title: Integrated approach to testing and assessment for predicting rodent genotoxic carcinogenicity.
abstract: We investigated the performance of an integrated approach to testing and assessment (IATA), designed to cover different genotoxic mechanisms causing cancer and to replicate measured carcinogenicity data included in a new consolidated database. Genotoxic carcinogenicity was predicted based on positive results from at least two genotoxicity tests: one in vitro and one in vivo (which were associated with mutagenicity categories according to the Globally Harmonized System classification). Substances belonging to double positives mutagenicity categories were assigned to be genotoxic carcinogens. In turn, substances that were positive only in a single mutagenicity test were assigned to be mutagens. Chemicals not classified by the selected genotoxicity endpoints were assigned to be negative genotoxic carcinogens and subsequently evaluated for their capability to elicit non-genotoxic carcinogenicity. However, non-genotoxic carcinogenicity mechanisms were not currently included in the developed IATA. The IATA is docked to the OECD Toolbox and uses measured data for different genotoxicity endpoints when available. Alternatively, the system automatically provides predictions by SAR genotoxicity models using the OASIS Tissue Metabolism Simulator platform. When the developed IATA was tested against the consolidated database, its performance was found to be high, with sensitivity of 74% and specificity of 83%, when measured carcinogenicity data were used along with predictions falling within the models' applicability domains. Performance of the IATA would be slightly changed to a sensitivity of 80% and specificity of 72% when the evaluation by non-genotoxic carcinogenicity mechanisms was taken into account. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Laboratory of Mathematical Chemistry (LMC), As. Zlatarov University, Bourgas, Bulgaria.
authors.forename: Petko I
authors.initials: PI
authors.lastname: Petkov
authors.affiliation: College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, 37996-4500, USA.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Schultz
authors.affiliation: DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, DE, USA.
authors.forename: E Maria
authors.initials: EM
authors.lastname: Donner
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
authors.affiliation: Division of Risk Assessment, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morita
authors.affiliation: LSI Medience Corporation, Ibaraki, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hamada
authors.affiliation: Astellas Pharma Inc, Osaka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Wakata
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Fuji Gotemba Research Labs, Shizuoka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mishima
authors.affiliation: Clinical Science Division, Research & Development AstraZeneca KK, Osaka, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Maniwa
authors.affiliation: Laboratory of Mathematical Chemistry (LMC), As. Zlatarov University, Bourgas, Bulgaria.
authors.forename: Milen
authors.initials: M
authors.lastname: Todorov
authors.affiliation: Laboratory of Mathematical Chemistry (LMC), As. Zlatarov University, Bourgas, Bulgaria.
authors.forename: Elena
authors.initials: E
authors.lastname: Kaloyanova
authors.affiliation: Laboratory of Mathematical Chemistry (LMC), As. Zlatarov University, Bourgas, Bulgaria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kotov
authors.affiliation: Laboratory of Mathematical Chemistry (LMC), As. Zlatarov University, Bourgas, Bulgaria. omekenya@btu.bg.
authors.forename: Ovanes G
authors.initials: OG
authors.lastname: Mekenyan
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D016208:Databases, Factual; D008954:Models, Biological; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D011237:Predictive Value of Tests; D051381:Rats; D018570:Risk Assessment / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D002273:Carcinogens; D009153:Mutagens
keywords: IATA; OECD Toolbox; TIMES; carcinogenicity; genotoxicity