News and Views. Cell Phones and Cancer: A Short Communication. Background Cellular telephone technology emerged in Europe in the

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1 Tony Soeyonggo, BHSc (1T2), Faculty of Medicine, University of Toronto Shelly Wang, BSc (1T2), Faculty of Medicine, University of Toronto Background Cellular telephone technology emerged in Europe in the 1980s, and came to widespread popularity in North America in the 1990s. Over the past decade, cellular telephone subscribers increased dramatically to 4.1 billion people, or more than half of the world s population. 1 While cellular telephones have created convenience in communication, their widespread use has spurred much concern about their potential risks to health namely their possible association with cancer. It is important to appreciate two main difficulties that arise from conducting epidemiologic research of radiofrequency radiation (RFR) exposure from cellular telephones. Firstly, the majority of RFR emissions are absorbed within a few centimeters of the cellular telephone's antenna. 2 Therefore, brain and other tissues in close proximity to the antenna would be at greater possible risk for developing malignancy. Examples include gliomas, meningiomas, acoustic neuromas, and salivary gland tumours, which are all rare. 3 Furthermore, the current understanding of RFR-induced carcinogenesis would suggest a long induction time, between exposure to the appearance of cancer. 3 Given the rarity of the proposed diseases and the necessary temporal exposure to RFR, it is appreciable that a holistic understanding of the cause and effect would not come from any single study, but rather from detailed reviews or meta-analyses of the accumulating literature. 3 Taking this approach, this article summarizes the current literature on the relationship between cell phones and cancer, using four recently published articles from a MEDLINE search. The search terms were cellular phone and neoplasm, and the results were limited to meta-analyses and reviews in the English language, published within the past year. Pathophysiology and Mechanisms of Damage The two common cell phone models used today utilize either the Global System for Mobile Communication (GSM) technology or the Universal Mobile Telecommunication System (UMTS/3G). The GSM phones operate using a frequency band of MHz, while the 3G uses a 1900 MHz broadband transmission. Regardless of the frequency range, all cell phones receive and transmit RFR. The rate of absorption of RFR energy in a homogenous volume of biological tissue is proportional to the temperature increase within this volume. However, the frequency of radiation produced by the cell phone is considered to be non-ionizing. 4 In other words, RFR in the range described above is unable to remove an electron from an atom or molecule; however, it is sufficient for electron excitation, allowing electrons to jump to a higher energy state. Clinically, this amount of radiation is not capable of creating tissue damage by thermal means. While the true mechanism of RFR-induced damage is unknown, a few non-thermal RFR mediated mechanisms of damage have been proposed, namely free radial production and heat shock protein induction. From an electrodynamic principle, the RFR produced by the cell phone may affect many important processes that occur at a cellular level, such as electron transfer across the membrane, ion crossing through selective channels, and activation/deactivation of proteins by enzymatic cascades. 5 This has been shown in an in vivo study where activations of proteins and genes are observed at non-thermal levels of RFR. 6 This observation is linked with a long-standing speculation that free radical formation may be involved in RFR-induced damage. 7 Recently, an in vitro study has further demonstrated that RFR can result in activation of an extracellular-signal regulated kinase that activates a downstream pathway to rapidly generate free radicals. 8 Another school of thought is that RFR activates heat shock protein 27 (hsp27), which inhibits apoptosis and increases the permeability of the blood brain barrier. 9 Over time, these could result in accumulated damage to the brain and prolonged exposure to RFR may predispose an individual to neoplasia. Research to Date Many independent case-control studies have analyzed cell phone use among patients with malignancies compared to population controls (Table 1). Tumours studied to date include brain tumours (such as glioma, neuroma, meningioma), parotid gland tumors, uveal melanoma, non-hodgkin s lymphoma (NHL), and testicular cancer. 2 The results were then analyzed for duration of use, frequency of use, preferred side, and type of phone used. The studies yielded varied results, spanning from a mild protective effect to an almost certain association to malignancy. Although current literature findings remain inconclusive, it is important to mention the multi-nation INTERPHONE studies and the seven Hardell et al. studies of. The INTERPHONE study, coordinated by the International Agency for Research on Cancer (IARC), is a multi-nation study investigating the association between cell phone use and malignancies. Thirteen and a total of 2,765 glioma, 2,425 meningioma, 1,121 acoustic neuroma, 109 malignant parotid gland tumour and 7,658 control subjects were involved, making it the largest coordinated study of its type to date. 10 Results from several have been published, mostly demonstrating a lack of association between cell phone use and malignancy. Contrary to the INTERPHONE studies, four studies by Hardell et al. have demonstrated a connection between cell phone use and brain tumours Since the 1990s, Hardell et al. has conducted seven case-control studies on the association between cell phone use to brain tumours, salivary gland tumours, non-hodgkin s lymphoma (NHL) and testicular cancer through self-administered questionnaires Cumulatively, the studies demonstrate that cell phone use leads to an increase in brain tumours, but not salivary gland tumours, NHL, or testicular cancer. 18 UTMJ Volume 87, Number 3, May

2 Table 1. Summary of the Current Literature on the Association between Cell Phone RFR and Various Cancers Study Year Size Tumour Type Conclusions Muscat et al cases Brain No association 422 controls Inskip et al glioma Brain No association 197 meningioma 96 acoustic neuroma 799 controls Stang et al cases Uveal melanoma Positive association between uveal melanoma Germany 475 controls and RFR exposure, including cell phones Auvinen et al malignant brain Malignant brain No association overall Finland 34 salivary gland Salivary grand Mild association between analogue phone use 2,156 controls and gliomas Warren et al cases Intratemporal facial nerve (IFN) No association 192 controls INTERPHONE STUDIES Christensen et al cases Acoustic neuroma No association 212 controls Christensen et al glioma Brain No association 175 meningioma 822 controls Schoemaker et al cases Acoustic neuroma No association overall 5 North European 3,553 controls Non-significant risk for tumors ipsilateral to side of phone use, for >10 years of use Hepworth et al cases Glioma No association overall Britain 1,716 controls Significantly increased risk for ipsilateral tumours and decreased risk for contralateral tumours may reflect recall bias Lönn et al glioma Brain No association 273 meningioma 674 controls Schuz et al glioma Brain No association overall Germany 381 meningioma Non-significant risk for glioma (but not meningioma) 1,494 controls among heavy users (>10 years of use) Takebayashi et al cases Acoustic neuroma No association Japan 339 controls Hours et al glioma Brain No association overall France 96 controls Non-significant risk for glioma among heavy 109 acoustic neuroma users (long-term users, users with the largest 214 controls numbers of telephones) Klaeboe et al glioma Brain No association Norway 207 meningioma 45 acoustic neuroma 358 controls Lahkola et al ,521 cases Glioma No association overall 5 North European 3,301 controls Inconclusive results regarding ipsilateral gliomas for long term users (>10 year) users Schlehofer et al cases Germany 194 controls Acoustic neuroma No association Lahkola et al ,209 cases Meningioma No association 5 North European 3,299 controls Sadetzki et al benign PGT Parotid gland tumors (PGT) No association overall Israel 58 malignant PGT Restricted analyses for regular use or conditions 1266 controls with higher exposure yielded risks Takebayashi et al glioma Brain No association overall Japan 132 meningioma Non-significant increase in glioma patients may 102 pituitary adenoma reflect recall bias 683 controls 126 UTMJ Volume 87, Number 3, May 2010

3 Table 1. Summary of the Current Literature on the Association between Cell Phone RFR and Various Cancers (continued) Study Year Size Tumour Type Conclusions HARDELL STUDIES Hardell et al cases Brain Non-significant increased risk for tumour in the 425 controls temporal or occipital lobe ipsilateral to cell phone use, for the NMT system Hardell et al cases Brain Positive association to ipsilateral use of analogue 581 controls cellular phones Hardell et al cases Salivary gland tumours No association 1,172 controls Hardell et al meningioma Brain Positive association 84 acoustic neuroma 24 other types 692 controls Hardell et al cases Non-Hodgkin s Lymphoma No association to B-cell NHL but positive association 1,016 controls (NHL) to T-cell NHL interpret limited data with caution Hardell et al cases Brain Significant positive association, increasing with 692 controls cumulative number of hours of use and was highest for high-grade astrocytoma Hardell et al semimoma Testicular cancer No association 346 non-semimoma 870 control COHORT STUDIES Dreyer et al ,423 Handheld Mobile Brain No association Phone, 152,138 portable bag Johansen et al No excesses were observed for cancers of the brain or nervous system (SIR = 0.95; 95% CI = 0.81 to 1.12) or of the salivary gland (SIR = 0.72; 95% CI = 0.29 to 1.49) or for leukemia (SIR = 0.97; 95% CI = ), cancers of a priori interest. Risk for these cancers also did not vary by duration of cellular telephone use, time since first subscription, age at first subscription, or type of cellular telephone (analogue or digital). Analysis of brain and nervous system tumors showed no statistically significant SIRs for any subtype or anatomic location Schuz et al No evidence for an association between tumor risk and cellular telephone use among either short-term or long-term users Legend: NMT = Nordic Mobile Telephone, analogue phone system used in Europe in the 1980s; GSM = Global System for Mobile Communications, introduced in 1991 and now the international standard Meta-analyses to Date Meta-analyses are excellent methods to combine data from independent studies to better understand a controversial topic. In a meta-analysis, 41 Myung et al. determined a clear link between cell phone use and cancer. The authors acknowledged discrepancies between the 23 case-control studies analyzed, but noted that studies of higher methodological quality, determined by the Newcastle-Ottawa Scale (NOS), were more likely to be associated with positive findings. The NOS is a 8-point scale that measures the power of an epidemiological study based on its population selection, comparability, and exposure. 41 Studies published by Hardell et al. suggested a positive correlation between cell phone use and brain tumour incidence; these studies were blinded and were considered to have higher quality. On the other hand, 9 of the 13 INTERPHONE studies, which reported negative findings, were not blinded and found to have lower quality. Myung et al. determined that higher quality studies supported a positive association with brain tumours. For other tumors, no link to cell phone use was found in any of the studies. The authors also found a significant positive association between cell phone use of 10 years or greater and the risk of tumors in a fixed-effect meta-analysis of 13 studies reporting this association. The authors concluded that for low-biased, case-control studies, a significant association between cell phone use and risk of tumors was observed. Following its publication, many researchers expressed concern about the analytical methodology employed by Myung et al. surrounding the use of the NOS. Critics pointed out that the validity of the NOS is at best undetermined, and study qualities such as blinding and identical non-response rates among cases and controls are poor ways of judging the validity of a case-control study In contrast to the findings of Myung et al., other researchers have identified little or no correlation between cell phone use and cancer. Kohli et al. reviewed 10 case control studies which demonstrated mixed findings, and found no relationship between RFR exposure from cell phones and the development of acoustic neuromas, parotid gland tumours, intra-temporal facial nerve tumours, gliomas, and meningiomas. 45 In addition, they analyzed eight other studies and concluded that there was no link between RFR from other sources (television, radio towers or occupational exposure) to an increased risk of hematopoietic or brain cancer. 45 Although some meta-analyses demonstrated conclusive findings, others advocate for additional research. Ahlbom et al. found no association between cell phone use and brain tumours, but emphasized the importance of further studies to better understand tumours with long latency periods. 2 The authors attributed the difference between the Hardell et al. studies and the other studies to the variation across the constitution of case groups, criteria for exclusion, exposure definitions, and UTMJ Volume 87, Number 3, May

4 the selection of results for presentation in Hardell's published studies. With the exception of the studies by Hardell et al., other studies showed only mild or no association between cell phone use and malignancy. Ahlbom et al. found that gliomas, a type of fast-growing tumour with short induction periods, were mildly associated with cell phone use. However, the studies that showed an increased risk of ipsilateral brain tumours were subject to recall biases, as those diagnosed with brain tumours were more inclined to report cell phone use on the same side. Meningiomas and acoustic neuromas are slower-growing tumours that take up to decades to develop, and their relationship to cell phone use cannot be appropriately analyzed at the present moment. Studies for these slowgrowing tumours are inconsistent and may be caused by exposure misclassification or selection bias. Lastly, Kundi et al. used 23 case-control studies and two cohort studies to illustrate the methodological challenges associated with meta-analyses and demonstrated a positive correlation between cell phone use and cancer. 46 The author described three methodological challenges in studying this topic. These included the difficulty in assessing exposure patterns to RFR from cell phones, the low number of long-term studies, as well as the lack of evidence-based approaches that can uniformly link carcinogenesis to RFR exposure. From an epidemiological perspective, exposure to an agent should be readily assessed and discriminated. However, absorption of RFR from cell phones may differ, depending on the phone, the phone network, the individual's anatomy, as well as the frequency of use. Therefore, meaningful exposure doses cannot be measured directly. Secondly, the observed durations of cell phone use in the current studies are generally too low. Therefore, the expected odds ratios from these studies are too small to be detected with acceptable power. Lastly, there are about 50 types of brain tumours and a dozen different histologic salivary gland tumours with multiple subtypes. The sample size of each specific tumour is small, and researchers cannot ascertain a link between cell phone use and RFR sensitive tumours, which may be specific to a few histological subtypes. In his systematic review of the literature, Kundi et al. concluded that the current evidence points toward an increased risk of brain tumour with cell phone use, specifically for gliomas, meningiomas and acoustic neuromas using combined estimates for ipsilateral cell phone use of greater than 10 years. 46 However, the risk estimates remain very low and recall bias may have increased these estimates. Another Consideration: Hands-Free Devices The boom of cell phone use was accompanied by a proliferation of hands-free devices. This also raised the consideration of the carcinogenesis from RFR emitted from these devices. Unfortunately, clinical research in this field has been very minimal. The current understanding of these devices are that most hands-free devices (e.g. Bluetooth or Wireless Local Area Network devices) operate by broadcasting a slightly higher RFR range, but act on a much shorter distance. From an ideological point of view, hands-free devices would have a lower risk for carcinogenesis simply by their decreased signal penetrance compared to cell phones. Cell phones are designed to receive signal from a base station that may be up to 35 km away, while a bluetooth device can only receive a signal from 30 feet away. 4,5,47 Furthermore, the strength of RFR radiation is typically expressed using Specific Absorption Rate (SAR), measured in watts per kilogram of tissue. 47 The current literature report the SAR produced by cell phones to be 1,600-4,500 W/Kg of tissue, using various models and measurement tools. 47,48,49 On the other hand, SAR produced by a bluetooth device is in the range of mw/kg, indicating a much lower RFR radiation level and presumably less carcinogenesis. 50 Therefore, while there are no case studies and limited understanding in the literature of how hands-free devices could affect cancer growth, one can assume that they would be less harmful than cell phones, given their much decreased RFR signal penetrance and smaller SAR. In the worst scenario, these devices would have the same risk of tissue damage as the RFR from cell phones. Further research would have to be conducted to definitively assess the risk of carcinogenesis of RFR by hands-free devices. Conclusion The arguments for or against an association between cell phone use and brain tumours are equally ambiguous. Epidemiologic studies that support the association between cell phone use and brain malignancies are heavily anchored on the series of published data by Hardell et al. On the other hand, studies that cite a null, or even a protective effect, of cell phone exposure to brain tumours are often based on the INTER- PHONE studies published by the IARC. Table 2. Summary of Problems or Difficulties Encountered by Case and Cohort Studies Analyzing the Relationship between Cell Phone Use and Cancer. Lack of exposure metric for mobile phones; different researchers use different variables to measure RFR exposure Lack of long-term prospective studies and difficulty in measuring exposure duration for tumours of long induction periods. Limited cell phone use in the older population, whom head and neck cancer most commonly affects. Therefore, the expected ORs are too small to be detected with appropriate power Lack of, or inappropriate, blinding for interviewers Selection and response bias for certain populations that may have a higher prevalence of cell phone use Misclassification bias because of a lack of a measurement unit for RFR exposure, exclusion of cordless phone use in some studies, neglect to document early symptoms of disease in some studies, etc. Recall bias recently diagnosed individuals are more likely to report cell phone use in general or on the same side as the tumour Lack of mechanistic model of damage caused by cell phone RFR Despite the lack of conclusive evidence, it is imperative to continue research in this field, as the number of cell phone users are expected to increase in the years to come. Therefore, even a small increase in the incidence of a particular cancer linked to cell phone use will have a significant clinical impact. Important research aspects that should be addressed in the future are the lack of uniform indicators for exposure dose, studies with short exposure duration, as well as the lack of understanding for the true mechanism of damage by RFR. 128 UTMJ Volume 87, Number 3, May 2010

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