Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)

Parsons, Barbara L.; Beal, Marc A.; Dearfield, Kerry L.; Douglas, George R.; Gi, Min; Gollapudi, B. Bhaskar; Heflich, Robert H.; Horibata, Katsuyoshi; Kenyon, Michelle; Long, Alexandra S.; Lovell, David P.; Lynch, Anthony M.; Myers, Meagan B.; Pfuhler, Stefan; Vespa, Alisa; Zeller, Andreas; Johnson, George; White, Paul A.

doi:10.1002/em.22599

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Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)

Barbara L. Parsons

, Marc A. Beal, Kerry L. Dearfield, George R. Douglas, Min Gi, B. Bhaskar Gollapudi, Robert H. Heflich, Katsuyoshi Horibata, Michelle Kenyon, Alexandra S. Long, David P. Lovell, Anthony M. Lynch, Meagan B. Myers, Stefan Pfuhler

, Alisa Vespa, Andreas Zeller

, George Johnson

, Paul A. White

Environmental and Molecular Mutagenesis

Swansea University Author: George Johnson

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DOI (Published version): 10.1002/em.22599

Abstract

Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose–response curve (e.g., benchmark dose) by a composite adjustment factor (AF). An “effect severity” AF (ESAF) is employed in some regulatory contexts. An ESAF of 10 may be incorporated in...

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Published in:	Environmental and Molecular Mutagenesis
ISSN:	0893-6692 1098-2280
Published:	Wiley 2024
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa70446

first_indexed	2025-09-22T16:02:05Z
last_indexed	2026-02-03T05:30:57Z
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An ESAF of 10 may be incorporated in the derivation of a health-based guidance value (HBGV) when a “severe” toxicological endpoint, such as teratogenicity, irreversible reproductive effects, neurotoxicity, or cancer was observed in the reference study. Although mutation data have been used historically for hazard identification, this endpoint is suitable for quantitative dose–response modeling and risk assessment. As part of the 8th International Workshops on Genotoxicity Testing, a sub-group of the Quantitative Analysis Work Group (WG) explored how the concept of effect severity could be applied to mutation. To approach this question, the WG reviewed the prevailing regulatory guidance on how an ESAF is incorporated into risk assessments, evaluated current knowledge of associations between germline or somatic mutation and severe disease risk, and mined available data on the fraction of human germline mutations expected to cause severe disease. 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spelling	2026-02-02T14:33:31.5780697 v2 70446 2025-09-22 Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT) 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2025-09-22 MEDS Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose–response curve (e.g., benchmark dose) by a composite adjustment factor (AF). An “effect severity” AF (ESAF) is employed in some regulatory contexts. An ESAF of 10 may be incorporated in the derivation of a health-based guidance value (HBGV) when a “severe” toxicological endpoint, such as teratogenicity, irreversible reproductive effects, neurotoxicity, or cancer was observed in the reference study. Although mutation data have been used historically for hazard identification, this endpoint is suitable for quantitative dose–response modeling and risk assessment. As part of the 8th International Workshops on Genotoxicity Testing, a sub-group of the Quantitative Analysis Work Group (WG) explored how the concept of effect severity could be applied to mutation. To approach this question, the WG reviewed the prevailing regulatory guidance on how an ESAF is incorporated into risk assessments, evaluated current knowledge of associations between germline or somatic mutation and severe disease risk, and mined available data on the fraction of human germline mutations expected to cause severe disease. Based on this review and given that mutations are irreversible and some cause severe human disease, in regulatory settings where an ESAF is used, a majority of the WG recommends applying an ESAF value between 2 and 10 when deriving a HBGV from mutation data. This recommendation may need to be revisited in the future if direct measurement of disease-causing mutations by error-corrected next generation sequencing clarifies selection of ESAF values. Journal Article Environmental and Molecular Mutagenesis 0 Wiley 0893-6692 1098-2280 genetic disease, germ-line mutation, mosaicism, mutation, risk assessment 3 6 2024 2024-06-03 10.1002/em.22599 Review COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee Government of Canada's Chemical Management Plan 2026-02-02T14:33:31.5780697 2025-09-22T10:56:53.4383649 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Barbara L. Parsons 0000-0002-3005-2552 1 Marc A. Beal 2 Kerry L. Dearfield 3 George R. Douglas 4 Min Gi 5 B. Bhaskar Gollapudi 6 Robert H. Heflich 7 Katsuyoshi Horibata 8 Michelle Kenyon 9 Alexandra S. Long 10 David P. Lovell 11 Anthony M. Lynch 12 Meagan B. Myers 13 Stefan Pfuhler 0000-0001-8869-5975 14 Alisa Vespa 15 Andreas Zeller 0000-0002-3565-6347 16 George Johnson 0000-0001-5643-9942 17 Paul A. White 18 70446__35313__75b169a7dec940bd85ced1cf0bdd8565.pdf 70446.VoR.pdf 2025-10-10T15:33:26.4392055 Output 3108627 application/pdf Version of Record true © 2024 His Majesty the King in Right of Canada. Pfizer Inc. GSK. P&G. Roche and The Author(s). 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	Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)
spellingShingle	Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT) George Johnson
title_short	Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)
title_full	Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)
title_fullStr	Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)
title_full_unstemmed	Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)
title_sort	Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)
author_id_str_mv	37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv	37d0f121db69fd09f364df89e4405e31_***_George Johnson
author	George Johnson
author2	Barbara L. Parsons Marc A. Beal Kerry L. Dearfield George R. Douglas Min Gi B. Bhaskar Gollapudi Robert H. Heflich Katsuyoshi Horibata Michelle Kenyon Alexandra S. Long David P. Lovell Anthony M. Lynch Meagan B. Myers Stefan Pfuhler Alisa Vespa Andreas Zeller George Johnson Paul A. White
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publishDate	2024
institution	Swansea University
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doi_str_mv	10.1002/em.22599
publisher	Wiley
college_str	Faculty of Medicine, Health and Life Sciences
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description	Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose–response curve (e.g., benchmark dose) by a composite adjustment factor (AF). An “effect severity” AF (ESAF) is employed in some regulatory contexts. An ESAF of 10 may be incorporated in the derivation of a health-based guidance value (HBGV) when a “severe” toxicological endpoint, such as teratogenicity, irreversible reproductive effects, neurotoxicity, or cancer was observed in the reference study. Although mutation data have been used historically for hazard identification, this endpoint is suitable for quantitative dose–response modeling and risk assessment. As part of the 8th International Workshops on Genotoxicity Testing, a sub-group of the Quantitative Analysis Work Group (WG) explored how the concept of effect severity could be applied to mutation. To approach this question, the WG reviewed the prevailing regulatory guidance on how an ESAF is incorporated into risk assessments, evaluated current knowledge of associations between germline or somatic mutation and severe disease risk, and mined available data on the fraction of human germline mutations expected to cause severe disease. Based on this review and given that mutations are irreversible and some cause severe human disease, in regulatory settings where an ESAF is used, a majority of the WG recommends applying an ESAF value between 2 and 10 when deriving a HBGV from mutation data. This recommendation may need to be revisited in the future if direct measurement of disease-causing mutations by error-corrected next generation sequencing clarifies selection of ESAF values.
published_date	2024-06-03T05:32:56Z
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Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT)

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