Toxicokinetics of methyl tert-butyl ether (MTBE) and tert-amyl methyl ether (TAME) in humans, and implications to their biological monitoring.

Healthy male volunteers were exposed via inhalation to gasoline oxygenates methyl tert-butyl ether (MTBE) or tert-amyl methyl ether (TAME). The 4-hr exposures were carried out in a dynamic chamber at 25 and 75 ppm for MTBE and at 15 and 50 ppm for TAME. The overall mean pulmonary retention of MTBE was 43 +/- 2.6%; the corresponding mean for TAME was 51 +/- 3.9%. Approximately 52% of the absorbed dose of MTBE was exhaled within 44 hr following the exposure; for TAME, the corresponding figure was 30%. MTBE and TAME in blood and exhaled air reached their highest concentrations at the end of exposure, whereas the concentrations of the metabolites tert-butanol (TBA) and tert-amyl alcohol (TAA) concentrations were highest 0.5-1 hr after the exposure and then declined slowly. Two consecutive half-times were observed for the disappearance of MTBE and TAME from blood and exhaled air. The half-times for MTBE in blood were about 1.7 and 3.8 hr and those for TAME 1.2 and 4.9 hr. For TAA, a single half-time of about 6 hr best described the disappearance from blood and exhaled air; for TBA, the disappearance was slow and seemed to follow zero-order kinetics for 24 hr. In urine, maximal concentrations of MTBE and TAME were observed toward the end of exposure or slightly (< or = 1 hr) after the exposure and showed half-times of about 4 hr and 8 hr, respectively. Urinary concentrations of TAA followed first-order kinetics with a half-time of about 8 hr, whereas the disappearance of TBA was slower and showed zero-order kinetics at concentrations above approx. 10 micro mol/L. Approximately 0.2% of the inhaled dose of MTBE and 0.1% of the dose of TAME was excreted unchanged in urine, whereas the urinary excretion of free TBA and TAA was 1.2% and 0.3% within 48 hr. The blood/air and oil/blood partition coefficients, determined in vitro, were 20 and 14 for MTBE and 20 and 37 for TAME. By intrapolation from the two experimental exposure concentrations, biomonitoring action limits corresponding to an 8-hr time-weighted average (TWA) exposure of 50 ppm was estimated to be 20 micro mol/L for post-shift urinary MTBE, 1 mu mol/L for exhaled air MTBE in a post-shift sample, and 30 micro mol/L for urinary TBA in a next-morning specimen. For TAME and TAA, concentrations corresponding to an 8-hr TWA exposure at 20 ppm were estimated to be 6 micro mol/L (TAME in post-shift urine), 0.2 micro mol/L (TAME in post-shift exhaled air), and 3 micro mol/L (TAA in next morning urine).

Exposure to MTBE, TAME and aromatic hydrocarbons during gasoline pump maintenance, repair and inspection.

The exposure of gasoline pump repairers and inspectors to gasoline was studied at service stations and repair shops in Finland in April-June 2004. The average air temperature ranged from 7 degrees C to 16 degrees C and wind speed from 2.5 to 7 m/s. The gasoline blends contained mixtures of methyl tert-butyl ether (MTBE) and tert-amyl methyl ether (TAME), the total content of oxygenates being 11-12%. The content of benzene was <1%. Breathing zone air was collected during the work task using passive monitors. The mean sampling period was 4.5 h. The mean TWA-8 h concentrations for MTBE, TAME, hexane, benzene, toluene, ethylbenzene and xylene were 4.5, 1.3, 0.55, 0.23, 2.2, 0.26 and 1.1 mg/m3, respectively. None of the individual benzene concentrations exceeded the binding limit value for benzene (3.25 mg/m3). The sum concentration of MTBE and TAME in urine was between 8.9 and 530 nmol/l in individual post-shift samples. The individual sum concentrations of the metabolites tert-butyl alcohol and tert-amyl alcohol collected the following morning after the exposure ranged from 81 to 916 nmol/l. All individual results were below corresponding biological action levels. Exposure to aromatic hydrocarbons was estimated from post-shift urine samples, with benzene showing the highest concentration (range 4.4 and 35 nmol/l in non-smokers). The exposure levels were similar to those measured in previous studies during unloading of tanker lorries and railway wagons. The results indicated a slightly higher exposure for inspectors, who calibrated fuel pump gauges at the service stations, than for pump repairers. No significant skin exposure occurred during the study.

Biological monitoring of benzene exposure during maintenance work in crude oil cargo tanks.

We investigated the association between the individual concentrations of benzene in the breathing zone and the concentrations of benzene in the blood and urine among workers maintaining crude oil cargo tanks. Benzene exposure was measured during three consecutive 12h work days among 13 tank workers and 9 unexposed referents (catering section). Blood and urine samples were collected pre-shift on the first day, post-shift on the third day, and pre-next shift on the following morning. The workers used half-mask air-purifying respirators, but not all workers used these systematically. The individual geometric mean benzene exposure in the breathing zone of tank workers over 3 days was 0.15 ppm (range 0.01-0.62 ppm). The tank workers' post-shift geometric mean benzene concentrations were 12.3 nmol/l in blood and 27.0 nmol/l in urine versus 0.7 nmol/l for both blood and urine among the referents. Benzene in the work atmosphere was highly correlated with the internal concentration of benzene both in post-shift blood (r=0.87, P<0.001) and post-shift urine (r=0.90, P<0.001), indicating that the varying use of respirators did not explain much of the variability in absorbed benzene. The results showed that, despite low benzene exposure in this work atmosphere and the use of personal protective equipment to a varying degree, the tank workers had a significant uptake of benzene that correlated highly with benzene exposure. The internal concentration of benzene was higher than expected considering the measured individual benzene exposure, probably due to an extended work schedule of 12h and physical strain during tank work. Control measures should be improved for processes, which impose a potential for increased absorption of benzene upon the workers.

Physiologically-based pharmacokinetic modeling of benzene in humans: a Bayesian approach.

Benzene is myelotoxic and leukemogenic in humans exposed at high doses (>1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry.

Worker exposure to polychlorinated biphenyls in elastic polysulphide sealant renovation.

Worker exposure to polychlorinated biphenyls (PCBs) in renovation of prefabricated houses was assessed by biological monitoring of 24 PCB congeners including the 10 most abundant PCBs in elastic polysulphide sealants. Serum samples from 22 exposed and 21 non-exposed men were analysed using gas chromatography-mass spectrometry with negative chemical ionization. Total PCB concentration of 24 PCB congeners in workers' serum varied between 0.6 and 17.8 microg/l (mean 3.9 microg/l, median 1.9 microg/l). The Finnish upper reference limit for occupationally non-exposed persons (3 microg/l) was exceeded in the serum samples of 10 workers. Concentrations for non-exposed persons were 0.3-3.0 microg/l (mean 1.7 microg/l, median 1.5 microg/l). The concentration for the sum of the 10 most abundant PCB congeners in elastic polysulphide sealants in serum samples taken in autumn after the renovation season was 2-10 times higher than in samples from the same workers (n=5) taken in the previous spring. The concentrations of PCB congeners PCB 28, 52, 77, 101, 138, 153 and 180 in hygienic samples taken from the breathing zone of the workers were low, ranging from not detected to 3.1 microg/m3. The concentrations of PCB 28 and 52 in sera were positively correlated with the concentrations in air samples taken from the breathing zone of six workers (r=0.70 and 0.80).

Determination of polychlorinated biphenyls in serum using gas chromatography-mass spectrometry with negative chemical ionization for exposure estimation.

A sensitive and selective method for the determination of 24 polychlorinated biphenyls (PCBs) by gas chromatography-mass spectrometry with negative chemical ionization (GC-MS-NCI) was applied for the recent needs of occupational exposure in waste incineration. The three most abundant ions were used in determining compounds with at least five chlorine atoms in the PCB molecule. Selecting ions Cl(35) and Cl(37) for di-, tri-, and tetrachlorinated PCBs resulted in reliable quantification of these compounds. The detection limits for the 24 individual compounds varied from 0.01 to 0.08 microg/l. The recovery of the method was 113+/-16%. Stability tests showed no degradation of the compounds studied during 6 weeks. The sum of 24 PCB compounds measured from the sera of workers in a disposal plant was 1.9-10.9 microg/l, and 0.3-3.0 microg/l for controls, respectively. The mean proportion of the low chlorinated PCB compounds (with four or less chlorine atoms) was 20% for workers in the disposal plant and 14% for the controls.