Reduce, refine and replace

Johns Hopkins and Agilent team up to pursue alternatives to the use of animal models in toxicity research

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BALTIMORE—One of the pharma and biotech industry's most daunting challenges at the moment is the rigorous regulation of toxicity testing on animal models. Recognizing that current animal-based methods are not very predictive of toxicity development in humans, researchers at the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) and Agilent Technologies Inc. have joined forces to pursue a toxicity research method that demonstrates superior prediction and presents better underlying causes of toxicity.

Agilent recently bestowed $500,000 upon Johns Hopkins, earmarking the funds for high-tech, 'omics-based instruments. Santa Clara, Calif.-based Agilent also awarded CAAT director Dr. Thomas Hartung its prestigious Agilent Thought Leader Award for his research into the use of toxicity pathways to predict developmental neurotoxicity by combining two promising cell culture models with emerging metabolomics technology.

The partnership aims to identify novel toxicity pathways in human embryonic stem cells and primary organotypic brain cell cultures in order to better predict the developmental neurotoxicity of substances. Agilent Technologies Foundation, the company's philanthropic arm, is providing the funding, as well as its latest 6520 QTOF mass spectrometer and a 1200 series HPLC system including Mass Profiler Professional software for data and pathway analysis.

Hartung's group will treat developing human embryonic stem cells and rat primary organotypic brain cell cultures with a library of well-known reference substances for developmental neurotoxicity. Researchers will then measure intra- and extracellular metabolomes of untreated and treated human embryonic stem cells and rat primary organotypic brain cell cultures using liquid chromatography-mass spectrometry.

The resulting metabolic signatures of developmental neurotoxicity and the integration of biochemical information to identify toxicity pathways will then be annotated in a public database, thus providing "an excellent basis for prediction of the developmental neurotoxicity potential of chemical and drug compounds," says Mark Vossenaar, senior director of strategic marketing for Agilent's Life Sciences group.

"Thomas believes that 'omics-based tools provide significant value in the quest to better understand underlying mechanisms of toxicity; a vision shared by Agilent, which has identified systems toxicology as a key enabler in the future development of safer drugs, exhibiting less off-pathway effects," Vossenaar says.

According to the two parties, this method could have a transformative impact on the way toxicology is performed in the future, but will still allow researchers to adhere to the new three "R's" of toxicity testing: reduce, refine and replace the need for animal testing.

"This award makes cutting-edge technology available for a project in the core of implementing the vision of a new regulatory toxicology," says Hartung, recently named a leading toxicologist by the science journal Nature. "Problems of the 21st century can only be solved with 21st century technologies."

A 2007 National Research Council report on toxicity testing, along with the award, is piloting the approach to move toxicity testing to work with human cells and computer modeling instead of animal tests to improve the prediction of human adverse effects, Agilent reports. This is considered the way to assess the tens of thousands of untested chemicals in the environment and consumer products.

"At this moment, we use mainly animals to substitute for testing on men," Hartung continues. "But the information we need to fully understand the toxic effect of chemical on humans cannot be obtained from using traditional animal models. After all, we are not 70-kilogram rats. Increasingly, we understand how small molecules such as industrial chemicals and drugs harm organisms. We call this pathways of toxicity."

The number of pathways of toxicity is finite, he says, adding, "if we can show that a certain dose of a substance activates no relevant pathway, we can consider it safe. Thus, we need to map these pathways. Some of them can be found in many cells, but for others, we construct new tests.

"We firmly believe that a revolution is about to happen," he adds. "For the first time, a critical mass of toxicologists and modern technologies come together to turn upside down how we assess safety of substances. It will allow us, for the first time, to assess the large number of old chemicals never tested, their mixtures and new, emerging health effects. This promises more meaningful results, faster and cheaper."

Hartung's work could also help identify possible contributions of chemicals to disorders of autism and attention hyperactivity disorder (AHD.) Because metabolites are the intermediaries and products of metabolism, they can serve as valuable biomarkers for disease or indicators for toxicology studies.

"If successful, this will place both Agilent and Johns Hopkins firmly on the toxicology map, as it would be the first clear demonstration of a method that can provide both mechanism and superior prediction through an MS-based assay of human embryonic stem cells," Vossenaar says.

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