New screen IDs vascular system's chemical enemies.

Sep 21, 2011

Kleinstreuer, NC, RS Judson, DM Reif, NS Sipes, AV Singh, KJ Chandler, R DeWoskin, DJ Dix, RJ Kavlock and TB Knudsen. 2011. Environmental impact on vascular development predicted by high throughput screening. Environmental Health Perspectives http://dx.doi.org/10.1289/ehp.1103412.

Synopsis by Tamara Tal

A study reports that cell-based tests can predict developmental vascular toxicity in animals.

Cell-based tests can predict with a high success rate if chemicals will damage the developing vessels that carry blood throughout the body, according to research published in the journal Environmental Health Perspectives. The laboratory tests are being developed and refined as a way to allow more rapid testing of chemical safety and to reduce the use of animals in toxicity testing of chemicals.

The researchers report a new method that can predict with a 92 percent success rate whether chemicals will be toxic to the developing vascular system. The vascular system is the first organ to develop due to its critical role for nutrient delivery and waste removal.

Scientists at the National Center for Computational Toxicology are part of a widespread effort to find new ways to rapidly and accurately predict if chemicals are toxic without using expensive and time-consuming tests in mammals. Their group has already developed computer-based algorithms that can predict whether chemicals trigger reproductive toxicity or endocrine disruption.

There are 10,000 to 30,000 chemicals sold worldwide that require additional toxicity testing to adequately assess potential health risks. The largest barriers to testing are the high cost and large amount of time required to run toxicity tests in animals. Because of these barriers and accompanying ethical considerations, massive government-funded research efforts are underway to refine, reduce or replace animal testing with alternative technologies that rely on computer predictions, cell-based tests or tests conducted in non-mammalian species like fish and worms.

To get at this problem, researchers identified six key cell events – or markers – that can collectively predict developmental toxicity to blood vessels and other parts of the vascular system.

They then assessed how well their predictive model worked. First, they exposed cells to two known vascular toxicants. They used thalidomide and a related chemical that block a key event in vascular development called angiogenesis – the formation of new blood vessels. As expected, both chemicals disrupted the six vascular markers for toxicity in the cells.

Next, they exposed the cells to 309 chemicals – mostly food-use pesticides - and measured the six key cell events.

They plugged the results into their computer program and predicted that 123 of the 309 chemicals are toxic to the developing vascular system.

To see how well the model worked, the researchers compared their cell-based predictions to animal data from rabbit and rat experiments. For all chemicals that had pre-existing animal data, their predictions were correct more than 90 percent of the time.

To put it another way, by using a combination of cell- and computer-based methods, researchers could correctly predict whether a chemical will cause developmental vascular toxicity in rats and rabbits 92 percent of the time.

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