Building confidence in mechanistic evidence derived from high throughput assay data to inform hazard evaluation
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New approach methods (NAMs) can rapidly provide mechanistic data in support of human health risk assessment, but the applicability of these data for developmental and reproductive hazards has yet to be fully interrogated. The Key Characteristics (KCs) approach provides a systematic method for identifying, organizing, and synthesizing mechanistic evidence to inform key event relationships in the mode of action (MOA) for a given toxicant and hazard. The extent to which existing NAM-based mechanistic evidence can be integrated into this type of evidence stream or how well NAM data covers this biological space is not well characterized for developmental and reproductive toxicants. To build scientific confidence in the use of NAMs to inform mechanistic evaluations in support of hazard characterization, we set out to interrogate the reliability and relevance of NAMs and determine how these data can be integrated with more traditional human or animal toxicity data to support weight of evidence in the context of MOA development and hazard assessment. The objectives of this project are to: (1) determine the extent to which the key characteristics of male and female reproductive toxicants are informed by currently available in vitro bioactivity data from the ToxCast/Tox21 database, using several established reproductive toxicants as case studies, (2) develop a user-friendly application for interacting with high-throughput screening (HTS) data in the ToxCast/CompTox database using the KCs as a basis for identifying and organizing the available in vitro data. This work will increase confidence in the application of NAM data by demonstrating ways to integrate the information into existing lines of evidence that inform reproductive toxicity and developmental neurotoxicity mechanisms while identifying data gaps to guide the development/inclusion of new assays.