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Published in final edited form as: Environ Adv. 2023 Feb 12;11:100354. doi: 10.1016/j.envadv.2023.100354

State of the science on outdoor air pollution exposure and liver cancer risk

Trang VoPham a,b,*, Rena R Jones c
PMCID: PMC9984166  NIHMSID: NIHMS1874384  PMID: 36875691

Abstract

Background:

There is emerging evidence that air pollution exposure increases the risk of developing liver cancer. To date, there have been four epidemiologic studies conducted in the United States, Taiwan, and Europe showing generally consistent positive associations between ambient exposure to air pollutants, including particulate matter <2.5 μm in aerodynamic diameter (PM2.5) and nitrogen dioxide (NO2), and liver cancer risk. There are several research gaps and thus valuable opportunities for future work to continue building on this expanding body of literature. The objectives of this paper are to narratively synthesize existing epidemiologic literature on the association between air pollution exposure and liver cancer incidence and describe future research directions to advance the science of understanding the role of air pollution exposure in liver cancer development.

Future research directions

include 1) accounting for potential confounding by established risk factors for the predominant histological subtype, hepatocellular carcinoma (HCC); 2) examination of incident primary liver cancer outcomes with consideration of potential differential associations according to histology; 3) air pollution exposure assessments considering early-life and/or historical exposures, residential histories, residual confounding from other sources of air pollution (e.g., tobacco smoking), and integration of geospatial ambient exposure modeling with novel biomarker technologies; 4) examination of air pollution mixtures experienced in the exposome; 5) consideration of increased opportunities for exposure to outdoor air pollution due to climate change (e.g., wildfires); and 6) consideration of modifying factors for air pollution exposure, such as socioeconomic status, that may contribute to disparities in liver cancer incidence.

Conclusions:

In light of mounting evidence demonstrating that higher levels of air pollution exposure increase the risk for developing liver cancer, methodological considerations primarily concerning residual confounding and improved exposure assessment are warranted to robustly demonstrate an independent association for air pollution as a hepatocarcinogen.

Keywords: air pollution, PM2.5, liver cancer, hepatocellular carcinoma, environmental epidemiology

1. Introduction

1.1. The pervasiveness and complexities of air pollution exposure

Air pollution is a complex mixture of thousands of hazardous substances and is a major contributor to morbidity and mortality across the world (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016; Khomenko et al. 2021). Air pollution exposure is a pervasive environmental health concern that is characterized by many complexities creating challenges in epidemiologic investigations, including but not limited to variability in concentrations over space and time; differential sources of origin (natural vs. anthropogenic and/or local, regional, vs. global); chemical composition; and generation and/or experienced by humans indoors and/or outdoors (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016). Major outdoor air pollutants include nitrogen oxides (NOx) (which include nitrogen oxide [NO] and nitrogen dioxide [NO2]), ozone (O3), and particulate matter (PM) of different size fractions (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016).

The United States (US) Environmental Protection Agency (EPA) identified a subset of 33 hazardous air pollutants (HAPs; also referred to as air toxics) that present the greatest threat to public health in the largest number of urban areas, which are characterized by relatively higher populations and a higher concentration of emission sources (Environmental Protection Agency 2022). These urban HAPs include polycyclic aromatic hydrocarbons (PAHs) (e.g., benzene), volatile organic compounds (VOCs) (e.g., 1,3-butadiene, carbon tetrachloride, chloroform, tetrachloroethylene, vinyl chloride), pesticides (e.g., 1,3-dichloropropene, hexachlorobenzene), metals (e.g., arsenic, beryllium, chromium, lead, manganese, mercury, nickel), aldehydes (e.g., acetaldehyde, formaldehyde), and dioxins and dioxin-like compounds (e.g., polychlorinated dibenzo-p-dioxins, PCDDs; polychlorinated dibenzofurans, PCDFs; polychlorinated biphenyls, PCBs) (Environmental Protection Agency 2022; McCarthy et al. 2006; Strum and Scheffe 2016; Zhou et al. 2015). Many of these urban HAPs (such as 1,3-butadiene, arsenic, benzene, formaldehyde, and some PCDD/Fs) have been classified by the International Agency for Research on Cancer (IARC) as Group 1 human carcinogens and by the US EPA National Air Toxics Assessment (NATA) as posing population cancer risk (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 1997; 2012a; b; 2016; 2018; Zhou et al. 2015). Some air pollutants are considered emerging, such as microplastics associated with industrialization (Sharma et al. 2020), while some are legacy pollutants, such as PAHs that are persistent organic pollutants (POPs) and can remain in the environment for an extended period of time (Amato-Lourenco et al. 2020; Souza et al. 2022). Rural areas may be relatively less populated compared with urban areas, but the most frequently occurring carcinogenic air pollutants (including acetaldehyde, benzene, carbon tetrachloride, and formaldehyde) are observed in both urban and rural areas in the US (Zhou et al. 2015). However, there may be urban-rural differences in emission sources for specific pollutants (e.g., benzene is primarily derived from motor vehicle exhaust in urban areas vs. from wood-burning heat sources in rural areas) and a wider variety of air pollutants is often characterized in urban areas (Zhou et al. 2015).

Irrespective of the heterogenous geographic patterning for outdoor air pollution, many of the aforementioned chemical compounds comprise PM2.5, or particulate matter <2.5 μm in aerodynamic diameter, a widely studied, regulated air pollutant, an IARC-classified carcinogenic agent (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016), and the focus of this paper. PM2.5 is primarily produced from combustion of fossil fuels and is comprised of metals, black carbon (BC; commonly referred to as soot), PAHs, and other chemical substances (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016). NO2 has been suggested to indicate a more specific type of PM2.5, such as traffic-related particles, given that the primary source of NO2 in urban areas is motor vehicle exhaust (Brook et al. 2007). There is an established body of evidence showing that PM2.5 exposure increases the risk for developing heart disease, stroke, lung cancer, chronic obstructive pulmonary disease, and other chronic health outcomes (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016; Laumbach et al. 2021; Rajagopalan et al. 2020). IARC classified outdoor air pollution in general and PM as Group 1 human carcinogens primarily based on evidence of associations with the development of lung cancer (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016). To protect public health, air quality standards have been established for PM2.5 at levels above which average annual concentrations should not be exceeded: 5 μg/m3 for the World Health Organization (WHO) (updated in 2021), 12 μg/m3 for the US EPA, and 25 μg/m3 for the European Union (EU) (Hoffmann et al. 2021; Rajagopalan et al. 2020; Sicard et al. 2021).

1.2. A plausible link with liver cancer

Although outdoor air pollution is an established risk factor for lung cancer, and evidence is accumulating for others (such as breast cancer (Gabet et al. 2021)), its association with other cancers has been relatively less explored (Turner et al. 2020). There is emerging epidemiologic evidence demonstrating that ambient air pollution exposure may increase the risk of developing liver cancer (Pan et al. 2016; Pedersen et al. 2017; So et al. 2021; VoPham et al. 2018). Globally, liver cancer is the seventh most common cancer and the second leading cause of cancer-related death, and incidence is increasing in parts of the world including India, North and South America, and most European countries (McGlynn et al. 2021). The most common histological subtype of primary liver cancer is hepatocellular carcinoma (HCC), comprising approximately 75% of total liver cancer diagnoses (McGlynn et al. 2021). Survival remains low, with incidence rates generally mirroring mortality rates (McGlynn et al. 2021). Geographic variability in HCC incidence is largely attributed to differences in the prevalence and/or age of acquisition of risk factors, which include chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, heavy alcohol consumption, aflatoxin exposure, tobacco smoking, obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) (McGlynn et al. 2021). Some chemical compounds in tobacco smoke, such as PAHs and metals, have documented hepatocarcinogenic effects in animal and epidemiologic studies and are also found in outdoor air pollution (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016). Figure 1 shows that some highly polluted areas, according to population-weighted outdoor PM2.5 concentrations, coincide with high-risk areas for liver cancer incidence, such as parts of Asia and Africa.

Figure 1. Population-weighted PM2.5 concentrations and age-adjusted liver cancer incidence.

Figure 1.

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Average annual PM2.5 data were provided by the State of Global Air 2019 and liver cancer incidence rates were provided by GLOBOCAN 2020. Choropleth maps are categorized according to quintiles.

Experimental studies have provided insights into mechanistic pathways for the potential role of PM2.5 in hepatocarcinogenesis. Due to its relatively fine particle size fraction, PM2.5 can be inhaled and deposited deep in the lung alveoli and translocate from the lungs entering the bloodstream via rapid diffusion into systematic circulation (Conklin 2013; Laing et al. 2010; Miller et al. 2017; Nemmar et al. 2002; Nemmar et al. 2001). In the liver of mice or rats, PM2.5 promotes cell proliferation, genotoxicity, oxidative stress, inflammation, lipid accumulation, alterations in glucose metabolism, collagen deposition, and fibrosis (Bourdon et al. 2012; Jackson et al. 2012; Kim et al. 2014; Tan et al. 2009; Tavera Busso et al. 2020; Tomaru et al. 2007; Wang et al. 2020; Yuan et al. 2021; Zheng et al. 2013; Zheng et al. 2015). Rats exposed to PM2.5 showed structural and functional changes in liver tissue, including elevated elemental tissue composition for barium, chromium, iron, lead, thallium, and zinc, higher aspartate aminotransferase (AST) levels (a biochemical marker of liver injury), increased levels of total cholesterol and triglycerides, and increased DNA damage (Tavera Busso et al. 2020). Animal models have demonstrated that benzene, a chemical component of PM2.5, can induce NAFLD and its more progressive form of nonalcoholic steatohepatitis (NASH), both of which increase the risk of HCC (Arciello et al. 2013; Larson and Koenig 1994; VoPham 2019; Wahlang et al. 2013; Wyzga and Rohr 2015).

Building on the body of experimental studies demonstrating biological plausibility and the growing epidemiologic literature showing evidence that air pollution exposure increases liver cancer risk, which we will summarize herein, there remain several research gaps and thus valuable opportunities for future work to continue improving our understanding of the potential etiologic role of air pollution exposure in liver cancer. Important research focus areas include methodological considerations regarding potential confounding by established risk factors for HCC; examination of incident primary outcomes with consideration of potential differential associations according to histology (i.e., etiologic heterogeneity in relation to PM2.5 exposure); improved air pollution exposure assessments considering early-life and/or historical exposures and combining geospatial ambient exposure modeling with novel biomarker technologies such as adductomics; statistical methods to examine air pollution mixtures; climate change and related increases in extreme weather events as an important source of ambient air pollution (e.g., wildfires); and considerations of modifying factors for air pollution exposure, such as socioeconomic status (SES) (and potential differences in toxic mixtures of pollutants and/or air pollution knowledge and preventive health behaviors) (Rajagopalan et al. 2020), that may contribute to disparities in liver cancer incidence.

The objectives of this paper are to narratively synthesize the existing epidemiologic literature on the association between air pollution exposure and liver cancer risk and discuss future research directions to advance the science of understanding this relationship.

2. Epidemiologic evidence on air pollution and liver cancer

To our knowledge, there have been four epidemiologic studies conducted in the US, Taiwan, and Europe examining air pollution exposure and liver cancer incidence (Pan et al. 2016; Pedersen et al. 2017; So et al. 2021; VoPham et al. 2018). This commentary focuses on describing literature that evaluated liver cancer incidence (not mortality) outcomes (to minimize misclassification of primary vs. secondary liver cancers) and studies specifically examining a liver cancer outcome rather than all cancers combined (and thus addressing potential confounding by liver cancer risk factors; studies examining multiple cancer sites may not adjust for liver cancer-specific covariates). Additional details on the studies described in this paper can be found elsewhere (Pritchett et al. 2022).

2.1. United States

A US-based ecological study was conducted using cancer registry data of 56,245 HCC cases diagnosed from 2000–2014 (VoPham et al. 2018). PM2.5 exposure was estimated using county administrative boundaries linked with an exposure model in 2000 based on spatial interpolation of data from air monitoring stations. Average annual PM2.5 exposure for study participants was 14.6 μg/m3 (SD 3.1). Results were adjusted for individual-level demographics and area-level prevalence of health conditions, lifestyle factors, environmental exposures, and SES. There was a positive association between ambient PM2.5 levels and HCC incidence (IRR per 10 μg/m3: 1.26, 95% CI 1.08–1.47) (VoPham et al. 2018). However, limitations of this work include an ecological study design, coarse-scale exposure assessment, and lack of adjustment for individual-level risk factors for HCC.

2.2. Taiwan

In a prospective cohort study in Taiwan, there were 464 HCC cases diagnosed from 1991–2009 with PM2.5 exposure from 2006–2009 estimated using geocoded residential addresses linked with a kriging model incorporating data from air monitoring stations (Pan et al. 2016). Average annual PM2.5 concentrations were 32.23 μg/m3 (SD 7.56) for the Main Island and 24.22 μg/m3 (SD 0.50) for the Penghu Islets. Results were adjusted for age, sex, hepatitis B surface antigen (HBsAg), hepatitis C antibody (anti-HCV), alanine transaminase (ALT), alcohol consumption, and smoking. Residential PM2.5 exposure was associated with an increased risk for HCC (HR per IQR [0.73 μg/m3]: 1.22, 95% CI 1.02–1.47) in the Penghu Islets (Pan et al. 2016). A positive association was also observed on the Main Island (Pan et al. 2016). There was evidence of mediation of this association by ALT levels, suggesting a chronic inflammation pathway.

2.3. Europe

In a prospective analysis as part of the European Study of Cohorts for Air Pollution Effects (ESCAPE) project, a total of 279 primary liver cancer cases diagnosed from 1985–2012 were examined from four cohorts in Austria, Denmark, and Italy (Pedersen et al. 2017). Land-use regression models for NO2, NOX, PM10, PM2.5, PM2.5–10, and PM2.5 absorbance were linked with baseline geocoded residential addresses. Exposure measures for traffic density and PM elemental components of PM2.5 and PM10 (copper, iron, nickel, potassium, silicon, sulfur, vanadium, zinc) were also examined. Average annual exposures across the included cohorts ranged from 16.4–54.1 μg/m3 (SD 7.0–17.3) for NO2 and from 11.3–13.6 μg/m3 (SD 0.9–1.2) for PM2.5 (PM2.5 was not available for all cohorts). Results were adjusted for age, sex, smoking, alcohol consumption, occupational exposures, employment status, education, and area-level SES. There were suggestive positive associations for air pollution exposure and liver cancer risk for NO2 (summary HR per 10 μg/m3: 1.10, 95% CI 0.93–1.30) and PM2.5 (summary HR per 5 μg/m3: 1.34, 95% CI 0.76–2.35) (Pedersen et al. 2017). Associations for other air pollution exposure measures were also generally positive, although similarly not statistically significant.

The Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) project included participants from six cohorts in Austria, Denmark, France, Netherlands, and Sweden (So et al. 2021). In contrast to the ESCAPE analysis (Pedersen et al. 2017), the ELAPSE study conducted a pooled analysis with a harmonized air pollution exposure assessment and longer duration of follow-up during which cases could accrue. Analyses included 512 primary liver cancer cases diagnosed from 1985–2015 and air pollution exposures assessed using baseline geocoded residential addresses linked with harmonized hybrid land-use regression models (developed using data from 2008–2011, depending on the pollutant). Average annual exposure levels were 24.9 μg/m3 (SD 8.0) for NO2, 15.0 μg/m3 (SD 3.2) for PM2.5, 1.5 10−5/m (SD 0.4) for BC, and 85.6 μg/m3 (SD 9.0) for O3. Results were adjusted for age, sex, cohort, baseline year, smoking, employment status, and neighborhood SES. There were increased risks for liver cancer with higher levels of exposure to NO2 (HR per 10 μg/m3: 1.17, 95% CI 1.02–1.35), PM2.5 (HR per 5 μg/m3: 1.12, 95% CI 0.92–1.36), and BC (HR per 0.5 10−5/m: 1.15, 95% CI 1.00–1.33) (So et al. 2021). Positive associations for NO2 and BC were robust in two-pollutant models with PM2.5 (assessing the independent effects of each pollutant). An inverse association was observed with O3 exposure (the authors cited previous research showing no association between O3 and liver cancer mortality).

A novel finding in the ELAPSE analysis included demonstrating generally positive associations for the elemental components of PM2.5 that may be driving the observed increased risk for liver cancer, where the strongest associations were shown for sulfur and vanadium (results were robust to adjustment for PM2.5 or NO2) (So et al. 2021). Further, in analyses considering current air quality standards for the EU (participants with residential concentrations above a standard were excluded), associations with NO2 and PM2.5 persisted below current EU standards of 40 μg/m3 for NO2 and 25 μg/m3 for PM2.5, while associations with BC persisted at levels below 1.5 10−5/m.

3. Future research directions

The results from these four studies represent a generally consistent body of epidemiologic evidence showing a positive association between air pollution exposure and the development of liver cancer (Pan et al. 2016; Pedersen et al. 2017; So et al. 2021; VoPham et al. 2018). This association was consistent across different study populations in different countries across the world, with varying exposure levels. Average annual PM2.5 concentrations in the described studies were higher than the WHO standard of 5 μg/m3 for PM2.5, with the highest levels observed in Taiwan (Pan et al. 2016; Pedersen et al. 2017; So et al. 2021; VoPham et al. 2018). Strengths of these studies include examining incident, confirmed, primary liver cancer (or HCC) cases minimizing outcome misclassification and estimating long-term exposure using objective geospatial methods that have been predictive of risk for other outcomes now established to be linked with air pollution (e.g., lung cancer) (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016). However, there are research gaps that could be addressed to improve our understanding of the etiologic relationship between air pollution and liver cancer.

3.1. Confounding by major HCC risk factors

Chronic HBV and HCV infection, each of which is characterized by geographic variability in prevalence, represent two of the major risk factors for HCC (McGlynn et al. 2021). To address potential residual confounding by HBV and HCV, previous studies have adjusted for correlates of infection (e.g., urbanicity, SES), noting a low likelihood of strong confounding given the low prevalence of HBV and/or HCV infection in the underlying study populations, and a likely lack of a strong association between HBV and HCV status with the fine-scale locally varying geographic patterns of air pollution (Pedersen et al. 2017). Results from the prospective analysis in Taiwan support an association for PM2.5 exposure and HCC risk, which were adjusted for HBV and HCV (Pan et al. 2016). However, PM2.5 levels in this study were associated with anti-HCV seropositivity (but not associated with HBsAg seropositivity), suggesting that HCV (and not HBV) may confound the relationship between air pollution exposure and HCC (Pan et al. 2016). Although the epidemiology of these viruses is changing, for example due to HBV vaccination campaigns and antiviral therapy (McGlynn et al. 2021), adjustment for HBV and HCV should be considered in future analyses to determine the independent effect of air pollution exposure on liver cancer risk and to rule out viral etiology.

Other potential confounders to consider include obesity, diabetes, and NAFLD, which are important to address in light of increasing prevalence of these metabolic diseases across different parts of the world (which have been shown to increase HCC risk (McGlynn et al. 2021)) and studies showing positive associations between PM2.5 and obesity, diabetes, and NAFLD (Bowe et al. 2018; Tamayo-Ortiz et al. 2021; VoPham et al. 2022). Adjustment for alcohol consumption is also an important consideration, as it is a known risk factor for cirrhosis and HCC (McGlynn et al. 2021). In the context of air pollution (and other environmental) epidemiology studies, analyses should control for measures of SES, as populations of low SES tend to experience higher levels of air pollution (Hajat et al. 2021; Rajagopalan et al. 2020).

3.2. Incident HCC outcome ascertainment

Given HCC is a rare outcome, pooled analyses combining information across multiple study populations could be explored to enhance statistical power (such as combining multiple prospective cohort studies as was conducted in the ELAPSE project (So et al. 2021)). Although HCC is the most commonly occurring histology for primary liver cancer, etiologic heterogeneity in relation to PM2.5 exposure should be considered, as some risk factors differ for HCC and intrahepatic cholangiocarcinoma (the second most commonly occurring histology). However, analyses by subtype may be impacted by small sample sizes and thus less statistical power to detect associations. Further, the liver is a common site of metastasis, thus examining incident, primary, confirmed HCC cases will minimize potential outcome misclassification. Another resource that includes data elements relevant to investigating this research question is electronic health records (EHRs), which can provide access to a large number of patients with detailed longitudinal information on demographics and clinical data (Casey et al. 2016). EHRs enable the identification of a large sample size of cancer outcomes, for which validated EHR algorithms have been established in comparison to chart review (gold standard). Further, EHRs can provide valuable information regarding patient geographic data for linkage with air pollution exposure (and other location-based) data to facilitate environmental exposure assessments. These advantages are balanced against some potential concerns such as regarding generalizability.

3.3. Enhancing air pollution exposure assessments

The exposure assessment in the studies described herein applied geospatial methods, estimating ambient exposure based on geographic variables (e.g., geocoded residential addresses) linked with exposure models predicting ambient PM2.5 (and other pollutant) levels across space and time (Pan et al. 2016; Pedersen et al. 2017; So et al. 2021; VoPham et al. 2018). Although several studies had temporal mismatches, where air pollution exposure was estimated after some liver cancer cases were diagnosed (Pan et al. 2016; Pedersen et al. 2017; So et al. 2021), sensitivity analyses restricting to participants who lived at the same address throughout follow-up (to minimize exposure measurement error) showed similar results. Perhaps more meaningfully, two studies confirmed similar associations using back-extrapolated time-varying exposures using residential histories (Pedersen et al. 2017; So et al. 2021). Results from the historical exposure assessments conducted by these studies are compelling in supporting the role of a latency period in PM2.5 exposure subsequently increasing the risk of developing HCC; known risk factors for HCC (and other solid tumors) are associated with long latency periods (McGlynn et al. 2021). Further, analyses considering exposure lags of 8–14 years prior to HCC diagnosis showed stronger positive associations, although these findings are difficult to interpret given the ecologic study design (VoPham et al. 2018). Future research directions include adopting a life course epidemiology approach, assessing historical long-term exposures to address potential critical periods of exposure (e.g., during early life) using available residential histories, especially as previous research has focused on long-term air pollution exposure only during adulthood (Pan et al. 2016; Pedersen et al. 2017; So et al. 2021; VoPham et al. 2018).

Other considerations include to evaluate residual confounding from other sources of exposures to chemicals found in PM2.5, including tobacco smoking (which is also an HCC risk factor (McGlynn et al. 2021)) through adjustment for smoking status and/or conducting sensitivity analyses among never-smokers, adjustment for environmental tobacco smoke (ETS) (e.g., secondhand smoke), diet (e.g., consumption of fried foods), and occupation (e.g., urban traffic police) (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2016). Chemicals that may be relevant to consider include PAHs and aldehydes from fried foods and heavy metals (e.g., cadmium, arsenic) from tobacco smoking and ETS.

Beyond ambient geospatial exposure estimates, the development of novel biomarker technologies, such as albumin adductomics, represents a promising scientific advancement and approach to provide biomarkers of exposure to air pollution (Smith et al. 2021). Adducts to human serum albumin (HSA), the most abundant protein in circulation, provide estimates of exposure to specific air pollutants in complex mixtures experienced by an individual over the preceding 1–3 months (Smith et al. 2021). Other biomonitoring methods include examining urinary metabolites, although these approaches may be less accurate for characterizing air pollution exposures across different time frames (Smith et al. 2021). Combining geospatial methods, which provide objective location-based ambient exposure estimates (not reliant on self-report), and these biomarkers of personal exposure (e.g., adductomics) can provide a comprehensive approach to assess air pollution exposure. Further highlighting the need to consider the integration of exposure biomarkers (and the precision in exposure estimation that these methods offer) is evidenced by results from the ELASPE project, where specific elemental components of PM2.5 were more strongly associated with liver cancer risk and that low-level exposures still posed adverse effects (So et al. 2021). These findings highlight opportunities to investigate specific emission sources and/or chemical compounds that may be hepatocarcinogenic as well as the potential impacts of air pollution on liver cancer risk in areas characterized by concentrations that do not exceed air quality standards.

3.4. Exposure to air pollution mixtures in the exposome

Chronic diseases, such as liver cancer, are complex and the result of exposures to a multitude of factors over the life course (Cheung et al. 2020; Vineis et al. 2017; Wild 2012). The exposome, defined as the totality of environmental exposures from conception onwards and is considered the environmental counterpart of the genome, provides a framework within which to understand and investigate liver cancer etiology (Cheung et al. 2020; Chung et al. 2021; Juarez et al. 2020; Vineis et al. 2017; Wild 2012). The exposome is comprised of the external exposome (measured using external assessment methods such as geospatial science tools; further categorized into the general and specific external) (DeBord et al. 2016) and the internal exposome (measured using omics methods) (Juarez et al. 2020). The exposome includes chemical and non-chemical exposures in the three domains of the natural, built, and social environments (Juarez et al. 2020). In extending the exposome framework to studying air pollution and liver cancer, the examination of a single air pollutant may not be an appropriate approach to investigate the likely diverse array of air pollutant (and other) exposures experienced in the exposome, which further varies according to a person’s microenvironments in the home, workplace, outdoors, and transit (Wong et al. 2021). Thus, alternative approaches have been developed to estimate the aggregate, sum, independent, and/or joint effects of mixtures or mixture components for air pollutants such as Bayesian hierarchical models, Bayesian kernel machine regression, least absolute shrinkage and selection operator, and quantile g-computation (Christensen et al. 2022; Hamra and Buckley 2018; Keil et al. 2020). These advanced methods may be useful to consider in liver cancer epidemiology depending on the specific research question of interest.

3.5. Climate change and air pollution

Climate change has important implications for outdoor air pollution levels and increased opportunities for exposure to carcinogenic air pollutants (Hiatt and Beyeler 2020; Nogueira et al. 2020). For example, multiple studies have shown that climate change has led to an increase in wildfire frequency, duration, and intensity (Korsiak et al. 2022; Turco et al. 2018; Xu et al. 2020). Climate change is also associated with extreme weather events characterized by high temperatures, droughts, strong winds, rainfall anomalies, and/or lightning strikes, which increase the opportunity for wildfires to occur and may thus amplify/enhance the effects of ambient air pollution on morbidity and mortality (Xu et al. 2020). Wildfire smoke can permeate areas surrounding wildfire events (upwards of 1,000 km in distance) (Shum and Zhong 2022), representing a significant source of ambient air pollution (Xu et al. 2020). The major air pollutants emitted during wildfires include a number of toxic and carcinogenic compounds such as carbon monoxide (CO), ozone, PM, PAHs, benzene, and formaldehyde (Korsiak et al. 2022; Messier et al. 2019; Xu et al. 2020). A study from 1988–2016 showed that the Northwest region of the US was characterized by statistically significant increases in PM2.5 levels specifically due to wildfire events, suggesting a hazardous climate change-related trend in ambient air pollution concentrations (McClure and Jaffe 2018). Thus, future work should consider how climate change is projected to exacerbate the prevalence and intensity of wildfires, particularly since communities may be disproportionately impacted by ensuing carcinogenic exposures, and some pollutant levels may persist in the environment for long periods of time (beyond the period of wildfire active burning), representing a chronic source of ambient air pollution exposure (Korsiak et al. 2022).

3.6. Disparities in air pollution exposures and liver cancer incidence

Another important facet of this research area is how different population subgroups, defined by characteristics such as age, race, ethnicity, sex, SES, and geography, may be disproportionately impacted by an exposure or a condition. In the US, liver cancer burden is characterized by marked disparities by race/ethnicity (higher incidence among people who are American Indian/Alaska Native, Hispanic, or Asian/Pacific Islander) and sex (higher incidence among men) (McGlynn et al. 2021). Environmental health disparities related to air pollution exposure include consideration of vulnerable populations, or population subgroups who are more likely to experience higher levels and/or more toxic mixtures of pollutants (e.g., low SES, individual residing in poor housing quality) (Hajat et al. 2021; Rajagopalan et al. 2020). Individuals in particular subgroups, based on factors such as race/ethnicity, may be more likely to reside in highly polluted areas, thus contributing to increased risk for developing liver cancer (Liu et al. 2021). Given the observed disparities with respect to exposure and outcome, future work regarding differential interrelationships and impacts of (and susceptibilities to) air pollution exposure on liver cancer risk, and exploration of underlying behavioral, systemic, environmental, social, and other differences is warranted.

4. Conclusions

In summary, there is growing evidence demonstrating that higher levels of air pollution exposure increase the risk for developing liver cancer. Four epidemiologic studies conducted in the US, Taiwan, and Europe, three of which were prospective analyses adjusting for HCC risk factors including alcohol consumption, found evidence for positive relationships. To continue expanding on this literature to robustly demonstrate that air pollution exposure is a risk factor for liver cancer, future research should rule out confounding by major HCC risk factors such as HBV, HCV, alcohol consumption, smoking, obesity, and diabetes. SES should also be considered. Examining incident, primary, confirmed liver cancer cases with consideration of etiologic heterogeneity in relation to PM2.5 exposure is warranted. Exposure assessments may be improved through determining early-life (in addition to adult) exposures using residential histories, accounting for residual confounding from other sources of air pollutants (particularly smoking, which is also a risk factor for HCC), and integration of biomarkers of exposure. Application of statistical methods to consider the independent and/joint effects of air pollution mixtures experienced in the exposome may be of interest depending on the research question. Climate change is associated with increased occurrences of extreme weather events that can promote wildfires, which are an important source of outdoor air pollution that may disproportionately impact particular communities. Finally, disparities in both air pollution exposure and liver cancer represent an important line of research to determine if air pollution exposure may contribute to observed disparities in liver cancer incidence.

Funding sources

This work was supported by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K01 DK125612].

Abbreviations

ALT

alanine transaminase

anti-HCV

hepatitis C antibody

AST

aspartate aminotransferase

BC

black carbon

CI

confidence interval

CO

carbon monoxide

EHR

electronic health record

ELAPSE

Effects of Low-Level Air Pollution: A Study in Europe

EPA

Environmental Protection Agency

ESCAPE

European Study of Cohorts for Air Pollution Effects

ETS

environmental tobacco smoke

EU

European Union

HAP

hazardous air pollutant

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

HR

hazard ratio

HSA

human serum albumin

IARC

International Agency for Research on Cancer

IRR

incidence rate ratio

IQR

interquartile range

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NATA

National Air Toxics Assessment

NO

nitrogen oxide

NOx

nitrogen oxides

NO2

nitrogen dioxide

O3

ozone

PAH

polycyclic aromatic hydrocarbon

PCB

polychlorinated biphenyl

PCDD

polychlorinated dibenzo-p-dioxin

PCDF

polychlorinated dibenzofuran

PM

particulate matter

PM2.5

particulate matter <2.5 μm in aerodynamic diameter

PM2.5–10

particulate matter between 2.5 μm and 10 μm in aerodynamic diameter

PM10

particulate matter <10 μm in aerodynamic diameter

POP

persistent organic pollutant

SD

standard deviation

SES

socioeconomic status

US

United States

WHO

World Health Organization

Footnotes

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Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare that they have no competing interests.

Research data

The datasets used to create Figure 1 are publicly available from the State of Global Air 2019 [https://www.stateofglobalair.org] and GLOBOCAN 2020 [https://gco.iarc.fr/today/home].

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