Postapprenticeship Isocyanate Exposure and Risk of Work-Related Respiratory Symptoms Using an Asthma-Specific Job Exposure Matrix, Self-Reported and Expert-Rated Exposure Estimates

Occupational exposures are responsible for a significant proportion of new-onset asthma in adulthood.1 Isocyanates, a family of low-molecular-weight chemicals, are well-known causative agents for occupational asthma.2 A study conducted in the spray-painting industry demonstrated exposure–response associations in both work-related and non–work-related respiratory symptoms in a population of workers exposed to hexamethylene diisocyanate, a common isocyanate.3 The asthma-specific job exposure matrix (JEM) developed by Kennedy et al4 has been used in several studies to evaluate the association between exposure to occupational asthmagens and subsequent risk of occupational asthma-related outcomes.5,6 We previously assessed job-training-related exposure to high-molecular-weight occupational agents in former apprentices in animal health technology, dental hygiene, and pastry-making, using self-reporting and investigator scoring. We also assessed exposure to occupational sensitizing agents in jobs held postapprenticeship, using the exposure categories derived from the JEM.7 The three methods showed a moderate to good agreement; postapprenticeship exposure was associated with increased risks of developing occupational sensitization, work-related rhinoconjunctival symptoms, and bronchial hyperresponsiveness.7 Our current analysis is an addendum to our previous analysis.7 First, it aims to evaluate the agreement among the different exposure assessment methods on continued exposure to isocyanates postapprenticeship. Second, it aims to estimate the association between work-related rhinoconjunctival and chest symptoms in former car-painting apprentices and continued exposure to isocyanates postapprenticeship, assessed by three different methods. Therefore, in total, this is the same approach applied to four different cohorts. The sample was derived from an inception cohort of 385 apprentices in car-painting from beginning to end of their apprenticeships.8 A follow-up 4 to 9 years postapprenticeship was completed with 202 former apprentices.9 Standardized respiratory questionnaires, spirometry and methacholine bronchial challenge tests were all administered at all visits. In addition, participants completed questionnaires on work-related ocular, nasal, and chest symptoms, and work history since the end of their apprenticeships.9 We used incident work-related rhinoconjunctival and chest symptoms post-apprenticeship as outcomes. Work-related sensitization and bronchial hyperresponsiveness postapprenticeship were not evaluated, as there was an insufficient number of cases. Work-related rhinoconjunctival symptoms were considered “incident” if a worker experienced at least one eye or nasal problem at work during the long-term follow-up and did not report these symptoms during the apprenticeship. Similarly, work-related chest symptoms were defined as “incident” when the subject experienced cough, wheezing, shortness of breath, and/or chest tightness at work during the long-term follow-up but did not report any of these symptoms during the apprenticeship. To assess exposure to isocyanates during follow-up, participants were asked to report if they were exposed to isocyanate-based paints at their workplace (ie, self-reported, yes or no answer). Two independent occupational hygienists assigned a three-point score to each job held during follow-up: score 0 = no exposure to isocyanates; 1 = possible exposure to isocyanates at the workplace (eg, salesman in an auto-body repair facility); 2 = probable exposure to isocyanates. The subject was considered exposed if any of the ratings were 1 or 2, and unexposed otherwise. The occupational hygienists also coded each job using the International Standard Classification of Occupations (ISCO-88) system.10 Subsequently, ISCO codes were linked to the asthma-specific JEM where jobs with a strong likelihood of exposure to isocyanates were assigned as “exposed.”4 Nevertheless, some jobs were flagged as “need verification by an expert”; by default, these jobs were classified as “unexposed to isocyanates.” For all types of measurements, a participant was considered to have continued exposure to isocyanates if he/she worked for the equivalent of 1 year or more in a job associated with isocyanate exposure. Kappa coefficients were calculated to evaluate the agreement between self-reporting, investigator scoring, and JEM exposure categories on estimates of continued exposure to isocyanates postapprenticeship. Cox regression analyses were carried out to evaluate the association between the incidence of outcomes postapprenticeship and each of the three different estimates of continued exposure to isocyanates in subjects who were free of work-related respiratory symptoms during their apprenticeships. Hazard ratios and the corresponding 95% confidence intervals were estimated. The reference group was defined as being unexposed or exposed for less than 1 year postapprenticeship. All statistical analyses were performed with SPSS® software, version 20 (IBM Inc, Chicago, IL). Of the 202 participants, 46 (23%) had one job, 60 (30%) had two jobs, 49 (24%) had three jobs, 32 (16%) had four jobs, and 13 (7%) had five jobs during follow-up. The median follow-up time was 6 years (range, 4 to 9 years). The proportion of participants who were continuously exposed to isocyanates postapprenticeship was 66.3% using self-reporting, 73.2% using investigator scoring, and 72.7% using JEM-based categorization. There were 46 participants who held 22 job titles for which their JEM-based isocyanate exposure estimates needed further verification by an expert. In all four cohorts, we have a peculiar setting where all subjects come from the same apprenticeship, which is closely associated with exposure. We could logically anticipate that they would tend to have jobs with the same tasks and so have the same postapprenticeship exposure. This might affect the “easiness” of the exposure assessment, reflected by high proportions of subjects who were continuously exposed postapprenticeship and the good correlation between exposure assessment methods. The agreement between self-reporting and investigator scoring on the assessment of continued isocyanate exposure was good (κ = 0.79). The kappa value between self-reporting and the isocyanate exposure category generated by the JEM was 0.82, reflecting a very good agreement. The investigator scoring and isocyanate exposure category generated by the JEM showed a good agreement (κ = 0.78). Subjects who did or did not develop work-related respiratory symptoms during the long-term follow-up shared similar demographic characteristics at the end of the apprenticeship (Table 1). Nevertheless, the proportion of subjects who had methacholine concentration that cause a 20% fall in forced expiratory volume in 1 second (PC20) ≤32 mg/mL at the end of the apprenticeship was, significantly, doubled in those who developed compared with those who did not develop work-related respiratory symptoms postapprenticeship. The proportion of subjects who reported wheezing (not work-related) at the end of the apprenticeship was, significantly, tripled in those who developed compared with those who did not develop work-related respiratory symptoms postapprenticeship.TABLE 1: Characteristics of Subjects at the End of the Apprenticeship on the Basis of Incidence of Work-Related Respiratory Symptoms During Long-Term Follow-UpWe found associations between the incidence of work-related respiratory symptoms and continued exposure to isocyanates, as assessed by the three different methods (Table 2). Although not all of the associations were statistically significant, there was a consistent trend of an increased risk of developing these symptoms in participants with continued exposure to isocyanates. The hazard ratios of developing work-related rhinoconjunctival symptoms postapprenticeship, after adjusting for wheezing and low PC20 at the end of the apprenticeship, were 2.41, 3.12, and 2.31 as estimated by self-reports, investigator scores, and JEM-based categories, respectively. These findings are similar to our previous study, where the three exposure assessment methods were used to estimate the risk of various outcomes of occupational allergies associated with continued exposure to high-molecular-weight and low-molecular-weight agents in three cohorts of apprentices in animal health technology, pastry-making, and dental hygiene.7TABLE 2: Association Between Incident Work-Related Respiratory Symptoms and Different Estimates of Continued Exposure to Isocyanates PostapprenticeshipThere are some potential limitations to this analysis. First of all, the previous study demonstrated that exposure verification could substantially improve sensitivity and specificity, as well as the hazard ratios produced by the JEM.7 Nevertheless, we did not perform this step because of limited resources, as this verification step is labour-intensive. This could result in potential misclassification, as some of the subjects should have been assigned to exposure to isocyanates, thus underestimating the association between exposure and outcomes. Second, because of the small sample size, our reference group was composed of unexposed subjects or those who were exposed for less than 1 year postapprenticeship. This could also result in underestimating the association between exposure and outcomes. Yet, we still observed a trend to an increased risk of outcome incidence associated with isocyanate exposures. The same findings were observed in the study of subjects exposed to high-molecular-weight agents.7 In summary, we demonstrated that self-reports, investigator scores, and JEM-based categories were closely related in evaluating isocyanate exposure postapprenticeship. Long-term exposure to isocyanates also seemed to be associated with an increased risk of work-related respiratory symptoms. Lama Saab, MSc Research Centre, Hôpital du Sacré-Coeur de Montréal, Canada Department of Social and Preventive Medicine, Université de Montréal, Canada Denyse Gautrin, PhD Research Centre, Hôpital du Sacré-Coeur de Montréal, Canada Jérôme Lavoué, PhD Department of Environmental and Occupational Health, Université de Montréal, Canada Eva Suarthana, MD, PhD Research Centre, Hôpital du Sacré-Coeur de Montréal, Canada Department of Social and Preventive Medicine, Université de Montréal, Canada ACKNOWLEDGMENTS We thank Charles Beaudry of the Université de Montréal and Mounia Rhazi of the Institut Armand-Frappier for providing their expertise in the exposure assessments.

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