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An Evaluation of 25 Selected ToxCast Chemicals in Medium-Throughput Assays to Detect Genotoxicity
Citation:
Kligerman, A., R. Young, L. Stankowski, K. Pant, T. Lawlor, M. Aardema, AND K. Houck. An Evaluation of 25 Selected ToxCast Chemicals in Medium-Throughput Assays to Detect Genotoxicity. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS. John Wiley & Sons, Inc, Hoboken, NJ, 56(5):468-476, (2015).
Impact/Purpose:
The results from this study show that there is a good correlation between the standard Ames Test and the Ames II MT assay and results gleaned from the literature and the results for the MT Flow MN Assay. The MT Comet Assay as run in this study did not show high specificity and selectivity. However, there was a reasonably good correlation between a HT 053 Induction assay and the genotoxicity literatun~ results for the 25 chemicals examined, lending some support to the usefulness of both the HT and MT assays.
Description:
ABSTRACTToxCast is a multi-year effort to develop a cost-effective approach for the US EPA to prioritize chemicals for toxicity testing. Initial evaluation of more than 500 high-throughput (HT) microwell-based assays without metabolic activation showed that most lacked high specificity and sensitivity for detecting genotoxicants. Thus, EPA initiated a project to generate data for standard genotoxicity endpoints using medium throughput genotoxicity (MTG) assays. Twenty- five chemicals were selected from the ToxCast program based in part on their known genotoxicity. The three MTG assays used were the Ames II assay, an 96-well In Vitro MicroFlow® Micronucleus (MN) assay, and a 96-well in vitro single cell gel electrophoresis (comet) assay. Though the dataset was small, the results were encouraging. The Ames II assay showed good correlation with published Ames test data and industry submissions. Overall concordance was 77% both with and without metabolic activation. The flow MN assay also had modest concordance of 75% and 61% with and without metabolic activation, respectively, when compared to published data from a variety of cytogenetic endpoints. However, the number of chemicals with definitive data from the literature was even smaller, so these analyses are limited. There were insufficient data from the literature to evaluate the performance of the comet assay. Importantly, a comparison of results without S9 from the MTG assays to an HT ToxCast immunofluorescence p53 assay showed a fairly good degree of concordance (67%). Taken together, these studies highlight considerations that may need to be taken into account for improving MTG and HT testing.
