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Evaluating ToxCast Assays for their Ability to Detect Genotoxicity
Citation:
KLIGERMAN, A. D. Evaluating ToxCast Assays for their Ability to Detect Genotoxicity. Presented at 2011 Genetic Toxicology Association (GTA) Meeting, RTP, NC, September 14 - 15, 2011.
Impact/Purpose:
This is a review article summarizing the current literature on organoarsenicals with regard to their metabolism, uptake, toxicity =, and genotoxicity with specific reference to mode of action.
Description:
It has become evident over the past several decades, that though the standard battery of genotoxicity tests including bacterial and in vitro mammalian mutagenesis and in vitro and in vivo clastogenicity assays have been quite useful in screening out potent genotoxicants during the development and manufacturing processes, the number of industrial and environmental chemicals that need to be tested overwhelms our ability to test them in a careful and efficient manner using the present battery of assays. This was clearly pointed out by the National Academy of Sciences' report entitled Toxicity Testing in the Twenty-first Century: A Vision and a Strategy. With this in mind, the U.S. EPA set out on an ambitious project to develop chemical screening tools. One such tool is the Toxicity Forecaster (ToxCast™). ToxCast™ is a multi-year effort to develop a cost-effective approach for prioritizing the thousands of chemicals that need toxicity testing. With more than 600 assays, Phase I of ToxCast™ was designed to screen a large number of toxicity endpoints using approximately 300 well-studied chemicals, mostly pesticides. Phase II, which is currently underway, will look at an additional 700 chemicals. However, only a few of the assays were designed to measure endpoints that were directly related to genetic toxicology, and most if not all systems lacked efficient metabolic activation capabilities. The goals of the present analysis were 1) to determine which Phase I chemicals were genotoxic without metabolic activation, and 2) to evaluate how some of the high-throughput assays performed in identifying direct-acting genotoxicants. A variety of information was used including various data bases, industry submissions, and the open literature to classify the chemicals according to their reported ability to induce point mutations, chromosome breakage, and/or chromosomal numerical changes. The chemicals were then assigned a numerical value from +5 (highly active) to -5 (no activity) for each endpoint. Results from several assays will be presented to illustrate their ability to detect genotoxicants, but to date, none of the assays investigated for genotoxicity shows high specificity or sensitivity for any of the endpoints. [This abstract does not necessarily reflect US EPA policy.]