Characterization of Naphthalene Metabolite-DNA Adducts in Mice and Firefighters

Abstract

Naphthalene (NA), the simplest polycyclic aromatic hydrocarbon (PAH), is persistently present in the environment as a byproduct of combustion of fossil fuels, tobacco products and more. Due to its ubiquitous presence, there is widespread exposure to the general population. Certain occupational groups, such as firefighters, have elevated levels of exposure. Firefighters also have increased incidences of certain types of cancer. NA is currently classified by the International Agency for Research on Cancer (IARC) as a Class 2B Carcinogen. There is direct evidence of tumor formation in mice and rats but no direct evidence of the carcinogenecity of NA in humans yet. The mechanism of carcinogenicity in mice and rats has yet to be elucidated but a combination of cytotoxic and genotoxic mechanisms is currently the leading hypothesis. NA metabolism results in the generation of reactive intermediates such as 1,2-epoxide (NAO) and reactive metabolites such as 1,2-naphthoquinone (NQ). Reactive quinone and epoxide metabolites of similar compounds, such as benzo[a]pyrene, have been shown to enact their carcinogenicity through DNA adduct formation. Published ex vivo and in vitro data have demonstrated that NA metabolites can form adducts with DNA. The objective of this study is to identify and quantify NA-DNA adducts in mouse lung as well as mouse and human blood to enable assessment of potential genotoxicity in firefighters. This project will provide direct evidence for the formation of NA-DNA adducts in vivo, lay the foundation for future studies of the genotoxicity of NA, obtain evidence to support more extensive assessments of the carcinogenic risks of NA to firefighters, and could have direct implications for the general population.