A game-changer in toxicity testing

RESEARCH TRIANGLE PARK, N.C.—The Hamner Institutes forHealth Sciences has established an Integrated Biology Initiative among multipleorganizations to facilitate bringing a 21st-century systems biology approachand modern computational biology to toxicity testing, with the goal ofrevolutionizing the toxicity-testing paradigm that has been in place for thepast 80 years.

If successfully developed, human cell-based assays thatmodel and help to evaluate dose responses should allow toxicity testing andrisk assessment of compounds to take place wholly via in-vitro tests, without the need for additional testing usingintact animals, according to Hamner researchers.

The multi-organization, precompetitive partnership consistsof several sponsoring providers, including Agilent Technologies Inc., Illumina,Dow Chemical, ExxonMobil, Unilever and others. The research will be conductedby Hamner and Brown University.

The new approach to toxicity testing stems from keyrecommendations 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 usingsystems biology approaches and computational biology to provide better, moreefficient tools for measuring chemicals' toxicity risks.

For decades, the standard approach to testing a compound'stoxicity has been to expose live animals—typically rats or mice—to high dosesof the compound, and then to wait and see what happens. If the compound provestoxic to the animals at high doses, scientists must "work backward" toultimately calculate what level of dosage would be sufficient to create arelevant toxic effect in humans. This approach calls for the extensive use ofanimals, and the results from animal-based testing don't always translateparticularly well to humans. Fundamentally, the NRC report's authors argue,this approach fails to take advantage of the extraordinary advances in theunderstanding of human biology made during the past decade.

"There has been extensive debate about the vision and howbest to implement it," says Dr. Melvin Andersen, associate director of theInstitute for Chemical Safety Sciences at Hamner. "We determined the best wayto progress would be to develop case studies based on specific pathways and thecompounds that affect them."

Participants in the Integrated Biology Initiative intend toimprove upon toxicity testing methods by developing novel in-vitro assays in which human cells are exposed to low dosesof the chemicals in question. These standalone in-vitro tools should be adequate for risk assessment withoutthe use of animals, and should be able to rapidly and inexpensively identifywhich chemicals pose the greatest hazard to human health.

"We need to understand the dose response in lower doses thantraditional toxicity testing considers," says Andersen. "There are otherparallel initiatives of this kind being conducted at the EnvironmentalProtection Agency, for example, but the lower-dose screening is unique to ourprograms."

The use of in-vitro-basedtoxicity testing holds significant ethical and financial advantages over thetraditional techniques that rely heavily on animal testing. The new approachwould reduce the use of animals in testing overall, provide data that moreclosely translates to human cell health and speed testing of new compounds andthose already in commercial use.

The main beneficiaries of an improved toxicity testingapproach fall into two main categories.

The first consists of what Andersen calls the "regulatedcommunities," which include the pharmaceutical and chemical sectors that mustensure the safety of their products before taking them to market. One of themajor failure modes of new compounds in the pharmaceutical industry is intoxicology testing. The typical two-year mouse bioassay doesn't yield finalresults on the toxicity of a novel compound until well after the pharmaceuticalcompany testing it has invested a great deal of time and money into itsproduct. Speeding the toxicity testing process will help pharmaceuticalcompanies to save money by allowing them to avoid wasting resources developinga product for two years that ultimately proves toxic and unmarketable.

The second beneficiary of improved toxicology methods is theconsumer public at large, because in-vitroschemes would allow for quick testing of existing chemicals that have not beenwell tested to date. Mary McBride, director of government relations, lifesciences and chemical analysis at Agilent—a major technology partner in theinitiative—says there is currently a backlog of between 80,000 to 120,000chemicals with no toxicology data on them at all. Addressing this backlog withthe cumbersome methods of yesteryear may be an exercise in futility, but rapidtoxicology testing using in-vitroassays will allow researchers to screen and prioritize compounds that seem themost problematic.

"We're in the early stages of demonstrating the feasibilityof an in-vitro approach to toxicitytesting, and we believe it is important to be involved in work that promises tomake a big difference to many sectors and many people," says McBride.

Discussions are ongoing with as many as a half dozen othertechnology providers, with an eye toward attracting still more companies andtechnology partners into the initiative. Several large companies, including GEHealthcare and Kraft Industries, have expressed interest in joining thepartnership by providing funding or technology.

"We're getting close to having the funding base and criticalmass 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 closedconsortium—we embrace others joining in this effort, especially if they areable to bring genuine interest, relevant technology or additional funding tothe table," says McBride.

Agilent, WiCell to offer microarray service

SANTA CLARA, Calif.—Agilent Technologies Inc. and WiCell, aprovider of cytogenetic testing of mouse and human embryonic stem cells andinduced pluripotent stem cells, announced last month that WiCell will offercomparative genomic hybridization plus single nucleotide polymorphismmicroarray analysis using the Agilent SurePrint G3 Human Genome CGH+SNPMicroarray.

Unlike previous assays that required performing CGH and SNPseparately, the CGH+SNP Microarray detects copy number changes by both SNP andCGH, and simultaneously delivers copy-neutral change information such as lossor absence of heterozygosity. The assay maintains the high-resolution qualityachieved with CGH-only microarrays, using probes that have been carefullyoptimized and validated for maximal sensitivity and specificity.

"WiCell's considerable experience and know-how incytogenetic analysis and their large CGH dataset for embryonic and inducedpluripotent stem cells, partners well with Agilent's technology to enablerobust detection capabilities vital for research and commercial development,"said Kathleen Shelton, senior director of genomics marketing at Agilent.