Biomolecular Screening Branch

Research Summary

The Biomolecular Screening Branch (BSB), headed by Raymond R. Tice, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/bmsb/staff/tice/), develops and carries out programs in medium and high throughput screening of environmental substances for rapid detection of biological activities of significance to toxicology. The Branch also develops analysis tools and approaches that integrate its assessment with findings from traditional toxicology. The BSB administers the National Toxicology Program's (NTP) (http://ntp-server.niehs.nih.gov/) high throughput screening (HTS) program (http://ntp.niehs.nih.gov/go/28213), a major new initiative within NTP's Roadmap (http://ntp.niehs.nih.gov/go/vision) to achieve its vision for toxicology in the 21st century. The Roadmap 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. The goals of the HTS Program are to:

• prioritize substances for further in-depth toxicological evaluation and judiciously allocate efforts and resources to maximize public health impact
• identify mechanisms of action, such as disease-associated pathways
• develop predictive models for human biological response, also known as predictive toxicology

In support of this Program, the BSB represents the NTP in the Toxicology in the 21st Century Partnership (Tox21) — see Tox21 memorandum of understanding (MOU) (http://ntp.niehs.nih.gov/files/ntpncgcepamou.pdf)   — 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 (EPA) National Center for Computational Toxicology (http://www.epa.gov/comptox/) , located within the Office of Research and Development. The goal of this partnership is to test at the NCGC approximately 10,000 compounds of toxicological concern using quantitative HTS assays that provide information on the ability of these compounds to affect key cellular pathways associated with the induction and/or progression of human disease.

Caenorhabditis elegans

NTP's in-house screening facility (aka WormTox) evaluates Caenorhabditis elegans as an alternative organism for in vivo toxicological testing. Short life cycles, easy and inexpensive maintenance and culturing, and detailed biological knowledge has allowed for the development of rapid, low-cost toxicity tests that readily lend themselves to mechanistic studies of toxicant actions. Because of the evolutionarily conserved nature of the stress-response and other relevant pathways, it is likely that responses elicited in C. elegans will be applicable to understanding similar processes in higher organisms, including humans.

A smaller set of compounds within this library is also being tested in WormTox and in Phase II of EPA's ToxCast™ Program (http://www.epa.gov/ncct/toxcast/) . Data from these assays, along with full chemical characterization and assay protocol details, are being deposited into publicly accessible relational databases, such as NIEHS-NTP's Chemical Effects in Biological Systems (CEBS) (http://www.niehs.nih.gov/research/resources/databases/cebs/) , EPA's Aggregated Computational Toxicology Resource (ACToR) (http://actor.epa.gov/actor/faces/ACToRHome.jsp) , and the National Center for Biotechnology Information's (NCBI) PubChem (http://pubchem.ncbi.nlm.nih.gov/) .

The work is expected to result in methods for toxicity testing that are more mechanistically based and economically efficient; as a consequence, a reduction or replacement of animals in regulatory testing is anticipated to occur in parallel with an increased ability to evaluate the large numbers of chemicals that currently lack adequate toxicological evaluation. The initial focus of this collaboration has been on identifying toxicity-related pathways and assays for those pathways, establishing a Tox21 library of ~10,000 compounds, and developing the databases and bioinformatic tools needed to mine the resulting data. 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 Web page. (http://ntp.niehs.nih.gov/index.cfm?objectid=B30E8A75-F1F6-975E-7B2C9D612CA7137D)

Scientific Support Staff

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