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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.

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 ...

Toxicological effects and chemical structure can be related quantitatively or qualitatively through QSAR modeling (Quantitative structure-activity relationship). During the past decade, the development of QSAR tools has continued to progress especially because of the requirements of new European legislations (REACH and 7th amendment to the EU Cosmetics Directive) that encourage and support the implementation of alternative methods to animal testing including QSAR models. In order to facilitate the regulatory use of QSAR tools, the management of the environment directorate of the OECD and the former ECB (European Chemicals Bureau) have made available two free software tools (the "QSAR Toolbox" and "Toxtree"). Both tools allow the user to use several QSAR models and in particular the "Benigni/Bossa" rule-based system for predicting the mutagenic and carcinogenic potential of chemicals on the sole basis of chemical structure. Given the regulatory role of the OECD QSAR Toolbox and Toxtree, the INERIS and the CTIS jointly carried out a scientific validation of the QSAR models that form the "Benigni-Bossa" rule-based system. The main results of this study show that several conceptual and software related problems can, in some specific cases, give raise to wrong predictions. ; La mutagenèse et la carcinogenèse sont deux effets toxicologiques qui font partie des informations toxicologiques à fournir dans le cadre de plusieurs règlements sur les substances chimiques et notamment du règlement RE ACH. Les effets mutagènes sont habituellement caractérisés de façon relativement économique et rapide par le biais du test d'Ames qui quantifie le potentiel mutagène d'une substance grâce à une quantification du taux de révertants de souches de S. typhimurium auxotrophes pour l'histidine. En revanche, la détermination expérimentale du potentiel cancérogène des produits chimiques est particulièrement onéreuse. Le coût d'une étude de cancérogenèse chez le rongeur peut aller jusqu'à un million de dollars par substance. Ce coût élevé, ...

Toxicological effects and chemical structure can be related quantitatively or qualitatively through QSAR modeling (Quantitative structure-activity relationship). During the past decade, the development of QSAR tools has continued to progress especially because of the requirements of new European legislations (REACH and 7th amendment to the EU Cosmetics Directive) that encourage and support the implementation of alternative methods to animal testing including QSAR models. In order to facilitate the regulatory use of QSAR tools, the management of the environment directorate of the OECD and the former ECB (European Chemicals Bureau) have made available two free software tools (the "QSAR Toolbox" and "Toxtree"). Both tools allow the user to use several QSAR models and in particular the "Benigni/Bossa" rule-based system for predicting the mutagenic and carcinogenic potential of chemicals on the sole basis of chemical structure. Given the regulatory role of the OECD QSAR Toolbox and Toxtree, the INERIS and the CTIS jointly carried out a scientific validation of the QSAR models that form the "Benigni-Bossa" rule-based system. The main results of this study show that several conceptual and software related problems can, in some specific cases, give raise to wrong predictions. ; La mutagenèse et la carcinogenèse sont deux effets toxicologiques qui font partie des informations toxicologiques à fournir dans le cadre de plusieurs règlements sur les substances chimiques et notamment du règlement RE ACH. Les effets mutagènes sont habituellement caractérisés de façon relativement économique et rapide par le biais du test d'Ames qui quantifie le potentiel mutagène d'une substance grâce à une quantification du taux de révertants de souches de S. typhimurium auxotrophes pour l'histidine. En revanche, la détermination expérimentale du potentiel cancérogène des produits chimiques est particulièrement onéreuse. Le coût d'une étude de cancérogenèse chez le rongeur peut aller jusqu'à un million de dollars par substance. Ce coût élevé, ajouté à la préoccupation croissante pour le bien-être des animaux, encourage, en particulier, la mise au point de modèles QSAR pour la prédiction du potentiel cancérogène des produits chimiques. Dans ce contexte, le système « Benigni/Bossa » pour l'analyse des propriétés carcinogènes et mutagènes joue un rôle important en raison de son exhaustivité et de son intégration dans deux outils disponibles gratuitement : la boîte à outils QSAR de l'OCDE (OCDE, 2010) et Toxtree. Le travail effectué en collaboration entre l'INER IS et le CTIS (Centre de traitement de l'information scientifique) se proposait d'analyser la validité du système « Benigni/Bossa » en tant que tel et de son implémentation dans ces deux outils (boîte à outils QSAR de l'OCDE versions 1.1.01 et 1.1.02 et Toxtree version 1.6).

International audience ; Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

International audience ; Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

International audience ; Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

International audience ; Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

International audience ; Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

International audience ; Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

International audience ; Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

The European Union's ban on animal testing for cosmetic ingredients and products has generated a strong momentum for the development of in silico and in vitro alternative methods. One of the focus of the COSMOS project was ab initio prediction of kinetics and toxic effects through multiscale pharmacokinetic modeling and in vitro data integration. In our experience, mathematical or computer modeling and in vitro experiments are complementary. We present here a summary of the main models and results obtained within the framework of the project on these topics. A first section presents our work at the organelle and cellular level. We then go toward modeling cell levels effects (monitored continuously), multiscale physiologically based pharmacokinetic and effect models, and route to route extrapolation. We follow with a short presentation of the automated KNIME workflows developed for dissemination and easy use of the models. We end with a discussion of two challenges to the field: our limited ability to deal with massive data and complex computations.

The European Union's ban on animal testing for cosmetic ingredients and products has generated a strong momentum for the development of in silico and in vitro alternative methods. One of the focus of the COSMOS project was ab initio prediction of kinetics and toxic effects through multiscale pharmacokinetic modeling and in vitro data integration. In our experience, mathematical or computer modeling and in vitro experiments are complementary. We present here a summary of the main models and results obtained within the framework of the project on these topics. A first section presents our work at the organelle and cellular level. We then go toward modeling cell levels effects (monitored continuously), multiscale physiologically based pharmacokinetic and effect models, and route to route extrapolation. We follow with a short presentation of the automated KNIME workflows developed for dissemination and easy use of the models. We end with a discussion of two challenges to the field: our limited ability to deal with massive data and complex computations.