In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project
By Richard S. Judson, K. Houck, R. Kavlock, T. Knudsen, Matt T. Martin, Holly M. Mortensen, David M. Reif, Daniel M. Rotroff, I. Shah, Ann M. Richard and 1 more. 2009
588 citations recorded by the source corpus.
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. Objectives 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.
Subfields: Computational Theory and Mathematics, Health, Toxicology and Mutagenesis, Small Animals
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Computational Theory and Mathematics
- R. Kavlock
- Christopher M. Grulke
- Richard S. Judson
- Kamel Mansouri
- Antony J. Williams
- Douglas B. Kell
- David Broadhurst
In Health, Toxicology and Mutagenesis
In Small Animals
Citations in the corpus
- The CompTox Chemistry Dashboard: a community data resource for environmental chemistry (2017, methodology): “The ToxCast and Tox21 in vitro high-throughput screening (HTS) programs have generated data for ~ 10,000 compounds in hundreds of assays [55].”
- Integrated Model of Chemical Perturbations of a Biological Pathway Using 18 In Vitro High-Throughput Screening Assays for the Estrogen Receptor. (2015, methodology): “These 18 in vitro assays are a subset of a larger collection of assays (821 individual assay endpoints) used in the EPA ToxCast program (Dix et al. , 2007; Judson et al. , 2010; Kavlock et al. , 2012).”
- Improving the Human Hazard Characterization of Chemicals: A Tox21 Update (2013, methodology): “The results are corrected to remove arti facts due to cytotoxicity and parameters such as concentration for half maximal activity, maximum efficacy, and minimal response are used to make activity calls based on algorithms for specific assay types and platforms (Judson et al. 2010).”