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SYMPOSIUM
Year : 2010  |  Volume : 2  |  Issue : 3  |  Page : 202-212 Table of Contents     

Medical radiation countermeasures for nuclear and radiological emergencies: Current status and future perspectives


1 Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization (DRDO), Brig. SK Mazumdar Road, Timarpur, Delhi - 110 054, India
2 Centre for Disaster Management Studies, Guru Gobind Singh Indraprastha University, Kashmere Gate, Delhi - 110 006, India
3 Department of Plant Sciences, Room 4D70-51, Campus Drive College of Agriculture and Bioresources, University of Saskatchewan Saskatoon, Saskatchewan S7N 5A8, Canada

Date of Submission04-Jul-2010
Date of Decision04-Jul-2010
Date of Acceptance06-Jul-2010
Date of Web Publication16-Aug-2010

Correspondence Address:
Rajesh Arora
Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization (DRDO), Brig. SK Mazumdar Road, Timarpur, Delhi - 110 054
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.68502

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   Abstract 

Nuclear and radiological emergencies (NREs) occurred globally and recent incidences in India are indicating toward the need for comprehensive medical preparedness required both at incident site and hospitals. The enhanced threat attributed toward insurgency is another causative factor of worry. The response capabilities and operational readiness of responders (both health and non-health service providers) in contaminated environment need to be supported by advancement in R & D and technological efforts to develop prophylactics and radiation mitigators. It is essential to develop phase 1 alternatives of such drugs for unseen threats as a part of initial preparedness. At the incident site and hospital level, external decontamination procedures need to be standardized and supported by protective clothing and Shudika kits developed by INMAS. The medical management of exposure requires systematic approach to perform triage, resuscitation and curative care. The internal contamination requires decorporation agents to be administered based on procedural diagnostics. Various key issues pertaining to policy decisions, R & D promotion, community awareness, specialized infrastructure for NREs preparedness has been discussed. The present review is an attempt to provide vital information about the current status of various radiation countermeasures and future perspective(s) ahead.

Keywords: Free radicals, linear energy transfer, radiation countermeasures


How to cite this article:
Arora R, Chawla R, Marwah R, Kumar V, Goel R, Arora P, Jaiswal S, Sharma RK. Medical radiation countermeasures for nuclear and radiological emergencies: Current status and future perspectives. J Pharm Bioall Sci 2010;2:202-12

How to cite this URL:
Arora R, Chawla R, Marwah R, Kumar V, Goel R, Arora P, Jaiswal S, Sharma RK. Medical radiation countermeasures for nuclear and radiological emergencies: Current status and future perspectives. J Pharm Bioall Sci [serial online] 2010 [cited 2019 Aug 17];2:202-12. Available from: http://www.jpbsonline.org/text.asp?2010/2/3/202/68502

Nuclear and radiological emergencies (NREs) continue to haunt humanity, particularly in the aftermath of the 9/11 attacks in the US, the 11/26 attacks of Mumbai, the Chernobyl incident and the Goiania accident of Brazil. Nuclear Emergency is a situation in which there is an energy release resulting from a nuclear chain reaction or from the decay of toxic radiological products of reaction, e.g., Chernobyl, Tokamura Kysthym, etc. All the emergencies other than nuclear emergency, which have the potential hazard of radiation exposure, are referred to as radiological emergencies, e.g., accidents at Goiania, San Salvador, Lilo, Istanbul, Yanango, Tammiku, Panama and a recent accident in Mayapuri with level 4 severity at an international scale. The Mayapuri incidence in New Delhi in April 2010 exhibited that any inadvertent lapse in the product life cycle of even sealed radioactive substances may lead to release of open radiation source in the civilian domain. One death has already been reported attributing toward acute radiation sickness and six other cases of local radiation injuries, beta burns and radiation sickness have also been observed. [1] Although the likelihood of a major accident at a nuclear facility is low, should such an accident occur, protective actions near the incident site and monitoring of radiation at longer distances need to be taken to protect the public. If a radiological source from an industry or a medical center is leaked out, it must be assumed that the source may be in the possession of people who may not know its nature and hazard, who can handle it, break it and spread contamination. Unknowingly handling unshielded/unconfined dangerous quantities of radioactive material can result in permanent injuries from external exposure or inadvertent ingestion and in localized contamination, requiring cleanup. Unknowingly handling quantities 10-100 times larger than what is considered "dangerous" could be immediately life threatening. A comparative analysis of WMD effects revealed that release of Sarin nerve gas with a density of 70 mg/cm 3 in a covered area of 0.22 km 2 leads to an average death count of 60-200, while in a covered area of 10 km 2 , 30 kg of anthrax with a density of 0.1 mg/cm 3 or 12.5 kt device achieving 5 lbs/in 3 over pressure leads to an average death count of 30,000-100,000 and 23,000-80,000, respectively. A 1.0-Mt hydrogen bomb can lead to deaths of 570,000-1,900,000 in a covered area of 190 km 2 . [2] It indicates the vast range of potential of nuclear and radiological devices.

Radioactive contamination of the public or of public places could occur as a result of members of the public, unaware of the hazard, handling a lost or stolen dangerous source. Contamination could also occur as the result of a deliberate act. Many thousands of transport operations occur daily throughout the world in connection with the use of radioactive materials. All forms of transport are involved, including road, rail, air and sea. A transport accident involving radioactive material can occur anywhere. Transport emergencies involving correctly packaged radioactive material, and where the packages have not been damaged in the accident, normally presents no significant radiological hazard. Minor traffic accidents are unlikely to damage a package sufficiently to create a significant radiological hazard. Nevertheless, there is a small possibility of a release resulting in an inhalation hazard near the source, contamination that is hazardous if ingested, and hazardous levels of external exposure from being near the accident for an extended time. These emergencies are often discovered, unfortunately, after several people have been exposed and there has been considerable spread of radioactive material. [3]

The necessity to develop radiation countermeasure agents has emerged as a priority area for most nations. Ionizing radiation can be extremely harmful to exposed individuals. Radiation could be dispersed in several ways: without detonation, detonation with conventional explosives, and nuclear detonation. All the above means, especially the last one, can lead to mass casualties within seconds. This may occur during reactor accidents as described above, or nuclear warfare or a terrorist activity. Hence, radiation countermeasures both at medical and physical levels are the need of the hour.


   History of Radiological Emergencies Top


Nuclear weapon development and testing has been conducted by many countries since the 1940s. Because leaders of the allied nations during World War II were concerned that Germany was producing nuclear weapons, the Manhattan Project was born. The project brought together many of the world's leading scientists. The project was unable to produce a fission-based weapon before the surrender of Germany in 1945 but was able to produce two weapons later that year that were used in the US atomic bombings in Japan. In 1949, the Soviet Union conducted its first nuclear explosion test, which marked the beginning of the Cold War. The United Kingdom, France, and the People's Republic of China also demonstrated nuclear capabilities during the Cold War. It is thought that since 1949 there have been around 2000 nuclear test explosions throughout the world. In 1950, President Truman announced a program to develop a hydrogen or fusion bomb in response to the Soviet Union's nuclear testing. The first bomb tested by the United States on a remote island in 1952 was 450 times the power of the bomb that fell on Nagasaki. Other countries, including the Soviet Union, France, the United Kingdom, and the People's Republic of China, also developed similar devices in the years to follow. The historical perspectives describe the needs of society from radiobiologists and radiation protection community. [4]

The atomic bomb

The first radiological public health emergency followed the use of the atomic bomb during World War II. The United States dropped the first bomb on Hiroshima, Japan, on August 6, 1945, resulting in about 60,000-70,000 deaths. When that failed to persuade Japan to surrender, the United States dropped a second bomb on Nagasaki on August 9. That bomb resulted in about 40,000 deaths. Five hours after the second bomb was dropped, the Japanese surrendered unconditionally. Most of the damage from these bombs resulted from the flash, shockwave, and subsequent fire.

Three Mile Island

The threat of accidental radiological contamination became real to Americans with the Three Mile Island accident on March 28, 1979, near Middletown, Pennsylvania. Equipment malfunction and human error combined to cause one of the reactor cores to melt down and release radioactive gases into the atmosphere. In the following few days, additional radioactive releases took place. There was a precautionary evacuation advisory for pregnant women and young children within a 5-mile radius of the plant. Most of the radiation was contained; therefore, offsite releases were minimal and no apparent injuries resulted. The major health effect for portions of the nearby population was mental stress. The plant experienced significant damage. The cleanup process raised health concerns because of the radioactive material trapped in the containment and auxiliary buildings. This accident was a close call. The scope of what could have happened served as a wakeup call for regulators who subsequently tightened and heightened the plant's safety oversight. Several factors contributed to the accident: inadequate training of Three Mile Island operators, unclear operator instructions, and design flaws in the control room instructions and layout.

Chernobyl

The most severe radiological accident to date occurred at the Chernobyl Nuclear Power Plant in the former Soviet Union on April 25-26, 1986. A reactor exploded, releasing massive amounts of radiation into the environment. The local population of about 135,000 within an 18-mile radius of the plant was evacuated. The accident caused 31 deaths, but the extent of delayed health effects is uncertain. The Chernobyl reactor would not have met Western safety standards. Fourteen such reactors are still operational in the former Soviet Union. [1]


   Radiological Terrorism Top


All criminal acts are directed against a state, anticipated or calculated, to create a state of terror in the minds of general public. Society's and individuals' concerns about the contrary effects from radiation are rationally augmented many times when radiological terrorism is considered where the threat of possible terrorist attacks using radioactive materials or nuclear warheads has become prominent. The continuum of events includes industrial sabotage, the use of an explosive or non-explosive radiological dispersal device, the placement of a radiological exposure device in a public facility and the use of an improvised nuclear device. Contaminated or exposed individuals could suffer radiation injuries warranting specialized treatment. The source of exposure or contamination could represent a severe hazard unsuspected by those in the vicinity. The material could be further dispersed by human activity and could involve widespread contamination of areas and local products. If public and financial institution concerns are not promptly addressed, there can be significant adverse and inappropriate public reaction and economic consequences. [5]

Limited stays (minutes) near the material by response personnel should not be hazardous but holding the material could produce injuries in minutes. The inhalation hazard is probably limited to the plume (e.g., within the smoke) within 100 m of a source in a fire or explosion. Resuspension of material on the ground should not be hazardous except for Plutonium (Pu) contamination. External contamination is probably not hazardous but inadvertent ingestion (e.g., by putting hands in the mouth) of contamination could be hazardous. Excess radiation-induced cancers should not be detected following these types of emergencies, even those involving large amounts of radioactive material.

The consequences of an event relate to the physical and medical damage of the event itself, the financial impact, and the acute and long-term medical consequences, including fear of radiation-induced cancer. The enormity of a state-sponsored nuclear event is so great that limited detailed response planning had been done in the past, as compared to the work now ongoing. On the basis of scenario modeling, some attention has been paid to this area. Medical response planning includes medical triage, distribution of victims to care by experienced physicians, developing medical countermeasures to mitigate or treat radiation injury, counseling and appropriately following exposed or potentially exposed people, and helping the local community develop confidence in their own response plan. Optimal response must be based on the best available science. This requires scientists who can define, prioritize and address the gaps in knowledge with the range of expertise from basic physics to biology to translational research to systems expertise to response planning to healthcare policy to communications. Not only are there unique needs and career opportunities, but also there is the opportunity for individuals to serve their communities and country with education regarding radiation effects and by formulating scientifically based government policy. [6]


   Radiation and its Biological Effects Top


The nature and extent of damage caused by ionizing radiation depend on a number of factors including the amount of exposure (energy strength), the frequency and/or duration of exposure, and the penetrating power of the radiation to which an individual is exposed. Acute exposure to very high doses of ionizing radiation is rare but can cause death within a few days or months. The sensitivity of the exposed cells also influences the extent of damage. For example, rapidly growing tissues, such as developing embryos, are particularly vulnerable to harm from ionizing radiation. The direct effect on cells refers to direct impact with a particularly sensitive atom or molecule in a cell while indirect effect on cells includes interaction with water molecules in the body (80%) where the deposited energy in the water leads to the creation of unstable, toxic hyperoxide molecules which then damage sensitive molecules and afflict subcellular structures like nucleic acids, membrane lipids and proteins. This impact can lead to the detrimental effects. [7]

Linear energy transfer

With the course of direct action of radiations, once exposed, the atoms of the target itself can get ionized or excited, thus initiating the chain of events that lead to damage. This is the dominant process as far as high linear energy transfer (LET) radiation is concerned, e.g., neutrons or alpha particles. On the other hand, radiation may interact with other atoms or molecules in the cell to produce free radicals that diffuse and damage the cellular components. This is called the indirect action of radiation. A free radical is a free atom or molecule carrying an unpaired orbital electron in the outer shell. The effects of low-LET radiations are caused mainly by generation of reactive oxygen species (ROS).

Free radical induced damage

Most of the radiation-induced damage to biomolecules in aqueous media is caused by the formation of free radicals resulting from the radiolysis of water. Exposure of biological systems to radiation results in radiolytic cleavage of water, giving rise to e-aq., OH, and H . Radiation causes breakage of one of the oxygen-hydrogen covalent bonds in water, leaving a single electron on the hydrogen atom and one on the oxygen atom and creates radicals, especially hydroxyl radicals. Molecular oxygen, being biradical in nature, is an important electron acceptor. It accepts unpaired electrons, giving rise to several partially reduced reactive species like superoxide, hydroxyl, peroxyl, and hydroperoxyl radicals. The generation of singlet oxygen, a major reactive species formed by the action of hydroperoxyl radical with superoxide anion, can lead to damaging effects on the biological system. These radicals then undergo secondary reactions with dissolved O 2 , ROS, or with cellular solutes, leading to development of oxidative stress or multiorgan dysfunction syndrome. [1],[7]


   Radiation-Induced Syndromes Top


The local exposure of radiation on the body leads to Local Radiation Injury (LRI) while the whole body exposure may lead to Acute Radiation Syndrome (ARS).

Local radiation injury

LRI, [1] caused by high doses of radiation (>8-10 Gy), produces signs and symptoms similar to a thermal burn except for the striking delay in the onset of clinical changes, from several days to a week or longer. The most important underlying fact is that in most of the cases, it is generally observed that the exposed individual does not know that it is a local radiation injury. The chances of misdiagnosis cannot be overruled as generally prodromal symptoms are not present. The severity of LRI depends not only on the dose and type of radiation, but also on the location and size of the area exposed. Although not usually life threatening, its delayed effects can result in serious impairment.

Clinical effects on skin can be related as: a) 4-5 Gy: Simple and transitory hair loss; b) 5-12 Gy: Erythema, followed by hyperpigmentation; c) 12-15 Gy: Dry epithelitis, with erythema and desquamation; d) 15-25 Gy: Moist epithelitis; and e) 25-30 Gy: Skin radio-necrosis. With respect to radiation dose rate, effects on the skin are not well established. Late effects of skin include skin atrophy, cutaneous fibrosis, hyper/hypo pigmentation, telangiectasia, hyperkeratosis, and alterations in nails and hair. It may lead to functional impairment, secondary necrosis, and even cancer.

Acute radiation syndrome

ARS [1] is an acute illness caused by irradiation of the whole body (or a significant portion of it). It follows a somewhat predictable course and is characterized by signs and symptoms which are manifestations of cellular deficiencies and the reactions of various cells, tissues, and organ systems to ionizing radiation. Immediate, overt manifestations of the acute radiation syndrome require a large (i.e., hundreds of rem, usually whole body) dose of penetrating radiation delivered over a short period of time. Penetrating radiation comes from a radioactive source or machine that emits gamma rays, X-rays, or neutrons. The signs and symptoms of this syndrome are nonspecific and may be indistinguishable from those of other injuries or illness.

The ARS is characterized by four distinct phases: a prodromal period, a latent period, a period of illness, and one of recovery or death. During the prodromal period patients might experience loss of appetite, nausea, vomiting, fatigue, and diarrhea; after extremely high doses, additional symptoms such as fever, prostration, respiratory distress, and hyperexcitability can occur. However, all of these symptoms usually disappear in a day or two, and a symptom-free, latent period follows, varying in length depending upon the size of the radiation dose. A period of overt illness follows and can be characterized by infection, electrolyte imbalance, diarrhea, bleeding, cardiovascular collapse, and sometimes short periods of unconsciousness. Death or a period of recovery follows the period of overt illness. In general, the higher the dose, the greater the severity of early effects and the greater the possibility of late effects. Depending on dose, the following syndromes [7] can be manifested.







  1. Hematopoietic syndrome characterized by deficiencies of WBC, lymphocytes and platelets, with immunodeficiency, increased infectious complications, bleeding, anemia, and impaired wound healing.




  2. Gastrointestinal syndrome characterized by loss of cells lining intestinal crypts and loss of mucosal barrier, with alterations in intestinal motility, fluid and electrolyte loss with vomiting and diarrhea, loss of normal intestinal bacteria, sepsis, and damage to the intestinal microcirculation, along with the hematopoietic syndrome.




  3. Cerebrovascular/central nervous system syndrome primarily associated with effects on the vasculature and resultant fluid shifts. Signs and symptoms include vomiting and diarrhea within minutes of exposure, confusion, disorientation, cerebral edema, hypotension, and hyperpyrexia. Fatal in a short time.




  4. Skin syndrome can occur with other syndromes; characterized by loss of epidermis (and possibly dermis) with "radiation burns."





   Medical Countermeasures for Radiological and Nuclear Emergencies Top


The countermeasures can be divided into various categories; a) radiation mitigators; b) radiation prophylactics; and c) therapeutic regime. Radiation mitigators include prophylactics to be given prior to known exposure in a certain time window extendible to immediate care to the victims at the incident site after exposure to mitigate its impact. Radiation prophylactics include radiation protectors, antidotes that need to be immediately administered to restore constitution levels of enzymes (especially in case of Chemical, Biological, Radiological, and Nuclear combined exposure incidents) and antioxidant supplementation/food aid prophylactics to enhance the immune status of an individual (responder) by strategic development of physiological status. Therapeutic regime [1] includes decontamination, decorporation agents, antibiotics and symptomatic care drugs, etc.

Managing prior to radiation exposure

The use of radiation for therapeutic and human welfare has been associated with skeptical cynicism. Radiation exposure may be of low level (industrial, medical, and other related fields) or of high level as in the case of nuclear accidents or nuclear wars. There arises a need for protection of masses at all costs. Deleterious effects of radiation on biological system develop in a chronological sequence, starting from the induction of primary lesions in the biomolecules and their structures, educing repair processes leading to cell death or transformation responsible for morbidity, genetic disorder, and cancer. Hence, it is not ambiguous to necessitate effective measures to counter the health hazards associated with ionizing radiation exposure. Effect of radiation depends upon three guiding factors: time, distance, and shielding. The radiation countermeasure development will be based on the four major hazardous effects of the radiation [Figure 1]. Once the generation of free radicals occurs, the immediate effects are lipid peroxidation, DNA damage, and protein oxidation. Hence, the drugs that prevent the initial radiation injury can hopefully comprise a) free radical antioxidants, b) hypoxia management, c) enzymatic detoxification, and d) oncogene targeting agents. Also, prevention of macromolecular damage becomes the next urgent priority when it comes to radiation countermeasure. A potent countermeasure will require a) hydrogen transfer and b) enzymatic repair. [1] A cocktail should comprise drugs that stimulate proliferation of surviving stem and progenitor cells, i.e., immunomodulators, growth factors and cytokines, and maintenance of homeostasis. A radiation countermeasure agent is expected to provide good protection against acute and chronic radiation damage, to be suitable for oral administration, should be rapidly absorbed and distributed throughout the body, should not show any toxicity including that on the behavior, should have long shelf life, should be easy in handling and storage, and readily available and inexpensive for mass usage. Some of the research products (under different stages of research levels) are given in [Table 1]. [7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17] Recently, a novel class of radiation countermeasures (5-androstene steroids) 5-androstenediol (5-AED), a naturally-occurring steroid hormone, enhances resistance to infection and survival after exposure to ionizing radiation. Development of enzyme mimetics, e.g., superoxide dismutase (SOD)/catalase mimetic and hematopoietic microenvironment mechanisms including elucidation of signaling molecules involved in hematopoietic niche function of human osteoblasts after radiation injury are some of potential technologies. Apart from the conventional approaches, new ways to mitigate the impact of radiation exposure are also needed.
Table 1 :Potental agents available for radiation exposure management

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Figure 1 :Major hazards of radiation exposure (cascading effects)

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Pharmacologic strategy

It is the most common out of all strategies currently being used. The intent here is to deliver the pharmacologic [18] sometime prior to exposure either orally, by injection, or even by transdermal or transmucosal absorption. Ideally, the protectant should be easily administered and well tolerated, with no signs of toxicity or performance decrement. It also provides an extended time window of protection, as from hours to days depending upon the nature of exposure threat, suspected or otherwise. An approach that can be used to provide adequate radioprotection over an extended period in non-clinical situations may be achieved by using one of the following methods: a) simple dose reduction alone or coupled with supplementation with non-toxic drug adjuvants; b) use of anti-emetics like granisteron to quench drug induced toxicity; c) slow release drug delivery systems designed to reduce the toxic effects of bolus drug administration; and d) chemical engineering.

Radioprotective pharmacologics

Amifostine, phosphorothioates, phosphonol are very potent and systemic radioprotective agents, [18] but they are not widely used due to their limited use in clinical application only. There have been efforts to develop new formulation and delivery systems for amifostine in order to better manage drug toxicity and to enhance drug efficacy.

Chemical re-engineering

Attempts to chemically engineer [18] , or to re-engineer, phosphorothioate analogs for optimal radioprotection have been pursued for close to five decades, with research efforts being focused on enhancing radioprotective attributes, improving pharmacology, and reducing toxicity.

Nitroxides

In electron paramagnetic resonance spectroscopy, nitroxides [18] , a class of stable free radical compounds, have been used as biophysical probes. More importantly, recent studies on nitroxides have corroborated their in vitro antioxidant activity, i.e., protecting mammalian cells against radiation cytotoxicity induced by proxidants. Getting positive results from the above mentioned studies led to the interest of nitroxides as radiation countermeasure agents. Tempol, a cell permeable hydrophilic nitroxide, though carries substantial risk of symptoms relating to reduction of arterial blood pressure, when administered, has been shown to be an in vitro as well as an in vivo radiation countermeasure agent.

Reducing drug dosing levels

It has been shown previously that low doses of amifostine (~25-75 mg/kg) delivered shortly prior (~30 minutes) to acute, whole-body gamma irradiation surprisingly can provide significant protection to hematopoietic tissues of experimental mice and, in particular, to vital progenitorial marrow compartments where protection ratios generally range from 2 to 3. Comparable findings of amifostine being well tolerated by radiotherapy patients following administration by subcutaneous injections have been reported by several workers. Similarly, oral administration of phosphonal (WR-3689) at substantially higher dose levels to naοve, non-human primates were reported to be well tolerated with good bioavailability for the orally administered drug and sustained presence in blood for several hours following drug administration.

Managing after radiation exposure/contamination

The practice of standard methodological protocol for medical management of exposure and external and internal contamination is one of the primary aspects. Exposure management is based on symptomatic assessment of dose reconstruction strategies. [Figure 2] illustrates the basics of such protocols.
Figure 2 :Basic strategy for triage and decisions over medical therapies (based on Meteropol grading and lymphocyte counts, combining as a decision tool)

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Treatment of exposed victims

The various therapies suggested for medical management of acute radiation syndrome include substitution, simulation, and stem cell transplantation. Choosing an appropriate therapy is based on RC category or simply lymphocyte counts [Figure 2] will determine it. If the lymphocyte count during the first week is within 0.2-0.5 g/l (200-500 cells/΅l), spontaneous recovery is possible, and the therapy should comprise isolation, antibiotics, and supportive treatment, including platelet infusion. Growth factors can also be used. If the lymphocyte count in the first week is lower than 0.2-0.5 g/l, the stem cells are probably irreversibly damaged. In such cases, in addition to therapy described in the former case, additional growth factor therapy is a method of choice. Treatment with growth factors and bone marrow transplantation (BMT) has to be considered if the lymphocyte count within the first week is less than 0.1 g/l. In severe cases involving patients exposed to whole body doses exceeding 9 Gy, it is necessary to observe the HLA compatibility for allogenic BMT and continue with BMT. It is essential to provide necessary supportive therapy which is critical for overall management of exposed victims. The supportive therapies include anti-emetic, analgesic, brain edema management, adapted nutrition, modalities to prevent infections, and skin treatment. [1]

Managing external contamination

Radioactive decontamination aims toward preventing the spread of radioactivity and to reduce the radioactive contaminant burden from the body. Decontamination should be performed with the following priorities: breathing zone, site of intravenous access, wounds, mouth, eyes, hairs, high level skin areas and low level skin areas (head down body to toes). It is essential to take necessary precautions so that the washed radioactive material does not enter into the nose, mouth, or wounds. Avoid mechanical and/or thermal trauma; do not use harsh cleansers which may compromise skin integrity. Change gloves and survey hands frequently to prevent the spread of contamination to other sites. Perform decontamination by single inward movements or circular motion so that the contaminant gets concentrated prior to removal. After washing, rinse the area with tepid water and gently dry using the same motions. After drying, the skin should be remonitored to determine the effectiveness of decontamination. Washing may be repeated three times. According to the radionuclide involved, specific solutions may be used instead of nonspecific solutions. Nail clippers can be used to remove most of the residual contamination under the nails. Hair should be washed with a mild shampoo (avoid protein based shampoos with conditioners). For people extensively contaminated, start showering at the head and proceed downward to the feet, keeping materials out of natural orifices and wounds. Replace shower by bathing for seriously injured patients. For oral cavities, brush teeth with toothpaste, rinse mouth with 3% citric acid. To decontaminate pharyngeal region, gargle with 3% hydrogen peroxide solution. Noses need to be rinsed with tap water or physiological saline. Blow your nose gently. Eyes should be rinsed by directing stream of sterile water or physiological isotonic saline solution from inner to outer canthus while avoiding contamination of naso-lacrimal gland. Ear rinsing is required to be done externally with water; rinse auditory canal using ear syringe. It is essential to take necessary steps to decontaminate cavities, especially folds of skin areas, as these are the sites where contaminants are generally ignored. Institute of Nuclear Medicine and Allied Sciences (INMAS), Defence Research and Development Organization (DRDO) has developed a skin decontamination kit housed with all the required decontamination solutions and medicare essentialities to manage external radioactive contamination. [1],[19]

Complete decontamination is generally not possible because some radioactive material can be fixed to the skin surface. The objective of contamination efforts is to lower contamination levels to a level twice that of background (background is considered to be 0.05 mR/hour). Decontamination should be performed until the radiation level has reached twice the background level or until no further reduction in radiation level can be achieved (not to exceed three attempts). After decontamination, the victim will be monitored by the radiation safety officer and/or the nuclear medicine technologist. No item within the decontamination area should be removed from this area without this item being monitored by these individuals. After decontamination, the victim should be admitted to the hospital for observation. Documentation of clinical symptoms and recording laboratory test results should be done at regular intervals as per the prescribed procedures. [1]

Treatment of internal contamination

Once radioactive materials cross cell membranes, they are said to be incorporated. Incorporation is a time-dependent, physiological phenomenon related to both the physical and chemical natures of the contaminant. Incorporation can be quite rapid, occurring in minutes, or it can take days to months. Thus, time can be critical and prevention of uptake is urgent. Several methods of preventing uptake (e.g., catharsis, gastric lavage) might be applicable and can be prescribed by a physician. Some of the medications or preparations used in decorporation might not be available locally and should be stocked when a decontamination station is being planned and equipped. Examples of specific agents used for selected radionuclides are mentioned as in [Table 2]. The details of some specific decorporation agents have been discussed below.
Table 2 :Decorporation agents: Medical management of internal radioactive contamination*

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Potassium iodide

Potassium iodide was also approved in 1982 by the US Food and Drug Administration (FDA) to protect the thyroid glands from radioactive iodine (CDER, 2001). In the event of an accident or attack at a nuclear power plant, or fallout from a nuclear bomb, several volatile fission product radionuclides may be released. Iodine-131 is a common fission by-product and is particularly dangerous as the body concentrates it in the thyroid gland, which may lead to thyroid cancer. By saturating the body with a source of stable iodide prior to exposure, inhaled or ingested iodine-131 tends to be excreted. Potassium iodide 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 ferric hexacyanoferrate(II) calcium and zinc salts of diethylenetriamene pentaacetate. Potassium iodide's (KI) value as a radiation protective (thyroid blocking) agent was demonstrated at the time of the Chernobyl nuclear accident, [20],[21] when Soviet authorities distributed it in a 30-km zone around the plant. The purpose was to protect residents from radioactive iodine, a highly carcinogenic material found in nuclear reactors which had been released by the damaged reactor.

5-Androstenediol

5-Androstenediol (androst-5-ene-3-beta,17-beta-diol or 5-AED) is one of two androstenediols. Its potential use as a radiation countermeasure was studied by Hollis-Eden Pharmaceuticals under the tradename "Neumune" for the treatment of acute radiation syndrome. [22] The clinical trials on rhesus monkeys were successful. According to the Hollis-Eden report, only 12.5% of the 40 Neumune-treated animals died versus 32.5% in the placebo group (Hollis-Eden, 2007). 5-AED stimulated interleukin-6 and granulocyte colony-stimulating factor (G-CSF) secretion. The survival-enhancing effects of 5-AED on clonogenic cells were abrogated by small interfering RNA inhibition of NFkB gene expression and by neutralization of G-CSF with antibody. The effects of 5-AED on survival and G-CSF secretion were blocked by the NFkB inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). [23] 5-AED is a direct metabolite of the most abundant steroid produced by the human adrenal cortex, dehydroepiandrosterone (DHEA). 5-AED is less androgenic than 4-AED, and stimulates the immune system. When administered to rats in vivo, 5-AED has approximately 1/70 the androgenicity of DHEA and 1/185 the androgenicity of androstenedione. Because it induces production of white blood cells and platelets, 5-AED is being developed as a radiation countermeasure by the Armed Forces Radiobiology Research Institute.

Prussian blue

The key colored substance in Prussian blue pigment is an insoluble inorganic compound composed of iron and cyanide ions, with water. It has the idealized formula Fe 7 (CN) 18 with 14-16 H 2 O. Prussian blue's ability to incorporate cations that have one unit of positive charge makes it useful as a sequestering agent for certain heavy metal ions. Pharmaceutical grade Prussian blue in particular is used for patients who have ingested thallium or radioactive cesium. According to the International Atomic Energy Agency, an adult male can have at least 10 grams of Prussian blue per day without any serious harm. The US FDA has determined that the "500 mg Prussian blue capsules, when manufactured under the conditions of an approved New Drug Application (NDA), can be found safe and effective therapy" in certain poisoning cases. [24] Radiogardase (Prussian blue insoluble capsules) is a commercial product for the removal of cesium-137 from the bloodstream.


   Key Medical Issues that Need Urgent Attention: Medical Management Top


Nuclear emergencies, including covert terrorist attacks and high radiation environments, warrant the development of radioprotective agents. Radioprotective drug development is a very tedious process and encompasses the application of techniques in drug design, chemistry, radiation biology, and pharmacy. The issues of toxicity and effectiveness are of paramount importance. In addition, the shelf life of the formulation, effective therapeutic window, suitability of different routes of administration, etc. have to be taken into account. A plethora of drugs of synthetic origin have been tested, and amifostine (WR-2721) is being used in clinical practice. However, its use is associated with inherent toxicity. Attention has now been directed toward natural products as an alternative safe, yet effective modality. DRDO has taken up an ambitious program for screening of indigenous herbs with antioxidant properties from the high-altitude region Himalayan plants. Many of the plants screened exhibited radioprotective efficacy, and some promising plants, viz., Podophyllum hexandrum, Hippophae rhamnoides, and Rhodiola imbricate, were found to possess immense potential as radioprotective agents and were therefore subjected to fractionation and evaluation of bioactivity. There are several developmental and formulation issues that need urgent attention. [7]

Pre-formulation studies include toxicity studies (LD50 determination), effective dose determination to be incorporated in dosage form, dose response relationship to determine minimum effective dose and maximum tolerable dose (therapeutic window), pharmacokinetics of drug through different routes, determination of plasma half life (t1/2 ), biotransformation and metabolic studies, mode and route of excretion, plasma protein binding, pre-systemic metabolism (first pass effect), studies on herb-drug and food-drug interactions, etc. Pharmaceutical considerations that need to be assessed include solubility, particle size, surface area, partition coefficient, color, odor, taste, interaction and compatibility with other drugs/excipients and in formulation, etc. Physicochemical stability and shelf life of the radioprotective drug also need to be worked out. Formulation considerations include choice of dosage form, e.g., tablet/capsules/oral liquid/cream or injectible, etc. Conventional and novel forms of formulations need to be assessed, e.g., controlled release/sustained release, use of polymers to reduce dose and dosage frequency, use of drug carrier system formulated with suitable bioreactor. [18] Advances in nanotechnology also need to be harnessed along with other methods involving drug carriers, e.g., micro/nanoparticles, micro and nano emulsion, liposomes, etc. Good Manufacturing Practices (GMP), current Good Manufacturing Practices (CGMP) and Good Laboratory Practice (GLP) norms need to be followed and approval of regulatory authorities is also essential. Pharmaceutical testing of dosage form, drug content and content uniformity, drug release, shelf life, bioavailability and bioequivalence studies are the other important parameters to be studied. Attention needs to be paid to these areas so that radioprotective drugs of herbal origin become a reality. [7]

The areas of medical management calls for measures for assessment of radiation dose, triage of victims, definitive treatment of radiation and combined-injury casualties, and planning for emergency services. However, the complexities linked with each step pose research queries to be answered by the researchers. To quote an example, the field of combined injury is relatively unfamiliar to burn surgeons. [1] The mortality and morbidity of combined injury victims is higher than that of the injuries separately. The secondary consequences of radiation exposure, e.g., immunosuppression, infection, bleeding, and fluid and electrolyte loss, significantly affect the management plan for burn victims. Thus, it is imperative to give a comprehensive view to the overall effects caused by burns, blast injuries, physical and psychosocial trauma, and/or sepsis during a radiological and nuclear emergency.

The medical management of each aspect requires intervention of a specific expert, which indicates the integrated role of various medical specialists. In terms of medical preparedness for burns, the guidelines on medical preparedness and mass casualty management have mentioned the number of burn centers to be developed with respect to the risk and threat analysis of the area. The guidelines have also described the development of apex, regional, and local trauma centers. [6] However, these two isolated management approaches will be brought together under a single roof for the management of radiation injuries. Such analysis revealed the need for the training of the medical professionals in the areas of management of such patient/casualties and makes themselves acquainted with advanced technologies which can support fast and reliable diagnosis and defining the course of treatment thereafter.


   Managing the Overall Menace Top


A large-scale radiological incident would result in an immediate critical need to assess the radiation doses received, which requires diverse, integrated diagnostic and dosimetric tools with accuracy and precision. [ 25] The post disaster scenario will create a hue and cry scene amongst the masses affected. Not only medical but also physical countermeasures will prove equally important. Till date, we have no affirmative answer to the first few hours of the post radiation incident. Planning and management of the affected masses can come into the action only at a 12-24 hour push. [ 26] The medical needs of a patient exposed to radiation initiate with the question whether an individual is really exposed to any radiation or specifically sufficient radiation dosage that can illicit biological problems or may cause death. However, the precise answer can only be achieved by dose reconstruction by using evidences from the incident site, biodosimetry, dynamic changes in symptoms over a period of time. The information whether the victims is evacuated from the affected site in the radiation contaminated zones or nearby zones where there are limited spreads etc., can provide significant clues in dose reconstruction which led to the basis of medical diagnostics. During a mass casualty incidence, the medical professionals at the hospitals are generally based on the triage band given at the incident site and time of exposure in the first sheet of investigation. The various biological samples are required to be taken for diagnostic purposes to affirm the internal status of the patient followed by adequate symptomatic care. The clinical approach requires medical management of all vital systems of body to be protected, however the probabilistic models to predict the radiation dose based on the biological status are not available in the country, limiting the approach to supportive care. It is therefore essential to acquire global partnership to address these issues. An integration of global resources for biodosimetric assessment is essential to manage large-scale incidences. [ 27] Such systems in place can reassure the decision making for a) efficient secondary triage, 2) multi-parameter approach for defining best-treatment strategies, 3) clinical prognosis and assessment of risk, and 4) reassurance and psychological support for those potentially exposed, or "worried-well". [ 27] Development of dedicated homeland defence security, comprising well-trained and equipped officials would prove combative and to be an immediate relief delivery option. Planning done on the basis of scenario modeling includes medical response, i.e., medical triage, distribution of victims, developing medical countermeasures to mitigate or treat radiation injury, counseling and appropriately following exposed or potentially exposed people, and helping the local community develop confidence in their own response plan. [ 4] Optimal response must be based on the best available science. Assessment of Health and Medical Care Delivery would include the following points for consideration: delivery of health and medical care, pharmaceutical supply, potable water, safe food, and sanitation and hygiene, injury and illness surveillance, vector control, solid waste, hazardous materials, mental health, sheltering and housing, mass congregation, handling of the deceased (humans and animals), staffing, rumor control, public service announcements, and media access. National preparedness standards will also include the strategic national stockpile (already adopted in USA). National Disaster management association is already working in this direction.

 
   References Top

1.Sharma RK, Chawla R, Tripathi R. Management of CBRN Casualties at Hospitals. New Delhi: INMAS; 2010.  Back to cited text no. 1      
2.Wagner AR. Terrorist Use of New Technologies. In: Katona P, Intriligator MD, Sullivan JP, editors. Countering Terrorism and WMD: Creating a global counter-terrorism network. London and New York: Routledge, Taylor and Francis Group; 2006.   Back to cited text no. 2      
3.Mettler FA, Voelz GL. Major radiation exposure-what to expect and how to respond. N Engl J Med 2002;346:1554-61.   Back to cited text no. 3      
4.Coleman CM, Parker GW. Radiation terrorism: What society needs from the radiobiology-radiation protection and radiation oncology communitie. J Radiol Prot 2009;29:A159-69.  Back to cited text no. 4      
5.National Disaster Management Guidelines. Management of Nuclear and Radiological Emergencies. New Delhi: A Publication of NDMA; 2009.  Back to cited text no. 5      
6.National Disaster Management Guidelines. Medical Preparedness and Mass Casualty Management. New Delhi: A Publication of NDMA; 2007.  Back to cited text no. 6      
7.Arora R, Gupta D, Chawla R, Prasad J, Singh S, Sharma AK,et al. Radioprotection by plant products: Present status and future prospects. Phytotherap Res 2005;19:1-22.  Back to cited text no. 7      
8.Tan DX. Melatonin: A potent, endogenous hydroxyl radical scavenger. Endocr J 1993;1:57-60.  Back to cited text no. 8      
9.Tan DX, Manchester LC, Reiter RJ, Qi W, Karbownik M, Calvo JR. Significance of melatonin in anti oxidative defense system: Reactions and products. Biol Signals Recept 2000;9:137-59.  Back to cited text no. 9      
10.Puri SC, Nazir A, Chawla R, Arora R, Riyaz-Ul-Hasan S, Amna T, et al. The endophytic Trametes hirsuta as a novel alternative source of Podophyllotoxin and related aryl tetralin lignans J Biotechnol 2006;122:494-510.  Back to cited text no. 10      
11.Chawla R, Arora R, Kumar R, Sharma AK, Prasad J, Singh S, et al. Antioxidant activities of fractionated extracts of high altitude podophyllum hexandrum in radiation protection. Molecul. Cell Biochem 2005;273:193-208.  Back to cited text no. 11      
12.Chawla R, Arora R, Singh S, Sagar RK, Sharma RK, Kumar R, et al. Podophyllum hexandrum offers radioprotection by modulating free radical flux: Role of aryl-tetralin lignans. Evid Based Complement Alternat Med 2006;3:503-11.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Arora R, Chawla R, Prasad J, Singh S, Kumar R, Sharma A, et al. Radioprotective activity of Rhodiola imbricata-a high altitude medicinal plant. Mol Cell Biochem 2005;273:209-23.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Grace MB, Blakelya WB, Landauera MR. Genistein-induced alterations of radiation-responsive gene expression. Radiat Meas 2007;42:1152-7.  Back to cited text no. 14      
15.Davis TA, Clarke TK, Mog SR, Landauer MR. Subcutaneous administration of genistein prior to lethal irradiation supports multilineage, hematopoietic progenitor cell recovery and survival. Int J Radiat Biol 2007;83:141-51.  Back to cited text no. 15  [PUBMED]    
16.Kaufman PB, Duke JA, Brielmann H, Boik J, Hoyt JE. A comparative survey of leguminous plants as sources of the isoflavones, genistein and daidzein: Implications for human nutrition and health. J Altern Complement Med 1997;3:7-12.  Back to cited text no. 16      
17.Han RM, Tian YX, Liu Y, Chen CH, Ai XC, Zhang JP, et al. Comparison of flavonoids and isoflavonoids as antioxidants. J Agric Food Chem 2009;57:3780-5.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]  
18.Arora R, Chawla R, Singh S, Sagar RK, Kumar R, Sharma A, et al. Bioprospection of Radioprotective Molecules from Indigeneous Flora. In: Govil JN, Singh VK, Bhardwaj R, editors. Recent progress in medicinal plants. Vol. 16. Texas, USA: Phytomedicine; 2007. p. 179-219.  Back to cited text no. 18      
19.Sharma RK, Chawla R, Goel R, Silambarasan M, Kumar V. Nuclear and Radiological Emergency Preparedness: Decontamination Issues. Radiat Protect Environ 2008;31:1-4.  Back to cited text no. 19      
20.US FDA, "Potassium Iodide as a Thyroid Blocking Agent in Radiation Emergencies," U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER); December, 2001.  Back to cited text no. 20      
21.World Health Organization, Guidelines for Iodine Prophylaxis Following Nuclear Accidents, Update Geneva: World Health Organization; 1999.  Back to cited text no. 21      
22.Whitnall MH, Elliott TB, Harding RA, Inal CE, Landauer MR, Wilhelmsen CL, et al. Androstenediol stimulates myelopoiesis and enhances resistance to infection in gamma-irradiated mice. Int J Immunopharmacol 2001;22:1-14.  Back to cited text no. 22      
23.Xiao M, Inal CE, Parekh VI, Chang CM, Whitnall MH. 5-Androstenediol promotes survival of g-Irradiated human hematopoietic progenitors through induction of nuclear factor-kB activation and granulocyte colony-stimulating factor expression. Molecul Pharmacol 2007;72:370-9.  Back to cited text no. 23      
24.Dunbar KR, Heintz RA. Chemistry of transition metal cyanide compounds: Modern perspectives. Progress in Inorg. Chem 1997;45:283-391.  Back to cited text no. 24      
25.Grace MB, Moyer BR, Prasher J,Cliffer KD, Ramakrishnan N, Kaminski J, et al. Rapid radiation dose assessment for radiological public health emergencies: Roles of NIAID and BARDA. Health Phys 2010;98:172-8.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]  
26.Pradeepkumar KS. Nuclear and radiological threats and emergency: Preparedness at national level. Radiat Environ Protect 2008;31:48-53.  Back to cited text no. 26      
27.Christie DH, Chu MC, Carr Z. Global networking for biodosimetry laboratory capacity surge in radiation emergencies. Health Phys 2010;98:168-71.  Back to cited text no. 27  [PUBMED]  [FULLTEXT]  


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]


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