The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluoroalkyl substances (PFASs) in food. Based on several similar effects in animals, toxicokinetics and observed concentrations in human blood, the CONTAM Panel decided to perform the assessment for the sum of four PFASs: PFOA, PFNA, PFHxS and PFOS. These made up half of the lower bound (LB) exposure to those PFASs with available occurrence data, the remaining contribution being primarily from PFASs with short half‐lives. Equal potencies were assumed for the four PFASs included in the assessment. The mean LB exposure in adolescents and adult age groups ranged from 3 to 22, the 95th percentile from 9 to 70 ng/kg body weight (bw) per week. Toddlers and ‘other children’ showed a twofold higher exposure. Upper bound exposure was 4‐ to 49‐fold higher than LB levels, but the latter were considered more reliable. ‘Fish meat’, ‘Fruit and fruit products’ and ‘Eggs and egg products’ contributed most to the exposure. Based on available studies in animals and humans, effects on the immune system were considered the most critical for the risk assessment. From a human study, a lowest BMDL 10 of 17.5 ng/mL for the sum of the four PFASs in serum was identified for 1‐year‐old children. Using PBPK modelling, this serum level of 17.5 ng/mL in children was estimated to correspond to long‐term maternal exposure of 0.63 ng/kg bw per day. Since accumulation over time is important, a tolerable weekly intake (TWI) of 4.4 ng/kg bw per week was established. This TWI also protects against other potential adverse effects observed in humans. Based on the estimated LB exposure, but also reported serum levels, the CONTAM Panel concluded that parts of the European population exceed this TWI, which is of concern.

Risk to human health related to the presence of perfluoroalkyl substances in food

Accumulation of perfluorinated alkyl substances (PFAS) in agricultural plants : A review

Here, we report on the occurrence of a novel perfluoroalkyl ether carboxylic acid, ammonium perfluoro-2-[(propoxy)propoxy]-1-propanoate (HFPO-TA), in surface water and common carp (Cyprinus carpio) collected from the Xiaoqing River and in residents residing near a fluoropolymer production plant in Huantai County, China. Compared with the levels upstream of the Xiaoqing River, HFPO-TA concentrations (5200–68500 ng/L) were approximately 120–1600-times higher downstream after receiving fluoropolymer plant effluent from a tributary. The riverine discharge of HFPO-TA was estimated to be 4.6 t/yr, accounting for 22% of total PFAS discharge. In the wild common carp collected downstream from the point source, HFPO-TA was detected in the blood (median: 1510 ng/mL), liver (587 ng/g ww), and muscle (118 ng/g ww). The log BCFblood of HFPO-TA (2.18) was significantly higher than that of PFOA (1.93). Detectable levels of HFPO-TA were also found in the sera of residents (median: 2.93 ng/mL). This is the first report on ...

First Report on the Occurrence and Bioaccumulation of Hexafluoropropylene Oxide Trimer Acid: An Emerging Concern

Although shorter chain homologues and other types of fluorinated chemicals are currently used as alternatives to long-chain perfluoroalkyl substances (PFASs), their safety information remains unclear and urgently needed. Here, the cytotoxicity of several fluorinated alternatives (i.e., 6:2 fluorotelomer carboxylic acid (6:2 FTCA), 6:2 fluorotelomer sulfonic acid (6:2 FTSA), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), and hexafluoropropylene oxide (HFPO) homologues) to human liver HL-7702 cell line were measured and compared with perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Their binding mode and affinity to human liver fatty acid binding protein (hL-FABP) were also determined. Compared with PFOA and PFOS, 6:2 Cl-PFESA, HFPO trimer acid (HFPO-TA), HFPO tetramer acid (HFPO-TeA), and 6:2 FTSA showed greater toxic effects on cell viabilities. At low exposure doses, these alternatives induced cell proliferation with similar mechanism which was different from that of PFOA and PFOS. Furthermore, binding affinity to hL-FABP decreased in the order of 6:2 FTCA < 6:2 FTSA < HFPO dimer acid (HFPO-DA) < PFOA < PFOS/6:2 Cl-PFESA/HFPO-TA. Due to their distinctive structure, 6:2 Cl-PFESA and HFPO homologues were bound to the hL-FABP inner pocket with unique binding modes and higher binding energy compared with PFOA and PFOS. This research enhances our understanding of the toxicity of PFAS alternatives during usage and provides useful evidence for the development of new alternatives.

Cytotoxicity of novel fluorinated alternatives to long-chain perfluoroalkyl substances to human liver cell line and their binding capacity to human liver fatty acid binding protein

Grouping strategies are needed for per- and polyfluoroalkyl substances (PFAS), in part, because it would be time and resource intensive to test and evaluate the more than 4700 PFAS on the global market on a chemical-by-chemical basis. In this paper we review various grouping strategies that could be used to inform actions on these chemicals and outline the motivations, advantages and disadvantages for each. Grouping strategies are subdivided into (1) those based on the intrinsic properties of the PFAS (e.g. persistence, bioaccumulation potential, toxicity, mobility, molecular size) and (2) those that inform risk assessment through estimation of cumulative exposure and/or effects. The most precautionary grouping approach of those reviewed within this article suggests phasing out PFAS based on their high persistence alone (the so-called "P-sufficient" approach). The least precautionary grouping approach reviewed advocates only grouping PFAS for risk assessment that have the same toxicological effects, modes and mechanisms of action, and elimination kinetics, which would need to be well documented across different PFAS. It is recognised that, given jurisdictional differences in chemical assessment philosophies and methodologies, no one strategy will be generally acceptable. The guiding question we apply to the reviewed grouping strategies is: grouping for what purpose? The motivation behind the grouping (e.g. determining use in products vs. setting guideline levels for contaminated environments) may lead to different grouping decisions. This assessment provides the necessary context for grouping strategies such that they can be adopted as they are, or built on further, to protect human and environmental health from potential PFAS-related effects.

/pdf/strategies-for-grouping-per-and-polyfluoroalkyl-substances-2uibx3gkca.pdf

Strategies for grouping per- and polyfluoroalkyl substances (PFAS) to protect human and environmental health

Perfluoroalkyl acids (PFAAs) are highly persistent and bioaccumulative, resulting in their broad distribution in humans and the environment. The liver is an important target for PFAAs, but the mechanisms behind PFAAs interaction with hepatocyte proteins remain poorly understood. We characterized the binding of PFAAs to human liver fatty acid-binding protein (hL-FABP) and identified critical structural features in their interaction. The binding interaction of PFAAs with hL-FABP was determined by fluorescence displacement and isothermal titration calorimetry (ITC) assay. Molecular simulation was conducted to define interactions at the binding sites. ITC measurement revealed that PFOA/PFNA displayed a moderate affinity for hL-FABP at a 1:1 molar ratio, a weak binding affinity for PFHxS and no binding for PFHxA. Moreover, the interaction was mainly mediated by electrostatic attraction and hydrogen bonding. Substitution of Asn111 with Asp caused loss of binding affinity to PFAA, indicating its crucial role for the initial PFAA binding to the outer binding site. Substitution of Arg122 with Gly caused only one molecule of PFAA to bind to hL-FABP. Molecular simulation showed that substitution of Arg122 increased the volume of the outer binding pocket, making it impossible to form intensive hydrophobic stacking and hydrogen bonds with PFOA, and highlighting its crucial role in the binding process. The binding affinity of PFAAs increased significantly with their carbon number. Arg122 and Asn111 played a pivotal role in these interactions. Our findings may help understand the distribution pattern, bioaccumulation, elimination, and toxicity of PFAAs in humans.

/pdf/interaction-of-perfluoroalkyl-acids-with-human-liver-fatty-1in2ydosz7.pdf

Interaction of perfluoroalkyl acids with human liver fatty acid-binding protein

Perfluorononanoic acid (PFNA) is a nine-carbon perfluoroalkyl acid widely used in industrial and domestic products. It is a persistent organic pollutant found in the environment as well as in the tissues of humans and wildlife. There is a concern that this chemical might be a developmental toxicant and teratogen in various ecosystems. In the present study, the toxic effects of PFNA were evaluated in zebrafish (Danio rerio) embryos. One hour post-fertilization embryos were treated with 0, 25, 50, 100, 200, 300, 350, and 400 μmol/L PFNA for 96 hr in 6-well plates. Developmental phenotypes and hatching rates were observed and recorded. Nineteen genes related to oxidative stress and lipid metabolism were examined using Quantitative RT-PCR and confirmed by whole mount in situ hybridization (WISH). Results showed that PFNA delayed the development of zebrafish embryos, reduced the hatching rate, and caused ventricular edema and malformation of the spine. In addition, the amount of reactive oxygen species in the embryo bodies increased significantly after exposure to PFNA compared with that of the control group. The Quantitative RT-PCR and WISH experiments demonstrated that mRNA expression of the lfabp and ucp2 genes increased significantly while that of sod1 and mt-nd1 decreased significantly after PFNA exposure. The mRNA expression levels of gpx1 and mt-atp6 decreased significantly in the high concentration group. However, the mRNA expression levels of both ppara and pparg did not show any significant variation after exposure. These findings suggest that PFNA affected the development of zebrafish embryos at relatively low concentrations.

/pdf/toxic-effects-of-perfluorononanoic-acid-on-the-development-12mr0sby0e.pdf

Toxic effects of perfluorononanoic acid on the development of Zebrafish (Danio rerio) embryos.

Liver cancer is a malignant cancer phenotype for which there currently remains a lack of reliable biomarkers and therapeutic targets for disease management. Tryptophan 2,3‑dioxygenase (TDO2), a heme‑containing polyoxygenase enzyme, is primarily expressed in cells of the liver and nervous systems. In the present study, through the combination of cancer bioinformatics and analysis of clinical patient samples, it was shown that TDO2 expression in liver cancer tissue samples was significantly higher than that in normal tissues, and liver cancer patients with high TDO2 expression had a poor prognosis. Mechanistic studies on liver cancer cells showed that TDO2 promoted cancer cell migration and invasion via signal transduction through the Wnt5a pathway. Such regulation impacted the expression of cancer‑associated biomarkers, such as matrix metalloprotease 7 (MMP7) and the cell adhesion receptor CD44. Treatment with a calcium channel blocker (azelnidipine) reduced TDO2 levels and inhibited liver cancer cell migration and invasion. A mouse xenograft cancer model showed that TDO2 promoted tumorigenesis. Furthermore, azelnidipine treatment to downregulate TDO2 also decreased liver cancer development in this mouse cancer model. TDO2 is thus not only a useful liver cancer biomarker but a potential drug target for management of liver cancer.

TDO2 modulates liver cancer cell migration and invasion via the Wnt5a pathway.

Acot1 is a sensitive indicator for PPARα activation after perfluorooctanoic acid exposure in primary hepatocytes of Sprague-Dawley rats.

lncRNA IGF2-AS regulates miR-500a-3p/PPP4R1/p-VEGFR2 signalling pathway to promote thyroid carcinoma progression and tubulogenesis.

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