Asbestos Exposure and Laryngeal Cancer Mortality

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1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Systematic Review Asbestos Exposure and Laryngeal Cancer Mortality Wen-jia Peng, MM; Jing Mi, MM; Yu-hong Jiang, MM Objectives/Hypothesis: Occupational exposure to asbestos occurs in many workplaces and is well known to cause asbestosis, lung cancer, and mesothelioma. However, the link between asbestos exposure and other malignancies was not confirmed. The aim of the current meta-analysis was to provide a summary measure of risk for laryngeal cancer associated with occupational asbestos exposure. Study Design: Systematic review and meta-analysis. Methods: Electronic databases were searched for studies characterizing the association between asbestos and laryngeal cancer. Standardized mortality rate (SMR) with its 95% confidence interval (CI) of each study was combined using a fixed or random effect model. Results: Significantly increased SMR for laryngeal cancer was observed when subjects were exposed to asbestos (SMR , 95% CI , P <.001), with little evidence of heterogeneity among studies (Q , P 5.803, I %). Effect estimates were larger for cohorts controlling for male subjects, Europe and Oceania, mining and textile industries, exposure to crocidolite, long study follow-up (>25 years), and SMR for lung cancer > 2.0. Publication bias was not detect by Begg test (P 5.910) and Egger test (P 5.340). Conclusions: Our study supports the association of exposure to asbestos with an increased risk of laryngeal cancer mortality among male workers. Key Words: Asbestos, larynx, cancer, mortality. Level of Evidence: NA Laryngoscope, 126: , 2016 From the Department of Epidemiology and Health Statistics, Bengbu Medical College, Bengbu, Anhui, China. Editor s Note: This Manuscript was accepted for publication August 31, This work was supported by the Natural Science Fund of the Education Department of Anhui Province (KJ2013Z212) and National Science Fund of Bengbu Medical College (BYKJ1448). The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jing Mi, MM, Department of Epidemiology and Health Statistics, Bengbu Medical College, 2600# Donghai Avenue, Bengbu, Anhui, , PR China. xiaomi05011@sina.com DOI: /lary INTRODUCTION Laryngeal cancer is the main neoplasm of the upper respiratory and digestive tract, with approximately 150,000 new cases in 2008 worldwide. However, incidence rates have marked differences internationally, with higher incidence rates in Central and Eastern European countries. 1 In China, it is estimated that 20,875 new cases and 11,488 deaths occurred in 2011, with a 1.55/100,000 incidence rate. Laryngeal cancer is more frequently observed in males, with a ratio of 8:1. 2 It is widely accepted that smoking and alcohol use are the most important risk factors. Occupational exposure factors also play a critical role, including polycyclic aromatic hydrocarbons, 3 solvents, 3 and silica. 4 Asbestos is an important nonmetallic mineral raw material. The most common types of asbestos are chrysolite (white) asbestos, amosite (brown), and crocidolite (blue) asbestos. Due to the properties of high intensity, flexibility, heat resistance, electrical nonconductivity, and spinnability, asbestos is widely used in various industries, such as the building, vehicle, and textile industries. There are many asbestos mines in China. Most of them are chrysotile mines, and they are distributed throughout variance provinces, such as Sichuan, Liaoning, Qinghai, Jilin, and Hebei provinces. 5 The relationship between asbestos exposure and malignant tumors has been studied since the 1970s, but the existence of a causal relation remains controversial. Recent meta-analysis quantitatively assessed the relative risk. Camargo et al. 6 yielded a total of 18 cohort studies and found an increased risk of ovarian cancer in those exposed to asbestos. Two recent meta-analyses published by Fortunato and Rushton 7 and Peng et al. 8 both suggested elevated risk of stomach cancer mortality. Numerous occupational epidemiological studies have investigated an association between asbestos and the risk of laryngeal cancer. Purdue et al. 9 analyzed 307,799 male workers in the Swedish construction industry, and found that asbestos exposure was associated with increased laryngeal cancer incidence (relative risk 5 1.9, 95% confidence interval [CI] ). However, some cohorts failed to detect this association. Considering the lower statistical power from a single study, we attempted to summarize evidence from published cohort 1169

2 studies regarding the association between asbestos and laryngeal cancer by using a meta-analysis approach. MATERIALS AND METHODS Study Selection The electronic databases of PubMed, Springer, and Cochrane library were systematically searched for studies of workers exposed to asbestos published in English or Chinese from December 31, 1980 to December 31, The following search terms were used: asbestos, cancer of larynx, laryngeal cancer, mortality, incidence. The references of relevant publications were also reviewed manually to identify additional studies. If the same cohort was published several times, only the newest or most informative single article was included. If one study contained different cohorts, we treated them independently. The study was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses) statement. 10 Data Extraction Relevant information was extracted from each study, including name of first author, publication year, country of origin, industry type, asbestos type, cohort size, follow-up period, observed and expected cases or deaths, standardized mortality rate (SMR) for lung cancer, and SMR for laryngeal cancer. Two members independently completed the data extraction process. Statistical Analysis SMR with 95% CI was extracted from each study. Pooled estimates were combined based on a fixed-effect (Mantel-Haenszel method) or a random-effect (DerSimonian-Laird method) model according to the heterogeneity test. 11,12 Heterogeneity among studies was assessed using the Cochran Q test and I 2 statistic. A P value <.10 of Q statistics was considered statistically significant for heterogeneity. A value for I 2 ranges from 0% to 100% and a value > 25% were considered significant for heterogeneity. 13 Subgroup analyses were also performed by gender, industry type (mining, textile, and cement), asbestos type (chrysotile, crocidolite, and mixed), geographic region (Europe, TABLE I. Basic Information of Included Studies. First Author; Publication Year Country Industry Type Asbestos Type Cohort Size Follow-up Period Observed/ Expected Deaths or Cases SMR for Lung Cancer SMR for Laryngeal Cancer Wang; 2013 China Textile Chrysotile / Menegozzo; Italy Cement Mixed 1, / Harding; 2009 Great Britain Mixed Mixed 98, / Loomis; 2009 United States Textile Chrysotile 5, / Pira; 2009 Italy Mining Chrysotile 1, / Frost; 2008 Great Britain Stripping/ Mixed 31, / removal work Musk; 2008 Australia Mining and Crocidolite 6, / milling Hein; 2007 United States Textile Chrysotile 3, / Magnani; 2007 Italy Cement Mixed 3, Male: 15/12; female: 1/0.2 Male: 2.43; female: 2.21 Male: 1.25; female: 4.81 Pira; 2005 Italy Textile Mixed 1,966 Up to / Wilczynska; 2005 Poland Plant Mixed 4, / manufacturing Reid; 2004 Australia Mining and milling Crocidolite 535 NA 19/10 NA 1.82 Sun; 2003 China Manual spinning Chrysotile 5, / Berry; 2000 United Kingdom Textile and prefabricated cement pipes Mixed 700 Up to June, / Battista; 1999 Italy Railway carriage construction Mixed / Germani; 1999 Italy Textile Chrysotile / Tsai; 1996 United States Refinery and petrochemical plant Mixed 2, / Dement; 1994 South Carolina Textile Chrysotile 3, / Tarchi; 1994 Italy Mining Chrysotile / Raffn; 1989 Denmark Cement Mixed 8, / Armstrong; 1988 Australia Gas mask assemblers NA 5 not available; SMR 5 standardized mortality rate. Crocidolite 6, /

3 Asia, America, and Oceania), and follow-up period (25 and >25 years). Dose response association between asbestos exposure and laryngeal cancer were analyzed based on the method reported by Fortunato and Rushton. 7 The International Agency for Research on Cancer (IARC) reported a clear dose response relation between asbestos exposure and lung cancer. Studies were separated into two groups according to the SMR for lung cancer (2.0 and >2.0), corresponding to low- and high-exposure groups. The method of leave-one-out was conducted to determine whether our assumptions or decisions had a major effect on the results of the review by omitting each study. Publication bias was analyzed first intuitively by funnel plot and then by Begg and Egger bias indicator test. 14,15 RESULTS Characteristics of Selected Studies Totally, 21 publications that met the inclusion criteria were subjected to this meta-analysis The detailed characteristics of these studies are listed in Table I and combined results in Table II. These studies were published between 1988 and 2013, with the cohort size ranging from 276 to 98,117. Twelve studies were carried out in Europe. Four studies were conducted in the United States, three in Oceania, and two in Asia. The industries involved included the manufacture of mining or milling equipment, textiles, cement, gas masks, and so on. Nine cohorts reported an SMR for lung cancer >2.0. The type of exposed asbestos included crocidolite, chrysotile, and mixed asbestos. We included a total of 185 laryngeal cancer deaths or cases in our main analysis. Quantitative Data Synthesis Twenty-one independent studies were combined, with an SMR of 1.69 (95% CI , P <.001) based on a fixed-effect model. Heterogeneity among studies was absent (Q , P 5.803, I %). The forest plot is shown in Figure 1. Gender stratification. We found a significant association of asbestos exposure with laryngeal cancer mortality in male (SMR , 95% CI , P <.001; Fig. 2) but not in female cohorts (SMR , 95% CI , P ). Industry type stratification. The pooled SMRs were significantly elevated for manufacture of mining or milling equipment (SMR , 95% CI , P <.001) and textiles (SMR , 95% CI , P 5.002) but not cement. Asbestos type stratification. Exposure to chrysotile (SMR , 95% CI , P ), crocidolite (SMR , 95% CI , P <.001), and mixed asbestos (SMR , 95% CI , P <.001) all contributed to significantly increased risk. Geographic region stratification. Europe (SMR , 95% CI , P <.001) and Oceania TABLE II. Combined Results of Laryngeal Cancer Associated With Asbestos Exposure by Study Characteristics. Association Test Heterogeneity Test Characteristics No. of Studies SMR 95% CI P Q I 2,% P All < Gender Male < Female Industry type Mining < Textile Cement Asbestos type Chrysotile Crocidolite < Mixed < Geographic region Europe < Asia America Oceania < Follow-up period, yr > < SMR for lung cancer > < < CI 5 confidence interval; SMR 5 standardized mortality rate. 1171

4 Fig. 1. Forest plot of laryngeal cancer risk associated with the asbestos exposure. CI 5 confidence interval; SMR 5 standardized mortality rate. [Color figure can be viewed in the online issue, which is available at cohorts (SMR , 95% CI , P <.001) exhibited an elevated risk of laryngeal cancer. Follow-up period stratification. The long study follow-up (>25 years) revealed a significantly higher risk of laryngeal cancer (SMR , 95% CI , P <.001). Dose Response Relation High-exposure cohorts reporting an SMR for lung cancer > 2.0 provided a higher SMR (SMR , 95% CI ) compared with lower-exposure cohorts (SMR , 95% CI ). Fig. 2. Forest plot of laryngeal cancer risk associated with the asbestos exposure in male workers. CI 5 confidence interval; SMR 5 standardized mortality rate. [Color figure can be viewed in the online issue, which is available at com.] 1172

5 Fig. 3. Funnel plot for evaluating the publication bias. s.e. 5 standard error. lnsmr 5 Natural logarithm of standardized mortality rate. [Color figure can be viewed in the online issue, which is available at Sensitivity Analysis A sensitivity analysis was performed to evaluate the stability of results based on the leave-one-out method. The corresponding pooled SMRs were not significantly altered (data not shown). Publication Bias As shown in Figure 3, the funnel plot including all publications did not show obvious asymmetry. Begg and Egger tests produced a P-value of.910 and.340, respectively, which suggested the absence of publication bias. DISCUSSION Asbestos exposure was confirmed to be a group 1 carcinogen by the IARC in Strong epidemiological evidence has supported that occupational asbestos exposure could result in an increased risk of lung cancer and mesothelioma. Meta-analysis has been widely used in epidemiology. Its principal value lies in enhancing the precision of the estimate of an association. Several systematic reviews have assessed the relationship between asbestos exposure and laryngeal cancer. A study from Griffiths and Molony in 2003 reviewed 14 case control studies and found a statistically significant association. 38 Goodman et al. performed a meta-analysis in 1999 and yielded a meta-smr of 1.57 (95% CI , P 5.23). 39 Browne and Gee analyzed prospective studies in 2000 and found that no association exists between asbestos exposure and laryngeal cancer. 40 A meta-analysis published by Li et al. of eight studies yielded an SMR of 1.42 (95% CI ), suggesting a nonsignificant association between laryngeal cancer and asbestos exposure. 41 Therefore, the link between asbestos and laryngeal cancer remains uncertain. All of the above reviews were published in the past 2 decades. Our meta-analysis provided an association between asbestos and laryngeal cancer through combining 21 published cohorts. A significantly increased meta-smr (1.69) was observed, that is to say, workers exposed to asbestos have 1.69 times the likelihood of suffering from laryngeal cancer compared with the general population. Although all forms of asbestos are thought to be harmful to humans, different types of asbestos contributed to different health risks. We performed subgroup analysis by asbestos type, and found a significant association in all kinds of asbestos. However, exposure only to crocidolite seemed to contribute to a higher SMR (1.99) than other groups (1.73, 1.60). This was consistent with the point that crocidolite was more harmful than chrysotile and amosite. A significant association of asbestos with laryngeal cancer was only observed in male cohort. That is not surprising, because males have more exposure to risk factors related to laryngeal cancer, such as smoking and alcohol. Evidence suggested a causal association between laryngeal cancer and cigarette smoking. The IARC indicated in the World Cancer Report 2008 that smoking cessation would decrease incidence rates of laryngeal cancer by 90%. The risk of laryngeal cancer associated with asbestos exposure might be higher among smokers. 42 Another way to put this is that the observed female cases of laryngeal cancer in included studies were too small to detect this association due to lower statistical power. As shown in Figure 1, the studies by Harding et al. 18 and Reid et al. 27 had more weight than others. We performed a sensitivity analysis by omitting each study in turn, and found the pooled SMR was not materially reversed. Thus, this meta-analysis provided a fairly stable result. What is the exact mechanism of asbestos exposure leading to laryngeal cancer? The role of asbestos in the etiology of laryngeal cancer has been investigated over the past years, but the results are inconsistent. The larynx lies directly in the path of an inhaled air stream and is the necessary pathway for inhaled asbestos dust. Asbestos fibers can easily become lodged in the laryngeal mucosa. Asbestos could affect the human immune system, and make people sensitive to the development of malignancies. A review by Kumagai-Takei et al. summarized possible mechanisms for asbestos resulting in cancer; the authors proposed that asbestos fibers having iron produce reactive oxygen/nitrogen species that cause DNA damage to nearby cells, and moreover that fibers are directly inserted into the cells and injure chromosomes. 43 However, two major limitations should be noted in the current meta-analysis. First, the pooled SMRs were based on unadjusted estimates, and potential confounding factors, such as alcohol and smoking, could not be adjusted for due to the lack of data from original cohort studies. Second, detailed exposure assessment in the selected studies is often missing, and risk estimates by duration or level of exposure are not quantified. Thus, a further dose response relationship of laryngeal cancer with asbestos could not be performed. Yet we considered lung cancer mortality as a substitute for the exposure measurements. High-exposure cohorts (SMR for lung cancer >2.0) had a higher SMR (2.07) than other cohorts (1.52), which seems to suggest a dose response relation 1173

6 between asbestos exposure level and risk of laryngeal cancer. CONCLUSION In summary, the current meta-analysis clarified the association between asbestos exposure and laryngeal cancer risk, and supported the hypothesis that exposure to asbestos was associated with an increased risk of laryngeal cancer, especially in male workers. The exact mechanisms of asbestos exposure resulting in laryngeal cancer should be further investigated. BIBLIOGRAPHY 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBO- CAN 2008, Cancer Incidence and Mortality Worldwide: IARC Cancer- Base No. 10. Lyon, France: International Agency for Research on Cancer; Du L, Li H, Zhu C, Zheng R, Zhang S, Chen W. Incidence and mortality of laryngeal cancer in China, Chin J Cancer Res 2015;27: Paget-Bailly S, Cyr D, Luce D. Occupational exposures and cancer of the larynx systematic review and meta-analysis. J Occup Environ Med 2012;54: Chen M, Tse LA. 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