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EA.uowwrwr kurwar.owal, YaL 16. pp: t7S-193; 1990 Prumad m tbe l'S.A. AL r&hu e..erv.d A.W. l2),~{ ~75-179.1`~`liL LETTERS TO THE EDITOR AN ESTIMATE OF ADULT MORTALiTY IN THE UNITED STATES FROM PASSIVE SMOKING; A RESPONSE Dear Edi'tor- The health implicatintts of environmental tobacco smoke (ETS) remain controversial. Neither the pub- lished reporu nor statements from public health of- ficials and agencies have resolved the question of ETS health effects, nor are they likely to in the near future.. A. Judson Wells' paper, 'Estitnate of Adult Mor- tality in the United States from Passive Smoking" (1988) is yet another effort to draw scientific verity from a reassessment of published' epidemiological data. But this new look does not change the quality or meaning of the existing evidence, which remains equivocal. Neither does it substantively support the author's statement that exposure to ETS 'can have adverse long term health effects that are more serious than previously thought'. The conclusions of nonsmokers' increased risk of lung cancer from ETS exposure found in the reports of the National Academy of Sciences (NRC 1986) and of the Surgeon General (USSG 1986) were based on epidemiological studies-tbatproduced a wide range of findings. The relative risk (RR) values summa- rized in Table 12.4 of the NAS report ranged from 0.50 to 3.25, with 17 out of 20 risk estimates (for subgroups by sex) lacking statistical significance. In seven additional reports since the NAS docu- ment was published, relative risk values ranged from 'c1.00' to 1.65, with only the latter being ststisu- caIly signifitant. The RR values from aTl 29 sub- groups in the 20 studies included in the NAS repon plus those published later are summarized in Table 1 herein. All of the epidemiological studies that comprise the data base for estimating nonsmokers"rislt of lung cancer in relation to ETS are actually estimates of association based on spousal smoking. Im not a single study was either exposure to ETS or retained dosage determined. A few studies have attempted' to estimate OItD-4 1aY90sJ00 •DO Coqynght 01990 Pcrsamm Prsar pIc pQTiCL rMq fhAtstial tr.ay 66 ~Ww ~ c°eyrrgnt yprr (1o~ U U.S CoCel, the degree of exposure to spousal smoking in terms of hours per day or total years of exposure, but none of the studies measured ETS exposure in objective and quantitative terms or even estimated ETS expo- sure with any degree of reliability. Proximity to a smoker sittiag across the dining table does notpermit an estimate of the nonsmoker's exposure to ETS, which will vary according to room volume, ventila- tion rates, the physical and chemical changes in ETS as it ages., and other factois that influence the con- centrations and duration of ETS exposure. A spouse's smoking in another room or in another building can have even less or no significance at a1J, in assessing the possible role of passive smoking on a subject's health. It should be reeognized, also, that association can never, establish causality. At best, association can only suggest the possibility of causality. Feinsteifl (1988), discussing public alarms based on epidemio- logieal studies, recently pointed ouc<hat'a causal suspicion is supported if aM impressive statistical'. association appears in the 2 by 2 tabulition for sub- groups of people reported as being exposed or non- exposed, diseased or nondiseased'. There are many ways to look at data and try to draw meaning from the aggTegation of values. After deciding that the 13 studies which survi~ved critical assessment did not, individually or collectively, tup- porta definitive conclusion on the risk of lung cancer in relation to spousal smoking, the NAS Committee performed a meta analysis on the aggregated' dau, leading to an estimated risk increase of about 34% for nonsmokers married to smokers. This estimate has been questioned on a variety of grounds by a number of investigators (Letzel et al. 1988). It can be argued that even if a first order relation- ship does notexistbetween diseue and passive smok- ing in the epidemioCogical studies, the data used by Wells are the best evidence available. And it can be argued tbat even the array of values shown in Table 1 is not impressive in the sense that Feinstein specifies, there are other ways of testing the data, as has been done by Wells. 173

176 Letien to :De .dita+ Table 1. Statietieal sianificence of risk valaes for lung eaecer in ralatiaa to spomal smoking. lnMesticatcr Not Statistically SiGniflcint Ststistically tiQ:_:.ilc__3 nt Male Feaale Y.al e Eeaale , •Chan and Funq (1982) 0.75 •8uffler et al. (1984) 0.50 0.78 DalaqEr et al. (1986) (1.00 *Kabat and Yyndrr (1984) 1.00 0.79 Gao et al. (1987) 0.9 • =Gillis et al. (1984) 1.00 •Lee et all. (1986) 1.00 Gao et aL. (1987) 1.1 • Shifiizu et al. (1988) 1.1 •Gartinkell (1981) 1.17e •Pershaqen et al. (1987) 1.20 Yu at al. (1985): 1.20 •Lee at al., (1986) 1.30 •Garfinkel, et al. (1985) 1.31e •Akiba at al. (1986) 1.80 1.50 •Koo at all. (1984) 1.64 Drovnscn et al., (1987) 1.68 Sunble et al. (1987) >1.80 1.80 •Correa et al. (1983) 2.00 2.07e •Hirayiea (19811) 2.=5 1.63 Las at al. (1987) 1.65 •Tri:hopoulos et al. (1981) 2.11 •Gilllis et al. (1984) 3.25 • Risk valuu from Table 12.4, Naa;onal Academy of Scieaoes Report (1996) a E:posuss in aduli life. b Exposure is childhood. c Sutistically ai8nificant aseda is aoe or more data sobasta witlie the study. There remains, however, the fundamental question of the quality of the individual underlying studies whose data are under consideration. Many of the epidemiological studies assessing the risk of lung cancer from spousal smoking have been criticized for a variety of methodological flaws and weaknesses, especially with regard to the potential for misclassi- fication (Oberla 1987; Batter et al. 1986; Lebowitz 1986; OTA 1986)6 Misclassification of subjects is a source of error where patienu claiming to be never smokers are in fact current or exsmokers. Wells conceded the likeli- hood of 5% misclassi6cation. But misclassification of smoker status has been found at levels from 10% to 40% (Schwartz et ai. 1988; Weiss 1988). NAS noted the likelihood of misclassification and lowered iu estimate of the elevated risk to 25% from 349,, but it failed to indicate whether the lower value was statistical]y significant. (NAS found the combined risk from American studies a 14% increase, which was not statistically significant.) Misclassification of disease can also be a source of error. There was a marked potenciaP for misclassi- fied disease in the studies having statistitally signif- icant risk ratios in the NAS and Surgeom General's reports. In Hirayama'e study of Japanese women, his 1984 report suggests that only 21 of the 200 lung cancer cases (10:3%) were histologically confirmed, while tlfe Surgeon Gsneral's report states that'none' were verified. Akiba et al. (1986) studying survivors of the Hiroshima and Nagasalti atom bombings, noted 43% of the lung cancer cases had not been histolog- ically confirmed. Weiss (1988) notes that 'thirteen percent of the cases (in Garfinkel's study), proved on review not to involve lung cancer'. 202 33 511884

Lattsn to tbe editor Misclassifrcation of exposure can be a source of uncertainty in studies that attempt to find exposure- response relationships. There is little basis for con- sidering estimates of spouses'smoking to be reliable. Pron et al. (1988) concluded that "test-retest esti- mates of reliability [over a six-month time span] would suggest that misclassification of such expo- sures may be extensive". Vogt (1977) found"twenty- two percent of persons gave differenranswers on the two questionnaires (on the number of cigarettes smoked per day] given about an hour apart". Among the variety of flaws and weaknesses found in the various epidemiological' studies on ETS and lung cancer, it is worth noting the age bias found by Ahlborn an&Uberla (1988) in Hirayama's study and their conclusion that "the risk increase ... disappears completely when one removes selection bias by age'. Oberla (1987), highlighting the weaknesses of the epidemiological studies comprising the NAS data base, bad earlier concluded, `False plus false does not: equal trite.` In addition, most of the epidemiological studies have fai9ed'to take into account significant confound- ing factors in assessing lnng cancer risk in relation to ETS. Many risk factors for lung cancer have been identified, including exposure to heavy metals, or- ganic chemicals, combustion by-products, natural and man-made radiation, diet, and nutritional status, per- sonal health history, emotional, and psychological factors. Holst et al. (1988)' recently reported signifi- cantly inereased' risk in relation to keeping pet birds and to reduced vitamin C intake. Gao et al. (1987) found no significant increased risk for Chinese women in relation to passive smoking or type of employment but did rind significantly increased risk in relation to previous lung disease, cooking practices„and shorter menstrual cycles, reflecting hormonal factors. Some of these factors may act independently, but many may interact. Any attempt to assess the role of one factor must take into account all other relevant factors. None of the epidemiological studies on spousal smoking took into account confounding factors other than attempting to matcb cases with controls by age,, residence, and general socio-economic status. Of the 20 epidemiological: studies, those by Huayama and by Lam et al. (1987) have the two largest number of lung cancer cases, with the increased risk in both being statistically significant_ Both studies are of Oriental populations, which suggests that many fac- tors like cooking practices and fuels for cooking and heating should have been controlled. All of the studies included in Wells' Table 4, on which he based his estimate of heart disease deaths related to passive smoking, similarly fail to consider the confounding effect ofthe many cardiovascular disease risk factors that have already been estab- lished for thatdisease. Some observers have commented that increased~ risk of lung cancer from ETS exposure seems implau- sible because the ETS components are so dilute in ambient air comparet to the concentrations of these substances in mainstream smoke. In addition, it has been found that nonsmokers retain far less of inhaled ETS than active smokers retain of mainstream smoke. Wells noted that'smoke retention by a passive smoker is only about U/4Xthat retained by a direct smoker in a 16 hour day'. This ia more than one order of magni- tude;reater than Rickert's calculation (1988 ) thatnon- smokers exposed to ETS retain about 1/8000 the amount of particulate matter retained by the active smoker. Lee (1988) cited estimates of the same range: 1/5000 for males, 1/10 000 for females. All of these estimates are probably on the high side, since none of the studies appears to have considered the chemi- cal and physical changes that occur as ETS ages and the losses of ETS through evaporation, fallout, and deposition over time. Other observers have commented on the implausi- bility that lung cancer in nonsmokers might be caused by ETS. Aviado (1988) noted thatn.one of 17 constit- uents of ETS 'designated as suspect carcinogens ... [has] been adequately shown to cause pulmonary cancer via inhalation in animals'. Crawford (1988) noted that 'no atypical cellular changes have been found in the lungs of nonsmokers'. Lee (1987) con- eluded 'that exposure to smoke conatituents of non- smokers is too low to explain the moderate increase in risk of lung cancer seen in epidemiological studies in self-reported never smokers masricd~ to smokers.. This increase in risk is much more plausibly ex- plained by misclassification of smokers as nonsmok- ers thanm by a direct effect of passive smoking'. Wells has attempted to make his calculation of annual deaths from exposure to ETS appear more reasonable by comparing it to the larger estimate of Repace and Lowrey, but their estimate has been se- verely criticized because the controls were Seventh Day Adventists (SDA) whose life style is so radically different from that of the non-SDAs married to smok- ers that the comparison is considered inappropriate (OTA 1985; Balter et al. 1986; Oberla 1987). Taking these and other factors into account. Gostomzyk (1986) concluded, following the Interna- tional Experimental Toxicology Symposium on Pas- sive Smoking in Essen,,FRG, that 'even toxicology has not been able to ascertain with any greater degree

171 of probability thsn did' epidemiology that there exisu a link between damage to bealtb and pusive smok• inQ'. Perhaps it is the rveitbrof these facts, interpreta- tions, and opinions that caused no less ao antbority tRan the American Cancer Society to assert last year that 'tAe currently available evidence is not :atG- cient to conclude that passive of involantary smokin8 causes lung cancer in noosmokers..' (ACS 1988). A final comment: both the title and the contsnt of the editoriall tlsat accompanied the Wellrt paper sn=- =ests tlsat the paper provides stronjer evidence of risk of cardiovascalar disease (EVD) for nonsmokers married to smokers than the paper in fact offers. In 1986, both the NAS and USSO reports noted the lack of convincing evidence of siWicant CVD risk from ETS exposure. More recentir, Fielding and Pbenor (1988) commented on papers reporting an associa- tion between ETS exposure and CV?) risk, conelod'- iaj tbst 'na fil3a-concitaioa 'bst a saasil re1 3tion exists is yet M arnnaed'. Wells' calcuLuiona with respect to CVD a3+e based on data from tpidemiolotical studies that ba.e the same weaknesses as the 1'on= cancer studies. There is, thns, no buis for =reater confidence in his essti- mate of bezrt disease deaths la relation to ETS tdan his estimate of lung cancer destiss. It is commendable thu tbose who ue not aatisfled contiaoe to seek more meaninj from the data. Bnt in an issue as serious as this, it is important to note when the data fail to meet the sundards for scientific in- ference. Alan W. Latresstei. L.tse>atein Associates Luclmost, tiY 10538 REFERENCES AAlbc*s, wL; Cb.ds, L Pusfw aelfms asd lai ea•er. r.aaalyw of Hlrq...'s dri Is: Arry, L; [tit. L M., or. Iadooi ad amhi.u alr pdiry. 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t Lenen to the editor 179 Pron, C. E.; Burch. J. D.; Hos, C.R.; Miller. A.B. Tbe reliability of patetve emoking hiiwriee reported in s eaee-eontrol etody of lung cancer. Amer. J. Epidemiol. 127:267-273; 1999. Repace, J. L; Lowrey, A. H. A qoaautsove eseimateof sonamokm" lung cancer ritk from pusivs amokins. Ea.zras. IsL 11: 3-22; 1915. Ricken, W. S. Some eoneidentione .hen eatimatin{ espoeure to eovironmentalitobacco emoke (ETS) rith panicular refercnee to the home environment. Can. 1. Public Hsalth 71:S33-S39; 1939. Schwaru, S. L; Balur, N. J. ETS-lssg eaaar epidemiology: aupportability of miaclarei8cant and riak aewmptiooa.ln! PerrY,. R.;' Kirk, P.W., edi. Indoor and smbiest air quality. Loedos: Se1peT Ltd.;19t1: pp. 159-1". Shimisa, H. et aL A case-eontrol etody of lteg caeesr ie eommok- ia6 women. Tobotu J. Etp. Mad. 13d:319-397; 19911. Teichopoolot, D.; Kalaadidi, A.; Sperms. L; MacMahon, 8. Lm{ cancer and passive emokina. lttt. J. Cancer 27:1-d; 1991. AN' ESTIMATE OF ADULT MORTALITY IN THE fVITED STATES FROM PASSIVE SMOKING; ~ A REAPONSE Dear Editor: Wells (1988) estima that exposure to envi'ron- menul tobacco smote (E causes 46 000 deaths per year in the U.S.; 3000 fro uag cancer, 11 000 from other cancers, and 32 000 fr heart disease. These estimates are scientifically unju 'fied'. Far too much faith is placed on results hom o fragile epidemiologica) studies, with major sources bias ignored or totally underestimated. In contrast, f 00 little faith is placed on evidence that nonsmoke have very much lower exposure to tobacco smoke Table 1. Fsmale eslati.e risks for 406 88 494 ive smokiag in Japaneee stodx. Non-smoker 1 0. 1 2.95 1 1.10 .30 t Estimate4!{fom 1966-79 dau (Hirayams 1991) and from 1966-i2 dau (Hirayama 19a4); 7its 19 papet pro ded releove sembeta of deatba as 1J1„240; and 136. Oaerla. K. Lant cancer fram pusi.e emot'iad: lypotdeaii or ooe- rincing evideacet Jnt. Arcd. Oceop. Eoviree. Htaith 39:A21- 477; 1917: USSG (U.S. Surgeon General) Tbe health conseqnences of invol- unury smokins: a report of the Surgeon General. DHHS' (CDC) 11743911. Waahialton, D:C.: U.S. Public Haalth Serviee;A9i6. Yo{tl T. M. Smoking behavioral factore u predicton of ritkt. Ia: Research oo smoking behavior. NIDA Monograph 17, Natuonal IaniWta of Drug Abuse. U.S. Public Health Service; 1977:,pp. 9i-110: Weiss, S. T. Wbu are the health sffsas of pasei.e emokint7 1. Rasp. Die. 9:46-62; 1991. 9Vsila, A. 1. As snimas of adnlt eortality is t6e Uaitsd States fres peesive smotinS. 8s.iran. Isn 14:249-26J; 1988. We, A. H.; Headenon, B. E.; Pike. M.C; Ys, lS.C. Smoking and ether risk factors for l®g cancer is Woaeea.l. NIL Cancer lnat_ 74:747-731; 1911. constituents tham do smokers, and that smokers ~ much more exposed to ETS than nonsmokers,,% The evidence that exposure to ETS incr;.ases the risk of developing beart disease is ez-1 pmely uncon- vinting. Of, the studies cited by Wells: some are based on unacceptably small numbe land et al. (1985) where on t women married to nev •smo the only two studi with su deaths are both n to questi When refe cing the Japaa Wells use irayama's 1984 r signifi n t posi'tire trend in w acc smoki ing to husband's m of cases, e.g., Gar- wo deaths occutsed' ia~ king husbands, while bstantial numbers of on. ` ese prospective study, eporr of a statistically ife's age-adjusted risk ng, but does not com- nt on the fact that, in 1981, Hirayama reported no association whatsoever. As shown in Table 1, the disease freim p