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EPA Taps Four CBA Shops to Help Classify Potential Toxins for New ToxCast Program

The US Environmental Protection Agency has asked four cell-based assay companies, including Cellumen and Acea, to participate in its newly launched ToxCast program, which aims to discern how chemicals such as pesticides will interact with the environment, humans, and animals.
The EPA is betting that as the program grows, so too will researchers’ confidence in using potential mechanisms of action to help predict toxins. This new information, in turn, could help to refine and reduce the use of animals in toxicity testing.
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 in the summer of 2008. 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, according to Robert Kavlock, director of the EPA’s National Center for Computational Toxicology.  
“We had been studying how the pharma industry approaches drug discovery and we thought many of the tools that they were using in this HTS capacity may be useful for looking at the biological profile and toxic effects of environmental chemicals,” Kavlock told CBA News this week.
“ToxCast is an attempt to use that HTS technology to look at environmental toxicology,” he added. “Each one of the contracts that we’ve awarded addresses a certain aspect of HTS technology.”
The program will evaluate chemicals based on their physical and chemical properties; predicted biological activities based on existing structure and activity models; biochemical properties based on HTS assays, cell-based phenotypic assays; and genomic and metabolomic analyses of cells.
According to an article in the January 2007 issue of Toxicological Sciences, data generated from assays using complex formats of rodent, human, and non-human primate cells can clarify data derived from HTS enzyme and receptor assays. The authors of the article, Kavlock and his colleagues from the NCCT state that these assays will detect biotransformation and complex toxicities, in addition to secondary effects such as altered membrane permeability caused by chemically induced perturbations of the interactome.  
According to the EPA web site, the agency awarded a contract worth $5,742,400 for cell systems toxicity screening to In Vitro ADMET; contracts for high-content multi-endpoint cell analysis, worth $5,500,000 and $12,799,000, to Cellumen and BioSeek, respectively; and a contract for microelectronic cell monitoring worth $3,980,000 to Acea. In addition, the EPA awarded Expression Analysis a contract worth $5,839,973 for genomic profiling and Phylonix a contract worth $4,306,560 for zebrafish toxicity modeling
These amounts are the predicted maximum for the life of the contract, which will be for at least two years but up to five years, the EPA said.
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.

“We had been studying how the pharma industry approaches drug discovery and we thought many of the HTS tools that they were using may be useful for looking at the biological profile and toxic effects of environmental 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.
Cellumen CEO Lansing Taylor said Cellumen uses its HCS platform measures 11 different cellular parameters at three different time points with a 10-point dose response curve for each compound.
The end result, Taylor said, is a cytotoxicity index that the EPA can use in a screening environment to better prioritize lead compounds.
Taylor said the company will initially use its hepatotoxicity panel to profile the agency’s compounds, but will have additional panels over time. He added that Cellumen will use exactly the same protocol and assays it uses with its pharmaceutical customers.
Acea Biosciences this week said it will use its RT-CES system to classify the ToxCast compounds. The company will use the label-free, real-time microelectronic cell-based assay technology to monitor live cells in culture.
It will also measure and profile altered cellular physiology and pathology by the way the toxins affect the cells when they are exposed in a precisely controlled fashion.
Xiaobo Wang, Acea’s VP of research and CTO said that although cytotoxic compounds ultimately result in cell death, how the cell population responds to various compounds before they die can be very different.
He said that such differences would be important to understand the compounds’ mechanism of action. He added that the dynamic curves generated by monitoring cell impedance could be used to study and predict these mechanisms.
According to Wang, continuous measurement yields kinetic data. For example, researchers can use cytotoxicity assays to learn how quickly a compound causes cell death. 
The agency will make ToxCast data freely available in the PubChem databse to ensure transparency and collaboration. The approach and the chosen assays will also be discussed at the upcoming International Science Forum on Computational Toxicology to be held at the EPA campus in Research Triangle Park, NC, May 21-23.

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