title: Nonlinear responses for chromosome and gene level effects induced by vinyl acetate monomer and its metabolite, acetaldehyde in TK6 cells.
abstract: Vinyl acetate monomer (VAM) produced rat nasal tumors at concentrations in the hundreds of parts per million. However, VAM is weakly genotoxic in vitro and shows no genotoxicity in vivo. A European Union Risk Assessment concluded that VAM's hydrolysis to acetaldehyde (AA), via carboxylesterase, is a critical key event in VAM's carcinogenic potential. In the following study, we observed increases in micronuclei (MN) and thymidine kinase (Tk) mutants that were dependent on the ability of TK6 cell culture conditions to rapidly hydrolyze VAM to AA. Heat-inactivated horse serum demonstrated a high capacity to hydrolyze VAM to AA; this activity was highly correlated with a concomitant increase in MN. In contrast, heat-inactivated fetal bovine serum (FBS) did not hydrolyze VAM and no increase in MN was observed. AA's ability to induce MN was not impacted by either serum since it directly forms Schiff bases with DNA and proteins. Increased mutant frequency at the Tk locus was similarly mitigated when AA formation was not sufficiently rapid, such as incubating VAM in the presence of FBS for 4 hr. Interestingly, neither VAM nor AA induced mutations at the HPRT locus. Finally, cytotoxicity paralleled genotoxicity demonstrating that a small degree of cytotoxicity occurred prior to increases in MN. These results established 0.25 mM as a consistent concentration where genotoxicity first occurred for both VAM and AA provided VAM is hydrolyzed to AA. This information further informs significant key events related to the mode of action of VAM-induced nasal mucosal tumors in rats.
authors.affiliation: The Dow Chemical Company, Midland, Michigan.
authors.forename: Robert
authors.initials: R
authors.lastname: Budinsky
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Gollapudi
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Albertini
authors.forename: Rudolph
authors.initials: R
authors.lastname: Valentine
authors.forename: Mari
authors.initials: M
authors.lastname: Stavanja
authors.forename: Justin
authors.initials: J
authors.lastname: Teeguarden
authors.forename: Robert
authors.initials: R
authors.lastname: Fensterheim
authors.forename: David
authors.initials: D
authors.lastname: Rick
authors.forename: Thomas
authors.initials: T
authors.lastname: Lardie
authors.forename: Lisa
authors.initials: L
authors.lastname: McFadden
authors.forename: Amanda
authors.initials: A
authors.lastname: Green
authors.forename: Leslie
authors.initials: L
authors.lastname: Recio
mesh_terms: D000079:Acetaldehyde / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002877:Chromosomes, Human / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D015162:Micronucleus Tests; D009153:Mutagens / Q000009:adverse effects*; D009154:Mutation / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014753:Vinyl Compounds / Q000009:adverse effects*
chemical_list: D009153:Mutagens; D014753:Vinyl Compounds; D013937:Thymidine Kinase; D000079:Acetaldehyde; C011566:vinyl acetate
keywords: acetaldehyde; cytotoxicity; dose-response; genotoxic mode-of-action; key events; rat nasal tumors; vinyl acetate