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7. Radiologic Science for Technologists

7. Radiologic Science for Technologists - Radiologic...

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Unformatted text preview: Radiologic Science for Technologis‘rs S‘rewar’r Bushong [Mosby: 8 edifion (c2004), ISBN—10: 0323025552] pages: 463 — 482 LAW OF BERGONIE AND TRIBONDEAU In 1906, two French scientists, Bergonie and Tribon- deau, theorized and observed that radiosensitivity was a function of the metabolic state of the tissue being irradi- atecl. This has come to be known as the law of Bergonie and Tribondemt and has been verified many times. Basi— cally, the law states that the radiosensitivity of living tis— sue varies with maturation and metabolism, as follows: 1. Stem cells are radiosensitive. The more mature a cell, the more resistant to radiation it is. 2. The younger the tissue and organs, the more ra- diosensitive they are. 3. When the level of metabolic activity is high, ra- diosensitivity is also high. 4. As the proliferation rate for cells and the growth rate for tissues increase, the radiosensitivity also increases. Box 34—1 summarizes the law of Bergonie and Tribondeau. This law is of interest principally as a historical note in the development of radiobiology. It has found some application in radiotherapy. In diagnostic imaging, it re- minds us that the fetus is considerably more sensitive to radiation exposure than the child or the adult. PHYSICAL FACTORS AFFECTING RADIOSENSITIVITY When tissue is irradiated, the response of that tissue is determined principally by the amount of energy de- posited per unit mass: the dose in rads (Gyl). Even under controlled experimental conditions, however, when equal doses are delivered to equal specimens, the re- sponse may not be the same because of other modifying B MS'l/to a co] Chapter 34 Fundamental Principles of Radiobiology 463 factors. A number of physical factors, including linear energy transfer, relative biologic effectiveness, and frac— tionation and protraction, affect the degree of radiation response. Linear Energy Transfer Linear energy transfer (LET) is a measure of the rate at which energy is transferred from ionizing radiation to soft tissue. It is another method 'of expressing radiation quality and determining the value of the tissue weight- ing factor (WT) used in radiation protection. The tissue weighting factor accounts for the relative radiosensitivity of various tissues and organs (see Chapter 38). LET is expressed in units of kiloelectron volts of energy trans— ferred per micrometer of track length in soft tissue (keV/ttm). The ability of ionizing radiation to produce a biologic response increases as the LET of the radiation increases. When the LET is high, ionizations occur frequently, so the probability of interaction with the target molecule is higher. Relative Biologic Effectiveness As the LET of radiation increases, the ability to produce biologic damage also increases. This is quantitatively de— scribed as the relative biologic effectiveness (REE): The standard radiation, by convention, is orthovolt— age x—radiation in the 200- to 250—kVp range. This type of x-ray beam was used for many years in radiation on- cology and in essentiaily all early radiobiology research. Diagnostic x—rays have an RBE of 1. Radiation with a lower LET than that of diagnostic x-rays has an RBE less than 1, whereas radiation with a higher LET has a higher REE. 464 PartV Radiation Protection FIGURE 34-1 As the LEI' increases, the RBE increases also, but a maximum value is reached beyond which the RBE can increase no further. Figure 34-1 shows the relationship between RBE and LET and identifies some of the more common types of radiation. The maximum value of the RBE is approxi- mately 3. Table 34—1 lists the approximate LET and RBE of various types of ionizing radiation. Question: When mice are irradiated with ZSO—kVp x—rays, 650 rad (6.5 Gy,) is necessary to pro- duce death. If similar mice are irradiated with fast neutrons, only 210 rad (2.1 Gy,) is needed. What is the RBE for the fast neutrons? H 650 rad RBE-H 2.10 rad = 3.1 Answer: Fractionation and Protraction If a dose of radiation is delivered over a long time rather than quickly, the effect of that dose will be less. Stated dif- ferently, if the time of irradiation is lengthened, a higher dose will be required to produce the same effect. This lengdieniug of time can be accomplished in two ways. If the dose is delivered continuously but at a lower dose rate, it is said to be protracted. A total of 600 rad (6 Gy,) delivered in 3 minutes (2.00 rad/min [2. GmeinD is lethal for a mouse. However, when 600 rad is deliv- ered at the rate of 1 radlhr (10 ruGthr) for a total of 600 hours, the mouse survives. Dose protraction causes less effect because of the lower dose rate, which allows time for intracellular repair and tissue recovery. If the GOO-rad dose is delivered at the same dose rate, 200 rad/ruin, but in 12 equal fractions of 50 rad (500 LE_l' arid RBE ofVaritius Types of Radiation mGyJ, each separated by 24 hours, the mouse will sur- vive. In this situation the dose is said to be fractionated. Dose fractionation causes less effect because intracellular repair and recovery oceur between doses. Dose fraction- ation is used routinely in radiation oncology. BlOLOGiC FACTORS AFFECTING RADlOSENSlTlVlTY In addition to these physical factors, a number of bio- logical conditions alter the radiation response of tissue. Some of these factors have to do with the inherent state of the tissue, such as age and metabolic rate. Other fac- tors are related to artificially introduced modifiers of the biologic system. Oxygen Effect Tissue is more sensitive to radiation when irradiated in the oxygenated, or aerobic, state than when irradiated under anoxic (without oxygen) or hypoxic (low-oxygen) conditions. This characteristic of tissue is called the oxy- gen effect and is described numerically by the oxygen en— hancement ratio (OER), as follows: Generally, the irradiation of tissue is conducted un- der conditions of full oxygenation. Hyperbaric (high- pressure) oxygen has been used in radiation oncology in an attempt to increase the radioseusitiviry of modular, avascular tumors, which are less radiosensitive than tu- mors with an adequate blood supply. mewwmmmwWH-"'- FIGURE 34-2 The OER is high for low-LEI' radiation and decreases in value as the LET increases. Question: When experimental mouse mammary carci— nomas are clamped and irradiated under hy- posn'c conditions, the tumor control dose is 10,600 rad (106 Gy,}. When the tumors are not clamped and are irradiated under aero- bic conditions, the tumor control dose is 4050 rad (40.5 cm. What is the OER for this system? _ _ 10,600 Answer. OER —-4050 = 2.6 The OER is LET dependent (Figure 34—2). The OER is highest for low-LET radiation, having a maximum of approximately 3, and decreases toapproximately 1 for high-LET radiation. Age The age of a biologic structure affects its radiosensitivity. The response of humans is characteristic of this age— related radiosensitivity (Figure 34—3). Humans are most sensitive before birth. The sensitivity then decreases un- til maturity, which is when humans are mosr resistant to radiation effects. In old age, humans again become somewhat more radiosensitive. Many theories have been developed to explain this pattern of response, but none is universally accepted. Recovery In vitro experiments show that human cells are capable of recovering from radiation damage. If the radiation dose is sufficient to kill the cell before its next division, interphase death will occur. If the radiation dose is not sufficient to kill the cell before its next division, the cell will recover from the sublethal radiation damage it has sustained. Chapter 34 Fundamental Principles of Radiohiology 465 FIGURE 34-3 Radiosensitivity varies with age. Experiments with animals have shown that the very young and the very old are more sensitive to radiation. This intracellular recovery is due to a repair mecha— uism inherent in the biochemistry of the cell. Some types of cells have greater capacity for the repair of sublethal damage than others. At the whole-body level, this recovery from radiation damage is assisted through repopulation by the surviving cells. If a tissue or organ receives a sufficient radiation dose, it will respond by shrinking in size. This is called at- rophy and occurs because some cells die, disintegrate, and are carried away as waste products. if a sufficient number of cells sustain only sublethal damage and survive, they may proliferate and repopulate the irradiated tissue or or— gan. The combined processes of repair and repopulation contribute to recovery from radiation damage. Chemical Agents Some chemicals can modify the radiation response of cells, tissues, and organs. For the chemical agents to be effective, they must be present at the time of irradiation. Application after irradiation does not usually alter the degree of radiation response. Radiosensitizers. Agents that enhance the effect of ta— diation are called sensitizing agents. Some examples are halogenated pyrimidines, methotrexate, actinomycin D, hydroxyurea, and vitamin K. The halogenated pyrim— idines become incorporated into the deoxyribonncleic acid (DNA) of the cell and cause the radiation effects on that molecule to be amplified. All the radiosensitizers 455 PartV Radiation Protection have an effectiveness ratio of approximately 2; that is, if 90% of a cell culture is killed by 200 rad (2 Gy,), then in the presence of a sensitizing agent, only 100 rad (1 Gy,) will he required for the same percentage of lethality. Radioprotectors. The radioprotective compounds in- clude molecules containing a sulfhydryl group (sulfur and hydrogen bound together), such as cysteine and cys~ teamine. Hundreds of others compounds have been tested and found effective by a factor of approximately 2. For example, if 600 rad (6 Gy,} is a lethal dose to a mouse, then in the presence of a radioprotective agent, 1200 rad (12 Gy,) would be required to produce death. Radioprotective agents have not found human applica- tion because to be effecn've, they must be administered in toxic levels. The protective agent can be worse than the radiation. Hormesis Some evidence suggests that a little radiation actually produces a helpful effect. Several animal studies have shown that those receiving low-radiation doses live longer than controls. The prevailing explanation is that a little radiation stimulates hormonal and immune re- sponses to other toxic environmental agents. There are many nonradiation examples of hormesis. In large quan— tities, fluoride is deadly; in small quantities, it is a known tooth preservative. RADIATION DOSE-RESPONSE RELATIONSHIPS Radiobiology is a relatively new science. Although some scientists were working with animals to observe the ef~ fects of radiation, within a few years after the discovery of x-rays, these studies were not experimentally sound. Interest in radiobiology increased enormously, however, with the advent of the atomic age during the 19405. The object of nearly all radiobiologic research is the establishment of radiation dose-response relationships. A radiation dose-response relationship is a mathematic relationship between various radiation dose levels and the magnitude of the observed response. Radiation dose-response relationships have two im~ portant applications in radiology. First, these experi- mentally determined relationships are used to design therapeutic treannent routines for patients with cancer. Second, radiobiologic studies have been designed to pro- vide information on the effects of low-dose irradiation. These studies and the dose-response relationships ob- tained are the basis for radiation—control activities and are of particular significance to diagnostic radiology. Every radiation dose-response relationship has two characteristics: it is either linear or nonlinear and it is ei- ther threshold or nonthreshold. These characteristics can be described mathematically or graphically. This discus- sion avoids the math. FIGURE 34—4 Linear dose-response relationships A and B are nonthreshold types; C and D are threshold types. Linear Dose-Response Relationships Figure 34—4 shows examples of a linear dose-response relationship, so called because the response is directly proportional to the dose. When the radiation dose is doubled, the response to radiation is likewise doubled. Dose—response relationships A and B intersect the dose axis at zero or below in Figure 34—4. These rela- tionships are therefore the linear, nonthreshold type. In a nonthreshold dose-response relationship, any dose, re- gardless of its size, is expected to produce a response. At zero close, relationship A exhibits a measurable response, RN. The level RN is called the natural response level and indicates that even without a radiation exposure, that type of response (cancer, for example) occurs. Dose~response relationships C and D in Figure 34-4 are linear, threshold type because they intercept the dose axis at some value greater than zero. The threshold doses for C and D is Dr. At doses below these values, no re- sponse would be expected. Relationship D has a steeper slope than C, and therefore above the threshold dose, any increment of dose will produce a larger response if that response follows relationship D rather than C. Nonlinear Dose-Response Relationships All other radiation dose-response relationships are de- fined as nonlinear (Figure 34-5]. Curves A and B are nonlinear, nonthreshold. Curve A shows that a large {6‘ sponse results from very little radiation dose. At high- dose levels the radiation is not as efficient, since an in- ...—..»n.wuuuwmmiuwmdfl -' " " ' 'i "' .I.. m... FIGURE 34-5 Nonlinear dose—response relationships can assume several shapes. Curves A and B are nonthreshold. Curve C is threshold. cremental dose at high levels results in less relative dam- age than the same incremental dose at low levels. The dose-response relationship represented by curve B in Figure 34-5 is just the opposite. Incremental doses in the low—dose range result in very little response- At high doses, however, the same increment of dose pro- duces a much larger response. Curve C in Figure 34-5 is a nonlinear, threshold rela- tionship. At doses below DT, no response is measured. As the dose is increased above the D; for C, it becomes increasingly effective per increment of dose until it reaches the dose corresponding to the inflection point of the curve. The inflection point occurs when the curve stops bending up and begins bending clown. Above this level, incremental doses become less effective. Relation- ship C is sometimes called an S-type, or sigmoid-type, radiation dose-response relationship. We refer to these general types of radiation dose— response relationships in discussing the type and degree of human radiation injury. Diagnostic radiology is al- most exclusively concerned with the late effects of radi— ation exposure and therefore with linear, nonthreshold dose-response relationships. For completeness, howeveg Chapter 36 contains a brief discussion of early radiation damage. Constructing a Dose-Response Relationship Determining the radiation dose-response relationship for the whole body is tricky. It is very difficult to determine the degree of response, even that of early effects, because the number of experimental animals that can be used is Chapter 34 Fundamental Principles of Radiobiology 467 FIGURE 34~6 A dose-response relationship is produced by extrapolating high-dose experimental data to low doses. usually small. It is nearly impossible to measure low- dose, late effects, and that is the area of greatest interest to diagnostic imaging. Therefore we resort to irradiating a limited number of animals to very large doses of radiation in hopes of observing a statistically significant response. Figure 34-6 shows the results of such an eitperiment in which four groups of animals were irradiated to a different dose. The observations on each group results in an ordered pair of data: a dose and the associated biologic response. The error bars in each ordered pair indicate the con— fidence associated with each data point. The error bars on the dose measurements are very narrow; the radia- tion dose can be measured very accurately. The error bars on the response, however, are very wide because of biologic variability and the limited number of observa‘ tions at each dose. The principal interest in diagnostic imaging is to esti‘ mate the response at very low doses. Since this cannot be done directly, the dose-response relationship is ex- trapolated from the high—dose, known region into the low-dose, unknown region. This invariably results in a linear, nonthreshold dose-response relationship. Such an extrapolation, however, may not be correct because of the many qualifying conditions on the experiment. @——————-———-——-—— SUMMARY In 1906, two French scientists first theorized that ra- diosensitivity was a function of the metabolic state of tis- sue being irradiated. Their theory is known as the law of Bergonie and Tribondeau and state the following: (1) stem cells are radiosensitive, and mature cells are less so; (2) young tissue is more radiosensin've than older tissue; [3) high metabolic activity is radiosensitive, and low metabolic rate is radioresistant; and (4) increases in the 468 PartV Radiation Protection proliferation and growth rates of cells makes them more radiosensitive. Physical and biologic factors affect tissue radiosensi— tivity. The physical factors are the LET {rate at which en- ergy is transferred from radiation to soft tissue), RBE (as LET increases, the damage to tissue increases), fraction— ation (dose delivered over a long time), and protraction (a lower dose delivered continuously). The biologic fac- tors affecting radiosensitivity are the oxygen eHect (the aerobic state of tissue is more radiosensitive), the age- related effect (the human fetus is most sensitive to ra- diation than an adult), and the recovery effect (intracel- lular recovery is due to intrinsic repair mechanisms and the progression of the cell through the cell cycle). Some chemicals can modify the response of cells. They are called radiosensitizers and radioprotectors. Radiobiology research concentrates on radiation dose-response relationships. A radiation dose-response relationship is the relationship between different radia- tion doses and the magnitude of the observed response. In linear dose-response relationships the response is di- rectly proportional to the close. In nonlinear dose- response relationships, varied responses are produced from varied doses. The threshold dose-response is the level below which there is no response. The nonthresh- old dose-response relationship means that any close is ex- pected to produce a response. For establishing radiation- protection guidelines for diagnostic imaging, the linear, nonthreshold dose-response model is used. @—————————-—~———- CHALLENGE QUESTIONS 1. Define or otherwise identify: Linear energy transfer Standard radiation Oxygen enhancement ratio Repopuiation ‘ Interphase death . Dose protraction Tissue weighting factor \J a. b. c. d. e. f g. W rite the formula for relative biologic effectiveness. 3. Give an example of fractionated radiation. 4. When is high-pressure (hyperbaric) oxygen used in radiation oncology? 5. Write the formula for the oxygen enhancement ratio. 6. How does age affect the radiosensitivity of tissue? 7. Name three agents that enhance the effect of radia. tion. 8. Name three radioprotective agents. 9. Are radioprotective agents used for human applica- tion? Why or why not? 10. Explain the meaning of a radiation dose-responsc relationship. 11. What occurs in a nonlinear radiation dose-response relationship? 12. Explain why the linear, nonthreshold dose—response relationship is used as the model for radiation— protection guides for diagnostic imaging. 13. State two of the corollaries to the law of Bergonie and Tribondeau. 14. Approximately 800...
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