Nephrotoxicity and hepatotoxicity induced by inhaled bromodichloromethane in wild-type and p53-heterozygous mice

Bromodichloromethane (BDCM) is a common municipal drinking water disinfecti on by-product, resulting in widespread trace human exposure via ingestion a nd inhalation. The present studies were designed to define organ-specific, BDCM-induced toxicity in wild type (p53(+/+)) and heterozygous (p53(+/-)) m ice on both the FVB/N and C57BL/6 genetic backgrounds. Mice were exposed to BDCM vapor daily for 6 h/day and 7 days/week at concentrations of 0, 1, 10 , 30, 100, or 150 ppm for 1 week and at 0, 0.3, 1, 3, 10, or 30 ppm for 3 w eeks. In the 1-week exposure study, dose-dependent mortality and morbidity were observed at concentrations of 30 ppm and above and were as high as 100 % at 150 ppm. In the 3-week exposure study, mortality and morbidity were fo und only in the 30-ppm exposure groups and were 0, 17, 67, and 33% for the wild-type C57BL/6, p53(+/-) C57BL/6, wild-type FVB/N, and p53(+/-) FVB/N mi ce, respectively. BDCM was a particularly potent kidney cytotoxicant. Dose- dependent tubular degeneration, necrosis, and associated regenerative cell proliferation greater than 10-fold over controls were seen at concentration s as low as 10 ppm in the kidneys of all strains at 1 week. Similar dose-de pendent increases in hepatic necrosis, degeneration, and regenerative cell proliferation were observed but were induced only at concentrations of 30 p pm and higher. Pathological changes were more severe in the FVB/N compared to the C57BL/6 mice and were more severe in the heterozygotes compared to t he wild-type mice. However, recovery and return of the percentage of kidney cells in S-phase to control levels was seen at 3 weeks. The estimated maxi mum tolerated dose for longer-term exposures was 15 ppm, based on mortality , induced kidney pathology, and regenerative cell proliferation. A one-year cancer bioassay was initiated with doses of 0, 0.5, 3, 10, and 15 ppm, bas ed on this information. No pathological changes in the livers were found at the 13-week time point of that study. At 13 weeks, the kidney lesions and regenerative cell proliferation seen at the 1-week time point at doses of 1 0 ppm and above had resolved, and the cell proliferation rates had returned to baseline. Differences in toxicity indicate that caution be used in subs tituting wild-type mice for transgenic mice for range-finding studies to se lect doses for p53(+/-) cancer studies. Resolution of the kidney lesions in dicates that periods of very high regenerative cell proliferation, potentia lly important in the carcinogenic process, may not be observed if measureme nts are taken only at 3 weeks of exposure or later.