FURTHER EVALUATION OF COMPACT, THE MOLECULAR-ORBITAL APPROACH FOR THEPROSPECTIVE SAFETY EVALUATION OF CHEMICALS

The molecular dimensions and electronic structures of the first group of 100 US NCI/NTP miscellaneous chemicals, evaluated for potential car cinogenicity by computer-optimized molecular parametric analysis for c hemical toxicity (COM-PACT) have been re-determined. Using improved cr iteria for cytochrome P450 (CYP) substrate specificity, re-defined for CYP1 as having a COMPACT radius [root(Delta E-9.5)(2) + (a/d(2)-7.8)( 2)] of <6.5, and for CYP2E as having a collision diameter of 6.5 Angst rom or less and Delta E<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 activ ating cytochrome enzymes, and have been regarded as non-carcinogens. T he second group of 100 US NCI/NTP chemicals have also now been categor ized by COMPACT into CYP1 and CYP2E substrates, and their potential ca rcinogenicities evaluated. Of the 203 chemicals in the 2 groups, those positive in the rodent two-species life-span carcinogenicity study (r odent 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 COMPAC T prediction of carcinogenicity/cytotoxicity and rodent two species li fe-span carcinogenicity data for the 203 chemicals is 69%, and correla tion 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 sh owed correlation with the COMPACT predictive evaluations of the chemic als. (C) 1998 Elsevier Science B.V.