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Keywords:

  • electromagnetic fields;
  • childhood leukemia;
  • extremely low frequency;
  • radiofrequency

Abstract

  1. Top of page
  2. Abstract
  3. Childhood Leukemia
  4. Electromagnetic Fields
  5. Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF
  6. Possible Biological Mechanisms
  7. Impact
  8. Conclusion
  9. Acknowledgements
  10. References

The increasing exposure to electromagnetic fields (EMFs) has raised concern, as increased exposure may result in an increased risk of childhood leukemia (CL). Besides a short introduction of CL and EMF, our article gives an evaluation of the evidence of a causal relation between EMF and CL by critically appraising the epidemiological and biological evidence. The potential impact is also estimated by the population attributable risk. The etiology of CL is largely unknown, but is probably multifactorial. EMF may be one of the environmental exposures involved. Three pooled analyses of case–control studies showed a 1.4- to 1.7-fold increased CL risk for extremely low-frequency EMF (ELF-EMF) exposure levels above 0.3 μT. Several biases may have played a role in these studies, but are unlikely to fully explain the increased risk. For effects of radiofrequency ELF evidence is lacking. None of the proposed biological mechanisms by which ELF-EMF might cause CL have been confirmed. The estimated overall population attributable risk was 1.9%, with the highest estimates in Northern America and Brazil (4.2% and 4.1%, respectively). The potential impact of EMF exposure on public health is probably limited, although in some countries exposure might be relatively high and thus might have a more substantial impact. We recommend nationwide surveys to gain more insight into the contemporary exposure levels among children. Reducing exposure from power lines near densely populated areas and schools is advised. Future epidemiological studies should focus on limiting bias.

Research on possible long-term adverse health effects of electromagnetic fields (EMF), such as cancers, neurodegenerative diseases, psychiatric disorders, cardiovascular diseases and reproductive disorders, has been ongoing for several years.1 Because children may be more sensitive to EMF,2 a large part of the research has focused on adverse health effects in this group, especially on childhood cancer.3 Since the first publication of a possible link between EMF and childhood cancer by Wertheimer and Leeper in 1979,4 several studies have been performed on this topic. Till date, epidemiological research did not reveal any relation between EMF and childhood cancers, except for childhood leukemia (CL) for which studies suggested an increased risk at high EMF exposure levels.5–7 However, because these observational studies are prone to several types of biases and biological evidence is lacking, uncertainty prevails, and after more than 30 years of research, there is still no clarity about a presumed causal relation.

Since the introduction of artificial EMF in the beginning of the 20th century, exposure to EMF has been increasing substantially.8 The number and variety of EMF sources have expanded due to technological developments and increasing use of electric appliances. For example, the worldwide increase of mobile phone use in the last decades has led to an important new source of EMF exposure.

Because of the increasing exposure to EMF, public concern about possible adverse health effects has been growing.9 Despite the fact that most studies do not consistently show adverse health effects of EMF exposure below the guideline limits,1 research has not been able to abate this public anxiety. After all, lack of evidence does not mean absence of effect. Media also play a role in raising public concern as they tend to report more extensively on research that does find adverse health effects of EMF than on research that does not.

Our study has several aims. The first is to give a short introduction of CL. Further, we discuss EMF. Next, we discuss the epidemiological evidence suggesting an increased risk of CL due to EMF. Subsequently, possible biological mechanisms are discussed. The final aim is to discuss the possible impact of EMF on CL incidence on a population level.

Childhood Leukemia

  1. Top of page
  2. Abstract
  3. Childhood Leukemia
  4. Electromagnetic Fields
  5. Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF
  6. Possible Biological Mechanisms
  7. Impact
  8. Conclusion
  9. Acknowledgements
  10. References

CL is the most frequent malignancy among children, accounting for approximately one-third of all childhood cancers. In Europe, the age-standardized (world standard) annual incidence of CL (0–14 years) during 1993–1997 was 45.1 per one million children.10 Over the period 1978–1997, the incidence increased with ∼0.6% per year on average.10 Acute lymphoblastic leukemia (ALL) is the most common subtype of CL (circa 85%) and has a peak in incidence between the ages of 2 and 4 years. Acute myeloid leukemia (AML) risk is highest in the first 2 years after birth and decreases afterward. Boys have a slightly higher risk of developing CL than girls.11

Little is known about the etiological mechanism of CL. It is thought that the pathogenesis of leukemia consists of multiple steps. The initiating step for leukemia development has been hypothesized to occur during fetal development. After birth, several events are needed to convert preleukemia into overt leukemia.12 Some possible events are described in the following paragraphs, although it is likely that a combination of multiple events is needed to develop CL.

Some genetic factors have been described in relation to CL. Children with Down syndrome have a higher risk of developing CL. Also, some high-penetrance germline mutations have been linked to a genetic predisposition for CL, although it was estimated that they contribute to less than 5% of CL cases.13 Furthermore, some low-penetrance genes that increase susceptibility for certain exposures have been reported to be possibly associated with CL. Most low-penetrance genes are involved in the folate metabolism pathway and the xenobiotic metabolism pathway.14

There is some evidence of space–time and/or spatial clustering of the incidence of CL, suggesting that environmental exposures may be involved.15–18 Some environmental exposures have been identified as potential causative factors for CL. Ionizing radiation, which is capable of directly damaging DNA, can cause CL at very high exposure levels.19 Furthermore, exposure to pesticides is suggested to be linked with an increased CL risk.20 Benzene is known to increase AML risk in highly exposed persons such as occupationally exposed workers, but current evidence does not suggest an association between environmental exposure levels to children and childhood ALL or AML.21 Many other environmental exposures, such as parental smoking and alcohol consumption and paternal chemical exposure at work, have also been investigated, but none of these were proven to be causative for CL.22 A delayed abnormal immune response to an infection has been proposed as an etiological mechanism for CL. Epidemiological findings, such as worldwide variation of CL incidence, the ALL peak between 2–4 years and space–time and spatial clustering of CL, support this theory.12

Electromagnetic Fields

  1. Top of page
  2. Abstract
  3. Childhood Leukemia
  4. Electromagnetic Fields
  5. Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF
  6. Possible Biological Mechanisms
  7. Impact
  8. Conclusion
  9. Acknowledgements
  10. References

Another exposure that may be one of the environmental factors involved in the development of CL is EMF. In the next paragraphs, we give a short description about what EMF are and an overview about current guidelines.

Radiation can be divided into ionizing radiation and nonionizing radiation. Ionizing radiation has a higher frequency than nonionizing radiation and thus a shorter wavelength. The shorter the wavelength, the higher the energy it carries. Ionizing radiation has sufficient energy to directly damage the DNA molecule.23 A high exposure to this type of radiation can cause several types of cancer, including CL.24, 25 Nonionizing radiation, however, is not able to break bonds of DNA molecules. Nonionizing radiation can be subdivided into extremely low-frequency EMF (ELF-EMF; 0–100 kHz) and radiofrequency EMF (RF-EMF; 100 kHz–300 GHz). ELF-EMF account for an important part of EMF exposure. Major sources of ELF-EMF are power lines (50/60 Hz). Closer distances to power lines generally mean higher ELF-EMF exposures. Other important sources of ELF-EMF are domestic electric appliances. The International Agency for Research on Cancer (IARC) has considered ELF-EMF as “possibly carcinogenic to humans” based on their evaluation of limited evidence for the carcinogenicity in relation to CL.26 RF-EMF account for another part of EMF exposure. Sources of RF-EMF include televisions, radios, microwaves and mobile phones and their base stations. With the increasing use of mobile phones and its use at younger ages, exposure to RF-EMF may be increasing nowadays. Recently, the IARC has classified RF-EMF as “possibly carcinogenic to humans” based on an increased glioma risk.27

The International Commission on Non-Ionizing Radiation Protection (ICNIRP) has set guidelines for exposure limits to EMF.28 The guidelines for 1 Hz–100 kHz have recently been revised.29 Table 1 shows current guidelines for EMF exposure. These guidelines are not based on the possible relation between EMF and CL, as the ICNIRP concluded that evidence for a causal relation is too weak.29

Table 1. Reference levels for general public exposure to time-varying electric and magnetic fields (adapted from ICNIRP guidelines28, 29)
inline image

Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF

  1. Top of page
  2. Abstract
  3. Childhood Leukemia
  4. Electromagnetic Fields
  5. Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF
  6. Possible Biological Mechanisms
  7. Impact
  8. Conclusion
  9. Acknowledgements
  10. References

Epidemiological evidence for the possible relation between EMF and CL is summarized and discussed by considering pooled analyses and recent case–control studies published after the most recent pooled analysis.5–7, 30 For RF-EMF, studies with an ecological design are also considered, because case–control studies on this topic are lacking. Furthermore, only studies that reported results in children and for total leukemia or ALL alone were evaluated, whereas exposure measurements had to consist of either calculated EMF fields or long-term residential spot measurements.

ELF-EMF

Since the study of Wertheimer and Leeper in 1979,4 many studies have been investigating the association between ELF-EMF and CL. In some studies, the exposure to magnetic fields was calculated based on the distance from and characteristics of power lines, whereas in other studies exposures were directly measured inside the children's homes. The epidemiological studies have been summarized by three pooled analyses.5–7 The results of these analyses are shown in Table 2. In 2000, Ahlbom et al. pooled data from nine case–control studies including 3,203 children with CL and 10,338 controls.5 The summary relative risk (RR) for exposure to ≥0.4 μT was increased compared to <0.1 μT (RR = 2.0; 95% CI = 1.27–3.13). For the four studies using calculated fields (RR = 2.13; 95% CI = 0.93–4.88) RR was slightly higher than for the five studies using direct measurements (RR = 1.87; 95% CI = 1.10–3.18). A pooled analysis by Greenland et al.6 included 11 case–control studies with magnetic fields estimates and covariate data; eight of these were also included in Ahlbom's study, whereas one large case–control study included in Ahlbom's study was not included because the data were not received in time. Greenland et al. described a statistically significant increased summary odds ratio (OR) for exposures of >0.3 μT compared to ≤0.1 μT (OR = 1.68; 95% CI = 1.23–2.31). The exposure categories differ from those used by Ahlbom who used ≥ 0.4 μT as the highest exposure category. After the publication of these two pooled analyses, several other studies have been conducted. In 2010, a pooled analysis only including studies published since the two pooled analyses from 2000 was performed by Kheifets et al.7 This study included six case–control studies with a total of 9,830 cases and 10,337 controls for whom magnetic field exposures were estimated. An increased risk for exposure to ≥0.3 μT compared to ≤0.1 μT (OR = 1.44; 95% CI = 0.88–2.36) was reported. The risk estimate in this recent pooled analysis is slightly lower than those in older analyses and is not statistically significant. After this study by Kheifets et al., only one case–control study could be identified. Does et al. performed residential spot measurements in 245 cases and 269 controls. No increased risk was found for exposures above 0.3 μT compared to ≤0.1 μT (OR = 0.57; 95% CI = 0.14–2.36).30

Table 2. Pooled analyses of case–control studies on extremely low-frequency electromagnetic fields and childhood leukemia
inline image

Problems in exposure assessment

Some limitations of both calculated field studies and direct measurement studies have to be addressed. Calculated field studies only take EMF exposures from power lines into consideration and ignore other possible sources, which results in an underestimation of EMF exposure. It is yet unclear to which extent other sources may contribute to the total EMF exposure. In an investigation of the sources of magnetic field exposures in the UK Childhood Cancer Study,31 it was concluded that power lines accounted for 23% in the category of exposures >0.2 μT and for 43% in the category >0.4 μT.32 Vistnes et al.33 found high correlations (>80%) between calculated exposures based on proximity to power lines and actual exposures measured from personal dosimetry and concluded that calculated fields could be used to assess EMF exposure in epidemiological research. Moreover, results of calculated field studies and direct measurement studies are generally comparable, as can be seen from Table 2.

Direct measurement studies are limited by the fact that measurements usually take place for a short period of time (24 hr or a couple of days), whereas EMF may vary over time. Therefore, such relatively short measurements may not be representative for exposure over a longer period and could lead to exposure misclassification. This also holds for calculated field measurements, although these exposures are expected to be more stable over time, because they depend on distance from and characteristics of power lines, which are not likely to vary much over time. However, it seems unlikely that the extent of these types of exposure misclassification is associated with the disease status. If misclassification is nondifferential, this will mostly lead to bias toward the null and thus to an underestimation of the effect.34

Possible selection bias

Another limitation of direct measurement studies is that in-home measurements have to be performed. As cases are usually more willing to participate than controls, the participation rate is much lower for controls than for cases, and even less for controls with low socioeconomic status (SES). Selection bias might have occurred, because low SES is associated with higher EMF exposure.35 Some studies investigated the probability that selection bias could explain their positive findings. In two studies, subjects who refused indoor measurements had lower SESs than subjects who allowed this assessment.36, 37 Wire codes (a proxy for EMF exposure) of both participants and nonparticipants were assessed, which was possible because participation of the subjects was not required. Smaller ORs were found when all subjects were included if compared to only participants. This might imply that selection bias could explain part of the observed association between EMF and CL. However, wire codes are merely a proxy of EMF exposure, and therefore, the attenuated risk when including all subjects might not hold for real EMF exposure. Furthermore, studies using calculated fields measurements generally show the same results as direct measurement studies, despite the fact that these studies are usually less vulnerable to selection bias as they do not require participation of the subjects.5–7

Confounding bias

Confounding bias may also have played a role. Hatch et al.37 evaluated the impact of several possible confounding factors, but none of these factors did change the risk estimates significantly. For a confounder to fully account for the increase in risk, it should be a reasonably strong risk factor and also strongly correlated with exposure to EMF. Such a factor has not yet been identified and the existence of it seems unlikely.38

RF-EMF

Less attention has been paid to the possible relation between RF-EMF and CL. Only three case–control studies could be identified.39–41 In addition, we found four studies with an ecological design.42–45 Table 3 shows results of all studies.

Table 3. Epidemiological studies of radiofrequency electromagnetic fields and childhood leukemia
inline image

One case–control study did not show an increased risk for the highest exposed subjects (95–<100th percentile of exposure) compared to subjects with a low exposure (0–<90th percentile; OR = 0.86; 95% CI = 0.67–1.11).41 Another case–control study did show an increased risk of CL for children who were living within 2 km of an AM radio transmitter compared to children living >20 km from the transmitter (OR = 2.15; 95% CI = 1.00–4.67). However, children living between 2 and 4 km from the transmitter had a decreased risk of CL compared to the same reference category of >20 km, which probably means that there was no real association between distance from the transmitter and CL. In addition, individual exposure estimates based on a geographical information system were performed. Children in the highest exposure quartile did not have an increased risk compared to the lowest quartile (OR = 0.77; 95% CI = 0.54–1.10).39 Another case–control study, based on a cluster investigation, did not have sufficient power to study the association between RF-EMF exposure and CL.40

Ecological studies showed varying results. One study found an increased risk of CL for children living within 6 km of a radio station (standardized incidence ratio = 2.2; 95% CI = 1.0–4.1).45 Three other ecological studies did not find an increased risk.42–44

In conclusion, currently there is a lack of evidence and especially a lack of well-designed studies regarding a possible link between RF-EMF and CL. Most studies have an ecological design, in which aggregate, population-level data on exposure and disease rates are compared. The results of these studies cannot reliably be extrapolated to individual-level exposure-disease relations, because of specific biases of ecological studies due to missing information on within-group distribution of exposures and potential confounders.47, 48

Possible Biological Mechanisms

  1. Top of page
  2. Abstract
  3. Childhood Leukemia
  4. Electromagnetic Fields
  5. Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF
  6. Possible Biological Mechanisms
  7. Impact
  8. Conclusion
  9. Acknowledgements
  10. References

To confirm a causal relation between EMF and CL, a plausible biological mechanism is needed. One of the proposed mechanisms by which EMF might cause CL is via melatonin disruption. According to a review, several studies have demonstrated EMF to reduce melatonin levels in different animal species.49 Some human studies on this subject did show a statistically significant melatonin suppression by acute exposure to EMF, but in most studies, this effect was not observed. Most studies on long-term chronic exposures of EMF did find evidence for melatonin disruption. Possible mechanisms by which melatonin disruption may lead to leukemia have been addressed. Melatonin may protect against oxidative damage to the hematopoietic system.50, 51 Furthermore, protection against oxidative damage to the fetus may be provided by melatonin, which has been suggested in several animal studies.52, 53 This makes melatonin disruption a plausible mechanism by which EMF might cause CL, although more research is needed.49

Another mechanism might be contact currents, which flow through the body when someone touches two surfaces with a different electrical potential. A relatively weak contact current may generate a strong internal electric field, which can produce several carcinogenic effects, such as cell proliferation, disruption of signal transduction pathways and inhibition of differentiation.54, 55 A study by Kavet and Zaffanella found a correlation between the voltage between the water pipe and earth, attributable to ground currents in the water system, and the magnetic induction from nearby power lines and electromagnetic fields. The same study also revealed that the dose of contact current exposure is high enough to may cause biological effects to the bone marrow.54 However, in a recent study by Does et al.,30 only a weak correlation was found between contact currents and EMF exposure and no relation between contact currents and CL was observed.

Despite the efforts to elucidate a possible biological mechanism by which exposure to EMF might cause CL, none of these mechanisms have been yet confirmed.

Impact

  1. Top of page
  2. Abstract
  3. Childhood Leukemia
  4. Electromagnetic Fields
  5. Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF
  6. Possible Biological Mechanisms
  7. Impact
  8. Conclusion
  9. Acknowledgements
  10. References

To better understand the impact of an increased risk of CL due to high exposures of ELF-EMF, one must consider the proportion of children exposed to these levels and the increase in risk associated with these levels. The population attributable risk percent (PAR%) is a suitable measure for this. The PAR% is the percentage of the incidence of the disease in the total population that may be attributable to the exposure. The PAR% is calculated by the following formula:56

  • equation image

where p = proportion exposed; OR = odds ratio; 1 = 0.1–0.2 μT; 2 = 0.2–0.3 μT; 3 = ≥0.3 μT.

The estimation of the proportions of exposed children were based on the studies included in the pooled analyses of Greenland et al.6 and Kheifets et al.,7 because both pooled analyses used the same exposure categories (0.1–0.2 μT, 0.2–0.3 μT and ≥0.3 μT).57–74 For the estimation of population exposure, we used control group exposure and grouped studies based on country or region. Because exposures were found to vary greatly between studies, we performed a sensitivity analysis with variable exposure proportions. For the estimation of the OR of the exposure categories, we took the point estimates of the most recent pooled analysis (OR1 = 1.07, OR2 = 1.16 and OR3 = 1.44)7 as a best-guess scenario and also the highest confidence limits (OR1 = 1.41, OR2 = 1.93 and OR3 = 2.36)7 as a worst-case scenario. We included ORs for all exposure categories as even a small increased OR might have a huge impact on PAR% if the proportion of children in these categories is large.

As shown in Table 4, the overall mean percentage of children exposed to ≥0.3 μT for all studies was 2.0%, with a range from 0 to 7.0%.57–74 The PAR% in the best-guess scenario was 1.9%, which means that about 2% of the CL incidence in the population might be attributable to ELF-EMF exposure. All studies from Northern America63, 64, 66, 69 showed higher PAR% than European studies.57, 58, 60, 62, 65, 67, 68, 70–73 In the worst-case scenario, the overall PAR% was 8.3% and ranged from 0.1 to 19.6%.

Table 4. Estimated PAR% based on study data from Greenland et al. and Kheifets et al
inline image

Currently, little survey data are available about exposure of children to ELF-EMF. In a Dutch population estimation, it was estimated that 13,000 of the 3,000,000 children were exposed to ELF-EMF above 0.3 μT.75 This would mean that in the worst-case scenario, 0.6% of the CL incidence in the Dutch population is caused by ELF-EMF exposure above 0.3 μT.

Conclusion

  1. Top of page
  2. Abstract
  3. Childhood Leukemia
  4. Electromagnetic Fields
  5. Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF
  6. Possible Biological Mechanisms
  7. Impact
  8. Conclusion
  9. Acknowledgements
  10. References

Epidemiological studies show a consistent association between ELF-EMF and CL. A 1.4- to 1.7-fold increased risk for exposure levels above 0.3 μT compared to <0.1 μT was found in pooled analyses. Although some bias may persist, it is possible that this is a causal association. Till date, research on RF-EMF and CL is limited and thus no firm conclusions can be drawn. The development of CL is likely to be a “multihit” process in which EMF might play a role. Some hypothesized biological mechanisms are proposed by which EMF could cause CL; however, none of these mechanisms have been consistently confirmed in experimental research. The impact of ELF-EMF exposure on CL incidence is likely to be limited, showing an overall PAR% of 1.9% worldwide. However, considering the variability of exposures between countries and regions, a substantial contribution of ELF-EMF to CL incidence cannot be ruled out.

Future epidemiological studies on ELF-EMF will only be informative if advancements will be made in reducing bias and/or if a better insight will be gained into the possible effect of bias on the results of these studies. In biological studies, the hypothesized mechanisms could be further explored. For RF-EMF, there is a need for well-performed epidemiological studies. As novel techniques, such as Bluetooth and Wi-Fi, make use of this type of EMF, it is likely that its exposure has increased over the past few years. The assessment of RF-EMF exposure is a challenge, because RF-EMF has various sources and is difficult to characterize. Recent advancements in exposure measurement can contribute to an improved quality of studies in this field.76 To gain a better insight into the proportion of highly exposed children, it can be helpful to perform nationwide surveys. In some countries, such studies are already ongoing.77

As the impact of exposure to electromagnetic radiation seems to be limited, we do not recommend more strict guidelines. However, reducing the exposure of highly exposed children, especially in regions with a large proportion of highly exposed children like Northern America and Brazil, is advised. Governments may consider precautionary measures such as reducing exposure from power lines near densely populated areas or take power lines into consideration in spatial planning of schools and living areas in order to minimize the number of highly exposed children.

References

  1. Top of page
  2. Abstract
  3. Childhood Leukemia
  4. Electromagnetic Fields
  5. Epidemiological Evidence for an Increased Risk of CL by Exposure to EMF
  6. Possible Biological Mechanisms
  7. Impact
  8. Conclusion
  9. Acknowledgements
  10. References
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