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4 PASSIVE SMOKING AS A CAUSATIVE FACTOR OF LUNG CAI4CER IN'NONSMOKING 1+OMEN by A.-Xnoth, H. Bohn and F. Schmidt of Preventive Oncol:ogy Research Institute, Mannheim Faculty of Clinical Medicine, University of Heidelberg, Mr.nnheim, West Germany f rom Med. Rlin. Prax. 78(2), 56-59 (19B3) Translation frc¢n German IETS/mlb 16016

PASSIVE SMOKING AS A CAUSATIVE FACTOR OF LUNG CANCER IN NONSI+fOKIt3G WOI+iEN by A. Knoth, H. Bohn and F. Schmidt ABSTRACT: In a studv on 792 paritnts with bron- chogrnit carcinoma of both srses in thc region Mannheim-Ludwisa- bafcn-Heidelbrrg 59 fcrnalr brun- claQefnic carcinomas were found:.39 af thern appeared in non-srnoking female paticnu. 61.5% of them had lived in domestic community with srnokrrs. This v near/w the threefold as could be rrpened on thr basis o f srnoking behavior of men in the rrsprctivr groups of age. Svgacstions On profrifional tsposition to con- eeroarnit substances could nor br found just as little as references to hrrrd'itary facrors. Passive srnoking it by far the obvious intrrprrratinn for thr hig/i sl+are of non-srnukrrs in our female patirnts with bron- chogeniC carcinoma thc mnrr su since tlrr prrcentugc of squa.nou.c trll onil smaN-cellcorcinnmac waeich are valid at typical curcinomus of srnokrrJ, did not Ge rssrntially lower in our non-smnking wives (6rS.ls°.h) in tornparuon to female srnokrrt (1(D"ti.J. ,fs a further sulfpnrt of thit interprrtatiun is rrfrrcd tu similor re.rylts in the world literarurr pruv,ng our findehs.ras not surprivnk. In a study on 792 lung cancer patients published in a previous paper (Med. Klin. Prax., 1/1983) we had investigated the question of whether "light smoking" (smoking of filter-tipped cigarettes) reduces the lung cancer risk, and had found at least five indicators to refute this hypothesis. However, we also came upon another significant finding which called for further analysis: while 97.3% of the 733 male patients with bronchial carcinomas were smokers, there were 39 nonsmokers amona the 59 women with lung cancer, i.e., more than half the female patients. As it was not possible to demonstrate any evidence of special occupational exposure to carcinogens either in the men with lung cancer or in the women -- 47.1% of the women with bronchial carcinomas, being housewives, had no occupation whatsoever, 23.5% were unskilled working women and

17.6% were office workers -- the question arose of what other harmful agents could be considered as being responsible for the especially high percentage of nonsmoking women among our female patients. The fact that general air pollutants play a secondary role as a causative agent of bronchial cancer as well has been shown again just recently by Ulmer [153 in a meticulous study from Northrhine-Westfalia. Concerning the methods, we refer to our previous publication j5). Bereditary factors were ruled out already because the great increase in the incidence of bronchial carcinoma in women as well would require a radical change in the hereditary composition in numerous countries in the past decades. Nor is there any indication of such a change (12]. In view of the sensational findings of PJirayama (41 and Trichopoulos et al. [14), we focused our attention primarily on the smoking habits of the husbands and other family members living in the same household with the nonsmoking female lung cancer patients. A comprehensive review of passive smoking and cancer had been published by Schmidt in !+lEDIZINISCHE lLINIK in 1979 [9). In that review he listed, inter alia, more than 4D carcinogenic substances which had been detected in tobacco smoke. Especially High Carcinogen Level in Sidestream Smoke The possibility of a cancer-causing effect not only of active smoking but also of passive smoking can no longer be challenged with scientific arguments for the following reasons: -2-

1. The overwhelming majority of the above-mentioned more than 40 carcinogenic substances present in tobacco smoke enter the surround- ing air with the sidestream smoke, and thus the passive smoker is forced to inhale them as well.i 'The sidestream smoke does not differ qualitatively,- ~ut only quantitatively from the mainstream smoke which is inhaled by % =Jthe smoker himself when puffing on the cigarette11 Consequently, the '' r ~talth hazard of passive smoking is directly related to the•health hazards/ lof the smoker proper. The severe health damage which the "active" smoker must expect makes it ab initio very unlikely for passive smoking to be merely a nuisance. Even though the passive smoker inhales the tobacco smoke in more or less dilute form, the significance of this dilution factor is rendered relative by the fact that the level of the carcinogens among the harmful substances is much higher in the sidestream smoke than in the mainsteam which is inhaled only by the smoker himself. 2. The carcinogenic effect.,cf passive smoking has been clearly f" ~i~stablished in animal experiments. Ca. 10% of the golden hamsters used ldeveloped laryngeal carcinomas even in the experiment designed in the Forschungsinstitut der Deutschen Zigarettenindustrie (Research Institute of the West German Cigarette Industry), and the corresponding percentage was even higher, 20% in a U. S. study. It was possible to increase the lung tumor incidence by passive smoking to 91% in seme cases in predisposed mouse strains (reference in [9)). 3. The more than a dozen nitrosamines detected in tobacco smoke deserve particular attention in this respect both qualitatively and quantitatively. One ppm (- parts per million) of them is already -3-

considered to be potentially carcinogenic. All animal species in- vestigated so far (more than 20) responded to nitrosamine by tumor development without exception. Therefore, we must assume that nitrosamines induce cancer in humans as well. It is also of particular significance that the nitrosamine level in tobacco smoke is so high that smoking must be considered to be the most important source of exogenous nitrosamine in the environment in general. The situation is further aggravated by the circumstance that according to Brunnemann et al. [1,23, the nitrosamine level in the side- stream smoke is up to 50 times higher than in the mainstream smoke which is inhaled only by the smoker. This especially strongly increased nitrosamine level, in the sidestream smoke renders the dilution effect so strongly relative that -- according to the same authors -- the nitrosamine uptake by passive smokers in rooaas filled with smoke can reach levels which correspond to the nitrosamine content in the main- stream smoke of up to 30 cigarettes per hour! The nitrosamine level in the sidestream smoke of tobacco is, for example, at least 1,000 times higher than in beer or in aminophenazone, an otherwise good medicine, which was withdrawn fraa circulation because of minute traces of nitrosamine, or than the maximvm values which have been specified re- cently in the nitrosamine ordinance for pacifiers for babies. ?There is No Harmless Dose' 4. Carcinogens are d_stinguished froan other toxic substances by their pronounced summation effect. The individual partial doses add up to a critical threshold value beyond which cancer usually -4-

becomes clinically manifest. Even very small doses -- one millionth of one gram -- produce irreversible changes in the cell (= tumor blastoderm). Therefore,.in principle, there is no fully harmless dose for carcinogenic substances, because the possibility cannot be ruled out that the partial doses inhaled by passive smoking lead to levels exceeding the carcinogenic threshold value which perhaps would not have been reached otherwise during the life of the patient by su:mnation with other carcinogens present in the environment which none of us can fully escape, and thus cancer becomes clinically manifest during the lifetime. For the same reason, there are no MAC [Maximum Allowable Concentrations) for carcinogenic substances either. 5.# Based on these facts the present epidemiological findings . are by no means surprising. Hirayama's study [4) on more than 91,000 nonsmoking married Japanese women above the age of 40 years should be mentioned in particular in this connection. According to this study, I nonsmoking women married to smokers had more than double the lung cancer incidence of women married to nonsmokers. He also found a statistically significant relationship between the lung cancer risk of the nonsmoking women and the intensity of smoking of the spouses, but no such relation- ship for other forms of cancer (gastric and endometrial cancers). Similar findings were also obtained by Trichopoulos et al. (14] in Athens by a totally different methodological approach: When comparing the smoking habits of the husbands of 51 women with lung cancer with those of 163 women with other diseases, the lung cancer incidence of nonsmoking women married to smokers was found to increase, on an average, -5- 1

by a factor of 2.4, and even by a factor of 3.4 when the husband smoked more than two packs of cigarettes a day. In a subsequent evaluation of the materials of the prospective study of the American Cancer Society on the pattern of Hirayama's study [41, Garfinkel [37 also found at least a similar tendency, even though it was not.possible to demonstrate any statistical significance: When taking the age-adjusted lung cancer incidence in nonsmoking wives of nonsmokers for 1, the figure rose to 1.37 when the nonsmoking wosaen were married to smokers who smoked more than 20 cigarettes a day. These findings of Garfinkel, which show the same tsend as Hirayama's studies, could be plausibly explained when considering the following circumstances: The rooms in Japanese wooden houses, especially in the country, are known to be very small and have low ceilings. Harmful concentrations are reached within a short time due to the small air volume; in agreement herewith the risk for nonsmoking women in the country was especially high. American homes are, however, not only more spacious and the rooms generally bigger, but a higher percentage of them are also air-conditioned. As the homes are bigger, the nonsmoking women in the United States also have more possibility to withdraw to other rooms when they feel excessively bothered by the smoking of their husbands, aside from the tobacco smoke concentration being also generally lower. Unproportionately High Percentage of Nonsmoking Women with Bronchial Carcinoma Live with Smoking Men 61.5% of the, 39 nonsmoking women with bronchial carcinomas in oq r ,fstudy lived in the same household with smoking men. This percentage -6-

is far higher than was to be expected based on the percentage of smoking• Aen in the age groups being considered. The data on the smoking habits were obtained from the family members themselves, usually from the husband, in this study as well. As it was quasi in the interest of these subjects to supply data, they can be assumed to be especially reliable. According to the recent "microcensus" of the Statistisches Bundesamt [Bureau of Statistics of West Germany] covering 2 million citizens (13), 38.6% of the men were smokers. The majority is accounted for by younger smokers in the age group of 20-40 years. Only 22.4% of the men were smokers in the age bracket 50-69 years, i.e., in the age group which includes most of the husbands of our nonsmoking female patients 16). When taking this into account, twice or even three times as many of the nonsmoking women with bronchialcarcinoma lived together with smoking men than was to be expected statistically, which remarkably duplicates Hirayama''s [4] findings in Japan and Trichopoulos' [14] findings in Athens. Yhe fact that 66.6% of the bronchial carcinomas in the nonsmoking kmarried women were squamous epithelial and small-cell carcinomas is ! also indicative of the involvement of passive smoking in the development of,cancer, because the corresponding percentage was not substantially,r }bigher among the smoking wo®en (80%). Since -= as was mentioned before -- joccupational exposure to carcinogens and hereditary factors as the cause of the increased incidence of bronchial carcinoma in nonsmoking female patients are ruled out, it could hardly be disputed that the causal involvement of passive smoking in the bronchial carcinomas of the -7-

nonsmoking married women is by far the most plausible explanation in our study as well. Sufficient Evidence of Health Hazard It was demonstrated by Schmidt elsewhere that passive smoking ~ ~-- completely regardless of a possible carcinogenic effect -- is a true ~health risk.-17,8,10,11). The exaggerated criticism of the results, especially of Hirayama [4), must therefore be opposed all the more emphatically: The cigarette industry even attempted to make these findings appear incredible in full-page ads in leading newspapers in West Germany. The chief witnesses were, without exception, members of the Forschungsrat Rauchen und Gesundheit der Zigarettenindustrie [Research Council on Smoking and Health of the Cigarette Industry) which distributed 20 million DM made available by the industry for research purposes during the past years without making it public. The inglorious role played by this "Research Council" has already been exposed by one of us elsewhere [10) in detail. With good reason this can be described as no less a scandal than the exposure of the "Neue Heimat". Therefore, the Medical Task Force on Smoking and Health passed the following resolution in its 1981 annual general meeting in Berlin: "The cigarette industry is increasingly misusing the so-called Research Council on Smoking and Sealth sponsored by it to manipulate public opinion regarding the question of passive smoking. Therefore, we regard the direct sponsorship of research on the problems of smokin5 by the cigarette industry and the financial grants, e.g., even to'i;;Ldical journals, bypassing established research institutions, such as the -8- i

Deutsche Forschungsgemeinschaft [West German Research Association), as a serious threat to scientific freedom which comes alarmingly close to disguised corruption. Therefore, we urge the West German Federal Minister for Science to guarantee, as a minimum, at least the disclosure by the cigarette industry of how these millions granted for 'promoting research' on smoking are used. In addition, the name of the sponsor should be indicated in all publications of independent institutes on the problem of smoking, which were sponsored by the cigarette industry." We are pleased to report that von Billow, West German Federal Minister for Research, has informed the Medical Task Force on Smoking and Health on January 27, 1982 that he considered our demands to be justified -- and not only in this special case -- and that he would take them into account in his further discussions with prof. Schm~hl. It is also shame- ful that leading members of the board of directors of Deutsche Gesellschaft fiir Arbeitsmedizin (West German Society for Industrial Medicine), e.g., G. Lehnert and H. Valentin, being heavy smokers themselves, do not shrink from turning all principles of preventive medicine upside down and consid- ering passive smoking only as a nuisance until proof of the health hazard, which should be watertight in every respect, is available. According to the principles of preventive medicine, any harmful agent whose health hazards can be supported with an impressive wealth of data as in the case of tobacco smoke in general, should be considered hazardous for health even when diluted until the opposite, i.e., the harmlessness of passive smoking, is proved. -9- r