Update in Occupational and Environmental Respiratory Disease 2007 Tim S. Nawrot1, Ernesto Alfaro-Moreno1,2, and Benoit Nemery1 1 2
School of Public Health, Occupational and Environmental Medicine, Unit of Lung Toxicology, K.U. Leuven, Leuven, Belgium; and Investigacio´n Ba´sica, Instituto Nacional de Cancerologı´a, Mexico, DF, Mexico
Several original epidemiologic studies showing associations between specific environmental or occupational exposures and adverse respiratory effects were published in 2007. Such studies in large populations often rely, by necessity, on crude endpoints, such as mortality, respiratory symptoms obtained by questionnaires, or simple pulmonary function measurements. Although such observational studies may point to causal links between (presumed) exposure and disease, they must be completed by further epidemiologic studies that use more refined endpoints and/or more sophisticated designs, and by experimental studies that are needed to provide plausibility as well as mechanistic explanations for the observed findings. Thus, in an editorial, Kaufman (1) pointed to the importance to integrate epidemiologic and toxicology approaches to elucidate the mechanism of the effects of air pollution on health.
OUTDOOR AIR POLLUTION Although air pollution consists of a heterogeneous mixture of gases and particles, most recent research has concentrated on the adverse effects of particulate matter (PM). PM consists of primary particles, such as diesel soot or other combustion-derived particles, which are emitted directly into the atmosphere, and secondary particles, which are created in the atmosphere through complex physicochemical transformation of gases. Airborne PM is generally defined on the basis of the size distribution of the particles. Thus, PM10 and PM2.5 stand for PM with median aerodynamic diameters of less than 10 mm and 2.5 mm, respectively. Ultrafine particles have a diameter of less than 100 nm (0.1 mm). These particles exhibit a high rate of deposition in human alveoli. Risk groups have been clearly identified, including children, elderly people, and those with preexisting cardiopulmonary diseases. During the past year, a number of studies strengthened previous observations (2, 3) suggesting that exposure to trafficrelated air pollution adversely affects the airways, especially in children. In a panel study of 200 children living in a Mexican town close to the U.S. border, Holguin and coworkers observed that FEV1 and exhaled NO were associated with the distance of a major road from school among the children with asthma (4). These observations are in line with those of McCreanor and colleagues (5), who examined, in adults with asthma, the functional and inflammatory effects of short-term real-life exposure to roadside diesel traffic. They showed that walking for 2 hours along a street where only diesel-powered vehicles were permitted (Oxford Street in London) resulted in a significant (though (Received in original form January 17, 2008; accepted in final form January 17, 2008) T.S.N. is a fellow of the Flemish Scientific Fund; E.A.M. is a fellow of the Belgian Science Policy. Correspondence and requests for reprints should be addressed to Prof. Benoit Nemery, M.D., Ph.D., Laboratory of Pneumology, K.U. Leuven, Laboratorium voor Pneumologie (Longtoxicologie), Herestraat 49, B 3000 Leuven, Belgium. E-mail:
[email protected] Am J Respir Crit Care Med Vol 177. pp 696–700, 2008 DOI: 10.1164/rccm.200801-116UP Internet address: www.atsjournals.org
asymptomatic) reduction in lung function, whereas this did not occur when walking in a nearby urban park. These functional alterations were accompanied by inflammatory changes in sputum and exhaled breath condensate. In a cohort of 3,170 children from Mexico City aged 8 years at baseline and followed during 3 years, Rojas-Martinez and colleagues (6) showed an annual deficit in FEV1 of 11 ml in girls and 15 ml in boys for an increase of 36.4 mg/m3 (interquartile range, 24-h PM10 means averaged over 6 mo) in PM10. These observations are compatible with those observed in a longitudinal study of 3,677 Southern California children (7), indicating that living close to freeways negatively affects lung development in children. Children living within 500 m of a freeway had substantial deficits in 8-year lung growth as measured by FEV1 (281 ml/s) and maximum midexpiratory flow rate (2127 ml/s) compared with children living at least 1,500 m from such roads (7). In agreement with this finding, a large cross-sectional study of more than 15,000 adults showed that traffic density and distance to major roads were inversely related with FEV1 and FVC in women (8). Conversely, recent prospective data (with median follow-up of 11 yr) of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) show that improvement in air quality may slow the annual rate of decline in lung function in adulthood (6). One of the most impressive aspects of the initial Harvard Six Cities study (9) and other studies (reviewed in References 10–12) is that the risk of death associated with exposure to air pollution is higher for cardiac diseases than for all other causes, including lung diseases. The mechanisms for these acute and chronic cardiovascular effects of inhaled pollutants have not yet been entirely elucidated, but the lungs are likely to play an important role, presumably via PM-induced pulmonary inflammation. In other words, the lungs are not merely a portal of entry for pollutants, they probably also mediate cardiovascular responses. Using a panel approach, Chuang and colleagues (13) linked particulate levels in the air with markers of inflammation (Creactive protein [CRP], 8-hydroxy-29-deoxyguanosine), coagulation (plasma plasminogen activator fibrinogen inhibitor [PAI]-1 and tissue type plasminogen activator), and heart rate variability measured in 76 university students who were examined on three occasions about 4 weeks apart. Not all markers rose consistently at the same time. For example, CRP, PAI-1, and fibrinogen were associated with the averaged 24-hour PM10 level, whereas heart rate variability was associated with 1- to 3-day averaged PM10 concentrations. The strength of this study is that it shows that, even in healthy young subjects, preclinical effects of particulate air pollution can be demonstrated. Although such subclinical effects are unlikely to have any serious immediate consequences in young healthy subjects, they may, if repeated or sustained, contribute to excess cardiovascular morbidity and mortality in later life. Thus, Miller and colleagues (14) found, in a longitudinal follow-up of postmenopausal women, that a higher annual average PM2.5 of 10 mg/m3 near one’s residence was associated with a 24% increase in the risk of developing a first-time cardiovascular event and a 76% increase in the risk of any death
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from a cardiovascular cause. Mills and coworkers (15) also showed clinically important ECG alterations in men who had had a myocardial infarction and who were studied during exercise while exposed to diluted diesel exhaust in an exposure chamber. Different mechanisms have been proposed to explain the cardiovascular effects of particulate exposure, but endothelial dysfunction seems to be a common event. In vitro and in vivo studies have shown that PM is capable of inducing the expression of adhesion molecules, such as E-selectin (16), P-selectin, intercellular adhesion molecules (ICAM), vascular cell adhesion molecules (VCAM), and platelet endothelial cell adhesion molecules (PCAM) (17, 18). Nemmar and associates (17) showed that neutralization of P-selectin abrogates the procoagulant effect in mice exposed by intratracheal instillation to carbon nanotubes, whereas Nurkiewicz and colleagues (19) showed systemic microvascular dysfunction in rats exposed to residual oil fly ash. In this context, To¨rnqvist and coworkers (20) presented a study where humans were exposed to diesel exhaust (300 mg/m3) or filtered air during 1 hour using a randomized, double-blind, crossover design. No significant differences were observed in the hemodynamic variables (heart rate, blood pressure, infused and noninfused forearm blood flow) measured 24 hours after exposure. However, exposure to diesel exhaust induced a selective and persistent impairment of endothelium-dependent vasodilation. This occurred concomitantly with a mild systemic inflammatory pattern (increases in tumor necrosis factor [TNF]-a, IL-6) related to oxidative stress (Trolox equivalent antioxidant capacity). The exposure to diesel exhaust did not only involve the particulate fraction but also the gases, the correlation between inflammatory markers (TNF-a and IL-6), adhesion molecules (soluble P-selectin), and vasodilatation; however, previous experimental evidence suggests that the particulate fraction plays a main role (16–19). Gaseous compounds such as ozone also exert potent effects on the respiratory tract. Different studies have shown increases in mortality between 0.39 and 0.87% for each 10-ppb increase in 1-hour daily maximum of O3, This association persists with increased mortality at levels of ambient O3 below the current U.S. Environmental Protection Agency standard. Innate immunity appears to play an important role in the susceptibility to O3 (21). This has been studied especially in relation to Toll-like receptors (12). In relation to this, Cho and colleagues (22) studied the signal transduction pathways of TNF in a mouse model of ozone injury, using mice deficient in TNF receptor (TNFr2/2). The main observation was that the nuclear factor (NF)-kB and mitogenactivated protein kinase (MAPK)/AP-1 pathways are the main components of the TNF-mediated injury by O3. Both pathways presented a significantly lower activation in the TNFr2/2 in comparison to the TNFr1/1 mice. However, because the NF-kB and MAPK/AP-1 pathways were activated even in the TNFr2/2 animals, other receptors are also activated after O3 exposure.
INDOOR AIR POLLUTION Although the effects of outdoor air pollution on morbidity and mortality have been widely studied, in industrially developed countries most people, especially the elderly, spend most of their time indoors. The impact of the domestic indoor environment has been more difficult to investigate, partly because of a presumed large variation in exposure levels between different individuals. The main merit of the study of Osman and coworkers (23) is that they were able to assess indoor levels of PM2.5 and NO2 in the homes of 148 elderly patients with severe chronic obstructive pulmonary disease (COPD). The authors noted an association
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between poorer health status, as assessed by the St. George’s Respiratory Health Questionnaire, and indoor PM2.5 levels, which were mainly driven by the presence of smokers in the home. Interestingly, Brauner and colleagues (24) investigated the effects of lowering particulate levels in the homes of 21 elderly couples and found that indoor air filtration for 48 hours significantly improved microvascular function in these subjects. Indoor pollution by tobacco smoke does not only occur in the home; it represents an occupational hazard for various categories of workers, most notably those of the hospitality industry, at least in areas where smoking is allowed in this sector. Although local or regional authorities had previously instituted more or less comprehensive bans on smoking in public places, in 2004 Ireland became the first country to prohibit smoking in all indoor workplaces, including in restaurants and bars. Since 2004, more countries including Norway, New Zealand, Uruguay, Malta, Italy, Sweden, Scotland, Bhutan, Lithuania, and the British Virgin Islands have gone smoke free (25). Goodman and coworkers (26) assessed pulmonary function and measured exhaled breath carbon monoxide and salivary cotinine concentrations in 81 Irish barmen before the ban and repeated these measurements 1 year after the ban. They documented an 83% reduction in fine particulate matter—although the reduction was probably much higher (27)—and an 80% reduction in benzene concentrations in the pubs, together with a 79% reduction in exhaled breath carbon monoxide and an 81% reduction in salivary cotinine among nonsmoking pub workers. The authors further observed a significant improvement in FVC (92% predicted to 95% predicted) but not in FEV1 (26). A similar study (28) did show an increase in FEV1 after the ban. In that study, asthmatic bar workers also had reduced airway inflammation and improved quality of life (28). These and other studies clearly indicate a beneficial effect of comprehensive smoking bans for bar workers (29). A much less studied source of indoor pollution of the domestic environment consists of the array of chemical products used for cleaning in the home. Many of these products have potent irritant properties and have been known to be capable of causing clinically severe inhalation injuries, as seen, for example, after mixing bleach with ammonia (i.e., mixing incompatibilities). Moreover, there has been an increasing trend to sell these consumer products as sprays, which probably increases the likelihood and extent of inhalation exposure. In follow-up of a series of studies that had shown a higher risk of asthma in women exposed to cleaning products through their work (30), Zock and associates (31) investigated the incidence of new asthma symptoms, use of asthma medication, and reported physician-diagnosed asthma in 3,504 adults drawn from the multicenter European Community Respiratory Health Survey (ECRHS). These subjects had no evidence of asthma at their first examination (baseline), and they were examined again 9 years later, on average. The nonprofessional use of cleaning sprays at least once a week significantly increased the risk of new-onset asthma symptoms or medication use (relative risk [RR], 1.49) and wheeze (RR, 1.39), irrespective of atopy. The risk of physician-diagnosed asthma was doubled (RR, 2.11) in frequent users of cleaning sprays (at least 4 d/wk). The findings suggested that one in seven incident cases of asthma could be attributed to common spray use. Cleaning products not applied in spray form did not show associations with the incidence of asthma. A problematic issue in the study is that the findings could not be entirely corroborated when bronchial hyperreactivity was used as an endpoint. This study represents an important contribution to the issue of the role of common environmental exposures in the causation of asthma (32). It remains to be investigated whether sprayed cleaning agents induce asthma symptoms as a result of their irritant properties or whether specific immunologic sensitization also plays a role.
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OCCUPATIONAL RESPIRATORY DISEASE Concerns about occupationally related respiratory disease also apply to occupations where workers are exposed to chemicals with irritant and sensitizing properties, including cleaning agents. This is especially relevant for health care workers (33). Thus, Delclos and colleagues (34) performed a cross-sectional questionnaire study of a large number (3,650 in total) of physicians, nurses, respiratory therapists, and occupational therapists selected to represent the health care professionals working in Texas hospitals. Occupational exposures were determined on the basis of a job-exposure matrix developed for studying asthma risk factors. Reported asthma was significantly associated with cleaning medical instruments (odds ratio [OR], 2.22), general cleaning (OR, 2.02), use of powdered latex gloves in the 1990s (OR, 2.17), and administration of aerosolized medications (OR, 1.72). Symptoms of bronchial hyperresponsiveness were also associated with general cleaning (OR, 1.63), administration of aerosolized medication (OR, 1.40), and exposure to a chemical spill (OR, 2.02). In the ECRHS, nursing was also identified as an occupation with a significantly increased risk of adult-onset asthma (35, 36). Overall, the population-attributable risk for adult asthma due to occupational exposure was estimated at 10 to 25%, corresponding to 250 to 300 new cases of work-related asthma per million people per year, with acute inhalation incidents appearing to represent a significant risk factor (35). That exposure to workplace irritants may induce prolonged respiratory symptoms was also shown by a survey of workers who had been involved in cleaning up a major oil spill on the northwestern coast of Spain (37). Data from 6,780 fishermen indicated that excess lower respiratory tract symptoms could persist for up to 2 years after the clean-up operations. Although the risk of respiratory symptoms showed a convincing relation with exposure intensity, these findings are intriguing because the concentrations of irritant chemicals to which these clean-up workers were exposed were unlikely to have been very high, at least in comparison to workers handling oil-derived chemicals on a regular basis. Although the above studies point to a role of domestic or workplace irritants in the induction of asthma, ‘‘true’’ occupational asthma is often considered by clinicians to be due to specific sensitization to high-molecular-weight or low-molecular-weight agents (38). Of the latter agents, isocyanates are the most frequently involved. However, despite numerous studies, many questions still remain open, such as the risk factors and mechanisms of sensitization and occupational asthma caused by isocyanates. Pronk and coworkers (39) studied 581 workers from 128 companies of the spray-painting industry, where paints containing hexamethylene diisocyanate are widely used. Exposure– response relationships were found for both work-related asthma symptoms and non–work-related COPD-like symptoms, and for specific sensitization to isocyanate. However, as in many other studies of isocyanate asthma, specific IgE sensitization was rare (0.4 to 4% in spray painters). Environmental and occupational agents may also contribute to COPD. Mostly, these agents consist of complex aerosols of nonspecific particulates and fumes, such as those emitted from burning wood or other biomass. This type of domestic exposure is particularly relevant in less affluent countries, as shown by recent studies on the epidemiology of COPD in China (40, 41). As summarized by Tore´n and Balmes (42), occupational exposures to dusts and fumes are also important contributors to COPD. In a nice analysis of the data of 5,724 participants in the Lung Health Study, Harber and associates (43) showed that ongoing exposure to fumes at work was associated with a more rapid decline in FEV1 in men with COPD.
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COPD may be a misnomer in a number of patients. In some cases, obstructive impairment may in fact be due to (occupational) bronchiolitis obliterans, as in ‘‘popcorn worker’s lung’’ (44). This condition was first described in workers from microwave popcorn plants in the United States, and the causal agent was tentatively identified as diacetyl, one of the many volatile components of butter flavoring. An important independent confirmation of the implication of diacetyl has come from a retrospective study of workers from a Dutch chemical company that produced diacetyl between 1960 and 2003 (45). Among 102 investigated process operators, three cases were identified by pulmonary function testing and high-resolution computed tomography as having bronchiolitis obliterans. A fourth case was discovered after completion of the actual survey. All these cases were initially diagnosed as having COPD, even though two of them were life-long nonsmokers. A widely publicized case of bronchiolitis obliterans in a heavy consumer of microwave popcorn has now led to the removal of butter flavoring from popcorn. The diacetyl story is a tragic illustration that chemicals, even those generally regarded as safe (i.e., chemicals that may be included in food), should not be considered safe when inhaled unless this has been properly demonstrated by adequate inhalation studies. Occupational respiratory disease may also affect the lung parenchyma. Asbestosis is an interstitial lung disease that has many features of idiopathic pulmonary fibrosis. This is why asbestos is often used to investigate the pathogenesis of fibrotic lung disease. Various growth factors (i.e., TNF-a, platelet-derived growth factor [PDGF], transforming growth factor-b), reactive oxygen species, and signal transduction pathways (i.e., MAPK) have been investigated (46–48). To evaluate the role of bone marrow progenitor cells in the development of pulmonary fibrosis, Spees and colleagues (49) used an asbestos-exposure model in which female rats were irradiated to eliminate the bone marrow, and then transplanted with bone marrow obtained from male rats. The bone marrow from the male rats had a constitutive expression of green fluorescent protein. Animals that were confirmed as chimeric were exposed to asbestos and the fibrotic lesions were evaluated at the bronchiolar–alveolar bifurcations. The animals exposed to asbestos presented typical asbestos lesions 1 day and 2.5 weeks after the last exposure. The lesions in the chimeric animals had a large proportion of green fluorescent protein– positive cells, indicating participation of bone marrow–derived cells in the developing fibrosis. These results open the opportunity to evaluate the mechanisms of recruitment and migration of bone marrow–derived cells into the areas of damaged lung. Hard metal lung disease is a rare occupational interstitial lung disease (50). As summarized in an editorial (51), the pathogenesis of this disease has not been elucidated, particularly its unique pathologic features of giant cell interstitial pneumonitis (GIP), although the notion that GIP is pathognomonic for hard metal lung has been questioned (52). Moriyama and coworkers (53) produced a remarkable study of the lung pathology of 23 patients diagnosed with GIP. Using a sensitive electron probe microanalysis they showed the preferential presence of tungsten (an essential component, besides cobalt, of hard metal) in the fibrotic areas of the lung, and using immunohistochemistry they provided interesting clues that macrophages may be instrumental in the pathogenesis of this intriguing disease. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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