Investigations on Cell Proliferation and Enzyme Induction in Male Rat Kidney and Female Mouse Liver Caused by Tetrahydrofuran

Abstract

To elucidate possible mechanism(s) of carcinogenic action of tetrahydrofuran (THF) that had been demonstrated in previous inhalation studies, groups of male F344 rats and female B6C3F(1) mice were exposed to dynamic atmospheric concentrations of 0, 600, 1800, or 5400 mg/m(3) for 6 h per day, either for 5 consecutive days or for a period of 4 weeks (5 days per week). The reversibility of treatment-related changes was investigated in rats and mice exposed for 5 days and sacrificed 21 days after the last exposure. Female B6C3F(1) mice exposed to 5400 mg/m(3) showed significantly increased cytochrome P450 content, increased ethoxyresorufin-O-deethylase and pentoxyresorufin-O-depentylase activities, increased cell proliferation (5-bromo-2'-deoxyuridine-method) and an increased mitotic index in liver zones 2 (midzonal region) and 3 (central vein region). The changes were found to be reversible after a 3-week treatment-free period (cell proliferation examined, only). Male F344 rats showed dose-related alpha2u-globulin (alpha2u) accumulation in the renal cortex after 5 or 20 exposures, and there were no signs of reversal after a 3-week treatment-free period. After 20 exposures at 5400 mg/m(3), the alpha2u accumulation was found to be associated with increased cell proliferation in "hot spots" of the renal cortex and increased apoptosis. Increased cell proliferation was also detected after 20 exposures at 1800 mg/m(3). There were no effects at 600 mg/m(3). It is concluded that THF enhances tumor formation in male rat kidney and female mouse liver via induction of cell proliferation. These features present essential elements that should be taken into account for the carcinogenic risk assessment of THF.

Genomic Sensitivity of Small Mammals - A Suitable Test System in the Genetic Monitoring

“…The data of the cytogenetic analysis conducted on the treated bone marrow cells with 3.8 mg/kg THF on small mammal species is presented on The results obtained in our cytogenetic study evidence that THF have a clastogenic effect and confirm previous data (Gamer et al, 2002) showing an increase of sister chromatid exchanges and chromosomal aberrations following an i.p. treatment with that genotoxin.…”

“…Chhabra et al (1998) found a clear evidence of carcinogenic activity in female B6C3F 1 mice observing increased incidences of hepatocellular neoplasms at the 1800 ppm exposure level, but these authors did not observe carcinogenic effect of THF in female rats and male mice. Inhalation studies with rats and B6C3F 1 mice also provided evidence of carcinogenic activity for THF (Gamer et al, 2002).…”

“…THF was not mutagenic in Salmonella, micronucleus and DEL tests and did not induce sister chromatid exchanges or chromosomal aberrations in ovary cells (Gamer et al, 2002). According to the data of NTP (1998) in male B6C3F 1 mice after i.p.…”

Effect of cytochrome P-450 inhibition on tetrahydrofuran-induced hepatocellular proliferation in female mice

“…Slightly higher absolute (10% increase) and relative (5% increase) liver weights were recorded at 5,400 mg/m 3 , but there were no morphological signs of liver cell degeneration or necrosis or changes in the number of apoptotic cells, and electron microscopy did not reveal changes in cell organelles or subcellular compartments. Thus, slight liver enlargement and significant microsomal enzyme induction induced by THF in female B6C3F 1 mice were not accompanied by morphological evidence of hepatocellular hypertrophy or proliferation of smooth endoplasmic reticulum (Gamer et al, 2002). Similar observations have been reported in the literature.…”

Tetrahydrofuran [MAK Value Documentation, 2004]

“…In another mechanistic study, the influence of cytochrome P450 oxidases (CYP) on the proliferation-enhancing effect of tetrahydrofuran was investigated (Gamer et al 2002;Tetrahydrofurane Task Force 2002;). Two groups of female B6C3F 1 mice were exposed to tetrahydrofuran concentrations of 0.5512 mg/m 3 and another two groups to 14739 mg/m 3 (0.1900 ml/m 3 and 5000 ml/m 3 )f or 6h ours a day, on 5c onsecutive days.…”