Perfluorinated carboxylates (PFCAs) are persistent and ubiquitous in the environment. Humans are exposed to PFCAs through direct and indirect sources, although the relative importance of each is uncertain. Direct sources of PFCAs have been attributed to two primary fluorochemical manufacturing processes: electrochemical fluorination (ECF) and telomerization. A focus of this thesis was to elucidate an additional direct source of PFCAs resulting from the direct fluorination of polyolefin materials. High density polyethylene bottles with varying levels of fluorination were observed to contain significant amounts of PFCAs, particularly those with carbon chain-lengths ≤ C6, marking an unexplored source of PFCA exposure. PFCAs are also produced indirectly from the biotransformation of fluorotelomer-based compounds, such as polyfluoroalkyl phosphate esters (PAPs) and fluorotelomer alcohols (FTOHs). During this transformation process, two predominant classes of metabolic intermediates are formed: the fluorotelomer unsaturated aldehydes (FTUALs) and the fluorotelomer unsaturated carboxylic acids (FTUCAs). Another focus of this thesis was to examine the reactivity of FTUALs and FTUCAs with endogenous nucleophiles such as glutathione (GSH), select amino acids, and model proteins. FTUALs formed adducts with all nucleophiles examined, where those having shorter carbon chain lengths (i.e. 6:2 and 8:2 FTUAL) were more reactive than longer carbon chains (i.e. 10:2 FTUAL). By contrast, FTUCAs had comparably limited reactivity; although FTUCAs showed mild reactivity with GSH, they did not react with any other nucleophiles. In vitro and in vivo experiments were carried out to determine the extent of protein binding formed from the biotransformation of fluorotelomer-based compounds, including the 8:2 FTOH and the 6:2 PAP diester. A significant portion of these biotransformations yielded covalent protein binding at nmol/mg protein concentrations. Protein adducts were observed predominantly in rat liver and also in plasma and kidney. The formation of reactive intermediates may be toxicologically important through protein deactivation. Cellular toxicity of FTUALs was significantly higher compared to PFCAs and the acid metabolic intermediates (i.e. FTUCAs). The EC50 values calculated from dose-response incubations were dependant on chain length and functional group. The work in this thesis examined an unexplored consequence of indirect exposure to PFCAs, potentially impacting the relative importance of PFCA exposure sources.

Perfluorinated carboxylates (PFCAs) are persistent and ubiquitous in the environment. Humans are exposed to PFCAs through direct and indirect sources, although the relative importance of each is uncertain. Direct sources of PFCAs have been attributed to two primary fluorochemical manufacturing processes: electrochemical fluorination (ECF) and telomerization. A focus of this thesis was to elucidate an additional direct source of PFCAs resulting from the direct fluorination of polyolefin materials. High density polyethylene bottles with varying levels of fluorination were observed to contain significant amounts of PFCAs, particularly those with carbon chain-lengths ≤ C6, marking an unexplored source of PFCA exposure. PFCAs are also produced indirectly from the biotransformation of fluorotelomer-based compounds, such as polyfluoroalkyl phosphate esters (PAPs) and fluorotelomer alcohols (FTOHs). During this transformation process, two predominant classes of metabolic intermediates are formed: the fluorotelomer unsaturated aldehydes (FTUALs) and the fluorotelomer unsaturated carboxylic acids (FTUCAs). Another focus of this thesis was to examine the reactivity of FTUALs and FTUCAs with endogenous nucleophiles such as glutathione (GSH), select amino acids, and model proteins. FTUALs formed adducts with all nucleophiles examined, where those having shorter carbon chain lengths (i.e. 6:2 and 8:2 FTUAL) were more reactive than longer carbon chains (i.e. 10:2 FTUAL). By contrast, FTUCAs had comparably limited reactivity; although FTUCAs showed mild reactivity with GSH, they did not react with any other nucleophiles. In vitro and in vivo experiments were carried out to determine the extent of protein binding formed from the biotransformation of fluorotelomer-based compounds, including the 8:2 FTOH and the 6:2 PAP diester. A significant portion of these biotransformations yielded covalent protein binding at nmol/mg protein concentrations. Protein adducts were observed predominantly in rat liver and also in plasma and kidney. The formation of reactive intermediates may be toxicologically important through protein deactivation. Cellular toxicity of FTUALs was significantly higher compared to PFCAs and the acid metabolic intermediates (i.e. FTUCAs). The EC50 values calculated from dose-response incubations were dependant on chain length and functional group. The work in this thesis examined an unexplored consequence of indirect exposure to PFCAs, potentially impacting the relative importance of PFCA exposure sources.