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Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization
Citation:
Friedman, K., M. Gagne, L. Loo, P. Karamertzanis, T. Netzeva, T. Sobanski, J. Franzosa, A. Richard, R. Lougee, A. Gissi, J. Lee, M. Angrish, J. Dorne, S. Foster, K. Raffaele, T. Bahadori, M. Gwinn, J. Lambert, M. Whelan, M. Rasenberg, T. Barton-Maclaren, AND R. Thomas. Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 173(1):202-225, (2020). https://doi.org/10.1093/toxsci/kfz201
Impact/Purpose:
This case study aims to evaluate how a point-of-departure derived from new approach methods compares to the traditional estimates of point-of-departure across 448 chemicals with high-throughput hazard and toxicokinetic information in the context of screening-level assessments. In addition, this case study incorporates high-throughput exposure information to examine the bioactivity:exposure ratio as a potential metric for prioritization. This work intends to increase confidence in workflows based on new approach methods that could be used in regulatory decision making by demonstrating just one example of how this might be applied.
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 safety evaluation by informing screening level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM,50) and the 95th (PODNAM,95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses (AEDs). Of the 448 substances, 90% had a PODNAM,95 that was less than the traditional POD (PODtraditional) value. For the 48 substances for which PODtraditional < PODNAM,95, the PODNAM and POD¬traditional were typically within a factor of 10 of each other, and there was an enrichment of chemical structural features associated with organophosphate and carbamate insecticides. When PODtraditional < PODNAM,95, it did not appear to result from an enrichment of PODtraditional based on a particular study type, (e.g. developmental, reproductive, chronic studies). Bioactivity:exposure ratios (BERs), useful for identification of substances with potential priority, demonstrated that high-throughput exposure predictions were greater than the PODNAM,95 for 11 substances. When compared to threshold of toxicological concern (TTC) values, the PODNAM,95 was greater than the corresponding TTC value 90% of the time. This work demonstrates the feasibility, and continuing challenges, of using in vitro bioactivity as a protective estimate of POD in screening level assessments via a large case study.
URLs/Downloads:
DOI: Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization
https://pubmed.ncbi.nlm.nih.gov/31532525/