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CHAPTER 11: PASSIVE SMOKING AND HEART DISEASE: EPIDEMIOLOGY, PHYSIOLOGY, AND BIOCHEMISTRY CARR J. SMITH, PH.D. SENIOR SCIENTIST

CARR JOSEPH SMITH Birthdate: January 11, 1957 Married, 3 children U.S. Citizen Current January 1989 - Present Position: Senior Scientist, R. J. Reynolds Tobacco Co. December 1986 - January 1989; R & D Scientist, R. J. Reynolds Tobacco Co. September 1986 - Present Adjunct .Instructor of Pathology, University of South Alabama College of Medicine Education: B.S. Biology, Minor in Chemistry. University of South Alabama, 1978. Ph.D. Molecular Biophysics. Florida State University, 1984. Teaching Experience: Spring, 1985 and 1986. Course coordinator for "Understanding Cancer", University of South Alabama Department of Allied Health Work September 1986 - November 1986: Staff Fellow, Food Experience: and Drug Administration September 1984 - August 1986: Instructor of Pathology and Allied Health, University of South Alabama College of Medicine Publications: 1. Carr Smith, Harold E. Van Wart, and David E. Schwartz, A Quantitative Assay for the Hydrolysis of Structurally Intact Basement Membranes, Anal. Biochem., 139, p.448-458 (1984). 2. C. J. Smith, J. C. Smith, and M. C. Finn. Possible Role of Mast Cells (Allergy) in the Production of Keloid and Hypertrophic Scar, Journal of Burn Care and Rehabilitation, Vol. 8, No. 2, p. 125-131 (1987). (Cited in Skin and Allergy News, June 1987.) r

3. C. J. Smith and W. A. Gardner. Inflammation-Pro- liferation: Possible Relationships in the Prostate, Chapter 3, section 5, in Current Concepts in Prostate Cancer, ed. D. S. Coffey, N. Bruchovsky, W. A. Gardner, M. I., Resni.ck, J. P. Karr; Alan R. Liss, New Y-ork, 1987, p. 317-325. 4. C. J. Smith, A. M. Leggett, and J. J. Lefante. Allergic Etiology of Benign Fibrocystic Changes of the Breast, Medical Hypotheses, 24, p. 21-28 (1987). 5. Carr J. Smith. Effect of a Low-Fat Diet on Hormone Levels in Women with Cystic Breast Disease, Letter to the editor in JNCI, Vol. 79, No. 3, September 1987, p. 607. 6. Denys F. LeClerc, Carr J. Smith, and E. Clifford Toren, Jr. Axial Dispersion in Coiled Tubular Reactors, Analytica Chimica Acta, 194 (1987) P. 109-117. 7. E. C. Toren and C. J. Smi th. HPLC of Isoenzymes, book chaptei acc:epted for pubiica tion in 'riPLi of PY'oteins and Macromolecules, editor, Fre d Regnier. Mar cel Dekker, Inc. 8. B.S. Baliga, L.J. Sindel, C.J. Smith, L.D. Jenkins, A. Bendich, and V.N. Mankad. Chemiluminescence Response of Polymorphonuclear Leukocytes From Vitamin E Deficient Sickle Cell Patients, Nutrition Reports International, Vol. 39, No. 4, 1989, P. 761-771. Presentations (Last two years): "The Possible Role of Mast Cells (Allergy) in the Production of Keloid and Hypertrophic Scarring". Presented at Surgery Grand Rounds, November 12, 1987, to the Department of Surgery, University of North Carolina, Chapel Hill. "Development of a Human Chromosome - Intact Hepatocyte Co- Cultivation System for Assessment of Mutagenicity". Presented at the RJR Nabisco Science Forum, November 16, 1988. References: William A. Gardner, M.D. Chairman of Pathology University of South Alabama (205) 471-7790 E. Clifford Toren, Jr., Ph.D. Professor of Pathology University of South Alabama (205) 471-7321

Surrendra B. Baliga, Ph.D. Associate Professor of Pediatrics University of South Alabama (205) 471-7099

A REVIEW AND ANALYSIS OF CHAPTER 11- PASSIVE SMORING AND HEART DISEASE: EPIDEMIOLOGY, PHYSIOLOGY, AND BIOCHEMISTRY In this chapter, Stanton A. Glantz, Ph.D., and William W. Parmley, M.D., make a large number of statements concerning environmental tobacco smoke (ETS) and coronary heart disease. Many of these statements deserve comment, but the following five state- ments especially so: 1. "The action of ETS to increase platelet aggregation is another way in which ETS can acutely increase the risk of a coronary event." (page 9, paragraph 2, lines 1-2) 2. "Regardless of whether the monoclonal hypothesis proves to be true (or, more likely, one of several initiators of the atherosclerotic process), the fact is that there is clear evidence that components of ETS, in particular PAHs such as benzo(a)pyrene, initiate or accelerate the development of plaque....The PAHs in ETS are clearly implicated at epidemiological, physiological and biochemical levels in the genesis of heart disease." (page 16, paragraph 2, beginning at line 4) 3. "Exposure to ETS also increased resting heart rate and systolic and diastolic blood pressure, and resulted in a lower 1

heart rate at the onset of angina (Aronow, 1978)." (page 7, paragraph 1, lines 8-12) 4. "There are ten epidemiological studies, done in a variety of locations, which reflect a 20%-30% increase in risk of death from ischemic heart disease or myocardial infarction among nonsmokers living with smokers." (page 16, paragraph 3, lines 4-7) 5. "The combination of epidemiological studies with demonstration of physiological changes with exposure to ETS, together with biochemical evidence that elements of ETS have significant effects on the cardiovascular system, lead to the conclusion that ETS causes heart disease." (page 17, paragraph 3, lines 2-6 ) Analysis of Statement 1 This section gives the reader who is not familiar with the literature the impression that cigarette smoking is consistently associated with shortened bleeding times and enhanced platelet aggregation. The following summary illustrates that there is a significant body of recent literature (1980's) which does not suggest an association between smoking and increased platelet aggregation. This summary is by no means comprehensive as there are many additonal studies which could be discussed. 2

M.T. Kampman and G. Hornstra. No acute effect of cigarette smoking on bleeding time of habitual smokers. Thrombosis Research 51; 287- 294, 1988 (1): "To study the influence of cigarette smoking on blood platelet function, bleeding time was measured in two groups of 14 habitual smokers before and after a 20-minute period during which the subjects either smoked two cigarettes (experimental group) or rested (control group). The second bleeding time appeared to be slightly shortened upon cigarette-smoking (-0.1 min) and was found to be prolonged in the control group (+0.4 min). These changes did not differ significantly from each other (P = 0.38). Consequently, bleeding time of habitual smokers is not affected by smoking two cigarettes." R.R. Taylor et al. Whole blood platelet aggregation is not affected by cigarette smoking but is sex-related. Clinical and Experimental Pharmacology & Physiolody 14; 665-671, 1987 (2). "1. In normal subjects, 18-49 years old, the effects of the smoking habit (> 10 cigarettes/day) and the act of smoking two cigarettes over 10 min were studied on whole blood aggregation (in vitro impedance method). "2. Acute smoking (n = 10) did not affect platelet aggregation to 3

ADP, collagen or to platelet activating factor (PAF) nor thromboxane B2 production during aggregation. There was no difference between smokers (n = 13) and nonsmokers (n = 12) (ADP and collagen, P < 0.001; PAF, P < 0.01; ANOVA). "3. Although others have obtained diverse results studying platelet-rich plasma, the absence of an effect of cigarette smoking on whole blood platelet aggregation is consistent with many of those observations. Greater in vitro aggregability in females than males is consistent with the few studies of platelet-rich plasma. It seems unlikely that the role of cigarette smoking as a risk factor for ischaemic heart disease is related to a direct effect on platelet aggregability." Matti Hillbom et al. Platelet thromboxane formation and bleeding time is influenced by ethanol withdrawal but not by cigarette smoking. Thrombosis and Haemostasis 53(3); 419-422, 1985 (3): "Platelet count, mean volume, aggregation and associated thromboxane (TXB2) formation, circulating platelet aggregates and bleeding time were examined in 19 noncirrhotic male alcoholic cigarette smokers for four weeks following cessation of prolonged heavy drinking, and in 24 nonalcoholic healthy male volunteers (10 smokers and 14 nonsmokers). The alcoholics showed a 9-fold increase (p < 0.001) in ADP-stimulated platelet thromboxane formation one to two weeks after ethanol withdrawal. The effect 4

was transient and coincided with a significant (p < 0.01) shortening of skin bleeding time and a slight increase in circulating platelet aggregates suggesting proneness to thrombosis. No differences were seen between the smoking and nonsmoking healthy volunteers. We conclude that the recovery phase after prolonged heavy drinking is characterized by a transient increase in platelet reactivity which may lead to increased spontaneous formation of circulating platelet aggregates and shortening of bleeding time." T.W. Mead et al. Epidemiological characteristics of platelet aggrega.-_~i i +-~y... nL ~.. a~..;~1--0~.7~. MeAinal .Tn~4rnal ?9f12 79f~5 (4)S ~~ ~ l.L .-.~~..~~ . .,- "The epidemiological characteristics of platelet aggregability were established in 958 participants in the Northwick Park Heart Study. The main analyses were based on the dose of adenosine diphosphate at which primary aggregation occurred at half its maximum velocity. Aggregability increased with age in both sexes, was greater in whites than blacks (particularly among men) and tended to decrease with the level of habitual alcohol consumption. Aggregability was, however, greater in women than men and in nonsmokers than smokers. There was no relation betwen aggregability on the one hand and obesity, current or past oral contraceptive use, menopausal state, or blood cholesterol and triglyceride concentrations on the other. Aggregability was somewhat, though not significantly, higher in men with a history of ischaemic heart disease and in those with electrocardiographic evidence of ischaemia than in those without. 5

There was a strong association between the plasma fibrinogen concentration and aggregability." R.F. Davis and J.W. Davis. The effect of smoking on the stressed template bleeding time: Annals of Clinical Research 15; 131-133, 1983 (5). "Tobacco cigarette smoking is known to affect platelet function. The purpose of this study was to determine whether cigarette smoking acutely shortens the bleeding time of healthy men. The mean initial stressed template bleeding time of 10 nonsmokers (9.0 minutes) was not significantly different from that of nine habitual smokers (9.2 minutes) who were asked to abstain from smoking for 12 hours before determination of the bleeding time. The mean bleeding time was the same immediately before and after the 21 men smoked two filtered tobaccco cigarettes in 20 minutes. Separate analyses showed that the mean bleeding time of neither the nonsmokers nor the habitual smokers changed significantly after experimental smoking. We conclude that smoking two cigarettes has no effect on the stressed template bleeding time of healthy men." Analysis of Statement 2 The contention that the extremely low levels of chemical compounds found in ETS are atherogenic is not supported by evidence 6