Determination of thorium in organs from thorotrast patients by inductively coupled plasma mass spectroscopy and x-ray fluorescence.

Concentrations of thorium were determined by inductively coupled plasma mass spectroscopy in various organs collected from Japanese Thorotrast autopsy subjects to provide information on dosimetry for Thorotrast patients. Duplicate analyses were performed for 98 samples, and data for thorium in 27 different organs were obtained. The highest thorium level was found in spleen (mean: 16,000 microgram/g wet weight), followed by liver (2100 microgram/g wet weight) and bone marrow (600 microgram/g wet weight). The other concentrations decreased in the following order: lymph node, gallbladder, testis, lung, small intestine, adrenal gland, pancreas, dura, esophagus, muscle, thyroid, large intestine, stomach, fat, kidney, urinary bladder, main artery, prostate, diaphragm, trachea, heart, cerebellum, cerebrum and intervertebral disk. The last four organs showed markedly low concentrations of 2-7 microgram/g wet weight. Compared to the background thorium levels reported in the literature for human organs, the values for the organs from Thorotrast patients (even in the organs with the lowest concentrations) were at least several thousand times higher, suggesting the importance of also considering organs with minor deposition in dosimetry. Distributions of thorium in some selected organs were studied by microbeam X-ray fluorescence. The thorium conglomerates could be identified, and images of microdistributions of thorium in the organ slices were obtained.

Partition of thorium between organs of monkeys injected with thorotrast: implications for alpha-particle dosimetry.

Risk estimates for alpha-particle-induced malignancies have been based mainly on studies of Thorotrast patients, but certain aspects of its deposition in the body have been at issue: the partition between the liver, spleen and red bone marrow, and the deposition at lower concentrations in other organs, such as muscle and fat, which may contribute to the risk. To supplement the existing data for humans, thorium concentrations were measured in the organs of two female monkeys 3-4 years after injection with Thorotrast. Relative deposits (liver:spleen:red bone marrow) were 54:6:41 and 75:4:21, in better agreement with the most recent observations in Thorotrast patients than with previous reports. Whereas the human testis had ranked among intermediate-level organs such as the adrenal glands and pancreas, the ovary of the monkey was among the organs with the lowest concentrations. The data suggest that risk factors for induction of malignancies by alpha-particle irradiation should be re-examined.

Revised organ partition of thorium-232 in thorotrast patients.

Risk estimates for internally deposited alpha particles in humans, such as those for alpha-particle-induced leukemia, have been derived from data on the toxicity of (232)Th in patients injected with Thorotrast. Their derivation requires both epidemiological data and organ doses calculated from the volume of Thorotrast injected and a knowledge of its pattern of deposition within the body. However, accumulating evidence suggests that the organ partition of (232)Th that has commonly been used for dosimetry (i.e. liver:spleen:red bone marrow: others tissues = 59:29:9:3) is inaccurate. In the present study, the organ distribution of (232)Th has been recalculated using a revised averaging method and both published data and our own unpublished data. For the three major organs of deposition (liver, spleen and bone marrow), activity concentration data were selected from 27 published papers and data sets including 140 newly compiled Japanese cases. For organs of minor storage, both published data for 38 German and 24 Japanese autopsy cases and new data were used. The revised estimate of the relative partition of (232)Th among the above organs was 53:14:25:8. It follows that doses calculated to date are essentially correct for the liver but are too high for the spleen and about three times too low for the red bone marrow. This suggests that the risk of alpha-particle-induced leukemia, per unit of alpha-particle dose, in Thorotrast patients is about three times lower than previously thought.

Systemic deposits of thorium in thorotrast patients with particular reference to sites of minor storage.

It is well established that injected Thorotrast is deposited in the liver, spleen, bone marrow, and lymph nodes, but accumulations in organs with lower macrophage activity have previously been given little attention. In this work, neutron activation analysis has been used to investigate concentrations of thorium in autopsy samples taken at sites of major and minor deposition in 24 Thorotrast patients. In the latter category, the highest values were found in the testis [40 x 10(-6) g/g(wet)], followed by those in the adrenal gland, gallbladder, lung, and pancreas. The resulting alpha-particle dose rates (mGy/year) are tentatively estimated to be 8.5 to the testis, 5.5 to the gallbladder, and 5.3 to the lung. These results may be relevant to the residual excess mortality among Thorotrast patients after diseases of the principal organs of deposition have been excluded; they also support previous indications that thorium deposited in pulmonary tissues is responsible for an important component of the total dose to the lung. In another context, our data may bear on the connection, postulated elsewhere, between exposure to alpha-particle emitters and elevated incidence of leukemia in the children of workers engaged in the reprocessing of nuclear fuel.

Tissue distribution of Thorotrast and role of internal irradiation in carcinogenesis.

Carcinogenesis in Thorotrastosis has been assumed due to direct bombardment by alpha-particle with high linear energy transfer during decay of 232Th. To revisit the mechanism of carcinogenesis by Thorotrast (THR), we examined the tissue distribution of THR granules and two-dimensional distribution of radioactivity in the organs of Thorotrastosis patients and studied their spatial relationship to histopathological changes. The high radioactivity in the patients' organ was predominantly derived from decay of Thorium series and showed unique distribution, while the far lower natural radioactivity was mainly from Uranium series decay and fairly evenly distributed. It was found that a large majority of THR granules were phagocytized by macrophages and were embedded in extensive fibrosis. Cancer was rarely in the center of THR deposition but rather at a distance from the deposits. These observations may indicate that the predominant feature of THR deposition is the tissue damage by direct hit of alpha-particles and subsequent fibrosis. The effect of THR resembles action of toxic chemical agents, as several authors have pointed out. We therefore assume that carcinogenesis in Thorotrastosis is a combination of events, such as regeneration of liver tissue after radiation damage, emission of secondary electrons, ionization of the surrounding tissue, and beta- or gamma-ray from daughter nuclei of Thorium (Th). In this context, the role of alpha-particle is important but more intriguing.

Alpha-particle carcinogenesis in Thorotrast patients: epidemiology, dosimetry, pathology, and molecular analysis.

We studied the alpha-radiation risks in patients who received injections of Thorotrast, an X-ray contrast medium used in Europe, Japan, and the United States from 1930 to 1955. Thorotrast was composed of thorium dioxide (ThO2) and Th-232, a naturally occurring radionuclide. Because the physical half-life of ThO2 is 14 billion years and Thorotrast is hardly eliminated from the body, tissues in which it was deposited are irradiated by alpha-radiation for the entire lifetime of the subject. The dosimetry of Thorotrast patients is very complicated, but currently its reliability is quite high compared with other irradiated populations. The major causes of the death of Thorotrast patients are liver cancer, liver cirrhosis, leukemia, and other cancers. Three histologies of liver cancer are found: cholangiocarcinoma, hepatocellular carcinoma, and angiosarcoma. Although cholangiocarcinoma is the most frequent, angiosarcoma is characteristic of alpha-radiation. Among blood neoplasms with a higher incidence of increase than the general population, erythroleukemia and myelodysplastic syndrome were remarkable. Thorotrast patients exhaled a high concentration of radon (Rn-220), a progeny of Th-232, but no excesses of lung cancer in the patients of Japan, Germany, and Denmark were reported. Mutation analyses of p53 genes and loss of heterozygosity (LOH) studies at 17p locus were performed to characterize the genetic changes in Thorotrast-induced liver tumors. Interestingly, LOH, supposedly corresponding to large deletions was not frequent; most mutations were transitions, also seen in tumors of the general population, suggesting that genetic changes of Thorotrast-induced cancers are mainly delayed mutations, and not the result of the direct effects of radiation.

Analysis of tissue samples containing colloidal thorium dioxide (Thorotrast) or zirconium dioxide (Zirconotrast): radiochemical preparation and alpha-spectrometry.

The aim of the present study is to assess the activity of the thorium isotopes, Th-232, Th-230, and Th-228 in tissue samples containing Thorotrast or Radiozirconotrast, i.e. Th-230 and Th-228 enriched Zirconotrast, in order to enable calculations of tissue doses. Therefore: 1. a procedure was developed for radiochemical processing of these samples, and 2. a computerised alpha-spectroscopy system has been constructed for routine activity measurements. The procedure developed for sample preparation permitted complete radiochemical processing of the above tissue samples. By subsequent electrodeposition of the thorium isotopes as well as the internal isotopic tracer Th-229, almost massless sources were obtained for alpha-spectrometry. The recovery amounts to a mean of 85% and 70% for tissues containing Thorotrast and Radiozirconotrast. With regard to the great number of samples to be measured and the expected counting times of more than 1500 min, a computerised alpha-spectroscopy system with a sample conveyor has been constructed. The energy resolution is between 45 keV and 75 keV FWHM. The detection efficiency amounts to 12%. The values of the detection level for the thorium isotopes are between 1,4 mBq and 3,1 mBq.

MRI in thorotrastosis.

Magnetic resonance imaging (MRI) and computed tomography (CT) were performed in four patients with thorotrastosis. On CT scan, Thorotrast (thorium oxide) deposition was shown as high-density areas in the liver and spleen and the abdominal lymph nodes. These deposits were not found on MRIs. Splenic volume was significantly small due to atrophy. The contrast-noise ratio in the spleen on T1-weighted images was significantly lower. Thorotrast deposition does not affect MRI appearance; therefore it may be useful for the early detection of malignant tumors as a complication of thorotrastosis.

Comprehensive evaluation of a Thorotrast patient: an overview.

For several decades, thousands of people received Thorotrast during the course of angiography and other radiologic procedures. Eventually, as the hazards of this radioactive, radiographic contrast agent became apparent, research was initiated to further evaluate its associated adverse effects. In 1988 and 1989, Charles W. Mays, together with colleagues at a variety of sites, developed a detailed protocol for the comprehensive postmortem evaluation of one subject who had been administered Thorotrast 36 y previously. This case represents the first holistic approach to the analysis of Thorotrast in a whole body, simultaneously assembling clinical and autopsy findings with dosimetric, radiochemical, autoradiographic, and molecular evaluations.

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.

Measurement of thorium isotopes and 228Ra in soft tissues and bones of a deceased Thorotrast patient.

The whole body of an individual injected with Thorotrast 36 y prior to her death was analyzed for 232Th, 228Ra, 228Th, and 230Th. Measurement of these isotopes in all tissues of the body will provide data necessary to caculate the radiation dose to individual tissues and to evaluate the risk potential associated with deposition of thorium and progeny in humans. The tissues were ashed, dissolved in acid, and the thorium isolated by ion exchange and electrodeposition. The 228Ra was determined by measuring the 0.991-MeV gamma rays associated with decay of the 228Ac daughter. It was estimated that almost all of the 232Th from the original injection was retained in the body, mostly in the tissues of the reticuloendothelial system. A total of 28 kBq (0.76 microCi) of 232Th was measured in the soft tissues and bones. The body also contained 13 kBq 228Ra, 12 kBq 228Th, and 3.9 kBq 230Th. A Thorotrastoma contained about 3.5% of the total activity. Excluding the Thorotrastoma, approximately 45% of all the activity (232Th, 228Ra, 228Th, and 230Th) was retained in the liver, 13% in the spleen, 2% in muscle, 1% in skin, slightly less than 1% in the respiratory tract, 4% in all other soft tissues, and 33% in the skeleton (bone and bone marrow). Sixty to 80% of the thorium activity in bones containing red marrow was located in the marrow. Bones containing yellow marrow had less than 40% of the thorium activity in the marrow. Highest concentrations were found in the hepatic and other abdominal lymph nodes, spleen, hilar lymph nodes, liver, trachea, and bone. Approximately 60% of the 228Ra formed from the decay of the 232Th had been excreted from the body. The 228Ra and 228Th were in approximate equilibrium throughout the body.

External gamma-ray counting of selected tissues from a Thorotrast patient.

Results of gamma-ray measurements of selected tissues from a patient who was injected with Thorotrast almost 36 y ago are reported. The purposes of this study were: 1) to determine the relative tissue distribution and activities of specific radionuclides in the 232Th decay chain, specifically 228Ra (as measured by 228Ac), 212Pb, and 224Ra (measured directly and as measured by 212Pb), and 2) to evaluate the level of radioactive disequilibrium among the daughter products. The spleen and liver had the highest concentrations of radioactivity. Bone also appears to be a long-term sink for 232Th daughter products based on estimates from a small portion of one rib. Larynx and esophagus contained measurable activity, which may have been due to their proximity to the "Thorotrastoma." Radioactivity in the remaining measured tissues were low, as expected. Secular equilibrium could be demonstrated in bone, pancreas, larynx, esophagus, and breast. Significant disequilibrium was observed for spleen, liver, kidney, and red blood cells. Radioactivity measurements reported here will be useful in estimating radiation doses to selected tissues. Such dose estimates are valuable in refining current risk estimates (e.g., liver) and in identifying tissues at risk for further epidemiologic studies. These results, while consistent with other published studies, should be interpreted with caution since measurements were made on only one patient.

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.

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.

Distribution of natural thorium in the tissues of a whole body.

The distribution of thorium in the tissues of a whole body donor to the United States Transuranium and Uranium Registries is described. This case, identified by the USTUR as Case 0212, had two documented intakes of plutonium and americium from occupational accidents while employed at Hanford but no known occupational exposure to thorium. Concentrations of 239+240Pu, 241Am, and 232Th in the tissues are compared and the distribution of these isotopes in this case is evaluated. The distribution data for 232Th are compared to those from previous studies of thorium in human tissues resulting from environmental exposure and to an individual exposed to Thorotrast (colloidal ThO2) in a medical diagnostic procedure. The 232Th distribution data from this work are also compared against ICRP 30 and ICRP 69 models for the behaviour of thorium in the human body.

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.

Erythroleukemia and gastric cancer following thorotrast injection.

A 63-year-old male, who had undergone angiography using thorium dioxide (Thorotrast) at the age of 15 for investigation of a giant hemangioma on his left thigh, developed anemia in September 1986 (47 yrs after the angiography). A diagnosis of erythroleukemia was made from a bone marrow study which showed 56.4% megaloblastoid erythroblasts and 12.8% myeloblasts. Autopsy revealed Thorotrast deposition in the liver, spleen, bone marrow, and lymph nodes, and monotonous proliferation of myeloblasts in the bone marrow. He also had differentiated tubular adenocarcinoma of the posterior wall of the stomach.

Tissue studies of persons with intakes of the actinide elements: the U.S. Transuranium and Uranium Registries.

For more than three decades, the United States Transuranium and Uranium Registries (USTUR) have studied the biokinetics, dosimetry, and biological effects of plutonium, uranium, and americium through voluntary postmortem tissues from persons with known intakes. Radiochemical analyses of tissue obtained at autopsy have shown that plutonium and americium have different biokinetics and an appreciable deposition in the soft tissues of the body as well as the known depots in skeleton and liver. Studies of whole-body Thorotrast donors to the USTUR indicate that commonly accepted risk coefficients for alpha induction of bone sarcoma may be too high while those for leukemia are a factor of six too low. This review considers these and other major contributions of the USTUR.

Spurious dual-energy X-ray absorptiometry images in a patient exposed to the contrast agent Thorotrast.

A 69-year-old woman presented with a 20-year history of back pain and a 10 cm height loss. She had received an injection of the contrast agent, Thorotrast, at age 23. There was no history of fluoride exposure. Multiple vertebral compression fractures were seen on radiographs. Dual-energy X-ray absorptiometry (DXA) scans revealed high normal bone mineral content on the spine and, on whole body scan, visualization of the liver and spleen regions. Given the attenuation coefficient of thorium and the thorium concentrations reported for liver, spleen and vertebral bodies, it is likely that thorium was visualized in the liver and spleen and that it caused spurious elevation in her DXA bone mineral content values.