A comparison of the lowest effective concentration in culture media for detection of chromosomal damage in vitro and in blood or plasma for detection of micronuclei in vivo

• Published in: Mutation research. Genetic toxicology and environmental mutagenesis Vol. 879-880; p. 503503
• Main Authors: Kirkland, David, Whitwell, James, Smith, Robert, Hashimoto, Kiyohiro, Ji, Zhiying, Kenny, Julia, Koyama, Naoki, Lovell, David P., Martus, Hans-Jörg, Meurer, Krista, Roberts, Daniel, Takeiri, Akira, Uno, Yoshifumi, van der Leede, Bas-Jan, White, Paul, Zeller, Andreas
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.07.2022
• Subjects: Aneugens; Chromosomal damage; Clastogens; In vitro concentration; Plasma concentrations in vivo; LOED; LOEC; MLA; PoD; IVIVE; GLP; NTP; Clastogens; SD; Chromosomal damage; retics; In vitro concentration; CA; CBMN; AED; Cmax; MN; Plasma concentrations in vivo; ADME; ICH; NCE; PCE; Aneugens; MTD; MoA
• ISSN: 1383-5718; 1879-3592
• DOI: 10.1016/j.mrgentox.2022.503503

It is often assumed that genotoxic substances will be detected more easily by using in vitro rather than in vivo genotoxicity tests since higher concentrations, more cytotoxicity and static exposures can be achieved. However, there is a paucity of data demonstrating whether genotoxic substances are detected at lower concentrations in cell culture in vitro than can be reached in the blood of animals treated in vivo. To investigate this issue, we compared the lowest concentration required for induction of chromosomal damage in vitro (lowest observed effective concentration, or LOEC) with the concentration of the test substance in blood at the lowest dose required for biologically relevant induction of micronuclei in vivo (lowest observed effective dose, or LOED). In total, 83 substances were found for which the LOED could be identified or estimated, where concentrations in blood and micronucleus data were available via the same route of administration in the same species, and in vitro chromosomal damage data were available. 39.8 % of substances were positive in vivo at blood concentrations that were lower than the LOEC in vitro, 22.9 % were positive at similar concentrations, and 37.3 % of substances were positive in vivo at higher concentrations. Distribution analysis showed a very wide scatter of > 6 orders of magnitude across these 3 categories. When mode of action was evaluated, the distribution of clastogens and aneugens across the 3 categories was very similar. Thus, the ability to detect induction of micronuclei in bone marrow in vivo regardless of the mechanism for micronucleus induction, is clearly not solely determined by the concentration of test substance which induced chromosomal damage in vitro. •Blood concentrations at lowest MN-inducing dose in vivo identified for 83 substances.•Compared with lowest concentrations inducing chromosome damage in vitro.•39.8 % of substances positive in vivo at blood concentrations lower than in vitro.•37.3 % of substances were positive in vivo at higher concentrations than in vitro.•Ability to detect MN induction in vivo is not determined by blood concentration alone.