THE EFFECT OF THE TWELVE-HOUR WORKSHIFT ON THE TOXICOLOGY, DISPOSITION AND PHARMACOKINETICS OF CARBON TETRACHLORIDE IN THE RAT

Abstract

Male Sprague-Dawley Rats were exposed in a closed-loop inhalation chamber to 100 ppm of (\u2714)C-CCl(,4) vapor for 8 hr/day for 10 of 12 days or 12 hr/day for 7 (4 + 3) of 12 days. Following one and two weeks of exposure to either the 8 hr/day or 12 hr/day dosing regimens, the fat, liver, lung and adrenals had the highest concentration of CCl(,4). The kidneys, spleen, brain, and heart contained 40-70% less CCl(,4) than that of the fat. Following each days exposure, the CCl(,4) concentration in the brain was significantly greater for the 12 hr/day group. Following a typical weekend off work, the fat contained 3-8 times more CCl(,4) than other organs. Histological damage was similar for either group following each week of exposure. However, the rats exposed for 12 hr/day had significantly higher sorbitol dehydrogenase (SDH) levels than the 8 hr/day groups. It was noted that the 12 hr/day dosage regimen produced differences in the relative rates and routes of elimination of CCl(,4) when compared with rats exposed 8 hr/day. Following two weeks of exposure to the 8 hr/day schedule, expired CCl(,4) and fecal (\u2714)C-activity comprised 45% and 48% respectively of the total (\u2714)C excreted. Following two weeks of exposure to the 12 hr/day dosing regimen, the values were 32% and 62%. In both cases, the urine accounted for less than 6% of the total (\u2714)C excreted and exhaled (\u2714)CO(,2) for 2% or less. Elimination of CCl(,4) in the expired air of the 8 hr group had an average fast phase ((alpha)) half-life of approximately 100 min and for the slow phase ((beta)), 450 min. For the 12 hr group, the half-lives were 90 min ((alpha)) and 635 min ((beta)). 80% of the total amount of expired CCl(,4) was eliminated within 6 hours. The average t(, 1/2) for urinary excretion was 1320 min and 3050 min and the average t(, 1/2) for elimination of (\u2714)CO(,2) in the expired air was 1700 min and 4250 min for the 8 hr and 12 hr groups, respectively. Rats exposed to the 12 hr/day dosing regimen had a greater percentage of CCl(,4) distributed to the feces and the fat than those exposed for 8 hr/day. The slow release of CCl(,4) from these peripheral compartments to the blood was reflected by the much longer half-lives of (\u2714)C elimination in the expired air and urine of rats exposed to the 12 hr/day schedule. This study suggests that adjustments to occupational exposure limits (TLVs and PELs) are necessary to protect workers exposed to extraordinary workshifts since a slight change in the work schedule has been shown to influence the distribution, toxicity and the pharmacokinetics of an inhaled toxicant