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GeneTox21: An Integrated In Vitro Genetic Toxicity Assessment Platform for the 21st Century
Citation:
Hanna, J., J. Cox, A. Long, N. Chepelev, M. Beal, B. Engelward, C. Yauk, S. Dertinger, K. Witt, S. Smith-Roe, T. Barton-Maclaren, C. Woodland, S. Ferguson, R. Thomas, AND P. White. GeneTox21: An Integrated In Vitro Genetic Toxicity Assessment Platform for the 21st Century. Environmental Mutagenesis and Genomics Society (EMGS) Annual Meeting, Palm Springs, CA, September 12 - 16, 2020.
Impact/Purpose:
Abstract submitted to the Environmental Mutagenesis and Genomics Society (EMGS) Annual Meeting held in September 2020. The topic of this conference is Environmental Genomics: Mechanisms & Approaches for Genomic Integrity.
Description:
Traditional in vitro genotoxicity testing is relatively slow, costly, and laborious. Higher-throughput in vitro assays, based on modern tools and technologies, have been developed to support the global shift towards animal-free chemical screening and regulatory decision-making. The present work aims to establish a multi-endpoint, higher-throughput, in vitro genotoxicity assessment platform dubbed GeneTox21. The six assays included in the platform are the Ames II and MutaMouse FE1 cell mutagenicity assays, the MicroFlow® and MultiFlow® chromosome abnormality assays, the CometChip® DNA strand-break assay, and the TGx-DDI gene expression assay for the identification of DNA-damaging agents. To evaluate performance, the platform was employed to assess the genotoxicity of 35 reference chemicals selected by an external research advisory committee; the reference chemicals include weak and strong genotoxicants and non-genotoxicants. The test battery was also employed to evaluate 20 data-poor compounds prioritized for regulatory screening. Initial results indicate that the platform is capable of reliably identifying genotoxicants, and providing valuable mode-of-action information for data-poor chemicals. To facilitate data analysis and interpretation, a user-friendly bioinformatic tool was developed for multiplexed dose-response analysis and potency ranking, i.e., the Integrated Analysis Tool for Genotoxicity Assessment (IATGA). Further development of IATGA will include the incorporation of functionality to calculate administered equivalent dose (AED), which can in turn be used to calculate a bioactivity-exposure ratio (BER). Additional development will permit calculation of a genotoxic activity index similar to ToxPi. It is anticipated that the GeneTox21 platform will expedite and improve effective chemical screening to support prioritization and risk assessment. The views expressed are those of the authors and do not necessarily represent the policies of the US EPA.