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PubMed1988

Alpha-particle-induced cancer in humans.

Updated information is given on alpha-particle-induced cancer in persons internally exposed to 222Rn progeny, Thorotrast, long-lived 226Ra and 228Ra, and short-lived 224Ra. The lung cancer risk to persons breathing 222Rn progeny in the indoor air of offices, schools, and homes is of increasing concern. About half of the recent deaths among the German Thorotrast patients have been from liver cancer. Animal studies indicate that the liver cancer risk from Thorotrast is mainly from its radioactivity and that the risk coefficient for the Thorotrast patients can be used provisionally for other alpha emitters in the human liver. Six skeletal cancers have occurred in persons with average skeletal doses between 0.85 and 11.8 Gy from 226Ra and 228Ra. In the low-dose German 224Ra patients, two skeletal sarcomas have occurred at about 0.7 Gy compared to about six cases predicted by results from 224Ra patients at higher doses. The minimal appearance time for radiation-induced bone sarcomas in humans is about 4 y. Following brief irradiation, the vast majority of induced bone sarcomas are expressed by about 30 y. Recent evidence against the "practical threshold" hypothesis is given. With the downward revision of neutron doses to the atomic-bomb survivors, the follow-up of persons exposed to alpha particles may be the best opportunity to evaluate directly the effects of high LET radiation on humans.

Alpha Particles↗
PubMed1989

Radionuclide contents in building materials used in Hong Kong.

The radionuclide contents of conventional natural raw building materials, coal ash and slag, and finished building products have been determined using gamma-ray spectrometry. Results of brick measurements in their original geometry and in crushed form are compared. The radioactive concentrations in cement and sand, mostly imported from China, are among the lowest measured. However, due to the high radioactivity of aggregates, composed of granite mainly extracted locally, the mean Ra equivalent activity of concrete is high compared with that in some countries. The radioactivity levels of coal ash and slag in Hong Kong are about the average values in other countries. The incorporation of coal ash and slag in ordinary concrete does not alter the radioactivity significantly.

Construction Materials↗
PubMed1990

Lung dosimetry of thorotrast patients.

Deposits of intravascularly injected Thorotrast in the reticulo-endothelial system of Thorotrast patients are a continuous source of 220Rn. In this study, we modeled the transport of 220Rn from these deposits through the body into the lungs, exhalation of 220Rn from the lungs, production of 220Rn progeny in the lungs and their exhalation, and mucociliary clearance of 220Rn progeny deposited on airway surfaces. The injection of 1 mL Thorotrast produces annual doses of 0.48 mGy y-1 to the bronchial epithelium and 0.95 mGy y-1 to pulmonary tissue. Based on a mean injected volume of about 25 mL and an average exposure time of 30 y, German Thorotrast patients received a mean bronchial lifetime dose of 357 mGy. Despite these relatively high doses, comparable to exposure in uranium miners, no excess lung cancers could be observed in the epidemiologic follow-up study. This apparent discrepancy between predicted and observed bronchial tumors may have important implications for lung dosimetry and risk assessment of inhaled 222Rn progeny.

Bismuth↗
PubMed1992

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.

Aged↗
PubMed1992

Alteration of the c-fms gene in a blood sample from a Thorotrast individual.

We analyzed six different tissue DNA samples from a leukemic individual who received an injection of Thorotrast for alterations in proto-oncogene or tumor-suppressor gene structure. Our examination of the DNA indicated an alteration of the c-fms gene in the blood sample from this individual. This locus showed a deletion in which the 3' end of the deleted region maps between exons 11 and 12. In this particular case, the type of leukemia is unknown but myeloid leukemia is a neoplasm associated with individuals injected with Thorotrast. It is possible that the alteration in the c-fms gene of this individual is a consequence of the radiation exposure. No apparent alterations in the c-mos gene were observed in any of the tissues from the individual. This is in contrast to previous studies that described alterations in methylation patterns associated with the c-mos locus in radium-exposed individuals. A number of the individuals exposed to radium also had alterations of the retinoblastoma gene while no such alterations were observed in any tissue DNA samples from this Thorotrast case. It is possible that our inability to detect alterations of the c-mos and retinoblastoma gene may be attributable to the nature of alpha-emitting radionuclides or their distribution, or to the limited set of tissues available for analysis.

Aged↗
PubMed1992

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.

Aged↗
PubMed1992

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.

Aged↗
PubMed1992

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.

Aged↗
PubMed1992

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.

Aged↗
PubMed1992

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.

Aged↗
PubMed1992

Cancer risk following exposure to Thorotrast: overview in relation to a case report.

Radioactive measurements and histopathologic findings are described in a patient administered Thorotrast, a radiographic contrast agent, 36 y prior to death and compared with cancer risks noted in epidemiologic studies. This person [designated as U.S. Uranium Registry (USUR) Case 1001] had prearranged for donation of her body to the USUR and the National Cancer Institute for study. Elevated levels of radioactivity were noted in those organs in which excess cancers have been reported in epidemiologic surveys of Thorotrast-exposed subjects. Hepatic tissue in USUR Case 1001 was estimated to have received an average lifetime absorbed dose of 16.2 Gy, based on radiochemical analyses, consistent with the high risks for liver tumors reported in all studied populations. Thorotrast was present throughout the bone marrow of USUR Case 1001, who died secondary to complications of refractory anemia with excess blasts (RAEB). Elevated risks for acute myeloid leukemia have been noted in Thorotrast patients, and more recently, cases of RAEB and RAEB in transformation have been reported. The thorium decay series includes the bone-seeking radionuclides 224Ra and 228Ra, which have been associated with high risks for osteosarcomas, although the association between Thorotrast and bone cancer is not as convincing. The skeleton of USUR Case 1001, however, contained significant levels of radioactivity. Other tissues evaluated in USUR Case 1001 included lung, eye, kidney, and breast, which did not contain elevated levels of radioactivity.

Aged↗
PubMed1992

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.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1992

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.

Body Burden↗
PubMed1993

Liver cancer induction by 239Pu, 241Am, and thorotrast in the grasshopper mouse, Onychomys leukogaster.

Forty young adult grasshopper mice (Onychomys leukogaster) of both genders were injected with either 129 or 44 kBq kg-1 of monomeric 239Pu and were maintained for lifetime observation. Average liver doses to death (mean times +/- standard deviation (SD) from injection to death = 405 +/- 133 and 756 +/- 189 d) were calculated as approximately 16 and 9 Gy, respectively. These animals developed a total of 18 primary liver tumors (neoplasms, malignant, and benign). Comparison of these mice to a previously published study involving 49 control animals of the same species, 70 mice given 241Am, and 73 given Thorotrast, indicated that the liver cancer induction of Thorotrast can be attributed almost exclusively to the effects of the radioactivity and not to its nonradiation properties. This suggests that projected risks of liver cancer induction from 239Pu, 241Am, or other liver-seeking actinides in humans probably can be estimated from the liver cancer experience in Thorotrast patients using the calculated radiation doses to liver. For this species, the linear risk coefficient for induction of liver neoplasia (percent of mice with liver tumor) by 241Am or Thorotrast was estimated to be about 14.6 +/- 5.4 times the average liver dose (in Gy) for groups of animals with average liver doses of 5 Gy or less. The lowest average liver dose among groups of these mice given 239Pu was about 9 Gy, the dose was not in the linear range, and it was too high to yield reliable results for determining a risk coefficient for low dose irradiation. However, the estimates for a risk coefficient were similar for the plutonium and americium mice with liver doses of approximately 9 Gy or 16 Gy.

Americium↗
PubMed1993

Alpha-particle dose to the liver and spleen tissues of Japanese Thorotrast patients.

We set out to establish an appropriate and convenient method for calculating alpha-particle absorbed doses to the liver and spleen of Thorotrast patients and to estimate a representative dose rate to the liver for the whole population of surviving and deceased Thorotrast patients in Japan. First, we determined steady-state activity ratios of 232Th progeny from 13 autopsy cases and found them to be identical to those reported in German subjects. Second, we estimated the alpha dose rates in 206 subjects at autopsy from radioactivity measurements and terminal weights of the organs. Combining these results with measurements of exhaled 220Rn in survivors, we considered the representative dose rates at injection to be 0.22 Gy y-1. Additionally, our data suggest that deposition in the spleen has previously been overestimated. This is an error with some bearing on the evaluation of leukemia risks from alpha-particle irradiation.

Adult↗
PubMed1995

Alpha radiation risk coefficients for liver cancer, bone sarcomas, and leukemia.

This study compares published risk coefficients with those determined from dose rates established by postmortem radiochemical analysis of tissues from two whole body donors to the U. S. Transuranium and Uranium Registries, both of whom had been injected with Thorotrast approximately four decades prior to death. The dose data from these cases were used in combination with published latent periods and epidemiologic study results to calculate the following risk coefficients: 0.020 liver cancers Gy-1, 0.002 bone sarcomas Gy-1, and 0.032 leukemias Gy-1. These compare with the ranges of 0.013 to 0.074 liver cancers Gy-1, 0.0016 to 0.0120 bone sarcomas Gy-1, and 0.005 to 0.060 leukemias Gy-1 reported in the literature. The results of this study are generally consistent with previously reported values with two exceptions: the values for bone sarcomas fall below the range given by BEIR IV and the values for leukemia are a factor of 6 greater than those reported by BEIR IV. This suggests that the BEIR IV risk coefficient for bone sarcomas may be too high, and that for leukemia may be too low.

Aged↗
PubMed1995

Somatic-cell mutations as a possible predictor of cancer risk.

The somatic-mutation theory of carcinogenesis has received strong scientific support from results of recent studies on tumor-suppressor genes. We anticipated that people among the high risk for cancer group, either through exposure to various ionizing radiations or by virtue of unique genotypes, would also manifest increased frequencies of somatic mutation. This report presents the results of two somatic-mutation assays--at the erythrocyte glycophorin A (GPA) and lymphocyte T-cell receptor (TCR) genes--in various groups at high risk for cancer development, including atomic-bomb survivors, patients with various cancers, patients administered Thorotrast, and patients with genetic disorders that make them cancer prone. Although neither the GPA-mutation nor the TCR-mutation assay detects gene mutations directly related to carcinogenesis, increased mutation frequencies were detected by both assays in many individuals among the high-risk groups and among cancer patients. We have continued to follow up those individuals who show values of about three times higher than those of the control group. Thus, these assays may prove useful for identifying high-risk cancer groups and for estimating the effects of mutagens. Such information would constitute a valuable data base for epidemiological studies.

Adult↗
PubMed1998

Thorotrast distribution in monkey bone marrow at early and late times after injection.

Thorotrast, a 25% colloidal suspension of 232ThO2, was formerly used as a radiographic contrast medium. Although epidemiological studies have shown that alpha particles emitted from 232Th and its decay products incorporated in the bone marrow cause leukemia, the use of these data for alpha particle induced leukemogenesis risk estimation has been criticized mainly for inhomogeneity of Thorotrast distribution. Four monkeys were injected with Thorotrast to investigate the degree of inhomogeneity in the thorium content of different bone marrow sites and the cellular localization of Thorotrast. Two were injected via an artery and two via a vein and sacrificed either at 1 wk or 3 to 4 y after injection. Microscopic, solid state autoradiography and back scatter electron imaging methods were applied to several bone sites to determine the degree of inhomogeneity. Quantification was performed using x-ray fluorescence for trabecular bone and bone marrow and neutron activation analysis for compact bones. At 1 wk Thorotrast was found to be distributed evenly in the red marrow; by 3 and 4 y conglomerates were seen which were restricted to macrophages. The monkey was found to be a good model for humans. The choice of injection route did not noticeably affect the Thorotrast distribution in bones of the skeletal system. Considering the even distribution of Thorotrast within the red bone marrow at early times after its injection, the inevitable diffusion of thorium progeny from the particles, the mobility of bone marrow macrophages, and the well established correction factor of self-absorption within conglomerates, these results suggest that data derived from Thorotrast patients are useful for risk estimation of alpha particle induced leukemia.

Animals↗