Occupational and environmental exposure to volatile organic solvents is an important concern due to the widespread presence of these substances and the diversity of associated toxicities. The relationships among human exposures, time-varying levels of toxicants or metabolites in body tissues or fluids, and short or long term biological responses are greatly influenced by factors that are specific to the person exposed or even to the actual exposure event. Important tools for the investigation of these intricate relationships that we have developed in prior phases of this project include: controlled exposures to stable isotope-labeled and unlabeled compounds; accurate measurements of these compounds and metabolites in blood, breath, and urine; and implementation of physiologically-based models. This project will utilize all these tools to accomplish the following goals; I. Continue to characterize fundamental parameters that underlie the toxicokinetics of toluene; styrene; and o-,m-, and p-xylene. These efforts will include determination of human tissue/blood partition coefficients, a physiologic model sensitivity analysis, and the use of individual-specific in vitro and in vivo metabolic probes. II. Test the ability of the stable isotope probes and model framework to account for the toxicokinetic variability introduced by variations in subject gender, extremes of subject body weight and adipose fraction, conditions of exercise, co-administration of ethanol, and prior chronic solvent exposures. Models for retrospective dose estimation using post=exposure biological samples will be evaluated under these varying conditions. III. Apply the probe/model framework to the characterization of uncontrolled exposures. This goal will include the validation of results- to-date through comparison of measured biomarkers to conventional exposure measurements, the assessment of environmental solvent exposure through a community survey, and the identification and study enrollment of a pilot solvent-exposed occupational cohort.
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