Beevers, Carol, Uno, Yoshifumi, Meurer, Krista, Hamada, Shuichi, Hashimoto, Kiyohiro, Le Hegarat, Lodowig, Kirkland, David, Le Baron, Matthew, Le Curieux, Frank, Martus, Hans-Joerg, Masumura, Kenichi, Ohyama, Wakako, Roberts, Daniel, Vasquez, Marie, Whitwell, James and Witt, Kristine (2024) In Vivo Genotoxicity Testing Strategies: Report from the 8th International Workshop on Genotoxicity Testing (IWGT). Environmental and molecular mutagenesis.

Abstract

The working group reached complete or majority agreement on many issues.
A negative in vivo erythrocyte MN study should be acceptable if dosing is conducted up to a dose level recommended by OECD TG 474, and if sufficient bone marrow exposure is demonstrated. Full consensus on the evidence required to demonstrate “sufficient” bone marrow exposure was not reached.
The liver MN test using six-week-old rats is sufficiently validated to develop an OECD Test Guideline, however, the impact of animal age warrants further study. Ki-67 is a reliable marker for cellular proliferation in hepatocytes.
The GI tract MN test is useful for the genotoxicity evaluation of in vitro aneugens that are poorly absorbed or rapidly degraded, and therefore unlikely to reach the bone marrow, or for metabolites formed in the colon. There are insufficient validation data to support the development of a new OECD guideline, however the methodologies are sufficiently advanced to consider creating an appendix to OECD TG 474.
Comparison of comet results to historical control data [HCD]) should not be used for data evaluation, unless it is demonstrated that the HCD distribution is stable, and animal not study factors are the predominant source of HCD variance. A universally acceptable negative control range of %TI for any tissue cannot be identified at this time. Methodological differences in comet studies could result in misleading conclusions, however, more data are required before best practice recommendations can be made. Hedgehogs alone are unreliable for the measurement of cytotoxicity and further discussion is required.

Item Type:	Article
Keywords:	Genetic toxicology, International Workshop on Genotoxicity Testing (IWGT), Liver micronucleus, GI tract micronucleus, Comet assay, In vivo
Date Deposited:	27 Feb 2025 00:46
Last Modified:	27 Feb 2025 00:46
URI:	https://oak.novartis.com/id/eprint/50031