Unexpected tumour findings in lifetime rodent bioassay studies--what to do?

Currently, the majority of substances tested in lifetime bioassays in rodents are not mutagenic and, therefore, at the most weakly carcinogenic, generally by epigenetic mechanisms. It thus appears obvious that only marginal increases of tumour incidences can be expected in lifetime bioassays and that, therefore, every aspect of a potential carcinogenic effect must be thoroughly evaluated. This paper describes a series of key factors, which should be looked at in order to exclude that the lifetime bioassay in question is flawed for design, technical or qualification reasons. It also provides some hints whether there is indeed a real effect and not just a variation of the spontaneous tumour incidences. Tumour findings must be seen in the context of the animal model, the pharmcokinetics and pharmcodynamics of the test substance, as well as any other observation in the present or other studies with the test substance, including non-tumour findings and--in particular--potential precursor lesions and effects on feed intake and survival. The possibility that the observed carcinogenic effects may be species-specific and not relevant for man is discussed. It is also important to check what findings are reported with similar substances or substances with the same pharmacological effect. Data from additional investigations on material of the same study and/or mechanistic studies are often needed to support the final risk assessment.