Susanna Lagorio

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.

Validation of short term recall of mobile phone use for the Interphone study

Aim: To validate short term recall of mobile phone use within Interphone, an international collaborative case control study of tumours of the brain, acoustic nerve, and salivary glands related to mobile telephone use. Methods: Mobile phone use of 672 volunteers in 11 countries was recorded by operators or through the use of software modified phones, and compared to use recalled six months later using the Interphone study questionnaire. Agreement between recalled and actual phone use was analysed using both categorical and continuous measures of number and duration of phone calls. Results: Correlations between recalled and actual phone use were moderate to high (ranging from 0.5 to 0.8 across countries) and of the same order for number and duration of calls. The kappa statistic demonstrated fair to moderate agreement for both number and duration of calls (weighted kappa ranging from 0.20 to 0.60 across countries). On average, subjects underestimated the number of calls per month (geometric mean ratio of recalled to actual = 0.92, 95% CI 0.85 to 0.99), whereas duration of calls was overestimated (geometric mean ratio = 1.42, 95% CI 1.29 to 1.56). The ratio of recalled to actual use increased with level of use, showing underestimation in light users and overestimation in heavy users. There was substantial heterogeneity in this ratio between countries. Inter-individual variation was also large, and increased with level of use. Conclusions: Volunteer subjects recalled their recent phone use with moderate systematic error and substantial random error. This large random error can be expected to reduce the power of the Interphone study to detect an increase in risk of brain, acoustic nerve, and parotid gland tumours with increasing mobile phone use, if one exists.

Air pollution and lung function among susceptible adult subjects: a panel study

BackgroundAdverse health effects at relatively low levels of ambient air pollution have consistently been reported in the last years. We conducted a time-series panel study of subjects with chronic obstructive pulmonary disease (COPD), asthma, and ischemic heart disease (IHD) to evaluate whether daily levels of air pollutants have a measurable impact on the lung function of adult subjects with pre-existing lung or heart diseases.MethodsTwenty-nine patients with COPD, asthma, or IHD underwent repeated lung function tests by supervised spirometry in two one-month surveys. Daily samples of coarse (PM10–2.5) and fine (PM2.5) particulate matter were collected by means of dichotomous samplers, and the dust was gravimetrically analyzed. The particulate content of selected metals (cadmium, chrome, iron, nickel, lead, platinum, vanadium, and zinc) was determined by atomic absorption spectrometry. Ambient concentrations of nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), and sulphur dioxide (SO2) were obtained from the regional air-quality monitoring network. The relationships between concentrations of air pollutants and lung function parameters were analyzed by generalized estimating equations (GEE) for panel data.ResultsDecrements in lung function indices (FVC and/or FEV1) associated with increasing concentrations of PM2.5, NO2 and some metals (especially zinc and iron) were observed in COPD cases. Among the asthmatics, NO2 was associated with a decrease in FEV1. No association between average ambient concentrations of any air pollutant and lung function was observed among IHD cases.ConclusionThis study suggests that the short-term negative impact of exposure to air pollutants on respiratory volume and flow is limited to individuals with already impaired respiratory function. The fine fraction of ambient PM seems responsible for the observed effects among COPD cases, with zinc and iron having a potential role via oxidative stress. The respiratory function of the relatively young and mild asthmatics included in this study seems to worsen when ambient levels of NO2 increase.

Recall bias in the assessment of exposure to mobile phones

Most studies of mobile phone use are case–control studies that rely on participants’ reports of past phone use for their exposure assessment. Differential errors in recalled phone use are a major concern in such studies. INTERPHONE, a multinational case–control study of brain tumour risk and mobile phone use, included validation studies to quantify such errors and evaluate the potential for recall bias. Mobile phone records of 212 cases and 296 controls were collected from network operators in three INTERPHONE countries over an average of 2 years, and compared with mobile phone use reported at interview. The ratio of reported to recorded phone use was analysed as measure of agreement. Mean ratios were virtually the same for cases and controls: both underestimated number of calls by a factor of 0.81 and overestimated call duration by a factor of 1.4. For cases, but not controls, ratios increased with increasing time before the interview; however, these trends were based on few subjects with long-term data. Ratios increased by level of use. Random recall errors were large. In conclusion, there was little evidence for differential recall errors overall or in recent time periods. However, apparent overestimation by cases in more distant time periods could cause positive bias in estimates of disease risk associated with mobile phone use.

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.

Determinants of mobile phone output power in a multinational study: implications for exposure assessment

Objectives: The output power of a mobile phone is directly related to its radiofrequency (RF) electromagnetic field strength, and may theoretically vary substantially in different networks and phone use circumstances due to power control technologies. To improve indices of RF exposure for epidemiological studies, we assessed determinants of mobile phone output power in a multinational study. Methods: More than 500 volunteers in 12 countries used Global System for Mobile communications software-modified phones (GSM SMPs) for approximately 1 month each. The SMPs recorded date, time, and duration of each call, and the frequency band and output power at fixed sampling intervals throughout each call. Questionnaires provided information on the typical circumstances of an individual’s phone use. Linear regression models were used to analyse the influence of possible explanatory variables on the average output power and the percentage call time at maximum power for each call. Results: Measurements of over 60 000 phone calls showed that the average output power was approximately 50% of the maximum, and that output power varied by a factor of up to 2 to 3 between study centres and network operators. Maximum power was used during a considerable proportion of call time (39% on average). Output power decreased with increasing call duration, but showed little variation in relation to reported frequency of use while in a moving vehicle or inside buildings. Higher output powers for rural compared with urban use of the SMP were observed principally in Sweden where the study covered very sparsely populated areas. Conclusions: Average power levels are substantially higher than the minimum levels theoretically achievable in GSM networks. Exposure indices could be improved by accounting for average power levels of different telecommunications systems. There appears to be little value in gathering information on circumstances of phone use other than use in very sparsely populated regions.

Risk of childhood leukaemia and non-Hodgkin's lymphoma after parental occupational exposure to solvents and other agents: the SETIL Study

Aim In the context of the Italian Multicentric Epidemiological Study on Risk Factors for Childhood Leukaemia and Non-Hodgkins Lymphoma (SETIL), the risk of childhood cancer was investigated in relation to parental occupational exposures. Methods All cases of childhood leukaemia and non-Hodgkins lymphoma (NHL) in children aged 0–10 years were identified. Controls were chosen at random from the local population in each region. Parents were interviewed using a structured questionnaire. The collected data were blindly reviewed by expert industrial hygienists in order to estimate exposure to a list of agents. Statistical analyses were performed for each agent using unconditional multivariable logistic regression models, taking into account timing of exposure. Results 683 cases of acute childhood leukaemia, 97 cases of NHL and 1044 controls were identified. Increased risk of childhood leukaemia was found for maternal exposure to aliphatic (OR 4.3) or aromatic hydrocarbons (OR 3.8) in the preconception period, and for paternal exposure to diesel exhaust (OR 1.4), lead exposure (OR 1.4) and mineral oils (OR 1.7). Risk of NHL appeared to be related to paternal exposure to oxygenated solvents (OR 2.5) and petrol exhaust (OR 2.2). Conclusions We found increased risk for childhood leukaemia associated with maternal occupational exposure to aromatic and aliphatic hydrocarbons, particularly in the preconception period; increased risks were also observed for paternal exposure to diesel exhaust fumes, mineral oils and lead. The risk of NHL appeared to be related to paternal exposure to oxygenated solvent and petrol exhausts.

Survival of European patients with central nervous system tumors

We present estimates of population‐based 5‐year relative survival for adult Europeans diagnosed with central nervous system tumors, by morphology (14 categories based on cell lineage and malignancy grade), sex, age at diagnosis and region (UK and Ireland, Northern, Central, Eastern and Southern Europe) for the most recent period with available data (2000–2002). Sources were 39 EUROCARE cancer registries with continuous data from 1996 to 2002. Survival time trends (1988 to 2002) were estimated from 24 cancer registries with continuous data from 1988. Overall 5‐year relative survival was 85.0% for benign, 19.9% for malignant tumors. Benign tumor survival ranged from 90.6% (Northern Europe) to 77.4% (UK and Ireland); for malignant tumors the range was 25.1% (Northern Europe) to 15.6% (UK and Ireland). Survival decreased with age at diagnosis and was slightly better for women (malignant tumors only). For glial tumors, survival varied from 83.5% (ependymoma and choroid plexus) to 2.7% (glioblastoma); and for non‐glioma tumors from 96.5% (neurinoma) to 44.9% (primitive neuroectoderm tumor/medulloblastoma). Survival differences between regions narrowed after adjustment for morphology and age, and were mainly attributable to differences in morphology mix; however UK and Ireland and Eastern Europe patients still had 40% and 30% higher excess risk of death, respectively, than Northern Europe patients (reference). Survival for benign tumors increased from 69.3% (1988–1990) to 77.1% (2000–2002); but survival for malignant tumors did not improve indicating no useful advances in treatment over the 14‐year study period, notwithstanding major improvement in the diagnosis and treatment of other solid cancers.

Mortality of plastic-ware workers exposed to radiofrequencies

The mortality experience of a cohort of Italian plastic-ware workers exposed to radiofrequency (RF)-electromagnetic fields generated by dielectric heat sealers was investigated. Follow-up extended from 1962 to 1992. The standardised mortality ratio (SMR) analysis was restricted to 481 women workers, representing 78% of the total person-years at risk. Mortality from malignant neoplasms was slightly elevated, and increased risks of leukemia and accidents were detected. The all-cancer SMR was higher among women employed in the sealing department, where exposure to RF occurred, than in the whole cohort. This study raises interest in a possible association between exposure to RF radiation and cancer risk. However, the study power was very small, and the possible confounding effects of exposure to solvents and vinyl chloride monomer (VCM) could not be ruled out. The hypothesis of an increased risk of cancer after radiofrequency exposure should be further explored by means of analytical studies characterised by adequate power and more accurate exposure assessment.