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Objectives: Little is known about risk factors for new onset and loss of atopic sensitisation in adulthood. The aim is to examine the longitudinal effect of quantitatively assessed endotoxin exposures on changes in specific allergen sensitisation in young adults., Methods: The cohort consisted of 1113 young Danish farmers and rural controls, with a mean age of 19 years at baseline. Sensitisation to birch pollen, grass pollen, cat dander and house dust mite was measured by specific IgE levels in serum samples from baseline and at 15 years' follow-up. Changes in sensitisation were analysed in relation to cumulative endotoxin exposure during follow-up, considering early life farm exposure., Results: Endotoxin exposure during follow-up was significantly associated with less new onset of specifically grass and birch pollen sensitisation. For the highest versus lowest quartile of cumulative endotoxin exposure, the OR for new-onset IgE sensitisation was 0.35 (0.13-0.91) for birch and 0.14 (0.05-0.50) for grass. On the other hand, loss of pollen sensitisation showed a positive, although mostly non-significant, association with increased levels of endotoxin exposure. Endotoxin exposure was not associated with significant changes in cat dander and house dust mite sensitisation., Conclusions: High exposure to endotoxin during young adulthood appears to protect against new onset of pollen sensitisation, independent of childhood farm exposure., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Respiratory health effects of damp housing are well recognised, but less is known about the effect of dampness and water damage in schools. The HITEA study previously reported a higher prevalence of respiratory symptoms in pupils from moisture damaged schools, but the role of specific microbial exposures remained unclear., Objectives: To study associations between school dampness, levels of fungal and bacterial markers, respiratory symptoms and lung function in children., Methods: Primary schools in Spain, the Netherlands and Finland were selected on the basis of the observed presence (n=15) or absence (n=10) of moisture, dampness and/or mould. Settled dust was repeatedly sampled in 232 classrooms and levels of 14 different microbial markers and groups of microbes were determined. Parental reports of respiratory symptoms were available from 3843 children aged 6-12 years, of whom 2736 provided acceptable forced spirometry testing. Country-specific associations between exposure and respiratory health were evaluated by multilevel mixed-effects logistic and linear regression models and combined using random-effects meta-analysis., Results: The prevalence of respiratory symptoms was higher in moisture damaged schools, being more pronounced in Finnish pupils. Effects on lung function were not apparent. Levels of microbial markers were generally higher in moisture damaged schools, varied by season and were lower in Finnish schools. Wheeze tended to be inversely associated with microbial levels. All other respiratory symptoms were not consistently associated with microbial marker levels., Conclusions: Health effects of moisture and microbial exposures may vary between countries, but this requires further study., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Isocyanate asthma is one of the most frequently identified forms of occupational asthma in industrialised countries. The underlying mechanisms have not been clarified. There is only limited information about the relationship between exhaled nitric oxide (eNO) and occupational exposure to isocyanates and asthma., Objectives: To investigate the association between isocyanate exposure and eNO levels in isocyanate-exposed workers and to elucidate whether eNO acts as a marker of airway inflammation controlling for smoking and atopy in an industry-wide survey., Methods: Information on estimated personal isocyanate exposure, measured eNO levels, health effects and sensitisation were analysed in 229 workers from a cross-sectional study. Univariate and multiple regression analyses were used to explore the exposure-response relationships between isocyanate exposure and eNO, stratified by smoking and atopy., Results: A marginally significant exposure-response relationship was found between isocyanate exposure and eNO in atopic, non-smokers (p=0.054). eNO was significantly associated with atopy and smoking, bronchial hyper-responsiveness (BHR), work-related conjunctivitis and rhinitis after adjustment for age, gender, atopy and smoking (p<0.05). A borderline significant association was found between eNO and asthma-like symptoms after adjustment for age, gender, atopy and current smoking (p=0.055). In a small group of isocyanate-exposed workers with positive serum-specific immunoglobulin E (IgE) antibodies to hexamethylene diisocyanate (HDI), elevated eNO levels were clearly exposure related. eNO was associated with the positive specific IgG antibodies to HDI in non-atopic, non-smokers (p=0.03)., Conclusions: Increased eNO levels may indicate increased airway inflammation in atopic, non-smokers exposed to isocyanates especially at higher levels of isocyanate exposure.

Objectives: Endotoxin-exposed workers are at an increased risk of non-atopic asthma and lung-function decline. Genetic variants may influence susceptibility to these effects. The objective of the present study was to assess whether the association between occupational endotoxin exposure and wheeze is modified by innate immunity gene variants., Methods: Twenty-four single nucleotide polymorphisms (SNPs) in CD14, Toll-like receptor 4 (TLR4), TLR2, MD2 and MyD88 were genotyped in 408 agricultural workers with spirometry and questionnaire data on asthma symptoms available. Personal airborne endotoxin exposure levels were estimated in 249 exposure measurements., Results: The association between endotoxin exposure and wheeze was modified by three CD14 SNPs: -260 C/T (rs2569190), -1247 T/C (rs2569191) and -1721 A/G (rs2915863), and one MD2 SNP (rs10808798 T/C). In individuals carrying the CD14 and MD2 major allele variants, the prevalence of wheeze increased with increasing endotoxin concentration, whereas this was the opposite in minor allele homozygotes. Interaction between endotoxin exposure and genotype was statistically significant under the best-fitting recessive model (p=0.05 to 0.006). Correction for multiple comparisons resulted in marginally significant p values for interaction (p<0.06) for CD14 -260 C/T and -1247 T/C, and for MD2 rs10808798 T/C. The CD14 SNPs appeared to modify associations between endotoxin exposure and forced expiratory volume in 1 s in a similar direction (p interaction=0.07 to 0.15)., Conclusions: The association between occupational endotoxin exposure and wheeze in agricultural workers was significantly modified by genetic variants in CD14 and MD2. Our study suggests that carriers of the functional CD14/-260 C allele are more responsive to endotoxin exposure than T allele homozygotes.

Objectives: Occupational exposure to endotoxin is associated with non-allergic asthma and other airway inflammatory reactions. Little is known about the role of mucosal nitric oxide (NO) production in endotoxin-induced airway inflammation. The objective was to explore exposure-response relationships between occupational endotoxin exposure and fractional concentrations of exhaled NO (FE(NO)) and study the role of FE(NO) as an intermediate factor in the relationship between endotoxin exposure and asthma-like symptoms., Methods: FE(NO) was measured online in 425 farmers and agricultural processing workers. For each participant (cumulative) endotoxin level was modelled on the basis of 249 personal measurements and job history. Atopy was assessed as specific serum IgE to common inhalant allergens, and other health data and personal characteristics by standardised questionnaires., Results: A significant positive exposure-response relationship was found between endotoxin and FE(NO), but only in non-atopic, non-smoking subjects (p = 0.001). FE(NO) was significantly associated with current wheeze and other asthma-like symptoms irrespective of atopy and current smoking. Associations between endotoxin exposure and symptoms changed slightly after adjusting for FE(NO)., Conclusions: A positive association was found between occupational endotoxin exposure and exhaled nitric oxide in non-smoking, non-atopic adults. Increased FE(NO) was associated with asthma-like symptoms, but the role of FE(NO) as an intermediate factor between endotoxin exposure and airway symptoms appears to be limited.

Objectives: To obtain an overview of inhalable beta(1-->3)glucans levels in Dutch industrial bakeries and explore possible associations with reported respiratory health effects in bakery workers., Methods: beta(1-->3)glucan levels were analysed in 186 personal inhalable dust measurements obtained from a random population of bakery workers. Association between respiratory health effects and exposure to beta(1-->3)glucan was explored in a population of industrial bakery workers participating in a Health Surveillance System for flour processing sectors. Based on their job, bakery workers were assigned to low or high exposure categories given the average job exposure estimates obtained from the measurement study., Results: Bread bakers and dough makers had the highest exposures to beta(1-->3)glucans (GM 1.48 mug/m3 and 1.37 mug/m3 respectively). Strong correlations were found between airborne levels of inhalable dust and beta(1-->3)glucans, and between beta(1-->3)glucans and wheat allergens (Pearson correlation coefficients were 0.74 and 0.68 respectively). No significant associations could be identified between beta(1-->3)glucan exposure and work-related respiratory symptoms., Conclusion: This study has shown that bakery workers are exposed to inhalable beta(1-->3)glucan levels comparable with exposure levels found in other occupational settings. More refined exposure assessment is necessary to fully understand the role of beta(1-->3)glucan exposure on respiratory health in bakery workers.

Background: Family members of laboratory animal workers are at risk of developing allergy to laboratory animals. Little is known about the spreading of laboratory animal allergens outside the animal facilities., Objective: To assess the presence of laboratory animal allergens in dust collected from mattresses of laboratory animal workers and unexposed controls., Methods: Mouse and rat urinary proteins were measured in samples of mattress dust collected by laboratory animal workers and unexposed controls. In addition, rat and mouse allergens were determined in extracts of hair-covering caps, used during laboratory animal work, to estimate spreading of allergen through dust captured on hair. Allergen concentrations on hair caps were compared with exposure measured by personal airborne dust sampling., Results: Levels of rat urinary allergens (RUA) and mouse urinary allergens (MUA) and mouse urinary protein (MUP) 8, a specific pheromone-binding mouse allergen, were significantly higher in mattress samples of laboratory animal workers than in those of controls. Hair-covering caps used in animal facilities harboured large amounts of RUA and MUA, which correlated significantly with exposure measured by the personal sampling technique in the animal facility., Conclusions: Occupational laboratory animal allergens are detectable in mattress dust of laboratory animal workers. Transfer of allergens via uncovered hair of animal workers is likely contributing to this phenomenon. This study stresses the importance of using hair caps to prevent spreading of occupational allergens.

Background: Farming has been associated with respiratory symptoms and with protection against atopy. To date, effects of organic farming on respiratory health have not been studied., Aims: To (1) compare hay fever and asthma-like symptoms in organic and conventional farmers and (2) assess associations between current and childhood farm exposures and respiratory health effects by conducting a survey., Methods: Questionnaire data from 1205 conventional and 593 organic farmers were evaluated. Associations between health effects and farm exposures were assessed by logistic regression analyses., Results: Organic farmers reported less wheezing with shortness of breath and slightly more hay fever than conventional farmers. However, organic farming was not an independent determinant of hay fever when adjusted for farming practices and potential confounders. Livestock farmers who grew up on a farm had a threefold lower prevalence of hay fever than crop farmers without a farm childhood (odds ratio (OR) 0.3, 95% confidence interval (CI) 0.1 to 0.5). Both crop farmers who grew up on a farm and livestock farmers who did not grow up on a farm had a reduced prevalence, although less pronounced and not statistically significant. Use of disinfectants containing quaternary ammonium compounds was positively related to hay fever (OR 2.1, 95% CI 1 to 4.4). No effects of farming practices were found for asthma., Conclusions: Our study adds to the evidence that a farm childhood in combination with current livestock farming protects against allergic disorders. This effect was found for both organic and conventional farmers.

Aims: Episodes of serious work related health problems resembling organic dust toxic syndrome (ODTS) in workers of a grass seed quality inspection laboratory prompted the authors to study personal endotoxin exposure levels in this facility and in the agricultural seed processing industry. In addition, microbial and inflammatory characteristics of agricultural seeds were studied., Methods: The authors assessed inhalable dust and endotoxin levels in 101 samples from 57 workers in grass, cereal, and vegetable seed plants who were handling mainly grass seeds as bulk product, and horticulture seeds in smaller quantities. Additionally, real-time dust exposure was measured using a DataRAM monitor in 12 grass seed workers to obtain more information on exposure patterns during specific tasks. Endotoxin concentrations in seed extracts were determined by LAL assay and seed samples were analysed by scanning electron microscopy. Release of inflammatory cytokines was measured in supernatants of whole blood samples stimulated with lipopolysaccharide (LPS) or agricultural seed extracts in a human whole blood assay (WBA)., Results: Endotoxin concentrations in personal samples were high (geometric mean 1800 EU/m3), particularly in the grass seed quality inspection lab where endotoxin levels up to 274 000 EU/m3 were measured. The recommended health based endotoxin exposure limit of 50 EU/m3 was amply exceeded in almost all personal samples. Job tasks dumping and mixing were associated with highest dust and endotoxin exposures, which was confirmed by real-time measurements. Microbial infestation was found in almost all seed samples. WBA results showed that most seed extracts were capable of inducing a pronounced dose dependent cytokine release., Conclusions: Workers handling grass, cereal, or vegetable seeds are at risk of exposure to high levels of endotoxin containing seed dust. Occupational exposure to inhalable agricultural seed dust can induce inflammatory responses, and is a potential cause of ODTS.

Background: Little is known about the relation between allergic sensitisation and subsequent long term lung function changes in working populations exposed to sensitising agents., Aims: To investigate whether exposure and work related sensitisation to laboratory animals are associated with lung function decline., Methods: The relation between exposure and sensitisation to laboratory animal allergens and changes in lung function was investigated in a longitudinal study (median follow up 2.0 years) among 319 laboratory animal workers. Subjects who had been working with laboratory animals for less than 4 years (n = 102) were analysed separately, since an earlier cross sectional analysis had suggested a strong healthy worker effect in more experienced workers., Results: In multiple regression analyses both sensitisation and exposure appeared to contribute independently to lung function decline in subjects who had been working with laboratory animals for less than 4 years, adjusting for gender, age, smoking, and atopy. Lung function decline was most pronounced in sensitised subjects who continued to be in contact with the animals to which they were sensitised, with estimated average excess declines in FEV1, FVC, and MMEF of 83 ml/y (p < 0.05), 148 ml/y (p < 0.01), and 7 ml/s/y (p = 0.9)., Conclusions: We conclude that exposure to laboratory animals is a significant risk factor for accelerated lung function decline, and that sensitised workers are especially at risk.

Objectives: To compare respiratory symptoms and upper airway inflammation in domestic waste collectors and controls, and to find the association between measures of upper airway inflammation on the one hand and exposure concentrations of organic dust or respiratory symptoms on the other hand., Methods: In a cross sectional study among 47 waste collectors and 15 controls, questionnaire data on respiratory symptoms were collected. Nasal lavage (NAL), to assess upper airway inflammation, was performed before and after a work shift at the beginning and at the end of the working week. In NAL fluid, cells were counted and differentiated and concentrations of interleukin 6 (IL6), IL8, tumour necrosis factor-alpha (TNF alpha), and IL1 beta were measured. In collectors, inhalable dust samples were collected in which bacterial endotoxin and mould beta(1-->3)-glucan were assessed., Results: Prevalence of respiratory symptoms was higher in waste collectors than in controls. Geometric mean exposure concentrations were 0.58 mg/m(3) for dust, 39 EU/m(3) for endotoxin, and 1.3 microg/m(3) for beta(1-->3)-glucan. At the end of the week collectors had higher concentrations of total cells and IL8 in NAL before and after a shift than controls (cells, before 1.9-fold p<0.10, after 3.3-fold p<0.01; IL8, before and after 1.8-fold p<0.05), and after/before work shift ratios of total cells were also higher (2.3-fold p=0.06) in collectors than in controls. Cells in NAL fluid consisted predominantly of neutrophils and epithelial cells, whereas eosinophils and mononuclear cells were rarely found. Exposure to dust and endotoxin was associated with concentrations of IL8 after the shift (p<0.05). Increased concentrations of IL8 (p<0.05) and total cells (p<0.10) after the shift were associated with respiratory symptoms. Concentrations of IL6, TNF alpha, and IL1 beta were not associated with waste collecting, symptoms, or exposure., Conclusions: Waste collectors show signs of increased upper airway inflammation and respiratory symptoms compared with controls. Exposure to organic dust probably underlies the inflammation mediated by neutrophils that result in respiratory symptoms.

An important group of sensitising agents are so called high molecular weight sensitisers--proteins or glycoproteins with molecular weights in the 5-70 kDa range that can provoke a specific IgE response in workers exposed to these agents. Exposure to high molecular weight sensitisers could only be evaluated indirectly in the recent past. Few measurement techniques existed that made it possible to measure the allergens directly. As a result, few studies focused on establishing exposure-response relations, and exposure standards have not been established for high molecular weight sensitisers, or those that have are of doubtful scientific basis. Recent use of immunoassays changed this perspective dramatically. Antibodies used in the assays can originate from human serum (sensitized workers), serum from sensitised animals (rabbits producing polyclonal antibodies), or animal derived cell cultures producing monoclonal antibodies. Although few comparative studies exist, the available evidence suggests that although the correlation of allergen concentrations obtained with different assays is good, large systematic differences occur. The use of conversion factors to make data from previously performed allergen measurements comparable or exchangeable is limited and thorough standardization of assays is preferred. Validation and comparison of different assays by comparisons between laboratories seem important issues that have not received the attention needed. Epidemiological studies in several industries that used immunoassay for the exposure characterisation have shown that risk of sensitisation increases with increasing exposure to allergens. Several studies have also shown that clear differences in potency seem to exist. Sensitisation to rat urinary allergens and fungal alpha-amylase occurred in the pg/m3 and ng/m3 range. The main research questions of the near future have to focus on the prevention of occupational sensitisation. Standard setting seems possible for some allergenson the basis of the available scientific evidence for the existence of exposure response relations. However, assays for characterising exposure to allergens have to be rigorously standardised before they can be used under field conditions.

Objective: Phytase is a phosphatase derived from Aspergillus niger that enhances phosphate bioavailability in the gut, and therefore has been increasingly used as an animal feed additive since the early 1990s. The aim of this study was to assess whether work related respiratory symptoms among workers in a so called premix factory producing animal feed additives, could be due to type I (mediated by immunoglobulin E (IgE) allergic sensitisation to phytase., Methods: Preparations of specific IgE against phytase as used in the factory were assessed by enzyme immunoassay (EIA) in serum samples of 11 exposed workers who regularly handled the enzyme, in 11 office and laboratory workers of the same plant (non-exposed internal controls), and in 19 laboratory animal workers as external controls. The factory workers also completed a questionnaire on common and work related respiratory symptoms., Results: Depending on the cut off level in the EIA for IgE, and the preparation used as coated allergen, antiphytase sensitisation was found in one to four of the 19 external controls, in one to five of the 11 internal controls, and in four to 10 of the 11 exposed workers. Strongest IgE reactions were found in four exposed workers who reported work related respiratory symptoms, particularly wheezing, and in one internal control who possibly had become sensitised because the structure of the factory building did not preclude airborne exposure in the offices and corridors of the plant. Experiments with inhibition EIA for IgE showed that (a) phytase of another commercial source was only partially cross reactive with phytase as used in the premix factory, and (b) phytase used as an animal feed additive did not cross react with common mould extracts, except for extracts from the species of origin, Aspergillus niger. The amount of IgE binding phytase in Aspergillus niger was estimated to be between 0.1% and 1% of the extractable mould proteins., Conclusions: Phytase is a potentially important new occupational allergen causing specific IgE immune responses among exposed workers. Such IgE sensitisation could probably be the cause of work related asthmatic and other respiratory symptoms if no effective measures are taken to prevent airborne occupational exposure at sites where phytase is handled, particularly during addition of enzyme preparations to animal feed.

Objectives: To describe the levels of exposure to fungal alpha-amylase in British bakeries and flour mills, and to describe the relation between exposure to alpha-amylase and sensitisation to fungal alpha-amylase., Methods: 495 personal flour dust samples were taken in seven British bakeries and flour mills and analysed for alpha-amylase with an immunoassay. Workers at the sites were asked to fill out questionnaires on work related symptoms, smoking history, and work history, and they were skin prick tested with common allergens and fungal alpha-amylase to assess sensitisation., Results: Exposure to high concentrations of alpha-amylase occur in a few areas of British bakeries and flour mills, and there can be considerable differences in exposures to alpha-amylase between sites and between exposure groups, and even within similar exposure groups from different sites. Exposure to the highest concentrations of alpha-amylase was found in the dispensing and mixing areas of the bakeries (geometric mean (GM) 39.7 ng/m3). Exposure to alpha-amylase showed only a moderate correlation with concentrations of dust (r = 0.42) and flour aeroallergen (r = 0.46). The results also showed a relation between exposure to alpha-amylase and sensitisation to fungal alpha-amylase (prevalence ratio (PR) for medium exposure 3.9, 95% confidence interval (95% CI) 0.8 to 20.2, PR for high exposure 9.9, 95% CI 2.8 to 34.6) compared with the low exposure category). Atopic subjects had an increased risk of sensitisation, but this was not significant., Conclusion: This study suggests that exposure to alpha-amylase is a considerable health risk in British bakeries and flour mills. A small proportion of workers are exposed to alpha-amylase at concentrations that result in high rates of sensitisation. A reduction in exposure to alpha-amylase is likely to reduce this risk.

Objective: To investigate the occurrence of chronic respiratory effects of exposure to organic dust in the potato processing industry., Methods: Self reported chronic respiratory symptoms and spirometric lung function were assessed in a cross sectional study among 135 potato processing workers. A comprehensive study of current exposure to dust, endotoxin, and potato antigens had been performed previously. Workers were grouped into low and high exposure categories for each of the three exposure indices. Relations between exposure concentrations and respiratory health variables were investigated either by calculating prevalence rate ratios or by performing linear regression analyses. Atopy was assessed by measuring total immunoglobulin E (IgE) and specific IgE to five common aeroallergens in serum samples of workers., Results: Evident relations between current exposure indices and respiratory health in the entire group were not found. Workers employed < or = 5 years showed a two-fold higher prevalence of respiratory symptoms, lower lung function, and higher endotoxin exposure than workers employed for > 5 years. Also, atopy was more prevalent in workers employed < or = 5 years. After stratification for duration of employment, negative effects of endotoxin on lung function among workers employed < or = 5 years were suggested., Conclusions: This study does not show chronic respiratory effects of exposure to organic dust in the potato processing industry, despite the fact that the levels of exposure to endotoxin found in this industry have been reported to be associated with decreases in lung function in other occupational settings. A likely explanation for not detecting apparent effects might be that many symptomatic workers drop out of this industry a few years after starting the job, suggesting a healthy worker effect.

Objective: Extensive IgE serology in occupational or environmental health studies is often hampered by a lack of technical facilities and finance. The use in population studies of relatively simple and inexpensive enzyme immunoassays (EIAs) was therefore evaluated for the assessment of total serum immunoglobulin E (IgE), and of specific IgE reactions with various common (house dust mites, grass and birch pollen, and cat) or occupational (fungal alpha-amylase and rat urinary protein) allergens., Methods: Total IgE was measured with a sandwich EIA, calibrated with commercially available IgE standards. Reproducibility was studied by testing pooled normal human serum samples in each of a large series of test plates. A panel of 156 children's serum samples with known IgE values was used to compare the assay with other total IgE assays. A previously developed EIA for anti-yeast IgE was adapted for the measurement of IgE reacting with various common and occupational allergens. Binding of IgE to microwells coated with commercially available allergen extracts, or allergen preparations from our own laboratory, was measured with a monoclonal anti-human IgE antibody and subsequent incubations with biotinylated rabbit anti-mouse Ig and avidin-peroxidase. Panels of serum samples from school children (n = 116), bakery workers (n = 126), and laboratory animal workers (n = 52) were used to study sensitivity and specificity, with reference to skin prick tests as the standard, and to compare the EIAs with commercially available test kits., Results: The detection limit of the EIA for total IgE was 0.5-1 kU/l for undiluted serum samples, and the coefficient of variation between assays was less than 15% at serum concentrations between 1 and 150 kU/l. Results obtained with the panel of 156 children's serum samples were strongly correlated (r2 = 0.86) with IgE concentrations measured previously by radioimmunoassay. The results of the EIA for various occupational allergens correlated very well, both qualitatively and quantitatively, with the results of commercial test kits. Sensitivity and specificity of the EIA results as a predictor of skin prick test reactivity towards common allergens (house dust mite, grass pollen, birch pollen, and cat) were remarkably high (> 80%-90%) in the series of 116 children's serum samples. In a population of bakery workers the specificity of the EIAs was also very high (> 90%). The sensitivity was notably lower (30%-70%) in this adult population, which is, however, in agreement with results reported for conventional IgE tests., Conclusion: As the costs were estimated to be at least five to 10-fold lower than those of commercial test kits, the EIAs for total and specific IgE may be very useful tools in epidemiological studies of atopic respiratory or other disorders.