Acceptance of in vitro studies by regulatory authorities

There has been relatively little progress regarding the acceptance of in vitro tests by regulatory authorities since the second Practical In Vitro Toxicology Conference in 1989. Advances have been made in the international acceptance of the use of in vitro methods to identify compounds with mutagenic potential. The recognition, in international guidelines on skin and eye irritancy studies, of the need for a hierarchical approach, including the use of in vitro methods to screen out severe irritants, has also been welcome. The reasons for the relatively slow progress are considered. In the case of repeated-dose animal toxicity studies, these represent an effective broad-spectrum approach to identifying the general toxic effects and target organs. It will be difficult to design in vitro methods capable of mirroring the complex interactions seen in the whole animal or the multitudes of potential targets for toxic effects. In vitro studies may, however, be valuable in characterizing such effects once identified from the animal studies. Similar considerations apply to teratogenicity, where possible mechanisms include disturbances in placental function or in maternal metabolism. These examples illustrate the fairly substantial scientific obstacles that exist in some areas. The relatively rapid acceptance of mutagenicity studies was, to some extent, due to their single, underlying mechanism, namely, damage to DNA. In view of these problems, effort has concentrated on local effects such as skin and eye irritancy. Even here, the in vivo response is a complex series of reactions, and there is the assumption that a battery of in vitro tests will be needed. There have been difficulties in identifying the most promising combination of tests to subject to detailed validation. In addition, the number and identity of the 'reference' chemicals to be used and the comparative data (in vivo animal data or human data) needed has proved to be a matter of much debate. In addition to these difficulties, the need for international acceptance of the validation data has necessitated the adoption of a more international perspective. However, a large international study is now underway which, it is hoped, will lead to some real progress in the eye irritancy area.