TOXICITY AND CELL-PROLIFERATION IN THE LIVER, KIDNEYS AND NASAL PASSAGES OF FEMALE F344 RATS, INDUCED BY CHLOROFORM ADMINISTERED BY GAVAGE

Dose-response relationships were determined for the induction of cytol ethality and regenerative cell proliferation in the established target organs (liver, kidneys, and nasal passages) of female F-344 rats give n chloroform daily by gavage. Rats were administered chloroform dissol ved in corn oil at doses of 0, 34, 100, 200 or 400 mg/kg/day for 4 con secutive days or for 5 days/wk for 3 wk. Bromodeoxyuridine (BrdU) was administered through an implanted osmotic pump 3.5 days prior to autop sy to label cells in S-phase. Cells in S-phase were visualized immunoh istochemically in tissue sections and the labelling index (LI) calcula ted as the percentage of cells in S-phase. Mild degenerative centrilob ular changes and dose-dependent increases in the hepatocyte LI were ob served after administration of 100 mg or more chloroform/kg/day. Rats given 200 or 400 mg/kg/day for 4 days or 3 wk had degeneration and nec rosis of the proximal tubules of the renal cortex. Regenerating epithe lium lining proximal tubules was seen histologically and as an increas e in LI. Dose-dependent increases in LI were observed in the kidneys a t doses of 100 mg or more cholorform/kg/day at both 4 days and 3 wk. T wo distinct treatment-induced responses were observed in specific regi ons of the olfactory mucosa lining the ethmoid region of the nose. A p eripheral lesion was seen at all doses used and included new bone form ation, periosteal hypercellularity and increased cell replication. A c entral lesion was seen at doses of 100 mg or more chloroform/kg/day an d was characterized by degeneration of the olfactory epithelium and su perficial Bowman's glands. These observations define the dose-response relationships for the liver, kidneys and nasal passages as target org ans for chloroform administered by gavage in the female F-344 rat.