Furan-induced dose-response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity)

Exp Toxicol Pathol. 2009 Mar;61(2):101-11. doi: 10.1016/j.etp.2008.06.006. Epub 2008 Sep 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Proliferation / drug effects*
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / pathology
  • Dose-Response Relationship, Drug
  • Female
  • Furans / toxicity*
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Liver Function Tests
  • Liver Neoplasms, Experimental / chemically induced*
  • Liver Neoplasms, Experimental / pathology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Necrosis


  • Furans
  • furan