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BIODOSIMETRY AND BIODOSIMETRY NETWORKS FOR MANAGING RADIATION EMERGENCY

BIODOSIMETRY AND BIODOSIMETRY NETWORKS FOR MANAGING RADIATION EMERGENCY Abstract Biological dosimetry enables individual dose reconstruction in the case of unclear or inconsistent radiation exposure situations, especially when a direct measurement of ionizing radiation is not or is no longer possible. To be prepared for large-scale radiological incidents, networking between well-trained laboratories has been identified as a useful approach for provision of the fast and trustworthy dose assessments needed in such circumstances. To this end, various biodosimetry laboratories worldwide have joined forces and set up regional and/or nationwide networks either on a formal or informal basis. Many of these laboratories are also a part of global networks such as those organized by World Health Organization, International Atomic Energy Agency or Global Health Security Initiative. In the present report, biodosimetry networks from different parts of the world are presented, and the partners, activities and cooperation actions are detailed. Moreover, guidance for situational application of tools used for individual dosimetry is given. INTRODUCTION Accidents leading to unplanned or unregulated exposure of humans and the environment to ionizing radiation have occurred many times, despite strict safety regulations and precautionary measures(1). It also happens that persons at risk of exposure do not carry the obligatory personal dosemeter, or that a dosemeter is not stored correctly after use. Each of these situations can lead to unclear or inconsistent findings, e.g. appearance of apparent acute symptoms in humans without an exposure high enough to cause acute radiation effects or vice versa, a high dose value reported by the dosemeter but no acute radiation effects expressed by the apparently irradiated person. In many such cases, biological dosimetry offers the only possibility for an individual dose estimation, even weeks or months after a potential exposure. This is possible because, from the physical point of view, the dose is not measured directly but by analyzing radiation-induced biological changes in a sample taken from the individual. Thus, a measurement of the direct biological/biochemical or physical effect on an individual level, particularly in the cellular DNA is possible. The results gained by biological dosimetry are generally appreciated by affected individuals and in many countries also acknowledged by court and professional associations as a proof of exposure. As a consequence, biodosimetry laboratories have been established in many countries, and in case no national competence is available, such requests are forwarded to neighboring states in Europe, e.g. by Finland, Norway, Switzerland and Austria. A large challenge is presented by large-scale nuclear or radiological incidents. Such disasters can happen anytime and anywhere, without any prewarning. They can be caused by technical breakdown or human failure but also by malevolent actions such as terrorist attacks, as emphasized in the Communiqué of the Nuclear Security Summit 2016 (http://www.nss2016.org/2016-joint-statements/). Each of these scenarios can have severe consequences for human health, the environment and economy of one or more countries. In such circumstances, knowledge about the doses received by individuals is highly relevant for proper diagnosis of the exposed persons(2, 3). However, the consequences of nuclear disasters on the public health and economy of a country very often exceed the nominal damage caused by irradiation. To a large extent, this is due to the fear and insecurity of the population regarding the possible radiation effects and proximate consequences. This, again, can have major consequences for the health and quality of life of individuals and also for the economy of a country, much more so than the actual radiation exposure. Incidents with a radiation background, especially, lead to enormous stress for affected persons and recollection of the individual location, duration and movement profile are often subjectively influenced and not reliable(4–6) as a result of this. Therefore, an essential aspect of individual radiation dosimetry, especially in large-scale scenarios, is the possibility to exclude a putative high radiation exposure on an individual level. By this, ‘worried well’ persons showing prodromal symptoms of a radiation exposure (often interchangeable with symptoms induced by high levels of stress) but without having received a dose high enough to cause acute effects can be effectively distinguished from exposed persons needing immediate medical help and specialized care. In this context, individual dose estimation not only for potentially exposed persons and first responders but also for extremely distressed persons (the worried well) can clearly contribute to confidence building in radiological crisis situations. Approaches to cooperate in this field were started in 1986 by laboratories in Ukraine and Russia following the reactor catastrophe in Chernobyl. Another radiological incident with a significant impact on public life was the 1987 Goiania accident in Brazil, with about 250 persons showing various levels of 137Cs incorporation after contact with a stolen cesium source. However, when offered the possibility, more than 120 000 persons volunteered to be monitored for possible contamination in order to exclude the remote possibility of being exposed. In this scenario, the incorporated nuclides could be measured with the help of whole-body counters; however, these measurements were not sufficient because they did not take into account external radiation due to the high-dose cesium source. These information are urgently needed for a best possible patient-centered care; therefore, blood samples of several contaminated persons were sent to biodosimetric laboratories for cytogenetic analysis, e.g. to confirm the findings and optimize medical treatment. Even at this early stage in the development of biodosimetry, it was concluded by the International Atomic Energy Agency (IAEA) that these techniques were most useful for estimating the radiation doses(2). In Japan, 1999, experienced laboratories collaborated and performed biological dosimetry after a critically accident in a conversion test facility in Tokai-mura(7, 8). Since then, networking between specialized biodosimetry laboratories has been recognized to be a pragmatic and important emergency preparedness and response (EPR) strategy not only to overcome the limited capacities within single countries but also to cover countries without the capability to perform biodosimetry. In addition, collaboration of laboratories can also improve the capabilities of a network, e.g. by offering a wider range of complementary biological and retrospective physical techniques. By broadening the analysis spectrum, the best possible approach for a particular emergency situation can be chosen. A multistep approach is also conceivable, starting with fast screening of the potential victims, and followed by precise analysis of radiation markers for an individual dose estimation, as a second step in those persons who have shown positive initial screening results. Besides the increase in capability, there is also an increase in the quality of the dose estimations performed by networking laboratories, due to e.g. interlaboratory exchange or performing interlaboratory comparisons between institutions. In recent years, regional biodosimetry networks have been established all over the world. Presented here will be the Latin American Biological Dosimetry Network (LBDNet), the network from Canada and The United States of America (USA)A (North American BD Network), the Chromosome Network Council organized by Japan, the Asian Network of Biological Dosimetry within ARADOS, the Biological Dose Network in China and the European Network for biological and retrospective physical dosimetry (RENEB). Besides these regional networks, global networks have been set up by the WHO (BioDoseNet), the IAEA (within RANET), EURADOS and the Global Health Security Initiative (GHSI). In addition to the networks, the MULTIBIODOSE approach to handle large-scale irradiation incidents is presented. In each case, the requirements on the network partners are quite demanding and challenging as the results have to be reliable and trustworthy, also in stressful situations as real emergencies. BIODOSIMERTY TOOLS AND NETWORKS MULTIBIODOSE guidance for large-scale radiological emergencies Between May 2010 and April 2013, the European Commission funded the collaborative research project MULTIBIODOSE, in which a variety of biodosimetric tools were analyzed, validated and adapted to different mass casualty scenarios (www.multibiodose.eu)(9). Emphasis was placed on harmonizing tools in the partner institutions in order to create a network of competent laboratories with a capacity high enough to cope with a mass radiation emergency event in a timely manner. The 14 partners included representatives from radiation protection authorities, health protection authorities, independent research institutes, military institutions and universities. The following seven dosimetric methods were tested and evaluated for their suitability as tools to triage exposed individuals in case of a large-scale radiological emergency: manual and automated dicentric assay, automated cytokinesis-block micronucleus assay, gamma H2AX assay, electron paramagnetic resonance spectroscopy, optically stimulated luminescence, skin speckle assay, serum protein assay. The assays were tested for their ability to categorize an exposed person according to three exposure levels(10): below 1 Gy, between 1 and 2 Gy, above 2 Gy. These tools were chosen because they complement each other with respect to sensitivity, specificity to radiation and the exposure scenario as well as speed of performance. Moreover, some of them were well established as biodosimetric tools and only needed to be adapted to a mass casualty scenario, while other assays required further validation. Assays 1–5 were found to be suitable for retrospective dosimetry in large-scale accidents requiring a multi-laboratory response even though some of them still have limitations. Common standard operation procedures could be established and automation was pursued in an attempt to reduce the assay implementation time. Assays 6 and 7 were not found suitable due to lack of sufficient sensitivity to radiation and high inter-donor variability. Assays 1–5 are now being implemented in a large number of laboratories in the framework of the European network RENEB. The MULTIBIODOSE Guidance (http://www.reneb.net/wp-content/uploads/2017/09/multibiodose-guidance-small.pdf) was developed during the project and is intended for authorities involved in radiation protection and emergency preparedness as a source of information about the possibilities and limitations of biodosimetric triage tools developed and implemented during the MULTIBIODOSE project. The guidance can be updated for particular networks. REGIONAL NETWORKS North American BD network The North American Network, established in Canada in 2002, was originally comprised of four Canadian reference laboratories (Health Canada (HC), Defence Research and Development Canada–Ottawa (DRDC), McMaster University, and Canadian Nuclear Laboratories, Chalk River (CNL))(11) and focused on the dicentric chromosome assay (DCA). At that time, 18 cytogenetics laboratories in hospitals were also recruited and trained for dicentric scoring to act as satellite laboratories when the reference laboratories became overwhelmed. Between 2007 and 2016, dicentric scoring was taught as a part of the cytogenetics training program at two Canadian schools with the goal of populating the cytogenetic laboratories across the country with staff that were already familiar with biodosimetry. In 2008, two USA laboratories (Armed Forces Radiobiology Research Institute and Oak Ridge Institute for Science and Education) joined the annual interlaboratory comparison, establishing the North American Network. Unfortunately, in 2013, the biodosimetry laboratory at DRDC was closed, so there are three remaining Canadian reference laboratories. The primary method used in this network is the DCA, however, several of the partner laboratories have also established the cytokinesis-block micronucleus (CBMN) assay and translocation analysis using Fluorescence in situ hybridization (FISH). The HC laboratory acts as the lead of the network and would be first point of contact during an emergency with the partner laboratories being activated when the HC capacity becomes overwhelmed. In this capacity, HC is linked into the Canadian Federal Nuclear Emergency Plan which would trigger a request for biodosimetry during an emergency event. Work has also been conducted on improving throughput for emergency response with the main outcome being the introduction of QuickScan scoring to our developed protocol(12, 13). Since 2007, exercises have been conducted on a regular basis to maintain capabilities and validate the partnering laboratories, testing the DCA, QuickScan DCA and the CBMN assay(14). Other biodosimetry-related researches are ongoing within the network including, but not limited to, developing high-throughput imaging flow cytometry methods for the CBMN assay.(15) Members of the North American Network have been very active in the international biodosimetry community. Several of the partner laboratories played a key role in establishing the World Health Organization (WHO) BioDoseNet and continue to participate(16–18). The HC and CNL laboratories have registered their capabilities with the International Atomic Energy Agency Response Assistance Network (IAEA RANET). The North American Network has also participated in recent interlaboratory comparisons led by RENEB(19). Furthermore, members have contributed greatly to the development of standards for biodosimetry assays through participation in the International Organization of Standardization working group(20–22). Chromosome network council organized in Japan The National Institute of Radiological Sciences (the radiological science research development directorate) of National Institutes for Quantum and Radiological Science and Technology (QST-NIRS) has organized three domestic networks for radiation emergency preparedness: the radiation emergency medical response network council, the chromosome network council and the physical dose assessment network council. Officially, the chromosome network council was established in July 2002. However, activities toward networking for biological dosimetry had already been conducted by the NIRS experts and other cytogeneticists before 2002. For instance, they collaborated to conduct biological dosimetry at the JCO criticality accident in Tokai-mura (1999)(8). Since 2002, the chromosome network council has made efforts to standardize chromosome analysis protocols and to improve biological dosimetric techniques. After the reorganization of some national institutes and establishment of five advanced radiation emergency medicine support centers designated by the government (2016), QST-NIRS reorganized the councils, and the new network councils including younger experts, started in April 2017. The Chromosome Network Council is now composed of five members from NIRS, four other advanced radiation emergency medicine support centers (Hirosaki University, Fukushima Medical University, Hiroshima University, Nagasaki University), and two members from other institutions (Osaka Prefecture University, Radiation Effects Research Foundation). These seven members are all experts in cytogenetics and biological dosimetry. Although each member has established several biodosimetric techniques such as premature chromosome condensation analysis (PCC) or CBMN assay, the council has selected the dicentric chromosome assay (DCA) as the gold standard method for biological dosimetry in radiation emergency preparedness in Japan. From April till December 2017, three meetings have been held and the following achievements have been implemented: (1) the standardized experimental protocol for DCA, (2) the standardized criteria for metaphase image analysis and (3) laboratory information including materials for cell culture, dose–response curves, number and roles of staff members, automated microscopic image analysis systems and maximum number of blood samples they can handle at a time (per week/month). The five advanced radiation emergency medicine support centers are well-geographically distributed along the Japanese islands. Considering the past cases of radiological accidents, the concept is, in principle, that the first emergency response to a radiological accident would be conducted by the nearest center to the site of the accident and the nearest council member of the chromosome network. When the number of patients to examine is over the maximum limit of the nearest laboratory, support from other members would be requested. The council is now discussing improved protocols for blood collection and transportation that should be comprehensible and feasible to the first responding medical staff at the site of the radiation accident, based on the council members’ experience both in research and radiation emergency medicine. Regarding help with metaphase image analysis, the council still has some issues to be solved around information transmission systems from the viewpoint of information security under the recently amended (i.e. stricter) act on protection of personal information in Japan as well as efficiency within the available budget. The networking for biological dosimetry is now expanding by involving Asian countries. The council decided to participate in the second ARADOS WG03 intercomparison exercise which will be conducted by China in 2018. The chromosome network council is becoming increasingly active through recruitment of younger members as well as experienced experts and by having a wider and substantial collaboration with Asian countries. Biological dosimetry network in China The Biodose Network in China was initiated in 2003, by the National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention (China CDC), in order to assess the national capability of biodosimetry, standardize and harmonize the biological dose estimation procedure and its quality control for the medical preparation for the nuclear accident or radiation emergency. The main work of the Biological Dose Network in China focuses on technical training on composing biodosimetry standards, organizing national biodosimetry interlaboratory comparisons and selecting biodosimetry reference laboratories. From 2004 to 2014, five national biodosimetry technique training courses were carried out in Beijing (2004, 2008, 2009), in Changchun city (2012) and in Suzhou city (2014). In total, 213 attendees were trained during these courses. The content of the training courses was not only focused on traditional biodosimetry techniques such as DCA and CBMN assay but also included new developing techniques such as PCC assay FISH assay, gene expression assay and analysis of γH2AX foci and nucleoplasmic bridges. Biodosimetry has been presented at the annual national training courses on Medical Response to Radiation Emergency since 1997. Four national occupational standards or health field standards, including DCA, CBMN, FISH and single-cell gel electrophoresis for biological dose estimation have been issued. A standard on PCC rings for dose estimation will be issued in the near future. Until now, national interlaboratory comparisons focusing on DCA have been organized 10 times and these were held in 2003, 2007, 2010, 2011, 2012, 2014, 2015, 2016 and 2017. At the beginning, in 2003, only seven laboratories participated in this intercomparison; since then, the number of laboratories has increased to 48 in 2017. At least one laboratory in each province, autonomous region or special administrative region took part in the 2017 national interlaboratory comparison, except Macau, Tibet, Heilongjiang, Qinghai, Ningxia and Hainan. The participating laboratories came from universities, research institutes and provincial or municipal centers of disease control and prevention. The rate of qualified laboratories has been gradually increasing. Before 2012, the exercises focused on the identification of dicentric chromosomes. Since 2014, the whole process, including cell culture of human peripheral blood cells, chromosome preparation, dicentric scoring and dose estimation has been compared and tested. Biodosimetry reference laboratories have been selected since 2016. There are four laboratories, which have applied to become a biodosimetry reference laboratory. A list with the qualified reference laboratories will be publicized in the near future. The Chinese Biodose Network participated in activities of the Asian Biodosimetry Network and twice joined the Asian interlaboratory comparisons. In 2017, three laboratories from China joined the intercomparison of biological dosimetry organized by the Asian Radiation Dosimetry Group (ARADOS). LBDNet—the Latin American biological dosimetry network The LBDNet, established in 2007, is a consortium of reference laboratories. The integration of LBDNet is based on a voluntary and consensual participation of seven laboratories responsible for biological dosimetry from Argentina, Brazil, Chile, Cuba, Mexico, Peru and Uruguay. Laboratories from Bolivia, Costa Rica, Ecuador, Paraguay, Venezuela and an associated laboratory from Brazil have recently joined the LBDNet activities. Representation of laboratories is solely institutional, not personal. All the laboratories of the network work within national emergency response systems, which is relevant for the network mission, the operational actions, the research activities and the maintenance of the LBDNet laboratories. At the international level, the network cooperates with REMPAN/WHO-Global Biodosimetry Laboratories Network and with the IAEA Incident and Emergency Centre (IEC), in the frame of the Convention of Early Notification of a Nuclear Accident and the Convention on Assistance in the Case of a Nuclear Accident or Radiological Emergency. The LBDNet mission is (1) to strength the service capacities of Biological Dosimetry laboratories existing in the region to provide an early biodosimetric response for mutual assistance, (2) to provide support to other Latin American countries that do not have biological dosimetry laboratories and (3) to work cooperatively and articulately with other international networks. Most of the laboratories have other dosimetric techniques established besides the DCA assay. These comprise the CBMN assay, FISH technique, PCC-ring (PCC-r) induction and the H2AX assay. Since the establishment of the LBDNet, nine meetings and courses have been organized, supported by IAEA Regional Projects RLA9054, RLA9061, RLA9074 and RLA9076. Individual training was carried out within the region or in the biological dosimetry laboratories of Spain, Greece and France. Additionally, nine interlaboratory comparisons were performed, involving: (1) DCA applying conventional and triage scoring criteria evaluating interlaboratory reproducibility and intralaboratory repeatability using robust methods(23), (2) Interlaboratory comparison of the DCA using electronically transmitted images(24), (3) Joint IAEA, PAHO and WHO Exercise ‘ShipEx-1’ on the intracontinental and intercontinental shipment of blood samples for biodosimetry assessment(25), (4) quality parameters in microscopic image acquisition, (5) exercise on harmonization and intercomparison using PCC-r test for dose estimation in high dose exposures situations, (6) exercise for the development of calibration curves based on PCC-r images, (7) micronuclei images and slides for rapid screening in accidents involving mass-casualties, (8) participation in EU interlaboratory comparisons within the project ‘Realizing the European Network of Biodosimetry (RENEB)’ 2014–15(19) and (9) multiparametric intercomparison in physical, biological, retrospective and computational dosimetry in a simulated scenario of accidental exposure in industrial gamma radiography. The experience gained by intercomparisons, training activities, courses and meetings has allowed the region to be prepared to produce an effective and coordinated response in cases of radiological or nuclear emergencies. Nevertheless, improvements in scoring criteria, sustainable integration of research activities, introduction of other techniques for the interpretation of different overexposure scenarios, continuity of training programs and periodic intercomparison exercises are necessary to maintain the operative capacity of the network. Actions for a steady quality assurance and quality control such as the implementation of quality management systems in the network laboratories are to be pursued as future activities within the network. Future challenges on the biodosimetry role in the LBDNet are (1) to expand biodosimetry capability to clinical applications, including evaluation of individual radiosensitivity, (2) to perform long-term health risk studies following radiation exposure (radiation epidemiology)—FISH and EPR (retrospective dose) and (3) to develop new biomarkers. EURADOS WG10—retrospective dosimetry The European Radiation Dosimetry Group, EURADOS, was established in 1981 with the original aim ‘to advance the scientific understanding and the technical development of the dosimetry of ionizing radiation in the fields of radiation protection, radiobiology, radiation therapy and medical diagnosis by the simulation of collaboration between European laboratories, especially those of the European Communities’. Today, EURADOS is a network of over 70 European institutions (Voting Members) and 560 scientists (Associate Members) promoting technical development and implementation of dosimetry techniques and contributing to compatibility and conformity within Europe and worldwide(26). EURADOS Working Group 10, Retrospective Dosimetry, was established in 2009 with the objective of bringing together contacts and collaborations throughout European laboratories with expertise in the area of physical and biological retrospective dosimetry. Recent activities include a number of biological and physical retrospective dosimetry intercomparisons(27)—many carried out in partnership with RENEB and the other networks. In common with most, if not all, of the other networks, intercomparisons are a key component of the WG10 activities, particular as they provide a framework for development and validation of advances to existing and new techniques. Recent development in statistical analysis techniques has resulted in a review of uncertainty estimation methods for biological and physical retrospective dosimetry methods(28) and organization of a CONCERT funded training school on uncertainty analysis techniques, with a view to sharing knowledge regarding best practise in use of the ISO standard methods and more intensive techniques including Bayesian and Monte Carlo modeling, ongoing work is focused on consideration of dose conversion coefficients for physical retrospective dosimetry and on writing a review of biological dosimetry techniques after internal or mixed external and internal exposure. Future work will focus on further development, consolidation, standardization and validation of techniques in partnership with colleagues from across Europe and internationally, underpinning provision of the best possible dosimetry techniques for both routine radiation dosimetry and emergency response. RENEB—the European network for biological and retrospective physical dosimetry The nucleus of the RENEB network was a tripartite pact between the IRSN, PHE and BfS, set up in 2004. Later, from 2012 to 2015, the network Realizing the European network for biological and retrospective physical dosimetry (RENEB) was established with support from the European Commission (EURATOM FP7, GA 295 513) (www.reneb.eu)(29). Project partners were 23 organizations from 16 European countries, most of them had been identified with the help of the ‘TENEB’ survey(30). During the project, the necessary procedures for efficient dose estimation and for the sustainability of the current network have been initiated, tested and established, as follows: Operational network basis with approved assays(31): most of the integrated assays had been identified before and adapted to large-scale scenarios by the MULTIBIODOSE project, EURADOS WG10. Assays included in the operational basis to this moment are DCA, FISH, CBMN, PCC, gamma H2AX, Gene Expression (test phase) and EPR/OSL techniques (partly test phase). Fundamental for the operational basis are interlaboratory comparisons, performed on a regular level. Between 2012 and 2017, several tabletop exercises and practical interlaboratory comparison were performed. While the first interlaboratory comparison in 2013 was for network partners only, the second interlaboratory comparison (2014) was open for interested laboratories beyond Europe and for global networks, such as the WHO BioDoseNet, and members of IAEA's Response Assistance Network (RANET). In this exercise, 42 labs from 31 countries participated with the DCA. At the end of 2015, the third exercise was jointly performed with the EURADOS platform and in 2017, the fourth exercise was accomplished. Each exercise was organized by another partner and had a different focus. Development of the network: a strategy was suggested to continuously develop the network with regard to technological progress and membership. This includes identification, validation and as far as possible integration of new and upcoming technologies and/or new partners. E&T and QA&QM program(32): a program and manual were developed to guarantee harmonized application of the assays and correct calculation of dose estimates by the partners. This includes practical training in partner laboratories, seminars on QA&QM and ISO standards or statistics. The program is mandatory for network partners and open to non-members. Since 2014, nine training courses in partner laboratories were performed with focus on practical performance of particular biological and EPR/OSL techniques. In addition, seminars on statistics, ISO standards, quality assurance and quality management and on metrology were given. Organization structure: a hierarchical, communicational and logistical infrastructure for the network was initiated. In addition, options for sustainability and financing were compiled and the memorandum of understanding (MoU) as the first step for a legal network basis was prepared. Integration in EPR and link to research: contact to national and international organizations such as the WHO and IAEA was initiated for cross linking the network. In 2016, the RENEB network, based on an MoU was signed by 26 organizations from 16 European countries, including BfS/Germany, CEA/France, ENEA/Italy, ICHTJ/Poland, INSP/Romania, IRSN/France, ISS/Italy, IST/Portugal, LAFE/Spain, NCRRP/Bulgaria, NCSRD/Greece, NRPA/Norway, OSSKI/ Hungary, PHE/UK, SERMAS/Spain, CRPR-SU/Sweden, UAB/Spain, UGent/Belgium, UNITUS/Italy, AMVRC/Italy, DIT/Ireland, FZJülich/Germany, INFN/ Italy, RPC/Lithuania, SCK-CEN/Belgium, USA/Spain. Activities within the RENEB project have been published during the project and in a special issue ‘Networking in biological and EPR/OSL dosimetry: the European RENEB platform for emergency preparedness and research’ including 17 articles(33). In 2017, the RENEB association (www.reneb.net) was inaugurated and became an independent legal entity with 10 organizations as decision-making ‘voting members’ (BfS, BIR, PHE, IRSN, NCRRP, SERMAS, CRPR-SU, UAB, UGent, INFN), in 2018, three more voting members (IST, NCSRF, IRBA) joined. The association serves directly and exclusively public benefit, it can be a contractual partner to institutions and organizations. It has to be pointed out that RENEB is not restricted to European organizations or partner from EU countries, membership is open to all interested parties. Beginning of the Asian network of biological dosimetry: ARADOS-WG03 ARADOS (Asian Radiation Dosimetry Group) was started in October 2015 with several young scientists involving the cooperation of three institutes (CIRP, QST-NIRS and KIRAMS), from three Asian countries (China, Japan and South Korea). The purpose of ARADOS is to construct a sustainable network in physical and biological dosimetry in preparation for regional large-scale nuclear and/or radiological emergency situations. Therefore, ARADOS-WG03 (Working group 3) also aimed to establish, harmonize and develop an Asian biological dosimetry network that can be activated in emergency situations. The development and harmonization of the scientific and technical capabilities existing within the ARADOS-WG03 members could also be helpful to other neighboring countries with less or no capacity for biological dosimetry in case of mass-casualties with a large number of victims. Regular members of ARADOS-WG03 are Korea Institute of Radiological and Medical Sciences (KIRAMS) from Seoul/Korea, China Institute of Radiation Protection (CIRP) from Taiyuan/China, National Institute of Radiation Protection (NIRP) from Beijing/China, Nuclear Research Institute (NRI) from Dalat/Vietnam, and the National Institute of Radiological Sciences (QST-NIRS) from Chiba/Japan, which is both a regular members of ARADOS-WG03 and associated with the Japanese Chromosome Network. The first intercomparison exercise was successfully carried out by 11 laboratories from 4 countries with three galleries of electronically transmitted metaphase images in August 2017. Participants were the biological dosimetry laboratories of Asian institutes, the five regular menbers of ARADOS-WG03 and the six new participants which are associated with the Japanese Chromosome Network, as Hirosaki University/Japan, Radiation Effect Research Foundation (RERF) from Hiroshima/Japan, Fukushima Medical University/Japan, Nagasaki University/Japan and Osaka Prefac. University/Japan. GLOBAL INFORMAL NETWORKS GHSI initiative to establish a laboratory network for radionuclide bioassay The GHSI is an informal, worldwide network of countries formed in 2001 to ensure health sector exchange and coordination of practices in confronting risks to global health posed by chemical, biological and radionuclear threats, as well as by pandemic influenza(34). The member countries/organizations of the GHSI are Canada, France, Germany, Italy, Japan, Mexico, UK, USA and the European commission. The WHO is a technical advisor. The GHSI Rad-Nuc Threats Working Group (RNWG) was created to facilitate sharing and collaboration on policies and capability development to enhance public health preparedness and response to radiological and nuclear threats. As a result of discussions and consultations, the RNWG proposes to establish a laboratory network to improve our collective surge capacity for radionuclide bioassay within the GHSI community. Within this network, laboratories can share their expertise through training activities, exercise their preparedness through intercomparisons, develop new capabilities through collaborative R&D and assist in bioassay analysis when multiple laboratories are required following an emergency. In 2013, the network laboratories were surveyed on their current capabilities in emergency radionuclide bioassay and the technological and operational gaps they had identified in this area. Based on the survey results, the RNWG conducted two exercises. The first exercise was organized in 2014 to test the participating laboratories (eight from seven countries) for their response capabilities in assaying a single radionuclide (241Am) in a urine sample, performing internal dose assessment and providing advice on medical intervention when necessary(35), while the second exercise was organized in early 2016(36) to test the participating laboratories (18 from 16 countries including laboratories contributing to the WHO REMPAN (Radiation Emergency Medical Preparedness and Assistance Network, World Health Organization)(37)—and IAEA RANET database(38)—networks) for their response capabilities in assaying multiple radionuclides (90 Sr, 106Ru, 137Cs, 239Pu) in a single urine sample, focusing on the procedures and methods/techniques used and the results obtained by the participating laboratories.(36) Some laboratories from the collaborating centers or liaison institutions of the WHO REMPAN and two laboratories that had registered their bioassay capabilities in the IAEA RANET participated in the second exercise as well. Results for the two exercises, including gaps identified, have been published(35, 38). A workshop may be organized to allow exercise participating laboratories (and other interested ones) to further discuss the findings/gaps and to plan out the next steps; and hand-on training sessions may be coordinated to facilitate learning for the individuals and/or laboratories that have interest. INTERNATIONAL ASSOCIATION OF BIOLOGICAL AND EPR RADIATION DOSIMETRY The International Association of Biological and EPR Radiation Dosimetry (IABERD, http://iaberd.org/) is a scientific association, established to advance research, development and education in the biological dosimetry and EPR dosimetry applied to ionizing radiation. The aim of IABERD is to stimulate and coordinate biological and EPR radiation dosimetry activities around the world, with two major objectives: to hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields. Scientific meetings of IABERD are held every 2 or 3 years and are also open to non-members. These meetings provide opportunities for the presentation of original communications, demonstrations and symposia. The meetings can also be organized by a host member in collaboration and under supervision of the IABERD committee. Among others, IABERD contributes to the financial security for the scientific meetings, selecting the venue of each scientific meeting, providing start-up funds and support funds for each scientific meeting if requested by the local organizing committee, providing additional assistance, where possible, as requested by the local organizing committee, selecting or approving the members of the scientific advisory committee for each scientific meeting and selecting or approving the mode of publication, the refereeing standards and the publishers, of the proceedings of each scientific meeting. Conferences have been organized 2006 in Washington-Bethesda, 2008 in Hanover/New Hampshire, 2010 in Mandelieu-Lanapoule/France and 2013 in Leiden/The Netherlands. In 2015, the meeting was again held in Hanover/New Hampshire in combination with the International Symposium on EPR Dosimetry and Dating, the International Conference on Biodosimetry and with a symposium of the International EPR Society. The primary focus of this conference was on medical response to events in which large numbers of individuals may be exposed to significant levels of ionizing radiation; topics included biodosimetry techniques, radiation mitigators and model systems to develop countermeasures, new data from different exposure events and the implication of these methods in a radiological emergency or in terrorist attack scenarios. The EPRBioDose 2018 in Munich/Germany covered aspects of biomarkers, biological and EPR dosimetry for medicine, radiological emergency and epidemiology as well as EPR dating and dosimetry networks including quality assurance and management. WHO BioDoseNet Establishment of this network resulted from of a consultation held at the WHO headquarters in Geneva in 2007(39). The main purpose of BioDoseNet (BDN) is to facilitate a global network that brings together several smaller regional or national groups described above with the key objectives of fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building. The ultimate goal of this collaboration would be provision of support in case of a large radiological or nuclear emergency, where a number of persons requiring biological dosimetry would outweigh country’s national capacity. BDN membership therefore includes a wide range of laboratories from well-advanced reference labs that are partners in the regional/national networks to more isolated laboratories, often less advanced and from lesser developed countries, which have no other formalized international partnership. For latter category of labs, BioDoseNet provides an access to expertise and information worldwide. More detailed information on the structure, functions and setup of BioDoseNet is provided elsewhere(17, 39, 40). Wilkins et al.(18) provided the most recent update of BioDoseNet capacities, at the time comprising 67 laboratories, including some statistical analysis of number of trained staff available, available assays and number of samples that can be handled by a given laboratory. Bearing in mind that a number of the laboratories are also members of the smaller regional or national networks this survey provides a unique view of the global status of biodosimetry. In addition, the WHO BioDoseNet complements the RANET, established by the IAEA. RANET is a network, set up by formal agreements at the governmental level, to provide expert assistance, if requested by a country experiencing a radiological or nuclear emergency. The scope of the assistance covered by RANET includes several emergency assistance types, including among others biodosimetry and medical response. Some laboratories enlisted under RANET for provision of assistance are also members of BioDoseNet. By contrast, BioDoseNet is an informal arrangement, made at the laboratory/institutional level with the main focus of activities on building relevant capacities in countries, facilitating international cooperation for harmonization of methods, improving quality assurance, information sharing and training. In the event of a major radiological or nuclear emergency, the response assistance could be facilitated through a formal request via RANET. Depending on the scale, and geographical location of the accident, and availability of the support through RANET, the BioDoseNet laboratories may prove useful in sharing the burden of dose assessment through exchanging samples or images for scoring aberrations, whilst in some circumstances the existing regional or national network response will suffice. For the countries with no established formal links with RANET, and in case of a RANET assistant being insufficient, BioDoseNet labs can be called upon as a complementary to the RANET response. The communication in this case would be handled between WHO and IAEA secretariats. Even though, this scenario has neither been tested in real emergencies, nor in an exercise, there are clear links for communication and liaison between BioDoseNet and RANET and the other networking structures so that, whatever the event, and wherever it occurs, the international biodosimetry community should be able to mobilize its combined resources in the most effective manner. An overview of operational biological and physical retrospective dosimetry networks for emergency preparedness and response and networks contributing to biological and physical retrospective dosimetry is given in Table 1. Table 1. Networks dealing with/including biodosimetry. Operational biological and physical retrospective dosimetry networks for EPR Network name Start Countries/regions Partners Assays applied in the operational networks DCAa FISHb PCCc CBMNd Gamma H2AX Gene expression Other North American Network 2002 Canada, USA 5 MA A A DCA quick scan; high-throughput imaging flow cytometry Chromosome network council Japan 2002 Japan 7 MA A A A Biodose Network in China 2003 China 48 MA A A A A TP Single-cell gel electrophoresis, nucleoplasmic bridges Latin American Biological Dosimetry Network (LBDNet) 2007 Latin American 13 MA A A A A RENEB-MoU 2012 Europe 26 MA A A A A TP EPRe, OSLf techniques RENEB e.V. 2017 Europe (+) 11 ARADOS-WG03 2015 Asia (South Korea, Vietnam, China, Japan) 10 MA A A A aDCA, dicentric chromosome assay; bFISH, fluorescence in situ hybridization assay; cPCC, premature chromosome condensation assay, dCBMN, cytokinesis-block micronucleus assay; eEPR, electron paramagnetic resonance dosimetry; fOSL, optically stimulated luminescence dosimetry. MA, most applied assay for dose estimation; A, assay applied for dose estimation (not all partners); TP, assay in test phase. Operational biological and physical retrospective dosimetry networks for EPR Network name Start Countries/regions Partners Assays applied in the operational networks DCAa FISHb PCCc CBMNd Gamma H2AX Gene expression Other North American Network 2002 Canada, USA 5 MA A A DCA quick scan; high-throughput imaging flow cytometry Chromosome network council Japan 2002 Japan 7 MA A A A Biodose Network in China 2003 China 48 MA A A A A TP Single-cell gel electrophoresis, nucleoplasmic bridges Latin American Biological Dosimetry Network (LBDNet) 2007 Latin American 13 MA A A A A RENEB-MoU 2012 Europe 26 MA A A A A TP EPRe, OSLf techniques RENEB e.V. 2017 Europe (+) 11 ARADOS-WG03 2015 Asia (South Korea, Vietnam, China, Japan) 10 MA A A A aDCA, dicentric chromosome assay; bFISH, fluorescence in situ hybridization assay; cPCC, premature chromosome condensation assay, dCBMN, cytokinesis-block micronucleus assay; eEPR, electron paramagnetic resonance dosimetry; fOSL, optically stimulated luminescence dosimetry. MA, most applied assay for dose estimation; A, assay applied for dose estimation (not all partners); TP, assay in test phase. Networks contributing to biological and physical retrospective dosimetry Network name Start Countries/regions Motivation EURADOS WG10 2009 global To maintain a network of laboratories with expertise in biological and physical retrospective dosimetry. This enables specialist groups to be formed in a timely manner to address research issues and contribute to strategic research agendas GHSI Rad-Nuc Threats Working Group (RNWG) 2001 global Informal network to facilitate sharing and collaboration on policies and capability development and to enhance public health preparedness and response to radiological and nuclear threats IABERD 2005 global To hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields WHO BioDoseNet 2007 global To facilitate worldwide networking by fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building Networks contributing to biological and physical retrospective dosimetry Network name Start Countries/regions Motivation EURADOS WG10 2009 global To maintain a network of laboratories with expertise in biological and physical retrospective dosimetry. This enables specialist groups to be formed in a timely manner to address research issues and contribute to strategic research agendas GHSI Rad-Nuc Threats Working Group (RNWG) 2001 global Informal network to facilitate sharing and collaboration on policies and capability development and to enhance public health preparedness and response to radiological and nuclear threats IABERD 2005 global To hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields WHO BioDoseNet 2007 global To facilitate worldwide networking by fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building Table 1. Networks dealing with/including biodosimetry. Operational biological and physical retrospective dosimetry networks for EPR Network name Start Countries/regions Partners Assays applied in the operational networks DCAa FISHb PCCc CBMNd Gamma H2AX Gene expression Other North American Network 2002 Canada, USA 5 MA A A DCA quick scan; high-throughput imaging flow cytometry Chromosome network council Japan 2002 Japan 7 MA A A A Biodose Network in China 2003 China 48 MA A A A A TP Single-cell gel electrophoresis, nucleoplasmic bridges Latin American Biological Dosimetry Network (LBDNet) 2007 Latin American 13 MA A A A A RENEB-MoU 2012 Europe 26 MA A A A A TP EPRe, OSLf techniques RENEB e.V. 2017 Europe (+) 11 ARADOS-WG03 2015 Asia (South Korea, Vietnam, China, Japan) 10 MA A A A aDCA, dicentric chromosome assay; bFISH, fluorescence in situ hybridization assay; cPCC, premature chromosome condensation assay, dCBMN, cytokinesis-block micronucleus assay; eEPR, electron paramagnetic resonance dosimetry; fOSL, optically stimulated luminescence dosimetry. MA, most applied assay for dose estimation; A, assay applied for dose estimation (not all partners); TP, assay in test phase. Operational biological and physical retrospective dosimetry networks for EPR Network name Start Countries/regions Partners Assays applied in the operational networks DCAa FISHb PCCc CBMNd Gamma H2AX Gene expression Other North American Network 2002 Canada, USA 5 MA A A DCA quick scan; high-throughput imaging flow cytometry Chromosome network council Japan 2002 Japan 7 MA A A A Biodose Network in China 2003 China 48 MA A A A A TP Single-cell gel electrophoresis, nucleoplasmic bridges Latin American Biological Dosimetry Network (LBDNet) 2007 Latin American 13 MA A A A A RENEB-MoU 2012 Europe 26 MA A A A A TP EPRe, OSLf techniques RENEB e.V. 2017 Europe (+) 11 ARADOS-WG03 2015 Asia (South Korea, Vietnam, China, Japan) 10 MA A A A aDCA, dicentric chromosome assay; bFISH, fluorescence in situ hybridization assay; cPCC, premature chromosome condensation assay, dCBMN, cytokinesis-block micronucleus assay; eEPR, electron paramagnetic resonance dosimetry; fOSL, optically stimulated luminescence dosimetry. MA, most applied assay for dose estimation; A, assay applied for dose estimation (not all partners); TP, assay in test phase. Networks contributing to biological and physical retrospective dosimetry Network name Start Countries/regions Motivation EURADOS WG10 2009 global To maintain a network of laboratories with expertise in biological and physical retrospective dosimetry. This enables specialist groups to be formed in a timely manner to address research issues and contribute to strategic research agendas GHSI Rad-Nuc Threats Working Group (RNWG) 2001 global Informal network to facilitate sharing and collaboration on policies and capability development and to enhance public health preparedness and response to radiological and nuclear threats IABERD 2005 global To hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields WHO BioDoseNet 2007 global To facilitate worldwide networking by fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building Networks contributing to biological and physical retrospective dosimetry Network name Start Countries/regions Motivation EURADOS WG10 2009 global To maintain a network of laboratories with expertise in biological and physical retrospective dosimetry. This enables specialist groups to be formed in a timely manner to address research issues and contribute to strategic research agendas GHSI Rad-Nuc Threats Working Group (RNWG) 2001 global Informal network to facilitate sharing and collaboration on policies and capability development and to enhance public health preparedness and response to radiological and nuclear threats IABERD 2005 global To hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields WHO BioDoseNet 2007 global To facilitate worldwide networking by fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building CONCLUSIONS Biological and retrospective physical dosimetry is needed in the case of various exposure scenarios, especially in the case of unknown or conflicting irradiation situations. The results gained by these techniques are generally well accepted by affected persons, due to the individual aspect of the applied methods. To be prepared for large-scale radiological incidents, biodosimetry laboratories of different countries have joined forces and established regional and/or global networks, either on a formal or informal basis. This approach has already resulted in a significant increase in the efficiency of dose estimation with regard to analysis capacity and capabilities. Different radiation exposure scenarios can be handled according to their specific characteristics and needs by choosing the best available techniques and approaches for dose estimation. The precision of dose estimates is fundamental for successful cooperation between laboratories and especially for the credibility of the networks. In addition, the reliability of the supporting infrastructure, for example, for shipment of samples and secure communication of the results is also essential, especially for networking. To facilitate this, to test and guarantee the high quality and consistency of the partner laboratories, regular interlaboratory comparisons and exercises are performed by the networks. For sustainability, reliability and efficiency in real radiological disasters, the utilization of established networks within existing national and international EPR systems is urgently required. This necessity is becoming increasingly urgent, as currently, several countries worldwide are closing their national biodosimetry laboratories for financial reasons (e.g. laboratories in Germany, Finland, Canada). 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For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Protection Dosimetry Oxford University Press

BIODOSIMETRY AND BIODOSIMETRY NETWORKS FOR MANAGING RADIATION EMERGENCY

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Abstract

Abstract Biological dosimetry enables individual dose reconstruction in the case of unclear or inconsistent radiation exposure situations, especially when a direct measurement of ionizing radiation is not or is no longer possible. To be prepared for large-scale radiological incidents, networking between well-trained laboratories has been identified as a useful approach for provision of the fast and trustworthy dose assessments needed in such circumstances. To this end, various biodosimetry laboratories worldwide have joined forces and set up regional and/or nationwide networks either on a formal or informal basis. Many of these laboratories are also a part of global networks such as those organized by World Health Organization, International Atomic Energy Agency or Global Health Security Initiative. In the present report, biodosimetry networks from different parts of the world are presented, and the partners, activities and cooperation actions are detailed. Moreover, guidance for situational application of tools used for individual dosimetry is given. INTRODUCTION Accidents leading to unplanned or unregulated exposure of humans and the environment to ionizing radiation have occurred many times, despite strict safety regulations and precautionary measures(1). It also happens that persons at risk of exposure do not carry the obligatory personal dosemeter, or that a dosemeter is not stored correctly after use. Each of these situations can lead to unclear or inconsistent findings, e.g. appearance of apparent acute symptoms in humans without an exposure high enough to cause acute radiation effects or vice versa, a high dose value reported by the dosemeter but no acute radiation effects expressed by the apparently irradiated person. In many such cases, biological dosimetry offers the only possibility for an individual dose estimation, even weeks or months after a potential exposure. This is possible because, from the physical point of view, the dose is not measured directly but by analyzing radiation-induced biological changes in a sample taken from the individual. Thus, a measurement of the direct biological/biochemical or physical effect on an individual level, particularly in the cellular DNA is possible. The results gained by biological dosimetry are generally appreciated by affected individuals and in many countries also acknowledged by court and professional associations as a proof of exposure. As a consequence, biodosimetry laboratories have been established in many countries, and in case no national competence is available, such requests are forwarded to neighboring states in Europe, e.g. by Finland, Norway, Switzerland and Austria. A large challenge is presented by large-scale nuclear or radiological incidents. Such disasters can happen anytime and anywhere, without any prewarning. They can be caused by technical breakdown or human failure but also by malevolent actions such as terrorist attacks, as emphasized in the Communiqué of the Nuclear Security Summit 2016 (http://www.nss2016.org/2016-joint-statements/). Each of these scenarios can have severe consequences for human health, the environment and economy of one or more countries. In such circumstances, knowledge about the doses received by individuals is highly relevant for proper diagnosis of the exposed persons(2, 3). However, the consequences of nuclear disasters on the public health and economy of a country very often exceed the nominal damage caused by irradiation. To a large extent, this is due to the fear and insecurity of the population regarding the possible radiation effects and proximate consequences. This, again, can have major consequences for the health and quality of life of individuals and also for the economy of a country, much more so than the actual radiation exposure. Incidents with a radiation background, especially, lead to enormous stress for affected persons and recollection of the individual location, duration and movement profile are often subjectively influenced and not reliable(4–6) as a result of this. Therefore, an essential aspect of individual radiation dosimetry, especially in large-scale scenarios, is the possibility to exclude a putative high radiation exposure on an individual level. By this, ‘worried well’ persons showing prodromal symptoms of a radiation exposure (often interchangeable with symptoms induced by high levels of stress) but without having received a dose high enough to cause acute effects can be effectively distinguished from exposed persons needing immediate medical help and specialized care. In this context, individual dose estimation not only for potentially exposed persons and first responders but also for extremely distressed persons (the worried well) can clearly contribute to confidence building in radiological crisis situations. Approaches to cooperate in this field were started in 1986 by laboratories in Ukraine and Russia following the reactor catastrophe in Chernobyl. Another radiological incident with a significant impact on public life was the 1987 Goiania accident in Brazil, with about 250 persons showing various levels of 137Cs incorporation after contact with a stolen cesium source. However, when offered the possibility, more than 120 000 persons volunteered to be monitored for possible contamination in order to exclude the remote possibility of being exposed. In this scenario, the incorporated nuclides could be measured with the help of whole-body counters; however, these measurements were not sufficient because they did not take into account external radiation due to the high-dose cesium source. These information are urgently needed for a best possible patient-centered care; therefore, blood samples of several contaminated persons were sent to biodosimetric laboratories for cytogenetic analysis, e.g. to confirm the findings and optimize medical treatment. Even at this early stage in the development of biodosimetry, it was concluded by the International Atomic Energy Agency (IAEA) that these techniques were most useful for estimating the radiation doses(2). In Japan, 1999, experienced laboratories collaborated and performed biological dosimetry after a critically accident in a conversion test facility in Tokai-mura(7, 8). Since then, networking between specialized biodosimetry laboratories has been recognized to be a pragmatic and important emergency preparedness and response (EPR) strategy not only to overcome the limited capacities within single countries but also to cover countries without the capability to perform biodosimetry. In addition, collaboration of laboratories can also improve the capabilities of a network, e.g. by offering a wider range of complementary biological and retrospective physical techniques. By broadening the analysis spectrum, the best possible approach for a particular emergency situation can be chosen. A multistep approach is also conceivable, starting with fast screening of the potential victims, and followed by precise analysis of radiation markers for an individual dose estimation, as a second step in those persons who have shown positive initial screening results. Besides the increase in capability, there is also an increase in the quality of the dose estimations performed by networking laboratories, due to e.g. interlaboratory exchange or performing interlaboratory comparisons between institutions. In recent years, regional biodosimetry networks have been established all over the world. Presented here will be the Latin American Biological Dosimetry Network (LBDNet), the network from Canada and The United States of America (USA)A (North American BD Network), the Chromosome Network Council organized by Japan, the Asian Network of Biological Dosimetry within ARADOS, the Biological Dose Network in China and the European Network for biological and retrospective physical dosimetry (RENEB). Besides these regional networks, global networks have been set up by the WHO (BioDoseNet), the IAEA (within RANET), EURADOS and the Global Health Security Initiative (GHSI). In addition to the networks, the MULTIBIODOSE approach to handle large-scale irradiation incidents is presented. In each case, the requirements on the network partners are quite demanding and challenging as the results have to be reliable and trustworthy, also in stressful situations as real emergencies. BIODOSIMERTY TOOLS AND NETWORKS MULTIBIODOSE guidance for large-scale radiological emergencies Between May 2010 and April 2013, the European Commission funded the collaborative research project MULTIBIODOSE, in which a variety of biodosimetric tools were analyzed, validated and adapted to different mass casualty scenarios (www.multibiodose.eu)(9). Emphasis was placed on harmonizing tools in the partner institutions in order to create a network of competent laboratories with a capacity high enough to cope with a mass radiation emergency event in a timely manner. The 14 partners included representatives from radiation protection authorities, health protection authorities, independent research institutes, military institutions and universities. The following seven dosimetric methods were tested and evaluated for their suitability as tools to triage exposed individuals in case of a large-scale radiological emergency: manual and automated dicentric assay, automated cytokinesis-block micronucleus assay, gamma H2AX assay, electron paramagnetic resonance spectroscopy, optically stimulated luminescence, skin speckle assay, serum protein assay. The assays were tested for their ability to categorize an exposed person according to three exposure levels(10): below 1 Gy, between 1 and 2 Gy, above 2 Gy. These tools were chosen because they complement each other with respect to sensitivity, specificity to radiation and the exposure scenario as well as speed of performance. Moreover, some of them were well established as biodosimetric tools and only needed to be adapted to a mass casualty scenario, while other assays required further validation. Assays 1–5 were found to be suitable for retrospective dosimetry in large-scale accidents requiring a multi-laboratory response even though some of them still have limitations. Common standard operation procedures could be established and automation was pursued in an attempt to reduce the assay implementation time. Assays 6 and 7 were not found suitable due to lack of sufficient sensitivity to radiation and high inter-donor variability. Assays 1–5 are now being implemented in a large number of laboratories in the framework of the European network RENEB. The MULTIBIODOSE Guidance (http://www.reneb.net/wp-content/uploads/2017/09/multibiodose-guidance-small.pdf) was developed during the project and is intended for authorities involved in radiation protection and emergency preparedness as a source of information about the possibilities and limitations of biodosimetric triage tools developed and implemented during the MULTIBIODOSE project. The guidance can be updated for particular networks. REGIONAL NETWORKS North American BD network The North American Network, established in Canada in 2002, was originally comprised of four Canadian reference laboratories (Health Canada (HC), Defence Research and Development Canada–Ottawa (DRDC), McMaster University, and Canadian Nuclear Laboratories, Chalk River (CNL))(11) and focused on the dicentric chromosome assay (DCA). At that time, 18 cytogenetics laboratories in hospitals were also recruited and trained for dicentric scoring to act as satellite laboratories when the reference laboratories became overwhelmed. Between 2007 and 2016, dicentric scoring was taught as a part of the cytogenetics training program at two Canadian schools with the goal of populating the cytogenetic laboratories across the country with staff that were already familiar with biodosimetry. In 2008, two USA laboratories (Armed Forces Radiobiology Research Institute and Oak Ridge Institute for Science and Education) joined the annual interlaboratory comparison, establishing the North American Network. Unfortunately, in 2013, the biodosimetry laboratory at DRDC was closed, so there are three remaining Canadian reference laboratories. The primary method used in this network is the DCA, however, several of the partner laboratories have also established the cytokinesis-block micronucleus (CBMN) assay and translocation analysis using Fluorescence in situ hybridization (FISH). The HC laboratory acts as the lead of the network and would be first point of contact during an emergency with the partner laboratories being activated when the HC capacity becomes overwhelmed. In this capacity, HC is linked into the Canadian Federal Nuclear Emergency Plan which would trigger a request for biodosimetry during an emergency event. Work has also been conducted on improving throughput for emergency response with the main outcome being the introduction of QuickScan scoring to our developed protocol(12, 13). Since 2007, exercises have been conducted on a regular basis to maintain capabilities and validate the partnering laboratories, testing the DCA, QuickScan DCA and the CBMN assay(14). Other biodosimetry-related researches are ongoing within the network including, but not limited to, developing high-throughput imaging flow cytometry methods for the CBMN assay.(15) Members of the North American Network have been very active in the international biodosimetry community. Several of the partner laboratories played a key role in establishing the World Health Organization (WHO) BioDoseNet and continue to participate(16–18). The HC and CNL laboratories have registered their capabilities with the International Atomic Energy Agency Response Assistance Network (IAEA RANET). The North American Network has also participated in recent interlaboratory comparisons led by RENEB(19). Furthermore, members have contributed greatly to the development of standards for biodosimetry assays through participation in the International Organization of Standardization working group(20–22). Chromosome network council organized in Japan The National Institute of Radiological Sciences (the radiological science research development directorate) of National Institutes for Quantum and Radiological Science and Technology (QST-NIRS) has organized three domestic networks for radiation emergency preparedness: the radiation emergency medical response network council, the chromosome network council and the physical dose assessment network council. Officially, the chromosome network council was established in July 2002. However, activities toward networking for biological dosimetry had already been conducted by the NIRS experts and other cytogeneticists before 2002. For instance, they collaborated to conduct biological dosimetry at the JCO criticality accident in Tokai-mura (1999)(8). Since 2002, the chromosome network council has made efforts to standardize chromosome analysis protocols and to improve biological dosimetric techniques. After the reorganization of some national institutes and establishment of five advanced radiation emergency medicine support centers designated by the government (2016), QST-NIRS reorganized the councils, and the new network councils including younger experts, started in April 2017. The Chromosome Network Council is now composed of five members from NIRS, four other advanced radiation emergency medicine support centers (Hirosaki University, Fukushima Medical University, Hiroshima University, Nagasaki University), and two members from other institutions (Osaka Prefecture University, Radiation Effects Research Foundation). These seven members are all experts in cytogenetics and biological dosimetry. Although each member has established several biodosimetric techniques such as premature chromosome condensation analysis (PCC) or CBMN assay, the council has selected the dicentric chromosome assay (DCA) as the gold standard method for biological dosimetry in radiation emergency preparedness in Japan. From April till December 2017, three meetings have been held and the following achievements have been implemented: (1) the standardized experimental protocol for DCA, (2) the standardized criteria for metaphase image analysis and (3) laboratory information including materials for cell culture, dose–response curves, number and roles of staff members, automated microscopic image analysis systems and maximum number of blood samples they can handle at a time (per week/month). The five advanced radiation emergency medicine support centers are well-geographically distributed along the Japanese islands. Considering the past cases of radiological accidents, the concept is, in principle, that the first emergency response to a radiological accident would be conducted by the nearest center to the site of the accident and the nearest council member of the chromosome network. When the number of patients to examine is over the maximum limit of the nearest laboratory, support from other members would be requested. The council is now discussing improved protocols for blood collection and transportation that should be comprehensible and feasible to the first responding medical staff at the site of the radiation accident, based on the council members’ experience both in research and radiation emergency medicine. Regarding help with metaphase image analysis, the council still has some issues to be solved around information transmission systems from the viewpoint of information security under the recently amended (i.e. stricter) act on protection of personal information in Japan as well as efficiency within the available budget. The networking for biological dosimetry is now expanding by involving Asian countries. The council decided to participate in the second ARADOS WG03 intercomparison exercise which will be conducted by China in 2018. The chromosome network council is becoming increasingly active through recruitment of younger members as well as experienced experts and by having a wider and substantial collaboration with Asian countries. Biological dosimetry network in China The Biodose Network in China was initiated in 2003, by the National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention (China CDC), in order to assess the national capability of biodosimetry, standardize and harmonize the biological dose estimation procedure and its quality control for the medical preparation for the nuclear accident or radiation emergency. The main work of the Biological Dose Network in China focuses on technical training on composing biodosimetry standards, organizing national biodosimetry interlaboratory comparisons and selecting biodosimetry reference laboratories. From 2004 to 2014, five national biodosimetry technique training courses were carried out in Beijing (2004, 2008, 2009), in Changchun city (2012) and in Suzhou city (2014). In total, 213 attendees were trained during these courses. The content of the training courses was not only focused on traditional biodosimetry techniques such as DCA and CBMN assay but also included new developing techniques such as PCC assay FISH assay, gene expression assay and analysis of γH2AX foci and nucleoplasmic bridges. Biodosimetry has been presented at the annual national training courses on Medical Response to Radiation Emergency since 1997. Four national occupational standards or health field standards, including DCA, CBMN, FISH and single-cell gel electrophoresis for biological dose estimation have been issued. A standard on PCC rings for dose estimation will be issued in the near future. Until now, national interlaboratory comparisons focusing on DCA have been organized 10 times and these were held in 2003, 2007, 2010, 2011, 2012, 2014, 2015, 2016 and 2017. At the beginning, in 2003, only seven laboratories participated in this intercomparison; since then, the number of laboratories has increased to 48 in 2017. At least one laboratory in each province, autonomous region or special administrative region took part in the 2017 national interlaboratory comparison, except Macau, Tibet, Heilongjiang, Qinghai, Ningxia and Hainan. The participating laboratories came from universities, research institutes and provincial or municipal centers of disease control and prevention. The rate of qualified laboratories has been gradually increasing. Before 2012, the exercises focused on the identification of dicentric chromosomes. Since 2014, the whole process, including cell culture of human peripheral blood cells, chromosome preparation, dicentric scoring and dose estimation has been compared and tested. Biodosimetry reference laboratories have been selected since 2016. There are four laboratories, which have applied to become a biodosimetry reference laboratory. A list with the qualified reference laboratories will be publicized in the near future. The Chinese Biodose Network participated in activities of the Asian Biodosimetry Network and twice joined the Asian interlaboratory comparisons. In 2017, three laboratories from China joined the intercomparison of biological dosimetry organized by the Asian Radiation Dosimetry Group (ARADOS). LBDNet—the Latin American biological dosimetry network The LBDNet, established in 2007, is a consortium of reference laboratories. The integration of LBDNet is based on a voluntary and consensual participation of seven laboratories responsible for biological dosimetry from Argentina, Brazil, Chile, Cuba, Mexico, Peru and Uruguay. Laboratories from Bolivia, Costa Rica, Ecuador, Paraguay, Venezuela and an associated laboratory from Brazil have recently joined the LBDNet activities. Representation of laboratories is solely institutional, not personal. All the laboratories of the network work within national emergency response systems, which is relevant for the network mission, the operational actions, the research activities and the maintenance of the LBDNet laboratories. At the international level, the network cooperates with REMPAN/WHO-Global Biodosimetry Laboratories Network and with the IAEA Incident and Emergency Centre (IEC), in the frame of the Convention of Early Notification of a Nuclear Accident and the Convention on Assistance in the Case of a Nuclear Accident or Radiological Emergency. The LBDNet mission is (1) to strength the service capacities of Biological Dosimetry laboratories existing in the region to provide an early biodosimetric response for mutual assistance, (2) to provide support to other Latin American countries that do not have biological dosimetry laboratories and (3) to work cooperatively and articulately with other international networks. Most of the laboratories have other dosimetric techniques established besides the DCA assay. These comprise the CBMN assay, FISH technique, PCC-ring (PCC-r) induction and the H2AX assay. Since the establishment of the LBDNet, nine meetings and courses have been organized, supported by IAEA Regional Projects RLA9054, RLA9061, RLA9074 and RLA9076. Individual training was carried out within the region or in the biological dosimetry laboratories of Spain, Greece and France. Additionally, nine interlaboratory comparisons were performed, involving: (1) DCA applying conventional and triage scoring criteria evaluating interlaboratory reproducibility and intralaboratory repeatability using robust methods(23), (2) Interlaboratory comparison of the DCA using electronically transmitted images(24), (3) Joint IAEA, PAHO and WHO Exercise ‘ShipEx-1’ on the intracontinental and intercontinental shipment of blood samples for biodosimetry assessment(25), (4) quality parameters in microscopic image acquisition, (5) exercise on harmonization and intercomparison using PCC-r test for dose estimation in high dose exposures situations, (6) exercise for the development of calibration curves based on PCC-r images, (7) micronuclei images and slides for rapid screening in accidents involving mass-casualties, (8) participation in EU interlaboratory comparisons within the project ‘Realizing the European Network of Biodosimetry (RENEB)’ 2014–15(19) and (9) multiparametric intercomparison in physical, biological, retrospective and computational dosimetry in a simulated scenario of accidental exposure in industrial gamma radiography. The experience gained by intercomparisons, training activities, courses and meetings has allowed the region to be prepared to produce an effective and coordinated response in cases of radiological or nuclear emergencies. Nevertheless, improvements in scoring criteria, sustainable integration of research activities, introduction of other techniques for the interpretation of different overexposure scenarios, continuity of training programs and periodic intercomparison exercises are necessary to maintain the operative capacity of the network. Actions for a steady quality assurance and quality control such as the implementation of quality management systems in the network laboratories are to be pursued as future activities within the network. Future challenges on the biodosimetry role in the LBDNet are (1) to expand biodosimetry capability to clinical applications, including evaluation of individual radiosensitivity, (2) to perform long-term health risk studies following radiation exposure (radiation epidemiology)—FISH and EPR (retrospective dose) and (3) to develop new biomarkers. EURADOS WG10—retrospective dosimetry The European Radiation Dosimetry Group, EURADOS, was established in 1981 with the original aim ‘to advance the scientific understanding and the technical development of the dosimetry of ionizing radiation in the fields of radiation protection, radiobiology, radiation therapy and medical diagnosis by the simulation of collaboration between European laboratories, especially those of the European Communities’. Today, EURADOS is a network of over 70 European institutions (Voting Members) and 560 scientists (Associate Members) promoting technical development and implementation of dosimetry techniques and contributing to compatibility and conformity within Europe and worldwide(26). EURADOS Working Group 10, Retrospective Dosimetry, was established in 2009 with the objective of bringing together contacts and collaborations throughout European laboratories with expertise in the area of physical and biological retrospective dosimetry. Recent activities include a number of biological and physical retrospective dosimetry intercomparisons(27)—many carried out in partnership with RENEB and the other networks. In common with most, if not all, of the other networks, intercomparisons are a key component of the WG10 activities, particular as they provide a framework for development and validation of advances to existing and new techniques. Recent development in statistical analysis techniques has resulted in a review of uncertainty estimation methods for biological and physical retrospective dosimetry methods(28) and organization of a CONCERT funded training school on uncertainty analysis techniques, with a view to sharing knowledge regarding best practise in use of the ISO standard methods and more intensive techniques including Bayesian and Monte Carlo modeling, ongoing work is focused on consideration of dose conversion coefficients for physical retrospective dosimetry and on writing a review of biological dosimetry techniques after internal or mixed external and internal exposure. Future work will focus on further development, consolidation, standardization and validation of techniques in partnership with colleagues from across Europe and internationally, underpinning provision of the best possible dosimetry techniques for both routine radiation dosimetry and emergency response. RENEB—the European network for biological and retrospective physical dosimetry The nucleus of the RENEB network was a tripartite pact between the IRSN, PHE and BfS, set up in 2004. Later, from 2012 to 2015, the network Realizing the European network for biological and retrospective physical dosimetry (RENEB) was established with support from the European Commission (EURATOM FP7, GA 295 513) (www.reneb.eu)(29). Project partners were 23 organizations from 16 European countries, most of them had been identified with the help of the ‘TENEB’ survey(30). During the project, the necessary procedures for efficient dose estimation and for the sustainability of the current network have been initiated, tested and established, as follows: Operational network basis with approved assays(31): most of the integrated assays had been identified before and adapted to large-scale scenarios by the MULTIBIODOSE project, EURADOS WG10. Assays included in the operational basis to this moment are DCA, FISH, CBMN, PCC, gamma H2AX, Gene Expression (test phase) and EPR/OSL techniques (partly test phase). Fundamental for the operational basis are interlaboratory comparisons, performed on a regular level. Between 2012 and 2017, several tabletop exercises and practical interlaboratory comparison were performed. While the first interlaboratory comparison in 2013 was for network partners only, the second interlaboratory comparison (2014) was open for interested laboratories beyond Europe and for global networks, such as the WHO BioDoseNet, and members of IAEA's Response Assistance Network (RANET). In this exercise, 42 labs from 31 countries participated with the DCA. At the end of 2015, the third exercise was jointly performed with the EURADOS platform and in 2017, the fourth exercise was accomplished. Each exercise was organized by another partner and had a different focus. Development of the network: a strategy was suggested to continuously develop the network with regard to technological progress and membership. This includes identification, validation and as far as possible integration of new and upcoming technologies and/or new partners. E&T and QA&QM program(32): a program and manual were developed to guarantee harmonized application of the assays and correct calculation of dose estimates by the partners. This includes practical training in partner laboratories, seminars on QA&QM and ISO standards or statistics. The program is mandatory for network partners and open to non-members. Since 2014, nine training courses in partner laboratories were performed with focus on practical performance of particular biological and EPR/OSL techniques. In addition, seminars on statistics, ISO standards, quality assurance and quality management and on metrology were given. Organization structure: a hierarchical, communicational and logistical infrastructure for the network was initiated. In addition, options for sustainability and financing were compiled and the memorandum of understanding (MoU) as the first step for a legal network basis was prepared. Integration in EPR and link to research: contact to national and international organizations such as the WHO and IAEA was initiated for cross linking the network. In 2016, the RENEB network, based on an MoU was signed by 26 organizations from 16 European countries, including BfS/Germany, CEA/France, ENEA/Italy, ICHTJ/Poland, INSP/Romania, IRSN/France, ISS/Italy, IST/Portugal, LAFE/Spain, NCRRP/Bulgaria, NCSRD/Greece, NRPA/Norway, OSSKI/ Hungary, PHE/UK, SERMAS/Spain, CRPR-SU/Sweden, UAB/Spain, UGent/Belgium, UNITUS/Italy, AMVRC/Italy, DIT/Ireland, FZJülich/Germany, INFN/ Italy, RPC/Lithuania, SCK-CEN/Belgium, USA/Spain. Activities within the RENEB project have been published during the project and in a special issue ‘Networking in biological and EPR/OSL dosimetry: the European RENEB platform for emergency preparedness and research’ including 17 articles(33). In 2017, the RENEB association (www.reneb.net) was inaugurated and became an independent legal entity with 10 organizations as decision-making ‘voting members’ (BfS, BIR, PHE, IRSN, NCRRP, SERMAS, CRPR-SU, UAB, UGent, INFN), in 2018, three more voting members (IST, NCSRF, IRBA) joined. The association serves directly and exclusively public benefit, it can be a contractual partner to institutions and organizations. It has to be pointed out that RENEB is not restricted to European organizations or partner from EU countries, membership is open to all interested parties. Beginning of the Asian network of biological dosimetry: ARADOS-WG03 ARADOS (Asian Radiation Dosimetry Group) was started in October 2015 with several young scientists involving the cooperation of three institutes (CIRP, QST-NIRS and KIRAMS), from three Asian countries (China, Japan and South Korea). The purpose of ARADOS is to construct a sustainable network in physical and biological dosimetry in preparation for regional large-scale nuclear and/or radiological emergency situations. Therefore, ARADOS-WG03 (Working group 3) also aimed to establish, harmonize and develop an Asian biological dosimetry network that can be activated in emergency situations. The development and harmonization of the scientific and technical capabilities existing within the ARADOS-WG03 members could also be helpful to other neighboring countries with less or no capacity for biological dosimetry in case of mass-casualties with a large number of victims. Regular members of ARADOS-WG03 are Korea Institute of Radiological and Medical Sciences (KIRAMS) from Seoul/Korea, China Institute of Radiation Protection (CIRP) from Taiyuan/China, National Institute of Radiation Protection (NIRP) from Beijing/China, Nuclear Research Institute (NRI) from Dalat/Vietnam, and the National Institute of Radiological Sciences (QST-NIRS) from Chiba/Japan, which is both a regular members of ARADOS-WG03 and associated with the Japanese Chromosome Network. The first intercomparison exercise was successfully carried out by 11 laboratories from 4 countries with three galleries of electronically transmitted metaphase images in August 2017. Participants were the biological dosimetry laboratories of Asian institutes, the five regular menbers of ARADOS-WG03 and the six new participants which are associated with the Japanese Chromosome Network, as Hirosaki University/Japan, Radiation Effect Research Foundation (RERF) from Hiroshima/Japan, Fukushima Medical University/Japan, Nagasaki University/Japan and Osaka Prefac. University/Japan. GLOBAL INFORMAL NETWORKS GHSI initiative to establish a laboratory network for radionuclide bioassay The GHSI is an informal, worldwide network of countries formed in 2001 to ensure health sector exchange and coordination of practices in confronting risks to global health posed by chemical, biological and radionuclear threats, as well as by pandemic influenza(34). The member countries/organizations of the GHSI are Canada, France, Germany, Italy, Japan, Mexico, UK, USA and the European commission. The WHO is a technical advisor. The GHSI Rad-Nuc Threats Working Group (RNWG) was created to facilitate sharing and collaboration on policies and capability development to enhance public health preparedness and response to radiological and nuclear threats. As a result of discussions and consultations, the RNWG proposes to establish a laboratory network to improve our collective surge capacity for radionuclide bioassay within the GHSI community. Within this network, laboratories can share their expertise through training activities, exercise their preparedness through intercomparisons, develop new capabilities through collaborative R&D and assist in bioassay analysis when multiple laboratories are required following an emergency. In 2013, the network laboratories were surveyed on their current capabilities in emergency radionuclide bioassay and the technological and operational gaps they had identified in this area. Based on the survey results, the RNWG conducted two exercises. The first exercise was organized in 2014 to test the participating laboratories (eight from seven countries) for their response capabilities in assaying a single radionuclide (241Am) in a urine sample, performing internal dose assessment and providing advice on medical intervention when necessary(35), while the second exercise was organized in early 2016(36) to test the participating laboratories (18 from 16 countries including laboratories contributing to the WHO REMPAN (Radiation Emergency Medical Preparedness and Assistance Network, World Health Organization)(37)—and IAEA RANET database(38)—networks) for their response capabilities in assaying multiple radionuclides (90 Sr, 106Ru, 137Cs, 239Pu) in a single urine sample, focusing on the procedures and methods/techniques used and the results obtained by the participating laboratories.(36) Some laboratories from the collaborating centers or liaison institutions of the WHO REMPAN and two laboratories that had registered their bioassay capabilities in the IAEA RANET participated in the second exercise as well. Results for the two exercises, including gaps identified, have been published(35, 38). A workshop may be organized to allow exercise participating laboratories (and other interested ones) to further discuss the findings/gaps and to plan out the next steps; and hand-on training sessions may be coordinated to facilitate learning for the individuals and/or laboratories that have interest. INTERNATIONAL ASSOCIATION OF BIOLOGICAL AND EPR RADIATION DOSIMETRY The International Association of Biological and EPR Radiation Dosimetry (IABERD, http://iaberd.org/) is a scientific association, established to advance research, development and education in the biological dosimetry and EPR dosimetry applied to ionizing radiation. The aim of IABERD is to stimulate and coordinate biological and EPR radiation dosimetry activities around the world, with two major objectives: to hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields. Scientific meetings of IABERD are held every 2 or 3 years and are also open to non-members. These meetings provide opportunities for the presentation of original communications, demonstrations and symposia. The meetings can also be organized by a host member in collaboration and under supervision of the IABERD committee. Among others, IABERD contributes to the financial security for the scientific meetings, selecting the venue of each scientific meeting, providing start-up funds and support funds for each scientific meeting if requested by the local organizing committee, providing additional assistance, where possible, as requested by the local organizing committee, selecting or approving the members of the scientific advisory committee for each scientific meeting and selecting or approving the mode of publication, the refereeing standards and the publishers, of the proceedings of each scientific meeting. Conferences have been organized 2006 in Washington-Bethesda, 2008 in Hanover/New Hampshire, 2010 in Mandelieu-Lanapoule/France and 2013 in Leiden/The Netherlands. In 2015, the meeting was again held in Hanover/New Hampshire in combination with the International Symposium on EPR Dosimetry and Dating, the International Conference on Biodosimetry and with a symposium of the International EPR Society. The primary focus of this conference was on medical response to events in which large numbers of individuals may be exposed to significant levels of ionizing radiation; topics included biodosimetry techniques, radiation mitigators and model systems to develop countermeasures, new data from different exposure events and the implication of these methods in a radiological emergency or in terrorist attack scenarios. The EPRBioDose 2018 in Munich/Germany covered aspects of biomarkers, biological and EPR dosimetry for medicine, radiological emergency and epidemiology as well as EPR dating and dosimetry networks including quality assurance and management. WHO BioDoseNet Establishment of this network resulted from of a consultation held at the WHO headquarters in Geneva in 2007(39). The main purpose of BioDoseNet (BDN) is to facilitate a global network that brings together several smaller regional or national groups described above with the key objectives of fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building. The ultimate goal of this collaboration would be provision of support in case of a large radiological or nuclear emergency, where a number of persons requiring biological dosimetry would outweigh country’s national capacity. BDN membership therefore includes a wide range of laboratories from well-advanced reference labs that are partners in the regional/national networks to more isolated laboratories, often less advanced and from lesser developed countries, which have no other formalized international partnership. For latter category of labs, BioDoseNet provides an access to expertise and information worldwide. More detailed information on the structure, functions and setup of BioDoseNet is provided elsewhere(17, 39, 40). Wilkins et al.(18) provided the most recent update of BioDoseNet capacities, at the time comprising 67 laboratories, including some statistical analysis of number of trained staff available, available assays and number of samples that can be handled by a given laboratory. Bearing in mind that a number of the laboratories are also members of the smaller regional or national networks this survey provides a unique view of the global status of biodosimetry. In addition, the WHO BioDoseNet complements the RANET, established by the IAEA. RANET is a network, set up by formal agreements at the governmental level, to provide expert assistance, if requested by a country experiencing a radiological or nuclear emergency. The scope of the assistance covered by RANET includes several emergency assistance types, including among others biodosimetry and medical response. Some laboratories enlisted under RANET for provision of assistance are also members of BioDoseNet. By contrast, BioDoseNet is an informal arrangement, made at the laboratory/institutional level with the main focus of activities on building relevant capacities in countries, facilitating international cooperation for harmonization of methods, improving quality assurance, information sharing and training. In the event of a major radiological or nuclear emergency, the response assistance could be facilitated through a formal request via RANET. Depending on the scale, and geographical location of the accident, and availability of the support through RANET, the BioDoseNet laboratories may prove useful in sharing the burden of dose assessment through exchanging samples or images for scoring aberrations, whilst in some circumstances the existing regional or national network response will suffice. For the countries with no established formal links with RANET, and in case of a RANET assistant being insufficient, BioDoseNet labs can be called upon as a complementary to the RANET response. The communication in this case would be handled between WHO and IAEA secretariats. Even though, this scenario has neither been tested in real emergencies, nor in an exercise, there are clear links for communication and liaison between BioDoseNet and RANET and the other networking structures so that, whatever the event, and wherever it occurs, the international biodosimetry community should be able to mobilize its combined resources in the most effective manner. An overview of operational biological and physical retrospective dosimetry networks for emergency preparedness and response and networks contributing to biological and physical retrospective dosimetry is given in Table 1. Table 1. Networks dealing with/including biodosimetry. Operational biological and physical retrospective dosimetry networks for EPR Network name Start Countries/regions Partners Assays applied in the operational networks DCAa FISHb PCCc CBMNd Gamma H2AX Gene expression Other North American Network 2002 Canada, USA 5 MA A A DCA quick scan; high-throughput imaging flow cytometry Chromosome network council Japan 2002 Japan 7 MA A A A Biodose Network in China 2003 China 48 MA A A A A TP Single-cell gel electrophoresis, nucleoplasmic bridges Latin American Biological Dosimetry Network (LBDNet) 2007 Latin American 13 MA A A A A RENEB-MoU 2012 Europe 26 MA A A A A TP EPRe, OSLf techniques RENEB e.V. 2017 Europe (+) 11 ARADOS-WG03 2015 Asia (South Korea, Vietnam, China, Japan) 10 MA A A A aDCA, dicentric chromosome assay; bFISH, fluorescence in situ hybridization assay; cPCC, premature chromosome condensation assay, dCBMN, cytokinesis-block micronucleus assay; eEPR, electron paramagnetic resonance dosimetry; fOSL, optically stimulated luminescence dosimetry. MA, most applied assay for dose estimation; A, assay applied for dose estimation (not all partners); TP, assay in test phase. Operational biological and physical retrospective dosimetry networks for EPR Network name Start Countries/regions Partners Assays applied in the operational networks DCAa FISHb PCCc CBMNd Gamma H2AX Gene expression Other North American Network 2002 Canada, USA 5 MA A A DCA quick scan; high-throughput imaging flow cytometry Chromosome network council Japan 2002 Japan 7 MA A A A Biodose Network in China 2003 China 48 MA A A A A TP Single-cell gel electrophoresis, nucleoplasmic bridges Latin American Biological Dosimetry Network (LBDNet) 2007 Latin American 13 MA A A A A RENEB-MoU 2012 Europe 26 MA A A A A TP EPRe, OSLf techniques RENEB e.V. 2017 Europe (+) 11 ARADOS-WG03 2015 Asia (South Korea, Vietnam, China, Japan) 10 MA A A A aDCA, dicentric chromosome assay; bFISH, fluorescence in situ hybridization assay; cPCC, premature chromosome condensation assay, dCBMN, cytokinesis-block micronucleus assay; eEPR, electron paramagnetic resonance dosimetry; fOSL, optically stimulated luminescence dosimetry. MA, most applied assay for dose estimation; A, assay applied for dose estimation (not all partners); TP, assay in test phase. Networks contributing to biological and physical retrospective dosimetry Network name Start Countries/regions Motivation EURADOS WG10 2009 global To maintain a network of laboratories with expertise in biological and physical retrospective dosimetry. This enables specialist groups to be formed in a timely manner to address research issues and contribute to strategic research agendas GHSI Rad-Nuc Threats Working Group (RNWG) 2001 global Informal network to facilitate sharing and collaboration on policies and capability development and to enhance public health preparedness and response to radiological and nuclear threats IABERD 2005 global To hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields WHO BioDoseNet 2007 global To facilitate worldwide networking by fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building Networks contributing to biological and physical retrospective dosimetry Network name Start Countries/regions Motivation EURADOS WG10 2009 global To maintain a network of laboratories with expertise in biological and physical retrospective dosimetry. This enables specialist groups to be formed in a timely manner to address research issues and contribute to strategic research agendas GHSI Rad-Nuc Threats Working Group (RNWG) 2001 global Informal network to facilitate sharing and collaboration on policies and capability development and to enhance public health preparedness and response to radiological and nuclear threats IABERD 2005 global To hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields WHO BioDoseNet 2007 global To facilitate worldwide networking by fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building Table 1. Networks dealing with/including biodosimetry. Operational biological and physical retrospective dosimetry networks for EPR Network name Start Countries/regions Partners Assays applied in the operational networks DCAa FISHb PCCc CBMNd Gamma H2AX Gene expression Other North American Network 2002 Canada, USA 5 MA A A DCA quick scan; high-throughput imaging flow cytometry Chromosome network council Japan 2002 Japan 7 MA A A A Biodose Network in China 2003 China 48 MA A A A A TP Single-cell gel electrophoresis, nucleoplasmic bridges Latin American Biological Dosimetry Network (LBDNet) 2007 Latin American 13 MA A A A A RENEB-MoU 2012 Europe 26 MA A A A A TP EPRe, OSLf techniques RENEB e.V. 2017 Europe (+) 11 ARADOS-WG03 2015 Asia (South Korea, Vietnam, China, Japan) 10 MA A A A aDCA, dicentric chromosome assay; bFISH, fluorescence in situ hybridization assay; cPCC, premature chromosome condensation assay, dCBMN, cytokinesis-block micronucleus assay; eEPR, electron paramagnetic resonance dosimetry; fOSL, optically stimulated luminescence dosimetry. MA, most applied assay for dose estimation; A, assay applied for dose estimation (not all partners); TP, assay in test phase. Operational biological and physical retrospective dosimetry networks for EPR Network name Start Countries/regions Partners Assays applied in the operational networks DCAa FISHb PCCc CBMNd Gamma H2AX Gene expression Other North American Network 2002 Canada, USA 5 MA A A DCA quick scan; high-throughput imaging flow cytometry Chromosome network council Japan 2002 Japan 7 MA A A A Biodose Network in China 2003 China 48 MA A A A A TP Single-cell gel electrophoresis, nucleoplasmic bridges Latin American Biological Dosimetry Network (LBDNet) 2007 Latin American 13 MA A A A A RENEB-MoU 2012 Europe 26 MA A A A A TP EPRe, OSLf techniques RENEB e.V. 2017 Europe (+) 11 ARADOS-WG03 2015 Asia (South Korea, Vietnam, China, Japan) 10 MA A A A aDCA, dicentric chromosome assay; bFISH, fluorescence in situ hybridization assay; cPCC, premature chromosome condensation assay, dCBMN, cytokinesis-block micronucleus assay; eEPR, electron paramagnetic resonance dosimetry; fOSL, optically stimulated luminescence dosimetry. MA, most applied assay for dose estimation; A, assay applied for dose estimation (not all partners); TP, assay in test phase. Networks contributing to biological and physical retrospective dosimetry Network name Start Countries/regions Motivation EURADOS WG10 2009 global To maintain a network of laboratories with expertise in biological and physical retrospective dosimetry. This enables specialist groups to be formed in a timely manner to address research issues and contribute to strategic research agendas GHSI Rad-Nuc Threats Working Group (RNWG) 2001 global Informal network to facilitate sharing and collaboration on policies and capability development and to enhance public health preparedness and response to radiological and nuclear threats IABERD 2005 global To hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields WHO BioDoseNet 2007 global To facilitate worldwide networking by fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building Networks contributing to biological and physical retrospective dosimetry Network name Start Countries/regions Motivation EURADOS WG10 2009 global To maintain a network of laboratories with expertise in biological and physical retrospective dosimetry. This enables specialist groups to be formed in a timely manner to address research issues and contribute to strategic research agendas GHSI Rad-Nuc Threats Working Group (RNWG) 2001 global Informal network to facilitate sharing and collaboration on policies and capability development and to enhance public health preparedness and response to radiological and nuclear threats IABERD 2005 global To hold and arrange courses and meetings on matters connected to these fields and to promote the diffusion and exchange of information among people interested in these fields WHO BioDoseNet 2007 global To facilitate worldwide networking by fostering collaboration, harmonization of laboratory techniques and dose assessment methods, information sharing and capacity building CONCLUSIONS Biological and retrospective physical dosimetry is needed in the case of various exposure scenarios, especially in the case of unknown or conflicting irradiation situations. The results gained by these techniques are generally well accepted by affected persons, due to the individual aspect of the applied methods. To be prepared for large-scale radiological incidents, biodosimetry laboratories of different countries have joined forces and established regional and/or global networks, either on a formal or informal basis. This approach has already resulted in a significant increase in the efficiency of dose estimation with regard to analysis capacity and capabilities. Different radiation exposure scenarios can be handled according to their specific characteristics and needs by choosing the best available techniques and approaches for dose estimation. The precision of dose estimates is fundamental for successful cooperation between laboratories and especially for the credibility of the networks. In addition, the reliability of the supporting infrastructure, for example, for shipment of samples and secure communication of the results is also essential, especially for networking. To facilitate this, to test and guarantee the high quality and consistency of the partner laboratories, regular interlaboratory comparisons and exercises are performed by the networks. For sustainability, reliability and efficiency in real radiological disasters, the utilization of established networks within existing national and international EPR systems is urgently required. This necessity is becoming increasingly urgent, as currently, several countries worldwide are closing their national biodosimetry laboratories for financial reasons (e.g. laboratories in Germany, Finland, Canada). 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Radiation Protection Dosimetry – Oxford University Press

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