Structural determinants of developmental toxicity.
Developmental toxicity, an area of public concern, suffers from the lack of accessible, reliable, peer-reviewed compilations of data and substantial gaps in testing. These deficits frequently make it necessary for regulatory agencies to use other toxicological end points to regulate developmental toxicants. We have utilized a database of chemicals identified as developmental toxicants in rats, mice, rabbits, and humans and an expert system which learns the association between molecular structure and biological response (Computer Automated Structure Evaluation; CASE) to explore structure-activity relationships in developmental toxicity. Developmental toxicity was defined as death, growth retardation, or structural or functional malformations. In analyzing the data CASE selects its own molecular descriptors from a learning set of active and inactive molecules. Using randomly constructed learner and tester sets, the concordance of the predictions with the actual data was between 77 and 82%. CASE identified 13 major structural fragments associated with developmental toxicity in mice, 15 in rats, 9 in rabbits, and 7 in humans. These analyses indicate that there is indeed a structural basis for developmental toxicity which may be used to predict the developmental hazard of untested or inadequately tested chemicals.