Tobacco Documents Online

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

1990 Annual VKinter Toidcology Forum L'Eafant Plua Hotel Washiagton, D.C. February 19•21, 1990 NI riphts r.s.r+r.d. No poNon of this transerlpt may be rsproduo.d or utiliz.d in any form or by any m.ans, eIectronk or n»dunkal. indudinp eIsobostatio or phosoeopyfnp, rsoordinp. Mforsnstion atorsps or Mb{sval "ms, or computers, wiMbut prior psrmialoe In .rrNlnp trmm, th. Board of Dlr.etors of the Toxfoolopy Forum, Soma of tho maWlals In this transerlpl may be ava11ab1. .4.wh.r... In on form aLncnh.r, Aow.v.r, 1t ts availabM nowhsrs NsM p B is arranp.d herein. AMhouph the eoUsetJon and compilation of kHormation has bKn oarrfullyr prepared and represents a sipnificant employment mf sidf tlme and resowos.lM Toaloolopy Forum Is r+ocrnsponsibls for any stat.m.rtes or ancrs or omis.tons k+ the manustripb or In sAe transerlption of the recorded proceedings. 1990 Tosiooiopy Forum. Inc., 1sls cy. $tr..t, N.w., an Iloor, w.shtnpmn, o.c. 20o0S.

CONTENTS Monday, February 19, 1990 Session I-1lPPROPRIATENESS OF ASSUMING LA)W DOSE LINEARiTY Page FOR SECONDARY CARCINOGENS Chairman: W. Gary F4mm, Science Regulatory Systems International, DC i IMPACT OF ADDITI6?TY THEORY TO REGULATORS Richard Hill, Environmental Protection Agency, DC 2 DISCUSSION 10 STATISTICAL AR G UMENTS Daniel Krewsky, Health and Welfare, Canada 11 STAT/STIGlL AR GUMENTS Thomas B. Starr, Environ, VA 21 DISCUSSION 25 BIOLOGIGlL ARGUMENTS James A. Swenberg, University of North Carolina, Chapel Hi11 30 DISCUSSION 45 BIOLOGICAL ARGUMENTS R. Michael McClaia, Hof{man-La Roche, Inc., NJ 47 PANEL DISCUSSION Chairman: W. Gary Flamm, Science Regulatory Systems International, DC David W. Gaylor, National Center for Twocolog;cal Reseuch, AR 62 LUNCHEON SESSION 69 Session II • jMAXIMUM EXROSED INDiVIDUAL Chiirman: Paul Portney, Resources for the Futuee, DC 73 ~ GENERdL CONCEPTS John Graham, Hward School of Public Health, MA O N 74 ~ CRI77QUE I - PUBIJC XFSLTX PERSPECTIIZ CJ C~0 Bernard Goidstein, Environmental & Occupational ~ Health Sciences Institute, NJ 90 ~ © GB

Page CRIT7QUE 11 - FXPERfMENTALISTS PERSPECTIYE Angelo Turturo, National Center for ToxicoTogical Research, AR 97 DISCUSSION • 101 ASSESSING THE AIR TOXICS PROBLEM USING AMBIENT DATA William Hunt, Environmental Protection Agency, NC 108 DISCUSSION 128 NEW LEGISLlT1ON ON AIR POLL UFION Robert Barnard, Cleary, Gottlieb, Steen & Hamilton, DC 131 SOME THOUGHTS ON ME! PREDICTIVE EXPOSURE ASSESSMENTS Neil Hawkins,'Ibe Dow Chemical Comparny, MI 138 DISCUSSION 153 ii

CONTENTS Tuesday, February 20, 1990 Page Session Ill - HEALTH EFFECTS OF Eh'V11tONMETvTAL TOBACCO SN1OI:E Chairman: Gio B. Gori, Heahh Policy Center, MD 159 REVIEW OF A WORKSXOP: ASSESSING LOW RISK AGENTS FOR LUNG CANCER Rapar Rylander, University of Gothenborg, Sweden 159 DISCUSSION 167 ASSESSMENT OF EXPOSURE Nancy Haley, American Health Foundation, NY 170 DISCUSSION 184 EPIDEMIOLOGIC STUDIES OF TXE RELA T7ONSHIP FETWFEN P.tSSNL' SMOKING AND LUNG CANCER Geoffrey Kabat, American Health Foundation, NY 187 DISCUSSION 200 INVOLUNTARY SMOKfNG AND LUNG CANCER Lawrence Garfwkel. American Cancer Society, NY 202 DISCUSSION 205 RESPIR.4TORY EFFECTS Philip Witorsch, George Washington University, DC 209 DISCUSSION 220 HF.4RT DISEASE RISK IN PASSJVE SMOKERS Dale Sandler, National Institute ot Environmeatal Health Srieates, NC 223 DISCUSSION 231 C4RDIO VASG'UL4R EFFECTS lawrona M. Wszleu, New York Medical Colkge, NY 235 ~ DISCUSSION 245 ~ GJ W 4Z N tlt µ O

Page Session iV: BEOTECHNOLOGY • REPORT OF A PEER REVIEW DEBATE Chairman: Richard Ronk, Food and Drug Administration, DC 247 GENERAL OVERYIEW.• TXE PURPOSE AND CONTENT OF T1YE IFBC REPORT Richard Hall, International Food Biotechnology Council, DC 248 SAFETYEVALUA77ON PROCEDURES IN THE IFBC RFPORT Ian Munro, Canadian Centre for ToiocoloQy DISCUSSION ENVIRONMENT.lL REi?E'Ui' OF BIOENGINEERED PRODUCTS Bua Hoffman, Food and Drug Administration,, DC DISCUSSION PRACTICAL EXPERIENCE IN REGULATION PRODUCT APPROVAL Fred Shank, Food and Drug Administration, DC DISCUSSION BOYINE SOMATOTROPIN BSTfBGH Gerald B. Guest, Food and Drug Administration, MD FOOD SS1F'ETYASSESSMENT FOR THE USE OF BST IN DAIRY COWS ,252 263 268 283 291 295 Bruce Hammond,, Monsanto, MO 299 DISCUSSION 316 THE SAFETY OF FOODS DERNED FROM TRANSGENICANIJ1iA1.S David Berkowit4 U.S. Department of Agriculture, DC 318 DISCUSSION 331 CONSUMER AND CONGRESSIONAL VIEW POINTS Lesley Russell, , Committee on Energy and Commerce, U.S. House of Representativea, DC 332 DISCUSSION 335 1V >4

CONTENTS Wednesday, February 21,1994 Page Susion V: REGULA'I'ORY UPDATES C6airmaa: Robert J. Scheuplein, Food and Drug Administration, DC 337 FDdcC REl7 3 Robert J Scheuplein, Food and Drug Administration, DC 337 DISCUSSION 339 DIOXIN IN PAPER PRODUCTS Dwain L Winters, Environmtntal Protection Agency, DC 340 DISCUSSION 346 PROPOSIT?ON 65 Lauren Zeise, Department of Health, CA 349 DISCUSSION 354 NCI UPDATE ON IQ (?.dM1NO,3-METJIYI.JMIDA2O (4,5-F) QUINOLINE) Richard Adamson, National Cancer Institute, MD 357 DISCUSSION 363 RISKASSESSMENF AND THE WAXMAN PES77CIDE BILL Mike Taylor, King & Spalding, DC 367 DISCUSSION 371 TtIE BENZENE DECISION Jeanette Wiltsc, Envirommental Protection Agency, DC 373 DISCUSSION 389 v

DR. KABAT: Thank you. The problem of passive smoking and lung cancer has provoked a good deal of debate both oa a scientirc and on a public policy level. Do the studies that purport to show an association of exposure to environmental tobacco smoke (ETS) and lung cancer occurriag in lifetime nonsmokers provide adequate evidence to resolve the issue? As Nancy Haley has just shown, sbe and her colleagues are very good at measuring recent exposure to ETS using eotiaine measured in saliva, serum, and urine. Unfortunately, these biomarkers are not helpful for assessing exposure over the several decades relevant to the induction of lung ¢ancer. Given the lack of a biomarker for long• term exposure to ETS, epidemiologic studies have had to rely on self-reporas or proxy-reports of ETS exposure. I propose to raise what I consider to be some of the key aspects of the roughly 15 epidemiolog'sc studies of the issue of ETS and lung cancer and to point out certain areas that require fwther study. I will u-iefly refer to our own study which is atill in progress at the American Healtb Foundation. Finally, i will suggest a possible direction for further study of this issue.. EPIDEMIOLOGIC Table 1 lists studies examining the lung cancer risk of aon-smoking wives of smoking husbands compared to the non-smoking wives of non-smoking husbands. One Dotes that the greatest magaitude of the overall relative risk (RR) is 2.1. After the Tricbopoulos and Correa studies, the highest RR is 1.65 (Lam et al.). The national Rese.arch Council't committee on passive smoking carried our a meta-aaalysis of the aosting studies in 1986 and came up with an overail RR of 134 (95% confidence interval: 1.18-153) (1). In four out of the fifteen studies listed, the overall RR is statistically eigaificanf. When one examines the data by level of exposure, i.e., number of cigarettes per day smoked by the husband stratified into two or more levels, 8 of the 15 studies show evidence of a dose-respoase relationship. HISTOLOGY When we look at the effect of ETS exposure by histologic type, we see an interesting discrepancy (Table 2). Dalager et a1. (2) and Pershagen et al. (3) show roughly comparably elevated odds ratios (OR) for wuamous cell and small cell nrdaomas combines, but not for adenocara3noma. In contrast, Lam et al. (4) obtained a tigsificant elfeei for adenocarinoma but not for aquamous eell nrcinoma. The re:ults of Hirayama's study (5) presumably agree on this point with those of Lam et al, aince the majority of his lung eancer eases Were apparently adenocaronoma. Tricbopoulos et al. reaults (6) presumably.re.igb in em the aide of Dalager et al. and PershWn et al., aince Trichopoulos excluded adenocariaoma and termiaalbronchiaT carcinoma from their aeries. Since adenocaricoma ocatrs more commonly in aevtr smokers than in smoken and ienerally more commonly in women than in men ('7), ooe would expect that if ETS exposure is an apprecaable risk factor for lmtg cancer, it is associated with adenoearcinoma, as well as poasibly.vith ether types. The inconsistency in the results to date regarding listology indicates that this is one area that merits further study. 197

ASSESSMENT OF DISEASE STATUS MiscLssifiution on disease status occurs when diagnoses other than primary carciaoma of ~ the lung are included in the case series or when a primary cancer of the lung is included among the controls due to its haviag gone undetected. Garfinkel et al. reported that of 283 women listed as having lung cancer in hospital records but witb ao mention of their having smoked, 36 (12.7%) turned out to have diaposes other than lung cancer when the bittology was reviewed by one of the authors (8). In studies in which histologic verification of lung cancer is a criterion for inclusion in the 1 study, misdassification should be minimal. However, some of the studies listed in Table 1 were lacking this for all cases. It sbould also be mentioned that even .vben lung cancer is histologically verified, it is posstble that some cases judged to be primary cancer of the lung are actually secondary to a cancer of another site that has gone undetected. ASSESSMENT OF EXPOSURE STATUS This is a greater problem thaa assessment of disease status, and for some investigators it is the key problem of epidemiologic studies of ETS and lung cancer (9,10). Misdassification of exposure status can occur in a number of ways. Fust, subjects who have smoked for some period of their life can be erroneously included in a study of never smokers. Second, subjects may under-report (minimize) or over-report (inflate) their ETS exposure, or this may be done by proades. A third type of misclassification can occur when some indirect measure (such as whether the subjea is married to a smoker or bow much the spouse smokes) is used as an indicator of ETS exposure. The effect of misdassification on the estimate of the RR depends on whether the misclassification is random or differential'(that is systematic). Random miselassification will bias the estimate of the RR toward the null, thus making an effect, if there is one, more difficult to detect. If misclassification on esposure differs between cases aad' controls, the estimate of the RR can be biased eitber upwards or downwards depending on the direction of the bias (11). JldisclassifstQtion ojacrivc srnokcrs as never srnokcrs. GarLnkel and co-workers found that among lung cancer cases identiGed as 'nonsmokers' or lacking any mention of smoking in the hospital record, 40% were revealed to have smoked' upon reinterview (8). Although a detailed personal interview yields more accurate smoking histories than reliance on bospitaT ebarts, it is stiil likely tbat, even when subjects are directly interviewed and more so when various proxies are used, some miselassification of smokers as nonsmokers occurs. Lee has argued that random miwt«tfication of smokers as non-smokers coupled with a tendency of smokers to marty smokers could account for the observed association of a spouse's smoking and iaereased lung cancer risk in non-smoking spouses (9). Assuming a S:'o a,+d•«ifscation of smoking subjects, a RR of 20 for active smokiag, ao true effect of passive smoking, and a betrveen-spouse smoking concordance of 3.45, Lee demonstrates the effects of such a bias. Tbese include an apparent effect of passivt smoking (RR - 1.75) and the creation of a luge proportion of true smokers among the self-reported aon-smokers with lung cancer. 188

Alisdarsicaaon of selJ,rporud ETS aposure.. A study by Froa et a1. (12) suggests that mistlassification of self-reported ETS exposure may be wensive. They examined the reliability of responses in 117 control subjects who bad' participated in a study of passive smoking and wbo were reiaterviewed on average six months later. Responses to an initial question about exposure to ETS (yes/oo) were more reliable for exposure at home than at work (Table 3). Reprodudbi'lity of questions concerning exposure to a spouse's smoke (yes/ao) was high for both sexes, with the reliability being generaIly lower for other family members. Quantitative meuures of ETS exposure, i.e, number and duration of exposures,.vere generally less reliable than qualitative (or dichotomous) measures. In feneral, non-smoken gave more reliable information on all parameters of ETS exposure than smokers. Unfortunately the study by Pron et al, did not eumine the reliability of responses among cases as.vell as among controls. In case-control sudies particularly one must be concerned that the ease's reporting of exposure may be influenced by his diagnosis. In a study of lung cancer occurring in non-smokers, this could take the form of cases probing past exposures more intensively than controls and over-reporting exposures to ETS, since some cases may feel wmpelled to find an explanation for their disease. On the other hand, it is also possible that cases might minimize their exposures out of an unwillingness to blame a spouse. Aliscfossificariort due to use the spouse's srrso+ldn,g hebiu. Using the presence of a smoking spouse as an indicator of ETS exposure can lead to serious misclassification of exposure. Based on a survey of nearly 38,000 : never- and ex-smokers, Friedman et al. (13) reported that the sensitivity and specificity of using the presence of a smoking spouse as a predictor of actual ETS exposure .rere quire poor. Thirty-nine percent of inen and 4751 of women married to smokers reported zero hours of exposure at home. Conversely, 49% of inen aad 41% of women married to aon-smoken reported some ETS exposure. CONFOUNDING Confounding is another major problem area for the evaluation of epidemiologic studies of ETS and lung cancer and one that has rece'wed 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 negative relationship to reported ETS exposure. Hours per week of ETS exposure were associated with alcohol consumption, marijuana use, being currently unmarried, and, in a U6shaped fashi'on, with bo college education.' lCoo, Ho, and Rylander (14) e:amimed a wide variety of behaviors of the soo-smoking wives of smoking and aon-smoking httsbands in Hong Koag. Tbcy eonduded that in general wives with husbands who had never smoked h,ad healthier llifearyles than wives with smoking husbands. Specifically the former were of highcr socioeconomic status, were more eonscentious housewives N O ~ , , ate better diets, and had higher indices of family eohe:iveaess as well as better heahh status. C.) ~ A third study, by Sidney et at. (LS) repoRed that dietary B-carotene iatake was aigaiGnntly lower in non-smokers agtoaod to passive amoke at home than in non-smokers .vbo were aot eaposed, aher adjustment for ag e, ie; raa,, education atatus, body weight, and alcohol intakc. CA I-A C1T 189