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Biochemical Activities of 320 ToxCast Chemicals Evaluated Across 239 Functional Targets
KNUDSEN, T. B., K. A. HOUCK, R. JUDSON, A. V. Singh, D. J. DIX, AND R. J. KAVLOCK. Biochemical Activities of 320 ToxCast Chemicals Evaluated Across 239 Functional Targets. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
EPA’s ToxCast research program is profiling chemical bioactivity in order to generate predictive signatures of toxicity. The present study evaluated 320 chemicals across 239 biochemical assays. ToxCast phase I chemicals include 309 unique structures, most of which are pesticide actives and metabolites (www.epa.gov/ncct/toxcast) for which a rich complement of in vivo toxicity data is available, and several replicates for quality control.
The battery of 239 assay services provided by Caliper Life Sciences (www.caliperls.com) included 80 G-protein coupled receptors, 18 ion channels, 29 kinases, 19 phosphatases, 15 nuclear receptors, 11 transporters, 30 cytochrome P450s (CYPs), 15 proteases, and 14 other metabolic enzymes. Compounds were initially screened at 25 μM in 0.4% DMSO, or 10 μM in 1% ACN for CYPs. Normalized data were scaled to +1.0 (100% inhibition) and Z-score provided a composite measure of dynamic range and variability. To assess screening ‘hits’ we used median absolute deviation (MAD2) or >30%-inhibition. Preliminary results at >30% showed the following. Each chemical was active in an average of 10.2 assays (median 6); 12 chemicals were active in >15% assays and only 6 of 320 chemicals were inactive in all of the assays. Each assay on average had 14.3 chemical actives (median 7); 8 assays had >20% active chemicals and only 11 of 231 assays were not hit by any of the chemicals. These results suggest direct effects depending on the physics and chemistry of the platform, or effects of chemical depending on biochemistry of the system, or effects on target depending on the assay and selection criteria for 'hits'. Follow-up 8-point concentration response on a subset of 8,234 chemical-assay combinations is underway. Because ToxCast assay targets are both rodent- and human-based, the concentration-response may help build better linkage of existing rodent toxicity data to potential human health effects.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY