Human Inhalation Study with Zinc Oxide: Analysis of Zinc Levels and Biomarkers in Exhaled Breath Condensate.

Workers in the zinc processing, for example, welding or hot-dip galvanizing, are exposed to aerosols consisting of particles and gases, including zinc oxide (ZnO), which can affect human health. In this study, we addressed the effects of short-term controlled exposure to nano-sized ZnO on the airway inflammatory markers in healthy volunteers. To this end, we determined the influence of ZnO inhalation on the content of zinc and biomarkers (leukotriene B4 (LTB4), peptide leukotrienes (LTC4/D4/E4), 8-iso-PGF2α, pH, and prostaglandin E2 (PGE2)) in exhaled breath condensate (EBC). Sixteen non-smoking subjects (8 females, 8 men) were exposed to filtered air (sham) or ZnO nanoparticles (0.5, 1.0, and 2.0 mg/m3) for 4 h. EBC samples were collected according to specific study design. We found that the peptide leukotrienes were below the limit of quantification (LOQ) in all the EBC samples. ZnO exposure showed no detectable effect on any other parameters investigated when comparing the two groups. The content of Zn in EBC was unaffected by ZnO inhalation at any concentration used. Therefore, we conclude that the evaluation of Zn and biomarker content in EBC would not be a suitable way to assess the exposure to inhaled ZnO.

How to diagnose mould allergy? Comparison of skin prick tests with specific IgE results.

BACKGROUND: Diagnosis of mould allergy is complicated due to the heterogeneity of the test material and the decrease in the number of commercial mould skin test solutions that are currently available. OBJECTIVES: The aim of this study was to compare skin prick tests (SPT) from different manufacturers to one another and concurrently with sIgE tests for Aspergillus fumigatus (Asp f), Cladosporium herbarum (Cla h), Penicillium chrysogenum (Pen ch), Alternaria alternata (Alt a) and Aspergillus versicolor (Asp v) to ascertain a feasible diagnostic procedure for mould sensitization. METHODS: In this multi-centre study, 168 patients with mould exposure and/or mould-induced respiratory symptoms were included. Mould SPT solutions were analysed biochemically and tested in duplicate on patients' arms. Specific IgE (sIgE) concentrations to corresponding mould species and mould mix (mx1) were measured by ImmunoCAP. SPTs in accordance with one another and with sIgE were further considered. The test efficiency was calculated using receiver-operating characteristic (ROC) analysis. RESULTS: Mould sensitization was more frequently detected by the SPT (90 of 168) than by the sIgE tests (56 of 168). Concordances of double SPT positives were only sufficient (≥ 80%) for environmental allergens, two Asp f and three Alt a SPT solutions, whereas all other mould solutions revealed concordances < 80%. The antigen content of SPT solutions was positively associated with concordant SPT double values as well as with sIgE. Taking sIgE as the 'positive standard', all mould SPT solutions revealed test efficiencies > 80%, but varied up to 20% in sensitivity and positive predictive value with the exception of Alt a. CONCLUSIONS: SPT solutions are sensitive and essential diagnostic tools for the detection of mould sensitization. Our recommendation for diagnosis would be to test at least Alt a, Asp f and Pen ch using SPT and additional sIgE test to mx1.

Specific Inhalation Challenge in Persulfate Asthma.

Specific inhalation challenge (SIC) may be considered the 'gold standard' for the diagnosis of occupational asthma due to persulfate salts. The aim of the study was to develop a safe SIC protocol. Between 2003 and 2014, eight patients with suspected occupational asthma due to persulfate salts were examined (7 females, all hair-dressers). SIC was done with a dosimeter and a nebulizer using ammonium persulfate dissolved in phosphate buffer. Until 2009, a four-step-protocol (doses: 0.0004, 0.0045, 0.045, 0.45 mg; cumulative: 0.5 mg) was used, afterwards a six-step-protocol (doses: 0.0004, 0.0018, 0.007, 0.028, 0.113, 0.45 mg; cumulative: 0.6 mg). With each SIC protocol, four subjects were tested. Skin prick tests with ammonium persulfate (20 mg/mL) were performed in all and patch tests in four subjects. In total, four subjects showed a positive SIC, two with each protocol. All subjects showed an isolated late reaction. The greatest decrease of volume in 1 s was 35 % about 3.5 h after the last inhalation (four-step-protocol). Skin prick test with ammonium persulfate was positive in one SIC positive (2 mm wheal) and in two SIC negative patients (3 and 4 mm wheal). All four subjects tested with patch tests showed a positive reaction; three of them were SICpos. We recommend to include patch-testing in the diagnosis of suspected occupational asthma due to persulfate salts. Isolated late asthmatic reactions may occur after SIC. The proposed six-step SIC protocol was safe in this limited number of subjects.

Exhaled nitric oxide in specific inhalation challenge.

Exhaled nitric oxide (eNO) is a biological mediator in human lungs and can be measured easily in exhaled air. Increasing eNO concentrations after specific inhalation testing (SIT) have been described for subjects with occupational asthma. Nevertheless, interpreting eNO concentrations after SIT is still a challenge because eNO concentrations depend on various confounding factors. In this study, 24 women and 43 men with suspected occupational asthma were examined by a questionnaire, physical examination, routine laboratory testing, skin prick testing (atopy: at least one wheal reaction >3 mm), lung function including methacholine testing, and SIT with various occupational allergens. Exhaled NO was measured before SIT (t0), 2 h (t1) and 20-22 h (t2) afterwards (NIOX Flex, Aerocrine, Sweden). At baseline we observed significantly lower eNO concentrations in smokers than in non-smokers and in non-atopics than in atopics (significant only in SIT non-responders). In the SIT non-responders (n = 45), eNO concentrations showed no change after SIT (t0: 16.0, t1: 12.3, t2: 16.0 ppb). In the SIT responders (n = 22), eNO was elevated significantly at t2 (t0: 22.9, t1: 19.9, t2: 42.0 ppb). In addition to positive responder status and measuring time, missing atopy and exposure to isocyanates were the essential factors leading to increased eNO concentrations. We conclude that the measurements of eNO after SIT may provide valuable information concerning the allergenic status of a patient.

Occupational allergic respiratory diseases in garbage workers: relevance of molds and actinomycetes.

Exposures to molds and bacteria (especially actinomycetes) at workplaces are common in garbage workers, but allergic respiratory diseases due to these microorganisms have been described rarely. The aim of our study was a detailed analysis of mold or bacteria-associated occupational respiratory diseases in garbage workers. From 2002 to 2011 four cases of occupational respiratory diseases related to garbage handling were identified in our institute (IPA). Hypersensitivity pneumonitis (HP) was diagnosed in three subjects (cases 1-3, one smoker, two non-smokers), occupational asthma (OA) was diagnosed in one subject (case 4, smoker), but could not be excluded completely in case 2. Cases 1 and 2 worked in composting sites, while cases 3 and 4 worked in packaging recycling plants. Exposure periods were 2-4 years. Molds and actinomycetes were identified as allergens in all cases. Specific IgE antibodies to Aspergillus fumigatus were detected exclusively in case 4. Diagnoses of HP were essentially based on symptoms and the detection of specific IgG serum antibodies to molds and actinomycetes. OA was confirmed by bronchial provocation test with Aspergillus fumigatus in case 4. In conclusion, occupational HP and OA due to molds occur rarely in garbage workers. Technical prevention measures are insufficient and the diagnosis of HP is often inconclusive. Therefore, it is recommended to implement the full repertoire of diagnostic tools including bronchoalveolar lavage and high resolution computed tomography in the baseline examination.

Asbestos consumption, asbestos exposure and asbestos-related occupational diseases in Germany.

Like in most industrial countries, asbestos is a leading cause of occupational diseases, especially malignant diseases, in Germany. Following the increased consumption of asbestos after World War I, the recognition of asbestos related diseases developed. At the end of the 1930s, Germany was the first country to accept lung cancer in combination with asbestosis as an occupational disease and to initiate the endeavor for reduction of asbestos dust exposure. Nevertheless after World War II the usage of asbestos increased dramatically. The ban of asbestos first came into force in 1993. Until this time several hundreds of thousands of workers had inhaled asbestos and the number of asbestos related diseases increased. In this review the history and current status on asbestos consumption, asbestos exposure and asbestos related occupational diseases in Germany is presented.

[Ratio of confirmed versus suspected occupational diseases as a parameter of quality]. / Die Bestätigungsquote von Berufskrankheiten-Verdachtsanzeigen als Qualitätsmessparameter.

PURPOSE: To evaluate the notifications of suspected causes of occupational diseases (NSC) under quality assurance aspects. METHODS: We retrospectively analysed the NSC assessed by the institutions for statutory accident insurance and prevention (Berufsgenossenschaft) between 1998 and 2002. RESULTS: Physicians were most frequently represented among the 357,050 notifications (60.2 %). The number of notifications dropped continually between 1998 and 2002. The number and quality of the notifications (NSC) depend on the knowledge of the occupational diseases as well as on the knowledge of the insured persons and on their respective occupational histories. The NSC are issued via the statutory social insurance bodies who are in contact with the patients, and the NSC also depend on the present scientific knowledge of the types of relevant diseases. Usually, the physicians were most frequently the notifiers of occupational diseases, with one exception, namely, incapacitating diseases due to damage to vertebral discs of the lumbar spine caused by many years of lifting of carrying heavy loads or of many years of work in an extremely bent position, in which cases the statutory insurance bodies themselves issued the notifications. Altogether 123,262 notifications were confirmed. The average quota of confirmations was > 40 % with physicians issuing the notifications, > 30 % with statutory pension insurance bodies and only approx. 12 % with notifying statutory sickness insurance bodies. The lowest quota of confirmations - namely, only 3 % - concerned the incapacitating vertebral disc disease of the lumbar spine mentioned above. Non-confirmed notifications of suspected occupational diseases involved an estimated cost of at least 58 million Euro. DISCUSSION: On-target improvement of the quality of notification of suspected occupational diseases is possible by exploring several avenues, including on-target assessment of evaluation criteria reporting by the statutory accident insurance bodies concerned and by regular advice rendered to the statutory social insurance bodies by occupational therapists.

[New documentation sheet for medical examination due to exposures to dust]. / Neuer Dokumentationsbogen für Untersuchungen nach G1.

With beginning of the year 2004 a new documentation sheet for occupational preventive medical examinations according to exposures to mineral dust (quartz, asbestos, ceramic fibres) will replace the existing sheet. The new investigation sheet is presented in this publication and changes are described.

[Evaluation of the quality of spirometries by a scoring system]. / Evaluation der Qualität von Spirometrien mittels Scores.

BACKGROUND: The measurement of quality will gain in importance in the future. Suitable instruments for the measurement of the quality of lung function tests have not yet been developed. In order to evaluate the quality of lung function measurements, a score is introduced, based on current guideline recommendations for lung function test. MATERIALS AND METHODS: Records of spirometries were selected at random and evaluated retrospectively. The evaluation criteria were deduced from guideline recommendations. The evaluation criteria were used to calculate a score in order to compare the quality of single records. The individual time course of lung function parameters in a group of former uranium ore miners was used to validate the score. RESULTS: 417 spirometry records from 93 physicians of different specialisation were evaluated. From 111 documented calibrations only 10 were accomplished on the same day on which the measurement was made. 147 lung function curves were classified as "good". Only in 25 records the execution of three or more measuring manoeuvres had been documented. The mean score over all physicians was 0.58, which corresponds to a middle quality level. CONCLUSIONS: The study generates and validates for the first time a score with which the quality of spirometries can be evaluated. The scoring system retrospectively analyses lung function records and it can therefore be used in the framework of quality management. The application of the score showed an inconsistent application of guideline recommendations. In agreement with studies from other countries a lack of quality was also found in Germany.

[Validity of smoking histories]. / Validität von Raucheranamnesen.

Validity of smoking histories was investigated retrospectively in 185 cases of lung cancer, which are compensated as occupational diseases. We used the files inquiry of the occupational disease declarative statement, primary physicians information, information from the post-exposure medical surveillance examinations, and the files of the former company physicians as data sources. From these, the smoking status was determined and compared with single data sources. Self-reported information during post-exposure medical surveillance examinations tallied well (deviation: 6.5%), whilst physicians' information was lacking in 34.6% in (former) smokers. We propose improved sensitisation of physicians to the problem of nicotine dependence.

Paraganglioma of the lung--developed after exposure to nuclear radiation by the Tschernobyl atomic reactor accident?

A 36-year-old Russian patient had been exposed to severe nuclear radiation during the Tschernobyl accident and developed Cushing's syndrome in September 1991. After bilateral adrenalectomy a small centrally localized lung tumor in the left segment S6 was diagnosed, and the syndrome was correlated to primary lung cancer. Thoracotomy and resection of the segments S6 revealed a primary ACTH-producing lung tumor of the cell type of a paraganglioma. The patient lost his symptoms after curative tumor resection. The case is discussed under the aspects of tumor etiology, its clinical course and immunohistochemical findings.

Malignant teratoma of the lung with lymph node metastasis of the ectodermal compartment: a case report.

A rare case with a metastasizing teratocarcinoma of the lung is presented. The 51-year-old man developed a central tumour mass in the left lung. Bronchoscopy and intraoperative sections of an involved lymph node supplied histomorphologic findings that are indicative for an epidermoid carcinoma. Further detailed analysis resulted in the final classification as a malignant teratoma. This rare tumour was further analyzed for the expression of various cellular characteristics, namely binding sites for various carbohydrates including sequences such as saccharides of the ganglioside GM1, for erythropoietin, tumour necrosis factor-alpha, and epidermal growth factor. Immunohistochemistry was used to determine the expression of neuron-specific enolase, carcino-embryonic antigen, calcyclin, epidermal growth factor, beta-HCG, AFP, p53 protein, and heparin-specific lectin. The results revealed similarities to a case with a pulmonary blastoma, and remarkable differences to that of epidermoid carcinoma cases. Similar results were seen in the DNA- and syntactic-structure analysis. The tumour reported on here should, therefore, be considered as a rare, specific entity of primary lung malignancies.

Analysis of tumour necrosis factor alpha-specific, lactose-specific and mistletoe lectin-specific binding sites in human lung carcinomas by labelled ligands.

Receptor sites can be visualized by labelled ligands as an alternative to receptor-specific antibodies, as substantiated for two different receptor classes. Recombinant tumour necrosis factor alpha (TNF) was biotinylated via amino-groups and the resultant probe was applied to formalin-fixed, paraffin-embedded tissue sections of 94 primary bronchial carcinomas and to normal peripheral lung parenchyma. In addition, monoclonal antibodies specific for neuron-specific enolase (NSE) and TNF itself were used. The biotinylated beta-galactoside-specific mistletoe lectin, which exhibits dose-dependent immunomodulatory and toxic potency, and two probes that specifically detect certain types of sugar receptors were employed to illustrate further the feasibility of using ligands for receptor localisation. The tumours comprised 62 small cell lung carcinomas, 10 epidermoid carcinomas, 11 adenocarcinomas and 11 large cell anaplastic carcinomas. Expression of TNF-binding sites was found in 39 of the small cell lung carcinomas and in 13 of the non-small cell lung carcinomas. Binding capacity for the TNF-specific antibody was seen in similar proportions of small cell lung carcinomas and of non-small cell lung carcinomas. None of the normal lung parenchymas revealed significant staining. Binding capacities to mistletoe lectin were seen in all normal lung parenchymas and in nearly all cases of adenocarcinoma (10/11). A correlation between the expression of NSE and the binding capacities to TNF was detected. Endogenous lectins, specific for lactose or beta-GalNAc, were displayed in nearly one half of the small cell lung carcinoma cases (44% or 45% respectively) and in about 25% of the non-small cell lung carcinoma cases.

Stage related morphometry of sarcoid granulomas and inflammatory cell types in broncho-alveolar lavage.

The epithelioid granulomas, interstitial and intra-alveolar mononuclear inflammatory infiltrates and the cellular compartments obtained by broncho-alveolar lavage (BAL) were measured in 40 patients with pulmonary involvement of sarcoidosis. The granulomas were divided into a central (epithelioid-cellular) zone and into a peripheral (lymphocytic-fibrotic) zone, and the density of various inflammatory cells was measured in both compartments. The cases were grouped and analyzed according to the radiological and clinical stages. The results are as follows: neutrophilic granulocytes seen in the BAL probably originate from the sarcoid granulomas in patients with stage 1 of the disease and may derive from other compartments of the lung parenchyma in patients with stage 2 or stage 3. Lymphocytes seen in the BAL of patients with stage 1 or stage 2 of the disease probably derive from intra-alveolar lymphocytic agglutinations. They originate from the sarcoid granulomas only in patients with stage 3. Macrophages seen in the BAL probably derive from the sarcoid granulomas independent from the stage of sarcoidosis. No relationship was found between the morphometric parameters and the clinical outcome of the disease.

Morphologic lesions in non-neoplastic bronchial mucosa associated with bronchial carcinomas.

The histomorphologic alterations of bronchial mucosa were analyzed in 332 cases with primary bronchial carcinomas and 48 cases with intrapulmonary metastases. The surgical specimens (lobes and lungs) were cut into serial sections after expansion and fixation, and the bronchial mucosa was analyzed in relation to its distance from the tumor boundary. Samples of the bronchial mucosa were taken at distances 10 mm, 20 mm, 30 mm and 40 mm. The following results were obtained: In primary bronchial carcinomas 18% of cases revealed a normal mucosa at 10 mm distance and 45% at 40 mm distance. The histomorphological alterations included hyperplasia of basal cells and goblet cells and less frequent squamous metaplasia. They were seen twice as frequent in primary bronchial carcinomas as in intrapulmonary metastases and were found to be distance-related only in small-sized primary bronchial carcinomas (maximum diameter less than 30 mm). Epidermoid carcinomas and small cell carcinomas displayed hyperplasia of basal cells in 40-60% of cases, adenocarcinomas only in 20-40%. Squamous metaplasia was seen in 10-15% of epidermoid carcinomas and small cell carcinomas, and only rarely in adenocarcinomas and metastases. The histomorphologic changes of bronchial mucosa associated with primary bronchial carcinomas can clearly be separated from those seen in intrapulmonary metastases in respect to their frequency and distance-relation. The findings indicate that the analyzed morphological alterations are probably associated with the histogenesis of the bronchial carcinomas.