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Shortwood The Ryefield Little Baddow Essex CM3 4TR England 14th September, 1990 Project Officer for Environmental Tobacco Smoke Technical Information Staff Office of Health and Environmental Assessment (RD-689) U.S. Environmental Protection Agency 401 M Street, SW Washington, D.C. 20460 U.S.A. Dear Sir, RE: "HEALTH EFFECTS OF PASSIVE SMOKING: ASSESSMENT OF LUNG CANCER IN ADULTS AND RESPIRATORY DISORDERS IN CHILDREN- EPA/600/6-90/006A; MAY, 1990; REVIEW DRAFP I have reviewed the EPA Review Draft "Health Effects of Passive Smoking: Assessment of Lung Cancer in Adults and Respiratory Disorders in Children" EPA/600/6-90/006, and do. not consider that the evidence, as presented, justifies the conclusion that ETS has been identified as a Group A (known human) carcinogen. The most contentious issue concerns the adequacy of the epidemiological studies which have been relied upon in the Review Draft as evidence of a causal relationship between the incidence of lung cancer and the exposure of non-smoking women to ETS in the home. Several scientific criteria must be satisfied to support such a conclusion of causality: the individual epidemiological studies must be consistent in reporting a statistically significant association between exposure to ETS and the incidence of lung cancer; the reported associations must be of a magnitude greater than those relied upon by the Review Draft; there must be a clear relationship demonstrating an increasing effect with an increase in intensity and duration of exposure; and the inference must be

plausible biologically. The scientific data cited in the Review Draft in my opinion, fall far short of meeting these criteria. The vast majority of the epidemiological studies do not report a statistically significant association and hence are consistent with an interpretation and conclusion that there is no relationship between exposure to ETS and the development of lung cancer in non- smokers. When the epidemiological data in the Review Draft were combined in a meta-analysis, and after adjusting for possible errors in the classification of smoking habits, a relative risk value of 1.28 was obtained. This method of analysis is appropriate only when the individual studies are eminently comparable and free of confounding factors which otherwise tend to distort and magnify the estimate of the degree of risk. The pooling of the ETS epidemiological data for the purpose of meta-analysis is inappropriate and the calculated "overall relative risk" is unreliable because the individual ETS studies vary significantly in study design, methodology, sample population, confounding risk factors, etc. A relative risk value of less than 3.0 is generally considered to represent an extremely weak association. In my opinion, such small, positive associations cannot be interpreted as evidence of a causal relationship between ETS and lung cancer. There is sufficient diversity in respect of the type of lung cancer diagnosed which together with the absence of any objective quantitative measure of either the intensity or frequency of exposure to ETS casts further doubt on the biological significance of the presumed association, since it is unusual even under conditions of prolonged exposure to potent carcinogens to establish causality when the interval between the initial exposure and diagnosis of the disease is less than ten years. In my opinion, the evidence that ETS is a human carcinogen is severely limited and contradictory. Little is known about the actual composition of ETS, but it is generally reported that the exposure of non-smokers to ETS is two or more orders of magnitude less than the exposure of active smokers to mainstream smoke, and it has to be considered whether it is biologically plausible that the small dose of ETS to which non-smokers are exposed is sufficient to cause lung canCer. Although both mainstream and sidestream smoke contains several compounds that have been shown to induce tumours in experimental animals, few have been tested by other than oral, dermal or parenteral routes of administration and none have been identified unequivocally as risk factors in human cancer. The linear extrapolation from exposure to compounds present in mainstream smoke to the low concentrations found in ETS is questionable since it ignores the significant qualitative and quantitative differences in the physical properties and chemical composition of mainstream smoke and ETS. Extrapolations from high doses of mainstream smoke to the low dose levels of ETS exposure is controversial for it is

based on the assumption that there is no "safe" level for carcinogens. The scientific criteria that must be met to conclude that ETS induces pulmonary tumours either in experimental animals or in man following inhalation have not been met. Cancer is a complex, multifactorial process that is poorly understood by science and if the EPA's decision to classify ETS as a human carcinogen is accepted, it could conceivably inhibit further research into those genetic and environmental factors that have been implicated in the aetiology of lung cancer. The evidence, at best, is suggestive of only the possibility of a potential risk, rather than an absolute risk. Yours faithfully, Prol.,'ej;sbr J. W. Da 1 Ph.D., D.Sc., . Path.