Vinyl Acetate-Induced Intracellular Acidification: Implications for Risk Assessment

Abstract

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.

Characterization of Chemically Induced Hepatotoxicity in Collagen Sandwiches of Rat Hepatocytes

“…Hepatocytes were relatively resistant to vinyl acetate according to the urea and albumin assays, although there was an increase in the release of lactate dehydrogenase. Vinyl acetate has been shown by others to cause some intracellular acidification at doses between 10 and 1000 lM in fresh rat hepatocytes (Bogdanffy, 2002). It is possible that the hepatocytes in the sandwich have decreased carboxylesterase activity compared with fresh hepatocytes.…”

White glue intoxication in a plain parakeet (Brotogeris tirica) – Case report

“…By the action of those enzymes, PVAc is broken down into vinyl acetate monomers (Gross &Research, Society andDevelopment, v. 11, n. 12, e144111234047, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i12.34047 7 Kalra, 2020), which, in turn, is metabolized, mainly via hydrolysis, by B-esterase enzymes, such as carboxylesterases and to a minor extent, cholinesterases. Vinyl acetate hydrolysis forms acetic acid and acetaldehyde (Fedtke & Wiegand, 1990), which, in short exposures, do not cause toxic effects in humans nor in some mammal species (Bogdanffy, 2002). B-esterase enzymes are also related to the biotransformation of other substances, such as insecticides (Parker & Goldstein, 2000), representing an important detoxification pathway to vinyl acetate and other xenobiotics, for instance carbamates and organophosphates (Fedtke & Wiegand, 1990;Thompson, 1993).…”

Mechanism of Carcinogenicity of Vinyl Acetate

“…A recent hypothesis for the mitogenic stimulus in respiratory epithelium clarifies and unifies the modes of action in the upper gastrointestinal tract and nasal respiratory epithelium (Bogdanffy, 2002). Literature reports indicate that reductions in intracellular pH (pH i ) can induce mitogenesis in the absence of cytotoxicity.…”