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3,1110 '97 14:48 "~+49 2203 303362 INBIF0 Koeln ~ FTR S&T 15.$ep,g¢ KHO/MWO X:\MWO\MISC\GLANKHO.DOC PAGE 1 ~004 "Secondhand c/garotte smoke affects blood platelets, in a way which increases the likelihood of a thrombus." (page 1 O) This statement refers to Davis et el. (1989) who found a statistical significant decrease for the platelet aggregate ratio before and after ETS exposure which led to 2,8 ng/ml plasma nicotine concentration and an increase of 0.4 % in the carboxyhemoglobin level. According to Davis et al "a decrease in the platelet aggregate ratio reflects an increased formation of platelet aggregates". Burghuber et el. (1986) and Sinzinger et el. (1982) exposed volunteers to 20 rain and 60 rain, respectively, in an 18-m~ room where 30 heavy brand cigarettes (Gitanes, 1.5 mg nicotine, 25 mg tar) had been smoked just p,~i~,r_~ the exposure period. They found a significantly lowered platelet sensitivity to t~e'~,~gregatory effect of prostacyclln. They concluded that "this finding at least suggests that platelets of nonsmokers passively exposed to tobacco smoke might also exhibit a higher tendency to aggregate". Corn lent: These are findings with unclear biological significance. Davis et el. (1989): "The significance of enhanced platelet aggregate formation .... in. blood after passive smoking is not known". Burghuber et el. (1986): "Further investigation is needed to elucidate whether this finding (lowered platelet sensitivity) is important with respect to a possible increased incidence of thromboembolic disease among non-smokers passively exposed to cigarette smoke." References: Davis, J.W., Shelton, L., Watanabe, I.S., Arnold, J., Passive smoking affects gndothelium and platelets, Arch Intern Med, 149, 386-389, 1989 Burghuber, O.C., Punzengruber, Ch., Sinzinger, H., Haber, P., Silberbauer, K., Platelet sensitivity to prostacyclln in smokers and non-smokers, Chest 90,1, 34-38, 1986 Sinzinger, H., Kefalides, A., Passive smoking severely decreases platelet sensitivity to antiaggregatory prostaglandines, Lancet 2, 392-398, 1982

31/10 '97 14:48 ~'+49 2203 303362 INBIFO Koeln -~- FTR S&T 15.Sep.94 KHO/MWO X:\MWO\MI$~GI.ANKHO.DOC PAGI= 2 "The platelet activation factor itseff can damage the lining of the coronary arteries and "facilitate the development of atherosclerotic lesions." (page 10) and "The toxins in the cigarette smoke increase platelet activation factor by interfering with the activity of the plasma enzyme platelet activating factor acetylhydrolase PAF-AH." (page 12) The coronary effects of PAF are described to be complex (Feuerstein et el,, 1989; Benviste et el., 1983; Kenzora et el., 1984; Levi et el., 1984; Saeki et el., 1984; Stahlet el., 1987; Piper et el., 1986; Piper st el., 1987; Feuerstein eta[., 1984; Mshta st el., 1986; Jackson st el., 1986) and include the beneficial effect of vasodilation. Direct damage by PAF to endothelial ceils is construed by disruption of endothelial Junctions and vacuolization (Humphrey et el., 1984). PAF acetylhydrolase PAF-AH may regulate PAF concentration by catalyzing PAF degradation, The inhibition of PAF-AH activity by cigarette smoke extract in a dose dependent manner was demonstrated by M[yaura et el, (1992) in an in vitro experiment. This finding is discussed by the authors as a possible explanation for the increase of PAF in the plasma of smokers (imaizumi et el.1, 1989). In athercacleroti¢ patients, however, PAF-AH activity was increased (Ostermann et el., 1987). Commer~t; The significance of the observed changes in PAF and PAF-AH actMty for atherosclerotic changes and cardiovascular disease remains to be clarified. There are no data on ETS exposure and blood levels of PAF and PAF-AH in the literature to substantiate a possible link. R_e_ferences: Feuerstein, G.Z., PAF and the cardiovascular system from Platelet activating factor and human disease ed. by P.J. Bames, C.P. Page & P.M. Hanson, Blackwel[ S¢ientlfic Publications, Oxford, 1989 Benviste, J., Boullet, C., Brink, C., Labat, C., The action of PAF-acether (platelet activating factor) on guinea pig isolated heart preparations, Br J Pharmacol, 80, 81-83, 1983 Kenzora, J.L., Perez, J.E., Bermann, S.R., Large, L., Effects of ace~ylglycerylether- phosporylcholine (platelet activating factor) on ventricular preload, afterload and contractility in dogs, J Clin Invest, 74, 1193-1203, 1984

~1110 '97 14:~9 '~+49 2203 30~62 INBIFO Koeln ~ FTR S&T 15.$ep.94 KHO/MWO X:\MWO\MISC\GLANKHO.DOC PA~315 3 ~006 Levi, R., Burke, J.A., Guo, Z.G. et el., Acetylglyceryletherphosporylcholine (AGEPC). A putative mediator of a cardiac anaphylaxis in the guinea pig, Ciro. Res. 54, 117-124, 1984 Saeki, S., Masugi, F., Ogihara, R. et el., Effects of 1-O-alkyl-acetyl-glycero-3- phosphorcholine (platelet activating factor) on cardiac function in perfused guinea pig heart, Life S¢i., 37, 325-330, 1985 Stahl, G.L., Lefer, D.J., Lefer, A.M., PAF-aether induced cardiac dysfunction in the isolated perfused guinea pig heart, Arch Pharma¢ol 336, 459, 1987 Piper, P., Stewart, A.G., Coronary vasoconstriction in the rat isolated perfused heart induced b.y platelet-activating factor is mediated by leukotriene C,, Br J Pharmacol, 881,595-605, 1986 Feuerstein, G., Boyd, L.H., Azra, D., Goldstein, R.E., Effects of platelet activating factor on coronary circulation of the domestic pig, Am J Physiol, 246, H466-H471, 1984 Mehta, J., Wargovich, T., Nichols, W.W., Biphasic effects of platetet-activating facor on coronary blood flow in the anesthetized dog, Prostaglandins Leukotdenes Med, 21, 87- 95, 1986 Jackson, C.V., Sohumacher, W.A., Kunket, S.L., Ddsoll, E.M., Pope, T.K., Lucchesi, B.P., Platelet activating factor release of a platelet-derived coronary artery vasodilator substance in the canine, Cric Res 58, 218-229, 1986 Humphrey, D.M., McManus, I_M., Hanahan, D.J., Pinckard, R.N., Morphological basis of Increased vascular permeability induced by acetyl-glyceryl ether phosphoryloholine, Lab Invest, 50, 16-25, 1984 Mlyaura, S., Eguchi, H,, Johnston, J.M., Effect of a cigarette smoke extract on themetabolism of the proinflammatory autocoid, platelet-activating factor, Circulation Research 70, 341-347, 1992 lmaizumi, T., lntravascular release of platelet-activating factor.like lipid (PAF-LL) induced by cigarette smoking, in Proceedings of the Third International Conference on PIatelet-Activating Factor and Structurally Related Alkyl Upids. Tokyo 1989, 78 Ostermann, G., Ruhllng, K., Zabel-Langhennig, R., Winkler, L., 8chlage, B., Till, U,, Plasma from atherosclerotic patients exerts an increased degradation of ptatelet- activating factor, Thromb Res 47, 279-285, 1987

.31/10 '97 14:49 ~+49 220~ ~0~62 INBIFO Koeln ~ FTR $&T 1&Sep.94 KHO/MWO X:\MWO\MISC\GLANKHO.DOC PAGE; [~007 "ET$ can increase p/ate/et aggregability to leve/s approaching those observed in smokers." (page 10) This statement refers to "several studies in which nonsmokers ar exposed to realistic levels of environmental tobacco smoke". Corresponding studies are Davis et el., 1989; Sinzinger et el., 1982; Burghuber et el., 1986, and Sinzinger et el., 1989. In those studies no explicit platelet aggregabllity, but vadous parameters suitable to characterize the activity of platelet function were measured. The platelet aggreate ratio change between pre- and post a 20-min ETS exposure pedod was measured by Davis et el. (1989) to be about 10 %. However, that result [s dominated by the data of one individual (with a platelet aggregate ratio change of about 40 %~lf that outlier is removed the remaining shift will be about 7 % and of less stati~ical significance, in this experiment the exposed subjects had plasma nicotine levels of 2.8 ng/ml. In another study (Davis et el., 1986) habitual smokers had a 17 % reduction in platelet aggregate ratio after having smoked 2 tobacco cigarettes within 20 minutes. They had plasma nicotine levels of 19.6 ng/ml, Non-smokers with the same exposure had a 11% reduction in platelet aggregate ratio and 4.1 ng/ml plasma nicotine. Comment: In relation to the plasma nicotine concentration non-smokers showed comparable platelet aggregate ratio reduction after ETS exposure and after active smoking. In this single acute exposure experiment they were about 3 times as sensitive as habitual smokers after active smoking. R.,eferenqes; Davis, J.W., She!ton, L., Watanabe, 1.S., Arnold, J., Passive smoking affects endothelium and platelets, Arch Intern Med, 149, 386-389, 1989 Burghuber, O.C., Punzengruber, Ch., Sinzinger, H., Haber, P., Silberbauer, K., Platelet sensitivity to prostacyclIn in smokers and non-smokers, Chest 90,1,34-38, 1986 Sinzinger, H., Virgolini, I., Besitzen Passivraucher sin erhShtes Thromboserisiko?, Wiener klin Wochenschrfft, 101, 20, 694-698, 1989 Davis, J.W., Shelton, L, Hartman, C.R., Eigenberg, D.A., Ruttinger, H.A., Smoking- induced changes in endothelium and platelets are not affected by hydroxyethylrutosides, Br J exp Path 67, 765-771, 1986

31/10 '97 14:~0 "~+49 2203 30~362 INBIFO Koeln ~ FTR S&T 15.Sep.9,~ KHO/MWO X:\MWO\MISC\GLANKHO,DOC PAGE 4 ~008 "Both active and passive smoking increase the aggregation of platelets and thus the likelihood of thrombus formation at myocardial infarction and, through platelet activation, they increase the chances of developing atherosclero$i@. (page 10) This statement summarizes the first passage on page 10 and refers to the findings of Pittil[o et el., 1982; Davis et el, 1989; Sinzinger et el., 1982; Burghuber et el., 1986, and Steinberg et el., 1989. C, omment: (in addition to the points already made on page 1 to 3): The postulated link of platelet activation and myocardial infarction or atherosclerosis is discussed in the cited literature in terms of a biological rationale to be clarified by future experiments, in particular there are no data in the cited literature to underline a causal relationship between ETS exposure, ptatelet activation, and myocardial infarction or R~fer.e..nces: Pi~lio, R.M., Mackle, l.J., Rowle-~, P.M., Machine, S.J., Wootf, N., Effects of cigarette smoking on the ultrastructure of rat thoracic aorta and its ability to produce prostacyolin, Thromb. Haemostas. 48, 173-176, 1982 Davis, J.W., Shelton, L., Watanabe, I.S., Arnold, J., Passive smoking affects endothel[um and platelets, Arch Intern Mad, 149, 386-389, 1989 Sinzlnger, H., Kefalides, A., Passive smoking severely decreases piatelet sensitivity to anttaggregatory prostaglandines, Lancet 2, 392-393, 1982 Burghuber, O.C., Punzengruber, Ch., Sinzinger, H., Haber, P., Silberbauer, K., Platelet sensitivity to prostacyclin in smokers and non-smokers, Chest 90,1,34-38, 1986 Sinzinger, H., Virgolini, I,, Besitzen Passivraucher ein erhShtes Thromboserisiko?, Wiener klin Wochenschrift, 101, 20, 694-698, 1989 Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., Witztum, J.L., Beyond cholesterol: Modifications of low.density lipoprotein that increase its atherogenicity, N. Engl. J. Meal. 320, 915-942, 1989

31/10 '97 14:51 "~+49 2203 303362 IIVBIFO Koeln ~ FTR S&T 15.Sep.94 KHO/MWO X:\MWO\MISC\GLANKHO.DOC PAGE 6 ~009 "Nonsmokers are much more sensitive to secondhand smoke than smokers and very low levels of ETS exposure can have major Impact on nonsmokers' p/atelet activity." (page 11) and "Dose-based extrapolations from smokers to nonsmokers using cigarette equivalents will grossly underestimate the risks to nonsmokers of breathing secondhand smoke." (page 11) These statements refer to results of Davis et el. (1985a, 1985b, 1986, 1987, 1989) and Burghuber et aL (1986). Sinzinger et el. (1989) reported effects on platelet function parameters in smokers and non-smokers after a single 60-mtn exposure in a 18-m= room, where 30 heavy brand cigarettes (Gitanes, 1.5 mg nicotine, 2.5 mg tar) had been smoked. In this situation most platelet function parameters showed a change of about one third which in non-smokers had disappeared after 6 hours. In contrast to the group of smokers, who had already pathologically shifted basal values for platelet sensitivity prior to exposure, in non- smokers the influence of a single ETS exposure on platelet sensitivity was much higher. After 5 days of repeated exposure, however, in non-smokers the basal values for platelet aggregability already were pathologically disturbed and the basal values for platelet sensitivity approached those valid for smokers. 00mment: The postulated higher sensitivity of non-smokers to ETS can only be found in the magnitude of transient changes in platelet activity and the prostaglandin system after s~ngular exposures ,of about 1 hour duration. This certainly is not relevant for any postulated health effect of chronic exposure to ET8. For these situations the data indicate that there is no difference in sensitivity and thus no reason to discard dose- based extrapolations from smokers to non-smokers with respect to the interpretation of their f~ndings Sinzinger et al. (1989) doubt that, because of possible interindividual differences of tolerance and defense capacity of the platelet function and the prostaglandin system, a direct proof of a causal relationship between adverse effects and passive smoking will ever be scientifically possible. Reference.8: Davis, J.W., Shelton, L., Eigenberg, D.A., Hignite, C,E., Watanabe, l.S., Effects of tobacco and non-tobacco cigarette smoking on endothslium and platelets, Clin Pharmacol Thor, 37, 5, .529-533, 1985 Davis, J.W., Hartman, C.R., Lewis, H.D., Shelton, L., Eigenberg, D.A., Hassanein, K.M., Hignite, C.E., Rutt~nger, H.A., Cigarette smoking - induced enhancement of p]atelet function: Lack of prevention by aspirin in men with coronary artery disease, J Lab Clin Med 105, 479-483, 1985

31/10 '97 14:el '~'+49 2203 303362 INBIFO ~oeln ~ FTR S&T 15.Sep.94 KHO/MWO X:\MWO\MISC\GLANKHO.D OC PAGE 7 ~ OlO Davis, J.W., Shelton, L. Zucker, M.L., A comparison of some acute effects of smoking and smokeless tobacco on platelets and endothellum, J Vascular Med Biol, 2, 6, 289- 293, 1990 Davis, J.W., Shelton, L., Watanabe, I.S., Arnold, J., Passive smoking affects endothel[um and platelets, Arch Intern Med, 149, 386-389, 1989 Davis, J.W., Shelton, L, Hartman, C.R., Eigenberg, D.A., Ruttinger, H.A., Smoking- induced changes in endothelium and platelets are not affected by hydroxyethylrutosides, Br J exp Path 67, 765-771, 1986 Burghuber, O.C., Punzengruber, Ch., Slnz[nger, H., Haber, P., Siiberbauer, K., Platelet sensitivity to prcstacyclin in smokers and non-smokers, Chest 90,1, 34-38, 1986 Sinzinger, H., Virgolini, I., Besitz.en Passivraucher ein erhShtes Thromboserisiko?, Wiener kiln Wochenschrift, 101, 20, 694-698, 1989

220.3 303362 INBIFO Koeln -*~ FTR $&T 1 &Sop.94- KHO/MWO X:\MWO\MISC~GLANKHO.DOC PAGE 8 Bleeding time is significantly shortened in both rabbits and rats exposed at even the lowest doses of secondhand smoke. (page i 1) This study refers to both MS, SS exposure studies with rabbits of ,Sun et al. (1994) and Zhu et al. (199,3) and with rats (Z.hu et al., 1994). In the rabbit studies in the high dose group total particulate concentrations was about 30 mg/m3 and in the low dose group 4 mg/m~, In both studies there was a statistical significant shortening of bleeding time. However, in the same studies platelet aggregate ratio did not show any statistical significant difference between exposed and control group. According to Zhu etal. (1993) "platelet aggregate ratio at week 12 in the high ETS group was borderline_ lower than the control level (p ,, 0.07). In rats exposure RSP concentration were 18 mg/mz. Also in this experiment there was a statistical significant difference in bleeding time between exposed and control groups. However, this was independent of duration of ETS exposure (Zhu et al., 1994). In this study, there was also no r.~rrelation between infarct size and bleeding time. Com.m~_ent: Even the lowest dose of 4 rag/n1~ TPM was about 80 times above the U,S, National Ambient Air Quality Standard and 40 times above EPA's claimed maximum average ETS concentration in homes and offices. The limited significance of changes in the platelet aggregate ratio makes mediation of effects via altered platelet function questionable. The finding that there is no correlation between, infarct size and bleeding time reduces the biological significances of this parameter. References: Sun, Y., Zhu, B., Sievers, R.E., Glantz, S.A., Parmley, W.W., Metoprolol does not attenuate atherosclerosis in lipid-fed rabbits exposed to environmental tobacco smoke, Circulation, 89, 2260-2265, 1994 Zhu, B., Sun, Y., Sievers, R.E., Isenberg, W.M., Glantz_, S.A., Parrnley, W.W., Passive smoking increases experimental atherosclerosis in cholesterol-fed rabbits, J Am Coil • Cardiol 21,225-232, 1993 Zhu, B., Sun, Y., Sievers, R.E., Glantz, S.A., Parmley, W.W., Wolfe, C.L., Exposure to environmental tobacco smoke increases myocardial infarct size in rats, Circulation, 89, 1282-1290, 1994