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Determination of the chemical clearance rate from human blood is a critical component of toxicokinetic exposure assessment. Analysis of temporal biomonitoring data without consideration of ongoing exposure results in calculation of apparent elimination half-life values that are longer than the intrinsic value. The intrinsic elimination half-life is solely a function of the rate of elimination while the apparent elimination half-life reflects the processes of both elimination and ongoing exposure. Confusion between intrinsic and apparent half-life values can lead to misinterpretation of biomonitoring data and can result in exaggerated predictions in subsequent modeling efforts. This work provides a review of the first-order equations that have been developed to calculate intrinsic and apparent half-life values and the potential bias that can result from confusing these two values. Published human biomonitoring data for perfluorooctanoic acid (PFOA) are analyzed using these equations to provide examples of low, medium and high bias in determination of the intrinsic elimination half-life from plasma or serum, the components of blood typically analyzed for PFOA. An approach is also provided to estimate the extent of exposure reduction that is indicated by declining longitudinal or cross-sectional biomonitoring data. Based on the evaluation methodology presented in this work, the intrinsic elimination half-life of PFOA in humans is 2.4years, representing the average of independent estimates of 2.5years (95% CI, 2.4-2.7) and 2.3years (95% CI, 2.1-2.4). The declining concentration of PFOA in blood of the general USA adult population represents an estimated exposure reduction of 20-30% over the period 1999-2008., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The toxicokinetics of 6:2 fluorotelomer alcohol (6:2 FTOH) and its terminal perfluorinated and polyfluorinated metabolites (PFBA, PFHxA, PFHpA and 5:3 Acid) have been calculated from laboratory studies of rats and from a biomonitoring study of humans. In vitro studies with mouse, rat and human hepatocytes indicate qualitatively similar metabolic pathways of 6:2 FTOH. In a one-day inhalation study of 6:2 FTOH in rats, PFBA, PFHxA, PFHpA and 5:3 Acid were determined to be the major metabolites in plasma with calculated elimination half-lives of 1.3-15.4h and metabolic yields up to 2.7 mol%. In five-day and 23-day inhalation studies and a 90-day oral study of 6:2 FTOH, the plasma or serum concentration profile of 5:3 Acid was several-fold higher than concentrations observed in the single day study, resulting in an estimated elimination half-life of 20-30 d. In contrast, the concentrations of PFBA, PFHxA and PFHpA showed little or no concentration increase with repeated exposure. Elimination half-lives of PFHxA, PFHpA and 5:3 Acid in humans were estimated from a study of professional ski wax technicians who were occupationally exposed to aerosolized and volatilized components of fluorinated glide wax. The resulting human elimination half-life values of PFHxA, PFHpA and 5:3 Acid were 32, 70 and 43 d, respectively. Based on a one compartment toxicokinetic model, current environmental air concentrations of 6:2 FTOH are estimated to result in plasma concentrations of PFHxA, PFHpA and 5:3 Acid that are less than or equal to typical LOQ values, in agreement with extant biomonitoring results., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Major fluorinated chemical manufacturers have developed new short-chain per- and polyfluorinated substances with more favorable environmental, health and safety profiles. This study provides the first evaluation of the elimination half-life of perfluorohexanoic acid (PFHxA) from the blood of humans. PFHxA biomonitoring data were obtained from a recently published study of professional ski wax technicians. These data were analyzed to provide estimates of the apparent half-life of PFHxA from humans, and comparisons were made with kinetic studies of PFHxA elimination from mice, rats and monkeys. The apparent elimination half-life of PFHxA in highly exposed humans ranged between 14 and 49 d with a geomean of 32 d. The half-lives of PFHxA in mice, rats, monkeys and humans were proportional to body weight with no differences observed between genders, indicating similar volumes of distribution and similar elimination mechanisms among mammalian species. Compared to long-chain perfluoroalkyl acid analogs, PFHxA is rapidly cleared from biota. The consistent weight-normalized elimination half-lives for PFHxA in mammalian species indicates that results obtained from animal models are suitable for establishment of PFHxA benchmark dose and reference dose hazard endpoints for use in human risk assessments., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A next-generation mobile automobile air-conditioning (MAC) refrigerant, HFO-1234yf (CF(3) CF = CH(2)), is being developed with improved environmental characteristics. In the atmosphere, it ultimately forms trifluoroacetic acid (TFA(A); CF(3)COOH), which is subsequently scavenged by precipitation and deposited on land and water as trifluoroacetate (TFA; CF(3)COO(-)). Trifluoroacetate is environmentally stable and has the potential to accumulate in terminal water bodies, that is, aquatic systems receiving inflow but with little or no outflow and with high rates of evaporation. Previous studies have estimated the emission rates of HFO-1234yf and have modeled the deposition concentrations and rates of TFA across North America. The present study uses multimedia modeling and geographic information system (GIS)-based modeling to assess the potential concentrations of TFA in terminal water bodies over extended periods. After 10 years of emissions, predicted concentrations of TFA in terminal water bodies across North America are estimated to range between current background levels (i.e., 0.01-0.22 µg/L) and 1 to 6 µg/L. After 50 years of continuous emissions, aquatic concentrations of 1 to 15 µg/L are predicted, with extreme concentrations of up to 50 to 200 µg/L in settings such as the Sonoran Desert along the California/Arizona (USA) border. Based on the relative insensitivity of aquatic organisms to TFA, predicted concentrations of TFA in terminal water bodies are not expected to impair aquatic systems, even considering potential emissions over extended periods., (Copyright © 2012 SETAC.)

Sex-, species-, and chain length-dependent renal elimination is the hallmark of mammalian elimination of perfluorocarboxylates (PFCAs) and has been extensively studied for almost 30 years. In this review, toxicokinetic data of PFCAs (chain lengths ranging from 4 to 10) in different species are compared with an emphasis on their relevance to renal elimination. PFCAs vary in their affinities to bind to serum albumins in plasma, which is an important factor in determining the renal clearance of PFCAs. PFCA-albumin binding has been well characterized and is summarized in this review. The mechanism of the sex-, species-, and chain length-dependent renal PFCA elimination is a research area that has gained continuous interest since the beginning of toxicological studies of PFCAs. It is now recognized that organic anion transport proteins play a key role in PFCA renal tubular reabsorption, a process that is sex-, species-, and chain length-dependent. Recent studies on the identification of PFCA renal transport proteins and characterization of their transport kinetics have greatly improved our understanding of the PFCA renal transport mechanism at the molecular level. A mathematical representation of this renal tubular reabsorption mechanism has been incorporated in physiologically based pharmacokinetic (PBPK) modeling of perfluorooctanoate (PFOA). Improvement of PBPK models in the future will require more accurate and quantitative characterization of renal transport pathways of PFCAs. To that end, a basolateral membrane efflux pathway for the reabsorption of PFCAs in the kidney is discussed in this review, which could provide a future research direction toward a better understanding of the mechanisms of PFCA renal elimination.

This work assessed the usefulness of a current air quality model (American Meteorological Society/Environmental Protection Agency Regulatory Model [AERMOD]) for predicting air concentrations and deposition of perfluorooctanoate (PFO) near a manufacturing facility. Air quality models play an important role in providing information for verifying permitting conditions and for exposure assessment purposes. It is important to ensure traditional modeling approaches are applicable to perfluorinated compounds, which are known to have unusual properties. Measured field data were compared with modeling predictions to show that AERMOD adequately located the maximum air concentration in the study area, provided representative or conservative air concentration estimates, and demonstrated bias and scatter not significantly different than that reported for other compounds. Surface soil/grass concentrations resulting from modeled deposition flux also showed acceptable bias and scatter compared with measured concentrations of PFO in soil/grass samples. Errors in predictions of air concentrations or deposition may be best explained by meteorological input uncertainty and conservatism in the PRIME algorithm used to account for building downwash. In general, AERMOD was found to be a useful screening tool for modeling the dispersion and deposition of PFO in air near a manufacturing facility.

The environment contains various direct and indirect sources of perfluorooctanoic acid (PFOA). The present study uses a dynamic multispecies environmental fate model to analyze the potential formation of perfluorooctanoate (PFO), the anion of PFOA, in the environment from fluorotelomer acrylate polymer (FTacrylate) emitted to landfills and wastewater, residual fluorotelomer alcohol (8:2 FTOH) in FTacrylate, and residual PFOA in FTacrylate. A multispecies version of the SimpleBox model, which is capable of determining the fate of a chemical and its degradation products, was developed for this purpose. An uncertainty analysis on the chemical-specific input parameters was performed to examine for uncertainty in modeled concentrations. In 2005, residual 8:2 FTOH made up 80% of the total contribution of FTacrylate use to PFO concentrations in global oceans, and residual PFOA in FTacrylate contributed 15% to PFO concentrations from FTacrylate use in global oceans. After hundreds of years, however, the main source of PFO from total historical FTacrylate production is predicted to be FTacrylate degrading in soil following land application of sludge from sewage treatment plants, followed by FTacrylate still present in landfills. Uncertainty in modeled PFO concentrations was up to a factor of 3.3. Current FTacrylate use contributes less than 1% of the PFO in seawater, but because direct PFOA emission sources are reduced and PFOA continues to be formed from FTacrylate in soil and in landfills, this fraction grows over time.

Perfluorinated acids, including perfluorinated carboxylates (PFCAs), and perfluorinated sulfonates (PFASs), are environmentally persistent and have been detected in a variety of wildlife across the globe. The most commonly detected PFAS, perfluorooctane sulfonate (PFOS), has been classified as a persistent and bioaccumulative substance. Similarities in chemical structure and environmental behavior of PFOS and the PFCAs that have been detected in wildlife have generated concerns about the bioaccumulation potential of PFCAs. Differences between partitioning behavior of perfluorinated acids and persistent lipophilic compounds complicate the understanding of PFCA bioaccumulation and the subsequent classification of the bioaccumulation potential of PFCAs according to existing regulatory criteria. Based on available research on the bioaccumulation of perfluorinated acids, five key points are highlighted in this review: (1) bioconcentration and bioaccumulation of perfluorinated acids are directly related to the length of each compound's fluorinated carbon chain; (2) PFASs are more bioaccumulative than PFCAs of the same fluorinated carbon chain length; (3) PFCAs with seven fluorinated carbons or less (perfluorooctanoate (PFO) and shorter PFCAs) are not considered bioaccumulative according to the range of promulgated bioaccumulation,"B", regulatory criteria of 1000-5000 L/kg; (4) PFCAs with seven fluorinated carbons or less have low biomagnification potential in food webs, and (5) more research is necessary to fully characterize the bioaccumulation potential of PFCAs with longer fluorinated carbon chains (>7 fluorinated carbons), as PFCAs with longer fluorinated carbon chains may exhibit partitioning behavior similar to or greater than PFOS. The bioaccumulation potential of perfluorinated acids with seven fluorinated carbons or less appears to be several orders of magnitude lower than "legacy" persistent lipophilic compounds classified as bioaccumulative. Thus, although many PFCAs are environmentally persistent and can be present at detectable concentrations in wildlife, it is clear that PFCAs with seven fluorinated carbons or less (including PFO) are not bioaccumulative according to regulatory criteria.

This study reports on an investigation of the presence of polyfluorinated chemicals in a spatially and temporally integrated set of biological samples representing an Arctic food web. Zooplankton, Arctic cod, and seal tissues from the western Canadian Arctic were analyzed for perfluoroalkyl sulfonates [PFAS], perfluorocarboxylates [PFCAs], and other polyfluorinated acids. Perfluorooctane sulfonate [PFOS] was found in all samples [0.20-34 ng/g] and in the highest concentrations. PFCAs from nine to 12 carbons were quantified in most of the samples [0.28-6.9 ng/g]. PFCAs with carbon chain lengths of eight or less were not detected. Likewise, 8-2 fluorotelomer acid [8-2 FTA] and 8-2 fluorotelomer unsaturated acid [8-2 FTUA], products of fluorotelomer environmental transformation, were not detected. 2H,2H,3H,3H, heptadecafluoro decanoic acid [7-3 Acid], an additional metabolite from fluorotelomer biological transformation, was detected only in seal liver tissue [0.5-2.5 ng/g]. The ratios of branched to linear PFOS isomers in fish and seal tissue were not similar and did not match that of technical PFOS as manufactured. No branched PFCA isomers were detected in any samples. It is concluded that differing pharmacokinetics complicate the use of branched to linear ratios of PFCAs in attributing their presence to a specific manufacturing process. A statistical analysis of the data revealed significant correlations between PFOS and the PFCAs detected as well as among the PFCAs themselves. The 7-3 Acid was not correlated with either PFCAs or PFAS, which suggests that it may have a different exposure pathway.

A high spatial and temporal resolution atmospheric model is used to evaluate the potential contribution of fluorotelomer alcohol (FTOH) and perfluorocarboxylate (PFCA) emissions associated with the manufacture, use, and disposal of DuPont fluorotelomer-based products in North America to air concentrations of FTOH, perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in North America and the Canadian Arctic. A bottom-up emission inventory for PFCAs and FTOHs was developed from sales and product composition data. A detailed FTOH atmospheric degradation mechanism was developed to simulate FTOH degradation to PFCAs and model atmospheric transport of PFCAs and FTOHs. Modeled PFCA yields from FTOH degradation agree with experimental smog-chamber results supporting the degradation mechanism used. Estimated PFCA and FTOH air concentrations and PFCA deposition fluxes are compared to monitoring data and previous global modeling. Predicted FTOH air concentrations are generally in agreement with available monitoring data. Overall emissions from the global fluorotelomer industry are estimated to contribute approximately 1-2% of the PFCAs in North American rainfall, consistent with previous global emissions estimates. Emission calculations and modeling results indicate that atmospheric inputs of PFCAs in North America from fluorotelomer-based products will decline by an order of magnitude in the near future as a result of current industry commitments to reduce manufacturing emissions and lower the residual fluorotelomer alcohol raw material and trace PFCA product content.

The potential for airborne emissions to undergo long-range transport or to be removed from the atmosphere is influenced by their physical-chemical properties. When perfluorooctanate (PFO) enters the environment, its physical-chemical properties can vary significantly, depending on whether it exists as an acid, a salt, or a dissociated ion. A summary of the physical-chemical properties of the three most likely environmental states: ammonium perfluorooctanoate (APFO), perfluorooctanoic acid (PFOA) and the dissociated perfluorooctanoate anion (PFO(-)) is presented to illustrate the distinct environmental properties of each. The most volatile species, PFOA, is shown to have a pH-dependent air-water partitioning coefficient (K(aw)). The variability of K(aw) with pH influences the potential for vapor formation from aqueous environments, including rain events. Using the pH-dependent K(aw) and measured rain and air concentrations, it is shown that vapor-phase PFOA is not likely to be present above measurable levels of 0.2 ng m(-3) (12 parts per quadrillion v/v) during a rain event. Because rain concentrations determined in this work are comparable to measurements in other parts of North America, it is unlikely that rain events are a significant source of vapor-phase PFOA for the general North American region. It is shown that PFOA exists primarily in the particle phase in ambient air near direct sources of emissions and is efficiently scavenged by rain droplets, making wet deposition an important removal mechanism for emissions originating as either PFOA or APFO. Washout ratios of particle-associated PFO were determined to range between 1 x 10(5) and 5 x 10(5), in the same range as other semi-volatile compounds for which wet deposition is an important mechanism for atmospheric removal and deposition onto soils and water bodies.

The long-term (1950-2050) global fate of perfluorooctanoate (PFO) is investigated using the global distribution model, GloboPOP. The model is used to test the hypotheses that direct PFO emissions can account for levels observed in the global oceans and that ocean water transport to the Arctic is an important global distribution pathway. The model emission scenarios are derived from historical and projected PFO emissions solely from direct sources. Modeled ocean water concentrations compare favorably to observed PFO concentrations in the world's oceans and thus ocean inventories can be accounted for by direct sources. The model results support the hypothesis that long-range ocean transport of PFO to the Arctic is important and estimate a net PFO influx of approximately 8-23 tons per year flowing into the model's Northern Polar zone in 2005, an amount at least 1 order of magnitude greater than estimated PFO flux to the Arctic from potential indirect sources such as atmospheric transport and degradation of fluorotelomer alcohols. Modeled doubling times of ocean water concentrations in the Arctic between 1975 and 2005 of approximately 7.5-10 years are in good agreement with doubling times of PFO in Arctic biota estimated from monitoring data. The model is further applied to predict future trends in PFO contamination levels using forecasted (2005-2050) direct emissions, including substantial reductions committed to by industry. Modeled ocean water concentrations in zones near to sources decline markedly after 2005, whereas modeled concentrations in the Arctic are predicted to continue to increase until approximately 2030 and show no significant decrease for the remaining 20 years of the model simulation. Since water is the primary exposure medium for Arctic biota, these model results suggest that concentrations in Arctic biota may continue to rise long after direct emissions have been substantially reduced or eliminated.