Biomarkers of genetic damage and inflammation in blood and bronchoalveolar lavage fluid among former German uranium miners: a pilot study.

Former East German uranium miners who are known to have been exposed to radon are estimated to be at high risk for lung carcinogenesis. Among these miners over 200 occupationally caused lung cancer cases are expected to occur each year, resulting in a total of 7,000-24,000 excess lung cancer cases in the coming years. It is still unknown whether there is a correlation between biomarkers and the exposure of the uranium miners to ionizing radiation that might enable us to trace those miners with high lung cancer risk. The primary aim of this pilot study was to test the possibility of performing a biomarker study in this unique cohort of former uranium miners in spite of several limitations that had to be taken into consideration when comparing them with healthy controls, such as old age, age-dependent diseases and potential confounding artefacts from dissimilar smoking patterns. The second aim was to test a range of biomarkers for DNA damage and inflammation in leukocytes and bronchoalveolar fluid for their ability to detect biological effects. In this cohort of miners we found an increased frequency of chromosomal aberrations in blood lymphocytes and an increased prevalence of both fibronectin and tumour necrosis factor alpha in the bronchoalveolar fluid.

[Occupational exposure to paint, lacquer and solvents, and cancer risk in the area of the upper aero-digestive tract]. / Berufliche Exposition gegenüber Farben, Lacken und Lösungsmitteln und Krebsrisiko im Bereich des oberen Aerodigestivtraktes.

So far, only few studies exist that have investigated the influence of occupational exposure to paint and lacquer on the risk of cancer in the upper aerodigestive tract. Based on data from the Heidelberg case control study which enrolled 369 patients with carcinomas of the upper aerodigestive tract and 1476 randomized control subjects, the relative risk of head and neck cancer in patients exposed to paint, lacquer and varnish was analyzed. The relative risk (RR) of squamous cell cancer (after adjustment for possible alcohol and tobacco effects) was significantly increased for the larynx (RR = 2.3) and the oral cavity (RR = 3.6). However, this risk was not increased for the pharynx. Our findings and a critical analysis of the literature provide evidence that chronic exposure to paint, varnish and lacquer is a definite risk factor for cancer of the upper aerodigestive tract. Further studies are required to confirm these findings, and to identify more precisely toxic substances encountered in the workplace.

[Cancer of the oral cavity in machine workers]. / Mundhöhlenkrebs bei Maschinenarbeitern.

BACKGROUND: So far, only few studies exist which investigated the influence of occupational factors on the risk of oral cancer. PATIENTS: A case control study enrolling 100 patients with carcinomas of the oral cavity and 400 randomized control persons was performed to analyze occupational risk factors for oral cancer. RESULTS: Twenty-two percent of the tumor patients and only 8.5% of the control persons were employed as machine workers. The relative risk for squamous cell carcinoma of the oral cavity was 3.4 (K.I.: 1.7-7.0) for machine workers (adjusted for alcohol and tobacco). Single case analysis showed that 96.3% of the machine workers with oral cancer and only 17.3% of the machine workers in the control group were exposed to dust, especially metal dust (55.5% vs. 9.7%). Also the exposure to paint, lacquer, and varnish containing chromium and nickel was significantly higher in machine workers with cancer of the oral cavity than in the machine workers without cancer (29.6% vs. 10.9%). CONCLUSIONS: The findings suggest that exposition to various types of dust, especially metal dust, increases the risk of oral cancer in machine worker patients.

Bile ductular proliferation and altered leukotriene elimination in thioacetamide-induced fibrosis of rat liver.

BACKGROUND/AIMS: Liver fibrosis is accompanied by both bile ductular proliferation and inflammation under various conditions. The functional consequences and the interrelationships between these changes are unknown. Altered biliary elimination and retention of cholephilic mediators may be a factor in fibrogenesis. Therefore, the relationship between fibrosis, ductular proliferation and functional changes in biliary elimination was studied. METHODS: Micronodular liver fibrosis was induced by thioacetamide in rats. The relative amount of bile ductular epithelial cells was determined by microscopic morphometry. The functional changes in bile secretion and metabolism of leukotriene C4 were assessed in isolated perfused livers of treated rats. RESULTS: Pretreatment with thioacetamide in vivo resulted in enhanced bile fluid formation in subsequently isolated and perfused livers. Infusion of isoproterenol into the portal vein stimulated bile flow. Both unstimulated and isoproterenol-stimulated bile flows were increased in fibrotic livers and were correlated with liver content of bile ductular epithelia. In contrast, biliary secretion of infused leukotriene C4 was lowered in correlation with that of taurocholate. Enhanced metabolism resulted in a shift of the major fraction in bile from leukotriene C4 to leukotriene D4. CONCLUSIONS: Thioacetamide-induced liver fibrosis is associated with an increased number of functionally intact bile ductules that are responsive to isoproterenol stimulating bile fluid formation. In contrast, biliary secretion of cysteinyl-leukotrienes and taurocholate is inhibited and the relative amount of leukotriene D4 is increased. Bile ductular proliferation as well as retention and altered metabolism of leukotrienes are factors associated with the development of liver fibrosis.

East German uranium miners (Wismut)--exposure conditions and health consequences.

Underground uranium mining was performed in East Germany after World War II on a large scale. East Germany was the main supplier of uranium for the Soviet Union. This review gives a historical summary and describes the broad spectrum of exposure to potential health hazards and the health consequences. Working conditions were very poor during the postwar years from approximately 1946-1955: there was drilling with air floating and a lack of forced ventilation. Dust levels were very high and there was a significant inhalative incorporation of alpha-radiating substances, mostly from short-lived radon progeny. However, long-lived alpha-radiating substances such as uranium-238 contributed considerably to the radiation dose. There was also exposure to toxic chemicals, such as arsenic (in some mines) or crystalline silica, and a variety of other health hazards. From approximately 1956-1970, mining conditions improved: there was drilling with the addition of water and forced ventilation of the mines. As of approximately 1970, compliance with rules of industrial hygiene and international standards of radiation protection was evident. In 1990, uranium production was generally stopped. To date, more than 5,000 cases of bronchial carcinoma are accepted as compensable occupational diseases and more are expected. The extensive data from Wismut uranium mining could improve our understanding of a complex exposure situation resulting in a variety of health impairments other than lung cancer.

Different pathomechanisms of altered biliary leukotriene C4 elimination in isolated perfused rat livers.

Hepatic retention of cysteinyl leukotrienes is a consequence of impaired bile secretion and may be involved in the pathogenesis of intrahepatic cholestasis. In order to assess the mechanisms of altered biliary leukotriene elimination, we studied the secretion and metabolic pattern of leukotriene C4 (LTC4) in bile early in the alterations of bile formation by xenobiotics. To this end, rats were pretreated with alpha-naphthylisothiocyanate (ANIT), ethionine (ETH), or estradiol valerate (EV) at doses which did not increase serum marker enzymes of cholestasis. Bile secretion was assessed in perfused livers isolated from the treated rats. In all models, the access of [14C]sucrose into bile was increased, indicating increased permeability of the bile tract. Biliary recovery of radioactivity infused as [3H]LTC4 was decreased by ANIT and ETH while 3H-efflux into the perfusate was increased concomitantly. The secretion rate of 3H-radioactivity into bile was correlated with that of [14C]taurocholate infused at the same time. After pretreatment with ANIT (but not in the other models) the venous efflux of [3H]LTC4-ANIT pretreatment was increased [14C]sucrose clearance into bile associated with greatly enhanced biliary access of [32P]phosphate. Thus, altered charge selectivity of the paracellular pathway appears to be a prerequisite for reflux of cholephilic anions. HPLC analysis of [3H]LTC4-derived radioactivity in bile revealed that in all models of altered bile secretion the relative amount of LTD4 in bile was elevated. These results demonstrate differential changes in hepatobiliary transport and metabolism of LTC4 in developing cholestasis. ANIT inhibits leukotriene secretion by increasing paracellular permeability with loss of charge selectivity. In contrast, ETH treatment inhibits transcellular transport while treatment with EV only results in enhanced LTC4 metabolism.

Incidental finding of a hepatic lesion: differential diagnostic problems for fibrolamellar hepatic carcinoma.

We report the case of a 39-yr-old female with a liver lesion that was incidentally detected by ultrasound. Examination of biopsy specimens revealed focal nodular hyperplasia. A metastatic tumor in the right os ilium developed in the following weeks and showed specific uptake of 99mTc-hepatic 2,6-dimethyliminodiacetic acid (HIDA), suggesting metastasis from a differentiated hepatocellular carcinoma. The final pathologic diagnosis was multifocal, solid and glandular hepatocellular carcinoma, partly differentiated as fibrolamellar carcinoma, and an osseous metastasis from the differentiated hepatocellular carcinoma.

Cholestasis: pathophysiology and pathobiochemistry.

Clinical and morphological diagnosis of cholestasis involves a variety of different parameters, but bile fluid formation and composition of bile are usually not accessible in patients. In contrast, a pathophysiological definition of cholestasis can be based on current knowledge on the mechanisms of bile formation. Hence, causes of cholestasis may be localized in each step of the process of bile formation. 1. Inhibition of fluid formation reduces maximal secretory capacity. 2. Inhibition of the transcellular hepatobiliary transport may involve transport carriers, binding proteins, and the systems of biotransformation. 3. Mechanical obstruction or regurgitation of bile constituents due to increased permeability of the bile tract may inhibit the biliary elimination of cholephilic compounds. Consequences of the inhibition of biliary elimination are retention in the liver and the whole organism of potentially toxic compounds. Among these are endogenous compounds such as bile acids and cysteinyl-leukotrienes, but xenobiotics as well may become more toxic in cholestasis. The composition of bile and portal venous blood is altered. In experimental animals, changes in secretory function can already be observed before clinically used indicator enzymes of cholestasis increase. This functional inhibition of biliary elimination can be characterized as "subclinical" cholestasis that may, nevertheless, inhibit the elimination and potentiate the toxicity of cholephilic endo- and xenobiotics.