Methodological considerations of the Canadian job-exposure matrix and the evaluation of the risk of brain cancer in relation to occupational exposure to metallic compounds

Brain cancer is associated with substantial lifelong morbidity and considerable economic burden for public health systems, patients, and their families. Very little is known regarding the etiology of this disease. Metals, metalloids, and welding fumes are a large family of potential occupational carcinogens to which millions of workers are exposed. The literature provides some evidence that occupational exposure to a few metallic compounds could increase the risk of brain cancer, but most published studies were limited in sample size and ability to effectively measure lifetime occupational exposure. In this thesis, we aimed to provide new evidence concerning the association between occupational exposure to selected metallic compounds and glioma and meningioma, the two major histological subtypes of brain cancer.  Two existing projects provided the basis for the thesis: INTEROCC, a large international pooled case-control study on the association between occupational exposures and brain cancer, including 2,054 glioma cases, 1,924 meningioma cases, and 5,601 controls; CANJEM a new job exposure matrix based on the expert assessment of > 30,000 jobs. CANJEM is a cross-tabulation of three axes: an occupation code axis, a time period axis, and a chemical agent axis that provides various metrics of exposure to selected occupational agents based on a job title and a time period. However, CANJEM is also a complex tool designed to offer considerable flexibility to the user. The first two components of this thesis focused on the examination of some of the methodological considerations associated with the use of CANJEM in the context of an epidemiological study.  First we examined how changing the resolution of the occupational code and time period axes, affected the proportion of jobs in the INTEROCC study that could be linked to CANJEM. We then compared the agreement among pairs of versions of CANJEM for the probability and frequency weighted concentration of exposure to 19 metallic compounds using Gwet’s agreement coefficient (AC2). We observed that, depending on the resolution used, CANJEM could be linked to 70.7% to 98.1% of all jobs available in the INTEROCC study. Furthermore, we observed that varying the occupation code axis had a greater impact than varying the time period axis. Neither the metrics of exposure nor the linkage rate were strongly affected by other aspects of CANJEM examined.  Second, expert assessment is usually considered the gold standard in retrospective occupational exposure assessment. Different cutpoints can be applied to the probability of exposure provided by CANJEM to distinguish “exposed” from “unexposed”. We compared odds ratios (ORs) obtained using multiple versions of a binary ever and a cumulative exposure variable for nine potential and known lung carcinogens with ORs obtained using expert assessment. Unconditional logistic regression models adjusted for potential confounders were used to examine the association between each exposure variable and lung cancer in 1,200 lung cancer cases and 1,505 controls from a Montreal based case-control study. Sensitivity of the CANJEM-derived assessment vs. the expert assessment ranged from 0.12 to 0.78 while Specificity ranged from 0.84 to 0.99. Overall, CANJEM was fairly successful in reproducing the associations obtained with the expert assessment method, with the use of probability thresholds of 25% or 50% generally providing the best results for both exposure variables.  Finally, we examined the association between occupational exposure to 21 metallic compound and glioma and meningioma in the INTEROCC study using conditional logistic regression adjusted for potential confounders. The analytical strategy was based on the observations made in the two previous components. We observed no evidence of association between the selected agents and glioma, but there was evidence of positive associations between some of the agents and meningioma. Statistically significant associations with OR (95% confidence interval) were also observed between < 15 years of exposure to lead fumes (1.67 (1.02-2.74)), zinc compounds (2.14 (1.02-3.89)), soldering fumes (1.80 (1.17-2.77)), and metal oxide fumes (1.51 (1.03-2.21)) and low cumulative exposure to chromium VI (1.99 (1.03-3.84)) and soldering fumes (1.83 (1.17-2.87)) and meningioma.  One of the main challenges in occupational cancer epidemiology is retrospective exposure assessment. In this thesis we found that, while imperfect, CANJEM was a cost-efficient approach to occupational exposure in epidemiological studies. Although it is difficult to determine the exact role played by individual agents examined, our results provide some support for the presence of a positive association between metallic compounds, and more particularly metallic fumes, and meningioma.

Keyphrases: Brain cancer, Glioma, Meningioma, Job-exposure matrix, Occupational exposure, Metallic compounds