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PROF. DR. MED. 0. SCHMAHL GesCNfts/0hrender Direktor des Instituts fur Toxikoloqie und Chemotherape Deutsches Krebstorschunqszentr,im 6900 Heidelberg, Im Neuenheimer Feltl 280 Tele/on : (06221) 4841 purChwahl, 484300 July 25, 1990 schm/bi Project Officer for ETS Policy Guide Indoor Air Division (A.NR-445) Environmental Protection Agency 401 M Street, SW Washington, DC 20460 U.SA. Ladies and Gentlemen: . I received your draft of June 25,1990 on the risk assessment of environmental tobacco smoke (ETS). You have asked for a critical comment on this draft, and I would like to give you my opinion. I think I am qualified, because during my scientific life I have carried out or promoted numerous investigations on this subject of experimental as well as clinical nature. In your draft you correctly dicussed the papers published so far on ETS and you based your conclusions predominantly on epidemiologic studies. You also correctly mentioned all the biases which, for instance, are inherent in the individual epidemiologic papers. You did, however, not or only incompletely deal with a bias which I consider especially important, i.e., the fact that the histologic evidence for the diagnosis of lung cancer is missing in the majority of the epidemiologic studies. Without histologic data it is hardly possible to make a conclusive diagnosis. This applies in particular to lung carcinomas. M.J. Macfarlane et al. (Chest 90:520- 523, 1986) recently reported on the multiple possibilities of error regarding etiologic conclusions. We are confronted with the phenomenon that tobacco smoke-induced bronchial carcinomas mostly are squamous cell carcinomas and to a lesser extent small and large cell carcinomas, whereas the adenocarcinoma in women cannot clearly be correlated with tobacco smoke. It is interesting to note that in wifes who live together with their smoking husbands, adenocarcinomas wem diagnosed which can only conditionally be correlated with tobacco smoke inhalation, as stated above (e.g., T.H. Lam et aL: Br. J. Cancer 56:673-678,198'n. In this connection I would like to hint at a pathophysiologic aspect which I consider essential. It is well known that bronchial carcinomas never develop on healthy mucosa, but that the carcinogenesis is preceded by quite characteristic histologic changes in the brochial mucosa. Prior to squamous cell metaplasia including the ttansfocmation of cylindric epithelium into squamous epithelium, an experienced lung pathologist will find these characteristic changes (reported e.g., by Dr. Oscar Auerbach in the U.S.A.). I do not know any study in which such changes were described in passive smokers. These cotnpulsory changes should, however, appear J

in passive smokers as well. I consider the lack of corresponding investigations an essential disadvantage. We also know that actively inhaled smoke, which directly and at high concentratlons reaches the bronchial tree without passing through the nasal filter, at first inhibits the ciliary function and finally causes complete damage of the cilia. Later on, the changes in the self-clearing capacity of the bronchial tract or its complete lack result in pathologic changes which can finally form the basis of a bronchial carcinoma. I do not know any study which describes ciliary changes caused by ETS in experimental systems or in humans. What I want to show in the above paragraphs is that your draft does not sufficiently take 'pathophysiologic aspects in ETS-induced carcinogenesis into consideration. Let me say a few words on the doses. The majority of epidemiologic studies on actively inhaling smokers give evidence of a statistically significant risk compared to nonsmokers, if the daily dose exceeds 3-5 cigarettes. Again I would like to stress the importance of concentrated smoke in the bronchial trze. You are right in stating that cotinine is detectable as a metabolite of nicotine in passive smokers and that thus passive smokers indeed take in tobacco smoke, the components of which can be detected. More convincing than the mere evidence of cotinine would for me be the evidence of mutagenicity due to the intake of ETS. As far as I know, investigations on the detection of mutagenicity in urine of passive smokers yielded negative results (G. Scherer et al.: Environment International 15:49-56, 1989), whereas the urine of active smokers is highly mutagenic. These negative results should make one think. You favor the generally accepted theory that even low and very low doses will finally sum up to a carcinogenic effect. I principally agree with this concept on which we have published numerous papers. On the other hand, I think that the initially mentioned damage to the mucosa caused by concentrated tobacco smoke is a conditio sine qua non effecting that the carcinogenic substances contained in tobacco smoke can deploy their activity. Let me make a comparison, which is applicable, although it is lame like all comparisons. If you administer a drop of 99% hydrochloric acid to your skin, a deep necrosis will form at the site of administration. If you, however, use 100 drops of 0.1% hydrochloric acid solution, you will not observe any necrosis. The concentration thus plays a role in the activation of local carcinogens which like tobacco smoke probably need preliminary damaging of the mucosa. Simple extrapolation from high doses to low doses is, however, problematic. In this context mention should be made of the thesis of irreversibility of effects of carcinogenic genotoxic agents, which ate also contained in tobacco smoke. You rightly discussed this thesis in your draft, but it is the tobacco smoke-induced carcinogenesis in men that has taught us the phenomenon of revertt"bility, for how else can the drastic reduction of the RR in ex-smokers be explained. A pathophysiologic phenomenon plays an important role in roversibt7ity, namely the bceakthrough of precancerous changes through the basal membrane. 'I1iis again shows the great importance of pathophysiologic aspects. I

k Let me finally refer to a problem which I also discussed with Dr. Hirayama in Vienna: How do you define passive smoking? He very globally stated that at a distance of more than I m from the smoker you are not at risk. Let me add a calculation. Assuming a husband who smokes 30 cigarettes a day, i.e. a heavy smoker, spends 10 hrsJday away from home (at his workplace etc.) and 7-8 hrs sleeping, then he will be able to smoke at home for approximately 7 hrs. Based on the assumption of 30 smoked cigarettes/day, he will probably smoke not more than 10 cigarettes at home. Taking the dilution of tobacco smoke into account in addition to ventilation, thene must be a very strong carcinogenicity in ETS to affect the passive smoker. Is there any experimental evidence to prove this? I am a nonsmoker and prefer to work in rooms in which nobody smokes. However, before presenting a quantitative analysis with numerical data on bronchial cancer related to passive smoking, as in your draft, you should have a really unassailable basis for such an assessment. Best regards sincerely yours, i i Prof. Dr. med. D. Sch hl J