Review Article

Power Frequency Magnetic Field Exposure and Childhood Leukemia – Epidemiologic Evidence and Research Perspectives

Gábor Mezei1, 2 and Robert Kavet1

1 Electric Power Research Institute (EPRI), Palo Alto, California
2 Frédéric Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary

Corresponding author: Dr. Gábor Mezei
    P.O. Box 101
    H-1221 Budapest, Hungary
    Telephone: +36 30 622-1345
    Fax number: +36 1 482-2020
    E-mail: gmezei@epri.com

CEJOEM 2004, Vol.10. No.2.: 115–126


Key words:
Magnetic field exposure, childhood leukemia, epidemiology, control selection bias, contact current exposure


Abstract:
The potential association between childhood leukemia development and exposure to power frequency magnetic fields has been investigated extensively both in laboratory settings and in epidemiologic studies. Evidence supporting a possible link between childhood leukemia and magnetic fields, however, has been provided mostly by epidemiology. In this paper we give a short overview of how epidemiologic evidence regarding a possible link between childhood leukemia and magnetic field exposure developed over the past two and a half decades and discuss possible future research directions focusing on control selection bias and contact current hypotheses.



INTRODUCTION

The potential association between childhood leukemia development and exposure to power frequency magnetic fields has been investigated extensively both in laboratory settings and in epidemiologic studies. Evidence supporting a possible link between childhood leukemia and magnetic fields, however, has been provided mostly by epidemiology. In fact, the entire magnetic field-childhood leukemia research field was initiated by an epidemiologic study published by Wertheimer and Leeper in 1979, which described an association between childhood cancer and electrical wiring configurations of children’s homes.
    Epidemiology and epidemiologic observations have contributed to the identification of a number of associations between various adverse health outcomes and various exposures. As historical examples, we can mention Percival Pott’s conclusion from 1775 on the soot’s causative role in scrotal cancer development among the London chimneysweepers or John Snow’s description of the relationship between a cholera outbreak and the water supply system in London in 1853. More recent examples include the identification of a causal link between smoking and lung cancer in the 1960s, and the recognition of the acquired immunodeficiency syndrome epidemic in the 1980s.
    In this paper we give a short overview of how epidemiologic evidence regarding a possible link between childhood leukemia and magnetic field exposure developed over the past two and a half decades. We also discuss possible future research directions we feel could lead to the resolution of the magnetic field–childhood leukemia question.


EVOLUTION OF EPIDEMIOLOGIC EVIDENCE

Exposure assessment

A very important aspect of all epidemiologic studies is reliable exposure assessment. For studies of power frequency electric and magnetic field exposures, it has not been a simple task. Exposure is ubiquitous in modern societies wherever electricity is used, but exposure cannot be detected (i.e., seen, heard or sensed) without instrumentation. For both electric and magnetic fields many physical characteristics can be measured, but due to lack of any known and accepted biophysical mechanism to explain a carcinogenic effect, it is not known which parameter or combination of parameters should be measured in an epidemiologic study. Exposures to electric and magnetic fields are also highly variable both in space and time. Intensity of exposure decreases exponentially with distance from many sources; therefore, sharp differences in exposure could be observed within relatively short distances. Temporal changes in exposure may occur rapidly within seconds or minutes (short-term variability), but exposure patterns may also change with seasons and years (long-term variability) (Foliart et al., 2002). Exposure to electric and magnetic fields may also exhibit variation by behavioral characteristics; more active individuals may encounter sources of high exposures more frequently (EPRI, 2003b).
    Exposure assessment methods evolved greatly in epidemiologic studies examining potential health effects of electric and magnetic fields. The first published study used a crude dichotomous categorization (high current configuration code versus low current configuration code) based on characteristics of transmission and distribution lines near the subjects’ homes and the estimated distance between the lines and homes both obtained through visual inspection and simple measurements (Wertheimer and Leeper, 1979). In later studies, wire code categories were further refined to include four, and – with the inclusion of buried cables – five categories (Savitz et al, 1988; Linet et al., 1997). Some studies also used, as exposure measures, the simple distance from the subjects’ homes to transmission and distribution lines and substations (UKCCS, 2000).
    In comparison to wire code categories, historical magnetic field calculations near transmission lines represented further refinement in exposure assessment (Feychting and Ahlbom, 1993). Calculated fields relied not only on the power lines’ physical characteristics and their distance from the homes, but it also incorporated information on the lines’ recorded historical load over the study years.
    With the development and introduction of appropriate instrumentation, actual measurements of electric and magnetic fields became feasible in epidemiologic studies. Measurements were first taken for short durations in various fixed locations in the home (spot measurements) (Savitz et al., 1988). To diminish exposure misclassification due to short-term variability, the measurements were later extended to include 24 or 48 hours or even longer time intervals (Linet et al., 1997). Measurements taken in fixed locations, however, do not capture all exposures encountered by subjects actively moving around in various environments. To account for all exposures experienced by study subjects, investigators in more recent studies employed personal magnetic field exposure monitoring (McBride et al., 1999). Personal exposure monitoring means that magnetic field meters – measuring and recording various characteristics of the encountered magnetic fields – are worn and carried by the study subjects for 24 to 48 hours.
    Both descriptive exposure assessment methods and exposure assessment methods relying on actual measurements have their own advantages for use in epidemiologic studies. Descriptive methods, in general, do not require subject participation or consent. This characteristic may make these methods very appealing for epidemiologists since subject participation and the resulting potential for selection and participation bias are usually serious concerns in epidemiologic studies. With the use of wire codes and historical calculated fields it is also possible to assess exposures that occurred in the past, in an etiologically relevant period, prior to the development of the investigated diseases. Unfortunately, however, non-measurement exposure assessment methods provide only very rough and approximate measures of exposures. Wire code categories and historical calculated fields tend to correlate, but only poorly with actual measured fields (Kavet, 1995).
    Measurements, on the other hand, provide us with very accurate data on ambient magnetic field. In the case of measured fields, however, the main question becomes that how well a short-term (minutes to days) measurement, taken after diagnosis, represents a long-term (months to years) target period prior to or during disease development. Measurements also provide the investigators with data on a number of physical characteristics of the measured fields. In the absence of any known biophysical mechanism for the carcinogenic effect of magnetic fields, however, the investigators face the question of with metric to choose for analysis. Most frequently measures of central tendency, such as time-weighted average, have been used in epidemiologic studies; these metrics are among the ones easiest to measure, they are fairly reproducible over time and it is also easy to understand what they mean.
    Questionnaire-based data on use of electric household appliances, and assessed parental occupational exposure to m agnetic fields have also been used as exposure measures in a number of studies. Questionnaire-based data on appliance use, however, proved to be fairly unreliable (Mezei et al., 2001) and parental occupational exposure may only be relevant for preconceptional and intrauterine physiologic and pathologic changes.

Selected epidemiologic studies of childhood leukemia and magnetic field exposure

The epidemiologic study by Wertheimer and Leeper published in 1979 (Wertheimer and Leeper, 1979) was the first to raise the question of a potential carcinogenic effect of low-level power frequency magnetic fields. The study examined and found an association between childhood cancer mortality and indicators of potentially higher than average magnetic field exposure. The study was not limited to leukemia cases only, but it included all types of cancer cases, and it examined mortality rather than incident events. Exposure was assessed with a crude two-category classification of exposure based on power lines outside the children’s homes. In spite of its limitations, the study showed a 2-3-fold increase in risk of cancer development in association with higher estimated residential exposure.
    The case-control study by Savitz and colleagues published in 1988 (Savitz et al., 1988) provided the next big impetus for the research field. This study exhibited numerous improvements over the first study. It included newly diagnosed, incident cases of childhood cancer; therefore, eliminating the possibility that survival influences the results. The investigators improved exposure assessment by developing a more sophisticated 5-category wire code classification, and by conducting spot measurements in the children’s homes. The study included interviews with the parents of the participating children in order to assess and control for potentially confounding factors. The findings of Savitz and his coworkers were in support of an association between childhood cancer and magnetic field exposure. However, since control subjects were selected by random digit dialing of telephone numbers and were required to be residentially stable between index date and date of exposure assessment and interview, there were concerns that the included controls may not be fully representative of the base population the cases arose from. Differential participation of controls may introduce bias and it may distort the results of the study.
    With the publication of the next follow-up study by London and colleagues in 1991 (London et al., 1991), the focus of the research field narrowed to childhood leukemia as opposed to all childhood cancers. The investigators of this study broadened exposure assessment with the inclusion of 24-hour measurements in the children’s homes. Interestingly, the results of the study showed that childhood leukemia was associated with wire code categories, but not with measured magnetic fields.
    In a 1993 Swedish study (Feychting and Ahlbom, 1993), primary exposure assessment relied on historical calculations of residential magnetic fields. Since field calculations did not require subject participation, the study was considered less vulnerable to selection bias. The authors of the study found stronger association of childhood leukemia with calculated fields than with measured fields. Although the risk increases in the highest exposure categories were statistically significant, the relative risk estimates were based on a very small number of exposed cases, making these estimates imprecise.
    The largest study from the United States was published in 1997 (Linet et al., 1997). It focused on incident cases of acute lymphoblastic leukemia and included more than 600 matched case-control pairs. Exposure assessment included 24-hour measurements in the children’s bedroom, spot measurements in every room and outside the front door of the homes, and wire code categories based on power line configuration and proximity to the homes. Leukemia risk showed no relation to wire code categories. Although their analyses showed risk increases in association with mean exposures above 0.3 or 0.4 µT, based on an a priori 0.2 µT cut-point the authors of the paper concluded that, overall, measured fields were also not associated with childhood leukemia development.
    The 1999 Canadian study by McBride and colleagues (McBride et al., 1999) were the first large epidemiologic study of childhood leukemia to use personal monitoring for exposure assessment. The results showed only moderate or no associations between magnetic field exposure indices and childhood leukemia. A study published in the same year and conducted in the United Kingdom (UKCCS, 1999) has been so far the largest epidemiologic study of childhood cancer and magnetic field exposure including more than 2000 childhood cancer cases of which over 1000 were cases of childhood leukemia. In spite of the study’s large size and multistage, elaborate exposure assessment methods relying on both measured and calculated fields, the study provided little information on a potential association between childhood leukemia and magnetic field exposure above 0.4 µT since only 5 leukemia cases and 3 controls had mean exposures above that level.
    In 2000, two research groups – independently of each other – published the results of their respective pooled analysis combining and analyzing original data from previously published studies of childhood leukemia and magnetic field exposure (Ahlbom et al., 2000; Greenland et al., 2000). Although the two groups used somewhat different inclusion criteria and analytical approaches, their analyses used largely overlapping data sets and arrived at very similar conclusions. Ahlbom and colleagues used original data from nine studies with measured and calculated fields including 3,247 leukemia cases and 10,400 controls in total. Greenland and colleagues pooled data from 12 studies including 2,656 leukemia cases and 7,084 controls in their analyses. Both studies found an approximate doubling of childhood leukemia risk in the highest exposure category – exposure above 0.4 µT and 0.3  µT, respectively – but no excess risk below those levels.

Expert panel evaluations

In recent years, several national and international expert panels completed their evaluations on potential health effects of power frequency magnetic field exposures. All recent expert evaluations concluded that there is an association between childhood leukemia development and exposure to power frequency magnetic fields. The United States National Institute of Environmental Health Sciences Working Group reported that there is limited evidence that residential exposure to extremely low-frequency magnetic fields is carcinogenic in children (Portier and Wolfe, 1998). The National Radiological Protection Board (NRPB) in the UK stated that relatively high average exposure to extremely low-frequency magnetic fields (0.4 µT or more) is associated with a doubling of the risk of childhood leukemia (NRPB, 2001). The International Agency for Research on Cancer (IARC) classified power-frequency magnetic field as a “possible carcinogen” (class 2B) in June 2001 (IARC, 2002). The International Commission for Non-Ionizing Radiation Protection (ICNIRP) Standing Committee on Epidemiology concluded that among all the health outcomes evaluated in epidemiologic studies of extremely low frequency of magnetic fields, the strongest evidence for an association exists between childhood leukemia and postnatal exposure to magnetic fields above 0.4 µT (Ahlbom et al., 2001).


RESEARCH DIRECTIONS

Overall, there appears to be an epidemiologic association between childhood leukemia and exposure to power frequency magnetic fields. This epidemiologic association, however, is difficult to interpret without clear supporting evidence from experimental laboratory work and without known biophysical mechanism (IARC, 2002). Chance was largely discounted as a likely explanation for the observed association mainly based on the results of the pooled analyses (Ahlbom et al., 2000; Greenland et al., 2000). Although it has not been experimentally or theoretically substantiated, a potential causal relationship, likely or not, remains a hypothetical explanation for the association.
    Alternative explanations for the epidemiologic association also include confounding and bias. Confounding could occur in an epidemiologic study if a second exposure (other than magnetic field) had a real carcinogenic effect (i.e., it could induce childhood leukemia) and this second exposure was also associated with magnetic field exposure. If the investigator has no knowledge on the second exposure and cannot adjust for its effect then a spurious association between magnetic field and childhood leukemia may appear in the study, even if there is no causal relationship between them.
    Bias occurs in an epidemiologic study if, due to systematic errors, the effect of exposure on the risk of the disease is erroneously over- or underestimated. Most common concern in case-control epidemiologic studies is control selection bias, which occurs if the ratio of the selection probabilities of exposed cases and unexposed cases is not equal to the ratio of selection probabilities of exposed controls and unexposed controls.
    Currently there is a scientific uncertainty regarding the nature of the association between magnetic field and childhood leukemia. This uncertainty could only be resolved with new insights and new results provided by targeted and focused scientific research. Research work being conducted at the EMF Health Assessment Program of the Electric Power Research Institute (EPRI) targets two potential explanations for the observed epidemiologic association: 1) control selection bias; and 2) confounding by exposure to contact current.

Control selection bias hypothesis

The majority of epidemiologic studies of magnetic fields and childhood leukemia have been case-control studies where control selection bias could be a legitimate and serious concern. Most of the expert panels have acknowledged that control selection bias cannot be ruled out as a possible explanation for the observed epidemiologic association (Ahlbom et al., 2001; NRPB, 2001; IARC, 2002). In spite of the commonly expressed concern of control selection bias, there is only limited data available to assess whether this type of bias really occurred in these studies, and if it occurred then whether it explains the entire observed association or is only partially responsible.
    Selection bias is hypothesized to occur through differential participation of controls and cases based on their socio-economic status. Healthy subjects are, in general, less likely to participate in epidemiologic studies as controls than subjects with specific diseases as cases. Participation may also vary by socioeconomic status; economically disadvantaged individuals are usually less likely to volunteer to partake in an epidemiologic study. In addition, people in lower socioeconomic classes are thought more likely to live in homes with higher than average magnetic field exposure. If there is a preponderance of non-participation among poorer and higher exposed controls than among cases then it could result in a biased overestimation of relative risk in a case-control epidemiologic study.
    Some evidence already exists showing that selection bias may be – at least partially – responsible for the association found in epidemiologic studies. In their 1988 study, Savitz and colleagues (Savitz et al., 1988) reported that those subjects who did not allow indoor measurements in their homes more frequently lived in high wire code homes than subjects who did allow indoor measurements. Hatch and colleagues (Hatch et al., 2000), in their reanalysis of the 1997 U.S. study (Linet et al., 1997), also showed that full participants (allowing more complete exposure assessment) were more likely to have higher socioeconomic status (higher education, higher income, and more likely to own residence), but were less likely to live in homes with high wire codes (VHCC) or high measured fields (measurements at front door above 0.2 µT). In addition, Hatch et al. (2000) also showed that a positive association between higher wire code (VHCC) and childhood leukemia could only be shown when the analyses were restricted to full participants (relative risk, 1.2). When partial participants were also included in the analyses, the association diminished (relative risk, 1.0). Michaelis et al. (1997) and Spinelli et al. (2001) reported that differential participation of cases and controls based on their socioeconomic status might also have occurred in the Canadian and German epidemiologic studies of childhood leukemia and magnetic field exposure (Spinelli et al., 2001; EPRI, 2003a). It was also reported, although not in childhood leukemia studies, that lower socioeconomic status (lower family income) and higher residential mobility are also associated with higher residential wire codes (Jones et al., 1993; Gurney et al., 1995).
    In spite of the available, sporadic evidence, it is still not clear whether control selection bias could fully or partially be responsible for the observed epidemiologic association. In a 2001 expert workshop organized in Whistler (British Columbia, Canada), by the Electric Power Research Institute and the World Health Organization, further research to elucidate the exact role of selection bias was recommended in several areas (EPRI, 2003a). Selection bias related research conducted by the EMF Health Assessment Program of the Electric Power Research Institute has been developed based on the 2001 Whistler workshop recommendations and focuses on three main issues: 1) reexamining the association between socioeconomic status and childhood leukemia, 2) inclusion of non-participants in the magnetic field–childhood leukemia analyses, and 3) identification of highly exposed populations.
    In the past, it has been commonly accepted that childhood leukemia occurs more commonly in families of higher socioeconomic status (Greenberg and Shuster, 1985). In recent studies of magnetic fields and childhood leukemia, however, an inverse association was observed between measures of social class and childhood leukemia (EPRI, 2003a). It needs to be clarified whether the inverse trend observed in magnetic field studies is simply an indicator of control selection bias or it represents a real association between social class and leukemia incidence. To shed light on the nature of the association between socioeconomic status and childhood leukemia, a thorough review of the relevant literature is under way.
    The best possible way to assess the role of selection bias and to evaluate unbiased magnetic field-related relative risk estimates would be to include a truly random sample of the base population as controls and to include even those subjects in the analyses who decline to participate in the study. This, however, is not possible since residential magnetic field exposure cannot be measured in the homes w ithout the subjects’ consent. Wire code determinations and in limited instances field calculations, however, are possible for known addresses even without the subjects’ participation. In two epidemiologic studies of childhood leukemia, the Canadian study published in 1999 (McBride et al., 1999) and the ongoing Northern California Childhood Leukemia Study (Ma et al., 2002a, 2002b), it is possible to enlist an unbiased group of potential controls. In these studies, controls were selected from provincial health insurance lists and lists of birth certificates, respectively, therefore first-choice controls represent a close to ideal, and practically unbiased control group. Further analyses are planned in these studies to assess the potential role of control selection bias by comparing wire code distributions among cases, first-choice controls, and participating controls.
    In most epidemiologic studies of magnetic fields, the relative scarcity of highly exposed subjects limited the statistical precision of relative risk estimates. In North America approximately 3%, and in Europe less than 1% of the population lives in homes with average magnetic fields above 0.4 µT (Linet et al., 1997; UKCCS, 1999). Higher exposure prevalence may allow for a more accurate and less bias prone assessment of exposure-related relative risks. Based on sporadic evidence, it was thought that in highly developed and densely populated Asian regions this proportion may be significantly higher. To determine whether it is really the case, a residential magnetic field exposure assessment survey is under way in Taiwan.
    The inherent potential for control selection bias in case-control studies may even preclude scientists to arrive to a definitive answer regarding the nature of relationship between magnetic fields and childhood leukemia using solely case-control epidemiologic studies. To settle the question it may be necessary to conduct a large cohort study to examine the association. The rarity of childhood leukemia and the low prevalence of exposure above 0.4 µT, however, would require such a large cohort size that such a study of this kind could be extremely and inhibitively expensive.

Contact current hypothesis

Contact current occurs when two or more extremities (e.g., a hand and a foot) touch conductive surfaces that are at different electrical potentials. Because the body is electrically conductive, current flows so long as contact is maintained. Much of the body’s electrical resistance is concentrated in the epidermal layer under dry conditions; under moist or wet conditions, the skin’s resistance decreases dramatically and a body’s resistance is on the order of 1 to 3 kohms (kΩ), depending on body dimensions, fat and muscle content, etc. (Reilly, 1998).
    Research conducted over the past few years has identified contact current as an exposure that may plausibly explain the association of childhood leukemia with residential magnetic fields. Thus far, in the United States (US) the research has considered conditions in residential electrical systems that may predispose to contact current exposure, with an emphasis on single, detached homes. In the US, the National Electrical Code requires, for electrical and fire safety, that a grounding wire connect the service panel neutral to the residential water line (if the latter is conductive). Consequently, the water line acquires a small voltage, VW-E, relative to the earth (usually less than 1 volt). This voltage is affected by current in the primary and secondary grounding systems, as well as by inductive effects from heavily loaded lines nearby.
    If the drainpipe from the bathtub drain into the earth is conductive, then VW-E can serve as a voltage source that drives current into a bathing child touching the faucet, the spout, or the water stream. This voltage from the point of contact to the drain, Vbath, is a variable fraction of VW-E that depends on conditions in the soil beneath the residence and on the child’s electrical resistance. In the absence of both a conductive water line and a conductive drainpipe, exposure does not occur.
    Two measurement studies have examined the relationship between both VW-E and Vbath and the average residential magnetic field, Bavg. A methods development study in a small sample of residences in Pittsfield, MA reported a statistically significant positive correlation between VW-E and Bavg (Kavet and Zaffanella, 2002). A larger study in the Denver area at the site of the studies of Wertheimer and Leeper (1979) and Savitz et al. (1988), reported a statistically significant association between VW-E and Bavg and statistically significant upward trends of association across Bavg strata for both VW-E and Vbath (Kavet et al., in press). Subsequent computer modeling of typical US neighborhoods predicts positive association between VW-E and Bavg similar to those measured (Kavet, submitted).
    In the Denver study Vbath was estimated by inserting a 1,000-ohm resistor between the faucet and the drain. About 12% of the homes had voltage levels that could produce up to 10s of microamperes into a child’s hand while making contact. Dosimetry modeling estimates that in a small child, currents of this magnitude can produce dose to bone marrow of 100s of millivolts per meter (Dawson et al., 2001), far greater than doses induced by ambient residential magnetic fields, and much greater than the lowest doses associated with plausible experimentally induced biological effects. Both the National Institute of Environmental Health Sciences (NIEHS) in the US and the National Radiological Protection Board (NRPB) in the United Kingdom (UK) identify 100 µT and greater as an exposure range associated with biological effects, although the two differ with respect to their respective certainties regarding the validity of the experimental studies (NIEHS, 1999; NRPB, 2001). This exposure level crudely translates to induced field strengths on the order of 1 mV/m. Although experiments relevant to leukemogenesis in appropriate model systems are yet to be conducted, the exposure scenario described for contact currents projects electric fields in bone marrow on the order of 100s of mV/m, which are dosimetrically plausible levels.
    If the average residential magnetic field has been serving as a surrogate for another exposure, the latter must produce adequate dose to the target tissue, and must be positively associated with the average residential magnetic field. Additionally, children must have access to exposure on a reasonably regular basis. As the discussion above indicates, exposure to contact current has demonstrated features that qualify it as a plausible factor that could be responsible for the association of childhood leukemia with residential magnetic fields. The observation that young children bathe frequently and further engage in behavior that produces contact with potential sources of exposure (P. Buffler and M. Does, personal communication) further legitimizes the contact current hypothesis’ plausibility. The role of contact current is currently under investigation in the Northern California Childhood Leukemia Study (e.g., see Ma et al., 2002a, 2002b) with results anticipated in the 2006–2007 time frame.


CONCLUSION

An epidemiologic association has been reported between residential magnetic field exposure and childhood leukemia development. Causal relationship, however, cannot be established without clear supporting evidence from experimental laboratory work and without known biophysical mechanism. Chance is now considered an unlikely explanation for the observed association. Potential alternative explanations include systematic epidemiologic error (i.e., control selection bias) and confounding due to a second exposure (i.e., contact current) related to magnetic field exposure. The scientific uncertainty regarding the nature of the association between childhood leukemia and residential magnetic field exposure could only be resolved with further targeted and focused scientific research work in these areas.


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Received: 24 August 2004
Accepted: 23 September 2004

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