Time- and concentration-dependent increases in cell proliferation in rats and mice administered vinyl acetate in drinking water.
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.
Valentine
Rudolph
R
Haskell Laboratory for Toxicology and Environmental Sciences, E.I. du Pont de Nemours and Company, Elkton Road, P.O. Box 50, Newark, DE 19714, USA. rudolph.valentine@usa.dupont.com
Bamberger
J R
JR
Szostek
B
B
Frame
S R
SR
Hansen
J F
JF
Bogdanffy
M S
MS
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D018675:Toxicity Tests; D014753:Vinyl Compounds / Q000008:administration & dosage / Q000633:toxicity*; D014881:Water Supply
D002273:Carcinogens; D014753:Vinyl Compounds; D004247:DNA; D001973:Bromodeoxyuridine; C011566:vinyl acetate