Implementation of the key characteristics of male reproductive toxicants to synthesize mechanistic evidence: a case study of benzo[a]pyrene
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Mechanistic evidence plays a critical role in the hazard identification of reproductive toxicants and requires synthesis of complex data across studies that differ in experimental methods, models, and scope. The eight key characteristics (KCs) of male reproductive toxicants provide an approach for systematically identifying and organizing data across mechanistic studies of male reproductive toxicity. Here we demonstrate the utility of applying the eight KCs of male reproductive toxicants to identify, organize, and analyze the toxicological and mechanistic evidence for male reproductive effects induced by the chemical benzo[a]pyrene (B[a]P). A literature search was performed, and 2,172 studies were identified then screened using both SWIFT-Active Screener and DistillerSR, resulting in 64 in vitro and in vivo studies that met predefined inclusion criteria for full text review. Relevant study information was manually extracted and compiled into an evidence inventory which underwent quality control by a second reviewer. Mechanistic information in the literature inventory was organized using the eight KCs of male reproductive toxicants, which led to the development of a putative mode of action (MOA) for B[a]P for male reproductive effects by facilitating the identification of potential key events and key event relationships within the MOA. This MOA is informed by the mechanistic evidence across the literature inventory and illustrates where the KCs contribute to B[a]P-induced male reproductive effects at the molecular, cellular, organ, and organism levels. Given the importance of mechanistic evidence in establishing biological plausibility and human relevance of effects observed in experimental models, this work demonstrates the KCs approach is a systematic, efficient, and transparent qualitative method for identifying, organizing, and summarizing mechanistic data for male reproductive hazard identification that can be expanded to other toxicants of interest.