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Commentary

Cholangiocarcinoma among workers in the printing industry Tim R Driscoll Many countries have registries of certain diseases and most developed countries have high-quality cancer registries. Some of these registries contain information regarding the occupation of the registrant or an ability to link to other databases that contain this information. Such registries seem a potentially valuable resource for examining the relationship between occupation and cancer but there are several methodological challenges to their appropriate use. The study by Vlaanderen and co-workers1 provides an interesting example of the use of a disease database to provide insight into a practical occupational medical problem. The paper describes an analysis of the Nordic Occupational Cancer Study (NOCCA) database2 undertaken to examine the hypothesis that there is a relationship between employment in printing occupations and risk of cholangiocarcinoma. The analysis was of interest because of a recently published report of a very high incidence of cholangiocarcinoma in printers at a printing premises in Japan and suggestion that either or both of dichloromethane or 1,2-propylene dichloride might have been responsible.3 The analysis reported in the Vlaanderen paper supports the hypothesis in men, in whom there were enough cases to have at least moderately precise estimates. There were raised standardised incidence ratios (SIRs) in all printers and related workers, and higher risks when the more specific employment category of ‘printers’ was used. There were also raised risks for all intrahepatic tumours (which included cancers other than cholangiocarcinoma as well as intrahepatic cholangiocarcinoma) and higher risks when the more specific category of intrahepatic cholangiocarcinoma was examined. No increased risks were seen for extrahepatic tumours (which included cancers other than extrahepatic cholangiocarcinoma as well as extrahepatic cholangiocarcinoma). What might explain the study findings —chance; bias arising from selection or measurement issues; confounding; or a Correspondence to Associate Professor Tim R Driscoll, School of Public Health, University of Sydney, New South Wales, Australia; [email protected]

true increased risk of cholangiocarcinoma arising from an exposure or exposures associated with work as a printer or some related occupation? There is always a danger in analysis of databases such as the one used here that investigators can dredge the data looking for a suggestion of increased risk and reporting this as an important finding, when in reality, it is just a chance occurrence that would be expected when multiple analyses of a database are made. However, this analysis is less subject to that criticism because there was a clear underlying hypothesis, with the results supporting the hypothesis (or supporting the rejection of the relevant null hypothesis). So, chance is not easily seen as a likely explanation for the observed raised SIRs. There is likely to be considerable error in the measurement of exposure (occupation) as this is typical in a database such as NOCCA. This error is very likely to have no relationship to the outcome of interest unless the analysis was conducted in such a way as to introduce this and there is no suggestion of that in the way the analysis is described. Therefore, any such error is likely to be non-differential, and so very likely to result in bias towards the null. The measure of outcome (cancer) would be expected to be very accurate in such a database, and again, if there was any important error arising from this aspect, it would almost certainly be independent of exposure and so result in bias towards the null. Therefore, selection and measurement error do not seem likely explanations of the observed raised SIRs. Another common problem with this sort of database is that there is usually no information on potential confounders, apart from age and sex. The study analysis stratified for the potential confounders’ age, sex, calendar-period and country of residence. The other identified known potential confounders as listed in the paper do not seem likely to be associated with work as printers (or in related occupations), and therefore, unlikely to have confounded the analysis presented in the paper. Therefore, confounding does not seem a likely explanation of the observed raised SIRs. The risks were higher with the more specific category of exposure ( printers as

Driscoll TR. Occup Environ Med December 2013 Vol 70 No 12

opposed to all printing occupations) and more specific categorisation of the outcome (cholangiocarcinoma as opposed to all intrahepatic tumours), as would be expected if the hypothesis was true. On the basis of this consideration, it is reasonable not to reject the reported findings on the basis of likely chance, bias or confounding. This does not mean that they identify a true causal relationship between printing occupations and cholangiocarcinoma occurrence, but the findings are certainly supportive of this. The paper that was the stimulus for the study by Vlaanderen and coworkers was disturbing in terms of the high exposures apparently involved, the very high incidence of cholangiocarcinoma in exposed workers, the absence of a likely alternative explanation for the finding and the lack of similar reports in the published literature. That finding certainly deserves further investigation, and one of the useful approaches can be to look at the risk of cholangiocarcinoma in other cohorts with similar exposures. This is essentially what was undertaken in the current analysis. It is a good example of the sensible use of disease registries for epidemiological enquiry, and provides useful information supportive of the need to not dismiss the Japanese occurrence as just yet another cancer cluster of no importance, and to undertake more definitive studies if possible. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed. To cite Driscoll TR. Occup Environ Med 2013;70:827. Received 27 July 2013 Accepted 16 August 2013 Published Online First 18 September 2013

▸ http://dx.doi.org/10.1136/oemed-2013-101500 Occup Environ Med 2013;70:827. doi:10.1136/oemed-2013-101726

REFERENCES 1

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Vlaanderen J, Straif K, Martinsen J, et al. Cholangiocarcinoma among workers in the printing industry: Using the NOCCA database to elucidate the generalisability of a cluster report from Japan. Occup Environ Med 2013;70:828–30. Pukkala E, Martinsen JI, Lynge E, et al. Occupation and cancer—follow-up of 15 million people in five Nordic countries. Acta Oncol 2009;48: 646–790. Kumagai S, Kurumatani N, Arimoto A, et al. Cholangiocarcinoma among offset colour proof-printing workers exposed to 1,2-dichloropropane and/or dichloromethane. Occup Environ Med 2013;70: 508–10.

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Cholangiocarcinoma among workers in the printing industry Tim R Driscoll Occup Environ Med 2013 70: 827 originally published online September 18, 2013

doi: 10.1136/oemed-2013-101726 Updated information and services can be found at: http://oem.bmj.com/content/70/12/827

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