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Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose

Marc A. Beal Orcid Logo, Marc Audebert, Tara Barton‐Maclaren, Hannah Battaion, Jeffrey C. Bemis, Xuefei Cao, Connie Chen, Stephen D. Dertinger, Roland Froetschl Orcid Logo, Xiaoqing Guo Orcid Logo, George Johnson Orcid Logo, Giel Hendriks, Laure Khoury, Alexandra S. Long, Stefan Pfuhler Orcid Logo, Raja S. Settivari, Shamika Wickramasuriya, Paul White

Environmental and Molecular Mutagenesis, Volume: 64, Issue: 2

Swansea University Author: George Johnson Orcid Logo

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DOI (Published version): 10.1002/em.22521

Abstract

Genotoxicity assessment is a critical component in the development and evaluation of chemicals. Traditional genotoxicity assays (i.e., mutagenicity, clastogenicity, and aneugenicity) have been limited to dichotomous hazard classification, while other toxicity endpoints are assessed through quantitat...

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Published in: Environmental and Molecular Mutagenesis
ISSN: 0893-6692 1098-2280
Published: Wiley 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa62211
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Traditional genotoxicity assays (i.e., mutagenicity, clastogenicity, and aneugenicity) have been limited to dichotomous hazard classification, while other toxicity endpoints are assessed through quantitative determination of points-of-departures (PODs) for setting exposure limits. The more recent higher-throughput in vitro genotoxicity assays, many of which also provide mechanistic information, offer a powerful approach for determining defined PODs for potency ranking and risk assessment. In order to obtain relevant human dose context from the in vitro assays, in vitro to in vivo extrapolation (IVIVE) models are required to determine what dose would elicit a concentration in the body demonstrated to be genotoxic using in vitro assays. Previous work has demonstrated that application of IVIVE models to in vitro bioactivity data can provide PODs that are protective of human health, but there has been no evaluation of how these models perform with in vitro genotoxicity data. Thus, the Genetic Toxicology Technical Committee, under the Health and Environmental Sciences Institute, conducted a case study on 31 reference chemicals to evaluate the performance of IVIVE application to genotoxicity data. The results demonstrate that for most chemicals considered here (20/31), the PODs derived from in vitro data and IVIVE are health protective relative to in vivo PODs from animal studies. PODs were also protective by assay target: mutations (8/13 chemicals), micronuclei (9/12), and aneugenicity markers (4/4). 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spelling v2 62211 2022-12-23 Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2022-12-23 BMS Genotoxicity assessment is a critical component in the development and evaluation of chemicals. Traditional genotoxicity assays (i.e., mutagenicity, clastogenicity, and aneugenicity) have been limited to dichotomous hazard classification, while other toxicity endpoints are assessed through quantitative determination of points-of-departures (PODs) for setting exposure limits. The more recent higher-throughput in vitro genotoxicity assays, many of which also provide mechanistic information, offer a powerful approach for determining defined PODs for potency ranking and risk assessment. In order to obtain relevant human dose context from the in vitro assays, in vitro to in vivo extrapolation (IVIVE) models are required to determine what dose would elicit a concentration in the body demonstrated to be genotoxic using in vitro assays. Previous work has demonstrated that application of IVIVE models to in vitro bioactivity data can provide PODs that are protective of human health, but there has been no evaluation of how these models perform with in vitro genotoxicity data. Thus, the Genetic Toxicology Technical Committee, under the Health and Environmental Sciences Institute, conducted a case study on 31 reference chemicals to evaluate the performance of IVIVE application to genotoxicity data. The results demonstrate that for most chemicals considered here (20/31), the PODs derived from in vitro data and IVIVE are health protective relative to in vivo PODs from animal studies. PODs were also protective by assay target: mutations (8/13 chemicals), micronuclei (9/12), and aneugenicity markers (4/4). It is envisioned that this novel testing strategy could enhance prioritization, rapid screening, and risk assessment of genotoxic chemicals. Journal Article Environmental and Molecular Mutagenesis 64 2 Wiley 0893-6692 1098-2280 clastogen, genetic toxicology, in vitro to in vivo extrapolation, mutation, new approachmethodologies 22 2 2023 2023-02-22 10.1002/em.22521 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee 2024-01-08T13:24:19.9487218 2022-12-23T12:32:30.6560608 Professional Services Marc A. Beal 0000-0003-2760-4368 1 Marc Audebert 2 Tara Barton‐Maclaren 3 Hannah Battaion 4 Jeffrey C. Bemis 5 Xuefei Cao 6 Connie Chen 7 Stephen D. Dertinger 8 Roland Froetschl 0000-0001-8721-7509 9 Xiaoqing Guo 0000-0001-5951-2156 10 George Johnson 0000-0001-5643-9942 11 Giel Hendriks 12 Laure Khoury 13 Alexandra S. Long 14 Stefan Pfuhler 0000-0001-8869-5975 15 Raja S. Settivari 16 Shamika Wickramasuriya 17 Paul White 18 62211__26253__1c0605c1aac2425aa8759cd8d33eb1be.pdf 62211.pdf 2023-01-11T14:08:27.3380710 Output 4468178 application/pdf Version of Record true © 2022 His Majesty the King in Right of Canada and The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose
spellingShingle Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose
George Johnson
title_short Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose
title_full Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose
title_fullStr Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose
title_full_unstemmed Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose
title_sort Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose
author_id_str_mv 37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv 37d0f121db69fd09f364df89e4405e31_***_George Johnson
author George Johnson
author2 Marc A. Beal
Marc Audebert
Tara Barton‐Maclaren
Hannah Battaion
Jeffrey C. Bemis
Xuefei Cao
Connie Chen
Stephen D. Dertinger
Roland Froetschl
Xiaoqing Guo
George Johnson
Giel Hendriks
Laure Khoury
Alexandra S. Long
Stefan Pfuhler
Raja S. Settivari
Shamika Wickramasuriya
Paul White
format Journal article
container_title Environmental and Molecular Mutagenesis
container_volume 64
container_issue 2
publishDate 2023
institution Swansea University
issn 0893-6692
1098-2280
doi_str_mv 10.1002/em.22521
publisher Wiley
college_str Professional Services
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hierarchy_top_title Professional Services
hierarchy_parent_id professionalservices
hierarchy_parent_title Professional Services
document_store_str 1
active_str 0
description Genotoxicity assessment is a critical component in the development and evaluation of chemicals. Traditional genotoxicity assays (i.e., mutagenicity, clastogenicity, and aneugenicity) have been limited to dichotomous hazard classification, while other toxicity endpoints are assessed through quantitative determination of points-of-departures (PODs) for setting exposure limits. The more recent higher-throughput in vitro genotoxicity assays, many of which also provide mechanistic information, offer a powerful approach for determining defined PODs for potency ranking and risk assessment. In order to obtain relevant human dose context from the in vitro assays, in vitro to in vivo extrapolation (IVIVE) models are required to determine what dose would elicit a concentration in the body demonstrated to be genotoxic using in vitro assays. Previous work has demonstrated that application of IVIVE models to in vitro bioactivity data can provide PODs that are protective of human health, but there has been no evaluation of how these models perform with in vitro genotoxicity data. Thus, the Genetic Toxicology Technical Committee, under the Health and Environmental Sciences Institute, conducted a case study on 31 reference chemicals to evaluate the performance of IVIVE application to genotoxicity data. The results demonstrate that for most chemicals considered here (20/31), the PODs derived from in vitro data and IVIVE are health protective relative to in vivo PODs from animal studies. PODs were also protective by assay target: mutations (8/13 chemicals), micronuclei (9/12), and aneugenicity markers (4/4). It is envisioned that this novel testing strategy could enhance prioritization, rapid screening, and risk assessment of genotoxic chemicals.
published_date 2023-02-22T13:24:21Z
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