Bioavailability of endocrine disrupting chemicals (EDCs): liposome-water partitioning and lipid membrane permeation

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Kwon, Jung-Hwan

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The bioavailability of endocrine disrupting chemicals (EDCs) is a function of a number of parameters including the ability of the chemical to partition into organic tissue and reach receptor sites within an organism. In this dissertation, equilibrium partition coefficients between water and lipid membrane vesicles and artificial lipid membrane permeability were investigated for evaluating bioavailability of aqueous pollutants. Structurally diverse endocrine disrupting chemicals were chosen as model compounds for partitioning experiments and simple hydrophobic organic chemicals were used for the evaluation of a parallel artificial membrane device developed to mimic bioconcentration rates in fish. Hydrophobic interactions represented by octanol/water partition coefficients (KOWs) were not appropriate for estimating lipid membrane/water partition coefficients (Klipws) for the selected EDCs having a relatively large molar liquid volume (MLV) and containing polar functional groups. Correlations that include MLV and polar surface area (PSA) reduce the predicted value of log Klipw, suggesting that lipid membranes are less vii favorable than 1-octanol for a hydrophobic solute because of the changes in membrane fluidity and the amount of cholesterol in the lipid bilayers. These results suggested that KOW alone has limited potential for estimating Klipw, and MLV or PSA may be used as additional descriptors for developing quantitative structure-activity relationships (QSARs). The poor correlations between KOW and Klipw observed in this research may be due to the highly organized structure of lipid bilayers. Measured thermodynamic constants demonstrated that the entropy contribution becomes more dominant for more organized liposomes having saturated lipid tails. This implies that entropy-driven partitioning process makes Klipw different from KOW especially for more saturated lipid bilayer membranes. In the parallel artificial membrane system developed, a membrane filter-supported lipid bilayer separates two aqueous phases that represent the external and internal aqueous environments of fish. The thickness of the aqueous mass transfer boundary layer was carefully adjusted to mimic bioconcentration rate parameters in small fish. For the selected twenty-three simple aromatic hydrocarbons, literature absorption/elimination rates fall within the range predicted from measured membrane permeabilities and elimination rates of the selected chemicals using a diffusion mass transfer model. A simple equilibrium binding model for EDCs to estrogen receptors was applied to potentially link the developed artificial membrane system to existing toxicity assays and to better utilize in vitro toxicity data.