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|Year : 2009 | Volume
| Issue : 1 | Page : 5--12
Cell phones and tumor: Still in no man's land
DR Kohli1, A Sachdev2, HS Vats3,
1 Government Medical College and Hospital, Sector 32, Chandigarh-160 030, India
2 Department of Internal Medicine, Sector 32, Chandigarh-160 030, India
3 Hospitalist at Marshfield Clinic, Wisconsin - USA
Department of Internal Medicine, Sector 32, Chandigarh-160 030, India
The use of cell phones is increasing worldwide at a phenomenal pace. While cellular communication has dramatically influenced our lifestyle, its impact on human health has not been completely assessed. Widespread concern continues in the community about the deleterious effects of radiofrequency radiations (with which cell phones operate) on human tissues and the subsequent potential for carcinogenesis. A detailed survey of published studies researching this question was done in preparation of this manuscript. Included in the survey were case reports, in vitro studies, population based retrospective studies and other investigations. The database of indexed journals was searched for key words like «SQ»cell phone«SQ», «SQ»radiation«SQ», «SQ»cancer«SQ» and «SQ»radio waves«SQ». Guidelines issued by the World Health Organization, federal and technical authorities, Institute of Electrical and Electronic Engineers and the International Commission for Non-Ionizing Radiation Protection were reviewed. The evaluation of current evidence provided by various studies to suggest the possible carcinogenic potential of radiofrequency radiation is inconclusive. This risk assumes significance in light of the burgeoning number of people who are continually exposed to the high frequency radiation from cell phones and towers that serve as receiving and transmitting stations. The aim of this review is to identify limitations in past studies, present available data for consideration, and identify gaps in the current knowledge base. This will provide impetus and direction for further research and allow informed decisions pertaining to cell phone use to be made.
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Kohli D R, Sachdev A, Vats H S. Cell phones and tumor: Still in no man's land.Indian J Cancer 2009;46:5-12
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Kohli D R, Sachdev A, Vats H S. Cell phones and tumor: Still in no man's land. Indian J Cancer [serial online] 2009 [cited 2021 Apr 12 ];46:5-12
Available from: https://www.indianjcancer.com/text.asp?2009/46/1/5/48589
Since the commercial introduction of cell phones in Sweden in 1981, their use has become prolific across the world. Several countries across the globe, including Italy,  Israel,  Hong Kong  and the Czech Republic,  have more cell phones than people. Concerns, however, have developed that exposure to radiofrequency radiation (RFR) from cell phones may cause/ promote carcinogenesis. Given the ubiquity of cell phones and the potential for significant impact, conclusive investigation of the risk of cancer is critical. This article presents a review of the current scientific understanding of cell phone use and health, specifically whether or not use is associated with an increased risk of brain cancer.
A systematic review of the medical literature was done in preparation of this manuscript. Using the database of indexed journals (PubMed and Ovid), an analysis of the relevant case reports, in vitro studies and population based retrospective studies was undertaken. The database was searched for key words like 'cell phone', 'radiation', 'cancer', 'malignancy', 'electromagnetic waves' and 'radio waves'. Other online search engines were utilized to source the pertinent numeric data. The guidelines issued by international bodies including the WHO database were also studied.
As will be shown, studies on cell phone use and cancer to date have drawn contradictory conclusions, making scientific consensus on the safety of cell phone use impossible. This article seeks to suggest new avenues of research so that gaps in current understanding may be clarified.
What is Radiofrequency Radiation and does it affect Human Tissues?
Electromagnetic radiation is often described by its frequency-the number of oscillations of the perpendicular electric and magnetic fields per second-expressed in hertz (one Hertz = one per second). Electromagnetic radiation is also usually measured in kilohertz (kHz), megahertz (MHz) or gigahertz (GHz).
Cell phones operate by the bidirectional transmission of radio waves of ultra-high frequency. The Global System of Mobile (GSM) communication cell phones operate at a frequency of 900 or 1800 MHz. The base stations of cell phones form a grid-like network similar to a honeycomb. A single such 'cell' can cover about 35 kilometers (22 miles). The interaction of cell phones with the base station via RFR occurs even when the phone is not in use (for talking). The frequency at which cell phones operate is in the same spectrum as that utilized by televisions and radios, thus identified as RFR. 
RFR in this range is non-ionizing radiation. It does not carry enough energy to completely move an electron none from an atom or molecule. Instead, the energy is sufficient only for excitation, the movement of an electron to a higher energy state. Therefore, RFR emitted by cell phones does not cause damage to tissues via thermal means, the normal means of radiation damage.  Herein lies the crux of the ambiguity surrounding claims of adverse health as a result of using cell phones. If the radiation emitted by cell phones is too weak to create heat damage, then by what means, if it all, could RFR emitted by a cell phone cause human tissue cellular harm?
Thus, investigation into cell phone safety must look for non-thermal means of cancer promotion. In a review article dealing primarily with the observed effects of extremely low frequency magnetic fields, several means of non-thermal damage or cellular alteration are suggested.  A hypothesis draws parallels between the head and an antenna. It proposes that the brain acts as a radio receiver to the head which catches the RFR like an antenna leading to potentially harmful effects.  Although extremely low frequency magnetic fields are not exactly the same as the RFR of cell phones, due to the non-thermal nature of the observations, it may be worthwhile to conduct similar research in the context of cell phones and brain cancer.
Suggested theories as to mechanisms of non-thermal damage have explored the possibility that exposure to extremely low frequency magnetic fields might inhibit the production of chemicals that normally prevent cellular mutation. For example, several studies suggest that such magnetic fields might affect the function of the pineal gland ,,,,, and thereby discourage the production of melatonin, an antioxidant.
Other studies suggest that extremely low frequency magnetic fields might prolong the half-life of free radicals and if production of antioxidant melatonin is simultaneously diminished, this becomes especially dangerous. , It is also suggested that such exposure deranges DNA repair leading to an increased potential for mutation, significantly increasing risk of cancer. 
In contrast to theories based primarily upon chemical concepts, another theory as to how extremely low frequency magnetic fields might damage cells is from the realm of electromagnetic physics. It has been shown that the double helix form of DNA makes it capable of conducting electricity and that when charges are applied, the helix bends. , Further investigation reports that rats exposed to 2.45 GHz of RFR (the same type, but of a much higher quantity as that emitted by cell phones) resulted in structural and genomic changes in the brain and testes  and in an increase of single and double strand breaks in the DNA of the brain. 
Alternate to investigation of a direct link between exposure to RFR emitted by cell phones and an increase in cancer risk, investigators might look for indirect indicators. Another indicator of uncontrolled cell growth is an increase in levels of ornithine decarboxylase (ODC), a rate-limiting enzyme. Its activity is elevated in all rapidly growing cells, such as transformed or cancer cells, and is markedly stimulated by tumor promoting (phorbol ester) compounds.  Over-expression of ODC in cultured cells facilitates and in some cases causes cell transformation. ,,, Its activity has been shown to be a possible indicator of electromagnetic field-induced cellular responses.  Thus, ODC could be a biomarker of cell phone induced genetic changes.
Exposure to extremely low frequency magnetic fields has been reported to enhance apoptosis, indicating a possible increase in DNA damage as a result of exposure.  Another hypothesis proposes that the radiofrequency from cell phones activates the heat shock protein 27 (hsp27), which further inhibits the apoptosis pathway (facilitating the development of brain cancer) and also increases the permeability of the blood brain barrier. These events, when occurring repeatedly over a long period, may result in cumulative brain damage. 
Clearly, should these presumptions hold true, they may all work synergistically to promote or encourage, if not directly cause, carcinogenesis. While the bulk of existing data concludes that no link exists between cell phone use and increased risk of brain cancer, such complex interactions definitely require more study before valid conclusions can be drawn.
Various public health agencies have taken the initiative to develop safety standards for occupational and public exposure to RFR. The Institute of Electrical and Electronic Engineers (IEEE) has developed RFR exposure standards. It is required by law that the standards developed thereof be periodically updated and reviewed.  The standards can be revised if new evidence is brought to light. The current scientific consensus of the IEEE is that if the radiation exposure is below the standards recommended by it, no evidence has yet been presented indicating that RFR exposure creates public health concerns. The most recent standards set by the committee for occupational exposure is 0.4 W/kg and 0.08 W/kg for environmental exposure. This is a power-to-weight measurement of acceptable exposure, expressing the relationship between electrical output and produced heat. 
The World Health Organization (WHO) is also investigating the possible effects of RFR exposure as a result of cell phone and Internet use and base stations. According to WHO, exposure to RFR from base stations is actually only 0.0002% to 2% of the levels of international exposure guidelines, lower or comparable to exposure from radio or television broadcast transmitters.  WHO, via the International Electromagnetic Field Project, has established a program to monitor the electromagnetic field scientific literature to evaluate the health effects from exposure to RFR. By these means WHO is able to provide advice about possible hazards and to identify suitable mitigation measures. WHO support has promoted research to fill gaps in the knowledge of RFR exposure concerns. 
Another multinational consortium of independent experts, the International Commission on Non-Ionizing Radiation Protection (ICNIRP), aims to review current literature and offer advice on the effects of non-ionizing radiation, which includes RFR from cell phones and base towers. ICNIRP and WHO periodically review the scientific literature and proceedings of scientific meetings in comparison with exposure guidelines published by ICNIRP. 
Agencies and initiatives such as these are important in guiding future research directives by identifying gaps in current research. They also provide unbiased and reputable guidelines to a public concerned about the influence of special interest groups.
An extensive literature search was done on topics related to RFR exposure, WHO and state guidelines, associations reported/hypothesized between RFR exposure and tumors, and various means of cellular injury by RFR hypothesized to date. Below is a survey of the pertinent existing studies. While by no means an exhaustive compilation of all existing data, this summary highlights problems with existing data and studies, early studies and their implications and suggests new directions for future research.
Concerns about Existing Data
Although most studies conducted thus far show no correlation between cell phone use and increased cancer risk, the overall results of these studies cannot be deemed conclusive because of significant limitations in data collection accuracy. Most significant are the following:
few studies assess the risk of cell phone use of more than 10 years,many studies have relied on either self-reporting or retrospective interviews to determine amount of cell phone use,exposure to RFR varies with different phone models, use of hands-free devices, whether calls were made from rural or urban locations andit is virtually impossible to eliminate exposure to RFR from other sources for studying the isolated effects of cell phones on health.
With the exception of certain studies conducted in Sweden, , few studies have been able to assess the risk of cell phone usage of more than 10 years. Only in Sweden have cell phones been in widespread use for more than a decade, , thus only the effects of short-term cell phone use have been heavily analyzed.
The nature of data collection in existing human studies remains another limitation. Documentation of amount of cell phone use has often been through retrospective interviews with users, allowing possible recall bias. In fact, reported duration of use has been up to 2.8 times the recorded time, indicating a strong tendency to overestimate true use.  Additionally, the anxiety of diagnosis of a brain tumor, the nature of the tumor or treatment thereof may affect the quality of reporting. Quality of information obtained via interviews was rated in the Finnish Interphone Study where nurses rated the quality of information obtained from glioma patients to be lower than that of control and acoustic neuroma patients.  This is an important issue to recognize when assessing accuracy of self-reported cell phone usage.
Phone model and network characteristics have a significant influence on the range of exposure. While cell phones originally operated using an analog system, since 1991 most cell phone networks have begun operating via GSM communications. GSM operates at two frequencies, 900 and 1800 MHz. The analog system utilized only one frequency, usually around 900 MHz.  Site-specific absorption rate (SAR) would be the optimal exposure measure for studies of cell phones. However, SAR measurements vary considerably depending on which phone model is used and whether the phone is utilizing the 900 or 1800 MHz frequency range.  Whether the cell phone is being used in an urban or rural area can determine the frequency utilized. One study indicated that in rural areas the highest output frequency was used 50% of the time and the lowest output used only 3% of the time.  Another study indicated a higher risk of brain tumor for cell phone users living in rural areas.  Therefore, epidemiological concerns have been raised as to whether usage reported in population studies occurred mainly in rural or urban areas, and if stratification of such data would indicate a different assessment of risk from cell phone usage.
Antenna structure also varies between phone models and can have an impact on SAR. SAR value of cell phones depends on several factors, making it practically impossible to predict SAR without assessing each model separately. The use of hands-free devices considerably reduces the SAR in the head, and utilization of this equipment should be taken into account when stratifying results of cell phone safety studies. ,,,
Another difficulty is to eliminate exposure to all other sources of RFR exposure as contributory factors, given the proliferation of electronic technology that surrounds us. This prevalence also makes finding a control group difficult beyond matching cell phone users with counterparts who simply use cell phones less often.
Review of Existing Studies Involving Exposure to RFR
Although some early studies indicated a possible correlation between non-ionizing radiation exposure, such as that emitted by cell phones, television towers and certain military technology, and increased cancer incidence, after reanalysis the findings of most of those studies have been discredited.  A 1996 Australian study initially indicated higher rates of leukemia for children living in the vicinity of FM/TV towers.  However, in 1998 reanalysis discredited these results because it was found that the increased incidence was based upon data from a single area and from cases diagnosed before the 24-hour TV transmission was introduced at most of the stations.  Later studies as to the effects of TV tower RFR on cancer rates also found no evidence of increased risk as a result of exposure. 
A 1996 study of Polish military personnel occupationally exposed to RFR reported a substantial excess risk of overall cancer and hematopoietic cancer rates.  A review of the study found several fundamental flaws in methodology and assessment that may have created a systematic bias leading to results of positive associated risk.  A study analyzing cancer incidence in conjunction with occupational exposure to RFR did not find increased mortality among workers with high exposure versus those with lower exposure, or between highly exposed workers versus the general public. This study spanning 40 years of follow-up included 40,000 Korean War veterans.  Yet another large-scale study, which included the entire workforce of a company that designed, manufactured and tested wireless devices, found no evidence of increased risk of hematopoietic or brain cancer. This study involved 17,004 workers and 20 years of follow-up. 
Although the above studies did not always focus solely on cancer incidence as related to cell phone RFR, they did analyze similar RFR exposure from other sources. The large numbers of participants and long-term follow-up of the latter two studies bolster evidence of non-association. However, like other reported case studies, ,, without further investigation, no firm conclusions can yet be drawn from this data [Table 1].
Other studies directly related to cell phone usage and brain cancer have also produced mixed results. Two Swedish studies have found links between cell phone use and increased risk of brain tumors. One study analyzed the incidence of benign brain tumors during two time periods, 1960-1979 and 1980-1998.  The rate of incidence for vestibular schwannoma increased significantly in the latter time period by an odds ratio (OR) of 3.45. For all other brain tumors taken together, the incidence significantly increased yearly by +0.80% for the time period 1960-1998, although the increase was only significant for benign tumors other than vestibular schwannoma during the first time period, 1960-1979.  The other study looked for possible associations between cell phone use and brain tumors in different age groups.  In this study analog phone use yielded significantly increased risk (OR = 1.31). The risk was highest (but not statistically significant) for the age group 20 to 29 years with OR = 1.68 and for ipsilateral use with OR = 5.91 for that age group. Digital cell phones also increased the risk for ipsilateral use, OR = 1.34, in the same age group and also in the age group 70 to 80 years. Again, it was highest in 20 to 29 years, OR = 2.84. Confidence interval (CI) for all statistics above was 95%. 
Another study conducted in Sweden did not find an association related to short-term cell phone use and acoustic neuroma but did again find an increase in the risk of developing brain cancer ipsilateral to side of phone use for those who had used cell phones for at least 10 years.  Yet another study found that cerebral tumors occurred more frequently ipsilateral to phone use but that in cases of temporal lobe tumors, the growth was more likely to be contralateral to cell phone use.  Of the few non-Swedish studies of cell phone use of 10 years or more, two found no association of increased risk with long-term use, but did again find an increased incidence of tumor ipsilateral to reported phone use. , To reiterate, these findings may be a result of recall bias. The International Agency for Research in Cancer sponsored an Interphone study that involved 13 countries (Australia, Canada, Finland, Denmark, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden and United Kingdom) to investigate the effects of cell phones in relation to the possibility of brain tumors.  The results failed to find any concrete evidence of increased risk of intracranial tumors in relation to cell phone use. At least one other study specifically mentions that no association was found among patients with brain tumors who used cell phones and tumor location,  while numerous other studies have simply found no correlation between the two.
In vitro studies provide no definitive answers either. Three studies have found noticeable differences in specimens exposed to RFR. Rats moderately predisposed to developing lymphoma were exposed to RFR to determine the potential dangers of long-term exposure to RFR of the type emitted by cell phones. Lymphoma risk was found to be significantly higher in exposed rats as opposed to sham-exposed rats (OR = 2.4, CI = 95%).  However, studies analyzing mice exposed to RFR but not predisposed to cancer have seen no similar increase in risk. ,,, Similar studies on human blood cells failed to demonstrate any effect on the human immune system. ,
Another study examined whether in vitro exposure of human peripheral blood lymphocytes to cell phone RFR resulted in cellular abnormalities.  This study observed a higher propensity for aneuploidy in chromosome 17 among exposed samples. Control samples did not exhibit the same results. Because aneuploidy is known to increase risk of cancer, the results were interpreted as meaning cell phone RFR may indeed increase risk of cancer.  Furthermore, because temperatures between exposed and non-exposed samples were matched, a non-thermal means of mutation is suggested. Since this study was conducted, other studies using human blood cultures have found no evidence of a direct effect of RFR on cytogenic endpoints or on primary DNA damage.  Further replication of this study is necessary to validate and verify its results.
A study further exploring RFR mediated non-thermal cellular damage was conducted. Cultures of the human endothelial cell line EA.hy926 were exposed to 900 MHz GSM RFR to see whether an adverse response could be observed.  Results were positive. Exposure increased the expression of the hsp27 protein. An increase in this protein may facilitate the development of cancer by inhibiting an enzyme, cytochrome c/caspase-3, important in promoting death of mutant cells.  According to the study, activation of hsp27 may also cause an increase in blood-brain permeability through stabilization of endothelial cell stress fibers.  The results of this study warrant further investigation. In contrast, a study by Hirose et al .  demonstrated no induction of phosphorylation of hsp27 or expression hsp gene family human glioblastoma cell line after exposure to cellular base station emitted radiation.
To investigate the effects of RFR on cell proliferation and apoptosis, a neuroblastoma cell line was exposed to RFR for 72 hours. Despite the exposure, the cell line did not show any significant alteration in the cellular activity.  Similar studies in rat neuronal cell lines did not demonstrate any increased apoptosis rate.  Several other recent studies have not supported DNA or significant gene-expression changes post-exposure to radiofrequency fields. ,
Acknowledging the above studies, the vast majority of studies have found no positive correlation between cell phone usage and increased risk of brain cancer. These included research of the effects of RFR exposure from cell phones on the promotion or development of neuroblastoma,  acoustic neuroma, ,,,, parotid gland tumors,  intra-temporal facial nerve tumors,  and glioma or meningioma. ,,, Numerous studies with the same conclusions exist; ,, the body of literature indicating no increased risk of cancer in conjunction with cell phone use is larger and more diverse than the culmination of existing studies indicating an increased risk of cancer [Table 2]. Nonetheless, as WHO initiatives indicate, it is also important to close any remaining gaps in research before drawing firm conclusions.
So where does all this information leave us? Safety of cell phone use remains ambiguous in all but a few areas. It has been firmly concluded that talking on cell phones while driving is dangerous. In fact, one study equated talking on a cell phone while driving as the equivalent of driving at the legal blood alcohol limit. , Legitimate concerns also exist about the safety of using cell phones outside during stormy weather; doing so increases chances of attracting a lightning strike.  At least one study indicated that cell phones can potentially affect the functioning of pacemakers, but only when the phone was held near the chest.  Cursory analysis of this information might lead one to conclude that cell phone use won't cause problems with pacemakers, as phones are essentially for talking and thus held near the head. However, as cell phones evolve from purely audio communication devices to entertainment/organizational gadgets it becomes likely that positions in which they are held will vary. Thus, it is important to keep in mind the possible interactions of cell phones with implanted medical devices.
In order to better establish potential cell phone safety standards, it is imperative to resolve gaps in the current body of knowledge through well-designed, preferably prospective, studies. Large-scale and long-term prospective studies have been difficult to conduct due to the relatively recent introduction of cell phones. However, since use is increasing exponentially, it is now feasible to begin long-term prospective studies among diverse populations.
Of note, children of grade-school age have recently become the new marketing target for cell phones. This previously unstudied population is especially important for two reasons: (1) children's skulls are of thinner bone; so stimuli may have stronger effects on children than on adults and (2) this trend is novel, therefore, the optimal time to begin prospective studies so that if adverse effects are indeed discovered, there is less exposure before solutions are implemented.
Of the few long-term studies previously discussed, analyses included phone users exposed to both analog and GSM phones. This distinction may be important because analog phones emit RFR in pulses, while the emission of RFR from GSM phones is continuous.  Since the majority of phones now operate via GSM, it is possible to eliminate this ambiguity as well.
It would also be beneficial to the current body of evidence to conduct in vitro studies of animals more closely related to humans, such as pigs and primates. The majority of existing in vitro animal studies are of the effects of RFR on rats or mice. Well-designed studies on animals more closely related to humans might serve to eliminate concerns that arise from potential recall bias among human users of cell phones, especially in studies that are retrospective/ rely on self-reporting of use.
With few undisputed studies indicating increased risk of brain cancer in relation to cell phone use, current standards regarding RFR exposure appear to be adequate. Continued valid research will eventually resolve current uncertainties and public policy will be reanalyzed and adjusted accordingly.
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