Refined PBPK model of aggregate exposure to methyl tertiary-butyl ether.

Aggregate (multiple pathway) exposures to methyl tertiary-butyl ether (MTBE) in air and water occur via dermal, inhalation, and oral routes. Previously, physiologically based pharmacokinetic (PBPK) models have been used to quantify the kinetic behavior of MTBE and its primary metabolite, tertiary-butyl alcohol (TBA), from inhalation exposures. However, the contribution of dermal and oral exposures to the internal dose of MTBE and TBA were not characterized well. The objective of this study was to develop a multi-route PBPK model of MTBE and TBA in humans. The model was based entirely on blood MTBE and TBA measurements from controlled human exposures. The PBPK model consists of nine primary compartments representing the lungs, skin, fat, kidney, stomach, intestine, liver, rapidly perfused tissue, and slowly perfused tissue. The MTBE and TBA models are linked by a single metabolic pathway. Although the general structure of the model is similar to previously published models of volatile organic compounds, we have now developed a detailed mathematical description of the lung, skin, and gastrointestinal tract. This PBPK model represents the most comprehensive and accurate description of MTBE and TBA pharmacokinetics in humans to date. The aggregate exposure model application for MTBE can be generalized to other environmental chemicals under this framework given appropriate empirical measurement data.

A real-time method to evaluate the nasal deposition and clearance of acetone in the human volunteer.

Nasal dosimetry models have become increasingly quantitative as insights into tissue deposition/clearance and computational fluid dynamics have become available. Validation of these models requires sufficient experimental data. However, investigations into respiratory deposition, particularly in human volunteers, have been historically limited due to methodological limitations. To overcome this, a method for evaluating the nasal wash-in, wash-out phenomena of a highly water-soluble compound in human volunteers was developed and characterized. This methodology was assessed using controlled human inhalation exposures to uniformly labeled [(13)C]acetone at approximately 1 ppm concentration for 30 min under different breathing maneuvers (inhale nose/exhale nose; inhale nose/exhale mouth; inhale mouth/exhale nose). A small-diameter air-sampling probe inserted in the nasopharyngeal cavity of the volunteer was connected directly to an ion-trap mass spectrometer capable of sampling every 0.8 s. A second ion-trap mass spectrometer simultaneously sampled from the volunteer's exhaled breath stream via a breath-inlet device interface. Together, the two mass spectrometers provided real-time appraisal of the [(13)C]acetone concentrations in the nasopharyngeal region and in the exhaled breath stream before, during, and after the different breathing maneuvers. The breathing cycle (depth and frequency) and heart rate were concurrently monitored throughout the exposure using a heart-rate monitor and a human plethysmograph to differentiate inhalation and exhalation. Graphical overlay of the plethysmography results with the mass spectrometer measurements show clear quantifiable differences in [(13)C]acetone levels at the nasal probe as a function of breathing maneuvers. Breath-by-breath analyses of [(13)C]acetone concentrations indicate that between 40 and 75% of the compound is absorbed upon inhalation and nearly all of that absorbed is released back into the breath stream during exhalation.

The development and testing of a dermal exposure system for pharmacokinetic studies of administered and ambient water contaminants.

INTRODUCTION: In order to investigate the pharmacokinetics of water-borne chemicals while eliminating exposures by other routes, a dermal exposure system was developed to expose the hand and forearm of human subjects. METHODS: The goal was, primarily, to study the dermal pharmacokinetics of methyl tertiary butyl ether (MTBE), a water contaminant, and, secondarily, the ambient disinfection byproducts (DBPs). MTBE is used as a fuel oxygenate and DBPs result from chlorination of drinking water. The DBPs measured in the water and blood of the subjects were chloroform, bromodichloromethane, and dibromochloromethane. The dermal exposure system was constructed of inert and impervious materials. The interface between the glass and Teflon exposure tank and the subject was custom-made of clear Tedlar (polyvinylfluoride) so that the depth of the arm in the media could be monitored. RESULTS: Sampling of the water concentration of the test chemical, MTBE, demonstrated stability over the duration of the exposure. A temperature loss of about 1.5 degrees C occurred over the course of the 1-h exposure. Blood concentrations taken from 14 human subjects before, during, and after the 1-h exposure demonstrated that measurable MTBE and DBPs were absorbed. DISCUSSION: This system has the advantages of maintaining contaminant concentration and exposing an anatomically distinct body region, and the convenience of blood sampling.