Occupational physical workload and risk of lung cancer and chronic respiratory diseases: a prospective cohort study of the UK Biobank

Introduction

Lung cancer is one of the leading causes of cancer-related mortality worldwide, with an estimated 2.3 million new cases and 2 million deaths (1,2), while chronic respiratory diseases (CRDs) comprise a group of conditions that affect the airways and pulmonary structures and were the third leading cause of death responsible for 4.0 million deaths with a prevalence of 454.6 million cases globally. Among them, chronic obstructive pulmonary disease (COPD) affects more than 212 million people and accounts for approximately 3.3 million deaths annually. Asthma affects around 3.7% of the global population, while idiopathic pulmonary fibrosis (IPF) remains a fatal interstitial lung disease with a median survival of only 3–5 years (3). These conditions represent a growing public health challenge, for which modifiable risk factors have long been a focus of research (4).

As early as the late 20th century, researchers recognized that occupational exposures may constitute an important risk factor for CRDs beyond the well-established role of smoking (5). According to the joint statement by the American Thoracic Society (ATS) and European Respiratory Society (ERS), approximately one in six adult asthma cases and one in seven COPD cases are attributable to occupational factors (6). While previous studies have predominantly focused on inhalational hazards such as dusts, fumes, and vapors, or on the disruptive effects of shift work, the role of physical workload has been largely overlooked (7-10). Despite growing evidence linking occupational physical workload to cardiovascular and mortality outcomes (11-13), its associations with major CRDs—including lung cancer, COPD, asthma, and IPF—have not been systematically assessed in large-scale prospective cohorts. Addressing this question is critical for informing clinical risk assessment and the development of occupational health policies.

In this study, leveraging the UK Biobank, a large population-based cohort with long-term follow-up (14), we aimed to evaluate the associations between occupational physical workload and the incidence of lung cancer and other major CRDs, including COPD, asthma, and IPF. We present this article in accordance with the STROBE reporting checklist (15) (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1385/rc).

Methods

Study population

The UK Biobank is a large, population-based prospective cohort comprising 503,317 adults aged 40–69 years at recruitment between 2006 and 2010, enrolled from 22 assessment centers across England, Scotland, and Wales. Baseline data collection included touchscreen questionnaires, physical measurements, and biological samples. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The UK Biobank has received ethical approval from the North West Multi-Centre Research Ethics Committee (REC reference 11/NW/0382). All participants provided written informed consent to the UK Biobank at baseline, and all data were fully anonymized prior to access (14).

Of the 502,128 participants in the work-related dataset extract, we first excluded individuals with missing or indeterminate values for any baseline covariates (n=142,581). We then excluded participants with missing data in any of the three components used to derive occupational physical workload measures, which captured aspects of working hours, physical demands, and workplace posture (n=157,513). This yielded a sample of 202,034 participants with complete baseline exposure and covariate data.

To minimize reverse causality, follow-up for incident outcomes was initiated 1 year after the initial UK Biobank assessment (instance 0). Participants with a diagnosis of the target condition before the start of follow-up, as well as those with invalid diagnostic records, were excluded. The final analytic cohort sizes were 183,827 for lung cancer, 201,399 for COPD, 194,952 for asthma, and 201,944 for IPF. Details of participant selection and exclusion criteria are shown in Figure 1.

Figure 1 Flow of participants and construction of analytic cohorts. COPD sensitivity cohort additionally excluded participants with pre-baseline asthma. BMI, body mass index; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; PM2.5, particulate matter with an aerodynamic diameter ≤2.5 μm.

Exposure assessment

Occupational physical workload was assessed at baseline using the UK Biobank touchscreen questionnaire for participants’ main job. Three items were included: weekly working hours (Data-Field 767), standing or walking at work (Data-Field 806), and heavy manual or physical work (Data-Field 816). We then assigned a score to each item according to the participant’s response, reflecting the intensity of occupational workload (see Table S1). The occupational physical workload score was derived as the sum of the three item scores (range, 0–6) and was categorized into low (0–2), medium (3–4), and high (5–6) workload group, with the low workload group serving as the reference in all analyses (see Table S2).

Outcome ascertainment

Outcomes were ascertained through linkage to UK Biobank hospital admission records, national cancer registries, and death registries, and were defined using the International Classification of Diseases, 10th Revision (ICD-10): C33–C34 for lung cancer, J44 for COPD, J45 for asthma, and J84.1 for IPF (see Table S3). Eligible outcomes were restricted to diagnoses first recorded after the start of follow-up.

Covariates

Covariates were selected based on previously reported risk factors for lung cancer and other CRDs, and on data availability in the UK Biobank. Accordingly, the following variables were included: sex (female or male), age at baseline (continuous, years), body mass index (BMI; continuous, kg/m²), smoking status (current, previous, or never), alcohol intake (current, previous, or never), educational attainment (below secondary education, secondary education, or bachelor’s degree and above), ethnicity (White, Asian, Black, mixed, other, or unspecified), Townsend Deprivation Index (TDI; continuous, a composite measure of area-level socioeconomic deprivation, with higher scores indicating worse socioeconomic status neighborhoods) (16), long-term exposure to fine particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5; continuous, µg/m³), occupational inhalation exposure [assessed using a job-exposure matrix derived from the Finnish Information System on Occupational Exposure (FINJEM) (17), considering exposure to diesel exhaust, asbestos, silica, and welding fumes; yes or no], history of hypertension (yes or no), history of diabetes (yes or no), and family history of cancer (yes or no).

Statistical analysis

Participant characteristics at baseline were summarized across occupational physical workload groups (low, medium, and high). Means and standard deviations were reported for continuous variables, and frequencies and percentages for categorical variables.

Kaplan-Meier curves were used to visualize cumulative incidence across occupational physical workload groups, and group differences were compared using the log-rank test.

Cox proportional hazards models were used to assess the association between occupational physical workload and the risk of lung cancer and other CRDs. We constructed sequential Cox proportional hazards models with progressive adjustment for demographic characteristics, socioeconomic status, environmental exposure, and lifestyle factors. The fully adjusted model included age, sex, BMI, smoking status, educational attainment, ethnicity, Townsend Deprivation Index, PM2.5, occupational inhalation exposure. Family history of cancer was additionally included in models for lung cancer. Model adjustment details are provided in Table S4.

Stratified Cox proportional hazards models were performed by sex (female or male), age group [<60 or ≥60 years (18)], and area-level deprivation [TDI ≤0 or >0; 0 as national average (16)].

We further performed two sensitivity analyses. First, the heavy workload score was treated as a continuous variable to estimate the hazard per one-point increase. Second, an additional model was fitted with further adjustment for alcohol intake, hypertension, and diabetes. Third, competing risk analyses were conducted using Fine-Gray subdistribution hazard models, with death treated as a competing event. Fourth, in the COPD analysis, individuals with a recorded history of asthma prior to baseline were excluded.

All statistical analyses were conducted using R version 4.5.0 (19). Key packages included tableone (20) for baseline summary statistics, survival (21) for Kaplan-Meier estimation and Cox proportional hazards modelling, survminer (22) for Kaplan-Meier curve visualization, and cmprsk (23) for competing risk analyses. Results were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). All hypothesis tests were two-sided, and a P value of <0.05 was considered statistically significant.

Results

Baseline characteristics

Baseline characteristics of the study population were stratified by occupational physical workload into low (n=47,448, 23.49%), medium (n=104,579, 51.76%), and high (n=50,007, 24.75%) workload groups. In general, participants in the high workload group, with a mean age of 52.30 years, were more likely to be male, current alcohol consumers, have higher BMI, live in more deprived areas, and have a higher proportion of individuals with below secondary education. Detailed characteristics are presented in Table 1.

Main analysis

In multivariable-adjusted analyses, occupational physical workload was associated with increased risks of lung cancer and other CRDs (Table 2, Tables S5-S10).

For lung cancer, participants with greater occupational physical workload exhibited higher cumulative risk across follow-up (Figure 2A). Compared with participants in the low workload group, those in the medium and high workload groups had higher risks, with HRs of 1.30 (95% CI: 1.06–1.59; P=1.29×10⁻²) and 1.54 (95% CI: 1.23–2.93; P=1.74×10⁻⁴), respectively. The risk also increased per 1-unit increment in workload score (HR =1.10; 95% CI: 1.05–1.16; P=1.85×10⁻⁴). These associations remained materially unchanged after accounting for the competing risk of death (Table S11).

Figure 2 Cumulative incidence of lung cancer and chronic respiratory diseases by occupational physical workload. Kaplan-Meier cumulative incidence curves for (A) lung cancer, (B) COPD, (C) asthma, and (D) IPF across low, medium, and high occupational physical workload categories. COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis.

For COPD, cumulative incidence increased consistently with higher occupational physical workload (Figure 2B). An elevated risk was observed in the high workload group (HR =1.45; 95% CI: 1.32–1.58; P=1.66×10⁻¹⁵), while the medium workload group showed no significant association (HR =1.01; 95% CI: 0.93–1.10; P=0.77). Each unit increase in workload score was associated with a 11% higher risk (HR =1.11; 95% CI: 1.09–1.14; P<2×10⁻¹⁶). Results remained consistent after excluding participants with asthma prior to the start of follow-up (see Table S6). Results were consistent in competing risk analyses treating death as a competing event (Table S11).

For asthma, higher occupational physical workload was associated with higher cumulative risk (Figure 2C). Both medium and high workload groups had increased risks, with HRs of 1.08 (95% CI: 1.03–1.13; P=2.53×10⁻³) and 1.15 (95% CI: 1.08–1.21; P=2.78×10⁻⁶), respectively. Each unit increase in workload score was associated with a higher asthma risk (HR =1.04; 95% CI: 1.02–1.05; P=8.91×10⁻⁷). Similar associations were observed in competing risk analyses accounting for death (Table S11).

For IPF, cumulative incidence was higher among participants with higher occupational physical workload (Figure 2D). Participants in the high workload group had a significantly higher risk (HR =1.40; 95% CI: 1.11–1.76; P=3.94×10⁻³), while the medium workload group showed no clear association (HR =1.12; 95% CI: 0.91–1.37; P=0.30). The continuous workload score was also associated with a higher risk of IPF (HR =1.11; 95% CI: 1.05–1.17; P=1.33×10⁻⁴). Accounting for the competing risk of death did not materially alter the observed associations (Table S11).

Stratified analyses

Figure 3 presents stratified associations by sex, age group, and area-level deprivation (TDI). No evidence of interaction was observed for sex, age, or TDI across lung cancer and other CRDs, with HRs ranging from 1.07 to 1.77 and P values for interaction ranging from 0.08 to 0.79 (Table S10; Tables S12-S15).

Figure 3 Stratified associations between occupational physical workload and risk of lung cancer and other chronic respiratory diseases. TDI ≤0 indicates less-deprived areas (at or below the national average), and >0 indicates more-deprived areas. CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; IPF, idiopathic pulmonary fibrosis; TDI, Townsend Deprivation Index.

Discussion

Based on this study, we assessed occupational physical workload using a composite measure that incorporated three key dimensions: weekly working hours, frequency of standing or walking, and frequency of heavy manual labor. Higher occupational physical workload was associated with increased incidence of lung cancer, COPD, asthma, and IPF. These associations were largely consistent across sex, age, and deprivation strata.

In recent years, occupational physical activity has increasingly been recognized as an important work-related risk factor independent of inhalational exposures. Multiple large prospective studies (24-26) across different populations have consistently observed that higher levels of occupational physical activity are associated with an increased risk of lung cancer, with risk estimates rising alongside greater physical workload at work (26). This pattern is concordant with our findings, in which lung cancer risk increased progressively across higher levels of occupational physical workload. Beyond lung cancer, existing epidemiological evidence also indicates that occupations characterized by high physical demands, or high levels of physical workload per se, are associated with elevated risks of other respiratory diseases, including COPD (27), asthma (28), and IPF (29). These observations are broadly consistent with the direction of associations observed in the present study across multiple respiratory outcomes, supporting occupational physical workload as an important work-related risk characteristic with potentially adverse implications for chronic respiratory health.

Growing evidence suggests that sustained excessive physical activity may exert considerable stress on respiratory structures (26). In occupations requiring sustained physical labor, repetitive physical movements such as bending, lifting, and prolonged standing or walking may impose cyclical mechanical strain and elevate intrathoracic pressure, resulting in microinjuries of the airway epithelium and thoracic structures (30). In some cases, elevated diaphragmatic pressure or forward flexion may even provoke gastroesophageal reflux, which in turn contributes to airway irritation and inflammatory responses (31). The mechanical strain-induced damage may gradually trigger persistent low-grade inflammation, which is characterized by elevated circulating levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) (32), and may compromise mucosal immunity and tissue homeostasis over time (33). In parallel, repetitive physical overload may act as a chronic physiological stressor (34), promoting excessive generation of reactive oxygen species (ROS), which in turn intensify oxidative DNA damage (35), disrupt mitochondrial function, and impair cellular repair capacity—cascading toward cellular aging and telomere shortening (36), and potentially contributing to pulmonary senescence and fibrotic remodeling (37). Additionally, previous studies have reported that sustained physical workload may interfere with autonomic nervous regulation, disrupting the balance between sympathetic and parasympathetic activity, and thereby contributing to altered respiratory rhythm and airway tone. occupational workload has also been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (38), depressive symptoms, and impaired immune surveillance (39), which may collectively increase individual susceptibility to respiratory damage. Overall, the mechanical stress and psychological strain induced by sustained occupational physical workload may converge to disrupt molecular homeostasis, thereby contributing to the development of CRDs.

In the context of lung cancer, we observed that individuals with medium and high levels of occupational physical workload had a higher incidence risk, with risk increasing progressively across workload scores, indicating a dose-response relationship, a pattern that has been more commonly described for occupational inhalational exposures (40). At the mechanistic level, chronic low-grade inflammation induced by sustained occupational physical workload may create a tumor-promoting microenvironment that favors cell proliferation and survival (33). High-intensity physical activity may also increase minute ventilation, leading to a greater absolute deposition of inhaled particulate matter within the lungs (41). Together with repetitive mechanical strain and prolonged oxidative stress, these processes lead to DNA damage and telomere shortening, both of which contribute to genomic instability and the accumulation of somatic mutations that drive malignant transformation (42). Moreover, chronic activation of stress-related neuroendocrine pathways, such as the HPA axis, can suppress cytotoxic T-cell and natural killer cell functions (43), thereby weaken immune surveillance and reduce the body’s ability to eliminate transformed cells. Nevertheless, some studies have reported that physical activity can promote immune cell circulation and their recruitment into tissues (44), while also enhancing antioxidant defenses (45), thereby potentially exerting antitumor effects. These observations suggest that the biological impact of occupational physical workload is not unidirectional; rather, the epidemiological associations observed in the present study likely reflect the overall effects of multiple biological pathways operating concurrently.

In COPD, an increased risk was observed only among individuals with high physical workload, with no evident association at moderate levels. At the mechanistic level, chronic low-grade inflammation and repetitive mechanical strain caused by sustained occupational workload may induce airway wall fibrosis, mucus hypersecretion, and alveolar destruction, leading to irreversible airflow limitation (46). At the cellular level, excessive oxidative stress and telomere shortening compromise epithelial repair, promote premature cellular senescence, and impair the lung’s ability to recover from recurrent injury (37). These inflammatory, oxidative, and regenerative disturbances collectively contribute to airway remodeling and the progressive decline characteristic of COPD (47).

For asthma, repetitive physical overload may exacerbate airway inflammation and enhance bronchial hyperresponsiveness through both immunologic and neuroendocrine mechanisms (48,49). Chronic workload stress may amplify Th2-driven immune activation (32,50), facilitating sustained release of cytokines such as IL-4 that perpetuate airway inflammation and mucus production (51). Meanwhile, disruption of autonomic balance leads to sympathetic-parasympathetic dysregulation, increasing airway tone and reactivity, while HPA-axis dysfunction further lowers the threshold for bronchial constriction (52).

In IPF, the sample size was relatively limited compared with other outcomes, which is consistent with the epidemiological characteristics of this disease (3). Our results showed that a significantly increased risk of IPF was observed only at high levels of occupational physical workload, suggesting that sustained or intensive workload may be required to initiate fibrotic processes. Prior epidemiological evidence (53) similarly indicates that longer duration or higher cumulative occupational exposures are more likely to be associated with increased risks of fibrotic lung outcomes. At the mechanistic level, sustained mechanical strain from heavy occupational workload may cause repetitive microinjury to alveolar epithelial cells, disrupting the balance between injury and repair (54). These repeated insults stimulate profibrotic signaling, including activation of transforming growth factor-β (TGF-β) and fibroblast proliferation, leading to excessive extracellular matrix deposition (55). Chronic oxidative stress and telomere shortening further impair epithelial regeneration, reinforcing maladaptive tissue repair and progressive fibrotic remodeling characteristic of IPF (56).

There are several strengths and limitations in this study. It is based on the UK Biobank, a large, population-based prospective cohort with long-term follow-up and reliable linkage to national health records (14), ensuring robust and accurate outcome ascertainment. We adopted an innovative approach by combining three complementary dimensions—working hours, standing/walking frequency, and manual labor intensity—to evaluate occupational physical workload in a comprehensive and stable manner. In addition, detailed adjustment for a wide range of demographic, socioeconomic, and lifestyle factors helped minimize potential confounding and enhanced the credibility of our findings. However, most UK Biobank participants are of White European ancestry and tend to have higher educational levels, which may limit the generalizability of our findings. Although we adjusted for a wide range of covariates, residual confounding from unmeasured or misclassified variables cannot be fully excluded. In addition, more detailed smoking metrics, such as pack-years and time since smoking cessation, were not included in the main analyses due to substantial missingness, which may have resulted in residual confounding. Moreover, physical workload was self-reported at baseline, which may introduce recall bias or exposure misclassification. While disease outcomes were ascertained using validated registry-based algorithms, milder or undiagnosed cases may not have been captured.

Conclusions

This large prospective cohort provides strong evidence that occupational physical workload is associated with an increased incidence of lung cancer, COPD, asthma, and IPF. These findings indicate that occupational physical workload should be recognized as a modifiable risk factor in respiratory disease prevention and control. Targeted workplace interventions and strengthened regulatory measures are needed to mitigate these risks.

Acknowledgments

We would like to thank the UK Biobank participants and staff for their invaluable contributions to this research. This study was conducted under the approval of UK Biobank (Application Number 622952).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1385/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1385/prf

Funding: This study was supported by the 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYGD23010, to L.L.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1385/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The UK Biobank has received ethical approval from the North West Multi-Centre Research Ethics Committee (REC reference 11/NW/0382). All participants provided written informed consent to the UK Biobank at baseline, and all data were fully anonymized prior to access.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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