Citation:

LITTLE, S., A. W. Knight, L. Birrell, G. Akerman, N. McCarroll, D. J. DIX, K. A. HOUCK, R. JUDSON, R. J. KAVLOCK, M. T. MARTIN, A. M. RICHARD, C. Yang, AND R. M. Walmsley. High Throughput Genotoxicity Profiling of the US EPA ToxCast Chemical Library. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 15 - 19, 2009.

Impact/Purpose:

In addition, compound structures were analysed in silico for predicted genotoxicity and carcinogenicity endpoints using DEREK for Windows. Results from these assays were compared to historical mutagenicity, genotoxicity, tumorigenicity and carcinogenic potential data collected from a variety of sources, including the ToxRefDB database. Historical data indicated some level of mutagenic concern for approximately 20% of the ToxCast chemicals, over 50% of the chemicals caused some form of tumor in high-dose chronic tests, and approximately 20% of the chemicals were classified as possible or probable human carcinogens. Similar percentages of chemicals had either ToxCast HTS genotoxicity assay or DEREK in silico alerts for mutagenicity or carcinogenicity, and these data will be used for ToxCast predictive modeling.

Description:

A key aim of the ToxCast project is to investigate modern molecular and genetic high content and high throughput screening (HTS) assays, along with various computational tools to supplement and perhaps replace traditional assays for evaluating chemical toxicity. Genotoxicity is an area of toxicity testing that would greatly benefit from this approach. The hypothesis tested was that useful and predictive genotoxicity data can be obtained by integrating the results from a battery of individual HTS in vitro tests. The ToxCast Phase I set of 320 chemicals, primarily pesticides with significant in vivo toxicity data, were subjected to various HTS genotoxicity assays including the GADD45a-GFP (GreenScreen HC) assay from Gentronix, and p53 based assays from other ToxCast assay sources.

Record Details: