Mechanism of Biologic Damage
Manifestation of bioinjury caused by radiation is always preceded by a complex series of physiochemical events, as shown in Figure 17.1
The first step in this series of events is the deposition of energy by radiation in the form of ionization and excitation of some atoms or molecules of the biologic system. This is almost instantaneous and lasts about 10-12
seconds or less. As was explained in Chapter 6
, charged particles, such as α and β, cause ionization and excitations directly in the interacting medium. Hence, these are called directly ionizing radiations. On the other hand, x- or γ-rays first produce an electron (through photoelectric, Compton, or pair production interactions) that then causes ionizations and excitations in the medium. Hence, x- or γ-rays are sometimes referred to as indirectly ionizing radiation.
Figure 17.1. Stages in the development of bioinjury by high-energy radiation exposure.
The second step, which may last from 10-12 to about 10-3 seconds, is the transfer of energy from these ionized or excited molecules, either to neighboring molecules (intermolecular) or, quite often, within the molecule itself (intramolecular), leading to various short-lived and chemically active species known as free radicals (atomic or molecular entities with an unpaired electron, shown by a dot to the right side of the chemical symbol, such as H·). Because water (H2O) constitutes 75% to 85% of the mass of a living system, most ionizations and excitations are produced in water, and the two most common radicals formed are H· and OH·. Of course, other large molecular radicals are also formed from excitation and ionization in large molecules, such as proteins and DNA, but these are less abundant.
In the next stage, that may last from milliseconds to about several seconds, the free radicals react either among themselves or, more significantly, with other important biomolecules (e.g., DNA, RNA) to produce alterations in them. Reactions of H· and OH· radicals with important biologic molecules cause most radiation damage observed in living systems.
The final step (i.e., the expression of the biologic alteration produced in the important biomolecules in the previous stage) is the biologic damage that is tied to the fate of these altered biomolecules. In case the damaged biomolecules get repaired, there will be no biologic damage. However, if they remain damaged, eventual deleterious effects may be manifested within a short time or may be delayed up to several generations, depending on the type and function of these altered molecules.
Factors Affecting Biologic Damage
Biologic damage (or effect) to a system caused by radiation depends on the following factors.
Radiation Dose. Any biologic effect of radiation, whether deleterious or benign, strongly depends on the radiation dose. Generally, more effects, and more serious effects, are produced by high than low doses. The exact relationship of the dose to the effect produced, however, depends on the nature of the effect. For example, the dose-effect relationship for the induction of cancer differs from that causing genetic mutation.
Depending on the dose-effect relationship, radiation effects are termed as stochastic
. In stochastic
effects, the probability of occurrence, and not the severity of the effect, depends on the radiation dose. Two important examples are induction of cancer and genetic damage, where the probabilities of induction are a function of radiation dose but their severity is not. Stochastic
effects do not have a threshold, a dose level below which the probability of occurrence is zero. Therefore, in radiation protection, where stochastic effects are of major concern, a common assumption is made that states that risk from radiation is directly proportional to dose without a threshold. This assumption forms the basis of the so-called “as low as reasonably acceptable” (ALARA) principle of radiation protection, discussed in Chapter 18
In deterministic effects, on the other hand, the severity of effect depends on the radiation dose and has a threshold, a dose below which no effect is observed. Two examples of deterministic effects of radiation are production of cataracts and erythema.
Dose Rate. In the case of low linear energy transfer (LET) radiations, if the same dose is delivered to two identical biologic systems, one with a short duration (high dose rate) and the other over a longer period (low dose rate), the biologic responses of the two systems will differ. High dose rates are more damaging than low dose rates.
LET or Type of Radiation.
(see p. 62
) radiations (α particles and protons) per unit of absorbed dose produce greater damage in a biologic system than lower LET
radiations (electrons and γ- and x-rays). The relative biologic effectiveness (RBE) of a radiation for producing a given effect in a biologic system under the same conditions is defined as follows:
For example, the RBE of 10-MeV neutrons for killing cells is about 10. In other words, 10-MeV neutrons are 10 times more effective at cell killing
than x-rays (generally, 250-kVp x-rays are used as a reference). The “quality factor” Q and radiation weighting factor WR
discussed later in this chapter are estimated from the RBE of a radiation.
Type of Tissue. Biologic response of a system varies widely depending on the type of tissue (e.g., liver, bone marrow, or nerve tissue) involved. Given the same radiation dose and dose rate, bone marrow is much more sensitive than nerve tissue to certain types of radiation damage. The tissue weighting factor WT, discussed later in this chapter, takes account of this variation when one compares radiation exposures from different sources.
Amount of Tissue. Injury to a biologic system also depends on the amount of tissue irradiated. For example, a mammal can tolerate a much higher dose to a part of the body than irradiation of the total body.
Rate of Cell Turnover. The rate of cell turnover in tissues is deemed to affect the latent period for the expression of tissue damage. For tissues with a rapid cell turnover (bone marrow), damage appears earlier than for a slow cell turnover (liver).
Biologic Variation. The response of a biologic system, even with all other factors constant, may vary enormously even among closely related individuals. One person may survive a total body dose of 400 rad (cGy), whereas a dose of only 200 rad (cGy) in another person may be lethal.
Chemical Modifiers. The presence of certain chemicals is known to modify the response of a biologic system to radiation. Substance that makes biologic systems more radioresistant is called radioprotector. A good example of a radioprotector is the protein cysteine. Substance that makes biologic systems more radiosensitive is called radiosensitizer. An example of a radiosensitizer is molecular oxygen. For a radioprotector or radiosensitizer to have any effect, it must be present in the biologic system during irradiation.
Deleterious Effects in Humans
Deleterious effects in humans may be acute (mainly deterministic) or late (mainly stochastic). Acute effects are manifested within a short period after irradiation and range from transient nausea and vomiting to death. Late effects may take as long as several generations for eventual manifestation. These include stochastic effects, for example, induction of cancer and leukemia, birth defects, and other abnormalities in the offspring of the irradiated person (genetic damage), and nonstochastic effects, for example, cataracts, shortening of the overall life span, and production of temporary or permanent sterility in an individual.
These are generally produced when the radiation dose is high and delivered to a large part of the body in a short duration. Five clinically distinct stages can be identified as the radiation dose is progressively increased: no effect, mild damage to bone marrow, severe damage to bone marrow and mild damage to the gastrointestinal tract, severe damage to the gastrointestinal tract, and damage to the central nervous system. Table 17.1
lists the radiation doses and the typical symptoms of the four stages.
In nuclear medicine, high radiation doses are encountered only in the case of therapeutic uses of radiopharmaceuticals as described in Chapter 5
. Radiation dose in some of these cases may be high enough to cause mild damage to bone marrow (stage 1 in Table 17.1
Late Effects. Late effects may occur in cases where acute reactions are minimal (i.e., when the radiation dose to the total body is low or only part of the body is involved in the irradiation). In diagnostic uses of radiation, whether in radiology or nuclear medicine, the range of radiation doses generally delivered to a patient falls in this category. Therefore, the dose-effect relationship of late effects is of special interest.
Low Dose Relationship for Stochastic Effects.
Regrettably, precise information about the stochastic risks involving low radiation doses is difficult to obtain for the following reasons. First, the probability of occurrence of any late effect after low doses is small. Therefore, to perform statistically valid studies, large populations have to be considered. In practice, this is difficult to implement. Second, the occurrence of a latent period in the expression of late effects requires
a long follow-up (10 years or more). Finally, late effects also occur naturally and more frequently than those caused by low doses of radiation. Because accurate information is lacking on the natural frequency of these effects, it is difficult to estimate the influence (increase or decrease) of low radiation doses. In addition, the frequency of natural occurrence is influenced by many complex factors, such as age, sex, genetic history, geography, and various environmental and socioeconomic factors.
Table 17.1 Radiation Doses and Acute Effects
Dose Range (rad)
No acute effect
Transient nausea and vomiting; some evidence of damage to hematopoietic system, recovering in 1-2 mo
Severe damage to hematopoietic system; bone marrow transplant essential; survival chances moderate
Gastrointestinal damage; severe nausea, vomiting, and diarrhea; very small chance of recovery; death follows in 10-24 d
1,000 and above (10 and higher)
Confusion, shock, burning sensation; death follows within hours
a Values in parentheses are in Gy.
Despite these obstacles, a good estimation has been made of the risks to a person or a population exposed to low radiation doses. Most information in this regard is derived from two sources: extrapolation from experiments conducted on laboratory animals (e.g., mice) and retrospective studies of the victims of the atomic bomb explosions in Nagasaki and Hiroshima; the inhabitants of Bikini and other Pacific islands who were exposed to radiation as a result of fallout; persons irradiated for medical reasons; and occupational workers, such as uranium mine workers and radiation workers (e.g., radiologists). Two scientific committees, the United Nations Scientific Committee on the Effects of Atomic Radiation and the National Academy of Sciences Committee on the Biological Effects of Ionizing Radiations, are actively involved in evaluating these studies and estimating biologic risk from radiation. The Committee on the Biological Effects of Ionizing Radiations (BEIR) has issued a number of reports, including BEIR VII (2006) on “Health risks from exposure to low levels of ionizing radiation.”
Of all late effects, the induction of cancer and genetic damage are the most important. The lifetime risk of a cancer (any type) from a single uniform exposure to the total body depends on the age at the time of exposure and the dose. The International Commission on Radiation Protection (ICRP) report 103 (2007) estimates the cancer risks (probabilities) per 1 Sv of radiation exposure for average populations (all ages and adult workers), as given in Table 17.2
(units of Sv and rem are defined later in this chapter).
It is important to note that children are more vulnerable to radiation than adults because of the higher radiosensitivity of their tissues and the longer lifespans during which stochastic radiation effects may develop. Based on Atomic bomb survivor data, a lifetime cancer risk of about 15% per Sv at an exposure age less than 10 years has been concluded, compared with only 1% per Sv at age 60. This is why there have been significant efforts (e.g., “Image Gently” campaign) to significantly limit radiation exposure from medical procedures to children.
Information on genetic damage has been deduced mostly from results obtained in experiments with Mediterranean fruit flies (Drosophila
) and laboratory
mice. The present estimate of the doubling dose for genetic effects (the dose needed to double the natural incidence of a genetic or somatic anomaly) is in the range of 60 to 160 rad (0.6 to 1.6 Gy). This may be an overestimate because recent data indicate that humans are less sensitive to genetic damage than the fruit fly. For radiation protection, ICRP report 103 also estimates the hereditary risk as given in Table 17.2
. As can be safely inferred from these data, carcinogenic effects of radiation are more significant than genetic effects. Total detriment from radiation for cancer induction and genetic damage is then determined by adding the two risks, also shown in Table 17.2
Table 17.2 Radiation Risk of Cancer, Heritable Effects, and Total Stochastic Detriment to Populations from Low Level of Radiation Exposure (International Council on Radiation Protection report 103)
General population (all ages)
5.5% per Sv
0.2% per Sv
5.7% per Sv
4.1% per Sv
0.1% per Sv
4.2% per Sv
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