Regulatory Genotoxicity Testing: A Critical Appraisal

Abstract

This review considers current approaches to regulatory genotoxicity testing, focusing on how the use of animals can be further replaced, reduced and refined. The complementary roles of in vitro and in vivo testing, and the justification for using animals, are discussed in detail. Recommendations are made for improvements and further work, in the light of the considerable current controversy surrounding the composition and deployment of testing strategies, and the interpretation of the data generated, particularly for carcinogenicity prediction. The major problems are the oversensitivity of in vitro tests and the insensitivity of in vivo assays. On the basis of an analysis of some published databases, it is concluded that there is insufficient support for using in vivo genotoxicity assays for screening. Also, it is questionable whether the scientific benefits of using such assays always outweigh the costs to the animals involved. The considerable efforts being made to harmonise in vivo protocols and to develop improved methods for detecting genotoxicity are discussed. It is recommended that more emphasis be placed on characterising genotoxins in vitro, especially for mechanisms of activity, to optimise the benefits of any confirmatory animal tests.. Also, regulatory agencies are urged to require better-designed and more-scientifically sound protocols, in which animal numbers are minimised and data interpretation, particularly that of negative results, is facilitated. Lastly, in the development and validation of transgenic rodent systems, emphasis should be placed on developing protocols in which other acute toxicity and metabolism endpoints can be measured simultaneously with in vivo mutagenesis, while minimising animal numbers.