Functional and proliferative effects of repeated low-dose oral administration of furan in rat liver.
METHODS
Furan, a food contaminant formed during heat processing, induces hepatocellular tumors in rodents and high incidences of cholangiocarcinomas in rats even at the lowest dose (2 mg/kg b.w.) administered. Initial estimates suggested that human intake of furan may be as high as 3.5 μg/kg b.w./day, indicating a relatively narrow margin of exposure. The aim of this study was to establish dose-response data for cytotoxicity, regenerative cell proliferation and secondary oxidative DNA damage in livers of male F344 rats treated with furan at doses ≤2 mg/kg b.w. for 28 days.


RESULTS
No significant signs of hepatotoxicity other than a mild, dose-dependent increase in serum cholesterol and unconjugated bile acids, and no evidence of oxidative DNA damage were seen. Histopathological alterations and proliferative changes were restricted to subcapsular areas of the left and caudate liver lobes.


CONCLUSIONS
Although statistically significant effects were only seen at the 2 mg/kg b.w. dose during the course of our study, a ∼two and ∼threefold increase in 5-bromo-2'-deoxyuridine labeling index was observed at 0.1 and 0.5 mg/kg b.w., respectively, suggesting that chronic exposure to doses even below 2 mg/kg b.w. may cause proliferative changes in rat liver and highlighting the need to assess furan carcinogenicity at lower doses.
Mally
Angela
A
Department of Toxicology, University of Würzburg, Würzburg, Germany. mally@toxi.uni-wuerzburg.de
Graff
Carmen
C
Schmal
Olga
O
Moro
Sabrina
S
Hamberger
Carolin
C
Schauer
Ute M
UM
Brück
Jens
J
Ozden
Sibel
S
Sieber
Max
M
Steger
Ulrich
U
Schrenk
Dieter
D
Hard
Gordon C
GC
Chipman
James Kevin
JK
Dekant
Wolfgang
W
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000032:analysis / Q000097:blood; D015197:Carcinogenicity Tests; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D049109:Cell Proliferation; D004249:DNA Damage; D005663:Furans / Q000008:administration & dosage* / Q000633:toxicity*; D008099:Liver / Q000503:physiopathology*; D008297:Male; D055432:Metabolomics; D009929:Organ Size; D051381:Rats; D011916:Rats, Inbred F344
D001647:Bile Acids and Salts; D002274:Carcinogens, Environmental; D005663:Furans; C039281:furan