The INTERPHONE Study Group.

Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case–control study. International Journal of Epidemiology. EPub ahead of print, May 18, 2010.

Introduction and Objective
The INTERPHONE study is an international case-control study of mobile phone use and the risk of brain tumors. The objective was to determine whether mobile phone use increases the risk of these tumors i.e. whether the radiofrequency radiation emitted by mobile phones is tumorigenic. The study was conducted at 16 centers in 13 countries (Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden and the UK) and coordinated by the International Agency for Research on Cancer (IARC). This is the largest case-control study on mobile phone risks to date that includes the largest number of long-term (≥10 years) mobile phone users.

Methods
Cases of brain tumors (glioma and meningioma) diagnosed between 2000 and 2004 in patients 30-59 years of age were actively ascertained from all neurological and neurosurgical facilities in the study areas. In some centers, cancer registries were also used as sources of information. For each case, one control matched for age, sex and region of residence (in Israel also for ethnic origin) was selected from population-based sampling frame in each area. In Germany, two controls per case were selected.

Detailed information on mobile phone use was collected during face-to-face interviews with the study subjects or, if the study subject had died or was too ill, with a proxy respondent. The questionnaire used for the interviews also included questions about socio-demographic factors, occupational and medical exposures to ionizing and non-ionizing radiation, medical history and smoking. Information on anatomical location of the tumors was obtained from MRI reports or images, surgical or clinical records.

The analyses were conducted using conditional logistic regression for matched sets. The reference category for computation of odd ratios (ORs), “never regular users”, included subjects who had never used a mobile phone and subjects who used mobile phones occasionally, but never as much as one call a week for ≥6 months. Cumulative number and duration of calls were analyzed by categories based on deciles of the distribution of these variables among controls and regular mobile phone users.

Results
Analyses included 2,708 glioma cases, 2,972 controls matched to glioma cases, 2,409 meningioma cases and their 2,662 matched controls. The risk of both types of brain tumors was significantly reduced (OR<1.0, confidence intervals do not include 1.0) in individuals who regularly used mobile phone for at least one year compared to never regular users (see table). The reduction in risk was seen in all (but one) categories of cumulative number of calls and in the first nine categories of cumulative call time. This reduction was not statistically significant in most categories. In the highest category of cumulative call time (≥1640 hours), the risk was slightly increased for meningioma (OR = 1.15; 95% CI 0.81-1.62) and significantly increased for glioma (OR=1.40; 95% 1.03-1.89). When cumulative call time was analyzed separately for short-term users (1-4 years), medium-term users (5-9 years) and long-term users (≥10 years), a significant increase in risk in the cumulative call time category of ≥1640 hours was seen for short-term users only: OR=4.80; 95% CI 1.49-15.4 for meningioma and OR=3.77; 95% CI 1.25-11.4 for glioma.

For meningioma, the OR for tumors in the temporal lobe was significantly below 1.0 (see table). The risk of meningioma located in the temporal lobe was reduced (though not always significantly) in all categories of duration of use, cumulative call time and cumulative number of calls. For glioma, the risk of tumors in the temporal lobe was reduced, but not significantly. The OR for temporal lobe glioma was above 1.0 in the highest categories of duration of use (≥10 years), cumulative call time (≥1640 hours) and cumulative number of calls (≥27,000); in the highest category of cumulative call time this increase was significant (OR=1.87; 95% CI 1.09-3.22).

The ORs for ipsilateral mobile phone use (i.e. use on the side on which the tumor occurred) for meningioma were below or around 1.0 in most categories of duration of phone use, cumulative call time or cumulative number of calls; a slight non-significant increase was observed in the highest category of cumulative call time and second highest category of cumulative number of calls. For glioma, the OR for ipsilateral mobile phone use was significantly increased in the highest category of cumulative call time (OR=1.96; 95% CI 1.22-3.16); a non-significant increase was observed in the highest category of duration of use and the highest category of cumulative number of calls. For both meningioma and glioma, the OR for ipsilateral mobile phone use was higher than OR for contralateral use, and this was the case for most categories of duration of use, cumulative call time and cumulative number of calls. For meningioma, the ipsilateral/contralateral ratio of the ORs was the highest in the two highest categories of cumulative call time and in the second highest category of cumulative number of calls. For glioma, the ipsilateral/contralateral ratio of the ORs was the highest in the highest category of cumulative number of calls.

*Reference category - “never regular users” as described in the “Methods” section; adjusted for sex, age, study center, ethnicity in Israel, and education 

Interpretation
The authors pointed out that their analysis involved examination of hundreds of ORs. Therefore, the interpretation should be based on the overall balance of evidence rather than on the most extreme values. The results include 1) a disproportionally high number of ORs below 1.0 indicating a decreased risk of brain tumors in regular mobile phone users, and 2) a small number of elevated ORs, indicating, in particular, an increased risk of glioma among the heaviest phone users, gliomas in the temporal lobe and on the preferred side of mobile phone use in the heavy users.

Regarding the apparently decreased risk among regular mobile phone users, the authors reject a genuine protective effect as implausible and explore a number of alternative explanations, such as possible sampling bias, relatively low level of participation (78% among meningioma cases, 64% among glioma cases and 53% among controls), timing of interviews, and confounding. Based on the results of previously conducted work to characterize possible sources of bias and on the results of sensitivity analyses presented in this article, the authors have concluded that these potential sources of error cannot fully explain the observed reduction in risk. The possibility of mathematical correction of the OR estimates for the effects of these errors are now being explored.

Regarding the apparently elevated risks of glioma among heavy users, some subjects (more cases than controls) reported implausible values of reported use, such as >5 hours a day and even ≥12 hours a day. Previously conducted validation studies indicated that heavy users tended to over-report their phone use (errors were larger for duration of calls than for number of calls), and that cases tended to overestimate their mobile phone use more than controls. These errors could contribute to the apparently increased risk of glioma in the highest category of cumulative duration of calls.

At all levels of exposure, the ORs for ipsilateral mobile phone use were greater than the ORs for contralateral use, even though there was a tendency towards higher ipsilateral/contralateral ratio at higher levels. It is possible that at least part of this effect results from over-reporting by cases of phone use on the side of the tumor. However, true effect cannot be ruled out. The results for tumors in different lobes are less susceptible to reporting bias, and it was demonstrated that, for glioma, the ORs in the highest exposure categories were higher for tumors in the temporal lobe (where the exposure is generally highest) than in other lobes. However, the lobe-specific OR estimates were imprecise (with wide confidence intervals).

Despite similar patterns in ORs for glioma and meningioma, the ORs for meningioma were generally lower than those for glioma, and, unlike glioma, there was no evidence of increase in risk of meningioma in the temporal lobe. The authors have concluded that their study provides no evidence of an increased risk of meningioma among users of mobile telephones. The similar patterns in ORs for these two types of brain tumors “could indicate shared etiology or shared bias”.
The results of this study are consistent with the results of most epidemiological studies on mobile phone use and brain tumors. These results are also consistent with in vivo and in vitro laboratory research showing no evidence of carcinogenicity of radiofrequency fields.

Conclusion
The authors have concluded that “overall, no increase in risk of either glioma or meningioma was observed in association with use of mobile phones. There were suggestions of an increased risk of glioma, and much less so meningioma, at the highest exposure levels, for ipsilateral exposures and, for glioma, for tumours in the temporal lobe. However, biases and errors limit the strength of the conclusions we can draw from these analyses and prevent a causal interpretation.”