The hepatotoxic potential of combined toluene-chronic ethanol exposure.

The hepatotoxic properties of concurrent chronic oral ethanol ingestion and acute toluene inhalation were evaluated. Male rats were maintained on ethanol-containing or control liquid diets for 29 days. Animals of each group were subjected to five 20-min exposures to 10 000 ppm toluene with 30 min of room air inhalation between exposures on days 22, 24, 26, and 28 of liquid diet feeding. Some of the ethanol-fed animals were withdrawn from ethanol 14 h before exposure. Ethanol-withdrawn animals displayed an increased sensitivity to the narcotic action of toluene. Animals were sacrificed and assays performed on day 29. Stress markers (plasma corticosterone, free fatty acid, and glucose) were not affected by treatments. A modest elevation in plasma aspartate aminotransferase occurred in non-withdrawn animals receiving both ethanol and toluene. Ethanol-toluene exposure increased both relative liver weight and liver triglycerides. Toluene antagonized the hypertriglyceridemia associated with chronic ethanol ingestion. This study indicates that combined ethanol and toluene exposure has minor potential to induce acute liver injury, but results in altered deposition of hepatic triglycerides.

A comparative study of the pharmacokinetics of carbon tetrachloride in the rat following repeated inhalation exposures of 8 and 11.5 hr/day.

To evaluate whether exposure to inhaled vapors for periods longer than 8 hr/day could affect the rates and routes of elimination, male Sprague-Dawley rats were repeatedly exposed to 100 ppm of radiolabeled carbon tetrachloride (14CCl4) in a closed-loop chamber. One group was exposed for 8 hr/day for 5 days and another group for 11.5 hr/day for 4 days. Two other groups were exposed for either 8 hr/day for 10 of 12 consecutive days or 11.5 hr/day for 7 of 10 days. The elimination of 14C activity was measured in the expired air, urine, and feces for up to 100 hr following exposure and the pharmacokinetic parameters were determined. Following 2 weeks of exposure to the 8-hr/day schedule, 14CCl4 in the breath and 14C activity in the feces comprised 45 and 48% of the total 14C excreted, respectively. Following 2 weeks of exposure to the 11.5-hr/day schedule, the values were 32 and 62%, respectively, indicating that repeated exposure to the longer schedule altered the route of elimination of CCl4. Regardless of the period of exposure, less than 8% of the inhaled 14CCl4 was excreted in the urine and less than 2% was exhaled in the breath as the 14CO2 metabolite. Approximately 97-98% of the 14C activity in the expired air was 14CCl4. The quantities of 14C noted in the feces and urine suggest that more than 60% of the inhaled CCl4 was metabolized. Elimination of 14CCl4 and 14CO2 in the breath followed a two-compartment, first-order pharmacokinetic model (r2 = 0.98). For rats exposed 8 hr/day and 11.5 hr/day for 2 weeks, the average half-lives for elimination of 14CCl4 in the breath for the fast (alpha) and slow (beta) phases averaged 96 and 455 min, and 89 and 568 min, respectively. The average alpha and beta half-lives for elimination of 14CO2 in the breath of rats exposed to the 11.5-hr/day schedule were 455 and 1824 min, and these were significantly longer than for the 8-hr/day groups, 305 and 829 min. The longer half-lives of elimination for 14CO2 and 14CCl4 which were observed for the groups exposed to the 11.5-hr/day schedule suggest that the 3.5 additional hr of daily exposure places a relatively greater percentage of the absorbed dose into poorly perfused lipophilic depots such as the fat.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of an 11.5-hr/day exposure schedule on the distribution and toxicity of inhaled carbon tetrachloride in the rat.

This study evaluated the differences in toxicity and tissue distribution for 16 groups of male rats repeatedly exposed to 100 ppm of 14CCl4 vapors for 8 or 11.5 hr/day for periods of 1 to 10 days. Serum sorbitol dehydrogenase (SDH) was also evaluated for its sensitivity at detecting CCl4-induced hepatotoxicity. Following 1, 2, 3, 4, 5, 7, 11, and 14 days, one group of rats from each exposure schedule was sacrificed and 14C activity in seven tissues and serum SDH levels were measured. To compare the effects of CCl4 on the liver and kidney following repeated exposure to the two schedules, one group of rats was exposed for 8 hr/day for 10 of 12 consecutive days and another for 11.5 hr/day for 7 of 12 consecutive days so that each group received essentially the same dose (8000 ppm-hr) of CCl4. The 11.5-hr/day exposure schedule, compared to rats exposed 8-hr/day, produced minor changes in the distribution and concentration of 14C (CCl4 equivalents) in various tissues. Following 1 and 2 weeks of exposure to either schedule, the fat, liver, lungs, and adrenals had the highest concentration of CCl4 equivalents. There were no significant differences in CCl4-induced hepatotoxicity or nephrotoxicity between rats exposed to the two schedules following either 1 or 2 weeks of exposure as measured by histopathology. In contrast, rats exposed 11.5 hr/day had significantly higher SDH levels than those exposed to the 8-hr/day schedule; thus suggesting that the 11.5-hr schedule did produce a measurably greater degree of hepatotoxicity, although it was too subtle to detect pathologically. Rats exposed for a fourth and fifth day during the second week of the 11.5-hr schedule had a significantly greater concentration of 14C activity in the fat than rats exposed to the 8-hr/day schedule as well as severe fatty infiltration of the liver and higher serum SDH activity. This study demonstrated that SDH is a very useful assay for detecting subtle changes in liver injury as compared to histopathology. It was also shown that even at relatively low vapor concentrations, modest changes in dosage regimen, like those involving unusual (e.g., 10- or 12-hr/day) work schedules, can have a measurable effect on the distribution of the chemical and the degree of toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

A dynamic closed-loop recirculating inhalation chamber for conducting pharmacokinetic and short-term toxicity studies.

Tests for evaluating the hazard of inhalation exposure generally require large quantities of the chemical of interest. This paper describes an inhalation technique that involves a dynamic closed-loop recirculating system which uses only small amounts of toxicant since the test atmosphere to which the animals are exposed is recycled. Carbon dioxide and water are continually removed while the oxygen and test substance absorbed by the animals are replenished. The approach described is different from other closed-loop chambers since the test substance is continuously added to the chamber and the air concentration is continuously measured. The technique was successfully used to expose 20 adult rats for up to 12 consecutive hours to 100 ppm of 14C-carbon tetrachloride yet only 2-3 mL of test material were consumed. The inhalation chambers were fabricated from standard 40-liter cylindrical glass bell jars. A high number of air changes (35-40 equivalent chamber volumes per hour) permitted exposure of as many as five adult rats per 10 liters of chamber volume. This closed-loop approach should prove to be especially useful for evaluating the risk of exposure to very expensive materials or when only limited quantities of a test material are available. These systems may also be used to expose rats and other small animals to radioisotopes in studies which evaluate the uptake, distribution, metabolism, and excretion of volatile xenobiotics.

A comparative study of iodine and potassium perchlorate metabolism in the laying hen. 2. Uptake, distribution, and excretion of potassium perchlorate.

The concentrations of 36Cl-labeled potassium perchlorate (K36CiO4) and previously reported iodide (131I) in the ova, thyroid gland, and blood of the laying hen were compared in this investigation. Radioperchlorate concentration and deposition properties showed a remarkable resemblance to those of iodide (131I). The topographic distribution of radioperchlorate in ova followed a peripheral and concentric ring deposition identical to that observed in the 131I investigation. The studies of the distribution of radioperchlorate showed that about 10.3, 2.0, and 1.4% of a single intramuscular injection of K36CiO4 was retained in the body at 3, 24, and 48 hours, respectively. The largest total concentration in the 3-hour group was found in the blood (2.9%), followed by muscles (2.4%), internal organs (1.1%), and the 10 largest ova (1.0%). The 24 and 48-hour hens' ova showed the largest concentrations with values of 1.5 and 1.2% of the dose, respectively. This represented 76.9 and 81.3% of the total activity retained in the body at these times. The excreta in the 3 and 24-hour experiments accounted for most of the radioperchlorate dose.

A comparative study of iodine and potassium perchlorate metabolism in the laying hen. 1. incorporation of I-131 in chicken ova.

The uptake of 131-I in chicken ova was studied for 3 hours after a single intramuscular dose. There was uptake as early as 10 minutes and it continued throughout the 3 hours in spite of a rapid decrease in blood activity. The fast growing ova, weightin 0.5 to 2.0 grams, were the most efficient in the uptake of 131-I per unit weight. Autoradiograms of the topographic distribution of 131-I showed a peripheral deposition. When multiple doses were given, concentric rings in the growing ovocytes were seen.