Occupational exposure to high-frequency electromagnetic fields and brain tumor risk in the INTEROCC study: An individualized assessment approach
Introduction
Glioma and meningioma are the most frequent primary brain tumor types in adults. Gliomas originate in the glial tissue and are mostly malignant, representing around 80% of all malignant brain tumors (Bondy et al., 2008; Schwartzbaum et al., 2006; Wiemels et al., 2010). Meningiomas are commonly benign, although approximately 5% are malignant (Wiemels et al., 2010). The etiologies of these diseases remain largely unknown. The only well-established risk factors, ionizing radiation and genetic disorders, account for a small portion of cases (Bondy et al., 2008; Ostrom et al., 2014). The current evidence for other possible risk factors, such as non-ionizing radiation (mostly for extremely-low frequency and radiofrequency electromagnetic fields) and certain chemicals, is inconclusive (Bondy et al., 2008; Braganza et al., 2012; Quach et al., 2016; SCENIHR, 2015).
High-frequency electromagnetic fields (EMF) are a form of non-ionizing radiation and comprise, as defined in the international INTEROCC study, intermediate frequency (IF) EMF, between 3 kHz and 10 MHz, and radiofrequency (RF) EMF, between 10 MHz and 300 GHz. The International Agency for Research on Cancer (IARC) classified RF-EMF as possibly carcinogenic to humans (group 2B) in 2011, based on limited animal evidence, mostly from co-carcinogenicity experiments, and limited epidemiological evidence, mainly based on associations between use of cellular telephones and glioma and acoustic neuroma risk (IARC, 2013). The limited evidence from animal experiments was partly based on studies that examined RF-EMF exposure in combination with known carcinogens whose results, recently replicated (Lerchl et al., 2015), suggested that RF-EMF may act in the promotion and/or progression of already initiated tumors.
The biophysical mechanism(s) by which RF-EMF might play a role in brain tumors are not clear. Both thermal effects, caused by the absorption of RF energy at a rate greater than the body's cooling mechanism (ICNIRP, 1998), and non-thermal hypotheses (Barnes and Greenebaum, 2016, Barnes and Greenebaum, 2015; Blackman et al., 1980; Castello et al., 2014; Rao et al., 2008) have been proposed, including oxidative stress, due to the formation of radical pairs, and calcium efflux, due to activation of voltage-gated calcium channels. For IF-EMF, only very limited evidence exists from some available in vivo studies while, to our knowledge, no specific epidemiologic study of IF exposure has been conducted (SCENIHR, 2015; Sienkiewicz et al., 2010).
Epidemiologic evidence on brain tumor risk from occupational exposure to RF-EMF is inadequate and few recent studies have been performed (Armstrong et al., 1994; Baldi et al., 2011; Berg et al., 2006; Degrave et al., 2009; Grayson, 1996; Groves et al., 2002; Karipidis et al., 2007; Lagorio et al., 1997; Lilienfeld et al., 1978; Morgan et al., 2000; Robinette et al., 1980; Szmigielski, 1996; Thomas et al., 1987; Tynes et al., 1996). Exposure assessment in most of these studies was mainly based on exposure surrogates, such as distance to the source or specific job titles or groups of workers thought to be exposed to RF fields, using occupational duties, qualitative exposure estimates assigned by hygienists (Berg et al., 2006) or job-exposure matrices based on expert judgments (Groves et al., 2002; Karipidis et al., 2007; Morgan et al., 2000; Robinette et al., 1980). Only a few studies, involving military personnel (Szmigielski, 1996), radio and telegraph operators (Tynes et al., 1996) or embassy employees (Lilienfeld et al., 1978) used quantitative exposure estimates based on measurements of RF field intensities. However, exposure estimates were generally based on a small number of measurements and changes in exposure levels over time were not considered. Sample sizes in these studies were also small (Smith and Kriebel, 2010).
As part of the INTEROCC study's aim to improve upon the exposure assessments in previous studies, a source-exposure matrix (SEM) was developed (Vila et al., 2017), containing confidence-weighted mean estimates, based mainly on measurements collected from the literature (Vila et al., 2016), for the EMF sources reported by the study participants. In the current paper, we used the SEM, together with detailed information collected through interviews on work with or nearby occupational EMF sources to derive individual indices of cumulative RF and IF exposure. These metrics were used to study the possible association between cumulative occupational exposure to RF or IF-EMF and glioma or meningioma risk, both overall and in specific exposure time windows.
Section snippets
Study population
The INTEROCC study comprises data from seven of the thirteen countries included in the international case-control study on mobile phone use and brain cancer risk, INTERPHONE (Cardis et al., 2007). In these seven countries, together with the mobile phone-specific data, detailed occupational information was also collected from study participants. Incident cases of primary brain tumors (i.e. glioma and meningioma) were identified between 2000 and 2004 in participating hospitals in the study
Results
In total, 1943 glioma cases, 1862 meningioma cases, and 5387 controls were included in the analysis. A small number of participants were excluded due to insufficient information on exposure intensity (i.e. EMF source(s) not clearly identified) and/or exposure duration (n = 355), or missing data on education (n = 32). Table 1 describes cases and controls included in the analysis. Meningioma cases tended to be slightly older on average than glioma cases, and were mainly (74%) female, compared
Discussion
This study, based on the analysis of nearly 4000 brain tumor cases and over 5000 controls, is the largest case-control study of brain tumors and occupational RF and IF-EMF exposure to date. The work on exposure assessment, based on a detailed source-based questionnaire and a source-exposure matrix specifically developed for the project is, to our knowledge, the most comprehensive effort aimed at estimating occupational exposure to high-frequency EMF in a large population-based epidemiological
Disclaimer
The findings and conclusions in this paper have not been formally disseminated by the National Institute for Occupational Safety and Health and should not be construed to represent any agency determination or policy.
Financial support
This work was funded by the European Commission grant 603794 (GERoNiMO project). The conduct of the INTEROCC study was funded by the National Institutes for Health (NIH) Grant No. 1R01CA124759-01. The work on the French occupational data was in part funded by AFSSET (Convention N° ST-2005-004). The INTERPHONE study was supported by funding from the European Fifth Framework Program, ‘Quality of Life and Management of Living Resources’ (contract 100 QLK4-CT-1999901563) and the International Union
Conflict of interest
The authors have no conflicts of interest to declare.
Acknowledgements
The authors would like to give special thanks to Dr. Dave Conover (deceased), USA, for his contribution in the assignment of RF and IF-EMF sources to study subjects, as well as to Taichi Murata, Japan, and Martin Doczkat, USA, for their work on exposure models for military radars and antennas. We also would like to thank Myles Capstick, UK, and Wout Joseph, Belgium, for their input on the calculation of cumulative exposure to electromagnetic fields. We are also grateful to Patricia McKinney and
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INTEROCC Study Group members: International coordination - Elisabeth Cardis (ISGlobal), Laurel Kincl (Oregon State University), Lesley Richardson (University of Montreal Hospital Research Centre); Australia - Geza Benke (Monash University); Canada - Jérôme Lavoué and Jack Siemiatycki (University of Montreal Hospital Research Centre), Daniel Krewski (University of Ottawa); Marie-Elise Parent (INRS-Institut Armand-Frappier); France - Martine Hours (IFSTTAR); Germany - Brigitte Schlehofer and Klaus Schlaefer (DKFZ); Joachim Schüz (now at IARC), Maria Blettner (IMBEI, University of Mainz); Israel - Siegal Sadetzki (Gertner Institute, Chaim Sheba Medical Center and Tel Aviv University); New Zealand - Dave McLean (Massey University); UK - Sarah Fleming (University of Leeds), Martie van Tongeren (Institute of Occupational Medicine – IOM & University of Manchester); USA - Joseph D Bowman (NIOSH).