Effect of pretreatment of rats with carbon tetrachloride on tolerance development

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To evaluate the effect of pretreatment of rats with CCl 4 on tolerance development to subsequent exposures, rats were exposed 25–7500 ppm of CCl 4 vapor or given CCl 4 orally, 3.25 mg/g body weight. Forty-eight hours later these rats were reexposed to a normally lethal 7500 ppm CCl 4 concentration. Mortality, blood clotting time, serum bilirubin, serum and liver triglycerides, and CCl 4 and CHCl 3 concentrations in tissues and in the whole rat were used as a measure of the response to CCl 4 exposure. Conversion of CCl 4 to CHCl 3 in vitro was also determined in normal and pretreated animals. It was found that animals exposed to 4000 ppm for 6 hr or given 3.25 mg/g of CCl 4 orally developed tolerance to subsequent normally lethal CCl 4 exposures. Serum bilirubin levels in animals protected by CCl 4 pretreatment were significantly lower than in those receiving only a single exposure to CCl 4. Blood clotting times in protected animals were normal, while in those not protected by pretreatment, they were greatly prolonged. Serum triglyceride levels in protected animals were normal whereas they were considerably depressed in the nonprotected animals. Liver triglycerides were elevated in both protected and nonprotected, but were not as high in the protected animals. Carbon tetrachloride conversion to CHCl 3 was slower in protected than in the non-protected animals. Tolerance to CCl 4 developed in animals whose ability to metabolize CCl 4 had been depressed by pretreatment with the same compound. This suggests that the toxicity of CCl 4 is related to its metabolic pathway or to the production of toxic intermediates.