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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 B 4 (LTB 4 ), peptide leukotrienes (LTC 4 /D 4 /E 4 ), 8-iso-PGF 2α , pH, and prostaglandin E 2 (PGE 2 )) 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/m 3 ) 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.

Atopic, allergic, and especially asthmatic subjects might be particularly susceptible to sensory irritation induced by airborne chemicals compared to healthy individuals. Therefore, a good characterization of subjects is essential in inhalation exposure studies on sensory irritants. A total of 105 volunteers, 87% of whom reported to be non-allergic, participated in a medical examination that included skin prick test (SPT), measurements of total IgE, specific IgE (sIgE) to an ubiquitous allergen mix (sx1), and fractionated exhaled nitric oxide (FeNO), as well as pulmonary function and methacholine test. The median value of sIgE to sx1 was 0.20 kU/L (0.07-91.3 kU/L) and correlated significantly with total IgE (28.8 kU/L (2-756 kU/L)) and FeNO (14 ppb (5-100 ppb)). Forty-three subjects (41%) had sIgE to sx1 ≥ 0.35 kU/L and were classified as atopic. Thirty-five subjects, all also sx1-positive, were positive in SPT. Obstruction, small airway disease, and/or bronchial hyperreactivity were diagnosed in 18 subjects. Receiver operating characteristics (ROC) were performed to check whether signs of sensitization are useful to discriminate subjects with and without airway diseases. However, sx1, total IgE, FeNO, and SPT reached only low areas under the curve (AUC: 0.57-0.66). Although predominantly young and, according to their own statements, mostly non-allergic subjects participated in the study, almost half of them were atopic, and 10% had airway disease or bronchial hyperreactivity. This indicates that the validity of self-reported data might be inaccurate. In summary, diversified investigations of the allergy-related health status appear necessary for a thorough characterization of subjects for exposure studies on sensory irritants.

Nitric oxide (NO) from upper (nasal NO, nNO) or lower airways (fractional exhaled NO, FeNO) is considered a surrogate marker for Th2-type inflammation, which is influenced by atopy. The aim of this study was to analyze nNO and FeNO in regard to qualitative and quantitative aspects of sensitization. We evaluated 244 non-smoking young adults. All of them were first-year students recruited for a longitudinal study. An inhalation allergy screening tool was used for atopy definition (specific immunoglobulin E (sIgE) to sx1 ≥ 0.35 kU/L), and also sIgE response to three inhalant perennial allergens, house dust mite (HDM, d1), cat (e1), and dog (e5), was determined in the non-pollen season. With respect to sx1, 100 subjects could be classified as atopic. Sensitization to one, two, or three perennial allergens could be demonstrated in 46, 10, and 16 students, respectively. The subjects with positive IgE response to sx1, but not sensitized to HDM, cat, and/or dog, had FeNO levels comparable to those of non-atopic subjects (13.5 vs. 13.0 ppb, respectively; p = 0.485). These levels were significantly lower compared to atopic subjects being sensitized to any perennial allergen (19.0 ppb; p = 0.0003). After grouping the atopic subjects for perennial sensitization patterns, significantly higher FeNO could be detected in subjects with poly-sensitization (n = 26; 26.0 ppb) compared to the mono-sensitized ones (n = 46; 18.0 ppb; p = 0.023). Regarding nNO, no differences could be observed. Applying a two-way ANOVA, we could reveal a significant correlation of specific HDM-IgE CAP-class with FeNO (p < 0.0001) and nNO levels (p = 0.007). Finally, a significant relationship was found between nNO and FeNO for the whole cohort (p < 0.0001). In summary, our findings support the argument that atopy and perennial sensitization should be considered for the interpretation of NO.

Controlled human exposure studies on sensory irritation effects are usually performed with healthy volunteers. Therefore, in most studies pre-screening by a health questionnaire and a detailed medical examination are combined. The aim of this report is to investigate whether self-reported information about smoking and health status is sufficient or whether additional clinical tests are necessary for a successful and safe enrollment of healthy volunteers. There were 409 volunteers (55% female; 17-57 years; 79% non-smokers) who declared interest in participation in the study. However, 87 subjects failed to meet specific inclusion criteria, and further 138 had to be excluded due to the presence of chronic health problems. In effect, 184 subjects passed the initial questionnaire screening and proceed to further examination. Medical examination included electrocardiogram, blood and urine screening, and an olfactory function test. Atopy status was assessed by skin prick or specific IgE testing. Lung function and a methacholine challenge test were performed to assess respiratory health and bronchial hyperresponsiveness. Overall, only 107 non-smoking subjects (58% female; 19-40 years) who had no respiratory diseases, allergies, or chronic illnesses could be finally selected. Out of the 107 subjects, 8 were excluded due to positive cotinine tests, laboratory test results outside the reference range, or atypical ECGs. In another 12 subjects, obstruction or a bronchial hyperreactivity was diagnosed. Among the remaining 87 healthy subjects, 26 were classified as atopic and further two as hyposmic. In conclusion, although young and non-smoking volunteers considered themselves healthy by questionnaire, 20% showed signs of a heart, liver, or airway disease, and additional 24% were classified as atopics. This suggests that more detailed clinical testing may be necessary to safely exclude those who may adversely react to controlled exposure with sensory irritants.

Usually the diagnosis of baker's asthma is based on specific inhalation challenge with flours. To a certain extent the concentration of specific IgE to flour predicts the outcome of challenge test in bakers. The aim of this study was to evaluate whether the ratio of specific IgE (sIgE) to total IgE (tIgE) improves challenge test prediction in comparison to sIgE alone. Ninety-five bakers with work-related respiratory symptoms were challenged with rye flour. Total IgE, sIgE, and the sIgE/tIgE ratio were determined. Receiver operator characteristic (ROC) plots including the area under the curve (AUC) were calculated using the challenge test as gold-standard. Total IgE and sIgE concentrations, and their ratio were significantly higher in bakers with a positive challenge test than in those with a negative one (p < 0.0001, p < 0.0001, and p = 0.023, respectively). In ROC analysis, AUC was 0.83 for sIgE alone, 0.79 for tIgE, and 0.64 for the ratio. At optimal cut-offs, tIgE, sIgE, and the ratio reached a positive predicted value (PPV) of 95%, 84% and 77%, respectively. In conclusion, calculating the ratio of rye flour-sIgE to tIgE failed to improve the challenge test prediction in our study group.

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.

Waste collectors may suffer from acute and chronic health effects caused by organic dust (bioaerosols). Pathophysiological symptoms may originate either from allergic or irritative pathomechanisms, but an explicit distinction of the etiology is often complicated although crucial for proper risk assessment and workplace prevention. In this cross-sectional study, a total of 69 male waste collectors from the Ruhr area in Germany underwent a customized testing protocol including a modified questionnaire, basic clinical examination, spirometry, and immunologic parameters. Subjects were classified according to their work tasks into loaders (n=27), floaters (n=29), and drivers (n=13). We found that a high percentage of the workers had complaints (eyes 29.0%, nose 39.1%, and cough 34.8%) which were strongly work-related. Multiple logistic regression analyses indicated that duration of employment in waste collection (per 10 years) was associated with an increased prevalence of cough (OR=1.64, 95% CI 0.81; 3.35) and chronic bronchitis (OR=2.18, 95% CI 0.80; 5.92). An association between rhinitis and cough (OR=2.62, 95% CI 0.94; 7.27) was found, which supports the association between the prevalence of upper and lower airway disease. Furthermore, when adjusting for smoking status, atopic subjects suffered more frequently from irritation of the lower airways as indicated by cough (OR=2.71, 95% CI 0.91; 8.08). In conclusion, the study demonstrates associations between the prevalence of upper and lower airway disease in waste collectors. Notably, an underlying allergic disease in waste collectors could be suspected more commonly than previously reported.

Whereas serial measurements of lung function at work and at home are a well-known diagnostic tool for the diagnosis of occupational asthma (OA), little is known about the serial measurements of non-invasive parameters such as exhaled nitric oxide (eNO). A 51-year-old baker with variable shortness of breath without relation to work was examined for suspected OA. Skin prick test showed weak sensitizations to wheat and rye flour (without sensitizations to environmental allergens) that were corroborated by in vitro testing (CAP class 3). Baseline FEV1 of 58% predicted and a decrease of forced expiratory volume in 1 s (FEV1) after placebo (sugar powder) of 17% did not allow inhalational challenge testing. The patient performed daily measurements of FEV1 and eNO for about a month during a holiday at home and at work. Whereas symptoms and FEV1 did not show differences between holidays and work periods, eNO showed a clear increase from below 10 ppb to a maximum of 75 ppb. A diagnosis of baker's asthma was made, and the patient quit his job immediately after medical advice. A year afterwards, the patient was still taking asthma medication, but his symptoms had improved, FEV1 had increased to 73% predicted, and eNO was 25 ppb. We conclude that serial measurements of eNO at home and at work may be a useful tool for the diagnosis of OA.

Inflammatory processes, including respiratory symptoms, can be induced among workers in composting plants exposed to bioaerosols containing microorganisms and their compounds. We evaluated inflammatory processes in the lower respiratory tract via cellular and soluble mediator profiles in induced sputum (IS). IS samples of 140 current (35% smokers) and 49 former compost workers (29% smokers) as well as 29 white-collar workers (17% smokers) were collected and analyzed for the cell count and composition, and for soluble biomarkers. Significant differences between current and former compost workers and white-collar workers were detected for total cell count (p=0.0004), neutrophils (p=0.0045), sCD14 (p=0.008), and 8-isoprostane (p<0.0001). IS of non-smoking former compost workers showed lower concentrations of IL-8, total protein, immunoreactive MMP-9 and sCD14, compared with non-smoking current compost workers. 10.1% of the study population was suffering from chronic bronchitis with significant differences (p=0.018) between former compost workers (24.5%), current workers (5%), and white-collar workers (10.3%). Significantly lower IL-8 (p=0.0002), neutrophils (p=0.001), and MMP-9 (p=0.0023) values were measured in healthy subjects compared with subjects with chronic bronchitis. In conclusion, changes in lower airways were detected by analysis of biomarkers in IS of current exposed and, to a lesser extent, in IS of former compost workers. These effects are especially pronounced in subjects with chronic bronchitis.

Occupational bioaerosol exposures are capable to cause respiratory diseases. We studied the relationship between exposure to bioaerosols and biomarkers' concentration in exhaled breath condensate (EBC) and fractional exhaled nitric oxide (FeNO) in 119 bioaerosol-exposed compost workers taking into account atopy and smoking habits. Atopy was classified according to specific IgE concentrations to common inhalant allergens (sx1). Bioaerosol exposure was estimated according to job title, duration of employment, results of ambient monitoring at the workplaces, and shift time worked under protection of filtered air supply. Concentrations of 8-iso-prostaglandin F2α (8-iso-PGF2α), prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and acid-base balance (pH) in EBC and FeNO were assessed in 59 never-smoking (NS) and 60 smoking (S) compost workers. We found that atopic subjects were equally distributed among NS and S (n=16 each). Levels of 8-iso-PGF2α were significantly higher in workers considered highly exposed to bioaerosols than in low exposed workers (86.6 (66.1; 128.8) pg/mL vs. 74.4 (56.3; 96.7) pg/mL, p=0.047). No associations could be observed between exposures and biomarkers concerning compost workers in total, but there were some in atopic workers (duration of employment and FeNO: r=0.376, p=0.041; filtered air supply and FeNO: r=-0.335, p=0.071). Smokers had significantly lower pH values compared to NS (non-atopic, p=0.041; atopic p=0.050). In conclusion, EBC and FeNO might be useful tools for monitoring of inflammation due to bioaerosol exposures, especially in atopic subjects. Besides smoking also atopy should be considered when investigating airway inflammation.

Allergic immediate-type reactions by halogenated compounds of platinum (Pt) (platinum salts) have been described in workers in precious metal refineries and catalyst productions. In both industries there are exposures to many different Pt compounds. It is believed that the most important allergens are those compounds with the highest number of halide ligands. It is unknown whether sensitizations to compounds with a lower number of halide ligands represent co-sensitizations or are due to cross-reactivity. We report a worker engaged in the production of cytotoxic drugs with occupational asthma and exposure to only one Pt salt with four halide ligands. The 22-year-old worker developed work-related sneezing, runny nose, and variable dyspnea about a year after he had started to work in the cytotoxic drugs production with exposure to potassium tetrachloroplatinate(II) (K(2)PtCl(4)). He was immediately removed from his workplace and admitted for a medical opinion about 6 months afterwards. Spirometry was normal, but asthma was corroborated by a positive response to methacholine. The results of skin prick testing could not be interpreted due to urticaria factitia. Challenge with K(2)PtCl(4) by a dosimeter method yielded a clear immediate-type reaction with an increase of exhaled nitric oxide from 32 to 156 ppb after 24 h indicating an increased airway inflammation. Pt salts with four halide ligands like K(2)PtCl(4) may cause an allergic immediate-type reaction and occupational asthma. Workers in the production of Pt-containing cytotoxic drugs with exposure to these substances should be included in medical surveillance programs for the prevention of occupational asthma caused by Pt salts.

Inhalation challenges with allergens are considered the gold standard for the diagnosis of occupational asthma. However, no standardized methods are available. One open question is the degree of dose augmentation in the stepwise challenge protocols. Recently, it was recommended to increase the allergen concentrations by no more than doubling between dosing steps for safety reasons. We analyzed retrospectively our dosimeter allergen challenges performed with quadrupling dose steps during the last 10 years. Allergens were inhaled by an APSpro dosimeter and a DeVilbiss 646 nebulizer. The test was terminated after a fall of FEV(1) of at least 20%. Seventeen tests in 13 subjects were considered positive. The mean FEV(1) decreases 10 and 20-30 min after the last allergen dose were 26.7 ± 6.4 and 26.2 ± 6.5%baseline, respectively. Terminal dose response slopes did not differ between doubling (Cockcroft and Davis, J Allergy Clin Immunol, 122:1034-1035, 2008) and quadrupling doses, nor were there any differences concerning the maximal responses. The results suggest that quadrupling dose steps may be an acceptable alternative, without serious increase in risk of severe asthmatic reactions. We assume that by shortening the test duration, physicians might choose lower starting doses and thus make allergen inhalation challenges safer.

Non-invasive methods to assess inflammation of lower airways are induced sputum (IS), exhaled nitric oxide (eNO), and exhaled breath condensate (EBC). Here we focused on the assessment of airway inflammation with a panel of non-invasive methods in health care workers (HCWs) with suspected latex allergy with and without current allergic respiratory symptoms about 10 years after the latex ban in German health care facilities. Seventy-seven non-smoking subjects were examined by skin prick test and specific IgE measurements, eNO, IS, and EBC. Sensitivity, specificity, and positive and negative predicted values for relevant biomarkers were calculated using current asthma symptoms as the gold standard. Twenty-nine subjects (38%) reported ongoing asthmatic symptoms (AS). In these subjects the EBC concentrations of nitrogen oxides (NO(x); p=0.027) and leukotriene B(4) (p=0.025) were significantly higher than in subjects without AS. In addition, in the subjects with AS the numbers of eosinophils (p=0.015) and the concentrations of IL-5 (p= 0.021) in IS samples were significantly higher than in the subjects without AS. A good correlation between several inflammatory markers in IS was detected. The maximum Youden Index was reached for IS total eosinophils ≥3.5·10(4) with a test efficiency of 0.72. In conclusion, non-invasive inflammatory monitoring with EBC and IS may assist the diagnosis of allergic asthma. Self-reported current asthmatic symptoms were reflected by eosinophilic inflammation and the best parameter to support the asthma diagnosis is a total number of eosinophils ≥3.5·10(4) in IS.