Evaluation of in vitro genotoxicity tests

In  human health risk assessment of chemicals and pharmaceuticals, assessment of genetic toxicity for regulatory purposes usually starts with a standard battery of in vitro genotoxicity tests. This battery is needed to cover the different genetic toxicity endpoints. The tests included in the battery (partly) differ in biology, due to which resulting data may seem contradictory, thereby complicating accurate interpretation of the findings. This could be overcome through application of mathematical modelling. One of the advantages of mathematical modelling is that strengths and weaknesses of each test are taken into account. Furthermore, the generated predictions are objective and inform on the associated uncertainties. This approach was explored by the working group “Predictivity of In Vitro Genotoxicity Testing”, formed in the context of the 8th International Workshop on Genotoxicity Testing (IWGT). We applied mathematical modelling to a database with (partly) publicly available in vitro and in vivo data for genotoxicity. The results indicate that a mammalian in vitro clastogenicity test and a mammalian cell gene mutation test together provide the strongest weight-of-evidence for predicting genotoxic potential. Remarkably, the Ames bacterial mutation test appeared to contribute very little to these predictions when used in combination with in vitro genetic toxicity tests using cells of mammalian origin. Further research comparing additional in vitro genotoxicity data with in vivo data will provide additional insights  whether it is indeed time to reconsider the composition of the standard in vitro genotoxicity battery.