Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints

White, Paul A.; Chen, Guangchao; Chepelev, Nikolai; Bell, Madison A.; Gallant, Lauren R.; Johnson, George; Zeller, Andreas; Beal, Marc A.; Long, Alexandra S.

doi:10.1002/em.70006

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Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints

Paul A. White, Guangchao Chen, Nikolai Chepelev, Madison A. Bell, Lauren R. Gallant, George Johnson

, Andreas Zeller

, Marc A. Beal, Alexandra S. Long

Environmental and Molecular Mutagenesis

Swansea University Author: George Johnson

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DOI (Published version): 10.1002/em.70006

Abstract

The benchmark dose (BMD) approach constitutes the most effective and pragmatic strategy for the derivation of a point of departure (PoD) for comparative potency analysis, risk assessment, and regulatory decision‐making. There is considerable controversy regarding the most appropriate benchmark respo...

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Published in:	Environmental and Molecular Mutagenesis
ISSN:	0893-6692 1098-2280
Published:	Wiley 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa69287

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last_indexed	2025-04-15T04:31:46Z
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This work employed the Slob (2017) Effect Size (ES) theory to define robust BMR values for the in vivo transgenic rodent (TGR) and Pig‐a mutagenicity endpoints. An extensive database of dose–response data was prepared and curated; BMD analyses were used to determine endpoint‐specific maxima (i.e., parameter c) and within‐group variance (i.e., var). Detailed analyses investigated the dependence of var on experimental factors such as tissue, administration route, treatment duration, and post‐exposure tissue sampling time. The overall lack of influence of these experimental factors on var permitted the determination of typical values for the endpoints investigated. Typical var for the TGR endpoint is 0.19; the value for the Pig‐a endpoint is 0.29. Endpoint‐specific var values were used to calculate endpoint‐specific BMR values; the values are 47% for TGR and 60% for Pig‐a. 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spelling	2025-04-14T12:06:14.9156787 v2 69287 2025-04-14 Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2025-04-14 MEDS The benchmark dose (BMD) approach constitutes the most effective and pragmatic strategy for the derivation of a point of departure (PoD) for comparative potency analysis, risk assessment, and regulatory decision‐making. There is considerable controversy regarding the most appropriate benchmark response (BMR) for genotoxicity endpoints. This work employed the Slob (2017) Effect Size (ES) theory to define robust BMR values for the in vivo transgenic rodent (TGR) and Pig‐a mutagenicity endpoints. An extensive database of dose–response data was prepared and curated; BMD analyses were used to determine endpoint‐specific maxima (i.e., parameter c) and within‐group variance (i.e., var). Detailed analyses investigated the dependence of var on experimental factors such as tissue, administration route, treatment duration, and post‐exposure tissue sampling time. The overall lack of influence of these experimental factors on var permitted the determination of typical values for the endpoints investigated. Typical var for the TGR endpoint is 0.19; the value for the Pig‐a endpoint is 0.29. Endpoint‐specific var values were used to calculate endpoint‐specific BMR values; the values are 47% for TGR and 60% for Pig‐a. Endpoint‐specific BMR values were also calculated using the trimmed distribution of study‐specific standard deviation (SD) values for concurrent controls. Those analyses yielded endpoint‐specific BMR values for the TGR and Pig‐a endpoints of 33% and 58%, respectively. Considering the results obtained, and the in vivo genetic toxicity BMR values noted in the literature, we recommend a BMR of 50% for in vivo mutagenicity endpoints. The value can be employed to interpret mutagenicity dose–response data in a risk assessment context. Journal Article Environmental and Molecular Mutagenesis 0 Wiley 0893-6692 1098-2280 4 4 2025 2025-04-04 10.1002/em.70006 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This work was supported by Rijksinstituut voor Volksgezondheid en Milieu, I/133002/02/DR and Health Canada. Open Access funding provided by the Health Canada library. 2025-04-14T12:06:14.9156787 2025-04-14T10:44:21.0971498 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Paul A. White 1 Guangchao Chen 2 Nikolai Chepelev 3 Madison A. Bell 4 Lauren R. Gallant 5 George Johnson 0000-0001-5643-9942 6 Andreas Zeller 0000-0002-3565-6347 7 Marc A. Beal 8 Alexandra S. Long 9 69287__34025__b38f51c87fc6431fb3bfacf4a5618944.pdf 69287.VOR.pdf 2025-04-14T12:02:32.4329987 Output 2520711 application/pdf Version of Record true This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (CC BY-NC-ND). true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title	Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints
spellingShingle	Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints George Johnson
title_short	Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints
title_full	Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints
title_fullStr	Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints
title_full_unstemmed	Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints
title_sort	Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints
author_id_str_mv	37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv	37d0f121db69fd09f364df89e4405e31_***_George Johnson
author	George Johnson
author2	Paul A. White Guangchao Chen Nikolai Chepelev Madison A. Bell Lauren R. Gallant George Johnson Andreas Zeller Marc A. Beal Alexandra S. Long
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container_title	Environmental and Molecular Mutagenesis
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publishDate	2025
institution	Swansea University
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doi_str_mv	10.1002/em.70006
publisher	Wiley
college_str	Faculty of Medicine, Health and Life Sciences
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department_str	Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description	The benchmark dose (BMD) approach constitutes the most effective and pragmatic strategy for the derivation of a point of departure (PoD) for comparative potency analysis, risk assessment, and regulatory decision‐making. There is considerable controversy regarding the most appropriate benchmark response (BMR) for genotoxicity endpoints. This work employed the Slob (2017) Effect Size (ES) theory to define robust BMR values for the in vivo transgenic rodent (TGR) and Pig‐a mutagenicity endpoints. An extensive database of dose–response data was prepared and curated; BMD analyses were used to determine endpoint‐specific maxima (i.e., parameter c) and within‐group variance (i.e., var). Detailed analyses investigated the dependence of var on experimental factors such as tissue, administration route, treatment duration, and post‐exposure tissue sampling time. The overall lack of influence of these experimental factors on var permitted the determination of typical values for the endpoints investigated. Typical var for the TGR endpoint is 0.19; the value for the Pig‐a endpoint is 0.29. Endpoint‐specific var values were used to calculate endpoint‐specific BMR values; the values are 47% for TGR and 60% for Pig‐a. Endpoint‐specific BMR values were also calculated using the trimmed distribution of study‐specific standard deviation (SD) values for concurrent controls. Those analyses yielded endpoint‐specific BMR values for the TGR and Pig‐a endpoints of 33% and 58%, respectively. Considering the results obtained, and the in vivo genetic toxicity BMR values noted in the literature, we recommend a BMR of 50% for in vivo mutagenicity endpoints. The value can be employed to interpret mutagenicity dose–response data in a risk assessment context.
published_date	2025-04-04T18:31:19Z
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Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints

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