After implementation of current ICHS2A and B and OECD guidelines for genotoxicity testing of human pharmaceuticals, positive results in mammalian cells have frequently been reported that were not confirmed by other tests of the genotoxicity standard battery. In order to avoid discrepancies between studies and unnecessary clarification in follow-up investigations, revision of the methodological recommendations for mammalian cell tests have been proposed by the ICHS2(R1) draft guideline. However, finalisation of this document has been recently impeded by some FDA representatives. Especially the lower maximum substance concentration in mammalian cell assays has been criticised, as potentially genotoxic agents might remain undiscovered.

This evaluation of submissions to the German competent authority BfArM between 1998 and 2010 confirmed the large amount of positive results in mammalian cell tests. Two thirds of these positively tested compounds were negative in bacterial reverse mutation assays and invivo studies. Repetitive investigations disclosed contradictory findings between different mammalian cell tests, which further increased if the comparison was confined to clastogenicity assays in human lymphocytes and hamster cells only. These conflicting results indicate the well known high susceptibility of mammalian cell assays. Among mammalian cell types, human lymphocytes seem to be less prone to ambiguous results than mouse or hamster cell lines with deficient DNA-repair functionality.

In addition, the influence of test procedures on the outcome of mammalian cell assays was closely evaluated using individual data of 20APIs with an unrelated activity to mechanisms of genotoxicity. The positive results of these compounds in mammalian cell tests contravened those of other studies of the standard genotoxicity battery. In most cases, prominent cytotoxicity accounted for genotoxic effects. Hence, appropriate endpoints of cellular viability are essential for correct evaluation of genotoxicity data. If the upper test item concentration was restricted as advised by the ICHS2(R1) draft guidance, just two agents remained, whose genotoxic potential was considered irrelevant because of sufficiently high safety margins towards human exposure. Thus, the revised genotoxicity test conditions proposed by the ICHS2(R1) draft guideline are promising to reduce the amount of irrelevant results without unjustifiable elimination of hazardous substance detection.

Pages 37