Occupational asbestos exposure and risk of esophageal, gastric and colorectal cancer in the prospective Netherlands Cohort Study

Occupational asbestos exposure and risk of esophageal,gastric and colorectal cancer in the prospective NetherlandsCohort Study

Nadine S.M. Offermans1, Roel Vermeulen2,3, Alex Burdorf4, R. Alexandra Goldbohm5, Andr�as P. Keszei1,

Susan Peters2,6, Timo Kauppinen7, Hans Kromhout2 and Piet A. van den Brandt1

1 Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands2 Institute for Risk Assessment Sciences, Environmental Epidemiology Division, Utrecht University, Utrecht, The Netherlands3 Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands4 Department of Public Health, Erasmus MC, Rotterdam, The Netherlands5 TNO, Leiden, The Netherlands6 Epidemiology Group, Centre for Medical Research, University of Western Australia, Perth, WA, Australia7 Finnish Institute of Occupational Health, Helsinki, Finland

The evidence for an association between occupational asbestos exposure and esophageal, gastric and colorectal cancer is lim-

ited. We studied this association specifically addressing risk differences between relatively low and high exposure, risk asso-

ciated 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 55–69 years at baseline), asbestos expo-

sure 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 ade-

nocarcinoma (EAC), total and distal colon cancer and rectal cancer. For overall gastric cancer and gastric non-cardia adenocar-

cinoma (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 multivariable-

adjusted model, except for the prolonged highly exposed subjects (tertile 3 vs. never: HR 2.67, 95% CI: 1.11–6.44 and HR

3.35, 95% CI: 1.33–8.44, 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.

The International Agency for Research on Cancer evaluatedthe evidence for an association between asbestos exposureand gastric and colorectal cancer as limited, though for colo-rectal cancer they were evenly divided as to whether the evi-dence was strong enough to justify classification assufficient.1 For esophageal cancer, a relatively rare cancer,results of epidemiological studies on associations with asbes-tos are mixed and together with the fact that animal experi-ments do not support biological activity of asbestos at thissite, the evidence was considered to be inadequate.2 There-fore, the question remains whether asbestos entails anincreased risk of developing gastrointestinal tumors, and ifso, whether risk differs for relatively low and high exposurelevels. As there are numerous other risk factors for gastro-intestinal cancers, an additional question relates to the influ-ence of potential confounders. Furthermore, cancer subtypesmay have different etiologies and should be studied separatelyif possible. Finally, as for lung cancer, the question arises ifinteraction between asbestos and smoking is present in rela-tion to gastrointestinal cancers.1,2

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: gas-

tric 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: 50-50-500-98-6153.

DOI: 10.1002/ijc.28817

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.: 131–43-3882361, Fax:

131–43-3884128, E-mail: [email protected]

ShortReport

Int. J. Cancer: 00, 00–00 (2014) VC 2014 UICC

International Journal of Cancer

IJC

Population-based studies are well suited to address thesequestions given their overall wide range in exposure levels,possibility to control for potential confounders and oftenlarger number of cases. One of these population-based stud-ies is the prospective Netherlands Cohort Study (NLCS), con-ducted among 120,852 men and women of the generalpopulation.3 Within the framework of this study, we had thefollowing objectives:

1. To investigate the overall association between occupationalasbestos exposure and risk of esophageal, gastric and colo-rectal cancer with special attention to risk differencesbetween relatively low and high exposure and to potentialconfounding;

2. To study the association between occupational asbestosexposure and subtypes of esophageal, gastric and colorectalcancer;

3. To examine the presence of additive or multiplicative inter-action between asbestos and smoking in relation to esopha-geal, gastric and colorectal cancer.

As the proportion of long-term employed women wasrather low, this study was only conducted among men.

Material and MethodsStudy population and cancer follow-up

In brief, the NLCS started in September 1986 when 58,279men from the Netherlands aged 55–69 years were enrolled inthe cohort. At baseline, participants completed a self-administered questionnaire on dietary habits and lifestyle,occupational history and other potential risk factors for can-cer.3 For reasons of efficiency in questionnaire processingand follow-up (a total of 17.3 years of follow-up was availableat the time of analysis), the case–cohort approach was used.4

End-points for this study were incident, microscopicallyconfirmed esophageal, gastric and colorectal cancer cases,obtained by record linkage to cancer registries and classifiedby anatomic site or histological type. Accompanying codesare available online (Supporting Information Table S1).Esophagus carcinomas included squamous cell carcinomas(ESCC) and adenocarcinomas (EAC). Gastric cancer wasclassified as cardia adenocarcinomas (GCA) and non-cardiaadenocarcinomas (GNCA). Colorectal cancer cases were clas-sified as proximal colon, distal colon, rectosigmoid or rectaltumors. All prevalent cases at baseline other than skin cancerand subjects without any, or only uncodable, information on

occupational history or who never worked professionallywere omitted from the analyses.

Occupational exposure assessment

Information on lifetime occupational history until 1986 wasobtained from the questionnaire completed at study enrol-ment. Questions concerned the job title, name and type of thecompany, products made in the department and period ofemployment. Subjects could enter a maximum of five occupa-tions. This was generally sufficient to cover the lifetime occu-pational history for the large majority of the cohort, as cohortsubjects held on average 1.9 jobs during their working life.

Occupational asbestos exposure was estimated by linkageto a job-exposure matrix (JEM), DOMJEM,5 as describedpreviously.6,7 Several exposure variables were defined: everversus never exposed to asbestos (yes/no), duration of expo-sure (years), cumulative exposure (CE; unit-years), ever ver-sus never highly exposed to asbestos (yes/no) and duration ofhigh exposure (years).

Ever versus never exposed is based on the CE, in that sub-jects were classified as being ever exposed to asbestos whenCE> 0. For occupations with P 3 I> 0, duration of employ-ment was summed in order to obtain the duration ofexposure.

The CE measure was estimated by summing the productof P 3 I and duration over the reported occupations. TheDOMJEM scores of no, low and high exposure for P 3 Iwere arbitrarily assigned values of 0, 1 and 4 to mirror thelog-normal (multiplicative) nature of occupational exposurelevels, hence the expression in unit-years. The weighting wasbased on reported levels for semi-quantitatively scored expo-sure, thereby assuring a balanced weighting between intensityand duration in the calculation of cumulative exposure.8

For the duration of high exposure, first the P 3 I peroccupation was categorized into no, low or high exposurebased on the distribution in the subcohort. Second, durationof employment was summed for those occupations with ahigh P 3 I in order to obtain the duration of high exposure.

For 10% of the population, some information on occupa-tional history could not be coded. In these cases, asbestosexposure was set to zero for the job or period with lackingoccupational history information.

Statistical analyses

Hazard ratios (HR) and corresponding 95% confidence inter-vals (95% CI) were estimated by using Cox proportional

What’s new?

Occupational asbestos exposure is thought to be a possible risk factor for esophageal, gastric, and colorectal cancers, but evi-

dence 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 adenocarci-

noma (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.

ShortReport

2 Occupational asbestos exposure and gastrointestinal tract tumors


hazards models. The models were adjusted for age and familyhistory of cancer (yes/no), as well as multivariable-adjusted.The covariates included in the multivariable-adjusted modelswere either a priori-selected risk factors based on the litera-ture or variables that changed the age-adjusted regressioncoefficients by at least 10% (using a backwards stepwise pro-cedure). To enable comparison, the models adjusted for ageand family history of cancer were restricted to subjectsincluded in the multivariable-adjusted analyses (i.e., with nomissing values on confounding variables), which left 1,866subcohort members and 187 esophageal (61 ESCC and 126EAC), 486 gastric (143 GCA and 343 GNCA) and 1,724colorectal [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 thescaled Schoenfeld residuals.9 Trends for all subjects and onlyincluding the exposed were evaluated with the Wald testby assigning subjects the median value for each level of thecategorical variable among the subcohort members, andthis variable was entered as a continuous term in the Coxregression model.

We tested for a possible interaction between asbestosexposure (yes/no) and smoking status (never/former/current)in relation to gastrointestinal cancers. Statistically significantdeparture from multiplicativity was tested by including aninteraction term in the Cox regression model. Statistically sig-nificant departure from additivity was tested using the confi-dence interval of the relative excess risk of cancer due tointeraction (RERI), according to methods described by Knoland VanderWeele,10 which were adapted for use in Stata. Alltests (2-tailed) were performed using Stata (version 10), anddifferences were regarded as statistically significant atp< 0.05.

Sensitivity analysis

In order to provide insight into the methodological uncer-tainty associated with the choice of JEM, we also used a Fin-nish JEM (FINJEM)11 as described previously.6,7 Results arepresented in the Supporting Information Tables S4–S6, aswell as a brief comparison of results of both JEMs.

ResultsThe distribution of asbestos exposure and potential con-founders among male subcohort members and cancer casesin the NLCS is given in Supporting Information Table S2.On average, cases for all three cancers were more often, lon-ger and higher exposed to asbestos.

Except for (prolonged) higher asbestos exposure, mostasbestos exposure variables showed no statistically significantincreased risk of esophageal, gastric and colorectal cancer inthe multivariable-adjusted model (Tables (1–3)). Adjustingfor potential confounders was generally of minor influence,except for overall gastric cancer and GNCA. Therefore, onlymultivariable-adjusted results are presented below, unlessmentioned otherwise.

For esophageal cancer (Table 1), no statistically significantresults were observed, though the HR (95% CI) for ever ver-sus never highly exposed and for the duration of high expo-sure (continuous variable; per 10 years) was borderlinesignificant [HR 2.22 (1.00–4.94) and 1.45(1.00–2.10), respec-tively]. Results by histology of esophageal cancer showed astatistically significant association with EAC, not only forever versus never highly exposed [HR 2.52 (1.01–6.26)], butalso for other asbestos exposure variables. Additionally, a sig-nificant exposure–response relation for the duration of expo-sure and the cumulative exposure (ptrend< 0.05) wasobserved, which disappeared when only the exposed wereconsidered.

For gastric cancer (Table 2), several asbestos exposure var-iables revealed statistically significant increased HRs in themodel adjusted for age and family history of gastric cancer.These associations mostly disappeared in the multivariable-adjusted model, especially after adjusting for smoking status.The same was true for the exposure–response relations. Theonly exception was the duration of high exposure whichremained significant [tertile 3 vs. never: HR 2.67 (1.11–6.44);ptrend< 0.05, also when only the exposed were considered].Results by location of gastric cancer showed statistically sig-nificant associations with most exposure variables for GNCAin the model adjusted for age and family history of gastriccancer (results not shown). Again, in the multivariable-adjusted model only the association with the duration ofhigh exposure remained significant [tertile 3 vs. never: HR3.35 (1.33–8.44); ptrend< 0.05, also when only the exposedwere considered). GCA showed no statistically significantassociations or exposure–response relations.

For colorectal cancer (Table 3), no statistically significantresults were noted, though the HR for ever versus neverhighly exposed was borderline significant [HR 1.53(1.00–2.34)]. Results by location of colorectal cancer showed statis-tically significant associations for the duration of high expo-sure with total colon and distal colon cancer [tertile 3 vs.never: HR 2.19 (1.04–4.62) and 2.54 (1.09–5.93), respec-tively], and for ever versus never highly exposed with rectalcancer [HR 2.15 (1.23–3.77)]. For proximal colon cancer,none of the associations or exposure–response relations wasstatistically significant.

When testing for departure from multiplicativity or addi-tivity (Supporting Information Table S3), esophageal cancershowed a p for multiplicative interaction of 0.09. For theother cancer (sub)types, there was no indication of a multi-plicative or additive interaction between asbestos andsmoking.

DiscussionMainly after (prolonged) exposure to high levels of asbestos,this population-based study showed multivariable-adjustedstatistically significant increased HRs for overall gastric can-cer, EAC, GNCA, total and distal colon and rectal cancer inthe NLCS. Adjusting for potential confounders, especially

ShortReport

Offermans et al. 3


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ShortReport



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No

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ShortReport

Offermans et al. 5


Tab

le3

.H

aza

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tio

s(H

Rs)

an

d9

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CIs

for

ove

rall

colo

rect

al

can

cer

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sfo

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teg

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es

of

asb

est

os

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osu

re,1

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ima

ted

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hD

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JEM

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20

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Tota

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nce

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olo

nP

roxi

ma

lco

lon

Dis

tal

colo

nR

ect

um

Pe

rso

nye

ars

insu

bco

ho

rtN

o.

of

case

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%C

I)H

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%C

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of

case

sH

R3

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case

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ver

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6)

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ort

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his

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),fa

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isto

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ok

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curr

en

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nu

mb

er

of

cig

are

tte

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ok

ed

pe

rd

ay

(ce

nte

red

vari

ab

le),

yea

rso

fsm

ok

ing

cig

are

tte

s(c

en

tere

dva

ria

ble

),le

vel

of

ed

uca

tio

n(l

ow

er

voca

tio

na

l,se

con

da

rya

nd

me

diu

mvo

cati

on

al

an

dh

igh

er

voca

tio

na

l/u

niv

ers

ity)

,B

MI

(kg

/m2)

an

da

lco

ho

lco

nsu

mp

tio

n(g

/da

y).

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xpo

sure

ba

sed

on

the

cum

ula

tive

pro

ba

bil

ity

3in

ten

sity

of

exp

osu

re(u

nit

-ye

ars

).5E

xpo

sure

ba

sed

on

the

pro

ba

bil

ity

3in

ten

sity

of

exp

osu

re(u

nit

-ye

ars

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er

job

.6Tr

en

ds

ove

rth

ee

xpo

sed

sub

ject

sw

ere

ad

de

do

nly

iftr

en

ds

ove

ra

llsu

bje

cts

we

rest

ati

stic

all

ysi

gn

ifica

nt

inth

efu

llco

vari

ate

mo

de

l.

ShortReport

smoking status, yielded non-significant associations withoverall gastric cancer and GNCA for those exposed to lowerlevels of asbestos. There was no statistically significant addi-tive or multiplicative interaction between asbestos and smok-ing in relation to esophageal, gastric and colorectal cancer.

Esophageal cancer

Several occupational cohort studies have observed elevatedcancer rates after asbestos exposure, and have suggested thatrisk might be dose-dependent.1 A meta-analysis conductedby the Institute of Medicine (IOM) reported a summary rela-tive risk (RR) of 0.99 (0.79–1.27) for any versus no asbestosexposure.2 In contrast, a meta-analysis examining studieswith heavier exposures reported an elevated summary stand-ardized mortality ratio [SMR 2.38 (1.45–3.68)] in asbestosexposed workers.12 Our study also showed an increased HRfor the (prolonged) highly exposed subjects, which was bor-derline significant. This may support the notion that onlyhigher asbestos exposure levels entail an increased risk ofesophageal cancer.

Our study showed significantly increased HRs for EAC.As esophageal cancer is a relatively rare cancer, only fewstudies looked at subtypes. For both histological types, resultsare mixed, with a suggestion of an exposure–response rela-tion only for EAC.13–16 As such, the analyses reported hereprovide some further support for an association with EACbut not ESCC.

Gastric cancer

For overall gastric cancer, increased risks and exposure–response relations have been observed in occupationalcohorts with higher asbestos exposure,1,2,17,18 which is com-parable to our study. The IOM meta-analysis of occupationalcohorts reported a summary RR of 1.17 (1.07–1.28) for anyversus no asbestos exposure, while results for case–controlstudies were inconsistent.2 We hypothesize that, also for gas-tric cancer only prolonged exposure to higher asbestos levelsmay be associated.

To our knowledge, this is the first prospective population-based cohort study to investigate the association betweenasbestos and both gastric cancer subtypes. In other studydesigns, no increased risk of GCA has been observed,15,19

which is comparable to our study in which there was only anincreased risk of GNCA. Diverging trends and marked geo-graphic variation suggest GCA and GNCA to be separate dis-ease entities with different etiologies.20 This may besupported by these diverging results for asbestos exposure.An industry-based study, however, did not observe an associ-ation with GNCA after either moderate or high asbestosexposure.21

Colorectal cancer

Occupational cohorts fairly consistently show increased risksof colorectal cancer after asbestos exposure and exposure–response relations,1 while results from case–control studies

are less consistent.2 Meta-analyses reported increased risksafter asbestos exposure only when SMRs for lung cancerexceeded 2 or 3.17 We also found an increased HR for everversus never highly exposed, which was borderline significant.As the IOM meta-analysis of occupational cohorts reported asummary RR of 1.15 (1.02–1.31) for any versus no asbestosexposure,2 only (prolonged) exposure to higher asbestos lev-els may increase the risk of colorectal cancer as well.

For colorectal cancer subtypes, there is some suggestion inthe literature that the association with asbestos might bestronger for colon than for rectal cancer,1 which is also basedon studies that found a higher RR of right (or proximal)colon than left (or distal) colon cancer,22,23 or found an asso-ciation with colorectal cancer but not with rectal cancer.17

One study found, however, a higher SMR of rectal cancerversus intestine and rectal cancer together.24 Our study foundsignificantly 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 beexplained by asbestos’ relation to smoking carcinogenesis andthe fact that associations with smoking have been appreciablystronger for rectal cancer than (proximal) colon cancer.25

It is not surprising that increased HRs are most likely tobe observed in those with prolonged exposure to high levelsof asbestos. In this respect, evidence for an associationbetween asbestos and all three cancers comes mainly fromoccupational cohort studies with generally higher exposurelevels.1,2,17,18 As the NLCS is a population-based study with awide range in exposure levels, including those at the lowerend of the exposure distribution, this might explain theabsence of an association with the other asbestos exposurevariables. Another explanation may relate to the fact thatoccupations with known high asbestos exposure are usuallybetter classified (i.e., with higher specificity) in JEMs thanoccupations with lower and more variable asbestos exposure,which may lead to false-negative results. This holds in partic-ular for DOMJEM. Furthermore, our JEM-based exposureassessment possibly entailed non-differential exposure mis-classification resulting in bias towards the null value. A previ-ous study in the NLCS using DOMJEM was, however, ableto corroborate the well-known association between asbestosand pleural mesothelioma.7 Finally, several associations withoverall gastric cancer and GNCA were reduced and becamenon-significant after adjusting for smoking status. Therefore,the assumption that potential confounders are only weaklycorrelated with asbestos exposure seems not totally justified.However, HRs were in most instances only marginally signifi-cant to begin with.

Contrary to lung cancer, there is almost no epidemiologicalor experimental evidence addressing whether asbestos is acofactor of tobacco smoking in the development of esophageal,gastric or colorectal cancer.2 A study by Liddell et al.26 showeda modest interaction between cumulative asbestos exposureand smoking in relation to gastric cancer, and Aliyu et al.27

reported a RR of colorectal cancer of 1.36 (0.96–1.93) for

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Offermans et al. 7


asbestos and smoking together as compared to smoking alone.Our study found no statistically significant interaction on anadditive or multiplicative scale for any of the cancers. Samplesizes 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, andthe possibility to adjust for several lifestyle confounders asalcohol and smoking.

In conclusion, this study suggests that increased HRs ofoverall gastric cancer, and possibly also of overall esophagealand colorectal cancer, are observed after (prolonged) expo-sure to high asbestos levels. This was also true for EAC,GNCA, total colon, distal colon and rectal cancer. Adjust-ment for smoking may be relevant when studying overallgastric cancer and GNCA, as several HRs were reduced and

became non-significant after adjusting for smoking status. Nostatistically significant additive or multiplicative interactionbetween asbestos and smoking was observed for any of thestudied cancers.

AcknowledgementsThe authors are indebted to the participants of this study and further wish tothank 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 assistancewith data-entry and/or data management; L. Preller for guidance regardingdata-analyses with FINJEM; A. Volovics and A. Kester for statistical advice;and H. van Montfort, T. van Moergastel, E. Dutman and R. Schmeitz forprogramming assistance. Funding: This study was supported by a grantfrom ZonMw. The sponsor had no role in the study design; collection, analy-sis and interpretation of data; writing process; or decision where to submitthe paper for publication.

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Occupational asbestos exposure and risk of esophageal, gastric and colorectal cancer in the prospective Netherlands Cohort Study