Exposure to electromagnetic fields and the risk of childhood leukaemia: a review

Extremely low-frequency magnetic fields have been classified as possibly carcinogenic to humans, mainly based on epidemiological studies consistently showing an association between long-term average exposures to magnetic fields above 0.3/0.4 microT and the risk of childhood leukaemia. No mechanism to explain this finding has been established and no support for a causal link emerged from experimental studies. Chance or bias cannot be ruled out with reasonable confidence as an explanation for the observed association. If the association is causal, it explains only a small fraction of childhood leukaemia cases. There were some reports of childhood leukaemia clusters in the vicinity of high-power radio and television broadcast transmitters in studies in Australia and Italy. However, recent large-scale systematic studies in Korea and Germany show no association between exposure to radio frequency electromagnetic fields emitted from broadcast towers and childhood leukaemia risk. Studies on mobile phone use and leukaemia risk in adolescents and young adults may be indicated.     

Exposure to infections through day-care attendance and risk of childhood leukaemia

There is growing evidence supporting a role for infections in the aetiology of childhood leukaemia. Hypotheses proposed by both Greaves and Kinlen describe childhood leukaemia to be a rare response to one or more common infections acquired through personal contacts. Previous epidemiological studies have used day-care attendance as an indicator of the increased likelihood of early and frequent exposure to infections. It is well-documented that in developed countries, exposures to common infections occur more frequently in this type of setting. Within the Northern California Childhood Leukaemia Study, the role of social contact has been assessed and a unique 'child-hours' summary measure incorporating information on the number of months attending a day-care, mean hours per week at this day-care and the number of children in the day-care setting was constructed. In this review, the previously reported day-care results have been described, showing that in non-Hispanic White children, children in the highest category of total child-hours of exposure had a reduced risk of acute lymphoblastic leukaemia (ALL), particularly common B-cell precursor ALL (c-ALL), compared with children without such exposures, with evidence of a dose-response effect. In addition, a literature review of relevant studies has been conducted, examining the relationship between day-care attendance and risk of childhood ALL. Overall, the 14 studies identified provided consistent support for this hypothesis, with the majority of studies reporting some evidence of a reduced risk. A meta-analysis is currently underway, which will provide a quantitative evaluation of the overall consistency and strength of the association between day-care attendance or social contact and risk of childhood ALL.     

'Lifestyle' and cancer rates in former East and West Germany: the possible contribution of diagnostic radiation exposures

Breast and prostatic cancer as well as leukaemia in childhood have remarkably increased over some decades in the Federal Republic of Germany as well as in several other highly developed industrial nations. Such increase was much less or not observable in East Germany between 1960 and 1989 where diagnostic exposures were applied to a lesser extent. Low-level radiation can cause these diseases and the difference of cancer rates gives rise to renewed evaluation of current risk estimates. Risk factors for radiation-induced childhood leukaemia and breast cancer are derived from the literature, considering a higher relative biological effectiveness of diagnostic X rays in comparison to the A-bomb gamma rays in Hiroshima and Nagasaki. The prostate is not considered as radiation sensitive by the ICRP. But following a variety of low-level findings in the last two decades it was shown by Myles et al. in the UK that prostatic cancer is inducible by diagnostic X-ray procedures. From their study in men below the age of 60, a doubling dose of about 20 mSv can be estimated. Medical exposures of the considered tissues are taken from published data for East and West Germany. The difference in breast cancer mortality can be explained by diagnostic exposures. The contribution of these to prostatic cancer and childhood leukaemia must be regarded as relevant in current incidences. Reduction of diagnostic exposures would be an important measure for preventing several prominent cancer diseases.     

Childhood leukaemia and socioeconomic status: what is the evidence?

The objectives of this systematic review are to summarise the current literature on socioeconomic status (SES) and the risk of childhood leukaemia, to highlight methodological problems and formulate recommendations for future research. Starting from the systematic review of Poole et al. (Socioeconomic status and childhood leukaemia: a review. Int. J. Epidemiol. 2006;35(2):370-384.), an electronic literature search was performed covering August 2002-April 2008. It showed that (1) the results are heterogeneous, with no clear evidence to support a relation between SES and childhood leukaemia; (2) a number of factors, most importantly selection bias, might explain inconsistencies between studies; (3) there is some support for an association between SES at birth (rather than later in childhood) and childhood leukaemia and (4) if there are any associations, these are weak, limited to the most extreme SES groups (the 10-20% most or least deprived). This makes it unlikely that they would act as strong confounders in research addressing associations between other exposures and childhood leukaemia. Future research should minimise case and control selection bias, distinguish between different SES measures and leukaemia subtypes and consider timing of exposures and cancer outcomes.     

Residential exposures to pesticides and childhood leukaemia

Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case-control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of approximately 600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene-environment interaction studies.     

Risk estimates for meningiomas and other late effects after diagnostic X-ray exposure of the skull

This study aims to investigate the contribution of diagnostic exposures to the rising rates of brain tumours and other neoplasms which are observed in several industrial nations. Included are benign tumours in the head and neck region and cataracts which are neglected in usual risk estimates by international and national radiation protection committees. Dose-effect relationships for tumours of the brain, skin, thyroid and other sites of the head region, leukaemia and cataracts are taken from the literature. Risk estimates are derived for paediatric head computed tomographies (CTs) as well as for brain tumours in adults. On the basis of estimates for Germany about the number of head scans, the annual rate of radiation-induced diseases is calculated. About 1000 annual paediatric CT investigations of the skull will lead to about three excess neoplasms in the head region, i.e. the probability of an induced late effect must be suspected in the range of some thousands. Additionally, a relevant increase of cataracts must be considered. The radiation-induced occurrence of meningiomas and other brain tumours most probably contributes to the continuously increasing incidence of these diseases which is observed in several industrial nations, as well as the exposure of the bone marrow by CT to the increase of childhood leukaemia.     

Leukaemia following childhood radiation exposure in the Japanese atomic bomb survivors and in medically exposed groups

Incidence and mortality risks of radiation-associated leukaemia are surveyed in the Japanese atomic bomb (A-bomb) survivors exposed in early childhood and in utero. Leukaemia incidence and mortality risks are also surveyed in 16 other studies of persons who received appreciable doses of ionizing radiation in the course of treatment in childhood and for whom there is adequate dosimetry and cancer incidence or mortality follow-up. Relative risks tend to be lower in the medical series than in the Japanese A-bomb survivors. The relative risks in the medical studies tend to diminish with increasing average therapy dose. After taking account of cell sterilisation and dose fractionation, the apparent differences between the relative risks for leukaemia in the Japanese A-bomb survivors and in the medical series largely disappear. This suggests that cell sterilisation largely accounts for the discrepancy between the relative risks in the Japanese data and the medical studies. Excess absolute risk has also been assessed in four studies, and there is found to be more variability in this measure than in excess relative risk. In particular, there is a substantial difference between the absolute risk in the Japanese atomic bomb survivor data and those in three other (European) populations. In summary, the relative risks of leukaemia in studies of persons exposed to appreciable doses of ionizing radiation in the course of treatment for a variety of malignant and non-malignant conditions in childhood are generally less than those in the Japanese A-bomb survivor data. The effects of cell sterilisation can largely explain the discrepancy between the Japanese and the medical series.     

The role of driver sleepiness in car crashes: a systematic review of epidemiological studies

To assess the available evidence for a causal role of driver sleepiness in car crashes or car crash injury, and to quantify the effect, a systematic review of the international literature was conducted. The review included all studies with a fatigue-related exposure measure, a crash or crash injury outcome measure and a comparison group, regardless of publication status, language or date of the study. Eighteen cross-sectional studies and one case-control study fulfilled the inclusion criteria. The fatigue-related exposures investigated in these studies were sleep disorders (n = 14), shift work (n = 2), sleep deprivation/fragmentation (n = 1), and excessive daytime sleepiness (n = 2). Only one study used an injury outcome measure. Studies were limited in their ability to establish a causal relationship by their design, by biases, and in many cases, by small sample sizes. The better quality cross-sectional studies were suggestive of a positive relationship between fatigue and crash risk, but could not provide reliable estimates of the strength of the association. The case-control study provided moderately strong evidence for an association between sleep apnoea and risk of driver injury, with an adjusted odds ratio of 7.2 (95% confidence interval 2.4-21.8). We conclude that the direct epidemiological evidence for a causal role of fatigue in car crashes is weak, but suggestive of an effect. To estimate the burden of injury due to fatigue-related crashes in the population, information is required from well-designed observational epidemiological studies about the prevalence of fatigue in the car driving population and the size of the risk this confers.     

The 'Kinderkrebs in der Umgebung von Kernkraftwerken' study: results put into perspective

A German case-control study on leukaemia in children below 5 y of age near nuclear installations showed a trend of increasing risk with decreasing distance of place of residence from the sites. The radiation exposure from the sites is considered as being too low by a factor of at least 1000 to explain the observed effect, but little is known about radiation effects from pre- or postnatal exposures on the leukaemia risk for ages up to 4 y. Within the study, it was shown that the observed trend in risk decreases over time. That could be indicative of some agent being involved for which the prevalence is reduced over time. Previous ecological studies showed increased risks among the youngest age groups in the closest vicinity of the sites, but no elevated risks for children of all ages (0-14). This could implicate a shift towards an earlier onset of the disease.     

Assessment of environmental exposures from agricultural pesticides in childhood leukaemia studies: challenges and opportunities

Pesticides are ubiquitous in environments of many rural communities due to drift from agricultural applications and home/garden use. Studies of childhood leukaemia predominantly relied on retrospective pesticide exposure assessment and parental recall of use or proximity to fields or pesticide applications. Sample size requirements mostly preclude the collection of individual-level exposure information, biomarkers or environmental measurements of pesticides prospectively in cohorts. Yet such measures can be used in nested case-control approaches or for validating exposure models that can be applied to large populations. Recently developed models incorporate geographic information system technology and environmental databases of pesticide and/or crop data to assess exposure. Models developed in California to estimate residential exposures are presented by linking addresses to agricultural pesticide application data and land-use maps. Results from exposure validation and simulation studies and exposure measurement error issues are discussed.     

Preconception exposures to potential germ-cell mutagens

Radiation and other agents can cause germ-cell mutations in animal systems. No human germ-cell mutagen has been identified, but this does not mean that human germ-cells are not vulnerable to mutagenesis. There has been particular concern about the possible health effects on offspring following parental preconception exposure to ionizing radiation-both occupational and therapeutic. A strong association with preconception radiation exposure in the fathers of the cases was found in a case-control study of young people with leukaemia living near the Sellafield nuclear plant in the UK. Subsequent studies of workers occupationally exposed to ionizing radiation have failed to confirm these findings. No statistically significant effects have been reported from studies of possible indicators of germ-cell mutagenesis in the A-bomb survivors. Studies of offspring of cancer survivors who receive radiotherapy and mutagenic chemotherapy have found no evidence of germ-cell mutagenesis. Failure to detect human germ-cell mutagenic agents may be a consequence of inadequate study sizes or insufficiently sensitive laboratory techniques.     

Exposure assessment and other challenges in non-ionizing radiation studies of childhood leukaemia

Studies of electromagnetic fields (EMF) and the development of childhood leukaemia face unique difficulties. EMF are imperceptible, ubiquitous, have multiple sources, and can vary greatly over time and distances. Childhood leukaemia and high average exposures to magnetic fields are both quite rare. Thus, a major challenge in EMF epidemiology is the small number of highly exposed cases and the necessity for retrospective assessment of exposure. Only studies designed to minimize bias while maximizing our ability to detect an association, should one exist, would have a potential to contribute to our understanding. New approaches are needed; the most promising in the extremely low-frequency range involves a study of a highly exposed cohort of children who have lived in apartments next to built-in transformers or electrical equipment rooms. Another promising avenue is an investigation of possible joint effects of environmental exposures and genetic co-factors. An exposure assessment methodology for residential radiofrequency fields is still in its infancy. Rapid changes in technology and exponential increases in its use make exposure assessment more difficult and urgent.     

A case-control study of child bicycle injuries: relationship of risk to exposure

In order to assess the relationship of the risk of injury requiring hospital attendance in children riding bicycles to sociodemographic factors and to measures of exposure, a population-based case-control study is being undertaken in a large area of suburban Melbourne, Australia. Particular attention is given to the measurement of individual exposure in several dimensions. Analysis of interim data from 109 cases and 118 controls shows that 51% of injuries occurred while the child was playing rather than making a trip on the bicycle and only 22% involved another vehicle. Boys used bicycles more commonly than girls but there was minimal evidence of an increased risk of injury in boys, adjusting for exposure. There was no evidence for an age trend in injury risk, but children from families in the lowest income category were at significantly increased risk. Exposure measures showed complex patterns of association with injury risk. Estimated time spent riding was more closely associated with risk than distance travelled, with an odds ratio of 2.2 (95% confidence interval 1.1–4.2) for children riding for more than 3 hours per week compared to children riding less than 1 hour. Riding more than 5 km on the sidewalk was also associated with increased risk (odds ratio 3.1, 95% CI 1.1–8.5). The elevated risk associated with sidewalk riding may be due to difficulties in negotiating uneven surfaces. The case-control study provides an ideal design for this type of investigation but valid and reliable measurement of exposure is difficult.     

Epidemiological studies of leukaemia in children and young adults around nuclear facilities: a critical review

The existence of an increased risk of childhood leukaemia near nuclear installations is a recurrent issue. A review of the related epidemiological literature is presented here. Results for 198 nuclear sites throughout 10 countries were included in the review. In addition to local studies, 25 multi-site studies have been published for eight countries. A large variability was noticed in the quality of the data as well as in the definition of the study population and in the methods of analysis. Many studies present important limits that make the results difficult to interpret. The review confirms that some clusters of childhood leukaemia cases exist locally. However, results based on multi-site studies around nuclear installations do not indicate an increased risk globally. Many studies were launched to investigate possible origins of the observed clusters around specific sites, but up to now, none of the proposed hypotheses have explained them.     

Aetiology of childhood acute leukaemias: current status of knowledge

Acute leukaemia is a consequence of malignant transformation of a haematopoetic progenitor cell. Molecular studies have revealed a prenatal origin of many childhood leukaemias. According to current models, a preleukaemic stem cell clone is generated by a first mutation in utero which, in a minority of children, progresses to leukaemia after receiving further postnatal genetic hits. The nature of pre- and postnatal events involved in leukaemogenesis in children is not well understood. Although genetic predisposition and specific environmental exposures may account for individual cases, the bulk of childhood leukaemia cannot be explained by any of these factors. The higher incidence of the most common leukaemia subtype in affluent societies, as well as the age peak between 2-5 y, suggest a contributory role of socioeconomic factors. An abnormal immune response during delayed exposure to common infections provides a plausible mechanism for malignant progression of preleukaemic clones in a subgroup of children. As highlighted in this review, a common cause for all types and subtypes of childhood leukaemia is highly unlikely. Deeper insights into the pathogenesis of childhood leukaemia will rely on large-scale and combined epidemiological and biomolecular studies.     

WHO's health risk assessment of ELF fields

The World Health Organization (WHO), the International Commission on Non-Ionizing Radiation Protection (ICNIRP), WHO's scientific collaborating centres (including the UK's National Radiological Protection Board (NRPB)) and over 50 participating Member States are participants of WHO's International EMF Project. As part of WHO's health risk assessment process for extremely low frequency fields (ELF), this workshop was convened by NRPB to assist WHO in evaluating the potential health impacts of electrical currents and fields induced by ELF in molecules, cells, tissues and organs of the body. This paper describes the process by which WHO will conduct its health risk assessment. WHO is also trying to provide information on why exposure to ELF magnetic fields seems to be associated with an increased incidence of childhood leukaemia. Are there mechanisms that could lead to this health outcome or does the epidemiological evidence incorporate biases or other factors that need to be further explored?     

Gene expression profiles for monitoring radiation exposure.

Previous demonstrations that the dose, dose rate, radiation quality, and elapsed time since ionising radiation exposure result in variations in the response of stress genes suggest that gene expression signatures may be informative markers of radiation exposure. Defining sets of genes that ate specific for different outcomes of interest will be key to such an approach. A generalised post-exposure prolile may identify exposed individuals within a population, while more specific fingerprints may reveal details of a radiation exposure. Changes in gene expression in human cell lines occur after as little as 0.02 Gy rays, and in peripheral blood lymphocytes alter as little as 0.2 Gy. Diverse genes are also elevated in vivo in mice 24 h after 0.2 Gy irradiation. Ongoing microarray analyses meanwhile continue to identify large numbers of potential biomarkers from varied irradiation protocols. Development of computation-intensive informatics analysis methods will be needed for management of the complex gene expression profiles resulting from such experiments. Although the preliminary data are encouraging, significant work remains before meaningful correlations with risk or practical assessment of exposure can be made by gene expression profiling.     

A review of some epidemiological studies on cancer risk from low-dose radiation or other carcinogenic agents

It is extremely difficult to assess cancer risks accurately due to health effects of low-dose radiation exposure or other carcinogens based on epidemiological studies. For the detection of minute increases of the risk at low-level exposure, most of epidemiological studies lack statistical power, and they involve various complicated confounding factors. This paper reports on a literature survey of epidemiological studies published since 2000 on cancer risks associated with low-dose radiation and other carcinogens to gather major epidemiological data. Integrated risk indices were derived from those data by using, where possible, statistical models. Regarding risk assessment of low-dose radiation exposure, it is important to lower the degree of uncertainty arising from risk estimation. Risk assessment of low-dose radiation exposure could be scientific evidence when uncertainty is considered in comparing carcinogenic risks of radiation with those of other carcinogens.     

Radiation-epidemiological studies of thyroid cancer incidence in Russia after the Chernobyl accident (estimation of radiation risks, 1991-2008 follow-up period)

This study presents an analysis of the thyroid cancer incidence in the population of the most contaminated territories of Bryansk, Kaluga, Oryol and Tula oblasts affected by the Chernobyl accident. The follow-up period is 1991-2008, and the cohort size is 309 130 people. For that period 978 thyroid cancer cases were detected. The excess relative risk per 1 Gy (ERR/Gy) is found to be statistically significant for children and adolescents (0-17 y of age) at the time of the Chernobyl accident (ERR/Gy=3.22; 95 % confidence interval (1.56; 5.81). In boys, the ERR/Gy was higher than in girls -6.54 and 2.24, respectively. A statistically significant decrease in ERR/Gy with time since exposure, by a factor of 0.37 per 10 y, was observed for the whole cohort and for boys separately, but not for girls. No radiation risks of a thyroid cancer among people of 18 y of age at exposure and older were found.     

Premature chromosome condensation associated with fluorescence in situ hybridisation detects cytogenetic abnormalities after a CT scan: evaluaton of the low-dose effect

The purpose of this study was to assess the cytogenetic effects of the X ray irradiation used during a CT scan in order to estimate the mean absorbed dose in circulating lymphocytes. Chromosomal aberrations were scored in blood lymphocytes of ten patients undergoing CT scans, by applying fluorescence in situ hybridisation (FISH) to metaphase cells and premature chromosome condensation (PCC) with chromosomes 1, 3 and 4 painting probes immediately after exposure. This generated a dosimetric index that reflects the dose to the circulating lymphocytes. By using PCC a significant increase in the frequency of chromosomal fragment was observed immediately after a CT scan. However, no significant increase in chromosomal aberration was detected in metaphase cells. The mean dosimetric index immediately after exposure was 0.057 Gy (95% CI: 0.052-0.082 Gy). This dosimetric index depends essentially on the size of the examined and exposed blood volumes. This dose is in close agreement with the dose length product (DLP) (Gy cm) (R = 0.80). It should be kept in mind when justifying requests for diagnostic CT scan especially in young patients. The presence of chromosomal fragments after a CT scan indicated the cytogenetic effect of a low dose. PCC associated with chromosome painting is a method for detecting the cytogenetic effect of a low dose immediately after exposure.