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Objectives

Outline

Introduction

Section 2.0: The physical basis of radiation

Section 2.1: Cell structure and function

Section 2.2: Cellular Response to Ionizing Radiation Absorption

Section 2.3: Chromosomal Aberrations

Section 2.4: Effects of Ionizing Radiation on the Human Body

Section 2.5: Radiation Effects on the Embryo/Fetus

Summary and References

Bottom

Objectives

• Describe the basic physical units LET and Quality factor (Q) and discuss what they tell us in terms of biological tissue response.
• Describe the units of LET and discuss the relative number of ionization x-rays cause relative to alpha particle radiation.
• Discuss the relationship between the RBE and specific ionization (SI).
• Discuss the role of oxygen in the enhancement of low LET radiation effects.
• Discuss the theory of radiation hormesis and the role of the peroxisome in preventing free radical formation.
• List the four types of dose-response curves and define their meanings (linear, nonlinear, threshold, and Nonthreshold).
• State the law of Bergonie and Tribondeau and tell what the law means.
• Define the term specific ionization and state how it affects tissues according to the LET of the ionizing radiation.
• Discuss the radiation hormesis theory and tell why it has gained recognition.
• Explain the various types of dose-response curves and state which applies to ionizing radiation.
• State the role of the stem cell and discuss how cells respond to ionizing radiation exposure.
• Discuss the cell cycle and discuss the role of mitosis and meiosis in the cell cycle.
• Discuss the importance of the central dogma of DNA, RNA, and protein synthesis.
• State the target theory of ionizing radiation, and discuss what is the target cell and molecule of the theory.
• Discuss direct and indirect effects of ionizing radiation and discuss the mechanism of each.
• Define a clastogen and discuss some basic chromosomal aberrations caused by radiation damage.
• List the radiosensitivity of some common cell types (nerve, muscle, stem, lymphocyte, etc).
• Define the criteria for a radiation induced “Early Effect” and discuss the acute radiation syndrome it may cause.
• Discuss the radiation doses required to have the acute radiation syndrome state the consequence of each manifest illness.
• State what is considered to be the LD_50/60, and the absolute lethal dose.
• Define what is meant by late effects and discuss why late effects are very important to radiographers and to the patients they expose.

Outline

1. Ionization
2. Energy deposition
3. Linear energy transfer (LET)
4. Relative biological effectiveness (RBE)
5. Specific ionization (SI)
6. Oxygen enhancement
7. Radiation hormesis theory
8. Dose-response relationships
9. Law of Bergonie and Tribondeau

1. Cytoplasmic structures
2. Nuclear structure

1. The pluripotent and unipotent stem cells
2. The cell cycle
3. Mitosis and meiosis
4. The human genome and karyotyping
5. Cell cycle and target theory
6. Mechanism of indirect ionization effects

1. Early effects of ionizing radiation
2. Lethal dose(s)
3. Late effects

1. The classic triad of radiation effects
2. Radiation teratogenic effects on congenital disorders
3. Hereditary effects

Introduction

Wilhelm Conrad Roentgen, discovered x-rays in 1895. The picture next to him is of his wife’s hand which is considered to be the first radiograph. It was several years after his discovery that the harmful effects of ionizing radiation were realized. Pictures purchased from the Wilhelm Roentgen museum bookstore, Germany.

No no discussion of radiology or its ionizing effects would be complete without a tribute to Whelm Conrad Roentgen, who on November 8, 1895 discovered ionizing electromagnetic radiation while simultaneously realizing its potential for medical diagnosis. From the very beginning it was not realized that ionizing radiation has harmful effects that could be avoided if safe practices had been implemented. But with the lives of those who experimented with radiation as pioneers in the disciple, namely Thomas Edison, the discipline of radiology blossomed. Clarence Dally, Edison¡¦s assistant, suffered severe x-ray burns that required amputation of both arms and eventually claimed his life in 1904 making him the first U.S. radiation fatality. Over time the world has known the awesome power of radiation and nuclear energy, that is, to provide for our daily energy needs or to destroy peace through war and the threat of war. Understanding the harmful effects of ionizing radiations has come at the price of foolish practices, by scientific discovery, and war. In this module we will examine the principles of biological effects of ionizing radiation and those scientific principles underlying safe practices and dose equivalent limits set by the National Council on Radiation Protection and Measurement (NCRP).

Radiologic technologists practice radiation protection based on risk versus benefit models of radiation exposure mindful to prevent hereditary and somatic radiation induced consequences from occurring to self and to progeny. Recent documents from the latest BEIR reports (Committee on Biological Effects of Ionizing Radiation) suggest that the risk of radiation injury is 3 to 4 times higher than previous estimates. The community of radiologist and radiographers together are responsible for the cumulative radiation dose upon the population for medical diagnostic purpose and the social consequences that follow.

Section 2.0: The physical basis of radiation

Ionization is the most fundamental mechanism of radiation injury; without ionization no injury to cells occurs. Ionization is a subatomic process in which an electron is either removed from an atom or gained by an atom; this creates either a positive or a negative atom. Therefore, cellular injury begins at the atomic level affecting biomolecules. How energy is transferred from ionizing radiation to tissue is described by the concept of LET (linear energy transfer). Energy from ionizing radiation is transferred to living tissue in a straight line path called LET, which is expressed in units of keV/cm. Electromagnetic radiation transfers energy at a rate of approximately 3 keV per μm of travel. Particulate radiation, such as the photoelectron, and the fast moving beta particle can deposit upwards to 20 keV of energy for each cm traveled. What happens to that energy is our present concern. That energy can directly affect biomolecules, or can indirectly affect biomolecules through interaction with water. There are five concerns of energy absorbed into living tissue: Linear energy transferred (LET), relative biological effectiveness (RBE), Oxygen enhancement, hormesis, dose-response, and the law of Bergonie and Tribondeau.

Linear Energy Transfer (LET)

LET describes the rate at which energy is transferred from ionizing radiations to soft tissue. The unit that quantifies LET is kiloelectron volts of energy transferred to soft tissue per micrometer of length traveled (keV/μm). Diagnostic x-ray imparts approximately 3.0 keV/μm travel in soft tissue and is considered low LET radiation. As the energy of a photon of electromagnetic radiation increases its LET decreases, for example a 25-MeV photon will impart a LET of approximately 0.2 keV/μm. X-rays and gamma rays are highly penetrating radiations as such do not easily give up their energy and are considered low LET radiations. Less penetrating radiations such as particulate radiation, photoelectrons, alpha particles, and beta radiation are high LET radiations. What LET tells us is that the number of ionization events increase as the LET increases and decrease as the LET decreases.

Ionizing radiation particles, like the alpha particles, have mass and charge, and interact with matter as it traverses it through the breaking of chemical bonds and the ionization of matter. The alpha particle has a +2 charge on emission and will very aggressively ionize adjacent atoms to acquire two electrons returning it to a stable electrically neutral helium atom. This process causes primary and secondary ionization events. The alpha particle loses an average of 34 eV per ionization event and therefore a 34 meV alpha particle could cause up to 100,000 ionizations creating 100,000 ion pairs before coming to rest in a few centimeters of air. Soft tissue being denser than air would suffer 100,000 ionizations from the same 34 meV alpha particle; however, its ionization events would be closer together along the path traveled and the alpha particle would be less penetrating. As LET increases the energy of the radiation decreases and its range of travel also decrease.

Although the RBE expresses the relative effectiveness of two different types of radiation; the factor used in radiation protection to express this effectiveness is the quality factor written Q. The quality factor or Q is a symbol for expressing the LET dependent response by a biological system. If the biological response per rad of two different radiations is the same then their Q is the same. X-rays, gamma rays, and beta particles all have the same Q, which is equal to 1.

Relative Biological Effectiveness

The relative biological effectiveness is a term for quantifying specific radiation effects not general or relative risks. It includes the various effects caused by different types of ionizing radiation, the tissue type into which the energy is imparted, the biological effect under investigation, and the rate at which that dose is delivered. The RBE always compares the amount of orthovoltage radiation to another type of radiation (e.g. alpha or beta radiation), and a specific biological effect produced by those tested radiations, such as cataract. Orthovoltage radiation is electromagnetic radiation with a range of 200-250 kVp. If it takes 15 rad of 250 keV x-rays to produce cataracts and only 5 rad of alpha particles the RBE is said to be 3.

Notice that the RBE is without a unit description, in our example; it simply means that alpha particles are 3 times more effective in producing cataracts than are x-rays. This is because the specific ionizations of alpha particles are greater than the specific ionizations caused by x-rays or gamma rays. We have already described the specific ionization as the average number of ion pairs produced per unit of path traversed by the incident radiation.

The pictures below of a thin vertical slice through skin tissue show the effect of Low and high LET radiations on specific ionization. Low LET radiations like x-rays and gamma rays are highly penetrating and will pass through skin and soft tissue imparting only part of their energy in those tissue causing limited ionizations along their path. High LET radiations such as alpha particles and fast neutrons cause many closely spaced ionizations along their path transferring their energy to the soft tissues with each ionization event. This is why low LET radiation having relatively few ionization events will also have a low RBE, and high LET radiation will yield many closely spaced ionizations and have a high RBE.

The specific ionization of low LET radiation such as x-rays and gamma rays do not create ion pairs close together as do charged particles of ionizing radiations such as alpha particles and fast neutrons.

The specific ionization of particulate radiations (e.g. alpha particles) is high as ionization occurs more frequently and at closer intervals along the radiation’s path.

The LET, RBE, and specific ionization of radiation directly affects the potential of a cell type for survival of the ionization events. Generally speaking cells may suffer sub lethal injury and recover, or may suffer irreparable damage and die. Reversible injury involves mechanisms that replace damaged macromolecules such as carbohydrates, lipids, and proteins. Irreversible damage that leads to cell death involve mechanisms that cause damage to the cell's DNA. Cell survival is a measure of the reproductive ability of the cell, that is, its ability to divide following replication of its DNA sustaining unlimited proliferation. Lethally irradiated cells die of apoptosis or mitotic death; notwithstanding, cell survival depends on the cell type and degree of differentiation.

Oxygen Enhancement

Radiation therapy technologists know and depend on oxygen effect to enhance the effect of low LET high energy radiation. Tissue is more sensitive to radiation when it is in an aerobic state than when in hypoxic or anoxic states. Fully oxygenated cells can have a radiosensitivity of 2.5 to 3 times that of anoxic or hypoxic cells⁵. Oxygen enhancement is dependent on the radiation's LET. Only low let radiations (x-rays and gamma rays) are significantly enhanced by oxygenation of tissues. This is because low LET radiation has a RBE and Q of 1. Their effect on tissues can be enhance up to the maximum RBE value of 3, whereas high LET radiation has a high RBE and therefore, the effect on the tissue cannot be further enhanced. The mechanism of increased injury to cells by oxygen effect is greater free radical formation. The mechanism for cell injury by high LET radiation is direct DNA damage not free radical formation. The mechanism of cell injury for low LET radiation is indirect damage to DNA by free radical formation.

Radiation Hormesis

There is some evidence that a little radiation can be effective in stimulating the body's natural defenses against free radical formation that damages cells. Bushong states that "the prevailing explanation is that a little radiation stimulates hormonal and immune responses to other toxic environmental agents." Bushong further states that "a little radiation dose, less than approximately 10 rad, may be good for you." Bushong further acknowledges that the theoretical crossover risk dose is between 5 and 20 rad.

Research by Christian de Duve, winner of the Nobel Prize in Physiology and Medicine (1974) who discovered the cell organelle he called the peroxisome is responsible for preventing damage to cells by free radical formation. Peroxisomes are numerous subcellular organelles that contain the enzyme catalase that break down hydrogen peroxide in cells. Hydrogen peroxide (H₂O₂) is the byproduct mediator of free radical injury by indirect radiation energy. This remains the predominate mechanism of free radical recovery by mammalian cells. Low dose radiation may stimulate the formation of peroxisomes. Liver and kidney cells are known to have hundreds of peroxisomes that degrade hydrogen peroxide.

Dose-Response

There are 4 types of dose response curves that are important to radiology and represent risk due to exposure to ionizing radiation. They are and their meaning is:

• Threshold - there is a level below which the response is not seen. For example, pain, there is a threshold below which not pain is felt.
• Nonthreshold - meaning there is no safe level because all dose levels regardless to how small is potentially harmful. For example, ingesting cyanide. There is no safe dose for the ingestion of cyanide and the event can be lethal or non lethal and therefore carries risk.
• Linear - meaning the response is directly related to dose. For example, if one is exposed to hepatitis C virus, then as the exposure dose increases the risk of contracting hepatitis increases proportionately.
• Nonlinear - meaning the dose is not proportionate to the response but varies according to the mathematical shape of the curve.

Figure above of the types of dose-response curves. Curve A is linear and positioned on the zero axis meaning it is also Nonthreshold. Its position on the x axis shows it represents an ambient dose from background and cosmic radiation. Curve B is also linear-nonthreshold and represents the response of humans to ionizing radiation late effects. Line C represents a linear-threshold dose response; an administered dose value to the left of the line will not manifest the specified response, whereas a dose to the right of the line will manifest the specified response. Curve D is a nonlinear-threshold dose response. A response that is represented by this sigmoidal curve does not follow a directly proportionate dose response.

The law of Bergonie and Tribondeau

In 1895 Roentgen discovered x-rays, and in 1896 Becquerel references radioactivity, and in 1898 Curie discovers radium, and the first U.S radiation fatality (Clarence Daly) was reported. In 1906 one of radiology's most important discoveries was made-the law of Bergonie and Tribondeau. By exposing rabbit testicles to ionizing radiation and observing its effects, the relationship between metabolic state and radiosensitivity was established. The law specifically states that:

• Stem cells are radiosensitive.
• Immature or young cells and tissues are more radiosensitive; resistance to radiation increases with increased cell maturity.
• Low metabolic rate decreases radiosensitivity and high metabolic rate increases radiosensitivity.
• High proliferation (reproductive) rate for cells and fast growth rate increases the radiosensitivity of those cells.

Section 2.1: Cell structure and function

The cell is the most fundamental functional unit of all tissues and constitutes the essential functions of life.

The two pictures above represent the basic unit of life, the cell and its role in forming tissues and organ-systems. The picture on the left is an electron microscope image of a cell; the nucleus that contains DNA is surrounded by a nuclear membrane (N). The picture on the right shows the organization of cells into tissue with stratified layers that compose the architecture of an organ.

The body's tissues contain many specialized cell types which amplify cell functions through diverse structural architectures. Cells form tissues, tissues form organs, organs form systems, and systems work together for the good of the organism. Within the cell are two main compartments: the nucleus that contains the master copy of molecular life processes called the DNA, and the cytoplasm that surrounds the nucleus where metabolic functions of the cell are performed. Cells function as tissues through welded junctions, and communicate through channels in their cell membranes, and through nerve and hormonal controls. Some of the main components of the cytoplasm and nucleus are listed in the table below: the cell membrane, endoplasmic reticulum, lysosomes, peroxisomes, mitochondria, ribosomes, and the like (see chart below).

Section 2.2: Cellular Response to Ionizing Radiation Absorption

Understanding cellular responses to ionizing radiation begins with an understanding of the typical cell cycle. The basic dogma of the cell cycle is that some cells called stem cells repopulate cells in tissues by undergoing self replication and cell division to produce a non stem cell duplicate that will differentiate into a predetermined cell type in the pluripotent stem cell lineage (see figure below). Pluripotent stem cells retain their ability to replicate by existing in the gap 1 phase (G₁) from which they spawn unipotent stem cells. The unipotent stem cell will carry on the lineage of the cell that will differentiate into a specific subset of a cell genre. For example, the blood cell line in which erythrocytes, lymphocytes, neutrophils, eosinophils, basophils, monocytes, and platelets are made begin with the pluripotent stem cell begetting a unipotent stem cell. For example, a unipotent stem cell is made to the procession of the lymphoblast that becomes the prolymphoblast, that becomes the lymphocyte. Within these cell types there are many subsets such as T3, and T4 lymphocytes, etc. The most fundamental cell types even from gestation are the pluripotent stem cell and unipotent stem cells. All tissue types have stem cells that repopulate tissues for growth and repair.

Cells replenish their pool through a process of cell division and differentiation. For example, if there is an injury to a tissue, cells of that tissue type through a common lineage can repair that tissue. By causing certain cells to undergo replication and division a repopulation of the tissue with like cells carry out repair. The process of repopulation and growth involves certain cells that retain their ability to enter the cell cycle even if they are differentiated and can replenish a tissue's cell populations and do foster growth of tissues. We see this in the process of endochondrial growth where the cartilaginous skeleton of the newborn is replaced by a bony skeleton suitable for weight bearing allowing the toddler to walk. By extending the reference we see that the aging process also occurs in which the body lay down cells imperfectly and may result in wrinkles and moles, and cancer, etc. Damage to cells that are born to be differentiated into a specific cell type by irradiation can be repaired; however, if damage occurs to the stem cell, that damage is propagated throughout that cell lineage if the stem cell is a pluripotent stem cell, and only partially throughout the lineage if it is a unipotent stem cell.

Cells and cellular components are not openly vulnerable to ionizing radiation, in fact, only the DNA within the cell nucleus is a potentially unforgivable target molecule of radiation injury and damage for all cell types. However, it is only those cells according the law of Tribondeau and Bergonie that are "targets" for irreversible radiation induced damage. Furthermore, there are specific stages in the cell cycle in which the cell is most radiosensitive, and therefore, those cells that are not in active cell division, are mature, and have low metabolic rates are considered radioresistant.

The table above is of the ancestry of the formed elements of blood. Blood cells are of a common lineage through a pluripotent stem cell that gives rise to a unipotent stem cell precursor to its cells. A similar patter exists for all cell types, that is , their origin is from a stem cell that replenishes the cell population during growth and repair. The most radiosensitive cell types are lymphocytes and spermatagonia. The most radioresistant cell types are neurons and muscle cells.

The cell cycle

The cell cycle is important to us because stem cells that remain in G₁ to replenish the cell's pool of needed cells are targets for radiation injury. Furthermore, the technologist should understand that cells in active cell division are occurring throughout the organism and can be damaged by irradiation. A thorough understanding of the implications of irradiating humans for medical purposes is becoming of the technologist. Now let's review the cell cycle to further understand its importance to radiation injury and damage. The stages of the cell cycle are interphase (G₁, S, and G₂), and mitosis. The cell cycle begins with a stem cell in gap phase 1. In this stage the cell replicates its nuclear components, ribosomes, endoplasmic reticulum, mitochondria, and the like anticipating cell division. It progresses to S-phase which is called synthesis phase because the DNA of the cell is raised from diploid to a complement of 4n. Gap phase 2 (G₂) is a preparatory stage to cell division. The process whereby somatic cells divide is called mitosis. The process by which germ cells divide is called meiosis. Notwithstanding in all cells cytokinesis follows karyokinesis, that is DNA is replicated prior to cell division, and phylogeny recapitulates phylogeny, like cells begat like cells.

Briefly, the stages of cell division or mitosis are:

• Prophase - The nucleus begins to dissolute, chromatin becomes visible.
• Metaphase - Chromosomes line up on the equatorial plate.
• Anaphase - Cells begin migration along spindle fibers towards the poles.
• Telophase - Cytokinesis with the production of like daughter cells.

The stages of the cell cycle are important to us for mainly two reasons, 1) the cell's stage is one of the determining factors of radiosensitivity, and 2) during metaphase of mitosis chromosomal damage can be evaluated. Before we look at the mechanisms of radiation injury we should state that observation of chromosomal damages can be seen by karyotyping. The basic process for observing chromosomes is to arrest the cell in metaphase, then carefully burst it and harvest the chromosomes. Once the chromosomes are recovered they can be organized into a spread sheet called a karyotype.

Picture to the left is a magnified photograph of chromosomes that were arrested in metaphase and the cell lysed to recover the chromosomes. A skilled cytologist is then able to arrange them by identical pairs so that observation for chromosomal damage can be assessed.

The human genome consists of 22 pairs of homologous chromosomes that code for somatic cells, and 1 pair of homologous sex (heredity) chromosomes XX if female, or 1 pair of nonhomologous sex chromosomes XY if male.

Humans store genetic information on chromosomes within the nucleus of cells. The central dogma is that DNA is the master copy of the human genome which is present in almost every human cell (some cells such as the mature RBE is void of a nucleus and DNA). DNA never leaves the nucleus and is protected by a double membrane that surrounds it. DNA functions in the control of messages to the cells cytoplasm in response to messages sent to it by electrochemical, neural, or hormonal communications. It responds by creating a specific copy of a set of instruction in the form of mRNA (called messenger RNA) that leaves the cell nucleus through pores to be read by ribosomes in the cell's cytoplasm. At the ribosome(s) the message is translated into a protein that performs the specific instructions of the DNA because of its structure.

For example, insulin is a molecule we know is required to bring glucose into the cell for metabolism that releases its energy to the cell for bodily functions. Insulin is primarily made in pancreatic endocrine tissue that house beta cells called islets of Langerhans. In these cells the DNA code for insulin produces single stranded mRNA that is released into the cell's cytoplasm where the protein insulin is made by ribosomes. The insulin is then released into the blood where cells take up the insulin into their membranes. Then when glucose is available in the blood the cell is able to transport it into its interior because it has insulin in its membrane. Although this is a simple example of how DNA functions it describes the importance of DNA. If the insulin molecule is damaged by irradiation and it cannot perform its function, the cell is not inactivated because through feedback mechanisms the DNA will know that there is insufficient insulin for the body's energy needs and makes more mRNA. The new insulin will not be damaged because the DNA that makes it is not damaged. However, if the DNA of that cell is damaged, then it is no longer able to make usable insulin because the genetic code in that cell is damaged.

Target Theory

According to target theory, the sensitivity of a cell is related to a key molecule within the cell; research supports that that molecule is DNA. Furthermore, the target is a specific location on the DNA that if hit, will inactivate the cell. DNA as a whole is not a target, only a specific location on the DNA that will inactivate the cell is that target. When an ionizing event results in a hit on the required target on the DNA molecule the cell is inactivated and will die. Cell lethality is measured by the cell's inability to divide. Following irradiation cells may divide several times then lose their reproductive ability. In such case the cell is still said to be inactivated. The mathematical expression of the observed cell survival correlation gives us a model for mammalian cells called the multitarget, single-hit model. What this means is that following random irradiation of DNA there appears to be a specific target on the DNA that requires two specific ionizing events in order to inactivate the cell. The model is called a multitarget because it requires two events on the target to equal one hit. A "hit" being defined as ionization events that result in the inactivation of the cell manifest by its inability to replicate.

The specific target on the DNA can be hit by direct irradiation, or by indirect interactions that have intermediate molecules that cause the hit on the DNA molecule. High LET radiations such as alpha particles are the mediators of direct DNA damage. Highly penetrating radiations such as x-rays and gamma radiation have low LET and mediate their effects through an indirect mechanism that involves splitting of water molecules causing free radical formation. Regardless of the mechanism, the results are that the DNA of the cell is altered according to the law of Bergonie and Tribondeau.

Radiation damage to macromolecules other than to DNA constitutes sublethal damage to the cell and can be repaired through mechanisms that degrade used or damaged biomolecules through normal metabolic pathways (beta oxidation of lipids, or aerobic respiration of carbohydrates, or acid hydrolysis of proteins). Even DNA can be repaired through proofreading mechanisms, being a double stranded nucleic acid chain the opposite normal chain of a damage molecule can be read for making normal single strand mRNA. Ionization or excitation to DNA that leaves it in an chemically unstable state is a direct effect, and the same effect to water molecules is an indirect effect.

Indirect Ionization Effects

When the initial ionization event begins with water, to form free radicals (a highly reactive chemical species with an unpaired electron in its valance shell), that cause a cascade of biological responses in macromolecules, the mechanism is collectively called an indirect effect. The primary mechanism of biological damage to macromolecules from ionizing radiation is an indirect interaction that begins with the radiolysis of water.

Radiolysis. Ionization of water molecules cause them to split by a process called radiolysis. The event is a cascade of chemical transformations that result in the formation of free radicals. Free radicals are highly reactive particles that can indirectly harm the DNA causing "hit" that inactivates that cell. Free radicals are indicated chemically by a dot beside the molecule representing its unpaired electron.

The net products of radiolysis of water molecules are the formation of highly reactive free radicals, namely a hydrogen free radical (H˙), and a hydroxyl free radical (OH˙). The third type of free radical from radiolysis of water is formed when the hydrogen free radical interacts with molecular oxygen to form a highly reactive species called hydroperoxyl radical (HO₂˙); these three free radicals are the results of ionization of water molecules and radiolysis. Also note that a free electron (e-) combines with water and forms the negative water molecule called "heavy water," a precursor to the hydroxyl radical (OH˙). An example of free electrons is the photoelectron (e-) that gives rise to characteristic radiation, and the beta particle (e-) encountered in nuclear medicine.

There are four (4) potential outcomes for those chemical species formed by radiolysis:

Section 2.3: Chromosomal Aberrations

Indirect damage to DNA by ionizing radiation usually causes point mutations. Point mutations are a type of single base substitution that causes a single replacement of an amino acid in a protein to another. Most point mutations are not harmful unless it occurs on the active site where the function of the protein is altered. An example of a point mutation is sickle-cell disease. Sickle-cell disease is caused by a single substitution of an amino acid in the hemoglobin protein. This causes a defective hemoglobin molecule that is heavier than regular hemoglobin and causes the red blood cell to be heavier than normal hemoglobin, causing the bent sickle like appearance of the red blood cell. This is caused by the polymerization of the defective hemoglobin under reduced oxygen situations as the RBC circulates through the vascular system. Point mutations from indirect damage to DNA are characteristic of low LET radiation like gamma radiation and x-rays.

Lefy. Sickle-cell disease is caused by a point mutation that substituted the amino acid valine for glutamic acid causing it to be sticky. Hemoglobin S as it is called tends to polymerize at reduced oxygen occasions causing micro-clots in the circulation.

Direct ionization of DNA caused by high LET radiation having low penetrability most likely will cause double strand breaks and frameshift mutations of the DNA. The fine structure of DNA reveals that it is a double stranded coiled molecule consisting of four types of nitrogenous bases (adenine, thymine, cytosine, and guanine) on a sugar phosphate backbone; the sugar is deoxyribose. These bases are complementary so that adenine always connects to thymine by two hydrogen bonds; cytosine and guanine always combine to each other by three hydrogen bonds. Unique to DNA is the presence of thymine as a nitrogenous base.

Chromosomes in the nucleus of each cell contain DNA organized into genes that code for genetic traits. DNA is made of 4 nitrogenous bases: adenosine, thymine, guanine, and cytosine that complimentary connect through hydrogen bonds. These bases are attached to a repetitive sugar phosphate backbone whose arrangement is a double stranded coiled helical architecture.

Direct ionization causes double strand breaks and frameshift mutations. Abnormalities of the chromosomes may be either numerical or structural as well as involve more than one chromosome. If the aberration occurs in the cell of the individual's somatic tissues, then the damage is to that cell and to the individual. Likewise, if the damage is to the individual's germ tissues, affecting spermatagonia or oogonia, the damage may involve the individual, and at conception-their progeny. In terms of irradiation of the embryo, more than one cell line may exist in which some is normal and others abnormal producing mosaicism. Damage to DNA is a fundamental event in both carcinogenesis and mutagenesis.

An aberration of chromosomal structure is a result of chromosomal breakage and reconstitution in an abnormal recombination. Besides viruses and certain chemicals, high LET ionizing radiation is one of the most potent clastogenic agents of DNA. A clastogen is an agent that causes breakage or disruption, as of to chromosomes. Stable aberrations are those that can complete cell division and the cell is not inactivated. The stable aberrations are duplications, deletions, inversions, insertions, and translocations of portions of a chromosome(s).

Some of the more common chromosomal aberrations: deletion, duplication, inversion, and trisomy. Because these aberrations can be stable they may be passed on to offspring if they occur on the gamete or on somatic chromosomes during early stages of gestation.

All cells are not equally sensitive to irradiation. This is in part because in order for a hit to occur on the DNA the specific target on the DNA must be exposed. DNA is an extremely large amount of chemical information especially if viewed from the perspective of the size of chromosomes. Depending on the cell type the DNA may be more or less tightly coiled on itself and the sites that constitute a hit are more or less unavailable. Lymphocytes and spermatagonia are the most radiosensitive cells in the human body while nerve and muscle are the most radioresistant cell types. Notwithstanding, highly proliferative cells, cells with a high metabolic rate, and immature cells are radiosensitive.

Section 2.4: Effects of Ionizing Radiation on the Human Body

Radiation dose to the human body can be divided into whole body radiation exposure and localized radiation exposure; and the effects thereupon to somatic tissues and to germ tissues. The effects of radiation exposure can be acute or be manifested as a late effect whose damaging results are not seen upwards to 20-30 years following exposure. In this section we will discuss acute radiation effects, late radiation effects, and the implication of dose on somatic and germ cells.

Early Effects of Ionizing Radiation

A biological response to ionizing radiation that occurs within hours, weeks, or months following exposure is called an early effect. Early effects resulting in death from a medical diagnostic point of view is purely academic and cannot occur in the radiology practice. Radiation from an x-ray tube is a partial body exposure and lacks sufficient energy or intensity to cause radiation death. Acute radiation lethality is an important issue today in our world of terrorism and the risk of biochemical and/or radiation terrorism does exist. The most profound example of acute radiation effects is the acute radiation syndrome. The syndrome can be divided into three distinct subset syndromes that are collectively called the acute radiation syndromes based on the radiation dose.

Following a whole body high dose exposure to ionizing radiation (>100 rad) within a few hours or days there is nausea, vomiting, and diarrhea ensues during a period called the prodromal period. As the initial radiation dose increases the violence of the symptoms increases. Shortly thereafter the symptoms diminish and there is no outward evidence of radiation sickness, this is called the latent period. If the dose is not enough to produce illness the person is not in danger of a manifest illness; however, there is a high risk of disorders that are collectively called late radiation effects. If the dose is greater than 200 rad but less than 1000 rad the hematologic syndrome will manifest. If the dose is greater than 1000 rad but less than 5000 rad the gastrointestinal syndrome will manifest, and at greater than 5000 rad the central nervous system syndrome will manifest.

Lethal Dose

The most devastating response to irradiation is death! Whole body exposure as seen in the Chernobyl nuclear reactor disasters, in Russia (April 1986), is capable of and did cause death of civilians. The causes of death were related to the acute radiation syndrome. The risk of death from whole-body radiation exposure increases with increasing dose, and the mean survival time decreases as the dose increases. The mean survival time is defined as the average time between exposure and death due to whole body radiation exposure. As we have seen with the acute radiation syndrome anyone exposed to below 100 rad would experience NVD and would recover, but are potentially at risk to late effects and the MST could be >30 years.

Lethal dose is expressed in values called the LD_50/60, or LD_50/30. The LD_50/60 would represent that amount of whole body radiation exposure that results in mortality to 50% of the exposed in sixty days. Research and experimentation confirms that radiation induced death in humans follows a nonlinear, threshold dose-response with the absolute lethal dose being about 1000 rad (10 Gy). The LD_50/60 for humans is estimated to be about 350 rad and the survivors of such a dose would have severe medical consequences. Again these doses are not possible in medical radiology practice and could only occur from a devastating nuclear episode.

Late Effects

In radiology as a whole, patients are exposed to a relatively safe dose of ionizing radiation in "As Low as Reasonably Achievable" (ALARA) dose to get a diagnostic study. For all imaging studies the benefit outweighs the risk. Patients are intermittently exposed over days, weeks or even years for imaging procedures and their exposure is minimal. Imaging personnel are occupationally exposed to low dose ionizing radiation primarily from scatter. The potential effects of this low dose ionizing radiation exposure over many years are what are meant by late effects. The two most important concerns that are considered late effects are carcinogenesis and genetic (hereditary) effects.

Much is known about the late effects of ionizing radiation from numerous historical studies that include Japanese atomic bomb survivors, uranium miners, radium dial painters, and the like. Specific work by H. J. Mueller on the genetic effects of radiation won the Nobel prize for the discovery of radiation mutagenesis. Even today radiologic technologists serve as an ongoing study on the harmful effects of low dose ionizing radiation late effects. The sum of these studies, observations, and statistical analysis has brought our profession to respect that there is no such thing as a safe dose of ionizing radiation. We must all do our part to protect our patients and ourselves from the harmful effects of radiation being that it follows a linear-Nonthreshold dose-response model for late radiation effects.

There are two terms that the radiographer must be familiar with in describing late effects: these are stochastic and nonstochastic effects. The term stochastic mean randomly occurring in nature. Radiation induced carcinogenesis and mutagenesis are stochastic effects. Stochastic effects are nonthreshold effects whose probability of occurrence increases with increasing dose; however, the severity of the disease is not increased with increased dose. Steven B. Dowd describes stochastic effects using an analogy of investing money in a lottery:

If this money (radiation dose) is invested in the lottery, there is only a small chance that any return will be seen. There is no threshold in that someone or some amount of people will receive a payoff (have a radiation effect). As the amount of money invested increases, the individual investing that money have a greater (though still remote)) chance of winning, and the overall cash pot (number of effects) increases⁵.

If we take this analogy literally, then we can understand that our profession with each new technology increases the chance of radiation effects (cancer and mutagenesis), and the number of these absolute effects increase. But because none of these effects are radiounique the complacency of our profession remains. But our profession does profess and remain a safe profession and safe practice of radiation dosing for diagnostic purpose. And we are not without blame and cause of carcinogenesis and mutagenesis upon society, likewise are we praised for our diligence in diagnosis and treatment of diseases that plague mankind. Leukemia is the best studied radiation induced cancer. We know that it has a latent period of between 4 and 7 years with an at risk period that spans over 20 years. Radiation safety was so poorly practiced in the United States between 1929 and 1943 that nearly 8 of 180 deaths in radiologist occurred because of leukemia. The period was infested with the misuse of ionizing radiation both in the medical community and the commercial community as well.

Deterministic (Nonstochastic) effects are those with a threshold and increase in severity with increase in dose. Nonmalignant skin diseases (erythema), radiation induced infertility, induced cataract, and blood disorders that are not cancer are all deterministic effects. By remaining below the threshold one is able to avoid these effects; however, the risk of stochastic effects remains superimposed upon deterministic effects.

Section 2.5: Radiation Effects on the Embryo/Fetus

Radiation effects on the germ tissues or on the fetus can cause both somatic effects and genetic (hereditary) effects on the parent and offspring. Data on the effects of ionizing radiation on the fetus and embryo is mostly obtained from experimental studies involving animal research and drosophila. There emerged a "classic triad" of radiation effects which are lethal effects, congenital malformation, and growth effects. Irradiation of the embryo during the first few days prior to implantation of the blastocyst on the uterine wall if sufficient enough to cause chromosomal or gene damage will spontaneously abort. If the embryo is still forming and is still a ball of undifferentiated cells (morula or blastocyst) it is extremely sensitive to irradiation or any other injury that prevents the normal development of the embryo. Nature has it that these will spontaneously abort and the female usually does not even know that she is pregnant. Therefore, this period of irradiation is still comprehensively safe. During the period of organogenesis which begins about the third through the sixth weeks of gestation in which the rudimentary organs are formed, irradiation can cause skeletal and CNS disorders in the progeny. During the time of fetal growth, fetal exposure could result in birth defects which manifest in congenital disorders. Ionizing radiation is one of the most potent teratogenic agents known. A teratogen is an agent that causes congenital birth defects. Notwithstanding, the effect is dependent on the stage of embryonic or fetal development, and to a lesser degree, the radiation dose.

• Prenatal death
• Mental retardation
• Microcephly
• Growth retardation
• Congenital defects
• Carcinogenesis (leukemia)
• Cleft palate
• Cataract

Suffice it to say that in order to see many of these effects the dose must exceed 10 rad, and even at 2 weeks would only raise the spontaneous abortion rate by 0.1%. The technologist should keep in mind however, that growth and developmental effects on the fetus are deterministic, whereas induction of carcinogenesis (leukemia) is stochastic. Stewart Bushong asserts that doses below 10 rad to the fetus should not be medically aborted, doses between 10-25 rad should be discussed, and doses above 25 rad to the fetus terminating the pregnancy should be seriously considered.

The work of H. J. Muller, who won the Nobel Prize for discovery of radiogenic mutagenesis concluded: most radiogenic mutations are recessive and cumulative having a single-hit phenomenon without a threshold, and there is no increase in the quality of the mutations seen. J.H. Muller's work with drosophila proved that ionizing radiation increases the occurrence of naturally occurring mutations. These mutations would occur with the frequency seen naturally to those exposed to background and cosmic radiations. Because the mutations were observed to be recessive this is an additional protection mechanism inherent to the DNA molecule. By being recessive in order for the trait to be passed on to a successive generation both parents must have the recessive gene. It is much like sickle cell disease in which the parents are carriers if they have one copy of the gene. Muller's work also identified that there is no threshold and that the effect is linear. Fractionation of the doses and summed doses led to the conclusion that late effects are cumulative and require a single-hit acting as a multitarget.

The amount of radiation that will produce twice the frequency of a genetic mutation in the population as its frequency without that dose is called the doubling dose. The genetically significant dose (GSD) is a mathematical average of the actual gonadal dose received by the population. It is assumed that any individual that receives the GSD will exhibit the same genetic mutagenesis as those individuals that actually received that dose.

• X-rays were discovered by Wilhelm Conrad Roentgen, on November 8, 1895.
• Latest documents from the ICRP and BEIR reports conclude the risk of radiation injury is 3-4 times higher than previously estimated.
• Ionization is the most fundamental mechanism of radiation injury, without ionization no injury to cells or DNA occurs.
• Ionization is a subatomic process in which an electron is either removed or gained by an atom.
• Linear energy transfer (LET) describes the rate at which energy is transferred from ionizing radiation to soft tissue.
• Diagnostic x-rays and gamma radiation imparts approximately 3.0 keV/μm travel in soft tissue. As the energy of the photon increases its LET further decreases, e.g. a 25-meV photon will impart 0.2 keV/μm.
• An alpha particle is the least penetrating of ionizing radiation. A 34 meV alpha particle would undergo 100,000 ionizations closely spaced before complete deionization.
• The quality factor or Q is a symbol for expressing the LET dependent response by a biological system. X-rays, gamma rays, and beta particles all have the same Q, which is equal to "1."
• The LET, RBE, and specific ionization of radiation directly affects the potential of a cell type for survival of ionization event.
• The mechanism of cell injury by high LET radiation is direct DNA hits, and for low LET radiation the mechanism is indirect through the formation of free radicals that injure DNA.
• Oxygen has an effect of enhancing free radical formation in cells. Only low LET radiation is affected by oxygen enhancement. High LET radiation exceeds the "Q" that causes cell death so oxygen enhancement has no greater effect than cell death.
• A theory that is gaining in scientific evidence is the radiation hormesis theory. It eludes that fractionated low dose radiation may in fact provide some protection by stimulating the body's defenses against ionization and free radical formation.
• Ionizing radiation administered by the medical radiology discipline as a whole follows a linear, nonthreshold dose-response curve.
• Christian de Duve received the Nobel prize in Physiology for the discovery of the peroxisome and its relationship to converting hydrogen peroxide from free radical injury in cells back to water.
• Cells replenish and repopulate in tissues by undergoing cell division. These cells are called stem cells that will regenerate a daughter cell that will become a differentiated cell.
• Somatic cells divide by a process called mitosis, and germ cells divide by a process called meiosis. Karyokinesis (division of the DNA) always precedes cytokinesis (division of the cytoplasm, and like cells begat like cells.
• The Cell stage is one of the determining factors of radiosensitivity, immature cells are more radiosensitive that differentiated mature cells. Chromosomal damage can be evaluated in cells that are in metaphase of mitosis.
• The target theory supports that the target cells are those that follow the law of Bergonie and Tribondeau; and the target molecule of cellular inactivation is DNA.
• The primary mechanism of indirect radiation damage to macromolecules including DNA begins with the radiolysis (splitting) of water.
• The net products of radiolysis of water are the formation of highly reactive free radicals. Free radicals are atoms with an unpaired electron in their valance shell.
• Along with hydrogen peroxide, hydrogen free radical (H˙), hydroxyl free radical (OH˙), and hydroperoxyl radical (HO₂˙) are produced.
• Indirect damage to DNA by ionizing radiation usually causes point mutations whereas direct damage to DNA by high LET radiation causes double strand breaks and frameshift mutations. Point mutations are substitution of a base nucleotide that results in a substitution in an amino acid of a newly formed protein.
• High LET radiations such as alpha particles are potent clastogen (agents that cause breakage of a chromosome).
• The most radiosensitive cells in the human are the lymphocytes and spermatagonia, the most radioresistant cells are nerve and muscle cells.
• A high whole body dose of radiation that manifest itself in hours, weeks or months following exposure are classified as early effect.
• Prodromal period is following a high dose exposure to ionizing radiation (greater than 100 rad) and is distinguished by nausea, vomiting, and diarrhea. A dose below 100 rad will lead to recovery with risk of late effects.
• There are three manifest syndromes of the acute radiation syndrome: hematologic syndrome (200-1000 rad), gastrointestinal syndrome (1000-5000 rad), and central nervous system syndrome (>5000 rad). At LD_50/60 50% of those exposed to whole body ionizing radiation will die within 60 days. Survivors will be at risk of late effects: carcinogenesis and hereditary mutations. LD_50/60 for humans estimated to be about 350 rad, and no survivors of a dose above 1000 rad.
• Late effects caused by ionizing radiation follow a linear, nonthreshold dose-response relationship.
• The two most important implications of ionizing radiation's late effects are: mutagenesis and carcinogenesis.
• Radiation induced carcinogenesis and mutagenesis are stochastic effects meaning they are nonthreshold with the probability of occurrence increasing with exposure dose.
• Radiation induced cataract, infertility, blood disorders, and nonmalignant skin diseases, etc., are all deterministic or nonstochastic effects meaning they exhibit a threshold.
• Ionizing radiation is one of the most potent teratogen known. A teratogen is any agent that causes birth (congenital) defects.
• Radiogenic mutagenesis is recessive.
• The safest period to irradiate the embryo is in the first 2 weeks because if damaged it will spontaneously abort. Thereafter, the 1^st trimester is the most unsafe period for irradiation.

References

1. Bushong, S.C., Radiologic Science for Technologist: Physics, Biology, and Protection, 7th ed., St. Louis, Missouri: Mosby, Inc. 2001.
2. Early, P.J., Principles and Practice of Nuclear Medicine, 2nd ed., St. Louis, Missouri, Mosby Co. 1995.
3. Seeram, E., Computed Tomography, Philadelphia, Pennsylvania, W.B. Saunders Co. **1994.
4. Selman, J., The Fundamentals of X-ray and Radium Physics, 6th ed. Springfield, Illinois, Thomas Books, 1980.
5. Dowd, Steven B. Practical Radiation Protection and Applied Radiobiology, W.B. Saunders Company, Philadelphia, PA., 1994.
6. Sprawls, P., Physical Principles of Medical Imaging, Rockville, Maryland, 1987, Aspen Publishers, Inc.
7. Dorland Illustrated Medical Dictionary, W.B. Saunders Company, Philadelphia, PA., 1994.
8. Gelehrter, Thomas d., Collins, Francis S., Principles of Medical Genetics, Williams &Wilkins, Baltimore, MD., 1990.

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2006 Nicholas Joseph Jr.