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The comet assay can be applied to virtually any tissue and it has been noted that it can be particularly useful in evaluating directly acting genotoxins at their initial site of action. Consequently, it has become relatively common practice to use the stomach comet assay after oral administration to test chemicals that have given positive in vitro genotoxicity results in the absence of metabolic activation. However, to test nontoxic substances up to the limit doses of 1000/2000mg/kg formulations approaching molar concentrations must be used resulting in the stomach mucosa being exposed to excessively high levels. Evidence is beginning to accumulate which shows positive results that do not indicate that potential carcinogenicity may be associated with such high levels of exposure. For pharmaceutical agents, toxicokinetic data are usually available to demonstrate systemic exposure after oral administration. In such cases, it is proposed that exposure of any tissue to levels of the drug substance greater than those that have given positive in vitro results in the absence of metabolic activation is sufficient. However, it is recognised that toxicokinetic data are not available for all chemicals and there are also agents designed not to leave the gastrointestinal tract (GIT). Where it is necessary to examine the GIT, the dose levels selected for examination should cover the likely or intended exposure levels, not necessarily to achieve the maximum tolerated or limit doses, even if the higher doses are required for genotoxicity endpoints in other tissues to be valid. There are usually two or three dose levels in in vivo genotoxicity studies, so when both systemically exposed tissues and the stomach are being examined, it would be possible to use one of the lower doses for the latter without increasing the numbers of animals required. It is important to consider the local concentrations achieved in the stomach or other parts of the GIT in order to avoid the comet assay generating artefactual positive results and it is hoped this will be addressed in the imminent Organisation for Economic Co-operation and Development guideline.

Maximum dose levels for the rodent comet assay to examine damage at the site of contact or to the gastrointestinal tract