Biokinetics and assessment of intake of thorium dioxide.

The aim of this work was to investigate the biokinetics of thorium dioxide in animals for the purpose of assessing intakes of the compound by workers and the resulting doses. The results imply that measurements of the decay products in the chest or extrapolations from urine analysis data are unlikely to be of value for doses below 20 mSv. Even higher doses should be interpreted with caution as a consequence of uncertainties in particle size distribution and variations in dietary excretion.

Mortality after radiological investigation with radioactive Thorotrast: a follow-up study of up to fifty years in Portugal.

Cerebral angiography using a radioactive radiological contrast medium, Thorotrast, was pioneered by Moniz in Portugal in the 1920s. Thorotrast is retained by the reticuloendothelial system, with a biological half-life of several hundred years, so that such patients suffer lifetime exposure to internal radiation. We studied mortality in Portuguese patients who were administered Thorotrast during the period 1928-1959 and in a comparison group of patients who received nonradioactive contrast agents. There were 1096 systemically exposed, 1014 unexposed, and, unique to the Portuguese study, 240 locally exposed Thorotrast patients who were successfully traced and followed up to the end of 1996. Mortality was significantly raised among systemically exposed Thorotrast patients relative to those unexposed for all causes [relative risk (RR) = 2.63], all neoplasms (RR = 6.72), liver cancer (RR = 42.4), chronic liver disease (RR = 5.12), other non-neoplastic diseases of the digestive system (RR = 4.87), neoplastic (RR = 21.9) and non-neoplastic hematological disorders (RR = 6.00), and non-neoplastic diseases of the respiratory system (RR = 4.31). Risks for most of these conditions increased significantly with time since first administration of the contrast medium and with cumulative alpha-particle radiation dose. Mortality was also significantly raised for non-neoplastic disorders of the nervous system (RR = 12.7) and ill-defined conditions (RR = 3.74), but these associations are likely to reflect the initial diagnosis, not Thorotrast exposure, because risks declined significantly with time and/or dose. There were no significant excess deaths from oropharyngeal or nasal cancers, or from any other cause, among patients exposed to Thorotrast locally for visualization of the perinasal sinuses, and no clear trend in risk with time since exposure. This study shows an association between systemic, but not local, exposure to Thorotrast and mortality from liver cancer, chronic liver disease, and neoplastic and non-neoplastic hematological disorders, with risks for these conditions remaining high for over 40 years after administration. Liver conditions, but not hematological disorders, showed a strong and consistent gradient with cumulative alpha-particle radiation dose.

Implanted depleted uranium fragments cause soft tissue sarcomas in the muscles of rats.

In this study, we determined the carcinogenicity of depleted uranium (DU) metal fragments containing 0.75% titanium in muscle tissues of rats. The results have important implications for the medical management of Gulf War veterans who were wounded with DU fragments and who retain fragments in their soft tissues. We compared the tissue reactions in rats to the carcinogenicity of a tantalum metal (Ta), as a negative foreign-body control, and to a colloidal suspension of radioactive thorium dioxide ((232)Th), Thorotrast, as a positive radioactive control. DU was surgically implanted in the thigh muscles of male Wistar rats as four squares (2.5 x 2.5 x 1.5 mm or 5.0 x 5.0 x 1.5 mm) or four pellets (2.0 x 1.0 mm diameter) per rat. Ta was similarly implanted as four squares (5.0 x 5.0 x 1.1 mm) per rat. Thorotrast was injected at two sites in the thigh muscles of each rat. Control rats had only a surgical implantation procedure. Each treatment group included 50 rats. A connective tissue capsule formed around the metal implants, but not around the Thorotrast. Radiographs demonstrated corrosion of the DU implants shortly after implantation. At later times, rarifactions in the radiographic profiles correlated with proliferative tissue responses. After lifetime observation, the incidence of soft tissue sarcomas increased significantly around the 5.0 x 5.0 mm squares of DU and the positive control, Thorotrast. A slightly increased incidence occurred in rats implanted with the 2.5 x 2.5 mm DU squares and with 5.0 x 5.0 mm squares of Ta. No tumors were seen in rats with 2.0 x 1.0 mm diameter DU pellets or in the surgical controls. These results indicate that DU fragments of sufficient size cause localized proliferative reactions and soft tissue sarcomas that can be detected with radiography in the muscles of rats.

Pattern of mortality among Danish thorotrast patients.

The mortality pattern among 999 Danish patients who had been subjected to angiography of the carotid artery with the alpha-ray emitting X-ray contrast media Thorotrast during the period 1935-47 was assessed by record linkage with the National Death Registry through 1989. Standardized mortality ratios (SMR) were calculated relative to the general population. The overall SMR was increased by 18 times during the first 3 years after Thorotrast injection. This rate reflects the often serious, underlying neurological conditions for which angiography was performed, however, mortality was increased by 3-4 fold even for the follow up period after the first 3 years. The increase in mortality was evident for all categories of cause of death, the SMR being 11.1 (95% confidence interval (CI) 7.1-16.4) for cirrhosis of the liver, 4.7 (4.1-5.3) for cancer, 1.6 (1.3-1.9) for cardiac disease, 3.3 (2.6-4.2) for cerebrovascular diseases, 3.9 (3.3-4.5) for other natural causes, and 4.4 (3.4-5.6) for violent causes (including suicides). The SMR was generally related positively to young age at injection, to time since injection, and to the amount injected. The excess mortality can be explained only partially by underlying neurological conditions and by diseases known to be induced by Thorotrast (cirrhosis and cancer of the liver, leukaemia and other haematological diseases), and it is suggested that unspecific effects induced by the alpha-radiation of Thorotrast may have contributed.

Cancer incidence among Danish Thorotrast-exposed patients.

BACKGROUND: Studies of groups of patients given injections of the alpha-emitting x-ray contrast medium Thorotrast may provide information on human alpha-ray carcinogenesis. PURPOSE: We re-established a formerly identified cohort of neurological patients receiving injections of Thorotrast for cerebral arteriography and assessed their incidence of cancer. METHODS: Using the national population register, the Danish Cancer Registry, and other registers, we determined the incidence of cancer among Thorotrast-injected patients. Incidence ratios were standardized to the general population and computed for different cancer sites. RESULTS: The cumulative risk for cancer at all sites (excluding brain tumors where the standardized incidence ratio [SIR] was 28) reached 86% 50 years after Thorotrast injection. SIR was greatly elevated at all sites except the brain and CNS (3.3, 95% confidence interval = 3.0-3.7), mainly because of liver cancers (SIR = 126) as well as leukemia (SIR = 10) for which a relationship was found between the time since injection and the estimated dose (but not the age at injection). Other sites with significantly increased risks of cancer included the gallbladder and extrahepatic bile ducts (SIR = 14), peritoneum (SIR = 8.6), sites of multiple myeloma (SIR = 4.6), metastatic sites (SIR = 12), and unspecified sites (SIR = 11). Cancers of the lung and breast also occurred in significant excess, but no relationship between SIR and volume of injected Thorotrast or time since injection was observed. Cancer risk was increased at most other sites, although this increase was not statistically significant. CONCLUSION: Alpha radiation may account for the increased risk of tumors of the liver, gallbladder, and peritoneum as well as leukemia and multiple myeloma, whereas confounding factors most probably contribute to the increased risks at other sites.

Portable 220Rn detector used to assess Thorotrast exposure.

Patients who are exposed by injection to the radiological contrast medium Thorotrast (232ThO2) had been considered by early researchers to be an unfortunate but important model of alpha-particle carcinogenesis in the lung as well as liver and bone marrow because they continuously exhale 220Rn, in the breath of Thorotrast patients and (as the first step to lung dosimetry) to investigate the relationship between exhaled 220Rn activity concentration (Bq L-1) and 232Th body burden. Results revealed that reliable estimation of 232Th burden by 220Rn measurement is possible because a fairly good correlation was obtained between 220Rn in the breath and the known quantity of 232Th in the body. Mean 220Rn activity concentration in the breath was 9.21 Bq L-1 g-1 of 232Th deposited in the liver and spleen. This value was very close to that published for German patients. Our data and those of other investigators indicate that apparent discrepancies in mean 220Rn activity concentration among previous studies was caused by using different 228Th:232Th activity ratios.

Whole-body pathologic analysis of a patient with Thorotrast-induced myelodysplasia.

An autopsy was performed on a 72-y-old Caucasian female who had received a carotid artery injection of thorium dioxide in 1953. The body was dissected in such a manner as to provide for radiobiological evaluation as well as to determine histologically the distribution of Thorotrast in the tissues and its complications. Thorotrast was identified within the liver, spleen, lymph nodes, bone marrow, and surrounding the right carotid artery (the injection site). The cause of death was gastric hemorrhage complicating pancytopenia secondary to refractory anemia with excess of blasts (myelodysplastic syndrome).

Microdistribution and microdosimetry of thorium deposited in the liver.

The distribution of thorium in the liver of a patient 36 y after injection with Thorotrast was examined with autoradiographic and scanning electron microscope backscatter image techniques. Autoradiographic examination of randomly selected histologic sections of the liver showed a total alpha activity calculated at 33.7 Bq g-1, with the highest concentration of alpha activity sequestered in subcapsular scare tissue. Subcapsular scare tissue received 4.8 cGy d-1 of alpha radiation, periportal areas were accumulating 1.4 cGy d-1, and the hepatic cord areas 0.09 cGy d-1 of alpha radiation at the time of death. The concentration of dose in periportal areas correlates with higher incidence of bile duct tumors (than hepatocellular carcinomas) found in patients exposed to Thorotrast. The backscatter technique was demonstrated as useful for identifying thorium in liver specimens.

The distribution of Thorotrast in human bone marrow: a case report.

Samples of bone containing cellular and fatty bone marrow were removed at autopsy from the body of a woman who, following an automobile accident, had been injected with approximately 25 mL of the radiographic contrast medium Thorotrast. The woman survived for 36 y after the accident and died at age 72 y following bone marrow failure. The samples were analyzed to determine their thorium content by x-ray fluorescence and by image analysis. In addition, Thorotrast was visualized in the different bones examined by light microscopy and by backscattered electron imaging with a scanning electron microscope. The results showed Thorotrast to be largely restricted to areas of cellular bone marrow. In such regions, Thorotrast was present throughout the marrow tissue and was also concentrated within cells that were commonly aggregated within focalized areas of the marrow. Overall the results suggest a rather uniform pattern of Thorotrast uptake by the red bone marrow at different skeletal sites. Significant deposits of Thorotrast were not found in fatty yellow marrow. We conclude that Thorotrast-derived risk estimates for human leukemia following high LET, alpha irradiation may be used for calculating the risks of alpha exposure, but with caution.

Distribution and dosimetry of Thorotrast in USUR case 1001.

The distribution of radioactivity and the associated doses were evaluated postmortem for USUR Case 1001, a female who had been injected with Thorotrast some 36 y prior to death. The distribution was determined for four nuclides: 232Th and its decay products, 228Ra and 228Th; and 230Th, a contaminant associated with Thorotrast. More than 90% of the activity was associated with the reticuloendothelial system. Approximately 32% of the total activity was found in the total skeleton (mineral bone and bone marrow), which is somewhat higher than expected from the literature. The 44% found in the liver and 12% in the spleen were somewhat lower than expected. This difference may be attributable, in part, to the initial deposition as influenced by colloidal particle size and to the radiation-induced hyposplenism, splenic atrophy, and slight hepatic atrophy observed at autopsy. In addition, roughly 3% of the activity was found in the Thorotrastoma and surrounding carotid artery tissue. Estimated lifetime absorbed doses from the 232Th series were 15 Gy to the liver, 121 Gy to the spleen, 4 Gy to the skeleton, and 16 Gy to the Thorotrastoma. Comparable dose equivalents to these tissues are 300, 2420, 80, and 320 Sv, respectively, assuming a quality factor of 20 for alpha irradiation.

The effects of Thorotrast and quartz on the induction of lung tumors in rats.

In a long-term animal study, the combined and separate effects of Thorotrast (colloidal 232ThO2) and silica dust on the induction of lung tumors were investigated. Female Wistar rats were exposed for 29 d to aerosol concentrations of quartz of either 6 mg m-3, 30 mg m-3, or 0 mg m-3 (6 h d-1, 5 d wk-1). After inhalation, one-half of all exposed animals received a single intravenous injection of enriched Thorotrast (600 microL, 2960 Bq 228 Th mL-1). In all quartz-exposed groups the incidence of benign and malignant lung tumors turned out to be more than 40%. The additional Thorotrast treatment (lifelong exhalation of 220Rn) led to a marked shortening of latency times (first lung tumor was found 1 y after treatment) and to a higher total incidence in the animals exposed to 30 mg m-3 quartz (57 of 87 animals with lung tumors = 65.5%). In the group treated only with Thorotrast, three of 87 animals developed lung tumors. Statistical methods that correct for intercurrent mortality showed a significant increase of the lung tumor risk with respect to Thorotrast treatment, even for the low quartz groups with nearly similar incidences of lung tumors (in the group with ThO2, 39 out of 87 = 44.8%; in the group without ThO2, 37 out of 82 = 45.1%). The tumors were found predominantly in the peripheral regions of the lung and were preceded by proliferation and hyperplasia of the alveolar and bronchiolar epithelium. The results demonstrate a pronounced interactive effect of quartz and Thorotrast on carcinogenesis of the lung. The underlying possible mechanisms are discussed.

Long-term tissue distribution and steady state activity ratios of 232Th and its daughters in rats after intravascular injection of Thorotrast.

To estimate the absorbed dose in the critical organs of Thorotrast patients, it is necessary to know not only the distribution and concentration of 232Th but also its daughter nuclides in the body. The present investigation was undertaken in order to clarify the long-term 232Th tissue distribution and steady state activity ratios between subsequent daughters in the critical tissues using about 30 Wister male rats, as a basis for estimating absorbed doses. The tissue distribution of thorium was examined by means of an autoradiography of the whole body and/or the gamma-ray spectrometry at various times during 2 to 24 months following injection. The concentrations of daughter nuclides in tissues were determined by repetitive gamma examination over a period from 1 hr to 35 days after being sacrificed. The data indicate (1) that approximately 90% of injected Thorotrast is retained in the body for a prolonged period, but about 50% of radium and 10% of radon produced from thorium are eliminated from the body, (2) that the mean steady state activity ratios of 224Ra and 212Pb to 228Th for liver are 0.56 and 0.28, and 0.54 and 0.16 for spleen, 0.58 and 0.82 for lungs, respectively, and (3) that the parent 228Th is translocated to the bone.

[Late complication of angiography - thorotrastoma causing pharyngeal phlegmon]. / Pozdnee oslozhnenie angiografii - torotrastoma, vyzvavshaia flegmonu glotki.

Carotid angiography with the use of thorium dioxide for brain tumour diagnosis has been performed in a woman 35 years ago. In the course of angiography thorium dioxide penetrated into the paravascular space with subsequent development of "thorothrustoma" the clinical symptoms of which progressed for years (compression of neck organs and nerves, gradual disturbance of swallowing). As a result of compression a decubitus ulcer and phlegmona of the pharyngeal wall developed. Late diagnosis of the phlegmona and its inadequate treatment resulted in aspiration pneumonia which was a direct cause of the patients death.

Rapid identification of correctly located intracerebroventricular cannula in the rat.

We describe a radiographic technique to identify a correctly located cannula in the ventricular system of the rat brain during life. A suspension of thorium dioxide was infused into the left lateral ventricle through a cannula placed in the brain under stereotaxic guidance. Correctly located injections were identified by the presence of a distinct thorium shadow on lateral X-ray of the in situ brain. When 6-hydroxydopamine was co-injected with thorium the resultant depletion of striatal dopamine and the changes in a conditioned avoidance responses were correlated with the degree of spreading of thorium through the ventricular system.

Epidemiological follow-up study of Japanese Thorotrast cases--1980.

An epidemiological follow-up study was conducted on 272 Thorotrast-administered war-wounded ex-servicemen to determine their status as of 31 December 1980, after a lapse of 35-43 yr from Thorotrast injection. In the 251 cases who had been intravascularly injected with Thorotrast in the past, 40 malignant hepatic tumors, 3 blood diseases, 2 lung cancers, 1 osteosarcoma, 22 other malignant tumors, and 13 cases of liver cirrhosis were found. The mortality rates due to hepatic and other malignant tumors, blood diseases, and cirrhosis of the liver as well as the overall mortality rate were significantly higher in the intravascular-Thorotrast group than in the controls. In the remaining 21 cases, who had been given Thorotrast by a route other than intravascularly, none of the deaths was found to be related to Thorotrast administration.