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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)
,
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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© 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.
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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...
| Published in: | Environmental and Molecular Mutagenesis |
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| ISSN: | 0893-6692 1098-2280 |
| Published: |
Wiley
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70446 |
| 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 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. |
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| Keywords: |
genetic disease, germ-line mutation, mosaicism, mutation, risk assessment |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Government of Canada's Chemical Management Plan |