title: An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: II. Identification of genotoxicants, reprotoxicants, and carcinogens using in silico methods.
abstract: This study examined a novel method to identify carcinogens that employed expanded data sets composed of in silico data pooled with actual experimental genetic toxicity (genetox) and reproductive and developmental toxicity (reprotox) data. We constructed 21 modules using the MC4PC program including 13 of 14 (11 genetox and 3 reprotox) tests that we found correlated with results of rodent carcinogenicity bioassays (rcbioassays) [Matthews, E.J., Kruhlak, N.L., Cimino, M.C., Benz, R.D., Contrera, J.F., 2005b. An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints. Regul. Toxicol. Pharmacol.]. Each of the 21 modules was evaluated by cross-validation experiments and those with high specificity (SP) and positive predictivity (PPV) were used to predict activities of the 1442 chemicals tested for carcinogenicity for which actual genetox or reprotox data were missing. The expanded data sets had approximately 70% in silico data pooled with approximately 30% experimental data. Based upon SP and PPV, the expanded data sets showed good correlation with carcinogenicity testing results and had correlation indicator (CI, the average of SP and PPV) values of 75.5-88.7%. Conversely, expanded data sets for 9 non-correlated test endpoints were shown not to correlate with carcinogenicity results (CI values <75%). Results also showed that when Salmonella mutagenic carcinogens were removed from the 12 correlated, expanded data sets, only 7 endpoints showed added value by detecting significantly more additional carcinogens than non-carcinogens.
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Informatics and Computational Safety Analysis Staff (ICSAS), 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. matthewse@cder.fda.gov
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Matthews
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Kruhlak
authors.forename: Michael C
authors.initials: MC
authors.lastname: Cimino
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Benz
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Contrera
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000145:classification / Q000633:toxicity*; D003198:Computer Simulation; D005069:Evaluation Studies as Topic; D008954:Models, Biological; D009152:Mutagenicity Tests; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D012098:Reproduction / Q000187:drug effects*; D012680:Sensitivity and Specificity; D012984:Software; D036401:Toxicity Tests, Chronic
chemical_list: D002273:Carcinogens