THE ROLE OF STRUCTURE-ACTIVITY-RELATIONSHIPS AND EXPERT-SYSTEMS IN ALTERNATIVE STRATEGIES FOR THE DETERMINATION OF SKIN SENSITIZATION, SKINCORROSIVITY AND EYE IRRITATION

A historical database containing the results of 294 defined single sub stances tested in the guinea-pig maximisation test, carried out accord ing to a single protocol, was used to derive a set of structural alert s 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 id entification of contact allergens. Quantitative structure-activity rel ationships (QSARs) were derived for the skin corrosivity of organic ac ids and bases, and for the eye irritation potential of neutral organic chemicals. The independent variables used for these analyses were sel ected on the basis of the putative mechanisms for skin irritation or c orrosivity and for eye irritation, respectively. Data sets were analys ed using principal components analysis; plots of the first two princip al 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 techniqu es is still at a very early stage, they are already able to play an im portant part in proposed strategies for the reduction of experimental animal usage. In the long term, it should be possible to conduct safet y evaluations using fewer experimental animals or no animals at all. H owever, acceptance by regulatory authorities will be a key factor in r ealising the full benefits of the approach.