Performance of biomarkers SMRP, CA125, and CYFRA 21-1 as potential tumor markers for malignant mesothelioma and lung cancer in a cohort of workers formerly exposed to asbestos.

The aim of the study is to examine the cancer-predictive values of SMRP (soluble mesothelin-related peptides), CA125, and CYFRA21-1 as potential tumor markers for lung cancer and malignant mesothelioma in a cohort of workers formerly exposed to asbestos. A voluntary surveillance program has been established for German workers with former asbestos exposure. A subgroup of 626 subjects with a mean age of 63 years (range 53-70 years) at baseline was enrolled in an extended health examination program with high-resolution computer tomography (HRCT) of the chest and blood drawing between 1993 and 1997. Serum concentrations of SMRP, CA125, and CYFRA21-1 were measured in archived serum samples in 2005 and 2006. A mortality follow-up was conducted through 2007. So far, 12 cases with lung cancer and 20 cases with malignant mesothelioma have been observed in this cohort. The average time between sample collection and diagnosis was 4.7 years. Analyzed biomarkers showed low sensitivities (5-25%) and positive predictive values (4-30%) for both cancer sites. Marker combinations resulted in sensitivities between 5 and 50% and positive predictive values ranging from 3 to 14%. Even in those cases, where biomarker concentrations were available within 36 months before diagnosis, no trend for increasing biomarker levels was observed. The analyzed tumor markers were characterized by high specificities, but low sensitivities. SMRP, CA125, and CYFRA21-1 alone or in combination were less suitable to serve as predictors for the diagnosis of lung cancer or malignant mesothelioma. However, a prospective study with annual sampling might reveal a better predictive value of these markers.

[Examples for asbestos-related findings in HRCT - criteria for the assessment of causal relationships in surveillance programmes and medical expert opinion]. / Beispiele asbestfaserstaubbedingter Veränderungen im HRCT - Anhaltspunkte für die Kausalzuordnung bei Vorsorgeuntersuchungen und bei der gutachterlichen Beurteilung.

The increasing use of high-resolution computed tomography in formerly asbestos-exposed workers requires valid diagnostic criteria for the findings which have to be reported as suspicious for being asbestos-related in surveillance programmes and for the assessment of causal relationships between former asbestos exposure and findings in computed tomography. The present article gives examples for asbestos-related findings in HR-CT and discusses the specificity of parenchymal and pleural changes due to asbestos fibres.

[Recommendations for reporting benign asbestos-related findings in chest X-ray and CT to the accident insurances]. / Anzeigekriterien asbestfaserstaubbedingter Erkrankungen gemäss BK-Nr. 4103 BKV.

Asbestos-related diseases still play an important role in occupational medicine. The detection of benign asbestos-related diseases is one condition for the compensation of asbestos-related lung cancer in Germany. Due to the increasing use of computed tomography, asbestos-related diseases are more frequently detected in the early stages. The present article proposes recommendations for the findings which have to be reported as suspicious for being asbestos-related based on a) chest X-rays and b) computed tomography using the International Classification System for Occupational and Environmental Respiratory Diseases (ICOERD).

[Digital radiography in chest imaging of occupational and environmental lung diseases]. / Digitale Radiografie in der Untersuchung von arbeits- und umweltbedingten Lungen- und Pleuraerkrankungen.

The classification of pneumoconiosis according to ILO standard - comparing a X-ray of the lung with ILO radiographs - is well established in Germany. The extension of digital imaging is a challenging task in occupational medicine as well as in pneumology. Technical requirements are not known sufficiently and the necessary equipment is not well distributed. This paper describes the current position on recording, assessment and documentation of digital imaging of the lung and pleura.

Association between 8-hydroxy-2'-deoxyguanosine levels in DNA of workers highly exposed to asbestos and their clinical data, occupational and non-occupational confounding factors, and cancer.

In the preceding paper [B. Marczynski, P. Rozynek, T. Kraus, St. Schlösser, H.J. Raithel, X. Baur, Levels of 8-hydroxy-2'-deoxyguanosine in DNA of white blood cells from workers highly exposed to asbestos in Germany, Mutat. Res. (2000) submitted] we described significant increases (p<0.001) in the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) adducts in the DNA of white blood cells (WBC) of workers highly exposed to asbestos fibers at the workplace relative to those found in the control group in all three study years (period between 1994 and 1997). The results show that the oxidative DNA damage in exposed individuals is between 1.7 times and twice that found in control samples for all 3 years of the study (p<0.001). The aim of this study was to examine the association between the 8-OHdG levels in WBC DNA of workers highly exposed to asbestos fibers at the workplace and clinical data, occupational and non-occupational confounding factors, and cancer. There is no obvious correlation between the steady-state levels of 8-OHdG in the circulating WBC DNA of asbestos workers and possible confounding factors, such as the presence of benign asbestos-associated diseases, the duration of asbestos exposure, the latency period, the fixed cumulative fibrous dust dose ("fiber years"), age, smoking status, acute febrile infections, medicines, aspirin, calcium (Ca(2+)), magnesium (Mg(2+)), and the hormone and vitamin intake. This indicates that previous inhalation of asbestos fibers is the major factor responsible for the difference observed in oxidative DNA damage between asbestos workers and controls. For patients suffering from respiratory cancer, cancer of the gastrointestinal tract, mouth/pharynx/larynx, and urogenital tract the mean DNA-adduct level was significantly higher (p<0.01) than that found in controls, but not significantly higher (p>0.05) than that for asbestos-exposed patients without tumours. The formation of 8-OHdG adduct levels in WBC DNA of patients with hematopoietic cancer, chondrosarcomas and multiform glioblastomas was not significantly higher than that found in the control group (p>0.05). Our results support the hypothesis that oxidative DNA damage in man caused by asbestos fibers plays a role in the formation of malignant tumours.

Levels of 8-hydroxy-2'-deoxyguanosine in DNA of white blood cells from workers highly exposed to asbestos in Germany.

Asbestos fibers have genotoxic effects and are a potential carcinogenic hazard to occupationally exposed workers. The ability of inhaled asbestos fibers to induce the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the DNA of white blood cells (WBC) of workers highly exposed at the workplace has been studied. The 8-OHdG adduct level of asbestos-exposed workers was significantly increased (p<0.001) compared to that in the control group in all three years of the study. Asbestos-exposed individuals showed a mean value of 2.61+/-0.91 8-OHdG/10(5) dG (median 2.49, n=496) in 1994-1995, 2.96+/-1.10 8-OHdG/10(5) dG (median 2.76, n=437) in 1995-1996 and 2.55+/-0.56 8-OHdG/10(5) dG (median 2.53, n=447) in 1996-1997. For the control subjects, a mean of 1.52+/-0.39 (median 1.51, n=214) was determined. The results indicate that human DNA samples from exposed individuals contain between 1.7 times and twice the level of oxidative damage relative to that found in control samples in all 3 years of the study. The studies presented here show that asbestos exposure can result in oxidative DNA damage. Our data confirm that oxidative DNA damage occurs in the WBC of workers highly exposed to asbestos fibers, thus supporting the hypothesis that asbestos fibers damage cells through an oxidative mechanism. These in vivo findings underline the importance of oxidative damage in asbestos-induced carcinogenesis and highlight the need for exploring the molecular basis of asbestos-induced diseases, and for more effective diagnosis, prevention and therapy of mesothelioma, lung cancer and pulmonary fibrosis. In addition, preventive and therapeutic approaches using antioxidants may be relevant.

Quantitative determination of chromium and nickel in tumour and tumour-free human tissue.

Environmental pollution with carcinogenic substances, in addition to individual abuse, are discussed as important factors causing development of cancer. We must assume that certain nickel and chromium compounds, which are ubiquitous in our ecosystem, must have carcinogenic effects on humans too. The aim of this study is therefore to examine the extent to which the accumulation of the potentially carcinogenic metal ions nickel and chromium could be measured in tissue from tumour patients. We examined tumour and tumour-free tissue obtained from a total of 48 patients who had carcinomas of the stomach, bowel, or kidney. We also analyzed nickel and chromium content in whole blood and urine samples from these persons. The quantitative metal estimations were done using atomic absorption spectrophotometry. Differences between chromium and/or nickel content in tumour or tumour-free tissue were not observed. An accumulation of these metal ions in tumour tissue is therefore improbable. We were also unable to find differences in metal content with regard to chromium and nickel as related to the appearance of tumour in the organ. In contrast, tumour patients had a 5- to 7-fold increase over normal values for chromium and nickel in blood and urine. This was attributable to unavoidable contamination of tissue and body fluids with chromium- and nickel-containing instruments during major surgical procedures.

Increased content of chromium and nickel in lung tissues from patients with bronchial carcinoma.

Epidemiological studies have shown that occupational exposure to certain chromium and nickel compounds is followed by an increased lung cancer incidence. However, few data exist on the content of these metals in lung cancer patients in general. In the present study, central and peripheral lung tissue, bronchial tissue and hilar lymph nodes were collected from 20 patients with bronchial carcinoma and 21 control individuals, and the tissue concentration of chromium and nickel was measured by use of atomic absorption analysis. Increased levels of both metals were found in cancer patients as compared to controls. Lung tissue concentration of chromium was two-fold increased, while the bronchial wall content of nickel was three times the level in control individuals. Smokers showed a dose-related increase in the deposition of both chromium and nickel. Furthermore, in cancer patients an inverse relationship between smoking and the tissue level of chromium in regional lymph nodes was found, possibly indicating a depressive effect on pulmonary clearance mechanisms. Our results emphasize the possible role of small amounts of chromium and nickel as agents in bronchial carcinogenesis, unrelated to occupation and probably related to tobacco smoking.

[Toxicity and carcinogenicity of nickel and its compounds. A review of the current status (author's transl)]. / Zur Toxizität und Kanzerogenität von Nickel und seinen Verbindungen. Eine Ubersicht zum derzeitigen Erkenntnisstand.

Since half a century the toxicity and carcinogenicity of nickel and its compounds is in discussion. Problems coming therefrom are of high relevance concerning occupational medicine. According to the new national and international literature the present findings are described and discussed. Starting from occurrence, refining and occupational hazards, in the first part, toxicologic mechanisms and characteristic symptoms are represented in detail. Inorganic and organic Ni-compounds are handled separately. In the second part of this study we are giving opinion to the questions of carcinogenicity. Experiences to occupationally nickel-exposed workers as well as a review about the topical findings in animal experiments are described. Of importance there are questions referring to the different carcinogenic potential of nickel and its compounds and the influence to techniques of application. Current results to the mechanism of carcinogenesis, which can be derived from animal experiments, are shown. The carcinogenicity for nickel and some especial water insoluble Ni-compounds in human beings must be seen as a fact. Malignoms in the respiratory tract are regarded by workers breathing dust/aerosols of metallic nickel, nickel subsulfide, Ni-oxide and in electrolysis. By critical review of the present literature a cancerogenicity of nickel-carbonyl has to be assumed too. According to this review measures in the field of occupational hygiene and medicine are required. Illness caused by nickel or its compounds should be included to the valid list of occupational diseases in the FRG.

Computer-assisted classification system for chest X-ray and computed tomography findings in occupational lung disease.

The ILO classification of pneumoconiotic changes in the lungs and pleura has become a standardized and widely accepted method of documentation in occupational medicine. Recently a classification system for computed tomography/high-resolution computed tomography (CT/HRCT) findings in the lung has been proposed as well. For both classification systems, computed-assisted programs have been developed that allow the storage and archiving of the results as well as further statistical processing. The programs are compatible with usual hardware configurations, have a comprehensible and transparent structure, and are easy to learn and adaptable to individual needs. The use of the computer-assisted classification systems is presented in the example of an insulator exposed to asbestos. The system of data documentation and processing has proved to be very practicable in the more than 2000 patients studied thus far.

Acute fatal selenium poisoning. Toxicological and occupational medical aspects.

Neutralizing selenic acid with caustic soda caused a hyperintensive exothermic reaction, with about 450 1 of the reaction mixture erupting in a factory hall. A 44-year-old industrial worker was fatally intoxicated, suffering from second-degree skin burns, necrosis of oral mucous membranes and hemorrhagic lung edema. He died 90 min later. Analysis of body fluids and tissue samples showed high selenium concentrations in blood serum, urine, stomach content and lungs. The analytical results are discussed in comparison with normal selenium levels of non-exposed groups.

The association of occupational asbestos dust exposure and laryngeal carcinoma.

Controversy exists as to whether occupational asbestos dust exposure is responsible, or at least partially responsible, for the development of laryngeal carcinoma. The aim of this study is to present the current scientific knowledge on this subject based on a comprehensive literature research and to critically review the epidemiological investigations published. The results of 31 cohort studies and 24 case-control studies, and the conclusions in 11 more recent reviews are contradictory. In most studies there was no statistically significant indication of a casual relationship. It is noteworthy that an increased risk of laryngeal carcinoma among persons exposed to asbestos dust was observed mostly in older studies in which smoking habits and/or alcohol consumption as the most important nonoccupational risk factors were usually not taken into account. In addition, since most of the calculated positive associations are very weak, no reliable conclusion can be reached. While there may be a causal relationship between occupational exposure to asbestos dust and the occurrence of laryngeal carcinoma, this cannot be regarded as certain on the basis of the evidence reviewed.

Respiratory symptoms and diseases among workers in the soft tissue producing industry.

AIMS: To correlate the prevalence of respiratory tract symptoms and diseases with dust and fibre exposure in the soft tissue industry in Germany. METHODS: Ambient monitoring was performed for inhalable, respirable dust and fibres in seven soft tissue producing factories. In 441 workers (72 controls, 90 moderate, 279 high exposure) a standardised questionnaire on respiratory symptoms, diseases, occupational history, and smoking habits was used. Crude differences in the prevalence of respiratory symptoms and diseases were assessed. Logistic regression analysis was used to determine the relation between the respiratory symptoms/diseases and the cumulative dust and fibre exposure, respectively, while adjusting for age, gender, smoking habits, and factory. The effects of exposure intensity and duration were differentiated by categorising dust/fibre concentrations and years of exposure separately and setting up logistic regression models. RESULTS: The mean concentrations for inhalable, respirable, and fibrous dusts were 10.3 mg/m(3), 0.22 mg/m(3), and 415,000 fibres/m(3). Adjusted odds ratios (OR) with relation to cumulative dust exposure intensity were significantly raised for blocked nose (18.2), mucosal irritation (6.5), dry nose (8.9), cough (3.5), phlegm (7.5), exercise induced dyspnoea (2.6), hoarseness (11.3), and sneezing attacks (7.9) (ORs for highest exposure categories). Cumulative dust or fibre exposure had no significant effects on the prevalence of respiratory diseases. For all symptoms with significantly raised ORs, combined effects of intensity and duration of exposure were found. CONCLUSIONS: Because of the high prevalence of respiratory symptoms a reduction of dust exposures is recommended. Chronic exposure effects could not be found in this study, however, a healthy worker effect has to be considered.

Evaluation and classification of high-resolution computed tomographic findings in patients with pneumoconiosis.

The standard ILO classification for pneumoconiotic changes using conventional X-ray films has become well established. In recent years computed tomography has played an increasing role in occupational medicine and above all in the assessment of pneumoconiosis. Therefore a standardised method of classification for CT also seems necessary. A system of classification developed by occupational hygienists and radiologists allows a detailed description of parenchymal and pleural changes and the use of 28 additional symbols. Furthermore, special diagnoses relevant to occupational medicine and additional comments can be made. The classification system was tested in practice in the research project "Early diagnosis of asbestos-related diseases" (Frühdiagnostik asbestverursachter Erkrankungen). It was shown to be both practicable and easily reproducible, intra-individually and interindividually.

Health hazards from fine asbestos dusts. An analysis of 70,656 occupational preventive medical investigations from 1973 to the end of 1986.

For the period from 1973 to the end of 1986, 70,656 data sets on occupational preventive medical examinations in employees exposed occupationally to asbestos dust (G 1.2) were made available to us by the Central Registry for Employees Exposed to Asbestos Dust (ZAS). On the basis of this data, an analysis of asbestosis risk was to be made in relation to specific areas of work, taking into consideration the beginning and duration of exposure. Proceedings for declaratory appraisal in accordance with occupational disease no. 4103 were instituted in 1760 cases in the report period. In accordance with the character of the available data, the X-ray findings in the lungs were available from the persons investigated as parameters of possible asbestosis risk on the basis of coding consistent with the International Pneumoconiosis Classification (ILO U/C 1971 and/or ILO 1980 West Germany). The major result of the statistical analyses on the mainframe macrocomputer of the University of Erlangen-Nuremberg was that the relatively highest risk of asbestosis was present in persons whose exposure began before 1955. On the other hand, with increasing duration of exposure, an unequivocal rise of the asbestosis risk could not be detected on the basis of the overall population. In relation to the individual fields of work, the relatively highest risk of asbestosis was shown to be in the asbestos textile and paper industry, as well as in the asbestos cement industry. No detectable risk of asbestosis was present in the fields of mining, traffic and health service and for women in the industrial sectors of building material, gas and water, catering trade, building, commerce as well as banking and insurance. Accordingly, it can be assumed that certain fields of work are or were exposed to such a small extent or not at all that a risk of asbestosis which is relevant in terms of occupational medicine is no longer to be assumed or was not to be assumed. This applies above all to certain work in the frictional coating (brake lining) and asbestos paper industry. Furthermore, the analysis of the data material did not provide any unequivocal indications that inhalative smoking habits have a negative effect on the risk of asbestosis. In principle, it can be stated that the occupational preventive medical investigations according to G 1.2 are effective.(ABSTRACT TRUNCATED AT 400 WORDS)

[Quantitation of manganese and vanadium levels in the lung of "normal" and occupationally exposed persons]. / Untersuchungen zur Quantifizierung des Mangan- und Vanadium-Gehalts im Lungengewebe bei "Normalpersonen" und beruflich Exponierten.

Manganese and vanadium concentrations were measured in the lung and in hilus tissue of 30 non-exposed and 10 occupationally exposed patients. The analyses were performed by electrothermal atomic absorption spectrometry with Zeeman background compensation after wet oxidative digestion. The pulmonary tissue sampling of 30 non-exposed persons was carried out in terms of topographic anatomical criteria from different lung segments and lobes, resp. The manganese concentrations vary between 70 and 360 ng/g, and for vanadium between 9 and 40 ng/g in relation to wet weight. On the average manganese concentrations are 3 to 5 times higher compared to vanadium concentrations, 2 to 4 times higher values were detected in hilus tissue compared to the lung parenchyme. With regard to the topographic anatomy 1.1 to 1.5 higher manganese and vanadium concentrations have been found in the upper lung areas. In 10 of the occupationally exposed persons the sampling was taken from various segments as far as available. In some cases only one lung tissue sample could be analysed. Two former high-grade steel welders and eight former workers from a Norwegian nickel refinery have been investigated. Esp. the manganese concentrations in lung tissue of the welders raised by the factor 100. The manganese content in other occupationally exposed persons has also been increased in comparison to the normal group whereas the vanadium concentrations were - with one exception - in the normal range. Synoptically these results demonstrate that the determination of manganese and vanadium concentrations in the lung tissue might give additional information especially concerning a former occupational exposure. Such investigations can also be of interest when giving medical expertise opinion.

Medical and toxicological aspects of occupational nickel exposure in the Federal Republic of Germany--clinical results (carcinogenicity, sensitization) and preventive measures (biological monitoring).

In recent years reports on nickel-related diseases in the Federal Republic of Germany have been increasingly frequent. As a result, medical scientific institutions were called upon to clarify both the occupational medical and clinical, as well as the toxicological aspects of the situation. The main clinical finding was the increased incidence of malignant neoplasias in the respiratory tracts, in particular after many years of nickel exposure in refineries. Between 1967 and 1981, seven malignant neoplasms were legally recognized as occupation-related. Additionally, in the last two years, the existence of nickel-induced malignant neoplasms has been suspected in 16 cases, and the statutory procedure for the recognition of occupational diseases instituted. Our overview presents occupational-medical and clinical aspects. Among allergic nickel-induced conditions, eczematous skin diseases predominate. In addition, case reports of asthma have been published. Statistical evaluations showed that up to 17% of all occupational allergies may be related to occupational exposure to nickel. In this situation, preventive measure are of particular importance. To estimate exposure levels, both the measurement of the agent at the workplace and the quantitative determination of nickel in biological material can be used. The measurement of nickel excretion by the kidney has proved particularly useful in occupational medicine. In addition to clinical surveillance, it is recommended that this measurement should be performed on exposed persons at regular intervals.

Biomonitoring of nickel and chromium in human pulmonary tissue.

Nickel (Ni) and chromium (Cr) and some of its compounds may be able to induce cancer in the lungs as well as in the nose and paranasal sinuses after occupational exposure. Latency periods amount to 20 years and more. Therefore objective exposure data are not available in the most cases and expert evaluation of the causal connection is often difficult. Recent investigations have shown, that Ni and Cr can cumulate in human lung tissue after occupational exposure. For the evaluation of "normal" Ni- and Cr-values a total of 495 human lung tissue samples of 30 occupationally non-exposed persons were analysed by AAS including ZEEMAN-compensation after wet oxidative digestion. Additional samples of 10 deceased persons who have been occupationally exposed to nickel in previous times by nickel-refining and welding, especially flame spraying have been investigated. The median Ni- and Cr- concentrations in the lungs of the non-exposed persons ranged between 20-40 resp. 133-277 ng/g (wet weight). In nickel refinery workers Ni- concentrations were found which exceeded the normal range about 1,000. In welders, especially flame sprayers, also values more than 100 times higher could be analysed for Ni and Cr. Partially these concentrations were found years after the end of the inhalative exposure.

Investigations of thallium-exposed workers in cement factories.

Thallium and its compounds have a high toxic potency. For the production of particularly resistant sorts of cement, additives containing thallium, among other things, are employed. In conformity with our present toxicological knowledge, the determination of the concentration of thallium in the urine must be considered a suitable parameter for the assessment of the presence of thallium in the body. Occupational-medical preventive examinations were carried out in a total of 128 male employees from all areas of production in three cement factories. An exposure of these employees to thallium was objectified by analyses of the roasted pyrites employed and the dust from the electric filter. The study included the questioning of the employees with respect to their previous history of health, and also a physical examination aimed at detecting clinical symptoms of a possible effect of thallium. The analysis of thallium was carried out in samples of "spontaneous" urine. The analytical method employed was flameless atomic absorption spectroscopy (carbon-rod atomizer). In part, the group of persons investigated revealed excretions of thallium slightly or moderately above the normal level (range: < 0.3-6.3 micrograms/g creatinine). As the upper normal limit of thallium excretion, we computed a value of 1.1 micrograms/g creatinine. In no case, however, did the case history data or the findings of the physical examination reveal any indication of the symptoms characteristic of thallium poisoning.