Transgenic Mouse Bioassays for Carcinogenicity Testing: A Step in the Right Direction?
Anne-Marie van Zeller and Robert D. Combes
The relevance of the rodent bioassay for assessing human risk to carcinogens has long been questioned. This has prompted several regulatory authorities and the International Conference on Harmonisation (ICH) to discuss the need for studies in two rodent species. Currently, six alternative tests are being evaluated in an interlaboratory collaborative study being organised by the International Life Sciences Institute (ILSI). These tests include four transgenic carcinogenicity assays in mice (the c-Ha-ras, Tg.AC, p53+/– and XPA systems). These assays are discussed in this review, and it is concluded that, to date, the data suggest that none of these assays is appropriate for inclusion in a carcinogenicity testing strategy. It is suggested that more emphasis should be placed on developing replacement alternative assays which are capable of identifying and characterising carcinogens of human relevance, rather than focusing on tests which are likely to merely duplicate the results of the rodent chronic bioassay. In this respect, the outcome of studies using the Syrian Hamster Embryo cell transformation assay, also being evaluated as part of the ILSI programme, will be of great interest. Ultimately, it is expected that cell transformation systems based on human cells will provide useful data for predicting human hazard from carcinogen exposures, and efforts to develop such systems should be encouraged.