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Physiologically based kinetic (PBK) models are widely used in pharmacology and toxicology for predicting the internal disposition of substances upon exposure, voluntarily or not. Due to their complexity, a large number of model parameters need to be estimated, either through in silico tools, in vitro experiments, or by fitting the model to in vivo data. In the latter case, fitting complex structural models on in vivo data can result in overparameterization and produce unrealistic parameter estimates. To address these issues, we propose a novel parameter grouping approach, which reduces the parametric space by co-estimating groups of parameters across compartments. Grouping of parameters is performed using genetic algorithms and is fully automated, based on a novel goodness-of-fit metric. To illustrate the practical application of the proposed methodology, two case studies were conducted. The first case study demonstrates the development of a new PBK model, while the second focuses on model refinement. In the first case study, a PBK model was developed to elucidate the biodistribution of titanium dioxide (TiO2) nanoparticles in rats following intravenous injection. A variety of parameter estimation schemes were employed. Comparative analysis based on goodness-of-fit metrics demonstrated that the proposed methodology yields models that outperform standard estimation approaches, while utilizing a reduced number of parameters. In the second case study, an existing PBK model for perfluorooctanoic acid (PFOA) in rats was extended to incorporate additional tissues, providing a more comprehensive portrayal of PFOA biodistribution. Both models were validated through independent in vivo studies to ensure their reliability., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology.)

This study aimed to investigate sex, age, and species differences of perfluorooctanoic acid (PFOA) using physiologically-based pharmacokinetic (PBPK) models in rats and humans. PBPK models were generally developed as either flow- or permeability-limited models. The flow-limited model is cost-effective and allows for human PK prediction through simple allometric scaling, while the permeability-limited model can incorporate detailed information on the disposition process through in vitro-in vivo extrapolation (IVIVE). PFOA was administered via oral or intravenous administration with 5 mg/kg in male and female rats of different ages and the data was used to develop the PBPK models. Our results showed that both models successfully captured sex differences in rats, while only the flow-limited model with male rats and the permeability-limited model with both male and female rats provided comparable predictions in the human clinical study. More than the flow-limited model, the permeability-limited model effectively explained sex differences in rats and species differences through IVIVE. Additionally, the ontogeny-based mechanistic description of PFOA disposition enabled the interpretation of age- and sex-dependent pharmacokinetics. Although the flow-limited PBPK model lacked mechanistic interpretability compared to the permeability-limited model, it demonstrated reliable human prediction through simple allometric scaling. In conclusion, the permeability PBPK model could interpret age, sex, and species differences and it could improve the accuracy of human prediction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Metformin hydrochloride is a highly hydrophilic molecule with low permeability. In the present study, to develop an effective drug to treat the metastatic breast cancer, metformin caprylic acid was synthesized using metformin hydrochloride as a permeable agent., Main Methods: The cytotoxic effects of various concentrations of metformin caprylic acid and metformin hydrochloride (0 to 20 mM) on MCF-7 and MDA-MB-231 breast cancer cells and MCF-10A human mammary epithelial cell line were assessed by the MTT assay. Furthermore, Annexin V, PI staining, and cell flow cytometry assays were performed to evaluate the apoptotic effects. The invasion and migration ability of these cells were evaluated following treatment with equal concentration (3 mM) of the two compounds., Key Findings: The treatment of tested cell lines with an equal concentration of two chemicals decreased cell viability in a time and dose-dependent manner, where in all cases, metformin caprylic acid caused significantly more apoptosis and invasion inhibition than that of metformin hydrochloride (*p < 0.05). Chemical structures of both compounds were confirmed by FTIR and 1 H NMR, 13 C NMR. Both chemicals inhibited the migration of MCF-7 and MCF-10A cells, but had no effect on MDA-MB-231 migration. All data are expressed as mean ± SD (n = 3)., Significance: It seems that in an equal concentration, the similarity of the hydrophobic tail of caprylic acid to the cell membrane improves its entrance, while decreasing the drug excretion., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Perfluorooctanoic acid (PFOA) as an emerging environmental contaminant, has become ubiquitous in the environment. It is of significance to study bioconcentration and tissue distribution of aquatic organisms for predicting the persistence of PFOA and its adverse effects on the environment and human body. However, the distribution of PFOA in different tissues is a complex physiological process affected by many factors. It is difficult to be accurately described by a simple kinetic model. In present study, a new strategy was introduced to research the PFOA distribution in tissues and estimate the exposure stages. Zebrafish were continuously exposed to 25 mg/L PFOA for 30 days to simulate environmental process. Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) method was used to monitor the spatio-temporal distribution of PFOA in zebrafish tissues. By analyzing the law of change obtained from the high spatial resolution MSI data, two different enrichment trends in ten tissues were summarized by performing curve fitting. Analyzing the ratio of two types of curves, a new "exposure curve" was defined to evaluate the exposure stages. With this model, three levels (mild, moderate, and deep pollution stage) of PFOA pollution in zebrafish can be simply evaluated., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Abiraterone acetate tablets (I)(N-AbA) is a novel tablet co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). This study aimed to compare the pharmacokinetics, bioequivalence, safety, and food effects of N-AbA with the reference ZYTIGA ® (R-AbA) in healthy Chinese male subjects., Patients and Methods: This study was conducted in three parts. Part I was an open, dose-escalation trial conducted in 16 Chinese healthy males; Part II was a randomized, open-label, 2 × 4 crossover, single-dose bioequivalence trial conducted in 36 subjects; Part III was a randomized, 3 × 3 crossover trial conducted on 24 volunteers to investigate the effect of food on the pharmacokinetics of N-AbA., Results: The exposure (AUC 0-∞ ) and maximum concentration (C max ) of abiraterone and excipient SNAC were linear in the range of 75-450 mg dose. The bioavailability of N-AbA 300 mg was equivalent to that of R-AbA 1000 mg. The drug exposure of prednisone and prednisolone was not affected by SNAC co-administration. The C max of orally administered abiraterone as R-AbA in a modified fed state was 5.9 times and AUC 0-∞ was 4.3 times, respectively, higher than those in of orally administered abiraterone as N-AbA in a high-fat diet. The C max and AUC 0-∞ of orally administered abiraterone as N-AbA on a high-fat diet were 2.2 times and 2 times, respectively, higher than those on a fasting state. All adverse events reported in the three parts of the study were grade 1 or 2, and no serious adverse events were reported., Conclusion: These three Phase I trials showed that N-AbA and excipient SNAC had excellent linear pharmacokinetic characteristics. A single dose of N-AbA 300 mg was bioequivalent to R-AbA 1000 mg in healthy subjects under fasting conditions. Meanwhile, SNAC had no effect on the pharmacokinetics of prednisone and prednisolone. The effect of food on N-AbA was significantly lower than that on R-AbA., Competing Interests: YH was employed by Jiangsu Hengrui Medicine Co., Ltd. The authors report no other conflicts of interest in this work., (© 2022 Feng et al.)

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.

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The first determination of presence and biodistribution of PFOA in ninety specimens of sea urchin Paracentrotus lividus from two differently contaminated sites along Palermo's coastline (Sicily) is reported. Analyses were performed on the sea urchins' coelomic fluids, coelomocytes, gonads or mixed organs, as well as on seawater and Posidonia oceanica leaves samples from the collection sites. PFOA concentration ranged between 1 and 13 ng/L in seawater and between 0 and 794 ng/g in P. oceanica. The analyses carried out on individuals of P. lividus from the least polluted site (A) showed PFOA median values equal to 0 in all the matrices (coelomic fluid, coelomocytes and gonads). Conversely, individuals collected from the most polluted site (B) showed median PFOA concentrations of 21 ng/g in coelomic fluid, 153 ng/g in coelomocytes, and 195 ng/g in gonads. Calculated bioconcentration factors of log 10 BCF > 3.7 confirmed the very bioaccumulative nature of PFOA. Significant correlations were found between the PFOA concentration of the coelomic fluid versus the total PFOA concentration of the entire sea urchin. PERMANOVA (p = 0.001) end Welch's t-test (p < 0.001) analyses showed a difference between specimens collected from the two sites highlighting the potential application of P. lividus as sentinel species for PFOA biomonitoring., (© 2021. The Author(s).)

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.

High grade glial tumors (HGGs) including anaplastic astrocytoma (WHO Grade-III) and glioblastoma multiforme (GBM, WHO Grade-IV) are among the most malignant cancers known to man. Due to their defective mitochondria, HGG cells consume glucose via glycolysis even in the presence of oxygen. Overall survival is worse in HGG patients that are hyperglycemic. Unlike normal neural cells, HGG cells cannot efficiently metabolize ketone bodies for energy. Thus, a metabolic treatment based on therapeutic ketosis (reduced glucose with elevated ketone bodies) was proposed to treat GBM and was supoported from preclinical studies. Caprylic (octanoic) acid, a monocarboxylated saturated fatty acid, is among the best producers of ketone bodies and induces necrosis of experimental tumors at high dose. Caprylic acid is enriched in coconut and in goat's milk. It is also a posttranslational modifier of the ghrelin hormone and is produced in trace amounts in human tissues. Caprylic acid is a straight-chain isomer of the antiepileptic valproic acid, which is used in treatment of HGG-associated seizures and which may increase survival in GBM patients according to epidemiological observations. Among the valproic acids analogs tested, caprylic acid is the most potent molecule to block C6 astrocytoma cell growth in vitro and accumulates selectively within glial cells as shown by Positron Emission Tomography in vivo. Caprylic acid blocks glycolysis both in healthy liver and in malignant liver cells, which is more prominent in the latter and also lowers blood glucose. Noteworthy, caprylic acid exerts neuroprotective- and mitochondria-protective effects in several models of neurodegenerative diseases. Boost injections of caprylic acid at non-toxic levels during classical ketogenic metabolic therapy may fortify antitumor actions and reduce systemic toxicity by differential programming of mitochondrial and other metabolic pathways., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Silica-lipid hybrid (SLH) microparticles are a solidified lipid-based drug delivery system under investigation for their aptitude to enhance the oral bioavailability of poorly water-soluble drugs. The cholesterol-lowering agent, simvastatin (SIM), is poorly water-soluble and undergoes extensive first pass metabolism, resulting in a low oral bioavailability of approximately 5%. Hence, the current pre-clinical studies investigated the application of SLH technology to SIM with a supersaturation approach, aiming to enhance bioavailability and drug loading capacity. Additionally, the effect of silica was explored by evaluating the performance of SLH fabricated with silica of different particle geometries. SLH microparticles with supersaturated SIM loading levels ranging from 100% to 400% above the equilibrium solubility were successfully fabricated using either Aerosil® 300 or Syloid® 244 silica. All SLH formulations existed as white free-flowing powders, consisting of spherical porous microparticles for Aerosil® 300, and aggregated irregular microparticles for Syloid® 244. During in vitro dissolution in pH 7.0 media, the SLH formulations performed up to 4.4-fold greater than pure SIM powder. Furthermore, in vivo oral pharmacokinetics in male Sprague-Dawley rats revealed that the SLH formulations enhanced the oral bioavailability of SIM up to 6.1-fold and 2.9-fold, in comparison to pure SIM powder and a commercially available formulation (Simvastatin Sandoz®), respectively. The greatest in vivo performance enhancement was observed for the SLH formulation manufactured with Syloid® 244 silica with a supersaturation level of 200%. SLH technology demonstrated to be a successful formulation strategy to significantly improve the oral bioavailability of SIM in rodents and therefore, has a strong potential to also improve the oral bioavailability of SIM in humans., Competing Interests: Declarations of Competing Interest None., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.

Ellagic acid (EA) is a potent antioxidant substance of natural origin characterized by poor biopharmaceutical properties and low solubility in water that limit its use. The aim of the present study was to develop lipid-based nanoparticle formulations able to encapsulate EA for dermal delivery. The EA-loaded nanoparticles were prepared using two different lipid compositions, namely tristearin/tricaprylin (NLC-EA1) and tristearin/labrasol (NLC-EA2). The influence of formulations on size, entrapment efficiency, and stability of EA-loaded nanoparticles was investigated. Cryo-TEM and small-angle X-ray scattering (SAXS) analyses showed that no morphological differences are evident among all the types of loaded and unloaded nanostructured lipid carriers (NLCs). The macroscopic aspect of both NLC-EA1 and NLC-EA2 did not change with time. No difference in size was appreciable between empty and drug-containing NLC, thus the nanoparticle diameter was not affected by the presence of EA and in general no variations of the diameters occurred during this time. The entrapment efficiency of both EA-loaded nanoparticles was almost quantitative. In addition, NLC-EA1 maintained EA stability for almost two months, while NLC-EA2 up to 40 days. FRAP (Ferric reducing ability of plasma) assay showed an antioxidant activity around 60% for both the loaded NLC, as compared to the solution. Although both types of NLC are characterized by some toxicity on HaCaT cells, NLC-EA1 are less cytotoxic than NLC-EA2. Taken together these results demonstrated that the inclusion of EA within NLC could improve the water solubility, allowing for a reduction of the dosage. Moreover, both types of NLC-EA maintained a high antioxidant effect and low toxicity.

Perfluorooctane sulfonyl fluoride (PFOSF) is the precursor of many fluorochemicals that are ubiquitous in the environment. However, its distribution and toxicology are rarely studied. In this work, the oxidability of PFOSF was found. PFOSF can accelerate oxidation of glutathione (GSH) to its oxidized form GSSG, and itself is reduced to a sulfinic acid. The yielded sulfinic acid was prepared and identified with high resolution mass spectrometry and NMR. Similar redox reactions were observed for PFOSF's short chain alternatives. The reduction potentials of perfluoroalkane sulfonyl fluorides (PFASFs) were determined to be -2.13 V vs. SCE with cyclic voltammetry, further demonstrating their oxidability. The peptide mixtures of GSH plus another cysteine-containing peptide were also oxidized by PFASFs to GSSG and an asymmetric disulfide GS-S-PEP. A single short-sequence PEP-SH could be oxidized to the symmetric disulfide PEP-S-S-PEP as the final product. In vitro experiments were carried out by adding PFASFs into rat liver S9 fractions. The turnover ratio of PFASFs were calculated to be about 4-10% by quantification of sulfinic acid with LC-MS/MS. Our work illustrates one of the potential metabolic pathways of PFASFs and demonstrates the oxidation of PEP-SHs by PFASFs, thus providing a preliminary exploration in the toxicology of these fluorochemicals., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Perfluorooctanoic acid (PFOA), a global environmental pollutant detected in both wildlife and human populations, has several pathophysiological effects in experimental animals, including hepatotoxicity, immunotoxicity, and developmental toxicity. However, details concerning the tissue distribution of PFOA, in particular at levels relevant to humans, are lacking, which limits our understanding of how humans, and other mammals, may be affected by this compound. Therefore, we characterized the tissue distribution of 14 C-PFOA in mice in the same manner as we earlier examined its analogues perfluorooctanesulfonate (PFOS) and perfluorobutanesulfonate (PFBS) in order to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1, 3 or 5 days to a low dose (0.06 mg/kg/day) or a higher experimental dose (22 mg/kg/day) of 14 C-PFOA, both scintillation counting and whole-body autoradiography revealed the presence of PFOA in most of the 19 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. There were no differences in the pattern of tissue distribution with the low and high dose and the tissue-to-blood ratios were similar. At both doses, PFOA levels were highest in the liver, followed by blood, lungs and kidneys. The body compartments estimated to contain the largest amounts of PFOA were the liver, blood, skin and muscle. In comparison with our identical studies on PFOS and PFBS, PFOA reached considerably higher tissue levels than PFBS, but lower than PFOS. Furthermore, the distribution of PFOA differed notably from that of PFOS, with lower tissue-to-blood ratios in the liver, lungs, kidneys and skin., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are highly effective at lowering hemoglobin A1c (HbA1c) and facilitating weight loss. Four agents in the GLP-1 RA class, albiglutide, liraglutide, dulaglutide, and semaglutide, also have cardioprotective effects. However, subcutaneous administration of these agents remains a major reason for their underutilization. A new coformulation of semaglutide with sodium N-[8-(2-hydroxybenzoyl) amino caprylate (SNAC) is the first oral GLP-1 RA reviewed by the U.S. Food and Drug Administration (FDA). The SNAC technology prevents destruction of semaglutide in the stomach and facilitates transcellular absorption through the gastric membrane enabling semaglutide to reach systemic circulation intact. The oral formulation of semaglutide was studied in the PIONEER trials, demonstrating similar efficacy to the presently available GLP-1 RAs with regard to HbA1c lowering and weight loss. Although the PIONEER 6 trial suggests positive effects on cardiovascular mortality with oral semaglutide, these benefits may not fully be appreciated until the completion of the SOUL trial.

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)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The alteration of thyroxine (T 4 ) cellular uptake by an environmental chemical can serve as a contributing factor in thyroid hormone (TH) disruption. Herein, we describe a non-radiolabeled (LC-MS/MS) oil-filtration technique designed to characterize the mechanism(s) responsible for T 4 cellular uptake in cryopreserved rat hepatocyte suspensions. The environmental chemicals perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) were evaluated for their effect on T 4 hepatic uptake. At 37 °C, hepatic assays demonstrated saturable kinetics with increasing T 4 concentrations, while a linear uptake rate consistent with passive diffusion was detected at 4 °C. Carrier-mediated (37-4 °C) transport of T 4 was the predominant hepatic uptake process versus passive diffusion. Cyclosporin A (CsA) chemically inhibited T 4 hepatic uptake, whereas PFOA/PFOS displayed no inhibition of T 4 translocation. Increasing PFOA/PFOS concentration levels with the T 4 serum carrier-protein transthyretin (TTR) present resulted in a dose-response increase in T 4 hepatic uptake rates, correlating with increased T 4 free fraction values. Hepatic assays conducted in the presence of PFOA/PFOS and TTR displayed an enhanced first-order T 4 hepatic uptake rate consistent with carrier-mediated transport. These in vitro findings characterizing increased T 4 hepatic uptake provides mechanistic insight regarding decreased T 4 serum levels (hypothyroxinemia) previously observed within in vivo rodent studies following perfluorinated chemical exposure., (Copyright © 2019. Published by Elsevier Ltd.)

Wildlife species, such as roe deer, moose, brown hare, wild boar, etc., are known to accumulate persistent environmental contaminants and thus are useful as bioindicators for environmental pollution. Wild boars become exposed to perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) from flora, fauna, water, and soil. The main exposure pathway to PFOA and PFOS is assumed to be the oral intake. From studies in domestic pigs (belonging to the same species Sus scrofa), it has been established that the oral exposure results in the liver accumulation of PFOA and PFOS. Thus, we posit that wild boars can be quantitatively used as suitable bioindicators for the presence of these substances in the environment. After the environmental pollution case in the Hessian region Sauerland in 2006, monitoring programs of individual Federal States from 2007 to 2013 showed that almost all wild boar liver samples contained PFOA and PFOS. In 2014, the analyses of PFOA and PFOS in liver of wild boars hunted in the south, north, and west of Germany showed liver concentrations at the same level among regions. Overall, an average ratio of PFOS:PFOA concentration in liver of 20.5:1 was found. To estimate the actual ratio of PFOS:PFOA in the wild boars' dietary exposure, we performed toxicokinetic modeling. According to the model, the PFOS exposure is only 2.2 times that of PFOA (because PFOS has slower elimination kinetics and higher affinity for the liver than PFOA). Overall, the determination of PFOA and PFOS in liver of wild boars indicates that both substances are ubiquitously distributed in the environment. At the same time, higher exposures were found for animals living in closer proximity to dense human populations.

The effects of combined exposure to perfluoroalkyl acids (PFAAs) and heavy metals (HMs) including cadmium (Cd), copper (Cu), zinc (Zn), nickel (Ni), and lead (Pb) on earthworms (Eisenia fetida) were investigated. The results have demonstrated that the concentrations of labile acid exchangeable Cd, Zn, Ni, Pb, and Cu in soil were enhanced in addition of PFAAs. With PFAAs, the uptake of Cd, Zn, Ni, Pb, and Cu in earthworms was increased compared to those without PFAAs with the order of Cd > Zn > Pb > Ni > Cu. In the presence of HMs, the average biota-to-soil accumulation factors (BSAFs) of PFAAs in earthworms were decreased by 0.498-0.729 times for perfluorooctane sulfonate (PFOS) and 0.606-0.978 times for perfluorooctanoic acid (PFOA), indicating decrease rates of PFOS were higher than those of PFOA. And different levels of HMs led to insignificant different responses on the inhibiting effects of PFAAs uptake in earthworms. The increase of Cd in fraction C (associated with cytosol) and decrease of PFAAs in fraction C and fraction P (associated with tissue fragments, cell membranes, and intact cells) especially for fraction C were revealed when they were combined, suggesting cytosolic PFAAs and Cd were susceptibly mutual effected. This study indicated that PFAAs and metals mutually affected their bioaccumulation and subcellular distribution in earthworms, which will help to understand the fate and risks of PFAAs and metals in co-contaminated soil.

A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50-1200 mg) for 6 weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured predose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDLs), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations were examined by: Standard statistical analyses using generalized estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a 2-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimate mean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately -1.2×10-3 mmol/l/μM and 2.8×10-3 pmol/l/μM, respectively. The PK/PD model predicted more closely the trends observed in the data as well as the pdfs of biomarkers. A decline in total cholesterol was observed, with a clear transition in shape and range of the pdfs, manifested by the maximum value of the Kullback-Leibler (KL) divergence, that occurred at plasma PFOA between 420 and 565 μM (175 000-230 000 ng/ml). High-density lipoprotein was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animal models and may motivate re-examination of the epidemiologic studies to PFOA at levels several orders of magnitude lower than this study. These observational studies have reported contrary associations, but currently understood biology does not support the existence of such conflicting effects.

Background: Multiple agencies have developed health-based toxicity values for exposure to perfluorooctanoic acid (PFOA). Although PFOA exposure occurs in utero and through breastfeeding, current health-based toxicity values have not been derived using fetal or child dosimetry. Therefore, current values may underestimate the potential risks to fetuses and nursing infants., Objective: Using fetal and child dosimetry, we aimed to calculate PFOA maternal human equivalent doses (HEDs), corresponding to a developmental mouse study lowest observed adverse effect level (LOAEL, 1mg/kg/day). Further, we investigated the impact of breastfeeding duration and PFOA half-life on the estimated HEDs., Methods: First, a pharmacokinetic model of pregnancy and lactation in mice was used to estimate plasma PFOA levels in pups following a maternal exposure to 1mg PFOA/kg/day for gestational days 1-17. Four plasma PFOA concentration metrics were estimated in pups: i) average prenatal; ii) average postnatal; iii) average overall (prenatal and postnatal); and iv) maximum. Then, Monte Carlo simulations were performed using a pharmacokinetic model of pregnancy and lactation in humans to generate distributions of maternal HEDs that would result in fetal/child plasma levels equivalent to those estimated in pups using the mouse model. Median (HED 50 ) and 1st percentile (HED 01 ) of calculated HEDs were calculated., Results: Estimated PFOA maternal HED 50 s ranged from 3.0×10 -4 to 1.1×10 -3 mg/kg/day and HED 01 s ranged from 4.7×10 -5 to 2.1×10 -4 mg/kg/day. All calculated HEDs were lower than the HED based on adult dosimetry derived by the Environmental Protection Agency (EPA) (5.3×10 -3 mg/kg/day)., Conclusion: Our results suggest that fetal/child dosimetry should be considered when deriving health-based toxicity values for potential developmental toxicants., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Physiologically based pharmacokinetic (PBPK) models are considered useful tools to describe the absorption, distribution, metabolism and excretion of xenobiotics. For accurate predictions, PBPK models require species-specific and compound-specific parameters. Zebrafish are considered an appropriate vertebrate model for investigating the toxicity of a wide variety of compounds. However, no specific mechanistic model exists for the pharmacokinetics of perfluoroalkyl acids (PFAAs) in zebrafish, despite growing concern about this class of ubiquitous environmental contaminants. The purpose of this study was to evaluate the current state of knowledge for the parameters that would be needed to construct such a model for zebrafish. We chose perfluorooctanoic acid (PFOA) as a model PFAA with greater data availability. We have updated a previous PBPK model for rainbow trout to simulate PFOA fate in zebrafish following waterborne exposure. For the first time, the model considers hepatobiliary circulation. In order to evaluate the availability of parameters to implement this model, we performed an extensive literature review to find zebrafish-specific parameters. As in previous approaches, we broadened our search to include mammalian and other fish studies when zebrafish-specific data were lacking. Based on the method used to measure or estimate parameters, or based on their species-specific origin, we scored and ranked the quality of available parameters. These scores were then used in Monte Carlo and partial rank correlation analyses to identify the most critical data gaps. The liver, where fatty acid binding proteins (FABPs) and plasma proteins are considered, represented the best model-data agreement. Lack of agreement in other tissues suggest better parameters are needed. The results of our study highlight the lack of zebrafish-specific parameters. Based on sensitivity and uncertainty analysis, parameters associated with PFAA-protein interactions and passive diffusion need further refinement to enable development of predictive models for these emerging chemicals in zebrafish.

Background: Municipal drinking water contaminated with perfluorinated alkyl acids had been distributed to one-third of households in Ronneby, Sweden. The source was firefighting foam used in a nearby airfield since the mid-1980s. Clean water was provided from 16 December 2013., Objective: To determine the rates of decline in serum perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), and their corresponding half-lives., Methods: Up to seven blood samples were collected between June 2014 and September 2016 from 106 participants (age 4-84 years, 53% female)., Results: Median initial serum concentrations were PFHxS, 277 ng/mL (range 12-1660); PFOS, 345 ng/mL (range 24-1500); and PFOA, 18 ng/mL (range 2.4-92). The covariate-adjusted average rates of decrease in serum were PFHxS, 13% per year (95% CI 12% to 15%); PFOS, 20% per year (95% CI 19% to 22%); and PFOA, 26% per year (95% CI 24% to 28%). The observed data are consistent with a first-order elimination model. The mean estimated half-life was 5.3 years (95% CI 4.6 to 6.0) for PFHxS, 3.4 years (95% CI 3.1 to 3.7) for PFOS and 2.7 years (95% CI 2.5 to 2.9) for PFOA. The interindividual variation of half-life was around threefold when comparing the 5th and 95th percentiles. There was a marked sex difference with more rapid elimination in women for PFHxS and PFOS, but only marginally for PFOA., Conclusions: The estimated half-life for PFHxS was considerably longer than for PFOS and PFOA. For PFHxS and PFOS, the average half-life is shorter than the previously published estimates. For PFOA the half-life is in line with the range of published estimates., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Two types of biocompatible surfactants were evaluated for their capability to formulate skin-friendly/non-irritant microemulsions as vehicles for two poorly water-soluble model drugs differing in properties and concentrations: alkyl polyglucosides (decyl glucoside and caprylyl/capryl glucoside) and ethoxylated surfactants (glycereth-7-caprylate/ caprate and polysorbate 80). Phase behavior, structural inversion and microemulsion solubilization potential for sertaconazole nitrate and adapalene were found to be highly dependent on the surfactants structure and HLB value. Performed characterization (polarized light microscopy, pH, electrical conductivity, rheological, FTIR and DSC measurements) indicated a formulation containing glycereth- 7-caprylate/caprate as suitable for incorporation of both drugs, whereas alkyl polyglucoside-based systems did not exhibit satisfying solubilization capacity for sertaconazole nitrate. Further, monitored parameters were strongly affected by sertaconazole nitrate incorporation, while they remained almost unchanged in adapalene-loaded vehicles. In addition, results of the in vivo skin performance study supported acceptable tolerability for all investigated formulations, suggesting selected microemulsions as promising carriers worth exploring further for effective skin delivery of model drugs.

Physiologically based pharmacokinetic (PBPK) modeling is a powerful in silico tool that can be used to simulate the toxicokinetics and tissue distribution of xenobiotic substances, such as perfluorooctanoic acid (PFOA), in organisms. However, most existing PBPK models have been based on the flow-limited assumption and largely rely on in vivo data for parametrization. In this study, we propose a permeability-limited PBPK model to estimate the toxicokinetics and tissue distribution of PFOA in male rats. Our model considers the cellular uptake and efflux of PFOA via both passive diffusion and transport facilitated by various membrane transporters, association with serum albumin in circulatory and extracellular spaces, and association with intracellular proteins in liver and kidney. Model performance is assessed using seven experimental data sets extracted from three different studies. Comparing model predictions with these experimental data, our model successfully predicts the toxicokinetics and tissue distribution of PFOA in rats following exposure via both IV and oral routes. More importantly, rather than requiring in vivo data fitting, all PFOA-related parameters were obtained from in vitro assays. Our model thus provides an effective framework to test in vitro-in vivo extrapolation and holds great promise for predicting toxicokinetics of per- and polyfluorinated alkyl substances in humans.

In this study, investigation was conducted into concentrations of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in Chinese farmed Trachinotus ovatus between 2014 and 2015 using a modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) and ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method. The tissue distribution (muscle, skin, liver, kidney and gill) in Trachinotus ovatus was also assessed. The detection frequencies of PFOS and PFOA in fish were 92% and 3%, respectively, and the mean concentrations were 0.392 and 0.015 μg/kg wet weight. The analysis of PFOS distribution in different tissues in Trachinotus ovatus showed the following trend: skin> gill> kidney> liver> flesh. Results revealeded farmed Trachinotus ovatus in China to generally be contaminated with PFOS. Moreover, the average daily intake for Chinese urban residents calculated on the basis of pollution content was 0.268 ng/kg body weight/d (PFOS) and 0.014 ng/kg body weight /d (PFOA), respectively. Both hazard ratio values were less than 1, indicating that exposure levels of PFOS and PFOA through Trachinotus ovatus consumption may not lead to adverse health effects in the Chinese population.

Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations. In vitro to in vivo extrapolation was utilized to inform descriptions of PFOA transport in the kidney. Monte Carlo simulations were incorporated to evaluate factors that account for the large inter-individual variability of serum PFOA concentrations measured in individuals from North Alabama in 2010 and 2016, and the Mid-Ohio River Valley between 2005 and 2008. Predicted serum PFOA concentrations were within two-fold of experimental data. With incorporation of Monte Carlo simulations, the model successfully tracked the large variability of serum PFOA concentrations measured in populations from the Mid-Ohio River Valley. Simulation of exposure in a population of 45 adults from North Alabama successfully predicted 98% of individual serum PFOA concentrations measured in 2010 and 2016, respectively, when non-drinking water ingestion of PFOA exposure was included. Variation in serum PFOA concentrations may be due to inter-individual variability in the disposition of PFOA and potentially elevated historical non-drinking water exposures., (Published by Elsevier Inc.)

On 25th May 2016, the U.S. EPA released reference doses (RfDs) for Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoic Acid (PFOA) of 20ng/kg/day, which were much more conservative than previous values. These RfDs rely on the choices of animal point of departure (PoD) and the toxicokinetics (TK) model. At this stage, considering that the human evidence is not strong enough for RfD determination, using animal data may be appropriate but with more uncertainties. In this article, the uncertainties concerning RfDs from the choices of PoD and TK models are addressed. Firstly, the candidate PoDs should include more critical endpoints (such as immunotoxicity), which may lead to lower RfDs. Secondly, the reliability of the adopted three-compartment TK model is compromised: the parameters are not non-biologically plausible; and this TK model was applied to simulate gestation and lactation exposures, while the two exposure scenarios were not actually included in the model structure., (Copyright © 2017. Published by Elsevier Ltd.)

Perfluoroalkyl substances (PFAS), including two most commonly studied compounds perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are widely distributed environmental pollutants, used extensively earlier. Due to their toxicological effects the use of PFAS is now regulated. Based on earlier studies on PFOA's distribution in bone and bone marrow in mice, we investigated PFAS levels and their possible link to bone microarchitecture of human femoral bone samples (n = 18). Soft tissue and bone biopsies were also taken from a 49-year old female cadaver for PFAS analyses. We also studied how PFOA exposure affects differentiation of human osteoblasts and osteoclasts. PFAS were detectable from all dry bone and bone marrow samples, PFOS and PFOA being the most prominent. In cadaver biopsies, lungs and liver contained the highest concentrations of PFAS, whereas PFAS were absent in bone marrow. Perfluorononanoic acid (PFNA) was present in the bones, PFOA and PFOS were absent. In vitro results showed no disturbance in osteogenic differentiation after PFOA exposure, but in osteoclasts, lower concentrations led to increased resorption, which eventually dropped to zero after increase in PFOA concentration. In conclusion, PFAS are present in bone and have the potential to affect human bone cells partly at environmentally relevant concentrations.

A vegetation study was conducted to investigate the interactive effects of perfluoroalkyl substances (PFASs), including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and Cadmium (Cd) on soil enzyme activities, phytotoxicity and bioaccumulation of wheat (Triticum aestivum L.) and rapeseed (Brassica campestris L.) from co-contaminated soil. Soil urease activities were inhibited significantly but catalase activities were promoted significantly by interaction of PFASs and Cd which had few effects on sucrase activities. Joint stress with PFASs and Cd decreased the biomass of plants and chlorophyll (Chl) content in both wheat and rapeseed, and malondialdehyde (MDA) content, superoxide dismutase (SOD) and peroxidase (POD) activities were increased in wheat but inhibited in rapeseed compared with single treatments. The bioconcentration abilities of PFASs in wheat and rapeseed were decreased, and the translocation factor of PFASs was decreased in wheat but increased in rapeseed with Cd addition. The bioaccumulation and translocation abilities of Cd were increased significantly in both wheat and rapeseed with PFASs addition. These findings suggested important evidence that the co-existence of PFASs and Cd reduced the bioavailability of PFASs while enhanced the bioavailability of Cd in soil, which increased the associated environmental risk for Cd but decreased for PFASs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To examine the kinetics of low doses of perfluoro compounds (PFCs), we administered perfluorohexanoic acid (C6A), perfluorooctanoic acid (C8A), perfluorononanoic acid (C9A) and perfluorooctane sulfonate (C8S) with a single oral dose (50-100 μg/kg BW), and in drinking water at 1, 5, and 25 μg/L for one and three months to male rats; and examined the distribution in the brain, heart, liver, spleen, kidney, whole blood and serum. C6A was very rapidly absorbed, distributed and eliminated from the tissues with nearly the same tissue t 1/2 of 2-3 hr. Considering serum Vd, and the tissue delivery, C6A was mainly in the serum with the lowest delivery to the brain; and no tissue accumulation was observed in the chronic studies as estimated from the single dose study. For the other PFCs, the body seemed to be an assortment of independent one-compartments with a longer elimination t 1/2 for the liver than the serum. The concentration ratio of liver/serum increased gradually from C 0 to a steady state. The high binding capacity of plasma protein may be the reason for the unusual kinetics, with only a very small fraction of free PFCs moving gradually to the liver. Although the tissue specific distribution was time dependent and different among the PFCs, the Vd and k e of each tissue were constant throughout the study. The possibility of extremely high C6A accumulation in the human brain and liver was suggested, by comparing the steady state tissue concentration of this study with the human data reported by Pérez et al. (2013).

The aim of this study was to confirm and investigate the gender differences in pharmacokinetic (PK) characteristics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances (PFASs) consisted of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) in both male and female rats. For this study, a simultaneous determination method of the 3 PFASs in rat plasma and tissues was developed and validated using a UPLC-MS/MS system. The PK parameters after a single oral or intravenous administration of the 3 PFASs in both rats were calculated using WinNonlin ® software. The mean half-life of the 3 PFASs in female and male rats was in the range of 0.15-0.19 and 1.6-1.8 days for PFOA, 23.5-24.8 and 26.4-28.7 days for PFOS, and 0.9-1.7 and 20.7-26.9 days for PFHxS, respectively. The 3 PFASs were highly distributed in the liver and kidney. These results suggest that there are gender differences in the PKs for PFOA and PFHxS in rats, whereas the PFOS represented no significant gender differences except the Kp value of liver. The validated simultaneous determination method of the 3 PFASs was also within the accepted criteria of the international guidance., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The effects of four types of dissolved organic matters (DOM) on the bioconcentration of perfluoroalkyl substances (PFASs) in Chironomus plumosus larvae have been studied. The PFASs included perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnA), and perfluorododecanoic acid (PFDoA). The DOM included humic acid (HA), fulvic acid (FA), tannic acid (TA), and a protein, peptone (PEP), and their concentrations ranged from 0 to 50 mg L(-1). The results showed that, upon bioconcentration equilibrium, the body burdens of longer perfluoroalkyl chain PFASs (PFOS, PFDA, PFUnA and PFDoA) decreased with PEP and HA concentrations while increased with FA and TA concentrations. When FA and TA concentrations increased from 0 to 50 mg L(-1), body burdens of these PFASs increased by 7.5%-148.8% and 5.7%-37.1%, respectively. However, the DOM had no significant impact on the body burdens of shorter perfluoroalkyl chain PFASs (PFOA and PFNA). All of the four types of DOM lowered not only the uptake rate constants (ku) of PFASs due to the decrease of freely dissolved PFAS concentrations, but also the elimination rate constants (ke) due to the inhibition effect of DOM on the PFAS elimination from the larvae. The reduction in the two constants varied with both DOM and PFAS types. In the presence of PEP and HA with larger molecular weights, the ku values decreased more than ke, leading to the decreased body burdens of longer perfluoroalkyl chain PFASs. As for FA and TA with smaller molecular weights, the ke values decreased more than ku, resulting in increased body burdens of longer perfluoroalkyl chain PFASs. This study suggests that the effects of DOM on PFAS bioconcentration depend not only on the concentration but also on the molecule weight of DOM, which should be considered in the bioavailability assessment of PFASs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Physiologically-based pharmacokinetic (PBPK) models are mathematical representations of the human body aimed at describing the time course distribution of chemicals in human tissues. Since parameterization of PBPK models is based on empirical estimation and experimental data, simulation results may have high degree of uncertainty. As a consequence, the reliability of model validation is highly affected. In this study, the parametric uncertainty associated with PBPK models developed for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were analyzed and the different validation approaches were discussed for a case-study in Tarragona County (NE of Spain). Physicochemical parameters and dietary intake of PFOS and PFOA were estimated from previous investigations performed in Tarragona County. A sensitivity analysis (SA) was performed to understand the degree of influence of input parameters on the final outcomes. The uncertainty of the PBPK models' outcome was assessed by propagating the parametric uncertainty using the Latin Hypercube Sampling (LHS) technique. The elimination constants (Tm and Kt) as well as the Free fraction and the Intake, were the most influential parameters according to the SA results, being up to 83% for PFOS and 99.9% for PFOA. The validation of the PBPK model, which was performed using different approaches, showed clear discrepancies in the visual validation when compared with the statistical analysis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In spite of numerous advantages, transdermal drug delivery systems are unfeasible for most drugs because of the barrier effect of the stratum corneum. Ionic liquids were recently used to enhance transdermal drug delivery by improving drug solubility. In the present study, safe and effective ionic liquids for transdermal absorption were obtained as salts generated by a neutralization reaction between highly biocompatible aliphatic carboxylic acids (octanoic acid or isostearic acid) and aliphatic amines (diisopropanolamine or triisopropanolamine) (Medrx Co., Ltd., 2009). The mechanism of skin permeability enhancement by ionic liquids was investigated by hydrophilic phenol red and hydrophobic tulobuterol. Further, the skin permeation enhancing effect was remarkably superior in the acid excess state rather than the neutralization state. Infrared absorption spectrum analysis confirmed that ionic liquids/aliphatic carboxylic acid/aliphatic amine are coexisting at all mixing states. In the acid excess state, ionic liquids interact with aliphatic carboxylic acids via hydrogen bonds. Thus, the skin permeation enhancing effect is not caused by the ionic liquid alone. The "liquid salt mixture," referred to as a complex of ingredients coexisting with ionic liquids, forms a molecular assembly incorporating hydrophilic drug. This molecular assembly was considered an effective and safety enhancer of transdermal drug permeation., (Copyright © 2016. Published by Elsevier B.V.)

The endogenous disulfide α-lipoic acid (LA) is an essential mitochondrial co-factor. In addition, LA and its reduced counterpart dihydro lipoic acid form a potent redox couple with antioxidative functions, for which it is used as dietary supplement and therapeutic. Recently, it has gained attention due to its cytotoxic effects in cancer cells, which is the key aspect of this review. We initially recapitulate the dietary occurrence, gastrointestinal absorption and pharmacokinetics of LA, illustrating its diverse antioxidative mechanisms. We then focus on its mode of action in cancer cells, in which it triggers primarily the mitochondrial pathway of apoptosis, whereas non-transformed primary cells are hardly affected. Furthermore, LA impairs oncogenic signaling and displays anti-metastatic potential. Novel LA derivatives such as CPI-613, which target mitochondrial energy metabolism, are described and recent pre-clinical studies are presented, which demonstrate that LA and its derivatives exert antitumor activity in vivo. Finally, we highlight clinical studies currently performed with the LA analog CPI-613. In summary, LA and its derivatives are promising candidates to complement the arsenal of established anticancer drugs due to their mitochondria-targeted mode of action and non-genotoxic properties., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Most children are exposed to perfluoroalkyl substances (PFASs) through placental transfer, breastfeeding, and other environmental sources. To date, there are no validated tools to estimate exposure and body burden during infancy and childhood. In this study, we aimed to (i) develop a two-generation pharmacokinetic model of prenatal and postnatal exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), and perfluorohexanesulfonate (PFHxS); and to (ii) evaluate it against measured children's levels in two studies. We developed a pharmacokinetic model consisting of a maternal and a child compartment to simulate lifetime exposure in women and transfer to the child across the placenta and through breastfeeding. To evaluate the model, we performed simulations for each mother-child dyad from two studies in which maternal PFAS levels at delivery and children's PFAS levels were available. Model predictions based on maternal PFAS levels, sex of child, body weight, and duration of breastfeeding explained between 52% and 60% of the variability in measured children's levels at 6 months of age and between 52% and 62% at 36 months. Monte Carlo simulations showed that the daily intake through breastfeeding and resulting internal PFAS levels can be much higher in nursing infants than in mothers. This pharmacokinetic model shows potential for postnatal exposure assessment in the context of epidemiological studies and risk assessment.

Background: Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with lower birth weight in epidemiologic studies. This association could be attributable to glomerular filtration rate (GFR), which is related to PFAS concentration and birth weight., Objectives: We used a physiologically based pharmacokinetic (PBPK) model of pregnancy to assess how much of the PFAS-birth weight association observed in epidemiologic studies might be attributable to GFR., Methods: We modified a PBPK model to reflect the association of GFR with birth weight (estimated from three studies of GFR and birth weight) and used it to simulate PFAS concentrations in maternal and cord plasma. The model was run 250,000 times, with variation in parameters, to simulate a population. Simulated data were analyzed to evaluate the association between PFAS levels and birth weight due to GFR. We compared simulated estimates with those from a meta-analysis of epidemiologic data., Results: The reduction in birth weight for each 1-ng/mL increase in simulated cord plasma for perfluorooctane sulfonate (PFOS) was 2.72 g (95% CI: -3.40, -2.04), and for perfluorooctanoic acid (PFOA) was 7.13 g (95% CI: -8.46, -5.80); results based on maternal plasma at term were similar. Results were sensitive to variations in PFAS level distributions and the strength of the GFR-birth weight association. In comparison, our meta-analysis of epidemiologic studies suggested that each 1-ng/mL increase in prenatal PFOS and PFOA levels was associated with 5.00 g (95% CI: -21.66, -7.78) and 14.72 g (95% CI: -8.92, -1.09) reductions in birth weight, respectively., Conclusion: Results of our simulations suggest that a substantial proportion of the association between prenatal PFAS and birth weight may be attributable to confounding by GFR and that confounding by GFR may be more important in studies with sample collection later in pregnancy.

Hair analysis is potentially advantageous in exposure assessment of perfluoroalkyl acids (PFAAs) as a non-invasive method, combined with the ability to reflect long-term exposure. The present study aims to assess the feasibility of using hair as an indicator of PFAA exposure. Adult male and female rats were subchronically exposed to selected PFAAs, including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorooctanesulfonate (PFOS), for 90 days. Hair, serum, and other tissues, including liver, kidney, spleen, lung, brain and heart, as well as the urine and feces excretions, were analyzed for PFAA levels. PFOA/PFNA/PFOS were detected in rat hair in a dose-dependent manner, in the order of PFOS>PFNA>PFOA. Hair PFAA concentrations were higher in male rats than the female rats, except for PFOS at low dose. Moreover, significant positive correlations as well as similar PFAA profiles were observed between hair, serum, and other tissues. Besides, hair PFAAs were negatively correlated with the urinary excretion rate. Although the influencing factors in humans still need further investigation, the results suggested that hair is capable of reflecting PFAA exposure, and could be employed as an alternative exposure bioindicator of PFAAs.

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.)

Purpose: In this study we aimed to address the poor drug-like properties of Gonadotropin-Releasing Hormone (GnRH) peptide through modification with lipids and carbohydrates., Methods: GnRH peptide was conjugated to 2-amino-D,L-octanoic acid (C8) and 2-amino-D,L-dodecanoic acid (C12) in monomer and dimer, along with (6-9) or without (2-5 and 11) a glucose moiety. Peptides were tested for their biological activity using different tumour cell lines. The toxicity of the constructs was evaluated in peripheral blood mononuclear cells (PBMC)., Results: All (glyco)lipopeptides showed improved metabolic stability in Caco-2 cell homogenates. Those with single lipid moiety (2, 4 and 8) exhibited prodrug-like properties. Permeability across Caco-2 cell monolayers was enhanced in the dimer C8-modified (glyco)lipopeptide (3) and the lipopeptide with C12 inserted mid-sequence (11). Most of the constructs showed moderate-to-high antiproliferative activity against GnRH-receptor positive DU145 and OVCAR-3 cells (up to 60%). Compound 11 was the most effective with IC50 = 26.4 ± 1.07 μg.ml(-1), which was comparable to triptorelin (25.1 ± 1.14 μg.mL(-1)). The sensitivity of OVCAR-3 cells to the effect of all analogues except for 11 decreased significantly in estrogen-reconstituted media. Only compounds 2, 4, 5 and 8 showed a steroid-dependent effect in DU145 cells. No compounds exhibited significant toxicity on PBMCs., Conclusion: These results indicated lipidation and glycosylation improves the druggability of GnRH and could lead to an increased direct antitumour activity in some hormone dependent and independent reproductive cancers.

Food is a major source of human exposure to perfluorooctanoic acid (PFOA), however, PFOA bioavailability in food has not been studied. An in vivo mouse model and three in vitro methods (unified BARGE method, UBM; physiologically based extraction test, PBET; and in vitro digestion method, IVD) were used to determine the relative bioavailability and bioaccessibility of PFOA in the presence of 17 foods. PFOA was mixed with foods of different nutritional compositions and fed to mice over a 7-d period. PFOA relative bioavailability was determined by comparing PFOA accumulation in the liver following PFOA exposure via food to that in water. PFOA bioavailability relative to water ranged from 4.30 ± 0.80 to 69.0 ± 11.9% and was negatively correlated with lipid content (r = 0.76). This was possibly due to competitive sorption of free fatty acids with PFOA onto transporters on intestine epithelial cells. Besides, cations in the gastrointestinal tract, such as Ca(2+) and Mg(2+), are capable of complexing PFOA and partitioning to the lipid phase. On the other hand, when assessed using in vitro assays, PFOA bioaccessibility varied with methods, being 8.7-73% (UBM), 9.8-99% (PBET), and 21-114% (IVD). PFOA bioaccessibility was negatively correlated with lipid content when assessed using UBM (r = 0.82); however, a poor correlation with food composition was observed for PBET and IVD (r = 0.01-0.50). When in vivo and in vitro data were compared, a strong correlation was observed for UBM (r = 0.79), but poor relationships were observed for PBET and IVD (r = 0.11-0.22). This was probably because the higher lipolysis ability and presence of Ca(2+) and Mg(2+) in the gastrointestinal fluid of UBM resulted in a lower potential to form stable micelles compared to PBET and IVD. These results indicated that PFOA relative bioavailability was mainly affected by lipid content in foods, and UBM has the potential to determine PFOA bioaccessibility in food samples.

A perfluorinated alkylated substances (PFAS) biomonitoring study was conducted in European eel (Anguilla anguilla) in Italy for the first time. Perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) concentrations were assessed in the organs of 35 wild eels from two locations, the highly impacted Po River and the Comacchio Lagoon along the north-western Adriatic coast. PFAS were extracted by ion-pairing liquid extraction procedure and measured using high performance liquid chromatography with electrospray ionization tandem mass spectrometry. There were no significant differences in mean PFAS concentrations (p>0.05) between samples from the two sites. PFOS and PFOA were detectable (>0.4ngg(-1) wet weight, w.w) in 73% and 31% of the total samples, respectively. PFOS concentrations ranged from <0.4 to 6.28ngg(-1)w.w and PFOA from <0.4 to 92.77ngg(-1)w.w. The highest PFAS levels were observed in blood and the lowest in muscle. Histology showed macrophage aggregates and hepatocytic vacuolation in some liver samples. No tissue anomalies were seen in the gonads, suggesting no reproductive impairment. The PFAS contamination levels observed were comparable to, or lower than, those reported in fish in other European countries, seeming to indicate that PFAS pollution of the study area is not remarkable., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The bioavailability of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in seven biosolids-amended soils without any additionally spiking to earthworms (Eisenia fetida) was studied. The uptake and elimination kinetics of PFOS and PFOA fit a one-compartment first-order kinetic model. PFOS displayed higher uptake and lower elimination rate coefficients, and longer time to reach steady-state (t(ss)) than those of PFOA. The bioaccumulation factors (BAFs) of PFOS and PFOA ranged 1.54–4.12 and 0.52–1.34 g(soil) g(worm)(−1), respectively. The BAFs and tss decreased with increasing concentrations of PFOS and PFOA in soils. Stepwise multiple regression analysis was used to elucidate the bioavailability of PFOS and PFOA. The results showed that the total concentrations of PFOS and PFOA, and organic matter (OM) contents in soils explained 87.2% and 91.3% of the variation in bioavailable PFOS and PFOA, respectively. PFOS and PFOA concentrations exhibited positive influence and OM contents showed the negative influence on the accumulation of PFOS and PFOA in earthworms. Soil pH and clay contents played relatively unimportant role in PFOS and PFOA bioavailability.

Objectives: Perfluoroalkyl carboxylic acids (PFCAs) consist of analogs with various carbon chain lengths. Their toxicokinetics have remained unexplored except in the case of perfluorooctanoic acid (8 carbon chemicals). This study aimed to investigate the toxicokinetics of PFCAs with six to fourteen carbon atoms (C6 to C14) in mice and humans., Methods: We applied a two-compartment model to mice administered PFCAs intravenously or by gavage. The time courses of the serum concentration and tissue distribution and elimination were evaluated for 24 hours after treatment. For human samples, urine from healthy volunteers, bile from patients who underwent biliary drainage, and cerebral spinal fluid (CSF) from brain drainage were collected., Results: The mouse experiment showed that short-chained PFCAs (C6 and C7) were rapidly eliminated in the urine, whereas long-chain PFCAs (C8 to C14) accumulated in the liver and were excreted slowly in feces. Urinary clearance of PFCAs in humans also decreased with increasing alkyl chain lengths, while biliary clearances increased. C9 to C10 had the smallest total clearance for both mice and humans. However, disparities existed in the magnitude of the total clearance between mice and humans. A slightly higher partition ratio (brain/serum) was observed for long-chained PFCAs in mice, but this was not observed in the corresponding partition ratio in humans (CSF/serum)., Conclusions: The large sequestration volumes of PFCAs in the liver seem to be attributable to the liver's large binding capacity in both species. This will be useful in evaluating PFCA bioaccumulation in other species.

Rainbow trout (Oncorhynchus mykiss) confined to respirometer-metabolism chambers were dosed with perfluorooctanoate (PFOA) by intra-arterial (i.a.) injection and sampled to obtain concentration time-course data for plasma, urine, and expired water. The data were then analyzed by compartmental modeling to estimate rates of renal and branchial clearance. Averaged across all animals, the renal clearance rate (1.35mL/h/kg) was more than ten times greater than the branchial clearance rate (0.12mL/h/kg). The average whole-body elimination half-life was 12.6d, which is somewhat longer than values obtained in previous studies with smaller trout. The tissue distribution of PFOA was assessed by collecting tissues at the end of chambered exposures and in a separate tissue time-course experiment. From the time-course study it appeared that an internal steady-state was established within 24h of i.a. injection. Consistent with previous studies, the rank order of PFOA concentration in tissues at steady state was: plasma>liver>kidney>muscle. In a second set of chambered experiments, fish were exposed to PFOA in water to determine the rate of branchial uptake. Branchial uptake rates were too low to assess directly by measuring PFOA concentrations in inspired and expired water. Uptake rate constants (mean 0.19L/d/kg; 0.1% uptake efficiency) were therefore estimated by compartmental modeling using plasma concentration time-course data and model parameters derived from the elimination experiments. It is clear from this effort that elimination of PFOA by trout occurs primarily via the renal route. This finding is consistent with numerous studies of mammals and suggests that trout possess membrane transporters that facilitate the movement of PFOA from plasma to urine., (Published by Elsevier B.V.)

In recent years, because of the potential human toxicity, concern on perfluoroalkyl substances (PFASs) has increased notably with special attention to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Unfortunately, there is currently an important knowledge gap on the burdens of these chemicals in most human tissues, as the reported studies have been mainly focused on plasma. In order to overcome these limitations, the use of physiologically-based pharmacokinetic (PBPK) models has been extended. The present study was aimed at testing an existing PBPK model for their predictability of PFOS and PFOA in a new case-study, and also to adapt it to estimate the PFAS content in human tissue compartments. Model validation was conducted by means of PFOA and PFOS concentrations in food and human drinking water from Tarragona County (Catalonia, Spain), and being the predicted results compared with those experimentally found in human tissues (blood, liver, kidney, liver and brain) of subjects from the same area of study. The use of human-derived partition coefficient (Pk) data was proven as more suitable for application to this PBPK model than rat-based Pk values. However, the uncertainty and variability of the data are still too high to get conclusive results. Consequently, further efforts should be carried out to reduce parametric uncertainty of PBPK models. More specifically, a deeper knowledge on the distribution of PFOA and PFOS within the human body should be obtained by enlarging the number of biological monitoring studies on PFASs., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

In order to compare between in vivo toxicity studies, dosimetry is needed to translate study-specific dose regimens into dose metrics such as tissue concentration. These tissue concentrations may then be compared with in vitro bioactivity assays to perhaps identify mechanisms relevant to the lowest observed effect level (LOEL) dose group and the onset of the observed in vivo toxicity. Here, we examine the perfluorinated compounds (PFCs) perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS). We analyzed 9 in vivo toxicity studies for PFOA and 13 in vivo toxicity studies for PFOS. Both PFCs caused multiple effects in various test species, strains, and genders. We used a Bayesian pharmacokinetic (PK) modeling framework to incorporate data from 6 PFOA PK studies and 2 PFOS PK studies (conducted in 3 species) to predict dose metrics for the in vivo LOELs and no observed effect levels (NOELs). We estimated PK parameters for 11 combinations of chemical, species, strain, and gender. Despite divergent study designs and species-specific PK, for a given effect, we found that the predicted dose metrics corresponding to the LOELs (and NOELs where available) occur at similar concentrations. In vitro assay results for PFOA and PFOS from EPA's ToxCast project were then examined. We found that most in vitro bioactivity occurs at concentrations lower than the predicted concentrations for the in vivo LOELs and higher than the predicted concentrations for the in vivo NOELs (where available), for a variety of nonimmunological effects. These results indicate that given sufficient PK data, the in vivo LOELs dose regimens, but not necessarily the effects, could have been predicted from in vitro studies for these 2 PFCs.

Perfluorinated chemicals (PFCs) have been used for many years in numerous industrial products and are known to accumulate in organisms. A recent survey showed that tissue levels of PFCs in aquatic organisms varied among compounds and species being undetected in freshwater zebra mussels Dreissena polymorpha. Here we studied the bioaccumulation kinetics and effects of two major PFCs, perfluorooctane sulfonic acid compound (PFOS) and perfluorooctanoic acid (PFOA), in multixenobiotic transporter activity (MXR) and filtration and oxygen consumption rates in zebra mussel exposed to a range of concentrations of a PCF mixture (1-1,000 μg/L) during 10 days. Results indicate a low potential of the studied PFCs to bioaccumulate in zebra mussel tissues. PFCs altered mussel MXR transporter activity being inhibited at day 1 but not at day 10. Bioaccumulation kinetics of PFCs were inversely related with MXR transporter activity above 9 ng/g wet weight and unrelated at tissue concentration lower than 2 ng/g wet weight suggesting that at high tissue concentrations, these type of compounds may be effluxed out by MXR transporters and as a result have a low potential to be bioaccumulated in zebra mussels. Oxygen consumption rates but not filtering rates were increased in all exposure levels and periods indicating that at environmental relevant concentrations of 1 μg/L, the studied PFCs enhanced oxidative metabolism of mussels. Overall, the results obtained in this study confirm previous findings in the field indicating that an important fraction of PFC accumulated in mussel tissues is eliminated actively by MXR transporters or other processes that are metabolically costly.