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Accelerating the transition to a toxicity pathway-based paradigm for chemical safety assessment through internationally coordinated research and technology development

Final Report Summary - AXLR8 (Accelerating the transition to a toxicity pathway-based paradigm for chemical safety assessment through internationally coordinated research and technology development)



Executive Summary:

Challenge: Existing testing tools are not fit for purpose

Chemicals are essential to modern life, yet we lack innovative, efficient and human-relevant testing tools to inform regulatory safety decisions that protect against adverse health and environmental impacts of chemicals, replace animal use, and support economic growth and greener chemistries. The AXLR8 project was founded on the recognition that scientific advances over the past two decades have yielded powerful new tools for studying the health and environmental effects of chemicals and other stressors with greater efficiency, mechanistic insight and species relevance than ever before, without the use of animals.

Solution: A new approach to safety assessment

“A not-so-distant future in which virtually all routine toxicity testing would be conducted in human cells or cell lines” is the way one eminent scientific panel has described its vision of toxicity testing in the 21st century, or Tox21. The approach involves—

1. Understanding and cataloguing ‘adverse outcome pathways’ in humans and other animals, i.e. the linear sequence of events across levels of biological organization (sub-cellular, cellular, tissue, organ, etc.) from exposure to a chemical or other environmental stressor through to an adverse health outcome (disease/toxicity), and
2. Targeted development of species-appropriate in vitro (cell-based) systems to test for perturbations at key events within each pathway, together with advanced pharmacokinetic, systems biology and other computational modeling tools to relate in vitro findings to a ‘real world’, whole-body scenario.

Approach: Examination and alignment of public-private research efforts

A four-year collaboration between the Humane Society International/United Kingdom, the Freie Universität Berlin and the Flemish Institute for Technological Research, AXLR8 served as a focal point for strategic dialogue and coordination among leading European and global research teams working to develop advanced tools for safety testing and risk assessment. AXLR8 organized annual scientific workshops and public information events axlr8.eu/workshops) and published ‘state of the science’ reports (axlr8.eu/publications). AXLR8 also served as a bridge between test method developers and end-users to ensure that the needs of industry and regulators are understood in order to support efficient uptake of novel testing and assessment tools as they become available.

Outcomes: Defining strategic priorities for Horizon 2020

AXLR8 has provided strategic inputs into Europe’s latest research and innovation funding framework, Horizon 2020, to address pressing health and economic challenges facing industry, regulators and health scientists through an ambitious program of internationally coordinated research, 21st century infrastructure development, and accelerated translation of novel tools and approaches into real-world use to support safe innovation for European industry and consumers. Scientific recommendations emerging from AXLR8 workshops have already been taken up and reflected in the first calls of Horizon 2020, and in its final report, AXLR8 has highlighted additional research and coordination avenues as candidates for priority investment by the EU.

Project Context and Objectives:

Objectives

The goal of AXLR8 - to lay the groundwork in Europe for a transition in toxicology toward a more mechanistic, cell- and computer-based approach, and to position the EU as a global leader in this R&D effort - are directly responsive to the principal topic of the call, i.e. better coordination of the various activities involved in the development of new 3R methods as modern alternative approaches to safety testing. These overarching goals can be subdivided into the following specific objectives:

• To monitor the progress of EU-funded 3Rs research projects and to prepare, publish and disseminate progress reports on an annual basis.
• To convene a Scientific Panel (SP) with experts from the EU corporate, governmental and academic sectors, together with a small number of leading international scientists, to provide an external expert review of the progress of EU-funded 3Rs projects, and assist in the development of program for annual AXLR8 scientific workshops, and in the preparation of annual R&D “roadmaps” to aid the Commission in determining future EU research priorities and funding calls.
• To organize and convene annual scientific workshops to bring together scientific coordinators and/or work package leaders from EU-funded health projects, members of the AXLR8 SP and other selected experts to discuss the progress of ongoing actions, identify knowledge gaps, and recommend strategic priorities for future EU funding calls.
• To promote scientific, stakeholder and public awareness and communication regarding the outcomes of AXLR8 scientific workshops and “21st century” approaches to toxicology and risk assessment.
• To promote active and ongoing engagement by European regulatory authorities to ensure that authorities are kept informed of progress at the R&D level and that regulatory considerations are understood and fed back to the scientists developing 3Rs methods in order to encourage and lay the groundwork for more expeditious and efficient uptake of alternative approaches in the future.

Each of these objectives is tied to multiple deliverables within the time frame of the 46 months funding period. It was the main objective of the AXLR8 project to critically review the on-going FP6 and FP7 projects of the “Alternative Testing Strategies” program at annual workshops with international experts from 2010-2012 and to publish annual progress reports and recommendations for future EU research and innovation funding under Horizon2020.

Approach

Conventional approaches to toxicity testing and risk assessment are often decades old, costly and low-throughput, and of dubious relevance to humans. The call for a transition to a 21st century toxicity testing paradigm will require a robust understanding of the cellular response/toxicity pathways that can lead to adverse effects when disturbed; appropriate in vitro systems to study chemical interactions at key targets along a pathway; and computational systems biology models to describe the underlying pathways as a basis for creating biologically realistic dose-response models.

The EU FP7 coordination support action project AXLR8 (= accelerate), which managed by the Freie Universität Berlin (Germany), the Human Society International (UK) and the Flemish Institute for Toxicology (Belgium), aims to support the transition to a toxicity pathway-based paradigm for quantitative risk assessment. To achieve this goal the AXLR8 consortium has:

1. organized a series of annual workshops to map research progress, gaps and needs in the FP6/FP7 program on alternative testing strategies.
2. provided a range of tools and opportunities for enhanced interdisciplinary and international communication, coordination and collaboration in order to maximize the impact of available resources.
3. worked to streamline regulatory acceptance procedures to provide for the uptake of validated 3Rs methods, including a smooth transition to 21st century systems as they become available.
4. produced annual progress reports on the state of the science, including recommendations on priority research and funding targets, in order to ensure a prominent role for European science in this rapidly developing global research area.

The three AXLLR8 workshops in 2010, 2011 and 2012 (AXLR8-1, AXLR8-2 & AXLR8-3) have in the first place focused on progress made in the EU FP6/FP7 projects funded by the health theme of the DG RTD “Alternative Testing Strategies: Replacing, reducing and refining use of animals in research”. In addition at the AXLR8 workshops progress achieved in projects not funded by the EU Commission were presented and discussed, e.g. in national European projects and also in Japan and the USA. The AXLR8 Scientific Panel, which is comprised of independent international experts in advanced molecular toxicology, discussed the results of progress achieved during the FP6 and FP7 funding periods and devised recommendations in order to serve the main goal of the AXLR8 project to “accelerate” the transition to pathway driven non-animal but human cell and tissue based molecular safety testing (=toxicology).

Results

Based on the AXLR8 workshops the results reported and the recommendations provided by the AXLR8 Scientific Panel have been published in the “AXLR8 Progress Reports” 2010 and 2011 and the report for 2012:

● In the first annual AXLR8 Progress Report for 2010 provides as summary of the progress achieved in developing “Alternative Testing Strategies” that allow to replace, reduce and refine the use of animals in safety testing.
● The second annual AXLR8 Progress Report for 2011 has not only given an update on progress achieved in EU and international projects but is also reporting the recommendations of the AXLR8 Scientific Panel on a “Roadmap to Innovative Toxicity Testing”.
● The third annual AXLR8 Progress Report for 2012 provides an update on progress in EU and international projects in order to draft a “Roadmap to Next Generation Safety Testing under Horizon 2020”.

It was the intention of the AXLR8 Scientific Panel and of the AXLR8 Consortium in the year 2013 to provide the DG Research and Innovation of the EU Commission with recommendations for the Horizon2020 Program. However, the first call of the Horizon2020 Program has been published late in 2013, while the AXLR8 Consortium was drafting the

● "AXLR8 Final Report and Recommendations" and as a consequence, we had to re-draft the AXLR8 Final Report on very short notice.

Since not all of the objectives that were recommended by the AXLR8 Scientific Panel have been covered in the first call of Horizon2020, we propose that in future calls, establishing a steering group for the area of safety testing should be added for funding and six additional objectives.

Deliverables

The main contributions of the AXLR8 project to research on “Alternative Testing Strategies” are the four AXLR8 Progress reports

● Progress Report 2010 on “Replacing, Reducing and Refining use of Animals in Research”
● Progress Report 2011 including a “Roadmap to Innovative Toxicity Testing”
● Progress Report 2012 including a “Roadmap to Next Generation Safety Testing Under Horizon 2020”
● The AXLR8 Project – “Final Report & Recommendations”

To disseminate the four reports effectively among the international scientific community, all of them have been published on the AXLR8 website (www.axlr8.eu) and the three annual progress reports for 2010, 2011 and 2012 also as hard copies, which were disseminated to all of the stakeholders of the AXLR8 project, in particular to the coordinators of EU FP6 & FP7 projects funded under the "Alternative Testing Strategies Program" of the Health Theme of the DG Research and Innovation of the EU Commission.

The results of the AXLR8 project prove that at the international level Europe has taken the lead in establishing molecular methods for safety testing by effective funding of integrated and targeted research projects in the FP6 and FP7 Alternative Testing Strategies Program.

Project Results:

AXLR8 WORKHSOPS

After establishing the AXLR8 Scientific Panel (SP) early in 2010, the first annual AXLR8 workshop was held (AXLR8-1) in 2010 in Potsdam, Germany, to review progress reported by the coordinators of the EU FP6/7 projects in the EU DG R&I funding program "Alternative Testing Strategies - Replacing, reducing and refining use of animals in research". In addition, 3R centers from EU member states, from Japan and the USA reported the current status of research on alternatives in their countries. In September 2010, AXLR8 hosted a half-day public information forum in Linz, Austria, at the International 2010 ESTIV/EUSAAT conference in Linz/Austria to inform on the results of the AXLR8-1 workshop. Later in 2010 AXLR8 published the Progress Report 2010 on "Alternative Testing Strategies" - both as a hard copy and on the AXLR8 website AXLR8.eu/workshops - as an annual update on the activities and achievements of research funded under the FP6/7 Health program.

The second annual AXLR8 workshop (AXLR8-2), on developing a "Roadmap to Innovative

Toxicity Testing (ITT)", was held in 2011 in Berlin including a Satellite Meeting on "Disease

Models and Innovative Techniques". Results and recommendations of the AXLR8-2 workshop were well received when published in 2011 in the “AXLR8 Progress Report 2011 on Alternative Testing Strategies", including the “AXLR8-2 Workshop Report Roadmap to Innovative Toxicity Testing” both as hard copy and on the AXLR8 website.

The third annual AXLR8 workshop (AXLR8-3) on a "Roadmap to Next Generation Safety Testing under Horizon 2020" was held in 2012 in Berlin, Germany, in conjunction with a Satellite Meeting on “The REACH experience - new tools applied to risk assessment”. The workshop consisted of presentations on progress achieved during the past 12 months in EU Member States and internationally in advancing testing tools in key health areas (i.e. cancer/carcinogenicity, reproductive and developmental disorders/toxicity and immune disorders/sensitization), as well as on adverse outcome pathway’ (AOP) approaches in toxicology. The results and recommendations of the AXLR8-3 workshop were well received when they were published in 2012 in the “AXLR8 Progress Report 2012 on Alternative Testing Strategies", including the "Roadmap to Next Generation Safety Testing under Horizon 2020” both as hard copy and on the AXLR8 website AXLR8.eu/workshops.

In 2013 Horst Spielmann and Troy Seidle gave presentations at several international conferences on the results and recommendations of the AXLR8 workshop reports for funding of advanced toxicology under the Horizon2020 program of the EU DG R&I, e.g. in January 2013 at the ICAAE conference in Lisbon, in March 2013 at the Messerli Institute of the Veterinary University in Vienna, in September at the conference of the European Society for Alternatives to Animal testing EUSAAT in Linz/Austria, in October 2013 at the Toxicology Forum in Brussels and in December at the Annual Conference of the Japanese Society for Alternatives to Animal Experiments JSAAE in Kyoto/Japan.

RECOMMENDATIOSN AND DISSEMINATION

Based on the results of the annual AXLR8 workshops 2010, 2011 and 2012 and discussions with the AXLR8 Scientific Panel and international stakeholders the AXLR8 Consortium have in 2013 drafted its final report and recommendations for a “Roadmap to Next Generation Safety Testing under the EU Horizon2020 Program”.

It was the intention of the AXLR8 Scientific Panel and of the AXLR8 Consortium in the year 2013 to provide the DG Research and Innovation of the EU Commission with recommendations for the Horizon2020 Program. However, the first call of the Horizon2020 Program has been published late in 2013, while the AXLR8 Consortium was drafting the "AXLR8 Final Report and Recommendations" and as a consequence, we had to re-draft the AXLR8 Final Report on very short notice.

Since not all of the objectives that were recommended by the AXLR8 Scientific Panel have been covered in the first call of Horizon2020, we propose that in future calls, establishing a steering group for the area of safety testing should be added for funding and six additional objectives. The final report of the AXLR8 project and the recommendations for research priorities for next generation safety testing under Horizon 2020 have been published on the project website http://axlr8.eu.

To disseminate the four AXLR8 reports effectively among the international scientific community, all of them have been published on the AXLR8 website (www.axlr8.eu) and the three annual progress reports for 2010, 2011 and 2012 also as hard copies, which were disseminated to all of the stakeholders of the AXLR8 project, in particular to the coordinators of EU FP6 & FP7 projects funded under the "Alternative Testing Strategies Program" of the Health Theme of the DG Research and Innovation of the EU Commission.

The results of the AXLR8 project prove that at the international level Europe has taken the lead in establishing molecular methods for safety testing by effectively funding integrated and targeted research projects in the FP6 and FP7 Alternative Testing Strategies Program.

Potential Impact:

POTENTIAL IMPACT

Today industry must rely on globally harmonized approaches to safety testing and risk assessment to ensure mutual acceptance of product safety test data. In order to bring about meaningful, system-wide and lasting changes to the conventional risk assessment paradigm, such changes must occur at the international level (e.g. EU, OECD & ICH). Therefore, AXLR8 supports an internationally coordinated research strategy that is aimed at providing new regulatory concepts in toxicology at European and the worldwide/ international levels.

To achieve this goal, AXLR8 has created a framework and opportunities for focused scientific

discussions, synergistic exchanges and momentum to propel forward European research on 21st century approaches to toxicology and risk assessment while taking steps to ensure that processes are in place to allow for the uptake of these new methodologies as they become available.

A substantial component of the AXLR8 work program was dedicated to outreach and engagement of a wider audience of stakeholders,, since the ultimate success of this coordination initiative will depend on securing acceptance by key stakeholders, in particular scientists and regulators, but also policy-makers, public interest NGOs, and the European public at large. For example:

• Engagement with scientists from across disciplines and sectors has proven vital for ensuring their active participation in the AXLR8 Scientific Panel and expert workshops and their ongoing contribution to address the science and technology problems that are addressed by this coordination action.
• Engagement with policy-makers (e.g. through dissemination of AXLR8 annual reports) to inform future EU research policy, priorities and funding decisions, and ensure that these decisions reflect the evolving needs and take fully account of other relevant national and international research initiatives and programs.
• Engagement with regulators to initiate a dialogue that will be critical to ensuring that barriers to the acceptance of 3Rs methods and testing strategies will be overcome and that new processes are developed, to provide for a smooth and internationally harmonized acceptance of new hazard and risk assessment methods and approaches as they become available.
• Engagement with the media, NGOs and the general public is important to establish understanding, confidence, and ultimate acceptance of the new paradigm that is envisioned from the perspective of public health, consumer, environmental and animal protection.

Since the first call of the Horizon2020 Program has been published while the AXLR8 Consortium was drafting the "AXLR8 Final Report and Recommendations" the AXLR8 Final Report and Recommendations had to be redrafted. Since not all of the objectives that were recommended by the AXLR8 Scientific Panel have been covered in the first call of Horizon2020, it is propsed that in future calls, establishing a steering group for the area of safety testing should be added for funding and also six additional objectives.

DISSEMINATION ACTIVITIES

During the 46 months funding period the activities and publications of the AXLR8 projects have created wide interest in the new concept of toxicity testing among leading scientists in industry, academia and regulatory agencies in Europe, the USA and Japan. Scientists of the AXLR8 consortium have been invited to present the new concept at high level international conferences. Moreover, they were also asked to give input to research funding activities in Europe and Japan.

The publication of the AXLR8 “Progress Reports 2010, 2011 and 2012 ” on results of FP6 and FP7 projects funded by the DG R&I funding program “Alternative Testing Strategies” have been covered by international media. This indicates that an effective web-based dissemination network has successfully been established by the AXLR8 consortium.

In particular the "Roadmap to Innovative Toxicity Testing (ITT)”, which was developed at the

AXLR8-2 workshop in 2011 and published in the AXLR8 Progress Report 2011, and the "Roadmap to Next Generation Safety Testing under Horizon 2020”, which was developed at the AXLR8-3 workshop in 2012 and published in the AXLR8 Progress Report 2012, have generated considerable interest among scientists, regulators and the media.

The new approach of safety assessment based on the use of human cells and tissues rather than on data generated in experimental animals will be the real challenge for academia and industry and require the combined use of advanced technologies in cell and tissue culture, molecular biology and genetics, bioinformatics and computational toxicology. Investments in this field of modern biology will keep Europe at the forefront of the biosciences.

List of Websites:

http://axlr8.eu/

Project Coordination:

FREIE UNIVERSITAET BERLIN
Kaiserswertherstrasse 16-18
14195 BERLIN, Germany
www.fu-berlin.de

Financial Coordination:

Carsten Malmwieck
VI C-DMV 11
Freie Universität Berlin
Referat VI C-DMV - Drittmittelverwaltung
Tel.: + 49 30 838 52990
Fax: + 49 30 838 53448
E-Mail: c.malmwieck@fu-berlin.de

Scientific Coordination:

Prof. Dr. med. Horst Spielmann
Freie Universität Berlin
Department of Biology, Chemistry, Pharmacy
Freie Universität Berlin
Institute of Pharmacy
Königin-Luise-Str. 2 + 4
14195 Berlin, Germany
E-Mail: horst.spielmann@fu-berlin.de