IJC International Journal of Cancer

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1 IJC International Journal of Cancer Occupational asbestos exposure and risk of esophageal, gastric and colorectal cancer in the prospective Netherlands Cohort Study Nadine S.M. Offermans 1, Roel Vermeulen 2,3, Alex Burdorf 4, R. Alexandra Goldbohm 5, Andras P. Keszei 1, Susan Peters 2,6, Timo Kauppinen 7, Hans Kromhout 2 and Piet A. van den Brandt 1 1 Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands 2 Institute for Risk Assessment Sciences, Environmental Epidemiology Division, Utrecht University, Utrecht, The Netherlands 3 Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands 4 Department of Public Health, Erasmus MC, Rotterdam, The Netherlands 5 TNO, Leiden, The Netherlands 6 Epidemiology Group, Centre for Medical Research, University of Western Australia, Perth, WA, Australia 7 Finnish Institute of Occupational Health, Helsinki, Finland The evidence for an association between occupational asbestos exposure and esophageal, gastric and colorectal cancer is limited. We studied this association specifically addressing risk differences between relatively low and high exposure, risk associated with cancer subtypes, the influence of potential confounders and the interaction between asbestos and smoking in relation to cancer risk. Using the Netherlands Cohort Study (n 5 58,279 men, aged years at baseline), asbestos exposure was estimated by linkage to a job-exposure matrix. After 17.3 years of follow-up, 187 esophageal, 486 gastric and 1,724 colorectal cancer cases were available for analysis. The models adjusted for age and family history of cancer showed that mainly (prolonged) exposure to high levels of asbestos was statistically significantly associated with risk of esophageal adenocarcinoma (EAC), total and distal colon cancer and rectal cancer. For overall gastric cancer and gastric non-cardia adenocarcinoma (GNCA), also exposure to lower levels of asbestos was associated. Additional adjustment for lifestyle confounders, especially smoking status, yielded non-significant associations with overall gastric cancer and GNCA in the multivariableadjusted model, except for the prolonged highly exposed subjects (tertile 3 vs. never: HR 2.67, 95% CI: and HR 3.35, 95% CI: , respectively). No statistically significant additive or multiplicative interaction between asbestos and smoking was observed for any of the studied cancers. This prospective population-based study showed that (prolonged) high asbestos exposure was associated with overall gastric cancer, EAC, GNCA, total and distal colon cancer and rectal cancer. Key words: population-based study, asbestos exposure, job-exposure matrix, cancer risk, confounder adjustment Abbreviations: CE: cumulative exposure; CI: confidence interval; EAC: esophageal adenocarcinoma; ESCC: esophageal squamous cell carcinoma; GCA: gastric cardia adenocarcinoma; GNCA: gastric non-cardia adenocarcinoma; HR: hazard ratio; IOM: Institute of Medicine; JEM: job-exposure matrix; NLCS: Netherlands Cohort Study; RERI: relative excess risk due to interaction; RR: relative risk; SMR: standardized mortality ratio Additional Supporting Information may be found in the online version of this article. Grant sponsor: ZonMw; Grant number: DOI: /ijc History: Received 26 Sep 2013; Accepted 4 Feb 2014; Online 28 Feb 2014 Correspondence to: Piet A. van den Brandt, Department of Epidemiology, Maastricht University Medical Centre, P.O. Box 616, 6200 MD Maastricht, The Netherlands, Tel.: , Fax: , pa.vandenbrandt@maastrichtuniversity.nl The International Agency for Research on Cancer evaluated the evidence for an association between asbestos exposure and gastric and colorectal cancer as limited, though for colorectal cancer they were evenly divided as to whether the evidence was strong enough to justify classification as sufficient. 1 For esophageal cancer, a relatively rare cancer, results of epidemiological studies on associations with asbestos are mixed and together with the fact that animal experiments do not support biological activity of asbestos at this site, the evidence was considered to be inadequate. 2 Therefore, the question remains whether asbestos entails an increased risk of developing gastrointestinal tumors, and if so, whether risk differs for relatively low and high exposure levels. As there are numerous other risk factors for gastrointestinal cancers, an additional question relates to the influence of potential confounders. Furthermore, cancer subtypes may have different etiologies and should be studied separately if possible. Finally, as for lung cancer, the question arises if interaction between asbestos and smoking is present in relation to gastrointestinal cancers. 1,2

2 Offermans et al What s new? Occupational asbestos exposure is thought to be a possible risk factor for esophageal, gastric, and colorectal cancers, but evidence for an association is limited. In this prospective population-based cohort study, (prolonged) exposure to high levels of asbestos was found to be associated with overall gastric cancer, esophageal adenocarcinoma, gastric non-cardia adenocarcinoma (GNCA), total and distal colon cancer, and rectal cancer risk. While the risk of overall gastric cancer and GNCA risk was further associated with lower levels of asbestos exposure, statistical significance for lower-level exposure was lost following adjustment for potential confounders, particularly smoking. Population-based studies are well suited to address these questions given their overall wide range in exposure levels, possibility to control for potential confounders and often larger number of cases. One of these population-based studies is the prospective Netherlands Cohort Study (NLCS), conducted among 120,852 men and women of the general population. 3 Within the framework of this study, we had the following objectives: 1. To investigate the overall association between occupational asbestos exposure and risk of esophageal, gastric and colorectal cancer with special attention to risk differences between relatively low and high exposure and to potential confounding; 2. To study the association between occupational asbestos exposure and subtypes of esophageal, gastric and colorectal cancer; 3. To examine the presence of additive or multiplicative interaction between asbestos and smoking in relation to esophageal, gastric and colorectal cancer. As the proportion of long-term employed women was rather low, this study was only conducted among men. Material and Methods Study population and cancer follow-up In brief, the NLCS started in September 1986 when 58,279 men from the Netherlands aged years were enrolled in the cohort. At baseline, participants completed a selfadministered questionnaire on dietary habits and lifestyle, occupational history and other potential risk factors for cancer. 3 For reasons of efficiency in questionnaire processing and follow-up (a total of 17.3 years of follow-up was available at the time of analysis), the case cohort approach was used. 4 End-points for this study were incident, microscopically confirmed esophageal, gastric and colorectal cancer cases, obtained by record linkage to cancer registries and classified by anatomic site or histological type. Accompanying codes are available online (Supporting Information Table S1). Esophagus carcinomas included squamous cell carcinomas (ESCC) and adenocarcinomas (EAC). Gastric cancer was classified as cardia adenocarcinomas (GCA) and non-cardia adenocarcinomas (GNCA). Colorectal cancer cases were classified as proximal colon, distal colon, rectosigmoid or rectal tumors. All prevalent cases at baseline other than skin cancer and subjects without any, or only uncodable, information on occupational history or who never worked professionally were omitted from the analyses. Occupational exposure assessment Information on lifetime occupational history until 1986 was obtained from the questionnaire completed at study enrolment. Questions concerned the job title, name and type of the company, products made in the department and period of employment. Subjects could enter a maximum of five occupations. This was generally sufficient to cover the lifetime occupational history for the large majority of the cohort, as cohort subjects held on average 1.9 jobs during their working life. Occupational asbestos exposure was estimated by linkage to a job-exposure matrix (JEM), DOMJEM, 5 as described previously. 6,7 Several exposure variables were defined: ever versus never exposed to asbestos (yes/no), duration of exposure (years), cumulative exposure (CE; unit-years), ever versus never highly exposed to asbestos (yes/no) and duration of high exposure (years). Ever versus never exposed is based on the CE, in that subjects were classified as being ever exposed to asbestos when CE > 0. For occupations with P 3 I > 0, duration of employment was summed in order to obtain the duration of exposure. The CE measure was estimated by summing the product of P 3 I and duration over the reported occupations. The DOMJEM scores of no, low and high exposure for P 3 I were arbitrarily assigned values of 0, 1 and 4 to mirror the log-normal (multiplicative) nature of occupational exposure levels, hence the expression in unit-years. The weighting was based on reported levels for semi-quantitatively scored exposure, thereby assuring a balanced weighting between intensity and duration in the calculation of cumulative exposure. 8 For the duration of high exposure, first the P 3 I per occupation was categorized into no, low or high exposure based on the distribution in the subcohort. Second, duration of employment was summed for those occupations with a high P 3 I in order to obtain the duration of high exposure. For 10% of the population, some information on occupational history could not be coded. In these cases, asbestos exposure was set to zero for the job or period with lacking occupational history information. Statistical analyses Hazard ratios (HR) and corresponding 95% confidence intervals (95% CI) were estimated by using Cox proportional

3 1972 Occupational asbestos exposure and gastrointestinal tract tumors hazards models. The models were adjusted for age and family history of cancer (yes/no), as well as multivariable-adjusted. The covariates included in the multivariable-adjusted models were either a priori-selected risk factors based on the literature or variables that changed the age-adjusted regression coefficients by at least 10% (using a backwards stepwise procedure). To enable comparison, the models adjusted for age and family history of cancer were restricted to subjects included in the multivariable-adjusted analyses (i.e., with no missing values on confounding variables), which left 1,866 subcohort members and 187 esophageal (61 ESCC and 126 EAC), 486 gastric (143 GCA and 343 GNCA) and 1,724 colorectal [1,113 total colon (503 proximal and 568 distal), and 425 rectum] cancer cases for analyses. For each analysis, the proportional hazards assumption was tested by using the scaled Schoenfeld residuals. 9 Trends for all subjects and only including the exposed were evaluated with the Wald test by assigning subjects the median value for each level of the categorical variable among the subcohort members, and this variable was entered as a continuous term in the Cox regression model. We tested for a possible interaction between asbestos exposure (yes/no) and smoking status (never/former/current) in relation to gastrointestinal cancers. Statistically significant departure from multiplicativity was tested by including an interaction term in the Cox regression model. Statistically significant departure from additivity was tested using the confidence interval of the relative excess risk of cancer due to interaction (RERI), according to methods described by Knol and VanderWeele, 10 which were adapted for use in Stata. All tests (2-tailed) were performed using Stata (version 10), and differences were regarded as statistically significant at p < Sensitivity analysis In order to provide insight into the methodological uncertainty associated with the choice of JEM, we also used a Finnish JEM (FINJEM) 11 as described previously. 6,7 Results are presented in the Supporting Information Tables S4 S6, as well as a brief comparison of results of both JEMs. Results The distribution of asbestos exposure and potential confounders among male subcohort members and cancer cases in the NLCS is given in Supporting Information Table S2. On average, cases for all three cancers were more often, longer and higher exposed to asbestos. Except for (prolonged) higher asbestos exposure, most asbestos exposure variables showed no statistically significant increased risk of esophageal, gastric and colorectal cancer in the multivariable-adjusted model (Tables (1 3)). Adjusting for potential confounders was generally of minor influence, except for overall gastric cancer and GNCA. Therefore, only multivariable-adjusted results are presented below, unless mentioned otherwise. For esophageal cancer (Table 1), no statistically significant results were observed, though the HR (95% CI) for ever versus never highly exposed and for the duration of high exposure (continuous variable; per 10 years) was borderline significant [HR 2.22 ( ) and 1.45( ), respectively]. Results by histology of esophageal cancer showed a statistically significant association with EAC, not only for ever versus never highly exposed [HR 2.52 ( )], but also for other asbestos exposure variables. Additionally, a significant exposure response relation for the duration of exposure and the cumulative exposure (p trend < 0.05) was observed, which disappeared when only the exposed were considered. For gastric cancer (Table 2), several asbestos exposure variables revealed statistically significant increased HRs in the model adjusted for age and family history of gastric cancer. These associations mostly disappeared in the multivariableadjusted model, especially after adjusting for smoking status. The same was true for the exposure response relations. The only exception was the duration of high exposure which remained significant [tertile 3 vs. never: HR 2.67 ( ); p trend < 0.05, also when only the exposed were considered]. Results by location of gastric cancer showed statistically significant associations with most exposure variables for GNCA in the model adjusted for age and family history of gastric cancer (results not shown). Again, in the multivariableadjusted model only the association with the duration of high exposure remained significant [tertile 3 vs. never: HR 3.35 ( ); p trend < 0.05, also when only the exposed were considered). GCA showed no statistically significant associations or exposure response relations. For colorectal cancer (Table 3), no statistically significant results were noted, though the HR for ever versus never highly exposed was borderline significant [HR 1.53( )]. Results by location of colorectal cancer showed statistically significant associations for the duration of high exposure with total colon and distal colon cancer [tertile 3 vs. never: HR 2.19 ( ) and 2.54 ( ), respectively], and for ever versus never highly exposed with rectal cancer [HR 2.15 ( )]. For proximal colon cancer, none of the associations or exposure response relations was statistically significant. When testing for departure from multiplicativity or additivity (Supporting Information Table S3), esophageal cancer showed a p for multiplicative interaction of For the other cancer (sub)types, there was no indication of a multiplicative or additive interaction between asbestos and smoking. Discussion Mainly after (prolonged) exposure to high levels of asbestos, this population-based study showed multivariable-adjusted statistically significant increased HRs for overall gastric cancer, EAC, GNCA, total and distal colon and rectal cancer in the NLCS. Adjusting for potential confounders, especially

4 Offermans et al Table 1. Hazard ratios (HRs) and 95% CIs for overall esophageal cancer and subtypes for categories of asbestos exposure, 1 estimated with DOMJEM in the NLCS, Esophageal cancer ESCC EAC Person years in subcohort cases HR 2 (95% CI) HR 3 (95% CI) Never exposed 4 19, (ref) 1 (ref) 44 1 (ref) 78 1 (ref) Ever exposed 4 7, ( ) 1.35 ( ) ( ) ( ) Duration of exposure 5 (years) T1 (median:4) 2, ( ) 1.45 ( ) ( ) ( ) T2 (median:18) 2, ( ) 1.10 ( ) ( ) ( ) T3 (median:37) 2, ( ) 1.44 ( ) ( ) ( ) p for trend (over the exposed only) <0.05 (0.175) Continuous, per 10 years 26, ( ) 1.10 ( ) ( ) ( ) Cumulative probability 3 intensity of exposure (unit-years) T1 (median:4) 2, ( ) 1.31 ( ) ( ) ( ) T2 (median:20) 2, ( ) 1.35 ( ) ( ) ( ) T3 (median:38) 2, ( ) 1.40 ( ) ( ) ( ) p for trend (over the exposed only) <0.05 (0.753) Continuous, per 1 unit-year 26, ( ) 1.01 ( ) ( ) ( ) Never highly exposed 26, (ref) 1 (ref) 59 1 (ref) (ref) Ever highly exposed ( ) 2.22 ( ) ( ) ( ) Duration of high exposure 5 (years) T1 (median:4) ( ) 2.27 ( ) ( ) ( ) T2 (median:10.5) ( ) 1.44 ( ) ( ) T3 (median:30.5) ( ) 2.50 ( ) ( ) ( ) p for trend Continuous, per 10 years 26, ( ) 1.45 ( ) ( ) ( ) 1 Exposure dichotomized or categorized in never-exposed and tertiles (T) of exposed in the subcohort. 2 Adjusted for age (years) and family history of esophageal cancer (yes/no). 3 Adjusted for age (years), family history of esophageal cancer (yes/no), smoking status (never/former/current), number of cigarettes smoked per day (centered variable), years of smoking cigarettes (centered variable), level of education (lower vocational, secondary and medium vocational and higher vocational/university), BMI (kg/m 2 ) and alcohol consumption (g/day). 4 Exposure based on the cumulative probability 3 intensity of exposure (unit-years). 5 Exposure based on the probability 3 intensity of exposure (unit-years) per job. 6 Trends over the exposed subjects were added only if trends over all subjects were statistically significant in the full covariate model.

5 1974 Occupational asbestos exposure and gastrointestinal tract tumors Table 2. Hazard ratios (HRs) and 95% CIs for overall gastric cancer and subtypes for categories of asbestos exposure, 1 estimated with DOMJEM in the NLCS, Gastric cancer GCA GNCA Person years in subcohort cases HR 2 (95% CI) HR 3 (95% CI) Never exposed 4 19, (ref) 1 (ref) (ref) (ref) Ever exposed 4 7, ( ) 1.02 ( ) ( ) ( ) Duration of exposure 5 (years) T1 (median:4) 2, ( ) 0.63 ( ) ( ) ( ) T2 (median:18) 2, ( ) 1.38 ( ) ( ) ( ) T3 (median:37) 2, ( ) 1.15 ( ) ( ) ( ) p for trend < Continuous, per 10 years 26, ( ) 1.06 ( ) ( ) ( ) Cumulative probability 3 intensity of exposure (unit-years) T1 (median:4) 2, ( ) 0.69 ( ) ( ) ( ) T2 (median:20) 2, ( ) 1.22 ( ) ( ) ( ) T3 (median:38) 2, ( ) 1.22 ( ) ( ) ( ) p for trend < Continuous, per 1 unit-year 26, ( ) 1.01 ( ) ( ) ( ) Never highly exposed 26, (ref) 1 (ref) (ref) (ref) Ever highly exposed ( ) 1.72 ( ) ( ) ( ) Duration of high exposure 5 (years) T1 (median:4) ( ) 0.56 ( ) ( ) ( ) T2 (median:10.5) ( ) 2.07 ( ) ( ) ( ) T3 (median:30.5) ( ) 2.67 ( ) ( ) ( ) p for trend (over the exposed only) 6 <0.05 <0.05 (<0.05) <0.05 (<0.05) Continuous, per 10 years 26, ( ) 1.41 ( ) ( ) ( ) 1 Exposure dichotomized or categorized in never-exposed and tertiles (T) of exposed in the subcohort. 2 Adjusted for age (years) and family history of gastric cancer (yes/no). 3 Adjusted for age (years), family history of gastric cancer (yes/no), smoking status (never/former/current), number of cigarettes smoked per day (centered variable), years of smoking cigarettes (centered variable), level of education (lower vocational, secondary and medium vocational and higher vocational/university), BMI (kg/m 2 ) and alcohol consumption (g/day). 4 Exposure based on the cumulative probability 3 intensity of exposure (unit-years). 5 Exposure based on the probability 3 intensity of exposure (unit-years) per job. 6 Trends over the exposed subjects were added only if trends over all subjects were statistically significant in the full covariate model.

6 Table 3. Hazard ratios (HRs) and 95% CIs for overall colorectal cancer and subtypes for categories of asbestos exposure, 1 estimated with DOMJEM in the NLCS, Total colorectal cancer Colon Proximal colon Distal colon Rectum Person years in subcohort cases HR 2 (95% CI) HR 3 (95% CI) Never exposed 4 19,022 1,258 1 (ref) 1 (ref) (ref) (ref) (ref) (ref) Ever exposed 4 7, ( ) 0.95 ( ) ( ) ( ) ( ) ( ) Duration of exposure 5 (years) T1 (median:4) 2, ( ) 0.77 ( ) ( ) ( ) ( ) ( ) T2 (median:18) 2, ( ) 1.05 ( ) ( ) ( ) ( ) ( ) T3 (median:37) 2, ( ) 1.07 ( ) ( ) ( ) ( ) ( ) p for trend Continuous, per 10 years 26,530 1, ( ) 1.02 ( ) 1, ( ) ( ) ( ) ( ) Cumulative probability 3 intensity of exposure (unit-years) T1 (median:4) 2, ( ) 0.78 ( ) ( ) ( ) ( ) ( ) T2 (median:20) 2, ( ) 1.01 ( ) ( ) ( ) ( ) ( ) T3 (median:38) 2, ( ) 1.10 ( ) ( ) ( ) ( ) ( ) p for trend Continuous, per 1 unit-year 26,530 1, ( ) 1.00 ( ) 1, ( ) ( ) ( ) ( ) Never highly exposed 25, (ref) 1 (ref) 1,084 1 (ref) (ref) (ref) (ref) Ever highly exposed ( ) 1.53 ( ) ( ) ( ) ( ) ( ) Duration of high exposure 5 (years) T1 (median:4) ( ) 1.69 ( ) ( ) ( ) ( ) ( ) T2 (median:10.5) ( ) 1.22 ( ) ( ) ( ) ( ) ( ) T3 (median:30.5) ( ) 1.87 ( ) ( ) ( ) ( ) ( ) p for trend (over the exposed only) 6 <0.05 <0.05 (0.833) <0.05 (0.183) Continuous, per 10 years 26,530 1, ( ) 1.23 ( ) 1, ( ) ( ) ( ) ( ) 1 Exposure dichotomized or categorized in never-exposed and tertiles (T) of exposed in the subcohort. 2 Adjusted for age (years) and family history of colorectal cancer (yes/no). 3 Adjusted for age (years), family history of colorectal cancer (yes/no), smoking status (never/former/current), number of cigarettes smoked per day (centered variable), years of smoking cigarettes (centered variable), level of education (lower vocational, secondary and medium vocational and higher vocational/university), BMI (kg/m 2 ) and alcohol consumption (g/day). 4 Exposure based on the cumulative probability 3 intensity of exposure (unit-years). 5 Exposure based on the probability 3 intensity of exposure (unit-years) per job. 6 Trends over the exposed subjects were added only if trends over all subjects were statistically significant in the full covariate model.

7 1976 Occupational asbestos exposure and gastrointestinal tract tumors smoking status, yielded non-significant associations with overall gastric cancer and GNCA for those exposed to lower levels of asbestos. There was no statistically significant additive or multiplicative interaction between asbestos and smoking in relation to esophageal, gastric and colorectal cancer. Esophageal cancer Several occupational cohort studies have observed elevated cancer rates after asbestos exposure, and have suggested that risk might be dose-dependent. 1 A meta-analysis conducted by the Institute of Medicine (IOM) reported a summary relative risk (RR) of 0.99 ( ) for any versus no asbestos exposure. 2 In contrast, a meta-analysis examining studies with heavier exposures reported an elevated summary standardized mortality ratio [SMR 2.38 ( )] in asbestos exposed workers. 12 Our study also showed an increased HR for the (prolonged) highly exposed subjects, which was borderline significant. This may support the notion that only higher asbestos exposure levels entail an increased risk of esophageal cancer. Our study showed significantly increased HRs for EAC. As esophageal cancer is a relatively rare cancer, only few studies looked at subtypes. For both histological types, results are mixed, with a suggestion of an exposure response relation only for EAC As such, the analyses reported here provide some further support for an association with EAC but not ESCC. Gastric cancer For overall gastric cancer, increased risks and exposure response relations have been observed in occupational cohorts with higher asbestos exposure, 1,2,17,18 which is comparable to our study. The IOM meta-analysis of occupational cohorts reported a summary RR of 1.17 ( ) for any versus no asbestos exposure, while results for case control studies were inconsistent. 2 We hypothesize that, also for gastric cancer only prolonged exposure to higher asbestos levels may be associated. To our knowledge, this is the first prospective populationbased cohort study to investigate the association between asbestos and both gastric cancer subtypes. In other study designs, no increased risk of GCA has been observed, 15,19 which is comparable to our study in which there was only an increased risk of GNCA. Diverging trends and marked geographic variation suggest GCA and GNCA to be separate disease entities with different etiologies. 20 This may be supported by these diverging results for asbestos exposure. An industry-based study, however, did not observe an association with GNCA after either moderate or high asbestos exposure. 21 Colorectal cancer Occupational cohorts fairly consistently show increased risks of colorectal cancer after asbestos exposure and exposure response relations, 1 while results from case control studies are less consistent. 2 Meta-analyses reported increased risks after asbestos exposure only when SMRs for lung cancer exceeded 2 or We also found an increased HR for ever versus never highly exposed, which was borderline significant. As the IOM meta-analysis of occupational cohorts reported a summary RR of 1.15 ( ) for any versus no asbestos exposure, 2 only (prolonged) exposure to higher asbestos levels may increase the risk of colorectal cancer as well. For colorectal cancer subtypes, there is some suggestion in the literature that the association with asbestos might be stronger for colon than for rectal cancer, 1 which is also based on studies that found a higher RR of right (or proximal) colon than left (or distal) colon cancer, 22,23 or found an association with colorectal cancer but not with rectal cancer. 17 One study found, however, a higher SMR of rectal cancer versus intestine and rectal cancer together. 24 Our study found significantly increased HRs for colon (both total and distal) and rectal cancer. The association with rectal cancer and, given the location, with distal colon cancer could be explained by asbestos relation to smoking carcinogenesis and the fact that associations with smoking have been appreciably stronger for rectal cancer than (proximal) colon cancer. 25 It is not surprising that increased HRs are most likely to be observed in those with prolonged exposure to high levels of asbestos. In this respect, evidence for an association between asbestos and all three cancers comes mainly from occupational cohort studies with generally higher exposure levels. 1,2,17,18 As the NLCS is a population-based study with a wide range in exposure levels, including those at the lower end of the exposure distribution, this might explain the absence of an association with the other asbestos exposure variables. Another explanation may relate to the fact that occupations with known high asbestos exposure are usually better classified (i.e., with higher specificity) in JEMs than occupations with lower and more variable asbestos exposure, which may lead to false-negative results. This holds in particular for DOMJEM. Furthermore, our JEM-based exposure assessment possibly entailed non-differential exposure misclassification resulting in bias towards the null value. A previous study in the NLCS using DOMJEM was, however, able to corroborate the well-known association between asbestos and pleural mesothelioma. 7 Finally, several associations with overall gastric cancer and GNCA were reduced and became non-significant after adjusting for smoking status. Therefore, the assumption that potential confounders are only weakly correlated with asbestos exposure seems not totally justified. However, HRs were in most instances only marginally significant to begin with. Contrary to lung cancer, there is almost no epidemiological or experimental evidence addressing whether asbestos is a cofactor of tobacco smoking in the development of esophageal, gastric or colorectal cancer. 2 A study by Liddell et al. 26 showed a modest interaction between cumulative asbestos exposure and smoking in relation to gastric cancer, and Aliyu et al. 27 reported a RR of colorectal cancer of 1.36 ( ) for

8 Offermans et al asbestos and smoking together as compared to smoking alone. Our study found no statistically significant interaction on an additive or multiplicative scale for any of the cancers. Sample sizes were small, however, especially for esophageal cancer. Strengths of our study included the prospective design, the long, nearly complete follow-up and large study size, and the possibility to adjust for several lifestyle confounders as alcohol and smoking. In conclusion, this study suggests that increased HRs of overall gastric cancer, and possibly also of overall esophageal and colorectal cancer, are observed after (prolonged) exposure to high asbestos levels. This was also true for EAC, GNCA, total colon, distal colon and rectal cancer. Adjustment for smoking may be relevant when studying overall gastric cancer and GNCA, as several HRs were reduced and became non-significant after adjusting for smoking status. No statistically significant additive or multiplicative interaction between asbestos and smoking was observed for any of the studied cancers. Acknowledgements The authors are indebted to the participants of this study and further wish to thank the Netherlands Cancer Registry and the Dutch Pathology Registry (PALGA). We also thank S. van de Crommert, Dr. L. Schouten, J. Nelissen, C. de Zwart, M. Moll, S. van den Heuvel and A. Pisters for their assistance with data-entry and/or data management; L. Preller for guidance regarding data-analyses with FINJEM; A. Volovics and A. Kester for statistical advice; and H. van Montfort, T. van Moergastel, E. Dutman and R. Schmeitz for programming assistance. Funding: This study was supported by a grant from ZonMw. The sponsor had no role in the study design; collection, analysis and interpretation of data; writing process; or decision where to submit the paper for publication. References 1. IARC. Asbestos (Chrysotile, Amosite, Crocidolite, Tremolite, Actinolite and Anthophyllite). In: A review of human carcinogens: arsenic, metals, fibres, and dusts. Lyon, France: International Agency for Research on Cancer (IARC), NAS. Asbestos: selected cancers. Washington, DC: The National Academies Press, p. 3. van den Brandt PA, Goldbohm RA, van t Veer P, et al. A large-scale prospective cohort study on diet and cancer in The Netherlands. J Clin Epidemiol 1990;43: Prentice RL. A case cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika 1986;73: Peters S, Vermeulen R, Cassidy A, et al. Comparison of exposure assessment methods for occupational carcinogens in a multi-centre lung cancer case control study. Occup Environ Med 2011;68: Offermans NS, Vermeulen R, Burdorf A, et al. Comparison of expert and job-exposure matrixbased retrospective exposure assessment of occupational carcinogens in the Netherlands Cohort Study. Occup Environ Med 2012;69: Offermans NS, Vermeulen R, Burdorf A, et al. Occupational asbestos exposure and risk of pleural mesothelioma, lung cancer, and laryngeal cancer in the prospective Netherlands cohort study. J Occup Environ Med 2014;56: Stewart PA, Herrick RF, Blair A, et al. Highlights of the 1990 Leesburg, Virginia, International Workshop on Retrospective Exposure Assessment for Occupational Epidemiology Studies. Scand J Work Environ Health. 1991;17: Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika 1982; 69: Knol MJ, VanderWeele TJ. Recommendations for presenting analyses of effect modification and interaction. Int J Epidemiol 2012;41: Kauppinen T, Toikkanen J, Pukkala E. From cross-tabulations to multipurpose exposure information systems: a new job-exposure matrix. Am J Ind Med 1998;33: Morgan RW, Foliart DE, Wong O. Asbestos and gastrointestinal cancer. A review of the literature. West J Med 1985;143: Gustavsson P, Jakobsson R, Johansson H, et al. Occupational exposures and squamous cell carcinoma of the oral cavity, pharynx, larynx, and oesophagus: a case control study in Sweden. Occup Environ Med 1998;55: Parent ME, Siemiatycki J, Fritschi L. Workplace exposures and oesophageal cancer. Occup Environ Med 2000;57: Jansson C, Johansson AL, Bergdahl IA, et al. Occupational exposures and risk of esophageal and gastric cardia cancers among male Swedish construction workers. Cancer Causes Control 2005;16: Santiba~nez M, Vioque J, Alguacil J, et al. Occupational exposures and risk of oesophageal cancer by histological type: a case control study in eastern Spain. Occup Environ Med 2008;65: Gamble J. Risk of gastrointestinal cancers from inhalation and ingestion of asbestos. Regul Toxicol Pharmacol 2008;52:S Frumkin H, Berlin J. Asbestos exposure and gastrointestinal malignancy review and meta-analysis. Am J Ind Med 1988;14: Jansson C, Plato N, Johansson AL, et al. Airborne occupational exposures and risk of oesophageal and cardia adenocarcinoma. Occup Environ Med 2006;63: Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006;12: Sjodahl K, Jansson C, Bergdahl IA, et al. Airborne exposures and risk of gastric cancer: a prospective cohort study. Int J Cancer 2007;120: Jakobsson K, Albin M, Hagmar L. Asbestos, cement, and cancer in the right part of the colon. Occup Environ Med 1994;51: Gerhardsson de Verdier M, Plato N, Steineck G, et al. Occupational exposures and cancer of the colon and rectum. Am J Ind Med 1992;22: Ferrante D, Bertolotti M, Todesco A, et al. Cancer mortality and incidence of mesothelioma in a cohort of wives of asbestos workers in Casale Monferrato, Italy. Environ Health Perspect 2007; 115: Liang PS, Chen TY, Giovannucci E. Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int J Cancer 2009;124: Liddell FD, McDonald AD, McDonald JC. The birth cohort of Quebec chrysotile miners and millers: development from 1904 and mortality to Ann Occup Hyg 1997;41: Aliyu OA, Cullen MR, Barnett MJ, et al. Evidence for excess colorectal cancer incidence among asbestos-exposed men in the Beta-Carotene and Retinol Efficacy Trial. Am J Epidemiol 2005;162: