1 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
2 Institute for Medical Biostatistics, Epidemiology and Informatics, University of Mainz, Mainz, Germany.
3 Neurosurgical Department, Neuroscience Centre, University Hospital of Copenhagen, Copenhagen, Denmark.
4 Department of Radiation Biology, Finsen Centre, University Hospital of Copenhagen, Copenhagen, Denmark.
5 Department of OtolaryngologyHead and Neck Surgery, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
Received for publication September 15, 2003; accepted for publication October 8, 2003.
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ABSTRACT |
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case-control studies; cellular phone; ear neoplasms; neuroma, acoustic
Abbreviations: Abbreviation: CI, confidence interval.
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INTRODUCTION |
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The incidence of acoustic neuroma has increased over the past 20 years and is currently 120 per million population per year in most industrialized countries (2, 3). This recorded increase in incidence may be due to better diagnostic tools and increased awareness of the disease (3); however, a number of environmental factors have been suspected to increase the risk of acoustic neuroma. The suspected factors include electromagnetic fields emitted by hand-held cellular telephones (4), since this type of tumor is located in an anatomic region where a considerable amount of the power emitted from cell phones is absorbed. The power absorption is attenuated by more than 90 percent within 45 cm (5).
In contrast to ionizing radiation, electromagnetic fields emitted from cellular telephones do not have enough energy to break chemical bonds or damage DNA. Electromagnetic radiation from a cell phone can penetrate the skull and deposit energy 46 cm into the brain. This can potentially result in a heating of the tissue of up to 0.1°C (6, 7). Therefore, it has been debated whether these fields could initiate or promote cancer (8, 9). The most provocative experimental study to date is that of Repacholi et al. (10), who reported an excess risk of lymphoma in genetically engineered mice exposed to a pulsed 900-MHz electromagnetic field for 1 hour per day for 18 months. However, the relevance of that finding for human health has been questioned, both by the authors and by others (11, 12). Because radio-frequency signals are unlikely to cause genetic mutations, the biologic basis for a possible association between cell phone use and cancer risk has been proposed to be a thermal mechanism, such as changes in protein phosphorylation, or a nonthermal mechanism that promotes tumor growth (11, 13).
Four epidemiologic studies have examined the association between use of cellular telephones and risk of acoustic neuroma (9, 1417). However, only the most recent case-control study of prevalence showed a significantly increased risk of acoustic neuroma among users of analogue cellular telephones (17).
Here we report the first results from the Danish portion of the Interphone project, an international case-control study of incident glioma, meningioma, parotid gland tumors, and acoustic neuroma based on a common core protocol in 14 countries (18). In this nationwide, population-based study, we were able to obtain detailed information on patterns of cell phone use among 107 patients with incident acoustic neuroma and 214 matched population-based controls.
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MATERIALS AND METHODS |
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Of the 141 eligible case patients, we excluded eight cases because they were prevalent or occurred in persons aged 69 years or more at diagnosis, and we excluded a further three cases because the patients died before we were able to approach them. Twenty-three case patients refused to participate, leaving 107 (82 percent) patients for interview. Eighty cases (75 percent) were diagnosed on the basis of magnetic resonance scanning, and 27 cases (25 percent) were confirmed by histologic examination. One case patient and two matched controls were excluded from the study base, because the patient was found to have had neurofibromatosis type II before the diagnosis of acoustic neuroma.
We selected two controls for each case, individually matched according to age (within 5 years) and sex. The controls were randomly sampled from the Danish Central Population Register on the basis of the unique 10-digit personal identification number that has been assigned to all Danish residents since April 1, 1968; those data include information on age and sex. All controls were free of cancer prior to the date of interview. The response rate was 64 percent (n = 214). Each control was contacted by mail, and both patients and controls were asked to give written and oral informed consent before the interview was conducted.
Data collection
A computerized personal questionnaire was developed as part of the Interphone Study (18). Face-to-face interviews were conducted by either a research nurse or a specially trained medical student. Subjects were asked whether they had ever used a cellular telephone, and those who had used one were asked whether they were regular users (more than one call per week for 6 months or more) and how many different cell phones they used regularly. For each cell phone used regularly, starting and stopping dates of use were recorded. If the respondent was still using a cell phone on the day of the interview, the stopping date was set at the date of diagnosis (for cases) or the date of diagnosis of the corresponding matched case (for controls).
The questionnaire sought information on numbers of calls made or received, average duration of calls for each cell phone used by the respondent, and changes in the pattern of use over a period of more than 6 months. On the basis of this information, we calculated the lifetime number of calls made and the lifetime number of hours of cell phone use. For each cell phone, we recorded information on use of a handset with a microphone in terms of period of use and proportion of use, as well as use of a hands-free set installed in a vehicle. This information was used to modify the exposure estimate (see below). Furthermore, the interview also contained questions on hearing loss or tinnitus. Finally, information on the educational level of cases and controls and their spouses was obtained during the interview and was used as a proxy for socioeconomic status in the regression analysis.
In all cases, clinical data were used to calculate tumor size from the diameter of the portion of the tumor reaching out of the internal auditory canal (extrameatal proportion) (20) and to characterize the laterality of the tumor.
We obtained information on the socioeconomic status of all of the eligible patients (n = 129) and controls (n = 332), including educational level, marital status, employment, income in the year 2001, and wealth, defined as taxable assets in 2001, from the Integrated Database for Labor Market Research at Statistics Denmark (21). Since this information was provided in an anonymous form, we could not adjust for it in the conditional logistic regression models (see below). Nevertheless, it enabled us to compare the distributions of various socioeconomic characteristics between cases and controls eligible for the study (table 1).
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Statistical analysis
Conditional logistic regression models for data sets matched 1:2 were used to estimate odds ratios and their respective 95 percent confidence intervals (PROC PHREG in SAS, version 8; SAS Institute, Inc., Cary, North Carolina). The odds ratio was used as an estimate of the relative risk. All analyses accounted for educational level (low, intermediate, or high), region of residence (eastern part of Denmark, Fünen, or western part of Denmark), marital status (married vs. single, divorced, or widowed), and use of hands-free devices in vehicles (ever vs. never). Cumulative use of cellular telephones was modified according to the use of hands-free sets, by a factor that varied with the answers given. Thus, we reduced exposure by 100 percent, 75 percent, 50 percent, or 25 percent when respondents reported use of hands-free devices all of the time, most of the time, half of the time, or less than half of the time, respectively. Cumulative use was multiplied by the modification factor for the periods in which hands-free devices were used. The possible association between the laterality of the tumor and self-reported handedness was examined using a method described elsewhere (14). To examine the impact of pre-diagnostic hearing loss on our risk estimates, we also created a regression model with long-term hearing loss and long-term cell phone use included as possibly competing risk factors. Finally, the associations between the degree of participation and the baseline variables were evaluated by means of generalized logistic regression with four outcome categories: case participant, case nonparticipant, control participant, and control nonparticipant.
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RESULTS |
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We did not observe increased risk of acoustic neuroma among regular cell phone users (odds ratio = 0.90, 95 percent confidence interval (CI): 0.51, 1.57) (table 2). In addition, no association was observed between risk of acoustic neuroma and cell phone use with increasing time since first regular exposure (reflecting latency), with increasing amount of use (reflecting dose), or with amount of use during the period 5 or more years before diagnosis (reflecting both latency and dose) (table 2). The risk of acoustic neuroma among regular cell phone users did not differ by sex: The odds ratio was 0.79 (95 percent CI: 0.36, 1.75) for males and 1.05 (95 percent CI: 0.45, 2.47) for females.
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The mean size of the tumors was 1.66 cm3 for regular cell phone users and 1.39 cm3 for nonusers (Wilcoxon test: p = 0.03). The mean size of the tumors of cases who had had a hearing problem for 5 years or more was 1.54 cm3, whereas that of cases with a shorter history or no history of hearing problems was 1.44 cm3 (Wilcoxon test: p = 0.42). The risk of developing a larger acoustic neuroma (with a volume of 1.51 cm3) was 1.87 (95 percent CI: 0.75, 4.64) for regular users of cell phones in comparison with nonusers or rare users. Increasing duration of use did not increase the risk of larger tumors significantly (odds ratios were 1.67 for 14 years of regular cell phone use and 1.44 for 5 or more years of regular use; data not shown).
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DISCUSSION |
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The main result of this study is in line with the majority of epidemiologic findings reported so far (9, 14, 15, 22). In two US case-control studies comprising 96 and 90 cases of acoustic neuroma, respectively, no association was observed between use of cellular telephones and risk of acoustic neuroma (14, 15). Likewise, in our previous cohort study of more than 420,000 Danish cellular telephone subscribers, only seven cases of acoustic neuroma were observed, with 11 cases having been expected (standard incidence ratio = 0.64, 95 percent CI: 0.26, 1.32) (9). In a Swedish case-control study of 159 cases of acoustic neuroma, the authors found a significant association between use of analogue cellular telephones and risk of this type of tumor (odds ratio = 3.5, 95 percent CI: 1.8, 6.6); however, there was no clear trend in the risk estimates by latency period (>1, >5, or >10 years) since first use (23). In an update of this analysis, the risk of acoustic neuroma was found to be significantly increased among persons who had used digital cellular telephones for more than 5 years and among persons who had used cordless telephones for more than 10 years (17). This study (23) has been criticized for several methodological weaknesses, including a high rate of loss of cases due to death, the use of retrospective case ascertainment, possible interviewer bias, and a lack of information on how the controls were approached (24). The other studies had low statistical power to detect moderate risk increases among long-term users (12, 13, 20).
Our study had statistical power of more than 75 percent to detect a doubling in the risk of acoustic neuroma with a latency of 5 or more years. Furthermore, it was a population-based study based on complete, high-quality registers. We used standardized face-to-face interviews, which are superior to self-administered questionnaires in terms of obtaining reliable answers to complex questions and in terms of diminishing recall bias (25, 26). In addition, we observed that cases and controls spent equal amounts of time answering the questions. The individual matched design diminished bias due to the longer exposure of controls, because their exposure was cut off at the date of diagnosis of the corresponding case.
If radio-frequency fields promote cancer, one would expect that cumulative exposure would be associated with tumor size; however, we did not observe this association. It may be argued that persons with poor hearing might have larger tumors and therefore might be discouraged from using a cellular telephone. However, tumor size is not associated with hearing loss (27).
We have no reason to believe that our overall findings are due to selection bias. The information we obtained on socioeconomic factors came from public registers and was established independently of the study hypothesis, thus excluding information bias. In particular, there were no differences in socioeconomic characteristics between participants and nonparticipants among either patients or controls. This is reassuring, because long-term use of cell phones might have been related to higher income or higher education, thus introducing selection bias.
In general, patients with acoustic neuroma do not have memory deficits, so this should not have compromised the quality of the data collected (27). The presence of hearing problems prior to diagnosis might have prevented some cases from becoming regular cell phone users and might have reduced their lifetime calling time. Hence, hearing loss might act as a negative confounder, being positively related to diagnosis of acoustic neuroma and negatively related to use of cell phones. This may partially explain why we observed some decreased odds ratios in our risk analyses and why we found a significant disagreement between tumor laterality and preferred side of cell phone use. Nevertheless, comparison of the risk of acoustic neuroma among long-term users (5 years) who had not developed hearing problems with that among nonusers or rare users gave a odds ratio of 0.96 (95 percent CI: 0.40, 2.26), which is somewhat higher that the overall odds ratio of 0.68 (95 percent CI: 0.32, 1.44) (table 2).
On the basis of these first data from the Interphone Study, we conclude that there is no evidence for an association between use of cellular telephones and the risk of developing acoustic neuroma.
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ACKNOWLEDGMENTS |
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The authors thank Lars H. Thomassen for skillful computer assistance and Gitte Havlide for assistance with preparation of the tables.
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NOTES |
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REFERENCES |
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