Mobile phone and cordless phone use and the risk for glioma

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Mobile phone and cordless phone use and the risk for glioma – Analysis of pooled case-control studies in Sweden, 1997–2003 and 2007–2009

Lennart Hardell

^∗

, Michael Carlberg

DepartmentofOncology,UniversityHospital,ÖrebroSE-70185,Sweden

Received16April2014;receivedinrevisedform25September2014;accepted16October2014

Abstract

Wemade apooledanalysis of twocase-controlstudies on malignantbraintumours withpatients diagnosedduring1997–2003and 2007–2009.Theywereaged20–80yearsand18–75years,respectively,atthetimeofdiagnosis.Onlycaseswithhistopathologicalverification ofthetumourwereincluded.Population-basedcontrols,matchedonageandgender,wereused.Exposureswereassessedbyquestionnaire.

Thewholereferencegroupwasusedintheunconditionalregressionanalysisadjustedforgender,age,yearofdiagnosis,andsocio-economic index.In total,1498(89%)casesand 3530(87%)controlsparticipated.Mobilephoneuseincreasedtheriskof glioma,OR=1.3,95%

CI=1.1–1.6overall,increasingtoOR=3.0,95%CI=1.7–5.2inthe>25yearlatencygroup.Useofcordlessphonesincreasedtheriskto OR=1.4,95%CI=1.1–1.7,withhighestriskinthe>15–20yearslatencygroupyieldingOR=1.7,95%CI=1.1–2.5.TheORincreased statisticallysignificantbothper100hofcumulativeuse,andperyearoflatencyformobileandcordlessphoneuse.HighestORsoverallwere foundforipsilateralmobileorcordlessphoneuse,OR=1.8,95%CI=1.4–2.2andOR=1.7,95%CI=1.3–2.1,respectively.Thehighestrisk wasfoundforgliomainthetemporallobe.Firstuseofmobileorcordlessphonebeforetheageof20gavehigherORforgliomathaninlater agegroups.

Keywords: Ipsilateral;25yearslatency;Timesincefirstexposure;Glioma;Wirelessphones

1. Introduction

There has been a large worldwide increase during the last decade in the use of wireless communication, with greater exposure to radiofrequency electromagnetic fields (RF-EMF). Thishas caused increasing concern for health risk.Duringuseofbothmobileandcordlessphones,thebrain isthemaintargetofRF-EMF.Thehighestexposureisonthe samesideofthebrainwhenthehandheldphoneisused(ipsilateral),whereasthecontralateralsideislessexposed[1].Due tothesmallerheadsize,thinnerskullbonesandhigherbrain conductivity,achildabsorbshigherratesthanadults[2–4].

Our group reportedthe first indication of an increased braintumourriskassociatedwithuseofwirelessphonessome

∗Correspondingauthor.Tel.:+46196021000;fax:+4619183510.

E-mailaddress:[email protected](L.Hardell).

15yearsago[5–7].Thiswasfollowedbyadditionalcase- control studiesas reviewedinHardelletal.[8].ADanish cohortstudyonmobilephoneusershasbeeninitiated[9],but poorexposureassessmentmakesituninformative[10,11].

TheInternationalAgencyforResearchonCancer(IARC) atWHOevaluatedhumancancerrisksfromRF-EMFexpo- sureinMay2011.Itincluded allsourcesinthefrequency range of 30kHz–300GHz.A totalof 29 invited scientists participated.ThefinalclassificationasGroup2Bmeansthat RF-EMFexposureis‘possibly’ahumancarcinogen,acon- clusion based on an overwhelming majorityof the voting experts[10,12].

Theevaluationonthelong-termuseofwirelessphones, i.e.>10years,wereintheIARCclassificationbasedonour results[13–15]andtheInterphonestudygroup,alsopreprint studiesavailable[16–18].Thebraintumoursassociatedwith theuseofwirelessphones arethemalignanttypes,mostly

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2 L.Hardell,M.Carlberg/Pathophysiology22(2015)1–13

glioma,andacousticneuroma,abenigntumourof the8th cranialnerve.Incontrast,noconsistentpatternof anasso- ciationhas beenfoundfor themostcommon benignbrain tumour,meningioma[seealsoreviewsin[8,19,20].TheInter- phoneresultswerereportedonlyontheuseofmobilephones, whereaswealsoincludedcordlessphonesinourassessment.

Thepotentialbiasduetothisdifferentclassificationofexpo- surethatdistortsoftheoverallrisktowardsunityhasbeen discussedelsewhere[8,21].

TheIARCevaluationwas basedonfairly shortlatency period(timefromfirstexposureuntildiagnosis),withresults on atmost the latency group ≥10 years. To study longer periodsofuse,wemadeanewcase-controlstudyencompass- ingpatientsdiagnosedfrom2007to2009.Datahavealready beenpublishedonacousticneuroma[22],meningioma,[23]

andmalignantbraintumoursintotal[24].

Toenlargethestudygroup,wehavenowpooledourresults onmalignantbraintumoursfor1997–2003and2007–2009, becausethesamemethodswereusedfor bothperiods.We presentinthefollowingresultsforthemostcommontypeof malignantbraintumour,glioma.Itisofimportancetopresent separateresultsongliomatocompareourresultswithInter- phone[16].Also,separateanalysisofothermalignantbrain tumourtypesispresented.The ethicscommitteeapproved thesestudies.

2. Materialsandmethods

Detailedinformationonmaterialsandmethodshasbeen givenpreviously[13,24].Inshort,sixadministrativeregions withoncologycentrescoveringSwedenregisterednewcan- cercases.For1997–2003,casesandcontrolscoveredcentral Sweden [13], whereas the 2007–2009 study included the wholecountry[24].Theoncologycentresreportednewcases withhistopathologicallyverifiedbraintumour,eitherbenign ormalignant,tousduringtheseperiods,althoughtheactual reportingintervalvariedforcentretocentre.Bothmenand womenwereincluded aged 20–80 years(1997–2003) and 18–75years(2007–2009)atthetimeofdiagnosis.Onlyliv- ingcaseswereincluded,eachpatientgivingpermissiontothe responsiblephysicianbeforeinclusioninthestudy.Tumour localisation inthe brain was based on reports tothe can- cerregistriesandmedicalrecords,whichwereobtainedafter informedconsentfromthepatients.

Controlswereascertainedfrom theSwedishPopulation Registry,coveringthewholecountryandbeingcontinuously updated,such thateach personwas tracedby auniqueID number.Theregistryalsorecordstheaddresstoeachperson.

Foreachcase,onecontrolsubjectofthesamegenderinthe same5-yeargroupwasdrawnatrandomfromthisregistry.

Theywereassignedthesameyearforcut-offofallexposure asthediagnosisoftheeachcase.Allthesecontrolswereused intheanalysisofriskofglioma.

Exposurewasassessedusingamailedquestionnairesent toeachperson.Regardinguseof amobilephone, thetime

ofaverageuse(minperday)wasestimated.Thetechnology haschangedsincethefirstintroductionofmobilephones.The firstgenerationwasanaloguephoneswithanoutputpower of 1W atabout 900MHz followedby the 2nd generation GSMphones(2G)witheither900or1800MHzfrequency andwithapulsedoutputpower.Themeanoutputpowerwas oftheorderoftensofmW.Inthe3rdgenerationphones(3G) theoutputismoretobecharacterisedasamplitudemodulated thanpulsedandtheoutputpowerisoftheorderoftensof

!W. Thetypeof mobilephonewas recordedandchecked bytheprefixforthephonenumber;010foranaloguephones and07fordigitalphones(2G,3G).

Somespecialquestionscoveredtheextentofuseinacar withanexternalantenna,anduseofahands-freedevice,both regardedasnon-exposuretoRF-EMF.Theearmostlyused duringphonecalls,orequallybothears,wasalsonoted.

Use of cordless desktop phones was covered by simi- larquestions;years,averagedailyuse,useofahands-free device,andpreferredear.Theprocedurewasconductedwith- out knowledge of case/control status. Use of the wireless phonewasreferredtoasipsilateral(≥50%ofthe time)or contralateral(<50%ofthetime)inrelationtotumourside.

The same methodwas also applied for the control group;

the subjects were assigned the same ‘tumour’ side as the respectivecasetothematchedcontrol.

Thequestionnairealsocontainedanumberofquestions relatingtotheoverallworkinghistory,exposuretodifferent chemicalsandotheragents,smoking habits,X-rayinvesti- gationsoftheheadandneck,andhereditytraitsforcancer.

Theseotherexposurefactorswillbepublishedseparatelyfor the wholestudy period.Whenquestionnaireanswers were unclear,theywereresolvedbyphoneusingtrainedinterview- ers. Thereby, awritten protocol was used for clarification of eachquestion. Theinterviewersupplementedthewhole questionnaireduringthephonecall.Eachquestionnairehad receivedauniqueIDnumberthatdidnotdisclosewhether itwasacaseoracontrol;i.e.theinterviewerwasunaware ofthestatusduringfurtherdataprocessing.Allinformation wascodedandenteredintoadatabase.Caseorcontrolstatus wasnotdiscloseduntilstatisticalanalyseswereundertaken.

We made in addition a separate case-control study on deceasedcasesduringfor1997–2003, usingdeceasedper- sons as reference entities by interviewing the next of kin [25],seediscussionbelow.Thesecasesandcontrolsarenot includedinthepresentstudy.

2.1. Statisticalmethods

StataSE 12.1 (Stata/SE 12.1 for Windows; StataCorp., CollegeStationTX)wasusedfortheanalyses.Oddsratios (OR) and 95% confidence intervals (CI) were calculated usingunconditionallogisticregressionincludingthewhole controlsample (i.e.matchedtobothmalignantandbenign cases)toincreasethepowerofthestudy.

Latency(timefromfirstuse)wasdefinedas theyearof first use of awireless phoneto the yearof diagnosis (the

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Table1

Histopathologyofallmalignantbraintumours(n=1498).

Histopathology Men Women Total

n % n % n %

Glioma 817 92.9 563 91.0 1380 92.1

-AstrocytomagradeI–II 123 14.0 98 15.8 221 14.8

–GradeI 14 1.6 20 3.2 34 2.3

–GradeII 109 12.4 78 12.6 187 12.5

-AstrocytomagradeIII–IV^a,b 540 61.4 317 51.2 857 57.2

–GradeIII^a 105 11.9 55 8.9 160 10.7

–GradeIV^a,b 434 49.4 260 42.0 694 46.3

-Oligodendroglioma 71 8.1 91 14.7 162 10.8

-Other/mixedglioma 83 9.4 57 9.2 140 9.3

Medulloblastoma 9 1.0 2 0.3 11 0.7

Ependymoma^c 19 2.2 19 3.1 38 2.5

Othermalignant^d 34 3.9 35 5.7 69 4.6

Total,malignant 879 619 1498

aOnecasehadbothanastrocytomagradeIVandameningioma.

bThreecaseshadnoinformationaboutspecificgrade(IIIorIV).

cOnecasehadbothanependymomaandanacousticneuroma.

dOnecasehadbothanothermalignanttumourandanacousticneuroma.

sameyearsbeingusedforthematchedcontrol).Thecumula- tivenumberofhoursofusewascalculated(numberofyears multiplied byaveragetimeperyearbasedonuseperday).

Useinacarwithexternalantennawasdisregarded,aswasuse ofahands-freedevice.Aminimumlatencyperiodof≤1year ofexposurewasadopted,lessthanwhichwasincludedinthe unexposedcategory.Thesameyearasforeachcase’sdiag- nosiswasusedforthecorrespondingcontrol asthecut-off forexposureaccumulation.Notethatlatencywascalculated separatelyfor therespectivephonetypeor combinationof phonesthatwereanalysed.

Adjustment was made for the matching variables gender, age(as acontinuous variable)and year of diagnosis.

It was also made for socio-economicindex (SEI) divided intofourcategories(blue-collarworker,white-collarworker, self-employed, unemployed),sincean associationbetween white-collarworkandbraintumourswasreportedbyPres- ton MartinandMack in1996 [26]. Latencywas analysed using sixperiods,>1–5years,>5–10 years,>10–15years,

>15–20years,>20–25years,and>25years.Cumulativeuse ofthedifferentphonetypesandcombinationswasanalysed inquartilesbasedonthedistributionoftotaluseofwireless phonesamongthecontrols.Latencyandcumulativeusewere also analysed ascontinuousvariables(per yearoflatency, per100hcumulativeuse)toexploredose-responserelation- ships. Laterality wasnot analysed for the wholegroup of wirelessphoneusers,sincethesidecoulddifferformobile andcordlessphoneusebythesameperson.

Restrictedcubicsplineswereusedtodisplaytherelation- shipbetweencumulativeuseandlatencyofwirelessphones withglioma. Adjustmentwasmade forthe samevariables asinthelogisticregression.Fourknotswereusedatthe5th, 35th,65th,and95thpercentiles,assuggestedbyHarrell[27].

P-valuesfornon-linearitywereestimatedbytestingwhether

the coefficientofthe second andthird splinewasequal to zerobyusingtheWaldtest.

3. Results 3.1. Numbers

Thenumberofreportedcasesfromtheoncologycentres, aswellasreasonsfornotinclusioninthestudybase,have beenpublishedforbothstudyperiods[13,24].Intotal,1691 casesfulfillingtheinclusioncriteriawereenrolled.Ofthese cases,1498(89%)answeredthequestionnaire,ofwhom879 weremenand619women.Themeanagewas52(median 54,range18–80).Thehistopathologicaldistribution(Table1) showsthatmosthadadiagnosisofglioma,n=1380(92%).

Thus,theresultsarepresentedforthegroupofgliomacases, but also in brief for the other groups of malignant brain tumours.

Ofthe4038controls,3530(87%)participated,1492men and2038women.Themeanagewas54(median55,range 19–80);furtherdetailsareavailableinpreviouspublications [13,24].

3.2. Overallresultsandlatency

The median latency time for use of mobile phones in gliomacaseswas 9.0years(mean 10.1,range 2–28).The correspondingresultsforcordlessphonesweremedian7.0 years(mean8.0,range2–21).TheresultsareshowninTable2 forgliomaandtheuseofwirelessphonesindifferentlatency groups.AnaloguephonesgaveOR=1.6,95%CI=1.2–2.0, increasingtoOR=4.8,95%CI=2.5–9.1inthelatencygroup of>25 years.Notethatthelatencytimewascounted from

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Table2

Oddsratio(OR)and95%confidenceinterval(CI)forglioma(n=1380)foruseofmobileandcordlessphonesindifferentlatencygroups.Numbersofexposedcases(Ca)andpopulation-basedcontrols(Co) aregiven.Adjustmentwasmadeforageatdiagnosis,gender,SEI-code,andyearfordiagnosis.

Latency Analogue Digital(2G) Digital(UMTS,3G) Mobilephone,total Mobilephone, digital(2G,3G)

Cordlessphone Digitaltype(2G, 3G,cordless)

Wirelessphone OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) Glioma(n=1380)

Total>1year 1.6 1.3 2.0 1.3 1.3 1.4 1.3 1.3

1.2–2.0 1.1–1.6 0.95–4.4 1.1–1.6 1.1–1.6 1.1–1.7 1.1–1.6 1.1–1.6

(299/558) (884/2014) (58/141) (945/2148) (885/2019) (752/1724) (1037/2393) (1074/2472)

>1–5years 1.1 1.2 1.9 1.2 1.2 1.3 1.2 1.1

0.7–1.7 0.99–1.5 0.9–4.1 0.98–1.5 0.99–1.5 1.1–1.6 0.9–1.4 0.9–1.4

(34/87) (283/714) (46/127) (262/674) (284/719) (271/653) (295/796) (271/748)

>5–10years 1.1 1.7 4.1 1.5 1.7 1.4 1.6 1.5

0.8–1.6 1.3–2.2 1.3–12 1.2–1.8 1.3–2.2 1.1–1.8 1.3–2.0 1.2–1.9

(56/137) (314/659) (12/14) (301/688) (314/659) (294/655) (363/758) (351/767)

>10–15years 2.2 1.4 - 1.4 1.4 1.4 1.4 1.4

1.5–3.2 1.04–1.9 1.1–1.9 1.04–1.9 1.1–1.9 1.1–1.9 1.1–1.8

(71/113) (189/471) (0/0) (211/476) (189/471) (131/294) (242/584) (248/578)

>15–20years 2.4 2.1 – 1.6 2.1 1.7 2.0 1.7

1.5–3.7 1.5–3.0 1.1–2.2 1.5–3.0 1.1–2.5 1.5–2.8 1.2–2.3

(59/107) (98/170) (0/0) (92/196) (98/170) (50/109) (131/242) (121/253)

>20–25years 3.2 – – 2.1 – 1.4 1.6 1.9

1.9–5.5 1.3–3.2 0.5–3.8 0.6–4.4 1.3–2.9

(50/81) (0/0) (0/0) (50/81) (0/0) (6/13) (6/13) (54/93)

>25years 4.8 – – 3.0 – – – 3.0

2.5–9.1 1.7–5.2 1.7–5.2

(29/33) (0/0) (0/0) (29/33) (0/0) (0/0) (0/0) (29/33)

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Table3

Oddsratio(OR)and95%confidenceinterval(CI)forgliomaper100hcumulativeuseandperyearoflatency.Adjustmentwasmadeforageatdiagnosis, gender,SEI-codeandyearfordiagnosis.Populationbasedcontrolswereused.

Per100hcumulativeuse Peryearoflatency

OR 95%CI OR 95%CI

Analogue 1.043 1.026–1.061 1.055 1.036–1.075

Digital(2G) 1.014 1.009–1.018 1.035 1.014–1.057

Digital(UMTS,3G) 1.047 1.002–1.093 1.157 0.994–1.345

Mobilephone,total 1.013 1.009–1.017 1.032 1.017–1.046

Cordlessphone 1.014 1.008–1.019 1.027 1.009–1.046

Digitaltype(2G,3G,cordless) 1.011 1.008–1.014 1.035 1.017–1.053

Wirelessphone 1.011 1.008–1.014 1.032 1.019–1.046

the first use of the specifictelephone type;for instance,a 2Gdigitalphoneusermayhavepreviouslyusedananalogue phone.

Use of digital 2G phones gave overall OR=1.3, 95%

CI=1.1–1.6increasing toOR=2.1,95% CI=1.5–3.0with a latency >15–20 years, the longest latency interval. The resultsfordigital3Gphonesshowedhighestriskinthe>5–10 yearslatencygroup,OR=4.1,95%CI=1.3–12.Thiswasthe longestlatencygroupfor3Gusesincethetechnologyisnew;

thecalculationswerebasedonsmallnumbers.

Digital type of mobile phones (2G, 3G) gave in total OR=1.3, 95% CI=1.1–1.6, increasing to OR=2.1, 95%

CI=1.5–3.0inthelongestlatencygroup(>15–20years).

UseofcordlessphonesgaveOR=1.4,95%CI=1.1–1.7, withhighestriskinthelatencygroup>15–20years,OR=1.7, 95%CI=1.1–2.5.Fewsubjectswereincludedinthelatency group>20–25years.

Thedigitaltypeofwirelessphones(2G,3G,and/orcord- less phone)gaveOR=1.3, 95%CI=1.1–1.6,increasingto OR=1.6,95%CI=1.3–2.0inthelatencygroup>5–10years, thentendingtodrop,andagainincreasingtoOR=2.0,95%

CI=1.5–2.8riskinthelatencygroup>15–20years.

The group of total wireless phone use (mobile phone and/orcordlessphone)gavesimilarresultstomobilephone use,withincreasingrisk withlatencyyieldinghighest risk in the longest latency group >25 years; OR=3.0, 95%

CI=1.7–5.2.

The risk increased per additionalyear of latencygiven for wireless phones; OR=1.032, 95% CI=1.019–1.046 (Table3).

3.3. Temporallobe

SomewhathigherORswereobtainedforgliomalocalised in the temporal or overlapping lobes (n=505). Thus, mobilephoneuseyieldedOR=3.6,95%CI=1.8–7.4versus OR=3.0,95%CI=1.7–5.2intotalinthe>25yearslatency group(datanotinTable).Theresultsforcordlessphoneinthe

>20–25yearslatencygroupwereOR=2.1,95%CI=0.6–7.0 versusOR=1.4,95%CI=0.5–3.8,respectively.

Thecorrespondingresultsforgliomainthetemporallobe only(n=367)wereOR=4.3,95%CI=2.0–9.3for mobile phonesandOR=2.4,95%CI=0.6–9.5forcordlessphones

(datanotinTable).Wirelessphoneuseintotalinthe>25year latencygroupgaveOR=3.7,95%CI=1.8–7.4forgliomain temporaloroverlappinglobes,increasingtoOR=4.2,95%

CI=1.9–9.1forgliomalocalisedonlyintemporallobe.

3.4. Laterality

Forallphonetypes, ipsilateraluse wasassociated with thehighestrisk(Table4).Ipsilateralmobilephoneusegave OR=1.8,95%CI=1.4–2.2,whereascontralateralusegave OR=1.1,95%CI=0.8–1.4.Thesamepatternofassociation was seenfor cordless phones,OR=1.7, 95% CI=1.3–2.1 andOR=1.2,95%CI=0.9–1.6,respectively.

Theseresultsare alsogiveninTable5for the different latencygroups.Regardingmobilephoneuse,highestriskwas associatedwithipsilateraluseinthe>25yearlatencygroup, OR=4.6,95%CI=2.1–10.Contralateralmobilephoneuse also gave a statistically significant increased risk in the longest latencygroup, although withalowerOR thanfor ipsilateraluse.HigherORswerealsocalculatedforipsilat- eralcordlessphoneuseinthedifferentlatencygroups,except forlatency>20–25years.However,theselatterresultswere basedonsmallnumbers.

3.5. LateralityaccordingtoInskip

Lateralitywasalsoanalysedwiththemethoddescribedby Inskip[28].Self-reportedlateralityofuseofamobilephone orcordlessphoneamongcaseswithgliomawasassociated withstatisticallysignificantincreasedrisk.Thus,therelative risk(RR)foruseofmobilephonewas1.5,P<0.001andfor useofcordlessphoneRR=1.4,P<0.001(datanotinTable).

3.6. Cumulativeuse

Cumulativeuseofwirelessphoneswasanalysedinquar- tiles,basedontotaluseofwirelessphonesamongthecontrols (Table6).Thecumulativetimewascountedforuseofthespe- cificphoneinthedifferentcategories,includingin“mobile phones”alltypesofmobilephones,andfor“wirelessphones”

alsotheuseofcordlessphones.Forallphonetypesexcept3G, thehighestriskwithastatisticallysignificanttrendwasinthe 4thquartile.Nostatisticallysignificanttrendwasfoundfor

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6 L.Hardell,M.Carlberg/Pathophysiology22(2015)1–13 Table4

Oddsratio(OR)and95%confidenceinterval(CI)forglioma,total,ipsilateral,andcontralateralexposure.Numbersofexposedcases(Ca)andpopulation basedcontrols(Co)aregiven.Adjustmentwasmadeforageatdiagnosis,gender,SEI-code,andyearfordiagnosis.

All Ipsilateral Contralateral

Ca/Co OR 95%CI Ca/Co OR 95%CI Ca/Co OR 95%CI

Analogue 299/558 1.6 1.2–2.0 190/252 2.0 1.5–2.7 98/184 1.3 0.9–1.9

Digital(2G) 884/2014 1.3 1.1–1.6 550/865 1.8 1.4–2.2 298/684 1.1 0.8–1.4

Digital(UMTS,3G) 58/141 2.0 0.95–4.4 35/70 2.3 0.99–5.4 21/45 1.9 0.7–4.8

Mobilephone,total 945/2148 1.3 1.1–1.6 592/920 1.8 1.4–2.2 316/729 1.1 0.8–1.4

Cordlessphone 752/1724 1.4 1.1–1.7 461/766 1.7 1.3–2.1 259/565 1.2 0.9–1.6

Ipsilateral:≥50%useofthephoneonthesamesideasthetumourwaslocated.

Contralateral:<50%useofthephoneonthesamesideasthetumourwaslocated.

Tumourlateralitynotavailablefor77casesand836controls.

3Gdigitalphones,buttheseresultswerealsobasedonsmall numbers.Wirelessphonetotaluse(>1486h)gaveOR=2.0, 95%CI=1.6–2.6inthe4thquartile,withsimilarresultsfor totalmobileandcordlessphoneuse.

ORsincreasedstatisticallysignificantper100hofcumu- lativeuseforalltypesofphones(Table3).Wirelessphone increased therisk withOR=1.011, 95% CI=1.008–1.014 per100hofcumulativeuse.

3.7. Multivariateanalysis

ResultsareshowninTable7formultivariateanalysisof ORand95%CIper100hcumulativeuse.Theriskincreased statisticallysignificantforthedifferent phonetypesexcept 3G(UMTS).Theriskperyearoflatencywasalsocalculated,

adjustedfor yearsof useof any mobileor cordlessphone beforetherespectivetype.ORincreasedstatisticallysignif- icantfor the differentphonetypes,except for3G yielding OR=1.127,95%CI=0.955–1.329.

3.8. Agegroups

Therisksofglioma,basedondifferentagegroupsforfirst useofwirelessphones,aregiveninTable8.Regardingmobile phoneuse,thehighestORwasobtainedforfirstusebefore the ageof 20 years, OR=1.8, 95% CI=1.2–2.8. Therisk increasedfor ipsilateralusetoOR=2.3,95%CI=1.3–4.2.

Cordless phone gave OR=2.3, 95% CI=1.4–3.9 in total for the age group<20 years, increasing to OR=3.1, 95%

CI=1.6–6.3for ipsilateraluse. Lower ORswere seenfor

Table5

Oddsratio(OR)and95%confidenceinterval(CI)forglioma(n=1380)foripsilateralandcontralateralmobile,andcordlessphoneuseindifferentlatency groups.Numbersofexposedcases(Ca)andpopulation-basedcontrols(Co)aregiven.Adjustmentwasmadeforageatdiagnosis,gender,SEI-code,andyear fordiagnosis.

Latency Mobilephone Cordlessphone

Total Ipsilateral Contralateral Total Ipsilateral Contralateral

OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) Glioma(n=1380)

Total,>1year 1.3 1.8 1.1 1.4 1.7 1.2

1.1–1.6 1.4–2.2 0.8–1.4 1.1–1.7 1.3–2.1 0.9–1.6

(945/2148) (592/920) (316/729) (752/1724) (461/766) (259/565)

>1–5years 1.2 1.6 0.9 1.3 1.5 1.3

0.98–1.5 1.3–2.1 0.7–1.2 1.1–1.6 1.2–2.0 0.9–1.7

(262/674) (167/271) (80/234) (271/653) (161/292) (98/205)

>5–10years 1.5 1.9 1.3 1.4 1.8 1.2

1.2–1.8 1.4–2.5 0.9–1.8 1.1–1.8 1.3–3.4 0.9–1.7

(301/688) (187/289) (106/238) (294/655) (180/295) (100/220)

>10–15years 1.4 1.7 1.3 1.4 2.0 1.2

1.1–1.9 1.2–2.3 0.9–2.0 1.1–1.9 1.3–2.9 0.8–1.9

(211/476) (131/225) (74/152) (131/294) (82/126) (46/99)

>15–20years 1.6 2.2 1.0 1.7 2.6 0.9

1.1–2.2 1.5–3.4 0.6–1.7 1.1–2.5 1.5–4.4 0.4–1.8

(92/196) (59/84) (29/76) (50/109) (35/47) (12/38)

>20–25years 2.1 2.3 2.2 1.4 1.4 1.9

1.3–3.2 1.3–4.1 1.1–4.6 0.5–3.8 0.3–5.9 0.4–10

(50/81) (29/38) (17/20) (6/13) (3/6) (3/3)

>25years 3.0 4.6 3.2 – – –

1.7–5.2 2.1–10 1.2–8.6

(29/33) (19/13) (10/9) (0/0) (0/0) (0/0)

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Table6

Oddsratio(OR)and95%confidenceinterval(CI)forglioma(n=1380)forcumulativeuseofwirelessphonesinquartilesbasedonuseofwirelessphones amongcontrolsintotal.Numbersofexposedcases(Ca)andpopulation–basedcontrols(Co)aregiven.Adjustmentwasmadeforageatdiagnosis,gender, SEI–code,andyearfordiagnosis.

Quartile Analogue Digital(2G) Digital(UMTS,

3G) Mobilephone,

total Cordlessphone Digitaltype(2G,

3G,cordless) Wirelessphone OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co) OR,CI(Ca/Co)

Firstquartile 1.2 1.3 1.8 1.3 1.1 1.2 1.2

0.9–1.6 1.1–1.6 0.7–4.5 1.05–1.5 0.9–1.4 0.9–1.4 0.9–1.4

(119/304) (328/885) (16/47) (340/920) (174/478) (214/618) (223/641)

Secondquartile 1.8 1.3 1.5 1.3 1.2 1.3 1.3

1.3–2.5 1.01–1.7 0.6–3.8 1.02–1.6 0.97–1.6 1.1–1.6 1.04–1.6

(88/146) (187/467) (17/54) (198/492) (203/534) (232/583) (235/596)

Thirdquartile 1.8 1.5 3.0 1.4 1.6 1.4 1.4

1.2–2.8 1.1–1.9 1.2–7.5 1.04–1.8 1.3–2.1 1.1–1.7 1.1–1.7

(50/82) (174/388) (20/31) (179/416) (210/451) (241/613) (249/617)

Fourthquartile 4.8 2.3 2.7 2.2 2.3 2.1 2.0

2.8–8.2 1.7–3.1 0.7–10 1.7–2.9 1.8–3.1 1.7–2.7 1.6–2.6

(42/26) (195/274) (5/9) (228/320) (165/261) (350/579) (367/618)

P,trend <0.0001 0.0001 0.37 <0.0001 <0.0001 <0.0001 <0.0001

Firstquartile1–122h;secondquartile123–511h;thirdquartile512–1486h,fourthquartile>1486h

firstuseintheagegroups20–49yearsand≥50years,being still statisticallysignificant.TheseORsalsoincreased with ipsilateraluse.Contralateraluseofmobileorcordlessphone usedidnotincreasestatisticallysignificanttheriskofglioma.

3.9. Usingmeningiomacasesasreferents

These case-control studies included all types of brain tumoursreportedtotheSwedishcancerregister,themajority of benignbraintumours beingmeningioma. In oneanaly- sis,meningiomacases(n=1624)wereusedasthereference

entitytogliomacases(n=1379).Table9showsastatistically significantincreasedriskforgliomaassociatedwithipsilat- eraluseofallphonetypes.Ipsilateralmobilephoneusegave OR=1.4, 95% CI=1.1–1.8,andipsilateralcordlessphone OR=1.4,95%CI=1.1–1.9.

3.10. Differenttypesofglioma

Astrocytoma is the most common type of glioma.

Regarding astrocytoma grade I–II (low grade; n=221) mobile phone use yielded OR=1.5, 95% CI=0.9–2.3,

Table7

Oddsratio(OR)and95%confidenceinterval(CI)forgliomaper100hcumulativeuseinamultivariateanalysis,andperyearoflatencyadjustedforyearsof useofanymobileorcordlessphonepriortotherespectivetype.Inallcalculationsadjustmentwasmadeforageatdiagnosis,gender,SEI–code,andyearfor diagnosis.Populationbasedcontrolswereused.

Per100hcumulativeuse Peryearoflatency

OR 95%CI OR 95%CI

Analogue 1.025 1.010–1.041 1.056 1.036–1.076

Digital(2G) 1.009 1.005–1.014 1.030 1.009–1.052

Digital(UMTS,3G) 0.980 0.944–1.017 1.127 0.955–1.329

Cordlessphone 1.011 1.006–1.016 1.034 1.016–1.054

Table8

Oddsratio(OR)and95%confidenceinterval(CI)forgliomaforageatfirstuseofwirelessphone.Numbersofexposedcases(Ca)andpopulation–based controls(Co)aregiven.Adjustmentwasmadeforageatdiagnosis,gender,SEI-code,andyearfordiagnosis.

<20yearsold 69/93 1.8 1.2–2.8 39/38 2.3 1.3–4.2 22/28 1.9 0.9–3.7

20–49yearsold 605/1337 1.3 1.1–1.6 384/573 1.8 1.4–2.3 198/447 1.1 0.8–1.5

≥50yearsold 271/718 1.3 1.1–1.6 169/309 1.7 1.3–2.2 96/254 1.1 0.8–1.5

Cordlessphone 752/1724 1.4 1.1–1.7 461/766 1.7 1.3–2.1 259/565 1.2 0.9–1.6

<20yearsold 46/48 2.3 1.4–3.9 28/19 3.1 1.6–6.3 10/15 1.5 0.6–3.8

20–49yearsold 436/1022 1.3 1.02–1.6 265/458 1.5 1.2–2.0 158/334 1.2 0.9–1.7

≥50yearsold 270/654 1.4 1.2–1.8 168/289 1.8 1.4–2.3 91/216 1.2 0.9–1.7

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8 L.Hardell,M.Carlberg/Pathophysiology22(2015)1–13 Table9

Oddsratio(OR)and95%confidenceinterval(CI)forglioma(n=1379)andmeningiomacases(n=1624)asthereferenceentity.Numbersofexposedcases (Ca)andcontrols(Co)aregiven.Onesubjectwithbothamalignantbraintumourandmeningiomawasexcludedfromtheanalysis.Adjustmentwasmadefor ageatdiagnosis,gender,SEI-code,andyearfordiagnosis.

Analogue 299/221 1.3 0.98–1.8 190/106 1.7 1.2–2.5 98/75 1.2 0.8–2.0

Digital(2G) 883/902 1.3 0.99–1.6 549/432 1.5 1.1–2.0 298/329 1.0 0.7–1.4

Digital(UMTS,3G) 58/47 2.8 1.2–6.7 35/26 3.3 1.2–8.8 21/17 1.8 0.6–5.2

Cordlessphone 751/816 1.2 0.9–1.5 461/378 1.4 1.1–1.9 258/289 1.1 0.8–1.6

increasing to OR=2.1, 95% CI=0.8–5.8 in the >20 year latencygroup.Ipsilateralmobilephoneuse inthatlatency categorygaveOR=3.0,95%CI=0.96–9.1;cordlessphone usegaveoverallOR=1.4,95%CI=0.9–2.3,andwithlatency

>15–20 years OR=1.6, 95% CI=0.6–4.4, ipsilateral use OR=3.2, 95% CI=0.99–10. The calculations withlonger latencytimewerebasedonsmallnumbersofexposedcases (datanotinTable).

RegardingastrocytomagradeIII–IV(highgrade;n=857), mobilephoneusegaveoverallOR=1.4,95%CI=1.1–1.8.

Theriskincreasedinthe>20yearlatencygrouptoOR=2.5, 95% CI=1.6–3.8and for ipsilateraluse toOR=3.3, 95%

CI=1.9–5.7. Cordless phone use gave OR=1.5, 95%

CI=1.2–1.9.Ipsilateraluseinthelatencygroup>15–20years gaveOR=2.5,95%CI=1.3–4.8.Only4caseshadusedthe cordless phone >20 years, making these calculations less meaningful(datanotinTable).

Wirelessphoneusegaveforoligodendroglioma(n=162) OR=1.6,95%CI0.998–2.5overall,increasingtoOR=3.2, 95%CI=1.2–8.3inthe>20yearslatencygroup.Forother typesor mixed glioma(n=140), wireless phoneuse gave intotalOR=1.1,95%CI=0.7–1.8,increasingtoOR=2.7, 95% CI=1.02–7.4 using >20 years latency (data not in Table).

3.11. Othertumourtypesthanglioma

Intotal118caseshadsomeothertypeofmalignantbrain tumour than glioma (including medulloblastoma, ependymoma,othermalignant;Table1).Mobilephoneuseintotal gave OR=1.4, 95% CI=0.8–2.4, increasing to OR=2.9, 95%CI=0.9–9.6inthe>20yearlatencygroup.Thecorre- spondingvaluesforcordlessphoneusewereOR=1.3,95%

CI=0.8–2.4andOR=2.8,95%CI=0.98–7.9,respectively.

Severalofthecalculationswerebasedonsmallnumbers(data notinTable).

3.12. Unconditionalversusconditionallogistic regressionanalysis

Wealso used conditionallogistic regressionanalysis to find if dissolving of the matching and including all con- trolsinthe study had an impacton the results.This gave OR=1.3, 95% CI=1.1–1.6 for mobile phone use, which

is the same as in the unconditional analysis. For cordless phoneuse,theresult wasOR=1.5, 95%CI=1.3–1.9,and forwirelessphoneuseintotalOR=1.4,95%CI=1.2–1.7, i.e. slightlyhigher ORsthan in the unconditional logistic regressionanalysis.

3.13. Restrictedcubicsplineplots

A restricted cubic spline plot (Fig. 1) shows the relationship between cumulative use of wireless phones and glioma, there being a linear trend of increasing risk up to 10,000h of cumulative use (non-linearity, P=0.08). A linear relationship between latency of wireless phone use andthe risk of gliomawasdetected (Fig.2; non-linearity, P=0.71).

Theresultsfor latencyandipsilateralmobilephoneuse (Fig.3)showthattherewasahigherORwithshortlatency, andaftersomedeclinewasseentogiveanincreasingrisk with longer latency (non-linearity, P=0.01). This finding is different from the result for contralateral mobilephone use, see Fig. 4 (non-linearity, P=0.74). The results were similar for cordless phone use, data not in figures (ipsilateral, non-linearity, P=0.04, contralateral, non-linearity, P=0.26).

Fig.1. Restrictedcubicsplineplotoftherelationshipbetweencumulative useofwirelessphonesandglioma.ThesolidlineindicatestheORestimate andthebrokenlinesrepresentthe95%CI.Adjustmentwasmadeforage atdiagnosis,gender,SEI-code,andyearfordiagnosis.Populationbased controlswereused.

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Fig.2.Restrictedcubicsplineplotoftherelationshipbetweenlatencyof wirelessphonesandglioma.ThesolidlineindicatestheORestimateandthe brokenlinesrepresentthe95%CI.Adjustmentwasmadeforageatdiagnosis, gender,SEI-code,andyearfordiagnosis.Populationbasedcontrolswere used.

4. Discussion

4.1. Themainfindings

Mostofthetypesofmalignantbraintumourswereglioma (n=1380,92.1%).Themostmalignantvariety,astrocytoma grade IV (glioblastoma multiforme) constituted 50.3% of thegliomas.Incontrasttoe.g.,Interphone[16],wepublish alsoresultsfordifferenttypesofglioma.Thisstudyclearly shows an increasedrisk for gliomaassociated withuse of bothmobileandcordlessphones,ariskthatincreased sig- nificantlywithlatencyandcumulativeuse.Thehighestrisk was inthelongest latencygroup(>25 years),givingasta- tisticallysignificant3-foldincreasedrisk.Overallahighrisk wasfoundforuseofthethirdgeneration(3G;UMTS)mobile

Fig.3.Restrictedcubicsplineplotoftherelationshipbetweenlatencyof ipsilateralmobilephoneuseandglioma.ThesolidlineindicatestheOR estimateandthebrokenlinesrepresentthe95%CI.Adjustmentwasmade forageatdiagnosis,gender,SEI-code,andyearfordiagnosis.Population basedcontrolswereused.

Fig.4.Restrictedcubicsplineplotoftherelationshipbetweenlatencyof contralateralmobilephoneuseandglioma.ThesolidlineindicatestheOR estimateandthebrokenlinesrepresentthe95%CI.Adjustmentwasmade forageatdiagnosis,gender,SEI-code,andyearfordiagnosis.Population basedcontrolswereused.

phones,withOR=4.1,95%CI=1.3–12inthelatencygroup

>5–10years. Theriskfor 3Guseincreased with4.7% per 100h cumulativeuse andwith15.7% peryear of latency.

Severalcalculations,however,werebasedonsmallnumbers, andmostofthesubjectshadpreviouslyusedanothermobile phonetype.Inamultivariateanalysis,nostatisticallysignif- icantincreasedriskper100hcumulativeusewasfoundfor 3G;thiswasalsothecaseintheanalysisofORperyearof latencywithadjustmentofprevioususeofotherphonetypes.

AsexpectedbasedonthedistributionofRF-EMFonthe brain,ipsilateraluseofbothmobileandcordlessphonesgave astatisticallysignificantincreasedrisk,whereasnostatisti- cally significantincreased risk was foundfor contralateral use, whichis inagreement withprevious results (for dis- cussionsee[8,29]).Therewasahigherriskforgliomainthe temporaloroverlappinglobes,especiallyforgliomalocalised onlyinthetemporallobe.Basedondosimetry,theseresults are also expected, being similar to our previous findings [24,30].

ChildrenandadolescentsaremoreexposedtoRF-EMF thanadultsduetothinnerskullbone,higherconductivityin thebraintissue,andasmallerhead.Alsothedevelopingbrain ismorevulnerablethaninadultsanditisstilldevelopinguntil about20yearsofage[31].Weanalysedgliomariskindif- ferentagegroupsforfirstuseofawirelessphone.Regarding bothmobileandcordlessphonesORwashighestamongsub- jectswithfirstusebefore20yearsofage.Theriskincreased furtherforipsilateralusetoOR=2.3,95%CI=1.3–4.2for mobilephoneuseandtoOR=3.1,95%CI=1.6–6.3forcord- lessphoneuse.Theseresultsareconsistentwithourprevious findings[8,15,29,30].

Weusedrestrictedcubicsplineplotstoillustratetherela- tionshipbetweenbothcumulativeuseandlatencyofwireless phones andglioma. Therewas alinear increaseinrisk up to10,000hcumulativeuse(non-linearity,P=0.08).Latency

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10 L.Hardell,M.Carlberg/Pathophysiology22(2015)1–13

alsogavealinearincreasing riskwithdataup to28years (non-linearityP=0.71).Foripsilateralmobilephoneuseand latency,thecurvewasslightlydifferentcomparedwithtotal wirelessphoneuse,withanincreasedriskforshortlatency (<10 years), whichdropped off slightly before increasing againwithlongerlatency>20years(non-linearityP=0.01).

This finding differs from contralateral mobile phone use, compareFigs.3and4.Itshouldbenotedthatcontralateral usewasdefinedaslessthan50%ofthetime.Similarresults werefoundforcordlessphoneuse.Theseresultsindicatean earlyeffectinbraintumourigenicity (initiation) andalate effect(promotion),asdiscussedelsewhere[24].

4.2. Strengthsandlimitations

Patientsinthisstudy,withhistopathologicalverification ofamalignantbraintumour,were reportedtous fromthe cancerregistriesinSweden;for1997–2003,caseswereascer- tained from central Sweden, whereas for 2007–2009 the wholecountrywas included. Controls were selected from the same geographical area as the cases, with matching made on year of diagnosis, gender, and age, making the controlscomparablewiththecases. Allthe controlscould beincludedintheunconditionallogisticregressionanalysis becauseadjustmentwasmadeforyearofdiagnosis,gender, age,andSEI-code.Inthelateralityanalysis,thematchedcon- trolwasassignedthesamesideoflocalisationasthetumour fortherespectivecase.

Inoneoftheanalyses,weusedconditionallogisticregres- sion,andthustheoverallresultsweresimilarorgaveslightly higherORsthanintheunconditionalanalysisusingthewhole setofcontrols.Thus,ouranalysis gaveratherconservative riskestimates.Usingthewholematerialallowedustomake severalsubgroupanalysesthat would otherwisehavebeen hamperedbysmallnumbersofexposedsubjects.

Onestrengthofourstudywasthehighpercentageofpar- ticipating cases and controls,89% and 87%, respectively, makingitunlikelythatselectionbiasinfluencedtheresults.It mightbearguedthatexcludingdeceasedcasescouldbiasthe results,howeverinaspecialstudythatincludedthedeceased casesfor1997–2003,usingdeceasedcontrols,weconcluded thatmobilephoneusewasariskfactorforglioma[25].For bothstudygroups,thenextofkinansweredthequestionnaire ontheuseofwirelessphones.Thus,theinclusionofonlyliv- ingsubjectsinthepresentstudywouldnothavebiasedthe results.

Recall bias might have been an issue, such that cases wouldhaveoverestimatedtheiruseof wirelessphones.To addressthispoint,weusedmeningiomacasesfromthesame studyasthereferenceentityinoneanalysis,whichshowed anincreasedrisk of gliomawithwirelessphoneuse.Thus itisunlikelythatourpresentresultsusingpopulation-based controlsareexplainedbyrecallbias.

Observationalbiasmighthavebeenintroducedbythesup- plementaryphoneinterviews.However,the identityof the subjectseither as acaseor acontrol was not disclosedto

theinterviewer.Astructuredprotocolwasalsousedandthe interviewerhadtofollowthatprocedurestrictlyduringthe interviews.Alsothedifferentresultsaccordingtotumourtype inthisstudydonotsupportobservationalbias,sinceevenhad anintervieweridentifiedasubjectbeingacase,noinforma- tionwasavailableregardingthehistopathologyofthebrain tumour.

All dataprocessingbefore statistical analysiswas done without information about case/control status of the subjects. Histopathological classification of the tumour was madewithoutknowledgeofexposure.Tumourpathologywas codedinaseparatedata filethat wasnot disclosedbefore statisticalanalysis.

4.3. Biologicalconsiderations

Several findings, discussed to some extent above, give thefindingsinthisstudytheirbiologicalrelevance.Wealso foundhighestriskinthemostexposedpartofthebrain,i.e.

ipsilateralexposureandthetemporallobe.

Asmightalsobeanticipated,ORincreasedwithcumula- tiveuseandlatency.Regardingthelatter,ipsilateralexposure indicatedanearlyeffectingliomadevelopment,whichisan increased risk withlong latency. However, we also found anincreasedriskwithshortlatency,indicatingalateeffect intumourdevelopment.Thus,asdiscussedelsewhere[24], theseresultscouldbecompatiblewithbothtumourinitiation andpromotion.

Of certain interest is the higher risk we observed for 3G mobile phone use compared with other types. How- ever,thisobservationwasbasedonshortlatencyandrather low numbers of exposed subjects. Contrary to 2G GSM, 3G universal global telecommunications system (UMTS) mobile phones emit wide-band microwave (MW) signals.

Hypothetically, UMTSMWs mayresult in higher biolog- ical effects compared toGSM signal because of eventual

“effective”frequencieswithinthewideband[32,33].Toour knowledge, thereare onlytwo mechanistic studies, which compareeffectsof2Gand3Gsignalsusingthesameexper- imentalapproachunderwell-definedconditionsofexposure [32,34]. UMTS MWs affected chromatin and inhibit for- mationof DNAdouble-strand breaks (DSB) co-localizing 53BP1/gamma-H2AXDNArepair fociinhumanlympho- cytesfromhypersensitiveandhealthypersons[32].Thedata wereinlinewiththehypothesisthatthetypeofsignal,UMTS MWs, mayhave higher biologicalefficiency andpossibly largerhealthriskeffectscomparedtoGSMradiationemis- sions.TheeffectsofUMTSMWsandGSM-915MHzMWs ontheformationof theDNArepairfoci,werestatistically differentforhypersensitivebutnotforcontrolsubjects[32].

Chronic exposure to GSM and UMTS signalsresulted insignificantinhibitionofDSBrepairinhumanstemcells [34]. Statistical analysis revealed that UMTS exposure affectedhumanstemcellsmorestronglythandidtheGSM exposure[34].Inhibitoryeffectsof MWexposureonDSB repairinstemcellsmayresultinformationofchromosomal

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aberrations and therefore origination of cancer. Alterna- tively, MW exposuresmay inducea stressresponse. Both possible interpretations provided a mechanistic link to increased cancerrisk because stemcells are consideredas mostrelevanttargetsfororiginationoftumoursofdifferent types including glioma [34]. One interesting gene is the p53 protein. It is a transcription factor that plays a vital role inregulating cellgrowth, DNA repairand apoptosis, and p53 mutationsare involved in diseaseprogression. In a recentstudy itwas foundthat use of mobilephones for

≥3 hoursadaywasassociated withincreased riskfor the mutanttypeofp53geneexpressionintheperipheralzoneof astrocytoma gradeIV. Furthermore,this mutationincrease was statistically significant correlated withshorter overall survival time[35].Thestudywasrathersmall(n=63)and nodataonlatencyofmobilephoneusewasgiven.

Ionizingradiationandheredityareknownriskfactorsfor glioma,butthesewereindependentriskfactorswithnointer- actionwithwirelessphones[36].Thus,itwasunnecessaryto makeadjustmentforthesefactorsinthestatisticalanalysis.

In analysis of survival of glioma casesinour previous studies[13,15,25],we foundadecreasedsurvival of cases withglioblastomamultiformeandlong-termuseofwireless phones [37,38]; thisindicates acomplex biologicaleffect fromRF-EMFexposureandstrengthensacausalassociation betweengliomaandtheuseofwirelessphones.

Wehavealreadyshownahigherrisk forgliomaamong subjectswithfirstuseofamobileorcordlessphonebeforethe ageof20years[8,15,29,30],whichwasalsotheresultfound inthepresentstudy.Inparticular,thenearfieldexposuretothe brainfromahandsetisworryingsincetheexposureishigher inchildrenthanadultsduetothethinnerbone,smallerhead andhigherconductivityof microwavesinthebrain. More- over,thedevelopingbrainisdiscussedtobemoresensitive totoxinsthanthatoftheadult[39].

In short,thesefindingsonbiologicalrelevanceare con- sistent with wireless phones causing glioma. The Hill viewpoints on association and causation are usefulin this context. As published elsewhere [20], adopting the Hill criteria agreeswiththeconclusionthatRF-EMFemissions fromwirelessphonescauseglioma.Laboratorystudiesalso supportthisnotion.Thesefindingshavebeendiscussedelse- where[24]andhavealsobeen reviewedbyIARC[10,12], andthereforewillnotbecommentedonanyfurther.

4.4. Otherhumanstudies

Wepreviouslyreviewedthistopic[8]andwilltherefore giveonlyashortsummary.InInterphone,astatisticallysig- nificantincreasedriskforgliomawasseeninthegroup2–4 yearsforregularuse,with1–1.9yearsuseasreferencecate- gory,OR=1.68,95%CI=1.16–2.41(seeAppendix2)[16].

The highestORwas inthe10+ yearscategoryfor regular use,OR=2.18,95% CI=1.43–3.31.Resultshavenotbeen presentedaccordingtotypeofmobilephoneused.Overall, cumulativeuse≥1640hintheshortestlatencygroupof1–4

yearsbefore reference date wasassociated withincreased risk,OR=3.77,95%CI=1.25–11.4.

In Interphone, cumulative call-time of mobile phones

≥1640h resulted in OR=1.87, 95% CI=1.09–3.22 for gliomainthetemporallobe,andforipsilateralmobilephone OR=1.96,95%CI=1.22–3.16[16].Likewise,inthepresent study, the OR was higher for ipsilateral use of mobileor cordlessphones,andforgliomainthetemporalandoverlap- pinglobes.Re-analysisof ourdatausingthesamecriteria for inclusionandexposuregavesimilarresultsas inInter- phone[40]. Alsoin the current pooledanalysis excluding cordless phoneuse(regarded as noexposureto RF-EMF) andlimitingtheagegroupto30–59yearsgaveconservative riskestimates.ThusmobilephoneuseintotalgaveOR=1.2, 95%CI=0.95–1.5.Nostatisticallysignificantincreasedrisk was found inthe different latencygroups except for time sincefirstuse>25years(latency).Thatresultwasbasedon use of analoguephones (n=18 cases, seven controls) and gaveOR=6.7,95%CI=2.6–17usingtheInterphonecrite- ria (data not in Table).These results indicate that several methodologicallimitationsinInterphone,suchasexcluding useofcordlessphonesandthelimitedagegroup,hampered thepossibilitytofindatrueriskincrease.Ofcourseresultson cordlessphoneuseandtheuseofareferencecategoryofno wirelessphoneusewouldhavebeendesirableinInterphone.

The highest incidence of astrocytoma WHO grade IV (glioblastomamultiforme)isfoundintheagegroup45to75 yearswithmeanage61yearsand80%olderthan50years[8].

Limitingupperageto59yearsasinInterphonediminishes thepossibilitytofindanincreasedrisktakingareasonable tumourinductionperiod.Itseemsasiftheagedistributionin Interphonewasmoredecidedbyprevalenceofmobilephone useinthepopulationthanagedistributionforgliomacases andareasonablelatencytime. Excludingtheyoungestage group,asinInterphone,makesalsoanevaluationofyoung usersmoredifficult.

Therearefewothercurrentstudies.IntheFrenchCERE- NATstudy,regularuseofmobilephonegaveforbraintumour OR=1.24,95%CI=0.86–1.77[41].However,astatistically significantassociationwasobservedforgliomasintheheavi- estuserswhenconsideringalife-longcumulativedurationof calls≥896hyieldingOR=2.89,95%CI=1.41–5.93.Risks were higher for temporal tumours, occupational or urban mobilephoneuse.

Inarecordlinkagestudy fromDenmark, mobilephone subscribersfromJanuary1,1982,untilDecember31,1995, were identified from the computerisedfiles of the 2 Dan- ishoperatingcompanies,TeleDenmarkMobilandSonofon, whichalsopartlyfundedthestudy[9].Ithasproducedfour articlesthatwethoroughlyreviewed[11].Weconcludedthat itsmanylimitations–embeddedinthestudydesignfromthe verybeginningandmainlyrelatedtopoorexposureassess- ment– obscure thefindings ofthe fourreports tosuch an extentthat,atbest,renderthemuninformative.ThisDanish cohort study was included inthe IARCevaluationof RF- EMF,buttheconclusionwasthatthe“phoneprovider,asa