GOVERNMENT & POLICY
GENES, COMPUTERS & CHEMICALS EPA is working to incorporate computational toxicology into its regulatory decisions CHERYL H0GUE, C&EN WASHINGTON
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S T H E FIELDS OF GENOMICS,
proteomics, and metabonomics develop, researchers in creasingly can provide greater insight into the hows and whys of chemical toxicity To incorporate this new type of information into its work, the
icology—techniques that meld mathe matical or computer models with data from molecular biology studies about the effects of chemical exposure. EPA officials and others plumbed the future of compu tational toxicology at a Sept. 29-30 meet ing at the agency's research complex in
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MERGER EPA is combining genomics data and computational techniques to determine toxic effects of chemicals.
Environmental Protection Agency is gear ing up to analyze "omic" data that will im pact its regulatory decisions on chemicals. EPAs emphasis is on computational tox-
ResearchTriangle Park, N.C. EPA set a course to develop computa tional toxicology after Congress directed the agency, as part of fiscal 2002 funding,
to pursue alternatives to chemical testing methods involving laboratory animals, ac cording to Robert J. Kavlock, director of EPAs Reproductive Toxicology Division. Overall, computational toxicology is ex pected to lead EPA to more efficient and effective assessments of the health and en vironmentalrisksposed by chemicals, said Lawrence W Reiter, director ofthe agency's National Health & Environmental Effects Research Laboratory Impacts ofthis tech nology will take many forms within EPA. FOR INSTANCE, Gregory Ρ Toth, program manager for computational toxicology at the agency's National Exposure Research Laboratory based in Cincinnati, said com putational toxicology is expected to en hance scientific understanding of how chemicals can adversely affect health. This technology will elucidate the path from re lease of a substance into the environment to exposure to health problems. For ex ample, Tbth said, computational toxicolo gy will help researchers determine which components of chemical mixtures, such as different congeners of polychlorinated biphenyls, are "biologically relevant"—as sociated with health effects. Computational toxicology will not be limited to EPAs research efforts. Steven R Bradbury, of EPAs Office of Prevention, Pesticides & Toxic Substances, said com putational toxicology has the potential for causing a major "paradigm shift" by help ing speed agency assessments of chemi cals. That is important to EPA and to manufacturers of chemicals, who have to pay for toxicity tests on their products. For instance, under the federal pesticides law, compa nies pay between $15 million and $20 million for a battery of tests to support reg istration of a pesticide to be used on food, Bradbury continued. It costs the agency about $1 million to assess the results. This process of getting a new pesticide to mar ket can take five to seven years. Compu tational toxicology eventually may help quicken the pace of these assessments, Bradbury said. Kerry L. Dearfield, of EPAs Office of the Science Adviser, said computational
"The linking of genomic, proteomic, environmental, clinical, and a myriad of other information will revolutionize our understanding of ourselves and our environment/' 50
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toxicology could improve the predictive ca pability of traditional approaches to struc ture-activity relationships (SARs). The agency relies heavily on SARs during the 90 days it has to determine whether new indutrial chemicals that are subjects ofpremanufacture notices need toxicity tests. One of the major ways computational toxicology is expected to improve the qual ity ofriskassessments on chemicals is by
sessing the environmental effects ofwater pollutants, said Marvin E. Frazier, direc tor of the Life Sciences Division in DOE's Office of Science. DOE intends to se quence the genes of frogs and daphnia, which are tiny, freshwater crustaceans known as water fleas, Frazier said. Daph nia are often used in aquatic toxicology tests, while researchers use frogs to deter mine whether a substance impairs limb Organic Intermediates from FMC
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PROPONENT Gilman, EPA assistant administrator for R&D, challenged the agency to implement computational toxicology in specific applications.
providing insight into exactly how a sub stance causes a toxic effect. How a com pound induces cancer, Dearfield said, may end up being more important in consider ations ofriskthan the fact the chemical is carcinogenic in laboratory animals. In addition, computational toxicology could lead to development of new tools for environmental monitoring, such as deter mining the level ofpollutants at hazardous waste sites or in a company's wastewater discharge, Dearfield said. And computa tional toxicology may help identify more chemicals for listing on the Toxics Release Inventory, he added. EPA has forged links with other feder al agencies—including the Energy De partment, the National Institutes of Health, and the Food & Drug Adminis tration—on development of computa tional and genomic tools, explainedJ. Paul Gilman, EPA assistant administrator for research and development. The Energy Department will be gener ating genetic data that could help EPAs computational toxicology program in asHTTP://WWW.CEN-ONLINE.ORG
development. Additionally, DOE will do some gene-related work on the fathead minnow, also used in aquatic toxicology, but does not plan to sequence its large genome, he added. AT THE WORKSHOP, Gilman challenged EPA to move from the vision ofwhat com putational toxicology could accomplish at the agency and to focus on specific ways to put these techniques to work in specific applications. Bradbury suggested two concrete ways computational toxicology could be inte grated soon into his office's regulatory tasks. One is that, by the end of 2005, EPA regulators will be using computa tional toxicology tools to help prioritize chemicals for screening tests to deter mine their potential to disrupt endocrine function. In other words, he explained, computational toxicology could help EPA select chemicals for further study. A second suggestion is that the agency could, by the end of 2006, use first-gen eration computational toxicology tech-
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GOVERNMENT & POLICY
PRACTICAL
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Computational Toxicology Differentiates Among Aldehydes
W
hile risk assessors and regula tors at the Environmental Pro tection Agency are making plans for developing and using computa tional toxicology, some EPA researchers are already integrating it into their work. Susan D. Hester, a molecular patholo gist in EPA's Office of Research & Devel opment, is one of those scientists. She works with aldehydes. "Aldehydes are everywhere in our en vironment," from cosmetics and clothes to cigarette smoke, Hester tells C&EN. "We are concerned about aldehydes be cause some exposures have been shown to result in adverse health outcomes, from mild irritation all the way to cancer development in some animal species." Hester is focused on differentiating between aldehydes, including formalde hyde, that cause cancer in laboratory rats and those, such as glutaraldehyde, that are not carcinogenic. Ultimately, she wants to build a computational toxi-
niques as toxicity screening tools in as sessing pesticides' inert ingredients, pes ticides' active ingredients of low toxici ty, and premanufacture notices for new industrial chemicals. Meanwhile, a number of issues have to be resolved if EPA is to implement com putational toxicology, speakers told the workshop.
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RESEARCHING RISK Pathologists Hester and Douglas C. Wolf direct their studies from EPA's Office of Research & Development in Research Triangle Park, N.C.
Dearfield said EPA will have to train its risk assessors on the use ofgenomic data In addition, it plans to work with stakehold ers—such as chemical manufacturers who would submit the results ofgenomic tests to EPA—tofigureout the form and format of information that would be the most useful and usable for crunching these data. Marshall R. Peterson, chief technology
officer at theJ. Craig Venter Science Foun dation in Rockville, Md., warned that com putational toxicology will require more than "omics" data and the software tools to analyze it. Data access and management will be significant challenges, he said, call ing for development of an appropriate computer infrastructure that can handle this.
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cology tool that can give regulators an in dication of whether an untested aldehyde may be one of those cancer inducers when an expensive two-year bioassay of the chemical in rodents has not been conducted. In recent work, Hester exposed rats to formaldehyde and glutaraldehyde for one, five, or 28 days. Both chemicals produce nasal lesions, but only those from formaldehyde exposure will devel op tumors. Initially, Hester conducted classic pathology—she compared the lesions from both sets of exposed animals. "I can't tell under the microscope which one is which," she says. Next, she did genomics studies to de termine which genes were turned on—or off—in the affected tissues to study what happens early in exposure on the molecu lar level. Studies of a total of 20,000 genes from 36 treated animals produced an enormous amount of data—a stack of paper that weighed 8 lb, Hester says. Unable to deal with the huge amount of data in conventional ways, she turned to
bioinformatics software to sort through the data in three separate types of analyses, all of which pointed her to ward genes involved with DNA repair. She found that critical tissue responses that lead to cancer were apparent on the fifth day of exposure. Hester foresees creation of a database allowing comparison between aldehydes that have been shown to trigger cancer in rodents and those that do not. A computa tional toxicology tool that uses this data base could guide regulators and others in making assumptions about the toxicity of aldehydes that have not been tested in two-year bioassays. "The value of combining toxicity and genomic data into comprehensive data bases will be realized, as this approach will reduce the number of animal stud ies that are needed to provide credible and relevant science," Hester tells C&EN. In addition, she says, use of computa tional toxicology approaches to answer difficult health problems holds the promise of using existing and new data in smarter ways.
"We are at the beginning of the genomic era where the linking of genomic, proteomic, environmental, clinical, and a myr iad of other information will revolution ize our understanding of ourselves and our environment," Peterson said. No one can own all the data needed for computational toxicology, Peterson ex plained. Instead, this information will be dis tributed over a variety of databases. Newways are needed to allow researchers to obtain and analyze data from many sources. Meth ods are also needed for processing and com paring data that de scribe responses of ex posure to a chemical ranging from the mo lecular level to individ uals to exposure of populations and to ecosystems. The volume of data available for re searchers to use is a mounting challenge because current and planned computing designs place a greater emphasis on com putation than on data distribution, Peter son said. The overarching need is for ways to
manage massive amounts of a variety of data types, which include capturing, stor ing, archiving, distributing, cataloging, re trieving, and analyzing data, Peterson told the workshop. This is best undertaken though collaboration among government, industry, academic, and other research or ganizations, he said. Meanwhile, Dearfield said EPAmust re solve a sticky regulato ry issue regarding the results of genomics tests done by chemical manufacturers—even if the studies are not done to fulfill EPAregulatory requirements. Two laws —the Toxic Substances Control Act and the Federal In secticide, Fungicide & Rodenticide Act—require companies to re port to EPA any find ings of adverse effects from chemicals. But it is unclear what combination of changes in gene expression could lead to health problems and, therefore, what would trigger the legal reporting require ments. "We haven't worked this out, but it's going to be very, very important," Dearfield said. •
Computational toxicology has the potential for causing a major "paradigm shift" by helping speed agency assessments of chemicals.
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