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JUN 2 ~ 1990 TOXICOLOGY FORUM 1990 Annual Winter Meeting February 19-21, 1990 L'Enfant Plaza Hotel Washington, D.C.

1990 Annual Winter Toidcology Forum VEnfaat Plaza Hotel WZshington, D.C. February 19-21, 1990 NI 69" rasannd. No portion of this tranaaript may be nproduoad or utilit.d In any form or try any m.ans, asvonie or m.cRanical; Indudinp electrostatic or pl+atooopyinp,,noordinp. {nformation storaps or retrieval tyttams, or oomput.rs, witfwut priorparrtnission ln.rrltinp horn tM 9oard of Dlractars of the Toxloolofly Forum. Soma of tM mat.rials In this transcript may be avsllabl..Is.wfi.ra, In on fcxm or anotf»r, Aowev.r. It is availrbie nowtr.r..lsa as It is artanp.d hMr.in. Aftl/oupM " ocRact{on and oompilation of Information has bsan qr.tuily pr.par.d and rnpr.sents a siflnificant ampioymant of staM time and rasourass, tM Toxicology Forum is not r.sponsibie for any rtatam.nts or arrors or omisalons in C+a manuscripts or in tha tfanscription of tM r.oordad prooa.dinps. t990 Toxioolbqy Forum, Ine., 1375 Eye StrNt. N.VY., dtn floor, MVasAinpton, D.C. 2OQOS.

CONTENTS Monday, February 19, 1990 Session I- APPROI'RIATENESS OF ASSUN'I1NG LOW DOSE LiNEARI'IY Pagc FOR SECONDARY' CARCCNOGENS Chairman: W. Gary Flamm, Science Regulatory Systems International, DC I IMPACT OFSDDITIi?TY THEORY TO REGULATORS Richard Hill, Envitonmental Protection Agency, DC 2 DISCUSSION 10 STATISTIC4L .4RGUMEhTS Daniel Krewslry, Health and Welfare, Canada 11 ST.9 TISTIUL. AR GUMENTS Thomas B. Starr, Environ, VA 21 DISCUSSION 25 BIOLOGICAL .lRGUMENTS James A. Swenberg„ Universit}r of North Carolina, Chapel Hill 30 DISCUSSION 45 BIOLOGICAL ARGUMENTS R. Michael McClain, Hoffman-La Roche, Inc., NJ 47 PANEL DISCUSSION Chairman: W. Gary Flamm, Science Regulatory Systems Intemational, DC David W. Gaylor, National Center for Toxicological Research, AR 62 LUNCHEON SESSION 69 Session 11 - rtlXiMUM EXPOSED 1NDIVIDUAL Chairman: Paul Portney, Resourees for the Future, DC 73 ~ GENERAL CONCEPTS C John Graham, Harvard School of Public Health, MA 74 ~ CRITIQUE I- PUBLIC N'E4LTF1 PERSPECT71rE ~ Bernard Goldstein, Environmental & Oceupational ~ Health Sciences Institute, NJ 90 ~ C11 ~ i

Page CR7TTQUE 11- EXPERIMENTALISTS PERSPE'CTlVE Angelo Turturo, National Center for Twoaological Researcb, AR 97 DISCUSSION - 101 ASSESSING TFIE.41R TOXICS PR OBLEM USINGAMBIFNT DA TA William Hunt, Environmental Protection Agency, NC 108 DISCUSSION 128 NETi' LE'GISL.4TION ON.41R POLLUTION Robert Barnard, Clcary, Gottlieb, Steea & Hamilton, DC 131 SOME THOUGHTS ON ME1 PREDICTIYE EXPOSURE ASSESSMENTS Neil' Hawkins, The Dow Cbemical: Company, MI 138 DISCUSSION 153 E5

CONTENTS Tuesday, February 20, 1990 Page Session III • HEALTH EFFECTS Of ENVIRONMEhTAL TOBACCO SN1OI:E Chairman: Gio B. Gori, Health PoGcy Center, MD 159 R,EVIEW OF A WORKSXOP: ASSESSING LOW RISK AGENTS FOR LUNG CANCER Ragnar Rylander, University of Gotbenborg, Sweden 159' DISCUSSION 167 ASSESSMENT OF EXPOS URE Nancy Haley, American Health Foundation, NY 17& DISCUSSION 1&t EPIDEMIOLOGIC STUDIES OF THE RELATIONSXIP BETWEEN PASSIVE SMOKING AND L UNG CG! NCER' Geoffrey Kabat, American Health Foundation, NY 187 DISCUSSI ON' 200 INVOLUNTARY SMOKING AND LUNG CANCER Lawrence GarfinkeL American Cancer Society, NY' 202 DISCUSSION 205 RESPIRATORY EFFECTS Phitip Witorsch, George Wash'sngton University, DC DISCUSSION 220 HEART DISEASE RISK IN PASSIVg SMOKERS Dale Sandler, National, Institute of Eovironmental Health Sdences, NC 223 DISCUSSION 231 G4RDIOVASCULAR EFFECTS Lwrence M. Wcader, New York Medical College, NY 235 DISCUSSION ~ 245 ~ ~ ~ iu

Page Session iV. BIOTECHNOLC)GY • REPORT OF A P'EER R.EN'lEW DEBATE Chairman: Richard Ronk, Food and Drug Administration, DC 247 GFNER.4L OYER;1EW.• THE PURPOSE AND CONTENT OF THE IFBC REPORT Richard Hall, International Food Biotcchnology Council; DC 248 SAFETY EVA1. UA TION PROCEDURES IN THE IFBC REPORT Ian Munro, Canadian Centre for Tooocology 252 DISCUSSION 263 ENL7RONMENT.IL REi?Elif OF BIOENGINfERED PRODUCTS Buzz Hoffman, Food and Drug Administration, DC 268' DISCUSSION 283 PRACT7Gl1. EXPERIENCE IN RFGULlT7ON PRODUCTAPPROWAL Fred Shank, Food and Drug Administration, DC 284 DISCUSSION 291 BOVINE SOM.9 TOTROPIN BST/BGH Gerald B. Guest, Food and Drug Administration, MD 295 FOOD SAFElY.lSSESSMENT FOR THE USE OF BST IN DAJRY COWS Bruce Hammond, Monsanto, MO 299 ~ DISCUSSION 316 THE SAFETY OF FOODS DERIVED FROM TRlNSGENIC ANIMALS David Berkowitz, U.S. Department of Agriculture, DC 318 DISCUSSION 331 CONSUMER AND CONGRESSIONAL KEW POINTS Lesley Russell, Committee on Energy and Commerce. U.S. House of Representatives, DC 332 DISCUSSION 335 IV C iv G'l ~ ra ~ ~ 0

CONTENTS Wednesday, February 21, 1990 Page Sesai~on V: REGULATORY UPDATES Chairman: Robert J. Scbeuplein; Food and Drug Administration, DC 337 FD&C RED 3 Robert J Scheupicin, Food and Drug Administration, DC 337 DISCUSSION 339 DIOXIN IN PAPER PRODUCTS Dwain L. Winters, Enviuonmental Protection Agency, DC 340 DISCUSSION 346 PROPOSITION 6S Lauren Zeise, Department of Health, CA 3.49 DISCUSSION 354 ~ NC! UPDATE ON IQ (2-AM1NO-3-METHYLIMIDAZO (4,5-F) QUINOUNE) Richard Adamson, National Cancer Institute, MD 357 DISCUSSION 363 R1SK.4.SSESSMENTAND THE 1+I•'AXMAN PESTICIDE BILL Mike Taylor, King & Spaldiag, DC 367 DISCUSSION 371 T7IE BENZENE DECISION Jeanette Wiltse, Environmental Protection Agency, DC 373 DISCUSSION 388

DR. KABAT: Thank you. The problem of passive smoking and lung cancer has provoked a good' deal of debate boih on a scientific and on a public policy level. Do the studies that purport to show an association~ of: exposure to environmental tobaceo smoke (ETS) and lung cancer occurriag in 1'ufetime nonsmokers provide adequate evidence to resofve the issue? As Nancy Haley has just shown, she and her colleagues are very good at measuring reeent exposure to ETS using cotinine measured in saliva,, serum, and urine. IJtsfortunately, these biomarkers are not helpful for assessing exposure over the several decades relevant to the induction of lung cancer. Given the lack of a biomarker for long- term exposure to ETS, epidemiologic studies have had to rely on sclf-reports or proxy-reports of ETS exposure. I propose to raise what I consider to be some of tbe key aspects of the roughly 15 epidemiologic studies of the issue of ETS and lung cancer and to point out certain areas that require further study. I will1 "iefly refer to our own study.vhich is still in progress at the Amcrican Hca):fi Foundation. FiaaTly, i will suggest a possible direction for further study of this issue. EPIDEIviIOLOGIC Table 1 lists studies examining tbe lung cancer risk of non-smoking wives of smoking busbands compared to the non-smoking wives of aon-smokiag husbands. One notes that the greatest magnitude of the overall'relatie+e risk (RR) is 2.1. After the Trichopoulos and Correa studies, the highest RR is 1.65 (Lam et al.). The nati!onal Researeh Council's committee on passive smoking carried our a meta-analysis of the aastiag studies in 1986 and came up with an overall RR of 1.34 (95 ro confidence interval: 1.18-153) (1). In four out of the fifteen studies listed; the overall RR is statistically sigziificani. Whcn one examines the data by level of exposure, i.e., number of algarettes per day smoked by the husband stratified into two or more levels, 8 of the 15 studies sbow evidenct of a dose-response relation.ship. HISTOLOGY When we look at the effect of ETS exposure by histologic type,.ve sce an interesting discrepancy (Table 2). Dal'ager et al. (2) and Pershagen ct a1. (3) show roughly comparably elevated odds ratios (OR) for squamous cell and small cell carcinomas combines, but not for adenocarcinoma. In contrast, Lam et al. (4) obtained a sigaiGcant effect for adeaotarinoma but not for squamous tell carcinoma. The results of Hirayama's study (5) presumably agree on this point.vi.th those of Lam et al., since the majority of his lung cancer cases were apparently adeoocardnoma. Tricbopoulos et al. ~ results (6) presumably .veigh in on the side of Datager et a1L and Ptrshagen et aL, since ~ Triehopoulos excluded adenocarinoma and terminal bronchial carcinoma from their series. N ciSince adenocarinoma octurs more eommonly in nevsr smokers than in smokers and (A generally more eommonly in women tlhan in men (7), one would expect that if ETS exposure is an W appreciable risk factor for hm,g cancxr, it is assodited' wub adenoeardnoma, as well as powbly with rJ otber types. The inconsistency in the results to date regarding histology indicates that this is one ~ area that merits further study. N 187

ASSESSMEN? OF DISEASE STATUS MiulassiGution on disease status occurs wben diagnoses other than pri;mary carcinoma of the l'ung are ineluded in the case series or wben a primary cancer of the lung is included among the controLs due to its having gone tmdatected. Garfinkel' et al; reported that of 283 women listed as having lung cancer in hospital retords but witb no mention of their having smoked, 36 (12:7~'~) turned out to have diagnoses other than lung cancer when the listology .vas reviewed by one of the authors (8): In studies in which histologic verification of lung cancer is a eriterion for inclusion in the study, m'~~t«ification should be minimal. However, some of the studies Tuted in Table 1 were lacking this for all cases. It should also be mentioned that even when lung cancer is histologically verified; it is pos*ble that some cases judged to be primary cancer of the lung are actually secondary to a cancer of another site that has gone undeteued'. ASSESSMEh? OF EXPOSURE STATUS This is a greater problem than assessment of disease status, and for some investigators it is the key problem~ of epidemiologic studies of ETS and lung cancer (9,10). Misclassitication of exposure status can oceur in a number of ways. First, subjects who have smoked for some period of their life can be erroneousty ineluded in a study of never smokers. Second, subjecu may under-report (minimize) or over-report (inflate) their ETS exposure, or this may be done by proxies. A third type of misclassification can occur when some iadireu measurc (such as whether the subject is married to a smoker or bow much the spouse smokes) is'used as an indicator of ETS exposure. Tbe effect of misdassifcation on the estimate of the RR depends on whetber the misclassification is random or differentaal (that is systematic). Random misclassification .vi1l bias the estimate of the RR toward the null, thus making an effect, if there is one, more difficult to detect. If misclassification on exposure differs betwcen cases and controls, the estimate of the RR can be biased either upwards or downwards depending on the direction of the bias (11). Afisclcssrficarron of active smokers as never smokcrs. Garfiaheland co-workers found that among lung cancer cases identired as 'nonsmokers' or lacking any mention of smoking in the hospital record, 40% were rcvealed to have smoked upon reinterview (8). Although a detailed personaI interview yields more aecuratc smoking histories than reliance on bospital:charls, it is still likely that, even when subjects are d'uux1y interviewed and more so when vuious proxies ue used, some misdassificatioo of smokers as nonsmokers occurs. Lee has argue& that random miu]assifintion of smokers as non-smokers ooupl'ed with a tendency of smokers to marry smokers could account for the observed association of a spousc's smoking and increased lung cancer risk in non-smoking spouses (9). Assuming a S% a,i tasetf,4tion of smoking subjects, a RR of 20 for active smokiag, no true effect of passive smoking, and a bttwun-spouse smoking concordance of 3.45, Lee demonstrates the eBects of such a bias. Tbese include an apparent effett of passive smoking (RR - 1.75) and the ceation of a large proportion of true smokers among the self-reported non-smokers with lung eanccr. 188 1 I 20203512963

Jtlisclassificanon oCself-nrpo'ted ETS aposu.e. A study by Pron et al. (12) suggests that misclaszifiution of self-reponed ETS exposure may, be extensivc. They examined the reliability of responses in 117 control subjects who had participated in a study of passive smoking and who were reinterviewe.d on average six months later. Responses to an initial' question about exposure to ETS (yes/no) were more reliable for exposure at home than at work (Table 3). Reproducibility of questions eoncerning exposure to a spouse's smoke (yes/no) was high for bot.h sexes, witb the reliability being generally lower for otber family members. Quantitativc measures of ETS exposure, i.e., number and duration of exposures, were generally less reliable than qualitative (or dichotomous) measures. in general, non-smokers gave more reliable iaformztion on all parameters of ETS exposure than smokers. Unfortunately the study by Pron et aI, did not examine the reliability of responses among cases as well as among controls. In case-control atudies partkularly one must be eoncerned tbat the case's reporting of exposure may be influenced by his dia,gnosis. In a study of lung cancer occurring in non-smokers, this could take the form of cases probing past exposures more intensively tban controls and over-reporting exposures to ETS, since some cases may feel compelled to find an explanation for their distase. On the other hand,, it is also possible that cases might minimizc their exposures out of an unwzllingness to blame a spouse. 11lisclassification due to use the spouse's smolang habits. Using the presence of a smoking spouse as an iadicator of ETS exposure can lead to serious misclassilcation of exposure. Based on a survey of nearly 38,000 never- and ex-smokers,, Friedman et al~: (13) reported that tbe sensitivity and specificity of using the presenct of a smoking spouse as a predictor of aetual ETS exposure were quire poor. Thirty-nine percent of =oen and 471/-c of women married to smokers reported zero hours of exposure at home. Conversely, 49ei'c of men and 41% of women married to non-smokers reported some ETS exposure. CONFOUNDING Confounding is another major problem area for the evaluation of epidemiologic studies of ETS and lung eancer and one that has received relatively little attention. Several studies suggest that a variety of factors could' act as confounders of an ETS-lung cancer association. Friedman (13) found that age bore a strong negitive relationship to reported ETS exposure. Hours per week of ETS exposure were associate.d .vith alcohol consumption; marijuana use, being currently unmarried; and, in a U=shaped fashion, with 'no college education.' Koo, Ho„ and Rylaader (14) examined a.vide variety of behaviors of the non-smoking wives of smoking and non-smokiag husbands in Hong Kong. Tbey eondudsd that in general wives ry witb husbands who had never smoked had beahhier liffestyles tban wives with smoking husbands. ~ Spedfically, the former were of higher sooacmnomic status, were more eonscientious bousewives, j~ ate better diets, and had higher indices of family eobc=iveness as well as better health status. ~~ Vl A third study, by Sidney et al. (1S) reported that dietasy B-carotene iatake was ~ sign,ificant?y lower in non-smokers exposed to passive smoke at home tban in non-smokers who were ~ no( exposc.d, after adjustment for ag e, se.x, race, education status, body.+eight; and aJaohol iatike. cr) 04 189