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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 -