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Catecholamine producing tumours of childhood include neuroblastic tumours, phaeochromocytoma and paraganglioma (PPGL). PPGL and neuroblastic tumours can arise in similar anatomical locations and clinical presentations can overlap resulting in diagnostic challenges. Distinguishing between these tumour types is critical as management and long-term surveillance strategies differ depending on the diagnosis. Herein we describe two clinical cases and illustrate key considerations in the diagnostic work up of a neuroblastoma versus PPGL for patients presenting with adrenal, pelvic, and retroperitoneal masses in childhood.
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The aim of this study was to explore the relationship between pesticide contamination at 16 locations in 14 Dutch nature conservation areas and the abundance of Coleoptera (among which dung beetles) in excrements of grazing cattle. A wide spectrum of pesticides was measured in soil, vegetation and excrements of cattle, obtained from all locations. In the fresh dung pats sampled for chemical analysis, beetle numbers were counted and beetle species were identified. In total, 31 different pesticides (including some metabolites) were detected: 14 in fresh excrements, 17 in soil and 20 in vegetation. Total pesticide concentrations in soil, vegetation and excrements varied between 2.6 and 200 µg kg -1 dry matter. In vegetation, the most frequently encountered classes of pesticides (including some of their metabolites) were fungicides (9), herbicides (4) and insecticides (6). The total number of Coleoptera beetles in dung pats correlated negatively with the total concentration of insecticides in vegetation (Kendall's τ -0.501 at p < 0.05). The total concentrations of herbicides and fungicides were not statistically significant correlated with Coleoptera beetle numbers in the dung pats. Yet, the concentration of one single herbicide, viz. chlorpropham in vegetation correlated significantly negative with Coleoptera counts (Kendall's τ -0.603 at p < 0.01).
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Escarabajos , Monitoreo del Ambiente , Plaguicidas , Animales , Plaguicidas/análisis , Bovinos , Heces/química , Conservación de los Recursos Naturales , Países BajosRESUMEN
Per- and polyfluoroalkyl substances (PFAS) are a large class of stable toxic chemicals which have ended up in the environment and in organisms in significant concentrations. Toxicokinetic models are needed to facilitate extrapolation of bioaccumulation data across PFAS congeners and species. For the present study, we carried out an inventory of accumulation processes specific for PFAS, deviating from traditional Persistent Organic Pollutants (POPs). In addition, we reviewed toxicokinetic models on PFAS reported in literature, classifying them according to the number of compartments distinguished as a one-compartment model (1-CM), two-compartment model (2- CM) or a multi-compartment model, (multi-CM) as well as the accumulation processes included and the parameters used. As the inventory showed that simple 1-CMs were lacking, we developed a generic 1-CM of ourselves to include PFAS specific processes and validated the model for legacy perfluoroalkyl acids. Predicted summed elimination constants were accurate for long carbon chains (>C6), indicating that the model properly represented toxicokinetic processes for most congeners. Results for urinary elimination rate constants were mixed, which might be caused by the exclusion of reabsorption processes (renal reabsorption, enterohepatic circulation). The 1-CM needs to be improved further in order to better predict individual elimination pathways. Besides that, more data on PFAS-transporter specific processes are needed to extrapolate across PFAS congeners and species.
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Bioacumulación , Fluorocarburos , Fluorocarburos/metabolismo , Humanos , Toxicocinética , Contaminantes Orgánicos Persistentes/metabolismo , Monitoreo del Ambiente , Contaminantes Ambientales/metabolismo , Modelos BiológicosRESUMEN
Offering meaningful care to patients with an addiction is not always easy. This also holds true for general physicians. In this article we provide a legal and practical framework for general physicians on how to provide meaningful care for this group of patients. Various interventions are described. In case meaningful care does not seem to be an option, then the general physician has to draw his conclusions.
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Atención Primaria de Salud , Trastornos Relacionados con Sustancias , Humanos , Trastornos Relacionados con Sustancias/terapia , Países BajosRESUMEN
AIMS/HYPOTHESIS: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. METHODS: Data were collected from the large INNODIA cohort of individuals (aged 1.0-45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10-17 years; and ≥18 years. RESULTS: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). CONCLUSIONS/INTERPRETATION: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline.
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Autoanticuerpos , Péptido C , Diabetes Mellitus Tipo 1 , Hemoglobina Glucada , Humanos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/epidemiología , Adolescente , Niño , Masculino , Femenino , Péptido C/sangre , Adulto , Adulto Joven , Preescolar , Autoanticuerpos/sangre , Hemoglobina Glucada/metabolismo , Glucemia/metabolismo , Estudios de Cohortes , Lactante , Europa (Continente)/epidemiología , Persona de Mediana Edad , Células Secretoras de Insulina/metabolismoRESUMEN
BACKGROUND/AIM: Type 1 diabetes is an autoimmune disease that involves the development of autoantibodies against pancreatic islet beta-cell antigens, preceding clinical diagnosis by a period of preclinical disease activity. As screening activity to identify autoantibody-positive individuals increases, a rise in presymptomatic type 1 diabetes individuals seeking medical attention is expected. Current guidance on how to monitor these individuals in a safe but minimally invasive way is limited. This article aims to provide clinical guidance for monitoring individuals with presymptomatic type 1 diabetes to reduce the risk of diabetic ketoacidosis (DKA) at diagnosis. METHODS: Expert consensus was obtained from members of the Fr1da, GPPAD, and INNODIA consortia, three European diabetes research groups. The guidance covers both specialist and primary care follow-up strategies. RESULTS: The guidance outlines recommended monitoring approaches based on age, disease stage and clinical setting. Individuals with presymptomatic type 1 diabetes are best followed up in specialist care. For stage 1, biannual assessments of random plasma glucose and HbA1c are suggested for children, while annual assessments are recommended for adolescents and adults. For stage 2, 3-monthly clinic visits with additional home monitoring are advised. The value of repeat OGTT in stage 1 and the use of continuous glucose monitoring in stage 2 are discussed. Primary care is encouraged to monitor individuals who decline specialist care, following the guidance presented. CONCLUSIONS: As type 1 diabetes screening programs become more prevalent, effective monitoring strategies are essential to mitigate the risk of complications such as DKA. This guidance serves as a valuable resource for clinicians, providing practical recommendations tailored to an individual's age and disease stage, both within specialist and primary care settings.
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Diabetes Mellitus Tipo 1 , Cetoacidosis Diabética , Niño , Adolescente , Adulto , Humanos , Autoanticuerpos , Automonitorización de la Glucosa Sanguínea , GlucemiaRESUMEN
It regularly occurs that a physicians is abused by a patient. For physicians this may be a reason to consider to end the relationship with such patients, particularly if patients become violent. But is this permitted? The Dutch law and professional standards restrict physicians from doing so, unless there are 'serious reasons' to do so and only after having investigated all possibilities to restore the treatment relationship, including a discussion with the patient. We argue that these restrictions are too strict. Physicians should be able the end the relationship with patients that fail to respect the physical or mental integrity of physicians or their colleagues.
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Pacientes , Médicos , Humanos , Etnicidad , Responsabilidad Legal , Examen FísicoRESUMEN
Albuminuria is a marker of diabetic kidney disease. Raised albuminuria in children and young people with diabetes is associated with an increased risk of microvascular and macrovascular complications. This review provides guidance for paediatricians caring for children and young people with type 1 and type 2 diabetes on screening, investigations and treatments for albuminuria in line with relevant national and international recommendations.
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Organic micropollutants (OMPs) consist of widely used chemicals such as pharmaceuticals and pesticides that can persist in surface and groundwaters at low concentrations (ng/L to µg/L) for a long time. The presence of OMPs in water can disrupt aquatic ecosystems and threaten the quality of drinking water sources. Wastewater treatment plants (WWTPs) rely on microorganisms to remove major nutrients from water, but their effectiveness at removing OMPs varies. Low removal efficiency might be the result of low concentrations, inherent stable chemical structures of OMPs, or suboptimal conditions in WWTPs. In this review, we discuss these factors, with special emphasis on the ongoing adaptation of microorganisms to degrade OMPs. Finally, recommendations are drawn to improve the prediction of OMP removal in WWTPs and to optimize the design of new microbial treatment strategies. OMP removal seems to be concentration-, compound-, and process-dependent, which poses a great complexity to develop accurate prediction models and effective microbial processes targeting all OMPs.
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Agua Potable , Contaminantes Químicos del Agua , Purificación del Agua , Aguas Residuales , Eliminación de Residuos Líquidos , Ecosistema , Contaminantes Químicos del Agua/análisisRESUMEN
Data from in vitro studies are routinely used to estimate in vivo hepatic clearance of chemicals and this information is needed to parameterise physiologically based kinetic models. Such clearance data can be obtained from laboratory experiments using liver microsomes, hepatocytes, precision-cut liver slices or recombinant enzymes. Irrespective of the selected test system, scaling factors are required to convert the in vitro measured intrinsic clearance to a whole liver intrinsic clearance. Scaling factors such as the hepatic microsomal protein per gram of liver and/or the amount of cytochrome P450 per hepatocyte provide a means to calculate the whole liver intrinsic clearance. Here, a database from the peer-reviewed literature has been developed and provides quantitative metrics on microsomal protein (MP) and cytochrome P450 contents in vertebrate orders namely amphibians, mammals, birds, fish and reptiles. This database allows to address allometric relationships between body weight and MP content, and body weight and cytochrome P450 content. A total of 85 and 74 vertebrate species were included to assess the relationships between log10 body weight versus log10 MP, and between log10 body weight and log10 cytochrome P450 content, respectively. The resulting slopes range from 0.76 to 1.45 in a range of vertebrate species. Such data-driven allometric relationships can be used to estimate the MP content necessary for in vitro to in vivo extrapolation of in vitro clearance data. Future work includes applications of these relationships for different vertebrate taxa using quantitative in vitro to in vivo extrapolation models coupled to physiologically based kinetic models using chemicals of relevance as case studies including pesticides, contaminants and feed additives.
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Sistema Enzimático del Citocromo P-450 , Hígado , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/metabolismo , Microsomas Hepáticos/metabolismo , Peso Corporal , Vertebrados/metabolismo , Mamíferos/metabolismoRESUMEN
Petroleum refinery effluents (PRE) are wastewaters from industries associated with oil refining. Within Europe, PREs are regulated through local discharge permits and receive substantial treatment before emission. After treatment, PREs can still contain low levels of various pollutants potentially toxic to organisms. Earlier work, including whole-effluent toxicity assessments, has shown that the toxicity of permitted PREs is often limited. However, the extent to which PREs contribute to chemical pollution already present in the receiving environment is unknown. Therefore, our study aimed to assess the contribution of PREs to mixture toxic pressure in the environment, using the multi-substance potentially affected fraction of species (msPAF) as an indicator. Based on measured chemical concentrations, compiled species sensitivity distributions (SSD) and a mechanistic solubility model, msPAF levels were estimated for undiluted effluents at discharge points and diluted effluents downstream in receiving waters. Median msPAF-chronic and msPAF-acute levels of PREs at discharge points were 74% (P50) and 40% (P95), respectively. The calculated msPAF levels were reduced substantially to <5% downstream for most effluents (82%), indicating low to negligible toxicity of PREs in receiving environments beyond the initial mixing zone. Regardless of differences in endpoints and locations, hydrocarbons (mainly total petroleum hydrocarbons) and inorganics (mainly ammonia) explained at least 85% of the mixture toxic pressure. The msPAF levels of PREs were on average 2.5-4.5 orders of magnitude lower than msPAF levels derived from background pollution levels, suggesting that PREs were minor contributors to the toxic pressure in the environment. This study presents a generic methodology for quantifying the potential toxic pressure of PREs in the environment, identifying hotspots where more effective wastewater treatment could be needed. We explicitly discuss the uncertainties for further refinement and development of the method.
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Contaminantes Ambientales , Petróleo , Contaminantes Químicos del Agua , Petróleo/toxicidad , Contaminación Ambiental , Aguas Residuales , Hidrocarburos , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisisRESUMEN
Healthcare providers regularly discuss the situation of a patient and his or her care needs with colleagues. This in an effort to compare experiences and provide in a coordinated way high quality care to patients. These multidisciplinary meetings are sometimes also attended by healthcare professionals that do not themselves have a treatment relation with the patient, such as medical students and junior doctors for learning purposes. This raises the question whether it is allowed for non-treating professionals to attend these meetings without the prior informed consent of the patient. We argue that the attendance on non-treating professionals is in accordance with the rules of the General Data Protection Regulation and the Dutch Act on Patients' Rights provided that they are bound by the duty of confidentiality.
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Etnicidad , Personal de Salud , Femenino , Masculino , Humanos , Consentimiento Informado , Aprendizaje , Grupo de Atención al PacienteRESUMEN
There is increasing evidence to support the use of temozolomide therapy for the treatment of metastatic phaeochromocytoma/paraganglioma (PPGL) in adults, particularly in patients with SDHx mutations. In children however, very little data is available. In this report, we present the case of a 12-year-old female with a SDHB-related metastatic paraganglioma treated with surgery followed by temozolomide therapy. The patient presented with symptoms of palpitations, sweating, flushing and hypertension and was diagnosed with a paraganglioma. The primary mass was surgically resected six weeks later after appropriate alpha- and beta-blockade. During the surgery extensive nodal disease was identified that had been masked by the larger paraganglioma. Histological review confirmed a diagnosis of a metastatic SDHB-deficient paraganglioma with nodal involvement. Post-operatively, these nodal lesions demonstrated tracer uptake on 18F-FDG PET-CT. Due to poor tumour tracer uptake on 68Ga-DOTATATE and 123I-MIBG functional imaging studies radionuclide therapy was not undertaken as a potential therapeutic option for this patient. Due to the low tumour burden and lack of clinical symptoms, the multi-disciplinary team opted for close surveillance for the first year, during which time the patient continued to thrive and progress through puberty. 13 months after surgery, evidence of radiological and biochemical progression prompted the decision to start systemic monotherapy using temozolomide. The patient has now completed ten cycles of therapy with limited adverse effects and has benefited from a partial radiological and biochemical response.
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Neoplasias de las Glándulas Suprarrenales , Neoplasias Encefálicas , Neoplasias Primarias Secundarias , Paraganglioma , Feocromocitoma , Adulto , Femenino , Humanos , Niño , Feocromocitoma/genética , Temozolomida/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Paraganglioma/tratamiento farmacológico , Paraganglioma/genética , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológicoRESUMEN
Nanotechnology brings benefits in fields such as biomedicine but nanoparticles (NPs) may also have adverse health effects. The effects of surface-modified NPs at the cellular level have major implications for both medicine and toxicology. Semi-empirical and mechanism-based models aid to understand the cellular transport of various NPs and its implications for quantitatively biological exposure while avoiding large-scale experiments. We hypothesized relationships between NPs-cellular elimination, surface functionality and elimination pathways by cells. Surface free energy components were used to characterize the transport of NPs onto membranes and with lipid vesicles, covering both influences by size and hydrophobicity of NPs. The model was built based on properties of neutral NPs and cells, defining Van de Waals forces, electrostatic forces and Lewis acid-base (polar) interactions between NPs and vesicles as well as between vesicles and cell membranes. We yielded a generic model for estimating exocytosis rate constants of various neutral NPs by cells based on the vesicle-transported exocytosis pathways. Our results indicate that most models are well fitted (R2 ranging from 0.61 to 0.98) and may provide good predictions of exocytosis rate constants for NPs with differing surface functionalities (prediction errors are within 2 times for macrophages). Exocytosis rates differ between cancerous cells with metastatic potential and non-cancerous cells. Our model provides a reference for cellular elimination of NPs, and intends for medical applications and risk assessment.
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Ácidos de Lewis , Nanopartículas , Nanopartículas/metabolismo , Exocitosis , Nanotecnología , LípidosRESUMEN
Preserving human and environmental health requires anthropogenic pollutants to be biologically degradable. Depending on concentration, both nutrients and pollutants induce and activate metabolic capacity in the endemic bacterial consortium, which in turn aids their degradation. Knowledge on such 'acclimation' is rarely implemented in risk assessment cost-effectively. As a result, an accurate description of the mechanisms and kinetics of biodegradation remains problematic. In this study, we defined a yield 'effectivity', comprising the effectiveness at which a pollutant (substrate) enhances its own degradation by inducing (biomass) cofactors involved therein. Our architecture for calculation represents the interplay between concentration and metabolism via both stoichiometric and thermodynamic concepts. The calculus for yield 'effectivity' is biochemically intuitive, implicitly embeds co-metabolism and distinguishes 'endogenic' from 'exogenic' substances' reflecting various phenomena in biodegradation and bio-transformation studies. We combined data on half-lives of pollutants/nutrients in wastewater and surface water with transition-state rate theory to obtain also experimental values for effective yields. These quantify the state of acclimation: the portion of biodegradation kinetics attributable to (contributed by) 'natural metabolism', in view of similarity to natural substances. Calculated and experimental values showed statistically significant correspondence. Particularly, carbohydrate metabolism and nucleic acid metabolism appeared relevant for acclimation (R2â¯=â¯0.11-0.42), affecting rates up to 104.9(±0.7) times: under steady-state acclimation, a compound stoichiometrically identical to carbohydrates or nucleic acids, is 103.2 to 104.9 times faster aerobically degraded than a compound marginally similar. Our new method, simulating (contribution by) the state of acclimation, supplements existing structure-biodegradation and kinetic models for predicting biodegradation in wastewater and surface water. The accuracy of prediction may increase when characterizing nutrients/co-metabolites in terms of, e.g., elemental analysis. We discuss strengths and limitations of our approach by comparison to empirical and mechanism-based methods.
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Contaminantes Ambientales , Contaminantes Químicos del Agua , Biodegradación Ambiental , Contaminantes Ambientales/metabolismo , Humanos , Aguas Residuales , Agua , Contaminantes Químicos del Agua/metabolismo , XenobióticosRESUMEN
An increasing number of pharmaceuticals found in the environment potentially impose adverse effects on organisms such as fish. Physiologically based kinetic (PBK) models are essential risk assessment tools, allowing a mechanistic approach to understanding chemical effects within organisms. However, fish PBK models have been restricted to a few species, limiting the overall applicability given the countless species. Moreover, many pharmaceuticals are ionizable, and fish PBK models accounting for ionization are rare. Here, we developed a generalized PBK model, estimating required parameters as functions of fish and chemical properties. We assessed the model performance for five pharmaceuticals (covering neutral and ionic structures). With biotransformation half-lives (HLs) from EPI Suite, 73 and 41% of the time-course estimations were within a 10-fold and a 3-fold difference from measurements, respectively. The performance improved using experimental biotransformation HLs (87 and 59%, respectively). Estimations for ionizable substances were more accurate than any of the existing species-specific PBK models. The present study is the first to develop a generalized fish PBK model focusing on mechanism-based parameterization and explicitly accounting for ionization. Our generalized model facilitates its application across chemicals and species, improving efficiency for environmental risk assessment and supporting an animal-free toxicity testing paradigm.
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Peces , Modelos Biológicos , Animales , Cinética , Preparaciones Farmacéuticas , Medición de RiesgoRESUMEN
Neonicotinoids are currently the most widely used and sold insecticides in the world, providing effective pest control. Risk assessment of these and other pesticides by lab-based indicators is common. Yet, empirically and theoretically underpinning of extrapolation to indicators used in field surveys is severely limited. Consequently, the aim of our study was to quantify the toxicological and ecological impact of the neonicotinoids imidacloprid and thiacloprid to aquatic invertebrates. We derived Species Sensitivity Distributions (SSDs) based on chronic LC50 data and Mean Species Abundance Relationships (MSARs), comparing these lab-based approaches to field data as well. MSARs are changes in mean species abundance (MSA) as a function of chemical exposure, providing insight into the overall decline of a community. The MSA expresses the mean abundance of species in disturbed conditions relative to their abundance in undisturbed habitat. The medians of the SSD of imidacloprid and thiacloprid for the different species were 16.45 µg/L and 26.40 µg/L, respectively. HC50s of the MSAR of imidacloprid and thiacloprid were 4.25 µg/L and 5.12 µg/L, respectively. The three taxonomic groups tested (insects, crustaceans and mollusks) did not differ significantly in sensitivity for imidacloprid and thiacloprid, both according to the SSDs and MSARs derived. Quantile exposure-response curves (99%-tile) were plotted showing the relative abundance (RA) of aquatic invertebrate species at increasing imidacloprid levels. The 99%-tile of the Relative Abundances (RA99) of species and corresponding imidacloprid concentrations monitored in field surveys in the Netherlands was significantly lower than the Potentially Affected Fraction (PAF) calculated from the SSD. Yet, the MSA was similar to the RA99, suggesting that MSAR is an ecologically meaningful relationship for toxic stress estimated from lab data. Future efforts should be directed to additional empirical underpinning as well as determining the relationship of PAF to other metrics for ecosystem diversity and productivity.
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Insecticidas , Contaminantes Químicos del Agua , Animales , Ecosistema , Insecticidas/análisis , Insecticidas/toxicidad , Neonicotinoides/toxicidad , Nitrocompuestos/toxicidad , Tiazinas , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidadRESUMEN
The EU Water Framework Directive and Priority Substance Directive provide a framework to identify substances that potentially pose a risk to surface waters and provide a legal basis whereby member states are required to monitor and comply with environmental quality standards (EQSs) set for those substances. The cost and effort to continuously measure and analyse real world concentrations in all water bodies across Europe are high. Establishing the reliability of environmental exposure models to predict concentrations of priority substances is key, both to fill data gaps left by monitoring campaigns, and to predict the outcomes of actions that might be taken to reduce exposure. In this study, we aimed to validate the ePiE model for the pharmaceutical ibuprofen by comparing predictions made using the best possible consumption data with measured river concentrations. The results demonstrate that the ePiE model makes useful, conservative exposure predictions for ibuprofen, typically within a factor of 3 of mean measured values. This exercise was performed across a number of basins within Europe, representative of varying conditions, including consumption rates, population densities and climates. Incorporating specific information pertaining to the basin or country being assessed, such as custom WWTP removal rates, was found to improve the realism and accuracy of predictions. We found that the extrapolation of consumption data between countries should be kept to a minimum when modelling the exposure of pharmaceuticals, with the per capita consumption of ibuprofen varying by nearly a factor of 10.
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Ibuprofeno , Contaminantes Químicos del Agua , Monitoreo del Ambiente/métodos , Europa (Continente) , Reproducibilidad de los Resultados , Ríos , Contaminantes Químicos del Agua/análisisRESUMEN
Nanoparticles (NPs) are widely used in industry and technology due to their small size and versatility, which makes them easy to enter organisms and pose threats to human and ecological health. Given the particularity and complex structure of NPs, statistical models alone cannot reliably predict uptake. Hence, we developed a generic model for predicting the cellular uptake of NPs with organic coatings, based on physicochemical interactions underlying uptake. The model utilized the concentration, experimental conditions and properties of NPs viz. size, surface coating and coverage. These parameters were converted to surface energy components and surface potentials, and combined with the components and potential for a cell membrane. For NPs uptake, we constructed energetic profiles and barriers for adsorption and permeation onto/through cell membranes. The relationships derived were compared to experimental uptake data. The model provided accurate and robust uptake estimates for neutrally charged unhalogenated NPs and six different cell types. We envision that the model provides a reference for cellular accumulation of neutral NPs and (ecological/human) risk assessment of NPs or microparticles.
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Nanopartículas , Humanos , Adsorción , Transporte Biológico , Membrana Celular/metabolismo , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
A toxicokinetic-toxicodynamic model was constructed to delineate the exposure-response causality. The model could be used: to predict metal accumulation considering the influence of water chemistry and biotic ligand characteristics; to simulate the dynamics of subcellular partitioning considering metabolism, detoxification, and elimination; and to predict chronic toxicity as represented by biomarker responses from the concentration of metals in the fraction of potentially toxic metal. The model was calibrated with data generated from an experiment in which the Zebra mussel Dreissena polymorpha was exposed to Cu at nominal concentrations of 25 and 50 µg/L and with varied Na+ concentrations in water up to 4.0 mmol/L for 24 days. Data used in the calibration included physicochemical conditions of the exposure environment, Cu concentrations in subcellular fractions, and oxidative stress-induced responses, i.e. glutathione-S-transferase activity and lipid peroxidation. The model explained the dynamics of subcellular Cu partitioning and the effect mechanism reasonably well. With a low affinity constant for Na + binding to Cu2+ uptake sites, Na + had limited influence on Cu2+ uptake at low Na+ concentrations in water. Copper was taken up into the metabolically available pool (MAP) at a largely higher rate than into the cellular debris. Similar Cu concentrations were found in these two fractions at low exposure levels, which could be attributed to sequestration pathways (metabolism, detoxification, and elimination) in the MAP. However, such sequestration was inefficient as shown by similar Cu concentrations in detoxified fractions with increasing exposure level accompanied by the increasing Cu concentration in the MAP.