Naphthalene (NA) is a ubiquitous and highly abundant pollutant found in vehicle exhaust, fossil fuels and wildfire smoke. NA causes nasal and lung toxicity, including tumors, in rats and mice, respectively, and is a possible human carcinogen. The mechanism of NA carcinogenicity, which may involve both genotoxic and non- genotoxic events, is not clear and may involve several reactive NA metabolites. A prerequisite for NA toxicity is bioactivation by cytochrome P450 (CYP) to form NA-epoxide (NAO) which can undergo further metabolism in the lung and liver to 1,2-naphthoquinone (1,2-NQ). Both NAO and 1,2-NQ can react with DNA. We have recently uncovered a significant contribution of liver-generated NA metabolites to acute lung toxicity in vivo; identified several NQ-DNA adducts in the mouse lung, liver, and blood following NA exposure and in blood samples from human firefighters and lung biopsy samples of lung cancer patients; and gained novel insights on the toxicokinetics of various NA metabolites. These exciting findings led to the current proposal, to test the novel hypothesis that liver-generated reactive NA metabolites are transported to the lung where they contribute to NA's cytotoxicity, genotoxicity, and carcinogenesis. We are well positioned to address this hypothesis due to the genetically modified mouse models we have developed, the recent methodologic advances we have made in metabolite and DNA adduct characterization, and the exposure systems we have in place to expose mice acutely and/or chronically to NA vapor at defined doses. A series of mechanistic and translational studies will be carried out in four Specific Aims that will 1) identify key metabolic events that control NA DNA adduct formation in the lung, 2) determine whether serum albumin facilitates transport of liver-generated reactive NA metabolites to the lung, 3) identify whether key metabolic events in the liver mediate NA-induced lung tumorigenesis in vivo, and 4) characterize profiles of NA