Downloaded from http://oem.bmj.com/ on February 17, 2016 - Published by group.bmj.com
OEM Online First, published on February 16, 2016 as 10.1136/oemed-2015-103479 Commentary
Setting new standards for epidemiological research on mesothelioma Paolo Boffetta,1 Carlo La Vecchia2 The paper by Gilham et al,1 published in Occupational and Environmental Medicine, is important for a number of methodological and substantive reasons, and contributes novel information on the body of epidemiology evidence on the association between asbestos exposure and subsequent risk of pleural mesothelioma. The use of lung fibre burden as a method to estimate past asbestos exposure has been advocated for a long time,2 and these authors have, for the first time, applied this approach to their large-scale population study, which has already provided important results on the association between asbestos and mesothelioma, based on conventional epidemiological indicators of exposure, that is, occupational categories and time-related factors.3 The method is not free from possible bias, in particular resulting from the difficulty in obtaining lung tissue samples from unbiased groups of mesothelioma cases and controls. In the study by Gilham et al, samples were analysed for 134 cases, which represent 21.5% of those included in the original case– control study,3 which in turn may be a somewhat biased sample of all mesothelioma cases occurring in Great Britain during the study period. The authors used resected lung cancer cases as controls for the lung burden analysis. Two important sources of bias can result from this choice: resected cases of lung cancer represent a subgroup of patients with less advanced/aggressive disease, and (as discussed by the authors) given the association between asbestos exposure and lung cancer, the lung fibre burden of such a comparison group is expected to be higher than that of the population at large. In addition, the sample retrieval rate in this group of controls was also suboptimal (262/420, or 62.4%). It would not be possible to collect an unbiased population-based series of lung samples; however, given the ample 1
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 2Department of Clinical Sciences and Community Health, Milan University, Milan, Italy Correspondence to Dr Paolo Boffetta, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA; [email protected]
opportunity for selection bias, a quantitative assessment of its possible impact on the results4 would have been helpful. Bringing these limitations into account, the study provides important evidence on several aspects of the role of asbestos as a cause of mesothelioma. The study confirms the predominant role of amphibole exposure in causing mesothelioma5 6; although lung fibre burden studies are inadequate to estimate the effect of chrysotile because of the short biopersistence of this type of fibre,2 the results on crocidolite and amosite exposure appear to adequately explain mesothelioma risk. The single most important result of this analysis is the linear dose–response between lung fibre (ie, amphibole) burden and mesothelioma risk, as predicted by the model of asbestosrelated mesothelioma carcinogenesis proposed by Peto et al7 in 1982. In addition, this study provides the first estimate of the relative effect of exposure to crocidolite versus amosite, based on lung fibre burden, which is consistent (and refines) previous estimates based on data from environmental sampling.8 One of the most important pieces of evidence brought by the new study is the demonstration that a substantial number of cases of mesothelioma occurred among patients employed in low-risk occupations who were found to have relative high lung fibre burden. In other words, assessment of exposure based on job and industry titles would miss a sizable proportion of (occupation-related) cases of mesothelioma, and lung fibre burden analysis could be added to the standard approaches used for identifying cases deserving compensation for occupation-related mesothelioma. Alternatively, environmental exposures may have had a relevant contributory impact on fibre burden of selected populations in the past. Gilham et al also discuss the possible implications of lung fibre burden in young people for future mesothelioma rates. This is important on a public health level, but—as in any prediction—it has to be considered with due caution. The study by Gilham et al sets a new standard for epidemiological research on
asbestos and mesothelioma, and in general stresses the importance of collecting tissue samples (both neoplastic and normal) in cancer epidemiology studies. In the case of asbestos-related mesothelioma, such samples would be uniquely important for exposure assessment, as shown in the study by Gilham et al. Tissue samples will also be important for outcome assessment (a relatively large proportion of cases of mesothelioma cannot be confirmed when stringent diagnostic criteria are applied 9) and for mechanistic studies, given the recent increase in the understanding of genetic pathways leading to the disease.10 Competing interests PB and CLV acted as expert witnesses in asbestos-related litigations. Provenance and peer review Commissioned; internally peer reviewed. To cite Boffetta P, La Vecchia C. Occup Environ Med Published Online First: [ please include Day Month Year] doi:10.1136/oemed-2015-103479 Received 17 December 2015 Accepted 29 January 2016
▸ http://dx.doi.org/10.1136/oemed-2015-103074 Occup Environ Med 2016;0:1. doi:10.1136/oemed-2015-103479
REFERENCES 1
2
3
4
5 6 7
8
9
10
Gilham C, Rake C, Burdett G, et al. Pleural mesothelioma and lung cancer risks in relation to occupational history and asbestos lung burden. Occup Environ Med 2015; doi:10.1136/ oemed-2015-103074 McDonald JC. Epidemiological significance of mineral fiber persistence in human lung tissue. Environ Health Perspect 1994;102(Suppl 5):221–4. Rake C, Gilham C, Hatch J, et al. Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. Br J Cancer 2009;100:1175–83. Lash TL, Fox MP, Fink AK. Applying quantitative bias analysis to epidemiologic data. New York, NY: Springer, 2009. McDonald JC. Epidemiology of malignant mesothelioma —an outline. Ann Occup Hyg 2010;54:851–7. Bernstein D, Dunnigan J, Hesterberg T, et al. Health risk of chrysotile revisited. Crit Rev Toxicol 2013;43:154–83. Peto J, Seidman H, Selikoff IJ. Mesothelioma mortality in asbestos workers: implications for models of carcinogenesis and risk assessment. Br J Cancer 1982;45:124–35. Hodgson JT, Darnton A. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann Occup Hyg 2000;44:565–601. Wolff H, Vehmas T, Oksa P, et al. Asbestos, asbestosis, and cancer, the Helsinki criteria for diagnosis and attribution 2014: recommendations. Scand J Work Environ Health 2015;41:5–15. Carbone M, Ly BH, Dodson RF, et al. Malignant mesothelioma: facts, myths, and hypotheses. J Cell Physiol 2012;227:44–58.
Boffetta P, La Vecchia C. Occup Environ Med Month 2016 Vol 0 No 0
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://oem.bmj.com/ on February 17, 2016 - Published by group.bmj.com
Setting new standards for epidemiological research on mesothelioma Paolo Boffetta and Carlo La Vecchia Occup Environ Med published online February 16, 2016
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References Email alerting service
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OEM Online First, published on February 16, 2016 as 10.1136/oemed-2015-103479 Commentary
Setting new standards for epidemiological research on mesothelioma Paolo Boffetta,1 Carlo La Vecchia2 The paper by Gilham et al,1 published in Occupational and Environmental Medicine, is important for a number of methodological and substantive reasons, and contributes novel information on the body of epidemiology evidence on the association between asbestos exposure and subsequent risk of pleural mesothelioma. The use of lung fibre burden as a method to estimate past asbestos exposure has been advocated for a long time,2 and these authors have, for the first time, applied this approach to their large-scale population study, which has already provided important results on the association between asbestos and mesothelioma, based on conventional epidemiological indicators of exposure, that is, occupational categories and time-related factors.3 The method is not free from possible bias, in particular resulting from the difficulty in obtaining lung tissue samples from unbiased groups of mesothelioma cases and controls. In the study by Gilham et al, samples were analysed for 134 cases, which represent 21.5% of those included in the original case– control study,3 which in turn may be a somewhat biased sample of all mesothelioma cases occurring in Great Britain during the study period. The authors used resected lung cancer cases as controls for the lung burden analysis. Two important sources of bias can result from this choice: resected cases of lung cancer represent a subgroup of patients with less advanced/aggressive disease, and (as discussed by the authors) given the association between asbestos exposure and lung cancer, the lung fibre burden of such a comparison group is expected to be higher than that of the population at large. In addition, the sample retrieval rate in this group of controls was also suboptimal (262/420, or 62.4%). It would not be possible to collect an unbiased population-based series of lung samples; however, given the ample 1
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 2Department of Clinical Sciences and Community Health, Milan University, Milan, Italy Correspondence to Dr Paolo Boffetta, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA; [email protected]
opportunity for selection bias, a quantitative assessment of its possible impact on the results4 would have been helpful. Bringing these limitations into account, the study provides important evidence on several aspects of the role of asbestos as a cause of mesothelioma. The study confirms the predominant role of amphibole exposure in causing mesothelioma5 6; although lung fibre burden studies are inadequate to estimate the effect of chrysotile because of the short biopersistence of this type of fibre,2 the results on crocidolite and amosite exposure appear to adequately explain mesothelioma risk. The single most important result of this analysis is the linear dose–response between lung fibre (ie, amphibole) burden and mesothelioma risk, as predicted by the model of asbestosrelated mesothelioma carcinogenesis proposed by Peto et al7 in 1982. In addition, this study provides the first estimate of the relative effect of exposure to crocidolite versus amosite, based on lung fibre burden, which is consistent (and refines) previous estimates based on data from environmental sampling.8 One of the most important pieces of evidence brought by the new study is the demonstration that a substantial number of cases of mesothelioma occurred among patients employed in low-risk occupations who were found to have relative high lung fibre burden. In other words, assessment of exposure based on job and industry titles would miss a sizable proportion of (occupation-related) cases of mesothelioma, and lung fibre burden analysis could be added to the standard approaches used for identifying cases deserving compensation for occupation-related mesothelioma. Alternatively, environmental exposures may have had a relevant contributory impact on fibre burden of selected populations in the past. Gilham et al also discuss the possible implications of lung fibre burden in young people for future mesothelioma rates. This is important on a public health level, but—as in any prediction—it has to be considered with due caution. The study by Gilham et al sets a new standard for epidemiological research on
asbestos and mesothelioma, and in general stresses the importance of collecting tissue samples (both neoplastic and normal) in cancer epidemiology studies. In the case of asbestos-related mesothelioma, such samples would be uniquely important for exposure assessment, as shown in the study by Gilham et al. Tissue samples will also be important for outcome assessment (a relatively large proportion of cases of mesothelioma cannot be confirmed when stringent diagnostic criteria are applied 9) and for mechanistic studies, given the recent increase in the understanding of genetic pathways leading to the disease.10 Competing interests PB and CLV acted as expert witnesses in asbestos-related litigations. Provenance and peer review Commissioned; internally peer reviewed. To cite Boffetta P, La Vecchia C. Occup Environ Med Published Online First: [ please include Day Month Year] doi:10.1136/oemed-2015-103479 Received 17 December 2015 Accepted 29 January 2016
▸ http://dx.doi.org/10.1136/oemed-2015-103074 Occup Environ Med 2016;0:1. doi:10.1136/oemed-2015-103479
REFERENCES 1
2
3
4
5 6 7
8
9
10
Gilham C, Rake C, Burdett G, et al. Pleural mesothelioma and lung cancer risks in relation to occupational history and asbestos lung burden. Occup Environ Med 2015; doi:10.1136/ oemed-2015-103074 McDonald JC. Epidemiological significance of mineral fiber persistence in human lung tissue. Environ Health Perspect 1994;102(Suppl 5):221–4. Rake C, Gilham C, Hatch J, et al. Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. Br J Cancer 2009;100:1175–83. Lash TL, Fox MP, Fink AK. Applying quantitative bias analysis to epidemiologic data. New York, NY: Springer, 2009. McDonald JC. Epidemiology of malignant mesothelioma —an outline. Ann Occup Hyg 2010;54:851–7. Bernstein D, Dunnigan J, Hesterberg T, et al. Health risk of chrysotile revisited. Crit Rev Toxicol 2013;43:154–83. Peto J, Seidman H, Selikoff IJ. Mesothelioma mortality in asbestos workers: implications for models of carcinogenesis and risk assessment. Br J Cancer 1982;45:124–35. Hodgson JT, Darnton A. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann Occup Hyg 2000;44:565–601. Wolff H, Vehmas T, Oksa P, et al. Asbestos, asbestosis, and cancer, the Helsinki criteria for diagnosis and attribution 2014: recommendations. Scand J Work Environ Health 2015;41:5–15. Carbone M, Ly BH, Dodson RF, et al. Malignant mesothelioma: facts, myths, and hypotheses. J Cell Physiol 2012;227:44–58.
Boffetta P, La Vecchia C. Occup Environ Med Month 2016 Vol 0 No 0
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://oem.bmj.com/ on February 17, 2016 - Published by group.bmj.com
Setting new standards for epidemiological research on mesothelioma Paolo Boffetta and Carlo La Vecchia Occup Environ Med published online February 16, 2016
Updated information and services can be found at: http://oem.bmj.com/content/early/2016/02/16/oemed-2015-103479
These include:
References Email alerting service
This article cites 8 articles, 2 of which you can access for free at: http://oem.bmj.com/content/early/2016/02/16/oemed-2015-103479 #BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
