Mobile phone use, exposure to radiofrequency = electromagnetic field, and brain tumour: a casecontrol study

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Epidemiology

British Journal of Cancer (2008) = 98,=20 652-659.
doi:10.1038/sj.bjc.6604214 = http://www.bjcancer.com/ = Published=20 online 5 February 2008

Mobile phone=20 use, exposure to radiofrequency electromagnetic field, and brain = tumour: a=20 case-control study

T Takebayashi¹, N = Varsier^2,3, Y=20 Kikuchi¹, K Wake³, M Taki², S=20 Watanabe³, S Akiba⁴ and N=20 Yamaguchi⁵

¹Department of Preventive Medicine = and Public=20 Health, Keio University School of Medicine, Tokyo,=20 Japan

²Department = of=20 Electrical and Electronic Engineering, Tokyo Metropolitan = University,=20 Tokyo, Japan

³EMC = Group,=20 Applied Electromagnetic Engineering, National Institute of = Information and=20 Communications Technology, Tokyo, Japan

⁴Department of Epidemiology and = Preventive=20 Medicine, Kagoshima University Graduate School of Medical and = Dental=20 Sciences, Kagoshima, Kagoshima

⁵Department of Public Health, Tokyo = Women's=20 Medical University, Tokyo 162-8666, = Japan

3D""=20

Correspondence to: Dr N Yamaguchi, E-mail: yamaguch@research.twmu.ac.jp=

Received=20 17 September 2007; revised 19 December 2007; accepted 4 January = 2008;=20 published online 5 February 2008

3D""=20

In a case-control study in Japan of brain tumours in = relation to=20 mobile phone use, we used a novel approach for estimating the = specific=20 absorption rate (SAR) inside the tumour, taking account of spatial = relationships between tumour localisation and intracranial = radiofrequency=20 distribution. Personal interviews were carried out with 88 = patients with=20 glioma, 132 with meningioma, and 102 with pituitary adenoma (322 = cases in=20 total), and with 683 individually matched controls. All maximal = SAR values=20 were below 0.1 W kg^-1, far lower than the level at = which=20 thermal effects may occur, the adjusted odds ratios (ORs) for = regular=20 mobile phone users being 1.22 (95% confidence interval (CI): = 0.63-2.37) for glioma and 0.70 (0.42-1.16) for meningioma. When the maximal SAR = value=20 inside the tumour tissue was accounted for in the exposure = indices, the=20 overall OR was again not increased and there was no significant = trend=20 towards an increasing OR in relation to SAR-derived exposure = indices. A=20 non-significant increase in OR among glioma patients in the = heavily=20 exposed group may reflect recall bias.

Keywords: glioma; meningioma; mobile = phone;=20 case-control study;=20 epidemiology

3D""=20

The rapid increase in mobile phone use has raised = public=20 concern about their safety (Rothman=20 et al, 1996; Violanti=20 and Marshall, 1996; Repacholi,=20 1998; Blettner=20 and Berg, 2000; Rothman,=20 2000). Since only glial and meningial tissue close to the = surface of=20 the head is exposed to relatively high electromagnetic fields = (EMFs)=20 emitted from mobile phones, brain tumours, especially glioma and=20 meningioma, have received particular attention, along with = acoustic=20 neurinoma and salivary gland tumours. To investigate whether = mobile phone=20 users have an increased risk for these tumours, a collaborative = case-control study in 13 countries, the = INTERPHONE study,=20 was initiated in 2000, coordinated by the International Agency for = Research on Cancer (IARC) and is still underway (Cardis=20 and Kilkenny, 1999; Christensen=20 et al, 2005; L=F6nn=20 et al, 2005; Hepworth=20 et al, 2006; Schuz=20 et al, 2006; Takebayashi=20 et al, 2006; Cardis=20 et al, 2007; Hours=20 et al, 2007). Some national reports are already = published, with=20 mixed findings.

A central = issue has=20 been how precisely to estimate the actual EMF exposure, given the=20 necessary reliance on self-reported use. Different parts of the = brain are=20 known to be exposed to EMFs of different magnitudes, related not = only to=20 which ear the phone is placed on, but also to the characteristics = of=20 different mobile phone models. The specific absorption rate (SAR) = is=20 widely accepted as a dosimetric quantity in guidelines on EMF = exposure=20 (e.g., the International=20 Commission on Non-Ionizing Radiation Protection (ICNIRP), = 1998) in=20 frequency ranges including those used for mobile phones. The SAR,=20 representing absorbed radiofrequency (RF) power per unit mass of = body=20 tissue, is closely related to thermal effects. If non-thermal = effects are=20 involved, SAR is also relevant, being as it is closely correlated = with=20 internal electric and magnetic fields in tissue near the radiation = source=20 (Mochizuki=20 et al, 2002).

We = have=20 investigated whether mobile phone use increased brain tumour risk = in=20 Japan. The study followed the common, core protocol of the = INTERPHONE=20 study, but for estimating RF exposure level in different areas of = the=20 brain in light of its great variability, we adopted a new approach = using a=20 heterogeneous head model (Japanese numerical TARO model's head) = (Nagaoka=20 et al, 2004).

3D""=20

METHODS

The study area encompassed Tokyo, consisting of = 23 wards=20 (the metropolitan area) and 14 cities (the municipal area), along = with 25=20 adjacent cities. In a preliminary survey, it was found that 30 of = the 172=20 hospital neurosurgery departments in Tokyo treated approximately = 90% of=20 brain tumours in the area. Of these 30 departments, 21 agreed to=20 participate in the study, and so it was estimated that about 75% = of the=20 meningioma and glioma cases in the study area would be covered. = There were=20 no differences in patients' socioeconomic status between = participating and=20 non-participating hospitals. The case group consisted of newly = diagnosed=20 meningiomas, gliomas, and pituitary adenomas at ages 30-69 years treated in participating hospitals, = with case=20 recruitment performed prospectively from December 2000 to November = 2004.=20 Participation was 58.7% (88 out of 150) for glioma, 77.6% (132 out = of 170)=20 for meningioma, and 75.6% (102 out of 135) for pituitary adenoma. = The main=20 reason for non-participation was failure to contact the patients; = for=20 example, only 5% of glioma eligible patients refused, whereas the = rest=20 (37%) were not informed of the study during their hospital stay by = their=20 attending physicians. The 10 cases found to have been diagnosed = before=20 June 2000, more than 6 months before the study began, were = excluded from=20 the analysis (with their controls) leaving 83 gliomas, 128 = meningiomas,=20 and 101 pituitary adenomas. Cases treated surgically were verified = histopathologically (codes of ICD-O 3rd ed.: glioma, 9380-9384, 9390-9394, = 9400-9401, 9410-9411, = 9420-9424, 9430, 9440-9443,=20 9450-9451, 9460, 9480-9481; meningioma, 9530-9539),=20 but some were diagnosed by magnetic resonance imaging. Among the = 83=20 gliomas and 128 meningiomas, 78 (94%) and 118 (92.2%), = respectively,=20 underwent surgery. The date of diagnosis was defined as when the = tumour=20 was first identified radiologically.

Controls were selected from the general = population by=20 random digit dialling, in which phone numbers for home = fixed-phones were=20 generated randomly. Volunteers to act as controls were sought = until at=20 least one for each case was identified who agreed to participate; = they=20 were individually matched for age (within a 5-year range), sex, = and=20 residence with the cases. Participation among contacted controls = was 52.5%=20 (196 out of 373) for glioma, 51.6% (279 out of 541) for = meningioma, and=20 49.4% (208 out of 421) for pituitary adenoma. A brief = questionnaire was=20 administered over the phone or via a self-administered paper = questionnaire=20 to those who did not agree to face-to-face interviews, to compare = phone=20 use between participants and non-participants among eligible = controls.=20 Basic information on age, sex, brief history of mobile phone use, = and some=20 life-style factors was available for 75.6, 73.0, and 72.0% of the = control=20 for glioma, meningioma, and pituitary cases,=20 respectively.

Each case = subject and=20 matched control was interviewed by the same nurse or other health=20 professional specifically trained for this study. A Japanese = version of=20 the computer-assisted interview system developed for the = INTERPHONE study=20 was used for the face-to-face interviews (Cardis=20 and Kilkenny, 1999). Subjects were asked about their mobile = phone use,=20 including the dates of starting and stopping to use each phone, = the=20 average duration and frequency of calls, and other usage patterns = in=20 chronological order. Use of the Personal Handy-phone System (PHS), = a type=20 of cordless telephone system, was also recorded. Demographic = variables,=20 medical history, and occupational history were also recorded. = Clinical=20 information on the cases was obtained from the relevant=20 department.

When a case had = over four=20 matched controls, the latter was reduced randomly to make a 4 : 1 = ratio=20 for each case. Thus, 83 gliomas had 163 matched controls, 128 = meningiomas=20 had 229 controls, and 101 pituitary adenomas had 161=20 controls.

Regular mobile = phone use was=20 defined as used at least once a week for 6 months, and the = reference date=20 for phone use was set at one year before diagnosis for each case = to=20 eliminate any effect of disease in its prodromal stage; the same = date=20 being applied to matched controls. Furthermore, for regular phone = users,=20 two indices were created: cumulative length of use and cumulative = call=20 time, the former defined as the time (years) since first use, = excluding=20 any period when it was not regularly used. For recent use, either = the=20 reference date or the stop date of the last phone, whichever came = first,=20 was adopted as the end of use date. The cumulative call time was = the total=20 call durations (hours) since first use, which was the sum of call=20 durations with all phones. Typically, the daily call duration was=20 calculated by multiplying the average call duration per call by = the number=20 of calls per day, the call duration for each phone being the = product of=20 the daily call duration and the length of use.

An odds ratio (OR), in which the reference = category was the=20 non-user, unless otherwise specified, was calculated with the = conditional=20 logistic regression model, in which the educational level (junior = high=20 school, high school, 2-year college, 4-year college or graduate = school)=20 and marital status (married or others) were simultaneously = adjusted for as=20 categorical variables.

To = examine for=20 an association with laterality of phone use, we employed a = conditional=20 logistic regression analysis, in which EMF exposure was assumed = only when=20 the self-reported side of phone use was the same as the tumour's=20 (ipsilateral use). A similar analysis was performed for = contralateral use,=20 with exposure assumed when the self-reported side of phone use was = the=20 opposite of the tumour's. If both ears were reported used for = phone use,=20 exposure was assumed for both analyses.

To account for the three-dimensional, spatial = relationship=20 between tumour and RF exposure distribution, we attempted to = estimate the=20 maximal SAR value inside the tumour. Since pituitary adenomas = occur in the=20 sellar region, where RF exposure is negligible, SAR was estimated = only for=20 gliomas and meningiomas as follows. Mobile phones were categorised = into a=20 small number of groups in terms of SAR distribution (Wake=20 et al, 2006), since each phone model has a different=20 intracranial SAR distribution and it is impossible to estimate the = actual=20 SAR distributions for the hundreds of mobile phones used by the = cases and=20 controls. We used the SAR distribution data from 76 phones on the = Japanese=20 market in January 2001 measured with a phantom using standard = procedure=20 for compliance testing in Japan similar to the international = standard=20 procedure (IEC 62209). Surface SAR was measured in a limited = region near=20 the phone, and cube SAR data was measured in a small = three-dimensional=20 region around the maximal SAR location. The cluster analysis was = then=20 applied to categorise the phones, in which SAR distributions were=20 represented by location of maximal SAR, surface area larger than = 50% of=20 the maximal SAR, or depth larger than 50% of the maximal SAR. The = results=20 of categorisation depended on the conditions of phone use. Mobile = phones=20 could be classified into four categories assuming normal use = condition as=20 cheek position with antenna extracted: (1) flip/flop phones of both 800-MHz and 1.5-GHz band = with an=20 antenna in the centre; (2) flip/flop = phones of=20 800-MHz band with an antenna on the top; (3) 1.5-GHz band phones = with an=20 antenna on top; and (4) straight phones of 800-MHz band with an = antenna on=20 top. On the basis of this finding, a hypothetical = three-dimensional SAR=20 distribution was constructed for each category of mobile phone on = the=20 above head model, Japanese numerical TARO model's head (Nagaoka=20 et al, 2004). First, we estimated three-dimensional SAR = distribution for each phone in TARO model's head with the measured = SAR=20 data (Wake=20 et al, 2005). The surface SAR data measured in the = limited=20 regions of the phantom was extrapolated to its whole head, and was = further=20 projected to the surface of TARO model's head. Then, SAR in depth=20 direction was estimated assuming exponential decay of the first = three=20 layers. Finally, SAR distribution for each phone category was = obtained by=20 averaging SAR distributions for all phones belonging to the = category (Varsier=20 et al, 2007).

Each = mobile=20 phone actually used was allocated to one of four categories and = the=20 hypothetical SAR distribution assigned, taking into account which = ear was=20 in contact (Varsier=20 et al, 2007). The tumour location for each case was = measured on=20 a 12 computed tomography scan-cut chart model. Because of their=20 differences, the TARO's head was transformed to match the chart = model by=20 projection. Then the SAR value inside the tumour was estimated at = a 1-cm=20 resolution and the maximal SAR was identified for each phone. For = matched=20 controls, the maximal SAR value was estimated for the tumour = location of=20 the corresponding cases.

Three exposure=20 indices were constructed based on the SAR distribution inside the = tumour.=20 The mean maximal SAR (mean maxSAR) was calculated for each subject = by=20 averaging the maximal SAR value over the mobile phone used by the = subject.=20 The cumulative maxSAR-year was defined as the cumulative years of = use=20 weighted by maxSAR, or calculated by summing the product of maxSAR = and=20 length of use in years for each phone over the different mobile = phones=20 used by each subject. The cumulative maxSAR-hour was defined as = the=20 cumulative call time weighted by maxSAR, or calculated by summing = the=20 product of the maxSAR and call time in hours for each phone over = the=20 different mobile phones used by each subject.

In a case-only analysis, the mean maxSAR, = cumulative=20 maxSAR-year, and cumulative maxSAR-hour were estimated for the = actual and=20 for a hypothetical tumour location, which was the mirror image of = the=20 tumour on the opposite side across the sagittal plane. The = rationale was=20 that the above SAR indices should have a higher value for the = actual than=20 for the hypothetical tumour location if RF exposure increased = tumour risk.=20 Each of the three indices was dichotomised into high and low = values using=20 the median distribution among the controls as the cut-off point: = 0.0012=20 (glioma) and 0.0011 (meningioma) for average maxSAR; 0.0059 = (glioma) and=20 0.0041 (meningioma) for cumulative maxSAR-year; and 0.447 (glioma) = and=20 0.146 (meningioma) for cumulative maxSAR-hour; the McNemar test = was used=20 for comparisons.

Statistical = analyses=20 used STATA/SE version 8.2 (College = Station,=20 StataCorp, TX, USA). All statistical tests were two-sided; = separate=20 analyses were performed including and excluding the PHS system, = which has=20 a much lower emission power than mobile telephones, and as the = results=20 showed no substantial differences (data not shown), those analyses = excluding the PHS system are presented here.

This study was approved by the Institutional = Review Boards=20 of the participating institutes. Its protocol was reviewed by the = research=20 group's Privacy Protection Subcommittee, which also monitored the=20 procedures employed.

3D""=20

RESULTS

The basic characteristics of the cases and = controls are=20 shown in Table=20 1. For time-varying items, the situations at the reference = date are=20 displayed. Cases and controls showed no substantial differences = with=20 respect to age, sex, residential area, educational level, or = marital=20 status. Educational level and marital status were considered to = reflect=20 their socioeconomic status and were selected a priori as=20 confounding variables. The overall participation rate of the = controls in=20 the full study was 51.2%, but an additional 28.8% of eligible = controls=20 answered the brief survey about their mobile phone use. The age- = and=20 sex-adjusted proportions of regular users were 66.4% (glioma) and = 55.1%=20 (meningioma) in the brief survey, and were comparable with 65% = (glioma)=20 and 51.5% (meningioma) in the full study.

Table 1
Case-control comparison of basic = characteristics at=20 reference date

The adjusted OR (95% confidence interval (CI)) = for regular=20 mobile phone use was 1.22 (0.63-2.37) = for glioma,=20 0.70 (0.42-1.16) for meningioma, and = 0.90=20 (0.50-1.61) for pituitary adenoma, the = reference=20 date being set at 1 year before diagnosis (Table=20 2). The adjusted OR did not change significantly when the = reference=20 date was set at 5 years before diagnosis: 0.90 (0.47-1.72) for glioma, 1.32 (0.72-2.43) for meningioma, and 0.96 (0.52-1.79) for pituitary adenoma.

Table 2
Case-control comparison of the indices of = mobile=20 phone use

When cumulative length of use and call time were=20 categorised into quartiles according to distribution among the = controls=20 for each tumour type, as shown in Table=20 2, no increasing trend was found in risks of glioma, = meningioma, or=20 pituitary adenoma. In addition, the OR for a cumulative use of 10 = years or=20 longer was 0.58 (0.09-3.86) for glioma, = 1.35=20 (0.31-5.93) for meningioma, and 1.15 = (0.22-5.18) for pituitary adenoma, although the = numbers were=20 very small: 2 cases and 6 controls for glioma; 4 cases and 4 = controls for=20 meningioma; and 4 cases and 5 controls for pituitary adenoma. The = OR for a=20 cumulative call time of 2000 h or more was 1.47 (0.41-5.28) for glioma, 0.64 (0.14-3.86) for meningioma, and 1.41 (0.46-4.37) for pituitary adenoma, again on the = basis of=20 very small numbers: 6 cases and 9 controls for glioma; 3 cases and = 6=20 controls for meningioma; and 9 cases and 12 controls for pituitary = adenoma.

No subject had used=20 analogue-type phones alone. No difference in OR was identified for = use of=20 both analogue and digital phones vs digital phones only: = 0.83=20 (0.23-3.00) vs 1.29 (0.66-2.53) for glioma; 1.06 (0.36-3.09) vs 0.67 (0.40-1.13) for meningioma; and 0.54 (0.17-1.75) vs 0.95 (0.53-1.71) for pituitary adenoma,=20 respectively.

In the = laterality=20 analysis, in which it was simply assumed that exposure existed = when the=20 tumour location (left or right) matched that for phone use, the = ORs for=20 ipsilateral and contralateral use were 1.24 (0.67-2.29) and 1.08 (0.57-2.03)=20 for glioma, and 1.14 (0.65-2.01) and = 0.65=20 (0.37-1.13) for meningioma,=20 respectively.

For the = analysis using=20 maxSAR-derived exposure indices, 77 of 83 glioma cases and 125 of = 128=20 meningioma cases with tumour location charts available, with 151 = and 221=20 controls, respectively, were included. Mean maxSAR was estimated = for each=20 case, ranging from 1.2 =B4 = 10^-6 to=20 0.0599 W kg^-1 for glioma and 6.8 =B4=20 10^-7 to 0.0619 W kg^-1 for meningioma (Figure=20 1). The distribution of cumulative maxSAR-year and cumulative=20 maxSAR-hour are also presented in Figure=20 1. The non-exposed group consisted of non-users and regular = users=20 whose mean maxSAR was extremely low (less than 1 =B4 10^-4): 34 (44.2%) cases and 71 = (47.0%)=20 controls for glioma, and 81 (64.8%) cases and 127 (75.5%) controls = for=20 meningioma. The OR for exposed to non-exposed was 1.28 (0.63-2.57) for glioma and 0.72 (0.42-1.24) for meningioma. In addition, the = exposed group=20 was divided into four subgroups on the basis of the quartiles of=20 distribution of maxSAR-derived indices among the controls. No = increasing=20 trend was found for either glioma or meningioma risk with an = increase in=20 mean maxSAR, cumulative maxSAR-year, or cumulative maxSAR-hour (Table=20 3).

Figure 1
Distribution=20 of estimated maxSAR-derived exposure indices in the tumour.=20 (A) Glioma; (a) mean maxSAR; (b) cumulative = maxSAR-year; (c)=20 cumulative maxSAR-hour. (B) Meningioma; (a) mean = maxSAR; (b)=20 cumulative maxSAR-year; (c) cumulative=20 maxSAR-hour.

Table 3
Risk of brain=20 tumour with relation to mobile phone use, considering = estimated=20 maximal SAR in the tumour as an exposure=20 index

Since=20 the ORs for the highest quartile were all higher than unity for = glioma=20 (1.04 (0.37-2.93) for mean maxSAR, 1.75 = (0.63-4.85) for cumulative maxSAR-year, = and 1.55=20 (0.57-4.19) for cumulative = maxSAR-hour), we=20 further examined risk associated with a very high exposure. When=20 categorised by cut-off points of 0.001 and 0.01 W kg^-1, = the=20 adjusted OR for those with mean maxSAR over 0.01 W kg^-1 = as=20 compared with the non-exposed was 0.87 (0.28-2.75) for glioma and 1.17 (0.40-3.39) for meningioma, indicating no = substantial=20 increase in risk. When categorised by cut-off points of 0.001, = 0.01, and=20 0.1 W kg^-1-year, the adjusted OR for those with = cumulative=20 maxSAR-year over 0.1 W kg^-1-year as compared with the=20 non-exposed was 0.63 (0.14-2.93) for = glioma and=20 2.72 (0.47-15.98) for meningioma, again = indicating no substantial increase in risk. When categorised by = cut-off=20 points of 0.1, 1, and 10 W kg^-1-hour, on the other = hand, the=20 adjusted OR for the highest vs lowest category increased, = although=20 not significantly, to 5.84 (0.96-35.60) for glioma, on the basis = of 7=20 cases (9.1%) and 4 controls (2.7%) in the highest category. No = increase in=20 risk was found for meningioma: 1.14 (0.28-4.61),=20 on the basis of 4 cases (3.2%) and 6 controls = (2.7%).

In the case-only analysis, no differences were = identified=20 when three dichotomised maxSAR-derived indices were compared = between the=20 actual and hypothetical opposite tumour location (as shown in Table=20 4).

Table 4
Case-only=20 analysis to compare the distribution of maximal SAR-related = indices=20 within the tumour and its axis-symmetrical=20 location

DISCUSSION

No consistent increase was observed in the = overall risk of=20 glioma or meningioma among mobile phone users, nor increasing = trend in=20 risk in relation to cumulative length of use or cumulative call = time. We=20 further estimated the SAR in the intracranial space with a = resolution of 1=20 cm³, and constructed three SAR-derived exposure indices = (mean=20 maxSAR, cumulative maxSAR-year, and cumulative maxSAR-hour) to = estimate=20 the cumulative exposure level inside the tumour as precisely as = possible.=20 Again, no substantial increase in risk was observed for glioma or=20 meningioma. Maximal SAR inside the tumour was estimated to be = lower than=20 0.1 W kg^-1 in all eligible cases, far below the = ICNIRP's=20 recommended value of 2 W kg^-1 for localised SAR (head = and=20 trunk) in the general population.

This=20 is to our knowledge, the first epidemiological study to take into = account=20 the different exposure levels inside the intracranial space. = Exposure is=20 localised close to the relevant ear, whereas glioma and meningioma = develop=20 at a variety of sites. Estimation of the actual exposure level = inside the=20 tumour is essential, therefore, to avoid exposure = misclassification, which=20 bias risk estimates towards the null. Nevertheless, recall bias is = a=20 possibility and awareness of tumour location among the cases might = have=20 affected their recall concerning which ear they used for mobile = phone=20 calls. The non-significant increase in OR of 5.84 for those with=20 cumulative maxSAR-hour over 10 W kg^-1-hour as compared = with the=20 non-exposed group could reflect recall bias, since increased OR = was=20 observed only for this heavily exposed group; it needs to be = interpreted=20 with caution.

We masked the = study's=20 purpose during recruitment, since this could have affected = participation=20 differentially among cases and controls, with consequently a = biased risk=20 estimate. During the random digit dialling control selection, we = tried to=20 ensure that this did not vary between those who were regularly at = home and=20 those who were out more often: mobile phone users tend to be more = active=20 and busier, staying at home for shorter periods than non-users, = and risk=20 could be overestimated if controls included an unbalanced number = of=20 non-users. Although participation among controls in the full = interview=20 remained around 50%, we were able to examine its impact on risk = estimates=20 by using the information obtained from the brief questionnaire = completed=20 by non-participating controls. The age- and sex-adjusted = proportions of=20 regular mobile phone users among the control candidates who did = not=20 participate in the full interview but agreed to respond to the = brief=20 questionnaire (28.8% of eligible controls) were 66.4% (glioma) and = 55.1%=20 (meningioma) as compared with 65.0% (glioma) and 51.5% = (meningioma) for=20 the controls who participated in the full, face-to-face interview = (51.2%=20 of eligible controls), respectively, indicating that the = interviewed=20 controls did not constitute a biased sample in terms of mobile = phone use.=20 Adjusted ORs for regular mobile phone users did not vary = significantly,=20 irrespective of whether the controls were taken as those who = responded to=20 the brief questionnaire or those who took part in the full = interview (the=20 ORs were 1.21 for glioma and 0.70 for = meningioma).

To date, several case-control=20 studies have been reported from the United States (Muscat=20 et al, 2000; Inskip=20 et al, 2001), Finland (Auvinen=20 et al, 2002), and Sweden (Hardell=20 et al, 1999, 2002,=20 2003,=20 2004)=20 before the INTERPHONE study. Two US studies showed negative = results for=20 the overall risk of brain tumours, whereas in a Finnish population = register-based study, the OR for glioma with relation to ever use = of=20 analogue mobile phones was 2.1 (95% CI: 1.3-3.4).=20 Risk was estimated for the left/right = laterality=20 of the tumour or for the affected lobe in relation to that of = mobile phone=20 use, but no increased risk was observed for tumours on the same = side as=20 phone use. In a series of Swedish studies, the risk of tumours in = the=20 temporal area on the same side as that used for mobile phone calls = was=20 increased for analogue phones, OR 2.3 (95% CI: 1.2-4.1). However, no increased risks by = histological=20 types were observed (Hardell=20 et al, 2003).

Four = studies=20 from the INTERPHONE study showed no increased overall risk of = glioma or=20 meningioma in relation to regular mobile phone use (Christensen=20 et al, 2004, 2005;=20 Hepworth=20 et al, 2006; Schuz=20 et al, 2006), although glioma risk increased = non-significantly=20 (OR=3D2.20; 95% CI: 0.94-5.11) among = long-term=20 users (10 years or more), but no excess risk was found for = temporal lobe=20 tumours, considered to be exposed to the highest radio frequency = (RF)-EMF (Schuz=20 et al, 2006). In a Swedish study, the OR for glioma on = the same=20 side as mobile phone use increased to 1.8 (95% CI: 0.8-3.9) among long-term (10 years) mobile phone users, but the corresponding = OR for=20 glioma on the opposite side was found to decrease to 0.6 (95% CI: = 0.3-1.4) among long-term users (L=F6nn=20 et al, 2005). In a UK study, the OR for glioma on the = same side=20 as mobile phone use was 1.24 (95% CI: 1.02-1.52),=20 but for gliomas on the opposite side, it decreased significantly = to 0.75=20 (95% CI: 0.61-0.93) (Hepworth=20 et al, 2006). In both studies, it was suggested that = such=20 'complementary risks' above and below unity could reflect recall = bias, in=20 which glioma patients tended to recall that they used mobile = phones on the=20 same side as the tumour location simply because they knew where = the tumour=20 was. In summary, the findings to date on mobile phone use and = glioma and=20 meningioma risks are inconsistent.

Most=20 studies of the non-thermal effects of RF-EMF=20 indicate no direct DNA effects such as mutagenicity or = genotoxicity of=20 RF-EMF exposure in the range of = 800-1900 MHz and an SAR of less than 2 W = kg^-1.=20 There is also little evidence for indirect DNA effects, including=20 alterations in gene expression, cell proliferation, or apoptosis = (Laszlo=20 et al, 2005; Chauhan=20 et al, 2006; Lixia=20 et al, 2006; Qutob=20 et al, 2006; Joubert=20 et al, 2007). Thus, laboratory studies do not support = the=20 possibility that mobile phone use increases the risk of brain=20 tumours.

In conclusion, we = observed no=20 increase in overall risk of glioma or meningioma in relation to = regular=20 mobile phone use among our Japanese subjects.

3D""=20

Acknowledgements

The study=20 conducted in Japan was fully funded by the Ministry of Internal = Affairs=20 and Communications of Japan. We appreciate with grateful = cooperation of=20 the surgeons and the staffs of the participating=20 institutions.

Competing interest

None.

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