Based on a compilation of 222 reports of rodent nominal lifetime carcinogenicity bioassays by the NCI/NTP on the one hand, and corresponding Salmonella mutagenicity bioassays (Ames tests) on the other, Ashby and Tennant (1988) have divided the carcinogens and non-carcinogens into genotoxic (Ames test positive) and non-genotoxic (Ames test negative) groups and discussed structural characteristics common to each of these groups. The Ames test alone was deemed to be adequate for the identification of genotoxicity because other short-term bioassays, and even combinations, or batteries, appeared to offer no significant advantages. From the results of this study it is possible to achieve (1) a division of the carcinogens into the same genotoxic and non-genotoxic groups, and (2) a division of the non-genotoxic compounds into the same carcinogenic and non-carcinogenic groups, solely on the basis of structure-activity relationships, with a classification accuracy of approx. 95%. (1) An equation comprising 8 sigma molecular charge descriptors, 2 molecular connectivity indices (MCIs), 2 kappa molecular shape descriptors and one MOLSTAC substructure descriptor achieved discrimination between genotoxic and non-genotoxic carcinogens with an accuracy of 94.5%. (2) Another equation comprising 8 sigma molecular charge descriptors, 3 MCIs, one kappa shape descriptor and 12 substructural descriptors achieved discrimination between non-genotoxic carcinogens and non-genotoxic non-carcinogens with an accuracy of 95.2%. These SAR models are suitable for the distinction between (1) genotoxic and non-genotoxic carcinogens and (2) carcinogenic and non-carcinogenic non-genotoxins, both in the absence of animal bioassay data.
[1]
J. Gasteiger,et al.
ITERATIVE PARTIAL EQUALIZATION OF ORBITAL ELECTRONEGATIVITY – A RAPID ACCESS TO ATOMIC CHARGES
,
1980
.
[2]
S. Unger.
Molecular Connectivity in Structure–activity Analysis
,
1987
.
[3]
L. Kier.
Shape Indexes of Orders One and Three from Molecular Graphs
,
1986
.
[4]
R. Tennant,et al.
Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP.
,
1988,
Mutation research.
[5]
S. Snapinn,et al.
An Evaluation of Smoothed Classification Error- Rate Estimators
,
1985
.
[6]
K Enslein,et al.
A Structure-Activity Prediction Model of Carcinogenicity Based on Nci/Ntp Assays and Food Additives
,
1987,
Toxicology and industrial health.
[7]
Abdelmonem A. Afifi,et al.
Comparison of Stopping Rules in Forward Stepwise Discriminant Analysis
,
1979
.
[8]
K. Enslein,et al.
Prediction of Ames test results by structure-activity relationships
,
1986
.