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A game-changer in toxicity testing
RESEARCH TRIANGLE PARK, N.C.—The Hamner Institutes for Health Sciences has established an Integrated Biology Initiative among multiple organizations to facilitate bringing a 21st-century systems biology approach and modern computational biology to toxicity testing, with the goal of revolutionizing the toxicity-testing paradigm that has been in place for the past 80 years.
If successfully developed, human cell-based assays that model and help to evaluate dose responses should allow toxicity testing and risk assessment of compounds to take place wholly via in-vitro tests, without the need for additional testing using intact animals, according to Hamner researchers.
The multi-organization, precompetitive partnership consists of several sponsoring providers, including Agilent Technologies Inc., Illumina, Dow Chemical, ExxonMobil, Unilever and others. The research will be conducted by Hamner and Brown University.
The new approach to toxicity testing stems from key recommendations from a 2007 National Research Council (NRC) report titled, "Toxicity Testing in the 21st Century: Toxicity Pathways and Network Biology." The report set forth a vision for the modernization of toxicity testing using systems biology approaches and computational biology to provide better, more efficient tools for measuring chemicals' toxicity risks.
For decades, the standard approach to testing a compound's toxicity has been to expose live animals—typically rats or mice—to high doses of the compound, and then to wait and see what happens. If the compound proves toxic to the animals at high doses, scientists must "work backward" to ultimately calculate what level of dosage would be sufficient to create a relevant toxic effect in humans. This approach calls for the extensive use of animals, and the results from animal-based testing don't always translate particularly well to humans. Fundamentally, the NRC report's authors argue, this approach fails to take advantage of the extraordinary advances in the understanding of human biology made during the past decade.
"There has been extensive debate about the vision and how best to implement it," says Dr. Melvin Andersen, associate director of the Institute for Chemical Safety Sciences at Hamner. "We determined the best way to progress would be to develop case studies based on specific pathways and the compounds that affect them."
Participants in the Integrated Biology Initiative intend to improve upon toxicity testing methods by developing novel in-vitro assays in which human cells are exposed to low doses of the chemicals in question. These standalone in-vitro tools should be adequate for risk assessment without the use of animals, and should be able to rapidly and inexpensively identify which chemicals pose the greatest hazard to human health.
"We need to understand the dose response in lower doses than traditional toxicity testing considers," says Andersen. "There are other parallel initiatives of this kind being conducted at the Environmental Protection Agency, for example, but the lower-dose screening is unique to our programs."
The use of in-vitro-based toxicity testing holds significant ethical and financial advantages over the traditional techniques that rely heavily on animal testing. The new approach would reduce the use of animals in testing overall, provide data that more closely translates to human cell health and speed testing of new compounds and those already in commercial use.
The main beneficiaries of an improved toxicity testing approach fall into two main categories.
The first consists of what Andersen calls the "regulated communities," which include the pharmaceutical and chemical sectors that must ensure the safety of their products before taking them to market. One of the major failure modes of new compounds in the pharmaceutical industry is in toxicology testing. The typical two-year mouse bioassay doesn't yield final results on the toxicity of a novel compound until well after the pharmaceutical company testing it has invested a great deal of time and money into its product. Speeding the toxicity testing process will help pharmaceutical companies to save money by allowing them to avoid wasting resources developing a product for two years that ultimately proves toxic and unmarketable.
The second beneficiary of improved toxicology methods is the consumer public at large, because in-vitro schemes would allow for quick testing of existing chemicals that have not been well tested to date. Mary McBride, director of government relations, life sciences and chemical analysis at Agilent—a major technology partner in the initiative—says there is currently a backlog of between 80,000 to 120,000 chemicals with no toxicology data on them at all. Addressing this backlog with the cumbersome methods of yesteryear may be an exercise in futility, but rapid toxicology testing using in- vitro assays will allow researchers to screen and prioritize compounds that seem the most problematic.
"We're in the early stages of demonstrating the feasibility of an in-vitro approach to toxicity testing, and we believe it is important to be involved in work that promises to make a big difference to many sectors and many people," says McBride.
Discussions are ongoing with as many as a half dozen other technology providers, with an eye toward attracting still more companies and technology partners into the initiative. Several large companies, including GE Healthcare and Kraft Industries, have expressed interest in joining the partnership by providing funding or technology.
"We're getting close to having the funding base and critical mass of technology partners to be able to begin to apply these appropriate, contemporary tools," says Andersen.
"It's important to remember that this is not a closed consortium—we embrace others joining in this effort, especially if they are able to bring genuine interest, relevant technology or additional funding to the table," says McBride.
Agilent, WiCell to offer microarray service
SANTA CLARA, Calif.—Agilent Technologies Inc. and WiCell, a provider of cytogenetic testing of mouse and human embryonic stem cells and induced pluripotent stem cells, announced last month that WiCell will offer comparative genomic hybridization plus single nucleotide polymorphism microarray analysis using the Agilent SurePrint G3 Human Genome CGH+SNP Microarray.
Unlike previous assays that required performing CGH and SNP separately, the CGH+SNP Microarray detects copy number changes by both SNP and CGH, and simultaneously delivers copy-neutral change information such as loss or absence of heterozygosity. The assay maintains the high-resolution quality achieved with CGH-only microarrays, using probes that have been carefully optimized and validated for maximal sensitivity and specificity.
"WiCell's considerable experience and know-how in cytogenetic analysis and their large CGH dataset for embryonic and induced pluripotent stem cells, partners well with Agilent's technology to enable robust detection capabilities vital for research and commercial development," said Kathleen Shelton, senior director of genomics marketing at Agilent.