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FILE NAME Kent KNT DATE 1956 DOC KNT103 DOCUMENT DESCRIPTION Journal Article - The Role of Atmospheric Pollution in the Pathogenesis of Pulmonary Cancer A Review CancerResearch Cancer Research 375-393.1956 375-393.1956 375-393.1956 375-393.1956 The Role of Atmospheric Pollution in the Pathogenesis ing of Pulmonary Cancer A Review ind PAUL KOTIN ute University of Southern California School of Medicine Los Angeles Calif I. Introduction .......... 00.02.0002 eee 375 A. Lung cancer increase rcal B. Exogenous environment etiologically implicated II Historical 2.0022 376 A. Nonpulmonary occupational cancer and lung cancers of occupational origin B. Incrimination of atmospheric envi- ronment III C. Incrimination of tobacco Epidemiologic Considerations ........ 376 A. Limitations of data B. Variations in lung cancer rates among countries C. Variations in lung cancer rates within countries urban 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. economic differences in lung cancer rates H. Occupational lung cancer I. R^'sum^' IV Environmental Carcinogenic Agents 384 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 500.0258 e eee 387 A. Epidemiologic considerations in interpretation of pathogenesis * Part of the work reported here is supported by grants from the Field Investigations and Demonstrations 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 datain pathogenesis D. A theoretical mechanism for the pathogenesis of lung cancer VI Conclusion 06500024002 390 INTRODUCTION A. Lung cancer increase real marked in- mortality crease in the absolute from cancer of the lung has been demonstratedin various regions of the world during the past several decades 36 83 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 12,55 12,55 9798 and cigarette smoking 7 28 30 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 pathogenesis with its Any analysis of the atmos- phere as a carcinogenic entity must thereforein- 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 thesc will be evaluated possible in the light of its association with atmos pheric pollutionin the initiation of lung cancer Sufficient time has elapsed and enough informa- tion has been accumulated relating atmospheric pollution to theincrease 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- experimental cinogenesis based upon ologic studies and epidemi- 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 laboratoryinvestigations B. Exogenous environment etiologically implicat-implicat- 875 376 Cancer Research There is no convincing evidence that an intrinsic biological change might be responsible for the emergence of nonoccupational lung cancer from the status of a medical curiosity at the beginning of the century to a position of major importance at century In the absence of such data an exogenous source of the carcinogenic agents must be postulated These exogenous environmental agents did not become manifest simultaneously throughout the world as noted by significant differences existing from country to country relative to the time of onset of the increase in lung cancer the rapidity and intensity of the increase and variations in the age groups manifesting the peak incidence These variations are accompanied by similarities which point to the exogenous origin of the causal agent or agents These include a greater frequency of the disease in urban residents 31 53 58 69 86 88 97 98 and an intensely exaggerated almost exclusive increase in males 17 22 44 58 97 A clinical historical association of heavy cigarette smoking has been reported in a majority of the cases of lung cancer Sociologic investigations have attempted to associate characteristic histopathologic patterns of pulmonary neoplasms with specific environmental factors As is evident from the reports of Kirklin et al 59 and Walters and Price 101 the absolute pathologic classification of lung cancers is at present exceedingly difficult The hazards of establishing cell types and cellular origins are especially marked in relation to anaplastic or called cell cancer HISTORICAL A. Nonpulmonary occupational cancer and lung cancers of occupational origin Percival Pott 87 first correlated clinical cancer with carcinogenic materials from one source of atmospheric pollution The local atmospheric pollution incidental to the function of chimneys is evident Whether the sweeping of chimneys carried an increased liability to the development of lung cancer in addition to scrotal cancer is at present undeter minable B. Incrimination of atmospheric environment.Atmospheric contamination as an environmental source of pulmonary carcinogens was first demonstrated when II^/rtigand Hesse 51 identified the pulmonary disease in radioactive ore miners in Schneeberg as lung cancer There of course the atmospheric pollution was a highly localized one limited specifically to the occupational environment of the miners The epidemiologic and pathologic study of the Schneeberg miners resulted in the establishment of environmental lung cancer as a definite entity Concepts of latency the interval between first exposure to the carcinogenic agent and the clinical manifestation of lung cancer were initially derived from these studies An increased risk in the development of lung cancer has since been demonstrated to be associated with occupa- tional exposure to nickel 80 chromates 1 4 78 and working operations 26 C. Incrimination of Among the first to describe a correlation between the development of cancer of the lung and factors other than strictly occupational ones was M^...ller81 who in 1939 reported a statistical study purporting to show a correlation between smoking and lung cancer An analysis of the occupational exposure of his subjects in the light of current environmental cancer knowledge indicates that his conclusions of a positive etiologic association are open to question Following M^...ller'soriginal report numerous studies have been undertaken to ascertain any relation- ships existing between lung cancer and a broader spectrum of environmental factors A majority of recent investigations noted an association between lung cancer and heavy smoking 47 72 89 104 105 Numerous investigators have by means of comparative retrospective studies adjudged that heavy cigarette smoking embodies an enhanced risk to the development of lung cancer The con- clusion that this association demonstrates a effect relationship has been most eloquently advanced by Hammond and Horn 50 who observed For reasons discussed we are of the opinion that the associations found .. .. . between regular cigarette smoking and death rates from lung cancer reflect cause and effect relationships Contrary opinions have been voiced by other students of the problem who emphasize that the real increase in lung cancer is markedly less than is generally accepted and thus question whether reported associations between cigarette smoking and lung cancer signify any etiologic implication Berkson 3 in reviewing the data of Hammond and Horn reported My thesis is only that it is unwarranted to conclude from them data that a meaningful association already has been proved beyond doubt as some writers have asserted and as appears to be widely accepted in the United States Much less do I believe that causation has been established EPIDEMIOLOGIC CONSIDERATIONS A. Limitations of data evaluating the epidemiologic factors relating to this review cer- tain deficiencies inherent in the available crude data must be considered ncy the interval rcinogenic agent ung cancer were es An increased cancer has since ed with occupa- mates1 4 78 Among the first the development her than strictly ) who in 1939 re- rting to show a 2 lung cancer An sure of his subonmental cancer usions of a posito question Fol- umerous studies in any relationr and a broader s A majority of ciation between 47 72 89 104 ve by means of adjudged that es an enhanced ancer The conlemonstrates a been most elo- and Horn 50 issed we are of + found . . beand death rates effect relation- oiced by other hasize that the edly less than is on whether re- te smoking and plication Berk- Hammond and <that it is un- 1 data that a is been proved . re asserted and in the United t causation has ATIONS valuating the his review cer- vailable crude Atmospheric Pollution and Pulmonary Cancer 377 _ 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 workers questioned the use 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 death data as a basis for epidemiological studies of degenerative diseases The unjustified use of necropsy data was decried by Gilliam 43 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 interval represents the period between the first exposure 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 1930'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 arc reviewed a great disparity can be noted in the specific 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 2 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- tries urban 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 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 78 demonstrated urban differences in lung cancer as part of a comparative study of death rates in male industrial holders and males holding ordinary insurance policies with the Metropolitan Life Insurance Company He correlated the 30-50 per cent higher rate in the former group with urban residence low economic level and industrial or manu- facturing occupational environment In contrast ordinary holders belonged to the higher income groups with significantly fewer opportunities for protracted exposure to industrial hazards Eastcott 38 in an analysis of native New Zealanders 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 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 82 when reviewed in the light of the degree of their industrialization shows a consistent positive association between intensity of industrialization and mortality from lung cancer D. Variations in age peak incidence and sex in- 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 ee teet ALE TURat . doh SOAS alee = a 0 we -_ tae SOREL ENGLAND AND WALES SCOTLAND FINLAND - 1930 1932 1949 1952 12.9 1930 - 1932 10.6 1949 1952 1936-1938 1936-1938 1949 1952 13.6 49.5 61.4 B 41.4 56.3 |29.8 I 38.0 SWITZERLAND 1929-1931 12.0 1949 1952 NEW ZEALAND 30-32 7.1 1949 1952 126.1 J 33.5 21.6 31.5 NETHERLANDS NETHERLANDS 29-31 7.2 1949 1952 FRANCE 1949 1952 24.5 _ J 30.3 J 21.7 } 28.2 UNITED STATES 4.3 1929-1931 1949 J 1952 21.5 _] 26.1 DENMARK 4.5 1949 1952 1934-1936 | 16.7 Jj 24.6 IRELAND 5.4 1935-1937 1949 15.1 1952 jf 22.2 AUSTRALIA ] 6.3 1932-1934 1949 16.7 1962 _] 20.8 CANADA ITALY NORWAY 4.2 1949 1952 1930-1932 fi 16.4 ] 19.0 3.0 1949 1952 1931 11.3 16.4 1.8 1929-1931 1949 9.0 1952 11.5 JAJPAANPAN 3.3 1949 4.9 1952 ~. ConCsuHlAtRaTntDoe n a Het alhthrSattaetfiosrticcasnc Weorrlodf rHeesaplitrhatoOrrygasnyisztaetmioinn males rates per 100,000 deaths Data obtained from Director- eee Be, 1 from Director- + Atmospheric Pollution and Pulmonary Cancer 379 _ 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 proportionately sooner or in greater concentrations Further ENGLAND ANC WALES SCOTLAND 4.3 1949 1952 1930-1932 9.8 11.3 5.6 7 1949 1952 1930-1932 10.8 10.9 differences in urban and rural lung cancer mortality figures may be nothing more than another manifestation of the time of peak incidence The dose of a carcinogenic agent represents the product of the duration of exposure multiplied by the concentration of the carcinogen Rural areas differ from urban areas in that pollutants are present in lower concentrations rather than by their complete absence TABLE 1 LUNG CANCER INCIDENCE PEAKS BY YEARS FINLAND 2.3 1936-193B [ 1949 5.4 1952 6.5 2.0 1929-1931 SWITZERLAND 4.7 1949 4.7 1952 NEW ZEALAND | 2.5 3.9 5.1 1930-1932 1949 1952 2.2 1929-1931 NETHERLANDS 4.4 4.0 1949 1952 FRANCE 5.6 1949 6.1 1952 FOR VARIOUS COUNTRIES Male Norway 50-59 Italy England Finland Netherlands Scotland Ireland Switzerland Japan France Australia Germany United States 50-54 55-59 55-59 55-59 60-64 60-64 60-64 60-64 60-64 60-64 60-64 60-64 Canada 65-69 New Zealand 65-69 1949 Female 70 and over 55-59 65-69 60-61 60-64 60-64 60-64 70-74 65-69 65-69 60-64 60-64 65-69 60-69 65-69 1952 Male Female 60-64 55-59 60 64 60-64 60 64 60-64 65-69 70-74 60-64 55-64 65-69 60-64 60-64 65-69 65-69 70 and over 65-69 65-69 70-74 65-69 60-64 60-64 70-74 65-69 65-69 60-69 65-69 70-74 65-69 70-74 1.9 1929-1931 UNITED STATES 4.9 1949 5.4 1952 | DENMARK IRELAND 12.5 . 1934-1936 4.3 1949 = 6.5 1962 1962 3.2 4.5 7.3 1935-1937 1949 1952 AUSTRALIAA USTRALIA CANADA 2.3 3.6 4.3 1932-191394 491932-1934 1952 TE 2.0 '1930-1932 1930-1932 4.6 1949 4.0 1952 TABLE 2 RATIO OF MALE TO FEMALE WITH GARD TO DEATH RATES FROM CANCER OF THE RESPIRATORY TRACT Early 1980's England and Wales Scotland Finland = 3.0 1.9 5.9 Switzerland Netherlands New Zealand 6.0 3.3 2.8 United States 2.3 Denmark 1.8 Union of South Africa 3.8 Ireland Republic Australia Canada Italy Norway 1.7 2.7 2.1 2.1 1.5 1951 5.4 4.3 5.3 6.1 5.8 4.4 4.7 8 9 3.5 2.7 4.1 4.2 8.5 2.2 ITALY 1.4 3.4 4.5 1931 1949 1952 NORWAY 1929-1931 2 3.6 | 1949 5.4 ( 1952 JAPAN 1.2 2.2 1949 1952 CHART Death rate for cancer of respiratory system in females rates per 100,000 deaths Data obtained from Consultant on Health Statistics World Health Organization 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 2 for the two periods early 1930'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- 380 Cancer Research tion can be noted in the increase in the male rate from country to country Explanations for this flecting a true difference in the risk in the develop- ment of lung cancer he ascribed the different rates disparity on the basis of better and more readily to a delay of 8 years in the onset of the carcino- available diagnostic facilities for men greater genic influence in provincial towns and 10 years in susceptibility in men or an as yet cryptic sex- rural areas This conclusion followed an analysis of linkage for lung cancer development are unten- incidence rates for successive cohorts The cohort able Lilienfeld 74 however very recently sum- studies further indicated that a decade period of marized a preliminary study on nonsexual exposure was necessary for the carcinogenic effect cancers including lung cancer by stating that his to become clinically manifest He placed the intro- findings suggested an determined sus- duction of etiologic agents into the environment ceptibility to these cancers There remains as prob- during the period between 1900 and 1910. He ably a more valid explanation for the lower inci- could find no reason to assume any carcinogenic 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 influence due to atmospheric pollution but rather correlated the increased development of lung cancer with heavy cigarette smoking response to it For in fact where exposure to iden- Norway Kreyberg 68 69 in reporting the tical environments has been recorded the liability increasing incidence of lung cancer in Norway to lung cancer between the sexes is similar 27 In noted a seven increase in men and a four and like fashion Lew 73 found no difference in the a quarter increase for women in lung cancer lung cancer rates of women holders belong- between the years 1930 and 1950. In analyzing the ing to the two insurance groups in his study phenomenon of lung cancer in Norway he detect- Those ascribing a predominant initiating and ed the first evidence of a rise in approximately the promoting role to cigarette smoking offer as an middle 1940's with a progressive increase occurring explanation the almost universal onset of smoking since then He concluded from a detailed analysis in women two to three decades later than in men of his data that the panorama of lung cancer in- and as a corollary they postulate a future rise in crease is not as yet perceptible in true rural dis- the lung cancer rates in women They neglect to tricts in Norway which continue to have the same consider that fewer opportunities exist in the in- distribution histological type and sex ratio as stance of women for daily industrial and urban presented by Oslo a few decades ago In parallel exposure to carcinogenic air pollutants Women with Clemmessen he demonstrated a progressive only to a very limited degree in the past have decrease in lung cancer incidence with decreasing worked in manufacturing installations have urban community size He concluded on the basis driven in heavy traffic to and from work and have of a review of 235 cases that the new development performed heavy manual labor in dirty polluted lung cancer increase was as yet not manifest in environments Rather they formerly spent most truly rural districts On the other hand the in- of their time in residential areas within cities or crease was definitely established in all types of rural suburban communities A note of cau- urban settlements In spite of a decreasing inci- tion appears necessary in interpreting any future deuce in progressively smaller towns he noted that rise in female lung cancer rates Perhaps even the urban predominance was a reflection of an more dramatic than the increase in smoking that essential urban factor other than smoke and fumes has occurred in women during the past several from industry since towns of identical size had decades has been their entry into the previously similar rates independent of the degree of indus- almost exclusively male business industrial and trialization By applying the year exposure or occupational domain The implications of this are latency period the onset of the rise may be postu- clear lated as having begun between World War I and E. Interpretation of epidemiologic datafor selected the middle 1920's countries by local investigators The interpreta- tions by investigators of their data which were Sweden Specific death rates for lung cancer from Sweden as reported by Henschen 52 show freely utilized in compiling Charts 1 and 2 and a pattern of lung cancer increase dissimilar from Tables 1 and 2 are important and will be dis- that of either Norway or Denmark This increase cussed by countries has been at a slower rate than that noted in either Denmark Clemmessen 14 15 17 and his co- Norway or Denmark with the over incidence workers reported the increase in mortality from figures being more nearly akin to those of the tet I lung cancer as beginning approximately in 1931 Netherlands 60 Worthy of special comment is This increase was most marked in Copenhagen the fact that the sex ratio in Sweden differs sig- t and a progressively lower incidence was noted in nificantly from that of Denmark and Norway provincial towns and rural areas Rather than re- United States Dorn 81 82 noted that the in the develop- "different rates of the carcinoand 10 years in 1 an analysis of ts The cohort ecade period of cinogenic effect laced the introenvironment and 1910. He y carcinogenic tion but rather ment of lung ig reporting the er in Norway and a four and in lung cancer A analyzing the way he detect- roximately the rease occurring tailed analysis ung cancer intrue rural dishave the same d sex ratio as go In parallel a progressive ith decreasing ed on the basis v development ot manifest in hand the inn all types of ecreasing inci- , he noted that flection of an oke and fumes itical size had gree of indusar exposure or may be postu- rld War I and lung cancer hen 52 show issimilar from . This increase noted in either all incidence those of the al comment is en differs sigd Norway oted that the Atmospheric Pollution and Pulmonary 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 divergence is becoming more marked with the passage of time The increase shows a progressive acceleration from 1930 to 1952. 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 60 65 It has been postulated that the increase in lung cancer incidence in the United States became clinically manifest in 1920. By assuming the 20year 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 1943-47 period are surprisingly similar to those for the United States in the 1947-48 period A primary difference ob- served was that the maximum incidence in the Danish data occurred between the ages of 55-59 or about 5 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 geographic distribution of lung cancer mortality in mortality the United States showed that cancer 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 geographic 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 ratios They summarized their findings in saying that " in our opinion the data available today do not justify the conclusions 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 1920-30 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 largest towns were more than twice as high as in the country districts Subsequent studies in 1946-49 and 1952-54 verified this difference in urban mortality Curwen Kennaway and Kennaway 22 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 the Standard 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 These trends 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 undertook a study for the purpose of evaluating the lung cancer death rates among smokers and nonsmokers in relation to air pollution He summarized his findings with the statement The abso- lute urban excess is much the same in each smok- ing group suggesting that an urban factor is added to the effects of smoking Hefurther noted Differences in 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 25 report a regular increase in lung cancer as far back as records exist The evolution has been regular with no acceleration being demonstrated at any given point Further the increase in morbidity is shared by all ages The over death rate from lung cancer in males has increased 30 per cent during the years 1949-52 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 42 reported a uniform in- crease in the rate of lung cancer of 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 begun in 1930 with a fragmentary increase occurring in the previous two decades 382 Cancer Research New Zealand Eastcott 38 in analyzing his data was cognizant of the role that immigration to New Zealand played in the modification of his sample By integrating this factor into his epidemiologic data he concluded that immigrants from Great Britain to New Zealand are affected by their former environment and that this effect is related to the length of exposure to that environ- ment The exclusive effect demonstrated was in relation to lung cancer and was established as prior urban residence Ile noted The chances of dying of cancer of the lung are 30 per cent higher for all United Kingdom immigrants but for those who are 30 years of age or more on entering New Zealand the risk is 75 per cent higher . . . Differences in habits of tobacco smoking are unlikely to contribute to this picture Iceland Dungal 34 in 1950 concluded that the rarity of lung cancer in Iceland was associated with a slow rate of increase in the cigarette smoking habit throughout his country He felt that atmos- pheric pollution would play little if any role in any future increase in lung cancer He predicted that a rise in the lung cancer rates would become manifest between 1960 and 1965 if smoking were chiefly responsible for its initiation In a more re- cent report 35 he noted a beginning rise in incidence Though the number of cases is too few to permit any epidemiologic conclusion he relates the cases to heavy smoking on the part of older people in whom lung cancer is now beginning to The foregoing data permit of no conclusion other than indicating a need for future intensive studies G. economic differences in lung cancer Numerous investigators have been impressed with the variations in cancer incidence on the basis of the economic status of different population groups In applying this criterion to patients with lung cancer Clemmessen and Niel- Niel- sen 16 noted a significant acclivity in the inci- dence of lung cancer in the male population of the poorer classes in Copenhagen Kennaway 57 in reviewing the data relating to cancer in the publications of the General Register Office could not discern any influence of social class upon the lia- bility to lung cancer He did however emphasize . the very considerable effect of urban condi- tions which suggest some carcinogenic factor to which all classes are exposed Very recently Cohart 19 in a limited study paralleled the find- ings of Clemmessen and Nielsen and concluded The incidence of lung cancer was more than 40 per cent greater among the poor than among other economic classes Unless it is assumed that cigarette smoking is inversely related to socio- economic status an assumption that probably cannot be supported in fact then it is reasonable to conclude that important environmental factors other than cigarette smoking exist that contribute to causation of lung cancer Density of population proximity to industrial installations atmos- pheric pollution poor economic status and crop up increased liability to lung cancer constitute a con- F. Racial differences in lung cancer rates figuration repeated frequently in epidemiologic study of racial differences in the susceptibility to studies on lung cancer lung cancer is indicated especially in terins of the H. Occupational lung cancer significance guidance it can provide for future studies Steiner of occupational respiratory cancers resides not al 95 in study of the necropsy records at the only in their role as an important group of indus- Los Angeles County General Hospital reported trial discases but also as denotations of environ- For present purposes it may be stated that in mental lung cancer truly secondary to atmospheric Mexicans the incidence of lung cancer was as high pollution They therefore should serve as guide- in women as in men and that the incidence in the posts for the study of lung cancer in relation to air ty, latter equalled that in caucasoid men Hoffman pollution of a general rather than occupational roa and Gilliam 53 reported a lower lung cancer rate type Specific pulmonary carcinogens which have in Negroes and summarized their findings The been identified in the occupational environment eta total rates for the white population are considera- include nickel and chromium as unequivocal ex- DE bly higher than those for the nonwhite but the amples of inorganic chemicals and combustion SAIL difference is more pronounced among males than and distillation products of coal and petroleum as ale? among females In marked contrast Duchen 33 examples of organic chemicals The data incrimi- he in South Africa found no increased incidence in nating radioactive substances have been referred ir Caucasians when contrasted with the Bantu na- tive that could not be explained by difference in longevity Warwick and Phillips 102 in a study of cancer among the Canadian Indians detected . no differences in incidence they could attribute to to previously Though there is no unanimity of opinion Doll 29 Weil and his workers 104 Perry et al 85 and Bonser and her associates 6 have reported highly suggestive data associating increased lung cancer rates with exposure to as- . racc Finally Sitbon 92 in Algeria reported no racial variations in the incidence in lung cancer bestos isopropyl oil arsenic and iron respectively usion other ive studies ung cancer been im- cidence on of different criterion to n and Nielin the inciation of the way 57 in n the publi- > could not pon the lia- , emphasize irban condiic factor to ry recently -led the find1 concluded ore than 40 among other ssumed that ed to socio- at probably is reasonable ental factors at contribute ty of popula tions atmosc status and stitute a con- epidemiologic e significance s resides not roup of indusas of environ- o atmospheric erve as guide- relation to air ~ - occupational ns which have 1 environment nequivocal ex- id combustion i petroleum as e data incrimi; been referred , unanimity of workers 104 associates 6 ata associating - Exposure to asiron respec- 383 Atmospheric Pollution and Pulmonary Cancer _ Worthy of comment is the paradoxical situation relating to chromates and beryllium While little exists as to the increased pulmonary can- question to chro- cer incidence associated with exposure mates extensive attempts to induce experimental cancers in a broad spectrum of mam- mpaullimaonnasrpyecies have been uniformly unsuccessful 2 Conversely beryllium which has but a ques- tionable association with increased lung cancer in those occupationally exposed has been rates carcinomas in the used to produce bronchogenic lungs of rats 99 The experimental corroboration 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 Comparable analyses with respect to motor fuel consumption 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 correlate the data with the period of introduction of the carcinogen into the environment rather than with INDEX 600 _ 500- 2 f 3 2 STATE ASPHALT HIGHWAYS MOTOR FUEL CONSUMPTION 400- i 300 300 200- - 2 Pon Lr fo7g - 7 ; / a wed CIGARETTE CONSUMPTION PER ADULT FUEL OIL SALES MOTOR VEHICLE REGISTRATION / Ps / . vee NO ee aa att eters toa Fart 100 Ae, * at. COAL CONSUMPTION ^' yar a EE eee en ee 1930 1940 1950 +o 1900 1900 1910 1920 CHART Trends in selected environmental 1900-1953 1924-26 = 100 Note Cigarette per adult reflects entire population rather than VER 1930 1940 factors U.S. consumption that segment which smokes Data Hammond obtained 1950 through courtesy ee 1960 of Dr. E. C. In bas the increase in lung cancer rates other words of radioactivity as a pulmonary carcinogen of the latency period are been reported following the development of bron- the role and importance either overlooked or minimized If the latent chogenic carcinomas in rats 75 mentioned the cases of occupa- period is regarded as being approximately two As previously recorded thus far are too few to decades in duration reference to Chart 3 will show tional lung cancer nation incidence figures that not only does the rise in lung cancer follow affect materially Nevertheless neighborhood contamination and more closely factors other than tobacco but in general atmospheric pollution with these sub- addition the increase in these environmental fac- stances is well documented Additional details re- tors is more capable of correlation with the latent f ferring to these factors will be discussed subse- period Hueper 55 has similarly shown that a - quently of the epi- parallelism exists between the increased produc- ff I. R^'sum^u' nbiased analysis that tion of related chemicals and the rise in demiologic data reviewed here clearly shows cancer Chart 4 -: at this time the data are capable of more than one lung enee 4 Ker SR CEO ~~ 384 Cancer Research ENVIRONMENTAL CARCINOGENIC AGENTS A. Occupational respiratory carcinogens siderable basic information has been derived from a detailed study of established respiratory carcinogens in occupational environments First and most obvious is a broadening of the spectrum of environmental 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 Regardless of the particular agent studied the average cancers have been identified in nickel workers As noted by Hueper 55 Carcinogenic dusts consisting mainly of coarse particles are mainly arrested in the nares where they cause cancer of the turbinates The nasal cancers observed among copper matte refinery workers inhaling the coarse dust of the roasters illustrates this interrelation The bronchogenic cancers found in oven and 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 permit penetration into the arborization of the tracheobronchial tree Failure in this report to detail the association between increased liability to lung cancer in asbes- 1. 2 3 4 S fi COAL PRODUCTION BITUMINUS PRODUCTION IN 05 MILLIONS OF NOT TONS FULL MAIQUETS TOTAL PRODUCTION THOUSANDS OF NEY TONS CARBON BLACK - PRODUCTION IN MILLIONS OF POUNOS PETROLEUM - PRODUCTION OF CRUDE MILLIONS OF HARRELS PETROLEUM PETROLEUM COAL TAR ASPHALT ASPHALT - PRODUCTION OF ASPHALT FROM PETROLEUM THOUSANDS OF SHORT TONS PRODUCTION- PRODUCTION- THOUSANDS OF GALLONS % ISOPROPANOL-ISOPROPANOL- PRODUCTION- PRODUCTION- THOUSANDS OF POUNDS 8. ASBESTOS 9 ARSENIC 10 CHROMITE - APPARENT CONSUMPTION THOUSANDS OF SHORT MYMYRSKR MYRSS K 19K 30 PRODUCTION PRODUCTION AND IMPORTS THOUSANDS OF SHORT TONS TOTAL SUPPLY THOUSANDS OF TONS SOURCE MINERALS YEARBOOK 1945 1925 1930 1935 1940 } U 1945 1 i 1950 CHART Rise in annual production or consumption of related industrial chemicals between 1940 and 1948. Data obtained through the courtesy of Dr. W. C. Hueper latent period invariably falls in a 15-25 time period 55 This is not unanticipated in view of our knowledge that many of these agents in larger doses are sufficiently toxic so as to produce morbidity or mortality well in advance of the time necessary for clinical cancer to develop As a result 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 matter 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 discussed The reader is referred to the comprehensive and excellent review of Hueper in Recent Derelopments in Environmental Cancer 54 for a critical study of the newer data relating to occupation- m al cancer B. Sources of carcinogenic atmospheric pollutants 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 kel workers As enicdusts con- are mainly ar- sc cancer of the bserved among ers inhaling the ates this intericers found in s and among ent instances of dusts vapors ly small to perization of the the association cancer in asbes- ne, s TONS ^ PETROLEUM * ASPHALT THOUSANDS or JDS OF UNDS OF TION IT MYMYRSKR MYRSS K 19K 39 ORT 5 T TONS SANDS OF TONS DOK 1945 ) and 1948. Data ropyloil and I not be inter- e and validity to be derived already dise comprehen- in Recent De- 54 for a critio occupation- spheric polluls present in . lting from the atter are most aically recog e time of Sir Atmospheric Pollution and Pulmonary Cancer 385 Percival Pott 87 is a major component of the smoke formed and emitted into the atmosphere following the partial combustion of solid liquid and gaseous fuels Compounds introduced into the atmosphere from these sources belong primarily to the group of aromatic polycyclic hydrocarbons A typical carcinogenic representative of this group is benzpyrene Although the gradual shift from solid to liquid or gaseous fuels throughout the world has resulted in quantitative variations in the pollutants emitted into the air qualitative changes have been minimal Additional sources of these complex aromatic compounds include the tars and asphalt used for road surfacing The increase in mileage of asphalt roads has already been referred to in Chart 3. Added to this source of car- cinogenic materials is the carbon black introduced into the air secondary to rubber tire wear tear and degradation An ever expanding and increasing source of emission of carcinogenic hydrocarbons into the atmosphere is liquid fuel used in internal combustion engines Gasoline engines represent the most universal type of motive power in urban areas and diesel fuel engines power our buses trucks railroad locomotives and electric power facilities to an ever expanding degree Not only are large amounts of the known carcinogen benzpyrene introduced into the air by the combustion of petroleum fuels but the reaction products of noncombusted gasoline in their aliphatic nonaromatic polycyclic state possess experimental carcinogenic potency 63 67 Supplementing these compounds there are emitted into the atmosphere measurable concentrations of inorganic materials demonstrated to be occupationally associated with increased liability to lung cancer development Included would be heavy metals light metals and inorganic dusts Quantitation of a known carcinogenic substance obtained from an atmospheric pollution source was first reported in 1949 by Goulden and Tipler 46 who by means of fluorescence spectroscopy identified benzpyrene in a representative sample of chimney sweep's stock in a concentration of 300 mg of soot C. Known and suspected carcinogenic agents in the atmosphere 100 sampled the atmosphere at ten different sites in several cities in Great Britain and demonstrated the presence of 3,4benzpyrene in the air The highest concentration of 4.5 100 cubic meters was obtained in Lon- don and the lowest noted was in Bristol with 1.3 100 cubic meters measured there A mean con- centration of 2.6 100 cubic meters was obtained for all sites studied The concentration in London was half again as great during the winter as it was during the summer and during foggy weather the concentration was over 4 times that on clear days While the amount of benzpyrene retained in the lungs is of course impossible to assess at present he calculated the respiration of approximately 12 mg of benzpyrene during an average year life span Blacklock Kennaway Lewis and Urquhart 5 following an analysis of the carbon content of human lungs estimated that approximately 16 mg of benzpyrene may be inhaled during a life- time It should be noted that the primary atmospheric source of these compounds in Great Britain is from combustion of coal with as yet undetermined amounts contributed by velicular exhausts Kotin 64 and his associates studied the Los Angeles atmosphere and demonstrated a presence of 0.84 mg of benzpyrene per million cubic feet of atmosphere In marked contrast with Lon- don this carcinogen could be attributed almost entirely to the exhaust products of gasoline and diesel engines A detailed study of gasoline and diesel engine exhausts revealed quantities estimated up to 120 gof benzpyrene in minute samples of gasoline engine exhausts and up to 1.7 mg benzpyrene from diesel engine exhausts 65 66 In comparing the ratio of pyrene to benzpyrene in the atmosphere with that at the vehicular exhaust source Falk and his workers 40 noted a reversal of the ratio with benzpyrene being present in greater concentration than pyrene in the atmosphere This phenomenon was ex- plained through study of the survival of various polycyclic aromatic hydrocarbons in the atmos- phere Compounds were tested in their pure state and while adsorbed on soot and following exposure to washed air and smog In all instances benz- pyrene was significantly more stable than was pyrene In fact it was virtually indestructible in the dark Cooper and Lindsey 20 emphasized the ubiquity of atmospheric pollution following analysis of 1 kg of freshly fallen snow in Hertfordshire England The snow contained 1-2 pg of pyrenc and traces of benzpyrene and anthanthrene Clemo and Miller 18 divided the city smoke they collected into three fractions The presence of benzpyrene was detected in one of these fractions The spectrum of carcinogenic agents present in the atmosphere has very recently been broadened following the report of Kotin and Falk Following skin painting in C57BL mice and following inhalation in strain A mice and C57BL mice 63 67 they found the oxidation products of aliphatic hydrocarbons to be carcinogenic The implications of the pulmonary neoplasms induced with these 386 Cancer Research agents will be discussed The chief source of ali- phatic materials in the atmosphere is unburned gasoline Mention should be made of the presence of arsenic in the atmosphere The sources would include primarily the burning of fuels and secondarily insecticide use and metallurgical sources Goulden 45 and his workers measured the arsenic con- tent of the atmosphere at eight sites in England 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 course of 1 year While this amount is low its possible role in association with other known car- cinogens should be kept in mind The concentration of metals in the atmosphere has been determined by investigations of the Stanford Research Institute 93 for Los Angeles and by Chambers and his workers 18 for several other American cities The amounts present espe- cially of chromium and nickel are minimal As in the case of arsenic however possible additive or cancers in C57BL mice following painting with extracts of Los Angeles atmosphere and materials collected from the exhaust of gasoline engines and diesel engines 64 66 The preceding representative examples of skin tumor production in mice coupled with analytical studies previously mentioned provide direct bio- 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 his workers reported the successful production of skin tumors in mice using aromatic poly- cyclic hydrocarbon atmospheric extracts 61 The samples used for the tumor production con- sisted of oxidation products of aliphatic hydrocarbons formed in the atmosphere in accordance with the theory as developed by Haagen 48 49 and since confirmed by others 103 He postulated a primary photochemical reaction between oxides of nitrogen a product of internal combus- synergistic effects with hydrocarbon carcinogens should not be forgotten Perhaps the most controversial of atmospheric tion engine exhaust and organic molecules alco- hols aldehydes ketones acids and hydrocarbons both as emitted from vehicular exhaust and as in- factors of theoretical carcinogenic significance are those relating to ionizing radiation In a compre- troduced into the atmosphere through the volatilization of uncombusted gasoline Ozone forms as a hensive study of radioactive material in the at- result of a radical chain reaction While less is mosphere carried out in London in Manchester and in the country at Rothamsted Dawson 24 concluded that no considerable difference existed known about the reaction products other than ozone the ozone itself is known to react spontaneously with unsaturated molecules which also are between urban and rural districts Day present in gasoline engine exhaust and unburned variations were marked and could be related to the gasoline The reaction products consist of an activity of the atmosphere in terms of wind veloci ty The more stationary the air the greater the activity At all times amounts present were exceedingly small in comparison with the lowest 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 concentration considered harmful to man primary free radical reaction This reaction is in- D. Biologic demonstrations of carcinogens with stantaneous and produces an ozonide which in the atmospheric Biological demonstration of carcinogenicity with materials which are fre- quent sources of air pollution was successfully undertaken by Passey 84 who in 1922 reported the production of experimental cancers in mice following painting with ether extracts of household 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 chimney soot Campbell 11 similarly produced these reactions is shown in Chart 5. It should be RTE skin tumors in mice following painting with tars noted however that many additional side reac- TRE extracted from chimney soot Leiter 70 71 and his workers reported the development of sub- tions take place simultaneously reducing the yield of these compounds The tumor yield with these PE cutaneous sarcomas in mice injected with tars compounds was less than that observed with at- OS extracted from the atmospheric dusts of several mospheric extracts containing aromatic polycyclic American cities The extracted tars were injected hydrocarbons BO in amounts varying from 21 to 71 mg suspended The broadening of the spectrum of carcinogens in 0.25 cc of tricaprylin More recently Kotin and in the atmosphere with these agents is of special his workers reported the production of skin significance in that their entry into the environ- ng with naterials ines and > of skin alytical ect bio- elonging group of d in the genicity 5 Kotin produc- ic polyits 61 on con- hydro- ordance mit 48 p ostu- etween ombus- s alcoarbons d as involatili- ms as less is than ontane- Also are burned of an ozone ere are of the n is inin the iety of ehydes y with which o yield tion of uld be e reac- e yield 1 these ith at- vcyclic jogens special viron- Atmospheric Pollution and Pulmonary Cancer 387 ment is compatible with their action as initiating or promoting agents in the increasing incidence of cancer of the lung Attempts to induce or increase the yield of pulmonary tumors by inhalation experiments were first reported by Campbell 8-10 who exposed Inice in inhalation chambers to resuspended sweep- ings of dust from tarred roads In addition to the development of cutaneous tumors he noted a higher incidence of pulmonary tumors in his test mice than in his controls Seelig and Benignus 90 91 in one of two experiments used chimney soot as an inhalant for Buffalo strain mice and reported an 8 per cent pri- mary pulmonary tumor yield in contrast with a 2 of exposure and ending with the 52d week At all intervals the number of bearing mice the number of multiple bearing mice and the total tumors in the test chamber were significantly greater than those in the control chamber Kotin further has demonstrated the production of pulmonary tumors in C57BL mice exposed to a similar atmosphere of ozonized gasoline Bronchogenic cancers apparently of the type seen clinically have thus far been produced experimentally only in rats Vorwald 99 exposed rats for over 1 year to an atmosphere containing soluble and insoluble beryllium salts and noted the development of true bronchogenic neoplasms Dutra 7 produced osteogenic sarcomas in ex- Os x CH CH .oO CH OZONIDE % HO HO CH= CH R UNSATURATED HYDROCARBONS HYDROCARBONS + R CH 0 EPOXIDE EPOXIDE R CH -- ---- CH PEROXIDE oO 00H R'C 00H PERACIO R CHO ALDEHYDE + H O COOH ACID UNDERLINED COMPOUNDS ARE SUSPECTED OF CARCINOGENICITY CHART Schematic representation of oxidation reactions of aliphatic compounds per cent yield in their controls In a second experiment they adsorbed work tar onto carbon black for inhalation by C57BL mice No pulmonary tumors were produced in the test mice McDonald and Woodhouse 77 exposed mice of apparently indifferent strains to dust obtained from city thoroughfares and to dust collected from the purifying system of a hospital adjoining an industrial area While they reported that they were unable to show the striking increase in their test mice that Campbell reported in a similar experiment they did show an exaggerated production of pulmonary adenomas in their test mice Kotin and Falk 63 reported an exaggerated incidence of pulmonary tumors in strain A mice exposed to an atmosphere of ozonized gasoline They removed mice from the inhalation chamber at week intervals beginning with the 24th week perimental animals exposed to an atmosphere containing beryllium oxide Lisco and Finkel 75 observed neoplastic changes in the bronchial epithelium in rats exposed to an aerosol of radioactive cerium The carcinogenic powers of ionizing radia- tion for tissues other than the lung are well known DISCUSSION A. Epidemiologic considerations in interpretation of pathogenesis epidemiologic data relating to lung cancer as reviewed here show marked contradictions The inconsistencies appear to be wholly irreconcilable if but a single initiating and promoting agent were to be regarded as being responsible for the increasing incidence of lung cancer Of the two suggested major etiologic factors cigarette smoking alone appears the least P. Kotin unpublished data Cancer Research capable of adaptation to the panorama of lung cancer as it is currently manifest The limitations of the tobacco concept of etiology are evident in studies showing differences in lung cancer rates on the basis of economic status Geographic studies singling out urbanization as the exclusive variable in groups with contrasting lung cancer rates cast further doubt on the validity of the major role assigned to tobacco in pulmonary can- cer The urban difference in incidence could very possibly in one or even several countries be a manifestation of difference in smoking habits It is unlikely however that peoples with different cultures economies and mores should have iden- tical smoking habits and patterns More readily tenable is the hypothesis that urban 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- logic studies made in Norway 68 69 New Zea- land 38 the United States 31 32 43 44 55 and Denmark 14 1T7hese data emphasize dif- ferences in urban cancer rates and the great- er incidence in the low economic groups Clemmessen interprets differences in urban incidences as evidence of difference in the onset of exposure to the carcinogenic agent A more likely explanation would be that the concentrations of carcinogens in the atmosphere in 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 in urban rates as a function of at- mospheric pollution one can readily reconcile the parallelisms noted between lung cancer rates and density of population and degree of urbanization Not the least significant of the epidemiologic considerations concerned with atmospheric pollution are the documented instances of occupational lung cancer The parameters of the exposure and the response of the host are defined within measurable limits Sex differences in lung cancer rates are not irreconcilable with the concept of atmospheric pollution as a major etiologic factor The contrasting social and economic roles of men and women result in a more prolonged exposure to a greater concentration of polluted atmosphere on the part of men The conviction that air pollutants possess the ability to initiate and promote pulmonary cancer in no way precludes the role of other possible factors Stocks and Campbell 98 in their recent study of the combined effect of smoking and air pollution on lung cancer death rates demonstrated an urban ratio of 9 1 for nonsmokers residing in Liverpool as compared with those living in adjacent rural areas At every level of smoking intensity Liverpool rates exceeded the rural rates As smoking increased the disparity progressively decreased to a level where the difference ap- proached a factor of less than two They concluded that a dual role now appears to be tenable as a working hypothesis for the guidance of future studies Since not all residents in any area smoke and the very method of smoking varies from individual to individual attempts to correlate lung cancer incidences with tobacco consumption on a per capita basis in any given population group denote a type of epidemiologic gerrymandering In a given community however a constancy in exposure to atmospheric pollution or lack of exposure can be related to residence site occupation and duration of these two The inconsistencies and the irreconcilable fac- tors in the epidemiologic data make it amply ap- parent to this reviewer that the contributions of laboratory data will be of ever increasing signifi- cance in the ultimate revelation of the mechanisms and etiologies of lung cancer B. Role of chemical and physical factors in patho- genesis equal significance to the epidemiologic data are the chemical and physical data relating atmospheric pollution to the pathogenesis of lung cancer The demonstration of benzpyrene in urban atmospheres has been successful wherever undertaken On the basis of current knowledge the concentration and the atmospheric survival of this carcinogen are sufficiently great to postulate a biological effect in humans The recent demonstration by Kotin and his workers of the carcinogenicity of oxidation products of aliphatic hydrocarbons made the incrimination of the atmosphere more certain The ubiquity of gasoline the most common source of these compounds combined with the temporal aspects of the introduction of liquid fuels permits of epidemiologic integration as well The combination of carcinogenic aromatic polycyclic hydrocarbons oxidation products of aliphatic hydrocarbons and known occupational carcinogenic agents which pollute the atmosphere warrants suspicion of the atmosphere as a factor in the pathogenesis of human lung cancer Complete ignorance of any possible additive or synergistic effects they may manifest and the absence of exactitude of dosage in man make their diligent study imperative The presence of benzpyrene in the combustion products of tobacco has been reported Cooper and Lindsey 21 recovered 4 gof this carcinogenic agent from the smoke of 500 cigarettes This hose living in of smoking in- he rural rates progressively difference ap- hey concluded > tenable as a nce of future y area smoke ries from indi- correlate lung sumption on a ulation group rymandering constancy in or lack of ex- e occupation oncilable far- it amply ap- tributions of easing signifi- e mechanisms ctors in pathohe epidemio- sical data re- pathogenesis of benz- en successful is of current atmospheric ently great to is The recent workers of the s of aliphatic nation of the uity of gasocompounds of the intro- pidemiologic romatic poly- ducts of ali- occupational atmosphere e as a factor cancer Comive or syner- the absence their diligent | the combus- rted Cooper this carcinoarettes This Atmospheric Pollution and Pulmonary Cancer 389 concentration is less than that noted in the atmosphere in terms of total amounts respired by those exposed It is clear that the alleged cause effect relationship ascribed to smoking cannot currently be predicated on the presence of benz- pyrene in tobacco smoke Assuming that the average total of inspired air measures up to 7,500 cubic meters per year as calculated by Stocks 98 the average resident of Liverpool whether smoker or nonsmoker would inhale 450 gof 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 respiratory tract The per cent retention of particulate matter in the lung on the basis of particle size is shown in Charts 6 and 7. Dautrebande 23 cor- related the location of particulate deposition with specific sites in the tracheobronchial tree The particle 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 rather reflects the failure of particles to settle out Those particles capable of settling out on the tracheal mucosa are identical in size with those trapped in the nose epipharynx and accessory nasal sinuses Particles of smaller size down to approximately 0.25 ...settle progressively distally in the arborization of the bronchi Those less than 0.25 ...remain suspended in tidal air until a sufficiently miniscule size is reached so that Brownian movement can produce precipitation C. Significance of experimental laboratory data in pathogenesis suggested above the inconsistencies and contradictions in the epidemiologic data placed increasing responsibility and emphasis on the laboratory for the elucidation of etiologic RETENTION 80 it | A 70 o so Py] ! : | i 1 Thy AY H + | H : ! an | i t LJ= { Retention in LUNG | Vs. PARTICLE SIZE q 40 \ 30 20 ! A 10 \ > .25.5.75 / 2 3 4 5.4 PARTICLE SIZE CHART Per cent retention of particulate matter in lung in relation to particle size 14 1.2 10 A -- 6 .4 -t \ lm .2 J 06 4 0.24 0.24 0.24 7 2 | 0.06 ... Cle 67 | TRACHEA .07 BRONCHIOLES .39 ALVEOLI 2.02 BRONCHI PASSAGE TIME SEC CHART Anatomical pattern of deposition and time of passage of particulate matter in relation to particle size after Dautrebande 390 Cancer Research agents and mechanisms for lung cancer development The chemical demonstration of carcinogenic agents in the environment and their successful use for the production of tumors in experimental animals do not prove or even especially strongly suggest a like relationship in the instance of man When however a demonstrable parallelism exists between epidemiologic data and laboratory findings greater significance accrues to both Medical history is replete with examples in which laboratory findings have been proved ultimately to have their counterpart in the human experience Excep- tions have been very few D. A theoretical mechanism for the pathogenesis of lung cancer means of integrating laboratory findings and experimental data the author has arrived at a theoretical mechanism for the pathogenesis of lung cancer In spite of the presence 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 carcinogenic hydrocarbons adsorbed on soot are bio- logically ineffective until they are separated by elution from the soot particles It has been postulated that in the case of the skin sebaceous secretions provide the necessary polar substances for the elution of the carcinogenic materials Experimentally Kotin and his workers 62 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 source of an eluting agent capable of entry into the respiratory tract The simultaneous respiration of the carcinogenladen soot and the eluting agent provides a mechanism 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 introduced into the atmospheric environment at a time consistent with their having etiologic significance for they In addition to the eluting role and ty demonstrated for these aliphatic mactaerrciinaolgsenlcarceinogenlheh have been shown to be potent irritants respiratory mucosa In common with other mospheric irritants introduced secondary to indum 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 . mits the accumulation of particulate matter selected sites in the tracheobronchial tree t - shown by Kotin The sites are chiefly at bifurca tions and angulations in the respiratoryrespiratory arboriza : tions This accumulation allows prolonged real 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 epithelium in lungs obtained at recropsy from un selected cases shows that the most common sites of metaplasia are similar to those in which soot accumulates in experimental animals In essence it has been demonstrated that car cinogens have become significant in the patho al |<) 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 carcinogens 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 respiratory mucosa c interference with the normal defensive mechanisms of the bronchial epithelium by abnormally affecting ciliary motion and mucous secretion d the introduction of cancerigenic nonaromatic polycyclic hydrocarbon agents into hydro- the air Included in this group are aliphatic carbons and their oxidation products metals inorganic dusts and probably macromolecular sub- stances Any conceivable role of tobacco smoking in the pathogenesis of lung cancer appears to this reviewer 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 neoplasms may be properly regarded as having several D Tatter E. M. Butt and P. Kotin unpublished data - arcinogeniciterials they ants for the h other atary to indusly affect the with ciliary 1. The interfactors per- e matter at ial tree as v at bifurcary arboriza- longed resiepithelium ated as has cedures Difinto the res- onstrated by : respiratory psy from unommon sites 1 which soot ted that car- t the patho- he past halfpresence for ion may be sence of carith their res- g b the in- lar substance ns from soot . the respira- e normal de- pithelium by and mucous cancerigenic agents into hatic hydro- 5 metals inolecular sub- oking in the $ to this refic irritant or carcinogenic ing evidence qualifications ing cancer ith all neo- aving several published data Atmospheric Pollution and Pulmonary Cancer 391 factors concerned with its initiation and promo- tion A review of the factors relating atmospheric pollution to lung cancer both on the epidemiologic and experimental levels warrants its incrimination as one of the dominant agents etiologically asso- ciated with the increase in mortality from lung cancer now being reported in various regions of the world Other agents including the frequently accused excessive use of tobacco appear to be capable of playing only a secondary role in the increase in lung cancer rates They may conceivably act as promoting agents so that in the presence of a prepared or initiated soil they can act either synergis- tically as additives or as cocarcinogenic agents Refinements in both epidemiologic and labora- tory data are indicated as are the new methodolo- gies for the study of the phenomenon of lung cancer ACKNOWLEDGMENTS The assistance of Dr. Hans L. Falk is gratefully acknowledged in relation to the chemical phases of this review diagnosi e indirizzi terapeutici Lotta C. Tuberc 25 19 1955 13. CHAMBERS L. A FOTER M. .; and Cholak J. A. A Comparison of Particulate Loadings in the Atmosphere of Certain American Cities Proc 3d Nat Air Pollution Symposium pp 25 311955 14. CLEMMESSEN J. Bronchial Carcinoma Pandemic Danish Med Bull 87-46 1954 15 . Bronchial Carcinoma Pendemic I. Incidence and Tobacco Consumption in Various Countries Ibid pp 194-99 16. CLEMMESSEN J. and NIELSEN A. Social Distribution of Cancer in Copenhagen 1943 to 1947. Brit J. Cancer 159 711951 17. CLEMMESSEN J NIELSEN A and JENSEN E. The In- crease in Incidence of Carcinoma of the Lung in Denmark 1981 to 1950. Brit J. Cancer 1 19 953 18. Clamo G. R. and MILLER E. W. The Carcinogenic Action of City Smoke Chem & Ind p 38 1955 19. COHART E. M. Socioeconomic Distribution of Cancer of the Lung in New Haven Cancer 1126-29 1955 20. COOPER R. L. and LINDSEY A. J. Atmospheric Pollution by Polycyclic Hydrocarbons Chem & Ind pp 1177 718953 21 . Benzpyrene and Polycyclic Hydrocarbons in Cigarette Smoke Brit J. Cancer 804 19955 22. CURWEN M. P KENN E. L and KENNAWAY M. The Incidence of Cancer of the Lung and Larynx in Urban and Rural Districts Brit J. Cancer 181-98 REFERENCES 1. Baetjer A. M. Pulmonary Carcinoma in the Chromate - Workers I. A Review of the Literature and Report of the Cases A.M.A. Arch Indust Hyg & Occup Med 1954 23. DAUTREBANDE L. Physiological and Pharmacological Characteristics of Liquid Aerosols Physiol Rev. 32 214-51 1952 24. DAWSON K. B. Radioactive Material in the Atmosphere 487-504 1950 Q. Presentation at Conference on Environmental _ Carcinogens National Cancer Inst Sept. 12-18 1955 3. BERKSON J. The Statistical Study of Association between Smoking and Lung Cancer Proc Staff Meetings Mayo Clinic 319 418955 4. BIDSTRUP P. L. Carcinoma in Lung of Chromate Work- ers Brit J. Indust Med 302 15951 5. Blacklock J. W. KENNAWAY E. 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