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MEASUREMENT OF EXHALED BREATH AND VENOUS BLOOD TO DEVELOP A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR HUMAN EXPOSURE TO METHYL TERTIARY-BUTYL ETHER AND THE PRODUCTION OF THE BIOMARKER TERTIARY-BUTYL ALCOHOL
Citation:
Pleil, J D., T L. Leavens, M Colon, M W. Case, J D. Prah, AND D. L. Ashley. MEASUREMENT OF EXHALED BREATH AND VENOUS BLOOD TO DEVELOP A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR HUMAN EXPOSURE TO METHYL TERTIARY-BUTYL ETHER AND THE PRODUCTION OF THE BIOMARKER TERTIARY-BUTYL ALCOHOL. Presented at Environmental Sampling and Analysis Seminar, Okinawa, Japan, July 8-22, 2001.
Impact/Purpose:
The objective of this task is to develop state-of-the-art methods for measuring xenobiotic compounds, to include the isolation of the analyte from the appropriate matrix (extraction), preconcentration (typically sorbent-based), and analysis via GC/MS and/or LC/MS. Once established, these methods will be applied in small scale pilot studies or demonstration projects. Particular emphasis will be placed on methods which are readily transferable to other laboratories, including those within the Human Exposure and Atmospheric Sciences Division (HEASD), the National Exposure Research Laboratory (NERL), other EPA Laboratories, Program Offices, Regions, and academic institutions.
Specific objectives of this task include the following:
1) Development of GC/MS and LC/MS methods for the measurement of key xenobiotic compounds and their metabolites (to include the pyrethroid pesticides, perfluorinated organic compounds, and the BFRs) in relevant environmental and biological matrices.
2) Development of efficient low cost methods for the extraction and clean up of these compounds collected from relevant matrices.
3) Determination of xenobiotic compound and metabolite concentrations in samples derived from laboratory and field monitoring studies to help assess exposures and evaluate associated risks.
Description:
Methyl tertiary-butyl ether (MTBE) is a common fuel additive used to increase the availability of oxygen in gasoline to reduce winter-time carbon monoxide emissions from automobiles. Also, MTBE boosts gasoline "octane" rating and, as such, allows reduction of benzene (and other aromatics) content without compromising automobile performance. Two less desirable properties of this additive are that it has a very low odor threshold and that it is highly soluble in water. This solubility poses unique problems when fuel is spilled and enters the water table in that MTBE (in contrast to the less soluble hydrocarbons in fuel) is rapidly dispersed in water and is then very difficult to remove. In addition to the distinctive odor in air and water, MTBE has been identified as an animal carcinogen at high concentrations.
There are two primary exposure scenarios for MTBE in the general public: inhalation exposure during self-refueling of automobiles (and/or incidental exposure through accidental dermal contact at the fuel pump), and the use of fuel contaminated water that results in dermal and inhalation exposure during bathing, ingestion exposure from water consumption, and inhalation exposure from volatilization during general water usage. For the purposes of studying MTBE pharmacokinetics in humans, we focused on the water borne pathway because these exposures are more amenable to controlled study. Blood and breath measurements were made before, during, and after controlled inhalation, ingestion or dermal exposure to levels of MTBE similar to high range of typical exposures from contaminated water in certain regions of California. Specifically, we used the following MTBE levels: 3 ppmv in air for 60 minutes for inhalation, one arm in 60 ug/L water for 60 minutes for dermal, and 250 ml at 14 ug/L bolus in Gatorade for ingestion.
The resultant data were used to test a pharmacokinetic model developed for these experiments and for MTBE in general. Compartments in the model included alveolar space, arterial and venous blood, brain, fat, gastrointestinal tract, kidney, liver, rapidly perfused tissues, sampled and arms, and slowly perfused tissues. To accurately simulate the clinical human exposure and sampling conditions, the exposed arm and sampled arm were described by subcompartments for arterial blood, upper arm tissue, forearm tissue, forearm skin, antecubital venous blood, and venous blood. Metabolism of MTBE and TBA was assumed to occur only in the liver, and elimination was assumed to occur via exhalation of MTBE and TBA and urinary elimination of TBA. Dermal absorption was described by Fick's law, and oral absorption was described as first order for the bioavailable dose. Initial estimates for parameters were obtained from the literature. The model with the optimized parameters accurately simulated pharmacokinetics of MTBE and TBA in humans for all three routes. Of the inhaled, oral, and dermal doses 54, 47, and 54%, respectively, were exhaled as MTBE, and 44, 52, and 44%, respectively, were metabolized to TBA. This model can now be used to simulate environmental exposure to MTBE.
This work has been reviewed in accordance with the U.S. Environmental Protection Agency's peer and administrative review process and approved for presentation and publication. Mention of tradenames or commercial products does not constitute endorsement or recommendation for use.