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EPA, NTP, NCGC Launch Program to Use CBAs to Screen Environmental Chemicals

Three large US government agencies this week said they plan to establish a collaborative research program to overhaul how environmental chemicals are tested by shifting the focus away from animal testing and toward cell-based or biomolecular assays and computer models.   
The program, which has not yet been funded, was spearheaded by the National Toxicology Program, the National Institutes of Health Chemical Genomics Center, and the Environmental Protection Agency’s National Center for Computational Toxicology.
The goal is to propose a strategy for toxicity testing that would allow investigators to test large compound libraries more efficiently; incorporate recent advances in molecular toxicology, computational sciences, and information technology; rely more on human data instead of animal data; and increase the efficiency of toxicological testing design and costs.  
For instance, investigators using a rodent model can complete between 10 and 100 studies per year, while those using cells and molecules can perform more than 10,000 screens in a single day, Robert Kavlock, director of the NCCT, told CBA News this week.
The three agencies have put together a memorandum of understanding and the three heads of the organizations have written a paper that is going to be published in Science, which describes this program and the science behind it. 
Christopher Austin, the director of the NCGC, told CBA News this week that the project is expected to last between five and 10 years, and “depends on funding, to a great degree.”
“We know what needs to be done, we have the chemicals, we have the assays, we know how to do the work, but it is just a question of how much funding gets put into this every year,” he said. “That has yet to be determined.”
The Bush administration has supported the project, Austin said. “Secretary [of Health and Human Services Mike] Leavitt has said in public multiple times that this kind of approach to the testing of environmental chemicals is something that he is very interested in.”
Ultimately, though, the question of funding will be up to the administration that takes office next January, Austin said.
In the meantime, he said, the three agencies are currently working with a large number of public- and private-sector researchers to create a list of the assays that the program ought to include because toxicology includes many different types of biology.
“It is likely that the panel will include upwards of 100 assays, so we will be doing a lot of different assays,” according to Austin. “So far, in terms of the assays that we have worked with and on, over 80 percent of them have been cell-based assays.”
He said that the assays are either phenotypic assays, such as cytotoxicity assays, or reporter assays on a given cellular pathway. “I have no doubt that we will end up doing some biochemical assays too, but my sense is that the majority of them will be cell-based assays,” said Austin.
A Combined Effort
Austin said that the project took root around two years ago when the EPA, the NCGC, and the NTP came together to discuss whether they could “use this new technology of high-throughput screening to develop non-animal, or cell-based, in vitro assays on which chemicals could be tested as part of an assay panel that could act as a proxy for some types of animal toxicities.”
At the time, the NCGC started working with the NTP to obtain, for the first time, a uniform collection of compounds that were of interest to the NTP, Austin said. Both the NTP and the EPA sent the NCGC about 1,400 different compounds.
Working with the toxicologists at the NTP, the NCGC developed a series of cell-based assays that originally just looked at cytotoxicity, which would allow its researchers to do proof-of-principle studies, Austin said. “In other words, if we took compounds like this and used them in typical HTS campaigns, could we get reliable, reproducible, interpretable, and meaningful data?”
Austin mentioned that these compounds are very nonmedicinal, and are not compounds that are typically used in this HTS format. A paper that was recently published online in Environmental Health Perspectives talked about the results of this work, and the answer was, “Yes, we can get reliable, reproducible, interpretable data that allows us to generate some very interesting hypotheses,” Austin said.

“We know what needs to be done, we have the chemicals, we have the assays, we know how to do the work, but it is just a question of how much funding gets put into this every year. That has yet to be determined.”

He said that the study authors have also done some computational modeling to try to look at these data across different assays and ask, “Are there some mechanistic things that can be learned about how these compounds are acting?” That paper is now in press in Chemical Research in Toxicology, and should be published online very soon.
“Based on the EHP proof-of-principle study, we had planned on expanding the collaboration to include more compounds, more kinds of assays and readouts, and more environmental conditions,” said Austin.
At about the same time, a National Research Council report came out that had been commissioned by the NTP and the EPA, said Austin. “That report, which had been done independently of our efforts, proposed to do exactly what we had been doing. So this served as an enormous, mutual shot in the arm.”
Coming from the NRC, the NTP, and the EPA, it was a significant validation of what we were doing,” Austin said.
This program builds on the knowledge gained through the EPA’s ToxCast program, which the agency launched last year (see CBA News, 4/13/07).
The agency has asked four cell-based assay companies, including Cellumen and Acea, to participate in the ToxCast program, which aims to discern how chemicals such as pesticides will interact with the environment, humans, and animals.
Overall, the EPA awarded ToxCast contracts to eight companies, including Attagene, BioSeek, Expression Analysis, In Vitro ADMET, NovaScreen (now part of Caliper), and Phylonix.
The five-year project is divided into three phases. The initial proof-of-concept phase is anticipated to last a little more than a year, with data expected this summer. During this phase, ToxCast will examine more than 300 chemicals using hundreds of different high-throughput screening bioassays.
The analyses will create a context within which to interpret the rest of the ToxCast data, based on the known toxicity of these chemicals. Included among the reference chemicals being tested are known tumorigens, teratogens, neurotoxins, and immunotoxins, Kavlock told CBA News last year. 
The second phase, for which data is expected in 2010, will expand and validate data from the first phase, and will also generate data from more than 1,000 additional chemicals.
The second phase will also look at thousands of environmental chemicals that require prioritization by the agency because their potential toxicity is unknown.
Data from the third phase is anticipated in 2012, for which at least 9,000 additional chemicals will be analyzed and prioritized.
The NTP-EPA-NCGC collaborative effort also follows closely on the heels of last week’s release of the Interagency Coordinating Committee on the Validation of Alternative Methods (or ICVAAM) National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (or NICEATM) Five-Year Plan (see CBA News, 2/8/08).
The plan, available here, identifies priority areas for research, development, translation, and validation activities necessary to achieve regulatory acceptance of alternative in vitro testing methods, such as high-throughput screens, William Stokes, director of NICEATM, told CBA News last week.
An integral part of the plan is to work with the pharmaceutical and biotech companies and other US and international stakeholders to accept and use alternative methods, Marilyn Wind, ICCVAM chair and the deputy associate director of the Consumer Products Safety Commission, told CBA News last week.
This project involves screening thousands of chemicals for various types of biological activity in human cells, primarily, although it does use some animal cells, and generating a profile of that biological activity. Stokes explained these profiles will allow researchers to look for patterns that are associated with toxicity.
NICEATM and the NCGC hope that this initiative will identify predictive biomarkers that they can use for prioritizing chemicals for testing and making a preliminary assessment of their potential toxicity, said Stokes.

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