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Injuries from Ionizing Radiation
Injuries from Ionizing Radiation CHARLES G. FOSTER, M.D.*
MOST physicians are acquainted with the clinical uses and effects of ionizing radiation in the form of x-rays in the practice of medicine. However, not until the bombing of Hiroshima and Nagasaki did mass casualties occur as a result of excessive exposure to ionizing radiations. For the first time physicians encountered casualties not only from blast and heat, as with conventional bombs, but also from acute whole-body exposure to ionizing radiation. Although it is estimated that only 10 to 20 per cent of the deaths in Hiroshima and Nagasaki were due to irradiation, it is undoubtedly true that many more people would have died from the effects of radiation had they survived the injuries from blast and burns.
IONIZING RADIATION
All ionizing radiations are similar in that they dissipate energy in cells and tissues by a process known as ionization. Ionzation, as used here, refers to the dislodgment of an electron from an atom or molecule, resulting in the formation of two ions. One ion is the negatively charged electron; the other is the positively charged residual atom or molecule. It is felt that the vast majority of biological effects from ionizing radiation is due to tissue ionization. Although all ionizing radiation produces the same tissue reaction, the efficiency with which the tissue reaction is produced, or biological effectiveness, varies with the nature of the radiation. Symptomatology and objective findings vary with the quantity of tissue damaged and its site. Only four types of ionizing radiation will be discussed, namely, alpha and beta particles, gamma rays and neutrons. Alpha Radiation. Alpha particles are helium nuclei and consist of two protons and two neutrons. They lack orbital electrons. Because of their relatively heavy mass and double positive charge, alpha particles cause dense ionization, but, because of their size, have only limited ability to penetrate. Consequently their range in tissue is only in terms of microns and in air can be stopped by paper or cloth. Generally speaking, they are
* Internist, Snyder Clinic, Winfield, Kansas. 1415
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important as an external radiation hazard only under exceptional circumstances. If alpha-emitting substances gain entrance into the body and are not rapidly excreted, considerable harm may result. Beta Radiation. Beta particles are electrons. They are more penetrating but less ionizing than alpha particles. Beta particles can cause serious skin damage and are also an important internal radiation hazard. Gamma Radiation. Gamma rays are ionizing electromagnetic radiations. They are similar to x-rays, but usually have shorter wavelengths and greater frequencies. Gamma rays are very penetrating and their range great, although their ionizing power is low. They are extremely important as a cause of radiation injury and illness. Neutron Radiation. Neutrons have no charge, but have a mass about that of a proton or hydrogen nucleus and have considerable kinetic energy. They penetrate readily and have a moderate range. Because of their great energy and penetrability, neutrons are of considerable importance as a radiation hazard. In addition, they may also induce radioactivity. Effects
The effects of radiation on living cells and tissues depend not only on the total amount absorbed, but also on the rate of absorption, whether it is chronic or acute, and on the area of the body exposed. Genetic effects are apparently independent of the rate of delivery of the radiation and depend only on the total dose. In general, the biological effect of a given dose of radiation decreases as the rate of dose decreases. For example, 600 roentgens' total body irradiation in one day would almost certainly be a lethal dose, whereas the same amount would probably have no harmful effect if fractionated over a period of many years. A reasonable explanation of this fact is that if the amount of radiation absorbed per day is small enough, the damaged tissues have a chance to recover. If the rate of delivery is increased, recovery cannot compensate for the damage. Apparently it is this ability of tissue to recover which makes it possible for humans to accept limited whole-body doses of irradiation (0.3 roentgen per week) for long periods of time without seemingly harmful consequences. For many years it has been known that excessive exposure to radiation from any source capable of producing ionization in living tissues can cause injury. After the discovery of x-rays and radioactivity serious and sometimes fatal exposures were sustained by personnel before the dangers were fully realized. Slowly, means for providing protection were devised, and serious overexposure has become uncommon. However, occasional ,mishaps of a serious nature still occur to persons operating radiographic equipment, x-ray machines in industrial laboratories, cyclotrons and other equipment, or working with radioactive materials. Generally, the
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overexposures were limited to localized areas of the body, and the effects were termed radiation injuries. When, in some instances, large parts of the body were accidentally exposed to an overdose of radiation, a systemic rather than a localized effect was noted. This systemic reaction is called radiation sickness. Although a rare occurrence prior to the atomic bombing of Hiroshima and Nagasaki, it was observed in various degrees of severity among large numbers after the atomic attacks. Units
There are several units of ionizing radiation in common usage. These are the roentgen (r), roentgen-equivalent physical (rep), roentgenequivalent man (rem) and the gram-roentgen. A roentgen of x-rays or gamma rays is that amount which will produce 2.08 times 10 9 ion pairs in a cubic centimeter of air under standard conditions of temperature and pressure. It is important to understand that the term "roentgen" does not refer to the rate of radiation or the amount of tissue irradiated. A roentgen-equivalent physical is that amount of energy dissipated in 1 gram of wet tissue by 1 roentgen of hard x-rays or gamma rays and is equivalent to 93 ergs. This unit is used to calculate tissue dose from beta particles, neutrons and so on. Since the biological effectiveness of ionization varies with the type of radiation, the term "roentgen-equivalent man" was introduced so that doses of radiation from different sources could be compared. Thus a roentgen-equivalent man of any type of radiation is that amount which is equivalent in its biological action to 1 roentgen of hard x-rays. Since the roentgen, roentgen-equivalent physical and roentgen-equivalent man do not take into consideration the amount of tissue radiated, the term "gram-roentgen" was formulated. A gramroentgen is the energy lost in 1 gram of air by 1 roentgen-equivalent physical of ionizing radiation, or 83.8 ergs. This unit is sometimes used to integrate the total energy dissipated in a mass or volume of tissue. Thus the same integral dose is delivered whether 100 grams of tissue are irradiated with 1 roentgen or 1 gram of tissue is irradiated with 100 roentgens. When using radioisotopes (other than radium, which is measured in terms of milligrams and grams), one uses the terms "microcurie," "millicurie" and "curie" as activity units. A curie is that amount of radioactive material which produces 3.7 times 1010 disintegrations per second. A millicurie and microcurie produce 3.7 times 10 7 and 3.7 times 104 disintegrations per second respectively. Cellular Effects
When a sufficient number of molecules is disrupted by ionization, changes in function, including death of the cell, occur. The cellular effects of ionization are not uniform, since there is considerable variation in the susceptibility of different cells. In addition, the lethal nuclear effects are
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greatest during cellular reproduction. Hence the cells which most frequently divide in the body are also those which are most sensitive to radiation. The cells of the blood-forming organs and gonads, for example, are more sensitive to radiation than the cells of skin. In man, sensitivity to radiation of the various tissues decreases in the following order: lymphoid tissue, bone marrow, reproductive organs, salivary glands, skin, mucous membranes, endothelial cells of blood vessels and peritoneum, connective tissue, bone, liver, pancreas, kidney, nerve tissue and muscle. The histopathological effects of radiation as quoted from Warren and Bowers! include changes in the cells, stroma and blood vessels. The cellular effects include cessation of mitosis followed by disorganization of cellular structure and swelling. As the cell resumes mitosis, bizarre mitotic figures appear. The stromal effects are first manifested as swelling which is followed by fibrosis and hyalinization. The initial vascular effects are thrombosis, which may be followed by fibrosis, hyalinization and telangiectasia. The nature of the constitutional effects as seen in the acute radiation syndrome is not known. It is probable that such phenomena as inhibition of enzyme production, alterations in cell membrane permeability, protein denaturation, production and absorption of toxins all play a part. RADIATION INJURY
Since the production and manner of radiation injury from ionizing radiation used in clinical medicine are well known, consideration of the sources and nature of radiation injuries following an atomic explosion will now be made. Atomic weapons represent two types of nuclear energy release-nuclear fission, as used in the uranium and plutonium bombs, and nuclear fusion, as used in the hydrogen or thermonuclear bombs. There is no important difference between the two types as to the cause and effect of radiation injury. The major difference lies in the range of effectiveness. Although the blast and fire effects of a hydrogen bomb would be many times that of the fission type, the radiation hazard would not be increased to the same extent. Persons close enough to the center of the explosion to receive a lethal dose of radiation would be killed by heat or blast. After an atomic explosion four kinds of radiation are emitted, namely, alpha and beta particles, gamma rays and neutrons. The alpha radiation emitted at the center of an explosion is absorbed nearby because of the low penetrating power; the same is true of the beta radiation, and hence neither is a direct radiation hazard. Gamma rays are a major radiation hazard, and in Japan fatalities occurred from gamma radiation as far as one mile from the explosion center. Although the hazard to life from neutrons is considerable at a half-mile from the explosion center, at this distance exposed persons would receive a lethal dose of gamma radiation.
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It is likely, however, that neutrons may have a deleterious biological effect at much greater distances than a half-mile, since opacities of the lens caused by neutrons have been found at 1700 meters.2 AtOlnic Bom.b Injuries
In general, there are four ways in which radiation injuries may be caused by an atomic explosion. First, direct exposure may be sustained from the instantaneous burst of nuclear radiation. The only hazard from this type of exposure is from gamma rays and neutrons. Secondly, exposure to radiation may occur as a result of "fall-out." Fall-out is not a hazard following a high air burst, but may be so after a low air or ground burst. In contrast to the short duration of danger from the initial radiation, radioactivity resulting from fall-out after a low air burst or ground burst may persist for long periods of time. A third method by which radiation injuries may be produced is the base-surge which follows an underwater explosion. The droplets of water contain radioactive materials which may be transported many miles from the explosion site and fall out as radioactive rain. Induced radioactivity by neutrons comprises the fourth method of radiation injury. Just as artificial radioactivity is produced by neutron bombardment of atoms in a nuclear reactor, the neutrons from an atomic explosion may produce artificial radioactivity in food, water, human or animal tissues, reinforced concrete buildings and so forth. In addition to the initial radiation from an atomic explosion, there is also radiation from fission products, plutonium and uranium. A radiological hazard due to radiation from these sources would occur under special circumstances only. In case there is a high or moderately high air burst, the danger would be practically nil. However, an underground burst or an underwater burst accompanied by a base-surge would lead to a significant contamination wherein residual radiation would be important. External radiation would be mainly from gamma rays and beta particles. Internal radiation would occur if radioactive materials gained entrance into the body by ingestion, inhalation or through breaks in the skin. Although the amounts of fission products that need to be fixed within the body to produce injurious effects are minute, it is felt that in general, if a dosage due to external radiation is down to a safe level, there is little or no danger of enough radioactive material being fixed in the system for it to constitute an internal hazard. 3 Acute Radiation Syndrom.e
After an acute, whole-body overexposure to ionizing radiation there occurs a group of signs and symptoms known as the acute radiation syndrome. The symptoms and their severity, together with their time of appearance, are in direct proportion to the dosage absorbed and indi-
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vidual susceptibility. Although commonly seen after an atom bomb explosion, this syndrome has not occurred in man from the administration of radioactive materials. Symptoms and Signs. In the premonitory phase of the acute radiation syndrome, weakness, nausea and vomiting are prominent. Diarrhea then occurs and, together with the nausea and vomiting, may temporarily subside. However, all recur with increased severity, at which time the diarrhea may be bloody. Although petechiae and purpura are found during the first week after exposure and may be accompanied by hemorrhage from various parts of the body, the hemorrhagic manifestations are most prominent between the sixteenth and twenty-second days. Epilation, predominantly of the scalp and without regard to sex, occurs by the end of the second week along with infected, ulcerative lesions of the mucous membranes. Fever is a constant finding and rises in a steplike manner until death, although an interval of several days may supervene between exposure and onset of fever. The pulse rate is often increased out of proportion to visible evidences of injury. Clinically, Warren and Bowers! divide the acute radiation syndrome into several forms according to the degree of exposure. The fulminating form is characterized by the onset of nausea, vomiting, prostration and mild diarrhea within 2 to 6 hours after exposure. These manifestations gradually increase in severity and are associated with pronounced fall in the white blood count. The diarrhea becomes severe and grossly bloody stools may appear. There is a step-like rise in fever and death occurs from the fifth to the tenth day. This course is observed in individuals who have received greater than lethal doses. The hemorrhagic form presents initially nausea, vomiting, prostration and, at times, mild diarrhea of about two days duration. A well period of about five days then ensues followed by prostration, bloody diarrhea and increasing fever. Petechiae and purpura appear and are associated with frank bleeding from body orifices. Ulcerative lesions of mucosal surfaces become increasingly extensive and death may occur from three to six weeks after exposure. Patients in this group have received irradiation doses in the lethal or near lethal range. A number of the patients in the hemorrhagic group will survive but exhibit continued weakness, pallor and ulcerative lesions characteristic of the pancytopenic form of the syndrome. Death may finally ensue after a prolonged period of illness during which cachexia may be pronounced.
The hematologic changes following whole body irradiation have been extensively studied. A decrease in the number of circulating lymphocytes is found after as small a dose as 15 roentgens. With doses about 75 to 100 roentgens an increase in the total white blood cell count is sometimes observed initially. By the end of 24 hours, however, the total white cell count is decreased and continues to decrease or remain reduced for five to six days. Leukocyte counts below 2000 per cubic millimeter are indicative of severe injury, and recovery is rare in patients having white blood
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cell counts below 600 per cubic millimeter.5 By the end of the first week the white cell count begins to rise in patients who are recovering and by two to four weeks is normal. Platelet reduction followed by anemia occurs later than lymphopenia and leukopenia. Reticulocytes are uniformly decreased or absent. Those patients surviving six weeks may have red cell counts as low as 800,000 to 900,000 per cubic millimeter of blood. Platelet increases are observed by the end of the second week and are usually normal in three to four weeks if recovery is occurring. Complications. It is well established that acute and/or chronic exposure to ionizing radiation can cause sequelae in both man and animals. Among these are bone, skin and bladder neoplasms, leukemia, cataracts, burns and probably genetic changes. Almost always there is a latent period of several years between the time of exposure and the onset of sequelae. Since Roentgen's discovery of the x-ray in 1895 and Becquerel's discovery of natural radioactivity in 1896, many skin injuries were sustained by persons utilizing these sources of ionizing radiation for investigative and diagnostic purposes. Since nothing was known about the skin effects from these new and interesting tools, no precautionary measures were taken to provide shielding. According to Behrens,6 no heed was given to erythema of the hands and face, and fluoroscopic apparatus was tested by placing a hand in front of the screen to see whether the tube was functioning. For purposes of reassurance and demonstration to patients, workers often exposed themselves to x-rays. Mild skin injuries such as brittleness and ridging of the nails, increased susceptibility to chapping, blunting of the fingernail ridges, dryness and epilation are followed by inflammation, edema, atrophy, loss of fingernails, keratosis, warts, telangiectases, ulceration and cancer if exposure is continued. The high incidence of lung cancer in miners working in the uranium mines in Bohemia and Saxony is now known to have been due to the inhalation of uranium dust. The production of aplastic anemia, bone sarcomas, bladder tumors, ulcerative stomatitis, osteomyelitis and bone necrosis in the radium dial workers is familiar to all physicians. The leukemogenic effect of irradiation in man has been amply demonstrated by the increased incidence of leukemia in radiologists. Furthermore, as of January 1, 1954,92 proved cases of leukemia occurred in the survivors of the Hiroshima and Nagasaki atomic bombings. 7 Calculating from clinical onset, the peak years were 1950, 1951 and 1952. In 1953 there was a sharp decline. Acute and chronic myelocytic leukemias were the most common types. Only one case of chronic lymphocytic leukemia was seen. However, chronic lymphocytic leukemia among Japanese (nonirradiated) is much less commonly found that in Western people. That cataracts can be caused by ionizing radiation is well established. They have been noted in persons overexposed to x-rays and in cyclotron workers receiving excessive amounts of radiation from neutrons. Since
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the atom bombing of Hiroshima and Nagasaki, increased incidence of cataracts was found in the survivors. Usually a latent period of six months to two years occurs between an acute exposure of the eyes to x-rays and the development of lenticular opacities. However, the latent period may be eight to twelve years.8 It is felt that those persons who suffered cataracts after the atom bombing of Hiroshima and Nagasaki received considerable intensities of radiation, since all cases showed epilation and several patients experienced radiation sickness. The genetic effects of radiation are thought to be cumulative and,within limits, independent of the dosage rate of the radiation. Mutation rates are increased by radiation. The mutations may be due to chromosomal aberrations which are microscopically visible or to gene mutations which consist in changes in the chemical composition of the normal genes. The study of human genetics is complicated by the longevity of man, limited number of offspring and the difficulty of making long-term observations. In addition, although dominant mutations would be expressed in the next generation, recessives may not be manifested for many generations. The results obtained so far by the Atomic Bomb Casualty Commission for survivors of Hiroshima and Nagasaki indicate that no significant increase in abnormality has been found in the first generation. The cooperative study by Japanese and American scientists will need to be continued for many years, however, before conclusive results are available. Treatment. To date only supportive care be offered patients suffering from the acute radiation syndrome. Almost certainly all those who receive an acute whole-body exposure of 600 or more roentgens will die despite any efforts in their behalf. The following treatment is suggested when possible in the hopes of salvaging patients who have received median lethal or moderate (100 to 300 roentgen) doses of acute total body irradiation: 1. Morphine, meperidine (Demerol) or phenobarbital should be given as required for pain and sedation. 2. Ambulation, including lavatory privileges, will depend upon the severity of the reaction. 3. A bland, low residue diet should be offered patients who are able to eat. The protein intake should be increased as soon as it can be accomplished. 4. Penicillin and streptomycin by intramuscular injection, preferably in combination, are indicated at least every two days and once daily when possible until the neutrophils are normal. In the presence of infection the penicillin and streptomycin would be indicated every twelve hours. 5. In the presence of infections not responding to penicillin and streptomycin, the broad-spectrum antibiotics (oxytetracycline, chlortetracycline, tetracycline) may be given orally or intramuscularly or added to intravenous fluids, depending upon the clinical condition of the patient.
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The use of antifungal preparation such as Mycostatin, alone or in combination, should be considered for all patients on long-term broadspectrum antibiotic treatment. In special circumstances other antibiotics such as bacitracin, neomycin, polymyxin, Albamycin may be useful. 6. Blood transfusions of 250 to 500 ml. should be administered every four to six days. If facilities are available for obtaining whole blood and plasma, specific gravities, the frequency and amount of transfused blood should be varied accordingly. 7. Tetanus antitoxin, 1500 to 3000 units, is indicated for all patients. If possible, a dose of tetanus toxoid should also be administered. 8. Antiemetics, such as Thorazine or Marezine, can be given by intramuscular injection every four to eight hours to control nausea and vomiting. 9. The administration of fluids and electrolytes will, in the vast majority of instances, be based on clinical grounds alone. Potassium, if added to intravenous fluids, should be infused slowly, and probably not more than 2 grams of potassium chloride per day should be given intravenously unless there is considerable vomiting and diarrhea. Potassium, by any route, is contraindicated in the presence of anuria. 10. Normal human serum albumin, plasma and amino acids may be useful for correcting the negative nitrog~n balance and hypoproteinemia. Plasma and albumin, as well as synthetic plasma expanders, may also be used to combat shock, as described elsewhere in this volume. 11. ACTH, cortisone, hydrocortisone and the delta analogues of cortisone and hydrocortisone may be useful in certain patients having the pancytopenic form of the syndrome.
SUMMARY The nature of ionizing radiation has been considered and four types of ionizing radiation discussed. Several units in common usage for measuring ionizing radiation are defined. The sources of radiation injury from atomic and thermonuclear bombs are stated, and certain sequelae of ionizing radiation are mentioned. The acute radiation syndrome is described and its treatment is outlined.
REFERENCES 1. Warren, S. and Bowers, J.: The Acute Radiation Syndrome in Man. J. Int. Med. 32: 207-215, 1950.
2. Sinskey, R. M.: Status of Lenticular Opacities Caused by Atomic Radiation: Hiroshima, Japan, 1951-1952 (Special report to Atomic Bomb Casualty Commission, December 31,1952), as quoted by Maloney, W. C.7 3. The Effects of Atomic Weapons, edited by J. O. Hirschfelder et al. Washington, D.C., Government Printing Office, 1950. 4. Ibid. p. 1 5. Leroy, G. V.: Medical Sequelae of Atomic Bomb Explosion. J.A.M.A. 134: 11431148,1947.
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6. Behrens, C. F.: Cumulative Effects and Permissible Dosage Limits of Ionizing Radiations. Atomic Med. 1949. 7. Maloney, W. C.: Leukemia in Survivors of Atomic Bombing. New England J. Med. 253: 88-90, 1955. 8. Cogan, O. G.: Lesions of the Eye from Radiant Injury. J.A.M.A. 142: 145, 1950. First National Bank Building Winfield, Kansas
MOST physicians are acquainted with the clinical uses and effects of ionizing radiation in the form of x-rays in the practice of medicine. However, not until the bombing of Hiroshima and Nagasaki did mass casualties occur as a result of excessive exposure to ionizing radiations. For the first time physicians encountered casualties not only from blast and heat, as with conventional bombs, but also from acute whole-body exposure to ionizing radiation. Although it is estimated that only 10 to 20 per cent of the deaths in Hiroshima and Nagasaki were due to irradiation, it is undoubtedly true that many more people would have died from the effects of radiation had they survived the injuries from blast and burns.
IONIZING RADIATION
All ionizing radiations are similar in that they dissipate energy in cells and tissues by a process known as ionization. Ionzation, as used here, refers to the dislodgment of an electron from an atom or molecule, resulting in the formation of two ions. One ion is the negatively charged electron; the other is the positively charged residual atom or molecule. It is felt that the vast majority of biological effects from ionizing radiation is due to tissue ionization. Although all ionizing radiation produces the same tissue reaction, the efficiency with which the tissue reaction is produced, or biological effectiveness, varies with the nature of the radiation. Symptomatology and objective findings vary with the quantity of tissue damaged and its site. Only four types of ionizing radiation will be discussed, namely, alpha and beta particles, gamma rays and neutrons. Alpha Radiation. Alpha particles are helium nuclei and consist of two protons and two neutrons. They lack orbital electrons. Because of their relatively heavy mass and double positive charge, alpha particles cause dense ionization, but, because of their size, have only limited ability to penetrate. Consequently their range in tissue is only in terms of microns and in air can be stopped by paper or cloth. Generally speaking, they are
* Internist, Snyder Clinic, Winfield, Kansas. 1415
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important as an external radiation hazard only under exceptional circumstances. If alpha-emitting substances gain entrance into the body and are not rapidly excreted, considerable harm may result. Beta Radiation. Beta particles are electrons. They are more penetrating but less ionizing than alpha particles. Beta particles can cause serious skin damage and are also an important internal radiation hazard. Gamma Radiation. Gamma rays are ionizing electromagnetic radiations. They are similar to x-rays, but usually have shorter wavelengths and greater frequencies. Gamma rays are very penetrating and their range great, although their ionizing power is low. They are extremely important as a cause of radiation injury and illness. Neutron Radiation. Neutrons have no charge, but have a mass about that of a proton or hydrogen nucleus and have considerable kinetic energy. They penetrate readily and have a moderate range. Because of their great energy and penetrability, neutrons are of considerable importance as a radiation hazard. In addition, they may also induce radioactivity. Effects
The effects of radiation on living cells and tissues depend not only on the total amount absorbed, but also on the rate of absorption, whether it is chronic or acute, and on the area of the body exposed. Genetic effects are apparently independent of the rate of delivery of the radiation and depend only on the total dose. In general, the biological effect of a given dose of radiation decreases as the rate of dose decreases. For example, 600 roentgens' total body irradiation in one day would almost certainly be a lethal dose, whereas the same amount would probably have no harmful effect if fractionated over a period of many years. A reasonable explanation of this fact is that if the amount of radiation absorbed per day is small enough, the damaged tissues have a chance to recover. If the rate of delivery is increased, recovery cannot compensate for the damage. Apparently it is this ability of tissue to recover which makes it possible for humans to accept limited whole-body doses of irradiation (0.3 roentgen per week) for long periods of time without seemingly harmful consequences. For many years it has been known that excessive exposure to radiation from any source capable of producing ionization in living tissues can cause injury. After the discovery of x-rays and radioactivity serious and sometimes fatal exposures were sustained by personnel before the dangers were fully realized. Slowly, means for providing protection were devised, and serious overexposure has become uncommon. However, occasional ,mishaps of a serious nature still occur to persons operating radiographic equipment, x-ray machines in industrial laboratories, cyclotrons and other equipment, or working with radioactive materials. Generally, the
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overexposures were limited to localized areas of the body, and the effects were termed radiation injuries. When, in some instances, large parts of the body were accidentally exposed to an overdose of radiation, a systemic rather than a localized effect was noted. This systemic reaction is called radiation sickness. Although a rare occurrence prior to the atomic bombing of Hiroshima and Nagasaki, it was observed in various degrees of severity among large numbers after the atomic attacks. Units
There are several units of ionizing radiation in common usage. These are the roentgen (r), roentgen-equivalent physical (rep), roentgenequivalent man (rem) and the gram-roentgen. A roentgen of x-rays or gamma rays is that amount which will produce 2.08 times 10 9 ion pairs in a cubic centimeter of air under standard conditions of temperature and pressure. It is important to understand that the term "roentgen" does not refer to the rate of radiation or the amount of tissue irradiated. A roentgen-equivalent physical is that amount of energy dissipated in 1 gram of wet tissue by 1 roentgen of hard x-rays or gamma rays and is equivalent to 93 ergs. This unit is used to calculate tissue dose from beta particles, neutrons and so on. Since the biological effectiveness of ionization varies with the type of radiation, the term "roentgen-equivalent man" was introduced so that doses of radiation from different sources could be compared. Thus a roentgen-equivalent man of any type of radiation is that amount which is equivalent in its biological action to 1 roentgen of hard x-rays. Since the roentgen, roentgen-equivalent physical and roentgen-equivalent man do not take into consideration the amount of tissue radiated, the term "gram-roentgen" was formulated. A gramroentgen is the energy lost in 1 gram of air by 1 roentgen-equivalent physical of ionizing radiation, or 83.8 ergs. This unit is sometimes used to integrate the total energy dissipated in a mass or volume of tissue. Thus the same integral dose is delivered whether 100 grams of tissue are irradiated with 1 roentgen or 1 gram of tissue is irradiated with 100 roentgens. When using radioisotopes (other than radium, which is measured in terms of milligrams and grams), one uses the terms "microcurie," "millicurie" and "curie" as activity units. A curie is that amount of radioactive material which produces 3.7 times 1010 disintegrations per second. A millicurie and microcurie produce 3.7 times 10 7 and 3.7 times 104 disintegrations per second respectively. Cellular Effects
When a sufficient number of molecules is disrupted by ionization, changes in function, including death of the cell, occur. The cellular effects of ionization are not uniform, since there is considerable variation in the susceptibility of different cells. In addition, the lethal nuclear effects are
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greatest during cellular reproduction. Hence the cells which most frequently divide in the body are also those which are most sensitive to radiation. The cells of the blood-forming organs and gonads, for example, are more sensitive to radiation than the cells of skin. In man, sensitivity to radiation of the various tissues decreases in the following order: lymphoid tissue, bone marrow, reproductive organs, salivary glands, skin, mucous membranes, endothelial cells of blood vessels and peritoneum, connective tissue, bone, liver, pancreas, kidney, nerve tissue and muscle. The histopathological effects of radiation as quoted from Warren and Bowers! include changes in the cells, stroma and blood vessels. The cellular effects include cessation of mitosis followed by disorganization of cellular structure and swelling. As the cell resumes mitosis, bizarre mitotic figures appear. The stromal effects are first manifested as swelling which is followed by fibrosis and hyalinization. The initial vascular effects are thrombosis, which may be followed by fibrosis, hyalinization and telangiectasia. The nature of the constitutional effects as seen in the acute radiation syndrome is not known. It is probable that such phenomena as inhibition of enzyme production, alterations in cell membrane permeability, protein denaturation, production and absorption of toxins all play a part. RADIATION INJURY
Since the production and manner of radiation injury from ionizing radiation used in clinical medicine are well known, consideration of the sources and nature of radiation injuries following an atomic explosion will now be made. Atomic weapons represent two types of nuclear energy release-nuclear fission, as used in the uranium and plutonium bombs, and nuclear fusion, as used in the hydrogen or thermonuclear bombs. There is no important difference between the two types as to the cause and effect of radiation injury. The major difference lies in the range of effectiveness. Although the blast and fire effects of a hydrogen bomb would be many times that of the fission type, the radiation hazard would not be increased to the same extent. Persons close enough to the center of the explosion to receive a lethal dose of radiation would be killed by heat or blast. After an atomic explosion four kinds of radiation are emitted, namely, alpha and beta particles, gamma rays and neutrons. The alpha radiation emitted at the center of an explosion is absorbed nearby because of the low penetrating power; the same is true of the beta radiation, and hence neither is a direct radiation hazard. Gamma rays are a major radiation hazard, and in Japan fatalities occurred from gamma radiation as far as one mile from the explosion center. Although the hazard to life from neutrons is considerable at a half-mile from the explosion center, at this distance exposed persons would receive a lethal dose of gamma radiation.
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It is likely, however, that neutrons may have a deleterious biological effect at much greater distances than a half-mile, since opacities of the lens caused by neutrons have been found at 1700 meters.2 AtOlnic Bom.b Injuries
In general, there are four ways in which radiation injuries may be caused by an atomic explosion. First, direct exposure may be sustained from the instantaneous burst of nuclear radiation. The only hazard from this type of exposure is from gamma rays and neutrons. Secondly, exposure to radiation may occur as a result of "fall-out." Fall-out is not a hazard following a high air burst, but may be so after a low air or ground burst. In contrast to the short duration of danger from the initial radiation, radioactivity resulting from fall-out after a low air burst or ground burst may persist for long periods of time. A third method by which radiation injuries may be produced is the base-surge which follows an underwater explosion. The droplets of water contain radioactive materials which may be transported many miles from the explosion site and fall out as radioactive rain. Induced radioactivity by neutrons comprises the fourth method of radiation injury. Just as artificial radioactivity is produced by neutron bombardment of atoms in a nuclear reactor, the neutrons from an atomic explosion may produce artificial radioactivity in food, water, human or animal tissues, reinforced concrete buildings and so forth. In addition to the initial radiation from an atomic explosion, there is also radiation from fission products, plutonium and uranium. A radiological hazard due to radiation from these sources would occur under special circumstances only. In case there is a high or moderately high air burst, the danger would be practically nil. However, an underground burst or an underwater burst accompanied by a base-surge would lead to a significant contamination wherein residual radiation would be important. External radiation would be mainly from gamma rays and beta particles. Internal radiation would occur if radioactive materials gained entrance into the body by ingestion, inhalation or through breaks in the skin. Although the amounts of fission products that need to be fixed within the body to produce injurious effects are minute, it is felt that in general, if a dosage due to external radiation is down to a safe level, there is little or no danger of enough radioactive material being fixed in the system for it to constitute an internal hazard. 3 Acute Radiation Syndrom.e
After an acute, whole-body overexposure to ionizing radiation there occurs a group of signs and symptoms known as the acute radiation syndrome. The symptoms and their severity, together with their time of appearance, are in direct proportion to the dosage absorbed and indi-
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vidual susceptibility. Although commonly seen after an atom bomb explosion, this syndrome has not occurred in man from the administration of radioactive materials. Symptoms and Signs. In the premonitory phase of the acute radiation syndrome, weakness, nausea and vomiting are prominent. Diarrhea then occurs and, together with the nausea and vomiting, may temporarily subside. However, all recur with increased severity, at which time the diarrhea may be bloody. Although petechiae and purpura are found during the first week after exposure and may be accompanied by hemorrhage from various parts of the body, the hemorrhagic manifestations are most prominent between the sixteenth and twenty-second days. Epilation, predominantly of the scalp and without regard to sex, occurs by the end of the second week along with infected, ulcerative lesions of the mucous membranes. Fever is a constant finding and rises in a steplike manner until death, although an interval of several days may supervene between exposure and onset of fever. The pulse rate is often increased out of proportion to visible evidences of injury. Clinically, Warren and Bowers! divide the acute radiation syndrome into several forms according to the degree of exposure. The fulminating form is characterized by the onset of nausea, vomiting, prostration and mild diarrhea within 2 to 6 hours after exposure. These manifestations gradually increase in severity and are associated with pronounced fall in the white blood count. The diarrhea becomes severe and grossly bloody stools may appear. There is a step-like rise in fever and death occurs from the fifth to the tenth day. This course is observed in individuals who have received greater than lethal doses. The hemorrhagic form presents initially nausea, vomiting, prostration and, at times, mild diarrhea of about two days duration. A well period of about five days then ensues followed by prostration, bloody diarrhea and increasing fever. Petechiae and purpura appear and are associated with frank bleeding from body orifices. Ulcerative lesions of mucosal surfaces become increasingly extensive and death may occur from three to six weeks after exposure. Patients in this group have received irradiation doses in the lethal or near lethal range. A number of the patients in the hemorrhagic group will survive but exhibit continued weakness, pallor and ulcerative lesions characteristic of the pancytopenic form of the syndrome. Death may finally ensue after a prolonged period of illness during which cachexia may be pronounced.
The hematologic changes following whole body irradiation have been extensively studied. A decrease in the number of circulating lymphocytes is found after as small a dose as 15 roentgens. With doses about 75 to 100 roentgens an increase in the total white blood cell count is sometimes observed initially. By the end of 24 hours, however, the total white cell count is decreased and continues to decrease or remain reduced for five to six days. Leukocyte counts below 2000 per cubic millimeter are indicative of severe injury, and recovery is rare in patients having white blood
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cell counts below 600 per cubic millimeter.5 By the end of the first week the white cell count begins to rise in patients who are recovering and by two to four weeks is normal. Platelet reduction followed by anemia occurs later than lymphopenia and leukopenia. Reticulocytes are uniformly decreased or absent. Those patients surviving six weeks may have red cell counts as low as 800,000 to 900,000 per cubic millimeter of blood. Platelet increases are observed by the end of the second week and are usually normal in three to four weeks if recovery is occurring. Complications. It is well established that acute and/or chronic exposure to ionizing radiation can cause sequelae in both man and animals. Among these are bone, skin and bladder neoplasms, leukemia, cataracts, burns and probably genetic changes. Almost always there is a latent period of several years between the time of exposure and the onset of sequelae. Since Roentgen's discovery of the x-ray in 1895 and Becquerel's discovery of natural radioactivity in 1896, many skin injuries were sustained by persons utilizing these sources of ionizing radiation for investigative and diagnostic purposes. Since nothing was known about the skin effects from these new and interesting tools, no precautionary measures were taken to provide shielding. According to Behrens,6 no heed was given to erythema of the hands and face, and fluoroscopic apparatus was tested by placing a hand in front of the screen to see whether the tube was functioning. For purposes of reassurance and demonstration to patients, workers often exposed themselves to x-rays. Mild skin injuries such as brittleness and ridging of the nails, increased susceptibility to chapping, blunting of the fingernail ridges, dryness and epilation are followed by inflammation, edema, atrophy, loss of fingernails, keratosis, warts, telangiectases, ulceration and cancer if exposure is continued. The high incidence of lung cancer in miners working in the uranium mines in Bohemia and Saxony is now known to have been due to the inhalation of uranium dust. The production of aplastic anemia, bone sarcomas, bladder tumors, ulcerative stomatitis, osteomyelitis and bone necrosis in the radium dial workers is familiar to all physicians. The leukemogenic effect of irradiation in man has been amply demonstrated by the increased incidence of leukemia in radiologists. Furthermore, as of January 1, 1954,92 proved cases of leukemia occurred in the survivors of the Hiroshima and Nagasaki atomic bombings. 7 Calculating from clinical onset, the peak years were 1950, 1951 and 1952. In 1953 there was a sharp decline. Acute and chronic myelocytic leukemias were the most common types. Only one case of chronic lymphocytic leukemia was seen. However, chronic lymphocytic leukemia among Japanese (nonirradiated) is much less commonly found that in Western people. That cataracts can be caused by ionizing radiation is well established. They have been noted in persons overexposed to x-rays and in cyclotron workers receiving excessive amounts of radiation from neutrons. Since
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the atom bombing of Hiroshima and Nagasaki, increased incidence of cataracts was found in the survivors. Usually a latent period of six months to two years occurs between an acute exposure of the eyes to x-rays and the development of lenticular opacities. However, the latent period may be eight to twelve years.8 It is felt that those persons who suffered cataracts after the atom bombing of Hiroshima and Nagasaki received considerable intensities of radiation, since all cases showed epilation and several patients experienced radiation sickness. The genetic effects of radiation are thought to be cumulative and,within limits, independent of the dosage rate of the radiation. Mutation rates are increased by radiation. The mutations may be due to chromosomal aberrations which are microscopically visible or to gene mutations which consist in changes in the chemical composition of the normal genes. The study of human genetics is complicated by the longevity of man, limited number of offspring and the difficulty of making long-term observations. In addition, although dominant mutations would be expressed in the next generation, recessives may not be manifested for many generations. The results obtained so far by the Atomic Bomb Casualty Commission for survivors of Hiroshima and Nagasaki indicate that no significant increase in abnormality has been found in the first generation. The cooperative study by Japanese and American scientists will need to be continued for many years, however, before conclusive results are available. Treatment. To date only supportive care be offered patients suffering from the acute radiation syndrome. Almost certainly all those who receive an acute whole-body exposure of 600 or more roentgens will die despite any efforts in their behalf. The following treatment is suggested when possible in the hopes of salvaging patients who have received median lethal or moderate (100 to 300 roentgen) doses of acute total body irradiation: 1. Morphine, meperidine (Demerol) or phenobarbital should be given as required for pain and sedation. 2. Ambulation, including lavatory privileges, will depend upon the severity of the reaction. 3. A bland, low residue diet should be offered patients who are able to eat. The protein intake should be increased as soon as it can be accomplished. 4. Penicillin and streptomycin by intramuscular injection, preferably in combination, are indicated at least every two days and once daily when possible until the neutrophils are normal. In the presence of infection the penicillin and streptomycin would be indicated every twelve hours. 5. In the presence of infections not responding to penicillin and streptomycin, the broad-spectrum antibiotics (oxytetracycline, chlortetracycline, tetracycline) may be given orally or intramuscularly or added to intravenous fluids, depending upon the clinical condition of the patient.
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The use of antifungal preparation such as Mycostatin, alone or in combination, should be considered for all patients on long-term broadspectrum antibiotic treatment. In special circumstances other antibiotics such as bacitracin, neomycin, polymyxin, Albamycin may be useful. 6. Blood transfusions of 250 to 500 ml. should be administered every four to six days. If facilities are available for obtaining whole blood and plasma, specific gravities, the frequency and amount of transfused blood should be varied accordingly. 7. Tetanus antitoxin, 1500 to 3000 units, is indicated for all patients. If possible, a dose of tetanus toxoid should also be administered. 8. Antiemetics, such as Thorazine or Marezine, can be given by intramuscular injection every four to eight hours to control nausea and vomiting. 9. The administration of fluids and electrolytes will, in the vast majority of instances, be based on clinical grounds alone. Potassium, if added to intravenous fluids, should be infused slowly, and probably not more than 2 grams of potassium chloride per day should be given intravenously unless there is considerable vomiting and diarrhea. Potassium, by any route, is contraindicated in the presence of anuria. 10. Normal human serum albumin, plasma and amino acids may be useful for correcting the negative nitrog~n balance and hypoproteinemia. Plasma and albumin, as well as synthetic plasma expanders, may also be used to combat shock, as described elsewhere in this volume. 11. ACTH, cortisone, hydrocortisone and the delta analogues of cortisone and hydrocortisone may be useful in certain patients having the pancytopenic form of the syndrome.
SUMMARY The nature of ionizing radiation has been considered and four types of ionizing radiation discussed. Several units in common usage for measuring ionizing radiation are defined. The sources of radiation injury from atomic and thermonuclear bombs are stated, and certain sequelae of ionizing radiation are mentioned. The acute radiation syndrome is described and its treatment is outlined.
REFERENCES 1. Warren, S. and Bowers, J.: The Acute Radiation Syndrome in Man. J. Int. Med. 32: 207-215, 1950.
2. Sinskey, R. M.: Status of Lenticular Opacities Caused by Atomic Radiation: Hiroshima, Japan, 1951-1952 (Special report to Atomic Bomb Casualty Commission, December 31,1952), as quoted by Maloney, W. C.7 3. The Effects of Atomic Weapons, edited by J. O. Hirschfelder et al. Washington, D.C., Government Printing Office, 1950. 4. Ibid. p. 1 5. Leroy, G. V.: Medical Sequelae of Atomic Bomb Explosion. J.A.M.A. 134: 11431148,1947.
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6. Behrens, C. F.: Cumulative Effects and Permissible Dosage Limits of Ionizing Radiations. Atomic Med. 1949. 7. Maloney, W. C.: Leukemia in Survivors of Atomic Bombing. New England J. Med. 253: 88-90, 1955. 8. Cogan, O. G.: Lesions of the Eye from Radiant Injury. J.A.M.A. 142: 145, 1950. First National Bank Building Winfield, Kansas