Evaluation of high-throughput genotoxicity assays used in profiling the US EPA ToxCast™ chemicals

Andrew W. Knight, Stephen Little, Keith Houck, David Dix, Richard Judson, Ann Richard, Nancy McCarroll, Gregory Akerman, Chihae Yang, Louise Birrell, Richard M. Walmsley

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Three high-throughput screening (HTS) genotoxicity assays-GreenScreen HC GADD45a-GFP (Gentronix Ltd.), CellCiphr p53 (Cellumen Inc.) and CellSensor p53RE-bla (Invitrogen Corp.)-were used to analyze the collection of 320 predominantly pesticide active compounds being tested in Phase I of US. Environmental Protection Agency's ToxCast™ research project. Between 9% and 12% of compounds were positive for genotoxicity in the assays. However, results of the varied tests only partially overlapped, suggesting a strategy of combining data from a battery of assays. The HTS results were compared to mutagenicity (Ames) and animal tumorigenicity data. Overall, the HTS assays demonstrated low sensitivity for rodent tumorigens, likely due to: screening at a low concentration, coverage of selected genotoxic mechanisms, lack of metabolic activation and difficulty detecting non-genotoxic carcinogens. Conversely, HTS results demonstrated high specificity, >88%. Overall concordance of the HTS assays with tumorigenicity data was low, around 50% for all tumorigens, but increased to 74-78% (vs. 60% for Ames) for those compounds producing tumors in rodents at multiple sites and, thus, more likely genotoxic carcinogens. The aim of the present study was to evaluate the utility of HTS assays to identify potential genotoxicity hazard in the larger context of the ToxCast project, to aid prioritization of environmentally relevant chemicals for further testing and assessment of carcinogenicity risk to humans. © 2009 Elsevier Inc.
    Original languageEnglish
    Pages (from-to)188-199
    Number of pages11
    JournalRegulatory Toxicology and Pharmacology
    Volume55
    Issue number2
    DOIs
    Publication statusPublished - Nov 2009

    Keywords

    • CellCiphr
    • CellSensor
    • GADD45 alpha
    • Genotoxicity
    • GreenScreen HC
    • Hazard assessment
    • High-throughput screening
    • In vitro
    • p53
    • Pesticides
    • ToxCast

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