Exposure to high doses of ionizing radiation over a short period of time would be expected following detonation of a nuclear weapon, explosion of a large radiation dispersal device [dirty bomb], placement of a radiation exposure device in a public area, and during certain medical procedures. The meltdown of a nuclear reactor, which is of great concern in Japan following the most powerful earthquake in the country’s recorded history, can also lead to radiation exposure.
Since the atomic bombings against the cities of Hiroshima and Nagasaki in Japan during World War II, radiation exposure to large populations has been largely limited to industrial accidents, including the April 1986 event at the Chernobyl Nuclear Power Plant in the Ukraine. Ironically, radiation accidents involving medical uses have accounted for more acute radiation deaths than from any other source, including Chernobyl [Reference 1].
The effects of radiation exposure manifest quickly and depend on a variety of factors, including the dose absorbed by different parts of the body, the route and rate at which it is delivered, and the type of radiation [alpha, beta, gamma, or neutrons]. The effects from various levels of radiation exposure can be found in Table 1 [adapted from Reference 2].
Table 1. Effects from Various Levels of Radiation Exposure
|Radiation Exposure |
in Gray Dose Units
|0.15 gy||Chromosome damage in circulating lymphocytes; sperm anomalies|
|0.3-0.7||Mild nausea, headache, lymphocyte decrease||6 hours|
|0.7-1.2||Vomiting in 5%-30% of people; delayed wound healing; decreases in lymphocytes, platelets, and granulocytes; increased susceptibility to pathogens||3-5 hours|
|1.2-3.0||Fatigue, weakness in 25%-60% of people; vomiting in 20%-70%; infection, fever, bleeding, wound and burn morbidity||2-3 hours|
|2.0||Reversible skin effects; early erythema|
|3.0-6.0||Significant skin effects|
|3.0-5.0||Fatigue, weakness in 80%-100% of people; transient, moderate vomiting in 50%-90%; diarrhea; loss of fluids; anorexia; ulceration; death of crypt cells||Hours to days|
|5.0-7.0||Moderate to severe vomiting in 50%-90%; fever; bloody diarrhea; gastrointestinal ulcerations; infections; hemorrhage; marrow hypoplasia; pancytopenia||1 hour|
|7.0-8.0||Death highly probable|
Acute Radiation Syndrome and Treatment
Acute radiation syndrome [ARS], also known as radiation toxicity or radiation sickness, is caused by exposure to a high dose of radiation over a short period of time, usually in a manner of minutes [Reference 3]. The cells that are lost the earliest following exposure are rapidly dividing hematopoietic stem cells and progenitor cells of the bone marrow that are highly sensitive to the effects of radiation, whereas the nervous system is generally regarded as the least sensitive. These differences in cellular sensitivity help categorize ARS into three syndromes, which occur with increasing dose exposure in the following order:
- Hematopoietic or bone marrow syndrome [HP/BM]
- Gastrointestinal syndrome [GI]
- Central nervous system or cardiovascular syndrome [CNS/CV]
Depending on the level and location of radiation exposure, the management of early-onset ARS is mainly supportive, including supportive care with fluids, antibiotics, and growth factors such as Amgen, Inc.’s (NASDAQ:AMGN) Neupogen [filgrastim] and Neulasta [peg-filgrastim]. While these growth factor products have not been approved by the U.S. Food and Drug Administration [FDA] for treating radiation-induced neutropenia, they have been recommended by the Strategic National Stockpile [SNS] Radiation Working Group [Reference 4].
When patients survive HP/BM and GI syndromes, respiratory failure may become a major cause of morbidity. Radiation can impair lung cells either directly via generation of reactive oxygen species [ROS] or indirectly via the action on parenchymal and inflammatory cells through biological mediators [Reference 5].
There are no approved products to treat or prevent ARS.
Potassium iodide [KI] was approved by the FDA in 1982 to reduce the risk of thyroid cancer in radiation emergencies involving the release of radioactive iodine. For example, the Chernobyl reactor accident resulted in massive releases of I-131 [radioactive iodine] and other radioiodines. Beginning approximately 4 years after the accident, a sharp increase in the incidence of thyroid cancer among children and adolescents in areas covered by the radioactive plume was observed.
By saturating the body with a source of stable iodide prior to exposure, inhaled or ingested I-131 tends to be excreted. Accordingly, following the Chernobyl incident approximately 10.5 million children under age 16 and 7 million adults in Poland received at least one dose of KI as a prophylactic measure against accumulation of I-131 in the thyroid gland.
However, it is important to note that KI cannot protect against any other causes of radiation poisoning, nor can it provide any degree of protection against dirty bombs that produce radionuclides other than isotopes of iodine.
Ethyol [amifostine], a prescription drug by MedImmune, a member of AstraZeneca plc (NYSE:AZN), is administered as a 15-minute i.v. infusion prior to each postoperative radiation treatment session for head and neck cancer when the radiation area includes a large part of the parotid glands. Ethyol is used to lower the rate of moderate to severe xerostomia [dry mouth] and is not approved for use in combination with other radiation therapy.
Investigational Approaches to Treat ARS
In view of the fact that many potential chemical, biological, radiological, and nuclear [CBRN] terrorism agents lack available countermeasures, the Project BioShield Act was passed into law in July 2004. Subsequently, Congress has passed additional measures to further encourage countermeasure development. For example, the 109th Congress passed the Pandemic and All-Hazard Preparedness Act, which created the Biomedical Advanced Research and Development Authority [BARDA] in the Department of Health and Human Services [HHS]. This office oversees all of HHS’ Project BioShield activities, among other duties.
Project BioShield Act has three main provisions: (1) relaxing procedures for some CBRN terrorism-related spending, including hiring and awarding research grants; (2) guaranteeing a federal government market for new CBRN medical countermeasures; and (3) permitting emergency use of unapproved countermeasures [reference 6]. The HHS has used each of these authorities, including the approval of BARDA contract awards for the development of new treatments for radiation exposure and using its authority to guarantee a government market to obligate approximately $2.3 billion to acquire countermeasures against anthrax, botulism, radiation, and smallpox.
Several companies developing product candidates for the treatment and/or prevention of ARS have received government awards under the Project BioShield Act, including those referenced in Table 2.
Table 2. Select Companies with Government Contracts for ARS
|Company||Product Candidate||Fully Valued Government Award||Market Capitalization|
|Aeolus Pharmaceuticals, Inc. (AOLS.OB)||AEOL-10150||$118 million over 5 years||$30 million|
|Cellerant Therapeutics, Inc. (private)||CLT-008||$153 million over 5 years||n/a|
|Cleveland BioLabs, Inc. (NASDAQ:CBLI)||CBLB502||$15.6 million over 3 years||$197 million|
|Derma Sciences, Inc. (NASDAQ:DSCI)||DSC127||$14 million over 5 years||$64 million|
|Osiris Therapeutics, Inc. (NASDAQ:OSIR)||Prochymal||$224.7 million contract, including purchase options, from the United States Department of Defense (DoD) to develop and stockpile Prochymal||$201 million|
What is now happening with troubled nuclear power plants in Japan could happen in the U.S., as there are nuclear power plants situated near significant seismic areas in the Midwest [reference 7]. This risk is much greater than other places, like California, because seismic energy is conveyed over 10-times more efficiently due to less fractured basement rocks. Combined with the threat of nuclear terrorism, there is a worldwide concern about exposure to radiation. Given the lack of prophylactic treatment options and the fact that management of ARS is mainly supportive, a large unmet need exists in this area.
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- The importance and unique aspects of radiation protection in medicine. Holmberg O, Czarwinski R, Mettler F. Eur J Radiol. 2010 Oct;76(1):6-10. Epub 2010 Jul 17.
- Medical response to a major radiologic emergency: a primer for medical and public health practitioners. Wolbarst AB, Wiley AL Jr, Nemhauser JB, Christensen DM, Hendee WR. Radiology. 2010 Mar;254(3):660-77. Review.
- Acute radiation syndrome: assessment and management. Donnelly EH, Nemhauser JB, Smith JM, Kazzi ZN, Farfán EB, Chang AS, Naeem SF. South Med J. 2010 Jun;103(6):541-6. Review.
- Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Waselenko JK, MacVittie TJ, Blakely WF, Pesik N, Wiley AL, Dickerson WE, Tsu H, Confer DL, Coleman CN, Seed T, Lowry P, Armitage JO, Dainiak N; Strategic National Stockpile Radiation Working Group. Ann Intern Med. 2004 Jun 15;140(12):1037-51.
- Radiation effects on the respiratory system. Hill RP. BJR Suppl. 2005;27:75-81.
- CRS Report for Congress, Prepared for Members and Committees of Congress, dated July 6, 2009, "Project BioShield: Purposes and Authorities" by Frank Gottron, Specialist in Science and Technology Policy.
- Overview of likely consequences of a magnitude 6.5+ earthquake in the central United States. J. David Rogers, Missouri University of Science & Technology.