Use of study-specific MOE-like estimates to prioritize health effects from chemical exposure for analysis in human health assessments
A December, 2013 report from the National Research Council (NRC) made a number of recommendations pertaining to evidence evaluation, systematic review, and dose-response (including meta-analysis) to the United States Environmental Protection Agency (EPA) for the development of an inorganic arsenic risk assessment. One recommendation was to derive risk estimates for inorganic arsenic through dose-response analyses for health effects with adequate epidemiologic evidence. In response to this recommendation, systematic review methods were used to identify and evaluate epidemiologic studies, which were categorized based on study design (case-control, cohort, cross-sectional), various study quality criteria specific to dose-response analysis (number of dose groups, exposure ascertainment, exposure uncertainty), and availability of necessary dose-response data. Given the extensive epidemiologic evidence base for inorganic arsenic, EPA developed a tiered approach to dose-response analysis that begins with a margin of exposure (MOE) type of analysis designed to assist in identifying studies and health outcomes that warrant more complex, higher tier dose-response analyses. Both case-control and cohort studies were included in the MOE analysis. To account for covariates when modeling, effective counts of cases and controls were estimated from study-reported adjusted odds ratios and relative risks. These effective counts and corresponding exposure or dose information were evaluated using traditional dichotomous benchmark dose models to estimate the exposure or dose associated with a 20% increase in relative risk (RRD20). The RRD20 from each study was compared to corresponding background United States inorganic arsenic exposures or doses to approximate MOEs. Consistent with the NRC’s hierarchy of health endpoints of concern, the results of our MOE analysis suggest that diseases of the circulatory system, bladder cancer, and lung cancer are endpoints that warrant and allow for further analysis based on the number of dose-response datasets demonstrating an effect and MOEs close to 1 (i.e., RRD20 values close to background exposure levels).