Quantitative in vitro-in vivo extrapolation of biotransformation rates for bioaccumulation assessment: Focus on organic sunscreen agents in rainbow trout

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Thesis type
(Thesis) Ph.D.
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An improved understanding of chemical biotransformation has been identified as a key requirement for the bioaccumulation assessment of commercial chemicals. In vitro biotransformation assays, in combination with in vitro-in vivo extrapolation (IVIVE) represents one initiative to generate chemical biotransformation rates for use in bioaccumulation modeling efforts. However, rigorous evaluation of the IVIVE approach requires studies with well-matched animals to ensure in vitro tests adequately predict in vivo biotransformation potential. Therefore, the overarching objective of this thesis was to evaluate factors that may influence the extrapolation of hepatic in vitro biotransformation rate constants (kdep) using well-matched studies with rainbow trout. Hydrophobic organic ultraviolet filters (UVFs) 4-methylbenzylidene camphor, 2-ethylhexyl-4-methoxycinnamate (EHMC), and octocrylene (OCT) represented model chemicals in this investigation. The first study showed that measured kdep values for UVFs were highly dependent on the selected assay concentration. Modeled bioconcentration factors (BCF) derived from kdep measured at concentrations well below corresponding Michaelis-Menten constants (KM) were closer to empirical BCFs than those calculated from kdep measured at higher test concentrations. A corresponding in vivo study demonstrated that during standardized dietary exposures that measured UVF concentrations in trout were well below the previously derived KM values This demonstrated that biotransformation pathways in trout operate under first-order conditions and that working at an appropriate concentration range in in vitro assays (i.e., C0
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Thesis advisor: Gobas, Frank
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