The German Thorotrast Cohort Study: a review and how to get access to the data.

It is well known that exposures like those from (226)Ra, (224)Ra and Thorotrast(®) injections increase the risk of neoplasia in bone marrow and liver. The thorium-based radioactive contrast agent Thorotrast(®) was introduced in 1929 and applied worldwide until the 1950s, especially in angiography and arteriography. Due to the extremely long half-life of several hundred years and the life-long retention of the thorium dioxide particles in the human body, patients suffer lifetime internal exposure.

Association between lymph node silicosis and lung silicosis in 4,384 German uranium miners with lung cancer.

This study investigates the association between lymph node-only and lung silicosis in uranium miners with lung cancer and exposure to quartz dust. Tissue slides of 4,384 German uranium miners with lung cancer were retrieved from an autopsy archive and reviewed by 3 pathologists regarding silicosis in the lungs and lymph nodes. Cumulative exposure to quartz dust was assessed with a quantitative job-exposure matrix.

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners.

Objective: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung.

Methods: A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer.

A study on lung cancer mortality related to radon, quartz, and arsenic exposures in German uranium miners.

Between 1946 and 1990 uranium mining was undertaken on a large scale in East Germany. This study evaluates the proportional lung cancer risk of German uranium miners from radon, quartz, and arsenic exposure during mining operations at the WISMUT Corporation. The database of the WISMUT tissue repository and a comprehensive job-exposure matrix were used to compare exposure levels of lung cancer cases with deaths from diseases of the circulatory system for risk analysis.

Mortality among Thorotrast-exposed patients and an unexposed comparison group in the German Thorotrast study.

Thorotrast was the brand name of a stabilised colloidal solution of thorium dioxide which was used preferentially as an X-ray contrast medium for arteriography between 1930 and 1950. The administration of the medium led to lifelong chronic alpha-particle irradiation by thorium decay products, mainly in the organs of deposition. Several epidemiological follow-up studies were set up after recognition of these side-effects among which the German study was the largest.

Investigating the formation and growth of alpha-particle radiation-induced foci of altered hepatocytes: a model-based approach.

The effect of alpha-particle radiation on the formation and increase in volume of preneoplastic liver lesions was investigated in an animal experiment. Mice were divided into four groups; two groups received different doses of the alpha-particle-labeled antibody (213)Bi-anti CD19 ((213)Bi-CD19), Thorotrast was administered to one group, and one group was left untreated. Hematoxylin and eosin-stained liver sections were evaluated for preneoplastic foci of altered hepatocytes 6, 12 and 17 months after treatment.

Role of exposure to radon and silicosis on the cell type of lung carcinoma in German uranium miners.

Background: In East Germany, uranium mining was undertaken on a large scale from 1946 to 1990. Poor working conditions led to a high level of exposure to ionizing radiation and quartz dust. This analysis evaluates the histopathology of lung carcinoma in uranium miners in relation to radon exposure and silicosis.

Apoptosis and age-dependant induction of nuclear and mitochondrial etheno-DNA adducts in Long-Evans Cinnamon (LEC) rats: enhanced DNA damage by dietary curcumin upon copper accumulation.

Long-Evans Cinnamon (LEC) rats, a model for human Wilson's disease, develop chronic hepatitis and liver tumors owing to accumulation of copper and induced oxidative stress. Lipid peroxidation (LPO)-induced etheno-DNA adducts in nuclear- and mitochondrial-DNA along with apoptosis was measured in LEC rat liver. Levels of etheno-DNA adducts (1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytidine) increased with age reaching a peak at 8 and 12 weeks in nuclear and mitochondrial DNA, respectively.

No prevention of liver and kidney tumors in Long-Evans Cinnamon rats by dietary curcumin, but inhibition at other sites and of metastases.

Long-Evans Cinnamon (LEC) rats, an inbred mutant strain which accumulates copper due to an aberrant copper-transporting ATPase gene, develop acute hepatitis, chronic liver injury and liver tumors as a result of copper-induced oxidative stress, lipid peroxidation and DNA damage. Curcumin, an antioxidant and anti-inflammatory agent, has shown anticancer properties in many rodent models. We investigated the modulating role of curcumin in liver and kidney carcinogenesis in LEC rats.

Chances and shortcomins of adenovirus-mediated ATP7B gene transfer in Wilson disease: proof of principle demonstrated in a pilot study with LEC rats.

Background & Aims: Wilson disease (WD) is an autosomal recessively inherited copper storage disease due to mutations in the ATP7B gene. It results in impaired biliary copper excretion followed by liver injury leading to cirrhosis. In parallel, copper accumulates in other tissues e.

Protein phosphorylation degree: determination by capillary liquid chromatography and inductively coupled plasma mass spectrometry.

Capillary liquid chromatography (muLC) interfaced to inductively coupled plasma mass spectrometry (ICPMS) is introduced as a new micromethod to determine the phosphorylation degree in phosphoproteins and phosphopeptides containing cysteine and/or methionine residues. The stoichiometric phosphorus to sulfur (31P to 32S) ratio is experimentally determined by muLC-ICPMS and converted into the degree of phosphorylation using protein/ peptide sequence information. The method is applied to the phosphoproteins beta-casein, beta-casein, and recombinant protein kinase A catalytic subunit and to synthetic phosphopeptides.

Antitumoral activity of a sulphur-containing platinum complex with an acidic pH optimum.

Unlabelled: Platinum complexes are essential tools for cancer treatment despite their toxic side effects. Here we describe a new platinum complex with sulphurs as complexing atoms (thioplatin).

Purpose: To demonstrate that the antitumoral activity of a new sulphur-containing platinum compound (thioplatin) depends on a slightly acidic pH.

Analysis of protein phosphorylation by capillary liquid chromatography coupled to element mass spectrometry with 31P detection and to electrospray mass spectrometry.

A method for phosphopeptide identification by capillary liquid chromatography (muLC) interfaced alternatively to element mass spectrometry (inductively coupled plasma mass spectrometry, ICPMS) and to electrospray ionization mass spectrometry (ESI-MS) is described. ICPMS is used for 31P detection and ESI-MS provides the corresponding molecular weight information. Alignment of the two separate muLC runs is performed using the baseline distortion at the elution front, which shows up in both muLC-ICPMS and muLC-ESI-MS.

Daily but not pulse calcitriol therapy improves growth in experimental uremia.

Calcitriol (C) pulse therapy is widely used to suppress secondary renal hyperparathyroidism. However, high C serum concentrations may have an antiproliferative effect on growth cartilage cells and may suppress growth rate. The study was designed to evaluate whether daily C and pulse C therapy have differential effects on growth in uremic rats.

Analysis of radon-associated squamous cell carcinomas of the lung for a p53 gene hotspot mutation.

Squamous cell lung carcinomas (SCC) from former employees of the Wismut uranium mining company (Saxony, Germany) were obtained from the Stollberg Archive in order to screen for p53 tumour suppressor gene codon 249 arg-->met hotspot mutations, a putative molecular bio-dosimeter of alpha-particle (radon) exposure (Taylor et al (1994) Lancet 343: 86-87; McDonald et al (1995) Cancer Epidemiol Biomarkers Prevent 4: 791-793). Of the 29 archived samples of SCC meeting quality criteria for DNA analysis by polymerase chain reaction (PCR) and Haelll restriction enzyme digestion, two tumours were found that harboured this mutation. DNA sequencing confirmed the presence of a G to T base substitution within the Haelll site spanning codons 249 and 250 of the p53 gene that results in replacement of arginine (wild-type) by methionine at residue 249.

Ras gene mutations in vinyl chloride-induced liver tumours are carcinogen-specific but vary with cell type and species.

Previous studies have shown that a high proportion (5/6) of human liver angiosarcomas (ASL) associated with exposure to vinyl chloride (VC) contains a GC-->AT mutation at the Ki-ras codon 13. This mutation, however, has not been found in 5 ASL or 2 hepatocellular carcinomas (HCC) induced in rats by VC. These 2 HCC did contain a mutation at codon 61 of the Ha-ras gene.

The german thorotrast study: recent results and assessment of risks.

The German Thorotrast study comprises 2,326 patients and 1,890 controls. Forty-eight Thorotrast patients and 239 controls are still alive and are invited for a follow-up examination every 2 years. In the deceased patients, the following neoplastic diseases with excess rates were registered (Thorotrast/controls): liver cancer (454/3); cancer of the bile ducts, including gallbladder (42/7); myeloid leukemia (40/7); myelodysplastic syndrome (30/4); plasmacytoma (10/2); non-Hodgkin's lymphoma (15/5); bone sarcoma (4/1); malignant peritoneal or pleural mesothelioma (9/0).

German uranium miner study--pathological and molecular genetic findings. German Uranium Miner Study, Research Group Pathology.

Uranium miners of the former Wismut company in Germany form the largest cohort of workers exposed to (222)Rn and dust in the world. The German Uranium Miner Study, Research Group Pathology, is evaluating the central pathology archive of the Wismut company. The main tasks of our study are pathological-anatomical and molecular genetic investigations of 28,975 autopsy cases and the evaluation of mining pollutants in the lungs by neutron activation analysis.

German uranium miner study--historical background and available histopathological material.

Mining activities in the former German Democratic Republic were documented as early as 1168 in the ore mountains (Erzgebirge) of Saxony. Silver, bismuth, cobalt, nickel and tungsten were mined from then up to the end of the 19th century. After the Second World War, the Soviet Occupation Authorities reopened the old silver mines in Saxony to mine uranium for the Soviet nuclear industry.

[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.

Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of BigBlue rats and Muta Mouse mice in vivo after inhalation.

Carcinogenic nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, nickel subsulfide (Ni3S2) increased mutation frequency up to 4.

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.

Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis.

Wilson's disease can result in fulminant liver failure due to hepatic copper overload. The CD95 system mediates apoptosis and has been demonstrated to be involved in liver disease. In this study CD95 mediated apoptosis was investigated in patients with fulminant hepatic failure in the course of Wilson's disease and in an in vitro model of copper treated human hepatoma cells.

p53 gene mutation analysis in tumors of patients exposed to alpha-particles.

The p53 gene was examined for point mutations in archived, alpha-radiation-associated lung and liver cancers. Lung tumors of 50 uranium miners in Germany were screened by restriction fragment length analysis for the putative hotspot mutation at codon 249 (Arg-->Met) previously detected in a significant fraction of miners from the Colorado Plateau, USA. This mutation has been proposed as a marker of radon exposure.