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Applying the Key Characteristics Approach to Evaluate Mechanistic Evidence for Qualitative and Quantitative Weight of Evidence to Support Risk Assessment: A Case Study with Benzo[a]Pyrene-Induced Male Reproductive Toxicity
Citation:
Druwe, I., B. Blake, Allen Davis, J. Dean, C. Gibbons, AND L. Lizarraga. Applying the Key Characteristics Approach to Evaluate Mechanistic Evidence for Qualitative and Quantitative Weight of Evidence to Support Risk Assessment: A Case Study with Benzo[a]Pyrene-Induced Male Reproductive Toxicity. Birth Defects Research and Prevention virtual meeting, NA, NC, June 28 - July 01, 2021.
Impact/Purpose:
To illustrate how key characteristics of male reproductive toxicants may be used to evaluate data mechanistic data qualitatively and quantitatively using BaP as an example.
Description:
In order to derive health protective reference dose values (RfD), a qualitative evaluation and integration of toxicological, epidemiological, and mechanistic evidence must first be performed in order to identify potential hazard(s) and their operative mode(s) of action (MOA). In particular, consideration of mechanistic studies in this evaluation process may inform biological plausibility along with human relevance of effects observed in experimental animal models, identify database uncertainties, and facilitate decision-making that impacts quantitative assessment. Here we integrate eight proposed key characteristics of male reproductive toxicants with established pathways for loss of reproductive function to identify and analyze the mechanistic evidence on benzo[a]pyrene (B[a]P)-induced male reproductive effects. The weight of evidence for support of each key event (KE) and key event relationship (KER) along the proposed MOA for reduced male fertility were evaluated for biological plausibility and human relevance. The quantitative data informing the KE and KER in this putative MOA were further appraised for dose response modeling and where the data allowed, Points of Departure (PODs) for KE along the MOA continuum were derived using EPAs Benchmark Dose Modeling Software (BMDS). Qualitative and quantitative evaluations of mechanistic studies are ongoing to identify potential causal pathways of B[a]P-induced male reproductive toxicity, inform biological plausibility, and facilitate dose response interpretation and assessment. This B[a]P case study demonstrates that the key characteristics approach serves as a practical and objective tool for identifying and organizing mechanistic evidence as well as quantitative information along key event continuums in male reproductive toxicity in support of human health risk assessment.