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Applying the Key Characteristics Approach for the Quantitative Evaluation of the Toxicological and Mechanistic Evidence on Benzo[a]Pyrene-Induced Male Reproductive Toxicity.
Citation:
Druwe, I., B. Blake, Allen Davis, J. Dean, C. Gibbons, J. Lambert, L. Lizarraga, AND X. Arzuaga. Applying the Key Characteristics Approach for the Quantitative Evaluation of the Toxicological and Mechanistic Evidence on Benzo[a]Pyrene-Induced Male Reproductive Toxicity. Birth Defects Research and Prevention Annual Meeting (Virtually), NA, Virtual, June 28 - 30, 2021.
Impact/Purpose:
to present at the Birth Defects Research and Prevention virtual meeting in June 2021
Description:
In order to derive health protective Reference dose values (RfD), a qualitative evaluation and integration of toxicological, epidemiological, and mechanistic evidence must be 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 strength of the evidence supporting each key event (KE) and key event relationship (KER) along the proposed MOA for reduced male fertility were evaluated. 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. 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. The 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.