Chronic occupational exposures to irritants and asthma in the CONSTANCES cohort.

OBJECTIVES: The impact of chronic occupational exposures to irritants on asthma remains discussed. We studied the associations between occupational exposures and asthma, with specific interest for chronic exposure to irritants, including disinfectants and cleaning products (DCPs) and solvents. METHODS: Cross-sectional analyses included 115 540 adults (55% women, mean age 43 years, 10% current asthma) working at inclusion in the French population-based CONSTANCES cohort (2012-2020). Current asthma was defined by ever asthma with symptoms, medication or asthma attacks (past 12 months), and the asthma symptom score by the sum of 5 respiratory symptoms (past 12 months). Both lifetime and current occupational exposures were assessed by the Occupational Asthma-specific Job-Exposure Matrix. Associations were evaluated by gender using logistic and binomial negative regressions adjusted for age, smoking status and body mass index. RESULTS: In women, associations were observed between current asthma and lifetime exposure to irritants (OR 1.05, 95% CI 1.00 to 1.11), DCPs (1.06, 95% CI 1.00 to 1.12) and solvents (1.06, 95% CI 0.98 to 1.14). In men, only lifetime exposure to DCPs (1.10, 95% CI 1.01 to 1.20) was associated with current asthma. Lifetime exposure to irritants was associated with higher asthma symptom score both in women (mean score ratio: 1.08, 95% CI 1.05 to 1.11) and men (1.11, 95% CI 1.07 to 1.15), especially for DCPs (women: 1.09, 95% CI 1.06 to 1.13, men: 1.21, 95% CI 1.15 to 1.27) and solvents (women 1.14, 95% CI 1.10 to 1.19, men: 1.10, 95% CI 1.05 to 1.15). For current exposures, no consistent associations were observed with current asthma and asthma symptom score. CONCLUSIONS: Lifetime occupational exposures to irritants were associated with current asthma and higher asthma symptom score. These exposures should be carefully considered in asthma management.

4,4'-Methylene diphenyl diisocyanate exposure induces expression of alternatively activated macrophage-associated markers and chemokines partially through Krüppel-like factor 4 mediated signaling in macrophages.

Occupational exposure to the most widely used monomeric diisocyanate (dNCO), 4,4'-methylene diphenyl diisocyanate (MDI), may lead to the development of occupational asthma (OA). Alveolar macrophages with alternatively activated (M2) phenotype have been implicated in allergic airway responses and the pathogenesis of asthma. Recent in vivo studies demonstrate that M2 macrophage-associated markers and chemokines are induced by MDI-exposure, however, the underlying molecular mechanism(s) by which this proceeds is unclear.Following MDI exposure (in vivo and in vitro) M2 macrophage-associated transcription factors (TFs), markers, and chemokines were determined by RT-qPCR, western blots, and ELISA.Expression of M2 macrophage-associated TFs and markers including Klf4/KLF4, Cd206/CD206, Tgm2/TGM2, Ccl17/CCL17, Ccl22/CCL22, and CCL24 were induced by MDI/MDI-GSH exposure in bronchoalveolar lavage cells (BALCs)/THP-1 macrophages. The expression of CD206, TGM2, CCL17, CCL22, and CCL24 are upregulated by 3.83-, 7.69-, 6.22-, 6.08-, and 1.90-fold in KLF4-overexpressed macrophages, respectively. Endogenous CD206 and TGM2 were downregulated by 1.65-5.17-fold, and 1.15-1.78-fold, whereas CCL17, CCL22, and CCL24 remain unchanged in KLF4-knockdown macrophages. Finally, MDI-glutathione (GSH) conjugate-treated macrophages show increased chemotactic ability to T-cells and eosinophils, which may be attenuated by KLF4 knockdown.Our data suggest that MDI exposure may induce M2 macrophage-associated markers partially through induction of KLF4.

Occupational asthma induced by fish exposure.

Occupational asthma triggered by inhaling fish-derived aerosols is estimated to affect 2-8% of exposed individuals. This primarily affects workers in the fish processing industry. Fishmongers, rarely experience this issue, as recent research found no significant difference in asthma rates compared to a control group. We report the case of a fishmonger who presented with a 1-year history of rhinoconjunctivitis and asthma. The patient attributed these symptoms to his occupational exposure within the fish market environment, which worsened in the cold storage warehouse. Symptoms improved during holidays. Diagnosis involved skin-prick tests, sIgE (ImmunoCAP-specific IgE) measurements, and bronchial challenge tests, confirming occupational asthma from fish bioaerosol exposure. Parvalbumins, common fish proteins, share structural similarities, leading to cross-reactivity in fish allergy sufferers. In this case, sensitivity to rGad c1 (cod parvalbumin) was identified as the primary trigger for the patient's asthma, and responsible for sensitizations observed across various tested fish species.

The relationship between toluene diisocyanate exposure and respiratory health problems: A meta-analysis of epidemiological studies.

Human epidemiological studies have shown inconclusive results over the effects of diisocyanates on respiratory health problems. A meta-analysis combined evidence on the association between occupational asthma (OA), respiratory function, and toluene diisocyanate (TDI) inhalation exposure. Sixty-one articles on occupational toluene diisocyanate exposure were identified via two databases. Fourteen studies were included in the meta-analysis. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the studies. Odds ratios (ORasthma) for the association between TDI exposure compared to non-exposure and OA were calculated. The difference in mean differences (MD) of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), and the annual mean change differences-in milliliters per year (mL/yr)-in FEV1 and FVC pulmonary function between TDI exposed and non-exposed, were calculated. When applicable, a random effects meta-analysis was performed. The overall summary ORasthma for TDI exposed versus non-exposed was 1.18 (95% CI = 0.78-1.79). The summary of the predicted mean percentage difference (MD%predicted) between exposed versus non-exposed was 2.96% for FEV1 and 3.75% for FVC. A very small decrease of 5 mL/yr for FEV1 and 10 mL/yr for FVC, respectively, was observed between the exposed and the non-exposed groups. There was moderate to low heterogeneity between study results, and most studies were evaluated as high-quality. This meta-analysis found no statistically significant adverse association between TDI occupational exposure and OA. No meaningful differences in lung function were detected between exposed and unexposed groups.

Association between occupational exposure to irritant agents and a distinct asthma endotype in adults.

AIM: The biological mechanisms of work-related asthma induced by irritants remain unclear. We investigated the associations between occupational exposure to irritants and respiratory endotypes previously identified among never asthmatics (NA) and current asthmatics (CA) integrating clinical characteristics and biomarkers related to oxidative stress and inflammation. METHODS: We used cross-sectional data from 999 adults (mean 45 years old, 46% men) from the case-control and familial Epidemiological study on the Genetics and Environments of Asthma (EGEA) study. Five respiratory endotypes have been identified using a cluster-based approach: NA1 (n=463) asymptomatic, NA2 (n=169) with respiratory symptoms, CA1 (n=50) with active treated adult-onset asthma, poor lung function, high blood neutrophil counts and high fluorescent oxidation products level, CA2 (n=203) with mild middle-age asthma, rhinitis and low immunoglobulin E level, and CA3 (n=114) with inactive/mild untreated allergic childhood-onset asthma. Occupational exposure to irritants during the current or last held job was assessed by the updated occupational asthma-specific job-exposure matrix (levels of exposure: no/medium/high). Associations between irritants and each respiratory endotype (NA1 asymptomatic as reference) were studied using logistic regressions adjusted for age, sex and smoking status. RESULTS: Prevalence of high occupational exposure to irritants was 7% in NA1, 6% in NA2, 16% in CA1, 7% in CA2 and 10% in CA3. High exposure to irritants was associated with CA1 (adjusted OR aOR, (95% CI) 2.7 (1.0 to 7.3)). Exposure to irritants was not significantly associated with other endotypes (aOR range: 0.8 to 1.5). CONCLUSION: Occupational exposure to irritants was associated with a distinct respiratory endotype suggesting oxidative stress and neutrophilic inflammation as potential associated biological mechanisms.

Is Isocyanate Exposure and Occupational Asthma Still a Major Occupational Health Concern? Systematic Literature Review.

Isocyanate, whose disease-inducing mechanism is poorly understood, with poor prognosis, is widely used. Asthma is the most frequent manifestation of prolonged exposure. We assessed the evolution of the incidence of isocyanate-induced occupational asthma over time. PubMed and Cochrane databases were systematically searched for studies published since 1990 that assessed the relationship between occupational exposure to isocyanates and asthma. We identified 39 studies: five retrospective cohort studies, seven prospective cohort studies, three of which were inception cohorts), seven observational cross-sectional studies, five literature reviews, two case series, and 13 registry studies. The incidence of occupational asthma secondary to isocyanate exposure has decreased from more than 5% in the early 1990s to 0.9% in 2017 in the United States. Despite the wide use of optimal collective and individual protection measures, the risk of occupational asthma has stabilized. Occupational asthma risk can be assessed with good sensitivity using self-questionnaires and pulmonary function tests. Occupational avoidance should be implemented as soon as possible after the first symptoms appear because the prognosis becomes increasingly poor with the persistence of exposure. It is now necessary to study specifically cutaneous sensitization to isocyanates and to define what protective equipment is effective against this mode of exposure.

Asthma onset after exposure to fluorinated hydrocarbons in the presence of combustion.

Fluorinated hydrocarbons, which can thermally degrade into toxic hydrofluoric acid, are widely used as, for example, cooling agents in refrigerators and air conditioning systems and as medical aerosol propellants. Hydrofluoric acid is a known causative agent of irritant-induced asthma. We report on two patients with asthma initiation shortly after exposure to fluorinated hydrocarbon-based cooling agents while welding or smoking cigarettes in a confined space. Both cases developed respiratory symptoms and headache and later demonstrated nonspecific bronchial hyperresponsiveness. In follow-up, asthma was persistent and responded poorly to asthma medication. Exposure to the fluorinated hydrocarbons themselves is unlikely to have caused asthma due to their low toxicity. Instead, exposure to small amounts of hydrofluoric acid via the thermal degradation of the fluorinated hydrocarbons was considered the most likely cause of asthma onset. This is supported by the typical clinical picture of irritant-induced asthma and acute symptoms resembling hydrofluoric acid poisoning. When fluorinated hydrocarbons are used in the presence of combustion, thermal degradation may lead to the formation of hydrofluoric acid. In confined spaces, this exposure may induce asthma via irritation. Welding, smoking, and other sources of combustion in confined spaces may be a risk in workplaces and other places in which fluorinated hydrocarbons are used.

Potential classification of chemical immunologic response based on gene expression profiles.

Occupational immune diseases are a serious public health burden and are often a result of exposure to low molecular weight (LMW) chemicals. The complete immunological mechanisms driving these responses are not fully understood which has made the classification of chemical allergens difficult. Antimicrobials are a large group of immunologically-diverse LMW agents. In these studies, mice were dermally exposed to representative antimicrobial chemicals (sensitizers: didecyldimethylammonium chloride (DDAC), ortho-phthalaldehyde (OPA), irritants: benzal-konium chloride (BAC), and adjuvant: triclosan (TCS)) and the mRNA expression of cytokines and cellular mediators was evaluated using real-time qPCR in various tissues over a 7-days period. All antimicrobials caused increases in the mRNA expression of the danger signals Tslp (skin), and S100a8 (skin, blood, lung). Expression of the TH2 cytokine Il4 peaked at different timepoints for the chemicals based on exposure duration. Unique expression profiles were identified for OPA (Il10 in lymph node, Il4 and Il13 in lung) and TCS (Tlr4 in skin). Additionally, all chemicals except OPA induced decreased expression of the cellular adhesion molecule Ecad. Overall, the results from these studies suggest that unique gene expression profiles are implicated following dermal exposure to various antimicrobial agents, warranting the need for additional studies. In order to advance the development of preventative and therapeutic strategies to combat immunological disease, underlying mechanisms of antimicrobial-induced immunomodulation must be fully understood. This understanding will aid in the development of more effective methods to screen for chemical toxicity, and may potentially lead to more effective treatment strategies for those suffering from immune diseases.

Occupational exposure to disinfectants and asthma incidence in U.S. nurses: A prospective cohort study.

BACKGROUND: Exposure to disinfectants among healthcare workers has been associated with respiratory health effects, in particular, asthma. However, most studies are cross-sectional and the role of disinfectant exposures in asthma development requires longitudinal studies. We investigated the association between occupational exposure to disinfectants and incident asthma in a large cohort of U.S. female nurses. METHODS: The Nurses' Health Study II is a prospective cohort of 116 429 female nurses enrolled in 1989. Analyses included 61 539 participants who were still in a nursing job and with no history of asthma in 2009 (baseline; mean age: 55 years). During 277 744 person-years of follow-up (2009-2015), 370 nurses reported incident physician-diagnosed asthma. Occupational exposure was evaluated by questionnaire and a Job-Task-Exposure Matrix (JTEM). We examined the association between disinfectant exposure and subsequent asthma development, adjusted for age, race, ethnicity, smoking status, and body mass index. RESULTS: Weekly use of disinfectants to clean surfaces only (23% exposed) or to clean medical instruments (19% exposed) was not associated with incident asthma (adjusted hazard ratio [95% confidence interval] for surfaces, 1.12 [0.87-1.43]; for instruments, 1.13 [0.87-1.48]). No association was observed between high-level exposure to specific disinfectants/cleaning products evaluated by the JTEM (formaldehyde, glutaraldehyde, bleach, hydrogen peroxide, alcohol quats, or enzymatic cleaners) and asthma incidence. CONCLUSIONS: In a population of late career nurses, we observed no significant association between exposure to disinfectants and asthma incidence. A potential role of disinfectant exposures in asthma development warrants further study among healthcare workers at earlier career stage to limit the healthy worker effect.

Claudins, VEGF, Nrf2, Keap1, and Nonspecific Airway Hyper-Reactivity Are Increased in Mice Co-Exposed to Allergen and Acrolein.

Acrolein, an α/ß-unsaturated aldehyde, is volatile at room temperature. It is a respiratory irritant found in environmental tobacco smoke, which can be generated during cooking or endogenously at sites of injury. An acute high concentration of uncontrolled irritant exposure can lead to an asthma-like syndrome known as reactive airways dysfunction syndrome (RADS). However, whether acrolein can induce RADS remains poorly understood. The aim of study is to develop a RADS model of acrolein inhalation in mice and to clarify the mechanism of RADS. Mice were treated with ovalbumin (OVA) and exposed to acrolein (5 ppm/10 min). Airway hyper-responsiveness (AHR) was measured on days 24 and 56, and samples were collected on days 25 and 57. Tight junction protein, antioxidant-associated protein, and vascular endothelial growth factor (VEGF) levels were estimated by Western blotting and immunohistochemical staining. Reactive oxygen species (ROS) was calculated using enzyme linked immunosorbent assays. Acrolein or OVA groups exhibited an increase in airway inflammatory cells and AHR compared to a sham group. These effects were further increased in mice in the OVA + acrolein exposure group than in the OVA exposure group and persisted in the acrolein exposure group for 8 weeks. CLDNs, carbonyls, VEGF, Nrf2, and Keap1 were observed in the lungs. Our data demonstrate that acrolein induces RADS and that ROS, angiogenesis, and tight junction proteins are involved in RADS in a mouse model.

Bayesian Correction for Exposure Misclassification and Evolution of Evidence in Two Studies of the Association Between Maternal Occupational Exposure to Asthmagens and Risk of Autism Spectrum Disorder.

PURPOSE OF REVIEW: Inference in epidemiologic studies is plagued by exposure misclassification. Several methods exist to correct for misclassification error. One approach is to use point estimates for the sensitivity (Sn) and specificity (Sp) of the tool used for exposure assessment. Unfortunately, we typically do not know the Sn and Sp with certainty. Bayesian methods for exposure misclassification correction allow us to model this uncertainty via distributions for Sn and Sp. These methods have been applied in epidemiologic literature, but are not considered a mainstream approach, especially in occupational epidemiology. RECENT FINDINGS: Here, we illustrate an occupational epidemiology application of a Bayesian approach to correct for the differential misclassification error generated by estimating occupational exposures from job codes using a job exposure matrix (JEM). We argue that analyses accounting for exposure misclassification should become more commonplace in the literature.

Role of clusterin/progranulin in toluene diisocyanate-induced occupational asthma.

Toluene diisocyanate (TDI) exposure induces oxidative stress and epithelial cell-derived inflammation, which affect the pathogenesis of TDI-induced occupational asthma (TDI-OA). Recent studies suggested a role for clusterin (CLU) and progranulin (PGRN) in oxidative stress-mediated airway inflammation. To evaluate CLU and PGRN involvement in airway inflammation in TDI-OA, we measured their serum levels in patients with TDI-OA, asymptomatic exposed controls (AECs), and unexposed healthy normal controls (NCs). Serum CLU and PGRN levels were significantly lower in the TDI-OA group than in the AEC and NC groups (P < 0.05). The sensitivity and specificity for predicting the TDI-OA phenotype were 72.4% and 53.4% when either CLU or PGRN levels were below the cutoff values (≤125 µg/mL and ≤68.4 ng/mL, respectively). If both parameters were below the cutoff levels, the sensitivity and specificity were 58.6% and 89.8%, respectively. To investigate CLU and PGRN function, we evaluated their production by human airway epithelial cells (HAECs) in response to TDI exposure and co-culturing with neutrophils. TDI-human serum albumin stimulation induced significant CLU/PGRN release from HAECs in a dose-dependent manner, which positively correlated with IL-8 and folliculin levels. Co-culturing with neutrophils significantly decreased CLU/PGRN production by HAECs. Intracellular ROS production in epithelial cells co-cultured with neutrophils tended to increase initially, but the ROS production decreased gradually at a higher ratio of neutrophils. Our results suggest that CLU and PGRN may be involved in TDI-OA pathogenesis by protecting against TDI-induced oxidative stress-mediated inflammation. The combined CLU/PGRN serum level may be used as a potential serological marker for identifying patients with TDI-OA among TDI-exposed workers.

Update of an occupational asthma-specific job exposure matrix to assess exposure to 30 specific agents.

OBJECTIVES: We aimed to update an asthmagen job exposure matrix (JEM) developed in the late 1990s. Main reasons were: the number of suspected and recognised asthmagens has since tripled; understanding of the aetiological role of irritants in asthma and methodological insights in application of JEMs have emerged in the period. METHODS: For each agent of the new occupational asthma-specific JEM (OAsJEM), a working group of three experts out of eight evaluated exposure for each International Standard Classification of Occupations, 1988 (ISCO-88) job code into three categories: 'high' (high probability of exposure and moderate-to-high intensity), 'medium' (low-to-moderate probability or low intensity) and 'unexposed'. Within a working group, experts evaluated exposures independently from each other. If expert assessments were inconsistent the final decision was taken by consensus. Specificity was favoured over sensitivity, that is, jobs were classified with high exposure only if the probability of exposure was high and the intensity moderate-to-high. In the final review, all experts checked assigned exposures and proposed/improved recommendations for expert re-evaluation after default application of the JEM. RESULTS: The OAsJEM covers exposures to 30 sensitisers/irritants, including 12 newly recognised, classified into seven broad groups. Initial agreement between the three experts was mostly fair to moderate (κ values 0.2-0.5). Out of 506 ISCO-88 codes, the majority was classified as unexposed (from 82.6% (organic solvents) to 99.8% (persulfates)) and a minority as 'high-exposed' (0.2% (persulfates) to 2.6% (organic solvents)). CONCLUSIONS: The OAsJEM developed to improve occupational exposure assessment may improve evaluations of associations with asthma in epidemiological studies and contribute to assessment of the burden of work-related asthma.

Incidence of Occupational Asthma and Exposure to Toluene Diisocyanate in the United States Toluene Diisocyanate Production Industry.

OBJECTIVE: This study examines asthma risk in facilities producing toluene diisocyanate (TDI). METHODS: A total of 197 workers were monitored from 2007 to 2012. TDI air concentrations were used to estimate exposures. RESULTS: The incidence of cases consistent with TDI-induced asthma was 0.009 per person-years (seven cases) or consistent with TDI-induced asthma or asthma indeterminate regarding work-relatedness was 0.012 (nine cases). Increased risk of cases consistent with TDI asthma was observed for cumulative (odds ratio [OR] = 2.08, 95% confidence interval [CI] 1.07 to 4.05) per logarithm parts per billion-years and peak TDI exposures (OR = 1.18, 95% CI 1.06 to 1.32) (logarithm parts per billion). There was a weak association with cumulative and peak exposures for decline of short-term forced expiratory volume in one second (FEV1). Asthma symptoms were associated with workers noticing an odor of TDI (OR 6.02; 95% CI 1.36 to 26.68). CONCLUSIONS: There is evidence that cumulative and peak exposures are associated with TDI-induced asthma.

Trends in Occupations and Work Sectors Among Patients With Work-Related Asthma at a Canadian Tertiary Care Clinic.

BACKGROUND: Work-related asthma (WRA) is the most common chronic occupational lung disease in the developed world. Several factors including sociodemographic status and occupation/industry increase the risks of developing WRA. In this study, we sought to identify changes in patterns and characteristics among patients with WRA over a 15-year period in an occupational lung disease clinic. METHODS: We performed a retrospective analysis of patients with WRA charts at the Occupational Lung Disease Clinic of a University Hospital in Toronto, Canada. Patients were divided into two periods classified by first attendance at the clinic 2000 through 2007 and 2008 through 2015. Comparisons between the two periods included: sociodemographic characteristics, smoking status, occupations, exposures, and submitted workers' compensation claims. RESULTS: Fewer occupational asthma cases were seen in the more recent period vs the earlier period (40 vs 74 cases), with a smaller reduction in work-exacerbated asthma cases (40 vs 58). The recent period included a significantly smaller proportion employed in the manufacturing industry and isocyanate-induced cases compared with the earlier period. An increased proportion were employed in health-care and education industries (primarily cleaners and teachers) in the recent period, consistent with a corresponding increased frequency of cleaning agents and dust exposures. CONCLUSIONS: The changes observed in work sectors in the patients with WRA in this clinic in Toronto are consistent with reductions reported in Ontario workers' compensation claims for occupational asthma and may relate to preventive measures. Cleaners and teachers should be a focus of further intervention measures for work-related asthma.

Genetic variants in TNFα, TGFB1, PTGS1 and PTGS2 genes are associated with diisocyanate-induced asthma.

Diisocyanates are the most common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants in inflammatory response genes (TNFα, IL1α, IL1ß, IL1RN, IL10, TGFB1, ADAM33, ALOX-5, PTGS1, PTGS2 and NAG-1/GDF15) are associated with increased susceptibility to diisocyanate asthma (DA). These genes were selected based on their role in asthmatic inflammatory processes and previously reported associations with asthma phenotypes. The main study population consisted of 237 Caucasian French Canadians from among a larger sample of 280 diisocyanate-exposed workers in two groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95) and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5' nuclease PCR assay. After adjusting for potentially confounding variables of age, smoking status and duration of exposure, the PTGS1 rs5788 and TGFB1 rs1800469 single nucleotide polymorphisms (SNP) showed a protective effect under a dominant model (OR = 0.38; 95% CI = 0.17, 0.89 and OR = 0.38; 95% CI = 0.18, 0.74, respectively) while the TNFα rs1800629 SNP was associated with an increased risk of DA (OR = 2.08; 95% CI = 1.03, 4.17). Additionally, the PTGS2 rs20417 variant showed an association with increased risk of DA in a recessive genetic model (OR = 6.40; 95% CI = 1.06, 38.75). These results suggest that genetic variations in TNFα, TGFB1, PTGS1 and PTGS2 genes contribute to DA susceptibility.