Exploring Indirect Sources of Human Exposure to Perfluoroalkyl Carboxylates (PFCAs): Evaluating Uptake, Elimination, and Biotransformation of Polyfluoroalkyl Phosphate Esters (PAPs) in the Rat

Abstract

BackgroundPerfluorinated carboxylic acids (PFCAs) are ubiquitous in human sera worldwide. Biotransformation of the polyfluoroalkyl phosphate esters (PAPs) is a possible source of PFCA exposure, because PAPs are used in food-contact paper packaging and have been observed in human sera.ObjectivesWe determined pharmacokinetic parameters for the PAP monoesters (monoPAPs) and PAP diesters (diPAPs), as well as biotransformation yields to the PFCAs, using a rat model.MethodsThe animals were dosed intravenously or by oral gavage with a mixture of 4:2, 6:2, 8:2, and 10:2 monoPAP or diPAP chain lengths. Concentrations of the PAPs and PFCAs, as well as metabolic intermediates and phase II metabolites, were monitored over time in blood, urine, and feces.ResultsThe diPAPs were bioavailable, with bioavailability decreasing as the chain length increased from 4 to 10 perfluorinated carbons. The monoPAPs were not absorbed from the gut; however, we found evidence to suggest phosphate-ester cleavage within the gut contents. We observed biotransformation to the PFCAs for both monoPAP and diPAP congeners.ConclusionsUsing experimentally derived biotransformation yields, perfluorooctanoic acid (PFOA) sera concentrations were predicted from the biotransformation of 8:2 diPAP at concentrations observed in human serum. Because of the long human serum half-life of PFOA, biotransformation of diPAP even with low-level exposure could over time result in significant exposure to PFOA. Although humans are exposed directly to PFCAs in food and dust, the pharmacokinetic parameters determined here suggest that PAP exposure should be considered a significant indirect source of human PFCA contamination.

Methodology for studying biotransformation of polyfluoroalkyl precursors in the environment

“…To elucidate the metabolism mechanism and possible adverse effects due to covalent binding of unsaturated polyfluoroalkyl intermediate metabolites to biological macromolecules, in-vitro bioassays were performed using hepatocytes, cytosol fractions and liver microsomes from mammalian and fish species [19,21]. In-vivo dietary exposure studies were also conducted to evaluate uptake, metabolism and elimination dynamics of PFASs in Sprague-Dawley rats and juvenile rainbow trout [20,33,34].…”

Polyfluorinated Alkyl Phosphate Ester Surfactants – Current Knowledge and Knowledge Gaps

“…These findings are supported by animal studies showing that diPAPs can be absorbed across the gastrointestinal tract, both when administered as single diPAPs [24] or a mixture of homologues of diPAPs, but the absorption seems to decrease with increasing chain lengths [25]. Finally, the presence of PAPs in human milk (at ng/mL levels) was recently reported [26] suggesting that the newborn child may be exposed through breastfeeding.…”

“…2). Biotransformation of PAPs to PFCA is thought to be a contributing source to PFCA exposure [25]. The excretion of mixtures of diPAPs homologues or monoPAPs homologues in male rats showed that renal excretion is not the major direct elimination pathway [24].…”

Per- and polyfluorinated substances in the Nordic Countries

“…In rats biotransformation of monoPAP and diPAP congeners to FTOH and PFCAs have been observed (D'Eon J and Mabury, 2011). The animals were dosed with a mixture of 4:2, 6:2, 8:2, and 10:2 monoPAP or diPAP chain lengths.…”

“…The monoPAPs were not absorbed from the gut. However, the PAP dosing concentrations at 50 mg/kg used in the studies (D'Eon J and Mabury, 2011;D'Eon and Mabury, 2007), where not toxic for the animals.…”