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COMMENTS THE EPA REVIEW DRAFT: "HEALTH EFFECTS OF PASSIVE SMOKING: ASSESSMENT OF LUNG CANCER IN ADULTS AND RESPIRATORY DISORDERS IN CHILDREN" by Dr. Karl Jonas In 1986, the National Research Council and the U.S. Surgeon General assessed the health effects of exposure to environmental tobacco smoke (ETS). Both of the 1986 reports conclude that ETS exposure is causally associated with lung cancer and that children of parents who smoke have increased frequency of respiratory symptoms and acute respiratory illnesses and evidence of reduced lung function. The EPA document extends the analyses of these reports to include subsequent evidence on the potential association between ETS and lung cancer in nonsmoking adults. It concludes that exposure to ETS is causally associated with lung cancer in adults and that exposure in young children to ETS from parental smoking, particularly during infancy, is associated with increased problems of acute lower respiratory tract infections (bronchitis and pneumonia), respiratory symptoms of irritation (cough, sputum, wheeze), and middle ear effusions (a sign of chronic middle ear disease). The report estimates that approximately 3800 lung cancer deaths per year among nonsmokers (never smokers and former smokers)l M of both sexes are attributable to ETS in the United States. tA N m

- 2 - Sidestream smoke (SS) emitted from a smoldering cigarette between puffs (the main component of ETS) has been reported to contain many of the same compounds (known and suspected human and animal carcinogens) that have been identified in the mainstream smoke (MS) inhaled by smokers. Exposure concentrations of these compounds in nonsmokers are variable but much lower than for active smokers. An excess cancer risk from exposure to ETS, however, is believed "biologically plausible" because the Review Draft assumes that unless there is evidence to the contrary, any level of exposure to a carcinogen carries a potential risk of cancer. This assumption, which is basic to the issue of ETS, is far from proven and is, in fact, contradicted by a considerable body of evidence. The early EPA definition of a carcinogen is a production of cellular change in one cell by one molecule of the agent. The only way a substance could be proven noncarcinogenic was to demonstrate that it produced no cellular changes that could be identified. This in essence was attempting to prove a negative which is, of course, impossible. The Review. Draft's conclusion that ETS is a Group A (known human) car cinogen is based on the fol lowing observations: (Review Draft pp. 1-3, 1-4) OD ~ d7 ~ 1. Biological plausibility. ETS is taken up by the d7 M+ lungs and distributed throughout the body. The similarity ~0

- 3 - of carcinogens identified in SS and MS along with the established causal relationship between lung cancer and smoking make it reasonable to suspect that ETS is also a lung carcinogen. 2. Consistency of response. The two completed cohort studies and 16 of the 21 case-control studies observed a higher risk of lung cancer among the female never- smokers classified as exposed to ETS. Evaluation of the total study evidence from several perspectives leads to the conclusion that the observed association between ETS exposure and increased lung cancer occurrence is not attributable to chance. 3. Upward trend in dose-response. Of the two major cohort studies, the Japanese study (Hirayama) demonstrates a strong association between passive smoking and lung cancer, including an upward trend in dose-response. The upward trend is well supported by the preponderance of evidence in the 13 case-control studies that classified data by exposure level. The Hirayama study has undergone extensive critical review that led to some corrections and revisions but failed to discredit the findings. Differences in life-style and culture may be a factor in the Japanese study reporting a stronger association between ETS and lung cancer than the American study (American Cancer Society). 4. Detectable association at environmental exposure levels. Within the population of women who are lifelong nonsmokers, the excess lung cancer risk of those married to a smoker is large enough to be observed. Carcinogenic responses are usually detectable only in-high exposure circumstances, such as occupational settings or in highly dosed experimental-animals. 5. Broad-based evidence. The 21 case-control and three prospective studies provide data from eight different countries and from a wide variety of study designs and protocols conducted by many different research teams. No alternative explanatory variables for the observed association between ETS and lung cancer have been indicated that would be broadly applicable across studies. 6. Effects remain after adjustment for potential bias. Current and ex-smokers may be misreported as never- smokers, thus inflating the apparent cancer risk from ETS exposure. The evidence remains statistically

4 conclusive, however, after adjustments for smoker misclassification. The summary estimate of relative risk from raw data of both the case-control and cohort studies is 1.41 before adjustment for misclassification and 1.28 afterward. The individual risk of lung cancer from exposure to ETS does not have to be very large, according to the Review Draft, to translate into a significant health hazard to the U.S. population because of the large number of smokers and the ubiquity of ETS exposure. Current smokers comprise approximately 30% of the adult U.S. population and consume over one-half trillion cigarettes annually (1.5 packs per day on average) causing nearly universal exposure to -ETS. Cotinine, a metabolite of the tobacco-specific compound nicotine, is detectable in the blood, saliva, and urine of persons recently exposed to tobacco smoke. Cotinine has typically been detected in 50-75% of the reported nonsmokers tested (50% equates to 62 million U.S. nonsmokers age 18 or above). The estimate - of 3800 lung cancer deaths per year in nonsmokers attributable to ETS is based on conclusions from various epidemiological studies on environmental tobacco smoke exposure. Much emphasis was placed in the Review Draft on the report of ~ Hirayama from Japan in January 1981. He followed 265,118 adults ~ N (122,261 men and 142,857 women) age 40 years and over. The study ~ focused on the reported effects of spousal smoking on the risk of 1

5 lung cancer in-their nonsmoking wives. A total of 346 deaths from lung cancer in women was recorded during 14 years of follow-up (1966-1979). Of these women, 245 were married and 174 of these were also nonsmokers. These 174 nonsmoking, married women comprised the basis of his report; their husbands' smoking habits were studied. Hirayama concluded that wives of heavy smokers were found to have a higher risk of developing lung cancer and that a dose- response relation was observable. A serious defect in the Hirayama study involves the accuracy of the diagnosis of lung cancer. The diagnoses of lung cancer were obtained from death certificates which are notoriously unreliable and have a large built-in error in favor of lung cancer. (See Rosenblatt, et al., New York State Journal of Medicine, September 1971). In my career as a chest surgeon, I became acutely aware of the importance of reliable diagnoses and the difficulties in determining accurate information on cause of death in the absence of an autopsy. In the American Cancer Society's study, begun in 1959, microscopic-confirmation of the diagnosis was obtained in only 69% of the cases. Garfinkel, in 1981, and 1985, had reported data revealing that death certificates over-stated the lung cancer rates by 11.8%. The ACS study was essentially terminated after six years OD ~ C~d1 N1 ~ IV N

6 in 1965 until it was decided to conduct a second follow-up beginning in 1971. - The follow-up was terminated because tracing became increasingly difficult due to death or movement of the volunteers and their substitutes. The American study data do not support an association of lung cancer with ETS exposure. In particular, Garfinkel (1981) reported that the mortality ratio was 1.27 for nonsmoking women with husbands who smoked fewer than 20 cigarettes a day and 1.10 for nonsmoking women with husbands who smoked more than -20 cigarettes per day. This is precisely the opposite of what would be expected under the assumption that ETS exposure causes lung cancer. It is interesting here to observe the attempts in the Review Draft to explain away conflicting data. The Draft reconciles the differences between apparently contradictory studies by discussing differences in risk in the populations studied, differences in the way the studies were designed, conducted, or interpreted, or by chance occurrence alone. The American study which failed to confirm Hirayama's study is explained away by such variables as the number of women in Japan who worked in offices, their exposure to ETS at work, the size of the house, the number of smokers per volume of air, proximity of nonsmoking spouse's sleeping area to spouse's smoking area, and the amount of time the nonsmoking spouse is in

7 the home. on the other hand, if a study tends to support the theory that ETS is a carcinogen, no such conjectures are made. The EPA report extensively discusses the contradictions between the U.S. study by the American Cancer Society and the Japanese study by Hirayama. It states: The Japanese cohort study alone -provides compelling evidence of lung cancer risk associated with ETS exposure. Although some corrections to the initial calculations were required, it has withstood extensive critical examination since its appearance in 1981. Results of the American cohort study are less conclusive. Differences in culture and life-style between the U.S. and Japan suggests that ETS exposure from spousal smoking may be higher, and exposure from background sources lower in the U.S. than in Japan. In view of other study evidence of an upward trend in response, the more pronounced outcome observed in the Japanese study might be anticipated. Although the American cohort study reports a statistically nonsignificant increased lung cancer risk from ETS exposure, the data reveal an inversion in dose-response, i.e., lower response at high exposure to spousal smoking than at moderate exposure. Further study of the data to see if this inversion can be explained may be ~ ~ warranted especially since this study is the largest in the United 4m States and is the only U.S. cohort study. It appears that if a,0 ZU study supports the belief that ETS causes lung cancer, it is more ~

8 readily accepted by the authors of the Draft. On the other hand, studies whose conclusions are inconsistent with this belief are challenged. The EPA concludes the chapter on the epidemiologic evidence of lung cancer from ETS with the following statement: Based on the statistical results of this chapter, this report concludes that passive smoking- is associated with an increased risk of lung cancer. The stronger conclusion of a causal association, however, is not warranted from these statistical tests alone. Other factors must be considered as well, including the- likelihood that the observed association is attributable to systematic bias or the presence of a confounding variable. I agree that a causal association is not a warranted conclusion. Chapter IV in the Review Draft provides an assessment of lung cancer risk from ETS. The Review Draft states: "Statistical tests alone . . . do not generally warrant the conclusion that two variables are causally related, i.e., that one of the variables is a contributing cause of the other." ' This chapter is largely a technical analysis of the statistical problem posed by this effort. As an example of the comments, Robins of the National Research Council explores three approaches to the assessment of lung cancer risks from exposure to ETS, each with attendant assumptions clearly

9 stated. Method I is based solely on evaluation of the epidemiologic data applying two assumptions: one, adjustment of relative risk for background exposure to ETS independent of age, and two, the excess relative risk in a nonsmoker is proportional to the life-time dose of ETS. The validity of both assumptions was questioned by the author's later remarks. Analysis is made of approaches to risk assessment based on cigarette equivalents. The U.S. Surgeon General's Report devotes a three page section to the concept of cigarette equivalents, quantitatively demonstrating how it varies as a measure of exposure. It concludes: "These limitations make extrapolation from atmospheric measures to cigarette equivalent units of disease risk a complex and potentially meaningless process." However, Vutuc assessed the exposure of nonsmokers to cigarette smoke as equivalent to 0.1 to 1.0 cigarettes per day actively smoked. After more thorough analysis, he concluded that "as it applies to passive smokers this range of exposure may be neglected because it has no major effect on lung cancer incidence." A personal communication from the American Cancer Society to Vutuc notes that the number of lung cancer deaths among nonsmokers in the U.S. in 1988 was about 6500 females and 3000 males. Robins extrapolates from data on active smoking and along with several assumptions, pronounces the excess lung cancer deaths due to ETS

as 540 to 2940 for females and 153 to 1090 for males. These are so wide that the reliability of these estimates must be challenged. Arundel, et al., attribute five lung cancer deaths among female nonsmokers to ETS exposure and seven among males. Using the cigarette equivalent method, Arundel, et al. demonstrated_that reported risks from ETS exposure cannot be distinguished from what epidemiologists call "background noise"; i.e., that a precise risk estimate is not possible. The Review Draft rejects the methods employed by Vutuc and Arundel, et al. Instead, it adopts a method of estimating risk based solely upon human epidemiologic studies. Some of those studies illustrate the uncertainty regarding the Review Draft's method. For example, a study by Trichopoulos, et al., in 1981 reported on 51 women with lung cancer and 163 other hospital patients wh-o were interviewed regarding the smoking habits of themselves and their husbands. Forty of the lung cancer cases and 149 of the °other patients were nonsmokers. Among the nonsmoking women, a statistically significant difference between the cancer cases and the other patients with respect to their husband's smoking habits was reported. Estimates for the relative risk of lung cancer associated with having a husband who smokes were 2.4 for smokers of less than one pack and 3.4 for women whose husbands smoked more