title: Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity.
abstract: Vinyl acetate monomer (VAM) is a site-of-contact carcinogen in rodents. It is also DNA reactive and mutagenic, but only after its carboxylesterase mediated conversion to acetaldehyde (AA), a metabolic reaction that also produces acetic acid and protons. As VAM's mutagenic metabolite, AA is normally produced endogenously; detoxification by aldehyde dehydrogenase (ALDH) is required to maintain intra-cellular AA homeostasis. This review examines VAM's overall genotoxicity, which is due to and limited by AA, and the processes leading to mutation induction. VAM and AA have both been universally negative in mutation studies in bacteria but both have tested positive in several in vitro studies in higher organisms that usually employed high concentrations of test agents. Recently however, in vitro studies evaluating submillimolar concentrations of VAM or AA have shown threshold dose-responses for mutagenicity in human cultured cells. Neither VAM nor AA induced systemic mutagenicity in in vivo studies in metabolically competent mice when tested at non-lethal doses while treatments of animals deficient in aldehyde dehydrogenase (Aldh in animals) did induce both gene and chromosome level mutations. The results of several studies have reinforced the critical role for aldehyde dehydrogenase 2 (ALDH2 in humans) in limiting AA's (and therefore VAM's) mutagenicity. The overall aim of this review of VAM's mutagenic potential through its AA metabolite is to propose a mode of action (MOA) for VAM's site-of-contact carcinogenesis that incorporates the overall process of mutation induction that includes both background mutations due to endogenous AA and those resulting from exogenous exposures.
authors.affiliation: Department of Pathology, The University of Vermont, Burlington, VT, USA. Ralbert315@aol.com
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Albertini
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009153:Mutagens / Q000633:toxicity; D014753:Vinyl Compounds / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D009153:Mutagens; D014753:Vinyl Compounds; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; C011566:vinyl acetate