Document 9zrvEv8BQpL1VpwnqDb0dz5q

FILE NAME Kent KNT DATE 1955 DOC KNT139 DOCUMENT DESCRIPTION Book Excerpt - Advances in Cancer Research Asbestos Pgs 33 & 35 ADVANCEISN CANCER RESEARCH . EDITED BY e JESSE P. GREENSTEIN National Cancer Institute National Institutes of Health U.S. Public Health Service Bethesda Maryland ALEXANDER HADDOW Chester Beatty Research Institute Royal Cancer Hospital London England Volume III ACADEMIC PRESS INC PUBLISHERS NEW YORK N.Y. 1955 viii CONTENTS . Some Aspects of Carcinogenesis BY P. RONDONI Cancer Institute MilanMilan Italy 171 I. Introduction . 2. Pathology II Cancer as a Regressive Process in General PatholEntropy o in Pathog l- Patholy - Pathol- 172 III The Energy Changes in Carcinogenesis The Concept of Entropy in Pathol- . 174 ogy Derangements of Derangements of Oxidative Metabolism in IV The Supposed Significance 180 . '. Po ee CarciInnotgeernaecstiison .be6tw2 e. en s Se omet Cae rcinogenic Agents and Cell Constituents 185 V. The 194 . VI Cancer as a Problem of Protein Chemistry - - 6 6 6 ee es 213 ' VII Summary De 6 ee es 6 214 . References ee 0. Pulmonary Tumors in Experimental Animals BY MICHAEL B. SHIMKIN National Cancer Institute National Institutes of Health Bethesda Maryland 223 I. Historical Introduction 6) 2-6 et - and Distribution of Pulmonary Tumors in Mice -. - . 225 II Frequency 227 . III Pulmonary Tumors in Other Animals 0. ee ttt - - - IV Morphology and Biochemistry of Pulmonary Tumors in Mice 223239 V. Histogenesis of Pulmonary Tumors in Mice ee . 235 -" VI Influence of Heredity in Pulmonary Tumors Mice ------- 237 VII Polycyclic Hydrocarbons and Related Compounds .---- - 242 tae Including Inhalants VIII Urethane and Related Compounds 2.0. - - - IX Other Chemical and Physical Agents Including Inhalants 244 X. Factors Affecting Pulmonary Tumor Induction in Mice -.. --- - 248 - -- + + of Induction of Pulmonary Tumors Mice 252 XI Mechanism 256 XII Pulmonary Tumors in Man and General Discussion - .- - , . 261 . . References ee , Oxidative Metabolism of Neoplastic Tissues BY SIDNEY WEINHOUSE The Lankenau Hospital Research Institute and The Institute for Cancer Research Philadelphia Pennsylvania ", 270 I. The Concepts of Warburg ' 6 0 274 II The Pasteur Effect 0 et 278 - - - - III Present Concept of Carbohydrate Oxidation Co eee 282 IV -Oxidation of Fatty Acids - 2 0 6 0 V. Mechanisms of Glycolysis Tumors . - 2 2 ee tt 283 288 VI Electron Transport in Tumors 6 6 315 VII Oxidation in Tumor Homogenates ' 2 323 References 0 327 . . . AUTHOR INDEX 2 2. ee et 339 SUBJECT INDEX 2 Le Etiology of Lung Cancer RICHARD DOLL a. Statistical Research Unit of the Medical Research Council London School . . * of Hygiene and Tropical Medicine London England Page I. Introduction .... 0.2... cee ee 1 n een err tees 6.- eee terre eteteens 1 1. Conclusions of Louvain Symposium . II Increase in Incidence 2 cece ee eet eee rene ee 1. Extent of Increase 2 eee enter 02022 et tenet Histological Changes Sex Distribution 2. in 5 - 2252s e reer 2.00.60 Changes Age 3. in Distribution 5 0.6.66. 6-0 eee e ete tte 662. eee 4. Changes in 7 Distribute i er ost ne 8 III Etiological Factors 1. Tobacco cece & eee teen tenet ten eee Retrospective Inquiries A. 8 c .. 066: e eee etree tees 11 B. Prospective Inquiries ... 15 C. Method of Smoking D. Extent of Risk 2.0.0... 0.22 c cee eer eet teen e tenn 16 60sec ee E. Difference between Histological Types reece 19 F. Vital Statistics and Tobacco Consumption 20 0260s e ere e reer ee 23 G. Identification of Carcinogenic Agent 29 H. Various Criticisms 0.000 eee teen cee .....0 nannies I. Conclusion 00. ...000 a ence ent e enter teen eeee 32 2. Industrial Hazards ...... 6. ccc eee eee ee tet teen teense 33 3. Atmospheric Pollution 0.0.06... 0 6c e cece eee teeter e teens 36 A. Mortality in Town and Country 0.6066 r eee ee eens 88 B. Pollution of Town Air .. ee eet tenes *** C. Differences in Urban and Rural Habits 25055 *** D. Conclusionbode ec ee nee betes b ee renee eee *** teens 060-222. 6 seer eeeee ee .. = 4. Atmospheric Radioactivity . 5. Previous Respiratory Infections ..... e ee eee nes 0.002.660 * IV Conclusion ccc eee eee ee nn te eee nner eens 95 References 0c e cc cece eee eee ee eee enn n nent eee es 95 : I. INTRODUCTION Conclusions of Louvain Symposium * rf 1. Conclusions Symposium Louvain Knowledge of the causes of lung cancer was reviewed at an international symposium on the Endemiology of Lung Cancer held at Louvain in 1952 Council for International Organizations of Medical Sciences 1953 The members of the symposium were unablteo decide what factors were responsible for the majority of cases but important conclusions 1 reached on more limited problems Firstly it was agreed that a were significant part of the increase in mortality which had been reported from many countries is absolute and represents a real increase in the number of people suffering from primary cancer of the lung secondly that there is now evidence of an association between cigarette smoking and cancer of the lung and that this association is in general proportional to the total consumption and thirdly that occupational hazards been giving rise to lung carcinoma have demonstrated in a number of industries in particular in the handling of asbestos and chromates in works in a factory refining nickel and in certain mines bearing active ores Other possible etiological factors were considered particular atmospheric pollution by effluvia and smoke from factories and domestic chimneys and by exhaust fumes from petrol and diesel engines The possibility that carcinogenic agents might be absorbed through ingestion or skin contact was reviewed as was the possibility that individuals might vary in their susceptibility to the environmental influences to which they were exposed No positive conclusions were reached with obtained regard to these latter problems In the last two years however much new evidence has been and it is now possible to give a more complete picture of the etiology of nS the disease 4 II INCREASE IN INCDENC INCIDENCE INCIDENCE 1. Extent of Increase The highest death rate from lung cancer is recorded in Britain where 1953 it was 342 per million persons For both sexes taken together lung cancer was the commonest type of fatal cancer accounting for % of all cancer deaths it accounted for % of male deaths from all causes at all deaths ages and in the age group 45 to 64 years for 10 of all male In other countries for which detailed statistics are available the rate varies from a seventh to approximately thirds the British rate Table * The disparity between the rates is mainly due to a disparity between the rates for men with the exception of England and Wales - Scotland and Finland the female rates are similar varying only between 34 and 47 per million women Each of the countries listed has experienced an increase in the mortality attributed to lung cancer in the last half century and the increase appears to be still continuing Fig ) In Table I the figures for England and Wales and for Scotland are shown . separately The Scottish rate for all persons has usually been lower than the English and Welsh rate but in 1953 the rate was slightly higher per million against 342 per million ETIOLOGY OF LUNG CANCER 3 In England and Wales the rate of increase has slackened in the last five years and the death rate among men under the age of 50 years is now steady On the assumption that the rates at the younger ages remain steady and that the rates at the older ages continue to increase until the distribution of deaths from lung cancer resembles that of other extra- age genital epithelial cancers Mackenzie personal communication estimates that the male death rate may increase to approximately 1350 per million men i.e. to more than twice its present level of 602 per million before| it stabilizes By a similar method Clemmesen Nielsen and Jensen 1953 TABLE I , , Crude Death Rate from Lung Cancer in Various Countries Crude Death Rate per 1,000,000 Country Year Men Women Persons E and Wales E E E E E E E E E E E E Iceland 1951 530 1951 470 1950 353 1951 271 1950 252 1951 214 1951 185 1951-52 173 1951 154 1950 161 1951 111 1951 81 1950 _ 91 303 104 279 61 201 45 158 38 136 45 129 46 115 37 106 34 95 47 87 43 77 39 60 42 Rates have been shown for 1951 whenever possible as data were available for the greatest number of countries around that year estimate that the death rate among men in Copenhagen may become even greater i.e. 2200 per million Much of the recorded increase is due to the advancing average age of the population This factor can however be allowed for In England and Wales for example the recorded death rate from lung cancer rose from 8 per million in 1900 to 342 per million in 1953 i.e. 43 times But if the sex and specific death rates of 1953 had occurred in a population with the sex and age distribution characteristic of the population at the beginning of century the total death rate would have been only 188 per million The extent of the recorded increase after allowing for demographic changes is therefore 24 times or little more than half the figure given by the comparison of the crude rates Similar conclusions apply to the increases recorded in other countries . i 4 RICHARD DOLL ..:. How much of the increase is absolute and represents a real increase in the number of people suffering from primary cancer of the lung and how much is merely due to better diagnosis is uncertain It is doubtful if the nature of the data concerned will ever permit a precise answer to be given Rigdon and Kirchoff 1953 still maintain that the whole increase may be spurious but in this opinion they are almost alone 400r 350- persons persons persons persons 300- persons million mil ion milion 250- mil ion per per per 200+ rate rate death 150 death death death Annual 100 Annual Annual Annual Annual 50- 50- oo - & SCOSTCLAONTDLANWDALES HOLLAND * SWITZERLAND a ot : 0 , 1920 1925 1930 1940 1945 1950 1953 Date FIG 1. Increase in crude death rate from lung cancer in various countries 19201953. The trend of the death rate in those countries shown in parentheses has been . similar to that in the countries against which they are placed Clemmesen Nielsen and Jensen 1953 in Denmark Doll 1953a and Stocks 1953a in England Kreyberg 1954b in Norway and Dorn 1954 in the United States have recently cited the reasons for believing that part of the increase is real Three of the reasons are based on observa- tions which are of special significance for the etiology of the disease The observations are that the increase has fallen unevenly on 1. The two sexes 2. Different age groups 3. Different histological types 55 ETIOLOGY OF LUNG CANCER 2. Changes in Sex Distribution National mortality statistics and autopsy series both agree that the in incidence of the disease has been accompanied by an increasing change how in different countries preponderance of male cases Figure 2 shows ENGLAND 350+ ~ AND WALES 300+ PERSONS PERSONS PERSON PERSONS PERSONS 250+ MIL ION MILLION MILION 200 PER PER PER RATE 150F RATE RATE DEATH DEATH 100 DEATH ANNUAL AN UAL ANUAL 50 x s . Pa HOLLAND (9?SWITZERLAND Ae 10 1 2.0 3.01 4,011 5,0 60 Z.Otl RATIO OF MALE TO FEMALE DEATH RATES FIG 2. Increase in ratio of male to female death rates with the increase in the crude lung cancer mortality in various countries the proportion of male to female deaths has become progressively greater as the total mortality has arisen The reality and implication of this change are too well recognized to warrant further comment 3. Changes in Age Distribution It has long been noted that the age distribution of lung cancer in men differs from that in women and from that of other extragenital epithelial tumors in that in countries with a high incidence the male mortality rises to a maximum comparatively early and falls off rapidly in the later age groups The increase in mortality over the last 50 years did not affect all ages equally at first the younger age groups were principally affected 6. RICHARD DOLL and the maximum mortality came be between the ages of 60 and 64 years recently the increase has been most marked in the older age groups and the age of maximum mortality has risen Korteweg 1951 has pointed out that these trends can be understood if comparisons are made between the specific death rates of groups of men all of whom were born at a given period rather than between groups of men living at a given date as is the normal custom By this method of cohort analysis similar results have been obtained in Australia Lancaster personal communication Denmark Clemmesen Nielsen and Jensen 1953 England and 100 50 White males 30 he 20 10 10,0 10,00 LO 3 per 2 Rate Rate - 0.5 axa 0.2 rw wu 0.1 oe : : . : 10 20 30 40 50 60 70 80 90 FIG 3. Male death rates from lung cancer in the U.S.A. by age in 1914 1930 32 1939-41 and 1949 5s0howing heavy lines the increase in mortality with age for men born in 1850 1860 1870 1880 and 1890. Reproduced from a paper by Dr. H. F. Dorn in Industrial Medicine and Surgery 23 253 2517954. Wales Korteweg 1951 and a modified Stocks 1953a and the United States Dorn 1954 Dorn's data are reproduced in Fig 3 The dotted lines indicate the pattern of specific death rates when studied at different dates 1914 1930-32 etc. the solid lines indicate the pattern when men who were born at a given period 1850 519860 69 etc. are followed throughout their lifetime It is seen that for each cohort the mortality increases continuously with age but that the later cohorts have a progressively higher mortality at each age than the earlier ones The changes in the shape of the customary age distribution curve for lung cancer can therefore be understood if it is postulated 1 that groups of men born at each period suffer a mortality which ETIOLOGY OF LUNG CANCER 7 increases in a way similar to that observed for other forms of extragenital epithelial cancer and 2 that men born at successive periods were increasingly exposed to an environmental carcinogen On the other hand the observed changes cannot be explained as Clemmesen 1954 has pointed out if men of all age groups were equally exposed to a new agent at the same time 4. Changes in Histological Distribution . With the increase in lung cancer the proportions recorded as belonging to the various histological types have altered adenocarcinoma has be- come relatively less common and its incidence must therefore be pre- sumed to have increased less than that of other types In conformity with this and with the comparatively small increase of lung cancer in women the sex ratio for adenocarcinoma has remained close to equality whereas that for other types has shown a marked male predominance Moreover adenocarcinoma was not observed among the industrial tumors from which the Schneeberg and Joachimstal miners suffered Schmorl 1928 Hueper 1942 ikl1950 For these and other reasons Womack and Graham 1938 1941 Lickint 1953 and Kreyberg 1954a have concluded that lung cancer may be divided into two essentially different endogenous and exogenous in origin Kreyberg's papers are particularly important because the data have been collected in a country where the total lung cancer mortality is low and during a period when changes similar to those which took place in Britain and the United States 20 to 30 years ago are only beginning to his cases appear Kreyberg classified into two main groups group I con- sisting of squamous and large- and small carcinomas and group II of adenocarcinomas bronchiolar cell carcinomas and benign and malig- nant adenomas and salivary gland type tumors The group I tumors were predominantly male 273 M to 31 F and when related to the size of the Norwegian population in 1950 showed an age distribution similar to that observed for all lung cancer in countries with a high incidence save only that the characteristics of the distribution were more pro- nounced i.e. the incidence had an earlier peak 50 to 59 years and fell off more sharply in the older age groups The group II tumors were found almost equally often in each sex 81 M to 76 F and showed an incidence which increased steadily with age in the case of adenocar- cinoma and was approximately evenly distributed throughout the range of adult ages in the case of the adenomas and the salivary gland type tumors When the cases were subdivided according to their date of occur- rence Kreyberg found that there had been no increase in the proportion of group I to group II cases among women over the whole period 1925 a RICHARD DOLL 1953 despite the fact that the standardized mortality rate for women increased four and a half times On the other hand group I tumors became relatively much more frequent among men compared with group II tumors while the standardized male mortality rate increased seven- fold Despite the considerable difference in the total mortality experience of the two sexes the sex ratio for the group II tumors remained close to : to equality It is easy criticize Kreyberg's material on the grounds that it was heterogeneous in origin part collected from clinical and part from autopsy series and that the relative amounts collected in the different ways varied over the period studied Moreover it is likely that his cases provided a larger sample of those occurring in the younger age groups than in the older groups Nevertheless the characteristics of the histological types varied markedly and the observations agree so well with the trend of the data obtained in other countries that it would be unreasonable to dismiss the material because it falls short of perfection Kreyberg interpreted his findings to mean that the group I tumors were largely the result of the introduction of some new carcinogenic agent into the environment to which men were more exposed than women whereas the adenocarcinomas are probably caused by comparatively weak carcinogenic influences evenly distributed over large areas well established in the society and striking both sexes with equal forceforce The recorded increase in mortality in women in Norway may he suggests indicate the extent of the increase due to better diagnosis and the total mortality in women including a small proportion due to group I tumors may with present knowledge be regarded as unavoidable cancer In contrast the increased mortality in men additional to that recorded in women and attributed solely to group I tumors can be regarded as avoidable cancer It may well prove that these conclusions are of general significance and also apply to many countries other than the one in which the data were collected III ETIOLOGICAL FACTORS 1. Tobacco A. Retrospective Inquiries When the Louvain symposium concluded that there is now evidence of an association between cigarette smoking and cancer of the lung it did so on the basis of evidence which was derived entirely from retrospective studies of patient's histories In these studies the histories given by patients with lung cancer had been compared with the histories given by patients without lung cancer who in one or other way had been selected as controls Many studies of this general type have been reported and the principal results obtained from .9 ETIOLOGY OF LUNG CANCER them are summarized in Table II All agree in showing that there are more heavy smokers and fewer nonsmokers among patients with lung cancer than among patients with other diseases With one exception the difference between the proportions of nonsmokers found by McConnell TABLE II Principal Characteristics of Smoking Histories of Men with and without Lung Cancer Reported by Various Authors ss Number of Men Percentage of Percentage of Nonsmokers Heavy Smokers among Men among Men Author With Without With Without With Without Lung Lung Lung Lung Lung Lung Date Cancer Cancer Cancer Cancer Cancer Cancer M^...ller 86 1939 86 3.5 16.3 3232153218 08 82-1221858263 Schairer and Sch^niger 1943 93 270 3.2 15.9 323215321808 82-1221858263 Wassink 1948 134 100 4.5 19.0 3232153218 08 82-1221858263 Schrek et al Mills and Porter 1950 522 82 14.6 23.9 3232153218 08 82-12185263 1950 444 430 7 31 3232153218808 822-112221858263 Levin et al 1950 236 481 15.3 21.7 323215321808 822-112221858263 = 780 Wynder and Graham 1950 605 1.3 14.6 3232153218 08 82-1221858263 1952 82-12 185263 McConnell et al 93 186 5.4 6.5 3232153218 08 Doll and Hill 1952 1357 1357 0.5 4.5 323215321808 82-1221858263 82-12 185263 Sadowsky et al 1953 477 615 3.8 13.2 3232153218808 20.6 Wynder and Cornfield 1953 63 133 4.1 3232153218 08 82-1221858263 1953 812 0.6 18.0 323215321808 82-1221858263 Koulumies 300 1953 224 1.8 16.0 3232153218 08 82-12 185263 Lickint 1000 Breslow et al 1954 518 518 3.7 10.8 3232153218 08 82-1221858263 1954 Watson and Conte 265 277 1.9 9.7 3232153218 08 82-1221858263 32 15321808 1954 135 135 0.7 16.7 82-1221858263 GRsaenldlig 9= 1954 415 381 1.2 5.8 * 18 Note It has not been possible to make all the figures in this Table completely proportions comparable Some series include for example a few women in others the of heavy smokers are based on totals which are different from those used to calculate the proportion of nonsmokers One series excludes adenocarcinoma The individual papers should be referred to before any detailed use is made of the figures Gordon and Jones the differences are large enough to be important More detailed results of two of the investigations are shown in Tables III and IV From these it is seen 1 that there is a steady increase in the relative proportions of lung cancer to control patients as the amount smoked daily increases and 2 that the difference in smoking habits between persons with and without the disease is more marked for men than for women Average Amount of Tobacco Smoked Daily Lung Carcinoma Patients and Control Patients with Other Diseases : % Smoking a Daily Average for 20 Years of No. of % Non- Sex Disease Group Patients smokers 1g.- 10 16 g.- 35 Lung Carcinoma 605 squamous or 100.1 1.3 2.3 10.1 35.2 30.9 20.3 M undifferentiated Other Diseasest 780 99.8 14.6 11.5 19.0 35.6 11.5 7.6 Lung Carcinoma 25 i ; squamous 100.0 40.0 4.0 16.0 24.0 8.0 8.0 F undifferentiated Other Diseasest 522 100.1 79.6 9.2 6.9 3.2 0.6 0.6 After Wynder and Graham 1950 Nonsmokers defined as persons smoking an average of less than 1 cigarette a day or its equivalent in pipe tobacco or cigars over the previous 20 years The age distributions of the control patients were different from those of the lung carcinoma ; the percentages quoted by percentages therefore obtained were the age groups so as to make them have the same relative importance as they had in the group of 605 men with squamous cancer ; TABLE IV Average Amount of Tobacco Smoked Daily Lung Carcinoma Patients and Control Patients with Other Diseases . % Smoking a Daily Average for 10 Years of No. of % Non- Sex Disease Group Patients smokersf < g. g-- 25 50 + Lung Carcinoma 9 .9 1357 M 99.9 0.5 Other Diseases 1357 100.0 4.5 4.0 36.0 35.0 21.6 2.8 9.5 42.0 31.8 11.3 0.9 Lung Carcinoma 108 F 100.0 Other Diseases 108 100.0 37.0 14.8 22.2 13.0 13.0 0.0 54.6 23.1 16.7 5.6 0.0 0.0 . * After Doll and Hill 1952 Nonsmokers defined as persons who had never consistently smoked as much as 1 g of tobacco a day for as long as one year hospi- t Patients with other diseases matched to be within the same year age group and to be in time the patients carcinoma patients tals of the same type type and in the same region at approximately the same lung ETIOLOGY OF LUNG CANCER 11 The conclusions to be drawn from these investigations depend on whether the comparisons between the smoking histories of the various groups of lung cancer and control patients are valid and on the extent to which the control patients were representative of the populations from which the lung cancer patients were drawn In some of the earlier investigations there were reasons for doubting whether the comparisons were valid example when the histories of the two groups of patients were recorded by different methods Other investigations in which the patients were interviewed by the same persons and by the same methods throughout and in which the control patients were chosen to match _ the lung cancer patients with regard to sex and age the date of interview * and the hospital in which they were treated were not open to objection this score Nevertheless there was the possibility that bias of one or another sort could have entered into the selection of the patients or the recording of the results The various types of bias which might have oc- curred were considered in detail by Doll and Hill 1950 1952 They concluded that bias could not be responsible for their results and that the only logical explanation was that the observed association between the smoking of tobacco and the development of lung cancer was real Further important evidence has been obtained from the preliminary results of two prospective inquiries These inquiries have been conducted on a different principle and are not subjected to the types of bias which might theoretically have occurred in the retrospective studies Since they lead to the same conclusion it is not now necessary to give further detailed consideration to the evidence from which it was deduced that the association shown by the retrospective studies was real B. Prospective Inquiries In the prospective inquiries the smoking habits of large numbers of normal persons have been recorded and the subjects have subsequently been watched to see what diseases they developed Preliminary results of studies of this type have been reported by Doll and Hill 1954a and by Hammond and Horn 1954 In Hammond and Horn's inquiry a large number of people who volunteered to help the American Cancer Society were each asked to interview approximately 10 white men aged between 50 and 69 years to be chosen from among acquaintances with whom they expected to remain in contact for several years The smoking histories obtained at the interview were recorded on a standard questionnaire Subsequently on the 1st of November each year the interviewers filled in a follow form stating whether the men were alive or dead or had been lost sight of The State Health Department was then asked to supply an abstract of the death certificate of each man reported to have died When cancer was certified as the cause of death an attempt was made to obtain further 12 RICHARD DOLL details from the certifying physician A total of 204,547 questionnaires was collected of which 14,413 were eliminated because they referred to inappropriate subjects or to subjects who were interviewed outside the specified period 1.1.52 to 31.5.52 or because they were inadequately completed Of the subjects corresponding to the remaining questionnaires 187,766 98.8 were successfully traced at 1.11.53 Altogether 4854 TABLE V Lung Cancer Death Rates among Men by Type of Smoking and by Amount Smoked All Cases Reported as Primary Lung Cancer Microscopically Proved Lung Cancer Excluding Adenocarcinoma Type of Smoking Population No. of Deaths Death Rates No. Deaths Death Rates Never smoked or occasional only Cigar and pipe smoking but never smoked cigarettes regularly . History of regular cigarette smoking 44,091 35,853 107,822 107,822 Total 187,766 187,766 12 27.2 12 35.5 143 132.6 167 88.9 4 9.1 3 8.4 45 41.7 52 27.7 Regular cigarette smoking less than 1 pack a day at time of questioning Regular cigarette smoking 1 pack or more a day at time of questioning 54,799 25,497 62 113.1 17 31.0 61 239.2 24 94.1 * Reproduced from the Journal of the American Medical Association Hammond and Horn 1954 men were reported to have died and the certified cause of death was obtained for 4710 i.e. in 97 Cancer of the lung was certified as the cause in 167 instances According to the authors The evidence at present at hand does not warrant presenting the findings in any greater detail than is shown in Table 13 reproduced above as Table V The lung cancer death rate was higher among men with a history of regular cigarette smoking than among men who had never smoked regularly and even higher among men who currently smoked one pack or more of cigarettes a day at the time of questioning The differences are statistically ETIOLOGY OF LUNG CANCER 13 significant P = 0.002 or less In fact even the men smoking less than one pack cigarettes daily have significantly higher death rates from lung cancer than those who have never smoked regularly P = 0.03 or less The best estimate that can be made at the present time at the % level of confidence is that lung cancer deaths are from 3 to 9 times as common among men with a history of cigarette smoking as among men who have never smoked regularly and that lung cancer deaths are from more 5 to 16 times as common among men smoke one pack or per day Differences in the age distributions of the men in the different cate- gories have not been allowed for in Table V. Such differences cannot however be responsible for the results because Hammond and Horn have also shown that the proportion of nonsmokers is greater and the proportion of cigarette smokers is smaller in the older age groups in e - which lung cancer is more common If therefore an allowance for age differences is made it will be found that the real difference in mortality between cigarette smokers and nonsmokers is in fact even greater than would appear from the above data The investigation reported by Doll and Hill 1954a was on a smaller scale and was organized differently but the trend of the results is similar A postal questionnaire was sent to nearly 60,000 men and women on the British Medical Register Just over 40,000 replied giving details of their smoking habits Subsequently the national offices for the registration of deaths notified the causes of death of all doctors and clinical details of the deaths attributed to lung cancer were obtained through the physicians who had signed the death certificates In the first 29 months following the date when the questionnaires were sent out 789 deaths occurred among the 24,389 male doctors aged 35 years and above whose smoking habits had previously been recorded and classified The numbers of deaths from lung cancer which occurred among men in the different smoking categories are shown in Table VI in comparison with the numbers which would TABLE VI Number of Deaths from Lung Cancer Observed and Expected among Doctors : Smoking Different Amounts of Tobacco Most Recent Amount Smoked Dailyt 0 1-14 15-24 g 25 No. of Observed Deaths No. of Expected Deaths 0 12 3.77 14.20 14 13 10.73 7.33 Observed as Percentage of Expected 0 85 130 177 * After Doll and Hill 1954a Defined as the amount smoked at the time of completing the questionnaire or if smoking had been stopped immediately before stopping RICHARD DOLL 4 prospective to occur if smoking had been unrelated to the disease have been expected of nonsmokers of in the American investigation the proportions As smokers were greatest in the oldest pipe smokers and of light cigarette be calculated separately that the expected numbers had to age groups and added for all ages The number of cases so far for each age group there is a steady and striking increase in the ratio studied is small but expected in each smoking between the numbers of cases observed and increases When this biologically im- category as the amount smoked the differences are statistically highly portant trend is taken into account of the quantitative relationships significant P < 0.01 The similarity estimated from the between smoking and mortality which have been retrospective and the inquiries is also striking Doll and Hill estimated by the two methods for each 1952 1954a The mortality rates of the un- of the smoking categories have been expressed as percentages of the four rates and a comparison of the relationships wbeeitgwheteendtahveemraigsesshown in Fig 4. The slopes of the two graphs are almost identical questionnaire Fou1. rDolelxpalnadnaHtiilol'nss raerseultthseomriegthitcahllayvepobseseinblperoduced if heavy smokers who suspected that they had lung cancer had replied to the than nonsmokers or lighter smokers in similar situation more readily off as the duration If this had been so the effect would necessarily wear increased between the completion of the questionnaire and death of time the relationship occurred In fact no such diminution in the strength of months of the inquiry It is in any case unlikely that a over the first 29 similar form of selection could have entered into the choice of subjects for interview in Hammond and Horn's inquiry 2. Certification of the cause of death may have been biased by knowl- edge of the subject's smoking history Iinf hheoawveyvesrmotkheerreswtahse adetaentdhernactye to diagnose lung cancer more readily in this category would be expected attributed to other causes among men less than average and this was not so in either tionvbeestipgraotpioorntiIonnaftaecltyby no means all doctors are convinced of the reality of the association was shown for example in response to a ques- sent to Massachusetts physicians by Snegireff and Lombard tionnaire if it existed at all may well have operated in 1954 bias in diagnosis the 3o.ppSomsoitkeindgirmecatyiobne associated with lung cancer only indirectly being linked with another factor which is associated with it directly Such an indirect link may perhaps account for some of the association found by Hammond and Horn since both smoking and the disease may be commoner in certain social and occupational groups within the population ETIOLOGY OF LUNG CANCER 15 Such factors are unlikely to have contributed to Doll and Hill's results was since the population studied was entirely composed of doctors and therefore homogeneous In both inquiries an indirect link comparatively may have because cigarette smoking and lung cancer are both arisen commoner in towns than in the countryside But this cannot account for 225 ~ spective inquiry X < <x spective Inquiry o Percntage if Non- smokers 1. : Light Smokers 1-149 a day 1 L Moderate Moderate 15-24g day 1 1 Smokers 259.or more a day 4. Standardized death rate from lung cancer among men smoking four differ- amounts of expressed as a percentage of the unweighted average of the amounts tobacco four rates Hill estimated and from observd Hil Hill retrospective inquiry into patients smoking histories prospective inquiry into mortality and observed during during a prospective inquiry into the mortality Hill of doctors Doll and 1954a much of the observed differences the association between smoking and place of residence Doll and Hill 1952 Hammond and Horn hdaisbeiatsseis weaker much than the association between smoking and the association is 4. There remains therefore, the possipobssiibillitiy ty that the association is real and direct Smoking C. Method of The evidence suggests that all forms of smoking are not equally associated with the disease Pipe smoking and cigar smok- 16 RICHARD DOLL ing are less closely associated with than cigarette smoking Wynder and Graham 1950 Levin et al 1950 Schrek et al 1950 Doll and Hill 1952 1954a Sadowsky Gilliam and Cornfield 1953 Breslow et al 1954 Watson and Conte 1954 and Hammond and Horn 1954 Only McCon- nell Gordon and Jones 1952 and Randig 1954 failed to find any distinction between the various methods of consumption of tobacco From the mortality rates estimated by Doll and Hill 1952 it would appear that the risk among pure pipe smokers may be as much as thirds the risk among pure cigarette smokers but they hesitated to draw any precise conclusion because of the variatioinn the average amounts of tobacco smoked by the different types of smoker and because of the difficulty of separating with certainty a group of smokers who had never smoked Gilliam cigarettes at all Sadowsky and Cornfield 1953 found a greater difference between pipe and cigarette smokers and Hammond and Horn 1954 found that the mortality among smokers who had never smoked cigarettes was practically identical with that among nonsmokers see Table V Hammond and Horn's evidence is particularly important because it was obtained from a prospective inquiry in which great care had been taken to eliminate from the pipe and cigar group all men who had ever smoked as much as ten packs of cigarettes in their entire lives The investigation was on such a scale that even with this definition it was still possible to secure a large group for study and these results are likely to be more reliable than those of other workers who defined the categories ; of smokers less strictly Few people outside South Africa have smoked tipped cigarettes or used cigarette holders regularly for any length of time and it has therefore been difficultto obtain evidence regarding the possible protective effect of these methods of smoking The data obtained by Doll and Hill 1952 are shown in Table VII A smaller proportion of the lung cancer patients than of the control patients had used holders and a smaller proportion had smoked tipped cigarettes but the numbers are small and it would be unwise to draw any positive conclusions from this very limited evidence It might be that the use of cigarette holders and of tipped cigarettes are both associated with light smoking but this did not appear to be the explanation among the patients referred to above D. Extent of Risk The results of the two prospective inquiries which have been reported do not as yet permit direct measurements to be made of the full extent of the lung cancer mortality among smokers of different quantities of tobacco Persons who were seriously ill when the inquiries were started are relatively unlikely to have been included in the initial population and consequently the mortality rates recorded in the first year ETIOLOGY OF LUNG CANCER , 17 or two of follow are almost certainly too low Until a few more years have elapsed estimates of the risks to which the different categories of smokers are exposed must therefore still be based on the data derived from the retrospective studies Estimates have been made by Doil and Hill 1952 Heady and Barley 1953 Sadowsky Gilliam and Cornfield 1953 and Wynder and Corn- field 1953 The results obtained in Britain and the United States have TABLE VII Use of Cigarette Holders and of Tipped Cigarettes Male Lung Cancer Patients and Matched Control Patients Male Lung Cancer Patients Male Control Patients Type of Smoker No. % No. % Use of Cigarette Holders Regularly Occasionally Never Total Cigarette Smokers 10 2.0 15 3.0 479 95.0 504 100.0 27 5.8 27 5.8 413 88.4 467 100.0 Use of Tipped Cigarettes Ever regularly Never regularly - 3 0.6 501 99.4 Total Cigarette Smokers 504 100.0 Smokers Who Had Never Smoked Cigarettes 15 Nonsmokers 4 Total men 523+ 15 3.2 452 96.8 467 100.0 30 26 523+ * After Doll and Hill 1952 The total numbers of men are different from the numbers shown in Table IV because questions about the use of cigarette holders and tipped cigarettes were only introduced in the last part of the inquiry been compared by the two latter groups of authors and in a more detailed fashion by Cutler and Loveland 1954 Cutler and Loveland's estimates are summarized in Table VIII From the table it appears that for a man aged 40 years who smokes 20 or more cigarettes a day 1 the risk of dying of lung cancer before the age of 80 years is of the order of % and that 2 this risk is some 6 to 30 times as high as that among nonsmokers The reliability of these estimates depends on the validity of certain RICHARD DOLL assumptions which had to be made before the rates could be calculated These are 1. That the deaths recorded nationally as being due to lung cancer a provide fair estimate of the actual number of deaths due to the disease 2. That the smoking habits recorded by patients with lung cancer were at each age and in each sex typical of all those persons who died of the disease during the period of the survey 3. That the smoking habits recorded by the control patients without lung cancer were similarly representative of those of all members ~~ of the population from which the lung cancer patients were drawn . TABLE VIII Risk of Developing Lung Cancer among Men Smoking Different Amounts of Tobacco : Estimated from the Results of Three Groups of Investigators Estimated Risk of Developing Lung Cancer by the Age of 80 Years per 1000 Men Aged 40 Years Amount Smoked Sadowsky Gilliam and Cornfield 1953 Wynder and Graham 1950 Doll and Hill Combined 1952 Results Nonsmokers 10 3 Smokers of under 10 g a day 22 19 Smokers of 10-20 g a day 46 52 Smokers of more than 20 g a day 65 90 5 16 : 34 25 48 49 ; ; 86 80 * After Cutler and Loveland 1954 Further assumptions are also required about the trend of future changes in mortality in order to present the risks in the form chosen by Heady and Barley 1953 and by Cutler and Loveland 1954 but these are of minor importance in that they have little effect on the relative sizes of the risks for the different smoking categories _ Whether the assumptions are justified is impossible to say with cer- tainty and the rates must be regarded as provisional In view however of the conformity of the estimates calculated from data from independent investigations in different countries and the further confirmation of the relative sizes of the risks by the preliminary results of the prospective inquiries it is unlikely that the estimated rates are seriously in error The correspondence between the results of Doll and Hill's two investigations has been shown previously in Fig 4 and Hammond and Horn's ETIOLOGY OF LUNG CANCER 19 best estimate . . . that lung cancer deaths are from 5 to 16 times as common among men who smoke one pack or more per day as among nonsmokers largely overlaps the estimates made by Cutler and Loveland Table VIII On the other hand the fact that smoking habits are not invariable and that the amounts which have been related to mortality have been recorded only at one point in time must have blurred the differences between the smoking categories so that the estimated rates for light smokers are probably somewhat overestimated whereas the rates for heavy smokers are likely to have been underestimated The estimated rate for nonsmokers is low but it is not intrinsically _ unreasonable At ages 45 to 74 the rates calculated from the English * data are slightly lower than the rates which actually occurred among women in rural areas in England Doll 1953b and they are similar to the rates now recorded among women in Denmark and several other countries see Table ) If these rates represent the mortality risk in the absence of smoking then the number of deaths from lung cancer attributable to causes other than smoking among persons aged 25 to 74 years in England and Wales in 1950 would have been about fifth of the total number actually recorded E. Difference between Histological Types In the foregoing discussion no consideration has been given to the possibility that the different his- a tological types of carcinoma of the lung may have different etiological relationships to smoking It has however been suggested that the relationship with smoking holds only for squamous cell and anaplastic carcinomas This qualification makes little difference to the conclusions which have already been drawn because wherever lung cancer is com- mon the great majority of cases are of the squamous cell or ana- plastic types The distinction is however of considerable theoretical interest Three reports have paid special attention to histological differences Wynder and Graham 1950 found that the smoking habits of 39 men and 15 women with adenocarcinoma were closely similar to those of con- trol patients with diseases other than lung cancer Doll and Hill 1952 reported that there was no statistically significant difference between the amounts smoked by patients in the different histological groups in either sex The number of cases of adenocarcinoma is however too small 33 male and 10 female to conclude that no difference exists There were in fact relatively more smokers and very light smokers . among the patients with adenocarcinoma in both sexes Breslow et al 1954 noted that Six out of 46 13 per cent of the cases of adenocarcinoma did not smoke cigarettes whereas only 28 out of 472 6 per cent of the patients with other types of carcinoma . . . did not smoke ciga- RICHARD DOLL is rettes The interpretation of these data complicated by the inclusion men and women in a single series When however the sexes are sepa- of communication rated the distinction still persists Breslow personal The most striking evidence has however been obtained by Kreyberg communication and the author is indebted to him for permis- personal sion to cite his results obtained up to the end of 1954. Smoking histories taken from patients in the wards of the Rikshospitalet Oslo before Iwere and the histological typing of the tumors was made inde- operation without knowledge of the patient's history sex or age The pendently most recent amount of tobacco smoked daily by men whose tumors were classified as belonging to the two main histological groups see page 7 was as follows * Type of Tumor - Group 1 Group 2 Ratio of group 1 to group 2 tumors No. of Nonsmokers 3 2 1.5 No. of Men Smoking Daily 1-9 10-19 20 + 40 98 52 11 14 5 3.6 7.0 7.0 10.4 Total No. of Men 193 32 6.0 details Finally Wynder 1954 has studied the problem by collecting of the cases of lung cancer which are reported to have _ of the histology cent i.e. 14 out of occurred among male nonsmokers Twenty nine per adenocarcinomatous whereas only % i.e. 54 out of 1019 48 were male smokers with lung cancer in his were adenocarcinomatous among smoking habits persIotnamlussetritehserefore be concluded that adenocarcinoma of the lung is less closely related to than are the squamous cell and undifferentiated types of cancer and it may well prove that smoking reason plays no part at all in its production increase in F. Vital Statistics and Tobacco Consumption The sharp the number of deaths attributed to lung cancer during a period when consumption was also increasing has been cited as one tobacco of the disease In fact correlations for believing that tobacco is a cause and often entirely irrelevant so that they are of in time may On the other no value in proving the existence of a causal relationship hand if a relationship can be demonstrated by other means it is reason- able to test its significance by seeing if it is consistent with such temporal - changes as are observed to occur The changes which have taken place in tobacco and cigarette con- sumption and in lung cancer mortality in England and Wales in the last 70 are illustrated in Fig 5 and Table IX Whether the correlation betyweeaerns cigarette consumption and mortality is as close as would be expected if cigarettes were one of the principal causes of the disease is * ETIOLOGY OF LUNG CANCER 21 21 PERSONS s PERSON a PERSONS FOG * CANCER DEATH RATE se-= TOBACCO CONSUMPTION 0 CIGARETTE CONSUMPTION i, . ia nA ff 4 MILLION MIL ION 280 MILION va f vr oA SF ify MILION i A as PER 8 PER vb oa : ea & fay - ww 150 RATE Ueoheneee 7 we 7 ue 7or a ees DEATH pee Y 50} DEATH we DEATH er ; wee ; 7.0 ANNUAL ad ANUAL AN UAL 6.0 5.0 CONSUMPTION CONSUMPTION 4.0 CONSUMPTION 4.0 CONSUMPTION CONSUMPTION 3.0 LBS 12.0 PER PER PER PERSON ee on ANUAL PERSON ANUAL 1900 1910 1910 Saat 2 PERSON 1920 1930 1940 1950 FIG 5. Crude death rate from lung cancer in England and Wales and per capita consumption of cigarettes and of all tobacco products in Great Britain 1900-1953 TABLE IX Crude Lung Cancer Death Rate and Consumption of Cigarettes and Other Tobacco Products for Men and Women Separately in England and Wales 1881-1950 Annual Consumption Lbs per Adult aged 15 years + Men Women Lung Cancer Death Rate per 1,000,000 Persons aged 15 years + Period Cigarettes Other Tobacco Cigarettes Date Men Women 1881-90 0.006 1891-1900 0.4 1901-10 1.8 1911-20 3.8 1921-30 5.1 1931-40 6.9 1941-50 8.3 6.1 6.2 4.9 ' 4.3 3.7 2.7 2.4 0.0 0.0 0.0 1920 0.0 25 13 0.2 1930 74 27 0.8 1940 256 68 2.4 1950 624 111 Note The figures shown in this table are derived from a different source from those shown in Fig 5 and differ in that the estimates of tobacco consumption exclude the amounts consumed duty in the Merchant Navy and in the Armed Forces abroad Except in wartime these amounts are negligible The figures also differ in that the table shows rates per adult or per 1,000,000 adults and the figure shows rates per person or per million persons RICHARD DOLL uncertain because many of the relevant facts are unknown It is for example not known 1. What proportion of the increase in recorded mortality is real 2. What are the relative risks attached to the smoking of tobacco in cigarettes and in other forms 3. What is the biological relationship between the dose of cigarette smoke and the development of the disease On the basis of present knowledge one may perhaps suggest more or less reasonable solutions to the first two problems although it must be admitted that no estimate of the extent of the real increase in mortality can be more than an intelligent guess Save however that the evidence indicates that mortality varies in direct arithmetical proportion with the amount smoked at a given time we are completely ignorant of the third We neither know the induction time of the tumor nor the relative effects ~ of the same dose at different periods of life and different hypotheses about either of these must lead to gross differences in the temporal relationship between consumption and mortality If for example it is postulated that the mechanism of carcinogenesis is of the type suggested by Nordling 1953 Stocks 1953b and Ambrose 1954 it might well be that the effect of a dose of cigarette smoke at a given time is pro- portional to the fourth or fifth power of the time elapsing after its administration Armitage and Doll 1954 On such a hypothesis a reasonable agreement between the figures in Table IX can be demonstrated In the present state of ignorance however it is probably better not to attempt any exact correlation but to note only that if smoking is a major cause of lung cancer it will be difficult to account for the figures unless there is also a considerable difference in the relative effects of smoking cigarettes _ and pipes ; It is almost equally difficult to decide whether differences in smoking habits are adequate to account for the difference in mortality observed in men and women At first sight it would seem unlikely that they were since women have been responsible for an increasing proportion of the total amount smoked and in all countries the preponderance of men among subjects of the disease has become more marked difficulty however is the same as was encountered previously that is we do not know the induction time of the disease nor the relative importance of smoking at different periods of life From the figures which are available for Britain Table IX it would seem that so long as the effect of smoking : does not reach its maximum till after 20 years differences in smoking a habits could readily account for a large and still increasing difference in the mortality of men and women In fact it may well be that the cases of ETIOLOGY OF LUNG CANCER 23 lung cancer among women still include only a small proportion specifically related to tobacco and that the major increase in female mortality is to come An alternative approach is to estimate the mortality among male and female nonsmokers According to Doll 1953b the proportions of men and women found among the nonsmokers with lung cancer in Doll and Hill's 1952 series are consistent with the hypothesis that in the absence of smoking and exposure to certain industrial carcinogens the death rates are equal in the two sexes The attempt to compare mortality and tobacco consumption in dif- ferent countries is even more hazardous for not only do standards of . death certification vary but so do methods of smoking It is said for example that few Europeans throw away as large an unsmoked butt as . is commonly discarded in the United States It is however of interest to make the comparisons provided that the deficiencies of the data are recognized Statistics for 8 countries have been collected by Nielsen and Clemmesen 1955 and these have largely been drawn on in the preparation of Figs 6 and 7. In Fig 6 the male death rate from lung cancer in 11 countries in 1950 or in the nearest year for which the information is available has been plotted against the annual consumption of all tobacco products per head of the population 20 years earlier in Fig 7 * it has been plotted against the annual consumption of cigarettes per head 20 years earlier In fact nearly all the tobacco consumed in 1930 was = consumed by men even in the Scandinavian countries the amount of tobacco smoked by women at that period was small so that it is not unreasonable to compare the male death rate with the per capita con- sumption In nearly all the countries the consumption per man in 1930 is likely to have been approximately double the consumption per person Figure 6 fails to show any relationship between lung cancer mortality and total tobacco consumption in the various countries but from Fig 7 it would appear that the data with the exception of those from the United States are not inconsistent with the existence of a relationship with cigarette consumption To a small extent the anomalous position of the United States can be explained by the high proportion of young people in its population whether the sort of consideration which has been referred to above can account for the rest is a matter for conjecture What is cer- tain is that the observed facts fit the hypothesis of a relationship between the disease and cigarettes much better than the hypothesis of a relation- ship with tobacco generally G. Identification of Carcinogenic Agent Numerous attempts have been made to induce cancer with tobacco products in animals A significantly increased incidence of the common pulmonary adenoma of mice was ob- : 24 RICHARD DOLL served on one occasion by exposing animals with a high spontaneous incidence of the tumor to strong concentrations of cigarette smoke Essenberg 1952 but no change or very little change in incidence has been observed by others Passey 1929 Campbell 1936 Lorenz et al 1943 500- @ 400+ 1950 men 300-- milon per 200- rate death Anual t N I t 1 i 3 1-0 2.0 3.0 Annual tobacco consumption kg per person 1930 FIG 6. Crude male death rate from lung cancer in 1950 and per capita consumption of all tobacco products in 1930 in various countries 1 Great Britain 2 Finland 3 Switzerland tobacco consumption estimated from data published by Gsell 1951 and Nielsen and Clemmesen 1954 4 Holland 5 U.S.A. 6 Australia death rate for 1951-52 7 Denmark 8 Canada 9 Sweden and 10 Norway Coefficient of correlation between death rate and tobacco consumption 0.10 -0.31 Wright 1955 in particular exposed 80 mice of the Strong A strain to an average concentration of 0.08 mg of smoke per liter for 20 hours a day for 5 days a week There were many deaths in the early weeks of exposure and Wright doubts if a stronger concentration could be used successfully The average number of tumors in the 34 mice which survived ETIOLOGY OF LUNG CANCER 25 from 3 to 15 months exposure was higher in the experimental group than in a control group of paired litter mates killed at the same ages 1.15 against 0.76 but the number of bearing mice was less 44 against 56 Neither difference is statistically significant According to Moore 500-- . Oo 400- ) / 1950 f @ 1950 / men men men 300h 0 -- .30 y milion million milion +f per per 200- rate 200- rate / a 2 + / / y, fi death co death 5 death ' / An ual 4fi L/ AAnnuuaall LOOF @ 50 0 7 re) 250 250 500 250 500 750 750 10 0 1250 150 1000 1250 1500 Annual cigarette consumption cigarettes . per person FIG 7. Crude male death rate from lung cancer in 1950 and per capita consumption of cigarettes in 1930 in various countries key as in Fig 6 with the addition of 11 Iceland death rate estimated from cancer notification rate Coefficient of correlation between death rate and cigarette consumption 0.73 -0.30 1953 Graham produced what appeared to be one small papilloma in the bronchus of a dog by painting tar from cigarette smoke through a fistula onto the bronchial mucosa but the report proved to be erroneous and no tumor has appeared after three years Graham personal communication Tumors comparable to bronchial carcinoma as it appears in man have not been produced by tobacco products by any method RICHARD : DOLL =: Occasional tumors on the skin of mice and rabbits have on the other hand been produced by several workers The literature is reviewed by Wynder Graham and Croninger 1953 who have themselves been able to produce tumors in a high proportion of treated animals They obtained tar from cigarettes smoked mechanically under conditions which approximated to the physical conditions of normal smoking and applied it three times a week to the skin of mice until a carcinoma appeared or the animal died To avoid toxic reactions from the nicotine content of the tar the dose given initially was small and it was increased gradually over the following two months The first papilloma appeared after eight months of painting the first carcinoma after one year Of 81 mice ini- tially included in the series 62 survived for a year or more and 36 of them i.e. 58 finally developed cancer Passey personal communica- tion has however pointed out that with the method of combustion used Temperatures up to 966 were obtained and that this is appreciably higher than the combustion temperatures in normal smoking see page 27 Tar obtained from cigarettes burnt at temperatures not exceeding 750 has in the hands of Passey et al 1955 not reproduced Wynder Graham and Croninger's results Three potentially carcinogenic substances have been distinguished in tobacco smoke arsenic benzpyrene and radioactive potassium Arsenic is present in many tobaccos probably because of its use as an insecticide It is present in greatest amounts in tobacco of American origin and is completely or almost completely absent from Oriental types Daff and Kennaway 1950 estimated that an ordinary Virginian cigarette as smoked in England contains about 50 gexpressed as As aOnd that approximately 15 is volatilized in smoking Smoking 10 cigarettes a day means therefore that as much arsenic as is present in one maximum official dose of Fowler's solution is volatilized in 10 weeks Arsenic is believed to be capable of inducing bronchial carcinoma in man see page 33 but it is unlikely to be the responsible agent in tobacco smoke since 1 the amount to which smokers are exposed is very small compared with the amounts encountered industrially and 2 bronchial carcinoma forms a high proportion of cancer cases found at necropsy in Istanbul Schwartz reported by Daff Doll and Kennaway 1951 and arsenic is almost completely absent from Turkish tobacco The presence of polycyclic hydrocarbons in tobacco smoke has long been suspected but no individual substances were identified until Cooper and Lindsey 1953 and Commins Cooper and Lindsey 1954 reported the presence of anthracene and pyrene in tar obtained from cigarette smoke Subsequently Cooper Lindsey and Waller 1954 reported that they had also distinguished the presence of benzpyrene To obtain ETIOLOGY OF LUNG CANCER 27 the tar the cigarettes were smoked mechanically but care was taken to make the physical conditions of combustion correspond closely to those which occur in normal smoking The substances were detected by means of chromatography followed by absorption spectrophotometry 10.2 g of anthracene 9.0 ...gof pyrene and 1.0 gof benzpyrene were estimated to be present in the tar collected from the smoke of 100 cigarettes The amount of benzpyrene is small and it is necessary to smoke 200 | cigarettes to obtain enough to produce by local injection a sarcoma in ~ a mouse Quantitatively it is less important than the amount in town air since it would be necessary to smoke 50 cigarettes in order to inspire as much as is inspired from the air in one day by a standard man in an average English industrial town Waller 1952 Blacklock et al 1954 On the other hand the benzpyrene in cigarette smoke being dissolved in the form of a fine suspension in a solvent material may well be more active than the atmospheric benzpyrene which is largely adsorbed on carbon particles and is in this state relatively inactive Steiner 1954 Part of the atmospheric benzpyrene likely to be filtered off by the nose Benzpyrene has also been identified in the tar collected from the smoke of cigarettes made entirely of paper Cooper and Lindsey 1954 Lefemine 1954 The quantity present was however such that the combustion of the paper could account for only about % of the > benzpyrene present in the smoke from ordinary tobacco cigarettes Lindsey 1954 and personal communication has moreover also found * that benzpyrene is present in the smoke from tobacco burnt in a pipe in > the same order of quantity weight for weight of tobacco as was obtained from cigarette smoke Commins Cooper and Lindsey 1954 suggest that the polycyclic hydrocarbons may be formed by the pyrolysis of acetylene Kennaway 1924 1925 has shown that strong heating of acetylene and other unsaturated materials produces carcinogenic tars at temperatures of 700 and above and Fishel and Haskins 1949 showed that acetylene was present in tobacco smoke The temperature of combustion in ordinary cigarettes in paper " cigarettes in a pipe and in a cigar were according to Lindsey 1954 and personal communication as follows , i Ordinary cigarette Paper cigarette Pipe Cigar Havana Quiescent Combustion Temperature 650 Varies Varies -500 Suction Combustion Temperature 700 655 470 560 Surface Temperature 900 + 900 + 700 + 800 + 28 RICHARD DOLL Closely similar temperatures in burning cigarettes have been recorded by Wynder Graham and Croninger 1953 and by Hamer 1954 and a similar temperature for combustion in pipes was recorded by Cooper et al 1932 If Lindsey's observations on the presence of benzpyrene in the smoke from tobacco burnt in pipes are confirmed it would seem likely that polycyclic compounds can be formed at lower temperatures than have hitherto been thought to be necessary If benzpyrene is the active agent responsible for tobacco cancer the finding of its presence in pipe smoke will accord with the high incidence of cancer of the lip and buccal cavity known to occur among pipe smokers In this case it will be necessary to explain the considerable difference in the incidence of lung cancer which is found between pipe and cigarette smokers on the basis of differences in the physical dispersal of the smoke and of particles and droplets in the smoke associated with the two methods of smokingfor example in the proportion of smokers who inhale It will however be recalled that although benzpyrene is a strong carcinogen to which man and animals are both susceptible it has yet to be directly established that it has any such action on the bronchial mucosa It is possible that the active agent is in fact some substance hitherto not recognized as being carcinogenic On the other hand the high mortality from lung cancer among gasworkers who are specifically exposed to large quantities of benzpyrene in the course of their work see page 34 supports the hypothesis that benzpyrene is also carcino- ; genic in the human bronchus Mulvaney 1953 suggested that radioactive potassium present in tobacco as a naturally occurring isotope might be an effective carcinogen Swinbank personal communication found that a typical cigarette contained 24 mg of potassium and that the radioactivity corresponded to 2 -1.7 mg more The errors of the experiment were likely to have been greater than the statistical error so that there was probably no excess activity at all Even if there were and it were all due to the presence of the most dangerous substance radium the amount estimated would not be biologically important Swinbank estimates that if the whole potassium content of cigarettes were inspired and if 20 cigarettes were smoked per day for 50 years it is unlikely that the total dose would amount to more than the maximum permissible weekly dose recommended by the International Commission on Radiological Protection Spiers 1954 found however that such radioactivity as is present in cigarettes remains almost entirely in the ash and he was able to detect only the equivalent of 6 gof potassium in the smoke It is therefore not possible to attribute any significant carcinogenic effect to radioactivity in tobacco ETIOLOGY OF LUNG CANCER 29 The further possibility remains that cigarette smoke is not in itself carcinogenic but that it acts as an activator or a carcinogen to substances already present in the air from other sources This hypothesis is less attractive than it was now that benzpyrene has been found to be present in appreciable quantities in cigarette smoke but it is possible that the effect of tobacco is enhanced by the presence of solvents in the smoke such as pyridine and pyrrole which could theoretically elute the benzpyrene adsorbed on to carbon particles in the inspired town air and so render the atmospheric benzpyrene more active Such a secondary effect can readily be envisaged as being responsible for some of the differ- . ences in mortality in urban and rural areas referred to below H. Various Criticisms The conclusion that cigarette smoking is a cause of lung cancer has not been uniformly accepted It has not to the author's knowledge been argued that the basic data are factually erroneous this would hardly be possible since all who have investigated the subject have found the same general trends but it has been suggested that the wrong interpretation has been put on the results interpretation incompatible with all the known facts At first the principal objections were 1 that the retrospective study of patients histories provided too many opportunities of bias for the results to be relied on Hammond and Horn 1953 Shapiro 1954 and 2 that no known carcinogen had been identified in tobacco smoke In the light of the follow studies on men of known smoking habits and of the recent biological and chemical stud> ies on cigarette smoke these criticisms are now only of historical interest -* The current objections may be considered under five main heads 1. That the evidence is purely statistical and that it has not been possible to produce the disease in laboratory animals by means of tobacco smoke Shapiro 1954 A similar type of objection could have been made to Snow's conclusion that cholera was a borne disease or to Pott's conclusion that employment as a chimney sweep in childhood led to cancer of the scrotum It is difficult to see what can be more relevant to the etiology of human cancer than observations on the extent of human mortality under different environmental conditions and in this instance nature has performed the appropriate experiment in which the amount smoked has been varied while so far as can be seen other variables have been kept constant In view of the variation in animal susceptibility and the impracticability of reproducing the exact conditions of human smoking in animal experiments the failure to reproduce the human type of bronchial carcinoma by exposing animals to tobacco smoke cannot outweigh the extensive positive evidence obtained from direct observa- tions on men RICHARD DOLL portion in the various investigations are not wholly 2. That the data recorded of all the results has been consistent Although the general trend risks attached consistent inconsistencies in the reports of the relative there have been and in regard to the significance of to cigarette cigar and pipe smionkcionnsgistencies reported in relation to the Hueper 1954 The been considered see page 16 inhaling different methods of smoking have already would commonly be reference has yet been made to inhaling It but no effect of cigarette smoking would be most noticeable expected that any inhaled the smoke and both Lickint 1953 and among persons who found that a higher proportion of Breslow and his workers 1954 said they inhaled patients with lung cancer than of control patients found difference in the pro- On the other hand iDnoltlheantdwoHigllro1u9ps52althoughnothere was a suggestion of inhalers men with peripheral growths that inhaling might be commoner among with central than among the controls in men and even less common of these conflicting reports is unknown It growths The explanation failure on the part of the patients to under- may perhaps derive from a stand correctly the import of the questions results is incompatible with the interpretation put on the of this type 3. That thveital statistics Several of the principal criticisms ehvaivdeenaclerferaodmy been discussed and they will therefore only be listed here of tobacco has undoubtedly in- a That although the consumption that there has been creased it has not yet been shownosfattihsefadcitsoeraisley Rigdon and Kirch- any real increase in the incidence ' off 1953 Shapiro 1954thSeeeinpcargeeas4e in tobacco consumption has b That on the contraryto account for the increase in the incidence not been great enough of the disease Toddb1et9w5e4enSmeoertpaalgiety22and cigarette consumption 1954 c That the correlation in number of countries is imperfect Hueper aasndretchoartdetdhe daata from Britain and the United States are in par- ticular incompatible Russ 1954 Seecapsaegseo2f 3the disease persists d That the male predomtihneanicnecraeamsoenign cigarette smoking has been despite the fact that 22 in women Hueper 1954 See page relatively greater practically which have not been referred to previously are Other objections _ the fact that the sex ratio of cases of According to Hueper 1954 until about 1930 e equal in Norway the disease was to be recorded which is and that since then an increase has begun the view that most marked in men and in towns weighs against ETIOLOGY OF LUNG CANCER 31 of smoking is an important cause of the disease He considers that factors must have influenced the epidemiological behavior special Norwegians smoke the same of lung cancer in Norway whereas type of cigarette as that smoked in the United States He omits however to take into consideration the very small quantity which were consumed in Norway before 1930 and the cNiograwreetgtieasn experience may with greater justification be cited in support of the view that cigarettes are one of the principal causes of lip the disease Several authors have pointed out that the mucosa of the . smok~ mouth and larynx also comes into contact with cigarette contrast with and yet the mortality from cancer of these sites in the mortality from lung cancer has remained stationary or has fallen Hueper 1954 Passey 1954 Maxwell 1955 Many investigators have however shown that cancer of the lip and is if anything associated with the smoking of cigars and mouthLevin et al 1950 Sadowsky et al 1953 so that a reduction pipesin mortality from cancer at these sites would have been expected to occur as smoking habits were switched from cigars and pipes to cigarettes The evidence with regard to laryngeal cancer is more conflicting There is no a priori reason to suppose that it is neces- produced by the same factors as produce lung cancer and sarily cancer are in fact none of the known industrial causes of lung to cause laryngeal cancer On the other hand there is known that laryngeal cancer is associated with cigarette smoking evidence Levin et al 1950 Sadowsky et al 1953 It is possible that the lack of any marked increase in the recorded mortality from laryncancer results partly from improvements in the treatment gealof intrinsic cancer of the larynx and partly from confusion by the under one head of cancer of the extrinsic and intrinsic cllaasrsniyfxication 4. That an association is not necessarily causal and that both lung cancer smoking may be the end results of a third common factor It is not pos- sainbdle any to give any conclusive answer to this type of criticism and indeed alternative to 2 explanation a hypothesis always provides an similar scientific theory The principle of Occam's razor has however proved it of value to the development of scientific thought in the past and would reasonable to adhere to it now and to work on the basis of the most ---, seecoenmomical hypothesis or until some conclusive reason is shown for abandoning it The possibility that lung cancer and smoking may both be end results of a third common cause is as much applicable to the results 32 RICHARD DOLL prospective of the studies on mortality among smokers and nonsmokers as it was to the results of the retrospective studies among patients There is however no evidence to suggest that it is the explanation of them Some of the theoretically possible common factors have been considered above see page 14 another which has been suggested is that persons of a particular physical constitution might be prone to lung cancer and to heavy smoking Parnell 1951 There is no evidence of such a physical constitution characteristic of patients with lung cancer and if one did exist we should still have to find some environmental factor to account for the increase in the incidence of the disease 5. That the effect of smoking is limited to determining the site of the growth in persons previously destined to develop cancer Fairweather 1954 Loxton 1954 This objection derives from Cramer's 1936 hypothesis that the total incidence of cancer in a population is constant and that environmental and hormonal factors exert their effect by determining the site at which the cancers develop In this general form it can readily be demonstrated to be not true Case 1954 In the particular case of cigarette smoking it can also be shown to be untrue for if it were true it would follow that cancer of sites other than the lung would have to be relatively more common among nonsmokers and light smokers than among heavy smokers Several reports of the smoking habits of persons with cancer in other sites have been made Except for a report by Gilliam 1954 none has in fact shown a negative association between smoking and the type of cancer investigated though several have suggested the possibility of other positive associations e.g. between cigarette smoking and cancer of the larynx and between pipe smoking and cancer of the lip Levin et al 1950 Doll and Hill 1950 1954a Sadowsky et al 1953 Hammond and Horn 1954 Gilliam added details of the data on cancer of the skin to the data previously reported in conjunction with Sadowsky and Cornfield and these showed a greater prevalence among nonsmokers than among cigarette smokers The excess prevalence of skin cancer among nonsmokers could conceivably result if it were found that there were fewer smokers in the South of the United States than in the North I. Conclusion In a review of the evidence relating lung cancer to smoking Gilliam 1954 concludes that Proof in the mathematical sense is unobtainable in dealing with medical prob- lems Direct experimental verification in humans is possible to conceive but impossible to conduct Indirect experimental verification in humans through country discontinuance of smoking and subsequent determination of trends of the disease could be practically accomplished only by informing the public that the disease is caused by cigarettes If this is true the procedure is unnecessary as an experiment ETIOLOGY OF LUNG CANCER 33 disease Production of the in experimental animals under conditions simulating human smoking would strengthen though not establish the hypothesis but inability to do so could in no circumferences justify its rejection . . . We are left for proof therefore with indirect and circumstantial evidenca derived largely from considerations of the pathogenesis of the disease in individuals and its observed distribution in human populations in short with epidemiological evidence It is a matter of opinion how many and what facts must be consistent before this hypothesis may justifiably be accepted or rejected In the author's opinion taking into consideration the philosophical principle of Occam's razor which has already been referred to the facts are such that the hypothesis that cigarette smoking is a cause of the main histological types of lung cancer should be accepted They also in his Kopinion justify a strong presumption that the smoking of pipes and cigars is in this respect relatively innocuous The discovery that a known and powerful carcinogen is present in tobacco smoke in significant quantity strengthens the credibility of the conclusion but it has yet to be shown experimentally that the substance concerned has a direct action on the bronchial mucosa The great majority of the observed facts accord with the hypothesis but the picture is not yet complete We need to know in particular why the mortality from the disease in the United States is so low relative to the past consumption of cigarettes and why the association which appears to exist between cancer of the larynx and cigarette smoking has not been reflected in an increase in the incidence of cancer of the larynx comparable to that believed to have occurred with cancer of the lung The data on the significance of inhaling are also conflicting and it is uncertain whether the difference between the effects of smoking tobacco in the form of cigarettes and in a pipe can be attributed to differences in the extent to which the smoke is usually inhaled or whether it is necessary to postu- late some other mechanism These fields of uncertainty are however small in relation to the extent of established knowledge and do not justify throwing doubt on the main conclusion 2. Industrial Hazards When Smith 1953 presented his report to the Louvain symposium five industrial processes the mining of certain radioactive ores the refining of nickel and the manufacture of asbestos chromates and coal gas had been recognized as involving a special risk of lung cancer and there was fairly strong evidence to suggest that exposure to heavy con- centrations of arsenic in the air up to 1000 gper cubic meter- might also produce the disease Hill and Faning 1948 Perry et al 1948 Bonser 1955 has now suggested that hematite miners should be added to the list During the last 20 years 17 cases of lung cancer were RICHARD DOLL observed at autopsy among 192 hematite miners 8.9 whereas the is same pathologist found only 44 lung cancers among 2378 autopsies on men over 20 years old from the same area 1.9 The evidence is suggestive but it not conclusive since it possible that miners with chest symptoms may have been more likely to come to autopsy than men with similar symptoms in nondusty occupations The extent of the risk has now been defined more closely in the case of asbestos chromates and coal gas Brinton Frasier and Koven 1952 extended the initial observations of Machle and Gregorius 1948 and compared the sickness and mortality experience of insured workers in the seven producing plants in the United States with the whole sickness data obtained by the U.S. Public Health Service and the death rates for the U.S. population They found that over the period 1940 to ~ 1948 the mortality from lung cancer among white males employed by the plants was 14 times the expected and among colored males it was 80 times the expected In view of the small number of cases these esti- mates must be liable to considerable error but it is clear that employees of the industry were exposed to a risk which was many times the normal The physical conditions to which the workers were exposed have been investigated by the Division of Occupational Health of the U.S. Public Health Service Federal Security Agency 1953 but it has not as yet been possible to define which of the substances involved in the manufacturing process are carcinogenic The authors suggest that solubleinsoluble compounds found principally in the residue from the leaching tanks may be responsible If this were so it might explain why the hazard has been less apparent in British factories where the residue : is discarded Bidstrup 1951 The British industry has however only recently come under observation and the possibility that a considerable risk exists has not yet been excluded Doll 1952 studied the causes of death among 2071 male pensioners of a London gas company and found that the number of deaths from lung cancer was approximately double that expected by comparison with male inhabitants of London of the same age distribution 25 deaths against that is showed practically the same excess as had been estimated by Kennaway and Kennaway 1947 from study of the national mortality statistics In both cases the gasworkers covered a multiplicity of occupations and it is possible that the risk may have been greater for those most closely concerned with the production process In a more detailed study Sutherland personal communication found an incidence of respiratory cancer among the employees and pensioners of a Canadian gas company who had worked in the retort house which was several times higher than that recorded in the general population of the district The excess was ETIOLOGY OF LUNG CANCER 35 apparent only among men who had worked at a particular station where the gas was manufactured in horizontal retorts No excess was observed among employees who had never worked in the retort houses According to the earlier reports of Kuroda and Kawahata 1936 the risk experienced by men employed in generator gas plants of a Japanese steel mill is likely to have been greater still 21 cases of lung cancer occurred in a year period among 100 workers who had been employed for more than 10 : yearsThe risk to which asbestos workers were exposed has been defined more fully by a study of the mortality among 113 men who had been . exposed to the dust for 20 or more years Doll 1955 Eleven of the thirty- . | nine men who had died were found to have asbestosis and cancer of the lung at autopsy whereas the number of deaths expected to have been due to lung cancer was estimated as less than one 0.8 Since the mortality was considerably less among men who had been employed for less than 10 years in the conditions which existed before 1932 when measures were taken to reduce the amount of dust in the atmosphere it must be presumed that the risk had at one time been appreciably greater than the average estimated over the whole period The occurrence of lung cancer in 14 out of 72 subjects found to have asbestosis at autopsy has been reported by Bonser 1955 The number of men employed in all these occupations taken together constitutes only a small fraction of the total number of men employed in industry and the number of cases of lung cancer due to these special hazards can have contributed only a very small proportion to the total number of cases Some of the occupations are however of particular - interest since the carcinogenic agents which are presumed to be responsible for the added risks also have a more general distribution i.e. radio- active substances and benzpyrene It is also of interest as was pointed out by Smith 1953 that the majority of the specific industrial risks appear to be related to inorganic substances whereas occupational tumors of other organs have usually been traced to organic compounds Numerous other occupations have been suggested as possibly giving rise rise to specific risks The evidence has been fully reviewed by Hueper 1951 1952 but in no other instance is it adequate to justify a positive conclusion Recent studies by Wynder and Graham 1951 Doll 1953a and Breslow et al 1954 have compared the occupational histories of men with lung cancer with the histories of comparable groups of men with other diseases and Kreyberg 1954a has compared the occupational histories of patients with his group " tumors with the histories of * Nor is the recent evidence adduced by Dunner and Hicks 1953 with regard to boiler boiler scalers and grain dockers RICHARD DOLL patients with group II tumors and with the occupational distribution of the population of Norway as shown by the Census The most interest- _ ing finding has been the negative one that workers who were particularly exposed to the fumes of motor exhausts road transport drivers etc. were not disproportionately represented among the lung cancer patients in any of the series 3. Atmospheric Pollution A. Mortality in Town and Country The principal reason for thinking that atmospheric pollution may be responsible for some cases of lung 4000 3000 milon per rate 2000 death x- * Men - - - Women Anual . ** Conurbations Other towns > 100,000 popr * a \. Towns < 100,000 popn YVay \* Rural districts Conurbations Other towns ao ' * 100,000 popn =e Towns - eeeeetde= 9 ) ao 100,000 popn Rural districts . ; 15 25 35 45 55 65 75 85 Age in years FIG 8. Male and female death rates from lung cancer in England and Wales in 1953 by age and place of residence cancer is that the mortality has consistently been recorded as being higher in urban than in rural areas Stocks 1947 1952 Clemmesen Nielsen and Jensen 1953 McKinlay 1953 Curwen Kennaway and Kennaway 1954 Hoffman and Gilliam 1954 Kreyberg 1954c Sax^'n 1955 The difference has not been great mortality in Copenhagen London Oslo and American and Finnish cities being some one and a half to four times the rate in the corresponding countryside in each country for which detailed data are available the mortality has increased steadily with the degree of urbanization Data for England and Wales for 1953 are illustrated in Figure 8. Particularly striking was the correla- ETIOLOGY OF LUNG CANCER 37 tion demonstrated by Stocks 1952 between lung cancer mortality in men and the number of occupied houses in 84 large towns Table X and the finding that a similar correlation between density of population and male lung cancer mortality also holds for rural areas Table XI Curwen Kennaway and Kennaway 1954 Three explanations of these findings are possible 1 that they are artifacts due to a greater efficiency of diagnosis in the areas of greater TABLE X Standardized Mortality Ratios Due to Lung Cancer for Men in 84 Towns of England and Wales 1946-1949 Compared with No. of Occupied Dwellings and Density of Population per Acre Towns Standardized No. Persons Mortality Ratio for Occupied Dwellings 1931 per Acre 1951 Lung Cancer in Men 1946-49 London Croydon East Ham and West Ham = 862,500 7 156 Birmingham Smethwick Walsall and West Bromwich Manchester Salford and Stockport _. 297,600 297,600 833 134 259,900 259,900 833 159 Liverpool Bootle Birkenhead and Wallasey 242,400 833 162 Leeds Bradford and Halifax 237,700 237,700 11 132 Sheffield + Newcastle on Tyne and Gateshead 123,800 123,800 222 135 86,700 222 114 Average of 6 towns 66,700 222 113 Average of 3 towns 43,600 43,600 16 106 . Average of 12 towns 33,100 16 105 Average of 13 towns Average of 29 towns 24,000 16 101 14,700 11 89 * After Stocks 1952. Some of the mortality ratios shown differ very slightly from those quoted by Stocks because the data for the last groups are for simplicity of tabulation shown as averages Groups of adjacent towns treated as one unit population density 2 that they result from the presence of a carcinogenic pollutant in town air and 3 that they result from differences in the way of life of individuals in town and country The first possibility cannot be entirely excluded Bonser and Thomas 1955 found for example that during the years 1950 to 1952 the number of cases diagnosed in hospital in a largely rural region of Scotland was 21 less than the number of persons recorded as having died of the dis- ease whereas in Leeds the deficiency was only % Clemmesen Nielsen and Jensen 1953 found a similar difference between the proportion of cases not admitted to hospital in the rural districts of Denmark and in RICHARD DOLL Copenhagen 25 against % There has therefore clearly been less ready access to hospital for patients in rural areas and the possibility must be admitted that some of the difference in mortality may be spuri- ous Doll and Hill 1952 on the other hand found that the proportion of lung cancer patients who had lived for 10 or more years in the country was less than that among a matched group of control irrespective of the place of residence at the time of interview The differences were small and were not statistically significant but they were all in the same direction and provide some support for the belief that the risk of developing lung cancer has been in fact lower in the countryside TABLE XI Standardized Mortality Ratios Due to Lung Cancer in the Rural Districts of 11 Geographical Regions of England and Wales 1946-1949 Compared with the Average Population per 100 Acres Density of Population Persons per 100 Acres 39 38 36 32 27 24 22 20 19 13 12 S.M.R. Male S.M.R. Female 69 63 76 60 98 22 77 96 84 98 65 55 50 58 55 45 61 61 65 72 60 84 f Coefficient of correlation between density of population and male S.M.S.RMR. . Coefficient of correlation between density of population and female S.M.R. S.M.R. 0.81 S.E. 0.30 0.1S1.E. 0.30 * After Curwen Kenneway and Kennaway 1954 + Based on 17 deaths other figures in parentheses on 25-100 deaths and all others on more than 100 deaths B. Pollution of Town Air Three known carcinogens have been detected among the pollutants of town air arsenic benzpyrene and radium The amount of arsenic was however of the order of 6 g As p0er 100 m.Goulden Kennaway and Urquhart 1952 and was minute in comparison with the amount to which men have been exposed in industry without the apparent production of any great excess of lung cancer see page 33 Waller 1952 Kotin Falk Mader and Thomas 1954 and Kotin Falk and Thomas 1954 reported that 3,4- benzpyrene was present in town smoke and in the exhaust fumes of cars but if as is likely it occurs adsorbed onto particles of carbon it must be presumed to be biologically inactive Steiner 1954 The extent to which the radium and radon content of coal smoke may be significant is uncertain Anderson Mayneord and Turner 1954 see page 42 ETIOLOGY OF LUNG CANCER 39 The chemical findings do not as yet give material support to the suggestion that the increased mortality from lung cancer in urban areas may be due to pollution of the atmosphere but it is possible that further work may show the pollutants to be effectively carcinogenic For example the petrol vapors present with benzpyrene in motor exhaust fumes may themselves act as adequate eluents Kotin Falk Mader and Thomas 1954 In the present state of knowledge conclusions about the role of atmospheric pollution must be based on the epidemiological findings L 600 500 F 400 Index Index 300 IndexIndex 200 L State asphalt , highways Motor fuel consumption J ! Cigarette ra consumption a per adult io LMS Fuel oil sales F ; a , Y , Motor vehicle vayy. registration ^' r 100 . ~~ Coal consumption 0 soannoymae 1900 1910 1920 . 1930 1940 Year . 1950 1960 FIG 9. Trends in prevalence of selected environmental factors expressed as a percentage of the prevalence in 1926 U.S.A. 1900-1953 Reproduced from a paper by Dr. E. C. Hammond in Cancer 7 1100-1109 1954. From this point of view it is difficult to believe that the increase in mortality from lung cancer can have been directly due to pollution with chimney smoke or with petrol or oil fumes On the one hand the amount of coal consumed in the industrialized countries has not increased greatly and the total amount of smoke pollution has probably decreased because of greater efficiency of combustion in Britain for example coal consumption increased from about 165 million tons in 1900 to 206 million tons in 1953 but the amount burnt in gasworks and generating stations increased from 23 million tons in 1921 to 64 million tons in 1953. The pattern of coal consumption in the U.S.A. is shown in Fig 9 On the other hand there has been a marked increase in the amount of petrol and oil burnt Hammond 1954 see Fig 9 but men who have * Earlier Sgures not available RICHARD DOLL 1 had special occupational exposure to the fumes do not appear to have suffered any abnormally high mortality from the disease see page 35 Diesel fumes are a special case in that burning engines have not been in general use on the roads for a sufficient length of time judge from the induction time of industrial cancers have exerted any significant carcinogenic effect In England and Wales the excess urban mortality has until recently increased pari passu with the total lung cancer mortality in Denmark it has increased even more rapidly Unless therefore it is postulated that the whole increase in mortality is due to improved diagnosis which is contrary to the general opinion see page 4 it must be concluded either that atmospheric pollution acts as a carcinogen to some other substance has increased in prevalence for example in cigarette smoke or that it cannot be responsible for more than a relatively small and constant part of the specific urban mortality In either of these cases a number of apparently anomalous findings will have to be accounted for 1. The difference between urban and rural mortality is greater for Copenhagen and the Danish countryside 4 to ) than it is for large English towns and the English countryside 2 to 1 although the smoke pollution of Copenhagen judged colorimetrically only about onetenth of the level of a typical English industrial town Kennaway and Wilkins personal communications 2. A general atmospheric pollutant could be expected to affect both sexes equally whereas in fact a urban areas with a high mortality . show a greater predominance of male cases than rural areas with a low mortality Stocks 1952 Clemmesen Nielsen and Jensen 1953 and b the correlation between mortality and density of population in rural regions which Curwen Kennaway and Kennaway 1954 found to be strong for men was absent for women see Table XI 3. No consistent difference in lung cancer mortality has been found among nonsmokers in areas of different population densities Doll 1953b C. Differences in Urban and Rural Habits The urban excess may also _ be due to differences in the personal habits of townsmen and countrymen Kreyberg 1954c 1954d came to the conclusion that this was the most probable explanation from comparing the place of residence and the occupation of patients with his group " and group II tumors He found that the ratio was greater for towns than for rural areas but that it was unaffected by the degree of industrialization of the town or by the extent to which the town was exposed to wind from the sea One possibly relevant difference to have been recorded is a difference in smoking habits Doll and Hill 1952 found that townsmen tended to ETIOLOGY OF LUNG CANCER 41 smoke more than countrymen and that a higher proportion of townsmen who smoked smoked cigarettes Moreover the difference was greater for men in big towns than for men in small towns Stocks 1954 Hammond and Horn 1954 and Kreyberg personal communication have reported similar differences The differences are not themselves great enough to a account for more than a small part of the excess urban mortality Present habits are however unlikely to be relevant to present mortality and it is possible that the differences may have been greater 20 or 30 years . ago Unfortunately precise data about prewar differences are not / , available ' D. Conclusion The present evidence is inadequate to allow an ex- planation of the urban difference in mortality to be given with confidence Several considerations weigh against the suggestion that it is primarily due to atmospheric pollution with chimney smoke or motor exhaust fumes but the possibility has not been excluded that chimney smoke may be responsible for a proportion of perhaps as a consequence of its radium content that it may act as a carcinogen with say tobacco The urban difference can be partly accounted for by 1 geographical differences in the efficiency of diagnosis and 2 differences in the past smoking habits of townsmen and countrymen The . effect of these factors is likely to diminish and it may therefore be anticipated that the differences will also gradually diminish Postwar experience in England and Wales suggests that this may in fact have begun to happen Waller personal communication Standardized male D.R. in Greater London Standardized male D.R. as a percentage of the rate in Greater London 1950 667 per million 1953 782 per million Greater London Other conurbations 100 100 87 90 Towns more than 100,000 popn 82 83 Towns 100,000 popn 64 72 Towns less than 50,000 popn 58 64 Rural districts 47 49 * Standardised on the age distribution of the male population of England and Wales in 1950 4. Atmospheric Radioactivity Uranium and thorium are widely distributed throughout the earth's crust both materials is decay through radioactive series one member of which is gaseous The radioactive gases i.e. radon and thoron escape into the atmosphere where their respective decay products eventually attach themselves to dust particles In addition a small amount of radon and * The small amount of radioactivity attributable to thoron is not distinguished from that attributable to radonin the remainder of this discussion RICHARD DOLL of radium is released into the atmosphere by the combustion of coal Minute quantities of the radioactive isotopes of the common elements e.g. potassium and carbon are also present but their effect would be insignificant in comparison with the effect of members of the uranium and thorium series ; Whether atmospheric radioactivity is a cause of any cases of lung cancer is uncertain It cannot have been responsible for the increase in incidence which took place before 1954 and there is no evident reason why it should affect men more than women There is however a possi- bility that it might contribute to the increased incidence in towns because of the presence of radium in coal smoke Anderson Mayneord and Turner 1954 During conditions of fog both coal smoke and the radon naturally diffusing from buildings and the soil are likely to be retained near the surface of the earth and a considerable increase in radioactivity may be observed On the first day of the London smog of December 1952 Anderson Mayneord and Turner found a level 400 times that previously recorded on a clear sunny day Dawson 1952 found that radioactivity indoors was approximately double that in the open air and in a closed cellar it was increased a hundredfold On the other hand he could not find any appreciable difference between the average radioactivity of the air towns and country The large day day variations which occurred in all districts were chiefly related to meteorological conditions The average amount of radioactivity present was estimated by Dawson 1952 to be of the order of 5 ^ 10-11 ...cper milliliter and this agrees fairly well with estimates made earlier in the century in England Canada and the United States 2 ^ 10-1 to 2 X 10-10 ...cper milliliter Dawson's estimates were however made by drawing air through filter - papers and deducing the radon content of the air samples by assuming that the radon was in equilibrium with the radium A B and C on the _ retained particles Anderson Mayneord and Turner 1954 suggest however that the method may underestimate the amount when the suspended particles are small By measuring whole air samples in an ionchamber apparatus they obtained values 10 to 100 times greater than with the filter paper method and the average value for air on the roof of the Institute of Cancer Research London was found to be 2 to 3 X 10 ...cper milliliter The tolerance concentration of radon is at present set at 10-7 e per milliliter but it is not possible to determine whether atmospheric radioactivity can ever be carcinogenic by reference to such an arbitrary standard since the standard has been set in relation to the safety of individuals The only way at present available of testing whether a given ETIOLOGY OF LUNG CANCER 43 level might produce an incidence of say 1 in 100,000 in a large popula- tion is by comparison with the effects produced by the known levels in the highly radioactive mines in Schneeberg and Jachymov and in other similar areas According to Evans 1950 the mean concentration of radon in the air of the mines was equivalent to an activity of 3 ^ 10-8 cper milliliter The content of the air varied in different parts of the mines and other estimates have set the average value 10 times higher Mitchell personal communication Evans calculates that an activity of 3 ^ 10 cper milliliter would have delivered a dose of approximately 0.5 r.e.m. per . working day to the epithelium of the larger bronchi The average ^finduc- tion time for the development of the tumors was 17 years ikl1950 so that the total dose received would in this case have been of the order of 3000 r.e.m. Shapiro 1954 and Anderson Mayneord and Turner 1955 1955 point out that Evans ignored the effect of the particulate matter in the air bearing the radioactive breakdown products of radon and they estimate that the total dose received by some areas of the bronchi is likely to have been 70 times higher Since persons suffering from chronic radium poisoning who developed bone sarcoma are estimated to have received local doses of about 35,000 r.e.m. Evans 1950 the physical data may be considered reasonably consistent with the hypothesis that the Jachymov cancers were due to exposure to radon in the air If it is assumed that there is a linear relationship between strength of dose and cancer incidence the assumption is not necessarily justifiable particularly for very small doses is possible to estimate the incidence of lung cancer which may be produced by normal atmospheric radiation According to ik 1950 the mortality among the miners of Jachymov was approximately % per year so that exposure to normal atmospheric radioactivity for the length of time the miners were exposed to the air of the mines might be expected to produce 10-11 an annual mortality of 10-5 between % the ratio of the mini- mum estimate of normal atmospheric radioactivity and the maximum mortality estimate of the radioactivity of the air in the mines times the 2.5 ^ 10- miners ratio among the miners and ^ 10- X1 % the ratio of the maximum estimate of normal atmospheric radioactivity and the minimum estimate of the radioactivity of the air in the mines times the mortality among the miners i.e. between 0.017 and 8.333 per million Evans assumed that the miners were exposed for 12 hours out of the 24 whereas people are exposed to normal atmospheric radiation through- out the day More importantly people are normally exposed from birth RICHARD DOLL whereas the miners were exposed on the average for 17 years from the age 33 years If the effect were proportional to the total dose irrespec- tive of the period of life at which it was administered the expected annual mortality would be between 0.017 ^ 2 ^ 3 and 8.333 ^ 2 ^ 3 per million i.e. between 0.1 and 50.0 per million sy, In England and Wales the annual mortality from lung cancer among men aged 25 to 74 was 912 per million in 1953 but much of this appeared to be attributable to smoking Estimates of the rates among nonsmokers have been made by Doll 1953b from which it can be calculated that the mortalitiyn this age group attributable to causes other than smokimnagy be of the order of 69 per million The Jachymov population cannot have contained as high a proportion of old people as does the adult population of England and Wales so that the comparable mortality due to causes other than smoking is certainly much less than 69 per perhaps as little as 30 or 40 per million On the basis of these calculations it seems that atmospheric radiation might well be a significant cause of lung cancer in Britain This conclusion is strengthened if it is considered from analogy with other types of cancer that the total dose of the carcinogenic agent is not the only determinant of the incidence of the disease As with other types of cancer there appears to have been an appreciable induction time between initial exposure and the appearance of the Jachymov cancers and it is possible that exposure to a given dose of radiation early in life may have a greater effect at the age of 50 years than exposure to the same dose at the age of say 35 years In these circumstances the expected mortality due to atmospheric radiation may be many times greater than the annual rate estimated above On the other hand the fact that the Jachymov and Schneeberg cancers were almost invariably squamous cell or undifferentiated cancers Schmorl 1928 Hueper 1942 ikl1950 whereas an important part of the nontobacco cancers appears to consist of adenocarcinomas weighs against the concept that radioactivity could account for all the cancers not attributable to smoking or to specific industrial hazards 5. Previous Respiratory Infections Previous inflammation and the formation of scar tissue in the lungs have long been thought to be possible precursors of lung cancer but there is little firm evidence to implicate them Woodruff and Nahas 1951 and Woodruff et al 1952 found that large calcified larger than in any other part of the were present in the same lobe as the tumor * If the entire population of miners and retired miners observed by iklis assumed to have been aged 25 to 44 years the comparable mortality among nonsmokers would be 20 per million ETIOLOGY OF LUNG CANCER 45 or in the tracheobronchial nodes draining the lobe in 27 out of 40 cases of squamous and anaplastic bronchial cancer They suggested that calcified foci might increase the susceptibility of the neighboring bronchial mucosa to carcinogenic substances reaching it from the inspired air or that bronchiectasis following primary tuberculosis might be a predisposing factor A similar type of conclusion was suggested by Schwartz 1950 who described cases of bronchial carcinoma in association with lesions of the bronchial wall brought about by neighboring tuberculous lymph nodes Raeburn and Spencer 1953 reported a close histological association Z . between the site of origin of cancer and lung fibrosis and bronchiectasis They sectioned the whole of both lungs at autopsy and removed all suspicious nodules and scars for microscopy In 750 autopsies they found 9 unsuspected microscopic cancers in association with scars in the periphery of the lung and one unsuspected small carcinoma in a large bronchus The authors acknowledged that great difficulty has been experienced in determining the borderline between innocent reparative proliferation and true malignant change but they were satisfied that only cases which have shown obvious malignant change have been included in the series If the lesions were in fact true cancers it must be postulated that their evolution into clinical malignancy would have taken many years since otherwise their incidence was much greater than could be explained by the known rate of cancer mortality The observation em- phasizes the need for a term study of the end results of respiratory infection It has often been noted that a standing bronchitis is a common complaint of persons with lung cancer e.g. Bryson and Spencer 1951 but there have been few studies of the frequency of its occurrence in comparable control series Doll and Hill 1952 compared the history of previous respiratory disease in 1465 patients with carcinoma of the lung and in 853 patients with cancer in other sites After making allow- ance for the age and sex of the patients they found that the proportions of patients complaining of attacks of respiratory tuberculosis pleural effusion asthma or chronic nasal catarrh more than five years previously practically were the same in both groups but that the proportions com- plaining of chronic bronchitis or of pneumonia more than five years pre- significantly viously were greater in the lung carcinoma group When however the lung carcinoma patients were compared with another group of 335 patients who had been thought to have lung cancer at the time they were interviewed but who were finally proved not to have it no significant contained difference was detected This latter group however a high proportion of patients with other respiratory diseases and may not - 46 RICHARD DOLL have been a suitable control group All that could be concluded was that either chronic bronchitis and pneumonia predispose to a whole group of respiratory disorders including bronchial carcinoma or that patients previous with respiratory disorders recall chronic bronchitis and pneu- monia more readily than do patients with diseases in other systems Lea 1952 compared the incidence of standing pulmonary symp- toms in men with different histological types of lung cancer and found that it was significantly higher in men with squamous carcinoma than in men with cell carcinoma or adenocarcinoma 20 out of 91 against 33 out of - 303 He did not however allow the greater average age of the pa- tients with squamous carcinoma and this may have accounted for some . of the difference ace i Direct evidence implicating chronic bronchitis has recently been ob- tained by Case and Lea 1955 In a large group of chronic bronchitics who were followed for more than 30 years they found that the mortality from cancer in sites other than the lung was close to the expected mor- tality whereas the mortality from lung cancer was about double what they had calculated it should be A result of this type might be accounted for if the development of bronchitis was itself closely related to smoking habits According to Palmer 1954 bronchitis is commoner among smokers than among nonsmokers and its incidence increases with the amount smoked the data are however insufficient to exclude the possi- bility that the association between bronchitis and lung cancer may be at least in part independent and direct On the other hand bronchitis cannot be the effective intermediate stage in the carcinogenic process initiated by smoking since the relationship between smoking and cancer is closer than the relationship between cancer and bronchitis IV CONCLUSION From the work which has been reviewed in the preceding sections a fairly distinct picture of the etiology of the disease is beginning to : appear Firstly there is the rise in incidence which has taken place in many countries and which has principally affected men Corresponding to this rise it must be postulated that there has been an increased prevalence of one or more causal factors in the environment Secondly there is the evidence that cigarette smoking is an important factor in the production of squamous cell and undifferentiated lung cancer and that a few individual cases result from exposure to five or moreindependent industrial processes Whether the increase in cigarette consumption and the growth of the specific industries can together ac- count for the real increase in mortality and for the extent of the male ETIOLOGY OF LUNG CANCER 47 preponderance cannot be seen with certainty Knowledge of the true extent of the change in mortality and of the fundamental mechanisms of is unfortunately insufficient to permit the preparation of carcinogenesis a precise balance sheet There is however no direct evidence to implicate those other environmental factors which are also known to have increased in prevalence in the last four or five decades and it is a reasonable pre- sumption that the changes which have taken place in tobacco consump- tion and in method are responsible for the major part of the - in amount increase in mortality Whether the action of cigarette smoke is due . realto its benzpyrene content or to some other substance and why it - should be different from that of smoke from pipes and cigars is unknown there is a group of cases of relatively stable incidence and Thirdlyalmost equally in men and women which is characterized occurring histologically by the inclusion of a high proportion of adenocarcinomas Some of these though perhaps not the adenocarcinomas be due to atmospheric radioactivity others may conceivably result from standing respiratory infections . Two other factors have at times received considerable prominence namely atmospheric pollution and hereditary susceptibility The evidence concerning the former permits no definite conclusion save only that it is not independently responsible for a large proportion of cases nor for the recent increase in mortality There is no evidence concerning the latter though doubtless susceptibility to inspired carcinogens varies as _ does susceptibility to other environmental stimuli Perhaps the most striking conclusion is the wide range of substances several of them inorganic can induce cancer in the bronchial mucosa Whether there may be a common mechanism through which each exerts its effect remains one of the principal problems for future research ACKNOWLEDGMENTS I am most grateful to Prof. A. Bradford Hill for his advice in the preparation of R. A. paper and to Dr. P. Bidstrup Mr. W. Binks Dr. G. Bonser Dr. M. Case this Clemmesen Dr. H. F. Dorn Dr. E. A. Graham Sir Ernest Kennaway Prof. L. 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