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EPA sets up centers to test thousands of chemicals we come in contact with daily

June 1, 2015


PITTSBURGH ó They are present in soil, water and air, and exist in products used daily at home, at work and in our vehicles. So itís no surprise that many end up in our bodies.

And yet the U.S. Environmental Protection Agency remains largely unaware of the toxic impact of more than 80,000 commercially used man-made chemicals on our blood, bones, joints, skin, organs, brains and our babies.

As it turns out, less than 10 percent of all widely used chemicals have been tested for toxicity and health risks, amid 500 million tons of synthetic chemicals produced annually, Vanderbilt University reports.

Given the unknown health effects of so many common chemicals, the EPA now has established three centers to develop technology to test chemicals without using animals.

With a $6 million EPA grant over four years, Vanderbilt and the University of Pittsburgh are establishing one of the centers ó the Vanderbilt-Pittsburgh Resource for Organotypic Models for Predictive Toxicity, or VPROMPT.

Pitt researchers already have been designing "tissue chips" that are being adapted to test chemical impacts on liver cells; other chips soon will go into development for limbs and joints. The Vanderbilt team is working on similar chips to test chemical impact on fetal-membrane and mammary cells. One goal is an accurate and efficient determination of a chemicalís potential to hinder limb development or cause birth defects.

"The whole point of doing this is to reduce, replace or substitute animal testing with a higher-fidelity system thatís completely human ó but not a human being," said Rocky Tuan, who holds many positions including director of the Pitt School of Medicineís Cellular and Molecular Engineering. "Itís human tissue on a chip."

Donít confuse tissue chips with silicon chips used in computers. Tissue chips comprise human-organ cells engineered from stem cells or established cell lines used in different organ studies that are placed in a micro-chamber or bioreactor fitted with channels where a chemical can be introduced and fluids can exit to allow for analysis of biological response to potential toxins.

The 3-D cell groups used in the chips actually are liver, limb, cartilage and bone, mammary and fetal-membrane cells to be tagged with markers that, Tuan said, may turn fluorescent red when exposed to toxic substances causing cellular stress, or green when the chemical is biologically benign or beneficial.

To test the system, the team will first apply toxic chemicals whose impacts on cells already are known to produce the same results in the tissue chips.

Cellular response to toxic stress, the researcher said, can be assessed using many approaches: for example, by measuring levels of cell calcium and metabolic changes in pH, oxygen and glucose levels, and changes in cell or tissue shape. Investigators at Vanderbilt are developing bioreactors and computerized devices to analyze the cellular response to chemical exposures.

"The EPA has stockpiled a large number of possible chemical suspects, but itís not humanely feasible to test all of them on animals," said Tuan, who holds a Ph.D. in life sciences. He said animal testing is only 50 percent predictive of a chemicalís impact on humans.

"Just imagine the complexity of using animals," he said. "The cost is enormous. So with this, we have a chance of simplifying it, and at the end of the day, when all is said and done, it all will be automated. We will inject compounds. For each model, if it glows red, itís bad, or if it glows green, itís good."

In time, the idea also could hold potential in assessing the safety of food additives, drugs and pesticides.

Such research already is underway.

Under a $5.8 million National Institutes of Health grant issued last fall, D. Lansing Taylor, director of Pittís Drug Discovery Institute and part of the Pitt team, has led the development of a tissue chip involving liver cells and designed to mimic the structure and function of the liver, for use in testing the safety and effectiveness of drugs. He said he is adapting that liver-chip technology to test the impact of chemicals on liver cells.

"This is a very exciting field, and weíre in the early stages," said Taylor, who holds a Ph.D. in cell biology. "Thereís more to do and itís not a done deal, but this has great promise, and weíve made great strides."

National Institutes of Health director Francis S. Collins has said that "the development of tissue chips is a remarkable marriage of biology and engineering," with potential to test drug treatments and serve as valuable tools for biomedical research.

Researchers from both universities have worked jointly in the past on tissue-chip projects, the Pitt team offering specific expertise needed for the project in liver, joint and limb tissue.

"Dr. Tuan brings incredible expertise in the biology of limb development and in understanding chemicals that cause defects in development, and has been studying the process in limbs for years and years," said M. Shane Hutson, a Vanderbilt physics professor who serves as VPROMPT director.

"Dr. Taylor and his group bring expertise and have been making liver-on-chip models and bring expertise in using those chips in drug discovery," he said. "That was his primary focus before this, which parallels what EPA is interested in."

 

 


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