Chinese Benzene Cohort Study 74,828 exposed and 35,805 unexposed workers Leukemia deaths: RR 2.3, 95% CI 1.1-5.0 Malignant lymphoma deaths: RR 4.5, 95% CI 1.3-28.4 No deaths from multiple myeloma in either population

Wong and Raabe, 2000

Meta-Analysis of Risk of Multiple Myeloma in Petroleum Workers 22 cohort studies of >250,000 workers 220.93 deaths expected; 205 observed SMR 0.93; 95% CI 0.81-1.07 Bergsagel et al; Blood, 1999 Metr

Nested Case Control Study of Multiple Myeloma and AML >18,000 petroleum distribution workers Up to 5 controls for each of 11 cases with multiple myeloma and 13 with AML Cumulative mean exposure (ppm-yrs THC): MM 672; controls 800 AML 773; controls 837 Wong, Trent & Harris, 1999

Why is it harder to find an elevated SMR for MM than for AML in benzene-exposed cohorts? Benzene does not cause MM Benzene is a relatively less potent myelogen than it is a leukemogen Benzene is as or more potent a myelogen than it is a leukemogen, but the background incidence of MM is less than AML The latency period for MM is longer than for AML

Healthy Worker Effect: Reasons Specific to Hematopoietic Cancer Acute Myelogenous Leukemia Down’s syndrome, Fanconi’s anemia, etc Status post cancer chemotherapy Non-Hodgkin’s Lymphoma HIV AIDs Immune suppression diseases or therapies

Exposure Dose Relationships in Determining Causality Is this a useful approach when there are only small numbers and borderline statistical significance?

Challenges to Epidemiological Identification of Environmental Causes of Cancer Cancer as a final common pathway Unknown susceptibility factors Uncertain exposure levels Powerless negative Cluster fallacy

Different Levels of Certainty Required for Decisions SCIENTIFIC (p < .05) TORT (p < .50) REGULATORY (p = whatever)

Is Relative Risk Greater Than Two Required for Proof of Causation Is Relative Risk Greater Than Two Required for Proof of Causation? (Carruth and Goldstein, 2001) Threshold: Required to support inference of causation 12 Threshold: Determinative of ultimate issue 2 Not required for inference of causation 14 Sufficient for inference of causation (not clear if required) 1 Total # of published decisions 29

Total # of published cases 11 10 Is Relative Risk Greater Than Two Required for Admissibility? (Carruth and Goldstein, 2001) 21 Total # of published cases 11 Not required for admissibility 10 Required for admissibility

Required 10 Not Required 5 6 Not Considered 9 1 Cases Before and After Daubert II Addressing Whether Relative Risk Greater Than Two is Required for Admissibility of Causation Opinion Before Daubert II Daubert II and After Required 10 Not Required 5 6 Not Considered 9 1

Inadequate exposure data Dilution of high risk group Shortcomings of Occupational Epidemiology for Establishing an Odds Ratio for a Specific Risk Healthy worker effect Inadequate exposure data Dilution of high risk group Appropriateness of time period