Use of study-specific MOE-like estimates to prioritize health effects from chemical exposure for analysis in human health assessments

Abstract

There are unique challenges in estimating dose-response with chemicals that are associated with multiple health outcomes and numerous studies. Some studies are more suitable than others for quantitative dose-response analyses. For such chemicals, an efficient method of screening studies and endpoints to identify suitable studies and potentially important health effects for dose-response modeling is valuable. Using inorganic arsenic as a test case, we developed a tiered approach that involves estimating study-specific margin of exposure (MOE)-like unitless ratios for two hypothetical scenarios. These study-specific unitless ratios are derived by dividing the exposure estimated to result in a 20% increase in relative risk over the background exposure (RRE₂₀) by the background exposure, as estimated in two different ways. In our case study illustration, separate study-specific ratios are derived using estimates of United States population background exposure (RRB-US) and the mean study population reference group background exposure (RRB-SP). 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. Both case-control and cohort studies were included in the RRB analysis. The RRE₂₀ estimates were derived by modeling effective counts of cases and controls estimated from study-reported adjusted odds ratios and relative risks. Using a broad (but not necessarily comprehensive) set of epidemiologic studies of multiple health outcomes selected for the purposes of illustrating the RRB approach, this test case analysis would suggest that diseases of the circulatory system, bladder cancer, and lung cancer may be arsenic health outcomes that warrant further analysis. This is suggested by the number of datasets from adequate dose-response studies demonstrating an effect with RRBs close to 1 (i.e., RRE₂₀ values close to estimated background arsenic exposure levels).

Keywords: Benchmark dose; Case-control; Cohort; Inorganic arsenic; Margin of exposure.