Introduction
Air pollution, contaminated water, soil, food, and occupational exposure to various harmful materials are well-known environmental risk factors with potential adverse effects on human health [1]. These environmental exposures are known to induce a number of cellular and molecular processes, including oxidative stress, inflammation, genetic alterations, mutations, epigenetic alterations, mitochondrial dysfunction, endocrine disruption, and altered intracellular communication [1]. Exposure of lung epithelial cells to particulate matter (PM) consisting of mixtures of transition metals and other secondary substances produced from gaseous pollution, induces the production of reactive oxygen species, resulting in inflammation, cell death, and organ damage [2,3]. Furthermore, somatic mutations and epigenetic alterations, such as DNA methylation, induced by environmental exposures can affect the development of chronic diseases or cancer [4,5]. In the pulmonary system, immune cell interactions, altered lung microbiome, and virus activation are also important pathogenetic processes that result in the increased incidence of infectious lung diseases, such as pneumonia and bronchitis, as well as exacerbation of respiratory diseases [1]. In addition, there is evidence that air pollution affects all organs through these processes, including the occurrence and exacerbation of chronic diseases, such as cancer, cardiovascular, cerebrovascular, and metabolic diseases [1].
The World Health Organization (WHO) has estimated that 12.6 million deaths are attributable to environmental factors annually around the world [6]. Among these environmental risks, the burden of disease caused by air pollution is increasing, and PM was estimated to be responsible for 9 million premature deaths, representing to one in six deaths globally every year [7].
The main ambient air pollutants for which there is accumulating evidence of adverse health effects include PM, nitrogen oxides (NOx and NO2), ozone (O3), sulfur dioxide (SO2), and carbon monoxide (CO) [8]. PM is classified according to particle size as PM2.5 and PM10 with particle diameters of <2.5 μm and <10 μm, respectively [9]. The levels of these pollutants are continuously monitored worldwide as a means of determining air quality in a given area. Indoor air pollution represents household air pollution from multiple sources, such as cooking and heating using solid fuels or burning of biomass [8].
Here, we present a review of recent studies regarding the effects of ambient and indoor air pollution on the development, morbidity, and mortality of pulmonary diseases.
Air Pollution and Mortality
Many previous studies performed around the world have yielded convincing evidence for associations of short- and long-term exposure to air pollution with mortality. In 1992, Dockery et al. [10] reported increases of 16%-17% in daily mortality risk for each 100 μg/m3 increase in PM, and Pope et al. [11] reported that an increase in 5-day moving average PM10 level of 100 μg/m3 was associated with an estimated increase in daily mortality rate of 16%. A recent systematic evaluation of time-series studies regarding the association of PM10 and PM2.5 with daily mortality in more than 600 cities around the world indicated that an increase of 10 μg/m3 in the 2-day moving average of PM10 concentration was associated with increases of 0.44% in daily all-cause mortality rate and 0.47% in daily pulmonary mortality rate, with corresponding increases of 0.68% and 0.74% in daily mortality rates for the same change in PM2.5 concentration, respectively [12].
A study in six cities in the United States reported that long-term exposure to PM2.5 was associated with increases of 1.26-fold in all-cause mortality rate and 1.37-fold in the cardiopulmonary mortality rate for the cities with the highest versus the lowest levels of air pollution [13]. Recently, Di et al. [14] reported increases in annual all-cause mortality rates of 7.3% per increase of 10 μg/m3 in PM2.5 and 1.1% per increase of 10 ppb in O3 . These authors reported that air pollution can have adverse effects at low concentrations, below the current national standards [14]. Similar to this study, exposure to air pollution at concentrations below the WHO guidelines has been shown to affect mortality. A population-based study of Medicare beneficiaries over 65 years old in the southeastern USA suggested that long-term exposure to low levels of NO2 at concentrations below the guidelines can increase mortality risk by 4.7% [15].
A recent study based on the Effects of Low-level Air Pollution Study in Europe (ELAPSE) cohort, which extended the European Study of Cohorts for Air Pollution Effects (ESCAPE) cohort from six European countries, suggested that the increase in mortality due to long-term PM2.5 exposure is most likely due to vanadium [16].
Air Pollution and Lung Cancer
The ESCAPE study evaluated the association between long-term exposure to ambient air pollution and incidence of lung cancer, and showed significant hazard ratios (HRs) for PM10 of 1.22 for all lung cancers and 1.51 for adenocarcinoma [17]. Based on these results, the International Agency for Research on Cancer (IARC) has classified PM as group 1 carcinogen to humans [18].
Recently, results from the ELAPSE study about the relations of low-level air pollutants, including PM2.5, NO2, black carbon, and O3 , with the incidence of lung cancer were reported [19-21]. The risk of lung cancer was shown to increase with higher levels of exposure to PM2.5, with a HR of 1.13 [19]. However, NO2, black carbon, and O3 showed no associations with the development of lung cancer [19]. A prospective study using data from the UK Biobank reported significant associations between the incidence of lung cancer and air pollutants, with HRs of 1.63 per increase of 5 μg/m3 in PM2.5, 1.53 per increase of 10 μg/m3 in PM10, 1.10 per increase of 10 μg/m3 in NO2, and 1.13 per increase of 20 μg/m3 in NOx [20].
Air Pollution and Chronic Obstructive Pulmonary Disease
Although the most important risk factor for the onset of chronic obstructive pulmonary disease (COPD) is smoking, about 30% of patients are never-smokers [22]. Air pollution has been considered another risk factor for the incidence of COPD; urban PM significantly decreases cell viability and increased oxidative stress and autophagy levels on human bronchial epithelial cells [23]. However, there was still insufficient direct epidemiological evidence linking long-term air pollution exposure to the onset of COPD [22].
Many studies have shown positive relations between pollutants and COPD incidence, with long-term exposure to air pollution associated with impairment of lung function [24-28]. However, other studies, such as those using data from the ESCAPE cohort, showed no such associations [29]. A recent study of ELAPSE project data reported the incidence of COPD according to long-term exposure to low concentrations of air pollution [30]. Of the total of 98,058 participants with a mean follow-up period of 16.6 years, 4,928 developed COPD, and the excess risks of COPD occurrence were 17% per increase of 5 μg/m3 in PM2.5, 11% per increase of 10 μg/m3 in NO2, and 11% per increase of 0.5×10 −5 m −1 in black carbon [30]. In a population-based cohort study performed in Canada, Shin et al. [31] also reported that the risk of COPD increased by 7%, 4%, and 4% per interquartile range (IQR) increase of 3.4 μg/m3 in PM2.5, NO2, and O3 , respectively.
In a trial performed in UK, to evaluate individual exposure, to allow precise evaluation of the effect of air pollution on patients with COPD, personal monitoring of exposure to pollutants and their effects in 115 COPD patients showed that higher levels of NO2, NO, and CO exposure increased exacerbation risk, and exposure to O3 was related to dyspnea and peak expiratory flow [32].
Furthermore, recent studies have evaluated improvements in respiratory morbidity of COPD after interventions to reduce indoor pollution [33]. In a blinded randomized controlled trial, Hansel et al. [33] reported a significant difference in St. George’s Respiratory Questionnaire score between a group using a portable high-efficiency particulate air (HEPA) filter and a control group using a sham filter for 6 months. This was the first environmental intervention study in patients with COPD, and the results suggested that improvement of air quality can improve symptoms in these patients.
Air Pollution and Asthma
PM2.5, NO2, and O3 are the major pollutants related to airway inflammation and oxidative stress: NO2 and O3 produce airway hyperresponsiveness. Through these several responses and pathways, air pollution is associated with exacerbations, mortality, and even the development of asthma [34].
The association air pollution and incidence of asthma has been well known in children that meta-analysis study showed statistically significant associations for black carbon, NO2, PM2.5, and PM10 exposures and risk of asthma onset [35]. Furthermore, Garcia et al. [36] reported that decreases in the levels of NO2 and PM2.5 for 10 years were associated with lower asthma incidence among children in United States. Additionally, ELAPSE project showed that long-term exposure to PM2.5, NO2, and black carbon was associated adult-onset asthma [37].
A case-crossover study was performed to assess the association between short-term exposure to air pollution and asthma mortality in China [38]. The study provided that each IQR increase of PM2.5, NO2, and O3 was associated with asthma mortality, with odds ratios of 1.07, 1.11, and 1.09, respectively.
There was a randomized clinical trial about effect of classroom air filter purifiers on asthma symptoms in students with active asthma [39]. The number of symptom-days with asthma during a 2-week period in the group used HEPA filter purifiers was 1.6 and the mean was 1.8 symptom-days in children with asthma used sham HEPA filter purifiers. However, results showed that use of HEPA filters in the classrooms did not significantly reduce symptom-days with asthma. Further interventional study may need to consider allergen levels, other source of particle exposure, and asthma symptom at baseline.
Air Pollution and Idiopathic Pulmonary Fibrosis
Acute exacerbations and worsening of idiopathic pulmonary fibrosis (IPF) have been shown to be associated with exposure to O3 , NO2, and PM, but the association between chronic exposure to air pollution and incidence of IPF was not clear.
Consistent with the results of earlier epidemiological studies, a recent study in a population of 1,114 IPF patients in Korea showed a 17% increase in mortality in association with an increase of 10 ppb in NO2 level estimated based on residential address [40].
The results of a study by Conti et al. [41] suggested a weak association between NO2 and IPF incidence. Furthermore, pollution factors, such as metal and wood dust, were shown to have meaningful effects on occupational and environmental risks of IPF [42]. Further detailed studies are required to elucidate the associations between pollution and the incidence of IPF.
Air Pollution and Infectious Lung Disease
The risks of infectious lung diseases, such as pneumonia and bronchiolitis, are increased by exposure to air pollution, especially in childhood [43]. The ESCAPE study investigated the associations of air pollutants, such as NO2, NOx, PM2.5, PM10, with pneumonia [43]. The adjust-ed odds ratios of pneumonia increased significantly for 1.3 per increase of 10 μg/m3 in NO2 and 1.76 per increase of 10 μg/m3 in PM10 [43]. Children have greater susceptibility to the effects of environmental pollution than adults due to their less developed immune system, small-sized airways, higher respiratory rates, and longer-term exposure to air pollution of the lower respiratory tract. In a time-series study of ambient PM pollution and adult hospital admissions for pneumonia in China, short-term increases of 10 μg/m3 in 3-day moving average levels of PM2.5 and PM10 were shown to be associated with 0.31% and 0.19% increases in hospital admissions due to pneumonia, respectively [44].
A recent study showed associations between indoor air pollution and susceptibility to tuberculosis infection [45]. Briefly, higher levels of indoor air pollution exposure were shown to increase the odds ratio of latent tuberculosis infection in a cohort of 107 children living with 71 patients with active tuberculosis [45]. Based on these results, further studies regarding the associations of pollution with transmission risk of transmittable diseases, such as tuberculosis, and evaluation of the underlying mechanisms are required.
Both long-term and short-term air pollution may play an important role in the airborne spreading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and may enhance the incidence of coronavirus disease 2019 (COVID-19). Recently, many studies have reported the influence of PM2.5 and PM10 on SARS-CoV-2 transmission [46-51]. PM could aggravate neurological symptoms of SARS-CoV-2 and exacerbate respiratory and cardiovascular injuries of COVID-19 [52-54]. Moreover, there was a report that air pollution is an important cofactor increasing the risk of mortality from COVID-19 [55]. Some studies proposed that PM operates as a virus carrier, promoting its transport through the air [56,57].
However, most studies showing an association between air pollution and COVID-19 infection did not consider potential confounding factors in the correlation analysis. Therefore, more rigorous studies considering several additional confounding factors, such as individual age, population density, and pre-existing comorbidities, should be conducted to determine the impact of air pollution on COVID-19 infection.
Conclusion
Recent large-scale cohort studies have confirmed the correlations of long-term exposure to air pollution with the incidence and clinical exacerbation of respiratory diseases. New findings have shown that exposure to pollution at levels below the WHO guidelines can have adverse health effects, suggesting the necessity of revising the guidelines for air quality.
More precise exposure evaluation, such as individual monitoring, is required to clarify the underlying mechanisms and develop suitable interventions to reduce the adverse health effects of air pollution. Recent studies involving precise monitoring of air pollutant exposure levels in patients with COPD reported that interventions to improve indoor air quality can improve COPD symptoms. Thus, such precise evaluation of exposure and trials to improve air quality are meaningful for patients with chronic pulmonary diseases who are at increased vulnerability to the adverse effects of air pollution.
Recent studies have provided evidence supporting the association between PM and lung cancer incidence risk. From observations showing vulnerability to respiratory infection, it should be considered that infants, children, and people with weakened immune systems are vulnerable to the adverse effects of air pollution.
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