National Toxicology Program

The last two decades have produced dramatic technological advances in molecular biology and computer science. The NTP has evaluated how best to incorporate these advances into its research and testing strategies in order to broaden scientific knowledge of exposure-related disease mechanisms. The NTP Vision for the 21st Century is to move toxicology from a predominantly observational science at the level of disease-specific models to a predominantly predictive science focused upon a broad inclusion of target-specific, mechanism-based, biological observations.

To implement the Vision, the NTP developed a Roadmap that places an increased emphasis on the use of alternative assays for targeting the key pathways, molecular events, or processes linked to disease or injury, and attempts to incorporate them into a research and testing framework. As a logical outgrowth of the Roadmap, NTP established a High Throughput Screening (HTS) program, representing a new paradigm in toxicological testing. NTP is using this HTS approach to screen for mechanistic targets active within cellular pathways critical to carcinogenicity, reproductive and developmental toxicity, genotoxicity, neurotoxicity, and immunotoxicity. NTP's HTS program is administered through the newly created Biomolecular Screening Branch (BSB).

The goals of the HTS Program are three-fold:

• To prioritize substances for further in-depth toxicological evaluation (to judiciously allocate efforts and resources to maximize public health impact)
• To identify mechanisms of action for further investigation (e.g., disease-associated pathways)
• To develop predictive models for in vivo biological response (predictive toxicology)

Through a memorandum of understanding (MOU) (see February 2008 News Release), the NTP is partnering with the National Human Genome Research Institute's NIH Chemical Genomics Center (NCGC) (http://www.ncgc.nih.gov/index.html) and the U.S. Environmental Protection Agency's National Center for Computational Toxicology ToxCast™ program (http://www.epa.gov/comptox/), located within the Office of Research and Development, to test a large number of compounds (~ 8,000) broadly characterizing and defining the chemical-biological space occupied by chemicals of toxicological concern. Quantitative HTS assays are being run on NTP and EPA chemical libraries submitted to NCGC and data from these assays, along with full chemical characterization and assay protocol details, are being deposited into publicly accessible relational databases, such as PubChem (http://pubchem.ncbi.nlm.nih.gov/). Secondary screens using the C. elegans model (http://www.niehs.nih.gov/research/atniehs/labs/lmt/cg/index.cfm), are under development and the tripartite collaboration between the NTP, EPA, and NCGC will establish a full spectrum of secondary and tertiary screening assays to further define and characterize activities identified in initial high throughput screens.

For further information on NTP's High Throughput Screening program, contact:

Raymond Tice, Ph.D.
Chief, Biomolecular Screening Branch
NIEHS/NTP
P. O. Box 12233, MD K2-17 
111 T. W. Alexander Drive
Durham, NC 27713
T: (919) 541-4482
F: (919) 541-0947
[Send Email]

Publications:

Xia M, Huang R, Witt KL, Southall N, Fostel J, Cho MH, Jadhav A, Smith CS, Inglese J, Portier CJ, Tice RR, Austin CP. Compound cytotoxicity profiling using quantitative high-throughput screening. Environ Health Perspect. 2008 Mar;116(3):284-91

Huang R, Southall N, Cho MH, Xia M, Inglese J, Austin CP. Characterization of diversity in toxicity mechanism using in vitro cytotoxicity assays in quantitative high throughput screening. Chem Res Toxicol. 2008 Mar;21(3):659-67.

Collins FS, Gray GM, Bucher JR. Toxicology. Transforming environmental health protection. Science. 2008 Feb 15;319(5865):906-7.