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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

Thus we have ample biologic evidence that passive smoking can affect the blood in ways that are injurious to the heart, and that these effects are often stronger than one would expect considering the difference in dose between active and passive smoking. To get some idea of the magnitude of the heart risk from passive smoking one must turn to the epidemiology. There are now thirteen studies7 based on over 3000 cases where either heart disease or heart death was studied relative to ETS exposure. This is an enormous data base compared to what is usually available in regulating workplace toxins. Five of the studies • 0 are U.S. based. The others come from Australia, China, England, Japan, New Zealand and Scotland. Eight of the studies are mortality studies, and four of them have data for both males and females resulting in twelve separate data points which are shown in Figure 2. The twelve odds ratios, or relative risks for the prospective studies, are plotted on a log scale against the statistical weights for each data point. As you can see, for the smaller studies there is considerable scatter, but when the statistical weight gets beyond abut 20, the odds ratios become very stable in the 1.15 to 1.30 range. The combined odds ratio for all of the studies, as shown at the right, is 1.22 and is dominated by the large, statistically significant, Helsing, et al.18 study which comprises 42% of the total cases. Many of the other studies are too small to reach statistical significance at the 95% level but they do indicate appreciable increased risks. 8 IJ 0 Oo ~ -4 CD 4~1 C) V w

• 0 OSHA has used as a lung cancer relative risk the occupational risk of 1.34 for women from the preliminary report by Fontham, et al.Z1 This is without doubt the best U.S. study and is an appropriate choice. However, the final report22 for that study is now available so the updated occupational relative risk of 1.39 with a 95% confidence interval of 1.11 to 1.74 should be used. For heart disease OSHA used the relative risk for household ETS exposure from the largest U.S. heart study, namely, Helsing et al.76 This again is appropriate. However, an alternative analysis of the data based on a somewhat different mathematical model appears in Sandler, et al.a The relative risk for males at 1.31 is the same in both papers but the relative risk for females is slightly different, namely, 1.19 in Sandler versus 1.24 in Helsing. Dr. Sandler advises that these two estimates are statistically equivalent so an average of, say, i 1.21 might be appropriate for the female relative risk. OSHA's discussion of why the household exposure data can be used for occupational exposure is appropriate and well done. Major • support for OSHA's position that there is an adverse heart effect from ETS exposure at the workplace comes from the new He, et al19 paper from Xian, China, that was mentioned earlier. This very recent study covers females only. Although the number of cases is not large, this is an excellent paper wit4 about 15 heart disease risk factors including all of the important ones either adjusted for or accounted for. These authors found a relative risk for spousal ETS exposure of 1.24, not significant but very 16

sub-classes of smokers to estimate the proportions of each category misclassified. These are then subtracted from the proportions of observed never smokers to yield the proportion of true never smokers among exposed and unexposed cases and controls. From these numbers a corrected relative risk can be calculated. Our method has been peer reviewed by EPA's Science Advisory Board. In late 1991 Peter Lee, a consultant to the tobacco industry, came up with an alternative methodaD for estimating the smoker misclassification bias. As shown in EPA's Appendix B, which is shown in condensed form in Table 2, when the same inputs are used, their method and ours give essentially the same results. However, their inputs are different so their results are different, namely, much higher bias. There are four important inputs for these calculations. They are, as shown in Table 3, (1) the misclassification rates, (2) the prevalence of smoking among the subjects (the more smokers, the more will misclassified), (3) the relative risks assumed for the misclassified smokers, and (4): the marriage concordance among smokers and non smokers, i.e., the relative degree to which smokers marry smokers and nogsmokers marry nonsmokers. Regarding the first important input, namely, misclassification rates, we used, for current smokers, all of the literature data on females where we could get individual cotinine measurements from the authors. This allowed us to tell exactly 12 T

et al studyZl on which OSSA's lung cancer risk assessment is based the correction for smoker misclassification is very small • because the authors were able to eliminate most smokers from the study by cotinine tests. of the current For heart disease there is an even smaller correction for smoker misclassification. The reason is that the relative risk for active smoking for heart disease is much lower than for lung cancer, about 1.7 versus about 4 world wide for lung cancer in females or about 8 in recent U.S. studies. This lower relative risk carries over to the smokers misclassified as never smokers, thus lowering the correction. In Wells' recent paperT on passive smoking and heart disease the pooled heart relative risk for females was lowered only from 1.25 to 1.24 by the smoker misclassification correction. For males the correction was larger, 1.38 to 1.30, because of the larger proportion of smokers. Again, these corrections are probably too large by a factor of two to four. Comments on the O8HA Preliminarv Risk Rssessment The passive smoking risk assessments that have been carried out so far both for lung cancer and for heart disease have covered the entire U.S. population. This risk assessment by OSHA is the first, to my knowledge, that is restricted entirely to workplace exposure. Although I might differ on some of the details, the assessment methodology is well conceived and the N 0 00 results are reasonable. s V 00 A O1 15 00 N

similiar to the combined result for home exposure from all of the other studies. In addition they found an almost statistically significant relative risk for workplace exposure of 1.85 with a highly statistically significant upward trencl as workplace exposure increased. As I noted earlier, Xian is a good place to study the effects of ETS exposure on the heart because very few women smoke there, about 8%, thereby cutting down on background and misclassification effects, but most of the men smoke, and they smoke freely both at home and at work. The high workplace • for significant at the 954 level, and when the risks are applied to the large number of people exposed, a very large public health risk is indicated. In the risk assessments for the total population3'S•7 it is customary to adjust the relative risks upward to account for exposure to background ETS. This is done in order to estimate the risk relative to a hypothetical population that has no ETS exposure at all. However, in OSHA's case where they are trying to determine the effect of workplace exposure alone, using a relative risk without adjusting for background is more relative risk mayy result from higher exposure than is typical U.S. workplaces, but this paper indicates strongly that ETS exposure at work can indeed result in coronary heart disease, just as the Fontham, et al paper22 suggests the same for lung cancer. Although the risk elevations from Fontham, et al.a and Helsing, et al.18 are small, the results are statistically 17 ~

how many of the false negatives among the never smokers were really regular smokers and how many were only occasional smokers. We are the only group that has gone to this extent to develop accurate current smoker misclassification rates. Similar care • was taken with the exsmoker surveys. We concluded that 1.09% of regular smokers would say never, plus 24.2% of occasionals and 11.7% of exsmokers. Lee used a single overall misclassification rate which was in effect, about 30% larger than ours. We used smoking prevalence and smoker relative risks that were appropriate for each study. Lee used values that in some cases were twice as high as indicated in the studies themselves. On marriage concordance he and we used similar values. The overall effect when these overages were all multiplied together was, that his estimated bias was in some cases several times as large as ours. There is evidence that even our estimates of the misclassification effect are too high. Our data come from some epidemiologic studies but mostly from community survey type studies. For the regular smokers and the exqmokers, the two most important classes, the misclassification rates from the community type surveys tend to run about seven times as large as those from the few epidemiolologic studies that we have. For example, Fontham, et al.,r is one of the best lung cancer epidemiologic studies. After they went through all of their normal questionnaire procedures, they ran cotinine levels on the N remaining subjects who said they never smoked. They found no 0 C* i V 00 13 ~ ~ 00 O

regular smokers misclassified versus our estimate of 1.09%, and about 10% of occasional smokers versus our estimate of 24%. Another indication that our bias estimate is high is found in the male data. Here smoking prevalences are high. When we used male misclassification rates derived as above for the female rates, we found in some studies that the number of smokers misclassified as never smokers exceeded the number of self-reported never smokers that we had to start with. This is evidently impossible, again indicating that our misclassification rates are too high. To get a measure of the impact of these corrections on the lung cancer relative risks Dr. Stewart and I pooled the relative risks from 25 of the lung cancer studies in the EPA report. The EPA had divided the epidemiologic studies on ETS exposure and lung cancer into four quality tier levels based on scores for ` various factors either included in or excluded from the various ' studies. They then based their lung cancer risk assessment on the top three quality tiers. We also used their quality assignments and drew our 25 studies from the top three tiers. These were all studies on females. We then corrected each of the studies for smoker misclassification and pooled the corrected relative risks. The pooled uncorrected risk was 1.40. The pooled corrected risk was 1.37. So, for lung cancer, the overall effect is small. For studies in western countries where female smoking prevalence is high, the corrections are larger. For Asian and other studies in conservative societies where female N O smoking is low, the corrections are very small. For the Fontham, ca v Oo A 14 0~ • 00 -a

appropriate. In the final draft some discussion of the point may be in order. OSHA may have underestimated the number of nonsmoking workers exposed to ETS at work based on the Cummings data in Table IV-9. Those exposed at work but not at home totalled 48.67% but an additional 29.22% said they were exposed both at home and at work. Therefore the range should be from 18.81% to 77.89%. OSHA used an incidence rate for lung cancer for nonsmokers. With the low survival rate this is almost equivalent to a mortality rate. However, they used a mortality rate for heart disease. Therefore the risk estimates in Table IV-lo and surrounding text are inconsistent. They are disease estimates for lung cancer and death estimates for heart disease. Since the incidence rate for heart disease is about three times the mortality rate, the true number of workers exposed to ETS who "will develop heart disease" could be about three times the numbers of 7 to 16 per thousand mentioned in the text and shown in Table IV-10. Perhaps Table IV-10 should be amended to show three cases, lung cancer incidence, heart disease deaths, and heart disease incidence. The reason that the heart disease numbers are so large relative to lung cancer is that lung cancer 4mong nonsmokers is a rare disease, so even with an appreciable increase in risk from ETS exposure, the number of lung cancer deaths from ETS exposure (about 3000 for the U.S.) is small relative to the number for N 0 ~ 18 y

heart disease (about 35,000 to 50,000). However, the ETS lung cancer deaths are still enormous when compared to those from what EPA usually regulates, such as asbestos at 15 and vinyl chloride at 27". With heart disease the underlying death or incidence rate for nonsmokers is large. The death rate is about 3/0.121 or 25 time as large as for lung cancer. So when this large rate is multiplied by even a small increase in risk from ETS exposure, very large numbers result. In conclusion OSHA is to be commended fqr quantifying these workplace risks. They are real and they need to be attended to. • 19 •

Table 1. Peer reviewed papers that have assessed the available evidence on adult mortality from passive smoking and heart disease. Wells, A.J. An Estimate of Adult Mortality in the United states from Passive smoking. Environment International 14:249-265, 1988. Glantz, S.A., Parmlay, W.W. Passive Smoking and Heart Disease; Epidemiology, Physiology, circulation 83:1-12, 1991. and Biochemistry. Steenland, K. Passive Smoking and Risk of Heart Disease. Journal of the American Medical Association 267:94-99, 1992. Taylor, A.E., Johnson, D.C., Kazemi, H. Environmental Tobacco Smoke and Cardiovascular Disease; a Position Paper from the Council on Cardiopulmonary and Critical Care, American Heart Association. Circulation 86:699-702, 1992. Wells, A.J. Passive Smoking as a Cause of Heart Disease. Journal of the American College of Cardiology 24:546-554, 1994. 689v81L80Z 3

Table 3. The four important inputs in smoker misclassification bias calculations in passive smoking studies. 1. The misclassification rates for smokers who say they never smoked. 2. The prevalence of smoking among the study subjects. 3. The relative risks assumed for the misclassified smokers. 4. The degree of marriage concordance among the smokers and the nonsmokers. 5

Table 2. Examples, using five U.S. studies,of differences in smoker misclassification bias between EPA estimates and those of P.N. Lee regarding passive smoking relative risks for females. - Lee Hode1 Nells-stewart Nodel studp Lee inouts Lee inputs EPA Inputs B&,/88, = Bias &Ra/RAe = Bias RR,/BR, = Bias Fontham at al 1.32/1.18 - 1.11 1.32/1.13 - 1.16 1.29/1.28 1.01 Garfinkel 1981 1.17/1.02 - 1.14 1.17/1.02 - 1.14 1.17/1.16 1.01 Garfinkel et al 1985 1.23/1.10 - 1.12 1.23/1.08 = 1.14 1.31/1.27 1.03 Janerich et al 0.75/0.62 = 1.21 0.75/0.61 = 1.24 0.86/0.79 1.09 Correa et al 2.07/1.84 - 1.12 2.07/1.70 = 1.22 2.07/1.89 1.10 Adapted from the EPA report', Table B-2. RRo is the observed relative risk. RR, is the observed relative risk corrected for smoker misclassification. 4 069ti8L680Z 0 •

REFERENCES • i 1. Respiratory Health Effects of Passive Smoking: Lung Cancer and other Disorders. Washington, D.C., U.S. Environmental Protection Agency, 1992, EPA/600/6-90/OQ6F, pp. 6-10 to 6-26 and B-1 to B-28. 2. Department of Labor, Occupational Safety and Health Administration. Indoor Air Quality; Proposed Rule. 59 Federal Register 15968, pp. 15992-16000; April 5, 1994. 3. Wells AJ. An estimate of adult mortality in the United States from passive smoking. Environ Int 1988; 14:249-265. 4. Glantz SA, Parmley W.W. Passive smoking and heart disease; epidemiology, physiology, and biochemistry. Circulation 1991; 83:1-12. 5. Steenland K. Passive smoking and risk of heart disease. JAMA 1992; 267:94-99. 6. Taylor AE, Johnson, DC, Kazemi H. Environmental tobacco smoke and cardiovascular disease; a position paper from the Council on Cardiopulmonary and Critical Care, American Heart Association. Circulation 1992; 86: 699-702. 7. Wells AJ. Passive smoking as a cause of heart disease. J Am Coll Cardiol 1994; 24:546-554. 8. U.S. Surgeon General. The Health Consequences of Smoking: Cardiovascular Disease. A report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office on Smoking and Health,'1983:7. 9. Davis JW, Shelton L, Watanabe IS, Arnold J. Passive smoking affects endothelium and platelets. Arch Intern Med 1989; 386-389. 1 10. Davis JW, Shelton L, Zucker ML. A comparison of some acute effects of smoking and smokeless tobacca on platelets and endothelium. J. Vascular Med Biol 1990; 2:289-293. 11. Burghuber OC, Punzengruber C, Sinzinger H, Haber P, Silberbauer K. Platelet sensitivity in smokers and non- smokers. Chest 19861 90:34-38. ' 12. sinzinger H, Virgolini I. Besitzen Passivraucher ein erhohtes Thromboserisiko? Wien Klin Wochenschr 1989; 20:694-698.

13. Davis JW, Shelton L, Eigenberg DA, Hignite CE, Watanabe IS. Effects of tobacco and non-tobacco cigarette smoking on endotheliuim and platelets. Clin Pharmacol Ther 1985; 37:529-533. 0 14. National Research Council. Prudent practices for handling hazardous chemicals in laboratories. Washington, DC: National Academy Press, 1981, p. 92 15. Penn A, Chen L-C. Smuder CA., Inhalation of steady-state sidestream smoke from one cigarette promotes arteriosclerotic plaque development. Ci'rculation 1994 (in press). 16. Howard G, Szklo M, Evans G, Tell G, Eckfeldt J, Heiss G. Passive smoking and carotid artery wall thickness: the ARIC study (abstr). Circulation 1992;85:862. 17. Tribble DL, Fortmann SP. Reduced plasma ascorbic acid concentrations in women regularly exposed to environmental tobacco smoke (ETS). (abstr). Circulation 1992; 86(suppl No. 4); 1-675. 18. Helsing KJ, Sandler DP, Comstock GW, Chee E. Heart disease mortality in nonsmokers living with smokers. Am J. Epidemiol 1988; 127:915-22. 19. He Y, Lam TH, Li LS, et al. Passive smoking at work as a risk factor for coronary heart disease in Chinese women who have never smoked. Brit Med J 1994;308:380-384. 20. Lee PN. Correcting meta-analyses of the association of lung cancer in females with spouse (or household) exposure for bias due to misclassification of active'smoking status.. Report submitted to U.S. Environmental Protection Agency, dated November 29, 1991.. 21. Fontham ETH, Correa P, Wu-Williams A, et al. Lung cancer in nonsmoking women: a multicenter case-control study. Cancer Epidemiol Biomark Prev 1991; 1:35-43. 22. Fontham ETH, Correa P, Reynolds P, et al. Environmental tobacco smoke and lung cancer in nonsmoking women; a multicenter study. JAMA 1994; 271:1752-1759. 23. Sandler DP, Comstock GW, Helsing KJ, Shore DL. Deaths from all causes in nonsmokers who lived withtsmokers. Am J Public Health 1989; 79:163-7. 24. Repace JL, Lowrey AH. Risk Assessment methodologies for passive smoking-induced lung cancer. Risk Anal 1990;10:27- 37. 2