Superfund Research Program

Biomarkers of Exposure to Pulmonary Toxicants

Project Leader: Alan R. Buckpitt
Grant Number: P42ES004699
Funding Period: 1995-2010

Project-Specific Links

Final Progress Reports

Year:   2009  2004  1999 

This project continues to focus on understanding the mechanisms of action and cross species comparisons from rodents to non human primates to humans for the volatile aromatic hydrocarbon, naphthalene. There are several important sources of human naphthalene exposure which range from tobacco smoke, to fossil fuels, to degassing of cold tar waste sites to jet fuel. In fact it is the latter source that has raised significant concerns in the US DOD as jet fuels are 1-3% by weight naphthalene and estimates of the cost of removal would be $1.5-6 billion annually. Several markers of exposure have been published which include urinary water soluble metabolites, blood protein adducts and protein adducts in the skin but, because of the known species differences in the rates of naphthalene metabolism, these may not be good predictors of toxicity. Researchers studies build on previous work in which a number of specific adducts to tissue proteins have been identified in rodent and primate models and are intended to focus on adducted peptides and relatively small proteins which are eliminated in the urine. The majority of the effort has been spent in methods development beginning with the synthesis of all 5 reactive metabolite standards and the reaction of these metabolites with model peptides containing known nucleophilic amino acids (cysteine and lysine). Fragmentation patterns are being used to assist in the interpretation of mass spectra obtained from putative adducted peptides (mass range 500 to 900 Da) found in the urine of naphthalene treated mice. The second question that they are addressing is related to determining which proteins are ‘critical’ to the cytotoxicity associated with naphthalene. These comparative studies are identifying differences in adduct patterns for diethyl maleate, a non toxic glutathione depletor which binds covalently to proteins in the lung to naphthalene. The long range goal is to obtain samples from a study being conducted on military personnel where naphthalene levels will be monitored using a small breathing zone analyzer (under development) and where they will use adduct markers in the urine to determine the possible risk of these exposures.