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diseases. TESTS sig/total 0/1 1/3 0/10 0/30 2/17 24/47 10/22 1/5 0/24, 2/12 -ated in Table - comparisons ed in different =ome will be .ble 3, :hOughL to be n exposure to epid'emiologi- for cardiovas- and'the extent 'Table 3). Assessment of the Toxic Effects of Combusnon Products, Table 3]vfissing evidence (potential confounding variables) in the positive epid'emiological studies STL'DY Obesitv I Hypenension Alcohol I Fatty Diet HIRAY;tiMP. [1011 NO NO YES I NO SVENDSEN 111] YES YHS YES YES HE [8] YES YES YES YES HELSING [7] NO NO I NO NO HOLE [9) YE.S YES NO YES DOBSON 1161 NO NO: NO NO. In no study was the following controlled'foc diabetes. exercise and menopausal'status in women. Family history ofi cardiovascular disease was not controlled for, except in the study by He et al [81. The Svendsen ~ et a1 study ll i l was the onN., one to employ a marker to detect smoking behaviour. Table 4 The best established cardiovascular risk factors RISK FACTOR SELECTED REFERENCES Family history of disease [18, 19, 201 Hypertension [21, 22] Cigarette smoking 117, 221 Dieery fat load 122. 2311 Diabetes 11811 Lack of exercise 124;,251 Menopausal status [18, 26, 27) Al'cohol consumption, l4) Obesity 128] From table 3 it is apparent that the epiderniological studies are not all of the same standard. Perhaps the best designed! study was that performed by Svendsen et al (11]. This was the only study that attempted to confirm the exposure to ETS by measuring a marker of exposure (serum thiocyanate concentration). The potential confounders of hypertension, bod'y weight, dietary fat intake and alcohol consumption were all controlled for, but the population selected for study was atypical. The subjects were from the 15% of the U.S. population thought to be at greatest risk from cardiovascul.ar disease. The cardiovascular disease risk factors considered to be important in this study were high blood pressure, cigarette smoking and high blood cholesterol levels, and those most at risk possessedtwo of the three risk factors. When it came to any effect of ETS, this was measured' in non-smokers by the spousal smoking 281 ® M 9 19M e ® a m

Nam Y ~ 9 MM Assessment of rhe Toxic Effects of Combustion Products status method. Thus all ETS exposed subjects must have been both hypenensive and had high blood cholesterol levels. H'owever„3 rea11y important cardiovas- cular disease risk factors (family history of cardiovascular disease, glucose tolerance and'whether or not the subjects exercised) were not controlled for. The final point thar: needs to be made from this welld designed study was that exposure to ETS was not'associated with possession of a cardiovascular disease in a statistically significant manner: the significant result that qualifies it for examina_ don in Table 3 was between surrogate exposure to ETS and death from all causes,. The ra ostudies that provided the highest proportion of statisvcally significant associations between ETS exposure and~death from cardiovascular disease were by Helsing and others f71 and by He et al [6]. The study by Helsinget al was the least well controlled of all the studies considered here. There was no attempt to confirm exposure to: tobacco smoke (either from ETS or undisclosed~ smoking). No information was reponed about blood pressure, bod'}7 weight, dietary fat intake, alcohol consumption, familv history of cardiovascular disease„ glucose tolerance, exercise, and menopausal status of the female subjects. In fact this study is best considered to be a linkins,of death certificate information to the response to a self-administered questionnaire: When one considers the absence of control over potential confound'ers, no reliance can be placed on the findings. The case-control study from. China [811 has only been~ published in Chinese; but the 34 female coronary hearr disease patients were shown to be at risk from spousall smoking (OR = 3.52, confidence limits, P' = 0.05, 1.26 - 7.17). This remarkable level ofl risk greatly exceeds many estimates of the direcr effects of' smoking (9, 1711 The effects of potential confounding influences was assessed in a multivariate logistical regressionanahysis, where it was shown that the effects of surrogate exposure to ETS persisted when the following risk factors were controlled for;: previous history of hypertension, family history of hypertension, family history of coronary heart disease, history of passive smoking, amount of' exercise, and previous history of hyper-cholesterolaemia. However, this study on a!small group of only 34 patients needs to be extended, evidence of the effects of direct smoking d'etermined, and evidence of difference in diet between the cases and controls added. The quality of the other studies considered here lie between those of' Svendsen et 21 and Helsing etal. All are poorlytontrolled. A study of appropriate standard and size has not yet been performed, so it is not yet possible to decide whether or northere is an association between exposure to ETS and cardiovas- cular disease. The fundamental problems in study design consist of: a: the selection of the exposed' and control groups,, b: the exact classification,of disease; and c: the exercise of adequate control over the numerous potential confounding variables, h9uch, the same difficuln• arises withi anu attempts to examine the ® possible associauor. Table 5 To progrc medicall c taken. T criteria. The associauom, less than 3 1291 The effi:at shou There should t more cases tha: All the evidene tn vinually all cases, d the more persuasive 3 If one were a', cornbustion.produ, the case-controll st cause the diseasee causes the conditi properves of an causation can be amongst epidemic all cases, there is ry outcorne is causec WurcentJH Th: "n Occ1y1+ H Hill AB A Shc Hill RB, Ander~ 195E 1.2941

M Assessment of'trye Toxic Effects of'Gomba.estion Products n hypertensive ant cardiovas- sease, glucose :rolled for. The ; that exposure 3r disease in a it for examiraa- from all causes. ;allv significant ar disease were -1g et al was the was no attempt or undisclose6 _, body weight, ascular disease, subjects. In fact = information ~ to e considers the )e placed on the h iil Chinese„ ): nisk from -'6 - 7.17). This direct effects of es was assessed 'n that the effects -isk factors were of hypertension, )king, amount of vever, this study ~nce of the effects diet between the °tween those of dy of appropriate )ossible to decide i S and cardiovas- ,nsist of: possible association between combustion products and common diseases. Table 5 To progress from the associatzon~ of an environmental factor with a medical outcome to establishing causaliry, several' steps have to be taken. The whole of the evidence should conform to the following criteria. 1. The association should be strong enough to be persuasive: it is seldom the case a•ith RR less than 3 129); 3' There should be consistency of findings between diffuent studies. 3: The effect should be specific, or as near to this as possimle, with the exposed group. 4. The temporal! relationship with respect to exposure should be appropnate to the pat.hologrcal sequence oflthe disease. 5. There should be a dose-response relationship„whereby, the greater exposures result in more cases than occurs in the less exposed group of individuals. 6: There should be a'freedom from implausibility" with respecrto biological mechansms. ',:. All the evidence should be coherent and poinutoa-ards one concilrsion,. In virtually all cases, the full set of cnteria are not fulfilled, burithe nearer one is to achieving this,, the more persuasive is the argument, (Adaptedlfrom I21i) If one were able to show a statistically significant, association betweenn combusdonproducts anddisease inan epidemiologicalstnldy, as is the case with, the case-control study from China [$J', it is still! not evidence that the products cause the disease. Association is only association: to conclude that exposure causes the condition, further steps are needed. Table 5 indicates some of the properties of an association that would have to be demonstrated before causation cam be concluded. It should! be noted that there is much debate amongst epidemiologists as to the exact criteria for taking this further step. In all cases, there is an element of' subjectivity in reaching the decision that the outcome is causedl bv the infVuence studied. REFEREI\ C:l;.S M a © ntial confounding s to examine the 1. Vincent7H`.Thefateofinhaledaerosols:areviewoflobservedtrendsandsomegeneralizatioris: Ann Occun Hy 1996,34(6)`.623-637: 2. Hill AB: A Short Textbook of Medical I Statistics. London: Edward Arnold, 1984. 3. Hill RB. Anderson RE:-Rte Autopsy-Medical Practice and Public Policy. Boston: Butterworths, 196B:1-294. 283 a

Assessment of the Toxic Effects of Combustio1l Products 4: Hopkins Pr; Willianss RR: A survey of 246 sugge-sted'coronary+ risk:factors., h,r r 1981;40;1-52. 5. McCotTnick J, Skrabanek P: Coronary, heart disease is not preventable byy populauon interventions. Lancet 1988;3-839-841. 6. Glantz SA, Patmley )X'W: Passive smoking and heart disease: epidemiology„physiology, and biochemistry,. Circulation 1991;83:1-12: 7. Helsing I€J, Sandier, Comstocl: Gu'', Chee E: Hean disease mortality in nonsmokers livtng o,.itb smokers. Amencan loumal of Epidemioloev 1988;127c915-9Z2. 8: He Y, Li L, Wan Z, Li L, Zheng )C, Jia G. Passive smoking and coronary hean disease in wome~ China loumal of Preventive Medicine 1989;23;19-22. 9. Hole DJ, Gillis CR, Chopn C, Hawthome VM: Passive smoking and tardiorespirntory liealth in a general population in the west of Scotland. Br Med 1 1989:299,423-427. 10, Hirayarrta T:,Lung cancer in Japaa: effects of nutnuon and passive smoking. in: Mizell lL Coaea P ed. Lung cancer: Causes and Prevenuon. New York: Veriag Chemie lntemauortaL 1984: 175-195. 11. Svendsen L'Ii„Kuller LH, Martin MJ, Ockene JH: Effects of passive smoking in:ttie multiple risk factor intervention tnal. pmerican: loumal of Er?idemiolqM~ 1987;126:783-795. 12. Bualer •P: The relationship of passwe smoking to various health ~outcomes among Seventh- Day ttdven[ists in California. VII World Conference on Tobacco and Health 1990,316:(Absuaq). 13. Garland C„Barren-Connor E, Suarez L, Criqui MH, Wingard DL Effeots of passive smoking on ischemic heart disease mortality of nonsmokers: a prospecuve study. Am 1 Fnideminl 1985:121:645-650. 14. Humble C„Croft J', Gerber A.,Casper M, Hames CG: Tyroler HA: Passive smoking and 20-year cardiovascular disease mortality among nonsmoking wives, Evans County, Georgia. Amenca n, loumal of'Public Health, 1990;80:~599-601. 15. Lee P, Chaatberiain J, Ald'erson M: Relationship of passivc smoking to risk of lung cancer and other smoking-associated diseases. $ntish loumal of'Cancer 1986;54:97-105. 16. , Dobson A), Alexander HM! Heller RF, Lloy,d DM: Passive smoking and the risk of heart attack or coronary death. n at I991;154:793-797. 17. Weintraub WS: Cigarette smoking as a risk factor for coronary artery disease. In: Diana JI< ed. Tobacco Smoking and Atherosclerosis. Pathogenesis and Cellular Mechanisms. Nea• York: Plenum Press, 1990: 27, 37. 16. Lemer D, I+annel W: Patterns of coronary hean disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. American Hear ioumal 1956t111:383-390 19. O'Connor GT, Buring JE, Moore LL, Goldhaber SZ, Stampfer MJ, Willen WC, Hennekens CH:. Familv history of premature myocardial infarcuon and the risk of nonfatel myocardial infarcuon. Am I Epidemiol 1988:126(4):916, 20. Slack J, Evans h1t: The increased risk of death from ischaemic heart disease in first degree relatives of'121 men and 96 women with ischaemic hean disease. I Med'Genetica 19663:239-257:. 21. Nora JJ, Lonscher RH„Spangler RD, Nora AH, Kimberling u7; Geneuc-epidenvologic study of earlv.onset ischaemic heart disease. Circulanon 198Q,61:503-506. 22: Pekkanen J, Nusinen A, Puska P, Punsar S• I:arvonen MJ: Risk factors and 25 year risk of coronary , hean disease in a male population with a high incidence of the disease: the Firtnish cohorts of the seven countnes study. r, M 1989s299:81-85: 23. MacmahonS,PetoR,,CuderJ,CollinsR,SorlieP,NeatonJlAbbottR,GodR•inJ,DyerA,Stamler J: Blood pressure, stroke, and coronary heart disease. Pan 1, prolongcd difference in blood pressure:, prospective obsennuonal studies corrected for regression dilution bias. LIncei 1940;335`.765-774: 24. Morris JN, Everiit MG, PollardR, Chave SPW: Vigorous exercise in liesure time: protection agarrsst coronary heart disease. Lancet 1960:2:1207-1210:, 25. Morns )N;,Cla}ton DG, Eventt,MGi Semmence Ahil Burgess EH: Exercise in liessure time: coronary attack and death dates. Br Heart l 1990;63325-334.. 284 26. Karinel WB. Framinghan 27. Eaker ED; Pz Am li Cardi, . 28'Hopkuu P,\ Cardiol' Clln 29, Wynd'erEL Mtd 1987:1 :

0 risk faetors. Atherosclerosis preventablt by population idemiology; physiologyand' ry in nonsmokers living with .ary hean disease in women. and rudiorespintory health .299:423-427: sive smoking. In: Mizel] Mi, eriag Chemie intetnationalJ ve smoking in the multiple 1987:126:753-79>. outcomes among 5eventh- i Health 1990;316:(Absuact): fiffects of passive smoking ive study. Am I Enidemiol assive smoking and 20-year County, Georgia. *rt+erican i ) ofJung cancer and y¢, ,-105. and the risk oftiean attack -ry disease. In: Diana JN ed ir Mechanisms. New YO& and morraliry in the sexes: irt Iournal 1986;111:3833390. uillett WC, Hennekens GK ;k of nonfatel! myocardial can disease in first degree .l.ri1956:3:239•257. :netic-epidemiologic study 16. aaors and 25 year risk of' of the disease: the Firmisb God,bvin J, pyer A, 5t2ralcr onged difference in blood sion dilution bias. LUIW :n liesure time: protecuon Exercise in hessure tiID~ M Assessment of the Toxic Effects of Combustion Products 26. Kannel WB: Metabolic risk factors for coronary heart disease in women: perspective from the Framingham study: Am Hean I 1987;114(2):413-419. 27. Eaker ED, Packard B, WengerK, Clarkson TB, Tyroler HA: Coronary artery disease in women. Am I Cardiol 1988:61:641:~644:. 28. Hopkins PN, Witlisms RRldenaficuion and relative weight of cardiovascvlar risk factors. Cardiol lini c 1986:4:3•31. 29. Wynder El: Workshop on guidlines to the epidemiology of weak associations. Preventive !kd 1987;16:139-141L 285 I I

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