According to the latest global cancer data published by IARC, lung cancer is the top-ranking cause of cancer incidence and mortality worldwide. It is responsible for the highest number of either new cases or deaths, approximately 11.6% and 18.4% of the total, respectively [
15]. So far, while smoking or consumption of tobacco products is the main cause of lung cancer that accounts for about 90% of cases; other risk factors, including environmental and occupational exposure, might contribute to the etiology of lung cancer [
16,
17]. As mentioned above, PM2.5 easily penetrates deeper into the lungs or bronchi alveoli and persistently remains in these areas due to its extremely small size. Thus, the most vulnerable organ that is compromised by exposure to these invisible particles is the lung. On the other hand, the conclusion that the increased risk of lung cancer associated with the increasing levels of exposure to PM was officially claimed by IARC [
1]. Since then, numerous epidemiological studies have further demonstrated the positive relationship between PM2.5 and lung cancer. Measurements of disease (incidence) and/or death (mortality) within populations are important to evaluate the association between risk factors with a specific disease [
18]. However, for lung cancer, it is well-established that the survival rate is relatively low and probably drops from 59% in stage 1 to only 5.9% in stage 4 [
19]. Due to this high case-fatality rate, mortality might be considered as comparable as incidence for lung cancer. As a result, the majority of studies have investigated the influence of PM2.5 on lung cancer mortality. Based on 17 cohort studies (from 2008 to 2013) and one case-control study of lung cancer, including four studies from Europe, eight studies from North America, and two studies from other regions, Hamra and coworkers performed the overall meta-estimates for PM2.5 [
20]. The authors found that lung cancer mortality increases by 9% for every 10 μg/m
3 PM2.5 increase, consistent with a subsequent meta-analysis which included 19 cohort studies [
21]. However, there are two main limitations of these publications. Firstly, they collected mortality and incidence studies together, which might cause inaccurate calculation and interpretation. Secondly, almost all of studies were carried out in developed countries where the annual medium concentration of PM2.5 is greatly lower than that in developing countries, thus inappropriately representing the global scenario. To fill these gaps, one meta-analysis of 30 cohort studies between 1999 and 2017 that involved more than 1 million cases in 14 countries all over the world was conducted [
22]. The key strength of this study is the separation of cancer mortality from cancer incidence. The results showed that long-term exposure to PM2.5 also increases mortality from lung cancer but at higher risk, 14% per 10 μg/m
3 increase in PM2.5. Collectively, it could be concluded that PM2.5 is prospectively related to a significantly increased risk of lung cancer mortality. Actually, not every patient who suffers lung cancer would die by this disease; it is thus important to separately determine the impact of PM2.5 on the development of lung cancer. Since urbanization coupled with industrialization originally progressed in North America and Western countries, the earlier reports on PM2.5-associated lung cancer incidence came from these population groups. The positive relationship between long-term PM2.5 exposure and lung cancer incidence was demonstrated in three large-scale prospective cohort studies. The first report was the Canadian population-based case-control study, which included 2390 incident cases of histologically diagnosed lung cancer in 8 out of 10 provinces between 1994 and 1997, in order to estimate the ambient air pollution (fine PM, nitrogen dioxide, and ozone)-related lung cancer incidence over 20-year-exposure [
23]. The second report was the United States population-based cohort using Nurse’ Health Study (NHS) data to investigate the lung cancer incidence from 1994 through 2010 in relation with 72-month average exposures to outdoor PM, but specifically focused on females [
24]. The third report was the European population-based meta-analysis, which collected 17 cohort studies in 9 European countries during a 12.8-year average follow-up from The European Study of Cohorts for Air Pollution Effects (ESCAPE) data in order to determine the association between long-term exposure to ambient air pollution and lung cancer incidence [
25]. After full adjustment, all three analyses consistently confirmed the positive relationship between long-term exposure to PM2.5 and incidence for lung cancer. The former work showed the increase in lung cancer incidence was 1.29 (OR = 1.29, 95% CI = 0.95–1.76) with 10 μg/m
3 increase in PM2.5, whereas the two latter studies estimated the hazard ratio of 1.06 (HR = 1.06, 95% CI = 0.91–1.25) and 1.40 (HR = 1.40, 95% CI = 0.92–2.13) per 10 μg/m
3 of PM2.5, respectively. In the present, Asian countries, especially China, have become hot spots in terms of air pollution in the world. Thus, the majority of recent studies on PM2.5-associated lung cancer incidence have been carried out in these areas. A meta-analysis by Huang et al. (2017) [
26] found that the lung cancer incidence associated with PM2.5 was greatest in Asia, followed by North America, and then Europe. This might be due to the greater population densities and higher levels of PM2.5 derived from the urbanization combined with industrialization in Asia compared to that in North America and Europe. The latest report from China is a nationwide study in 295 Chinese counties about the effects of ambient PM2.5 exposure on annual incidence rates of lung cancer for both genders in China. In this study, the mean incidence rates of lung cancer for males and females were 50.38 and 22.16 per 100,000 people, respectively, whereas the annual mean PM2.5 value was 43.02 μg/m
3. Then, it was demonstrated that for an increment of 10 μg/m
3 PM2.5, the incidence rates of lung cancer change by 3.57% and 2.71% compared to the mean values for males and females, respectively [
27]. Previously, a prospective analysis of 89,234 Canadian women who participated between 1980 and 1985 to determine the incidence of lung cancer through 2004 was conducted [
28]. Although the PM2.5 concentration was relatively low with a mean value of 9.50 μg/m
3, the increment of 10 µg/m
3 PM2.5 was associated with an increased risk of lung cancer of 34%, which is considerably stronger than the mentioned estimation from China. Guo and colleagues suggested two possible explanations for this conflict. It firstly might be due to the high proportion of less toxic crustal materials and dust in PM2.5 compositions in China. Furthermore, the proportion of elderly, who are more vulnerable to PM2.5 exposure, in China is still significantly lower than that in other developed countries [
27]. Taken together, existing findings have demonstrated a positive association between PM2.5 and the incidence of lung cancer, even at low-level concentrations. In addition to mortality and incidence rates, it is important to examine the lag time between the previous exposure to risk factors and definite diagnosis since the cancer process might have been asymptomatically triggered for a long time. However, the lag effects of PM2.5 on the risk of lung cancer have been largely overlooked. Limited literature suggested the long-term lag effects of PM2.5 on lung cancer incidence, subsequently highlighting the possibility that the incidence of lung cancer is correlated with both current and previous exposure to PM2.5 [
27].
In summary, while epidemiology has produced a variety of strong evidences on PM2.5-associated lung cancer, there are three major gaps that require further study to provide an in-depth understanding on the influence of these invisible particles. Firstly, there are diverse air pollutants existing in the ambient atmosphere that might synergistically affect the human body. This might lead to the overestimation of the actual effects of PM2.5. Secondly, there are relatively few cohort studies that examine the long-term effects of PM2.5 on lung cancer incidence because of the restrictions in available data. Simultaneously, cross-sectional studies that show PM2.5 effects that might be ignored in cohort studies are also quite sparse. Finally, exclusive evaluation of current PM2.5 exposure might underestimate the actual impact of PM2.5 due to the lack of lag effect observations.