White and Pharoh ORAL RADIOLOGY- 7E (1)_240526_085644-16-27.pdf

CHAPTER 2 Biology m OUTLINE...

CHAPTER 2 Biology m OUTLINE o Radiation Chemistry Deterministic Effects on Tissues and Organs Deterministic Effects of Whole-Body Irradiation t.c Direct Effect Short-Term Effects Acute Radiation Syndrome Indirect Effects Long-Term Effects Radiation Effects on Embryos and Fetuses DNA Changes Modifying Factors Late Effects Deterministic and Stochastic Effects Radiotherapy in the Oral Cavity Stochastic Effects po Deterministic Effects on Cells Rationale Carcinogenesis Intracellular Structures Effect on Oral Tissues Heritable Effects Cell Replication R adiobiology is the study of the effects of ionizing radiation gsFree radical fates: on living systems. This discipline studies many levels of lo Dissociation: organization within biologic systems spanning broad ranges in size and time (Fig. 2-1). The initial interaction between ionizing R → X + Y y.b radiation and matter occurs at the level of the electron within the first 10−13 seconds after exposure. These changes result in modifica- Cross-linking: tion of biologic molecules within the following seconds to hours. The molecular changes may lead to alterations in cells and organ- R + S → RS isms that persist for hours, decades, and possibly generations. r These changes may result in injury or death. Because the altered biologic molecules differ structurally and functionally from the original molecules, the consequence is a ra RADIATION CHEMISTRY biologic change in the irradiated organism. Approximately one third of the biologic effects of x-ray exposure result from direct effects. Radiation acts on living systems through direct and indirect effects. llib When the energy of a photon or secondary electron ionizes bio- INDIRECT EFFECTS logic macromolecules, the effect is termed direct. Alternatively, a Because water is the predominant molecule in biologic systems photon may be absorbed by water in an organism, ionizing some (about 70%), it frequently participates in the interactions between of its water molecules. The resulting ions form free radicals that x-ray photons and biologic molecules. A complex series of chemi- interact with and produce changes in biologic molecules. Because cal changes occurs in water after exposure to ionizing radiation. a intermediate changes involving water molecules are required to Collectively, these reactions result in the radiolysis of water: alter the biologic molecules, this series of events is termed indirect. nt x-radiation + H2O → H + OH DIRECT EFFECT In direct effects, biologic molecules (RH, where R is the molecule Although the radiolysis of water is complex, on balance, water and H is a hydrogen atom) absorb energy from ionizing radiation is largely converted to hydrogen and hydroxyl free radicals. de and form unstable free radicals (atoms or molecules having an Indirect effects are effects in which hydrogen and hydroxyl unpaired electron in the valence orbital). Generation of free free radicals, produced by the action of radiation on water, radicals occurs in less than 10−10 seconds after interaction with a interact with organic molecules. The interaction of hydrogen photon. Free radicals are extremely reactive and have very short and hydroxyl free radicals with organic molecules results in the lives, quickly reforming into stable configurations by dissociation formation of organic free radicals. About two thirds of radiation- (breaking apart) or cross-linking (joining of two molecules). Free induced biologic damage results from indirect effects. Such radicals play a dominant role in producing molecular changes in reactions may involve the removal of hydrogen: biologic molecules. Free radical production: RH + OH → R + H2O x-radiation + RH → R + H+ + e − RH + H → R + H2 16  C H A P T E R 2 Biology 17 Radiation exposure Incident photon Ionization H2O Direct effects H2O H + OH e Indirect effects Electron m Biochemical lesions Enzymatic repair Deterministic effects Stochastic effects FIGURE 2-2 DNA damage cluster. A single photon may cause multiple ionizations in DNA, o Lethal DNA damage Sub-lethal DNA damage resulting in a cluster of double-strand breakage. In this instance, an incident photon causes ioniza- Cell death Gene mutation tion of a water molecule, and the recoil electron causes a cluster of damage to multiple sites t.c Tissue and organ function Replication of mutated cells in a DNA molecule. Such cluster damage is difficult to repair and is believed to be responsible Examples Examples for most radiation cell killing, carcinogenesis, and heritable effects. Xerostomia Leukemia Osteoradionecrosis Thyroid cancer Cataracts Salivary gland tumors po Fetal development Heritable disorders Breakage of one or both DNA strands FIGURE 2-1 Overview of events after exposure of humans to ionizing radiation. The initial Cross-linking of DNA strands within the helix to other DNA ionization, direct and indirect effects, and initial molecular changes in organic molecules occur strands or to proteins gs in less than a second. The enzymatic repair or development of further biochemical lesions occurs Change or loss of a base in minutes to hours. The deterministic and stochastic effects occur over a time scale of months Disruption of hydrogen bonds between DNA strands to decades to generations. The most important of these types of damage are single-strand and double-strand breakage. Most single-strand breakage is of little lo biologic consequence because the broken strand is readily repaired by using the intact second strand as a template. Radiation may also The OH free radical is more important than H in forming cause clusters of double-strand damage in DNA (Fig. 2-2). A cluster y.b organic free radicals (R ). The resulting organic free radicals are is defined as two or more double-strand breaks within two turns unstable and transform into stable, altered molecules as described of DNA. Such double-strand breakage is believed to be responsible in the previous section on direct effects. These altered molecules for most cell killing, carcinogenesis, and heritable effects. A single have different chemical and biologic properties from the original photon may cause these damage clusters. When damage clusters molecules. may result in cell killing, it is good for killing tumor cells. However, r Radiation effects are thus caused primarily by direct effects and when there are not enough clusters to cause cell killing, there is the diffusion of OH. Both direct effects and indirect effects are the risk that they will induce mutations that may lead to cancer. ra completed within 10−5 seconds. The resulting damage may take hours to decades to become evident. When dissolved oxygen is present, as is the case in normal DETERMINISTIC AND STOCHASTIC EFFECTS llib tissues, hydroperoxyl free radicals may also be formed: Radiation injury to organisms results from either the killing of large numbers of cells (deterministic effects) or sublethal damage to the H + O2 → HO2 genome of individual cells (stochastic effects) that results in cancer formation or heritable mutation. The differences between deter- Hydroperoxyl free radicals contribute to the formation of ministic and stochastic effects are summarized in Table 2-1. Deter- a hydrogen peroxide in tissues: ministic effects of radiation are effects seen when the radiation exposure to an organ or tissue exceeds a particular threshold level. nt HO 2 + H → H2O2 The severity of this change is proportional to the dose; greater exposure leads to greater cell killing. At doses below the threshold, HO 2 + HO 2 → O2 + H2O2 the effect does not occur. Stochastic effects are caused by sublethal radiation-induced damage to DNA. They have no minimum de Both peroxyl radicals and hydrogen peroxide are oxidizing threshold for causation. Any dose of radiation has the potential to agents and are the primary toxins produced in the tissues by ion- induce a stochastic effect. The probability of causing a stochastic izing radiation. The reactions of these oxidizing agents with organic effect increases as the radiation dose is increased. molecules are another form of indirect effects. DETERMINISTIC EFFECTS ON CELLS DNA CHANGES Damage to a cell’s deoxyribonucleic acid (DNA) is the primary INTRACELLULAR STRUCTURES cause of radiation-induced cell death, heritable (genetic) muta- The effects of radiation on intracellular structures result from tions, and cancer formation (carcinogenesis). Radiation produces radiation-induced changes in their macromolecules. These changes many different types of alterations in DNA, including the are seen as structural and functional changes in cellular organelles. following: The changes may cause cell death. 18 PART I Foundations TABLE 2-1 Comparison of Deterministic and Stochastic Effects of Radiation G1 Deterministic Effects Stochastic Effects Gap 1 Examples Mucositis resulting from Radiation-induced cancer radiation therapy to oral Mitosis S cavity DNA G2 synthetic Radiation-induced cataract Heritable effects Gap 2 m period formation Caused by Killing of many cells Sublethal damage to DNA o Threshold Yes: Sufficient cell killing No: Even one photon could dose? required to cause a clinical cause a change in DNA that t.c response leads to a cancer or FIGURE 2-3 Cell cycle. A proliferating cell moves in the cycle from mitosis phase when heritable effect chromosomes are condensed and visible to gap 1 (G1) to the period of DNA synthesis (S) to gap 2 (G2) to the next mitosis. Cells are most radiosensitive in the G2 and mitosis phase, less Severity of Severity of clinical effects is Severity of clinical effects is sensitive in the G1 phase, and least sensitive during the latter part of the S phase. clinical effects proportional to dose; the independent of dose; po and dose greater the dose, the all-or-none response—an greater the effect individual either has effect or does not + DNA Probability of Probability of effect Frequency of effect + X-ray gs A synthesis having effect independent of dose; all proportional to dose; the and dose individuals show effect greater the dose, the greater when dose is above the chance of having the threshold effect lo y.b Nucleus B + X-ray + DNA synthesis A wide variety of radiobiologic data indicate that the nucleus is far more radiosensitive (in terms of lethality) than the cytoplasm, r especially in dividing cells. The sensitive site in the nucleus is the DNA within chromosomes. ra FIGURE 2-4 Chromosome aberrations. A, Irradiation of a cell after DNA synthesis results in a single-arm (chromatid) aberration. B, Irradiation before DNA synthesis results in a double- Chromosome Aberrations arm (chromosome) aberration because the damage is replicated in the next S phase and Chromosomes serve as useful markers for radiation injury. They becomes visible in the next mitosis phase. llib may be easily visualized and quantified, and the extent of their damage is related to cell survival. Chromosome aberrations are observed in irradiated cells at the time of mitosis when the DNA condenses to form chromosomes. The type of damage that may be observed depends on the stage of the cell in the cell cycle at survivors of the atomic bombings of Hiroshima and Nagasaki have a the time of irradiation. demonstrated chromosome aberrations in circulating lymphocytes Figure 2-3 shows the stages of the cell cycle. If radiation expo- more than 2 decades after the radiation exposure. The frequency nt sure occurs after DNA synthesis (i.e., in late S or G2 phase), only of aberrations is generally proportional to the radiation dose one arm of the affected chromosome is broken (chromatid aber- received. ration) (Fig. 2-4, A). However, if the radiation-induced break occurs before the DNA has replicated (i.e., in G1 or early S phase), CELL REPLICATION de the damage is seen as a break in both arms (chromosome aberra- Radiation is especially damaging to rapidly dividing cell systems, tion) at the next mitosis (Fig. 2-4, B). Most simple breaks are such as skin and intestinal mucosa, and hematopoietic tissues repaired by biologic processes and go unrecognized. Figure 2-5 (Table 2-2). Irradiation of such cell populations causes a reduction illustrates several common forms of chromosome aberrations in size of the irradiated tissue as a result of mitotic delay (inhibition resulting from incorrect repair. Formation of rings (Fig. 2-5, A) and of progression of the cells through the cell cycle) and reproductive dicentrics (Fig. 2-5, B) is lethal because the cell cannot complete cell death (usually during mitosis). The three mechanisms of repro- mitosis. Translocations (Fig. 2-5, C) result in unequal distribution ductive death are DNA damage, bystander effect, and apoptosis. of chromatin material to daughter cells, and they may prevent completion of a subsequent mitosis. Chromosome aberrations DNA Damage have been detected in peripheral blood lymphocytes of patients Cell death is caused by damage to DNA, which causes chromo- exposed to medical diagnostic procedures. Additionally, the some aberrations that cause the cell to die during the first few  C H A P T E R 2 Biology 19 TABLE 2-2 Relative Radiosensitivity of Various Cells High Intermediate Low Characteristics Divide regularly Divide occasionally in response to demand for more cells Highly differentiated Long mitotic futures When mature are incapable of division Undergo no or little differentiation between mitoses Examples Spermatogenic and erythroblastic stem cells Vascular endothelial cells Neurons Basal cells of oral mucous membrane Fibroblasts Striated muscle cells m Acinar and ductal salivary gland cells Squamous epithelial cells Parenchymal cells of liver, kidney, and thyroid Erythrocytes o t.c Bystander Effect A Cells that are damaged by radiation release into their immediate environment molecules that kill nearby cells. This bystander effect can cause chromosome aberrations, cell killing, gene mutations, po and carcinogenesis. Apoptosis Apoptosis, also known as programmed cell death, occurs during gs normal embryogenesis. Cells round up, draw away from their B neighbors, and condense nuclear chromatin. This characteristic pattern, which is different from necrosis, can be induced by radia- tion in both normal tissue and some tumors. Apoptosis is particu- lo larly common in hematopoietic and lymphoid tissues. Recovery y.b Cell recovery from DNA damage and the bystander effect involves enzymatic repair of single-strand breaks of DNA. Because of this repair, a higher total dose is required to achieve a given degree of C cell killing when multiple fractions are used (e.g., in radiation therapy) than when the same total dose is given in a single brief r exposure. Damage to both strands of DNA at the same site is usually lethal to the cell. ra DETERMINISTIC EFFECTS ON TISSUES llib AND ORGANS The radiosensitivity of a tissue or organ is measured by its response to irradiation. Loss of moderate numbers of cells does not affect D E the function of most organs. However, with the loss of large a numbers of cells, all affected organisms display an observable result. The severity of this change depends on the dose and thus nt the amount of cell loss. The following discussion pertains to the effect of irradiation of tissues and organs when the exposure is restricted to a small area, such as in radiation therapy. Comparable FIGURE 2-5 Chromosome aberrations. A, Ring formation plus acentric fragment. doses to the whole animal may result in death from damage to the de B, Dicentric formation. C, Translocation. D and E, Tetracentric exchange and chromatid most radiation-sensitive systems. exchange (arrows) taking place in Trandescantia, a New World perennial having a small number of large chromosomes. (D and E, Courtesy Dr. M. Miller, Rochester, NY.) SHORT-TERM EFFECTS The short-term effects of radiation on a tissue (effects seen in the first days or weeks after exposure) are determined primarily mitoses after irradiation. The rate of cell replication in various by the sensitivity of its parenchymal cells. When continuously tissues—and thus the rate of reproductive death—accounts for the proliferating tissues (e.g., bone marrow, oral mucous membranes) varying radiosensitivity of tissues. When a population of slowly are irradiated with a moderate dose, cells are lost primarily by dividing cells is irradiated, larger doses and longer time intervals reproductive death, bystander effect, and apoptosis. The extent are required for induction of deterministic effects than when a of cell loss depends on damage to the stem cell pools and the rapidly dividing cell system is involved. proliferative rate of the cell population. The effects of irradiation 20 PART I Foundations on such tissues become apparent quickly as a reduction in the related to the increased amounts of hydrogen peroxide and hydro- number of mature cells in the series. Tissues composed of cells peroxyl free radicals formed (described earlier). This is important that rarely or never divide (e.g., neurons or muscle) demonstrate clinically because hyperbaric oxygen therapy may be used during little or no radiation-induced hypoplasia over the short-term. The radiation therapy of tumors having hypoxic cells. relative radiosensitivities of various tissues and organs are shown in Box 2-1. Linear Energy Transfer In general, the dose required to produce a certain biologic effect LONG-TERM EFFECTS is reduced as the linear energy transfer (LET) of the radiation is The long-term deterministic effects of radiation on tissues and increased. Higher LET radiations (e.g., α particles) are more effi- m organs (seen months and years after exposure) are a loss of paren- cient in damaging biologic systems because their high ionization chymal cells and replacement with fibrous connective tissue. These density is more likely than x rays to induce double-strand break- changes are caused by reproductive death of replicating cells and age in DNA. Low LET radiations such as x rays deposit their by damage to the fine vasculature. Damage to capillaries leads to energy more sparsely, or uniformly, in the absorber and thus are o narrowing and eventual obliteration of vascular lumens. This more likely to cause single-strand breakage and less biologic impairs the transport of oxygen, nutrients, and waste products and damage. t.c results in death of all cell types dependent on this vascular supply. Thus both dividing (radiosensitive) and nondividing (radioresis- RADIOTHERAPY IN THE ORAL CAVITY tant) parenchymal cells are replaced by fibrous connective tissue, a progressive fibroatrophy of the irradiated tissue. RATIONALE po The oral cavity is exposed to large doses of radiation when radia- MODIFYING FACTORS tion therapy is used to treat oral cancer, usually squamous cell The response of cells, tissues, and organs to irradiation depends carcinoma. Radiation therapy for malignant lesions in the oral on exposure conditions and the cell environment. cavity is usually indicated when the lesion is radiosensitive, gs advanced, or deeply invasive and cannot be approached surgically. Dose Combined surgical and radiotherapeutic treatment often provides The severity of deterministic damage seen in irradiated tissues or optimal treatment. Chemotherapy is increasingly being combined organs depends on the amount of radiation received. Often a clini- with radiation therapy and surgery. lo cal threshold dose exists below which no adverse effects are seen. The radiation treatment is administered as many daily small In all individuals receiving doses above the threshold level, the doses (fractions). Such fractionation of the total x-ray dose provides amount of damage is proportional to the dose. greater tumor destruction than is possible with a large single dose. y.b Fractionation also allows increased cellular repair of surrounding Dose Rate normal tissues that are unavoidably exposed. Fractionation also The term dose rate indicates the rate of exposure. For example, a increases the mean oxygen tension in an irradiated tumor, render- total dose of 5 Gy may be given at a high dose rate (1 Gy/min) or ing the tumor cells more radiosensitive. This results from killing a low dose rate (1 mGy/min). Exposure of biologic systems to a rapidly dividing tumor cells and shrinking the tumor mass after r given dose at a high dose rate causes more damage than exposure the first few fractions, reducing the distance that oxygen must to the same total dose given at a lower dose rate. When organisms diffuse from the fine vasculature through the tumor to reach the ra are exposed at lower dose rates, a greater opportunity exists for remaining viable tumor cells. repair of damage, resulting in less net damage. Although the dose from diagnostic exposures is low, they are given at a high dose rate EFFECT ON ORAL TISSUES llib compared with natural background exposure. The following sections describe the complications (deterministic effects) of a course of radiotherapy on the normal tissue of the oral Oxygen cavity (Fig. 2-6). Typically, 2 Gy is delivered daily for a weekly The radioresistance of many biologic systems increases by a factor exposure of 10 Gy. The radiotherapy course continues for 6 to 7 of 2 or 3 when the exposure is made with reduced oxygen (hypoxia). weeks until a total of 60 to 70 Gy is administered. In recent years, a The greater cell damage sustained in the presence of oxygen is a new three-dimensional technique called intensity-modulated radiotherapy (IMRT) has been used to control the dose distribu- nt tion with high accuracy, minimizing exposure to adjacent normal tissues. The effects described in the next section result only from therapeutic exposures, not from the far lower levels of radiation BOX 2-1 Relative Radiosensitivity used for diagnostic imaging. de of Various Organs Oral Mucous Membrane High Intermediate Low The oral mucous membrane contains a basal layer composed of Lymphoid organs Fine vasculature Neurons rapidly dividing, radiosensitive stem cells. Near the end of the Bone marrow Growing cartilage Muscle second week of therapy, as some of these cells die, the mucous Testes Growing bone membranes begin to show areas of redness and inflammation Intestines Salivary glands (mucositis). As the therapy continues, the irradiated mucous mem- Mucous membranes Lungs brane begins to separate from the underlying connective tissue, Kidney with the formation of a white-to-yellow pseudomembrane (the Liver desquamated epithelial layer) (Fig. 2-7). At the end of therapy, the mucositis is usually most severe, discomfort is at a maximum, and  C H A P T E R 2 Biology 21 Radiation dose (Gy) 0 20 40 60 Taste Buds Taste buds are sensitive to radiation. Doses in the therapeutic range Taste loss cause extensive degeneration of the normal histologic architecture of taste buds. Patients often notice a loss of taste acuity during the Mucositis second or third week of radiotherapy. Bitter and acid flavors are more severely affected when the posterior two thirds of the tongue Complications Hyposalivation is irradiated, and salt and sweet flavors are affected more when the anterior third of the tongue is irradiated. Taste acuity usually m decreases by a factor of 1000 to 10,000 during the course of radio- Radiation caries therapy. Alterations in the saliva may partly account for this reduc- tion, which may proceed to a state of virtual insensitivity. Taste Trismus loss is reversible, and recovery takes 60 to 120 days. o Salivary Glands t.c Susceptibility to osteoradionecrosis The major salivary glands are sometimes unavoidably exposed to 20 to 30 Gy during radiotherapy for cancer in the oral cavity or 0 1 2 3 4 5 6 10 14 18 32 64 110 weeks oropharynx. The parenchymal component of the salivary glands is During radiosensitive (parotid glands more so than submandibular or sub- After radiotherapy po radiotherapy lingual glands). A marked and progressive loss of saliva is usually FIGURE 2-6 Oral complications. Typical time course of complications seen during and after seen in the first few weeks after initiation of radiotherapy. The a course of radiation therapy to the head and neck. Shaded area in first 6 weeks represents extent of reduced flow is dose dependent and may reach essentially accumulated dose. Shading within bars indicates severity of complication. Note recovery of taste zero at 60 Gy. The mouth becomes dry (xerostomia) and tender, gs and healing of mucositis. Changes persisting after 2 years pose lifelong risks. (Adapted from and swallowing is difficult and painful. Histologically, an acute Kielbassa AM, Hinkelbein W, Hellwig E, et al: Radiation-related damage to dentition, Lancet inflammatory response may occur soon after the initiation of Oncol 7:326–335, 2006.) therapy, particularly involving the serous acini. In the months after irradiation, the inflammatory response becomes more chronic, and lo the glands demonstrate marked loss of acini and ducts and a pro- gressive fibrosis (Fig. 2-8). The loss of saliva-producing acini results in xerostomia. Patients with irradiation of both parotid glands are y.b more likely to complain of dry mouth and difficulty with chewing and swallowing than patients with unilateral irradiation. Various saliva substitutes are available to help restore function. Use of intensity-modulated radiotherapy has helped to spare the contra- lateral salivary glands and thus minimize the loss of salivary r function. The reduced volume of saliva in patients receiving radiation ra therapy that includes the major salivary glands is altered from normal. Because serous cells are more radiosensitive than mucous cells, the residual saliva is more viscous than usual. The small llib volume of viscous saliva that is secreted usually has a pH value 1 unit below normal (i.e., an average of 5.5 in irradiated patients compared with 6.5 in unexposed individuals). This pH FIGURE 2-7 Mucositis of hard and soft palate. This patient is at the end of a course of is low enough to initiate decalcification of normal enamel. In radiotherapy and demonstrates an inflammatory response in the oral mucosa and areas of white addition, the buffering capacity of saliva decreases up to 44% a pseudomembrane, areas where the oral epithelium separated from the underlying connective during radiation therapy. If some portions of the major salivary tissue. glands are spared, dryness of the mouth usually subsides in 6 nt to 12 months because of compensatory hypertrophy of residual salivary gland tissue. Reduced salivary flow that persists beyond food intake is difficult. Good oral hygiene minimizes infection. 1 year is unlikely to show significant recovery. Patients with Topical anesthetics may be required at mealtimes. Secondary yeast persistent xerostomia typically take frequent sips of water they de infection by Candida albicans is a common complication and may carry with them. require treatment. After irradiation is completed, the mucosa begins to heal Teeth rapidly. Healing is usually complete by about 2 months. However, Children receiving radiation therapy to the jaws may show defects the mucous membrane later tends to become atrophic, thin, and in the permanent dentition, such as retarded root development, relatively avascular. This long-term atrophy results from fibrosis of dwarfed teeth, or failure to form one or more teeth (Fig. 2-9). the underlying connective tissue. These atrophic changes compli- If exposure precedes calcification, irradiation may destroy the cate denture wearing because they may cause oral ulcerations of tooth bud. Irradiation after calcification has begun may inhibit the compromised tissue. Ulcers may also result from radiation cellular differentiation, causing malformations and arresting necrosis or tumor recurrence. A biopsy may be required to make general growth. Such exposure may retard or abort root forma- the differentiation. tion, but the eruptive mechanism of teeth is relatively radiation 22 PART I Foundations A o m t.c po B C gs lo y.b FIGURE 2-8 Radiation effects on human parotid salivary gland. A, Normal gland demonstrating mostly serous glandular cells (purple) with ducts and occasional adipocytes (clear). B, Gland 6 months after exposure to radiotherapy. Note the loss of acini and the presence of chronic inflammatory cells (dark). C, Gland 1 year after exposure to radiotherapy. Note the loss of acini, extensive fibrosis (pink), and persistent inflammatory cells (dark). r ra resistant. Irradiated teeth with altered root formation typically primarily the cementum and dentin in the cervical region. These erupt, even if rootless. In general, the severity of the damage is lesions may progress around the teeth circumferentially and result dose dependent. in loss of the crown. The third type appears as a dark pigmentation llib of the entire crown. The incisal edges may be markedly worn. Radiation Caries Combinations of all these lesions develop in some patients. The Radiation caries is a rampant form of dental decay that may occur location, rapid course, and widespread attack distinguish radiation in individuals who receive a course of radiotherapy that includes caries. There is also evidence that radiation caries is more likely to exposure of the salivary glands. Patients receiving radiation therapy lead to periapical inflammatory lesions (see Chapter 20) if the a to oral structures have increases in Streptococcus mutans, Lactobacil- periapical bone received a high dose of radiation. lus, and Candida. Caries results from changes in the salivary glands The best method of reducing radiation caries is daily applica- nt and saliva, including reduced flow, decreased pH, reduced buffer- tion of a viscous topical 1% neutral sodium fluoride gel in custom- ing capacity, increased viscosity, and altered flora. The residual made applicator trays. The best results are achieved from a saliva in individuals with xerostomia also has a low concentration combination of restorative dental procedures, excellent oral of Ca2+ ion; this results in greater solubility of tooth structure and hygiene, a diet restricted in cariogenic foods, and topical applica- de reduced remineralization. Because of the reduced or absent cleans- tions of sodium fluoride. Patient cooperation in maintaining oral ing action of normal saliva, debris accumulates quickly. There is hygiene is extremely important because radiation caries is a lifelong also growing evidence that radiation has direct effects on teeth that threat. Teeth with gross caries or periodontal involvement are often make them more prone to breakdown with flaking of enamel, extracted before irradiation. particularly in areas of occlusal loading or stress, such as at the incisal, cuspal, and cervical regions of teeth. The destruction is seen Bone with doses greater than 30 Gy and is pronounced when the teeth Treatment of cancers in the oral region often includes irradiation receive more than 60 Gy. of the mandible or maxilla. The primary damage to mature bone Clinically, three types of radiation caries exist. The most results from radiation-induced damage to the vasculature of the common is widespread superficial lesions attacking buccal, occlu- periosteum and cortical bone, which are normally already sparse. sal, incisal, and palatal surfaces (Fig. 2-10). Another type involves Radiation also acts by destroying osteoblasts and, to a lesser extent,  C H A P T E R 2 Biology 23 B o m t.c A po C gs lo y.b FIGURE 2-9 Dental abnormalities after radiotherapy in two patients. The first patient, a 9-year-old girl who received 35 Gy at age 4 years because of Hodgkin’s disease, had severe stunting of the incisor roots with premature closure of the apices at 8 years (A) and r retarded development of the mandibular second premolar crowns with stunting of the mandibular incisor, canine, and premolar roots at 9 years (B). The second patient (C), a 10-year-old boy who received 41 Gy to the jaws at age 4 years, had severely stunted root develop- ra ment of all permanent teeth with a normal primary molar. (A and B, Courtesy Mr. P. N. Hirschmann, Leeds, UK; C, Courtesy Dr. James Eischen, San Diego, CA.) llib osteoclasts. In addition, the endosteum becomes atrophic, showing a a lack of osteoblastic and osteoclastic activity. The degree of min- eralization may be reduced, leading to brittleness. Typically, the nt oral mucosa breaks down with exposure of the underlying bone. This condition is termed osteoradionecrosis. It is the most serious clinical complication that occurs in bone after irradiation. The decreased vascularity of the mandible renders it easily infected de by microorganisms from the oral cavity. This bone infection may result from radiation-induced breakdown of the oral mucous membrane, from mechanical damage to the weakened oral mucous membrane such as by a denture sore or tooth extraction, through a periodontal lesion, or from radiation caries. This infection may cause a nonhealing wound in irradiated bone that is treated with débridement with varying degrees of success (Fig. 2-11). It is more common in the mandible than in the maxilla, probably because of the richer vascular supply to the maxilla and the fact that the mandible is more frequently irradiated. The higher the radiation FIGURE 2-10 Radiation caries. Note the extensive loss of structure on the occlusal surface dose absorbed by the bone, especially more than 60 Gy, the of the mandibular teeth resulting from radiation-induced xerostomia. 24 PART I Foundations greater the risk for osteoradionecrosis. The risk is also greater in Patients who have had radiation therapy often require a radio- the presence of odontogenic or periodontal disease and in indi- graphic examination to supplement clinical examinations. Radio- viduals with poor oral hygiene or ill-fitting dentures. Patients with graphs are especially important to detect caries early. The amount osteoradionecrosis typically also have numerous other complica- of radiation from such diagnostic exposures is negligible compared tions, including trismus, loss of taste, difficulty in swallowing, with the amount received during therapy and should not serve as and xerostomia. a reason to defer radiographs. However, whenever possible, it is Patients should be referred for dental care before undergoing a desirable to avoid taking radiographs during the first 6 months course of radiation therapy to minimize radiation caries and osteo- after completion of radiotherapy to avoid injury to the mucous radionecrosis. Radiation caries can be minimized by restoring all membrane by the sensor. m carious lesions before radiation therapy and initiating preventive techniques of good oral hygiene and daily topical fluoride. The Musculature risk for osteoradionecrosis and infection can be minimized by Radiation may cause inflammation and fibrosis resulting in con- removing teeth with extensive caries or with poor periodontal tracture and trismus in the muscles of mastication. The masseter o support (allowing 2 to 3 weeks for the extraction wounds to heal or pterygoid muscles usually are involved. Restriction in mouth before beginning radiation therapy) and adjusting dentures to opening usually starts about 2 months after radiotherapy is com- t.c minimize the risk of denture sores. Removal of teeth after irradia- pleted and progresses thereafter. An exercise program may be tion should be avoided when possible. helpful in increasing opening distance. DETERMINISTIC EFFECTS OF po WHOLE-BODY IRRADIATION ACUTE RADIATION SYNDROME gs The acute radiation syndrome is a collection of signs and symp- toms experienced by individuals after a brief whole-body exposure to radiation (Table 2-3). Information about this syndrome comes from animal experiments and human exposures from medical lo radiotherapy, the atom bomb blasts in 1945, and radiation acci- dents such as at Chernobyl in 1986. A y.b Prodromal Period Within the first minutes to hours after exposure to whole-body irradiation of about 1.5 Gy, an individual may have anorexia, nausea, vomiting, diarrhea, weakness, and fatigue. These early symptoms constitute the prodromal period of the acute radiation r syndrome. The higher the dose, the more rapid the onset, and the greater the severity of symptoms. ra Latent Period After the prodromal reaction comes a latent period, during which llib the exposed person shows no signs or symptoms of radiation sick- ness. The extent of the latent period is also dose related, lasting hours or days after supralethal exposures (approximately >5 Gy) to a few weeks after exposures of about 2 Gy. a Hematopoietic Syndrome Whole-body exposures of 2 to 7 Gy cause injury to the mitotically nt active hematopoietic stem cells in the bone marrow and spleen. B de TABLE 2-3 Acute Radiation Syndrome Dose (Gy) Manifestation 1–2 Prodromal symptoms 2–4 Mild hematopoietic symptoms 4–7 Severe hematopoietic symptoms 7–15 Gastrointestinal symptoms FIGURE 2-11 Osteoradionecrosis. A, Area of exposed mandible after radiotherapy. Note 50 Cardiovascular and central nervous system symptoms the loss of oral mucosa (arrows). B, Destruction of irradiated bone resulting from infection.  C H A P T E R 2 Biology 25 few months of development of the hematopoietic or gastrointes- tinal syndrome. 100 Cardiovascular and Central Nervous System Syndrome 80 Exposures greater than 50 Gy usually cause death in 1 to 2 days. Percent of control cells Erythrocytes The few humans who have been exposed at this level showed col- 60 lapse of the circulatory system with a precipitous fall in blood pressure in the hours preceding death. Autopsy revealed necrosis Platelets of cardiac muscle. Victims also may present with intermittent m 40 stupor, incoordination, disorientation, and convulsions suggestive of extensive damage to the nervous system. Although the precise 20 Granulocytes mechanism is not fully understood, these latter symptoms most likely result from damage to the neurons and fine vasculature of o Lymphocytes the brain. 0 t.c 0 5 10 15 20 25 Management of Acute Radiation Syndrome Time after radiation exposure (days) The presenting clinical problems govern the management of dif- FIGURE 2-12 Radiation effects on blood cells. Whole-body exposure inhibits replication ferent forms of acute radiation syndrome. Antibiotics are indicated of blood stem cell precursors in bone marrow. This inhibits the replacement of circulating cells. when the granulocyte count decreases. Fluid and electrolyte po As a result, the duration of the circulating cells’ survival is largely determined by their life span replacement is used as necessary. Whole-blood transfusions are in circulation. In this instance, the bone marrow damage is incomplete, and recovery is evident used to treat anemia, and platelets may be administered to arrest after 1 to 2 weeks. bleeding. RADIATION EFFECTS ON EMBRYOS AND FETUSES gs Doses in this range cause a rapid decrease in the numbers of cir- The effects of radiation on human embryos and fetuses have been culating granulocytes, platelets, and finally erythrocytes (Fig. 2-12). studied in animals, women exposed to diagnostic or therapeutic Although mature circulating granulocytes, platelets, and erythro- radiation during pregnancy, and women exposed to radiation from cytes are radioresistant, nonreplicating cells, their paucity in the lo the atomic bombs dropped at Hiroshima and Nagasaki. Embryos peripheral blood after irradiation reflects the radiosensitivity of and fetuses are considerably more radiosensitive than adults their precursors. Granulocytes, with short lives in circulation, fall because most embryonic cells are relatively undifferentiated and y.b off in a few days, whereas red blood cells, with long lives in circula- rapidly mitotic. tion, fall off slowly. Exposures of 1 to 3 Gy during the first few days after concep- The clinical signs of the hematopoietic syndrome include infec- tion are thought to cause undetectable death of the embryo tion (from lymphopenia and granulocytopenia), hemorrhage (from because many of these embryos fail to implant in the uterine wall. loss of platelets), and anemia (from erythrocyte depletion). The The period of organogenesis, when the major organ systems form, r probability of death is low after exposures at the low end of this is 3 to 8 weeks after conception. The most common abnormalities range but much higher at the high end. When death results from among the Japanese children exposed early in gestation were ra the hematopoietic syndrome, it usually occurs 10 to 30 days after reduced growth that persisted through life and reduced head cir- irradiation. cumference (microcephaly), often associated with mental retarda- tion. Other abnormalities included small birth size, cataracts, llib Gastrointestinal Syndrome genital and skeletal malformations, and microphthalmia. The Gastrointestinal syndrome is caused by whole-body exposures period of maximal sensitivity of the brain is 8 to 15 weeks after of 7 to 15 Gy. Exposures in this range cause extensive damage conception. These effects are deterministic in nature and are to the gastrointestinal system in addition to the hematopoietic believed to have a threshold of about 0.1 Gy. This threshold dose damage described previously. Exposure in this dose range causes is 400 times higher than the fetal exposure from a dental examina- a considerable injury to the rapidly proliferating basal epithelial cells tion (0.25 mGy from a full-mouth examination when a leaded of the intestinal villi and leads to rapid loss of the epithelial layer apron is used). By comparison, the dose to an embryo and fetus nt of the intestinal mucosa. Because of the denuded mucosal surface, from natural background radiation is approximately 2250 mGy there is loss of plasma and electrolytes, loss of efficient intestinal during the 9 months of gestation. absorption, and ulceration of the mucosal lining with hemorrhag- Radiation has been shown to increase the probability of leuke- ing into the intestines. These changes are responsible for diarrhea, mia and other types of cancer (see later) during childhood of de dehydration, and weight loss. Endogenous intestinal bacteria individuals exposed in utero. It is assumed that embryos and fetuses readily invade the denuded surface, producing septicemia. have approximately the same risk for carcinogenic effects as chil- At about the time that developing damage to the gastrointesti- dren (about three times that of the population as a whole). There nal system reaches a maximum, the effect of bone marrow depres- is no known threshold for leukemia or other cancers. Because of sion begins to manifest. The result is a marked lowering of the these considerations, it is important to consider effects on the body’s defense against bacterial infection and a decrease in effec- embryo and fetus when ordering dental radiographs for a pregnant tiveness of the clotting mechanism. The combined effects of patient. It is recommended to defer optional imaging until the end damage to these hematopoietic and gastrointestinal stem cell of pregnancy (e.g., bitewings only indicated by the length of time systems cause death within 2 weeks from fluid and electrolyte loss, since the previous examination) but to make radiographs when infection, and possibly nutritional impairment. Of the plant staff there is a specific indication based on the patient’s history or and firefighters at the Chernobyl accident, 28 died within the first clinical findings. 26 PART I Foundations result of blast or burn injury or of the acute radiation syndrome LATE EFFECTS (described earlier). Starting in 1950, systematic studies were initi- Numerous late deterministic effects have been found in the survi- ated to follow the health of the survivors, children exposed in utero, vors of the atomic bombing of Hiroshima and Nagasaki. and the offspring of exposed parents. In the survivor cohort, the histories of more than 120,000 individuals have been followed Growth and Development since 1950. The in utero study involved 3600 subjects, and the Children exposed in the bombings showed impairment of growth offspring study involved about 77,000 subjects. The incidences of and development, including reduced height, weight, and skeletal deaths from leukemias and solid cancers in the survivor study are development. The younger the individual was at the time of expo- shown in Table 2-4 and Figure 2-13. The risk for most solid cancers m sure, the more pronounced the effects. increases linearly with dose and lasts for the lifetime of the exposed individual. The risk from exposure during childhood is two to three Cataracts times as great as the risk during adulthood. The number of cancers The threshold for induction of cataracts (opacities in the lens of induced by radiation is most likely a multiple of their spontaneous o the eye) is unclear, but it is now believed to be in the range of frequency. Box 2-2 shows the radiosensitivity of various tissues in 0.5 Gy. Although these cataracts are clinically detectable, most t.c affected individuals are unaware of their presence. Although expo- TABLE 2-4 Cancer Mortality Rate in 86,611 sures to the eye from dental radiography are quite small, they nonetheless should be avoided when possible during radiographic Atomic Bomb Survivors Having examinations. 50,620 Deaths from All Causes po (1950–2003) Shortened Life Span The survivors of the atomic bombings show a clear decrease in Leukemias Solid Cancers median life expectancy with increasing radiation dose (other than Deaths 296 10,929 gs shortened life expectancy caused by cancer). The reduction in life span ranges from 2 months to 2.6 years by dose group, with an Radiation induced 93 527 overall mean of 4 months. Survivors demonstrate increased fre- Data adapted from Preston DL, Pierce DA, Shimizu Y, et al: Effect of recent changes in atomic bomb quency of heart disease, stroke, and noncancer diseases of the lo digestive, respiratory, and hematopoietic systems. It is believed that survivor dosimetry on cancer mortality risk estimates, Radiat Res 162:377-389, 2004 (through 2000 for leukemias) and Ozasa K, Shimizu Y, Suyama A, Kasagi F, Soda M, Grant EJ, et al: Studies of the number of noncancer deaths resulting from radiation exposure is mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer about half as many as deaths from cancer. diseases. Radiat Res 177:229-243, 2012 (for solid cancers). y.b STOCHASTIC EFFECTS deaths due to radiation exposure Number of leukemia and cancer Stochastic effects result from sublethal changes in the DNA of Solid cancers (e.g., individual cells. The most important consequence of such damage thyroid, breast, lung, r large intestine, stomach) is radiation-induced cancer. The severity of radiation-induced cancer does not vary with dose—either it is present or it is not. ra Leukemia Many studies show increased cancer incidence in humans after exposure to radiation. Heritable effects, although much less likely, can also occur. llib CARCINOGENESIS Radiation causes cancer by modifying DNA. The most likely 0 10 20 30 40 50 Number of years after A-bomb radiation exposure mechanism is a multistep process including accumulation of radiation-induced gene mutation. These mutations are usually base a substitutions, insertions and deletions of bases, rearrangements FIGURE 2-13 Schematic model of incidence of leukemia (orange plus pale green) and caused by breakage and abnormal rejoining of DNA strands, or solid cancers (pale green plus dark green) shown by years after radiation exposure. Leukemias nt changes in the copy number of DNA segments. When the muta- are initially seen in the first few years after exposure and cease after 3 decades. In contrast, tions involve growth-regulating genes—activation of oncogenes or solid tumors have a latent period of about a decade and remain in excess for the remainder of inactivation of tumor suppressor genes—they can deregulate cell the exposed person’s life. (Adapted from Introduction to the Radiation Effects Research Founda- growth or differentiation or both and ultimately lead to neoplastic tion: http://www.rerf.jp/shared/introd/introRERFe.pdf.) de development. In principle, even one radiation photon may initiate cancer formation. BOX 2-2 Susceptibility of Different Organs Estimation of the number of cancers induced by radiation is to Radiation-Induced Cancer difficult. Radiation-induced cancers are not distinguishable from cancers produced by other causes. This means that the number of High Intermediate Low cancers can be estimated only as the number of excess cases found Colon Bladder Bone surface in exposed groups compared with the number in unexposed Stomach Liver Brain groups of people. The group of individuals most intensively Lung Thyroid Salivary glands studied for estimating the cancer risk from radiation is the Japanese Bone marrow (leukemia) Skin atomic bomb survivors. These bombings occurred in 1945. Female breast Approximately 200,000 people died with the first 2 months as a  C H A P T E R 2 Biology 27 terms of susceptibility to radiation-induced cancer. The following discussion pertains primarily to organs exposed in the course of BOX 2-3 Basic Principles of dental radiography. Radiation Genetics Leukemia Radiation causes increased frequency of spontaneous mutations rather than The incidence of leukemia (other than chronic lymphocytic leuke- inducing new mutations. mia) increases after exposure of the bone marrow to radiation. Frequency of mutations increases in direct proportion to dose, even at very low Atomic bomb survivors and patients irradiated for ankylosing doses, with no evidence of a threshold. spondylitis show a wave of leukemias beginning soon after expo- Most mutations are deleterious to the organism. m sure, peaking at around 7 years, and ceasing after about 30 years. Dose rate is important; at low dose rates, the frequency of induced mutations is greatly reduced. Thyroid Cancer Males are much more radiosensitive than females. The incidence of thyroid carcinomas (arising from the follicular Rate of mutations is reduced as the time between exposure and conception o epithelium) increases in humans after exposure. Only about 10% increases. or less of individuals with such cancers die of their disease. The t.c best-studied groups are Israeli children irradiated to the scalp for ringworm, children irradiated to the thymus gland, survivors of the exposure, such as encountered in dentistry, they are far less impor- atomic bombs in Japan, and individuals exposed after the accident tant than carcinogenesis. at Chernobyl. Susceptibility to radiation-induced thyroid cancer is Our knowledge of heritable effects of radiation on humans po greater early in childhood than at any time later in life, and children comes largely from the atomic bomb survivors. To date, no such are more susceptible than adults. Females are two to three times radiation-related genetic damage has been demonstrated. No more susceptible than males to radiogenic and spontaneous thyroid increase has occurred in adverse pregnancy outcome, leukemia or cancers. The fallout from the accident at the Chernobyl nuclear other cancers, or impairment of growth and development in the gs power plant, primarily iodine-131, is thought to have caused about children of atomic bomb survivors. Similarly, studies of the chil- 7000 cases of thyroid cancer in children and 15 fatalities. dren of patients who received radiotherapy show no detectable increase in the frequency of genetic diseases. These findings do not Esophageal Cancer exclude the possibility that such damage occurs but do show that lo Excess numbers of esophageal cancers are found in the Japanese it must be at a very low frequency. atomic bomb survivors and in patients treated with x radiation for ankylosing spondylitis. BIBLIOGRAPHY y.b Brain and Nervous System Cancers Bushong SC: Radiologic science for technologists: physics, biology, and Patients exposed to diagnostic x-ray examinations in utero and to protection, ed 9, St Louis, 2008, Mosby. therapeutic doses in childhood or as adults (average midbrain dose Gusev I, Guskova A, Mettler F: Medical management of radiation accidents, of about 1 Gy) show excess numbers of malignant and benign ed 2, Boca Raton, FL, 2001, CRC. r brain tumors. Additionally, case-control studies have shown an Hall EJ, Giaccia AJ: Radiobiology for the radiologist, ed 7, Philadelphia, association between intracranial meningiomas and previous 2011, Lippincott Williams & Wilkins. ra Joiner M, van der Kogel A: Basic clinical radiobiology, ed 4, London, 2002, medical or dental radiography. If the association is real, it is most Hodder Arnold. likely that the nature of the association is that more dental images were made in response to facial pain referred from the tumor rather llib than the radiation causing more meningiomas. SUGGESTED READINGS Salivary Gland Cancer Genetic Effects The incidence of salivary gland tumors is increased in patients United Nations Scientific Committee on the Effects of Atomic Radiation: treated with irradiation for diseases of the head and neck, in Japa- Hereditary effects of radiation (2001): http://www.unscear.org/unscear/ a nese atomic bomb survivors, and in persons exposed to diagnostic en/publications/2001.html. x radiation. An association between tumors of the salivary glands Odontogenesis nt and dental radiography has been shown. As with meningiomas, Dahllof G: Craniofacial growth in children treated for malignant the association most likely is explained by dental radiographs made diseases, Acta Odontol Scand 56:378, 1998. in response to the presence of the tumors. Kielbassa AM, Hinkelbein W, Hellwig E, et al: Radiation-related damage de to dentition, Lancet Oncol 7:326–335, 2006. Other Organs Other organs, such as the skin, paranasal sinuses, and bone marrow, Oral Sequelae of Head and Neck Radiotherapy also show excess neoplasia after exposure. However, the mortality Chopra S, Kamdar D, Ugur OE, et al: Factors predictive of severity of and morbidity rates expected after head and neck exposure are osteoradionecrosis of the mandible, Head Neck 33:1600–1605, 2011. much lower than for the organs described previously. Chung EM, Sung EC: Dental management of chemoradiation patients, J Calif Dent Assoc 34:735–742, 2006. HERITABLE EFFECTS Hommez GM, De Meerleer GO, De Neve WJ, et al: Effect of radiation dose on the prevalence of apical periodontitis—a dosimetric analysis, Heritable effects are changes seen in the offspring of irradiated Clin Oral Invest 16:1543–1547, 2012. individuals. They are the consequence of damage to the genetic Jacobson AS, Buchbinder D, Hu K, et al: Paradigm shifts in the material of reproductive cells. The basic findings of radiation- management of osteoradionecrosis of the mandible, Oral Oncol induced heritable effects are listed in Box 2-3. At low levels of 46:795–801, 2010.