No abstract

No abstract

Oncogenicity studies of methyl tertiary‐butyl ether (MTBE) vapor were conducted in CD‐1 mice and Fischer 344 rats. Fifty animals of each sex per species per group were exposed for 6 h a day, 5 days per week to 0 (control), 400, 3000 and 8000 ppm MTBE vapor in air for 18 months (mice) and 24 months (rats). Both species showed reversible central nervous system depression at 8000 ppm for the first week of exposure, which continued for mice for the study duration. For the 8000 ppm mice, reduced body weight gain and early mortality prior to terminal euthanasia were exposure related. In the males, these deaths appear to be due to exacerbation of uropathy or dysuria, which occurs spontaneously in this strain. Increases in absolute and relative liver (both sexes) and kidney weight (males only) were seen at 3000 and 8000 ppm and decreases in brain and spleen weights were also noted (the latter decreases were without microscopic lesions and occurred at 8000 ppm only). An increase in hepatocellular hypertrophy occurred in both sexes at the two highest concentrations. The only neoplastic lesion found in this study in mice was an increased incidence of hepatocellular adenomas in females at the 8000 ppm exposure. In a follow‐up study, a statistically significant elevation of cell proliferation in female mouse liver has been shown to occur following 5 days, but not 28 days, of exposure to 8000 ppm MTBE, suggesting that MTBE induces mitogenesis. For male rats, early euthanasia was required at week 82 and week 97 for the 8000 and 3000 ppm groups, respectively, due to excessive mortality from a severe progressive nephrosis. The end stage of this process appeared earlier in the male rats of all MTBE exposure groups; the incidence of this lesion and mortality for exposed females was comparable to control females. No exposure‐related changes in hematological parameters were observed for any group at any time point, but a decrease in corticosterone levels was seen for male rats from the 8000 ppm group. Absolute and relative kidney and liver weight increases occurred in 3000 and 8000 ppm exposure groups, but the liver weight change was not accompanied by histopathological change. At study termination, increases in the incidence and severity of a chronic nephropathy in males from all exposure groups and in females exposed to 3000 and 8000 ppm was associated with secondary lesions of hyperplasia of the parathyroid and mineralization of tissues. Renal tubular cell tumors were increased in male rats exposed to 3000 and 8000 ppm. This may be associated with an accumulation of a protein (stainable by Mallory's Heidenhain) in kidney tubular epithelial cells after 4 weeks of exposure. An increased incidence of interstitial cell adenomas of the testes was seen in males exposed to 3000 and 8000 ppm but was believed to be an artefact of an unusually low control incidence and not considered to be exposure related. Based on the above effects, the no‐observed‐effect level (NOEL) for chronic toxicity is 400 ppm, and the NOEL for carcinogenic...

Despite the more complex cardiac surgery required at implantation and longer donor ischemic time, heart transplantation can be performed in children with complex congenital heart disease with success similar to that in patients with other cardiac diseases.

Methyl t‐butyl ether (MTBE) is a commonly used octane booster in gasoline. This study examines the pharmacokinetics and disposition of MTBE in Fischer‐344 rats after i.v., oral, dermal and inhalation routes of administration. Groups of male and female rats were given single i.v. (40 mg kg−1), oral (40 and 400 mg kg−1) and dermal (40 and 400 mg kg−1 in occluded chambers) doses of [14C]MTBE. For inhalation studies, rats were exposed nose‐only for 6 h to low (400 ppm), high (8000 ppm) and repeated daily 6‐h low (400 ppm × 15 days) chamber concentrations of [14C]MTBE. Blood, expired air, and excreta (urine and feces) were collected at selected times up to 7 days post‐dose and quantified for 14C content. Plasma concentrations of MTBE and t‐butyl alcohol (TBA) were quantified and mean values used for pharmacokinetic analysis. The mean total recoveries of 14C ranged from 91 to 105%. Methyl t‐butyl ether was rapidly and completely absorbed after oral and inhalation exposures; dermal absorption was low. After all routes, MTBE was rapidly eliminated from blood (t½ = 0.5 h) by exhalation and metabolism to TBA. At the high doses, metabolism was saturated and the proportion of renal 14C excretion decreased relative to the pulmonary route. At 48 h post‐exposure, virtually all of the 14C was eliminated. The major metabolites recovered in urine were 2‐methyl‐1,2‐propanediol and α‐hydroxyisobutyric acid. There were no significant gender or route‐dependent differences in the pharmacokinetics and disposition of MTBE. © 1997 by John Wiley & Sons, Ltd.