Late effects (twenty-five to forty years) of the early medical and industrial use of radioactive materials; their relation to the more accurate establishment of maximum permissible amounts of radioactive elements in the body. III.

Fifty patients who were given radium salts either orally or intravenously for medical purposes and twenty-eight luminous-dial workers who ingested or inhaled radium, mesothorium, or radiothorium, or all three, were recently evaluated. If enough radium is in the body to produce clinical changes it can be detected by radiochemical analysis of the faeces, collection of radon in the breath, or by external counting. The history of radium intake and the characteristic skeletal roentgenographic changes are usually sufficient in order to establish the diagnosis of the deposition of radioactive elements. A negative history of radium intake does not rule out this possibility since some of the patients did not remember receiving radium. Any patient with a malignant tumor, skeletal roentgenographic changes characteristic of the deposition of radioactive elements, or unexplained aseptic necrosis should be evaluated in regard to previous exposure to or administration of radioactive materials. The amounts of radium remaining in the skeletons of these patients were estimated by measuring the amount of radon, the first daughter element of radium, given off in the breath, and by measuring the gamma-ray activity given off by the body. Almost all of the radium is rapidly eliminated so that at one year only about 0.1 to 10 per cent of the initial amount is still present. Smaller and smaller fractions of the radium body content are excreted with increasing time after administration. The coefficient of elimination after twenty years is about .02 to .016 per cent of the body content. Radium is deposited in small highly concentrated areas irregularly distributed throughout the skeleton. The concentration of radium in samples from various parts of the skeleton in one patient varied by a factor of ten*. It is reasonable to assume that radium concentration in some of the Haversian systems will have many times the upper limits of these variations because of the inherent difficulties in bone sampling. Atypical osseous tissue in trabecular spaces is a characteristic histopathological finding following the deposition of radioactive elements. Small areas of increased density were found in cancellous bone on skeletal roentgenographic examination as a result of the atypical osseous tissue. Small well differentiated areas of destruction were found in compact bone. Small areas of decreased density were found in compact bone on skeletal roentgenographic examination as a result of the destroyed bone. These changes developed years after the deposition of radioactive elements. The humeral and femoral heads, glenoid processes, and bones of the feet most frequently had areas of increased density. The long bones and skull most frequently had areas of decreased density. In the autoradiographic, roentgenographic, and histopathological studies on bone specimens, radium was found as often in the absence of histological change as in the presence of histological change. Because of this lack of correlation of the deposition of radioactive elements and pathological change it is considered that the deposited radioactive elements initiate a sequence of events that eventually produce pathological alterations. These changes are probably the result of many augmenting factors such as trauma, damage to blood supply, decreased bone repair, and increased bone destruction. It is evident that the relationship between the deposition of radioactive elements and skeletal change is complex. Therefore, it is reasonable to conclude that when the destructive effects of the radioactive elements and one or more of the augmenting factors become greater than the reparative processes, permanent alterations in the skeleton occur. The destructive effects of the deposited radioactive elements made the skeleton more fragile so that aseptic necrosis and fractures of the bones subjected to the greatest stress frequently occurred. Symptoms were similar to those following skeletal destruction from other causes. The anaemia that developed was usually not pronounced. Poikilocytosis, anisocytosis, and hypochromia seem to occur more frequently in patients having over one microgram of retained radium compared with those having under one microgram. The erythrocytesedimentation rate was almost always above 20 millimeters in one hour. Management of these cases consists primarily in vigilance in regard to the development of malignant tumors and orthopaedic care for skeletal lesions. Roentgenographic examination of any site at which pain persists is the most practical method for the early detection of malignant change. This should be followed by biopsy of any areas which are suspicious on roentgenographic examination and by surgical removal if the presence of malignant change is confirmed. A repeated roentgenographic examination every one to three years is important for following the course of the disease, for the early detection of malignant change, and for the accumulation of valuable information on the late effects of internally deposited radioactive elements. In the well advanced stages of the disease, supportive measures and relief of pain are of primary concern. The severe anaemia that develops infrequently is usually refractory to therapy, so that transfusions are the only satisfactory means of management. ACTH and cortisone have given some relief from pain. The patients were divided into two groups and the time from the deposition of the radioactive elements until symptoms developed was compared. The average time for symptoms to occur in the two groups was about fifteen years, even though the second group of patients had from ten to 100 times as much retained radium in their bodies as the first group. The mean age at the time of deposition for the luminous-dial workers was twenty-one years contrasted with thirty-four years for the patients who had been given radium. Almost no clinical changes and no tumors developed in either the luminous-dial workers or patients who had been given radium who had under 0.5 microgram of ratained radium in their bodies. In addition there were almost no roentgenographic changes found in the few patients who had under 0.5 microgram of radium and in whom deposition occurred as much as thirty years before. Attempts at correlation of the roentgenographic changes, symptoms, and tumor formation with increasing amounts of radium were made. A proportionate increase in the severity of the clinical changes with increasing amounts of radium in the body was not found. However, there was a marked variation in the clinical response when related to the amount of radium present in the body. Some patients who had ten to fourteen micrograms of radium in their bodies had minor changes while others having as little as 0.5 to 1 microgram of radium had major skeletal changes or tumor formation. This great variation in clinical response emphasizes the importance of the dynamic relationship between the destructive and reparative processes of the body in the eventual production of clinical change. A definite correlation exists between the frequency of skeletal roentgenographic change and tumor formation and the retained radium within a certain range. A marked increase in frequency of roentgenographic changes was found in patients having over one microgram of radium compared with those patients having under one microgram. The patients, who were evaluated, were about fifty years of age and had had radium present in their bodies for about twenty-five years. The frequency of malignant neoplasms of the skeleton was 14 per cent. All malignant tumors occurred in patients who had 0.5 microgram of more radium in their bodies.