Implementation of the key characteristics of male reproductive toxicity to synthesize mechanistic evidence: a case study of benzo[a]pyrene
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Mechanistic evidence plays a critical role in hazard evaluation of reproductive toxicants and requires synthesis of complex data across studies that differ in experimental methods, models, and scope. Currently, there are no generally accepted approaches for systematically identifying and organizing data across mechanistic studies of male reproductive toxicity. Here we demonstrate the utility of applying the eight key characteristics (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 population, exposure, comparator, and outcome (PECO) 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 toxicity into a putative mode of action (MOA) for B[a]P on male reproductive effects. This MOA is informed by the weight of mechanistic evidence across the literature inventory and illustrates where the KCs contribute to B[a]P-induced male reproductive effects at the molecular interaction, cellular effects, organ effects, and organism effect levels. For example, alteration of development, function, or death of germ (KC1) or somatic cells (KC2) is implicated at the molecular, cellular, and organ levels (KC1 only) while the remaining KCs are involved at the cellular effects level. This approach also facilitated the identification of potential key event relationships within the MOA, providing a necessary framework for subsequent quantitative analyses. 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 method for identifying, organizing, and summarizing mechanistic data for male reproductive hazard identification that can be expanded to other toxicants of interest. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.