THE TOXICITY OF 1-WEEK EXPOSURES TO INHALED CHLOROFORM IN FEMALE B6C3F(1) MICE AND MALE F344 RATS

Detailed quantitative descriptions of the toxicity of inhaled chloroform are lacking, despite the fact that the majority of environmental exposures occur by this route. We investigated the ability of chloroform vapors to produce toxicity and regenerative-cell proliferation in the livers and kidneys, the principal target organs for carcinogenicity of female B6C3F(1) mice and male F-344 rats, respectively. Nasal passages were also examined for toxic responses. Rodents were exposed to chloroform vapors at concentrations of 0, 1, 3, 10, 30, 100, or 300 ppm for 6 hr/day for 7 consecutive days and necropsied on Day 8. Animals were administered bromodeoxyuridine (BrdU) via implanted osmotic pump for the previous 3.5 days before necropsy. Cell proliferation was quantitated as the percentage of cells in S-phase (labeling index; LI) measured by immunohistochemical detection of BrdU-labeled nuclei. Mice exposed to 100 or 300 ppm exhibited centrilobular hepatocyte necrosis and severe vacuolar degeneration of midzonal and periportal hepatocytes, while exposure to 10 or 30 ppm resulted in mild to moderate vacuolar changes in centrilobular hepatocytes. Slight, dose-related increases in the hepatocyte LI were observed for exposure concentrations of 10 and 30 ppm, while the LI was increased more than 30-fold in the 100 and 300 ppm groups. The kidneys of mice were affected only at the 300 ppm exposure, with approximately half of the proximal tubules lined by regenerating epithelium and an increased LI of tubule cells of 8-fold over control. In rats, mild centrilobular vacuolation was observed only in the livers of rats exposed to 300 ppm. The hepatocyte LI in rats were increased only at 100 and 300 ppm, 3- and 7-fold over control, respectively. In the kidneys of the male rats exposed to 300 ppm, about 25 to 50% of the proximal tubules were lined by regenerating epithelium. The LI for tubule cells in the cortex was increased at 30 ppm and above. In the nasal passages of rats, chloroform concentrations of 10 ppm and above induced histopathological changes that exhibited clear concentration-related severity. These lesions consisted of respiratory epithelial goblet cell hyperplasia and degeneration of Bowman's glands in olfactory mucosa with an associated osseous hyperplasia of the endo- and ectoturbinates in the periphery of the ethmoid region. These nasal lesions were not observed in mice. Knowledge of the dose-dependent responses in rats and mice will be valuable in assessing the potential risks to humans posed by inhaled chloroform and in setting exposure concentrations for longer-term studies. (C) 1994 Society of Toxicology.