Objectives

1. To understand the relative importance of the occupational contribution to the burden of COPD.
2. To become aware of potential mechanisms by which exposures in the workplace could cause chronic bronchitis and/or emphysema.
3. To identify the common occupational exposures that can cause or contribute to COPD.
4. To recognize the importance of taking a good occupational and environmental exposure history to the appropriate management of COPD.
5. To understand some basic approaches to reducing the impact of occupational exposures on patients who are at risk of COPD or already have disease.

Abbreviations

PAR = population-attributable risk

Smoking is clearly the major preventable cause of COPD, but because this disease is so prevalent, reduction of other preventable risk factors can have a major impact on reducing disease burden. There are approximately 16 million people in the United States in whom COPD has been diagnosed, and many more people who have abnormal lung function consistent with the diagnosis but who currently have minimal or no symptoms.¹ COPD is the fourth leading cause of death worldwide and accounts for more than 100,000 deaths per year in the United States alone.^1,2 Thus, the burden of COPD is high. If occupational factors contribute substantially to the overall risk of COPD, exposure to these risk factors is preventable.
COPD is defined as a disease state characterized by the presence of airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.³ COPD can result from chronic bronchitis accompanied by hypersecretion of mucus and/or emphysema characterized by destruction of alveolar walls. COPD does not have a clinical subcategory that is clearly identified as occupational, largely because the condition develops slowly and, given that the airflow obstruction is chronic, does not reverse when exposure is discontinued. Thus, a clinical attribution of occupationally related COPD is rarely made by clinicians.

Identification of COPD caused by occupational exposures typically rests on a knowledge of the epidemiologic or toxicologic literature (eg, chronic bronchitis after many years of work as an underground coal miner or emphysema in a battery factory worker exposed to cadmium fumes). In practice, the epidemiologic link between and occupation and COPD is based on observing excess occurrence of COPD among exposed workers (see below).

Some work-related obstructive airway disorders may be classified as COPD, but others do not neatly fit into this category. For example, work-related variable airway limitation may occur with occupational exposure to organic dusts such as cotton (ie, byssinosis), flax, hemp, jute, sisal, and various grains. Such organic dust–induced airway disease is sometimes classified as an asthma-like disorder,4 but both chronic bronchitis (by clinical definition) and poorly reversible airflow limitation classically develop with chronic exposure. Bronchiolitis obliterans and irritant-induced asthma are two other conditions that may overlap clinically with work-related COPD.

Epidemiology

While there is consensus that cigarette smoking is a specific cause of COPD, most of the data on which this is based come from longitudinal epidemiologic studies in which a dose-response relationship for amount smoked and decline in ventilatory function has been observed for the population studied. This effect has consistently been confined to a minority of smokers, however, and it is still not possible to predict based on smoking exposure alone which individual smokers will develop chronic bronchitis, emphysema, or both. Cigarette smoke is analogous to a mixed inhalational exposure at a workplace, ie, a complex mixture of particles and gases. Epidemiologic studies of the effects of cigarette smoke have not attempted to determine the specific etiologic role of any of its more than 400 constituents. The airway dysfunction that has been clearly associated with cigarette smoking may be, therefore, a nonspecific response to inhaled irritants in predisposed individuals.

Although there is a priori biological reason to believe that a similar response to inhaled workplace irritants should also occur, it has been somewhat more difficult to demonstrate an association between occupational exposures and COPD in epidemiologic studies. This may be related to several factors. First, COPD is multifactorial in etiology, with critical (and mostly unknown) host as well as nonoccupational environmental determinants of risk. Second, unlike workers with pneumoconioses, individuals with COPD due to occupational exposures cannot be distinguished from those with the disease due to other causes. Third, many workers with COPD have concurrent exposure to cigarette smoke (direct and/or secondhand) and workplace dusts, gases, or fumes. Fourth, exposed workers at baseline tend to have better overall health and higher ventilatory function than the general population, the so-called healthy worker effect. Fifth, workforce studies are often limited to a “survivor” population because of an inability to assess or follow workers who leave their jobs, thereby underestimating the chronic effects of occupational exposures.

Despite the difficulties listed above, an increasingly impressive body of literature demonstrating that specific occupational exposures contribute to the development of COPD has accumulated over the past two decades^5-15; see Table 1 for a list of agents associated with work-related COPD. Longitudinal studies of the effects of occupational exposures have been performed in coal miners,^16-19 hard-rock miners,^8,20 tunnel workers,²¹ concrete-manufacturing workers,²² and in a cohort of nonmining industrial workers in Paris.²³ As Becklake²⁴ has pointed out, a consistent feature of these studies is a roughly comparable magnitude of effect for moderate smoking and occupational exposures. For example, in UK coal miners, the excess annual loss of FEV₁ attributable to average exposure in mines was 8 mL/yr after accounting for age and smoking, compared with 11 mL/yr attributable to smoking after accounting for age and dust exposure.¹⁶ For US coal miners the data were remarkably similar: 7 and 9 mL/yr, respectively.¹⁷ In Parisian workers exposed to a variety of potential respiratory irritants, the findings were again similar, 8 mL/yr excess loss attributable to occupational exposure and 11 mL/yr attributable to smoking.²³ Acute obstructive changes in response to occupational exposures to organic and inorganic dusts, diisocyanates, and irritant gases appear to predict subsequent chronic (ie, fixed) airflow limitation.²⁵

Table 1. Selected Occupational Agents Associated With COPD

Quantitative pathologic assessment of emphysema as an outcome variable has confirmed a relationship between dust exposure and degree of emphysema in several studies of coal and hard-rock miners. In one cross-sectional study of South African gold miners, the predictors of emphysema at autopsy included smoking and dust exposure, with odds ratios of 5.5 for each 10 cigarettes smoked per day and 3.3 for each 10 years of dust exposure.²⁶ In a second study of gold miners, cumulative respirable dust exposure prior to age 45 was the strongest predictor of panacinar emphysema at autopsy, with silicosis the strongest predictor of centrilobular emphysema.²⁷ There is also evidence from autopsy studies that exposure to coal dust increases the risk of centrilobular emphysema.^28,29 The relationship is stronger among smokers than nonsmokers and easier to demonstrate when coal dust–induced fibrosis is present.³⁰

Perhaps the strongest evidence implicating occupational exposures in the pathogenesis of COPD comes from community-based studies. Although these studies were typically not designed to examine the relationship of occupational exposures to COPD, they nonetheless yielded evidence of such a relationship. A major advantage of community-based studies is that the problem of survivor bias is largely avoided. Community-based studies from China, France, Italy, the Netherlands, New Zealand, Norway, Poland, Spain, and the United States have demonstrated increased relative risks for respiratory symptoms and/or chronic airflow limitation consistent with COPD,^31-41 as well as for excess annual declines in FEV₁ associated with occupational exposure to dusts, gases, and fumes.^31,37,38 Because the predictor variable used in these studies, self-reported “occupational exposure to dusts, gases, and/or fumes,” is only a crude index of exposure, it is likely that these studies are biased towards the null (ie, the finding of no effect of occupational exposures). The fact that these studies show a consistent association provides strong evidence that the observed effect is real.

Etiology

COPD remains a syndrome that likely involves multiple etiologic pathways. At least three pathologic processes can contribute to COPD: chronic bronchitis (mucus hypersecretion, mucus gland enlargement, goblet cell hyperplasia, squamous metaplasia, and proximal airway inflammation), chronic bronchiolitis (inflammation and remodeling of small airways), and emphysema (destructive enlargement of air spaces distal terminal bronchioli). While advances in mechanistic information about all of these processes have been made recently, our overall understanding of why only some humans with sufficient exposure to known risk factors actually develop COPD remains surprisingly limited.^42-46

Experimental studies have demonstrated that several agents known to be associated with clinically defined chronic bronchitis in humans (eg, endotoxin, mineral dusts, sulfur dioxide, and vanadium) are capable of inducing pathologically defined chronic bronchitis in animal models.^47-50

Severe deficiency of a₁-antitrypsin [protease inhibitor phenotype Z (PI*Z)] remains the only genetic factor that has clearly been associated with COPD in humans. While exposure to tobacco smoke is the major environmental risk factor for PI*Z individuals, occupational exposure to dusts, gases, fumes, and/or smoke has been shown to increase the risk of chronic cough, lower FEV₁, and lower FEV₁/FVC independent of personal tobacco use.^51,52

It is also important to note that the list of agents that can cause emphysema in animals includes several for which occupational exposure occurs, such as cadmium, coal, endotoxin, and silica.⁵³ These occupationally relevant agents all cause centrilobular rather than panacinar emphysema associated with antitrypsin deficiency, so that mechanisms other than uninhibited neutrophil elastase activity are likely operative. In summary, then, there is biological evidence to support a role for workplace toxins in each of the major pathologic entities subsumed within COPD.

Population-Attributable Risk

An ad hoc Committee of the American Thoracic Society has reviewed population-based studies in which associations between occupational factors and COPD have been reported in order to assess the contribution of occupational exposures to the overall burden of this disease.⁵⁴ For COPD, a population-attributable risk (PAR) of approximately 15 to 20% was estimated to be due to occupational factors. Ten papers that were reviewed had sufficient data to calculate a PAR; several of the papers presented data supporting a >20% PAR for respiratory symptoms and lung function impairment due to work-related factors.

Two recent papers published since the completion of the American Thoracic Society statement provide further evidence in support of a major contribution of occupational exposures to the burden of COPD. Hnizdo and coworkers55 from the National Institute for Occupational Safety and Health used data collected in the US population–based Third National Health and Nutrition Examination Survey on more than 9,800 subjects to estimate the PAR for COPD (defined by a decreased FEV₁/FVC) due to work. The PAR for COPD due to work was estimated at 19% overall and 31% among never-smokers.

A second US population–based study conducted by Blanc and coworkers (Trupin et al56) obtained survey information on more than 2,000 subjects. The PAR for COPD due to these exposures was 20%; it was 31% for a narrower definition of COPD (excluding chronic bronchitis). In this study, the PAR for combined current and former smoking was 56%. Smoking and occupational exposures to dusts, gases, and/or fumes had greater than additive effects.

A conservative estimate of the annual costs of work-related COPD is nearly $5 billion in the United States alone.57 Based on the estimated PAR due to occupational exposures for COPD (15 to 20%), strategies designed to prevent occupationally induced obstructive airways disease should receive high priority in the global and national efforts to reduce disease burden.^4,58

Diagnosis, Management, and Prevention

The literature on management of work-related asthma is richer than that for work-related COPD. Guidelines for the identification and management of individuals with work-related asthma were recently published and are relevant to work-related COPD.⁵⁹ The treating clinician should attempt to understand the patient’s occupational exposures and whether he/she has been adequately educated about the dangers of these exposures and trained how to avoid them. Effective clinical management requires efforts to reduce exposures as well as medical treatment following internationally accepted guidelines including smoking cessation, bronchodilator administration, influenza vaccination, and antibiotic and glucocorticoid therapy for exacerbations.³

Appropriate strategies to reduce exposures to respiratory tract irritants, in order of decreasing efficacy, include elimination (eg, substitute alternate materials), engineering controls (eg, exhaust ventilation or process enclosure), administrative controls (eg, transfer to another job or change in work practices), and personal protective equipment (eg, masks or respirators).

Prevention must be the primary tool for decreasing the incidence of morbidity and disability from work-related COPD, which can become severely disabling. Prevention must involve cooperation between employers, workers and their representatives, regulators, and medical personnel.^59,60 A component of prevention is medical surveillance for early signs of disease in workers exposed to irritating dusts, gases, and/or fumes. Methods of surveillance that have been used effectively in workplaces include serial spirometry or peak expiratory flow measurements, respiratory questionnaires, and reviews of materials lists by a qualified professional (eg, industrial hygienist).⁶¹

Above all, the clinician must be aware of the potential occupational etiologies for obstructive airway disease and consider them in every patient with COPD. Identifying occupational risk factors on the individual level is important for prevention of disease before it is advanced and for modifying disability risk once disease is established.⁵⁸ In addition, the clinician has a critical role in case identification for the purposes of public health surveillance and appropriate work-related insurance compensation.

The key tool for identifying work-related factors that may be contributing to a patient’s COPD is the occupational exposure history. A detailed occupational history (see Table 2) consists of a chronological list of all jobs, including job title, a description of the job activities, potential toxins at each job, and an assessment of the extent and duration of exposure. The length of time exposed to the agent, the use of personal protective equipment such as respirators, and a description of the ventilation and overall hygiene of the workplace are helpful in attempting to quantify exposure from the patient’s history.

Table 2. Taking a Detailed Occupational History

References

1. National Heart Lung and Blood Institute. Morbidity and mortality: 1998 chart book on cardiovascular, lung and blood diseases. Hyattsville, MD: National Institutes of Health, 1998
2. Mannino DM, Brown C, Giovino GA. Obstructive lung disease deaths in the United States from 1979 through 1993: an analysis using multiple-cause
3. National Heart, Lung, and Blood Institute and World Health Organization. Global initiative for chronic obstructive lung disease: a collaborative project of the National, Heart, Lung, and Blood Institute and the World Health Organization. Bethesda, MD: National Institutes of Health, 2001
4. Bernstein IL, Chan-Yeung M, Malo J-L, et al. Definition and classification of asthma. In: Bernstein IL, Chan-Yeung M, Malo J-L, et al, editors. Asthma in the workplace. 2nd ed. New York, NY: Marcel Dekker, 1999; 1–4
5. Hendrick DJ. Occupation and chronic obstructive pulmonary disease. Thorax 1996; 51:947–955
6. Viegi G, Scognamiglio A, Baldacci S, et al. Epidemiology of chronic obstructive pulmonary disease (COPD). Respiration 2001; 68:4–19
7. Coggon D, Taylor AN. Coal mining and chronic obstructive pulmonary disease: a review of the evidence. Thorax 1998; 53:398–407
8. Hnizdo E, Baskind E, Sluis-Cremer GK. Combined effect of silica dust exposure and tobacco smoking on the prevalence of respiratory impairments among gold miners. Scand J Work Environ Health 1990; 16:411–422
9. Nakadate T, Aizawa Y, Yagami T, et al. Change in obstructive pulmonary function as a result of cumulative exposure to welding fumes as determined by magnetopneumography in Japanese arc welders. Occup Environ Med 1998; 55:673–677
10. Davison AG, Fayers PM, Newman-Taylor AJ, et al. Cadmium fume inhalation and emphysema. Lancet 1988; 1(8587):663–667
11. Irsigler GB, Visser PJ, Spangenberg PA. Asthma and chemical bronchitis in vanadium workers. Am J Ind Med 1999; 35:366–374
12. Becklake MR, Goldman HI, Bosman AR, et al. The long-term effects of exposure to nitrous fumes. Am Rev Tuberc Pulm Dis 1957; 76:398–409
13. Piirila PL, Nordman H, Korhonen OS, et al. A thirteen-year follow-up of respiratory effects of acute exposure to sulfur dioxide. Scand J Work Environ Health 1996; 22:191–196
14. Becklake MR. Chronic airflow limitation: its relationship to work in dusty occupations. Chest 1985; 88:606–617
15. Becklake MR. Occupational exposures: evidence for a causal association with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140:S85–S91
16. Love RG, Miller BG. Longitudinal study of lung function in coalminers. Thorax 1982; 37:193–197
17. Attfield MD. Longitudinal decline in FEV₁ in United States coalminers. Thorax 1985; 40:132–137
18. Attfield MD, Hodus TK. Pulmonary function of US coalminers related to dust exposure estimates. Am Rev Respir Dis 1992; 145:605–609
19. Seixas NS, Robins TG, Attfield MD, et al. Longitudinal and cross-sectional analyses of coal mine dust and pulmonary function in new miners. Br J Ind Med 1993; 50:929–937
20. Holman CD, Psaila-Savona P, Roberts M, et al. Determinants of chronic bronchitis and lung dysfunction in Western Australian gold miners. Br J Ind Med 1987; 44:810–818
21. Ulvestad B, Bakke B, Eduard W, et al. Cumulative exposure to dust causes accelerated decline in lung function in tunnel workers. Occup Environ Med 2001; 58:663–669
22. Meijer E, Kromhout H, Heederik D. Respiratory effects of exposure to low levels of concrete dust containing crystalline silica. Am J Ind Med 2001; 40:133–140
23. Kauffmann F, Drouet D, Lellouch J, et al. Occupational exposure and 12-year spirometric changes among Paris area workers. Br J Ind Med 1982; 39:221–232
24. Becklake MR. The workrelatedness of airways dysfunction. In: Proceedings of the 9th International Symposium in Epidemiology in Occupational Health. Rockville, MD: US Department of Health and Human Services, 1994; Publication No. 94-4445; 1–28
25. Becklake MR. Relationship of acute obstructive airway change to chronic (fixed) obstruction. Thorax 1995; 50:516–521
26. Becklake MR, Irwig L, Kielkowski D, et al. The predictors of emphysema in South African goldminers. Am Rev Respir Dis 1987; 135:1234–1241
27. Hnizdo E, Sluis-Cremer GK, Abramowits JA. Emphysema type in relation to silica dust exposure in South African gold miners. Am Rev Respir Dis 1991; 143:1241–1247
28. Cockcroft A, Seal AM, Wagner JC, et al. Postmortem study of emphysema in coalworkers and non-coalworkers. Lancet 1982; 2(8298):600–603
29. Ruckley VA, Fernie JM, Chapman JS, et al. Comparison of radiographic appearances with associated pathology and lung dust content in a group of coalworkers. Br J Ind Med 1984; 41:459–467
30. Leigh J, Driscoll TR, Cole BD, et al. Quantitative relation between emphysema and lung mineral content in coal workers. Occup Environ Med 1994; 51:400–407
31. Xu X, Christiani DC, Dockery DW, et al. Exposure-response relationships between occupational exposures and chronic respiratory illness: a community-based study. Am Rev Respir Dis 1992; 146:413–418
32. Viegi G, Prediletto R, Paoletti P, et al. Respiratory effects of occupational exposure in a general population sample in North Italy. Am Rev Respir Dis 1991; 143:510–515
33. Krzyzanowski M, Kauffmann F. The relation of respiratory symptoms and ventilatory function to moderate occupational exposure in a general population: results from the French PAARC study of 16,000 adults. Int J Epidemiol 1988; 17:397–406
34. Post WK, Heederik D, Kromhout H, et al. Occupational exposures estimated by a population specific job exposure matrix and 25 year incidence rate of chronic nonspecific lung disease (CNSLD): the Zutphen Study. Eur Respir J 1994; 7:1048–1055
35. Fishwick D, Bradshaw LM, D’souza W, et al. Chronic bronchitis, shortness of breath, and airway obstruction by occupation in New Zealand. Am J Respir Crit Care Med 1997; 156:1440–1446
36. Bakke P, Eide GE, Hanoa R, et al. Occupational dust or gas exposure and prevalence of respiratory symptoms and asthma in a general population. Eur Respir J 1991; 4:273–278
37. Humerfelt S, Gulsvik A, Skjaerven R, et al. Decline in FEV₁ and airflow limitation related to occupational exposures in men of an urban community. Eur Respir J 1993; 6:1095–1103
38. Krzyzanowski M, Jedrychowski W, Wysocki M. Factors associated with the change in ventilatory function and the development of chronic obstructive pulmonary disease in a 13-year follow-up of the Cracow study. Am Rev Respir Dis 1986; 134:1011–1019
39. Sunyer J, Kogevinas M, Kromhout H, et al. Pulmonary ventilatory defects and occupational exposures in a population-based study in Spain. Am J Respir Crit Care Med 1998; 157:512–517
40. Lebowitz MD. Occupational exposures in relation to symptomatology and lung function in a community population. Environ Res 1977; 14:59–67
41. Korn RJ, Dockery DW, Speizer FE, et al. Occupational exposures and chronic respiratory symptoms: a population-based study. Am Rev Respir Dis 1987; 136:298–304
42. Pesci A, Balbi B, Majori M, et al. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 1998; 12:380–386
43. Jeffrey PK. Comparison of the structural and inflammatory features of COPD and asthma. Chest 2000; 117:251S–260S
44. O’Shaughnessy TC, Ansari TW, Barnes NC, et al. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse realtionship of CD8+ T lymphocytes with FEV₁. Am J Respir Crit Care Med 1997; 155:852–857
45. Saetta M, Di Stefano A, Turato G, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:822–826
46. Maestrelli P, Del Prete GF, De Carli M, et al. CD-8 T-cells producing interleukin-5 and interferon-gamma in bronchial mucosa of patients with asthma induced by toluene diisocyanate. Scand J Work Environ Health 1994; 20:376–381
47. Shore S, Kobzik L, Long NC, et al. Increased airway responsiveness to inhaled methacholine in a rat model of chronic bronchitis. Am J Respir Crit Care Med 1995; 151:1931–1938
48. Churg A, Hobson J, Wright J. Functional and morphologic comparison of silica- and elastase-induced airflow obstruction. Exp Lung Res 1989; 15:813–822
49. Bonner JC, Rice AB, Moomaw CR, et al. Airway fibrosis in rats induced by vanadium pentoxide. Am J Physiol (Lung Cell Mol Physiol) 2000; 278:L209–L216
50. Harkema JR, Hotchkiss JA. Ozone- and endotoxin-induced mucous metaplasia in rat airway epithelium: novel animal models to study toxicant-induced epithelial transformation in airways. Toxicol Lett 1993; 68:251–263
51. Putulainen E, Tornling G, Erickson S. Effect of age and occupational exposure to airway irritants on lung function in nonsmoking individuals with severe a1-antitrypsin deficiency (PiZZ). Thorax 1997; 52:244–248
52. Mayer AS, Stoller JK, Bucher-Bartelson B, et al. Occupational exposure risks in individuals with PI*Z a1-antitrypsin deficiency. Am J Respir Crit Care Med 2000; 162:553–558
53. Shapiro, SD. Animal models for COPD. Chest 2000; 117:223S–227S
54. Balmes J, Becklake M, Blanc P, et al. Occupational contribution to the burden of airway disease (an official statement of the American Thoracic Society). Am J Respir Crit Care Med 2003; 167:787–797
55. Hnizdo E, Sullivan PA, Bang KM, et al. Association between chronic obstructive pulmonary disease and employment by industry and occupation in the U.S. population: a study of data from the Third National Health and Nutrition Examination Survey. Am J Epidemiol 2002; 156:738–746
56. Trupin L, Earnest G, San Pedro M, et al. The occupational burden of chronic obstructive pulmonary disease. Eur Respir J 2003; 22:462–469
57. Leigh JP, Romano PS, Schenker MB, et al. Costs of occupational chronic obstructive pulmonary disease and asthma. Chest 2002; 121:264–272
58. Petty TL, Weinmann GG. Building a national strategy for the prevention and management of and research in chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute workshop summary. JAMA 1997; 277:246–253
59. Friedman-Jimenez G, Beckett WS, Szeinuk J, et al. Clinical evaluation, management, and prevention of work-related asthma. Am J Ind Med 2000; 37:121–141
60. Venables KM. Prevention of occupational asthma. Eur Respir J 1994; 7:768–778
61. Balmes JR. Surveillance for occupational asthma. Occup Med 1991; 6:101–110