Induced cytolethality and regenerative cell proliferation in the livers and kidneys of male B6C3F1 mice given chloroform by gavage.
It has been reported that chloroform administered to male B6C3F1 mice at doses of 138 and 277 mg/kg/day in corn oil by gavage 5 days/week for 2 years resulted in incidences of hepatocellular carcinomas of 36 and 98% relative to an incidence in controls of 6%. Cytotoxicity and regenerative cell proliferation have been implicated in the tumorigenic process for this non-genotoxic compound. Although chloroform is known to be nephrotoxic in the male mouse, no treatment-related increase was observed in the frequency of kidney tumors. To better understand the relationship of these endpoints, this study evaluated chloroform-induced cytotoxicity and cell proliferation in the liver and kidney under conditions of the cancer study. B6C3F1 mice were administered oral doses of 0, 34, 90, 138, or 277 mg/kg/day of chloroform dissolved in corn oil for 4 days or 5 days/week for 3 weeks. Bromo-2'-deoxyuridine (BrdU) was administered via osmotic pumps implanted 3.5 days prior to necropsy to label cells in S-phase. Cell proliferation was evaluated in tissue sections immunohistochemically as the percentage of cells in S-phase (nuclear labeling index; LI). Mice given 34 and 90 mg/kg/day by gavage had mild degenerative changes in centrilobular hepatocytes after 4 days of treatment, which was absent at 3 weeks. Centrilobular necrosis was observed in mice given 138 or 277 mg/kg chloroform for 4 days, with increased severity of necrosis at 3 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Larson
J L
JL
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Wolf
D C
DC
Butterworth
B E
BE
D000818:Animals; D001973:Bromodeoxyuridine / Q000032:analysis; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002725:Chloroform / Q000633:toxicity*; D007441:Intubation, Gastrointestinal; D007668:Kidney / Q000166:cytology / Q000187:drug effects*; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains
D002725:Chloroform; D001973:Bromodeoxyuridine