Tobacco Documents Online

ETS and Lung Cancer "The absence of a threshold for respiratory carcinogenesis -in active smoking, the presence of the same carcinogens in mainstream and sidestream smoke, the demonstrated uptake of tobacco smoke constituents by involuntary smokers, and the demonstration of an increased lung cancer risk in some populations with exposures to ETS leads to the conclusion that involuntary smoking is a cause of lung cancer." The Health Consequences of Involuntary Smoking (U.S. Surgeon General, 1986) OtiLZ OLSZS

Bayard

ETS and Lung Cancer "Examination of smoke from the different sources shows that all three types contain chemicals that are both carcinogenic and mutagenic. The amounts absorbed by passive smokers are, however, small, and effects are unlikely to be detectable unless exposure is substantial and very large numbers of people are observed. The observations on nonsmokers that have been made so far are compatible with either an increased risk from 'passive' smoking or an absence of risk. Knowledge of the nature of SirlclStrcnam anrm mainstrnar~ Smnlsn7 nf thn matorials ahsnrhorl rle er'nrs I%..v a9 v o.. I I%.. III n~ .~v III II1v~ v v~ .~~v ~~~ a~~~ ~ v v1 a/vv %..vl if Iy 'passive' smoking, and of the quantitative relationships between dose and effect that are commonly observed from exposure to carcinogens, however, leads to the conclusion that passive smoking gives rise to some risk of cancer." --~ There is sufficient evidence that tobacco smoke is carcinogenic to humans. - IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Vol 38 Tobacco Smoking, 1986. Zt'LZ OLSTS

Uniqueness of ETS for EPA 1. Wealth of human studies at true environmental levels. (3 cohort and 21 case-control) A. Smaller expected relative risks B. Use of meta analysis to combine results C. No need to use mathematical models for low-dose extrapolation 2. Knowledge that ETS contains the same chemical constituents as mainstream cigarette smoke - known human carcinogen - and that the lung is exposed to both forms. jSLZ 0L5ti5

Health Eftcts of Passive Sr.:oking: Lung Cancer in Adults and Respiratory Disorders in Children Prepared By: U. S. EPA OFFICE OF RESEARCH AND DEVELOPMENT OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT Human Health Assessment Group At the Request of (major fundingJ: OFFICE OF AIR AND RADIATION OFFICE OF ATMOSPHERIC AND INDOOR AIR PROGRAMS Indoor Air Division PROJECT MANAGER Steven Bayard, Ph.D. PRIMARY AUTHORS Ch. 2-5, App. B Kenneth Brown, Ph.D. Appendix A Charles G. Humble Appendix C Douglas Crawford-Brown, Ph.D. Appendix D Todd Thorslund, Sc.D. ALSO HERE TODAY EPA Research on ETS Joellen Lewtas, Ph.D. Ch. 5 Apama Koppikar, M.D., Ph.D. LELZ OLSiS

Ste ven Ba yard, Ph. D. Presentation before the Science Advisory Board on The Health Risks of Passive Smoking December 4 - 5, 1990 9ELZ OLSTS

IARC GROUP 1 AGENTS KNOWN HUMAN CARCINOGENS IARC MONOGRAPHS SUPPLEMENT 7,1987 50 AGENTS Melphalan 8-Methoxypsoralen (Methoxsalen) plus ultraviolet radiation Mineral oils, untreated and mildly-treated MOPP (combined therapy with nitrogen mustard, vincristine, procarbazine and prednisone) and other combined chemotherapy including alkylating agents Mustard gas (Sulphur mustard) + 2-Naphthyiamine + Nickel and nickel compounds' Oestrogen replacement therapy Oestrogens, nonsteriodal' Oestrogens, steroidal' Oral contraceptives, combinedi Oral contraceptives, sequential The rubber industry Shale-oils + Soots Talc containing asbestiform fibres -Abo.. TosvaQ+ccv prvVVCts, .s7rl~iokeie~3J '~ Tobacco smoke Treosulphan + Vinyl chloride 'This evaluation applies to the group of chemicals as a whole and not necessarily to alt individual chemicals within the group (see also Methods, p. 38). +Identitied in ETS ~f1LZ 0LST5

CONCLUSION ETS is causally associated with Lung Cancer (EPA Group A) based on: 1. Consistency of Response 2. Association 3. Consistent Dose - Response Trend 4. Effects Remain After Adjustment for Bias 5. Broad-based Evidence 6. Biological Plausibility 7. Collateral Evidence SS` Z 0Z S rS

ETS and Lung Cancer "The weight of evidence derived from epidemiologic studies shows an association between ETS exposure of nonsmokers and lung cancer that taken as a whole is unlikely to be due to chance or system atic bias." pg. 245 "Considering the evidence as a whole, exposure to ETS increases the incidence of lung cancer in nonsmokers." pg. 10 . ETS: Measuring Exposures and Assessing Health Effects (National Research Council, 1986) jiILZ OLSTS

CONCL USIONS A. L UNG CANCER IN ADUL TS 1. ETS is a Group A or known human carcinogen. (Hazard idei iti f icatioi i or 'viieig h t-of-evidence) 2. ETS causes on estimated 3,700 lung cancer deaths per year among non-smoking adults aged 35 and over. The confidence limits are 1,700 and 6,000 (quantitative assessment). 8ELZ 0LSt5

EPA Carcinogen Assessment Guidelines Overall Weight of Evidence for Human Carcinogenicity Group A This group is used only when there is sufficient evidence from epidemiologic studies to support a causal association between exposure to the agents and cancer. Group B This group includes agents for which the weight of evidence of human carcinogenicity based on epidemiologic studies is "limited". pg. 1-12 9t,(,z OLSIS ' /n

Current EPA Group A Carcinogens -15 Agents +' Arsenic ' Asbestos Benzene • Benzidine ' Bis (chioromethyl) ether [BCME] ' Chromium (Hexavalent) • Coke oven emissions ' Diethylstilbestrol [DES] o Direct Black 38 o Direct Blue 6 o Direct Brown 95 +' 2-Napthylamine +` Nickel Refinery Dust, Nickel Subsulfide ' Radon +' Vinyl Chloride St'LZ OLSTS ' IARC Group 1 o IARC Group 2A + identitied in ETS

CONCLUSIONS B. RESPIRA TORY DISORDERS IN CHILDREN 1. ETS exposure from parental smoking, especially during infancy is associated with increased prevalence of acute lower respiratory tract infections, respiratory symptoms of irritation and middle ear eff usions. 2. ETS exposu re is associated with reduced l u ng function and with a small reduction in the rate of pulmonary growth and development in children of mothers who smoke during early childhood. 6CLZ OLSiS

LUNG CANCER RELATIVE RISK FROM HIRAYAMA STUDY (1984), AGE-ADJUSTED BY WIFE'S AGE 2.5 2.0 0 f- 4 Q 1.5 Y N ~ R W U z V .0 (7 z 0.6 0.0 (1-TAILED TEST FOR TREND, P=.001) NONSMOKER EXSMOKER/1-19 CPD SPOUSES' SMOKING CATEGORY 1.74 20+ CPD OSLZ OLSLS

EPA Carcinogen Assessment Guidelines pg. 1-11 Three criteria must be met for a causal association to be inferred between exposure and cancer in humans. 1 . There is no identified bias that could explain the association. 2. The possibility of confounding has been considered and ruled out as explaining the association. 3. The association is unlikely, to be due to chance. In general, although a single study may be indicative of a cause-effect relationship, confidence in inferring a causal association is increased when several independent studies are concordant in showing the association, when the association is strong, when there is a dose-response relationship, or when a reduction in exposure is followed by a reduction in the incidence of cancer. LVLZ OLSTS / /

Other Criteria for Causality - none should be considered either necessary or sufficient in itself. 1. Consistency - usually two or more epidemiologic studies. 2. Strength (magnitude) of- association - increased risk of cancer typically greater than 5. 3. Temporality - exposure occurs before disease. 4. Dose-Response - a strong dose-response relationship across several categories of exposure can be strong evidence for causality if confounding effects are unlikely to be associated with dose. 5. Specificity of the association 6. Biological Plausibility cosistent with what is known about biological mechanisms, biology and natural history of the 7. Collateral Evidence disease. 8t'LZ OLStS /z

ETS AND THE USE OF META ANALYSIS II. Quantitative Assessment: M14 , . . ~  • 19 Case-Control 3 Cohort Combined Unadjusted Adjusted for Misclassification Adjusted for Misclassification plus background Population Attributable Risk Annual Attributable Lung cancer deaths to non-smokers do to ETS (all sources) 1.42 (1.24, 1.63) 1.39 (1.15, 1.67) .1.41 (1.26, 1.57) -------- 1.28 (1.12, 1.45) -------- -------- 1.48 (1.21, 1.87) -------- -------- 0.26 ' ~ -------- ~ -------- 3,700 ` (1700, 6000) * Slightly less than values given in report due to error in formula B-3 9SLZ OLSIS

E T S and the Use of Meta Anaiysis - Hazard identification Meta Analysis The statistical analysis of a large collection of analysis results from individual studies for the purpose of integrating the findings. Association In(ODDS RATIO) i S. - - ° S. E. In(ODD RATIO)~ under H o: Relative Risk = 1 and Si - N (0,1) P is the one-tailed test value Causal Association * extended Mantel-Haenzel test for trencLllnder H o: slope = 0 Pslope is the one-tailed test value * overall relative risk estimate and z5~z OLSTS adjustment for misclassification

L UNG CANCER 1?ELAT!VE RlSK FROM .!APAIdcSC PROSPECTIVE STUDY OF Q., .. 54^ WOMEN, .,. . BY DAILY CIGARETTE CONSUMPTION OF SPOUSE, AGE ADJUSTED BY HUSBANDS' AGE. 14-YEAR FOLLOWUP; 200 TOTAL CASES. NO MISCLASS. BIAS EXPECTED iN PROSPECTIVE STUDY. (HIRAYAMA, 1984) (1-TAILED TEST FOR TREND, P= .002) 1.58 1.42 1.36 1.91 NONSMOKER EXSMOKER 1-14 CPD 15-19 CPD >20 CPD SPOUSES' SMOKING CATEGORY (CIG/DAY) 6vLZ aLStS

Calculation of Population Attributable Risk (PAR) Assu'rrme 60% female non-smokers married to a smoker =• P(E/N) 40% female non-smokers married to a non-smoker =' (1- P(E/N) % Unmarrieds exposed to ETS = % Marrieds exposed to ETS Relative Risk females N.S. married to a smoker = RRB = 1.48 truley unexposed Relative Risk female N.S. married to a non-smoker truly unexposed = RRB _ 1.16 RRM PAR males = PAR females PAR = Excess Risk due to ETS Ex~o, ure_ total risk from all sources P(E/N) (RRB-1) + l1 -P(E/N) ~R .26 P(E/N)RRB+(1-P(E/N) R (.149.41) ~ ~ o 95 /o C l LSLZ OLSTS

IA°C GRO:lD 1 AGENTS KNOWN HUMAN CARCINOGENS IARC MONOGRAPHS SUPPLEMENT 7, 1987 50 AGENTS Aflatoxins Aluminum production + 4-Aminobiphenyl Analgesic mixtures containing phenacetin + Arsenic and arsenic compounds' Asbestos Auramine, manufacture of Azathioprine + Benzene Benzidine -W- Betel quid with tobacco N,N-Bis(2-chloroethyl)-2-naphthyiamine (Chiornaphazine) Bis(chioromethyl)ether and chloromethyl methyl ether (technical-grade) Boot and shoe manufacture and repair 1,4-Butanedioi dimethanesuiphonate (Myleran) Chlorambucil 1-(2-Chioroethyl)-3-(4-methyicyclohexyl)-1-n itrosourea (Methyl-CCNU) + Chromium compounds, hexavaient' Coal gasification Coal-tar pitches Coal-tars Coke production Cyclophosphamide Diethylstilboestrol Erionite Furniture and cabinet making Haematite mining, undergound, with exposure to radon Iron and steel founding Isopropyl alcohol manufacture, strong-acid process Magenta, manufacture of 'This evaluation applies to the group of chemicals as a whole and not necessarily to all individual chemicals within the group (see also Methods, p. 38). +Identified in ETS EtiLZ OLSTS

ETS AND THE USE OF META ANALYSIS i. Hazard Identification - Qualitative Assessment A. Association : Case-Control Studies Only S Statistic based on odds ratio S UNADJUSTED ANALYSIS TABLE,¢5 19 CASE-CONTROL ADJUSTED ANALYSIS TABLE 3-6 12 CASE-CONTROL PS P° 01 4 False + at 05 Ievel P<.001 • P<.001 . 10 Fa lse + a'r.101eve l P=.01 - P<.001 5 False + af.05 Ievel B. Causal Association : Case-Control + Cohort Studies Number of Studies Pvalue i. Adjustment for Misclassification Bias ii. Dose-Response Trend ' a. No. CiglDay b. No. of years smoking * Based on Wu-Williams and Samet. (1990) 19 CAS E-CONTROL 3 COHORT P <.01 Overall Relative Risk Adjusted 10 CAS E-CONTROL Psbo2 P< 1 0-8 9 False + at.05 level 2 COHORT 7 CAS E-CONTROL P <.01 3 False + at.05 level ~:SLZ OLSTS

Calculation of Annual Number of Lung Cancer Deaths LUNG CANCER FEMALES MALES Deaths N.S. 6,500 3,000 (19n $.0.) x .26 x .26 Attributable 1,690 780 to ETS (never smoker) Former Smokers 520 690 Total Attributable 2210 1470 to ETS Total - 3,700 LCD's to non-smoker Attributable to ETS BSLZ OLSTS

.Sofd/Q<e wu' Wi'llorimS' aNl Sd.ne"r', ~t'rK ftNAly s,"s N m r- ~ ~ Tebie IV. Relative Risks of Lung Cancer by Amount and Duration of Exposure :o Spouse's Smoking LO Study No. ci8arettes/diy No. years of sm oking Hireyama 0 ex• 1-14 15- 19 20 +• N ^. ~ 19841'" 1.0-1.4 1.4 1.6 1.9 ,c Trichopoulos. 0 ex• 1-20 21 ~ • NA 19840" 1.0 1.9 1.9 2.5 Garfinkel. 0 < 1-19 20 20 4- NA 1981'3" 1.0 1.3 1.1 ' Corna, 0 1-409" 41 +- Ak<Yr• NA I t 19831'e1 1.0 1.5 3.1 Koo, 19840" 0 1-10 11-20 21 + 1-•19 20-34 35 - 1.0 2.3 1.7 1.2 2.0 1.4 2.3 X Garfinkel, 0 1-10 11-19 20+0 Rllt - 2.9 for 20-29 1985~"' 1.0 1.2 1.1 2.1 yr, RRS fof > 29 yr •vere lower Wu, 1953M" NA 0 1-20 21 - 1.0 1.4 1.2 ' "' = --flala10ftr-. 0- 21-3, ::-: -_ ' 19 '0 2 _, . . . . . . AbbI. 0 1-19 20-29 30 +• 1•-19 20-39 40 + ac 19"s0 1.0 1.3 1.3 2.1 2 .1 1.3 0 1.3 Humble, 0 1-20 21 + 1 -26 27 +• ~ 19f1~"~ 1.0 2. 9 2.2 2 .2 2.7 ~ Paskeses. 0 1-29pt& 30 + Pk/Yt' NA - 1.0 1.0 3.2 Clo 190'1r"e NA « 20 20-29 30-39 40 +• ~ , 1 .0 1.1 1.3 1.7 ~- Ls, 190F'" 0 1-10 11-M 21 +• NA 0 2 2 1 9 2 1 1. . . . A Ieory% 0 1-19 20+• NA 19iMAO 1Ali 3.1 ~. GaO, 19p~"+ 0 1-0 10-1! 20 +• 1-1' 20-3! 40 +• ,~ , 1.0 1.4 2.0 2.8 1.3 2.2 3.3 • P vwiw OOt a..w MR ro aPtort. • O" sot er.iMi9. TR r"N~ Te STS l1 S t'14o'cs pRp6 (~ q Fs+1sP < !O-g -1-14 A Ll) rRe.ra csTs 7 5 T44 Di,0s ~}'oB ~> ~ ffiLSe f- 1/'/0 E'4'ecT) •C .045