Molecular Approach Promises Biomarkers of Naphthalene and Nitronaphthalene Toxicity

Linking environmental exposures to disease outcomes can be a challenge: exposure data is often unreliable, and even in the best scenarios it's nearly impossible to tease apart a lifetime of exposures to find a single toxic culprit.

However, if the impact of a toxic chemical at the molecular level can be identified by a biomarker, the scientist's job of linking exposure to disease will be made that much easier. The work in Alan Buckpitt's lab at the University of California, Davis has made great strides toward revealing how naphthalene and nitronaphthalene are toxic to the lung. His research team's findings will hopefully enable them to identify biomarkers that can ultimately be used to verify naphthalene and nitronaphthalene toxicity in human lungs.

"If we understand the mechanism by which these compounds produce toxicity in animals, then we will be able to tell whether the same mechanisms are important in primates. And we will also be able to develop good biomarkers that are closely related to the processes that produce the toxicity," Buckpitt explained.

Buckpitt, a professor of molecular biosciences at Davis, has spent the last 25 years focusing on the two byproducts of combustion, which are widespread in the atmosphere and in groundwater. A major source of naphthalene is cigarette smoke -both mainstream and secondhand- but it also results from any type of burning, including fuel combustion. A decade ago, the chemical was also widely used as a dispersant for insecticide.

Nitronaphthalene is a secondary pollutant, formed from naphthalene in the atmosphere. Early studies of the chemicals suggested they were both toxic to the respiratory systems of animals, which set off a flurry of interest in their human toxicity.

Buckpitt's work has revealed that naphthalene and nitronaphthalene must be metabolized to produce a toxic effect, that is, altered in the body by internal processes. Studies showed that nitronaphthalene's metabolites are toxic to the nasal and pulmonary epithelium of mice and rats. Naphthalene is similarly toxic - except that it does not affect the pulmonary epithelium of rats.

Examination of this phenomenon revealed that rats have very small quantities of the enzyme that catalyzes the first step in the metabolism of naphthalene- and unmetabolized, the chemical causes no harm to the lung. This finding- along with more than two decades of work on the topic- has led Buckpitt to surmise that humans may also lack the enzyme systems for metabolizing naphthalene, meaning the compound could prove to be less toxic to human lungs, too.

More recently, Buckpitt's team has found that the compounds' reactive metabolites bind covalently to proteins in the epithelial cells. Buckpitt said his research group is now focused on whether this process of covalent attachment is involved in the compounds' toxicity.

"If we could identify that, then we could look for things in the serum that are related to that [binding] process," Buckpitt explained. "Then the issue is, are the same biomarkers present in exposed humans?" Buckpitt acknowledged that finding biomarkers that could be applied to a human context could take years of work, but his research group is making rapid progress. "I hope to get there before I retire," he said.