Pulmonary, Sleep, and Critical Care Updates

Update in Environmental and Occupational Medicine 2011

Anders Blomberg1
1

University, Umea , Sweden Department of Public Health and Clinical Medicine, Division of Medicine, Umea

As of consequence of rapid urbanization all over the world, more intense energy consumption gives rise to increased emissions from transport and industrial sources. Thus the human airways are exposed to an increased quantity as well as a more diverse variety of ambient air pollution, which causes increased incidence of airway disease (1). However, the cardiovascular effects of exposure to air pollution have been further emphasized, especially in sensitive subpopulations, and the increase in chronic cardiorespiratory diseases is probably one of the most important mechanisms for the reduction in life expectancy associated with exposure to air pollution (2). Furthermore, an association between air pollution and the development of lung cancer has been put forward, as diesel exhaust has been classied as a probable lung carcinogen (3). In this update, the more recent publications in this journal within the eld of environmental and occupational medicine are highlighted along with other work within this research area.

AIR POLLUTION
Particulate Matter

Air pollution, primarily of trafc-related sources, is related to increased cardiovascular morbidity and mortality. The main underlying mechanisms behind these adverse health effects are still not fully understood, but a series of clinical experimental exposure studies employing diesel exhaust have suggested endothelial dysfunction and reduced NO bioavailability, as a consequence of increased vascular oxidative stress. It has thus been suggested that exposure to particulate matter has the potential to impair vascular reactivity, accelerate atherogenesis, and precipitate acute adverse thrombotic events (4). Particulate matter and cardiorespiratory disease. Lund and coauthors (5) aimed to elucidate the role of oxidized low-density lipoprotein (oxLDL) and its receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in the regulation of endothelin-1 (ET-1) expression and matrix metalloproteinase (MMP) activity after exposure to vehicular engine emissions. Atherosclerotic ApoE2/2 mice were exposed to a mixture of gasoline and diesel exhaust, and healthy human volunteers were exposed to 100 mg of particulate matter (PM) per cubic meter of diesel exhaust; both exposure scenarios were compared with ltered air. In mice, exposure to the mixed air pollution emission increased oxLDL and vascular reactive oxygen species, as

(Received in original form February 24, 2012; accepted in nal form April 12, 2012) Correspondence and requests for reprints should be addressed to Anders Blomberg, M.D., Ph.D., Department of Public Health and Clinical Medicine, Division of Medicine, University, SE-90187 Umea , Sweden. E-mail: anders.blomberg@lung.umu.se Umea
Am J Respir Crit Care Med Vol 185, Iss. 11, pp 11661170, Jun 1, 2012 Copyright 2012 by the American Thoracic Society DOI: 10.1164/rccm.201202-0324UP Internet address: www.atsjournals.org

well as LOX-1, MMP-9, and ET-1 mRNA expression, along with enhanced monocyte/macrophage inltration into the vascular walls. Each of these responses was attenuated when LOX-1 antibody treatment was given. In the human part of the study, exposure to diesel exhaust signicantly increased soluble LOX-1 (sLOX) in plasma. Taken together, these data indicate that LOX-1 may play an important role in mitigating systemic vascular effects of combustion-derived emissions and that sLOX may serve as a novel biomarker in the risk assessment of air pollution exposure. Also, the increase in LOX-1mediated expression of MMP, as a novel predictor of cardiovascular mortality, may suggest a link between air pollution and increased cardiovascular events. Oxidized LDL has also been addressed in a Belgian study by Jacobs and colleagues (6), who have related distance of residence from major roads and carbon load of airway macrophages with plasma oxidized LDL in a nonsmoking group of patients with diabetes. They found a positive association between the markers of trafc-related air pollution exposure and plasma levels of oxidized LDL, a marker of early atherosclerosis. On the basis of this nding they imply a mechanistic plausibility to the hypothesis that air pollution exposure may accelerate the development of atherosclerosis. Furthermore, in Indian women using biofuel for cooking, Dutta and colleagues (7) reported high concentrations of particulate matter pollution in kitchens, together with a positive association with elevated oxidized LDL, indicating that PM arising from biomass would also be a cardiovascular risk factor. In a large study of approximately 100,000 California teachers, individualized long-term exposure to air pollution was related to incident myocardial infarction and stroke (8). Individual exposure to particulate matter less than 10 mm in aerodynamic diameter (PM10), PM2.5, ozone, and nitrogen oxides (NOx) was estimated using geocoding of the residential addresses and linked to governmental mortality and hospitalization les, with median durations of follow-up between 5.6 and 8.3 years. An increment of 10 mg/m3 in PM2.5 was associated with elevated hazard ratios (HRs) for mortality from ischemic heart disease (HR, 1.20) and incident stroke, particularly among postmenopausal women (HR, 1.19). Long-term exposure to PM10 was also associated with elevated risks for ischemic heart disease mortality and incident stroke (HR for both, 1.06). Exposure to NOx was related to elevated risks for ischemic heart disease and all cardiovascular mortality. One great advantage in this study is the low prevalence of current smoking (only 5%) of the participants. The study indicates slightly greater associations between ischemic heart disease mortality and PM2.5 and NOx in never-smokers and supports the notion that long-term exposure to air pollution may play a role in the development of cardiovascular disease. In a Chinese study (9), similar results were reported, with an even stronger association between long-term exposure to ambient air pollution and cardiovascular disease. The authors found an increase of 10 mg/m3 in PM10 to be

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associated with a 55% increase in the risk of death from cardiovascular disease, after adjusting for important confounders such as smoking, occupational exposure, and so on. They found that females, nonsmokers, and subjects with a body mass index less than 18.5 were more vulnerable to outdoor air pollution. Although a considerable decrease in background PM10 concentrations has been found in China over the last 10 years, it is important to note that the PM level in this study was approximately three to four times higher compared with the Lipsett study (8). In contrast, a similar Japanese study was not able to detect any association between long-term exposure to particulate matter and cardiovascular mortality (10). Here, the average PM concentrations were much lower (mean, approximately 35 mg/m3) than in the Chinese investigation and more similar to the U.S. situation. The hazard ratio per 10-mg/m3 increase in annual PM concentration was 0.98. The authors speculate about the reasons behind the lack of an association and imply that chemical composition of ambient particles and differences in cardiovascular disease pattern and study designs may contribute to the variation in results compared with preferentially North American and European studies. Particulate matter and lung cancer. Although there is compelling evidence of an association between exposure to ambient ne PM (PM2.5) and increased cardiorespiratory mortality, the role of PM2.5 in the etiology of lung cancer is less clear. In the study by Turner and coworkers (11), the association between longterm ambient PM2.5 levels and lung cancer was addressed among almost 190,000 never-smokers. As each 10-mg/m3 increase in PM2.5 level was related to a 1527% increase in lung cancer mortality in both males and females, the authors suggest a small but measureable PM-related increase in lung cancer mortality. Furthermore, in a Danish study, support was found for an association between increased lung cancer risk and various markers of trafc-related air pollution such as NOx concentrations and living close to a major road, with stronger associations among nonsmokers (12). In a large pooled study by Olsson and colleagues (3), in which the relationship between lung cancer risk and occupational exposure to diesel exhaust was investigated, a consistent association was found with an odds ratio of 1.3 in the highest exposure quartile compared with nonexposed. In this cohort, no difference in risk estimate was found for nonsmall-cell versus smallcell lung carcinoma. Similar ndings are reported in a Chinese study by Tse and colleagues (13), who found an increased lung cancer risk in nonsmoking workers occupationally exposed to diesel exhaust (odds ratio, 3.47). An important issue that is acknowledged in the Olsson paper (3) is the shift toward modern engines with low-sulfur fuels and the use of particle traps. Yet the number of emitted particles may still be high and, because of the robustness of diesel engines, older technology will still be used for many years. In an editorial comment by Laumbach and Kipen (14), some important study issues are raised: the lack of quantitative measurement of diesel exhaust exposure and the potential confounding by smoking. However, they conclude that there is now evidence that supports the carcinogenicity of diesel exhaust and that the widespread occupational and community exposures to diesel exhaust have public health signicance. Effect of trafc exposure on parental stress and chronic obstructive pulmonary disease. It is known that exposure to trafc-related air pollution is associated with asthma incidence, prevalence, exacerbations, and lung function decits. In addition, psychosocial stress affects the risk of asthma related to trafc exposure in children. In a study published in this journal, Islam and coauthors (15) hypothesized that children exposed to high levels of chronic stress would be more susceptible to

the detrimental effects of trafc-related air pollution on lung function. Psychosocial stress was based on parental responses to the perceived stress scale and the concentration of NOx was used as a surrogate of trafc-related air pollution mixture. It was found that children growing up in household with high levels of psychosocial stress were more susceptible to the detrimental effects of exposure to trafc-related air pollution compared with children from homes with less parental stress. As a potential explanation for this nding, the authors put forth the biological pathways by which both exposure to trafcrelated air pollution and psychosocial stress have been linked to oxidative stress and inammation. In an editorial, Wright (16) addresses one of the shortcomings of the present study, that is, that parental stress is assessed only once and that repeated assessments or more comprehensive measurements of life events and chronic stressors are important. However, Wright agrees with the authors that a more direct assessment of stress experienced by the children would be more appropriate, yet difcult in small children. Although cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD) development, occupational and environmental factors are increasingly believed to play important roles. In a Danish prospective cohort study, Andersen and colleagues (17) assessed the effects of trafc-related air pollution exposure (determined as annual mean levels of NO2 and NOx) over 35 years on COPD incidence, dened as rst-ever hospital admission for COPD. The authors report a positive association between 35-year exposure to NO2 and NOx and the incidence of COPD. Furthermore, they found that the effect of trafc-related air pollution was strongest in people with diabetes and asthma, suggesting that patients with these diseases may be more vulnerable to the negative effects of air pollution, leading to an increased risk of COPD development. Wood smoke and solid biomass fuel exposure. Residential wood combustion is an important source of ambient particulate matter pollution in many communities. In a review and meta-analysis published in Thorax, it is well recognized that exposure to biomass fuel emissions is associated with signicant risks for acute respiratory infections in children and chronic bronchitis and COPD in women (18). In contrast, there is limited evidence about the impact of wood smoke on cardiovascular health. However, it is hypothesized that particulate matterinduced oxidative stress, systemic inammation, and endothelial dysfunction are important underlying mechanisms. Allen and coworkers (19) addressed the underlying effects on oxidative stress, endothelial dysfunction, and systemic inammation of residential wood smoke exposure and evaluated the effects of portable air lters in a study of 45 healthy subjects. They found that the highefciency particulate air (HEPA) lters reduced the indoor ne particle concentration by 60% (from approximately 11 to 4 mg of PM2.5/m3), which was associated with improved endothelial function (measured as reactive hyperemia index) and decreased systemic inammation (decreased C-reactive protein). In contrast, no lter-associated effects on oxidative stress, determined as malondialdehyde or 8-isoprostane, were found. The authors suggest a link between a wood smokeimpacted air shed and systemic inammation along with impaired endothelial function. Given these results, they imply that the cardiovascular effects produced by exposure to indoor wood smokerelated particulate matter pollution may be favorably inuenced by a reduction of particle concentrations. It should, however, be noted that the indoor levels of PM were quite low in the present study. In homes using biomass fuels for cooking and heating, indoor levels of several thousand micrograms per cubic meter can be exceeded (20).

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Ozone

Ozone, as a major component of photochemical smog, is know to induce lung function decrements and airway inammation after exposure to relatively high concentrations (0.10.4 ppm) for short time periods (usually 2 h), even if an increased airway inammatory response has been reported at concentrations as low as 0.08 ppm. As the current U.S. National Ambient Air Quality Standard (NAAQS) is 0.075 ppm over 8 hours, Kim and coworkers (21) performed a study in which healthy volunteers were exposed to 0.06 ppm of ozone for 6.6 hours during intermittent moderate exercise. To address whether the ozone-induced responses were more pronounced in potentially susceptible individuals, half of the subjects had the glutathione S-transferase m1 null genotype (GSTM1-null) and were thus believed to have reduced antioxidant defenses. The study showed that exposure to 0.06 ppm of ozone for 6.6 hours caused a small (1.71%) but signicant decrement in FEV1 and increased neutrophilic airway inammation, as shown in induced sputum. No signicant modication of the effects was seen between the two GSTM1 genotypes in this study group. The authors imply that the GSTM1-null genotype group may need to be present with other genotypes (NQO1 and GSTP1) or that there may be individuals or subpopulations with enhanced sensitivity (such as those with asthma) at these low ozone levels. On the basis of the message of this paper with lung function and airway inammatory responses below the current NAAQS, Frampton (22) raises the question of whether there is a safe threshold concentration for air pollutants, as the levels at which effects are seen are now approaching background levels (0.0150.045 ppm). In this context, many considerations must be undertaken, out of which the multipollutant approach is of interest and is discussed later in this review. As little is known about the effects of chronic exposure to ozone and survival in susceptible populations, Zanobetti and Schwartz (23) investigated whether long-term exposure to ozone would be associated with reduced survival in a cohort with chronic conditions that might predispose negative ozonerelated health effects, that is, patients with COPD, diabetes, congestive heart failure, and myocardial infarction. The study population comprised residents aged 65 years and older within the U.S. Medicare program. The authors reported a signicant association with a hazard ratio for mortality of between 1.06 and 1.09 per 5-ppb increase in summer average ozone concentrations for all these conditions. The effects of ozone exposure varied by residence region, which was explained mostly by variations in mean temperature. Of importance, not only long-term exposures, but also year-to-year uctuations, inuenced survival. The authors put forth some limitations of the study such as the lack of control for PM2.5 concentrations as well as the absence of information on underlying cause of death and subject characteristics. However, the study indicates that long-term ozone exposure is associated with increased risk of death in patients older then 65 years within these disease groups, even if more studies are needed on this issue. In an editorial, Ito (24) implies that the study design used in the Zanobetti and Schwartz study captured not only the long-term effects occurring within the same year, but also the accumulation of shortterm effects. The use of the model in the present study will be of importance in future explorations of the time scale of associations between ozone and mortality.
Multipollutant Exposure

traditionally been employed to study one pollutant at a time. Although this approach has a number of limitations, there is no clear consensus as to what a so-called multipollutant approach would involve. Using a multipollutant model including PM, SO2, and NO2, Hart and coworkers (25) performed a study in more than 53,000 men, in which concurrent occupational exposure was also acknowledged. They reported that PM10, PM2.5, SO2, and NO2 were all independently associated with all-cause mortality (with a 38% increased risk) and that enhanced associations between the latter two also were found with cardiovascular and respiratory disease. None of these pollutant effects were confounded by occupational exposure. When using a multipollutant model, the associations were attenuated, most strongly for PM, but remained positive for NO2, which may indicate that trafc is an important source of residential ambient air pollution exposure. Vedal and Kaufman (26) commented on this paper in an editorial. They imply that the central aspect of a new multipollutant approach to air pollution epidemiology would be to attempt to model complex air pollution mixture effects more explicitly to gain better insight into the features of an air pollution mix that are most toxic. Possible approaches here, yet with specicity problems, would be to reect pollution sources rather than the specic pollutant and to use chemical components as markers of source. Problems include available data on only a part of the air pollutant mix and that pollutant interactions cannot be addressed. Thus the issue of employing a multipollutant exposure scenario is not easy, as it will require measurements of a rich array of air pollutants and application and development of more suitable statistical methods. However, increased knowledge in this eld would yield a better understanding of the features of a complex air pollution mixture that are most deleterious to health and, thus, of signicant importance in understanding the complexity of ambient air pollution exposure.
Long-Term Respiratory Symptoms and Lung Function

It is well known that the air we breathe contains a mixture of different air pollutants and, when it comes to studying the adverse health effects of ambient air pollution, attempts have

It has been acknowledged that residents and area workers who inhaled dust and fumes from the World Trade Center disaster report lower respiratory symptoms, but the association between symptoms and lung function has not been elucidated. In a study by Friedman and colleagues (27), 180 cases with on-going lower respiratory symptoms (cough, dyspnea, and wheeze) were investigated by spirometry and impulse oscillometry (IOS) and compared with 473 control subjects. Abnormal spirometry as well as elevated airway resistance and frequency dependence of resistance was more often found in subjects with on-going respiratory symptoms. Even when spirometry was normal, case subjects more often had affected airway resistance. IOS assesses airway resistance and frequency dependence of resistance, which has been suggested to reect regional functional abnormalities in the distal airways. The authors link the long-term respiratory symptoms to lung function abnormalities not identied by ordinary spirometry and imply the value of assessing distal airway function in the evaluation of individuals with persistent respiratory symptoms and normal spirometry. However, in an editorial, Irvin (28) argues about the difculty of measuring small airway disease and that the use of respiratory system resistance (i.e., with IOS) has limitations. Irvin also puts forth that the World Trade Center exposure was unique and implies that the long-term respiratory symptoms may be the result of a persistent inammatory process of the intermediate airways, as indicated in induced sputum studies. In any case, this study emphasizes the importance of, and the need for, detailed assessment of lung function, including the functionality of all the airways.

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OCCUPATIONAL LUNG DISEASE

Occupational exposure to beryllium may induce beryllium sensitization (BeS) and chronic beryllium disease (CBD). In some patients, BeS may progress to CBD, which is a progressive lung disease characterized by noncaseating granulomas. These diseases are, apart from exposure to beryllium, determined by at least one genetic factor, a glutamic acid at position 69 (E69) encoded by the HLA-DPB1 gene. In a casecontrol study performed by Van Dyke and coworkers (29), the aim was to dene the association between beryllium exposure and E69 in patients with BeS and CBD. HLA-DPB1 genotypes were determined and related to quantitative beryllium exposure in workers and compared with control subjects. It was shown that any E69 carriage increased the odds for chronic beryllium disease (odds ratio, 7.61). However, the increased odds for CBD and beryllium sensitization due to HLA-DPB1 E69 appeared to be differentially distributed by genotype, with non-*02 E69 carriers and E69 homozygotes at higher odds than those with *02 genotypes, indicating that both beryllium exposure and the E69 genotype individually contribute to CBD odds.

GENETIC AND EPIGENETIC MECHANISMS IN LUNG DISEASE

The Dutch hypothesis (30) stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, and smoking) that ultimately lead to clinical disease, depending on the timing and type of environmental exposure. Multiple genes have been found for both asthma and COPD, some of which are unique to these diseases, whereas some shared genetic risk factors also exist. In a pulmonary perspective, Postma and Boezen (31) put forward that genes affecting lung development in utero and lung growth in early childhood interact with environmental detrimental stimuli (smoking and air pollution) and contribute to asthma in childhood and the ultimate development of COPD. Additional genes and environmental factors then drive specic immunological mechanisms underlying asthma and others may contribute to the development of various COPD phenotypes. Thus the genetic predisposition to the derailment of certain pathways may help to dene subgroups of asthma and COPD, which may lead to stratication of patients by their genetic make-up and open new therapeutic prospects. Whereas air pollution has been associated with decits in lung function development and respiratory illness in children, little is known concerning whether genetic variation contributes to underlying differences in susceptibility to air pollution. Glutathione is of importance in antioxidant and inammatory processes in the lung, and alterations in its metabolism are a central feature of many chronic lung diseases, Breton and coworkers (32) determined whether sequence variation in genes in the glutathione pathway would alter susceptibility to air pollutioninduced effects on lung function. Tagging single-nucleotide polymorphisms in glutathione metabolism pathway genes (GSS, GSR, GCLM, and GCLC ) were genotyped and related to air pollution exposure. It was found that only GSS, a gene involved in glutathione production and oxidative injury, was associated with differences in susceptibility to the harmful effects of ambient air pollution on childrens lung function growth. As the prevalence of the GSS haplotype is high (48% in the study population), continued emphasis to reduce exposure to urban air pollution for the most susceptible populations is warranted. Epigenetics is traditionally dened as the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence. Evidence suggests that epigenomic marks can be inuenced by environment exposure,

diet, disease, and ageing. In a pulmonary perspective, Yang and Schwartz (33) address the three main classes of epigenetic marks: (1) DNA methylation, (2) modication of histone tails, and (3) noncoding RNAs in the lung. Data suggest that epigenetic mechanisms are important in guiding T-cell differentiation and as one of the factors that may explain the increasing prevalence of asthma. Also, in the development of other chronic lung diseases, such as idiopathic pulmonary brosis and COPD, epigenetic mechanisms are likely to be involved. There are still some challenges when it comes to understanding epigenetics in lung disease. Epigenetic markers are cell specic; peripheral blood may in some cases be the only accessible sample; epigenetic marks have a dynamic nature; and, nally, a major challenge with epigenomics is to experimentally and analytically integrate the epigenetic mechanisms that affect transcription and translation. In a study by Rabinovitch and coworkers (34), albuterol use and urinary leukotriene E4 (LTE4) levels were monitored in children with asthma and related to concentrations of morning maximal ambient particulate matter less than 2.5 mm (mmPM2.5) and the effects of environmental tobacco smoke exposure, determined as urine cotinine levels. During the three consecutive study years, the mmPM2.5 concentration was low with yearly means ranging between 16.8 and 22.9 mg/m3. The main nding of the study was that environmental tobacco smoke modied the acute effects of low-level ambient PM2.5 exposure on childhood asthma, in terms of albuterol use and urinary LTE4 levels, indicating a smaller effect of PM exposure in children with higher tobacco smoke exposure. These results were commented on in an editorial by Baccarelli and Kaufman (35), who put forward the important issue that two common environmental exposures, PM and tobacco smoke, which might be considered to act in a similar fashion, do not simply add on to each other. Thus, the nding of an attenuated effect of PM in the presence of a tobacco smoke coexposure raises questions about the mechanisms underlying the cellular and molecular interaction between these two risk factors, as both are considered to induce local and systemic oxidative stress and inammation. Here, the authors suggest that the potential biological mechanisms underlying the interaction of PM and environmental tobacco smoke in determining asthma exacerbation may be related to the epigenetics. The epigenome, together with microRNAs, appears intricately sensitive to environmental exposures and may contribute to mediate rapid changes in gene expression, protein activities, and metabolite levels that may parallel the uctuating phenotypes typical of patients with asthma. It is implicated that further studies within this eld are important to identify which mechanisms determine the doseeffect response proles in the presence of multiple exposures.
Author disclosures are available with the text of this article at www.atsjournals.org.

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