Development and application of an interactive generic physiologically based pharmacokinetic (igPBPK) model for adult beef cattle and lactating dairy cows to estimate tissue distribution and edible tissue and milk withdrawal intervals for per- and polyfluoroalkyl substances (PFAS).

Humans can be exposed to per- and polyfluoroalkyl substances (PFAS) through dietary intake from milk and edible tissues from food animals. This study developed a physiologically based pharmacokinetic (PBPK) model to predict tissue and milk residues and estimate withdrawal intervals (WDIs) for multiple PFAS including PFOA, PFOS and PFHxS in beef cattle and lactating dairy cows. Results showed that model predictions were mostly within a two-fold factor of experimental data for plasma, tissues, and milk with an estimated coefficient of determination (R2) of >0.95. The predicted muscle WDIs for beef cattle were <1 day for PFOA, 449 days for PFOS, and 69 days for PFHxS, while the predicted milk WDIs in dairy cows were <1 day for PFOA, 1345 days for PFOS, and zero day for PFHxS following a high environmental exposure scenario (e.g., 49.3, 193, and 161 ng/kg/day for PFOA, PFOS, and PFHxS, respectively, for beef cattle for 2 years). The model was converted to a web-based interactive generic PBPK (igPBPK) platform to provide a user-friendly dashboard for predictions of tissue and milk WDIs for PFAS in cattle. This model serves as a foundation for extrapolation to other PFAS compounds to improve safety assessment of cattle-derived food products.

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

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

Plasma, liver, and kidney exposures in rats after oral doses of industrial chemicals predicted using physiologically based pharmacokinetic models: A case study of perfluorooctane sulfonic acid.

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 perfluorooctane 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 perfluorobutane sulfonic acid, perfluorohexane sulfonic acid, and perfluorooctane sulfonic acid were consistent with the reported mean values in rats. Using the rat models and scaled-up human PBPK models, some accumulation of perfluorooctane sulfonic acid in plasma and liver was seen after repeated doses. The reported 50th and 95th percentile concentrations of perfluorooctane 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.

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

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

Perfluorooctanesulfonic acid (PFOS) and perfluorobutanesulfonic acid (PFBS) impaired reproduction and altered offspring physiological functions in Caenorhabditis elegans.

Perfluorobutanesulfonic acid (PFBS), a shorter chain Per- and polyfluoroalkyl substances (PFASs) cognate of perfluorooctanesulfonic acid (PFOS), has been used as replacement for the toxic surfactant PFOS. However, emerging evidences suggest safety concerns for PFBS and its effect on reproductive health is still understudied. Therefore, the current work aimed to investigate the effect of PFBS, in comparison to PFOS, on reproductive health using Caenorhabditis elegans as an in vivo animal model. PFOS (≥10 µM) and PFBS (≥1000 µM) significantly impaired the reproduction capacity of C. elegans, represented as reduced brood size (total egg number) and progeny number (hatched offspring number), without affecting the hatchability. Additionally, the preconception exposure of PFOS and PFBS significantly altered the embryonic nutrient loading and composition, which further led to abnormalities in growth rate, body size and locomotive activity in F1 offspring. Though the effective exposure concentration of PFBS was approximately 100 times higher than PFOS, the internal concentration of PFBS was lower than that of PFOS to produce the similar effects of PFOS. In conclusion, PFOS and PFBS significantly impaired the reproductive capacities in C. elegans and the preconception exposure of these two compounds can lead to offspring physiological dysfunctions.

Pharmacokinetic functions of human induced pluripotent stem cell-derived small intestinal epithelial cells.

To develop a novel intestinal drug absorption system using intestinal epithelial cells derived from human induced pluripotent stem (iPS) cells, the cells must possess sufficient pharmacokinetic functions. However, the CYP3A4/5 activities of human iPS cell-derived small intestinal epithelial cells prepared using conventional differentiation methods is low. Further, studies of the CYP3A4/5 activities of human iPS-derived and primary small intestinal cells are not available. To fill this gap in our knowledge, here we used forskolin to develop a new differentiation protocol that activates adenosine monophosphate signaling. mRNA expressions of human iPS cell-derived small intestinal epithelial cells, such as small intestine markers, drug-metabolizing enzymes, and drug transporters, were comparable to or greater than those of the adult small intestine. The activities of CYP3A4/5 in the differentiated cells were equal to those of human primary small intestinal cells. The differentiated cells had P-glycoprotein and PEPT1 activities equivalent to those of Caco-2 cells. Differentiated cells were superior to Caco-2 cells for predicting the membrane permeability of drugs that were absorbed through a paracellular pathway and via drug transporters. In summary, here we produced human iPS cell-derived small intestinal epithelial cells with CYP3A4/5 activities equivalent to those of human primary small intestinal cells.

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

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

Bayesian evaluation of a physiologically based pharmacokinetic (PBPK) model for perfluorooctane sulfonate (PFOS) to characterize the interspecies uncertainty between mice, rats, monkeys, and humans: Development and performance verification.

A challenge in the risk assessment of perfluorooctane sulfonate (PFOS) is the large interspecies differences in its toxicokinetics that results in substantial uncertainty in the dosimetry and toxicity extrapolation from animals to humans. To address this challenge, the objective of this study was to develop an open-source physiologically based pharmacokinetic (PBPK) model accounting for species-specific toxicokinetic parameters of PFOS. Considering available knowledge about the toxicokinetic properties of PFOS, a PBPK model for PFOS in mice, rats, monkeys, and humans after intravenous and oral administrations was created. Available species-specific toxicokinetic data were used for model calibration and optimization, and independent datasets were used for model evaluation. Bayesian statistical analysis using Markov chain Monte Carlo (MCMC) simulation was performed to optimize the model and to characterize the uncertainty and interspecies variability of chemical-specific parameters. The model predictions well correlated with the majority of datasets for all four species, and the model was validated with independent data in rats, monkeys, and humans. The model was applied to predict human equivalent doses (HEDs) based on reported points of departure in selected critical toxicity studies in rats and monkeys following U.S. EPA's guidelines. The lower bounds of the model-derived HEDs were overall lower than the HEDs estimated by U.S. EPA (e.g., 0.2 vs. 1.3 µg/kg/day based on the rat plasma data). This integrated and comparative analysis provides an important step towards improving interspecies extrapolation and quantitative risk assessment of PFOS, and this open-source model provides a foundation for developing models for other perfluoroalkyl substances.

Occurrence and tissue distribution of perfluoroalkyl substances (PFASs) in sharks and rays from the eastern Mediterranean Sea.

Persistent organic pollutants (POPs), including Perfluoroalkyl substances (PFASs), enter into the marine ecosystem, raising questions on possible adverse effects caused to the health of marine organisms and especially of top predators. Thus, there is an urge to assess the occurrence and the tissue distribution of PFASs in apex predators. To this end, the current study examines concentrations and distribution of 15 PFASs among 85 samples of different tissues from 9 shark and ray species collected in Greece. The results showed a similar PFAS pattern among the different tissues, with long carbon chain PFASs being the most frequently detected compounds. PFTrDA was the most predominant compound in terms of concentration and frequency of detection, followed by PFUnDA and PFOS. PFTrDA concentrations ranged between < LOQ and 27.1 ng/g ww, while PFUnDA and PFOS levels ranged from  heart > liver ≈ gills > muscle. Relative contribution (%) of individual compounds to ΣPFAS concentration varied among the different shark tissues, and also among the different shark species. No correlation between PFASs levels in tissues and sharks' gender, length and geographical origin was observed.

Does water temperature influence the distribution and elimination of perfluorinated substances in rainbow trout (Oncorhynchus mykiss)?

Perfluorinated and polyfluorinated substances (PFASs) are widely found in freshwater ecosystems because of their resistance to degradation and their ability to accumulate in aquatic organisms. While water temperature controls many physiological processes in fish, knowledge of the effects of this factor on PFAS toxicokinetic is still limited. This study presents experimental results of internal distribution and elimination rates of two perfluorinated acid compounds, namely perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) in adult rainbow trout (Oncorhynchus mykiss) exposed to three temperatures. Dietary exposure experiments were conducted at 7 °C, 11 °C, and 19 °C and liver, blood, muscle, brain, and kidney were sampled for analysis. PFOS concentrations were comparable to or exceeded those of PFHxS, while PFHxS was eliminated faster than PFOS, whatever the temperature. Internal distribution changed significantly for both substances when fish were exposed to a range of temperatures from 7 to 19 °C. Indeed, PFOS and PFHxS relative distribution increased in blood, liver, and brain while they decreased in muscle when the water temperature rose. The water temperature variation affected the elimination half-lives, depending on the substances and organs.

Long-term storage of PEGylated liposomal oxaliplatin with improved stability and long circulation times in vivo.

Liposomal anticancer drugs have been developed with improved clinical effects and reduced side effects. We have developed a PEGylated liposomal formulation of oxaliplatin that has anticancer effects in animal models of colorectal cancer with a favorable toxicity profile. To move this formulation into clinical development, a formulation that is stable during long term storage is needed, which has similar pharmacokinetics and therapeutic activity against solid tumors to the original formulation. In this study, we found that PEGylated liposomal oxaliplatin showed no changes in particle size after long term storage (12 months at 2-8 °C), but phospholipid degradation had occurred. Hence, the stored formulation had compromised membrane integrity, resulting in decreased in vivo circulation times of the liposomes. To improve the stability during long-term storage, a screening study to obtain an appropriate stabilizer was carried out. The buffer 2-morpholinoethansulfonic acid (MES) attenuated not only phospholipid degradation but also oxaliplatin degradation, unlike most other excipients. After 12 months storage at 2-8 °C in the presence of MES only slight degradation of phospholipids in PEGylated liposomal oxaliplatin occurred, resulting in similar in vivo pharmacokinetic profiles of the encapsulated oxaliplatin to the original formulation. Long term stability of PEGylated liposomal oxaliplatin was achieved by addition of MES, resulting in long circulation half-lives in vivo, a property which would be expected to lead to increased suppression of tumor growth and reduced side effects. Our formulation may now be suitable for clinical development.

Characterization of non-radiolabeled Thyroxine (T4) uptake in cryopreserved rat hepatocyte suspensions: Pharmacokinetic implications for PFOA and PFOS chemical exposure.

The alteration of thyroxine (T4) 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 T4 cellular uptake in cryopreserved rat hepatocyte suspensions. The environmental chemicals perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) were evaluated for their effect on T4 hepatic uptake. At 37 °C, hepatic assays demonstrated saturable kinetics with increasing T4 concentrations, while a linear uptake rate consistent with passive diffusion was detected at 4 °C. Carrier-mediated (37-4 °C) transport of T4 was the predominant hepatic uptake process versus passive diffusion. Cyclosporin A (CsA) chemically inhibited T4 hepatic uptake, whereas PFOA/PFOS displayed no inhibition of T4 translocation. Increasing PFOA/PFOS concentration levels with the T4 serum carrier-protein transthyretin (TTR) present resulted in a dose-response increase in T4 hepatic uptake rates, correlating with increased T4 free fraction values. Hepatic assays conducted in the presence of PFOA/PFOS and TTR displayed an enhanced first-order T4 hepatic uptake rate consistent with carrier-mediated transport. These in vitro findings characterizing increased T4 hepatic uptake provides mechanistic insight regarding decreased T4 serum levels (hypothyroxinemia) previously observed within in vivo rodent studies following perfluorinated chemical exposure.

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

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

Suitability of Wild Boar (Sus scrofa) as a Bioindicator for Environmental Pollution with Perfluorooctanoic Acid (PFOA) and Perfluorooctanesulfonic Acid (PFOS).

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.

Effects of combined exposure to perfluoroalkyl acids and heavy metals on bioaccumulation and subcellular distribution in earthworms (Eisenia fetida) from co-contaminated soil.

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.

Internal concentrations of perfluorobutane sulfonate (PFBS) comparable to those of perfluorooctane sulfonate (PFOS) induce reproductive toxicity in Caenorhabditis elegans.

Perfluorobutane sulfonate (PFBS) is considered a less-toxic replacement for perfluorooctane sulfonate (PFOS), with multiple applications in industrial and consumer products. Previous studies comparing their toxicity generally used similar exposure levels, without taking internal concentrations into account. The current study compared the reproductive toxicity of PFOS and PFBS, at similar internal concentrations, to Caenorhabditis elegans (C. elegans). PFBS was much less bioaccumulative than PFOS. The 48-h median lethal concentrations (LC50) for PFOS and PFBS were 1.4 µM (95% confidence interval [CI]: 1.1-1.6) and 794 µM (95% CI: 624-1009), respectively. Egg production and brood number of C. elegans decreased markedly following exposure to 0.1 µM PFOS or 1000 or 1500 µM PFBS. Germ-cell apoptosis and production of reactive oxygen species increased significantly following exposure to 2 µM PFOS or 500 or 1000 µM PFBS. Expression of the antioxidant genes sod-3, ctl-2, and gst-4 and the pro-apoptotic genes egl-1 and ced-13 was altered significantly following PFOS and PFBS exposure. These findings indicate that both chemicals exert reproductive toxicity in C. elegans, probably owing to germ-cell apoptosis resulting from elevated levels of reactive oxygen species. The vastly different exposure concentrations of PFBS and PFOS used in this study produced similar internal concentrations, leading to the reproductive toxicities observed.

High concentrations of perfluorooctane sulfonate in mucus of tiger puffer fish Takifugu rubripes: a laboratory exposure study.

Distribution of perfluorooctane sulfonate (PFOS) was investigated in tissues (plasma, blood clot, mucus, skin, liver, muscle, and gonad) of tiger puffer fish Takifugu rubripes. A single dose of PFOS was intraperitoneally injected at 0.1 mg/kg body weight with samples taken over a 14-day period. The highest concentration of PFOS was found in the plasma, 861 ng/mL at 14 days, followed by the mucus, liver, blood clot, gonads, muscles, and skin of fish. A gradual upward trend in PFOS concentration was observed in the mucus and liver whereas there was no change in the plasma, blood clot, gonad, muscle, and skin after the initial increase in PFOS concentrations following injection. No significant trend for estimated total PFOS content in whole body was observed during the experimental period. Relatively high concentrations of PFOS (690 ng/g ww after 14 days) were detected in body surface mucus that continuously oozes from the skin. These results may suggest that mucus is one of the elimination pathways of PFOS in tiger puffer fish.

Half-lives of PFOS, PFHxS and PFOA after end of exposure to contaminated drinking water.

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.

Developing integrated PBPK/PD coupled mechanistic pathway model (miRNA-BDNF): An approach towards system toxicology.

Integration of a dynamic signal transduction pathway into the tissue dosimetry model is a major advancement in the area of computational toxicology. This paper illustrates the ways to incorporate the use of existing system biological model in the field of toxicology via its coupling to the Physiological based Pharmacokinetics and Pharmacodynamics (PBPK/PD) model. This expansion framework of integrated PBPK/PD coupled mechanistic system pathway model can be called as system toxicology that describes the kinetics of both - the chemicals and - biomolecules, help us to understand the dynamic and steady-state behaviors of molecular pathways under perturbed condition. The objective of this article is to illustrate a system toxicology based approach by developing an integrated PBPK/PD coupled miRNA-BDNF pathway model and to demonstrate its application by taking a case study of the PFOS mediated neurotoxicity. System dynamic involves miRNA-mediated BDNF regulation, which plays an important role in the control of neuronal cell proliferation, differentiation, and survivability.