An in vitro-in silico workflow for predicting renal clearance of PFAS.

Per- and poly-fluoroalkyl substances (PFAS) have a wide range of elimination half-lives (days to years) in humans, thought to be in part due to variation in proximal tubule reabsorption. While human biomonitoring studies provide important data for some PFAS, renal clearance (CLrenal) predictions for hundreds of PFAS in commerce requires experimental studies with in vitro models and physiologically-based in vitro-to-in vivo extrapolation (IVIVE). Options for studying renal proximal tubule pharmacokinetics include cultures of renal proximal tubule epithelial cells (RPTECs) and/or microphysiological systems. This study aimed to compare CLrenal predictions for PFAS using in vitro models of varying complexity (96-well plates, static 24-well Transwells and a fluidic microphysiological model, all using human telomerase reverse transcriptase-immortalized and OAT1-overexpressing RPTECs combined with in silico physiologically-based IVIVE. Three PFAS were tested: one with a long half-life (PFOS) and two with shorter half-lives (PFHxA and PFBS). PFAS were added either individually (5 µM) or as a mixture (2 µM of each substance) for 48 h. Bayesian methods were used to fit concentrations measured in media and cells to a three-compartmental model to obtain the in vitro permeability rates, which were then used as inputs for a physiologically-based IVIVE model to estimate in vivo CLrenal. Our predictions for human CLrenal of PFAS were highly concordant with available values from in vivo human studies. The relative values of CLrenal between slow- and faster-clearance PFAS were most highly concordant between predictions from 2D culture and corresponding in vivo values. However, the predictions from the more complex model (with or without flow) exhibited greater concordance with absolute CLrenal. Overall, we conclude that a combined in vitro-in silico workflow can predict absolute CLrenal values, and effectively distinguish between PFAS with slow and faster clearance, thereby allowing prioritization of PFAS with a greater potential for bioaccumulation in humans.

Occurrence of Major Perfluorinated Alkylate Substances in Human Blood and Target Organs.

Human exposure to perfluorinated alkylate substances (PFASs) is usually assessed from the concentrations in serum or plasma, assuming one-compartment toxicokinetics. To characterize body distributions of major PFASs, we obtained and extracted tissue samples from 19 forensic autopsies of healthy adult subjects who had died suddenly and were not known to have elevated levels of PFAS exposure. As target organs of toxicological importance, we selected the liver, kidneys, lungs, spleen, and brain, as well as whole blood. Samples weighing about 0.1 g were analyzed by liquid chromatography coupled to triple mass spectrometers. Minor variations in PFAS concentrations were found between the kidney cortex and medulla and between lung lobes. Organ concentrations of perfluorooctanoic sulfonate (PFOS) and perfluorononanoate (PFNA) correlated well with blood concentrations, while perfluorooctanoate (PFOA) and perfluorohexanoic sulfonate (PFHxS) showed more variable associations. Likewise, the liver concentrations correlated well with those of other organs. Calculations of relative distributions were carried out to assess the interdependence of organ retentions. Equilibrium model predictions largely explained the observed PFAS distributions, except for the brain. Although the samples were small and affected by a possible lack of homogeneity, these findings support the use of blood-PFAS concentrations as a measure of PFAS exposure, with the liver possibly acting as the main organ of retention.

Predicting PFAS fate in fish: Assessing the roles of dietary, respiratory, and dermal uptake in bioaccumulation modeling.

An increasing number of per- and polyfluoroalkyl substances (PFAS) exposed to the environment may pose a threat to organisms and human beings. However, there is a lack of simulations comprehensively addressing and comparing the bioaccumulation of PFAS across all three major exposure routes (oral, inhalation, and dermal), especially for dermal uptake. In this study, we proposed a physiologically based kinetic (PBK) model for PFAS, aiming to predict bioaccumulation factors (BAF) in fish by considering these diverse exposure routes. 15 PFAS were used for model validation, and 11 PFAS from Taihu Lake were used for exposure contribution modeling. Approximately 64% of estimations fell within 10-fold model bias from measurements in Taihu Lake, underscoring the potential efficacy of the developed PBK model in predicting BAFs for fish. The dermal route emerges as a contributor to short-chain PFAS exposure. For example, it ranged widely from 46% to 75% (mean) for all modeling short-chain PFAS (C6-C7) in Taihu Lake. It indicated the criticality of considering dermal exposure for PFAS in fish, highlighting a gap in field studies to unravel cutaneous intake mechanisms and contributions. For longer carbon chains of PFAS (C8-C12), dermal exposure accounted for 2%-27% for all species of aquatic organisms. The fish's lipid fraction and water content played a significant role in the contribution of PFAS intake through cutaneous exposure and inhalation. Kow had a significant positive correlation with skin intake rate (p < 0.05) and gill intake rate (p < 0.001), while having a significant negative correlation with skin intake (p < 0.05) and skin intake contribution (p < 0.001). Based on the proposed modeling approach, we have introduced a simulation spreadsheet for projecting PFAS BAFs in fish tissues, hopefully broadening the predictive operational tool for a variety of chemical species.

Acoustic Activation Imaging With Intravenous Perfluoropropane Nanodroplets Results in Selective Bioactivation of the Risk Area.

BACKGROUND: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within myocardial infarct zones (IZ). OBJECTIVE: We hypothesized that the AA area following acute coronary ischemia/reperfusion (I/R) would selectively enhance the developing scar zone, and target bioeffects specifically to this region. METHODS: We administered intravenous PD in 36 rats and 20 pigs at various stages of myocardial scar formation (30 minutes, 1 day, and 7 days post I/R) to determine what effect infarct age had on the AA within the IZ. This was correlated with histology, myeloperoxidase activity, and tissue nitrite activity. RESULTS: The degree of AA within the IZ in rats was not associated with collagen content, neutrophil infiltration, or infarct age. AA within 24 hours of I/R was associated with increased nitric oxide utilization selectively within the IZ (P < .05 compared with remote zone). The spatial extent of AA in pigs correlated with infarct size only when performed before sacrifice at 7 days (r = .74, P < .01). CONCLUSIONS: Acoustic activation of intravenous PD enhances the developing scar zone following I/R, and results in selective tissue nitric oxide utilization.

Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans.

Perfluorooctanoic acid (PFOA) is an environmental toxicant exhibiting a years-long biological half-life (t1/2) in humans and is linked with adverse health effects. However, limited understanding of its toxicokinetics (TK) has obstructed the necessary risk assessment. Here, we constructed the first middle-out physiologically based toxicokinetic (PBTK) model to mechanistically explain the persistence of PFOA in humans. In vitro transporter kinetics were thoroughly characterized and scaled up to in vivo clearances using quantitative proteomics-based in vitro-to-in vivo extrapolation. These data and physicochemical parameters of PFOA were used to parameterize our model. We uncovered a novel uptake transporter for PFOA, highly likely to be monocarboxylate transporter 1 which is ubiquitously expressed in body tissues and may mediate broad tissue penetration. Our model was able to recapitulate clinical data from a phase I dose-escalation trial and divergent half-lives from clinical trial and biomonitoring studies. Simulations and sensitivity analyses confirmed the importance of renal transporters in driving extensive PFOA reabsorption, reducing its clearance and augmenting its t1/2. Crucially, the inclusion of a hypothetical, saturable renal basolateral efflux transporter provided the first unified explanation for the divergent t1/2 of PFOA reported in clinical (116 days) versus biomonitoring studies (1.3-3.9 years). Efforts are underway to build PBTK models for other perfluoroalkyl substances using similar workflows to assess their TK profiles and facilitate risk assessments.

Physiologically based pharmacokinetic (PBPK) modeling of perfluorohexane sulfonate (PFHxS) in humans.

Per- and polyfluoroalkyl substances (PFAS) are persistent, man-made compounds prevalent in the environment and consistently identified in human biomonitoring samples. In particular, perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS) have been identified at U.S. Air Force installations. The study of human toxicokinetics and physiologically based pharmacokinetic (PBPK) modeling of PFHxS has been less robust and has been limited in scope and application as compared to PFOS and PFOA. The primary goal of the current effort was to develop a PBPK model describing PFHxS disposition in humans that can be applied to retrospective, current, and future human health risk assessment of PFHxS. An existing model developed for PFOS and PFOA was modified and key parameter values for exposure and toxicokinetics were calibrated for PFHxS prediction based on human biomonitoring data, particularly general population serum levels from the U.S. Centers for Disease Prevention and Control (CDC) National Health and Nutrition Examination Survey (NHANES). Agreement between the model and the calibration and evaluation data was excellent and recapitulated observed trends across sex, age, and calendar years. Confidence in the model is greatest for application to adults in the 2000-2018 time frame and for shorter-term future projections.

Reproducibility of 19 F-MR ventilation imaging in healthy volunteers.

PURPOSE: To assess the reproducibility of percentage ventilated lung volume (%VV) measurements in healthy volunteers acquired by fluorine (19 F)-MRI of inhaled perfluoropropane, implemented at two research sites. METHODS: In this prospective, ethically approved study, 40 healthy participants were recruited (May 2018-June 2019) to one of two research sites. Participants underwent a single MRI scan session on a 3T scanner, involving periodic inhalation of a 79% perfluoropropane/21% oxygen gas mixture. Each gas inhalation session lasted about 30 seconds, consisting of three deep breaths of gas followed by a breath-hold. Four 19 F-MR ventilation images were acquired per participant, each separated by approximately 6 minutes. The value of %VV was determined by registering separately acquired 1 H images to ventilation images before semi-automated image segmentation, performed independently by two observers. Reproducibility of %VV measurements was assessed by components of variance, intraclass correlation coefficients, coefficients of variation (CoV), and the Dice similarity coefficient. RESULTS: The MRI scans were well tolerated throughout, with no adverse events. There was a high degree of consistency in %VV measurements for each participant (CoVobserver1 = 0.43%; CoVobserver2 = 0.63%), with overall precision of %VV measurements determined to be within ± 1.7% (95% confidence interval). Interobserver agreement in %VV measurements revealed a high mean Dice similarity coefficient (SD) of 0.97 (0.02), with only minor discrepancies between observers. CONCLUSION: We demonstrate good reproducibility of %VV measurements in a group of healthy participants using 19 F-MRI of inhaled perfluoropropane. Our methods have been successfully implemented across two different study sites, supporting the feasibility of performing larger multicenter clinical studies.

Bayesian Refinement of the Permeability-Limited Physiologically Based Pharmacokinetic Model for Perfluorooctanoic Acid in Male Rats.

Physiologically based pharmacokinetic (PBPK) modeling is a powerful technique to inform risk assessment of xenobiotic substances such as perfluorooctanoic acid (PFOA). In our previous study, a permeability-limited PBPK model was developed to simulate the toxicokinetics and tissue distribution of PFOA in male rats. However, due to limited information on some key model parameters (e.g., protein binding and active transport rates), the uncertainty of the permeability-limited PBPK model was quite high. To address this issue, a hierarchical Bayesian analysis with Markov chain Monte Carlo (MCMC) was applied to reduce the uncertainty of parameters and improve the performance of the PBPK model. With the optimized posterior parameters, the PBPK model was evaluated by comparing its prediction with experimental data from three different studies. The results show that the uncertainties of the posterior model parameters were reduced substantially. In addition, most of the PBPK model predictions were improved: with the posterior parameters, most of the predicted plasma toxicokinetics (e.g., half-life) and tissue distribution fell well within a factor of 2.0 of the experimental data. Finally, the Bayesian framework could provide insights into the molecular mechanisms driving PFOA toxicokinetics: PFOA-protein binding, membrane permeability, and active transport.

The Dilemma of perfluorooctanoate (PFOA) human half-life.

Disparity in the results from human observational and clinical studies is not uncommon, but risk assessment efforts often judge one set of data more relevant with the loss of valuable information. The assessment for perfluorooctanoate (PFOA) is a good example of this problem. The estimation of its safe dose is disparate among government groups due in part to differences in understanding of its half-life in humans. These differences are due in part to incomplete information on sources of exposure in the human observational half-life studies, which have been routinely acknowledged, but until recently not well understood. Exposure information is thus critical in understanding, and possibly resolving, this disparity in PFOA safe dose, and potentially for disparities with similar chemistries when both human observational and clinical findings are available. We explore several hypotheses to explain this disparity in PFOA half-life from human observational studies in light of findings of a clinical study in humans and relevant exposure information from a recent international meeting of the Society of Toxicology and Environmental Chemistry (SETAC). Based on information from both human observational studies and clinical data, we proposed a range for the half-life for PFOA of 0.5-1.5 years, which would likely raise many existing regulatory safe levels if all other parameters stayed the same.

Effect of soil organic matter on the plant uptake of perfluorooctanoic acid (PFOA) and perfluorooctanesulphonic acid (PFOS) in lettuce on granular activated carbon-applied soil.

The presence of perfluorooctanoic acid (PFOA) and perfluorooctanesulphonic acid (PFOS) in crops is an important consideration for food safety. The soil organic matter (SOM) content may affect the adsorption potential of PFOA and PFOS in water and soil and their subsequent uptake in crops. To better understand these dynamics, the adsorption and uptake of PFOA and PFOS in lettuce were investigated using granular activated carbon (GAC)-treated soils with varying SOM content. The adsorption potential of GAC was investigated, with maximum adsorption capacities for PFOA and PFOS calculated to be 9.091 mg g-1 and 27.778 mg g-1, respectively. These values decreased to 5.208 mg g-1 and 17.241 mg g-1, respectively, after the addition of 0.04 wt% humic acid. The average plant uptake factor (PUF) in low and high perfluoroalkyl and polyfluoroalkyl acid (PFAA)-contaminated soils with 4.0 wt% SOM was restricted to 0.353 for PFOA and 0.108 for PFOS. The PUFs were approximately two times lower than those for soil with 2.6 wt% SOM. Addition of 1 wt% GAC to the soil successfully reduced the PUF by up to 99.4%, with values of 0.006 (PFOA) and 0.005 (PFOS) in 2.6 wt% SOM-treated soil and 0.079 (PFOA) and 0.023 (PFOS) in 4.0 wt% SOM-treated soil. Although the PUF in the GAC-treated soil was drastically decreased, the PUF of the soil with 4.0 wt% SOM was at least four times higher than that with 2.6 wt% SOM. Therefore, SOM content is an important consideration in the remediation of PFOA- and PFOS-contaminated farmland soil using carbonaceous adsorbent.

Perfluorooctanesulfonic acid (PFOS) administration shifts the hepatic proteome and augments dietary outcomes related to hepatic steatosis in mice.

Hepatic steatosis increases risk of fatty liver and cardiovascular disease. Perfluorooctanesulfonic acid (PFOS) is a persistent, bio-accumulative pollutant that has been used in industrial and commercial applications. PFOS administration induces hepatic steatosis in rodents and increases lipogenic gene expression signatures in cultured hepatocytes. We hypothesized that PFOS treatment interferes with lipid loss when switching from a high fat diet (HFD) to a standard diet (SD), and augments HFD-induced hepatic steatosis. Male C57BL/6 N mice were fed standard chow diet or 60% kCal high-fat diet (HFD) for 4 weeks to increase body weight. Then, some HFD mice were switched to SD and mice were further divided to diet only or diet containing 0.0003% PFOS, for six treatment groups: SD, HFD to SD (H-SD), HFD, SD + PFOS, H-SD + PFOS, or HFD + PFOS. After 10 weeks on study, blood and livers were collected. HFD for 14 weeks increased body weight and hepatic steatosis, whereas H-SD mice returned to SD measures. PFOS administration reduced body weight in mice fed a SD, but not H-SD or HFD. PFOS administration increased liver weight in H-SD + PFOS and HFD + PFOS mice. PFOS increased hepatic steatosis in H-SD and HFD groups. Hepatic mRNA expression and SWATH-MS proteomic analysis revealed that PFOS induced lipid and xenobiotic transporters, as well as metabolism pathways. Overall, the findings herein suggest that PFOS treatment did interfere with lipid loss associated with switch to a SD and similarly augmented hepatic lipid accumulation in mice established on an HFD.

Nanoscale perfluorocarbon expediates bone fracture healing through selectively activating osteoblastic differentiation and functions.

BACKGROUND AND RATIONALE: Fracture incidence increases with ageing and other contingencies. However, the strategy of accelerating fracture repair in clinical therapeutics remain a huge challenge due to its complexity and a long-lasting period. The emergence of nano-based drug delivery systems provides a highly efficient, targeted and controllable drug release at the diseased site. Thus far, fairly limited studies have been carried out using nanomedicines for the bone repair applications. Perfluorocarbon (PFC), FDA-approved clinical drug, is received increasing attention in nanomedicine due to its favorable chemical and biologic inertness, great biocompatibility, high oxygen affinity and serum-resistant capability. In the premise, the purpose of the current study is to prepare nano-sized PFC materials and to evaluate their advisable effects on promoting bone fracture repair. RESULTS: Our data unveiled that nano-PFC significantly enhanced the fracture repair in the rabbit model with radial fractures, as evidenced by increased soft callus formation, collagen synthesis and accumulation of beneficial cytokines (e.g., vascular endothelial growth factor (VEGF), matrix metalloprotein 9 (MMP-9) and osteocalcin). Mechanistic studies unraveled that nano-PFC functioned to target osteoblasts by stimulating their differentiation and activities in bone formation, leading to accelerated bone remodeling in the fractured zones. Otherwise, osteoclasts were not affected upon nano-PFC treatment, ruling out the potential target of nano-PFC on osteoclasts and their progenitors. CONCLUSIONS: These results suggest that nano-PFC provides a potential perspective for selectively targeting osteoblast cell and facilitating callus generation. This study opens up a new avenue for nano-PFC as a promising agent in therapeutics to shorten healing time in treating bone fracture.

Accumulation and effects of perfluoroalkyl substances in three hydroponically grown Salix L. species.

The potential of young rooted cuttings of three Salix L. species plants to accumulate a mixture of eleven perfluoroalkyl substances (PFASs), in particular, perfluoroalkyl acids (PFAAs), from the nutrient solution and their effects on plant growth and photosynthesis were assessed in an 8-day experiment. The growth rate of the willow plants exposed to the PFAA mixture was not much affected except for S. triandra. Regarding photosynthesis, the gas exchange parameters were affected more than those related to chlorophyll fluorescence, with significant increase of the net CO2 assimilation rate and parameters related to stomatal conductance. A decreasing trend in the PFAA concentration in leaves with increasing carbon chain length was observed, whereas long-chain PFAAs showed higher concentrations in roots. Accordingly, the foliage to root concentration factor highlighted that PFAAs with shorter carbon chain length (C ≤ 7) translocated and accumulated relatively more in leaves compared to roots. Removal efficiency of individual PFAAs for leaves and roots were comparatively higher with S. eleagnos and S. purpurea than S. triandra, with mean removal values at the whole plant level ranging around 10% of the amount initially spiked, suggesting their potential for phytoremediation of PFASs.

(Z)-1-Chloro-2,3,3,3-tetrafluoropropene (2017).

(Z)-1-Chloro-2,3,3,3-tetrafluoropropene (HCFO-1224yd(Z)) is a colorless gas used as a single substance or in a mixture with other substances for refrigeration. The 4-h rat inhalation LC50 values from two studies were reported to be >20,180 ppm and >213,100 ppm. HCFO-1224yd(Z) is not expected to undergo significant metabolism. The no-observed-effect level of HCFO-1224yd(Z) for cardiac sensitization (in dogs) was 75,000 ppm. In a 5-day repeat inhalation study in rats, the only observation noted was repetitive movement of the mouth/jaws in some animals in the 50,000-ppm exposure group for 1-2 days during the first 3 exposure days. The toxicological significance of this observation was unknown; therefore, the study no-observed-adverse-effect level (NOAEL) was established at 50,000 ppm. In a good laboratory practice (GLP)-compliant, 4-week inhalation study in rats, there were no test substance-related adverse effects noted at any exposure concentration. The study NOAEL was established at 40,000 ppm. In a GLP-compliant inhalation developmental toxicity study, female rats were exposed for 6 h/day from gestation day 6 through 19. There were no test substance-related adverse effects on either the maternal or fetal rats at any exposure concentration. The NOAEL for developmental effects was established at 20,000 ppm. There are no chronic toxicity or carcinogenicity studies available. HCFO-1224yd(Z) gave mixed results in in vitro genotoxicity assays but was negative in an in vivo micronucleus assay. The NOAEL of 40,000 ppm for HCFO-1224yd(Z) from the 4-week, GLP-compliant inhalation study in rats was used at the point of departure (POD) for workplace environmental exposure level (WEEL) value development. This POD was adjusted to account for interindividual variability, duration of exposure, and database limitations. The resulting 8-h time-weighted average WEEL value of 1000 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to HCFO-1224yd(Z).

Exploring sex differences in human health risk assessment for PFNA and PFDA using a PBPK model.

Perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), which are classified as perfluoroalkyl and polyfluoroalkyl substances (PFASs), have been widely used in industrial applications as a surface protectant. PFASs have been detected in wildlife and in humans around the globe. The purposes of this study are to develop and validate a physiologically based pharmacokinetic (PBPK) model for detecting PFNA and PFDA in male and female rats, and to apply the model to a human health risk assessment regarding the sex difference. A PBPK model of PFNA and PFDA was established based on an in vivo study in male and female rats. Analytes in biological samples (plasma, nine tissues, urine, and feces) were determined by ultra-liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS) method. PFNA and PFDA showed a gender differences in the elimination half-life and volume of distribution. The tissue-plasma partition coefficients were the highest in the liver in both male and female rats. The predicted rat plasma and urine concentrations simulated and fitted were in good agreement with the observed values. The PBPK models of PFNA and PFDA in male and female rats were then extrapolated to a human PBPK model based on human physiological parameters. The external doses were calculated at 3.35 ng/kg/day (male) and 17.0 ng/kg/day (female) for PFNA and 0.530 ng/kg/day (male) and 0.661 ng/kg/day (female) for PFDA. Human risk assessment was estimated using Korean biomonitoring values considering the gender differences. This study provides valuable insight into human health risk assessment regarding PFNA and PFDA exposure.

Data derived Extrapolation Factors for developmental toxicity: A preliminary research case study with perfluorooctanoate (PFOA).

Guidelines of the United States Environmental Protection Agency (EPA, 1991) and the International Programme on Chemical Safety (IPCS, 2005) suggest two different default positions for dosimetric extrapolation from experimental animals to humans when the dosimetry of the critical effect is not known. The default position of EPA (1991) for developmental toxicity is to use peak concentration (or Cmax) for this dosimetric extrapolation. In contrast, IPCS (2005, page 39) states its default position for dosimetric choice in the absence of data is to use the area under the curve (or AUC). The choice of the appropriate dose metric is important in the development of either a Chemical Specific Adjustment Factor (CSAF) of IPCS (2005) or a Data Derived Extrapolation Factor (DDEF) of EPA (2014). This research shows the derivation of a DDEF for developmental toxicity for perfluorooctanoate (PFOA), a chemical of current interest. Here, identification of the appropriate dosimetric adjustment from a review of developmental effects identified by EPA (2016) is attempted. Although some of these effects appear to be related to Cmax, most appear to be related to the average concentration or its AUC, but only during the critical period of development for a particular effect. A comparison was made of kinetic data from PFOA exposure in mice with newly available and carefully monitored kinetic data in humans after up to 36 weeks of PFOA exposure in a phase 1 clinical trial by Elcombe et al. (2013). Using the average concentration during the various exposure windows of concern, the DDEF for PFOA was determined to be 1.3 or 14. These values are significantly different than comparable extrapolations by several other authorities based on differences in PFOA half-life among species. Although current population exposures to PFOA are generally much lower than both the experimental animal data and the clinical human study, the development of these DDEFs is consistent with current guidelines of both EPA (2014) and IPCS (2005).

Interspecies differences in perfluoroalkyl substances (PFAS) toxicokinetics and application to health-based criteria.

Toxicokinetics are important for extrapolating health effects and effect levels observed in laboratory animals to humans for purposes of establishing health-based criteria. We conducted a comprehensive review of key absorption, distribution, metabolism, and excretion (ADME) parameters across different mammalian species for five perfluoroalkyl substances (PFAS) and discussed how these data can be used to inform human health risk assessment of these substances. Our analysis revealed several notable differences among the different PFAS regarding species- and substance-specific tissue partitioning, half-life, and transfer to developing offspring via the placenta or lactation, as well as highlighted data gaps for certain substances. We incorporated these observations in an analysis of whether health-based values for specific PFAS can be applied to other PFAS of differing chain length or toxicological mode of action. Overall, our analysis provides one of the first syntheses of available empirical PFAS toxicokinetic data to facilitate interpreting human relevance of animal study findings and developing health-based criteria for PFAS from such studies.

Toxicokinetics and toxic effects of a Chinese PFOS alternative F-53B in adult zebrafish.

6:2 chlorinated polyfluorinated ether sulfonate (F-53B), a Chinese PFOS alternative, has recently been identified in river water, sewage sludge, wildlife and humans, causing great concerns about its potential toxic effects. Here, we report the first investigation of the toxicokinetics and oxidative stress of F-53B in adult zebrafish. Adult male and female zebrafish were exposed to 10 and 100 µg/L of F-53B for 7 days followed by a 5-d depuration period to examine bioaccumulation, distribution, and depuration of F-53B in fish. The results showed that F-53B was readily accumulated in fish tissues with log BCF values of 2.36-3.65, but was eliminated slowly (t1/2 = 152.4-358.5 h). F-53B accumulation was greater in males than in females and the concentration in tissues decreased in the following order: gonad ≈ liver ≫ gill ≫ brain in females and liver ≈ gill ≫ gonad ≫ brain in males, showing sex- and tissue- specific accumulation of F-53B in fish. After chronic exposure to F-53B for 28 days, a significant dose-dependent increase in histopathological changes in the liver were mainly manifested by vacuolation. Furthermore, F-53B also significantly reduced the enzyme activity (or content) of most of the measured oxidative stress-related markers (e.g., SOD, CAT and MDA) except for an increase in GSH-Px activity, indicating that oxidative stress was induced in zebrafish after treatment with F-53B. The results of this study provide important information on the toxicokinetics and toxic effects of F-53B, which will contribute to the ecological risk assessments of F-53B released into surface waters.

Comparisons of tissue distributions and health risks of perfluoroalkyl acids (PFAAs) in two fish species with different trophic levels from Lake Chaohu, China.

Perfluoroalkyl acids (PFAAs) are a type of persistent organic pollutants that are widely distributed in multiple environmental media and organisms and have a teratogenic effect on and toxicity to animals and humans. The residual levels of seventeen PFAAs in the tissues of two regular consumption fish species, Culter erythropterus and Aristichthys nobilis in Lake Chaohu were measured by a high-performance liquid chromatograph - mass spectrometer (HPLC-MS). The distributions of PFAAs and the effect of the lipid contents were analyzed, and the health risks of typical PFAAs were evaluated. The results showed that perfluorohexanoic acid (PFHxA) was the predominant contaminant (80.50 ±â€¯58.31 ng/g and 19.17 ±â€¯12.57 ng/g wet weight, ww), followed by perfluorooctanesulfonic acid (PFOS) (55.02 ±â€¯34.82 and 14.79 ±â€¯6.24 ng/g, ww) in both fish. The level of total PFAAs was the highest in the liver tissues of Culter erythropterus (359.87 ng/g, ww) and the lowest in the kidney tissues in A. nobilis (10.06 ng/g, ww). Due to the higher trophic level of C. erythropteru, the total PFAA concentrations were significantly higher in all tissues than those in A. nobilis. Liver muscle ratio of C. erythropteru was the highest, indicating the most accumulation in the liver. The concentrations of PFAAs in fish tissues were influenced by the lipid content, resulting in a difference between the lipid-normalized concentrations and the wet weight concentrations of the PFAAs. The non-carcinogenic risks of PFOS were higher than those of PFOA through the ingestion of C. erythropterus and A. nobilis. Both the carcinogenic and non-carcinogenic risks of C. erythropterus were greater than those of A. nobilis, and fish tissue intake could cause an increasing of risks up to 60%, indicating that long-term and large amount ingestion of carnivorous fish and related tissues with higher trophic level, such as C. erythropterus should be avoided.

Quantification of vascular damage in acute kidney injury with fluorine magnetic resonance imaging and spectroscopy.

PURPOSE: To design a fluorine MRI/MR spectroscopy approach to quantify renal vascular damage after ischemia-reperfusion injury, and the therapeutic response to antithrombin nanoparticles (NPs) to protect kidney function. METHODS: A total of 53 rats underwent 45 min of bilateral renal artery occlusion and were treated at reperfusion with either plain perfluorocarbon NPs or NPs functionalized with a direct thrombin inhibitor (PPACK:phenyalanine-proline-arginine-chloromethylketone). Three hours after reperfusion, kidneys underwent ex vivo fluorine MRI/MR spectroscopy at 4.7 T to quantify the extent and volume of trapped NPs, as an index of vascular damage and ischemia-reperfusion injury. Microscopic evaluation of structural damage and NP trapping in non-reperfused renal segments was performed. Serum creatinine was quantified serially over 7 days. RESULTS: The damaged renal cortico-medullary junction trapped a significant volume of NPs (P = 0.04), which correlated linearly (r = 0.64) with the severity of kidney injury 3 h after reperfusion. Despite global large vessel reperfusion, non-reperfusion in medullary peritubular capillaries was confirmed by MRI and microscopy, indicative of continuing hypoxia due to vascular compromise. Treatment of animals with PPACK NPs after acute kidney injury did not accelerate kidney functional recovery. CONCLUSIONS: Quantification of ischemia-reperfusion injury after acute kidney injury with fluorine MRI/MR spectroscopy of perfluorocarbon NPs objectively depicts the extent and severity of vascular injury and its linear relationship to renal dysfunction. The lack of kidney function improvement after early posttreatment thrombin inhibition confirms the rapid onset of ischemia-reperfusion injury as a consequence of vascular damage and non-reperfusion. The prolongation of medullary ischemia renders cortico-medullary tubular structures susceptible to continued necrosis despite restoration of large vessel flow, which suggests limitations to acute interventions after acute kidney injury, designed to interdict renal tubular damage. Magn Reson Med 79:3144-3153, 2018. © 2017 International Society for Magnetic Resonance in Medicine.