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Toxicology in the 21st Century

Tox21 Program Goals

The goal of Tox21 is to develop more efficient and less time-consuming approaches to predict how chemicals may affect human health. Initially, the main focus of Tox21 is to help prioritize chemicals for more extensive testing using traditional methods. Tox21’s ultimate aim is to develop strategies for agencies to use in regulating chemicals and reducing the current reliance on animal testing for toxicological evaluations.

To achieve these goals, the objectives of the Tox21 program are to:

  • Identify environmental chemicals that lead to biological responses and determine their mechanisms of action on biological systems.
  • Prioritize specific compounds for more extensive toxicological evaluation.
  • Develop models that predict chemicals’ negative health effects in humans.
  • Annotate all human biochemical pathways and design assays (tests) that can measure these pathways’ responses to chemicals.

Tox21 Scientific Themes

Within Tox21, the current screening effort includes two themes:

  1. Generating fit-for-purpose cellular models for secondary screening
    Tox21 experts are developing a range of hepatocyte (liver), neuron, endothelial (skin) and cardiomyocyte (heart) cell models — including “disease-in-a-dish” models, 3-D culture methods and multicellular co-culture models, all derived from inducible pluripotent stem cells (iPSCs) — to further characterize hits from primary screening of 10,000 compounds (Tox21 10K library). The group uses an iPSC-derived endothelial cell model from the National Heart, Lung and Blood Institute to investigate tobacco lung toxicity through a grant from the Food and Drug Administration and NIH.
  2. Developing a high-throughput gene expression core facility
    Tox21 scientists have developed a high-throughput gene expression platform core facility with the goal of generating data from hundreds of thousands of samples across 1,400 human genes each year. Although the team uses RNAseq technology to analyze all genes in a few samples, evaluating the effects of many compounds at multiple doses and times, each on several cell lines, requires higher throughput. To this end, the group is developing the RASL-Seq technology platform, which includes approximately 1,400 human gene assays and a streamlined, automated procedure to serve both Tox21 collaborators and NCATS projects. The data analysis team is implementing a pipeline to enable data processing and statistical and systems analyses, which will be useful for RASL-Seq and RNAseq data.