Chronic Toxicity and Oncogenicity Study with Vinyl Acetate in the Rat: <i>In Utero</i> Exposure in Drinking Water

Bogdanffy, Matthew S.; TYLER, T. R.; Vinegar, Marlee; Rickard, Robert W.; Carpanini, F.M.B.; CASCIERI, T. C.

doi:10.1093/toxsci/23.2.206

Cited by 3 publications

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“…The present finding of VA-induced squamous cell carcinomas and papilloma in the upper digestive tract of mice and rats is in apparent contrast to the results from the VA-formulated drinking water studies by Bogdanffy et al 7) and Lijinsky and Reuber 5) , but consistent with the results by Maltoni et al 8) The difference and similarity in the VA-induced carcinogenicity between the results so far reported and the present findings appear to exist in a difference in the amount of daily VA intake. Indeed, a BMDL 10 value resulted in 477 mg/kg/d for the oral cavity squamous cell tumors as shown in Figure 6.…”

Section: Discussioncontrasting

confidence: 99%

“…Indeed, a BMDL 10 value resulted in 477 mg/kg/d for the oral cavity squamous cell tumors as shown in Figure 6. Judging from the dose-response curve, the estimated daily VA intakes employed by Lijinsky and Reuber 5) and Bogdanffy et al 7) appear to be lower than a dose level enough to significantly increase the tumor incidence. In the study of Lijinsky and Reuber 5) , oral administration of the 1,000 ppm (40 g/kg for females and 25 g/kg for males during the 100-wk administration period) and 2,500 ppm water (100 g/kg for females and 62 g/kg for males) was estimated to correspond to 35 and 88 mg/kg/d for male rats and 57 and 143 mg/kg/d for female rats, respectively, on the daily intake basis.…”

Section: Discussionmentioning

confidence: 90%

“…In the study of Lijinsky and Reuber 5) , oral administration of the 1,000 ppm (40 g/kg for females and 25 g/kg for males during the 100-wk administration period) and 2,500 ppm water (100 g/kg for females and 62 g/kg for males) was estimated to correspond to 35 and 88 mg/kg/d for male rats and 57 and 143 mg/kg/d for female rats, respectively, on the daily intake basis. Bogdanffy et al 7) reported that oral administration of drinking water containing 200, 1,000 and 5,000 ppm VA corresponded to 10, 47 and 202 mg/kg/d for male rats and 16, 76 and 302 mg/kg/d for female rats, respectively. In the study of Maltoni et al 8) who reported positive induction of multiple site squamous cell carcinomas in Swiss mice, however, the daily VA intake of the 5,000 ppm-administered mice was estimated as 506 mg/kg/d for males and 533 mg/kg/d for females, assuming that the male and female Swiss mice consumed 4.3 g and 4.0 g of the 5,000 ppm VA-formulated drinking water, the same amounts consumed by the male and female Crj:BDF 1 mice used in the present study, respectively.…”

Section: Discussionmentioning

confidence: 99%

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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: 99%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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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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“…No treatment-related increase in tumor incidence was observed. 20 Fifty male and 50 female F344 rats received 0-10,000 ppm vinyl acetate (98% pure) for 104 weeks. Statistically significant increases in preneoplastic changes and squamous cell neoplasms were observed at several sites in the upper digestive tract, but only at the 10,000 ppm dose (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Results of Long‐Term Carcinogenicity Bioassay on Vinyl Acetate Monomer in Sprague‐Dawley Rats

Minardi

Belpoggi

Soffritti

et al. 2002

Annals of the New York Academy of Sciences

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Vinyl acetate monomer (VAM) was administered in drinking water supplied ad libitum at doses of 5,000, 1,000, and 0 ppm (v/v) to 17-week-old Sprague-Dawley rats (breeders) and to 12-day embryos (offspring). Treatment lasted for 104 weeks; thereafter, animals were kept under control conditions until spontaneous death. VAM was found to cause an increase in total malignant tumors and in carcinomas and/or precursor lesions of the oral cavity, lips, tongue, esophagus, and forestomach. Based on these data, VAM must be considered a multipotent carcinogen.

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“…By the inhalation route of exposure, vinyl acetate is carcinogenic in rats (600 ppm) but not mice (Bogdanffy et al, 1994a). When administered in drinking water, vinyl acetate is carcinogenic in rats and mice (Ն2000 ppm) (Bogdanffy et al, 1994b; Japan Bioassay Research Center reported in U.S. EPA, 1997). Vinyl acetate is only carcinogenic at the portal of entry, inducing nasal tumors by the inhalation route and oral cavity and esophageal tumors by the oral route.…”

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Vinyl Acetate-Induced Intracellular Acidification: Implications for Risk Assessment

Bogdanffy¹

2002

Toxicological Sciences

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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.

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Chronic Toxicity and Oncogenicity Study with Vinyl Acetate in the Rat: In Utero Exposure in Drinking Water

Cited by 3 publications

References 0 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

Results of Long‐Term Carcinogenicity Bioassay on Vinyl Acetate Monomer in Sprague‐Dawley Rats

Vinyl Acetate-Induced Intracellular Acidification: Implications for Risk Assessment

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