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PubMed1999

Cancer mortality of thorotrast patients in Japan: the second series updated 1998.

The 150 male patients exposed to Thorotrast who were confirmed by a 1975-1978 national survey with diagnostic X rays of 50,860 war-wounded soldiers were followed up between 1979 and 1998 (Aichi series or second series). Age-adjusted rate ratios of deaths from all causes were 3.0 times higher in Thorotrast patients compared to controls; this was statistically significant. Rate ratios for liver cancer, liver cirrhosis and leukemia were 35.0, 7.5 and 18.2, respectively.

Adult↗
PubMed1999

Summary of entire Japanese thorotrast follow-up study: updated 1998.

Updated data from two series in a cancer mortality study for a total of 412 Japanese Thorotrast patients were combined. The rate ratio for all deaths of Thorotrast patients, compared to controls, started to increase after a latent period of 20 years after injection of Thorotrast. Rate ratios for liver cancer, liver cirrhosis, leukemia and lung cancer were 35.9, 6.9, 12.5 and 2.0 times higher, respectively, than those for controls.

Adult↗
PubMed1999

Mortality in the Portuguese thorotrast study.

The Portuguese Thorotrast study cohort consists of a group of patients who received Thorotrast for diagnostic reasons between 1929 and 1956, and a group of similar patients who were given nonradioactive contrast agents. The cohort members were identified from medical records that contained information on reasons for the radiological investigation, type of procedure employed, and name and dose of the contrast medium used. This cohort was assembled in 1961, but its follow-up was interrupted in 1976. We have now reactivated this cohort and extended its follow-up through the end of 1996. Similar methods were used to follow up and ascertain cause of death for the Thorotrast-exposed and unexposed subjects. A total of 1931 patients who received Thorotrast systemically and 2258 unexposed subjects were initially identified from medical records. We were able to successfully follow up 58.6% (1131) of the Thorotrast patients and 45.7% (1032) of the unexposed patients. By the end of 1996, 92.2% of the Thorotrast patients and 75.2% of the unexposed patients were dead. Mortality from all causes was increased in the Thorotrast patients compared to those who were not exposed. This excess in mortality increased with time since exposure, peaking 30 years after administration of Thorotrast. The rise in overall mortality was essentially due to neoplasms [relative risk (RR) adjusted for sex, age and period = 6.04, 95% CI = 4.42-8.26], nonmalignant liver disorders (RR = 5.67, 95% CI 3.13-10.3) and nonmalignant hematological conditions (RR = 14.2, 95% CI = 2.54-79.3). The increase in mortality from neoplasms was explained mainly by increases in the risk of liver cancer (RR = 70.8, 95% CI = 19.9-251.3) and, to a much lesser extent, leukemia (RR = 15.2, 95% CI = 1. 28-181.7).

Adolescent↗
PubMed1999

Lung dosimetry for thorotrast patients: implications for inhalation of radon progeny.

A peculiar feature of radiation-induced carcinogenesis in German Thorotrast patients is that no excess lung cancers have been observed so far in the epidemiological follow-up study. Two possibilities have been explored here to explain the apparent discrepancy between predicted and observed bronchial tumors: (1) Bronchial doses are smaller than presently predicted; and/or (2) lung cancer risk per unit exposure in Thorotrast patients is smaller than that derived from inhalation of (222)Rn progeny. First, the mean bronchial doses computed with an updated dosimetric model for the different radiation sources are indeed substantially smaller than previous dose estimates; however, the epidemiological findings still cannot be explained in terms of bronchial doses. Second, lung cancer risk estimates based on the revised dose estimates and relative risk coefficients specifically derived from chronic indoor exposures still yield a relative risk of 1.66 for the German Thorotrast patients. This suggests that either the lung cancer risk coefficient for inhalation of radon progeny cannot be applied to Thorotrast patients because of differences in dose distributions or exposure conditions, or the current tissue weighting factor should be applied primarily to the bronchial region of the lung in the case of exposure to radon progeny.

Administration, Inhalation↗
PubMed1999

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.

Humans↗
PubMed1999

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.

Bone Marrow↗
PubMed1999

The reticuloendothelial system and macrophage-monocyte system in thorotrast patients.

To evaluate the function of the reticuloendothelial system and macrophage-monocyte system, blood samples from Thorotrast patients and age-matched healthy controls were used to determine the titer of plasma antibodies to lipid A and the numbers of several lymphocyte subclasses in peripheral blood and for an autoradiographic study of peripheral blood monocytes. The titer of plasma IgM class antibodies to lipid A was significantly elevated in the Thorotrast patients. Counts of CD 11-positive lymphocytes and CD 57-positive lymphocytes, which correspond to monocytes and natural killer cells, respectively, were significantly increased in the Thorotrast patients. Autoradiography showed that alpha-particle tracks were emitted from the monocytes isolated from the peripheral blood of Thorotrast patients. Thus the depressed function of the reticuloendothelial system resulted in the activation of the macrophage-monocyte system in the Thorotrast patients.

Aged↗
PubMed1999

Analysis of genetic changes in intrahepatic cholangiocarcinoma induced by thorotrast.

Thorotrast, a colloidal suspension of radioactive (232)ThO(2) that emits alpha particles, was used as a radiographic contrast agent in the 1930s-1950s. Several decades after injection, Thorotrast causes liver cancers, among which intrahepatic cholangiocarcinoma (ICC) is prominent. We investigated mutations of the RAS and the TP53 genes in archival sections of ICC induced by Thorotrast. Compared to ICC that was not associated with Thorotrast, the frequency of mutation of the KRAS gene was lower, while that of the TP53 gene was more than two times higher. The most common mutation of the TP53 gene was A-G transitions. Interestingly, TP53 mutations were also found in noncancerous areas of livers in which Thorotrast had been deposited. Furthermore, mutations tended to accumulate in tissues from more advanced tumors. These results suggest that deposited Thorotrast continuously damages DNA in liver cells in some way, resulting in A-G transitions of the TP53 gene. However, we have not been able to rule out the possibility that genetic insults occur indirectly in the proliferating cells adjacent to the necrosis rather than being a direct effect of alpha particles.

Aged↗
PubMed1999

Chromosome aberrations in bone marrow cells from Japanese patients with thorotrastosis.

Exposure of bone marrow cells to alpha-particle radiation causes various types of chromosome abnormalities and hematological malignancies. We performed chromosome analysis of hematopoietic stem cells from the bone marrow of 52 Japanese patients with thorotrastosis and 21 age-matched controls. The frequency of cells with stable chromosome abnormalities was significantly higher in the patients with thorotrastosis. Further studies found 14 clonal chromosome aberrations in cells from 11 patients (21.2%); clones observed in the cells from 2 of these patients had high frequencies of chromosome abnormalities. In one case, 68 to 100% of the cells analyzed had a large partial loss in the short arm of chromosome 1 and a translocation between the short arms of chromosomes 2 and 3 [46,XY,1p-,t(2p+;3p-)]. The cells from the other patient contained a clone with partial loss of both the short and long arms of chromosome 5 (46,XX,5p-,5q-). The frequency of this clone has been constant for the last 15 years (6-24%). We also analyzed bone marrow mononuclear cells from 17 of the patients for mutations of the TP53 tumor suppressor gene (formerly known as p53). However, no mutation was found in any of the cells, including those from the 2 patients with abnormal clones. Moreover, repeated medical examinations showed no evidence of leukemia or myelodysplasia in these patients. Our study suggests that exposure of bone marrow cells to alpha-particle radiation may induce clonal chromosomal aberrations at a high frequency.

Aged↗
PubMed1975

On thorotrast leucaemia. Evolution of clone of bone marrow cells with radiation-induced chromosome aberrations.

Results are presented of chromosome studies of bone marrow cells from a 62-year-old woman. The patient had been given 40 ml of Thorotrast in connection with a neuro-radiological examination 34 years earlier. Clinically, the patient was now considered to be in an incipient myeloid leucaemic phase. Ninety-seven per cent of the bone marrow cells belonged to a clone with characteristic marker chromosomes induced by radiation. Few data are available on chromosome analysis of bone marrow cells from Thorotrast patients. Therefore, the results of the present study are compared with data from chromosome analyses of 32P-treated patients with polycythaemia vera, in whom large clones were found in the bone marrow. The results of chromosome analysis of bone marrow cells from the Thorotrast patient support previous hypotheses concerning the carcinogenesis in radiation-induced leucaemia in patients with polycythaemia vera, treated with 32P. In the latter patients, the clone cells are pressumed to represent cell populations with selective qualities, originating from radiation-damaged cells, which possibly possess an increased tendency to malignant transformation because of a more pronounced sensitivity to carcinogenic agents. The cells might also be potentially malignant and manifest themselves as leucaemic cells, if the patient's immunological defence mechanism is broken.

Bone Marrow↗
PubMed1999

Vinyl chloride-specific mutations in humans and animals.

Vinyl chloride is a potent hepatocarcinogen which reacts with DNA to generate etheno bases. In order to determine whether mutational patterns in target genes in vivo are characteristic of vinyl chloride and could be explained by the mutagenic properties of the etheno bases, human and rat liver tumours associated with exposure to vinyl chloride were analysed for point mutations in the ras and p53 genes. In this paper, we review these data and report our latest results on animal tumours. Two alterations were found which could be attributed to a direct effect of vinyl chloride: a GC-->AT transition which leads to a GGC-->GAC mutation at codon 13 of the Ki-ras gene in human liver angiosarcomas, and lesions at AT base pairs, mostly AT-->TA transversions, which lead to mutations in the p53 gene in human and rat angiosarcomas and to a CAA-->CTA mutation at codon 61 of the Ha-ras gene in rat hepatocellular carcinomas.

Alleles↗
PubMed1975

Inhibition of intravascular fibrin deposition by dipyridamole in experimental animals.

Intravascular fibrin deposition was induced in rabbits by endotoxin, the infusion of fibrin monomer (FM), and by the infusion of thrombin and EACA. A previously developed radioisotope technique was used to measure the fibrin deposits in various organs. Dipyridamole treatment of rabbits caused significant inhibition of fibrin deposition in all three experimental models. The drug also inhibited platelet consumption and, in the thrombin- and EACA-infused animals, fibrinogen consumption as well. The results obtained with dipyridamole were compared with the effect of thorotrast. It was concluded from this comparison that the effect of dipyridamole could not be attributed to inhibition of the reticuloendothelial system. It is postulated that dipyridamole inhibits the final step at which soluble FM is precipitated as fibrin in vivo.

Aminocaproates↗
PubMed2000

Locoregional late effects of paravascular thorotrast deposits: results of the german thorotrast study.

PURPOSE: The aim of this study was to assess late effects of long-term exposure to alpha irradiation caused by paravascular Thorotrast deposits. SUBJECTS AND METHODS: 899 patients, who had received the radioactive contrast medium Thorotrast for angiography in the 1930s and 1940s, and 662 controls were followed-up since 1968 every two years by standardized clinical and laboratory examinations. Initially, X-ray plain films of the thorax, upper abdomen and the former injection site were performed. In selected patients the sites of paravascular Thorotrast deposits were evaluated by ultrasonography, CT and MRI. RESULTS: Paravascular Thorotrast deposits were detected in 245 patients. Clinical symptoms related to deposits appeared 10 to 30 years after Thorotrast administration. The severity of symptoms depended on the location and extension of granulomas and were mainly caused by fibrosis, nerve paralysis and vascular changes. Four malignant tumors adjacent to granulomas were observed (one soft tissue sarcoma in the groin, two squamous cell carcinomas of the parotid gland and one lymphoepithelial carcinoma of the nasopharynx). MRI including MRA allowed an accurate determination of tissue damage, whereas the utility of US and CT was restricted due to strong sound attenuation and streak artefacts caused by the high X-ray absorption of Thorotrast. DISCUSSION AND CONCLUSION: Locoregional late effects of paravascular Thorotrast deposits mainly comprise radiation induced, fibrotic tissue destruction. The incidence of malignant tumors, in particular sarcomas, adjacent to deposits, however, is much lower than initially expected.

Adolescent↗
PubMedDate not supplied

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.

Actinoid Series Elements↗