Time- and Concentration-Dependent Increases in Cell Proliferation in Rats and Mice Administered Vinyl Acetate in Drinking Water

Abstract

Chronic administration of vinyl acetate (VA) in drinking water to rats and mice has produced upper digestive tract neoplasms. These tumors were believed to arise from the intracellular metabolism of VA by carboxylesterases to cytotoxic and genotoxic compounds. We hypothesized that prolonged VA exposure at high concentrations would induce cytotoxicity and a restorative cell proliferation (CP). These endpoints were measured in F-344 rats and BDF1 mice administered drinking water containing 0, 1000, 5000, 10,000, or 24,000 ppm VA for 92 days. On test days, Days 1, 8, 29, and 92, upper digestive tract histopathology and oral cavity CP (pulsed 5-bromodeoxyuridine [BrdU] to measure S-phase DNA synthesis) were evaluated. Analysis of test solutions showed that VA spontaneously hydrolyzed, slowly releasing acetic acid and thereby lowering pH. Statistically significant, concentration-related increases in CP occurred in basal cells of the mandibular oral cavity mucosa of mice at 10,000 and 24,000 ppm but only after 92 days. CP increases were approximately 2.4- and 3.4-fold above controls and were considered to be toxicologically significant. Some statistically significant increases in CP were also measured in the oral cavity mucosa of rats; however, these changes were considered to be of equivocal biological relevance. No histopathological evidence of mucosal injury was seen in either species. The absence of cytotoxicity in the upper digestive tract mucosa suggests that the increased CP at high administered VA concentrations may be due to a mitogenic response, ostensibly from the loss of cell growth controls in oral cavity mucosa.

13-week oral toxicity study of vinyl laurate in rats

“…Nonetheless, this VL treatment did not cause histopathological changes in the digestive tract or the liver. This observation is in keeping with the fact that VAc induced restorative cell proliferation of the oral mucosa occurred in rats only when it was administered in the drinking water at very high concentrations of P10,000 ppm for 92 days (Valentine et al, 2002).…”

“…The mean body weight of these animals was 8% lower than that of controls. The weekly water consumption of male and female rats at 5000 ppm was significantly lower than that of the controls, presumably due to a taste aversion which has been observed also in another rat study with VAc (Valentine et al, 2002). Thus, the high-dose VAc level was a NOAEL in both the mouse and rat study (Gale, 1980a,b).…”

“…Accordingly, vinyl acetate could be administered to the test animals with the drinking water at concentrations of 10,000 or even 24,000 ppm (Valentine et al, 2002). In contrast, VL is a colorless liquid with a very low water solubility (0.24 mg/L).…”

Response to Dr. Bogdanffy et al.'s comments on our paper

“…Valentine, Bogdanffy and their associates 3) reported that oral cell proliferation significantly increased in mice after 3 months of exposure to 10,000 ppm VA, whereas no significant changes occurred at 5,000 and 1,000 ppm. We think that neoplastic and pre-neoplastic proliferative lesions, indicative of altered tissue homeostasis, occur at : The first time point at which a decrease of greater than 10% in body weight gain as compared to the control was observed.…”

Response to Umeda et al.

“…Valentine et al 3) reported a 2-fold increase in oral cavity cell proliferation in mice following 3 months of exposure to 10,000 ppm VA, yet no significant changes occurred at 5,000 or 1,000 ppm. The observation that neoplastic and preneoplastic changes occurred in mice only where cell proliferation was significantly elevated, suggests that the MTD for tissue homeostasis was exceeded at 10,000 ppm.…”