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"The Health Effects of Passive Smoking: Assessment of Lung Cancer in Adults and Respiratory Disorders in Children," Review Draft EPA May, 1990 STATEZiENP OF JOHN WESLEY CLAYTON, JR., Ph.D., D.A.T.S. I am Professor Emeritus of Pharmacology and Toxicology at the University of Arizona in Tucson, Arizona. I served as Acting Director of the Health Effects Division of the EPA's Office of Research and Development in 1973-1974. I held the position of Professor of Pharmacology and Toxicology, College of Pharmacy and Professor of Microbiology and Medical Immunology at the University of Arizona from 1974 to October, 1989. A copy of my curriculum vitae is attached for your review. I have reviewed the EPA's Review Draft Risk Assessment on ETS, with particular attention to the Draft's claim that ETS is a "known human carcinogen." I was struck by the conspicuous absence of anv consideration of pertinent toxicological data in the Assessment. In my opinion, the available toxicological data on ETS do not support the contention that ETS is a known human (Group A) carcinogen. The reasons for my opinion are presented below. In order to evaluate the hypothesis as to whether or not ~ environmental tobacco smoke (ETS) causes lung cancer in humans, we N A must consider two major types of data: epidemiological and N 0 toxicological.

Epidemiology is a statistical discipline. It is the study of human populations in order to determine the existence of statistical relationships between certain factors, such as lifestyle factors or environmental exposures, and the frequency and distribution of certain diseases. Epidemiology alone is not sufficient to establish a cause and effect relationship regarding chronic diseases such as lung cancer, because it cannot control for numerous confounding variables. Epidemiology identifies risk factors for disease. If questions regarding possible causal relationships arise, then it is necessary for toxicologists to test these hypotheses by conducting appropriate animal experiments. Toxicology is the science of evaluating the potential adverse effects of chemicals on living systems. Toxicologists conduct carefully controlled animal experiments to observe what . effects, if any, test substances at different doses have on those animals. In the field of toxicology there is a fundamental principle that when there is a response, the greater the dose of a substance the greater the response produced. In addition, the OD ~ accepted toxicological theory is that until a certain dose is A attained, no effect will be observed. This relationship between ~N - 2 -

dose and response is a basic tenet in toxicology and takes the graphic form of the S-shaped curve. Within the parameters set by the dose-response curve, there will be a wide variety of responses extending between the extremes of no observed response at one end of the curve to a complete response at the other end. Toxicology is a more definitive science than epidemiology because a well-designed, well-conducted animal experiment controls possible confounding variables which cannot be eliminated or controlled for in epidemiological studies. In my opinion, positive animal experiments in addition to epidemiological data are required before scientists can conclude that exposure to a particular agent causes a specific disease. In order to evaluate the disease causing potential of an agent using animal inhalation experiments, the following criteria must be considered: - A. Approvriate Control GrouRs_: There must be appro- priate numbers of both cage-maintained and sham- exposed animals to account for background disease, including spontaneous tumor incidence and the effects of stress.

B. Genetics: Animals used in these studies must be bred to maximize genetic uniformity. C. Healthy Animals: Animals must be monitored for their health status because intercurrent disease can cause pathological changes unrelated to the test agent. D. PatholoQical Diagnosis: Histopathological changes must be evaluated by a qualified pathologist. E. Dose Route and Duration of Administration: Route of administration must reflect the hazard/health effect of the substance(s) in question. Several dose levels, including those simulating the human situation, should be employed. The highest dose level should not materially shorten the lifespan of the test-animals, and the animals should be studied for their lifetime. F. End Point: Animals must be capable of developing cancer at the same site and of the same histological type as in the human population. G. Statistics: Results should be significantly dif- ferent from appropriate control groups. Control 4

groups should have low incidence of spontaneous lesions. H. Confirmation: Results should be capable of being reproduced independently by other scientists at other research laboratories, and in other animal species. To my knowledge there are only two published animal inhalation experiments investigating the effects of ETS. Although animal inhalation experiments have been conducted to investigate the effects of mainstream smoke on laboratory animals, they are not ETS experiments. It is not scientifically acceptable to extrapolate from the results of mainstream smoke animal inhalation exposures to ETS exposures, for reasons discussed below. While neither of two published studies on animal exposures to ETS completely fulfills the criteria discussed earlier, they provide the only available animal inhalation data to date on ETS. Significantly, both studies conclude that there are no meaningful histopathological differences among animals exposed to ETS and those which were not exposed. The first study was a 90-day ETS inhalation study of rats and hamsters (Adlkofer, 1988). Animals were exposed to ETS concentrations up to 100 times the concentrations encountered by - 5 -

nonsmokers. The researchers reported no histopathological differences between exposed and control animals. Electron microscopy revealed pulmonary changes which could be expected to occur under similar exposure conditions with other sources of respirable particles. The changes were shown to be reversible upon discontinuation of exposure. In the second study, conducted by the American Health Foundation, (Haley, 1987a,b; Haley, 1988) the investigators exposed one group of hamsters to mainstream smoke and another group to ETS. The data indicate that the animals exposed to mainstream smoke and ETS lived longer than the sham treated controls. The investigators reported that overall there was no marked increase in tumor incidence in animals exposed to either mainstream smoke or ETS after 18 months of exposure. I also have reviewed the body of scientific literature in- volving the inhalation of mainstream smoke by experimental animals; in my opinion, the properly designed and conducted inhalation experiments have not demonstrated the production of lung cancer in laboratory animals. Despite frequent attempts involving many different species and strains of animals, the animal inhalation studies involving mainstream smoke have been negative and do not support the claim that cigarette smoking causes lung cancer in humans.

The most recent large scale state-of-the-art mainstream smoke animal inhalation experiment using mice was conducted at Microbiological Associates (Henry, 1986). The results of this study disclosed that there was no statistically significant difference in the number of lung cancers observed in the smoke- exposed mice compared to the sham smoke-exposed and cage-control groups of mice. This study was specifically designed and conducted to address the question of whether or not mainstream smoke causes lung cancer. Even if there existed a well-designed and well-conducted mainstream smoke inhalation experiment that produced statistically significant numbers of lung cancers in the smoke-exposed group, it would be inappropriate to extrapolate from such an experiment to conclude that ETS would have a similar effect because ETS is quantitatively and qualitatively different from mainstream smoke, as described below. There are significant differences in both the kind and the amount of smoke to which the active smoker and the nonsmoker are exposed. Therefore, an animal inhalation experiment designed to assess the potential effects of exposure to ETS must utilize the same kind of exposure as that experienced by the human nonsmoker. For this reason, mainstream smoke exposure, as described

in the studies discussed above, is not applicable to the situation of ETS exposure. There also are profound qualitative and quantitative dif- ferences among (1) mainstream smoke, (2) sidestream smoke and (3) ETS. Sidestream smoke is defined as the smoke emitted into the environment from the burning cone of the cigarette. It is measured quantitatively between puffs on a smoking machine. Many of the same constituents found in mainstream smoke are also found in sidestream smoke, and the relative amounts are commonly expressed in terms of mainstream smoke to sidestream smoke ratios. However, there are differences between mainstream and sidestream smoke: (1) sidestream smoke particles are smaller than mainstream smoke particles; (2) sidestream smoke has a higher pH than mainstream smoke; and (3) the burn temperature of sidestream smoke is approximately 600'C while that of mainstream smoke is approximately 800-900'C. In addition, ETS is composed of sidestream smoke and exhaled mainstream smoke (EMS). All of these factors result in sidestream smoke being physically and chemically different from mainstream smoke. ETS, the smoke to which the nonsmoker is exposed, is qualitatively and quantitatively different from either mainstream or sidestream smoke (plus EMS). The nonsmoker is not exposed to sidestream smoke per se but to a highly diluted, aged and chemically - 8 -

altered form of sidestream smoke (plus EMS). Quantitatively, constituents found in ETS are diluted from 100 to 1000 times the quantities measured in sidestream smoke (Nystrom, 1986). The composition of sidestream smoke and ETS differs as well. ETS is a dynamic mixture which, as it ages, undergoes chemical change. As ETS ages, it is mixed with substances in the ambient air other than tobacco smoke. Analytical chemists continue to conduct analyses of ETS to determine the chemical composition and concentration of ETS as it ages in the environment. For example, scientists found that nicotine exists in the gas phase of ETS whereas the nicotine found in mainstream smoke partitions mainly in the particulate phase (Eudy, 1986). Other substances undergo conversions as they age, such as the change of nitrogen oxides to nitrogen dioxide. There are also profound differences between active smoking and nonsmoker exposure to ETS. The most obvious are those of exposure and dose. Recent studies of nonsmoker exposure to ETS in the ambient air report that the typical nonsmoker is exposed to the nicotine equivalent of one one-hundredth to one one-thousandth of a cigarette per hour (Kirk, 1988; Carson, 1988). When based upon body fluid measurements of cotinine, a~ metabolite of nicotine, nonsmoker exposure approximates 0.5% that N OD - 9 -

of the smoker. When based upon retained particulate matter, the percentage is even less -- 0.05t that of the average active smoker (Lee, 1989). Inhalation patterns for smokers and nonsmokers exposed to ETS also differ. The nonsmoker is exposed to ETS through nasal breathing which results in the filtration of particulate matter. In contrast, smokers inhale mainstream smoke through their mouths. All of these differences demonstrate that only animal inhalation experiments using ETS would provide the toxicological data necessary to evaluate whether or not ETS causes lung cancer. As previously mentioned, the only two studies which provide such data clearly do not provide any toxicological evidence supporting the claim that ETS causes lung cancer in nonsmokers. I am aware that there are different theories regarding the mechanism of cancer causation; however, scientists do not at present have sufficient data to define events at the cellular level which transform healthy cells into cancerous cells. Extensive research in this field is continuing. Although much has been learned about the development of cancer, there are important gaps in what is known about the process of carcinogenesis. Thus, it is not ~ appropriate for the EPA to declare that ETS is a known carcinogen, ~ ~ CR tD - 10 -