Vinyl acetate-induced intracellular acidification: implications for risk assessment.
Cancerbioassays have demonstrated the carcinogenic activity of vinyl acetate in rodents. Tumors appear only at the site of contact and mechanistic data suggest that the carcinogenic mechanism involves carboxylesterase-mediated metabolism of vinyl acetate to acetic acid. It has been hypothesized that intracellular formation of acetate causes a reduction of intracellular pH (pH(i)) at noncytotoxic levels, but that prolonged exposure to reduced pH(i) is cytotoxic and/or mitogenic and drives proliferative responses. Coupled with exposure to metabolically formed acetaldehyde at high administered concentrations, nonlinear dose-response curves for epithelial tumors are produced. Freshly isolated rat hepatocytes were used as a model system to test the concept that exposure of cells to vinyl acetate causes a reduction in pH(i). Quantitative fluorescence imaging ratio microscopy showed that exposure of hepatocytes to vinyl acetate concentrations ranging from 10 to 1000 microM caused rapid and sustained reductions of approximately 0.03 to 0.65 pH units. Cellular acidification was rapidly reversed to control pH(i) upon removal of vinyl acetate. There was minimal accumulation of protons during the exposure period, as suggested by minor differences in pH(i) of cells with or without prior exposure to vinyl acetate. The effect of vinyl acetate on pH(i) was attenuated by prior exposure to the carboxylesterase inhibitor bis(p-nitrophenyl)phosphate. These results support the concept that intracellular acidification is a sentinel pharmacodynamic response of cells to vinyl acetate exposure and that pH(i) is an appropriate metric dose for use in quantitative risk assessments of cancer and noncancer human health risk assessment.
Bogdanffy
Matthew S
MS
DuPont Haskell Laboratory, E. I. du Pont de Nemours and Co., Inc., P.O. Box 50, Newark, Delaware 19714, USA. bogdanffy@usa.dupont.com
D000818:Animals; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009596:Nitrophenols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D018570:Risk Assessment; D013997:Time Factors; D014753:Vinyl Compounds / Q000633:toxicity*
D004791:Enzyme Inhibitors; D009596:Nitrophenols; D014753:Vinyl Compounds; C002887:bis(4-nitrophenyl)phosphate; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; C011566:vinyl acetate