| Despite its small contribution to global production and usage of polybrominated diphenyl ethers, BDE 47 is the major flame-retardant congener found in environmental samples and human tissue. Limited toxicology studies suggest that BDE 47 is a developmental reproductive and neurotoxicant, as well as an endocrine disrupter. This dissertation investigates the link between exposure, dose, and response needed for the risk assessment of BDE 47. We hypothesized that BDE 47 is a persistent, bioaccumulative and toxic chemical that has toxicokinetic properties similar to other polyhalogenated aromatic hydrocarbons. To test this hypothesis and provide information essential to the human health risk assessment of BDE 47: the basic toxicokinetic parameters of BDE 47 were characterized in mice, the impact of repeated dosing on the disposition and excretion of BDE 47 and the disposition and excretion of BDE 47 in a developmental model were investigated, the mechanism of rapid BDE 47 excretion in mice was researched, and the toxicokinetics of BDE congeners 47, 99, 100, and 153 toxicokinetics were compared.; In adult, female mice, BDE 47 is well absorbed, distribution is dictated by lipophilicity, metabolism is a minor component of elimination, and has a terminal whole-body half life of 22 days. Repeated exposure results in higher body burdens than a single exposure alone, therefore demonstrating the potential for bioaccumulation. BDE 47 has toxicokinetic properties similar to other polyhalogenated aromatic hydrocarbons with the exception of a rapid urinary excretion process. Tissue distribution in developing animals is similar to adults; however, actual concentrations are higher in younger animals because of a reduced ability to excrete BDE 47. Several efforts to characterize the mechanism of rapid renal excretion resulted in a narrowed field of active transport proteins that may be responsible for the net movement of BDE 47 out of the body. The continued development of a PBPK model will predict BDE 47 disposition across routes of exposure, dose, gender, and species. Risk estimates utilizing the toxicokinetic data generated in this study suggest that currently there is no margin of safety between BDE 47 exposure to human infants and developmental neurotoxicity observed in rodent studies. |
