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Untersuchung der durch künstliche Bestrahlung Bewirkten Spaetschaeden beim Menschen (Thorotrast-Patienten) - Follow-up-Studie

Objective


Within the framework of clinical examinations of the German group liver cancers at an early stage could be detected by using modern imaging methods. The tumors were surgically removed. Analysis of 82 Thorotrast patients with liver lesions revealed a dependency on the size of the tumor and the time of survival.
High concentration of thorium dioxide were found by X-ray and computed tomography (CT) in the spleen, the abdominal lymph nodes and paravascular deposits. Neoplastic diseases in these areas of high exposure, however, were extremely rare.
Preliminary results of ophthalmological examinations could not prove radiation induced cataracts in Thorotrast patients.
Liver cancer continues to be the leading cause of death among Thorotrast patients, whereas leukemias were not registered during the reporting period. Excess rates of Thorotrast induced neoplastic diseases stabilized with the exception of the carcinoma of the esophagus.
Several approaches were performed to optimize the dosimetric calculations. Translocation of Thorotrast particles in two patients after liver transplantation proved to be very low. This was confirmed and analysed in an animal experiment with rats.
CT evaluation of liver and spleen volume revealed substantial shrinkage of the organs which changed the former calculations of Thorotrast distribution and concentration in the body.
Animal studies on the pathogenesis of Thorotrast induced liver and lung tumors were performed. The results show that in the liver the carcinogenic property of Thorotrast can be exclusively attributed to radiation without any foreign body effect. In the lung, however, the additional treatment of Thorotrast injected rats with quartz had a pronounced tumor promoting effect.

The activities of the British group were concentrated on distribution and biokinetics of Thorotrast particles and the local dose in the red and yellow bone marrow. Concentration of thorium in the bone marrow of selected human and monkey bones were measured (2 body donations and 4 monkeys). Thorium concentrations were also measured in German and Japanese bone marrow samples. The level of thorium in these samples are in general agreement with those levels measured in the USTUR case bones and monkey bones with relatively small differences at different red marrow sites. The level of injected Thorotrast had no effect on its final distribution. Within the red bone marrow there were two components of distribution: diffuse and locally concentrated deposits. The important conclusion of this study is that the ICRP quality factor for alpha-emitters with respect to leukemia seems to be too high.

The data of the Danish study were evaluated and published in eight very good papers. Taking into account that the number of the Danish Thorotrast patients, who died more than three years after injection of Thorotrast, are about one third of the German Thorotrast group the figures of primary liver cancer and leukemia are closely related. As excess rate of malignant mesotheliomas was also registered in both studies. Another important result of the Danish group was the fact that children of Thorotrast patients had no elevated risk for cancer.

The study sponsored by the EC dealt with the examination of the existence of a specific pattern of mutations in the tumor suppressor gene p53 in Thorotrast induced tumors. Paraffin embedded, formalin fixed archival tissues of 36 liver cancers in Thorotrast patients were analysed. The message of this study was that the rate of p53 point mutations in liver and lung tumors and in malignant mesotheliomas seems to be lower than in tumors with other etiology.

The Portugese Thorotrast study was reactivated. The total number of studied subjects was markedly enlarged using information on 'place of birth' to ascertain the vital status of those patients who were identified from hospital records but who, in the past, could not be traced by other means. Computer programs for data entry and validation were developed and two new standardized data extraction forms were created: an administrative and a clinical one.
The past records of 87 patients, who died from primary liver cancer until 1977, were reviewed.
The intravascularly injected X-ray contrast medium "Thorotrast" causes life-long alpha-irradiation in the depositing organs such as liver, spleen and bone marrow. The lungs are exposed by the exhaled 220Radon. The ongoing epidemiological and clinical Thorotrast studies in Danmark (Dr. H.H. Storm) and Germany should be continued to uncover the late effects of Thorotrast in the still living persons (e.g. in Germany 153 Thorotrast patients and 385 controls). The longterm results of the Thorotrast studies are most important for the risk calculation of liver cancer (15-20% cause of death). The alpha-exposure to bone marrow and bone leads to a high increase of non-lymphocytic-leukaemia and lethal myelodysplastic syndrom and to a smaller increase in plasmacytoma and bone sarcoma. The high LET risk estimates of ICRP cannot be confirmed by these results. Reevaluation of the effective dose to bone marrow and skeletton in Thorotrast patients will be done by Dr. N. Priest, Oxfordshire, U.K.. Important for the calculation of the risk caused by 220Radon is the lack of an excess rate for lung cancer in the German Thorotrast study. In the Danish study however there is a small excess of lung cancer compared to the normal incidence in Denmark. For a better comparison a Danish control group should be set up consisting of patients who underwent angiography without Thorotrast. In Germany the tumor incidence of the control group is compared with the figures of the cancer registry of the state of Saarland. The Danish and the German Thorotrast studies will follow the effects of the alpha-radiation on the germ cells and the exposure to the fetus during pregnancy in female Thorotrast patients (F1-study); therefore the radiation late effect on the children of Thorotrast patients is followed especially with regard : to an increase of leukaemias. The results of the Thorotrast studies up to now demonstrate that the survival time of exposed persons is decreased corresponding to the amount of Thorotrast injected. This effect exists also when the patients who died by Thorotrast specific diseases like liver cancer, leukaemia and liver cirrhosis were excluded from the evaluation. The continuation of the Thorotrast studies and combined analysis with renewed dosimetry will result in important answers for radiation biology and radiation protection.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

GERMAN CANCER RESEARCH CENTER
Address
Im Neuenheimer Feld 280
69120 Heidelberg
Germany

Participants (4)

AEA Technology plc
United Kingdom
Address
Harwell Laboratory
OX11 0RA Didcot
DANISH CANCER SOCIETY
Denmark
Address
35,Strandboulevarden 49
2100 Koepenhagen
London School of Hygiene and Tropical Medicine
United Kingdom
Address
Keppel Street
WC1E 7HT London
UNIVERSIDADE NOVA DE LISBOA
Portugal
Address
96,Rua De Junqueira 96
1349-008 Lisboa