1 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
2 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Correspondence to Stefan Lönn, Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden (e-mail: Stefan.Lonn{at}imm.ki.se).
Received for publication August 26, 2004. Accepted for publication January 12, 2005.
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ABSTRACT |
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case-control studies; cellular phone; glioma; meningioma
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INTRODUCTION |
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Handheld mobile phones were introduced in Sweden during the late 1980s and were in common use relatively early. This makes the Swedish population suitable for a study aiming at testing the hypothesis that long-term mobile phone use increases the risk of brain tumors. The specific aim of this study was to investigate the association between mobile phone use and the risk of glioma and meningioma, the two most common types of intracranial tumors. The Swedish study of brain tumors reported here is part of the INTERPHONE Study (6). We have previously reported results for acoustic neuroma (7
).
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MATERIALS AND METHODS |
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Case ascertainment
Eligible cases were all individuals diagnosed during the study period with intracranial glioma (International Classification of Diseases, Tenth Revision, code C71; International Classification of Diseases for Oncology, Second Edition, codes 93809384, 93909394, 94009401, 94109411, 94209424, 9430, 94409443, 94509451, 9460, 94809481, and 9505) or meningioma (International Classification of Diseases, Tenth Revision, code C70; International Classification of Diseases for Oncology, Second Edition, codes 95309539). Cases were identified continuously during the study period at the neurosurgery, oncology, and neurology clinics at all hospitals within the study area. Trained nurses or a psychologist visited the clinics every week to ensure a rapid ascertainment of cases. The regional cancer registries were searched approximately every third month for additional case identification, to make sure that no cases had been missed. We identified in total 499 glioma cases and 320 meningioma cases. Four percent (n = 20) of the glioma cases and 9 percent (n = 28) of the meningioma cases were identified from the cancer registry.
Medical records for all cases were examined to confirm the diagnosis, to establish the date of diagnosis (defined as the date of the first medical examination leading to the diagnosis, usually when the first radiograph was taken), and to determine the location of the tumor. The date of diagnosis was used as the reference date in the exposure assessment.
Control selection
Controls were randomly selected from the study population stratified on age (in 5-year groups), gender, and residential area. The control selection was made from the continuously updated registry of the Swedish population approximately every second month during the study period. Controls were selected to cover the required number per case stipulated by the common core protocol for the INTERPHONE Study (one per brain tumor case, two per acoustic neuroma case, and three per parotid gland tumor case). As we did not use a matched control selection, the entire set of controls was used for all studied outcomes. In total, 956 controls were identified. The "referent date" for controls was defined as the date of identification of the control, adjusted for the average time difference between the date of identification and the date of diagnosis of the cases. Referent dates for controls were adjusted separately for glioma and meningioma cases, because the average time between diagnosis and identification was shorter for glioma cases.
Data collection
All interviews and contacts with cases and controls were made by nurses and one psychologist employed for this purpose. Before the data collection, an interviewer-training workshop was held in Copenhagen, Denmark, for interviewers in all the Scandinavian centers participating in the INTERPHONE Study, according to the protocol of the international study to ensure uniform data collection procedures. Regular refresher meetings were held nationally.
All cases and controls were approached as soon as possible after identification. Cases were contacted after permission from the treating physician or the head of the clinic. For both cases and controls, we excluded persons who were completely deaf (no cases and one control) prior to the referent date or who did not possess the intellectual and linguistic skills necessary to complete an interview (23 cases and 26 controls), as judged by the nurses or the psychologist.
Information about mobile phone use and other possible risk factors, such as family history of cancer and ionization radiation, was collected through personal interviews using a computer program that guided the interview with questions read by the interviewer from a laptop computer screen. The responses were entered directly into the computer by the interviewer. All interviewers were provided with cards displaying photographs of mobile phones with information about make, model, and year of introduction. An interview lasted approximately 45 minutes. Interviews with glioma and meningioma cases took on average 23 minutes longer than interviews with control participants. Directly after all personal interviews, the interviewer made an assessment of the quality of the interview on a five-grade scale. Persons that were unable to participate in a personal interview would offered a telephone interview instead. Those who refused participation in any kind of interview were asked if they would answer a paper questionnaire. If a person still refused, we asked if he/she could answer three short questions over the phone. The purpose of the three questions was to evaluate potential selection bias due to nonparticipation. If a case had died, the closest relative was contacted as a proxy respondent. More details about data collection and exposure assessment have been described previously (7).
Classification of exposure
Regular mobile phone use was defined as use of a mobile phone on average once per week during at least 6 months. Exposure within 1 year of the referent date was not considered. We defined as unexposed those subjects who reported that they had never or only rarely (not regularly) used a mobile phone. We calculated cumulative mobile phone use, categorized into less than 30 hours, 30499 hours, and 500 hours or more (cutpoints approximately at the 25th and 75th percentiles for controls). The cumulative number of mobile phone calls was calculated and categorized into less than 650 calls, 6508,449 calls, and 8,550 calls or more (cutpoints at approximately the 25th and 75th percentiles for controls). The number of years of regular use was categorized into less than 5 years, 59 years, and 10 years or more. Time since first regular use was categorized into less than 5 years, 59 years, and 10 years or more. Usages of analog (Nordic Mobile Telephone (NMT), continuous-signal) and digital (Global System Mobile (GSM), varying-radiofrequency) mobile phones were also analyzed separately. Sensitivity analyses were performed defining as unexposed only those who had never used a mobile phone.
Usage of hands-free devices reduces the exposure from radiofrequency radiation to the head by more than 90 percent (8). In an analysis of the cumulative hours of mobile phone use, the participants who reported almost always using a hands-free device were considered as unexposed. For participants reporting use of a hands-free device more than half of the time, 75 percent of the time used for calling was excluded; for usage half of the time, 50 percent of the time was excluded; and for usage less than half of the time, 25 percent of the time was excluded.
Separate analyses were performed for mobile phone use in urban and rural areas because the radiofrequency radiation exposure from a mobile phone is directly related to the output power level used by the phone to communicate with the base station. There are indications of higher power levels in rural than in urban areas (9).
In the analyses, glioma was also stratified according to grade and histopathologic subtype, where low-grade glioma was categorized as World Health Organization grade III and high-grade glioma was categorized as World Health Organization grade IIIIV. The histopathologic subtype glioblastoma was analyzed separately. In addition, for both glioma and meningioma, analyses were performed stratified on tumor localization. Tumors partly or totally located in the parietal and temporal lobes were categorized into one subgroup that was considered to have the highest exposure from the mobile phone (10, 11
). Tumors in the frontal lobe were treated as one subgroup, and tumors located elsewhere were treated as a third group.
If radiofrequency exposure from mobile phone use has an effect on brain tumor risk, one would expect the highest risk for those places that receive the highest exposure, that is, the side of the head where the phone is usually held. To analyze the possible association between laterality of phone use and laterality of tumors, we studied left- and right-side tumors separately. The cases were divided into left-side and right-side groups, depending on the localization of the tumor. The controls were randomly (within strata of stratification variables) assigned to two separate control groups: one for cases with left-side tumors and one for cases with right-side tumors. For both cases and controls, exposure was defined as ipsilateral phone use or use of the phone on both sides, whereas contralateral use was considered unexposed. Based on this, side-specific odds ratios were calculated and then pooled into one odds ratio. In addition, laterality analyses were made with restriction to tumors in the temporal and parietal lobes. To test for potential recall bias, we made similar analyses where contralateral phone use or use on both sides was considered exposed, and ipsilateral use was considered unexposed. Results showing no overall risk increase but an increased risk for ipsilateral phone use and a decreased risk (protective effect) for contralateral use would be taken as an indication of recall bias, that is, a tendency among cases to overreport use of the phone on the same side as the tumor is located.
In addition to our analysis of mobile phones, we analyzed if the use of European digital enhanced cordless telecommunications (DECT) phones increases the risk of glioma or meningioma. Regular DECT phone use was defined with the same criteria as for mobile phone use.
Statistical analysis
Associations between indicators of mobile phone use and the tumors were shown as odds ratios, using unconditional logistic regression models (12), with 95 percent confidence intervals. Adjustments for the stratification variables (age, gender, residential area) and education (compulsory school, vocational or secondary school, upper secondary school, university) were made in all analyses. Analyses were also performed to investigate possible confounding from a family history of cancer or exposure from ionization radiation during medical examinations or treatment.
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RESULTS |
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The odds ratios did not differ between men and women, and therefore results are presented only for the genders combined. Results were unchanged when adjustments were made for family history of cancer and ionization radiation, and these variables were therefore not included in the final analyses. Moreover, results were also unchanged if answers through mailed questionnaires were excluded (data not shown).
For regular mobile phone use, regardless of duration, the odds ratio was 0.8 (95 percent confidence interval (CI): 0.6, 1.0) for glioma and 0.7 (95 percent CI: 0.5, 0.9) for meningioma (table 2). The odds ratio did not increase with duration of use for any of the tumor types, and the effect was not modified when digital and analog phone users were analyzed separately. All analog phone users had also used a digital phone. The results did not change when the referent category was defined as never use of a mobile phone. Furthermore, excluding interviews with poor quality in the quality assessment did not change the odds ratios (data not shown).
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DISCUSSION |
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This study is population based with a rapid ascertainment of cases through active participation by all clinics involved in the treatment of glioma and meningioma cases. The rapid ascertainment is essential in a study of brain tumors because of the severity of the disease and the relatively short survival time. Control selection randomly from population registries continuously throughout the study period and adjustment of controls' referent dates ensured that controls did not have a longer opportunity for exposure than cases. All contacts and personal interviews were performed by trained nurses and a psychologist, ensuring professional and standardized treatment of cases and controls.
Participation rates were similar to what is generally found in Swedish case-control studies. Nevertheless, nonparticipation is a source of potential selection bias. If mobile phone users were more willing to participate than nonusers, the risk might be underestimated. To test this problem, individuals that declined participation when contacted by phone were asked if they had regularly used a mobile phone. Among controls who refused participation, 34 percent reported regular use compared with 59 percent among participating controls. The corresponding numbers for cases were 50 percent and 52 percent, respectively. On the other hand, only 18 percent of the nonparticipating controls and only 13 percent of the nonparticipating cases answered the question. Among those whom we were unable to contact, mobile phone use might be more prevalent; these subjects were either not at home when we on numerous occasions tried to reach them or had unlisted telephone numbers. It is, however, possible that nonparticipation among controls might explain why the observed odds ratios are slightly less than 1.0. Mobile phone use was more frequent among men than women, especially long-term use, and meningioma is more common among women. This could explain the lower proportion of mobile phone users among meningioma cases.
Differential misclassification of the exposure is a potential problem, since mobile phone use is self-reported and recall of past mobile phone use may be difficult, especially for long-term use. The disease might have had some impact on cases' ability to recall past events and habits as accurately as healthy persons recall these. However, the results from the quality assessment of the interviews did not indicate that the observed odds ratios were related to the interview quality, and cases and controls needed on average the same amount of time to complete the interview. Furthermore, impairment of memory is less common in young and middle-aged patients than in elderly patients (17). Long-term mobile phone use is most common among young and middle-aged persons.
The slightly increased odds ratio for glioma and meningioma associated with duration of years of ipsilateral mobile phone use could not be verified in the analysis of ipsilateral mobile phone use restricted to the temporal or parietal lobes. If there is a causal association between radiofrequency exposure from mobile phone use and brain tumors, we would have expected the highest odds ratio in the analysis restricted to the temporal or parietal lobes where the exposure from the mobile phone is highest. This, together with the finding of a decreased odds ratio for contralateral mobile phone use, indicates that recall bias may have affected these results. It is not biologically plausible that radiofrequency exposure from mobile phone use would increase the brain tumor risk on the side of the head where the phone is usually held and protect against brain tumors on the opposite side of the head.
Some previous studies have used a laterality analysis restricted to cases only, to describe the association between laterality of the tumor and laterality of phone use, assuming an even distribution of the tumors on both sides of the head (14, 16
). We randomly distributed our controls into two control groups and analyzed left-side and right-side tumors separately. Thus, these laterality analyses can be viewed as two separate case-control studies, where exposure in one study was defined as mobile phone use on the left side of the head and, in the other, defined as right-side use. A person could only be included in either the left-side analyses or the right-side analyses. Persons who used the phone on both sides are exposed in both substudies. Our data show that they are more extensive mobile phone users than persons who use the phone on only one side; the median number of hours of phone use was 293 hours for persons using both sides compared with 112 hours for persons who use the phone on only one side. The results from the two studies were pooled into one odds ratio.
No previously reported study has found any association between mobile phone use and meningioma (3, 4
, 13
16
), and the majority of the studies report similar results for glioma (13
16
). Some associations with glioma have been reported (3
, 4
), but there are methodological considerations that limit the interpretability of these few positive findings. The Finnish study (3
) that reported an increased risk of glioma among analog mobile phone users after only 2 years of use was a register-based, case-control study with limitation in exposure assessment. If exposure to radiofrequency fields from mobile phones has a short-term promotional effect on glioma development, we would have expected to see an increase in the incidence of intracranial tumors among young or middle-aged men during the end of the 1990s. A descriptive epidemiologic study of intracerebral tumors did not report any indication of such increase in the Nordic countries (18
). The incidence trend of glioma for both men and women was reported to be stable for those aged 2059 years during increasing prevalence of mobile phone use. A Swedish case-control study (4
) has also reported an increased risk of glioma, but the study has been criticized for limitations in methods, analysis, and presentation of the study (2
, 19
).
Limitations of previous epidemiologic studies (3, 4
, 13
16
) are the small number of individuals with long-term exposure and the lack of power to study the effects of long-term mobile phone use. Current knowledge about human cancer development indicates that the period from first exposure to clinical detection of the cancer can be more than 10 years and sometimes even more than 20 years (5
). Given that mobile phone use increases the risk of cancer, a risk increase cannot be observed until several years after first exposure. However, if radiofrequency radiation acts as a promoter, an effect could possibly be seen after a shorter duration of mobile phone use. Our Swedish study, which includes a large number of long-term mobile phone users, does not support the few previously reported positive findings and does not indicate any risk increases for either short-term or long-term exposures.
Our previously reported results for acoustic neuroma, indicating an increased risk related to mobile phone use of at least 10 years' duration, were confined to the side of the head where the phone was usually held (7). Results for contralateral use did not indicate recall bias when cases reported side of use, as was the case in the results for brain tumors presented here. The lack of association for glioma and meningioma speaks against underreporting of mobile phone use among controls as an explanation for the acoustic neuroma findings, which strengthens the finding of an increased risk for acoustic neuroma.
We conclude that these data do not support the hypothesis that mobile phone use is related to an increased risk of glioma or meningioma. It is, however, important to note that a carcinogenic effect after a very long induction time would remain undetected.
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ACKNOWLEDGMENTS |
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The authors thank the regional cancer registries for their collaboration. They also thank the research nurses for skillful work.
The Swedish INTERPHONE Study Group consists of the authors of this article and the following contributors: T. Bergenheim, L. Damber, and B. Malmer (Umeå University Hospital); J. Boethius, O. Flodmark, I. Langmoen, A. Lilja, T. Mathiesen, I. Ohlsson Lindblom, and H. Stibler (Karolinska University Hospital); J. Lycke, A. Michanek, and L. Pellettieri (Sahlgrenska University Hospital); and T. Möller and L. Salford (Lund University Hospital).
Provision of funds to the INTERPHONE Study investigators via the UICC was governed by agreements that guaranteed INTERPHONE's complete scientific independence. These agreements are available from the corresponding author upon request or at http://www.iarc.fr/pageroot/UNITS/RCA4.html.
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References |
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