RESUMEN
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.
Asunto(s)
Simulación por Computador , Fluorocarburos , Túbulos Renales Proximales , Modelos Biológicos , Humanos , Fluorocarburos/farmacocinética , Túbulos Renales Proximales/metabolismo , Semivida , Tasa de Depuración Metabólica , Flujo de Trabajo , Eliminación Renal , Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/metabolismo , Células Epiteliales/metabolismoRESUMEN
In the evolving field of drug discovery and development, multiorgans-on-a-chip and microphysiological systems are gaining popularity owing to their ability to emulate in vivo biological environments. Among the various gut-liver-on-a-chip systems for studying oral drug absorption, the chip developed in this study stands out with two distinct features: incorporation of perfluoropolyether (PFPE) to effectively mitigate drug sorption and a unique enterohepatic single-passage system, which simplifies the analysis of first-pass metabolism and oral bioavailability. By introducing a bolus drug injection into the liver compartment, hepatic extraction alone could be evaluated, further enhancing our estimation of intestinal availability. In a study on midazolam (MDZ), PFPE-based chips showed more than 20-times the appearance of intact MDZ in the liver compartment effluent compared to PDMS-based counterparts. Notably, saturation of hepatic metabolism at higher concentrations was confirmed by observations when the dose was reduced from 200 µM to 10 µM. This result was further emphasized when the metabolism was significantly inhibited by the coadministration of ketoconazole. Our chip, which is designed to minimize the dead volume between the gut and liver compartments, is adept at sensitively observing the saturation of metabolism and the effect of inhibitors. Using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal and hepatic availabilities were 0.96 and 0.82, respectively; these values are higher than the known human in vivo values. Although the metabolic activity in each compartment can be further improved, this gut-liver-on-a-chip can not only be used to evaluate oral bioavailability but also to carry out individual assessment of both intestinal and hepatic availability.
Asunto(s)
Disponibilidad Biológica , Éteres , Fluorocarburos , Hígado , Hígado/metabolismo , Fluorocarburos/química , Fluorocarburos/farmacocinética , Fluorocarburos/metabolismo , Humanos , Administración Oral , Dispositivos Laboratorio en un Chip , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , AnimalesRESUMEN
Perfluoroalkyl substances (PFAS) have been identified in various products that come in contact with human skin, ranging from school uniforms to personal care products. Despite this, knowledge on human dermal uptake of PFAS is lacking. Thus, the human dermal absorption of 17 PFAS was assessed, for the first time, using in vitro 3D-human skin equivalent models exposed to 500 ng/cm2 PFAS dissolved in methanol over 24-36 h. The distribution of target PFAS is presented, based on three fractions: absorbed, un-absorbed, and retained within skin tissue (absorbable dose). Perfluoropentanoic acid (PFPeA) and perfluorobutane sulfonate (PFBS) had the highest absorbed fraction, 58.9 % and 48.7 % respectively, with the absorbed fraction decreasing with increasing carbon chain length of the studied perfluorocarboxylic acids (PFCAs) (r = 0.97, p = 0.001) and perfluorosulfonic acids (PFSAs) (r = 0.97, p = 0.004). Interestingly, while longer chain PFAS (Cn ≥ 9) were not directly absorbed, a large fraction of the exposure dose was detected within the skin tissue at the end of the exposure. This was most apparent for perfluoroundecanoic acid (PFUnDA) and perfluorononane sulfonate (PFNS) for which 66.5 % and 68.3 % of the exposure dose was found within the skin tissue, while neither compound was detected in the absorbed fraction. For compounds with a carbon chain length > 11, the fraction found within the skin tissue, decreases with increasing chain length. Physicochemical properties played a role in dermal permeation of PFAS, with a clear inverse correlation between logKOW and absorbed fraction for both PFCAs (r = -0.97; p ≤ 0.001) and PFSAs (r = -0.99; p ≤ 0.001). Steady-state flux (JSS) and permeation coefficients (Papp) were determined for target compounds with significant permeation after 36 h exposure (C5-C8 PFCAs and C4-C7 PFSAs). In general, both the flux and permeation coefficient decreased with increasing chain length.
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Fluorocarburos , Absorción Cutánea , Piel , Fluorocarburos/metabolismo , Fluorocarburos/farmacocinética , Humanos , Piel/metabolismo , Disponibilidad Biológica , Modelos Biológicos , Contaminantes Ambientales/metabolismo , Contaminantes Ambientales/farmacocinética , Técnicas In VitroRESUMEN
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.
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Peces , Fluorocarburos , Contaminantes Químicos del Agua , Animales , Peces/metabolismo , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/metabolismo , Fluorocarburos/metabolismo , Fluorocarburos/análisis , Fluorocarburos/farmacocinética , Bioacumulación , Modelos Biológicos , Lagos/química , Monitoreo del Ambiente/métodosRESUMEN
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.
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Algoritmos , Modelos Biológicos , Titanio , Animales , Ratas , Titanio/farmacocinética , Titanio/toxicidad , Titanio/química , Distribución Tisular , Caprilatos/farmacocinética , Caprilatos/toxicidad , Fluorocarburos/farmacocinética , Fluorocarburos/toxicidad , Fluorocarburos/química , Nanopartículas/toxicidad , Masculino , Cinética , Simulación por ComputadorRESUMEN
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 5â¯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.
Asunto(s)
Caprilatos , Fluorocarburos , Modelos Biológicos , Permeabilidad , Especificidad de la Especie , Caprilatos/farmacocinética , Fluorocarburos/farmacocinética , Animales , Masculino , Femenino , Humanos , Ratas , Factores de Edad , Ratas Sprague-Dawley , Factores Sexuales , Administración Oral , Caracteres SexualesRESUMEN
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.
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Fluorocarburos , Infarto del Miocardio , Animales , Fluorocarburos/farmacocinética , Porcinos , Ratas , Infarto del Miocardio/diagnóstico por imagen , Masculino , Medios de Contraste/farmacocinética , Nanopartículas , Ratas Sprague-Dawley , Miocardio/metabolismo , Modelos Animales de Enfermedad , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Microburbujas , Femenino , Ultrasonografía/métodosRESUMEN
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.
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Ácidos Alcanesulfónicos , Contaminantes Ambientales , Fluorocarburos , Adulto , Humanos , Alcanosulfonatos , Plasma , Fluorocarburos/farmacocinéticaRESUMEN
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.
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Caprilatos , Fluorocarburos , Humanos , Toxicocinética , Fluorocarburos/farmacocinética , Medición de Riesgo , Proteínas de Transporte de Membrana , Modelos BiológicosRESUMEN
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.
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Fluorocarburos/farmacocinética , Modelos Biológicos , Adolescente , Adulto , Factores de Edad , Niño , Relación Dosis-Respuesta a Droga , Femenino , Fluorocarburos/sangre , Fluorocarburos/orina , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Adulto JovenRESUMEN
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.
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Caprilatos , Contaminantes Ambientales/farmacocinética , Fluorocarburos , Pez Cebra , Animales , Caprilatos/farmacocinética , Fluorocarburos/farmacocinética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Distribución TisularRESUMEN
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.
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Caprilatos/farmacocinética , Fluorocarburos/farmacocinética , Animales , Teorema de Bayes , Masculino , Permeabilidad , Ratas , Distribución TisularRESUMEN
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 log10BCF > 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.
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Caprilatos/farmacocinética , Monitoreo del Ambiente/métodos , Fluorocarburos/farmacocinética , Paracentrotus/metabolismo , Animales , Aguas Salinas/química , Agua de Mar/química , Distribución Tisular , Contaminantes Químicos del Agua/farmacocinéticaRESUMEN
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.
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Caprilatos/farmacocinética , Fluorocarburos/farmacocinética , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Estudios Observacionales como Asunto , Medición de RiesgoRESUMEN
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.
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Flúor , Pulmón/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Medios de Contraste/administración & dosificación , Medios de Contraste/farmacocinética , Femenino , Flúor/administración & dosificación , Flúor/farmacocinética , Fluorocarburos/administración & dosificación , Fluorocarburos/farmacocinética , Humanos , Pulmón/metabolismo , Mediciones del Volumen Pulmonar/métodos , Imagen por Resonancia Magnética/normas , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Estudios Prospectivos , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
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.
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Ácidos Alcanesulfónicos/farmacocinética , Caprilatos/farmacocinética , Fluorocarburos/farmacocinética , Lactuca/efectos de los fármacos , Contaminantes del Suelo/farmacocinética , Suelo/química , Adsorción , Carbón Orgánico/química , Productos Agrícolas , Lactuca/metabolismo , Contaminantes del Suelo/análisisRESUMEN
A simplified physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor, metabolizing and/or excreting, and central compartments was recently proposed. In the current study, this type of PBPK model was set up for perï¬uorooctane sulfonate, an environmental toxicant with liver effects, as a model compound; the model was then used to estimate tissue concentrations. The pharmacokinetic parameter input values for the model were calculated to give the best fit to reported/measured blood substrate concentrations in rats. The maximum concentrations and areas under the concentration versus time curves in plasma, liver, and kidney extrapolated using PBPK models for perï¬uorobutane sulfonic acid, perï¬uorohexane sulfonic acid, and perï¬uorooctane sulfonic acid were consistent with the reported mean values in rats. Using the rat models and scaled-up human PBPK models, some accumulation of perï¬uorooctane sulfonic acid in plasma and liver was seen after repeated doses. The reported 50th and 95th percentile concentrations of perï¬uorooctane sulfonic acid in human blood (0.0048 and 0.0183 ng/mL, respectively) in the general population underwent reverse dosimetry analysis using our PBPK models. These human blood concentrations potentially imply exposures of 0.041 and 0.16 µg/kg/day, respectively, for 90 days, values that are roughly similar to the reference dose (0.02 µg/kg/day) with an uncertainty factor of 30. These results indicate the relatively good estimates for tissue and blood exposures of chemical substrates after oral doses generated using the latest PBPK models.
Asunto(s)
Ácidos Alcanesulfónicos/farmacocinética , Ácidos Alcanesulfónicos/toxicidad , Fluorocarburos/farmacocinética , Fluorocarburos/toxicidad , Riñón/metabolismo , Hígado/metabolismo , Modelos Biológicos , Administración Oral , Ácidos Alcanesulfónicos/administración & dosificación , Ácidos Alcanesulfónicos/sangre , Animales , Relación Dosis-Respuesta a Droga , Fluorocarburos/administración & dosificación , Fluorocarburos/sangre , Humanos , Nivel sin Efectos Adversos Observados , Ratas , Distribución Tisular , ToxicocinéticaRESUMEN
BACKGROUND: The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are immunotoxic and may contribute to an association with disease severity. METHODS: From Danish biobanks, we obtained plasma samples from 323 subjects aged 30-70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be immunotoxic. Register data was obtained to classify disease status, other health information, and demographic variables. We used ordered logistic regression analyses to determine associations between PFAS concentrations and disease outcome. RESULTS: Plasma-PFAS concentrations were higher in males, in subjects with Western European background, and tended to increase with age, but were not associated with the presence of chronic disease. Of the study population, 108 (33%) had not been hospitalized, and of those hospitalized, 53 (16%) had been in intensive care or were deceased. Among the five PFASs considered, perfluorobutanoic acid (PFBA) showed an unadjusted odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39-3.46) for increasing severities of the disease. Among those hospitalized, the fully adjusted OR for getting into intensive care or expiring was 5.18 (1.29, 20.72) when based on plasma samples obtained at the time of diagnosis or up to one week before. CONCLUSIONS: Measures of individual exposures to immunotoxic PFASs included short-chain PFBA known to accumulate in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of a more severe course of COVID-19. Given the low background exposure levels in this study, the role of exposure to PFASs in COVID-19 needs to be ascertained in populations with elevated exposures.
Asunto(s)
Bancos de Muestras Biológicas , COVID-19 , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales , Fluorocarburos , Sistema de Registros , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Adulto , Anciano , COVID-19/sangre , COVID-19/mortalidad , COVID-19/terapia , Contaminantes Ambientales/farmacología , Contaminantes Ambientales/toxicidad , Femenino , Fluorocarburos/farmacocinética , Fluorocarburos/toxicidad , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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.