Electromagnetic Fields

3. Can mobile phones cause cancer?

• 3.1 Have studies on mobile phone users revealed an increased cancer risk?
• 3.2 Have studies on laboratory animals revealed an increased cancer risk?
• 3.3 Have studies on cell cultures revealed genetic effects?

3.1 Have studies on mobile phone users revealed an increased cancer risk?

The source document for this Digest states:

3.3.2 Cancer

Studies on cancer in relation to mobile telephony have focused on intracranial tumours because deposition of energy from RF fields from a mobile phone is mainly within a small area of the skull near the handset. When whole body exposure is considered, as in some occupational and environmental studies, also other forms of cancer have been investigated.

3.3.2.1. Epidemiology

What was already known on this subject?

At the time of the previous CSTEE opinion of 2001, most epidemiological studies on exposure to RF fields had examined exposures at the workplace. The overall evidence did not suggest consistent cancer excesses. With regard to mobile phones, only few studies were available at the time of the previous opinion and the short exposure period in these studies did not allow any firm conclusions. The few studies on residential exposure to RF fields from transmitters had serious methodological limitations.

What has been achieved since then?

In total, about 30 papers of original studies on mobile phone use and cancer were published in the last five years. Results are summarized in Table 2 for brain tumours and in Table 3 for acoustic neuroma. All but one study were case-control studies, mostly on brain tumours, some on salivary gland tumours or uveal melanoma. One was a large cohort study of all Danish mobile phone subscribers between 1982 and 1995 who were followed up for a variety of cancers; no increased risk for any cancer was observed but follow up time was short (Johansen et al. 2001). A recent update of the cohort study with an average follow up time of 8.5 years yielded 14,249 cancer cases observed in the cohort versus 15,001 expected cases based on cancer rates observed in the rest of the Danish adult population (Schüz et al. 2006b). The deficit was mainly attributable to smoking-related cancers, suggesting a healthy cohort effect. The overall relative risk estimates for brain tumours and leukaemia were close to one, however, only 28 brain tumour cases occurred in subscribers of a mobile phone of 10 years or more, whereas 42.5 cases were expected.

The Interphone study is a multinational case-control study coordinated by the International Agency for Research on Cancer (IARC). It is a population-based study with prospective ascertainment of incident cases and face-to-face interviews for exposure assessment. With regard to brain tumours, results from the first four components of the Interphone study suggest no risk increase for meningioma or glioma. This is consistently so among subjects with less than 10 years of use. For regular mobile phone users of 10 years or more, no indications of risk increases were seen in three out of four components, namely in Sweden (Lönn et al. 2005), Denmark (Christensen et al. 2005) and the UK (Hepworth et al. 2006), but the German component does reveal a somewhat raised relative risk estimate for glioma (Schüz et al. 2006a). This increase, however, is based on small numbers and due to the wide confidence interval the result is not in contradiction with the other Interphone components.

In contrast, a Swedish group not participating in the Interphone-study, conducting several case-control studies using self-administered questionnaires for exposure assessment, has repeatedly observed increased relative risk estimates for brain tumours. In 2006, the group revisited their previously published studies and reported statistically significant risk increases for both analogue and digital mobile phones as well as cordless phones already after one year of use (Hardell et al. 2006). After ten years of use they observed about a doubling of the relative risk estimates, with the strongest increase for high grade glioma.

Acoustic neuromas, benign tumours that develop very slowly, arise from the Schwann cells, which enfold the vestibulocochlear nerve (VIII. cranial nerve). They are of particular interest because of their location. The Hardell-group from Sweden has in several studies reported raised relative risk estimates for acoustic neuroma, also with very short induction periods (Hardell et al. 2005b). Three of the Interphone components, Denmark, Sweden, and Japan, have reported their country specific acoustic neuroma results (Christensen et al. 2004, Lönn et al. 2004, Takebayashi et al. 2006). Lönn et al. (2004) reported a doubling of the relative risk estimate after ten years of regular mobile phone use compared to subjects who never used a mobile phone regularly. This association became stronger when the analysis was restricted to preferred phone use at the same side as the tumour. Christensen’s and Takebayashi’s results did not support this, but they were based on fewer long-term users. Five of thirteen countries of the Interphone study (including Denmark, Finland, Norway, Sweden, and the UK) were pooled for a joint analysis to examine the association between mobile phone use and risk of acoustic neuroma (Schoemaker et al. 2005). While no overall association was seen among all long-term users (see Table 3), the data suggest that there may be an increased risk when the preferred side of the head of use is considered in the analysis. For 10+ years of use of mobile phones, the relative risk for acoustic neuroma at the preferred side of use was 1.8 (95%-CI 1.1-3.1). Because of methodological inter-study differences it would have been of considerable interest to compare the results across the six studies, but small numbers in most of the centres preclude that analysis.

All those studies are facing limitations in their exposure assessment, which was either a list of subscribers from the operators or self-reported mobile phone use. While the first method is an objective measure, it has limitations because subscription predicts use of a mobile phone only to some extent. Recent validation studies in volunteers comparing current self-reported use with traffic records from network operators show a moderate agreement, but it cannot be excluded that agreement is worse with respect to past mobile phone use or among patients with brain tumours (Vrijheid et al. 2006). Especially patients with high stage glioma showed some memory performance problems in the Danish Interphone study (Christensen et al. 2005). What seems to be reassuring despite these shortcomings is, that once the amount of mobile phone use is estimated with some validity, this is a satisfactory proxy for RF field exposure from these devices, as was shown in studies recording output power of mobile phones during operation (Berg et al. 2005). Laterality (side) of use is not easy to obtain in a retrospective study, as early symptoms may affect the side of use. Although some results are now available for long- term users, their numbers are still small and the results of the whole Interphone dataset should be awaited before drawing conclusions.

No striking new results appeared for studies on occupational and residential RF fields exposures since the previous opinion. While some positive associations have been reported from occupational studies, the overall picture is far from clear (Ahlbom et al. 2004). Many studies lack individual exposure assessment and only job titles or branches were used as exposure proxies. Studies on exposure from transmitters are limited by crude exposure measures and small numbers of exposed subjects, and the ecological nature of most studies.

Discussion

Mobile phones in relation to health are now being studied with great effort and in comprehensive studies, particularly in the Interphone Study. The results of the Interphone Study will soon become available. It has to be doubted, however, that the results will be entirely conclusive, as the first results from published national components of this study already raise a number of questions with respect to the potential of bias. Another limitation is that also in the current studies, long-term mobile phone users have had hardly more than 10 years of regular use of mobile phones, which still may be a relatively short latency period, particularly for slowly growing benign tumours. Among those long-term users, most were initially users of analogue mobile phone and thus, the number of long-term users of the digital technology is even smaller. Prospective long term follow up studies overcome both the limitations of retrospective exposure assessment and the latency problem and are recommended as a powerful long-term surveillance system for a variety of potential endpoints, including cancer, to fill current gaps in knowledge.

Table 2. Results of epidemiological studies on mobile phone use and brain tumours 

Table 3. Results of epidemiological studies on mobile phone use and acoustic neuroma 

Source & ©: ,  Possible Effects of Electromagnetic Fields (EMF) on Human Health (2007)
Section 3.3 Radio Frequency Fields, 3.3.2 Cancer, p.15-20

3.2 Have studies on laboratory animals revealed an increased cancer risk?

The source document for this Digest states:

3.3.2.2. In vivo

What was already known on this subject?

The possible carcinogenicity of RF field exposure had been investigated in a number of experimental systems. Results had been essentially negative. An interesting exception is that of Repacholi et al. (1997), who had induced a two-fold increase in lymphoma incidence in a strain of lymphoma-prone transgenic mice (Eµ-Pim1) following exposure (2x30 min daily for up to 18 months) to 900 MHz RF fields with a signal similar to the GSM modulation (pulse repetition frequency of 217 Hz and a pulse width of 0.6 ms). No attempt to replicate this finding had been published at the time of publication of the previous opinion.

What has been achieved since then?

Utteridge et al. (2002) failed to confirm the results of the Repacholi et al. (1997) study. Utteridge and co-workers found that exposure to RF fields (898 MHz; GSM modulation; 0.25/1.0/2.0/4.0 W/kg; 1 hour/day, 5 days/week for 104 weeks) had no statistically significant effect (95%-CI) on the incidence of lymphoma. Utteridge et al. (2002) used the same strain of mouse as the earlier study and they were obtained from same supplier; the investigators also fed the same food to the mice. The later study had some refinements in experimental design: four SAR levels were used instead of one in the original study, animals were restrained during the exposure for better control of variations in exposure level, and full necropsy was performed on all mice at the end of the study. Other differences from the Repacholi et al study were that animals were exposed once per day instead of during two episodes of 30 minutes 5 days per week.

Several other recent studies have evaluated carcinogenicity of RF fields in a variety of experimental models. Several studies have tested whether RF fields alone induce any type of cancer in normal or genetically predisposed animals (Zook and Simmens 2001, La Regina et al. 2003, Anderson et al. 2004, Sommer et al. 2004b), and several other studies investigated whether exposure to RF fields could enhance the development of tumours induced by chemical carcinogens, X-rays or UV radiation (Zook and Simmens 2001, Anane et al. 2003a, Bartsch et al. 2002, Imaida et al. 2001, Huang et al. 2005, Shirai et al. 2005, Heikkinen et al. 2001, Heikkinen et al. 2003, Heikkinen et al. 2006). No statistically significant increase of tumour incidence has been reported in any of these studies.

Most of the recent and earlier co-carcinogenicity studies on RF fields have used initiation- promotion protocols, which, however, may not be sufficient to test all aspects of co- carcinogenicity (Juutilainen et al. 2000). In addition, most of the carcinogenicity studies have used only one, relatively low, RF field exposure level.

Source & ©: ,  Possible Effects of Electromagnetic Fields (EMF) on Human Health (2007)
Section 3.3 Radio Frequency Fields, 3.3.2 Cancer, p.20-21

3.3 Have studies on cell cultures revealed genetic effects?

The source document for this Digest states:

3.3.2.3. In vitro

What was already known on this subject?

Various biological endpoints have been investigated after RF field exposure in vitro. Much of the work had focused on genotoxic effects, although there was no prior indication that non-thermal RF fields induce DNA damage. However, since some reports indicated genotoxic effects from RF fields, theearlier CSTEE opinion recommended the confirmation of these findings.

What has been achieved since then?”

Genotoxic effects

The photon energy of radiation from mobile phones is much lower than the energy necessary to break chemical bonds. It is therefore generally accepted that RF fields do not directly damage DNA. However, it is possible that certain cellular constituents altered by exposure to EMF, such as free radicals, indirectly affect DNA. In most studies, the genotoxic effects have been investigated after short-term exposure (for review see Moulder et al. 1999, Vijayalaxmi and Obe 2004).

The REFLEX study performed by twelve research groups in seven European countries, investigated basic mechanisms induced by EMF using toxicological and molecular biological technologies at cellular and sub-cellular levels in vitro. One of the REFLEX investigators (Diem et al. 2005) reported DNA strand breaks (measured by both the neutral and alkaline versions of the “comet” assay) in human diploid fibroblasts and cultured rat granulosa cells after RF field exposure (1800 MHz; SAR 1.2 or 2 W/kg; different modulations; during 4, 16 and 24h; intermittent 5 min on/10 min off or continuous wave), whereas it is not clear if continuous exposure of non-modulated or modulated 1800 MHz was used. Statistically significant increases in micronucleus formation and in chromosomal aberrations were observed in fibroblasts as well. In a recent replication study, (Speit et al. 2007) continuous wave with intermittent exposure (1800 MHz; SAR 2 W/kg) was applied using the same cell system and clearly negative results were obtained. Nikolova et al. (2005) reported after a 6-h but not after a 48-h RF field exposure a low and transient increase of DNA strand breaks in embryonic stem cell- derived neural progenitor cells.

Non-genotoxic effects

Several studies investigated the influence of RF fields on cell cycle kinetics, but in the majority of the investigations no effects were detected (Vijayalaxmi et al. 2001, Higashikubo et al. 2001, Zeni et al. 2003, Miyakoshi et al. 2005, Lantow et al. 2006c). Alteration in cell proliferation was described only in a few reports (Pacini et al. 2002, Capri et al. 2004b).

Programmed cell death which is also called apoptosis is a physiological mode of cell death occurring in development and cell differentiation and in response to mild damaging stimuli. It is an important protection mechanism against cancer, as it removes potential tumour cells. Several reports have investigated whether RF fields can induce apoptosis in human peripheral blood mononuclear cells (Capri et al. 2004a), lymphoblastoid cells (Marinelli et al. 2004), epidermis cancer cells (Caraglia et al. 2005), human Mono Mac 6 cells (Lantow et al. 2006c) and in Molt4 cells (Hook et al. 2004). No difference in apoptosis induction was detected between sham-exposed and RF field exposed cells. On the other hand, Marinelli et al. reported better survival rate of T lymphoblastoid leukaemia cells exposed to 900 MHz non-modulated RF fields and Caraglia et al. (2005) found apoptosis induction in human epidermoid cancer cells after exposure to 1.95 GHz RF fields.

Participants of the REFLEX-study reported no effects of RF fields on cell cycle, cell proliferation, cell differentiation, apoptosis induction, DNA synthesis, and immune cell functionality. The authors described some findings after RF fields exposure on the transcript level of genes related to apoptosis and cell cycle control; however, these responses were not associated with detectable changes of cell physiology (Nikolova et al. 2005). Analysis on whole-genome cDNA arrays showed alterations in gene expression after various RF exposure conditions using different cell types, but no consistent RF- signature such as stress response could be identified (Remondini et al. 2006)

Heat-shock proteins (HSP) are an important group of cell response proteins. They act primarily as molecular chaperones to eliminate unfolded or miss-folded proteins, which can also appear from cellular stress. This stress response can be induced by many different external factors, including temperature, chemicals, oxidative stress, heavy metals, ionizing and non-ionizing radiation and ultrafine carbon black particles. Hsp70 has been shown to interfere with post-mitochondrial events to prevent free radical mediated apoptosis (Gotoh et al. 2001). An increased expression level of Hsp70 can thus confer protection against cellular stress. On the other hand, it is discussed that heat- shock proteins are also involved in oncogenic processes (Jolly et al. 2000, Inoue et al. 1999, French et al. 2001). Some investigators have described increased heat-shock protein level after RF field exposure (Leszczynski et al. 2002, Kwee et al. 2001, de Pomerai et al. 2000). However, these results are controversial, because there are other negative findings (for a review see Cotgreave (2005)). Interestingly, de Pomerai and his co-workers could not confirm their earlier findings, and the new data indicate that small temperature differences may have contributed to the earlier results (Dawe et al. 2006).

Nikolova et al. (2005), authors of the REFLEX-study, described modulation in gene regulation after RF fields exposure at a SAR of 1.5 W/kg in p53-deficient embryonic stem cells. Proteomic analyses of human endothelial cell lines showed RF fields induced changes in the expression and phosphorylation state of numerous proteins including the heat shock protein hsp27.

Free radicals are able to interact with DNA or other cellular components and are involved in many cell regulatory processes.

In leukocytes, physiological activation is associated with the onset of phagocytosis and leads to increased formation of reactive oxygen species (ROS). These cells exert a wide variety of functions including the regulation of the immune response (pro and anti inflammatory processes), scavenging of senescent cells, phagocytosis of infected or malignant cells, wound healing, repair, and detoxification, but also the generation of free radicals to kill invading micro-organisms. Each type and source of free radicals enhances important physiological processes, e.g., signal transduction of various membrane receptors and further immunological functions. An imbalance between excessive formation of reactive oxygen species and the limited antioxidant defense, known as oxidative burst (Sies and Cadenas 1985), can cause damage to nucleic acids, membranes, proteins, lipids and polysaccharides (Beckman and Ames 1998). During healthy conditions free radicals are neutralized by an elaborate defense system. Only a few publications are available describing the capacity of RF fields to affect free radical dependent processes in cells. In recent studies (Lantow et al. 2006a, Lantow et al. 2006b, Simkó et al. 2006) no increased free radical level was detected.

Influences on immune system cells were investigated in a few studies. No significant effects were observed on intracellular production of interleukin-2 (IL-2) and interferon (INF) gamma in lymphocytes, IL-1 and tumour necrosis factor (TNF)-alpha in monocytes, on immune-relevant genes (IL 1-alpha and beta, IL-2, IL-2-receptor, IL-4, macrophage colony stimulating factor (MCSF)-receptor, TNF-alpha, TNF-alpha-receptor) (Tuschl et al. 2005, Black and Heynick 2003).

Discussion

Effects of RF fields on different biological systems have been investigated. Although the majority of studies have found no evidence of genotoxic effects, there are a few positive findings that should be followed up. Some in vitro studies provide evidence that gene expression is affected at RF exposure close to the guidelines. If these studies are confirmed they will be important for a mechanistic understanding of the interaction of RF fields with cellular tissue. Overall, there is little evidence of any health-relevant in vitro effects of RF electromagnetic fields below guidelines. While it seems appropriate to perform experimental studies using pure experimental RF fields, it may be needed to emulate the complex modulation patterns and intensity variations typical to real mobile phone use in future studies. This way data can be obtained which are better suited for comparison to epidemiologic studies.

Source & ©: ,  Possible Effects of Electromagnetic Fields (EMF) on Human Health (2007)
Section 3.3 Radio Frequency Fields, 3.3.3 Symptoms, p.22-23