Community Research and Development Information Service - CORDIS

FP7

COACH Report Summary

Project ID: 267044
Funded under: FP7-HEALTH
Country: France

Final Report Summary - COACH (Coordination of projects on new approaches to replace current repeated dose systemic toxicity testing of cosmetics and chemicals)

Executive Summary:
COACH was a coordination and support action of the FP7 HEALTH programme that started on 1 January 2011, at the same time as six complementary RTD projects, altogether forming a cluster referred to as the SEURAT-1 Research Initiative.
The main role of COACH was to:
• facilitate the cluster internal cooperation
• provide strategic guidance with the help of a Scientific Expert Panel
• write and distribute annual reports
• organise the cluster annual meetings
• coordinate cluster level dissemination and outreach activities
COACH provided a central scientific secretariat to the SEURAT-1 Research Initiative (the ‘COACH Office’), organising the cluster level interactions and activities and being the main entry point at the cluster level for all organisations, including the funding organisations, i.e. the European Commission and Cosmetics Europe and all external organisations which were searching contact with this initiative (Figure 1).
The aim of the SEURAT-1 Research Initiative was the development of a long-term research strategy leading to pathway-based human safety assessments in the field of repeated dose systemic toxicity testing of chemicals. The overall goal was to establish animal-free innovative toxicity testing methods, enabling robust safety assessments that are more predictive than existing testing procedures. In order to achieve this, a cluster of five research projects spread over 70 European universities, public research institutes and private companies has been set up, supported by a ‘data handling and servicing’ project and a ‘coordination and support’ project. The Scientific Expert Panel (SEP), composed of the SEURAT-1 project coordinators and external international experts in the field of repeated dose systemic toxicity, provided scientific advice regarding the research work and future direction of the SEURAT-1 Research Initiative and, thus, played a key role in its scientific coordination.
SEURAT-1 combined expertise in cell culture for the preparation of stable human cell lines with the establishment of sophisticated experimental systems such as organ-simulating devices. This experimental work was linked with advanced methods of computational modelling and estimation techniques, taking innovative systems biology approaches into consideration. This large research collaboration required an efficient coordination at the SEURAT-1 cluster level.
The focal point of the joint activities was given by proof-of-concept studies (case studies) on three levels, demonstrating that:
(i) mode-of-action theory provides a solid foundation for mechanistic understanding of adverse effects at the subcellular scale (theoretical level), which
(ii) can be converted into the development of integrated animal-free prediction methods (product level) that will
(iii) ultimately support regulatory safety assessment (application level).
The achievement of these proof-of-concept studies forms the backbone for the SEURAT-1 roadmap, which was developed based on key contributions from each of the projects addressing the cluster-level objectives. It is as yet impossible to cover all toxicological endpoints with such a strategy, but the mechanism-based SEURAT-1 case study approach was designed to provide a cornerstone in the transition from descriptive to predictive toxicology.

Project Context and Objectives:
1. Project Context

Risk assessment is a prerequisite to guarantee human safety. A crucial step in this process is hazard identification which includes the determination of the intrinsic toxic potential of chemical substances. Hazard identification relies on a series of toxicity studies that are usually carried out in experimental animals. Over time, economical, ethical and scientific developments have motivated the scientific community to initiate the search for alternatives to animal experimentation. At the same time, scientific advances in the biomedical field, computer science and biotechnology are enabling progress in human toxicity testing.
In the last decade, European legislations have been calling for the use of alternative methods to animal testing. The animal testing ban of cosmetic ingredients came into force on 11 March 2009 (Anon, 2003) , for all human health effects. The marketing ban of cosmetic ingredients and finished products tested on animals became effective on the same date with the exception of repeated dose toxicity (including skin sensitisation and carcinogenicity, reproductive toxicity and toxicokinetics). For these specific health effects, the marketing ban came into force on 11 March 2013, despite the fact that alternative methods were not available for a number of end-points.
Since cosmetic ingredients are chemicals, the data required for their safety assessments in cosmetics may already be available as a result of compliance with the provisions of the EU REACH chemicals legislation (Regulation 2006/1907/EC ). For some defined product classes (e.g., new or revised colorants, preservatives and UV-filters) the submission of safety data to SCCS is a legal requirement before their use in cosmetics is permitted. In the REACH legislation, article 1 promotes alternative methods for safety testing, article 25 states that animal testing must be used as a last resort, and encourages the exploitation of useful alternative methods. In addition, article 13 states that information on hazards (regarding positive results) and risks may be generated by suitable alternative methods that have not yet been taken up as official regulatory test methods, upon the condition that such methods fulfil the requirements of Annex XI (e.g., ECVAM criteria for the entry of a test into the prevalidation process). Moreover, if such methods are validated, both positive and negative results from these methods will be accepted. Thus, REACH also provides a strong impetus towards the development, acceptance and use of alternative methods that could reduce the number of animals used for toxicological testing.
Furthermore, the European Commission Directive 86/609 on animal protection also promotes the use of alternative methods and states that “an experiment shall not be performed if another scientifically satisfactory method of obtaining the result sought, not entailing the use of an animal, is reasonably and practicably available” (EC, 1986 ).
However, despite of this strong regulatory pressure, alternative methods that have yet been developed and taken up in the European legislation are limited to local and acute toxicity. For repeated dose and systemic toxicity testing, consuming the largest number of laboratory animals, no alternatives are currently available . A number of European projects in the field of alternative methods have been launched before the SEURAT-1 initiative. However, none of these projects addressed the development of alternatives to in vivo repeated dose systemic toxicity testing.
It is generally accepted that it will not be possible to simply replace a 28-days and 90-days rat study (that is currently the standard information requirement of relevant regulatory frameworks) with a battery of in vitro and in silico techniques. The first step was therefore to define what a new alternative integrated risk assessment approach would look like. The development of such an integrated approach requires considerable investment in basic research to develop and validate a range of in vitro models, QSAR/SAR and read across methods, as well as novel technologies
During 2008, a DG RTD Research Initiative was established, which was supported by Cosmetics Europe and which resulted in the FP7 call HEALTH.2010.4.2.9, addressing repeated dose systemic toxicity in an integrated approach (see the research strategy diagram in Figure 2). The 6 projects (building blocks) funded under this call would focus on (1) the optimisation of current and development of new methods for differentiation of human-based cells in vitro, (2) the use of organ-simulating devices, (3) establishment of endpoints and intermediate biomarkers in human-based target cells, (4) computational modelling and estimation techniques, (5) systems biology, and (6) integrated data analysis and servicing. The building blocks would be supported by a Coordination Action. The ultimate long-term goal of this cluster was the integration of all data generated in order to understand how these novel approaches can be used to devise an overall strategy for a future replacement of repeated dose systemic toxicity testing in human safety assessment. The cluster constituted phase I of the long-term research initiative SEURAT (“Safety Evaluation Ultimately Replacing Animal Testing”).

The six RTD projects selected in this call were:

• SCR&TOX: "Stem Cells for Relevant Efficient Extended and Normalized Toxicology", Project ID: 266753
• HEMIBIO: "HEPATIC MICROFLUIDIC BIOREACTOR", Project ID: 266777
• DETECTIVE: "Detection of endpoints and biomarkers of repeated dose toxicity using in vitro systems", Project ID: 266838
• COSMOS: "Integrated In Silico Models for the Prediction of Human Repeated Dose Toxicity of Cosmetics to Optimise Safety", Project ID: 266835
• NOTOX: "Predicting long-term toxic effects using computer models based on systems characterization of organotypic cultures" Project ID: 267038
• ToxBank: "Supporting Integrated Data Analysis and Servicing of Alternative Testing Methods in Toxicology", Project ID: 267042

More detailed information on the objectives, scope and main results of the SEURAT-1 cluster projects can be found here on Cordis.
The success of the cluster (and thus of the following phases of the SEURAT initiative) was dependent on a close and structured interaction across all the building blocks and the elaboration of the strategy for future research activities needed to achieve the long-term goal of SEURAT. This was the main purpose of the Coordination and Support Action project COACH: "Coordination of projects on new approaches to replace current repeated dose systemic toxicity testing of cosmetics and chemical".

2. COACH Objectives

COACH had defined the following objectives:
• To facilitate information exchange and collaboration between the different cluster projects
• To monitor progress towards the goals of the SEURAT-1 initiative
• To prepare the strategy for future research activities in an international context
• To collect, elaborate and disseminate information, results and proposed future strategic research orientations to relevant stakeholder groups via:
o Organisation of annual workshops
o Publishing of annual reports
o Animation of a Scientific Expert Panel
o Preparation of strategic information material and targeted dissemination activities, including press relations
The work needed to carry out the activities, specified in the list above, was organised into three distinct work-packages:
• WP1 “Facilitation of cluster-internal cooperation” to facilitate achievement of the cluster goals by fostering cooperation and cohesion between the six building blocks. To this aim, an appropriate level of transparency and exchange among the building blocks at different levels needed to be created by identifying what the projects could share, taking intellectual property rights into account via a cluster agreement.
• WP2 “Preparation and distribution of the annual books” was dedicated to the production of one of the key outcomes of COACH: an annual book. This book, published in six volumes (one per year), presents the context and objectives of the SEURAT-1 research initiative, the achievements of the cluster as compared to the SEURAT-1 objectives, and the international state of the art, and proposals for the future research strategy.
• WP3 “Organisation of meetings” provided the adequate support to foster face-to-face exchanges in well-planned meetings organised throughout the cluster duration: annual meetings, Scientific Expert Panel meetings, ad-hoc meetings (to tackle issues necessitating a more profound discussion between the different partners from two or more projects), and summer-schools (dedicated in particular to the younger researchers in the cluster).
Two additional work packages completed the services of COACH regarding the dissemination of the research strategy (WP4) and the provision of the adequate support for the contract to smooth out the COACH consortium collaboration and to ensure work in WP1 to WP4 was most efficient (WP5). These two additional work packages are:
• WP4 “Dissemination”, which disseminated the SEURAT research strategy towards the relevant stakeholders (industry, regulators, research policy makers, academia). To this aim, the cluster’s visibility has been enhanced through different means, including a public website and the preparation of the required material, e.g. for meetings.
• WP5 “Consortium Management”, which provided the adequate structure to properly organise the work and strategy of the COACH consortium and sort out all administrative issues related to the contract with the EC and Cosmetics Europe.

Project Results:
Since COACH focused on supporting the collaboration of the 6 individual research projects in the SEURAT-1 cluster, and on defining the overarching strategy and objectives of the programme, we describe hereafter the main achievements of the whole SEURAT-1 programme, both at SEURAT-1 cluster level (which COACH was much involved in) and on project individual level.

1.Long-term strategy leading to safety evaluation ultimately replacing animal testing

In the first year of SEURAT-1 programme, the vision of this research initiative was formulated. It states that SEURAT is aiming to fundamentally change the way the safety of chemicals is assessed, by superseding traditional animal experiments with a predictive toxicology that is based on a comprehensive understanding of how chemicals can cause adverse effects in humans. To achieve this vision, the overarching research strategy was also defined: to adopt a toxicological mode-of-action framework to describe how any substance may adversely affect human health, and to use this knowledge to develop complimentary theoretical, computational and experimental (in vitro) models that predict quantitative points of departure needed for safety assessment (SEURAT-1 vol. 1, 2011).
This was followed-up by defining more explicitly the cluster level objectives, which were to:
• Formulate and implement a mode-of-action based research strategy for repeated dose systemic toxicity.
• Develop new predictive toxicology tools and methods that are relevant for regulatory decision making.
• Demonstrate proof-of-concept at multiple levels - knowledge, systems, application.
• Provide the blueprint for applying the strategy to other chemical, toxicological and regulatory domains.
Setting up Integrated Approaches for Testing and Assessment of chemicals for prediction of other health effects has evolved also outside the SEURAT-1 programme during the last years. The SEURAT-1 stated an example, and due to the large number of partners and interactions with other research initiatives, SEURAT-1 became a centre for dissemination of ideas and acceptance of innovative and integrated alternative testing methods. A core group of the Scientific Expert Panel also provided a strategy paper suggesting how to proceed beyond SEURAT-1 based on the lessons learned within the initiative (Daston et al., 2015).
The main objective for each project of the SEURAT-1 programme was of course to produce the methods and tools within the scientific field of alternative methods in which the specific project had gathered expertise. How these methods could be combined based on mode-of-action thinking and underpinning a chemical safety assessment was shown through the SEURAT-1 proof-of-concepts.

2.The ‘conceptual framework’ to combine evidence in a biologically-rational manner

A flexible ‘conceptual framework’ has emerged from SEURAT-1 and sets out a structure to guide assessors in devising a fit-for-purpose Integrated Assessment and Testing Approach (IATA) that combines information from predictive tools with a stated protection goal in the context of repeated dose systemic toxicity.

The conceptual framework can be visualised as a flexible workflow that is adapted for a particular case depending on the regulatory purpose of the prediction, and hence the degree of uncertainty that can be tolerated, particularities of the substance to be assessed and the resources available to the assessor.
Briefly, the Conceptual Framework consists of the following steps:
• Decide the degree of confidence needed for prediction (low degree of confidence may be acceptable in case of well-controlled and low human exposure);
• Examine existing knowledge (toxicological studies, ‘read-across’ from chemical or biological analogues, QSARs and structural alerts, expert judgement);
• Distinguish between ‘general chemicals’ (expected to be unselective in interacting with biological targets) and a drugs/pesticides (designed to be selectively biologically-active);
• Two parallel lines of consideration: (i) ‘general’ adverse effects not associated with a particular organ and (ii) organ based adverse effects;
• Consideration of toxicokinetics/toxicodynamics (for both lines of consideration);
• Effects on organs can be assessed by (several) AOPs incorporating existing knowledge and with new data as a combination of in vitro assays (‘-omics’ data etc.) and in silico predictions in a battery of tools.
The overall outcome of an assessment based on the framework is anticipated to be robust as it is not based on single pieces of evidence; nevertheless the type and degree of uncertainty in the predictions would need to be validated as ‘fit for purpose’. Case studies were developed in SEURAT-1 using the integrated in vitro molecular screening, ‘omics’ data, and computational models within the conceptual framework for typical safety assessment scenarios.

3.The tools and methods

One of the most valuable outputs of SEURAT-1 is the large portfolio of cutting-edge computational and in vitro tools and methods that will underpin new animal-free approaches to the safety assessment. It is important therefore to clearly present the new tools and methods in their own right, as independent building blocks that can be assembled in a wide variety of ways for many different purposes. For that purpose the SEURAT-1 Tools & Methods Catalogue was created and disseminated via the public EURL ECVAM DataBase service on Alternative Methods (DB-ALM) (EC 2014), developed and maintained by the Commission's Joint Research Centre, which makes possible to update the methods also after the finalisation of SEURAT-1.

4.The gold compound database

The first sign of how the guiding principles of the research strategy outlined above (adoption of a toxicological mode-of-action approach) have influenced the research cluster is reflected in the approach for the selection of standard reference compounds to be used across the projects. Mechanistic understanding of chemical induced perturbation is at the heart of the much heralded paradigm shift in toxicology. Toxicogenomics and complementary ‘-omic’ techniques have accelerated the discovery and delineation of a plethora of pathways which can aid in understanding mode of action of chemical toxins. To expand this knowledge and to investigate the quality of the in vitro systems developed in SEURAT-1 and elsewhere, there is a need to test more compounds. The question is which compounds should be tested and why?
With this fundamental question in mind, a cross-cluster working group led by the servicing project ToxBank was established within SEURAT-1 for defining selection criteria according to the overarching research strategy and, ultimately, providing the research projects with a list of reference compounds. The selection was governed by the following basic considerations: (i) The standard reference compounds should be associated with well-known modes-of-action; (ii) the standard reference compounds should be relevant for repeated dose toxicity; (iii) promiscuity, i.e. lack of structural specificity in interactions with biological targets, should be considered; and (iv) extrapolation from well-studied reference compounds to a broader chemical space taking into account different uptake routes should be possible.
The working group first identified and described a range of known modes-of-action more commonly cited in repeated dose toxicity studies, and then picked molecules for which there is ample mechanistic evidence of association with toxicological effects or pathways underpinning those modes-of-action.
The resulting list of standard reference compounds is publicly available as an online resource (http://www.toxbank.net/compound-wiki) along with extensive descriptions with respect to the above-mentioned criteria, including further considerations regarding their applicability in cell-based in vitro assays (e.g., stable to storage, soluble in buffer, commercially available, etc.). Not surprisingly, many of the reference chemicals are pharmaceuticals or failed drugs since these molecules typically have specific mechanisms or modes-of-action that are extensively described in the literature. It is precisely these mode-of-action-related properties that make them reliable candidates for nomination as reference compounds, rather than their actual origin or commercial use. The rationale behind the mode-of-action derived selection of chemicals to be used as standard reference compounds was published recently (Jennings et al., 2014).

5.SEURAT-1 research data stored in ToxBank

A critical infrastructure project, the ToxBank Data Warehouse, came online at the beginning of 2013. The aim of ToxBank was to facilitate data storage and support the data analysis needs across the cluster including data collection, integration, analysis, as well as experimental design (http://www.toxbank.net/data-warehouse). It provides a web-accessible shared repository of know-how and experimental results to support the SEURAT-1 Research Initiative. Results and protocols were uploaded from the research activities of the cluster partners, as well as relevant data and protocols from other sources, such as public databases containing toxicogenomics data. The data is being made publicly available considering critical aspects of intellectual property rights.

6.The proof of concept demonstrated on 3 levels

The multiple proof-of-concepts are based on the idea that the application of a toxicological mode-of-action framework for chemicals safety assessment can be split into three steps. Firstly, development of a theoretical Adverse Outcome Pathway (AOP) describing the key events of the biological process initiated by a chemical stressor, if possible including quantitative considerations, i.e. resulting in a qAOP (quantitative AOP). Secondly, a testing strategy is needed for toxicity prediction, based on (q)AOP(s) knowledge relevant to the toxicity to be predicted. Typically more than one test method would be needed to trigger selected key events, in combination with in silico profilers or in chemico predictors. Finally, the results of testing strategies in combination with already existing data (physical chemical information, animal or human in vivo data or other) and kinetic modelling, could provide sufficient evidence to support chemical safety assessment. In the last and third step, careful consideration should be made to include the reasoning as lined out in the conceptual framework developed within SEURAT-1.
Level 1 – Development of theoretical Adverse Outcome Pathway (AOP) constructs
Many of the SEURAT-1 activities are connected to target organ systemic toxicity after repeated exposure to liver. Theoretical AOP constructs were drafted for fibrosis, steatosis and cholestasis (Landesmann and Vinken 2013). A level 1 case study on drug induced cholestasis was conducted for further elucidating this pathway.
Level 2 – Development of Integrated Testing Strategies to predict toxicity
Within SEURAT-1 seven level 2 case studies have been performed. The prediction goals of those are:
1. Liver fibrosis
2. Liver steatosis
3. Liver and kidney toxicity (organ specific AOPs)
4. Liver and heart toxicity (non-organ specific or 'general' AOPs)
5. Mitocondrial toxicity (non-organ specific or 'general' AOPs)
6. Molecular Initial Events (MIEs) associated to liver steatosis
7. Liver/ non liver toxicity
The chemicals selected to be tested in the case studies are used for bench marking, i.e. they are chosen to test the predictive system, based on their already known mode-of-actions and related adverse effects. SEURAT-1 gold compounds (see above) relevant for the target and the predictive toxicity have been included in the test systems. In a few case studies it was necessary to select additional substances. The chemical selection was then carefully described to enable interpretation of the results.
The results from the predictive toxicity testing at the level 2 proof-of-concept, besides having a value in themselves, also contributed to the level 3 case studies.
Level 3 – Application of predictive systems to support safety assessment
Three safety assessment case studies have been set up under SEURAT-1 all following the reasoning behind the general conceptual framework.

• The read-across case study (for immediate use in regulatory toxicology)
The primary goal of the read-across case study is to increase confidence in read-across assessment by using data from alternative methods. This approach will use a no-effect level based on existing data for one substance (the source) and read it across to a similar substance (the target), and the resulting safety assessment is expected to reach regulatory acceptable standards within the SEURAT-1 timeframes. Several separate examples were elaborated in the context of this case study, illustrating the most relevant read-across situations:
1. Chemical similarity of compounds that do not require (or do not undergo) metabolism to exert a potential adverse human health effect;
2. Chemical similarity involving metabolism (resulting in exposure to the same/similar toxicant);
3. Chemical similarity with general low or no toxicity;
4. Distinguishing chemicals in a structurally similar category with different toxicological premises.
The two major aspects of any read-across exercise, namely similarity and uncertainty, are assessed for each example, using a common strategy that was developed and published as structured templates that will guide any read-across assessment.

• The ab initio case study (illustrating proof of concept of how a risk assessment for a cosmetic ingredient might be done without animal testing)
The ab initio case study uses data from the SEURAT-1 methods to make a risk assessment for repeated dose toxicity and predict a no-effect level of a cosmetic ingredient assuming a certain exposure scenario. This case study is rather focusing on setting up a workflow how to build up an safety assessment solely relying on data from alternative methods, and is considered an initial step towards a new alternative assessment strategy.

• The Threshold of Toxicological Concern (TCC) case study
The Threshold of Toxicological Concern (TTC) approach is a non-testing method that allows a preliminary risk assessment of chemicals based on the availability of reliable exposure information. It is an exposure threshold for chemicals, below which there is a low probability of an appreciable risk to humans. The COSMOS project has supported the evaluation and extension of the TTC approach to cosmetics ingredients and chemicals in formulations. Overall, there are two goals in this case study: to use the databases for TTC values and skin permeability, and to apply the new methods to confirm that the approach is practical and yet scientifically sound enough to be useful for both regulatory bodies and industries.

7.Key achievements of the COACH project

This section describes only the high level key achievements. The detailed results of the various project activities are described in the following sections.

- SEURAT-1 strategic reviews
SEURAT-1 strategic reviews were made on a yearly basis from the second year of the project. Three reports were prepared by COACH partner JRC and discussed with the SEP in June 2012, June 2013 and May 2014, and then distributed to all SEURAT-1 partners. The strategic reviews include progress information on key deliverables identified for each project together with the coordinators. In addition, there is a strategic action table, including concerns primarily identified at SEP meetings or in the SWOT analysis, and actions taken to address these concerns. Each strategic review contains a SWOT analysis, carried out as a brainstorming exercise by the Cosmetics Europe Advisory Board members and the coordinators, with support from their project partners and COACH. The strategic reviews also include a summary of the SEP discussions and agreed follow-up to the reported outcome.
In the last year of RTD activities, the strategic review, was transformed in a final, more general review of the global results and outcomes of SEURAT-1. Therefore the last SEURAT-1 review was finalised and circulated at the SEURAT-1 Symposium that was organised in December 2015.

- Increased awareness of stakeholders, resulting from dissemination activities
COACH, with the help of the SEP, elaborated a comprehensive dissemination plan covering the various target groups to be reached by SEURAT-1 dissemination activities that are further detailed hereafter. For each group the most suitable dissemination channels, support material and activities were defined. Those included the organisation of dedicated workshops, the participation to all major scientific conferences, the production of Annual Reports, press releases and articles, the creation of communication support material (leaflets, USB keys, roll-up banners, posters, videos, etc.), and the web presence of SEURAT-1 through its public website.
These dissemination activities can be considered as a successful contribution to increasing the awareness of stakeholders on the important changes that are ongoing in the domain of human safety assessment:
Firstly, the fragmentation in alternative testing research must be overcome. Europe needs to join its forces from private and public sector to accelerate scientific and technological progress, to be at the forefront of alternative human safety testing at the international level, and to offer a partner of choice for efficient cooperation with major research initiatives in other countries and regions in the world.
This message has been received. SEURAT-1 has been the first step to achieve this aim and after SEURAT-1 there will be a new large European research initiative that will further strengthen the collaboration of European leading experts from public and private sectors.
Secondly, research on animal-free safety testing has made significant progress over the last years. The contours of future human safety assessment methods become perceptible, and those will lead to fundamental changes in regulatory practices. A close collaboration between scientists and regulators in the next steps of research and innovation is needed.
The engagement of regulators with the research community has increased in the course of SEURAT-1 and will be further strengthened in the follow on research initiative.
Thirdly, research effort to develop robust alternative testing methods will take many more years and there is a need for a common long-term strategy to define a way forward and optimise efficiency of efforts invested in research and technology developments. SEURAT-1 has developed such a strategy and it has been widely disseminated in the community of stakeholders and the scientific community through publications in peer-reviewed journals (Gocht et al., 2015; Daston et al., 2015). The SEURAT research strategy has been acknowledged as an important reference for guiding further research in alternative testing approaches.
Globally, the increased awareness of stakeholders in SEURAT-1 can also be measured with the interest in the Annual Reports (~700 persons registered in the Annual Report mail list, about 2,500 electronic copies distributed on USB keys), the interest shown in the SEURAT-1 Symposium, the continued exchanges and collaborations with stakeholder organisations and initiatives in this field, including international research programmes.

Potential Impact:
1.Impact of the SEURAT-1 initiative

DEVELOPMENT OF SAFETY TESTING METHODS WITH HIGHER PREDICTED VALUE
The 6 cluster projects generated a large amount of information addressing the area of repeated dose systemic toxicity. In order to strengthen the coherence and collaboration, and create synergy among the six projects, COACH created a structure to facilitate cooperation leading to the development of novel approaches for human safety assessment.

THE CONSTRUCTION OF A SOLID FOUNDATION FOR A LONG-TERM RESEARCH AND DEVELOPMENT STRATEGY IN REPEATED DOSE SYSTEMIC TOXICITY TESTING
COACH ensured that the cooperation between the six SEURAT-1 RTD projects of the cluster was optimised. COACH also facilitated the conception of future strategies for repeated dose systemic toxicity testing. For this purpose, the article SEURAT: Safety Evaluation Ultimately Replacing Animal Testing—Recommendations for future research in the field of predictive toxicology was published in Archives of Toxicology (Daston, G., Knight, D.J., Schwarz, M. et al. Arch Toxicol (2015) 89: 15.).
Furthermore, an important objective of COACH was to carry out a thorough analysis of the results from the six RTD projects, to monitor the international “state of the art” in order to identify knowledge gaps and define the future research priorities. The Annual Reports cover the major results obtained in the different projects each year and the progress made towards reaching the final goal of the cluster and of the SEURAT initiative, the identified knowledge gaps, as well as proposed research priorities, strategies, and future actions.

SUPPORT TO VALIDATION OF NEW TEST METHODS
The participation of EURL ECVAM (JRC) in the COACH Secretariat could inform the SEURAT-1 projects on the importance of standardisation and replicability of a test method for the further use in safety assessment for legal requirements and the possibility to also formally validate test methods. ECVAM has a bridging role in between the science and the applicability in EU legislation.

IMPACT ON COMPETITIVENESS OF EUROPEAN INDUSTRY
The European Industry has much to gain from SEURAT-1, in particular in the areas of reducing or replacing animal testing, increasing competitiveness, and foundation of new and increased success of existing SMEs. The assessment and optimisation of new technologies planned in the different projects such as stem cells, systems biology, computational toxicology, organotypic devices, “omics” technologies, should on a long run result in the development of better predictive, integrative approaches for toxicological safety assessment. The use of these novel approaches in regulatory/safety testing will lead to a reduction in cost and time required for safety testing of new products, improve product characteristics and safety profiles, and consequently increase the competitiveness of European industry.

STRENGTHENING OF THE EUROPEAN RESEARCH AREA (ERA) AND INTERNATIONAL COOPERATION
The COACH project acted in the spirit of ERA: it provided a basis for exchange of information and strengthened the coherence and collaboration among the six cluster RTD projects. COACH also provided a platform to facilitate exchanges between European scientists with the partners of these six projects, as well as members of the Scientific Expert Panel. This structure results in new international scientific collaborations within, but most importantly, also beyond the cluster such as with the Toxicology in the 21st Century (Tox21) initiative in the United States.

2.Dissemination and Exploitation Activities

The COACH dissemination activities have evolved together with SEURAT-1, as each phase of the initiative has required a specific attention. Since 2011, the activities have ranged from creating the SEURAT-1 visual identity as a new player in the field of alternative testing and presenting the objectives of the research initiative to the entire scientific world, to showcasing the targeted achievements for key stakeholders, the general public and other target groups via a number of channels. The following activities and tools were developed to support the dissemination as efficiently as possible:
• A consistent visual identity for SEURAT-1 (logo, colour scheme, layout of printed and electronic dissemination material, website appearance, etc.) was created at the outset of the initiative in collaboration with a professional design company;
• A variety of information dissemination support materials were created and distributed, including:
o Four leaflets (available on the SEURAT-1 website):
▪ an initial leaflet published in year 2011 contained a comprehensive presentation of the initiative;
▪ a new leaflet, issued in 2013 provided a more concise general presentation of SEURAT-1, and was designed for carrying an USB stick, the content of which was progressively updated with available SEURAT-1 documents;
▪ the “ SEURAT-1 highlights” leaflet, issued in 2015 in view of the SEURAT-1 Symposium;
▪ "Alternative testing: SEURAT-1 achievements and way forward" produced for the EC conference “Non-animal approaches – the way forward” on 6-7 December 2016;

o The SEURAT-1, COACH and cluster roadmap posters;

o A ‘who’s who’ booklet, which was distributed at each Annual Meeting (also available online);

o A standard PowerPoint presentation presenting the initiative and showcasing main results;

o Unique roll-up banners illustrating the cluster composition and the conceptual framework, which were used during the SEURAT-1 & ESTIV Joint Summer School, at the SEURAT-1 corner at the 9th World Congress on Alternatives and Animal Use in the Life Sciences in Prague, Czech Republic, in August 2014, at the EUROTOX 2015 conference in September 2015 in Porto, Portugal and during the SEURAT-1 Symposium on 4 December 2015.

• The SEURAT-1 public website (http://www.seurat-1.eu), one of the key channels of SEURAT-1 outreach activities, was launched in 2011. The website disseminates information from the cluster to a large audience of stakeholders, scientists and the general public, and serves as a source of statistically important information regarding the impact of the dissemination activity.
The regularly updated content of the website includes a general overview of the SEURAT-1 Research Initiative, detailed information about the objectives and results, its future vision and strategy, the work structure, overviews of the seven cluster projects involved and their contributions. New cluster-level and individual projects’ dissemination material, such as the COACH film, was immediately published in the ‘Publications’ section; the ‘Who is Who’ section is now a well-known depository of important information about the experts involved in SEURAT 1; the ‘Bibliography’ contains articles about SEURAT-1 and the domain of alternative testing in general; and the section ‘Online library’, launched in early 2015, lists the scientific publications resulting from SEURAT-1 research work. The website also provides information on upcoming events and training activities and other important news within the cluster.
In 2015, as part of mass media outreach activities, a ‘Press corner’ was created targeting the general public in particular. It contains press releases and articles about SEURAT-1, as well as links to various information sources (videos, project brochures, FAQs, etc.).

• The preparation of the SEURAT-1 Annual Reports was coordinated by the COACH partner University of Tübingen (EKUT), which proposed the content structure and specified the contributions required. For each report, the proposed structure and approach was reviewed and endorsed by the Scientific Expert Panel, which contributed actively to the writing and validation of the books’ contents. EKUT collected, reviewed and edited the contributions, while ARTTIC took care of the book layout in collaboration with an appointed professional designer. Further to this well-established collaboration, the following Annual Reports were published and distributed in more than 1,000 copies each:
o First Annual Report (Schwarz & Gocht, 2011) published in September 2011;
o Second Annual Report (Gocht & Schwarz, 2012) published in July 2012 and launched at the Euroscience Open Forum (ESOF) in July 2012;
o Third Annual Report (Gocht & Schwarz, 2013) published in July 2013 and launched at the SEURAT-1 & EPAA Stakeholders Event in September 2013;
o Fourth Annual Report (Gocht & Schwarz, 2014) published in August 2014 and launched at the 9th World Congress in August 2014;
o The fifth Annual Report (Gocht & Schwarz, 2015), published in September 2015 and launched at the 51st Congress of the European Societies of Toxicology in September 2015 (EUROTOX 2015);
o The sixth and final Annual Report (Gocht & Schwarz, 2016), published in December 2016 and launched at the "European Commission Scientific Conference Non-animal approaches - the way forward" (Brussels) in December 2016.
The Annual Reports were printed and distributed to individuals by post and at relevant conferences. The electronic versions of the Annual Reports are also made available for download from the SEURAT-1 public website and distributed using USB sticks, thereby reaching even more of the target audience.
A dedicated dissemination channel for the Annual Reports was created in the form of a mailing list, containing over 700 postal addresses of scientists, experts and stakeholders in SEURAT-1 research results. It has been regularly updated each year before the Annual Report’s distribution.

• The excellent visibility of SEURAT-1 and its recognition as the major European research initiative in the field of alternative human safety testing methods is the fruit of a dissemination plan prepared by COACH in 2011. It defined the dissemination objectives and the appropriate means required to reach the targets, implemented through a series of dissemination actions. In order to refocus and prioritise the dissemination strategy more towards the stakeholders of SEURAT-1, i.e. the industry, regulators, the public and policy- and opinion-makers, a paper describing an updated dissemination strategy was prepared by COACH and presented during the SEP meeting in 2013. Aiming to define dissemination objectives, means and channels to better target the stakeholder groups, and to establish a plan of appropriate concrete dissemination actions, this dissemination strategy was considered a living document that was reviewed in each SEP meeting.

• COACH partners were aware of the importance of promoting the objectives, approach and progress of SEURAT-1 at international conferences and workshops. Participation to a very large number of events (90) with the aim of presenting the progress and main achievements has strongly contributed to increasing the visibility of the SEURAT-1 Research Initiative in the scientific community.

• Associated with the above-mentioned dissemination strategy, a plan for communication in mass media was developed in 2014. The creation of this plan was actively supported by the newly established Editorial Review Board containing representatives from the SEP, European Commission and Cosmetics Europe. Its objective was to reach out to public journals, radio, television and other media outlets to spread information about the SEURAT-1 results.

In 2015, COACH invested important efforts in the communication on and representation of the SEURAT-1 Research Initiative in mass media. COACH has achieved the objectives of informing the general public through the following activities:
o Contact with over 70 journals and magazines, including newspapers from across Europe ;
o Four press releases written in accessible language were published in 2015:
▪ The first, published in April 2015, intended to attract the attention of science journalists to the SEURAT-1 Research Initiative;
▪ The second was published in June 2015, further to the European Citizen’s Initiative ‘Stop Vivisection’, and gave SEURAT-1’s perspective on the issue;
▪ The third press release was published in September 2015, in connection with the EUROTOX 2015 congress, to communicate about the achievements presented at EUROTOX and provide information on the upcoming SEURAT-1 Symposium on 4 December 2015 in Brussels;
▪ The fourth press release, published at the occasion of the SEURAT 1 Symposium, highlighted the most significant results of the initiative.
All press releases were sent to the 70 contacts made earlier and were also posted on the Alpha Galileo web service linking research with the media (http://www.alphagalileo.org). Press offices at partner organisations also received the press releases for further distribution in their networks.
All press releases and other information considered useful for journalists were posted on the SEURAT-1 website’s press corner;

• The SEURAT-1 Symposium, held on 4 December 2015 in Brussels was organised to present the main results achieved by the initiative to a large audience of stakeholders at the end of 2015, when the six RTD projects of the cluster concluded their activities. Several dissemination materials were designed for the event and have been used in 2016:
o The SEURAT-1 film highlighting the achievements of the SEURAT-1 Research Initiative was produced as part of the dissemination strategy. This film was shown during the SEURAT-1 Final Symposium and remains available on YouTube : www.youtube.com/watch?v=Ymzsh9p5pwM);
o A Guided Educational Tour was conceived and implemented as a series of stations addressing the different steps required to answer a safety assessment question, highlighting the use of non-animal testing tools and methods in this context. Following the success of the Guided Tour, a guided tour brochure was produced by COACH, as printed and electronic document, which included the posters used in the Guided Tour and the associated explanation;
o The “SEURAT-1 highlights” flyer with the highlights from SEURAT-1, both for each project and on cluster level.
An exhibition and poster space was also part of the event, consisting of posters and hands-on demonstrations presented by scientists from SEURAT-1 and other EU and US initiatives. The posters abstracts were included in the Symposium booklet which was handed out to delegates at the event.
The presentations from the plenary sessions were filmed and made available on the SEURAT-1 website and on YouTube:
https://www.youtube.com/watch?v=FeToRRxMo1A&list=PL6ukeL16xdCV85WwcMygdlOqLf7zukEL1

• Summer-Schools
Training activities have been essential for SEURAT-1 from outset of the initiative. At the instigation of COACH, a common cluster-level training strategy was developed at the beginning of SEURAT-1, going beyond the project-level training activities planned in the individual project work-plans. COACH analysed the training activities of the individual projects, drew up a proposal for a cluster training concept, and set up the SEURAT-1 Training Task Force (STTF). The STTF became an important cluster task force, meeting annually to discuss the training programme’s implementation in the most efficient way.
The first SEURAT-1 summer school took place in June 2012 in Oeiras (near Lisbon, Portugal) and was hosted by IBET, the Instituto de Biologia Experimental e Tecnológica. The 5-days event gathered close to 100 participants. As planned in the training strategy, the next year (2013) was dedicated to individual project training programmes focusing on project level training needs.
During 2013, COACH started preparing the organisation of the next cluster-level training activities for 2014 by carefully analysing feedback from the first summer school. Based on this input, the STTF agreed to take the opportunity suggested by the European Society of Toxicology In Vitro (ESTIV) and organise a joint summer school in June 2014. This second SEURAT-1 Summer School, organised in conjunction with ESTIV, turned out to be a very fruitful collaboration, bringing a new dimension to the cluster training activities. In addition to the scientific discussions and networking between participants on their ongoing research and development work, the event brought visibility to SEURAT-1 and enabled advanced dissemination activities. The feedback received from participants on-site was extremely positive, especially as they could learn something of all different research domains within SEURAT-1.

Overall, the SEURAT-1 dissemination strategy was successfully implemented and increased substantially the visibility, and the awareness of its results and impact of this research initiative.

3. Exploitation

Exploitation here stands for how the COACH partners are able to get a return on investment from the effort that they engaged in this research initiative. Due to the nature of the coordinating project, partners in COACH do not create any IPR for the consortium partners resulting from research and innovation activities, that create return on investment through marketable results.

ARTTIC
- Use of project results: Experience in coordination of large research initiatives.
- Expected impact: The experience in managing and ensuring the dissemination of results in SEURAT-1 will be of benefit for the management of EU-ToxRisk and other similar initiatives in the future.

JRC
- Use of project results: Experience in how to logically construct safety assessment of chemicals for complex long term health effects such as repeated dose toxicity based on weight of evidence reasoning collecting existing data and additional information from alternative methods.
Increased awareness among method developers on the importance to provide robust, reliable and reproducible test methods for regulatory application.
A large toolbox of new approach methods. By integration of methods on the purpose of safety assessment in case studies, further define gaps and uncertainties to be addressed in future research initiative.
- Expected impact: Major progress towards new integrated approaches to testing and assessment of repeated dose toxicity and other complex systemic effects applying non-animal methodologies within the EU as well as outside the EU.

EKUT
- Use of project results: Experience in mechanisms regarding repeated dose systemic toxicity and the implementation of new methods into regulation. Definition of case studies together with industry and partners from regulatory agencies to demonstrate added value of developed methods. Definition of gaps as the basis for future research. Dissemination materials are used in the context of teaching students.
- Expected impact: Acceptance of mechanistic knowledge as the first choice for human health safety assessment approaches in both the scientific and the regulatory community. Pushing alternative methods into regulation within defined areas of application.

List of Websites:
COACH/SEURAT-1 public website: www.seurat-1.eu

COACH Coordinator : Bruno Cucinelli
ARTTIC International Management Services
58A rue du Dessous des Berges
75013 Paris
France
Phone: +33 (0)1 53 94 54 61
Email: bcucinelli@arttic.eu

Related information

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ARTTIC
France
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