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The results of chromosome aberration analyses in 68 Thorotrast patients are discussed. In all patients dicentric chromosome aberrations were found but the chromosome aberration rate neither corresponds with the calculated whole body activity or the estimated absorbed dose in the organs of the RHS nor with the “radium-224-equivalent value” calculated from the radon-220 activity measured in the expired air. From X-ray examinations and histologic studies of lymph nodes the conclusion is drawn that the “microdose” absorbed from one lymphocyte is not in relation to the mean absorbed RHS dose, calculated from biophysical measurements.

Within the scope of the German Thorotrast study 156 persons probably injected with Thorotrast were examined in a field study. Those persons unwilling or unable to consult the clinical examination centers at Heidelberg or Homburg were contacted at their homes. By means of a mobile laboratory in all patients the concentration of radon-220 (thoron) was measured in the exhaled air. The activity of the expired thoron, respectively the calculated “radium-224-equivalent value” is in accordance with the amount of Thorotrast formerly injected. In 116 persons Thorotrast deposits were found in the RHS as a consequence of angiography between 1934 and 1951. The results of these biophysical measurements will be reported and discussed. Moreover all clinical examinations corresponding to our questionnaires were made. Some of these results will be reported.

The causes of death of 144 Japanese autopsy cases during 1945–1975, who had been intravascularly injected with Thorotrast in life, were compared with those of non-Thorotrast-administered autopsy cases in the same age bracket, recorded in the Annals of Japanese Pathological Autopsy Cases during 1958–1973. This comparison revealed that the incidence of malignant hepatic tumors was more than 10 times higher in the Thorotrast-administered cases. The increase was attributable to an increased incidence of hemangioen-dothelioma and cholangiocarcinoma of the liver. The only significant increase of liver cirrhosis found to exist in the Thorotrast group occurred in the female cases. Some of the Thorotrast-administered cases were found to have developed myeloid leukemia and erythroleukemia. There was also a significant increase in the number of cases of aplastic anemia in the Thorotrast group, but clinically and pathologically these were atypical. Lymphatic leukemia was not observed. No significant difference was found in the incidence of either malignant lymphomas or osteosarcomas in the Thorotrast group and the controls. Lung cancer, on the other hand, showed a significantly higher incidence among the controls than among the Thorotrast-administered cases.

The authors present a case of a woman injected with thorium dioxide in 1942, who 35 years later developed clinical, laboratory, scintigraphic, and echographic data very suggestive of liver tumor, as has been described in patients injected with thorium dioxide. However in this case the patient recovered subjectively and objectively, after symptomatic therapy. This is unusual in the evolution of those patients, as our group had shown in other papers.

INTRODUCTION Analysis of chromosome aberrations is of great interest for medical and for radiobiological investigations. Many studies have been undertaken, either in VOW or in vitro, to the monitoring of the effects of radiation, in mammals and man, since the publications of Bender (1957) and Puck (1958). More recently aberrations in the somatic tissues of irradiated individuals were demonstrated by several investigators: in persons X-rayed for diagnostic purposes (Conen, l%l); in people subjected to occupational exposure (Norman er ui., 1964); in patients therapeutically irradiated (Tough and Gooch, et ul., l%O); and in persons accidentally exposed to radiation (Bender, 1957). In contrast to the acute external irradiation, patients who were injected with thorium dioxide (232Th) are under a chronic internal irradation for the rest of their life. Thorium dioxide is a contrast colloidal suspension marketed under the trade name of “Thorotrast” and was mainly used throughout the world as a radiological contrast medium. Colloidal thorium was used in Portugal since 1939 and it is believed that more than 2000 individuals were injected with it (da Silva Horta et ui., 1%5). The purpose of this paper is to report the results of cytogenetic studies in patients followed up by the “Portuguese Study Group of Thorium Dioxide Side Effects.”

Data are tabulated for 1026 cases over a 28-year use period from 1935 through 1973. The validity and significance of the increased incidence of tumors probably is about 5% margin of error. Death certificates do not give adequate information and autopsy percentages are low. Further studies are needed to give a qualitative estimte of the carcinogenic action. (PCS)

We have done a thorough time study, morphologic and autoradiographic, concerning the movement of thorium dioxide in time, based on bone marrow from corpses of Thorotrast-injected people. The fragments have been taken from bone marrow of the femur and bone marrow together with bone tissue from other bones. The time elapsed since injection and death went from 1 day to 40 years. We concluded that in the beginning the thorium has a uniform distribution and about 7 months later it constitutes aggregates of various sizes that tend to reunite themselves in great groups. We also concluded that Thorotrast, whether forming aggregates or not, has a movement towards the bone trabeculae. In the liver and spleen the explanation of the movements of the aggregates was very simple. The thorium follows the lymphatic pathways towards the hilum. I think that in the bone other conditions prevail that are not of hydraulic order but interfere with others of a special physical order. We have found by chance a small osteolytic sarcoma in the compact of a sternum.

The action of radiation on proliferative activity of blastic elements is already very well known. The particularity of our cases comes from the fact that radiation starts from the cells of RHS, where a radioactive substance was fixed many years before our observations. We can conclude, from these results, that the pathogenesis of anemia can be explained through proliferative asthenia. Alterations of granuloblastic series, although not so often, can be explained in a similar way. What is more difficult to be interpreted is noncorrelation between results of myeloid-erythroid radio and leukocyte count in peripheral blood. In fact, in bone marrow, myeloid series seems to be more depressed but, peripherically, anemia is more frequent. Correlation between the degree of bone marrow hypoplasia and the period of action of radiation was not observed.

In order to clarify the differences in past history, nutritional condition and, consumption of alcohol and tobacco, and liver dysfunction between the thorotrast patients who developed primary liver cancer and those who did not, 103 persons who had no primary liver cancer in January 1980 were studied. All subjects were military men who had undergone angiography with thorotrast between 1943 and 1946. Twenty persons developed hepatocellular carcinoma and 16 developed intrahepatic bile duct carcinoma by April 1987, whereas 67 are still alive without any cancer. There was no difference in age or period after thorotrast infusion between those two groups of patients in January 1980. A difference in history of hepatitis and/or jaundice and presence of hepatic dysfunction was found between the subjects who developed primary liver cancers and those who did not. These findings suggest that an anamnestic history of hepatitis and liver dysfunction are risks for development of thorotrast-induced liver cancer. On the basis of the above findings, early detection of liver dysfunction offers a possibility of early diagnosis of primary liver cancer.

Of individuals who have received Thorotrast (a colloidal suspension of ThO2 used as intravascular radiological contrast drug) in Portugal, mostly between 1930 and 1950, 1244 of 2436 (51%) have been traced and followed up since then. Similarly 924 of 2086 (44%) of a control group, injected for the same purpose with nonradioactive contrast drugs, have also been traced and followed up. Until 31 December 1976, 955 of the traced Thorotrast and 656 of the control traced cases had died. Of the 955 deaths among Thorotrast cases, 16 died as a direct result of the consequences of local granulomata developed from drug spillage around blood vessels (cervical granulomata in 15 cases), 137 from malignant tumors (of which 6 developed on the edge of local granulomata, 87 were primary liver tumors—32 of which with complete histological confirmation, 18 of these being hemangioendotheliomas—4 were biliary duct carcinomas, 8 were carcinomas of the stomach, 5 were carcinomas of the bronchus and lung, 2 were carcinomas of the larynx, 5 were primary bone tumors, and 20 had other localizations), 23 cases died from fatal blood dyscrasias (12 of which were leukemias, mostly acute and myeloid in type), and 27 from liver “cirrhosis” (actually a particular form of liver fibrosis). Of the 656 control deaths only 15 were caused by malignant tumors (of which there were 4 carcinomas of the stomach, 1 carcinoma of the bronchus, 1 of the larynx, and 1 probable primary liver tumor); there were no deaths from leukemia or other fatal blood diseases among controls and only 6 deaths were attributed to liver cirrhosis. A statistical analysis of the data has shown that the number of observed deaths from malignancies in general—and particularly from primary liver, bone, bronchus, and larynx tumors, and from leukemias—and from liver cirrhosis in the Thorotrast cases is significantly (P < 0.05) higher than among controls and also higher than the expected corresponding figures in the general Portuguese population. The significance and implications of these findings, particularly of the high incidence of liver, bone, and lung cancer and of leukemias in the Thorotrast-exposed population are discussed.

The authors conducted a follow-up study on 243 Thorotrast-administered war-wounded ex-servicemen in 1975, after a lapse of 30 to 38 years from Thorotrast injections, and found 18 cases of malignant hepatic tumor, 15 cases of other malignant tumors, 2 cases of blood diseases, and 9 cases of liver cirrhosis in 224 cases who had been given Thorotrast intravascularly. The incidence of hepatic and other malignant tumors, blood diseases, and liver cirrhosis was significantly higher than in the controls. The total number of deaths in the Thorotrast-administered cases was also significantly higher than in the controls. In the remaining 19 cases who had been given Thorotrast by a route other than intravascularly, no fatal case related to Thorotrast administration was discovered. In the living cases, however, one sarcoma was observed to have developed at the site of the Thorotrast injection.

Twenty-four patients followed up by the Portuguese Thorotrast Study Group had liver radioisotopic visualization. A high rate of scans typical of advanced malignancy was found and the authors feel that these patients (knowing they suffer from iatrogenic disease) refuse repeated examinations and laboratory testing, searching medical aid only when malignancy is far advanced. The difficulties of clinical and laboratory follow-up and early liver detection are presented.