REGULATORY GENOTOXICITY TESTING - A CRITICAL-APPRAISAL

This review considers current approaches to regulatory genotoxicity te sting, focusing on how the use of animals can be further replaced, red uced and refined. The complementary roles of in vitro and in vivo test ing, and the justification for using animals, are discussed in detail. Recommendations are made for improvements and further work, in the li ght of the considerable current controversy surrounding the compositio n 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 insensitiv ity of in vivo assays. On the basis of an analysis of some published d atabases, it is concluded that there is insufficient support for using in vivo genotoxicity assays for screening. Also, it is questionable w hether the scientific benefits of using such assays always outweigh th e costs to the animals involved. The considerable efforts being made t o harmonise in vivo protocols and to develop improved methods for dete cting genotoxicity are discussed. It is recommended that more emphasis be placed on characterising genotoxins in vitro, especially for mecha nisms 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 resul ts, is facilitated. Lastly, in the development and validation of trans genic rodent systems, emphasis should be placed on developing protocol s in which other acute toxicity and metabolism endpoints can be measur ed simultaneously with in vivo mutagenesis, while minimising animal nu mbers.