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.

EURL ECVAM Genotoxicity and Carcinogenicity Database of Substances Eliciting Negative Results in the Ames Test: Construction of the Database

“…The Ames-positive database is populated with all available information for genotoxicity endpoints in vitro and in vivo , plus available carcinogenicity data. It constitutes a powerful resource for developing and evaluating alternative approaches to animal testing for genotoxicity and carcinogenicity assessment and has proved its utility as reference source for a number of genotoxicity-related regulatory and research activities [ 10 , 11 ].…”

Detection and analysis of chemical-induced chromosomal damage for public health: integrating new approach methodologies and non-animal methods

“…IATA incorporates and integrates toxicity, physicochemical, pharmacokinetic and bioactivity data for target chemicals (Tcheremenskaia and Benigni, 2021). IATA for carcinogenicity detection was developed using genotoxicity testing results and chemical properties (Petkov et al, 2016;Fujita et al, 2019). Fujita et al (2019) developed an Integrated Testing Strategy (model) for carcinogenicity evaluation using mutation and chromosomal damage assay data as well as chemical molecular weights and partial chemical structure information.…”

“…Hence, the integrated testing model using chromosomal damage information effectively detected carcinogenicity. Petkov et al (2016) developed an IATA scheme to predict genotoxic carcinogens using both in vivo and in vitro genotoxicity test results that include chromosomal damage information. They showed that chromosomal aberration is an important factor covering all carcinogen mechanisms.…”

Genotoxicity study of 2-methoxyethanol and benzalkonium chloride through Comet assay using 3D cultured HepG2 cells

“…747). In the evaluation of carcinogenicity, a new genotoxicity test method is also being developed because the strategic limitation of the existing genotoxicity evaluation is also confirmed, and improvement of the strategy of carcinogenicity evaluation is also required [9][10][11][12].…”