| Literature DB >> 31532525 |
Katie Paul Friedman1, Matthew Gagne2, Lit-Hsin Loo3, Panagiotis Karamertzanis4, Tatiana Netzeva4, Tomasz Sobanski4, Jill A Franzosa5, Ann M Richard1, Ryan R Lougee1,6, Andrea Gissi4, Jia-Ying Joey Lee3, Michelle Angrish7, Jean Lou Dorne8, Stiven Foster9, Kathleen Raffaele9, Tina Bahadori6, Maureen R Gwinn1, Jason Lambert1, Maurice Whelan10, Mike Rasenberg4, Tara Barton-Maclaren2, Russell S Thomas1.
Abstract
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. Of the 448 substances, 89% 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 PODtraditional 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 (eg, developmental, reproductive, and chronic studies). Bioactivity:exposure ratios, 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 with 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 case study. Published by Oxford University Press on behalf of the Society of Toxicology 2019. This work is written by US Government employees and is in the public domain in the US.Entities:
Keywords: high-throughput screening; high-throughput toxicokinetics; new approach methodologies; point-of-departure (POD); threshold of toxicological concern (TTC)
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Year: 2020 PMID： 31532525 PMCID： PMC7720780 DOI： 10.1093/toxsci/kfz201
Source DB: PubMed Journal: Toxicol Sci ISSN： 1096-0929 Impact factor: 4.849