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EPA Ramps up Computational Tox Initiative; Awards $9M to Two Bioinformatics Centers

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The US Environmental Protection Agency has expanded its nascent computational toxicology initiative by awarding $9 million to establish a pair of bioinformatics research centers at the University of North Carolina, Chapel Hill, and the University of Medicine and Dentistry of New Jersey.

The new five-year grants bring the total awarded under the computational toxicology program to $11.7 million (see table, below, for details of the grants awarded to date), and will complement research underway at the EPA's National Center for Computational Toxicology (NCCT), which was established in 2004 in Research Triangle Park, NC [BioInform 1-12-04].

EPA Computational Toxicology Awards to Date
Grant Title Institution
Grant Amount
Project Period
Research Center for Environmental Bioinformatics and Computational Toxicology Princeton University, Rutgers University, University of Medicine and Dentistry of New Jersey
$4,500,000
Sept. 2005 — Aug. 2010
The Carolina Environmental Bioinformatics Research Center University of North Carolina at Chapel Hill
$4,498,096
Aug. 2005 —- July 2010
Mechanistic Approach to Screening Chemicals and Mixtures for Endocrine Activity Using an Invertebrate Model North Carolina State University
$391,598
Oct. 2004 — Sept. 2007
A High Throughput Zebrafish Embryo Gene Expression System for Screening Endocrine Disrupting Chemicals Boston University
$400,000
Aug. 2003 — July 2006
Development and Application of a Bioluminescent Yeast-Reporter System for Screening Chemicals for Estrogenic and Androgenic Effects University of Tennessee - Knoxville
$391,505
Aug. 2003 — July 2006
Systems Biology Modeling of Fathead Minnow Response to Endocrine Disruptors University of Florida, Oregon Health Sciences University, Saint Mary College
$722,851
Aug. 2004 — July 2007
Chemical induced Changes in Gene Expression Patterns Along the HPG-axis at Different Organizational Levels Using a Small Animal Model (Japanese medaka) Michigan State University
$49,904
Aug. 2004 — July 2007
Estrogen Elicited Gene Expression Network Elucidation in the Rat Uterus Michigan State University
$747,960
Aug. 2004 — July 2007

Robert Kavlock, director of the NCCT, told BioInform that the EPA center currently has a staff of around 15 people, and will likely hire around five more before the end of the year. "We're recruiting slowly as we get established as an organizational unit" of the EPA's Office of Research and Development, he said.

The mission of the NCCT and the new academic centers "is to promote the use of new modeling techniques in EPA's hazard- and risk-assessment processes," he said.

"There's been a lot of pressure on EPA to figure out ways to identify hazard more efficiently," he added. "That was one of the motivating factors behind creating the computational toxicology program because the thought was if we blend some of the new approaches in molecular biology and computational chemistry together, then we can develop new approaches for looking at this."

Ultimately, Kavlock said, "EPA is getting ready for the impact of omics in risk assessment, and there's a lot of groundwork that has to be laid — similar to what FDA is going through now. How are we going to handle the data, how are we going to train our people to interpret this data?"

One of the shorter-term goals of the computational toxicology initiative is a predictive toxicology program called ToxCast — a name intended to connote the ability to forecast toxicity as well as "casting a big net in what we're going to be looking for," Kavlock said. The program will collect high-throughput data on the toxic effects of thousands of chemicals. "Then we're going to try to create fingerprints of those interactions and use statistical clustering techniques to see which chemicals look like they have the same kind of targets, and then compare that to the toxicology. If those fingerprints match up with the toxicology for chemicals we know a lot about, then we think we can take chemicals we don't know a lot about and try to fingerprint them that way," Kavlock said.

The NCCT will likely start with the active ingredients in several pesticides "because we know a lot about what they do. … So that's our proof of concept that this technique can correctly identify the toxicities that we know about."

Kavlock said that the NCCT expects to award several competitive contracts to high-throughput screening service firms by the summer, and that data should start coming in about a year after that. While the EPA is "still working out the details" of particular biological targets that it intends to study, likely candidates include nuclear receptors, metabolic enzymes like the cytochrome P450s, kinases, phosphatases, signaling pathways, oxidative pathways, and cell-death pathways, Kavlock said.

The hope is that improved toxicity forecasting will enable the EPA to cut back on animal testing. "We might be able to get to the point where we can say, 'This chemical looks like it is an immunotoxicant,' so [the] pesticides [group] could say, 'What we really want is an immunotoxicity test now,' and be able to more target the testing."

Kavlock estimated that current toxicity tests for a typical pesticide can cost around $20 million, and much of that data currently gets thrown away. "We're not going to get away from using animals for a long time, but if we can use them more intelligently, that's helpful," he said.

While the economic drivers and the technology are very similar to predictive toxicology methods used in drug discovery, Kavlock said there are a few key differences.

"In drug discovery, as I understand it, they accept a very high false negative rate," he said. "If they have a false negative in their process, they'll catch it later in drug development, whereas if we have a false negative in our process, we're likely not to look at that chemical again."

Another difference, he said, "is that the pharmaceutical industry generally knows the target they're looking for, because they're looking for the drug against some particular receptor or protein, and they probably know something about the side effects of that chemical class, so they can screen for that off-target effect right at the start. Whereas we tend to not know what these chemicals are going to be hitting, so we have to be a lot more global in how we look at the problem."

ToxCast does overlap a bit with the goals of the NIH Molecular Libraries roadmap initiative, Kavlock said, and the two organizations will likely work together to "bring a little bit of an EPA flavor" to the NIH screening initiative.

The ToxCast project "will be one of the first real products out of the Computational Toxicology Center," Kavlock said, but the NCCT has longer-term plans for more complex computational projects, including "computational models of important cell properties" that can be built into quantitative risk-assessment models.

For example, Kavlock said, "we could look at the shape of the dose response curve and make extrapolations across species that might have slightly different cell biology pathways."


"EPA is getting ready for the impact of omics in risk assessment, and there's a lot of groundwork that has to be laid — similar to what FDA is going through now."

The two bioinformatics centers announced last week will play a role in developing some of these new modeling methods, and will also be responsible for creating "a lot of web-based tools that can be put in the public domain so that people who will be generating this type of data and who are not card-carrying bioinformaticists will be able to access these tools and at least do some preliminary analysis of their data," Kavlock said.

Kavlock noted that the NIH has funded many public bioinformatics resources targeted toward human health and disease, "but the environmental aspect and the toxicology aspect really hasn't been a focus of NIH, so these centers I think are going to be able to fill a void that exists for that."

Looking forward, the EPA plans to issue an RFA this summer for a still-undetermined topic, but Kavlock said that computational modeling of metabolic pathways is a strong possibility.

The computational toxicology program has a budget of around $12.5 million for the 2005 fiscal year. While Kavlock was unable to estimate what next year's budget may hold, he said that the initiative so far has "a lot of support" from the EPA's Office of Research and Development and EPA program officers.

"We're hopeful that if we can do a good job with ToxCast, if we can show with a demonstration project that this works, that the support will continue," he said.

— Bernadette Toner ([email protected])

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