Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization

Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization

Toxicological Sciences

10.1093/toxsci/kfz201

https://doi.org/10.1093/toxsci/kfz201

Katie Paul Friedman, Matthew Gagne, Lit-Hsin Loo, Panagiotis Karamertzanis, Tatiana Netzeva, Tomasz Sobanski, Jill A. Franzosa, Ann M. Richard, Ryan R. Lougee, Andrea Gissi, Jia-Ying Joey Lee, Michelle Angrish, Jean Lou Dorne, Stiven Foster, Kathleen Raffaele, Tina Bahadori, Maureen R. Gwinn, Jason Lambert, Maurice Whelan, Mike Rasenberg, Tara Barton-Maclaren, Russell S. Thomas

Toxicology

18 September 2019

Katie Paul Friedman, Matthew Gagne, Lit-Hsin Loo, Panagiotis Karamertzanis, Tatiana Netzeva, Tomasz Sobanski, Jill A Franzosa, Ann M Richard, Ryan R Lougee, Andrea Gissi, Jia-Ying Joey Lee, Michelle Angrish, Jean Lou Dorne, Stiven Foster, Kathleen Raffaele, Tina Bahadori, Maureen R Gwinn, Jason Lambert, Maurice Whelan, Mike Rasenberg, Tara Barton-Maclaren, Russell S Thomas, Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization, Toxicological Sciences, Volume 173, Issue 1, January 2020, Pages 202–225, https://doi.org/10.1093/toxsci/kfz201

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.

PublisherCopyrights

Contributions from A*STAR were supported by intramural funding grants ((IAF-311017E and H18/01/a0/B14) as part of the A*STAR Innovations in Food and Chemical Safety (IFCS) Programme.

This is a pre-copyedited, author-produced version of an article accepted for publication in Toxicological Sciences following peer review. The version of record Katie Paul Friedman, Matthew Gagne, Lit-Hsin Loo, Panagiotis Karamertzanis, Tatiana Netzeva, Tomasz Sobanski, Jill A Franzosa, Ann M Richard, Ryan R Lougee, Andrea Gissi, Jia-Ying Joey Lee, Michelle Angrish, Jean Lou Dorne, Stiven Foster, Kathleen Raffaele, Tina Bahadori, Maureen R Gwinn, Jason Lambert, Maurice Whelan, Mike Rasenberg, Tara Barton-Maclaren, Russell S Thomas, Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization, Toxicological Sciences, Volume 173, Issue 1, January 2020, Pages 202–225, https://doi.org/10.1093/toxsci/kfz201 is available online at: https://doi.org/10.1093/toxsci/kfz201

https://oar.a-star.edu.sg/communities-collections/articles/15595

1096-6080
1096-0929

Bioinformatics Institute