title: An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints.
abstract: A retrospective analysis of standard genetic toxicity (genetox) tests, reproductive and developmental toxicity (reprotox) studies, and rodent carcinogenicity bioassays (rcbioassay) was performed to identify the genetox and reprotox endpoints whose results best correlate with rcbioassay observations. A database of 7205 chemicals with genetox (n = 4961), reprotox (n = 2173), and rcbioassay (n = 1442) toxicity data was constructed; 1112 of the chemicals have both genetox and rcbioassay data and 721 chemicals have both reprotox and rcbioassay data. This study differed from previous studies by using conservative weight of evidence criteria to classify chemical carcinogens, data from 63 genetox and reprotox toxicological endpoints, and a new statistical parameter of correlation indicator (CI, the average of specificity and positive predictivity) to identify good surrogate endpoints for predicting carcinogenicity. Among 63 endpoints, results revealed that carcinogenicity was well correlated with certain tests for gene mutation (n = 8), in vivo clastogenicity (n = 2), unscheduled DNA synthesis assay (n = 1), and reprotox (n = 3). The current FDA regulatory battery of four genetox tests used to predict carcinogenicity includes two tests with good correlation (gene mutation in Salmonella and in vivo micronucleus) and two tests with poor correlation (mouse lymphoma gene mutation and in vitro chromosome aberrations) by our criteria.
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*; D016208:Databases, Factual; D009152:Mutagenicity Tests; D011237:Predictive Value of Tests; D012098:Reproduction / Q000187:drug effects*; D012680:Sensitivity and Specificity; D036401:Toxicity Tests, Chronic
chemical_list: D002273:Carcinogens