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Workplace

ORIGINAL ARTICLE

Exposure to chlorinated solvents and lung cancer: results of the ICARE study Francesca Mattei,1,2 Florence Guida,1,2 Mireille Matrat,3,4 Sylvie Cenée,1,2 Diane Cyr,5,6 Marie Sanchez,1,2 Loredana Radoi,7,8 Gwenn Menvielle,9,10 Fatima Jellouli,7,11 Matthieu Carton,5,6 Simona Bara,12 Emilie Marrer,13 Danièle Luce,14,15 Isabelle Stücker1,2 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ oemed-2014-102182). For numbered affiliations see end of article. Correspondence to Dr Isabelle Stücker, CESP Centre for Research in Epidemiology and Population Health, 16 avenue Paul Vaillant Couturier, Villejuif, Cedex 94807, France; [email protected] Received 21 February 2014 Revised 4 June 2014 Accepted 18 June 2014 Published Online First 11 July 2014

ABSTRACT Objective To investigate the role of occupational exposure to chlorinated solvents in lung cancer aetiology. Methods ICARE (Investigation of occupational and environmental CAuses of REspiratory cancers) is a French, multicentre, population-based, case–control study. Information on the lifelong work history of 2926 cases and 3555 controls was collected using standardised questionnaires. Occupational exposures were assessed using job-exposure matrices for five chlorinated solvents. Solvents were studied separately and in combinations. ORs were computed using unconditional logistic regression models adjusted for classic risk factors, including a history of cigarette smoking and exposure to asbestos. Adjustment for socioeconomic status (SES) was also made. Results After adjustment for exposure to asbestos, we observed a positive, statistically significant association with lung cancer for men and women exposed to a combination of perchloroethylene (PCE), trichloroethylene and dichloromethane (DCM). Further adjustment for SES slightly decreased this association. In contrast, no statistically significant associations were found for other solvent combinations. Conclusions These results suggest that exposure to PCE may constitute a risk factor for lung cancer, especially among women, who seem to have a higher prevalence of exposure than men.

INTRODUCTION

To cite: Mattei F, Guida F, Matrat M, et al. Occup Environ Med 2014;71: 681–689.

In the 1950s, chlorinated solvents were used extensively in industry, especially in sectors where degreasing was required. During the 1970s, regulations were introduced, leading to reduction of their use.1 Today, chlorinated solvents are still used in a variety of work places and industries because of their good solvency and low flammability.2 Trichloroethylene (TCE) is one of the most used chlorinated solvents. In 1990, 95% of TCE production in Europe was for metal cleaning or degreasing. In 2012, the International Agency for Research on Cancer (IARC) classified TCE as carcinogenic for humans (group 1) because of convincing evidence for an association with renal-cell carcinoma.3–6 Less consistent epidemiological evidence was found for associations with liver cancer and non-Hodgkin’s lymphoma (NHL).4

What this paper adds ▸ In 2012, IARC classified trichloroethylene as carcinogenic for humans (group 1), but no epidemiological evidence has shown an association with lung cancer. ▸ Only one study has investigated the role of exposure to chlorinated solvents in lung cancer and this suggested that exposure to perchloroethylene (PCE) and carbon tetrachloride may increase the risk of lung cancer. ▸ Our findings suggest that the exposure to PCE may be a risk factor for lung cancer. ▸ Unlike other solvents, exposure to PCE may also be more frequent in some sectors, such as dry-cleaning for women. ▸ No positive association has been found for other chlorinated solvents. ▸ These results contribute to improving prevention of lung cancer.

Perchloroethylene (PCE), another widely used chlorinated solvent, especially in the dry-cleaning sector, was classified as a probable carcinogen (group 2A) in 2012.4 Epidemiological evidence across studies showed consistent patterns of association between PCE and bladder cancer, and some positive associations have also been reported for cervical, kidney, oesophageal cancer and NHL.4 7 A critical review summarising the results of various cohort studies, mainly focusing on the dry-cleaning sector, showed weak associations with lung cancer.7 Subsequently, a cohort study among dry-cleaners and laundry workers showed an increased incidence of lung cancer, but no data on smoking habits were given.8 To our knowledge, only one case–control study from Canada has investigated the role of chlorinated solvent exposure in lung cancer. That study suggested that exposure to PCE and carbon tetrachloride (CT) may increase the risk of lung cancer.9 Among the other chlorinated solvents, dichloromethane (DCM), CT and chloroform (CF) are considered to be possibly carcinogenic (group 2B).10 11 A large case–control study, ICARE (Investigation of occupational and environmental CAuses of

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Workplace REspiratory cancers), was conducted in France to investigate the association between main occupational exposures and respiratory tract cancers (lung and upper aerodigestive tract). Using ICARE’s data, we focused in our study on the risk of lung cancer for subjects occupationally exposed to chlorinated solvents.

METHODS Study design and population The ICARE study is a French multicentre, population-based, case–control study, conducted between 2001 and 2007.12 It was set up in 10 administrative departments, including a cancer registry. Case recruitment was performed in collaboration with the French network of cancer registries (FRANCIM) in almost all of the healthcare establishments in each department. All new patients with histologically confirmed lung cancer,13 aged 18– 75 years, who were diagnosed during the study period were eligible for the study. Population-based controls were selected by incidence density sampling. In each department, controls were frequency-matched to cases by gender and age (70 ( ppm×years) for women, finding again, after adjustment for asbestos, no association with lung cancer (see online supplementary eTable 4). Finally, no evidence of differential effects of tumour histology emerged from multinomial logistic regression analyses. The number of subjects was large enough to detect a minimum OR of 1.3, considering a lifelong exposure prevalence of 9% and statistical power of 80%, suggesting that failure to observe an association between lung cancer and TCE is not due to low statistical power. Increased incidence of lung cancer in association with TCE occurred only in studies of animals.25 Some evidence has emerged about the potential TCE carcinogenicity in human populations for the kidney,3 26–28 liver29 and NHL.30 31 The 2012 IARC evaluation of TCE carcinogenicity concluded that there was convincing evidence of a positive association with kidney cancer and limited evidence for an association with liver cancer and NHL; thus, the substance was classified into group 1.4 Our findings do not suggest any association between TCE and lung cancer. Because it was not possible to isolate sufficient subjects exposed to DCM only, it is difficult to identify its role. Eighty-seven per cent of the subjects exposed to DCM had also been exposed to TCE, and the results of analyses on subjects who had ever been exposed to DCM in at least one job also exactly reflected the results for exposure to TCE. Only five subjects had been exposed to PCE exclusively and therefore the effects could not be studied. Fifty-one subjects had been exposed to PCE and TCE only and 153 to PCE, TCE and DCM only. For these combinations, we found positive associations with lung cancer both among men and women, which remained after adjustment for asbestos exposure, although statistical significance was reached (with a wide CI) only for women. However, because we grouped TCE, PCE and DCM together it is more difficult to identify which of the three is responsible for the observed association. No association was found for exposure to TCE or exposure to TCE and DCM, leading us to believe that PCE is probably responsible for the observed increased risk of lung cancer. We found that the associations were slightly stronger among women than among men. However, before reaching any conclusion, it is important to keep in mind that the number of women exposed was much smaller than that of men, leading to wide CIs. In addition, asbestos was not a confounding factor for the association between lung cancer and PCE exposure in women, whereas asbestos adjustment among men slightly decreased the observed associations. The analysis based on self-reported exposure to specific agents in the questionnaire confirmed the association between lung cancer and exposure to PCE, despite the reduced sample size, while the analysis of self-reported TCE again did not show any association. Furthermore, it is interesting to note that the magnitude of the association was similar in men and women. It might be suspected that cases tend to over-report their occupational exposure in comparison with controls, but we believe that the lack of information and knowledge on the effects of exposure to PCE on lung cancer exclude this possibility almost entirely. The percentage of controls declaring exposure to PCE reflected the lifelong exposure prevalence expected according to InVS estimation. This is probably because only those subjects who were used to using this substance knew that they were exposed to it, making this self-report fairly reliable. Mattei F, et al. Occup Environ Med 2014;71:681–689. doi:10.1136/oemed-2014-102182

Various cancer sites associated with exposure to PCE have been identified in the literature—for example, bladder, oesophagus, kidney, cervix and NHL, but only the findings for bladder cancer were consistent across studies.4 7 IARC classified PCE as carcinogenic to animals with sufficient evidence and possibly carcinogenic to humans (group 2A).4 The lung was not considered a likely target organ.32 Interestingly, one study recently published also suggested an association with lung cancer risk for ‘substantial’ levels of exposure to PCE, although the number of subjects was small.9 Because PCE is used extensively in the dry-cleaning sector, several cohort studies were conducted on subjects employed in dry-cleaning as a proxy for PCE exposure,8 33 34 and reported a moderately increased risk of lung cancer. However, according to a critical review on occupational exposure to PCE and cancer risk, the controlling of confounding factors, such as smoking habits and asbestos exposure, was often inadequate.7 In our study, we also found that PCE is a solvent typically found in sectors such as dry-cleaning or printing. However, we were unable to assess the effects of exclusive exposure to PCE because almost all subjects were simultaneously exposed to other solvents. Adjustment for SES in occupational cancer studies is debated because SES is strongly associated with occupational risk factors.35 36 According to the rules proposed by Richiardi et al,35 based on directed acyclic graphs, all results not adjusted and adjusted for SES are presented in the tables. SES is a complex index that comprises different elements—for example, education, diet, smoking habits and jobs, and consequently also occupational exposures including asbestos. While we had previously carefully adjusted our results for smoking habits using the CSI index, which accounts for the three main smoking characteristics that affect lung cancer risk (ie, intensity, duration and time since quitting) and for asbestos exposure, using a lifelong CEI, all the associations decreased after adjustment for SES. This indicates that the possibility of confounding by SES cannot be excluded even after adjustment for smoking habits and occupational exposure to asbestos. Adjustment for SES should therefore be considered. On the other hand, the complex link between SES, exposure to an agent widely used in the working environment such as asbestos and the job may lead to overadjustment when SES is considered. For this reason, results with and without adjustment have been presented. Overall, adjustment for SES affected the analyses among women less than those among men. The association between TCE, PCE and DCM and lung cancer was clearly visible in women (model not adjusted for SES: OR=5.16, 95% CI 1.30 to 20.54; model adjusted for SES: OR=4.57, 95% CI 1.14 to 18.34). Among men, the association decreased from 1.45 (95% CI 0.94 to 2.24) to 1.28 (95% CI 0.83 to 1.98). Although this modest result might be explained by residual confounding among men, this is unlikely among women given the strength of the association. Overall, these two independent results suggest that PCE alone or in combination with other solvents may increase the risk of lung cancer. The large number of analyses raises concern about multiple testing. This could also apply to the multiple hypotheses explored in the ICARE study. Whether or not adjustment for multiple comparisons is required in epidemiological studies has been extensively debated, although no obvious solution has been found.37 We preferred to focus on the consistency of the results rather than their statistical significance. For exposure to PCE, we observed indications for an association with lung cancer (i) for ever exposure, as assessed by a JEM and (ii) for self-reported exposure; (iii) we identified a dose–response 687

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Workplace relationship with cumulative duration of exposure and (iv) when investigating exposure to a combination of substances, the group of solvents including PCE almost always resulted in association. On the other hand, although we followed the same statistical analysis strategy, we almost never found that exposure to TCE was associated with lung cancer, despite all the analyses performed. In conclusion, our findings suggest that the exposure to PCE may be a risk factor for lung cancer. Exposure to PCE was less common than exposure to TCE and was more typical of sectors such as dry-cleaning for women and printing for men. Nevertheless, further investigations are necessary to replicate these results in a larger exposed population.

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Author affiliations 1 INSERM, UMRS 1018, CESP Centre for Research in Epidemiology and Population Health, Environmental Epidemiology of Cancer, Villejuif, France 2 University of Paris Sud 11, UMRS 1018, Villejuif, France 3 INSERM, U955, Créteil Cedex, France 4 Centre Hospitalier Intercommunal, Créteil Cedex, France 5 INSERM, Epidemiologic Cohorts Unit—UMS 011 INSERM-UVSQ, Villejuif, France 6 University of Versailles St-Quentin, UMS 011, Villejuif, France 7 INSERM, UMRS 1018, CESP Centre for Research in Epidemiology and Population Health, Epidemiology of Occupational and Social Determinants of Health, Villejuif, France 8 Faculty of Dental Surgery, University Paris Descartes, Paris, France 9 INSERM, UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Villejuif, France 10 Sorbonne University, UPMC University of Paris 06, UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Villejuif, France 11 University of Versailles St-Quentin, UMRS 1018, Villejuif, France 12 Registre des Cancers de la Manche, Cherbourg-Octeville, France 13 Registre des Cancers du Haut-Rhin, Mulhouse, France 14 INSERM, U 1085_IRSET, Campus de Fouillole—BP 145, Pointe-à-Pitre, Guadeloupe, French West Indies 15 University of Rennes 1, Campus de Fouillole—BP 145, Pointe-à-Pitre, Guadeloupe, French West Indies

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Acknowledgements The authors thank Ms Joëlle Fevotte for designing occupational questionnaires and all members of the MatGéné working group from the Institut de Veille Sanitaire and, in particular,r Ms Brigitte Dananché for providing job exposure matrices. Contributors IS and DL are the co-principal investigators of the ICARE (Investigation of occupational and environmental CAuses of REspiratory cancers) Study. They designed the study, directed its implementation and oversaw all aspect of the study, including recruitment of patients and controls, funding and quality control of data. FM carried out the statistical analyses, interpreted the results and wrote the manuscript. FG contributed to the statistical analysis and interpretation of the results. SC, DC, MS managed the data, applied job exposure matrices and prepared datasets for statistical analyses. MM, LR, GM, FJ, MC conceived the variables included in the analysis and the strategy of the analysis. They participated in writing the manuscript. SB and EM are responsible for two cancer registries and coded the histology of the lung cancer cases. Funding This analysis was supported by La Fondation ARC pour la Recherche sur le Cancer. The ICARE study was funded by French National Research Agency (ANR); French National Cancer Institute (INCA); French Agency for Food, Environmental and Occupational Health and Safety (ANSES); French Institute for Public Health Surveillance (InVS); Fondation pour la Recherche Médicale (FRM); Fondation de France; La Fondation ARC pour la Recherche sur le Cancer; Ministry of Labour (Direction Générale du Travail); Ministry of Health (Direction Générale de la Santé). Competing interests None.

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Patient consent Obtained. Ethics approval Institutional review board of the French National Institute of Health and Medical Research (IRB-Inserm, No 01-036 and CNIL No 90120). Provenance and peer review Not commissioned; externally peer reviewed.

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Exposure to chlorinated solvents and lung cancer: results of the ICARE study Francesca Mattei, Florence Guida, Mireille Matrat, Sylvie Cenée, Diane Cyr, Marie Sanchez, Loredana Radoi, Gwenn Menvielle, Fatima Jellouli, Matthieu Carton, Simona Bara, Emilie Marrer, Danièle Luce and Isabelle Stücker Occup Environ Med 2014 71: 681-689 originally published online July 11, 2014

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Exposure to chlorinated solvents and lung cancer: results of the ICARE study.

To investigate the role of occupational exposure to chlorinated solvents in lung cancer aetiology...
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