Tobacco Documents Online

SUBJECT: Comment on the External Review Draft of EPA's "Health Effects of Passive Smoking: Assessment of Lung Cancer in Adults and Respiratory Disorders in Children" TO: Project Officer for Technical Information Staff Office of Health & Environmental Assessment (RD689) USEPA Room 3703 Mall 401 M St. NV Washington, DC 20460 FROM: Thomas J. Bucci, VHD, PhD P.O. Box 26 Jefferson, AR 72079 I am a veterinary pathologist with 30 years of professional experience in biomedical research, the last nine exclusively in toxicologic pathology. In particular, I have been coinvestigator and pathologist on a number of studies ~ concerning carcinogenesis of aromatic hydrocarbons in laboratory animals, and reviever of hundreds of published reports of studies involving tobacco products and animal exposures. In the folloving comments, I use abbreviations as they were used in the subject document.

I am concerned that the subject document conveys a degree of precision that cannot be substantiated in fact. I am villing to accept, as did the NRC, The Surgeon General, and, more recently, Spitzer et al., (Clinical and Investigative Ned. 1990, 13:17-42) that the overall occurrence of lung cancer deaths in never-smoking vives of smokers has been associated in the scientific literature vith spousal smoking. Given the evidence available, hovever, I am not yet villing to accept that spousal tobacco smoke is unequivocally causative, much less that a quantified relative risk can be assigned vith confidence to this specific cause. It is one thing to document a larger-than-expected number of lung cancer deaths among the NS vomen married to smokers relative to those married to nonsmokers. (Notvithstanding that one could•vish for greater consistency among the various reports in such critical items as histologic classification of tumors, duration of marriage, age at death, as vell as other possible sources of ETS). It is quite another thing to presume to ascribe the excess number of deaths solely to spousal smoking vhen so many other influential factors are undetermined. Except for the general argument that outcomes of the several studies are consistent across different cultures and methods, potential causes of lung cancer other than exposure to tobacco products vere really not quantified, eliminated, controlled or even sought. Sources of variation in incidence of lung cancer need be sought not only in ETS, (vhere bodily cotinine determination can only reveal recent tobacco exposure dose) but also in total environmental exposure to the same constituents from other sources, e.g., diet, fuel used for cooking and heating, and vehicle exhaust. Recent vork is pointing tovards genetic susceptibility as perhaps the major predisposing factor in carcinogenesis. Could there be unconscious 2

selection of a never-smoking lifestyle disproportionally among those biochemically at greater risk to develop cancer? Have the studies been controlled sufficiently vell to distinguish the correlates of socioeconomic level of the patients, e.g., housing (ventilation, heating, crowding), nutrition, sedical care and eedications, ethnicity? Such "alternative explanatory variables" have not been accounted for adequately, in the Reviev Draft. These factors are even more influential vhen evaluating the reported association between ETS and childhood diseases. Just as genetic susceptibility (deletion of suppressor genes, p-450 genotype, etc.) is providing another dimension to carcinogenesis, there are suggestions of yet another horizon, that of interaction between non-ionizing radiation and chemical carcinogens (see, for•example, Odey, RV., Joint actions of environmental non-ionizing electromagnetic fields and chemical pollution in cancer promotion. Environ. Health Persp. 1990, 86: 297-305). Decades of research have identified causes for very few human cancers, least of all environmental causes. There is good reason to believe we have placed too much emphasis in the wrong places. (See, for example, the editorial by Rudiger, HW., Endogenous Carcinogens: implications of an emerging concept. Mutation Research. 1990, 283, 173-174.) It is uncertainties like these that make me unwilling to accept the idea that ve are ready to calculate the risk from exposure to any one specified potential cause. I am one of those who believes that linear extrapolation to low dose, in the case of exposure to tobacco smoke, is unjustified. About the only argument in its favor is that qualitatively similar chemical compounds are present in tobacco smoke at both high and lov exposure dose. But even that argument is veak regarding the comparison of SS vith MS smoke. There are myriad differences betveen lov and high dose exposures to tobacco smoke, and these are N 3

exaggerated when one is SS and the other MS. These differences were discussed cogently in the proposed document, but the linear assumption was used despite thisl Not thoroughly discussed were the ameliorating biologic implications of low-dose exposures to ETS: upper respiratory removal of particulates, adequate clearance and/or repair at rates equal to low exposure rate, including repair of DNA damage; reduced induction of biotransformation enzyme systems with concomitant decrease in production of harmful reactive intermediates; and reduced injury to the immune system. The Review Draft, in keeping with EPA's Carcinogen Risk Assessment guidelines, restricted its analysis to reports on humans. In the literature relating to ETS in animal studies, virtually no adverse effects have been reported at realistic exposure levels. (For•example, see Adlkofer, FX, et al, Exposure to ETS and its biological effects: A Review, in Present and Future Indoor Air Quality, Bieva, Courtois and Govaerts, eds. Elsevier Science Publishers, 1989). Laboratory animals have generally been negative as models for human exposure to mainstream smoke, especially in regard to pulmonary neoplasia. Animals exposed to tobacco smoke in various MS and SS exposure regimens do, however, manifest a reproducible constellation of responses including systemic biochemical changes, mobilization of inflammatory cells, epithelial metaplasia and responses by the immune system. However, when similarly exposed to ETS at realistic doses, laboratory animals do not respond with decisive cellular changes despite having measurable cotinine. These outcomes persuade me that a threshold exists at these lover doses and should be accounted for in interpreting the human data, as well. Further, it is my opinion that meta-analysis may be an inappropriate statistical technique when the studies being analyzed are as heterogeneous as 4

those in the subject document. Spitzer, et al used "Best Evidence Synthesis", following Slavin, RE (Educ. Res. 1986, 15:5-11). Spitzer also quotes Letzel, et al (Spitzer refs #111 and #113), who obtained relative risks not different from unity, when considering these ETS studies (women only) by meta analysis. One day there may be genomic fingerprints in neoplastic cells that reveal unequivocally the proximate cause of the neoplastic transformation. Prospective epidemiologic studies may currently be able to identify risk factors but only when all potential alternative explanatory variables have been eliminated. I don't believe we are there yet with regard to ETS. 5