Luo, Yu-Syuan (2018-07). Inter-individual Variability in Metabolism and Toxicity of Trichloroethylene and Tetrachloroethylene. Doctoral Dissertation.
Thesis
From the standpoint of public health, the purpose of chemical health risk assessment is to protect the susceptible individuals and to set up an action threshold against chemical hazards. Chemical toxicity is usually associated with toxicokinetics (absorption, distribution, metabolism, and excretion). One of the critical challenges in human health risk assessment is to address the inter-individual variability in metabolism and toxicity of chemicals. The inter-individual differences may be due to sex, genetics, dietary habits, and disease states. We hypothesized that the inter-individual variability in genetics and disease states could affect the xenobiotic metabolism, which in turn has pronounced impacts on individual susceptibility toward chemical exposures. Herein, we use two structurally similar chlorinated chemicals, trichloroethylene (TCE) and tetrachloroethylene (PCE), as model compounds. Organ-specific toxicities of TCE and PCE have been linked to their respective oxidative and glutathione (GSH) conjugation metabolism; however, little is known regarding GSH conjugation metabolism at target organs (i.e., liver and kidney) due to the lack of sensitive analytical assays. In this dissertation, we successfully developed two LC-MS/MS methods for simultaneous detection of GSH conjugation metabolites in multiple mouse tissues for TCE and. With these validated methods, we advanced our knowledge in metabolism and toxicity of TCE and PCE from several aspects. First, our data show that the default uncertainty factor of 3.16 for the toxicokinetic variability of TCE GSH conjugation metabolites is inadequate to protect 99% of the population for organ-specific toxicity mediated by DCVG, DCVC, and NAcDCVC. Second, we found that nonalcoholic fatty liver disease states can also influence the kidney metabolism and toxicity of PCE. Third, our results demonstrate that the oxidative enzyme, cytochrome P450 2E1, can alter not only the oxidative but also the GSH conjugative metabolism, which in turn have pronounced impacts on the organ-specific toxicity of TCE and PCE. Finally, we observed that the one-atom replacement of chlorine can substantially affect the oxidative and GSH conjugative metabolism of TCE and PCE. Collectively, this doctoral dissertation advances our understanding of metabolism and toxicity of TCE and PCE, and provides data for more refined health risk assessment of TCE and PCE.
