Physiologically-based pharmacokinetic modeling of simple and complex mixtures of gasoline and the gasoline components N-hexane, benzene, toluene, ethylbenzene, and xylene

Physiologically-based pharmacokinetic (PBPK) models are often used to place the pharmacokinetics of chemicals on a firm quantitative basis. They are also useful in describing the pharmacokinetics of mixtures of chemicals, especially when interactions occur between mixture components. However, the models are relatively data-intensive, and to date, PBPK models have been developed only for mixtures of up to five components. In this thesis, we explore the ability of PBPK models to provide a quantitative description of the pharmacokinetics of gasoline and several of its principal components. The research included examining the pharmacokinetics of chemicals on several levels. First, the pharmacokinetics of simple mixtures of gasoline components were examined using a previously-validated approach. Subsequently, the pharmacokinetics of whole gasoline and some of its principal components were investigated. The research developed a new method for describing the pharmacokinetics of such a "complex" mixture. The new approach involved using chemical lumping to describe the pharmacokinetics of the majority of the mixture, yet permitted the investigator to evaluate the pharmacokinetics of key compounds in the mixture individually. This approach was validated with both different blends of whole gasoline as well as with evaporated volatile components of gasoline. Finally, the research evaluated pharmacokinetic interactions that occur between n-hexane and some of its metabolites. A PBPK model that was able to describe the complex behavior of n-hexane and its neurotoxic metabolite, 2,5-hexanedione, was developed using the interactive properties of the chemical. Using a suite of models that describe the pharmacokinetics of simple mixtures, complex mixtures, single chemicals, and chemicals that exhibit interactions with their metabolites provides a robust ability to describe the important aspects of metabolic disposition in animals.