Mobile Phone Use and Risk of Tumors: A Meta-Analysis
Publication: Journal of Clinical Oncology
Abstract
Purpose
Case-control studies have reported inconsistent findings regarding the association between mobile phone use and tumor risk. We investigated these associations using a meta-analysis.
Methods
We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library in August 2008. Two evaluators independently reviewed and selected articles based on predetermined selection criteria.
Results
Of 465 articles meeting our initial criteria, 23 case-control studies, which involved 37,916 participants (12,344 patient cases and 25,572 controls), were included in the final analyses. Compared with never or rarely having used a mobile phone, the odds ratio for overall use was 0.98 for malignant and benign tumors (95% CI, 0.89 to 1.07) in a random-effects meta-analysis of all 23 studies. However, a significant positive association (harmful effect) was observed in a random-effects meta-analysis of eight studies using blinding, whereas a significant negative association (protective effect) was observed in a fixed-effects meta-analysis of 15 studies not using blinding. Mobile phone use of 10 years or longer was associated with a risk of tumors in 13 studies reporting this association (odds ratio = 1.18; 95% CI, 1.04 to 1.34). Further, these findings were also observed in the subgroup analyses by methodologic quality of study. Blinding and methodologic quality of study were strongly associated with the research group.
Conclusion
The current study found that there is possible evidence linking mobile phone use to an increased risk of tumors from a meta-analysis of low-biased case-control studies. Prospective cohort studies providing a higher level of evidence are needed.
Introduction
The worldwide use of mobile phones has rapidly increased over the past decade. According to data from the International Telecommunication Union, the number of worldwide mobile cellular subscribers was 12.2 per 100 inhabitants in 2000 but grew to 49.5 per 100 inhabitants in 2007.1 With the increasing use of mobile phones (ie, cellular phones and cordless phones), concern has been raised about the possible carcinogenic effects as a result of exposure to radiofrequency electromagnetic fields (EMFs) emitted from cellular phones ranging from 800 to 2,000 MHz,2,3 which fall in the microwave spectrum. Although some in vitro studies reported the potential effects of high-frequency EMFs on cell proliferation and activation of oncogene transcription,4–6 those biologic effects and mechanisms in developing neoplasm remain unclear. Over the past decade, epidemiologic studies (mainly case-control) also have reported the relationships between the use of mobile phones and malignant or benign tumors such as brain tumors, head and neck tumors, non-Hodgkin's lymphoma, and testicular cancer.7–28
Some case-control studies have suggested a positive (ie, harmful) association between the use of mobile phones and the risk of tumors,7,10–12,15–18,23,25,27 whereas other case-control studies have reported no significant association.8,9,11,13,14,19–22,24,26,28 Also, the only retrospective cohort study reported no evidence for the association among either short-term or long-term users.29,30
Regarding the conflicting scientific evidence, three meta-analyses reported no association or a slight increased risk.31–33 However, these meta-analyses involved only brain tumors. In the current study, we investigated the associations between the use of mobile phones and the risk of tumors, including both malignant and benign conditions, via a meta-analysis of case-control studies.
Methods
Literature Search
We searched MEDLINE (PubMed; 1968 to August 2008), EMBASE (1977 to August 2008), and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (1953 to August 2008) using common keywords related to mobile phones and tumor or cancer. The keywords were as follows: “mobile phones,” “cellular phones,” or “cordless phones” and “tumors” or “cancer.” We also reviewed the bibliographies of relevant articles to locate additional publications. The language of publication was not restricted.
Selection Criteria
We included epidemiologic studies that met all of the following criteria: case-control study (to date, no randomized controlled trials and only one retrospective cohort study published in four different articles have been reported; therefore, we included only case-control studies in this study); investigated the associations between the use of mobile phones, cellular phones, or cordless phones and malignant or benign tumors; reported outcome measures with adjusted odds ratios and 95% CIs, crude odds ratios and 95% CIs, or values in cells of a 2 × 2 table (from which odds ratios could be calculated). If data were duplicated or shared in more than one study, the first published or more comprehensive study was included in the analysis.
Selection of Relevant Studies
Two of the authors (S.-K.M. and W.J.) independently evaluated eligibility of all studies retrieved from the databases based on the predetermined selection criteria. Disagreements between evaluators were resolved by discussion or in consultation with a third author (D.D.M.).
Assessment of Methodologic Quality
We assessed the methodologic quality of included studies based on the Newcastle-Ottawa Scale (NOS) for quality of case-control studies in meta-analyses.34 A star system of the NOS (range, 0 to 9 stars) has been developed for the assessment. In the current study, we considered a study awarded 7 or more stars as a high-quality study because standard criteria have not been established. The mean value for the 23 studies assessed was 6.3 stars.
Main and Subgroup Analyses
We investigated the association between the use of mobile phones (use v never or rarely use, if possible) and the overall risk of all tumors by using adjusted data as a main analysis. We also performed subgroup analyses by whether the status of patient cases and controls was blinded at interview (blinded or not blinded/no description), research group (adjusted or crude data), methodologic quality (high or low quality), type of tumor, malignancy of tumor (malignant or benign), type of mobile phone (analog or digital), laterality of tumor (ipsilateral or contralateral), and type of case-control study (hospital based or population based). Furthermore, we investigated the association between long-term mobile phone use (≥ 10 years) and the risk of tumors, including subgroup analyses by the factors listed earlier.
Statistical Analyses
To compute a pooled odds ratio with 95% CI, we used the adjusted odds ratio and 95% CIs reported in each article whenever possible. We examined heterogeneity in results across studies using Higgins I2, which measures the percentage of total variation across studies.35 We considered an I2 value of greater than 50% as indicative of substantial heterogeneity.
When substantial heterogeneity was not observed, the pooled estimate calculated based on the fixed-effects model was reported using the Woolf's (inverse variance) method. When substantial heterogeneity was observed, the pooled estimate calculated based on the random-effects model was reported using the DerSimonian and Laird method.36
We evaluated publication bias of the studies included in the final analysis using Begg's funnel plot and Egger's test. If publication bias exists, Begg's funnel plot is asymmetric or the P value is less than .05 by Egger's test. Also, a meta-regression analysis was performed to assess the effect of subgroups and study characteristics, such as research group, year of publication, type of tumor, and study design, on the study results. Blinding and methodologic quality were excluded because of multicollinearity with research group. We used Stata SE version 10.0 software package (StataCorp, College Station, TX) for statistical analysis.
Results
Identification of Relevant Studies
Figure 1 shows a flow diagram of how we identified relevant studies. A total of 465 articles were identified by searching three databases and hand-searching relevant bibliographies. We excluded 135 duplicate articles and an additional 287 articles that did not satisfy the selection criteria. After reviewing the full texts of the remaining 43 articles, 21 articles37–57 were excluded because of several reasons, as shown in Figure 1. The remaining 23 case-control studies from 22 articles7–28 were included in the final analysis (the study by Auvinen et al11 was considered as two individual case-control studies).
Characteristics of Studies Included in the Final Analysis
In the 23 case-control studies, we identified a total of 37,916 participants (12,344 patient cases and 25,572 controls). For studies reporting age and sex, the mean age was 52.6 years (range, 18 to 90 years), and 51% of the participants were women.
Appendix Table A1 (online only) shows the general characteristics of the 23 case-control studies (22 articles) included in the final analysis. The percentage of study participants who reported having used a mobile phone was 43.5% among the patient cases and 45.2% among the controls (data not shown in Appendix Table A1).
Overall Use of Mobile Phones and Risk of Tumors
As shown in Figure 2, the overall use of mobile phones (use v never or rarely use) was not significantly associated with the risk of tumors in a random-effects model meta-analysis of all 23 case-control studies (odds ratio = 0.98; 95% CI, 0.89 to 1.07). However, a significant positive association (ie, harmful effect) was observed in eight studies7,12,14–16,18,23 and one study by another group10) using blinding (odds ratio = 1.17; 95% CI, 1.02 to 1.36), whereas a significant negative association (ie, protective effect) was observed in 15 studies (nine INTERPHONE-related studies17,20–22,24–28 and six studies by other groups8,9,11,13,19) not using blinding (odds ratio = 0.85; 95% CI, 0.80 to 0.91). No publication bias was observed in the selected studies (Begg's funnel plot was symmetric; Egger's test, P for bias = .21; Fig 3).
Table 1 shows the methodologic quality of studies included in the final analysis. The range of quality scores was 5 to 8; the average score was 6.3. The high-quality studies (score of ≥ 7) included all seven of the studies by Hardell et al, one INTERPHONE-related study, and two studies by other groups. The low-quality studies (score of < 7) included eight INTERPHONE-related studies and six studies by other groups.
| Study | Selection (score) | Comparability (score) | Exposure (score) | Total Score† | |||||
|---|---|---|---|---|---|---|---|---|---|
| Adequate Definition of Patient Cases | Representativeness of Patient Cases | Selection of Controls | Definition of Controls | Control for Important Factor or Additional Factor | Ascertainment of Exposure (blinding) | Same Method of Ascertainment for Participants | Nonresponse Rate* | ||
| Hardell et al7 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 7 |
| Muscat et al8 | 1 | 0 | 0 | 1 | 2 | 0 | 1 | 0 | 5 |
| Inskip et al9 | 1 | 0 | 0 | 1 | 2 | 0 | 1 | 0 | 5 |
| Stang et al10 (hospital based) | 1 | 1 | 0 | 0 | 2 | 1 | 1 | 0 | 6 |
| Stang et al10 (population based) | 1 | 1 | 1 | 0 | 2 | 1 | 1 | 0 | 7 |
| Auvinen et al11 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 6 |
| Auvinen et al11 2 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 6 |
| Hardell et al12 | 1 | 1 | 1 | 0 | 2 | 1 | 1 | 0 | 7 |
| Warren et al13 | 1 | 1 | 0 | 1 | 1 | 0 | 1 | 0 | 5 |
| Hardell et al14 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 7 |
| Hardell et al15 | 1 | 1 | 1 | 0 | 2 | 1 | 1 | 1 | 8 |
| Hardell et al16 | 1 | 1 | 1 | 0 | 2 | 1 | 1 | 0 | 7 |
| Schoemaker et al17 | 1 | 1 | 1 | 1 | 2 | 0 | 1 | 0 | 7 |
| Hardell et al18 | 1 | 1 | 1 | 0 | 2 | 1 | 1 | 1 | 8 |
| Linet et al19 | 1 | 1 | 1 | 1 | 2 | 0 | 1 | 0 | 7 |
| Lönn et al20 | 1 | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 6 |
| Schüz et al21 | 1 | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 6 |
| Takebayashi et al22 | 1 | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 6 |
| Hardell et al23 | 1 | 1 | 1 | 0 | 2 | 1 | 1 | 1 | 8 |
| Hours et al24 | 1 | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 6 |
| Lahkola et al25 | 1 | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 6 |
| Lahkola et al26 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 5 |
| Sadetzki et al27 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 5 |
| Takebayashi et al28 | 1 | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 6 |
*
When there was no significant difference in the response rate between both groups by using a χ2 test (P > .05), one point was awarded.
†
Total score could range from 0 to 9 points.
A subgroup meta-analysis by research group showed a significant positive association for the seven studies reported by Hardell et al but a significant negative association for nine INTERPHONE-related studies (Table 2). When using crude data, a significant association was not found in any of the 23 studies or in subgroup analyses by research group.
| Factor | No. of Studies | Summary OR | 95% CI of OR | Heterogeneity, I2 (%) | Model Used |
|---|---|---|---|---|---|
| All | 23 | 0.98 | 0.89 to 1.07 | 59.7 | Random effects |
| Research group | |||||
| Hardell et al* | 7 | 1.15 | 1.01 to 1.32 | 52.1 | Random effects |
| INTERPHONE† | 9 | 0.83 | 0.77 to 0.89 | 0 | Fixed effects |
| Other groups | 7 | 0.99 | 0.86 to 1.14 | 30.6 | Fixed effects |
| Research group (crude data) | 23 | 0.97 | 0.87 to 1.08 | 73.6 | Random effects |
| Hardell et al | 7 | 1.14 | 0.96 to 1.35 | 71.0 | Random effects |
| INTERPHONE | 9 | 0.88 | 0.75 to 1.03 | 79.8 | Random effects |
| Other groups | 7 | 0.90 | 0.79 to 1.03 | 22.6 | Fixed effects |
| Methodologic quality | |||||
| High (low bias: ≥ 7 points)* | 10 | 1.09 | 1.01 to 1.18 | 46.3 | Fixed effects |
| Hardell et al* | 7 | 1.15 | 1.00 to 1.32 | 52.1 | Random effects |
| INTERPHONE | 1 | 0.90 | 0.70 to 1.10 | NA | NA |
| Other group | 2 | 1.02 | 0.75 to 1.38 | 0 | Fixed effects |
| Low (high bias: < 7 points)† | 14 | 0.85 | 0.79 to 0.91 | 5.7 | Fixed effects |
| INTERPHONE† | 8 | 0.82 | 0.76 to 0.88 | 0 | Fixed effects |
| Other groups | 6 | 0.97 | 0.83 to 1.14 | 24.2 | Fixed effects |
| Malignancy of tumor | |||||
| Malignant | 15 | 1.00 | 0.89 to 1.13 | 52.0 | Random effects |
| Hardell et al | 6 | 1.11 | 0.96 to 1.29 | 50.5 | Random effects |
| INTERPHONE† | 4 | 0.78 | 0.67 to 0.91 | 0 | Fixed effects |
| Other groups | 5 | 0.97 | 0.80 to 1.18 | 19.6 | Fixed effects |
| Benign | 15 | 0.87 | 0.80 to 0.95 | 20.7 | Fixed effects |
| Hardell et al | 4 | 1.17 | 0.97 to 1.42 | 3.8 | Fixed effects |
| INTERPHONE† | 8 | 0.81 | 0.73 to 0.90 | 0 | Fixed effects |
| Other groups | 3 | 0.82 | 0.61 to 1.11 | 0 | Fixed effects |
| Type of mobile phone | |||||
| Analog | 12 | 0.96 | 0.87 to 1.07 | 49.9 | Fixed effects |
| Hardell et al | 7 | 1.04 | 0.89 to 1.22 | 34.5 | Fixed effects |
| INTERPHONE† | 3 | 0.84 | 0.72 to 0.96 | 0 | Fixed effects |
| Other groups* | 2 | 1.55 | 1.08 to 2.2 | 0 | Fixed effects |
| Digital | 14 | 0.95 | 0.84 to 1.08 | 55.8 | Random effects |
| Hardell et al | 7 | 1.10 | 0.97 to 1.24 | 12.7 | Fixed effects |
| INTERPHONE† | 5 | 0.78 | 0.71 to 0.85 | 0 | Fixed effects |
| Other groups | 2 | 0.93 | 0.55 to 1.59 | 0 | Fixed effects |
| Laterality of tumor | |||||
| Ipsilateral | 12 | 1.22 | 0.99 to 1.51 | 85.9 | Random effects |
| Hardell et al* | 4 | 1.80 | 1.24 to 2.62 | 84.9 | Random effects |
| INTERPHONE | 8 | 1.00 | 0.91 to 1.10 | 37.0 | Fixed effects |
| Contralateral | 11 | 0.94 | 0.77 to 1.15 | 82.3 | Random effects |
| Hardell et al | 3 | 1.31 | 0.74 to 2.31 | 93.0 | Random effects |
| INTERPHONE† | 8 | 0.81 | 0.74 to 0.89 | 48.2 | Fixed effects |
| Type of case-control study | |||||
| Hospital based (all other groups) | 4 | 0.89 | 0.74 to 1.07 | 0.0 | Fixed effects |
| Population based | 20 | 0.99 | 0.89 to 1.09 | 61.8 | Random effects |
| Hardell et al* | 7 | 1.15 | 1.01 to 1.32 | 52.1 | Random effects |
| INTERPHONE† | 9 | 0.83 | 0.77 to 0.89 | 0 | Fixed effects |
| Other groups | 4 | 1.14 | 0.91 to 1.43 | 0 | Fixed effects |
Abbreviations: OR, odds ratio; NA, not applicable.
*
Statistically significant positive association.
†
Statistically significant negative association.
Subgroup meta-analyses by methodologic quality of study revealed a significant positive association in the high-quality studies (odds ratio = 1.09; 95% CI, 1.01 to 1.18), whereas a negative association was observed in the low-quality studies. In subgroup meta-analyses by malignancy of tumor, no significant association was observed for malignant tumors. However, a significant negative association was observed for benign tumors. Neither the use of analog phones nor the use of digital phones was associated with the risk of tumors. The ipsilateral use of mobile phones (ie, on the same side of the head where the tumor exists) was marginally associated with the risk of tumors in the 12 studies reporting tumor laterality.
Mobile Phone Use of 10 Years or Longer and Risk of Tumors
Among the 23 studies, there was a significant positive association between mobile phone use of 10 years or longer and the risk of tumors in a fixed-effects meta-analysis of 13 studies reporting this association (odds ratio = 1.18; 95% CI, 1.04 to 1.34; Fig 4; Appendix Table A2, online only). As for blinding, a fixed-effects meta-analysis of the seven blinded studies showed a positive association, whereas a fixed-effects meta-analysis of the six unblinded studies showed no significant association.
In the subgroup meta-analyses by methodologic quality, a significant positive association was found in the eight high-quality studies but not in the seven low-quality studies. With regard to tumor malignancy, mobile phone use of 10 years or longer was significantly positively associated with the risk of benign tumors but not with the risk of malignant tumors.
The use of analog phones for 10 years or longer was positively associated with the risk of tumors. However, further subgroup analyses by research group showed a significant association only in the studies by Hardell et al.7,12,14–16,18,23 Regarding the laterality of tumors and mobile phone use of 10 years or longer, a significantly increased odds ratio was identified for ipsilateral use but not for contralateral use.
Overall Mobile Phone Use and the Risk of Brain Tumors
As shown in Appendix Table A3 (online only), no significant association was observed in a meta-analysis of 15 studies involving brain tumors. For meningiomas, a preventive effect was observed, and this effect was largely a result of a decreased odds ratio in INTERPHONE-related studies.
A significant negative association was found in a meta-analysis of studies involving benign brain tumors, and this was largely a result of a decreased odds ratio in the INTERPHONE-related studies. No association between mobile phone use and tumor risk was observed in both analog phone users and digital phone users. With regard to research group, blinding, and methodologic quality, similar findings to those of the subgroup analyses were observed (ie, a significant association in the studies by Hardell et al, a negative association in INTERPHONE-related studies, and no association in the studies by other groups).
Overall Mobile Phone Use and the Risk of Other Tumors
Appendix Table A4 (online only) shows the findings of the subgroup analyses of studies involving tumors other than brain tumors. Unlike brain tumors, all of the subgroup meta-analyses based on various factors showed no significant associations between overall mobile phone use and the risk of other tumors.
Meta-Regression Analysis
A meta-regression analysis showed that only the variable indicating research group was significantly associated with the study results (P = .001). No significant association was observed for year of publication, type of tumor, or study design.
Discussion
We found that the use of mobile phones was associated with a mild increased risk of tumors, when compared with never or rare use of mobile phones, in the meta-analyses of case-control studies that used blinding or had a high methodologic quality, whereas no significant association was observed in a meta-analysis of all included studies. Also, mobile phone use of 10 years or longer increased the risk of tumors in a meta-analysis of all the studies reporting this association. Furthermore, in the subgroup meta-analyses by research group, a distinct pattern of the findings was observed as follows: a positive association (ie, harmful effect) in the Hardell et al studies, a negative association (ie, protective effect) in the INTERPHONE-related studies, and no association in other research groups' studies.
These findings were strongly related to the fact that all of the studies by Hardell et al used blinding to the status of patient cases or controls at the interview and were categorized as having a high methodologic quality when assessed based on the NOS, whereas most of the INTERPHONE-related studies and studies by other groups did not use blinding and were thus categorized as having low methodologic quality. The blinding item is one of the eight items in the NOS. Nevertheless, we also used the blinding item independently as well as the NOS as a kind of indicator of the quality assessment for the studies because the NOS has not been fully validated and the blinding item was considered an important factor that affects the findings of each study.
Also, similar findings concerning the research group were observed in subgroup analyses by malignancy of tumor, type of laterality, type of case-control study, and type of tumor. Regarding type of brain tumor, a negative association was observed for meningiomas but not for gliomas and acoustic neuromas, and this negative association was largely a result of a decreased odds ratio in INTERPHONE-related studies.
Besides blinding and methodologic quality of studies, we should consider two potential biases regarding the differences we found by research groups—recall bias and selection bias, both of which have been described in detail elsewhere.57 In a validation study of short-term recall for mobile phone use, Vrijheid et al58 reported that substantial random errors could reduce the power of the INTERPHONE study to detect an increased risk of brain and parotid gland tumors. Furthermore, they found that random errors and selection bias could lead to finding a decreased risk of brain cancer through Monte-Carlo simulation using the INTERPHONE data.57 These findings may explain why a significant decreased risk for tumor was observed among mobile phone users in the INTERPHONE-related studies.
To reduce recall and selection biases, a prospective cohort study is needed. A large nationwide Danish retrospective cohort study,29,30,59,60 which is the only cohort study published so far, reported that there was no evidence for an association between cellular telephone use and tumor risk based on standardized incidence ratios for cancer that were calculated from the cancer prevalence among cellular telephone subscribers compared with the rates expected among the general population. However, this study relied on phone subscription information and did not evaluate actual exposure to mobile phones.
If we do not consider subgroup meta-analyses by research group or blinding/methodologic quality of studies, our overall results are similar to the previous three meta-analyses31–33 evaluating mobile phone use and the risk of brain tumor, which reported no overall increased risk of brain tumors among cellular phone users and slightly increased risk of brain tumors for use of 10 years or longer.
Unlike the previous meta-analyses, however, we found significant associations between mobile phone use and risk of tumors in low-biased, case-control studies, which were mostly studies by Hardell et al, when performing subgroup analyses by use of blinding or the methodologic quality of studies. That is, the methodologic quality of study and blinding were strongly related to both the research group and the studies' findings. In particular, among the items of the NOS for assessing the quality of case-control studies, blinding and response rates between patient cases and controls were the major contributing factors to differentiate a high-quality study from a low-quality study. All seven studies by Hardell et al7,12,14–16,18,23 used blinding, and five of them showed no significant difference in response rates between patient cases and controls, whereas INTERPHONE-related studies and the other studies, except for the study by Stang et al,10 did not use blinding and showed a significant difference in response rates.
We feel the need to mention the funding sources for each research group because it is possible that these may have influenced the respective study designs and results. According to the acknowledgments that appeared in the publications, the Hardell et al group was supported by grants from the Swedish Work Environment Fund, Orebro Cancer Fund, Orebro University Hospital Cancer Fund, and so on. Most of the INTERPHONE-related studies were mainly supported by the Quality of Life and Management of Living Resources program of the European Union and the International Union Against Cancer; the International Union Against Cancer received funds for those studies from the Mobile Manufacturers Forum and the Global System for Mobile Communication Association.
The association between mobile phone use and tumor risk also remains unresolved in experimental studies using in vivo animal models or in vitro cancer cell lines. Although it has been established that low-frequency EMF (microwave) exposure induces biologic change of cytoplasmic membranes, nuclear levels, and specific gene levels,6,61–63 the effect of high-frequency EMF exposure on health is still controversial.64–70
Our study has several limitations. First, it does not provide the highest level of evidence because only case-control studies were involved. As mentioned previously, recall bias and selection bias might reduce the quality of mobile phone exposure data and, therefore, cause a spurious association. Second, we did not explore potential confounding factors in the studies by Hardell et al7,12,14–16,18,23 that reported positive results not found by other study groups. Those issues need to be explored in future studies.
In sum, in our meta-analyses of case-control studies, we found evidence linking mobile phone use to an increased risk of tumors, especially among users of 10 or more years. Furthermore, we found a large discrepancy in the association between mobile phone use and tumor risk by research group, which is confounded with the methodologic quality of the research. Our findings should be confirmed in prospective cohort studies to provide a higher level of evidence.
Written on behalf of the Korean Meta-Analysis (KORMA) Study Group.
The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention.
Authors' Disclosures of Potential Conflicts of Interest
The author(s) indicated no potential conflicts of interest.
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Appendix
| Study | Year of Publication | Country and Study Name | Study Design | Study Period | Study Length (years) | Type of Tumor | Type of Mobile Phone and Exposure | Study | OR | 95% CI | Adjustment | Exposed | Unexposed | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of Patient Cases | No. of Controls | No. of Patient Cases | No. of Controls | ||||||||||||
| Hardell et al7 | 1999 | Sweden | PCC | 1994-1996 | 2 | Malignant and benign brain tumors (gliomas, meningiomas, and acoustic neuromas) | Cellular phone (analog and digital); latency period > 1 year v within 1 year | Hardell et al7 | 0.98 | 0.69 to 1.41 | Age, sex, and study region (matched) | 78 | 161 | 131 | 264 |
| Muscat et al8 | 2000 | United States | HCC | 1994-1998 | 4 | Primary brain cancers (gliomas and other malignant brain tumors) | Handheld cellular phone; regular past or current use v never use | Muscat et al8 | 0.85* | 0.6 to 1.2 | Age, years of education, sex, race, study center, proxy subject, and month and year of interview | 66 | 76 | 403 | 346 |
| Inskip et al9 | 2001 | United States | HCC | 1994-1998 | 4 | Malignant and benign brain tumors (gliomas, meningiomas, and acoustic neuromas) | Handheld cellular phone; cumulative use of > 100 hours v never or rarely use | Inskip et al9 | 0.9* | 0.7 to 1.1 | Date of interview, type of respondent, educational level, annual household income, type of health coverage, marital status, religion, history of radiotherapy to the head or neck, and handedness | 52 | 54 | 637 | 625 |
| Stang et al10 | 2001 | Germany | HCC and PCC | 1995-1998 | 3 | Uveal melanomas | Mobile phone; possible/probable/certain ever exposure v never exposure | Stang et al10 | 2.8 | 1.0 to 7.9 | Social class with 9 years at school or less | 7 | 25 | 111 | 450 |
| Auvinen et al11 | 2002 | Finland | PCC | 1996 | Malignant and benign brain tumors (gliomas and meningiomas) and salivary gland cancers | Cellular phone (analog and digital); ever use v never use | Auvinen et al11 | Brain tumors: 1.3; salivary gland cancers: 1.3 | Brain tumors: 0.9 to 1.8; salivary gland cancers: 0.4 to 4.7 | Place of residence, occupation, and socioeconomic status | Brain tumors: 56; salivary gland cancers: 4 | Brain tumors: 223; salivary gland cancers: 18 | Brain tumors: 342; salivary gland cancers: 30 | Brain tumors: 1,763; salivary gland cancers: 152 | |
| Hardell et al12 | 2002 | Sweden | PCC | 1997-2000 | 3 | Malignant and benign brain tumors (gliomas, meningiomas, pituitary tumors, and acoustic neuromas) | Cellular or cordless phone (analog and digital); use v no use | Hardell et al12 | Analog cellular phone: 1.3*; digital cellular phone: 1.0*; cordless phone: 1.0*; combined OR: 1.15 | Analog cellular phone: 1.04 to 1.6; digital cellular phone: 0.8 to 1.2; cordless phone: 0.8 to 1.2; combined OR: 0.99 to 1.33 | Use of different types of phones | 650 | 618 | 779 | 852 |
| Warren et al13 | 2003 | United States | HCC | 1995-2000 | 5 | Intratemporal facial nerve tumors | Handheld cellular phone; use v no use | Warren et al13 | 0.6 | 0.2 to 1.9 | Age, sex, and race (matched) | 5 | 53 | 13 | 88 |
| Hardell et al14 | 2004 | Sweden | PCC | 1994-2000 | 6 | Malignant and benign salivary gland tumors | Cellular or cordless phone; use v no use | Hardell et al14 | 1.02* | 0.75 to 1.38 | Age and sex | 91 | 352 | 176 | 701 |
| Hardell et al15 | 2005 | Sweden | PCC | 1999-2002 | 3 | Non-Hodgkin's lymphomas | Cellular or cordless phone (analog and digital); use v no use | Hardell et al15 | 1.06* | 0.87 to 1.31 | Age, sex, and year of diagnosis (patient cases) or enrollment (controls) | 607 | 695 | 303 | 321 |
| Hardell et al16 | 2005 | Sweden | PCC | 2000-2003 | 3 | Benign brain tumors (meningiomas, acoustic neuromas, and other benign brain tumors) | Cellular or cordless telephone (analog and digital); use v no use | Hardell et al16 | 1.4* | 1.03 to 1.9 | Age, sex, socioeconomic index, and year of diagnosis | 290 | 459 | 123 | 233 |
| Schoemaker et al17 | 2005 | Five North European countries: Denmark, Finland, Norway, Stockholm, and United Kingdom; followed a protocol of the INTERPHONE Study | PCC | 1999-2004 | 5 | Benign brain tumors (acoustic neuromas) | Mobile phone (analog and digital); regular use v never or nonregular use | Schoemaker et al17 | 0.9* | 0.7 to 1.1 | Highest educational level and combination of interview year and interview lag time | 360 | 1,934 | 316 | 1,612 |
| Hardell et al18 | 2006 | Sweden | PCC | 2000-2003 | 3 | Malignant brain tumors (gliomas and other malignant tumors) | Cellular or cordless phone (analog and digital; use v no use | Hardell et al18 | 1.9* | 1.3 to 2.7 | Age, sex, socioeconomic index, and the year of diagnosis | 254 | 459 | 63 | 233 |
| Linet et al19 | 2006 | United States | PCC | 1998-2000 | 2 | Non-Hodgkin's lymphomas | Cellular phone; lifetime ever use v never use | Linet et al19 | 1.0* | 0.7 to 1.3 | Age, race, education, and geographic site | 317 | 247 | 234 | 215 |
| Lönn et al20 | 2006 | Denmark and Sweden; part of the INTERPHONE Study | PCC | 2000-2002 | 2 | Malignant and benign parotid gland tumors | Mobile phone; regular use v never or rarely use | Lönn et al20 | 0.80* (combined ORs of malignant parotid gland and benign pleomorphic adenoid) | 0.54 to 1.20 | Age, sex, geographic region, and education | 102 | 603 | 70 | 399 |
| Schüz et al21 | 2006 | Germany; part of the INTERPHONE Study | PCC | 2000-2003 | 3 | Malignant and benign brain tumors (glioma and meningioma) | Cellular phone; ever regular use v never use | Schüz et al21 | 0.91* (combined ORs of glioma and meningioma) | 0.75 to 1.1 | Age, socioeconomic status, and living in a city | 242 | 517 | 505 | 977 |
| Takebayashi et al22 | 2006 | Japan; followed a protocol of the INTERPHONE Study | PCC | 2000-2004 | 4 | Benign brain tumors (acoustic neuromas) | Mobile phone (analog and digital); regular use v no use | Takebayashi et al22 | 0.73* | 0.43 to 1.23 | Education and marital status | 51 | 192 | 46 | 138 |
| Hardell et al23 | 2007 | Sweden | PCC | 1993-1997 | 4 | Testicular cancers (seminomas and nonseminomas) | Cellular or cordless phone; use v not use | Hardell et al23 | 1.0* | 0.8 to 1.2 | Age, year of diagnosis, and cryptorchidism | 372 | 358 | 516 | 512 |
| Hours et al24 | 2007 | France; part of the INTERPHONE Study | PCC | 2001-2003 | 2 | Malignant and benign brain tumors (gliomas, meningiomas, and acoustic neuromas) | Mobile phone; regular use v no or nonregular use | Hours et al24 | 0.93* | 0.69 to 1.27 | Socioeconomic status, smoking status, and marital status | 188 | 257 | 162 | 198 |
| Lahkola et al25 | 2007 | 5 North European countries: Denmark, Finland, Norway, Sweden, and United Kingdom; followed a protocol of the INTERPHONE Study | PCC | 2000-2004 | 4 | Malignant brain tumors (gliomas) | Mobile phone (analog and digital); regular use v never or nonregular use | Lahkola et al25 | 0.78* | 0.68 to 0.91 | Education and family history of glioma | 867 | 1,853 | 629 | 1,281 |
| Lahkola et al26 | 2008 | 5 North European countries: Denmark, Finland, Norway, Sweden, and United Kingdom; followed a protocol of the INTERPHONE Study | PCC | 2000-2004 | 4 | Benign brain tumors (meningiomas) | Mobile phone (analog and digital); regular use v never or nonregular use | Lahkola et al26 | 0.76 | 0.65 to 0.89 | Sex, 5-year age group, region, and county (matched) | 573 | 1,696 | 631 | 1,249 |
| Sadetzki et al27 | 2008 | Israel; followed a protocol of the INTERPHONE Study | PCC | 2001-2003 | 2 | Malignant and benign parotid gland tumors | Cellular phone; regular use v nonregular use (< 1 year) | Sadetzki et al27 | 0.87* | 0.68 to 1.13 | Cigarette smoking | 285 | 691 | 175 | 575 |
| Takebayashi et al28 | 2008 | Japan; followed a protocol of the INTERPHONE Study | PCC | 2000-2004 | 4 | Malignant and benign brain tumors | Mobile phone (analog and digital; regular use v no use | Takebayashi et al28 | 0.87* (combined ORs of glioma, meningioma, and pituitary) | 0.63 to 1.22 | Education and marital status | 173 | 329 | 139 | 224 |
Abbreviations: OR, odds ratio; PCC, population-based case-control study; HCC, hospital-based case-control study.
*
Adjusted OR.
| Factor | No. of Studies | Summary OR | 95% CI of OR | Heterogeneity, I2 (%) | Model Used |
|---|---|---|---|---|---|
| All* | 13 | 1.18 | 1.04 to 1.34 | 33.1 | Fixed effects |
| Research group | |||||
| Hardell et al* | 7 | 1.35 | 1.14 to 1.59 | 35.1 | Fixed effects |
| INTERPHONE | 6 | 0.99 | 0.82 to 1.21 | 0 | Fixed effects |
| Methodologic quality | |||||
| High (low bias: ≥ 7 points)* | 8 | 1.32 | 1.12 to 1.54 | 29.1 | Fixed effects |
| Hardell et al* | 7 | 1.35 | 1.14 to 1.59 | 35.1 | Fixed effects |
| INTERPHONE | 1 | 1.10 | 0.70 to 1.80 | NA | NA |
| Low (high bias: < 7 points, all INTERPHONE) | 5 | 0.97 | 0.79 to 1.21 | 0 | Fixed effects |
| Type of tumor | |||||
| Brain tumor* | 8 | 1.24 | 1.00 to 1.55 | 50.8 | Random effects |
| Hardell et al* | 4 | 1.54 | 1.26 to 1.89 | 0 | Fixed effects |
| INTERPHONE | 4 | 1.00 | 0.81 to 1.22 | 10.9 | Fixed effects |
| Other tumors† | 5 | 1.00 | 0.76 to 1.30 | 0 | Fixed effects |
| Hardell et al | 3 | 1.00 | 0.74 to 1.35 | 0 | Fixed effects |
| INTERPHONE | 2 | 0.97 | 0.54 to 1.77 | 0 | Fixed effects |
| Malignancy of tumor | |||||
| Malignant | 7 | 1.15 | 0.78 to 1.71 | 58.8 | Random effects |
| Hardell et al | 4 | 1.42 | 0.94 to 2.14 | 54.5 | Random effects |
| INTERPHONE | 3 | 0.74 | 0.50 to 1.11 | 0 | Fixed effects |
| Benign* | 8 | 1.33 | 1.11 to 1.58 | 39.3 | Fixed effects |
| Hardell et al* | 3 | 1.66 | 1.32 to 2.09 | 1.9 | Fixed effects |
| INTERPHONE | 5 | 0.98 | 0.75 to 1.28 | 0 | Fixed effects |
| Type of mobile phone | |||||
| Analog* | 10 | 1.34 | 1.07 to 1.66 | 29.8 | Fixed effects |
| Hardell et al* | 7 | 1.52 | 1.19 to 1.95 | 0 | Fixed effects |
| INTERPHONE | 3 | 0.82 | 0.51 to 1.32 | 0 | Fixed effects |
| Digital (all Hardell et al)* | 3 | 1.68 | 1.01 to 2.81 | 0 | Fixed effects |
| Laterality of tumor (all INTERPHONE)† | |||||
| Ipsilateral* | 5 | 1.32 | 1.02 to 1.70 | 0 | Fixed effects |
| Contralateral | 4 | 0.89 | 0.68 to 1.15 | 0 | Fixed effects |
NOTE. All included studies were population-based case-control studies.
Abbreviations: OR, odds ratio; NA, not applicable.
*
Statistically significant positive association.
†
Salivary gland tumor, non-Hodgkin's lymphoma, and testicular tumor.
| Factor | No. of Studies | Summary OR | 95% CI of OR | Heterogeneity, I2 (%) | Model Used |
|---|---|---|---|---|---|
| All brain tumors | 15 | 0.97 | 0.86 to 1.10 | 70.3 | Random effects |
| Type of brain tumor | |||||
| Gliomas | 10 | 1.09 | 0.89 to 1.34 | 67.9 | Random effects |
| Hardell et al | 3 | 1.37 | 0.88 to 2.12 | 68.5 | Random effects |
| INTERPHONE* | 4 | 0.84 | 0.75 to 0.96 | 33.9 | Fixed effects |
| Other groups | 3 | 1.06 | 0.76 to 1.48 | 51.3 | Random effects |
| Meningiomas* | 9 | 0.83 | 0.75 to 0.92 | 11.9 | Fixed effects |
| INTERPHONE* | 4 | 0.77 | 0.68 to 0.88 | 0 | Fixed effects |
| Other groups | 5 | 0.95 | 0.80 to 1.13 | 18.0 | Fixed effects |
| Acoustic neuromas | 6 | 0.94 | 0.79 to 1.11 | 5.4 | Fixed effects |
| Hardell et al | 2 | 1.38 | 0.92 to 2.08 | 0 | Fixed effects |
| INTERPHONE | 3 | 0.88 | 0.72 to 1.07 | 0 | Fixed Effecst |
| Other groups | 1 | 0.80 | 0.50 to 1.40 | NA | NA |
| Malignancy of brain tumor | |||||
| Malignant | 7 | 0.99 | 0.79 to 1.23 | 74.1 | Random effects |
| Hardell et al | 3 | 1.26 | 0.88 to 1.81 | 74.9 | Random effects |
| INTERPHONE* | 2 | 0.77 | 0.65 to 0.91 | 0 | Fixed effects |
| Other groups | 2 | 0.87 | 0.67 to 1.14 | 0 | Fixed effects |
| Benign* | 12 | 0.87 | 0.80 to 0.95 | 31.0 | Fixed effects |
| Hardell et al | 3 | 1.16 | 0.96 to 1.40 | 17.5 | Fixed effects |
| INTERPHONE* | 6 | 0.80 | 0.72 to 0.89 | 0 | Fixed effects |
| Other groups | 3 | 0.82 | 0.61 to 1.11 | 0 | Fixed effects |
| Type of mobile phone | |||||
| Analog | 8 | 1.02 | 0.83 to 1.24 | 62.2 | Random effects |
| Digital | 10 | 0.92 | 0.79 to 1.07 | 62.5 | Random effects |
| Laterality of brain tumor | |||||
| Ipsilateral | 10 | 1.23 | 0.97 to 1.58 | 88.2 | Random effects |
| Contralateral | 8 | 0.92 | 0.74 to 1.15 | 82.0 | Random effects |
| Research group | |||||
| Hardell et al† | 4 | 1.29 | 1.02 to 1.64 | 64.6 | Random effects |
| INTERPHONE* | 7 | 0.82 | 0.76 to 0.89 | 0 | Fixed effects |
| Other groups | 4 | 0.96 | 0.81 to 1.13 | 31.7 | Fixed effects |
| Methodologic quality | |||||
| High (low bias: ≥ 7 points) | 5 | 1.19 | 0.96 to 1.49 | 71.7 | Random effects |
| Hardell et al† | 4 | 1.29 | 1.02 to 1.64 | 64.6 | Random effects |
| INTERPHONE | 1 | 0.90 | 0.70 to 1.10 | NA | NA |
| Low (high bias: < 7 points)* | 10 | 0.84 | 0.78 to 0.91 | 16.2 | Fixed effects |
| INTERPHONE* | 6 | 0.81 | 0.75 to 0.89 | 0 | Fixed effects |
| Other groups | 4 | 0.96 | 0.81 to 1.13 | 31.7 | Fixed effects |
| Interview blinded to patient case/control status | |||||
| Blinded (all Hardell et al)† | 4 | 1.29 | 1.02 to 1.64 | 64.6 | Random effects |
| Not blinded or no description* | 11 | 0.85 | 0.79 to 0.91 | 9.5 | Fixed effects |
| INTERPHONE* | 7 | 0.82 | 0.76 to 0.89 | 0 | Fixed effects |
| Other groups | 4 | 0.96 | 0.81 to 1.13 | 31.7 | Fixed effects |
Abbreviations: OR, odds ratio; NA, not applicable.
*
Statistically significant negative association.
†
Statistically significant positive association.
| Factor | No. of Studies | Summary OR | 95% CI of OR | Heterogeneity, I2 (%) | Model Used |
|---|---|---|---|---|---|
| All | 8 | 0.99 | 0.89 to 1.10 | 0 | Fixed effects |
| Type of tumor | |||||
| Salivary gland tumor | 4 | 0.91 | 0.76 to 1.08 | 0 | Fixed effects |
| Non-Hodgkin's lymphoma | 2 | 1.04 | 0.88 to 1.24 | 0 | Fixed effects |
| Testicular cancer | 1 | 1.00 | 0.80 to 1.20 | NA | NA |
| Uveal melanoma* | 1 | 2.80 | 1.00 to 7.90 | NA | NA |
| Malignancy of tumor | |||||
| Malignant | 8 | 1.02 | 0.91 to 1.15 | 0 | Fixed effects |
| Hardell et al | 3 | 1.03 | 0.90 to 1.17 | 0 | Fixed effects |
| INTERPHONE | 2 | 0.84 | 0.54 to 1.31 | 0 | Fixed effects |
| Other groups | 3 | 1.10 | 0.82 to 1.47 | 44.1 | Fixed effects |
| Benign | 3 | 0.90 | 0.70 to 1.15 | 0 | Fixed effects |
| Hardell et al | 1 | 2.03 | 0.55 to 7.50 | NA | NA |
| INTERPHONE | 2 | 0.87 | 0.68 to 1.12 | 0 | Fixed effects |
| Type of mobile phone | |||||
| Analog | 4 | 0.80 | 0.62 to 1.04 | 0 | Fixed effects |
| Hardell et al | 3 | 0.80 | 0.61 to 1.03 | 0 | Fixed effects |
| Other group | 1 | 1.00 | 0.30 to 4.00 | NA | NA |
| Digital | 4 | 1.10 | 0.89 to 1.31 | 0 | Fixed effects |
| Hardell et al | 3 | 1.07 | 0.88 to 1.30 | 0 | Fixed effects |
| Other group | 1 | 1.70 | 0.20 to 16.00 | NA | NA |
| Laterality of tumor (all INTERPHONE) | |||||
| Ipsilateral | 2 | 1.12 | 0.89 to 1.42 | 24.7 | Fixed effects |
| Contralateral | 2 | 0.78 | 0.60 to 1.01 | 20.6 | Fixed effects |
| Research group | |||||
| Hardell et al | 3 | 1.03 | 0.90 to 1.17 | 0 | Fixed effects |
| INTERPHONE | 2 | 0.85 | 0.69 to 1.05 | 0 | Fixed effects |
| Other groups | 3 | 1.10 | 0.82 to 1.47 | 44.1 | Fixed effects |
| Methodologic quality | |||||
| High (low bias: ≥ 7 points) | 3 | 1.02 | 0.90 to 1.17 | 0 | Fixed effects |
| Hardell et al | 2 | 1.03 | 0.89 to 1.19 | 0 | Fixed effects |
| Other group | 1 | 1.00 | 0.70 to 1.30 | NA | NA |
| Low (high bias: < 7 points) | 5 | 0.94 | 0.79 to 1.11 | 31.1 | Fixed effects |
| Hardell et al | 1 | 1.02 | 0.75 to 1.38 | NA | NA |
| INTERPHONE | 2 | 0.85 | 0.69 to 1.05 | 0 | Fixed effects |
| Other groups | 2 | 2.04 | 0.92 to 4.50 | 0 | Fixed effects |
| Interview blinded to patient case/control status | |||||
| Blinded | 4 | 1.04 | 0.92 to 1.19 | 19.3 | Fixed effects |
| Hardell et al | 3 | 1.03 | 0.90 to 1.17 | 0 | Fixed effects |
| Other group* | 1 | 2.80 | 1.00 to 7.90 | NA | NA |
| Not blinded or no description | 4 | 0.90 | 0.76 to 1.07 | 0 | Fixed effects |
| INTERPHONE | 2 | 0.85 | 0.69 to 1.05 | 0 | Fixed effects |
| Other groups | 2 | 1.02 | 0.75 to 1.37 | 0 | Fixed effects |
Abbreviations: OR, odds ratio; NA, not applicable.
*
Statistically significant positive association.
Information & Authors
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© 2009 by American Society of Clinical Oncology.
History
Published online: October 13, 2009
Published in print: November 20, 2009
Authors
Author Contributions
Conception and design: Seung-Kwon Myung, Woong Ju
Administrative support: Seung-Kwon Myung, Woong Ju
Provision of study materials or patients: Seung-Kwon Myung
Collection and assembly of data: Seung-Kwon Myung, Woong Ju, Diana D. McDonnell, Yeon Ji Lee, Gene Kazinets, Chih-Tao Cheng
Data analysis and interpretation: Seung-Kwon Myung, Woong Ju, Diana D. McDonnell, Yeon Ji Lee, Gene Kazinets, Chih-Tao Cheng, Joel M. Moskowitz
Manuscript writing: Seung-Kwon Myung, Diana D. McDonnell, Joel M. Moskowitz
Final approval of manuscript: Seung-Kwon Myung
Disclosures
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Funding Information
Supported in part by the Centers for Disease Control and Prevention through Cooperative Agreement No. U48/DP000033 (D.D.M., G.K., J.M.M.).
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Mobile Phone Use and Risk of Tumors: A Meta-Analysis. JCO 27, 5565-5572(2009).
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