In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project.
BACKGROUND
Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches.


OBJECTIVE
This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity.


METHODS
We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed.


RESULTS
Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation.


CONCLUSIONS
This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants.
Judson
Richard S
RS
National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. judson.richard@epa.gov
Houck
Keith A
KA
Kavlock
Robert J
RJ
Knudsen
Thomas B
TB
Martin
Matthew T
MT
Mortensen
Holly M
HM
Reif
David M
DM
Rotroff
Daniel M
DM
Shah
Imran
I
Richard
Ann M
AM
Dix
David J
DJ
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D051381:Rats; D018675:Toxicity Tests / Q000379:methods*; D014481:United States; D014484:United States Environmental Protection Agency
D004785:Environmental Pollutants