手机辐射与脑肿瘤没有必然关系

Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case–control study The INTERPHONE Study Group* 5 Corresponding author. Elisabeth Cardis; CREAL, Doctor Aiguader 88, 08003 Barcelona, Spain. E-mail: ecardis@creal.cat *List of members of this study group is available in the Appendix. Accepted 8 March 2010 Background The rapid increase in mobile telephone use has generated concern about possible health risks related to radiofrequency electromagnet- 10 ic fields from this technology. Methods An interview-based case–control study with 2708 glioma and 2409 meningioma cases and matched controls was conducted in 13 coun- tries using a common protocol. Results A reduced odds ratio (OR) related to ever having been a regular 15 mobile phone user was seen for glioma [OR 0.81; 95% confidence interval (CI) 0.70–0.94] and meningioma (OR 0.79; 95% CI 0.68–0.91), possibly reflecting participation bias or other meth- odological limitations. No elevated OR was observed 510 years after first phone use (glioma: OR 0.98; 95% CI 0.76–1.26; meningi- 20 oma: OR 0.83; 95% CI 0.61–1.14). ORs were <1.0 for all deciles of lifetime number of phone calls and nine deciles of cumulative call time. In the 10th decile of recalled cumulative call time, 51640 h, the OR was 1.40 (95% CI 1.03–1.89) for glioma, and 1.15 (95% CI 0.81–1.62) for meningioma; but there are implausible values of re- 25 ported use in this group. ORs for glioma tended to be greater in the temporal lobe than in other lobes of the brain, but the CIs around the lobe-specific estimates were wide. ORs for glioma tended to be greater in subjects who reported usual phone use on the same side of the head as their tumour than on the opposite side. 30 Conclusions Overall, no increase in risk of glioma or meningioma was observed with use of mobile phones. There were suggestions of an increased risk of glioma at the highest exposure levels, but biases and error prevent a causal interpretation. The possible effects of long-term heavy use of mobile phones require further investigation. 35 Keywords Brain tumours, mobile phones, radiofrequency fields Introduction Mobile phone use has increased dramatically in many countries since its introduction in the early-to-mid 40 1980s. The expanding use of this technology has been accompanied by concerns about health and safety. In the late 1990s, several expert groups critic- ally reviewed the evidence on health effects of low-level exposure to radiofrequency (RF) Published by Oxford University Press on behalf of the International Epidemiological Association � The Author 2010; all rights reserved. International Journal of Epidemiology 2010;1–20 doi:10.1093/ije/dyq079 1 electromagnetic fields, and recommended research into the possible adverse health effects of mobile tel- ephony.1–4 As a result, the International Agency for Research on Cancer (IARC) coordinated a feasibility 5 study in 1998 and 1999, which concluded that an international study of the relationship between mobile phone use and brain tumour risk would be feasible and informative.5,6 INTERPHONE was therefore initiated as an interna- 10 tional set of case–control studies focussing on four types of tumours in tissues that most absorb RF energy emitted by mobile phones: tumours of the brain (glioma and meningioma), acoustic nerve (schwannoma) and parotid gland. The objective was 15 to determine whether mobile phone use increases the risk of these tumours and, specifically, whether RF energy emitted by mobile phones is tumourigenic. This article presents the results of analyses of brain tumour risk in relation to mobile phone use in all 20 INTERPHONE study centres combined. Analyses of brain tumours in relation to mobile phone use have been reported from a number of cohort7–9 and case– control studies, including several of the national com- ponents of INTERPHONE.10–25 No studies, however, 25 have included as many exposed cases, particularly long-term and heavy users of mobile phones, as this study. Methods Study design 30 The INTERPHONE study is an international, largely population-based case–control study. The common core study protocol is described in detail elsewhere.5,26 Sixteen study centres from 13 countries (Australia, Canada, Denmark, Finland, France, Germany, Israel, 35 Italy, Japan, New Zealand, Norway, Sweden and the UK) were included. To maximize statistical power, the INTERPHONE study focussed on tumours in younger people, 30–59 years of age, as they were expected to have had the highest prevalence of mobile phone use 40 in the previous 5–10 years, and on regions likely to have the longest and highest use of mobile phones (mainly large urban areas). Eligible cases were all patients with a glioma or meningioma of the brain diagnosed in the study re- 45 gions during study periods of 2–4 years between 2000 and 2004. Cases were ascertained from all neuro- logical and neurosurgical facilities in the study re- gions (except in Paris and Tokyo where some did not agree to participate), and in some centres also 50 from cancer registries. All diagnoses were histologi- cally confirmed or based on unequivocal diagnostic imaging. To facilitate interviews soon after diagnosis, cases were ascertained actively within treatment facil- ities wherever possible. Completeness of ascertain- 55 ment was checked through secondary sources, such as population- or hospital-based cancer registries, medical archives and hospital discharge or billing files.26 One control was selected for each case from a locally 60appropriate population-based sampling frame, except in Germany where two controls were chosen. The sampling procedure involved individual matching in seven centres (Canada – Ottawa, Canada – Vancouver, France, Israel, Japan, New Zealand and UK North) 65and frequency matching elsewhere. The matching variables were age (within 5 years), sex and region of residence within each study centre. In Israel, the subjects were also matched on ethnic origin. Where stratified matching had been used, individual match- 70ing was conducted post hoc, with cases being assigned one control (two in Germany), interviewed as close as possible in time to the case, from those who fitted the matching criteria. Detailed information on past mobile phone use was 75collected during face-to-face interviews with the study subject, or a proxy, if the subject had ever been a regular user of a mobile phone (had an average of at least one call per week for a period of 56 months).26 A proxy was sought when the study 80subject had died or was too ill to be interviewed. The interviews were conducted by a trained interviewer using a computer-assisted questionnaire, except in Finland where a paper version was used. The ques- tionnaire also included sections on socio-demographic 85factors, occupational exposure to electromagnetic fields and ionizing radiation, medical history (sub- ject’s and family), medical ionizing and non-ionizing radiation exposure and smoking. For cases, informa- tion was also collected on the anatomic location 90and histological type of the tumours. Where possible, location data were obtained from magnetic resonance imaging (MRI) reports or images; they were otherwise obtained from surgical records or clinical notes. Details of the specific source for each case were not 95recorded in the INTERPHONE database. Those collect- ing the data did not know the reported mobile phone use of individual cases. Statistical methods Data from countries with multiple centres were com- 100bined for the analyses, except in the UK where the UK South and UK North, each with large numbers of subjects, were kept separate. The word ‘centre’ in the remainder of this article is used to refer to the 14 analytic entities (12 countries, UK North and UK 105South). All analyses were carried out for all centres combined and for each centre separately. Formal tests for heterogeneity of risk across centres were con- ducted by allowing for an interaction between centre and the exposure variables. 110The analyses presented here focus on past mobile phone use as reported by or for the study subjects. The main analyses were based on conditional logistic regression for matched sets.27 The date of diagnosis of the case was used as the reference date for cases and 2 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY controls in each matched set. For the main analyses, the reference category for odds ratios (ORs) was the set of subjects who reported that they had never been regular users. Exposure variables included ever having 5 been a regular user (as defined above), time (years) since first regular use, cumulative number of calls and cumulative duration of calls. To allow for a latency period of 1 year, the year before the reference date was included in the reference category for time since 10 first regular use and all other exposure variables were censored at 1 year before the reference date. Cumulative number and duration of calls were ana- lysed as categorical variables, based on deciles of the distribution of these variables among all controls who 15 were regular users, including those matched to pa- tients with an acoustic neuroma or a parotid gland tumour, so that the same cut-off points are used in all analyses.26 Cumulative use excluded use of mobile phones with hands-free devices: for all time periods 20 for which the subject reported the use of hands-free devices the amount of use was reduced by 100, 75, 50 or 25% depending on whether hands-free devices were used always or almost always, more than half, about half or less than half of the time, respectively. 25 For ease of presentation, some results are shown for the following grouping of deciles: 1, 2–5, 6–7, 8–9 and 10, chosen post hoc to reflect the spread of the highly skewed distribution of these variables. For conveni- ence, we will systematically use the term ‘regular 30 user’ in text and tables to refer to ever having been a regular user. The reference group for these analyses, never regular users, included people who had some mobile phone use but never as much as one call a week on average 35 for 56 months (�32% of meningioma and 26% of glioma cases, and 30% of meningioma and 26% of glioma controls) and people who had never used a mobile phone (�11% of meningioma and 9% of glioma cases, and 8% of meningioma and 6% of 40 glioma controls). These percentages are approximate because never use and never regular use were defined at different dates; the reference date and the date of interview, respectively. We are not able to determine whether inclusion of subjects with some occasional 45 mobile phone use in the reference group had a ma- terial effect on our results because this difference in definition dates prevented us from distinguishing par- ticipants with only occasional use from those with no use at all at their reference dates. Moreover, because 50 numbers of never users at the date of interview were small, particularly in certain age- and gender-specific sub-groups (such as young men), never users were not a suitable reference group for this analysis. All analyses were adjusted for educational level; an 55 a priori decision had been made to adjust for it as a surrogate for socio-economic status (SES). Creation of consistent educational levels across the 13 countries is described elsewhere.26 In practice, this adjustment had little impact on OR estimates, changing their 60values by 42% in most instances and in all cases by <5%. Using a 10% change-in-estimate criterion for confounding,28 no other covariate among those collected (see list above) was included in the main analyses. The interval between the start date of inter- 65views in the study centre and the date of each sub- ject’s interview was modelled by fitting the interaction of this interval with study centre. A common protocol was applied to impute missing data for cases and controls.26 The study questionnaire 70allowed ranges to be given instead of exact answers to a number of questions, including number and dur- ation of calls and dates of start and end of mobile phone use; in such instances, the main analyses in this article were based on the mid-point of the re- 75ported range. Because absorption of RF energy from mobile phones is highly localized,29 three different types of analyses were conducted to account for tumour loca- tion. First, analyses were conducted by the anatomical 80lobe of the brain in which the tumour occurred. Secondly, separate analyses were conducted for the subjects who reported using the mobile phone mainly on one or the other side of the head, and the preferred side was compared with the side on 85which the tumour occurred. For this, each control was assigned the location of the tumour of his or her matched case. Exposure was considered to be ip- silateral if the phone was used predominantly on the same side as the tumour or on both sides of the head, 90and contralateral if used mainly on the side of the head opposite to the tumour. Laterality was not as- signed if the tumour was reported to be centrally located (i.e. it crossed the midline of the brain); these cases were excluded from laterality analyses. 95Thirdly, case–case analyses were carried out on the concordance between tumour side and laterality of phone use using the method proposed by Inskip and collaborators.18 Sensitivity analyses 100To complement these primary analyses, we undertook sensitivity analyses to try to determine whether any of the following might have biased the results: (i) any study centre; (ii) required mention of mobile phones in the introductory letter to subjects in some centres; 105(iii) centres with a hospital-based design or particu- larly low participation rates; (iv) respondents whose interviews were considered by the interviewer to be of poor quality; (v) subjects for whom proxies provided the responses or a telephone interview was given; (vi) 110interviewers who had little experience or who had unbalanced case to control workloads; (vii) difference between the interview dates of cases and their matched controls (on average, each control was inter- viewed 3 months later than its matched case26 and 115mobile phone use was increasing rapidly during the study period); (viii) subject’s choice between two ways of responding to call time questions (time per INTERPHONE INTERNATIONAL CASE–CONTROL STUDY 3 day, week or month, or time per call); (ix) subjects who reported implausibly high amounts of mobile phone use (by excluding them or by retaining them and truncating their use at a specific lower value 5 when they reported a higher one); (x) method of calculating accumulated call time; (xi) use of match- ing and conditional analysis; (xii) the choice of a par- ticular imputation algorithm; and (xiii) adjustment for possible confounders. 10 Results During the study period, 3115 meningioma and 4301 glioma cases, and 14 354 potential controls were iden- tified. Interviews were completed with 2425 meningi- oma cases (78%; range 56–92%), 2765 glioma cases 15 (64% participation; range by centre 36–92%) and 7658 controls (53%; range 42–74%; Appendix 1, Table 1, Supplementary data are available at IJE online). The most common reasons for non- participation were subject refusal (11% of men- 20 ingiomas, 11% of glioma cases and 30% of controls); illness, death or physician refusal (4% of meningi- omas, 20% of gliomas and 1% of controls); and inabil- ity to contact the subject (7% of meningiomas, 5% of gliomas and 15% of controls). 25 The main analyses, based on matched sets only, included 2409 meningioma cases with 2662 matched controls and 2708 glioma cases with 2972 matched controls. Among meningioma cases, 24% were men and 76% women; among glioma cases, 60% were 30 men and 40% women (Table 1). Although the median age of meningioma cases was only slightly older than that of glioma cases (51 and 49 years, re- spectively), 23% of glioma cases were diagnosed before the age of 40, compared with 13% of meningi- 35 oma cases. The proportion of proxy interviews was higher in glioma cases (13%) than in controls (1%) or meningi- oma cases (2%). Whereas 17% of glioma cases who were regular users had imputations because of miss- 40 ing information in at least one of their mobile phone-related variables, the corresponding fractions were 9% among regular user meningioma cases and 8% among regular user controls. The proportion of subjects who answered questions about mobile 45 phone use by giving a range of values rather than a particular amount of use (for any of the use dimen- sions) was very similar (�42%) for meningioma cases, glioma cases and controls. The prevalence of regular mobile phone use 1 year 50 before the reference date was 52% for meningioma cases (ranging from 34 to 73% across study centres) and 56% in matched controls (35–78%). It was higher for glioma cases (62% overall, range: 42–80%) and controls (64% overall, range: 45–84%), reflecting the 55 different sex distributions of these tumours. The majority of subjects in the study were not heavy mobile phone users; the median lifetime cumulative call time among meningioma controls using mobile phones was �75 h, with a median call time of 60�2 h/month and a median lifetime number of calls about 1500. Corresponding values for glioma controls were �100 h lifetime, 2.5 h/month and about 2000 calls. The distributions of time since start of mobile phone use and cumulative call time were highly 65skewed, with few long-term and heavy users, and varied across study centres and by age and sex (not shown). Relation between mobile phone use and risk of brain tumours 70Meningioma A reduced OR of meningioma was found for regular mobile phone use in the past 51 year, OR 0.79 [95% confidence interval (CI) 0.68–0.91; Table 2]. There was some suggestion of heterogeneity of risk across 75centres (P¼ 0.08) with ORs <1.0 except in Canada, Denmark, Germany and Italy (data not shown). ORs were <1.0 for regular users in all categories of time since start of use and cumulative number of calls. Analyses by cumulative call time showed ORs <1.0 80in the first nine deciles and an OR of 1.15 (95% CI 0.81–1.62) in the highest decile. Analyses of cumula- tive call time among recent-, medium- and long-term users (Table 3) showed no indication of excess risk except in the highest call time category in those who 85started phone use 1–4 years before the reference date: OR 4.80 (95% CI 1.49–15.4). There was no appreciable effect modification by age or sex on any of these results (data not shown). In analyses by anatomical location of the meningi- 90oma, the OR for temporal lobe tumours with regular use was 0.55 (95% CI 0.36–0.82) and the ORs were <1.0 in all categories of time since start of use, cu- mulative call time and cumulative number of calls. ORs for other lobes were also mostly <1.0 (Table 4). 95The OR for mainly ipsilateral use among regular users was 0.86 (95% CI 0.69–1.08), and that for contralateral use was 0.59 (95% CI 0.46–0.76; Table 5). The ORs by time since start of use were <1.0 in all categories of ipsilateral and contralateral 100use. When analysing by any of the exposure metrics in Table 5, the ratios of the ORs for ipsilateral use to contralateral use were always one or above one regardless of level of exposure and they were highest (�2 or 3) for the two highest categories of cumulative 105call time and the second highest category of cumula- tive number of calls. A case–case analysis, based on Inskip’s method, showed an OR of 1.07 (95% CI 1.00– 1.16; Appendix 1, Table 2, Supplementary data are available at IJE online) for ipsilateral use. 110The OR for those who reported regular use of only an analogue phone was 0.81 (95% CI 0.65–1.03) and for only a digital phone it was 0.79 (95% CI 0.68– 0.92). Focussing on the highest decile of cumulativ