Paper describing novel inhalation toxicology research methods attracts attention

US Army Engineer Research and Development Center
Published Aug. 6, 2019
Adverse Outcome Pathway

This figure is an Adverse Outcome Pathway, or an overview of one way chemicals may cause pulmonary (lung) fibrosis. Pulmonary fibrosis is the development of scar tissue (similar to a scab on the skin) within the lung. This makes it difficult for people to breathe by preventing the lungs from expanding to fill with air. As a result, people can die from a lack of oxygen in their blood. Ordinarily, if chemicals caused some type of mild lung injury, PPAR-gamma would prevent the development of pulmonary fibrosis. Here, we show that it is possible for chemicals to drive the development of pulmonary fibrosis by inactivating the PPAR-gamma receptor. This allows TGF-beta to stimulate pulmonary fibrosis, as a result of lung injury either by the chemical or some other cause (e.g., inhaled sand, smoke, or other chemicals) that may irritate the lung. Unfortunately, once pulmonary fibrosis has developed, it is not reversible ⸺ the scar tissue remains forever.

VICKSBURG, Miss. (Aug. 1, 2019) -- When three U.S. Army Corps of Engineers researchers published a paper in the journal “Chemical Research in Toxicology,” they expected it would generate buzz, but they weren’t expecting a tsunami of attention. As of this writing, the paper has received 816 views; for a paper of its age, 20-30 views would be typical.

Drs. Lyle Burgoon and Natalia Vinas, both research biologists, and Dr. Ed Perkins, a senior scientist ⸺ all with the U.S. Army Engineer Research and Development Center’s Environmental Laboratory ⸺ wrote about novel techniques for determining whether chemical disinfectants diffused into the air by humidifiers in South Korea could trigger lung illness leading to death in humans. Instead of experimenting on people or animals, the three are at the forefront of the U.S. movement to use a modeling technique called adverse outcome pathways, which can be coupled with computer artificial intelligence methods.  

“In the ideal world, we would have used experiments on humans to test whether the chemicals were detrimental to people,” Burgoon said. “For obvious reasons, it would be very difficult to use people, so we then might turn to animals, but using animals is costly and raises many ethical questions. The next option would be using in vitro cells, or cells grown on plates, but that technique takes time, because we would have to grow the cells.”  

Burgoon said that inhalation toxicology is an understudied research field in general exactly because these and many other challenges lie in the path of testing.

“The AOP is a structured diagram of the unbroken chain of biological reactions that lead to the adverse effects,” Burgoon said. “We used cell-based data that the U.S. Environmental Protection Agency and their partners generated for the Tox21 database. They tested thousands of chemicals through different cells, and we can use their data and make predictions based on the information that’s been collected already using deep learning models, which are a type of artificial intelligence.”

“USEPA really started using the AOP method of testing; it’s how they want to regulate,” Vinas said. “And the European Union has strict regulations about animal testing, so they adopted the methodology early as well.”

The three ERDC researchers are also leading AOP research in the U.S. Vinas said, “We’ve been working with AOPs since 2009, when the concept was born.”

Burgoon points out that the South Korean government didn’t approve of the use of disinfectants in humidifiers, it was some private companies that advertised them as beneficial. “Using disinfectants is fine on counters, but the toxicity for aerosolized disinfectants was never tested,” he said. “Beginning in 2006, there was an epidemic of lung injury in children and adults.

The South Korean government assembled a research team to determine the cause, thinking at first it might be particulate caused by dust storms.”

Enter Dr. Jinhee Choi, one of the ERDC team’s collaborators from South Korea on the research and the paper. “I met her a few years ago, I believe it was through the Society of Environmental Toxicology and Chemistry,” Vinas said. Dr. Choi was able to get the research program funded by the South Korean government, and she and Vinas set up the U.S.-South Korean collaboration.

Vinas said this research is also valuable to the U.S. Army because many Soldiers are concerned about inhaling chemicals in theater. “I’ve spoken with Soldiers who have told me they’ve been on several tours and they are worried about getting lung disease from the chemicals they’re inhaling in the environment.

“We need to have a rapid testing mechanism capability in the Army and for the public to screen chemicals. The most rapid way to screen chemicals is using the chemical structure. In this study, at first it wasn’t clear how the disinfectants were toxic to people, just that pulmonary fibrosis was going way up.

“We had to determine how you get the illness at the molecular level from the toxicant ⸺ what is the process of the AOP ⸺ to get to the illness.”

The paper is in the top 25% right now of all papers scored by Altmetric, a general tool that calculates metrics from all scientific journals. “There are lots of opportunities for technology transfer on the military and civilian sides,” Burgoon said.