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I I I I I I ~ I PASST'VE SMOKING A.*ID `ORONARy HEART SYNDROMES . 291 by the profoundly different conditions under which they concentrations two to three orders of magnitude higher are obtained. that for typical ETS exposures, reaching COHb levels Olson (1985) reported increased ornithine decarbox- near 9% in plasma and plasma nicotine levels two to ylase activity in tracheas of rats exposed to sidestream three times higher than in average active smokers. Base- _e cigarette smoke. However, this study failed to show in- line hematologic values were substantially different creased activity in the lungs, and no erfect`whatsoever among different groups. Paradoxically, the exposure sig- was noted at the 10% sidestream smoke dose, despite nificantly reduced total plasma cholesterol. The animals considerable exposure documented by COHb levels .. were also implanted with a snare occiuder to the left an- around 6%. ...:. .terior descending coronary artery, which was eventually Because they could both inactivate and activate xeno- activated to cause left ventricle infarction. No controls biotic to electrophiles of concern, a possible pathogno- were provided to account for the obviously severe gen- monic meaning is still a matter of conjecture in regard to eral and cardiac stress. Studies in cockerels produced the active-smoking induction of such polymorphic enzy- weaker results and are even less interpretable in relative matic systems as cytosolic glutthione S-transferase, human terms {Penn and Snyder, 1993; Penn et al., 1994). P450 cytochromes for aromatic hydrocarbons and de ...O _ ne of the largest, best-planned, and rigorously con- brisoquine-aryl hydrocarbon hydroxylases (AHH) or ducted inhalation studies of cigarette smoke ever per- microsomal monooxygenases (MMO) -and the arylam- formed was a 2-year massive inhalation study sponsored ine acetylators. The interpretation of their significance and directed by the National Cancer Institute (NCI) and is further complicated by a multitude of..genetic controls the National Heart, Lung, and Blood Institute and determinants in specific phenotypes (Ketterer et al., (NHLBI). It was performed between February 1978 and 1992; Anttila et al., 1992; Bartsch et al.,,. i992;,. Caporaso March 1980 on 220 purebred beagles fed a 5% cholesterol et al., 1992; Vineis and Ronco, 1992). For instance, Gair- diet and exposed by tracheostomy to mainstream ciga- ola (1987) found thatt such induction happened in mice rette smoke variously spiked to provide excesses of nico- . and rats but not in guinea pigs, the latter actually expe- tine or CO or of both (Hazleton Laboratories America riencing a small reduction of activity; a finding con- Inc., 1980). The study was designe d. and monitored by firmed by other studies and in other animal species (Bil- a group of top experts specifically assembled by NCI- imoria et al., 1977; Lubawy and Isaac, 1980). In any NHLBI. After 2 years of exposure, the unexpected re- event, HHA-MMO activity may be necessary to both ac- - suits gave unequivocal indication that increasing levels tivate and deactivate xenobiotics, and therefore the sig- of cigarette smoke, CO, and nicotine reduced the sever- nificance of such changes remains moot. ity of atherosclerotic lesions. The final report concluded The studies by Zhu et al. (1993, 1994) are equally re- . that "jtJhese results appear more indicative of a possible markable for their lack of adverse findings. The rabbits protective effect from cigarette smoking and/or CO in- of the first study were exposed to extreme concentra- halation than of an atherogenic effect." The study could tions of what amounts to freshly d...il..ute.d. sidestream . not find incidental lesions of the respiratory system nor smoke, with particulate concentrations 100 times and significant change.s in _blood lipids among the exposed 1000 times higher than for typical ETS at the low and groups. . ... .high doses, respectively, when considering that typical Thus, the data from laboratory and animal experi- ETS particulate concentrations listed by the EPA A are ments offer no plausible argument to classify ETS as a in the order of, 30 µg/m3 (USEPA, 1992c). There were human CHD risk, they do not contradict or rather sup- _.:. conflicting effects on serum triglycerides, ch .olesterol, port the evidence of NOAELs for active smoking and and high-density lipoprotein cholesterol. Bleeding time CHD, and therefore contribute to falsify the hypothesis decreased in the treated groups, but paradoxically plate- o.f CHD risks from ETS. let aggregation and platelet count also decreased in con- ;: tioned in trol . trol animals. The at .herosclerotic changes men .: the paper actually amounted to somewhat increased lipid deposits in the arterial walls, although the study does not provide the micrographs necessary for an inde- pendent evaluation. The pathognomonic significance of such changes is unknown, given that..they were similar in unexposed control animals and that no report is given of the likely effects of the stress induced by smoke exposure. Also, the results presented and the presence of lesions in control animals must be interpreted in the context of the natural predisposition of New Zealand rabbits to atherosclerosis, especially when fed a high- cholesterol diet as in this study. The second Zhu et aL study also entailed exposures to si..d.estream .smoke_ at CONCLUSION Plausible ETS doses are thousands of time less than MS doses that appear to have no adverse CHD effects in active smokers. Such determination precludes the infer- ence that ETS is a CHD risk, unless we are prepared to forgo all we have learned since Paracelsus about phar- macodynamic and kinetic discontinuities at low doses. By far the majority of experimental reports in man or ~ animals either do not contradict or support this conclu- 0 sion and together indicate that epidemiologic studies ~ have been chasing an absent CHD effect-a conclusion ~ sustained by the generally equivocal or null reports from ~ epidemiologic studies of ETS. The instability of data ~~ I

292 .' GIO BATTA GORI t I I ~ fzom most epidemiologic. studies, the heterogeneity in let aensitivity to prostacyclin in. smokers and non-smokers. Chesc study design, data collection, and evaluation methods, 90, a4-aa precludes a metaanalysis numerical summation that is Bush. T. LandComstock,G.W.(1983).Smokingandcardiovascular scientifically justifiable. The evidence favoring the ETS- mortality in women Am• J. Ept•demiol. 118, 480-488. $utler, T. L 11988) The relationship of passive smo ing to various CHD association remains conjectural, while the evi- health outcomes among Seven Day Adventists in California. Ph.D. dence against the association is suitably documented. Dissert'atxon,tiniversitv of California, Los Angeles. According to the scientific method, the only justifiable Caporaso, N. E., $hields, P. G., Landi, M. T.. et at. (1992). The de- conclusion is that available data continue to falsify the bri5oquine metabolic phenotype and DNA-based assavs: Implica- hypothesis that ETS is a CHD risk factor. tions'of misclassification for the association of lung cancer and the ;. _ debrisoquine metabolic phenotype. Environ. Health Perspect. 98, 101-105. REFERENCES Conlan, M G.,.Folsom, A. R., Finch, A., et al. (1994). Antithrombin III: Associations with age, race, sex and cardiovascular disease risk Ames, B. N.. and Gold. L. S. (1991). Endogenous mutagens and the factors. Thromb. H.aemostasis 72, 551-556. causes of aging and cancer, Mutat. Res 250,.3 16 .. : Cress, R. D.• Holly, E. Fl„ Aston, D.A., et al. 119941: Characteristics of Angerer, -1•, Heinzow, B., and Reimann. D. O. (1992). internal women nonsmokers exposed to passive smoke. Pree. Med. 23, 40- exposure to organic substances in a municipal waste incinerator. 47. Int. Arch. Occup. Enuiron: Health 64, '165=273. Cuckle, H. S., Alberman, E., Wald, N. J., et al. 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