Neutron Radiobiology and Dosimetry.

As the U.S. prepares for the possibility of a radiological or nuclear incident, or anticipated lunar and Mars missions, the exposure of individuals to neutron radiation must be considered. More information is needed on how to determine the neutron dose to better estimate the true biological effects of neutrons and mixed-field (i.e., neutron and photon) radiation exposures. While exposure to gamma-ray radiation will cause significant health issues, the addition of neutrons will likely exacerbate the biological effects already anticipated after radiation exposure. To begin to understand the issues and knowledge gaps in these areas, the National Institute of Allergy and Infectious Diseases (NIAID), Radiation Nuclear Countermeasures Program (RNCP), Department of Defense (DoD), Defense Threat Reduction Agency (DTRA), and National Aeronautics and Space Administration (NASA) formed an inter-agency working group to host a Neutron Radiobiology and Dosimetry Workshop on March 7, 2019 in Rockville, MD. Stakeholder interests were clearly positioned, given the differences in the missions of each agency. An overview of neutron dosimetry and neutron radiobiology was included, as well as a historical overview of neutron exposure research. In addition, current research in the fields of biodosimetry and diagnostics, medical countermeasures (MCMs) and treatment, long-term health effects, and computational studies were presented and discussed.

The integration of the adverse outcome pathway framework to radiation risk assessment.

BACKGROUND: A large body of radiobiological data has been generated over the past century using in vitro, animal and epidemiological models. This information represents global efforts to understand the mechanistic basis of radiation-induced health effects. However, it has been difficult to effectively integrate this data to derive meaningful information for refining the guidance on chronic, low dose radiation exposure for workers and the public. METHODS: To increase our understanding of radiation risks and the biological processes that contribute to those risks, a paradigm shift is needed that will enable integration of information across levels of biological organization from a 'stressor' centric to an 'adverse outcome' approach to risk assessment. In chemical and ecological toxicity, a framework has been developed that captures available biologically-based knowledge in the literature and links it to outcomes of relevance to chemical toxicity, resulting in an adverse outcome pathway (AOP). RESULTS: In this paper, we discuss the AOP concept, how it can be applied to the radiation field, and our vision for the next steps. For the approach to be successful, the radiation research community will need to work collaboratively to vet the vast amount of literature and harness the data in a systematic manner for incorporation into a framework based on the AOP approach. CONCLUSION: We anticipate that AOPs could be adopted as a method to synthesize current available information to facilitate the identification of knowledge gaps, better co-ordinate research and qualitatively and quantitatively link key events to an adverse outcome. This can further assist in identifying biomarkers relevant to radiation exposures, refining risk from co-exposures and understanding critical events at the molecular, cellular, tissue, organ and whole animal level related to low dose/dose-rate exposures.

Bringing Radiation Exposures and Associated Health Risks into Perspective-Development of an App.

The NATO HFM 291 research task group (RTG) on "Ionizing Radiation Bioeffects and Countermeasures" represents a group of scientists from military and civilian academic and scientific institutions primarily working in the field of radiobiology. Among other tasks, the RTG intends to extend their work on risk estimation and communication to bridge the gap in appropriate judgment of health risks given a certain radiation exposure. The group has no explicit psychological background but an expertise in radiobiology and risk assessment. The group believes that, as one of the essential first steps in risk communication, it is required to put radiation risk into perspective. Radiation risk requires a weight in comparison to already-known risks. What we envision is to Compare Radiation exposure-associated health Risks (CRRis App) with daily life health risks caused by other common exposures such as cigarette smoking, driving a car, etc. Within this paper, we provide (1) an overview of health risks after radiation exposure, (2) an explanation of the task and concept of an envisioned CRRis App, (3) an overview of existing software tools related to this issue, (4) a summary of inputs and discussions with experts in the field of radiation protection and risk communication during the ConRad conference, and finally, (5) identification of the next steps in the development of the App.

Impact analysis of age on radiation casualty estimations for nuclear detonation scenarios.

Purpose: The purpose of this research was to demonstrate the impact of accounting for age-based radiation response when estimating radiation casualties in a nuclear detonation scenario.Materials and methods: Three nuclear device detonation scenarios were simulated using densely populated regions to compare traditional casualty estimates with age-dependent casualty estimates. Fatalities were estimated using age-based dose-response curves. The surviving population was assumed injured (requiring medical care) if their dose exceeded a lower bound, represented by the minimum dose required to cause deterministic effects, for each age group.Results: In each of the three scenarios, the affected area increased significantly for radiosensitive age groups. In two of the three scenarios, accounting for age-dependent radiosensitivity resulted in up to a 10% increase in fatalities and up to a 12% increase in radiation injuries compared to traditional estimates. This study demonstrates that the differences in casualty estimates are dependent on the relative density and location of radiosensitive populations.Conclusions: These results demonstrate that the inclusion of age-based demographic data and associated dose responses may result in significantly higher estimates of casualties depending on the location and age of the affected population. This information could be useful for the emergency management planning community.

Development of age-dependent dose modification factors for acute radiation lethality.

Purpose: The aim of our work was to develop an approach to account for the impact of age at exposure on acute radiation lethality risk for the purpose of improving casualty estimation tools when applied to a diverse population.Materials and Methods: Age-dependent radiation lethality data were collected from published animal studies. The 50% lethal dose responses (LD50) were extracted, grouped according to developmental stages in humans and average LD50 values calculated for select age categories. Dose modification factors (DMFs) were developed by dividing LD50 values of non-young, adult groups to the reference adult category within each study. DMFs were combined across each age group to provide a DMF for each age category.Results: Data from 12 studies with age-dependent LD50 values from 5 species (>21,000 animals) demonstrate increased sensitivity to acute radiation in elderly and young animals compared to young adults. DMFs were developed for infant (0.80), juvenile (0.86), late adult (0.86), and elderly (0.71) populations.Conclusions: Animal and human data support increased radiosensitivity in infants, juveniles, and aging adults. DMFs provide a mechanism to account for age-dependent variability in health effects models and to determine the impact of age on casualty estimates.

Automated Translation of Clinical Parameters in Evaluating Acute Radiation Injury: Results From a Mass Casualty Exercise.

OBJECTIVE: A radiological disaster could result in a large number of patients potentially exposed to harmful levels of radiation. Currently, early triage of patients for radiation exposure relies heavily on a clinical evaluation of signs and symptoms. However, detailed clinical assessment takes significant time and requires specialized training to accurately interpret the results. METHODS: During planning of a recent exercise, SMEs estimated that it would take up to 15 minutes per patient. Patient load would quickly overwhelm the number of qualified clinicians providing treatment. In this exercise organized by the NATO RTG HFM 222, we examined using automated translation of clinical data to facilitate clinic evaluations. We used two triage evaluation approaches; REAC/TS and METREPOL. These approaches allowed us to translate tabulated clinical data, first into categorical data for grouping patients, and then into recommendations for follow-up diagnostics and care. RESULTS: The organizers provided clinical evaluations of 191 case studies that were estimated to require up to 50 total hours for completion. However, using our application, we were able to evaluate all cases in less than 2 minutes. CONCLUSION: This study clearly demonstrates the need for automated tools to help translate clinical data for effective patient triage after a nuclear or radiological incident. (Disaster Med Public Health Preparedness. 2018;12:569-573).

Benefit-Cost Analysis of Radiocesium Decorporation by a Prussian Blue Treatment and Stockpiling.

In the case of an attack by a "dirty bomb" with cesium-137 there is a risk of internal contamination. The excretion of cesium-137 can be enhanced by Prussian Blue (PB), and thus the committed effective dose be reduced. We analyzed the benefit and costs of PB decorporation treatment. We simulated the reduction of the radiological dose by PB treatment after cesium-137 incorporation by inhalation. The saving of life time was quantified using the monetary "value of a statistical life" (VSL). Treatment costs were based on the market price of PB in Germany. Moreover we considered the holding costs of stockpiling. The benefit of PB treatment increases with its duration up to about 90 days. If treatment initiation is delayed, the maximum achievable benefit is decreased. For a VSL of 1.646 million €, the net benefit of a 90-days treatment started 1 day after the incorporation remains positive up to a stockpiling duration of 10 years. If starting PB treatment as late as the 180th day after incorporation, the costs will surpass the benefit. We conclude that a prompt decision making and early treatment initiation greatly impacts on the medical but also economic efficiency of a PB treatment.

The Incorporation of Radionuclides After Wounding by a "Dirty Bomb": The Impact of Time for Decorporation Efficacy and a Model for Cases of Disseminated Fragmentation Wounds.

Objective: In the case of a terrorist attack by a "dirty bomb" there is a risk of internal contamination with radionuclides through inhalation and wounds. We studied the efficacy of a decorporation treatment depending on the initiation time and duration. Approach: Based on biokinetic models, we simulated the impact of different diethylenetriaminepentaacetic acid treatments on the committed effective dose after the incorporation of plutonium-239. Results: For the same level of radioactivity, the dose was higher after the fast absorption from the wound than after a slow invasion following inhalation. The impact of the treatment initiation time was particularly important in the case of the internal contamination through the wound. Ending the treatment at an early point in time was followed by an augmentation of radioactivity in the blood compartment, reflecting insufficient treatment duration. Treatment efficacy increased only marginally if extended over 90 days. Innovation and Conclusion: For plutonium-239, the committed effective dose and the impact of the treatment initiation time on therapeutic efficacy predominantly depend on the speed of invasion, i.e., the pathway and the physicochemical properties of the compounds involved. Thus, it is prudent to start decorporation therapy as soon as possible, as a loss of efficacy resulting from a delay in treatment initiation cannot be compensated later on. In the case of plutonium-239 incorporation, the treatment must be continued for several months. Multiple fragmentation wounds might be aggregated to a single wound model suited for internal dosimetry calculations by using the "rule of nine."

Analysis of the antidote requirements and outcomes of different radionuclide decorporation strategies for a scenario of a "dirty bomb" attack.

OBJECTIVE: In radiological emergencies, there is a risk of radionuclide incorporation. The radiological doses absorbed can be reduced by decorporation treatment. Antidote requirements depend on the scenario and treatment strategy ("urgent approach": immediate treatment of all patients with possible incorporation; "precautionary approach": treatment only after confirmation of incorporation). We calculated the number of daily antidote doses for different scenarios and the differences in outcome for both treatment strategies. DESIGN: The number of potentially contaminated victims was varied from 1,000 to 60,000 (a maximum that might seem plausible for "dirty bomb" scenarios in Germany), the proportion of patients actually needing decorporation treatment from 0.1 percent to 100 percent, the radioactive screening capacities from 250 to 2,500 people/day and treatment duration from 10 to 90 days. The outcomes were assessed as total statistical lifetime saved assuming an inhalation of 1 mCi cesium-137 and the achievable dose reductions by a Prussian Blue treatment. RESULTS: Assuming 1 percent of the potentially contaminated people actually needing treatment, applying an "urgent approach" the requirements for 1,000 victims range from 1,100 to 3,400 and for 60,000 victims from 489,000 to 4,400,000 daily doses, depending on treatment duration and screening capacities. The "urgent approach" is associated with larger stockpile requirements than the "precautionary approach", up to several hundred times in large-scale scenarios if the proportion of people actually needing treatment is low. The impact of the screening capacities is particularly important in large-scale scenarios, a low proportion of people needing treatment and extended treatment duration. The outcome is better for an "urgent approach" particularly in large-scale scenarios and low screening capacities. CONCLUSIONS: If only a small fraction of the victims actually needs treatment, their timely identification by enhancing screening capacities may be the most efficacious way to reduce antidote requirements. In large-scale scenarios, it might be necessary to abandon the medically preferable "urgent approach" for an antidote-sparing "precautionary approach".

Workshop Report on Atomic Bomb Dosimetry--Review of Dose Related Factors for the Evaluation of Exposures to Residual Radiation at Hiroshima and Nagasaki.

Groups of Japanese and American scientists, supported by international collaborators, have worked for many years to ensure the accuracy of the radiation dosimetry used in studies of health effects in the Japanese atomic bomb survivors. Reliable dosimetric models and systems are especially critical to epidemiologic studies of this population because of their importance in the development of worldwide radiation protection standards. While dosimetry systems, such as Dosimetry System 1986 (DS86) and Dosimetry System 2002 (DS02), have improved, the research groups that developed them were unable to propose or confirm an additional contribution by residual radiation to the survivor's total body dose. In recognition of the need for an up-to-date review of residual radiation exposures in Hiroshima and Nagasaki, a half-day technical session was held for reports on newer studies at the 59 th Annual HPS Meeting in 2014 in Baltimore, MD. A day-and-a-half workshop was also held to provide time for detailed discussion of the newer studies and to evaluate their potential use in clarifying the residual radiation exposure to atomic bomb survivors at Hiroshima and Nagasaki. The process also involved a re-examination of very early surveys of radioisotope emissions from ground surfaces at Hiroshima and Nagasaki and early reports of health effects. New insights were reported on the potential contribution to residual radiation from neutron-activated radionuclides in the airburst's dust stem and pedestal and in unlofted soil, as well as from fission products and weapon debris from the nuclear cloud. However, disparate views remain concerning the actual residual radiation doses received by the atomic bomb survivors at different distances from the hypocenter. The workshop discussion indicated that measurements made using thermal luminescence and optically stimulated luminescence, like earlier measurements, especially in very thin layers of the samples, could be expanded to detect possible radiation exposures to beta particles and to determine their significance plus the extent of the various residual radiation areas at Hiroshima and Nagasaki. Other suggestions for future residual radiation studies are included in this workshop report.

Evaluation of demographic factors that influence acute radiation response.

Casualty estimation tools are critical in planning for nuclear event scenarios. Current consequence assessment models based on healthy adult males may not adequately represent the population. To develop an understanding of the impact of demographic variables on casualty estimates, human data was surveyed to identify key demographic factors that affect acute radiation response. Information on in utero exposures, gender, age, and comorbidity status was collected from atomic bomb survivors, radiation accidents, and clinical oncology. Burn and trauma studies were also examined to gain insight into the impact of demographic variables on acute injury outcomes. Fetal radiation sensitivity is well documented; increased mortality or malformations are observed depending on gestational age. A greater incidence of radiation syndrome was observed among male atomic bomb survivors. Trauma data show increased mortality in males, apparently due to immunological differences between genders. Limited data suggest vulnerability in the very young and old due to immunological status and comorbidities, respectively. Certain genetically susceptible subpopulations demonstrate marked increased sensitivity to radiation exposure. Interaction of radiation and comorbid conditions has not been well studied; however, burn and trauma data indicate that comorbidities negatively impact response to acute injury. Key factors evaluated together with their prevalence indicate the importance of modeling demographic variability in casualty estimations. Also they can help identify vulnerable subpopulations and provide insight on treatment requirements.

Mass casualties and health care following the release of toxic chemicals or radioactive material--contribution of modern biotechnology.

Catastrophic chemical or radiological events can cause thousands of casualties. Such disasters require triage procedures to identify the development of health consequences requiring medical intervention. Our objective is to analyze recent advancements in biotechnology for triage in mass emergency situations. In addition to identifying persons "at risk" of developing health problems, these technologies can aid in securing the unaffected or "worried well". We also highlight the need for public/private partnerships to engage in some of the underpinning sciences, such as patho-physiological mechanisms of chemical and radiological hazards, and for the necessary investment in the development of rapid assessment tools through identification of biochemical, molecular, and genetic biomarkers to predict health effects. For chemical agents, biomarkers of neurotoxicity, lung damage, and clinical and epidemiological databases are needed to assess acute and chronic effects of exposures. For radiological exposures, development of rapid, sensitive biomarkers using advanced biotechnologies are needed to sort exposed persons at risk of life-threatening effects from persons with long-term risk or no risk. The final implementation of rapid and portable diagnostics tools suitable for emergency care providers to guide triage and medical countermeasures use will need public support, since commercial incentives are lacking.

Premature chromosome condensation (PCC) assay for dose assessment in mass casualty accidents.

The study was undertaken to establish a dose calibration curve for a practical PCC ring assay and to apply it in a simulated mass casualty accident. The PCC assay was validated against the conventional dicentric assay. A linear relationship was established for PCC rings after (60)Co gamma irradiation with doses up to 20 Gy. In the simulated accident experiment, 62 blood samples were analyzed with both the PCC ring assay and the conventional dicentric assay, applying a triage approach. Samples received various uniform and non-uniform (10-40% partial-body) irradiations up to doses of 13 Gy. The results indicated that both assays yielded good dose estimates for the whole-body exposure scenario, although in the lower-dose range (0-6 Gy) dicentric scoring resulted in more accurate whole-body estimates, whereas PCC rings were better in the high-dose range (>6 Gy). Neither assay was successful in identifying partial-body exposures, most likely due to the low numbers of cells scored in the triage mode. In conclusion, the study confirmed that the PCC ring assay is suitable for use as a biodosimeter after whole-body exposure to high doses of radiation. However, there are limitations for its use in the triage of people exposed to high, partial-body doses.

Risk assessment in international operations.

During international peace-keeping missions, a diverse number of non-battle hazards may be encountered, which range from heavily polluted areas, endemic disease, toxic industrial materials, local violence, traffic, and even psychological factors. Hence, elevated risk levels from a variety of sources are encountered during deployments. With the emphasis within the Swedish military moving from national defense towards prioritization of international missions in atypical environments, the risk of health consequences, including long term health effects, has received greater consideration. The Swedish military is interested in designing an optimal approach for assessment of health threats during deployments. The Medical Intelligence group at FOI CBRN Security and Defence in Umeå has, on request from and in collaboration with the Swedish Armed Forces, reviewed a variety of international health threat and risk assessment models for military operations. Application of risk assessment methods used in different phases of military operations will be reviewed. An overview of different international approaches used in operational risk management (ORM) will be presented as well as a discussion of the specific needs and constraints for health risk assessment in military operations. This work highlights the specific challenges of risk assessment that are unique to the deployment setting such as the assessment of exposures to a variety of diverse hazards concurrently.