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misclassification. I will also comment on the ETS part of OSHA's Preliminary Quantitative Risk Assessment as published in the Federal Register,2 April 5, 1994. 0 I. Heart Disease and Passive Smoking Exposure to environmental tobacco smoke, also known as passive or involuntary-smoking, results in a number of adverse health effects. Although most of the attention, for adults, has been directed toward lung cancer, heart diselse, at least in terms of probable deaths, is much more important. The reason is that the percent increase in risk from ETS exposure is about the L same for both diseases, but lung cancer among people who have never smoked is a rare disease while heart disease among never smokers is many times more common. Therefore the same small fraction of deaths multiplied by a much large number of total deaths results in a large number of deaths attributed to passive smoking. Over the past six years there have been five papers in the peer-reviewed literature that have assessed the available evidence on adult mortality from passive smoking and heart disease. Each of these papers is appended as part of this testimony. The five papers are also listed in Table 1. The first is a paper of mine3 published in December 1988 in the journal Environment International. The seven epidemiologic studies then available on passive smoking and heart disease were N 0 00 ' ~ reviewed. The relative risks from the seven studies were pooled v 00 A O1 2

to develop a combined relative risk which indicates a 30% increase in risk for ETS exposure and a predicted 32,000 heart deaths per year in the U.S. among nonsmokers that are caused by passive smoking. The second, important peer-reviewed paper is that of Glantz and Parmley4 published in January'1991 in Circulation which is the leading medical journal of the American Heart Association. They reviewed not only the epidemiologic studies and Wells' death estimate but also provided a thorough review of the physiology and biochemistry that connects ETS exposure with heart disease. They conclude that "ETS causes heart disease." The third important papers came from Kyle Steenland of the National Institute for Occupational Safety and Health in the January 1992 issue of the Journal of the American Medical Association. He reviewed again the epidemiologic studies, now grown to nine, and the biologic plausibility. He then made a risk assessment based on the relative risk from the largest U.S. study and concluded that if the epidemiologic results are valid, then there were 35,000 to 40,b00 ischemic heIrt disease deaths per year in the United States that were associated with passive smoking. Ischemic heart disease is that type of heart disease where there is obstruction in the coronary arteries so that part of the heart muscle becomes disabled because of lack of oxygen. The fourth paperb is a medical/scientifip position statement from the American Heart Association published in the August 1992 issue of Circulation. The authors, Taylor, Johnson and Kazemi, 3

statement before oBHA informal, Public Hearing on Proposed Rulemaking vis-o-via lndoor'Air Quality on (i) Passive smoking and Heart Disease, and (2) Smoker 1[isclassification Effects in Passive Smoking Studies by A. Judson Wells ' Volunteer Consultant, Smoking and Health My name is A. Judson Wells. I hold a Ph.D. in physical chemistry from Harvard University. I was employed in the chemical industry, specifically by E.I. dupont de Nemours and Company, from 1941 until 1980 in chemical research, research management and general management. From 1969 to 1980 I was director of a business division with revenues of $125,000,000 per year. Since 1981 I have served as a volunteer consultant in the . 0 smoking and health area for the American Lung Association. For the whole of that time I have studied the scientific literature on the health effects of passive smoking. From 1989 to 1993 I was an unpaid consultant to Kenneth G. Brown, Inc., a subcontractor to the U.S. Environmental Protection Agency in their work leading up to the publication of their report: Respiratory Health Effects of Passive Smoking: Lung Cancer and other Disorders.' I am a co-author of that report. More recently I have consulted, again unpaid, for the U.S. Occupational Safety and Health Administration on health effects of passive smoking and am testifying on their behalf today. In my testimony today I will be covering two topics: (1) the association of exposure to environmental tobacco smoke (ETS) and heart disease, and (2) methods for correcting observed passive smoking relative risks for the effects of smoker • N 0 ao ~ v 0 A rn ~ 00

! reviewed again the available evidence and concluded that "ETS is a major preventable cause of cardiovascular disease and death." The fifth important peer-reviewed paper7 is one of mine published August 1, 1994, in the Journal of the American College of Cardiology, another leading medical journal in the heart field. This paper reviews the newer studies since Glantz and Parmley that support the biologic plausibility of a link between passive smoking and heart disease. Results qf the epidemiologic studies, now grown to 13, are again pooled. They indicate a 37% increase in ischemic heart disease morbidity and a 22% increase in heart disease death for those exposed to ETS at home versus those not so exposed. Then, using the EPA's methods of calculating deaths from the relative risksi, it is concluded that in 1985 there were 62,000 heart deaths per year in the U.S. caused by passive smoking. These five papers covering some 48 pages of medical journal text cannot be reviewed in detail here, but the main points will be summarized. There are several ways in which tobacco smoke can affect the heart even though there is no direct contact between the smoke and the heart itself. As with lung cancer, active smoking causes heart disease.8 Therefore we would expect passive smoking also to cause heart disease but in lesser amounts. There is one important difference between lung cancer and heart disease as far as ETS exposure is concerned. With lung cancer the only effect is long term, say 20 years exposure, before a cancer N appears. With ETS and heart disease there are both long term and 0 00 ~ V Co 4 ~ ~ V s

Another short term effect is that provided by the carbon monoxide in the smoke. Carbon monoxide is the odorless, colorless, toxic gas that also occurs in the exhaust from automobiles. Carbon monoxide reacts with the hemoglobin in the blood and renders it incapable of transporting oxygen. It is the ability of the blood hemoglobin to carry oxygen from the lungs to the heart, brain and muscles that sustains life. Typical ETS atmospheres contain from 3 to 25 parts per million of carbon monoxide resulting in 0.4% to 5% of the hemoglobin being inactivated.7 A typical situation would be 15 parts per million resulting in 2% being inactivated. When 30% of the hemoglobin is inactivated the result is death.14 With part of the blood hemoglobin inactivated by carbon monoxide from ETS exposure, the heart must work harder for the same level of physical exertion. But the carbon monoxide also affects the ability of the heart to process oxygen by attacking some of the proteins and enzymes in the heart muscle that are essential to what is called myocardial mitochondrial respiration.4 Thus ETS exposure reduces the effective blood supply to the heart while at the same time reducing the heart's ability to process the blood it receives. This results in reduced exercise capability both in healthy people and particularly in people with existing coronary disease. Going on now to long term effects, one theory about how heart attacks arise is that first there is damage to the coronary artery wall. Then plaque builds up around the injury, eventually N reducing the blood supply to the heart and thereby causing the O CD 03 4 6 o) • V W

heart attack. In the platelet experiments that I described earlier9'11 it was also noticed that short term ETS exposure of • nonsmokers results in an increase in endothelial cell carcasses in the blood. This indicates damage to the endothelium which is the very thin lining in artery walls. Such qamage could provide a starting point for plaque formation. Once.the initial damage is done researchers have found that exposure'to cigarette smoke accelerates the growth of these plaques. In other words, not more plaques form, but bigger ones form sooner. These experiments, in mice, pigeons, chickens, rabbits and dogs so far,4 indicate that it is the polyaromatic hydrocarbons in the smoke that are causing the effect. The most recent of these papers, namely that by Penn, et al.'s shows a significant increase in plaque development when cockerels were exposed to the smoke from one cigarette over a 16 week period. Moreover, one researcher16 has found through ultrasound experiments that the arterial walls in humans become thicker if t4e subjects smoke or are exposed to ETS. Another long term effect is that ETS exposure appears to raise total cholesterol in the blood while lowering the high density or good cholesterol7. This is another known heart disease risk factor. Other researchersl'f have found that ETS exposure reduces plasma ascorbic acid (vitamin C) levels in nonsmokers by an amount that is 65% of the reduction experienced N by active smokers. o~o i V CD 7 A ~ 0 4

very short term effects, some apparent after only 20 minutes exposure. Let's look at the short term effects first. The platelets in the blood are one of the factors that determine the blood's tendency to coagulate, and platelet sensitivity is a measure of this tendency. Active smokers have a lower platelet sensitivity than nonsmokers, meaning that their blood is less resistant to clotting. The evidence for decreased platelet sensitivity among s I* nonsmokers exposed to ETS comes from the laboratories of J.W. Davis in Kansas City9 18and H. Sinzinger in Vienna, Austria". For example, Davis found that nonsmokers exposed only 20 minutes in a hospital lobby where smoking was allowed lost about 60% of their r platelet sensitivity advantage over active smokers. However, their platelet sensitivity returned to normal shortly after the exposure ceased. Similar results from Burghqber, et al.11 in sinzinger's group are shown in Figure 1. Here the ETS exposure is also for 20 minutes but at a somewhat higher level. As you can see, the nonsmokers have lost about 80% of their platelet sensitivity advantage over the smokers. Sinzinger's group12 also found that after repeated ETS exposures, nonsmokers' baseline platelet sensitivity was reduced to a level nearer to that of the smokers. Low platelet sensitivity is a known heart risk factor. Experiments by Davisl3 with sham cigarettes indicate that the lowered platelet sensitivity is related to the nicotine in the cigarette smoke. 5

Summarizing the epidemiology, there is a 20$ to 30% increase in risk of ischemic heart disease death associated with exposure to spousal or household ETS.7 The increase in morbidity risk is similar to that for mortality. There is also strong evidence that the risks from ETS exposure at work are similar to those experienced at home. Also these increases risk cannot be accounted for by the other known heart risk factors, and, as I shall note later, they are not accounted for by the misclassification of smokers as nonsmokers. S II. The Effects of Smoker Misclassification on Passive Smoking Relative Risks In this part of my testimony I will be discussing the misclassification of current and past smokers as never smokers and the effects that such misclassification has on the observed relative risks in passive smoking studies. In doing so I will be defending Appendix B in the EPA reportl on ETS and lung cancer. Appendix B describes EPA's methods of dealinq with this type of misclassification; I was the author of Appenc}ix B; and the tobacco industry consultants have criticized our methods. I will deal with the effects of smoker misclassification on heart disease relative risks later. Why is smoker misclassification an issue? It is known that a small percentage of smokers, if asked if they ever smoked, will say no. It is also known that smokers tend to marry smokers and N 0 nonsmokers tend to marry nonsmokers. Therefore, for a given ~ V W 4. 10 V • 4

i level of misclassification; more of these real smokers will show up in the group of so-called never smokers married to the smokers than in the group married to the never smokers. In the case of lung cancer the high relative risk among those few misclassified smokers will raise the average lung cancer risk of the self- reported never smokers, and it will raise it more for those married to the smokers than for those married to the never smokers. This then will create a perceived increase in risk that could be mistaken for a passive smoking effect. There is no question that such a misclassification effect exists. The real question is, how big is it? The EPA method for estimating the bias introduced by smoker misclassification was developed by Dr. Walter Stewart of the Johns Hopkins School of Public Health and myself. Dr. Stewart is an expert in occupational health epidemiology. The method is basically his which I have adapted to passive smoking. Our method involves dividing the misclassified smokers into three groups, (1) current regular smokers, with cotinine levels like average self-reported current smokers, (2) current occasional smokers, and (3) ex-smokers. Misclassification rates are then developed for each class of misclassifieds using cotinine data for the current smokers and discordant answer studies for the exsmokers. Proportionate distributions of controls and cases by smoking status of subjects and spouses are developed using s demographic data and smoking relative risks. The misclassification rates are then applied to the various 11 1 o>

The results of these smaller studies can be pooled to see if, together, they indicate higher statistical significance. When this is done we find that, in mortality studies for both men and women, when the Helsing study is removed, the pooled results for the remaining studies show an odds ratio of 1.26 that is still highly statistically significant. A new study from Xian, China19 not included by OSHA in their proposal in thq Federal Register, while too small (59 cases) to show statistically significant adjusted relative risks, did investigate the heart effects on nonsmoking women exposed to ETS both at home and at work. For exposure at work there was an 85% increase i~ risk with a highly statistically significant trend of increasinq risk with 0 increasing amounts of ETS exposure. Only 8% of women in that part of China smoke, but most of the men smoke and they smoke freely at work, so the study provides an excellent opportunity to judge the effects of ETS exposure at work on heart disease in nonsmokers. In many of the ETS/heart studies the crude risks were adjusted for various other heart risk factors. The relative risks noted above: are the adjusted relative risks after adjusting for such factors as high blood pressure, high cholesterol, personal or family history of heart disease, weight or body mass index, and education or social status. Thus the potentially most important confounders have been considered and found not to explain the observed increased xisk. 9