Unravelling sex-specific BPA toxicokinetics in children using a pediatric PBPK model.

Bisphenol A (BPA) is a widely known endocrine disruptor (ED) found in many children's products such as toys, feeding utensils, and teething rings. Recent epidemiology association studies have shown postnatal BPA exposure resulted in developing various diseases such as diabetes, obesity, and neurodegeneration, etc., later in their lives. However, little is known about its sex-specific metabolism and consequently internal exposure. The aim of this study was to develop a sex-specific pediatric physiologically based pharmacokinetic model (PBPK) for BPA to compare their toxicokinetic differences. First, the published adult PBPK model was re-validated, and then this model was extended by interpolation to incorporate pediatric sex specific physiological and biochemical parameters. We used both the classical body weight and ontogeny-based scaling approach to interpolate the metabolic process. Then, the pharmacokinetic attributes of the models using the two-scaling approach mentioned above were compared with adult model. Further, a sex-specific PBPK model with an ontogeny scaling approach was preferred to evaluate the pharmacokinetic differences. Moreover, this model was used to reconstruct the BPA exposure from two cohorts (Helix and PBAT Cohort) from 7 EU countries. The half-life of BPA was found to be almost the same in boys and girls at the same exposure levels. Our model estimated BPA children's exposure to be about 1500 times higher than the tolerable daily intake (TDI) recently set by European Food Safety Authority (EFSA) i.e., 0.04 ng/kg BW/day. The model demonstrated feasibility of extending the adult PBPK to sex-specific pediatric, thus investigate a gender-specific health risk assessment.

Evaluation of acetamiprid and azoxystrobin residues and their hormonal disrupting effects on male rats using liquid chromatography-tandem mass spectrometry.

Endocrine-disrupting compounds as pesticides affect the hormonal balance, and this can result in several diseases. Therefore, the analysis of representative hormones with acetamiprid (AC) and azoxystrobin (AZ) was a good strategy for the investigation of the endocrine-disrupting activity of pesticides. Hence, a sensitive and rapid analytical method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. The method was validated for the analysis of AC, AZ, estriol, estrone, progesterone, and testosterone in the serum, testis, and liver of rats. The correlation between the residues of pesticides and the disturbance of the endocrine system was evaluated. The different mass parameters, mobile phase types, analytical columns, injection volumes, and extraction solvents were compared to get the lowest limit of detection of the studied compounds. The detection limits of AC, AZ, estriol, estrone, progesterone, and testosterone were 0.05, 0.05, 1.0, 10, and 1.0 ng/ml, respectively. The method developed was applied to evaluate the changes in these hormones induced by the duration of exposure to AC and AZ in rat testis and serum. The hormones level in rat serum and testis had a significant decrease as they were oral gavage treated with different high concentrations of studied pesticides. Both pesticides were distributed in the body of rats by the multi-compartment model (liver, testis, and serum).

The adsorption, kinetics, and interaction mechanisms of various types of estrogen on electrospun polymeric nanofiber membranes.

This study focuses on the adsorption kinetics of four highly potent sex hormones (estrone (E1), 17ß-estradiol (E2), 17α-ethinylestradiol (EE2), and estriol (E3)), present in water reservoirs, which are considered a major cause of fish feminization, low sperm count in males, breast and ovarian cancer in females induced by hormonal imbalance. Herein, electrospun polymeric nanostructures were produced from cellulose acetate, polyamide, polyethersulfone, polyurethanes (918 and elastollan), and polyacrylonitrile (PAN) to simultaneously adsorbing these estrogenic hormones in a single step process and to compare their performance. These nanofibers possessed an average fiber diameter in the range 174-330 nm and their specific surface area ranged between 10.2 and 20.9 m2g-1. The adsorption-desorption process was investigated in four cycles to determine the effective reusability of the adsorption systems. A one-step high-performance liquid chromatography technique was developed to detect and quantify concurrently each hormone present in the solution. Experimental data were obtained to determine the adsorption kinetics by applying pseudo-first-order, pseudo-second-order and intraparticle diffusion models. Findings showed that E1, E2 and EE2 best fitted pseudo-second-order kinetics, while E3 followed pseudo-first-order kinetics. It was found that polyurethane Elastollan nanofibers had maximum adsorption capacities of 0.801, 0.590, 0.736 and 0.382 mg g-1for E1, E2, EE2 and E3, respectively. In addition, the results revealed that polyurethane Elastollan nanofibers had the highest percentage efficiency of estrogens removal at ∼58.9% due to its strong hydrogen bonding with estrogenic hormones, while the least removal efficiency for PAN at ∼35.1%. Consecutive adsorption-desorption cycles demonstrated that polyurethane maintained the best efficiency, even after being repeatedly used four times compared to the other polymers. Overall, the findings indicate that all the studied nanostructures have the potential to be effective adsorbents for concurrently eradicating such estrogens from the environment.

Toxic Effects of Tetrabromobisphenol A: Focus on Endocrine Disruption.

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is used in a variety of consumer products such as electronic equipment, fire extinguishers, furniture, plastics, textiles, and kitchen hoods. Most studies show that the TBBPA production process and TBBPA in industrial and urban sewage waste result in extensive human exposure and environmental contamination. TBBPA can accumulate in organisms, particularly aquatic life, and is classified as a group 2A carcinogen (likely carcinogenic to humans) by the International Agency for Research on Cancer. This compound produces low acute toxicity, but chronic exposure may produce serious consequences. In this review, we focus on TBBPA toxicity by discussing results of various studies that were published in the last two decades. Studies show that TBBPA acts as an endocrine disruptor, causing neurobehavioral and immunotoxic effects, oxidative stress, and apoptosis. Although several experiments were performed in vitro and in vivo, human data are lacking, and thus, chronic toxic effects of TBBPA on humans are not well known, particularly in sensitive populations including pregnant women, newborns, children, and the elderly. Epidemiological studies that comprehensively assess TBBPA levels in biological fluids of different populations and in different pathological conditions are needed. Research on the impact of TBBPA, particularly regarding endocrine disorders and cancer, must also be performed.

Endocrine disruption caused by the aquatic exposure to aluminum and manganese in Astyanax altiparanae (Teleostei: Characidae) females during the final ovarian maturation.

Aluminum (Al) and manganese (Mn) can be toxic to aquatic biota and cause endocrine disruption in fish, affecting reproduction. This study evaluates the physiological responses of the ray-finned teleost fish Astyanax altiparanae vitellogenic females after acute exposure (96 h) to Al and Mn (alone and combined) in acid pH followed by the same period of exposure to metal-free water in neutral pH. The aim of this second period of exposure was to assess the recovery capacity from the toxic effects these metals. Five experimental groups were established: a control in neutral pH (Ctrl), and acidic pH (Ac), aluminum (Al), manganese (Mn), and Al + Mn groups, maintaining the acidic pH in the groups to which metals were added. The following biological parameters were evaluated: metal tissue concentration, relative fecundity (RF: absolute fecundity/body mass). Plasma levels of cortisol (proxy for stress) and 17α hydroxyprogesterone (17α-OHP), and gene expression of pituitary lhß mRNA (proxies for final maturation) were measured to evaluate endocrine disruption. In the synchronic exposure, the presence of Mn potentiated the accumulation of Al in gills. The females from acidic pH and Al groups showed a reduced RF. Exposure to Al and Mn triggered an endocrine disruption response, evidenced by a decrease in the plasma concentration of 17α-OHP and cortisol. Despite this anti-steroidogenic effect, no changes occurred in the pituitary gene expression of lhß. The endocrine changes and the metal accumulation were temporary, while the impacts on RF under the experimental conditions suggest permanent impairment in the reproduction of this species.

The Role of Biotransformation in the Activity of Endocrine Disruptors.

An "endocrine disruptor" has been broadly defined as an exogenous chemical that interferes with the production, release, transportation, metabolism, binding, action, or the elimination of endogenous hormones, which are responsible for homeostasis, reproduction, development or behaviour. Diverse groups of chemicals such as pharmaceuticals, phytoestrogens, natural hormones, and synthetic chemicals such as pesticides, plasticizers, phthalates, parabens, polychlorinated/polybrominated biphenyls, bisphenols are shown to interfere with the endocrine system, and they have been defined as EDs in the last three decades. As for all chemicals, the biotransformation of EDs has a decisive role in their potential toxic effects. Humans are exposed to vast amounts of diverse chemicals throughout their lives. Fortunately, most of the chemicals are converted via biotransformation reactions catalyzed by the enzymes, into more hydrophilic metabolites, which are readily excreted in urine or bile. Biotransformation reactions resulting in less toxic metabolites are known as detoxification. However, some biotransformation reactions are called bioactivation, in which more toxic metabolites are formed. In the case of EDs, metabolites formed via bioactivation usually have a higher affinity for a hormone receptor or induce/inhibit an enzyme involved in the synthesis or catabolism of an endogenous hormone more dramatically compared to their parent compound. In the present review, the role of bioactivation in endocrine modulating effects of chemicals from all groups of EDs, namely endogenous estrogens, phytoestrogens, synthetic/industrial chemicals, and pharmaceuticals it can be were discussed.

Epigenetic Modifications Associated with Exposure to Endocrine Disrupting Chemicals in Patients with Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) remains a significant clinical and public health issue due to its increasing prevalence and the possibility for numerous short- and long-term complications. The growing incidence of GDM seems to coincide with the widespread use of endocrine disrupting chemicals (EDCs). The extensive production and common use of these substances in everyday life has resulted in constant exposure to harmful substances from the environment. That may result in epigenetic changes, which may manifest themselves also after many years and be passed on to future generations. It is important to consider the possible link between environmental exposure to endocrine disrupting chemicals (EDCs) during pregnancy, epigenetic mechanisms and an increased risk for developing gestational diabetes mellitus (GDM). This manuscript attempts to summarize data on epigenetic changes in pregnant women suffering from gestational diabetes in association with EDCs. There is a chance that epigenetic marks may serve as a tool for diagnostic, prognostic, and therapeutic measures.

Human-relevant concentrations of the antifungal drug clotrimazole disrupt maternal and fetal steroid hormone profiles in rats.

Clotrimazole is a non-prescription and broad-spectrum antifungal drug sold under brand names such as Canesten® and Lotrimin®. It is used to treat different types of fungal infections, from oral thrush to athlete's foot and vaginal mycosis. The level of exposure to clotrimazole is uncertain, as the exact usage amongst self-medicating patients is unclear. Recent studies have raised potential concern about the unsupervised use of clotrimazole during pregnancy, especially since it is a potent inhibitor of CYP enzymes of the steroidogenesis pathway. To address some of these concerns, we have assessed the effects of intrauterine exposure to clotrimazole on developing rat fetuses. By exposing pregnant rats to clotrimazole 25 or 75 mg/kg bw/day during gestation days 7-21, we obtained internal fetal concentrations close to those observed in humans. These in vivo data are in strong agreement with our physiologically-based pharmacokinetic (PBK)-modelled levels. At these doses, we observed no obvious morphological changes to the reproductive system, nor shorter male anogenital distance; a well-established morphometric marker for anti-androgenic effects in male offspring. However, steroid hormone profiles were significantly affected in both maternal and fetal plasma, in particular pronounced suppression of estrogens was seen. In fetal testes, marked up-concentration of hydroxyprogesterone was observed, which indicates a specific action on steroidogenesis. Since systemic clotrimazole is rapidly metabolized in humans, relevant exposure levels may not in itself cause adverse changes to the reproductive systems. Its capacity to significantly alter steroid hormone concentrations, however, suggests that clotrimazole should be used with caution during pregnancy.

The controversies of parabens - an overview nowadays.

Effects of paraben toxicity, i.e., endocrine-disruption properties, are in the focus of researchers for decades, but still - they are a hot subject of debate. Parabens are aliphatic esters of p-hydroxybenzoic acid, which are widely used as antimicrobial agents for the preservation of cosmetics, pharmaceuticals and foods. Mostly used parabens are methyl-, ethyl-, propyl- and butylparaben. Although the toxicity of parabens is reported in animals and in in vitro studies, it cannot be taken for granted when discussing hazards for human health due to an unrealistic exposure -safety profile. Many studies have demonstrated that parabens are non-teratogenic, non-mutagenic, non-carcinogenic and the real evidence for their toxicity in humans has not been established. For now, methyl-, ethyl- and propylparaben are considered safe for use in cosmetics and pharmaceuticals within the recommended range of doses. Regarding alternatives for parabens, a variety of approaches have been proposed, but every substitute would need to be tested rigorously for toxicity and safety.

Safety Concerns of Organic Ultraviolet Filters: Special Focus on Endocrine-Disrupting Properties.

Acute and chronic effects of ultraviolet radiation (UVR) on human health have long been a concern. It is well known that acute UVR causes epidermal hyperplasia, erythema, delayed tanning, pigment darkening, and free-radical formation. Apart from acute effects of UVR, its chronic effects involve immunosuppression, photoaging, exacerbation, photodermatoses, and photocarcinogenesis. To protect skin from harmful effects of UVR, UV filters were developed. But these may cause harmful effects in humans and on the environment; adverse effects of these chemicals have been evaluated for > 20 yr. Studies show that UV filters may lead to endocrine disruption, hepatotoxicity, mutagenicity, and systemic toxicity. Literature on environmental effects of UV filters suggests that they are bioaccumulative, pseudopersistent, and possibly toxic to aquatic ecosystems. The objective of this review is to summarize toxic effects and safety concerns of organic UV filters on human beings and the environment. We focus on UV filters' organic endocrine-disrupting effects by reviewing both in vivo and in vitro studies.

Silver nanoparticles compromise the development of mouse pubertal mammary glands through disrupting internal estrogen signaling.

Despite numerous studies on the environmental health and safety (EHS) of silver nanoparticles (AgNPs), most studies looked into their gross toxicities with rather limited understanding on their labyrinthine implicit effects on the target sites, such as the endocrine system. Burgeoning evidence documents the disrupting effects of AgNPs on endocrine functions; however, little research has been invested to recognize the potential impacts on the mammary gland, a susceptible estrogen-responsive organ. Under this setting, we here aimed to scrutinize AgNP-induced effects on the development of pubertal mammary glands at various concentrations that bear significant EHS relevance. We unearthed that AgNPs could accumulate in mouse mammary glands and result in a decrease in the percentage of ducts and terminal ducts in the adult mice after chronic exposure. Strikingly, smaller sized AgNPs showed greater capability to alter the pubertal mammary development than larger sized particles. Intriguingly, mechanistic investigation revealed that the reduction of epithelial proliferation in response to AgNPs was ascribed to reduced ERα expression, which, at least partially, accounted for diseased epithelial morphology in mammary glands. Meanwhile, the decline in fibrous collagen deposition around the epithelium was found to contribute to the compromised development of mammary glands under the exposure of AgNPs. Moreover, as an extension of the mechanism, AgNPs diminished serum levels of estradiol in exposed animals. Together, these results uncovered a novel toxicity feature of AgNPs: compromised development of mouse pubertal mammary glands through the endocrine-disrupting actions. This study would open a new avenue to unveil the EHS impacts of AgNPs.

Critical Review of Read-Across Potential in Testing for Endocrine-Related Effects in Vertebrate Ecological Receptors.

Recent regulatory testing programs have been designed to evaluate whether a chemical has the potential to interact with the endocrine system and could cause adverse effects. Some endocrine pathways are highly conserved among vertebrates, providing a potential to extrapolate data generated for one vertebrate taxonomic group to others (i.e., biological read-across). To assess the potential for biological read-across, we reviewed tools and approaches that support species extrapolation for fish, amphibians, birds, and reptiles. For each of the estrogen, androgen, thyroid, and steroidogenesis (EATS) pathways, we considered the pathway conservation across species and the responses of endocrine-sensitive endpoints. The available data show a high degree of confidence in the conservation of the hypothalamus-pituitary-gonadal axis between fish and mammals and the hypothalamus-pituitary-thyroid axis between amphibians and mammals. Comparatively, there is less empirical evidence for the conservation of other EATS pathways between other taxonomic groups, but this may be due to limited data. Although more information on sensitive pathways and endpoints would be useful, current developments in the use of molecular target sequencing similarity tools and thoughtful application of the adverse outcome pathway concept show promise for further advancement of read-across approaches for testing EATS pathways in vertebrate ecological receptors. Environ Toxicol Chem 2020;39:739-753. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Toward a better understanding of the effects of endocrine disrupting compounds on health: Human-relevant case studies from sheep models.

There are many challenges to overcome in order to properly understand both the exposure to, and effects of, endocrine disruptors (EDs). This is particularly true with respect to fetal life where ED exposures are a major issue requiring toxicokinetic studies of materno-fetal exchange and identification of pathophysiological consequences. The sheep, a large, monotocous, species, is very suitable for in utero fetal catheterization allowing a modelling approach predictive of human fetal exposure. Predicting adverse effects of EDs on human health is frequently impeded by the wide interspecies differences in the regulation of endocrine functions and their effects on biological processes. Because of its similarity to humans as regards gestational and thyroid physiologies and brain ontogeny, the sheep constitutes a highly appropriate model to move one step further on thyroid disruptor hazard assessment. As a grazing animal, the sheep has also proven to be useful in the evaluation of the consequences of chronic environmental exposure to "real-life" complex mixtures at different stages of the reproductive life cycle.

The challenging use and interpretation of blood biomarkers of exposure related to lipophilic endocrine disrupting chemicals in environmental health studies.

The use of exposure biomarkers has been growing during the last decades, being considered the 'gold-standard' approach for individual exposure assessment to environmental chemicals. However, lipophilic endocrine disrupting chemicals (LEDC) have specific physicochemical and biological properties implying particular analytical challenges and interpretative caveats. The epidemiological literature is therefore afflicted by methodological inconsistencies and results divergences, in part due to recognised sources of exposure measurement error and misinterpretation of results. The aim of the present review is to identify external and endogenous sources of variability and uncertainty associated with the LEDC blood biomarkers in epidemiological studies. The dynamic nature of blood and an overview of the known mechanisms of transport, storage and partition of LEDCs in the organism are first described. The external sources of variability and uncertainty introduced at pre-analytical and analytical level are subsequently presented. Subsequently, we present some specific cases where the dynamics of lipids and LEDCs may be substantially modified and thus, the interpretation of biomarkers can be particularly challenging. The environmental obesogens as source of biomarkers variability is also discussed in the light of the most recent findings. Finally, different modelling approaches (statistical and pharmacokinetic models) proposed to improve the use and interpretation of biomarkers are appraised.

Computational evaluation of interactions between organophosphate esters and nuclear hormone receptors.

Organophosphate esters (OPEs) have gained considerable interest from many environmental chemists and toxicologists due to their frequent detection in the environment and potential adverse effects on health. Nuclear hormone receptors (NHRs) were found to mediate many of their adverse effects. However, our knowledge regarding the direct binding and interaction between OPEs and NHRs is limited. In this study, Endocrine Disruptome, an online computational tool based on the technique of inverse docking, was used to calculate the binding affinity score of 25 individual OPEs with 12 different human NHRs. Results showed that 20% of potential binding interactions between the OPEs and NHRs had medium-to-high probabilities. The accuracy, sensitivity and specificity of the predictions were 78.8, 60.0 and 80.9%, respectively. OPEs with a benzene ring were more active than those without, among which, tri-o-tolyl phosphate and tri-m-tolyl phosphate displayed the highest activities, suggesting that they might pose the greatest potential risks for interference with endocrine functions. In addition, the antagonistic conformations of androgen receptor and estrogen receptor ß were found to be the two most vulnerable NHR conformations. Our findings can further the understanding about the health risk(s) of OPEs.

Development and evaluation of a harmonized whole body physiologically based pharmacokinetic (PBPK) model for flutamide in rats and its extrapolation to humans.

By their definition, inadvertent exposure to endocrine disrupting compounds (EDCs) intervenes with the endocrine signalling system, even at low dose. On the one hand, some EDCs are used as important pharmaceutical drugs that one would not want to dismiss. On the other hand, these pharmaceutical drugs are having off-target effects and increasingly significant exposure to the general population with unwanted health implications. Flutamide, one of the top pharmaceutical products marketed all over the world for the treatment of prostate cancer, is also a pollutant. Its therapeutic action mainly depends on targeting the androgen receptors and inhibiting the androgen action that is essential for growth and survival of prostate tissue. Currently flutamide is of concern with respect to its categorization as an endocrine disruptor. In this work we have developed a physiologically based pharmacokinetic (PBPK) model of flutamide that could serve as a standard tool for its human risk assessment. First we built the model for rat (where many parameters have been measured). The rat PBPK model was extrapolated to human where the re-parameterization involved human-specific physiology, metabolic kinetics derived from in-vitro studies, and the partition coefficient same as the rat model. We have harmonized the model by integrating different sets of in-vitro, in-vivo and physiological data into a PBPK model. Then the model was used to simulate different exposure scenarios and the results were compared against the observed data. Both uncertainty and sensitivity analysis was done. Since this new whole-body PBPK model can predict flutamide concentrations not only in plasma but also in various organs, the model may have clinical applications in efficacy and safety assessment of flutamide. The model can also be used for reverse dosimetry in the context of interpreting the available biomonitoring data to estimate the degree to which the population is currently being exposed, and a tool for the pharmaceutical companies to validate the estimated Permitted Daily Exposure (PDE) for flutamide.

Silicon dioxide nanoparticles induce insulin resistance through endoplasmic reticulum stress and generation of reactive oxygen species.

BACKGROUND: Silicon dioxide nanoparticles (SiO2 NPs) are one of the most widely utilized NPs in various food sectors. However, the potential endocrine toxicity of SiO2 NPs has not been characterized. RESULTS: In the present study, mice were orally administered a series of doses of SiO2 NPs. All doses of SiO2 NPs were absorbed into the blood, liver, and pancreas of the mice. Administration of 100 mg/kg bw (body weight) of SiO2 NPs significantly increased blood glucose levels in mice. However, the same dose of SiO2 fine-particles (FPs) did not result in altered blood glucose. Whole-genome analysis showed that SiO2 NPs affected the expression of genes associated with reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress. In addition, we showed that SiO2 NPs activated xenobiotic metabolism, resulting in ER stress. Endoplasmic reticulum stress resulted in increased ROS production, which activated the NF-κB pathway leading to expression of inflammatory cytokines. Increased inflammatory cytokine expression resulted in serine phosphorylation of IRS1, which induced insulin resistance (IR). Furthermore these inflammatory cytokines activated the MAPK pathway, which further promoted the serine phosphorylation of IRS1. Insulin resistance resulted in elevated blood glucose. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) inhibited SiO2 NP-induced ROS production. The ROS scavenger N-acetylcysteine (NAC) did not affect SiO2 NP-induced ER stress, but inhibited SiO2 NP-induced activation of the NF-κB and MAPK pathways, expression of inflammatory cytokines, SiO2 NP-induced serine phosphorylation of IRS1, and SiO2 NP-induced elevations of blood glucose. CONCLUSION: Silicon dioxide NPs induced IR through ER stress and generation of ROS, but SiO2 FPs did not. Therefore, lifelong exposure of humans to SiO2 NPs may result in detrimental effects on blood glucose. The results of this study strongly suggested that non-nanoformed SiO2 should be used as food additives.

Oxidative stress in testes of rats exposed to n-butylparaben.

This study was aimed at determining if oxidative stress imbalance in testes of rats occurs after n-butylparaben (n-ButP) exposure. Young male Sprague-Dawley rats were subcutaneously treated with n-ButP during one spermatogenic cycle (57 days) at 0 (control-oil), 150, 300 and 600 mg/kg/d with peanut oil as vehicle. A non-vehicle control group was also included. Antioxidant enzyme activities (superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase) and levels of reduced and oxidized glutathione were measured in testes. Lipid peroxidation and H2O2 concentrations were also assessed. Results showed an increase of oxidative stress in oil-treated groups, excepting 600 mg/kg/d, suggesting oxidative stress due to peanut oil. A possible antioxidant effect due to n-ButP and its metabolites was suggested at 600 mg/kg/d, the only group not showing oxidative stress. An increase of calcium concentration in testes was also observed. On the other hand, a physiologically-based pharmacokinetic (PBPK) model was developed and the concentrations of n-ButP and its metabolites were simulated in plasma and testes. The peak concentration (Cmax) in testes was found slightly higher than that in plasma. The current results indicate that peanut oil can cause oxidative stress while high doses of n-ButP can act as antioxidant agent in testes.

The Effect of Dissolved Organic Matter (DOM) on the Release and Distribution of Endocrine-Disrupting Chemicals (Edcs) from Sediment under Hydrodynamic Forces, A Case Study of Bisphenol A (BPA) and Nonylphenol (NP).

Endocrine-disrupting chemicals (EDCs) that exist in the aquatic system bring severe environmental risks. In this study, we investigate the dissolved organic matter (DOM) effect on the release and distribution of EDCs under varied hydrodynamic conditions. A water chamber mesocosm was designed to simulate the hydrodynamic forces in a shallow lake. The contents of bisphenol A (BPA) and nonylphenol (NP) in colloid-bound and soluble phases were measured under four increasing hydrodynamic intensities that were 5%, 20%, 50%, and 80% of the critical shear stress. The total BPA and NP contents in overlying water grew linearly with the hydrodynamic intensity (R2 = 0.997 and 0.987), from 108.28 to 415.92 ng/L of BPA and 87.73 to 255.52 ng/L of NP. The exponential relationships of EDC content and hydrodynamic intensity in soluble phase (R2 = 0.985 of BPA and 0.987 of NP) and colloid phase (R2 = 0.992 of BPA and 0.995 of NP) were also detected. The DOM concentrations in colloid-bound phase (cDOM) and in soluble phase (sDOM) were measured and the linear relationships with BPA content (R2 = 0.967 of cDOM and 0.989 of sDOM) and NP content (R2 = 0.978 of cDOM and 0.965 of sDOM) were detected. We analyzed the ratio (αDOM) of sDOM and cDOM that grew logarithmically with the hydrodynamic intensity (R2 = 0.999). Moreover, the ratio (αEDCs) of BPA and NP contents in soluble and colloid-bound phases varied differently with αDOM. The results suggested that BPA tended to be in the soluble phase and NP tended to be in the colloid-bound phase due to the increasing value of αDOM.

Toxicokinetics and bioavailability of bisphenol AF following oral administration in rodents: A dose, species, and sex comparison.

We investigated the toxicokinetics and bioavailability of bisphenol AF (BPAF) in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following a single gavage administration of 34, 110, or 340 mg/kg. A validated analytical method was used to quantitate free (unconjugated parent) and total (unconjugated and conjugated) BPAF in plasma. BPAF was rapidly absorbed in rats with the maximum plasma concentration, Cmax, of free BPAF reached at ≤2.20 h. BPAF was cleared rapidly with a plasma elimination half-life of ≤3.35 h. Cmax and the area under the concentration versus time curve, AUC0-∞, increased proportionally to the dose. Total BPAF Cmax was reached ≤1.07 h in rats with both Cmax (≥27-fold) and AUC0-∞ (≥52-fold) much higher than corresponding free values demonstrating rapid and extensive conjugation of BPAF following oral administration. Absorption of BPAF following a 34 mg/kg gavage dose in mice was more rapid than in rats with free BPAF Cmax reached ≤0.455 h. Free BPAF was cleared rapidly in mice with an elimination half-life of ≤4.22 h. Similar to rats, total BPAF was much higher than corresponding free BPAF. There was no apparent sex-related effect in plasma toxicokinetic parameters of free or total BPAF in mice and rats. Bioavailability in rats was ~ 1% with no apparent dose-related effect. Bioavailability in mice was slightly higher than in rats (male ~ 6%, female 3%). These data demonstrate that BPAF was rapidly absorbed following gavage administration in rodents, rapidly and extensively conjugated with low bioavailability.