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Dose response screening of the Toxcast chemical library using a Zebrafish developmental assay
Citation:
PADILLA, S. J., D. L. HUNTER, B. K. PADNOS, D. Corum, D. REIF, K. A. HOUCK, T. B. Knudson, M. T. Martin, AND D. J. Dix. Dose response screening of the Toxcast chemical library using a Zebrafish developmental assay. Presented at Society of Toxicology 49th annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
As part of the chemical screening and prioritization research program of the U.S. Environmental Protection Agency, the toxicity of the 320 ToxCaspM Phase I chemicals was assessed using a vertebrate screen of developmental toxicity. Zebrafish embryos/larvae (Danio rerio) were exposed in 96-well plates from late blastula stage (approximately 6hr post fertilization, pf) to day 5pf (1 day post hatch).
Description:
As part of the chemical screening and prioritization research program of the U.S. Environmental Protection Agency, the toxicity of the 320 ToxCaspM Phase I chemicals was assessed using a vertebrate screen of developmental toxicity. Zebrafish embryos/larvae (Danio rerio) were exposed in 96-well plates from late blastula stage (approximately 6hr post fertilization, pf) to day 5pf (1 day post hatch). The 320 chemicals tested included 309 unique chemicals, most of which are pesticide actives and. metabolites, and several replicates for quality control. All exposures were by continuous immersion, with a dose range of 1 nM to 80 IJM (semilog spacing, 11 concentrations). On day 5pf, fish were removed from the exposure solution to a control solution without chemicals, and on day 6pf were assessed for death and structural defects (n=2-3 independent embryos per chemical/concentration). All inter-and intra-plate replicates showed excellent concordance with regard to potency. Gross structural abnormalities or death were not observed after treatment for 36% of the chemicals. Of chemicals that produced lethality or structural abnormalities, approximately 90% showed a lowest effective concentration (LEC) between 80 and 1 uM; less than 10% had LEC between 1 uM and 1 nM. Bioavailability to the embryo appeared to influence toxicity for some chemicals. Approximately 90% of chemicals with a LogP below 1.5 had no effects, while only 23% of chemicals with LogP equal to or greater than 1.5 had no effects at any concentration. Analyses are underway comparing relative potency of chemicals in this zebrafish developmental assay with ToxCast in vitro assays, and with in vivo mammalian developmental toxicity captured in the U.S. EPA ToxRefDB database. This abstract may not necessarily reflect official Agency policy.