Binding of Per- and Polyfluoroalkyl Substances (PFAS) to Serum Proteins: Implications for Toxicokinetics in Humans.

Per- and polyfluoroalkyl substances (PFAS) are a diverse class of highly persistent anthropogenic chemicals that are detectable in the serum of most humans. PFAS exposure has been associated with many adverse effects on human health including immunotoxicity, increased risk of certain cancers, and metabolic disruption. PFAS binding to the most abundant blood serum proteins (human serum albumin [HSA] and globulins) is thought to affect transport to active sites, toxicity, and elimination half-lives. However, few studies have investigated the competitive binding of PFAS to these proteins in human serum. Here, we use C18 solid-phase microextraction fibers to measure HSA-water and globulin-water distribution coefficients (DHSA/w, Dglob/w) for PFAS with carbon chains containing 4 to 13 perfluorinated carbons (ηpfc = 4-13) and several functional head-groups. PFAS with ηpfc < 7 were highly bound to HSA relative to globulins, whereas PFAS with ηpfc ≥ 7 showed a greater propensity for binding to globulins. Experimentally measured DHSA/w and Dglob/w and concentrations of serum proteins successfully predicted the variability in PFAS binding in human serum. We estimated that the unbound fraction of serum PFAS varied by up to a factor of 2.5 among individuals participating in the 2017-2018 U.S. National Health and Nutrition Examination Survey. These results suggest that serum HSA and globulins are important covariates for epidemiological studies aimed at understanding the effects of PFAS exposure.

PFAS and Precursor Bioaccumulation in Freshwater Recreational Fish: Implications for Fish Advisories.

Per- and polyfluoroalkyl substances (PFAS) are a diverse class of fluorinated anthropogenic chemicals that include perfluoroalkyl acids (PFAA), which are widely used in modern commerce. Many products and environmental samples contain abundant precursors that can degrade into terminal PFAA associated with adverse health effects. Fish consumption is an important dietary exposure source for PFAS that bioaccumulate in food webs. However, little is known about bioaccumulation of PFAA precursors. Here, we identify and quantify PFAS in recreational fish species collected from surface waters across New Hampshire, US, using a toolbox of analytical methods. Targeted analysis of paired water and tissue samples suggests that many precursors below detection in water have a higher bioaccumulation potential than their terminal PFAA. Perfluorobutane sulfonamide (FBSA), a short-chain precursor produced by electrochemical fluorination, was detected in all fish samples analyzed for this compound. The total oxidizable precursor assay interpreted using Bayesian inference revealed fish muscle tissue contained additional, short-chain precursors in high concentration samples. Suspect screening analysis indicated these were perfluoroalkyl sulfonamide precursors with three and five perfluorinated carbons. Fish consumption advisories are primarily being developed for perfluorooctane sulfonate (PFOS), but this work reinforces the need for risk evaluations to consider additional bioaccumulative PFAS, including perfluoroalkyl sulfonamide precursors.

PFAS Exposure Pathways for Humans and Wildlife: A Synthesis of Current Knowledge and Key Gaps in Understanding.

We synthesize current understanding of the magnitudes and methods for assessing human and wildlife exposures to poly- and perfluoroalkyl substances (PFAS). Most human exposure assessments have focused on 2 to 5 legacy PFAS, and wildlife assessments are typically limited to targeted PFAS (up to ~30 substances). However, shifts in chemical production are occurring rapidly, and targeted methods for detecting PFAS have not kept pace with these changes. Total fluorine measurements complemented by suspect screening using high-resolution mass spectrometry are thus emerging as essential tools for PFAS exposure assessment. Such methods enable researchers to better understand contributions from precursor compounds that degrade into terminal perfluoroalkyl acids. Available data suggest that diet is the major human exposure pathway for some PFAS, but there is large variability across populations and PFAS compounds. Additional data on total fluorine in exposure media and the fraction of unidentified organofluorine are needed. Drinking water has been established as the major exposure source in contaminated communities. As water supplies are remediated, for the general population, exposures from dust, personal care products, indoor environments, and other sources may be more important. A major challenge for exposure assessments is the lack of statistically representative population surveys. For wildlife, bioaccumulation processes differ substantially between PFAS and neutral lipophilic organic compounds, prompting a reevaluation of traditional bioaccumulation metrics. There is evidence that both phospholipids and proteins are important for the tissue partitioning and accumulation of PFAS. New mechanistic models for PFAS bioaccumulation are being developed that will assist in wildlife risk evaluations. Environ Toxicol Chem 2021;40:631-657. © 2020 SETAC.

Selenium and stable mercury isotopes provide new insights into mercury toxicokinetics in pilot whales.

High exposures of mammalian species to inorganic mercury (HgII) and methylmercury (MeHg) have been associated with adverse effects on behavior and reproduction. Different mammalian species exhibit varying responses to similar external exposure levels, reflecting potential differences in Hg toxicokinetics. Here, we use Hg stable isotopes, total Hg, MeHg and selenium (Se) concentrations measured in multiple tissues of North Atlantic pilot whales (Globicephala melas) to investigate processes affecting the distribution and accumulation of HgII and MeHg. We find that simple mixing of two distinct isotopic end-members: MeHg (1.4‰) and HgII (-1.6‰) can explain the observed variability of δ202Hg in brain tissue. A similar isotopic composition for the MeHg end-member in the brain, muscle, heart, and kidney suggests efficient exchange of MeHg in blood throughout the body. By contrast, the Hg isotopic composition of the liver of adult whales is different from younger whales and other tissues that follow the two-end member mixing model. Measured Se:Hg ratios are lowest in adult whales with the highest levels of MeHg exposure. In these individuals, Se availability is likely reduced by complexation with demethylated HgII. We speculate that this results in a higher fraction of labile HgII eliminated from the liver of adult whales compared to young whales and subsequent redistribution to other tissues, potentially affecting toxicity.

Climate change and overfishing increase neurotoxicant in marine predators.

More than three billion people rely on seafood for nutrition. However, fish are the predominant source of human exposure to methylmercury (MeHg), a potent neurotoxic substance. In the United States, 82% of population-wide exposure to MeHg is from the consumption of marine seafood and almost 40% is from fresh and canned tuna alone1. Around 80% of the inorganic mercury (Hg) that is emitted to the atmosphere from natural and human sources is deposited in the ocean2, where some is converted by microorganisms to MeHg. In predatory fish, environmental MeHg concentrations are amplified by a million times or more. Human exposure to MeHg has been associated with long-term neurocognitive deficits in children that persist into adulthood, with global costs to society that exceed US$20 billion3. The first global treaty on reductions in anthropogenic Hg emissions (the Minamata Convention on Mercury) entered into force in 2017. However, effects of ongoing changes in marine ecosystems on bioaccumulation of MeHg in marine predators that are frequently consumed by humans (for example, tuna, cod and swordfish) have not been considered when setting global policy targets. Here we use more than 30 years of data and ecosystem modelling to show that MeHg concentrations in Atlantic cod (Gadus morhua) increased by up to 23% between the 1970s and 2000s as a result of dietary shifts initiated by overfishing. Our model also predicts an estimated 56% increase in tissue MeHg concentrations in Atlantic bluefin tuna (Thunnus thynnus) due to increases in seawater temperature between a low point in 1969 and recent peak levels-which is consistent with 2017 observations. This estimated increase in tissue MeHg exceeds the modelled 22% reduction that was achieved in the late 1990s and 2000s as a result of decreased seawater MeHg concentrations. The recently reported plateau in global anthropogenic Hg emissions4 suggests that ocean warming and fisheries management programmes will be major drivers of future MeHg concentrations in marine predators.

Phospholipid Levels Predict the Tissue Distribution of Poly- and Perfluoroalkyl Substances in a Marine Mammal.

Exposure to poly- and perfluoroalkyl substances (PFASs) has been linked to many negative health impacts in humans and wildlife. Unlike neutral hydrophobic organic pollutants, many PFASs are ionic and have been hypothesized to accumulate in both phospholipids and protein-rich tissues. Here we investigate the role of phospholipids for PFAS accumulation by analyzing associations among concurrent measurements of phospholipid, total protein, total lipid and 24 PFASs in the heart, muscle, brain, kidney, liver, blubber, placenta and spleen of North Atlantic pilot whales (Globicephala melas). The sum of 24 PFASs ( ∑ 24 PFAS ) was highest in the liver (median 260 ng g-1; interquartile range (IQR) 216-295 ng g-1) and brain (86.0; IQR 54.5-91.3 ng g-1), while phospholipid levels were highest in brain. The relative abundance of PFASs in the brain greatly increases with carbon chain lengths of 10 or greater, suggesting shorter-chained compounds may cross the blood-brain barrier less efficiently. Phospholipids were significant predictors of the tissue distribution of the longest-chained PFASs: perfluorodecanesulfonate (PFDS), perfluorododecanoate (PFDoA), perfluorotridecanoate (PFTrA), and perfluorotetradecanoic acid (PFTA) (rs = 0.5-0.6). In all tissues except the brain, each 1 mg g-1 increase in phospholipids led to a 12%-25% increase in the concentration of each PFAS. We conclude that partitioning to phospholipids is an important mechanism of bioaccumulation for long-chained PFASs in marine mammals.

A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects.

Here, we review present understanding of sources and trends in human exposure to poly- and perfluoroalkyl substances (PFASs) and epidemiologic evidence for impacts on cancer, immune function, metabolic outcomes, and neurodevelopment. More than 4000 PFASs have been manufactured by humans and hundreds have been detected in environmental samples. Direct exposures due to use in products can be quickly phased out by shifts in chemical production but exposures driven by PFAS accumulation in the ocean and marine food chains and contamination of groundwater persist over long timescales. Serum concentrations of legacy PFASs in humans are declining globally but total exposures to newer PFASs and precursor compounds have not been well characterized. Human exposures to legacy PFASs from seafood and drinking water are stable or increasing in many regions, suggesting observed declines reflect phase-outs in legacy PFAS use in consumer products. Many regions globally are continuing to discover PFAS contaminated sites from aqueous film forming foam (AFFF) use, particularly next to airports and military bases. Exposures from food packaging and indoor environments are uncertain due to a rapidly changing chemical landscape where legacy PFASs have been replaced by diverse precursors and custom molecules that are difficult to detect. Multiple studies find significant associations between PFAS exposure and adverse immune outcomes in children. Dyslipidemia is the strongest metabolic outcome associated with PFAS exposure. Evidence for cancer is limited to manufacturing locations with extremely high exposures and insufficient data are available to characterize impacts of PFAS exposures on neurodevelopment. Preliminary evidence suggests significant health effects associated with exposures to emerging PFASs. Lessons learned from legacy PFASs indicate that limited data should not be used as a justification to delay risk mitigation actions for replacement PFASs.

Shifting Global Exposures to Poly- and Perfluoroalkyl Substances (PFASs) Evident in Longitudinal Birth Cohorts from a Seafood-Consuming Population.

Rapid declines in legacy poly- and perfluoroalkyl substances (PFASs) have been reported in human populations globally following changes in production since 2000. However, changes in exposure sources are not well understood. Here, we report serum concentrations of 19 PFASs (∑19PFAS) measured in children between 1993 and 2012 from a North Atlantic fishing community (Faroe Islands). Median ∑19PFAS concentrations in children (ages 5-13 years) peaked in 2000 (47.7 ng mL-1) and declined significantly by 14.4% year-1 until 2012. Principal component analysis (PCA) identified two groups of PFASs that likely reflect exposures from diverse consumer products and a third group that consisted of perfluorocarboxylic acids (PFCAs) with nine or more carbons (C ≥ 9). These C ≥ 9 PFASs are strongly associated with mercury in children's hair, a well-established proxy for seafood consumption, especially perfluoroundecanoic acid (PFUnDA, r = 0.72). Toxicokinetic modeling shows PFAS exposures from seafood have become increasingly important (53% of perfluorooctanesulfonate, PFOS, in 2012), despite a decline in whale consumption in recent years. We infer that even in a major seafood-consuming population, declines in legacy PFAS exposure after 2000 were achieved by the rapid phase out of PFOS and its precursors in consumer products. These results emphasize the importance of better understanding exposures to replacement PFASs in these sources.

Can profiles of poly- and Perfluoroalkyl substances (PFASs) in human serum provide information on major exposure sources?

BACKGROUND: Humans are exposed to poly- and perfluoroalkyl substances (PFASs) from diverse sources and this has been associated with negative health impacts. Advances in analytical methods have enabled routine detection of more than 15 PFASs in human sera, allowing better profiling of PFAS exposures. The composition of PFASs in human sera reflects the complexity of exposure sources but source identification can be confounded by differences in toxicokinetics affecting uptake, distribution, and elimination. Common PFASs, such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and their precursors are ubiquitous in multiple exposure sources. However, their composition varies among sources, which may impact associated adverse health effects. METHODS: We use available PFAS concentrations from several demographic groups in a North Atlantic seafood consuming population (Faroe Islands) to explore whether chemical fingerprints in human sera provide insights into predominant exposure sources. We compare serum PFAS profiles from Faroese individuals to other North American populations to investigate commonalities in potential exposure sources. We compare individuals with similar demographic and physiological characteristics and samples from the same years to reduce confounding by toxicokinetic differences and changing environmental releases. RESULTS: Using principal components analysis (PCA) confirmed by hierarchical clustering, we assess variability in serum PFAS concentrations across three Faroese groups. The first principal component (PC)/cluster consists of C9-C12 perfluoroalkyl carboxylates (PFCAs) and is consistent with measured PFAS profiles in consumed seafood. The second PC/cluster includes perfluorohexanesulfonic acid (PFHxS) and the PFOS precursor N-ethyl perfluorooctane sulfonamidoacetate (N-EtFOSAA), which are directly used or metabolized from fluorochemicals in consumer products such as carpet and food packaging. We find that the same compounds are associated with the same exposure sources in two North American populations, suggesting generalizability of results from the Faroese population. CONCLUSIONS: We conclude that PFAS homologue profiles in serum provide valuable information on major exposure sources. It is essential to compare samples collected at similar time periods and to correct for demographic groups that are highly affected by differences in physiological processes (e.g., pregnancy). Information on PFAS homologue profiles is crucial for attributing adverse health effects to the proper mixtures or individual PFASs.

A Model for Methylmercury Uptake and Trophic Transfer by Marine Plankton.

Methylmercury (MeHg) concentrations can increase by 100 000 times between seawater and marine phytoplankton, but levels vary across sites. To better understand how ecosystem properties affect variability in planktonic MeHg concentrations, we develop a model for MeHg uptake and trophic transfer at the base of marine food webs. The model successfully reproduces measured concentrations in phytoplankton and zooplankton across diverse sites from the Northwest Atlantic Ocean. Highest MeHg concentrations in phytoplankton are simulated under low dissolved organic carbon (DOC) concentrations and ultraoligotrophic conditions typical of open ocean regions. This occurs because large organic complexes bound to MeHg inhibit cellular uptake and cell surface area to volume ratios are greatest under low productivity conditions. Modeled bioaccumulation factors for phytoplankton (102.4-105.9) are more variable than those for zooplankton (104.6-106.2) across ranges in DOC (40-500 µM) and productivities (ultraoligotrophic to hypereutrophic) typically found in marine ecosystems. Zooplankton growth dilutes their MeHg body burden, but they also consume greater quantities of MeHg enriched prey at larger sizes. These competing processes lead to lower variability in MeHg concentrations in zooplankton compared to phytoplankton. Even under hypereutrophic conditions, modeled growth dilution in marine zooplankton is insufficient to lower their MeHg concentrations, contrasting findings from freshwater ecosystems.

Vertical Profiles, Sources, and Transport of PFASs in the Arctic Ocean.

The relative importance of atmospheric versus oceanic transport for poly- and perfluorinated alkyl substances (PFASs) reaching the Arctic Ocean is not well understood. Vertical profiles from the Central Arctic Ocean and shelf water, snow and meltwater samples were collected in 2012; 13 PFASs (C6-C12 PFCAs; C6, 8, 10 PFSAs; MeFOSAA and EtFOSAA; and FOSA) were routinely detected (range: <5-343 pg/L). PFASs were only detectable above 150 m depth in the polar mixed layer (PML) and halocline. Enhanced concentrations were observed in snow and meltpond samples, implying atmospheric deposition as an important source of PFASs. Model results suggested atmospheric inputs to account for 34-59% (∼11-19 pg/L) of measured PFOA concentrations in the PML (mean 32 ± 15 pg/L). Modeled surface and halocline measurements for PFOS based on North Atlantic inflow (11-36 pg/L) agreed with measurements (mean, 17, range <5-41 pg/L). Modeled deep water concentrations below 200 m (5-15 pg/L) were slightly higher than measurements (<5 pg/L), suggesting the lower bound of PFAS emissions estimates from wastewater and rivers may provide the best estimate of inputs to the Arctic. Despite low concentrations in deep water, this reservoir is expected to contain most of the PFOS mass in the Arctic (63-180 Mg) and is projected to continue increasing to 2038.

Temporal Shifts in Poly- and Perfluoroalkyl Substances (PFASs) in North Atlantic Pilot Whales Indicate Large Contribution of Atmospheric Precursors.

Poly- and perfluoroalkyl substances (PFASs) are persistent, bioaccumulative anthropogenic compounds associated with adverse health impacts on humans and wildlife. PFAS production changed in North America and Europe around the year 2000, but impacts on wildlife appear to vary across species and location. Unlike other mammal species, cetaceans lack the enzyme for transforming an important intermediate precursor (perfluorooctane sulfonamide: FOSA), into a prevalent compound in most wildlife (perfluorooctanesulfonate: PFOS). Thus, their tissue burden differentiates these two compounds while other mammals contain PFOS from both direct exposure and precursor degradation. Here we report temporal trends in 15 PFASs measured in muscle from juvenile male North Atlantic pilot whales (Globicephala melas) harvested between 1986 and 2013. FOSA accounted for a peak of 84% of the 15 PFASs around 2000 but declined to 34% in recent years. PFOS and long-chained PFCAs (C9-C13) increased significantly over the whole period (2.8% yr-1 to 8.3% yr-1), but FOSA declined by 13% yr-1 after 2006. Results from FOSA partitioning and bioaccumulation modeling forced by changes in atmospheric inputs reasonably capture magnitudes and temporal patterns in FOSA concentrations measured in pilot whales. Rapid changes in atmospheric FOSA in polar and subpolar regions around 2000 helps to explain large declines in PFOS exposure for species that metabolize FOSA, including seafood consuming human populations. This work reinforces the importance of accounting for biological exposures to PFAS precursors.

Source attribution of poly- and perfluoroalkyl substances (PFASs) in surface waters from Rhode Island and the New York Metropolitan Area.

Exposure to poly and perfluoroalkyl substances (PFASs) has been associated with adverse health effects in humans and wildlife. Understanding pollution sources is essential for environmental regulation but source attribution for PFASs has been confounded by limited information on industrial releases and rapid changes in chemical production. Here we use principal component analysis (PCA), hierarchical clustering, and geospatial analysis to understand source contributions to 14 PFASs measured across 37 sites in the Northeastern United States in 2014. PFASs are significantly elevated in urban areas compared to rural sites except for perfluorobutane sulfonate (PFBS), N-methyl perfluorooctanesulfonamidoacetic acid (N-MeFOSAA), perfluoroundecanate (PFUnDA) and perfluorododecanate (PFDoDA). The highest PFAS concentrations across sites were for perfluorooctanate (PFOA, 56 ng L-1) and perfluorohexane sulfonate (PFOS, 43 ng L-1) and PFOS levels are lower than earlier measurements of U.S. surface waters. PCA and cluster analysis indicates three main statistical groupings of PFASs. Geospatial analysis of watersheds reveals the first component/cluster originates from a mixture of contemporary point sources such as airports and textile mills. Atmospheric sources from the waste sector are consistent with the second component, and the metal smelting industry plausibly explains the third component. We find this source-attribution technique is effective for better understanding PFAS sources in urban areas.