Parsons, BL;
Beal, MA;
Dearfield, KL;
Douglas, GR;
Gi, M;
Gollapudi, BB;
Heflich, RH;
Horibata, K;
Kenyon, M;
Long, AS;
et al.
Parsons, BL; Beal, MA; Dearfield, KL; Douglas, GR; Gi, M; Gollapudi, BB; Heflich, RH; Horibata, K; Kenyon, M; Long, AS; Lovell, DP; Lynch, AM; Myers, MB; Pfuhler, S; Vespa, A; Zeller, A; Johnson, GE; White, PA
(2024)
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).
Environ Mol Mutagen.
ISSN 1098-2280
https://doi.org/10.1002/em.22599
SGUL Authors: Lovell, David
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.
Item Type: |
Article
|
Additional Information: |
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2024 His Majesty the King in Right of Canada. Pfizer Inc. GSK. P&G. Roche and The Author(s). Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagenesis and Genomics Society. Reproduced with the permission of the Minister of Health Canada. This article has been contributed
to by U.S. Government employees and their work is in the public domain in the USA. |
Keywords: |
genetic disease, germ‐line mutation, mosaicism, mutation, risk assessment, genetic disease, germ-line mutation, mosaicism, mutation, risk assessment, genetic disease, germ‐line mutation, mosaicism, mutation, risk assessment, 05 Environmental Sciences, 06 Biological Sciences, 11 Medical and Health Sciences, Toxicology |
SGUL Research Institute / Research Centre: |
Academic Structure > Population Health Research Institute (INPH) |
Journal or Publication Title: |
Environ Mol Mutagen |
ISSN: |
1098-2280 |
Language: |
eng |
Dates: |
Date | Event |
---|
3 June 2024 | Published Online | 15 April 2024 | Accepted |
|
Publisher License: |
Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0 |
Projects: |
Project ID | Funder | Funder ID |
---|
UNSPECIFIED | Government of Canada's Chemical Management Plan | UNSPECIFIED |
|
PubMed ID: |
38828778 |
Web of Science ID: |
WOS:001237616000001 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/116713 |
Publisher's version: |
https://doi.org/10.1002/em.22599 |
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