Effect of Emulphor, an emulsifier, on the pharmacokinetics and hepatotoxicity of oral carbon tetrachloride in the rat.

Emulphor, a polyethoxylated vegetable oil, is now being used widely to incorporate volatile organic compounds (VOCs) and other lipophilic compounds into aqueous solutions for biochemical, pharmacokinetic, and toxicological studies. Previous work in this laboratory demonstrated that 0.25% Emulphor did not alter the kinetics or hepatotoxicity of low doses of CCl4 compared to when the halocarbon was given to rats orally in water. The present study was undertaken as there was concern that higher concentrations of Emulphor (necessary to maintain lipophilic VOCs in stable aqueous emulsions for extended periods) might alter the VOCs' absorption, disposition, and/or toxicity. Dosages of 10 and 180 mg CCl4/kg bw were given, as an aqueous emulsion using 1, 2.5, 5, or 10% Emulphor, by gavage to fasted male Sprague-Dawley rats. Serial microsamples of blood were collected from an indwelling cannula in unanesthetized, freely moving rats at intervals of 2-60 min for up to 12 hr. The samples' CCl4 content was measured by headspace gas chromatography. Thereby, it was possible to obtain blood CCl4 concentration-versus-time profiles. Animals were euthanized 24 hr postdosing and blood was collected for measurement of serum enzymes as indices of hepatotoxicity. No toxicologically significant differences in pharmacokinetic parameters as a function of Emulphor concentration were found. Similarly the hepatotoxic potency of 10 and 180 mg/kg CCl4, as reflected by elevation in serum enzyme activities, did not vary significantly with the concentration of Emulphor utilized. Hence, it can be concluded that Emulphor, in concentrations as high as 10% (equivalent to 260 mg Emulphor/kg bw) in aqueous emulsions, does not significantly affect the absorption, disposition, or acute hepatotoxicity of CCl4 in male Sprague-Dawley rats.

Uptake, distribution, and elimination of carbon tetrachloride in rat tissues following inhalation and ingestion exposures.

Carbon tetrachloride (CCl4) has been studied extensively for its hepatotoxic effects. There is a paucity of information, however, about its tissue deposition following administration by different routes and patterns of exposure. The specific objective of this study was to delineate the uptake, distribution, and elimination of CCl4 in tissues of rats subjected to equivalent oral and inhalation exposures. Male Sprague-Dawley rats (325-375 g) were exposed to 1000 ppm CCl4 for 2 hr. The total absorbed dose (179 mg CCl4/kg bw) was administered to other groups of rats as a single oral bolus or by constant gastric infusion over a period of 2 hr. Animals were terminated at selected time intervals during and postexposure and tissues (liver, kidney, lung, brain, fat, skeletal muscle, spleen, heart, and GI tract) removed for measurement of their CCl4 content by headspace gas chromatography. CCl4 levels in all tissues were much lower in the gastric infusion group than in the oral bolus and inhalation groups. Inhalation resulted in relatively high tissue CCl4 concentrations, because inhaled chemicals enter the arterial circulation and are transported directly to organs throughout the body. It seems logical that the liver should accumulate more CCl4 following ingestion than following inhalation. This did not prove to be the case when comparing liver AUC values for the gastric infusion and inhalation groups. Substantially lower CCl4 concentrations in the liver of animals in the gastric infusion group appeared to be due to very rapid metabolic clearance of the relatively small amounts of CCl4 entering the liver over the 2-hr infusion period. It was hypothesized that the capacity of first-pass hepatic and pulmonary elimination could be exceeded, if CCl4 were given as a single, large oral bolus. Indeed, deposition of CCl4 in all tissues was greater in the oral bolus group than in the gastric infusion group. The time courses of uptake and elimination of CCl4 appeared to be governed largely by a tissue's rate of blood perfusion and lipid content. CCl4 was rapidly taken up, for example, by the brain and liver. These organs' CCl4 content then diminished, as CCl4 was metabolized and redistributed to adipose tissue. CCl4 accumulated slowly, but to very high concentrations, in fat and remained elevated for a prolonged period. Thus, concentrations of CCl4 in some tissues may not be reflective of blood levels. The most appropriate measure of internal dose for CCl4 acute hepatotoxicity appears to be the area under tissue concentrations versus time curve from 0 to 30 min. Tissue time-course data sets are essential for the refinement and validation of physiological models for CCl4 and other volatile organic chemicals.

Effect of route and pattern of exposure on the pharmacokinetics and acute hepatotoxicity of carbon tetrachloride.

The objectives of this study were to evaluate the influence of both route and pattern of exposure on the pharmacokinetics (PK) and target organ toxicity of a common volatile organic chemical, carbon tetrachloride (CCl4). Male Sprague-Dawley rats, 325-375 g, inhaled 100 or 1000 ppm CCl4 for 2 hr through a one-way breathing valve. The total amount of CCl4 retained by each rat (i.e., the systemically absorbed dose) during the 2-hr period was determined to be 17.5 and 179 mg CCl4/kg body wt, respectively. CCl4, in doses of 17.5 and 179 mg/kg body wt, was administered in an aqueous emulsion by bolus gavage or by constant gastric infusion over 2 hr. Serial micro blood samples from the animals were analyzed for CCl4, in order to delineate blood concentration-versus-time profiles. Serum enzyme activities and total liver microsomal cytochrome P450 level and glucose 6-phosphatase activity were measured 24 hr postdosing as indices of CCl4 hepatotoxicity. The pattern of oral exposure, or dosage regimen, had a significant effect on the PK and acute the hepatotoxicity of CCl4. Arterial blood levels in the gastric infusion group were much lower than in the oral bolus group with both doses. Since CCl4 is quickly and extensively absorbed from the GI tract, large amounts of CCl4 in the portal blood following the oral bolus apparently exceeded the capacity of the liver to metabolize the chemical. Thus, substantially higher Cmax and AUC0 integral of infinity values were manifest. Hepatotoxicity was also significantly greater in these animals. The route of exposure also had a significant effect on the PK of CCl4. Levels of CCl4 in the arterial blood were much higher during inhalation than during gastric infusion. However, AUC0 integral of infinity vales for the two groups were not significantly different, due to relatively slow elimination after gastric infusion. There was little difference between the two groups in hepatotoxicity indices 24 hr postdosing.