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Building confidence in mechanistic evidence derived from new approach methodologies to inform toxicological pathways of male and female reproductive toxicants
Citation:
Blake, B., T. Anderson, I. Druwe, AND X. Arzuaga. Building confidence in mechanistic evidence derived from new approach methodologies to inform toxicological pathways of male and female reproductive toxicants. EDC-NC Day, Raleigh, NC, September 30, 2022.
Impact/Purpose:
This poster is to be presented to an informed scientific audience at the 2022 Endocrine Disrupting Chemicals North Carolina (EDC-NC) meeting. This work uses bioactivity data obtained from the US EPA ToxCast/Tox21 database to evaluate the ability of new approach methodologies (NAMs)-based evidence to inform reproductive toxicity caused by diethylstilbestrol (DES). DES is a known reproductive toxicant, so this work serves as a case study to test the ability of NAMs-based evidence to supplement existing streams of evidence used in weight of evidence (WoE) and mode of action (MOA) analysis.
Description:
Mechanistic evidence can play a critical role in human health hazard risk evaluation. New approach methodologies (NAMs) can provide mechanistic data in support of weight of evidence (WoE), particularly for data poor chemicals. While NAMs have provided valuable evidence in support of hazards such as skin sensitization, their applicability 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. When used in tandem with the mode of action (MOA) framework, the KCs approach can inform key event relationships using mechanistic evidence for a given toxicant and hazard. Previously assessed chemicals with existing MOAs for a given hazard can be used to validate and build confidence in using the KCs approach to organize and integrate mechanistic and NAM-based data into an MOA. However, the extent to which existing NAM-based mechanistic evidence can be integrated into this type of evidence stream or how well NAMs data informs this biological space is not well characterized for developmental and reproductive toxicants. Building scientific confidence in using NAMs to inform mechanistic evaluation in the hazard characterization process will first require interrogating the reliability and relevance of NAMs and then determining how these data can be integrated to support WoE in the context of MOA development. The objective of this project is to determine the extent to which the KCs of male and female reproductive toxicants are informed by currently available in vitro bioactivity data from the ToxCast/Tox21 database using an established reproductive toxicant, diethylstilbestrol (DES) as case study. This work is the first step towards exploring integration of ToxCast/Tox21 NAMs data into evidence streams such as MOA. Confidence in the application of NAM data will be increased by demonstrating ways to integrate DES mechanistic evidence into existing lines of evidence informing reproductive toxicity mechanisms while identifying data gaps to guide the development/inclusion of new assays.