THE INTERACTIVE TOXICITY OF CHCL3 AND BRCCL3 IN PRECISION-CUT RAT-LIVER SLICES

The interactive toxicity of two nontoxic concentrations of chloroform (CHCl3) and bromotrichloromethane (BrCCl3) was examined in precision-c ut rat liver slices. Liver slices were prepared from male Sprague-Dawl ey rats (220-250 g) pretreated with phenobarbital for 4 days. Toxicant s were administered 1 hr apart. Intracellular K+ levels were similar t o untreated controls in slices treated with 0.2 mM CHCl3 or 0.125 mu l (0.25 mg, 1.26 mu mol) BrCCl3 alone, indicating that these concentrat ions were nontoxic. However, addition of both toxicants, irrespective of order, resulted in a time-dependent loss of intracellular K+ which was significant at 9 hr following administration. This was interpreted as evidence of synergistic toxicity. Cytochrome P450 loss was signifi cant as early as 3 hr following exposure to BrCCl3, alone or when adde d with CHCl3. This loss may be attributed to BrCCl3-induced suicide in activation of cytochrome P450. Centrilobular hepatocytes may be more s usceptible to the interactive toxicity of CHCl3, and BrCCl3. Activity of enzymes found predominantly in this area was significantly decrease d in slices exposed to both toxicants relative to controls. Conversely , activity of enzymes found predominantly in the periportal region was similar to that of untreated and treated controls. Interactive toxici ty of BrCCl3 and CHCl3 was not a consequence of increased lipid peroxi dation or depletion of slice glutathione content. Further studies need to be conducted to elucidate the mechanisms mediating the interactive toxicity of BrCCl3 and CHCl3. (C) 1994 Society of Toxicology.