Radiation Biology and Safety
Joshua Adam Tarrence, DO
LEARNING OBJECTIVES
1. Understand the ways ionizing radiation interacts with molecules and cells in organic tissue.
2. Be able to describe the ways ionizing radiation exposure can cause harm to humans.
3. Understand the relationship between radiation exposure and carcinogenesis.
4. Be familiar with the various dose-response curves.
5. Understand the principles behind radiation safety and their implementation.
6. Know how radiation exposure is monitored and regulated.
7. Recognize the expected organ system responses and whole-body responses to radiation injury based on dose.
INTRODUCTION
Radiation energy allows for many of the conveniences enjoyed by modern society, not least of which is advanced medical imaging for the diagnosis of disease. However, most understand to a certain degree that radiation carries with it the potential for harmful effects. The study of the effects of radiation on the human body has closely accompanied the study of radiation as an imaging modality from the earliest stages. As such, it is imperative for one working in the field of medical imaging or in medicine in general to be familiar with the potentially harmful effects radiation can have on the human body and how the potential for harm can be kept to the lowest level possible.
This chapter consists of two main sections: radiation biology and radiation safety. Radiation biology examines the mechanisms through which radiation interacts with the human body down to the molecular level and the implications those mechanisms have on analyzing, treating, and preventing the body’s response to radiation exposure. This is followed by a review of radiation as a carcinogen, a hereditary risk factor, and a potentially harmful agent in utero. Radiation safety details how radiation exposure is measured and the preventative measure implemented to ensure that patient and personnel exposure to harmful amounts of radiation is avoided. This is followed by a brief review of radiation regulatory bodies and exposure limits, radiation exposure emergencies, and special considerations for radiation exposure in female pregnant patients.
RADIATION BIOLOGY
The response to radiation exposure is not uniform across different biologic systems or even across time in the same biologic system. Factors that determine how a biologic system reacts to radiation include variables in the radiation source and in the biologic system itself. Variables related to the radiation source include the absorbed dose, the dose rate, and the type of radiation. Variables related to the irradiated biologic system include factors that are inherent to the system and factors related to the conditions in the cells at the time of radiation exposure.
Stochastic effects and deterministic effects
There are two categories of effects of radiation exposure on biologic tissues: stochastic effects and deterministic effects. Stochastic effects have an increased risk of occurring with an increase in dose. However, the severity of disease, once disease is present, it not affected by dose. For example, a substantial exposure to ionizing radiation can increase the risk of certain types of cancer, such as thyroid cancer. In the stochastic effect model, theoretically the radiation only needs to affect a very small number of cells to create the potential for cancer growth. Therefore, as the dose increases, so does the opportunity of damage to cells and, as a result, the risk of cancer increases. However, once a cancer has been caused by the radiation exposure (thyroid cancer in this case), the severity of the cancer is not dependent on the dose of the radiation exposure. Although unproven, this model of increasing risk of disease with increasing dose and no dose under which the risk will be zero is the model on which the modern approach to radiation protection is based. Because the risk increases and decreases with the dose in this model, the current approach of “ALARA” (as low as reasonably achievable) seeks to decrease the risk of radiation-induced disease as much as possible by always using the lowest possible dose.
In contrast, deterministic effects are those of which the severity increases with an increase in dose. Deterministic effects have an approximate threshold dose, under which the risk of the effect occurring is essentially zero. For example, if a patient receives an X-ray of her hand, there is essentially no chance of her receiving
skin damage from the single radiograph under standard methodology. If the same patient were to undergo fluoroscopy on her hand, for a procedure for instance, and were to receive a much higher dose of radiation to that skin surface area, she would eventually experience skin and tissue damage after a certain dose is reached and the damage would increase as the dose increases.
skin damage from the single radiograph under standard methodology. If the same patient were to undergo fluoroscopy on her hand, for a procedure for instance, and were to receive a much higher dose of radiation to that skin surface area, she would eventually experience skin and tissue damage after a certain dose is reached and the damage would increase as the dose increases.
Interaction of low energy electrons with tissue
The known physical effects of radiation on tissues are the result of chemical changes in biomolecules, and these changes are brought about by a series of serial excitations and the resulting release of kinetic energy following a single ionizing event. When X-ray or gamma rays come into contact with tissues, energetic free electrons are released. The kinetic energy of these electrons is in turn dissipated by excitation, ionization, and heat. As the energy is released, it will interact with and excite surrounding electrons in a rapid and random fashion, exciting a large number of secondary, low-energy electrons in its path. This is known as secondary ionization. For example, a single electron with an energy of 30 keV set in motion by absorption of an X-ray or gamma-ray photon may produce over 1000 secondary electrons of lower energy. The secondary electrons, known as delta rays, may then each cause their own set of ionizations in the tissues, resulting in a chain of ionization events. Eventually, as energy is lost during these reactions, the electrons will be excited below the threshold of excitation of liquid water (7.4 eV), leaving them in a so-called subexcitation state. These electrons then release their energies in the form of rotation, vibration, and collision events with surrounding water molecules.
The low-energy electrons set in motion by the initial ionizing event will form shorter tracks off of the path of the sentinel electron and will each result in three additional ionizing events on average. These secondary tracks along the path of the sentinel electron path are known as spurs. Approximately 95% of the energy deposited in tissues by X-rays and gamma rays is estimated to occur in spurs.1 Additionally, longer secondary tracks that occur less frequently along the sentinel path and deposit more energy are known as blobs. The higher energy released along the path of blobs results in more ionization events along their paths on average. The areas around spurs and blobs experience a high concentration of reactive chemical species, which increases the opportunity for molecular damage in these locations. Should such a cluster of ionizations occur near deoxyribonucleic acid (DNA), there is the potential for several, closely grouped areas of damage to occur in the DNA. Such groups of multiple damage sites are more difficult for the cell to repair correctly.2,3 This type of damage can be referred to as clustered damage, complex damage, or multiply damaged sites. This form of clustered damage is characteristic of ionizing radiation-induced damage to DNA, but the functional changes to molecules, cells, tissues, and organs brought about by this damage cannot be distinguished from those caused by other types of damage. Although these types of ionizing radiation-induced damage are more difficult for the cell to repair, the cell remains very efficient in correcting the damage or killing and replacing the cell. Only a fraction of the energy deposited into irradiated tissues brings about any chemical changes, and the effects of these changes may never be made apparent or may declare themselves at any time ranging from minutes to years.
Interactions of free radicals with tissue
Biologic changes in irradiated tissues can occur directly or indirectly. Direct damage occurs when macromolecules such as DNA, RNA, or proteins are ionized by an ionizing particle or photon passing nearby. Indirect damage is caused by chemically reactive species that are the result of radiation interactions with other molecules, usually water. Radiation interaction with water produces several types of reactive chemical species. When water is contacted by radiation, it is first ionized to form H2O+ and e–. Immediately the e– thermalizes and becomes hydrated and is surrounded by water molecules to form an aqueous electron (eaq–). The eaq– subsequently reacts with another water molecule and forms a negative water ion H2O–. The H2O+ and H2O– ions are unstable and quickly react with water to form another ion and a free radicle
+2O+ + H2O → H3O+ + • OH (hydroxyl radical)
H2O– → OH– + H • (hydrogen radical)
The majority of biologic damage caused by radiation in medical imaging is caused by free radicals. Free radicals are atoms or molecules with unpaired orbital electrons. Hydrogen and hydroxyl radicals can also be created, among other pathways, through radiation-induced excitation and disassociation of a molecule of water. The resulting H+ and OH– ions have extremely short half-lives and typically do not cause a significant amount of biologic damage. They also tend to recombine to form water, also limiting their interactions with other nearby biologic molecules. Once free radicals have formed, they can undergo reactions with other free radicals to form nonreactive molecules such as water and no biologic damage occurs. Additionally, a free radical can undergo a reaction with a free radical of the same type to form other molecules such as hydrogen peroxide. Hydrogen peroxide can cause damage to a cell, but the majority of damage caused by linear energy transfer (LET) radiation does not involve hydrogen peroxide. Instead, the majority of indirect damage caused by X-rays and gamma rays is the result of hydroxyl radicals reacting with biologic molecules such as DNA. The potential for harmful effects by free radicals is increased in the presence of oxygen, because oxygen acts as a stabilizer of the free radicals and makes it less likely that they will combine to form nonharmful molecules such as water or molecular hydrogen. Oxygen can also combine with a hydrogen radical to form highly reactive oxygen species such as the hydroperoxyl radical (HO2•). Free radicals can act as strong oxidizing or reducing agents when they combine directly with macromolecules. Although free radicals have short half-lives, they can diffuse sufficiently far in the cell to cause damage in locations away from their origin. Approximately two-third of total damage caused by medical imaging radiation is caused by the indirect effects of free radicals.
Relative biologic effectiveness
The biologic effects of radiation depend on several factors, including dose, dose rate, tissues being irradiated, and so on. An additional factor is the linear energy transfer (LET). LET refers to the energy deposition of an ionizing particle per unit distance of the material it transverses. Experiments are performed to determine the relative effectiveness of different types of radiation and their LETs by comparing the dose required to produce the same biologic effect as a particular dose of a reference form of radiation. The term relative biologic effectiveness (RBE) refers to the relationship of the effectiveness of the test radiation to the reference radiation
 FIG. 10.1 • The relative biologic effectiveness (RBE) of a given radiation generally increases with the linear energy transfer (LET) of the radiation. However, beyond ˜100 keV/mm, radiation becomes less efficient and further increase in LET results in wasted dose. Reprinted with permission from Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 8th ed. Philadelphia, PA: Wolters Kluwer; 2018. |
RBE is initially proportional to LET. The increase in the RBE with increasing LET (Figure 10.1) is thought to be due to the increased specific ionization (ionization density) associated with high-LET radiation, which results in more cellular damage. RBE is directly proportional to LET until approximately 100 keV/µm in tissue, beyond which the RBE decreases with increasing LET (Figure 10.1). This can be explained by the overkill or wasted dose effect. Overkill refers to the deposition of radiation energy in tissues beyond the levels necessary to produce maximum biologic effects.
Molecular and cellular responses to radiation
DNA damage and repair
Ionizing energy deposition in tissues results in chemical and subsequent structural changes in molecules. These structural changes include hydrogen bond breakage, molecular degradation or breakage, and intermolecular and intramolecular cross-linking. These processes occurring in DNA molecules may result in single-strand breaks (SSBs) or double-strand breaks (DSBs) in the DNA, base loss, base changes, or cross-links between DNA strands or between DNA and proteins. SSBs in DNA are usually rejoined with high repair fidelity. DSBs that are incompletely or incorrectly repaired may lead to activation of oncogenes or inactivation of tumor suppressor genes, which is the basis of carcinogenesis. Such changes can also result in loss of heterozygosity.
The low-LET radiation used in medical imaging is capable of causing DSBs, but is more likely to produce SSBs, which are more likely to be correctly repaired. However, the low-energy secondary electrons produced along the course of the path of initial ionizing radiations, as discussed earlier in the chapter, increases the chances that complex damage including SSBs and DSBs as well as base damage will occur near one another. These areas of complex damage prove much more difficult to repair correctly and may lead to permanent damage.2,4
The loss or damage of a base is termed a mutation. Some mutations can cause physical changes to a chromosome. When a chromosome is damaged before DNA replication, it is termed a chromosome aberration. Damage occurring in a chromosome after DNA replication is termed a chromatid aberration. Chromatid aberrations result in only one daughter cell being affected as long as only one of the chromatids of a pair is damaged. This is not true of chromosome aberrations. Chromosomal aberrations occur spontaneously to a certain extent. Quantifying chromosomal aberrations in human lymphocytes is even used as a means of estimating a dose of radiation received after an accidental exposure by comparing the number of aberrations against the expected background number of aberrations. The extent of genetic damage transmitted with chromosomal aberrations depends on factors such as the type of cell, the types and number of genes deleted, and the lesion occurring in either a somatic or gametic cell.
DNA is constantly undergoing damage and repair even in the absence of radiation. The cell is normally quite capable of repairing the damage to avoid mutations. When DNA is damaged, there are cellular responses that either repair the damage or allow the cell to cope in spite of the damage. There are checkpoints in the reproductive pathway of a cell that will either arrest the cell cycle while the DNA damage is repaired or will initiate apoptosis if the damage cannot be repaired and is harmful enough to the cell.
There are many types of DNA repair, including SSB repair, DSB repair, cross-link repair, direct nucleotide repair, nucleotide excision repair, and short- and long-patch base excision repair. Homologous recombination repair (Figure 10.2), which involves exchanges with homologous DNA strands from sister chromatids, preserves DNA fidelity. However, most DSBs are repaired by nonhomologous end-joining, which involves the ends of the broken strands being joined together (Figure 10.2). This method of repair is prone to errors, but most DSBs are repaired correctly.
There is strong cohesion between the ends of chromatin material, and during these repairs, interchromosomal and intrachromosomal recombination can occur. In approximately 50% of these instances of double-strand misrepair, a translocation occurs. Translocations are large-scale rearrangements of chromosomes, and they may change the phenotype of the cell dramatically without resulting in cell death.
Cellular response to radiation
Radiation exposure initiates a number of cellular responses, depending of the type of cell, the stage of the cell cycle during the exposure, the dose of the radiation exposure, and so on. The cell may respond by dying (apoptosis), delaying reproduction, failing to reproduce, delaying expression of the genome, DNA mutation, phenotypic transformation, or bystander effects (damaging neighboring unirradiated cells). Cells may also become altered to be more radioresistant, termed an adaptive response.
One marker of the biologic effects of radiation exposure is reproductive integrity. Irradiated cells in culture may not show physical changes for a long time, but reproductive failure will eventually occur. This allows the radiosensitivity of a particular cell line to be determined by irradiating individual cells in vitro and counting the number of colonies that arise from that known number of irradiated cells. This method may also be used to determine the biologic effectiveness of different types of radiation as well as the effects of environmental condition on the radiation effects.
Cell survival curves are a plot of the loss of ability of a cell to reproduce as a function of the cell’s exposure to radiation (Figure 10.3). The shape of a cell survival curve is an indication of the cell line radiosensitivity. There is a “shoulder” before the semilogarithmic plot of the cell survival curve, dependent on Dq. Dq is a measure of sublethal damage, an entity based on the concept
that when certain radiation doses are split into fractions, more than one exposure to the radiation is required to kill the cell and that the cell is capable of repairing the damage between fractions of the dose.
that when certain radiation doses are split into fractions, more than one exposure to the radiation is required to kill the cell and that the cell is capable of repairing the damage between fractions of the dose.
 FIG. 10.2 • Two main DNA double-strand break damage repair mechanisms. Homologous recombination uses an identical DNA strand as template for precise repair. Nonhomologous end joining (NHEJ), in comparison, is more prone to errors in repair. Reprinted with permission from Halperin EC, Wazer DE, Perez CA, Brady LW. Perez & Brady’s Principles and Practice of Radiation Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer; 2018. |
An additional method of describing cell survival is the linear quadratic (LQ) model. This model is used more commonly than the model described earlier because it fits most experimental data on human cell lines and is more useful in explaining fractionation effects in late-responding versus early-responding tissues for radiotherapy. The LQ model is expressed by the following equation:
 FIG. 10.3 • Typical cell survival curve characterized by the initial slope D1, the final slopt D0, and a parameter related to the width of the shoulder, Dq. Reprinted with permission from Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 8th ed. Philadelphia, PA: Wolters Kluwer; 2018. |
SF(D) = e-αD+βD2
where D is the dose (in Gy), α is the coefficient of cell killing proportional to dose, and β is the coefficient of cell killing proportional to the square of the dose. The α and β constants can be used to predict dose-response of certain tissues. The linear portion of the survival curve (α) represents cell killing by individual radioactive particle tracts without interaction, making it independent of dose rate. Conversely, the quadratic (β) portion of the curve represents cell killing as a result of interacting particles. The linear portion of the curve (α) dominates in high-LET radiation and the quadratic portion (β) dominates in low-LET radiation. When a radiation dose causes equal linear and quadratic cell killing, this is termed the α/β ratio. The α/β ratio is a measure of certain tissues’ sensitivity to radiation dose fractionation. Early-responding tissues such as bone marrow have a larger α/β ratio, meaning the tissues have less ability to repair damage in between doses. Thus, fractionating the dose in these tissues would have less effect than in those which are late-responding tissues with a lower α/β ratio. A lower α/β ratio would indicate the tissues are more capable of repair in between dose fractions and thus fractionating the dose would decrease lasting damage in these tissues.
Tissue radiosensitivity
As discussed earlier, there are many factors that must be considered when determining radiation dose and its effect on tissues. However, there are many factors apart from the dose of radiation itself, which affect the response of tissues to a certain dose of radiation. These can be classified as conditional or inherent factors.
Conditional factors exist before or during an irradiation even, whereas inherent factors are the physical characteristics of the irradiated cells themselves.
Conditional factors exist before or during an irradiation even, whereas inherent factors are the physical characteristics of the irradiated cells themselves.
Conditional Factors
The effects of radiation are partly determined by the dose rate and fractionation of the dose. Changes in the rate at which low-LET radiation is delivered has been shown to affect the degree of chromosomal aberrations, reproductive delay, and cell death in the irradiated tissues. High-dose rates are generally more effective in causing biologic damage due to the lower potential for radiation damage repair to take place (Figure 10.4).
 FIG. 10.4 • Different cell survival curves as a result of different dose rate. The observed dose-rate effect results from repair of sublethal damage, redistribution in the cycle and cell proliferation. Reprinted with permission from Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 8th ed. Philadelphia, PA: Wolters Kluwer; 2018. |
Table 10.1 CLASSIFICATION OF CELLULAR RADIOSENSITIVITY | ||||||||||||||||||||||||||||||||||||
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Such a phenomenon is not observed with high-LET radiation due to the increased potential for clustered damage to occur and the lower potential for DNA repair at baseline. Fractionation of a given dose over time also decreases the potential for radiation-induced biologic damage, with the intervals between doses allowing for repair mechanisms in the healthy tissues to repair sublethal damage. This concept is important in radiotherapy due to the ability of noncancerous tissues to be repaired when therapeutic radiation doses are fractionated.
The presence of oxygen increases damage caused by low-LET radiation because it prevents the recombination of free radicals and the formation of harmless chemical species. Oxygen also inhibits repair of damage caused by free radicals. Increasing the oxygen concentration at the time of irradiation has been shown to lead to increased killing of otherwise resistant cells in some tumors. The oxygen enhancement ratio (OER) is an expression of the effectiveness of radiation to cause damage at different oxygen tensions. The OER is defined as the dose of radiation required to produce a given response in the absence of oxygen divided by the dose required to produce the same response in the presence of oxygen. The OER for low-LET radiation in mammalian cells is usually between 2 and 3. OER is lower for high-LET radiation because its damage is not dependent on free radicals.
Inherent Factors
Cells have inherent properties that determine their relative radiosensitivity. Cells that are rapidly dividing will continue to undergo mitosis for a long period of time, and are undifferentiated and typically more radiosensitive. A more detailed classification scheme of cells and their relative radiosensitivity is included below. An exception to these general rules is lymphocytes, which are very radiosensitive despite possessing characteristics of radioresistant cells (Table 10.1). In addition to these characteristics, the phase of reproduction the cell is found in during irradiation greatly affects its radiosensitivity. Cells are most sensitive in the M-phase (mitosis) as well as the time between the S-phase and mitosis (G2) (Figure 10.5).
 FIG. 10.5 • Phases of a cell’s reproductive cycle and checkpoints. Different phases of a cell’s cycle have different susceptibilities to radiation damage. Checkpoints are critical control points in the cycle that have built-in stop signals that may halt the cell cycle. Reprinted with permission from Halperin EC, Wazer DE, Perez CA, Brady LW. Perez & Brady’s Principles and Practice of Radiation Oncology. 7th ed. Philadelphia, PA: Wolters Kluwer; 2018. |
Additional responses to radiation have been observed in vitro, which are not completely understood. For example, there is evidence of an adaptive response that results in decreased effectiveness of a subsequent dose of radiation following exposure of the affected material to an initial dose. Additionally, there is a so-called “bystander effect” with which effects in nearby, nonirradiated cells are observed when certain nearby cells are irradiated. Finally, genomic instability has been observed in vitro, which refers to a phenomenon involving delayed lethal mutations in irradiated cells, possibly due to errors in DNA repair. While these phenomena raise interesting questions about possible other factors affecting radiosensitivity and response to radiation, they are still incompletely understood and their observed effects are typically limited to experimental environments.
Organ system responses to radiation
In addition to analyzing responses to radiation on the molecular and cellular level, the response of organ systems to radiation is also of interest, namely the functional and morphologic changes observed in the organ system as a whole. When analyzing organ responses to radiation, there is a latent period between the exposure and the observed effects, which typically decreases in length as dose increases. Higher dose also decreases the amount of time required for the full physiologic effects caused by the dose to occur. Additionally, threshold doses do exist in some cases under which no observable effects will occur.
Repair and regeneration
When damage to an organ system occurs as a result of radiation exposure, cellular regeneration and repair occur to heal the damage. Regeneration is replacement of damaged cells by the same type of cells. Repair is the replacement of the damaged cells by fibrotic tissue and the functionality of the organ system is reduced or lost. Whether repair or regeneration occurs and how much repair or regeneration occurs depends on the dose of radiation, the type and amount of tissue irradiated, and the capacity of the irradiated tissues to repair or regenerate. When a radiation dose is fractionated, it allows regeneration to occur in between fractions while also allowing for reoxygenation of tumor cells (increasing the potential for biologic damage in the cells upon subsequent exposures) and redistribution of irradiated cells into more sensitive phases of the cell cycle thus increasing effectiveness of radiotherapy.
Specific organ system responses
There are specific and characteristic physiologic responses that have been observed in vivo in certain organ systems in the human body. These will be described in the following paragraphs.
Skin
Skin damage is the most common tissue reaction resulting from high-dose image-guided procedures. The degree of damage to skin by ionizing radiation (also termed the cutaneous radiation syndrome) depends on the dose, quality, and quantity of the radiation as well as the location and extent of exposure to the radiation. Damage ranges from mild erythema to chronic necrosis based on these factors.
Often, there are no immediate symptoms of skin damage caused by radiation exposure. The earliest symptoms such as pruritus and erythema can be delayed up to months following the
exposure. When the skin is exposed to damaging levels of radiation, there is an oxidative stress placed on the tissues resulting in a series of inflammatory responses, reduction/impairment of stem cells, changes to endothelial cells, and apoptosis and necrosis of epidermal cells. These reactions are deterministic, meaning there is a threshold dose of approximately 1 Gy that must be reached before effects are observed. As doses increase, there may be eventual loss of mitotic activity of the germinal cells of the hair follicles, sebaceous glands, basal layer, and intimal cells of the microvasculature.
exposure. When the skin is exposed to damaging levels of radiation, there is an oxidative stress placed on the tissues resulting in a series of inflammatory responses, reduction/impairment of stem cells, changes to endothelial cells, and apoptosis and necrosis of epidermal cells. These reactions are deterministic, meaning there is a threshold dose of approximately 1 Gy that must be reached before effects are observed. As doses increase, there may be eventual loss of mitotic activity of the germinal cells of the hair follicles, sebaceous glands, basal layer, and intimal cells of the microvasculature.
Following an acute dose ≥2 Gy of low-LET radiation, early transient erythema may occur. This consists of a generalized erythema that subsequently fades and is thought to be the result of release of vasoactive amines, resulting in increased vascular permeability. A secondary erythema, termed main erythema, can appear as early as 2 weeks after initial exposure to a high dose of radiation or after repeated exposures to lower doses. This response reaches its peak around the third week following exposure, with edema, erythema, and tenderness of the skin. Main erythema is thought to be the result of the release of proteolytic enzymes from damaged basal cells of the epithelium as well as a reflection of the loss of those epithelial cells. Several pathways of vascular damage are also upregulated as a result of the presence of radiation-induced free radicals. Finally, late erythema may be seen 8 to 52 weeks after exposure and is a result of dermal ischemia, which causes a bluish color of the skin. Temporary hair loss is associated with doses of 3 to 6 Gy, occurring approximately 3 weeks following exposure. Regrowth typically begins approximately 2 months later.
Following moderately large doses (20 Gy single dose or 40 Gy over 4 weeks), acute radiation dermatitis and moist desquamation occur. This is characterized by edema, inflammation, vascular damage, dermal hypoplasia, and permanent hair loss. Moist desquamation is a predictor of future development of telangiectasia. Reepithelialization will occur within 6 to 8 weeks if the vasculature and germinal epithelium are not too severely damaged. The skin will return to normal in 2 to 3 months. If vascular or germinal layer damage is too extensive, the skin will undergo healing but may remain atrophic with altered pigmentation. The skin in this state is easily damaged by physical trauma and is prone to recurrent infections and lesions, including necrotic ulcerations. Following repeated low-level exposures of 10 to 20 mGy per day with the total dose close to 20 Gy, chronic radiation dermatitis can develop. This causes hypertrophy or atrophy of the skin and places it at increased risk of skin neoplasms, especially squamous cell carcinoma (Figure 10.6).
Reproductive Organs
The gonads are very radiosensitive. Radiosensitivity of the cell populations found in the male testes ranges from very sensitive (spermatogonia) to relatively radioresistant (mature spermatozoa). Radiation effects on the male reproductive system include decreased fertility, temporary sterility, and permanent sterility.5 Reduced fertility secondary to decreased sperm count and motility can occur following doses of 150 mGy. These effects typically occur after 6 weeks. Doses of 500 mGy can produce temporary sterility, with the duration ranging from 1 to 3.5 years based on dose. Chronic exposures to 20 to 50 mGy per week with total doses exceeding 2.5 to 3 Gy can produce permanent sterility. Exposures related to medical imaging are not likely to exceed 100 mGy and are thus unlikely to affect the testes.
The ova within ovarian follicles are radiosensitive. Small and large (mature) follicles are relatively more radioresistant than intermediate follicles. A period of reduced fertility can be seen after an exposure of 1.5 Gy after an initial period of fertility preservation due to the presence of mature follicles. Fertility will eventually return to normal as long as the exposure is not high enough to kill the small, relatively radioresistant primordial follicles. Doses resulting in permanent sterility are age-dependent, with higher doses (˜10 Gy) needed to sterilize a prepubescent female than in premenopausal women over age 40 (˜2-3 Gy).
Eyes
Radiation can damage or kill cells in the lens of the eye; however, there is no system for the body to remove these cells from the lens. Sufficient accumulation of these damaged cells may lead to cataracts. Cataracts caused by radiation exposure begin forming in the anterior subcapsular region and travel posteriorly, unlike senile cataracts that usually develop in the anterior pole of the lens. The posterior subcapsular cataracts can impair vision by causing a “halo effect” around lights at night even at minor levels of cataract formation. The formation of cataracts was previously viewed as deterministic. There was thought to be a threshold dose under which the formation of cataracts will not occur. Recent data have indicated that if a threshold does exist, it is likely much lower than originally thought. There is some thought that the formation of cataracts is actually better represented by a stochastic model. The International Commission on Radiological Protection (ICRP) has recently changed recommendations for occupational exposure limits from 150 mSv per year to 20 mSv per year averaged over 5 years (with no year exceeding 50 mSv).
Whole-body response to radiation
As discussed previously, the various tissues of the body vary in their relative radiosensitivities, and an acute exposure to radiation results in more cellular damage than exposure to the same dose of radiation delivered over a protracted period of time. In addition to the localized effects on certain tissues following radiation exposure discussed above, there is a series of observed responses by the body to an acute exposure of a large portion of the body to a high radiation dose. This is known as the acute radiation syndrome (ARS). The ARS is distinct form of localized radiation injuries such as skin ulceration consisting of a group of hematopoietic, gastrointestinal (GI), and neurovascular syndromes occurring in stages over the course of hours to weeks following a radiation exposure event as a result of the differing radiosensitivities of the irradiated tissues.
Following an adequately high exposure, the sequence of events occurring in the body follows a predictable course. The typical sequence of events consists of prodromal illness, latent illness, manifest illness, and recovery (if the dose is not fatal). Prodromal symptoms can occur within minutes of exposure with a high exposure dose. Prodromal symptoms include nausea, vomiting, diarrhea, fever, anorexia, lethargy, headache, and altered mental status. As the dose increases, the severity of the effects increases and the latency of the onset of symptoms decreases. The latent period follows the prodromal period and may last for up to 4 weeks for exposures less than 1 Gy. Higher exposures result in a shorter latent period. The manifest illness stage represents organ tissue damage and its clinical manifestations. This stage may last for 2 to 4 weeks and is characterized by immune system compromise due to damage to the hematopoietic system. For this reason, treatment of ARS should be started within 6 to 8 weeks of the initial exposure, before significant immunocompromise, to increase chances of recovery. Survival of the manifest illness stage is a good predictor of recovery but the patient remains at risk of future cancers.
 FIG. 10.6 • Examples of radiation-induced effects on skin. A, National Cancer Institute (NCI) skin toxicity grade 1: Two fluoroscopically guided procedures were performed through overlapping skin ports in a 65-year-old man. Note enhanced reaction in the overlap zone. The first procedure was performed 6 weeks before and the second procedure was performed 2 weeks before the photograph was obtained (Reprinted from Balter S, Hopewell JW, Miller DL, et al. Fluoroscopically guided interventional procedures: a review of radiation effects on patients’ skin and hair. Radiology. 2010;254(2):326-341. Copyright © 2010 Radiological Society of North America. With permission). B, Radionuclide skin contamination. Slight erythema after accidental contamination by F-18 fluorodeoxyglucose (https://rpop.iaea.org/rpop/rpop/content/informationfor/healthprofessionals/5_interventionalcardiology/phaseserythema.htm, Accessed July 11, 2011). C, Epilation following unnecessarily high-dose CT perfusion scan. (Photo courtesy of New York Times: The Radiation Boom After Stroke Scans, Patients Face Serious Health Risks by Walt Bogdanich Published: July 31, 2010.) D, NCI skin toxicity grade 3 (Copyright © The Regents of the University of California, Davis campus. Originally published in Dermatology Online Journal. All Rights Reserved. Used with permission.). Chronic radiodermatitis after interventional cardiac catheterization. Grade 3 is classified as moist desquamation in areas other than skinfolds and creases. Note the increased severity of reaction in an area of radiation field overlap (From Henry FA, Maender JL, Shen Y, et al. Fluoroscopy-induced chronic radiation dermatitis: a report of three cases. Dermatol Online J. 2009;15(1):3. Copyright © 2009 The Regents of the University of California, Davis campus. Originally published in Dermatology Online Journal. All Rights Reserved. Used with permission). E, Dry desquamation (poikiloderma) at 1 month in a patient receiving approximately 11 Gy calculated peak skin dose (From Chambers C, Fetterly K, Holzer R, et al. Radiation safety program for the cardiac catheterization laboratory. Catheter Cardiovasc Interv. 2011;77:546-556. Copyright © 2011 Wiley & Liss, Inc. Reprinted by permission of John Wiley & Sons, Inc). F-H, NCI skin toxicity grade 4. A 40-year-old male who underwent multiple coronary angiography and angioplasty procedures. The photographs show the time sequence of a major radiation injury (From FDA. Radiation-Induced Skin Injuries from Fluoroscopy. Rockville, MD: U.S. Food and Drug Administration; 1995. http://www.fda.gov/Radiation-EmittingProducts/RadiationEmittingProductsandProcedures/MedicalImaging/MedicalX-Rays/ucm116682.htm. Accessed February 1, 2011). F, Six to eight weeks postexposure (prolonged erythema with mauve central area, suggestive of ischemia). The injury was described as “turning red about 1 month after the procedure and peeling a week later.” By 6 weeks, it had the appearance of a second-degree burn; (G) 16 to 21 weeks postexposure (depigmented skin with central area of necrosis); and (H) 18 to 21 months postexposure (deep necrosis with atrophic borders). Skin breakdown continued over the following months with progressive necrosis. The injury eventually required a skin graft. Although the magnitude of the skin dose received by this patient is not known, from the nature of the injury it is probable that the dose exceeded 20 Gy. This sequence is available on the FDA Web site (From FDA. Radiation-Induced Skin Injuries from Fluoroscopy. Rockville, MD: U.S. Food and Drug Administration; 1995. http://www.fda.gov/Radiation-EmittingProducts/RadiationEmittingProductsandProcedures/MedicalImaging/MedicalX-Rays/ucm116682.htm. Accessed February 1, 2011.). https://ncrponline.org/publications/reports/ncrp-report-168/. Reprinted with permission from Bushberg JT, Seibert JA, Leidholdt EM, Boone JM. The Essential Physics of Medical Imaging. 3rd ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.
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