A 90-DAY CHLOROFORM INHALATION STUDY IN F344 RATS - PROFILE OF TOXICITY AND RELEVANCE TO CANCER STUDIES

Chloroform acts via a nongenotoxic-cytotoxic mode of action to produce cancer if given in doses and at dose rates sufficiently high to produ ce organ-specific toxicity. In a recent study, chloroform failed to in duce cancer in male or female F-344 rats when administered by inhalati on for 2 years at 90 ppm, 5 days/week. The present study was undertake n to define the concentration-response curves for chloroform-induced l esions and regenerative cell proliferation in the F-344 rat when expos ed by inhalation and to correlate those patterns of toxicity with the results from the inhalation cancer bioassay. Male and female F-344 rat s were exposed to airborne concentrations of 0, 2, 10, 30, 90, or 300 ppm chloroform 6 hr/day, 7 days/week for 4 days or 3, 6, or 13 weeks. Additional treatment groups were exposed 5 days/week for 13 weeks or w ere exposed for 6 weeks and held until Week 13. Bromodeoxyuridine was administered via osmotic pumps implanted 3.5 days prior to necropsy an d the labeling index (LI, percentage of nuclei in S-phase) was evaluat ed immunohistochemically. A full-screen necropsy identified the kidney , liver, and nasal passages as the only target organs. This study conf irmed that 300 ppm is extremely toxic and would be inappropriate for l onger-term cancer studies. The primary target in the kidney was the ep ithelial cells of the proximal tubules of the cortex, with significant ly elevated increases in the LI at concentrations of 30 ppm and above. However, only a marginal increase in the renal LI in the males was se en after exposures of 90 ppm, 5 days/week. Chloroform induced hepatic lesions in the midzonal and centrilobular regions with increases in th e LI throughout the liver, but only at 300 ppm exposures. An additiona l liver lesion seen only at the highly hepatotoxic concentration of 30 0 ppm was numerous intestinal crypt-like ducts surrounded by dense con nective tissue. Enhanced bone growth and hypercellularity in the lamin a propria of the ethmoid turbinates of the nose occurred at the early time points at concentrations of 10 ppm and above. At 90 days there wa s a generalized atrophy of the ethmoid turbinates at concentrations of 2 ppm and above. Cytolethality and regenerative cell proliferation ar e necessary but not always sufficient to induce cancer because of tiss ue, sex, and species differences in susceptibility. A combination of a lack of direct genotoxic activity by chloroform, only a marginal indu ction of cell proliferation in the male rat kidney, and lower tissue-s pecific susceptibility in the female rat is apparently responsible for the reported lack of chloroform-induced cancer in a longterm inhalati on bioassay with F-344 rats. (C) 1996 Society of Toxicology