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

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. Cohort studies, lung cancer risk, meta-analysis, polycyclic aromatic hydrocarbons, workers 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. Table 1. PAHs: molecular weight, molecular formulas and structure Sl. no. Compound Molecular weight Molecular formula Structure 1 Naphthalene 128.17 C13H10 2 Acenaphthylene 152.19 C12H18 3 Acenaphthene 154.21 C12 H10 4 Fluorene 166.26 C13H10 5 Phenanthrene 178.23 C14H10 6 Anthracene 178.23 C14H10 7 Pyrene 202.25 C16H10 8 Fluoranthene 202.26 C16H10 9 Chrysene 228.28 C18H12 10 Benzanthracene 228.29 C18H12 11 Benzo[b]fluoranthene 252.30 C20H12 12 Benzo[k] fluoranthene 252.30 C20H12 13 Benzopyrene 252.31 C20H12 14 Benzo[g,h,i] perylene 276.338 C22H12 15 Indeno[1,2,3-cd] pyrene 276.330 C22H12 16 Dibenzo(a,h) anthracene 278.34 C22H14 Sl. no. Compound Molecular weight Molecular formula Structure 1 Naphthalene 128.17 C13H10 2 Acenaphthylene 152.19 C12H18 3 Acenaphthene 154.21 C12 H10 4 Fluorene 166.26 C13H10 5 Phenanthrene 178.23 C14H10 6 Anthracene 178.23 C14H10 7 Pyrene 202.25 C16H10 8 Fluoranthene 202.26 C16H10 9 Chrysene 228.28 C18H12 10 Benzanthracene 228.29 C18H12 11 Benzo[b]fluoranthene 252.30 C20H12 12 Benzo[k] fluoranthene 252.30 C20H12 13 Benzopyrene 252.31 C20H12 14 Benzo[g,h,i] perylene 276.338 C22H12 15 Indeno[1,2,3-cd] pyrene 276.330 C22H12 16 Dibenzo(a,h) anthracene 278.34 C22H14 View Large Table 1. PAHs: molecular weight, molecular formulas and structure Sl. no. Compound Molecular weight Molecular formula Structure 1 Naphthalene 128.17 C13H10 2 Acenaphthylene 152.19 C12H18 3 Acenaphthene 154.21 C12 H10 4 Fluorene 166.26 C13H10 5 Phenanthrene 178.23 C14H10 6 Anthracene 178.23 C14H10 7 Pyrene 202.25 C16H10 8 Fluoranthene 202.26 C16H10 9 Chrysene 228.28 C18H12 10 Benzanthracene 228.29 C18H12 11 Benzo[b]fluoranthene 252.30 C20H12 12 Benzo[k] fluoranthene 252.30 C20H12 13 Benzopyrene 252.31 C20H12 14 Benzo[g,h,i] perylene 276.338 C22H12 15 Indeno[1,2,3-cd] pyrene 276.330 C22H12 16 Dibenzo(a,h) anthracene 278.34 C22H14 Sl. no. Compound Molecular weight Molecular formula Structure 1 Naphthalene 128.17 C13H10 2 Acenaphthylene 152.19 C12H18 3 Acenaphthene 154.21 C12 H10 4 Fluorene 166.26 C13H10 5 Phenanthrene 178.23 C14H10 6 Anthracene 178.23 C14H10 7 Pyrene 202.25 C16H10 8 Fluoranthene 202.26 C16H10 9 Chrysene 228.28 C18H12 10 Benzanthracene 228.29 C18H12 11 Benzo[b]fluoranthene 252.30 C20H12 12 Benzo[k] fluoranthene 252.30 C20H12 13 Benzopyrene 252.31 C20H12 14 Benzo[g,h,i] perylene 276.338 C22H12 15 Indeno[1,2,3-cd] pyrene 276.330 C22H12 16 Dibenzo(a,h) anthracene 278.34 C22H14 View Large 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). Table 2. Details of studies included in the analysis Sl. no Author Year Industry/ exposure Country Exposure Types of study Cancer Outcome Period of follow-up No. of subjects Deaths/ cases SMR/ SIR 95% CI 1 Gibson 1977 Steel foundry Canada PAH (B[α]P) Cohort study Lung Mort 1967–76 439 21 2.5 1.59–3.76 2 Hensen 1989 Asphalt or bitumen Denmark PAH (B[α]P) Cohort study Lung Mort 1959–84 679 27 3.44 2.27–5.01 3 Gustavsson 1990 Coal gasification Sweden PAH (B[α]P) Cohort study Lung Mort 1966–86 295 4 0.82 0.22–2.11 4 Armstrong 1994 Aluminium smelter Canada PAH (B[α]P) Case–cohort Study Lung Mort 1950–88 16297 338 2.25 1.5–3.38 5 Gustavsson 1995 Graphite electrode Sweden PAH (B[α]P) Cohort study Lung Mort 1968–88 901 2 1.68 0.2–6.07 6 Liu 1997 Carbon manufacturing China PAH (B[α]P) Retrospective cohort Lung Mort 1970–85 6635 50 2.16 1.62–2.83 7 Ronneberg a 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 2888 42 0.96 0.69–1.29 8 Ronneberg b 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 373 10 2.11 1.01–3.87 9 Moulin 2000 Steel alloys France PAH (B[α]P) Cohort study Lung Mort 1968–92 4288 54 1.19 0.89–1.55 10 Romundstad a1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1962–95 5627 46 0.93 0.68–1.24 11 Menvielle 2010 Heavy metal, asbestos 10 European countries PAH (B[α]P) Cohort study Lung Morb 2002–06 88265 703 1.02 0.68–1.53 12 Romudstad b1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1953–95 1790 27 0.9 0.6–1.3 13 Romudstad c1 2000 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–96 11103 189 1.01 0.9–1.2 14 Miller 2013 Coke oven Britain PAH (B[α]P) Cohort study Lung Mort 1966–87 6362 42 1.51 1.06–2.15 15 Verma 1992 Nickel copper Smelters/ refinery Canada PAH (B[α]P) Cohort study Lung Mort 1950–84 54000 50 1.37 1.02–1.81 16 Koskela 2007 Iron foundry Finland PAH (B[α]P) Cohort study Lung Morb 1950–72 931 60 1.34 1.02–1.72 17 Spinelli 2006 Aluminum reduction Canada PAH (B[α]P) Cohort study Lung Mort 1954–97 6423 120 1.07 0.89–1.28 18 Carta 2004 Aluminum smelter Italy PAH (B[α]P) Cohort study Lung Mort 1972–80 1152 11 0.7 0.39–1.26 19 Bye 1998 Coke plant Norway PAH (B[α]P) Cohort study Lung Morb 1962–93 888 7 0.82 0.33–1.70 20 Loon 1997 Mixed occupation Netherlands PAH (B[α]P) Cohort study Lung Morb 1979–90 58279 12 0.28 0.09–0.89 21 Karlehagen 1992 Creosote- exposed Sweden and Norway PAH (B[α]P) Cohort study Lung Morb 1950–75 922 13 0.79 0.42–1.35 22 Armstrong 2009 Aluminium smelter Canada PAH (B[α]P) Cohort study Lung Mort 1950–99 15703 677 1.32 1.22–1.42 23 Wu a2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 46 2.40 1.85–3.07 24 Wu b2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 20 1.35 1.10–1.64 Sl. no Author Year Industry/ exposure Country Exposure Types of study Cancer Outcome Period of follow-up No. of subjects Deaths/ cases SMR/ SIR 95% CI 1 Gibson 1977 Steel foundry Canada PAH (B[α]P) Cohort study Lung Mort 1967–76 439 21 2.5 1.59–3.76 2 Hensen 1989 Asphalt or bitumen Denmark PAH (B[α]P) Cohort study Lung Mort 1959–84 679 27 3.44 2.27–5.01 3 Gustavsson 1990 Coal gasification Sweden PAH (B[α]P) Cohort study Lung Mort 1966–86 295 4 0.82 0.22–2.11 4 Armstrong 1994 Aluminium smelter Canada PAH (B[α]P) Case–cohort Study Lung Mort 1950–88 16297 338 2.25 1.5–3.38 5 Gustavsson 1995 Graphite electrode Sweden PAH (B[α]P) Cohort study Lung Mort 1968–88 901 2 1.68 0.2–6.07 6 Liu 1997 Carbon manufacturing China PAH (B[α]P) Retrospective cohort Lung Mort 1970–85 6635 50 2.16 1.62–2.83 7 Ronneberg a 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 2888 42 0.96 0.69–1.29 8 Ronneberg b 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 373 10 2.11 1.01–3.87 9 Moulin 2000 Steel alloys France PAH (B[α]P) Cohort study Lung Mort 1968–92 4288 54 1.19 0.89–1.55 10 Romundstad a1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1962–95 5627 46 0.93 0.68–1.24 11 Menvielle 2010 Heavy metal, asbestos 10 European countries PAH (B[α]P) Cohort study Lung Morb 2002–06 88265 703 1.02 0.68–1.53 12 Romudstad b1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1953–95 1790 27 0.9 0.6–1.3 13 Romudstad c1 2000 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–96 11103 189 1.01 0.9–1.2 14 Miller 2013 Coke oven Britain PAH (B[α]P) Cohort study Lung Mort 1966–87 6362 42 1.51 1.06–2.15 15 Verma 1992 Nickel copper Smelters/ refinery Canada PAH (B[α]P) Cohort study Lung Mort 1950–84 54000 50 1.37 1.02–1.81 16 Koskela 2007 Iron foundry Finland PAH (B[α]P) Cohort study Lung Morb 1950–72 931 60 1.34 1.02–1.72 17 Spinelli 2006 Aluminum reduction Canada PAH (B[α]P) Cohort study Lung Mort 1954–97 6423 120 1.07 0.89–1.28 18 Carta 2004 Aluminum smelter Italy PAH (B[α]P) Cohort study Lung Mort 1972–80 1152 11 0.7 0.39–1.26 19 Bye 1998 Coke plant Norway PAH (B[α]P) Cohort study Lung Morb 1962–93 888 7 0.82 0.33–1.70 20 Loon 1997 Mixed occupation Netherlands PAH (B[α]P) Cohort study Lung Morb 1979–90 58279 12 0.28 0.09–0.89 21 Karlehagen 1992 Creosote- exposed Sweden and Norway PAH (B[α]P) Cohort study Lung Morb 1950–75 922 13 0.79 0.42–1.35 22 Armstrong 2009 Aluminium smelter Canada PAH (B[α]P) Cohort study Lung Mort 1950–99 15703 677 1.32 1.22–1.42 23 Wu a2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 46 2.40 1.85–3.07 24 Wu b2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 20 1.35 1.10–1.64 a, b, a2, b2 are cohort estimates from same study by same author; a1, b1, c1 are same author study in the separate paper in same year. View Large Table 2. Details of studies included in the analysis Sl. no Author Year Industry/ exposure Country Exposure Types of study Cancer Outcome Period of follow-up No. of subjects Deaths/ cases SMR/ SIR 95% CI 1 Gibson 1977 Steel foundry Canada PAH (B[α]P) Cohort study Lung Mort 1967–76 439 21 2.5 1.59–3.76 2 Hensen 1989 Asphalt or bitumen Denmark PAH (B[α]P) Cohort study Lung Mort 1959–84 679 27 3.44 2.27–5.01 3 Gustavsson 1990 Coal gasification Sweden PAH (B[α]P) Cohort study Lung Mort 1966–86 295 4 0.82 0.22–2.11 4 Armstrong 1994 Aluminium smelter Canada PAH (B[α]P) Case–cohort Study Lung Mort 1950–88 16297 338 2.25 1.5–3.38 5 Gustavsson 1995 Graphite electrode Sweden PAH (B[α]P) Cohort study Lung Mort 1968–88 901 2 1.68 0.2–6.07 6 Liu 1997 Carbon manufacturing China PAH (B[α]P) Retrospective cohort Lung Mort 1970–85 6635 50 2.16 1.62–2.83 7 Ronneberg a 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 2888 42 0.96 0.69–1.29 8 Ronneberg b 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 373 10 2.11 1.01–3.87 9 Moulin 2000 Steel alloys France PAH (B[α]P) Cohort study Lung Mort 1968–92 4288 54 1.19 0.89–1.55 10 Romundstad a1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1962–95 5627 46 0.93 0.68–1.24 11 Menvielle 2010 Heavy metal, asbestos 10 European countries PAH (B[α]P) Cohort study Lung Morb 2002–06 88265 703 1.02 0.68–1.53 12 Romudstad b1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1953–95 1790 27 0.9 0.6–1.3 13 Romudstad c1 2000 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–96 11103 189 1.01 0.9–1.2 14 Miller 2013 Coke oven Britain PAH (B[α]P) Cohort study Lung Mort 1966–87 6362 42 1.51 1.06–2.15 15 Verma 1992 Nickel copper Smelters/ refinery Canada PAH (B[α]P) Cohort study Lung Mort 1950–84 54000 50 1.37 1.02–1.81 16 Koskela 2007 Iron foundry Finland PAH (B[α]P) Cohort study Lung Morb 1950–72 931 60 1.34 1.02–1.72 17 Spinelli 2006 Aluminum reduction Canada PAH (B[α]P) Cohort study Lung Mort 1954–97 6423 120 1.07 0.89–1.28 18 Carta 2004 Aluminum smelter Italy PAH (B[α]P) Cohort study Lung Mort 1972–80 1152 11 0.7 0.39–1.26 19 Bye 1998 Coke plant Norway PAH (B[α]P) Cohort study Lung Morb 1962–93 888 7 0.82 0.33–1.70 20 Loon 1997 Mixed occupation Netherlands PAH (B[α]P) Cohort study Lung Morb 1979–90 58279 12 0.28 0.09–0.89 21 Karlehagen 1992 Creosote- exposed Sweden and Norway PAH (B[α]P) Cohort study Lung Morb 1950–75 922 13 0.79 0.42–1.35 22 Armstrong 2009 Aluminium smelter Canada PAH (B[α]P) Cohort study Lung Mort 1950–99 15703 677 1.32 1.22–1.42 23 Wu a2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 46 2.40 1.85–3.07 24 Wu b2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 20 1.35 1.10–1.64 Sl. no Author Year Industry/ exposure Country Exposure Types of study Cancer Outcome Period of follow-up No. of subjects Deaths/ cases SMR/ SIR 95% CI 1 Gibson 1977 Steel foundry Canada PAH (B[α]P) Cohort study Lung Mort 1967–76 439 21 2.5 1.59–3.76 2 Hensen 1989 Asphalt or bitumen Denmark PAH (B[α]P) Cohort study Lung Mort 1959–84 679 27 3.44 2.27–5.01 3 Gustavsson 1990 Coal gasification Sweden PAH (B[α]P) Cohort study Lung Mort 1966–86 295 4 0.82 0.22–2.11 4 Armstrong 1994 Aluminium smelter Canada PAH (B[α]P) Case–cohort Study Lung Mort 1950–88 16297 338 2.25 1.5–3.38 5 Gustavsson 1995 Graphite electrode Sweden PAH (B[α]P) Cohort study Lung Mort 1968–88 901 2 1.68 0.2–6.07 6 Liu 1997 Carbon manufacturing China PAH (B[α]P) Retrospective cohort Lung Mort 1970–85 6635 50 2.16 1.62–2.83 7 Ronneberg a 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 2888 42 0.96 0.69–1.29 8 Ronneberg b 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 373 10 2.11 1.01–3.87 9 Moulin 2000 Steel alloys France PAH (B[α]P) Cohort study Lung Mort 1968–92 4288 54 1.19 0.89–1.55 10 Romundstad a1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1962–95 5627 46 0.93 0.68–1.24 11 Menvielle 2010 Heavy metal, asbestos 10 European countries PAH (B[α]P) Cohort study Lung Morb 2002–06 88265 703 1.02 0.68–1.53 12 Romudstad b1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1953–95 1790 27 0.9 0.6–1.3 13 Romudstad c1 2000 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–96 11103 189 1.01 0.9–1.2 14 Miller 2013 Coke oven Britain PAH (B[α]P) Cohort study Lung Mort 1966–87 6362 42 1.51 1.06–2.15 15 Verma 1992 Nickel copper Smelters/ refinery Canada PAH (B[α]P) Cohort study Lung Mort 1950–84 54000 50 1.37 1.02–1.81 16 Koskela 2007 Iron foundry Finland PAH (B[α]P) Cohort study Lung Morb 1950–72 931 60 1.34 1.02–1.72 17 Spinelli 2006 Aluminum reduction Canada PAH (B[α]P) Cohort study Lung Mort 1954–97 6423 120 1.07 0.89–1.28 18 Carta 2004 Aluminum smelter Italy PAH (B[α]P) Cohort study Lung Mort 1972–80 1152 11 0.7 0.39–1.26 19 Bye 1998 Coke plant Norway PAH (B[α]P) Cohort study Lung Morb 1962–93 888 7 0.82 0.33–1.70 20 Loon 1997 Mixed occupation Netherlands PAH (B[α]P) Cohort study Lung Morb 1979–90 58279 12 0.28 0.09–0.89 21 Karlehagen 1992 Creosote- exposed Sweden and Norway PAH (B[α]P) Cohort study Lung Morb 1950–75 922 13 0.79 0.42–1.35 22 Armstrong 2009 Aluminium smelter Canada PAH (B[α]P) Cohort study Lung Mort 1950–99 15703 677 1.32 1.22–1.42 23 Wu a2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 46 2.40 1.85–3.07 24 Wu b2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 20 1.35 1.10–1.64 a, b, a2, b2 are cohort estimates from same study by same author; a1, b1, c1 are same author study in the separate paper in same year. View Large Figure 1. View largeDownload slide Forest plot analysis of risk of lung cancer stratified by types of occupation. Figure 1. View largeDownload slide Forest plot analysis of risk of lung cancer stratified by types of occupation. 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. Key points Among workers exposed to polycyclic aromatic hydrocarbons, those in the coal/coke industry and the iron/steel industry showed the highest risk of lung cancer. The limitations of the data analysis include lack of adjusting for the confounding effects of smoking, and lack of data on exposure levels of polycyclic aromatic hydrocarbons. Periodic monitoring of polycyclic aromatic hydrocarbons, biomonitoring of polycyclic aromatic hydrocarbons among workers, use of efficient ventilation strategies and use of personal protective equipment may reduce polycyclic aromatic hydrocarbon exposure in the workplace. 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 1. Fitzmaurice C , Dicker D , Pain A et al. The global burden of cancer 2013 . J Am Med Assoc Oncol 2015 ; 1 : 505 – 527 . 2. Bosetti C , Boffetta P , La Vecchia C . Occupational exposures to polycyclic aromatic hydrocarbons, and respiratory and urinary tract cancers: a quantitative review to 2005 . Ann Oncol 2007 ; 18 : 431 – 446 . Google Scholar CrossRef Search ADS PubMed 3. IARC . Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures . IARC Monogr Eval Carcinog Risks Hum 2010 ; 92 : 1 – 853 . PubMed 4. IARC . A review of human carcinogens: chemical agents and related occupations . Monogr Eval Carcinog Risks Hum 2012;100F:1–559 . 5. Binková B , Srám RJ . The genotoxic effect of carcinogenic PAHs, their artificial and environmental mixtures (EOM) on human diploid lung fibroblasts . Mutat Res 2004 ; 547 : 109 – 121 . Google Scholar CrossRef Search ADS PubMed 6. Rengarajan T , Rajendran P , Nandakumar N , Lokeshkumar B , Rajendran P , Nishigaki I . Exposure to polycyclic aromatic hydrocarbons with special focus on cancer . Asian Pac J Trop Biomed 2015 ; 5 : 182 – 189 . Google Scholar CrossRef Search ADS 7. WHO . Selected Pollutants: WHO Guidelines for Indoor Air Quality . Copenhagen, Denmark : World Health Organization . 2010 : 1 – 144 . 8. Srogi K . Monitoring of environmental exposure to polycyclic aromatic hydrocarbons: a review . Environ Chem Lett 2007 ; 5 : 169 – 195 . Google Scholar CrossRef Search ADS PubMed 9. Menzie CA , Potocki BB , Santodonato J . Exposure to carcinogenic PAHs in the environment . Environ Sci Technol 1992 ; 26 : 1278 – 1284 . Google Scholar CrossRef Search ADS 10. Shimada T , Fujii-Kuriyama Y . Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1 . Cancer Sci 2004 ; 95 : 1 – 6 . Google Scholar CrossRef Search ADS PubMed 11. Pratt MM , John K , MacLean AB , Afework S , Phillips DH , Poirier MC . Polycyclic aromatic hydrocarbon (PAH) exposure and DNA adduct semi-quantitation in archived human tissues . Int J Environ Res Public Health 2011 ; 8 : 2675 – 2691 . Google Scholar CrossRef Search ADS PubMed 12. Shimada T , Inoue K , Suzuki Y et al. Arylhydrocarbon receptor-dependent induction of liver and lung cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in genetically engineered C57BL/6J mice . Carcinogenesis 2002 ; 23 : 1199 – 1207 . Google Scholar CrossRef Search ADS PubMed 13. Wagner M , Bolm-Audorff U , Hegewald J et al. Occupational polycyclic aromatic hydrocarbon exposure and risk of larynx cancer: a systematic review and meta-analysis . Occup Environ Med 2015 ; 72 : 226 – 233 . Google Scholar CrossRef Search ADS PubMed 14. Moher D , Shamseer L , Clarke M et al. ; PRISMA-P Group . Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement . Syst Rev 2015 ; 4 : 1 . Google Scholar CrossRef Search ADS PubMed 15. Rota M , Bosetti C , Boccia S , Boffetta P , La Vecchia C . Occupational exposures to polycyclic aromatic hydrocarbons and respiratory and urinary tract cancers: an updated systematic review and a meta-analysis to 2014 . Arch Toxicol 2014 ; 88 : 1479 – 1490 . Google Scholar CrossRef Search ADS PubMed 16. Armstrong B , Hutchinson E , Unwin J , Fletcher T . Lung cancer risk after exposure to polycyclic aromatic hydrocarbons: a review and meta-analysis . Environ Health Perspect 2004 ; 112 : 970 – 978 . Google Scholar CrossRef Search ADS PubMed 17. Boffetta P , Jourenkova N , Gustavsson P . Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons . Cancer Causes Control 1997 ; 8 : 444 – 472 . Google Scholar CrossRef Search ADS PubMed 18. Berger J , Manz A . Cancer of the stomach and the colon-rectum among workers in a coke gas plant . Am J Ind Med 1992 ; 22 : 825 – 834 . Google Scholar CrossRef Search ADS PubMed 19. Miller BG , Doust E , Cherrie JW , Hurley JF . Lung cancer mortality and exposure to polycyclic aromatic hydrocarbons in British coke oven workers . BMC Public Health 2013 ; 13 : 962 . Google Scholar CrossRef Search ADS PubMed 20. IARC . Polynuclear aromatic compounds. Part 3, industrial exposures in aluminium production, coal gasification, coke production and iron and steel founding . IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans , Lyon, France , 1984 . 21. Gibson ES , Martin RH , Lockington JN, Eng JNP . Lung cancer mortality in a steel foundry . J Occup Med 1977 ; 1 2: 807 – 812 . Google Scholar CrossRef Search ADS © The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Occupational Medicine Oxford University Press

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

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© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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1471-8405
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Abstract

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. Cohort studies, lung cancer risk, meta-analysis, polycyclic aromatic hydrocarbons, workers 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. Table 1. PAHs: molecular weight, molecular formulas and structure Sl. no. Compound Molecular weight Molecular formula Structure 1 Naphthalene 128.17 C13H10 2 Acenaphthylene 152.19 C12H18 3 Acenaphthene 154.21 C12 H10 4 Fluorene 166.26 C13H10 5 Phenanthrene 178.23 C14H10 6 Anthracene 178.23 C14H10 7 Pyrene 202.25 C16H10 8 Fluoranthene 202.26 C16H10 9 Chrysene 228.28 C18H12 10 Benzanthracene 228.29 C18H12 11 Benzo[b]fluoranthene 252.30 C20H12 12 Benzo[k] fluoranthene 252.30 C20H12 13 Benzopyrene 252.31 C20H12 14 Benzo[g,h,i] perylene 276.338 C22H12 15 Indeno[1,2,3-cd] pyrene 276.330 C22H12 16 Dibenzo(a,h) anthracene 278.34 C22H14 Sl. no. Compound Molecular weight Molecular formula Structure 1 Naphthalene 128.17 C13H10 2 Acenaphthylene 152.19 C12H18 3 Acenaphthene 154.21 C12 H10 4 Fluorene 166.26 C13H10 5 Phenanthrene 178.23 C14H10 6 Anthracene 178.23 C14H10 7 Pyrene 202.25 C16H10 8 Fluoranthene 202.26 C16H10 9 Chrysene 228.28 C18H12 10 Benzanthracene 228.29 C18H12 11 Benzo[b]fluoranthene 252.30 C20H12 12 Benzo[k] fluoranthene 252.30 C20H12 13 Benzopyrene 252.31 C20H12 14 Benzo[g,h,i] perylene 276.338 C22H12 15 Indeno[1,2,3-cd] pyrene 276.330 C22H12 16 Dibenzo(a,h) anthracene 278.34 C22H14 View Large Table 1. PAHs: molecular weight, molecular formulas and structure Sl. no. Compound Molecular weight Molecular formula Structure 1 Naphthalene 128.17 C13H10 2 Acenaphthylene 152.19 C12H18 3 Acenaphthene 154.21 C12 H10 4 Fluorene 166.26 C13H10 5 Phenanthrene 178.23 C14H10 6 Anthracene 178.23 C14H10 7 Pyrene 202.25 C16H10 8 Fluoranthene 202.26 C16H10 9 Chrysene 228.28 C18H12 10 Benzanthracene 228.29 C18H12 11 Benzo[b]fluoranthene 252.30 C20H12 12 Benzo[k] fluoranthene 252.30 C20H12 13 Benzopyrene 252.31 C20H12 14 Benzo[g,h,i] perylene 276.338 C22H12 15 Indeno[1,2,3-cd] pyrene 276.330 C22H12 16 Dibenzo(a,h) anthracene 278.34 C22H14 Sl. no. Compound Molecular weight Molecular formula Structure 1 Naphthalene 128.17 C13H10 2 Acenaphthylene 152.19 C12H18 3 Acenaphthene 154.21 C12 H10 4 Fluorene 166.26 C13H10 5 Phenanthrene 178.23 C14H10 6 Anthracene 178.23 C14H10 7 Pyrene 202.25 C16H10 8 Fluoranthene 202.26 C16H10 9 Chrysene 228.28 C18H12 10 Benzanthracene 228.29 C18H12 11 Benzo[b]fluoranthene 252.30 C20H12 12 Benzo[k] fluoranthene 252.30 C20H12 13 Benzopyrene 252.31 C20H12 14 Benzo[g,h,i] perylene 276.338 C22H12 15 Indeno[1,2,3-cd] pyrene 276.330 C22H12 16 Dibenzo(a,h) anthracene 278.34 C22H14 View Large 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). Table 2. Details of studies included in the analysis Sl. no Author Year Industry/ exposure Country Exposure Types of study Cancer Outcome Period of follow-up No. of subjects Deaths/ cases SMR/ SIR 95% CI 1 Gibson 1977 Steel foundry Canada PAH (B[α]P) Cohort study Lung Mort 1967–76 439 21 2.5 1.59–3.76 2 Hensen 1989 Asphalt or bitumen Denmark PAH (B[α]P) Cohort study Lung Mort 1959–84 679 27 3.44 2.27–5.01 3 Gustavsson 1990 Coal gasification Sweden PAH (B[α]P) Cohort study Lung Mort 1966–86 295 4 0.82 0.22–2.11 4 Armstrong 1994 Aluminium smelter Canada PAH (B[α]P) Case–cohort Study Lung Mort 1950–88 16297 338 2.25 1.5–3.38 5 Gustavsson 1995 Graphite electrode Sweden PAH (B[α]P) Cohort study Lung Mort 1968–88 901 2 1.68 0.2–6.07 6 Liu 1997 Carbon manufacturing China PAH (B[α]P) Retrospective cohort Lung Mort 1970–85 6635 50 2.16 1.62–2.83 7 Ronneberg a 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 2888 42 0.96 0.69–1.29 8 Ronneberg b 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 373 10 2.11 1.01–3.87 9 Moulin 2000 Steel alloys France PAH (B[α]P) Cohort study Lung Mort 1968–92 4288 54 1.19 0.89–1.55 10 Romundstad a1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1962–95 5627 46 0.93 0.68–1.24 11 Menvielle 2010 Heavy metal, asbestos 10 European countries PAH (B[α]P) Cohort study Lung Morb 2002–06 88265 703 1.02 0.68–1.53 12 Romudstad b1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1953–95 1790 27 0.9 0.6–1.3 13 Romudstad c1 2000 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–96 11103 189 1.01 0.9–1.2 14 Miller 2013 Coke oven Britain PAH (B[α]P) Cohort study Lung Mort 1966–87 6362 42 1.51 1.06–2.15 15 Verma 1992 Nickel copper Smelters/ refinery Canada PAH (B[α]P) Cohort study Lung Mort 1950–84 54000 50 1.37 1.02–1.81 16 Koskela 2007 Iron foundry Finland PAH (B[α]P) Cohort study Lung Morb 1950–72 931 60 1.34 1.02–1.72 17 Spinelli 2006 Aluminum reduction Canada PAH (B[α]P) Cohort study Lung Mort 1954–97 6423 120 1.07 0.89–1.28 18 Carta 2004 Aluminum smelter Italy PAH (B[α]P) Cohort study Lung Mort 1972–80 1152 11 0.7 0.39–1.26 19 Bye 1998 Coke plant Norway PAH (B[α]P) Cohort study Lung Morb 1962–93 888 7 0.82 0.33–1.70 20 Loon 1997 Mixed occupation Netherlands PAH (B[α]P) Cohort study Lung Morb 1979–90 58279 12 0.28 0.09–0.89 21 Karlehagen 1992 Creosote- exposed Sweden and Norway PAH (B[α]P) Cohort study Lung Morb 1950–75 922 13 0.79 0.42–1.35 22 Armstrong 2009 Aluminium smelter Canada PAH (B[α]P) Cohort study Lung Mort 1950–99 15703 677 1.32 1.22–1.42 23 Wu a2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 46 2.40 1.85–3.07 24 Wu b2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 20 1.35 1.10–1.64 Sl. no Author Year Industry/ exposure Country Exposure Types of study Cancer Outcome Period of follow-up No. of subjects Deaths/ cases SMR/ SIR 95% CI 1 Gibson 1977 Steel foundry Canada PAH (B[α]P) Cohort study Lung Mort 1967–76 439 21 2.5 1.59–3.76 2 Hensen 1989 Asphalt or bitumen Denmark PAH (B[α]P) Cohort study Lung Mort 1959–84 679 27 3.44 2.27–5.01 3 Gustavsson 1990 Coal gasification Sweden PAH (B[α]P) Cohort study Lung Mort 1966–86 295 4 0.82 0.22–2.11 4 Armstrong 1994 Aluminium smelter Canada PAH (B[α]P) Case–cohort Study Lung Mort 1950–88 16297 338 2.25 1.5–3.38 5 Gustavsson 1995 Graphite electrode Sweden PAH (B[α]P) Cohort study Lung Mort 1968–88 901 2 1.68 0.2–6.07 6 Liu 1997 Carbon manufacturing China PAH (B[α]P) Retrospective cohort Lung Mort 1970–85 6635 50 2.16 1.62–2.83 7 Ronneberg a 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 2888 42 0.96 0.69–1.29 8 Ronneberg b 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 373 10 2.11 1.01–3.87 9 Moulin 2000 Steel alloys France PAH (B[α]P) Cohort study Lung Mort 1968–92 4288 54 1.19 0.89–1.55 10 Romundstad a1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1962–95 5627 46 0.93 0.68–1.24 11 Menvielle 2010 Heavy metal, asbestos 10 European countries PAH (B[α]P) Cohort study Lung Morb 2002–06 88265 703 1.02 0.68–1.53 12 Romudstad b1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1953–95 1790 27 0.9 0.6–1.3 13 Romudstad c1 2000 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–96 11103 189 1.01 0.9–1.2 14 Miller 2013 Coke oven Britain PAH (B[α]P) Cohort study Lung Mort 1966–87 6362 42 1.51 1.06–2.15 15 Verma 1992 Nickel copper Smelters/ refinery Canada PAH (B[α]P) Cohort study Lung Mort 1950–84 54000 50 1.37 1.02–1.81 16 Koskela 2007 Iron foundry Finland PAH (B[α]P) Cohort study Lung Morb 1950–72 931 60 1.34 1.02–1.72 17 Spinelli 2006 Aluminum reduction Canada PAH (B[α]P) Cohort study Lung Mort 1954–97 6423 120 1.07 0.89–1.28 18 Carta 2004 Aluminum smelter Italy PAH (B[α]P) Cohort study Lung Mort 1972–80 1152 11 0.7 0.39–1.26 19 Bye 1998 Coke plant Norway PAH (B[α]P) Cohort study Lung Morb 1962–93 888 7 0.82 0.33–1.70 20 Loon 1997 Mixed occupation Netherlands PAH (B[α]P) Cohort study Lung Morb 1979–90 58279 12 0.28 0.09–0.89 21 Karlehagen 1992 Creosote- exposed Sweden and Norway PAH (B[α]P) Cohort study Lung Morb 1950–75 922 13 0.79 0.42–1.35 22 Armstrong 2009 Aluminium smelter Canada PAH (B[α]P) Cohort study Lung Mort 1950–99 15703 677 1.32 1.22–1.42 23 Wu a2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 46 2.40 1.85–3.07 24 Wu b2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 20 1.35 1.10–1.64 a, b, a2, b2 are cohort estimates from same study by same author; a1, b1, c1 are same author study in the separate paper in same year. View Large Table 2. Details of studies included in the analysis Sl. no Author Year Industry/ exposure Country Exposure Types of study Cancer Outcome Period of follow-up No. of subjects Deaths/ cases SMR/ SIR 95% CI 1 Gibson 1977 Steel foundry Canada PAH (B[α]P) Cohort study Lung Mort 1967–76 439 21 2.5 1.59–3.76 2 Hensen 1989 Asphalt or bitumen Denmark PAH (B[α]P) Cohort study Lung Mort 1959–84 679 27 3.44 2.27–5.01 3 Gustavsson 1990 Coal gasification Sweden PAH (B[α]P) Cohort study Lung Mort 1966–86 295 4 0.82 0.22–2.11 4 Armstrong 1994 Aluminium smelter Canada PAH (B[α]P) Case–cohort Study Lung Mort 1950–88 16297 338 2.25 1.5–3.38 5 Gustavsson 1995 Graphite electrode Sweden PAH (B[α]P) Cohort study Lung Mort 1968–88 901 2 1.68 0.2–6.07 6 Liu 1997 Carbon manufacturing China PAH (B[α]P) Retrospective cohort Lung Mort 1970–85 6635 50 2.16 1.62–2.83 7 Ronneberg a 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 2888 42 0.96 0.69–1.29 8 Ronneberg b 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 373 10 2.11 1.01–3.87 9 Moulin 2000 Steel alloys France PAH (B[α]P) Cohort study Lung Mort 1968–92 4288 54 1.19 0.89–1.55 10 Romundstad a1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1962–95 5627 46 0.93 0.68–1.24 11 Menvielle 2010 Heavy metal, asbestos 10 European countries PAH (B[α]P) Cohort study Lung Morb 2002–06 88265 703 1.02 0.68–1.53 12 Romudstad b1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1953–95 1790 27 0.9 0.6–1.3 13 Romudstad c1 2000 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–96 11103 189 1.01 0.9–1.2 14 Miller 2013 Coke oven Britain PAH (B[α]P) Cohort study Lung Mort 1966–87 6362 42 1.51 1.06–2.15 15 Verma 1992 Nickel copper Smelters/ refinery Canada PAH (B[α]P) Cohort study Lung Mort 1950–84 54000 50 1.37 1.02–1.81 16 Koskela 2007 Iron foundry Finland PAH (B[α]P) Cohort study Lung Morb 1950–72 931 60 1.34 1.02–1.72 17 Spinelli 2006 Aluminum reduction Canada PAH (B[α]P) Cohort study Lung Mort 1954–97 6423 120 1.07 0.89–1.28 18 Carta 2004 Aluminum smelter Italy PAH (B[α]P) Cohort study Lung Mort 1972–80 1152 11 0.7 0.39–1.26 19 Bye 1998 Coke plant Norway PAH (B[α]P) Cohort study Lung Morb 1962–93 888 7 0.82 0.33–1.70 20 Loon 1997 Mixed occupation Netherlands PAH (B[α]P) Cohort study Lung Morb 1979–90 58279 12 0.28 0.09–0.89 21 Karlehagen 1992 Creosote- exposed Sweden and Norway PAH (B[α]P) Cohort study Lung Morb 1950–75 922 13 0.79 0.42–1.35 22 Armstrong 2009 Aluminium smelter Canada PAH (B[α]P) Cohort study Lung Mort 1950–99 15703 677 1.32 1.22–1.42 23 Wu a2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 46 2.40 1.85–3.07 24 Wu b2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 20 1.35 1.10–1.64 Sl. no Author Year Industry/ exposure Country Exposure Types of study Cancer Outcome Period of follow-up No. of subjects Deaths/ cases SMR/ SIR 95% CI 1 Gibson 1977 Steel foundry Canada PAH (B[α]P) Cohort study Lung Mort 1967–76 439 21 2.5 1.59–3.76 2 Hensen 1989 Asphalt or bitumen Denmark PAH (B[α]P) Cohort study Lung Mort 1959–84 679 27 3.44 2.27–5.01 3 Gustavsson 1990 Coal gasification Sweden PAH (B[α]P) Cohort study Lung Mort 1966–86 295 4 0.82 0.22–2.11 4 Armstrong 1994 Aluminium smelter Canada PAH (B[α]P) Case–cohort Study Lung Mort 1950–88 16297 338 2.25 1.5–3.38 5 Gustavsson 1995 Graphite electrode Sweden PAH (B[α]P) Cohort study Lung Mort 1968–88 901 2 1.68 0.2–6.07 6 Liu 1997 Carbon manufacturing China PAH (B[α]P) Retrospective cohort Lung Mort 1970–85 6635 50 2.16 1.62–2.83 7 Ronneberg a 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 2888 42 0.96 0.69–1.29 8 Ronneberg b 1999 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–93 373 10 2.11 1.01–3.87 9 Moulin 2000 Steel alloys France PAH (B[α]P) Cohort study Lung Mort 1968–92 4288 54 1.19 0.89–1.55 10 Romundstad a1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1962–95 5627 46 0.93 0.68–1.24 11 Menvielle 2010 Heavy metal, asbestos 10 European countries PAH (B[α]P) Cohort study Lung Morb 2002–06 88265 703 1.02 0.68–1.53 12 Romudstad b1 2000 Aluminium reduction Norway PAH (B[α]P) Cohort study Lung Morb 1953–95 1790 27 0.9 0.6–1.3 13 Romudstad c1 2000 Aluminium smelter Norway PAH (B[α]P) Cohort study Lung Morb 1953–96 11103 189 1.01 0.9–1.2 14 Miller 2013 Coke oven Britain PAH (B[α]P) Cohort study Lung Mort 1966–87 6362 42 1.51 1.06–2.15 15 Verma 1992 Nickel copper Smelters/ refinery Canada PAH (B[α]P) Cohort study Lung Mort 1950–84 54000 50 1.37 1.02–1.81 16 Koskela 2007 Iron foundry Finland PAH (B[α]P) Cohort study Lung Morb 1950–72 931 60 1.34 1.02–1.72 17 Spinelli 2006 Aluminum reduction Canada PAH (B[α]P) Cohort study Lung Mort 1954–97 6423 120 1.07 0.89–1.28 18 Carta 2004 Aluminum smelter Italy PAH (B[α]P) Cohort study Lung Mort 1972–80 1152 11 0.7 0.39–1.26 19 Bye 1998 Coke plant Norway PAH (B[α]P) Cohort study Lung Morb 1962–93 888 7 0.82 0.33–1.70 20 Loon 1997 Mixed occupation Netherlands PAH (B[α]P) Cohort study Lung Morb 1979–90 58279 12 0.28 0.09–0.89 21 Karlehagen 1992 Creosote- exposed Sweden and Norway PAH (B[α]P) Cohort study Lung Morb 1950–75 922 13 0.79 0.42–1.35 22 Armstrong 2009 Aluminium smelter Canada PAH (B[α]P) Cohort study Lung Mort 1950–99 15703 677 1.32 1.22–1.42 23 Wu a2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 46 2.40 1.85–3.07 24 Wu b2 1998 Oil refining plant China PAH (B[α]P) Retrospective cohort study Lung Mort 6285 20 1.35 1.10–1.64 a, b, a2, b2 are cohort estimates from same study by same author; a1, b1, c1 are same author study in the separate paper in same year. View Large Figure 1. View largeDownload slide Forest plot analysis of risk of lung cancer stratified by types of occupation. Figure 1. View largeDownload slide Forest plot analysis of risk of lung cancer stratified by types of occupation. 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. Key points Among workers exposed to polycyclic aromatic hydrocarbons, those in the coal/coke industry and the iron/steel industry showed the highest risk of lung cancer. The limitations of the data analysis include lack of adjusting for the confounding effects of smoking, and lack of data on exposure levels of polycyclic aromatic hydrocarbons. Periodic monitoring of polycyclic aromatic hydrocarbons, biomonitoring of polycyclic aromatic hydrocarbons among workers, use of efficient ventilation strategies and use of personal protective equipment may reduce polycyclic aromatic hydrocarbon exposure in the workplace. 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 1. Fitzmaurice C , Dicker D , Pain A et al. The global burden of cancer 2013 . J Am Med Assoc Oncol 2015 ; 1 : 505 – 527 . 2. Bosetti C , Boffetta P , La Vecchia C . Occupational exposures to polycyclic aromatic hydrocarbons, and respiratory and urinary tract cancers: a quantitative review to 2005 . Ann Oncol 2007 ; 18 : 431 – 446 . Google Scholar CrossRef Search ADS PubMed 3. IARC . Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures . 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Menzie CA , Potocki BB , Santodonato J . Exposure to carcinogenic PAHs in the environment . Environ Sci Technol 1992 ; 26 : 1278 – 1284 . Google Scholar CrossRef Search ADS 10. Shimada T , Fujii-Kuriyama Y . Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1 . Cancer Sci 2004 ; 95 : 1 – 6 . Google Scholar CrossRef Search ADS PubMed 11. Pratt MM , John K , MacLean AB , Afework S , Phillips DH , Poirier MC . Polycyclic aromatic hydrocarbon (PAH) exposure and DNA adduct semi-quantitation in archived human tissues . Int J Environ Res Public Health 2011 ; 8 : 2675 – 2691 . Google Scholar CrossRef Search ADS PubMed 12. Shimada T , Inoue K , Suzuki Y et al. Arylhydrocarbon receptor-dependent induction of liver and lung cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in genetically engineered C57BL/6J mice . Carcinogenesis 2002 ; 23 : 1199 – 1207 . Google Scholar CrossRef Search ADS PubMed 13. Wagner M , Bolm-Audorff U , Hegewald J et al. Occupational polycyclic aromatic hydrocarbon exposure and risk of larynx cancer: a systematic review and meta-analysis . Occup Environ Med 2015 ; 72 : 226 – 233 . Google Scholar CrossRef Search ADS PubMed 14. Moher D , Shamseer L , Clarke M et al. ; PRISMA-P Group . Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement . Syst Rev 2015 ; 4 : 1 . Google Scholar CrossRef Search ADS PubMed 15. Rota M , Bosetti C , Boccia S , Boffetta P , La Vecchia C . Occupational exposures to polycyclic aromatic hydrocarbons and respiratory and urinary tract cancers: an updated systematic review and a meta-analysis to 2014 . Arch Toxicol 2014 ; 88 : 1479 – 1490 . Google Scholar CrossRef Search ADS PubMed 16. Armstrong B , Hutchinson E , Unwin J , Fletcher T . Lung cancer risk after exposure to polycyclic aromatic hydrocarbons: a review and meta-analysis . Environ Health Perspect 2004 ; 112 : 970 – 978 . Google Scholar CrossRef Search ADS PubMed 17. Boffetta P , Jourenkova N , Gustavsson P . Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons . Cancer Causes Control 1997 ; 8 : 444 – 472 . Google Scholar CrossRef Search ADS PubMed 18. Berger J , Manz A . Cancer of the stomach and the colon-rectum among workers in a coke gas plant . Am J Ind Med 1992 ; 22 : 825 – 834 . Google Scholar CrossRef Search ADS PubMed 19. Miller BG , Doust E , Cherrie JW , Hurley JF . Lung cancer mortality and exposure to polycyclic aromatic hydrocarbons in British coke oven workers . BMC Public Health 2013 ; 13 : 962 . Google Scholar CrossRef Search ADS PubMed 20. IARC . Polynuclear aromatic compounds. Part 3, industrial exposures in aluminium production, coal gasification, coke production and iron and steel founding . IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans , Lyon, France , 1984 . 21. Gibson ES , Martin RH , Lockington JN, Eng JNP . Lung cancer mortality in a steel foundry . J Occup Med 1977 ; 1 2: 807 – 812 . Google Scholar CrossRef Search ADS © The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Occupational MedicineOxford University Press

Published: Mar 20, 2018

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