Suchergebnisse

The 4FUN project funded under the European Union's 7th Framework Programme produced a software, named MERLINExpo, containing a library of models for exposure assessment, coupling environmental multimedia and pharmacokinetic models. The main challenges in exposure modelling that MERLIN-Expo has tackled are: (a) the integration of multimedia models simulating the fate of chemicals in environmental media, and of physiologically based pharmacokinetic models simulating the fate of chemicals in human body. MERLIN-Expo thus allows the determination of internal effective chemical concentrations; (b) the incorporation of a set of functionalities for uncertainty/ sensitivity analysis, from screening to variance-based approaches. The availability of such tools for uncertainty and sensitivity analysis aimed to facilitate the incorporation of such issues in future decision making; (c) the integration of human and wildlife biota targets with common fate modelling in the environment. The models can be linked together to create flexible scenarios relevant for both human and wildlife biota exposure. Three case studies based on actual datasets were performed using MERLIN-Expo. ; Le projet 4FUN financé dans le cadre du 7e programme-cadre de l'Union européenne a produit un logiciel nommé MERLIN-Expo permettant de construire des scénarios complexes d'exposition des milieux environnementaux, de la faune sauvage et de l'homme. L'objectif était de fournir aux décideurs et évaluateurs de risque un outil intégré pouvant gérer plusieurs sources et cibles de pollution et caractériser les incertitudes à chaque étape du processus d'exposition. MERLIN-Expo se compose d'une bibliothèque de modèles dédiés aux milieux récepteurs abiotiques (eaux de surface, sols, air extérieur), aux milieux d'intérêt pour l'exposition humaine (cultures, élevage), ainsi qu'à la faune (les invertébrés, les poissons) et aux humains. Ces modèles peuvent être couplés pour créer une grande diversité de scénarios d'exposition. Une documentation standardisée de chaque modèle ainsi que des outils de formation sont disponibles en ligne.

The 4FUN project funded under the European Union's 7th Framework Programme produced a software, named MERLINExpo, containing a library of models for exposure assessment, coupling environmental multimedia and pharmacokinetic models. The main challenges in exposure modelling that MERLIN-Expo has tackled are: (a) the integration of multimedia models simulating the fate of chemicals in environmental media, and of physiologically based pharmacokinetic models simulating the fate of chemicals in human body. MERLIN-Expo thus allows the determination of internal effective chemical concentrations; (b) the incorporation of a set of functionalities for uncertainty/ sensitivity analysis, from screening to variance-based approaches. The availability of such tools for uncertainty and sensitivity analysis aimed to facilitate the incorporation of such issues in future decision making; (c) the integration of human and wildlife biota targets with common fate modelling in the environment. The models can be linked together to create flexible scenarios relevant for both human and wildlife biota exposure. Three case studies based on actual datasets were performed using MERLIN-Expo. ; Le projet 4FUN financé dans le cadre du 7e programme-cadre de l'Union européenne a produit un logiciel nommé MERLIN-Expo permettant de construire des scénarios complexes d'exposition des milieux environnementaux, de la faune sauvage et de l'homme. L'objectif était de fournir aux décideurs et évaluateurs de risque un outil intégré pouvant gérer plusieurs sources et cibles de pollution et caractériser les incertitudes à chaque étape du processus d'exposition. MERLIN-Expo se compose d'une bibliothèque de modèles dédiés aux milieux récepteurs abiotiques (eaux de surface, sols, air extérieur), aux milieux d'intérêt pour l'exposition humaine (cultures, élevage), ainsi qu'à la faune (les invertébrés, les poissons) et aux humains. Ces modèles peuvent être couplés pour créer une grande diversité de scénarios d'exposition. Une documentation standardisée de chaque ...

To avoid interspecies extrapolation in toxicokinetics and drug development, it is convenient to directly develop human data. In that case, exposure dose should pose null or negligible risk to the exposed individual, but still be sufficiently high to allow quantification. We propose to reduce the dose received by human volunteers during exposure, and to compensate for loss of information by exposing the same volunteers to a nontoxic agent. This method was applied to develop 1,3‐butadiene (BD) exposure protocols for humans. To study the potential of such a procedure, we worked with simulated data. Three exposure times (20, 10, and 5 minutes) and four exposure concentrations (2, 1, 0.8, and 0.5 ppm) were used to define 12 inhalation exposure scenarios for BD. Isoflurane was used as a probe, with simulated exposure of 20 subjects to 20 ppm isoflurane during 15 minutes. Isoflurane or BD‐exhaled air concentrations were supposed to be measured 10 times. A three‐compartment physiological toxicokinetic model was used to jointly describe BD and isoflurane data. For each subject, BD data were analyzed, in a Bayesian framework, either alone or together with the isoflurane data. The precision of BD metabolic rate constant or fraction metabolized was increased, and bias reduced, when BD and probe data were considered jointly. An exposure to 10 ppm × min BD and 300 ppm × min isoflurane gave equivalent precision and bias as a unique exposure to 40 ppm × min BD. The BD dose received by volunteers could therefore be at least quartered if BD exposure was supplemented with that of a probe.

Abstract
The zebrafish eleutheroembryo model is increasingly used to assess the toxicity and developmental adverse effects of xenobiotics. However, the actual exposure is seldom measured (poorly accessible), while a predictive model could estimate these concentrations. The predictions with a new eleutheroembryo physiologically based pharmacokinetic (PBPK) model have been evaluated using datasets obtained from literature data for several bisphenols. The model simulated the toxicokinetics of bisphenols A (BPA), AF, F, and S through the eleutheroembryo tissues while considering the body and organ growth. We further improved the predictions by adding dynamic flows through the embryo and/or its chorion, impact of experimental temperature, metabolic clearance, and saturation of the absorption by Bayesian calibration. The model structure was determined using the BPA dataset and generalized to the other bisphenols. This model revealed the central role of the chorion in the compound uptake in the first 48 h post-fertilization. The predictions for the BPA substitutes estimated by our PBPK model were compared to available toxicokinetics data for zebrafish embryos, and 63% and 88% of them were within a twofold and fivefold error intervals of the corresponding experimental values, respectively. This model provides a tool to design new eleutheroembryo assays and evaluate the actual exposure.

Graphical abstract

We report on model simulations performed using the newly developed exposure tool, MERLIN-Expo, in order to assess lead (Pb) exposure to pre-school children resulting from past emissions by non-ferrous smelters in Belgium (Northern Campine area). Exposure scenarios were constructed to estimate internal Pb exposure in children living in the vicinity of the former industrial sites as compared to children living in adjacent areas and a reference area. Model simulations at individual level are compared with biomonitoring data from a Belgian monitoring campaign (Flemish Government, 2008; Van Holderbeke et al., 2008) in order to verify the model performance of MERLIN-Expo when simulating complex scenarios that account for subject mobility, i.e., duration at the different considered locations (both indoors and outdoors) with varying exposure levels, and individual food consumption patterns. Adopting an assessment approach at individual level improves on more commonly performed generic exposure assessments at population level, by including intake of Pb from local and purchased food products, and taking into account the mobility of the participants, which results in a more comprehensive assessment of individual recent intake of lead. Also, the accuracy of the model predictions as compared to Pb biomonitoring data has been tested via different accuracy approaches and metrics. We calculated a Probability of detection (or true positive rate) of 0.93, reflecting that almost all blood levels above a chosen trigger value of 2.25 mg.L-1 are predicted as such by the model; a Bias of 1.87, i.e. reflecting a slight overestimation of the model, and F1 and F2 scores of 0.65 and 0.8, respectively, confirming that most of the measured positives are detected as such by the model (high F2 score) with a slight overestimation (lower F1 score). Although the model predictions for individual children slightly overpredict the biomonitoring data, they overlap with the prediction interval calculated by MERLIN-Expo based on population averages ...

We report on model simulations performed using the newly developed exposure tool, MERLIN-Expo, in order to assess lead (Pb) exposure to pre-school children resulting from past emissions by non-ferrous smelters in Belgium (Northern Campine area). Exposure scenarios were constructed to estimate internal Pb exposure in children living in the vicinity of the former industrial sites as compared to children living in adjacent areas and a reference area. Model simulations at individual level are compared with biomonitoring data from a Belgian monitoring campaign (Flemish Government, 2008; Van Holderbeke et al., 2008) in order to verify the model performance of MERLIN-Expo when simulating complex scenarios that account for subject mobility, i.e., duration at the different considered locations (both indoors and outdoors) with varying exposure levels, and individual food consumption patterns. Adopting an assessment approach at individual level improves on more commonly performed generic exposure assessments at population level, by including intake of Pb from local and purchased food products, and taking into account the mobility of the participants, which results in a more comprehensive assessment of individual recent intake of lead. Also, the accuracy of the model predictions as compared to Pb biomonitoring data has been tested via different accuracy approaches and metrics. We calculated a Probability of detection (or true positive rate) of 0.93, reflecting that almost all blood levels above a chosen trigger value of 2.25 mg.L-1 are predicted as such by the model; a Bias of 1.87, i.e. reflecting a slight overestimation of the model, and F1 and F2 scores of 0.65 and 0.8, respectively, confirming that most of the measured positives are detected as such by the model (high F2 score) with a slight overestimation (lower F1 score). Although the model predictions for individual children slightly overpredict the biomonitoring data, they overlap with the prediction interval calculated by MERLIN-Expo based on population averages (Fierens et al., 2016). Modelling exposure at individual level allows risk assessors to attribute the relative contribution of different exposure routes at various locations, reconstructing the exposure history for each individual in a complex site-specific exposure scenario. The slight overprediction of the actual observed Pb blood levels with a factor 2 is compatible with conservative decision-making.

International audience ; In the present legislations, the use of methods alternative to animal testing is explicitly encouraged, to use animal testing only 'as a last resort' or to ban it. The use of alternative methods to replace kinetics or repeated dose in vivo tests is a challenging issue. We propose here a strategy based on in vitro tests and QSAR (Quantitative Structure Activity Relationship) models to calibrate a dose-response model predicting hepatotoxicity. The dose response consists in calibrating and coupling a PBPK (physiologically-based pharmacokinetic) model with a toxicodynamic model for cell viability. We applied our strategy to acetaminophen and compared three different ways to calibrate the PBPK model: only with in vitro and in silico methods, using rat data or using all available data including data on humans. Some estimates of kinetic parameters differed substantially among the three calibration processes, but, at the end, the three models were quite comparable in terms of liver toxicity predictions and close to the usual range of human overdose. For the model based on alternative methods, the good adequation with the two other models resulted from an overestimated renal elimination rate which compensated for the underestimation of the metabolism rate. Our study points out that toxicokinetics/toxicodynamics approaches, based on alternative methods and modelling only, can predict in vivo liver toxicity with accuracy comparable to in vivo methods.

International audience ; In the present legislations, the use of methods alternative to animal testing is explicitly encouraged, to use animal testing only 'as a last resort' or to ban it. The use of alternative methods to replace kinetics or repeated dose in vivo tests is a challenging issue. We propose here a strategy based on in vitro tests and QSAR (Quantitative Structure Activity Relationship) models to calibrate a dose-response model predicting hepatotoxicity. The dose response consists in calibrating and coupling a PBPK (physiologically-based pharmacokinetic) model with a toxicodynamic model for cell viability. We applied our strategy to acetaminophen and compared three different ways to calibrate the PBPK model: only with in vitro and in silico methods, using rat data or using all available data including data on humans. Some estimates of kinetic parameters differed substantially among the three calibration processes, but, at the end, the three models were quite comparable in terms of liver toxicity predictions and close to the usual range of human overdose. For the model based on alternative methods, the good adequation with the two other models resulted from an overestimated renal elimination rate which compensated for the underestimation of the metabolism rate. Our study points out that toxicokinetics/toxicodynamics approaches, based on alternative methods and modelling only, can predict in vivo liver toxicity with accuracy comparable to in vivo methods.

International audience ; Exposure to chemical substances that can produce endocrine disrupting effects represents one of the most critical public health threats nowadays. In line with the regulatory framework implemented within the European Union (EU) to reduce the levels of endocrine disruptors (EDs) for consumers, new and effective methods for ED testing are needed. The OBERON project will build an integrated testing strategy (ITS) to detect ED-related metabolic disorders by developing, improving and validating a battery of test systems. It will be based on the concept of an integrated approach for testing and assessment (IATA). OBERON will combine (1) experimental methods (in vitro, e.g., using 2D and 3D human-derived cells and tissues, and in vivo, i.e., using zebrafish at different stages), (2) high throughput omics technologies, (3) epidemiology and human biomonitoring studies and (4) advanced computational models (in silico and systems biology) on functional endpoints related to metabolism. Such interdisciplinary framework will help in deciphering EDs based on a mechanistic understanding of toxicity by providing and making available more effective alternative test methods relevant for human health that are in line with regulatory needs. Data generated in OBERON will also allow the development of novel adverse outcome pathways (AOPs). The assays will be pre-validated in order to select the test systems that will show acceptable performance in terms of relevance for the second step of the validation process, i.e., the inter-laboratory validation as ring tests. Therefore, the aim of the OBERON project is to support the organization for economic co-operation and development (OECD) conceptual framework for testing and assessment of single and/or mixture of EDs by developing specific assays not covered by the current tests, and to propose an IATA for ED-related metabolic disorder detection, which will be submitted to the Joint Research Center (JRC) and OECD community.

International audience ; Exposure to chemical substances that can produce endocrine disrupting effects represents one of the most critical public health threats nowadays. In line with the regulatory framework implemented within the European Union (EU) to reduce the levels of endocrine disruptors (EDs) for consumers, new and effective methods for ED testing are needed. The OBERON project will build an integrated testing strategy (ITS) to detect ED-related metabolic disorders by developing, improving and validating a battery of test systems. It will be based on the concept of an integrated approach for testing and assessment (IATA). OBERON will combine (1) experimental methods (in vitro, e.g., using 2D and 3D human-derived cells and tissues, and in vivo, i.e., using zebrafish at different stages), (2) high throughput omics technologies, (3) epidemiology and human biomonitoring studies and (4) advanced computational models (in silico and systems biology) on functional endpoints related to metabolism. Such interdisciplinary framework will help in deciphering EDs based on a mechanistic understanding of toxicity by providing and making available more effective alternative test methods relevant for human health that are in line with regulatory needs. Data generated in OBERON will also allow the development of novel adverse outcome pathways (AOPs). The assays will be pre-validated in order to select the test systems that will show acceptable performance in terms of relevance for the second step of the validation process, i.e., the inter-laboratory validation as ring tests. Therefore, the aim of the OBERON project is to support the organization for economic co-operation and development (OECD) conceptual framework for testing and assessment of single and/or mixture of EDs by developing specific assays not covered by the current tests, and to propose an IATA for ED-related metabolic disorder detection, which will be submitted to the Joint Research Center (JRC) and OECD community.

International audience ; Exposure to chemical substances that can produce endocrine disrupting effects represents one of the most critical public health threats nowadays. In line with the regulatory framework implemented within the European Union (EU) to reduce the levels of endocrine disruptors (EDs) for consumers, new and effective methods for ED testing are needed. The OBERON project will build an integrated testing strategy (ITS) to detect ED-related metabolic disorders by developing, improving and validating a battery of test systems. It will be based on the concept of an integrated approach for testing and assessment (IATA). OBERON will combine (1) experimental methods (in vitro, e.g., using 2D and 3D human-derived cells and tissues, and in vivo, i.e., using zebrafish at different stages), (2) high throughput omics technologies, (3) epidemiology and human biomonitoring studies and (4) advanced computational models (in silico and systems biology) on functional endpoints related to metabolism. Such interdisciplinary framework will help in deciphering EDs based on a mechanistic understanding of toxicity by providing and making available more effective alternative test methods relevant for human health that are in line with regulatory needs. Data generated in OBERON will also allow the development of novel adverse outcome pathways (AOPs). The assays will be pre-validated in order to select the test systems that will show acceptable performance in terms of relevance for the second step of the validation process, i.e., the inter-laboratory validation as ring tests. Therefore, the aim of the OBERON project is to support the organization for economic co-operation and development (OECD) conceptual framework for testing and assessment of single and/or mixture of EDs by developing specific assays not covered by the current tests, and to propose an IATA for ED-related metabolic disorder detection, which will be submitted to the Joint Research Center (JRC) and OECD community.

International audience ; Exposure to chemical substances that can produce endocrine disrupting effects represents one of the most critical public health threats nowadays. In line with the regulatory framework implemented within the European Union (EU) to reduce the levels of endocrine disruptors (EDs) for consumers, new and effective methods for ED testing are needed. The OBERON project will build an integrated testing strategy (ITS) to detect ED-related metabolic disorders by developing, improving and validating a battery of test systems. It will be based on the concept of an integrated approach for testing and assessment (IATA). OBERON will combine (1) experimental methods (in vitro, e.g., using 2D and 3D human-derived cells and tissues, and in vivo, i.e., using zebrafish at different stages), (2) high throughput omics technologies, (3) epidemiology and human biomonitoring studies and (4) advanced computational models (in silico and systems biology) on functional endpoints related to metabolism. Such interdisciplinary framework will help in deciphering EDs based on a mechanistic understanding of toxicity by providing and making available more effective alternative test methods relevant for human health that are in line with regulatory needs. Data generated in OBERON will also allow the development of novel adverse outcome pathways (AOPs). The assays will be pre-validated in order to select the test systems that will show acceptable performance in terms of relevance for the second step of the validation process, i.e., the inter-laboratory validation as ring tests. Therefore, the aim of the OBERON project is to support the organization for economic co-operation and development (OECD) conceptual framework for testing and assessment of single and/or mixture of EDs by developing specific assays not covered by the current tests, and to propose an IATA for ED-related metabolic disorder detection, which will be submitted to the Joint Research Center (JRC) and OECD community.

Purpose Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations ; The research leading to these results has received funding from theb European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333—the HELIX project. Dr Maribel Casas and Dr Jordi Julvez received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128, MS14/00108). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, the Conselleria de Sanitat, Generalitat Valenciana, Department of Health of the Basque Government; the Provincial Government of Gipuzkoa, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), and NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; 'Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). The work was also supported by MICINN (MTM2015-68140-R) and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII. CW received funding from the Fondation de France ; SI