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I I I I I I I I I I I I I I COMMENTS ON CHAPTER 11 OF THE DRAFT EPA HANDBOOK ON THE EFFECTS OF ENVIRONMENTAL TOBACCO SMOKE ON THE CARDIOVASCULAR SYSTEM JAMES A. WILL, DVM, PHD I am a professor at the University of Wisconsin with appointments as a Director of an administrative unit of the Graduate School, in the Department of Veterinary Science of the College of Agricultural and Life Sciences, and in the Department of Anesthesiology in the School of Medicine. My entire research career has been focused on comparative medicine and on the cardiopulmonary system in particular. My bibliography illustrates a concentration on the physiology, pharmacology, and morphology of these organ systems. A copy of my curriculum vitae is attached. I have been asked to review "Passive Smoking and Heart Disease: Epidemiology, Physiology, and Biochemistry," by Stanton A. Glantz, Ph.D. and William W. Parmley, M.D., which is Chapter Eleven in a draft EPA compendium of technical literature on environmental tob?cco smoke (ETS). My purpose of reviewing the draft chapter is purely scientific, i.e., my concern is that the data presented are appropriately cited and that the referenced literature represents a valid, objective, and unbiased picture of the present state of knowledge of the potential effects of ETS on the cardiovascular system. The basic conclusions of my review can be summarized in two statements: (1) The validity of much of the cited literature is I

I I I I I I I I I I I I I I I I I I inherently weak and Chapter 11 often overstates the conclusions of the original authors. (2) The scientific objectivity that one would expect from a document from a regulatory agency, which should be a concise and critical review of the subject, providing both positive and negative viewpoints, is absent. I will now provide support for these statements. My remarks will focus primarily on the sections of the draft chapter under the headings "Acute Effects of ETS Exposure," "Effects on Platelets," and "The Role of Polycyclic Aromatic Hydrocarbons in ETS." I do believe it is important, however, to comment on the introductory section because the authors' introductory statements can exert an influence over the reader's interpretation of the manuscript as a whole. My initial concern is that the reader is immediately presented in the introductory paragraph of Chapter 11 with the unequivocal assertion that a cause-and-effect relationship between passive smoking and lung cancer has been "definitively" established by the ETS reports of the Surgeon General (U.S. Public Health Service 1986) and the National Academy of Sciences (NRC 1986). Neither of these documents draws that conclusion. For example, the summary statement of the National Academy of Sciences report for the chapter on lung cancer and ETS includes the following: "The weight of evidence derived from epidemiologic studies shows an association between ETS exposure of non-smokers and lung cancer, that taken as a whole, is unlikely to be due to 2

One must consider the chance or systematic bias. I I I I I I alternative explanation that this excess [34% increase in risk for spouses of smokers] either reflects bias inherent in most of the studies or that it represents a causal effect." In other words, a statistical association between ETS and lung cancer was found, but the NAS report made no finding of a causal relationship and did not conclude that the issue was settled definitively. The Glantz and Parmley statement that exposure to ETS has I I I I I I I I I now been linked to heart disease in nonsmokers is likewise premature. The 1986 NAS report states in its summary that "No statistically significant effects of ETS exposure on heart rate or blood pressure were found in healthy men, women, and school-aged children during resting conditions. During exercise, there is no difference in the cardiovascular changes for men and women between conditions of exposure to ETS and control conditions." And the 1986 Surgeon General's report states, "Further studies on the relationship between involuntary smoking and cardiovascular disease are needed in order to determine whether involuntary smoking increases the risk of cardiovascular disease." The newer publications cited in Chapter 11 do not alter the scientific validity of the conclusions by the NAS and the Surgeon General with regard to cardiovascular disease. Unless and until all criteria showing a cause and effect could be clearly and 3

I I I I I I I I I I I I I I I I I I I scientifically established, a much more cautious statement must be made if this effort by the EPA is to have any credibility. The authors should be aware and acknowledge that other scientists, expert in the disciplines of epidemiology and environmental toxicology, have considered the hypothesis that ETS is a causative agent of cardiovascular disease and completely disagree with the conclusions drawn by the authors in the opening paragraphs of Chapter 11. (See "Environmental Tobacco Smoke and Cardiovascular Disease; A Critique of the Epidemiological Literature and Recommendations for Future Research" by L. M. Wexler, and the following panel discussion published in Ecobichon and Wu (1990)). Furthermore, there are various conclusory and unsupported statements in the Chapter 11 introduction concerning the possible relationships of atherosclerosis, platelet aggregation, acute reduced exercise capacity, and carcinogenic compounds to the development of cardiovascular disease in the presence of ETS. This introduction is reminiscent of the introduction to an academic thesis where all factors that could possibly influence the outcome of the relevant studies are presented, even though most of the arguments involve more speculation than hard data. This methodology has a purpose in a thesis but has no place in a compendium that purports to present objectively the status of scientific research and an understanding of morbidity, mortality, and mechanisms. The arguments for supporting or rejecting the 4

I I various conclusions offered by Glantz will now be considered. and Parmley in Chapter 11 COMMENTS ON "ACUTE EFFECTS OF ETS EXPOSURE" I I I I I I I I I I I I I I Several statements by the authors which serve as an introduction to this section are either totally wrong or are so overstated that they cannot be supported by the current scientific evidence. The mechanism of how chronic exposure to ETS assertedly causes cancer is not demonstrated; if Glantz and Parmley feel it has been demonstrated, they must document this and provide appropriate references. The authors next imply that chronic exposure to ETS causes the development of atherosclerotic lesions. Again, this is purely speculative and has not been proven. In the sentence referring to the acute effects of ETS, the word "may" is correctly used, because the implication that there is an increase in myocardial oxygen demand somehow related to ETS is unsubstantiated. The physiological implications of insufficient oxygen are relatively well presented. It is true that the Khalfen and Klochkov (1987) paper offers no important additional information. The publication by Aronow (1978) and the follow-up study done by Sheps et al. (1987) have been critically reviewed by others, who disagree with the original authors' conclusions because of concerns about the methodology and analysis (1). And Sheps and co-workers state: "There is no clinically significant effect of 5

I I I I I I I I I I I I I I I 3.8% COHb (representing a 2.2% increase from resting values) on the cardiovascular system in this study." No conclusions can be drawn from the premature ventricular contraction data in the Aronow (1978) paper since they were only recorded in one group after exercise. Aronow did find increases in heart rate, and in systolic and diastolic blood pressure, presumably due to absorbed nicotine; these findings were compared to those of Russell and Feyerabend (1975) who quantified urine nicotine contents both from "normal exposure to tobacco smoke" in nonsmokers and from nonsmokers in a confined room with a level of 38 ppm C0. Subjects in the confined space had eight times the urinary content of nicotine of subjects in the "normal" exposure -- an indication that the exposures in the confined room studies may be vastly exaggerated. There are additional problems with these data because active smokers were also exposed to ETS in this study. If these data are to be believed, it would seem that nicotine absorption in itself was a much more likely cause of the coronary artery vasoconstriction than the proposed hypoxemia theory. The major difficulty is the lack of biological plausibility that any nonsmoker in usual conditions of exposure to ETS would have levels of urinary nicotine above a small fraction of those reported by these investigators. The cotinine data from other studies would seem to substantiate that the reported levels of nicotine were unusually 6

I I I I I I I I I I I I I I I I I I I high. If the carboxyhemoglobin and nicotine data from the volunteer smokers are used as criteria to establish a baseline, then these baseline levels of three to four times the highest levels obtained during exercise should-severely limit any activity of the test subjects when they are smoking. The other major problem comes from relatively recent studies of nicotine receptors and their possible changes in sensitivity after smoking cessation, which is temporally consistent with the timeframe during which these subjects were tested. In fact, this effect of cessation could possibly influence exercise capacity. It would seem that an experiment utilizing graded levels of carboxyhemoglobin may be necessary in order to test this hypothesis in patients who are smokers, or who were recent smokers, both during the pre- and post-smoking cessation periods. Some of these problems were addressed by McMurray et al. (1985), who found that, in the presence of ETS, exercise tolerance was decreased in healthy young women volunteers who either were or were not smokers. There were methodological weaknesses in the McMurray study that certainly could have affected the results. For example, the smoke dilution factor was unknown, and rates of smoke inhalation were vastly different between resting and exercise states when cigarettes smoked and minute ventilation are considered. The increase in carboxyhemoglobin was not excessive, however; it does not seem scientifically plausible that the increases in carboxyhemoglobin could explain the decreased work capacity. It was likely that 7

I I I I I I I I I I I I I I I I I I subjects were able to determine if they were in a smoke test group or in a control group just by the nicotine flavor, since all of the ventilation was through a mouthpiece. This does not necessarily negate the results, as the conclusions were conservatively stated; however, there were, once again, many uncontrolled variables that could have influenced the results of this study. For example, ETS had no effect on maximal heart rate in contrast to other studies. This could have been due to the fact that these subjects were healthy and not pathologically or physiologically compromised patients. Smokers did have a higher baseline heart rate and reached higher levels at submaximal exercise. The study summary limits the differences as described above, plus it incorporates concerns about the increased blood lactate and about the perceived level of exertion, all of which may or may not have an effect other than acutely. The sample size was small but the results reported were significantly different, although perhaps not biologically significant. However, it is not clear that cardiac performance was the predominant limiting factor since heart rate at the maximal level of exercise was not different with or without smoke inhalation. In summary, Glantz and Parmley presented data from a few publications that test the hypothesis that exercise capacity might be reduced by ETS exposure, and careful analysis of these publications does not support the authors' thesis that the 8

I I I I I I I I I I I I I I I I I reductions in exercise capacity are due to impingement on the cardiovascular system alone. In the Aronow (1978) paper, the methodologies and the analyses made are questionable and many variables were not properly controlled, In the McMurray paper, the observed decrease in exercise capacity seems much more likely to be influenced by oxygen transport phenomena related to skeletal muscle physiology than to any cardiovascular physiological effect of ETS. The report of Lamb (1984) would be viewed as supportive of the skeletal muscle oxygen impingement hypothesis in that the oxygen carrying capacity of the blood would be reduced to less than 90% of normal in either of these cases. No oxygen content studies were carried out in either the Aronow or McMurray studies. The study by Moskowitz (1990) et al. attempted to control for as many factors as could be evaluated. This is not an exercise study as implied by Glantz and Parmley. The publication raises many interesting questions and provokes speculation, but it does not draw conclusions that exceed the limits of the data presented, except in the abstract where the statement is made that, "Significant adverse alterations in systemic oxygen transport and lipoprotein profiles are already present" in children studied. There is not sufficient evidence to conclude that these differences are biologically meaningful, even if statistically significant in a particular segment of the population (some of the parameters were different in the boys and others in the girls). The potential explanations presented in 9

I I I I I I I I I I I I I I I A I I the discussion are plausible and perhaps even probable, but are not sufficiently demonstrated to call these alterations "significant" and "adverse." The interpretations of the data by Moskowitz et al. differ greatly from,the interpretations by Glantz and Parmley, who ascribe much more significance to these data than did the original authors. Moskowitz et al. never speculated that these children of smoking parents suffered from chronic tissue hypoxia inferred from the 2,3-DPG data. The statement in the original publication that ETS might lead to earlier atherosclerosis is extremely speculative in view of the modest differences in HDL fractions and the well-established heritability of this trait. In fact, there were significant reductions of LDL levels for the female ETS group and of cholesterol for all children; both phenomena could be indicative of a reduced risk of heart disease. No data to support the early atherogenesis theory were presented, nor would any have been expected from an acute study. It is interesting to note that paternal smoking, whether or not the mother smoked, had no effect on the parameters measured. This fact alone would seem to call into question the data collected in the epidemiologic studies on the effects of ETS on wives. Such unwarranted interpretation of data in a review such as this by Glantz and Parmley makes the entire draft manuscript suspect. Glantz and Parmley also attempt to show how ETS affects cellular function. They begin by citing a Czech publication Gvozdjakova et al. (1984) on the effect of ETS exposure on I

I I I I I I I I I I I a I I I ~ I mitochondrial function in a rabbit model. The publication states that all smoke from three cigarettes was passed into the 50 liter exposure chamber, thus implying that there is already a source of confusion because the rabbits were actually exposed to.both mainstream smoke and ETS. These two kinds of smoke display different characteristics and the effects from the mixture used in the Gvozdjakova study may be quite different from those of ETS alone. The next problem with the Gvozdjakova study is that the reported methods do not explain how many rabbits were put in the chamber at one time; this could have had a significant effect because each rabbit would increase the concentration of contaminants in the smoke by decreasing the available volume by approximately 5-6% per rabbit (2500-3000 grams/50 liter, estimating the volume of the rabbit on a weight-volume basis). Finally, exposure to this smoke mixture would result in deposition of considerable amounts of nicotine and other smoke constituents on the rabbit fur, which would then be consumed by the rabbit through licking and preening during intervals between smoking sessions. The reported carboxyhemoglobin and nicotine levels are equivalent to those in active smokers, but not to those found in ETS-exposed individuals. The experimental methods used in this study are so poorly controlled that any reference to this article by Gvozdjakova should be purged from any credible - 11 -

I I I I I I I I I I I I I I ~ I I treatise on ETS. Glantz and Parmley's use of the paper is inappropriate. COMMENTS ON "EFFECTS ON PLATELETS" The comments in the opening paragraph of this section are a greatly oversimplified presentation of the events leading to the formation of a clot or thrombus and the role of the platelet in this process. Glantz and Parmley cite three papers by Davis et al. (1985, 1986, 1989) to support their claim that ETS has a role ) in accelerating or predisposing thrombus formation and that endothelial damage may also be important. Davis has attempted to demonstrate that exposure to ETS changes the propensity of platelets to aggregate and that there is a further effect on endothelial cell survival. The 1985 paper published by Davis et al., however, is about the effects of smoking of tobacco vs non-tobacco cigarettes; no information about the effects of ETS can be gained from this paper. Two factors are clear: nicotine does not seem to influence endothelial cell damage, and there is a good chance that there was misclassification of some of the subjects in this study. The second Davis study (Davis et al. 1986) shows the non-effect of aspirin on platelet aggregation in smokers with coronary artery disease. These data differ from previous reports in healthy subjects where aspirin did inhibit aggregation. One conclusion might be that severely compromised vessels no longer I

I I I I I I I I I I I I I I I have the capability to respond to pharmacological and physiological stimuli considered to be in the "normal" range; the healthy subjects in the previous study evidently retained that capability. Only the Davis study published in 1989 involving physicians and medical students exposed to ETS in a patient lounge demonstrates that such exposures can affect the variables studied, including platelet aggregation, plasma nicotine levels, circulating endothelial cell counts, and carboxyhemoglobin levels. The most significant criticism of the Davis articles, however, is that they may not even be relevant. The data on desquamation of the endothelium are unacceptable because only anecdotal data are furnished to show that the molecular probe the authors used is specific for circulating anuclear endothelial cells. Furthermore, the platelet aggregation method they used is considered to be non-standard. It would seem, then, that the selection of these papers by Glantz and Parmley to build the case that ETS exposure is hazardous is also suspect. The paper by Burghuber et al. (1986) demonstrates that either smoking or ETS exposure may account for a decreased sensitivity of a test subject's platelets to PGI2. This follows an in vitro study which demonstrated similar findings. The primary problem with this study is that the room size is very small to contain the smoke from 30 "heavy" cigarettes. The room would be approximately 9 foot square by 8 feet high. This I

t I I I I I I I I I 1 I I I I I certainly cannot mimic realistic concentrations. No quantitative measurements of COHb or respirable air particulates were made. The platelet data appear to demonstrate that acute exposure to ETS could have deleterious effects on platelet function. While it is conceivable that these findings may be true for the chronic as well as for the acute exposure situation, none of the referenced studies, no matter how good they are, provide hard evidence that the the same effect actually occurs in individuals with chronic ETS exposure. Many things happen transiently in biology that, if projected to the chronic state, would be life threatening; but, fortunately, the body has the capability of accommodating these temporary functional alterations so that homeostasis is preserved and life is not threatened. Glantz and Parmley should be more cautious in stating that ETS exposure has significant effects on platelet aggregation without qualifying the statement with the word "acute." They apparently are not trained in pharmacology since they do not seem to be acquainted with receptor dynamics and have not quoted any relevant studies regarding nicotine receptors. It is premature, therefore, to represent these hypothetical conjectures as the state-of-research when discussing the potential effects of ETS. What should be published is a summary of these possible effects with no implications that the same situations might occur in normal" chronic ETS exposure.

I I I I I I t ~ I I I I I I I I I I Furthermore, this is an appropriate place to point out the additional work that needs to be done in order to evaluate these hypotheses adequately. The authors correctly point out that the available scientific evidence suggests'that the potential mechanisms for the possible biological activity of ETS may be quite different from primary smoking, which leads one to recognize the need to validate the reasonableness of using "cigarette equivalent" doses in attempting to extrapolate possible effects from active smoking to those of ETS. Glantz and Parmiey aiso aadress the possible roie of platelets in the development of atherosclerosis. The article by Ross (1986) in the New England Journal of Medicine is a review and, using a reviewer's privilege, he explores all possible mechanisms in a manner similar to the thesis introduction approach previously discussed. Glantz and Parmley summarize Ross's premises. This is where the paragraph should end, rather than concluding with the sentence which begins, "If platelet aggregation. . . . " The next paragraph assumes that the role of platelet aggregation has been established by stating that ETS "also" plays a role in causing damage to endothelial cells. Once again, the authors extrapolate from acute data to chronic disease processes. But it may well be that the endothelium, as well as the platelet functions, adjust to chronic exposure to ETS. It is permissible to speculate, but scientifically it is incorrect to leap from one situation to the next without sufficient evidence. I

I I I I I I I I I I I I I I I To put the processes of atherogenesis and atherosclerosis in perspective, certain well-established criteria and facts should be understood. Fatty changes occur in the arteries of all humans; fatty streaks and intimal cell masses exist in animals and people. Neither type of lesion produces occlusive vascular disease; at best, these lesions may be precursors of clinically significant lesions. Understanding this, the implications from the evidence presented by Glantz and Parmley suggest at most that there may be an increase in the number of lesions per person or in the incidence of disease; however, nothing suggests that the severity of disease may be increased. In summary, the evidence that the development of the classical atherosclerotic lesion is linked to endothelial injury is not compelling. In fact, the current evidence is probably contrary to that notion. First of all, there does not seem to be a correlation between presence of the classical lesion and a fatal clinical event. Second, no strong support is available that shows that endothelial injury plays a role in the origin of atherosclerosis. Davis' work may suggest that there is an endothelial injury with acute exposure to ETS; however, his reports do not validate the methods used, i.e., there is no validation that the molecular probe is specific for circulating anuclear endothelial cells, and the platelet aggregation technique is considered non-standard. Additionally, even if it is true that acute exposure to ETS causes an increase in circulating anuclear endothelial cells, no evidence exists to - 16 -

I I I 1 I 1 I I I I I I I I indicate that this endothelial denudation leads.to atherosclerotic lesion formation. Indeed, the available evidence may suggest that just the opposite is true. The fat-fed rabbits studied by Walker et al. (1986) showed no evidence of denudation; kinetic studies show no increased turnover of endothelial cells overlying lesions. And with regard to Glantz and Parmley's quotations regarding Fuster's work (Fuster and Chesebro 1981) with swine showing an acceleration of atherogenesis, I note that the University of North Carolina, using the same strain of swine, was unable to repeat this work. COMMENTS ON "THE ROLE OF THE POLYCYCLIC AROMATIC HYDROCARBONS IN ETS" The role of polycyclic aromatic hydrocarbons, whether carcinogenic or not, and of other carcingenic compounds in the stimulation of plaque formation is also considered by Glantz and Parmley. They correctly observe that differences between studies, and the failure of dose-dependent effects, may represent species-specific differences. They further hypothesize that compounds may have to be carcinogens in order to cause these changes; however, the data presented are not consistent with this hypothesis. The result is that we cannot assume that humans will show the same effects of exposure to these chemical agents, especially when doses and routes of administration in animal studies are entirely different. The different routes of - 17 -

I I I I I I I I I I I I I I I 1 administration in themselves may result in different modes of metabolism and detoxification. Benditt attempts to show that atherogenesis is analogous to carcinogenesis (Benditt and Benditt 1973). This part of Benditt's argument is accepted by only a few scientists. There is no compelling evidence at this time to validate Benditt's hypothesis; in fact, Benditt's laboratory, as well as other laboratories, cannot reproduce the studies of Penn (Penn et al. (1981, 1986), which attempted to show an altered transforming potential resulting in monoclonal origin of atherogenic foci. Glantz and Parmley's further biased interpretation of the Moskowitz (1990) data is not appropriate. The authors are cautioned to read the summary of Moskowitz's article once again. Moskowitz was unable to account for the decreased HDL3 in girls as well as the decreased HDL2 in boys. He made no statements that this was unequivocally due to ETS. Recall that paternal smoking had no effects. Moskowitz further stated that the lower levels of HDLs are a natural phenomenon in adolescent children. The estimates of the stages of puberty were not confirmed by physical examinations in these children. The three most important events leading to a fatal clinical event are vascular spasm, accelerated thrombogenicity, and plaque necrosis. The relationship of these processes to lipid accumulation and smooth muscle proliferation is, unfortunately, unknown. I

I I I I I I I I I I I I I I I I Finally, the Glantz and Parmley quotations from the study of Majesky et al. (1983) are incomplete and uninterpretable. Some of the conclusions of the authors may be warranted, in that PAHs may have an accelerating effect on preexisting tendencies for plaque formation. Whether this is relevant to ETS exposure, however, is unknown. COMMENTS ON THE SUMMARY The summary of Chapter 11 is characterized by an overenthusiastic representation of data and unscientific conclusions. I will not comment on the epidemiological studies in detail, but the evidence I have seen for a cause and effect relationship between ETS and cardiovascular disease in humans is not convincing. Evidence discussed by Glantz and Parmley is conflicting and inconsistent, even within a series of papers by the same group of authors. These inconsistent results are of interest in themselves in that they serve to demonstrate that the etiology of cardiovascular disease has many facets. While ETS could potentially be one facet, this has not been established. The authors should exercise more restraint and present properly substantiated evidence, both positive and negative, without interjecting their obvious biases. CONCLUSION I

I I I 1 I I I I I I I ~ I I I I 1 I Glantz and Parmley present several hypotheses as to how a variety of lesions and events may lead to an increased probability of cardiovascular disease. However, no conclusive evidence nor potent theory of mechanism is offered to show that exposure to ETS increases the risk of cardiovascular disease. Whether ETS might be shown in the future to have such effects remains to be seen. - 20 -

I 1. I I 2. 3. 4. 5. 6. 7. I 8. 9. 10. I I 11. I 12. I REFERENCES Aronow, W. (1978). Effect of passive smoking on angina pectoris. N. Engi. J. Med. 299: 21-24. Benditt, E., Benditt, J. (1973). Evidence for a monoclonal origin of human artheroscierotic plaques. Proc. Nat. Acad. Sci. 70: 1753-1756. Burghuber, 0., Punzengruber, C., Sinzinger, H., Haber, P., Silberbauer (1986). Platelet sensitivity to prostacyclin in smokers and non-smokers. Chest 90: 34-38. Davis, J., Hartman, C., Lewis, D. Jr., Shelton. L., Eigenberg, D., Hassanein, K., Hignite, C., Ruttinger, H. (1985). J. Lab. Clin. Med. 105: 479-483. Davis, J., Shelton, L., Eigenberg, D., Hignite, C., Watanabe, I. (1985). Effects of tobacco and non-tobacco cigarette smoking on endothelium and platelets. Clin. Pharmacol. Ther. 37: 529-533. Davis, J., Shelton, L., Hartman, C., Eigenberg, D., Ruttinger, H. (1986). Smoking-induced changes in endothelium and platelets are not affected by hyproxethylrutosides. Br. J. Exp. Path. 67: 765-771. Davis, J., Shelton, L., Watanabe, I., Arnold J. (1989). Passive smoking affects endothelium and platelets. Arch. Intern. Med. 149: 386-389. Ecobichon, D.J., Wu, J.M. (1990). Environmental Tobacco Smoke: Proceedings of the International Symposium at McGill University 1989. Lexington Books. Fuster, V., Chesebro, J. (1981). Antithrombotic therapy: Role of platelet-inhibitor drugs: I. Current concepts of thrombogenesis: role of platelets. Mayo Clin. Proc. 56: 102-112. Glantz, S.A., Parmley, W.W. (1990). Chapter 11: Passive Smoking and Heart Disease: Epidemiology, physiology and biochemistry. Environmental Tobacco Smoke: A Compendium of Technical Information. United States Environmental Protection Agency. Gvozdjak, J., Gvozdjakova, A., Kucharska, Bada, V. (1987). The effect of smoking on myocardial metabolism. Czech. Med. 10: 47-53. Gvozdjakova, A., Bada, V., Sany, L., Kucharska, J., Kruty, F., Bozek, et al. (1984). Smoke cardiomyopathy: Disturbance of oxidative process in myocardial mitochondria. Cardiovasc. Res. 18: 229-232.

I I I I I I I I I I I I I I I I t 13. Khalfen, E., Klochkov, V. (1987). Effect of passive smoking on physical tolerance of ischemic heart disease patients. Ter. Arkh. 59: 112-115. 14. Lamb, D. (1984). Physiology of exercise: Responses and adaptation. MacMillan Publishing.Co.: New York. 15. Majesky, M., Yang, H., Benditt, E. (1983). Carcinogenesis and artherogenesis: Differences in monoxygenase inducibility and bioactivation of benzo[a]pyrene in aortic and hepatic tissues of artherosclerosis-susceptible versus resistant pigeons. Carcinogenesis 4: 647-652. 16. McMurray, R., Hicks, J., Thompson, D. (1985). The effects of passive inhalation of cigarette smoke on exercise performance. Eur. J. Appi. Physiol. 54: 196-200. 17. Moskowitz, W., Mosteller, M., Schieken, R., Bossano, R., Hewitt, J., Bodurtha, J., Segrest, J. (1990). Lipoprotein and oxygen transport alterations in passive smoking preadolescent children: The MCV twin study. Circulation 81: 586-592. 18. National Research Council, Committee on Passive Smoking (1986). Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects National Academy Press, Washington, D.C. 19. Penn, A., Batastini, G., Soloman, J., Burns, F., Albert, R. (1981). Dose-dependent size increases of aortic lesions following chronic exposure to 7,12-dimethylbenz(a)anthracene. Cancer Res. 41: 588-592. 20. Penn, A., Garte, S., Warren, L., Nesta, D., Mindich, B. (1986). Transforming gene is human artherosclerotic plaque DNA. Proc Nat. Acad. Sci. 83: 7951-7955. 21. Ross, R. (1986). The pathology of artherosclerosis -- An update. N. Engl. J. Med. 314: 488-500. 22. Russell, M.A.H., Feyerabend, C. (1975). Blood and urinary nicotine in non-smokers. Lancet 1: 179-181. 23. Sheps, D.S., Adams, K.F. Jr., Bromberg, P.A., et al. (1987). Lack of Effect of low levels of Carboxyhemoglobin on cardiovascular function in patients with ischemic heart disease. Arch. Environ. Health., 42: 108-115. 24. U.S. Public Health Service (1983). The Health Consequences of Smoking: Cardiovascular Disease. A Re ort to the Surgeon General. DHHS(PHS) Publ . No. 84-50204. Rockville, Maryland: U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health, 384 pp.

I I I I I I I I I I I I I I I I I 25. U.S. Public Health Service (1986). The Health Consequences of Smoking: A Report to the Surgeon General. DHHS(CDC) Publ. No. 87-8398. Rockville, Maryland: U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. 26. Walker, L.N., Reidy, M.A., Bowyer, D.E. (1986). Morphology and Cell Kinetics of Fatty Streak Lesion Formation in the Hypercholesterolemic Rabbit. Am J. Pathol. 125: 450-459. I

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