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Retrospective and Prospective Case Studies to Accelerate the Pace of Chemical Risk Assessment
Citation:
Paul-Friedman, K., M. Gagné, T. Barton-Maclaren, J. Bucher, R. Thomas, M. Rasenberg, AND T. Sobanksi. Retrospective and Prospective Case Studies to Accelerate the Pace of Chemical Risk Assessment. Presented at Society of Toxicology annual meeting, Baltimore, MD, March 10 - 14, 2019. https://doi.org/10.23645/epacomptox.7873742
Impact/Purpose:
How well does a NAM-based approach perform in the prospective case? This prospective case study builds upon learnings from the retrospective case study, addressing questions including 1) Can NAM-based POD estimates be improved using additional technologies or assumptions? 2) Are reasonable NAM-based POD estimates attainable for substances with limited in vitro bioactivity? 3) Can BER, and additional hazard flags, be used to select substances for in vivo screening? A major premise of this work is that the minimal concentration corresponding to in vitro bioactivity is likely to be a conservative threshold for any specific effects or toxicities that might be observed in vivo.
Description:
Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health risk assessments by chemical prioritization. In this work we describe two efforts of the Accelerating the Pace of Chemical Risk Assessment initiative, a consortium of international regulatory scientists. These efforts sought to elucidate whether a POD derived from in vitro bioactivity is a conservative estimate of in vivo PODs, and if hazard and exposure predictions combined into a bioactivity:exposure ratio (BER) is a useful prioritization metric. In the first project, we describe the outcome of a retrospective case study of 448 chemicals with high-throughput predictions of bioactivity, reverse dosimetry, and exposure, as well as traditional hazard information. For 92% of these chemicals, a POD derived from new approach methodologies (PODNAM) was a conservative prediction for the traditional POD (PODtraditional) value. Exposure predictions were greater than the PODNAM for 26/448 chemicals (i.e., BER<0), indicating higher priority for further investigation. The second, prospective study involves generation of NAM data for 200 chemicals to prioritize 20 chemicals for 90-day repeat dose testing in rats using a combination of the BER and bioactivity-based flags. Together these case studies enable regulatory scientists from different international contexts to develop efficient approaches for chemicals management, while possibly reducing the need for animal studies. This work demonstrates the feasibility, and continuing challenges, of using bioactivity and exposure NAMs in screening level safety assessment. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: Retrospective and Prospective Case Studies to Accelerate the Pace of Chemical Risk Assessment
SOT_2019_PAULFRIEDMAN_ETAL_APCRA_RET_PRO_V5C_FINAL.PDF (PDF, NA pp, 2949.29 KB, about PDF)