Tobacco Documents Online

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