Multidisciplinary European low dose initiative: an update of the MELODI program

Abstract

Purpose: This paper provides an update and summary on the organization of European research in the field of low dose risk and radiation protection. To address declining resources and competence in radiation protection and related research across European countries, a High Level and Expert Group (HLEG) was established in 2007. The HLEG identified key policy and scientific questions to be addressed through a strategic research agenda for low dose radiation risk. This initiated the establishment of a European Research Platform, called MELODI (Multidisciplinary European Low Dose Research Initiative). Dr Bill Morgan closely followed the European low dose programme and chaired the international Advisory Boards of DoReMi Network of Excellence and the MELODI platform.

Conclusion: The MELODI research platform is dedicated to low dose ionizing radiation risk. In 2010, MELODI was founded as a registered association with 15 members. As of September 2016, the association´s membership increased to 46. A major activity of MELODI is the establishment and updating of a long-term Strategic Research Agenda (SRA) for research on low dose risk in Europe. The SRA is intended to guide the priorities for national and European research programmes and the preparation of competitive calls at the European level. A key priority for radiation protection research is to improve health risk estimates for exposures corresponding to the dose limits for occupational exposures and to reference levels for the exposure of the population in emergency situations.

Keywords:

• Low dose effects
• radiation carcinogenesis
• non-cancer effects
• individual susceptibility

Introduction

Exposure of the population to natural radiation is to some extent unavoidable. Medical exposure of the patient during diagnosis and therapy, and of population groups during medical screening programs, is now an indispensable part of modern medicine. The exposure of workers and, to a smaller extent of the public, to low levels of radiation from nuclear energy production and from industrial uses of ionizing radiation is part of the life in industrialized societies. Any over-, or underestimation of the risks to health from ionizing radiation could lead either to unnecessary restriction or to a lower level of health protection than intended.

Judgements on radiation protection standards in Europe and elsewhere are highly dependent upon (a) scientific knowledge that is reviewed in cycles by national committees and by a committee of the United Nations (UNSCEAR) and (b) the recommendations made by the International Commission on Radiological Protection (ICRP) that seek to take account of such scientific development. The acquisition of new scientific knowledge through research is therefore a crucial element in improving radiation protection standards for the public, radiation workers and medical patients. Although current radiation protection standards are generally judged to be acceptably robust there remains considerable scientific uncertainty particularly with regard to health risks at low doses and/or low-dose rates (OECD, 2016). Consequent upon these uncertainties, the issue of low-dose risk is controversial in both scientific and political circles.

Structuring the European research area in low dose risk and radiation protection

The state of knowledge and the major elements of scientific uncertainty in the context of protection policy and risk assessment were reviewed in 2009 by the High Level and Expert Group (HLEG) on Low Dose Risk Research (European Commission 2009). Future research areas and activities that have the greatest potential to address these uncertainties were identified. Solving the uncertainties related to low-dose risk requires an integrated input from many scientific disciplines. Moreover, the over-arching policy question of the robustness of the current system of radiation protection and risk assessment has to be broken down into specific scientific questions that can only be answered by multidisciplinary research that takes into account the full breadth of the latest advances in scientific knowledge and techniques. A global description of these questions was presented by the HLEG, under the headings:

• Shape of dose response relationship and tissue sensitivity for cancer;

• Individual variability in cancer risk and genetic susceptibility to cancer;

• Radiation quality (type);

• Internal exposure risk;

• Risks of and dose response relationships for non-cancer effects.

The HLEG report described the key elements of a proposed research strategy for low-dose risk research. This required going beyond the expression of key research needs and challenges as described above. To achieve success, it was essential to have mechanisms for the specification and periodic updating of priorities for research, for ensuring the provision of long-term funding for focussed research projects, for ensuring the availability of key infrastructures and for attracting young researchers through education and training activities. The representatives from the funding bodies and the European Commission participating in HLEG considered it necessary and were willing to establish a sustainable governance structure, at European level, in order to consolidate, implement, and review as necessary over time, the agreed research strategy, and to provide guidance on the priorities for research which should be eligible for funding, in particular through the EURATOM instruments.

In 2010, MELODI (Multidisciplinary European Low Dose Risk Research Initiative) a European platform dedicated to low dose radiation risk research was founded as a registered association with 15 members. MELODI addresses three main aims: to propose R&T priorities for Europe in its field of competence and to contribute to EUROPE 2020 Strategy; to seek the views of stakeholders on the priorities for research and keep them informed on progress made, and contribute to the dissemination of knowledge; and to interface with international partners like WHO and IAEA (Belli et al. 2015). MELODI is an association of funding bodies and institutes with responsibilities in radiation protection research. The research platform has grown steadily. As of September 2016, there are already 46 members in MELODI.

In line with the policy agreed by the Euratom community following the HLEG report, several successive projects were funded by the EU, in order to (1) support the integration of research in this field at European level, and (2) fund on the basis of excellence research proposals to implement the research priorities collectively identified. The first of those wide-ranging projects was DoReMi (Low Dose Research towards Multidisciplinary Integration), a Network of Excellence in the EU instrument terminology. It was followed in 2012 by OPERRA (Open Project for European Radiation Research Area), and the latest such project is CONCERT (European Joint Programme for the Integration of Radiation Protection Research), a ‘joint programming instrument’ initiated in 2015. The funding available for research, rather than for research integration strategy purposes, was steadily increased as these projects followed each other.

Role of DoReMi in the operational consolidation of the MELODI platform

The DoReMi Network of Excellence funded by the European Commission via the Euratom program played an important role in the establishment of the operational structures and functions of the MELODI platform during 2010–2015 (Salomaa et al. 2015). The aim of the DoReMi consortium was to promote the sustainable integration of low dose risk research in Europe, in order to facilitate efforts to resolve the key policy questions identified by the ‘High Level Expert Group (HLEG) on Low Dose Risk Research’ (www.hleg.de). The research activities of DoReMi have focused on the research areas identified by the HLEG as being the most promising in terms of resolving the stated key policy questions. DoReMi has provided an operational tool to continue the development of the MELODI platform that represents the major national bodies and research programmes with a long-term commitment to low dose radiation risk research in Europe. The Joint Programme of Activities of DoReMi included: (i) a Joint Programme of Research covering the research priorities (key questions) outlined above and including the sharing and updating of existing infrastructures; (ii) a Joint Programme of Integration to promote sustainable integration between the key players in Europe; and (iii) a Joint Programme for the Spreading of Excellence, covering in particular knowledge management, training and mobility and the communication of significant DoReMi findings to stakeholders and policymakers.

Since the beginning of the DoReMi Network of Excellence in January 2010, there has been rapid progress in the establishment of a European research platform to focus on questions of low dose risk. DoReMi continued the initial work of HLEG by contributing to the development of the long-term SRA of MELODI, and by establishing the more detailed shorter-term DoReMi Transitional Research Agenda (TRA). The research agendas provided by MELODI and DoReMi have helped to identify priorities for low dose risk research not only by the organisations involved but also in national, European and global contexts. The planned enhancement of the DoReMi network through the calls for partners with new expertise resulted in the inclusion of 24 new beneficiaries. This enhanced the competence of the consortium in several key areas, by integrating research experts in biomarker identification, immunological/inflammatory pathways, and the effects of chronic low dose exposures, cataractogenesis, vascular effects, stem cells, epigenetics, novel mechanisms of genome reorganisation, as well as retrospective dosimetry. The three DoReMi competitive calls attracted proposals from 89 different organisations in 25 countries (including 21 European Member States).

DoReMi implemented research programs addressing the three key research areas: shape of dose-response curve for cancer, individual radiation sensitivity for cancer and non-cancer effects. All RTD activities also addressed the cross-cutting issues of radiation quality, tissue sensitivity and internal emitters. Several workshops were convened to develop strategies that focused on the most promising lines of research for the three areas. Experimental programs were launched and amended in all three areas and a total of 27 new tasks were amended in the project portfolio via the calls. The RTD approaches have been closely coordinated through discussions on needs for research infrastructures and analytical platforms, as well as targeted stimulation of training and education of next-generation researchers at the European level.

In studying radiation carcinogenesis, the two over-arching objectives were to improve knowledge of low dose/dose-rate radiation cancer risk in humans and to improve low dose/dose-rate risk projection models based on knowledge of the processes that drive carcinogenesis. The studies covered a range of topics, such as examining dose and dose-rate response relationships of cancer-related processes including gene expression responses and senescence, contributions that non-targeted and systemic effects make to carcinogenesis following low dose exposures, examination of pre-neoplastic changes, stem cell research, cancer risk associated with internal radiation exposure and modelling approaches.

For individual susceptibility, the overarching objective was to provide a scientific basis for decision-making on the inclusion of individual sensitivity as a modifier of risk at low doses. Current risk models use LNT to extrapolate from high to low doses. By convention this assumes an equal risk distribution amongst all members of an exposed population. Consequently, the risk assessments delivered by the models can only represent the average risk across the population. Despite inbuilt safety margins the present state-of-the-art knowledge does not allow us to assume that exposed individuals with a greater natural predisposition due to age, gender, genetic background or interactions of these variables with lifestyle and/or environment are effectively protected. Consequently, we were determined to understand how, and to what extent, individual susceptibility influences the carcinogenic effects of low doses and low dose rates.

In a context of a weak evidence from epidemiological studies for non-cancer effects at low-dose exposures, and recognizing that (i) multi-targeted biological effects observed in chronically exposed experimental models with internal emitters are quite puzzling; and (ii) no convincing mechanistic explanations are available that can account for the findings observed, the overarching strategic objective of the DoReMi programme on non-cancer effects was to implement a long-term, integrated approach involving several disciplines, namely, epidemiology, radiobiology, immunology and toxicology, for the purpose of risk evaluation for radiation-induced non-cancer effects. Therefore, the scientific objectives were:

1. To design well-controlled molecular epidemiology studies having in prospect the identification of markers of the initial steps of low-dose radiation-induced non-cancer health effects, the record of biological non-radiation ‘risk factors’ connected to diseases under study, and the monitoring of pertinent blood biomarkers of biological radiation effects;

2. To promote, in the field of experimental radiobiology and radiotoxicology, high-throughput technologies (e.g. ‘omics’) and systems biology approaches that would be expected to better describe the complexity of low-dose radiation-induced tissue level responses;

3. To challenge the classical molecular DNA strand break paradigm in search for the mechanisms behind non-cancer effects, and in this way to promote research activities in the field of cell physiology (i.e. cell senescence, long-term cell phenotypic changes), immunology and the radiobiology of intercellular communications and signaling;

4. To differentiate radiation-induced tissue and cell responses due to adaptation to the radiation stress, from true adverse alterations, involved in pathological processes;

5. To support research on mechanisms of radiation action, adopting a multi-scale/system biology approach and putting the emphasis on the relationship between initial stochastic track structures of low and high LET radiations, early chemical/biological processes and long term pathophysiological effects such as inflammatory response; and finally

6. To assess whether there are scientific arguments for replacing the classical ‘threshold’ paradigm for non-cancer effects with the ‘non-threshold’ paradigm.

The availability of suitable infrastructures for performing low dose risk research was specifically addressed by DoReMi. Experimental radiation research is highly dependent on the availability of appropriate radiation sources that are reliable, capable of delivering a range of radiations, are robust and accurate. Low dose research also needs access to well-defined epidemiological cohorts, reliable databases and biobanks and as well the appropriate platforms for analysis. After the initial mapping of infrastructures and their availability, DoReMi has provided access to several new infrastructures that will enhance the European capabilities in addressing scientific questions relevant for low dose risk. Prospects for molecular epidemiologic studies in the European scale were addressed by reviews on potential biomarkers for ionizing radiation (Pernot et al. 2012) and considering strategies for cardiovascular studies (Kreuzer et al. 2015). More information on DoReMi activities and references to more than 100 publications can be found at the DoReMi’s website (www.doremi-noe.net), which is still operational for some time after the end of the project.

Integration of radiation protection research in Europe

Encouraged by the progress of MELODI, several other research platforms have been established in Europe. Similar to MELODI and DoReMi Network of Excellence, the establishment of these platforms and organization of their activities were supported by parallel Networks of Excellence and other projects. The Strategic Research Agenda for the European Radioecology Alliance (ALLIANCE) was formulated during the STAR Network of Excellence (Hinton et al. 2013) and COMET project. For research and development on nuclear and radiological emergency response, the NERIS platform was established in 2010, supported by the NERIS-TP and PREPARE projects (Schneider et al. 2016). EURADOS (European Dosimetry Group) was established already in the 1980s to carry out development and training on various fields of dosimetry. More recently, EURADOS also prepared a structured research agenda to address current research needs (Rühm et al. 2016). The latest addition to the platform portfolio is EURAMED that was established in September 2016 by five medical associations working in the field of use of ionizing radiation in medicine: European Association of Nuclear Medicine (EANM), the European Federation of Organizations for Medical Physics (EFOMP), the European Federation of Radiographer Societies (EFRS), the European Society of Radiology (ESR) and the European Society for Radiotherapy and Oncology (ESTRO). All platforms work in close coordination, through a Memorandum of Understanding which establishes joint governance for decision making on topics of interest to all partners.

Euratom-funded projects such as DoReMi, STAR, NERIS-TP and PREPARE have established successful methods to promote radiation protection research by infrastructure and knowledge management, engaging wider scientific community and promoting the sharing of resources by integrating at the European level national research programmes, and organizing internal and competitive calls. Based on the experiences of the Networks of Excellence (NoE) and other projects working towards platform development and integration of European RP research, the integrative activities were generally organized in three main areas: (1) development of Transitional and Strategic Research Agendas, (2) management and coordination of infrastructures, and (3) education and training activities. These three main activity areas were subsequently adopted by the platforms that established Working Groups and Committees for operational organization of the scientific work. Members to the working groups were nominated among the platform members. While the activities of projects are short term (for the project duration), the platform Working Groups now provide sustainability.

A major activity of MELODI and the other radiation protection research platforms is the establishment and updating of long-term (>20 years) Strategic Research Agenda (SRA) for research on radiation protection in Europe. The SRA is intended to guide the priorities for national and European research programmes and the preparation of competitive calls at the European level. A key priority for radiation protection research is to improve health risk estimates for exposures corresponding to the dose limits for occupational exposures and to reference levels for the exposure of the population in emergency situations. The approaches need to be multidisciplinary and innovative. The integration of expertise outside the conventional fields of radiation research will widen the possibilities to integrate modern technologies in health research in the assessment of health risk relevant to radiation protection. The SRAs are updated annually by the SRA working Groups, taking into account results of ongoing and completed research and key radiation protection research issues, which arise during the year. An open consultation process via website and the annual workshops is regularly conducted, the results of which are taken into account in the revised SRA report. Prior to calls for research, in addition to the SRA report short statements presenting the top priorities are developed by the radiation protection research platforms and an open consultation process is initiated.

With regard to the sustainable data management, databases and procedures were developed throughout the 1990s and early 2000s to address the needs of the scientific community and radiation protection. Radiobiological archives were developed in ERA-PRO and STORE projects (Schofield et al. 2010). Later on, STORE was adopted in DoReMi to provide a sustainable infrastructure for knowledge management in the area of low dose risk. In radioecology, extensive radioecological databases such as FREDERICA were developed (Garnier-Laplace et al. 2008). Such developments have been carried on and continued in the infrastructure activities of OPERRA, COMET and CONCERT. To ensure sustainability of infrastructures, MELODI and Radioecology ALLIANCE have established dedicated Working Groups on Infrastructures with the aim of ensuring availability, continuous development and quality assurance of necessary research infrastructures at the European level. These infrastructures include low dose and low dose rate irradiation facilities, databases and biobanks, analytical platforms and radioecological observatories (i.e. contaminated sites for field studies).

Educating the next generation of researchers in radiation sciences is one of the major aims of the European radiation protection research community. The research platforms have established Working Groups that coordinate training events at the European level. With the support from European Commission’s Euratom programme, more than 10 training courses lasting 2–3 weeks are organized each year, covering different fields of radiation biology, radiation epidemiology, dosimetry, radioecology and emergency preparedness. Travel grants and Young Scientist Awards are additional ways promoting the participation of young investigators in radiation protection research.

Currently, radiation protection research is organized within a European Joint Programme Co-fund Action (EJP). The aim of the EJP is to bring together relevant funding agencies from the EC and the Member States to integrate European research and to administer calls for research proposals in radiation protection on behalf of the European Commission. This activity builds upon the Strategic Research Agendas from five European radiation protection research platforms and aims to establish interaction and synergies between the different areas of expertise. The five platforms are MELODI, ALLIANCE (radioecology), NERIS (Emergency management), EURADOS (dosimetry) and EURAMED (Medical associations). An important operational tool for the establishment of EJP is the European project OPERRA (Open Project for European Radiation Research Area). In the radiation protection area, the CONCERT EJP was launched in 2015, bringing together European and national programs in all major fields of radiation protection research.

Acknowledgements

Dr William (Bill) Morgan closely followed the development of the European radiation research area. During the years, he participated in advisory committees of several EU projects, including NOTE, EpiRadBio and DoReMi. Bill was a wonderful advisor, very knowledgeable, critical but encouraging. The first author of this paper (Dr Salomaa) met him for the last time at the ICRP meeting in Soeul, Korea, just 3 weeks before he passed away. Bill spoke about his retirement plans and looked forward to the final DoReMi meeting in Budapest in the first week of December. Bill never made it but he was there anyway. In our minds and hearts.

Disclosure statement

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Additional information

Funding

The research leading to these results has received funding from the European Atomic Energy Community Seventh Framework Programme FP7/2007-2011 under grant agreement no. 249689 (DoReMi), the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 604984 (OPERRA) and from the Euratom research and training programme 2014-2018 under grant agreement no. 662287 (CONCERT).