Four-Week Inhalation Cell Proliferation Study of the Effects of Vinyl Acetate on Rat Nasal Epithelium

Bogdanffy, Matthew S.; Gladnick, N. Larry; Kegelman, Thomas; Frame, Steven R.

doi:10.1080/089583797198178

Cited by 26 publications

(18 citation statements)

References 16 publications

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“…The tumor predominance in the caudal and exterior region of the mandible may be causally related to the anatomical structure of this mandibular region which allows long retention of the VAformulated drinking water in the mouth, resulting in longer time exposure of the regional squamous epithelium to VA than the other regions. Nevertheless, the tumor predominance in the oral cavity and in the causal and exterior mandibular region is not compatible with the findings by Morris et al 28) and by Bogdanffy et al 6,29,30) Bogdanffy et al 29,30) proposed a mode-of-action hypothesis that intracellular, carboxylase-dependent metabolism of VA to acetic acid, a potent cytotoxicant, and acetaldehyde, a weak clastogen, was responsible for cell death and restorative cell proliferation leading to the development of the nasal cavity squamous cell tumors. Morris et al 28) reported that VA hydrolytic activity of the dorsal interior region of the oral mucosa was 3.3-and 7.6-fold higher for rats and mice, respectively, than that of the ventral interior region, but the VA hydrolytic activity of the oral mucosa as a whole was 100-fold lower than that of the nasal cavity.…”

Section: Discussioncontrasting

confidence: 55%

Carcinogenicity and Chronic Toxicity in Mice and Rats Administered Vinyl Acetate Monomer in Drinking Water

Umeda

Matsumoto

Yamazaki

et al. 2004

Journal of Occupational Health

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Carcinogenicity and Chronic Toxicity in Mice and Rats Administered Vinyl Acetate Monomer in Drinking Water: Yumi Umeda, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health Association—Carcinogenicity and chronic toxicity of vinyl acetate monomer (VA) were examined in male and female Crj:BDF1 mice and F344/DuCrj Rats. Groups of 50 mice and 50 rats of each sex were orally administered VA in drinking water containing 0, 400, 2,000 or 10,000 ppm (g/g) VA for 104 wk. Squamous cell tumors were clearly evident in the upper digestive tract of treated mice and rats, and in the larynx of treated mice of both sexes. In mice, squamous cell carcinomas and papillomas were observed in the oral cavity, esophagus, forestomach and larynx of the 10,000 ppm group, together with basal cell hyperplasia, squamous cell hyperplasia and epithelial dysplasia. In rats, incidences of squamous cell carcinomas and papillomas were increased in the oral cavity of the 10,000 ppm group of both sexes, and an esophagus squamous cell carcinoma was observed in a 10,000 ppm female. Pre‐neoplastic hyperplasias were also noted. Mapping of the neoplastic and pre‐neoplastic lesions in the oral cavity of the 10,000 ppm group revealed that both the lesions occurred predominantly at Level V in mice and at Level VI in rats. A lower confidence limit of a benchmark dose (BMDL10) of 477 mg/kg/d was obtained from a dose‐response relationship between combined incidence of squamous cell carcinomas and papillomas in the oral cavity of mice and rats and the estimated daily VA intakes per body weight, and compared with literature values.

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Section: Discussioncontrasting

confidence: 55%

Carcinogenicity and Chronic Toxicity in Mice and Rats Administered Vinyl Acetate Monomer in Drinking Water

Umeda

Matsumoto

Yamazaki

et al. 2004

Journal of Occupational Health

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“…Also, the nature of the cellular response to VA or its hydrolysis products may simply not produce remarkable signs of cellular degeneration within the time frame of this study. Collectively, these findings indicate that CP in the oral cavity may be considerably delayed in onset and, in contrast to the nasal mucosa (Bogdanffy et al, 1997), occur in the absence of frank cytotoxic or inflammatory changes. Although the observed findings do not exclude the possible involvement of apoptosis (programmed cell death) in the dynamics of cell death/renewal, its role is likely minor in comparison to the observed CP response, since apoptotic bodies were not observed microscopically.…”

Section: Discussionmentioning

confidence: 80%

“…This study was conducted specifically to determine whether histopathological and CP alterations occur in the upper digestive tract mucosa following continuous exposure to VA. VA was administered under conditions similar to those used in the JBRC bioassay, except that the high dose was increased to 24,000 ppm (the water solubility limit) to maximize the likelihood of detecting changes. We hypothesized that prolonged VA exposure at high concentrations would induce cytotoxicity and a restorative CP in mucosa comparable to that observed in nasal olfactory and respiratory epithelium by VA inhalation (Bogdanffy et al, 1997). Increased CP is considered an essential step in the multistage process of carcinogenesis for both initiation and promotion of neoplasia (Butterworth, 1990;Cohen and Ellwein, 1990) and is central to the hypothesized mode of action for VA-induced neoplasia.…”

mentioning

confidence: 99%

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

Valentine

Bamberger²,

Szostek³

et al. 2002

Toxicological Sciences

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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.

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“…The mode of action is thought to involve combined effects of cytotoxicity, clastogenesis, and induced cell proliferation (Bogdanffy et al, 1997b). The cytotoxic effects of vinyl acetate are believed to be the result of intracellular acidification induced by excessive proton burdens that overwhelm the buffer capacity and Na + / H + antiport mechanisms of the epithelium.…”

Section: Discussionmentioning

confidence: 99%

High-Affinity Nasal Extraction of Vinyl Acetate Vapor Is Carboxylesterase Dependent

Bogdanffy

1999

Inhalation Toxicology

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Vinyl acetate induces nasal tumors in rats, but not mice. Species differences in airflow patterns, physiology, and biochemistry complicate extrapolation of nasal dosimetry from rats to humans. Physiologically based pharmacokinetic modeling of vinyl acetate dosimetry in rats suggested the presence of a saturable metabolic removal pathway in rat nasal mucus. We explored the possibility that this pathway is either a cytochrome P-450 2E1 (CYP2E1) or high-affinity carboxylesterase. Nasal extraction of vinyl acetate vapor (150 ppm) was measured in the surgically isolated nasal cavity of anesthetized rats. Vinyl acetate (150 ppm) was extracted with 73% efficiency in controls. Pretreatment of rats with the CYP2E1 inhibitor diallyl sulfide (DAS) had no effect on extraction, despite significantly reducing CYP2E1 activity. Pretreatment with bis(p-nitrophenyl) phosphate (BNPP), a carboxylesterase inhibitor, reduced extraction to approximately 41%. Acetaldehyde production was similarly unaffected by DAS but was reduced to 55% of control by BNPP. Rat nasal mucus carboxylesterase activity had a K(m) value (32 microM) similar, within a factor of 2, to the value predicted by the physiologically based model, although V(max) was significantly lower than the model prediction. Histochemical observations support the inference that the high-affinity carboxylesterase is bound to the luminal plasma membrane of nasal tissue and is not readily released by nasal lavage, providing an explanation for the low V(max) of the lavage enzyme. This high-affinity isoenzyme could be important in the removal of odorants from the sensory cell-rich nasal olfactory epithelium.

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Four-Week Inhalation Cell Proliferation Study of the Effects of Vinyl Acetate on Rat Nasal Epithelium

Cited by 26 publications

References 16 publications

Carcinogenicity and Chronic Toxicity in Mice and Rats Administered Vinyl Acetate Monomer in Drinking Water

Carcinogenicity and Chronic Toxicity in Mice and Rats Administered Vinyl Acetate Monomer in Drinking Water

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

High-Affinity Nasal Extraction of Vinyl Acetate Vapor Is Carboxylesterase Dependent

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