Occupational Exposures and the Development of New-onset Asthma: A Population-based Cohort Study From the Ages of 13 to 44 Years

Hoy, Ryan F. MBBS; Burgess, John A. PhD; Benke, Geza PhD; Matheson, Melanie PhD; Morrison, Stephen PhD; Gurrin, Lyle PhD; Walters, E. Haydn DM; Dharmage, Shyamali C. PhD; Abramson, Michael J. PhD

Journal of Occupational & Environmental Medicine: March 2013 - Volume 55 - Issue 3 - p 235–239
doi: 10.1097/JOM.0b013e31827edefb
Original Articles

Objective: To evaluate the risk of asthma associated with occupational exposures in a population-based cohort.

Methods: The risk of asthma was analyzed in 792 subjects who were asthma free at the age of 13 years. Occupational histories were obtained from subjects at the age of 44 years and occupational exposures determined with an asthma-specific job exposure matrix. Cumulative exposure to latex and risk of asthma was examined using Cox proportional hazards regression.

Results: Development of asthma was modestly related to exposure at any time to high molecular weight latex (odds ratio, 1.4; 95% confidence interval, 0.9–2.3). Cumulative latex exposure of 6 to 15 years was associated with a hazard ratio of 1.6 for the development of asthma and after 16 years increased to 2.65 (95% confidence interval, 1.28–5.47).

Conclusion: There is a significant association between cumulative occupational exposure to latex and new-onset asthma.

From the Department of Epidemiology and Preventive Medicine (Drs Hoy and Benke and Prof Abramson), Monash University, Melbourne, Australia; Centre for MEGA Epidemiology (Drs Burgess, Dharmage, Matheson, and Gurrin), School of Population Health, University of Melbourne, Melbourne, Australia; Royal Brisbane Hospital (Dr Morrison), Brisbane, Australia; and Menzies Research Institute (Prof Walters), Hobart, Tasmania, Australia.

Address correspondence to: Shyamali C. Dharmage, PhD, Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Level 3, 207 Bouverie Street, Carlton, Victoria 3053, Australia (s.dharmage@unimelb.edu.au).

The Tasmanian Longitudinal Health Study is supported by grants from the National Health and Medical Research Council (NHMRC) of Australia, the Victorian and Tasmanian Asthma Foundations, the Clifford Craig Medical Research Trust, and the Royal Hobart Hospital Research Foundation. Authors MM, LG, and SCD are supported by NHMRC.

Authors Dharmage, Hoy, Burgess, Benke, Matheson, Morrison, Gurrin, Walters, and Abramson have no relationships/conditions/circumstances that present potential conflict of interest.

The JOEM editorial board and planners have no financial interest related to this research.

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Learning Objectives

* Become familiar with the challenges of determining the risk of occupational asthma and identifying relevant risk factors.

* Summarize the methods of the new population-based cohort study and the findings on occupational exposures associated with new-onset asthma.

* Discuss the study implications for reducing the burden of asthma in the adult population.

Occupational exposures contribute significantly to the overall burden of asthma in the community. The population burden of asthma attributable to occupational exposure has been estimated to be as high as 20%.1 The importance of occupational asthma (OA) to public health is that many, if not most, of these cases are preventable.

Workforce-based cohort studies have been used to determine the risk of OA in high-risk industries, such as bakeries or aluminium smelters. A limitation of workforce-based studies is selection and survivor bias, which is collectively referred to as the “healthy worker effect.”24 Entry to workplaces with respiratory hazards is influenced by factors that include health constraints (the so called healthy hire effect) and individuals who develop an occupational disease such as OA may leave the industry due to ill health.2 Long-term population-based cohort studies are required to reach all individuals ever exposed and are therefore less influenced by the healthy worker effect.2

This population-based cohort study aimed to investigate the association of new-onset asthma with exposure to known causes of OA. Natural rubber latex allergy has become an important occupational health concern in recent years; therefore, the association of asthma with cumulative latex exposure has been examined in detail.5

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The Tasmanian Longitudinal Health Study (TAHS) began in 1968 with a cohort (n = 8583) of 7-year-olds attending school in Tasmania, Australia. A questionnaire completed by parents detailed each child's history of asthma, hay fever, eczema, food or medicine allergy, and urticaria.6 In 2004, 85.2% (n = 7312) of the original 1968 cohort were traced to an address and achieved a response of 78.4% (n = 5729) to a postal survey. A subgroup of these respondents were selected on the basis of their participation in the previous follow-up studies, samples of which were enriched for asthma, and invited to participate in a more detailed laboratory study.7 Of 2373 invited, 1592 completed occupational histories.

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Asthma at the ages of 7 to 13 years was defined in the 1968 or 1974 questionnaire by an affirmative response to the question “Has your child ever suffered from attacks of asthma or wheezy breathing?” Asthma at the age of 44 years was defined by an affirmative answer to the validated question in the 2004 questionnaire “Have you ever in your life suffered from attacks of asthma or wheezy breathing?”8

New-onset asthma was defined by an affirmative response to asthma-specific question at the age of 44 years, with no asthma reported by parents at the age of 7 to 13 years.

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Occupational Exposures

It was assumed that subjects commenced work after 13 years of age and therefore did not have exposure to occupational asthmagens before this age. Exposure assessments were determined through the use of job histories and an asthma-specific Job Exposure Matrix (JEM).9 This asthma-specific JEM includes both exposure to specific agents and mixed environmental exposures linked to OA. In 2004, 1592 subjects completed a work history calendar at 44 years of age. On the basis of the histories provided, jobs were coded with the International Standard Classification of Occupations–88 including the year that each job commenced and ended. In accordance with the recommended methods for use of the asthma-specific JEM, the TAHS cohort data set with International Standard Classification of Occupations–88 codes was merged with the JEM.9 Exposures were coded “1” for a high likelihood that a subject was occupationally exposed to a potential cause of OA. Expert verification was performed (RH, GB) where each exposure generated by the JEM was revised on the basis of job description and local knowledge to increase the specificity of the assigned exposures. This process was blinded to disease outcomes.

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Analytical Methods

Categorical data were presented as numbers and percentages and compared using Pearson χ2 test. The associations between work exposures and new-onset asthma were first examined using univariate logistic regression models and then multivariate models adjusted for sex and smoking. The results were presented as odds ratios with 95% confidence intervals. On the basis of the results of initial logistic regression modeling, the relationship of cumulative work exposure to High Molecular Weight (HMW) latex and the risk of developing asthma over time was examined using Cox proportional hazards regression. The event in the Cox model was the development of asthma. For those with asthma, the age at asthma onset (and hence the corresponding calendar year, computed from the participant's date of birth) had been documented by the participant in the 2004 follow-up survey of the TAHS. The time variable in the Cox model was calendar years beginning in 1973 when the participant could have first entered the workforce. Each participant was observed until either asthma developed (at which point the participant was censored) or to the end of the study period. Latex exposure appeared in the Cox regression model as a time-varying covariate representing the cumulative exposure to latex in the workplace since the participant started work, calculated from participants' self-reported history of time spent in each occupational classification. Proportional hazards assumptions were tested. The results were presented as hazard ratios with 95% confidence intervals. The relationship between exposure to HMW latex antigens and the development of asthma over time was examined using survival analysis with the results presented as a Kaplan-Meier survival plot. Statistical analyses were carried out using Stata Statistical Software package, version 10.1 (StataCorp, College Station, TX).

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Of the participants who completed the work history calendar, 792 were asthma free before starting work (ie, no asthma reported at the ages of 7 to 13 years). Those who developed new-onset asthma were significantly more likely to be women or current smokers (Table 1).

Use of the asthma-specific JEM identified 419 subjects who were asthma free at first starting work and had exposure to any of 18 high-risk agents during their working career till the age of 44 years. The most frequently identified exposures were irritants (not high peak levels) (n = 280), combustion particles and fumes (n = 145), mixed agricultural exposures (n = 129), industrial cleaning agents (n = 122), and HMW latex (n = 94). In the latex exposed group, the majority were women and worked in the health care industry as nurses or in associated health care roles (Fig. 1).

Exposures to HMW latex, highly reactive cleaning and disinfecting products, at any time during work history were associated with new-onset asthma. When adjusted for sex and smoking, there was some evidence that latex was still related to new-onset asthma (Table 2). Conversely, peak exposures to irritants, cleaning products, and combustion particles or fumes appeared to be associated with a reduced risk of new-onset asthma. Nevertheless, these associations were no longer statistically significant after adjustment for sex and smoking.

None of the other occupational exposures were associated with new-onset asthma. Nevertheless, trends toward positive associations were identified for combined exposure to any of the 18 high-risk exposures, combined exposure to any of the HMW agents, and for exposure to highly reactive cleaning products (Table 2).

Cumulative exposure to latex was examined in more detail using survival analysis (Fig. 2) and proportional hazards models. Each year of cumulative exposure to latex compared with no latex exposure was associated on average with a 5% risk increase for developing new asthma, independent of the effects of sex and smoking. The risk was 1.6-fold greater after 6 to 15 years of cumulative exposure and 2.7-fold greater after 16 or more years of cumulative exposure, both compared with no exposure (Fig. 3). The risk of new asthma was 1.6-fold greater in current smokers compared with nonsmokers when sex and latex exposure were taken into account.

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Our study investigated subjects who were asthma free at the beginning of their working lives and subsequently exposed to potential causes of OA during their career till the age of 44 years. We identified a strong association between the development of new-onset asthma and cumulative exposure to HMW latex at any time in a subject's career. We did not find a positive association with isocyanates, the most common cause of OA in many developed countries.10 This was likely due to the small number (n = 29) exposed at any point in their careers.

Increasing cumulative length of time in a latex-exposed environment was associated with a higher risk of asthma. Over the span of working life, each year of cumulative exposure to latex compared with no latex exposure was associated on average with a 5% risk increase for developing new asthma, independent of the effects of sex and smoking. The risk was 1.6-fold greater after 6 to 15 years of cumulative exposure and 2.7-fold greater after 16 or more years of cumulative exposure, both compared with no exposure.

Although natural rubber latex is a commonly reported cause of OA, the incidence of asthma associated with latex exposure is not well described.5 Most studies have been in the setting of high-risk occupational environments, and have assessed markers of sensitization (latex-specific IgE and skin-prick tests) rather than disease outcomes. The proportion of hospital employees reported as being sensitized to latex using skin-prick tests has ranged between 2.9% and 17%.11 The prevalence of sensitization, however, does not correlate with the prevalence of natural rubber latex—induced allergic diseases—anaphylaxis, urticaria, rhinoconjunctivitis, and OA. Vandenplas11 reported a prevalence of OA due to latex allergy occurring in 2.5% (95% confidence interval, 1.0%–5.2%) of hospital personnel (nurses, cleaning staff, laboratory technologists) after an objective evaluation including specific inhalational challenges with latex gloves in a stepwise protocol.

The period of latency for the development of allergic symptoms from the time of the first occupational exposure to natural rubber latex has been estimated at an average of 5 years and the average interval to the onset of lower respiratory tract symptoms of 7 years.12 This is significantly longer than other HMW causes of OA. Our results similarly suggest a low risk of asthma during the first 5 years of exposure but increasing significantly beyond 6 years of cumulative exposure, consistent with a very long period of latency.

We identified weak negative associations between “peak exposure to irritants” and “exposure to combustion particles or fumes.” Analysis of the Spanish component of the European Community Respiratory Health Survey study also identified weak negative associations with irritant peak exposure and exposure to exhaust fumes and environmental tobacco smoke.13 We postulate that this is likely to be a result of self-selection—the so-called healthy hire effect rather than a true protective effect of these exposures.14,15 Analysis of the TAHS cohort enabled evaluation of all individuals who were exposed to potential causes of OA during their career till the age of 44 years. This method captured subjects who might be lost in industry-based studies, because less healthy workers are more likely than healthy coworkers to leave high-exposure jobs.4

Occupational asthma has been defined as de novo asthma or the recurrence of previously quiescent asthma caused by the workplace.16,17 We limited our study to new-onset asthma (de novo asthma) after excluding all subjects with childhood asthma (up to 13 years of age). Childhood wheeze is very common and adults generally have poor recollection of asthma remission–-therefore, accurately identifying the recurrence of quiescent childhood asthma in a population study is difficult.18,19 The restriction of our study to new-onset asthma reduced the numbers of eligible subjects and therefore was likely to have reduced our power to identify associations in comparison with other similar population studies.13,20 We relied on parental and self-reported asthma, without objective confirmation by respiratory function tests. Nevertheless, the asthma questionnaire used has been validated against bronchial hyper-responsiveness and respiratory physician asthma diagnosis.8 Objective assessment of the association of work with asthma was not performed; therefore, cases of OA could not be differentiated from new-onset asthma that was not caused or exacerbated by occupational exposures.

Exposure assessments were determined through the use of job histories and an asthma-specific JEM.9 The asthma-specific JEM developed by Kennedy and colleagues9 includes both specific agents and mixed environments linked to OA. The use of job histories and a JEM is less susceptible to recall bias than self-reported exposures.21 Exposures determined through the use of a JEM linked to job histories do not take into account variability due to an individual's job tasks that may result in differences in the intensity of exposures or interactions between exposures. A study identified 25% of individuals having four or more exposures in the JEM.13 In our cohort, the majority of HMW latex–exposed individuals were nurses. Nurses are exposed to substances other than latex that have also been associated with an increased risk of asthma. Arif et al22 reported bronchial symptoms to be significantly greater among nursing professionals exposed to general cleaning products, disinfectants, adhesives, glues, and/or solvents used in patient care.

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The use of an asthma-specific JEM allowed examination of associations between exposure to high-risk causes of OA and the development of new-onset asthma. Analysis of this community-based cohort identified associations with occupational exposures to HMW latex and highly reactive cleaning products. The risk of asthma increased significantly with cumulative exposure to latex, especially over 6 years of exposure. These occupational exposures need to be controlled to reduce the burden of asthma in the adult population.5

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