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.     

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.     

The UK Childhood Cancer Study: maternal occupational exposures and childhood leukaemia and lymphoma

Risks of childhood leukaemia and lymphoma were investigated for specific work-related exposures of mothers in the UK Childhood Cancer Study. Interviews with parents of 1881 leukaemia and lymphoma cases (0-14 years) and 3742 controls collected job histories recording exposure to eight specific agents. Exposure was (1) self-reported and (2) reviewed, based mainly on exposure probability and exposure level. Completeness, consistency and sufficiency evaluated data quality. Of all job exposures which were self-reported as exposed, 33% cases and 34% controls remained classified as exposed after review, with the remainder designated as partially exposed or unexposed. No review of underreporting of exposure was made. Data quality was 'good' for 26% of cases and 24% of controls. For self-reported exposure, significant risks of acute lymphoblastic leukaemia (ALL) were observed for solvents and petrol in all time windows. For reviewed exposure, solvents remained significant for ALL during pregnancy and postnatally. Restricting analyses to good-quality information removed all significant results. Refinement of exposure assessment revealed misclassification of self-reported exposures and data quality influenced risk assessment. Maternal exposure to solvents should further be investigated. These findings must invoke caution in the interpretation of risks reliant on self-reported occupational data.     

Childhood leukaemia following medical diagnostic exposure to ionizing radiation in utero or after birth

A statistical association between childhood leukaemia and an abdominal X-ray examination of the pregnant mother was first reported in 1956 from a case-control study of childhood cancer mortality conducted in Great Britain. This study, later called the Oxford Survey of Childhood Cancers (OSCC), was continued and eventually showed a highly statistically significant approximately 50% proportional increase in the risk of childhood leukaemia associated with antenatal diagnostic radiography. The association has been confirmed by many case-control studies carried out around the world, the appropriately combined results of which show a highly statistically significant increase in risk that is compatible with the OSCC finding. There is no doubt about the reality of the statistical association, but a causal interpretation has been questioned. On balance, however, the evidence points to low-level irradiation of the fetus increasing the risk of leukaemia in childhood, with an excess relative risk coefficient of around 50 Gy(-1) (equivalent to an excess absolute risk coefficient of about 3% Gy(-1)), although the uncertainty associated with these coefficients is considerable and they are likely to be overestimates. In contrast to exposure in utero, the evidence from case-control studies for an association between childhood leukaemia and postnatal exposure to medical diagnostic irradiation is equivocal and sometimes conflicting. Since standard radiation risk models predict that low-level exposure in the early years of life should produce an increased risk of childhood leukaemia that is roughly similar to that arising from fetal exposure, this absence of persuasive evidence is likely to be due to various problems with the studies. This is unfortunate given the rise in relatively high dose diagnostic procedures (e.g. paediatric CT scans) that would be predicted to materially increase the relative risk of childhood leukaemia.     

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.     

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.     

Exposure assessment: implications for epidemiological studies of ionizing radiation

Quantitative estimates of ionizing radiation exposure are often available for use in epidemiological studies. However, depending on the context, the quality of the exposure estimates can vary. For example, the estimates may be specific to individuals in the study or generic values averaged over populations; unavailable for some of the potential study subjects or vary in their form between individuals; based on contemporary measurements or assessed retrospectively; based on measurements alone, on surrogate measures of exposure, or on an exposure assessment model; or, as is often the case, cover one source of radiation exposure rather than all of them. Various ways in which ionizing radiation exposures have been assessed are illustrated through reference to some studies of childhood leukaemia, concerning environmental, medical, natural and parental occupational exposures. Based on this, implications for the interpretation of radiation epidemiological studies are discussed.     

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.     

Host, family and community proxies for infections potentially associated with leukaemia

Three hypotheses have proposed the involvement of infections in the aetiology of childhood leukaemia, suggesting either a specific leukaemogenic infection or a series of common infections that lead to a dysregulation of the immune system. Much of the evidence for the link with infections has been based on epidemiological observations, often using proxy measures of infection. Proxy measures include population mixing, parental occupation, age distribution of incidence, spatial and space-time clustering of cases, birth order and day care during infancy. This paper discusses the proxies used and examines to what extent a commonly used proxy measure, birth order, is a fair representation of either specific infections or general infectious load. It is clear that although leukaemia, and other diseases, may be linked with infections, one needs to (1) measure specific and general infections with more accuracy and (2) understand how proxy measures relate to real infections in the population.     

'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.     

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.     

The Fort Totten mercury pollution risk assessment: a case history

Operational activities have resulted in mercury in the sediments surrounding Little Bay in Queens, NY. This is adjacent to Fort Totten, a formerly used defense site. Some of the mercury levels in these sediments exceeded New York State screening values. A human health risk assessment was accomplished, based on conservative assumptions. The risk assessment examined the potential for adverse health effects from direct contact with and ingestion of contaminated sediments/surface water and ingestion of biota. Potential exposures to recreational receptors including adults and children were examined. The highest numerical risk results from finfish ingestion and then second for exposure from dermal contact to the sediments. The only exposure pathway showing a hazard quotient greater than unity is finfish ingestion for the child. In summary, overall risk to this mercury exposure is minimal in spite of the state screening value being exceeded.     

Can tissue weighting factors be established for the embryo and fetus?

For the calculation of effective dose (E), tissue weighting factors (wT) are needed to represent the varying radiosensitivity of the tissues in the human body with respect to the induction of stochastic effects. The wT-values have been determined by the International Commission on Radiological Protection according to the stochastic detriment of human populations during their postnatal life. This study discusses whether these wT-values can also be used for the embryo/fetus. For this purpose, the epidemiological data and some results from animal experiments on carcinogenesis after prenatal radiation exposures have been reviewed. Most human data have been obtained from studies of childhood cancers (<19 y of age) after exposures during prenatal development. These tumours differ from those observed later in life after radiation exposures of children and adults. From animal data and more recent results from the atomic bomb survivors, it appears that not only childhood cancers but also cancers occurring during adulthood would have to be considered for the determination of possible wT-values after prenatal irradiation. From the present data it is concluded that sufficient data for defining wT-values following exposure of the embryo/fetus are not available at present.     

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.     

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.     

Evidence of children's vulnerability to radiation in the context of radiological/nuclear events and considerations for emergency response

International organisations, such as International Atomic Energy Agency, United Nations Scientific Committee on the Effects of Atomic Radiation and World Health Organisation, together with committees of experts such as Biological Effects of Ionising Radiation and Committee on Medical Aspects of Radiation in the Environment, have assessed the effects of radiation on large exposed populations (Chernobyl accident, and Hiroshima/Nagasaki atomic bombings) and on nuclear energy workers and people living near nuclear facilities. Childhood and in utero exposure to moderate and high levels of ionizing radiation, such as those experienced during the atomic bombings of Japan, or from radiotherapy, is an established cause of leukaemia and solid cancer. There is no evidence of increase in solid cancers (excluding thyroid cancer) or leukaemia in the children from Chernobyl, and no evident link between worker's exposure to radiation and leukaemia in their offspring or with the presence of leukaemia clusters around nuclear power plants. It has also not been possible to demonstrate the evidence of radiation hereditary effects in human populations. In accordance with international guidance, Canadian Nuclear Safety Commission recommends optimisation of protection strategies to reduce doses to children. The development of credible radiological/nuclear event scenarios would assist in identifying probable sources of radioactivity and pathways of exposure for children. Such scenarios should then be used to identify protection strategies appropriate for children.     

Transmission lines, EMF and population mixing

Draper et al. found that the incidence of childhood leukaemia was slightly elevated for children living at distances of 200-600 m from high-voltage transmission lines. This elevation cannot be explained by EMF exposure and it is suggested that it may be due to population mixing in housing developments which followed the construction of the lines.     

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.