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PubMed1999

[Thorotrast-induced liver cancer: results of the German thorotrast study].

AIMS: The X-ray contrast medium Thorotrast, used worldwide between 1930 to 1950 predominantly for arteriography, consisted of a colloidal solution of thorium dioxide. The radioactive thorium-232 (half-life 1.4x10(10) years) is stored lifelong in the organs of the reticulo-endothelial system after intravascular injection, causing chronic exposure to alpha radiation. The aim of the German Thorotrast study is the assessment of radiation late effects and the calculation of risk estimates. MATERIAL AND METHODS: The German Thorotrast study started in 1968 as a cohort study and comprises 2326 Thorotrast patients and 1890 patients of a matched control group. The Thorotrast patients who were still alive at the beginning of the study were examined by X-ray plain films of the upper abdomen and of the injection site of the contrast medium as well as by whole-body counter measurements. At the beginning we offered the patients ultrasound and later on CT and MRI at regular intervals for early detection of liver cancer. RESULTS: To date 454 primary liver cancers have been registered in the group of Thorotrast patients compared to 3 cases in the control group. With the help of modern imaging methods relatively small liver cancers were detected and could be surgically removed. DISCUSSION: There is a correlation between the mean accumulated dose to the liver and the incidence of liver cancer. The cumulative risk for liver malignancies is about 600 diseases per 10(4) persons whose liver was exposed to 1 Gy. Also the incidence of liver cirrhosis is correlated with the mean accumulated dose to the liver.

Alpha Particles↗
PubMed1981

[Hepatic angiosarcomas].

The authors describe three cases of hepatic angiosarcoma diagnosed at postmortem examination, two of them being associated to thorium dioxide. The low incidence of these tumors amongst the general population is commented upon, and an update is made on the factors involved in their appearance, with special mention of thorium dioxide. An analysis of the clinical picture of the disease is undertaken, emphasizing its diagnostic difficulties. A tentative diagnosis can be made on the basis of clear-cut epidemiological data and or the presence of increased radiological density over the liver, spleen and paraaortic lymph nodes in the cases associated to thorium dioxide. Two of the reported patients presented hemolytic anemia, and disseminated intravascular coagulation, respectively; these findings, although nonspecific, may suggest the diagnosis in the presence of a toxic clinical picture or one of the above mentioned factors. The diagnosis should be made by the usual techniques utilized clinically to detect space occupying lesions within the liver. The evolution of such patients is rapidly progressive, with a fatal outcome within three to six months after beginning of symptoms.

Aged↗
PubMed1978

Transplacental transmission and fetal parasitosis of Trypanosoma cruzi in outbred white Swiss mice.

Two strains of Trypanosoma cruzi, isolated from humans and assayed for their biological capacity to kill outbred white Swiss mice (HaM/CR-CD) following reticuloendothelial system blockade with thorium dioxide, were used in these experiments: the Maria Cristina strain, which killed all blocked mice at a rate following a rectangular dose-response curve, and the José Cardoso strain, which did not kill blocked mice at comparable dosages. When inoculated into pregnant HaM/CR-CD mice, the non-pathogenic José Cardoso strain did not cross the placental barrier, in either blocked or unblocked mice, to cause fetal parasitosis. The pathogenic Maria Cristina strain did not cross the barrier in non-blocked mice, but in thorium-dioxide blocked mice it produced an incidence of fetal parasitosis of 8.9% (7 of 79 fetuses). These results indicate that the transplacental transmission of T. cruzi was dependent on two restrictions: pathogenicity of the strain of T. cruzi, and blockade of phagocytic activity by thorium dioxide, suggesting that transplacental transmission of T. cruzi is related to interference with the phagocytic activity of the placenta.

Animals↗
PubMed1975

Electron microscopic studies on the uptake of exogenous marker particles by different cell types in the guinea pig metaphysis.

Guinea pig metaphyseal bone was exposed to horse spleen ferritin in vitro and to colloidal thorium dioxide in vivo. The cellular uptake and intracellular accumulation of these marker particles were studied ultrastructurally. In vitro, the ferritin molecules were found to spread evely throughout the tissue. After 1-2 hours ferritin was mainly found in plasma membrane invaginations and in endocytic vesicles of varying size. At 4-6 hours a successive accumulation of the marker in secondary lysosomes could be observed. In addition to ferritin, the lysosomes and the large endocytic vesicles often contained other inclusions. In vivo, the pattern of intracellular accumulation of the marker particles was identical to that in vitro. Moreover, the presence within the cells of similar amounts of thorium dioxide after 1 and 4 days suggested that these indigestible molecules are stored intracellularly for a considerable time. In accordance therewith there were no definite signs of extrusion of labeled bodies or secretion of the exogenous marker by exocytosis. Ferritin and thorium dioxide were taken up by all cell types in the metaphysis. Both in vitro and in vivo perivascular cells type B ingested large amounts of marker particles, whereas chondroclasts, endothelial cells. perivascular cells type A and osteoblasts showed a more restricted endocytizing ability. On the basis of these observations, the functional significance of different cell types in the resorption of the epiphyseal cartilage and the formation of bone is discussed.

Animals↗
PubMed1984

[Late complication of angiography - thorotrastoma causing pharyngeal phlegmon].

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.

Aged↗
PubMed1985

Chemical blockade of the reticuloendothelial system results in arteriolar spasms: possible role of endothelial cells.

Scattered qualitative studies in the literature suggest that the reticuloendothelial system (RES) interacts with the microcirculation to effect host defense and that chemical or pharmacologic blockade of the RES might compromise the microcirculation. With this possibility in mind, we designed experiments in rats to determine whether colloid and pharmacologic blockade of the RES could alter microvascular tone and reactivity. The effects of colloidal carbon, thorium dioxide, tripalmitin and tetracycline on reticuloendothelial system phagocytic function, mesenteric terminal arteriolar tone and arteriolar reactivity to noradrenaline and acetylcholine were examined in situ at magnifications up to 5000x. Colloidal carbon and thorium dioxide, in the doses utilized, produced complete blockade of the RES. Treatment with tripalmitin and tetracycline produced pronounced RES depression. RES blockade and depression were associated with marked reductions in terminal arteriolar lumen sizes, curtailment of capillary inflow and outflow, hyper-reactivity to the constrictor, noradrenaline, and hypo-reactivity to the dilator, acetylcholine. Close examination of the endothelial linings of the capillaries, postcapillary venules and terminal arterioles of the experimentally-treated animals indicated pronounced uptake of carbon particles in the endothelial cells, different degrees of endothelial cell swelling and often bulging into the microvessel lumens. Our findings suggest that RES-induced alterations in microvascular tone and arteriolar reactivity may be related to injury of the microvascular endothelial cells.

Animals↗
PubMed1985

Cutaneous Thorotrast granulomas and chronic lymphocytic leukemia following Thorotrast angiography.

A patient underwent cerebral angiography with thorium dioxide (Thorotrast). Six years later, an acne-like eruption of the face and scalp occurred which persisted despite aggressive treatment. Twenty-six years after the angiography he developed chronic lymphocytic leukemia with massive lymphadenopathy. Review of three facial biopsies revealed collections of Thorotrast-laden histiocytes and free thorium dioxide within a background of chronic inflammation and dermal fibrosis. These changes are of the same type described in Thorotrast granulomas of the subcutaneous tissues. There is an increased incidence of myelogenous leukemia in Thorotrast-treated patients; lymphoproliferative disorders, however, are only rarely observed.

Cerebral Angiography↗
PubMed1986

Splenic angiosarcoma following chemotherapy for follicular lymphoma.

A case of splenic angiosarcoma in a patient who had been treated for a follicular lymphoma with chemotherapy over a period of about nine years is reported. The etiologic agents for angiosarcomas at various sites, and their associations with other tumors, are reviewed. The most important of these associations are radiotherapy and lymphedema with tumors of the skin and soft tissues; and vinyl chloride, arsenic, and thorium dioxide with hepatic tumors. For splenic angiosarcomas, only isolated associations with breast carcinoma and thorium dioxide exposure have been reported. In the present case long-term combination chemotherapy seems to be the most likely etiologic association.

Adult↗
PubMed1962

Studies on the cornea. I. The fine structure of the rabbit cornea and the uptake and transport of colloidal particles by the cornea in vivo.

Physiological studies have demonstrated that ions, as well as large molecules such as hemoglobin or fluorescein, can diffuse across and within the cornea. Most of the substrates for corneal metabolism are obtained from aqueous humor filling the anterior chamber. In order to receive its nutrients and in order to maintain its normal conditions of hydration, the avascular cornea must transport relatively large amounts of solute and solvent across the cellular layers which cover this structure. It has been suggested in the past that there may be a morphological basis for the transport of large amounts of solvents and solutes by cells by the mechanism of pinocytosis. The use of electron-opaque markers to study fluid movements at the electron microscope magnification level was described by Wissig (29). The present study describes the fine structure of the normal rabbit cornea and the pathways of transport of colloidal particles by the cornea in vivo. Rabbit corneas were exposed in vivo to suspensions of saccharated iron oxide, thorium dioxide, or ferritin by injection of the material into the anterior chamber. In other experiments thorium dioxide or saccharated iron oxide was injected into the corneal stroma, producing a small bleb. Particles presented at the aqueous humor surface of the rabbit corneal endothelium are first attached to the cell surface and then pinocytosed. It appears that the particles are carried around the terminal bar by an intracellular pathway involving the pinocytosis of the particles and their subsequent transport in vesicles to the lateral cell margin basal to the terminal bar. Particles introduced at the basal surface of the endothelium (via blebs in the corneal stroma) are apparently carried through the endothelial cells in membrane-bounded vesicles without appearing in the intercellular space. There appears to be free diffusion of these particles through Descemet's membrane and the corneal stroma. The stromal cells take up large quantities of the particles when blebs are injected into the stroma.

Animals↗
PubMed2001

Immunohistochemical and charge-specific localization of anionic constituents in pseudoexfoliation deposits on the central anterior lens capsule from individuals with pseudoexfoliation syndrome.

BACKGROUND: Pseudoexfoliation (PSX) syndrome is a degenerative systemic disorder that is characterized primarily by deposits of distinct fibrillar material on the surface lining the anterior and posterior chambers of the eye and is often associated with cataract and glaucoma. Although some components of the PSX material have been identified, the precise composition is obscure. METHODS: High-resolution scanning electron microscopy in conjunction with colloidal cationic gold labeling was used to localize anionic constituents at the surface of PSX aggregates. Transmission electron microscopy was applied for the immunocytochemical detection of glycosaminoglycans, and to monitor the charge-specific distribution of colloidal thorium dioxide and ferritin in PSX material. The specific binding of antibodies was confirmed by immunohistological staining of paraffin-embedded specimens. RESULTS: Paraffin-embedded tissue sections revealed immunoreactivity for keratan sulfate and dermatan sulfate proteoglycan within PSX material deposited on the surface of the anterior lens capsule. Post-embedding immunogold labeling of keratan sulfate demonstrated an intense label of PSX aggregates primarily associated with mature PSX fibrils, whereas dermatan sulfate proteoglycon appeared to be present in low quantities. Additionally, keratan sulfate was found at the humoral periphery of the lens capsules. To further investigate the distribution of anionic sites in PSX material, we used cationic colloidal tracers of different size, such as gold, thorium dioxide and ferritin. PSX aggregates exhibited a strong negative charge, resulting very likely from glycosaminoglycan chains of proteoglycans. The density of anionic sites was higher at the interfibrillar matrix. Lens capsules associated with PSX material revealed a diminished accumulation of cationic ferritin at the humoral surfaces. CONCLUSIONS: Increased amounts of different glycosaminoglycans identified in PSX material suggest an important role of proteoglycans for the pathogenic pathway in PSX.

Aged↗
PubMed1987

Liver tumors in rodents: extrapolation to man.

Man is a poor model for the prediction of agents that are hepatocarcinogenic for laboratory rodents. Relatively few agents are known to cause any form of primary liver cancer in man. The most important is hepatitis B virus, for which there is possibly a model in the woodchuck but not one in rats or mice. The only other agents known to cause primary liver cancer in man are certain steroid hormones, vinyl chloride, and thorium dioxide. There are animal models for the first two of these and a reasonable expectation that thorium dioxide would produce liver tumors in animals if the appropriate experiments were done. Aflatoxin, a potent hepatocarcinogen in rats and other species but not mice, is strongly suspected of being an important human hepatocarcinogen in certain geographical areas of the world, but the evidence is circumstantial. There is no more than a weak association between the nutritional type of cirrhosis secondary to excessive intake of alcohol and increased primary liver cancer in man, and no evidence at all that ethanol per se causes liver tumors in mice, rats, hamsters, or mastomys. By contrast, a very large number of chemicals to which people in the West have been exposed for many decades have been found to be hepatocarcinogens in laboratory rodents. In most cases the levels of exposure required to produce liver tumors in rodents far exceed those to which man is normally exposed. The problem is to guess whether low-level exposure to such rodent hepatocarcinogens poses any real liver cancer threat to man?The mortality from primary liver cancer is very low in countries such as England and Wales where there is widespread exposure to low doses of both natural and synthetic agents which, in high dosage, cause liver tumors in rodents. This suggests that, if there is any risk, it can only be very small. Death rate data collected in England and Wales by the Registrar General are consistent with there having been a small increase in the incidence of primary liver cancer in England and Wales during the past 20 years, but the apparent increase might well be a consequence of revisions in the International Classification of Diseases system and not real. During the first half of the present century the age-standardized incidence of primary liver cancer in England and Wales was falling.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2002

XAFS investigation of the structure of aqueous thorium(IV) species, colloids, and solid thorium(IV) oxide/hydroxide.

X-ray absorption fine structure (XAFS) spectroscopy at the Th L3 edge is applied for the characterization of crystalline, anhydrous ThO(2)(cr), microcrystalline ThO(2).xH(2)O(s), amorphous ThO(n)(OH)(4-2n).xH(2)O(am), aqueous Th(IV) solutions, and colloidal suspensions up to p(c)H 3.7. The microcrystalline, possibly hydrated thorium dioxide, is formed at p(c)H 1.5-2.5 by precipitation from suspensions of 16-23 nm thorium dioxide colloids. The solubility data determined for this solid is several orders of magnitude lower than the values for amorphous Th(IV) hydroxide or hydrous oxide. The EXAFS spectrum of the isolated microcrystalline particles shows that their structure is different from that of anhydrous crystalline ThO(2)(cr) and amorphous ThO(n)(OH)(4-2n).xH(2)O(am) precipitated at higher pH and dried at room temperature. The solubility measured for the amorphous Th(IV) precipitate is comparable to that previously reported for a solid prepared in a similar manner. In other solubility studies with amorphous Th(IV) hydroxide or hydrous oxide, considerably higher thorium concentrations are measured at p(c)H 3.5-5. The aqueous speciation is made by EXAFS for solutions prepared by careful coulometric titration under comparable conditions (p(c)H and thorium concentration). The spectra of these solutions demonstrate the presence of a large amount of Th(IV) polynuclear species or colloids of small size, having a highly asymmetric Th-O coordination. The EXAFS spectrum of these colloids is similar to that of the amorphous solid.

Journal Article↗
PubMed1988

Thorotrast-induced oro- and hypopharyngeal fibrosis with recurrent bleeding.

Thorium dioxide, widely used as a contrast material, is a producer of alpha particle radiation. This is well demonstrated by autoradiography. The case described illustrates that life-threatening, thorium dioxide-induced pharyngeal haemorrhage may occur even with an occluded carotid artery. The radiation exposure caused an intense foreign body reaction with a marked cell-deficient fibrosis. The alpha particles are well demonstrated by autoradiography. In addition, we were able to show a defect in the wall of the carotid artery due to the Thorotrast injection, which was closed by cell-depleted connective tissue. As the radioactivity of the nuclides of thorium dioxide peaks 30-40 years after its first application, the morbidity will increase and the disease has to be taken into careful consideration in head and neck tumour lesions.

Aneurysm↗
PubMed1979

Angiosarcoma of the spleen: a report of two cases and review of the literature.

Results of the ultrastructural study of one of two cases of splenic angiosarcoma established the blood vessel origin of this tumor. Fifty-three previously reported cases were reviewed. None of the 55 patients had a history of exposure to thorium dioxide, vinyl chloride, or arsenic, which are known to be associated with hepatic angiosarcoma and other tumors. A comparison of the splenic and hepatic angiosarcomas showed that tumors not associated with exogenous material frequently involve the spleen and liver simultaneously, and that tumors associated with thorium dioxide, vinyl chloride, or arsenic commonly involve the liver with sparing of the spleen.

Adult↗
PubMed1978

Anatomy of germinal centers in mouse spleen, with special reference to "follicular dendritic cells".

Lymphocyte proliferation in germinal centers (GC's) is thought to be triggered by antigen retained extracellularly on the surface of special "dendritic" cells. The anatomy and function of these cells have not been studied directly or in detail. We therefore examined mouse spleen GC's developing in response to sheep erythrocyte stimulation. We found that distincitve "follicular dendritic cells" (FDC's) were present in both the GC and adjacent mantle region of secondary follicles. The large, irregularly shaped nucleus, containing little heterochromatin, allowed for the light microscope (LM) identification of FDC's. By EM, the cell was stellate in shape sending out long, thin sheets of cytoplasm which could fold and coil into complex arrays. The processes were coated extracellularly by an amorphous electron-dense material of varying thickness, as well as particulates including variable numbers of virions. The FDC cytoplasm lacked organelles of active secretory and endocytic cells, such as well-developed rough endoplasmic reticulum (RER) and lysosomes. These anatomical features readily distinguished FDC's from other cell types, even those that were extended in shape. To pursue these descriptive findings, we injected three electron-dense tracers i.v. and sacrificed the mice 1 h-10 days thereafter. Colloidal carbon, colloidal thorium dioxide (cThO2), and soluble horseradish peroxidase (HRP) were actively sequestered into the vacuolar system of macrophages but were interiorized only in trace amounts by FDC's. Therefore, FDC's are not macrophages by cytologic and functional criteria. FDC's did display a unique property. Both colloidal carbon and thorium dioxide, which are nonimmunogens, could be visualized extracellularly on the cell surface for several days. The meaning of this is unclear, but the association of colloid with FDC's appeared to slow the movement of particulates through the extracellular space into the GC proper. FDC's were not readily identified in splenic white pulp lacking GC's. They must develop de novo then, possibly from novel dendritic cells that we have identified in vitro (Steinman, R. M., and Z. A. Cohn. 1973. J. Exp. Med. 137:1142-1162).

Animals↗
PubMed1982

Inhibition of vacuolar membrane fusion by intracellular symbiotic algae in Hydra viridis (Florida strain).

Hydra viridis (Florida strain) forms a stable symbiotic association with unicellular Chlorella-like algae. Algae are phagocytized by hydra phagocytes and maintained individually within vacuoles of the host-cell. The purpose of the studies presented in this paper was to determine how symbiotic algae avoid host-cell digestive processes. Viable symbiotic algae were found to inhibit the fusion of the algal vacuolar membrane and vacuoles labeled with thorium dioxide. By contrast, thorium-labeled vacuoles did fuse with vacuoles containing nonviable algae. Further, the absence of acid phosphatase activity within vacuoles containing established symbiotic algae implies that inhibition of membrane fusion by algae in hydras prevents the conversion of the algal vacuoles into phagolysosomes.

Acid Phosphatase↗
PubMed1980

Thorotrast-induced meningioma. Case report.

The authors report an adult patient with a symptomatic intracranial meningioma that was demonstrated by computerized tomography, angiography, and at surgery. The meningioma had occurred at a site where 19 years previously thorium dioxide had been injected into an abscess cavity. Pathological examination revealed the presence of thorium granules within the meningioma.

Brain Abscess↗