The genotoxic risk of hospital, pharmacy and medical personnel occupationally exposed to cytostatic drugs--evaluation by the micronucleus assay.

The aim of this study was to evaluate the genotoxicity of cytostatic drugs in hospital and pharmacy employees (n=100), occupationally exposed. The micronucleus assay was used to study lymphocytes in 247 peripheral blood samples. Samples were collected at "baseline level" without any cytostatic drugs exposure before recruiting or after at least 3 weeks without cytostatic drugs contact and at three times (cycle 1-3) post-exposure. Samples from 60 office employees served as controls. Furthermore, our results were compared to urinary analyses of cytostatic drugs (oxazaphosporines, anthracyclines, platinum) which were collected in parallel to the cytogenetic investigation. Statistical analyses were performed under consideration of age, gender and X-ray exposure. The frequency of micronuclei was significantly related to the age of the subjects (r(Spearman)=0.16; P<0.05). However, there were no significant differences in micronucleus rates between controls and exposed hospital workers. Similarly, micronucleus rates were not significantly different at the various sampling time points and there was no correlation between duration of employment and micronucleus rates. Furthermore, no correlation between current biomonitoring data of exposure (urine tests) and micronuclei frequency was found. Therefore, significantly increased genotoxic damage of the lymphocytes investigated in this study could not be demonstrated.

Urinary excretion of platinum from platinum industry workers.

OBJECTIVES: Assessment of level of exposure to platinum and platinum concentration in urine from platinum industry workers to evaluate internal exposures and excretion kinetics. METHODS: Platinum concentrations in urine samples from 34 workers were measured by adsorptive voltammetry after UV-photolysis. Morning and evening samples were taken two to six times during six months. Individual exposures were assessed by personal air sampling. Also, two male volunteers were exposed to platinum dust for four hours at a typical platinum refinery workplace. RESULTS: Urinary platinum excretion after a shift in platinum industry workers was found to be up to 6270 ng/g creatinine--that is, 1000 times above the median value of unexposed people. Urinary excretion reached the maximum nearly 10 hours after inhalative exposure to dust containing platinum. Elimination corresponded to a first half life of about 50 (95% confidence interval (95% CI) 36 to 66) hours, but there were indications that a part of the incorporated platinum is stored longer. The amount of urinary platinum excretion showed a close correlation with the exposure level monitored by personal air sampling. CONCLUSIONS: A newly developed analytical method enabled the detection of even natural background concentrations of platinum. Thus, increased urinary platinum concentrations could be detected early, which is important to avoid damaging health of exposed workers.

Aerosol bolus dispersion in patients with bronchiolitis obliterans after heart-lung and double-lung transplantation. The Munich Lung Transplantation Group.

Bronchiolitis obliterans (BO) is one of the main late complications in patients after lung transplantation. Because BO is located in small airways, conventional lung function tests are supposed to be rather insensitive to detect early stages of this disease. In this study, the capability of the aerosol bolus dispersion test to detect BO was tested in 12 subjects with heart-lung and double-lung transplantation. Four of these patients had histological evidence of BO. The broadening (dispersion) of inhaled boluses consisting of monodispersed inert test particles during respiration was repeatedly measured in each subject. Additional measurements of spirometric and bodyplethysmographic measurements were performed. Patients with evidence of BO showed significantly increased aerosol bolus dispersion and significantly reduced maximal airflow parameters. Calculation of receiver operating characteristics (ROCs) revealed that from all lung function parameters under consideration, aerosol bolus dispersion divided by the maximum expiratory flow rate at 50% of vital capacity (MEF50) and MEI50 had the highest sensitivity and specificity for the detection of BO. Both parameters showed a sensitivity and specificity of 100%. Therefore, it may be speculated that even in early stages of disease, the combination of MEF50 measurement with aerosol bolus dispersion measurements may be a powerful tool for the detection of BO in patients with lung transplantation.

Cardiopulmonary exercise testing following hay exposure challenge in farmer's lung.

In patients experiencing an acute episode of hypersensitivity pneumonitis (HP), the alveoli and interstitium show a marked inflammation. The effects of this infiltration with effector cells on gas exchange and the cardiopulmonary system are not well characterized, and there are no data regarding cardiopulmonary exercise testing during hypersensitivity pneumonitis. The aim of this study was to gain new insights into the pathophysiology of acute farmer's lung using cardiopulmonary exercise testing. Cardiopulmonary exercise testing was performed in patients who had farmer's lung (n=21) before and 4 h after a standardized exposure with mouldy hay. Farmers who were asymptomatic for this condition (n=15) served as controls. At baseline, patients who had farmer's lung had a decreased breathing reserve and a greater alveolar to arterial oxygen difference. Following exposure, all of these patients developed hypersensitivity pneumonitis. Compared to the asymptomatic farmers, they showed an increase of alveolar to arterial oxygen difference and functional dead space ventilation during exercise and a reduction of the breathing reserve. In addition, 40% of the asymptomatic farmers demonstrated a pathological increase of the alveolar to arterial oxygen difference during exercise following exposure. In conclusion, our data signify that acute hypersensitivity pneumonitis induces significant changes in pulmonary gas exchange during exercise. Cardiopulmonary exercise testing may help to identify individuals with possible subclinical farmer's lung disease.

Long-term augmentation therapy in twenty patients with severe alpha-1-antitrypsin deficiency--three-year follow-up.

The purpose of this uncontrolled, prospective study was to evaluate the influence of long-term augmentation therapy with plasma-derived alpha 1-antitrypsin (AAT) on lung function parameters in patients with severe emphysema caused by AAT deficiency. Twenty patients (mean age 48 years) received AAT infusions once weekly for up to 36 months. No adverse effects were observed. At the beginning of the study, mean (+/- SEM) FEV1 was 1.35 +/- 0.12 liters and mean TLCO was 54 +/- 4% of predicted. After 36 months of treatment, mean FEV1 was 1.25 +/- 0.12 liters (p = n.s) and the TLCO was 52 +/- 4% predicted (p = n.s). Similar values were obtained before and after therapy for FVC (2.79 +/- 0.23 vs. 2.82 +/- 0.21 liters), MEF50 (0.72 +/- 0.09 vs. 0.68 +/- 0.08 liters/s), RV (4.60 +/0 0.44 vs 4.45 +/- 0.311) and TLC (7.72 +/- 0.49 vs. 7.38 +/- 0.42 l). The calculated annual loss of FEV1 (35.6 ml/year) was smaller than in historical untreated patients with AAT deficiency.

Biological monitoring of hospital pharmacy personnel occupationally exposed to cytostatic drugs: urinary excretion and cytogenetics studies.

For evaluation of the risk borne by hospital pharmacy personnel exposed to antineoplastic agents, the incorporation of cyclophosphamide, ifosfamide, and platinum-containing drugs was quantified by the determination of urinary concentrations. In addition, the induction of micronuclei (MN) and sister-chromatid-exchange (SCE) rates in peripheral blood lymphocytes were studied for correlation with the urinary excretion of cytostatic drugs. Cyclophosphamide and ifosfamide were determined in 24-h urine samples using gas chromatography with electron capture (detection limit 2.5 micrograms/l). Voltammetric analysis enabled the determination of platinum concentrations of 4 ng/l. Heparinized blood (20 ml) was drawn and lymphocytes were cultured for MN and SCE studies. In all, 13 hospital pharmacists and pharmacy technicians regularly involved in the preparation of cytostatic drugs participated in this investigation (7 persons represent a follow-up group). All subjects applied standard safety precautions, including the use of a vertical laminar air-flow hood, protective gowns, and latex gloves. On the day of urine sampling an average of 4,870 mg cyclophosphamide, 5,580 mg ifosfamide, and 504 mg platinum-containing drugs were handled. The excretion of 5 and 9 micrograms cyclophosphamide/l urine was measured in two samples, respectively. An elevated level of urinary platinum was found in one pharmacist (22.3 ng/g creatinine) in comparison with a nonexposed control group. Mean frequencies of MN and SCE did not differ significantly between the drug exposed group and control group. The employees who had incorporated chemotherapeutic agents were part of the follow-up group and, thus, particularly cautious and sensitive to a possible hazard. The results emphasize the necessity of improving personal protection of hospital pharmacy personnel occupationally exposed to cytostatic drugs and support the importance of biological monitoring. In an ongoing project in our department the sources of contamination are being investigated parallel to biological monitoring so as to determine critical situations and improve personal protection.

Occupational asthma in hairdressers: results of inhalation tests with bleaching powder.

STUDY OBJECTIVE: To analyze the extent to which the clinical diagnosis of bleach-induced asthma can be confirmed by laboratory tests and to determine the role of work-related exposure to bleaching powder in a group of hairdressers with respiratory complaints. METHODS: The study population consisted of 55 female hairdressers who had regular contact with various hair products and a clinical history of job-related rhinitic and/or asthmatic symptoms. We divided the individuals into two groups: group I, with asthmatic symptoms (n = 38), and group II, without asthmatic symptoms (control group, n = 17). All subjects underwent immunological, pulmonary-function, and nonspecific bronchial provocation tests, and 46 study participants were subjected to a standardized bleaching-powder test in a designated chamber. RESULTS: There were 13 positive responses to bleaching powder in the skin test, and 32 individuals showed positive bronchial responsiveness to acetylcholine; positive responses to the challenge with bleaching powder occurred in 9 women (22% of those tested). None of the women in group II reacted to bleaching powder. There was no significant difference between persons with a positive or a negative bronchial provocation test with regard to the evaluated parameters. CONCLUSIONS: In the diagnostic workup of hairdressers with work-related respiratory symptoms, bleaching powder is one of the products that need to be tested. As not every patient with an asthmatic response to bleaching powder shows a positive response to the acetylcholine challenge test, in doubtful cases a specific exposure test may be recommendable.

Cardiorespiratory responses to incremental exercise in patients with systemic sclerosis.

Patients with systemic sclerosis are known to have histologic pulmonary abnormalities despite normal chest radiograph or conventional pulmonary function or both. In an attempt to detect early features of lung involvement in progressive systemic sclerosis, we investigated patients with systemic sclerosis using cardiopulmonary exercise testing. We have studied 78 patients who fulfilled the American Rheumatism Association criteria for the classification of systemic sclerosis, and according to the classification of LeRoy, 44 had limited cutaneous systemic sclerosis and 34 had diffuse cutaneous systemic sclerosis. A significantly decreased diffusing capacity (65 +/- 3% of that predicted) was present only in the group with diffuse cutaneous systemic sclerosis. The patients with lung involvement showed a significant reduction in exercise capacity (54 +/- 3% of that predicted) and in oxygen uptake (70 +/- 3% of that predicted). Additionally, we could demonstrate an increased functional dead space ventilation (0.34 +/- 0.02) and widened alveolar-arterial oxygen difference during exercise (44 +/- 3 mm Hg). By cardiopulmonary exercise testing, 12 of the 78 patients (15%) with normal single-breath diffusing capacity for carbon monoxide had increased dead space to tidal volume ratio. Our results suggest that occult pulmonary impairment may be present in patients with normal pulmonary function and that cardiopulmonary exercise testing enables detection of such impairment. Our study results show the limitations of resting data in predicting abnormalities during exercise in patients with systemic sclerosis.

Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung.

Fibrosing alveolitis (FA) is a frequent and often fatal complication of systemic sclerosis (SSC). Alveolar inflammation has been recognized as a primary event in the pulmonary manifestation of SSC. To evaluate the significance of the alveolitis in SSC, we performed bronchoalveolar lavage (BAL) and correlated the generated data with changes in lung function over time. Seventy nine SSC patients with pulmonary involvement were followed for 56.8 +/- 3.1 wk (mean +/- SEM) with a repeat lung function test at the end of the follow-up period. During follow-up, 38 patients were treated with a systemic immunosuppressive regimen. For evaluation, patients were assigned to two groups according to whether their BAL cell differential was normal (inactive BAL) or abnormal (active BAL: i.e., polymorphonuclear leukocytes > 5% and/or lymphocytes > 15%). Active BAL was associated with more severe lung function impairment than was inactive BAL, and patients with active BAL deteriorated during follow-up if untreated. In contrast, treated patients with active BAL stabilized or improved. In summary, active alveolitis as characterized by BAL is associated with progressive pulmonary disease in SSC patients, and a significant positive effect of immunosuppressive therapy on the course of pulmonary disease was observed in patients with active BAL.

Characterization of soybean allergens causing sensitization of occupationally exposed bakers.

Fourteen bakers suffering from workplace-related respiratory symptoms and sensitized to soybean were studied. Twelve of them were also allergic to wheat flour, 10 to rye flour, and five to alpha-amylase of Aspergillus oryzae (Asp o 2). IgE estimation by RAST strongly indicated that the trypsin inhibitor and lipoxidase are major allergens of soybean. Various allergenic components could be characterized by immunoblotting after two-dimensional electrophoresis. Our RAST and immunoblotting results show an interindividually different allergic response to inhalative soybean constituents, and that the trypsin inhibitor (20 kDa, pI approximately 4.5) is an important inhalative soybean allergen recognized by IgE antibodies in the sera of 86% of the examined sensitized bakers.

Airborne platinum concentrations in Munich city buses.

Airborne platinum concentrations sampled over 4 h in local buses in Munich during regular rides were analyzed by adsorptive stripping voltammetry. The detection limit was 0.5 pg/m3, related to an air-sampling of 5 m3. In 96 samples from 1993 and 1994 we found a mean concentration of 7.3 pg/m3 (S.D. 6.5). The route with highest traffic showed 33.0 pg/m3 compared to 3.0 pg/m3 at a suburban bus route.

Environmental ozone field study on pulmonary and subjective responses of assumed risk groups.

Lung function parameters (measured with a body plethysmograph) and subjective votes on irritations of eyes or airways were taken from subjects belonging to four assumed ozone risk groups and one control group (40 subjects each: senior citizens, juvenile asthmatics, forestry workers, athletes, and clerks). Every subject was examined on 8 days both in the morning and in the afternoon. The intention was to obtain an equal distribution of measuring days with elevated and low ozone concentrations, respectively, for each subject. On average the ozone concentrations reached 0.070 ppm on "ozone days" [maximum concentration 0.112 ppm for clerks (outdoors), 0.100 ppm for senior citizens, 0.091 for juvenile asthmatics, 0.086 ppm for athletes, and 0.077 ppm for forestry workers] and 0.028 ppm on "control days" (minimum 0.001 ppm). The results show no relevant ozone effect for the group with the lowest ventilation rate (senior citizens) and only marginal reductions of respiratory flows and volumes for athletes. Pulmonary decrements of juvenile asthmatics on ozone days were small but larger than those documented in the literature for healthy children. Forestry workers and clerks had significantly higher airway resistances on ozone days, although having been exposed to the lowest ozone concentrations of all groups. Thus, on days with moderately elevated levels of ozone in the environment it is assumed that ozone itself has a minor influence on pulmonary responses compared to that of other constituents of the air in certain locations like in forests or indoors on these days. These could be reaction products of ozone with motor tool exhausts in the case of forestry workers or substances originating from ozone deposition on the surfaces of the offices.

[Lung function and prevalence of irritation of eyes and respiratory airways on days with elevated ozone concentrations]. / Lungenfunktion and Prävalenz von Reizempfindungen an Augen und Atemwegen an Tagen mit erhöhten Ozonkonzentrationen.

In order to evaluate potential health effects on days with elevated ozone concentrations, lung function parameters and subjective votes on irritations of eyes and airways were taken repeatedly from subjects belonging to four assumed ozone risk groups and one control group (at least 40 subjects each) - senior citizens, juvenile asthmatics, forestry workers, athletes and clerks - in comparison of days with elevated (at least 100 micrograms/m3) and low ozone concentrations (at most 80 micrograms/m3). The results show no relevant ozone effects for the groups, "senior citizens" and "athletes", only minor pulmonary effects for "juvenile asthmatics", but significantly higher airway resistances on "ozone days" for "forestry workers" (by 21%) and "clerks" (by 16%). On days with moderately elevated levels of ozone in the environment it is assumed that ozone itself has minor influence on pulmonary responses compared to that of other constituents of the air in certain location like forest or indoors.

Increased oxidation of extracellular glutathione by bronchoalveolar inflammatory cells in diffuse fibrosing alveolitis.

An unbalanced oxidative stress is thought to be an important element in the pathogenesis of diffuse fibrosing alveolitis (DFA). The purpose of our study was to investigate the role of reactive oxygen metabolites (ROMs) released from cultured bronchoalveolar inflammatory cells (BA-cells) on glutathione oxidation. We studied bronchoalveolar lavage samples from 10 healthy controls and from 20 patients with diffuse fibrosing alveolitis (all were nonsmokers). BA-cells obtained by bronchoalveolar lavage (BAL) were incubated with 50 microM of reduced glutathione (GSH). Oxidation of GSH to glutathione disulphide (GSSG) by BA-cell derived oxidants was detected as a decline of GSH in the supernatants. Total glutathione (GSHtot = GSH + 2 GSSG) and GSSG in the epithelial lining fluid (ELF), and methionine sulphoxide (Met(O)) content of BAL proteins were determined. In diffuse fibrosing alveolitis the oxidative activity of BA-cells was enhanced, GSHtot and GSH were decreased, whereas the GSSG:GSH ratio was increased. The oxidative activity of BA-cells correlated positively with the GSSG:GSH ratio, but not with the methionine sulphoxide content. The methionine sulphoxide content was elevated in diffuse fibrosing alveolitis and inversely correlated with GSHtot. The methionine sulphoxide content also correlated positively with the percentage of BAL neutrophils. We conclude that BA-cell-derived reactive oxygen species are capable of oxidizing extracellular GSH in vitro. The positive correlation between the BA-cell oxidative activity in vitro and GSSG:GSH ratio in ELF suggests that a similar oxidative effect on extracellular GSH may also occur in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pulmonary manifestations of systemic scleroderma: pathophysiologic and clinical significance of the activation of lung fibroblasts]. / Die pulmonale Manifestation der systemischen Sklerodermie: Pathophysiologische und klinische Bedeutung der Aktivierung von Lungenfibroblasten.

Fibrosing alveolitis (FA) is a common and often fatal complication of systemic sclerosis (SSC). The purpose of this study was to characterize the fibrotic process within the lungs using bronchoalveolar lavage fluid (BALF). We investigated 25 healthy controls (CON) and 85 SSC patients. In 61 patients (72%) lung function tests, clinical, and radiological findings indicated manifest FA, whereas 24 patients (28%) where free of significant lung disease. Of the latter, 12 had pathologic BAL differential cell counts (= subclinical alveolitis; SUB), 12 had normal BAL cytology (NOR). BAL samples were analysed for chemoattractant activity (CAA) for fibroblasts using Boyden chambers. Procollagen-III-Peptide (P-III-P) and Laminin fragment P1 (Lam-P1) were measured radioimmunologically. CAA (expressed as % of the effect of conditioned medium) was increased in FA and SUB (CON: 17.3 +/- 3.2; FA: 40.8 +/- 5.8, p < 0.01 vs. CON; SUB: 58.6 +/- 11.8, p < 0.01 vs. CON; NOR: 23.7 +/- 6.3; n.s.). Lam-P1 [U/ml ELF] was also elevated in FA and SUB patients (CON: 0.90 +/- 0.17; FA: 2.07 +/- 0.48, p < 0.05 vs. CON; SUB: 2.61 +/- 1.14, p < 0.05 vs. CON; NOR: 1.05 +/- 0.35, n.s. vs. CON). P-III-P [U/ml ELF] was elevated in FA patients (CON: 8.3 +/- 1.1; FA: 26.9 +/- 5.5, p < 0.001 vs. CON) but not in SUB or NOR (SUB: 10.2 +/- 0.7, NOR: 7.9 +/- 2.9; n.s.). There was no significant relationship between P-III-P and LAM-P1 values in ELF and serum, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenetic and clinical significance of fibroblast activation in scleroderma lung disease.

Fibrosing alveolitis (FA) is a major and often fatal complication of systemic sclerosis (SSC). The critical role of fibroblasts in the pathogenesis of FA has long been recognized. Characterization of fibroblast activation in the lungs may improve our understanding and the management of this disease. We analyzed bronchoalveolar lavage (BAL) fluid samples from 9 healthy controls and 43 patients with FA caused by lung involvement form SSC. The chemoattractant activity (CAA) of cultured human fibroblasts elicited by native BAL fluid was measured in Boyden chambers. In addition, procollagen III peptide was measured in BAL fluid as a marker of collagen synthesis. CAA (expressed as percentage of the chemoattractant effect of 0.25 ng/ml platelet-derived growth factor; PDGF) was elevated in the SSC patients compared with that of the controls (control: 12.6 +/- 4.0%; SSC: 68.8 +/- 15.2%; p < 0.01). A positive correlation was found between BAL total cell count and CAA (r = 0.60, p < 0.01). An inverse correlation existed between CAA and total lung capacity (r = -0.55, p < 0.05). The patients were followed up for 13.3 +/- 1.4 months (mean +/- SEM). Twenty-seven patients received immunosuppressive therapy, whereas 16 refused therapy. The patients were assigned to two groups according to their CAA being lower or higher than 36% of the PDGF response (= mean value of the controls + 2 SD).

Allergens causing bird fancier's asthma.

The study investigates to what extent bird feathers contain relevant allergens/antigens involved in bird fancier's asthma. The study group consisted of two budgerigar fanciers, two parrot fanciers and one canary fancier. All subjects complained of asthmatic symptoms, caused by contact with their birds, and they showed a significant bronchial hyperreactivity to acetylcholine. Positive IgE antibody reactions to bird sera as well as to extracts of feathers were observed in RAST. Well-defined major allergenic bands could be detected and identified in the IgE immunoblots with feather extracts as well as with serum proteins of budgerigar, parrot, pigeon, canary, and hen (mol. mass 20-30 kDa and 67 kDa). The most pronounced bands appeared with the extracts of species to which an exposure had taken place. Weaker IgG-binding patterns were also observed. Our results show that inhalable feather dust contains several allergenic components which cross-react with serum allergens/antigens of the same as well as of other bird species. This emphasizes the significance of bird feathers for immediate-type allergic reactions.

Biological monitoring of cyclophosphamide and ifosfamide in urine of hospital personnel occupationally exposed to cytostatic drugs.

The occupational exposure of 21 nurses and pharmacy personnel from eight hospitals to cyclophosphamide and ifosfamide was determined by quantifying the amount of the drugs handled and by measuring the urinary excretion of the unmetabolised substances. Preparing antineoplastic drugs for intravenous treatment was the major task of all study participants. Twenty four hour urine was collected on days when cyclophosphamide and/or ifosfamide were mixed, on average 3900 mg cyclophosphamide and/or 5900 mg ifosfamide. The analyses were performed by gas chromatography with electron capture, detection limit 2.5 micrograms/24 hour urine. Despite standard safety precautions, including a vertical laminar air flow safety cabinet and gloves, cyclophosphamide was detected in 12 of 31 and ifosfamide in four of 21 urine samples on days when the drugs were handled. Excretion of cyclophosphamide ranged from 3.5 to 38 micrograms/24 h (mean 11.4 micrograms/24 h) urine, ifosfamide from 5 to 12.7 micrograms/24 h (mean 9 micrograms/24 h) urine. Based on an excretion rate of 11.3% unmetabolised cyclophosphamide, the average amount excreted corresponded to an uptake of 101 micrograms cyclophosphamide. For ifosfamide the mean quantity incorporated was 20 micrograms assuming that 45% of the drug was excreted. Pertaining to the doses handled, the uptake of cyclophosphamide and ifosfamide was estimated to be approximately 0.0025% and 0.0004% respectively. Despite time-consuming purification procedures, gas chromatographic analysis is a suitable method for monitoring personnel occupationally exposed to cyclophosphamide and ifosfamide and is a major contribution to the evaluation of potential health risks of exposed personnel.