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Purpose: In the framework of the 'Realizing the European Network of Biodosimetry' (RENEB) project, two intercomparison exercises were conducted to assess the suitability of an optimized version of the cytokinesis-block micronucleus assay, and to evaluate the capacity of a large laboratory network performing biodosimetry for radiation emergency triages. Twelve European institutions participated in the first exercise, and four non-RENEB labs were added in the second one., Materials and Methods: Irradiated blood samples were shipped to participating labs, whose task was to culture these samples and provide a blind dose estimate. Micronucleus analysis was performed by automated, semi-automated and manual procedures., Results: The dose estimates provided by network laboratories were in good agreement with true administered doses. The most accurate estimates were reported for low dose points (≤ 0.94 Gy). For higher dose points (≥ 2.7 Gy) a larger variation in estimates was observed, though in the second exercise the number of acceptable estimates increased satisfactorily. Higher accuracy was achieved with the semi-automated method., Conclusion: The results of the two exercises performed by our network demonstrate that the micronucleus assay is a useful tool for large-scale radiation emergencies, and can be successfully implemented within a large network of laboratories.

Purpose: Dose assessment intercomparisons within the RENEB network were performed for triage biodosimetry analyzing G 0 -lymphocyte PCC for harmonization, standardization and optimization of the PCC assay., Materials and Methods: Comparative analysis among different partners for dose assessment included shipment of PCC-slides and captured images to construct dose-response curves for up to 6 Gy γ-rays. Accident simulation exercises were performed to assess the suitability of the PCC assay by detecting speed of analysis and minimum number of cells required for categorization of potentially exposed individuals., Results: Calibration data based on Giemsa-stained fragments in excess of 46 PCC were obtained by different partners using galleries of PCC images for each dose-point. Mean values derived from all scores yielded a linear dose-response with approximately 4 excess-fragments/cell/Gy. To unify scoring criteria, exercises were carried out using coded PCC-slides and/or coded irradiated blood samples. Analysis of samples received 24 h post-exposure was successfully performed using Giemsa staining (1 excess-fragment/cell/Gy) or centromere/telomere FISH-staining for dicentrics., Conclusions: Dose assessments by RENEB partners using appropriate calibration curves were mostly in good agreement. The PCC assay is quick and reliable for whole- or partial-body triage biodosimetry by scoring excess-fragments or dicentrics in G 0 -lymphocytes. Particularly, analysis of Giemsa-stained excess PCC-fragments is simple, inexpensive and its automation could increase throughput and scoring objectivity of the PCC assay.

Purpose: The RENEB accident exercise was carried out in order to train the RENEB participants in coordinating and managing potentially large data sets that would be generated in case of a major radiological event., Materials and Methods: Each participant was offered the possibility to activate the network by sending an alerting email about a simulated radiation emergency. The same participant had to collect, compile and report capacity, triage categorization and exposure scenario results obtained from all other participants. The exercise was performed over 27 weeks and involved the network consisting of 28 institutes: 21 RENEB members, four candidates and three non-RENEB partners., Results: The duration of a single exercise never exceeded 10 days, while the response from the assisting laboratories never came later than within half a day. During each week of the exercise, around 4500 samples were reported by all service laboratories (SL) to be examined and 54 scenarios were coherently estimated by all laboratories (the standard deviation from the mean of all SL answers for a given scenario category and a set of data was not larger than 3 patient codes)., Conclusions: Each participant received training in both the role of a reference laboratory (activating the network) and of a service laboratory (responding to an activation request). The procedures in the case of radiological event were successfully established and tested.

Purpose: Reliable dose estimation is an important factor in appropriate dosimetric triage categorization of exposed individuals to support radiation emergency response., Materials and Methods: Following work done under the EU FP7 MULTIBIODOSE and RENEB projects, formal methods for defining uncertainties on biological dose estimates are compared using simulated and real data from recent exercises., Results: The results demonstrate that a Bayesian method of uncertainty assessment is the most appropriate, even in the absence of detailed prior information. The relative accuracy and relevance of techniques for calculating uncertainty and combining assay results to produce single dose and uncertainty estimates is further discussed., Conclusions: Finally, it is demonstrated that whatever uncertainty estimation method is employed, ignoring the uncertainty on fast dose assessments can have an important impact on rapid biodosimetric categorization.

Purpose: A European network was initiated in 2012 by 23 partners from 16 European countries with the aim to significantly increase individualized dose reconstruction in case of large-scale radiological emergency scenarios., Results: The network was built on three complementary pillars: (1) an operational basis with seven biological and physical dosimetric assays in ready-to-use mode, (2) a basis for education, training and quality assurance, and (3) a basis for further network development regarding new techniques and members. Techniques for individual dose estimation based on biological samples and/or inert personalized devices as mobile phones or smart phones were optimized to support rapid categorization of many potential victims according to the received dose to the blood or personal devices. Communication and cross-border collaboration were also standardized. To assure long-term sustainability of the network, cooperation with national and international emergency preparedness organizations was initiated and links to radiation protection and research platforms have been developed. A legal framework, based on a Memorandum of Understanding, was established and signed by 27 organizations by the end of 2015., Conclusions: RENEB is a European Network of biological and physical-retrospective dosimetry, with the capacity and capability to perform large-scale rapid individualized dose estimation. Specialized to handle large numbers of samples, RENEB is able to contribute to radiological emergency preparedness and wider large-scale research projects.

Purpose: The European Network of Biological and Physical Retrospective Dosimetry 'RENEB' has contributed to European radiation emergency preparedness. To give homogeneous dose estimation results, RENEB partners must harmonize their processes., Materials and Methods: A first inter-comparison focused on biological and physical dosimetry was used to detect the outliers in terms of dose estimation. Subsequently, trainings were organized to improve both tools dose estimation. A second inter-comparison was performed to validate training efficiency. Simultaneously, based on ISO standards, a QA&QM manual on all dosimetry assays was produced which states a common basis and harmonized procedures for each assay. The evaluation of the agreement of RENEB partners to follow the QA&QM manual was performed through a questionnaire. The integration of new members into the network was carried out in the same way, whatever the assays., Results: The training courses on biological and physical dosimetry were judged to be successful because most of the RENEB members' dose estimates improved in the second inter-comparison. The QA&QM manual describes the consensus for the minimum requirements and the performance criteria for both dosimetry assays. The questionnaire revealed that the whole network capacity currently can manage between 15 and 3800 samples once., Conclusion: The methodology used to harmonize all dosimetry practice within the network RENEB was highly successful. The network is operational to manage a mass casualty radiation accident for immediate dose assessment.

Purpose: To identify and assess, among the participants in the RENEB (Realizing the European Network of Biodosimetry) project, the emergency preparedness, response capabilities and resources that can be deployed in the event of a radiological or nuclear accident/incident affecting a large number of individuals. These capabilities include available biodosimetry techniques, infrastructure, human resources (existing trained staff), financial and organizational resources (including the role of national contact points and their articulation with other stakeholders in emergency response) as well as robust quality control/assurance systems., Materials and Methods: A survey was prepared and sent to the RENEB partners in order to acquire information about the existing, operational techniques and infrastructure in the laboratories of the different RENEB countries and to assess the capacity of response in the event of radiological or nuclear accident involving mass casualties. The survey focused on several main areas: laboratory's general information, country and staff involved in biological and physical dosimetry; retrospective assays used, the number of assays available per laboratory and other information related to biodosimetry and emergency preparedness. Following technical intercomparisons amongst RENEB members, an update of the survey was performed one year later concerning the staff and the available assays., Conclusions: The analysis of RENEB questionnaires allowed a detailed assessment of existing capacity of the RENEB network to respond to nuclear and radiological emergencies. This highlighted the key importance of international cooperation in order to guarantee an effective and timely response in the event of radiological or nuclear accidents involving a considerable number of casualties. The deployment of the scientific and technical capabilities existing within the RENEB network members seems mandatory, to help other countries with less or no capacity for biological or physical dosimetry, or countries overwhelmed in case of a radiological or nuclear accident involving a large number of individuals.

Purpose: In the frame of the QA program of RENEB, an inter-laboratory comparison (ILC) of calibration sources used in biological dosimetry was achieved to investigate the influence of calibration practices and protocols on the results of the dose estimation performance as a first step to harmonization and standardization of dosimetry and irradiation practices in the European biological dosimetry network., Materials and Methods: Delivered doses by irradiation facilities used by RENEB partners were determined with EPR/alanine dosimetry system. Dosimeters were irradiated in the same conditions as blood samples. A short survey was also performed to collect the information needed for the data analysis and evaluate the diversity of practices., Results: For most of partners the deviation of delivered dose from the targeted dose remains below 10%. Deviations larger than 10% were observed for five facilities out of 21. Origins of the largest discrepancies were identified. Correction actions were evaluated as satisfactory. The re-evaluation of some ILC results for the fluorescence in situ hybridization (FISH) and premature chromosome condensation (PCC) assays has been performed leading to an improvement of the overall performances., Conclusions: This work has shown the importance of dosimetry in radiobiology studies and the needs of harmonization, standardization in irradiation and dosimetry practices and educational training for biologists using ionizing radiation.

Purpose: To set up an operational basis of the Realizing the European Network of Biodosimetry (RENEB) network within which the application of seven established biodosimetric tools (the dicentric assay, the FISH assay, the micronucleus assay, the PCC assay, the gamma-H2AX assay, electron paramagnetic resonance and optically stimulated luminescence) will be compared and standardized among the participating laboratories., Methodology: Two intercomparisons were organized where blood samples and smartphone components were irradiated, coded and sent out to participating laboratories for dosimetric analysis. Moreover, an accident exercise was organized during which each RENEB partner had the chance to practice the procedure of activating the network and to handle large amounts of dosimetric results., Results: All activities were carried out as planned. Overall, the precision of dose estimates improved between intercomparisons 1 and 2, clearly showing the value of running such regular activities., Conclusions: The RENEB network is fully operational and ready to act in case of a major radiation emergency. Moreover, the high capacity for analyzing radiation-induced damage in cells and personal electronic devices makes the network suitable for large-scale analyses of low doses effects, where high numbers of samples must be scored in order to detect weak effects.

Purpose: Within the EU RENEB project, seven laboratories have taken part in training and harmonisation activities to strengthen triage gamma-H2AX-based radiation exposure assessment. This has culminated in a second triage biodosimetry exercise., Materials and Methods: Whole blood and separated lymphocyte samples were homogenously irradiated with 60 Co gamma rays at 0.5, 2.5 (blind samples), 0 and 2 Gy (reference samples). Following post-exposure incubations of 4 and 24 h, 16 samples were shipped on ice packs to each partner. The samples were stained and scored for gamma-H2AX foci, using manual and/or automated fluorescence microscope scoring strategies. Dose estimates were obtained and used to assign triage categories to the samples., Results: Average dose estimates across all the laboratories correlated well with true doses. The most accurate assignment of triage category was achieved by manual scoring of the 4-h blood and lymphocyte samples. Only three samples out of a total of 46 were miscategorized in a way that could have adversely effected the clinical management of a radiation casualty., Conclusions: This inter-comparison exercise has demonstrated that following a recent acute radiation exposure, the gamma-H2AX assay could be a useful triage tool that can be successfully applied across a network of laboratories.

Purpose: Two quality controlled inter-laboratory exercises were organized within the EU project 'Realizing the European Network of Biodosimetry (RENEB)' to further optimize the dicentric chromosome assay (DCA) and to identify needs for training and harmonization activities within the RENEB network., Materials and Methods: The general study design included blood shipment, sample processing, analysis of chromosome aberrations and radiation dose assessment. After manual scoring of dicentric chromosomes in different cell numbers dose estimations and corresponding 95% confidence intervals were submitted by the participants., Results: The shipment of blood samples to the partners in the European Community (EU) were performed successfully. Outside the EU unacceptable delays occurred. The results of the dose estimation demonstrate a very successful classification of the blood samples in medically relevant groups. In comparison to the 1st exercise the 2nd intercomparison showed an improvement in the accuracy of dose estimations especially for the high dose point., Conclusions: In case of a large-scale radiological incident, the pooling of ressources by networks can enhance the rapid classification of individuals in medically relevant treatment groups based on the DCA. The performance of the RENEB network as a whole has clearly benefited from harmonization processes and specific training activities for the network partners.

In the event of a large-scale radiological emergency, the triage of individuals according to their degree of exposure forms an important initial step of the accident management. Although clinical signs and symptoms of a serious exposure may be used for radiological triage, they are not necessarily radiation specific and can lead to a false diagnosis. Biodosimetry is a method based on the analysis of radiation-induced changes in cells of the human body or in portable electronic devices and enables the unequivocal identification of exposed people who should receive medical treatment. The MULTIBIODOSE (MBD) consortium developed and validated several biodosimetric assays and adapted and tested them as tools for biological dose assessment in a mass-casualty event. Different biodosimetric assays were validated against the 'gold standard' of biological dosimetry-the dicentric assay. The assays were harmonised in such a way that, in an emergency situation, they can be run in parallel in a network of European laboratories. The aim of this guidance is to give a concise overview of the developed biodosimetric tools as well as how and when they can be used in an emergency situation., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The identification of severely exposed individuals and reassurance of the 'worried well' are of prime importance for initial triage following a large scale radiation accident. We aim to develop the γ-H2AX foci assay into a rapid biomarker tool for use in accidents. Here, five laboratories established a standard operating procedure and analysed 100 ex vivo γ-irradiated, 4 or 24h incubated and overnight-shipped lymphocyte samples from four donors to generate γ-H2AX reference data, using manual and/or automated foci scoring strategies. In addition to acute, homogeneous exposures to 0, 1, 2 and 4Gy, acute simulated partial body (4Gy to 50% of cells) and protracted exposures (4Gy over 24h) were analysed. Data from all laboratories could be satisfactorily fitted with linear dose response functions. Average yields observed at 4h post exposure were 2-4 times higher than at 24h and varied considerably between laboratories. Automated scoring caused larger uncertainties than manual scoring and was unable to identify partial exposures, which were detectable in manually scored samples due to their overdispersed foci distributions. Protracted exposures were detectable but doses could not be accurately estimated with the γ-H2AX assay. We conclude that the γ-H2AX assay may be useful for rapid triage following a recent acute radiation exposure. The potentially higher speed and convenience of automated relative to manual foci scoring needs to be balanced against its compromised accuracy and inability to detect partial body exposures. Regular re-calibration or inclusion of reference samples may be necessary to ensure consistent results between laboratories or over long time periods., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)