Toxicokinetics of Perfluorinated Alkyl Acids Influences Their Toxic Potency in the Zebrafish Embryo ( Danio rerio).

Perfluorinated alkyl acids (PFAA) are highly persistent and bioaccumulative and have been associated with several adverse health effects. The chemical structure mainly differs in two ways: the length of the hydrophobic alkyl chain and the type of hydrophilic end group. Little is known how the chemical structure affects the toxicokinetics (TK) in different organisms. We studied the TK of four PFAA (PFOS, PFHxS, PFOA, and PFBA) with different chain lengths (4-8 carbons) and functional groups (sulfonic and carboxylic acid) in zebrafish ( Danio rerio) embryo. The time courses of the external (ambient water) and internal concentrations were determined at three exposure concentrations from 2 up to 120 h postfertilization (hpf). Three of the four PFAA showed a biphasic uptake pattern with slow uptake before hatching (around 48 hpf) and faster uptake thereafter. A two-compartment TK model adequately described the biphasic uptake pattern, suggesting that the chorion functions as an uptake barrier until 48 hpf. The bioconcentration factors (BCF) determined at 120 hpf varied widely between PFAA with averages of approximately 4000 (PFOS), 200 (PFHxS), 50 (PFOA), and 0.8 (PFBA) L kg dry weight-1, suggesting that both the alkyl chain length and the functional group influence the TK. The differences in toxic potency were reduced by 3 orders of magnitude when comparing internal effect concentrations instead of effective external concentrations.

Cellular accumulation and lipid binding of perfluorinated alkylated substances (PFASs) - A comparison with lysosomotropic drugs.

Many chemicals accumulate in organisms through a variety of different mechanisms. Cationic amphiphilic drugs (CADs) accumulate in lysosomes and bind to membranes causing phospholipidosis, whereas many lipophilic chemicals target adipose tissue. Perfluoroalkyl substances (PFASs) are widely used as surfactants, but many of them are highly bioaccumulating and persistent in the environment, making them notorious environmental toxicants. Understanding the mechanisms of their bioaccumulation is, therefore, important for their regulation and substitution with new, less harmful chemicals. We compared the highly bioaccumulative perfluorooctanesulfonic acid PFOS to its three less bioaccumulative alternatives perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA) and perfluorobutane sulfonic acid (PFBS), in their ability to accumulate and remain in lung epithelial cells (NCI-H292) and adipocytes (3T3-L1K) in vitro. As a reference point we tested a set of cationic amphiphilic drugs (CADs), known to highly accumulate in cells and strongly bind to phospholipids, together with their respective non-CAD controls. Finally, all compounds were examined for their ability to bind to neutral lipids and phospholipids in cell-free systems. Cellular accumulation and retention of the test compounds were highly correlated between the lung epithelial cells and adipocytes. Interestingly, although an anion itself, intensities of PFOS accumulation and retention in cells were comparable to those of CAD compounds, but PFOS failed to induce phospholipidosis or alter lysosomal volume. Compared to other lipophilicity measures, phospholipophilicity shows the highest correlation (Rˆ2 = 0.75) to cellular accumulation data in both cell types and best distinguishes between high and low accumulating compounds. This indicates that binding to phospholipids may be the most important component in driving high cellular accumulation in lung epithelial cells, as well as in adipocytes, and for both CADs and bioaccumulating PFASs. Obtained continuous PLS models based on compound's affinity for phospholipids and neutral lipids can be used as good prediction models of cellular accumulation and retention of PFASs and CADs.