The Tox21 Program is a multiagency collaborative effort among the Environmental Protection Agency (EPA), Food and Drug Administration (FDA), the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS), and NCATS to advance in vitro toxicological testing. The Tox21 Program is comprised of three NCATS teams: Systems Toxicology, Genomic Toxicology, and Computational Toxicology. The Genomic Toxicology group has used the Toxmatrix method (Tong 2018) to identify pathways that render neurons susceptible to 32 neurodegenerative toxicants investigated. Toxmatrix interactions identified iron transport, and oxidative metabolism as characteristic neuronal toxicity pathways. Transcriptional profiling of neurotoxicants has identified seven transcriptionally-induced biomarker genes that are particularly responsive to toxicants that cause, or increase risk for, Parkinsons disease (PD). These chemical interactions, culture conditions, and biomarkers, are being used to develop a qHTS assay to screen chemical libraries to identify potential neurodegenerative toxicants. The Genomic Toxicology and Computational Toxicology groups have also advanced high-throughput gene expression technology. In 2018, we worked with Computational Toxicology to adapt our Point-of-Departure (POD) algorithm to RNAseq, and applied it to identify endothelial cell gene responses to chemicals from tobacco smoke that lead to heart attack and stroke. The POD algorithm revealed multiple toxico-dynamic effects of individual chemicals that accumulated as the toxicant concentration was increased; a reductive analysis of the toxicological principle The dose makes the poison.
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| Xia, Menghang; Huang, Ruili; Shi, Qiang et al. (2018) Comprehensive Analyses and Prioritization of Tox21 10K Chemicals Affecting Mitochondrial Function by in-Depth Mechanistic Studies. Environ Health Perspect 126:077010 |
| Grimm, Fabian A; Iwata, Yasuhiro; Sirenko, Oksana et al. (2016) A chemical-biological similarity-based grouping of complex substances as a prototype approach for evaluating chemical alternatives. Green Chem 18:4407-4419 |
| Tong, Zhi-Bin; Hogberg, Helena; Kuo, David et al. (2016) Characterization of three human cell line models for high-throughput neuronal cytotoxicity screening. J Appl Toxicol : |
| Pamies, David; Bal-Price, Anna; Simeonov, Anton et al. (2016) Good Cell Culture Practice for stem cells and stem-cell-derived models. ALTEX : |
