ID Number		169
Study Type		Epidemiology
Model		INTERPHONE - IARC coordinating site 900, 1800 MHz (NMT, GSM, W-CDMA) mobile phone use and correlation with brain, acoustic nerve, parotid gland tumors
Details		Coordinated multi-national case-control analysis to study correlations between RF exposure from mobile telephones and brain, acoustic nerve, and parotid gland tumor incidence. Participating countries include Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden and the UK. Other countries (e.g., Korea) also have separately funded studies using the INTERPHONE protocol but are not part of the core INTERPHONE group. In an initial coordinated paper from several INTERPHONE project leaders (Lonn et al 2004), data from national cancer registries in Sweden, Finland, Denmark, and Norway from 1969 through 1998 was used and evaluated for possible geographical correlation between both benign and malignant primary intra-cerebral brain tumors (gliomas, astrocytoma, medulloblastoma, etc) identified in subjects 20 to 79 years old and the general use of mobile phones in these countries. The authors excluded neurinomas, meningiomas, lymphomas and pineal gland tumors as being non intra-cerebral. No correlation was identified with mobile phone use, but an increase in adult brain tumors (confined to the late 1970s and early 1980s was identified as corresponding to the introduction of improved diagnostic methods such as computerized tomography scans (CT) and magnetic resonance imaging (MRI). In pooled analysis of menningioma from Denmark and Scandanavia (Klaeboe et al), the authors report an OR = 1.2, 95% CI 0.6 - 2.2, with no increasing trend with duration of use, time of first use, or cumulative use. The authors conclude "there is little evidence that RF exposure has any effect on meningioma risk" and suggest small increases correlate better with introduction of new diagnostic technology and increased detection rates of such tumors. In the first publication of pooled acoustic neuroma data from case control analysis (Schoemaker 2005), with authorship from primary INTERPHONE studies in Sweden, Finland, Norway, France, Denmark, and the UK, the autors analyzed data from pooled cases of acoustic neuroma (n = 678) and controls (n = 3553 controls) and reported no overall association between acoustic neuroma (OR = 0.9; 95% CI 0.71.1) and mobile phone use (duration, lifetime cumulative use, or number of calls using either analogue, digital, or combined technology). Ipsilateral tumor incidence, however, was lowered when correlated with mobile phone use for less than 5 years (OR = 0.7; 95% CI 0.5  0.9) and increased with use more than 10 years (OR = 1.8; 95% CI 1.1  3.1). In both the < 5 yr and >10 yr data, the contralateral tumors showed no effect. THe authors also state that repeating laterality analyses for >10 yrs of use after excluding subjects reporting bilateral use increased the correlation (OR=1.8; 95% CI 1.03.3). The authors conclude from this overall pooled analysis that no substantial risk of acoustic neuroma exists in the first decade after starting mobile phone use. However, an increase in risk after longer term use or after a longer lag period could not be ruled out. A pooled case control study of glioma in from Denmark, Finland, Sweden, Norway, and England by Lahkola et al (2007) reported a statistically significant decrease in total glioma incidence with regular mobile phone use (OR = 0.78, 95% CI 0.68-0.95), although no dose response with duration of use, years since first use, or cumulative hours of use. When ipsilateral tumors for use of 10+ years was examined in this multi-site report, a statistically significant increase (OR=1.39, 95% CI 1.01-1.92) was observed. The authors concluded no apparent risk associated with short term mobile phone use, although the risk of long term use needed to be investigated further. In a related study in the same 5 countries, Lahkola et al (2008) reported a similar decreased association (OR = 0.76, 95% CI 0.65-0.89) between meningioma and all regular mobile phone users as compared to never- and non-regular users. However, selection and recall bias as described by may be an explanation. No association was observed with 10+ yrs of use. More detailed analysis of tumors, including 3-dimensional localization of tumor position and correlation with phone positions, is ongoing. In 2010, the paper on brain tumor risk (see Citation #4972) concluded that "Overall, no increase in risk of glioma or meningioma was observed with use of mobile phones." Larjavaave et al. 2011 (#5071) (Authors' abstract): The energy absorbed from the radio-frequency fields of mobile telephones depends strongly on distance from the source. The authors objective in this study was to evaluate whether gliomas occur preferentially in the areas of the brain having the highest radio-frequency exposure. The authors used 2 approaches: In a case-case analysis, tumor locations were compared with varying exposure levels; in a case-specular analysis, a hypothetical reference location was assigned for each glioma, and the distances from the actual and specular locations to the handset were compared. The study included 888 gliomas from 7 European countries (20002004), with tumor midpoints defined on a 3-dimensional grid based on radiologic images. The case-case analyses were carried out using unconditional logistic regression, whereas in the case-specular analysis, conditional logistic regression was used. In the case-case analyses, tumors were located closest to the source of exposure among never-regular and contralateral users, but not statistically significantly. In the case-specular analysis, the mean distances between exposure source and location were similar for cases and speculars. These results do not suggest that gliomas in mobile phone users are preferentially located in the parts of the brain with the highest radio-frequency fields from mobile phones. Authors's abstract: Swerdlow et al. 2011: Background In the past 15 years, mobile phone use has evolved from an uncommon activity to one with over 4.6 billion subscriptions worldwide. There is, however, public concern about the possibility that mobile phones might cause cancer, especially brain tumours. Objectives To review the evidence on whether mobile phone use raises risk of the main types of brain tumour, glioma and meningioma, with a particular focus on the recent publication of the largest epidemiological study yet  the 13-country Interphone Study. Discussion Methodological deficits limit the conclusions that can be drawn from Interphone, but its results, along with those from other epidemiological, biological and animal studies, and brain tumour incidence trends, suggest that within about 10-15 years after first use of mobile phones there is unlikely to be a material increase in the risk of brain tumours in adults. Data for childhood tumours and for periods beyond 15 years are currently lacking. Conclusions Although there remains some uncertainty, the trend in the accumulating evidence is increasingly against the hypothesis that mobile phone use can cause brain tumours in adults. AUTHORS' ABSTRACT: Turner et al. 2013 (IEEE #5221): PURPOSE: A history of allergy has been inversely associated with several types of cancer although the evidence is not entirely consistent. We examined the association between allergy history and risk of glioma, meningioma, acoustic neuroma, and parotid gland tumors using data on a large number of cases and controls from five INTERPHONE study countries (Australia, Canada, France, Israel, New Zealand), to better understand potential sources of bias in brain tumor case-control studies and to examine associations between allergy and tumor sites where few studies exist. METHODS: A total of 793 glioma, 832 meningioma, 394 acoustic neuroma, and 84 parotid gland tumor cases were analyzed with 2,520 controls recruited during 2000-2004. Conditional logistic regression models were used to obtain odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between self-reported allergy and tumor risk. RESULTS: A significant inverse association was observed between a history of any allergy and glioma (OR = 0.73, 95 % CI 0.60-0.88), meningioma (OR = 0.77, 95 % CI 0.63-0.93), and acoustic neuroma (OR = 0.64, 95 % CI 0.49-0.83). Inverse associations were also observed with specific allergic conditions. However, inverse associations with asthma and hay fever strengthened with increasing age of allergy onset and weakened with longer time since onset. No overall association was observed for parotid gland tumors (OR = 1.21, 95 % CI 0.73-2.02). CONCLUSIONS: While allergy history might influence glioma, meningioma, and acoustic neuroma risk, the observed associations could be due to information or selection bias or reverse causality. AUTHORS' ABSTRACT: Cardis et al. 2011 (IEEE #5469): Objectives The objective of this study was to develop an estimate of a radio frequency (RF) dose as the amount of mobile phone RF energy absorbed at the location of a brain tumour, for use in the Interphone Epidemiological Study. Methods We systematically evaluated and quantified all the main parameters thought to influence the amount of specific RF energy absorbed in the brain from mobile telephone use. For this, we identified the likely important determinants of RF specific energy absorption rate during protocol and questionnaire design, we collected information from study subjects, network operators and laboratories involved in specific energy absorption rate measurements and we studied potential modifiers of phone output through the use of software-modified phones. Data collected were analysed to assess the relative importance of the different factors, leading to the development of an algorithm to evaluate the total cumulative specific RF energy (in joules per kilogram), or dose, absorbed at a particular location in the brain. This algorithm was applied to Interphone Study subjects in five countries. Results The main determinants of total cumulative specific RF energy from mobile phones were communication system and frequency band, location in the brain and amount and duration of mobile phone use. Though there was substantial agreement between categorisation of subjects by cumulative specific RF energy and cumulative call time, misclassification was non-negligible, particularly at higher frequency bands. Factors such as adaptive power control (except in Code Division Multiple Access networks), discontinuous transmission and conditions of phone use were found to have a relatively minor influence on total cumulative specific RF energy. Conclusions While amount and duration of use are important determinants of RF dose in the brain, their impact can be substantially modified by communication system, frequency band and location in the brain. It is important to take these into account in analyses of risk of brain tumours from RF exposure from mobile phones. AUTHORS' ABSTRACT: Cardis et al. 2011 (IEEE #5470): OBJECTIVES: The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones. METHODS: Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the 'tumour location' of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants. RESULTS: ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0. CONCLUSIONS: There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made. AUTHORS' ABSTRACT: Grell, Cardis, Schuz et al. 2015 (IEEE #5974): We study methods for how to include the spatial distribution of tumours when investigating the relation between brain tumours and the exposure from radio frequency electromagnetic fields caused by mobile phone use. Our suggested point process model is adapted from studies investigating spatial aggregation of a disease around a source of potential hazard in environmental epidemiology, where now the source is the preferred ear of each phone user. In this context, the spatial distribution is a distribution over a sample of patients rather than over multiple disease cases within one geographical area. We show how the distance relation between tumour and phone can be modelled nonparametrically and, with various parametric functions, how covariates can be included in the model and how to test for the effect of distance. To illustrate the models, we apply them to a subset of the data from the Interphone Study, a large multinational case-control study on the association between brain tumours and mobile phone use. AUTHORS' ABSTRACT: Shrestha, Auvinen et al. 2015 (IEEE #5975): BACKGROUND: The number of mobile phone users has grown rapidly, which has generated mounting public concern regarding possible health hazards. This study aims to assess pituitary tumor risk, as it has rarely been investigated. MATERIAL AND METHODS: A case-control study was conducted with 80 eligible cases identified from all five university hospitals in Finland and frequency-matched 240 controls from the national population register. Controls were matched to cases by age, sex, region of residence and date of interview. A detailed history of mobile phone use was obtained using a structured interview. Several indicators of mobile phone use were assessed using conditional logistic regression. RESULTS: A reduced odds ratio was seen among regular mobile phone users [OR 0.39, 95% confidence interval (CI) 0.21, 0.72] relative to never/non-regular users, possibly reflecting methodological limitations. Pituitary tumor risk was not increased after 10 or more years since first use (OR 0.69, 95% CI 0.25, 1.89). The risk was not increased in relation to duration, cumulative hours of use, or cumulative number of calls. The results were similar for analog and digital phones. CONCLUSIONS: We found no excess risk associated with self-reported short- or medium-term use of mobile phones. This is consistent with most of the published studies. However, uncertainties remained for longer duration of use, as a very small proportion of study participants reported use beyond 10 years. AUTHORS' ABSTRACT: Frederiksen, Deltour, Schuz 2012 (IEEE #6224): Estimating exposure-outcome associations using laterality information on exposure and on outcome is an issue, when estimating associations of mobile phone use and brain tumour risk. The exposure is localized; therefore, a potential risk is expected to exist primarily on the side of the head, where the phone is usually held (ipsilateral exposure), and to a lesser extent at the opposite side of the head (contralateral exposure). Several measures of the associations with ipsilateral and contralateral exposure, dealing with different sampling designs, have been presented in the literature. This paper presents a general framework for the analysis of such studies using a likelihood-based approach in a competing risks model setting. The approach clarifies the implicit assumptions required for the validity of the presented estimators, particularly that in some approaches the risk with contralateral exposure is assumed to be zero. The performance of the estimators is illustrated in a simulation study showing for instance that while in some scenarios there is a loss of statistical power, others - in case of a positive ipsilateral exposure-outcome association - would result in a negatively biased estimate of the contralateral exposure parameter, irrespective of any additional recall bias. In conclusion, our theoretical evaluations and results from the simulation study emphasize the importance of setting up a formal model, which furthermore allows for estimation in more complicated and perhaps more realistic exposure settings, such as taking into account exposure to both sides of the head. AUTHORS' ABSTRACT: Grell et al. 2016 (IEEE #6565): When investigating the association between brain tumors and use of mobile telephones, accurate data on tumor position are essential, due to the highly localized absorption of energy in the human brain from the radio-frequency fields emitted. We used a point process model to investigate this association using information that included tumor localization data from the INTERPHONE Study (Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the United Kingdom). Our main analysis included 792 regular mobile phone users diagnosed with a glioma between 2000 and 2004. Similar to earlier results, we found a statistically significant association between the intracranial distribution of gliomas and the self-reported location of the phone. When we accounted for the preferred side of the head not being exclusively used for all mobile phone calls, the results were similar. The association was independent of the cumulative call time and cumulative number of calls. However, our model used reported side of mobile phone use, which is potentially inuenced by recall bias. The point process method provides an alternative to previously used epidemiologic research designs when one is including localization in the investigation of brain tumors and mobile phone use. AUTHORS' ABSTRACT: Turner, Cardis et al. 2016 (IEEE #6691): Purpose Associations between cellular telephone use and glioma risk have been examined in several epidemiological studies including the 13-country INTERPHONE study. Although results showed no positive association between cellular telephone use and glioma risk overall, no increased risk for long-term users, and no exposure-response relationship, there was an elevated risk for those in the highest decile of cumulative call time. However, results may be biased as data were collected during a period of rapidly increasing cellular telephone use, and as controls were usually interviewed later in time than cases. Methods Further analyses were conducted in a subset of five INTERPHONE study countries (Australia, Canada, France, Israel, New Zealand) using a post hoc matching strategy to optimize proximity of case-to-control interview dates and age. Results Although results were generally similar to the original INTERPHONE study, there was some attenuation of the reduced odds ratios and stronger positive associations among long-term users and those in the highest categories for cumulative call time and number of calls (eighthninth and 10th decile). Conclusions Proximity and symmetry in timing of case-to-control interviews should be optimized when exposure patterns are changing rapidly with time. AUTHORS' ABSTRACT: Momoli, Cardis et al. 2017 (IEEE #6760): We undertook a re-analysis of the Canadian data from the thirteen-country INTERPHONE case-control study (2001-2004), which evaluated the association between mobile phone use and risk of brain, acoustic neuroma, and parotid gland tumors. The main publication of the multinational INTERPHONE study concluded that biases and errors prevent a causal interpretation. We applied a probabilistic multiple-bias model to address possible biases simultaneously, using validation data from billing records and non-participant questionnaires as information on recall error and selective participation. Our modelling sought to adjust for these sources of uncertainty and to facilitate interpretation. For glioma, the odds ratio comparing highest quartile of use (over 558 lifetime hours) to non-regular users was 2.0 (95% confidence interval: 1.2, 3.4). The odds ratio was 2.2 (95% confidence interval: 1.3, 4.1) when adjusted for selection and recall biases. There was little evidence of an increase in the risk of meningioma, acoustic neuroma, or parotid gland tumors in relation to mobile phone use. Adjustments for selection and recall biases did not materially affect interpretation in our Canadian results.
Findings		Effects
Status		Completed With Publication
Principal Investigator		Univ Barcelona (CREAL) Spain (formerly IARC) - ecardis@creal.cat
Funding Agency		EU, INTERPHONE (IARC) coordinated studies, MMF, GSM Association
Country		FRANCE
References		Lahkola, A et al. Int J Epidemiol, (2008) 37:1304-1313 Cardis, E et al. Eur J Epidemiol, (2007) 22:647-664 Lahkola, A et al. Int J Cancer, (2007) 120:1769-1775 Schoemaker, MJ et al. Br J Cancer, (2005) 93:842-848 Milham , S Br J Cancer, (2006) 94:1354- Hardell, L et al. Br J Cancer, (2006) 94:1348-1349 Hocking, B Br J Cancer, (2006) 94:1350- Schoemaker, MJ et al. Br J Cancer, (2006) 94:1354- Cardis, E et al. Radiat Prot Dosimetry, (1999) 83:179-183 Klaeboe, L et al. Int J Cancer, (2005) 117:996-1001 Morgan, LL Int J Epi., (2010) 39:1117-1118 Milham, S Int J Epi., (2010) 39:1117-1117 Cardis, E et al. Int J Epidemiol., (2010) 39:675-694 Cardis, E et al. Occup Environ Med., (2011) 68:169-171 Larjavaara, S et al. Am J Epidemiol., (2011) 174:2-11 Swerdlow, AJ et al. Env Health Perspectives., (2011) 119:1534-1538 Cardis , E et al. Cancer Epidemiology. , (2011) 35:453-464 Turner , MC et al. Cancer Causes Control., (2013) 24:949-960 Cardis, E et al. Occup Environ Med., (2011) 68:686-693 Cardis, EK et al. Occup Environ Med., (2011) 68:631-640 Sim, MR et al. Occup Environ Med., (2011) 68:629-630 Grell, K et al. Stat Med., (2015) 34:3170-3180 Shrestha, M et al. Acta Oncol., (2015) 54:1159-1165 Frederiksen, K et al. Stat Med., (2012) 31:3681-3692 Grell, K et al. Am J Epidemiol., (2016) 184:818-828 Turner, M et al. Annals of Epidemiology., (2016) 26:827-832 Momoli, F et al. American Journal of Epidemiology., (2017) 186:885-893
Comments		In order to maximise the power of finding a risk if it exists, the studies are mainly focused on tumours in relatively young people (30-59) who had the highest prevalence of mobile phone use 5 to 10 years ago, and on regions within countries with longest and highest use of mobile phones. It is expected that the studies will include about 6000 cases of gliomas and meningiomas (both benign and malignant), 1000 cases of acoustic neurinoma, 600 cases of parotid gland tumours and their respective controls. The primary source of information is an in-person computer assisted interview (CAPI) conducted by a trained interviewer. Retrospective and prospective validation studies are conducted to investigate the accuracy of self-reported use of mobile phones by comparing questionnaire answers to information from records of mobile telephone companies and to information recorded by software modified phones. An RF exposure index is constructed based on information from the questionnaire, as well as on technical information on the characteristics of the network and of the telephones used and on the time period. In the Schoemaker (2005) pooled data study, for both the < 5 yr (decreased incidence) and > 10 yr (increased incidence) data, the contralateral tumors showed no effect. Further, the authors report "repeating the laterality analyses after excluding subjects reporting bilateral use gave a near identical result for 10 or more years of ipsilateral use (OR=1.8, 95% CI: 1.03.3)". The authors did not specifically say what contribution the Lonn (2004) study (OR=3.9; 95% CI 1.6-9.5 for laterality correlations) had on the pooled data, but did mention this and the Hardell (2003) studies. They also suggested in the conclusion that the six published studies that did NOT show evidence of raised risk had few long-term users. A series of critical comments were submitted: Milham pointed out that of 36 different ORs most were below 1.0 (suggesting potential bias or exposure assessment problems) and all OR in long-term (> 10 yr) users were above 1.0 (not equally distributed). Hocking as well as Hardell and Mild suggested that the findings of increased ipsilateral tumors correlation should have been interpreted more strongly. Questions were also raised concerning recall ability and questionnaire data that may not have been sufficiently blinded or taken too close to diagnosis. Comments by Duerrenberger, Froehlich, Wieser (http://www.mobile-research.ethz.ch/var/Comment_Interphone.pdf). The two main points were: 1. Since the mechanism and latency not known, many different tumor types evaluated, signals pooled, and time extended back > 10 yrs of use (potentially diluting any effect in the number of cases that were included in the study for statistical power). 2. Exposure assessment (and further stratification of user groups) not reliable (over-estimation in long term cases, under-estimation due to exposure classification errors and recall bias, selection bias in controls, etc) UICC acts as a firewall for funding by MMF and GSMA - see http://www.iarc.fr/pageroot/UNITS/RCA4.html for details). As of July 2007, the INTERPHONE study achieved its goal of 2700 gliomas, 2400 meningiomas and 1100 acoustic neurinomas but collected less than half of the goal of 400 parotid gland tumors. Gliomas: The published data accounts for almost all of the tumors in the overall study (2492/2765 X 100% = 90%). Meningiomas: The published data accounts for less than half of the tumors in the overall study (1036/2425 X 100% = 43%). Acoustic neuromas: The published data accounts for about 70% of the tumors in the overall study (779/1121 X 100% = 69.5%). The discrepancy in the number of parotid gland tumors (more tumors in published papers than in the overall study) may reflect the number of malignant vs benign tumors. In at least some of the country sites (e.g., FInland), the users (especially the cases) may have been informed of the nature of the study prior to assessment of thier exposure, and thus over-estimation bias may have existed.