Appropriate levels of cytotoxicity for genotoxicity tests using mammalian cells in vitro

Among standard battery genotoxicity assays, the in vitro chromosome aberration test and the mouse lymphoma tk assay (MLA) yield about fourfold higher incidences of positive test results than the bacterial reverse mutation test or in vivo bone marrow tests. This is a result of experience with submissions of 335 new pharmaceuticals to the German Federal Institute for Drugs and Medical Devices. While all of the standard systems have their value in detecting relevant genotoxins, there is no supportive evidence for DNA reactivity for a considerable number of in vitro clastogens and MLA positives. In particular the clastogenic response of such compounds is often associated with high cytotoxicity. This may invoke the need to change the approach to test for clastogenicity in vitro. A combination of measures such as (1) a change in the upper limits of cytotoxicity that are currently given in International Conference on Harmonisation (ICH) and Organization for Economic Co-Operation & Economic Development (OECD) guidelines, (2) the creation of a common ground of understanding for interpretation of in vitro (positive) test results, and (3) lowering the upper limits of test compound concentration irrespective of cytotoxicity may prove useful to ensure a sufficient reliability of genotoxicity testing with mammalian cells in vitro.