13C(2)-Labeled methyl tert-butyl ether: toxicokinetics and characterization of urinary metabolites in humans.

After exposure to methyl tert-butyl ether (MTBE), a gasoline additive, only one metabolite [tert-butyl alcohol (TBA), <1% of dose] has been identified in human urine [Nihlén, A., et al. (1998) Toxicol. Appl. Pharmacol. 148, 274-280]. In the study presented here, metabolites of MTBE were characterized by (1)H-decoupled (13)C NMR spectroscopy in urine obtained from four volunteers experimentally exposed to 50 ppm (13)C-labeled MTBE ([1,2-(13)C(2)]MTBE) vapor (facemask) for 2 h during a light physical work load (50 W). Chemical shifts for the two adjacent (13)C-labeled carbons in [1, 2-(13)C(2)]MTBE-derived metabolites were consistent with the shifts obtained for spiked standards of alpha-hydroxyisobutyric acid (HBA) and 2-methyl-1,2-propanediol (MPD). NMR signals were not detected for labeled MTBE, TBA, or possible MTBE-derived conjugates. Quantification of HBA and MPD was performed by NMR for two urine samples (collected 20 h after exposure). One subject had 11% HBA and 1% MPD, and the other individual had 3% HBA and 1% MPD in the urine, expressed as a percentage of MTBE uptake. This indicates that HBA and MPD occur at significantly higher levels in the urine (detected by NMR) than MTBE and TBA (detected by GC). To our knowledge, this is the first characterization of MTBE metabolites, other than TBA, in humans. Further urine, blood, and expired air were collected up to 22 h after exposure, and the toxicokinetics of MTBE, TBA, and acetone were determined by GC. Low relative uptake (39%), a low level of postexposure exhalation of MTBE (17%), and low recovery of TBA in the urine (<1%) were observed. The same subjects had previously been exposed to unlabeled MTBE in a whole-body exposure study [Nihlén, A., et al. (1998) Toxicol. Appl. Pharmacol. 148, 274-280], and the toxicokinetics of MTBE and TBA in this facemask exposure did not differ from the previous whole-body chamber exposure.