By Dr. Mary Sproull
Dr. Mary Sproull explores the potential of biodosimetry as an essential medical countermeasure in the management of radiation injuries.
In the realm of public health security, the threat of radiological or nuclear event scenarios continues to drive the research and development of new medical countermeasures, the creation of more comprehensive and actionable emergency planning guidebooks, and new scientific discoveries in the field of radiation injury. Improving existing medical management protocols for mass casualty radiation exposure, interagency emergency planning, execution of table-top and field exercises, and stockpiling of radiation-specific medical resources remain key elements of modern civil defense.
Future threat scenarios from radiation exposure encompass a wide variety of potential exposure paradigms including radiation dispersal devices (RDD), radiation exposure devices (RED), improvised nuclear devices (IND), or dispersal of radionuclides from a nuclear power plant (NPP) incident.
A RED event or exposure to a source would result in external exposure without the presence of contamination, whereas RDDs or a plume of radioactive material from an NPP would result in a combination of external/internal radiation exposure from radionuclides. With an IND, injury profiles would include an array of heterogeneous radiation exposures from a combination of the two.
A spectrum of injury profiles results from these inherently disparate types of possible radiation exposure. Although the biological mechanism of tissue injury from ionizing radiation – that of DNA damage – remains essentially the same, differences in types of radiation (alpha, beta, gamma, x-ray, neutron), the strength of the source of the radiation exposure, physical and physiological exposure patterns, and whether the exposure is external, internal, or both, all complicate the characterization and treatment of any individual instance of radiation exposure.
In general, when managing a radiological event scenario, it is primarily x-ray and gamma radiation that are of greatest concern, as these types of radiation possess sufficient energy and penetrating power to cause deep tissue damage.
Neutron radiation exposure is rarely a concern and would only be relevant in the case of a nuclear reactor, nuclear weapon, or IND event. An IND would engender the most complex heterogeneous radiation exposures resultant from a mix of prompt external radiation exposure (immediate radiation wave) after detonation, and/or fallout exposures which would include a mixture of radioisotopes.
Alpha and beta radiation do not possess the same tissue-penetrating power as the aforementioned types and, except in the case of cutaneous beta burns, are generally considered of medical concern only in the case of internal contamination through ingestion or inhalation. Moreover, although internalized radioactive isotopes may cause significant tissue damage, they are usually not of sufficient quantity to produce acute radiation syndrome (ARS).
Treating Acute Radiation Syndrome
This disparity in injury presentation poses unique medical management challenges and highlights the need for radiation-specific pharmaceuticals to treat radiation injury. Currently, there are several classes of medical countermeasures available including drugs which mitigate the effects of internal radionuclide contamination, burn treatments for cutaneous injury, treatment of multiorgan tissue injury including the myeloablative effects of ARS, and dosimetry diagnostics to determine the presence and severity of radiation exposure.
Drugs which aid the removal of internal radionuclides are well established, are referred to as decorporation or blocking agents, and vary in their respective mechanisms of action to promote excretion of radionuclides from the body. These drugs are specific for particular radionuclides with potassium iodide used for radioactive iodine, Prussian blue for radioactive cesium, and DTPA for radioactive forms of plutonium, americium, cobalt, and iridium.
Other medical countermeasures for radiation injury that have recently received U.S. Food and Drug Administration (FDA) approval for use treat radiation injury irrespective of the type of radiation exposure. These include the use of Silverlon® dressings for burn treatments and growth factors filgrastim (Neupogen®), pegfilgrastim (Neulasta®), Udenyca® (Neulasta biosimilar), Stimufend® (Neulasta biosimilar), sargramostim (Leukine®) and thrombopoietin receptor agonist romiplostim (Nplate®), which reverse the myelosuppressive effects of bone marrow damage within the hematopoietic subsyndrome of ARS.
Research also continues to seek licensure for new pharmaceuticals capable of mitigating all forms of radiation injury, as well those specific to the respiratory and gastrointestinal systems. There are almost a dozen drugs for radiation injury treatment with investigational new drug status with the FDA.
Novel Diagnostics for Radiation Exposure
Previous experience from large-scale radiological disasters has illustrated the debilitating effect of the “worried well” or “concerned citizens” on any type of triage or mass casualty management exercise. Historical precedent indicates these walking wounded or physically uninjured individuals are expected to overwhelm existing medical infrastructure, diverting critical resources in their effort to determine if they have been exposed to radiation.
As the initial step in medical management of any exposure is to determine whether radiation exposure has occurred and subsequently differentiate the degree of exposure, particular attention has been focused on research and development of biodosimetry diagnostics, to firstly alleviate the logistical problem of the worried well, and secondly to enable more efficient radiation-specific medical triage.
Biodosimetry diagnostics are a novel form of diagnostic which correlate surrogate physiological biomarkers in the body with radiation exposure. The only currently FDA-accepted biodosimetry diagnostics is the dicentric chromosome assay, an effective but low-throughput, labor-intensive biodosimetry assay not useful in field settings. This need has driven and expanded the field of biodosimetry research over the last two decades resulting in the characterization of countless new biomarkers and a greater understanding of radiation injury. Proof of concept studies have identified novel biodosimetry models using a variety of physiological markers including DNA, RNA, metabolites, protein, lymphocytes, and tooth enamel using animal models and validating findings with human clinical samples when available.
Several biodosimetry diagnostic assays are in late-stage development for approval with the FDA. To develop high-throughput laboratory network reachback capacity, genomic biodosimetry platforms such as the REDI-Dx assay developed by DxTerity and Duke University and the ARad test developed by MRIGlobal and Arizona State University, as well as the cytogenetic assay CytoRADx by ASELL, are being advanced for use in mass casualty screening. For point of care biodosimetry capability in the field, there is a proteomic biodosimetry fingerstick assay in late-stage development by SRI International and a complete blood cell count handheld analyzer by ASELL. These diagnostics tools are expected to be added to the Strategic National Stockpile following final FDA licensure.
Biodosimetry Assays
Given the disparate range of types of medical countermeasures respective to the specific presentation of radiation injury, is there a universal countermeasure or one treatment which is fit for all types of radiation exposure? Radiation biodosimetry diagnostics may indeed be that “universal countermeasure”. This supposition is predicated on several factors including the capacity of biodosimetry diagnostics to identify radiation exposures, give an estimate of the received dose, act as a surrogate marker for radiation injury, and guide medical treatment decisions.
The most difficult aspect of treating radiation injury is first to determine that it has occurred. Firstly, low-dose radiation exposures do not generate noticeable symptoms, hence there is no reasonable expectation of detection unless radiological material itself is detected. Secondly, even with high doses of radiation exposure and subsequent onset of ARS, the symptoms are non-specific and may include malaise, emesis, skin erythema, and diarrhea. There is also an absence of knowledge amongst clinicians nationwide regarding the health effects of radiation exposure, causing difficulty for medical personnel in making a correct diagnosis.
Case studies have shown that in actual incidences of radiation exposure most clinicians did not recognize the symptoms, both because of the difficulty of recognizing the syndrome and the lack of preparatory education. There is also the matter of contamination vs. exposure. Radionuclide bioassays can determine whether an individual is internally contaminated with radioactive material and the type of isotope to make an estimate of received dose, but if the individual has only been exposed and not contaminated, the assay will be negative. This is also true of many physical radiation detection technologies.
Physical dosimetry requires that radioactive material be present in or on the body to detect it, or that a known exposure has occurred to estimate the received dose based on time, distance, and shielding relative to the radioactive source. Biodosimetry diagnostics, however, will determine whether significant radiation exposure has occurred, irrespective of the type of radiation exposure.
Biodosimetry as the Essential Countermeasure for Radiation Exposure
Despite the existence of other ways to determine whether a person has received a radiation exposure and despite biodosimetry assays not playing a direct role in actual mitigation or protection against radiation injury, it may be argued that these diagnostics are fundamental to the treatment of radiation exposure. The universality of their application makes them the essential countermeasure for radiation exposure, as this diagnostic is the medical countermeasure on which all other subsequent countermeasures depend.
If you know that an exposure has occurred, you can select the appropriate medical countermeasures to treat the injury sooner than if you wait for the manifestation of late-stage symptoms to determine the severity. Knowing the estimated received dose, you know which treatment paradigm to use, including which sub-syndromes of ARS will present or whether to expect the onset of ARS at all.
If you can use biodosimetry diagnostics to determine whether a partial body exposure has occurred and the relative dose, you can estimate the probability of residual hematopoietic stem cells and avoid unnecessary bone marrow transplants. If you have a diagnostic that is useful in emergency management settings for triage and scarce resource allocation, you can improve the medical management of mass casualty events and save lives.
Ultimately, if you know the relative degree of radiation injury you provide better personalized medical management for the individual. Biodosimetry promises to be key to successful medical management of future radiological or nuclear mass casualty events.
These comments represent the work and opinions of the author and do not constitute official positions of the National Institutes of Health (NIH) or the U.S. Department of Health & Human Services (HHS). References to any specific commercial products by the trade name, trademark, manufacturer or otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favoring by NIH or HHS.
Mary Sproull, PhD, is a research scientist in the Radiation Oncology Branch of the National Cancer Institute at the National Institutes of Health. Her current work at the National Institutes of Health, in the laboratory of Kevin Camphausen, is funded by the Radiation and Nuclear Countermeasures Program/National Institute of Allergy and Infectious Diseases, as part of an initiative to develop new radiation biodosimetry models for dose prediction for use during mass casualty management during a radiological or nuclear event.
