© 1986 Oxford University Press
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The Effect of an 11.5-hr/Day Exposure Schedule on the Distribution and Toxicity of Inhaled Carbon Tetrachloride in the Rat1
School of Pharmacy and Pharmacal Sciences, Environmental Toxicology Program *Department of Pharmacology and Toxicology, Purdue University West Lafayette, Indiana 47907
The Effect of an 11.5-hr/Day Exposure Schedule on the Distribution and Toxicity of Inhaled Carbon Tetrachloride in the Rat. PAUSTENBACH, D. J., CHRISTIAN, J. E., CARLSON, G. P., AND BORN, G. S. (1986), Fundam. Appl. Toxicol. 6,472–483. 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/thy 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/thy 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 thy 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 l2-hr/ day) work schedules, can have a measurable effect on the distribution of the chemical and the degree of toxicity. These results support published recommendations which suggest that for persons working long shifts, occupational exposure limits for systemic toxicants with half-lives between 4 and 200 hr be reduced so that these persons will have the same margin of safety from any adverse effects.