Improving Toxicity Tests

A new initiative will work on cell-based toxicity tests for chemicals.

Credit: Technology Review

As chemical companies develop more pesticides, cleaners, and other potentially toxic compounds, traditional methods of safety testing can hardly keep up. Animal tests, which have been the gold standard for decades, are slow and expensive, and these sorts of tests are increasingly socially unacceptable, too. What's more, the results of animal testing sometimes don't translate to humans, so researchers are eager for better alternatives.

This week, at the annual meeting of the American Association for the Advancement of Science in Boston, the U.S. Environmental Protection Agency and the National Institutes of Health (NIH) announced a multiyear research partnership to develop a cell-based approach that they hope can replace animal testing in toxicity screening. Work has already begun, although it will take years to refine the techniques.

Using systems that are already employed in the search for new drugs, researchers hope to develop quick, accurate methods of toxicity testing for chemicals that are carried out on cells, rather than on whole animals.

That way, instead of having to spend weeks dosing and dissecting roomfuls of rabbits or rats, thousands of chemicals could be tested in a matter of hours using automated systems and human cells grown in a lab. Different kinds of cells could be used as proxies for particular tissues, providing a way for researchers to test the effects of a chemical on the liver, for example, and, ultimately, to predict toxic effects.

The approach "really has the potential to revolutionize the way toxic chemicals are identified," says Francis Collins, director of the National Human Genome Research Institute. Automated cell-based tests could screen many thousands of chemicals in a single day, compared with the decades spent so far gathering detailed information on a few thousand toxic chemicals.

"We need to be able to test thousands of compounds in thousands of conditions much faster than we did before," says Elias Zerhouni, director of the NIH. The new approach repurposes a technique that's a mainstay in pharmaceutical labs, where high-throughput screening is used to help identify new drugs. Automated systems can test hundreds of thousands of candidate compounds in a single day and identify those that have any effect on cells, and hence may have therapeutic value. The aim of the toxicity-testing research is "to try to turn that around to find compounds that might be toxic," Collins says. Their effects could be assessed according to the number of cells they kill, or by using markers that indicate whether certain functions in a cell are affected.

Because high-throughput screening can handle many thousands of tests at a time, a given chemical can be tested at different concentrations and for different exposure times during a single screening process, producing comprehensive and reliable data that's "not a statistical approximation," says Christopher Austin, director of the NIH Chemical Genomics Center. "It's pharmacology."

"In order to get the answers you want, you need to do all the concentrations, all the times, and that's why you need to have a high-throughput system," Austin says.

Researchers at the NIH have already used high-throughput screening to test several thousand chemicals over a range of 15 concentrations varying by several orders of magnitude, and for exposure times ranging from minutes to days. The chemicals they picked have well-known toxic effects, gleaned from animal studies. By comparing data from high-throughput tests with that from animals, researchers should be able to fine-tune cell-based tests so that they're at least as reliable and as informative as animal experiments.

"Animals are not always giving us the right answer," says John Bucher, associate director of the National Toxicology Program, "so we need to use all the information we can get from different systems."

In a sense, Austin says, this new approach turns the animal-testing procedure "upside down." Rather than giving a rat a chemical and then dissecting the animal and examining its tissues to see the effect of the compound, metaphorically, "we are dissecting the rat first into its component cells, then computationally putting the rat back together."

However, it will take years for researchers to prove--if they can--that cell-based toxicity screening can supercede animal tests so "you cannot abandon animal testing overnight," Zerhouni says. "It will have to be intertwined for a few years."

http://www.technologyreview.com/Biotech/20294/