Further evaluation of COMPACT, the molecular orbital approach for the prospective safety evaluation of chemicals

The molecular dimensions and electronic structures of the first group of 100 US NCI/NTP miscellaneous chemicals, evaluated for potential carcinogenicity by computer-optimized molecular parametric analysis for chemical toxicity (COMPACT) have been re-determined. Using improved criteria for cytochrome P450 (CYP) substrate specificity, re-defined for CYP1 as having a COMPACT radius [square root of (deltaE - 9.5)2 + (a/d(2) - 7.8)2] of < 6.5, and for CYP2E as having a collision diameter of 6.5 angstroms or less and deltaE < 15.5, the likely substrates of CYP1 and CYP2E, which are regarded as potential carcinogens, have been identified. In addition, log P values have been taken into account; those chemicals with log P < 0 are non-lipophilic substrates unlikely to reach the activating cytochrome enzymes, and have been regarded as non-carcinogens. The second group of 100 US NCI/NTP chemicals have also now been categorized by COMPACT into CYP1 and CYP2E substrates, and their potential carcinogenicities evaluated. Of the 203 chemicals in the 2 groups, those positive in the rodent two-species life-span carcinogenicity study (rodent assay) were 53%, those positive in the Ames test (mutagenicity) were 48%, and those positive in the COMPACT programme (carcinogenicity, mutagenicity, cytotoxicity) were 54%. Concordance between the COMPACT prediction of carcinogenicity/cytotoxicity and rodent two species life-span carcinogenicity data for the 203 chemicals is 69%, and correlation of COMPACT with Ames test data is 61%. The sensitivity of COMPACT for predicting rodent carcinogenicity is 72%, whereas the sensitivity of the Ames test for predicting carcinogenicity for the 203 chemicals was only 57%. The degree (severity) of rodent carcinogenicity also showed correlation with the COMPACT predictive evaluations of the chemicals.