Association of antimicrobial usage with faecal abundance of aph(3')-III, ermB, sul2 and tetW resistance genes in veal calves in three European countries.

BACKGROUND: High antimicrobial use (AMU) and antimicrobial resistance (AMR) in veal calves remain a source of concern. As part of the EFFORT project, the association between AMU and the abundance of faecal antimicrobial resistance genes (ARGs) in veal calves in three European countries was determined. METHODS: In 2015, faecal samples of veal calves close to slaughter were collected from farms located in France, Germany and the Netherlands (20 farms in France, 20 farms in the Netherlands and 21 farms in Germany; 25 calves per farm). Standardized questionnaires were used to record AMU and farm characteristics. In total, 405 faecal samples were selected for DNA extraction and quantitative polymerase chain reaction to quantify the abundance (16S normalized concentration) of four ARGs [aph(3')-III, ermB, sul2 and tetW] encoding for resistance to frequently used antimicrobials in veal calves. Multiple linear mixed models with random effects for country and farm were used to relate ARGs to AMU and farm characteristics. RESULTS: A significant positive association was found between the use of trimethoprim/sulfonamides and the concentration of sul2 in faeces from veal calves. A higher weight of calves on arrival at the farm was negatively associated with aph(3')-III and ermB. Lower concentrations of aph(3')-III were found at farms with non-commercial animals present. Furthermore, farms using only water for the cleaning of stables had a significantly lower abundance of faecal ermB and tetW compared with other farms. CONCLUSION: A positive association was found between the use of trimethoprim/sulfonamides and the abundance of sul2 in faeces in veal calves. Additionally, other relevant risk factors associated with ARGs in veal calves were identified, such as weight on arrival at the farm and cleaning practices.

Morbidity Rates in an Area with High Livestock Density: A Registry-Based Study Including Different Groups of Patients with Respiratory Health Problems.

There is continuing debate and public health concern regarding the previously confirmed association between high livestock density and human health. The primary aim of the current study is to assess the prevalence of respiratory and other health problems in a livestock dense area in the Netherlands, based on recent longitudinal health data and a large sample. Analyses are expanded with the investigation of different subgroups of patients with respiratory health problems and the inclusion of various chronic and acute health outcomes, as well as prescribed medication. Prevalence of health symptoms and chronic conditions was assessed for the period 2014-2016, based on electronic health records registered in 26 general practices located in areas with intensive livestock farming in the Netherlands ("livestock dense area", n = 117,459 unique residents in total). These were compared with corresponding health data from general practices (n = 22) in different rural regions with a low density of livestock farms or other major environmental exposures ("control area", n = 85,796 unique residents in total). Multilevel regression models showed a significantly higher prevalence of pneumonia in the total sample in the livestock dense area, which was also observed among susceptible subgroups of children, the elderly, and patients with chronic obstructive pulmonary disease (COPD). Lower respiratory tract infections, respiratory symptoms, vertigo, and depression were also more common in the livestock dense area compared to the control area. In general, there were no significant differences in chronic conditions such as asthma, COPD, or lung cancer. Prescription rates for broad-spectrum antibiotics were more common among patients with pneumonia in the livestock dense area. Acute respiratory infections and symptoms, but not chronic conditions, were considerably more common in areas with a high livestock density. Identification of causal pathogens on the basis of serological analyses could further elucidate the underlying mechanisms behind the observed health effects.

Occupational Exposure and Carriage of Antimicrobial Resistance Genes (tetW, ermB) in Pig Slaughterhouse Workers.

OBJECTIVES: Slaughterhouse staff is occupationally exposed to antimicrobial resistant bacteria. Studies reported high antimicrobial resistance gene (ARG) abundances in slaughter pigs. This cross-sectional study investigated occupational exposure to tetracycline (tetW) and macrolide (ermB) resistance genes and assessed determinants for faecal tetW and ermB carriage among pig slaughterhouse workers. METHODS: During 2015-2016, 483 faecal samples and personal questionnaires were collected from workers in a Dutch pig abattoir, together with 60 pig faecal samples. Human dermal and respiratory exposure was assessed by examining 198 carcass, 326 gloves, and 33 air samples along the line, next to 198 packed pork chops to indicate potential consumer exposure. Samples were analyzed by qPCR (tetW, ermB). A job exposure matrix was created by calculating the percentage of tetW and ermB positive carcasses or gloves for each job position. Multiple linear regression models were used to link exposure to tetW and ermB carriage. RESULTS: Workers are exposed to tetracycline and macrolide resistance genes along the slaughter line. Tetw and ermB gradients were found for carcasses, gloves, and air filters. One packed pork chop contained tetW, ermB was non-detectable. Human faecal tetW and ermB concentrations were lower than in pig faeces. Associations were found between occupational tetW exposure and human faecal tetW carriage, yet, not after model adjustments. Sampling round, nationality, and smoking were determinants for ARG carriage. CONCLUSION: We demonstrated clear environmental tetracycline and macrolide resistance gene exposure gradients along the slaughter line. No robust link was found between ARG exposure and human faecal ARG carriage.

A nationwide follow-up study of occupational organic dust exposure and risk of chronic obstructive pulmonary disease (COPD).

OBJECTIVES: To study exposure-response relations between cumulative organic dust exposure and incident chronic obstructive pulmonary disease (COPD) among subjects employed in the Danish farming and wood industry. METHODS: We studied exposure-response relations between cumulative organic dust exposure and incident COPD (1997-2013) among individuals born during 1950-1977 in Denmark ever employed in the farming or wood industry (n=1 75 409). Industry-specific employment history (1964-2007), combined with time-dependent farming and wood industry-specific exposure matrices defined cumulative exposure. We used logistic regression analysis with discrete survival function adjusting for age, sex and calendar year. Adjustment for smoking status was explored in a subgroup of 4023 with smoking information available. RESULTS: Cumulative organic dust exposure was inversely associated with COPD (adjusted rate ratios (RRadj (95% CIs) of 0.90 (0.82 to 0.99), 0.76 (0.69 to 0.84) and 0.52 (0.47 to 0.58) for intermediate-low, intermediate-high and high exposure quartiles, respectively, compared with the lowest exposure quartile). Lagging exposure 10 years was not consistently suggestive of an association between cumulative exposure and COPD; RRadj (95% CI): 1.05 (0.94 to 1.16), 0.92 (0.83 to 1.02) and 0.63 (0.56 to 0.70). Additional stratification by duration of employment showed no clear association between organic dust exposure and COPD except for the longer exposed (15-40 years) where an inverse association was indicated. Subgroup analyses showed that smoking had no impact on exposure-response estimates. CONCLUSIONS: Our findings show no increased risk of COPD with increasing occupational exposure to organic dust in the farming or wood industry. Potential residual confounding by smoking can, however, not be ruled out.

Occupational endotoxin exposure in association with atopic sensitization and respiratory health in adults: Results of a 5-year follow-up.

The objective of the present longitudinal study was to investigate the effects of occupational endotoxin exposure on respiratory health and atopic sensitization in adults. Health outcomes and personal endotoxin exposure estimates were determined for 234 farmers and agricultural workers both at baseline and 5 years later. A questionnaire was used to assess respiratory symptoms, spirometry tests were performed and total and specific IgE levels were measured in serum. A twofold increase in personal endotoxin exposure was associated with less hay fever (OR 0.68, 95%CI 0.54-0.87) and grass IgE positivity (OR 0.81, 95%CI 0.68-0.97) at both time points ("persistent" versus "never"). Although not statistically significant, a consistent protective pattern was observed for an increased loss of hay fever symptoms (OR 2.19, 95%CI 0.96-4.99) and grass IgE positivity (OR 1.24, 95%CI 0.76-2.02), and for less new-onset of hay fever (OR 0.87, 95%CI 0.65-1.17), grass IgE positivity (OR 0.83, 95%CI 0.61-1.12) and atopic sensitization (OR 0.75, 95%CI 0.55-1.02). Endotoxin exposure was not associated with changes in lung function. We showed that occupational endotoxin exposure is associated with a long-term protective effect on hay fever and grass IgE positivity. Results on longitudinal changes in hay fever, atopy and grass IgE positivity in adulthood were consistent with a protective effect of endotoxin exposure, but results need to be confirmed in larger cohorts. An effect of endotoxin exposure on lung function decline was not found.

Current and new challenges in occupational lung diseases.

Occupational lung diseases are an important public health issue and are avoidable through preventive interventions in the workplace. Up-to-date knowledge about changes in exposure to occupational hazards as a result of technological and industrial developments is essential to the design and implementation of efficient and effective workplace preventive measures. New occupational agents with unknown respiratory health effects are constantly introduced to the market and require periodic health surveillance among exposed workers to detect early signs of adverse respiratory effects. In addition, the ageing workforce, many of whom have pre-existing respiratory conditions, poses new challenges in terms of the diagnosis and management of occupational lung diseases. Primary preventive interventions aimed to reduce exposure levels in the workplace remain pivotal for elimination of the occupational lung disease burden. To achieve this goal there is still a clear need for setting standard occupational exposure limits based on transparent evidence-based methodology, in particular for carcinogens and sensitising agents that expose large working populations to risk. The present overview, focused on the occupational lung disease burden in Europe, proposes directions for all parties involved in the prevention of occupational lung disease, from researchers and occupational and respiratory health professionals to workers and employers.

A systematic review of occupational exposure to coal dust and the risk of interstitial lung diseases.

Objective: Exposure to coal dust can cause interstitial lung disease (ILD), but whether this is due to pure coal or to the contents of quartz in coal is less clear. Here, we systematically reviewed the relation between 'pure coal' and ILD. Methods: In a systematic review based on PRISMA criteria 2945 articles were identified. Strict eligibility criteria, which evaluated the 'pure coal effect', led to the inclusion of only nine studies. Results: Among these nine studies six studies indicated an independent effect of the non-quartz part of coal on the development and progression of ILD, two did not demonstrate an effect and one was inconclusive. Conclusions: Although an independent effect of non-quartz coal dust on the development of ILD is supported, due to methodological limitations the evidence is limited and further evidence is needed.

Exposure-response analyses for platinum salt-exposed workers and sensitization: A retrospective cohort study among newly exposed workers using routinely collected surveillance data.

BACKGROUND: Chloroplatinate salts are well-known respiratory sensitizing agents leading to work-related sensitization and allergies in the work environment. No quantitative exposure-response relation has been described for chloroplatinate salts. OBJECTIVE: We sought to evaluate the quantitative exposure-response relation between occupational chloroplatinate exposure and sensitization. METHODS: A retrospective cohort study was conducted using routinely collected health surveillance data and chloroplatinate exposure data. Workers who newly entered work between January 1, 2000, and December 31, 2010, were included, and the relation between measured chloroplatinate exposure and sensitization (as determined by skin prick test responses) was analyzed in more than 1000 refinery workers from 5 refineries for whom a total of more than 1700 personal exposure measurements were available. RESULTS: A clear exposure-response relation was observed, most strongly for more recent platinum salt exposure. Average or cumulative exposure over the follow-up period was less strongly associated with sensitization risk. The exposure-response relation was modified by smoking and atopy. CONCLUSIONS: Indications exist that recent exposure explains the risk of platinum salt sensitization most strongly. The precision of the estimate of the exposure-response relation derived from this data set appears superior to previous epidemiologic studies conducted on platinum salt sensitization and as a result, might have possible utility for the development of preventive strategies.

Increased respiratory symptoms in COPD patients living in the vicinity of livestock farms.

Several studies have investigated the effect of livestock farm emissions on the respiratory health of local residents, but results are inconsistent. This study aims to explore associations between the presence of livestock farms and respiratory health in an area of high-density livestock farming in the Netherlands. We focused especially on associations between farm exposures and respiratory symptoms within subgroups of potentially susceptible patients with a pre-existing lung disease.In total, 14 875 adults (response rate 53.4%) completed a questionnaire concerning respiratory health, smoking habits and personal characteristics. Different indicators of livestock farm exposures relative to the home address were computed using a geographic information system.Prevalence of chronic obstructive pulmonary disease (COPD) and asthma was lower among residents living within 100 m of a farm (OR 0.47, 95% CI 0.24-0.91 and OR 0.65, 95% CI 0.45-0.93, respectively). However, >11 farms in 1000 m compared to fewer than four farms in 1000 m (fourth quartile versus first quartile) was associated with wheezing among COPD patients (OR 1.71, 95% CI 1.01-2.89). Using general practitioners' electronic medical records, we demonstrated that selection bias did not affect the observed associations.Our data suggest a protective effect of livestock farm emissions on the respiratory health of residents. Nonetheless, COPD patients living near livestock farms reported more respiratory symptoms, suggesting an increased risk of exacerbations.

Process evaluation of an intervention program to reduce occupational quartz exposure among Dutch construction workers.

OBJECTIVES: Evaluate the process of an intervention in the construction industry to reduce quartz exposure. METHODS: In a cluster randomized controlled trial, data on seven process aspects (ie, recruitment, reach, dose delivered, dose received, fidelity, satisfaction, and context) were quantitatively collected on manager and worker levels. RESULTS: Dose delivered was 95% for the plenary sessions and 20% for the worksite visit. Although the protocol was mostly implemented as intended, dose received was lower than expected. Both managers and workers appreciated the intervention and recommended the intervention for future implementation. Workers attending all intervention sessions were most satisfied about the intervention. CONCLUSIONS: High rates for dose delivered and fidelity for the plenary sessions and relatively high satisfaction rates were achieved. Furthermore, continuous monitoring of contextual factors beforehand and alongside the implementation of interventions is recommended.

IARC monographs: 40 years of evaluating carcinogenic hazards to humans.

BACKGROUND: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans. OBJECTIVES: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed. DISCUSSION: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed. CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.

Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role?

Recently, a locus centred on rs9273349 in the HLA-DQ region emerged from genome-wide association studies of adult-onset asthma. We aimed to further investigate the role of human leukocyte antigen (HLA) class II in adult-onset asthma and a possible interaction with occupational exposures. We imputed classical HLA-II alleles from 7579 single-nucleotide polymorphisms in 6025 subjects (1202 with adult-onset asthma) from European cohorts: ECRHS, SAPALDIA, EGEA and B58C, and from surveys of bakers and agricultural workers. Based on an asthma-specific job-exposure matrix, 2629 subjects had ever been exposed to high molecular weight (HMW) allergens. We explored associations between 23 common HLA-II alleles and adult-onset asthma, and tested for gene-environment interaction with occupational exposure to HMW allergens. Interaction was also tested for rs9273349. Marginal associations of classical HLA-II alleles and adult-onset asthma were not statistically significant. Interaction was detected between the DPB1*03:01 allele and exposure to HMW allergens (p = 0.009), in particular to latex (p = 0.01). In the unexposed group, the DPB1*03:01 allele was associated with adult-onset asthma (OR 0.67, 95%CI 0.53-0.86). HMW allergen exposures did not modify the association of rs9273349 with adult-onset asthma. Common classical HLA-II alleles were not marginally associated with adult-onset asthma. The association of latex exposure and adult-onset asthma may be modified by DPB1*03:01.

'Relieved Working' study: systematic development and design of an intervention to decrease occupational quartz exposure at construction worksites.

BACKGROUND: Occupational quartz exposure continues to be a serious hazard in the construction industry. Until now, evidence-based interventions aimed at reducing quartz exposure are scarce. The aim of this study was to systematically develop an intervention and to describe the study to evaluate its effectiveness. METHODS/DESIGN: The intervention was developed according to the principles of the Intervention Mapping protocol, meaning that evidence from the literature was combined with information collected from stakeholders (e.g., construction workers, managers and researchers). The intervention aimed to integrate technical, behavioural and organizational factors. The intervention consists of two plenary meetings for all employers within the company, and individual visits at construction worksites, including specific intervention materials. Additionally, a demonstration session regarding control measures was organized for all managers. The effectiveness of the intervention will be evaluated in a cluster randomized controlled trial among eight construction companies, with measurements at baseline and follow-up. Outcome measures are personal respirable dust and quartz exposure by means of exposure assessment, and behavioural and organizational determinants which will be assessed by means of questionnaires. Additionally, a process evaluation will shed light on whether the intervention (does not) works, and, if so, the reasons for this. DISCUSSION: Applying Intervention Mapping in the development of an intervention to reduce occupational quartz exposure was useful, as different stakeholders provided input for the intervention as well as the implementation strategy. Therefore, the feasibility of the intervention has been enhanced, as it appeals to construction workers and managers and will not unduly interfere with the ongoing construction work. TRIAL REGISTRATION NUMBER: NTR4586 (May 7th 2014).

Exhaled nitric oxide in spray painters exposed to isocyanates: effect modification by atopy and smoking.

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.

The effect of assay type and sample matrix on detected cytokine concentrations in human blood serum and nasal lavage fluid.

Cytokine concentrations in biological fluids are widely used markers for activation of immunological processes. Confirming the reproducibility of measurements is important, especially in longitudinal or multicenter studies where time between analyses or different analyzing laboratories increases the intra-assay variability. In this study, the reproducibility of the cytokine analysis conducted with different assay platforms was studied by comparing the results of two cytokines [interleukin (IL)-6 in serum and nasal lavage fluid (NAL) and IL-8 in NAL] analyzed with Meso Scale Discovery (MSD) ultra-sensitive single and multiplex assay kits (n=76). In addition, the difference in cytokine levels between two biological sample matrices was studied by comparing the results of altogether 9 cytokines [IL-6, IL-2, IL-8, IL12p70, IL-1ß, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)γ, IL-10 and tumor necrosis factor (TNF)α] measured from serum and NAL of the same study subjects (n=460). The results show that the cytokine concentrations analyzed with single and multiplex assays are concordant but not equal. Comparison of the different matrices revealed that cytokine concentrations in serum do not correspond with concentrations detected in nasal lavage fluid. It can be concluded that comparability of the results from single and multiplex analysis of cytokines is high, but the concentrations should not be compared directly with each other. The differences between concentrations analyzed from serum and nasal lavage fluid indicate that the levels are specific for each matrix and represent distinct immunological conditions.