j, Soc.Cosmet.

Chem.,35, 391-410 (December1984)

Cutaneousirritationand inhibitionof galvanicskin

responsemeasuredelectrometrically in humanforearm
skinafter topicalapplicationsof metal-saltantiperspirants

G. P. SERBAN,* S. M. HENRY, G. L. COHEN, and

V. F. COTTY, Researchand Development Laboratories,
Bristol-Myers
Products,
1350 LibertyAven•e,Hillside, NJ 07207.

ReceivedJ•ly
11, 1984.

Synopsis
Skin resistance
(R) and capacitance(C) weremeasured as a functionof time afterexperimental exposure
to antiperspirants.
The changes in the two electricalparametersin relationto anidrosis
and irritancyare
analyzedin this report.
Exposureto 15% aqueous
aluminumchloridefor a few hourscaused an increase
in the skinresistance
baseline
anda markedreductionin the amplitudeof galvanicskinresponse(GSR)evokedby hyperven-
tilation.The effectwasdueto inhibitionof sweatingasdeterminedbymeansofevaporimetry,
iontophoresis
of methylene
blue,andcontrolexperiments with scopolamine.
Reduced
GSRamplitude wasalsodetected
in skinseverely
irritated(seebelow)with antiperspirants.
Heterogeneity
in thesensitivity
of sweatglands
to the saltsmay accountfor the persistence
of GSR in the damagedsites.
Prolonged
exposure
to antiperspirants
resulted
in a graduallossof impedance
(Z) whichinitiallyoccurred
in the absence
of visibleirritation. A correlationwasfoundbetweenthe earlydecrease
in Z and the ability
of antiperspirants
to produce
clinicalirritation.With the electrometric
procedure,
slightdifferences
be-
tweentwo formulaeweredetectedin a few daysusinga smallnumberof humansubjects.
The patternof changesin R andC observed duringthe inductionof irritationby antiperspirantswas
reproducedin normalskin by repeatedlyperforatingit with a fine needlebut not by tapestripping.
Iontophoresis
of methyleneblueperformed in antiperspirant-irritated
skinin vivofollowed by histological
examinationof biopsyspecimensrevealed
the presenceof damageto the intracorneal portionof the sweat
ducts.The bulk of the keratinaceous
matrixandthe corresponding
viableepidermisremainmicroscopically
unaffected.
This findingexplains
the similarities
in the patternof currentflowobserved
betweenneedle-
puncturedandantiperspirant-irritated
skin.

INTRODUCTION

Topicaluseof preparations containingaluminumand othermetal saltsproduces an

inhibitionof sweatglandfunctions aswell assomeincidence of skinirritation(1). For
investigationalpurposesbothof theseeffectshaveconveniently beeninducedby ap-
plyingthe testsolutionsunderocclusivepatches. Undersuchconditions, inhibitionof
sweatingis detectablein lessthan one hour (2), while prolongedcontactwith the
respectivepreparation
will eventually
resultin clinicalirritation(1). Usingthismethod
of applicationin combination
with semi-quantitativemethods, a numberof conclusions

* Presentaddress:
Clairol Inc., 1 BlachleyRoad, Stamford,CT 06922.

391
392 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

havebeenmade concerningthe anidrotic(2-4) and irritant (1,3) effectsof metal salt

antiperspirants.
Electrometrictechniqueshavebeenusedin the pastto detectchangesin eccrinesweat
gland activity (5) and skin damageproducedby topicalapplicationof differentdrugs
andotherchemicals (6). The basisfor theseexperimentalapproaches hasbeenreviewed
elsewhere(7,8). The presentwork was conductedin order to (a) observethe changes
in the resistiveand dielectricpropertiesof skin as a functionof time after application
of saltsunderocclusivepatchesand (b) determineif the changesrelateto the antiper-
spirant and irritant effectsof thesesalts.
The saltsare strongelectrolytes which are known(1) to bind firmly to keratin, oneof
the major macromolecular speciesresponsiblefor the (electrical)barrier characteristics
of epidermis.It is alsoknown (2,3) that thesesaltsform polymericprecipitateswithin
the distal segmentof the sweatducts.The main concernduring the presentinvesti-
gation was that metal complexes,as well as free metal ions expectedto be presentin
the testsites,may influencethe electricalmeasurements, therebyobscuringthe param-
etersof interest, especiallyirritation. For thesereasonsa number of approaches were
usedin an attempt to relate the electricalchangesoccurringduring the inductionof
damageto anatomicalevidenceof injury. With someof the formulations,regression
analyses weredoneto test for correlationbetweenthe electricalchanges and the degree
of irritation evaluatedsubjectively.Methyleneblue was applied iontophoretically to
selectedtest sitesin order to visualizewithin them changesin the pattern of current
flow. In normal skin, current flow of maximum densityoccursvia the sweatducts.
This resultsin the formationof visibledyedepositspredominantlywithin the epidermal
portion of the sweatglands (9). The possibilitythat exposureto antiperspirantsalts
may alter the normaliontophoretic patternduringboth the anidroticand irritatedstate
wassuggestedby the natureof the electricalchangesand by work reportedby others
(10). Sectionsof biopsyspecimens from sitesshowingan increasein the stainingpattern
wereexaminedmicroscopically to verifythe presence
of tissuedamageandto determine
its anatomical location.

Basedon this work, evidenceis presentedthat electricalmeasurements can be usedto

observeinhibition of sweatingin humanforearmskin, in agreementwith resultsob-
tained by others in foot pads of mice (11), and to test the irritation potential of
antiperspirantsalts.We alsoshowthat irritation with thesesaltsis secondary
to damage
to the epidermalportion of the sweatducts. The bulk of the cornealmatrix and the
corresponding underlyingepidermalcellsremainunaffected,basedon grosshistological
examination.An analysisof the resistiveand dielectriccharacteristics specificto this
type of epidermalinjury is made.

MATERIALS AND METHODS

INSTRUMENTATION AND ELECTRODE PLACEMENT

A Hewlett-Packard
© (Model4262A) capacitance-resistance
metergenerating1.5 volts
acrossthe terminalsand setto a frequency(f) of 100 Hz wasusedto take measurements.
The meter was interfacedwith a Hewlett-Packard
© microcomputer
(Model HP85)
programmedto controlthe meterand to calculateimpedance(Z), phaseangle(!3),and
 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE 39.3

capacitativereactance(Xc) from the primary resistance(R) and capacitance(C) values

as follows:

Z = (R2 + Xc2)•/2Ohms,
0 = arctanXc/R degreesand X c = 1/(2 w fC)Ohms
The data were printed as collected.
The test electrodeconsistedof a plastic cylinder (internal diameter 18 min., slightly
smaller than test area) affixed to the forearm with elastic bands and filled with isotonic
salinesolutionprior to startinga measurement.Approximatelyfifteen secondselapsed
betweenplacing the solutionin the cup and the applicationof externalcurrent. A
narrowstrip of aluminum attachedverticallyto the inner wall of the cylindermade
electricalcontactbetweenthe solutionand the test lead. The referenceelectrode,a strip
of aluminumfoil foldedto eliminatesharpedges,washeld by the subjectbetweenthe
tongue and the palate. The placementof the referenceelectrodein contactwith the
oral mucosa,in which the resistance is very low and constantin comparisonto skin,
improvesthe sensitivityof the measurements. The placementof the two electrodesin
relation to one anotherensurescurrent flow through the entire thicknessof stratum
comeurnand probablythe viable epidermis.Thus, a measurement yieldsdata con-
cerningboth superficialand deeperstructures.It shouldbe noted that the use of
aluminumelectrodes is likely to producepolarizationeffectsevenat 100 Hz frequency.
However, in the presentexperiments,electrodepolarizationdid not appearto present
a problem.It is expectedthat measurements, especially
at lowerfrequency,would be
more accurateif non-polarizableelectrodeswere used.

EFFECT OF ALUMINUM SALTS ON GALVANIC SKIN RESPONSE

Most of the experimentsin this portion of the studywereperformedon oneadult male

subject.A 15% solution of aluminum chloridein water was usedas a model antiper-
spirant.Aliquotsof 0.4 ml of test solutionwereappliedto severalsiteson the inner
aspectof the right forearm(right-handedsubject)under occlusivepatches.Corre-
spondingsiteson the contralateral arm receivedpatcheswettedwith 0.4 ml water.
Four to five hourslater the patcheswereremovedand the forearmswerewashedwith
Ivory© soapand lukewarmwater.The armsweretowel-driedandthe peripheryof the
test siteswasdelineatedwith an indeliblemarker. In orderto allow equilibrationwith
the environmentalhumidity, the forearmswereleft exposed.After onehourthe subject
exercisedby walking up four flights of stairsrepeatedlyat a sustainedpace.Then he
sat in the test room and electrical measurements were recorded from the sites for a
periodof five to ten minutes.During the recordingthe subjecthyperventilated vig-
orouslyat approximatelytwo-minuteintervals.Pulmonaryhyperventilation(hyperpnea)
produces rapid fluctuationsin skin resistance
(18) whichasdemonstrated
in this report
are due mainly to sweatsecretionand reabsorbtion.For details refer to Figures2
and 3.

INDUCTION OF IRRITATION AND ASSESSMENT OF ELECTRICAL CHANGES

(a) Subject
selection
andpreparation.
Groupsof six fair-skinned
volunteers
eighteenyears
of age or older (total average= 48) were usedfor the tests.Women were preferred
394 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

due to the lesseramount of hair on their forearms.Personswith known skin allergies

and other skin disorderswere excluded.The subjectswere instructedto wash their
forearmsexclusivelywith Ivory© soapandwarmwaterdailyfor sevendayspriorto the
tests.During thisperiodapplicationof topicalproductsto the armswasto be avoided.
(b) Treatmentwith testsolutions
and measurements
of electrical
changes.
Occlusivepatches
designedto produceminimal tapedamageto skin surroundingthe test site asa result
of prolonged
contactandrepeated
removalwereused.Thepresence
of a Teflon© washer
decreased
the chances
of tape strippingthe test sitesduring patchremoval(Figure 1).
Threepatches,eachimpregnatedwith a 0.4 ml test solution,wereappliedalongthe
longitudinalaxisof the innerforearms.In someexperiments onlyonearm wasexposed
while corresponding siteson the contralateralforearmswere left untreatedand served
as reference.In other experimentsin which two test solutionswere compared,one
solutionwasappliedto the left arm and the otherto the right arm. The treatmentwas
randomizedwith respectto left andright arms.In this case,measurements takenbefore
the patch applicationwere usedas the baseline.In orderto ensurethat the patches
remainedin place,Ace© or Compressogrip © bandages wereusedto coverthe forearms.
The next day the patcheswere removedand the forearmswerewashedwith Ivory©
soapand lukewarmwater. The armswerethoroughlyrinsedwith waterandthen towel
dried. The peripheryof the test sites,identifiablefrom the still visibleimpression
left
on the skin by the marginsof the pads,weredelineatedwith a fine point markerin
orderto allow preciselocationof the test sites.
During the next hour the subjectswerekept idle with the forearmsexposed in an air-
conditioned room(approximately 22øCand 55% RH). Then electricalmeasurements
weretakenas describedin the Instrumentation and ElectrodePlacementsection.Ap-
proximately30 secondselapsedbetweenbringing the electrolytein contactwith the
skinandthe completionof a measurement. In this intervalthe skinimpedance changes
very fast as the corneumbecomeshydrated.This couldresultin someerrorsinceit is
difficultto promptthe instrumentto takea readingexactlythirty seconds afterwetting.
Therefore,the instrumentwasprogrammedto take five replicatereadingsin the course
of the thirty seconds.The arithmeticmeanvaluescalculatedfrom the individualread-
ingswereusedto analyzethe data. This procedureincreased the sensitivityof the test
and eliminatedthe needfor the prolongedwetting which would be requiredin order
for the skin impedanceto reachnearassymptotic levels.The applicationof patchesand
the electricalmeasurements were repeateddaily for a maximum of six daysor until
clinical signsof irritation developed,whicheveroccurredfirst.

IONTOPHORESIS OF METHYLENE BLUE

Iontophoresis
of methyleneblue solution(1% in isotonicsaline)wasperformedin (a)

WebriI©pad• /Tef Ion

©washer
(diameter
=2cm• /(thickness =0,03rnm
)
thickness
=O'lScm)• •
•"---, ............................
, // /Ultrapore ©surgical tape
--'•:•'-- -'"(adhesive sidefacing
skin)

•Occlusive
lining
Figure 1. Occlusivepatchdesign.
 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE 395

control untreatedsites;(b) treated anidrotic sitesidentified by increasedelectricalre-

sistance,diminishedgalvanicskin response,and a lack of visiblesignsof irritation;
and (c) treatedsiteswhich showeda drop in electricalresistance
and evidenceof clinical
irritation(e.g. erythema
andpapules).
A 6V battery(Eveready
© No. 731 NEDA 918)
servedas the current source.A well, connectedto the positivelead, identical to that
usedfor taking electricalmeasurements, kept 2.5 ml of dye in contactwith the test
site. The negativepole of the battery was connectedto a strip of aluminum foil held
by the subjectin contactwith the tongue. Current was allowed to flow for three
minutes. In order to induceperspirationduring this period the subjectpedalledvig-
orouslyand hyperventilatedrepeatedlywhile sitting on an exercisebicycle. Sweating
has been shown(9) to enhancepassageof dye into the sweatducts. In most casesthe
subjectperceivedcurrentpassage asa tingling or asa metallictasteassociated
with the
oral electrode.Somedegreeof stingingwassometimesreportedwhen the iontophoresis
wasdonein severelyirritatedskin. However,it did not appearto be necessary to reduce
the currentflow. At the end of the periodthe dye wasremovedand the site waswashed
with soapand water and photographed.

HISTOLOGICAL STUDIES

In irritated skin iontophoresis

of methyleneblue produceddark blue dots someof
which had a larger surfacearea than those observedin normal skin. Selectedareas
showingthe enlargeddots were biopsiedwith a 2-mm punchafter local anesthesia.In
this manner specimenswere obtained which containeda centrally-locatedaltered dot
surroundedby unstainedareaswith normal macroscopic appearance.The tissueswere
fixed in formaldehyde,embeddedin paraffin, and sectionedtransversally
in relationto
the skin surface.The sectionswerestainedwith Hematoxylinand Eosinand examined
under a light-microscope.

MEASUREMENTS OF EVAPORATIVE WATER LOSS

Evaporative
waterloss(EWL) wasmeasured with a fast-response
Servoreed
© (Servomed,
Sweden)evaporimeter.A strip-chartrecorderconnected to the evaporimeter
wasused
to continuouslymonitor the rate of EWL.

TREATMENT WITH SCOPOLAMINE

Occlusive
patchescontainingscopolamine
(Transderm©-V,
Ciba-GeigyCorp.,U.S.A.)
were applied to test siteson the inner forearm. In order to avoid undesirableanticho-
linergic systemiceffects,no more than two patcheswere placedon the intact skin of
any individual. The patcheswere left on the sitesovernight, when sweatreabsorbtion
occurs.The latter process may enhancethe absorptionof the drug. After approximately
12 hours,the preparationswere removedand the test siteswere washedwith soapand
water, dried, and allowedto equilibratefor one hour beforetaking electricalmeasure-
ments.

FORMULATIONS

The antiperspirantpreparationsusedin the varioustestsdescribedin this report are:

396 JOURNAL OF THE SOCIETY OF COSMETICCHEMISTS

Formulation
A. 15% (w/w) aluminum chloridehexahydratebufferedwith magnesium
hydroxidein water; excipients.
Formulation
B. 22% (w/w) aluminumchlorhydroxide
in water; excipients.
FormulationC. 15% (w/w) aluminumchlorhydratebufferedwith magnesiumhydroxide
and glycine in water.
FormulationD. 22% (w/w) aluminumchlorhydratebufferedwith magnesiumhydroxide
and glycine in water--volatile siliconeemulsion.
Formulation
E. Similar to FormulationD but with additionalglycine.

RESULTS AND DISCUSSION

EFFECT OF ALUMINUM CHLORIDE ON GALVANIC SKIN RESPONSE AND RELATION TO ANIDROS1S

Exposureto a 15% aqueous solutionof aluminumchloridefor five hoursunderocclusive

patchesresultedin an increasein the skin resistance and a markedsuppression of
fluctuationsin skin resistancebaselineinducedby hyperventilation(Figure 2).

SITE A SITE B SITE C

281. *l
5 I0
:•.4•
* I 2.7I
5 I0 5 I0
Minutes Minutes Minutes

Figure 2. Skin resistanceafter topical applicationof aluminum chloride.T = treated, C = control,

water treated.The asterisksindicatepulmonaryhyperventilation.

Accordingto widelyaccepted criteria(12) rapidand reversible

changes in skin resis-
tance,suchas thoseevokedin the presentexperiments by hyperventilation,are clas-
siftableas galvanicskin response.
The electricalevents,mainlychanges in potential
differenceandresistanceto currentpassage associated
with the galvanicskinresponse,
havegenerallybeenattributedto skinhydrationwhichoccurs dueto filling andemp-
tying of the eccrinesweatducts(12,13). However,galvanicwavesof considerable
amplitudehavealsobeen recordedin fingernails,wherethe contributionfrom sweat
glandshas been shownto be absent(12,22). In addition, an increasein resistancehas
beenobserved (14) in excisedplantarskinaftersoaking in an electrolyte.
Therefore,
in
orderto verify the relationshipbetweenthe electricalphenomena shownin Figure2
and the eccrinesweatglandactivity,a seriesof experiments wasperformed.The fol-
lowing were observed:
a) Evaporativewaterloss(EWL) andresistance measured concurrently
in separatesites
while the subjecthyperventilatedrepeatedlyshoweda grossnegativecorrelation.As
shownin Figure 3, the temporarydrop in resistance
followinghyperventilationcoin-
cidedwith a massiverisein EWL, thusindicatingincreasedwaterat the skin surface.
b) The changes
in skin resistance
evokedby hyperventilation
wereabsentfrom sites
 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE 397

70-

60-

50

1 98

1 32

0 66 H H H

0 • 10
MINUTES

Figure 3. Evaporative
waterloss(EWL) recordedfroma Servomeal
© evaporimeter
andelectricalresistance
(Ohms)measuredconcurrentlyin two palmarsites.H = pulmonaryhyperventilation.

pretreatedwith an anticholinergicdrug (Figure 4). Anticholinergicsare known to

specificallyinhibit sweatproduction.
c) Iontophoreticapplicationof methyleneblue to aluminumchloride-treated
siteswhile
the subjecthyperventilatedrevealeda time dependentreductionin the number of

14
•,scopoiamine
E 13

untreated

I I
IO I
I 2 5 4
Minutes
Figure 4. The effectof scopolamine
(Transderm
© V) on the skin resistance
(R) changesevokedby hy-
perventilation (H).
398 JOURNALOF THE SOCIETYOF COSMETICCHEMISTS

%,

Figure 5 (A-C). Skin surfaceappearance producedby iontophoresis

of methyleneblue in three separate
sites,two of which were exposedto aluminum chlorideunderocclusivepatches.A = controlunexposed,
B, C = treatedfor five and eighteenhours,respectively.
Magnification1.56 X.

stainedsweatducts(Figure 5). This indicatesthat the electricalcurrentwhich serves

asa carrierfor the dyeis somehow
restricted
fromflowinginwardalongthe lumenof
the ducts.The absenceof a columnof sweat,which in the uninhibitedglandsprovides
a channel of low currentresistance
andrelativelyfreedyemovement betweenthesurface
of stratumcorneumandthe deeperlessresistive tissues,accountsfor the lackof dye
penetrationin the inhibitedglands.
The experiments describedaboveshowthat the galvanicskinresponse evokedby pul-
monaryhyperventilation isassociatedwith a temporary increasein sweatglandactivity.
The inhibition of skin galvanicresponse after treatmentwith an aluminum salt as
illustratedin Figure2 is due to inhibitionof sweating.
Treatmentwith the aluminumsalt and the anticholinergic drug showsimilareffects
on the electricalpropertiesof skin (Figure2 and Figure4, respectively). However,
there is evidencethat the mechanisms underlyingtheseeffectsare different.The an-
ticholinergic,scopolamine, inhibits initiation of sweatsecretionin the secretory tu-
bules. On the other hand, treatmentwith aluminum salt doesnot seemto interfere
with the latterprocesses,
sincecellularreserves
of glycogenin the secretory
tubulesare
depleted to the sameextentduringheatstress in treatedanduntreated skin(15). It is
generally agreed(2-4) that the mechanism of anidrosis
produced by metalsaltanti-
perspirants is dueat leastin partto a blockingof sweatdeliveryto the skinsurface
[referto anidroticplugs(AP) in Figure11]. The natureof the mechanisms involved
in the blockingeffectaredisputed(2). Our ownresultsaredifficultto explainif one
 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE 399

acceptsthe theory(3) that the saltsinhibit sweatdeliveryto the skin surfaceby simply
forming an obstructivemetal-saltpolymer in the upper portion of the sweatducts.
Assumingthat the polymeris conductive,it would form an electricalbridge between
the ascendingcolumnof sweatand the electrodeat the skin surface.This would result
in a lack of effecton the skin galvanicresponse
in contradictionwith our findings.We
sharethe view (2) that tissuecomponentscontributeto the anatomicalobstruction.
The latter is suchthat it interfereswith sweatdeliveryto the skin surfaceand conse-
quently with the inward flow of externallyappliedcurrent.
The reportsconcerningthe effectsof antiperspirantmetal saltson the galvanicskin
response arefew and somewhatcontradictory.Perryetal. (5) foundno effectsin human
palmar skin treated with aluminum chloride. Papa and Kligman (10) describean
increasein the staining pattern producedby iontophoreticapplicationof methylene
blue in thermallystressed humansand attribute the effectto anidrosiscausedby treat-
ment with aluminum chloride. Indirectly, the increasedstaining denotesa decreasein
the electricalresistance
during sweating.In anotherreport(16) the sameauthorsshow
a decreasein the staining pattern in agreementwith our observations.Marcy and
Quermonne(11) demonstratean increasein resistancein the pawsof physicallystressed
mice followingtreatmentwith a seriesof metal salt antiperspirants.It hasbeenargued
(17) that data obtainedin mice are difficult to extrapolateto humans.We now show
that electromerrycan be usedto observeanidrosisproducedin human forearmskin
after treatmentwith a metal saltantiperspirant.Accordingto a recentstudyby H/31zle
and Kligman (17), measurements of antiperspirant-induced anidrosisproducedin fore-
armscan be extrapolatedto a considerable extent to the axillaryvault. More work is
needed,however,in order to establishif electrometrictechniquespresentadvantages
over the semiquantitativemethodscurrentlyused(for example,see 17) for evaluating
the efficacyof antiperspirants.

THE PATTERN OF CURRENT FLOW IN RELATION TO ANATOMICAL DAMAGE TO THE STRATUM

CORNEUM IN ANTIPERSPIRANT IRRITATED SKIN

Figure 6 showschangesin the electricalpropertiesof skin recordedas a functionof

subjectivelyevaluatedirritation producedwith repeatedapplicationsof aluminumchlo-
ride (15% aqueous).Slight rednessis associatedwith a sizablefall in resistance(R).
Capacitance(C) remainsunchangedin comparisonto pretestlevels. As irritation pro-
gressesto distinct redness,R continuesto fall while C showssomeincrease.At this
stage,the phaseangle(0) is in the positiverangeof the graph, therebyindicatingthat
the increase in C is smaller in relation to the decrease in R. A reversal of this situation
is observedin the most advancedstagesof irritation when the increasein C is larger
than the drop in R.
The aluminum chloridesolutionwas chosenfor this experimentbecauseit is known
(1) to havea high irritation potential, thusenablingobservations
to be madein a short
time. The results illustrated in the figure were obtained in five days. In sensitive
subjects,bufferedaluminumchlorideaswell asotherantiperspirant saltswhichare less
irritating producesimilar changeswithin the sameperiodof time. Thus, the Figure 6
illustratesthe pattern of dielectricand resistivechangesgenerallyassociatedwith the
inductionof irritation with metal-saltantiperspirants.
The data obtainedin this experimentwere found to be significantin two respects.
400 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Log T/CI
1.8

0.0

-1.6
lot t I I i21
Subjecl•ve Irriletion
Figure 6. Changesin the electricalpropertiesof skin shownas a functionof subjectiveirritationcaused
by daily applicationof aluminum chlorideunder occlusivepatches.The points representthe log of the
ratio of treated (T) to contralateral control (Ct) sites. The vertical bars indicate standard error of the
geometricmeanscalculatedfrom six subjectseach having three treated sites. R = resistance,C =
capacitance,0 = phaseangle. Subjectiveirritation scores: 0 = absent;1 = slight transientredness; 2
= distinctredness; 3 = intenseredness,papules,and subjectdiscomfort.Note the C-independent drop
in R during the initial stagesof irritation and the relativelyhigher increasein C in relationto the decrease
in R observedfrom the reversalof 0 during advancedirritation (refer to instrumentationand Electrode
Placementsectionfor mathematicalrelationshipbetweenelectricalparameters).

First, somedegreeof correlationappearedto existbetweenthe changesin the electrical

propertiesof skin (e.g. lossof resistance)
and the degreeof subjectiveirritation. The
correlationis extensivelyanalyzedin the next section.Second,the pattern of electrical
changesas interpretedfrom the relativecontributionof C and R to the measurements
is similar to that which can be producedin normal skin by puncturingit repeatedly
with a fine needlebut not by tape stripping(Figures7 and 8, respectively). A quali-
tative similarity betweenthe electricalpropertiesof skin slightly injured by exposure
to antiperspirant(Irritation ScoreI in Figure 6) and thoseof normal skin during
increasedsweatingwas alsoobserved(Figure 9).
Both needlepuncturesand increased sweatingcreatechannelsof low electricalresistance
in parallelwith the much higherand relativelyconstantresistance of the keratinaceous
matrix. The relativeconstancyof the matrix hasbeenusedto explain(18) the lack of
changein the dielectric(i.e. capacitative)propertiesof skin duringincreased sweating.
This is alsolikely to be responsiblefor the C-independentlossin R initially observed
in antiperspirantand needle-puncturedskin. In contrast, tape stripping, which si-
multaneouslyremovesboth resistiveand capacitative elements,almostequallyaffects
the two parametersduring the inductionof skin damage.Severalmodelshavebeen
proposed (21) in an attemptto explainthe increase
in skincapacitance duringstripping.
A clue concerningthe anatomicalchangesunderlyingthe similaritiesin the patternof
currentflow betweenmetal salt-irritatedskin on one hand and needle-punctured and
perspiring skin on the other was provided by experimentsreported by Papa and
Kligman (10). They studiedthe effectof a 20% aqueoussolutionof aluminumchloride
 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE 401

Log P/C!
1.8-

0.00 ; _'2 _

/R
- .

i • • 4 ,5 6 7 8 9
l, Ii I
½onlrolpr•M$1 n•dl• pun½lur•$

The pointswerecalculatedfrom the log ratio of measurements obtainedin perforated(P) site to the average
of three control (Ct) measurements taken in the intact site. R = resistance,C = capacitance,and 0 =
phaseangle. Note the similaritieswith the electricalpattern illustratedin Figure 6, that is, the C-
independent dropin R duringearlystagesof the experimentand the reversalof 0, whichdenotesa higher
increasein C in relation to the decreasein R taking placein the final stagesof the experiment.Punctures
havenegligibleeffectsafterthe stratumcorneumis eliminatedby tapestripping(seeFigure8), indicating
that the changesshownhereare due to damageto the stratumcorneum.

on the stainingpatternproducedin the skin by iontophoreticapplicationof methylene

blue. When the dye was applied to sites exposedto the aluminum salt solutionfor
eighteenhoursunder an impermeabledressing,there occurreda pronouncedincrease
in periductal staining of someof the sweatducts. The corneumsurroundingthe ostia
of the respectiveglandsremainedmacroscopically unchanged.Thesefindingssuggested

Log S/Ct
,C
,,•L
I- ..-.-o-'-'-ø:: =: '-ø-'-'
.66[- 0•0_0_0_0_0_0
_0_0
_0..0_0..0_0_0_0..0
0.00 -

I 3 5 7 9 II 13 Iõ 2 4 6
I I t l

Tesf Condillon

Figure 8. The effectof tape strippingon the electricalpropertiesof skin. The pointswerecalculated
from the log ratio of measurements
obtainedin stripped(S) sitesto a control(Ct) measurement
performed
prior to stripping. R = resistance,
C = capacitance, 0 = phaseangle. Punctureswereperformedto
showthat they havenegligibleeffectsafter the stratumcorneumis eliminated(referto legendfor Figure
7 for explanation).
402 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

:5.5
B.5

3.3 m

6.0 w--/\C -

4i I I i 2.9
o I 2 4

M,nutes

Figure 9. Resistanceand capacitance measurements

during activationof sweatglandsby meansof pul-
monaryhyperventilation (H). R decreasesapproximately
40% from its initial levelwhile the changein C
is only about 5%. Explanationin text.

that the siteswith increaseddye depositionmay correspond to the pointsof low current
resistance inferredby us from the electricalbehaviorof antiperspirant-irritated
skin.
In orderto verifythishypothesiswe appliedmethyleneblueiontophoretically to sites
severely
irritatedwith an antiperspirant.
A stainingpatternidenticalto that reported
by Papaand Kligman was obtained(Figure 10). After iontophoresis, tissuebiopsies
were collectedto includepointswith increased
dye depositionas well as surrounding
areaswith a macroscopically
normal appearance.Histological examinationof sections
madefrom the biopsyspecimens
resultedin the followingobservations:
(a) Sectionsmade from areasof skin with a normal ,ttern of stainingdo not show

Figure 10. Skin surfaceappearanceproducedby iontophoreticapplicationof methyleneblue in skin

irritatedwith aluminumchloride.For comparison
to normaland anidroticsitesreferto Figure5 A-C.
Magnification 1.44 X.
 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE 403

any detectablesignsof injury to the stratum corneum,the corresponding underlying

viableepidermis,or the sweatglands(Figures11A and 1lB). Someof the sweatglands
in theseareascontainamorphous-precipitates whichare considered (2-4) to be asso-
ciatedwith the anidroticeffectsof the salts(Figure 1lB). Other glandsappearto be
unobstructedand functional.Their presence is mostlikely responsible
for the continued
presenceof galvanicwavesof low amplitudedetectablein severelyirritated skin (Fig-
ure 12).

(b) Sectionsmade throughareascontainingpoints with increasedstainingrevealthe

presenceof damageto periductalkeratinaceoustissue.The damagerangesfromthinning
and changesin textureto a completedisruptionin the continuityof stratumcorneum
tissueimmediatelyadjacentto the sweatgland ostia. In the latter case,severedamage
to the underlyingviable epidermisis alsopresent(Figures11C through 1IF).

Figure 11 (A-F). Histologicalappearance

of humanskinirritatedwith aluminumchloride.SC: stratum
corneum,VE: viableepidermis,D: dermis,SD --- sweatduct, AP: anidroticplug. Magnification
138.6x.
404 JOURNAL OF THE SOCIETY OF COSMETICCHEMISTS

1.2

I.I

i.o i i i i
I 2 • 4
Minutes

Figure 12. Galvanicskin responsemeasuredin skin severelyirritatedwith aluminumchloride.The

asteriskindicatespulmonaryhyperventilation
which, as shownin first part of Resultsand Discussion
section, inducesa brief increasein sweatgland activity.

The aboveobservationsindicate that skin irritation producedby antiperspirantsalts

containsa majorcomponentwhichconsists of a lossof sweatduct integrityandelectrical
resistanceat the level of stratum corneum. The points of low electrical resistance
alternatewith highly resistive,relativelylessaffectedstratum corneum.Thesefindings
explainthe similaritiesin the patternof currentflow observed in antiperspirant-irritated
and normalneedle-punctured skin. They specificallyrelatethe changesin the electrical
propertiesof skin to the presenceof epidermalinjury.
In a previousreport(6) we describedtheuseof capacitancemeasurements formonitoring
irritation producedin skin by exposure
to sodiumlauryl sulfate(SLS).Thiele andMalten
(20) havemeasuredimpedancein orderto studythe electricalpropertiesof skin during
exposureto dilute solutionsof sodiumhydroxide.Both studiesrelated the changesin
capacitance or impedanceto a graduallossin the barrierpropertiesof humanstratum
corneurn.However, the two electricalparameterstaken separatelydid not yield infor-
mation concerningthe pattern of current flow in relation to the type of anatomical
injury. It was assumedthat the current flow in the irritated siteswas identicalto that
taking placein skin damagedby tapestripping. A brief reportby Hi51zleand Kligman
(19) shows,basedon histologicalevidence,that in addition to severalmetallic salts,
including aluminum chloride, used in the presentstudy, other water-solublecom-
poundslike SLS, Hyamine 3500, and PolymyxinB causeselectivedamageto the
acrosyringiumwhen applied under occlusion.Thus, damageto the epidermalsweat
duct unit from water-solublecompounds appearsto be a rathercommonevent. Some
of the principal observations
made in the presentexperimentsare that damageto the
cornealportionof the sweatductscan be identifiedby analyzingthe relativechanges
in the dielectricand resistivepropertiesof skin and that the injuredsweatduct units
can be locatedby meansof iontophoresis of methyleneblue.
The histologicalsectionspresentedin Figure 11 reveala paucity of leucocytesin the
proximity of damagedepidermal sites. This is in apparentdiscrepancywith work
reportedby Relier and Leudde;•(3) who showedthat in metal salt-irritatedskin, areas
 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE 405

associated
with the distalsegmentof the eccrinesweatductsbecomeheavilyinfiltrated
with leucocytes.In our experiments,the biopsieswere collectedwithin a few hours
afterremoving
thepatches.
We believethatleucocytes
movein at laterstages
following
cessation
of exposureto salts,perhapswhenthe environmentof the injuredepidermal
sitesbecomes lesstoxic and therebymorepermissive
to chemotactic processes.

IRRITATION POTENTIAL OF ANTIPERSPIRANTS EVALUATED ELECTROMETRICALLY

Experiment 1. Figure 13 showsthe changesin skin impedance(Z) producedby daily

applicationsof formulationsA and B [Z was chosenas the electricalparameterto be
calculatedfrom the readingsbecauseit comprisesresistiveas well as capacitativecom-
ponentsof skin, both of which canbe affectedby the presenceof irritation (Figure 6)].
The drop in Z wasassociated with the developmentof irritation which waspresentin
almostall sitesat day five. Table I lists irritation scoresand correspondingZ values
recordedin each site at day five. A negative relationshipexistsbetweenthe average
irritation scoresand the averageZ values. However, the individual irritation scores
correlatedpoorlywith the respective Z valueswhentestedby regression analyses.Larger
differences in Z betweenthe two formulationsare recordedat day three. There is good
correlationbetweenZ at day three, when irritation wasabsentin most sites,and the
irritation scoresat day five (Figure 14).
Experiment 2. Figure 15 comparesZ measurements obtainedwith formulationsA and
C. FormulationA loweredZ more and producedhigher irritation scoresthan formu-
lation C (Table II). In this test formulationA causeda slightly small decreasein Z
and lessirritation than in Experiment 1 (comparedata from TablesI and II).
Experiment
3. FormulationsD and E are similar with respectto their ability to lower
Z (Figure 16). At day five the averageZ valuesare distinctivelyhigher than those
observedin the other tests for formulations A, B, and C. A transient increasein Z
occursbetweendaystwo and three. The two test materialsdid not induceany appre-
ciablesignsof clinical irritation.

O I .
I • 5

Day

Figure 13. Effectof formulationsA and B on skin impedance(Z). The barsrepresentstandarderror.

406 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Table I
Impedance
(Z) in OhmsX 104 andSubjectively
Evaluated
IrritationAfterDailyExposures
forFour
Days to FormulationsA and B

Formulation A Formulation B

--
Irritation Scores --
Irritation Scores
Evaluator Evaluator

Subject z100Hz A.G. M.H. A.M. J.F. D.L. z100Hz A.G. M.H. A.M. J.F. D.L.

M.P.
0.331
2 2 2 1 2{1.49
0.771
0.246
3
2 1 10 00 2
3 2
2
2
2
2
2
1.29
1.38
1
1
1
1
1
0
1
1
0
0

B.K. 0. 186 2 2 2 2 2 0.215 1 1 1 0 0

0.224 1 2 1 2 1 0.282 1 1 1 1 0

A.R. 0.212 3 3 2 3 2 0.247 1 1 1 1 0

0.228 3 2 1 2 2 2.31 1 1 0 1 0

H.S. 1.76 2 2 2 2 0 2.4 1 1 0 0 0

1.42 4 3 3 3 2 1.48 1 1 1 2 1

P.B.
0.323
3 3 2 2 2{0.347
0.445
0.283
3
1 2 2 1 11 4
3
4
3
3
1
2
2
0.467
0.453
2
2
1
1
1
1
0
1
1
1

J.S.

Mean
2.37
1 3 3 1 2{4.69
2.40
2.97

0.82
2
2 1 11 21 4
3
3
3

2.2
2
2
2
2
4.26
8.65

1.90
1
1
1
1
2
2

0.9
1
2
1
2

Irritation scores:0 = no reaction; 1 = faint erythema;2 = mild confluenterythema;3 = moderate

erythema;4 = intenseerythema,edemaand vesicles.

•'• o
c• o
• o o
• o

o o o ß ß

o • • I
Irrilalion Scores (Day 51
Figure 14. Correlation
betweenimpedance
valuesmeasured
at day threeand the subjectively
scored
irritationat dayfive. The slopeof the line is significantlydifferentfrom zero[(P < 0.01) testsitesfrom
eachsubjecttreatedasindependent samples].
 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE 407

12-

I 2 • 4

Figure 15. Effectof formulations

A and C on skin impedance
(Z). The barsrepresent
standarderror.
The three experimentsdescribedabovewere selectedfrom a seriesof testswhich were
performedin orderto determineif measurements of changesin Z relateto the irritation
potentialof antiperspirants.
Severalcriteriawereusedto establishif sucha relationship
existsand to determinewhether the electrometrictechniqueis of practicalvalue. For
Table II
Impedance
(Z) in OhmsX 104 andSubjectively
Evaluated
Irritation
AfterDailyExposures
forFour
Days to FormulationsA and C. (Irritation ScoresAssignedAs in Table I)

Formulation A Formulation C

--
Irritation Scores --
Irritation Scores
Evaluator Evaluator

Subject z100Hz D.L. R.R. J.Z. T.R. z100Hz D.L. R.R. J.Z. T.R.

A.R.
2.071 2 1 i {9.98
2.54
2.41
1
1 0 0 0 0 0
1
0
0
1
1
7.23
5.60
1
0
0
0
0
0
0
0

M.J. 2.69 1 0 0 1 7.65 0 0 0 0

2.19 1 0 0 1 8.64 0 0 0 0

H.F.
2.992 2 2 1 {5.940 1 1 0
3.16
4.66
2
2
2
2
2
1
1
1
7.72
7.07
0
0
0
0
0
0
0
0

P.D.
3.821 1 1 1 {8.99
2.53
2.57
1
0 0 0 1 0 1
0
1
1
1
1
10.70
8.65
0
0
0
0
0
0
0
0

C.M.
2.891 1 1 0 {8.92
4.65
5.10
1
0 0 0 1 0 0
1 1
0
0
0
8.66
15.40
0
0
0
0
1
0
0
0

B.A.
0.623 3 3 2 {2.97
0.22
0.32
3
2 0 0 0 0 3
2
3
2
2
2
3.18
2.90
0
0
0
0
0
0
0
0

Mean 2.64 1.2 7.62 0.1

408 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

o
x
N
6-
o=D
D=E

4-

2-

0 • • I • • I
I 2 ;5 4 5 6
DAYS
Figure 16. Effectof formulations
D andE on skinimpedance (Z). Note the slight increase
in Z taking
placebetweendaystwo and three. The increaseis statisticallysignificant(P < 0.05; data for two
formulations combined).

thoseformulationswhich producedclinicalsignsof injury in the courseof the exper-

imentalperiod,a correlationwassoughtbetweenthe irritation scoresand the Z values
measuredin the sites.The effectson skin impedanceproducedby theseformulations
and by thosewhich did not causevisible signsof irritation were comparedwith sub-
jectivedata from independentclinicalstudies.
Using any of the threecriteria, that is the amountof changein Z, the irritationscores
obtainedin the presenttests, or the resultsfrom independentclinical studies,the
irritation potentialof the five formulationscouldbe rankedas follows:
A > B > C > DandD • E

With the exceptionof A, the otherformulations areconsidered

to be mild on the basis
of either clinical and/or field-studyinformation.
Basedon the aboveobservations, it appearsthat the electrometric
techniqueyieldsvalid
data concerningthe irritation potentialof antiperspirants.A comparisonbetweentwo
or three formulationscan be made usingonly six subjectsovera periodof five days.
Therefore,it can alsobe concludedthat the techniqueis of practicalvaluefor clinical
irritation studies.

The data obtainedon formulationA in two separateexperimentsdiffer slightly with

respectto both the changesin Z and the amountof subjectiveirritation (Figures13,
15, andTablesI andII). The discrepancyis probablydueto differences
in the sensitivity
of the personsusedin the two tests.Differentenvironmental conditionsunderwhich
the testsmight have been conductedcould also accountfor the discrepancy.Thus,
extrapolationof data from one experimentto anothermay presentconsiderable limi-
tations.This is not unexpected,considering the small numberof subjectsin the ex-
perimental group.
The presentstudy raisesquestionsas to whether damageproducedto the stratum
409 CUTANEOUS IRRITATION AND GALVANIC SKIN RESPONSE

corneumby metallic antiperspirantsprecedesthe clinical signsof irritation related to

dermal tissueresponse.The data in Figure 14 showthat the skin impedancefalls to a
certainlevel beforeerythemabecomes evidentto the nakedeye. Throughoutthe course
of the experimentswe observedthat as long as the stratum corneumremainedintact
with respectto its electricalbarrierproperties,erythemafailedto develop.Perhapsthis
couldexplainwhy the increasein the patternof stainingcausedin aluminumchloride-
exposedskin was attributed by others(10) to anidrosisrather than to imminent irri-
tation. However, while theseobservations appearto indicatethat grosserythemais
secondary to damageto the epidermalbarrierfunction,it is still possiblethat the viable
tissuesare irritated in a more subtle way (e.g. itching and inconspicuous erythema)
beforedamageto the stratum corneumcan be detected.
The data presentedin Table I and II showthat in severelyirritated skin, a degreeof
correlationexistsbetweenthe lossof skin impedanceand the clincialsignsof irritation.
It appearsthat the level of correlationbetweenthe two parametersis affectedby
individualdifferencesin the sensitivityof the involvedtissues.This point is illustrated
well by the fact that, sporadically,older subjectsfailed to showerythemadespitethe
presenceof severeepidermaldamage.By contrast,other subjectsdevelopederythema
but relativelylessdamageto the epidermalbarrier.
A transientincreasein Z was observedduring the induction of irritation with all the
formulationsexceptA (Figures 13, 15, and 16). We have shownin the first part of
the Resultsand Discussionsectionthat treatmentwith an antiperspirantfor a few hours
resultsin an increasein resistance which is due to inhibition of sweatgland function.
It is possiblethat the temporaryincreasein Z during the inductionof irritationsis a
reflectionof overlappingincreasedanidroticactivity. This interpretationis supported
by the fact that there is an inverserelationshipbetweenthe irritation potential of the
formulationsidentifiedin the figuresandthe time elapsedbeforethe temporaryincrease
in Z. It has beenshownin Lansdown(1) that, in general,antiperspirantefficacyand
irritation potential relatedirectly to one another.Thesefactsindicatethat someof the
variationin the impedancerecordedduring the inductionof irritation reflectsevents
relatedto irritancyand anidrosisratherthan randomexperimentalerror.

CONCLUSIONS

(1) Anidrosisproducedin forearmskin by aluminumchloride(15% in water) under

occlusivepatchesis associatedwith an increasein skin resistancebaselineand a
reductionof galvanicskin response.
(2) A simple electrometrictechniquefor investigatingthe relativeirritation potential
of antiperspirantsis describedin this report.
(3) Irritation with antiperspirantsis associatedwith a lossof sweatduct integrity at
the levelof stratumcorneum.The bulk of the cornealmatrix andthe corresponding
underlyingepidermisremainintact as observedmicroscopically. This type of epi-
dermalinjury is associated with specificdielectricand resistivechanges.The dam-
agedsweatduct units canbe locatedby meansof iontophoresis of an ionizabledye
suchas methyleneblue.
(4) Underthe conditionsof the presentstudy,damageto the epidermalbarrierappears
to precedegrosserythemaand edema,two eventsrelatedto the vascularplexusin
410 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

the dermis.In fully damagedskin, a partial correlationexistsbetweenthe lossof

impedanceand the developmentof erythema.The lack of a better correlationmay
reflectindividualdifferences
in the sensitivityof cornealvs subcorneal
tissues.

REFERENCES

(1) A. B. G. Lansdown,Productionof epidermaldamagein mammalian skins by simple aluminum

compounds,
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(2) E. H61zleandA. M. Kligman, Mechanismof anti-perspirant
actionof aluminumsalts.J. Soc.Cosmet.
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(3) H. H. Relier and W. L. Luedders,"Pharmacologic and ToxicologicEffectsof TopicallyApplied
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