title: Induced cytolethality and regenerative cell proliferation in the livers and kidneys of male B6C3F1 mice given chloroform by gavage.
abstract: 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)
authors.affiliation: Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
authors.forename: J L
authors.initials: JL
authors.lastname: Larson
authors.forename: D C
authors.initials: DC
authors.lastname: Wolf
authors.forename: B E
authors.initials: BE
authors.lastname: Butterworth
mesh_terms: 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
chemical_list: D002725:Chloroform; D001973:Bromodeoxyuridine