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Radiation exposure: current and future treatments.

The March 2011 earthquake and associated tsunami in Japan damaged nuclear reactors in Fukushima and subsequently highlighted the need for better safeguards against radiation exposure. While some of the pharmaceuticals used to treat acute radiation sickness have been available for years, several others are in testing phases. These drugs hold promise not only in treating acute radiation sickness, but also in protecting the human body before it is exposed to radiation.

Effects of Radiation Exposure

Acute radiation sickness is caused by exposure of the human body to high levels of radiation in a short period of time. Mild symptoms of exposure are manifested at an exposure level of about 0.3 grays, while severe symptoms or death occur at about 50 grays. (1)

Symptoms of acute radiation sickness include nausea, vomiting, abdominal pain, diarrhea, loss of appetite, leukocytopenia (a decrease in the white blood cell count, which can lead to infection), anemia, thrombocytopenia (a low platelet count, which can lead to internal and external bleeding and poor healing of wounds), dizziness, fever, headache, hair loss, and cognitive impairment. (2) Skin damage (including redness, itching, blistering, and ulceration) may also occur. Cataracts and cancer are two complications of acute radiation sickness.

Most of the symptoms that occur are due to cellular damage caused by various types of radiation interacting with cellular molecules:

* Alpha particles. Alpha particles (helium nuclei) capture electrons from nearby atoms; if the electrons are shared by two atoms forming a molecule, then the molecule is broken. (3) The remnants of the molecule become very chemically reactive radicals that can form dangerous compounds. However, the penetrating ability of alpha radiation is limited; unless inhaled or ingested, alpha particles do not penetrate the human body.

* Beta particles. Beta particles (high-energy, high-speed electrons or positrons) can create radicals by pushing electrons from other atomic or molecular orbitals. As beta particles pass through matter, they decelerate and emit X-rays. (4) They may also excite other atoms and emit ultraviolet radiation. The ionizing power and penetrating ability of beta particles are moderate.

* Gamma rays and X-rays. Gamma rays and X-rays are high-energy, high-frequency forms of radiation that transfer energy to atoms. The atoms, in turn, transfer the energy to their electrons, which are then emitted by the atoms. These energetic electrons may behave like beta particles. (5) Although the penetrating ability of gamma rays and X-rays is high, these types of radiation are less damaging than alpha and beta particles.

* Neutrons. Due to electromagnetic and nuclear forces, neutrons interact with atoms. A high-energy neutron that encounters living material may collide with a proton, dislodging the proton from its atom. This causes the nucleus of the atom to become radioactive and to emit beta particles. In addition, the dislodged proton may ionize other atoms. (6)

When radiation breaks the chemical bonds between the atoms of molecules, radicals are created. The resulting damage to the human body depends on which molecules are broken and which nearby molecules react with the resulting radicals. (7) Cells are killed when ionizing radiation damages deoxyribonucleic acid (DNA) at the molecular level. DNA is hit by ionizing radiation. Atoms are ionized and break off of the main double-helix structure. Some of the ionized atoms bond with other parts of the DNA molecule, and some bond with other nearby atoms. These changes are considered single-strand or double-strand errors. Single-strand errors occur when atoms or molecules are missing or the wrong atoms or molecules are present on one strand of the DNA double helix. Single-strand errors are relatively easy to repair. Double-strand errors may involve complete breaks in the DNA structure. They are more difficult to repair. If there are enough DNA errors of either type, the "cell death mechanism" of the affected cell may be activated, while other nearby cells divide into new cells.

Method of Treatment

Potassium iodide is a well-known--but often misunderstood--radiation treatment drug. In reality, potassium iodide is not used to treat radiation exposure; rather, it is a prophylactic used to prevent thyroid damage due to radioactive iodine-131 (I-131). Iodine accumulates in the thyroid; and if the iodine that accumulates is radioactive, extensive thyroid damage can occur. Depending on the method by which it is absorbed and the length of time it remains in the body, radioactive I-131 is capable of damaging living cells. (8) When taken before exposure to radioactive I-131, potassium iodide saturates the thyroid's capacity for iodine so that additional iodine (such as radioactive I-131) cannot be absorbed into the body and is flushed out. However, potassium iodide does nothing to prevent radiation sickness and does not guard against any other form of radiation exposure. (9)

Prussian blue is a blue, nontoxic dye with the unique ability to bind to radioactive cesium-137 (Cs-137). Therefore, it is used as a treatment for exposure to Cs-137. (10) Prussian blue can be administered when a patient is suspected of having inhaled or ingested Cs-137. It binds to the Cs-137, which is then eliminated through bowel movements. This decreases the period of internal contamination from 110 days to about 30 days, thereby reducing internal radiation damage. (11) Substances of this nature are referred to as chelating agents.

Another chelating agent used to treat certain types of internal radiation poisoning is diethylenetriamine pentaacetic acid (DTPA). DTPA can be used for patients who have been exposed to americium, plutonium, or curium. (12) Unfortunately, DTPA is also capable of chelating minerals (such as zinc) that the body needs to produce blood cells. (13) Given that one of the potential effects of radiation poisoning is a decrease in the number of blood cells, the use of DTPA may complicate recovery.

An alternate strategy for the treatment of radiation sickness involves boosting the production of blood cells to help ward off infection. Radiation exposure can destroy bone marrow, which is responsible for the production of blood cells. Low white blood cell counts impair the body's ability to fight off pathogens, leaving an individual vulnerable to death by infection. Human granulocyte colony-stimulating factors (such as Neupogen[R] and Neulasta[R]) assist the body in producing more neutrophils (a type of white blood cell) by stimulating the production of white blood cells and aiding in their release into the bloodstream. (14) Individuals exposed to radioactive materials may be treated with human granulocyte colony-stimulating factors; however, this approach treats only one symptom of acute radiation poisoning and does not serve as a generalized prophylaxis.

The last option currently available to medical professionals for the treatment of acute radiation poisoning is supportive care. Supportive care involves treating the symptoms of acute radiation poisoning. Administering antibiotics to stave off infection and providing fluids in cases of severe diarrhea are examples of supportive care. Although supportive care does not prevent or cure radiation sickness, adequate support can improve the survival rate. (15)

Emerging Pharmaceuticals

A new class of pharmaceutical that promises to protect patients from acute radiation exposure has been developed. Two of the drugs within this class--Protectan and Ex-RAD--are currently undergoing testing. Both of these drugs may be administered well before exposure, and both help to mitigate the effects of radiation poisoning.

Human exposure to outside stimuli such as stress, infection, signals from death receptors, or ionizing radiation can result in cell apoptosis--a process of cellular death in which the number of undamaged cells that remain are insufficient to divide and replace the damaged ones. In untreated cases of acute radiation poisoning, large portions of the body are destroyed, leading to potential death. Protectan suppresses the cell death mechanism by repairing radiation-induced damage to gastrointestinal tract cells and the hematopoietic (blood and bone marrow) system. Protectan CBLB502 is a "rationally designed recombinant derivative of the bacterial protein flagellin, which binds and activates the mammalian TLR5 cell surface receptor." (16) CBLB600 Series Protectans are "synthetic derivatives of mycoplasma lipopeptide, which promote activation of the antiapoptotic NF-kappaB pathway associated with acute radiation syndrome." (17) Animal trials of Protectan have yielded promising results, and radical improvements in radiation exposure treatment are expected. However, information about the long-term cancer risks of Protectan are unavailable. The U.S. Food and Drug Administration approval of Protectan is anticipated sometime during 2012.

Ex-RAD, which is a protein kinase inhibitor, makes use of a different healing mechanism. (18) When DNA becomes damaged enough, proteins such as p53, p21, bax, c-ABI, and p73 are activated. (19) These proteins are integral in apoptotic cell death. Ex-RAD reduces the amounts of these proteins, thereby blocking cell death pathways. Studies suggest that this mechanism of inhibiting cell death signals increases the survivability of animals following a massive dose of radiation. Mice that received a dose of 7.5 grays of radiation (where the median lethal dose [LD50] is about 5 grays) exhibited an 80 percent survival rate when they were administered Ex-RAD from 24 to 36 hours after exposure--versus a 20 percent survival rate for the control group. (20) Other trials have demonstrated a prophylaxis effect when mice that sustained a dose of 8 grays of total body radiation survived after receiving Ex-RAD 24 hours before irradiation. (21) Human trials have indicated no adverse symptoms when individuals are orally or subcutaneously administered Ex-RAD. However, studies regarding long-term effects of Ex-RAD use have not been completed. (22)

Benefits of Innovative Treatments

According to the U.S. Nuclear Regulatory Commission, workers may receive a maximum dose of 1 gray of radiation to any extremity during a 1-year period as part of a planned, approved, special exposure and a maximum lifetime dose of 2.5 grays to any extremity. (23) Military guidance specifies that Soldiers involved in emergency missions may receive a dose of no more than 1.25 grays. (24)

With options for acute radiation sickness treatment and prevention expected to be available in the near future, domestic first responders and military commanders may be able to tolerate increased amounts of radiation exposure. In domestic emergency situations, it may be necessary to operate in very high-dose environments to limit the scope of disaster. In these cases, Protectan or Ex-RAD could be administered to workers to allow them to perform their duties in environments that, under current regulations, contain unacceptable levels of radiation. In addition, Soldiers may be called upon to perform missions under heavily contaminated conditions such as those encountered on a battlefield where nuclear weapons were used. The administration of drugs such as Protectan and ExRAD may allow commanders to increase allowable levels of radiation exposure for Soldiers involved in critical operations. Soldiers must continue to practice contamination avoidance and ensure that exposures remain as low as reasonably achievable; however, if these emerging pharmaceuticals prove to be effective, military forces could revise operational exposure guidelines to reflect the abilities of the pharmaceuticals.

A situation in which the enemy has detonated a radiological dispersal device poses particularly interesting challenges to operational exposure guidance. It could take several days to identify radioactive materials (which may require laboratory confirmation) in an emergency operational environment, and it is difficult to accurately predict the levels of radioactive contamination. Consequently, first responders may be exposed to high levels of various types of radiation. If radioactive I-131 or Cs-137 were used in the dispersal device, potassium iodide or Prussian blue could be used to provide a measure of treatment. However, because Protectan and Ex-RAD do not target specific isotopes, they could provide generalized protection against radiation exposure. Once radiation is identified as a hazard in a radiological dispersal attack, the administration of Protectan or Ex-RAD could be expected to increase survivability rates and possibly decrease the risk of acute radiation sickness symptoms interfering with lifesaving operations.

Several other types of drugs that may provide similar protections against acute radiation sickness are currently under development. If these pharmaceuticals are approved for human use, the number of deaths due to exposure to high-level radiation during emergency situations and wartime may be decreased. Emergency responders and Soldiers may be able to perform tasks in high-level radiation environments with few immediate adverse effects. However, due to the elevated risk of cancer associated with exposure to radiation, workers exposed to high doses of radiation must continue to be monitored throughout their lives.

Endnotes:

(1) "Acute Radiation Syndrome: A Fact Sheet for Physicians," Centers for Disease Control and Prevention, 18 March 2005, <http://www.bt.cdc.gov/radiation/arsphysicianfactsheet.asp>, accessed on 6 September 2012.

(2) Armed Forces Radiobiology Research Institute (AFRRI) Special Publication 10-1, "Medical Management of Radiological Casualties," June 2010, <http://www.usuhs.mil/afrri /outreach/pdf/3edmmrchandbook.pdf>, accessed on 6 September 2012.

(3) "Interaction of Radiation With Matter," International Web Site: Scientifically Validated Information on Chernobyl Disaster, April 1986, European Centre of Technological Safety, <http://www.tesec-int.org/TechHaz-site%2008 /Radiation-interaction.pdf>, accessed on 6 September 2012.

(4) Ibid.

(5) Ibid.

(6) Ibid.

(7) "How Radiation Affects Cells," Radiation Effects Research Foundation, 2007, <http://www.rerf.or.jp/radefx /basickno_e/radcell.htm>, accessed on 6 September 2012.

(8) "Potassium Iodide (KI)," Centers for Disease Control and Prevention, 13 March 2012, <http://www.bt.cdc.gov /radiation/ki.asp>, accessed on 6 September 2012.

(9) Ibid.

(10) "Prussian Blue," Centers for Disease Control and Prevention, 20 April 2010, <http://www.bt.cdc.gov/radiation /prussianblue.asp>, accessed on 6 September 2012.

(11) Ibid.

(12) "Facts About DTPA," Centers for Disease Control and Prevention, 11 October 2006, <http://www.bt.cdc.gov /radiation/dtpa.asp>, accessed on 6 September 2012.

(13) Ibid.

(14) "Facts about Neupogen[R]," Centers for Disease Control and Prevention, 1 March 2005, <http://www.bt.cdc.gov /radiation/neupogenfacts.asp>, accessed on 6 September 2012.

(15) AFRRI Special Publication 10-1, June 2010.

(16) "Radiation Antidote," Science Buzz, Science Museum of Minnesota, 20 April 2008, <http://www.sciencebuzz.org /buzz-tags/protectan>, accessed on 10 September 2012.

(17) Ibid.

(18) "Onconova Therapeutics Presents New Data Demonstrating Radioprotection by Ex-RAD at RRS Annual Meeting," EurekAlert! Onconova Therapeutics, 27 September 2012, <http://www.eurekalert.org/pub_releases /2010-09/poc-otp092710.php>, accessed on 10 September 2012.

(19) L. Stergiou and M.O. Hengartner, "Death and More: DNA Damage Response Pathways in the Nematode C. elegans," Cell Death & Differentiation, Scientific Reports, Nature Publishing Group, 2004, <http://www.nature.com/cdd/journal /v11/n1/full/4401340a.html>, accessed on 10 September 2012.

(20) Sanchita P. Ghosh, "Development of Ex-RAD[R] as a Radiation Countermeasure," Armed Forces Radiobiology Research Institute 50th Anniversary Radiation Countermeasures Symposium, Uniformed Services University of the Health Sciences, 15 June 2011, <http://www.usuhs.mil /afrrianniversary/events/rcsymposium/pdf/Ghosh.pdf>, accessed on 10 September 2012.

(21) Ibid.

(22) Ibid.

(23) Regulatory Guide 8.35, "Planned Special Exposure," Office of Nuclear Regulatory Research, U.S. Nuclear Regulatory Commission, August 2012, <http://pbadupws.nrc.gov/docs /ML1013/ML101370008.pdf>, accessed on 11 September 2012.

(24) Field Manual (FM) 3-11.4, Multiservice Tactics, Techniques, and Procedures for Nuclear, Biological, and Chemical (NBC) Protection, 2 June 2003.

By Captain Matthew Urban

At the time this article was written, Captain Urban was a student in the Chemical, Biological, Radiological, and Nuclear (CBRN) Captain's Career Course, Fort Leonard Wood, Missouri. He previously served as a CBRN officer, 2d Battalion, 27th Infantry Regiment, Schofield Barracks, Hawaii. He holds a bachelor's degree in chemical engineering from Texas A&M University, College Station, Texas.
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Author:Urban, Matthew
Publication:CML Army Chemical Review
Date:Dec 22, 2011
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