Dose assessment intercomparisons within the RENEB network using G0-lymphocyte prematurely condensed chromosomes (PCC assay)
Georgia I. TerzoudiGabriel E. PanteliasF. DarroudiKatarzyna BarszczewskaIwona BuraczewskaJulie DepuydtDimka GeorgievaValeria HadjidekovaVasiliki I. HatziIoanna KarachristouMaria KarakostaRoberta MeschiniRadhia M’KacherAlegría MontoroF. PalittiAntonio PanteliasGaetano PepeMichelle RicoulLaure SabatierNatividad SebastiàSylwester SommerAnne VralD. ZafiropoulosAndrzej Wójcik
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Purpose: Dose assessment intercomparisons within the RENEB network were performed for triage biodosimetry analyzing G0-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 G0-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.Keywords:
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Introduction: Mass casualty scenarios of radiation accidents require high throughput techniques of biological dosimetry for population triage to identify individuals for whom clinical treatment is indicated. To this end the dicentric assay in a triage mode is a very suitable technique. Within the MULTIBIODOSE EU FP7 project a network of eight biodosimetry laboratories has been established with expertise in dose estimations based on the dicentric assay. Results: In the first task the conventional dicentric assay was tested in the triage mode. Three types of irradiation scenarios were included: acute whole body, partial body and protracted exposure. Blood samples from 33 healthy donors (> 10 donors / scenario) were irradiated in vitro with gamma rays, simulating the 3 different types of exposure and the 3 different doses. All the blood samples were irradiated at the University of Gent, Belgium, and then shipped to the participating laboratories. The dose estimates of acute whole body exposure show a good agreement with actual radiation doses (0.5, 2.0 and 4.0 Gy) for all labs. Most labs could identify correctly the partial body doses at 4 and 6 Gy, but this was not possible at 2 Gy and indicates a need for more cells to be analysed. After protracted exposure, all labs performed these dose estimations well and attained good results at 1.0 and 2.0 Gy. Conclusions: The results obtained up to now within the MULTIBIODOSE project are very promising for the application of the dicentric assay in triage mode as a high throughput scoring strategy for biodosimetry in case of large scale accidents by a network of eight collaborating laboratories throughout Europe.
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In case of large scale accidental overexposure to ionizing radiation, a rapid triage of the population exposed is needed first, followed by an accurate dose estimation for each individual. Currently, these two steps are performed by scoring unstable chromosomal aberrations (dicentrics, rings and fragments) in peripheral blood lymphocytes after Giemsa staining. For the triage step, only 50 metaphases are currently manually analysed. This is rapid but not accurate and may introduce false negative dose classification. For the second step, 500 metaphases are currently manually analysed. This is very accurate but very long. To improve the method, we have studied the automatic dicentrics detection by Metafer 4 software (MetaSystems) on accidental overexposure victims of the Dakar accident (Africa). The study has been performed firstly by the manual scoring of dicentrics on 50 metaphases (50 MS) used for a population triage, secondly by the manual scoring of dicentrics on 500 metaphases (standard approach; 500 MS) and thirdly by the automatic scoring of dicentrics (ADS). The comparison between dose classification obtained by 50MS and obtained by 500MS methods shows 54.2% (32 on 59 individuals) correlation however there is 45.8% (27 on 59 individuals) of underestimation. Moreover, comparisons of dose classification between the results obtained by ADS and 500MS show 95.7% (44 on 46 individuals) of correlation and 4.3% (2 on 46 individuals) of underestimation. In addition, the mean doses obtained by ADS method are near to the mean doses obtained by 500MS. To conclude, ADS method is faster and more accurate than the manual scoring of 50 cells and could be used in case of triage. In addition, ADS method could also be used instead of 500MS in case of individual dose estimation as it is as accurate and much faster.
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A catastrophic event such as a nuclear device detonation in a major U.S. city would cause a mass casualty with millions affected. Such a disaster would require screening to accurately and effectively identify patients likely to develop acute radiation syndrome (ARS). A primary function of such screening is to sort the unaffected, or worried-well, from those patients who will truly become symptomatic. This paper reviews the current capability of high-accuracy biodosimetry methods as screening tools for populations and reviews the current triage and medical guidelines for diagnosing and managing ARS. This paper proposes that current triage categories, which broadly categorize patients by likelihood of survival based on current symptoms, be replaced with new triage categories that use high-accuracy biodosimetry methods. Using accurate whole-body exposure dose assessment to predict ARS symptoms and subsyndromes, clinical decision-makers can designate the appropriate care setting, initiate treatment and therapies, and best allocate limited clinical resources, facilitating mass-casualty care following a nuclear disaster.
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Following large-scale radiation events, an overwhelming number of people will potentially need mitigators or treatment for radiation-induced injuries. This necessitates having methods to triage people based on their dose and its likely distribution, so life-saving treatment is directed only to people who can benefit from such care. Using estimates of victims following an improvised nuclear device striking a major city, we illustrate a two-tier approach to triage. At the second tier, after first removing most who would not benefit from care, biodosimetry should provide accurate dose estimates and determine whether the dose was heterogeneous. We illustrate the value of using in vivo electron paramagnetic resonance nail biodosimetry to rapidly assess dose and determine its heterogeneity using independent measurements of nails from the hands and feet. Having previously established its feasibility, we review the benefits and challenges of potential improvements of this method that would make it particularly suitable for tier 2 triage. Improvements, guided by a user-centered approach to design and development, include expanding its capability to make simultaneous, independent measurements and improving its precision and universality.
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Abstract Following a large-scale radiological incident, there is a need for FDA-approved biodosimetry devices and biomarkers with the ability to rapidly determine past radiation exposure with sufficient accuracy for early population triage and medical management. Towards this goal, we have developed FAST-DOSE ( F luorescent A utomated S creening T ool for Dos im e try), an immunofluorescent, biomarker-based system designed to reconstruct absorbed radiation dose in peripheral blood samples collected from potentially exposed individuals. The objective of this study was to examine the performance of the FAST-DOSE assay system to quantify intracellular protein changes in blood leukocytes for early biodosimetry triage from humanized NOD-scid-gamma (Hu-NSG) mice and non-human primates (NHPs) exposed to ionizing radiation up to 8 days after radiation exposure. In the Hu-NSG mice studies, the FAST-DOSE biomarker panel was able to generate delivered dose estimates at days 1, 2 and 3 post exposure, whereas in the NHP studies, the biomarker panel was able to successfully classify samples by dose categories below or above 2 Gy up to 8 days after total body exposure. These results suggest that the FAST-DOSE bioassay has large potential as a useful diagnostic tool for rapid and reliable screening of potentially exposed individuals to aid early triage decisions within the first week post-exposure.
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The U.S. Department of Defense (USDOD) service members are at risk of exposure to ionizing radiation due to radiation accidents, terrorist attacks and national defense activities. The use of biodosimetry is a standard of care for the triage and treatment of radiation injuries. Resources and procedures need to be established to implement a multiple-parameter biodosimetry system coupled with expert medial guidance to provide an integrated radiation diagnostic system to meet USDOD requirements. Current USDOD biodosimetry capabilities were identified and recommendations to fill the identified gaps are provided. A USDOD Multi-parametric Biodosimetry Network, based on the expertise that resides at the Armed Forces Radiobiology Research Institute and the Naval Dosimetry Center, was designed. This network based on the use of multiple biodosimetry modalities would provide diagnostic and triage capabilities needed to meet USDOD requirements. These are not available with sufficient capacity elsewhere but could be needed urgently after a major radiological/nuclear event.
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Following a mass-casualty nuclear disaster, effective medical triage has the potential to save tens of thousands of lives. In order to best use the available scarce resources, there is an urgent need for biodosimetry tools to determine an individual's radiation dose. Initial triage for radiation exposure will include location during the incident, symptoms, and physical examination. Stepwise triage will include point of care assessment of less than or greater than 2 Gy, followed by secondary assessment, possibly with high throughput screening, to further define an individual's dose. Given the multisystem nature of radiation injury, it is unlikely that any single biodosimetry assay can be used as a standalone tool to meet the surge in capacity with the timeliness and accuracy needed. As part of the national preparedness and planning for a nuclear or radiological incident, the authors reviewed the primary literature to determine the capabilities and limitations of a number of biodosimetry assays currently available or under development for use in the initial and secondary triage of patients. Understanding the requirements from a response standpoint and the capability and logistics for the various assays will help inform future biodosimetry technology development and acquisition. Factors considered include: type of sample required, dose detection limit, time interval when the assay is feasible biologically, time for sample preparation and analysis, ease of use, logistical requirements, potential throughput, point-of-care capability, and the ability to support patient diagnosis and treatment within a therapeutically relevant time point.
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Medical management of radiation emergencies will require quick and reliable biodosimetric tools for assessment of absorbed dose. Dicentric chromosomal assay (Gold standard) has a limitation of being time intensive, requires specialised human skill and cannot be used for triage and mass screening. Dose assessments of suspected individuals are critical for the medical management of radiation emergencies. For effectively utilizing the available resources, there is an urgent need for developing triage biodosimetry tools for determining the exposure status of suspected individuals. High-throughput methods, utilising the novel “omics” science approaches are emerging as new technologies and gene expression-based biodosimetry is considered a promising technique for radiation dose assessment. Gene expression signatures of radiation have demonstrated the potential for triage biodosimetry. It is a minimally invasive, rapid and reliable approach that has the ability to be a robust field-deployable point-of-care high throughput technique. In addition gene expression based biodosimetry can be useful for long-term epidemiological assessment, clinical radiation oncology and radiodiagnosis.
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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.Whole blood and separated lymphocyte samples were homogenously irradiated with 60Co 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.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.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.
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Consideration of statistical methodology is essential for the application of cytogenetic and other biodosimetry techniques to triage for mass casualty situations. This is because the requirement for speed and accuracy in biodosimetric triage necessarily introduces greater uncertainties than would be acceptable in day-to-day biodosimetry. Additionally, in a large scale accident type situation, it is expected that a large number of laboratories from around the world will assist and it is likely that each laboratory will use one or more different dosimetry techniques. Thus issues arise regarding combination of results and the associated errors. In this article we discuss the statistical and computational aspects of radiation biodosimetry for triage in a large scale accident-type situation. The current status of statistical analysis techniques is reviewed and suggestions are made for improvements to these methods which will allow first responders to estimate doses quickly and reliably for suspected exposed persons.
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