Furan-induced dose-response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity).
Rodent studies of furan are associated with liver cell necrosis, release of liver-associated enzymes, increased hepatocyte proliferation, and hepatocarcinogenesis. For carcinogens whose proposed mode of action is cytolethality, it is hypothesized that the dose-response curve for tumor development would parallel the dose-response curve for cell death with compensatory proliferation in the target organ. To prospectively test this hypothesis, female B6C3F(1) mice were exposed to furan at carcinogenic doses and lower for 3 weeks or 2 years. At 3 weeks and in the 2-year study, there were dose-dependent and significant increases in hepatic cytotoxicity at 1.0, 2.0, 4.0, and 8.0mg furan/kg. For cell proliferation as measured by 5-bromo-2'-deoxyuridine (BrdU) labeling index (LI), there was a statistically significant trend with increasing dose levels of furan and increased LI at 8.0mg/kg. There was an increased incidence of foci of altered hepatocytes, hepatocellular adenomas, and adenomas or carcinomas at 4.0 and 8.0mg/kg and carcinomas at 8.0mg/kg. The multiplicity of microscopic tumors was increased and latency was decreased in mice exposed to 8.0mg/kg. Prevalence of hepatic nodules at necropsy was increased in mice exposed to 4.0 and 8.0mg/kg. Data demonstrate an association among furan-induced hepatic cytotoxicity, compensatory cell replication, and liver tumor formation in mice; at high doses >or=4.0mg/kg, furan induced hepatotoxicity, compensatory cell replication and tumorigenesis in a dose-related manner, while furan did not produce tumors at cytotoxic doses of 1.0 and 2.0mg/kg.
Moser
Glenda J
GJ
Integrated Laboratory Systems, Inc., Research Triangle Park, NC 27709, USA. gmoser@ils-inc.com
Foley
Julie
J
Burnett
Merrie
M
Goldsworthy
Thomas L
TL
Maronpot
Robert
R
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008111:Liver Function Tests; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis
D005663:Furans; C039281:furan