Validation of a novel molecular orbital approach (COMPACT) for the prospective safety evaluation of chemicals, by comparison with rodent carcinogenicity and Salmonella mutagenicity data evaluated by the U.S. NCI/NTP.

The molecular dimensions and electronic structures of 100 chemicals of structural diversity have been determined from molecular orbital calculations and molecular mechanics. From these parameters of molecular structure, those chemicals that are likely substrates of cytochromes P4501 and P4502E have been identified by the computer-optimized molecular parametric analysis of chemical toxicity (COMPACT) programme, and their potential toxicity, mutagenicity and carcinogenicity evaluated. The degree of correlation between COMPACT prediction of toxicity and rodent two species life-span carcinogenicity data is estimated to be 92%, and between COMPACT and Salmonella mutagenicity (Ames test) data is 64%. Anomalous rodent carcinogens are rationalized on the basis of biochemical mechanisms of metabolism, genotoxicity and carcinogenicity. Correlation of the Ames test data with rodent carcinogenicity data was 64%, but correlation of COMPACT plus Ames data versus rodent carcinogenicity data provided the highest correlation of 94%.