Update in Association between Lung Cancer and Air Pollution

Jiye Yoo; Yongchan Lee; Youngil Park; Jongin Lee; Joon Young Choi; Heekwan Lee; Jeong Uk Lim

doi:10.4046/trd.2024.0092

Tuberc Respir Dis > Volume 88(2); 2025 > Article

Yoo, Lee, Park, Lee, Choi, Lee, and Lim: Update in Association between Lung Cancer and Air Pollution

Review

Lung Cancer

Tuberculosis and Respiratory Diseases 2025;88(2):228-236.

Published online: December 11, 2024

DOI: https://doi.org/10.4046/trd.2024.0092

Update in Association between Lung Cancer and Air Pollution

Jiye Yoo, Ph.D.¹

, Yongchan Lee, Ph.D.¹, Youngil Park, M.S.¹, Jongin Lee, M.D., Ph.D.², Joon Young Choi, M.D., Ph.D.³, Heekwan Lee, Ph.D.¹, Jeong Uk Lim, M.D., Ph.D.⁴

¹Institute for Environmental Convergence Technology, Department of Environmental Engineering, Incheon National University, Incheon, Republic of Korea

²Department of Occupational and Environmental Medicine, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea

³Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea

⁴Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Address for correspondence Jeong Uk Lim, M.D., Ph.D. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeongdeungpo-gu, Seoul 07345, Republic of Korea Phone 82-2-3775-1035 Fax 82-2-780-3132 E-mail cracovian@catholic.ac.kr

Received June 28, 2024 Revised October 8, 2024 Accepted December 9, 2024

It is identical to the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/).

Abstract

A significant portion of newly diagnosed lung cancer cases occurs in populations exposed to air pollution. The World Health Organization has identified air pollution as a human carcinogen, prompting many countries to implement monitoring systems for ambient particulate matter (PM). PM is composed of a complex mixture of organic and inorganic particles, both solid and liquid, that are found in the air. Given the carcinogenic properties of PM and the high prevalence of lung cancer among exposed populations, exploring their connection and clinical implications is critical for effectively preventing lung cancer in this group. This review explores the relationship between ambient PM and lung cancer. Epidemiological studies have demonstrated a dose-response relationship between PM exposure and lung cancer risk. PM exposure induces oxidative stress, disrupts the body’s redox balance, and causes DNA damage, which is a crucial factor in cancer development. Recent findings on the strong correlation between ambient PM and adenocarcinoma highlight the importance of understanding the specific molecular and pathological mechanisms underlying pollution-related lung cancer. In addition to efforts to control emission sources at the international level, a more individualized approach is essential for preventing PM-related lung cancer.

Keywords: Particulate Matter; Lung Cancer; Never Smoker; Pathophysiology; Carcinogenesis

Introduction

Lung cancer is one of the leading causes of cancer-related deaths worldwide [1]. Tobacco smoking is a well-established cause of lung cancer; however, exposure to second-hand smoke, radon, household fumes, occupational carcinogens, and infections also significantly contribute to the disease’s development [2-4]. Beyond smoking, air pollution and indoor pollution are the second leading causes of lung cancer-related deaths, followed by occupational exposures [5]. The World Health Organization (WHO) categorizes air pollution as a group 1 carcinogen, as determined by the International Agency for Research on Cancer, underscoring its significant cancer-causing potential in humans. Worldwide, countries implement monitoring frameworks to track ambient air contaminants, including various particulate matters (PM10 and PM2.5) and gases such as nitrogen dioxide (NO₂), sulfur dioxide (SO₂), and ozone (O₃) [6,7]. Comprising a mix of organic and inorganic substances, PM, which includes solids and liquids in the air, plays a significant role in the global burden of lung cancer-related mortality [8]. In 2017, it was responsible for approximately 14.1% of lung cancer deaths worldwide [9]. Evidence indicates a strong association between prolonged exposure to air pollutants and the incidence of lung cancer in non-smoker populations [10,11].

The well-established link between PM exposure and lung cancer development highlights the need for further exploration of its underlying pathophysiology. Additionally, the occurrence and clinical presentation of PM-induced lung cancer vary by geographical location and other demographic factors including sex [12,13].

Given the carcinogenic potential of environmental PM coupled with the high prevalence of lung cancer, understanding the interactions and underlying clinical mechanisms is crucial for developing effective prevention strategies. This review elucidates the links and pathophysiological basis connecting ambient PM exposure with lung cancer rates.

Common Constituents of PM

PM comprises tiny solid and liquid particles in the air, categorized by size into PM10 and PM2.5 [14,15]. PM10 particles, which are particles with diameters <10 µm (PM10), are trapped in the upper respiratory tract, while PM2.5 particles, which are particles with diameters <2.5 µm (PM2.5), penetrate further into the lungs [16,17].

PM’s composition includes nitrates, sulfates, ammonium, organic and elemental carbon, metals, and polycyclic aromatic hydrocarbons (PAHs). Sources of urban PM include waste incineration, traffic emissions, mining, and the incomplete combustion of biomass or oil. These particles generate reactive oxygen species (ROS), triggering inflammatory responses and leading to genetic mutations and an increased cancer risk [7,8,18,19].

Epidemiologic Background of PM as a Cause of Lung Cancer

1. Association between ambient PM concentration and lung cancer development

Over the past three decades, numerous studies have revealed an epidemiological link between PM exposure and lung cancer risk in non-smokers, although this association is less pronounced than in smokers. Significant epidemiological evidence upholds this association. Major epidemiological studies have primarily focused on PM2.5 and PM10, which can be detected by air quality monitoring systems. Several extensive population-based studies have assessed the relationship between PM and lung cancer risk [20-24]. The Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) study in Europe meticulously determined exposure to key pollutants, particularly NO₂ and PM2.5, across seven European cohorts. Over an 18.1-year period, from 307,000 participants, nearly 4,000 developed lung cancer. The risk of lung cancer increased by 13% for every 5 µg/m³ increase in PM2.5 exposure [22].

There is a solid dose-response relationship between PM levels and lung cancer risk, as evidenced by major epidemiological studies demonstrating a linear relationship. The National Health Interview Survey (1987-2014) found that a 10 µg/m³ increase in PM2.5 was associated with higher all-cause mortality (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.06 to 1.33) and lung cancer mortality (HR, 1.73; 95% CI, 1.20 to 2.49)23. The Adventist Health and Smog Study-2 (AHSMOG-2) also demonstrated that a 10 µg/m³ increase in PM2.5 linearly correlated with a higher incidence of lung cancer (HR, 1.43; 95% CI, 1.03 to 2.00), notably including a high proportion of never-smokers (80.8%) [21]. Furthermore, the Nurse’s Health Study identified a significant association between PM2.5 and lung cancer incidence among never-smokers, with an incidence rate of 13.4 per 100,000 person-years (95% CI, 11.5 to 15.6) [25]. In addition, a 26-year prospective study involving 188,699 lifelong never-smokers associated each 10 µg/m³ increase in PM2.5 with a 15%-27% increase in lung cancer deaths [26]. Additionally, a European cohort study demonstrated that long-term exposure to ambient PM2.5 was linearly correlated with an increase in lung cancer incidence, even at concentrations below the European Union (EU) limit values (HR, 1.15; 95% CI, 1.01 to 1.31) [22]. A recent umbrella meta-analysis, encompassing six prior analyses, indicated a 1.16-fold higher likelihood of lung cancer development (95% CI, 1.1 to 1.22; p<0.00001). A significant link between PM2.5 and non-lung cancer types was identified, though the mortality risk associated with these cancers was not statistically significant [27]. Korean studies also identified a noteworthy association between PM10 exposure and lung cancer risk; an analysis involving 908 participants revealed that lung cancer incidence escalated with each 10-unit increase in PM10 concentration (adjusted odds ratio, 1.09; 95% CI, 0.96 to 1.23), with particularly robust associations observed among nonsmokers [28]. Together, these studies underline the substantial risk that PM exposure poses for lung cancer development in individuals who have never smoked.

Moreover, ambient PM can also originate from natural sources. A recent Canadian study assessed cancer risks linked to exposure to wildfire smoke while meticulously controlling for confounders, including the exclusion of individuals from urban centers, new immigrants, and certain age groups. The analysis highlighted a modest increase in lung cancer risk within a 50 km radius of wildfires over the preceding 5 years. Comparisons between groups exposed and not exposed to wildfires showed a consistent positive relationship with occurrences of lung and brain cancer, more pronounced in regions of lower exposure. An important aspect of wildfire exposure is that pollutants remain in the environment, affecting not only the air but also water and soil. Wildfires have been shown to deposit lasting residues, including environmentally persistent free radicals and heavy metals, in soils and water, potentially impacting human health well beyond the duration of the fire event. Notably, within a 50 km radius, lower-exposure groups displayed a significant increase in lung cancer risk (HR, 1.074; 95% CI, 1.047 to 1.101). This pronounced impact at lower-exposure levels suggests that even minimal interaction with wildfire-derived pollutants can escalate lung cancer risk due to the enduring and bioaccumulative nature of the carcinogens released [29,30].

Further studies have shown that PM influences not only the incidence but also the mortality of lung cancer. A study in Japan from 2010 to 2014 assessed the relationship between lung cancer mortality rates and concentrations of PM2.5, NO₂, SO₂, among other pollutants. Segmenting PM2.5 concentrations into quartiles revealed that each 25% increase in PM2.5 concentration corresponded to a 2.65% rise in lung cancer mortality [31]. Additionally, a significant correlation between ambient PM2.5 exposure and lung cancer mortality was observed in a cohort of 635,539 individuals from the U.S. National Health Interview Survey, with a HR of 1.13 per 10 µg/m³ increase in PM2.5 (95% CI, 1.00 to 1.26), and 7,420 lung cancer deaths reported [17,23].

Biochemical Background of the Interrelationship between PM and Lung Cancer

1. Oxidative stress and inflammation

Exposure to PM induces oxidative stress by disrupting the equilibrium between oxidants and antioxidants in the lungs, resulting in an excessive production of ROS that impairs cellular function and induces cell death [32,33]. Glutathione plays a crucial role in neutralizing oxidative stress [34-36], yet elevated PM levels can overpower this defense mechanism, leading to chronic inflammation, DNA damage, and an increased risk of lung cancer [33,37]. Research indicates dose-dependent increases in oxidative stress markers like malondialdehyde and reduced glutathione levels in human bronchial epithelial cells exposed to PM2.5 [38]. Furthermore, oxidative stress induced by PM triggers inflammatory responses via pathways involving intercellular adhesion molecule-1 [39] and pro-inflammatory cytokines through mitogen-activated protein kinase and nuclear factor-κB signaling [40]. Human studies also demonstrate a correlation between environmental exposure to PM2.5 and PAHs and increased urinary biomarkers of oxidative stress, suggesting a dose-dependent relationship between PM exposure and oxidative stress [41].

A study using a mouse model demonstrated that chronic exposure to carbon black diminished mitochondrial efficacy within macrophages. Additionally, T-cell exhaustion became evident, along with significant effects on regulatory T-cells. Transplanting these altered antigen-presenting cells into naïve mice led to the development of lung cancer, highlighting the critical role of the immune environment in PM-related carcinogenesis [42].

2. Genotoxicity

DNA damage, whether induced by oxidative stress or other factors, is a critical component in the development of cancer [43]. When DNA damage surpasses the cell’s repair capacity, it leads to the accumulation of unrepaired genetic alterations that may contribute to malignant transformations [1,44,45]. PM contains components, including mutagenic carcinogens such as PAHs, sulfur compounds, and dioxins [46], which can induce genetic mutations and defects in gene expression through long-term exposure, as demonstrated in animal and in vitro studies [47-53]. Additionally, PM influences cancer cell behavior by enhancing their invasive and proliferative properties [1,54]. Studies involving A549 cells have shown that PM2.5 exposure increases cancer cell migration and invasion, with mechanisms that include the suppression of miR-26a and the upregulation of lin28 homolog B (LIN28B), interleukin 6 (IL-6), and signal transducer and activator of transcription 3 (STAT3) [55,56]. PM2.5-induced exosomes have been demonstrated to promote lung tumor growth through the Wnt3a/ β-catenin pathway [57]. Additionally, human studies have shown that traffic policemen exposed to air pollution exhibited increases in 8-hydroxy-20deoxyguanosine, tail DNA, micronucleus frequency, and a decrease in glutathione [58]. Epigenetic changes, such as DNA methylation and histone modification, play a pivotal role in the onset of cancer caused by PAHs, the primary constituent of PM. DNA methylation inhibits the transcription of tumor suppressor genes, while histone acetylation influences DNA transcription, thus elevating cancer risk [59-61]. Concerning susceptibility to PM-related lung cancer, genetic risk factors are crucial. An analysis of health data from over 450,000 individuals in the UK used the construction of a ‘polygenic risk score’ to determine the genetic predisposition to developing lung cancer, considering 18 single nucleotide polymorphisms associated with the disease. It was noted that individuals with an elevated polygenic risk score, when exposed to high levels of air pollution, encountered an increased risk for lung cancer [62].

Indoor Air Pollution

Although many studies on PM focus on ambient particles due to available measurement levels, significant research also addresses indoor air pollution, particularly concerning cooking fumes. Indoor PM2.5, originating from sources such as smoldering combustion and cooking, contains different elemental carbon components compared to outdoor PM2.5 [63]. Key indoor PM sources include pollutants from indoor cooking, as well as second-hand and third-hand tobacco smoke [64-70].

Cooking oil fumes, produced during food preparation techniques such as high-heat stir frying, contain harmful compounds like benzo(a)pyrene and benzo(a) anthracene [71]. Poor ventilation and cooking approaches such as stir frying are identified as factors that elevate lung cancer risks. The chemical composition of PM2.5 from cooking oil fumes is distinct and includes benzo(a)pyrene, benzo(a)anthracene, SO₄^2-, NO₃^-, and NH₄⁺, showing higher concentrations of five PAHs than PM2.5 from other sources like ambient air or incense burning [71-73].

Recent studies indicate that to mitigate risks associated with indoor air pollution, it is essential to (1) use fume extractors, (2) ensure proper ventilation, and (3) adopt suitable cooking methods, including the use of oils that have appropriate burning points [74,75].

Association between Ambient PM and Epidermal Growth Factor Receptor Mutated Lung Cancer

Adenocarcinomas comprise 50%-60% of all lung cancer cases. Several studies have demonstrated a robust association between PM exposure and the development of adenocarcinoma [76,77]. Specifically, with each 10 µg/m³ increase in ambient PM2.5, the risk of developing adenocarcinoma increases significantly [76].

Epidermal growth factor receptor (EGFR) mutation is prevalent in 30%-50% of adenocarcinoma cases across all races and smoking statuses. EGFR mutated adenocarcinoma is recognized as a distinct disease entity in lung cancer for several reasons. First, specific mutations such as the exon 21 L858R mutation or exon 19 deletion enable the use of EGFR tyrosine kinase inhibitors, resulting in relatively favorable outcomes compared to advanced non-small cell lung cancer patients without targetable mutations. Second, EGFR mutations are more common in never-smokers, Asians, and women [78-80].

Last year, a study by Hill et al. [81] published in Nature focused on ambient PM exposure and the development of lung adenocarcinoma. The study indicated that PM2.5 exposure could significantly influence the progression of lung adenocarcinoma in individuals with EGFR gene mutations. An analysis of data from 32,957 cases of EGFR mutant lung cancer across diverse cohorts in England, Korea, Taiwan, and Canada showed a strong correlation between increased PM2.5 concentrations and the incidence of lung adenocarcinoma. This association was further validated through various study models. Functional mouse models demonstrated that air pollution exposure leads to significant recruitment of macrophages to the lungs, along with IL-1β release. This inflammatory response initiated a progenitor-like state in EGFR mutant lung alveolar type II epithelial cells, potentially accelerating the oncogenesis process in lung adenocarcinoma. Furthermore, it was observed that administering anti-IL-1β therapy, such as canakinumab, inhibited cancer formation in mice that exhibited an IL-1β-mediated inflammatory response. Additionally, ultra-deep mutational profiling of lung tissue samples from 295 individuals, which appeared histologically normal, revealed that oncogenic EGFR and KRAS driver mutations were present in 18% and 53% of the samples respectively [81,82].

Comparison of Heavy PM Burden Country and Moderate PM Burden Country

A study published in Environmental Research highlights the global spatio-temporal pattern of lung cancer burden attributable to ambient PM2.5 pollution from 1990 to 2019. The research shows that the heaviest burden occurs in East Asia, with over 50% of the worldwide impact attributed to China, which experiences the highest numbers [83]. Another article revealed that lung cancer deaths due to long-term ambient PM2.5 exposure have significantly increased in East Asian countries, particularly in China, the Democratic People’s Republic of Korea, and Mongolia. The study also indicated that the mortality rate among men was significantly higher than that among women, highlighting the gender disparity in lung cancer mortality rates attributable to PM2.5 [84].

Moreover, cities in low and middle-income countries tend to experience higher levels of PM2.5 pollution. The Health Effects Institute identifies India, Nigeria, Peru, Bangladesh, and China among the top 20 cities with the highest PM2.5 exposure rates for residents among 103 cities globally [85]. In these urban areas, PM2.5 levels significantly exceed the global average. Notably, in Delhi, India, the population-weighted PM 2.5 concentration was 110 µg/m³, which is over triple the WHO’s interim target of 35 µg/m³.

In China, where PM2.5 exposure substantially surpasses that in developed countries, a 10 g/m³ rise in PM2.5 levels correlates with a 12% increase in lung cancer mortality risk. Additionally, the concentration-response curve suggests a nonlinear relationship between PM2.5 exposure and mortality, indicating that health impacts intensify disproportionately at elevated pollution levels [12,86].

Cancer Prevention and Future Direction

Efforts to prevent cancer due to PM include strategies like reducing outdoor activities during periods of low air quality and wearing masks that filter particles. To manage indoor air pollution, it is vital to eliminate sources of elemental carbon via proper ventilation. Beyond these measures, a comprehensive, coordinated approach is required. Initiatives by public entities and governments to improve air quality are crucial, which include continuous monitoring of PM levels and stringent control of emissions from waste incineration, traffic, and combustion of biomass or oil. Furthermore, additional studies are necessary to understand how PM’s components trigger carcinogenesis and to pinpoint individuals with a high-risk of lung cancer upon PM exposure. Future research should incorporate regional variables such as air pollutant concentrations, climate, racial differences, and cultural contexts, which may affect PM’s impact. For example, indoor air pollution from cooking poses a greater threat in developing nations due to poor ventilation systems and the burning of indoor biomass fuel [87,88]. Currently, no predictive model exists to calculate the lifetime cumulative exposure to PM for individual lung cancer risk assessment. Additionally, although low-dose computed tomography screenings for early lung cancer detection are beneficial for high-risk, non-smoking individuals, the development of uniform screening guidelines is impeded by population diversity. It has been suggested that customized screening protocols be developed, reflecting specific regional characteristics [5].

As accurate measurement of air quality and emissions is crucial in reducing ambient PM, collaborative efforts among various countries are equally important. Air pollution is a cross-border issue, suggesting that air quality management policies in one country may affect others. Consequently, these issues should be addressed through international collaboration [89]. In particular, developing nations, which are experiencing rapid industrialization and urbanization, often lack the technology and infrastructure necessary for effective air quality management, monitoring, and control [90].

Satellite-based PM detection can contribute to air quality management in developing countries that lack extensive ground-based air quality stations. Satellite-based PM monitoring can provide insights into large-scale air quality with high spatial resolution [91,92]. The geostationary environmental monitoring spectrometer, developed by the Korean Ministry of Environment, employs a UV-visible hyperspectrometer to monitor air pollutants such as SO₂, NO₂, O₃, formaldehyde (HCHO), and aerosols in the atmosphere [93]. However, the limitations of various approaches to estimating ground-level PM concentrations using satellite data and supplementary data have been debated from multiple perspectives [92].

Therefore, it is necessary to enhance the air quality management capabilities of developing countries through international cooperation. This can be achieved by sharing technologies and experiences from developed countries and obtaining support from international organizations and associations. Additionally, international cooperation is essential to develop an integrated air pollution management system that encompasses air quality monitoring, inventory management, air pollution modeling, and the development and evaluation of reduction plans.

Other factors such as ultrafine PM (PM 0.1), which has received relatively less clinical attention, should also be evaluated for their potential roles in cancer development [17]. A recent longitudinal study, the Los Angeles Ultrafines Study, tracked approximately 45,000 subjects over two decades. This research explored the association between proximity to ultrafine particles (UFPs) and lung cancer incidence, accounting for the smoking patterns and residential timelines of the individuals. The results revealed a significant correlation between UFP exposure and an increased risk of lung cancer, particularly adenocarcinoma in the male cohort, a correlation absent in the female cohort [94].

Conclusion

Understanding the impact of both ambient and indoor PM on public health, particularly regarding the risk of lung cancer development, is crucial. Nevertheless, alongside international efforts to control PM sources, adopting a more individualized approach to prevent lung cancer related to PM is imperative.

Notes

Authors’ Contributions

Conceptualization: Lim JU. Methodology: all authors. Formal analysis: all authors. Data curation: all authors. Project administration: Lim JU. Visualization: all authors. Software: all authors. Validation: Lim JU. Investigation: all authors. Writing - original draft preparation: Lim JU. Writing - review and editing: Lim JU. Approval of final manuscript: all authors.

Conflicts of Interest

Jeong Uk Lim is an editor and Joon Young Choi is an early career editorial board member of the journal, but they were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Funding

No funding to declare.

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