Risk Evaluation: IARC (2002)Institute of Cancer EpidemiologyELF-MFGroup 1Asbest, Epstein-Barr Virus (EBV), Hepatitis C virus,X- and Gamma-radiation, salted fish (China-style),Tobacco smoke (incl. passive smoking), ... (102)Group 2 aAcrylamide, Diesel engine exhaust, Hairdresser, Sunbeds,... (69)Group 2 bNickel, Gasoline, Firefighter, Mixed pickles (Asian style), ELF-MF, ... (246)Group 3Tea, Jet fuel, Leather processing, Printing inks, ELF-EF, ... (516)Group 4Caprolactam (1)
Risk Evaluation: IARC (2002)Institute of Cancer EpidemiologyCarcinogenicity inanimals:inadequateCarcinogenicity inhumans:limitedMechanisms &Other relevantdata:irrelevantEvaluation of carcinogenicityLeukemiain childrenGroup 2B: possibly is carcinogenic
Risk Evaluation:EU SCENIHR (2007)Institute of Cancer Epidemiology• Confirms IARC classification• New studies do not alter previousclassification• Identifies need for more studies toclarify discrepancy between findingsfrom observational studies and fromexperimental / mechanistic research
WHO-EHC (2007)Institute of Cancer Epidemiology• IARC = Hazard assessment cancerWHO = Risk assessment(incl. hazard for other diseases)• Attributable risk fractions• Discussion of precautionary measures
Risk evaluationInstitute of Cancer EpidemiologyLimited evidence of carcinogenicity in humans......is usually based on evidence in humanswhich is considered credible,but chance, bias and confoundingcannot be ruled out withreasonable confidenceconsistent findingsfrom epidemiologicalstudiesIdentification of bias inobservational studies
History: some milestonesInstitute of Cancer Epidemiology• 1979:first study published by Wertheimer and Leeper• 1993:Swedish study by Feychting and Ahlbom• 1997:Large-scale study by the National Cancer Institute, USA• 2000:Meta-analysis by Ahlbom et al. and Greenland et al.• 2002:Risk evaluation by IARC
Consistency of studiesInstitute of Cancer EpidemiologyDenver 1979Sweden 1986Denver 1988California 1993Sweden 1993Finland 1993Denmark 1993US 1997USA 1997Norway 1997UK 1999Canada 1999Canada 1999Germany 2001Japan 20060.1 1 10RR
Consistency of studiesInstitute of Cancer EpidemiologyAverage magnetic fields [Meta-Analysis, Ahlbom et al., 2000]:< 0.1 T0.1 - 0.2 T0.2 - 0.4 T>= 0.4 T0.1 1 10
Consistency of studiesInstitute of Cancer EpidemiologyAhlbom et al., Br J Cancer, 2000
Consistency of studiesInstitute of Cancer EpidemiologyQuadratic logisticspline model with80%- and 99%-confidence bands OR (>0.3 T vs. < 0.1T): 1.7 (95%-CI: 1.2-2.4)Greenland et al. Epidemiology, 2000
Japan studyInstitute of Cancer EpidemiologyKabuto et al., Int J Cancer, 2005
Mexico studyInstitute of Cancer EpidemiologyMejia-Arangure et al, Epidemiology, 2007
Possible explanationsInstitute of Cancer Epidemiology Chance ? Confounding ? Exposure misclassification ? Selection bias ? Alternative / indirect explanations ? Causality ?
ChanceInstitute of Cancer EpidemiologyAverage magnetic fields 0,4 T:observed expectedCanada 13 10 US 17 5 UK 4 4 Norway 0 3 Germany 7 2 Sweden 5 2 Finland 1 0 Denmark 2 0 New Zealand 0 0 49 26 p
ConfoundingInstitute of Cancer EpidemiologyMany candidates were suggested, including:- traffic density- herbicides- accumulation of radon decay products- parental smoking unlikelyLangholz (2001), Bioelectromagnetics:To explain the association between wire codes and the risk ofleukemia, a confounder must be associated with the risk ofleukemia at the order of a RR >5 unlikely
Misclassification of exposureInstitute of Cancer Epidemiology• Non-differential misclassification expected direction of biastowards the null• Low prevalence of exposure lower specificity= loss of statistical power lower sensitivity= biasOdds Ratio Estimate of Relative Risk5,04,54,03,53,02,52,01,51,0,90,91Spezifität,92,93,94,95Prevalence = 1%,96,97,98Legend: Sensitivity100%80%50%20%,991,00
Voltage[kV]420230123Distance [m]0 to 2526 to 5051 to 5000 to 2526 to 5051 to 5000 to 2526 to 5051 to 500< 0.1 T(based on 1835 24 hrs measurements in Germany)Voltage[kV]275-400132Distance [m]0 to 2526 to 5051 to 5000 to 2526 to 5051 to 200< 0.1 T0224052911091005702200.1 – 0.2 T0130010050.1 – 0.2 T(based on 4452 2-48 hrs measurements in the UK)a: elevated magnetic field caused by other source than power line0180110.2 – 0.4T011 a213 a1000.2 – 0.4T001/2 a130 0.4 T000100200 0.4 T020300Institute of Cancer EpidemiologyMisclassificationof exposureMagnetic fieldsin the vicinityof high-voltagepower lines inGermany and inthe UK
Misclassification of exposureInstitute of Cancer EpidemiologyFN FPDifferential?Distance to high-voltage >90% yes nopower linesDistance to all power lines 25-75% yes noCalculated fields 25-75% no noSpot measurements yes yes unlikelyLong-term measurements few remove? unlikelyPersonal dosimetry few-many few-many likelyremove?
Selection biasInstitute of Cancer EpidemiologyHighcorrelationType of the house(number of parties)moderatecorrelationSES?But:Participationrates werelowResidentialmagnetic fieldsOR=2.8 (1.4 – 5.5)1.6Leukemia
Selection biasInstitute of Cancer EpidemiologyHatch et al., Epidemiology, 2000Mezei&Kheifets, Int J Epidemiol,2006
Selection biasAverage magnetic fields 0,4 T:Institute of Cancer Epidemiologyobserved expected BiasCanada 13 10 MovingUS 17 5 YesUK 4 4 ?Germany 7 2 YesPossible selection bias 41 21Sweden 5 2Finland 1 0Denmark 2 0Norway 0 3No selection bias 8 5
Biological plausibilityInstitute of Cancer EpidemiologyEvidence:1. Abberations found in neonatal blood spots2. Conversion rate lowALL2ndEvent1stEventpreleukemiccloneConceptionBirth1 2 3 4Source: Greaves, Eur J Cancer, 1999Age[Years]
ObservationOverview of explanationsPossible explanationInstitute of Cancer EpidemiologyLikelihoodStatisticalartifactsChanceVery unlikely due to robust findingsSelection biasDefinite but unclear whether entire associationExposure misclassificationVery unlikely to produce positive associationConfoundingUnlikely due to requirementsMixture of abovePossibleEpidemiological studiesshow an associationbetween exposure tomagnetic fields above0.3/0.4 T and the riskof childhood leukemiaAlternativeexplanationsEarlier suggestionsMelatoninContact currentsVery unlikely due to lack of supportive dataUnlikely, few supportive dataUnlikely, many assumptionsUnknown alternativeTheoretically possible, yet to be uncoveredInitiationVery unlikely due to negative experimental dataCausallinkPromotionEpigenetic/CocarcinogeneticTheoretically possible, no supportive dataTheoretically possible, no supportive dataSchüz&Lightfoot (2007) in: Obe G, Vijayalaxmi – Chromosomal Alterations
Night-time exposureInstitute of Cancer Epidemiology< 0,1 0.1 T0,1 0.1 -< 0,2 0.2 T0,1 -< 0,2T0,2 0.2 -< 0,4 0.4 T>= 0,4 0.4 TRRSchüz et al., Am J Epidemiol, 20070.1 1 10Night 24/48 hours
Alternative explanationsInstitute of Cancer Epidemiology• Radon decay products• Electric fields• Contact currentsCriteria to be fulfilled for a valid hypothesis:1. Strong correlation with residential magnetic field levels2. Independency from field source (particularly power lines vs.indoor wiring)3. Independency from regional characteristics (particularlyEurope vs. North America)4. Independent of time period
Magnetic fields and Survival ofChildhood LeukemiaInstitute of Cancer EpidemiologyUS Study:Replication using German data:Overall survivalExposure Cases Events HR 95% CI< 0.1 T 235 16 1.00.1-0.2 T 89 7 1.2 0.5 – 2.80.2-0.3 T 19 1 0.9 0.1 – 6.4 0.3 T 18 4 4.5 1.5–13.8Foliart et al., Br J Cancer, 2006Overall survivalExposure Cases Events PYRS HR 95% CI< 0.1 T 445 55 4016 1.00.1-0.2 T 29 7 247 2.8 1.2 – 6.2 0.2 T 12 3 93 3.0 0.9 – 9.8Per 0.1 T 1.4 1.0 – 1.8Svendsen et al., Cancer Epidemiol Biomarkers Prev, 2007
SummaryEpidemiological evidence: Limited- consistent results across several well-conducted studies- few studies have higher impact on overall results- selection bias in measurement studies leads to overestimation;but can it explain the entire association?- combination of chance, bias, and confounding possibleBiological evidence: Weak- no convincing facts, few promising hypotheses- no established large risk factors for childhood leukemia- even trends in incidence rates are discussed controversiallyPublic health effect: None or presumably small- few percent (maybe underestimated due to exposure measures)- detection by comparing incidence data difficultPromising areas of research:- pathways to childhood leukemia- cohorts (birth cohorts, cohorts of susceptible children, cohortsof highly exposed children)Institute of Cancer Epidemiology
???Institute of Cancer Epidemiology• No supportiveexperimental data• Nomen est omen• Low exposure levels• Quite homogenous resultsfrom well-conductedepidemiological studies• Little is known about causesof childhood leukemia• Susceptibility ?• Promotion ?• Co-carcinogenesis ?
LiteraturePooled Analysis:Ahlbom A, Day N, Feychting M, et al. A pooled analysis of magnetic fields and childhood leukaemia. Br JCancer 2000; 83: 692-8.Greenland S, Sheppard AR, Kaune WT, et al. A pooled analysis of magnetic fields, wire codes, andchildhood leukemia. Childhood Leukemia-EMF Study Group. Epidemiology 2000; 11:624-34.Schüz J, Svendsen AL, Linet M, et al. Night-time exposure to electromagnetic fields and childhood leukemia:an extended pooled analysis. Am J Epidemiol 2007; 166: 263-9.Institute of Cancer EpidemiologyFurther methodological reading:Langholz B. Factors that explain the power line configuration wiring code-childhood leukemia association:what would they look like? Bioelectromagnetics 2001; 5:S19-31.Mezei G, Kheifets L. Selection bias and its implications for case-control studies: a case study of magneticfield exposure and childhood leukaemia. Int J Epidemiol 2006; 35:397-406.Greenland S, Kheifets L. Leukemia attributable to residential magnetic fields: results from analyses allowingfor study biases. Risk Anal 2006; 26:471-82.Elwood JM. Childhood leukemia and residential magnetic fields: are pooled analyses more valid than theoriginal studies? Bioelectromagnetics 2006; 27:112-8Survival studies:Foliart DE, Pollock BH, Mezei G, et al. Magnetic field exposure and long-term survival among children withleukaemia. Br J Cancer 2006; 94: 161-4.Svendsen AL, Weihkopf T, Kaatsch P, Schüz J. Exposure to magnetic fields and survival after diagnosis ofchildhood leukaemia - a German cohort study. Cancer Epidemiol Biomarkers Prev 2007; 16:1167-71.Review (basis for this presentation):Schüz J. Implications from epidemiologic studies on magnetic fields and the risk of childhood leukemia onprotection guidelines. Health Phys 2007; 92:642-8.