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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