Cancer Res-1956-Kotin-375-93 PDF

1956;16:375-393.
Cancer Res

Paul Kotin

A Review Pulmonary Cancer:
The Role of Atmospheric Pollution in the Pathogenesis of

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Research.
I. Introduction 375
A. Lung cancer increase real
B. Exogenous environment etiologically
implicated
II. Historical 376
A. Nonpuhnonary occupational cancer
and lung cancers of occupational
origin
B. Incrimination of atmospheric envi
ronment
C. Incrimination of tobacco
Ifl. Epidemiologic Considerations 376
A. Limitations of data
B. Variations in iung cancer rates among
countries
C. Variations in lung cancer rates within
countries (urban-rural differences)
D. Variations in age peak incidence and
sex incidence
E. Interpretation of epidemiologic data
for selected countries by local inves
tigators
F. Racial differences in lung cancer rates
G. Socio-economic differences in lung
cancer rates
H. Occupational lung cancer
I. Rsum
IV. Environmental Carcinogenic Agents.... 884
A. Occupational respiratory carcinogens
B. Sources of carcinogenic atmospheric
pollutants
C. Known and suspected carcinogenic
agents in the atmosphere
D. Biologic demonstrations of carcino
gens with atmospheric pollutants
V. Discussion 387
A. Epidemiologic considerations in in
terpretation of pathogenesis
* Part of the work reported here is supported by grants
from the Field Investigations and Demonstzations Branch,
National Cancer Institute, United States Public Health
Service, Department of Health, Education, and Welfare,
and by a grant from the Ad Hoc Lung Cancer Committee of
the American Cancer Society.
B. Role of chemical and physical factors
in pathogenesis
C. Significance of experimental labora
tory data in pathogenesis
D. A theoretical mechanism for the
pathogenesis of lung cancer
VI. Conclusion 390
INTRODUCTION
A. Lung cancer increase real.Amarked in
crease in the absolute mortality from cancer of the
lung has been demonstrated in various regions of
the world during the past several decades (86, 88).
Certain epidemiologic aspects of this increase sug
gest etiologic association with carcinogenic agents
presumably introduced into the external environ
ment in the recent past. Of the causal agents ad
vanced, atmospheric pollution (1@,55, 97, 98) and
cigarette smoking (7, 15,@8, 80) have been regarded
as the two most significant. Lung cancer, in common
with all neoplasms, appears unlikely to have but
a single initiating and promoting agent concerned
with its pathogenesis. Any analysis of the atmos
phere as a carcinogenic entity must, therefore, in
clude reference to its possible role as an adjuvant
or associative factor to other potential environ
mental carcinogenic sources. Cigarette smoking,
the most often accused of these, will be evaluated
in the light of its possible association with atmos@
pheric pollution in the initiation of lung cancer.
Sufficient time has elapsed and enough informa
tion has been accumulated relating atmospheric
pollution to the increase in lung cancer to make a
critical review of the data advisable. This report
will conclude with a presentation of a suggested
theoretical mechanism of human pulmonary car
cinogenesis based upon experimental and epidemi
ologic studies.
Theories of lung cancer pathogenesis, to be
valid, should result from a synthesis of responsible
epidemiologic, clinical, and pathologic data.
Equally significant are supporting data derived
from laboratory investigations.
B. Exogenous environmentetiologicallyiniplicat
375
The Role of Atmospheric Pollution in the Pathogenesis
of Pulmonary Cancer: A Review*
PAUL K0TIN
(Unicersity of Southern Caitfornia, School of Medicine, Los Angeles, Calif.)
Research.
Cancer Research 876
ed. There i s no convi nci ng evi dence that an i n
tri nsi c bi ol ogi cal change mi ght be responsi bl e for
the emergence of nonoccupati onal l ung cancer
from the status of a medi cal curi osi ty at the be
gi nni ng of the century to a posi ti on of maj or i m
portance at mi d-century. In the absence of such
data an exogenous source of the carci nogeni c
agents must be postul ated.
These exogenous envi ronmental agents di d not
become mani fest si mul taneousl y throughout the
worl d, as noted by si gni fi cant di fferences exi sti ng
from country to country rel ati ve to the ti me of on
set of the i ncrease i n l ung cancer, the rapi di ty and
i ntensi ty of the i ncrease, and vari ati ons i n the age
groups mani festi ng the peak i nci dence. These vari
ati ons are accompani ed by si mi l ari ti es whi ch poi nt
to the exogenous ori gi n of the causal agent or
agents. These i ncl ude a greater frequency of the
di sease i n urban resi dents (81, 53, 58, 69, 86, 88,
97, 98) and an i ntensel y exaggerated, al most ex
cl usi ve i ncrease i n mal es (17, @%, 44, 58, 97). A
cl i ni cal hi stori cal associ ati on of heavy ci garette
smoki ng has been reported i n a maj ori ty of the
cases ofl ung cancer. Soci ol ogi c i nvesti gati ons have
attempted to associ ate characteri sti c hi stopatho
l ogi c patterns of pul monary neopl asms wi th spe
ci fi c envi ronmental factors. As i s evi dent from the
reports of Ki rkl i n et al . (59) and Wal ters and
Pri ce (101), the absol ute pathol ogi c cl assi fi cati on
of l ung cancers i s at present exceedi ngl y di ffi cul t.
The hazards of establ i shi ng cel l types and cel l ul ar
ori gi ns are especi al l y marked i n rel ati on to ana
pl asti c or so-cal l ed oat-cel l cancer.
HISTORICAL
A. Nonpulmonar y occupational cancer and lung
cancers of occupational origin.Sir Percival Pott
(87) fi rst correl ated cl i ni cal cancer wi th carci no
geni c materi al s from one source of atmospheri c
pol l uti on. The l ocal atmospheri c pol l uti on i nci den
tal to the functi on of chi mneys i s sel f-evi dent.
Whether the sweepi ng of chi mneys carri ed an i n
creased l i abi l i ty to the devel opment of l ung cancer
i n addi ti on to scrotal cancer i s at present undeter
mi nabl e.
B. Incr imination of atmospher ieenvir onment.
Atmospheri c contami nati on as an envi ronmental
source of pul monary carci nogens was fi rst demon
strated when Harti g and Hesse (51) i denti fi ed the
pul monary di sease i n radi oacti ve ore mi ners i n
Schneeberg as l ung cancer. There, of course, the
atmospheri c pol l uti on was a hi ghl y l ocal i zed one,
l i mi ted speci fi cal l y to the occupati onal envi ron
ment of the mi ners. The epi demi ol ogi c and patho
l ogi c study of the Schneeberg mi ners resul ted i n
the establ i shment of envi ronmental l ung cancer as
a defi ni te enti ty. Concepts of l atency, the i nterval
between fi rst exposure to the carci nogeni c agent
and the cl i ni cal mani festati on of l ung cancer, were
i ni ti al l y deri ved from these studi es. An i ncreased
ri sk i n the devel opment of l ung cancer has si nce
been demonstrated to be associ ated wi th occupa
ti onal exposure to ni ckel (80), chromates (1, 4, 78),
and gas-worki ng operati ons (@6).
C. Incr imination of tobacco.Amongthe fir st
to descri be a correl ati on between the devel opment
of cancer of the l ung and factors other than stri ctl y
occupati onal ones was Mul l er (81) who i n 1989 re
ported a stati sti cal study purporti ng to show a
correl ati on between smoki ng and l ung cancer. An
anal ysi s of the occupati onal exposure of hi s sub
j ects i n the l i ght of current envi ronmental cancer
knowl edge i ndi cates that hi s concl usi ons of a posi
ti ve eti ol ogi c associ ati on are open to questi on. Fol
l owi ng Mul l er's ori gi nal report, numerous studi es
have been undertaken to ascertai n any rel ati on
shi ps exi sti ng between l ung cancer and a broader
spectrum of envi ronmental factors. A maj ori ty of
recent i nvesti gati ons noted an associ ati on between
l ung cancer and heavy smoki ng (47, 7@, 89, 104,
105). Numer ous investigator s have by means of
comparati ve retrospecti ve studi es adj udged that
heavy ci garette smoki ng embodi es an enhanced
ri sk to the devel opment of l ung cancer. The con
el usi on that thi s associ ati on demonstrates a
cause-and-effect rel ati onshi p has been most el o
quentl y advanced by Hammond and Horn (50),
who observed, Forreasons di scussed, we are of
the opi ni on that the associ ati ons found . . . be
tween regul ar ci garette smoki ng and death rates
from l ung cancer refl ect cause and effect rel ati on
shi ps.
Contrary opi ni ons have been voi ced by other
students of the probl em, who emphasi ze that the
real i ncrease i n l ung cancer i s markedl y l ess than i s
general l y accepted and thus questi on whether re
ported associ ati ons between ci garette smoki ng and
l ung cancer si gni fy any eti ol ogi c i mpl i cati on. Berk
son (3) i n revi ewi ng the data of Hammond and
Horn reported, Mythesi s i s onl y that i t i s un
warranted to concl ude from them [dataj that a
meani ngful associ ati on al ready has been proved
beyond doubt, as some wri ters have asserted and
as appears to be wi del y accepted i n the Uni ted
States. Much l ess do I bel i eve that causati on has
been establ i shed.
EPIDEMIOLOGIC CONSIDERATIONS
A. Limitations of data.In evaluating the
epi demi ol ogi c factors rel ati ng to thi s revi ew, cer
tai n defi ci enci es i nherent i n the avai l abl e crude
data must be consi dered.
Research.
KoTINAtmos'ph 'ic Pollution and Pulmonary Cancer 877
First, the increase in lung cancer incidence as
reported by investigators in different countries in
some instances deals with mortality rates derived
from vital records, while others report incidence
figures obtained from necropsy records. Both
sources have limiting factors. James (56) and his
co-workers questioned the use of cause-of-death
statements on death certificates as he found
. . . the extent of the error in a large number of
specific cases raises serious doubts as to the validi
ty of the use of cause-of-death data as a basis for
epidemiological studies of degenerative diseases.
The unjustified use of necropsy data was decried
by Gilliam (48) when he directed attention to the
. . . deplorable and almost universal tendency in
the literature of pathology to draw from autopsy
data firm epidemiologic conclusions which at best
should be regarded in the same light as clinical
impression. This admonition should be tempered
by the knowledge that necropsy data have been of
great value in the study of certain infectious dis
eases. Regardless, the time of introduction of the
carcinogenic agent or agents into the atmospheric
environment can be arrived at only on the basis of
assuming an average period of latency. This inter
val represents the period between the first expo
sure to the carcinogenic agent and the clinical
manifestation or discovery of the lung cancer.
Second, great differences exist as to the time when
dependable reporting and recording of cancer
deaths started in various regions throughout the
world. Third, until recently there has been a lack
of standardization in the method of reporting and
recording cancer deaths.
B. Variations in lung cancer rates among coun
tries.While great differences continue to exist in
several of the preceding factors, an analysis of
available epidemiologic data indicates that prior
to the early 1980's records for several countries are
incomplete, inconsistent, and in many instances
inaccurate. Beginning with this period, however,
one may with some degree of assurance compare
death rates from lung cancer with those recorded
in the early 1950's. Though similarities in trend
exist in all countries, when the two series of death
rates as determined by vital statistics are re
viewed, a great disparity can be noted in the spe
cific rates (83). This disparity in actual incidence
rates tends to support the thesis that the environ
mental carcinogenic agent differed in the time of
its introduction and varied in its intensity from
country to country. Charts 1 and @ record com
parative death rates for a series of countries be
tween the two periods mentioned above.
C. Variations in lung cancer rates within coun
1rie@(urban-rural differences).Paralleling the dif
ferences noted from country to country are the
variations exhibited in local geographic areas with
in countries. A basic and almost universal obser
vation has been the demonstration that urban
residence carries with it an increased liability to
the development of lung cancer. The urban-rural
difference in death rates from lung cancer has been
demonstrated by a number of investigators using
contrasting methods of study. Stocks (96) in Great
Britain used density of population as the reference
line for lung cancer rates. Lew (73) demonstrated
urban-rural differences in lung cancer as part of a
comparative study of death rates in male indus
trial policy-holders and males holding ordinary
insurance policies with the Metropolitan Life In
surance Company. He correlated the 80SOper cent
higher rate in the former group with urban resi
dence, low economic level, and industrial or manu
facturing occupational environment. In contrast,
ordinary policy-holders belonged to the higher in
come groups with significantly fewer opportunities
for protracted exposure to industrial hazards.
Eastcott (38) in an analysis of native New Zea
landers and immigrants studied the effect of ur
banization on death rates for cancer of various
body sites. Of all visceral cancers, those of the lung
and bronchus exclusively showed variations at
tributable to exposure of the host to environment.
The effect was directly related to the intensity of
antecedent exposure. The exclusive factor in the
former environment capable of incrimination was
urban residence. Mancuso (79), in a study limited
to a single, highly populated and industrialized
state (Ohio), correlated urban residence with the
liability rate to lung cancer by showing that the
observed death rate was greater than expected in
the eight industrialized urban counties, and one
third less than expected in the remainder of the
state.
While it is unlikely that occupational exposure
to a specific carcinogenic atmospheric environment
can materially affect nation-wide incidence figures,
there is little question that the increased liability
to lung cancer is consistent with the increased in
dustrialization. An analysis of lung cancer death
rates by states in the central states (8@), when re
viewed in the light of the degree of their industri
alization, shows a consistent positive association
between intensity of industrialization and mortali
ty from lung cancer.
D. Variations in age peak incidence and sex in
cidence.Additional convincing supporting evi
dence for variations in the time of introduction of
the carcinogenic agent into the atmosphere can be
found when the peak age incidence for lung cancer
is compared from country to country as shown in
Research.
FNQIAND @l@3O@ 912 112.9
1944 1 495'
WAUS 1952 181.4
11930 -9321 0.'
ScOTLANDL $949 i @'@
9,2 J 56.3
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949 1 29.8
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929-1911 112.0
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1952 1 33.5
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1952. @II1.S
JAPAIV @j i 49(J952)
C@tnT 1.Death rate for cancer of respiratory system in males (rates per 100,000 deaths). Data obtained from Director
Consultant on Health Statistics, World Health Organization.
Research.
K0TINAtnwspheric Pollution and Pulmonary Cancer 879
Table 1. In those countries with peaks in the earli
er decades of life, the introduction of the carcino
genic agent must certainly have been proportion
ately sooner or in greater concentrations. Further,
FIV8LIA/D 1@@@14.3 (s930-191t)
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1I@.o (@@@o- 1932)
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4.0 (1952.)
differences in urban and rural lung cancer mortality
figures may be nothing more than another mani
festation of the time of peak incidence. The dose
of a carcinogenic agent represents the product of
the duration of exposure multiplied by the concen
tration of the carcinogen. Rural areas differ from
urban areas in that pollutants are present in lower
concentrations rather than by their complete
TABLE 1
LUNG CANCER INCIDENCE PEALS BY YEARs
FOR VARIous CouNTRIEs
absence.
19491955MaleFemaleMaleFemaleNorway
italy
England-Wales
Finland50-59
50-54
55-59
555970
and over
55-59
65-69
60-6460-64
55-69
60-64
60-6470
and over
65-69
65-69
70-74Netherlands555960-6460-6465-69Scotland60-6460-6460-6460-64Ireland60-6460-6465-6960-64Switzerland60-6470-7470-7470-74Japan
France60-64 606465-69 656960-64 55646569 6569Australia60-6460-6465-6960-69Germany
United States60-6460-6460-64 65-6960-64 60-6465-69 70-74Canada65-6960-6965-6965-69NewZealand65-6965-6965-6970-74
TABLE @
RATIO OF MALE TO FEMALE wrrnIRE
GARD TO DEATH RATES PROM
CANcER OF THE RESPIRATORY
TRACT
While there is universal recognition and accept
ance of the difference between men and women in
liability to the development of respiratory tract
cancer, great divergence of opinion exists as to its
significance. Changes in the ratio of male to female
death rates are shown in Table @ for the two
periods, early 1980's and early 1950's, for various
countries. It will be noted that the increase in
death rates from lung cancer has been almost ex
clusively limited to men and that the rate of cancer
for women has been relatively constant within
countries. It is equally apparent that great varia
Early 1930',
England and Wales 3.0:1
Scotland 1.9:1
Finland 5.9:1
Switzerland 6.0:1
Netherlands 3.3:1
NewZealand
UnitedStates L3:1
Denmark 1.8:1
Union of South Mrica 3.8:1
Ireland (Republic) 1.7:1
Australia
Canada L1:1
Italy
Norway 1.5:1
1951
5.4:1
4.3:1
5.8:1
6.1:1
5.8:1
4.4:1
4.7:1
3.9:1
3.5:1
4.1:1
4.@: 1
3.5:1
L@: 1
I, 1932-. 1934)
(i949)
C1952)
Il 1.4 (1931)
r13.4 (jQq9)
c::i @ .s (iqsi)
!IL_I.t (1929- 93@)
44Rw@4v' ri3.' (1949)
L 1 @ .4 $462)
JIPA*' I!122 @:@3
CHART @.Death rate for cancer of respiratory system in
females (rates per 100,000 deaths). Data obtained from
Director-Consultant on Health Statistics, World Health
Organization.
@ : (s935-% 9V1)
/@fLAMO 4.5 (1q49)
7.5
11 21
k$TA'AL/fl 3.(.
4.3
Research.
Cancer Research 880
tion can be noted in the increase in the male rate
from country to countiy. Explanations for this
disparity on the basis of better and more readily
available diagnostic facilities for men, greater
susceptibility in men, or an as yet cryptic sex
linkage for lung cancer development are unten
able. Lilienfeld (74), however, very recently sum
marized a preliminary study on nonsexual-site
cancers, including lung cancer, by stating that his
findings suggested an endocrine-determined sus
ceptibility to these cancers. There remains as prob
ably a more valid explanation for the lower inci
dence of lung cancer in women a difference in
exposure to the environmental carcinogenic agent
and perhaps to a very minor degree a difference in
response to it. For, in fact, where exposure to iden
tical environments has been recorded, the liability
to lung cancer between the sexes is similar (@7). In
like fashion, Lew (73) found no difference in the
lung cancer rates of women policy-holders belong
ing to the two insurance groups in his study.
Those ascribing a predominant initiating and
promoting role to cigarette smoking offer as an
explanation the almost universal onset of smoking
in women two to three decades later than in men,
and as a corollaiy they postulate a future rise in
the lung cancer rates in women. They neglect to
consider that fewer opportunities exist in the in
stance of women for daily industrial and urban
exposure to carcinogenic air pollutants. Women
only to a very limited degree in the past have
worked in manufacturing installations, have
driven in heavy traffic to and from work, and have
pei'formed heavy manual labor in dirty polluted
environments. Rather, they formerly spent most
of their time in residential areas within cities or
semi-rural suburban communities. A note of cau
tion appears necessary in interpreting any future
rise in female lung cancer rates. Perhaps even
more dramatic than the increase in smoking that
has occurred in women during the past several
decades has been their entry into the previously
almost exclusively male business, industrial, and
occupational domain. The implications of this are
clear.
E. I nt er pr et at i on of epi demi ol ogi c dat af or sel ect ed
countries by local investigators.The interpreta
tions by investigators of their data, which were
freely utilized in compiling Charts 1 and @ and
Tables 1 and @, are important and will be dis
cussed by countries.
Denmark: Clemmessen (14, 15, 17) and his co
workers reported the increase in mortality from
lung cancer as beginning approximately in 1931.
This increase was most marked in Copenhagen,
and a progressively lower incidence was noted in
provincial towns and rural areas. Rather than re
fleeting a true difference in the risk in the develop
ment of lung cancer, he ascribed the different rates
to a delay of 8 years in the onset of the carcino
genie influence in provincial towns and 10 years in
rural areas. This conclusion followed an analysis of
incidence rates for successive cohorts. The cohort
studies further indicated that a f-decade period of
exposure was necessary for the carcinogenic effect
to become clinically manifest. He placed the intro
duction of etiologic agents into the environment
during the period between 1900 and 1910. He
could find no reason to assume any carcinogenic
influence due to atmospheric pollution but rather
correlated the increased development of lung
cancer with heavy cigarette smoking.
Norway: Kreyberg (68, 69), in reporting the
increasing incidence of lung cancer in Norway,
noted a seven-fold increase in men and a four and
a quarter-fold increase for women in lung cancer
between the years 1930 and 1950. In analyzing the
phenomenon of lung cancer in Norway, he detect
ed the first evidence of a rise in approximately the
middle 1940's with a progressive increase occurring
since then. He concluded from a detailed analysis
of his data that the panorama of lung cancer in
crease is not as yet perceptible in true rural dis
tHeta in Norway, which continue to have the same
distribution, histological type, and sex ratio as
presented by Oslo a few decades ago. In parallel
with Clemmessen, he demonstrated a progressive
decrease in lung cancer incidence with decreasing
urban community size. He concluded on the basis
of a review of @35cases that the new development
(1ung cancer increase)was as yet not manifest in
truly rural districts. On the other hand, the in
crease was definitely established in all types of
urban settlements. In spite of a decreasing mci
dence in progressively smaller towns, he noted that
the urban predominance was a reflection of an
essential urban factor other than smoke and fumes
from industry, since towns of identical size had
similar rates independent of the degree of indus
trialization. By applying the @0-yearexposure or
latency period, the onset of the rise may be postu
lated as having begun between World War I and
the middle 19@O's.
Sweden: Specific death rates for lung cancer
from Sweden, as reported by Henschen (5@), show
a pattern of lung cancer increase dissimilar from
that of either Norway or Denmark. This increase
has been at a slower rate than that noted in either
Norway or Denmark, with the over-all incidence
figures being more nearly akin to those of the
Netherlands (60). Worthy of special comment is
the fact that the sex ratio in Sweden differs sig
nificantly from that of Denmark and Norway.
United SUites: Dorn (31, 3@) noted that the
Research.
K0TINAtmospheric Pollution and Pulvwnary Cancer 381
mortality from cancer of the lung in the United
States in both white and nonwhite populations is
greater in males than in females, and the diver
gence is becoming more marked with the passage
of time. The increase shows a progressive accelera
tion from 1930 to 195g. A study of cancer morbidi
ty data for the years 1937 and 1947 in nine metro
politan centers shows incidence differences and
variations in the rate that can be explained only by
environmental variations. The increase in lung
cancer in the United States is present in all ages,
with the peak age incidence occurring between the
ages of 6065.
It has been postulated that the increase in lung
cancer incidence in the United States became
clinically manifest in 19%0. By assuming the @0-
year period of exposure postulated by Clemmesen,
we see that 1900 represents the time of introduc
tion of carcinogens into the environment. This
parallelism of the time of onset in the United
States with that of Denmark is pointed out by
Dorn, who further noted that the incidence rates
for males in Copenhagen in the 194347period are
surprisingly similar to those for the United States
in the 194748period. A primary difference oh
served was that the maximum incidence in the
Danish data occurred between the ages of 55-59,
or about S years earlier than in the United States.
The similarity between Denmark and the United
States is even more remarkable in females.
Hoffman and Gilliam (53), in studying the geo
graphic distribution of lung cancer mortality in
the United States, showed that cancer mortality
is greater in towns than in rural areas among all
age, race, and sex groups. It is of interest to note
that they used the standardized mortality ratio
(S.M.R.) of the Registrar General of England and
Wales in reporting their data.
@ Rigdon and Kirchoff (88) in a more limited geo
graphic study reported an increased incidence of
lung cancer in urban residents. They felt that they
had correlated the presence of lung cancer with the
availability of medical diagnostic facilities and
with low patient-doctor ratios. They summarized
their findings in saying that . . . in our opinion
the data available today do not justify the conclu
sions that the increase in the frequency of cancer
of the lung is the result of cigarette smoking. The
statement that carcinoma of the bronchus has
actually increased in frequency is in our opinion
open to question.
England: Stocks (96, 97) showed that for the
years 19@O30 there was a marked increase in
cancer of the lung in Great Britain, an increase
that was real, progressive, and ever accelerating.
The distribution of mortality due to lung cancer
showed a positive association with the density of
population and maleness. Death rates in the larg
est towns were more than twice as high as in the
country districts. Subsequent studies in 1946-49
and 195@54 verified this difference in urban-rural
mortality. Curwen, Kennaway, and Kennaway
(@2) in studying cancer of the lung concluded that
. . . fresh evidence to support earlier findings that
mortality from cancer of the male and female lung
is positively correlated with population density.
Following an analysis over a prolonged period of
the same source material as Stocks, they concluded
that theStandard Mortality Ratio (S.M.R.) for
cancer of the lung in both sexes, and of the larynx
in males, increases with increasing urbanization,
that is to say, is greater in the County Boroughs
than the Urban Districts, and in the Urban Dis
tricts than the Rural Districts. Cancer of the fe
male larynx shows exactly the reverse relationship.
Thesetrends apply equally when the figures
are analyzed according to the separate regions, but
there are differences between the regions, which
may or may not be due to differences in degrees of
urbanization undetected by the classification we
have used.
More recently, Stocks and Campbell (98) un
dertook a study for the purpose of evaluating the
lung cancer death rates among smokers and non
smokers in relation to air pollution. He summa
rized his findings with the statement : Theabso
lute urban excess is much the same in each smok
ing group, suggesting that an urban' factor is
added to the effects of smoking. He further noted,
Differencesin smoking habits of the populations
can account for only a small fraction of the con
trast in total rates, and it is estimated that about
half the Liverpool deaths of men from lung cancer
arise from cigarette smoking and about three
quarters of the remaining half are due to a factor
which is only slightly present in the rural area. . . .
France: Denoix and Gelle (ES) report a regular
increase in lung cancer as far back as records exist.
The evolution has been regular with no accelera
tion being demonstrated at any given point. Fur
ther, the increase in morbidity is shared by all
ages. The over-all death rate from lung cancer in
males has increased 30 per cent during the years
19495g.The actual rate is close to that of the
Netherlands and Denmark, all three of which are
significantly lower than those for the British Isles.
Australia: Fowler (4@) reported a uniform in
crease in the rate of lung cancer of 7.7/100,000 per
year for males and 4.6 for females. He emphasized
that, though the rate of increase differs from that
of other countries, the exponential pattern is the
same. The increase may be presumed to have be
gun in 1930, with a fragmentary increase occurring
in the previous two decades.
Research.
38@ Cancer Research
New Zealand: Eastcott (38) in analyzing his
data was cogni zant of the rol e that i mmi grati on to
New Zeal and pl ayed i n the modi fi cati on of hi s
sampl e. By i ntegrati ng thi s factor i nto hi s epi
demi ol ogi c data, he concl uded that i mmi grants
from Great Bri tai n to New Zeal and are affected by
thei r former envi ronment and that thi s effect i s
rel ated to the l ength of exposure to that envi ron
ment. The excl usi ve effect demonstrated was i n
rel ati on to l ung cancer and was establ i shed as pri or
urban resi dence. He noted, Thechances of dyi ng
of cancer of the l ung are 30 per cent hi gher for al l
Uni ted Ki ngdom i mmi grants, but for those who
are 80 years of age or more on enteri ng New
Zeal and, the ri sk i s 75 per cent hi gher. . . . Di ffer
ences i n habi ts of tobacco smoki ng are unl i kel y to
contri bute to thi s pi cture.
Iceland: Dungal (34) in 1950 concluded that the
rari ty of l ung cancer i n Icel and was associ ated
wi th a sl ow rate of i ncrease i n the ci garette smoki ng
habi t throughout hi s country. He fel t that atmos
pheri c pol l uti on woul d pl ay l i ttl e, i f any, rol e i n
any future i ncrease i n l ung cancer. He predi cted
that a ri se i n the l ung cancer rates woul d become
mani fest between 1960 and 1965 i f smoki ng were
chi efl y responsi bl e for i ts i ni ti ati on. In a more re
cent report (35), he noted a begi nni ng ri se i n i n
ci dence. Though the number of cases i s too few to
permi t any epi demi ol ogi c concl usi on, he rel ates the
cases to heavy smoki ng on the part of ol der peopl e
i n whom l ungcancer i s now begi nni ng to
crop up.
F. Racial differencesin lung cancer rates.A
study of raci al di fferences i n the suscepti bi l i ty to
l ung cancer i s i ndi cated especi al l y i n terms of the
gui dance i t can provi de for future studi es. Stei ner
et at. (95), in a study of the necropsy records at the
Los Angel es County General Hospi tal , reported,
Forpresent purposes i t may be stated that i n
Mexi cans the i nci dence of l ung cancer was as hi gh
i n women as i n men, and that the i nci dence i n the
l atter equal l ed that i n caucasoi d men. Hoffman
and Gi l hi am (58) reported a l ower l ung cancer rate
i n Negroes and summari zed thei r fi ndi ngs: The
total rates for the whi te popul ati on are consi dera
bl y hi gher than those for the nonwhi te, but the
di fference i s more pronounced among mal es than
among femal es. In marked contrast, Duchen (33)
i n South Afri ca found no i ncreased i nci dence i n
Caucasi ans when contrasted wi th the Bantu na
ti ve that coul d not be expl ai ned by di fference i n
l ongevi ty. Warwi ck and Phi l l i ps (10@), i n a study
of cancer among the Canadi an Indi ans, detected
no di fferences i n i nci dence they coul d attri bute to
race. Fi nal l y, Si tbon (9@) i n Al geri a reported no
raci al vari ati ons i n the i nci dence i n l ung cancer.
The foregoi ng data permi t of no concl usi on other
than i ndi cati ng a need for future i ntensi ve studi es.
G. Socio-economiedifferencesin lung cancer
rates. Numerous i nvesti gators have been i m
pressed wi th the vari ati ons i n cancer i nci dence on
the basi s of the soci o-economi c status of di fferent
popul ati on groups. In appl yi ng thi s cri teri on to
pati ents wi th l ung cancer, Cl emmessen and Ni el
sen (16) noted a si gni fi cant accl i vi ty i n the mci
dence of l ung cancer i n the mal e popul ati on of the
poorer cl asses i n Copenhagen. Kennaway (57), i n
revi ewi ng the data rel ati ng to cancer i n the publ i
cati ons of the General Regi ster Offi ce, coul d not
di scern any i nfl uence of soci al cl ass upon the l i a
bi l i ty to l ung cancer. He di d, however, emphasi ze
. . . the very considerable effect of urban condi
ti ons whi ch suggest some carci nogeni c factor to
whi ch al l cl asses are exposed. Very recentl y,
Cohart (19) i n a l i mi ted study paral l el ed the fi nd
i ngs of Cl emmessen and Ni el sen and concl uded,
Thei nci dence of l ung cancer was more than 40
per cent greater among the poor than among other
soci o-economi c cl asses. Unl ess i t i s assumed that
ci garette smoki ng i s i nversel y rel ated to soci o
economi c status, an assumpti on that probabl y
cannot be supported i n fact, then i t i s reasonabl e
to concl ude that i mportant envi ronmental factors
other than ci garette smoki ng exi st that contri bute
to causati on of l ung cancer. Densi ty of popul a
ti on, proxi mi ty to i ndustri al i nstal l ati ons, atmos
pheri c pol l uti on, poor soci o-economi c status, and
i ncreased l i abi l i ty to l ung cancer consti tute a con
fi gurati on repeated frequentl y i n epi demi ol ogi c
studi es on l ung cancer.
H. Occupational lung cancer.The significance
of occupati onal respi ratory cancers resi des not
onl y i n thei r rol e as an i mportant group of i ndus
tri al di seases but al so as denotati ons of envi ron
mental l ung cancer trul y secondary to atmospheri c
pol l uti on. They, therefore, shoul d serve as gui de
posts for the study of l ung cancer i n rel ati on to ai r
pol l uti on of a general rather than occupati onal
type. Speci fi c pul monary carci nogens whi ch have
been i denti fi ed i n the occupati onal envi ronment
i ncl ude ni ckel and chromi um, as unequi vocal ex
ampl es of i norgani c chemi cal s, and combusti on
and di sti l l ati on products of coal and petrol eum, as
exampl es of organi c chemi cal s. The data i ncri mi
nati ng radi oacti ve substances have been referred
to previ ousl y. Though there i s no unani mi ty of
opi ni on, Dol l (@9), Wei l and hi s co-workers (104),
Perry et al . (85), and Bonser and her associ ates (6)
have reported hi ghl y suggesti ve data associ ati ng
i ncreased l ung cancer rates wi th exposure to as
bestos, i sopropyl oi l , arseni c, and i ron, respec
ti vel y.
Research.
K0TINAtmospheric Pollution and Pulmonary Cancer 888
Worthy of comment is the paradoxicaj situation
relating to chromates and beryllium. While little
question exists as to the increased pulmonary can
cer incidence associated with exposure to chro
mates, extensive attempts to induce experimental
pulmonary cancers in a broad spectrum of mam
malian species have been uniformly unsuccessful
(i). Conversely, beryllium, which has but a ques
tionable association with increased lung cancer
rates in those occupationally exposed, has been
used to produce bronchogenic carcinomas in the
lungs of rats (99). The experimental corroboration
of radioactivity as a pulmonary carcinogen has
been reported following the development of bron
chogenic carcinomas in rats (75).
As previously mentioned, the cases of occupa
tional lung cancer recorded thus far are too few to
affect materially nation-wide incidence figures.
Nevertheless, neighborhood contamination and
general atmospheric pollution with these sub
stances is well documented. Additional details re
ferring to these factors will be discussed subse
quently.
I . Rsum. An unbi ased anal ysi sof the epi
demiologic data reviewed here clearly shows that
at this time the data are capable of more than one
interpretation. Attempts to relate increasing lung
cancer rates with increasing tobacco consumption,
though falling into a broad and variable pattern,
may be considered relatively successful. Compa
rable analyses with respect to motor fuel consump
tion, increase in asphalt highway mileage, fuel oil
sales, and motor vehicle registration show an even
more pronounced relationship. It should be noted
that a uniform and perhaps critical deficiency in
all these associations is the gross failure to corre
late the data with the period of introduction of the
carcinogen into the environment rather than with
the increase in lung cancer rates. In other words,
the role and importance of the latency period are
either overlooked or minimized. If the latent
period is regarded as being approximately two
decades in duration, reference to Chart Swill show
that not only does the rise in lung cancer follow
more closely factors other than tobacco, but in
addition the increase in these environmental fac
tors is more capable of correlation with the latent
period. Hueper (55) has similarly shown that a
parallelism exists between the increased produc
tion of cancer-related chemicals and the rise in
lung cancer (Chart 4).
CHART 3. Tr ends i n sel ected envi r onmental factor s, US., whi ch smokes. Data obtai ned thr ough cour tesy of Dr . E. C.
1900-1953 (19@4-%6 = 100). Note: Cigarette consumption HAmmond.
per adult reflects entire population rather than that segment
Research.
384 Cancer Research
ENVIRONMENTAL CARCINOGENIC AGENTS
A. OCCUpati Onal r espi r ator ycar ci nogens. Con
siderable basic information has been derived from
a detailed study of established respiratory carcino
gens in occupational environments. First and most
obvious is a broadening of the spectrum of envi
ronmental carcinogens capable of producing pul
monary cancer.
Second, opportunities for specific documenta
tion of initial exposure time to these agents and
their concentrations are possible by referring to
industrial records or vital statistics. Latency
periods have been shown to vary from less than 10
years to as much as 50 years for the various ac
cepted occupational cancerigenic agents. Regard
less of the particular agent studied, the average
cancers have been identified in nickel workers. As
noted by Hueper (55), Carcinogenic dusts con
sisting mainly of coarse particles are mainly ar
rested in the nares where they cause cancer of the
turbinates. The nasal cancers observed among
copper-nickel matte refinery workers inhaling the
coarse dust of the roasters illustrates this inter
relation. The bronchogenic cancers found in
coke-oven and gas-retort workers, and among
those exposed to chromates, represent instances of
occupational exposure to aerosols, dusts, vapors,
or mists of a particle size sufficiently small to per
mit penetration into the arborization of the
tracheobronchial tree.
Failure in this report to detail the association
between increased liability to lung cancer in ashes
I. @TUM*A CDS &. -PRODUCTION IN U.S ..
MIWONS OI@PItT TONS
A FU(L BRIQUCTS-TOTSI. PRODUCTION.
THOUSANDS @ NC? TONS
A CARBON BlACK . PROOUCTICN IN
MIWONS OI@POUNDS
4. PCTROLCUM- PRODUCTI ON or c* i oc PCTROI .CUI I .
PILLIONS or BARRCLS
S. PCTROLCUU. ASPHALT - PROOUCTI ON CV ASPHALT
(rROMPCTN0LCUI4. mot,s*scs or
SHORT TONS
0. COAL TAR- PRODUCTION- THOUSANDS 01
7. ISOPROPANOL- PRODUCTION- THOUSANDS 01
POUNDS
0. ASBCSTOS - APPARCNT CONSUMPTI ON.
THOUSANDS or SHORT TONS.(MYRBK.103.)
9. ARSEPAC- PRODUCTI ON AND I MPORTS,
THOUSANDS 01 SHORT TONS
10 CHROMTC - TOTAL SUPPLY, THOUSANDS 01 TONS
SOURCC MINCRALS YEARBOOK I94@
CHART 4. Ri se i n annual pr oducti on or consumpti on of cancer -r el ated i ndustr i al chemi cal s between 1940 and 1948. Data
obtained through the courtesy of Dr. W. C. Hueper.
/
$900 ND5 SO SO
I I I I $
$920 $125 $930 1035 $940 $945 $950
latent period invariably falls in a 15@5-year time
period (55). This is not unanticipated in view of
our knowledge that many of these agents in larger
doses are su.fficiently toxic so as to produce mor
bidity or mortality well in advance of the time
necessary for clinical cancer to develop. As a re
suit, exposure to quantitatively small amounts
would appear to be the necessary antecedent for
any cancer development.
Third, the development of neoplasms in selec
tive sites of the respiratory tract provides informa
tion on the significance of the physical state of the
chemical carcinogens. Perhaps foremost among the
physical factors is the size of the particulate mat
ter of the carcinogen per se or the carrier on which
it is adsorbed. Nasal cancers as well as pulmonary
tos workers, workers exposed to isopropyl oil, and
those in contact with arsenic should not be inter
preted as minimizing the importance and validity
of the data. Rather, the conclusions to be derived
from the data are similar to those already dis
cussed. The reader is referred to the comprehen
sive and excellent review of Hueper in Recent De
velopment. in Environmental Cancer (54) for a criti
cal study of the newer data relating to occupation
al cancer.
B. Sour cesof car ci nogeni catmospher i cpol lu
tants. Of the carcinogenic materials present in
the atmosphere, certainly those resulting from the
incomplete combustion of organic matter are most
universally distributed. Soot, a clinically recog
nized cutaneous carcinogen from the time of Sir
Research.
K0TINAtnwspheric Pollution and Pulmonary Cancer 385
was hal f agai n as great duri ng the wi nter as i t was
duri ng the summer, and duri ng foggy weather the
concentrati on was over 4 ti mes that on cl ear days.
Whi l e the amount of benzpyrene retai ned i n the
l ungs i s, of course, i mpossi bl e to assess at present,
he cal cul ated the respi rati on of approxi matel y 1@
mg. of benzpyrene duri ng an average 70-year l i fe
span. Bl aci dock, Kennaway, Lewi s, and Urquhart
(5), fol l owi ng an anal ysi s of the carbon content of
human l ungs, esti mated that approxi matel y 16
mg. of bezi zpyrene may be i nhal ed duri ng a l i fe
ti me. It shoul d be noted that the pri mary atmos
pheri c source of these compounds i n Great Bri tai n
i s from combusti on of coal , wi th as yet undeter
mi ned amounts contri buted by vehi cul ar exhausts.
Koti n (64) and hi s associ ates studi ed the Los
Angel es atmosphere and demonstrated a presence
of 0.84 mg. of 3,4-benzpyrene per mi l l i on cubi c
feet of atmosphere. In marked contrast wi th Lon
don, thi s carci nogen coul d be attri buted al most
enti rel y to the exhaust products of gasol i ne and
di esel engi nes. A detai l ed study of gasol i ne and
di esel engi ne exhausts reveal ed quanti ti es esti
mated up to 1@0 @g. of benzpyrene i n 1-mi nute
sampl es of gasol i ne engi ne exhausts and up to 1.7
mg benzpyrene/mi nute from di esel engi ne cx
hausts (65, 66). In compari ng the rati o of pyrene
to benzpyrene i n the atmosphere wi th that at the
vehi cul ar exhaust source, Fal k and hi s co-workers
(40) noted a reversal of the rati o, wi th benzpyrene
bei ng present i n greater concentrati on than pyrene
i n the atmosphere. Thi s phenomenon was cx
pl ai ned through study of the survi val of vari ous
pol ycycl i c aromati c hydrocarbons i n the atmos
phere. Compounds were tested i n thei r pure state
and whi l e adsorbed on soot and fol l owi ng exposure
to washed ai r and smog. In al l i nstances benz
pyrene was si gni fi cantl y more stabl e than was
pyrene. In fact, i t was vi rtual l y i ndestructi bl e i n
the dark. Cooper and Li ndsey (@0)emphasi zed the
ubi qui ty of atmospheri c pol l uti on fol l owi ng anal y
si s of 1 kg. of freshl y fal l en snow i n Hertfordshi re,
Engl and. The snow contai ned 1 @@zg. of pyrene and
traces of 3,4-benzpyrene and anthanthrene.
Cl emo and Mi l l er (18) di vi ded the ci ty smoke
they col l ected i nto three fracti ons. The presence of
3,4-benzpyrene was detected i n one of these
fracti ons.
The spectrum of carci nogeni c agents present i n
the atmosphere has very recentl y been broadened
fol l owi ng the report of Koti n and Fal k. Fol l owi ng
ski n pai nti ng i n CS7BL mi ce and fol l owi ng i nhal a
ti on i n strai n A mi ce and CS7BL mi ce (63, 67),
they found the oxi dati on products of al i phati c
hydrocarbons to be carci nogeni c. The i mpl i cati ons
of the pul monary neopl asms i nduced wi th these
Perci val Pott (87), i s a maj or component of the
smoke formed and emi tted i nto the atmosphere
fol l owi ng the parti al combusti on of sol i d, l i qui d,
and gaseous fuel s. Compounds i ntroduced i nto the
atmosphere from these sources bel ong pri mari l y to
the group of aromati c pol ycyci c hydrocarbons. A
typi cal carci nogeni c representati ve of thi s group
i s 3,4-benzpyrene. Al though the gradual shi ft from
sol i d to l i qui d or gaseous fuel s throughout the
worl d has resul ted i n quanti tati ve vari ati ons i n the
pol l utants emi tted i nto the ai r, qual i tati ve changes
have been mi ni mal . Addi ti onal sources of these
compl ex aromati c compounds i ncl ude the tars and
asphal t used for road surfaci ng. The i ncrease i n
mi l eage of asphal t-topped roads has al ready been
referred to i n Chart 3. Added to thi s source of car
ci nogeni c materi al s i s the carbon bl ack i ntroduced
i nto the ai r secondary to rubber ti re wear, tear,
and degradati on.
An ever expandi ng and i ncreasi ng source of
emi ssi on of carci nogeni c hydrocarbons i nto the
atmosphere i s l i qui d fuel used i n i nternal combus
ti on engi nes. Gasol i ne engi nes represent the most
uni versal type of moti ve power i n urban areas,and
di esel fuel engi nes power our buses, trucks, rai l
road l ocomoti ves, and el ectri c power faci l i ti es to
an ever expandi ng degree. Not onl y are l arge
amounts of the known carci nogen, 8,4-benzpyrene,
i ntroduced i nto the ai r by the combusti on of
petrol eum fuel s, but the reacti on products of non
combusted gasol i ne i n thei r al i phati c, nonaro
mati c, pol ycycl i c state possess experi mental car
ci nogeni c potency (63, 67).
Suppl ementi ng these compounds there are
emi tted i nto the atmosphere measurabl e concen
trati ons of i norgani c materi al s demonstrated to be
occupati onal l y associ ated wi th i ncreased l i abi l i ty
to l ung cancer devel opment. Incl uded woul d be
heavy metal s, l i ght metal s, and i norgani c dusts.
Quanti tati on of a known carci nogeni c substance
obtai ned from an atmospheri c pol l uti on source was
fi rst reported i n 1949 by Goul den and Ti pl er (46)
who, by means of fl uorescence spectroscopy, i den
ti fi ed 3,4-benzpyrene i n a representati ve sampl e of
chi mney sweep's stock i n a concentrati on of 300
mg/kg of soot.
C. Known and suspectedcarcinogenicagentsin
the atmosphere.Waller(100) sampled the atmos
phere at ten di fferent si tes i n several ci ti es i n Great
Bri tai n and demonstrated the presence of 3,4-
benzpyrene i n the ai r. The hi ghest concentrati on
of 4.5 pg/100 cubi c meters was obtai ned i n Lon
don, and the l owest noted was i n Bri stol , wi th 1.3
@hg/1OOcubi c meters measured there. A mean con
centrati on of @.6@Lg/100cubi c meters was obtai ned
for al l si tes studi ed. The concentrati on i n London
Research.
386 Cancer Research
agents will be discussed. The chief source of all.-
phatic materials in the atmosphere is unburned
gasol i ne.
Menti on shoul d be made of the pr esence of ar
seni c i n the atmospher e. The sour ces woul d i ncl ude
primarily the burning of fuels and secondarily in
seeticide use and metallurgical sources. Goulden
(45) and his co-workers measured the arsenic con
tent of the atmospher e at ei ght si tes i n Engl and
during the winter and summer. They computed
from their data that approximately 0.5 mg. of
arsenic as arsenic trioxide would be respired during
the cour se of 1 year . Whi l e thi s amount i s l ow, i ts
possible role in association with other known car
ci nogens shoul d be kept i n mi nd.
The concentr ati on of metal s i n the atmospher e
has been determined by investigations of the Stan
for d Resear ch I nsti tute (93) for Los Angel es and
by Chambers and his co-workers (18) for several
other Amer i can ci ti es. The amounts pr esent, espe
cially of chromium and nickel, are minimal. As in
the case of ar seni c, however , possi bl e addi ti ve or
synergistic effects with hydrocarbon carciiiogens
should not be forgotten.
Perhaps the most controversial of atmospheric
factor s of theor eti cal car ci nogeni c si gni fi cance ar e
those r el ati ng to i oni zi ng r adi ati on. I n a compr e
hensi ve study of r adi oacti ve mater i al i n the at
mosphere carried out in London, in Manchester,
and in the country at B.othamsted, Dawson (@4)
concluded that no considerable difference existed
between urban and rural districts. Day-to-day
variations were marked and could be related to the
activity of the atmosphere in terms of wind veloci
ty : The mor e stati onar y the ai r , the gr eater the
activity. At all times amounts present were ex
ceedingly small in comparison with the lowest
concentration considered harmful to man.
D. Bi ol ogi cdemonstr ati ons of car ci nogenswi th
atmospheric pollutants. Biological demonstration
of car ci nogeni ci ty wi th mater i al s whi ch ar e fr e
quent sour ces of ai r pol l uti on was successful l y
undertaken by Passey (84), who in 199@reported
the pr oducti on of exper i mental cancer s i n mi ce
following painting with ether extracts of household
chimney soot. Campbell (11) similarly produced
skin tumors in mice following painting with tars
extracted from chimney soot. Leiter (70, 71) and
hi s co-wor ker s r epor ted the devel opment of sub
cutaneous sar comas i n mi ce i nj ected wi th tar s
extracted from the atmospheric dusts of several
American cities. The extracted tars were injected
i n amounts var yi ng fr om @1 to 71 mg. suspended
i n O.@5cc. of tr i capr yl i n. Mor e r ecentl y, Koti n and
hi s co-wor ker s r epor ted the pr oducti on of ski n
cancers in C&7BL mice following painting with
extracts of Los Angeles atmosphere and materials
col l ected fr om the exhaust of gasol i ne engi nes and
diesel engines (64-66).
The pr ecedi ng r epr esentati ve exampl es of ski n
tumor production in mice, coupled with analytical
studi es pr evi ousl y menti oned, pr ovi de di r ect bi o
logic evidence of carcinogenic materials belonging
to the aromatic polycyclic hydrocarbon group of
compounds in several pollution sources and in the
atmosphere per se. The traditional carcinogenicity
of these compounds is well known. In 1955 Kotin
and hi s co-wor ker s r epor ted the successful pr oduc
tion of skin tumors in mice using aromatic poly
cyclic hydrocarbon-free atmospheric extracts (61).
The samples used for the tumor production con
sided of oxidation products of aliphatic hydro
carbons formed in the atmosphere in accordance
with the theory as developed by Haagen-Smit (48,
49) andsi nceconfi r medby other s(108).Hepostu
lated a primary photochemical reaction between
oxides of nitrogen (a product of internal combus
tion engine exhaust) and organic molecules: abco
hols, aldehydes, ketones, acids, and hydrocarbons,
both as emitted from vehicular exhaust and as in
troduced into the atmosphere through the volatii
zation of uncombusted gasoline. Ozone forms as a
result of a radical chain reaction. While less is
known about the reaction products other than
ozone, the ozone itself is known to react spontane
ously with unsaturated molecules which also are
present in gasoline engine exhaust and unburned
gasoline. The reaction products consist of an
aerosol which was used for skin painting.
The products of this subsequent reaction (ozone
plus hydrocarbon) occurring in the atmosphere are
more completely understood than those of the
primary free radical reaction. This reaction is in
stantaneous and produces an ozonide which in the
presence of moisture gives rise to a variety of
peroxides. These compounds result in aldehydes
and acids. The peroxides react subsequently with
aldehydes and acids, producing peracids which
then react with unsaturated hydrocarbons to yield
epoxides. A simplified schematic representation of
these reactions is shown in Chart 5. It should be
noted, however, that many additional side reac
tions take place simultaneously, reducing the yield
of these compounds. The tumor yield with these
compounds was l ess than that obser ved wi th at
mospheric extracts containing aromatic polycydic
hydrocarbons.
The broadening of the spectrum of carcinogens
in the atmosphere with these agents is of special
si gni fi cance i n that thei r entr y i nto the envi r on
Research.
0MpqiIA/fD CO/'IPOUNOS 4@ce
@5us/'E-ci@-o o C.4Rc,i,o.@@ew,c/ry
CH&wr 5.Schematic r epr esentation of oxidation r eactions of aliphatic compounds
K0TIN Atmospheri c Pol l uti on and Pul monary Cancer 387
ment i s compati bl e wi th thei r acti on as i ni ti ati ng
or promoti ng agents i n the i ncreasi ng i nci dence of
cancer of the l ung.
Attempts to i nduce or i ncrease the yi el d of pul
monary tumors by i nhal ati on experi ments were
fi rst reported by Campbel l (8-10), who exposed
mi ce i n i nhal ati on chambers to resuspended sweep
i ngs of dust from tarred roads. In addi ti on to the
devel opment of cutaneous tumors, he noted a hi gh
er i nci dence of pul monary tumors i n hi s test mi ce
than i n hi s control s.
Seel i g and Beni gnus (90, 91), i n one of two ex
peri ments, used chi mney soot as an i nhal ant for
Buffal o strai n mi ce and reported an 8 per cent pri
mary pul monary tumor yi el d i n contrast wi th a @
R@. - CHa C, Li - R
O N$4TUA'ATKO
HYDRO CAR@ O M S
R'CH-C//--R O aR
a / PfPAC/O
fpax/Dr
of exposure and endi ng wi th the 594 week. At al l
i nterval s the number of tumor-beari ng mi ce, the
number of mul ti pl e tumor-beari ng mi ce, and the
total tumors i n the test chamber were si gni fi cantl y
greater than those i n the control chamber. Koti n
further has demonstrated the producti on of pul
monary tumors i n C57BL mi ce exposed to a si mi
l ar atmosphere of ozoni zed gasol i ne.'
Bronchogeni c cancers, apparentl y of the type
seen cl i ni cal l y, have thus far been produced ex
peri mental l y onl y i n rats. Vorwal d (99) exposed
rats for over 1 year to an atmosphere contai ni ng
sol ubl e and i nsol ubl e beryl l i um sal ts and noted the
devel opment of true bronchogeni c neopl asms.
Dutra (37) produced osteogeni c sarcomas i n ex
CH...PR
I@
I
,0...-
CH- R
0/1 0/1
PERO XIDE
1120
R-c/1Q R@C0OH
AlDEN ,4CID
per cent yi el d i n thei r control s. In a second experi
ment they adsor bed gas-wor k tar onto car bon
bl ack for i nhal ati on by C57BL mi ce. No puhno
nary tumors were produced i n the test mi ce.
McDonal d and Woodhouse (77) exposed mi ce
of apparentl y i ndi fferent strai ns to dust obtai ned
from ci ty thoroughfares and to dust col l ected from
the ai r-puri fyi ng system of a hospi tal adj oi ni ng an
i ndustri al area. Whi l e they reported that they
wer e unable to show the str iking incr ease in their
test mi ce that Campbel l reported i n a si mi l ar ex
peri ment, they di d show an exaggerated produc
ti on of pul monary adenomas i n thei r test mi ce.
Koti n and Fal k (63) reported an exaggerated
i nci dence of pul monary tumors i n strai n A mi ce
exposed to an atmosphere of ozoni zed gasol i ne.
They removed mi ce from the i nhal ati on chamber
at 4-week inter vals, beginning with the 9Ath week
per imental animals exposed to an atmospher e con
tami ng beryl l i um oxi de. Li sco and Fi nkel (75) oh
served neopl asti c changes i n the bronchi al epi
thel i um i n rats exposed to an aerosol of radi oacti ve
cer ium. The car cinogenic power s of ionizing r adia
tion for tissues other than the lung ar e well known.
DISCUSSION
A. Epidemiologicconsider ationsin inter pr eta
tion of pathogenesis.The epidemiologic data re
l ati ng to l ung cancer as revi ewed here show
marked contradi cti ons. The i nconsi stenci es appear
to be wholly ir r econcilable if but a single initiating
and promoti ng agent were to be regarded as bei ng
responsi bl e for the i ncreasi ng i nci dence of l ung
cancer. Of the two suggested maj or eti ol ogi c fac
tors, ci garette smoki ng al one appears the l east
P.Kotin, unpublished data.
Research.
388 Cancer Research
capable of adaptation to the panorama of lung
cancer as i t i s currentl y mani fest. The l i mi tati ons
of the tobacco concept of etiology are evident in
studi es showi ng di fferences i n l ung cancer rates on
the basis of socio-economic status. Geographic
studi es si ngl i ng out urbani zati on as the excl usi ve
variable in groups with contrasting lung cancer
rates cast further doubt on the val i di ty of the
major role assigned to tobacco in pulmonary can
cer. The urban-rural difference in incidence could
very possi bl y, i n one or even several countri es, be
a manifestation of difference in smoking habits.
It is unlikely,however,that peopleswithdifferent
cul tures, economi es, and mores shoul d have i den
ti cal smoki ng habi ts and patterns. More readi l y
tenable is the hypothesis that urban-rural differ
ences are a true reflection primarily of the differ
ence in the cleanliness of the atmospheric environ
ment. Data already referred to in the text as a basis
for this observation are available from epidemio..
l ogi c studi es made i n Norway (68, 69), New Zea
l and (38), the Uni ted States (31, 3@, 43, 44, 55),
and Denmark (14-17). These data emphasize dif
ferences in urban-rural cancer rates and the great
er incidence in the low socio-economic groups.
Cl emmessen i nterprets di fferences i n rural -urban
i nci dences as evi dence of di fference i n the onset of
exposure to the carci nogeni c agent. A more l i kel y
explanation would be that the concentrations of
carci nogens i n the atmosphere i n rural areas are
lower as a result of fewer sources of atmospheric
pollution and dilutions of the pollutants carried to
the country by winds from the city. Accepting dif
ferences i n urban-rural rates as a functi on of at
mospheri c pol l uti on, one can readi l y reconci l e the
paral l el i sms noted between l ung cancer rates and
densi ty of popul ati on and degree of urbani zati on.
Not the l east si gni fi cant of the epi demi ol ogi c con
si derati ons concerned wi th atmospheri c pol l uti on
are the documented i nstances of occupati onal l ung
cancer. The parameters of the exposure and the
response of the host are defi ned wi thi n measurabl e
l i mi ts. Sex di fferences i n l ung cancer rates are not
i rreconci l abl e wi th the concept of atmospheri c
pol l uti on as a maj or eti ol ogi c factor. The contrast
i ng soci al and economi c rol es of men and women
resul t i n a more prol onged exposure to a greater
concentrati on of pol l uted atmosphere on the part
of men.
The convi cti on that ai r pol l utants possess the
abi l i ty to i ni ti ate and promote pul monary cancer
i n no way precl udes the rol e of other possi bl e fac
tors. Stocks and Campbel l (98) i n thei r recent
study of the combi ned effect of smoki ng and ai r
pol l uti on on l ung cancer death rates demonstrated
an urban-rural rati o of 9:1 for nonsmokers resi di ng
i n Li verpool as compared wi th those l i vi ng i n
adjacent rural areas. At every level of smoking in
tensi ty, Li verpool rates exceeded the rural rates.
As smokingincreased,the disparityprogressively
decreased to a l evel where the di fference ap-.
proached a factor of l ess than two. They concl uded
that a dual rol e now appears to be tenabl e as a
worki ng hypothesi s for the gui dance of future
studi es. Si nce not al l resi dents i n any area smoke
and the very method of smoking varies from mdi
vi dual to i ndi vi dual , attempts to correl ate l ung
cancer incidences with tobacco consumption on a
per capi ta basi s i n any gi ven popul ati on group
denote a type of epi demi ol ogi c gerrymanderi ng.
In a gi ven communi ty, however, a constancy i n
exposure to atmospheri c pol l uti on or l ack of ex
posure can be rel ated to resi dence si te, occupati on,
and duration of these two.
The inconsistencies and the irreconcilable fac
tors i n the epi demi ol ogi c data make i t ampl y ap
parent to thi s revi ewer that the contri buti ons of
l aboratory data wi l l be of ever i ncreasi ng si gni fi
cance in the ultimate revelation of the mechanisms
and etiologies of lung cancer.
B. Roleof chemicaland physicalfactorsin patho
genesi@. Of equal significance to the epidemio
logic data are the chemical and physical data re
lating atmospheric pollution to the pathogenesis
of lung cancer. The demonstration of 3,4-benz
pyrene i n urban atmospheres has been successful
wherever undertaken. On the basi s of current
knowl edge, the concentrati on and the atmospheri c
survi val of thi s carci nogen are suffi ci entl y great to
postul ate a bi ol ogi cal effect i n humans. The recent
demonstrati on by Koti n and hi s co-workers of the
carcinogenicity of oxidation products of aliphatic
hydrocarbons has made the incrimination of the
atmosphere more certain. The ubiquity of gaso
l i ne, the most common source of these compounds,
combi ned wi th the temporal aspects of the i ntro
ducti on of l i qui d fuel s permi ts of epi demi ol ogi c
i ntegrati on as wel l .
The combination of carcinogenic aromatic poiy
cyclic hydrocarbons, oxidation products of ali
phati c hydrocarbons, and known occupati onal
carci nogeni c agents whi ch pol l ute the atmosphere
warrants suspi ci on of the atmosphere as a factor
i n the pathogenesi s of human l ung cancer. Com
pl ete i gnorance of any possi bl e addi ti ve or syner
gi sti c effects they may mani fest and the absence
of exacti tude of dosage i n man make thei r di l i gent
study i mperati ve.
The presence of 3,4-benzpyrene i n the combus
tion products of tobacco has been reported. Cooper
and Lindsey (@1) recovered 4 pg. of this carcino
geni c agent from the smoke of 500 ci garettes. Thi s
Research.
:::: @::-
RETENTION 1W LUIVG-
- -::
::::i:::
&c@.P4gri cL@rsi zE
@ ill,
@OTINAtmO8pherW Pollution and Pulmonary Cancer 389
nasal sinuses. Particles of smaller size down to
approximately O.Q5 p settle progressively distally
in the arborization of the bronchi. Those less than
0.@ 5 @ h remain suspended in tidal air until a suffi
ciently miniscule size is reached so that Brownian
movement can produce precipitation.
C. Significaiwe of experimental laboratory data
in pathogene.is.Assuggested above, the incon
sistencies and contradictions in the epidemiologic
data placed increasing responsibility and emphasis
on the laboratory for the elucidation of etiologic
80
70
C0
5@ 0
40
x
20
/0
0
concentration is less than that noted in the atmos
phere in terms of total amounts respired by those
exposed. It is clear that the alleged cause-and
effect relationship ascribed to smoking cannot cur
rently be predicated on the presence of 3,4-benz
pyrene in tobacco smoke, Assuming that the aver
age total of inspired air measures up to 7,500 cubic
meters per year as calculated by Stock s (98), the
average resident of Liverpool, whether smoker or
nonsmok er, would inhale 450 pg. of benzpyrene.
This does not take into account the other presuma
bly carcinogenic materials in the air.
Physical factors play a significant role in
the deposition of particulate matter in the res
piratory tract. The per cent retention of particu
late matter in the lung on the basis of particle size
is shown in Charts 6 and 7. Dautrebande (@3) cor
related the location of particulate deposition with
specific sites in the tracheobronchial tree. The par
tide size of the carcinogenic material in the Los
Angeles atmosphere as measured by Kotin' and
others is wholly consistent with penetration and
settling out of these particles distal to the trachea.
The relative absence of primary tracheal carcino
ma is not an indication of local tissue immunity
- but rathe r re fle c ts the failure of partic le s to s e ttle
out. Those particles capable of settling out on the
tracheal mucosa are identical in size with those
trapped in the nose, epipharynx, and accessory
RFTE,./T/o.v Z
.25J .75/ 2. 1 4.
PART/CL @SIZE
CHART 6.Per cent retention of particulate matter in lung
in relation to particle size.
1.4
1.2
/.O
4
.4
.2
0
T@c'Aew@cA
.07
DRONC/ / /
.12
BRaNCH/al (S ,tf1 VEOL I
.39 2.02
TThIE (3(c@ ) - PA5SAGE
CHART 7.Anatomical pattern of deposition and time of passage of particulate matter in relation to particle size (after
Dautrebande).
Research.
390 Cancer Research
agents and mechanisms for lung cancer develop
ment. The chemical demonstration of carcinogenic
agents in the environment and their successful use
for the production of tumors in experimental ani
mals do not prove or even especially strongly sug
gest a like relationship in the instance of man.
When, however, a demonstrable parallelism exists
between epidemiologic data and laboratory find
ings, greater significance accrues to both. Medical
history is replete with examples in which labora
tory findings have been proved ultimately to have
their counterpart in the human experience. Excep
tions have been very few.
D. A theor eti cal mechani r mfor thepathogenes' i s
of lung cancer. Bymeans of integrating labora
tory findings and experimental data, the author
has arrived at a theoretical mechanism for the
pathogenesis of lung cancer. In spite of the pres
ence of soot in the atmosphere for many centuries
and its association with cutaneous cancer, it is only
within the last several decades that lung cancer
has become a problem of epidemic proportions.
Skin cancers as occupational responses to soot
have long been known. It has been noted by
Steiner (94) and Falk and Steiner (41) that car
cinogenic hydrocarbons adsorbed on soot are bio
logically ineffective until they are separated by
elution from the soot particles. It has been postu
lated that in the case of the skin, sebaceous secre
tions provide the necessary polar substances for
the elution of the carcinogenic materials. Experi
mentally, Kotin and his co-workers (6@) have
demonstrated poor elution powers for the mucous
secretions in the respiratory tract. However, the
introduction of aliphatic polar compounds into the
atmosphere makes available an environmental
. s ource of an e luting age nt capable of e ntry into the
respiratory tract.
The simultaneous respiration of the carcinogen
laden soot and the eluting agent provides a mech
anism for biological activity of the carcinogen.
This mechanism is unlikely to occur when soot
alone is breathed.
Aliphatic hydrocarbons and their oxidation
products in the air were further incriminated in the
pathogenesis of cancer when it was shown that
they could induce both skin cancers and alveolo
genic carcinomas in mice. Cutaneous cancers re
sulted from the painting of mice, and lung tumors
were produced by inhalation. The dual capacity
shown for these compounds makes them suspect
on a laboratory basis. When the laboratory data
are considered along with epidemiologic data, it is
apparent that these aliphatic materials were intro
duced into the atmospheric environment at a time
consistent with their having etiologic significance.
In addition to the eluting role and carcinogenici
ty demonstrated for these aliphatic materials, they
have been shown to be potent irritants for the
respiratory mucosa. In common with other at
mospheric irritants introduced secondary to indus
trialization, these materials transiently affect the
respiratory mucosa by interfering with ciliary
activity and normal mucous secretion. The inter
ference with these normal resistance factors per
mits the accumulation of particulate matter at
selected sites in the tracheobronchial tree as
shown by Kotin. The sites are chiefly at bif urea
tions and angulations in the respiratory arboriza
tions. This accumulation allows prolonged resi
dence of particles on the respiratory epithelium.
The elution of carcinogens is facilitated, as has
been demonstrated by analytical procedures. Dif
fusion of intact soot particles occurs into the res
piratory epithelium, as has been demonstrated by
electron microscopy. A study of the respiratory
epitheium in lungs obtained at necropsy from un
selected cases shows that the most common sites
of metaplasia are similar to those in which soot
accumulates in experimental animals.2
In essence, it has been demonstrated that car
cinogens have become significant in the patho
genesis of pulmonary cancer within the past half
century in spite of their atmospheric presence for
several centuries. This transformation may be
attributed to (a) the atmospheric presence of car
cinogens in a size range consistent with their res
piration and retention within the lung; (b) the in
troduction into the atmosphere of polar substance
capable of eluting adsorbed carcinogens from soot
particles following their deposition in the respira
tory mucosa; (c) interference with the normal de
fensive mechanisms of the bronchial epithelium by
abnormally affecting ciliary motion and mucous
secretion; (d) the introduction of cancerigenic
nonaromatic polycydic hydrocarbon agents into
the air. Included in this group are aliphatic hydro
carbons and their oxidation products, metals, in
organic dusts, and probably macromolecular sub
stances.
Any conceivable role of tobacco smoking in the
pathogenesis of lung cancer appears to this re
viewer to be at the level of a nonspecific irritant or
eluting agent for previously deposited carcinogenic
agents. There is at present no convincing evidence
that tobacco possesses the necessary qualifications
for the initiation and promotion of lung cancer.
CONCLUSION
Pulmonary cancer in common with all neo
plasms may be properly regarded as having several
2D. Tatter , E. M. Butt, and P. Koti n, unpubl i shed data.
Research.
K0TINAtmospheric Pollution and Pulmonary Cancer 391
di agnosi e i ndi ri zzi terapeuti ci . Lotta C. Tuberc., 25:6
19, 1955.
13. CHAMBERS, L. A.; Fo@rau,M. .7.; and CHOLAX, .7. A. A
Compari son of Parti cul ate Loadi ngs i n the Atmosphere
of Certai n Ameri can Ci ti es. Proc. 3d Nat. Ai r Pol l uti on
Symposi um, pp. 25 Si , 1055.
14. CLzMMaRSEN,.7. Bronchi al Carci noma a Pandemi c.
Dani sh Med. Bul l . 1:87-46,1954.
15. . Bronchi al Carci noma aPendemi c. U. Inci dence
and Tobacco Consumpti on i n Vari ous Countri es. Ibi d.,
pp. 194 99.
16. Cx.masassa@, .7., and Nzai amr, A. Soci al Di stri buti on of
Cancer i n Copenhagen, 1948 to 1947. Bri t. J. Cancer,
5: 15971, 1951.
17. Ci .smwassm@,.7.; Ni axaar@r, A.; and JsnmEN, E. The In
crease i n Inci dence of Carci noma of the Lung i n Denmark,
1981 to 1950. Bri t. .7. Cancer, 7:1 9, 1958.
18. Cx@aaso, G. R., and Mi u@a, E. W. The Carci nogeni c
Acti on of Ci ty Smoke. Chars. & Lad., p. 88, 1955.
19. COHART, B. M. Soci oeconomi c Di stri buti on of Cancer of
the Lung i n New Haven. Cancer, 8:1126 2.9, 1955.
20. Coopsar, R. L., and Li wusay, A. J. Atmospheri c Pol l u
ti on by Pol ycydl i c Hydrocarbons. Chem. & md., pp.
117778, 1953.
2.1. . 3:4-Benzpyrene and Pol ycycl i c Hydrocarbons
in Cigar ette Smoke. Br it. .7. Cancer , 49:8049, 1955.
22.. CURWEN,M. P.; KENNAWAY, E. L.; and KENNAWAY,
N. M. The Inci dence of Cancer of the Lung and Larynx i n
Urban and Rural Di stri cts. Bri t. .7. Cancer, 8:181-98,
1954.
23. DAumza@nnt, L. Physi ol ogi cal and Pharmacol ogi cal
Characteri sti cs of Li qui d Aerosol s. Physi ol . Rev., 32:
2. 14- 51, 1952. .
2.4. DAWSON, K. B. Radi oacti ve Materi al i n the Atmosphere.
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27. . Mortal i ty from Lung Cancer among Non
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29. . Mortal i ty from Lung Cancer i n Asbestos Work
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30. Dow@,R., and Hmi ., A. B. A Study of the Aeti ol ogy of
Carci noma of the Lung. Bri t. Med. .7., 2:12.71 86, 1952.
81. DoEN, H. F. Is Lung Cancer on the Increase Eval un
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Eval uati on of the Probl em; Proc. Sci enti fi c Sessi on Ann.
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82.. . Morbi di ty and Mortal i ty from Cancer of the
Lung i n the Uni ted States. Acta Uni on i nternat. contre
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88. DUCHEN, L. W. Bronchogeni c Carci noma. Inci dence
and Pathol ogy as Seen on the Wi twatersrand. S. Ai r. J.
Med. Sc., 19:65 74, 1954.
84. DUNGAI., N. Carci noma of the Lung i n Icel and. Lancet,
2:245-47, 1950.
35. - Canc e ri n I c e l and. Ann. Roy . Coi l .Sur g.Eng
l and,16: 21126, 1955.
86. DuNN, H. L. Lung Canc e r i n t he Twe nt i e t hCe nt ur y .
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37. Duma, F. R.; Lanoawr, E. .7.; and ROTH,.7. L. Osteo
factors concerned wi th i ts i ni ti ati on and promo
tion.
Ar eviewofthefactor sr elatingatmospher ic pol
lution to lung cancer both on the epidemiologic
and exper imental levels war r ants its incr imination
as one of the domi nant agents eti ol ogi cal l y asso
el ated wi th the i ncrease i n mortal i ty from l ung
cancer now bei ng reported i n vari ous regi ons of
the worl d.
Other agents, i ncl udi ng the frequentl y accused
excessive use of tobacco, appear to be capable of
playing only a secondar y r ole in the incr ease in
lung cancer r ates. They may conceivably act as
pr omoting agents so that in the pr esence of a pr e
pared or i ni ti ated soi l they can act ei ther synergi s
tically, as additives, or as cocar cinogenic agents.
Refi nements i n both epi demi ol ogi c and l abora
tor y data ar e indicated as ar e the new methodolo
gi es for the study of the phenomenon of l ung
cancer.
ACKNOWLEDGMENTS
The assi stance of Dr. Hans L. Fal k i s grateful l y acknowl
edged i n rel ati on to the chemi cal phases of thi s revi ew.
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