Air Pollution and Its Health Effects in China

China is the world’s third largest country by land area and the world’s most populous country� China has been among the world’s fastest growing economies since economic liberalization began in 1978� China’s annual average gross domestic product (GDP) growth between 1990 and 2013 exceeded 10% (Figure 1�1) (National Bureau of Statistics of China, 2015)� As of 2014, China is the world’s second largest economic entity after the United States, with the nominal GDP totaling approximately USD 10�3554 trillion� Meanwhile, the urbanization process in China has been increasing

1�1 Background �������������������������������������������������������������������������������������������������������3 1�1�1 General Information about China����������������������������������������������������������3 1�1�2 Air Pollution Trend and Episodes in China �������������������������������������������4

1�2 Health Effects ����������������������������������������������������������������������������������������������������6 1�2�1 Ambient Air Pollution and Mortality and Morbidity ����������������������������7

1�2�1�1 Short-Term Effects of Ambient Air Pollution on Mortality ������ 7 1�2�1�2 Short-Term Effects of Ambient Air Pollution on Morbidity �����11 1�2�1�3 Long-Term Effects of Ambient Air Pollution ����������������������� 13

1�2�2 Ambient Air Pollution and Subclinical Health Effects������������������������ 14 1�2�2�1 Respiratory Health Effects of Air Pollution ������������������������� 15 1�2�2�2 Cardiovascular Health Effects of Air Pollution �������������������� 17 1�2�2�3 Other Subclinical Health Effects of Air Pollution ����������������20

1�2�3 Biological Mechanisms for the Health Effects of Ambient Air Pollution ����������������������������������������������������������������������������������������21

1�3 Exposures ��������������������������������������������������������������������������������������������������������26 1�3�1 Approach for Measurement and Related Methodological Issues ��������26 1�3�2 Air Pollutant Levels �����������������������������������������������������������������������������28

1�4 Risk Assessment and Management �����������������������������������������������������������������29 1�4�1 Sources ������������������������������������������������������������������������������������������������29 1�4�2 Economic Burden ��������������������������������������������������������������������������������30 1�4�3 Intervention �����������������������������������������������������������������������������������������30

1�5 Conclusions and Recommendations ��������������������������������������������������������������� 31 References ����������������������������������������������������������������������������������������������������������������34

in the past few decades� Only about 26% of the country’s population lived in urban areas in 1990, whereas this percent has markedly increased to 53�7% in 2013� China now has more than 160 cities with a population of over one million, most of which are located in east and south China, and it is estimated that the urban population in China will reach one billion by 2030 (McKinsey Global Institute, 2009)� Along with the rapidly expanding population in the urban areas, motorization becomes another epiphenomenon of the urbanization process� The scale of the civil vehicle fleet has reached 126�7 million by the end of 2013, which is more than five times higher than that of 10 years ago (National Bureau of Statistics of China, 2015)�

Along with the profound socioeconomic development, China has become the world’s largest energy consumer in 2010 and accounts for 21% of global energy use (Badkar, 2012)� China’s total energy use was 3617�32 million tons of coal equivalents in 2012� Coal and oil, two major forms of fossil fuels, accounted for 66�6% and 18�8% of the total energy demands in China in 2012, respectively� As a result, combustion of fossil fuels has become the major source of urban ambient air pollution in China, and air pollution levels remain relatively high over recent years� For example, a recent source appointment study suggests that over 70% of ambient particulate matter with an aerodynamic diameter of 2�5 μm or less (PM2�5) in Beijing (the capital of China) in 20102011 was related to the consumption of fossil fuels (Wu et al�, 2014c)� According to the governmental report, the annual average concentrations of several major air pollutants in 74 major cities in 2013 were high, which were 118 μg/m3 for particulate matter with an aerodynamic diameter of 10 μm or less (PM10), 40 μg/m3 for sulfur dioxide (SO2), and 44 μg/m3 for nitrogen dioxide (NO2) (Ministry of Environmental Protection of China, 2014)� Annual average levels of PM10 and SO2 showed decreasing trends, whereas annual average levels of NO2 remained relatively constant during recent years (2003-2012) in China’s 31 provincial capitals� However, levels of these air pollutants increased recently, with annual average levels in 2013 higher than those in 2012 (Figure 1�2) (National Bureau of Statistics of China, 2015)� Levels

FIGURE 1.1 GDP, urbanization rate, total energy consumption, and vehicle fleet in China during 1990-2013�

of these air pollutants in China are still at the higher end of the world� Particularly, ambient levels of PM10 during 2003-2010 in 32 major Chinese cities ranked at the higher end (all rankings >800) among the world’s 1,100 urban areas with a population above 100,000 inhabitants (World Health Organization, 2012); and eastern China was the world’s hot spot with the highest PM2�5 concentrations (values >100 μg/m3 in its major industrial regions) during 2001-2006, based on satellite observations of the National Aeronautics and Space Administration of the United States (US NASA) (van Donkelaar et al�, 2010)�

Before 2012, China’s national routine air-monitoring system did not include ambient PM2�5, which is thought to be an air pollutant that is very dangerous to human health� Ambient PM2�5 becomes a national standard air pollutant since the release of the modified national Ambient Air Quality Standards (AAQS) (Ministry of Environmental Protection of China, 2012)� Among the 74 major cities with routine ambient PM2�5 air-monitoring data in China in 2013, 69 cities (93%) did not reach the annual national AAQS II (35 μg/m3), and none of the cities reached the annual national AAQS I (15 μg/m3) (Figure 1�3)�

Ambient air pollution levels have apparent seasonal patterns in China, with lower levels generally observed in warm season and higher levels generally observed in cold season� In the past few years, ambient air pollution in northern China became particularly severe in heating-season time (typically from late October to March), when the pollution emissions are enhanced and the weather conditions are not favorable for the diffusion of air pollutants� The levels of major air pollutants in urban areas often increase severalfold (in the magnitude of several hundreds of μg/m3) of the average levels in normal years and can last for days, causing air pollution episodes of so-called haze or heavy smog� Sometimes the episodes are quite extensive, and other areas surrounding the heating areas may also be involved� The haze or smog during the episodes is often thick enough to block the sunlight from penetrating through the atmosphere and makes the sky looks gray in daytime� On the other

FIGURE 1.2 Average annual concentrations of three major air pollutants PM10, SO2, and NO2 (μg/m3) in 31 provincial capitals in China during 2003-2013�

hand, Asian dust storms from desert areas of China and Mongolia can also bring a large number of dry soil particles rich in heavy metals to eastern China during the spring season and elevate the ambient PM levels substantially� Exposure to ambient air pollution may cause significant health and economic burdens, which have been partly documented in a number of studies in recent years�

In summary, ambient air pollution has become a major environmental issue in China and has received great attention nationwide and worldwide� In this chapter, we review the current research literature on health effects, exposure measurements, risk assessment and management relevant to ambient air pollution in China, summarize the lessons learned, and recommend directions for further studies�

Ambient air pollution has been recognized as a major risk factor for population health in China� In a comprehensive study that performed analyses of disease burden for 231 diseases and injuries and 67 risk factors or clusters of risk factors relevant to China, ambient air pollution was estimated to cause 25,227 thousands of disability-adjusted life years in 2010, ranking fourth after dietary risk factors, high blood pressure (BP), and tobacco exposure (Yang et al�, 2013)� Another study suggests that an arbitrary policy, which provides free winter heating via the provision of coal for boilers in cities north of the Huai River but denies heat to the south, increases total suspended particles (TSP) air pollution and is causing the 500 million residents of northern China to lose more than 2�5 billion life-years of life expectancy (Chen et al�, 2013d)� The number of epidemiologic and toxicological studies conducted to investigate the health impact of ambient air pollution in China has been increasing during the most

FIGURE 1.3 Annual average ambient PM2�5 concentrations (μg/m3) in 74 major cities in China in 2013� The higher parallel line in the figure represents annual national Ambient Air Quality Standards (AAQS) II (35 μg/m3), and the lower parallel line represents annual national AAQS I (15 μg/m3)�

recent decade� Most of these studies focus on the short-term health effects within a few hours, days, or weeks after air pollution exposure, whereas potential long-term health effects over years have received less attention� Common study designs and health observational endpoints used in these studies include time-series and casecrossover studies examining the short-term effects of air pollution on clinically significant health outcomes (e�g�, mortality and morbidity); cohort, cross-sectional, and ecological studies attempting to link long-term air pollution exposure with adverse health outcomes; panel, experimental, and cross-sectional studies investigating the subclinical effects of air pollution (e�g�, changes in health indicators such as lung function and BP); and toxicological studies examining the biological mechanisms of air pollution action�

Disease mortality is the most extensively studied health endpoint in air pollution health studies in China� Disease morbidity measures, including hospital admissions, outpatient visits, and emergency room visits (ERVs), are less frequently investigated� Most of these epidemiologic studies have been focused on the short-term effects of air pollutants on mortality and morbidity within a few days, whereas only a few studies have been conducted to investigate the potential long-term effects of air pollutants on these health outcomes� In addition, other measures of disease burden, such as years of life lost and disability-adjusted life years, have also been used to assess the adverse health impact of air pollution (Guo et al�, 2013; Zhang et al�, 2006)�

1.2.1.1 Short-Term Effects of Ambient Air Pollution on Mortality Early epidemiologic studies investigating the association between day-to-day air pollution levels and mortality in China are generally restricted to one city or area� Meta-analyses and multicity studies comprising data from multiple Chinese cities have been increasing recently (Aunan and Pan, 2004; Chen et al�, 2011a,b, 2012a,b,c; Lai et al�, 2013; Shang et al�, 2013; Wong et al�, 2008; Tao et al�, 2012; Tao et al�, 2011; Lu et al�, 2015)� Locations most frequently studied are densely populated megacities, such as Beijing, Shanghai, and Hong Kong, where both routine air-monitoring system and mortality reporting system have been well established� There are also less frequent reports from other major Chinese cities including Guangzhou, Shenzhen, Wuhan, Chongqing, Shenyang, Xi’an, Taiyuan, Tianjin, and so on (Lai et al�, 2013; Shang et al�, 2013; Lu et al�, 2015)� PM10, SO2, and NO2 are the three major air pollutants most commonly studied, whereas data on the other three major air pollutants PM2�5, O3, and carbon monoxide (CO) are still limited� Three general health outcomes, including total mortality, cardiovascular mortality, and respiratory mortality, are typical observational endpoints investigated in these epidemiologic studies� Table 1�1 summarizes the pooled risk estimates for daily mortality per unit increase of major air pollutants reported by meta-analyses and multicity studies in China�

In a multicity time-series study comprising data from 16 Chinese cities with population sizes ranging from 1�2 million to 12�3 million, city-specific average PM10 levels were reported to be 52-156 μg/m3 during the study periods varying between 1996 and 2008, and a 10 μg/m3 increase in 2-day moving-average PM10 was associated

TABLE 1.1 Summary of the Pooled Estimated Percent Increase in Risk of Daily Mortality Associated with Major Air Pollutants Reported in Meta-Analyses and Multicity Studies in China

with a 0�35% (95% posterior interval [PI]: 0�18, 0�52) increase of total mortality, a 0�44% (95% PI: 0�23, 0�64) increase of cardiovascular mortality, and a 0�56% (95% PI: 0�31, 0�81) increase of respiratory mortality in the combined analysis (Chen et al�, 2012b)� Two additional time-series analyses using data of 17 cities from the same study group reported city-specific average NO2 levels between 23 and 67 μg/m3 and SO2 levels between 18 and 100 μg/m3 during the study periods, and a 10 μg/m3 increase in 2-day moving-average NO2 was found to be associated with a 1�63% (95% PI: 1�09, 2�17), 1�80% (95% PI: 1�00, 2�59), and 2�52% (95% PI: 1�44, 3�59) increase of total, cardiovascular, and respiratory mortality, respectively (Chen et al�, 2012c); whereas a 10 μg/m3 increase in 2-day moving-average SO2 was found to be associated with a 0�75% (95% PI: 0�47, 1�02), 0�83% (95% PI: 0�47, 1�19), and 1�25% (95% PI: 0�78, 1�73) increase of total, cardiovascular, and respiratory mortality, respectively (Chen et al�, 2012a)�

Most of the available studies are only able to examine the cardiovascular and respiratory mortality as two general health endpoints� Studies focusing on mortality

TABLE 1.1 (Continued ) Summary of the Pooled Estimated Percent Increase in Risk of Daily Mortality Associated with Major Air Pollutants Reported in Meta-Analyses and Multicity Studies in China

due to specific cardiovascular or respiratory diseases and other cause-specific mortality are limited� Specific diseases that have been investigated in the epidemiologic studies include heart disease (Kan et al�, 2010; Breitner et al�, 2011; Tao et al�, 2012; Wong et al�, 2002b; Xu et al�, 2014); cerebrovascular disease, including stroke (Chen et al�, 2013a; Tao et al�, 2012; Kan et al�, 2010; Wong et al�, 2002b); diabetes (Kan et al�, 2004); acute respiratory infections, including pneumonia and influenza (Wong et al�, 2002b, 2010; Kan et al�, 2010); and chronic obstructive pulmonary disease (COPD) (Tao et al�, 2012; Kan et al�, 2010; Wong et al�, 2002b)� There are also sporadic reports on other cause-specific mortality due to cancer (Venners et al�, 2003) and accident (Kan et al�, 2010)�

The levels of major air pollutants (especially ambient PM) reported in studies from China are generally higher than those reported in studies from the developed countries in North America and Europe� For example, a major study using data from 108 counties in the United States reported that the median of PM10 levels over the study areas during 1999-2005 was as low as 23�5 μg/m3 (interquartile range [IQR]: 20�6, 28�6) (Peng et al�, 2008)� In contrast, the changes in daily mortality associated with per-unit increase in air pollution levels tend to be lower in China than those reported in developed countries (often >0�50% per 10 μg/m3 increase of PM10 for total mortality) (Pope and Dockery, 2006; Samet et al�, 2000)� This difference may be explained by different characteristics of the study contexts, such as heterogeneity in local air pollution levels and sources, chemical constituents and associated toxicity, population sensitivity, age distribution, and socioeconomic factors (Kan et al�, 2012; Health Effects Institute [HEI], 2010)� Particularly, evidence from developed countries suggests that the exposure-response relationships for air pollution and daily mortality often tend to become flat at high concentrations (Pope et al�, 2011)� This flattening out of mortality risk at high exposure levels has been implicated in some studies (Chen et al�, 2012c; Kan et al�, 2007), though other studies also suggest a continuous increasing trend in mortality risk at higher exposure levels in China (Cao et al�, 2012; Chen et al�, 2013a)�

Among the major air pollutants, ambient PM has received increasing attention because of greater potentials to induce adverse health effects� However, the uncertainty of the PM’s health impact is substantial because of their varying sizes and chemical constituents, both of which may affect related biological toxicity critically (Valavanidis et al�, 2008)� Epidemiologic studies investigating the associations between daily mortality and size-fractioned PM and its chemical constituents are still rare in China� An earlier time-series study in Shanghai demonstrated that PM2�5 was significantly associated with increased mortality, whereas coarse particles (PM10-2�5) were not (Kan et al�, 2007)� Two later time-series studies further demonstrated that particles with smaller sizes were more strongly associated with daily mortality than were larger particles (Meng et al�, 2013; Breitner et al�, 2011)� For example, one study found that IQR increases in particle-number concentrations of 0�25-0�28 μm, 0�35-0�40 μm, and 0�45-0�50 μm particles were associated with 2�41% (95% confidence interval [CI]: 1�23, 3�58%), 1�31% (95% CI: 0�52, 2�09%), and 0�45% (95% CI: 0�04, 0�87%) higher total mortality, respectively, in a Chinese city Shenyang (Meng et al�, 2013)� In contrast, there was little association between larger particles (with sizes of 1�0-2�5 μm and 2�5-10 μm) and total mortality� Data from a severely polluted Chinese city, Xi’an, suggest that several secondary and

combustion-related chemical constituents of PM2�5, including ammonium, nitrate, elemental carbon (EC), chlorine, and nickel, appeared to be most strongly associated with daily mortality (Cao et al�, 2012; Huang et al�, 2012b)�

A few studies also reported the modification of the air pollution-daily mortality association by other covariates, such as demographic and socioeconomic characteristics of the study subjects and seasonal and meteorological factors (e�g�, ambient temperature)� Generally, air pollution-mortality association appears to be stronger among elders with age above 60, and subjects with low educational attainment (illiterate and primary school) (Kan et al�, 2008; Chen et al�, 2012b); appears to be stronger in warm season than in cold season (Kan et al�, 2008; Qian et al�, 2010); may vary by study locations (Chen et al�, 2012b; Zhou et al�, 2015b); and may be modified by changes in ambient temperature (Li et al�, 2011)�

1.2.1.2 Short-Term Effects of Ambient Air Pollution on Morbidity Epidemiologic studies assessing the short-term effects of air pollutants on disease morbidity in China have been increasing in recent years� Most of these studies have been limited to a single city (e�g�, Hong Kong, Beijing, or Shanghai)� Compared with disease mortality, the reporting system for disease morbidity has not been well established in most Chinese cities� Hospital admissions, outpatient visits (clinic consultations), and ERVs are the most common morbidity measures examined in the epidemiologic studies� A few studies also investigated potential adverse reproductive outcomes associated with medium-term (several weeks to a few months) air pollution exposure�

Among the three cities (Hong Kong, Beijing, and Shanghai) which are most frequently investigated for the air pollution-morbidity association, Hong Kong provides a majority of such data available to date, probably owing to its well established health care system and enhanced governmental supervision (Lai et al�, 2013; Wong et al�, 2010)� Morbidity due to respiratory diseases is the most commonly examined health endpoint in Hong Kong studies� Specific diseases investigated include respiratory tract infections (Tam et al�, 2012b, 2014; Tian et al�, 2013; Wong et al�, 1999, 2010), asthma (Ko et al�, 2007b; Lee et al�, 2006; Wong et al�, 1999, 2002a), COPD (Ko et al�, 2007a; Tam et al�, 2012b; Wong et al�, 1999), ischemic heart disease (Qiu et al�, 2013; Tam et al�, 2012a; Wong et al�, 1999, 2002a), heart failure (Tam et al�, 2012a; Wong et al�, 1999), cerebrovascular disease (Wong et al�, 1999), and so on� Generally, children of ages <15 and elders of age ≥65 are more susceptible subjects than adults aged 15-65 (Wong et al�, 2010; Ko et al�, 2007b)� A few studies also reported the short-term effects of Asian dust storms on emergency hospital admissions due to respiratory and cardiovascular diseases in Hong Kong (Tam et al�, 2012a,b)�

Data on the association between ambient air pollution and disease morbidity in mainland China are mainly contributed by studies from megacities such as Beijing and Shanghai� For example, several time-series and case-crossover studies in Beijing reported positive associations between major air pollutants and daily outpatient visits and ERVs based on records from a major hospital (Guo et al�, 2009, 2010a,b; Xu et al�, 1995); a cohort study reported a positive association between maternal exposures to SO2 and TSP during the third trimester of pregnancy and low infant birth weight (<2,500 g) among 74,671 first-parity live births in Beijing (Wang et al�, 1997); several time-series studies in Shanghai reported positive associations between major

air pollutants and daily hospital admissions, outpatient visits, and ERVs (Cao et al�, 2009; Chen et al�, 2010; Hua et al�, 2014; Wang et al�, 2013; Zhao et al�, 2014a); and another time-series study reported a positive association between 8-week averaged air pollution levels and preterm birth in Shanghai (Jiang et al�, 2007)� There are also reports from other Chinese cities such as Guangzhou, Shenzhen, and Lanzhou (Peng et al�, 2011; Tao et al�, 2014b; Yang et al�, 2014)�

According to a meta-analysis on the association between ambient air pollution and daily morbidity, the pooled relative risks ranged from 1�0021 (cardiovascular, PM10) to 1�0162 (asthma, O3) for five cause-specific hospital admissions (Lai et al�, 2013)� Data for outpatient visits and ERVs in China are not sufficient for a meaningful metaanalysis� Notably, the associations between air pollutants and daily morbidity rates are less consistent when compared with those between air pollutants and daily mortality rates� Although most epidemiologic studies reported positive associations between air pollutants and daily morbidity rates, significant inverse associations have also been reported for air pollutants and hospital admissions (Lai et al�, 2013; Tian et al�, 2013)�

Only a few epidemiologic studies have investigated the associations of certain PM chemical constituents and size-fractioned PM with morbidity in China� Two timeseries studies in Shanghai reported the associations of daily hospital visits and admissions with black carbon (BC), a combustion-related constituent (Wang et al�, 2013; Hua et al�, 2014)� Both studies showed that BC appeared to be more strongly associated with health outcomes as compared with PM variables� Another time-series study examined the associations of 10 PM2�5 chemical constituents and ERVs in Shanghai and found consistent positive associations of ERVs with organic carbon (OC) and EC, both of which are from the combustion of fossil fuel (Qiao et al�, 2014)� A few analyses also reported the association between various size-fractioned PM and ERVs due to respiratory and cardiovascular diseases in China (Leitte et al�, 2011; Liu et al�, 2013a)� Particles with smaller sizes were found to be more strongly associated with daily ERVs due to cardiovascular disease in a Beijing hospital (Liu et al�, 2013a)� In contrast, smaller particles were not found to be more strongly associated with daily respiratory ERVs (Leitte et al�, 2011) as well as daily mortality (Meng et al�, 2013) than larger particles� Whether these findings suggest heterogeneous effects of smaller particles on cardiovascular and respiratory health require further investigation�

Beijing held the 29th Olympic Games in 2008 summer, and the government implemented a series of air pollution control measures during the Olympics through which the air pollution levels were reduced substantially (Wang et al�, 2009c)� One study based on a major hospital in Beijing observed a significant lower number of daily outpatient asthma visits during the Olympics than that before the Olympics (7�3 vs� 12�5 visits; relative risk = 0�54, 95% CI: 0�39, 0�75), suggesting a beneficial health effect related to air pollution reduction (Li et al�, 2010)�

Severe air pollution episodes, so-called haze or heavy smog, in the cold season have become a major public concern in China in recent years� The involved areas may encompass the entire central and eastern China during peak times of such episodes� Levels of major air pollutants (i�e�, PM, SO2, and NO2) may all be elevated substantially during the episodes, and PM2�5 has received special public attention because it is thought to be the major contributor of the haze events� Acute adverse health consequences, including increased hospital admissions, outpatient visits, and

ERVs following the episodes, have been frequently noted in the public press� The potential health impact of such heavy smog has been implicated in only a few scientific reports (Chen et al�, 2013b; Zhou et al�, 2015a)� Further detailed assessments on the health burden associated with the air pollution episodes in the near future may help the government to tailor the relevant policies�

1.2.1.3 Long-Term Effects of Ambient Air Pollution Generally, data from studies on the short-term effects of ambient air pollution provide important evidence for the daily air quality guidelines, whereas data from longterm follow-up studies comprise the main body of the evidence for the long-term (i�e�, annual) air quality guidelines (US Environmental Protection Agency [USEPA], 2012; World Health Organization, 2006)� Most studies investigating the long-term effects of ambient air pollution have been conducted in the developed countries in North America and Europe, where the air pollution levels are typically low and the pollutant ranges are relatively narrow (Dockery et al�, 1993; Pope and Dockery, 2006; HEI, 2010)� Only a handful of epidemiologic studies have assessed the long-term effects of ambient air pollution in China� Study designs used in these epidemiologic studies include cohort, cross-sectional, and ecological studies� Overall, the evidence for long-term effects of air pollution is still very limited in China�

Only several cohort studies have investigated the association between long-term air pollution and mortality in China� The first one used data from the China National Hypertension Survey, an established prospective cohort with 70,947 middle-aged adult participants in 16 provinces in China during 1991-2000 (Cao et al�, 2011)� The second study examined the association between long-term air pollution and mortality among 9,941 residents in Shenyang during 1998-2009 (Dong et al�, 2012; Zhang et al�, 2011b)� The third study assessed the association of cardiovascular mortality with long-term exposure to PM10 among 39,054 subjects in four cities (including Shenyang) in northern China (Zhang et al�, 2014)� Another study investigated the association between long-term PM exposure and mortality among 71,431 middleaged men during 1990-2006 (Zhou et al�, 2014a)� In these studies, participants’ exposures to air pollutants were estimated according to fixed-site air-monitoring data averaged at the regional or community level, and significant positive associations were found between several major air pollutants and mortality due to cardiovascular and respiratory diseases� Notably, the magnitude of the associations varied substantially between studies� For example, a 10 μg/m3 increase in TSP, SO2, and nitrogen oxides (NOX) were associated with a respective 0�9% (95% CI: 0�3, 0�5), 3�2% (95% CI: 2�3, 4�0), and 2�3% (95% CI: 0�6, 4�1) increase in cardiovascular mortality in the China National Hypertension Survey (Cao et al�, 2011); whereas a 10 μg/m3 increase in annual average concentrations of PM10, SO2, and NO2 were found to be associated a respective 55% (95% CI: 1�51, 1�60), –4% (95% CI: –8, 1), and 146% (95% CI: 131, 163) increase in cardiovascular mortality among the Shenyang residents (Zhang et al�, 2011b)� The heterogeneous risk estimates may be associated with the different study contexts, as well as the unperfected study methodologies which may lead to exposure misclassification due to the use of regional-or community-level fixed-site air-monitoring data and information bias due to the retrospective characteristics of the data collection strategy�

Several cross-sectional studies and ecological studies also provide evidence for the associations or correlations between long-term air pollution levels and disease mortality and morbidity� One early ecological study found significant correlations between long-term airborne sulfate levels and total mortality and mortality due to cardiovascular disease, malignant tumor, and lung cancer in Beijing (Zhang et al�, 2000); another ecological study using 52-year historical haze data between 1954 and 2006 found increases in lung cancer incidence and mortality following the air pollution events in Guangzhou (Tie et al�, 2009); one recent ecological study also found significant correlations between annual NO2 concentrations and lung cancer incidence and mortality in 10 Chinese cities (Huang et al�, 2014b); one early cross-sectional study reported positive associations between long-term ambient PM levels and respiratory morbidity prevalence among 7,621 children in four Chinese cities (Zhang et al�, 2002); and another cross-sectional study found that residential long-term exposure to air pollution was associated with increased risk of hypertension among 24,845 Chinese adults in three northeastern cities (Dong et al�, 2013)� However, the evidence from cross-sectional and ecological studies is thought to be inferior as compared with that from prospective cohort studies, given that the timing relationship between air pollution exposure and occurrence of the health endpoint is often unclear in cross-sectional and ecological studies� In addition, air pollution exposure observed in these studies are often averaged at the population level rather than at the individual level, thereby resulting in great uncertainty in exposure estimation and substantial bias in estimated risk� Nevertheless, such preliminary studies may provide clues for further more informative investigations�

Exposure to ambient air pollution may also cause a range of subclinical health effects in addition to the clinically significant health outcomes (i�e�, mortality and morbidity)� These effects can be reflected by changes in various health indicators, such as lung function, respiratory symptoms, heart rate variability (HRV), BP, and biomarkers measured in biological samples (e�g�, blood, urine, exhaled breath condensate)� A popular study design used in the investigation of the air pollution’s subclinical effects is panel study� Panel studies usually include a few, several dozens of, or more than one hundred participants, who are observed repeatedly over time, thereby facilitating assessment of the health effects of changes in exposure over time (Janes et al�, 2008)� Methodologies including data collection and statistical analytic approaches used in panel studies are different from those used in traditional epidemiologic studies (e�g�, time-series studies or cross-sectional studies)� Furthermore, a few studies also used experimentally designed study protocols� In these studies, participants are intently exposed to different air pollution scenarios and measured for the same health variables under these scenarios, and the observed changes in health variables are then tested for difference statistically over the exposure scenarios� Nevertheless, the repeated assessment strategy of the panel and experimental study designs limits the number of participants that can be included in the investigation, and other study designs, including cross-sectional and cohort study designs, are used in larger-scale investigations� Studies on the subclinical effects of air pollution can provide important implications for the potential

health impact of hazardous air pollutants and can serve as the bridge to link population-based epidemiologic studies documenting the adverse health effects of air pollution and toxicological studies documenting the biological mechanisms of air pollution action� Generally, several well-conducted panel and experimentally designed studies during the past few years have provided useful clues for the mechanistic pathways through which air pollution may promote the development of adverse respiratory and cardiovascular health outcomes, while traditional cross-sectional studies continue to contribute to the investigation of air pollution health effects in China�

1.2.2.1 Respiratory Health Effects of Air Pollution The respiratory system is the first barrier that air pollutants encounter in the human body before entering the circulatory system and other parts of the body� Lung function is the most commonly investigated respiratory health indicator in association with air pollution in China, and most of the available studies are cross-sectional investigations among children (Liu and Zhang, 2009)� Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and maximal mid-expiratory flow rate (MMEF)/forced expiratory flow between the 25th and 75th percentile of forced vital capacity (FEF25-75) are the three major lung function measures examined in these studies� A previous literature review based on data from 11 cross-sectional studies among 7,588 children in China reported significant aggregated reductions of –17�6 mL in FVC and –16�2 mL in FEV1 per 10 μg/m3 increase in TSP (Liu and Zhang, 2009)� A few studies assessed the association between long-term air pollution exposure and lung function in children (Gao et al�, 2013; He et al�, 2010b)� One study followed 1,983 children prospectively for 6 months in three districts with different air pollution levels in Guangzhou and performed twice lung function tests among the children (He et al�, 2010b)� Compared with children living in the least polluted district, children living in the most polluted district generally had significantly lower annual growth rates in lung function, as measured by FEV1, forced expiratory flows at 25% (FEF25), and FEF25-75� Another cross-sectional study in Hong Kong provided risk estimates for lung function changes in 3,168 children associated with long-term PM10, which was measured at the population level (Gao et al�, 2013)� In addition, one cross-sectional study reported significant inverse associations between short-term levels of smaller particles (PM10 and PM2�5) and eight lung-function measures among 260 children in Beijing (Wang et al�, 2010)�

A panel study investigated the association between a number of air pollutants and 32 chemical constituents of PM2�5 and lung function in a group of healthy volunteers (40 university students) in Beijing during 2010-2011, and provided the first hand information for the potential respiratory effects of various PM chemical constituents in the context of suburban and urban air pollution in China (Wu et  al�, 2013a,d, 2014b,c)� Study participants were measured for lung function biweekly 12 times during three 2-month-long study periods before and after relocating from a suburban area to an urban area (one period in the suburban area and two periods in the urban area) with changing ambient air pollution levels and contents in Beijing� A subgroup of the participants also provided daily morning and evening peak expiratory flow (PEF) and FEV1 measurements over 6 months� Study results suggest that PM2�5 showed the most robust association with lung function among the

major air pollutants measured in the study (e�g�, PM10, PM2�5, PM10-2�5, CO, NOX, and NO2), and several PM2�5 metallic constituents (e�g�, copper, cadmium, arsenic, stannum, calcium, and magnesium) showed consistent inverse associations with lung function measures (Wu et al�, 2013a,d)� Further analyses suggest that PM2�5 from dust/soil and industry sources, which were enriched by these metallic constituents, were most strongly associated with the reductions in lung function measures (Wu et al�, 2014c)� Interestingly, the inverse associations between PM2�5 and lung function measures appeared to be stronger at longer exposure metrics up to 1-2 weeks as compared with those at shorter exposure metrics within a few days, suggesting a potential cumulative exposure effect over time (Wu et al�, 2013d, 2014b)� In addition, the air pollution-lung function association appeared to be modified by ambient temperature, suggesting that it is necessary to account for temperature levels in the assessment of short-term respiratory effects of air pollution exposure (Wu et al�, 2014b)� Another repeated-measure study among 60 truck drivers and 60 office workers measured their postwork lung function and personal PM2�5 exposures on two separate days, and found significant inverse associations of FEV1 and FVC with several crustal metals (i�e�, silicon, aluminum, and calcium) among nine measured PM2�5 elemental constituents (Baccarelli et al�, 2014)� Another panel study based on 40 days of continuously measured data on ambient PM and eight metallic constituents also found significant inverse associations between several metallic constituents (i�e, lead, nickel, iron, manganese, and chrome) and lung function among 107 children in Baotou, an industrial city in northern China (Madaniyazi et al�, 2013)� Most of the identified metallic constituents are transition metals, which are thought to be able to stimulate the production of reactive oxygen species when delivered to the airways, and then induce airway injury and inflammation followed by a series of cardiopulmonary responses (Gonzalez-Flecha, 2004)� However, a recent randomized, doubleblind crossover trial among 35 healthy college students in Shanghai did not observe apparent improvements in lung function after reducing indoor particles of outdoor origin using air purifiers for 48 hours (Chen et al� 2015a)� The reason for nonsignificant change in lung function may be due to the relatively short intervention period�

Several cross-sectional studies also reported positive associations between longterm air pollution exposure and the occurrence of respiratory symptoms in children (Liu et al�, 2013b; Pan et al�, 2010; Zhang et al�, 2002) or adults (Wang et al�, 2011)� The major respiratory symptoms found to be associated with air pollution include persistent cough, persistent phlegm, wheezing, and current asthma� However, air pollution levels in these cross-sectional studies were measured at the population level, and thus limit the reliability of the estimated respiratory effects of air pollution�

In addition, several studies also assessed the potential respiratory effects of air pollution using biomarkers determined in human biological samples (Chen et al�, 2015a; Lin et al�, 2011; Huang et al�, 2012c)� As aforementioned, stringent air pollution control reduced the air pollution levels during the 2008 Beijing Olympics substantially, providing a unique opportunity to observe the air pollution effects over time� One panel study examined the association between ambient PM2�5 and BC levels and exhaled nitric oxide (eNO), an acute respiratory inflammation biomarker, among 36 children over five visits before and during the Olympics (Lin et al�, 2011)� The study found that both air pollution concentrations and eNO were clearly lower during the

Olympics, and 24-hour average BC and PM2�5 concentrations showed significant positive associations with eNO� The association between BC and eNO also appeared to be stronger than that between PM2�5 and eNO� Another panel study also investigated the relationship between air pollution levels and a group of biomarkers reflecting pulmonary inflammation and pulmonary and systemic oxidative stress (i�e�, eNO, exhaled breath condensate markers, and urinary 8-hydroxy-2-deoxyguanosine) among 125 healthy adults over six visits in the pre-(high pollution), during-(low pollution), and post-Olympic (high pollution) periods (Huang et al�, 2012c; Gong et al�, 2014)� Study results suggest significant decreases in the biomarker levels from the pre-to the during-Olympic period and significant increases in the same biomarker levels from the during-Olympic to the post-Olympic period� Statistical analyses also found consistent positive associations between increased pollutant concentrations and biomarker levels� A further analysis from the study showed similar changes for malondialdehyde (MDA), a biomarker of oxidative stress, in exhaled breath condensate samples of the study subjects (Gong et al�, 2013)� In addition, the intervention trial among Shanghai college students also found a significant decrease in eNO associated with the use of air purifiers (Chen et al�, 2015a)� These findings support the important roles of oxidative stress and pulmonary inflammation in mediating air pollution health effects�

1.2.2.2 Cardiovascular Health Effects of Air Pollution The cardiovascular system is another human body system that is susceptible to air pollution, and cardiovascular health effects have been the hot spots in recent air pollution health studies in China� Several well-conducted panel studies have provided a general view for the potential subclinical cardiovascular effects that air pollution may induce� The most commonly investigated cardiovascular health indicator is HRV, followed by BP and circulating biomarkers�

Changes in HRV can reflect altered function in autonomic nervous system (ANS), which is considered as one of the pathophysiologic pathways through which air pollution influences the cardiovascular system (Pope et al�, 2004)� An earlier panel study which followed 11 taxi drivers around the Beijing Olympics provided the first detailed assessment on the subclinical health effects of air pollution changes around the Olympics (Wu et al�, 2010)� This study measured taxi drivers’ in-car exposure to PM2�5 and gaseous air pollutants and ambulatory electrocardiography (ECG) in a 12-hour work shift in each of the before, during, and after the Olympic periods, and found significant improvements in drivers’ HRV levels during the Olympics, when the air pollution levels were lower� In contrast, the HRV levels were much lower when the air pollution levels were higher, before and after the Olympics� Among the air pollutants, PM2�5 was found to have the strongest inverse association with changes in 5-min HRV indices during the measurement periods� Further analyses revealed significant associations between acute CO exposure and 5-min HRV (Wu et al�, 2011b) and between certain PM2�5 chemical constituents and 12-hour HRV (Wu et al�, 2011a)� Interestingly, the association between air pollution and HRV also appeared to be modified by temperature (Wu et al�, 2013c)� Significant improvements in HRV were also observed in another two panels of patients with cardiovascular disease during the Olympics, and ambient PM (PM10 or PM2�5) levels were found to be significantly inversely associated with HRV changes among the patients (Huang et al�, 2012d;

Jia et al�, 2009; Xu et al�, 2013)� The association between air pollution and HRV levels may vary by subject characteristics such as body mass index, gender, systemic inflammation status, and disease status such as type 2 diabetes (Huang et al�, 2012d; Sun et al�, 2015)� Another panel study also reported an inverse association between shortterm O3 exposure and HRV among 20 healthy elders in Beijing (Jia et al�, 2011a)� Notably, two panel studies among healthy elderly or young subjects found evidence for the positive associations between air pollution and HRV changes (Wu et al�, 2010; Jia et al�, 2012b), suggesting a potential heterogeneous pattern of cardiac response to external stimuli among healthy subjects as compared with that among susceptible subjects� Several randomized, crossover intervention studies in Beijing also observed higher HRV levels under exposure scenarios with lower air pollution levels (in parks or with a highly efficient facemask) and lower HRV levels under exposure scenarios with higher air pollution levels (in traffic centers or without the facemask) in either healthy subjects or patients with coronary heart disease (Huang et al�, 2013; Langrish et al�, 2009; Langrish et al�, 2012)� Specifically, one of the studies exposed 40 healthy participants to two different scenarios (traffic center and park) for 2 hours in two separate occasions and found amplified air pollution effects on HRV at high noise levels, (>65�6 A-weighted decibels (dB[A])) than at low noise levels, (<65�6 dB[A]), suggesting that noise is an important modifier of the air pollution effects on HRV (Huang et al�, 2013)� In addition, another panel study also found evidence for the association between size-fractioned ultrafine particles and BC and autonomic dysfunction in 53 subjects with diabetes or impaired glucose tolerance, and the association tended to be larger for particles with smaller size fractions (Sun et al�, 2015)�

BP is another cardiovascular health indicator frequently examined in air pollution health studies� The aforementioned study among truck drivers and office workers measured their postwork BP twice and found significant positive associations of ambient PM10 with systolic, diastolic, and mean BPs in the study subjects (Baccarelli et al�, 2011)� Two other repeated-measure studies reported significant increases in ambulatory BP levels in association with short-term PM2�5 and BC exposures within minutes and hours among patients with cardiovascular disease or metabolic syndrome (Huang et al�, 2012d; Zhao et al�, 2014b)� The aforementioned panel study among 125 healthy adults around the Olympics found a significant increase in systolic BP from during the Olympics to post-Olympics, whereas the association pattern with multiple pollutants was not consistent (Rich et al�, 2012)� A randomized crossover study found significant lower systolic BP in 15 healthy subjects during 2-hour city walk with a highly efficient facemask versus without the facemask (Langrish et al�, 2009), and a later similarly designed study also found significant lower mean arterial pressure in 98 patients with coronary heart disease under the exposure scenario with the facemask versus without the facemask (Langrish et al�, 2012)� A panel study among 35 diabetes patients with six repeated measurements found that the association of systolic BP and pulse pressure with airborne PM strengthened with decreasing diameter, and these effects occurred immediately even after 0-2h and lasted for up to two days following exposure (Zhao et al�, 2015)� These findings provide evidence for potentially important size and temporal patterns of airborne PM in elevating BP among susceptible individuals� The aforementioned panel study among 40 university students who relocated between the Beijing suburban and urban

areas provided a detailed investigation for the associations between various air pollutants and PM2�5 chemical constituents and BP changes observed over the study (Wu et al�, 2013b)� Study results suggest that several combustion-related constituents (i�e�, EC, OC, chloride) and metallic constituents (i�e�, nickel, zinc, magnesium, lead, and arsenic) showed the most consistent positive associations with BP variables� Further analyses revealed that PM2�5 from coal combustion, which was enriched by carbonaceous fractions and chloride, was most strongly associated with the increased BP in the study subjects (Wu et al�, 2014c)� In addition, this study also found significant interactions between major air pollutants and temperature, as evidenced by stronger estimated air pollution effects on BP at low temperature (<median) than at high temperature (≥median) (Wu et al�, 2015b)� Furthermore, the intervention trial among Shanghai college students found significant reductions in BP after using air purifiers (Chen et al�, 2015a)� In addition, there are also several reports on long-term exposure to air pollution and BP from large cross-sectional studies� One cross-sectional study reported a potential association between long-term air pollution and increased BP among 24,845 Chinese adults in three northeastern cities (Dong et al�, 2013)� A further cross-sectional study with 9,354 children found stronger associations between long-term air pollution exposure and BP and hypertension in obese/overweight children than those in normal weight children, suggesting that obesity may amplify the adverse effects of air pollution on BP and hypertension (Dong et al�, 2015)�

Several panel studies also collected repeated blood samples over time among the study subjects and attempted to quantify the association between air pollution exposure and levels of circulating biomarkers which could reflect cardiovascular health status� One study measured 24-hour personal PM2�5 exposure and a group of inflammatory and immune biomarkers twice among 110 traffic policemen in Shanghai and found that higher PM2�5 exposure was associated with increases in high-sensitivity C-reactive protein (CRP), IgG, IgM, and IgE, and decreases in IgA and CD8 T cells (Zhao et al�, 2013)� The panel study among 125 healthy adults examined several biomarkers of systemic inflammation (CRP, fibrinogen, and white blood cell count) and thrombosis or endothelial dysfunction (soluble P-selection, soluble CD40 ligand, and von Willebrand factor [vWF]) over six study visits and found generally similar changing trends in levels of these biomarkers and air pollutants around the Olympics (Rich et al�, 2012)� Statistical analyses further demonstrated significant associations between air pollution and biomarker levels, suggesting a potential effect of air pollution on cardiovascular physiology in healthy young persons (Rich et al�, 2012; Gong et al�, 2014)� A further analysis from this study found varying levels of vWF according to vWF gene polymorphism, which may have affected the participants’ response to air quality improvements (Yuan et al�, 2013)� The panel study among 40 university students in Beijing collected 12 repeated blood samples over the study and provided a detailed assessment for the associations between various air pollutants and PM2�5 chemical constituents and biomarkers of inflammation, coagulation, and homocysteine (Wu et al�, 2012)� Several metallic constituents (i�e�, zinc, stannum, magnesium, iron, titanium, cobalt) were found to have robust positive associations with levels of inflammatory biomarkers (tumor necrosis factor alpha [TNF-a] and fibrinogen), and further analyses revealed positive associations between levels of these biomarkers and PM2�5 from secondary sulfate/nitrate and dust/soil, which were

enriched by the identified metallic constituents (Wu et al�, 2014c)� In contrast, the associations of coagulation and homocysteine biomarkers with air pollutants have been less consistent Nevertheless, a recent panel study in 34 healthy young adults in Shanghai found significant increases in biomarkers of inflammation (e�g�, CRP, fibrinogen, monocyte chemoattractant protein-1), coagulation (vWF, plasminogen activator inhibitor-1, CD40 ligand) and vasoconstriction (endothelin-1) in association with PM with smaller size within 24 hours of exposure (Chen et al� 2015b)� The aformentioned intervention trial among college students also found significant decreases in several inflammation and coagulation biomarkers after using air purifiers, suggesting a consistent pattern of cardiovascular benefits associated with air quality improvement (Chen et al�, 2015a)�

1.2.2.3 Other Subclinical Health Effects of Air Pollution A few studies also investigated the associations between air pollution and other subclinical health effects, such as alterations in neurobehavioral function, systemic oxidative stress, micronuclei frequency, and epigenetics� For example, a cross-sectional study performed multiple neurobehavioral function tests (e�g�, line discrimination, visual retention, continuous performance, digit Symbol, pursuit Aiming, sign register) among 431 schoolchildren from a clean area with low air pollution levels and 430 schoolchildren from a polluted area with high air pollution levels in Quanzhou and found that children from the polluted area showed poor performance on all neurobehavioral function tests (Wang et al�, 2009a); a study in Beijing repeatedly measured two security guards’ exposures to ambient PM2�5 and related chemical species at the work site near a heavy traffic road and their pre-and post-work-shift urinary levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG, a biomarker of oxidative stress and DNA damage) for 29 days, and found that post-work-shift urinary 8-OHdG concentrations were significantly and positively associated with PM2�5, polycyclic aromatic hydrocarbons (PAHs), and metals, whereas pre-work-shift 8-OHdG concentrations were only associated with PM2�5 at the background site (Wei et al�, 2009, 2010); a study among 110 policemen and 110 controls measured their 24-hour personal PM2�5 exposures and blood benzo[a]pyrene (BaP) 7,8-diol-9,10-epoxide-DNA adducts (another biomarker of DNA damage) and urinary 1-hydroxypyrene (1-OHP, a metabolite of PAH exposure), and found that policemen had higher levels of these biomarkers compared with controls, and PM2�5 exposure was associated with a 0�8% increase in blood BaP 7,8-diol-9,10-epoxide-DNA adducts and 1�1% increase in 1-OHP after adjusting for potential confounders (Li et al�, 2014b); a panel study measured urinary MDA levels among 120 schoolchildren from two cities in China and two cities in Korea for five consecutive days, and found significant increases in urinary MDA levels associated with ambient PM levels (Bae et al�, 2010); the panel study among 40 university students found that a subset of PM2�5 metals (e�g�, iron and nickel) were more closely associated with increased plasma oxidized low-density lipoprotein, another biomarker of systemic oxidative stress, than major air pollutants (Wu et al�, 2015c)� the study among Beijing truck drivers and office workers also found a significant inverse association between ambient PM10 and shorter telomere length, a biomarker of cardiovascular risk that is modified by inflammation and oxidative stress (Hou et al�, 2012), and an inverse association between air pollution and

mitochondrial DNA copy number, a marker of mitochondrial damage and malfunctioning that is associated with various diseases or conditions (Hou et al�, 2013); a cross-sectional study evaluated the genotoxic effects of ambient air pollution among 129 rural and industrial female residents in Shenyang using micronuclei assays and polymorphic analyses of metabolic enzyme and DNA repair genes, and found that industrial female residents who exposed to higher air pollution levels had a higher micronuclei frequency, a sensitive marker of DNA damage (Ishikawa et al�, 2006); and several cross-sectional or longitudinal studies also reported a potential association between air pollution and adverse reproductive health, such as slower fetal and child growth and development and decreased semen quality in adult men (Tang et al�, 2014; Zhou et al�, 2014b)�

While human subclinical health studies provide clues for the mechanistic pathways through which ambient air pollution may promote the development of adverse health outcomes (i�e�, mortality and morbidity), more direct evidence for the biological mechanisms of air pollution action comes from toxicological studies� Toxicological studies include in vitro studies and in vivo studies, which expose cells and animals to air pollutants experimentally and compare the observed biological responses under different exposure conditions� The high doses used in the toxicological studies are usually able to induce a series of in vitro and in vivo biological responses in a dose-dependent manner, which may then help to clarify the mechanisms of air pollution action� To date, a majority of toxicological studies in China have been conducted to investigate the biological effects of ambient PM on the respiratory and cardiovascular systems� Among the ambient particles, PM2�5 has been shown to possess stronger cytotoxicity than larger particles (Hsiao et al�, 2000), and thus has received increasing attention in recent years� Table 1�2 summarizes the evidence for the biological pathways of air pollution action based on toxicological studies and subclinical health studies in China in recent years�

A significant body of evidence suggests that PM exposure may lead to increased pulmonary and systemic inflammation (Bai et al�, 2007), and pulmonary inflammation may play a major role in enhancing the extrapulmonary translocation of particles (Chen et al�, 2006)� Exposure to ambient particles has been shown to increase the secretion of inflammatory factors (e�g�, TNF-a, interleukins) in human and animal lung cells (Jia et al�, 2006) and animal respiratory and circulatory systems (Chen et al�, 2013c; Deng et al�, 2010; Yoshida et al�, 2010), cause lung and systemic inflammation by enhancing inflammatory cells recruitment (Liu et al�, 2014a; He et al�, 2010a), and induce airway injury in animals (Yoshida et al�, 2010)� Specifically, an in vivo study exposed mice to Beijing PM2�5 and filtered air during and after the 2008 Beijing Olympics, and found that short-term increases in exposure to ambient PM2�5 led to increased systemic inflammatory responses, as demonstrated by increased levels of several biomarkers (e�g�, monocyte chemoattractant protein 1 and interleukin 6) and enhanced recruitment of macrophages and neutrophils in the lung, spleen, and visceral adipose tissue, whereas short-term air quality improvements were significantly associated with reduced overall inflammatory responses (Xu et al�, 2012)�

TABLE 1.2 Summary of Evidence for the Biological Pathways of Air Pollution Action Based on Toxicological Studies and Subclinical Health Studies in China

TABLE 1.2 (Continued ) Summary of Evidence for the Biological Pathways of Air Pollution Action Based on Toxicological Studies and Subclinical Health Studies in China

Exposure to other gaseous air pollutants, such as O3 and SO2, has also been found to cause increased lung inflammation by triggering expressions of inflammatory factors in animals (Bao et al�, 2013; Li et al�, 2007)� Specifically, one study found that exposure to SO2 affects the mRNA and protein expression levels of several asthmarelated genes in asthmatic rats, suggesting that SO2 pollution may aggravate asthma disease through increasing the expressions of relevant genes at the transcriptional and translational levels in the lungs and tracheas (Li et al�, 2007, 2008)�

In addition, involvement of the immune system (e�g�, T-cell activation) has also been implicated in the animal’s response to PM exposure (He et al�, 2010a; Yoshida et al�, 2010), and exposure of pregnant mice to PM can result in postnatal immune dysfunction by exacerbation of Thl/Th2 cell deviation in mice offspring (Hong et al�, 2013)� An in vivo study showed that PM2�5 exposure can result in whole-body insulin resistance by regulating inflammation in visceral adipose tissues, hepatic lipid metabolism, and glucose utilization in skeletal muscle in mice via both CC-chemokine receptor 2 (CCR2, a molecule that plays a critical role in the entry of innate immune cells into tissue) –dependent and –independent pathways, providing new mechanistic links between air pollution and metabolic abnormalities (Liu et al�, 2014a)�

Oxidative stress is another pathway proposed to be involved in the air pollution effects� Exposure to PM10 has been shown to increase the MDA levels and decrease the activities of superoxide dismutase, an important antioxidant defense, in the serum, lung, and heart tissues in rats (Lu et al�, 2011)� Exposure to PM2�5 can trigger oxidative stress in brown adipose tissues, as demonstrated by increased production of reactive oxygen species in brown adipose depots (Xu et al�, 2011)� PM2�5-induced oxidative stress has been shown to trigger autophagy in human lung cells, which may contribute to the PM-induced impairment of lung function (Deng et al�, 2013)� An in vitro study also investigated the chemical constituents and pollution sources behind the PM2�5induced oxidative stress in human bronchial epithelial cells and found that a secondary source (e�g�, sulfate and nitrate) explained the largest fraction of reactive oxygen species variability observed in experiments (Liu et al�, 2014b)�

Cardiac ANS function is a cardiovascular health indicator that is sensitive to external stimuli, as reflected by changes in HRV� An in vivo study found that intratracheal instillation could cause arrhythmia in rats (Deng et al�, 2009a)� Another in vivo study explored the cardiac effects of BC, a major constituent of ambient PM, and found significant decreases in several HRV indices at higher BC exposure doses in mice (Jia et al�, 2012a)� Interestingly, only slight pulmonary inflammation and myocardial injury were observed in exposed mice, suggesting that BC can disturb cardiac ANS function through mechanisms independent of apparent myocardial and pulmonary injury�

Exposure to ambient PM also affects coagulation function� Animals exposed to PM2�5 showed decreased plasma prothrombin time and increased plasma levels of fibrinogen and tissue factor, suggesting a hypercoagulable status after exposure (Deng et al�, 2010)� Additionally, nickel sulfate-treated animals also showed similar changes in coagulation function, suggesting that nickel may play a role in PM-related coagulative effects�

Recent in vivo experiments have shown that PM2�5 modulates lipid metabolism (Liu et al�, 2014a), and results from another in vivo study suggest that PM exposure can accelerate atherosclerosis in animals (Chen et al�, 2013c)� The latter study investigated

the long-term effects of PM exposure by exposing apolipoprotein E knockout mice to ambient PM and filtered air in Beijing for 2 months, and found that the serum total cholesterol and low-density lipoprotein levels of PM-exposed mice were significantly higher than those of filtered-air-exposed mice� Pathological analysis revealed that the plaques area in the aortic arch of the PM-exposed mice increased significantly as compared with that of the filtered-air-exposed mice, suggesting that PM exposure could contribute to the progression of atherosclerosis (Chen et al�, 2013c)�

The neurotoxicity of air pollution has also been investigated� A toxicological study showed that SO2 exposure could produce a neuronal insult, and the neurotoxic effect was likely via stimulating cyclooxygenase-2 elevation by activation of nuclear factor (NF)-κB activity and its acting on the promoter-distal NF-κB-binding site of cyclooxygenase-2 promoter (Sang et al�, 2011)�

Several in vitro studies also investigated the cytotoxic effects of ambient PM, especially PM related to Asian dust storms (Deng et al�, 2007; Wang et al�, 2006; Wei and Meng, 2006)� An early study found that solvent-extractable organic compounds of PM2�5 could induce DNA damage (Hsiao et al�, 2000), and a later study demonstrated that dust-storm PM2�5 and its extract can induce increased chromosomal aberration (Wei and Meng, 2006)� Other studies showed that both organic and inorganic extracts of dust storms and normal PM2�5 could inhibit cell proliferation and induce cell arrest (Deng et al�, 2007), whereas organic extract of PM2�5 showed stronger inhibitory effects on the gap-junctional intercellular communication than inorganic extract (Wang et al�, 2006)�

An in vitro study demonstrated the first transcriptomic investigation in the air pollution research field in China using a genome-wide approach (Ding et al�, 2014)� The authors identified alterations in a series of genes and pathways after exposing human bronchial epithelial cells to different concentrations of PM2�5 collected in a Chinese megacity� The altered genes included those involved in inflammatory and immune response, response to oxidative stress, and response to DNA damage stimulus� Pathway analysis revealed that different doses of PM2�5 triggered partially common disturbed pathways for cellular processes, environmental information processing, genetic information processing, and metabolism� Flow cytometry assay suggested that there were statistically significant differences in the G1 phase of the cell cycle after low-or high-dose PM2�5 exposure when compared with the unexposed controls, and only high-dose PM2�5 significantly increased the proportion of cells in the S phase of the cell cycle� This study provides a novel approach to investigating the biological mechanisms underlying PM2�5-induced adverse health effects�

Epigenetic changes associated with air pollution exposure have become a new research spot in recent years� Reduced levels of DNA methylation have been linked to aging, oxidative stress, and cardiovascular disease� Several additional analyses from the Beijing truck driver study provide the first effort to link air pollution and epigenetic changes in China� While small mitochondrial DNA methylation was not associated with traffic-related PM exposure among the study participants (Byun et al�, 2013), significant associations between air pollution and methylation of three DNA tandem repeats (i�e�, SATa, NBL2, and D4Z4) were observed (Guo et al�, 2014; Hou et al�, 2014)� A recent study found decreases in DNA methylation of NOS2A (the encoding gene of eNO) and increases in eNO in association with PM2�5 and its major constituents (OC, EC, nitrate and ammonium), suggesting that NOS2A methylation

may be important in the pathway of PM2�5-mediated airway inflammation (Chen et al�, 2015c)� Nevertheless, the underlying mechanisms involved and the health implications of these air pollution-related epigenetic changes have not been fully understood and thus require further investigation�

Accurate measurement on exposure to air pollution is critical for the assessment of associated health effects, as inaccurate measurement could lead to misclassification of exposure and result in uncertainty in the estimated health effects�

Typical approaches used for exposure measurement in outside environment include proximity, fixed-site air-monitoring, and personal-level measurement� Proximity is a relatively inaccurate estimation method as it assumes that closer proximity to pollution sources (e�g�, busy roads) equates greater exposure, which is not always the case� China has established a national routine ambient air-monitoring system for several major air pollutants, including PM10, NO2, and SO2, and day-to-day data on these air pollutants have been frequently used in epidemiologic studies (e�g�, time-series studies) in China� Epidemiologic studies based on one single city may use air-monitoring data from one site or multiple sites� However, measurement error or misclassification associated with the use of fixed-site air-monitoring data is a major issue encountered by epidemiologic studies (Zeger et al�, 2000)� An exposure assessment compared the PM2�5 and CO exposure concentrations measured at personal levels under several commuting modes (taxi, bus, and cycling) and fixed-site air-monitoring data in a Beijing urban area, and found that exposures measured at personal levels were significantly different from those measured at a fixed site near the study location (Huang et al�, 2012a)� Generally, nondifferential misclassification of exposure will lead to underestimated health effects associated with air pollution� Interestingly, a recent panel study compared the effects of short-term exposure to outdoor PM obtained from fixed-site air-monitoring stations and outdoor-originated equivalent personal PM (calculated from outdoor PM with incorporation of time-activity data) on lung function in COPD patients, and found that the use of outdoor PM from central air-monitoring stations may overestimate the potential air pollution effects on lung function (Ni et al�, 2016)� Therefore, research findings based on fixed-site monitoring data should be interpreted cautiously, given the inherent limitation of exposure misclassification and additional efforts are needed to address this issue whenever possible�

Exposure measurement at personal levels could provide more accurate estimates for individuals’ “real exposure” to air pollution, and thus help to avoid the issue of exposure misclassification� Instruments are usually placed at or near participants’ breathing zone during the measurement periods, which commonly last for a few to 24 hours� However, personal-level exposure measurement is not applicable for large-scale epidemiologic studies due to the measurement burden and economic cost, and only several panel and experimentally designed studies in China have measured air pollution exposures at personal levels (Huang et al�, 2012a, 2013; Langrish et al�, 2009, 2012; Wu

et al�, 2010)� Studies using personal-level measurement data could provide more reliable estimates for the health effects associated with air pollution exposure for the study participants� Nevertheless, the generalizability of the study findings is often limited, given the limited numbers of participants that could be included in such studies�

Standard measurement protocols with stringent quality controls are essential for reliable air pollution measurement and assessment of associated health effects� This issue is especially important for investigator-self-administered measurement� Standard methods for the measurements of different air pollutants are provided in the modified national AAQS (Ministry of Environmental Protection of China, 2012)� Here, we give a brief summary on the measurement methodology for airborne PM in China as an example� The mainstream PM monitoring methods include β-ray method, tapered element oscillating microbalance technology, and gravimetric analysis� However, significant measurement inconsistency may exist for commercially available PM monitors� For example, a previous study demonstrated that PM2�5 concentrations measured by three different types of real-time laser light-scattering aerosol monitors varied substantially under the same measurement conditions (Deng et al�, 2009b)� The measured air pollution levels may also be affected by meteorological factors such as temperature, relative humidity, and wind (Jian et al�, 2012)� Therefore, it is important to calibrate or control for the potential measurement error in air pollution monitoring� A more reliable technique used for PM measurement is gravimetric analysis, which collects airborne particles on specific filters that are weighed before and after sampling� This technique has been recognized as an official PM measurement method (Ministry of Environmental Protection of China, 2013) and has been increasingly used in investigator-self-administered studies (Huang et al�, 2012a; Langrish et al�, 2012; Wu et al�, 2010, 2013b)�

Another approach used for exposure assessment is spatiotemporal air pollution modeling, which can predict general air pollution or individuals’ exposure based on routine fixed-site air-monitoring data as well as geographic information, including meteorology, land use and elevation, population density, road networks, and point source emission data (Yanosky et al�, 2008)� Utility of such modeled data in assessing health effects associated with air pollution has been demonstrated in epidemiologic studies in developed countries (Puett et al�, 2011; Beelen et al�, 2014)� A similar approach has also been applied to model regional air pollution in China (Fu et al�, 2009; Zhang et al�, 2013; Wu et al�, 2015a), whereas further work is needed to link the modeled air pollution data with health observations in China�

In contrast to traditional exposure assessment, which measures the air pollution levels in outside environment, internal exposure assessment estimates the exposure levels by measuring biomarkers in biological samples, which may provide more accurate information regarding the dose of exposure and retention of toxic chemicals� For example, a follow-up study estimated two groups of newborns’ exposure to PAHs by measuring PAH-DNA adduct levels in cord blood and found that lower PAH-DNA adduct levels correlated with the reduced levels of ambient PAHs (Tang et al�, 2014); the panel study among 120 schoolchildren in China and Korea measured urinary levels of 1-OHP and found a positive association between urinary 1-OHP and MDA levels (Bae et al�, 2010); another study measured urinary levels of nine monohydroxylated PAH metabolites among two groups of children from a polluted area near a heavy traffic road and a nonpolluted area near a university campus,

and found that children from the polluted area had higher urinary levels of six PAH metabolites than those from the nonpolluted area (Fan et al�, 2012)� Similar to the personal-level measurement, the biomarker approach for exposure assessment is also not feasible and cost-effective for large-scale studies�

As documented in the background, air pollution levels in China are still at the higher end of the world� The typical levels of ambient air pollutants reported in epidemiologic studies in China are generally higher than those reported in studies from developed countries� In a meta-analysis based on data from 33 epidemiologic studies in China, the summarized daily average concentration ranges of major air pollutants were 44-172 μg/m3 for PM10, 55-177 μg/m3 for PM2�5, 29-113 μg/m3 for SO2, 26-70 μg/m3 for NO2, and 1�10-1�80 mg/m3 for CO, and 8-hour average O3 concentrations ranged in 56-86 μg/m3 (Shang et al�, 2013)� Specifically, one previous study measured the ambient PM levels around the Beijing Olympics at a fixed site in Beijing (Peking University) and found that the PM10 levels in Beijing were 1�9-3�5 times higher than the other three Olympic cities (Wang et al�, 2009b)� The mean PM10 concentrations during the Olympics were 28�1, 23�7, 44�3, 82�4, and 53�7 μg/m3 in Atlanta (1996), Sydney (2000), Athens (2004), Peking University (2008), and Beijing average (2008), respectively (Wang et al�, 2009b)�

PM exposures measured at the personal level appear to be much higher in studies from China as compared with those in studies from developed countries, whereas the differences in levels of gaseous air pollutants are not apparent� For example, one panel study measured 11 taxi drivers’ in-car exposure to several air pollutants around the Beijing Olympics, and the average exposure levels were 55�6 μg/m3 for PM2�5, 4�2 μg/m3 for EC, 2�6 parts per million (ppm) for CO, and 38�2 parts per billion (ppb) for NO2 (Wu et al�, 2011a)� In contrast, another panel study in the United States measured 10 patrol troopers’ in-car exposure to air pollutants, and the average exposure levels were 23�0 μg/m3 for PM2�5, 2�3 μg/m3 for EC, 2�6 ppm for CO, and 41�7 ppb for NO2 (Riediker et al�, 2003)�

Several studies also reported levels of organic compounds including PAHs and volatile organic compounds (VOCs) in ambient air� One study determined concentrations of 17 carcinogenic PAHs in ambient PM2�5 samples during different periods around the Beijing Olympics, and the average total BaP equivalent concentrations of these PAHs changed from 5�95 ng/m3 in the source-control period (before and during the Olympics) to 11�1 ng/m3 in non-source-control period (after the Olympics) (Jia et al�, 2011b)� Another study reported an average BaP equivalent concentration of 82�4 ng/m3 for 16 PAHs that is much higher than the national AAQS (24-hour average: 2�5 ng/m3) at the road intersections where the traffic policemen stand during their work time in Tianjin (Hu et al�, 2007)� In addition, one study measured 27 VOC species in 14 sampling sites in nine southeast coastal cities of China over two 10-day periods in winter and summer, and the average total VOC concentration was 214�3 μg/m3 in winter and 111�8 μg/m3 in summer (Tong et al�, 2013)� Another study reported that the daily average concentration of total benzene homologues (e�g�, benzene, toluene, ethylbenzene), the typical components of VOCs, was 11�98 μg/m3 during summertime in Beijing (Li et al�, 2014a)�

Risk assessment is the determination of quantitative or qualitative value of risk related to a concrete situation and a recognized threat (also called hazard)� Ambient air pollution has been recognized as a strong risk factor for chronic respiratory and cardiovascular diseases worldwide, and outdoor air pollution has been classified as a group 1 carcinogen of human cancer (particularly lung cancer) by the International Agency for Research on Cancer� Many risk assessments have been conducted to identify the health risk associated with ambient air pollution in China, among which several assessments also provide quantitative estimates for the potential economic burden that air pollution may cause� To control for the adverse health impact of ambient air pollution, the government has released several modified editions of national AAQS and implemented a series of air pollution control measures�

Several studies have provided risk assessments for the health impact associated with ambient PM air pollution in China (Jahn et al�, 2011; Lai et al�, 2014)� A previous review based on 13 studies with ambient PM data in the Pearl River Delta (PRD) region estimated the potential preventable premature deaths due to PM air pollution in these cities (Jahn et al�, 2011)� Almost all PM data during the period 2000-2004 in the PRD region (PM10 ranged from 57�4 μg/m3 in Hong Kong to 88�3 μg/m3 in Guangzhou) exceeded national and international air quality guidelines, and the estimated impact of current ambient PM10 exposure relative to a standard of 40 μg/m3 causes approximately 117 excess deaths (lower and upper bound: 91, 164) in Guangzhou and 43 excess deaths (lower and upper bound: 32, 62) in Hong Kong per 100,000 population per year� Under the assumption that Guangzhou’s about 10 million inhabitants are on average equally burdened by PM, 11,700 (9100-16,400) premature deaths could have been prevented annually if the PM burden was reduced to 40 μg/m3�

Health risk associated with exposure to organic compounds including PAHs and VOCs is a major focus of air pollution risk assessment in China (Bai et al�, 2009; Hu et  al�, 2007; Jia et al�, 2011b; Li et al�, 2014a; Xia et al�, 2013; Yu et al�, 2008; Zhou et al�, 2011)� PAHs are known for their carcinogenic and mutagenic properties� One risk assessment estimated that the number of lifetime excess cancer cases due to exposure to 17 carcinogenic PAHs measured in ambient PM2�5 samples ranged from 6�5 to 518 per million people for the period before and during the Beijing Olympics and from 12�2 to 964 per million people for the period after the Olympics (Jia et al�, 2011b)� These results suggest a 46% reduction in estimated inhalation cancer risk due to source control measures, suggesting that source control measures during the Beijing Olympics can significantly reduce the inhalation cancer risk associated with PAH exposure in Chinese megacities similar to Beijing� The aforementioned study among policemen in Tianjin also assessed their occupational carcinogenic risk associated with exposure to PAHs, and the estimated risk ranged from 10−5 to 10−3, which was much higher than the acceptable risk level of 10−6 (one per million) (Hu et al�, 2007)�

A risk assessment study estimated health risk associated with ambient benzene homologues (e�g�, benzene, toluene, ethylbenzene) exposure based on measurement

data at a fixed site in Beijing urban area (Li et al�, 2014a)� The result showed that benzene homologues had no appreciable adverse noncancer health risks for the exposed population, while benzene had a potential carcinogenic risk of 13�4 per million� Another study measured 12 participants’ personal and outdoor exposure to VOCs for 5 days and estimated the associated cumulative cancer risk, which were 44 per million for personal exposure and 30 per million for outdoor exposure (Zhou et al�, 2011)�

A few studies also assessed the health risk associated with airborne heavy metals� For example, one study estimated that the hazard quotient associated with ambient lead exposure was 0�36 for adults and 2�8 for children in a Shanghai district, suggesting that the health risk in children from lead exposure was unacceptable (Chen et al�, 2011c)� Another study assessed the contamination and health risk of several metal(loid)s (e�g�, arsenic, manganese, copper, nickel, zinc, chrome, cadmium, mercury, lead) in outdoor and indoor particles in Guangzhou and found that arsenic was the most risky element in terms of noncarcinogenic risk (Huang et al�, 2014a)� A recent risk assessment also evaluated the noncarcinogenic risk and carcinogenic risk associated with several metals in PM2�5 and PM10 in Hangzhou and found that the excess lifetime carcinogenic risks of Cr in particles of five sampling sites were all higher by one or two orders of magnitude than 1 per million, which might pose cancer risks to human health (Niu et al�, 2015)�

Ambient air pollution in China may result in considerable economic burden� An earlier study assessed the economic burden related to particulate air pollution in 111 Chinese cities which accounted for 70% national GDP in 2004, and the total annual economic cost caused by PM10 was estimated to be approximately USD 29,178�7 million in 2004 (Zhang et al�, 2008)� Another economic assessment estimated that the implementation of several low-carbon energy scenarios could prevent 2804-8249 and 9870-23,100 ambient PM10-related avoidable deaths in 2010 and 2020, respectively, among Shanghai residents, and the associated economic benefits could reach USD 507-1492 and USD 2642-6192 million, respectively (Chen et al�, 2007)� A later economic assessment found that population-weighted PM10 exposure during the Beijing Olympics came down by 46% and 19% respectively, as compared with the pre-and post-Olympic periods, and the economic cost associated with human health during the Olympics came down by 38% and 16%, respectively, as compared with the preand post-Olympics (Hou et al�, 2010)� In addition, the daily health economic cost associated with ambient PM10 ranged from USD 17�12 to 24�52 million during 20052008 in Beijing, accounting for 4�61% to 7�27% of the daily GDP in respective years�

China’s government has implemented a series of intervention measures in order to control the exacerbating ambient air pollution along with the rapid socioeconomic development� These measures include the release of modified national AAQS, implementation of new vehicle emission standards, changes in industrial structure and improved energy efficiency, use of clean energy (e�g�, gas, electricity) and preferred use of clean coal, and controlled reduction in pollution sources and emissions� It has been reported that

Beijing’s air quality is mainly driven by the interaction between pollution sources change and implementation of air pollution control measures, and the air pollution control has contributed to the reduction in air pollution in Beijing (Zhang et al�, 2011a)� However, the appearance of haze episodes in recent years indicates that it will still be a long process to clean the ambient air in China, and temporary and less intensive control measures have limited effectiveness in reducing the frequency of hazy weather occurrence (Tao et al�, 2014a)� Nevertheless, a national monitoring system has been introduced for PM2�5, the central government has committed to spend ¥3�4 trillion yuan (~USD 0�55 trillion) on environmental protection in the 12th five-year plan period from 2011 to 2015, and the governmental air pollution prevention action plan has also proposed a series of more stringent control measures (Chinese Central Government, 2013)�

A number of studies ranging from epidemiology to toxicology have provided strong evidence that exposure to ambient air pollution has appreciable impact on human health in China� Although the evidence is not always consistent, given the various air pollutants and health endpoints that examined in the scientific investigation and the heterogeneous nature of the differentially designed studies, it is no doubt that ambient air pollution contributes to the increased health burden in the Chinese population� Based on the strength, consistency, and coherence of the existing scientific findings, we summarize the main points that have been achieved regarding ambient air pollution and its health effects in China as follows:

• The ambient levels of major air pollutants (i�e�, PM, SO2, NO2, CO, and O3) are generally higher in China than the levels reported in studies from developed countries� Ambient PM2�5 concentrations are particularly high in major Chinese cities during recent years�

• A substantial body of epidemiologic evidence supports the relationship between short-term (day-to-day) exposure to ambient air pollution and increased daily mortality� Evidence for the link between short-term exposure and increased morbidity has been accumulating but is less consistent� Cardiovascular and respiratory diseases are two major components that constitute the excess deaths and morbidity events associated with air pollution exposure�

• Several major air pollutants, including PM and gases (SO2, NO2, CO, and O3), all have been associated with the increased adverse health outcomes, although the relative importance between these pollutants has been uncertain, given that it is hard to differentiate the health effects of these pollutants on the exposed population in the context of the natural environment�

• The existing evidence suggests that the air pollution-health risk relationships may be monotonic without a “safe” threshold, though a “flattening out” phenomenon at higher concentrations has been implicated for the air pollution-mortality relationship (Kan et al�, 2007)�

• Available studies are suggestive that reductions in air pollution levels can improve cardiovascular function among healthy adults and patients within a few hours and days�

• Preliminary evidence suggests that PM’s health effects are affected by its physical and chemical properties� Smaller size-fractioned particles and certain chemical constituents of PM (e�g�, BC/EC, organics, metals) appear to be more closely related to the observed health effects associated with PM exposure�

• Many biological mechanisms have been proposed for the action of air pollution exposure� Epidemiologic and toxicological evidence has been increasingly supportive for several of the mechanisms, among which increased pulmonary and systemic inflammation and cardiac ANS imbalance have been most frequently documented�

However, the overall evidence for the adverse health impact of ambient air pollution is still underreported in China as compared with that from the developed countries in North America and Europe� A majority of the published studies in China have not been available until recently� Given the high air pollution levels present in China associated with the accelerating socioeconomic development of the nation and the fact that China’s population accounts for over 20% of the world’s total population, the potential health and economic burdens that could be attributed to exposure to ambient air pollution in China will be tremendous� Therefore, determining the directions for future air pollution health investigation is critical for the prevention of the air pollution-related health burden in China� Based on the lessons learned and shortages present in the available studies, the following strategic areas will be worth while to consider in future investigations in China:

• Investigate the health implications of exposure to the mixture of various air pollutants (e�g�, PM and gaseous air pollutants) and differentiate the relative importance of major air pollutants by using integrated research methodologies (e�g�, controlled exposure, improved study design, and stringent statistical analysis)�

• Better document the influence of PM physical and chemical properties on the observed PM-related health effects and explore the responsible pollution sources behind the observed health effects�

• Better investigate the effective biological mechanisms of pathophysiological relevance (e�g�, inflammation, oxidative stress, coagulation) through which short-term and long-term air pollution may promote the development of adverse health outcomes in the context of high air pollution in China� Evidence for the long-term exposure and development of chronic diseases (e�g�, hypertension, diabetes, metabolic syndrome, cancer) is especially lacking and needed�

• Integrate the subclinical health effects and adverse health outcomes observed in epidemiologic studies and biological mechanisms of air pollution action elucidated by toxicological studies, and clarify the public health implications of such integrated evidence�

• Determine the long-term effects of ambient air pollution in populations using prospective study design and better exposure assessment approaches� Although the potential long-term effects of air pollution have been implicated by a few epidemiologic studies in China, the risk estimates are diverse and less reliable due to the retrospective study design as well as unperfected exposure assessment methodologies which may lead to substantial exposure misclassification�

The current evidence is far from sufficient for the establishment of exposureresponse relationships between mediate (a few to 12 months) to long-term (years) air pollution exposure and adverse health outcomes (e�g�, increased incidence and mortality of diseases) in the context of high pollution levels in China� To control for the various biases present in the available studies, future studies using prospective study design (e�g�, cohort study) and more reliable exposure assessment methodologies are necessary� Specifically, a prospectively designed cohort study focusing on the pathogenesis of cardiopulmonary diseases associated with particulate air pollution has been established in China and the investigation is underway (Song et al�, 2014)� Evidence from such longterm follow-up studies will provide important base for the formulation of longterm air quality standards that are practically feasible for China�

• Determine the short-term and long-term health benefits in the population that may be gained owing to the reductions in air pollution levels� As China has strived to control the ambient air pollution with great efforts, pollution levels may vary over short-term periods in the future and gradually be reduced in the long term, and the determination of health benefits associated with pollution reductions will provide evidence for the public health improvements and help to tailor further relevant policies�

• Determine the susceptibility to air pollution in different population subgroups and the interactions between air pollution and traditional health risk factors (e�g�, cigarette smoking, alcohol abuse, obesity, dietary factors)� Although a few studies have found that certain groups (e�g�, elders and poorly educated subjects) are at higher risk of death in response to short-term air pollution exposure, evidence is still sparse in this field� More informative investigation will aid the identification of susceptible populations and provide important implications for the prevention of adverse air pollution effects�

• Compare the exposure-response characteristics of air pollution and health in China with those observed in developed countries in terms of geneenvironment interaction� Both genetic, epigenetic, and environmental factors may contribute to the observed air pollution effects (Chen et al�, 2015c; Peters et al�, 2009; Mordukhovich et al�, 2009)� However, few studies in China have investigated the potential interactions between air pollution and genetic/epigenetic susceptibility, leaving this topic as an under-investigated area�

• Document the environmental health impact in the context of air pollutionclimate change interaction� Climate change is another environmental issue in China and may also increase the health burden (Kan et al�, 2012)� A few studies have provided preliminary evidence that climate-relevant changes (e�g�, temperature) may interact with air pollution to affect the observed health effects (Li et al�, 2011; Wu et al�, 2013c, 2015b)� However, the extent and time course of such interaction have remained largely unclear� China’s landscape and related climates are diverse and thus will be an ideal environment for such investigation�

• Assess the health risks of different air pollutants at larger scales (e�g�, multicity or national) and provide evidence-based estimates for the health and economic burdens that air pollution may cause in China� Updating the risk

assessments over time may be critical for informative and timely policy making in view that the implementation of air pollution control measures may gradually reduce the air pollution levels over time�

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