Role in a testing strategy

Abstract

Toxicity to the genome encompasses gene mutation, clastogenicity and aneugenicity and is caused by diverse mechanisms. Therefore, no single assay can reliably detect all classes of genotoxic agents. International guidelines thus recommend the use of a battery of genotoxicity tests covering all genotoxicity endpoints. These guidelines, in general, foresee in vitro testing first. The initial in vitro battery, usually consisting of two or three assays, shows high sensitivity in terms of correct prediction of in vivo genotoxicants and carcinogens. However, the specificity (the ability to correctly identify in vivo non-genotoxic noncarcinogens) of such an in vitro battery has shown to be low. This often leads to in vivo follow-up testing (so-called ‘tier 2’ testing) that may be unnecessary since the relevance of the positive in vitro findings in the initial testing battery can now also be checked with newly developed in vitro methods. For dermally exposed chemicals, the previously described 3D human reconstructed skin-based micronucleus and comet assays are suggested as a replacement of the ‘tier 2’ studies currently often performed with animals. In the sense of the 3Rs (refine, reduce, replace) they can therefore be seen as a direct replacement of animal studies and can be used for following up unfavourable results from the ‘tier 1’ in vitro battery.