PATTERNS OF CHLOROFORM-INDUCED REGENERATIVE CELL-PROLIFERATION IN BDF1 MICE CORRELATE WITH ORGAN SPECIFICITY AND DOSE-RESPONSE OF TUMOR-FORMATION

It has been reported that chloroform administered to BDF1 mice by inha lation for 2 years at concentrations of 5, 30 or 90 p.p.m. for 6 h/day , 5 days/week induced an increase in renal cell tumors in male but not female mice exposed to the doses of 30 and 90 p.p.m. A small increase in liver tumors was statistically significant in the female mice at 9 0 p.p.m. if the incidences of carcinomas and adenomas mere combined, B ecause chloroform is not a DNA reactive mutagen, a 13-week time-course and dose-response study was conducted under conditions of the origina l bioassay to examine whether regenerative cell proliferation was an u nderlying mechanism of carcinogenesis, Mice were given bromodeoxyuridi ne via infusion during the last 3.5 days prior to necropsy to label ce lls in S-phase, Chloroform induced pathology and regenerative cell pro liferation, measured as the labeling index (LI, percentage of cells in S-phase), were assessed microscopically and immunohistochemically, Ma le mice exposed to 30 and 90 p.p.m. exhibited a dose-dependent increas e in regenerating tubules within the renal cortex and up to a 31-fold increase in LI. No renal lesions or increased LI mere observed in fema les, Increased centrilobular to midzonal hepatocyte degeneration and v acuolation and a 7-fold increase over controls in the hepatocyte LI we re observed in the female mice at 90 p.p.m. at 13 weeks, Males exhibit ed similar pathology, but the increase in LI was not sustained, The ob served correlations between cytolethality and regenerative cell prolif eration with tumor formation supports extensive evidence that chlorofo rm induces cancer via a non-genotoxic-cytotoxic mode of action, A conc entration of 5 p.p.m. is the no-observed-adverse-effect level for neph rotoxicity, cell proliferation and cancer, An appropriate safety facto r applied to this value is a straightforward approach to cancer risk a ssessment that is consistent with the mode of action of chloroform.