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FILE NAME Kent KNT DATE 1953 Sept 12 DOC KNT129 DOCUMENT DESCRIPTION Journal Article - Bronchial Carcinoma - British Medical Journal en Lace peers ST a SEPT 12 1953 BRONCHIAL CARCINOMA BRITISH MEDICAL JOURNAL 585 BRONCHIAL CARCINOMA INCIDENCE AND AETIOLOGY BY RICHARD DOLL M.D. M.R.C.P. Member of the Statistical Unit of the Medical Research Council Consumption of Tobacco The possibility that a relationship exists between the , smoking of tobacco and the development of bronchial - carcinoma has been suggested often over a period of many years At first the suggestion was made either on theoretical grounds or because of the clinical observation , that the patients tended to be heavy smokers In support it was pointed out that national figures for tobacco con- sumption showed increases over the same period in which * the recorded lung cancer death rates had increased In the 7 absence of positive animal experiments or of detailed knowledge of normal smoking habits such considerations carried little weight and it is invidious to try to determine who first suggested that tobacco might be factor ~. Direct evidence of a relationship was first secured in 1939 by M^...ller in Germany He obtained the smoking . histories of 86 male patients with bronchial carcinoma from = shospital notes by personal interview or from a questionary sent to the relatives of the patients who had died he com- - pared them with histories given by 86 healthy men of the ages The results showed gross differences between same / the groups in the proportions of smokers and of heavy J smokers but the different methods by which the data were . collected made it difficult to draw firm conclusions from the .. comparison Subsequently other workers have used similar methods to study the problem is to say they have obtained records of the smoking habits of patients with bronchial carcinoma and have compared these with records of other subjects assumed to be representative of the population TABLE Smoking Habits of Men With and Without Lung Cancer No. of Men Percentage of smokers Among Men Percentage of HeavyHeavy Smokers Among Men Author Date With | Without With Without | With | Without Lung | Lung Cancer Lung | Lung | Lung | Lung Cancer Cancer CancerCancer Cancer Cancer Cancer M^...ller 1939 - 86 3.5 16.3 65.1 36-0 Schairer and | Sch^niger 1943 93 Wassink 1948 134 270 100 3.2 4.8 15.9 19.0 51.6 82.0 26.7 45.0 Schrek et al 1950 82 522 14.6 23.9 18.3a 9.2a Mills and Porter 1950 4446 430 78 31 | _ | | > Levin al - 1950 236 Wynder and 481 McConel | Graham .. McConnell et 1950 | 605c | 780 er : .. 1952 186 Doll and Hi ( 1952 1,357 | 1,357 15.3 1.30 5.4 0.5 21-7 14.6 6.5 45-4 | 51.2 25-021-5d 25-021-5d 19-1 25-021-5d 25-021-5d * Definition varies from one author to another a Percentage of heavy cigarette smokers b Figures relate to all respiratory cancers c Figures relate to lung cancer other than adenocarcinoma a d Percentage among men and women 93 men and 7 women and 186 men ~ and 14 women respectively from which the bronchial carcinoma patients were drawn The principal results obtained in the reports to which I have - been able to refer are shown in Table III = The proportions of smokers and of heavy smokers found among both groups of those with . and those without lung cancer considerably from one - Second part of the Milroy Lectures delivered at the Royal Abridged - College of Physicians of London on February 10 and 12 1953 ) The first part was printed in last week's Journal p 521 author to another This is not surprising since the observa- tions were made in four different countries the definitions of " smoker and " heavy smoker varied considerably and so did the methods by which the records were obtained The notable fact is the consistency with which the pro- portions of smokers were lower and the proportions of heavy smokers were higher among the male patients with lung cancer than among the other men investigated In only one report is the difference in doubt According to McConnell Gordon and Jones 1952 the proportion of smokers among 93 male patients with lung carcinoma in the Liverpool area was only slightly less than that among 186 male patients of similar ages but with other diseases It is however possible that the definition of a smoker may not have been applied with equal rigour in both groups since most of the lung cancer patients were interviewed two years before the controls and before the form of the investi- gation had been finally determined In contrast the pr^- " portion of heavy smokers was found to be significantly higher in the cancer group than in the control group in all other reports The consistency of the results of investigations carried out with various techniques in four different countries is in itself suggestive that a real relationship between smoking and lung cancer exists The possibility that all the results could be due to bias in the selection or interviewing of patients has been eliminated and there are strong reasons for believing that the control patients at least some of the investigations adequately representative of the populations from which the cancer patients were drawn Doll and Hill 1950 1952 The results amount I believe to proof that smoking is a cause of bronchial carcinoma No proof is however absolute are susceptible to greater or smaller degrees of confidence It is only by further experiment by testing the hypothesis under fresh conditions that confidence can be gradually increased until finally its truth is unquestioned In the present case the simplest way of checking the con- clusion is by observation of the mortality from bronchial _ smoking carcinoma in subjects whose habits have been pre- viously defined Such a check is being carried out by Hammond in the U.S.A. by Kreyberg in Norway and by Bradford Hill and Doll in this country In the British investigation questionaries were sent to 59,600 doctors ask- ing them to classify themselves into three groups according to whether they continued to smoke had given up smoking or had never smoked regularly If they fell into either of the first two categories they were asked additional questions -namely the age at which they started to smoke the amount smoked and whether they smoked pipes or | cigarettes The questions were made short and few to : ensure the maximum number of replies and because the/ experience of interviews with nearly 5,000 patients in the earlier inquiry had shown that classification of smokers number according to the present amount smoked and the of years given up gave almost as sharp a differentiation \ patients between the bronchial carcinoma and other use of more complex statistics as the : Altogether 40,603 replies have been received The fact that this is only 68 of the number of questionaries sent out is immaterial since we are not concerned to estimate the smoking habits of doctors as a profession for compari- son with those of other but to define groups professions within the profession who differin the amount they smoke ~ By the courtesy of the Registrars of Great Britain and Northern Ireland it has been possible receive details of the causes of death all whohave died questionaries doctors since the were sent out In the first eleven months nine deaths have been recorded due to lung cancer among doctors aged 55 and over for whom details of the previous smoking histories are available From the know- replied ledge of the smoking histories of all the doctors who mortality rates can be calculated for different levels of .. tobacco consumption allowance for the variation - | of smoking habits with age Whilst the deaths are so few Nn BRONCHIAL CARCINOMA the calculated mortality rates are extremely unreliable but . so far as they go they are not inconsistent with the results : previously recorded equally All forms of smoking are it appears not dangerous _ smoking Wynder and Graham 1950 1952 . Levin et al McConnell - has with 1950 Schrek et al 1950 Doll Hill one exception et al 1952 been found to be less closcly associated with bronchial carcinoma than has smoking This can be partly accounted for by the lower average consumption of tobacco by smokers on the other hand Doll and Hill have estimated that the risk is lower among pure smokers than among pure cigarette at each level of tobacco - consumption According to the American authors cigar- smoking provides the same order of risk as smoking Table IV - TABLE Relative Proportions of Cigarette- Cigar- and Pipesmokers Lung Cancer and Other Patients American Authors Authority Wynder and Schrek et al Graham 1950 1950 Levei t anl 1950 Ratio of Cigaretteto smokers . Patients 22.8 16.4 5.0 Patients 5-3 5-1 1.7 Ratioof Cigaretteto smokers Patients 26.1 21.7 5.9 Patients 8.4 5.9 1.9 Users of cigarette and smokers of tipped cigarettes have been found less frequently among lung carcinoma patients than among patients with other diseases The proportion of persons who have been accustomed to smoke in this way is small and the number of recorded observations is too few for firm conclusions; they are how- ever consistent with the observations on smokers and it seems probable that each of these methods of smoking may partly separate out an active agent before it reaches the respiratory tract Doll and Hill 1952 _ In discussing the conclusions to be drawn from their pre- liminary data Doll and Hill 1950 pointed out that to say that a real association existed between carcinoma of the lung and smoking was not the same as saying that smoking caused carcinoma of the lung The association would occur if carcinoma of the lung caused people to smoke or if both attributes were effects of a common cause The habit of smoking was however invariably formed before the onset of the discase as revealed by the production of symptoms so that the disease cannot be held to have caused the habit nor can we ourselves envisage any common cause likely to lead both to the development of the habit and to the development of the discase 20 to 50 years later We therefore conclude important factor and an carcinoma of the lung factor in that smoking is a the production of " In the two and a half years that have since passed there has been reason to think that that conclusion needs to be challenged modified It has been on a number of grounds but only one appears to require serious consideration The fact that no carcinogen has been identified in tobacco smoke does not invalthie edviadet ncee; the recognition of the risk workers run by chimney and came many years before the carcinogenic polycyclic hydrocarbons were iso- lated Nor is it significant that theincrease in the recorded death ratebeengreater than the increase in tobacco consumption since we have little idea what proportion recorded increase in mortality is real The more serious objection is that it is theoretically possible for both smoking and the development of bronchial carcinoma to be themselves related to some third common factor In view apparently in of the linear increase the mortality from lung cancer withincreasing tobacco consumption we should need to postulate that this third factor was also linearly related both to smoking and to the risk of developing the disease In the absence of positive evidence that such a factor exists philosophical principle it is more reasonable to adopt the of Occam's razor which has served science so well in the past and to proceed on the basis of the simplest expianation that is that the more people smoke the more likely : they are to develop carcinoma of the lung It has often been suggested that it is not so much the tobacco which is responsible for the carcinogenic action of the smoke as the cigarette paper or the associated use of petrol lighter Such a position cannot I think be main- tained In the first place there would appear to be some risk associated with smoking even though it may be appreciably smaller than that associated with cigarettes and tar from tobacco burnt as in smoking has been shown to have a carcinogenic effect experimentally Sanders et al 1932 Flory 1941 Secondly petrol lighters have not been bronchial used any more extensively by patientswith : carcinoma than by other patients Arsenic is present in most forms of tobacco probably present through its use as an insecticide It is in greatest amounts in tobacco of American origin and is completely types or almost completely absent from Oriental Daff and Kennaway 1950 estimate that an ordinary Virginian cigarette as smoked in England contains about 50 gex- pressed as As2Os and 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 This is not a large amount and in any case arsenic is unlikely | to be the carcinogenic agent since 1 a bigh proportion of cancer cases in Istanbul are found at necropsy to arise from : the bronchi Schwartz reported by Daff Doll and Kenna- way 1951 and Turkish tobacco contains no or very little _ arsenic and 2 tar from tobacco smoke applied externally to the skin of animals is capable of inducing cancer which arsenic is not - The last observation also tells to some extent against the ' suggestion that the agent in tobacco might be a CO- - carcinogen which acted by enhancing the effect of another substance present in say the atmosphere of towns Benzpyrene has not been detected in tobacco smoke and it * would seem probable that the substance concerned is one which has not hitherto been recognized to be carcinogenic , Other Aetiological Factors Of other factors suggested as being of possible aetiological importance the greatest attention has been paid to previous respiratory disease disease apndredisposition Shawsuggested in 1924 that patients who recovered from influenzal pneumonia might have an increased susceptibility to lung cancer and he added in relation to the pandemic of 1918 1t9hat it would be of interest to see whether as ' a late manifestation there is an increase in the number of cases of pulmonary cancer which at present is a relatively :': care tumour His surmise was based on observation of . metaplastic changes in the bronchial mucosa of patients . dying of subacute influenzal pneumonia it has certainly~ been borne out in regard to the increased incidence of the- disease but the reason for the increase which he suggested seems unlikely to be correct Firstly there has been little increase of lung cancer in Iceland Dungal 1950 although that country suffered severely from the pandemic of influenza and secondly influenza affected both sexes almost equally in Britain in 1918-19 as judged by mortality while deaths from lung cancer occur predominantly in * men Schwartz 1950 has described cases of bronchial carcinoma arising in association with lesions of the bronchial wall brought about by neighbouring tuberculous lymph nodes Woodruff and Nahas 1951 and Woodruff et al 1952 have found that large calcified larger than in any other part of the were present in the same lobe as the tumour or in the bronchial nodes draining the lobe in thirds of 40 cases of squamous and anaplastic :4 bronchial tumours while they found a similar focus in only MESON S ENGNG Abelha ABBT HTB a0 Seg RISERS Yat RAS ESF IE EA, HOS SEPT 12 1953 BRONCHIAL CARCINOMA BRITISH MEDICAL Journal 587 one of six bronchial adenocarcinomas Woodruff suggests that calcified foci may increase the susceptibility of the neighbouring bronchial mucosa to carcinogenic substances reaching it from the inspired air or that bronchiectasis following primary tuberculosis may be a predisposing factor On these assumptions he suggests that part of the recent increase in bronchial carcinoma may be explained by the fall in mortality from pulmonary tuberculosis in young adult males leading to the occurrence of an increase in the incidence of healed primary foci in older men a generation later Whether such a corollary occurred is open to doubt and cannot be bas in fact assumed in the absence of direct evidence It is at least as likely that the common industrial cases Such substances appear to be radon and benzpyrene products associated with the refining of nickel and the manufacture of chromates and asbestos and probably arsenic Two other sources for the production of the disease have been recognized residence in towns and the smoking of tobacco The carcinogenic factors concerned are however not necessarily distinct There are for example fewer smokers more cigarette and more heavy smokers among Londoners than among the inhabitants of other towns and of rural districts so that the effect of the tobacco factor alone will result in the incidence of bronchial carcinoma being higher in the big the decreased mortality in young males should have been followed by a decreased incidence of healed primary foci Through the courtesy of Dr. Norman Smith of the Ministry of Health 1 am able to refer to the statistics of mass radiography; these show that the incidence of healed primary tuberculosis striking enough to be reported in miniature films is practically constant above the age of 35 -that is the incidence was 1.0 for men aged 35-44 and 1.1 for men aged 45-54 and for men over 60 Bronchiectasis and chronic bronchitis have also been thought to predispose to the disease No such action can however be deduced from the observation that a number of patients with bronchial carcinoma have suffered from these diseases Neither discase is rare and their inci- dence in bronchial carcinoma patients needs to be com- cities On the other hand from the death rates which have been calculated for persons smoking different average amounts over a year period the differences smoking habits seem to be insufficient to account for the observed differences in mortality These rates may not however be the appropriate ones to apply The amount consumed over carlier periods must also be of some possibly of major significanceand differences in cigarette consumption be- tween areas may have been greater 20 or 30 years ago than they are now In the present state of knowledge such possible differences cannot be allowed for and the most effective test of the independent action of the urban factor is the comparison of the mortality rates between different parts of the country in persons who do not now smoke and who have never done so in the past pared with some standard rate before any conclusion is The material collected by Doll and Hill has already been justified Doll and Hill 1952 have attempted to do this used to calculate the mortality rates among smokers and they concluded that either chronic bronchitis and pneumonia predispose to a whole group of respiratory disorders including bronchial carcinoma or and this seems more likely patients with respiratory disorders of different ages in Greater London It is less suitable for estimating the mortality rates in other areas since it was drawn from a few places only and may well not have been representative of the rest of the country Nevertheless it is recall previous chronic bronchitis and pneumonia more of interest to see what indications may be obtained from it readily than do patients with diseases in other systems Whether previous respiratory disease plays any part in the The material has therefore been divided into three parts according to the patient's place of residence and mortality aetiology of bronchial carcinoma is certainly not proved From analogy with pulmonary tumours in animals and with some types of cancer in man it might be expected that hereditary predisposition would be of some importance in the development of carcinoma of the lung Differences in incidence in different parts of the world may be partly attributable to racial differences in susceptibility but the rates have been calculated for smokers in towns other than London and in rural districts in the same way as rates were previously calculated for Greater London Doll 1953 As a check the rates have been recalculated using the figures obtained by the Government Social Survey for the estimation of the total numbers of smokers at risk The results are shown in Table V. contrast between the experience of native Africans in Africa and of negroes in the U.S.A. suggests that large ' The greatest numbers of patients with bronchial car- cinoma were interviewed in the age group 45-64 and this differences can readily be accounted for by the environment The recent increase in incidence of the disease and the clear effect of occupation in certain industries demonstrate the importance of environmental factors ; they do not however age group therefore provides the most reliable data The similarity of the results obtained for each of the three areas is striking; it suggests that in the absence of smoking the urban factor is of little relevance This may mean cither exclude the possibility that predisposition may also be variable The presumption must be that it is but that under optimum conditions it would seldom be strong enough to that the urban factor is nothing but a reflection of the tendency for cigarette consumption per person to be greater in the larger towns or that it acts principally by increas- result in clinical disease ing the effect of the tobacco factor If this is so it may be easier to understand why the male mortality in Greater Conclusion London should be only 2.1 times the mortality in English It is now becoming possible to piece together the various independent observations and to begin to get a picture of the aetiology of the disease as a whole Industrial hazards of great variety are responsible for a proportion of cases and Weish rural districts while the ratio of the rates between Norwegian towns and rural districts should be 2.5 to 1 and that between Copenhagen and Danish rural districts 4.3 to 1. It is unlikely that the air of Copenhagen and but with the exception of the productioonf gas the indus- tries with a recognized risk employ few workers and the total number of cases resulting each year is small Although TABLE Mortality from Lung Cancer among smokers in Different Types of Area ' the incidence of industrial cases varies from one country to another and falls most heavily on townsmen and almost exclusively on men it does not contribute any significant Age part to the difference in incidence between countries nor -except very locally the differences between urban and . rural areas and between inen and women The importance 25- of the observations is twofold Firstly they indicate the 45- sources of risks which it is none the less essential to eliminate 65-74 ., ' Estimated Annual Death Rate per 1,000 smokers Greater London 0.005 0.09 0.31 Other Towns 0.026 0.09 0.16 Rural Districts Less than .0.017 0.08 0.31 Source of Data for Estimate - of Proportion of smokers in Population Hill Doll and Hill 1952 although only few men are exposed to them ; and second y they provide evidence of the naturoef substances which can cause bronchial carcinoma and which may therefore when derived from other sources contribute to the production of 25- 4565-74 0-006 0.09 10-28 0-030 0.09 0.16 Less than 0.017 0.07 . 0.37 Government Social . Survey 2 ns 2 SEPT 12 1953 \ _ BRONCHIAL CARCINOMA MEDICAL 350- MILLION 3000 MILLION MILLION MILLION MILLION 250- P^ R P^ R P^ R 200- RATE RATE RATE RATE DEATH 150 DEATH DEATH DEATH ANNUAL AN UAL 100 50- - CANCER DEATH KATE O CIGARETTE CONSUMPTION ----- TOBACCO CONSUMPTION : a .E fi oO" oa wa 7.0 ANNUAL ANNUAL ANNUAL ANNUAL CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION , LB. LB. LB. PER PER PERSON PERSON PERSON = ~~ 1900 1910 1910 1920 1920 1930 1930 A iz 1940 1930 YEAR FIG 7.Death rate from lung cancer and consumption of cigarettes and of all tobacco England and Wales 1900-50 Cigarette and tobacco consumption estimated for Great Britain and Ireland prior to 1922 for Great Britain and Northern Ireland ; subsequently Board of Trade Statistics Oslo should be relatively more polluted than the air of London It may be on the other hand that the habit of cigarette smoking has spread less rapidly and less com pletely over the rural districts of Denmark and of Norway than it has over the countryside of Britain of the latent period before the tobacco factor exerts its which Clemmesen believes may be as long as 30 years nor do we know what proportion of the recorded increase in mortality is real All that can reasonably be concluded is that changes in national smoking habits in Britain are such as would have been expected to result in an increased incidence of carcinoma of the lung but whether they are adequate to account for the whole in crease is uncertain 300, MILLION MIL ION MILLION 250F MILLION PER PER 200- RATE LE 150 DIATH DIATH DIATH DIATH 100 ANNUAL ANNUAL ANNUAL ANUAL 50 ANNUAL . 1900 Th CANCER DEATH RAPE Ge cnn CICARETTE CICARETTE CONSUMPTION TOBACCO CONSUMPTION -~, : 3.0 3.0 : 6 a) 8 pan ANNUAL ANNUAL ANNUAL ANNUAL ANNUAL Pas sei $ uv s ey my Pe oor CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION cf] . a oo oa Pomel = oa. CONSUMPTION 00 LE o : rad PLR 3 20 PLK PLK SUN 1.0 SUN SUN . 1910 i 1920 YEAR t 1930 7a 1940 1950 The other outstanding epidemiological observations relating to bronchial carcinoma are the dramatic increase in the recorded mortality over the last 25 years the differences in incidence between different countries and the predilection of the disease for men Fig 7 shows the recorded mortality in England and Wales and the consumption of cigarettes and of all tobacco products in Britain from 1900 to 1950. The increase in the annual con- sumption of tobacco has been moderate 1.9 lb. 0.86 kg to a maximum of 6.1 lb. 2.77 kg per person in 1945 a marked change has taken place in the manner in which tobacco is used and a much larger increase has taken piace in the annual consumption of cigarettes approximately 0.2 to 3.9 lb. 0.09 to 1.77 kg per person with a maximum in 1945 of 5.1 lb. In other countries changes in the pattern of tobacco consumption have taken place more recently and have been even more marked; in the U.S.A. for example chewing and cigars accounted for large fractions of the tobacco consumed until 1930. In the present state of knowledge it is not possible in my opinion to relate such changes directly to the changes in mortality We do not know the relative weights to give the different tobacco products nor the length 190 - go. cot a 3, '. bX Meo Fy 3 . . 300h i 300h a pein Bree eae rg ts Beer ee a ve MILLION 2507 MIL ION MILION 200- PER PER PER Yemomt CANCER DEATH RATE OOCOOC GARETTE CONSUMPTION - TOBACCO CONSUMPTION : : 9 s RATE sor RATE RATE DEATH DEATH 100 DEATH DEATH ANNUAL ANNUAL soAN UAL ANNUAL * 1900 of ee 1910 1910 < we oo oe od . ad ral a 1 1920 1 rt 1930 1 1940 ANNUAL Piao) ANUAL ANNUAL ANNUAL ANNUAL CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION #0 LB. LB. LB. PER qsO PERSON PERSON 20 PERSON PERSON 1Q bd 1930 YEAR FIG Death rate from lung cancer and consumption of cigarettes and of all tobacco Switzerland Statistics of cancer death rate and total tobacco consumption provided by Bureau F^'d^'radl e cigarette Statistique Berne of from figures published consumption by Gsell 1951 calculated Rows CANCER DEATH RATE O CIGARETTE CONSUMPTION 300- Be---5 IOBACCO CONSUMPTION MILLION MILLION 250 250/ MILLION MILLION MILLION MILLION * PER 200- PER PER tee, " 60ANNUAL AN UAL ANNUAL ANNUAL sAo NNUAL CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION CONSUMPTION RATE 's0RATE DEATH DEATH DEATH 100DEATH DEATH ANNUALANNUAL ANNUAL sob AN UAL ANNUAL . 1900 , S69 LB. ae on" 1910 genres ' 1920 YEAR 0... o Tp ae Po onl PER 20 PER PERSON | PERSON teres ae fo PERSON > dee ya! PERSON PERSON j A 1930 + 1940 1950 FIG Death rate from lung cancer and consumption of cigarettes and of all tobacco Denmark For cancer death rate and cigarette consumption see Clemmesen Nielsen and Jensen 1953 for total tobacco consumption see " Anon 1950 300F MILLION MILLION 250- MILLION MILLION 200PER PER PER RATE 150- RATE DEATH 100-- DEATH 100-- DEATH DEATH ANNUAL AN UAL 50- ANNUAL 1900 , T CANCER DEATH RATE - oO CIGARETTE CONSUMPTION - Tobacco CONSUMPTION ee veveec OS, * 47-0 AN UAL AN UAL ANNUAL CONSUMPTION CONSUMPTION a CONSUMPTION CONSUMPTION CONSUMPTION g CONSUMPTION CONSUMPTION CONSUMPTION 340 LA LA n 1910 eS per Worn f v ~ Ky 30 PER PER PERSON */ PERSON f PERSON PERSON PERSON s pt i 10 _ t t. 1 1920 1930 YEAR 2 1940 ; 1930 : FIG Death rate from lung cancer and consumption of cigarettes and of all tobacco U.S.A. For cigarette and total see tobacco consumption Garner 1946 later figures provided by the Commercial Anach^'of the American Embassy FIG Death rate from lung cancer and consumption o cigarettes and of all tobacco Holland For cancer death rate and cigarette consumption see Kortweg sumption see 1953 for total tobacco con . Anon 1950 SEPT 12 1953 BRONCHIAL CARCINOMA BRITISH MEDICAL JOURNAL 589 300 CANC" ER DEATH RATE 0 CICARETTE CONSUMPTION Oreesny TOBACCO CONSUMPTION MILLION 250 MILLION MILLION truly comparable for men and for women This objection does not apply to the rates which can be calculated for non- smokers and I believe that it is within this group that the most proper comparison can be made The estimated rates ANUAL for each sex and for three age groups are shown in Table VI In view of the smallness of the numbers from which the rates in the two extreme groups were calculated the differ- MILLION MILLION 200- PER PER PER RATE 50> RATE RATE 10 - DEATH 100- DEATH : ANNUAL ANNUAL ANNUAL ANNUAL 1 1900 . 1 1910 eo . 4 ' 1920 g a yo Seo, CONSUMPTI 1.3.3.0.0 1.3.0 : J2.0 LB. 1.3.3.0.0 4 : ol PSR Lo 053000 se 053000 4 1 L jae L | PERSON 1930 1940 1950 YEAR consumption FIG Death rate from lung cancer and Statistics Statistics of provided cigarettes and of all tobacco Norway Statistics of cigarette - and tobacco consumption by Professor L. Kreyberg ; personal communication ences between the rates for each sex are quite insignificant The implication of the results can be appreciated more clearly if the female more reliable because derived TABLE Mortality from Lung Cancer among smokers in Men and Women gc | 254565-74 Estimated Annual Death Rate per 1,000 smokers Men 0-03 0-07 0-51 | Women 0.02 0.09 0.20 .Persons 0.02 * 0.09 0.22 from larger numbers used to calculate the numbers of Attempts to relate mortality rates and tobacco consump- tion in different countries encounter the same difficulties Estimates of the cigarette and total tobacco consumptions together with the recorded mortality rates for as far back as I have been able to obtain data are shown in Figs 8 9 10 11 and 12 for the U.S.A. Switzerland Denmark Holland and Norway In each case mortality rates show a closer correspondence with cigarette consumption than with tobacco consumption Falls in mortality occurred in Holland and in Norway towards the end of the war shortly after there had been a great reduction in the consumption of tobacco ; but it is difficult to believe that they are causally related to the fall in tobacco consumption in view of the long latent period usually present in human cancer Fig 13 shows the crude death rate in 1950 plotted against the average annual consumption of cigarettes per person over the preceding 20 years for the six countries for which I have obtained data I doubt whether much significance should be attached to the result but it is not inconsistent with the existence of a relationship between lung cancer and cigarette The mortality in England and Wales is however higher than would be expected while in the smokers expected among the men with bronchial carcinoma who were interviewed the expected number is then 6.1 The number actually observed was 7. Despite the large total number of patients interviewed the observed number of smokers is small and it is not possible to dogmatize from the results Nevertheless the similarity of the observed and expected numbers is striking and it seems probable that save for smoking and exposure to certain in- dustrial risks the disease may affect men and women equally If this is so and if as has been suggested the mortality among smokers is similar in town and country death rates can be calculated for smokers of both sexes combined which are based on reasonably sized numbers and which therefore from this point of view justify some confidence In submitting the rates I would however reemphasize that the calculations are based on a number of fairly bold assumptions The figures are therefore provisional and it is recognized that the errors may be large So long as this is borne in mind it is of interest to use the rates to estimate the number of cases of lung cancer which would have been expected in England and Wales if none of the population had ever smoked In 1950 the number between the ages of 25 and 74 would have been in round figures that is 17 of the number which actually occurred U.S.A. it is lower It is a common observation that men smoke more than women but it is not evident whether the difference in smoking habits is sufficient to account for the extent of the preponderance of men among subjects with the disease The mortality rates which have been estimated for different levels of smoking among men and women in London sug- ~ gest that sex differences still persist at each level Doll and Hill 1952 Women however did not start smoking at all until after the first world war and trade statistics show that although 22 of all tobacco was smoked by women in 1950 the proportion smoked by them 25 years earlier was only 2.5 Consequently there must be a much greater difference ; ; in the total ; amounts smoked MILON ENGLAND & . x WALES PER 200- ; RATE SWITZERLAND 2 DEATH 100-100- WORWAY 7 on wo DENMARK wo rae KUSA ANUAL ICELAND 1.0 1 2.0 J JC . 4.0 _, 3-0 by men and women now in the cancer age than is revealed by the histories of their recent oking habits It would seem likely therefore that the rates which have AVERAGE ANNUAL LB. CIGARETTE CONSUMPTION PEA PERSON been calculated for smokers of differ- No detailed figures are available to indicate the extent of the change in atmospheric pollution over the last half- century The amount of coal consumed has varied littlefrom about 165 million to 190 million tons annually Parker -but the amount burnt efficiently in gasworks and electricity generating stations has increased enormously It - all is likely therefore that there has actually been a decrease in smoke pollution though not the constituents of smoke will have decreased equally The changes in mortality from lung cancer clearly cannot be attributed to changes in the amount of coal smoke in the atmosphere Nor does there appear to be any reason why if smoke is responsi ible : factor men should be affected more than women To summarize most of the known epidemiological facts of about bronchial carcinoma are consistent with the effects a limited number of industrial carcinogens and the presence of a carcinogenic substance in tobacco particularly in that derived from cigarettes An exception may be the relatively low mortality from the disease in the U.S.A. : Animal experiments confirm the carcinogenic potency of tobacco smoke but the active agent has yet to be isolated The position with regard to pollution of the atmosphere with chimney smoke is uncertain The higher mortality urban areas and the larger towns may perhaps be explicabloen ~ the grounds that cigarette has been heavier in these areas on the other hand as suggested by Stocks cigarette FIG Death rate from lung cancer in 1950 and average consumption 1931-50 ent average amounts are not The detailed calculations made in obtaining the expected number will be published elsewhere Doll 1953 - _ BRONCHIAL CARCINOMA chimney smoke may be found to exacerbate the effect of the Flory C. M. 1941 Cancer Res 1 262 tobacco factor Apart from certain mass radiography statistics the meaning of which is difficult to assess there is no Fulton J. S. 1949 Proc roy Soc Med 42 775 Philadelphia Blakiston Garner W. W. 1946 The Production of Tobacco Gharpure P. V. 1948 Indian med Gaz 83 5 epidemiological evidence to implicate pollution of the air with the exhaust fumes of cars or with road dust Other Gloyne S. R. 1951 Lancet 1 810 Goulden F. Kennaway E. L. and Urquhart M. E. 1952 Beli Cancer 6 1 weakly carcinogenic factors must however be postulated to account for few remaining cases evenly distributed Graham Science Grady H. G. and Stewart H. L. 1940 Amer 1 Path 16 417 E. A. Wynder E. L. and Croninger A. B. 1952 among men country and women and throughout , town and Gsell O. 1951 Schweiz med Wschr 81. 662 Haerung F. H. and Hease W. 1879 Vjschr gerichtl Med 30 This year and next are centenaries of the great cholera Heady J. A. and Kennaway E. L. 1949 Brit J. Cancer 3 311 Hill A. B. and Faning E. L. 1948 Brit J. industr Med 5 1 epidemics in London when the observations of Snow led to Hueper W. C. 1952 Tex Rep Biol Med 10 167 4 the realization that cholera was spread by water I there- Kennaway E. L. and Keanaway N. M. 1947 Brit J. Cancer fore make no apology for reminding you that it was purely statistical and epidemiological observations which provided the reasons for the measures which were responsible for the control of the disease It is however with relief that I realize that measures of prevention are not within the scope of these lectures for I have no desire to incur such a reaction as was expressed by The Times when it rejoiced Korteweg R. 1951 Ibid 5 21 . 1953 Rep C.I.O.M.S. Symposium on the Endemiology of Cand of Lung Acta Un Int Cancr in press . . the Konwenaar W. 1950 In Symposium on Geographical Pathology Demography of Cancer Council for the ordination of Internation Congresses of Medical Sciences World Health Organization and Nations Educational Scientific and Cultural Organization Lange K. 1935 Z. Krebsforsch 42 306 Leiter 155 Shimkin M. B. and Shear M. J. 1942 J. nat Cancer Inst over the fall of the first General Board of Health Aescu- lapius and Chiron it said 66 . . have been deposed and Levin M. I. Goldstein H. Ass 143 336 Lisco H. and Finkel H. P. and Gerhardt P. R. 1950 1949 Fed Proc 8 360 J. Amer Amer med we prefer to take our chance of cholera and the rest than be bullied into health The writer did indeed take his chance of cholera which was raging in London within a LoreCnaznceEr. RSetsewa3rt 12H3. .. Daniel J. H. and Nelson V. 1941 McConnell R. B. Gordon K. C. T. and Jones T. 1952 Lancer month But the chance was not to persist much longer On the advice of the medical profession led by such men as Sir John Simon and concerned like Dr. Milroy to remedy the neglect . of those laws of healthy existence with the consideration of which the science of Public Health professes to deal the last major cholera epidemic in Britain was brought under control in seventeen years before Koch isolated the cholera vibrio It may also prove that it will be unnecessary to await the isolation and identification of the specific active agent before steps can be taken to Machle McDonald S. and Woodhouse D. L. 1942 J. Path Bact 54 1 W. and Gregorius F. 1948 1 14 Publ Hith Rep Wash 63 MackGeanyerDa.l R1e9gi5st1er SOtfufdiicees oHn.MM.eSd.iOc.al LaonnddoPnopulation Subjects No. Mason G. A. 1949 Lancet 2 587 : ended Government Mills C. A. and Porter M. M. 1950 Cancer Res 18 Miners Phthisis Medical Bureau 1936 Report for July 31 1935. Union of South Africa Pretoria 539 the three years Printers te M^...llerF. H. 1939 Z. Krebsforsch 49. 57 Nath V. and Grewal K. S. 1935 Indian J. med Res 23. 149 Parker A. 1950 J. roy Soc Arts 99. 85 Passey R. D. and Holmes J. McD 1935 Quart J. Med n.s. halt the rapid carcinoma and increase in to turn it the mortality from bronchial into an even more dramatic Peller S. 1939 Human Biol 11 130 Perry K. Bowler R. G. Buckell H. M. Druett H. A. R. S. F. 1948 Brit J. industr Med 5 6 decline Rigdon R. H. and Kirchoff H. 1951 Sth med J. 44 In concluding I would like to acknowledge my indebtedness to Sir Ernest Kennaway for his encouragement and for the stimulation provided by his ideas and to Professor awn + 1952 Tex Rep Biol Med 10 76 Sanders E. Thomson A. P. Cooper E. A. and Lamb F. W. M. 1932 J. Hyg Lond 32 293 , Krebsforsch Schairer E. and Sch^niger E. 1943 Z. 54 Schrek R. Baker L. A. Ballard G. P. and Dolgoff S. Bradford Hill not only for his constant because so much of the work which has was his in origin design and execution advice but also been referred to My thanks are due to Mrs. Julie E. Backer of the Central Bureau of Statistics Oslo Dr. J. Clemmesen Mr. H. F. Dorn Professor N. Dungal Mr. A. Koller Director of the Federal Res 10 49 Schwartz P. 1950 Bettr Klin Tuberk 103 192 Shaw A. F. B. 1924 Newc Tyne med J. April W. E. M. Wardle Lancet 1951 2 737 Rev. Soviet Shik R. G. 1946 Amer Med 4 142 Smith W. E. 1950 J. exp Med 91 87 Steiner P. E. 1944 Arch Path 37 185 4B9u7tt E. M. and Edmondson H. A. 1950 J. nat . 1924. Quoted by by Cancer Inst 11 Bureau of Statistics Berne Dr. R. Korteweg Professor L. Kreyberg Dr. W. Logan Dr. E. Pedersen Dr. J. A. Scott Mr. R. H. Thompson of the Office of the Commercial Attach^' American Embassy and Dr. G. Watkinson for providing me with figures and to Miss Freda Wadsworth and Mrs. Mary Young for drawing the diagrams Stocks P. 1950 Studies on Medical and Population Subjects General Register Office H.M.S.O. London ~ 1952 Brit J. Cancer 6 99 Strachan A. S. 1934 J. Path Bact 39 209 Turner H. M. and Grace H. G. 1938 J. Hyg Lond 38 90 = and Martin W. J. 1949 British Medical Journal 2 1148 Twort J. M. 1939 Sixteenth Annual Report of the British Empire Campaign p 239 No. Cancer : Waller R. E. 1952 Brit J. Cancer 6 8 REPERENCES Andervont H. B. 1937 Publ Hith Rep Wash 5. 1584 ** Anon 1950 J. roy statist Soc 113 487 Bidstrup P. L. 1951 Brit J. industr Med 8 302 Bonser G. M. 1934 J. Hyg Lond 34 218 Brinton H. P. Frasier E. S. and Koven A. L. 1952 Publ Wash 67 835 Hith Rep Brooks W. D. W. Davidson M. Thomas C. P. Robson K. and Smithers D. W. 1951 Thorax 6. 1 Wassink W. F. 1948 Ned T. Geneesk 92 3732 Willis R. A. 1948 Pathology of Tumours Butterworth London Woodruff C. E and Nahas H. 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Cancer 5 1 The World Health Organization has approved a 25,000 supply programme to aid the victims of the recent earth- quakes in the Ionian Islands Supplies to be sent out which are essentially to prevent epidemic diseases will include water purifiers tetanus prophylactics rat poison and galvanized piping There is an estimated rat population 100,000 in the islands which could not only make serious inroads into food supplies but might rapidly spread disease Dr. Duurt Rijkels from the W.H.O. Regional Office in Europe has recently returned from a visit to the affected areas made at the request of the Greek Government He and Hill A. B. 1950 British Medical Journal 2 ~ ~ ~~~ 1952 Ibid 2 1271 Dublin L. I. Spiegelman M. and Leland R. G. 1947 2. 188 Dungal N. 1950 Lancet 2 245 Essenberg J. M. 1952 Science 116 561 Evans R. D. 1950 Acta Un Int Caner 6 1229 739 Postgrad Med reports that the relief work is proceeding excellently and the food supplies are now well organized Many of those who were evacuated are returning home to repair their houses and to see to the grape harvest which is expected ty be very good this year :