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 considered critical to adverse health effects (e.g., carcinogenicity, reproductive and developmental toxicity, genotoxicity, neurotoxicity, and immunotoxicity) in humans. NTP's HTS program is administered through the recently 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) and the U.S. Environmental Protection Agency's National Center for Computational Toxicology, located within the Office of Research and Development, to test a large number of compounds broadly characterizing and defining the chemical-biological space occupied by chemicals of toxicological concern. In the first phase of quantitative HTS testing at the NCGC, the MOU partners (informally known as the "Tox21" community for Toxicology Testing in the 21st Century) tested ~2800 compounds in more than 50 screens. The resulting data, 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/). In the future, data will also be deposited in EPA's ACToR (Aggregated Computational Toxicology Resource) and NTP's CEBS (Chemical Effects in Biological Systems). Secondary screens using Caenorhabditis elegans, 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. Individuals interested in nominating an assay or assays for consideration by the NTP can do so by completing and submitting an Assay Nomination form available on the NTP Nominations webpage.

In the next phase, the MOU partners will be testing at the NCGC an expanded library of ~10000 compounds. This library is currently being constructed, with expectations that expanded testing at the NCGC will begin in late 2009/early 2010. In addition, a subset of these compounds will be tested in Phase II of EPA's ToxCast™ program.

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:

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

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.

Kavlock RJ, Austin CP, Tice RR. Toxicity Testing in the 21st Century: Implications for Human Health Risk Assessment, Risk Analysis 2009; 29(4):485-487.

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

Xia M, Huang R, Sun Y, Semenza GL, Aldred SF, Witt KL, Inglese J, Tice RR, Austin CP. Identification of Chemical Compounds that Induce 1 HIF-1α Activity. Toxicological Sciences 2009; doi:10.1093/toxsci/kfp123.