Quantitative analysis and toxicokinetics of trichloroethylene and its metabolites in rats
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Trichloroethylene (TCE) is a volatile organic compound commonly found in drinking water supplies as a result of its widespread use as a metal degreaser and dry cleaning solvent. Human exposure to TCE is primarily of concern due to its carcinogenicity in laboratory animals. The tumors evoked by TCE have been attributed to specific metabolites. Metabolites trichloroacetic acid (TCA) and dichloroacetic acid (DCA) are, in addition, frequently found in drinking water as byproducts of water chlorination. Doses of TCE typically given in animal studies are orders of magnitude higher than the levels to which individuals are exposed to environmentally. Nevertheless, there is concern on the part of EPA that even trace levels may present a cancer risk to humans. The human body possesses a number of defense mechanisms to protect against low-level toxic and mutagenic insults. First-pass, or presystemic elimination is one such process. Efforts to directly measure the capacity of first-pass elimination and metabolism of TCE under environmental exposure conditions have been hindered by difficulty with developing sufficiently sensitive, reliable analytical methods. Chapter 1 is the introduction and describes the scope of the dissertation. The optimization of headspace Solid Phase Microextraction (SPME) conditions for the determination of TCE in rat plasma is presented in Chapter 2. The development and validation of a headspace SPME GC/MS method for the determination of TCE in rat blood and tissues is described in Chapter 3. A highly sensitive method using headspace SPME GC-NCIMS for the determination of TCE in biological samples is presented in Chapter 4. The LOQ for this NCI method is 10 times lower than the method described in Chapter 3. Chapter 5 presents two sensitive methods for the determination of TCE in rat adipose using SPME GC-EIMS and GC-NCIMS. In Chapter 6, an in situ derivatization/SPME GC-NCIMS method is validated for the determination of TCE metabolites including TCA, DCA and TCOH, in rat blood. All of the methods presented here are simple, rapid, sensitive and validated for specificity, linearity, accuracy and precision. Using the methods developed in previous chapters, the toxicokinetics and presystemic elimination of TCE in rats following environmentally-relevant exposures were characterized in Chapter 7.