When is a Genotoxin not a Genotoxin?

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May 1, 2012

Richard Walmsley, Professor University of Manchester and Gentronix Ltd

Abstract
The in vitro genotoxicity tests were conceived to predict carcinogenicity in novel chemicals. The reality is more complex: a reproducibly positive in vitro genotoxicity result does not necessarily imply a human cancer hazard, and need not signal the end of a compound's development. There are many different reasons for this, aside from the more obvious examples of genotoxic drugs designed for life-threatening cancers. There are positive results which might be peculiar to a particular test system; there might be metabolites that are specific to rodent S9; there might be genotoxic intermediates in synthesis, breakdown products or other impurities which can avoided or excluded; the positive result might only be evident in the highest toxic dose reachable for a compound where exposure will be at trace levels; a compound showing a wider genotoxic dose response might show a clear threshold effect, such that low doses are entirely safe. This talk will consider some examples of non-concerning genotoxicity, with reference to some commonly used in vitro genotoxicity screening assays.

Drug DiscoveryGenomicsInformatics

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