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NTP Holds Meeting on High-Throughput Screening

By Eddy Ball
October 2008

Tice
At the end of his opening remarks, Tice asked attendees to join him in a few minutes of silence to acknowledge the anniversary of the tragic events of seven years earlier on September 11. (Photo courtesy of Steve McCaw)

Witt
Witt, foreground, was a gracious chair and moderator, who also made sure speakers stayed within their allotted 20 minutes. (Photo courtesy of Steve McCaw)

NTP scientists
Among the mixed audience from industry, academia and government were NTP scientists, such as Biologist Rachel Frawley, center foreground, and members of the computational toxicology community, including UNC researcher and NIEHS grantee Ivan Rusyn, M.D., Ph.D., seated to the left near the wall. (Photo courtesy of Steve McCaw)

The National Toxicology Program (NTP) took an important step forward in the development of a more rigorous and comprehensive high-throughput screening program for toxicology studies by hosting a Request for Information (RFI) meeting September 11 - 12 in Rodbell Auditorium at NIEHS.

The well-attended meeting brought together scientists from assay-development companies, government and universities to provide the NTP with information on how to identify and select critical cellular toxicity pathways to be evaluated by cell-based high-throughput screens. The NTP also solicited recommendations on particularly informative molecular targets within these pathways for both cell-based and biochemical assays.

The meeting featured 26 twenty-minute presentations on methodology, novel targets and pathway identification and was chaired by NTP Toxicologist Kristine Witt, who is involved in assay selection and study design for the NTP's High Throughput Screening (HTS) Initiative. According to event organizer Denise Lasko, more than 130 individuals registered for the meeting, including presenters, NTP, NIEHS and Environmental Protection Agency (EPA) scientists, and other scientists and individuals with interests in HTS and computational toxicology.

On hand to introduce the meeting and provide clarification was Raymond Tice, Ph.D., deputy director of the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), acting chief of the NTP Biomolecular Screening Branch and HTS Initiative coordinator.

As Tice explained, the meeting is intended to address one of the short-term goals of the 2005 NTP Roadmap for the 21st Century (http://ntp.niehs.nih.gov/index.cfm?objectid=EE4BBC8B-F1F6-975E-74B3110ABBF7A208) to identify or develop rapid, mechanism-based predictive screening assays for use in toxicity determinations. He said that the event should also be viewed within the context of the 2007 National Academy of Sciences report Toxicity Testing in the 21st Century: A Vision and a Strategy. (http://www.nap.edu/catalog.php?record_id=11970#toc) Exit NIEHS

During this same period of time, the NIEHS/NTP, EPA ToxCast Program and National Human Genome Research Institute explored ways to coordinate their work on alternative methodologies. "As a result of this publication and our own interests and efforts," Tice continued, "we put together a Memorandum of Understanding (MOU) (http://www.niehs.nih.gov/news/releases/2008/toxrelease.cfm) in February 2008... on high-throughput screening toxicity pathway profiling and biological interpretation of findings."

As part of the MOU, the interagency consortium, also known as Tox21, set up four focus groups with representatives from each of the three organizations as co-chairs. The RFI meeting is intended to identify information for the first of the groups, Pathways and Assays, whose goal, Tice maintained, is "to identify key toxicity pathways and suitable assays for those pathways, including bio-transformation and evaluating assay reliability."

Over the day and a half of presentations, speakers addressed one or more of the informational needs outlined in the July 7, 2008 announcement (http://grants.nih.gov/grants/guide/notice-files/NOT-ES-08-007.html) Exit NIEHS of the meeting:

  • Identification and selection of critical cellular pathways involved in toxicity and associated with disease outcome
  • Assays that can be used to measure the activity of a compound on a target within a critical pathway
  • Ways to select the best targets within pathways and networks
  • Assays, technologies or methods for identifying compounds that are relevant only after metabolic activation
  • New technologies or technologies under development that can help expand and more carefully characterize the findings from initial screens.

The next step, which Tice reminded the audience will take some time, is for the Assays and Pathways focus group to decide what test methods should be recommended to the NIH Chemical Genomics Center for further validation.



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