Although the theory of atomism originated with the Greeks in the fifth century B.C., it has been only a little more than a century that scientists could describe and measure atoms and the other particles of radiation. Today we use radiation and radionuclides for a vast array of purposes, ranging from mundane household uses such as detecting smoke to powering satellites, treating cancer, and examining the physical properties of individual molecules. Unfortunately, as our knowledge of how to use radiation has expanded, so too has our awareness of radiation as a toxin. Indeed, for three of the last four editions of this text, there has been a significant radiation event that captured the world’s attention and demonstrated clearly just how much more we need to know. The particles of radiation, their sources, and the mechanisms by which they pose a health risk are the subjects of the following discussion.
Soon after x-rays were discovered in 1895, a deepening understanding of radiation and radionuclides led to their wider use and their resulting injuries. In the early days of radiation, exposures were small and of low energy, which nevertheless created injuries for a relatively small number of individuals. Clarence Dally was the first known radiation-induced death in 1904 after repeated exposures to Thomas Edison’s early fluoroscopes. By 1927, nearly 100 women employed to create illuminated instrument dials became ill or died after exposure to radium-containing paint. Efforts to protect workers such as those by the British Roentgen Society were hampered by limitations on measurement of radiation despite the development in 1908 of the Geiger counter that could detect but not quantify radiation. Much later in 1984 and again in 1987, lack of proper remediation of closed radiation treatment centers led to scavengers releasing sources of 60Co and 137Cs, respectively. In the cobalt incident beginning in Juarez, Mexico, thousands of tiny metal pellets were spilled in a scrapyard and melted with other metals into table legs later shipped throughout Mexico and the United States. In the cesium incident in Goiânia, Brazil, scavengers were fascinated by the bluish glow of the material. Ultimately, 250 individuals were contaminated, 46 patients were treated with a chelator, and 4 died the month after the initial exposure with another dying several years afterward from radiation-induced injuries.
With the advent of the nuclear age, said to have begun with the first detonation of an atomic bomb in New Mexico in July 1945, suddenly the risks of radiation exposure grew to many thousands at once. After the use of the two atomic bombs in Japan at the end of World War II, estimates of dead and injured for both cities were well over 200,000. Most of the deaths were from the bomb blast, but many thousands died from acute radiation syndrome (ARS) and others subsequently from radiation-induced cancers. In addition to the people of those cities who were victims of the bombs, many thousands of military personnel assigned to cleanup tasks or to attend nuclear weapons testing over the following 20 years were also exposed to radiation resulting from nuclear explosions. One relatively well-studied group, the British Nuclear Tests Veterans Association (BNTVA), found that two-thirds of its study group died from neoplasms at ages 50 to 65 years, irrespective of the individual’s age at the time of the witnessed explosion.
More recently in the post–nuclear testing era, large radiation incidents occurred at the sites of nuclear reactors. In 1986, the Chernobyl nuclear reactor, built without a hard containment vessel, experienced a series of explosions, releasing an enormous cloud of radioactive material. Thirty-one people died of ARS in the first few weeks after that event, and an unknown number of millions potentially suffered other long-term sequelae in the surrounding geographic area.
On March 11, 2011, a powerful earthquake off the east coast of Japan triggered a destructive tsunami that struck the Fukushima Daiichi nuclear power plant complex, knocking out its own electrical power and disabling the ability to cool its nuclear material. Over the following week, a series of explosions released an amount of radioactive material second only to the Chernobyl incident. Over the intervening time, no conclusive data yet exist describing a change in cancer prevalence, but controversy regarding study methods continues.14,33,35
Perhaps one of the most notorious deaths from radiation was that of Alexander Litvinenko, a former Soviet KGB operative who was living in London. On November 1, 2006, shortly after meeting with several men in a public restaurant, Litvinenko experienced nausea and vomiting, prompting a visit to the emergency department (ED). He was treated and released only to return 3 days later for continued vomiting and worsening abdominal pain. Physicians were puzzled by his rapid deterioration, including weight loss, alopecia, hypotension, kidney failure, and leukopenia. He was initially thought to have been poisoned by thallium and later by radioactive thallium. Litvinenko died 22 days later, and it was only after his death that 210Po was discovered to be the cause, heralding what some consider to be a new era of nuclear terrorism.
In the realm of health care, radiologists of the early 20th century used a thorium-containing contrast called Thorotrast in the initial development of angiography. Unfortunately, this xenobiotic accumulated in hepatic tissue, resulting in malignancies and its eventual discontinuance in 1952 (Fig. 8–25). More recently, the steadily increasing use of computed tomography (CT) has led to increased concerns over their safety and potential for stochastic effects. One retrospective study suggests there is a small but measurably increased risk for certain neoplasms in children after the accumulated radiation dose of several CT scans.31 This topic is discussed in more detail later.
PRINCIPLES OF RADIOACTIVITY
Dating from the 15th century, radiation remains defined as energy sent out in the form of waves or particles. Although considered by physicists as incomplete, the particle-wave theory remains a useful model by which to understand the toxic aspects of radiation. Despite the strong nuclear force that holds the basic building blocks of atoms together, many isotopes are unstable. Various influences such as quantum fluctuations and the weak nuclear force can tip the balance toward instability to transform an isotope. This process can be intentional, as with the criticality events in a nuclear reactor or nuclear bomb, but mainly occurs spontaneously in nature as the process called radioactive decay.
In 1900, Marie Curie discovered that unstable nuclei decay or transform into more stable nuclei (daughters) via the emission of various particles or energy. Radioactive decay occurs mainly through five nuclear mechanisms: emission of gamma rays, alpha particles, beta particles, or positrons or by capture of an electron. The emission of these various particles makes radioactive decay dangerous because these particles are ionizing radiation. Each radioisotope has a specific decay energy signature. That is, the emitted particles from a given radioisotope have known energies, which make identification of radiation sources possible.
The half-life (t1/2) is the period of time it takes for a radioisotope to lose half of its radioactivity. Every radioisotope has a characteristic half-life, some lasting millionths of a second and others lasting billions of years. In every case, the activities of radioactive isotopes diminish exponentially with time (Table 128–1).
TABLE 128–1Physical Properties of Radioisotopes ||Download (.pdf) TABLE 128–1 Physical Properties of Radioisotopes
|Isotope ||Half-Life ||Mode of Decay ||Decay Energy (MeV) |
|Radioisotopes of Medicine and Research |
|2H ||Stable || || |
|131I ||8 days ||β− ||0.97 |
|201Tl ||73 hours ||EC ||0.41 |
|99mTc ||6 hours ||IT ||0.14 |
|133Xe ||5.27 days ||β− ||0.43 |
|67Ga ||78 hours ||EC ||1.00 |
|137Cs ||30.17 years ||β− ||1.17 |
|18F ||109 months ||β−, EC ||1.65 |
|Military Radioisotopes |
|3H ||12.26 years ||β− ||0.02 |
|90Sr ||28.79 years ||β− ||0.55 |
|235U ||7.1 × 108 years ||α, SF ||4.68 |
|238U ||4.51 × 109 years ||α, SF ||4.27 |
|210Po ||138 days ||α ||5.307 |
|239Pu ||24,400 years ||α, SF ||5.24 |
|241Am ||470 years ||α, γ ||5.14/0.02 |
Photons are elementary particles that mediate electromagnetic radiation. Depending on their energy, the radiation has different names ranging from extremely long radio waves to high-energy gamma rays.
X-rays and gamma rays are high-energy photons and are only distinguishable by their source. Gamma radiation is emitted by unstable atomic nuclei via radioactive decay and has a fixed wavelength depending on the energy that formed it. X-rays come from atomic processes outside the nucleus. For example, an x-ray machine generates x-rays by accelerating electrons through a large voltage and colliding them into a metal target. The rapid deceleration of electrons in the target generates x-rays, and in general, the higher the voltage, the greater the energy of the x-rays. Because of their nature, high-energy gamma and x-rays can penetrate several feet of insulating concrete.
Beta particles are electrons. They are emitted during beta decay from an unstable radionuclide. Positrons are positively charged electrons and are also emitted during some decay processes. Electrons have less penetrating ability than gamma radiation but can still pass several centimeters into human skin. Beta particles also cause health problems chiefly through incorporation, or internalization into living organisms.
Alpha particles are helium nuclei (two protons and two neutrons) stripped of their electrons and are emitted during alpha decay. These particles are the most easily shielded of the emitted particles mentioned and can be stopped by a piece of paper, skin, or clothing. Unlike beta particles, alpha particles principally cause health effects only when they are incorporated.
Neutrons are primarily released from nuclear processes, although high-energy photon beams used in radiotherapy can also produce them. The natural decay of radionuclides does not include emission of neutrons, which is mainly a health hazard for workers in a nuclear power facility or victims of a nuclear explosion. Unique among the particles of radioactivity, when neutrons are stopped or captured, they can cause a previously stable atom to become radioactive in a process known as neutron activation.
Cosmic rays complete the group of various kinds of radiation. Cosmic rays are streams of electrons, protons, and alpha particles thought to emanate from stars and supernovas. They rain down on the Earth from all directions only to give up their energy as they strike the nuclei of oxygen and nitrogen in the upper atmosphere of the Earth. By the time they reach the Earth, the energy of cosmic radiation is reduced by several orders of magnitude. Traveling or living at altitude where the atmosphere naturally shields relatively less cosmic radiation naturally means greater exposure to cosmic rays but in general is not considered a significant threat to humans.
Isotopes and nuclides are very closely related terms, and most experts in the field use them interchangeably. Isotopes are two or more species or variants of a particular chemical element (same number of protons) that have different amounts of neutrons (eg, 123I, 125I, 127I, 131I). Nuclide is a more general term that may or may not be isotopes of a given element, such as fissile nuclides or primordial nuclides. Radioisotopes are isotopes that are radioactive, that is, they spontaneously decay and emit energy. Of the iodine nuclides listed previously, 123I, 125I, and 131I are radionuclides. The nuclide 127I is stable (nonradioactive). Finally, radionuclides are simply nuclides that are radioactive.
Ionizing Radiation versus Nonionizing Radiation
Ionizing radiation refers to any radiation with sufficient energy to disrupt an atom or molecule with which it impacts. In this interaction, an electron is removed, or some other decay process occurs, leaving behind a changed atom. Depending on the specifics of the interaction, the chemical bonds become altered, producing ions or highly reactive free radicals. Hydroxyl free radicals, formed by ionizing water, are responsible for biochemical lesions that are the foundation of radiation toxicity.
The space between collisions of ionizing radiation and their target molecules varies with the particle type and its energy. A charged particle, such as an alpha particle, loses kinetic energy through a series of small energy transfers to other atomic electrons in the target medium, such as tissues. Most of the energy deposition occurs in the infratrack, a narrow region around the particle track extending about 10 atomic distances. The energy loss per unit length of particle track is called the linear energy transfer (LET), which is expressed in kiloelectron volts per micrometer (keV/μm). Heavy charged particles, such as alpha particles, are referred to as high-LET radiation, and x-rays, gamma rays, and fast electrons are low-LET radiation.
Because of its large size, collisions along the path of an alpha particle are clustered together, impeding its ability to penetrate tissue. By comparison, collisions along the path of gamma rays are spread out, increasing their ability to penetrate tissue. This ability to penetrate tissue and transfer energy accounts for the relative dangers of the forms of radiation and tissue susceptibility.
For a source of radiation to pose a threat to tissue, the ionizing particle must be placed in close proximity to vital components of tissue to inflict damage. High-energy photons penetrate deeply, so they pose a similar risk whether they come from an external source or from an incorporated source. Because alpha particles have much more limited tissue penetration, alpha emitters, radionuclides that radiate these particles, must first be incorporated to pose a threat to tissue. Beta particles similarly have limited tissue penetration and usually are incorporated before damage can occur, although a large external exposure to beta emitters can cause serious cutaneous injury that could be life threatening, as discussed next.
Nonionizing radiation spans a wide spectrum of electromagnetic radiation frequencies. Generally, nonionizing radiation consists of relatively low-energy photons and is used safely in cell phone and television signal transmission, radar, microwaves, and magnetic fields that emanate from high-voltage electricity and metal detectors. Although these are all considered radiation because they each represent energy released from a source, these photons lack the necessary energy required to cause ionization and cellular damage.
Radiation Units of Measure
The amount of radiation to which an object is exposed, that is, the amount emitted from a source that falls on an object, is given in units called roentgens (R), a term that is now considered obsolete. A roentgen is a unit for measuring the quantity of gamma- or x-radiation by measuring the amount of ionization produced in air. As an example, an individual standing at a given distance from the x-ray–generating tube of a particular x-ray machine is exposed, on the skin, to a particular number of roentgens of x-rays (Fig. 128–1).
The definitions associated with radiation. Both curies and becquerels describe a quantity of radionuclide in terms of the number of disintegrations rather than mass. Roentgens describes the amount of charge per volume of air ionized by either γ- or x-rays, which indirectly quantifies the amount of radiation in the air around a source. Rads and grays (Gy) describe the fraction of radiation that actually interacts with cellular material and potentially causes injury. Roentgen equivalents man (rem) and sieverts (Sv) calculate the effective dose, taking into account the different particles. For example, a 100-keV alpha particle causes more damage to cellular material than a 100-keV beta particle.
Not all radiation to which an individual is exposed poses a risk for cellular damage. Much of the radiation passes through the body and causes no harm. Only the fraction that is absorbed by the tissue has a chance of causing cellular damage. The International System (SI) unit that describes absorbed radiation is the gray (Gy), which has replaced the rad (radiation-absorbed dose). One Gy equals 100 rad.
To measure the risk of biologic damage regardless of the type of radiation, the effective dose is given in sievert (Sv), which has replaced the rem (roentgen equivalent man). One Sv equals 100 rem. This calculation, known as dosimetry, takes into account the type of exposure (external or internal, partial or total), the particle or particles involved (eg, alpha, beta, gamma), and the radiosensitivity of the organ or organs exposed. The effective dose is calculated according to the following equation:
where E is the dose in sieverts; D is the absorbed dose in gray; WR is the radiation weighting factor, also called Q; and WT is the tissue weighting factor indicating the radiosensitivity of each organ.
In 1910, the curie (Ci) became the unit describing the amount of radioactivity in a source. One curie equals 3.7 × 1010 disintegrations per second based on the decay of 1 g of radium. The curie was replaced by the SI unit the becquerel (Bq) in which 1 Bq is equivalent to 1 disintegration per second. Thus, 1 Ci is equivalent to 3.7 × 1010 Bq. For example, after the Chernobyl incident, 1.2 × 1019 disintegrations per second of radioactive material was released into the atmosphere. By comparison, the radioactive source of 137Cs in Goiânia contained 50.9 × 1012 Bq (13.7 × 105 mCi) of cesium. A thallium stress test uses 111 × 106 Bq (3 mCi) of 201Tl, and the average indoor concentration of 222Rn in the United States is 55 Bq/m3 (14.8 × 10–6 mCi).
Protection from Radiation
Shielding refers to the process by which one limits the amount of unwanted ionizing radiation in a given setting. Placing a specific material between a radiation source and a target will limit the amount of ionizing radiation that will interact with the target. When a particle of ionizing radiation is incident on a material, there exists some probability that it will interact with the material and be attenuated. What happens as a result of this interaction depends on several factors, including the type of particle, its energy, and the atomic number of the target material. The photoelectric effect for photons, Bremsstrahlung for beta particles, and elastic scattering for neutrons are several examples of specific interactions. The shielding equation below allows calculation of the efficacy of shielding
where I is the radiation intensity after shielding, I0 is the radiation intensity before shielding, μ is the linear attenuation coefficient, and x is the thickness material in centimeters. The linear attenuation coefficient is defined as the fraction of photons removed from the radiation field per centimeter of absorber through which it passes. Examples of shielding materials are acrylic, lead, and concrete.
Distance is an important safety factor in limiting radiation exposure. Because of their mass and electric charge, alpha and beta particles have a high probability of interacting with matter, such as the atmosphere. The result is that these particles do not travel more than a few centimeters through air and, in general, moving a few feet from the source of this kind of radiation is enough protection by distance. However, x-rays and gamma rays are uncharged and have no rest mass, greatly reducing their probability of interacting with matter, resulting in an unlimited range in space. Photon radiation that is emitted from a point source diverges from that source to cover an increasingly wider area. The intensity of this radiation follows the inverse square law:
where I1 is the initial intensity, I2 is the final intensity, r1 is the initial distance from the source, and r2 is the final distance from the source. For example, if the intensity of radiation 1 m from a source is 1 Gy, its intensity would be 0.11 Gy at 3 m from the source.
Time of exposure is another important safety factor in limiting radiation exposure. Obviously, the longer a person is exposed to radiation, the greater the exposure. The US federal and state regulations based on National Council on Radiation Protection and Measurement (NCRP) and US Food and Drug Administration (FDA) recommendations specify the limits of occupational exposure as well as exposure to patients designed to limit the potentially damaging effects of radiation.
Irradiation, Contamination, and Incorporation
An object is irradiated when it is exposed to ionizing radiation. One can be irradiated when handling radioactive isotopes, when undergoing medical diagnostic imaging such as radiography or CT, and during rare exposures to criticality events. These sources of ionizing radiation generate particles that can penetrate tissue well and possibly cause tissue damage. Whole-body irradiation is one in which the entire body is exposed at once. More commonly, shielding devices such as lead aprons and collimation techniques used in radiotherapy limit the amount of exposed tissue to the intended target. The risk of tissue damage depends on the total amount of radiation and the tissue type because different tissue types have their own intrinsic resistance to radiation damage. An irradiated object does not become radioactive itself unless exposed to neutrons, and therefore irradiated individuals pose no risk to others.
The FDA approved irradiation of wheat and flour in 1963. The FDA concluded from 40 years of study that irradiation is a safe and effective process for many foods to control bacteria such as Escherichia coli, Salmonella spp, and Campylobacter spp. Irradiation does not make food radioactive, compromise nutritional quality, or noticeably change the taste, texture, or appearance of food as long as it is applied properly to a suitable product. Organizations that support irradiation of food include the American Medical Association, the Centers for Disease Control and Prevention, and the World Health Organization.
Contamination occurs when a radioactive substance covers an object completely or in part. Several examples include a laboratory or industrial worker who unintentionally spills a radionuclide on clothing or skin or a victim of a radiologic dispersing device, a “dirty bomb,” in which a radionuclide is packaged with a conventional explosive and the resultant explosion disperses the radionuclide. In these similar cases, the source of radiation is the nuclide undergoing its normal decay process, and the individual is exposed to particles such as those mentioned in Table 128–1. The risk of tissue damage from the radiation particles is usually quite low, assuming that the contamination is detected and appropriate measures for decontamination are instituted.
Incorporation occurs when a radionuclide is taken up by tissue via some route that permits the radionuclide to enter the body. This principle is used in many diagnostic and therapeutic procedures such as a thallium stress test, gallium scan, or thyroid ablation therapy. Depending on the dose and type of radionuclide, incorporation may lead to tissue damage, as was the situation for several people after the event at Goiânia.
Everyone is exposed to radiation in one form or another each day (Table 128–2). In the United States, the estimated annual dose equivalent of radiation is now considered to be 6.2 mSv, a number revised sharply upward by the NCRP in 2009.24 In addition to the naturally occurring sources of radiation in the Earth’s crust that make a significant contribution to our overall radiation exposure, the contribution from human-made sources of radiation, specifically medical exposures, has increased greatly over the past few decades.
TABLE 128–2Annual Estimated Average Effective Dose Equivalent in the United States ||Download (.pdf) TABLE 128–2 Annual Estimated Average Effective Dose Equivalent in the United States
| ||Dosea |
|Source ||mSv/year ||mrem/year ||% of Total dose |
| Cosmic ||0.27 ||27 ||5 |
| Internal ||0.31 ||31 ||5 |
| Radonb ||2.29 ||233 ||37 |
| Terrestrial ||0.19 ||19 ||3 |
| Subtotal ||3.10 ||310 ||50 |
| Consumer products ||0.12 ||12.4 ||2 |
| Nuclear medicine ||0.74 ||74.4 ||12 |
| Occupational ||<0.01 ||0.62 ||0.1 |
| Medical procedures ||2.23 ||223.2 ||36 |
| Subtotal ||3.10 ||310 ||50 |
|Total ||6.20 ||620 ||100 |
Exposures to human-made sources of radiation are not required to be reported to poison control centers in most municipalities. Historically, those that have been reported have not resulted in significant morbidity. The American Association of Poison Control Centers National Poison Data System reports an average of about 300 exposures to radiation over the past 20 years. Of the 231 exposures reported in 2015, 77% were unintentional, and 8% involved children younger than 6 years of age. There were no deaths reported to poison control centers from exposure to radioisotopes, and only 5 patients experienced a moderate effect, meaning not life threatening (Chap. 130).28
Natural Sources of Radiation
A wide variety of natural sources expose humans on a daily basis to ionizing radiation. Terrestrial sources of radiation originate from radionuclides in the Earth’s crust that move into the air and water. These primordial radionuclides, so named because their physical half-lives are comparable with the age of the Earth, include uranium, actinium, and thorium. Geographic areas vary regarding the content of these radionuclides.
Radon, a radioactive noble gas, accounts for most of the human exposure to radiation from natural sources. This gas, a natural decay product of uranium and thorium, enters homes and other buildings from the building materials themselves or through microscopic cracks in the building’s structures. With a relatively short half-life of 3.82 days, 222Rn poses a health risk if decay occurs while in the respiratory space and one of its solid daughter isotopes deposits on respiratory tissue. These radon daughters emit alpha particles as they decay and are the principal causes in the associated increased incidence of lung cancer in those exposed to radon. The risk of lung cancer is further increased in heavy smokers who additionally expose their lungs to as much as 200 mSv from 210Po, a radon daughter that is naturally found in tobacco smoke. The US Environmental Protection Agency (EPA) has recommended household-level intervention when ambient radon concentrations exceed 147 Bq/m3 (4 pCi/L). Individuals can test their own homes for radon with either short-term (<90 days) or long-term (>90 days) commercially available measurement devices.
The second largest natural source of radiation originates from ingested radionuclides, of which 40K, a naturally occurring isotope is the most abundant. Potassium is the seventh most abundant element in the earth’s crust, and 40K represents about 0.012% of this naturally occurring element. With a half-life of 1.3 billion years, 40K decays via beta emission and electron capture. Because it is part of the environment, the average amount of 40K in the body is about 3,700 Bq (0.1 μCi), delivering about 0.18 and 0.14 mSv to soft tissue and bone, respectively. The lifetime cancer mortality risk calculated for 40K is 4 in 100,000 from external exposure compared with one in five from the group predicted to die of cancer from all other causes per the US average.
The NCRP report no. 160 sharply increased the estimated annual dose of radiation exposure from human-made sources of radiation largely from the steeply rising use of CT (Table 128–3).29 Evolving contemporaneously with the computer, CT technology has become extremely efficient and available contributing to the estimate that more than 70 million CT scans were performed in the United States during 2005 and 2006 compared with about 3 million scans in 1980, accounting for more than half of the human-made collective dose.24 Concern over potential cancer risks stemming from this new volume of exposure centers on children in whom doses are higher despite increasing practice to tailor scans to the size of the patient and because their relatively longer lives make children more likely to manifest slowly developing cancers. One retrospective study conducted over 7 years in Great Britain through the National Health Service examined data for more than 175,000 young patients each in two groups with certain leukemias and brain tumors.2,31 Based on typical machine settings and estimated absorbed doses, this study found an increased relative risk of these cancers resulting from accumulated doses of just a few CT scans. Importantly, this was one of very few studies on this topic that did not rely on extrapolated data from atomic bomb survivors. Perhaps influenced by data like these accompanied by increased availability of other alternative imaging modalities, such as magnetic resonance imaging, several studies report trends of decreasing use of CT for children.23,30
TABLE 128–3Diagnostic Imaging Procedures: Type and Amount of Radionuclide or Radiation25 ||Download (.pdf) TABLE 128–3 Diagnostic Imaging Procedures: Type and Amount of Radionuclide or Radiation25
|Test ||Radionuclide ||Amount ||Effective Dose |
|MBq ||mCi ||mSv ||mrem |
|Thyroid scan ||123I ||25 ||0.68 ||1.9 ||191 |
|Cardiac stress-rest test ||201Tl ||185 ||5 ||40.7 ||4,070 |
|Lung perfusion ||99mTc ||185 ||5 ||2.0 ||200 |
|Lung ventilation ||133Xe ||740 ||20 ||0.5 ||50 |
|Bone scan ||99mTc ||1,110 ||30 ||6.3 ||630 |
|Gallium scan ||67Ga ||150 ||4.05 ||15 ||1,500 |
|Tumor (PET) ||18F ||740 ||20 ||14.1 ||1,410 |
|Posteroanterior and lateral study of the chest || ||0.1 ||10 |
|Abdomen || || || ||0.7 ||70 |
|Pelvis || || || ||0.6 ||60 |
|Lumbar spine || || || ||1.5 ||150 |
|ERCP ||4.0 ||400 |
|Computed Tomography |
|Head || || || ||2 ||200 |
|Cervical spine || || || ||3 ||300 |
|Chest || || || ||7 ||700 |
|Chest for pulmonary embolism || ||15 ||1500 |
|Abdomen || || || ||8 ||800 |
|Pelvis || || || ||6 ||600 |
|Coronary angiography || || || ||16 ||1,600 |
Overall use of other non-CT radiologic studies has increased greatly over the past decades as well. Estimates show 377 million radiologic procedures in the United States in 2006, not including more than 500 million dental radiologic examinations, although these examinations are not thought to contribute significantly to the overall accumulated dose. Nuclear medicine scans, particularly in the field of cardiology diagnostics, increased sharply as well and account for 4% of all radiologic procedures and 26% of the total collective dose.24
Nuclear Occupational Exposure
Estimates of the annual number of workers occupationally exposed to radiation worldwide are several million.37 On average, the occupations with the highest exposures (about 4 mSv/year) are uranium miners and millers. Overall, as of 1994, the average annual effective dose to monitored workers in the nuclear fuel industry dropped from 4.1 to 1.8 mSv, mainly because of a large decline in underground mining. Despite the many factors that play a role in occupational exposure at more than 1,200 nuclear reactors worldwide, the estimated annual effective dose to measurably exposed workers fell to 2.7 mSv.
Medical occupational exposure principally includes physicians, nurses, radiology technologists, and laboratory workers who receive an additional annual effective dose of about 0.5 mSv, which is decreased from about 1 mSv 25 years ago, possibly because of efforts to improved protection practices. Exposures to health care workers were studied in a wide variety of subspecialties, including cardiology, orthopedics, radiology, urology, and others.17,39,40 Although each of these fields uses different modalities of radiation that pose different risks to the operator, studies continue to find low overall doses per procedure, suggesting more than 800 procedures would be necessary to approach yearly dose limits.40 Emergency medicine staff and trauma teams were exposed to higher radiation doses in the past, primarily from holding the cervical spine stable during x-ray studies, but this has largely been replaced by CT. Doses sustained by these staff are well below the upper limits of exposure set by the Nuclear Regulatory Commission (NRC).11,13 Thus, although the number of CT scans performed continues to rise, the radiation exposure to staff remains low because of collimation and low scatter, as well as proper shielding in properly designed facilities.
Fluoroscopy constitutes less than 10% of all examinations in the United States but remains the largest source of occupational exposure in medicine. Studies of physician exposure to radiation by fluoroscopy used in various procedures, including exploration of the biliary tract, extremity nailing, interventional cardiology, nephrolithotomy, vertebroplasty, and others report, effective doses ranging from 1 to 100 μSv (0.1–10 mrem). Depending on the procedure, doses to the hands, brain, lens of the eye, and thyroid could be much higher placing physicians at greater risk of stochastic effects (see Stochastic versus Deterministic Effects of Radiation) than is suggested by the effective dose.17,40 Estimated whole-body exposures to these procedures were considered not to exceed the limits established by the Occupational Safety and Health Administration (OSHA) of 50 mSv per year. Although the likelihood of exceeding established radiation limits is low regardless of the procedure and even assuming a reasonable increase in the number of procedures performed, appropriate shielding and safety training are emphasized to minimize the risk of exposure.
Worldwide, nearly 500,000 workers are monitored for exposures during dental radiography, but the annual effective dose averaged over 5 years has declined to 0.05 mSv. Close to 40 million nuclear medicine procedures are performed annually worldwide, but the radiation exposures from this type of procedure are quite small.24
Depleted uranium (DU) is used by the US military and by several other governments. Uranium ore mined from the earth is about 99% 238U and 1% 235U. Enrichment involves separating the isotopes—for example, via high-speed gas centrifuge—so that 235U can be used as nuclear fuel and the leftover 238U can be used in munitions. Consequently, although DU is radioactive, it is 40% less so than naturally occurring uranium. External exposure to solid 238U is considered to be negligible, although currently many studies are investigating the potential link between DU and the incidence of leukemias, other cancers, and birth defects.1 The Depleted Uranium Follow-Up Program that has surveyed exposed veterans since 1994 has not discovered any consistent, clinically significant differences in uranium-health parameters, which includes hematopoiesis, neuroendocrine, and kidney function.22
The NRC established the “Standards for Protection against Radiation,” which regulates radiation exposures using a twofold system of dose limitation: doses to individuals shall not exceed limits established by the NRC, and all exposures shall be kept as low as reasonably achievable (ALARA). The total effective dose equivalent may not exceed 50 mSv/year to reduce the risk of stochastic effects (see Stochastic versus Deterministic Effects of Radiation). The dose to the fetus of a pregnant radiation worker may not exceed 5 mSv over 9 months and should not substantially exceed 0.5 mSv in any 1 month.
The use of ionizing radiation, radiation sources, and the byproducts of nuclear energy are among the most heavily regulated processes worldwide. Regulations for medical use of radiation derive from multiple international and national organizations. Among the international groups are the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), the International Commission on Radiological Protection (ICRP), the Biological Effects of Ionizing Radiation (BEIR) Committee, the International Commission on Radiological Units and Measurements (ICRU), the Radiation Effects Research Foundation (RERF), and the International Radiation Protection Association (IRPA). Because international organizations do not have the authority to enforce their recommendations worldwide, most countries have their own regulatory groups that cooperate internationally. In the United States, the NCRP reviews recommendations from the ICRP and makes recommendations. The NCRP issues BEIR reports that have direct standards for ionizing radiation use. For medical imaging standards, recommendations from the NCRP are considered to be guidelines with which all radiology departments must comply. The goal is to foster a radiation protection program that prevents deterministic effects. Additionally, the Conference of Radiation Control Program Directors (CRCPD) suggests state regulations for control of radiation.
National regulatory agencies include the NRC, EPA, OSHA, and FDA. The NRC also runs an Agreement State Program under which the NRC relinquishes to the States portions of its regulatory authority to license and regulate nuclear materials. The US Department of Transportation (DOT) regulates transport of hazardous materials, including radioactive material.
The NRC, the EPA, and many state governments share the responsibility of licensing and regulating radionuclides in the United States. The Oak Ridge Institute for Science and Education’s (ORISE) supports the NRC by maintaining the NRC’s website for Radiation Exposure Information and Reporting System (REIRS) and the database of radiation exposure from NRC licensees (http://www.reirs.com). Individual states regulate radioactive substances that occur naturally or are produced by machines, such as linear accelerators or cyclotrons. The EPA oversees the general area of environmental monitoring of radiation. The FDA regulates the design and manufacture of electronic products, inspects diagnostic x-ray equipment, and establishes specific operational standards for x-ray equipment. The NRC regulates medical, academic, and industrial uses of nuclear materials generated by or from a nuclear reactor. The OSHA regulates occupational exposure to radiation and oversees regulations for training programs and “right to know” regulations.
The Oak Ridge Institute for Science and Education’s Radiation Emergency Assistance Center/Training Site (REAC/TS) and the International Atomic Energy Agency (IAEA) both maintain radiation incident registries that track US and foreign radiation incidents. Information for the REAC/TS registries is gathered from many sources, including the WHO Radiation Emergency Medical Preparedness and Assistance (REMPAN), IAEA, state health departments, and medical and health physics literature.
Ionizing radiation causes damage to tissue by several mechanisms called direct or indirect effects. Direct effects are when particles physically damage the DNA in a cell, which can occur at the sugar phosphate backbone, hydrogen bonds, or base molecules. Although any type of radiation can cause this damage, high-LET radiation is more likely to cause direct effects owing to its greater probability of interacting with DNA. When this kind of damage occurs, a mutation can arise, which may then result in alteration of a germ line, development of a neoplasm, or cell death. The risk of these consequences overall, however, is low because of the relative paucity of DNA within a cell, the even smaller percentage of active DNA within a given cell, and the ability of DNA to repair itself.
Although DNA represents a low-probability target for radiation, the rest of the cell media represents a higher probability target. Indirect effects are when radiation impacts a molecule and creates a reactive species, which then chemically reacts with organic molecules in cells altering their structure or function. These radiation-induced ions are unstable, however, and usually convert to free radicals. Water, which is in great abundance within cells, can transform into a hydroxyl radical (OH·) after interaction with incident radiation. The hydroxyl radical diffuses only a short distance through the cell because of its highly reactive nature and itself causes molecular damage. Indirect effects are predominantly caused by low-LET radiation (x-rays, gamma-rays, and fast electrons).
The bystander effect refers to cellular damage in unirradiated cells that neighbor irradiated cells. As early as the 1940s, there were reports of inactivation of cells by ionization of the surrounding medium. Recently, the use of a single-particle microbeam (a device that can fire a predefined exact number of alpha particles through a particular cell nucleus) demonstrated that cultured cells that were not hit by radiation showed increased chromosome damage, rearrangement, and rate of death. In one experiment, when 10% of cells on a dish were exposed to two or more alpha particles, the resulting frequency of induced oncogenic transformation was indistinguishable from that when all the cells on the dish were exposed to the same number of alpha particles.27 Studies demonstrate the bystander effect for proton beams, x-rays, and low-LET radiation.32,34
Genomic instability is a single mutation followed by a cascade of further mutations altering the fidelity of genomic replication. This modification can be found in cell progeny many generations after irradiation and can have unpredictable outcomes in succeeding generations. Although many hypotheses have been suggested, it appears most likely that the instability is due to irreversible regulatory change in the network of cellular gene products.12,15,21
Although any molecule can be damaged in a variety of ways that may lead to cell injury of varying severity, double-stranded breaks in DNA are the type of damage most likely to cause chromosomal aberrations or cell death. The radiosensitivity of the cell is directly related to its rate of proliferation and inversely related to its degree of differentiation.
Thousands of these types of lesions occur daily in the human body. There are several mechanisms by which the body effects its own repair, which forms the basis of fractionated radiation therapy, taking advantage of less efficient repair mechanisms of tumor cells. However, there is evidence that DNA damage induced by radiation is chemically different and more complex from DNA damage that occurs spontaneously, which contributes to a higher rate of mutation than that resulting from spontaneous damage. Dose–response relationships for mutation are approximately linear down to about 25 mGy, the statistical limit of these studies. Although repair mechanisms reduce substantially the radiation risk of mutation, there is no evidence yet that these mechanisms eliminate those risks at low doses, although some question this conclusion.18
STOCHASTIC VERSUS DETERMINISTIC EFFECTS OF RADIATION
The radiation damage just described has two consequential results: it kills cells or it alters cells and causes cancer. Injuries that do not require a threshold limit to be exceeded include mutagenic and carcinogenic changes to individual cells in which DNA is the critical and ultimate target. This is the stochastic effect of radiation. Theoretically, there is no dose of radiation too small to have the potential of causing cancer in an exposed individual.
Whereas the stochastic effects of radiation can follow less severe exposures, the deterministic effects of radiation usually follow a large whole-body exposure, such as a Chernobyl-type event. In terms of cell death, a relatively large number of cells of an organ system must be killed before an effect becomes clinically evident. This number of killed cells constitutes a threshold limit that must be exceeded, and this is what is known as the deterministic or nonstochastic effects of radiation.
To illustrate the differences between stochastic and nonstochastic effects, consider a single alpha particle, emitted from 210Po, which was incorporated after exposure in a radon-contaminated household. Theoretically, if this particle impacts on an active segment of DNA in a patient’s respiratory tract, it could give rise to a cancer—the stochastic effect. In contrast, after exposure to the criticality event in Tokaimura, Japan, the most severely injured worker received 17 Sv of neutron and gamma radiation and experienced so much cell death across so many systems in his body that he died well before any injured yet surviving cells could develop into a cancer—the deterministic effect.
The US Army Medical Corps first described ARS in 1946 when victims of the detonations at Hiroshima and Nagasaki were admitted for treatment at Osaka University Hospital.16 Understanding the features of ARS is essential for managing a patient who is exposed to massive whole-body irradiation, generally considered to be 1 Gy (160 times the average annual exposure) or more. In many cases, a reliable estimate of the radiation dose is difficult, making it more practical to focus on the clinical features of radiation injury and their prognostic utility.
Acute radiation syndrome involves a sequence of events that varies with the severity of the exposure.41 Generally, more extensive exposures lead to more rapid onset of symptoms and more severe clinical features. Four classic clinical stages are described, which begin with the early prodromal stage of nausea and vomiting. These symptoms begin anywhere from hours to days postexposure. Although the time to onset postexposure is inversely proportional to the dose received, the duration of the prodromal phase is directly proportional to the dose. That is, the greater the dose received, the more rapid the onset of symptoms, and the longer their duration, except in cases in which death follows rapidly. The latent period follows next as an apparent improvement of symptoms, during which time the patient appears to have recovered and has no clinically apparent difficulties. The duration of this stage is inversely related to dose and can last from several days to several weeks. The third stage usually begins in the third to fifth week after exposure and consists of manifest illness described in subsequent paragraphs. If the patient survives this stage, recovery, the fourth stage, is likely but can take weeks to months before it is completed. Those exposed to supralethal amounts of radiation can experience all the phases in a few hours before a rapid death.
These four stages describe the clinical manifestations that can be observed as a result of massive exposure, but the various systems of the body manifest their own injuries, which constitute several subsyndromes. These subsyndromes are not mutually exclusive of one another and often overlap as cell death or damage progresses. Once these subsyndromes are manifest, they often are irreversible.
The cerebrovascular syndrome describes the manifestations of injury to the central nervous system after massive irradiation. This syndrome, after exposure to doses of about 15 to 20 Gy or greater, is characterized by rapid or immediate onset of hyperthermia, ataxia, loss of motor control, apathy, lethargy, cardiovascular shock, and seizures. The mechanism of this injury may be a combination of radiation-induced vascular lesions and free radical–induced neuronal death and cerebral edema.
Despite autopsy evidence of some radiation-induced inflammatory changes to the heart, animal experiments demonstrate that the heart is relatively resistant to high doses of radiation. Cardiovascular shock is more likely because of systemic vascular damage, which can later compound shock resulting from other subsyndromes should the patient survive to that point. A “vascular radiation subsyndrome” might be considered to help explain the hemodynamic changes a patient experiences after a massive dose of radiation.
The pulmonary system is not spared injury from irradiation. Pneumonitis can occur within 1 to 3 months after a dose of 6 to 10 Gy. This can lead to respiratory failure, pulmonary fibrosis, or cor pulmonale months to years later.
The gastrointestinal (GI) syndrome begins after an exposure to about 6 Gy or more when GI mucosal cell injury and death occur. Findings and effects include anorexia, nausea, vomiting, and diarrhea. As the mucosal lining is sloughed, there is persistent bloody diarrhea, hypersecretion of cellular fluids into the lumen, and a loss of peristalsis, which can progress to abdominal distension and dehydration. Destruction of the mucosal lining allows for colonization by enteric organisms with ensuing sepsis.
The hematologic changes that occur after an exposure to about 1 Gy or greater are called the hematopoietic syndrome. Hematopoietic stem cells are highly radiosensitive, in contrast to the more mature erythrocytes and platelets. Lymphocytes are also radiosensitive and can die quickly from cell lysis after an exposure. This contrasts with granulocytes, which endure radiation better. In addition to stem cell death and white blood cell depletion with immunodeficiency, platelets are consumed in gingival and GI microhemorrhages. The main effect of radiation-induced hematopoietic syndrome is pancytopenia, leading to death from sepsis complicated by hemorrhage. The lymphocyte nadir typically occurs 8 to 30 days postexposure, with higher doses achieving earlier nadir.
The cutaneous syndrome, a local radiation injury, can develop early after exposure or can take years to manifest fully. Target cells include all layers, including the epidermis, hair follicle canals, and subcutaneous tissue. Signs and symptoms include bullae, blisters, hair loss, pruritus, ulceration, and onycholysis. Skin injury ranges from epilation beginning at doses of 3 Gy to moist desquamation at about 15 Gy, to necrosis at greater than 50 Gy.
As with other medical management in which determining a specific diagnosis is critical to providing appropriate care, determining an accurate dose of radiation exposure is critical to providing the best care for the irradiated patient because increasing radiation exposure will affect different organ systems, call for different therapies, require different levels of monitoring, and assign different prognoses. Indeed, some consider a dose of 1.5 to 2 Gy to be a critical threshold, beyond which some patients could die from their exposure despite treatment, making the determination of whether a patient has received more than this dose an essential feature of the initial assessment.9,36 Dose estimation is difficult, however, for a number of reasons, such as the absence of a radiation-monitoring device, exposure to radiation of mixed form (eg, gamma and neutron radiation), and partial shielding of various body parts.
Biodosimetry is the use of physiological, chemical, or biological markers to reconstruct radiation doses to individuals or populations and assess the probability of developing ARS. Key elements of dose estimation include time to onset of vomiting, lymphocyte depletion kinetics, and chromosomal assays. Today there are numerous tools available on the Internet to assist with dosimetry, including the Biological Assessment Tool available at the Armed Forces Radio-biology Research Institute’s website (https://www.usuhs.edu/afrri/biodosimetrytools), guidelines from the International Atomic Energy Agency, and the Radiation Emergency Medical Management website (https://www.remm.nlm.gov).
One early response biodosimetry method was developed by REAC/TS that combines post-incident emesis (which could be a sign of psychological stress) with lymphocyte depletion over the first 24 hours.
where T is the triage score, N/E is the neutrophil/lymphocyte ratio, and E is whether emesis has occurred. E equals 0 if no emesis and E equals 2 if emesis. Based on cases from the REAC/TS registry, for times longer than 4 hours postevent, if T is greater than 3.7, then the patient is deemed at risk of high dose exposure, that is, greater than 2 Gy, and should receive a more extensive hematological evaluation.
The broad ranges of radiation doses that correlate with lymphocyte count are described in the classic Andrews nomogram of 1965. Again, using historic data from exposed patients, a lymphocyte depletion constant was calculated using the equation
where L(t) is the lymphocyte count at time t, L0 is the lymphocyte count before the exposure (the population mean taken as 2.45 × 109 cells/L), K is the rate constant for a given dose of radiation, and D is the dose of radiation. Solving for K(D) will allow for an accurate estimate of a rapidly delivered, whole-body exposure.
Although there are still other methods of biodosimetry, such as interphase aberrations assessment and electron spin resonance of dental enamel, measurement of chromosomal aberrations has become the gold standard. Introduced in 1966, this technique analyzes the number of dicentric chromosomes that occur after a whole-body exposure to radiation. An exposure to radiation can cause breakage of the DNA molecule in two nonhomologous chromosomes and produce “sticky ends” that recombine end to end. In metaphase, these appear as a single chromosome with two centromeres and are called dicentric. The number of dicentrics in lymphocytes correlates reliably with a given dose of radiation. This assay conforms to International Organization for Standardization (ISO) but suffers from several drawbacks, including reduction of cells for assay in the setting of proliferative cell death, a low mitotic index for irradiated cells, a long time needed for cell cultures to reach metaphase in which dicentrics are measured, and migration of lymphocytes into tissue and the lymphatic system. These complications limit the time available to perform an accurate test as well as make the testing itself a relatively long affair, complicating its potential application to a mass casualty event. The translocation assay uses fluorescence in situ hybridization chromosome-painting technique and is used primarily for estimating doses of historical exposures. Unlike dicentrics, complete translocations persist in cell division and enable dose estimation over years after exposure. In fact, when this technique was used to evaluate the radiation dose experienced by clean-up workers at Chernobyl, the authors concluded that it was likely that recorded doses for these cleanup workers overestimate their average bone marrow doses, perhaps substantially.19 Another method includes the cytokinesis-block micronucleus (CBMN) assay in which other unstable cell nuclear aberrations form but then disappear over time. This method generates data comparable to dicentric analysis, and when used in a semiautomated fashion, it can greatly improve testing speed.8 The premature chromosome condensation assay in which chromosomes are stimulated to condense in interphase cells, has been combined experimentally with telomere and centromere staining to reduce greatly the amount of time needed to perform biodosimetry, although this technique is still in an early phase of development.26 Many of these techniques are not widely available, require incubation times of 48 to 72 hours, and cannot assess for doses greater than 5 Gy.
Radiation was recognized as a carcinogen soon after it was initially discovered in 1895. After decades of research, including animal models, epidemiologic studies, and the lifespan studies of Japanese nuclear bomb survivors, radiation was shown to be a “universal carcinogen” able to induce tumor in nearly every tissue type in nearly every species at all ages. In fact, radiation’s ability to induce cancer is so well established that the past three decades of research have used radiation-induced tumors to focus on DNA damage and repair mechanisms.
Double-stranded breaks are the biologically important lesion for inducing tumors. Although radiation induces point mutations, it also induces deletions, sometimes of an entire gene. Research on transcription-coupled repair, in which the transcribed strands of expressed genes are more rapidly repaired than the rest of the genome, were shown to be repaired most often by an illegitimate recombination process that is error prone, frequently resulting in the loss of heterozygosity, a “double-hit” mutation. This loss of heterozygosity suggests that radiation-induced carcinogenesis would more likely result from inactivation of a tumor suppressor gene than activation of a proto-oncogene.20
COMMONLY ENCOUNTERED RADIONUCLIDES
Most patients who come to medical attention are not exposed to large, whole-body irradiation but rather to small spills in a laboratory or inadvertent exposures from one of many products that are commercially available. With the notable exception of a well-known case of massive americium contamination in Oak Ridge, Tennessee, and the cesium exposure in Goiânia, Brazil, the vast majority of these types of cases are not reported in the medical literature.
Americium (symbol Am, atomic number 95, and atomic weight 243) was discovered in 1944 in Chicago during the Manhattan Project. Its most stable nuclide, 243Am, has a half-life of more than 7,500 years, although 241Am, with a half-life of 470 years, was the first americium isotope to be isolated. It decays by alpha and gamma emission and will accumulate in bone if incorporated. It is used to test machinery integrity, glass thickness, and in smoke detectors (about 0.26 mcg per detector), in which it ionizes the air between two electrodes and generates an electric current that soot impedes, triggering an alarm. Alpha particles from these detectors are easily absorbed within a few centimeters of the surrounding air and pose little risk. One gram of americium dioxide provides enough americium for more than 5,000 smoke detectors. In 1976, a worker at the Hanford Plutonium Finishing Plant suffered a large 241Am contamination in an explosion at the site. The patient was contaminated with 100 g or 70 MBq (500,000 smoke detectors’ worth) in the explosion. He was treated with long-term pentetic acid (DTPA), and despite some leukopenia from the radiation, he survived for 11 years before dying from unrelated cardiac disease.
Cesium (symbol Cs, atomic number 55, and atomic weight 132) was discovered by Bunsen in 1860. It decays by beta and gamma emissions and tends to follow the potassium cycle in nature. It is used as a radiation source in radiation therapy and as a radionuclide source for atomic clocks. Cesium, the radionuclide of the Goiânia incident, comes in the form of a powder, which would make dispersal relatively easy if used in a dirty bomb. Insoluble Prussian blue is the FDA-approved chelator for patients contaminated with cesium (Antidotes in Depth: A31).
Iodine (symbol I, atomic number 53, and atomic weight 126.9) was discovered by Courtois in 1811. Of the 23 isotopes of iodine, 127I is the only one that is stable. 129I and 131I are fission products that are released into the environment during an event. These isotopes will accumulate in thyroid tissue if incorporated and can cause local damage to thyroid tissue. It is this potential for incorporation that prophylaxis with potassium iodide (KI) is indicated in the event of a large exposure.
Polonium (symbol Po, atomic number 84, and atomic weights range from 192 to 218) was discovered by Marie Curie while she was searching for the cause of radioactivity of pitchblende (uranium ore) and was named after her native country of Poland. Polonium has 27 isotopes, the most isotopes of all the elements and all are radioactive. Polonium is a very rarely occurring natural element, and only 100 mcg is found in a ton of uranium ore. Polonium is chiefly manufactured by bombarding 210Bi with neutrons in nuclear reactors, and it exhibits several properties that make it extremely dangerous. The short half-life of 210Po, 138 days, and high specific activity of 4,490 Ci/g means it emits a great deal of high-energy alpha particles (5.3 MeV) that produce 140 W/g. For example, a capsule containing 500 mg of 210Po reaches a temperature of 932°F (500°C). It also demonstrates a high volatility in which 50% vaporizes in 45 hours at 131°F (55°C) and can contaminate a relatively large area even when left alone. Although only a small fraction of absorbed 210Po accumulates in tissue, cumulative doses of radiation can lead to organ systems failure and death. Animal data estimate an LD50 (median lethal dose in 50% of test subjects) of 1.3 MBq/kg and that various mammalian species die within 20 days after an ingestion of 1 to 3 GBq. Because of the extreme specific activity of 210Po, this corresponds to a dose of about 0.01 mcg/kg. Currently, there are no specific chelating agents for 210Po. Although there are limited data regarding the effects of 210Po on humans, Alexander Litvinenko’s death within 22 days of his poisoning with polonium is similar to animal survival data.
Radon (symbol Rn, atomic number 86, and atomic weights range from 204 to 224) was discovered in 1900 by Dorn and is the heaviest noble gas.222Radon decays by alpha and gamma emissions. Exposure of radon gas to the pulmonary epithelium is associated with an increased incidence of lung cancer in both uranium miners and in those who dwell in residences with increased concentrations of radon. Damage to bronchial epithelium results from the alpha emissions of radon and radiation from radon daughters that precipitate as solids and remain in the lungs. Good enclosed space ventilation, abstinence from cigarette smoking, and monitoring of radon concentrations help to minimize this risk.
Technetium (symbol Tc, atomic number 43, and atomic weight 98.9) was discovered in 1937 and was the first element to be produced artificially. Unusual among the lighter elements, Tc has no stable isotopes and is therefore found on earth as a product of spontaneous uranium fission. The majority of technetium is extracted from nuclear fuel rods and is used in nuclear medicine for imaging. 99mTechnetium (the m is for metastable referring to an intermediate energy state) emits gamma rays that are similar to diagnostic x-rays and easy to detect. 99mTechnetium decays to 99Tc with a half-life of 6 hours, and the half-life of 99Tc is 2.1 × 105 years, allowing it to be easily eliminated before it decays in turn. Most human contact with Tc is in medical scans in which Tc has a biological half-life of about 1 day. There are no reports of adverse effects resulting from overdose with Tc, and no specific therapy is recommended in that event.
Thallium (symbol Tl, atomic number 81, and atomic weight 204) was discovered by Crookes in 1861. 201Thallium is used for cardiac imaging, has a half-life of 73 hours, and decays by electron capture and gamma emission. Pharmaceutical 201Tl is created in a cyclotron by bombarding thallium with protons creating 201Pb and is shipped in this form, which decays into 201Tl. Because the radioactive decay process is continual, it is recommended to administer the 201Tl close to its calibration time to minimize the presence and effects of other radionuclide contaminants. Chelation can be accomplished with Prussian blue (Antidotes in Depth: A31).
Tritium is an isotope of hydrogen whose nucleus contains one proton and two neutrons, and its symbol is 3H. Tritium decays by beta activity and is used in basic science research as a radioactive label, for luminous dials, and self-powered exit signs, which can contain as much as 9.3 × 1011 Bq (25Ci). Tritium has a half-life of 12.3 years. Tritium emits very weak radiation in the form of 18.6 KeV beta particles, which are easily stopped by thin layers of material, and is safe for glow-in-the-dark watches. Tritium is not absorbed as a hydrogen gas, although, when in contact with oxygen it forms tritiated water, which can be absorbed via inhalation or transdermally. The estimated LD50 is 3.7 × 1011 Bq (10 Ci) given its extreme specific activity of 9,649 Ci/g. When absorbed as tritiated water, tritium tends to follow the water cycle in humans, providing a whole-body dose if incorporated. However, its biologic half-life is 10 to 12 days, which can be decreased by increasing urine output, greatly limiting its potential toxicity.
Initial Assessment and Early Triage
The initial management of patients exposed to radiation will depend on a number of different factors, including the amount of radiation in the exposure and the number of casualties in the event. Small-scale exposures to radiation still require at least a brief evaluation for burns and trauma, depending on the circumstances surrounding the nature of the exposure. Calls to the poison control center from a residence require referral to emergency services for an expert evaluation of the extent of the contamination of the site and appropriate decontamination measures. Exposures in the laboratory or nuclear medicine suites require referral to the radiation safety officer (RSO) in the building for a similar evaluation.
When considering a local incident involving nuclear material, first responders will likely include a hazardous materials team (HAZMAT) and local police and fire departments. Hospitals should involve their RSO, and public officials will involve a state agency such as the State Department of Environmental Protection. As part of its primary mission for the US Department of Energy, REAC/TS offers consultation with anyone on a 24/7 basis on questions regarding radiation exposure. Its emergency phone number is 865-576-1005 (ask for REAC/TS). For large incidents, other federal agencies will be involved led by the Federal Emergency Management Agency. Additional radiation expertise can be provided via the Department of Energy, and if applicable, the Federal Bureau of Investigation will be called to protect against further threats.
In a mass casualty event, established prehospital plans should be followed to provide the best management for the large numbers of variably injured given that an explosion of potentially catastrophic size also accompanies the radiation exposure. First responders must use universal precautions and should assume that all victims are contaminated; most events will only require C- or D-level protection (Chap. 132). Field triage protocols tailored to the kind of event in question will designate patients as minor, delayed, immediate, or deceased and should not be altered because of radiation exposure.
Preliminary decontamination, including removal of clothing and washing the victim, should be performed before transportation to a medical facility taking care not to contaminate prehospital providers or equipment. Uninjured patients who are contaminated should be relocated upwind of the incident site for further care.
Initial Emergency Department Management
It is not considered a medical emergency to have been irradiated or contaminated; even highly irradiated patients take days to die, which is why standard protocols regarding trauma and other medical complaints continue to be followed even in mass casualty events. In the event of a radiation incident, there will likely be little warning of these patients arriving, and information will be incomplete. Ideally, the ED is divided into clean and dirty areas where the floor of the dirty area is covered by plastic or butcher’s paper. Staff should don surgical scrubs, gowns, surgical caps, masks, booties, and face shields. Two sets of gloves should be worn with the inner set taped to the gown. Tape should also close the back of the gown and trousers to the booties. Dosimeters should be worn at the neck for easy access by the RSO, and staff should be reminded that medical personnel have never received a medically significant acute radiation dose when caring for an exposed patient.
Because of the complex nature of radiation and contamination, it will be necessary to call on the various consultation services, who will likely be a part of the hospital medical response team, that can lend their expertise. These services include burn specialists, dermatologists, nuclear medicine specialists, radiation oncologists, hematologists, toxicologists, and the RSO.
When patients arrive to the ED, it is essential to follow an algorithm that takes into account issues of irradiation or contamination and includes data collection specific to biodosimetry. One such algorithm is the REAC/TS patient treatment algorithm at https://orise.orau.gov/reacts/infographics/radiation-patient-treatment-algorithm.pdf. Important patient history includes their location during the incident, duration of the exposure, time interval between exposure and clinical evaluation, occupation of the victim, and whether the patient has had a recent nuclear medicine procedure. Physical examination, in addition to airway, breathing, and circulation, should focus on vital signs, skin (erythema, blisters, desquamation), GI symptoms (abdominal pain and cramping), neurologic findings (ataxia, headache, motor or sensory deficits), and hematologic signs (ecchymoses or petechiae). Vomiting very early after exposure is considered a sign of the central nervous system subsyndrome and is a poor prognostic indicator.
Recommended initial laboratory testing includes baseline complete blood count (CBC) with differential (including an extra sample in a heparinized tube for cytogenetics), serum amylase (increased from specific salivary gland inflammation and degeneration), urinalysis, baseline radiologic assessment of urine, and starting a 24-hour urine collection. Other laboratory tests, if possible, can include blood FLT-3 ligand concentration, blood citrulline, interleukin-6, quantitative granulocyte colony-stimulating factor, and C-reactive protein. Nasal swabs, emesis, and stool should be collected for radiologic monitoring. For patients with persistent vomiting erythema or fever, a repeat CBC with differential is recommended every 4 to 6 hours. If a patient requires surgery, we agree with the Armed Forces Radiobiology Research Institute recommendation that surgery proceed immediately because of the delayed and impaired wound healing associated expected decreases in leukocytes and platelets.
When a patient is medically stable, decontamination should proceed. Patients who were not decontaminated in the prehospital setting but who are grossly contaminated should be fairly easily detected as such by a quick evaluation with an appropriate instrument. As a first step, all clothing should be removed gently by cutting and not tearing as is typically done for trauma patients. Rolling supine patients allows contaminated clothes to be carefully gathered and bagged and marked. Bagged clothes and other contaminated articles should be removed from the ED to a site designated by the RSO so as not to present another source of radiation. A portable dosimeter should assist in external decontamination. After clothing removal, remonitor the patient for contamination, paying attention to exposed areas such as hair. Contaminated hair should be washed with soap and water before washing the body to avoid trickle-down contamination. For patients with contaminated wounds, decontamination should prioritize the wound first, then body orifices around the face, and then intact skin. Always wipe gently away from the wound. Irrigate gently to reduce splashing. Care must be taken not to abrade skin by too vigorous scrubbing or shaving of hair. Contaminated nares can be cleared often by having the patient blow his or her nose. Ideally, all irrigating fluids are collected for analysis, but this will be limited by resources and event details. There should be no eating, drinking, or smoking at the scene of decontamination.
For patients with smaller exposures to radionuclides, such as laboratory workers, decontamination is often the only management technique required to limit injury. Portable dosimeters will identify contaminated areas, which should be sealed off to limit spread of exposure, especially if the radionuclide is in gaseous form. As with larger exposures, contaminated clothing must be removed and collected. Contaminated skin must be washed with lukewarm soap and water, repeatedly if needed.
In evaluating an area where a spill of radioactive material has occurred, a judgment must be made regarding the severity of the incident so that appropriate steps are taken. If a major incident has occurred involving large amounts of radioactive material, a large contaminated area, airborne radioactivity, or spread of radiation outside an authorized area, evacuation, notification of the RSO in an institutional setting, and calling local or regional emergency response personnel are recommended. Minor incidents involve small amounts of radioactive material in which the individual knows how to clean the site, has appropriate decontamination material on hand, and can clean the area in a reasonably short time. Several different decontaminating soaps are commercially available from general stores and many scientific suppliers. These soaps come in the form of concentrated detergents, ready-to-use dispensers, or foaming sprays with which a small spill is quickly wiped clean and disposed of in an appropriate container. Most radiation management sources, such as Radiation Emergency Medical Management (REMM) and REAC/TS, recommend a neutral soap or shampoo.
Exposure to radiation can lead to a complex spectrum of organ damage that can be difficult and confusing for physicians when creating a treatment plan. Establishment of guidance in the form of a response category (RC) helps clarify a medical plan and disposition (Table 128–4). After exposure to radiation, quantitative and semiquantitative criteria should be used to describe different degrees of injury to affected organ systems. Combining descriptions of the patient’s severity among categories of hematopoietic, cutaneous, GI, and neurovascular subsyndromes allows assignment of a grade of injury. For example, a patient with a third-degree cutaneous injury but only first- or second-degree injuries to the other systems would be given an RC grade of 3, giving the cutaneous injury the greatest weighting because its severity would then carry the worst prognosis. This RC grade then suggests a certain level of care whether ambulatory versus inpatient versus intensive care unit, as well as use of specific treatments such as blood transfusion versus colony-stimulating factors (CSFs) versus bone marrow transplantation. (For specific suggestions, refer to the interactive version of this assessment tool at the REMM’s website at http://www.remm.nlm.gov.) It is essential to remember that after a mass casualty event, response assets from facilities to medications to personnel may be diminished significantly and that recommendations using this system can and should be modified in accordance with other recommendations concerning crisis standards of care.5
TABLE 128–4Grading System for Organ System Dysfunction and Response Category for Disposition6 ||Download (.pdf) TABLE 128–4 Grading System for Organ System Dysfunction and Response Category for Disposition6
|Symptom ||Degree 1 ||Degree 2 ||Degree 3 ||Degree 4 |
|Neurovascular System |
|Anorexia ||Able to eat ||Decreased ||Minimal ||Parenteral |
|Nausea ||Mild ||Moderate ||Severe ||Excruciating |
|Vomiting ||1/day ||2–5/day ||6–10/day ||> 10/day |
|Fatigue ||Able to work ||Impaired ||Assisted ADLs ||No ADL |
|Fever ||(<38°C) ||(38°–40°C) ||(>40°C) <24 hours ||(>40°C) >24 hours |
|Headache ||Minimal ||Moderate ||Severe ||Excruciating |
|Hypotension (BP, mm Hg) (Adult) ||>100/70 ||<100/70 ||<90/60 ||<80 systolic |
|Cognitive deficits ||Minor ||Moderate ||Major ||Complete |
|Neurological deficits ||Barely detectable ||Easily detectable ||Prominent ||Life threatening |
|Hematopoietic System (all counts × 109/L) |
|Lymphocytes ||1.5–3.5 ||0.5–1.5 ||0.25–1 ||0.1–0.25 |
|Granulocytes ||4–9 ||< 1a ||< 0.5a ||0–0.5 |
|Platelets ||150–350 ||50–100 ||0–50 ||Very lowb |
|Gastrointestinal System |
|Diarrhea || || || || |
|Frequency (/day) ||2–3 ||4–6 ||7–9 ||≥10 |
|Consistency ||Bulky ||Loose ||Loose ||Watery |
|Bleeding ||Occult ||Intermittent ||Persistent ||Large, persistent |
|Abdominal cramps/pain ||Minimal ||Moderate ||Severe ||Excruciating |
|Cutaneous System |
|Erythema ||Minimal ||<10% BSA ||10%–40% BSA ||>40% BSA |
|Edema ||Asymptomatic ||Symptomatic ||Secondary dysfunction ||Total dysfunction |
|Blistering ||Rare, sterile ||Rare, bloody ||Bullae, sterile ||Bullae, bloody |
|Desquamation ||Absent ||Patchy, dry ||Patchy, moist ||Confluent, moist |
|Ulceration or necrosis ||Epidermal ||Dermal ||Subcutaneous ||Muscle or bone |
|Hair loss ||Absent ||Partial ||Partial ||Complete |
|Response Category ||1 ||2 ||3 ||4 |
|Triage and Monitoring ||Ambulatory || |
| || || |
CSFs or SCT
Supportive care quality will determine the extent of the morbidity and mortality. The majority of patients with ARS who succumb usually do so from fluid loss, infection, or bleeding. Irradiated patients require treatment for nausea and vomiting, diarrhea, pain, and fluid and electrolyte losses. Vomiting is thought to occur as a result of serotonin release from damaged gut tissue. The 5-HT3 antagonists, such as ondansetron and granisetron, are the most effective medications to control vomiting. Prolonged antiemetic treatment is usually not necessary because emesis often resolves within 72 hours. Loperamide, anticholinergics, or aluminum hydroxide are reasonable to treat diarrhea. Mild pain should be managed with acetaminophen, but we recommend against the use of aspirin and nonsteroidal drugs because they exacerbate gastric bleeding. An opioid is recommended for the management of more severe pain.
Probiotics is the introduction of selective nonpathogenic strains of Lactobacillus and Bifidobacteria into the GI tract to suppress the number of pathogens. Experimentally, this technique increased survival in canine and rodent models. Probiotics were used to help care for three men exposed at the incident at Chernobyl, whose survival time was prolonged, although it was not statistically significant when compared, respectively, with case controls. Based on the existing data, it would be reasonable to treat patients who develop diarrhea with probiotics.4,38
Intravenous access should be established and maintained with care because these patients are prone to infection. If the patient is expected to become neutropenic and experience a long hospitalization, it would be reasonable to establish central venous access or place a peripherally inserted central catheter to minimize the risk of access-associated infection. Fluid replacement begins with crystalloid solution with the goal of replacing GI losses. The infusion rate will be modified by recorded inputs and outputs and assessment of surface area burns.
Prevention of infection includes attention to several aspects of care. Maintain the patient in a clean environment and institute reverse isolation for patients with at least moderate exposure or when neutrophil counts decline below 1,000/microliter. Prophylactic antibiotics and antifungals are recommended to neutropenic patients, as well as acyclovir or a congener for herpes simplex virus positive patients. If neutropenic patients become febrile we recommend following the Infectious Disease Society of America guidelines for antibiotic choices. It is reasonable to administer broad-spectrum prophylactic antibiotic coverage, including anaerobic coverage for patients with burns.7,10
Cutaneous injuries are cared for depending on the nature, location, and extent of the wounds. Care ranges from use of lanolin-free water-based moisturizers to topical steroids to debridement to skin grafting. For patients who develop radiation-induced fibrosis, it is reasonable to treat with pentoxifylline. Surgical consultation or referral to a burn center should be offered early in the clinical course.
Cytokine therapy (CSFs) use in radiation-exposed patients is based on demonstrated enhancement of neutrophil recovery in patients with cancer, a perceived benefit in a small number of radiation-incident victims, and several prospective trials using different animal models involving radiation exposure. These last studies demonstrated not only neutrophil recovery but also a survival advantage. The best outcomes were demonstrated when started less than 24 hours postradiation suggesting CSFs should be started as soon as possible for patients exposed to a survivable dose of radiation who are at risk for hematopoietic syndrome, that is, more than 3 Gy. Additionally, it is reasonable to administer cytokines to vulnerable patients at extremes of age, that is, those younger than 12 years and older adults who are exposed to lower threshold doses.10
Use of blood products is required for patients with significant blood loss or for those experiencing radiation-induced aplasia. This latter complication usually begins several weeks after exposure, allowing for time to identify potential donors. Use of leukoreduced and (ironically) irradiated blood products should be the rule to prevent transfusion-associated graft-versus-host disease. This hyperacute complication can be further complicated by its similarity to radiation-induced organ injury, including fever, pancytopenia, rash or desquamation, diarrhea, and hyperbilirubinemia.
Stem cell transplantation (SCT) can be used to treat patients with severe bone marrow injury, but the decision to use this therapy is very complicated. Currently, it is believed that with aggressive supportive care and early use of CSFs, patients only suffering from hematopoietic syndrome may survive a radiation dose of 7 to 8 Gy, but doses greater than 10 Gy are likely to be fatal, providing a narrow window of opportunity even if an appropriate match could be found. Stem cell transplantation use must also account for other factors, including the manner in which the exposed dose was estimated and its accuracy; the presence of other radiation syndromes; and whether other potentially significant concurrent organ injuries, such as burns or acute respiratory distress syndrome, are present because they have historically accounted for 70% of radiation deaths.7 Over the past 70 years, radiation incidents have generally produced only small numbers of patients requiring intensive care, the only exceptions being Chernobyl and Goiânia, although with the real threat of terrorism, emergency resources could become severely limited in the face of a large mass casualty event. If conditions were favorable and resources were available, it would be reasonable to attempt SCT in patients with a severe radiation exposure who have an otherwise grave prognosis.
Management of Internal Contamination
Internal contamination is assessed differently from external doses in that they are not measured but rather are calculated. These calculations are performed by a health physicist on samples such as nasal swabs, urine, or stool to estimate how much activity entered the body. Doses are termed committed doses defined as the doses received that last more than 50 years because of the internal deposit of the radionuclide. That is, the radionuclide dose is protracted and remains until it decays or is eliminated via normal kinetic processes. These doses are compared with the annual limits on intake (ALIs) provided by the EPA as a benchmark for medical decision making. Interpretation of committed doses from contaminated wounds requires special conversion factors provided by the NCRP.
Management of internal contamination is isotope dependent. There are more than 8,000 isotopes, making identification of the particular isotope critical. Although both radioactive decay and biologic elimination contribute to an even shorter effective half-life, medical treatment is directed at one of several categories, including reduction of GI absorption, blocking uptake (as with potassium iodide), isotopic dilution (water for tritium), chemical manipulation (sodium bicarbonate for uranium), excision of shrapnel, and chelation. Both NCRP reports No. 65 and No. 161 provide comprehensive information regarding decorporation of radionuclides; however, for the few isotopes of particular concern for industry, the military, and academic and medical centers, potassium iodide and pentetic acid (DTPA) are the most commonly applicable chelators (Antidotes in Depth: A44 and A45).
The prognosis of those exposed to radiation varies with the amount of the exposure, the type of medical care received, and the number of casualties in a given exposure scenario. Survival is inversely proportional to the radiation dose absorbed. Even relatively radioresistant cell types can be killed by high amounts of radiation. Historically, the mean lethal dose required to kill 50% of humans at 60 days (LD50/60) was about 3.5 Gy without supportive care. The addition of antibiotics and blood products increases that mean to 6 to 7 Gy. This dose is likely to be even higher for those treated early with CSFs in a specialized hospital. Coexisting traumatic injuries or burns will decrease the LD50/60. An acute dose of 20 Gy or more is considered supralethal. Historically, those who were exposed to greater than 10 Gy died despite care including 20 of 21 workers who were exposed anywhere from 6- to 16-Gy at Chernobyl and one worker at Tokaimura who was exposed to 17 Gy and died 3 months postexposure after requiring highly resource and labor-intensive care, including 10 L of fluid daily and extensive transfusion support.
During a catastrophic radiation incident, resources will likely become depleted to the extent that not all patients who require certain medical treatments to survive will be able to receive them. A consistent and transparent method to allocate scarce resources implemented by senior clinicians within their existing legal and ethical constructs should act to maximize the number of patients to survive, the number of life-years saved, and the individuals’ chances to live through each of life’s stages. The REMM Scarce Resources Triage Tool is available online for assistance in evaluating a patient’s prognosis, in which a patient’s injury extent may indicate an expectant prognosis assisting clinicians to help those who may survive instead.5,6,41
CONSIDERATION OF THE DECEASED
Contaminated bodies should be placed in a temporary morgue that is refrigerated. Use of the hospital morgue will lead to contamination there. These bodies should not be cremated because this will only redistribute the nuclear material, which is not destroyed by fire. Respect should be paid to the religious beliefs of family members of the deceased for whom cremation is the custom. Reconciling these personal and cultural beliefs necessitates extreme skill emphasizing cultural, religious and scientific understanding.
When exposure to radiation via medical examination is possible, pregnant women and physicians have exhibited great concern over possible injury to fetuses. In general, radiation effects to an embryo or fetus are dependent on its stage of development and the dose received. The medical decision to perform imaging or a diagnostic procedure that exposes any patient to radiation is always based on a risk-to-benefit analysis with a given patient’s situation.
In the normal course of events, uncertainty exists regarding the normal viability of the fertilized ovum in which the estimated baseline risks of birth defects and miscarriage at all stages are 3% and 15%, respectively, for women with normal genetic and reproductive histories. Very early in a pregnancy before implantation, the embryo is in an “all-or-none” period of development in which the greatest risk from radiation is miscarriage but not greater than baseline risk. Older than this, the fetus is next at greatest risk between 8 to 15 weeks of gestation during which major neuronal migration takes place.
The NCRP considers risk to fetuses to be negligible compared with other risks of pregnancy when the dose to a fetus is less than 50 mGy (5 rad), which corresponds to 50 mSv from x-ray examination, compared with about 6 mSv effective dose from a CT examination of the pelvis. The risk of malformation is increased only at doses above 150 mSv. As mentioned earlier, special attention must be paid to pregnant or potentially pregnant patients when deciding if an examination or procedure involving radiation is considered. Effective doses from various examinations and procedures are known to range from 0.1 mSv from posteroanterior and lateral x-ray examination of the chest to 15 mSv from CT angiography of the chest, to 40.7 mSv from cardiac stress test with 201Tl. The vast majority of routine diagnostic imaging procedures imparts less than 5 mSv to a fetus, increasing baseline risk by about 0.17%, and so is considered to be of negligible risk, but shared decision making should always balance the potential maternal benefit of the radiologic procedure and the potential risk to the fetus.
The use of CT scanning in children has markedly increased over the past 30 years. Estimates include data that, commensurate with the 20-fold increase in use of CT scans in the United States, the use of CT for pediatric patients has increased by about eight times. The reasons for this increase are many, including greater availability, greater use as a primary diagnostic tool, and an increased perception that the risk of being wrong about a diagnosis is high.3,24 Estimates calculate an increased risk of lifetime mortality rate in the range of 0.04% for a head CT for a young female patient (1 in 2,500) compared with a normal lifetime cancer mortality risk of 20% (1 in 5). This excess relative risk was supported by a large retrospective study of a pediatric population that found increased incidence of certain leukemias and certain brain tumors attributed to CT scans over a 23-year period.2,31
Although radiation is considered to be a weak carcinogen and radiographic studies should continue to be ordered in the best interest of the patient, it is likely that the number of scans performed could safely be diminished without compromising care. Reports on this topic commonly include problems with ordering unnecessary multiple CTs, follow-up CT scans, and CT scans that occur simply because of a lack of communication among the patient, health care professional, and technician. These problems, compounded by inappropriate CT protocol for pediatric patients, suggest that the medical community could be more proactive in reducing the health risk of those in our charge.
Ionizing radiation injures humans through the disruption of cellular structure and function that can lead to cell death and or mutagenesis.
Fortunately, large exposures of radiation to the general population are rare outside of the setting of an armed conflict, and most contaminations that occur are small and easily controlled.
Recognition of the exposure and thorough decontamination are the critical steps to minimizing the potential toxicity of an exposure.
Prognosis is based on dose which can be estimated on a number of clinical and laboratory grounds.
Although consequential, neither contamination nor incorporation should take precedence over the highest priorities of emergency care and urgent surgery.
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