Using biomass fuel linked to higher risk of esophageal squamous cell cancer

Globally, Esophageal Cancer is the seventh incident cancer and sixth leading cause of cancer-related deaths [1]. Of the 2 histological subtypes, Esophageal squamous cell carcinoma (ESCC) accounts for more than 90% of all esophageal cancers [1–3]. The ESCC subtype is most common in Asia and East Africa, while adenocarcinoma is predominant subtype in the Western countries [3–5].

Various lifestyle and environmental exposures are associated with esophageal squamous cell carcinoma (ESCC) [6] However, in areas with high ESCC incidence like East Africa and Asian known risk factors such as smoking and alcohol use explain just a fraction of disease causation [7, 8] compared to high income settings [9, 10]. Though the sharp geographical delineations of ESCC with younger ages (< 60 years) of disease presentation [7, 11, 12] point to multifactorial etiologies, many putative associations including polycyclic aromatic hydrocarbons from partial combustion of organic matter and diet, have been postulated to explain the epidemiological patterns and burden of ESCC [13–16].

In the poorer communities of Africa, Asia, and South America affected by ESCC, traditional solid biomass fuels (wood, charcoal, coal, dung, and crop residues) are the primary fuel source [17]. Open fires for cooking are often kept smouldering for hours and for indoor heating in the colder high altitude areas. These daily exposure to indoor pollution leads to premature deaths due to pneumonia, cancers, and cardiovascular disease [18, 19]. An association of biomass smoke with lung cancer is established but suggested with ESCC [20] though polycyclic aromatic hydrocarbons (PAHs), a major component of biomass fuel, have carcinogenic properties on mucosal and endothelial lining of upper aero digestive tract from inhalation [21].

In order to reduce the burden of esophageal squamous cell carcinoma, identification of risk factors is the first step to development of targeted interventions. We conducted a systematic review and meta-analysis to evaluate the risk of esophageal cancer based on biomass fuel status.

We carried out a systematic review and meta-analysis to test the association between biomass fuel and Esophageal squamous cell carcinoma along with a protocol developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [22] and registered at PROSPERO.

We searched EMBASE, PubMed, MEDLINE, Web of Knowledge, and Cochrane Database of Systematic Reviews from the year 2000 onwards. The search terms were (‘biomass’ or ‘fossil fuel*’ or fossil fuels or ‘stove*’ or ‘oven*’ or ‘smoke’ or ‘wood’ or ‘cook *’ or ‘fumes *’ or ‘indoor air’ or ‘indoor environment’ or ‘pollution’ or ‘pollutant’ or ‘exposure’ or ‘fuels’ or ‘coal’ or ‘charcoal*’ or ‘cake*’ or ‘briquette*’ or ‘solid fuel*’) AND (‘esophageal cancer’ or ‘esophageal neoplasms’ or ‘esophageal neoplasms/etiology’ or ‘esophageal neoplasms/pathology’ or ‘esophageal neoplasms/prevention and control’). We checked the bibliography of relevant articles for additional studies that met the inclusion criteria. The search and study selection was carried out independently by SO and SJA and consensus reached by discussion.

All 16 studies were of case–control study design with 16,189 participants: 5233 (range 75 to 830) cases of esophageal squamous cell carcinoma and 10,956 controls without disease (range 145 to 1779). Seven of them were large studies with more than 1000 participants [20, 21, 31, 35, 37, 38, 40].

All studies showed a positive association between biomass fuel use and ESCC, 11 of them had statistically significant associations [20, 29–34, 36–39, 41]. In addition, biomass fuel use heighten ESCC risk in studies evaluating CYP2D6 [30] and CYP1A1*4 [37] genotypes in India. In South Africa, SULT1A1*2/*2 [29], GSTP1 341C/T and T/T genotypes [32] and single nucleotide polymorphisms in miR-423 [38] together with environmental smoke exposure was associated with increased risk of ESCC.

All studies except 2 [20, 38] controlled for the major risk factors for ESCC: age, gender, alcohol, and smoking in matching or regression models (Table 1).

All studies used histology to diagnose ESCC as stipulated in inclusion criteria. The quality assessment of included studies is summarized in Table 1.

Combining all the 16 case–control studies showed a significantly increased risk of esophageal squamous cell carcinoma with biomass fuel, pooled overall odds ratio (OR 3.02 (95% CI 2.22, 4.11, I² = 79%). Similarly, our observed associations between biomass and ESCC remained significantly elevated when analyses were restricted to studies that controlled for smoking and alcohol.

Biomass fuel type, geographical setting (continent), and socioeconomic status (World Bank’s country income classification) were significant sources of the observed heterogeneity. Excluding studies one-by-one did not show any substantial change of pooled estimate.

Statistical heterogeneity was considerable (I² > 75%) for overall pooled effect; however, statistical power to evaluate other sources of heterogeneity was low. For assessment of publication bias, the Funnel plot (Additional file 1: Figure S1) and Begg’s test showed no significant asymmetry in the pattern of distribution of studies (p = 0.537).

Our meta-analyses showed that biomass fuel is associated with significantly higher risks of ESCC. The increased risks we observed were independent of other risk factors such as age, gender, smoking and alcohol use. This meta-analysis confirms prior results from a meta-analysis that observed household air pollution is associated with increased risk for esophageal cancers (subgroup meta-analysis of 2 studies) [46]. This is biologically plausible given that the esophageal mucosa may be exposed to inhaled combustion fumes and particles by retrograde ciliar transport in the bronchial tree and subsequent swallowing and thus exposing the esophageal mucosa to carcinogenic substances [47].

We observed an increased risk of esophageal cancers among those in low income followed by low middle income and least in upper middle income. Based on stratification by continents, studies from Africa had the highest risk, followed by Asia, then South America, and least in East and Central Europe. Taken together, these analyses point to variation of biomass use by continent, type of fuel used, and socioeconomic status of populations at high risk for ESCC. In lower income settings of Africa and Asia, cheap biomass fuels such as wood, charcoal, dung, and crop residues are main source of cooking and heating fuel [17].

Noteworthy, we found the ESCC risk varied with biomass type -- highest with wood. Though coal exposures tend to have higher carcinogenic potential than wood for lung cancer [23], it is unknown whether it is the same for esophageal cancer. Even then, our result exemplifies the fact that the types and proportions of carcinogens vary by the type of biomass used [48]. Compared to more expensive less toxic nonsolid fuels (e.g., electricity, liquid petroleum gas, and ethanol), biomass is poorly combustible and produces more toxic emissions with higher levels of sulfur dioxide, carbon monoxide, fluorine, and known carcinogens such polycyclic aromatic hydrocarbons (PAHs), benzene, arsenic, 1,3- butadiene and formaldehyde [49, 50] which are detrimental to human health and causes esophageal cancer [46].

This study has several strengths and limitations. This is the largest study to date with a sample of more than 5000 ESCC cases and estimates were pooled from 16 countries across five World Bank Regions from four continents to quantify the ESCC risk from use of biomass fuel with meta-analysis. The lack of studies from regions such as Australia, North America, and West Europe is likely not due to our English language restriction, but rather the prevalent use of nonsolid fuels as well as low burden ESCC in these regions making potential research unfeasible. This renders our results generalizable to different geographic locations. Another strength of our analysis is that all studies controlled for other known ESCC risk factors. A limitation of this study is that exposure measurements were restricted to one point in time yet biomass use may change over the life course and a single measurement may result in misclassification even among lifetime biomass users. In addition, the lack of individual patient data on exposure–response relationship between duration of biomass use and risk of ESCC limits further insight into the exposure–response relationship.

In conclusion, using biomass fuel increases the risk of Esophageal squamous cell carcinoma. Importantly, ESCC risk differed by study setting and population. While current evidence demonstrates association between age, gender, and lifestyle (smoking and alcohol use) with ESCC, environmental factors might be responsible for the heightened risk in Eastern sub-Saharan Africa. Biomass fuel status should be considered in the risk assessment for Esophageal squamous cell carcinoma in low-income countries.