Date of Award

2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Angela Slitt

Abstract

Per- and polyfluoroalkyl substances (PFAS) are a diverse class of anthropogenic chemicals associated with several adverse health outcomes in humans. The accumulation of these PFAS have been examined over several decades, however, the elucidation of the toxicokinetics of these chemicals are still in its infancy. The distribution and elimination mechanisms of specific PFAS, notably perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), have undergone comprehensive investigation, however, there are more than 10,000 currently detected PFAS in the environment that have not been examined. It is, therefore, imperative to not only address individual PFAS but also to encompass overarching trends and correlations within the entirety of the PFAS landscape. This thesis focuses on the protein/tissue binding, permeability, and transporter activity of PFAS, which are crucial for understanding their accumulation, distribution, and elimination. This thesis introduces novel ideas and findings with the potential to improve future strategies for reducing overall PFAS exposure.

In manuscript 1, 14 different PFAS were evaluated for their plasma protein and albumin fraction unbound (fu) values. Herein, a presaturation equilibrium dialysis method was used to measure different concentrations of albumin (3% and 4%) and whole plasma of mouse (C57BL/6 and CD-1), rat, and human. Species and matrix fu correlations of PFAS were examined against each other and their respective physiochemical descriptors. Analysis was done to determine the main protein of interest within plasma in terms of binding. Further equivalence-based analysis was executed against different species and matrixes to compare species differences for preclinical species and humans.

In manuscript 2, 16 different PFAS were evaluated for their tissue fraction unbound (fu) values. Herein, a presaturation equilibrium dialysis method was used to measure liver, lung, kidney, heart, or brain tissue of mouse (C57BL/6 and CD-1), rat, and human. Species and tissue fu correlations of PFAS were examined against each other and their respective physiochemical descriptors. Further equivalence-based comparisons were analyzed against varied species and tissues combinations to develop a surrogate preclinical model utilizing rat liver. Partial least squares regression (PLSR) model used to predict tissue fu was developed in parallel utilizing distinct species types and physiochemical properties of PFAS.

In manuscript 3, 14 PFAS were evaluated for substrate activity against several different human renal transporters including organic anion transporters (OAT)1, 2, 3, 4 and organic cation transporter (OCT) 2. PFAS with substrate activity against a 2-fold threshold were further validated with transporter specific inhibitors. Inhibition activity for this set of PFAS were evaluated against human renal transporters OAT1, 3, and OCT2 by measuring half maximal inhibitory concentration (IC50) values. Apparent permeability (Papp) values for PFAS were generated to determine permeability. PFAS was further evaluated using molecular weight (MW), ionization, permeability, and transporter activity against an established Extended Clearance Classification System (ECCS) framework to further predict clearance pathways.

In summary, manuscript 1 and 2 showed that logD and chain length play significant roles in PFAS ability to bind to either tissue or proteins. Rat liver was an apt surrogate for all tissue and species combinations for PFAS when an established scalar equation was applied. Plasma and albumin binding of different species against PFAS suggest similarities, however, there are species differences which require specific plasma species combinations to be used. The ECCS framework was further validated for PFAS utilizing pharmacokinetic parameters in manuscript 3. This research highlights several toxicokinetic parameters for various PFAS compounds, thereby guiding the development for future more effective strategies to mitigate their exposure and accumulation.

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