitor their
use fertilizers and weed killers. Household pest-control use, but none of these organizations keeps the detailed
agents contain some of the same pesticides used on annual statistics needed to properly assess the extent
farms. Chemical workers, professional exterminators, of use. The states follow and control pesticide use
animal-feed mill workers, and some food handlers are through various regulatory agencies. In California,
other workers who may make contact with these which ranks first in 36 of 60 major crops grown in the
compounds on a daily basis. U.S., the most detailed annual statistics of pesticide use
and exposure-related illnesses are kept. Their state
regulatory activities are the most comprehensive in the
U.S. and incIude enforcement, registration, informa-
tion services, medical toxicology, environmental mon-
itoring, and worker health and safety. These services
Adapted from: Occupational medicine: state of the art review - are all done within the state Department of Food and
vol 6, No. 3, July-September 1991 Agriculture (DFA) through the Divisions of Pest

782 W. Manuskiatti et al.
Management, Environmental Protection, and Worker Table 1. Illness/injury cases associated with occupational expo-
Health and Safety. sure to pesticides reported by physicians in California, 1982-1993,
by types of illness/injury. Adapted from [8]
Despite this concerted effort, it is still not known
exactly how much pesticide has been used on what Year Eye Skin Eye/skin Systemic Total
specific crops in California. Before 1991, farmers were
required only to register their pesticide purchases. 1982 283 396 27 828 1134
1983 243 410 25 592 1270
They are now additionally required to report their 1984 241 401 24 490 1156
intended pesticide usage, e.g., for storage, for mixing 1985 219 598 44 655 1516
with other pesticides, etc., and exactly how much is 1986 147 342 14 562 1085
1987 356 359 48 744 1507
used on which specific crops, how it is applied, and the 1988 551 529 33 903 2016
amount of acreage exposed. These new requirements 1989 574 343 37 718 1672
should give the Californian DFA more accurate 1990 556 375 32 956 1919
1991 507 282 37 849 1675
statistics of actual pesticide use. Large quantities of 1992 438 332 14 880 1664
pesticides are used in nonagricultural settings. Institu- 1993 372 218 22 695
tional, industrial, and structural pest control uses Total 4487 4585 357 8672 18101
Average 374 382 30 723 1508
accounted for an average of 34% of the pesticides used per year
in California; 15% of pesticides sold were used in Percentage (%) 25 25 2 48 100
hornes and gardens.
In California, approximately one-third of reported
illnesses and injuries due to pesticides involve the skin
[5].
Cutaneous Exposure to Pesticides
It has been stated that contact dermatitis due to

Health Risks of Pesticide Usage
pesticides is rare, considering the extent of their use
[9], but it is likely that pesticides cause more contact
The medical consequences from exposure to these dermatitis than is reported [10, 11]. In California,
compounds vary according to numerous factors, such between 1978 and 1983, 2722 claims were filed for lost
as types of exposure (inhalation vs cutaneous vs work time from the agricultural industry attributed to
ingestion), concentration of chemieal, exposure time, skin conditions [12]. Many cases were attributed to
physical states of the compounds (liquid vs solid), sites allergie contact dermatitis from plants, but these work-
of exposure (hand vs scalp), repeated versus single ers were also exposed to pesticides protecting the crops.
exposure, potential chemie al combinations or routes of Only through patch testing could one distinguish
exposure, body temperature, and numerous environ- irritant from allergie dermatitis and allergy to plants
mental influences, such as ambient temperature, versus allergy to pesticides. Experimentally, certain
relative humidity, wind direction, and speed. Above pesticides are strong sensitizers, even though proven
all, there are numerous human variables, such as cases of allergie contact dermatitis to pesticides are
wearing the same clothing day after day, not bathing infrequently reported [13-15]. Dilution of pesticides
after exposure, and eating food without washing hands, prior to their use in the field minimizes their capacity to
as weIl as interactions between chernicals and personal sensitize exposed workers, because induction of sensi-
medications, which can change the relative risk of tization requires a minimal concentration of an allergen
exposure. The adverse reactions to pesticides, especially [16]. Once individuals are sensitized to pesticides, they
fatal reactions, are more common in third-world may react on patch-testing to dilutions ofthe pesticide in
countries [6]. In California, the agriculture industry acetone as low as 1 in 1,000,000 [13,15].
ranked fourth in death rate among industries from Within the agricultural industry, pesticide handlers
1980-1985. There were 16 deaths per 100,000 workers have the greatest potential exposure to these chemieals.
compared with the statewide industry average of 7.1 They participate in mixing, loading and applying, and
deaths per 100,000. This disparity can be explained by a cleaning and maintaining the equipment. Their
higher rate of traumatic injuries rather than from potential dermal exposure (PDE), the amount of
pesticide exposure. Occupational fatalities attributed to pesticide found daily on the outermost garment, can
pesticide use averaged one per year from 1977 to 1987. sometimes be measured in grams per person. Protec-
The prevalence of pesticide-related illnesses has re- tive outer clothing and enclosed cabs are important
mained almost the same since 1950, even as the barriers that reduce the PDE by 90% and thus lower
pesticide use has increased fourfold (Table 1) [7, 8]. the absorbed daily dose [4]. It is estimated that less
This may reflect reduced toxicity of modern pesticides than 1-30% of daily dermal exposure (DDE) is
rather than safer application and pesticide use. absorbed percutaneously based on animal studies.
Pesticide-Related Dermatoses in Agricultural Workers 783
Contact dermatitis may be the main adverse health pesticide containers [22]. Skin exposure to pesticides is
effect of certain pesticides in man. In California, where maximal on the hands while mixing and loading
physicians are required by law to report all cases of pesticides and while spraying pesticides from tractor-
illness or injury that may have resulted from exposure powered sprayers. A study in fruit farmers of southern
to pesticides, there have been reports of epidemics of Taiwan found that most farmers reported regular use
contact dermatitis due to pesticides [17]. of hat, boots, and mask, but not gloves, raincoat, and
The precise prevalence and incidence of skin goggles [18]. In essence, the use of protective gloves
diseases in agriculture is unknown. A study in 122 markedly decreases cutaneous exposure to pesticides.
Taiwanese fruit farmers showed that 30% of farmers A knapsack sprayer with a boom helps minimize the
developed hand dermatitis, and more than two-thirds exposure of the hands to pesticides [23]. However, the
had pigmentation and thickening on hands [18]. Illness use ofknapsack spraying equipment results in the legs,
reports from workers' compensation boards are especially the lower legs, being the site most exposed to
inadequate to assess the incidence of occupational pesticides.
skin disease, because self-employed farmers are There is usually no certification program to ensure
exc1uded from workers' compensation laws in most that farmers and other agricultural workers are
jurisdictions. In certain jurisdictions, voluntary cover- competent to use pesticides and agricultural chemieals
age by workers' compensation boards is available for safely. Most farmers and agricultural workers do not
self-employed farmers, but most farmers do not elect always employ adequate skin protection. Surveys in
this coverage. Many transient agricultural workers may Saskatchewan confirm that only a minority of farmers
not report occupational diseases or do not know how always use skin protection while handling pesticides
to enter the health care system. Most centers for (data on file, Seetions of Dermatology and Respirology,
occupational medicine are located in urban areas and Department of Medicine, University of Saskatchewan).
may not emphasize occupational dis orders in agricul- Lack of adequate skin protection when using pesticides
ture. Despite these difficulties, the agricultural sector is most likely to occur in hot weather or during busy
was noted to have the highest rate of occupational skin work periods. In a 1985, study field workers in
disease of any industry in California [19]. Risk of Californian vineyards were most likely to develop
occupational skin disease was four times higher in rashes after thinning vines and during hot days [24].
agriculture than the all-industry average risk. The rate Pesticides in general and propargite in particular did
of occupational skin disease in agriculture was twice as not appear to be a major cause of skin rashes, though
high as the rate in the manufacturing sector. Occupa- outbreaks of rashes in grape-field workers have been
tional skin disease usually accounts for 40% of all attributed to propargite and/or sulfur exposure in
occupational disease, but occupational skin disease California.
accounted for approximately 70% of all occupational Adequate washing facilities are frequently absent in
disease in agriculture in California. The risk of the fields where the pesticides are being applied and
occupational skin disease and the types of occupa- most farmers believe they cannot afford expensive
tional skin disease vary with the crops, livestock, safety equipment. Barrier creams are not proven to be
farming practices, and c1imate of an area. In California, effective in protecting the skin from pesticides.
pesticides were second to poison oak as reported Pesticides may persist on the skin for long periods.
causes of occupational skin disease in agriculture. Chlordane and dieldrin have been claimed to persist
Irritant contact dermatitis as areaction to pesticides on skin for up to 2 years [25]. Ordinary laundering is
is more frequent than allergie contact dermatitis. The not a very effective way of removing pesticide residues
chief cutaneous irritants among the pesticides are from c1othing. The degree of contamination of the
inorganic compounds such as cop per sulfate. Insecti- worker's skin and c10thing by pesticides also varies
eides, such as carbamates, have been the most with the skill and attitude of the applicator, the type of
frequently reported causes of allergie contact derma- pesticide spray (low volume concentrate, conventional
titis due to pesticides [20]. spray, etc.), type of crop (orchard or row crop), wind,
and quality of spray equipment [26].
Certain highly toxic pesticides, such as the organo-
phosphate parathion, are rapidly absorbed through the
Field Conditions
skin without producing any dermatitis. Severe neuro-
logical symptoms or death have followed percutaneous
Under field conditions, the skin is the organ most absorption of certain organophosphate pesticides [27].
exposed to pesticides [21]. Farmers and agricultural Experimentally, percutaneous absorption is five times
workers are exposed to pesticides while mixing, greater in some individuals than others and may be
loading, and spraying pesticide formulations as well greater through infiamed skin than normal skin.
as while c1eaning spray equipment and disposing of Feldmann and Maibach [28] studied the percutaneous
absorption of 12 pesticides. The least absorbed of these Ecuador into the U.S. The active principals are
was diquat and the most absorbed was carbaryl. pyrethrins land 11, cinerins land 11, and jasmolin I
The EP A recommends that workers not be allowed and 11, collectively known as pyrethrins. Pyrethrins are
into fields that have been treated with pesticides until used extensively in stock sprays, pet sprays, household
an adequate time interval has elapsed. For organopho- sprays, aerosols, and food protection in warehouses.
sphate and n-methyl carbamate pesticides having acute Pyrethrins are stable for long periods in water-based
dermal toxicity, a 48-h interval is proposed. The EP A aerosols, in which modern emulsifiers are used.
proposals recommend rubber of chemical resistant Dermatitis from natural pyrethrins usually occurs on
gloves for exposed workers. Mixers and loaders would parts of the body exposed to the spray. The substance
be required to wear resistant aprons to reduce is a moderately potent allergie sensitizer. Cross-
exposure from splashes and spills from handling bulk reactions occur among pyrethrum, chrysanthemum,
pesticides. Other protective equipment includes head- shasta daisy, and ragweed oleo resin [31, 32]. Asthma
gear, face shields, and chemical-resistant footwear for and urticaria have also been reported as reactions to
high-toxicity compounds. EPA draft proposals also natural pyrethrin [33,34]. In 1972, Mitchell et al. found
require that water, soap, and single-use towels be that a sesquiterpene lactone, pyrethrosin, was the chief
available for decontamination, and that these must be allergen in pyrethrin [35]. Contact dermatitis due to
located ne ar the workers. Provisions would also pyrethrum is usually mild, but bullous reactions have
require that handlers and mixers of pesticides receive been reported [36]. In Denmark, positive patch-test
training. Workers using organophosphate com- reactions to pyrethrum were obtained in 1-2% of
pounds for three consecutive days should have their dermatitis patients [37].
serum cholinesterase level determined. Chemie al
manufacturers would also be required to update Pyrethroids
warning instructions on pesticide labels. The rules
would extend existing requirements to cover workers Pyrethroids are synthetic compounds produced to
in forests, nurseries, greenhouses, and all other duplicate the biologie activity of the active principals
handlers of pesticides. Enforcement would be up to of pyrethrum. Pyrethroids have a longer duration of
state agencies responsible for agricultural programs activity against insects than pyrethrum and are not
[29]. teratogenic or mutagenic. These compounds include:
Pesticide sprays contain emulsifiers, adjutants, allethrin, alphametrin, barthrin, bioresmethrin, bio-
carrier liquids, and surfactants. To prove that a case permethrin, cismethrin, cyclethrin, cytluthrin, cyper-
of allergie contact dermatitis is due to a particular methrin, decamethrin, deltamethrin, dimethrin, feno-
pesticide, it is necessary to perform patch testing to a thrin, fenpropanate, fenvalerate, fiucythrinate, fiuvali-
nonirritating concentration of analytic-grade pesticide nate, furethrin, indothrin, permethrin, phthalthrin,
in an appropriate vehicle. Contaminants may be the resmethrin, and tetramethrin. Allergie contact derma-
main allergen in pesticide formulations. For example, titis due to pyrethroids has not been reported.
diethyl fumarate was found to be the sensitizer in Temporary paresthesias manifested by numbness,
technical-grade malathion [15]. Predictive tests to itching, burning, tingling, and warmth have been
assess a pesticide's capacity of inducing allergie reported following cutaneous exposure to the synthetic
contact dermatitis is now required prior to registration pyrethroid fenvalerate. Fenvalerate, produced in the
of a pesticide for sale [30]. U.S., produces more paresthesias following topieal
exposure than pyrethrin and other pyrethroids. It has
been suggested that topieal vitamin E acetate is highly
effective in treating paresthesias induced by pyre-
Pesticide Types
throids [38].
Pesticides Derived trom Plants Nicotine
Pyrethrum Litde or no nicotine is now produced in the U.S. for

use as an insecticide, because organophosphate
Pyrethrum is comprised of the dried fiowers of insecticides have largely replaced it. Limited supplies
Chrysanthemum cinerariaefolium, containing not less are imported from India. Nicotine may be absorbed
than 1% pyrethrins. Pyrethrin esters constitute a through the skin of people harvesting tobacco leaves.
powerful degradable contact insecticide. They have a Vero and Genovese [39] patch-tested workers with
low order of systemic toxicity to man and produce no dermatitis who made cigars from various tobacco
harmful residues on food crops. The fiowers and leaves; no positive reactions were found. Exposed
extracts for pyrethrum are imported from Kenya and workers may develop nausea, vomiting, dizziness,
prostration, and weakness. Abrasions on the skin Inorganic arsenicals have been superseded because
occur during the harvesting of tobacco leaves, and of their hazard to man and animals. Sodium arsenate
abrasions increase the percutaneous absorption of was formerly the toxicant in many ant syrups for
nicotine. The use ofwork gloves significantly decreases household use, but this application has also been
nicotine absorption in workers [40]. discontinued. Organic arsenicals are at present of the
Nicotine skin effects have been reviewed in detail by most interest because of their value as selective
Smith et al. [41]. Transdermally absorbed nicotine herbicides.
induced predominantly sudorific and rubiform reac-
tions which may be accompanied by subtle piloerec- Sulfur
tion, hyperalgesia and pruritus.
Sulfur is a commonly used fungieide and acaricide.
Rotenone It is compatible with most other insecticides and
fungicides. Insoluble in water but soluble in organic
Rotenone is a selective contact insectieide with some solvents, wettable sulfur is prepared by adding
acarieidal properties. Cube is now the only commereial wetting and dispersing agents to finely ground
source in the U.S. of rotenone for insecticide produc- sulfur. Micronized wettable sulfur is made by means
tion, although derris, timbo, and other related of a special manufacturing process to ensure an
rotenone-containing plants have been utilized. Peru extremely fine particle size. Grapes and peanuts are
is the main source of the cube root. The root may be examples of crops requiring fungicides such as
ground as a dust or extracted to provide concentrate. sulfur. Many cases of irritant dermatitis are attrib-
Rotenone has been long used as dust for garden uted to sulfur in California [5], but there are few
insects, lice, and ticks on animals. Rotenone may also reports of allergie dermatitis [43].
be used in combination with pyrethrin and piperonyl Positive patch testings from sulfur (~ +) were
butoxide (a synergist) for control of a wide variety of reported in 5 of 39 exposed workers, compared with 1
insects on food crops. Skin irritation from rotenone of 21 control subjects. This article provides results of
has been reported among workers in rotenone- previously unreported irritant contact dermatitis [44].
processing plants in South America. Skin inflamma-
tion was most notable in intertriginous areas or where Triphenyltin Hydroxide
the powder had been trapped by perspiration on the
skin. A similar outbreak was reported among workers Triphenyltin hydroxide is a fungi eide used on many
in France, but improved ventilation and dust masks crops. Irritant patch-test reactions are frequent if
diminished the occurrence of dermatitis in these patients are patch tested to 1% triphenyltin (phentin
workers [36]. hydroxide) [20]. Tributyltin oxide is a severe skin
irritant but not a sensitizer [45].
Inorganic and Organo-Metal Pesticides
Copper Sulfate
Arsenic
Copper sulfate is a fungicide and algicide. List et al.
The earliest insecticides against chewing insects were reported positive patch-test reactions to 1% copper
the arsenicals, chiefly copper acetoarsenite (Paris sulfate in agricultural workers [20]. Additional normal
green) lead arsenate, and calcium arsenate. Sodium controls and use of provocative tests should help
arsenite has been used as a sterilant herbicide and a clarify whether these responses are irritant or allergie.
potato-vine killer. Inorganic arsenic is both a cuta-
neous irritant and sensitizer [10]. Hyperkeratosis, Phenylmercury Nitrate
hyperhidrosis and hypermelanosis are considered
evidence of chronic systemic exposure. The hyperpig- Phenylmercuric salts were previously widely used as
mentation is most marked on surfaces exposed to light; herbieides and agricultural fungieides. Phenylmercury
it does not extend to mucous membran es. There may nitrate is still used for tree wound dressings. Contact
be a speckled depigmentation of pigmented areas dermatitis to phenylmercury nitrate used as a herbi-
giving a "raindrop" appearance. Compounds similar eide has been reported [46]. Patch-testing with organic
or identical with those used as pestieides have caused mercuric salts presents technical challenges. Patch-test
skin cancer in man [36]. Agricultural workers are also concentrations currently used may be marginal
exposed to chronic ultraviolet (UV) light, and it had irritants. Until far more is known about current
been believed that UV -light exposure was a more concentration dose and vehicle, provocative tests
significant factor for these workers than their exposure provide a convenient method to help confirm the
to inorganic arsenic [42]. presence of allergy.
Solvents with a 2:1 mixture of aerylonitrile and earbon

tetrachloride [54]. Three of the four eases died. It is
Kerosene not clear whether these eases represented true toxie
epidermal neerolysis or a "pseudo-toxie epidermal
Kerosene, first used in 1877, was apparently the first neerolysis" due to irritation. This fumigant has
petroleum oil to be used for inseet eontrol. Presently, it subsequently been diseontinued.
is widely used as a solvent for household and industrial
pesticide sprays. The kerosene may be sulfonated to Metam-Sodium
provide an odorless oil or deodorants may be added.
Kerosene is a eutaneous irritant. Barnes and Wilkinson Metam-sodium, a broad-speetrum soil fumigant, is a
deseribed an eruption similar to that of toxie fungicide, inseeticide, nematoeide, and herbieide.
epidermal neerolysis "irritant pseudo-toxie epidermal Richter [55] states that allergie contaet dermatitis to
neerolysis" in a boy whose clothing beeame eontami- metam-sodium (methyl isothioeyanate) may be sig-
nated with kerosene [47]. nifieant among exposed persons. In his opinion,
metam-sodium is a potent sensitizer. He also attrib-
Fumigants uted hepatitis in one patient to exposure to metarn-
sodium.
A fumigant is a substanee or a mixture of substanees
that produces gas, vapor, fume or smoke intended to 00
destroy inseets, baeteria or rodents. Fumigants may be
volatile, liquids and solids as weIl as substanees already DD is a highly toxie mixture of 1,3-dichloropropene,
gaseous. They may be used to disinfeet the interiors of 1,2-diehloropropane, epiehlorhydrin, and related eom-
buildings or objeets and materials that ean be enclosed pounds, and is a eutaneous irritant. It is used as a soil
so as to eontain the fumigant [48]. fumigant. Nater and Gooskens obtained positive pateh
tests to 1% DD in acetone [56]. They eoncluded that
Ethylene Oxide oeeasionally DD eould provoke allergie eontaet der-
matitis.
Ethylene oxide or epoxy ethane is used as a fumigant
and a sterilant. Severe irritant dermatitis and chemie al Oazomet
burns have been reported from direet skin eontaet with
ethylene oxide [36]. Ethylene oxide, first used as an Dazomet is used as a nematoeide, soil fumigant,
agrieultural fumigant in 1928 is effeetive against all herbicide, and algicide. Dazomet hydrolyzes to for-
microorganisms [49]. It is a potent skin irritant and malin. Contaet dermatitis, probably irritant and
may produee immediate and possibly delayed eontaet allergie, has been reported to dazomet [57].
hypersensitivity. Beeause this ehemieal is a potent
irritant, it requires eareful testing to aseertain whether Chlorinated Hydrocarbon Insecticides
dermatitis is irritant or allergie. Pereutaneous absorp-
tion of ethylene oxide has been reported [50]. Oichloro-Oiphenyl-Trichloroethane
Epidemiological studies strongly suggest that ethylene
oxide is earcinogenie in man [51]. Sinee 1973, diehloro-diphenyl-triehloroethane (DDT)
has been banned in the U.S. for all exeept emergeney
Methyl Bromide publie health measures. Allergie eontaet dermatitis due
to DDT has not been eonvineingly reported [58-61].
Methyl bromide is a fumigant used for inseet eontrol in Positive pateh-test reaetions to 3% DDT were reported
grain elevators, mills, ships, and greenhouses. The gas in cotton workers with dermatitis of exposed areas. No
is also a soil fumigant. In addition, it is used for positive pateh-test reaetions to 1% DDT were obtained
termite eontrol, agrieultural fumigation, and rodent among 665 routine eezematous patients pateh-tested
eontrol. Direet skin contaet with methyl bromide by the International Contaet Dermatitis Research
pro duces ehemieal burns [52]. Methyl bromide ean Group (ICDRG) [10].
be absorbed through the skin and has eaused serious
oeeupational poisonings in California [53]. Lindane
Acrylonitrile Lindane is used for seed treatments for control of wire

worms and seed-eorn maggots on various erops. It is
Toxie epidermal neerolysis was reported in four also used to proteet tobaeeo transplants from eut-
patients 11-21 days after their hornes were fumigated worms and wire worms and as soil treatment,
application to foliage on fruit and nut trees, vegetables, However, it was found as part of the first study that
ornamentals, timber, and wood protection. It is a skin only about 3% of people with occupational exposure to
irritant but allergie contact dermatitis is rare. No malathion had a positive patch-test reaction to 1%
positive patch reactions to 1% lindane were obtained in malathion, and no worker had to change work because
665 routine eczematous patients patch tested by the of malathion allergy. Only one positive patch test
ICDRG [10]. re action to 0.5% malathion was obtained in 455 routine
eczematous patients patch tested by the ICDRG [67].
Oieldrin This one reaction was of unknown relevance. In
practice, malathion appears to be a weak allergie
Dieldrin is an insecticide. In the U.S. it is only used for contact sensitizer. Kligman has suggested that the
termite control. Dieldrin probably caused dermatitis of usage concentration of malathion is too low to provoke
the lower legs in 200 of 1209 police recruits exercised sensitization. Milby and Epstein determined that the
to sweating who wore socks mothproofed with dieldrin sensitizer in malathion is diethyl fumarate, which is
[62]. used in the manufacture of malathion. Diethyl
fumarate was present at a 3% concentration in
Methiocarb technical-grade malathion [14]. Diethyl fumarate can
produce nonimmunologic contact urticaria [68].
Methiocarb (Mesurol) is used as an insecticide or
molluscicide. A case of hand eczema with positive (++)
patch testing to methiocarb has been reported [63]. Oichlorvos
OrganoPhosphate Pesticides Dichlorvos (DDVP) is an insecticide used in sprays,

wettable powder, aerosols, resin strips, and flea collars.
Parathion and Methyl Parathion It is also formulated as an anthelmintic for swine,
horses, and dogs. It has an acute dermal LD 50 of 75 mgl
Organophosphate pesticides became widely used kg for rats (amount required to kill 50% of a
following the banning of DDT. Parathion is an population of animals within a certain time). Strong
insecticide that is extremely toxic to man and animals. positive reactions to flea collars were reported in two
It is a restricted-use pesticide in the U.S., and exposed patients who had dermatitis attributed to contact with
workers must wear rubber gloves, protective clothing, dogs wearing DDVP-impregnated flea collars [48].
goggles, and arespirator. The mask or respirator must Cronce and AIden [67] reported primary irritant
be approved by the V.S. Bureau of Mines for parathion contact dermatitis to DDVP flea collars in four
protection. Parathion was found on the skin of the patients. Patch-testing produced bullous primary
hands of one worker 2 months after his last known irritant reactions in four patients and five controls.
contact [25]. Mathias [69] noted negative patch tests to 1% and 0.1%
Parathion is an experimental contact sensitizer [20]. DDVP in petrolatum in a truck driver who developed
Allergie contact dermatitis to parathion has been prolonged contact dermatitis to DDVP. This man also
reported in a German vintner [64]. A garden er cut had systemic symptoms of organophosphate toxicity
his finger and used a concentrated spray containing following his exposure to DDVP from a spill of this
parathion and emulsifiers on begonias. The cut finger chemical in his truck. Mathias emphasized that
became swollen and bluish-red 1 day later. The finger individuals who develop dermatitis from skin contact
was cool and painless. The author believed the patient with pesticides should be carefully questioned about
had an unusual re action to parathion. The patient was general symptoms. This is particularly important for
treated with penicillin [65]. organophosphate insecticides.
Erythema multiforme has been reported in a woman
who inhaled methyl parathion [66]. Experimental re-
exposure reproduced her lesions. Tetmosol
Malathion Tetmosol is used to treat parasitic infestations in dogs

and cats and is used as a scabicide and a fungicide.
Malathion is an insecticide used to control a wide Cronin [10] has reported of a 58-year-old woman with
variety of insects. Milby and Epstein [15] found that chronic eczema whose dermatitis flared after treating
nearly half of 87 volunteers developed contact sensi- her cat with tetmosol and when she wore rubber
tization following a single exposure to 10% malathion gloves. She had positive patch tests to tetmosol
and that many of them reacted to dilutions as low as solution and both to 1% tetramethylthiuramdisulphide
1 ppm. Similar results were reported by Kligman [14]. and 1% tetramethylthiuramdisulphide in petrolatum.
Naled bacteria, fungi, and termites. The wood retains its

natural appearance [73].
Naled is an insecticide-acaricide, intermediate in Vaguely defined rashes and skin irritation, possible
toxicity between malathion and parathion. Allergie chloracne, and susceptibility to skin infections have
contact dermatitis to naled has been reported in a few been attributed to chronic exposure to pentachlor-
workers [70]. Naled is broken down by hydrolysis ophenol. Lambert et al. [74] associated pemphigus
within a few hours. Patients allergie to naled may work vulgaris in a 41-year-old man and a 28-year-old woman
with plants sprayed with naled once a suitable interval and chronic urticaria in a 35-year-old man to chronic
has elapsed. exposure to pentachlorophenol. No subsequent cases
have been documented.
Thiometon
Pentachlorophenate
Thiometon is a systemic insecticide used to control
Kentor reported of a patient who developed urticaria
aphids, thrips and mites. A case of contact dermatitis
and angioedema from contact with pentachlorophe-
has been attributed to thiometon [36].
nate [75]. This patient was feit to have immunologically
mediated contact urticaria. He developed urticaria and
Rodannitrobenzene
angioedema at sites distant from his hands, which were
the site of skin contact with pentachlorophenate.
Rodannitrobenzene has been used in insecticide sprays
for horne use. Fregert has reported a case of severe
Chlorocresol and Chloromethylphenoxyacetic Acid
contact dermatitis due to rodannitrobenzene [71].
A positive patch-test re action to 0.1% chlorocresol in
Omethoate and Oimethoate
alcohol was reported by Fregert in a man who
developed dermatitis on two occasions after using
Omethoate and dimethoate are organophosphorus
chloromethylphenoxyacetic acid (MCPA) spray [76].
insecticides with similar chemie al structures. Thus
Patch-testing to 1% MCPA was negative. Chlorocresol
cross-sensitivity is possible. Allergie contact dermatitis
is used in the manufacture of MCP A.
caused from omethoate and dimethoate have been
reported [72].
4,6,Oinitro-o-Cresol
Carbamate Insecticides
4,6,Dinitro-o-Cresol (DNOC) is an insecticide, fungi-
cide, herbicide, and defoliant used in North America as
Promecarb
a dormant spray for killing insect eggs and to control
apple scab. NaH dystrophy has been reported following
Promecarb is a contact insecticide. Contact dermatitis
fingernail contact with 5% DNOC [77].
to promecarb has been reported in two workers [36].
Carbaryl Oinocap
Carbaryl is a broad-spectrum insecticide used on more Dinocap is a foliage fungicide and acaricide. One case
than 120 different crops. A case of contact dermatitis to of allergie contact dermatitis has been ascribed to
carbaryl spray has been reported [36]. dinocap [36].
Nitro-Compounds and Related Phenolic Pesticides Tecnazene
Chlorinated phenols are effective fungieides but Tecnazene is a fungieide and growth regulator.
because of their toxicity are used only for fabrics and Cotterill reported of a farmer who developed an acute
woods. dermatitis while throwing tecnazene granules onto a
conveyor beIt carrying potatoes [78]. Patch testing to
Pentachlorophenol tecnazene was negative, but this farmer had a strong
positive patch-test reaction to 0.01% dinitrochloro-
Pentachlorophenol (PCP) has been used as a mollus- benzene (DNCB). Cotterill attributed his patient's
cide, insecticide, herbicide, fungi eide, bactericide, anti- contact dermatitis to DNCB contaminating the tecna-
mildewagent, and preservative, particularly for wood. zene granules. DNCB could have been formed during
Lumber impregnated with PCP is relatively resistant to the production of tecnazene.
Phenothiozine induced keratoses, Bowen's disease, and squamous cell

carcinoma of the skin [84, 85]. Paraquat itself is
Phenothiazine, an oral insecticide and anthelmintic probably not the etiologic agent for these premalignant
introduced in 1925, was the earliest organic insecticide and malignant skin lesions. Discoloration of the
known. It is fed in salt or mineral supplements to fingernail, nail deformity, onycholysis, and loss of the
control fly larvae and certain internal parasites. nail have been reported in workers whose fingernails
Workers spraying apple orchards with phenothia- came into contact with paraquat sprays and concen-
zine in the state of Washington developed severe trates [77, 86].
phototoxic reactions [79]. Photoreactions have also A case of periungual eczematous dermatitis with
occurred in workers preparing the raw materials. The striking nail lesions due to paraquat was reported by
reactions resembled sunburn and in hair became a Botella et al. [87]. Patch-testing to paraquat 0.001%
pinkish red and the fingernails brown [80]. Szolar- and 0.1% in water was negative. A necrotic ulcer of the
Platzer reviewed allergy to this and related antihista- seroturn following direct contact with paraquat solu-
mines [81]. tion was reported by Sharvill [88]. Deaths arising from
percutaneous absorption of paraquat have also been
Rodenticides reported [89].
Garnier et al. [90] reported two cases of paraquat
Warfarin poisoning resulted from skin absorption. One patient
died from respiratory failure 26 days after applying
Warfarin is a roden ti eide that is highly effective in paraquat onto his whole body as a treatment for
controlling Norway rats and house mice. A positive scabies. The other with a previous his tory of psoriasis
past re action to 0.05% warfarin in an agricultural developed extensive generalized pustular erythroder-
worker has been reported by Lisi and colleagues [20]. ma and a moderate, transitory renal and respiratory
impairment 13 days after exposure.
Naphthylthiourea
Nitra/in
Naphthylthiourea (ANTU) is a rodenticide for adult
Norway rats. A case of occupational contact dermatitis Allergie contact dermatitis to nitralin and its precursor
to ANTU has been reported [36]. - 4-chloro3,5-dinitrophenylmethyl sulfone - was re-
ported in a man working in a factory producing this
Herbicides herbicide. He also showed cross-sensitivity to DNCB
[91]. The manufacture of nitralin in the U.S. has been
Herbicides are now frequently used in place of hand subsequently discontinued.
labor or machine cultivation to control unwanted
plants. Amitrole
Glyphosphate Amitrole (Aminotriazole) is a systemic herbicide used

to control nonselective grasses, broadleaf weeds, cat-
Glyphosphate is a nonselective, postemergence herbi- tails, poison ivy, and certain aquatic weeds. One case of
eide. In 1986, contact dermatitis attributed to glypho- allergie contact dermatitis to aminotriazole has been
sphate was reported in 33 workers mixing or loading reported in a contract weed control operator [92].
this herbicide in California [5]. Maibach extensively
investigated glyphosphate and has found it to be a Chloridazon
nonsensitizer in the Draze Repeat Insult Patch Test
and less irritating to the skin than baby shampoo [82]. Chloridazone (Pyrazon), a herbicide used to protect
A phototoxic reaction to benzisothiazolone, a pre- beets, can pers ist in the soil for several months.
servative present in glyphosphate, has been reported. Allergie contact dermatitis to chloridazon spray has
Phototoxicity to glyphosphate itself was not demon- been reported in a farmer by Bruze and Fregert [93].
strated [83].
Phenmedipham
Paraquat
Phenmedipham is a postemergence herbicide. Severe
Paraquat is a contact herbicide and desiccant. Irritant allergie dermatitis to phenmedipham has been re-
contact dermatitis has been reported to occur with ported in two farmers [94]. Koch and Bahmer [95]
paraquat. Workers in factories where paraquat is reported a case of photo allergie dermatitis due to
manufactured have an increased risk of occupationally phenmedipham.
Dieh/obeni/ 2,4-Dich/orophenoxyacetic Acid
Dichlobenil is a herbicide. Six men engaged in mixing 2,4-Dichlorophenoxyacetic acid (2,4-D) is a selective
or bagging dichlobenil developed dermatitis within herbicide used for weed control, water hyacinth
1 week to 5 months of first exposure. Although the control, and various other uses. Several companies
condition involved comedones and was spoken of as manufacture 2,4-D. 2,4,5-T, salts, and esters are used
chloracne, no cysts were observed and, judging from widely to control woody plants on industrial sites and
the description and one photo graph, the dermatitis range land. Amine formulations are used extensively
was not severe. The possibility that this mild condition for weed control on rice. The action and properties of
may have been associated with a contaminant may not these compounds are similar to those of 4,5-T
have been explored [36]. preparations.
2,4-D-2,4,5-T mixtures are used in combination for
the destruction of mixed growth of woody plants and
Atrazine
herbaceous weeds. Severe contact dermatitis has been
reported to a mixture of 2,4-D and 2,4,5-T [36].
Atrazine is a selective herbicide. Severe contact
A major epidemiologie al study found an association
dermatitis to atrazine has been reported in a farmer
between the use of 2,4-D and non-Hodgkin's lympho-
with a history of dermatitis caused by propachlor. This
ma in Kansas. The greater the use of 2,4-D, the greater
patient had a positive patch-test reaction to 1:1000
the incidence of non-Hodgkin's lymphoma among
dilution of a commercial atrazine formulation [36].
exposed farmers [100]. This study did not confirm
previously reported associations between 2,4-D use
Propazine and soft-tissue sarcoma or Hodgkin's disease [75, 101-
105].
Propazine and simazine are selective herbicides. Many
cases of contact dermatitis have been reported among
workers manufacturing propazine and simazine [36].
Barban
Oxydiazo/ Barban (barbamate barbane, chlorinate) is a selective

herbicide of low systemic toxicity. Allergie contact
Chloracne has been reported in workers manufactur- dermatitis to barban has been documented [13, 106].
ing oxydiazol (methazole). This resulted from expo- Marked sensitivity to barman may develop when only
sure to 3,4,3',4'-tetrachloroazoxybenzene (TCAB), an minute concentrations of barman are sufficient to
extraneous intermediate produced during the manu- produce strongly positive patch-test reactions. Hypo-
facture of the herbicide [96]. pigmentation was noted following one case of allergie
contact dermatitis to barban [84l.
A/ach/or
Alachlor is a pre-emergence herbicide. Iden and Dazomet

Schroeter reported five individuals with positive
allergie patch-test reactions to alachlor [97]. Three of Dazomet is a herbicide, fungicide, slimicide and
21 patients patch tested to alachlor reacted to both nematocide. Black, in 1973, reported of a tomato
alachlor (Lasso) and propachlor (Ramro). Further grower using dazomet as a soil fumigant [57]. A 0.5%
studies may help clarify whether these were irritant concentration in water resulted in a positive re action
or allergie patch-test reactions. Won et al. [98] on patch testing, and a significant reaction also
documented allergie contact dermatitis from alacholor. occurred at 96 h following open testing. Black
Ten controls patch tested to alachor were performed; described dazomet as a strong sensitizer a primary
one had a late re action thought to be active sensitiza- irritant, and possibly a vesieant.
tion.
Trich/orobenzy/ Norflurazon
Trichlorobenzyl chloride is a herbicide used in Norfiurazon (Prediet) is a herbicide used for the
preemergence application only in combination with control of grass and broad-leaf weeds in field-grown
allidochlor (Randox). Skin irritation was also reported nursery stock. Allergie contact dermatitis to norfiur-
to this chemical by Spencer [99]. azon has been reported [107].
Fungicides appearanee of vesieulation and edema of the faee and

hands of a welder assoeiated with wheezing was
Benomyl attributed to eontaet with bags of eaptafol. Subsequent
re-exposure led to reeurrenees [36]. Irritant eontaet
Benomyl is a systemic fungicide widely used for the dermatitis has been associated with the use of eaptafol
eontrol of a broad range of diseases of fmits, nuts, by farmers in Japanese tangerine orehards; 25-30% of
vegetables, field erops, and ornamentals. Allergie workers were affeeted [10]. Some of these reaetions
eontaet dermatitis in areas exposed to benomyl was were severe [36]. Captafol was the pesticide aecounting
reported in seven Japanese women working in a hot, for the greatest number of eases of eontaet dermatitis
humid greenhouse where benomyl was being sprayed in Japanese reports [lll].
on earnations. Ten Hispanie eo-workers were unaf- Stoke states that at least one-third of exposed
feeted. Undiluted benomyl and benomyl diluted 1:5 in workers will develop dermatitis if adequate preeau-
olive oil produeed negative pateh tests in three tions are not taken [112]. Up to 65% of exposed
eontrols, but a Japanese medieal assistant developed workers have been reported to develop eaptafol
a 2+ reaetion when these pateh-test sites were exposed dermatitis. The risk of dermatitis from eaptafol ean
to 30 s of UV light. The seven Japanese workers had be minimized by appropriate worker training and
positive pateh-test reaetions to benomyl 1:10 in olive industrial hygiene. The manufaeturers of eaptafol
oil [108]. Fregert reported one ease with a positive regard it as a potent sensitizer [78]. Cottel also
pateh-test reaetion to benomyl 0.1% in water [109]. He reported two farmers with dermatitis of exposed areas
wondered whether most eases of dermatitis due to who had positive pateh tests to 0.1% eaptafol in water.
benomyl were transient. Van Ketel reported a begonia
grower with eontaet dermatitis due to this fungicide
[22]. The dermatitis was eaused not by spraying but by Captan
pieking the leaves. Pateh testing with 1% in petrolatum
was positive. Van Joost et al. [11] stated that pieking Captan is a widely used proteetant/eradieant fungicide.
plants eontaining residues of benomyl is an important Agrieultural workers may be heavily exposed to eaptan
souree of sensitization to benomyl. during and after spraying operations. One California
vineyard applied it 75 times in one season. The EP A
Hexachlorobenzene reviewed the ehemieal beeause baeterial and rodent
studies suggested that eaptan is mutagenie and
Hexaehlorobenzene is a seed proteetant used on wheat. earcinogenie. Urtiearia due to eaptan has been
Contaet with hexaehlorobenzene may eause slight skin doeumented in a gardener who reaeted to eaptan and
irritation. Hexaehlorobenzene produeed an epidemie to eaptan-treated plants [36]. Fregert reported of a fmit
of severe porphyria eutanea tarda in Turkey from 1955- farmer who developed dermatitis of his hands and faee
1959. The disease oeeurred almost exclusively in after 3 weeks exposure to eaptan [113]. Pateh-testing
persons who admitted eating wheat distributed for with eaptan and the related folpet (Phaltan), 1% in
seed not for food. This wheat had been treated with petrolatum, gave positive reaetions. Marzulli and
hexaehlorobenzene. Many in fants died from exposure Maibaeh demonstrated that eaptan in a eoneentration
to hexaehlorobenzene in this epidemie [80]. ofl% is a signifieant eontaet allergie sensitizer [114]. Of
205 human test subjeets, 9 were putatively sensitized.
Thiophanatemethyl The International and North American Contaet
Dermatitis Groups later found eaptan in a 1%
Thiophanatemethyl is a systemic fungicide with a eoneentration to be irritant on pateh testing; 0.25%
broad speetmm of aetivity for plant disease. Many in petrolatum is now preferred for pateh testing.
eases of apparent irritant eontaet dermatitis but few Relevant allergie reaetions to eaptan appear to be rare
eases of allergie eontaet dermatitis to thiophanate- [10]. Captan had been reported as a sueeessful topical
methyl have been reported [36]. treatment for tinea versieolor [36, 115].
Captafol Folpet
Captafol is used to prevent blight on potatoes and on Folpet is a proteetive fungieide used as a 50% wettable
fmit and farm erops. Camarasa reported severe powder and in various dusts on fmits, berries,
pruritus, morbiliform urtiearial emptions, and asthma vegetables, fiowers, and ornamentals. Six agrieultural
among 7 of 41 workers in a eompany that paeked workers had positive pateh-test reaetions to 0.1%
eaptafol (Difolatan) [110]. Four of these patients had folpet but irritant reactions were seen in some controls
strong pateh-test reaetions to captafol. The sudden [20].
The ICDRG patch-tested 509 patients with suspected pesticides, induding lindane, hexachlorobenzene, cap-
contact dermatitis. Fifty patients had positive patch- tan, and zineb. Zineb may be combined with other
test reactions but only one was relevant. One hundred pesticides, induding thiram and sulfur. Maneb and
and seven patients were patch tested to 0.1% folpet. zineb are related to the carbamate dass of rubber
Three patients had positive reactions but no positive accelerators and are of relatively low systemic toxicity;
patch-test reactions were deemed dinically relevant however, they are important allergie sensitizers.
[10]. Peluso et al. reported a case of 2-month history of
finger and hand eczema in a female agricultural
Oinitritochlorobenzene worker, which improved when she stopped work.
Patch testings gave positive results to carbamate-mix
Occupational allergie contact dermatitis has been 1% petrolatum, bis-dithiocarbamate (maneb) and
reported to DNCB used as an algicide [116, 117]. thiophthalimide (captan 0.1% petrolatum, captafol
Zimmerman et al. emphasized that this potent sensi- 0.1% petrolatum and folpet 0.1% petrolatum) at 2 days
tizer should be only used in completely endosed and 3 days (+1++) [119].
systems, not allowing skin contact with DNCB [117]. Piraccini et al. reported a case of allergie contact
dermatitis from pesticide maneb in an agricultural
Pentachloronitrobenzene worker with a 7-year history of recurrent dermatitis of
the face and arms each summer. Patch testing was
Pentachloronitrobenzene (PCNB) is used as a soil positive to maneb 1% petrolatum (Da/D3++). The
fungieide and seed-treatment chemieal. It is particu- patient had no recurrence of dermatitis the following
lariy useful for Brussel sprouts, broccoli, and arti- summer, after discontinuing maneb exposure [120].
chokes. Cronin described a 46-year-old man packing Matsushita et al., using the guinea-pig maximization
pesticide powders who developed dermatitis of his test, demonstrated the strong sensitization potential of
arms, legs, forehead, trunk, and seroturn [10]. Patch- maneb and zineb [111]. Six patients with dermatitis from
testing to PCNB, 1% in petrolatum, was positive. The zineb were reported by Scepa and Ippolito in 1959 [10].
patient's shoes were heavily contaminated with PCNB Cases of allergie contact dermatitis in workers spraying
dust. DCNA (2,6 dichloro-4-nitroaniline) is a related tobacco were reported by Laborie [121]. Nater et al.
compound. Positive patch testings from PCNB were described three cases of allergie contact sensitization
reported in 2 of 39 exposed nursery workers (»+). due to maneb [122]. Two of the patients worked in rooms
However, the biological significance of these findings heavily decorated with plants, and the third was a florist.
could not be definitely determined. The observed Patch testing was done at 1%, 2%, and 5%, but studies of
reactions could represent de novo sensitization in- cross-reactions to zineb and other dithiocarbamates
duced by the provocative procedure [44]. were not done. Cronin reported about a rose garden er
who had a strong patch-test reaction to maneb rose
Oitalmifos spray and zineb 1% [10]. Adams and Manchester
reported a case of allergie contact dermatitis to maneb
Ditalmifos (marketed only in Europe) is a contact in the wife of a residential gardener [23]. Several severe
fungicide used for the control of powdery mildews and episodes of dermatitis occurred before the cause was
scab of apples and pears. Allergie contact dermatitis to discovered. The patient's husband had stored a large bag
ditalmifos used as a rose spray was reported by van of maneb next to the washing machine in the garage.
Ketel [118]. Patch test to maneb 1% and thiram 1% in petrolatum
were strongly positive, whereas testing with zineb was
PIondrei negative.
Members of the ICDRG tested 655 eczematous
PIondrei is sprayed on roses to protect them from patients with zineb 1% and maneb 1% in petrolatum.
mildew. It is left on the roses as a deposit; therefore, Three patients had positive reactions to zineb, but
both sprayers and florists are exposed. Four patients none was thought dinically relevant; 35 patients had
with occupational allergie contact dermatitis to plon- positive reactions to maneb but only one was thought
dreI were reported by van Ketel [118]. Cronin reported to be relevant. Allergy contact dermatitis to ethylene-
a case of occupational contact dermatitis due to diamine used in the manufacture of zineb has been
piondrei [10]. reported [123].
Maneb and Zineb Ziram
Maneb and zineb are used to treat many plant diseases. Ziram, a fungicide used extensivelyon almonds and
Maneb may be used in combination with other peaches, is the most stable of the metallic dithiocarba-
mates [124]. A positive patch-test reaction to ziram in irritating, and 0.1% chlorothalonil in saline is non-
an agricultural worker has been reported by Lisi and irritating to the skin ofNew Zealand white rabbits [133].
colleagues [20]. Stable on exposure to UV light, it has a half-life of about
2 months. Contact dermatitis has been reported in
Mancozeb vegetable growers, woodworkers, and in flower growers
[134]. Patch-testing is performed with 0.01% chlorotha-
Mancozeb (manzeb), a fungicide related to both maneb lonil in petrolatum. This is a marginally irritant
and zineb, combines the benefits of these two earlier concentration of chlorothalonil. Chlorothalonil is a
fungieides into a distinctive chemical used on a wide strong cutaneous irritant at the concentrations used in
range of crops. It has an acute dermal LD so of more spraying. Penagos et al. [135] have recentlyreported that
than 15,000 mg/kg in rats. Burry reported allergie chlorothalonil is a possible cause of erythema dyschro-
contact dermatitis from maneozeb in South Australia micum perstans (ashy dermatitis). Positive patch-test
in a worker treating barley and wheat seeds and in a reactions to chlorothalonil (0.001% in acetone) were
farmer planting the seeds [125]. Patch testing was observed in 34 of 39 banana farm workers presented
performed at a concentration of 0.5%; ten controls with erythema-dyschromicum-perstans-like dermatitis.
were negative. Testing for cross-reactivity to thiram Biopsies from all patients were compatible with a
was not done. Allergie contact dermatitis due to chronic pigmented dermatitis or erythema-dyschromi-
mancozeb in an agricultural worker has also been cum-perstans-like dermatitis.
reported by Lisi and Carfinni [126]. This patient was Chlorothalonil is used as a wood preservative in
also allergie to maneb. Allergie contact dermatitis to Northern Europe. Johnson has reported an epidemie of
Rondo-M - a fungi eide containing pyrifenox and contact dermatitis in a Norwegian wooden-ware
mancozeb - has also been reported [127]. Testing with factory [136]. Of the 20 workers, 14 had work-related
dilutions of the individual components of Rondo-M skin complaints, and 7 had contact dermatitis. Bach
demonstrated a positive reaction to mancozeb and no and Pederson reported contact dermatitis to tetra-
re action to pyrifenox. chloroisophthalonitrile in a cabinet maker [137].
Absorption spectrum of mancozeb is in the UV A Spindeldreier and Deitchmann have also reported
and UVB range. Photo allergie contact dermatitis from three cases of contact dermatitis to tetrachloroi-
mancozeb has been reported in a patient presented sophthalonitrile [138].
with eczema on sun-exposed areas [128]. Photopatch Fatal toxic epidermal necrolysis (TEN) has been
test with mancozeb was positive while testings in 20 attributed to chlorothalonil. A 30-year-old navy pilot
control cases were negative. had played 81 holes of golf in the week prior to
developing TEN. The golf course had been sprayed
Thiram with chlorothalonil. The authors state that special
photographie techniques using UV light demonstrated
The chemical name for thiram is bis(dimethylthiocar- chlorothalonil on the deceased's golf clubs, balls, and
bamoyl) disulfide, or tetramethylthiruram disulfide. shoes [139]. It is not known whether this case
Thiram, thirame, and TMTD are common names for represented the TEN syndrome or an irritant variant.
this fungicide, seed protectant and animal repellent. It Aqueous chlorothalonil 0.01% used in open skin
was first reported as a cause of dermatitis by Shulz and testing (immediate type) produced severe immunolo-
Hermann in five dock laborers unloading bananas gical contact urtiearia with systemic signs, including
treated with the fungicide [129]. Shelley described an anaphylactoid reaction [140].
dermatitis from its use as a fungieide on a golf course
[130]. Cronin related dermatitis in a man who had Dithianone
applied thiram to his garden [10]. TMTD has been
reported to cause allergie contact dermatitis in a Polish Dithianone is a broad-spectrum fungicide. Calnan
flower vendor. She was in contact with flowers treated reported dermatitis in a female horticulturalist work-
with the Polish fungieide Sadoplon, which contains ing in a fruit orchard who became sensitive to
75% TMTD [131]. Fisher listed fungicides and animal dithianone [141]. Contact occurred from the sprayed
repellents that may contain thiuram [132]. trees while pruning and also from cleaning the
spraying machines. Patch testing was positive with
Ch/orotha/oni/ 1% dithianone in petrolatum.
Chlorothalonil is a broad-spectrum fungicide approved Dinobuton

for use on vegetables, fruits, flowers, and trees.
Chlorothalonil 0.1% in acetone is a moderate cutaneous Dinobuton is a fungicide and acaricide used to control
irritant; 0.1% chlorothalonil in petrolatum is much less the mites of deciduous fruits, citrus, cotton, cucum-
bers, and other vegetables. It is also valuable for documented in 1995 by van Ginkel and Sabapathy
controlling powdery mildew on apples, cucumbers, [147]. Positive patch tests to both the active ingredient
hops, and other crops. and the commercial formulation, Shirlan were demon-
In 1974, Wahlberg reported yellow staining of the strated among 7 of 9 farmers who developed dermatitis
hair and nails in workers with allergie contact about 1-4 weeks after initial contact. The irritant effect
dermatitis from dinobuton who were manufacturing of fiuazinam was ruled out by negative patch testings
dinobuton in a factory in northern Sweden [142]. with fiuazinam 2.S%, o.s%, 0.1% 0.02% and 0.04%
Wahlberg noted that dinobuton did not appear to be a petrolatum in ten consecutive control volunteers.
strong primary irritant; patch testing with 40%
dinobuton caused spontaneous fiare reactions (sensi- Slimicides
tization) in two workers 9-10 days after application.
The chemical relationship to picric acid was consid- Slimicides are used in paper manufacture. If the wood
ered significant. pulp slurry be comes contaminated with slime molds,
blemishes appear in the paper that is produced. Slime
Odhilinone molds are not true fungi, though they possess
characteristics resembling fungi. Slimicides are chemi-
Octhilinone is a bioeide used in cooling water plants, cal treatments added to wood pulp slurry to prevent
cutting oils, cosmetics, shampoos, and as a leather the growth of slime molds. Rycroft and Calnan [148]
preservative. Two cases of occupational allergie con- reported irritant contact dermatitis to slimicides in a
tact dermatitis to octhilinone used as a fungicide for paper mill. The active constituents in the slimicides
surface paint of roof sheets were reported by include bis-l,4 bromoacetoXY-2 butene and 2,3-di-
Thormann [143]. Both workers had severe allergie chloro-4-bromotetrahydrothiophene-l,l-dioxide.
contact dermatitis. Allergie reactions to other
chemically related preservatives have been reported Antibiotics
[1,2-benzisothiazolin-3-1- and 3-ethylamino-l,2-benzi-
sothiazolin-hydrochloride (etisazol)] [137, 144]. Etisa- Streptomycin is used to control bacterial plant
zol is a veterinary antifungal agent. diseases, such as fire blight. It may be used in
combination with oxytetracycline and tetracycline. It
Bupirimate has been reported to cause allergie contact dermatitis
among agricultural workers [149].
Bupirimate (S-butyl-2-aminoethylamino-6-pyrimidine- Olaquindox (Bayo-N-Ox and Proquindox) is an
4-yl dimethylsulphamate) is a systemic fungieide antimicrobial used to prevent bacterial enteritis in
particularly effective against powdery mildews. Me Fad- pigs. Kumar and Freeman reported of a case of
den et al. [14S] reported a case of allergie contact photoallergie contact dermatitis in a pig farmer caused
dermatitis from bupirimate in 1993. The patient by olaquindox [ISO].
developed rash on unprotected areas with coryzal
symptoms. Patch testing to bupirimate (0.01%, 0.1% Miticides
and 1.0% petrolatum) gave positive reaction (?+, + and
++, respectively, at D4) but was negative in one Propargite
control.
Irritant contact dermatitis to propargite has been
Triforine reported [39]. Propargite is the active ingredient in
Omite-30W, a miticide widely used on grapes in
Triforine (Saprol) is a fungieide for Ascochyta blight. California. Propargite is also the active ingredient of
In a mass examination of chrysanthemum growers Omite-CR for use on citrus. An outbreak of dermatitis
using triforine, the highest rate of positive patch among 114 of 198 orange pickers exposed to Omite-CR
re action was seen to 0.02% aqueous triforine (17%) has been reported. The dermatitis occurred predomi-
among the seven pesticides and chrysanthemum nantly on exposed areas of the neck and ehest. The
extracts tested. Cross-sensitization between triforine prolonged residual action of propargite in Omite-CR
and DDVP was also shown [146]. was suggested as the cause of this outbreak of
dermatitis [17].
Fluazinam
Oienochlor
Fluazinam (Shirlan) is a newly introduced broad-
spectrum antifungal and protects against many fungal Dienoehlor is a miticide of low toxicity. The Farm
disases. Allergie contact dermatitis from fiuazinam was Chemical handbook [ISI] stated that dienochlor was
neither a primary 1rntant nor a sensitizer, but a butor of permethrin recommends washing it off with
positive patch-test reaction to dienochlor has been soap and water [160].
reported in a florist with hand dermatitis by van Joost
[11].
Livestock
Plant-Growth Inhibitors
Choline Chloride Dairy farmers may develop irritant contact dermatitis

from extended wet work. Disinfectants that may cause
Choline chloride is a growth inhibitor used in irritant or allergic contact dermatitis are often used to
agriculture. Fischer [152] reported a case of contact clean the udders prior to milking [149]. Equipment is
dermatitis to choline chloride. cleaned with sodium hydroxide and nitric acid. Dairy
farmers are also exposed to hypochlorite iodine,
Insect Repellents phenolic compounds, quaternary ammonium com-
pounds, and hairs and secretions of cows. Dairy
Diethyltoluamide farmers may also develop allergic contact dermatitis
to rubber compounds such as isopropylphenyl-N-
Diethyltoluamide (DEET) was first synthesized in 1954 phenylenediamine (IPPD) [161].
and came into use as an insect repellent in 1957. Poorly Contact dermatitis due to cow saliva has been
soluble in water, it is soluble in ethanol and propylene documented in a farm worker by Camarasa [162].
glycol. Diethyltoluamide, considered the best all- Contact urticaria due to horse saliva was reported by
purpose insect repellent, is especially effective against van der Mark [24]. Itching and flaring of eczema is not
mosquitoes [153]. It remains effective for several ho urs uncommon among veterinarian surgeons doing ob-
post-application. The concentration of DEET present stetrie work. Veterinarians may be allergic to cowhair
in sprays, liquids, or sticks for application to skin or and dan der or the obstetric fluid of cows [163].
clothes varies from 1% to 100%. Farmers may develop irritant contact dermatitis to
Antecubital erythema progressing to hemorrhagic animal feeds. Medicaments mixed in the feeds may be
bullae was reported in ten young soldiers by Reuveni primary irritants as well as sensitizers. Farmers some-
and Yagupsky [153]. The antecubital area was the area times neglect to wear protective gloves while mixing
involved in two patients who had permanent scarring. drugs to be administered to animals. Antimicrobial
In Vietnam, some American soldiers developed bullae agents, including antibioties, are used in feed not only
followed by scarring from DEET [154]. DEET has been for the treatment of disease but also to promote growth
reported to exacerbate seborrhea and ac ne vulgaris as of animals. Contact dermatitis due to ethylenediame-
well as to produce contact dermatitis [36]. Irritant nedihydroiodine, as a source of iodine, furazolidone (a
contact dermatitis from diethyltobulamide (N,N- synthetic derivative of nitrofurazone), the antioxidant
diethyl-m-toluamide; DEET/deet) was documented by hydroquinone, and halquinol as an antibacterial agent
Amichai et al. [155] The patient developed three dark have been reported from animal feed ingredients [164,
livid patches with areas of erosions and blisters as well 165].
as a burning sensation on applied area at antecubital Allergie contact dermatitis to the antioxidant,
fossa. After healing, he continued using the same ethoxyquin, present in animal feed has been reported
product; by avoiding the flexural areas, there has been in farmers as well as feed-mill workers. Ethoxyquin
no recurrence of skin lesions. was also used to control scald in fruit. It was reported
Immunologic contact urtiearia to DEET was docu- to cause allergic contact dermatitis in apple pickers
mented in a patient reported by Maibach and Johnson [164, 165].
[156] and subsequently verified by others [157, 158]. Quindoxin was used as a growth-promoting factor
Toxic encephalopathy and death from skin contact in animal feeds. Photocontact dermatitis due to
with DEET have been rarely reported in children. quindoxin in animal feed has been reported. Quindox-
in photosensitivity with a persistent light reaction has
Permethrin been reported in pig farmers. Quindoxin is not
registered for use in the U.S. and Canada. Severe
Permethrin is both an insecticide and a repellent. It is contact eczema due to quinoxaline present in animal
active against a wide range of pests including lice, feed was reported by Dawson and Scott [166].
ticks, fleas, mites, mosquitoes, and black flies. Percu- Quinoxaline is also an acaricide.
taneous absorption of permethrin in human is Olaquindox is a derivative of quinoxaline used as a
minimal [159]. No side effects from skin contact with feed additive to prevent bacterial enteritis in pigs. Both
permethrin have been reported; however, the dis tri- allergic contact and photocontact dermatitis due to
olaquindox have been reported in Italy [167, 168]. Patch Testing

Photo allergie eontaet dermatitis has been reported to
farmers who used ehlorpromazine to tranquilize pigs
Agrieultural workers may have the greatest exposure
[169].
rate to the aforementioned eompounds, but one must
Piperazine, phenothiazine, and levamisole are anthel-
remember tlIat tlIese chemie als ean reside on clothing
minties that may eause allergie eontaet dermatitis.
that is brought back into tlIe household and are found
Allergie eontaet dermatitis to nitrofurazone has been
in many household exterminator preparations and
reported. This antieoecidian is used in eattle feed.
garden produets. Aeeumulation of these eompounds in
Formaldehyde is the allergen in nitrofurazone. Allergie
the skin after repeated exposures sometimes ereates
eontaet dermatitis to 3,5 dinitro-o-toluamide, an antie-
"reservoirs" of pesticide in the stratum eorneum that
oecidian used in ehicken feeds, has been reported [149].
effeetively inerease tlIeir eoneentration and their
Neomyein, etlIylenediamine, and thiabendazole have
irritant capacity, as weIl as potential toxie effeets. A
also been used as feed additives. Sulfaeetamide,
good investigative history will usually help verify a
sulfamethazine, chlortetracycline, oxytetraeycline, and
relationship between possible pesticide exposure and
baeitracin have been used as growth promoters for
dermatitis.
livestock [170]. Farmers have become allergie to both
It is easy to see just how eomplieated evaluation ean
nitrofurazone and tylosin in animal feed, partieularly
beeome of a patient witlI a history of possible pesticide
feed for hogs. Spiramyein and tylosin were the most
exposure. Separation of those patients in need of a
eommon sensitizers among antibioties used by farmers
eomplete diagnostic work-up to isolate the offending
in Denmark.
eompound from those who should be empirieally
Tylosin is a maerolide antibiotie used to eombat
treated for an irritant eontaet dermatitis with topical
swine dysentery in pigs and respiratory infeetions in
eortieosteroids and emollients may be relatively easy.
poultry in the U.K. Tylosin ean produee both irritant
The well-established and aeeepted diagnostie test for
and allergie eontaet dermatitis [171]. Cases of oeeupa-
allergie eontaet dermatitis is the pateh test. All
tional allergie eontaet dermatitis due to tlIe maerolide
agrieultural workers suspeeted of suffering from
spiramyein and tylosin have been reported in hog
ehronie dermatitis (for longer tlIan 1 month) or any
farmers and veterinarians [172, 173]. Allergie eontaet
patient requiring more than one course of oral
dermatitis to virginiamyein, a food additive for pigs
prednisone deserves furtlIer diagnostie testing and
and poultry, has also been reported [174]. Veien pateh-
should be pateh tested to all plants tlIey are in eontaet
tested 180 farmers to 5% virginiamyein in petrolatum
witlI, as weIl as to tlIe pesticides they use or are
but obtained no positive reaetions [161].
exposed to. It is simple, relatively inexpensive, and
Approximately one-half of veterinarians surveyed in
under optimal eonditions has a high sensitivity and
Seandinavia have oeeupational eontaet dermatitis,
specificity. The Finn Chamber with paper adhesive
predominantly irritant eontaet dermatitis. Oeeasion-
ally oeeupational derma tos es force veterinarians to tape is reeommended.
Pateh testing for a duration of 48 h should be done
abandon general veterinary praetice [28]. Penethamate
on tlIe upper back and observations made at 48 hand
has been reported as a eommon sensitizer in
96 h. Erythema, vesicles, papules, and edema at the
veterinarians. Penethamate is a strongly sensitizing
pateh-test site suggest eontaet allergy. Most pesticides
penicillin derivative used in Europe for loeal treatment
may be generally pateh tested at 1% dilution [11]. A
of mastitis in eows [28, 172].
dilution of 0.1% is also suggested to avoid false-
positive pateh-test reaetions. Table 2 lists pateh-test
eoneentration, based on reeently published literature
Milk Testers
[178-180], for pesticides suspeeted to be allergens. A
minority of pesticides are eommercially available in
Chromate has been used as a preservative for milk tlIat proper vehicles and eoneentrations for pateh testing.
is to be analyzed for quality-eontrol purposes. Several False-negative reaetions oeeur in pateh testing for
reports doeument chromate allergy in milk testers and inseetieides [1151. Fear of systemie toxicity may deter
in milk analysis laboratories [129, 175, 176]. one from pateh testing with adequate eoneentrations of
Milk preservative solutions in the U.K. now eontain organophosphorus in se etici des, such as parathion.
8% bronopol and 20% methyl-ehloroisotlIiazoline and Some pesticides are sometimes dissolved in primary
methylisothiazoline (KatlIonR CG). Allergie eontaet irritants, neeessitating extreme dilutions for pateh
dermatitis to bronopol and KathonR CG was reported testing. Using 15 111 of a 0.1-1% solution for pateh
in tlIree milk recorders by Grattan et al. [177]. testing excludes few eoneentrations beeause of acute
Bronopol has also been used as a seed treatment and toxicity. Pesticide manufaeturers have some informa-
foliar spray in some countries. tion on file regarding eutaneous irritation and
Table 2. Suggested patch test concentration for pesticides. Data sible dermatologists and research groups, the minimal
from references 178-180 irritant concentration and proper vehicle could be
Patch test Vehic\es
determined before the compound came to market.
Pesticides
concentration Their irritant potential to skin should be tested at low-
(%) and high-level exposures to simulate actual farming
situations.
Plant derivatives
Nicotine sulfate 5 Aqueous
Rotenone 5 Talcum power
Inorganic and organo-metal Recommendations for Improving the Current
Arsenic Petrolatum
Sulfur compound 5 Petrolatum State of Pesticide-Induced Dermatoses
Phenylmercuric Nitrate 0.01 Petrolatum
Fumigant
DD Acetone Improvement in the current state of science as it
Chlorinated hydrocarbon insecticides stands today is necessary. Anecdotal case reports in
DDT 1 Petrolatum
Lindane Petrolatum the literature only create misinterpretation, disorga-
Dieldrin Petrolatum nization, and nonstandardization when assigning a
Organophosphate pesticide an allergic- or irritant potential. There
Parathion 1 Alcohol
Malathion 0.5 Petrolatum needs to be a more scientific approach to determine
Tetmosol 1 Petrolatum the true nonirritant concentration of pesticides
Naled (dibrominated) Petrolatum through patch testing, using appropriate controls,
Rodannitrobenzene Petrolatum
Nitro-compounds and related phenols vehicles, and numbers of subjects. This would
Pentachlorophenol 1 Aqueous or ultimately create a listing of chemicals as to their
petrolatum irritant potential, their vehicle's irritant potential, and
Chlorocresol 1 Petrolatum
Dinocap 0.5 Petrolatum at what specific concentration the skin irritation
DNOC 0.5 Aqueous takes place.
Rodenticides The value of provocative use tests (PUTs) via repeat
Warfarin 0.05 Petrolatum
ANTU 1 Petrolatum open-application test (ROAT) should be incorporated
Herbicides into the investigation of pesticide allergic!irritant
Paraquat 0.1 Petrolatum dermatitis. Occasionally patch testing will not give a
Atrazine 1 Petrolatum
Alachlor 1 Petrolatum definitive answer, and the ROAT may clarify the issue.
Barbane 1 Petrolatum Careful interpretation of the literature regarding the
Dazomet 0.1 Petrolatum validity of the diagnosis made in case reports without
Fungicides
Benomyl 0.1 Petrolatum scientific proof (a positive patch test, or a positive
Captan 1 Petrolatum ROAT) regarding irritant versus allergy must be made.
PCNB 1 Petrolatum The so-called "excited skin syndrome" may alter the
DNCB 0.1 Aqueous
Folpet 0.1 Petrolatum validity of patch testing, and repeat testing on normal
Maneb 0.5 Petrolatum skin will confirm a true allergy. The contact urticaria
Zineb 1 Petrolatum syndrome needs to be explored. Photo-allergy patch
Ziram 1 Petrolatum
Mancozeb 1 Petrolatum testing is a valuable diagnostic test when the dermatitis
Thiram 1 Petrolatum is on the sun-exposed areas, as is common in field
Fluazinam 0.5 Petrolatum workers. Preexisting dermatitis may speed percuta-
PCNB, pentachloronitrobenzene; DNCB, dinitrochlorobenzene;
neous absorption of some pesticides, especially the
DNOC, 4,6 dinitro-o-cresol; ANTU, naphthylthiourea; DDT, organic phosphorus compounds. Dermatologists need
dichloro-diphenyl-trichloroethane; DD, mixture of 1,3-dichlor- to remember to search for unusual systemic toxic
opropene, 1,2-dichloropropane, epichlorhydrin and related
compounds
effects in all explored patients. Ale [181] defined an
operational definition of allergic contact dermatitis,
Marrakchi [182] tailored this for occupational allergic
dermatitis. Lachapelle [183] produced a numerical coda
allergenicity of their products. Access to these antigens
for recording clinical relevance.
by dermatologists for patch testing is limited and
difficult. Few dermatologists demand these chemicals
for testing. Manufacturers have litde incentive to
Zoonotic Infections
provide them, and there is no political motivation
through governmental regulations. Improving the
credibility of the current science is necessary. If the There are numerous dermatological consequences of
government required manufacturers to make their farming besides pesticide-induced dermatoses. Inter-
compounds available for diagnostic testing by respon- action with livestock presents a unique situation for
zoonotic skin diseases. These dermatophyte, viral, and Bacterial Infections

bacterial infectious diseases are transmitted from
direct exposure to an infected animal, an asympto- Tularemia, erysipelas, anthrax, brucellosis, salmonella
matic carrier, or sometimes from contact with an dermatitis, and staphylococcal folliculitis and cellu-
inanimate object such as a bush, saddle, or combo litis can all be transmitted to humans from farm and
wild animals. Diagnosis is made through bacterial
cultures taken from clinically suspected infected
Dermatophytosis (Tinea, Ringworm) individuals. Transmission requires direct contact,
often after animal bites. Appropriate antibiotics are
Among the three etiologic groups of dermatophytoses, given and vaccination programs work well to lower
only the zoophilic group will be discussed, because it is the incidence of erysipelas in pigs and turkeys and
far more common in the farming community. Com- anthrax in all animals. The best prevention from an
mon dermatophytes in farm animals and pets derive bacterial infections includes using protective gloves
from Trichophyton and Microsporum species. They are and good personal hygiene, especially after minor
T. mentagrophytes, T. verrucosum, T. equinum, and skin injuries.
M. canis. The hosts are cattle, dogs, and horses, but can Anthrax, caused by Bacillus anthracis, is a spore-
include sheep, pigs and wildlife. A pustular folliculitis forming, gram-positive rod that produces a lethal
with loss of hair, usually over the exposed areas of the endotoxin. An effective vaccine was discovered by
body, is generally more severe when in man than in Pasteur in 1881. In the V.S., almost an human
non-humans. Diagnosis is made microscopically and infections are cutaneous and limited to workers
through culture. Hyphae can remain viable on handling imported goat hair, wool, and hides from
inanimate objects for years if kept in a dry, cool endemic regions with poor infectious disease con-
environment, which makes direct contact with an trols.
infected animal nonessential. Direct inoculation from a puncture wound or
Infectious disease controls include treatment of all abrasion can cause cutaneous infection. A small papule
infected animals with antifungal agents, initial isola- forms and enlarges to a purplish red, sharply
tion, and cleaning of the infected animals' environ- marginated mass topped with a hemorrhagic vesicle
ment, use of gloved hands when in contact with the or bulla. Necrosis of the bulla ensues and satellite
animals, and good personal hygiene such as washing vesicles appear. Diagnosis is made by culture, and
hands with antifungal soaps and a change of clothes treatment is with penicillin and tetracycline.
when needed. Brucellosis is caused by three different gram-
negative rods: Brucella suis from pigs. B. abortus from
cattle, and B. melitensis from sheep and goats.
Viral Infections Infection is from handling infected animals or ingest-
ing contaminated unpasteurized milk or cheese.
The major infectious agents are from the pox viruses. The skin manifestations can include maculopapular
These infect cattle, causing pseudocowpox, and sheep, lesions, petechiae, a chronic ulcer at the site of
causing contagious ecthyma (sore mouth). These inoculation, and an urticarial eruption with subse-
viruses will produce milkers' nodule and orf virus quent vesiculopustules. Treatment is oral tetracycline
disease in man. Both diseases are transmitted via direct plus intramuscular streptomycin. Prevention of bru-
contact with infected animals or contaminated inani- cellosis in humans is based on elimination of animal
mate objects. The virus can withstand drying and is brucellosis. Immunization of animals is done using a
viable at room temperature for years. live attenuated Brucella vaccine.
The lesions seen in humans are indistinguishable for Tularemia is a disease found in many wild animals
both orf virus and milker's nodule. They begin as a in North America, but 90% of human cases occur
small red or reddish blue papule that enlarges to form after contact with cottontail rabbits. The pleo-
a flat-topped hemorrhagic pustule, often crusted in its morphic gram-negative coccobacillus causes an ulcer
umbilicated center. Diagnosis is made by clinical at the inoculation site, with massive regional
observation and by means of the complement-fixation lymphadenopathy and constitutional symptoms. The
test, tissue culture, or electron microscopy. ulcer becomes necrotic and a black eschar forms.
Infection control is essentially the same as derma- Treatment includes streptomycin, tetracycline, or
tophytic infections. Vaccination of noninfected ani- chloramphenicol.
mals for milker's nodule protection is recommended Salmonella dermatitis, caused by S. dublin, produces
after isolation and treatment of infected animals are an erythematous rash followed by a papular, pustular
complete. Vsing rubber gloves when handling infected eruption. These pustules are contagious and infected
animals usually will prevent human infection. humans can spread the disease.
Skin Cancer 8. Blondell J (1997) Epidemiology of pesticide poisonings in the

United States, with special reference to occupational cases.
In: Keifer MC (ed) Occupational medicine: state of the art
reviews, vol 12, 1st edn. Hanley & Belfus, Philadelphia,
Because the most common cause of non-melanoma pp 209-220
skin cancers (squamous and basal ceH carcinomas) is 9. Rycroft RJG, Wilkinson JD (1986) The principal irritants and
UV light, it is not surprising to find a slightly increased sensitizers, 3rd edn. Blackwell Scientific, Oxford
10. Cronin E (1980) Pesticides. Churchill Livingstone, Edin-
rate of skin cancers in outdoor workers compared with burgh
indoor workers [184]. Agricultural workers with light 11. van Joost T, Naafs B, van Ketel WG (1983) Sensitization to
skin, light eye coloring, and light-colored hair, who benomyl and related pesticides. Contact Dermatitis 9:153-154
12. 0' Malley MA, Mathias CG (1988) Distribution of lost-work-
sunburn easily and tan poorly, or of Celtic des cent, are time claims for skin disease in California agriculture: 1978-
even more susceptible. Women tend to have slightly 1983. Am J Ind Med 14:715-720
lower rates secondary to sun protection from increased 13. Hogan DJ, Lane PR (1985) Allergie contact dermatitis due to
a herbicide (barban). Can Med Assoc J 132:387-389
sun screen and cosmetic use [184]. It is therefore 14. Kligman AM (1966) The identification of contact allergens
recommended that aH persons working outdoors wear by human assay. III. The maximization test: a procedure for
sun protection at work. screening and rating contact sensitizers, 1966 [classical
articlel. J Invest Dermatol 47:92
15. Milby TH, Epstein WL (1964) Allergie contact sensitivity to
malathion. Arch Environ Health 9:434-437
Summary 16. Jung HO, Rothe A, Heise H (1987) Epicutaneous testing with
plant protective and pest control agents (pesticides).
Dermatosen 35:43-51
17. Saunders LD, Ames RG, KnaakJB, Jackson RJ (1987) Outbreak
We need to improve education of farm workers and of Omite-CR-induced dermatitis among orange pickers in
their families to the potential hazards of exposure to Tulare County, California. J Occup Med 29:409-413
the chemicals and other agents that they are in contact 18. Guo YL, Wang BJ, Lee CC, Wang JD (1996) Prevalence of
dermatoses and skin sensitisation associated with use of
with on a daily basis. Simple measures such as showers pesticides in fruit farmers of southern Taiwan. Occup
in the fields and a change of clothes after work might Environ Med 53:427-431
significantly lower the reactions to these chemicals. To 19. Mathias KE (1989) Epidemiology aspects of occupational
skin disease in agriculture. CRC Press, Boca Raton
that end, physicians can better educate themselves to 20. Lisi P, Caraffini S, Assalve 0 (1987) Irritation and sensitiza-
highlight this area more intensely to residents in tion potential of pesticides. Contact Dermatitis 17:212-218
training, to offer lectures on the subject at dermatology 21. Wolfe HR, Armstrong JF, Durharn WF (1966) Pesticide
exposure from concentrate spraying. Arch Environ Health
conferences, and to foster better communication 13:340-344
between our public health agencies and the pesticide 22. van Ketel WG (1976) Sensitivity to the pesticide benomyl.
industry itself. Companies are often cooperative when Contact Dermatitis 2:290-291
23. Abbott IM, Bonsall JL, Chester G (1987) Worker exposure to
made aware of the benefits of irritant- and aHergic- a herbicide applied with ground sprayers in the United
potential testing. Pesticide re gi strati on should include Kingdom. Am Ind Hyg Assoc J 48:167-175
patch testing before the product comes to market to 24. van der Mark S (1983) Contact urticaria from horse saliva.
determine the threshold irritant concentration and 25. Kazen C, Bloomer A, Welch R, Oudbier A, Price H (1974)
irritant potential of the vehicle. Persistence of pesticides on the hands of some occupation-
ally exposed people. Arch Environ Health 29:315-319
26. Yoshida K (1989) Cutaneous exposure of pesticide spray
applicators, 1st edn. CRC Press, Boca Raton, FL
27. Upholt WM, Kearney PC (1966) Pesticides. N Engl J Med
References 275:1419-1426
28. Falk ES, Hektoen H, Thune PO (1985) Skin and respiratory
tract symptoms in veterinary surgeons. Contact Dermatitis
1. Hogan DJ (1990) Pesticides and other agricultural chemie als, 12:274-278
2nd edn. Saunders, Philadelphia 29. Hanson 0 (1988) EP A pro pos es expanded rules to protect
2. Vial T, Descotes J (1996) Clinical immunotoxicity of pesticides workers. Chem Eng News 4:14-15
pesticide. J Toxicol Environ Health 48:215-229 30. Ritter L (1989) Assessment of pesticide toxicity: regulatory
3. California Department of Food and Agriculture DoPMaPEB viewpoints, 1st edn. CRC Press, Boca Raton, FL
(1990) Report of pesticides sold in California for 1989 by 31. Feinberg SM (1934) Pyrethrum sensitization: its important
pounds of active ingredients. Sacramento, CA and relation to pollen allergy. JAMA 102:1557-1558
4. Krieger R (1990) Gauging pesticide exposure of handlers 32. Mitchell JC (1969) Allergie contact dermatitis from compo-
(mixer/loaders/applicators) and harvesters in California sitae. Trans St John's Hosp Derm Soc 55:174-183
agriculture. Proceedings of the Pesticide Workshop. Milan 33. Epstein E (1938) Urticaria due to an insecticide (pyrethrum).
5. Edmiston S, Maddy KT (1987) Summary of illnesses and Urol Rev 48:829
injuries reported in California by physicians in 1986 as 34. Garratt JR, Bigger JW (1923) Asthma due to insect powder.
potentially related to pesticides. Vet Hum ToxicoI29:391-397 Br Med J 2:764
6. Ieyaratnam I, de Alwis Seneviratne RS, Copplestone JF 35. Mitchell JC, Dupuis G, Towers GH (1972) Allergie contact
(1982) Survey of pesticide poisoning in Sri Lanka. Bull dermatitis from pyrethrum (Chrysanthemum spp). The roles
WHO 60:615-619 of pyrethrosin, a sesquiterpene lactone, and of pyrethrin 11.
7. Maddy KT, Edmiston S, Richmond 0 (1990) Illness, injuries, Br J Dermatol 86:568-573
and deaths from pesticides exposures in California. Rev 36. Hayes WJ (1982) Pesticides studies in man. Williams &
Environ Contamination Toxicol 114:57-123 Wilkins, Baltimore
37. Magnusson B, Blohm SG, Fregert S, et al. (1968) Routine 68. Lailti A, Maibach HI (1985) Contact urticaria from diethyl
patch testing. IV. Supplementary series of test substances for fumarate. Contact Dermatitis 12:139-140
Scandinavian countries. Acta Derm Venereol 48:110-116 69. Mathias CG (1983) Persistent contact dermatitis from the
38. Flannigan SA, Tucker SB (1985) Infiuence of the vehic\e on insecticide diehlorvos. Contact Dermatitis 9:217-218
irritant contact dermatitis. Contact Dermatitis 12:177-178 70. Edmundson WF, Davies JE (1967) Occupational dermatitis
39. Vero F, Genovese S (1941) Occupational dermatitis in cigar from naled. A c\inieal report. Arch Environ Health 15:89-91
markers due to contact with tobacco leaves. Arch Dermatol 71. Fregert S (1967) Allergie contact dermatitis from the
43=257-263 pesticide rodannitrobenzene. Contact Dermatitis Newslett
40. Ghosh SK, Gokani VN, Parikh JR, Doctor PB, Kashyap SK, 2:4
Chatterjee BB (1987) Protection against "green symptoms" 72. Haenen C, De Moor A, Dooms-Goossens A (1996) Contact
from tobacco in Indian harvesters: a preliminary interven- dermatitis caused by the insecticides omethoate and
tion study. Arch Environ Health 42:121-124 dimethoate. Contact Dermatitis 35:54-55
41. Smith EW, Smith KA, Maibach HI, Anderson PO, Cleary G, n Wood S, Rom WN, White GL Jr, Logan DC (1983)
Wilson D (1992) The local side effects of transdermally Pentachlorophenol poisoning. J Occup Med 25:527-530
absorbed nieotine. Skin Pharmacol 5:69-76 74. Lambert J, Schepens P, Janssens J, Dockx P (1986) Skin
42. Emmett EA (1975) Occupational skin cancer: a review. lesions as a sign of subacute pentachlorophenol intoxieation.
J Occup Med 17:44-49 Acta Derm Venereol 66:170-172
43. Wilkinson DS (1975) Sulphur sensitivity. Contact Dermatitis 75. Kentor PM (1986) Urticaria from contact with pentachlor-
1:58 phenate. JAMA 256:3350
44. 0' Malley M, Rodriguez P, Maibach HI (1995) Pesticide patch 76. Fregert S (1968) Allergie contact dermatitis from p-chloro-o-
testing: California nursery workers and controls. Contact cresol in a pesticide. Contact Dermatitis Newslett 3:46
Dermatitis 32:61-63 77. Baran RL (1974) Nail damage caused by weed killers and
45. Gammeltoft M (1978) Tributyltinoxide is not allergenic. insecticides (letter). Arch Dermatol 110:467
Contact Dermatitis 4:238-239 78. Cottel WI (1972) Difolatan. Contact Dermatitis Newslett
46. Morris GE (1966) Dermatoses from phenylmercurie salts. 11:252
Arch Environ Health 1:53-55 79. De Eds F, Wilson RH, Thomas JO (1940) Photosensitization
47. Barnes RL, Wilkinson DS (1973) Epidermal necrolysis from by phenothiazine. JAMA 114:2095-2097
c\othing impregnated with paraffin. BMJ 4:466-467 80. Cripps DJ, Gocmen A, Peters HA (1980) Porphyria turcica.
48. Farber GA, Burks JW (1972) Flea-collar dermatitis. Cutis Twenty years after hexachlorobenzene intoxication. 116:
9:809-812 46-50
49. Taylor JS (1977) Dermatologic hazards from ethylene oxide. 81. Szolar-Platzer C, Maibach HI (1999) Allergie contact
Cutis 19:189-191 dermatitis to antihistamine. Dermatosen (in press)
50. Wester RC, Hartway T, Serranzana S, Maibach HI (1997) 82. Maibach HI (1986) Irritation, sensitization, photoirritation
Human skin in vitro percutaneous absorption of gaseous and photosensitization assays with a glyphosate herbicide.
ethylene oxide from fabrie. Food Chem Toxicol 35:513-515 Contact Dermatitis 15:152-155
51. Becker CE (1988) Recognizing the health hazards of ethylene 83. Hindson TC, Diffey BL (1984) Phototoxicity of a weedkiller:
oxide. West J Med 148:75 a correction. Contact Dermatitis 11:260
52. Hezemans-Boer M, Toonstra J, Meulenbeit J (1988) Skin 84. Bowra GT, Duffield DP, Osborn AJ, Purchase IF (1982)
lesions due to exposure to methyl bromide. Arch Dermatol Premalignant and neoplastie skin lesions associated with
124:917-921 occupational exposure to "tarry" byproducts during man-
53. Hine CH (1969) Methyl bromide poisoning. J Occup Med ufacture of 4,4' -bipyridyl. Br J Ind Med 39:76-81
11:1-10 85. Wang JD, Li WE, Hu FC, Hu KH (1987) Occupational risk
54. Radimer GF, Davis JH, Ackerman AB (1974) Fumigant -induced and the development of premalignant skin lesions among
toxic epidermal necrolysis. Arch DermatoI110:103-104 paraquat manufacturers. Br J Ind Med 44:196-200
55. Richter G (1980) Allergic contact dermatitis from methyli- 86. Hearn CE, Keir W (1971) Nail damage in spray operators
sothiocyanate in soil disinfectants. Contact Dermatitis 6: exposed to paraquat. Br J Ind Med 28:399-403
183-186 87. Botella R, Sastre A, Castells A (1985) Contact dermatitis to
56. Nasution D, Klokke AH, Nater JP (1973) A survey of paraquat. Contact Dermatitis 13:123-124
occupational dermatoses in Indonesia. Berufsdermatosen 88. Sharvill DE (1971) Reaction to paraquat. Contact Dermatitis
21:215-222 Newlett 9:210
57. Black H (1973) Dazomet and choropicrin. Contact Dermattits 89. Newhouse M, McEvoy D, RosenthaI D (1978) Percutaneous
Newslett 14:410-411 paraquat absorption. An association with cutaneous lesions
58. Dunn JE, Dunn RC, Smith BS (1946) Skin-sensitizing and respiratory failure. Arch DermatoI114:1516-1519
properties of DDT for guinea pig. Public Health Rep 61:1614 90. Garnier R, Chataigner D, Efthymiou ML, Moraillon I,
59. Leider M (1947) Allergie eczematous contact-type dermatitis Bramary F (1994) Paraquat poisoning by skin absorption:
caused by DDT. J Invest Dermatol 8:125-126 report of two cases. Vet Human Toxicol 36:313-315
60. Niedelman ML (1946) Contact dermatitis due to DDT. Occup 91. Nishioka K, Asagami C, Kurata M, Fujita H (1983) Sensitivity
Med 1:391-395 to the weed killer DNA-nitralin and cross-sensitivity to
61. Stryker GV, Godfrey B (1946) Dermatitis resulting from dinitrochlorobenzene. Arch Dermatol 119:304-306
exposure to DDT. J Missouri Med Assoc 43:384 92. English JS, Rycroft RJ, Calnan CD (1986) Allergic contact
62. Ross CM (1964) Sock dermatitis. Br J Dermatol 76:494-495 dermatitis from aminotriazole. Contact Dermatitis 14:
63. Willems PWJM, Geursen-Reitsma AM, van Joost TH (1997) 255-256
Allergic contact dermatitis due to methiocarb (Mesurol). 93. Bruze M, Fregert S (1982) Allergic contact dermatitis to
Contact Dermatitis 36:270 chloridazon. Contact Dermatitis 8:427
64. Pevny I (1980) Pesticide allergy. Derm Beruf Umwelt 94. Nater JP, Grosfeld JC (1979) Allergie contact dermatitis from
28:186-189 Betanal (phenmedipham). Contact Dermatitis 5:59-60
65. Svindland HB (1981) Subacute parathion poisoning with 95. Koch VP, Bahmer FA (1989) Photoallergische Dermatose
erysipeloid-like lesion. Contact Dermatitis 7:177-179 durch Herbizid Phenmedipham. Dermatosen 37:203-205
66. Bhargava RK, Singh V, Soni V (1977) Erythema multiforme 96. Taylor JS, Wuthrieh RC, Lloyd KM, Poland A (1977)
resulting from insecticide spray (letter). Arch Dermatol Chloracne from manufacture of a new herbicide. Arch
113:686-687 Dermatol 113:616-619
67. Cronce PC, Aiden H (1968) Flea-collar dermatitis. JAMA 97. Iden DL, Schroeter AL (1977) Allergic contact dermatitis to
206:1563-1564 herbicides. Arch Dermatol 113:983
98. Won JH, Ahn SK, Kim SC (1993) Allergie contact dermatitis 128. Higo A, Ohtake N, Kunihiko S, Kanzaki T (1996) Photo-
from the herbicide Alachlor. Contact Dermatitis 28:38-39 allergie contact dermatitis from mancozeb, an agrieultural
99. Spencer MC (1966) Herbicide dermatitis. JAMA 198:169-170 fungieide. Contact Dermatitis 35:183
100. Hoar SK, Blair A, Holmes FF, et al. (1986) Agrieultural 129. Rudski E, Czerwinska-Dihnz I (1977) Sensitivity to dichro-
herbicide use and risk oflymphoma and soft-tissue sarcoma. mate in milk testers. Contact Dermatitis 3:107-108
JAMA 256:1141-1147 [published erratum 256:3351] 130. Shelley WB (1964) Golf course dermatitis due to thiram
101. Buesching DP, Wollstadt L (1984) Cancer mortality among fungieide. JAMA 188:415-417
farmers. J Natl Cancer Inst 72:503 131. Rudzki E, Napiorkowska T (1980) Dermatitis caused by the
102. Burmeister LF, Everett GD, Van Lier SF, Isacson P (1983) Polish fungieide Sadoplon 75. Contact Dermatitis 6:300-301
Selected cancer mortality and farm practices in Iowa. Am J 132. Fisher AA (1986) Fisher's contact dermatitis. Lea & Febiger,
Epidemiol 118:72-77 Philadelphia
103. Cook RR (1981) Dioxin, chloracne, and soft tissue sarcoma 133. Flannigan SA, Tucker SB, Key MM, et al. (1985) Synthetie
(letter). Lancet 1:618-619 pyrethroid insectieides: a dermatologieal evaluation. Br J Ind
104. Honchar PA, Halperin WE (1981) 2,4,5-T, trichlorophenol, Med 42:363-372
and soft tissue sarcoma (letter). Lancet 1:268-269 134. Bruynzeel DP, van Ketel WG (1986) Contact dermatitis
105. Moses M, Selikoff IJ (1981) Soft tissue sarcomas, phenoxy due to chlorothalonil in floriculture. Contact Dermatitis 14:
herbicides, and chlorinated phenols. Lancet 1:1370 67-68
106. Brancaccio RR, Chamales MH (1977) Contact dermatitis and 135. Penagos H, Jimenez V, Fallas V, O'Malley M, Maibach HI
depigmentation produced by the herbicide Carbyne. Contact (1996) Chlorothalonil, a possible cause of erythema dys-
Dermatitis 3:108-109 chromieum perstan (ashy dermatitis). Contact Dermatitis
107. Leow YH, Maibach HI (1996) Allergie contact dermatitis 35:214-218
from norflurazon. Contact Dermatitis 35:369 136. Johnsson M, Buhagen M, Leira HL, Solvang S (1983)
108. Savitt LE (1972) Contact dermatitis due to benomyl Fungicide-induced contact dermatitis. Contact Dermatitis
insecticide. Arch DermatoI105:926-927 9:285-288
109. Fregert S (1973) Allergie contact dermatitis from two 137. Bach B, Pedersen NB (1980) Contact dermatitis from a wood
pesticides. Contact Dermatitis Newslett 13:367 preservative containing tetrachloroisophthalonitrile. Con-
110. Camarasa G (1975) Difolatan dermatitis. Contact Dermatitis tact Dermatitis 6:142
1:127 138. Spideldreier A, Deiehmann B (1980) Contact dermatitis
111. Matsushita T, Arimatsu Y, Nomura S (1976) Experimental against a wood preservative with a new fungieidal agent.
study on contact dermatitis caused by dithiocarbamates Derm Beruf Umwelt 28:88-90
maneb, mancozeb, zineb, and their related compounds. Int 139. Lord JT, Moat R, Jones J (1984) Too much golf. J Forensic Sei
Arch Occup Environ Health 37:169-178 Soc 24:359
112. Stoke JC (1979) Captafol dermatitis in the timber industry. 140. Dannaker q, Maibach HI, M OM (1993) Contact urticaria
Contact Dermatitis 5:284-292 and anaphylaxis to the fungieide chlorothalonil. Cutis
113. Fregert S (1967) Allergie contact dermatitis from the 52:312-315
pesticides captan and phaltan. Contact Dermatitis Newslett 141. Calnan CD (1969) Dithianone sensitivity. Contact Dermatitis
2:28 Newslett 6:119
114. Marzulli FN, Maibach HI (1973) Antimierobial: experimental 142. Wahlberg JE (1974) Yellow staining of hair and nails and
contact sensitization in man. J Soc Cosmetic Chemists contact sensitivity to dinobuton. Contact Dermatitis News-
24:399-421 lett 16:481
115. Hjorth N, Wilkinson DS (1968) Contact dermatitis Ir: 143. Thormann J (1982) Contact dermatitis to a new fungieide,
sensitization to pestieides. Br J Dermatol 80:272-274 2-n-octyl-4-isothiazolin-3-one. Contact Dermatitis 8:204
116. Malten KE (1974) DNCB in cooling water. Contact Derma- 144. Dahlquist I (1977) Contact allergy to 3-eiliylamino-1,2-
titis Newslett 15:466 benzisothiazol-hydrochloride, a veterinary fungieide. Con-
117. Zimmerman MC (1970) Dinitrochlorobenzene in water tact Dermatitis 3:277
systems. Contact Dermatitis Newslett 7:165 145. McFadden JP, Kinoulty M, Rycroft RJ (1993) Allergie contact
118. van Ketel WG (1975) Allergie dermatitis from a new dermatitis from the fungieide bupirimate. Contact Derma-
pesticide. Contact Dermatitis 1:297-300 titis 28:47
119. Peluso AM, Tardio M, Adamo F, Venturo N (1991) Multiple 146. Ueda A, Aoyama K, Manda F, Ueda T, Kawahara Y (1994)
sensitization due to bis-dithiocarbamate and thiophiliali- Delayed-type allergenieity of triforine (Saprol). Contact
mide pesticides. Contact Dermatitis 25:327 Dermatitis 31:140-145
120. Piraccini BM, Cameli N, Peluso AM, Tardio M (1991) A case 147. van Ginkel q, Sabapathy NN (1995) Allergie contact
of allergie contact dermatitis due to the pesticide maneb. dermatitis from the newly introduced fungieide fluazinam.
Contact Dermatitis 24:381-382 Contact Dermatitis 32:160-162
121. Laborie F, Laborie R, Dedieu EH (1964) Allergie aux 148. Rycroft RJ, Calnan CD (1980) Dermatitis from slimicides in a
fongicides de la gamme du menebe et du zinebe. Arch Mal paper mill. Contact Dermatitis 6:435-439
Prof Med Tavail Securite Soc 25:419-424 149. Foussereau J, Benezra C, Maibach HI, Hjorth N (1982)
122. Nater JP, Terpstra H, Bleumink E (1979) Allergie contact Agricultural occupations. Munkgaard, Copenhagen
sensitization to the fungicide Maneb. Contact Dermatitis 150. Kumar A, Freeman S (1996) Photoallergic contact dermatitis
5:24-26 in a pig farmer caused by olaquindox. Contact Dermatitis
123. Tsykunov LP (1987) Toxico-allergic dermatitis induced by 35:249-250
ethylenediamine in the manufacture of the herbicide zineb 151. Anonymous (1986) Farm chemie al handbook. Meister
(in Russian). Gig Tr Prof Zabol 8:45-46 Publishing Co, Willoughby
124. O'Malley MA (1997) Skin reactions to pesticides. In: Keifer 152. Fischer T (1984) Contact allergy to choline chloride. Contact
MC (ed) Occupational medicine: state of the art reviews, vol Dermatitis 10:316-317
12, 1st edn. Hanley & Belfus, Philadelphia, pp 327-345 153. Reuveni H, Yagupsky P (1982) Diethyltoluamide-containing
125. Burry JN (1976) Contact dermatitis from agricultural insect repellent: adverse effects in worldwide use. Arch
fungicide in South Australia. Contact Dermatitis 2:289 Dermatol 118:582-583
126. Lisi P, Caraffini S (1985) Pellagroid dermatitis from 154. Lamberg SI, Mulrennan JA Jr (1969) Bullous reaction to
mancozeb with vitiligo. Contact Dermatitis 13:124-125 diethyl toluamide (DEET). Resembling ablistering insect
127. Iliev D, Elsner P (1997) Allergic contact dermatitis from the eruption. Arch Dermatol 100:582-586
fungieide Rando-M and the insecticide Alfacron. Contact 155. Amichai B, Lozarov A, Halevy S (1994) Contact dermatitis
Dermatitis 36:51 from diethyltoluamide. Contact Dermatitis 30:188
802 W. Manuskiatti et al.: Pesticide-Related Dermatoses in Agricultural Workers
156. Maibach HI, Johnson HL (1975) Contact urticaria syndrome. 171. Verbov J (1983) Tylosin dermatitis. Contact Dermatitis
Contact urticaria to diethyltoluamide (immediate-type 9:325-326
hypersensitivity). Arch Dermatol11l:726-730 172. Hjorth N, Weismann K (1973) Occupational dermatitis
157. von Mayenburg J, Rakoski J (1983) Contact urticaria to among veterinary surgeons caused by spiramycin, tylosin,
diethyltoluamide. Contact Dermatitis 9:171 and penethamate. Acta Dermatol Venereol 53:229-232
158. Wantke F, Focke M, Hemmer W, Gotz M, Jarisch R (1996) 173. Veien NK, Hattel T, Justesen 0, Norholm A (1980)
Generalized urtiearia induced by a diethyltoluamide-con- Occupational contact dermatitis due to spiramycin and/or
taining insect repellent in a child. Contact Dermatitis 35: tylosin among farmers. Contact Dermatitis 6:410-413
186-187 174. Tennstedt D, Dumont-Fruytier M, Lachapelle JM (1978)
159. Couch P, Johnson CE (1992) Prevention of lyme disease: Occupational allergie contact dermatitis to virginiamycin, an
review. Am J Hosp Pharm 49:1164-1173 antibiotic used as a food additive for pigs and poultry.
160. Brown M, Hebert AA (1997) Insect repellents: an overview. Contact Dermatitis 4:133-134
J Am Acad Dermatol 36:243-249 175. Huriez C, Martin P, Lefebvre M (1975) Sensitivity to
161. Veien NK (1987) Occupational contact dermatoses in dichromate in a milk analysis laboratory. Contact Dermatitis
farmers, 2nd edn. Year Book, Chieago 1:247-248
162. Camarasa JG (1986) Contact eczema from cow saliva. 176. Rogers S, Burrows D (1975) Contact dermatitis to chrome in
Contact Dermatitis 15=117 milk testers. Contact Dermatitis 1:387
163. Prahl P, Roed-Petersen J (1979) Type I allergy from cows in 177. Grattan CE, Harman RR, Tan RS (1986) Milk recorder
veterinary surgeons. Contact Dermatitis 5:33-38 dermatitis. Contact Dermatitis 14:217-220
164. Burrows D (1975) Contact dermatitis in animal feed milk 178. Fisher AA (1983) Occupational dermatitis from pesticides:
workers. Br J Dermatol 92:167-170 patch testing procedures. Cutis 31:483-508
165. Wood WS, Fulton R (1972) Allergie contact dermatitis from 179. Lisi P, Caraffini S, Assalve D (1986) A test series for pesticide
the herbicide Alachlor. Contact Dermatitis Newslett 11: dermatitis. Contact Dermatitis 15:266-269
295-296 180. Andersen KE, Rycroft RJ (1991) Recommended patch test
166. Dawson TA, Scott KW (1972) Contact eczema in agricultural concentrations for preservatives, biocides and antimicro-
workers. BMJ 3:469-470 bials. Contact Dermatitis 25:1-18
167. Bedello PG, Goitre M, Cane D, Roncarolo G (1985) Allergic 181. Ale SI, Maibach HI (1995) Clinieal relevance in alIergic
contact dermatitis to Bayo-N-OX-1. Contact Dermatitis contact dermatitis: an algorithmie approach. Dermatosen
12:284 43:119-121
168. Francalanci S, Gola M, Giorgini S, Muccinelli A, Sertoli A 182. Marrakchi S, Maibach HI (1994) What is occupational
(1986) Occupational photocontact dermatitis from Olaquin- contact dermatitis? An operational definition. Dermatol Clin
dox. Contact Dermatitis 15:112-114 12:477-484
169. Klein HM, Schwanitz HJ (1987) Photocontact allergy to 183. Lachapelle JM, Ale SI, Freeman S, et al. (1997) Proposal for a
chlorpromazine in farmers. In: 17th World Congress of revised international standard series of patch tests. Contact
Dermatology Part 11. Verlage GBDu, Karlsruhe, Germany, Dermatitis 36:121-123
pp 346 184. Epstein JH, Ormsby A, Adams RM (1990) Occupational skin
170. Neider KH (1972) Contact dermatitis from animal feed cancer, 2nd edn. Saunders, Philadelphia
additives. Arch Dermatoll06:722-723
CHAPTER 93
Aircraft Industry
M. Isaksson and M. Bruze
The manufaeture of aireraft is still eharaeterized epoxy res in, whieh ean be molded or laminated into a
by eraftsmanship, where traditional meehanieal teeh- desired shape and then fused into solid objeets by heat
niques, often eombined with ehemieal teehniques, are euring at high temperature (Mathias 1987). This
used for the assembly. Consequently, handling and eomposite material is used where great strength but
exposure to ehernieals are extensive. light weight is required. Beeause of diffieulties with
Oeeupational skin diseases in this industry are weIl adherenee to earbon or graphite fiber, epoxy resins
known and figures from 2.35% in workers (Castelain other than those of the bisphenol A type are mostly
et al. 1992) to 16.1% (Bruze et al. 1996) of all employees used. The epoxy resins may be diglyeidyl ether of
are presented in the literature. Irritant eontaet derma- bis phenol A (DGEBA), 4-glycidyloxy-N,N-diglyeidyl-
titis is eonsidered to be more eommon than allergie aniline (GDODGA), diglyeidyl ether of tetrabromo-
eontaet dermatitis. bisphenol A (Br-DGEBA), tetraglyeidyl-4,4'-methylene
Many diverse oeeupations are found within the dianiline (TGMDA), triglycidyl derivative of p-amino-
aireraft industry. When eonsidering eauses of irritant phenol (TGP AP), and o-diglyeidyl phthalate (Burrows
eontaet dermatitis, one ean think of grinders, lathe et al. 1984).
operators, set-up men, milling workers, and hydraulie Resins and hardeners that must be heat eured
engineers who all may eome into eontaet with metal- prolong the pliability of the epoxy eomposite material
work fluids (Castelain et al. 1992), while runway at room temperature, permitting a longer set-up time.
meehanies, set-up men, and engine-fitter meehanies As the surfaee often feels slightly damp due to surfaee
are exposed to solvents. Meehanieal assemblers eome aeeumulation of uneured binder, and the set-up men
into eontaet with grease and lubrieating oils and do not always proteet their skin with the proper
hydraulie engineers with hydraulie oils, whieh may proteetive gloves, eontaet with uneured epoxy resin is
lead to oil acne. Airborne irritant eontaet dermatitis inevitable and several eases of allergie eontaet derma-
from metal dust adhering to a new semi-synthetie titis to different epoxy resins have been deseribed
working suit has been deseribed in two workers in a (Mathias 1987; Bruze et al. 1996). Some investigators
plasma spraying plant, where jet eomponents were mean that prepregs ean be pateh tested "as is"
re-eovered with a thin metallayer (Hafner et al. 1995). (Burrows et al. 1984), while others say that it should
Skin-irritating eomposite dust, frequent exposure to only be earried out on individuals suspeeted to be
organie solvents, repeated meehanieal trauma, expo- allergie on a clinieal basis (Mathias 1987) to minimize
sure to detergents to remove sealants, paints, and other the risk of aecidental sensitization.
ehernieals from the skin are all faetors that may A typieal epoxy resin system (ERS) pieture is
faeilitate irritant eontaet dermatitis. The dermatitis dermatitis on the finger pulp spaees, the dorsa and
may be eonfined to the interdigital webs, and irritant sides of fingers and forearms (Björkner 1992) (Burrows
reaetions on knuekles eonsidered to be meehanieally et al. 1984). Subungual pulpitis eaused by handling of
indueed from using fists for sealing in eonfined spaees epoxy res ins and sealants based on synthetie rubber
may also be seen (Bruze et al. 1996). In Table 1, some (polysulfide polymer) is eonsidered to be specifie to
irritants are listed. While dealing with allergie eontaet the aireraft industry (Castelain et al. 1992). Epoxy resin
dermatitis, the most eommon allergie eontaetants in an aeeeierators (hardeners or euring agents) make up less
aireraft faetory in Franee were found to be sealants, than 10% of allergie eontaet dermatitis from ERSs
epoxy resins, and 2-bromo-2-nitropropane-1,3-diol (Handley and Burrows 1994). Cold-euring hardeners
(Castelain et al. 1992). used are polyamines and polyamides as weIl as
Set-up men employ earbon or graphite fiber-rein- isoeyanates, and the most eommon allergens are
foreed plastie fabries, prepregs, supplied as pliable aliphatie and eycloaliphatie polyamines (Mathias
cloth impregnated with a liquefied binder, sueh as 1987). Due to their volatility, they ean result in faeial

involvement, which is seldom, if ever, seen with epoxy Table 1. Irritants

Organic solvents (Bruze et al. 1996)
resins themselves (Dahlquist and Fregert 1979). Other Fiberglass
curing agents or hardeners used are diaminodiphenyl Detergents (Bruze et al. 1996)
sulphone (DDS) (4,4-sulfonyldianiline) (Burrows et al. Metal dust (Hafner et al. 1995)
Surface-active agents
1984), methylene dianiline, boron trifluorine mono- Cutting fluids
ethylamine complex and dicyandiamide (Burrows Composite dust (Bruze et al. 1996)
et al. 1984).
Passivating is done with anti-rust coatings and
primer paints containing chromates, which are also Table 2. Standard allergens
found in yellow or green pigmented paints, galvanized
sheets, welding rods, and in solvents (Cronin 1980; PPDA-rubber mix
Burrows 1983). Chromate dermatitis in the aircraft Thiuram mix 1% pet (rubber gloves)
Formaldehyde 1% aq
industry was first reported in 1944 (Hall 1944). Nickel sulphate 5% pet (in wire and solder alloys)
Soldering fluxes can contain hydrazine or rosin, Rosin 20% pet (in soldering fluxes)
both liable to sensitize. Grinders, lathe operators, set-up Potassium dichromate 0.5% pet (in primer paints (Hall 1944)
and in hardeners for sealants based on polysulfides ) (Handley
men, milling workers, and hydraulic engineers can and Burrows 1994) (Bruze et al. 1996)
come into contact with metalwork fluids, with the risk Diglycidylether of bisphenol A (DGEBA) 1% pet (adhesives,
of being sensitized to anticorrosion chemicals, such as sealants)
chromates and benzotriazole, or biocides, such as
sodium pyrithione and benzisothiazolinone (Castelain
et al. 1992). Table 3. Additional allergens
Black rubber can sensitize hydraulic engineers.
O-diglycidyl phthalate 1% pet (Burrows et al. 1984)
Assembly workers build the frame and both rivet and TGPAP (epoxy compound in adhesive for composite bonding)
seal. Set-up men, riveters, retouching specialists, and (Bruze et al. 1996)
engine fitter-mechanics may come into contact with TGMDA 1% pet. (epoxy compound in adhesive for composite
bonding) (Burrows et al. 1984)
sealants that may contain phenol-formaldehyde resin Epoxy novolac (epoxy compound in adhesive for composite
(Beck 1989), epoxy base (Handley and Burrows 1994), bonding) (Bruze et al. 1996)
hexavalent chromate in hardeners for epoxy-based GDODGA 1% pet (Mathias 1987)
Prepregs as is (Burrows et al. 1984)
sealants (Handley and Burrows 1994) and polysulfides Cold-curing hardeners (polyamines, polyamides) 1% pet
in two-part sealant bases (Wilkinson and Beck 1993; (Rietschel and Fowler 1995)
Bruze et al. 1996). Thiocol, a synthetic rubber based on Aliphatic and cycioaliphatic amines 1% pet (Rietschel and Fowler
1995)
polysulfide polymers, is used by aircraft fitters to dip Triethylenetetramine (aliphatic polyfunctional amine) 1% pet
screws and rivets into before use, and a fingertip (Rietschel and Fowler 1995)
dermatitis localized to the thumb and first two fingers Diaminodiphenyl sulfone (DDS) 1% pet (polyfunctional amine)
(Burrows et al. 1984)
of the dominant hand was seen in five of six fitters with Triethanolamine 2% pet (tertiary amine)
positive patch-test reactions to the polysulfide-poly- phthalic anhydride 1% pet (acid anhydride) (Rietschel and
mer-containing system (Wilkinson and Beck 1993). Fowler 1995)
Isocyanates
Adhesives based on methyl methacrylate and epoxy 1,6-Hexamethylene diisocyanate (HDl) 0.1% pet (Bruze et al.
res ins are used by engine-fitter mechanics (Castelain 1996)
et al. 1992). In this way, they can co me into contact Epoxy sealant base (1 % pet, 5% pet) (Handley and Burrows 1994)
Polysulfide polymers 1% pet (synthetic rubber, sealant base)
with DGEBA, TGPAP, TGMDA, and epoxy novolac. (Pirilä 1950) (Wilkinson and Beck 1993)
Painters can work with products containing cyclo- Epoxy sealant accelerator (1 % pet, 5% pet)
hexanone peroxide, a catalyst for polyester finish. The Hydrazine 1% pet (ICDRG) (in soldering fluxes)
P-F-R-2 (resol resin based on phenol and formaldehyde) 1% pet
standard allergens to consider are listed in Table 2; (in sealants) (Bruze 1988)
additional allergens in the aircraft industry are listed in Acrylic res ins
Table 3. Methyl methacrylate 2% pet (in adhesive)
Ethyleneglycol dimethacrylate 2% pet
To prevent occupational contact dermatitis, several 2-Hydroxyethyl methacrylate 2% pet
measures can be taken. Using epoxy resins with high- Unsaturated polyester resin 10% ac (Rietschel and Fowler 1995)
medium molecular weight with as low concentrations Toluene 2,4-diisocyanate 0.1 % pet (ICDRG) (polyester hardener)
(in paints)
of oligomers of 340 as possible, using reactive diluents Cyciohexanone peroxide 0.5% (catalyst for polyester finish)
of high molecular weight, using hardeners of the (Rietschel and Fowler 1995)
adduct type with no remains of aliphatic amines, are all Benzotriazole 1% pet (ICDRG) (anticorrosive)
Sodium pyrithione 0.1 % aq (ICDRG) (biocide)
important preventive measures. Workers need to be Benzisothiazoline-3-one (BIT) 0.1 % pet (biocide)
educated regarding the potential allergenic hazards Rubber gloves-ultrasonic bath extract (Bruze et al. 1992)
when handling epoxy-based composites and sealants 2-Bromo-2-nitropropane-l,3-diol 0.25% pet (Rietschel and
Fowler 1995)
and should leam to use "no-touch" techniques when
Aircraft Industry 807
working with these materials, whether liquid or Burrows D (1983) Adverse chromate reactions in the skin. In:
prepregs. Ensuring that there is good ventilation by Burrows D (ed) Chromium metabolism and toxicity. CRC
press, Boca Raton, pp 137-163
using exhaust hoods and numerically controlled ma- Burrows D, Fregert S, Campbell H, Trulsson L (1984) Contact
chine tools with hoods will avoid machine dust from dermatitis from the epoxy res ins tetraglycidyl-4,4' -methylene
collecting and will reduce the risk of irritant contact dianiline and o-diglycidyl phthalate in composite material.
dermatitis. In addition, minimizing the contact with Castelain P-Y, Com I, Castelain M (1992) Occupational dermatitis
skin-irritating chemicals and/or allergenic chemicals in the aircraft industry: 35 years of progress. Contact
by using proper protective dothing when "no-touch" Dermatitis 27:311-316
Cronin E (1980) Metals. In: Cronin E (ed) Contact dermatitis.
techniques cannot be employed is also important. Churchill Livingstone, Edinburgh, pp 279-390
Dahlquist I, Fregert S (1979) Contact dermatitis from volatile
epoxy hardeners and reactive diluents. Contact Dermatitis
5:406-407
References Hafner J, Rüegger M, Kralicek P, Elsner P (1995) Airborne irritant
contact dermatitis from metal dust adhering to semisynthetic
working suits. Contact Dermatitis 32:285-288
Beck MH (1989) Experiences of contact dermatitis associated with Hall AF (1944) Occupational contact dermatitis among aircraft
phenol formaldehyde resins. In: Frosch PJ, Dooms-Goossens workers. JAMA 125:179-185
A, Lachapelle J-M, Rycroft RJG, Sheper RJ (eds) Current Handley J, Burrows D (1994) Dermatitis from hexavalent
topics in contact dermatitis. Springer, Berlin Heidelberg New chromate in the accelerator of an epoxy sealant (PRI422)
York, pp 374-376 used in the aircraft industry. Contact Dermatitis 30:193-196
Bjärkner B (1992) Plastic materials. In: Rycroft RJG, Menne T, Mathias CGT (1987) Allergic contact dermatitis from a nonbis-
Frosch PI, Benezra C (eds) Textbook of contact dermatitis. phenol A epoxy in a graphite fiber reinforced epoxy laminate.
Springer, Berlin Heidelberg New York, pp 540-567 J Occup Med 29:754-755
Bruze M (1988) Patch testing with a mixture of 2 phenol- Pirilä V (1950) Thiocol as a frequent cause of dermatitis. Acta
formaldehyde res ins. Contact Dermatitis 19:116-119 Allergoi II1:319-328
Bruze M, Trulsson L, Bendsäe N (1992) Patch testing with Rietschel RL, Fowler JF Jr (1995) Fisher's Contact dermatitis, 4th
ultrasonic bath extracts. Am J Contact Dermat 3:133-137 edn. Williams and Wilkins, Baltimore
Bruze M, Edenholm M, Engsträm K, Svensson G (1996) Occu- Wilkinson SM, Beck MH (1993) Allergic contact dermatitis from
pational dermatoses in a Swedish aircraft plant. Contact sealants containing polysulphide polymers (Thiocol ®).
CHAPTER 94
Air Hammer Operators

D.J. Gawkrodger
Introdurtion occupations infrequently mentioned include dentists

and dental hygienists, who may get sensory nerve
damage related to vibration exposure from dental
The main occupational disorder from which air
drills.
hammer operators suffer is vibration white finger,
now known as the hand-arm vibration syndrome
(HAVS; see Chap. by Gemne). An association between Epidemiology
vibration transmitted to the hands and the use of
hand-held power tools has been recognised since the
1920S. Vibration transmitted through the hands may In Italian forestry workers, the prevalence of HA VS
have an effect on the digital vasculature, peripheral was recently found to be 23% (Bovenzi et al. 1995). The
nerves and the musculoskeletal system. The most prevalence in chippers was reported as 36% compared
critical factor in the aetiology is the amount of energy with 5% in rammers and 3% in grinders (Harazin and
per unit time transmitted to the hands, in association Langauer-Lewowicka 1996). In a Dutch postal survey,
with the duration and frequency of this exposure. an overall prevalence of 17% for HAVS was found
among workers exposed to vibration tools (Musson
et al. 1989).
Occupations Afferted
Aetiology
HA VS affects workers exposed to a variety of forms of
occupational vibration (Table 1). The industries most
Exposure to vibration induces dysfunction of vascular
frequently involved vary between countries, but prom-
smooth muscle. Chronic vibration produces disruption
inent industries include the following: forestry, stone
of endothelial cells, with adherence of platelets which
quarrying and carving, mining and rock drilling, road
stimulate smooth muscle proliferation (Okada 1990).
and construction work, assembly line work, and the
Clinically, chronic vibration leads to an increased
aircraft, shipbuilding and railway industries. Other
sensitivity of the vasoconstrictive response to cold
(Olsen and Nielsen 1988). Nerve damage has been
Table 1. Vibrating tools and machinery demonstrated on biopsies of patients with HAVS
(Takeuchi et al. 1986). Epineural oedema is seen in
Tool Example the early and reversible stage; later, irreversible demy-
Percussive metal-working Rivetting, caulking, chipping,
elination and axon degeneration occur.
tools fettling, drilling, impact
wrench, metal cutting tools
Grinders and other
rotary tools
Pedestal grinders, hand-held
grinders, flex -driven grinders
Symptoms
and polishers, rotary burring
tools
Stone working, mining, Hammers, rock drills, road In the acute phase, severe vibration can cause tingling
road construction breaking tools in the hands and aching in the wrists and forearms.
Porest, garden, Chain saws, electrical These symptoms resolve rapidly within hours or days.
wood-working machinery screwdrivers, mowers, shears,
hedge trimmers, rotary hoes With repetitive and chronic exposure, patients com-
Other processes and tools Concrete vibrating pokers, plain of tingling and numbness towards the end of the
concrete level1ing vibrotables, day, with cessation of symptoms when away from
jigsaws, vibratory rollers
work, e.g. at the weekend or when on holiday. Further

Air Hammer Operators 809
exposure results in an increase in severity of the Table 2. Taylor and Pelmear scale: stages of Raynaud's phenom-
enon (complications are not used in this grading)
symptoms, which may become permanent (Bovenzi
1990). Subsequently, continued vibration leads to the Stage Condition of digits Work and sodal interference
onset of vascular symptoms of Raynaud's phenome-
non, characterised by blanching of the tip(s) of one or 0 No blanching of digits No complaints
more digit on exposure to cold (Cherniack 1990). The °T Intermittent tingling No interference with
activities
affected fingers are those most exposed to vibration. ON Intermittent numbness No interference with
During an attack, there is impairment of sensitivity in activities
the fingertips, with loss of dexterity for fine tasks such Blanching of one or No interference with
more fingertips with activities
as handling small objects. The attacks of cold-induced or without tingling
whiteness last 20-60 min and are followed by reactive and numbness
hyperaemia, which may be accompanied by painful 2 Blanching of one or Slight interference with
more fingers with horne and sodal
tingling, especially if there has been rapid re-warming. numbness. Usually activities. No interference
Progression of the condition is indicated by the confined to winter with work
development of loss of grip strength in the hands, with 3 Extensive blanching. Definite interference with
Frequent episodes work, at horne, and with
a reduction in sensation and a diminution in manual in summer as weil sodal and hobby activities
dexterity. These neurological symptoms are more as in winter
debilitating than the intermittent vascular symptoms, 4 Extensive blanching. Occupation changed to avoid
Most fingers affected; further vibration exposure
and can interfere significantly in normal daily activ- frequent episodes because of the severity of
ities. The carpal tunnel syndrome, bony changes, e.g. in both summer signs and symptoms
aseptic necrosis, fatigue fractures and degenerative and winter
joint disease, and tendinitis may occur with HAVS.
Table 3. The Stockholm workshop scale for the classification of
cold-induced Raynaud's phenomenon in the hand-arm vibration
Diagnosis and Classification syndrome: the staging is made separately for each hand. In the
evaluation of the subject, the grade of the dis order is indicated by
the stages of both hands and the number of affected fingers on
The diagnosis is based on the his tory. Details of the each hand
type, daily duration and length of vibration exposure
Stage Grade Description
are needed. Information about drug ingestion, alcohol
consumption, and smoking his tory should be recorded
together with pertinent data from the past medical °
1 Mild
No attacks
Occasional attacks affecting only the tips
of one or more fingers
history. The physical examination must indude an 2 Moderate Occasional attacks affecting distal and
assessment of the vascular, musculoskeletal and neu- middle (rarely also proximal) phalanges
rological systems, induding blood pressures, light of one or more fingers
3 Severe Frequent attacks affecting all phalanges of
touch, two-point discrimination and exdusion of the most fingers
thoracic outlet syndrome. Although it is possible to 4 Very severe As in stage 3, with trophic skin changes in
measure skin temperature, laser-Doppler fiowmetry the fingertips
through the digital arteries, and various neurological
parameters, these objective tests are not currently
useful for the routine diagnosis of HAVS (Ekenvall Table 4. The sensorineural stages of the hand-arm vibration
syndrome: the sensorineural stage is established for each hand
1987).
Classification of the degree of severity of HAVS can Stage Symptoms
be made from the his tory according to the scale
(Table 2) of Taylor and Pelmear (1975). However, this °1 SNSN Exposed to vibration but no symptoms
Intermittent numbness, with or without tingling
does not allow for seasonal change and underestimates 2 SN Intermittent or persistent numbness, reduced sensory
the neurological involvement, and has been replaced perception
by the Stockholm Workshop scale (Gemne et al. 1987) 3 SN Intermittent or persistent numbness, reduced tactile
discrimination and/or reduced manipulative dexterity
(Tables 3, 4).
the age at which exposure ceased, and the period of

Prognosis, Treatment and Prevention
continuing exposure after symptoms began (Petersen
et al. 1995). There is little evidence for improvement
Cessation of vibration exposure may result in a with time in the neurological symptoms.
reduction in the severity of the vascular symptoms, Treatment of the condition is difficult. Withdrawal
but this probably depends on the stage of the HA VS, from contact with vibration tools is most important.
810 D.J. Gawkrodger: Air Hammer Operators
Drug therapy, e.g. the use of vasodilator drugs, has (revision ofthe Taylor-Pelmear scale). Scand J Work Environ
been tried without much benefit (Matoba 1994). Health 13:275-278
Harazin B, Langauer-Lewowicka H (1996) Raynaud's phenome-
Exposure to vibration may be controlled by the use non in different groups of workers using handheld vibrating
of vibration dampening and isolation, and the use of tools. Cent Eur J Public Health 4:130-132
anti-vibration tools and gloves. Matoba T (1994) Pathophysiological and clinical picture of hand-
arm vibration syndrome in Japanese workers. Nagoya J Med
Sei 57[Suppl):19-26
Musson Y, Burdorf A, van Drimmelen D (1989) Exposure to
shock and vibration and symptoms in workers using impact
References power tools. Ann Occup Hyg 33:85-96
Petersen R, Andersen M, Mikkelsen S, Nielsen SL (1995)
Prognosis of vibration induced white finger: a follow-up
Bovenzi M (1990) Medical aspects of the hand-arm vibration study. Occup Environ Med 52:110-115
syndrome. Int J Industrial Ergonomics 6:61-73 Okada A (1990) Pathogenetic mechanism of vibration-induced
Bovenzi M, Franzinelli A, Maneini R, et al. (1995) Dose-response white finger. Recent findings and speculation. In: Proceedings
relation for vascular disorders induced by vibration in the of the Fifth International Conference on the Hand-Arm
fingers of forestry workers. Occup Environ Med 52:722-730 Vibration Syndrome. Kanazawa; Kyori Press
Cherniack MG (1990) Raynaud's phenomenon of occupational Olsen N, Nielson SL (1988) Vasoconstrictor response to cold in
origin. Arch Intern Med 150:519-522 forestry workers: a prospective study. Br J Ind Med 45:39-42
Ekenvall L (1987) Clinical assessment of suspected damage from Takeuchi T, Fatasuka M, Imanishi H, Yamada S (1986) Patho-
hand-held vibrating tools. Scand J Work Environ Health logical changes observed in the finger biopsies of patients
13:271-274 with vibration-induced white finger syndrome. Scand J Work
Gemne G, Pyykkö I Taylor W, Pelmear PL (1987) The Stockholm Environ 12:280-283
Workshop scale for the classification of cold-induced Ray- Taylor W, Pelmear PL (1975) Vibration white finger in industry.
naud's phenomenon in the hand-arm vibration syndrome Academic Press, London
CHAPTER 95
Aromatherapists
K. Alanko
Introduction burning rituals began in the Near East more than

4000 years ago. The ancient Egyptians, Greeks and
Romans all used fragrances. One thousand years ago,
Aromatherapy is a form of alternative medicine (com-
the Arabs discovered how to extract oils from flowers
plementary therapy, holistic practice) using essential
by distillation and, thereby, produced essential oils.
oils systemically or topically. Aromatic substances
These skills spread to Western Europe with the
extracted from flowers have been used for medical
crusades (Trevelyan 1993; Scheinman 1996). Until the
purposes from ancient times. The term 'aromatherapy'
mid-19th century, all perfumes were blends of essential
was introduced in 1936 by Rene-Maurice Gattefosse, a
oils. Chemists have, since then, learned to isolate
French chemist, after he had used lavender oil to heal
individual chemicals from essential oils and produce
his burned hand (Weiss and James 1997). According to
synthetic aroma chemicals from coal or petroleum
the International Federation of Aromatherapists, aro-
(Scheinman 1996). Currently, synthetic chemicals are
matherapy 'enhances well-being, relieves stress, and
more often used in fragrances, and essential oils seem
helps in the rejuvenation and regeneration of the
to be used more in aromatherapy than in perfumery
human body'. Aromatherapists also claim that it can
(De Groot and Frosch 1997). In addition to their use as
help in stress-related conditions, premenstrual syn-
fragrances in cosmetics, essential oils are used as
drome, moderate anxiety or depression, sleeping
flavourings in foods, drinks and, for example, in
problems, minor aches and pains, migraine, digestive
toothpastes and mouth washes (Scheinman 1996).
dis orders, skin problems such as eczema and acne, and
minor infections such as thrush and cystitis (Trevelyan
1993). Aromatherapy has become increasingly popular
Essential oils
in recent years together with other so-called alternative
treatments. However, aromatherapy has no evidence-
based foundation in medicine. Essential oils volatilise easily and can become gaseous
Essential oils are used in aromatherapy either by at room temperature; they are thus also known as
application to the skin or by inhalation through volatile oils. Essential oils come from many different
vaporisation. They are also used orally, usually given plants, from a limited number of animals, and can be
with drops of sugar or honey. For topical application, synthesised from two fossil oils (Scheinman 1996). The
they may be used as bath additives, added to shampoos, essential oils used in aromatherapy are of herbal
in skin oils and lotions, in hot and cold compresses, in origin. Essential oil can be extracted from plants and
flower waters, or in massage oils. Aromatherapy most flowers by distillation, extraction, enfleurage, macera-
often combines massage with the application of essen- tion and expression (Scheinman 1996). Oils of roses,
tial oils on the skin. In inhalation therapy, aroma lamps laurel and lavender are examples of essential oils
are usually used. The water vapour which is formed obtained by stern distillation of plant raw materials,
distributes the essential oils as aerosol into the air. such as blossoms, leaves and fruits of flowers. Cedar-
Inhalers can also be used (Trevelyan 1993; Schaller and wood oil and sandalwood oil come from the wood and
Korting 1995; Weiss and James 1997). Aromatherapists roots of trees (De Groot and Frosch 1997). Examples of
are often beauticians or cosmetologists, and aroma- isolates include eugenol from cloverleaf oil, cedrol
therapy is only apart of their work. The skin problems from cedarwood oil, citral from lemon grass oil, and
of cosmetologists and masseurs are discussed in other menthol from peppermint oil (Scheinman 1996).
sections of this book (P. Engasser, M. Isaksson). Terpenes are the most common constituents of essen-
Fragrant substances have been used for both secular tial oils, which also contain other organic chemistry
and religious purposes for thousands of years. Incense- compounds, including aromatics, aliphatics, alicyclics

812 K. Alanko
and heterocyclies. Fragrance materials derived from population. Fragrance allergy is treated in greater
terpenes are r:t and ß pinene, citral, geraniol, linalool, detail in Chap. 185 (A. de Groot).
citronellal, hydroxycitronellal and menthol (Schein-
man 1996).
Linalool, a monoterpinol present in many essential Allergie eontact dermatitis from aromatherapy
oils, has been shown to be one sensitising component
of the essential oils. It is a component of lavender,
There are only a few reports on occupational allergic
ylang-ylang, cananga, rosewood, Bulgarian rose and
contact dermatitis from aromatherapy. An aroma-
jasmine oils (Schaller and Korting 1995; Cockayne and
therapist, doing massage, developed hand eczema and
Gawkrodger 1997). Linalool was also the most common
contact allergy to the essential oil of French marigold
fragrance chemie al in two studies examining the
(Tagetes patula) (Bilsland and Strong 1990). Another
nature of fragrance materials in cosmetic products
aromatherapist suffering from extensive eczema dis-
(De Groot and Frosch 1997). The fragrance mixture,
played contact allergy with positive patch tests to 17 (of
which is a screening tool for fragrance allergy, consists
20 tested) essential oils that she had used in the
of eight fragrance materials. Six of them are natural
therapy (Selvaag et al. 1995). A third aromatherapist
fragrance chemie als and are constituents of essential
had patchy eczema on her hands and body, which
oils. Cinnamic alcohol is found in hyacinth oil,
improved when she had time off work. She performed
cinnamic aldehyde in patchouli oil, eugenol in patch-
aromatherapy massages and facials with essential oils.
ouli and clove oils, and isoeugenol in ylang-ylang oil.
On patch testing, she showed allergie reactions to the
Geraniol is present in most essential oils and is the
fragrance mixture in the standard series, to five
main component of rose and palmarose oil, geranium,
essential oils in the perfumes and fiavours series, to
citronella, laven der and jasmine oil (De Groot and
three essential oils of her own usage, as well as to two
Frosch 1997).
of her own beauty products containing essential oils
(Cockayne and Gawkrodger 1997).
Contact allergy from essential oils Allergic contact dermatitis from aromatherapy self-
treatment has also been only rarely reported. A 53-
year-old man had been treating himself with aroma
Patients suspected to have cosmetic dermatitis have
lamps for various minor illnesses. He developed severe
been patch tested with essential oils in several
airborne contact dermatitis and contact allergy to the
studies. Allergie reactions to many of them have
essential oils used in the therapy. Patch tests were
been observed, and more often to ylang-ylang,
positive to lavender, eucalyptus, pomerance, rosewood
citronella, narcissus, rose, sandalwood, cassia and
and jasmine oils, as well as to linalool (Schaller and
clove oils (Rudzki et al. 1976; Rudzki and Grzywa
Korting 1995). A 39-year-old woman had dermatitis on
1986; Larsen et al. 1996; De Groot and Frosch 1997).
her face, scalp and neck. She had used aromatherapy
On the grounds of a multieenter investigation, it has
shampoos, moisturisers and spray perfumes composed
been suggested that ylang-ylang oil, narsissus oil
of essential oils regularly. She had a positive patch test
and sandalwood oil should be added to the
to the fragrance mixture. Cessation of aromatherapy
fragrance mixture (Larsen et al. 1996). In patch
products led to resolution of her skin symptoms
testing, essential oils often co-react in patients
(Weiss and James 1997). Only one of the commonly
allergie to fragranees. Positive tests to essential oils
available aromatherapy textbooks mentions the possi-
have been related to reactions to balsam of Peru
bility of contact dermatitis secondary to treatment
(Rudzki et al. 1976). In 1986, Rudzki and Grzywa
(Cockayne and Gawkrodger 1997).
tested 86 patients positive to the fragrance mixture
with 35 essential oils; 49 (5iYo) reacted to one or
more of the essential oils, and 15 (31%) reacted to
Pateh testing
more than three oils. Positive reactions were seen to
33 oils, most frequently to cassia oil (24 reactions),
oak-moss absolute (14 reactions) and clove oil (l2 Patch testing with a perfume series and with the
reactions). Occupational allergy to an essential oil patient's own products is essential when aromatherapy
(lavender oil) in a hairdresser has also been is suspected as the source of allergic contact dermatitis
reported (Brandao 1986). Reported causes of allergic (Cockayne and Gawkrodger 1997). It is recommended
contact dermatitis or other adverse skin reactions to to use the extensive fragrance series with 21 com-
essential oils and their ingredients have been pounds, including the eight compounds of the fra-
reviewed thoroughly by De Groot and Frosch grance mixture (Chemotechnique Diagnostics AB,
(1997). Fragrance allergy is, in absolute numbers, Malmö, Sweden) together with the perfumes and
common, affecting approximately 1% of the general fiavours series (Trolab, Hermal, Reinbek, Germany).
Aromatherapists 813
Linalool may be tested separately (at 2%, Schaller and Cassia oil (Rudzki and Grzywa 1986)
Korting 1995; at 30% pet, De Groot et al. 1994). The Citronella oil (Rudzki et al. 1976, Rudzki and
products used on the skin, e.g. massage oils, can be Grzywa 1986)
tested 'as is'. Essential oils are recommended to be Jasmine oil (Schaller and Korting 1995)
patch tested at 2% in petrolatum (De Groot et al. Lavender oil (Brandao 1986, Schaller and
1994). Patch testing with fragrance chemicals, e.g. Korting 1995)
essential oils, has been reviewed thoroughly by Larsen Narcissus oil (Larsen et al. 1996)
(1985), De Groot et al. (1994) and De Groot and Frosch Rosewood oil (Schaller and Korting 1995)
(1997). Sandalwood oil (Larsen et al. 1996)
Irritants Additional Allergens
Allergens of masseurs
Cinnamic aldehyde (also allergenic)
5-methoxypsoralen in bergamot oil (phototoxic)
Irritants of masseurs
References
Standard Allergens Bilsland D, Strong A (1990) Allergic contact dermatitis from the
essential oil of French marigold (Tagetes patula) in an
Natural fragrance chemicals in essential oils, e.g.: aromatherapist. Contact Dermatitis 23:55-56
Brandao FM (1986) Occupational allergy to lavender oil. Contact
Cinnamic alcohol Dermatitis 15:249-250
Cinnamic aldehyde Cockayne SE, Gawkrodger DJ (1997) Occupational contact
Eugenol dermatitis in an aromatherapist. Contact Dermatitis 37:
306-307
Isoeugenol De Groot AC, Frosch PJ (1997) Adverse reactions to fragrances. A
Geraniol clinieal review. Contact Dermatitis 36:57-86
Linalool De Groot AC, Weyland JW, Nater JP (eds) (1994) Contact allergy
to fragrance materials. In: Unwanted effects of cosmeties and
Essential oils, commercially available for patch testing drugs used in dermatology, 3rd edn. Elsevier, Amsterdam,
(C = Chemotechnique Diagnostics, T = Trolab): Chap. 5.8-5.15, pp 65-72
Cananga oil (C) Larsen WG (1985) Perfurne dermatitis. J Am Acad Dermatol
12:1-9
Cedarwood oil (T) Larsen W, Nakayama H, Lindberg M, et al. (1996) Fragrance
Clove oil (T) contact dermatitis: a worldwide multieenter investigation
Eucalyptus oil (T) (part I). Am J Contact Dermat 7:77-83
Rudzki E, Grzywa Z (1986) Allergy to perfurne mixture. Contact
Laurel oil (T) Dermatitis 15:ll5-ll6
Lemon oil (T) Rudzki E, Grzywa Z, Bruo WS (1976) Sensitivity to 35 essential
Lemon grass oil (T) olls. Contact Dermatitis 2:196-200
Schaller M, Korting HC (1995) Allergic airborne contact derma-
Neroli oil (T) titis from essential oils used in aromatherapy. Clin Exp
Orange oil (T) Dermatol 20:143-145
Peppermint oil (T) Scheinman P (1996) Allergic contact dermatitis to fragrance:
a review. Am J Contact Dermat 7:65-76
Rose oil, Bulgarian (C) Selvaag E, Holm J-0, Thune P (1995) Allergie contact dermatitis
Ylang-ylang oil (C) in an aromatherapist with multiple sensitizations to essential
Essential oils, others, e.g.: olls. Contact Dermatitis 33:354-355
Trevelyan J (1993) Aromatherapy. Nursing Times 89:338-340
Bergamot oil (Rudzki et al. 1976, De Groot and Weiss RR, James WD (1997) Allergie contact dermatitis from
Frosch 1997) aromatherapy. Am J Contact Dermat 8:250-251
CHAPTER 96
Asphalt Workers (Paving)

R. Riala and P. Heikkilä
Bitumen is a residue obtained from the vacuum Road paving is work for groups of five to ten people;
distillation of petroleum crude oil. Bitumen varies a paving machine operator drives the machine into
from a highly viscous liquid to a brittle solid, and which lorries unload the hot mix. The machine
consists of hundreds of chemieals, such as asphalt- operator selects the correct speed and direction of
enes (high-molecular-weight aromatic and heterocy- the paving, the screed man rides with the paving
clic hydrocarbons), res ins (polymers formed from machine and monitors the evenness and spreading of
unsaturated hydrocarbons) and aromatic hydrocar- the bitumen. Behind the machine, two to four spade
bons containing benzene rings. Distilled bitumen is men or rakers follow on foot, manually soothing the
used for road paving, while the harder air-blown asphalt surface and the edges of the new layer. After
bitumen is used for roofing. About 90% of the the rakers comes a roller, driven by a roller operator,
bitumen is used for road paving, 10% for roofing and which presses the new layer to the desired thickness.
waterproofing. Machine operators carry out the maintenance of the
Asphalt consists of approximately 5-8% bitumen, machines and use mineral oils and naphtha for the
gravel and additives. There are various types of cleaning of the machines. Rakers also clean their tools
asphalt, depending on the intended use, the most with naphtha.
popular being the hot mix applied at 150-180 °C.
Elasticity needed, e.g., on bridges, is improved by
styrene-butadiene-styrene (SBS) rubber. In re-mixing, Irritants
old asphalt is heated to 150-200 °C by gas heaters,
then crushed and mixed with fresh bitumen and Asphalt
additives, such as tall oil pitch and long-chain fatty Bums (from hot asphalt)
amines, added to improve the adhesion. Oil gravel Solvents, naphtha
contains bitumen oil (soft bitumen gained from Mineral oils
petroleum distillation residues) and amine additives. Fatty amines
Cutback products used in paving contain distilled Aggregates (gravel' sand, crushed rock)
bitumen and organic solvents, usually Stoddard sol- Ultraviolet light (the combination of asphalt and UV
vent and fatty amines. In bitumen emulsions, the light enhances the development of actinic keratoses
bitumen is emulsified in mildly acidic water. Com- and other changes on the skin, Adams 1990)
mercial fatty amine products are contaminated with
low-molecular-weight polyamines and alkanol poly-
amines which are released from hot bitumen during Standard Allergens
paving, e.g., ethylene diamine and tetraethylene pent-
amine (Levin et al. 1994).
Asphalt is manufactured at a mixing plant, which is In chemicals
often constructed close to the neighborhood where the Epoxy resin (very rare use)
road construction is taking place. The mixing plant is Rosin: (possible additive in asphalt in so me countries,
operated by a small personnel of two to four men, who Adams 1990)
control the weighing of the materials, the heating
system and the loading of asphalt into trucks, which
Rubber Chemieals (either as an additive in the rubber
transport it to the paving site. When needed, mixing-
asphalt or rubber gloves)
plant operators maintain and repair the whole mixing
process and are then in direct contact with the asphalt, 2-Mercaptodiazole
solvents and naphtha (Riala et al. 1997). Carba mix

Asphalt Workers (Paving) 815
Mercapto mix eoal tar (in some countries not used in asphalt, in
PPD mix other countries Httle and decreasing use), photo al-
Thiuram mix lergen, 5% petrolatum
Tall oil pitch (?)
Leather Hand Protection
Potassium dichromate
References
p-tert- Butylphenol-formaldehyde resin
Adams RM (1990) Asphalt workers (paving). In: Adams RM (ed)

Hand lools Oeeupational skin diseases, 2nd edn. Saunders, Philadelphia,
pp 582-583
Nickel sulphate Kanerva L, Estlander T, Jolanki R (1996) Oeeupational allergie
eontaet dermatitis eaused by 2>4,6-tris-( dimethylaminometl1-
yl)phenol, and a review of sensitizing epoxy resin hardeners.
Int J Dermatol 35:852-856
Kanerva L, Jolanki R, Estlander T (1998) Oeeupational epoxy
Additional Allergens dermatitis with allergie pateh test reaetions to multiple
hardeners including tetraetl1ylene pentamine. Contaet Der-
matitis (in press)
Alkanol polyamines and polyamines (e.g. ethylenedi- Levin JO, Andersson K, Hallgren C (1994) Exposure to low
amine, diethylenetriamine, triethylenetetramine, moleeular polyamines during road paving. Ann Oeeup Hyg
tetraethylenepentamine, mono- and diethanolamine; 38:257-258
Riala R, Heikkilä P, Kanerva L (1998) A questionnaire study for
Kanerva et al. 1996, 1998) in fatty amines (Levin et al. road pavers' and roofers' work-related skin symptoms and
1994) bitumen exposure. Int J Dermatol 37:27-30
CHAPTER 97
Automobile Mechanics
U. Funke
Automobile mechanics perform all types of jobs in car joining and procedures such as soldering and welding
repair, preparation and service. The risk of occupa- and the use of different glues may occur. The
tional derma tos es varies to a large extent with the preparation of surfaces before spraying can include
specific type of work, the associated dermal exposure filling with polyester; benzoyl peroxide applied as
(and its duration) and protective measures. Generally, hardener can cause allergy. The disassembly and
all risks that appear in the car industry may be relevant adjustment works in repair or service may also be
for automobile mechanics, but whether there is a associated with dirty work, wet work and/or contact
dermatological risk depends on the size of the work- with petrol, oils, lubricants, greases, cooling water,
shop, the specific business, the organization of the brake fluids, hydraulic fluids, cleaners and polishers.
work, and the occupational health and safety standards Currendy, the work of automobile mechanics is
assumed in that work place. A wide range of tasks have increasingly characterized by the checking of electric,
to be taken into account. electronic, hydraulic and mechanic systems and their
All the basic manual metalworking processes, such interfaces. Therefore, the risk of irritant or allergic
as grinding, sawing, rubbing, countersinking, and dermatitis is decreasing. However, if jobs with contact
thread-cutting, and the machine metalworking pro- to irritants or allergens are limited to only one or a few
cesses, such as turning, milling, drilling, grinding and workers, if protective equipment is not available or not
honing connected with metal dust and chips, metal- used and if occupational health care is not performed
working fluids and cleaning procedures (dirty work, properly, different occupational skin diseases are
wet work, solvents), may come to pass. Furthermore, possible.

CHAPTER 98
Bakers
N.K. Veien
Description of Exposures The incidence rate of work-related derma tos es for

bakers was 191 per 10,000 employees, compared with
84 per 10,000 for confectioners (Tacke et a1. 1995).
The working conditions of bakers vary considerably,
The routine patch testing of 800 consecutive
depending on wh ether they work in traditional baker-
patients in Barcelona resulted in a diagnosis of
ies, in which bread and pastries are manufactured from
occupational contact dermatitis for 72 persons. Metal
basic ingredients, such as flour, yeast, water, shorten-
workers, with 19 cases of occupational dermatosis, and
ing and spices, or in highly industrialised operations,
hairdressers, with 17 cases, were the most common of
in which much of the work consists of monitoring the
13 occupations associated with occupational dermato-
operation of automated equipment. Specialised func-
sis. With five cases of occupational dermatosis, bakers
tions include the work of confectioners and sugar
and pastry makers ranked fourth (Serra-Baldrich et a1.
artists. In traditional bakeries, the hands and fore arms
1995). Nethercott and Holness (1989) found ten bakers
are subjected to extensive exposure to wet dough,
with occupational contact dermatitis among 1346 cases
water, detergents from frequent washing of the skin,
of suspected contact dermatitis in Toronto.
and dust, particularly from flour and various additives,
Kanerva et a1. (1996b) reviewed the cases of contact
such as enzymes.
urticaria, including protein-contact dermatitis, report-
ed to the Finnish Register of Occupational Diseases
from 1990 to 1994. Bakers ranked first among the 15
Epidemiology most common occupations associated with contact
urticaria with 140.5 cases per 100,000 employed
A cross-sectional study of 344 workers in three modern persons, compared with 21.2 cases among 100,000
British bakeries, a flour-packing factory and three flour nurses, the occupation that ranked 15th.
mills showed that 46 had work-related chest symp- Of 50 sugar artists, 30 completed a questionnaire
toms, 92 had eye/nose symptoms and 27 (9%) had skin detailing skin disease; 20 of the 30 had increased
symptoms. Skin-test reactivity to flour, ex-amylase and palmar sweating, while 12 had erythema, blistering and
a flour mite correlated poorly with the skin symptoms a burning sensation; 4 suffered from palmar vesicular
(Cullinan et a1. 1994). dermatitis (Bangha and Elsner 1996).
Over an 8-year period, from 1984 to 1991, 17,746
cases of work-related skin disease were registered with
Allergens
the Danish authorities. Of 16,688 persons with ecze-
matous dermatoses, 419 (2.5%) were employed in
bakeries or confectioner's shops. The cumulative Delayed-Type Hypersensitivity
frequency of work-related eczematous disease among
those employed was 4.7'Yo (419 of 9000 persons Until ammonium persulfate, used to bleach flour, was
employed in bakeries). The frequency per year for prohibited in most countries in the 1950S, bakers often
bakers was 0.59%, compared with 1.33% for hairdress- became sensitised to this substance. A law against the
ers and 0.05% for office workers. Bakers ranked fourth addition of ammonium persulfate to flour was one of
among the top 19 specific trades in which persons the early steps taken to prevent occupational allergic
suffered from eczematous dermatoses (Halkier-S0ren- contact dermatitis (Rietschel and Fowler 1995).
sen 1996). Benzoyl peroxide has also been used to bleach flour.
In a population-based study of 2562 persons with Fisher (1989) reported two bakers with contact sensi-
work-related dermatoses seen during a 3-year period in tivity to benzoyl peroxide, one of whom had a positive
Bavaria, 107 were bakers and 31 were confectioners. patch test to 1% benzoyl peroxide in petrolatum.

818 N.K. Veien
Due to the sensitising chernicals they contain, Of 234 bakery employees 18 had eczema; 1 of the 18
flavours and spie es have been a concern, but there had a positive patch test to balsam of Peru and to
are few reports of contact sensitivity to such com- thiuram (Järvinen et al. 1979).
pounds among bakers. Cinnamon has been noted as a
cause of hand eczema among bakers in several case Immediate-Type Hypersensitivity
reports (Malten 1979; Dooms-Goossens et al. 1990;
Nixon 1995). The patients were patch tested with Of 107 bakers with occupational skin diseases, 36% had
cinnamon powder. Nixon's patient reacted to balsam relevant immediate-type hypersensitivity, in most
of Peru, the perfurne mixture, cinnamic alcohol and cases caused by flour allergy (Tacke et al. 1995).
cinnamic aldehyde. Cardamom has also been de- Sensitisation to flour has been a much-feared occupa-
scribed as a contact allergen (Mobacken and Fregert tional problem among bakers. Herxheimer (1973)
1975). Positive patch tests were seen to cardamom carried out a long-term study of 880 bakers' appren-
powder, 50% cardamom powder in petrolatum, oil of tices and found that, over a 5-year period of appren-
cardamom, delta-carene, dipentene and oil of berga- ticeship, the overall percentage of those with a positive
mot. skin test to flour increased from 8 to 30. At the same
The systematic patch testing of patients with a time, a significant number of persons lost their flour
battery of spices, in addition those in the European sensitivity. The number of patients tested during the
Standard Series, showed positive patch tests to be most apprenticeship fell from 880 to 37 over the 5 years.
commonly caused by balsam of Peru. Spices not in the Allergie rhinitis, asthma and/or atopic dermatitis
standard series which most commonly gave rise to were seen in 58 of 234 bakery employees (25%); 14 had
positive reactions were clove, Jamaican pepper and atopic dermatitis. Of these 14, 3 had positive intracu-
cinnamon (Niinimäki 1984). taneous tests to one or more of the flours they used.
Bruynzeel and Prevoo (1990) found the perfume One of those who had a positive skin test experienced
mixture more useful than balsam of Peru as a predictor aggravation of hand eczema upon contact with flour,
of spiee allergy. It can be useful to carry out patch and another experienced aggravation of atopic derma-
testing with spie es in their natural form as a screening titis of the neck (Järvinen et al. 1979).
procedure; this should not be done with garlic, Heyl et al. (1970) carried out a careful investigation
however, as it is an irritant (Bruynzeel and Prevoo of a group of 28 bakers; 18 of 21 who only had skin
1990; Kanerva et al. 1996a). symptoms - usually hand eczema - had immediate-
Heine and Fox (1980) suggested that chrornates in type hypersensitivity to flour. For two of these patients,
flour had caused occupational allergie contact derma- inhalation of flour caused a flare of hand eczema.
titis on the hands of achromate-sensitive baker. There Systemic dermatitis of this type among bakers was also
have been few reports of delayed-type hypersensitivity seen by Wüthrich (1977). Heyl and Reinert-Dilthey
to grains. Calnan (1973) described a patient with (1968) suggested that an intracutaneous test with flour
eczema of the fingers who had a positive patch test to was more sensitive than the prick test.
malt flour on two occasions; she worked with malt Six bakers with hand eczema all demonstrated
flour in a bakery. Pigatto et al. (1987) studied six positive use tests and positive RAST tests to dough,
bakers with hand eczema who had positive radio- and all developed contact dermatitis upon contact with
allergosorbent tests (RASTs) and positive use tests to flour. The reaction pattern was likened to an atopic
cereals. Two of the bakers had positive patch tests to state (Pigatto et al. 1987).
2.5% and 10% wheat in a mixture of isopropyl alcohol, Grain allergens are not well defined. Twenty-one
propylene glycol and water. In another study, 15 of 138 patients had clinical hypersensitivity to flour. Patients
bakers or confectioners had occupationally relevant with dermatitis had antibodies to antigens in the 50-
delayed-type hypersensitivity (Tacke et al. 1995). kDa to 100-kDa range, while patients with respiratory
Scratch-chamber testing with Cl-amylase powder pro- symptoms typically had antibodies to antigens lighter
duced immediate-type as well as delayed-type hyper- than 50 kDa (Schonenberger and Savolainen 1995).
sensitivity reactions in two of seven bakers with hand Cross-reactions to various cereals and reactions to less
eczema (Morren et al. 1993). than 50-kDa fractions were seen by Varjonen et al.
Among 1039 persons with occupational dermatoses (1994), who examined serum samples from 40 patients.
diagnosed by dermatologists in Jutland, Denmark in Most of these patients had atopic dermatitis. The
1983-1984, 34 were bakers. They were all patch tested clinical relevance of these findings was uncertain.
with the European Standard Series. Three reacted to Cl-Amylase, an enzyme used to improve the baking
the perfume mixture, one to balsam of Peru and one to quality of flour, is an important cause of respiratory
black-rubber mix. For all five patients, the positive allergy in bakers. Morren et al. (1993) studied protein-
patch tests were considered to be occupationally contact dermatitis in bakers and found that 7 of 32
relevant (Veien et al. 1986). bakers had positive prick tests to Cl-amylase; 4 of the 7
Bakers 819
had positive prick tests to dilutions as weak as mites and a storage mite (van Hage Hamsten et al.
1:250,000. 1987). Theoretically, contact urticaria or the aggrava-
A cross-sectional study showed that 46 of 365 tion of atopic dermatitis caused by cockroaches could
workers in bakeries, a flour mill or a crisp-bread be thought of as an occupational dermatosis in bakers
factory (13%) had positive prick tests to flour or (Monk and Pembroke 1987; Wananukul et al. 1993;
enzymes, including ex-amylase, cellulase and xylanase; Kanerva et al. 1995).
57 (16%) had work-related skin or respiratory symp-
toms. Itching of the eyes or the skin of the face and
arms occurred in 4% of those employed in bakeries Irritants
and in 3% of crisp-bread factory employees (Vanhanen
et al. 1996). Wet work
Both the prick test and the RAST test were positive Soaps
to fungal but not to bacterialex-amylase in a baker with Detergents
rhino conjunctivitis and urticaria from flour (Kanerva Flour
et al. 1997). Urticariallesions on the hands of a baker Wet dough
were associated with immediate-type hypersensitivity Citrus fruit
to balsam of Peru, cinnamic aldehyde and benzalde- Flavoring agents
hyde. The lesions disappeared when he wore gloves at Spices
work (Seite-Bellezza et al. 1994). Enzymes
Irritants Standard Allergens
Balsam of Peru
In their study of 2562 persons with work-related Perfume mixture
dermatoses, Tacke et al. (1995) found irritant contact Thiuram mixture
dermatitis in 70% of 107 bakers, making this dermatitis Other rubber additives
twice as common as allergie contact dermatitis. Eight
of 31 confectioners (26%) had irritant contact derma-
titis, compared with 16% with allergie contact derma- Additional allergens
titis (Halkier-S0rensen 1996). Of 34 bakers with
occupational dermatoses, 12 had irritant contact der- ex-Amylase
matitis (Heine and Fox 1980) and, in another study, 3 Benzoyl peroxide
of 10 bakers with occupational dermatoses were Cinnamon
diagnosed with irritant contact dermatitis (Nethercott Cinnamic alcohol
and Holness 1989). Cinnamic aldehyde
The nature of the irritants to be found in bakeries is Cinnamon oil
not weIl defined in the literature. Most bakeries in Cardamom
Europe are small enterprises, and all employees Vanilla
participate in the necessary, frequent cleaning of Citrus fruit
equipment and of the bakery itself. There is intense Cloves
exposure to dust from grains, sugar and spices, and Flour
extensive contact with moist items such as dough. Lauryl gallate
Fisher (1982) has provided a list of irritants that may Propyl gallate
be encountered by bakers. Specialised areas, such as Butyl hydroxy anisoie (BHA)
sugar artistry, may involve a risk of physical irritancy, Butyl hydroxy toluene (BHT)
particularly thermal injury (Tacke et al. 1995).
References
Parasites
Bangha E, Elsner P (1996) Skin problems in sugar artists. Br J
Flour mites were described as a cause of papular Bruynzee1 DP, Prevoo RLMA (1990) Patch tests with some spices.
dermatoses on the backs of the hands of two bakers Dermatol Clin 8:85-87
(Fisher 1982). Flour and storage mites can aggravate Calnan CD (1973) Malt flour dermatitis. Contact Dermatitis
Newslett 14:390
atopic dermatitis (Gühring 1989). Among farmers, the Cullinan P, Lowson D, Nieuwenhuijsen MJ, Sandiford C, Tee RD,
most common positive RAST tests were to house-dust Venables KM, McDonald JC, Taylor AJN (1994) Work related
820 N.K. Veien: Bakers
symptoms, sensitisation, and estimated exposure in workers Morren M-A, Janssens V, Dooms-Goossens A, van Hoeyveld E,
not previously exposed to flour. Occup Environ Med 51: Cornelis A, de Wolf-Peeters C, Heremans A (1993) Cl-Amylase,
579-583 a flour additive: an important cause of protein contact
Dooms-Goossens A, Dubelloy R, Degreef H (1990) Contact and dermatitis in bakers. J Am Acad Dermatol 29:723-728
systemie contact-type dermatitis to spices. Dermatol Clin Nethercott JR, Holness DL (1989) Occupational dermatitis in food
8:89-93 handlers and bakers. J Am Acad Dermatol 21:485-490
Fisher AA (1982) Hand dermatitis - a "baker's dozen". Cutis Niinimäki A (1984) Delayed-type allergy to spices. Contact
29:216-221 Dermatitis 11:34-40
Fisher AA (1989) Allergie bakers' dermatitis due to benzoyl Nixon R (1995) Cinnamon allergy in a baker. Australas J
peroxide. Cutis 43:128-129 Dermatol 36:41
Gühring H (1989) Inhalative Milbenprovokation bei Atopikern Pigatto PD, Polenghi MM, Altomare GF (1987) Occupational
unter Hochgebirgsbedingungen. Z Hautkr 64:461-465 dermatitis in bakers: a clue for atopic contact dermatitis.
Halkier-S0rensen L (1996) Occupational skin diseases. Contact Contact Dermatitis 16:263-271
Dermatitis 35[Suppll]:I-120 Rietschel RL, Fowler JF Jr (eds) (1995) Fisher's contact dermatitis,
Heine A, Fox G (1980) Bäckerekzem durch Chromverbindung in 4th edn. Williams & Wilkins, Baltimore pp 577-580
Mehlen. Derm Beruf Umwelt 28:113-115 Schonenberger P, Savolainen H (1995) Proteinantigene in Fallen
Herxheimer H (1973) The skin sensitivity to flour of bakers' von Asthma, Rhinitis und Dermatitis bei beruflich me-
apprentices. Acta Allergoi 28:42-49 hlexponierten Personen. Schweiz Med Wochenschr 125:
Heyl U, Reinert-Dilthey I (1968) Neue Gesichtspunkte bei der 1046-1051
Beurteilung des "Bäckerekzems" . Berufsdermatosen 16: Serra-Baldrieh E, Lluch M, Valero A, Malet A, Camarasa JMG
204-214 (1995) Contact dermatitis: clinical review of 800 patients
Heyl U, Wolff U, Osten H (1970) Inhalative Provokation und tested using the standard European series. Allergoi et
Lungenfunktionsprüfung ekzemkranker Bäcker und Müller Immunopathol 23:67-72
mit nachgewiesener Mehlallergie vom cutan-vasculären Typ. Tacke J, Schmidt A, Fatasch M, Diepgen TL (1995) Occupational
Berufsdermatosen 18:77-88 contact dermatitis in bakers, confectioners and cooks.
Järvinen KAI, Pirilä V, Björksten F, Keskinen H, Lehtinen M, Contact Dermatitis 33:112-117
Stubb S (1979) Unsuitability of bakery work for a person van Hage Hamsten M, Johanssen SG, Zetterström 0 (1987)
with atopy: a study of 234 bakery workers. Ann Allergy Predominance of mite allergy over allergy to pollens and
42:192-195 animal danders in a farming population. Clin Allergy 17:
Kanerva L, Tarvainen K, Tupasela 0, Kaarsalo K, Estlander T 417-423
(1995) Occupational allergie contact urtiearia caused by Vanhanen M, Tuomi T, Hokkanen H, Tupasela 0, Tuomainen A,
cockroach (Blaberus giganteus). Contact Dermatitis 33: Holmberg PC, Leisola M, Nordman H (1996) Enzyme
445-446 exposure and enzyme sensitisation in the baking industry.
Kanerva L, Estlander T, Jolanki R (1996a) Occupational allergie Occup Environ Med 53:670-676
contact dermatitis from spices. Contact Dermatitis 3P57-162 Varjonen E, Savolainen J, Mattila L, Kalimo K (1994) IgE-binding
Kanerva L, Toikkanen J, Jolanki R, Estlander T (1996b) Statistical components of wheat, rye, badey and oats recognized by
data on occupational contact urtiearia. Contact Dermatitis immunoblotting analysis with sera from adult atopie derma-
35:229-233 titis patients. Clin Exp Allergy 24:481-489
Kanerva L, Vanhanen M, Tupasela 0 (1997) Occupational allergic Veien NK, Heydenreich G, Kaaber K, Willumsen P (1986)
contact urticaria from fungal but not bacterial Cl-amylase. Skin diseases. Occupational skin diseases diagnosed by
Contact Dermatitis 36:306-307 dermatologists in Jutland (in Danish). Arbejdsmilj0fondet,
Malten KE (1979) Four bakers showing positive patch-test to a Copenhagen
number of fragrance materials, which can also be used as Wananukul S, Huiprasert P, Pongprasit P (1993) Eczematous skin
flavors. Acta Derm Venereol Suppl (Stockh) 8P17-121 reaction from patch testing with aeroallergens in atopic
Mobacken H, Fregert S (1975) Allergie contact dermatitis from children wiili and wiiliout atopic dermatitis. Pedriatr De-
cardamom. Contact Dermatitis 1:175-176 rmatol 10:209-213
Monk BE, Pembroke AC (1987) Cockroach dermatitis: an Wüthrich B (1977) Berufsdermatosen per inhalationem oder
occupational hazard. BMJ 294:935 ingestionern. Berufsdermatosen 25:141-151
CHAPTER 99
Barbers and Hairdressers

A. Alomar and 1. Conde-Salazar
Introduction sacro-coxygeal ulcer. In 1880, Hodges coined the

current denomination of pilonidal cyst and mentioned
the possible appearance of these lesions in other
Occupational derma tos es in barbers are similar to those
topographical areas, witlt specific reference to hand
o~curring in hairdressers, even though some specific
lesions in barbers [2]. Louste and Thibaut reported an
d1fferences occur, mainly due to differing types of work.
instance of interdigital granuloma in barbers due to
Barbers have traditionallyworked in gentlemen's barber
the penetration of cut hairs 54 years later, in their
shops as well as in ladies' hairdressing parlors, even
paper "Un cas rare de dermite professionnelle chez un
though male hairdressers are fewer in number; female
coiffeur", and recognized the occupational nature of
hairdressers have usually tended to female customers,
these lesions [3]. Ewing, in 1947 [4], and Patey and
unisex hairdressing parlors being relatively new. Male
Scarff, in 1948, employed the term "barber's hand" to
hairdressers are a minority in their trade and generally
designate the interdigital location of a pilonidal cyst
do not use dyes, permanent waving fluids and other
chemieals, so eczematous lesions in male hairdressers
l5]. There appears to be some terminological confusion
in tlte first reports, "pilonidal cyst" being the most
are relatively infrequent. In our contact dermatitis
frequently used denomination. This confusion in
clinic, female hairdressers outnumber men by 10 to l.
nomenclature seems to be tlte only explanation for
Some male hairdressers presented with irritant der-
the erroneous assimilation of hair sinus es into pilon-
matitides and sensitizations similar to those seen in
idal cysts, usually sacral in location, and originated in a
fern ale hairdressers (PPDA group, thioglycolic acid) [1],
sequestration of skin along tlte embryo closure line [6,
and others presented with mechanical skin lesions, such
7,8,9]. In 1953, Curie et al. [10] published their study
as corns, callosities, and hair sinuses.
"Interdigital sinuses of barber's hands" and clearly
defined the pathomechanism of tltese lesions, which
Callosities are provoked by the implantation of cut hairs in the
interdigital spaces, most frequently in tlte second or
The use of mechanical cutting instruments, such as third interdigital spaces of the right hand. Hair
scissors and hair trimmers, not infrequently causes the penetration determines the progressive formation of
appearance of well-delimited hyperkeratotic lesions in fistulous tracts and a granulormatous reaction when
areas of friction, such as the inner lateral aspects of tlte hair fragments are buried in the dermis. The clinical
first, second and even third fingers (handling of scissors) appearance of these lesions is characteristic: a papule,
of the dominant hand. These lesions tend to be nodule or cyst located on the interdigital space, with a
disregarded by physicians and patients alike and are fistulous opening usually apparent, tltrough which
discovered only when tlte patients' hands are examined some amount of serous or purulent secretion can often
in detail, since they do not tend to impair dexterity at be extruded (Fig. 1). Local infection is a possible
work. They can be compared to other professional complication of these lesions.
stigmata (fiddlers' callosities, etc.). We agree with the widely accepted term "barber's
hair. sinus" used by Rook et al. [11], even though
preClse alternative denominations are available in
Hair Sinus other languages, such as "trichogranulome et fistule
du coiffeur" in French, or the term "Granulome und
History Fis.teln durch Haare" used by Rockl and Muller [12].
Smtable denominations in Spanish could be "fistula
The first report of a pilonidal cyst was made in 1847 by pilosa" or "tricogranuloma interdigital de los peluque-
Anderson, who described his finding of a hair in a ros", which reflect tlte true nature of this lesion,

822 A. Alomar and L. Conde-Salazar
Fig. 1. Clinical appearanee of an in-

terdigital hair sinus with two fistu-
lous openings in the seeond
interdigital spaee in a barber
completely unrelated to pilonidal cysts and other ofinterdigital granulomas [141. Thus, population stud-
congenital malformations. ies among barbers have revealed a significant prevalence
of hair sinus es, even though they were mostly asymp-
Incidence tomatic and did not cause enough concern to necessitate
a medical consultation. Most barbers did know about
The true incidence of this infrequently observed this entity, which they treated themselves [10,131. Most
dermatologie lesion can be estimated from several published reports deal with gentlemen's hairdressers,
published inquiries. Rockl and MuHer, in 1957, stated even though these lesions are known to be caused by
that these lesions are relatively frequent, but do not female hair and even by animal hair [15,161.
provide any figure regarding prevalence [121. Joseph and
Gifford [131 found 15 cases ofbarber's hair sinus with a Pathogenesis
total of 20 lesions among 115 barbers studied in their
series. Currie, Gibson and GoodaH [10], from England, Penetration ofhair fragments in the dermis is facilitated
observed 10 cases among 77 barbers, but no instance of by several physical and mechanical factors and leads to a
hair sinus among 61 male hairdressers. Hunziker, reactive epithelial proliferation, which causes an epi-
Orusco and Pilotto made another inquiry in Geneva dermal invagination to surround the hair (Fig. 2). Hair
among 58 "gentlemen's hairdressers" and found 4 cases fragments not surrounded by epithelium cause a
Fig. 2. Histopathologie examination

of a skin biopsy shows hair remnants
surround by a hyperkeratotic reae-
tive epidermal proliferation
Barbers and Hairdressers 823
foreign-body granulomatous reaction with giant cells in 3. Louste ET, Thibaut M (1934) Un cas rare de dermite
every case. Superinfection of these lesions is associated professionnelle chez un coiffeur. Bull Soc Fr Dermatol
Syphiligr 41:426-429
with an increased inflammatory response and may cause 4. Ewing MR (1947) Hair-bearing sinus. Lancet 252:427
suppuration to appear through the fistulous opening. 5. Patey DH, Scarff RW (1946) Pathology of postanal pilonidal
The clinical appearance, symptoms and histopatho- sinus. Its bearing on treatment. Lancet 251:484-486
6. Waisman M, Olivetti RG (1952) Pilonidal sinus of the hand.
logical findings in barbers show a chronologie se- Arch Dermatol 66:466-469
quence and correlation. Most cases of penetration in 7. Bazex A, Dupre ET (1953) Apropos du sinus pilonidal. Bull
the skin are not associated with granuloma or fistula Soc Fr Dermatol Syphiligr 160:497
8. Oldfield MC (1956) Barber's interdigital pilonidal sinus.
and resolve spontaneously. Lancet 261:1244-1245
9. Bonnet, MW, Calas E, Florens A (1966) Cyste pilonidal du
Treatment troisieme espace interdigital chez un coiffeur. Bull Soc Fr
Dermatol Syphiligr 73:521-522
10. Currie AR, Gibson J, Goodall AL (1953) Interdigital sinuses of
Surgical treatment is required in chronic lesions with barbers' hands. Br J Surg 41:278-286
fistulization and abscessation. They must be excised 11. Rook K, Wilkinson DS, Ebling FJG (1968) Barbers' hair sinus.
Textbook of dermatology, voll. Blackwell, Oxford, p 328
with ample margins, and the wound is left to sponta- 12. Rockl H, Muller E (1957) Granulome und Fisteln durch Haare.
neously heal or is closed by means of flaps or other Derm Wochenschr 136:912-916
reconstructive techniques. Rather surprisingly, specific 13. Joseph HL, Gifford H (1954) Barber's interdigital pilonidal
sinus. The incidence, pathology and pathogenesis. Arch
references to this entity in hand-surgery textbooks are Dermatol 70:616-624
scarce. 14. Hunziker N, Orusco M, Pilotto P (1970) A case of "pilonidal
sinus" in a hairdresser. Dermatologica 140:385-389
15. Price SM, Popkin GL (1976) Barber's interdigital hair sinus.
Arch Dermatol 112:523-524
References 16. Yaffee HS (1964) Imbedded hair resembling larva migrans.
Arch Dermatol 76:254
17. Conde-Salazar L, Romero LV, Guimaraens D, Sanchez Yus E,
1. Conde-Salazar L, Baz W, Guimaraens D, Cannavo A (1995) Gonzalez M (1985) Fistula y tricogranuloma interdigital de los
Contact dermatitis in hairdressers: patch test results in 379 peluqueros (barber's hair sinus). Med Seguridad Trab 32:
hairdressers (1980-1993). Am J Contact Dermat 6:19-23 27-30
2. Rockl H, MuUer E (1957) Granulome und fisteln durch haare.
Derm Wochenschr 136:914
CHAPTER 100
Bartenders
L. Kanerva
Introduction 1994; Emonet et al. 1998), asthma (Myou et al. 1996),

anaphylactoid reactions (Kelso et al. 1990), and even
death from anaphylaxis (McCormick and Young 1995).
Bartenders serve alcoholic and nonalcoholic drinks.
Ophaswongse and Maibach (1994) have reviewed skin
They mix ingredients such as liquor, water, soda and
reactions resulting from drinking ethanol and other
sugar. They prepare cocktails, wine, draft or bottled
alcohol beverages. The allergen in alcohol may be
beer and other drinks. They collect payment, order
ethanol itself, an impurity, an aldehyde tllat is a
supplies, and arrange bottles and glasses to make bars
metabolite of the primary alcohol (Ophaswongse and
look attractive. They slice and pit fruits and prepare
Maibach 1994), a colouring agent (Kagi et al. 1994;
appetisers, such as nuts, meats and cheese. They wash
Wütrich et al. 1997), or additional substances.
and rinse glasses and utensils (Adams 1999).
Irritant dermatitis and monilial paronychia may be
common among bartenders (Adams 1999). Onlya few Irritants
cases of occupational allergic contact dermatitis have
been reported. Sonnex and Rycroft (1986) reported of a
bar manager who became sensitised to the o-benzyl-p- Alcohols
chlorophenol in a drinking-glass cleaner. Kanerva Bitters
et al. (1993) reported of a female bartender who Detergents
developed occupational allergic contact dermatitis Fruit juices
from nickel in metal alcohol measuring cups. Cardullo Germicidical agents
et al. (1989) reported abartender with hand dermatitis Soaps
who had allergic contact sensitivity to the skins of Water (wet work)
lemons, limes and oranges but not to their juices.
Usually, citrus peel allergy is due to D-limonene but, in Standard Allergens
Cardullo and coworker's patient, patch tests for
geraniol and citral, two components of citrus-peel oils,
were positive, whereas those for D-limonene were Balsam of Peru, 25% petrolatum (cross reacts witll
negative. Arecent series of patients with dermatitis, fiavorings) (Hjorth 1961)
who were allergic to oxidised D-limonene on patch Colophony, 20% petrolatum
testing, included four cases of occupational exposure Formaldehyde, 1% aqueous solution (disinfectants)
to fruits, fiavours, and vegetables and six who had Fragrance mix, 8% petrolatum
contact witll cleaning products, another source of D- Nickel sulphate, 5% petrolatum (Kanerva et al. 1993)
limonene exposure. Patients reacting to D-limonene Rubber allergens
often reacted to fragrance mix, balsam of Peru and
colophony in the standard series (Karlberg and Additional Allergens
Dooms-Goossens 1997). Carmine anaphylaxis from
campari orange is a putative occupational hazard for
bartenders (Kagi et al. 1994; Wütrich et al. 1997), as are o-Benzyl-p-chlorophenol, 1% petrolatum (bacteriocidal
other allergies to alcoholic beverages. Alcohols, in- drinking-glass cleaner) (Sonnex and Rycroft 1986)
cluding ethyl alcohol, have been reported to cause Carmine (immediate allergy) (Kagi et al. 1994; Wütrich
allergic contact dermatitis (Ophaswongse and Maibach et al. 1997)
1994; Patruno et al. 1994; Okazawa et al. 1998), urti- Cinnamon oil, 0.5% petrolatum (fiavourings, citrus
caria (Ting et al. 1988; Ophaswongse and Maibach rinds, vermouth, bitters) (Hjorth 1961)

Bartenders 825
Ethanol (various concentrations) (Ophaswongse and Kagi MK, Wüthrich B, Johansson SG (1994) Campari-Orange
Maibach 1994) anaphylaxis due to carmine allergy (letter). Lancet 344:60-61
Kanerva L, Estlander T, Jolanki R (1993) Occupational allergie
D-Limonene (oxidised 2% petrolatum) (Chang et al. contact dermatitis from nickel in bartender's metallic mea-
1997; Karlberg and Dooms-Goossens 1997) suring cup. Am J Contact Dermat 4:39-41
Fragrances Karlberg AT, Dooms-Goossens A (1997) Contact allergy to
oxidized D-limonene among dermatitis patients. Contact
Fruits and vegetables (delayed and immediate allergy) Dermatitis 36:201-206
Sodium-N-chloro-p-toluene sulfonamide, 1% petrol- Kelso JM, Keating MV, Squillace DL, O'Conneli EJ, Yunginger
atum (sanitiser for glasses) (Adams 1999) JW, Sachs MI (1990) Anaphylactoid reaction to ethanol. Ann
Allergy Asthma Immunol 64:452-454
McCormick GM II, Young DB (1995) Death caused by an allergie
reaction to ethanol. Am J Forensie Med Pathol 16:45-47
Myou S, Fujimura M, Nishi K, Watanabe K, Matsuda M, Ohka T,
Matsuda T (1996) Effect of ethanol on airway caliber and
References nonspecific bronchial responsiveness in patients with alco-
hol-induced asthma. Allergy 51:52-55
Okazawa H, Aihara M, Nagatani T, Nakajima H (1998) Allergie
Adams RM (1999) Bartenders. In: Adams RM (ed) Occupational contact dermatitis due to ethyl alcohol. Contact Dermatitis
skin disease, 3rd ed, W.B. Saunders Co, Philadelphia, 641-642 38:233
Cardullo AC, Ruszkowski AM, DeLeo VA (1989) Allergie contact Ophaswongse S, Maibach HI (1994) Alcohol dermatitis: allergie
dermatitis resulting from sensitivity to citrus peel, geraniol, contact dermatitis and contact urtiearia syndrome. A review.
and citral. J Am Acad Dermatol 21:395-397 Contact Dermatitis 30:1-6
Chang YC, Karlberg AT, Maibach HI (1997) Allergie contact Patruno C, Suppa F, Sarracco G, Balato N (1994) Allergie contact
dermatitis from oxidized D-limonene. Contact Dermatitis dermatitis due to ethyl alcohol. Contact Dermatitis 31:124
37:308-309 Sonnex TS, Rycroft RJG (1986) Allergie contact dermatitis from
Emonet S, Hogendijk S, Voegeli J, Eigenmann PA, Roux N, orthobenzyl parachlorophenol in a drinking glass cleaner.
Hauser C (1998) Ethanol-induced urtiearia: elevated tryptase Contact Dermatitis 14:247-248
levels after double-blind, placebo-controlled challenge. Der- Ting S, Rauls DO, Ashbaugh P, Mansfield LE (1988) Ethanol-
matology 197:181-182 induced urticaria: a case report. Ann Allergy 60:527-530
Hjorth N (1961) Eczematous allergy to balsams, allied perfumes, Wüthrieh B, Kagi MK, Stucker W (1997) Anaphylactic reactions
and flavoring agents. Copenhagen, Munksgaard to ingested carmine (E12o). Allergy 52:1133-1137
CHAPTER 101
Bath Attendants
A. Barbaud
Introduction conditioning. Combination of chlorine with carbonat-

ed molecules produces trihalomethanes. Both trihalo-
methanes and chloramines may be involved in
Bath attendants can work in indoor or outdoor
respiratory symptoms and eye irritation.
swimming facilities or, less frequently, at the seaside.
Irritative and allergic occupational dermatitis can be
Bromine
induced by water; disinfectants used in the pools, in
the showers or on the pool edges; or by sunscreens,
Brominated compounds, such as 1-bromo-J-chloro-s,
swimming clothes or equipment.
s-dimethyl-hydantoin, can be formed as solid sticks
which, when in contact with water, will release
bromine, chlorine and leave s,s-dimethyl-hydantoin.
Public Swimming Pools' Disinfection
These compounds are commercialised under the
tradenames of Di-halo, Aquabrome or Halobrome.
A few disinfectants, such as sodium hypochlorite and Pools' organic contaminants, such as urea and
chlorine, bromine or ozonization, are allowed in public creatinine, degrade these disinfectants into brom-
swimming pools. Hexamethylene biguanide polymer, amines, chloramines, organic bromine and chlorine
oxygen peroxide, quaternary ammonium compounds, compounds that can act as irritants. High levels of total
sodium pentachlorophenate and copper sulphate, bromine residues (Rycroft and Penny 198J) and/or an
which are used in private swimming pools, are not anomaly in the water balance, leading to an excessively
allowed in public swimming pools (Hartemann 1994). "soft" corrosive water, could enhance the irritant
potency of brominated disinfectants, explaining why
Free Chlorine irritancy appears to be more troublesome in certain
pools than others (Gould 198J). When bromides are
Free chlorine is transformed into active residual free added to water together with chlorination, brominated
chlorine (0.J-o.6 mg/I). Active free chlorine is not a trihalomethanes (also called haloforms) are found, e.g.
stable chemical substance. In outdoor swimming bromodichloromethane, dibromo-chloromethane or
pools, chlorine gets degraded by ultraviolet (UV) tribromomethane (Camman and Hübner 1995). These
radiation. It can be stabilised with adjunction of compounds are volatile and can come in contact with
isochlorocyanuric acids. Combined stabilised products the skin and/or be inhaled. Trichloromethane and
are commercialised under the name chlorocyanurates bromodichloromethane are present at quantifiable
or isochlorocyanurates. concentrations in the peripheral blood of bath atten-
Chlorination of swimming-pool water results in the dants (Camman and Hübner 1995).
formation of many chlorinated products. The most
frequent derivative is trichloromethane (chloroform) Ozonisation
(Camman and Hübner 1995). Combined with organic
nitrogenous compounds (urea, creatinine) generated Ozonisation has to be associated with a residual
by swimmers (sweat, urine), active free chlorine disinfectant (bromine or chlorine) that remains in
produces combined chlorine compounds, such as the pool.
chloramines, which are irritants. When residual free
chlorine levels are lower than O.J mg/I, chloramines Filtration
increase. To decrease chloramine irritant levels and
dissociate trichloramines, it is necessary to add chlo- Filtration is performed through filters with sand,
rine, to provide water renewal and to ensure good air membrane or diatomae (algae). Aluminium sulphate,

Bath Attendants 827
aluminium chloride or iron chloride can be added as negative results. These patch tests could give irritant
floculating agents (Hartemann 1994). To stabilise pH results even in control subjects (Morgan 1983). Patch
levels between 7.2 and 7.4, soda or chlorhydric acid can testing with swimming pool water yie1ded negative
be added. Thirty litres of fresh water per swimmer per results (Gould 1983; Morgan 1983). Conversely, Fitz-
day are necessary to ensure proper water renewal. gerald et al. (1995) observed positive results in reading
patch tests performed with Halobrome diluted at 1%
and 0.1% in water in three sensitised patients
Disinfection of Pool Edges Ö2 negative controls). Patch tests performed with
dimethyl-hydantoin, adegradation product of Halob-
rome, tested diluted at 1% in water, yielded negative
Sodium hypo chlorite, aldehydes, quaternary ammo-
patch-test results. Prick tests with Di-Halo (diluted at
nium compounds or Tego G (dodecylic aminoethyl-
1% in water and 1% in petrolatum) performed in one
glycine hydro chloride) can be used to clean or to
patient yielded negative results (Rycroft and Penny
disinfect pool edges, showers or pediluva.
1983). Leg and foot eczema induced by Tego G was
reported in a swimming trainer (Valsecchi et al. 1985).
Tego G, used to clean and disinfect bath and pools,
Dermatoses
gave positive patch-test results when tested at 0.1% and
1% diluted in water (10 negative controls).
In brominated and chlorinated pools, wetting, wetting Sodium hypochlorite is a disinfectant and antiseptic
and drying cycles, previous skin disease and dry skin with the brief and rapid action of chlorine. It can be
contribute to swimming-pool rashes and cutaneous used in pools and on pool edges. Hypochlorite
irritation. Dermatoses of swimmers or swimming solutions may be irritating to the skin. Sodium
instructors are more commonly seen in brominated hypochlorite sensitisation is rare but may occur. A
pools disinfected with 1-bromo-3-chloro-5,5-dimethyl- 43-year-old woman was reported to have developed a
hydantoin than in chlorinated pools (Gould 1983; severe bullous contact dermatitis on both arms while
Morgan 1983; Rycroft and Penny 1983; Fitzgerald et al. handling sodium hypochlorite (Osmundsen 1978).
1995). After visiting 19 brominated pools because of Patch tests performed with sodium hypochlorite
reports of rashes, Rycroft and Penny (1983) published a diluted at 0.5% in water (222 negative control patients)
study showing that at least 5% of the users of a pool had strong positive results and induced a severe flare-
treated with Di-Halo (1-bromo-3-chloro-5,5-dimethyl- up of the dermatitis. The patient avoided swimming
hydantoin) had experienced dermatoses, and high pools because the heavy smell of chlorine "makes her
proportions of the staff were affected. Rashes cleared ill". Van Joost et al. (1987) reported two cases of
when the pool was treated with asolid chlorine sodium hypochlorite contact dermatitis in housewives
disinfectant (Rycroft and Penny 1983). with positive patch-test results when tested diluted at
Reported adverse symptoms are soreness of the 1% in water with no irritative results in 107 negative
mouth, throat, vulva, female urethra and breasts, but controls. Hostynek et al. (1989) recommend that an
dermatoses have also been observed. Rashes may open skin test or a skin prick test for immediate-type
develop within 12 h after swimming. Itching is the reaction to sodium hypochlorite precede patch testing
initial and sometimes only symptom. Dermatoses are with 48-h occlusion. Aquagenic pruritus may also
mainly eczematous, with discoid and/or vesicular occur (Kligman et al. 1986; Bircher and Meier-Ruge
eczema, but pruritus, urticaria or pruritic rashes have 1988).
been also reported (Rycroft and Penny 1983; Fitzgerald Urticaria induced by swimming in pools can be a
et al. 1995). The frequency and duration of exposure cold-induced urticaria (Neittaanmäki 1985; Bentley
seem to be important factors, but so me swimmers 1993) or aquagenic urticaria (Sibbald et al. 1981;
develop the eruption after only short-re-exposure to Martinez-Escribano et al. 1997). However, one has to
the pool water (Morgan 1983). Prolonged showering keep in mind a possible sensitisation to chlorinated
with hot water then cold water after swimming could water if urticaria appears only after swimming in
reduce the intensity of the symptoms (Morgan 1983). chlorinated swimming-pool water and not after swim-
The mechanisms of dermatoses associated with ming in fresh water or after sea bathing. Neering (1977)
brominated pools are not elucidated. They could be and Fisher (1984) have observed contact urticarias
due to irritancy but maybe also to a true sensitisation. from chlorinated swimming-pool water. In one case,
Patch tests have been performed using commercialised Neering (1977) observed positive results of scratch tests
compounds containing 1-bromo-3-chloro-5,5-dimethyl- performed with chlorinated swimming-pool water (five
hydantoin crumbled to make a 1% suspension in water. negative controls). Patch tests performed with sodium
Rycroft and Penny (1983) performed such patch tests hypochlorite and CaOCI 2 , both diluted at 1% in water,
in one patient and Gould (1983) in 12 patients with had negative results on readings performed at 20 min,
828 A. Barbaud
60 min and 3 h, but patch tests had to be terminated a young man who practised training with palms in a
after 3 h of exposure because they induced urtiearia swimming pool.
and angioedema.
In one patient who had developed a pruritie
maculopapular rash while cleaning a bathroom with Infectious Dermatosis
a hypochlorite-containing product, open application
on the fore arm of sodium hypo chlorite diluted at 1%
Mycotic or viral contamination from pool edges may
in water induced an immediate urtiearial reaction
induce dermatophytosis or plantar warts. Atypieal
(Hostynek et al. 1989).
mycobacterial infections can provoke swimming-pool
Occupational contact urticaria due to chloramine T
granulomas (EI Baze and Ortonne 1991). Epidemie
has been reported by Dooms-Goossens et al. (1983),
follieulitis induced by Pseudomonas aeruginosa has
not in bath attendants but in a nurse who had
been described in swimming pools and whirlpools
occupational exposure with chloramine T contained
(Gustafson et al. 1983; Fox and Hambriek 1984).
in hospital disinfectants. A closed patch test performed
Inadequate disinfection of the water can lead to this
with chloramine T at 0.2% in water produced erythema
Pseudomonas folliculitis with a papulopustular rash,
and wheal formation at the 48-h reading (negative at
predominantly involving the buttocks, hips and axillae,
96 h). Patch tests performed with chloramine T diluted
appearing within 8-48 h after swimming in the pool.
at 1.5, 3, 6 and 12.5% in water had to be terminated after
Pseudomonas aeruginosa can be isolated from the skin
8 h because they induced a relapse of urtiearia. A 48-
lesions or from the water.
year-old hospital bath attendant developed occupa-
tional allergie contact urtiearia, with rhinitis and
sneezing, induced by a chloramine-T solution (Kanerva
Irritants
et al. 1997). Priek tests performed with chloramine T
combined with human serum albumin (HSA) diluted
at 1.5% or 1% in water gave positive results when Chlor amines, chlorinated compounds
compared with histamine as positive control and HSA Bromamines
or water as negative controls. Kanerva et al. (1997) Sodium hypo chlorite
emphasised that chloramine (NHzCI) and chloramine Pool and pool edge disinfectants (aldehydes, quater-
T (crystalline powder, containing 11.5-13% active nary ammonium compounds)
chlorine, used as a disinfectant in hospitals) are two Tego (dodecylic aminoethylglycine hydro chloride)
different chemieals.
Sensitisation
Other Causes of Contact Dermatitis
Urticarla
In outdoor swimming pools, sunscreens may induce
Cold"induced urtiearia
contact dermatitis or photosensitivity. Contact derma-
Aquagenie urtiearia
titis to dibutylthiourea in swimming goggles was
Contact urtiearia to chlorinated water
reported by Alomar and Vilaltella (1985). A 13-year-
old boy developed intense bilateral eyelid eczema while Scratch test with chlorinated swimming pool water
using black neoprene goggles. Patch tests performed (Neering 1977)?
with 1,3 diphenylthiourea and 1,3 dibutylthiourea both Open application test with sodium hypo chlorite at 10/0
diluted at 1% in petrolatum gave positive results. in water (Hostynek et al. 1989)?
Neoprene rubber-lined swim-goggle-induced perior- Patch test with chloramine 0.2% in water (Dooms-
bital leukoderma was observed in swimmers (Goette Goossens et al. 1983)?
1984). Aseries of patients with facial dermatitis,
induced by sensitisation to N-isopropyl-N-phenylpa-
raphenylenediamine (IPPD) contained in scuba-diver Contact Dermatitis
face masks, were described by Maibach (1975) and
Tuyps and Mitchell (1983). Patch tests performed with Sodium hypochlorite, 0.5% or 1% diluted in water
the rubber from the mask and IPPD diluted at 0.05% in (Osmundsen 1978; van Joost et al. 1987), with reading
petrolatum had positive results (Maibach 1975). Re- at 20 min or after performing an open application
current contact dermatitis due to sensitisation to IPPD test (Hostynek et al. 1989).
in swimming palms was reported by Mougeolle et al. Commercialised compounds containing 1-bromo-3-
(1984). Eczema was located on both ankles and heels in chloro-5,5-dimethyl-hydantoin crumbled to make a
Bath Attendants 829
1% suspension in water (Gould 1983; Rycroft and Fisher AA (1984) Dermatitis from chlorine and certain chlori-
Penny 1983; Fitzgerald et al. 1995). It can be irritant nated products. Cutis 33:20-24
Fitzgerald DA, Wilkinson SM, Bhaggoe R, Beck MH, English JSC
(Gould 1983). (1995) Spa pool dermatitis. Contact Dermatitis 33:53
Aldehydes (pool-edges disinfectants). Fox AB, Hambriek GW (1984) Recreationally associated Pseudo-
monas aeruginosa folliculitis. Report of an epidemie. Arch
Quaternary ammonium compounds (pool-edges dis- Dermatol 120:1304-1307
infectants). Goette DK (1984) Raccoon-like periorbital leukoderma from
Tego (dodecylic aminoethylglycine hydrochloride ) at contact with swim goggles. Contact Dermatitis 10:129-131
0.1 or 1% in water (pool-edges disinfectants) (Valsec- Gould DJ (1983) Dermatoses associated with brominated swim-
ming pools. BMJ 287:913
chi et al. 1985). Gustafson TL, Band JD, Hutcheson RH, Schaffner W (1983)
1,3 Diphenylthiourea at 1% in petrolatum (neoprene Pseudomonas folliculitis: an outbreak and review. Rev Infect
Dis 5:1-8
goggles; Alomar and Vilaltella 1985). Hartemann P (1994) Hygiene des piscines. Pathologies et
1,3 Dibutylthiourea at 1% in petrolatum (neoprene pn!vention. Concours Med 116:969-975
goggles; Alomar and Vilaltella 1985). Kanerva L, Alanko K, Estlander T, Sihvonen T, Jolanki R (1997)
IPPD, 0.1% in petrolatum (scuba diver face masks, Occupational allergie contact urtiearia from chloramine-T
solution. Contact Dermatitis 37:180-181
Maibach 1975; palms, Mougeolle et al. 1984). Kligman AM, Greaves MW, Steinman H (1986) Water-induced
Mercaptobenzothiazole, thiuram mix (rubber in swim- itching without cutaneous signs. Arch Dermatol 122:183-186
ming material or clothes). Hostynek n, Patrick E, Younger B, Maibach HI (1989) Hypo-
chlorite sensitivity in man. Contact Dermatitis 20:32-37
Used sunscreens and their preservatives, vehicles, Maibach H (1975) Scuba diver facial dermatitis: allergic contact
photoprotective agents (patch tests and photopatch- dermatitis to N-isopropyl-N-phenylparaphenylenediamine.
testing). Contact Dermatitis 1:330
Martinez-Escribano JA, Quecedo E, De la Cuadra I, Sanchez-
Pedreno P, Aliaga A (1997) Treatment of aquagenic urticaria
with PUVA and astemizole. J Am Acad Dermatol 36:118-119
Morgan JM (1983) Dermatoses associated with brominated
References swimming pools. BMJ 287:913
Mougeolle JM, Weber M, Beurey J (1984) Allergie aux palmes de
plongee. Lettre du GERDA 1:11
Alomar A, Vilaltella I (1985) Contact dermatitis to dibutylthiourea Neering H (1977) Contact urticaria from chlorinated swimming
in swimming goggles. Contact Dermatitis 13:348-349 pool water. Contact Dermatitis 3:279
Bentley B (1993) Cold-induced urticaria and angioedema: diag- Neittaanmäki H (1985) Cold urticaria. Clinieal findings in 220
nosis and management. Am J Emerg Med 11:43-46 patients. J Am Acad Dermatol 13:636-634
Bircher AI, Meier-Ruge W (1988) Aquagenie pruritus. Water- Osmundsen E (1978) Contact dermatitis due to sodium hypo-
induced activation of acetylcholinesterase. Arch Dermatol chlorite. Contact Dermatitis 4:177-178
124:84-89 Rycroft RJG, Penny PT (1983) Dermatoses associated with
Camman K, Hübner K (1995) Trihalomethane concentrations in brominated swimming pools. BMJ 287:462
swimmers' and bath attendants' blood and urine after Sibbald RG, Kobza Black A, Eady RAI, James M, Greaves MW
swimming or working in indoor swimming pools. Arch (1981) Aquagenic urticaria: evidence of cholinergic and
Environ Health 50:61-65 histaminergic basis. Br J Dermatol 105:297-302
Dooms-Goossens A, Gevers D, Mertens A, Vanderheyden D Tuyps E, Mitchell JC (1983) Scuba diver facial dermatitis. Contact
(1983) Allergie contact urtiearia due to chloramine. Contact Dermatitis 9:334-335
Dermatitis 9:319-320 Valsecchi R, Cassina GP, Migliori M, Seghizzi P, Cainelli T (1985)
EI Baze P, Ortonne JP (1991) Les infections et les dermatoses Tego dermatitis. Contact Dermatitis 12:230
acquises dans les piscines. Ann Dermatol Venereol 118: Van Joost Th, Habets JMW, Stoltz E, Geursen-Reitsma AM (1987)
973-977 Sodium hypo chlorite sensitization. Contact Dermatitis 16:114
CHAPTER 102
Batik Manufacturing Workers

R. W. Soebaryo
Introduction drawing, with a tool called batik printing block. Both

products, traditional batik which is handmade by
drawing with canting and the modern batik produced
Batik is an art developed in Java-Indonesia, especially
using printing block (Figs. 2, 3), are called batik; thus,
central Java and is the most famous textile of Indone-
these are recognized as the written batik or handmade
sia. At one time, batik was used exclusively by the
batik and printed batik. Nowadays, there is a trend for
noble families of Java, but it has recently enjoyed a
designing fabrics with batik motifs that are produced
wider popularity. Nowadays, batik is also produced in
in a textile factory.
various countries in Southeast Asia [1-3].
Batik products must be labeled according to cate-
The original meaning of the word batik is: the a~t of
go ries as handmade batik, printed bat~k, co~binati.on
drawing or writing on a piece of cloth, formerly Wlth a
handmade and printed batik, and batIk motIf textIle,
special tool called canting (wax applicator) (Fig. 1).
especially for consumer protection [3].
Batik is traditionally worn for attending ceremonies.
Batik workers can be divided into two categories, the
The technique, which allows the production of fine,
traditional batik worker and factory batik worker.
multi-colored designs, has a very old history in several
In order to study the risk of the development of
parts of Indonesia [3]. Formerly, women ~erfor~ed
occupational skin disease among the batik manufac-
most parts of the production process, and th1S creatIve
turing workers and make the comparison with textile
activity has a special place in the Indonesian cult~re.
workers, we have performed two studies in different
Modern technology widens the purpose of producmg
areas in Java. Soebono and co-workers performed the
batik or printed batik, such as for household products
study of traditional batik workers in Yogyakarta,
or as artistry [2, 3]. Through the development of
Central Java [7], while the study on textile factory
modern technology, the methods of producing batik
workers was done in Tangerang, West Java, by
have changed. The new technique allows more rapid
Soebaryo. These works are parts of the program for
Fig. 1. Canting (wax applicator) with one, two, and three nozzles Fig. 2. Waxing the printing blocks

Batik Manufacturing Workers 831
Fig. 3. Drawing the cloth with printing blocks
multicenter study of occupational skin disease organ-

ized by the Indonesian Occupational Skin Disease Fig. 4. Waxing the reversed side (nerusi)
Study Group.
extract from boiling rice (tajin is the local term) and

Traditional Batik Workers soga, which is an extract from a plant called Peltopho-
rum pterocarpum Backer (Papilionaceae family), giving
a yellowish color [I, 4l. After the coloring process is
Traditional Batik Process completed, the fabric is treated with hot water to
remove the wax, rinsed in clean water and dried. The
Originally, handmade batik was made on a piece of local term is nglorot or nglungsur for de-waxing
cotton cloth, but today, silk can also be used. For (Fig. 5), ngemplang for drying. The whole process is
printed batik, any kind of cloth can be used. There are then completed.
four steps, to be followed in order, in either the
handmade or the printed batik processing [1, 4l: Dyes Used tor Traditional Batik
1. Preparing the cloth
2. Drawing or blocking the cloth with batik wax The dye used are usually of plant-derived stuffs, such
3. Giving or filling with colors as the leaf, root, bark, or fiower, which are extracted
4. Removing the batik wax
In processing handmade batik, first, some equip-
ment are needed, such as a frame for hanging the cloth,
canting for drawing the batik motive, wax on a clay or
iron pan which is placed on a fire for continuous
melting, a fan for maintaining the fire and a low bank
for sitting on while drawing on the cloth [I, 4l. There
are stages in drawing and blocking which have to be
followed in order: drawing the outline (the local term is
mola), filling in the small parts which do not need to be
colored (the local term is ngiseni), doing the same for
the reversed side of the cloth (nerusi is the local term)
(Fig. 4), and waxing over the big parts and the reversed
side which do not need to be colored (nemboki is the
local term). For printed batik, a printing block with
batik motive design and a table are needed.
The second step is coloring. The local term used for
this step is mbabar. The dye used is usually derived
from a plant that is extracted through simple methods.
Among others are indigo (Indigofera), sugar cane or
molasses and lime or calcium oxide as additives, Fig. 5. Dewaxing the uncolored parts
832 RW. Soebaryo
using simple methods. The dye used the most is Synthetic dyes, such as indigo with different con-
indigo, blue in color, traditionally derived from several centrations (20%-80%), alizarin for red, auramine for
species of Indigofera. Usually it is used in a mixture yellow, naphthol for red and yellow, and aniline for
with other materials, such as sugar cane or molasses blue or black color, have replaced the traditional
and lime or calcium oxide as additives. Soga is a natural dyestuffs [1, 2, 4, 6). Examples of the synthetic
yellowish color which is derived from an extract of dyes used in batik processing are Brenta Soga
various sources, such as tea leaf, Peltophorum pter- produced by ICI, Naphthol as produced by Bayer,
ocarpum Backer [1, 4) or bark of Acacia auriculiformis and Anthrasol produced by Hoechst (4).
(5). The green color is derived from the extract of the Some of the stuffs used in batik processing have the
Ricinus spp. plant, yellow from extract of Saffront, and property of irritants or allergens. Wax and detergents
orange from extract of a certain flower called pulu are irritants, but dyestuffs usually have the property of
(Carthamus tinctorus) [1, 4). An example of a pre- allergens.
scription for a yellow color is mixing saffron with lime
(calcium oxide) immersed in water soaked with pulu Occupational Skin Disease
flower (Carthamus tinctorus). The proportion of each Among Traditional Batik Workers
ingredient depends on the yellow color desired. A
desired color could be the result of more than seven In Java island, especially in the middle part, hand made
different kinds of ingredients [1, 2, 4, 6). batik is still ahorne industry. Steps one, two, and three
Formerly, the professional dyers took the cloth to be of the batik process are usually carried out in the
dyed from the batik workshops or from women who worker's own horne, while the fourth step is done at a
had drawn the wax pattern at horne. Each dyer has his batik-collector's house.
own secret prescription and the dyeing process is done Soebono (7), from his survey done in three villages
with a ritual atmosphere and considerable competi- located in surrounding Yogyakarta (middle Java),
tion, since no two exact colors could be achieved. recorded ten of the most frequent skin diseases among
Certain preferences to traditional colors distinguish 175 traditional handmade batik workers, as shown in
batik from one region of Java or other islands in Fig.6.
Indonesia to another. Batik from middle Java usually Only 126 (72%) from a total of175 batik workers had
have dark blue, brown or white colors, while batik skin diseases. So me of them suffered from one type of
from west Java usually uses a rich ivory background in skin diseases (67 workers or 38.3%), 47 workers
alandscape motif (1). (26.8%) suffered from two types of skin diseases, and
another 12 workers (6.9%) suffered from three types of
Fig. 6. Skin diseases profile of traditional batik workers skin diseases. Callus, keratoderma palmo-plantaris,
I~
10
1 11 1
Callus Kerat p ontac Pitted Pit ver Prurigo topic Tinea Burns thers
0 19 18 14 11 0 8 5 5 4
Adapted from Soebono (1995) =

Kerat pal plan Keratodenna palmo-plantaris Pit versicolor =Pityriasis versicolor
Contact derm = Contact dermatitis Atopic & neuro = Atopic & neuro dennatitis
=
Pitted keratol Pitted keratolysis
contact dermatitis, pitted keratolysis and pitYrIaSIS dyestuff, including nickel, chrome and cobalt) as
versicolor were the five most common skin diseases shown in Table 1, proving the correct diagnosis and
found in this survey. Not all of those types of skin finding the cause by patch testing are compulsory,
diseases were really caused by the work itself. although it is not an easy task. Even when a dye as the
Among those 175 workers, 47 (26,9%) were suspected offending agent is recognized as the cause of allergie
to suffer from occupational skin diseases. Contact contact dermatitis, one may leam that the final color
dermatitis was the highest (51%), followed by bums may be constructed from a mixture of different kinds
(17%), then callus and tinea pedis (14.9%); only one of dyes. Determining the correct diagnosis and cause
worker suffered from miliaria (2.1%). are especially difficult when using a natural dyestuff
All the diagnoses were based on clinical perfor- because the exact proportion in the prescription used
mance. Soebono (1995) found that the prevalence of is usually not clear.
occupational skin disease among tradition al batik Many workers suffered from bums were due to the
workers at three villages surrounding Yogyakarta use of hot wax in preparing the cloth in traditional
(Indonesia) was quite high: 72% compared with the batik processing. Occupational bums could occur on
prevalence of dermatosis in urban and rural areas in feet or hands caused by handling hot liquids. Occupa-
Yogyakarta by the same investigator of around 45-45% tional bums amounted to 7.5% of 38,504 accidents of
[8], as shown in Fig. 7. It was highly suspected that the occupational origin in Korea [12]. The frequency of
higher prevalence was due to the handling of stuff in callus was quite high due to the use of certain tools in
batik processing. Occupational skin disease in tradi- the tradition al batik processing. Tinea pedis was found
tional batik processing occurred at the 26.9% level, in those working on the fourth stage, because this step
higher than the 18.9% in textile factory workers as is a wet procedure involving rinsing the cloth and
reported by Mathias [9] . Contact dermatitis reached removing the wax.
the highest frequency (51%) among occupational skin The traditional batik process is comprised of four
diseases in traditional batik workers. Irritant contact steps and usually workers perform more than one
dermatitis comprised 79.2% (19 workers) of the total step when preparing the batik. Mostly, workers do the
group of contact dermatitis (Fig. 8), while allergie first and the second steps in their own hornes, thus
contact dermatitis was only found in five workers being able to choose the most convenient time
(20.8%), confirmed by the usual rule that irritant (Fig. 9).
contact dermatitis was the most common form of The relationship between age and working duration
occupational skin disease with a proportion of 80% to with the occurrence of occupational skin disease is
the 20% of allergie contact dermatitis cases [10, 11]. presented in Table 2. Occupational skin disease was
Some agents used in batik processing act as an found more frequently in older workers (P < 0.05).
irritant, such as hot water, detergents, strong acids, Age could be a risk factor for occurrence of occupa-
and several salts. Whereas some agents are suspected tional skin disease in traditional batik workers. Anal-
to be allergens, such as dye-stuff (for example, indigo, ysis of some risk factors for the occurrence of
naphthol, azo, indanthren, and metals containing occupational skin disease pointed out the role of age
Fig. 7. Occupational dermatoses of traditional batik workers Fig. 8. Contact dermatitis (nail discoloration)
834 R.w. Soebaryo
Table 1. Agents suspected as irritants or allergens in traditional batik processing
Steps in batik Irritant Allergen Concentration (%) Comments

processing recommended for
patch testing [13, 14]
1. Preparation Hot water

Soda
Detergent
2. Drawing Hot wax Nickel-sulfate 5%aq.sol Papular and pustural reaction
5% pet Erythema multiforme-like contact dermatitis
Contact urtiearia
Cobalt-chloride 2%aq. sol Erythema multiforme-like contact dermatitis
1% pet Allergie contact granuloma
Contact urtiearia
Pemphigoid following chronic dermatitis
Copper-sulfate 5% aq. sol
3. Dyeing Indigo Ferro-sulfate 1
Caustie-soda Naphthol 1,2 0.1 % pet or 5% 00
Chloride acid Naphtol AS 5% aq or 0.1 % pet
Sulfates Azo 2% pet Cross-react with para-amino compounds
Natrium sulfate Indigo (blue) 5% pet
Natrium nitrite Indigosol (1)
Indanthrene (1)
4. Finishing Hot water
pet, petrolatum; 00, olive oil; aq., aqueous
in that natural protection declined with the increased Table 2. Relationship of age and duration of work to the
of the worker's age [13l. Working duration was occurrence of occupational skin disease in traditional batik
probably not a risk factor for occupational skin disease workers at three villages surrounding Yogyakarta (Indonesia) in
1995
in traditional batik workers (P > 0.05).
The probability of the role of several other risk Variable Occupational Non-occupational Total P
factors in the occurrence of skin disease was over- skin disease skin disease
looked, such as the occurrence of atopy, the use of
Age/year 45.2 ± 14.3 39.3 ± 14.1 40.8 ± 14.3 <0.05
protective devices, the different stages of the work, and Working 17.3 ± 12.6 16.4 ± 15.7 16.7 ± 14.9 >0.05
education, as seen in Table 3. duration
Atopy, whether occurring on its own among the (year)
tradition al batik workers or in his/her family members Adapted from Soebono (1995)
as a risk factor in relation to occupational skin disease
has not been confirmed - maybe because of the few
sampies used. There has been a perception that atopic other factors, such as avoiding the use of protective
individuals should not develop allergie contact derma- devices (OR 2.88; CI 1.33-6.25, considered as signifi-
titis as frequently as normal individuals [14], whereas cant) and working at the third and fourth steps (OR
r-requency Fig. 9. Stepwise work distribution among

traditional batik processing workers at
three villages surrounding Yogyakarta
(Indonesia) in 1995
• Step l. 1I
o Step l ll. IV
• All step
Adopted from Soebono (1995)

Table 3. Univariate analysis for risk factors of occupational skin textile factory in Tangerang, West Java, observed that
disease in traditional batik workers at three villages surrounding contact dermatitis was mostly found in tlte dyeing/
Yogyakarta (Indonesia) in 1995
printing seetion in the form ofhand dermatitis (27.0%)
Risk N Occupational Non-occu- OR (95% CI) or 2.4% of 288 workers who participated in the survey.
factors skin disease pational skin Of 288 workers, 265 (92%) had skin disease (Fig. 10).
(%) disease (%)
Such figures might be a result of tlte selection of the
Atopy 175 8.5 5.5 1.61 analyzed sections being high-risk sections for the
(0.37-6.54) occurrence of occupational skin disease. Not all skin
No-protection 175 42.9 20.6 2.88 diseases found were related to occupation [161.
( 1.33-6.25)
Step 1+2 111 17.1 52.9 Miliaria was the most common skin disease found in
Step 3+4 34 55.9 44.1 6.13 the survey. In the four sections (spinning, weaving,
(2.46-15.51) dyeing/printing and power) which were surveyed,
Education
None 46 32.6 67.4 environmental temperature was increased due to the
Prirnary 82 28.0 72.0 0.81 movement of the machines used. This condition might
(0.34-1.90) be related to the high occurrence of miliaria in this
Junior high 25 20.0 80.0 0.52
(0.14-1.85) survey. Santoso (1986) compared the working condi-
Senior high 22 19.0 81.1 0.46 tions in three different batik industries in middle Java
(0.11-1.81) and found that the temperature in the workplace
Adapted frorn Soebono (1995)
increased up to 29.6 °C, whereas tlte comfortable
temperature for working used to be 24-26 °C [171.
Contact dermatitis was found mostly among workers
6.13; CI 2.46-15.51, considered as significant) of the from the dyeing/printing section. Dye was tlte most
traditional batik process, could be considered as high common sensitizer in textile workers [14, 151 and azo
risk factors for the occurrence of occupational skin dyes, which were around 40% of all tlte textile dyes,
disease. Neglecting to use of any form of protection were among the common causes of contact dermatitis
because of the uncomfortable feeling when using them [151. Hausen and Brandao (1986) reported Disperse
might cause disadvantages, especially in the younger Blue 106 as a strong sensitizer for tlte occurrence of
workers. allergie contact dermatitis [181. When dassified by the
metltod in which they were applied in textiles, these
azo dyes were usually found in tlte disperse dass. Azo
dyes could also cause occupational pigmented contact
Fadory Batik Workers
dermatitis as reported by Fujimoto et al. [191. Proving
tlte offending agent by patch testing was not easy
Batik mass production is performed in factories, because one must have some familiarity with the
exactly like textile factories. The finished textile nomendature and standard sources of dye information
products are categorized as batik motif textile. In a used. The occurrence of Pityriasis versicolor and tinea
textile factory, carding, spinning, weaving, dyeing and kruris could also be due to excess perspiration because
finishing fabrics are automated, thus there is a minimal of tlte high environmental temperature.
skin contact with allergens or irritants. The most The relationship between length of working and age
important causes of contact dermatitis were dyes and group among batik factory workers can be seen in
resin finishes [14, 151. The main dye sensitizers in Table 4. Most workers were young adults between ages
textiles were azo and anthraquinone dyes. Azo dyes of 25 years and 34 years (60.2%) and distribution of
ac count for 40% of all textile dyes and may cross-react the length of work was almost equal from less than
witlt p-phenylendiamine. Potassium dichrornate, used 5 years to 15 years.
as mordant to fasten dye to the fabric, was responsible
for an epidemie of allergie contact dermatitis among Table 4. Relationship of duration of work to age arnong workers
workers in blanket manufacturing [151. Classification with skin disease in a textile factory in Tangerang, West Java
(Indonesia) 1993
of dye used in textile materials was usually made
according to the procedure involved in applying tlte Age (year) Duration of work (year)
dye or textile use rather tltan by their chemical
composition [10, 151. Some of the dyes could cause <5 5-10 11-15 >15 Total
either irritant or allergie contact dermatitis, while p- 15-24 23 7 30
phenylene diamine and Disperse Blue could identify 25-34 29 35 40 2 106
most cases of dye allergy [151. 35-45 4 12 21 37
>45 1 2 3
Soebaryo [161 in a survey done on several sections Total 52 47 52 25 176
(spinning, weaving, dyeing/printing, and power) in a
836 R.w. Soebaryo
Spinning Weaving
Miliaria
Neurodermatitis
33.7%
Tinea krusis
3.9%
Contact dermatitis Neurodermatitis \. Pityriasis versicolor
16.3% 18.4% 9.2%
ContaCl dermatitis
13.2%
Dyeing printing Power

" Neurodermatitis
11 .3%
Miliaria Neu rodermatitis ~
16.1% 17.8%
Contact dermatitis Contact dermatitis

50.0% Tinea krusis 5.9%
11 .3% Tinea krusis
Pityriasis versicolor 20.3%
11 .3%
Adopted from Soebaryo (1993) • Miliaria • Pityriasis versicolor

o NeurOdermatitis • Tinea krusis
• Comact dermatitis
Fig. 10. Five most common skin diseases among textile factory Medieine, University of Indonesia, for reviewing the manuscript.
workers in Tangerang, West Java (Indonesia) in 1993 Special thanks is due to the skillful technical assistance of Miss
Devieta Sari for word processing the manuscript.
Comparison of Traditional Batik Workers

References
and Factory Batik Workers Concerning
the Type of Occupational Skin Diseases
1. Hamzuri (1994) Classical Batik. Djambatan, Jakarta, Indone-
sia, pp 21-33
Similarities between traditional batik workers and 2. Gibbs J (1975) Batik unlimited. Watson-Guptill, New York,
factory batik workers concerning the type of occupa- pp 13-21
tional skin diseases have been observed in the surveys 3. Simanjuntak ES (ed) (1983) Does traditional Batik have a
future? A special report on the Batik industry. Prisma 27:
done by Soebono [7] and Soebaryo [16], the data, 82-92
which are summarized in Figs. 6 and 10. Miliaria took 4. Susanto SKS (1980) The art of Batik (in Indonesian). Batik
the first place among the factory batik workers, but not and Art Centre. Ministry of Trade, Indonesia, pp 5-23
5. Nurhayati (1997) Acacia Auriculiformis bark as batik
in traditional batik workers because of the differences processing dye. University of Syiah Kuala, Banda Aceh,
in working environments. Traditional batik was usu- Indonesia
ally done at horne, at a comfortable time and in 6. Nea S (1970) Batik design materials technique. Van Nostrand
Reinhold Co, New York, pp 63-67
comfortable conditions. The occurrence of contact 7. Soebono H et al. (1995) Occupational dermatoses among
dermatitis took the first place among traditional batik batik workers. A preliminary report (in Indonesian).
workers but only in the third place among factory Presented at the Indonesian Scientific Meeting of the on
Occupational Skin Disease, Jakarta, Indonesia
batik workers, with a higher prevalence for the 8. Hardyanto (1985) Morbidity of skin diseases of rural and
traditional batik workers. Dyes were the most offend- urban area in Yogyakarta, Indonesia (in Indonesian). Public
ing agents as seen in both studies. Close contact with Health Bull1:3-7
9. Mathias CGT (1988) Occupational dermatoses. In: Zens C (ed)
the dyes was often seen in traditional batik workers Occupational medicine. Principles and applications. Year
unlike in factory batik workers. Burns and tinea pedis, Book, Chicago, pp 132-161
which were seen among tradition al batik workers, were 10. Rietschel RL, Fowler JF {1995} Fisher's Contact Dermatitis.
Williams and Wilkins, Baltimore, pp 379-387
not found among factory batik workers because of the 11. Kanerva L, Jolanki R, Toikkannen J et al. (1995) Statistics on
use of working protection devices supplied by the occupational dermatoses in Finland. Curr Probl Dermatol
factory as recommended by the government. 23:28-40
12. Eun HC, Kim KC, Chi CW (1984) Occupational bums.
Acknowledgements. The author would like to thank Dr. Santoso 13. De Groot AC (1986) Test concentration & vehicles for 2800
Comain, DSc, Head of Laboratory of Immunology, Faculty of allergens patch testing. Elsevier, Amsterdam, pp 28-139
14. Rietschel RL, Fowler JF (1995) Fisher's Contact Dermatitis. 17. Santoso MS (1986) Occupational health and hygiene in
Williams and Wilkins, Baltimore, pp 979-1011 industry. A comparative study among Batik Solo, Batik
15. Marks JG, DeLeo VA (eds) (1997) Textile workers. In: Pekalongan, and Batik Yogyakarta (in Indonesian). Research
Contact and occupational dermatology. Mosby, St Louis, Centre University of Sebelas Maret, Solo, Indonesia
pp 347-350 18. Hausen BM, Brandao FM (1986) Disperse Blue 106, a strong
16. Soebaryo RW (1995) Occupational dermatoses in textile sensitizer. Contact Dermatitis 15:102-103
industry (in Indonesian). Presented at the Scientific Meeting 19. Fujimoto K, Hashimoto S, Kozuka T et al. (1985) Occupa-
of the Indonesian Medical Association for Occupational tional pigmented contact dermatitis from azo dyes. Contact
Health, Malang, East Java, Indonesia Dermatitis 12:15-17
CHAPTER 103
Battery Makers
M.H. Beck
Batteries are of many different types, but they all ies can also be used as small high-powered batteries.
produce an electric current via a circuit using a Lithium salts may be used as the electrolyte. Newer
positive electrode, a negative electrode and an electro- rechargeable batteries use a nickel salt as the positive
lyte acting as an ionic conductor. If the electrolyte is electrode and a metal hydride as the negative electrode,
liquid, the battery is called 'wet' and if it is a powder or with potassium hydroxide as the electrolyte.
paste it is called 'dry'. Some batteries are re-chargeable. The main potential risk of dermatitis in battery
Most wet batteries are lead acid with grids or plates makers is from a chemical burn, or irritant contact
of lead and lead oxide acting as electrodes. During lead dermatitis from the acid or alkaline electrolytes. The
oxide manufacture, significant heat is generated when finished fibreglass materials used in batteries are not
lead reacts with oxygen under controlled conditions. usually a problem, but there is a possibility of an
The grids have a paste of lead oxide and sulphuric acid irritant dust being produced if they are ground or cut.
applied. The paste mayaiso contain additives such as Talc dust may act as an irritant when the lead castings
barium sulphate, carbon black and polyester fibres. are taken out of the moulds, where it is used as a
The electrolyte is a solution of sulphuric acid and the release agent. Asphalt fumes are irritant and may
plates mayaiso have fibreglass sheet separating them. induce photosensitivity and actinic damage (Adams
Fibreglass may additionally be used in battery casings 1990). Skin disorders may be exacerbated by the heat
and, occasionally, asphalt is used as asealant. Flooded generated by furnaces used to melt down the ingots.
lead acid batteries have synthetic separators, e.g. Apart from nickel and mercury, most electrode
polyvinylchloride or polyethylene. There are also materials are unlikely to induce contact allergy.
alkaline cell batteries, which are different by having a Welding and soldering activities represent a potential
positive nickel oxide electrode, a negative iron elec- hazard for a contact allergy, from solder fluxes and
trode, and the electrolyte is usually potassium hydrox- chromate in welding rods. Rubber and leather protec-
ide. The iron electrode is replaced by cadmium in the tive clothing may induce contact allergy. It should be
nickel!cadmium cell, and zinc powder is used as the noted that rubber footwear will need to be worn in
anode and silver oxide as the cathode in a silverlzinc areas where there is a potential for electrolyte spillage
battery. on to the floor.
The traditional 'dry' Leclanche battery has a nega- Reports of skin problems in this industry are few.
tive electrode and casing of zinc, while the positive During a 4-year period, Epi-derm, a voluntary report-
electrode is a carbon rod surrounded by a mixture of ing service for occupational skin dis orders in the UK,
carbon and manganese dioxide. A mixed ammonium received 5932 reports of dermatitis, of which one was in
chloride and zinc chloride paste is the electrolyte. the battery industry. This was a case of nickel allergy in
Button batteries are used in hearing aids and watches, a welder working in battery production (N. Cherry,
etc., because of their small size. They often use zinc as personal communication).
the negative electrode and mercury oxide as the The medicalliterature has sparse reports. Excessive
positive, with an alkaline electrolyte such as potassium environmental heat in a Nigerian battery manufactur-
hydroxide. Newer technology allows a zinc anode and ers induced sweating and maceration of the skin,
atmospheric oxygen or silver oxide as the cathode especially over the anterior abdominal wall; this
material. Longer life has been achieved with a zinc predisposed five individuals wearing dark-coloured
anode and magnesium dioxide as the cathode and uniforms to clothing dermatitis. In the same report,
potassium hydroxide being used as the electrolyte one person working with bitumen developed an
(alkaline battery). Lithiumlmanganese dioxide batter- acneiform skin eruption (Olumide et al. 1983).

Battery Makers 839
Irritants Additional Allergens
Heat Mercury, 1% petrolatum

Sulphuric acid Mercuric chloride, 0.1% petrolatum
Zinc chloride Latex, as is
Potassium hydroxide Carba mix, 3% petrolatum
Sodium hydroxide Hydrazine (flux), 1% petrolatum
Fibreglass Coal tar (asphalt), 5% petrolatum
Tale
Asphalt (also phototoxic and acnegenic) Acknowledgements. I am grateful to Dr Jacques Tamin, Consul-
tant Occupational Physician, and Barry Kelley, Occupational
Hygienist, at Chloride Batteries, Manchester UK, for their help
with information for this chapter.
Standard Battery
References
Nickel sulphate, 5% petrolatum
Potassium dichromate, 0.5% petrolatum
Colophony (solder fiux), 20% petrolatum Adams R (1990) Occupational skin disease, 2nd edn. Saunders,
Philadelphia, p 631
2-Mercaptobenzothiazole, 2% petrolatum Olumide YM, Olera GU, Enu CC (1983) Cutaneous implications of
Mercapto mix, 2% petrolatum excessive heat in the work place. Contact Dermatitis 9:
Thiuram mix, 1% petrolatum 360-363
N-Isopropyl-N-phenyl-4-phenylene diamine, 0.1% pet-
rolatum
CHAPTER 104
Beekeepers
T. Karamfilov and P. Elsner
Beekeepers cultivate bees for the production of honey. ulin (Ig)G- and low serum levels of IgE-specific
Honey is principally a mixture of sugars deposited in antibodies [8]. Immunologically, they are like "spon-
the honeycomb by the honeybee, and it is used taneously desensitized subjects" [8]. The annual num-
principally as a food. Furthermore, the royal jelly from ber of stings is critieal because, when beekeepers
queen bee cells is used for cosmetics and as a food. receive less than 25 stings a year, the sensitization is
Beekeepers manually insert honeycombs into beehives. maximal, and when beekeepers receive more than 200
The beehives are placed near some source of nectar stings a year, the "desensitization" is optimal [7].
and pollen (clover fields, orchards). The hives are Both the presence of nasal or eye symptoms while
cleaned using various caustic solutions. working at hives and a history of beekeeping for less
Propolis (bee glue), a potent allergie sensitizer, is a than 15 years increase the risk of systemic bee-sting
dark yellowish-brown resinous substance with strong reactions. A his tory of atopy is associated with
adhesive properties. Mixed with wax, it is used by bees systemic reactions [9]. The prediction of allergie
to seal up the services in their hives. The color and reactions in beekeepers can be attempted by means
composition of propolis varies from area to area, of honeybee venom skin tests (prick and intracutane-
depending on its tree source. Propolis preparations are ous tests) and honeybee venom-specific IgE antibodies
available as powders, ointments and cosmetic moisture (radioallergosorbent test). When honeybee venom skin
creams. The beekeeper inevitably comes into contact tests are positive, most beekeepers have either a local
with it whenever he handles his hives or honey combs. or a systemic allergie reaction [7]. Honeybee venom-
Allergie contact dermatitis from propolis is an occu- specific IgE antibodies appeared to be less predictive of
pational hazard for beekeepers [1, 2]. The hands and either a local or a systemic allergie reaction [7].
arms are usually affected but, in so me cases, the Immuntherapy with honeybee venom is effective
eruption starts on the face and neck [2]. Swelling of the under optimal conditions, but many untoward sys-
face and eyelids is a conspicuous feature [2]. temic reactions are observed when venom doses are
Propolis contact allergy is not caused by one main increased [10]. Self application of bee stings after
allergen, but by several allergens varying in chemical stopping immunotherapy with honeybee venom is a
composition; the presence of these in propolis depends safe and successful way to maintain protection in
on the nature of the source plant and the place and beekeepers [11].
time of collection by the bees [3]. Studies have shown
that 1,1-dimethylallyl and 3-methyl-2-butenyl caffeic
acid ester are the strongest sensitizers [3-6]. Propolis Irritants
allergy today is seen mainly in individuals who use
propolis as bio-cosmeties and in self treatment of
Honey
various diseases [4].
Honeycombs
Beekeepers who are seasonal workers represent a
Pollen
high allergie risk population against Hymenoptera
Caustics
venoms because of their frequent exposure to bee
stings. The degree of sensitization ofbeekeepers against
honeybee venom is strongly related to the annual
Standard Allergens
number of stings [7]. If beekeepers are stung often, they
appear to be protected, whereas if beekeepers receive
few stings, they often present allergie symptoms [7]. Balsam of Peru, 25% petrolatum (pollen)
Individuals who are relatively "immune" to bee stings Cinnamic alcohol, 5% petrolatum (pollen)
are characterized by high serum levels of immunoglob- Colophony, 20% petrolatum

Beekeepers 841
Formaldehyde, 1% aqua (disinfectants) 2. Bunney MH (1968) Contaet dermatitis in beekeepers due to

2-Mercaptobenzathiole, 2% petrolatum (rubber gloves, propolis (bee glue). Br J Dermatol 80:17-23
3. Hegyui E, Suehy V, Nagy M (1990) Propolis allergy. Hautarzt
rubber protective clothing) 41:675-679
Carba mix, 3% petrolatum (rubber gloves) 4. Hausen BM, Wollenweber E, Senff H, et al. (1987) Propolis
p-Phenylenediamine mix (black rubber mix), 1% allergy (I). Origin, properties usage and literature review.
Contaet Dermatitis 17:163-170
petrolatum (rubber gloves) 5. Hausen BM, Wollenweber E, Senff H, et al. (1987) Propolis
Thiuram mix, 1% petrolatum (rubber gloves) allergy (II). The sensitizing properties of 1,l-dimethylallyl
Mercapto mix, 1% petrolatum (rubber gloves) eaffeic acid ester. Contaet Dermatitis 17:171-77
6. Hausen BM, Evers P, Stüwe HT, et al. (1992) Propolis allergy
p-tert-Butylphenol-formaldehyde res in, 1% petrolatum (IV). Studies with further sensitizers from propolis and
(leather gloves) eonstituents eommon to propolis, poplar buds and balsam of
Nickel(II) sulfate, 5% petrolatum (tools) Peru. Contaet Dermatitis 26:34-44
7. Bousquet J, Menardo JL, Aznar R, et al. (1984) Clinieal and
immunologie survey in beekeepers in relation to their
sensitization. J Allergy Clin Immunol 73:332-340
Additional Allergens 8. Light WC, Reisman RE, Shimizu M, et al. (1977) Clinieal
applieation of measurements of serum level of bee venom-
speeifie IgE and IgG. J Allergy Clin Immunol 59:247-253
9. Annila IT, Karjalainen ES, Annila PA, et al. (1996) Bee and
Propolis, 10% petrolatum wasp sting reaetions in eurrent beekeepers. Ann Allergy
Asthma Immunol 77:423-427
10. Bousquet J, Fontez A, Aznar R, et al. (1987) Combination of
References passive and aetive immunization in honeybee venom
immunotherpy. J Allergy Clin Immunol 79:947-954
11. Eieh-Wanger C, Müller UR (1997) Bienengiftallergie bei
1. Rothenborg HW (1967) Oeeupational dermatitis in a bee- Imkern. Allergoi J 6 [Suppl 1] :12-14
keeper due to poplar res ins in beeswax. Areh Dermatol
95:381-384
CHAPTER 105
Biotechnical Industry Workers

T. Tuomi
Introduction involved. It is essential both to study the work and

exposure history of the patient and to also do the
testing with a relevant selection of the raw materials,
Biotechnology is defined as utilization of microbial,
intermediate products, and waste materials.
plant or animal cells or parts of them in process
technology. Essentially, the biotechnological processes
are applied fermentation processes. Traditional bio-
technology consists of methods to make products, such
Applications of Biotechnological Processes
as beer, cheese and sour milk, by non-aseptic fermen-
tation [1, 2]. The commonly applied biotechnological Brewing is the largest bulk biotechnology industry.
processes are also waste-water treatment and biogas The materials used include malted and roasted badey,
production, which utilize the natural microbial content maize, rice, wheat, hops, enzymes, and fermentation
of the raw material, as weIl as traditional wine with Saccharomyces spp.
production with indigenous flora of the grapes. These Milk fermentation includes production of cheese,
traditional processes have been improved by exploiting yoghurt, buttermilk, and kefir, for example. The use of
progress in science and engineering, especially in enzymes is essential in making these fermented
advanced fermentation design and process control. products and the background of their individual flavor
The essential parts of the modern biotechnology are and structural properties.
recombinant DNA techniques, hybridoma technology, Ethanol production uses a large number of sub-
enzyme engineering, and protein engineering. The strates such as sugar cane, cassava, grain, straw, and
modern biotechnology is applied in many areas and cellulose in yeast fermentation. In addition to yeast,
the applications are increasing [3]. The research and other organisms capable of utilizing cellulose and
product development is active and, in addition, a stareh, for example, are used. Enzymes are used to
great deal of the allergie occupational diseases have convert feedstock to a fermentable substrate.
appeared particulady as a result of this rather than Enzyme production is a large-volume application of
from production itself. It is typical to this industry that biotechnology. The industrial enzymes are produced
the enterprises are small, whieh is unfavorable to the by bacterial or fungal fermentation for several pur-
gathering of epidemiological data on occupational poses.
diseases. In general, the biotechnology is, however, Single-cell proteins are produced mainly for animal
considered as a safe industry with regard to occupa- feed and food products and to utilize waste or side
tional diseases. products, such as molasses, milk whey, starchy wastes,
The complete description of the biotechnical indus- and sulfite liquor. There are a range of microorganisms
try is difficult. The number of the potential causative used for these purposes.
substances of skin dis orders is large and often char- Microbial polysaccharides, such as dextrans, algin-
acteristic to the particular process. The large amount ates, and xanthan, are produced for food, pharmaceu-
of proteins, carbohydrates, amino acids, vitamins, etc. tical, biochemical, and chemical industries.
containing raw materials and end products often Medical and diagnostic products, such as mono-
constitutes an unsolved source of allergens, irritants, clonal antibodies, insulin, interferon, various cell-line
and substances causing contact dermatitis [4]. The stimulating factors, anti-clotting agents, enzyme in-
investigation of the application areas and some of the hibitors, steroids, antibiotics as weIl as bacterial and
typical work tasks help, however, in diagnosing viral vaccines, are manufactured by means of aseptic
occupational dermatoses and solving the typical prob- fermentation from different raw materials by microbial
lems of how to find the causative agents or conditions and animal cell cultures.

Biotechnical Industry Workers 843
Other industrial fermentations include production Job Descriptions

of n-butanol, glycerol, acetic acid, citric acid, lactic
acid, amino acids, vitamins, methane, and antibiotics.
Several raw-materials are used, for example, starch A fermentation process starts with ceil growth on a
sources such as corn and wheat, sugars, molasses, and small scale and continues with bioreactors, which
maintain controilable environment to cell replication.
organic wastes.
The size of a fermentor can vary from being small to
being one with several tons of biomass. Leaks and
spills may occur and pose a health hazard to workers.
The general characteristic of the biotechnical produc-
Table 1. Enzymes in biotechnical industry tion process is that it is automatic and run by only few
process workers. The control of the process automa-
Reported effect on tion and the necessary control measurements are the
skin or airways
basic tasks of the personnel. The loading and feeding
Starch processing and baking of the raw materials into process, the packing of the
Alpha-amylase CA, CU, RA product, and the cleaning of the process equipment are
Amyloglucosidase RA
Glucose isomerase the work phases, in which skin and respiratory
Pullulanase exposure to irritants and allergens most probably
Beta-amylase occur. Process phases such as filtration and centrifu-
Proteases CA, RA
Lipoxygenases gation, which require manual work, may expose to
Phospholipase substances originated from process. The airborne
Pentosanase exposure to microbes and their metabolites as weil as
Dairy industry
Rennet other dust or liquid aerosol have often been suspected
Proteases CA, RA as a cause of contact dermatitis. Especially in the waste
Chymosin
Pepsin
Glucose isomerase
Lysozymes Table 2. Examples of chemical substances used in biotechnical
Peroxidase industry with suspected or stated adverse effects to skin (the list
is not complete)
Catalase
Phosphatases
Lipases RA Reported effect on
Superoxide dismutase skin or airways
Glucose oxidase
Papain CU, RA Acids
Ficin Acrylamide CA
Trypsin CU, RA Animal pro teins CU
Chymotrypsin RA Antibiotics CA, CU
Sulthydryl oxidase Antineoplastics and cytotoxins
Beta-l,4-galactosidases Azides
Lactase Cyanide salts
Food industry Cyanogen bromide
Pectinases Detergents
Amylases CA, CU, RA Dimethylsulfate
Pectinesterase Enzymes see Table 1
Cellulases CA, CU, RA Ethanolamines CA
Hemicellulases CA, CU, RA Ethidium bromide
Pectin glycosidase Ethylene oxide
Protein industry Ethylene diamine CU
Bacterial proteases Formaldehyde CU
Papain CU, RA Hormones
Pancreatic proteinase RA Hydrazine CA, RA
Animal feed industry Hydrofluoric acid
Cellulases CA, CU, RA Kathon GC CA
Hemicellulases CA, RA Natural rubber latex CU
Proteases CA, RA Microbes
Amylases CA, CU, RA Phenol
Phytase CU, RA Piperazine CA
Pharmaceutical industry Piperidine
Acylase Silanes
Chymotrypsin RA Stainless steel (chromium, nickel) CA, RA
Streptokinase Tetramethylene diamine
Trypsin CU, RA Vaccines
Urokinase Yeast
CA substance causing contact allergy; CU substance causing CA substance causing contact allergy; CU substance causing
contact urticaria; RA respiratory allergen contact urticaria; RA respiratory allergen
844 T. Tuomi: Biotechnical Industry Workers
handling in a biotechnology factory, the possibility of References

dermal exposure to process side products is high.
The number of chemical and biological substances 1. Collins CH, Beale AJ (eds) (1992) Safety in industrial micro-
capable of causing skin disorders is substantial, and an biology and biotechnology. Butterworth, Heinemann Ltd.
exhaustive list of them is difficult to compose. Data in Oxford, p 257
2. Ducatman AM, Liberman D (eds) (1991) The biotechnology
Tables 1 and 2 are gathered from the references listed industry. State of the art reviews. The biotechnology industry,
below [1-5]. vol. 6, no. 2, Hanley and Belfus, Philadelphia, p 326
3. Gerhartz W (ed) (1990) Enzymes in industry. Production and
applications. VCH Verlagsgesellschaft, Weinheim, p 321
4. WHO (1984) Health impact of biotechnology. Report on a
WHO working group. WHO, Copenhagen, p 62
5. Kanerva L, Brisman J (1997) Contact urticaria, dermatitis and
respiratory symptoms caused by enzymes. In: Amin S, Lahti A,
Maibach HI (eds) Contact urticaria syndrome. CRC Press LLC,
Boca Raton, pp 129-142
CHAPTER 106
Boat Builders
K. Tarvainen and L. Kanerva
Boats are made of fibre-glass-reinforced plastics, fire-retardant chemicals. The boat builders are exposed
plywood, boards of various wood, aluminium or steel. to solvents, particularly toluene, thermosetting resin
The typical boat building facility is small with few compounds, natural resins, styrene, acetone, organic
workers. Due to manual working methods, workers' peroxides, wood dust and fibrous glass (Brigham and
exposure to hazardous materials is increased (Brigham Landrigan 1985; Tarvainen et al. 1993b). During the
and Landrigan 1985; Tarvainen et al. 1993b). The construction of wooden boats, moulds, cabinets and
workers may take part in all work shifts, from the structural parts, boat builders do tasks of cabinet
preparing of moulds to the finishing operations and makers, mill workers or carpenters. They may trim
packing. In large plants, mill workers or cabinet joints, drill holes, by hands or machines, glue, fit and
makers construct decks, cabinets and their fitting. clamp parts, sand and scrape surfaces, stain, vamish or
However, usually all jobs are made in the same paint they also cut woods or other materials, shape
industry hall. Therefore, the workers can be exposed them with hand tools and join materials with nails,
to dust from other processes than they are actually screws or glue (Adams 1990).
involved with themselves. Irritant contact dermatitis in boat builders usually
The production of a fibre-glass boat begins with results from contact with glass fibre, sawdust during
preparation of a plastic mould using glass-fibre rein- sawing or sanding woods, plywood or hardened
forcements and unsaturated polyester (UP) resin in reinforced plastic products or hulls (Brigham and
successive layers. Mould depressions are filled with UP Landriganm 1985; Tarvainen et al. 1993b). Concomitant
cement made from res in and catalyst mixed by hand. exposure to solvents, resins and other chemicals
The hardened cement is sanded some minutes after increase irritation of the skin (Tarvainen et al. 1993b).
mixing (Tarvainen et al. 1993a). The san ding pro duces Allergic contact dermatitis can be caused by epoxy-
huge amounts of fine dust in the environment. A resin compounds (Tarvainen et al. 1995), UP resin
plastic boat hull is laminated over the mould which has (Liden et al. 1984; Tarvainen et al. 1993a, 1995) and
a converse shape. A release agent chemical and a chemicals used as accelerators (cobalt) (Boume and
pigmented polyester resin, known as a gel coat, are Milner 1963; Tarvainen et al. 1993b, 1995) or hardeners
applied by hand or by means of a sprayer system. (organic peroxides) (Boume and Milner 1963), as
Thereafter, altemating layers of catalysed resin and well as by p-tert-butylphenol formaldehyde resin
fibre glass are applied. After the hull has been built up (Tarvainen et al. 1993b) and various woods (Hausen
to a proper thickness, the mould is removed. The cured and Adams 1990). Natural rubber latex in protective
hull usually requires finis hing by sawing, san ding or gloves has caused occupational contact urticaria (Tar-
cutting. Finally, structural support pieces of the boat vainen et al. 1993b).
are added and the interiors are placed.
A plywood or wood boat can have a layer of glass
Irritants
fibre coat on the surface for water. For this, a fibre-
glass cloth and UP or epoxy resins are used. Epoxy
resins are frequently used for the coating of wood Abrasives (abrasive wheels, sandpaper)
boats, as well as for gluing. However, epoxy resins are Adhesives
used less than UP resins for building of glass-fibre Fungicides
boats (Tarvainen et al. 1995). Glass fibres
Most workers are involved in the preliminary Lacquers
treatment of moulds with a release agent and in the Paints
formulation of resins by mixing the basic resin with Plastic dust
solvent, curing agent, accelerator, filler, colour and Resins and catalysts

846 K. Tarvainen and L. Kanerva: Boat Builders
Sawdust Methyl diisocyanate, 1% petrolatum

Shellacs Phenol formaldehyde resin, 1% (adhesives)
Soaps and detergents Polyester resin monomer, 5% (lamination, cement
Solvents resin)
Styrene Polyester cement, hardened as is
Propylene glycol, 2% (varnishes)
Phthalic anhydride, 1% (polyester resin component)
Standard Allergens Resorcinol, 2% petrolatum (adhesives and glues)
Styrene, 1% (polyester resin cross-linker)
Toluenediisocyanate, 2% petrolatum
Carba mix, 3% petrolatum (rubber)
Turpentine, 1% olive oil (furniture polishes)
Colophony, 20% petrolatum (solder)
Urea-formaldehyde res in, 10% petrolatum (fibre board
Epoxy resin, 1% petrolatum (lamination resin, adhe-
glue)
sives)
Wood dusts, 10% petrolatum
Formaldehyde, 2% aqua (solvents, cleaners)
Tricresyl phosphate, 2% (plasticiser in resin systems)
2-Mercaptobenzothiazole, 1% petrolatum (rubber)
Triethylenetetramine, 0.5% petrolatum (epoxy resin
Mercapto mix, 1% (rubber)
catalyst)
Potassium dichromate, 0.5% petrolatum (primer
paints)
Paraphenylediamine free base 1% (rubber)
p-tert-Butylphenol formaldehyde resin, 1% petrolatum
(adhesives) References
Adams R (1990) Job descriptions with their irritants and

Additional Allergens allergens. Cabinetmakers and mill workers. Carpenters. In:
Adams R (ed) Occupational skin disease, 2 edn. Saunders,
Benzoylperoxide, 1% petrolatum (resin catalyst) Boume L, Milner F (1963) Polyester resin hazards. Br J Ind Med
20:100-109
Cobalt chloride, 1% petrolatum (polyester resin accel- Brigham CR, Landrigan PJ (1985) Safety and health in boat
erator) building and repair. Am J Ind Med 8:169-182
Dibutyl phthalate, 5% petrolatum (plasticiser in resin Hausen BM, Adams RM (1990) Woods. In: Adams RM (ed)
Occupational skin disease, 2nd edn. Saunders, Philadelphia,
systems) pp 524-536
Diethylene triamine, 1% petrolatum (epoxy resin Liden C, Löfström A, Storgards-Hatam K (1984) Contact allergy
catalyst) to unsaturated polyester in a boat builder. Contact Dermatitis
11:262-264
Dipentene, 1% (furniture polishes) Tarvainen K, Jolanki R, Estlander T (1993a) Occupational contact
p-tert-Butylcatechol, 0.5% petrolatum (inhibitor in allergy due to unsaturated polyester cements. Contact Der-
polyester res in) matitis 28:220-224
Tarvainen K, Jolanki R, Forsman-Grönholm L, Estlander T, Pfäffli
Hexamethylene diisocyanate, 0.1% P, Juntunen J, Kanerva L (1993b) Exposure, skin protection
Hydroquinone, 1% petrolatum (polyester resin inhib- and occupational skin diseases in the glass-fibre reinforced
itor) plastics industry. Contact Dermatitis 29:119-127
Tarvainen K, Kanerva L, Jolanki R, Estlander T (1995) Occupa-
Methyl ethyl ketone (MEK) peroxide, 1% petrolatum tional dermatoses from manufacture of plastic composite
(resin catalyst) products. Am J Contact Dermatitis 6:95-104
CHAPTER 107
Brake-Lining Workers
M.H. Beck
Specially formulated friction materials for brake blocks methods are widespread in the developing world, with
were first developed in 1897 by Herbert Frood in higher risk of direct skin contact and consequent risk
Chapel-en-Ie-Frith, Derbyshire in the UK (Harper of dermatitis. All the aforementioned materials will
1997). They were produced as a more effective substi- need to be introduced into mixers that deli ver material
tute for natural materials, such as wood, metal, leather that is shaped into a curve for drum brake linings and
and camel hair. They were originally designed to be flat pads for disc brakes. They are then cured under
used on horse-drawn quarry wagons, but usage spread temperature and pressure before being cut and ground
rapidly to most other vehicle types for which braking and then painted and cured again. The anti-corrosive
was needed. The development of the motorcar and paints will also often be phenolic resin-based and the
later the aeroplane extended their use. The friction coating takes place using a spray electrophoretic or
material is generally fixed to a backing, which is powder coating process. Rubber coating may be
usually steel, being curved in drum brakes and flat in applied to the back. Epoxy res ins are not generally
disc brakes. The linings are abrasive on the surface and used except to attach the wear indicators to the brake
act as a thermal barrier and must resist wear. The pads.
composition of the materials is essentially similar, Reported skin dis orders from irritants in brake-
although there may be variations for friction level, lining workers in the UK are relatively few. In a 4-year
strength, compressibility, density and noise reduction. period, Epi-derm - a voluntary reporting scheme for
In modern day production, the abrasive materials occupational dermatoses in the UK, received eight
are metal oxides, silicates and carbides. Graphites, reports of irritant contact dermatitis from fibreglass,
waxes, stearates and metal sulphides may be used as brake pad mixes and graphite (N. Cherry, personal
lubricants. The fibrous reinforcement used to be communication). The industry is aware that grindings
asbestos based, but, in many countries, use of this may produce abrasive partieies with a potential to
material has been abandoned and alternatives substi- induce contact dermatitis. Contact with abrasives and
tuted, including aramid, polyacrylonitrile, cellulose, fibreglass at the mixing stage means there is a potential
mineral fibre, carbon fibre, steel and glass. Nitrile, risk of irritant contact dermatitis here. Phenol form-
butyl and styrene-butadiene rubbers are used as soft aldehyde res in powder has been reported as an irritant
binders. Sulphur, lime, thiurams and mercaptans, as (Fregert 1980). Solvents may be used to clean and
well as plasticisers including phthalates, may be added degrease metal parts and may induce irritant contact
as accelerators or curing agents. Harder resin binders dermatitis, especially if a protective glove made from
are made from phenol formaldehyde resins (both inappropriate material is used, allowing the solvent to
Novolak and Resol) or cashew-nut shell oil res in. penetrate with subsequent occlusion against the skin.
Hexamethylenetetramine, formaldehyde and paraform- Epi-derm has received four reports of allergie
aldehyde may be used as hardeners. There is partic- contact dermatitis from phenol-formaldehyde res ins
ulate reinforcement with mica or vermiculite and metal and brake pad mixes (N. Cherry, personal communi-
powder. Metal powders, especially cop per, zinc and cation). The medicalliterature has very few reports of
tin, may be added. Naturally occurring fillers are used, dermatitis in the brake-lining industry. Phenol-form-
including barytes, limestone and china clay. Industrial aldehyde resin is the main potential allergen in the
methylated spirits, ethanol and acetone may be used as occupational environment. Cashew-nut shell oil is well
solvents. Furthermore, solvents including trichloroeth- recognised as an allergen, but the materials used in
ylene may be used to clean materials and equipment. brake linings rarely appear to sensitise. (Adams 1990).
Production in modern-day factories in the West is The species Anacardium occidentale pro duces cashew
largely automated and the potential for dermatitis is nuts. It is in the same family as poison ivy, oak and
consequently minimised, but traditional production sumac found in North America and elsewhere. Cross-

848 M.H. Beck
sensitisation between these plants and Anacardium testing. Chemotechnique provides the aforementioned
occidentale is weIl recognised (Lovell 1993). Modifica- PFRn-452, which is now called P-F-R 2, at 1% in
tion of phenol formaldehyde resin with cashew-nut oil petrolatum. As previously indicated, in our experi-
may mean there is a potential for the resulting cashew- ence, this particular resin seems to be better at
nut formaldehyde resin also to induce allergic contact identifying individuals with allergy to phenol-form-
sensitisation. There is one report in the literature of aldehyde resin.
simultaneous sensitisation of phenol-formaldehyde The related para-tertiary butylphenol-formaldehyde
resin, cashew-nut formaldehyde resin and cashew-nut resin is recommended by the European Environmental
oil affecting a laboratory technician at a brake-lining and Contact Dermatitis Research Group (EECDRG) for
company (Beck 1989). The dermatitis affected this standard series patch testing (Bruynzeel et al. 1995). It
individual in an exposure pattern. I have seen does not, however, reliably cross-react with phenol-
individuals (not in the brake-lining industry) with formaldehyde resin and is, therefore, not a good
phenol-formaldehyde resin allergy with dermatitis also marker for such allergy (Bruze 1985).
involving the genital area due to contamination of this
site.
Phenol formaldehyde res ins may be Resol or Nov- Irritants
alak, according to whether the resin is made with
excess formaldehyde under alkaline conditions, or
whether phenol predominates under acid conditions, Heat
respectively. Bruze, in his 1985 thesis, looked exten- Graphite
sively at phenol-formaldehyde resins, and he has Hard spicular fibres (glass fibre, ceramic fibres)
shown considerable heterogeneity in their allergenicity Abrasives (metal oxides, silicates, carbides)
according to the source and manufacture of the resin. Grindings
A number of methylol phenols and dihydroxylphenyl- Solvents including industrial methylated spirits, ace-
methanes were identified by him as contact sensitisers tone, ethanol, toluene and trichloroethylene
within the resins. Subsequent guinea-pig maximisation
testing showed 4kdihydroxy-(hydroxyethyl)-diphe-
nylmethanes were the most potent allergens. Wehave
Standard Allergens
both shown that one particular res in (PFRn-452
provided for us by Bruze) was superior to the resins
then available from the commercial patch-test allergen Mercaptobenzothiazole (2-MBT), 2% petrolatum
suppliers at identifying allergy (Bruze 1985; Beck 1989). Mercapto mix, 1% petrolatum
Formaldehyde itself mayaIso be present within the Thiuram mix, 1% petrolatum
resin mixture and is, consequently, a potential sen- N-Isopropyl-N-phenyl-4-diamine, 0.1% petrolatum
sitiser. Hardening is usually carried out with heat and Epoxy res in, 1% petrolatum
pressure in a press, or in an oven, but Novalak res ins Formaldehyde, 1% water
may need to be cured with formaldehyde, para-
formaldehyde or hexamethylenetetramine, which may
also sensitise.
The use of rubber chemicals and also their presence Other Allergens
in protective gloves means there is a possibility of
contact allergy from chemicals used in this material. Phenol-formaldehyde resin (Resol), 5% petrolatum
Epoxy resins do not te nd to be used in the pads Phenol-formaldehyde resin (Novalak), 5% petrolatum
themselves, but mention is made as they are used to PFR-2 (recommended), 1% petrolatum
attach wear indicators to the pads. Own resin (important), 1% and 5% petrolatum
It is recommended that patch tests are undertaken Cashew-nut-shell oil, 3% alcohol (Fisher 1986)
with the res in the patients actually handle themselves, Cashew-nut formaldehyde res in, 1% and 5% petrol-
in addition to those allergens available from com- atum
mercial sources. If an individual brings their own Hexamethylenetetramine, 2% petrolatum
res in, we test at 1% and 5% and in petrolatum and, if Dibutyl phthalate, 5% petrolatum
positives are identified, controls will need to be Latex, as is
tested. I have not seen any false positives, but Carba mix, 3% petrolatum
Kanerva et al. (1997) showed that phenol-formalde-
Acknowledgements. I am grateful to Dr Tim Goffe, Wendy
hyde res in tested at 1% and 5% in petrolatum could Turner OHD, Henry Ramczyk, Martin Redfern and Drue Turner
produce false-positive reactions on occasions. Hermal of Ferodo, Chapel en le Frith, UK, for their help with the
provides aResol and Novalak resin at 5% for patch information provided in this chapter.
Brake-Lining Workers 849
References Bruze M (1985) Contact sensitisers in resins based on phenol and

formaldehyde. Acta Derm Venereol Suppl (Stockh) 119:11-83
Fisher AA (1986) Appendix. In: Contact dermatitis. Lea and
Adams R (1990) Occupational skin disease, 2nd edn. Saunders, Febiger, Philadelphia, p 864
Philadelphia, p 594 Fregert S (1980) Irritant dermatitis from phenol formaldehyde
Beck MH (1989) Experiences of contact dermatitis associated with resin powder. Contact Dermatitis 6:493
phenol formaldehyde res ins. In: Frosch PI, Dooms-Goossens Harper GA (1997) Brakes and friction materials. Mechanical
A, Lachapelle J-M, Rycroft RJG, Scheper RJ (eds) Current Engineering Publications Ud, Bury St Edmunds UK, p 19
topics in dermatitis. Springer, Berlin Heidelberg New York, Kanerva L, Jolanki R, Estlander T (1997) Allergie and irritant
pp 374-376 patch test reactions to plastic and glue allergens. Contact
Bruynzeel DP, Andersen KE, Camarasa JG, Lachapelle J-M, Dermatitis 37:301-302
Menne T, White IR (1995) The European standard series. Lovell CR (1993) Poison ivy and poison oak dermatitis. In: Plants
Contact Dermatitis 33:145-148 and ilie skin. Blackwell, Oxford, p 112
CHAPTER 108
Butchers and Slaughterhouse Workers

N.K. Veien
Description of Exposures Allergens
Butchers and slaughterhouse workers are exposed to Delayed-Type Hypersensitivity

various kinds of meat, intestinal enzymes, microor-
ganisms, detergents, and water. The work is physically There are only sporadic reports of occupational
demanding, and cuts from knives are common. allergic contact dermatitis among butchers and
Although the use of protective steel gloves can reduce slaughterhouse workers. In one study, 2 of 48
the number of injuries, repetitive work strains muscles slaughterhouse workers had positive patch tests to
and tendons and may cause painful calluses on fingers the thiuram mixture, and 1 had a positive patch test to
and palms. Butchers who process meat to make nickel (Veien et al. 1986). Dalbergia latifolia wood,
sandwich meat, sausages, etc., are exposed to nitrites, used for a knife handle, caused interdigital dermatitis
other preservatives and spices in addition to the meat on the right hand of a butcher. Patch tests with
itself. shavings from the knife handle and with an extract of
the shavings in alcohol were positive (Fancalanci et al.
1984). Hjorth (1978) reported a case of suspected
Epidemiology nickel dermatitis associated with protective steel
gloves. Several similar cases of dermatitis on the left
wrist of right-handed slaughterhouse workers who
Halkier-S0rensen (1996) reviewed 16,668 registered wore a protective steel glove on the left hand have also
cases of occupational dermatoses in Denmark from been reported (Veien 1994). Sensitization in each case
1984 to 1991 and found that slaughterhouse workers was caused by nickel in the metal button used to keep
ranked ninth with 536 cases among 16,500 employees the glove in place.
(3.2%). The most important exposures listed for these A slaughterhouse worker developed allergic contact
slaughterhouse workers were foodstuffs, water, deter- dermatitis on the hands after contact with povidone
gents, protective equipment, and rubber. iodine used to disinfect cuts. A patch test with 10%
Kanerva et al. (1996) studied the cases of occupa- povidone-iodine solution (Betadine) was positive, and
tional contact urticaria registered in Finland from 1990 a use test was also positive (Lachapelle 1984).
to 1994. Butchers and sausage factory workers ranked
12th with 28.9 cases per 100,000 workers. Bakers
ranked first with 140.5 cases per 100,000 workers, and Immediate-Type Hypersensitivity
shop assistants ranked 29th with 2.1 cases per 100,000
workers. Of 100,000 employed persons, 28.9 butchers and
Of 527 workers in a poultry slaughterhouse, 343 sausage makers had contact urticaria (Kanerva et al.
(65.1%) had skin diseases. This included 283 of 386 1996). The specific cause of the urticaria among
(73%) who worked in direct contact with the poultry, butchers was not listed, but in nine of all 815 patients
compared with 2 of 39 (5.1%) office workers or with contact urticaria who participated in the study,
supervisors in the same industry. The most common the cause was pork. The study does not list the
skin problems were maceration and interdigital ero- occupation of these nine persons. Northern Europe is
sion, paronychion, pompholyx, and eczema and ony- an area in which there is large-scale production and
chomycosis (Hayashi et al. 1989). The dermatoses were consumption of pork. The studies mentioned here
caused mainly by the wet work, and a marked suggest that allergic contact urticaria caused by pork is
reduction in number of derma tos es was seen after rare even among persons with extensive occupational
implementation of a program to protect the hands. contact with this meat.

Butchers and Slaughterhouse Workers 851
A woman employed in a poultry slaughterhouse affect workers who are in contact with freshly
developed dermatitis on the hand and forearms. slaughtered, still warm pigs. It is at this time that
A prick test with chicken heart and muscle was evisceration takes place, and it is possible that
positive, and the patient had positive patch tests to enzymes in the gut provoke the development of
chicken heart and liver (Beck and Nissen 1982). Two irritant contact dermatitis. Following this initial
similar cases have been described (Harrington 1981). procedure, the meat is cooled, and further cutting is
Cow and pig blood caused contact urticaria in two done on cold meat. Irritant contact dermatitis is
male slaughterhouse employees. An open test with the much less common among slaughterhouse workers
blood products was positive after 15-20 min, and the who cut up cold meat.
reaction subsided after about 1 h (Göransson 1981). Culture for candida organisms from the interdigital
spaces of 111 workers in a meat processing plant in
Poland showed the presence of 42 strains of candida. It
Irritants was suggested that the candida organisms could
aggravate existing gut eczema (Niczyporuk and
Due to the wetness of their work and the extensive use Krajewska-Kulak 1990).
of detergents, irritant contact dermatitis is common
among butchers and slaughterhouse workers. Of 1039
Infections
patients with occupational dermatoses seen over a
period of 13 months by dermatologists in Jutland,
Denmark, 48 were slaughterhouse workers. Of these, Bacterial Infections
20 (42%) had irritant contact dermatitis, while only 3
had allergie contact dermatitis (Veien et al. 1986). Outbreaks of bacterial infections in pork processing
Hjorth (1978) described "gut eczema" among factories have shown that cuts on the skin made with
slaughterhouse workers who eviscerate pigs. This bone were the most common port of entry of infection
pruritic dermatitis is eruptive and vesicular and is (Barnham and Kerby 1981). Streptococcus pyogenes and
seen in the fingerwebs and on the dorsal aspects of the Staphylococcus aureus were the causative organisms.
hands and forearms (Fig. 1). It is most pronounced Nail-biting was suspected as one important cause of
among workers who are in contact with intestines and transmission of Staphylococcus aureus. Erythromycin-
mesenteric fat. In a cross-sectional study, this type of resistant Streptococcus pyogenes affected 46 of 194
dermatitis was seen in 22% of 144 slaughterhouse workers in an outbreak that lasted 7 months (Sims and
workers (Hansen and Petersen 1989). In this study, less Riordan 1996).
than half the patients with this dermatitis had positive Erysipeloid (Fig. 2) is traditionally linked to cuts from
reactions to prick tests, scratch-patch tests or patch bone. Seven persons employed in a quail processing
tests on stripped skin with mesenteric fat, small plant developed infections compatible with erysipeloid,
intestine and blood. These tests were not considered and Erysipelothix rhusiopathiae was cultured from the
useful in making a dia gnosis. affected birds (Mutalib et al. 1995). This microorganism
It is characteristic that most cases of irritant may be identified by the electron microscopy of a biopsy
contact dermatitis among pig slaughterhouse workers oflesional skin (Barnett et al. 1983).
Fig. 2. Erysipeloid. Note central puncture site - puncture made

Fig. 1. "Gut eczema" on the dorsal aspect of the right hand by bone
852 N.K. Veien
Viral Infections
Human papilloma virus type 7 (HPV 7) infections are

common among butchers, slaughterhouse workers and
poultry processing workers (Stehr-Green et al. 1993).
One study showed the period prevalence rate of hand
warts among workers who slaughtered cows and pigs
(72% and 60%, respectively) to be higher than among
textile workers (22%) and other meat-industry workers
(27%) (Jennings et al. 1984). Of 536 workers in a meat
processing plant, 23.8% had hand warts compared with
8.5% of 965 controls (De Peuter et al. 1977). Keefe et al.
(1994a) found hand warts in 33.3% of 240 slaughter-
house workers, in 34.1% of 246 butchers, in 19.5% of
308 engineering fitters and in 14.iYo of 292 office Fig. 3. Painful callus on the second finger of the right hand where
a knife handle presses against the skin
workers.
Keefe et al. (1994b) also found that 164 of 486 men
employed in six slaughterhouses and 103 retail and
wholesale butcheries had hand warts. Scrapings taken Mechanical Trauma
from the warts of 156 of the workers showed that 112
harbored HPV, 74 of them HPV7. There was no The slaughtering of animals is physically demanding,
clustering, suggesting human to human transmission. repetitive work that strains muscles and tendons (Kivi
Of 71 slaughterhouse workers in three slaughterhouses 1984). A constant, firm grip on the handle of a knife
in Saudi Arabia, 42% had warts. The occurrence of the can cause very painful calluses on the fingers (Fig. 3).
warts was related to contact with meat (Aziz et al. A firm grip on the skin or meat of an animal with the
1996). In Poland, it was shown that the incidence of hand not used for cutting can cause pressure onycho-
hand warts was low (9%) if the slaughterhouse was lysis on the first and second fingers on the hand in
automated, compared with 49.2% in slaughterhouses question.
in which work was largely manual (Jablonska et al.
1988).
Clinically, infection with HPV7 appears as warts, Irritants
usually on the hands. The mode of transmission
remains unclear (Melchers et al. 1993). Transmission
Wet work
from animals is unlikely as animal papilloma virus is
Soaps
host specific. One possible explanation of the high
Detergents
prevalence of warts among slaughterhouse workers
Meat
and butchers is that components of meat facilitate
Intestinal enzymes
replication of HPV7 in keratinized epithelium (Keefe
Microorganisms
et al. 1994a).
Nitrites
The suggestion that there may be an induction of
Other preservatives
lung cancer in persons with HPV7 infections is of so me
Spices
concern (Coggon et al. 1989; Benton 1994).
Standard allergens
Infestations
Nickel
In slaughterhouses, the pigs are kept in pens prior to Thiuram-mixture
slaughtering. Persons who care for the penned animals Other rubber additives
are exposed to scabies mites from the pigs (Parish and
Schwartzman 1993). One study showed that 30 of 46
Additional allergens
persons exposed to infected pigs developed pruritus
and skin lesions on their hands and legs (Chakrabarti
1990). Although different types of scabies mites are Hard wood such as Dalbergia latifolia in knife handles
morphologically indistinguishable, scabies mites are Povidone iodine
highly host specific (Arlian et al. 1996). Meat
Butchers and Slaughterhouse Workers 853
Blood Jablonska S, Obalek S, Golebiowska A, Favre M, Orth G (1988)

Spices, including onion and garlic Epidemiology of butchers' warts. Arch Dermatol Res
280[Suppl] :S24-S28
Jennings LC, Ross AD, Faoagali JL (1984) The prevalence ofwarts
on the hands of workers in a New Zealand slaughterhouse.
References N Z Med J 97:473-476
Kanerva L, Toikkanen 1, Jolanki R, Estlander T (1996) Statistieal
data on occupational contact urtiearia. Contact Dermatitis
Arlian LG, Morgan MS, Arends JJ (1996) Immunologie cross- 35:229-233
reactivity among various strains of Sarcoptes scabiei. Keefe M, Al-Ghamdi A, Coggon D, Maitland NJ, Egger P, Keefe
J Parasitol 82:66-72 CI, Carey A, Sanders CM (1994a) Cutaneous warts in
Aziz MA, Bahamdan K, Moneim MA (1996) Prevalence and risk butchers. Br J DermatoI130:9-14
factors for warts among slaughterhouse workers. East Afr Keefe M, Al-Ghamdi A, Coggon D, Maitland NJ, Egger P, Keefe
Med J 73:194-197 CI, Carey A, Sanders CM (1994b) Butchers' warts: no evidence
Barnett JH, Estes SA, Wirman JA, Morris RE, Staneck JL (1983) for person to person transmission of HPV7. Br J Dermatol
Erysipeloid. J Am Acad Dermatol 9:116-123 130:15-17
Barnham M, Kerby J (1981) Skin sepsis in meat handlers: Kivi P (1984) Rheumatic disorders of the upper limbs associated
observations on the causes of injury with special reference to with repetitive occupational tasks in Finland in 1975-1979.
bone. J Hyg 87:465-476 Scand J RheumatoI13:101-107
Beck H-I, Nissen BK (1982) Type I and type IV allergy to specific Lachapelle JM (1984) Occupational allergic contact dermatitis to
chieken organs. Contact Dermatitis 8:217-218 povidone-iodine. Contact Dermatitis 1l:189-190
Benton EC (1994) Warts in butchers - a cause for concern? Lancet Melchers W, de Mare S, Kuitert E, Galama 1, Walboomers J, van
343:1114 den Brule AJC (1993) Human papillomavirus and cutaneous
Chakrabarti A (1990) Pig handler's itch. Int J Dermatol 29: warts in meat handlers. J Clin Microbiol 31:2547-2549
205-206 Mutalib A, Keirs R, Austin F (1995) Erysipelas in quai! and
Coggon D, Pannett B, Pippard EC, Winter PD (1989) Lung cancer suspected erysipeloid in processing plant employees. Avian
in the meat industry. Br J Ind Med 46:188-191 Dis 39:191-193
de Peuter M, de Clercq B, Minette A, Lachapelle JM (1977) An Niczyporuk W, Krajewska-Kulak E (1990) Incidence and enzy-
epidemiologieal survey of virus warts of the hands among matie properties of yeast -like fungi. Examination of workers
butchers. Br J Dermatol 96:427-431 of various departments of the distriet meat-processing
Fancalanci S, Giorgini S, Gola M, Sertoli A (1984) Occupational industry in Bialystok. Przegl Dermatol 77:118-121
dermatitis in a butcher. Contact Dermatitis 1l:320-321 Parish LC, Schwartzman RM (1993) Zoonoses of dermatologieal
Göransson K (1981) Occupational contact urticaria to fresh cow interest. Semin Dermatol 12:57-64
and pig blood in slaughtermen. Contact Dermatitis 7:281-282 Sims P, Riordan T (1996) A prolonged outbreak of streptococcal
Halkier-S0rensen L (1996) Occupational skin diseases. Contact infection among workers at a meat plant. Public Health
Dermatitis 35[Suppl1]:1-120 1l0:81-84
Hansen KS, Petersen HO (1989) Protein contact dermatitis in Stehr-Green PA, Hewer P, Meekin GE, Judd LE (1993) The
slaughterhouse workers. Contact Dermatitis 21:221-224 aetiology and risk factors for warts among poultry processing
Harrington CI (1981) Chicken sensitivity. Contact Dermatitis workers. Int J Epidemiol 22:294-298
7:126 Veien NK (1994) Nickel sensitivity and occupational skin disease.
Hayashi M, Saitoh M, Fujii N, Suzuki Y, Nishiyama K, Asano S, Occup Med 9:81-95
Hayashi H (1989) Dermatoses among poultry slaughterhouse Veien NK, Heydenreich G, Kaaber K, Willumsen P (1986) Skin
workers. Am J Ind Med 15:601-605 diseases. Occupational skin diseases diagnosed by derma-
Hjorth N (1978) Gut eczema in slaughterhouse workers. Contact tologists in Jutland (in Danish). Arbejdsmi!j0fondet,
Dermatitis 4:49-52 Copenhagen
CHAPTER 109
Contact Dermatitis in Cabinet Makers

D. Cohen and J. Krant
Introduction shavings, such as sanding and shaping, are most likely

to promote contact dermatitis in the craftsman. This
explains the more prevalent clinical scenario of the
As taxonomy and science have advanced, we have
'airborne contact dermatitis' distribution, since der-
become more adept not only at identifying and
matitis due to woodworking is most commonly seen
classifying the woods that can cause health problems
on the face, neck, ehest, armpits, waistband, and groin
in general, but at clarifying the specific physical or
areas (Rook 1992). The incidence of occupational
chemical cause of the problem and developing meth-
disease among cabinet makers is unknown. The
ods for prevention and treatment. Though there are
literature abounds with case reports; however, no
reports in the literature of contact dermatitis related to
epidemiologie studies exist on this subject (Rook
the use of finished wood products, such as utensils,
1992). Among sanders in the Singapore furniture
bowls, musical instruments, and jewelry (Hausen and
industry, the prevalence of wood-dust-related occupa-
Rothenborg 1981; Fisher 1989), by far the majority of
tional skin disease was found to be 3.8% (Gan et al.
cases of wood-related skin disease occur in occupa-
1987).
tional settings. Cabinet makers may react to raw-wood
components, such as the bark, sapwood, or heartwood
(Woods and Calnan 1976), or to other elements, such
Contact Dermatitis to Woods
as lichens, liverworts, or insects living on the tree
(Rook 1992). In addition to the wood, exposures to
chemieals used as fungicides, preservatives, and fire- Contact with wood may cause a skin reaction through
retardants have been known to cause occupational chemical irritation, sensitization, or both. The sensi-
disease (Bach and Pedersen 1980; Johnsson et al. 1983; tizers found in different woods have largely been
Sinks et al. 1991). members of a few categories: quinones, terpenes,
Though there are many occupations leading to wood phenols, stilbenes, and other miscellaneous allergens.
exposure, thus placing workers, including lumberjacks, The most notorious group of wood sensitizers, the
sawrnill workers, and carpenters, at risk of skin quinones, includes the dalbergiones, the sensitizers
problems, this chapter will focus on occupational skin found in Dalbergia spp., such as Brazilian rosewood
disease seen in cabinet makers. Since they generally and cocobolo, and 2,6-dimethoxy-p-benzoquinone
work with prepared timber, cabinet makers have less (2,6-DMBQ), a sensitizer found in several wood
occupational exposure to leaves, bark, lichens, and species, including elm, oak, sucupira, and dry-zone
liverworts than lumberjacks. Exposures to wood pre- mahogany (Fig. 1). Quinones have been shown to have
servatives, paints, glues, lacquers, res ins, and other an antibacterial role in wood and have even been
chemie als occur with great alacrity, and the problems suspected to help protect trees from termites (Hausen
caused by these substances in the workplace will be 1978). The dalbergione component of the Dalbergia
reviewed along with the woods. woods has been reported to cross-react with other
Contact dermatitis comprises a large segment of quinones, such as primin in prim rose (Primula obcon-
reported occupational illnesses from wood exposure. ica), deoxylapachol in teak, lapachenole in peroba, and
Allergie contact dermatitis is rare among woodworkers mansonone A in mansonia.
and occurs more commonly with hardwoods than The terpenes include Ll-3-carene, seen in pine, and
softwoods. Pao ferro and Brazilian rosewood are the sesquiterpene lactones, found in the Frullania
potent sensitizers, and Brazilian box tree wood (Asp i- genus. Frullania includes liverworts, chamomile,
dosperma spp.) and teak are known to be both irritants mugwort, and other potential sensitizers that may be
and sensitizers. Procedures that produce fine dust or found on or around wood. ·Phenols include the

Contact Dermatitis in Cabinet Makers 855
Forturf, Termil, and Chlorothalonil, it was developed

to replace the more toxic pentachlorophenol, and is
itself a benzene derivative (Fig. 2). Among 20 workers
in one wooden-ware factory, 7 of the 14 workers who
had reactions to TCPN were shown to be allergie by
positive patch testing (Johnsson et al. 1983). Symptoms
in exposed workers included contact dermatitis, xero-
sis, thinning of skin particularly on the upper eyelid,
Fig. 1. Structure of 2,6-dimethoxy-p-benzoquinone and yellow discoloration of hands and feet. TCPN has
been shown to elicit positive reactions in those allergic
at patch-test concentrations of 0.01% in acetone, and at
pentadecylcatechols found in the Anacardiaceae fam-
ily. Stilbenes include the ohlorophorin of iroko wood 1% produced reactions in both of two non-allergic
and the coniferyl benzoate in balsam of Peru. Other control subjects in a 1980 case report (Bach and
Pedersen 1980).
allergens do not fall into any partieular category, such
as anthothecol in the Khaya spp. of mahogany. Many
woods have no identified allergens or the active
chemie als have not yet been isolated (Rook 1992). Glues, Paints, and Lacquers
Since there is no commonly accepted international
nomenclature for woods, their taxonomy is very
confusing. Often, the same wood will be referred to Epoxy resins, hardeners, diluents, and acrylate com-
by two or more common names and be placed into pound glues are frequently present in the cabinet
entirely different families or genera by botanists. maker's shop (Kanerva et al. 1995b). A 1995 review of
patch testing results in Helsinki showed that 6% of
Table 1 is a selective listing of the timbers most
subjects showed a positive patch test to at least one of a
commonly known to cause dermatitis within the
cabinet-making and woodworking industry, with series of plastic and glue allergens, emphasizing the
botanical and common names, origins, known aller- sensitizing potential of these chemicals (Tarvainen
gens, and testing regimens included where feasible. 1995).
Anaerobic acrylic sealants or cyanoacrylates are
known sensitizers, while the modified acrylic structural
adhesives that cure in air more rarely cause allergy.
Preservatives and Treatments
Tosti et al. (1993) reported of three carpenters, each of
whom became sensitized to wood paints and glues with
When building cabinets and other furniture items, butyl acrylate, 2-ethoxyethyl methacrylate, or a phth-
craftsmen contact materials such as fire retardants, late. Epoxy resin compounds are another commonly
glues, lacquers, and paints. Though most often the used group of adhesives, which contain resins (gener-
worker is aware of the substances he or she is using, ally included in patch-test screening batteries), hard-
there are often cases in which the wood may have been eners, and reactive diluents, as well as many other
previously treated with an unknown substance or in potentially harmful ingredients, such as tar, fillers,
whieh the exact constituents of the paint or glue may colorants, and other plastics.
not be familiar. For this reason, it is important to Epoxy compounds may also be found in wood
investigate not only the actual woods used, but all paints and lacquers, along with many other potentially
other chemicals in the workplace when occupational sensitizing or irritating ingredients. Another hardener,
disease is suspected. Table 2 comprises a listing of polyfunctional aziridine (PFA), is a "water-based
common chemicals associated with the cabinet-making cross-linker in 2-component paints, paint primers,
industry. lacquers, topcoats, and other protective coatings"
Wood is preserved with a number of potentially (Kanerva et al. 1995a). It has been reported to cause
toxie chemieals, such as coal tar creosote, pentachloro- occupational asthma, allergic rhinitis, and contact
phenol, and other polychlorinated aromatics, many of urticaria, as weIl as sensitization and dermatitis. Patch
whieh are known or suspected carcinogens (Randerath testing to 0.5% PFA is suggested in patients with
et al. 1996). Contact with fire-retardant wood was dermatitis in whom exposure to PF A has occurred
shown to cause an outbreak of contact dermatitis but (Kanerva et al. 1995c).
the exact chemical culprit was unidentified (Sinks et al. Paints and lacquers mayaiso contain a legion of
1991). Tetrachloroisophthalonitrile (TCPN) is a com- sensitizing chemicals such as chromates, cobalt, nickel,
monly used fungicide, which is often a 1% component isothiozolinone, thimerosal, tetramethylthiuram, form-
of wood preservatives in northern Europe. Sold under aldehyde, Balsam of Peru, and natural rosin, or
several brand names, including Nopocide, Daconil, colophony (Fisher 1995). Balsam of Peru, used in oil
856 D. (ohen and J. Krant
Table 1. The woods
Botanical name( s) Common name(s) Known allergene s) Patch-testing regimen Notes
North America
Pinaceae family Soft woods, allergy
more commonly seen
in carpenters or joiners
Pinus spp. Pine y-Pinene, ,1.-3-carene, 20% Sawdust in pet.
thunbergol
Picea spp. Spruce 20% Sawdust in pet.
Thuja plicata Western red cedar B-Thujaplicin 20% Sawdust in pet.
Pseudotsuga Douglas fir, Oregon pine 20% Sawdust in pet.
menziesii
Ulmus spp. Elm, poplar, tulip tree
Brya Ebenus DC Cocus Used in musical
instruments
Swietenia Ameriean mahoganies: Anthothecol, 2,6-DMBQ True mahoganies.
mahogani Cuban, West Indian, S. mahogani most prized,
Spanish Honduran most allergenic.
Symptoms include
mucosal irritation,
asthma, and nail
discoloration
Swietenia Honduran,
macrophylla Tabasco, baywood
Shorea family "Philippine Not true mahogany
mahogany": red,
white, yellow
lauan and "narra"
South America
Machaerium Pao ferro, iron wood (R)-3,4-Dimethoxydalbergione 1% and 10% Brazil. Irritant and
sc/eroxylum, Tu!. tree of Brazil, Sawdust in pet. allergie, used as
morado, san tos substitute for
palisander, Brazilian rosewood
caviuna vermelha
Apuleia leiocarpa; Grapia, tatajuba, Oxyayanins A and B, 10% Sawdust in pet. Wood retains toxicity after
Apuleia molaris crebianco giono, whieh are also found in drying; used for anti-snake
bagasse, garapia, movingui, from venom in Brazil
amarelao, ferro, whieh it is microscopieally
muirataua, red wood, indistinguishable
garapa
Dalbergia nigra Brazilian rosewood, R-4-methoxydalbergione wood dust; alcoholic Now rare, used in
Rio rosewood, obtusaquinone extract; R- or S-MD jewelry as weil as furniture
Bahia rosewood,
Jacaranda (pardol,
Palissandre bresic,
Rio-Palisander,
grenadilla, caviuana
Dalbergia retusa Cocobolo Obtusaquinone; 1% and 10% in pet. Not same as coccoloba,
incidence of cocus, or Cocos genus;
dermatitis 10-30% used for instruments
and billiard cues
Bignoniaceae family
Paratecoma peroba White peroba, Lapachenole 10% Sawdust in pet. Brazil. Teak substitute
peroba jaune, ip with irritant properties
peroba, peroba de
campos, peroba
branca, peroba
amarella
Tabeuia spp. Lapacho, ip, Lapachol, lapachonone 10% Sawdust in pet. Dust penetration is
suayacan, mayflower especially painful
and irritating
Bowdichia nitida Sucupira, Bowdichione, 2,6-DMBQ Sawdust ether Heavy construciton:
sieopira, sebipira extract patch; floors, joists, railroad.
hydroquinone patch Will cross-react with
Dalbergia spp.
Cordia decandra Zerieote Cordiachromes 1% or 10% in pet. South America and Afriea.
A, B, E, F are sensi tizers Also used for boatbuilding
and interior construction
Cordia spp. Becote
Contact Dermatitis in Cabinet Makers 857
Table 1. (Contd.)
Botanical name(s) Common name(s) Known allergen(s) Patch-testing regimen Notes
Africa
ChiDrophora Iroko, African Ohlorophorin 10% Sawdust in pet. Irritant, may cause
excelsa teak, African oak, dishydrotic hand and foot
rokko, kambala, swamp eczema and erythematous
mahogany, rock elm, lesions as weil as
West African dermatitis
mulberry, bush oak
Khaya anthotheca; African mahoganies: Anthothecol, 2,6-DMBQ 10% Sawdust in pet. True mahoganies.
K. ivorensis white, dry zone, K. ivorensis most common
and big leaf mahogany mahogany in U.S.
Same symptoms as
American mahoganies
Distemonanthus Movingui, Oxyayanins A and B

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Part 1

Epidemiology, Treatment, and Prognosis

Prof. Jan E. Wahlberg, M.D., Ph.D. Prof. Howard I. Maibach, M.D.

ISBN 978-3-662-07679-8 ISBN 978-3-662-07677-4 (eBook)

Library of Congress Catatoging in-Publication Data

Part 1: Epidemiology. Treatment, Oeeupational Marks ......................... 137

Other Metals ............................... 551 Woods .................................... 771

Carpenters ................................. 868 Forestry Workers ............................ 938

Cheese Makers .............................. 880 Gardeners .................................. 952

Chemists .................................. 882 Glass Workers .............................. 956

Construction Workers ........................ 890 Health Care Workers ......................... 969

Cosmetologists ............................. 893 Highway Construction Workers ................ 974

Military Personnei .......................... 1007 Reindeer Herding .......................... 1086

Musicians ................................. 1015 Shoe Manufacturers and Repairers ............ 1094

Office Workers ............................. 1018 Silk-Screen Workers ........................ 1096

Oil-Rig Workers ............................ 1021 Stonemasons .............................. 1099

Operating-Room Staff ....................... 1028 Sugar Artists .............................. 1102

Pitch Workers .............................. 1060 Part 4: Chemistry and Concentrations

Professional Sports: Patch-Test Concentrations and Vehicles

Railroad Shop Workers ...................... 1084 Subject Index .............................. 1281

Kristiina Alanko, MD David A. Basketter Dr. Anders Boman, Med Sei

Dr. Eva Larmi, MD, PhD Woraphong Manuskiatti Giorgio Pasolini

Dr. Anne Schmidt Kyllikki Tarvainen, MD, PhD Wolfgang Uter, MD

Prof. Achille Sertoli, MD Department of Dermatology biso

Elizabeth Wolff Dr. Britta Wulfhorst, MD H. Zhai, M.D.

The Epidemiology of Occupational Contact Dermatitis

L. Kanerva et al. (ed.), Handbook of Occupational Dermatology

Type of errors Reasons

Misclassification Overlap between allergie and irritant contact dermatitis

No medical attention Table 3. Siek-leave, medical consultation due to "work-related"

Table 4. Prevalence of hand eczema in population-based studies (selection)

Country Method of case No.of Measures of Prevalence of hand eczema (%)

Netherlands (Coenraads et al. 1983; E 3140 3 years 4.6 8.0 6.2*

E dermatological examination; Q questionnaire

Fig. 3. Median of age and median of

Induction period (median)

Baker Confectioner Cook Total

No. of employees 5611 3691 23,252 32,554

Dichromate Fig. 5. Distribution of delayed-type sensitiza-

Table 9. Key points of determi-

The Role of Clinical Epidemiology

Introduction efficient methods of monitoring the frequency of

L. Kanerva et al. (ed.), Handbook of Occupational Dermatology

Health service workers

Men Women Total Men Women Total

Potassium dichromate 0.7 0.3 0.5 1.9 2.7 2.4

Occupation percent of 4.397

Cleaning personnel '~'i," __ :.- '_ - ._ 4.0

Dental technicians 2.2

Dental nurses 1.8

Pain ters 1.2

Allergen 1992 1993 1994 1995 1996

Population Allergen Test Number % Positive

Unselected Turpentine 1997 7.917 3.1

* MDBGNIPE methyldibromoglutonitril-phenoxyethanol after an increase of test concentration from 0.5% to 1%

Demographie Determinants of Sensitization Analysis of Oeeupational (auses of Sensitization

With formaldehyde Without formaldehyde With formaldehyde Without formaldehyde

n % positive n % positive n % positive n % positive

••i~ --- - ----

8~ , -, -L -- ,__- ,- L