Cancer Risk from Exposure to Particulate Matter and Ozone According to Obesity and Health-Related Behaviors: A Nationwide Population-Based Cross-Sectional Study Free

In 2013, the International Agency for Research on Cancer classified ambient air pollution as a human carcinogen (1). The air quality standards defined by the World Health Organization (WHO) announced that particulate matter (PM) and ozone (O₃) were the most harmful pollutants in 2006 (2). Long-term PM exposure increases mortality from diseased trachea or bronchus and lung cancer (3–5). Although less evidence is available to evaluate associations between air pollutants and some other cancers, cancer of the bladder (6), liver (7), prostate (8), cervix (9), and pancreas (10) has all been shown to have positive associations with air pollution exposure. In contrast, two studies found no association between air pollution and breast cancer (11, 12).

Weight and lifestyle factors may have an influence on the effects of long-term exposure to air pollution, resulting in a nonlinear relationship with cancer mortality. In one recent study, current smoking and alcohol consumption were positively associated with air pollution, whereas physical activity and overweight status were negatively associated with air pollution (13). Ever smokers exhibited increased cancer mortality from PM exposure, whereas never smokers did not (14). In a Canadian case–control study examining over 20 years of PM exposure, the incidence of lung cancer was increased in men, but no consistent patterns according to smoking status or education were observed (4). Therefore, a known risk factor–based approach with a focus on clustered risk factors is needed to understand the biological mechanisms that underlie the associations between air pollutant exposure and cancer risk.

O₃ is a secondary pollutant caused by photochemical reactions. The toxicological effects of O₃ result from inflammatory response, oxidative stress, and tissue injury (15). Previous study explored the carcinogenic influence of O₃ on microorganisms, plants, and cell lines in vitro (16), and showed some evidence linking O₃ exposure and cancer development in experimental studies (17). However, the effect of exposure to O₃ on lung cancer–related mortality was not significant in a 20-year Canadian study (18). Moreover, few studies have addressed the association between exposure of O₃ and cancer considering individual risk factors. As most previous studies were carried out in Western populations, differences in race, lifestyle, air-pollutant concentration, and exposure duration may have affected the results.

The aim of this study was to investigate the association between long-term exposure to PM <10 μm (PM₁₀) and O₃ and cancer risk according to obesity status, age, sex, and health-related behaviors in a nationwide population-based cross-sectional study.

We evaluated data from the 2012 Korean Community Health Survey (KCHS), which has been conducted annually by the Korea Centers for Disease Control and Prevention since 2003. A total of 228,921 participants, aged 19 or older, were enrolled in approximately 900 participants per unit, with units representing 254 communities, including 16 different metropolitan areas and provinces. The KCHS was performed between August and October via computer-assisted personal interviews. The KCHS had public confidence to represent the entire characteristics of Korean population (19). We selected 100,867 participants who had lived at the same residence for ≥10 years, after matching participant residence codes with location of surveillance stations for PM₁₀ and O₃.

The institutional review board (IRB) at the Korean Centers for Disease Control and Prevention approved the study protocol, and all of the participants provided written informed consent. The IRB at Konkuk University Medical Center (Seoul, South Korea) also approved this study (IRB File Number: KUH1230027).

We obtained the average concentrations of hourly measured PM₁₀ and O₃ at 268 nationwide surveillance stations from the Korean Air Pollutants Emission Service of the National Institute of Environmental Research (Icheon, South Korea). The surveillance stations were located in residential areas (Supplementary Fig. S1). We calculated the interquartile ranges of the yearly average concentrations for the period of 2003 to 2012. PM₁₀ was measured using β-ray attenuation (PM-711D; Dongil Greensys). O₃ was measured using ultraviolet photometry (202; Total Engineering Co., Ltd). These air pollutant measurements followed the standard reference protocol from the Korean Air Pollutants Emission Service (20). We obtained meteorologic data from the National Meteorological Office (Supplementary Table S1).

The KCHS surveyed socioeconomic parameters, health-related behaviors, and medical history including cancer, hypertension, diabetes mellitus, dyslipidemia, stroke, myocardial infarction, ischemic heart disease, and asthma. Cancer was limited to medical diagnosis regardless of cancer type. Obesity was defined as body mass index (BMI) >25. We categorized patients as never-smokers and ever-smokers, which included former smokers and current smokers. We categorized patients as never-drinkers or drinkers by a drinking frequency of at least one drink per week. We defined physical activity by intensity and frequency, separating patients into an active group and an inactive group. The active group performed moderately intense activity more than three times per week or vigorous activity more than one time per week. Patients who did not meet these criteria were categorized into the inactive group. We divided subjects into three age groups: A1 < 50 years, 50 ≤ A2 < 60 years, and A3 ≥ 60 years. We also obtained the following demographic information: years of education (<9, ≥9), marital status (married/with partner or divorced/widowed/unmarried), household income (<1,000,000 won/month or ≥1,000,000 won/month), and place of residence (rural or urban). We excluded participants who had lived at their residence for <10 years and then divided length of residence into three groups: 10 ≤ T1 < 15 years, 15 ≤ T2 < 20 years, and T3 ≥ 20 years.

Continuous variables are presented as means with SE and categorical variables are presented as percentages. We performed univariate analyses to determine the associations between cancer diagnosis and variables. We evaluated the ORs of cancer diagnosis by per-interquartile increase in PM₁₀ and O₃ exposure using multiple logistic regression analysis after adjusting for age, sex, BMI, smoking status, alcohol consumption, physical activity, education, marital status, income, place of residence, and medical history. We then performed a stratified analysis using obesity, age, sex, smoking, alcohol consumption, and physical activity. We conducted all analyses considering the survey weight using SAS software 9.4 (SAS Institute Inc.).

The demographic, socioeconomic, and health-related behavior characteristics of the study population are summarized in Table 1. The mean subject age was 47.8 years, and the study population was 50.1% women. Approximately 70% of the participants had lived at the same residence for >20 years. The associations between air pollution, health-related behaviors, socioeconomic factors and cancer diagnosis are presented in Table 2. PM₁₀ and O₃ were positively associated with cancer [OR and 95% confidence interval (CI) for PM₁₀: 1.18, 1.06–1.31; O₃: 1.04, 1.01–1.07]. Of the health-related behaviors, obesity, ever smoking, and alcohol consumption were associated with a cancer diagnosis.

We confirmed increased cancer risk among obese subjects aged >50 for exposure to both PM₁₀ and O₃ in multiple logistic regression analysis (PM₁₀: 50–60 years, OR 1.40, CI 1.01–1.96; ≥60 years, OR 1.34, CI 1.03–1.74; and O₃: 50–60 year, OR 1.20, CI 1.08–1.33; ≥60 years, OR 1.12, CI 1.04–1.20; Table 3.). However, subjects younger than 50 years did not experience an increase in cancer risk even if they were obese. Although we observed an increased risk of cancer from PM₁₀ exposure for obese men aged 50, we did not for obese women. Nonobese women aged 50 to 60 years showed a higher risk of cancer from PM₁₀ exposure than obese women of the same age. For O₃ exposure, all obese subjects aged 50 and older had an increased risk of cancer diagnosis, whereas nonobese subjects were not at significantly increased risk.

The cancer diagnosis risk for the interquartile exposure to PM₁₀ and O₃ according to age, obesity, and health-related behaviors is shown in Fig. 1. Obese subjects with ≥50 years old who reported unhealthy behaviors had an increased risk of cancer diagnosis. When we stratified by smoking status, obese ever-smokers aged 50 to 60 years who had been exposed to PM₁₀ were at greater risk of cancer diagnosis than nonobese ever-smokers of the same age group (Fig. 1A). For O₃ exposure, obese subjects ≥50 years were at increased risk of cancer regardless of smoking status and nonobese ever-smokers aged ≥60 years also showed increased cancer risk (Fig. 1B). We found no trends associated with alcohol consumption, although obese subjects aged ≥50 years who reported no alcohol consumption had an increased risk of cancer diagnosis with PM₁₀ and O₃ exposure. Obese subjects aged ≥60 years who reported regular alcohol consumption and who had PM₁₀ exposure and obese subjects aged 50 to 60 years who reported regular alcohol consumption and who had O₃ exposure both faced an increased risk of cancer diagnosis (Fig. 1C and D). Nonobese subjects aged 50 to 60 years who reported regular alcohol consumption were at an increased cancer risk if they also had PM₁₀ exposure. However, we found no association between cancer risk, O₃ exposure, and alcohol consumption status in nonobese subjects (Fig. 1D). The cancer diagnosis risk for exposure to PM₁₀ or O₃ was significantly higher among obese inactive subjects who were ≥50 years old. Despite their obesity, subjects <50 years old who were physically active had a decreased risk of cancer, but this risk was not significant (Fig. 1E and F).

In this study, long-term exposure to PM₁₀ and O₃ was found to increase cancer risk. In particular, the effect of PM₁₀ on cancer risk differed according to age, sex, obesity status, and health-related behaviors. Regarding O₃ exposure, cancer risk was strongly influenced by age and obesity. Finally, we found that long-term exposure to PM₁₀ and O₃ did not increase cancer risk among subjects who practiced healthy behaviors, compared with subjects who practiced unhealthy behaviors. Although alcohol consumption is a well-established risk factor of cancer, the effect on the cancer risk for PM₁₀ and O₃ exposure was not proven.

The incidence of most cancers increases with age, with more rapid increases at the onset of midlife. Obesity and unhealthy behaviors affect health status significantly in midlife (21). These multifactorial causes may lead to functional declines at the cellular, tissue, and organ levels, which can be augmented by air pollution, significantly elevating cancer risk among people 50 years and older (22). Our findings are compatible with a previous report stating that the age-specific incidence of common cancers rapidly increased after age 50 for both men and women in Korea and old people were susceptible to the exposure of air pollution (23, 24). Even more subjects 50 to 60 years old with unhealthy behaviors exhibited higher cancer risk than subjects aged ≥60 years in stratified analysis in this study. Exposure response may help explain uncertainties; subjects 50 to 60 years old frequently exposed to pollutants with high activity compared with subjects aged ≥60 years (24, 25).

Interestingly, the effects of sex- and health-related behaviors on the associations between PM₁₀ and O₃ exposure and cancer risk were markedly stronger in obese subjects. Obesity-induced proinflammatory cytokines, which increase oxidative stress-induced DNA damage, are associated with the development and progression of cancer (26). Polyaromatic hydrocarbons from air pollutants affect individual antioxidant activity, DNA repair, cell proliferation, and apoptosis (27). Inflammation of gut lining epithelial cells, after ingestion or inhalation, affect immune response and the gut microbiota in aerodigestive cancer (14). A case–control study of indoor air pollution from solid fuels on esophageal cancer and an ecological study of metallic emissions on liver and colorectal cancers have also indicated similar associations of air pollutants with cancer (28, 29). In addition, epigenetic approaches to analyzing DNA methylation changes have suggested it to be one of the biological mechanisms behind these associations (24).

Obese men ≥50 years old with PM₁₀ exposure had particularly elevated cancer risk, whereas nonobese women aged 50 to 60 years with PM₁₀ exposure faced relatively increased cancer risk. In the Veterans Affairs Normative Aging Study, obese men were most susceptible to air pollution's effects on cancer risk, similar to our study (30). These sex differences in the effects of air pollution exposure could be explained by sex-related variation in hormones and body size, which could influence biological transport of pollutants in the body (31). In a rodent model exposed to highly polluted air, brain and epididymal fat mass were significantly elevated in males (32). The obesity-related sex differences observed in this study offers explanatory insight into increased cancer risk in men. However, a meta-analysis of 19 prospective cohort studies could not identify any sex differences in lung cancer mortality according to air-pollutant exposure (33). Known cancer risk factors that vary according to sex, such as hypertension and socioeconomic factors, may have influenced other variables. Given the inconsistent findings among several studies, further research is needed to explore risk across different races and cancer types.

Previous studies confirmed that lung cancer mortality and incidence were elevated among smokers with air pollution exposure; meanwhile, other studies reported increased lung cancer mortality and incidence rates among nonsmokers or null associations for long-term exposure to ambient fine particles (4, 5, 34). Smoking enhances oxidative stress not only through the production of reactive oxygen radicals, but also through the weakening of antioxidant defense mechanisms. Therefore, the different cancer risk of subjects according to smoking status likely relates to variation in lung deposition and competition for metabolic activation (35, 36).

In this study, physical activity was negatively associated with cancer diagnosis. Regular exercise is thought to increase antioxidant capacity and to have anti-inflammatory effects, leading to a protective effect against cancer (37). Inconsistent findings with alcohol consumption is similar with Strak and colleagues' study (13), in which the association between air pollutants and alcohol consumption disappeared according to drinking pattern. In our study, participants were classified as drinkers based on consumption of more than one drink per week. Thus, the influence of alcohol on cancer risk might have been underestimated.

This study extended the association of cancer risk on the exposure of PM₁₀ and O₃ regarding the significant effects of smoking and physical activity, especially after stratifying by age and obesity to better understand confounding factors in these relationships.

This study has several limitations. First, the establishment of causalities was impossible because of the cross-sectional design. Second, cancer data relied on a self-reported diagnosis history, which may have biased the findings. Because of the lack of information about the timing and type of cancer diagnoses, we could only estimate the risk for all-cancer diagnosis with long-term exposure to PM₁₀ and O₃. Because the PM₁₀ and O₃ were measured from 2003 to 2012 in Korean Air Pollutants Emission Service, the findings should not be generalized to the other exposure times considering latency period. Furthermore, we could not obtain measurements of PM_2.5; therefore, the association between PM_2.5 and cancer risk could not be evaluated in this study. Third, we matched participants' community of residence and local PM₁₀ and O₃ levels using residential territories. Therefore, our matching system would not accurately reflect air-pollutant exposure levels if participants spent a lot of time away from their area of residence. Fourth, we could not obtain data on traffic-related air pollution, which may be a main source of PM in Korea (38). Although PM₁₀ plays a role in the formation of O₃ through photochemical processes, we could not assess additive risks of PM₁₀ and O₃ from the KCHS data. However, measuring exposure to PM₁₀ and O₃ for ≥10 years in 16 Korean metropolitan areas and provinces could overcome the temporal–spatial variation (39). Finally, other important cancer risk factors, such as nutrition and genetics, were not considered in our models.

Long-term exposure to PM₁₀ and O₃ is associated with elevated cancer risk, which is compounded by obesity, smoking, and physical inactivity among Koreans aged 50 years and older. Therefore, the cancer risk associated with air pollution exposure could be reduced by individual lifestyle modification, whereas community-level reductions will likely result from policies decreasing air pollution.

No potential conflicts of interest were disclosed.

Conception and design: K.J. Kim. J. Shin

Development of methodology: K.J. Kim, J. Shin

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J. Shin

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): K.J. Kim, J. Shin, J. Choi

Writing, review, and/or revision of the manuscript: K.J. Kim, J. Shin, J. Choi

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): K.J. Kim, J. Shin

The authors would like to thank the Korea Centers for Disease Control and Prevention for Community Health Survey 2012, and the National Institute of Environmental Research, 2003 to 2012.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.