Word
Action number 15018 Last updated 11/11/2011 10:47:24 Year 2011
Title Systems Toxicology
Acronym ST
Type Action
Url
Institute JRC.I Institute for Health and Consumer Protection (Ispra)
Leader BERGGREN Katarina JRC.I.5   E-Mail
1 Prosperity in a Knowledge intensive society
1.5 Life Sciences and biotechnology
European Chemicals Agency (ECHA)
European Food Safety Agency
Organisation for Economic Co-operation and Development (OECD)
World Health Organization
Customer DGs AGRI - Agriculture and Rural Development
ENTR - Enterprise and Industry
ENV - Environment
INFSO - Information Society and Media
SANCO - Health and Consumers
TAXUD - Taxation and Customs Union
toxicology, hazard assessment, risk assessment, in vitro method, non-testing method, computational modelling, structure-activity relationship, SAR, QSPR, QSAR, chemical category, read-across, molecular modelling, toxicokinetics, toxicodynamics, genomics, proteomics, metabonomics, high-throughput screening, bioinformatics, toxicoinformatics, statistics, biostatistics, chemometrics, nutrition
Rationale
Systems Toxicology is an emerging discipline that aims to describe and predict the effects of chemicals and other environmental stressors at different levels of biological organisation, from molecules to cells, to organs, and to the entire organism. It represents a paradigm shift away from a purely reductionist approach, to a theoretical framework guided by the principle that certain properties of a system cannot be understood by only examining the individual parts of the system, but it is also necessary to consider interactions between the different parts. This allows the study of phenomena such as positive and negative feedback, and emergence of behaviour and function, typical of the complex, irreducible systems frequently encountered in biology. Thus the methods of systems toxicology are being developed to understand and describe this complexity, and to determine the extent to which the behaviour of biological systems is predictable.
The Systems Toxicology Action serves EU policies on safety of food and consumer products by developing, testing and validating new methods to predict the toxicological hazard of chemicals and nanomaterials. Ultimately the aim is to assess a larger number of chemicals in a shorter time (high throughput), at a lower cost, and by avoiding testing on animals. The strategy is to intelligently integrate modern scientific methods and knowledge to support decision makers undertaking risk and risk/benefit assessments, in particular those requested by EU legislation. Reflecting the globalisation of the challenge to ensure the safety of chemicals for human health and the environment, the Action will invest significantly in developing an international collaboration with the four major USA governmental agencies (EPA, NIEHS-NTP, NIH-NCGC, FDA) behind the Tox21 ("toxicity testing in the 21st century") initiative, as well as continuing to activities within the OECD, the United Nations Intergovernmental Programme on Chemical Safety (IPCS) and the International Life Sciences Institute (ILSI). In collaboration with WHO it was agreed to start a joint project to create a global database on Mode of Action in 2011.
Summary of the activity
In the 2011 Work Programme the main aim of the Action is to further develop, evaluate and validate integrated methodologies for hazard assessment of chemicals and nanomaterials that do not rely on animal testing. In addition to investigating the testing strategies applicable to a wide range of chemicals, the Action also takes a substance-centric perspective, focusing on areas of specific concern such as nanomaterial toxicity, chemical mixtures, and chemicals used in food and consumer products. Reflecting the spirit of the newly proposed JRC Strategy (2011-2020), the 2011 Work Programme for Systems Toxicology is beginning to adopt a more holistic view of certain problems, for example incorporating socio-economical aspects and risk-benefit reasoning within the development and evaluation of selected integrated testing strategy projects.
Regarding methodology, the Action extensively applies its array of techniques in experimental toxicology (in vitro), with emphasis on assay automation for precision and high throughput, and new assay technologies for high content analysis of biological effects. These include NMR and MS spectroscopy for metabonomics, quantitative microscopy for cell morphometry and molecular imaging, and micro-electrode-arrays for electrophysiology. Within the action also cell models are further developed, standardised and tested. Sophisticated data analysis and modelling tools are employed for experimental design and for interpretation of the expansive sets of experimental data generated. Complimenting the experimental programme, a wide range of computational toxicology approaches are applied in the assessment of chemicals, including Quantitative Structure-Property Relationships (QSPRs), Quantitative Structure-Activity Relationships (QSARs) and chemical categories, and biophysical modelling such as PBBK (Physiologically Based BioKinetics). The development of databases and information management systems is an integral part of the overall attempt to understand the adverse effects of chemicals and other stressors on human health and the environment.
The Systems Toxicology Action assembles multi-disciplinary research teams, representing the expertise available in the different Competence Groups, to address each of the cross-cutting objectives and deliverables defined in the Action work programme. The Competence Groups supporting the Action are: Assay Technologies and High Throughput Screening (HTS), Computational Toxicology and Biostatistics (CTB), Metabonomics (MET), Biological Models (transferred from Action 15015 to 15018 in July 2011) and Informatics (ICG). The Action also includes a small Nutrition Team (NUT).

Note: JRC's Institute for Health and Consumer Protection (IHCP) differentiates between two classes of Actions: Policy Support Actions (PSAs) and Operational Actions (OAs). PSAs provide the formal interface to IHCP's customers. The PSAs describe all the main objectives and associated deliverables agreed beforehand with IHCP's customers. In contrast the OAs describe in more technical detail how IHCP will perform the objectives formalised in the PSAs. The starting place to understand IHCP's workprogramme 2011 is therefore the PSAs,where each objective identifies the customer(s) to whom it is relevant. Moreover, in order to allow a transparent and more detailed mapping of the work, each PSA objective is also cross referenced to the OAs which contributes to the work of the PSA. In similar fashion, each objective in the OAs is cross referenced to the PSA to which they contribute. This Action is one of IHCP's Operational Actions and therefore provides a more detailed breakdown of the work defined in the Policy Support Actions which it supports and to which reference has been made in the individual objectives.
 
  1
To plan and manage the Action
Deliverable  1.1
Updated project file and minutes of Action meetings
31/12/2011
Deliverable  1.2
ISO 9001 certification and 17025 accreditation
31/12/2011
Deliverable  1.3
Periodic Progress Reports & PR Material
31/12/2011
Deliverable  1.4
Work Program 2012 and estimated budget table
31/12/2011
  2
To develop, evaluate and validate methodologies for hazard assessment of chemicals with emphasis on aspects of systemic toxicity, including neurotoxicity, hepatotoxicity (including metabolism mediated effects), endocrine disruption, and toxicokinetics. Attention will also be given to local (topical) toxicity to eye and skin. The work will contribute to ECVAM validation studies and related activities, CPN support to DG ENV, the Tox21 initiative, and the following RTD projects: OSIRIS, PREDICT-IV, COSMOS and DETECTIVE. (Contributing to PSAs: AM&ECVAM, CPN)
  2.1
To address the feasibility of evaluating acute systemic toxicity without resorting to animal testing.
(HTS & CTB) Report on the design and evaluation of integrated testing strategies for acute (oral) systemic toxicity based on the combination of high-throughput in vitro cytotoxicity assays and computational methods such as QSAR/QSPR. The task will employ data gathered from external sources and generated in-house, curated and then stored within Activity Base (our scientific data management system). A range of biostatistical modelling approaches will be investigated for hazard prediction.
31/10/2011
CAT7 - Scientific publications
(CTB) Report on the feasibility of extrapolating from internal tissue concentrations to external doses by using an integrated modelling approach combining PBPK and biology-based models for cytotoxicity.
30/09/2011
CAT7 - Scientific publications
(HTS) Testing of selected chemicals on the MEA-platform to determine their potency to acutely disrupt neuronal electrophysiology. Dataset to be included in a suitable format in Activity Base.
30/06/2011
CAT7 - Scientific publications
(CTB) Report on the development of a risk/benefit analysis framework, illustrated by hypothetical scenarios, suitable for weighing up the pros and cons of adopting different testing strategies for acute systemic toxicity within a regulatory context. Factors to be considered include the adequacy of hazard information generated, financial cost, time, and reliance on animals.
31/12/2011
CAT7 - Scientific publications
(CTB) Development and evaluation of classification models for local (skin and eye) toxicity.
31/12/2011
CAT7 - Scientific publications
  2.2
To develop and optimise measurement techniques and testing protocols for in vitro toxicology, including high throughput screening (HTS), NMR and MS spectroscopy for physico-chemical characterisation and metabonomics, quantitative microscopy for cell morphometry and molecular imaging, and micro-electrode-array (MEA) techniques for electrophysiology.
(HTS) A series of short technical reports describing the implementation of new standardised automation protocols for quantitative-HTS and detection of biological effects or endpoints (e.g. robotic method for immunofluorescence labelling and algorithms for image processing for hepatotoxicity, genotoxicity, oxidative stress).
30/09/2011
CAT4 - Technical systems
(HTS) Extension of the MEA platform to allow simultaneous imaging and electrophysiology measurements of neuronal and cardiomyocyte cultures, including hardware and software expansion, and protocol definition and proving.
30/06/2011
CAT4 - Technical systems
(MET) Standard Operating Protocols (SOPs) for spectroscopic measurements (NMR and MS) and data processing for hazard assessment of chemicals with metabonomics approach.
31/12/2011
CAT4 - Technical systems
(MET) In-house production of cell metabolites data base in order to support hazard assessment of chemicals and identification of novel biomarkers
31/12/2011
CAT4 - Technical systems
(MET) Standard Operating Protocols (SOPs) for the production and storage (database) of NMR and MS spectra of chemicals from the STU substance repository for use in the determination of identity, purity and stability. Includes generation and analysis of spectra for a training set of selected reference chemicals.
31/12/2011
CAT4 - Technical systems
(MET) Standard Operating Protocols (SOPs) for the characterisation by NMR of the fate of chemicals when added to cell cultures in vitro, including determination of solubility, binding to medium proteins, and binding to plastic multi-well plates). Includes generation and analysis of spectra for a training set of selected reference chemicals and compartments.
31/10/2011
CAT4 - Technical systems
(CTB) Report on how experimental factors affect in vitro experiments and how process-based modelling of the in vitro system can be used to take account of these variations. Findings will be illustrated using selected case studies.
31/12/2011
CAT7 - Scientific publications
  2.3
To develop and evaluate methodology for determining the hepatotoxicity hazard of chemicals, including metabolism-mediated effects, by using a range of in vitro and in silico methods.
(HTS) Report/paper on the application of automated HTS and HCA (imaging) techniques to study a range of adverse biological effects observed on HepaRG and HepaG2 cultured cells after application of selected chemicals using high-throughput techniques. The data will be stored in the Activity Base.
06/11/2011
CAT7 - Scientific publications
(MET) To contribute to the Trial report as one of the test laboratories for the ECVAM validation study on Cytochrome P450 Induction using human liver cells, by implementing and applying a MS protocol for quantification of CYP enzyme activity (through PSA AM&ECVAM).
31/07/2011
CAT3 - Validated and harmonized methods and measurements
(MET) Collection and organisation in databases of metabolic profiles obtained by NMR and MS of HepaRG and HepaG2 cells before and after exposure to selected chemicals.
31/12/2011
CAT3 - Validated and harmonized methods and measurements
(HTS, CTB & MET) Case study on metabolism-mediated hepatotoxicity aiming to combine the knowledge and experience of the different experimental and computational methods already used within the Action.
31/12/2011
CAT7 - Scientific publications
  2.4
To evaluate in-house bioassay test data integrated with computational methods for a better understanding of observed endocrine activity at the cellular level, and to relate the findings to observed effects in animals or humans.
(HTS) To generate and evaluate data from the LumiCell and MELN assays and store them in Activity Base for subsequent biostatistical analysis.
31/12/2011
CAT3 - Validated and harmonized methods and measurements
(CTB) Biostatistical and computational analysis of endocrine activity, using the datasets stored in Activity Base.
31/12/2011
CAT7 - Scientific publications
  3
To conduct in vitro and in silico studies contributing to safety assessment of (a) Nanomaterials, (b) Chemicals in food and consumer products and (c) Mixtures. (Contributing to PSAs: NT, CPN)
Deliverable  3.1
(HTS) To generate in vitro toxicological data on nanomaterials available in the IHCP repository using a range of automated HTS and HCA assays. The data generated will be reported in Activity Base and NAPIRAhub and will serve as input to NanoTEST and the OECD Sponsorship programme (SG7).
31/12/2011
CAT3 - Validated and harmonized methods and measurements
Deliverable  3.2
(CTB) Report on a theoretical framework for predicting the reactivity and toxicological effects of nanomaterials. The results will contribute to the FP7 projects NanoTEST and ENPRA.
31/12/2011
CAT7 - Scientific publications
Deliverable  3.3
(CTB) Case studies on the application of in silico methods to chemicals in food and consumer products (e.g. pesticides)
31/12/2011
CAT7 - Scientific publications
Deliverable  3.4
(HTS & CTB) Report on the feasibility of using MEA chips to analyse the neurotoxic effects of mixtures.
31/12/2011
CAT7 - Scientific publications
Deliverable  3.5
(HTS & CTB) Report on the exploratory research project "Assessment of the effects of realistic mixtures on human toxicity: is there something from nothing?"
31/12/2011
CAT7 - Scientific publications
Deliverable  3.6
(CTB) Systematic investigation on the applicability of QSAR analysis in the evaluation of developmental toxicity and neurotoxicity of pesticides for dietary risk assessment, carried out in support of EFSA through Action 15022 CPN under the terms of a Service Level Agreement.
31/10/2011
CAT7 - Scientific publications
  4
To develop computational models with emphasis on a better understanding of biological processes at the molecular and cellular level. The use of a systems biology approach will provide the basis for eventual activities in the area of synthetic biology.
Deliverable  4.1
(CTB) Case study on the systems biology modelling of the cell cycle and the metabolic network for HTS cell lines including an assessment of the implications for predicting chemical carcinogenicity.
31/12/2011
CAT7 - Scientific publications
  5
To provide technical support to Action 15016 (Molecular Biology and Genomics) for the in-house production of pre-spotted plates for RT-PCR based GM detection systems. (Contributing to PSA: GMO)
Deliverable  5.1
(HTS) Development of automated protocols on the HTS platform for preparing batches of pre-spotted plates for RT-PCR.
31/12/2011
CAT4 - Technical systems
  6
To develop and maintain JRC-hosted databases and information systems on chemicals and nanomaterials to support scientific research in the area of hazard assessment and regulatory risk assessment. (Contributing to PSAs: NT, H&E, CPN)
Deliverable  6.1
(ICG with support from HTS, CTB & MET) Maintenance and update the Activity Base Database with internally produced data and scientific data from collaboration parties for creation of a scientific database.
31/12/2011
CAT4 - Technical systems
Deliverable  6.2
(ICG with support from HTS, CTB & MET) Creation of the scientific knowledge base ESIS 2.0 - test version. This Deliverable can potentially feed into all IHCP PSAs, but not necessarily in 2011 when the project is still in a development phase.
31/12/2011
CAT4 - Technical systems
Deliverable  6.3
(ICG) Maintenance and update of the NAPIRAhub database supporting PSA NT in coherence with ECHA IUCLID developments.
31/12/2011
CAT4 - Technical systems
Deliverable  6.4
(ICG) Maintenance and update of the NHECD database supporting RTD project NHECD.
31/12/2011
CAT4 - Technical systems
Deliverable  6.5
(ICG & CTB) Maintenance of the QSAR Model Database contributing to PSA AM&ECVAM. This includes the peer review of QSAR Model Reporting Formats (QMRFs) submitted for inclusion in the database.
31/12/2011
CAT4 - Technical systems
Deliverable  6.6
(ICG) Maintenance and development the Endocrine Active Chemicals Database supporting DG ENV through PSA CP&N.
31/12/2011
CAT4 - Technical systems
Deliverable  6.7
(ICG) Maintenance and update of the IHCP internet and intranet homepages.
31/12/2011
CAT4 - Technical systems
Deliverable  6.8
(ICG) Support to the OECD eChemPortal project through the PSA AM&ECVAM. Contributing to updated versions and the data of this web portal instrument.
31/12/2011
CAT4 - Technical systems
Deliverable  6.9
(ICG) Maintenance and update the European Database on Export and Import of Dangerous Chemicals (EDEXIM) to support DG ENV though PSA H&E.
31/12/2011
CAT4 - Technical systems
Deliverable  6.10
(ICG) Hosting of OECD SIDS database on behalf of OECD and exploiting synergies with this database and those developed and maintained in-house.
31/12/2010
CAT4 - Technical systems
  7
To provide targeted scientific information and advice in the area of Nutrition and Health to support EU policy making and to inform the consumer. (Contributing to PSA CPN)
Deliverable  7.1
(NUT) State-of-the art review on innovative approaches in nutritional science, such as "omics" and systems biology, to understand possible implications for future nutrition-related research strategy and policy making.
30/06/2011
CAT7 - Scientific publications
Deliverable  7.2
(NUT) Review of scientific information on selected nutritional topics to provide easy-to-understand overviews of the state-of-the art in a condensed format.
31/12/2011
CAT7 - Scientific publications
Deliverable  7.3
(CTB & NUT) Case study on the use of computational methods in understanding the potential physiological effects of food chemicals.
31/12/2011
CAT7 - Scientific publications
  8
To fulfil JRC's legal requirements in the context of BEVABS (the European Wine Office) and the Wine Databank supporting DG AGRI through the PSA CPN.
Deliverable  8.1
(MET) Continuous maintenance and development of the EU Wine databank presented in progress reports and validation of data produced by the Member States.
31/12/2011
CAT4 - Technical systems
Deliverable  8.2
(MET) Editing of the revised SNIF-NMR method to be proposed as new standard to the International Organisation for Wine and Vine (OIV).
31/03/2011
CAT4 - Technical systems
  9
To continue to participate in the RTD project COPHES on the establishment of a long-term European human biomonitoring system. (Contributing to PSA: H&E)
Deliverable  9.1
(MET) Contribution to reports compiled within the RTD project COPHES.
31/12/2011
CAT5 - Other policy support products and services
Deliverable  9.2
(MET) Workshop report on the potential of ''omics'' in human biomonitoring methods in the EU organised within the RTD project COPHES.
31/12/2011
CAT7 - Scientific publications
  10
To continue to participate in the RTD project OSIRIS on the development of in silico methods and Integrated Testing Strategies for industrial chemicals.
Deliverable  10.1
(CTB) Training materials on the use of in silico methods in chemical risk assessment.
30/06/2011
CAT8 - Training courses
Deliverable  10.2
(CTB) Investigation into the applicability of QSAR methodology for predicting genotoxicity.
31/12/2011
CAT7 - Scientific publications
  11
To participate in the RTD projects COSMOS, Scr&Tox, Detective and COACH included in the SEURAT-1 research initiative working towards the replacement of in vivo repeated dose systemic toxicity testing.
Deliverable  11.1
(CTB) Report on the development of a process-based model for in vitro experiments.
31/12/2011
CAT7 - Scientific publications
Deliverable  11.2
(CTB) Contribution to the use of QSAR methods in assessing cosmetic ingredients.
31/12/2011
CAT7 - Scientific publications
Deliverable  11.3
Deliverables as defined in FP7 project COACH - year 1 (the responsabilities under this deliverable was taken over from Action 15015 during the spring 2011)
31/12/2011
CAT7 - Scientific publications
Deliverable  11.4
Deliverables as defined in FP7 project Scr&Tox - year 1 (tranferred from Action 15015 July 2011)
31/12/2011
CAT7 - Scientific publications
Deliverable  11.5
Deliverables as defined in FP7 project DETECTIVE - year 1 (tranferred from Action 15015 July 2011)
31/12/2011
CAT7 - Scientific publications
  12
To validate, test and contribute to further standardisation of in vitro assays and cell models applied for in vitro testing.
Deliverable  12.1
Progress report on the validation project (reliability) of the MELN assay for assessing estrogenic activity (tranferred from Action 15015 July 2011)
31/10/2011
CAT3 - Validated and harmonized methods and measurements
Deliverable  12.2
Internal report on the use of the cell-production facility and supply of IHCP in vitro laboratories with high-quality human cells (tranferred from Action 15015 July 2011).
31/12/2012
CAT4 - Technical systems
Deliverable  12.3
Deliverables as defined in FP7 project ESNATS - year 4 (tranferred from Action 15015 July 2011)
31/12/2011
Deliverable  12.4
Guidance for test developers on ECVAM website, for comments. (tranferred from Action 15015 July 2011)
31/12/2011
CAT8 - Training courses
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