© 1986 Oxford University Press
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A Comparative Study of the Pharmacokinetics of Carbon Tetrachloride in the Rat following Repeated Inhalation Exposures of 8 and 11.5 hr/day1
School of Pharmacy and Pharmacal Sciences, Environmental Toxicology Program *Department of Pharmacology and Toxicology, Purdue University West Lafayette, Indiana 47907
A Comparative Study of the Pharmacokinetics of Carbon Tetrachloride in the Rat following Repeated Inhalation Exposures of 8 and 11.5 hr/day. PAUSTENBACH, D. J., CARLSON, G. P., CHRISTIAN, J. E., AND BORN, G. S. (1986). Fundam. Appl. Toxicol. 6, 484–497. 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 tetrachtoride (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 and14C 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 (
) and slow (ß) phases averaged 96 and 455 min, and 89 and 568 min respectively. The average and ß 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 halflives 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. These results indicate that modest changes in exposure regimen can influence the rate and route of elimination of certain chemicals. Furthermore, since the rat more rapidly metabolizes and eliminates CCl4 than man, workers exposed 11.5 hr/day or longer can be expected to store relatively larger quantities of CCl4 in fat and have higher peak blood levels of CCl4 than that indicated by these results. This study lends support to published recommendations to adjust occupational exposure limits for substances with half-lives between 4 and 200 hr whenever persons will be exposed during work schedules markedly longer than 8 hr/day to assure them the same margin of safety from adverse effects as those who work typical 8-hr/day schedules.