Molecular Dosimetry of DNA Adducts in Rats Exposed to Vinyl Acetate Monomer

Vinyl acetate monomer (VAM) is heavily used to synthesize polymers. Previous studies have shown that inhaled VAM, being metabolized to acetaldehyde, may form DNA adducts including N(2)-ethylidene-deoxyguanosine (N(2)-EtD-dG), which may subsequently cause mutations and contribute to its carcinogenesis. Currently, there is little knowledge on the molecular dosimetry between VAM exposure and DNA adducts under dosages relevant to human exposure. In this study, 0.02, 0.1, 1, 10, 50, 200, and 600 ppm VAM were exposed to rats by inhalation for 14 days (6 h/day). The use of [(13)C(2)]-VAM allows unambiguous differentiation and quantification of the exogenous and endogenous N(2)-EtD-dG by highly sensitive LC-MS/MS. Our data indicate that VAM-induced exogenous DNA adducts were formed in a non-linear manner. Exogenous DNA adducts were only detected in the nasal epithelium of rats exposed to 10, 50, 200, and 600 ppm VAM, whereas endogenous adducts were found in all nasal and other tissues analyzed. In addition, ratios of exogenous/endogenous DNA adducts were less than 1 with the dose up to 50 ppm, indicating that endogenous DNA adducts are predominant at low VAM concentrations. Moreover, differential dose-response in terms of exogenous DNA adduct formation were observed between nasal respiratory and olfactory epithelium. Furthermore, the lack of exogenous DNA adducts in distant tissues, including peripheral blood mononuclear cells, liver, brain, and bone marrow, indicates that VAM and/or its metabolite do not distribute systemically to cause DNA damage in distant tissues. Together, these results provided new molecular dosimetry to improve science-based cancer risk assessments of VAM.