Toxicokinetics in rats and modeling to support the interpretation of biomonitoring data for rare-earth elements
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Toxicokinetic models are useful tools to better understand the fate of contaminants in the human body and to establish biological guidance values to interpret biomonitoring data in human populations. This research aimed to develop a biologically-based toxicokinetic model for four rare earth elements (REEs), cerium (Ce), praseodymium (Pr), neodymium (Nd) and yttrium (Y), and to establish biomonitoring equivalents (BE) serving as biological guidance values. The model was constructed using physiological data taken from the literature as well as new experimental kinetic data. These new data indicated that REEs readily disappeared from blood and accumulated mostly in the liver; excretion occurred mainly through feces although a small fraction was eliminated in urine. To properly reproduce the observed kinetics, the model was represented as 19 compartments, which include main tissues and their components (such as retention by macrophages) supplied by blood, as well as routes of excretion. The transfer coefficients between compartments were determined numerically by adjustments to experimental data. Simulations gave good fits to available experimental kinetic data and confirmed that the same model structure is applicable to the four elements. BEs of 0.3 µg/L of Pr and Nd were derived from the provisional RfD of 0.5 mg/kg bw/day established by the U.S. EPA. These BEs can be updated according to new reference dose values (RfD). Overall, the model can contribute to a better understanding of the significance of biological measurements and to the inference of exposure levels; it can also be used for the modeling of other REEs. The BEs will further allow rapid screening of different populations using biological measurements in order to guide risk assessments.Toxicodynamics
Inhalation exposure
Pharmacodynamics
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The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations.
Xenobiotic
Toxicodynamics
ADME
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A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in humans. Compartments were included for gastrointestinal lumen, oral mucosa, stomach, small intestinal tissue, blood, liver, kidney, bone, and a combined compartment for remaining tissues. As chronic exposure to high concentrations of Cr(VI) in drinking water cause small intestinal cancer in mice, the toxicokinetics of Cr(VI) in the upper gastrointestinal tract of rodents and humans are important for assessing internal tissue dose in risk assessment. Fasted human stomach fluid was collected and ex vivo Cr(VI) reduction studies were conducted and used to characterize reduction of Cr(VI) in human stomach fluid as a mixed second-order, pH-dependent process. For model development, toxicokinetic data for total chromium in human tissues and excreta were identified from the published literature. Overall, the PBPK model provides a good description of chromium toxicokinetics and is consistent with the available total chromium data from Cr(III) and Cr(VI) exposures in typical humans (i.e., model predictions are within a factor of three for approximately 86% of available data). By accounting for key species differences, sources of saturable toxicokinetics, and sources of uncertainty and variation, the rodent and human PBPK models can provide a robust characterization of toxicokinetics in the target tissue of the small intestine allowing for improved health risk assessment of human populations exposed to environmentally-relevant concentrations.
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Hexabromocyclododecane
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Physiologically based pharmacokinetic (PBPK) modeling is a powerful in silico tool that can be used to simulate the toxicokinetics and tissue distribution of xenobiotic substances, such as perfluorooctanoic acid (PFOA), in organisms. However, most existing PBPK models have been based on the flow-limited assumption and largely rely on in vivo data for parametrization. In this study, we propose a permeability-limited PBPK model to estimate the toxicokinetics and tissue distribution of PFOA in male rats. Our model considers the cellular uptake and efflux of PFOA via both passive diffusion and transport facilitated by various membrane transporters, association with serum albumin in circulatory and extracellular spaces, and association with intracellular proteins in liver and kidney. Model performance is assessed using seven experimental data sets extracted from three different studies. Comparing model predictions with these experimental data, our model successfully predicts the toxicokinetics and tissue distribution of PFOA in rats following exposure via both IV and oral routes. More importantly, rather than requiring in vivo data fitting, all PFOA-related parameters were obtained from in vitro assays. Our model thus provides an effective framework to test in vitro-in vivo extrapolation and holds great promise for predicting toxicokinetics of per- and polyfluorinated alkyl substances in humans.
Perfluorooctanoic acid
Xenobiotic
Membrane permeability
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In this report a rodent Physiologically Based PharmacoKinetic (PBPK) model for 2,3,7,8-tetrachlorodibenzodioxin is described. Validation studies, in which model simulations of TCDD disposition were compared with in vivo TCDD disposition in rodents exposed to TCDD, showed that the model adequately predicted the in vivo toxicokinetics of TCDD across species (mouse, rat), dose-schedule (acute semi-chronic chronic) and route of administration (oral subcutaneous). It was concluded that PBPK models are suited to establish quantitative relationships between the external dose of TCDD (amount of TCDD administered per kg body weight) and the internal dose (concentration of TCDD at the organ level). The relationship between internal dose and the resulting organ toxicity will be elaborated in subsequent reports. The results will be used in a quantitative risk assessment of the human exposure situation, in particular the exposure of suckling infants to dioxins from mother's milk.
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Internal dose
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Sphagnum
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Abstract : As a follow-up on the development of the PBPK model for soman in the guinea pig and man a new model is being developed for VX. This report describes in short the work and results which has led to this model. Based on the Physiology (Physiologically-Based) of the investigated species the 'fate' or kinetics (Pharmaco Kinetics) of a compound can be predicted after an intoxication in several organs or compartments by using a computer simulation model. The toxicokinetics of the nerve agent VX are fundamentally different from those of the nerve agents sarin or soman. Especially the persistent character of VX in blood at equitoxic doses is apparent. Animal experiments have shown the presence of toxicologically relevant concentrations of VX in blood a long time after intoxication. A number of input parameters need to be obtained either through literature searches or by research. The 6-compartment model for soman was adapted and expanded with an additional compartment, the skin. Also the reactions with the enzymes, AChE, BuChE and CaE were described individually. With the implementation of a skin compartment it becomes possible to simulate dermal exposure scenarios. Using this model and the available set of input parameters it is not yet possible to simulate the intravenous kinetics of VX in the `normal' guinea pig. After adapting the numbers of slow binding sites (CaE) the toxicokinetics in the hairless guinea pig are simulated very well. Some preliminary simulations of percutaneuos exposure also show a reasonable fit of the VX toxicokinetics in the blood of the hairless guinea pig.
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