Genotoxicity assessment: opportunities, challenges and perspectives for quantitative evaluations of dose-response data.
Dose–response analysis
Genetic toxicology
Health-based guidance value
Margin of exposure
Point of departure
Risk assessment
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
28
04
2023
accepted:
21
06
2023
medline:
7
8
2023
pubmed:
5
7
2023
entrez:
4
7
2023
Statut:
ppublish
Résumé
Genotoxicity data are mainly interpreted in a qualitative way, which typically results in a binary classification of chemical entities. For more than a decade, there has been a discussion about the need for a paradigm shift in this regard. Here, we review current opportunities, challenges and perspectives for a more quantitative approach to genotoxicity assessment. Currently discussed opportunities mainly include the determination of a reference point (e.g., a benchmark dose) from genetic toxicity dose-response data, followed by calculation of a margin of exposure (MOE) or derivation of a health-based guidance value (HBGV). In addition to new opportunities, major challenges emerge with the quantitative interpretation of genotoxicity data. These are mainly rooted in the limited capability of standard in vivo genotoxicity testing methods to detect different types of genetic damage in multiple target tissues and the unknown quantitative relationships between measurable genotoxic effects and the probability of experiencing an adverse health outcome. In addition, with respect to DNA-reactive mutagens, the question arises whether the widely accepted assumption of a non-threshold dose-response relationship is at all compatible with the derivation of a HBGV. Therefore, at present, any quantitative genotoxicity assessment approach remains to be evaluated case-by-case. The quantitative interpretation of in vivo genotoxicity data for prioritization purposes, e.g., in connection with the MOE approach, could be seen as a promising opportunity for routine application. However, additional research is needed to assess whether it is possible to define a genotoxicity-derived MOE that can be considered indicative of a low level of concern. To further advance quantitative genotoxicity assessment, priority should be given to the development of new experimental methods to provide a deeper mechanistic understanding and a more comprehensive basis for the analysis of dose-response relationships.
Identifiants
pubmed: 37402810
doi: 10.1007/s00204-023-03553-w
pii: 10.1007/s00204-023-03553-w
pmc: PMC10404208
doi:
Substances chimiques
Mutagens
0
DNA
9007-49-2
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
2303-2328Informations de copyright
© 2023. The Author(s).
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