The effects of multiple administrations of sevoflurane to cynomolgus monkeys: clinical pathologic, hematologic, and pathologic study.

The effect of multiple administrations of sevoflurane was evaluated by several measures of toxicity. Cynomolgus monkeys assigned to a control group and three treatment groups were anesthetized with sevoflurane at 1.0, 1.6, and 2.0 times the minimum alveolar anesthetic concentration (MAC) for 3 h/day, 3 days/wk for 8 wk. Reductions in total erythrocyte and leukocyte counts and increases in serum enzymes were the only changes noted. The increases in the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and creatinine kinase (CK), occurred at Week 1 at all three concentrations of sevoflurane. These increases were dose-related, and returned to baseline by Week 2 for 1.0 MAC. All serum enzyme concentrations had returned to baseline by the end of the study. There were no gross pathologic, histopathologic, or ultrastructural differences found in any of the four groups of monkeys. At 2.0 MAC, three deaths occurred. The multiple administrations of 1.0 and 1.6 MAC sevoflurane anesthesia were well tolerated by the monkeys. The techniques of this study did not detect adverse effects from the above enzyme changes.

Chronic toxicity and carcinogenicity studies of olestra in Fischer 344 rats.

Two 2-year feeding studies were carried out in Fischer 344 rats with olestra, a mixture of the hexa-, hepta- and octaesters of sucrose formed with long-chain fatty acids. Olestra was fed at 0, 0.99, 4.76 or 9.09% (w/w) of the diet in the first study, and at 0 or 9.09% (w/w) of the diet in the second. Daily observations, feed consumption and body weights, ophthalmoscopic examinations, organ weights, serum chemistry, haematology, urinalysis and histopathological evaluations revealed no evidence of any adverse effects associated with olestra ingestion. Relative to controls, there was a higher incidence of basophilic liver foci in olestra-fed female rats at 12 months. At 24 months, foci were observed in most animals in all groups but were more numerous in olestra-fed females. The foci were not associated with hepatic tumours, alterations in liver function, or increases in liver weight and therefore not considered to represent a toxic response to olestra. Isolated statistically significant differences in mortality, mononuclear cell leukaemia, and pituitary adenomas were observed but were not considered to be related to olestra ingestion since they were not reproducible across the two studies, generally not dose responsive, not consistent between sexes, and the incidences were within the ranges for historical and contemporary laboratory controls. The results of the two studies show that olestra was not toxic or carcinogenic when fed to rats at up to 9% of the diet for 24 months.