The role of structure-activity relationships and expert systems in alternative strategies for the determination of skin sensitisation, skin corrosivity and eye irritation

By Barratt, M.D.

A historical database containing the results of 294 defined single substances tested in the guinea-pig maximisation test, carried out according to a single protocol, was used to derive a set of structural alerts for skin sensitisation, which have been incorporated into the expert system, DEREK. Together with an assessment of percutaneous absorption, this system forms an integral part of a strategic approach to the identification of contact allergens. Quantitative structure-activity relationships (QSARs) were derived for the skin corrosivity of organic acids and bases, and for the eye irritation potential of neutral organic chemicals. The independent variables used for these analyses were selected on the basis of the putative mechanisms for skin irritation or corrosivity and for eye irritation, respectively. Data sets were analysed using principal components analysis; plots of the first two principal components for each data set showed that the analyses were able to discriminate well between chemicals with different classifications of toxicological activity. The derived QSARs are expected to give useful predictions of skin corrosivity and eye irritancy for new or untested chemicals in these classes. Although the development of these techniques is still at a very early stage, they are already able to play an important part in proposed strategies for the reduction of experimental animal usage. In the long term, it should be possible to conduct safety evaluations using fewer experimental animals or no animals at all. However, acceptance by regulatory authorities will be a key factor in realising the full benefits of the approach.