Fundamentals of wildlife dosimetry and lessons learned from a decade of measuring external dose rates in the field.

Methods for determining the radiation dose received by exposed biota require major improvements to reduce uncertainties and increase precision. We share our experiences in attempting to quantify external dose rates to free-ranging wildlife using GPS-coupled dosimetry methods. The manuscript is a primer on fundamental concepts in wildlife dosimetry in which the complexities of quantifying dose rates are highlighted, and lessons learned are presented based on research with wild boar and snakes at Fukushima, wolves at Chornobyl, and reindeer in Norway. GPS-coupled dosimeters produced empirical data to which numerical simulations of external dose using computer software were compared. Our data did not support a standing paradigm in risk analyses: Using averaged soil contaminant levels to model external dose rates conservatively overestimate the dose to individuals within a population. Following this paradigm will likely lead to misguided recommendations for risk management. The GPS-dosimetry data also demonstrated the critical importance of how modeled external dose rates are impacted by the scale at which contaminants are mapped. When contaminant mapping scales are coarse even detailed knowledge about each animal's home range was inadequate to accurately predict external dose rates. Importantly, modeled external dose rates based on a single measurement at a trap site did not correlate to actual dose rates measured on free ranging animals. These findings provide empirical data to support published concerns about inadequate dosimetry in much of the published Chernobyl and Fukushima dose-effects research. Our data indicate that a huge portion of that literature should be challenged, and that improper dosimetry remains a significant source of controversy in radiation dose-effect research.

Radiological injuries under low energy x-rays in mice depending on dose and protocol: comparative characterization of lesion severity and impact of thein vivobone response on retrospective dose estimations.

Objective. To improve our knowledge about the biological effects of over exposures involving low-energy x-rays, we developed and characterized a preclinical mouse model allowing to mimic different lesion severity degrees induced by 80 kV x-ray depending on the dose and protocol (single or repeated exposure).Approach. Mice were locally exposed (paw) to 80 kV x-rays in a single (15, 30 or 45 Gy inKair) or repeated exposition (2 × 15 or 3 × 15 Gy inKair) to assess different degrees of lesion severity. Six post-irradiation euthanasia time points (0, 7, 14, 21, 42, and 84 days) were determined to follow up the evolution of lesions based on the lesion score, weighing and cutaneous blood perfusion. The bone dose was estimated at the different time points by electron paramagnetic resonance (EPR) spectroscopy.Main results. The monitoring of the lesion severity allows to classify the exposure protocols according to their severity. EPR spectroscopy measurements allow to determine the bone dose on the day of irradiation which is 7 times higher than the initial dose for single protocols. However, the initial signal measured at the end of the repeated exposure was 27% lower than the signal measured for a single dose. The study of the kinetics of EPR signal showed a decrease of the EPR signal which is dependent on the exposure protocol but not on dose highlighting the impact of bone physiology on the bone dose estimation.Significance: the preclinical model developed allows to assess the impact of the dose and protocol on the lesion severity induced by low-energy x-ray. For the first time, the dynamics of free radicals have been quantified in anin vivomodel, highlighting that the doses actually administered can be underestimated if samples are taken weeks or even months after exposure.

Minimum reporting standards should be expected for preclinical radiobiology irradiators and dosimetry in the published literature.

The cornerstones of science advancement are rigor in performing scientific research, reproducibility of research findings and unbiased reporting of design and results of the experiments. For radiation research, this requires rigor in describing experimental details as well as the irradiation protocols for accurate, precise and reproducible dosimetry. Most institutions conducting radiation biology research in in vitro or animal models do not have describe experimental irradiation protocols in sufficient details to allow for balanced review of their publication nor for other investigators to replicate published experiments. The need to increase and improve dosimetry standards, traceability to National Institute of Standards and Technology (NIST) standard beamlines, and to provide dosimetry harmonization within the radiation biology community has been noted for over a decade both within the United States and France. To address this requirement subject matter experts have outlined minimum reporting standards that should be included in published literature for preclinical irradiators and dosimetry.

Dosimetry of a self-shielded gamma irradiator small animal whole-body irradiations: comparisons between ionisation chamber and alanine.

Because of reproducibility and repeatability problems with reference measurements made with an ionisation chamber in a self-protected GSRD1 irradiator, a comparison was made with alanine dosimetry for a whole-body mouse irradiation setup in a sterile box. The twisting of the cables in the cable duct and in the irradiator cell and the irradiation of the ionisation chamber connector are likely to have caused the problems encountered. These problems are not observed on other types of irradiators with more suitable cable passages. A difference up to 8.4% was observed between the alanine dosimetry and ionisation chamber. The influence of the number of animals in the sterile box on the whole-body dose of the animals was also evaluated with alanine and found to be <2%.

Preclinical modeling of low energy X-rays radiological burn: Dosimetry study by monte carlo simulations and EPR spectroscopy.

Interventional radiology has grown considerably over the last decades and become an essential tool for treatment or diagnosis. This technique is mostly beneficial and mastered but accidental overexposure can occur and lead to the appearance of deterministic effects. The lack of knowledge about the radiobiological consequences for the low-energy X-rays used for these practices makes the prognosis very uncertain for the different tissues. In order to improve the radiation protection of patients and better predict the risk of complications, we implemented a new preclinical mouse model to mimic radiological burn in interventional radiology and performed a complete characterization of the dose deposition. A new setup and collimator were designed to irradiate the hind legs of 15 mice at 30 Gy in air kerma at 80 kV. After irradiation, mice tibias were collected to evaluate bone dose by Electron Paramagnetic Resonance (EPR) spectroscopy measurements. Monte Carlo simulations with Geant4 were performed in simplified and voxelized phantoms to characterize the dose deposition in different tissues and evaluate the characteristics of secondary electrons (energy, path, momentum). 30 mice tibias were collected for EPR analysis. An average absorbed dose of 194.0 ± 27.0 Gy was measured in bone initially irradiated at 30 Gy in air kerma. A bone to air conversion factor of 6.5 ± 0.9 was determined. Inter sample and inter mice variability has been estimated to 13.9%. Monte Carlo simulations shown the heterogeneity of the dose deposition for these low X-rays energies and the dose enhancement in dense tissue. The specificities of the secondary electrons were studied and showed the influence of the tissue density on energies and paths. A good agreement between the experimental and calculated bone to air conversion factor was obtained. A new preclinical model allowing to perform radiological burn in interventional radiology-like conditions was implemented. For the development of new preclinical radiobiological model where the exact knowledge of the dose deposited in the different tissues is essential, the complementarity of Monte Carlo simulations and experimental measurements for the dosimetric characterization has proven to be a considerable asset.

Simulation and experimental verification of ambient neutron doses in a pencil beam scanning proton therapy room as a function of treatment plan parameters.

Out-of-field patient doses in proton therapy are dominated by neutrons. Currently, they are not taken into account by treatment planning systems. There is an increasing need to include out-of-field doses in the dose calculation, especially when treating children, pregnant patients, and patients with implants. In response to this demand, this work presents the first steps towards a tool for the prediction of out-of-field neutron doses in pencil beam scanning proton therapy facilities. As a first step, a general Monte Carlo radiation transport model for simulation of out-of-field neutron doses was set up and successfully verified by comparison of simulated and measured ambient neutron dose equivalent and neutron fluence energy spectra around a solid water phantom irradiated with a variation of different treatment plan parameters. Simulations with the verified model enabled a detailed study of the variation of the neutron ambient dose equivalent with field size, range, modulation width, use of a range shifter, and position inside the treatment room. For future work, it is planned to use this verified model to simulate out-of-field neutron doses inside the phantom and to verify the simulation results by comparison with previous in-phantom measurement campaigns. Eventually, these verified simulations will be used to build a library and a corresponding tool to allow assessment of out-of-field neutron doses at pencil beam scanning proton therapy facilities.

Neutron Radiation Dose Measurements in a Scanning Proton Therapy Room: Can Parents Remain Near Their Children During Treatment?

Purpose: This study aims to characterize the neutron radiation field inside a scanning proton therapy treatment room including the impact of different pediatric patient sizes. Materials and Methods: Working Group 9 of the European Radiation Dosimetry Group (EURADOS) has performed a comprehensive measurement campaign to measure neutron ambient dose equivalent, H*(10), at eight different positions around 1-, 5-, and 10-year-old pediatric anthropomorphic phantoms irradiated with a simulated brain tumor treatment. Several active detector systems were used. Results: The neutron dose mapping within the gantry room showed that H*(10) values significantly decreased with distance and angular deviation with respect to the beam axis. A maximum value of about 19.5 µSv/Gy was measured along the beam axis at 1 m from the isocenter for a 10-year-old pediatric phantom at 270° gantry angle. A minimum value of 0.1 µSv/Gy was measured at a distance of 2.25 m perpendicular to the beam axis for a 1-year-old pediatric phantom at 140° gantry angle.The H*(10) dependence on the size of the pediatric patient was observed. At 270° gantry position, the measured neutron H*(10) values for the 10-year-old pediatric phantom were up to 20% higher than those measured for the 5-year-old and up to 410% higher than for the 1-year-old phantom, respectively. Conclusions: Using active neutron detectors, secondary neutron mapping was performed to characterize the neutron field generated during proton therapy of pediatric patients. It is shown that the neutron ambient dose equivalent H*(10) significantly decreases with distance and angle with respect to the beam axis. It is reported that the total neutron exposure of a person staying at a position perpendicular to the beam axis at a distance greater than 2 m from the isocenter remains well below the dose limit of 1 mSv per year for the general public (recommended by the International Commission on Radiological Protection) during the entire treatment course with a target dose of up to 60 Gy. This comprehensive analysis is key for general neutron shielding issues, for example, the safe operation of anesthetic equipment. However, it also enables the evaluation of whether it is safe for parents to remain near their children during treatment to bring them comfort. Currently, radiation protection protocols prohibit the occupancy of the treatment room during beam delivery.

Dose Variations Using an X-Ray Cabinet to Establish in vitro Dose-Response Curves for Biological Dosimetry Assays.

In biological dosimetry, dose-response curves are essential for reliable retrospective dose estimation of individual exposure in case of a radiation accident. Therefore, blood samples are irradiated in vitro and evaluated based on the applied assay. Accurate physical dosimetry of the irradiation performance is a critical part of the experimental procedure and is influenced by the experimental setup, especially when X-ray cabinets are used. The aim of this study was to investigate variations and pitfalls associated with the experimental setups used to establish calibration curves in biological dosimetry with X-ray cabinets. In this study, irradiation was performed with an X-ray source (195 kV, 10 mA, 0.5 mm Cu filter, dose rate 0.52 Gy/min, 1st and 2nd half-value layer = 1.01 and 1.76 mm Cu, respectively, average energy 86.9 keV). Blood collection tubes were irradiated with a dose of 1 Gy in vertical or horizontal orientation in the center of the beam area with or without usage of an additional fan heater. To evaluate the influence of the setups, physical dose measurements using thermoluminescence dosimeters, electron paramagnetic resonance dosimetry and ionization chamber as well as biological effects, quantified by dicentric chromosomes and micronuclei, were compared. This study revealed that the orientation of the sample tubes (vertical vs. horizontal) had a significant effect on the radiation dose with a variation of -41% up to +49% and contributed to a dose gradient of up to 870 mGy inside the vertical tubes due to the size of the sample tubes and the associated differences in the distance to the focal point of the tube. The number of dicentric chromosomes and micronuclei differed by ~30% between both orientations. An additional fan heater had no consistent impact. Therefore, dosimetric monitoring of experimental irradiation setups is mandatory prior to the establishment of calibration curves in biological dosimetry. Careful consideration of the experimental setup in collaboration with physicists is required to ensure traceability and reproducibility of irradiation conditions, to correlate the radiation dose and the number of aberrations correctly and to avoid systematical bias influencing the dose estimation in the frame of biological dosimetry.

Hematopoietic Recovery using Multi-Cytokine Therapy in 8 Patients Presenting Radiation-Induced Myelosuppression after Radiological Accidents.

Treatment of accidental radiation-induced myelosuppression is primarily based on supportive care and requires specific treatment based on hematopoietic growth factors injection or hematopoietic cell transplantation for the most severe cases. The cytokines used consisted of pegylated erythropoietin (darbepoetin alfa) 500 IU once per week, pegylated G-CSF (pegfilgrastim) 6 mg × 2 once, stem cell factor 20 µg.kg-1 for five days, and romiplostim (TPO analog) 10 µg.kg -1 once per week, with different combinations depending on the accidents. As the stem cell factor did not have regulatory approval for clinical use in France, the French regulatory authorities (ANSM, formerly, AFSSAPS) approved their compassionate use as an investigational drug "on a case-by-case basis". According to the evolution and clinical characteristics, each patient's treatment was adopted on an individual basis. Daily blood count allows initiating G-CSF and SCF delivery when granulocyte <1,000/mm3, TPO delivery when platelets <50,000/mm3, and EPO when Hb<80 g/L. The length of each treatment was based on blood cell recovery criteria. The concept of "stimulation strategy" is linked to each patient's residual hematopoiesis, which varies among them, depending on the radiation exposure's characteristics and heterogeneity. This paper reports the medical management of 8 overexposed patients to ionizing radiation. The recovery of bone marrow function after myelosuppression was accelerated using growth factors, optimized by multiple-line combinations. Particularly in the event of prolonged exposure to ionizing radiation in dose ranges inducing severe myelosuppression (in the order of 5 to 8 Gy), with no indication of hematopoietic stem cell transplantation.

RENEB/EURADOS field exercise 2019: robust dose estimation under outdoor conditions based on the dicentric chromosome assay.

PURPOSE: Biological and/or physical assays for retrospective dosimetry are valuable tools to recover the exposure situation and to aid medical decision making. To further validate and improve such biological and physical assays, in 2019, EURADOS Working Group 10 and RENEB performed a field exercise in Lund, Sweden, to simulate various real-life exposure scenarios. MATERIALS AND METHODS: For the dicentric chromosome assay (DCA), blood tubes were located at anthropomorphic phantoms positioned in different geometries and were irradiated with a 1.36 TBq 192Ir-source. For each exposure condition, dose estimates were provided by at least one laboratory and for four conditions by 17 participating RENEB laboratories. Three radio-photoluminescence glass dosimeters were placed at each tube to assess reference doses. RESULTS: The DCA results were homogeneous between participants and matched well with the reference doses (≥95% of estimates within ±0.5 Gy of the reference). For samples close to the source systematic underestimation could be corrected by accounting for exposure time. Heterogeneity within and between tubes was detected for reference doses as well as for DCA doses estimates. CONCLUSIONS: The participants were able to successfully estimate the doses and to provide important information on the exposure scenarios under conditions closely resembling a real-life situation.

Dosimetry for Cell Irradiation using Orthovoltage (40-300 kV) X-Ray Facilities.

The importance of dosimetry protocols and standards for radiobiological studies is self-evident. Several protocols have been proposed for dose determination using low energy X-ray facilities, but depending on the irradiation configurations, samples, materials or beam quality, it is sometimes difficult to know which protocol is the most appropriate to employ. We, therefore, propose a dosimetry protocol for cell irradiations using low energy X-ray facility. The aim of this method is to perform the dose estimation at the level of the cell monolayer to make it as close as possible to real cell irradiation conditions. The different steps of the protocol are as follows: determination of the irradiation parameters (high voltage, intensity, cell container etc.), determination of the beam quality index (high voltage-half value layer couple), dose rate measurement with ionization chamber calibrated in air kerma conditions, quantification of the attenuation and scattering of the cell culture medium with EBT3 radiochromic films, and determination of the dose rate at the cellular level. This methodology must be performed for each new cell irradiation configuration as the modification of only one parameter can strongly impact the real dose deposition at the level of the cell monolayer, particularly involving low energy X-rays.

GPS-coupled contaminant monitors on free-ranging Chernobyl wolves challenge a fundamental assumption in exposure assessments.

Measurements of external contaminant exposures on individual wildlife are rare because of difficulties in using contaminant monitors on free-ranging animals. Most wildlife contaminant exposure data are therefore simulated with computer models. Rarely are empirical exposure data available to verify model simulations, or to test fundamental assumptions inherent in exposure assessments. We used GPS-coupled contaminant monitors to quantify external exposures to individual wolves (Canis lupus) living within the Belarus portion of Chernobyl's 30-km exclusion zone. The study provided data on animal location and contaminant exposure every 35 min for 6 months, resulting in ~6600 individual locations and 137Cs external exposure readings per wolf, representing the most robust external exposure data published to date on free ranging animals. The data provided information on variation in external exposure for each animal over time, as well as variation in external exposure among the eight wolves across the landscape of Chernobyl. The exposure data were then used to test a fundamental assumption in screening-level risk assessments, espoused in guidance documents of the U.S. Environmental Protection Agency and U.S. Department of Energy, - Mean contaminant concentrations conservatively estimate individual external exposures. We tested this assumption by comparing our empirical data to a series of simulations using the ERICA modeling tool. We found that modeled simulations of mean external exposure (10.5 mGy y-1), based on various measures of central tendency, under-predicted mean exposures measured on five of the eight wolves wearing GPS-contaminant monitors (i.e., 12.3, 26.3, 28.0, 28.8 and 35.7 mGy y-1). If under-prediction of exposure occurs for some animals, then arguably the use of averaged contaminant concentrations to predict external exposure is not as conservative as proposed by current risk assessment guidance. Thus, a risk assessor's interpretation of simulated exposures in a screening-level risk analysis might be misguided if contaminant concentrations are based on measures of central tendency. We offer three suggestions for risk assessors to consider in order to reduce the probability of underestimating exposure in a screening-level risk assessment.

Importance of dosimetry protocol for cell irradiation on a low X-rays facility and consequences for the biological response.

PURPOSE: The main objective of radiobiology is to establish links between doses and radiation-induced biological effects. In this context, well-defined dosimetry protocols are crucial to the determination of experimental protocols. This work proposes a new dosimetry protocol for cell irradiation in a SARRP and shows the importance of the modification of some parameters defined in dosimetry protocol for physical dose and biological outcomes. MATERIALS AND METHODS: Once all parameters of the configuration were defined, dosimetry measurements with ionization chambers and EBT3 films were performed to evaluate the dose rate and the attenuation due to the cell culture medium. To evaluate the influence of changes in cell culture volume and/or additional filtration, 6-well plates containing EBT3 films with water were used to determine the impact on the physical dose at 80 kV. Then, experiments with the same irradiation conditions were performed by replacing EBT3 films by HUVECs. The biological response was assessed using clonogenic assay. RESULTS: Using a 0.15 mm copper filter lead to a variation of +1% using medium thickness of 0.104 cm to -8% using a medium thickness of 0.936 cm on the physical dose compare to the reference condition (0.313 cm). For the 1 mm aluminum filter, a variation of +8 to -40% for the same medium thickness conditions has been observed. Cells irradiated in the same conditions showed significant differences in survival fraction, corroborating the effects of dosimetric changes on physical dose. CONCLUSIONS: This work shows the importance of dosimetry in radiobiology studies and the need of an accurate description of the dosimetry protocol used for irradiation.

UNCERTAINTY ON RADIATION DOSES ESTIMATED BY BIOLOGICAL AND RETROSPECTIVE PHYSICAL METHODS.

Biological and physical retrospective dosimetry are recognised as key techniques to provide individual estimates of dose following unplanned exposures to ionising radiation. Whilst there has been a relatively large amount of recent development in the biological and physical procedures, development of statistical analysis techniques has failed to keep pace. The aim of this paper is to review the current state of the art in uncertainty analysis techniques across the 'EURADOS Working Group 10-Retrospective dosimetry' members, to give concrete examples of implementation of the techniques recommended in the international standards, and to further promote the use of Monte Carlo techniques to support characterisation of uncertainties. It is concluded that sufficient techniques are available and in use by most laboratories for acute, whole body exposures to highly penetrating radiation, but further work will be required to ensure that statistical analysis is always wholly sufficient for the more complex exposure scenarios.

Investigation of the influence of calibration practices on cytogenetic laboratory performance for dose estimation.

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.