Introduction
Glioma, the most common primary brain tumor that comprises morphologically distinct cancers such as astrocytoma, ependymoma, and oligodendro glioma [1], is a malignant tumor in the central nervous system with a corresponding high fatality rate. According to the data of the Statistics Korea, 1703 persons with brain or central nervous system tumors accounted for 0.7% of 244177 new cancer cases in 2012 [2]. There are several factors that may have increased the risk of gliomas, including exposure to radiation, genetic drift, and electromagnetic field [3], but the exact causes of gliomas are yet to be determined.
From a health-prospective, concerns have been raised regarding microwaves transmitted from the antenna of a mobile phone could cause brain tumors or increase the risk of the development of potential tumors [4-7] albeit its low-power. In particular, exposure to radiofrequency-electromagnetic field (RFEMF) has been receiving attention due to its negative effect on health, amidst the rapid spread of the use of wireless information service systems.
Most epidemiologic research studies conducted so far on the use of mobile phones and gliomas have failed to show any increase in danger caused by the long-term use of mobile phones [8-13].
However, some studies have reported findings on the relationship between gliomas or brain tumors and the use of mobile phones as follows: the odds ratios (OR) and 95% confidence intervals (CI), i.e., the risk of gliomas when using an analog mobile phone is 1.8 (1.1 to 3.2) [14], the OR (95% CI) for brain tumors based on the use of mobile phones in rural areas is 1.4 (0.98 to 2.0) [15] and 1.12 (0.79 to 1.61) [16], the OR (95% CI) for brain tumors based on the use of analog mobile phones is 2.3(1.2 to 4.1) [14], and the OR (95% CI) associated with use of an analog mobile phone and gliomas is 2.1 (1.3 to 3.4) [17].
In this regard, the International Agency for Research on Cancer (IARC), an international organization for cancer research under the World Health Organization (WHO), examined the validity of epidemiologic research in 1997 in order to investigate the association between the generation of electromagnetic waves from mobile phones and cancer. Subsequently, they started a set of international case-control studies on the link between the use of mobile phones and the development of brain tumors (Interphone study), in which a total of 13 countries participated [18].
The results of recent international epidemiologic studies have increased popular interest in possible health problems and gliomas and other brain tumors owing to the use of mobile phones [4,19-23]. However, little has been known as to their potential mechanisms. Furthermore, there is not enough evidence, either epidemiological or experimental, to support whether RF-EMF has detrimental effect on organisms [24]. Nevertheless, electromagnetic waves from mobile phones may have had a comparatively high effect on the nerves and meningeal tissues close to the surface of the head, thus gliomas and meningiomas become our main concerns.
In 2013, the leading cause of death in Korea was cancer: 144.4 in every a hundred thousand people died of cancer, and 2.4 in every a hundred thousandpeople died of brain tumors.
The use of mobile phones is increasing not only in overseas countries but also in Korea. Statistics showed that subscribers to mobile phones in Korea alone were 47944 thousand in 2009, 50767 thousand in 2010, 52507 thousand in 2011, and 53625 thousand in 2012 [25]. Korea is characterized by relatively high levels in terms of mobile penetration, cumulative hours of use, and lifetime years of use.
Given such an abrupt increase in mobile phone usage, it is important in terms of public health to determine whether electromagnetic waves transmitted by mobile phones are harmful and to carry out the epidemiologic study. Although considerable researches on the effect of electromagnetic waves from mobile phones have been carried out in many countries, there have been few studies that examine the possible link between electromagnetic waves and gliomas in Korea.
Therefore, this study aimed to investigate a possible association between mobile phone use and glioma using a case-control design in nine Korean hospitals based on the protocol of Interphone study [26].
Materials and Methods
Study Subjects
In its final analysis, this study examined 285 patients among 897 patients with gliomas, who were recruited from five areas including Seoul (Seoul, Gyeonggi-do, Gyeongsang-do, Jeolla-do, Chungcheong-do, Gangwon-do, and Jeju-do) and were checked at department of neurosurgery in nine hospitals (Korea University Hospitals (Anam, Guro, Ansan), Inje University Sanggye Paik Hospital, Samsung Medical Center in Seoul, Seoul National University Hospital, Asan Medical Center, Korea Cancer Center Hospital, and Hallym University Sacred Heart Hospital) from 2002 to 2007. The other 612 patients were excluded due to refusal of participation, excessive pain, and impossibility of individual matching (Table S1). The patient group consisted of those who were pathologically diagnosed with gliomas aged between 15 years and 69 years (International Classification of Diseases for Oncology-3 codes 9380-9384, 8391-9460, and 9480) (Table 1) [27].
The control group subjected to the final analysis consisted of 285 healthy persons out of a total of 1051 who randomly received health screenings at the same hospitals as the patient group and were individually matched according to the method for selecting patient-control groups as proposed by the IARC Interphone study team, excluding 766 for the reasons of refusal of participation, excessive pain, and insincere responses (Table S1). The nine hospitals that participated in the study reported patient groups of the diseases to our research team within one week after diagnosis. A questionnaire survey was performed in the individual interview to obtain information for general characteristics and potential confounders. The informed consent was obtained from each subject before enrollment and institutional review board of Korea University approved the study.
Mobile Phone Use Information
Information related with mobile phone use was obtained by a self-administered questionnaire. The types of mobile phone use analog, analog+digital, and digital mobile phones), the lifetime years of use before one year from diagnosis (non-user, <48 months, 48-84 months, and >84 months) the cumulative hours of use (non-user, <300 hours, 300-900 hours, and >900 hours) were obtained. The total amount of mobile phone use was calculated with cumulative hours and lifetime years of use. The monthly service fee was divided into < 30, 30-49, 50-80, and > 80 (unit: 103 Korean won, KRW). Moreover, the average daily receiving call and the average daily sending call were divided into ≤2 times, 3-5 times, 6-9 times, and ≥10 times; and the average call duration time was divided into ≤2 minutes, 3-4 minutes, and ≥5 minutes. The types of mobile phones were classified into flip-type, slide-type, and folder-type; and the regions for carrying a mobile phone during travel were divided into bag, neck, shoulder, pants, and hands. Finally, the usual use of a mobile phone has two categories, rural and urban area.
Confounders or Covariates
Independent variables in the analysis of case-control groups for this study include sex, age (20s, 30s, 40s, 50s, and 60s or older), residential region (Seoul, Gyeonggi, Gyeongsang, Jeolla, Chungcheong, Gangwon, and Jeju), marital status (married, unmarried, others), educational achievement (primary school or lower, middle school or lower, high school or lower, and university or above), annual income level ( < 10, 10-29, 30-49, and ≥ 50, unit: million KRW) respondent (patient in person and proxy: spouse or other family member), and the existence of a transmission tower within 300 m from the residential area. The alcohol drinking (non-drinking, one drink or more a month on average for last one year) and smoking (non-smoking, current smoking) were considered.
Statistical Analysis
To compare characteristics between cases and controls, χ2 test or Fisher’s exact test was performed. The unconditional logistic regression adjusted for sex, age, type of respondent, five residential regions, educational achievement, the use of dye, alcohol drinking, the use of computer, and the use of electric blanket was used to estimate the risk of the brain tumor in relation with usage of mobile phone. Adjusted odds ratios (aORs) and 95% CIs were calculated. As for whether tumor location corresponds to the hand and the body region primarily used during mobile phone call, statistical significance was assessed with relative risk (RR) and p-value the method proposed by Inskip et al. [9], (RR=[√OR+1] ÷2). All the statistical analyses of this study were conducted with SPSS version 12.0 (SPSS Inc., Chicago, IL, USA) and the significance level was 0.05.
Results
The general characteristics of the subjects are as shown in Table 2. Among 285 in the cases, 159 (55.8%) were male and 126 (44.2%) were female. The average ages of the cases and the controls were 42.3 (±14.1) and 42.5 (±14.0), respectively. As for the residential region, 182 resided in Seoul and Gyeonggi, accounting for 63.9% of the overall patients. For the marital status, married (73.7%, 2 in the patient group) were more than the unmarried and others. High school graduates were the most (46%, 131 in the patient group) and for the annual income level, 10-29 million KRW was the highest (49.5%, 137 in the patient group). Furthermore, there were significant differences between cases and controls, in residential region, educational achievement, respondent type, the use of dye, alcohol drinking, the use of computer, and the use of electric blanket.
As for the mobile phone non-users, 9 were male and 37 were female, and the average ages of the cases and controls were 47.3 (±16.0) and 50.4 (±16.4), respectively. There was no significant difference between the mobile phone non-user group and the mobile phone user group in residential region, marital status, and the type of respondent (data not shown).
While the aOR (95% CI) for those who used the mobile phone regularly was 1.17 (0.63 to 2.14), the aOR (95% CI) for the self-respondents was found to be 0.94 (0.46 to 1.89) compared with those who seldom or occasionally used the mobile phone. No significant relationship was found in the regular mobile phone use, the type of mobile phone, the lifetime years of use, the monthly average service fee, and the carriage during travel. However, aOR (95% CI) was 1.92 (0.83 to 4.44) in case the self-respondents used analog and digital simultaneously, 1.35 (0.63 to 2.89) in case the model of mobile phone was folder-type, and 1.42 (0.66 to 3.07) for urban residential region, which was found to be higher than 0.50 (0.22 to 1.13) for rural residential region at a non-significant level (Table 3).
As a result of analyzing the relation between the body side of usual mobile phone use and the location of glioma using the Inskipet et al.’s method [9], the RR was found to be 1.26 (p=0.05) for the overall respondents with the glioma, and 1.43 (p=0.01) for self-respondents (Table 4).
The relationship was adjusted for sex, age, residential region, educational achievement, the use of dye, alcohol drinking, the use of computer, and the use of electric blanket. The risks of glioma for different levels of mobile phone use by ipsilateral and contralateral body side were shown in the Table 5 (total respondents) and Table S2 (self-respondents). In the case of ipsilateral users for total respondents, aORs (95% CI) for the lifetime years of use, cumulative hours of use, the average daily frequency of receiving a call, and the average daily frequency of sending a call were 1.25 (0.55 to 2.88), 1.77 (0.32 to 1.84), 1.52 (0.56 to 4.10), and 3.13 (0.83 to 11.31), respectively, which were found to be high at a non-significant level. On the other hand, contralateral users showed slightly lower aORs (95% CI) than ipsilateral users (Table 5).
Discussion
After adjusting for sex, age, residential region, and other variables, this study found no significant relationship between gliomas and mobile phone use, i.e., hours since the initial use of a mobile phone, the period of use, the average daily frequency of receiving a call, the average daily frequency of sending a call, and the monthly average service fee. However, some findings, showed that the risk of gliomas increased at a non-significant level with the folder-type mobile phone and the urban region. It also increased with the simultaneous use of analog and digital phones, the lifetime years of use, the cumulative hours of use, the monthly average service fee, and the average daily frequency of sending a call, for the case of ipsilateral users.
It has been reported that data on the deposition of wireless frequency energy resulting from the form of a car phone or a mobile phone, or the mode of carrying a mobile phone during travel, can be used for an anatomic division of tumorigenesis [28]. The results of this research showed an increased risk, although not statistically significant, when the phone was placed in a shirt pocket among the body regions for carrying a mobile phone during travel. The same results were found for self-respondents. Thus, it is deemed that the location of a mobile phone or the body region has no effect on the development of gliomas. In addition, as a result of this study, it was found that the risk had no particular relationship with a mobile phone service company. The aOR (95% CI) for the folder type mobile phones was 1.35 (0.63 to 2.89) among the self-respondents, which seems to reflect its more users than those of the sliding type, and social and economic status and educational achievement.
In addition to the frequency and duration of mobile phone use, factors that can affect the degree of exposure to micro-electromagnetic waves include the distance from a base transceiver station, localized topography, vegetation, the indoor or outdoor use of a mobile phone, a particular mobile-phone model, the position of an antenna, and the relation between the head and a phone [29,30]. It is difficult to divide and explain these variables with respect to the degree of exposure, and it seemed that these factors were unable to artificially change the frequency of mobile phone use and the time of its use. Therefore, in this study, it was actually possible to investigate the frequency of mobile phone use and the length of its use alone. Some studies revealed that the electromagnetic effect is affected by the use of the electric blanket [31,32].
In this study, the ratio of self-respondents in the patient group and the control group was 86.3% (n = 492) higher than that of proxy respondents. This seems to be resulting from the fact that patients with gliomas do not have the symptoms of disease with hearing loss that can shift the position of using the mobile phone onto the other side, unlike those with other brain tumors or acoustic neurinomas. It seems to be also because with neurologically good condition, they remembered things well and were cooperative with the survey questions.
Overall, epidemiologic studies conducted so far on the relationship between mobile phone use and diseases have not found relationship between the use and cancer genesis [6,8,9]. Moreover, studies on Denmark [10] and Sweden [11] reported that there was no significant relationship between brain tumors and electromagnetic waves emitted by a mobile phone. Also, a case-control study (Interphone study) initiated as an international set of case-control studies in 13 countries around the world [26] focusing on mobile phone use and the risk of brain tumors, showed no risk of gliomas and meningiomas associated with mobile phone use [10,11], which agrees with the findings of this study.
On the other hand, a study reported borderline levels of effects on the risk of gliomas and the use of analog cellular phones, with 432 cases of brain tumor and salivary gland cancer diagnosed in Finland in 1996, with five controls per case [17]. In addition, a case-control study published in 2003 (1617 cases) reported the association of analog mobile phone use with brain tumors [14]. Health hazards, such as an increase in standardized mortality ratio [33] pursuant to the increase of the time of usage [29]and an increase of ocular melanoma occurrence [30] were reported additionally [34].
Overall, findings of studies conducted so far show inconsistent results on the link between electromagnetic waves emitted by mobile phones and brain tumors. Such conflicting results can be attributed to ecological error, inaccuracy of exposure evaluation, and failure to control the information on confounding variables.
In the case where the body side of usual mobile phone use agreed with the location of a glioma (ipsilateral use) for all the respondents, the aOR (95% CI) for the lifetime years of use, the cumulative hours of use, the average daily frequency of receiving a call, and the average daily frequency of sending a call were 1.25 (0.55 to 2.88), 1.77 (0.32 to 1.84), 1.52 (0.56 to 4.10), and 3.13 (0.83 to 11.31), respectively. On the contrary, in the case of disagreement, they showed aOR (95% CI) that was slightly lower. The results correspond to findings of other research on acoustic neurinomas [35] and gliomas [14]. However, some studies on gliomas and meningiomas did not show the increase in risk [11]. In addition, a study involving 678 cases and 3553 controls selected from Sweden, Denmark, Norway, Finland, and two regions in the UK found no relationship of risk with duration of mobile phone use, lifetime years of use or number of calls. Nevertheless, it reported that the risk of brain tumor on the same side of the head as mobile phone use was raised for use for 10 years or longer [36].
In the present study, the analysis result showed an RR of 1.43 (p= 0.01). The study conducted by Inskip et al. [9] showed an RR of 0.9 (p= 0.77) in gliomas, a Japanese study an RR of 0.72 (p= 0.001) in acoustic neurinomas [23] and an Israeli study an RR of 1.32 (p= 0.001) in parotid gland tumors [16], respectively. This showed a consistency among different studies to suggest a stronger association in the same laterality.
The limitations of this study were as follows: First, it is not possible to exclude the possibility of recall bias that might be caused by the patients’ untruthful response, avoidance, memory loss, or exaggeration as to some exposure factors of the questionnaire that included the situation in which the patients knew already they belonged to the patent group. Thus, this study excluded subjects aged 70 or older for the seeming difficulty of deriving accurate responses due to their advanced age. Second, it is probable that selection bias worked because persons relatively more interested in mobile phone radiation participated, and responses could differ between the self-respondents and the proxy respondents. Therefore, this study carried out analysis according to the types of respondents. Third, old subjects of this study aged 60 or older rarely use mobile phones, compared with the young. Therefore, the possibility should be considered that a proper number of samples failed to be obtained. Fourth, during the selection of the patient group, given the dead who died of serious conditions, selection bias may have resulted from including in this study only patients who survived the research period. Thus, it is possible that findings of the current study, which included only mild cases, but excluded the lost, have been underestimated.
Despite the many limitations mentioned above, this case-control study, could secure comparability between the two groups as much as possible. The patient group and the control group were selected by the same standard from the same source population, and the same method was applied to the process of obtaining necessary information from the questionnaire survey. That is, variability could be reduced in collecting information on risk factors since the institutions of the nine hospitals that participated in the research used the standardized common protocol. Furthermore, it was possible to explore the dose-response relationship by grasping the frequency and duration of use, using the personal exposure to the mobile phone found from an additional questionnaire survey on. Such were educational achievement, the type of respondent, the use of dye, alcohol drinking, the use of computer, and the use of electric blanket as well as sex, age, and residential region. This study has the advantage of being the first large-scale research ever performed in Korea on the relationship between gliomas and mobile phone radiation.
Future studies with longer time users and to elucidate the biological mechanism are needed.
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