Example of a disease caused by physical agents

Exposure of Humans to Ionizing Radiation

Ionizing radiation includes that part of the electromagnetic wave spectrum comprising x-rays and gamma rays (Figure 11-8) and certain types of particulate radiation (alpha and beta particles, neutrons, protons, and deuterons [Table 11-2]). All of these different types of radiation, which are derived from different sources, have in common the ability to produce ionization within tissues exposed to them. Natural radiation is derived from radioactive elements in the environment and cosmic rays. In addition, radioactive substances have been used in nuclear medicine, nuclear power plants, nuclear weapons, and nuclear propulsion. Modern nuclear bombs are immensely more destructive than the original atomic bombs, releasing energy in the form of blast or shock waves, heat, and ionizing radiation, both immediate and delayed (fallout).

Figure 11–8.

The electromagnetic wave spectrum. The shaded area between the infrared and ultraviolet regions is the visible spectrum. Longer x-rays penetrate poorly (so-called soft x-rays); shorter, higher-energy x-rays penetrate readily. Gamma rays resemble x-rays but are derived from natural sources (radioisotope decay); x-rays are artificially generated.

Table 11–2. Ionizing Radiation.

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Table 11–2. Ionizing Radiation.

Ionizing radiation is used in medicine for diagnostic and therapeutic purposes. Radiology is a branch of medicine that uses x-rays to visualize internal structures of the body and provide valuable diagnostic information. Nuclear medicine uses various radioisotopes for diagnosis—eg, administration of radioactive iodine enables the physician to detect uptake of iodine in tissues, mainly in the thyroid gland; and abnormal patterns of uptake provide information about possible disease of the thyroid gland. Such diagnostic tests use very small doses of radiation that are generally not harmful. Higher doses of radiation are used in the treatment of cancer (radiotherapy) because many types of cancer cells are more susceptible to radiation than are normal tissues. Such radiation treatment often includes use of x-rays in high doses directed at the tumor and isotopes that emit alpha and beta particles implanted directly in the tumor. Treatment may damage normal tissues included in the field of radiation.

The unit used to measure the radiation absorbed by tissues is the gray (Gy)—formerly the rad; 1 Gy = 100 cGy = 100 rads. (See Table 11-3.) The overall effect of radiation is determined not only by the dose but also by the amount of tissue exposed to that dose—eg, the effect of 1000 cGy to the whole body is different from that of 1000 cGy limited to the axillary lymph nodes.

Table 11–3. Radiation Terminology.

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Table 11–3. Radiation Terminology.

Mechanism of Radiation Injury

Ionizing radiation—by definition—has enough energy to displace electrons from the outer shell of atoms to produce ions (ionization). These charged particles react with one another to form free radicals (atoms or molecules that are highly reactive because they carry unpaired electrons in their outer shells). Free radicals interact with adjacent molecules to produce alterations of these molecules and subsequent cell injury (see also Chapter 1: Cell Degeneration & Necrosis).

Two principal mechanisms of cell damage caused by radiation are recognized (Figure 11-9):

Figure 11–9.

Effects of radiation on cells.

Direct Action

High-energy radiation directly alters or inactivates vital molecules in the cell, eg, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins.

Indirect Action

Radiation causes ionization of intracellular water, producing high-energy particles, eg, H2O+ and H2O−. These immediately dissociate and interact to form toxic free radicals such as H•, OH•, and H2O•, which are highly unstable particles that rapidly dissipate their energy by reacting with other molecules such as DNA, RNA, and proteins to cause cell injury. The intermediate interactions between radiation and water occur in a few microseconds.

Effects of Radiation Injury

DNA represents the main target of action of radiation. After high doses of radiation, extensive DNA injury leads to cellular necrosis. With smaller doses, less severe abnormalities result that cause varying structural and functional abnormalities of DNA—eg, the cell's ability to undergo normal mitosis may be affected. These DNA changes are permanent and may be associated with the later development of cancer in radiated cells; leukemia (cancer of white blood cells) developed in many Hiroshima survivors several years after the dropping of the atomic bomb (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia).

The effects of radiation on cells appear to be cumulative. For this reason, the maximum dose that a single target site can receive is limited if multiple doses of radiation are anticipated—even if there is a significant interval between treatments.

The severity of tissue damage produced by radiation depends on several factors.

Dose

Large doses of radiation cause more damage than small ones.

Penetration

The depth of penetration of tissue varies with the different types of radiation. Alpha particles have a limited ability to penetrate tissues, and their energy is dissipated in a small area surrounding the point of entry. The smaller beta particles (electrons) penetrate more deeply, and their energy dissipates over a larger area. X-rays and gamma rays penetrate deeply, often passing through the body with little dissipation of energy. These types of radiation are well suited to diagnostic tests because they can be detected externally (with x-ray film or gamma counters).

Sensitivity of Tissues

Different tissues are affected to varying degrees by radiation (Table 11-4).

Table 11–4. Radiosensitivity of Cells. 1

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Table 11–4. Radiosensitivity of Cells. 1

Duration of Exposure

Effects differ with the duration of exposure.

Total Body Irradiation

Causes

Total body irradiation occurs as a result of nuclear fallout from explosion of a nuclear weapon or following a nuclear accident.

Effects

The effect of total body irradiation is dose-dependent (Table 11-5). A dose of radiation greater than 1000 cGy to the whole body is invariably fatal, and one in excess of 200 cGy will cause death in a significant number of exposed individuals. These doses are not large when one considers that doses of 5000–7000 cGy are often delivered to a localized area of the body in the treatment of cancer. In a nuclear explosion, the dose received by an individual depends on the size of the explosion, the type of radiation emitted, and the distance from the source. Several well-defined syndromes are recognized with varying dosage levels.

Table 11–5. Effect of Total Body Irradiation.

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Table 11–5. Effect of Total Body Irradiation.

Vaporization

Vaporization of all body tissues occurs if the victim is in the immediate vicinity of a nuclear explosion.

Cerebral Syndrome

The cerebral syndrome appears after radiation doses in excess of 1000 cGy. It is invariably fatal, either instantaneously or within a few days. In the latter event, the brain shows diffuse hemorrhagic necrosis (Figure 11-10).

Figure 11–10.

Brain of mouse that received a high dose of radiation to the whole body. Shows extensive hemorrhagic necrosis.

Gastrointestinal Syndrome

The gastrointestinal syndrome occurs with radiation doses in the range of 300–1000 cGy. It is characterized by extensive necrosis of the intestinal mucosa, leading to nausea, vomiting, and diarrhea that begin a few hours after exposure. With doses above 500 cGy, diarrhea is severe, and death commonly occurs within a few days from fluid and electrolyte loss. With doses in the range of 300–500 cGy, symptoms are less severe but may persist for a long time. Patients who survive recover slowly, and return of the intestine to normal may take over 6 months. Patients who recover from a nonlethal gastrointestinal syndrome commonly succumb to the hematopoietic syndrome.

Hematopoietic Syndrome

Hematopoietic syndrome occurs after radiation doses of 200–600 cGy and is commonly associated with the gastrointestinal syndrome. The first change is a decrease in peripheral blood lymphocytes (lymphopenia), which occurs as early as 24 hours after exposure and is also associated with depletion of lymphocytes in the lymph nodes and spleen. Bone marrow hypoplasia follows (Figure 11-11), leading to decreased production of granulocytes, erythrocytes, and platelets. Death occurs in 20–50% of patients; infection is a major cause of death.

Figure 11–11.

Effect of radiation on bone marrow, showing marked depletion of hematopoietic cells. Low magnification.

Acute Radiation Syndrome (Systemic Radiation Sickness)

Radiation sickness occurs after radiation doses of 50–200 cGy. It is nonlethal and characterized by varying periods of fatigue, vomiting, and anorexia. A transient reduction in peripheral blood lymphocytes and granulocytes is common (mild hematopoietic syndrome). Variations of systemic radiation sickness may also occur in patients receiving much higher doses (> 2000 cGy) to localized areas as part of cancer therapy.

Long-Term Effects

Survivors of radiation exposure—even those who have been exposed to low levels—may demonstrate effects years later. Detailed study of survivors of Hiroshima and Nagasaki has shown an increased incidence of cancer (particularly leukemia), cataracts, infertility, and bone marrow aplasia. These changes appeared long after exposure, and even the offspring of exposed individuals appear to be at increased risk for development of abnormalities.

The lower limits of safe exposure to radiation are unknown, although various federal and international standards have established so-called safe dose limits for individuals and populations. The only absolutely safe dose of radiation is zero, but this cannot be achieved because of background radiation from natural sources (decay of naturally occurring radioisotopes, cosmic rays, etc). To place the risk of radiation exposure in perspective, a routine diagnostic x-ray delivers a smaller dose than is received from natural sources in a year or even from a single transatlantic flight at 30,000 feet.

Localized Irradiation

Localized irradiation to a limited area of the body is used in the treatment of cancer. The rationale behind such treatment is that cancer cells (which are rapidly proliferating) are more sensitive to radiation than are the normal (nonproliferating or slowly proliferating) cells surrounding them. In addition, normal tissues may recover more rapidly, so that repeated treatments result in greater destruction of tumor tissue. The radiation can also be focused on the cancer by a variety of different techniques so that the surrounding normal tissue will receive a minimal amount of radiation.

Sensitivity of Tissues

Cancer Cells (Malignant Neoplasms)

Cancers may be classified on the basis of their response to radiation into radiocurable, radiosensitive, and radioresistant neoplasms. Predictions about tumor response to radiation must take several factors into account: (1) Experience with radiation therapy as a form of treatment for that particular type of cancer, as reported in the literature; (2) Type of tissue (Table 11-4); (3) Rate of proliferation of cancer cells. Cancers of cells that have a high rate of division, eg, acute leukemias (cancers of blood cells) and germinomas (cancers of gonadal germ cells), are generally more radiosensitive. Cancers arising from cells that have a low turnover rate, eg, sarcomas (cancers of mesenchymal cells) and liver cell cancer, are more radioresistant.

Normal Tissues

The amount of radiation that may be given to a tumor is limited mainly by its toxic effect on normal tissue; eg, the local radiation dose to brain tumors cannot exceed 6000 cGy because necrosis of surrounding normal brain occurs with higher doses. Tissues composed of labile cells with a high turnover rate, eg, hematopoietic cells, intestinal mucosal cells, and testicular germ cells, are highly sensitive to the effects of radiation. Stable cells of solid organs such as the liver and kidney are less sensitive. Permanent cells such as muscle and nerve are radioresistant (Table 11-4).

Radiation Damage of Normal Tissues

Tissues exposed to radiation show damage to collagen that results in dense hyalinization. Blood vessel changes vary from the development of abnormal telangiectatic vessels to thickening and hyalinization of the walls. Fibroblasts and endothelial cells are enlarged and demonstrate nuclear abnormalities, including hyperchromatism and abnormal chromatin clumping. Karyotypic analysis shows aneuploidy and polyploidy with various chromosomal abnormalities. In addition to these general changes, specific changes occur in various organs.

Skin

In the first 2–6 weeks after radiation exposure, erythema, swelling, and epidermal desquamation (acute radiodermatitis) are seen. Later, chronic radiodermatitis occurs, characterized by epidermal atrophy with atypical cytologic features in the cells, dermal fibrosis, and the development of telan giectasias and hyalinized vessels. The skin becomes blotchy and atrophic, has an irregular surface, and, in severe cases, is ulcerated (Figure 11-12). Loss of pigmentation and hair also occurs. Chronic radiodermatitis persists for years. Cancer of the squamous epithelium may occur many years after exposure.

Figure 11–12.

Radiation dermatitis. Note discoloration and epidermal irregularity. Patient received radiation to the neck as treatment for cancer.

Bone and Bone Marrow

Marked hypoplasia of bone marrow may occur within hours after radiation exposure (Table 11-5 and Figure 11-11). The degree of hypoplasia depends on the dose of radiation received. If a significant percentage of active marrow has been irradiated, a decrease in blood granulocyte levels may occur at about the end of the first week, and anemia may develop after 2–3 weeks. Regeneration of bone marrow is rapid if stem cells survive elsewhere in the marrow. Total marrow irradiation is sometimes used in the treatment of leukemia and lymphoma. After radiation has caused necrosis of the entire bone marrow (normal and leukemic cells), it is repopulated by transplanted bone marrow (Figure 11-13). Although it is relatively radioresistant, bone itself may show periosteal loss and necrosis at higher doses (radio-osteonecrosis). Irradiation of epiphyses in children halts bone growth.

Figure 11–13.

Treatment of leukemia, using irradiation of total body bone marrow to destroy both cancerous and normal stem cells. Transplantation of donor or autologous bone marrow provides a new stem cell population for regeneration of normal marrow.

Lymphoid Tissues

Lymphoid tissues are extremely radiosensitive. Irradiation of large lymph nodes may cause a transient decline in the peripheral blood lymphocyte count and increased susceptibility to infection.

Lung

The lung is quite radioresistant, and changes appear only after high doses. However, when a large area of lung is affected, radiation pneumonitis can be fatal. In the acute phase, which occurs in the first few weeks, endothelial swelling and increased permeability of alveolar capillaries lead to pulmonary edema and formation of hyaline membranes (proteinaceous exudate; see adult respiratory distress syndrome, Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases). Chronic changes include interstitial fibrosis, which causes failure of diffusion that may lead to incapacitating dyspnea and even death.

Intestine

The mucosa of the intestine is radiosensitive and shows changes during abdominal and pelvic irradiation. In the acute phase, hyperemia and ulceration are seen; later, chronic mucosal atrophy may lead to malabsorption. In the colon, radiation colitis causes diarrhea with blood and mucus. When the rectum is involved, severe pain may occur. Mucosal telangiectasia, atypical epithelial cells, atrophy, and fibrosis are the usual histologic findings.

Long-Term Effects

Two important long-term effects of radiation exposure are difficult to predict with accuracy.

Carcinogenic Effect

The carcinogenic effect of radiation exposure is an important and well-known risk factor (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia). The later development of radiation-induced neoplasms in patients who have been successfully treated for cancer is an increasingly common problem.

Genetic Effect

Exposure to radiation causes an increased number of genetic abnormalities (mutations) that may be passed to subsequent generations (Chapter 15: Disorders of Development).

Methods to Minimize Injury of Normal Tissues

Shielding

Lead shields permit radiation to enter the body only through predetermined ports, or windows; eg, the lungs are shielded when the mediastinum is being irradiated.

Radioisotope Implants

Implants containing radioactive isotopes are inserted into neoplasms for local release of radiation; if alpha-particle radiation is used, a high dose is delivered locally to the tumor with little penetration into normal tissue.

Selective Uptake

Use of a radioactive isotope of a substance that is selectively taken up by cancer cells permits more selective radiation of the cancer cells, eg, the administration of radioactive iodine in the treatment of well-differentiated thyroid carcinoma. The thyroid cancer cells take up the iodine like normal thyroid cells.

Monoclonal Antibodies

A promising approach uses monoclonal antibodies targeted against specific tumor-associated antigens to carry small amounts of radioactive isotopes to the tumor site.

Fractionated Doses

The total radiation dose is divided into multiple graded doses that are administered over time to permit normal cells to recover in the interval between doses.

Ultraviolet Radiation

Ultraviolet rays are present in sunlight. They have very low penetrating capability and are rapidly absorbed by many types of clothing, some sunscreens,* and melanin. Dark-skinned individuals are protected almost completely by melanin skin pigment. Light-skinned individuals who are exposed to bright sunlight for long periods are at risk for radiation-induced injury. Farmers, other outdoor workers, and sunbathers in Australia and parts of the southwestern United States are among those at greatest risk.

*Recent evidence suggests that both ultraviolet A (UVA) and ultraviolet B (UVB) components must be blocked for full protection by sunscreens.

Ultraviolet radiation penetrates the superficial layer of the skin, causing damage to the epidermis and dermis. It causes direct cell injury. Acute overexposure to ultraviolet light causes thermal damage and inflammation of the skin. This is characterized by erythema and severe pain (sunburn). More chronic exposure leads to changes in the DNA of epidermal cells, characterized by abnormal dimeric linkage of pyrimidine bases. These changes predispose to various types of cancer of the skin, particularly basal cell carcinoma, squamous carcinoma, and malignant melanoma.

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