Naohito Yamaguchi

The INTERPHONE study: design, epidemiological methods, and description of the study population

The very rapid worldwide increase in mobile phone use in the last decade has generated considerable interest in the possible health effects of exposure to radio frequency (RF) fields. A multinational case–control study, INTERPHONE, was set-up to investigate whether mobile phone use increases the risk of cancer and, more specifically, whether the RF fields emitted by mobile phones are carcinogenic. The study focused on tumours arising in the tissues most exposed to RF fields from mobile phones: glioma, meningioma, acoustic neurinoma and parotid gland tumours. In addition to a detailed history of mobile phone use, information was collected on a number of known and potential risk factors for these tumours. The study was conducted in 13 countries. Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the UK using a common core protocol. This paper describes the study design and methods and the main characteristics of the study population. INTERPHONE is the largest case–control study to date investigating risks related to mobile phone use and to other potential risk factors for the tumours of interest and includes 2,765 glioma, 2,425 meningioma, 1,121 acoustic neurinoma, 109 malignant parotid gland tumour cases and 7,658 controls. Particular attention was paid to estimating the amount and direction of potential recall and participation biases and their impact on the study results.

Childhood leukemia and magnetic fields in Japan: A case-control study of childhood leukemia and residential power-frequency magnetic fields in Japan

Residential power‐frequency magnetic fields (MFs) were labeled as a possible human carcinogen by the International Agency for Research on Cancer panel. In response to great public concern, the World Health Organization urged that further epidemiologic studies be conducted in high‐exposure areas such as Japan. We conducted a population‐based case‐control study, which covered areas inhabited by 54% of Japanese children. We analyzed 312 case children (0–15 years old) newly diagnosed with acute lymphoblastic leukemia (ALL) or acute myelocytic leukemia (AML) in 1999–2001 (2.3 years) and 603 controls matched for gender, age and residential area. Weekly mean MF level was determined for the childs bedroom. MF measurements in each set of a case and controls were carried out as closely in time as possible to control for seasonal variation. We evaluated the association using conditional logistic regression models. The odds ratios for children whose bedrooms had MF levels of 0.4 μT or higher compared with the reference category (MF levels below 0.1 μT) was 2.6 (95% CI = 0.76–8.6) for AML + ALL and 4.7 (1.15–19.0) for ALL only. Controlling for some possible confounding factors did not alter the results appreciably. Even an analysis in which selection bias was maximized did not fully explain the association. Most of the leukemia cases in the highest exposure category had MF levels far above 0.4 μT. Our results provided additional evidence that high MF exposure was associated with a higher risk of childhood leukemia, particularly of ALL.

Mobile phone use and acoustic neuroma risk in Japan

Objectives: The rapid increase of mobile phone use has increased public concern about its possible health effects in Japan, where the mobile phone system is unique in the characteristics of its signal transmission. To examine the relation between mobile phone use and acoustic neuroma, a case-control study was initiated. Methods: The study followed the common, core protocol of the international collaborative study, INTERPHONE. A prospective case recruitment was done in Japan for 2000–04. One hundred and one acoustic neuroma cases, who were 30–69 years of age and resided in the Tokyo area, and 339 age, sex, and residency matched controls were interviewed using a common computer assisted personal interview system. Education and marital status adjusted odds ratio was calculated with a conditional logistic regression analysis. Results: Fifty one cases (52.6%) and 192 controls (58.2%) were regular mobile phone users on the reference date, which was set as one year before the diagnosis, and no significant increase of acoustic neuroma risk was observed, with the odds ratio (OR) being 0.73 (95% CI 0.43 to 1.23). No exposure related increase in the risk of acoustic neuroma was observed when the cumulative length of use (<4 years, 4–8 years, >8 years) or cumulative call time (<300 hours, 300–900 hours, >900 hours) was used as an exposure index. The OR was 1.09 (95% CI 0.58 to 2.06) when the reference date was set as five years before the diagnosis. Further, laterality of mobile phone use was not associated with tumours. Conclusions: These results suggest that there is no significant increase in the risk of acoustic neuroma in association with mobile phone use in Japan.

Elevated serum level of thioredoxin in patients with hepatocellular carcinoma.

Thioredoxin (TRX) is known to contain an active site with aredox-active disulfide and has various biological activities. The objectiveof the present study was to investigate whether circulating TRX levels areelevated in patients with chronic hepatitis (CH) or liver cirrhosis (LC) andhepatocellular carcinoma (HCC). An anti-TRX monoclonal antibody andpolyclonal antibodies that specifically recognize TRX, were generated andused for the development of an ELlSA system to measure TRX levels in humanserum. The geometric mean and its 95% confidence interval of serumlevel of TRX in healthy volunteers was 81.75 ng/ml (74.60-89.59 ng/ml). Theserum level of TRX in LC/CH patients without HCC was 80.87 ng/ml(69.66-93.88 ng/ml). The value was not statistically different from that inserum from normal volunteers (p=0.69). In contrast, the serum level of TRXin patients with HCC was 147.35 ng/ml (125.53-1 72.96 ng/ml), which wassignificantly higher when compared with the level in serum of normalvolunteers (p<0.001) and in serum of LC/CH patients without HCC(p<0.001). In four patients with HCC, the initially high level of serum TRX(>150 ng/ml) decreased below 150 ng/ml after surgical removal of the tumor.The data reported herein revealed that patients with HCC had a significantlyelevated serum level of TRX, suggesting that measurement of serum of TRXmight be a useful clinical parameter when HCC is suspected.

Acoustic neuroma risk in relation to mobile telephone use: Results of the INTERPHONE international case-control study

BACKGROUND The rapid increase in mobile telephone use has generated concern about possible health risks of radiofrequency electromagnetic fields from these devices. METHODS A case-control study of 1105 patients with newly diagnosed acoustic neuroma (vestibular schwannoma) and 2145 controls was conducted in 13 countries using a common protocol. Past mobile phone use was assessed by personal interview. In the primary analysis, exposure time was censored at one year before the reference date (date of diagnosis for cases and date of diagnosis of the matched case for controls); analyses censoring exposure at five years before the reference date were also done to allow for a possible longer latent period. RESULTS The odds ratio (OR) of acoustic neuroma with ever having been a regular mobile phone user was 0.85 (95% confidence interval 0.69-1.04). The OR for ≥10 years after first regular mobile phone use was 0.76 (0.52-1.11). There was no trend of increasing ORs with increasing cumulative call time or cumulative number of calls, with the lowest OR (0.48 (0.30-0.78)) observed in the 9th decile of cumulative call time. In the 10th decile (≥1640 h) of cumulative call time, the OR was 1.32 (0.88-1.97); there were, however, implausible values of reported use in those with ≥1640 h of accumulated mobile phone use. With censoring at 5 years before the reference date the OR for ≥10 years after first regular mobile phone use was 0.83 (0.58-1.19) and for ≥1640 h of cumulative call time it was 2.79 (1.51-5.16), but again with no trend in the lower nine deciles and with the lowest OR in the 9th decile. In general, ORs were not greater in subjects who reported usual phone use on the same side of the head as their tumour than in those who reported it on the opposite side, but it was greater in those in the 10th decile of cumulative hours of use. CONCLUSIONS There was no increase in risk of acoustic neuroma with ever regular use of a mobile phone or for users who began regular use 10 years or more before the reference date. Elevated odds ratios observed at the highest level of cumulative call time could be due to chance, reporting bias or a causal effect. As acoustic neuroma is usually a slowly growing tumour, the interval between introduction of mobile phones and occurrence of the tumour might have been too short to observe an effect, if there is one.

Quantifying the Impact of Selection Bias Caused by Nonparticipation in a Case–Control Study of Mobile Phone Use

PURPOSE To quantitatively assess the impact of selection bias caused by nonparticipation in a multinational case-control study of mobile phone use and brain tumor. METHODS Non-response questionnaires (NRQ) were completed by a sub-set of nonparticipants. Selection bias factors were calculated based on the prevalence of mobile phone use reported by nonparticipants with NRQ data, and on scenarios of hypothetical exposure prevalence for other nonparticipants. RESULTS Regular mobile phone use was reported less frequently by controls and cases who completed the NRQ (controls, 56%; cases, 50%) than by those who completed the full interview (controls, 69%; cases, 66%). This relationship was consistent across study centers, sex, and age groups. Lower education and more recent start of mobile phone use were associated with refusal to participate. Bias factors varied between 0.87 and 0.92 in the most plausible scenarios. CONCLUSIONS Refusal to participate in brain tumor case-control studies seems to be related to less prevalent use of mobile phones, and this could result in a downward bias of around 10% in odds ratios for regular mobile phone use. The use of simple selection bias estimation methods in case-control studies can give important insights into the extent of any bias, even when nonparticipant information is incomplete.

A case–case study of mobile phone use and acoustic neuroma risk in Japan

Results of case-control studies of mobile phone use and acoustic neuroma have been inconsistent. We conducted a case-case study of mobile phone use and acoustic neuroma using a self-administered postal questionnaire. A total of 1589 cases identified in 22 hospitals throughout Japan were invited to participate, and 787 cases (51%) actually participated. Associations between laterality of mobile phone use prior to the reference dates (1 and 5 years before diagnosis) and tumor location were analyzed. The overall risk ratio was 1.08 (95% confidence interval (CI), 0.93-1.28) for regular mobile phone use until 1 year before diagnosis and 1.14 (95% CI, 0.96-1.40) for regular mobile phone use until 5 years before diagnosis. A significantly increased risk was identified for mobile phone use for >20 min/day on average, with risk ratios of 2.74 at 1 year before diagnosis, and 3.08 at 5 years before diagnosis. Cases with ipsilateral combination of tumor location and more frequently used ear were found to have tumors with smaller diameters, suggesting an effect of detection bias. Furthermore, analysis of the distribution of left and right tumors suggested an effect of tumor-side-related recall bias for recall of mobile phone use at 5 years before diagnosis. The increased risk identified for mobile phone users with average call duration >20 min/day should be interpreted with caution, taking into account the possibilities of detection and recall biases. However, we could not conclude that the increased risk was entirely explicable by these biases, leaving open the possibility that mobile phone use increased the risk of acoustic neuroma.

The p16 (CDKN2A) gene is involved in the growth of neuroblastoma cells and its expression is associated with prognosis of neuroblastoma patients

We previously reported that loss of heterozygosity (LOH) on chromosome 9p21 correlates with poor prognosis of neuroblastoma and the p16 gene is not expressed in approximately two thirds of neuroblastoma cell lines. Here we demonstrated that p16 expression was induced by 5-aza-2-deoxycytidine treatment in cell lines with 5′ CpG island methylation but not in cell lines without methylation. Furthermore, the cell cycle of neuroblastoma cell lines significantly delayed with accumulation of cells in G1 phase by transfection of a wild-type p16 expression vector. These results indicate that p16 is inactivated in part by DNA methylation and its expression is involved in the growth of neuroblastoma cells in vitro. To assess the biological and clinical significance of p16 expression in primary tumors, we undertook immunohistochemical analysis in 74 paraffin sections of neuroblastomas. p16 protein was undetectable in 45 of 74 cases (61%) and lack of p16 expression significantly correlated with poor prognosis of patients and advanced stage of the disease. There was no correlation between loss of p16 expression and N-myc amplification in these tumors. These results indicate that inactivation of the p16 gene is involved in the progression of neuroblastoma independently of N-myc amplification.

The MOBI-Kids study protocol: challenges in assessing childhood and adolescent exposure to electromagnetic fields from wireless telecommunication technologies and possible association with brain tumor risk

The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case–control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10–24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.

Power-Frequency Magnetic Fields and Childhood Brain Tumors: A Case-Control Study in Japan

Background The strength of the association between brain tumors in children and residential power-frequency magnetic fields (MF) has varied in previous studies, which may be due in part to possible misclassification of MF exposure. This study aimed to examine this association in Japan by improving measurement techniques, and by extending measurement to a whole week. Methods This population-based case-control study encompassed 54% of Japanese children under 15 years of age. After excluding ineligible targeted children, 55 newly diagnosed brain tumor cases and 99 sex-, age-, and residential area-matched controls were included in the analyses. The MF exposures of each set of matching cases and controls were measured in close temporal proximity to control for seasonal variation; the average difference was 12.4 days. The mean interval between diagnosis and MF measurements was 1.1 years. The weekly mean MF level was defined as the exposure. The association was evaluated using conditional logistic regression analysis that controlled for possible confounding factors. Results The odds ratios (95% CI) for exposure categories of 0.1 to 0.2, 0.2 to 0.4, and above 0.4 µT, against a reference category of <0.1 µT, were 0.74 (0.17–3.18), 1.58 (0.25–9.83), and 10.9 (1.05–113), respectively, after adjusting for maternal education. This dose-response pattern was stable when other variables were included in the model as possible confounding factors. Conclusions A positive association was found between high-level exposure—above 0.4 µT—and the risk of brain tumors. This association could not be explained solely by confounding factors or selection bias.