Document Z4KO7n1M0xeygY3wQrv9p68zZ

FILE NAME Kent KNT DATE 1958 DOC KNT155 DOCUMENT DESCRIPTION Book Excerpt - Carcinoma of the Lung Asbestos & The Smoking of Tobacco hall allace Dukes usson ithers hyroid NEOPLASTIC DISEASE AT VARIOUS SITES avid are General Editor 1908- 1908- SMITHERS M.D. F.R.C.P. F.F.R. VOLUME I CARCINOMA OF THE LUNG Edited by J. R. BIGNALL M.D. M.R.C.P. Assistant Physician Brompton Hospital Senior Lecturer Institute of Diseases of the Chest Brompton Hospital Research Assistant Radiotherapy Department Institute of Cancer Research Royal Cancer Hospital E. & S. LIVINGSTONE LTD EDINBURGH AND LONDON 1958 CARCINOMA OF The lung SPECII ASBESTOS The first case of lung cancer to be described in association with asbestosis was reported by Lynch and Smith 1935 in the U.S.A. Since then over 60 cases have been reported from Britain Canada Germany and the U.S.A. from Britain That the association was not just coincidental was miandjiocraitteyd by comparison of the incidence of lung cancer at autopsy in cases asbestosis and cases of silicosis Merewether 1949 found that lung cancer was reported in 13.2 per cent of subjects with asbestosis 31 out of 235 and in. 1.3 cent of subjects with silicosis 91 out of 6,884 and Gloyne 1951 on per examination found corresponding incidences of 14.1 and 6.9 per cent personal be noted that women 17 out of 121 and 55 out of 796 It should moreover formed an appreciable proportion of the subjects with asbestosis and that the incidence among men with the disease was even higher per cent in Merewether's series and 19.6 per cent in Gloyne's Since or almost all silicotics are likely to have been men the contrast between subjects of the same sex is likely to have been somewhat greater than that actually reported for both sexes together These results are most readily explained if asbestosis to the development of lung cancer and this explanation was subse- | predisposes borne out by Doll's 1955 study of the mortality recorded among qausbeensttloys workers He studied 113 men who had worked for 20 or more years in places where they were liable to be exposed to asbestos dust and found that between 1922 and 1953 39 died whereas on the basis of the mortality rates suffered by men of the same ages in the whole population only 15.4 deaths would have been expected Of the 39 deaths 11 were due to lung cancer whereas less than 1 0-8 would have been expected All the cases of lung cancer were confirmed histologically and all were associated with asbestosis Precautions to prevent the dissemination of dust greatly reduced the amount to which the men were exposed from 1933 onwards and the incidence of the disease has become progressively less as the number of years during which the men were exposed to the 1933 conditions has diminished It is evident therefore that lung cancer is a specific industrial hazard of asbestos workers but that with scrupulous attention to the control of dust the risk may be greatly reduced and may perhaps be eliminated The fibrils of asbestos consist of giant molecules of polymerised silico- tetrahedra arranged in chains or bands In the case of Canadiani oxygen asbestos the silica is present as hydrated magnesium silicate containing 6 per cent of iron oxide in other industrially less important types the silicates may be calcium and magnesium or sodium and iron Animal experiments have failed to show any significant carcinogenic activity from asbestos fibres gaenndertahle mode of production of the disease is uncertain In Hueper's view result from the occurrence of the material in the form 1957a the activity may which cancer is produced may be of a linear polymer and the mechanism by similar to that with various polymerised carbon compounds which have been shown to be carcinogenic experimentally 50 The combustion and dist carcinogens and have for m cancer of the skin among m with the material It would the fumes and dust from tar > in fact such a risk is shown | The Japanese observati Kawahata 1936 Kuroda 19 cancer were recognised amo Yawata Steel Works betweer doubt that this indicates an logical data are not availabl in Japan and it is striking th cancer were observed amon observed among the other accounted for 80 per cent of appear to have constituted at 500 out of 20,000 and the n dissimilar from that among 49 out of 19,000 The men they stirred the coal yellow In Britain a high mortal was noted by Kennaway and tions given on the death cert - and 1938. Of the 56 occupat might be supposed to have estimated mortality from lu male population and 4 of the mortalities Table VIII Sul Occupations with t 56 sel Occupatio Labourers patcnt fuel Gas stokers and coke ,, Gas producer men Metal grinders Gas works foremen a * Extracted from a Ta WE CHAPTER VI THE SMOKING OF TOBACCO _ RICHARD DOLL THE evidence linking tobacco with the production of lung cancer is derived from two principal sources The great mass of evidence has been obtained from the retrospective study of patients with lung cancer and the comparison , of their past smoking habits with the past habits of patients with other diseases or with the habits of healthy persons More recently evidence of another type has been obtained by comparing over a period of years the mortality in groups of persons whose smoking habits had previously been defined Sh RETROSPECTIVE STUDIES | The first serious study of the subject was reported by M^...llerin Germany in 1939. He obtained the smoking histories of 86 men with bronchial carcinom|a| the . from hospital notes by personal interview or from a questionnaire sent to 4 relatives of those who had died and he compared the histories with those given by 86 healthy men of the same ages The results showed gross differences between the groups in the proportion of smokers and of heavy smokers that | By 1957 20 studies of this general type had been reported from 8 countries The principal results are summarisedin Table X. All agree in showing there are more heavy smokers and fewer smokers among patients with lung+ : cancer than among patients with other diseases and with one exception the difference between the proportions of smokers found by McConnell Gordon and Jones 1952 the differences are large enough to merit serious attention More detailed results of two of the investigations are shown in Tables XI and XII From these it is seen ) that there is a steady increase in the relative proportions of lung cancer to control patients as the amount smoked dailyincreases and 2 that the differencein smoking habits holds for both sexes but is more marked for men than for women : The method of smoking was not studied separatelyin all the investigations When it was the results agreed in showing that the difference between the lung cancer and the control groups was principally due to a differencein the } proportion of cigarette smokers The results with regard to pipe smoking and 4 cigar smoking were inconstant In some investigations it appeared that the | disease was equally associated with all types of smoking McConnell Gordon and Jones 1952 Randig 1954in the majority the disease was most closely associated with the smoking of cigarettes Few of the investigators made specificinquiries about inhaling In one study it was found that the proportion of patients who said they inhaled was similar among the lung cancer patients 60 2 Le : W THE SMOKING OF TOBACCO BACCO is derived on of lung cancer is derived . evidence has been obtained cancer and the comparison patients with other diseases cently evidence of another TABLE X Principal Characteristics of the Smoking Histories of Men with and without Lung Cancer Reported by Various Authors - Author ! Date Country M^...ller 1939 | Germany | Schairer and | Sch^niger 1943 | Germany | Number of men 5 Percentage of | Percentage of smokers | heavy smokers among men among men with without with without with | without lung without lung |: lung without lung without lung without lung cancer | cancer | cancer | cancer | cancer cancer 86 86 | 3.5 | 16.3 | 65 36 93 | 270 3.2 15.9 25 | 27 reviously been defined IES IES by orted M^...llerin Germany en with bronchial carcinoma Shrek et al 1950 | U.S.A. | Mills and Porter Levin et al | | Wynder and Graham Hill 1950 | U.S.A. 1950 U.S.A. | U.S.A. | 1950 U.S.A. Britain 82 522 | 14.6 | 23.9 | 18 9 444 430 | 7.0 31.0 | 236 | 481 | 15-3 ] 21.7 | 1932 605 | 780 1.3 | 14.6 | 51 | 1932 the histories with those given : Its showed gross differences okers and of heavy smokers 1 reported from 8 countries ; 4 All agree in showing that ers among patients with lung and with one exception the kers found by McConnell ; | ge enough to merit serious investigations are shown in at there is a steady increase itrol patients as the amount " in smoking habits holds for investigations investigations watoelmyenin all the investigations - the difference between the ly due to a difference in the . regard to pipe smoking and : gations it appeared that the noking McConnell Gordon disease was most disease the of the 4 disease closely ; investigators made : as found that the proportion ong the lung cancer patients McConnell et al | | Doll and Hill : Sadowsky et al 28] Wynder and Cornfield "| Koulumies Koulumies Lickint Lickint 1952 | Britain 1952 | Britain 1953 | U.S.A. | | 1953 | U.S.A. 1953 | Finland ; 1953 | Germany 93 | 186 708 | 708 5.4 6.5 | NW 22 0.7 | 4.8 24 | 14 477 615 3.8 13.2 | 63 133 | 4.1 | 20.6 | 68 29 812 | 300 0.6 | 18.0 66 | 31 224 1,000 1.8 16.0 74 29 Breslow et al 1954 | U.S.A. 518 518 | 3.7 | 10.8 | 74 42 gg Watson and Conte We Randig 3 Randig 1954 | U.S.A. 1954 | Germany 265 | 277 1.9 9.7 73 | 57 415 381 1.2 5.8 34 18 ipyegy Gsell 1956 | Switzerland | 150 ; 150 1.3 | 19.3 | 67 15 i Kreyberg | | | | gy : Schwartz Js 1956 Norway 213 4,158 1.4 13.2 18 7 and Denoix | 1957 | France 602 | 1,204 3.1 | 15-81 13 7 Note has not been possible to make all the figures completely comparable Some series for example include a few women The individual papers should be referred to before any a detailed use of the figuresis made . 3 Doll and Hill's 1952 paper gave results for 1,357 men with lung cancer the results shown here & elate only to those which were not includedin the 1950 paper 61 CARCINOMA OF THE LUNG 1956 who cultured human foetal lung in vitro with and without the addition j of benzpyrene The addition of the benzpyrene was found to result in hyper plasia of the bronchiolar epithelium with 3 or 4 layers replacing the normal one and irregular enlargement and abnormal mitosis in the hyperplastic cells similar to that described for the initial stages of carcinogenesis in mouse skin after painting with benzpyrene The possibility must also be considered that cigarette smoke does not # itself initiate carcinogenesis but that it acts as a carcinogen or activator to substances already present in the air from other sources For example pyridine 4 pyrrole and other solvents are found in the smoke and these might be supposed to elute the benzpyrene adsorbed on to carbon particles in town air and so render the town air more active Such an effect might contribute to the difference in lung cancer mortality between urban and rural areas but it is unlikely to account for the whole effect of cigarette smoking since there is a well marked relationship between smoking and the disease in areas of minimal atmospheric pollution pp 86 and 87 4 Evidence that cigarette tar might act as a carcinogen or as a promoting agent in conjunction with other environmental carcinogens has been obtained by Gellhorn Klausner and Hibbert 1956 It is conceivable also that it might act in conjunction with weak initiating agents produced in pulmonary scars CONCLUSION It was concluded earlier in this Chapter that cigarette smoking should be regarded as one of the causes of lung cancer so long as this conclusion did not conflict with any of the established facts which were relevant to it In the author's view the relevant facts are not inconsistent and the hypothesis should therefore be accepted The credibility of the conclusion is strengthened by 1 the observation that histological changes which commonly precede the development of cancer are also related to smoking 2 the discovery of several carcinogenic substances in tobacco including one which is believed to be widely effective in man and 3 the demonstration that extracts of tobacco tar can under suitable conditions cause cancer of the skin in animals The failure to reproduce the disease in the bronchi of animals cannot justify the rejection of the conclusion nor would it do so even if it were possible to reproduce the conditions of human smoking Species differences in susceptibility are a commonplace in cancer research and positive results in one animal can never be overthrown by negative results in others Moreover as Kennaway 1957 says Negative results of smoke inhalation experiments on rodents seem to me to be of no significance because the animals presumably unlike smokers keep their mouths shut and pass the smoke over their turbinates Positive results however would undoubtedly reinforce the conclusion and would be invaluable in helping to isolate the responsible agent In the author's view the conclusion that cigarette smoking is a cause an important cause the disease is inescapable but the picture is not yet complete It is not known whether the polycyclic hydrocarbons in tobacco smoke " 78 . without the addition | nd to result in hyper- j replacing the normal the hyperplastic cells genesis in mouse skin ette smoke does not nogen or activator to or example pyridine se might be supposed s in town air and so ht contribute to the rural areas but it is kingsince there is a se in areas of minimal gen or as a promoting ons has been obtained able also that it might n pulmonary scars te smoking should be his conclusion did not elevant to it In the he hypothesis should on is strengthened by mmonly precede the e discovery of several one which is believed at extracts of tobacco in in animals ni of animals cannot even if it were possible lifferences in suscepti- results in one animal reoveras Kennaway | ients on rodents seem nably unlike smokers | turbinates Positive lusion and would be kingis a cause the picture is not yet onsin tobacco smoke | THE SMOKing of tOBACCO are sufficient to account for the production of the disease or whether some other Carcinogenic agent has yet to be detected It is not clear whether the explanation hat has been offered is adequate to account for the whole of the difference in mortality between Britain and other countries particularly the U.S.A. nor i. what extent the temporal changes in mortality can be attributed to changes in tobacco consumption These questions cannot be answered until more is known about the mechanism of carcinogenesis and the part played in the production of the disease by atmospheric pollution The few data on the effect of inhaling are conflicting and there is also some conflict in the evidence regarding the relative risks of smoking tobacco in pipes and in the form of cigars and cigarettes The reason for these differences in risk is also unknown The fields of uncertainty are however small in relation to the extent of established knowledge and do not justify throwing doubt on the main conclusion This conclusion is not accepted by all who have studied the subject Kotin 1956 and Hueper 1957b believe that cigarette smoking is a relatively unimportant cause of the disease and Rigdon 1957 and Fisher 1957a doubt it is of any causal significance at all These views however do not represent the generality of scientific opinion for example they are not supported by any of the independent commissions which have been appointed to review the evidence In Holland a commission was set up at the request of the Director of Public Health and it concluded that there was a connection between cigarette smoking and lung cancer In the commission's view it was not possible to be sure that the connection was causal but the other possible factors which were also studied all proved to be less probable in this respect than smoking Netherlands Ministry of Social Affairs and Public Health 1957 In the U.S.A. a study group was organised by the American Cancer Society the American Heart Association the National Cancer Institute and the National Heart Institute Their report was published in extenso in the national press and provides a valuable survey of the principal data They concluded that The sum total of scientific evidence establishes beyond reasonable doubt that cigarette smoking is a causative factor in the rapidly increasing incidence of human epidermoid carcinoma of the lung Study Group on Smoking and Health 1957. In Britain the Ministry of Health constituted a panel under the chairmanship of the Government Actuary to advise on the statistical aspects of the subject and as a result of their report the Standing Advisory Committee on Cancer and Radiotherapy of the National Health Service advised the Minister of Health that ( It must be regarded as established that there is a relationship @ = between smoking and cancer of the lung 2 Though there is a strong presumption that the relationship is causal there is evidence that the relationship is not simple one Minister of Health 1954. Three years later more evidence was available and the Medical Research Council 1957 advised the Minister that In scientific work as in the practical affairs of everyday life conclusions have often to be founded on the most reasonable and probable explanation of the observed facts and so far no adequate explanation for the large increase 79 CARCINOMA OF THE LUNG in the incidence of lung cancer has been advanced save that cigarette smoking epidemiological is indeed the principal factorin the causation of the disease The evidenceis now extensive and very detailed and it follows the classical pattern upon which many advancesin preventive medicine have been madein the pasti impossible It is clearly to add to the evidence by means of an experiment if man Evidence from many investigations in different countries indicates major . a major part of the increase is associated with tobacco smoking particularly that form in the of cigarettes In the opinion of the Council the most reasonable of this evidence is that the relationship is one of direct cause interpretation and effect ATMO DIFFERENCE IN MOR THE principal reason fo responsible for some case been recorded as being hi 1952 Clemmesen Nielser oF Kennaway and Kennaway nae = Kreyberg 1956 The greate a Denmark where the ratios- fi p in the rural districts are ap i-U.S.A. the differences have { the ratio between the male districts is slightly less than for which detailed data are extent of urbanisation D shown in Table III of Chap Similar data for the period f. q : who showed that for 89 lar F cancer mortality in men an : Kennaway and Kennaway ( mortality increased in proj Correlation ; between Mortal Rural Distri " Sex Standardised mortality 22 69 3836 F 22 77 96 Coefficient of correlation bet i * After Cur Figures in