Toxicokinetics of methyl tert-butyl ether and its metabolites in humans after oral exposure.
Methyl tert-butyl ether (MTBE) is widely used as an additive to gasoline, to increase oxygen content and reduce tailpipe emission of pollutants. Widespread human exposure to MTBE may occur due to leakage of gasoline storage tanks and a high stability and mobility of MTBE in ground water. To compare disposition of MTBE after different routes of exposure, its biotransformation was studied in humans after oral administration in water. Human volunteers (3 males and 3 females, identical individuals, exposures were performed 4 weeks apart) were exposed to 5 and 15 mg 13C-MTBE dissolved in 100 ml of water. Urine samples from the volunteers were collected for 96 h after administration in 6-h intervals and blood samples were taken in intervals for 24 h. In urine, MTBE and the MTBE-metabolites tert-butanol (t-butanol), 2-methyl-1,2-propane diol, and 2-hydroxyisobutyrate were quantified, MTBE and t-butanol were determined in blood samples and in exhaled air in a limited study of 3 male volunteers given 15 mg MTBE in 100 ml of water. MTBE blood concentrations were 0.69 +/- 0.25 microM after 15 mg MTBE and 0.10 +/- 0.03 microM after 5 mg MTBE. MTBE was rapidly cleared from blood with terminal half-lives of 3.7 +/- 0.9 h (15 mg MTBE) and 8.1 +/- 3.0 h (5 mg MTBE). The blood concentrations of t-butanol were 1.82 +/- 0.63 microM after 15 mg MTBE and 0.45 +/- 0.13 microM after 5 mg MTBE. Approximately 30% of the MTBE dose was cleared by exhalation as unchanged MTBE and as t-butanol. MTBE exhalation was rapid and maximal MTBE concentrations (100 nmol/l) in exhaled air were achieved within 10-20 min. Clearance of MTBE by exhalation paralleled clearance of MTBE from blood. T-butanol was cleared from blood with half-lives of 8.5 +/- 2.4 h (15 mg MTBE) and 8.1 +/- 1.6 h (5 mg MTBE). In urine samples, 2-hydroxyisobutyrate was recovered as major excretory product, t-butanol and 2-methyl-1,2-propane diol were minor metabolites. Elimination half-lives for the different urinary metabolites of MTBE were between 7.7 and 17.8 h. Approximately 50% of the administered MTBE was recovered in urine of the volunteers after both exposures, another 30% was recovered in exhaled air as unchanged MTBE and t-butanol. The obtained data indicate that MTBE-biotransformation and excretion after oral exposure is similar to inhalation exposure and suggest the absence of a significant first-pass metabolism of MTBE in the liver after oral administration.
Amberg
A
A
Institut für Toxikologie, Universität Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany.
Rosner
E
E
Dekant
W
W
D000328:Adult; D001711:Biotransformation; D001944:Breath Tests; D002244:Carbon / Q000737:chemistry; D002247:Carbon Isotopes; D005260:Female; D006207:Half-Life; D006801:Humans; D006885:Hydroxybutyrates / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D013997:Time Factors; D020002:tert-Butyl Alcohol / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine
D002247:Carbon Isotopes; D006885:Hydroxybutyrates; D008738:Methyl Ethers; C043243:methyl tert-butyl ether; D002244:Carbon; C008039:2-hydroxyisobutyric acid; D020002:tert-Butyl Alcohol