https://orcid.org/0000-0002-6351-2383
Figures
Abstract
Background
Small airways obstruction (SAO) has been associated with occupational exposures. Whether exposure to harmful occupational agents impacts the survival of people with SAO is unknown. Our aim was to estimate the mortality risk associated with occupational exposures among people with SAO.
Methods
We used data from UK Biobank participants with SAO, defined as a ratio of forced expiratory volume in three seconds to forced expiratory volume in six seconds (FEV3/FEV6) below the lower limit of normal. We assigned lifetime occupational exposures to participants with available occupational histories using the ALOHA+ Job Exposure Matrix. Mortality data were provided by the National Death Registries. We used Cox regression to assess the association of all-cause mortality with lifetime occupational exposures (vapours, gases, dusts, fumes—VGDF; solvents; pesticides; metals), adjusting for potential confounders.
Results
The 13,942 participants with SAO had a mean age of 56±7 years, 59% were females and 94.2% were of White ancestry. Overall, there were 457 deaths over a median follow-up of 12.8 years. A greater mortality risk was associated with exposure to VGDF, with hazard ratios of 1.32 (95%CI: 1.04–1.78) for low levels and 1.41 (95%CI: 1.11–1.78) for moderate levels of cumulative exposure. There was no evidence of association for the other occupational exposures.
Citation: Quintero-Santofimio V, Minelli C, Potts J, Vermeulen R, Kromhout HJ, Knox-Brown B, et al. (2024) Mortality risk associated with occupational exposures in people with small airways obstruction. PLoS ONE 19(6): e0305125. https://doi.org/10.1371/journal.pone.0305125
Editor: Davor Plavec, Srebrnjak Children’s Hospital, CROATIA
Received: February 21, 2024; Accepted: May 24, 2024; Published: June 11, 2024
Copyright: © 2024 Quintero-Santofimio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The current study used data from the UK Biobank (www.ukbiobank.ac.uk) under application number 80005 and legal constraints do not permit public sharing of the data. The UK Biobank, is composed of over 500,000 volunteers and it is open to all qualified researchers anywhere in the world. Therefore, the data used in this study can be directly accessed by applying through the UK Biobank Access Management System (www.ukbiobank.ac.uk/register-apply).
Funding: The Colt Foundation (CF/01/21).
Competing interests: The authors have declared that no competing interests exist.
Introduction
Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. Both asthma and COPD are characterised by airflow obstruction, to which an increase in small airways resistance and obstruction are known contributors [1]. Even when traditional spirometric indices are normal, small airways obstruction (SAO) is common in the general population, and has been associated with occupational exposures to vapours, gases, dusts, and fumes (VGDF), as well as pesticides [2, 3].
Although tobacco smoking is an important risk factor for chronic respiratory diseases, harmful occupational exposures may also contribute to increased mortality among particular groups of people. Two large studies from Sweden have shown that workers exposed to VGDF have an increased risk of mortality [4, 5]. Whether people with SAO are more susceptible to occupational exposures and, as consequence of this, have reduced survival is unknown.
The aim of this study was to assess the association of all-cause mortality with lifetime occupational exposures in UK Biobank participants with spirometrically-defined SAO.
Methods
Study population
A total of 502,414 adults, aged 40–69 years, were recruited to UK Biobank between 2006 and 2010 [6]. In this analysis we included participants with SAO at baseline, defined as the ratio between the forced expiratory volume in three seconds and the forced expiratory volume in six seconds (FEV3/FEV6) less than the lower limit of normal (LLN). This definition was based on findings of our previous study which has shown minimal difference between the forced vital capacity (FVC) and FEV6 [7]. We defined isolated SAO as FEV3/FEV6<LLN in the absence of airflow obstruction (FEV1/FEV6>LLN). All participants included in this study had high quality spirometry with at least two spirograms, no cough, back extrapolated volume <5% FVC (or >5% but <150mL), reproducible FEV1 and FVC and a forced expiratory time ≥ 6 seconds on the best curve (curve with highest FEV1 and FVC).
Lifetime occupational histories based on job titles for all paid jobs held for longer than six months was collected between July and September 2015 using the Occupational Self-Coding and Automatic Recording tool (OSCAR) [8]. Using the ALOHA + Job Exposure Matrix (JEM), each individual was assigned a cumulative exposure for 10 individual agents and two compound agents, based on intensity and duration of exposure as described in our previous study [7]. Information on the causes of death was obtained via linkage of UK Biobank participants with the death records of the UK Office for National Statistics through National Health Service identification numbers. Death was classified according to its underlying (primary) cause using the International Classification of Diseases, edition 10 (ICD-10). All-cause mortality was defined as death of any cause, except external causes (V01–Y89). The date of latest mortality follow-up was 31 January 2022. Ethical approval was obtained for UK Biobank (National Research Ethics Service, 11/NW/0382, 21/NW/0157). Data was accessed on the 13/09/2022.
Statistical analysis
The lifetime all-cause mortality risk, from birth to January 2022 (censoring date), associated with lifetime occupational exposures at the time of baseline assessment was determined using a multivariable Cox proportional hazards regression model. This model was adjusted for the following potential confounders: sex, smoking status (never, ex- or current smoker), smoking pack-years, Townsend deprivation index, ethnicity, and UK Biobank assessment centre.
To estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between all-cause mortality and occupational exposures in participants with SAO, age instead of time-on-study was used as the time scale [9]. We performed an additional analysis among people with isolated SAO, occupational exposures and all-cause mortality. Analyses were conducted using the survival and survminer packages in R (version 4.1.1.).
Results
Included in this analysis were 13,942 (21.4%) UK Biobank participants with lifetime occupational histories available and high-quality spirometry demonstrating SAO at baseline. Of these, 59.4% were females, 51.4% were never smokers, and 94.2% were of white ethnicity. Regarding employment status at the baseline study visit, 61.6% of the participants were in full-time employment and 32.3% were retired. Airflow obstruction, defined as FEV1/FEV6<LLN, was present in 55.3% of females and 62.1% of males (Table 1). Among participants with SAO, 41.9% (n = 5,847) had isolated SAO defined as FEV3/FEV6<LLN and FEV1/FEV6>LLN, and their characteristics were similar to those with SAO.
There were 457 (3.3%) deaths, reported over a median follow-up of 12.8 years. The most common cause of death was neoplasms (59.1%), followed by cardiovascular (18.2%) and respiratory causes (6.8%) (Table 1). More deaths were reported in males (58.4%). Of the total deaths, 66.3% (n = 303) had concurrent airflow obstruction (FEV1/FEV6<LLN). Among participants with isolated SAO, there were a total of 154 (2.6%) deaths reported over a median of 12.8 years of follow up. Similar to those with SAO, the most common cause of death was neoplasm (55.8%), followed by cardiovascular (22.7%) and respiratory (3.9%). Nearly 50% of participants with SAO were exposed to at least one of the 12 occupational agents of interest, with the commonest exposures being to VGDF (48.5%), all solvents (30.2%), metals (11.5%) and pesticides (4.0%). The highest number of deaths were in participants with occupational exposures to VGDF (58.3%), and fewest deaths were in those exposed to pesticides (5.1%; Table 2).
Exposure to VGDF was associated with higher all-cause mortality risk, with a hazard ratio of 1.32 (95%CI 1.04–1.78) for low cumulative exposure and 1.41 (95%CI 1.11–1.78) for moderate cumulative exposure. However, among females the increased mortality risk was only associated with low cumulative exposure to VGDF with a hazard ratio of 1.52 (95%CI 1.09–2.13), while in males it was only associated with moderate cumulative exposure to VGDF with a hazard ratio of 1.39 (95%CI 1.03–1.88) (Table 2). Among participants with isolated SAO, the hazard ratios for high and moderate exposure to VGDF were not materially different from those for the whole sample. However, these were not statistically significant. There were no statistically significant associations between mortality and any of the other occupational agents.
Discussion
In this study of people with SAO, a greater all-cause mortality risk was associated with low and moderate lifetime exposure to VGDF. We found no statistical evidence of association of all-cause mortality with high lifetime exposure to VGDF, but it is possible this is due to the small number of deaths in this sub-group of people. Similarly, there was no association between mortality and lifetime occupational exposures among people with isolated SAO.
It has been shown that SAO may be associated with respiratory symptoms early on [10, 11], and that it may predict chronic airflow obstruction (as in COPD) later in life [10, 12]. It is plausible that this process may be additionally aggravated by occupational exposures. For example, in a longitudinal study of construction workers in Sweden, exposure to VGDF was associated with increased all-cause mortality and mortality from COPD [4]. Our findings suggest that individuals with SAO may be more susceptible to the negative effects of occupational VGDF due to their predisposition to develop obstructive lung disease over time [13]. It is conceivable that VGDF in the workplace may exacerbate the obstruction of the small airways, leading to faster lung function decline and ultimately impacting survival. However, the mechanism by which occupational exposures may cause increase mortality in those with isolated SAO needs further research. Primary prevention of disease through adequate control of exposure to VGDF in workplaces should be continually reviewed and changes implemented to provide a safer work environment. This includes carrying out air quality monitoring and implementing engineering controls such as ventilation systems, and if necessary, use of appropriate personal protective equipment. We observed no associations with other metal or solvents, however it is plausible that exposure to these agents may occur through alternative routes to inhalation, such as dermal contact, and may have a lesser impact on respiratory health.
The strengths of this study are its large sample size, the use of a standardised protocol for spirometry and lifetime occupational history. However, the UK Biobank is not representative of the UK population and has a healthy volunteer bias, meaning that the findings of this study may not be generalisable to other populations. Whilst there is lack of agreement about how best to define SAO using spirometric parameters, we recently reported FEV3/FEV6<LLN to be the best parameter in the UK Biobank [7]. This is supported by the findings of a recent study showing a correlation between FEV3/FEV6-defined SAO and SAO defined by gas trapping and chest computed tomography [10, 14].
Conclusion
Lifetime occupational exposure to VGDF may contribute to increased all-cause mortality in people with SAO. Our study highlights the need for primary prevention of disease through adequate control of exposures and to consider early monitoring of SAO on workers exposed to VGDF, and primary prevention through adequate exposure control as part of respiratory health surveillance. This will aid to identify and better manage those at risk of respiratory morbidity and mortality in the workplace.
Supporting information
S1 Table. Baseline characteristics on the participants with isolated FEV3/FEV6<LLN in the UK Biobank.
https://doi.org/10.1371/journal.pone.0305125.s001
(DOCX)
S2 Table. Hazard ratios of all-cause mortality for all occupational exposures among participants with isolated FEV3/FEV6<LLN.
https://doi.org/10.1371/journal.pone.0305125.s002
(DOCX)
S1 Fig. Directed acyclic graph (DAG) of relationship between occupational exposures in people with SAO and all-cause mortality.
https://doi.org/10.1371/journal.pone.0305125.s003
(TIF)
S2 Fig. Sex distribution of exposures to 12 occupational agents among UK Biobank participants with FEV3/FEV6<LLN.
https://doi.org/10.1371/journal.pone.0305125.s004
(TIF)
Acknowledgments
This research has been conducted using the UK Biobank Resource under application number 80005. We thank the participants, fieldworkers, and data managers of the UK Biobank for their time and assistance.
References
- 1. Burgel PR. The role of small airways in obstructive airway diseases. European Respiratory Review. 2011;20(119):023–33. pmid:21357889
- 2. Knox-Brown B, Patel J, Potts J, Ahmed R, Aquart-Stewart A, Cherkaski HH, et al. Small airways obstruction and its risk factors in the Burden of Obstructive Lung Disease (BOLD) study: a multinational cross-sectional study. Lancet Glob Health. 2023;11(1):e69–e82. pmid:36521955.
- 3. Sunyer J, Kogevinas M, Kromhout H, Anto JM, Roca J, Tobias A, et al. Pulmonary ventilatory defects and occupational exposures in a population-based study in Spain. Spanish Group of the European Community Respiratory Health Survey. Am J Respir Crit Care Med. 1998;157(2):512–7. Epub 1998/02/26. pmid:9476866.
- 4. Torén K, Järvholm B. Effect of occupational exposure to vapors, gases, dusts, and fumes on COPD mortality risk among Swedish construction workers: a longitudinal cohort study. Chest. 2014;145(5):992–7. pmid:24264472.
- 5. Torén K, Neitzel R, Sallsten G, Andersson E. Occupational exposure to soft paper dust and mortality. Occupational and environmental medicine. 2020;77(8):549–54. Epub 20200402. pmid:32241835; PubMed Central PMCID: PMC7402447.
- 6. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779. Epub 20150331. pmid:25826379; PubMed Central PMCID: PMC4380465.
- 7. Feary J, Quintero-Santofimio V, Potts J, Vermeulen R, Kromhout H, Knox-Brown B, et al. Occupational exposures and small airways obstruction in the UK Biobank Cohort. ERJ Open Research. 2023. https://doi.org/10.1183/23120541.00650-2022.
- 8. De Matteis S, Jarvis D, Young H, Young A, Allen N, Potts J, et al. Occupational self-coding and automatic recording (OSCAR): a novel web-based tool to collect and code lifetime job histories in large population-based studies. Scandinavian journal of work, environment & health. 2017;43(2):181–6. Epub 20161214. pmid:27973677.
- 9. Thiébaut AC, Bénichou J. Choice of time-scale in Cox’s model analysis of epidemiologic cohort data: a simulation study. Statistics in medicine. 2004;23(24):3803–20. pmid:15580597.
- 10. Yee N, Markovic D, Buhr RG, Fortis S, Arjomandi M, Couper D, et al. Significance of FEV(3)/FEV(6) in Recognition of Early Airway Disease in Smokers at Risk of Development of COPD: Analysis of the SPIROMICS Cohort. Chest. 2022;161(4):949–59. Epub 20211110. pmid:34767825; PubMed Central PMCID: PMC9005864.
- 11. Knox-Brown B, Patel J, Potts J, Ahmed R, Aquart-Stewart A, Barbara C, et al. The association of spirometric small airways obstruction with respiratory symptoms, cardiometabolic diseases, and quality of life: results from the Burden of Obstructive Lung Disease (BOLD) study. Resp Res. 2023;24(1). pmid:37221593
- 12. Knox-Brown B, Potts J, Santofimio VQ, Minelli C, Patel J, Abass NM, et al. Isolated small airways obstruction predicts future chronic airflow obstruction: a multinational longitudinal study. BMJ Open Respiratory Research. 2023;10(1):e002056. pmid:37989490
- 13. Boschetto P, Quintavalle S, Miotto D, Lo Cascio N, Zeni E, Mapp CE. Chronic obstructive pulmonary disease (COPD) and occupational exposures. J Occup Med Toxicol. 2006;1:11. Epub 20060607. pmid:16756686; PubMed Central PMCID: PMC1513231.
- 14. Dilektasli AG, Porszasz J, Casaburi R, Stringer WW, Bhatt SP, Pak Y, et al. A Novel Spirometric Measure Identifies Mild COPD Unidentified by Standard Criteria. Chest. 2016;150(5):1080–90. Epub 20160722. pmid:27452770; PubMed Central PMCID: PMC5103018.