ionizing radiation

Ionizing radiation is a type of particle radiation in which an individual particle (for example, a photon, electron, or helium nucleus) carries enough energy to ionize an atom or molecule (that is, to completely remove an electron from its orbit). If the individual particles do not carry this amount of energy, it is essentially impossible for even a large flood of particles to cause ionization. These ionizations, if enough occur, can be very destructive to living tissue.

The composition of ionizing radiation can vary. Electromagnetic radiation can cause ionization if the energy per photon is high enough (that is, the wavelength is short enough).

Far ultraviolet, X-rays, and gamma rays are all ionizing radiation, while visible light, microwaves, and radio waves are non-ionizing radiation. Ionizing radiation may also consist of fast-moving particles such as electrons, positrons, or small atomic nuclei.

Effects

The dose of ionizing radiation is measured in several units:

 roentgen: unit of charge produced by x-rays or gamma rays that ionize a specific volume of air
 rad: the dose of radiation that will produce absorption of 100 ergs of energy per gram of tissue; 1 gm of tissue exposed to 1 roentgen of gamma rays is equal to 93 ergs
 gray (Gy): the dose of radiation that will produce absorption of 1 joule of energy per kilogram of tissue; 1 Gy corresponds to 100 rad
 rem: the dose of radiation that causes a biologic effect equivalent to 1 rad of x-rays or gamma rays
 sievert (Sv): the dose of radiation that causes a biologic effect equivalent to 1 Gy of x-rays or gamma rays; 1 Sv corresponds to 100 rem.

These measurements do not directly quantify energy transferred per unit of tissue and therefore do not predict the biologic effects of radiation. The following terms provide a better approximation of such information.

 Linear energy transfer (LET) expresses energy loss per unit of distance traveled as electron volts per micrometer. This value depends on the type of ionizing radiation. LET is high for alpha particles, less so for beta particles, and even less for gamma rays and x-rays. Thus, alpha and beta particles penetrate short distances and interact with many molecules within that short distance. Gamma rays and x-rays penetrate deeply but interact with relatively few molecules per unit distance. It should be evident that if equivalent amounts of energy entered the body in the form of alpha and gamma radiation, the alpha particles would induce heavy damage in a restricted area, whereas gamma rays would dissipate energy over a longer course and produce considerably less damage per unit of tissue.

 Relative biologic effectiveness (RBE) is simply a ratio that represents the relationship of the LETs of various forms of irradiation to cobalt gamma rays and megavolt x-rays, both of which have an RBE of unity (1).

In addition to the physical properties of the radioactive material and the dose, the biologic effects of ionizing radiation depend on several factors:

 Dose rate: a single dose can cause greater injury than divided or fractionated doses that allow time for cellular repair.
 Since DNA is the most important subcellular target of ionizing radiation, rapidly dividing cells are more radiosensitive than are quiescent cells. Hematopoietic cells, germ cells, gastrointestinal epithelium, squamous epithelium, endothelial cells, and lymphocytes are highly susceptible to radiation injury; bone, cartilage, muscle, and peripheral nerves are more resistant.
 A single dose of external radiation administered to the whole body is more lethal than regional doses with shielding. For example, the median lethal dose (LD50) of ionizing radiation is 2.5 to 4.0 Gy (250 to 400 rad), whereas doses of 40 to 70 Gy (4000 to 7000 rad) can be delivered in a fractionated manner during several weeks for cancer therapy.
 Cells in the G2 and mitotic phases of the cell cycle are most sensitive to ionizing radiation.
 Different cell types differ in the extent of their adaptive and reparative responses.
 Since ionizing radiation produces oxygen-derived radicals from the radiolytic cleavage of water (Chapter 1), cell injury induced by x-rays and gamma rays is enhanced by hyperbaric oxygen. Halogenated pyrimidines can also increase radiosensitivity to tumor cells. Conversely, free radical scavengers and antioxidants protect against radiation injury.

Pathology

 Radiant energy, whether in the form of the UV rays of sunlight or as ionizing electromagnetic and particulate radiation, can transform virtually all cell types in vitro and induce neoplasms in vivo in both humans and experimental animals.

 UV light is clearly implicated in the causation of skin cancers, and ionizing radiation exposure from medical or occupational exposure, nuclear plant accidents, and atomic bomb detonations have produced a variety of forms of malignant neoplasia.

 Although the contribution of radiation to the total human burden of cancer is probably small, the well-known latency of radiant energy and its cumulative effect require extremely long periods of observation and make it difficult to ascertain its full significance.

 An increased incidence of breast cancer has become apparent decades later among women exposed during childhood to the atomic bomb. The incidence peaked during 1988-1992 and then declined during the period 1993-1997.

 Moreover, radiation’s possible additive or synergistic effects with other potential carcinogenic influences add another dimension to the picture. The effects of UV light on DNA differ from those of ionizing radiation.

 Ionizing radiation can produce a variety of lesions in DNA, including DNA-protein cross-links, cross-linking of DNA strands, oxidation and degradation of bases, cleavage of sugar-phosphate bonds, and single-stranded or double-stranded DNA breaks.

 This damage may be produced directly by particulate radiation, x-rays, or gamma rays or indirectly by oxygen-derived free radicals or soluble products derived from peroxidized lipids.

 Even relatively low doses of ionizing radiation (less than 0.5 Gy) induce alterations in gene expression in some target cell populations. Free radicals generated directly or indirectly by exposure to ionizing radiation may produce oxidant stress that activates transcription factors (such as NF-κB) that increase gene expression.

 DNA damage itself stimulates the expression of several genes involved in DNA repair, cell-cycle arrest, and apoptosis. The tumor-suppressor gene p53 is activated after many different forms of DNA damage. The end-points result from activation of this p53-mediated DNA damage response. Activation of p53 induces cell-cycle arrest, DNA repair and, in some cases, apoptosis. Apoptosis of microvascular endothelial cells may be the primary target of acute radiation in the GI tract, resulting in secondary damage to intestinal crypt stem cells56 and the GI syndrome.

Cellular and tissular mechanisms of Radiation Injury

The acute effects of ionizing radiation range from overt necrosis at high doses (>10 Gy), killing of proliferating cells at intermediate doses (1 to 2 Gy), and no histopathologic effect at doses less than 0.5 Gy.

Subcellular damage does occur at these lower doses, primarily targeting DNA; however, most cells show adaptive and reparative responses to low doses of ionizing radiation. If cells undergo extensive DNA damage or if they are unable to repair this damage, they undergo apoptosis.

Surviving cells may show delayed effects of radiation injury: mutations, chromosome aberrations, and genetic instability. These genetically damaged cells may become malignant; tissues with rapidly proliferating cell populations are especially susceptible to the carcinogenic effects of ionizing radiation. Most cancers induced by ionizing radiation have occurred after doses greater than 0.5 Gy.

Acute cell death, especially of vascular endothelial cells, can cause delayed organ dysfunction several months or years after radiation exposure. In general, this delayed injury is caused by a combination of atrophy of parenchymal cells, ischemia due to vascular damage, and fibrosis.

 Acute Effects

Ionizing radiation can produce a variety of lesions in DNA, including DNA-protein cross-links, cross-linking of DNA strands, oxidation and degradation of bases, cleavage of sugar-phosphate bonds, and single-stranded or double-stranded DNA breaks. This damage may be produced directly by particulate radiation, x-rays, or gamma rays or indirectly by oxygen-derived free radicals or soluble products derived from peroxidized lipids.54 Even relatively low doses of ionizing radiation (less than 0.5 Gy) induce alterations in gene expression in some target cell populations. Free radicals generated directly or indirectly by exposure to ionizing radiation may produce oxidant stress that activates transcription factors (such as NF-κB) that increase gene expression.

DNA damage itself stimulates the expression of several genes involved in DNA repair, cell-cycle arrest, and apoptosis. As discussed in Chapter 7, the tumor-suppressor gene p53 is activated after many different forms of DNA damage. The end-points resulting from activation of this p53-mediated DNA damage response are discussed in Chapter 7. Briefly, activation of p53 induces cell-cycle arrest, DNA repair and, in some cases, apoptosis. Apoptosis of microvascular endothelial cells may be the primary target of acute radiation in the GI tract, resulting in secondary damage to intestinal crypt stem cells56 and the GI syndrome.

 Fibrosis

An important delayed complication of ionizing radiation, usually at doses used for cancer therapy, is replacement of normal parenchymal tissue by fibrosis, resulting in scarring and loss of function. These fibrotic changes may be secondary to ischemic injury caused by vascular damage, death of parenchymal cells, or deletion of stem cells.

The mechanisms responsible for fibrosis have been explored in a murine model of radiation-induced pulmonary fibrosis using microarray analysis of gene expression. Up-regulation of chemokines that recruit inflammatory cells to the lungs as well as cytokines and growth factors involved in fibroblast activation and collagen deposition are central components of radiation-induced fibrosis.

Chemokines, cytokines, and growth factors also play important roles in wound healing.

Carcinogenesis

Occupational or accidental exposures to ionizing radiation produce an increased incidence of various types of cancer, including skin cancers, leukemia, osteogenic sarcomas, and lung cancer. There is usually a latent period of 10 to 20 years before appearance of these cancers. In survivors of the atomic blasts at Hiroshima and Nagasaki, all types of leukemias were especially common, with the exception of chronic lymphocytic leukemia.

Exposure of children to irradiation causes an increased incidence of breast and thyroid cancers as well as gastrointestinal and urinary tract tumors. The nuclear power accident at Chernobyl in 1986 caused more than 50 deaths, with estimated exposures of 50 to 300 rad. More than 20,000 people were exposed to up to 40 rem.

As early as 1990, an increased incidence of thyroid cancer was seen in exposed children. Approximately 2 million people living near Three Mile Island were exposed to low doses of 100 mrem in 1979; no adverse effects have yet been reported. Workers in the nuclear energy industry and in health care and research are exposed annually to doses ranging from 1 to 9 mSv.

The annual maximal permissible exposure level for these workers is 50 mSv or 1 rem. There is uncertainty about the potential carcinogenic risk at these low exposures because the shape of the dose-response curve is unknown.

The mechanisms responsible for the delayed carcinogenic effects of ionizing radiation are not completely understood. The latent period between acute exposure to ionizing radiation and the delayed appearance of cancer may be due to a phenomenon called induced genetic instability.

Quantitative analysis of mutation rates in irradiated cells in culture shows that mutations continue to be expressed in surviving cells after several generations. Accumulation of these delayed mutations may be the result of persistent DNA lesions that are not repaired or due to an epigenetic mechanism, such as altered methylation at CpG sites or shortening of telomeres.

Delayed chromosome aberrations are also observed after exposure to ionizing radiation, especially in human lymphocytes.59 These mechanisms may be responsible for induction of secondary cancers, especially leukemias, in cancer patients treated with radiation therapy.

Clinical Manifestations of Exposure to Ionizing Radiation

The clinical effects of ionizing radiation depend on the dose, duration, and mode of exposure. These are described next.

 Acute, Whole-Body Exposure

Whole-body irradiation is potentially lethal; the clinical manifestations are dose dependent and described as the acute radiation syndrome or radiation sickness. On the basis of calculated doses delivered in nuclear reactor accidents or the atomic bombing of Japan, the LD50 at 60 days for humans exposed to a single dose of x-rays or gamma radiation is 2.5 to 4.0 Gy (250 to 400 rad).

Depending on the dose, four clinical syndromes are produced: a subclinical or prodromal syndrome, hematopoietic syndrome, gastrointestinal syndrome, or central nervous system syndrome.

The acute symptoms are manifestations of the high sensitivity of rapidly proliferating tissues, such as the lymphohematopoietic cells and gastrointestinal epithelium, to acute radiation-induced necrosis or apoptosis.

If the patient survives the acute radiation syndrome, sublethally injured cells may repair the radiation damage, and the necrotic or apoptotic cells may be replaced by the progeny of more radioresistant stem cells.

Effects of Radiation Therapy

External radiation is delivered to malignant neoplasms at fractionated doses up to 40 to 70 Gy (4000 to 7000 rad), with shielding of adjacent normal tissues. Radiation therapy, especially when it is delivered to the chest or abdomen, can cause acute radiation sickness and neutrophil and platelet depression.

These patients may experience transient fatigue, vomiting, and anorexia that may require reduction of the dose. Acutely, radiation therapy may shrink the tumor mass and relieve pain or compression of adjacent tissues. Unfortunately, cancer patients treated with radiation therapy may develop sterility, a secondary malignant neoplasm, or delayed radiation injury (described later).

Effects on Growth and Development

The developing fetus and young children are highly sensitive to growth and developmental abnormalities induced by ionizing radiation. Four susceptible phases can be defined:

 Preimplantation embryo. Before implantation, irradiation of the mother can be lethal to the embryo.
 Critical stages of organogenesis. From the time of implantation until 9 weeks of gestation, exposure of the mother even to diagnostic radiation can produce a wide range of congenital malformations. This is the period of maximal growth and differentiation in the developing fetus, when it is most susceptible to a wide range of teratogenic agents.
 Fetal period. From 9 weeks of gestation until birth, functional abnormalities of the central nervous system and reproductive system may be produced by maternal irradiation. The reproductive organs may be underdeveloped. Mental retardation affected offspring of Japanese mothers who were exposed to the atomic bomb in the first trimester of pregnancy. Newborns exposed to irradiation in utero have an increased incidence of childhood leukemia and brain tumors.
 Postnatal period. In infants and young children exposed to radiation, bone growth and maturation may be retarded. Development of the central nervous system, eyes, and teeth may also be perturbed. Although external radiation has been shown to shorten the life span of rodents, it is controversial whether ionizing radiation accelerates the process of aging in humans.

Induction of Mutations

Drosophila and laboratory mice show heritable mutations and chromosome abnormalities when exposed to ionizing radiation. Although chromosome aberrations have been demonstrated in the peripheral blood lymphocytes of atomic bomb survivors and radiation workers, there is no evidence so far that radiation-induced mutations have been transmitted to future generations.

Geneticists are concerned, however, that recessive mutations induced by radiation may be accumulating in the human population. In addition, there are no dose-response data for the frequency of mutations induced by ionizing radiation in human germ cells.

Actions on organs

 Blood vessels. After an initial inflammatory reaction that may be accompanied by death of endothelial cells, blood vessels in the field of irradiation show subintimal fibrosis, fibrosis of the muscle wall, degeneration of the internal elastic lamina, and severe narrowing of the lumen. Capillaries may become thrombosed and obliterated or ectatic. The organs supplied by these damaged vessels will show ischemic changes, atrophy, and fibrosis.

 Skin. Hair follicles and the epidermis are sensitive to acute radiation-induced injury. Desquamation can occur, resulting in replacement of the normal epidermis by atrophic epidermis characterized by hyperkeratosis, hyperpigmentation, and hypopigmentation. The subcutaneous vessels may be weakened and dilated; they are surrounded by dense bands of collagen in the dermis. Impaired healing, increased susceptibility to infection, and ulceration may occur. These changes are called radiation dermatitis. As described earlier, skin cancer, especially basal cell and squamous cell carcinomas, may occur as long as 20 years after exposure.

 Heart. Radiotherapy delivered to the chest for malignant lymphoma, lung cancer, or breast cancer may damage the heart and pericardium. Fibrosis of the pericardium can cause constrictive pericarditis (Fig. 9-14). Less commonly, radiation-induced injury of capillaries and the coronary arteries can cause myocardial ischemia and fibrosis.

 Lungs. The lungs are highly susceptible to radiation-induced injury, leading to acute lung injury and delayed radiation pneumonitis. Delayed injury causes dyspnea, chronic cough, and diminished lung function. This is caused by intra-alveolar and interstitial fibrosis. Both internal and external irradiation increase the incidence of lung cancer; this effect is synergistic with cigarette smoking. In addition to carcinogenic chemicals, cigarette smoke contains two radionuclides: lead 210 and polonium 210. Underground miners are exposed to radon 222, which increases their risk of developing lung cancer. Lung cancers that develop in underground miners have a characteristic mutation (G → T) at codon 249 of the p53 tumor-suppressor gene.

 Kidneys and urinary bladder. The kidneys are moderately susceptible to radiation-induced injury. Delayed peritubular fibrosis, vascular damage, and hyalinization of glomeruli develop gradually, leading to hypertension and atrophy. The urinary bladder is sensitive to radiation injury, with acute necrosis of the epithelium followed by submucosal fibrosis, contracture, bleeding, and ulceration. Tumors of the bladder and kidney have been reported in Japanese atomic bomb survivors and in women irradiated for treatment of cervical carcinoma.

 Gastrointestinal tract. Esophagitis, gastritis, enteritis, colitis, and proctitis can result from irradiation. These are associated with exfoliation of the epithelial mucosa, susceptibility to infection, and loss of electrolytes and fluid. Delayed injury to small blood vessels causes chronic ischemia, ulceration and atrophy of the mucosa, and fibrosis that can cause strictures and obstruction.

 Breast. Diagnostic doses of ionizing radiation administered during adolescence increase the incidence of breast cancer after 15 to 20 years. Radiotherapy for breast cancer causes a dense, fibrotic reaction with extreme pleomorphism of epithelial cells.

 Ovary and testis. The spermatogonia are extremely sensitive to irradiation; even low doses may cause suppression of meiosis and infertility. Blood vessels may be obliterated and the seminiferous tubules become fibrotic, leaving the Sertoli cells and interstitial Leydig cells intact. Ovarian follicles degenerate acutely after irradiation; usually a few primordial oocytes and their follicular epithelium remain scattered in a fibrous stroma.

 Eyes and central nervous system. The lens is sensitive to ionizing radiation, and hence radiation gives rise to cataracts; the retinal and ciliary arteries may also be damaged. The brain may show focal necrosis and demyelination of the white matter. Irradiation of the spinal cord can damage small blood vessels, leading to necrosis, demyelination, and paraplegia. This is called transverse myelitis.

Delayed Radiation Injury

Months or years after irradiation, delayed complications, other than carcinogenesis, may occur. Radiation damage to the heart, lungs, central nervous system, or kidneys can be life threatening. Infertility can occur in men or women. Cataracts can impair vision, and excess connective tissue can cause intestinal obstruction. Fibrous strictures and chronic ulcers may affect the skin, gastrointestinal tract, urinary bladder, and vagina. Chronic vascular insufficiency and excess connective tissue also complicate subsequent surgical procedures. Wound healing is impaired, and infections are more common. Unfortunately, cancer patients who have received fractionated doses of radiation may also suffer from these delayed complications.

See also

 mutagens