Tox21 Initiative
Overview
The U.S. Tox21 Initiative has recently set forth an effort to use the quantitative high throughput screening (qHTS) approach to profile a collection of 10,000 compounds composed of environmental chemicals and drugs approved for human and animal use against a battery of cellular and biochemical assays for their potential to perturb biological pathways that may result in toxicity. Such a data set could be used to create a systematic view of the biological network and the interactions therein via its response to chemical perturbations.
To achieve this goal, a set of assays needs to be selected or designed to measure targets that encompass all pathways that are relevant to toxicity. However, what constitutes a "toxicity pathway" is not clearly defined as our current understanding of the biological system is not sufficient for us to pinpoint the specific subset of pathways the disruption of which could result in adverse health effects. Our strategy to overcome this hurdle is to collect a list of all annotated pathways, starting with all human pathways, and design assays that can measure the chemical responses of these pathways. We are in the process of development an integrated pathway resource, the NCTT BioPlanet, to allow easy browsing, visualization and analysis of the universe of pathways.
The BioPlanet will annotate pathways by source, species, biological function/process, disease/toxicity relevance and availability of probing assays (See: PubChem [pubchem.ncbi.nlm.nih.gov] and ToxCast [epa.gov]. Continued development of this resource will include compound activity data, sequence data, gene/protein expression data, incorporating pathways from non-human species, and organizing assays according to pathways/diseases/toxicity endpoints. This integrated platform will facilitate systematic analysis and modeling of toxicity responses.
The genomic toxicology component is expanding the Tox21 consortium's capabilities to screen environmental compounds for toxicity to the liver, to the kidneys, and to the nervous system. Such toxicities will be further dissected to elucidate specific mechanisms: primary insults to mitochondria, oxidative damage, or the cell cycle, for example.
The Tox21 Targeted Testing Working Group is extending the results of these in vitro screens both in vitro and in vivo, using secondary screens, as well as animal results and clinical data. These advances are made possible by new technologies and new discoveries in gene expression analysis, culture of human tissue stem cells and integrated pathway information.
The past and future advances of the Tox21 Consortium are a highly integrated, collaborative venture, in spirit and in practice. Such advances will lead to improved high throughput screens, detailed elucidation of toxic mechanisms, and, ultimately, to improved risk assessment for xenobiotic compounds.
See all related projects for the Tox21 Program
Contact
Menghang Xia, Ph.D.
Group Leader, Systems Toxicology
E-mail: mxia@mail.nih.gov
David Gerhold, Ph.D.
Group Leader, Genomic Toxicology
E-mail: gerholddl@mail.nih.gov
Ruili Huang, Ph.D.
Group Leader, Informatics
E-mail: huangru@mail.nih.gov
Last Updated: December 6, 2011
