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Alternatives Models in Carcinogenicity Testing—A European Perspective

Laboratory for Medicines and Medical Devices, National Institute of Public Health and the Environment, Bilthoven, The Netherlands, jan-willem.van.der.laan{at}rivm.nl

Beatriz Silva Lima

Unit of Pharmacology and Pharmacotoxicology of the University of Lisboa and Preclinical Assessment Group of INFARMED, Lisboa, Portugal

David Snodin

Medicines Control Agency, London, United Kingdom

Transgenic mouse strains offer the prospect of significant benefits in the in vivo assessment of carcinogenic potential. The European Regulatory Authorities have been supportive of their inclusion as one of the second-test options in the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human use (ICH). However, there is a concern regarding premature systematic use of these models. At present, the information from the International Life Sciences Institute (ILSI) project suggests that the transgenic models under study are similarly sensitive to genotoxic pharmaceuticals. There are apparently some false negatives and false positives. For regulatory purposes, it is not yet possible to differentiate the models with respect to hazard identification and risk assessment. The evaluation of the models has reached an interesting but, at certain points, equivocal stage. Based on the weight of evidence gathered thus far, regulatory authorities cannot neglect the outcome of such studies but need to be cautious in their interpretation of data from such models, and the application in risk assessment procedures.

Key Words: Carcinogenicity testing • transgenic animals • human pharmaceuticals.

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