PAH exposure-associated lung cancer: an updated meta-analysis

Abstract

Background

Occupational exposure to polycyclic aromatic hydrocarbons (PAHs) has been shown to be associated with lung cancer in various epidemiological studies in industries such as aluminium reduction/smelting, coal gasification, coke production, iron/steel foundries, coal/coke and related products and carbon/graphite electrodes production.

Aims

To update data on the association between PAH exposure and morbidity and mortality due to lung cancer among workers in different occupations, including smoking data.

Methods

A comprehensive literature search was conducted to retrieve relevant papers for meta-analysis. Cohort studies with standardized mortality ratios or standardized incidence ratios and calculated overall risk ratio with their corresponding 95% confidence intervals (CIs) were included in the analysis. Chi-square test for heterogeneity was used to evaluate the consistency of findings between the studies.

Results

A significant risk of lung cancer was observed among the coal/coke and related product industry 1.55 (95% CI 1.01–2.37) and the iron/steel foundry industry 1.52 (95% CI 1.05–2.20). There was a wide variation in smoking habits and PAHs exposure among studies.

Conclusions

Coal/coke industry and iron/steel industry workers showed a higher risk of lung cancer compared with other occupations exposed to PAHs. The confounding effects of smoking and individual exposure levels of PAH should be taken into account.

Introduction

In 2013, globally there were an estimated 14.9 million cancer cases and 8.2 million cancer deaths [1]. There were an estimated 1.8 million cases of lung cancer [1]. Workers employed in a number of sectors including coke ovens, commercial kitchens, aluminium smelters, coal gasification, iron and steel foundries, coal mines, chimney sweeps, crude oil extraction, coal tar, rail and road workers, carbon electrode production are exposed to polycyclic aromatic hydrocarbons (PAHs) and have an increased risk of lung cancer [2].

Most PAHs are carcinogenic and genotoxic to humans [3–5]. PAHs are formed during the incomplete combustion of fuels, organic materials, diesel engine exhaust, cooking oil fumes etc. [6]. PAHs are made up of two or more single or fused benzene rings [7]. PAHs are classified as: low molecular weight (two to three fused benzene rings and present in the atmosphere as vapour phase); intermediate molecular weight (four fused benzene rings and present in the atmosphere between the vapour and particulate phases, depending on atmospheric temperature) [8]; and high molecular weight (five to seven fused benzene rings present in the atmosphere and bound to particles). High-molecular-weight PAHs or particle-bound PAHs are considered to be very hazardous to human health. The molecular weight, formula and structure of 16 PAHs which are relevant to occupational hygiene studies are given in Table 1.

Humans are exposed to PAHs by inhalation, ingestion and skin contact [9]. Occupational exposure to PAHs mainly occurs through inhalation or skin contact due to the large surface area. PAHs are metabolized by cytochrome P450 [10] and form diol-epoxide that binds covalently with cellular macromolecules and affects various tissues, inducing pulmonary inflammation, cytotoxicity, genotoxicity and even carcinogenicity due to PAH–DNA adduct formation [11,12]. Occupational exposure to PAHs is associated with increased risk of lung cancer [13].

The aim of this study was to re-examine the existing evidence regarding PAH exposure and lung cancer risk in different industrial workers, taking into consideration smoking history and exposure data.

Methods

All potentially relevant publications (1977–2017) were reviewed using electronic search databases (PubMed, Google Scholar) using the keywords polycyclic aromatic hydrocarbons, benzo(a)pyrene, neoplasm, lung cancer risk, incidence, mortality, occupational exposure, cohort studies, systematic review and meta-analysis. All articles retrieved were screened and cross-checked independently by authors (A.S., R.K. and C.N.K.) for their relevance and to ensure that the articles included in the analysis satisfied the predefined inclusion and exclusion criteria. The percentage of agreement between the authors on the quality of the articles ranged between 90% and 100%. All the disagreements were resolved by consensus among the authors. The references from the selected publications were also screened and relevant articles included in the analysis.

We initially screened the titles and abstracts of all studies. Studies were excluded if they were not related to exposure levels of PAHs and lung cancer. The remaining studies were considered as potentially eligible for further specific screening. In this study, we used the following specific inclusion criteria: (i) cohort studies, (ii) data on PAH exposure level available in the studies, (iii) occupational exposure linked to PAHs, (iv) lung cancer due to PAH exposure and (v) standardized mortality ratio (SMR) and standardized incidence ratio (SIR) data were used to calculate the relative risk of lung cancer. We considered only cohort studies because they are less prone to bias than case–control studies. We excluded some studies, on the basis of the following: (i) design of the study was case–control or cross-sectional, (ii) insufficient data on PAH exposure and (iii) articles in a language other than English. Selection, identification, screening, eligibility, inclusion of articles and meta-analysis for the study was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [14]. The study was approved and registered in the International Prospective Register of Systematic Reviews (PROSPERO), National Institute for Health Research, UK (PROSPERO Registration No.: CRD42016038938).

The following information was extracted from each study: authors name, year of publication, country, type of industry, period of follow-up, outcome measures (mortality/morbidity), number of subjects in the study and number of deaths/cases. The SMR or SIR for lung cancer in relation to PAH exposure were also extracted from each paper to be included in the analysis. Additionally, the number of cancer deaths/cases observed was also extracted to provide estimates of SMR/SIR to be used in the meta-analysis. The abstracted data are presented in Table 2.

The SMR or SIR abstracted from each paper was used to calculate the overall risk ratio and corresponding 95% confidence interval (CI). If SMR/SIR was not stated in the paper, it was calculated as the ratio of observed and expected number of deaths/cases of lung cancer associated with PAH exposure. Subgroup analysis was performed for type of occupation (aluminium reduction/smelting, carbon/graphite electrode, coal/coke industry, iron steel foundry and other occupation) among workers. Chi-square test for heterogeneity was used to evaluate the consistency of findings between the studies. Where there was significant heterogeneity, a random effects model or else fixed effects model was used for the analysis. The results of the meta-analysis are presented as forest plots with each individual study result expressed as a square box with its size proportional to its weight in the study. The overall pooled results were presented as a rhomboid at the bottom of the forest plot with its centre representing the risk ratio and extremes as 95% CI. Analysis was performed using STATA (IC 13, StataCorp LP, TX, USA) and Comprehensive Meta-Analysis software (USA, version 2.2.064). The criterion for significance was P <0.05.

Results

Using the predefined search criteria, 24 cohort studies were included in the analysis, with 296810 lung cancer subjects. The details of the cohort studies are given in Table 2. Significant heterogeneity was observed among studies in aluminium reduction, coal/coke and other industries. The rhomboid of overall effect showed a relative risk of 1.55 (95% CI 1.02–2.37) for coal/coke, 1.52 (95% CI 1.05–2.21) for iron/steel foundry, 1.13 (95% CI 0.96–1.33) for aluminium and 1.29 (95% CI 0.88–1.89) for other industries (Figure 1).

The results of the meta-analysis by industry showed a significantly increased risk ratio for lung cancer for subjects occupationally exposed to PAHs in the coal/coke and the iron/steel foundry industry. The rest of the industries had an increased risk ratio for lung cancer, although the risk ratios were not significant. There was a wide variation in smoking habits among workers in each study and exposure to PAHs in the work place (Supplementary Material, available as Supplementary data at Occupational Medicine Online). Most of the studies did not adjust for the effect of smoking as a confounding factor.

Discussion

This meta-analysis of data from 296810 workers in 24 different publications up to October 2017 found a higher risk of lung cancer associated with PAH exposure among the coal/coke and iron/steel foundry industries compared to other industries. Irrespective of the study location or the occupation, workers exposed to PAHs showed a higher risk of lung cancer.

Only 12 out of 24 cohort studies mentioned smoking status. Smoking habits of workers were represented in different formats in each study (Supplementary Material, available as Supplementary data at Occupational Medicine Online). Only 10 studies mentioned the use of smoking-adjusted data for the statistical analysis. Due to the limited number of studies with smoking data, a meta-analysis based on smoking-adjusted data was not conducted in this study and may have influenced the study outcome. There was no uniformity in the sampling method or the criteria followed for exposure to PAHs. Hence large variations in exposure to PAHs were observed between the selected studies. Therefore, meta-analysis based on the exposure levels of PAHs was not conducted in this study and may be considered as another limitation.

The large sample size and a global representation of industries in this meta-analysis are the main strengths of this study with limited publication bias. However, there is no data available from Asian countries like India. In the developing world PAH exposure-related industries may be located in the informal sector, where control measures are less stringent. The advantages of the present analysis compared to earlier studies [2,15,16] were the inclusion of studies with mention of PAH exposure (Supplementary Material, available as Supplementary data at Occupational Medicine Online), the selection of cohort studies only (the best study design for evidence-based medicine), and that it focused only on lung cancers. The present study also focused on the critical details of PAHs exposure and lung cancer in cohort studies viz., smoking habits of worker status and exposure details data of PAHs at the workplace in each study.

Incomplete combustion of coal tar and coke during coal distillation and purification generates higher levels of PAHs, especially in industrial environments. Lung cancer mortality was reported to be higher among workers employed in coal gas production due to higher exposure to PAHs [17,18]. In the coke making process, PAHs are generated when coal is burned in the absence of oxygen at high temperature to concentrate carbon. Lung cancer deaths were reported among workers exposed to PAHs in the coke industry [19]. In the iron and steel foundries, coal powder, coal tar and engine exhaust produce PAHs in work environment [4,20]. Lung cancer incidence was reported to be 2.5 times higher among steel foundry industry workers compared to the reference population [21].

PAHs occur in the air as constituents of complex mixtures of particulate matter. Different countries have different workplace exposure limits for PAHs and industries should endeavour to comply with those limits including reducing emissions at source. Strategies may also include periodic monitoring of PAH levels and biomonitoring for PAHs in workers. Better ventilation strategies including heating, ventilation and air conditioning technologies and use of personal protective equipment may also reduce PAH exposure in the work place.

Competing interests

None declared.

Acknowledgements

IITR Pub No: 3416. A.S. acknowledges the Council of Scientific and Industrial Research, New Delhi for a Senior Research Fellowship grant for this study.

References