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A Brief Sunsmary of the Public Commeats Submitted to the US. EPA in Response to the Eaesnil Review+ Draft EPA/600/6-90/0d6A HFXLTH EFFECTS OF PASSIVE SMOIQNG: LUNG CANCER IN ADULTS AND RESPIRATORY DISORDrRS IN CHILDREN Science Advisory Board Meeting December 4 and 5,1990

A Brief Summary of the Public Comments Submitted to the U.S. EPA in Response to the External Review Draft EPA/600/6-90/006A HEALTH EFfECTS OF PASSIVE SMOIGriG: LUNG CANCER nd ADULTS AND RESPZRATORY DISORDERS IN C'HII.DREN L PREFACE Tbe portion of the EPA draft report (the Report) on hing cancer eonsists of I) hazard identification (Is ETS a lung carcinogen? What EPA weight-of-evidence classification should be assigaed, ie, Group A. B, C, D or E?) and 2) quantitative assessment of population rislt (What is the magnitude of risk to the US. popuiation, as measured by exacss lung cancer deaths due to passnn+e smokin& if ETS has been identified as a lung carcinogen?) With regard to hazard identification, the Report first concludes that there is human evidence of an assoaation between ETS exposure and lung cancer occursence. Coupled with knowledge that sidestream smoke contains several known and suspected carcinogens found in mainstream smoke and that tbere is substaatial6uman evidence to support a causal relationship between active smoking and lung cancer, the Report further concludes that exposure to ETS inaeases lung cancer risk and classifies ETS as a Group A carcinogen. Tbe Group A classification (known human carcinogen) refers only to the type of evidence (sufficient evidence from epidemiolo®c studies to support a causal association); no conclusions regarding potency, exposure concentrations, or number of persons at risk are required or implied. 7bese elements are all components of population risk. As in most risk assessments, attempts to quantitatively cbaracterize risk to a population introduce additional sauroe: of uncertainty that, aside from statistical variability, are generally oot very amenable to numerical expression. Although estimation of population risk is usually not attempted for eompounds ctsssified lo.ver than Group A or B m the har.ard identification pfiase, the two prooedures are essentially distinct. Consequently, a revie.vcr's comment will often be more relevant to oae of tbese topics or the other. 2

Unlike evaluation and dassi6ation of potential carcinogens, there is no,direct.veight-of-cvidence dassificatioo scheme for the noo-caneer health related endpoints from the studies of children. The objeaivc of the Report on respiratory disorders in chBdrea ta~itaed to household smohing, particularly lnfants whose mothers smoke near them, is to review, summarize, and assess the cpidcmiologic evidence. The total ewidence of an assadation with ETS e:pocure is persuasive for some endpoints, but the biological basis to anpport a eondusion of causality is weak. Additionally, latent eQeets from smohin,g during pregnancy is a oodaimding factor in almost all sindies. 2. DNIRODUCTION Foltowisg release of the Report on June 25,1990, the EPA received and fdkd requests for over 3600 copies of tbe Report. Over 200 comments from the public.vere submitted by the end of tbe public eomment period, Oct.1,199Q with the bulk of these pertaining to the chapters on lung cancer in adults. Although relatively fewer respondents addressed the chapter on respiratory disorders in children, some kngthy and detailed sets of comments were received on it as well. A number of reviews basically support the Report's conclusions on lung cancer, generally with some constructive criticism. A larger number of reviews, however, are quite kngaby, detailed, and highly aitical. A few reviewers feel' that some aoodusions on respiratory disorders should be strengtbened, with at least two persons referring specifically to asthma. Like the comments on lung caDcer, however, the preponderance of these are highly negative toward the Report. A brief overview is presented below followed by a breakdown by specific topics. The predominant theme in oxmments related to lung cancer is that the cLssifiatioo of ETS as a Group A carcinogen, causally related to inareasad risk of hurg cancer, is unwarranted (Group D elaaifiution it sometimes explicitly recommended instead). Tbe epidemiologic studies are heterogeneous and thus gosuitable for a statistical analysis that oombines their results. If one did so anyway, only the U. S. studies . should be used and the unpublished study by Varela should be included. The resultant overall relative risk is not ugriifiant. Issues of confounding and bias should be addressed to a much greater degree and by individual study: Reviewers disagree on wfiether there is evidence of a dose response ia the studies as a 3

whole. The model to adjust an overaD, risk for smoker misdassif,cstion bias can be improved upon. The Report uses parameter values for the U. S. population in its misclassification model that would yield an atimated overall relative risk of L14 when the true value is L0, i.e., when the overall true accss relative risk due to ETS espocure is zero. Alternative estimates submitted by revie~ ers include L00, L19, and the raage 1?S-L30. The upward adjustment for risk from background eytpocnre to ETS is not needed (because ETS is •ot a lung unoer hazard) and is not c+edibte (beeause of the tse of aotiaioe as a turrogate for ETS and the a::umptioa of liaear dose response at background Iere4 of E'IS, i.e,, due to sources other than spousal amokdag). The claim that it is biotogieaDy plausible that EIS is a lung araiaogen is oenteatious and unjustified in the Report. Regarding the aection of the Report on respiratory disorders in ehOdren, reviewers felt that additional studies should be included, and that eac3 study should be reviewed more carefully for quality, potential sources of confounding and bias, and endibility of study cooclusions. It is not posuble to summariu comprehensively in just a few pages the remarks from the thousands of pages of oommenta submitted. We have attempted, however, to objectively represent the major positions and their associated arguments, particularly those most at odds with the conclusions of,tbe Report. It is felt that this perspective will serve the review proeess most effectively and contribute to constructive eevision as warranted. Tbe material is largely preseated from the perspective of the reviewer,.vithout elaboration e=pt for iosertioa of occasional for clarification. Reviewers' remarks are sometimes lifted directly, or paraphrased, for adoption into this summary when they appear to be a good representation of the comments central to an issue. (fhis is largely an aid to fadlitate eoestruction of this summary and to accurately portray substance.) The discussion on a topic often contains conflicting comments of reviewers, so continuity should not be exputed. Citations are intentionally omitted; it would aot be posswble to cite an the revie+Ners who made similar comments on many topks. C&mrnentarv hv the author of this summarv has been gut in italics in placaes to seDarate it rlearlv from the Meseatatioa of revie.ver's eomments. Tbe major headinp and their order is as foUows: Impropriety of EPw; the .veight-of-tvidence supporting the conclusion for lung cancer, topics omitted or addressed inadequately 4

(lung eancer); topics treated inaccurately or inappropriately Oung canacr); issues related to respiratory disorders in children. 3. AOROpRMTY OF EPA nhe p.aoiraaon of thW tea Pa,t hoc Jo.wWd Lr pnsotaa /kxn the aranapoisr of the revie*w, w*h oonunauary far elonfcatiat rnraspastd be 1sa1'us. 'ltk EPA first began preparation of its workptace smoking guidelines and then eontraated work for a risk a:sessment to support the Aiency: preoonoeivod oondusion that ETS is a lung carcinogen. To support that eoadusion, the aooompanyiqY health risk assessmeat, i.e., the Report, selectively omitted studies (particularly the Varela study), ignored the IIaws of the studies aulixed, oied iaappropriate methods of analysis (particularly meta-analysis) and drew utuuppcxted coodusions by applyiog data for oon-US. studies to the US. population. Additionally, EPA was arbitrary and capricious in fat'bbg to follow its own guidelines for carcinogen risk assessment ,.vhicb requires consideration of all sources of information in evaluating the weight of evidence for bazard identif ation (physical- chemical propertiet, toiocolopc effects, short-term tests, long-term animal uudies, and human uudies.) EPA has not followed the same risk assessment procedure apparent in other chemicals classified as tarcioogens. No long-term controlled animal studies were conducted to provide data at known concentrations of ETS for evaluation of carcinogenicity and dose-response assessment. Uncharuxeriuicaily, the Report relies almost wholly oo human studies, with only a surrogate measure of ETS esposure. Even then, EPA does not follow its own 1989 workshop guidelines for drawing conclusions from epidcmiolopc data. M wvrksJiop doa not consaaete ETA-b,nred pdderina. Tbe Report does M satisfy EYA's three erueria for inferring a causal association Gom human studies, ie, adequately considering and diminatimg bias, eonfound'ung, and the likelihood of ehance as atptaaatioaa. The Report does not follow EPA guidelines for characterizing the weight of evideooe, ie, characxerizing the evidence from human studies and from animal studies individually, combining these characterizations into an overall we& of evidence for human eardnogenicity, and then evaluating the supporting evidence available to determine if the averaU weight of evidence should be modified. 5

EPA exceedcd its statutory authority from Tu1e IV of SIIperfund to tvvArc6 indoor air quality issues (but aot to regulate) and did not act in accordance with law. 7Le Report is an abuse of the Ageacy: discretion. As a health risk assessment, the report mifleads the public by m5dag policy prcfereaces with analysis and oMer•intcrpretiag the data. 4. THE WEIGHT OF EVIDENCE SUPPORTING THE OONCIUSION FOR LUNG GNCBR The topics in the }n!lowing sections conr.tpand to die Jfrst Jot+r statemaitt in du Repoat (p. 1-3 and J- l) descrsbiq the wrig/u of tVidrncr aupportirrg the daui/icatear of E75 as a G+vrp A carcinoren. lIu nanQining gwo statenunts on wright of evidencr on (1) Brond-ba:ed evidence and (2) EA'rcu rtmaiR ofur &djusoncnt for pottruidbics. Comments ntlaud to (1) pnn&*pcr;ain to hctaagentiry of Mdies (sss Section S.l~ sources of bias and confounding (see Secriau S.2 And S.3), and the claimed con.sisaacy of mpo+su (see Section 4-2). Remarks refated so (2) coocan the application of nuca-o,ralysit (see Section 6.2) and posenacl bias from mitnpovred srno+Ying status (see Section 6.3). 4.1. BIOLOGICAL PIAUSIBIIJTY The physical, chemical, and biological propertia of ETS have not been .veD characterized under real-life eavuonmental conditions,.vbere the concern regarding a potential bealtb hazard liec It is inaccurate to assume that aidestteam smoke is, for the most part, the same as ETS. The report notes 43 ideatifud ardaogens in tobaooo smoke tbat are in tidestream smoke, without dariTscatiog that these are not wxzurily related to devdopment of lung aecer in bnmaas and that some bear ao irelevaace to the Report's :ubjer,t. Only about 50 substances have been consistently identiGed in ETS noder real-Iife conditions (compared to bumdreds for sidestream smoke) and the alleged carcinogens have not been found . with consistency or certainty in doses that wrould reasonably be considered to pose a risk to Lumans. Active and passive smoking are vastly dissimilar with regard to exposure concentrations as well. Differences in breathing patterns and duration of exposure, as well as coocentratioas. likely affect uptake and F0 6

dcposition. Valid biolo®cal markers, including the use of DNA or protein adducxs, are not available for comparing active and passive smoking. Furthermore, adequate measures of ETS exposure arc lacking. By eontrast, wme persons auggest a dosimetric approach (called 'cigarcttetquiwaknts' in the Report) to estimate lung cancer risk from ETS expocnre from data oa active smoking An average M apocure is determined to be equivalent to acsiMely smoking some pe:oratage of one cigarette per day. Fssapolating downward on a doae-response auve for active tmoiung at that level at$gests a''oe"bk' lung canxr ri:tc. Zbe Report should aote that it is smokers wW receive the bulk of largely tmdiJuted, fresh sidestrcam smoke ftrom cigarettes and thus are the moct heavily c~oecd passive :mokers. U tidesueam smoke contributes to lung cancer risk in nonsmokers, then it is probably a contributing component in the lung ~ cancer risk associated with active smoking. Three potent carcinogens found in sidestream smoke include benxo(a)pyrene, N-Nitrosodimetbylamine, and N-Niuosodietbylamine. If these substances are carcinogenic at arbitrarily low doses, i.e, if there is no knowrm risk-free exposure level, then it is reasonable to wndude that they pose a hazard to smokers and to ETS- eaposed nonsmokers alilte. •2 CONSISTENCY OF RESPONSE 7his conclusiori has been hearily aftirized at irmccww,c and miskading. The studies are inconsistent in almost every characteristic one could compare (see Section 5.1) and the outcomes differ considerably. Although a aubstantial majority of the available epidemiologic studies have a relative risk estimate exceeding one, tbis comparison alone ignores eftect sizes and euimation unanruinty. T>se preseneo of systematic upward bim e.f., amoker misc]assification (see Section 63), may explain the apparent consistency. The two m4or prospective studies (Hirayama and Garfinkel) are quite diuimihr in most respeus, including their ooac]usions (see Section 6.1). Several revie.ven have suggested that the jU O ` N paragraph on eoasistency of response (Report, p. 1-4) should be retracted. W Q N ~ N ~ W I

<3 UPWARD TREND W DOSE RESPONSE Ahhougjt se+wal nviewers note the Wifuance of an vpward masd to suppon a conclusion of causariry, dtis ropic tat noceiNrd nlasivr[y lrss earenriort in At nHewt, in ratcnal, " some othM e, j, arse of rnaa. eaaysis. Among At nton daailed nriews, At rrina*r ind condusioru xW&V rhe prrssnce of a ornQ mu faconsirre,ic Mun nrvica+ars /Faw adrrcd dut[ At eridatce of an upwdrd ornd is wLUkely so be iu to drmtce. •n auociction (but not eausad auoriarioa) ir conchrded Only seven of the thirteen attdua which attempted to ditinguisb eatpoarre Ieve3s reported a consistent upward trend. One needs to consider whether sources of bias, e.g., due to amoker misdassification, may be dose related and thus eaplaim a false upward trend. The control groups should be omitted in assetsing dose-response trend since they may be qualitatively different in some respects. When that is done, none of the studies exhibit a aigaificant upward trend. Anodur nvieMrw surrnised tJtar evrn wich *e conaaa,oups n,R,ove4 the ovarall Nide,ice is caruister,r with an upper b=cC The Report is incorrect in concluding that there is an upward trend in dose response. After applying two different statistical metbods, one a test of homogeneity and one a test of liaear trend, there is so study.vith a statistically significant trend (at the 5% level) using either method. Given the number of analyses performed, this is quite consistent with there being absolutely no etiect. The Report's conclusions is based on a small number of inadequately reported and analyzed results in the literature, together with a misleading graphical representation of point estimates without consideration of the confidence intervals needed to assess bow statistically different the responses actually are at each of the dose levels. A quite &fferw caulusion is nacbed by miother indepcnQeau analysic included in the reviaws. .T6ere are little data om males but what are avalable show ao evidenee of a trend in ridc. Of fourteen studies evaluated for tread in females, using number of cigarettes smoked per day by the apouse as the esposure surrogate and induding the control dose in the statistical test, seven studies show a significant (p<O.OS) positive dose-related trend, three atudies show some indication of a positive trend, and the remaining four ?0 studies show no apparent relationship. An analysis for trend with duration of exposure from the data N avallable in seven studies shows only two significant outcomes and there is reason to suspect the valid'ity, of~ N ~ 8 N ~ ~

one of them. Overall, the evidence is consistent with somc inaease in risk with amount smoked. Also, risk in the highest exposure goup is higher than that in the lowest exposure poup in 10 out of 14 of the studies and is lower in the remaining four. No ianpGcation of causality s,fiould be d+awn hm. TTu Miewrr finds an msociaiion bn du tprdnniodogk dato but concludes oMadl that the epidcmiologic data do not proyidc omn*sciq tridcnce duN dke a€sociaoon is cmctatAy nlaud so FTS aWwm. •.4. DETECfABLE ASSOCIATION AT ENVIRONMF.NTAL DOSE LEVELS The environmental exposure levels in the studies apply only to exposure of never-smoking women married to tmokers, and these differ between siudies.uith no clear and consistent de5aitan of esposnre to ETS. Exposure to ETS outside the home, including the workplace, is not addressed except in the background adjustment for overaD relative risk. 'lUt adjustment, 6owever, is based on a constructed model tbu inappropriately uses cotiaine biosssays (similar to the cigarette equivalents approach for exorapolating hmg cancer risk from ETS exposure from the dose-response curve for active smoking, with whicb the Report finds fault). The credibility of the Report's a««ment of lnag cancer risk based on epidemiologic evidence ir undermined by the much loa+er estimates obtained from the dosimetric (cigarette eqrzivalents) approach. The Report needs to explain the wide discrepancy in outcomes between these two approaches. Some +m+icwers I+awe faulted the lack of animal data fa dosc-nsponse assessmauf when aposure lnrls to FTS would be bnowrt. Although the Report's assessment of lung cancer risk is based on data for women married to smokers, the population risk obtained for the U. S. indudes never-smoking women not married to a smoker, nev r-smoking men, and former smokers. This exarapolation of figures to an enended population is not Nuified in the repoR, and may be contributing to a large overstatement of populstioo risk. Some nviewrn Aavr felt tlw data for r»alea should lreue been combined with Aar for Jemales, or mnalyud in parnlltF with /ennalc4 in the Rcpoet Scvr>al pasau lurw ogr+ud with lrccpina tlu data for malu and Jemarlu scpmiarr. N . O W .~ rP 9 ~ ~ ~

5. TOPICS OMl'TTED OR INADEQUATELY ADDRESSED (LUNG CANCER) S.L STUDY MTEROGENE]TY Epidemiol'ogic studies differ in a variety of ways, some of which are under the esperimenter's control and some of which ara aot. Those under an experimeater's control iadude all aspects of design, etoectttion, tollo+v-up, and analysis. fsseatially aD the characteristia that determine stndy quality falW into this eategory. L~aaontrotlabk study differeaoes result firom .ariable eharacteristia of the populatioa: to which studies apply. For esample, studies use sponsal smoking as a ansogate to differeatiate between ETS exposure. The studies differ, bo+MCver, in the question(s) asked regarding exposure to spousal smokiag, the method of iatervie.v, and the acceptance of proxy responses. These variables are essentially under the experimenter's control. The true (but unknown risk olluag caacer from aoa•ETS sources, and the true relative risk of ETS exposure, may differ between studies due to culture, race,, ethaicity, lifestyle, diet, presence of other pollutants, and exposure to ETS in the workplace and elsewhere outside the home, which are largely beyond the esperimeater's control. All sources of study heterogeneity are problematic in an overall asseument from the available epidemiologic data. The Report should consider the quality of each study indiydually, including an assessment of potential sources of bias and confounding factors (see Sections 52 and S3). Adjustments for bias, e.g.,, smoker misclassification, should be made at the outset to mdevidual studies, rather than after some aggregation, as from meta-aaalysit (s4e Sections 62 and 63). S2 CONFOUNDING Causes of hrog aaar other than ETS may be responsible for a significant association asoibed to ETS, if not takea into account in the design and analysis of a study. Even a study that takes all potetttial oonfounders thought of into effect may inadvertently be excluding the unknown causal factor. Some potential confounders may result from use of spousal smoking instead of actual ETS exposure, e.g., marriage/divorce patterns, size of homes, proximity to smokers, climate and ventilation. The potential influence of factors 10

such as rao:, ethaicity, lifestyle, sodoeconomr"c ttatus, diet, and typc of tobacco smoked need to be addressed. Add•iti'odal confounders may be related to age, gender, family history of lung cancer or tttbertulocis, medications, aewpatioaal or household exposure to products from combusi',o4 and eaqosure to tsdoo. The epidemial4c studies Yary.rtth re:pm to potential eonfounderr taken into aooo+mt in the study desip oa the analysis, e{, faMura to adjust even for ap or marital itaws are oot anaommoa Tbe Report abouid talte sources of confounding into aecoRmt for each imdiwidual study and attempt to evaluate the impact ik 6ad oo the retahs. Comparisoos acrost studies should then be cooduaed to ideatify potential confounding variabtet that may play a signi .fiwtt role. Age appears to, be the only confounding variable reported to have ouc5 inDuepee, however, from what is atrrentliy known. Adjustmeot for confounding factors may be of particular value in countries where there is a high background rate of lung cancer in nonsmokers. Differences in susceptibility to lung carcinogens between raees is a poWbility. S3. BIAS An upward bias is expected from married female ever-smokers, i.e, current and former smokers, .vbo misreport tbemsetves as never-smokers, coupled with a tendency for smokers to be married to smokers. Numcricat adjustment for tbis misdassification effect is done incorrectly in the Report. Tbe figure for bias, which should be hie6er, is sufficient to explain the association seen in men and can explain a very 4rae proportion of the association seen in US. and Western European women. A much higher association, Lowever, would be required to esplaia the association seen in Asian women. The nutliodoloV Jor adjurernenr of tnioker mitclassijicario~t ii a oonteiuious topic in du Arcnm+nc. One woiewrr nrportr thot the .dusment /or wusclour%icariai biat in du Rspon is ewdi too larA if oow maxes o+r ad3usbneM aPP^opiate to each brdivi&al mdy priow to conzb=M rardy auca»es bvtsad of oftowwd (ue Sectiorr 63). Upward bias may result also from considering only studies reported io the open literature. An attempt should be made to include unpublished atudies, which may not Dave been published because no 11

aign`tFiant results were found. The omission of three or more studie:.vith RR - 1 would account for the significanoe of the combined study results. An upward bias results in the overall estimate of relative risk because some sttadiu lack comparability between cases and oootrols in the circumstances wrder which data .vere collected and those atudie: tend to bave aigas5antly higher observed relative risks. Aspects of a atudj+s desigq or aaulysi: of the data..vtth respect to the treatment of potential confounding variables is a source of bias, with the dvoetioo of the bias tnu]ear. For esample, some stndia did oot adjust for age in the design or in the analysis. Matching by age and other factors in attd'tes that.Nere intended for multiple purposes may not apply to the vibset of the data on ETS. In particutar, a number of studies included active smokers or former smokers in the total study.vitbout matching on smoking status for analysis of data on ETS. Some studies included former smokers or single persons, treating the single persons equivalent to som-etcposed marrieds. Additional sources of bias are present to varying degrees in most of the studies. Lung cancer pitients may tend to overstate their exposure to spousal smoking as an explanation for their illness. Bias may result from depending on memory recall of a subject's exposure to spousal smoking. Estimates of relative risk may differ markedly between data collected from the subjects and data obtained from a surrogate, such as their children. The potential bias may not be consistently in the upward or downward direction, e.g., a weaker association is observed from the data for surrogates in the Varela study (also, the Janericb study),.vhile the reverse is observed in the case-control study of Garfinkel. Histologic verification of lung cancer was not conducted in all studies and the error rate may be substantial, e.g, 13% of the lung cancer cases in the case-control study of Garfinkel et. al. were found to be incorrectly diagnosed when the histotogy was reviewed by ooe of the authors. In geseral, the Report oeeds to address potential sources of bias and confounding (we Section 52) for each study iadiwiduaHy. 5.4. kIISMLOGY Studies suggesting an elevated lung cancer prevalence associated with spousal smoking appear ioconsistent with regard to the distribution of tumor types that may be associated with ETS exposure. More . 12

oonsistent evidence regarding the type of tumor assoaated with ETS exposure would be expected if there were a causal relationship. Also, the tumor evidence in epidemiologic audics on ETS is bot consistent with v" has been observed for active smoking (a much :trooger assocaatio® with squamous and amall a1l cancer than with adeaocarcinoma and Iarge oell anotr), which might be expected if it is claimed that both active amd passive smoking are a lung cancer barsrd, and maiastrcam and aidestream smoking are qualitatively aimilar. Ia the case eootrol' atudies* some inm:t4atoR restricted the selection of lung cancer case: to a apeciGc histological type(s) and some did not. For attsdie: in which data are avaUbk by histological type, the comparison acoss studies of relative risks calculated by histological type pve sa indication of a 6istologicsl type(s) more Wcely to be associated with ETS exposure. Account needs to be made, bowwer, of potential errors in diagnosis of primary carcinoma of the lung (see Section S3). 5.5. DRAWING CONCLUSIONS FROM EPIDEMIOLOGIC STUDIES Epidemiologic studies are notoriously unreliable in outcome. An observed relative risk of less than 1S-2.C? (some would up to 3.0): is inadequate to reject the hypothesis of no etlect. T6e overaIl relative risk calculated across studies is well below a minimal value for seriously attributing it to the presence of a real effect, ie., it is within the raage easily due to the `Doise in epidemiologic data resulting from the limitations and vagaries iatriasic to the metbodology and its applicatioa. This same conclusion also applies to ncarly all of the studies on an individual basis. Anot6er rtasoo for conservative interpretation of the ETS atttdies is that several studies are of poor quality (good textbook examples of bow aot to do an epidemiologic study) and some were originally designed for adiHerent, or broader, purpose than a««ing bealth risks Gom ETS 'Iie EPA':1989 Workshop Report on the ttse of human evidencc lays out seven criteria for judging the adequacy of epidemioio®c studies and seven additional criteria for judging the strlengtb of support for a O causal iafereace. These criteria provide a useful framework for summarizing the weight of the epidemiologic W evidence (even if they ue not official EPA guidelines at this time). Studies not satisfying a criteria for ~ adequacy should not be considered further. The staticticil outcome has little meaning in a study judged to ~ 13

be inadequate, :iaoe statistial signifinnce magweld be the resutt of an artifus. The Report ateds to be based on guiding pcineipks, tucb as the two sets of aevea aiteria reculting Eom the EPA workshop oo that topic 7bar me .lro adtQia bi the titcrature and taftob applicable 10 epiderniafogic Nudes 1k jeno14 as woted by sevrrol reWewcrs. 6. TOPICS TREATED IIdAC.'CURATELY OR INAPPROPRIATELY (WNG GNCER) 7htr isction perraLw to cor++rneatr ditgaeirRtfindmr+enraly witJi d,e Repor[7r Asacuion of mnie topics snd the opproprietencss of some methods of mwysis auployrd h does nor oddrea ano+r dlarc wilf be e+eeed in an erraaua (or fn a nevisiori) acepc when they mial,t subuanrivey effecx coachrsians. Xoa+nrc., t+vo csarnpks are presented hen. ?7u violuer of the ttaastic S in Table }Q applicobk to crne{ono,ol studies with .n odlusred aruaysis, conraiirs du vdLes fro.rc du ori jinal cola~fotions by BROW dnd SVEN Jiorn whidi the S violuer of 1.78 mid 1.89 arr daiwed Ahanauve methods of daivin8 this statistic yield nan fiJnfJicarrt nrsults for these tA.n saidies oRly. If tJuu oiternaarr merhods arr use4 the aurnba of sWftcant awca•net (oae-arFfed p- s!iobie kss dran 0.05) !s 3(instead of 5) out of ll. 7Iu ovenoAF concGexion, hawrvrer, is eua:daly unahend-the chance of tJkrre or aiorr hudrs njeairea the hypod,e,rfs of no arsodatiore whar It is bue (Type I erma in statix8rel farpn) Lt sdll tnaall (QOIS). SeNnaW nevievert feei' that the p-valua used should be doubk4 wluch would impy t/mt the alternadw hypotliais jnd4des the possibiliry thar an ETS e,dect could influence the rrJarrve ritlt in either an upward or downwmd dinctioa, i.e, to <I or to >l. Two neviewrr: pobsted out duu some foamulac in Appendix B had eypogrophical errors, but that the calculations appeQned to be doru eorrrcety. The fbnreulQ for Populaxion .lmibutabk Risk (WA eq. B-3 is incor+rct but use of the eorrcu fonmulo Jieldt nemy ldenicard rrsults. 66.2. COHORT STUDIES The Japanese (Hirayama) study is iaaoasrately portrayed as a model by which to campare the American (Garfinkel) study. Tbere is no consensus on the Hirayama study. Although it has undergone oaasiderable scutiny, there are mumerous criticisms of it that remain unanswered. TDere are deficiencies 14

evidcat in the dcsigu, conduct, and analysis of the study, but Hirayama has refused to make study data available and to: adequately describe other aspects of the study that would permit an objective assessment. Some daims of the study that have aot been adequatefjr.eriSed ooee+ern the 'esasW of the study population, oompkteaess of the foII'ow-up, iotera:T iaoooitsteade: in the reported cohort mortality aqerieaee, and drnparate ruults when stratification of age at entry to the study reters to the wife or the husband. A setious defea iavoives the aeaoracy of the d'tapos'ts of Imng caaoe:. Data were obtained from death onti6ates which are aotoriously tm'reliable and have alarp built-in e:ror in 6vor of lung esaoer. H'irayama has never conducted swvival adjusted analyses, which would be aseful io assessiog study data. The unresolved issues regarding the H'irayama study ritse doubts about its quality and the credi'bility of the resuht reported. 'Fbe possibt'Lt y of upward bias must be considered siso, considering the nature of the issues left unanswered. The Report erroneously describes the study/s analysis as based on data grouped by time imtervals, instead of grouped by subject's entry age. Q also states iooorreuly that the relative rislt for .romea married to amoken ieeeases with age (declines aith age is correct). Tbe Report appears to have relied oo, and over-iaterpreted, summary remarks in the NRC and SG reports and elsewhere suggesting that the Hitayama had withstood thorough sautiay, witbout considering recent critical reviews (they are not tated in the report). T6e discussioa in the Report comparing the Hirayama and Garfinkel studies is incorrect and misleading. Tbe Garfinkel study has many merits not eonsiderad. The comparison of the Hirayama and Garfinkel studies is an unfair and misleading attempt to acptaia the observed respoose-itrversion in the Garfinkel study, or to support EPA's preconceived 'mteatioo to demonstrate an ETS lung caoeer risk. 62. USE OF NMA-ANALYSIS Combining study results stateitticagr (meta-aaalyus) is inappropriate in view of the marked d'issimilarities in study quaTity, dcsiga. location, and other characteristics (see Section S.i). Methods of ineta- ~ aaalysis are intended ody for highly sims7ar studies, whether they are experimeots, surveys, clinical trials, etc., 0 a condition severely violated by the epidemiologic studics. Furtbcrmore, overall relative risk from a meta- N ~ ~ u

analysis is meaningkss, because base-line risk of lung cancer from non-ETS sources differs between studies, i.e,, hmg ancer ratcs aot assodated with e3pocure to tobacco smoke are much higher in some countries where studies were conducted than io others. Coo:eqoendy, tbere a only a bypotbetical population to.vhich an overall relative risk from meta-anilytis would apply. SeNvot nwicWO% WtJyoW oUAo.riv dK use of n,aa.anaysi; oa"cerdeC dwr thar it no M!"+d basis Jor iwAudn, f non-U.1 smd+ct !n a combinsd miaTysis )ivr inoriaics on Jie U.S. If study results are combined for me US, for the Asean ooantries, and for the European countries indvidually, tbere is no ioc-tioa of an effect in the US, while the results are itatistically significant for both Europe and Asia. Furtbermore, there is a statistically significant difference between the US. and Europe, between the U. S. and A* and a non- eigaiGcant difference between Asia and Europe. The Varela study should be included in any meta-analy:is oonducted, using statistical methods appropriate for study results from adjusted methods of analysis as from raw data. Thc VancJa mdy is not ,atuaeafty sirijrcan; sacspt ar mi am+e,ruy Jupl, oevrc of espo,strnr to spasd tnoft and t/uur wnura,K,t *lter the ncrulu by conanent dtscrr3cd above. If the Vardh study is included in a meta-aaa}ysis of al1 the Sud'ie:, the ouen!a relative risk drops from the Report'r 1.41(4S% C.I. L26, L57) to 1.23 (95% C1.1A9, 138) (or, alternatively, to (113 (L13,. L35), with the Varela study, alI data for males and females; L2$ (1.16, L42), with the studies of Varela, Shimizu, and the recent study by Sobue et al., femak: only). Tlkc values showee waic roken /Fom Affe,iait ftnicws. When adjusted for upward bias due to smoker m'esrlissificstion (see Section 63), the resultant value is further reduced and does not support the conclusion of an asiodation. Two recent studies, Kabat a aL (their second study in the US.) and Sobue et al (Japan) do not aTport an a:sodatioo between E7`S and lung eaneer risk. They should be added to the Report, along with the Varels study. Siom neither study reports significant fmdimgs, their inclusion in a meta-aaalyrsic would reduce an extimue of overaD rr.lative risk. 16

63. ADJUST'MF.Nt' FOR SMOKER M1SeUSSIFICATION nu Rrporr's ntodrl to odjusr dwt o•+wou rrlamw ,itk dowrcwwd to accowr )roe dIt crpeatd cD'eul of rmoaka rnisclars~~casion ft a mirror cwtsion of she IVRC tPpraocl+. 7lit tcc)uzical iuua nJatcd to nialdg on .djusonent mtd the dcturnFnation of par,arneter viaArm so use how been a saurce of corttention in the liraatun as work on dus lopwr has been e++oUM or+v scmmJhems. Tbs m+e+aer's comne,its rsnd to be sonwM+hat tedYniral mid too latjtlry m duat3s wrU br this bricf rrNew. Tbe Repoet'i adjustment for snssrhte;ficat;,s sboWd; (1) implement concordance ratio and frequency of exposure in a.ray not aSected by mi:cEauiScation, (2) treat persoas incorrectly dassified as .ever-smoker: as a percentage of ever smokers ('mstesd of never-smokers), (3) dearly distinguish between risks relativd to never-smokers, in general, and risks relative to never-smokers not exposed to EFS, and (4) make the adjustment for misdassifcation to each study individual'ly instead of to an overall risk estimate. The report uses inappropriate estimates of the number of lung cancer deaths occurring annually among never smokers in the US.. Suitably corrected (excluding item (4)), an observed relative risk of 1.19 is expected when the true value is 1, i.e., if there is not eRect of ETS. ?he aorsespondina "e pvrn in the Report ir bh The Report should observe fwe basic principles, that include (2) and (4) above. Tbe remaining three recommendations refer to using only female misclassification data for application to study data on females, using parameters for adjustment in each individual study that reflect the time period and locale of the study, and basing the proportion of mis¢lassibed smokers on self-reportcd never-smoken only (instead of a+on-ltsers). Implementation of the pritadpks, Muditg adjustment to individual studies (item (4) above), indicates that only about 3% of the observed relative risk is due to smoker mischssifiation, on average.. 7Iu torrrspouEM NaTus for bioa in ths acport is IOWo, obtoined ftrn I.II/1.2$whe,e 1.28 is the or+croll nlooMr risx odjusud for ntiscJatsi jricotion . ~ Wubout taking estreme combinations from the plausible rsnge of parameter values given in the Report, observed relative risks of L1O -L1S could easily be observed in cohort studies when the true relative risk is 1. For the csse-cantrol studies, values in the range of 225-130 would not be unlikdy, due to smoker 17

ausdassibcatioa alone. These results, taken togetbu,lead to the overaU' conclusion that an overall estimated reLtive risk of 123 (obtained by induding the Varela study) should be adjusted to LOS-L10 to aacount for the kvels of bia: due to -;-4•«:ficxd= .SUlfBlQfcd dOtO !dT POrfl Co1nDU1adOliT of fwwf1lJCl mhiu in dK =ieC pMpl I11 fJlc RCpOrf jQbCQlt AgOi obflAKd oM00gIClOQ1K rLTk6r War 1JgCOlildo=ft, dY! l0 pnoAvm1lC~rS~~CQfJOrt t•10s OAplt, W6Ot lbc Vsjc VaJtu tr Z &<. ADJUSTMENT FOR BACKGROUND EXPOSURE The adjustment to risk for background esposure is predicated on ETS being causally related to increased occurrence of lung cancer. Since that condnsion is not supported by the weight of evidence, there is no basis for adjusting risk. Z3e nse of catiniae data is an unacceptable surrogate for use in adjusting for background exposure to ETS. It is not known to correlate with uptake of lung carcinogens in ETS. 'Ibere is some evidence that nicotiae, and hence its metabolite, is not specific to tobacco smoke as normally assumed. AdditiomaDy, the adjustment for background risk is based on an assumed linear dose-response relationship that is uveritud. 6.5. F.X'IRAPOIATION OF POPLJUI7ON ATTRIBU'TABLE RISK Sorne nWewers liavr fed tlw dota for inaJu =d janalu shoufd be combined in dhe oveeall analysir. Odias JiaNc wped thar data far nealu mrd Jaaoles tJForrtd be kept upmWe, p'our3lY devrloprig afsk uwnmu in P"llcl bi du Rtpnrt The Report obtaims an e:timate of risk applicable to the population of never-smoking.romen anarried to a smoker. ZLere is inadequate justification for eaQrapoTNion of risk to the larger population of esposed females, and then further earapolatioo to include males and former tmoke'rs. The data oa males .rere aot analyzed in the study. Ttiere is little known about the risk to formu-smokers. Ile total estimate of population risk may be very misleading. 7be conclusion that the number of lung cancer deatbs per year N O N CJ N ~ N ~ ~ 19

attrLbiuabk to passive smoking is between 1900 and 6100 is insupportable. Given the amy of sources of .neertainty it is irresponsible and misleading to make such an eact claim. 7. RESPIRATORY DISORDERS IN CHILDREN Cbnsidnobly /ew irview+ers .ddrrsted Mpttr S of die Report dm the dapeas at JM emua. A few rctpondattr, IiowrMCr, toFdy oddnsstd the anateriaJ on nspirotay dfsorderr and did so tn emsfdtrobJe detm2 Tbe Report's conclusion that parental smoking is associated with incrased prevalence of respiratory sYmptoms and dtseases, and with roduced pulmonary itmetiod, is not justified. Tbe Report is incomplete and ieaecttrate in reporting and interpreting the relative literature. SuppatinS amMpJss wer Latluded in the ieuiewAko, the treatment of data and concepts is oversimpliCed. Studies do not appear to have been .iewed critically, potential confounding variables are inadequately addressed, and statistical testing is omitted. Overall, the Report appean superGcial, evea using direct quotations from the NRC and the SG reports .ritbout complete attrtbution. A comprehensive review of all the pertinent literature suggests an association between parental (primarily maternal) smoking and respiratory symptoms and certain diseases in pre-school age children. The observed associations, however, could be due to a number of factors otber than passive smoking, e.g., ioadequate consideration of socioeeonomic status and other bctors, greater sensitivity of younger children to ETS or other agents, reported effects of maternal smoking on lactation or on the child's development in at . No consistent association edus, 6o.reru, for older children or other endpoints in chi]drea of any age. Wadiag asthmae:. s Fsposure assessment is inadequate in the epidemiologie uudia available. It is targeiy' based on measures of parental (or matetnal) smoking that vary between studies. Adequacy of questionnaire data regarding ED'S exposure of children has not beta supported by studies o[ cotinine levels in children. Very few of the fifty or more potential confounding variables that may affed the analysis of tbese studies have been controlled in the reported studies. 'ILis is a very important concern that cannot be ignored in the 19

F Report. The most important aonfoundiag vuiabks include Stnetic aisceptability to childhood reapiratory Moesset cocs-infectioo among family mcm6cr: arithio the bome, aoaiocconom.ic wtcu, number of bonsebold memben, demogtaphir cbaracteriuia of the stndy poQulatiaio, birth wtot, aursiag practiacc infant switioaal aattes, growtb rates, pryr~ [scuxs, age prevakox of pareatal rupintory qmptoms, damp bou4mg ontdoa air pollatioq fatbw'a occupation, iafoctioai acquired in day we aatem aatri6oo, bmily health habit:, parcatal Gtatyler and ot>ura The Report eaodudes avsst body of impoctaat 6toratura in tlsis a:ea which introduces mbstaatial Dias in the conclusions and aaifioes the Report's arodibOty.. ZO