Urinary trichlorophenol levels and increased risk of attention deficit hyperactivity disorder among US school-aged children
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Title: Urinary trichlorophenol levels and increased risk of attention deficit hyperactivity disorder among US school-aged children
Series Title: Occup Environ Med. 2011 Aug;68(8):557-61. Epub 2011 May 3.
Physical Description: Journal Article
Creator: Xu, Xiaohui
Nembhard, Wendy N.
Kan, Haidong
Kearney, Greg
Zhang, Zhi-Jiang
Talbott, Evelyn O.
Publisher: BMJ
Place of Publication: Occup Environ Med.
Publication Date: 2011/08
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Abstract: BACKGROUND: Trichlorophenols (TCPs) are organochlorine compounds which are ubiquitous in the environment and well known for their carcinogenic effects. However, little is known about their neurotoxicity in humans. OBJECTIVES: Our goal was to examine the association between body burden of TCPs (ie, 2,4,5-TCP and 2,4,6-TCP) and attention deficit hyperactivity disorder (ADHD). METHODS: We calculated ORs and 95% CIs from logistic regression analyses using data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to evaluate the association between urinary TCPs and parent-reported ADHD among 2546 children aged 6-15 years. RESULTS: Children with low levels (<3.58 μg/g) and high levels (≥3.58 μg/g) of urinary 2,4,6-TCP had a higher risk of parent-reported ADHD compared to children with levels below the limit of detection (OR 1.54, 95% CI 0.97 to 2.43 and OR 1.77, 95% CI 1.18 to 2.66, respectively; p for trend=0.006) after adjusting for covariates. No association was found between urinary 2,4,5-TCP and parent-reported ADHD. CONCLUSION: Exposure to TCP may increase the risk of behavioural impairment in children. The potential neurotoxicity of these chemicals should be considered in public health efforts to reduce environmental exposures/contamination, especially in countries where organochlorine pesticides are still commonly used.
Acquisition: Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Xiaohui Xu.
Publication Status: Published
Funding: Publication of this article was funded in part by the University of Florida Open-Access Publishing Fund.
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Holding Location: University of Florida
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Urinarytrichlorophenollevelsandincreasedriskof attentiondecithyperactivitydisorderamongUS school-agedchildrenXiaohuiXu,1WendyNNembhard,2HaidongKan,3GregKearney,4Zhi-JiangZhang,5EvelynOTalbott6ABSTRACT Background Trichlorophenols(TCPs)areorganochlorine compoundswhichareubiquitousintheenvironmentand wellknownfortheircarcinogeniceffects.However,little isknownabouttheirneurotoxicityinhumans. Objectives Ourgoalwastoexaminetheassociation betweenbodyburdenofTCPs(ie,2,4,5-TCPand2,4,6TCP)andattentiondecithyperactivitydisorder(ADHD). Methods WecalculatedORsand95%CIsfromlogistic regressionanalysesusingdatafromthe1999 e 2004 NationalHealthandNutritionExaminationSurvey (NHANES)toevaluatetheassociationbetweenurinary TCPsandparent-reportedADHDamong2546children aged6 e 15years. Results Childrenwithlowlevels( < 3.58 m g/g)andhigh levels( $ 3.58 m g/g)ofurinary2,4,6-TCPhadahigher riskofparent-reportedADHDcomparedtochildrenwith levelsbelowthelimitofdetection(OR1.54,95%CI0.97 to2.43andOR1.77,95%CI1.18to2.66,respectively;p fortrend 0.006)afteradjustingforcovariates.No associationwasfoundbetweenurinary2,4,5-TCPand parent-reportedADHD. Conclusion ExposuretoTCPmayincreasetheriskof behaviouralimpairmentinchildren.Thepotential neurotoxicityofthesechemicalsshouldbeconsideredin publichealtheffortstoreduceenvironmentalexposures/ contamination,especiallyincountrieswhere organochlorinepesticidesarestillcommonlyused. INTRODUCTIONTrichlorophenols(TCPs)including2,4,5-trichlorophenol(2,4,5-TCP)and2,4,6-trichlorophenol(2,4,6TCP)areformedwhenthreechlorineatomsare joinedtoonephenolmolecule.TCPswerehistoricallyusedaswoodpreservativesandasintermediates inthechemicalsynthesisofavarietyofpesticides.1 AlthoughmostusesofTCPshavebeenprohibitedin theUSA,theycontinuetobeusedintheproduction ofsomefungicides.2TCPsarealsoreleasedintothe environmentasby-productsduringthemanufacture ofotherchlorinatedaromaticcompoundsand duringthechlorinationofdrinkingwaterorwaste water.TCPsarealsothemetabolitesofseveral organochlorinechemicalsincludingchlorobenzenes, hexachlorocyclohexanesandchlorophenoxyacids, andarepresentintheair,surfacewater,soiland sediments.34Therefore,generalpopulationexposure toTCPscanoccurthroughingestionoffoodand waterorinhalationofaircontaminatedbyTCPsor otherorganochlorinechemicals. MeasuringindividualexposuretoTCPsischallengingduetothemanypotentialexposurepathways.UrinaryexcretionofTCPsisanindicationof exposuretoTCPsortoorganochlorinechemicals thataremetabolisedandexcretedasTCPs.5 Individualexposurecanbereliablyestimatedby measuringurinaryTCPs.6 Bothexperimentalstudiesandepidemiological studiesindicatethatsomeorganochlorinechemicals suchasdichlorodiphenyltrichloroethane(DDT)and dichlorodiphenyldichloroethylene(DDE)areneurodevelopmentaltoxicants.7 8Severalreviewshave systemicallydiscussedthedevelopmentalneurotoxicityoforganochlorinechemicals.910Brain developmentisacomplexprocessinvolvingcell proliferation,migration,differentiationandcell death,andcanbedisruptedbyexternalenvironmentalagents.Achild ’ scentralnervoussystemmay beparticularlyvulnerabletoneurotoxicityfrom environmentalagentssinceitisstilldevelopingand environmentalagentssuchasTCPsmayeasily disturbtheprocessbychangingneurotransmitter systemsandalteringintracellularsignalling processesresultinginbehaviouralimpairments.11However,asearchofPubMedandGoogleScholar databasesshowednopreviouslypublishedstudies investigatingtheneurodevelopmentaltoxicityof TCPsinhumans. Attentionde cithyperactivitydisorder(ADHD) isaneurodevelopmentaldisordercharacterised bypervasiveinattentionand/orhyperactivityimpulsivitycausingsigni cantfunctionalimpairments.12 13TheprevalenceofADHDrangesfrom 3%to8%inUSschool-agedchildren,accounting1DepartmentofEpidemiology andBiostatistics,Collegeof PublicHealthandHealth Professions,Universityof Florida,Gainesville,Florida,USA2DepartmentofEpidemiology andBiostatistics,Collegeof PublicHealth,Universityof SouthFlorida,Tampa,Florida, USA3DepartmentofEnvironmental Health,SchoolofPublicHealth, FudanUniversity,Shanghai, China4NationalCenterfor EnvironmentalHealth,Centers forDiseaseControland Prevention,Atlanta,Georgia, USA5DepartmentofEpidemiology, SchoolofPublicHealth, ShanghaiJiaoTongUniversity, Shanghai,China6DepartmentofEpidemiology, GraduateSchoolofPublic Health,UniversityofPittsburgh, Pittsburgh,USA Correspondenceto XiaohuiXu,101SNewellDrive, Room3119,Gainesville,FL 32610-0182,USA; xhxu@phhp.u.edu Accepted23March2011 PublishedOnlineFirst 3May2011 Thispaperisfreelyavailable onlineundertheBMJJournals unlockedscheme,seehttp:// oem.bmj.com/site/about/ unlocked.xhtml Whatthispaperadds
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for4 e 5millionADHDcasesamongchildrenaged4 e 17years, andhasdramaticallyincreasedduringthepasttwodecades.14 e 16Despitetheincreasingprevalence,theaetiologyandbiological mechanismsofADHD.Knownriskfactorsassociatedwith increasedriskofADHDinchildrenincludegeneticfactorsand awiderangeofenvironmentaltoxinsincludinglead,mercury andenvironmentaltobaccosmoke(ETS).17 e 19 However,PubMedandGoogleScholarsearchescombiningthe MeSHkeyterms, ‘ attention-de cithyperactivitydisorder ’ ‘ ADHD ’ ‘ trichlorophenols ’ and ‘ TCP ’ ,andreviewofthereferencesofrelevantarticlesidenti ednopublishedstudiesonTCPs andADHDinthepeer-reviewedliterature.Therefore,weused the1999 e 2004NationalHealthandNutritionExamination Survey(NHANES)datatoevaluatetheassociationsbetween urinaryTCPsandADHDamongUSchildren.METHODSANDMATERIALS Studypopulation TheNHANESisacross-sectionalhouseholdsurveythatcollects extensivehealthinformationinface-to-faceinterviewsandfrom medicalexaminationsamonganationallyrepresentativesample ofthenon-institutionalisedUScivilianpopulation,obtained withacomplex,multi-stageprobabilitysample.20 Weselectedall childrenbetween6and15yearsofage;wechosethisagerange becauseoftheavailabilityofdataonurinaryTCPsandother importantstudycovariates.Atotalof2546children,including 850childrenfromthe1999 e 2000NHANESdata,1035children fromthe2001 e 2002NHANESdataand661childrenfromthe 2003 e 2004NHANESdata,wereeligibleforthisstudy.AssessmentofADHD Weusedparentalreportoftheirchild ’ sdiagnosiswithADHDas theprimarydependentvariable.Theascertainmentofchildren ’ s ADHDdependedonhis/herparentorguardian ’ sresponsetothe question, “ Hasadoctororhealthprofessionalevertold[you/SP] that[you/s/he/SP]hadattentionde citdisorder ? ” (where ‘ SP ’ referredto ‘ sampleperson ’ )whichwaslocatedinthemedical historysectionofthehouseholdquestionnaires.Iftheparent orguardiananswered “ yes ” tothequestion,thechildwas categorisedasaprevalentcaseofADHD. MeasurementofurinaryTCPs InformationonurinaryTCPswasobtainedfromtheNHANES data.PerNHANESprotocol,urinespecimenswerecollected fromsubjectsinstandardurinecollectioncups.Thespecimens werelabelled,frozenimmediatelyat 20 8 Candstoredondry iceuntilanalysis.ASciexAPI4000massspectrometerwasused innegativeionAPCImode.Thenegativefragmentionswere usedforquanti cationoftheurinaryconcentrationsof 2,4,5-TCPand2,4,6-TCP.Detailsregardingurinespecimen collection,storage,handlingandtestinghavebeendescribed elsewhere.21 22Thecreatinine-correctedurinaryconcentrations of2,4,5-TCPand2,4,6-TCPwerecalculatedforfurther analysis.Creatininewasmeasuredinallurinesamplesthrough automatedcolorimetricdeterminationonaBermanSynchron CX3clinicalanalyser(BeckmanInstruments,Brea,California, USA)attheUniversityofMinnesota ’ sFairviewMedical Center.23TheurinaryTCPs( m g/l)weredividedbyurinary creatinine(mg/dl)and0.01,andexpressedasmicrogramper gram( m g/g)ofcreatinine.Covariates Covariateswerechosenonthebasisoftheirobservedassociations withADHDand/or ndingsfrompreviousstudies.Demographic variablesincludedchild ’ sage,gender,race/ethnicityandhouseholdsocioeconomicstatus.Speci cally,childrace/ethnicity includedthecategoriesnon-Hispanicwhite,non-Hispanicblack, MexicanAmericanandother(includingotherHispanicand multiracial)groups.Child ’ shouseholdsocioeconomicstatuswas measuredbythepoverty-to-incomeratio(PIR),whichistheratio offamilyincometothefamilypovertythresholdfortheyearof theinterviewandcategorisedasthreegroups(ie, < 1,1 e 2and $ 2).PIRvaluesbelow1.00arebelowtheof cialpoverty threshold,whilePIRvaluesof1.00orgreaterindicateincome abovethepovertylevel.24 Inaddition,areviewoftheliterature suggestedthatlowbirthweight,leadexposure,andprenataland postnatalexposuretoETSwerepotentialconfounders.18192526Inthisanalysis,thechildren ’ sserumcotininelevels,usedas abiomarkerofpostnatalETSexposure,wereobtainedfromthe NHANESdataandcategorisedintotertiles.Children ’ sblood leadlevels,measuredusinginductivelycoupledplasmamass spectrometry,werealsoavailableinthedatasetandcategorised intotertiles.Lastly,childbirthweight,de nedaslowbirth weight(yes/no)andprenatalETS(ie,prenatalmaternalsmoking: yes/no)wereobtainedthroughpersonalinterviewofanadult proxyrespondentinthechild ’ sfamily.Statisticalanalysis Descriptiveanalyses,suchastwo-sidedStudentttestsandWaldc2analysiswereperformedusingbivariableanalysisofthe associationsofADHDwiththecovariates.Variablesassociated withADHDindescriptiveanalyses(p < 0.2)wereselectedforthe multiplevariablelogisticregressionmodel.TheAkaikeinformationcriterion(smallervaluesindicateabetter t)wasusedto determinethebestmodelinouranalysis.Inthisanalysis,data fromthreedatacyclesweremergedtogethertorepresenttheUS childrenaged6 e 15yearsafteradjustingforthe nalweight usingthemethoddescribedbelow.Thecut-offpointsofurinary TCPsfromtheentirepopulationratherthanthosefromeach datacyclewereusedtode nethegroupsofurinaryTCPlevels becausesimilarmethodswereusedtodetectTCPsineachcycle. Speci cally,childrenwithurinaryTCPsbelowthelimitof detection(LOD)werethereferencegroupandthosewith urinaryTCPsabovetheLODwerecategorisedintotwogroups usingtheurinaryconcentrationmedianasthecut-offpoint:less thanthemedian(ie,alowlevelgroup)orabovethemedian(ie,a highlevelgroup). AllstatisticalanalyseswereperformedusingSAS9.1software surveyprocedures,whichaccountforthecomplexsampling designusedinNHANES.Thesampleweights,strati cationand clusteringdesignvariableswereincorporatedintoallSASsurvey procedurestoensurethecorrectestimationofsamplingerror. A6-yearsubsampleweightwascalculatedforthecombined 1999 e 2004databyfollowingtheNHANESanalyticaland reportingguidelinesbyassigningtwothirdsofthesubsample weightfor1999 e 2002ifaparticipantwassampledin 1999 e 2002andonethirdofthesubsampleweightforthose sampledin2003 e 2004.27 Thiscalculatedweightwasusedto analysethecombined6-yeardataofNHANES1999 e 2004. Thisstudyconformedwithallapplicablerequirementsofthe USAand/orinternationalregulationsforresearchonhuman subjects.Theresearchprotocolwasreviewedandapprovedby theUniversityofFloridaInstitutionalReviewBoard.RESULTSThedistributionsofselectedcharacteristicsbetweenADHD casesandcontrolsamongchildrenaged6 e 15yearsarepresented intable1.Ofthe2556eligiblechildrenaged6 e 15years,2539 558 OccupEnvironMed 2011; 68 :557 e 561.doi:10.1136/oem.2010.063859 Originalarticle

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(200ADHDcasesand2339controls)wereincludedinthe nal analysis.Seventeenchildrenwereexcludedfromtheanalysis becauseofmissingdataontheoutcomevariable.Inthebivariate analyses,ahigherprevalenceofADHDwasfoundamongboys (p < 0.0001),non-Hispanicwhitechildren(p < 0.0001),children inolderagegroups(p 0.0012),childrenexposedtoprenatal maternalsmoking(p 0.005)andchildrenwithhigherserum cotininelevels(p 0.0005).Theparentsoflowbirthweight childrenweremorelikelytoreportthattheirchildhadADHD thanparentsofnormalbirthweightchildren(p 0.09). Table2describesthedistributionsofthecreatinine-corrected concentrationsofurinaryTCPsamongchildren6 e 15yearsold. Theproportionofchildrenwithurinary2,4,6-TCPlevelsbelow theLODincreasedinthemostrecentdatacycle.However,this wasnotobservedforurinary2,4,5-TCP.Overall,therangeof urinaryTCPsamongchildren6 e 15yearsofagein2003 e 2004 wassmallerthanin1999 e 2002. TheassociationsbetweenurinaryTCPsandADHDare describedintable3.Thecut-offpointsfortheoverallmedian concentrationsofurinary2,4,6-TCPand2,4,5-TCPwere3.58 m g/ gand1.03 m g/g,respectively.Inmultivariableanalysis,wefound thatexposureto2,4,6-TCPwassigni cantlyassociatedwith ADHD.Childrenwithlow( < 3.58 m g/g)orhigh( $ 3.58 m g/g) levelsofurinary2,4,6-TCPweremorelikelytohaveaparental reportofadiagnosisofADHDcomparedwithchildrenwith 2,4,6TCPlevelsbelowtheLOD(OR1.54,95%CI0.97to2.43 andOR1.77,95%CI1.18to2.66,respectively)afteradjusting fordemographicfactors,earlychildhoodfactorsandother environmentaltoxins.Adose e responserelationshipbetween urinary2,4,6-TCPandADHDwasalsoobserved(pfor trend 0.006).However,wedidnot ndasigni cantassociation betweenexposureto2,4,5-TCPandADHD.Additionally,we de nedtheexposuregroupsofurinaryTCPsusingthecut-off pointsfromeachdatacycle.Werepeatedtheanalysisandthe conclusionremainedsimilar(ie,nosigni canteffectsfor 2,4,5-TCPbutasigni canteffectfor2,4,6-TCP).Wealsoevaluatedtheassociationsbyincludingadditionalcovariates,suchas dimethylthiophosphateexposure,inthemodelsandfound similarresults(dataarenotpresented). Furthermore,weexaminedtheinteractionsbetweenurinary TCPsandothercovariatesincludingage,gender,race/ethnicity, lowbirthweightandprenatalpassivesmoking.Nosigni cant interactionswerefound(dataarenotpresented).DISCUSSIONOurintentionwastoevaluatetheneurologicalhealtheffectsof lowlevelsof2,4,5-TCPand2,4,6-TCPamongschool-agedchildren.Wefoundthatexposureto2,4,6-TCPwasassociatedwith parentalreportofadiagnosisofADHD.Wealsodemonstrated asigni cantdose e responserelationshipbetweenexposureto 2,4,6-TCPandADHD.Incontrast,wedidnot ndasigni cant associationbetweenexposureto2,4,5-TCPandADHD.These ndingssuggestthat2,4,6-TCPmayhavedifferenthealtheffects than2,4,5-TCP,whichisconsistentwithpatternsofassociation previouslyreportedintheliterature.Experimentalevidence suggeststhat2,4,6-TCPbutnot2,4,5-TCPisassociatedwith increasedrisksofmultiplecancers.28 29 Both2,4,6-TCPand2,4,5-TCParemembersofafamilyof organochlorinepesticideswhicharealargeclassofmultipurpose chlorinatedhydrocarbonchemicalsthatbreakdownslowlyin theenvironmentandaccumulateinfattytissue.Thepresenceof urinaryTCPsindicatesdirectexposuretothesechemicalsor otherorganochlorinepesticidesincludinghexachlorobenzene (HCB)andhexachlorocyclohexanes(HCH)whichmetabolise toTCPsinhumans.30 31AlthoughmanyorganochlorinepesticidesarenolongerwidelyusedintheUSA,childrencanbe exposedtothesechemicalsthroughdietandcontaminatedair becauseoftheintensiveuseofthesechemicalsinthepast,and theirlipophilicandchemicallystablecharacters.32Exposureto Table1 Weightedfrequencyofselectedcharacteristicsforchildren aged6 e 15yearswithandwithoutparentalreportofattentiondecit hyperactivitydisorder(ADHD),NHANES,1999 e 2004Characteristics Parent-reportedADHD Yes(n [ 200)No(n [ 2339) N(95%CI)N(95%CI) Gender* Female25.1(17.1to33.2)50.2(47.4to53.0) Male74.9(66.8to82.9)49.8(47.0to52.6) Race/ethnicity* Non-Hispanicwhite71.7(62.8to80.7)59.6(54.2to65.1) Non-Hispanicblack13.0(9.5to16.6)15.7(12.4to19.1) MexicanAmerican4.7(2.7to6.7)12.4(9.3to15.4) Other10.5(2.6to18.5)12.2(7.8to16.5) Poverty-to-incomeratio < 127.1(18.5to35.7)22.2(19.8to24.6) 1 e 228.2(20.0to36.4)25.8(22.5to29.1) $ 244.6(34.6to54.7)52.0(48.5to55.4) Bloodleadlevels( m g/dl) 1sttertile( # 1.0)39.0(27.7to50.4)42.5(38.1to46.9) 2ndtertile(1.0 e 1.7)30.6(21.6to39.5)28.6(25.7to31.5) 3rdtertile( $ 1.7)30.4(19.0to41.8)28.9(25.5to32.3) Maternalprenataltobaccouse* Yes33.5(23.7to43.2)16.7(13.8to19.6) No66.5(56.8to76.2)83.3(80.4to86.2) Infantbirthweight < 2500g13.2(6.2to20.1)6.9(5.9to8.0) $ 2500g86.8(79.8to93.8)93.0(92.0to94.1) Serumcotininelevels(ng/ml)* 1sttertile( # 0.035)21.1(11.4to30.9)36.8(31.7to41.9) 2ndtertile(0.035 e 0.283)23.0(15.5to30.4)30.0(26.6to33.4) 3rdtertile( $ 0.283)55.9(47.3to64.5)33.2(29.7to36.70) Childage(years)*11.2(10.7to11.6)10.4(10.2to10.6)* pvaluefromaWaldc2testislessthan0.05. Table2 Distributionofcreatinine-correctedconcentrations( m g/g)ofurinaryTCPsamongchildrenaged6 e 15yearsinNHANES,1999 e 20042,4,5-TCP2,4,6-TCP DatacycleN < LOD(%) ‡ LOD N < LOD(%) ‡ LOD Median( m g/g)Range( m g/g)Median( m g/g)Range( m g/g) 1999 e 200084850.51.180.25 e 66.084512.03.710.34 e 1772.1 2001 e 2002101395.26.170.51 e 124.7101833.34.760.68 e 106.6 2003 e 200465761.30.120.03 e 5.265762.10.650.16 e 22.2 Overall251870.81.030.25 e 124.7252033.63.580.16 e 1772.2LOD,belowthelimitofdetection;TCP,trichlorophenol.OccupEnvironMed 2011; 68 :557 e 561.doi:10.1136/oem.2010.063859 559 Originalarticle

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thesechemicalsmayoccurearlyinlife.33Althoughinformation onthepotentialhealtheffectsofHCBandHCHonchild neurodevelopmentislimited,evidenceofneurotoxicityin humansexposedtoorganochlorinecompoundsincludingHCB andHCHhaspreviouslybeenpresented.3435Severalstudies suggestthatprenatalexposuretoorganochlorinecompoundsis associatedwithanincreaseinADHDsymptomsamongchildren at4yearsofage.36 e 39Therefore,theobservedassociation betweenurinary2,4,6-TCPandADHDinourstudydoesnot excludethepossibilitythattheADHDiscausedbyHCBand/or HCHexposures. Theobservedassociationalsosuggeststhatdirectexposureto 2,4,6-TCPdirectlyaffectschildneurodevelopment.However, thereislimitedinformationontheneurologicalhealtheffectsof 2,4,6-TCPinhumans.Because2,4,6-TCPisoneofthemajor chlorinatedorganiccompoundswhichareformedduringwater disinfection,childrencanbeexposedtothechemicalthrough drinkingwater.40 Con rmationofadirecthealtheffectof 2,4,6-TCPonchildbehaviouraldevelopmentwouldunderscore theimportanceoffurtherexaminingthepotentialneurological healtheffectsofprenatalandpostnatalexposureto2,4,6-TCP throughchlorinateddrinkingwater. Ourstudyhasseveralstrengths.First,alargepopulation-based samplewasusedtoexaminetheneurologicaleffectsofTCPsand valuableinformationontheeffectofbackgroundexposureto TCPsonchildneurodevelopmentinthegeneralpopulationwas collected.Second,weusedbiomarkersinurinetomeasure exposurestoorganochlorinecompounds.Thismethodprovided anoverallmeasurementofchemicalexposuresfromallsources andamoreaccuratemeasurementofbodyburdenofexposure. Third,awideofrangeofpotentialconfoundersincluding demographicfactorsandotherenvironmentaltoxinssuchaslead andETS,wasincludedinthemodels.Moreover,theexposuresto environmentaltoxinsweremeasuredusingbiomarkersinserum, whichcouldminimisemisclassi cationerrors.Fourth,totest thereliabilityofourestimationweconstructedseveralmodels withdifferentcovariatesandfoundconsistentresults.Our analysesprovidedreasonablyconsistent ndings,whichare strengthenedbyanobserveddose e responserelationship. Severalpotentiallimitationsshouldbeconsideredwheninterpretingtheresultsofourstudy.First,althoughtheuseofurineas amatrixtodeterminebiomarkersofexposureisespecially suitableforcompoundssuchasTCPsandothermetabolites, urinarylevelsmayre ectrecentexposure.Inaddition,thelarge variationinTCPlevelsbetweendatacyclessuggestsdataerrors duringtestingand/ordataprocessingunlessurinaryTCPsvaried greatlybetweendifferentcycles.Second,sincethisisacrosssectionalstudy,wecannotinterpretourresultsasproviding evidenceofacausalrelationshipbetweenearlyexposuretoTCPs andsubsequentriskofdevelopingADHD.Third,ascertainment ofADHDwassolelybasedonparentalreportwithoutcon rmationofdiagnosisthroughmedicalrecordabstractionor administrationoftheDiagnosticandStatisticalManualof MentalDisorders,FourthEdition(DSM-IV).Administrationof theDSMwouldprovideinformationonADHDsubtypesand behaviouralsymptomcounts,andincreasespeci cityindetecting behaviouralproblems.AlthoughdatafromtheDSM-based ADHDdiagnosticinstrumentsareavailableinNHANES,thereis limitedaccesstothisinformation.Inaddition,misclassi cationof ADHDfromparentalreportwouldmostlylikelyresultin underestimationofthetrueassociationbetweenTCPsand ADHD.Futureprospectivecohortstudieswithbettermeasures ofTCPexposureandbetterascertainmentofADHDareneeded tovalidateour ndings.Fourth,thedataavailableoncovariates suchassocioeconomicstatusandearlychildhoodfactorswere obtainedthroughpersonalinterviewofaproxyrespondentof achild ’ sfamilyandmaybeinaccurate.Finally,althoughmany importantcovariatesandpotentialconfounderswereincludedin ouranalysis,wewereunabletoadjustforthepotentialeffects ofotherimportantcovariatesincludingparentaleducation, breastfeeding,geneticfactors,psychosocialstressors,other prenataland/orpostnatalenvironmentalfactorssuchasprenatal alcoholdrinking,exposuretopolychlorinatedbiphenyls,dioxins, phthalateandbisphenolA,andparentalpsychopathology. Nevertheless,ourresultssuggestthatexposuretoorganochlorinecompoundsmaybeassociatedwithincreasedriskofADHD amongschool-agedchildren.Our ndingsunderscorethepotentialbehaviouralhealtheffectsofthesechemicalsandhighlight theneedtostrengthenpublichealtheffortstoreduceprenataland postnatalexposuretothesecompounds,especiallyincountries whereorganochlorinepesticidesarestillcommonlyused. Competinginterests None. Ethicsapproval ThisstudywasconductedwiththeapprovaloftheUniversityof FloridaIRB. Provenanceandpeerreview Notcommissioned;externallypeerreviewed.REFERENCES1. TaiC, JiangG.Dechlorinationanddestructionof2,4,6-trichlorophenoland pentachlorophenolusinghydrogenperoxideastheoxidantcatalyzedbymolybdate ionsunderbasiccondition. Chemosphere 2005; 59 :321 e 6. 2. ATSDR. Toxicologicalproleforchlorophenols[online] .1999.http://www.atsdr.cdc. gov/toxproles/tp107.html(accessed21May2010). Table3 ORsand95%CIsfromlogisticregressionanalysisfortheassociationbetweenurinary trichlorophenolsandattentiondecithyperactivitydisorderamongchildrenaged6 e 15years,NHANES, 1999 e 2004ChemicalsTotalsample(n)Cases(n)CrudeoddratiosAdjustedoddratios* 2,4,5-TCP BelowtheLOD1776145ReferentgroupReferentgroup < Median(1.03 m g/g)367301.27(0.78to2.06)1.01(0.47to2.20) $ Median(1.03 m g/g)368240.89(0.48to1.65)0.98(0.48to1.99) pfortrend ee 0.720.95 2,4,6-TCP BelowtheLOD84656ReferentgroupReferentgroup < Median(3.58 m g/g)834841.84(1.25to2.72)1.54(0.97to2.43) $ Median(3.58 m g/g)834591.56(1.12to2.16)1.77(1.18to2.66) pfortrend ee 0.0080.006* Adjustedforage,gender,poverty-to-incomeratio,maternalsmokingduringpregnancy,lowbirthweight,bloodleadandserum cotinine. LOD,limitofdetection;TCP,trichlorophenol.560 OccupEnvironMed 2011; 68 :557 e 561.doi:10.1136/oem.2010.063859 Originalarticle

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