Document pBYbGjovkO961YvML0XwoL2Qw

ag226-375"pY, FETAL EXPOSURE TO PERFLUORINATED COMPOUNDS: DISTRIBUTION AND DETERMINANTS OF EXPOSURE AND RELATIONSHIPS WITH WEIGHT AND SIZE AT BIRTH. by Benjamin Joseph Apelberg, M.H.S. A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degreeof Doctor ofPhilosophy Balimore, MD August 2006 CONTAINS NO CBI ` Benjamin Joseph Apelberg 2006 All rights reserved 2 30K45.2b 2 UM Number: 3240663 Copyright 2006 by Apelberg, Benjamin Joseph Allrights reserved. INFORMATION TO USERS C "The quali of this reproduction is dependent upon the quality of the copy psuhbomtiotgerda.phsB,ropkriennt loreeidn-ditshtrinocutgphr,ins,ubcsotlaonrdedarodr mpaorogrinqsu,aliatnydiliumsptraotpieorns and ` alignment can adversely affect reproduction andItnhtehree uanrleikmeilsysviengntpatgheast,thteheasuethwoirlldbiednnootteds.enAdlsao,coimf pulneauttehmoarnizuesdcript copyright materia had fo be removed, a note wil inicate the deletion. --------------------_ 4 . UM! Microform 3240663 `Copyright 2007 byProQuestInformation and Learning Company. Allright reserved. This microform edition is protected against unauthorized copying under Tile 17, United States Code. e ProQuest In3f0or0maNtoirotnhaZnedebLeRaornaidng Company AnnArbP.oOr., BMoIx481130465-1346 . : 3 ps Tmhaissteirs acnopayutohfortihzeedorfiagcisniamlildei,ssmeartdaetifornoomrthmeasmtiecrrtohfeislims published by UML cental source for accessing almost every doctoral `The bibliographic information for this thesis is contained in UMI's Dissertation Abstracts database, the only dissertation accepted in North America since 1861. uMIDiSsesrevritcaetsion From:ProQRuest Ao Aor3,00M7iN.c0ohBtgoaZnx4e19014a086-c1346 USA os2orboei0r0 ons7aaczoemrr0 roti2007bLyidlosc cess 0 I | | 25 vs Abstract BACKGROUND: Perfluorinated compounds (PFCs) such as perfluorooctane sulfonate (PFOS) and perfluorooctancate (PFOA) are surfactants used in a variety of commercial oafndwiinddusetriaanldapbpulimcaatniobnlso.odReaceontwsctoundcieesnthraavteiodno.cuFmienndtinegdswfidoemsparneaidmacosnttamiinaativoen included developmental toxicity; however, limited data exist on the extent of in utero exposure in humans. Thepurposeofthis dissertation is to describe the distribution and determinants of in utero exposure to PFCs and the relationship between cord serum concentrationsofthese compoanudsnizdeansd weight at birth. METHODS: A cross-sectional study of singleton newborn deliveries was conducted at the Johns Hopkins Hospital in Baltimore, MD. Cord blood samples were collected from the umbilical cord vein following delivery. We abstracted matemal and infant characteristics from clinical records maintained by the hospital. Cord serum samples were analyzed for 10 PFCs by online solid-phase extraction, coupled with reversed `phase high-performance liquid chromatography-tandem mass spectrometry. RESULTS: PFOS and PFOA were detected in 99 and 100 percent of samples, respectively, at concentrations lower than typically reported in adult serum collected from other regions in the United States. Other PFCs were detected less consistently. There were relatively few predictors of cord concentrations among the demographic characteristics available from the medical record, with the excepotfiroacne. On average, Asians and Blacks had higher PFOS concentrations than Whites. After adjusting for i 26 ps ` potential confounders, both PFOS and PFOA were negatively associated with birth weight and ponderal index. A negative association was also observed with head ` circumference among vaginal but not Caesarian deliveries. In contrast, no consistent i trendwas observed between PFOSor PFandO newbAom length. i CONCLUSION: The findings of this research confirm thai utero exposure to PFCs is ! occurring among babies bom in Baltimore City. Despite the relatively low serum Pk concentrations compared to adults, we detected negative associations between PFOS and PFOA concentrations in cord serum and birth weight, head circumference, and ponderal index. Given the limited data on in utero exposure to PFOS and PFOA and effects in humans, future studies are neetodconefirdm these findings. Thesis Advisor: Lynn R. Goldman, M.D, MPH, (Advisor), Epidemiology Thesis Readers: `Thomas A. Burke, Ph.D., M.P.H,, (Chair), Health Policy and Management Jonathan M. Samet, MD., M.S., Epidemiology ` FrankR. Witter, M.D, School ofMedicine RolfU. Halden, Ph.D, M.S., Environmental Health Sciences | Brad C. Astor, Ph.D, Epidemiology 2/7 07 Preface Thsdisertatonisorgeizdfnmance format. Chapter | presetsanroducion the dissertation. Chapters 2-4 make up the manuscript portion of the dissertation. Chapter2 isa literature review of PFOS and PFOA production, exposure, and toxicity. Chapter 3 is a manuscript describing the distribution and determinants ofcord serum PFC concentrations. Chapter 4 examines the relationships between cord serum PFOS and PFOA concentrations and measures of size and weight at birth. Chapter 5 summarizes the findings and implicationsofthis research. The appendices included at the end of the dissertation detail the extensive analyses conducted in supportofChapter 4. " od ps | Acknowledgements "This dissertation is the culminationofyearsofhard work and dedication, but could not ! have been completed without the supportof many people. 1 would like to thank my advisor, Dr. Lynn Goldman, for her support and mentorship during my time as a PhD student at Johns Hopkins. Dr. Goldman provided me with tremendous encouragement and advice throughout this process and her passion for her work and commitment to teaching and mentoring provide an example for me to strive for in my future professional development. T would like to acknowledge my thesis committee, comprisingofDr. Lynn Goldman, Dr. Jonathan Samet, and Dr. Xuguang (Grant) Tao, who provided valuable comments on my , research proposal. My dissertation readers, comprising of Dr. Lynn Goldman, Dr. "Thomas Burke, Dr. Jonathan Samet, Dr. Frank Witter, Dr. Rolf Halden, and Dr. Brad `Astor, provided critical feedback on draft versions of my dissertation. Their comments l i and suggestions contributed substantially to the developmentofthis work. In addition to 1 his role as a committee member, I would like to acknowledge Dr. Samet, whom I | consider amentor,forhis support and advice throughout my time as a student, ` J Tam especially indebed to Dr. Antonia Calafa, Dr.ZsuzsannaKuklenyik, and Dr. Larry Needham at the Centers for Disease Control and Prevention, who conducted the ' laboratory analyses for this study and provided insightful comments throughout the developmentofthis research. . a7 This dissertation was conducted within a broader research effort, called the Baltimore: `THREE Study. There are many individuals who have contributed to the success of this study. I would like to acknowledge the study principal investigators: Dr. Lynn Goldman, Dr. Rolf Halden, and Dr. Frank Witter, who provided great feedback and advice throughout the courseofthis research. I would like to thank Dr. Julie Herbstman, a friend and colleague, whose contributions were essential to the `successofthe study. Julie and I spent many hours collecting, storing, and shipping samples; abstracting and cleaning medical data; creating databases to house this information; and discussing `methodsofdata analysis. The following individuals also contributed to the successofthe Baltimore THREE Study: Jochen Heidler, Ruth Quinn, Ellen Wells, Carol Resnick, Dr. `Todd Miller, Dr. Ana Navas-Acien, David Colquhoun, and Sharron Hawkins. . `This study could not have been conducted without the exceptional cooperation of the `nursingstaffin the Labor and Delivery Unitofthe Johns Hopkins Hospital. Their tireless effort and commitment to collecting samples were critical tothestudy's success. T could not have achieved this without the help and support of my family, Estelle, Jacob, and Eytan. The impact of their unconditional support not only during this time, but throughout my life, is immeasurable. Finally, I am thankful for the friends with whom I have shared many great experiences during this time, including Meredith Shiels, Brett Ange, Erika Avila-Tang, Nrupen Bhavsar, Sufia Dadabhai, Jeanine Genkinger, Aimee Kreimer, Eric Richardson Maiese, Keeve Nachman, Rebecca Nachman, Sharon Nappier, and Matt w : LX0 p10 ` Table of Contents ACKAOWICAGEMENS...creeresssenssessssessnssssensrensonV . Listof Figures.......... - serssseses essaemsmemsommsso----------_k | Chapter 2: Perfluorinated Compounds: Production, Use, Exposure, and Toxicity .......9 Clipe: Dibuion nd Dele ofPelmied Compounds in Cord Bio, ` Chapter 4: An Epidemiologic InvestigationofFetal Exposure to Perfluorinated CHAP : COIUSONS.rrcss `Compounds and the Relationship with Weightand Size at Birth............cco.ccursesnnsis 87 123 . ADDEGES conn 146 APpOpReGnEdEiSxIAO:GERKery Derterminants of Birth Weight, Head Circumference, Length, a1n5d1 . Appendix B: Representativenessof Study Poa pulation and Subjects with Missing1 Appendix C: Full Model Results for Multivariate Regression Analyses ............ 165 hb Appendix D: Birth Weight Regression Sensitivity Analyses ............cuerveees 174 Appendix E: Newbom Head Circumference Regression Sensitivity Analyses... 150 Appendix F: Newbom Length Regression Sensitivity ARalses................ 186 ` Appendix G: Newbom Ponderal Index Regression Sensitivity Analyss........... 192 Appendix H: Relationships between PFOS or PFOA and Serum Lipids............. 200 | vit A2/ pt List of Tables Table 2-1. Summaryofstudies measuring PFOS concentrations in humanblood. . 32 Table 2-2. Summaryofstudies measuring PFOA concentrations in human blood... 34 `HTaUblBeS3-O1.FNPGer/flMuLor.inated chemicals (PFCs) measured in cord blood serum and reported68 ``Tcaobnlceen3t-r2a.tiRoanstiionsc(oarnddb9lo5o%dcsoenrfuimdebnycemaintteemrvaallsa)ondfignefoamntetcrhiarcamcteearinstPiFc.OS............ 69 `c"TToaanbbclleeen4t3-r-13a..tioSRntastuidioynscP(oOarPndUdIb9alto5oo%ndcsCoenrHfuimdAebnyTcemAainttCeemrvaIallEsa)onIdfgiSenfoaSmnett.crhi.acra.mctee.arins.tPiFrcO.Ac....r...r..r....17080 `Table 4-2. Distributionofcord concentrations ofBOS and PFOA and study endpoints. ET TPaFbOlSeo4r-3.PFEOstAimcaotnecdencthraatnigoensinebqiuratlh twoeiognhetIan-nudnibtirotrhfsrizoemptahrea2me5tertos7w5i%tphearccehnatnilgee.in110 Tcoanbcleent4-r4a.tioCnh,aanmgoenign ChaeeasdacrieracnumsefcetrieonnceanwditVhagaiunanltAcehlainVgeeTiens.I.n.(.PF.O.S.)..o.r.Iono(.P.FuO.A)111 TPaEbOlSe 51-1G. PBFeOncAhmark Dose Estimates from Sem lected Des velopmens tal Toxic, ity Studies1o3f0 Table 5-2. Data gaps and Faure FeSEarch NEES. occ 140 viii FHI2 p12 List of Figures Figure 2-1. Chemical structureof PFOS (19p) and POA (BHO)... 36 FOiFgSuerreu2m-,2.0SmumBmMaAryDoDfImOeMdOiRaOnFoIrNgmeSaUnESP.F.O.S concentrations (ng/mL) in blood plasma3.1 FOFigSuerreu2m-3.0mSuHmUmMaArNyoDfIOmMedOiBaOnFoNrgmeSaInEP.F.O.A concentrations (ng/mL) in blood plasm3a8. ` FEiXgPurOeS2E.41.0 PEEnrvIiUrOoTnmNeRnItEaAlCpOubMliPcOhSea.l.th.paradigm and possible pathways ofhuman 39 Figure 3-1. DistributionsofPFOS and PFOA concentrations in cord blood serum... 71 F3igEurOe 3-2n . Comm elatis on bet-- ween-- PFOS-- and P-- FOA-- concen-- tratio-- ns in-- cord b-- lood s-- erum (TnR Faingdairnete3-r3q.uarDtiislterFiabnugtei)onboYfsPeFleOcSt EanDdAPFTOAACcoAncEentTraStiConSs i.n c.or.d.bl.oord srerrumr(nmesdia7n3 ` Fmiagtuerrena3l-p4,rePpRrOoSga(atnocpy)baonddyPmFaOssA (Inbdoetxto(m)Rco=nc2en8tr8at)io.ns.in.c.or.d b.lorodvsrereumovneresus74 FBigCureE3-58. 6P(FFO2S99(t)o.p.).and PFOA (borttromr) concentrationsi cord blood serum versus15. FEiOgSurGeO3N-6L. 8GPFO(S1=(o2p9)9)an.d PFOA (bottom) concentrationsi cord blood serum versus76 . Fwiigtuhr(en3.-=72.86P)FaOnSd (wnigth/omuLt) (vaer=su2s11c)ottihneinienc(lnugs/iomnL)ofcnoonnc-ednettreacttiaonbsleincoctoirndinbelovaolduess.e.r.u.m,77 wFiitghur(en3=-8.286P)FaOnAd w(igt/hmouLt)(vne=rs2u1s1c)ottihneiinnec(lunsgi/omnLo)fcnoonnc-ednettreacttiaobnlseicnoctoirnidnbelvoaolduesse.r.u.m7,8 : FGiOgTurBeI3-O9. SCEoTmUpaOrFisPonAoSfmIe.an.P.FOr S and PFOAo concentratis ons (ngiml)s measured in19 Figure 4-1. FIOWchartfSudPOPUZHON. ccc 112. . FJigUurSeT4-E2. 1H0FeaPdONctiiraculmCferOenRceSveOrsuUs DIn(EPFTOS.) a.nd.I.n(rFO.A)e, brefroreramndrafteer oe. 13 FOiFguPrOeIC4A-3i.alPCoOnRdOeUrIaIlEiRnSd.ex versus Ir n(PFOS) andr In(FOA),r before and a, ftr adjustmen1t14 . p13 Figure 4-4. Relationship between head circumfereancned PFOS, usinglog-linearand FEiOgEu.r.e.4-5. Relationship betweenm ponderalinds exand PFOS,s using log-l, inearandlinea1r16 x SAF p14 ` CHAPTER 1 . INTRODUCTION 1 SHS p15 Perfluorinated compounds (PFCs) comprise a `class of man-made, fully fuorinated organic. compounds that have been used in a variety of consumer and industrial applications for more than 50 years. These products include protective coatings for foodcontact packaging, textile, carpet, and leather; non-stick cooking material; commercial and industrial surfactants (c.g. fire-fighting foams, electroplating baths); and insecticides (12). Although produced for many years, only recently have reports been published suggesting widespread exposure in wildlife and humans (3-5). The identification of pervasive exposureofthe general USS. population to one PFC, perfluorooctane sulfonate (PFOS), led its major manufecturer to announce in 2000 the phase-out of perfluorooctanyl-based products (6). The U.S. Environmental Protection Agency (EPA) has been evaluating a structurally-related compound, perfluorooctanoate (PFOA), on the basisof potential carcinogenic and developmental risks (7). PFOS, PFOA, and related compounds have recently drawn regulatory and scientific attention due to their extreme persistence in the environment and biological systems, `widespread contamination in the blood of wildlife and humans, and potential toxicity. Developmental toxicity is among the effects observed fiom PFOS and PFOA dosing in animal studies, including pregnancy loss, reduced birth weight, decreased gestational Tength, structural defects, developmental delays, and increased neonatal mortality (8-18). Although recent evidence suggests widespread human exposure to low levels of PFCs, there are limited data on fetal exposure to these chemicals and the potential effects of exposure on birth outcomes. Describing the extentof fetal exposure is important because. 2 FA6 p16 the fetus may be particularly susceptible fo chemical exposures due to its rapid cellular `rowth and differentiation. ` There are significant public health implicationsofdisruptions to normal fetal growth and . development. Babies bom carly or with low birth weight (<2,500 grams) ae at increased isk ofmortality in thefistyearof life (19:20). Babies bom smallo tin for gestational age due to fetal growth restriction are at greater risk for perinatal and childhood 0 morbidity, including hypothermia, hypoglycemia, andlor asphyia (21-27), neonatal intensive care unit admission (28), respiratory distress syndrome (29), reduced mental development in infancy (30), cerebral palsy (31), and reduced insulin sensitivity, a ` marker of type I diabetes isk (32). In addition to the neonatal and childhood impacts associated with fetal growth restriction, a growing body of research suggests that some. metabolic diseases in adulthood may have their origins in fetal development. Over the ' last decade, a number of studies conducted in different countries have shown that small size at birth, modified by rapid childhood growth, is associated with coronary heart ; disease, type TI diabetes, and. their metabolic risk factors, including hypertension, hyperlipidemia, and reduced insulin sensitivity (33-38). "The goal of this research was to describe the magnitude and determinants of in utero exposure to PFCs and the association between cord serum concentrations of these compounds and measures of size and weight at birth. This research was conducted ` through the implementation of a hospital-based cross-sectional study of newbom deliveries at the Johns Hopkins Hospital in Baltimore, MD. From late 2004 through early 3 327 ' 7 2005, cord blood specimens rom a sample of deliveries occurring at the hospital were collected and information from medical records was abstracted for the mothers and infants In Chapter 2, I begin with a review of the literature on PFOS and PFOA, including production and use, human biomonitoring, exposure pathways, animal toxicity, and occupational epidemiology studies. In subsequent chapters, I describe the designofthe cross-sectional study used to address the specific aimsofthis study. Chapter 3 focuses on the magnitude, distribution, and determinants of fetal exposure to PFCs. Chapter 4 preseats the results ofan epidemiological investigation into the association between fetal PFOS and PFOA exposure and measuresofbirth weight and birth size. The results of this research provide data on the extent to which in wero exposure is ocurring among pregnancies in Baltimore, MD. Such data are useful in the translation of developmental toxicity studies in animals to the estimation of potential human risk. Identification of determinantsofcord concentrations may provide insights into exposure pathways and means for reducing human exposure. Finally, the epidemiologic investigation examines whether these data are consistent with an effect of PFOS or PFOA on birth weight and birth size parameters at environmentally-relevant concentrations. 4 R28 p18 References (1) KMiasrscaelE.DeFlkukoerri,naIntce.d,s2u0r0f1a.ctants and repellents. Second ed. New York, NY: (2) 3DoMckCeotmp#aOnPyP.T-F2l0u0or2o-c0h0e4m3i.ca1l99u9s.e,5d-i2s6t-r1i9bu9t9i.on, and release overview. EPA ` RefType: Report (3) Kaslea.vnePnreaarlfnlcKuoou,nrtCorooircestsoa.lnieEnsniuvlSif,rooFnnaatlSeacniadnyTdsezcrehJln,aotileld2l0fm0la4un;onr3o8Gc(,h1e7Km)ui:cm4aa4l8rs9-Ki4nS4,h9u5L.moagnanbaltohoadnfBrGomet , (4) EGniveisryoJnP,ScKiaTnencahnnoKl.2G0l0o1b;al35d(i7s)t:r1ib3u3t9i-o4no2.fperfluorooctane sulfonate in wildlife (5) aPCneadrlaf2fl0au0to2rA.oMcEh,nevmKiiucrkaollnesnSyieinikpToeZo,clhCenadoulsdie2lr0lu0m6S;Ps,a40mR(pe7li)ed:sy21Jf2Ar8,o.m-N2eU1n3e4id.theadmStLaLt.es residents in 2001 (6) 3DoMckCeotmp2a0n02y-.00L4e3tt-e0r00to9.EP2A00r0e.: SpthPaasuel-,ouMtNp.la1n9f0o7.rPOSF-based products. EPA. RefType: Report (7) hUsaulStmsaE(nnPvhFieOraAol)nt.mheehnfttfpae:cl/tPs/rwaowstwse.ocectpiiaaot.negdAogvwe/iontpchpyte.ixnpDtor/sapufftroerai/tsopkfpaoessrrsfielssuksomrhoetonctmota.fn2to0hi05ce.apcoitdenatinadl its RefType: Electronic Citation (8) TEhxipboosdueraeutxo JpRe,rfHlauonrsooonctRaGne, sRuolgfeornasteJMd,urGirnegyprBeEg,nBaanrcbyeienBraDt,anRidcmhoaursdes.JIH: et al. ! `matemal and prenatal evaluations.Toxicol Sci 2003; 74(2):369-81 (9) pGerrafsltuyoRroCo,ctGarnecysBuElf,oLntaeu-CinSd,uRcoegdenresonJaMt.alPmroernattaallitwyiinndtohewoSfprsuasgcueep-tiDbaiwllietyytroat, Birth Defects Res Part B Dev Reprod Toxicol 2003; 68(6):465-71. (10) ELxapuoCs,urTehitboopdeerafluuxoJrRo,ocHtaannesosunlRfoGn,atReodguerrisngJMp,reGgrneayncByE,inSrtaatnatnodnMmoEueset,aI.T: postnatal evaluation. Toxicol Sci 2003; 74(2)382-92. (11) rLfaurseo:bmkdioensrueDt-eJrre,osYpeooxnrpskoes,RuGar,nedHtobainpoescrehfnelumKoiJrc,oaolMcotaoannrdeespuhJlaAfr,oanBmaautcetoe(kiPnnFheOtoSifJ)cLf.pinaNrSeapomnreaattgearulse.-mDoratwalleiyty Toxicology 2005; 215(1-2):149-169. 5 229 p19 (12) LguecnberkaetrioDnJ,reCparsodeuMctTi,onYaonrdkcRrGos,s-Mfoosotreer sJtAu,diHeasonsfepneKrfJl,uBoruotocetnanheosuJflLff.oTnawtoe(FOinSra)ts. Toxicology 2005; 215(1-2):126-148, (13) FdueevnetleospmSe,nCtoallotmoixincaolMoTgy,:RCoodnrciugrureezntJ,eVxipcoesnusreP,toDopemrifnlguooroJoLc.tIannteersaucltfioonnastein (PFOS) and stress in pregnant mice. Toxicol Lett 2006; 164(1):81-89. (14) LacaiudsC,aBnudttehneihrodfefriJvLa,tiRvoegse.rTsoJxMi.colThApepdlePvehloapmremntaa2lc0to0ox4li;ci1t9yo8(f2p)e:r2f3l1u-o4r1o.alkyl (15) BruetpreondhuocftfiJvLe,toKxeincnoleodgyy GoLfa,mJmr,oFnriaumme Toxicology 2004; 196(1-2):95-116. pSeRr,flOu'oCroonocntoarnoJaCt,eY(oArPkFROG).inTthhee rat. (16) YstourdkyoRfG.amOrmaoln(iguavmapgeer)ftlwuoor-ogoecntearnaotaitoen((AoPneFOli)teirnpreatrs.gen2e00r2a.tioHno)rsrehparmo,duPcAt,ion R`eArfgTusypRee:seRaerpcohr.t1926. (17) UdsaeSlvStesE.lnoUvpSimrEeonPntAmaelDntotocaxkliecPitrtoOytPaePscTsto-ic2oin0a0tA3eg-de0nw0ci1yt.2h-eP0xr0pe0ol2si.umir2ne0a0tro3y.preiOrsffkflaiuscosreoeosofcsPtmoaelnnlotuiotcfiatocnhied and ts RPerfevTeynpteio:nRaenpdorTtoxics; Risk Assessment Division. 1910. (18) LaTloa.xuEifcCfo,elcTtShscioibf2o0pde0er6af;ulx9u0oJ(rR2o,)o:cH5ta1an0ns-o5oi1cn8a.RcGi,d eNxaproostusrkey dMuGri,ngRopgreergsnaJnMc,y LiinntdhsetmrooumsAe.B et (19) sAtsaitaisstEc,sM-2a0c0D2.orPmedainatMrFic,sS2t0r0o3b;in1o1D2(M6,PtGu1y)e:1r21B5.-A3n0.nual summaryofvital (20) oHfoyvietratl DstLa,tisMtaicts:he2w00s4.TJP,eMdeiantarcikcser20F0,6S;tr1o1b7i(n1o):D1M68,-1G8u3y.er B. Annual summary (21) iPsatgtreorwstohn rReMt,arPdoeudl?iAotmMJRO.bsNteeotnaGtyanlecmoolrp1h9o8m7e;tr1i57c(s3a):n6d9p1e-r6i9n3a.tal outcome: who (22) ADaonmcdtJnoeOrobnBsatAte,atlOGo'yuRntiecocroodmlaens2o0M0fA1,s;ma1Kl8il5r(cf3ho)nr:e6gr5e2sH-tL6a,5ti9So.nhaalhaDg,e HinafcakntMs.boPemriantattaelrmcogrersetlaattieosn. (23) WsMtaealtdtuhs1ea9rt82Fb;iJr,t1Rh0a(a1mn)ad:e4tk2se-4rr7se.lLatHi.onTthoespoomnedearsaplecitnsdoefxnaesoanamteaalsmuorreboifdtithye. nJutPreirtiinonaatl 6 5.20 (24) NdiiseptroopAo,rMtiaotnoartreaisnRtr,aVuitlelrairneJ,grSoerwrtahMr.etaNredoantaitoanlatmotrerbmi.diJtOybasstseotciGaytnedaewciotlh 1998; 18(6):540-543. (25) KinrtarmauetrerMinSe,gOrloiwvtiherreMt,arMdcatLieonananFdHb,oWdiyllpirsopDoMrt,ioUnsahlietryRoHn.feItmaplaacntdonfeonatal outcome. Pediatrics 1990; 86(5):707-713. . (26) bLyubbcihrtehnwceoiLghOt,aBnadrdgeHs.taItniocniadlenacgee.ofPehdyipaotrgilcysce1m97i1a;in47n(e5)w:b8o3r1n-8i3n8f.ants classified (27) DArcocsusroaucyVo,fDaintahmraonptomEe,tNroiuctmseiaasHu,reKmoensnttasntiinnpirdeidsicTt,iKnagtssyomupgtioamnantoipcouSlGosAVa.nd } LGA neonates. Acta Paediatr 1995; 84(1):1-5. (28) TnMeaeomdnai2tma0l0H4,o;uBt3ec2oy(m6de)os:u:5n0b9Hi-,r5t1th3aw.neiigMht,,KbhoodgyalmiasMs,iCnhdoekxerorI,pYounndiesraKlAi.ndPerxe?diJcPteinrginat (29) RRoLbeerttasl.onNePoAn,atSanlimdoerrbmiadnitSyH,acLcaorrodsinRgKt,o Jgre,stCatoiwoananl Ra,geHeainldbrbiornthD,weGioglhdtenfbreormg, Gyfimveecteorltia1r9y9c2a;re1cen6tePrts61i)n:1t(6h2e9U-6n4i1t.ed States, 1983 through 1986. Am J Obstet : (30) VayeinaldrlsmaoeJnf,tlaSilmfee.dreiPvgeeldiliaootpVrm,iecnMstaor1t9fo8r4ie;nltl7r4aRu(,t5e)Br:ir7no8e3w-gn7r9oC1wH.t,h-KrleetiarndReEd.inHfeatnetrsodguernienogutshegrfiorwstth3 (31) JClaicnoObbssotnetB,GyHnaagebceorlg2G0.04A;nt1e8n(a3t)a:l42i5s-3k6.factors for cerebral palsy. Best Pract Res . (32) Hetoalf.maInnsuPlLi,n CreustifsitcalndceWSin,sRhoorbtincshiolndrEeMn,wiBtehrignmtraanutReNri,neMgernoownthRrKe,taSrpdeatriloinn.gJMA Clin Endocrinol Metab 1997; 82(2):402-406. (33) `BSaurpkpelr):DJ5.88TS-h5e95d5e.velopmental origins ofadult disease. JAmCollNutr 2004; 23(6 (34) BsatrreknegrthDoJf, EefrfiekcstssoannJdGb,ioFloorgsiecnalT,baOsissm.oInntdJCE.piFedteamlioorlig2i0n0so2;f3a1d(u6l)t:1d2i3s5e-a9s.e: (35) SR0o0bi2n0s0o2n;S6M1(,4)B:a5r3k7e-r54D2J.. Coronary heart disease: a disorder ofgrowth. Proc Nutr (36) Bianrsukleirn-DdJe,pHenadleenst)CNdi,sFbaeltlesCmHe,llOitsums,onhydpCe,rtPenhsiiopnpa,sndChlyaprekrPliMp.idTaycpmeia2 (aon(syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36(1):62-67. 7 23/ pot (37) Barker DJ. Adult consequencesoffetal 2006; 49(2):270-283. growth restriction. Clin Obstet Gynecol (38) J`caodndtroiebuVtWio,nsWoiftetpeimdaemniJoCl.ogHiycpaolthsteusdeiesso.EnutrheJEfeptialdeormiigoinlso20f0a6d;ul2t1(d2i)s:e9a1s-e1s0:2. 8 232 v.22 CHAPTER 2 . PERFLUORINATED COMPOUNDS: PRODUCTION, EXPOSURE, AND TOXICITY USE, 9 233 sero Perfluorinated compounds (PFCs) comprise a class of `man-made, fully fluorinated organic compounds that have been used in a variety of consumer and industrial applications, including protective coatings for textile, carpets, and food-contact `packaging; productionofnon-stick cooking material; and as industrial surfactants, Despite evidenceofwidespread contamination at low levels in human blood, the specific patlvays of human exposure to PFOS or PFOA are not well understood. Posible sources of exposure may include industrial releases, consumer product use, house dust ingestion, indoor air inhalation, or dietary pathways through environmental A contamination; however, there are no clear data to suggest the relative contribution of PFOS and PFOA are extremely persistent, both in the environment and inbiological systems. Unlike traditional persistent pollutants, these compounds accumulate in the liver and serum, where they are bound to proteins. Both PFOS and PFOA are peroxisome proliferators and adverse effects observed in animal studies have included liver toxicity, disruption to lipid metabolism, alterations in endocrine fmction, nd developmental toxicity. Limited occupational epidemiologic data are `available in the form of retrospective cohort and medical surveillance studies. Key data gaps include a xpos mt bum rp oon characterization of the pathways of human exposure and epidemiologic studies of 10 234 p.2s Introduction Perfluorinated compounds (PFCs) are man-made, fully fluorinited organic compounds ` found in a wide range of consumer and industrial products and processes. They are characterized by a carbon chain backbone in which carbon-hydrogen bonds have been . replaced by carbon-fluorine bonds (132). The strength of the carbon-fluorine bond imparts resistance against degradation in the environment and makes these compounds extremely persistent. Many PFCs are oleophobic and hydrophobic, hence, providing ` utiliatsy a repellentofsol, oil, and water. Further, the surface active propertiesofthese `compounds coupled with their thermal and chemical stability makes them particularly useful in harsh environments (e.g., semiconductor etching baths) (2). The chemical < structuresoftwoofthemore widely studied PFCs, perfluorooctane sulfonate (PFOS) and perlorooctanoate (PFOA), are shown in Figure 2-1. The following sections describe the characteristics of these compounds, including the extentofproduction and use, data ` on human biomonitoring, possible exposure pathways, and a summary of the potential adverse effects identified in the toxicoanldepoidgemiiolcogaiclal literature. . Perfluorooctane sulfonate (PFOS) Production, Use, and Characteristics ' Perfluorooctane sulfonate (PROS) and related precursor compounds (perfluorinated sulfonamides) are surfactants used in applications ranging from oil and water repellents for fabrics, apparel, carpets, and paper coatings to specialty chemical applications such as ! insecticides and fire fighting foams (3). These compounds are manufactured fiom a `common starting material, perfluorooctanesulfonyl fluoride (POSF), which is produced 1 A35 through a process known as electrochemical fluorination. This process results in a `mixture of fluorochemical residual compounds, which remain in the final product and `may ultimately degrade to PFOS (2). POSF-based chemicals had been produced for over 40 years by the 3M Company, the dominant global producer of sulfonyl-based fluorochemicals (1-3). In 2000, global production of POSF by 3M was estimated to be 3,665 metric tons, 1,820 of which was either produced in the U.S. or entered the country through importation (4). As a result of reports suggesting widespread wildlife and human exposure to PFOS, 3M announced in 2000 that it would phase out the productionofperfluorooctanyl-chemistries by 2002 (5). PFOS is a completely fluorinated, eight-carbon chain compound with a sulfonyl group `moiety (Figure 2-1). PFOS is relatively non-volatile and `widespread exposure is thought to be due in part to degradation of volatile perfluorinated sulfonamide precursors (6) Once released, PFOS does not appetoabre metabolized further in animals (1). The halflife in human serum has been estimated at 5.4 years from a study of 26 retired fluorochemical production workers (7). Although environmental monitoring suggests that PFOS can biomagnify in the food chain, PFCs are oleophobic and therefore do not `accumulate in fats asdotraditional persistent `organic chemicals. Instead, PFOS has been shown to preferentially concentrate in the liver and blood serum of animals (8;9), where it is bound to proteins (10;11). Experimental data have shown an affinity for albumin, fatty acid binding protein, and steroid `binding globulins in some species (10;11). PFOS also undergoes enterohepatic circulation in some species, which may contribute to the 2 236 5.26 ong biological half-life (7). Due tothisbehavior, POSandother PFCsarenot reported. onalipidbasis,ualike many other polyhalogenated compounds. ! Biomonitoring . Recent surveys of wildlife and humans have detected widespread contamination from PFOS. Measurable concentrations in serum have been observed in numerous species across many populated and remote regions of the world (;12-14). Further, evidence suggests that wildlife (15;16) and human exposure among the general population have increasedoverthe last several decades, at least through the 1980's (17518). Studiesofworkers exposed occupationally to PFOS have shown average serum levels on the order of one part per million and above (19,20). Among the general population, PFOS concentrations have been detected at parts per billion in the blood of most ! populations studied. Table 2-1 presents a summary ofrecent studies conducted across the world. These data show that significant variability in exposure may exist both between . `counties and within 2 country (Figure 2-2). In the U.S., serum PFOS concentrations in blood among adults (ages 20-69) was reported by Olsen et al. (2003) in a group of 645 blood donors in six different geographic regions. The median and the 90 percentile for . all subjects were reported as 35.8 ng/mL and 70.7 ng/mL, respectively (21). Similar serum levels were observed in a study of 238 elderly subjects (ages 65%) in Seattle, `Washington (22) and 598 children enrolled in a pediatric trial (23). These data suggest ` no significant age variation in human blood PFOS concentrations. These studies also found litte evidenceofgender differences inserum POS levels, consistent with many of 13 237 p27 the other reports. Other studies conducted in the U.S. have found similar results (24,25), with the exception of a small set (n= 30 adults) of whole blood samples from Kentucky, in which median concentrations inblood (adjusted from whole blood to serum-equivalent using a factor of two) were reported as 81 ng/mL among females and 72 ng/mL among males 25). More recently, Calafat et al. (2006) reported PFOS levels among 54 pooled serum samples from a subset of the 2001-2002 National Health and Nutition Examination `Survey (NHANES). The authors reported that White males and females had higher mean PFOS levels (40.2 and 24.0 ng/mL) than Black males (18.3 ngimL) and females (17.9 ng/mL) or Mexican-American males (13.7 ng/mL) and females (10.4 ng/mL) (26). These data suggest that racial differences may exist in the proximity to sourcesorpathways of exposure in the U.S, although limited conclusions can be drawn from pooled data. The Centers for Disease Control andPrevention (CDC) will analyze individual serum samples from NHANES foar ature National Human Exposure Report, which may shed light on the extent to which subgroups are differentially exposed to perflorinated chemicals in theUS. (26). Significant variations in PFOS concentrations in human blood have been reported worldwide. Kannan et al. (2004) conducted a survey of PFOS levels in human blood from various countries around the world. After the USS, the highest median levels were found in Poland, Korea, and Belgium. Median PFOS concentrationsofaround 10 ng/mL (serum-equivalent) were observed in samples fiom Malaysia, Brazil, and Colombia, 1" A379 re Ts - || lower than what has been reported in the US. In contrast, relatively low serum concentrations were observed in specimens from Htaly and India (25). Relatively high ` levels of PFOS were observed in another study in Poland (27), in which the median concentration in whole blood ranged from 9.7 to 34 ngimL, depending on the subgroup. . Studies conducted in Canada (28), Japan (12:18:29), and China (30) have also reported PROS concentrations in human blood that spprosch or surpass those reported for the U.S. In fact, a Chinese study of 85 blood samples collected in 2004 reported a mean PFOS, concentration of 52.7 ng/mL. (serum equivalent), wit the highest concentration reported at 310 ng/ml. (30) In contrast, among 44 human serum samples from Peru, only 20 percent of samples had detectable levels of PFOS (LOD: 0.4 ng/mL) and the 90 | percentile concentration was just 0.7 ngfL (31). When comparing these data it is important 0 note that manyofthese studies sce small and not necessary representative "of the whos populinofthe country om which they wer sampled, Ther may be ` significant variation in exposure within a country or geographic region, in addition to | `seographic variation between counties in exposure to fuorochemicals. Also t should be . noted that the analyses were completed by different labs, using a variety of anslytic methods, which may explain someof the observed variations. The only previous reports ofetl exposure to PFCscomefrom two small studiesof ord blood specimens. Inoue et al. (2004) measured PFOS in serum collected in Japan in 2003 from 15 matemal-fetal pairs. The authors reported the presenceof PFOS in all 15 cord ` blood samples tested, at concentrations ranging fiom 16 to 53 ngiml. PFOS concentrations in matemal and cord serum were highly corelted, with cord levels 15 | 239 p29 approximately one-third that of the mother (32). In 13 pooled cord plasma samples in `northern Canads,collectedfrom 1994-2001,themean PFOS level was 16.7ng/mL (33). Exposure Pathways To date, there are limited data on the pathwaysofhuman exposure to PFOS. Due to the long-range transport necessary to carry PFOS to remote regions such as the Arctic, it has been hypothesized that volatile perfluoroalkyl sulfonamide precursors, which can degrade. to PFOS (2), play a role in the widespread environmental contamination (6). Recent studies have identified these compounds in outdoor air (34-36) and it has been hypothesized that variations in atmospheric levels are due to the presence of point sources (34). In the indoor environment, PFOS and fluorinated sulfonamides have been detected in house dust (37,38) and indoor air (36,39) at concentrations significantly greater than outdoor air (36:39). Kubwabo et al. (2005) report the presence of PFOS (among other PFCs) inthedust in a sampleofhomesinCanada. The levels of these compounds were. positively correlated with the amount of carpet in the home and negatively correlated with the age of the home (37). Shoeib et al. (2005) measured perfloroalkyl `sulfonamides in dust and indoor air in Canadian homes and concluded that levels in air `were not correlated with age of the home or percent of the home that was carpeted. The authors suggested, however, that dust ingestion could be a significant pathway for children (39). Further, a recent study reported the presenceofresidual sulfonamides in a `commercial carpe protector, which could be apotential sourceofhuman exposure (40). 16 70 5.30 `The presence of measurable levels of these contaminants in wildlife and game suggests ` that dietary exposure could play a role. Relatively high PFOS concentrations have been observed in' Arctic polar bears (13;14;41), with evidence of biomagnification across . trophic levels in this region (14). Several studies have shown the ability of PFOS to bioconcentrate substantially in fish tissue (12;42-45) and biomagnify in aquatic food chains (8;42-44;46), suggesting that fish consumption could be a plausible source of ( exposure. For example, mean bioconcentration factors (BCFs) reported for PFOS have ranged from approximately 1,000 to greater than 10,000, depending on species and location (12;42,44;45). Biomagnification factors (BMFs) have been reported to range from approximately 10 to 20 for PFOS (42;44). Inarecent study in Poland, Falsndysz et al. (2006) found that individuals with high fish consumption had elevated levels ofPROS in their blood relative to other groups (27). PFOS has also been detected in beef cattle, ` but at lowerlevelsthan fish (47). In a 3M-sponsored studyofPEC concentration in food items, measurable concentrations of PFOS (LOD: 0.5 ng/g, wet weight) were found in . only a small number of samples (48). PFOS has also been detected in surface waters (12:42:44;49) and tap water (49:50) at part per trillion levels in the USS. and Japan, suggesting that exposure could occur through drinking waterconsumption. Adverse Effects GeneralToxicology . POS has been identified as a hepatic peroxisome proliferator that targets the liver and disrupts lipid metabolism in some animal species (51-53). Toxicity studies in animals " IY p31 have shown marked reductions in serum cholesterol and/or triglycerides (54-57), which may be mediated through down-regulation of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, a key enzyme in cholesterol synthesis (56). Recent animal studies have shown that PFOS can affect thyroid hormone levels and other aspectsofthe neuroendocrine system (5457-60). For example, Thibodeaux et al. (2003) found reductions in total and free thyroxine (T4) and serum triiodothyronine (T3) among pregnant rats dosed with PFOS, without a concomitant increase in serum thyroid stimulatinghormone (TSH) (57). Lueber et al. (2005) also noted reductions in total T4 and T3 without elevated TSH during lactation, among rats dosed with PFOS during pregnancy (60). In evaluating other endocrine markers, Austin etal. (2003) found that high doses (10 mgkg body weight intraperitoneally) of PFOS in rats affected estrus eyeling, reduced serum leptin, elevated serum corticosterone, and elevated hypothalamic norepinephrine concentrations (58). A single study evaluated PROS carcinogenicity in rats and identified increased riskof liver, thyroid, and mammary gland tumors (4). DevelopmentalToxicology Several studies have examined the potential for developmental toxicityof PFOS. PFOS has been shown to cross the placental barrier in rats, with fetal serum levels equivalent to or greater than matemal levels (60). Several effects on reproduction and development have been observed, including reduced matemal weight gain, reduced birth weight, decreased gestational length, birth defects, developmental delays, and increased neonatal mortality (5759-63). Grastyetal. (2003) reported that PFOSdoslaeiingenstatgion was sufficient to induce neonatal mortality in rats and suggested that lung immaturity may be 18 HR v.32 responsible (61). However, in a more recent study, trating the animals with a rescue agent. (dexamethasone) did not result in improved survival. The authors did note evidence of lung immaturity by histopathology at birth, among PFOS-treated animals (4). . Linited epidemiologic data are available in the formof a retrospective cohort study and medical surveillance in cetan fluorochemical production plant. A retrospective cohort mortality study was conducted at a 3M POSF manufacturing plant in Decatur, Alzbama, among all workers with at least one yearof cumulative employment through the end of 1997. The authors reported elervisksafortbleaddder cancer among workers employed in a high exposure ob, although based on only three observed cases, There were too few events to evaluate effects an liver cancer morality, one of the a prior endpoints of ! interest (65). In addition to the small umberof events for some ofthe endpoint, no data were available on potential confounders. . Medical surveillance of fluorochemical production employees has been conducted at 3M plants in Decatur, Alabama and Antwerp, Belgium. Tn a series of sudies using surveillance data from the last decade (1995, 1997, 2000), Olsen and colleagues examined the relationship between serum PFOS levels and hematology, clinical chemistry, and thyroid hormone assessments (19;66). In one study, PFOS exposure was ! significantly positively associated with total cholesterol (1997) and. low-density lipoprotein (LDL) cholesterol (1997) and negatively associated with high-density 15 #3 ' lipoprotein (HDL) cholesterol (1995). The authors suggest that these results could be confounded by body mass index (BMI) and age; however, the associations between serum PFOS and total cholesterol and HDL remained after adjusting for potential confounders (66). Although full details of the regression models were not provided, these results are noticeable because they differ in direction from the hypolipidemic effects observed in animal studies. man le chemical profusion workers ndergin mil lies in 2000, those in the highest quartile of PFOS exposure had significantly `higher serum triglycerides and serum triiodothyronine (T3). In multivariate analysis, significant positive associations were observed between PFOS exposure and total cholesterol and triglycerides. The positive association between PFOS and T3 levels remained in `multivariate regression analysis, although no association was observed with TSH or T4 (19). Occupational surveillance investigations of this type may be prone to selection biases due to low participation rates (<40% in the 1995 and 1997 assessments) and the potential for workers adversely affected by exposure to be more likely to have left the job (i.e., healthy worker effect). However, selection bias would be less likely for sub-clinical effects,suchas small changes in the clinical chemistry measurements reported here. Perfluorooctanoate (PFOA) Production, Use, and Characteristics Perfluorooctanoic acid (PFOA) and its salts are used as chemical intermediates and `processing aids in the production of fluoropolymers and fluoroclastomers (67). PFOA 244 p34 can be manufactured through electrochemical fluorination or a process known as elomerization. Its estimated thatfewerthan 600 metonsrofiPFOcA are manufactured ! or imported into the USS. per year (67). In 2002, 3M, the only USS. manufacturer of PFOA, ceased production, at which point Dupont began producing PFOA for its . uoropolymer business needs (68). PFOA is a fully fluorinated, ight carbon chain acid (Figure 2-1) which has theabilityto form various salt. The salt most commonly used in industrial applications is ammonium. perfluorooctanoate (AFPO), which dissociates to the free acid, PFOA, in water (69). Much like PFOS, PFOA is extremely stable in the environment and biological systems due to the strengthofthecarbon-fluorinebond (70). As a result, the half-life in humans ison theorodfyeearrs (~3.8 years) (7). Similar to other BECs, BFOA is oleophobic and therefore does not accumulate in fa tissue in the body. Instead, itis found in the liver ` and serum of animals (70), typically associated with proteins (11571). In experimental systems among different species, PFOA has been shown 10 bind to albumin, fatty acid . binding protein, nd steroid bindingglobulins (1031171). Human Biomonitoring . PFOA is the second most widely detected PFC in human blood; although it has generally been detected at levels lower than those ofPROS. A recent analysis ofstored human sera showed an increase in PFOA concentrations among the general populationfromthe mid- ` 1970 to the late 1980's (17). Much like PFOS, general population serum concentrations are ordersofmagnitude lower than thoseofexposed production workers. 2 HE `Table 2-2 and Figure 2-3 provide a summary of recent human biomonitoring studies of PFOA. In the series of studies conducted by Olsen and colleagues, among children (n = 598), adults (n = 645), and the elderly (n = 238) in various regions of the U.S., the median serum level reported was between 4.2 and 5.1 ng/mL (21-23). Other smaller studies in the U.S. have reported higher levels. Calafat et al. (2006) reported a median level of 11.6 `ng/mL among 23 pooled samplesofserum collected from 1990-2002 (31). Kannan et al. (2004) reported a wide variation in median levels between samples collected from Michigan, Kentucky, and New York City. Among 75 adults in Michigan in 2000, the median serum PFOA level was below the limit of quantification (LOQ) of 3 ng/mL. Conversely, the median plasma PFOA level `among 70 adults in New York City in 2002 `was 25.2 ng/mL (25). In an analysis of 2001-2002 NHANES pooled samples, Calafat et al. (2006) report mean PFOA concentrations ranging from 2 to 7 ng/mL, depending on race and gender. Similatro PFOS, the highest levels were observed among White males and femalesinthe study (26). Varying levels of PFOA concentrations in serum or whole blood have been reported outsideofthe U.S. Some of the highest levels havebeen observed in Poland. Kannan et al. (2004) report median PFOA levels (adjusted from whole blood to serum-equivalent using a factor of two) close to 20 ng/mL among a sampleof 25 adults collected in 2003 bseinteUS. 27). Se contcte on (25). However, another study in Poland reports median levels lod samples closer to collect omwhat Begin `has been Hb 5.36 (25), Canada (28:33), Colombia (25), Japan (18), and Sri Lanka (72) all report mean or `median PFOA plasma or serum concentrations in the range of3 to 6 ng/mL, similar to ! levels reported inthe U.S. Interesttihnegslamye, study that reported someofthe highest PFOS levels in China, showed a mean PFOA serum-equivalent concentration of 1.6 . ng/mL (30). This suggests that the patterns of fluorochemical exposure may differ by region. Once again, it is important to note that these studies were not necessarily intended 10 provide a representative snapshot of the level of contamination in the . population of a country, and cross-country comparisons should be made with this limitation in mind. Likewise some of the apparent geographic variability may be ateibuted to variability in laboratory methods. Only two studies have reported the analysis of PFOA concentrations in umbilical cord blood. Inoue et al. (2004) did not detect PFOA in any of the 15 cord serum samples ' (LOD: 0.5 ng/mL) and in only 3 of 15 maternal samples collected from a population in Japan (32). By comparison, Titlemier et al. (2004) reported detectable PFOA plasma . levels with a mean of 34 ng/mL in 13 pooled cord samples collected from northern Canadian populations (33). Exposure Pathways Industrial releases during PFOA production may contribute to local or regional sources of pollution. However, PFOA contamination has been documented in many areas of the ! world, including the Arctic. Similar to PFOS, the physicochemical characteristics of PFOAmake itunlikelyto undergo long-range air transport and contaminate such remote 2 247 p.37 regions, the mechanisth which dominates the global dispersionofother polyhalogenated organics. Recent studies have implicated fluorotelomer alcoholsa possible precursors to PFOA contamination in these regions. These compounds have been measured widely in outdoor air (34:35), are estimated to have atmospheric lifetimes long enough for substantial transport (~20 days) (73), and have been shown to degrade to PFOA and other perfluorinated carboxylic acids in experimental chamber studies (74). Oceanic transport has also been hypothesized to contribute to the accumulation of these chemicals in remote regions, such as the Arctic (75). Dinglasan-Panilio et al. (2006) reported the presence of residual telomer alcohols in commercially available consumer and industriel products, suggesting these products `ould be a sourceofperfluorinated acids found in the environment and a potential source. of human exposure (40). PFOA has also been detected in house dust (37:38), and like PFOS, in at least one study, levels correlated positively with the amountofcarpet in the home and negatively withteahge ofthe home (37). Begley et al. (2005) studied the residual levels of PFOA present in several consumer products and the abilityof PFOA to migrate into food during use. The authors detected only very low levels of PFOA residual in PTFE-coated pans and concluded that migration into food would not be a significant source of human exposure (76). Studies conducted by Dupont researchers failed to detect residual PFOA in PTFE-treated cookware (77). Some perfluorochemicals are approved for use as coatings on foodcontact paper. These coatings are particularly useful for foods with a high fat content, 2 24g 5.38 since the oleophobic properties ofthese compounds will prevent oil from leaking through the packaging (76). As a result, concem has arisen about the potential for exposure ` through fast food consumption (78). Begley et al. (2005) detected PFOA in microwave. popcom bags, though migration of PFOA nto food was low (76). The authors did report substantial migration of fluorotelomers, which are found in the coatings applied to food- contact paper, andarebelieved toultimatelybreak down to PFOA. To date, limited data arc available on the extent to which diet may playa role in exposure. PFOA has beendetectedin surface water (42;44;49) and drinking wateratpart pe trillion levels (49;50) in the U.S. and Japan. Drinking water contamination at higher Tevels has been reported in the US. as a result of direct PFOA releases (79). The poteniial for bioconcentration and biomagificationof PFOA appears to be less than that of PFOS (42-44). For cxample, BCFs for PFOA have been reported in the rangeofzero ' (ie., undetectable concentrations in fish tissue) to approximately 200 (compared with 1,000-10,000 for PFOS) (42;44;45;80). Similarly, environmental surveys have suggested . lower bioaccumulation potential for PFOA (42,44). In a study of PFC levels in food items by 3M, few samples were reported to be above the limits of detection for PFOA (0.5 ng/g, wet weight),similarto wh wasraeportted for PFOS (48). ` Adverse Effects General Toxicology ! `The primary target of PFOA toxicity is the liver (81-83). Like PFOS, PFOA has been identified as a peroxisome proliferator (84-86) and has been shown to have 2 "47 `hypolipidemic effects in some species (56). PFOA has been shown to cause liver tumors in rats, although it has been suggested that the proposed mechanism of peroxisome proliferation may not be relevant to humans (70;81). Increases in pancreatic and Leydig. cell tumors in rats have also been observed, the latterof which `may bedueto increased estradiol levels in male rats (81;87). On the basisofthis `evidence, a recentdraftreport from EPA's Science Advisory Board concluded that PFOA should be considered a "likely human carcinogen" (88). Developmental Toxicology Recent studies have shown the potential for `developmental toxicity, including reductions in body weight, delayed sexual `maturation, and increased postnatal mortality inoffspring (8389-92). PFOA has been shown to crosstheplacentina rats, with fetal levels at term approximately one-half of matemal levels (93). EPA recently conducted a draft risk assessment for PFOA developmental toxicity and concluded that the current margin of exposure may be cause for concem (91:94). However, the lackof measured serum levels in the offspring, uncertainty regarding whether the effects were due to prenatal, lactational, or postnatal exposure, and sex differences among rats in the elimination of PFOA have contributed to a large amount of uncertainty in the potential risk (91). In a recent studyof PFOAin mice (among which sex differences in pharmacokinetics are not observed), a hostofdevelopmental effects were observed, including increasedpregnancy loss, reduced fetal weight, reduced postnatal survival, and delays in postnatal growth and development (92). % 250 poo OccupationalEpidemiology Several epidemiologic studies have been conducted among workers in PFOA production ! facies. A retrospective cohort mortality study was conducted among 3,531 PFOA `production workers employed for at least six months from 1947 to 1983 (95). Subjects . were charactaesrexipzoseedd (1+monthofworkin thechemical division)orunexposed (non-chemical division employees) based on job histories. None of the cause-specific SMRs among chemical or non-chemical division employees was significantly elevated. However, in a proportional hazards model, length of employment in the chemical division was significantly associated with prostate cancer mortality, which could be. considered plausible given the evidence fom animal toxicity data suggesting reproductive hormone changes (87). An update of this study with longer follow-up. (trough 1997), modified eligibility requirements (including only workers employed for atleast | year), and different exposure categories (defined as definite, probable, and no ' exposure to PFOA) reportedly showed no prostate cancer excess (91). These studies are likely to have some degree of exposure misclassiication from the use of broad job . categories as surrogates for exposure and are limited by small numbers of events for someofthe endpoints. Olsen et al. (1998) examined the association between serum PFOA levels and reproductive and other hormones among mele PFOA manufacturing employees undergoing medical surveillance in 1993 and/or 1995. Significant associations between ! PFOA and hormone levels were not observed, with the exception of 17-alphahydroxyprogesterone in 1995. Subjects with PFOA levels above 30 ppm had serum 2 25/ [Xl estradiol levels that were approximately 10% higher than those found in other workers, although the results may be somewhat confounded by bi (96). The authors also report that prior research among this population found a similar increase in estradiol among the highly exposed,aswellas asignificant non-linear relationship. As described above, Olsen et al. (2003) conducted a medical surveillance study in 2000 of 3M fluorochemical production workers, which included serum PFOS and PFOA `measurements and hematological, clinical chemistry, and thyroid function tests (19). PFOA levels tended to track those of PFOS. Thus, PFOA was significantly positively associated with cholesterol, triglycerides, and serum T3, similar to associations observed for PFOS. Finally, the association between PFOA exposure and liver enzyme function and lipid levels was examined in a cross-sectional study of male 3M PFOA production workers in Cottage Grove, Minnesota. Total serum organic fluorine (TOF), which was used as a proxy for PFOA exposure, was not associated with cholesterol or hepatic enzyme activity, however, there was some evidence of interactions with other factors. One interaction observed was between PFOA and alcohol intake on HDL cholesterol, in which PFOA was found to diminish the protective effect of alcohol on HDL cholesterol level. Another significant interaction was observed between PFOA and bmi on hepatic enzyme concentrations in serum. Among obese workers only, PFOA exposure was. associated with increased serum concentration of two enzymes associated with liver problems. Although gross changes in hepatic function were not observed, the authors conclude that PFOA may modify "the effectsofendogenous and exogenous determinants of hepatic metabolism." (97) 28 252 p.42 Summary ' Perfluorinated compounds (PFCs) represent a class of man-made, fully fluorinated organic compounds found in a wide range of consumer and industrial products and . processes. Although produced for many years, only recently have reports documented widespread exposure of wildlife and humans. Variations in human blood concentrations have been reported between countries and within the USS., but no clear variation in concentrations by age or gender has been observed. Future editions of CDC's "National Report on Human Exposure to Environmental Chemicals" will include PFCs and may provide insights into the extent of variation in serum levels between different subpopulations i the US. Figure 2-4 summarizes the possible pathways of human exposure to these compounds in ! the context of the environmental public health paradigm. The specific pathways of human exposure to PFOS or PFOA are not well understood. Although possible sources ! of exposure may include industrial releases, consumer product use, dustindoor air inhalation, or dietary pathways through environmental contamination, there are no clear data to suggest the relative contribution, if any, ofthese sources to human body burdens. `Thus, key research is needed to elucidate the important pathways of human exposure. "This should include studying the extent to which residual compounds are present and can `escape householdor consumer products; the levelsofcontamination in food and drinking ` water and further defining the role of precursor compounds as sources of PFOS and PFOA in the environment 29 253 es TTT PFOS and PFOA are extremely persistent, both in the environment and in biological systems. Unlike traditional persistent pollutants, these compounds accumulate in the liver and serum, where they are bound to proteins. Both PFOS and PFOA are peroxisome proliferators and adverse effects observed in animal studies have included liver toxicity, disruption to lipid metabolism, and changes in endocrine function. Some `evidence of increased cancer risk has been reported in occupational epidemiology studies for both PFOS (bladder) and PFOA. (prostate). Limited cancer bioassay data are available for PFOS. The EPA is curently evaluating the relevance of PFOA animal carcinogenicity data to humans and a recent draft report from EPA's Science Advisory Board concluded that PFOA should be considered e "likely human carcinogen" (88). Recent animal data has also suggested that developmental toxicity is a concern for both PFOS and PFOA. Despite the growing body of animal data, key gaps exist in the understanding of the potential toxicity of these compounds to humans. There are limited data on in utero exposure to these compounds, which are necessary to extrapolate developmental toxicity data from animals to humans. The mechanisms by which PFOS and PFOA cause adverse developmental effects in animals and the relevance to humans is mot well understood. Finally, there are no studiesofpregnancy outcomes in humans, in anoccupational or general population setting. The remaining chapters describe a cross-sectional study of newboms at the Johns Hopkins Hospital, conducted to evaluate PFC exposure in utero and relationship with fetal growth as measured by size and weight at birth. Given the evidenceofwidespread 30 25F ptt contamination in humans and the evidence for placental transfer of these chemicals in `animals, we hypothesize that this study will document fetal exposure among our study ! populationofnewbom deliveries. We will aso test the hypothesis that in utero exposure 10 these compounds is associated with reduction in birth weight and/or bith ize. . 3 p45 PgSIlEgRIsAsER,3 52,T3f:eEdR%zEiI3de% l37806, 38 dEGdEbialE 3pb gr HBEoIRS32: it le gf 3 fz $g|| fc% ii:z ER e off EH 25 iNiEr oinf fER ifimar Hi g3282 aFlly BE 3 238888 TlhlgEeenan edule 8 5g 8 Sl ssse ste e oss Elz | 5 I. # f ft l gl, 8 Ss 38 #1 52 5 38. .., HE | $85 File egy 558 888 35g 333 Ss ts $S 13)$ EE R lF33 z5 1 PSuE8g 2tsa4 : 888 588% 5 838 3x El, 5d 2 oe seilsiis 233 8 `as P ga8:R3d 3 33u 88 3 F 3 El| i b5 E 38852 813 3383i 3 3s383:2 256 pas gE|lEs:,8 sBt8sRsEsRs3fdiei..cdEf L S BEaa zU saseE:L etfEsd L smeel ! sgFi1sr gisdi5 gliEl3 oas 3 i . Z| RELH E ivy sa$i3d8393b:e 3ff3 33 SEE : 2 fBiRnEeEs 23i88f:f fBF EBR RElREai iEdEsgs gis5sg9iia:s9gni3ii%n8iaFyd 83 8388 . Blpdrra3ei5 gss 5% zagaaoage ` f2i: sreisss s[iIties 3 i a :i E2 E8s s13s3: 3 5H 2lg sEEmLiyssay oE fEhCFsiy U8 IE3 E 2 2 2E 5 EE2IE2 E2E 2EE RE2 2 g =|eR3f8ei3dt cs 8c eg Els o3d,, 35 2893888 g % B18 257 ' E12Ln8 EnMIE858 !RL 3. P Z.88:r liH ssi .c. iBo fa5g I2E, 2 23 I 2o i. OB fgEpiEaS1ggs2 sagfhd diculEeys f LE 8E3 HFR 3E2R8 E23RR4R2R8: R23:E42 PlHleednaradstiy 8 5 og TFEYHe, 8 88 s338 8 88 4 il PPlfs g.::inihbs if:s | he BSIeFl|e89eF 288s say Lily os pes HZ NEEEsg I8EE2 x FIER23E % 2gI5 R ssas il i HE eresnBiziic 88 5g8 g 3 30g 5% Bl3pedids 3 35 5335 3: 2 3 ; ! 259 pas . i: LI | 68 fBRenRpdEe BRP E 1cc hdR sdasdad R dc, Gdadadsd ` gf 1P87R:OPii lg ogisdy dd PHL T EEHG iff is HEE fBH le os Spoite.. fo rat Hilmitmimnml fgfl 3 op gi2dgmg si iii2 2i2i23 g2gg et3fsef licsfecnassonas Els 51 2 ez f.8.5 257 } pas XXHKAXHKK CSCS LONSA NSANS ININ IN AN IN a SFoirgrucree: 2A-u1s.tiCnheetamli.ca2l0s0t3r)uctureofPFOS (op) and PFOA (bottom. 36 200 .50 = Eee I | - bf [- 0 gl _ fab i Hitt HH BULLEN LTT] . PS III esA VESEIIIE HSAER Figure 2-2. Summary of median or mean PFOS concentrations (ng/mL) in blood plasma or serum, from human biomonitoring studies.* * Some studies measured PFOS in whole blood and reported concentrations as serum. equivalent by multiplying by a factor of two. Sample size and midpoint year of collection are listed in parentheses. If only subgroups were presented, theaverage cdeotnaicle.ntrMaitsisoinngbebtawreiennditchaeteslomweedsitaannlde highest groups vel below LOD is or used. LOQ. See Table 2-1 for more . 7 26/ p51 I le Hl -- I PY PSS GIS Figure 2-3. Summary of median or mean PFOA concentrations (ng/mL) in blood plasma or serum from human biomonitoring studies.* * Some studies measured PFOS in whole blood and reported concentrations as serum- equivalent by multiplying by a factor of two. Sample size and midpoint year of collection are listed in parentheses. If only subgroups were presented, the average `dectoanicl.entMriastsioinngbbeatrweiennditchaetelsmoewedsitananedvehligbheelstowgLroOuDpsoris LusOeQd.. See Table 2-2 for more 38 p52 rePlIeOaUsCeION NG |P(+iIoonreosrctohiasmbioclarloapsmreiodscueocftsi(PonFF.OO5SS3P)8F:7Oh6Rr)aonmidorrpeorsssibhloepnrecuFrsEorDs ung ` Transport/ t +Longangar transportof FOSASandFO andnsfomaPiRoOSnanod fransformation |.cuminnfodchin ndsvionment maces. :12:46:41.4530) Exposurel poDpiccotmcbaog)ncownitthacianiongcnsetseduprnodPuFctOsSI(oPgF.GcAaarnpdltovrepsriecmuerrsoirsc.ro(m0e8ve76) jcontat + Ingeofsconttaiminoatned food, dus,andlor wate,(122736-30:42/4 47-50) Entry into body (Dose) | +Human sem and ersue concataions. (see igre 22, 29) Cortsom conce(ndasas fio thonots), ` era EEagtions Baa Figure human e2x4p.osurEenvtiorpoenrmfelnuotrailnaptuebdlcicomhpeoaultnhdsp,*aradigm and possible pathways of N*Aotdea:ptReedlefvraonmt aUSSr. tEPaiAr,ec2d0el0n3oet(es9d5).by reference numbers after each description, 39 p53 References (1) d3iMspeCrosmipoan,nyf.leSaunldfoenfaftecetds.peErfPlAuorDoocchkeentniOcPaPlsTi-n20t0h2e-e0n0v4i3r-o0n0me0n5t.; 2s0o0u0r.ce3s-,1-2000. RefType: Report (2) 030M43C-o0m0p06a.ny1.99T9h.e2-s5c-i1en9c9e9.of organic fluorochemistry. EPA Docket OPPT-2002RefType: Report (3) `3DMockCeotmp#aOPnPyT.-F2l0u0o2r-o0c0h4e3m.ica1l99u9s.e,5d-i2s6t-r1ib9u9t9i.on,andrelease overview. EPA Ref Type: Report (4) ENOVE/CIDM./HRaDz(a2r0d0A2s)s1ess/mFeInNtAoLf.Pe2r00f2l.uorOorogcatnainzeatSiuolnfofnoartEec(oPnFoOmSi)caCnodopietsraSatlitos.n `CaondmDmeivtetleopamnedntth;eEWnovrikrionngmPeanrttyDiorenctCohreamtei;caJlosi,ntPMeseteitciidnegs,oftahndeBCihoetmeicchnaollsogy. Re19f21T.ype: Report (5) D3oMckCeotm2p0a0n2y-.00L4e3tt-e0r00to9.EP20A00r.e:tphPaasuel-,ouMtNp.la1n9f0o7r POSF-based products. EPA RefType: Report (6) R3e8n(n5)e3r0RA..Perfluorinated sources outside and inside. Environ Sei Technol 2004; (7) (EvPaRlOuSa)t,iopneorffltuhoerohbaelfx-alniefseu(lTfoyn)aotfee(lPiFmiHnSa)tiaonndopfeprefrlfulourooroocotcatnaonaetseu(lfPoFnOaAte) fiom ohrugmaanincsseirnumt.heFeLnvUiOrRonOmSe:ntA;n05inAteumgat1i9o;na2l00s5y.mposium on fluorinated alkyl (8) `GEenvsiyroJnP,ScKianTencahnnoKl. 2G0l0o1b;al35d(i7s)tr:i1b3u3t9i-o4no2.fperfluorooetane sulfonate in wildlife. (6) a3nMdCtooxmipcaonlyo.gyPdeartal.uoErPooAcDtoancekestulOfPonPaTt-e2:0c0u2rr-e0n0t4s3u.m1m9a9r9.yo1f-2h1-u1m9a99n.sera, health RefType:Report (10) JiotnteysaPciDd,sHtousWe,ruDmeprCooteeinnsW.,EnNveiwrsotnedToJxLi,coGliCeshyeJmP.20B0i3n;di2n2g(o1f1)p2e6rf3l9u-o4r9i.nated (11) LAuueorbokcehreDmJi,caHlasnwsietnhKrIa,t lBiavsesr fNaMtt,y aBcuitde-nbhionfdfiJnLg,prSoetaeicna.t TAoMx.icoInltoegryac2t0i0o2n;s of 176(3)175-85. Jet p54 (12) pTearnfilyuaosruooSc,tKanaennsaun Kl,fHoaorniidnrYea,latHtaeendarpierNf,luYoarmiansatheidtoarNg.anAicscuorvmepyouofnds in water, fish, birds, and humans from Japan. Environ SeiTechnol2003; 37(12):2634-9. (13) SCimrictuhmwpioclkaMr,stMuadyboufrpyerSfAl,uoSroolaolkmyolncKoRnt,aSmionnannetsC,inMpaorltairnbJeWar,sB(oUrmsuEsW etal. `maritimus). Environ Sci Technol 2005; 39(15):5517-5523. (14) IMdaernttiinfiJcaWt,ioSnmoifltotnwgi-cckhMaiMn,peBrrfaluunoreiBnaMt,edHaoceikdsstirnabPiFo,taMfuriormDtCh,e CMaanbaudriyanSA. Arctic. Environ Sci Technol 2004; 38(2)373-380. (15) HguoillmlsetmortomegKgEs,fJraommbtehregBaUl,tiBcigSenae,rt1A9.68T-e2m0p0o3r.alEntvrienrdosnoSfciPFTeOcShnaonld2P00F5O;A in ` 3901804. (16) B`ocsosmipoRu,nRdisgientrFiFn,geDdicstezalR(.PTheomcpaohriaslpiadn)dfspraotmiaGlrtereennldasondf.pEernfvliuroorninSaeiteTdechnol 2005; 39(19):7416.7422. . (17) OHilssteonriGcaWl,coHmupaanrgisHoYno,fHpeelrzfllsuooureorocKtJa,neHsaunlsfeonnaKtJe,, BpeurtfleunorhoooIcftLfa,noMaatned,ealndJHo.ther fluorochemicals in human blood. Environ Health Perspect 2005; 113(5):539-545. (18) Hinafrluaednace,ofSatiitmoe,N,seIxnoaunedKg,eoYgorsahpihniacgfaacTt,orWsaotnanlaebveelTso,fSpaesrafkliuoreotoaclt.anTeh.e sHuelaflotnhat2e00a4n;d 4p6e(r2f)l:u1o4r1o-o7c,tanoate in human serum over the last 25 years. J Occup (19) OwlosreknerGsWe,ruBmurpreirsflJuMo,roBoucrtlanecwsuMlMfo,naMtaen(dPeFlOJSH).aEnpdipdeermfilouloorgoiocctaasnsoeastsem(enPtFOofA) \ c2o0n0c3e;nt4r5a(t3i)o:n2s60a-n7d0.medical surveillance examinations. J Occup Environ Med (20) AOlnseonccGupWa,tiLonoaglanexPpWos,urHeanassesensKsJm,enStiomfpsaopnerCfAlu,orBouorcrtiasnJeMsu,lBfounryllewflMuorMideet al. production site: biomonitoring. ATJ(FHairfAax, Va) 2003; 64(S) 651.9. (21) POelrsfelnuoGrWoo,ctCahnuersuclhfTonRa,teMialnlderotJhPe,rBfurlruiosroJcMh,emHiacanlsseninKtJh,eLsuenrdubmoerfgAJmKereit ca.an Red Cross adult blood donors. Environ Health Perspect 2003; 111(16):1892.901. (22) OSlesreunmGcWon,cCenhturractihoTnRso,fLpearrfslounotEoBo,ctvaannesBuellfloenGa,teLuannddboetrhegrJKfl,uoHraoncsheenmiKcJalestailn.an elderly 611 population from Seatle, Washington. Chemosphere 2004; 54(11):1599- 4 ---- T as (23) Olsen GW, Burris J.M., Lundberg JK, Hansen KJ, Mandel JH, Zobel LR. Identiofffilucoraocthemiicoalns in human sera. IIL. Pediatric participants in a RerTyp: Repon Group A Streptococci clinical trial investigation. EPA Docket AR226_1085. 3- 15-2002. Medical Department, 3M Company. (24) Hansen KJ, Clemen LA, Ellefson ME, Johnson HO. Compound-specific, quantitative characterizationoforganic fluorochemicals in biological matrices. Environ Sci Technol 2001; 35(4):766-770. (25) Kannan K, Corsolini , Falandysz J, Fillmann G, Kumar KS, Loganathan BG et al. Perfluorooctanesulfonate and related fluorochemicals in human blood from `several countries. Environ Sci Technol 2004; 38(17):4489-4495. (26) Calafat AM, Kuklenyik Z, Caudill SP, Reidy JA, Needham LL. Perfluorochemicals in pooled serum samples from United States residentsin 2001 and 2002. Environ Sci Technol 2006; 40(7):2128-2134. | (27) Falandysz J, Taniyasu S, Gulkowska A, Yamashita N, Schulte-Ohlmann U. Is fish a major sourceof fluorinated surfactants and repellents in humans living on `the Baltic Coast? Environ Sci Technol 2006; 40(3):748-751.. (28) pKeurbtlwuaobrooocCt,aVneasiuslNf,onBaetneoaintdFoMt.hAer ppeirlfoltusotruidnyatoend cthoempdeotuenrdmisnaintibolnooodf of | `Canadians. JEnviron Monit 2004; 6(6):540-545. Sona(FOR)moser compounds hebooofapnepent i (29) MasunagaS,KannK,aDoni R, Nakanishi J, Giesy JP. Levelsofperfluorooctane Organohalogen Compounds 2002; 59:319-322. Ferro ancl nd lated Dooce a ond samples (30) Yeung LW, SoMK, Jiang G, Taniyasu S, Yamashita N, Song M et al. | from China. Environ Sci Technol 2006; 40(3):715-720. | (31) CalafatAM, Needham LL, Kuklenyik Z, Reidy JA, Tully JS, guilar-VillalobMos i etal. Perfluorinated chemicals in selected residents oftheAmericancontinent. Chemosphere 2006; 63(3):490-496. (32) TnoueK, Okada F, Ito R, Kato S, Sasaki , Nakajima ct al. Perfluorooctane. Cosurldfohnaotoed(PsFaOmSp)leasndareleatedsperofflBuoFrOinSatecd comxpouindps itn ahoupmiannmpatoertneialoannd | during pregnancy. Environ Health Perspect 2004; 112(11):1204.7. (33) Tittlemier S, Ryan JJ, Van Oostdam J. Presence ofanionic organic compounds in | serum collected from northem Canadian populations. Organohalogen Compounds i 2004; 66. | 42 266 p.56 (34) StetloocmkeNrLa,lcLoahoulFsKa,ndElsluslfDoAn,amMiadretsiinnJtWhe,NMouritrhDACm,erMiacbaunrtyroSpAo.spPhoelrey.flEuonrviinraotned Sci Technol 2004; 38(4).991-996. : (35) MCcoahlrrlotemicanttiJooWgn,roafMpauhiiyr/rbcoDhrCenm,eiMcfaolluoodriioynnaiCtzAeadt,iooErnlglaminsaisDcsAs,sapnKedcwtaarnonamleyWtsrCiy,s.bSAyonlgaaolsmCohneKmR20e0t2a;l. T4(3):584-590. ` (36) cpSoohnlocyeebinrbtorMma,itniHaonatsemdeandridTpp,hheIanksyoelnpeoatrhmetoriust.iMoEn,nivnKgioarnfonnpaeSnrcfiKl.TuoeIrcnohdanolooklryl2a0ns0ud4l;ofuo3tn8da(om5oi)rd:ea1si3r1a3n-d1320. (37) KotuhberwapebroflCu,orSotcehweamritcBa,lZs hin udJu,stMafrrtoomLs.elOeccctuedrrheonmceeosfinpetrhfluciotryoosfulOftotnaatweas, and ` Canada. J Environ Monit 2005; 7(11):1074-1078. (38) M(oPrFiOwSa)kainHd,peTrafkltuoarhooYc,taAnroaickaawcaidR.(PCFoOnAce)nitnravtaiconusuomfcpleerafnleurodruosotctcaonlelescutlefdoniante . Japanese homes. JEnviron Monit 2003; S(5)753-757. (39) S`ienhxoipenoidsbuoroMer.,aEnHndvaimorueotrndoTSo,criWaiTilerfcaohnrnddoliBnH2d0,o0oJ5ro;nd3ue9sst(:K17Co),c:c6Zu5rh9ru9e-nJc6.e6P,0e6pr.afrutoirtiinonaitnegd, saunldfohnuammaidnes (40) Dpriensgelnatsainn-PvaanrliioluisofMluJo,riMnaatbeudrmyatSerAi.alSsi.gnEinfviicarnotnrSecsiidTueaclhfnloulor2i0n0a6te;d4a0l(c5o)h:o1l4s47- 1453. (41) Kannan, Yun SH, Evans TJ. Chlorinated, brominated, and perfluorinated. `3c9o(n2t3a)m:i9n0a5n7t-s90i6n3l.iversofpolarbears from Alaska. Environ Sci Technol 2005; . (42) pSeirncfllauiorroEa,lkMyalysaucrkfaDctTa,ntRsoibnlweaetKe,,Yfaismha,sahnidtabiNr,dsKfarnonmanNeKw. OYcocrukrrSetantcee,oAfrch Environ ContamToxicol2006; 50(3):398-410. . (43) PBaelrtfilcuoSreian.atFeLdUcOheRmOicSa:lsAinnibnltoeomdaotfiionsahl saynmdpwoastieurmfoownl fflruoomrignateoudfaGllkdyalnofsrkg,anics. in the environment; 05 Aug 19; 2005. (44) `Kcaonmnpoaunn,dsTianoaqLu,aStiinccolraigranEi,sPmasstavtavaSrDi,ouJsutdreopDhJi,cGlieevseylsJPi.n aPeGrrfelautorLiankateesdfood chain. Arch Environ ContamToxicol2005; 43(4):559-566. (45) bMthioaortcoiokfncapeewnratfrlAau,toiKrooanomcfetaiactnNoor,aotHfeapirenardfwliaulKdo,rtoIuorncloteuasen(eKT,sruYalocfsohnheaimtnyeasigssacsrTii,gpntSiaafietcloaengNtalnytsalalarn.gdeTrhtehan a TT --_-- [CA | Chinemys reeves): An Ai river ecological studyin Japan. Ecotoxicol Environ Saf 2006; 65(1):14-21. (46) Perfluorooctane sulfonate (PFOS) and related compounds in a Norwegian Arctic | `marine food chain. FLUOROS: An international symposium on fluorinated alkyl |1| (47) `GourrguangiecsKiSn,thTeaneinyvaisruonSm,eMnity;a0z5akAiug, 1Y9a;m2a0n0a5.ka N, Yamashita N. Age dependent || `Caocmcupmouulnatdison2o0f04p;er6f6l:u4o0r2i9n-at4e0d34c.hemicals inbeef cattles. Organohalogen || (48) vCaernitoruesfAnoaoldymtaictarlicLeasbuosraitnogrHiePsLI.CAenlaelcytsriossopfraPyF/OmSa,ssFsOpSecAt,roamnedtrPy.FO1A-1f51r.o6m:21. | 2001. 3M Environmental Technology and Safety Services. | RefType: Report | (49) Saito N, Harada K, Inoue K, Sasaki K, Yoshinaga T, Koizumi A. || PienrJfalpuacnr.ooJcOtacncouapteHeaanldtphe2rf0l0u4o;r4o6oc(t1a)n4e9-s5u9l.fonate concentrations in surface water | (50) 3M Company. Environmental Monitoring ~Multi-City Study. Water, Sludge, 1 `Sediment, POTW Effluent and Landfill Leachate Samples. 6-25-2001. 3M `Environmental Laboratory. Ref Type: Report (51) PSeorhflleunoiruosocAtKa,neErsiulkfsosnoincAaMci,d Hisoagsptorteonmt Ci,ndKuicmelroanfdpeMr,oxDiesPoimearlrefJaWt.y acid beta`oxmioduasteiloinvear.ndPohtahremraaccotilviTtoixeisckonlo1w9n93t;o7b2e(2af)f9e0c-t3e.d by peroxisome proliferators in (52) tSrhainpsl-eayctJvMa,tiHounrosft PCHP,ATRaanalkpaahSnSad, iDnedRucotoisonFoLf,PBPuAtRealnphhoaJfLtf,arSgeeatcgaetnAesMbyet al. `perfluorooctane-based chemicals. Toxicol Sci 2004; 80(1):151-60. (53) Fahimi HD, Sies H, European Cell Biology Organization. Peroxisomes in biology `and medicine. Berlin ; New York: Springer-Verlag, 1987. (54) SSeuabccahtroAnMi,c tTohxoimiftyorsdtuPdJi,esHoannspeernfKlJuc,rOoloscteannGesWu,lfoCnaastee MpoTt,asBsuiutmesnahltoiJfnLf. cynomolgus monkeys. ToxicolSci 2002; 68(1):249-64. [ (55) Seacat AM, Thomford BY, Hansen KJ, Clemen LA, Eldridge SR, ElcoCmRbeet | al. Sub-chronic dietary toxicity ofpotassium perfluorooctanesulfonate in rats. Toxicology 2003; 183(1-3):117-31. (56) Haughom B, Spydevold O. The mechanism underlying the hypolipemic effect of `perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid. Biochim Biophys Acta 1992; 1128(1):65-72. " 2:4 p.58 (57) TEhxipboosdueraeutxo JpRe,rfHlauonrsooonctRaGn,e sRuolgfeonrasteJMd,urGirnegyprBeEg,nBaanrcbyeienrBaDt,anRdicmhoaursdes.JHI: et al. r `maternal and prenatal evaluations. Toxicol Sei 2003; 74(2):369-81. (58) ASPeuMrs.stpiNenecuMtrEo2,e00nK3da;osct1ru1ir1in(e1B2Se)f,:f1eB4ca8tr5sb.oe9fr.pMer,flKuaonrnoaonctKa,neMsouhlafornKatuemianratPsS.,EMnovhiraonnKHuemaalrth (59) LExapuoCs,urTehiobopdeerafluuxoJroRo,cHtaannesosunlfRoGn,atReodguerrisngIMpr,eGgrneayncByE,inSrtaatnatnodnmMoEuseet.alI.l: postnatal evaluation. Toxicol Sci 2003; 74(2):382-92. (60) Lrfaurtcso:bmkdieonsrueDt-Jetr,eosYpeooxnrpskoes,RuGar,nedtHobainpoescrehfnelmuKoiJrc,oaoMlcotaoanrndeepshuJlaAfr,oanBmauattceeokn(ihPnoFefOtfSiJ)cL.pinaNreSaopmnreaattegarulse.-mDoratwalleiyty Toxicology 2005; 215(1-2):149-169. (61) pGerrafsltuyorRoCo,ctGarneeysuBlEf,onLaatue-CiSn,duRcoegdenresonJaMt.alPrmeonartatlawliinintdthoyewoSfpsruasgcueep-iDbaiwllteyytroat. . Birth DefectsRes PaBrDetv Reprod Toxicol 2003; 68(6):465-71. (62) Lg(uePneFebOrkSae)trinoDnJr,raetCsp.arsoTdeouxMcitTcio,olnYoagonyrdk20cR0rG5os;,s-2Mf1oo5so(tr1e-er2s)Jt:Au1,d2i6He-as1no4sf5e.pneKrfJl,uoBruootcetnanheosufJlLff.onTawteo.- (63) dFueevnetleospmSe,nCtoallotmoixincaolMoTgy,:RCoodnrciugrureezntJ,eVxipcoesnusreP,toDopemriinlugooroJLo.ctIannteersaucltfioonnastein (PFOS) and stress in pregnant mice. Toxicol Lett 2006; 164(1):81-89, (64) p`GprreearnsianttayatlaRlpCre,art.fBljBuoiorrrtkohJoDcAet,faenWceatlssluaRlcfeoesnKaBtBDe,e(WvPoFRlOefSp)rDCoe,dxpLTooasxuuircCeoSlo,n2R0lo0ug5ne;gr7sm4aI(tM3u).r4a0Etf5if-oe4nc1ti6sn,otfhe . (65) `AeElmnepvxliaornoyndeMeerseBodHfa2,0pO0el3rs;fel6nu0o(Gr1W0o),o:c7tB2au2nr-cr9si.uslIpMh,onMylanfdleuolriJdHe,mMaannudfaecltJuSr.inMgorftaacilliittyy.oOfccup ` (66) eOamlnpsdlehoneypGeaeWtsi,.c BJauOnrdcrcilsiuppJiMdE,cnlvMiinairncoadnleMclheJedHm,i1sZ9to9rb9ye;tl4es1Lt(Rs9.i)n:S7ef9lr9uu-o8mr0op6ce.hrefmliucoarloopcrtoadnuectsiuolnfonate (67) SPoelrifcliutoartoioocnotfainnoitceraecsitde(dPpFaOrAt)c,s oFlruoernifnoartceedabtleelocmoenrsse;nRteaqgureesetmfeonrtcdoemvmeelnotpm,ent, Raenfd nToytpiec:eoSftaptuubtelic meeting. Federal Register (73). 2003. (68) NEe.mLDouuprosnatnddeCNoemmpoaunrys ianndinCroemsppaonnsye.tCoo"mPemreflnutosrooofcttahneoEi.c IA.cDiudp(oPnFtOdAe):, 4 p59 FElnufoorricneaatbeldeTCeolnosmeenrts;AgRreequeemsetntfoDreCvoemlmopemnetn,t,SoalnidciNtoattiiocnoefoIfnPtuebrleiscteMdeePtairntgi'e.s for USEPA Docket OPPT-2003-0012. RefType: Report 2003. Wilmington, DE. 1916. (69) 3enMviCroomnmpeanntya.l Pfaetreflduatoar.ooUcStaEnPoiAc Dacoicdk:epthOyPsiPcTo-c2h0e0m3i-c0a0l1p2r-o0p1er6t4i.es2a0n0d3. St. Paul, RMeNf.Ty1p9e01:.Report (70) KhuumdaonNs,aKnadwaansimhailmsa. JY.ToTxoixciocliSteyian2d00t3o;xi2c8o(k2i)n:e4t9i-c5s1o.fperflvorooctanoic acid in (71) fV1a9at9nt2yd;eacn8i2dH(se3)ut3vo1ep7lr.o2Jt8Pe,,inKsusilnitkhiespBlIa,sPmeat,erlisvoenrRaEn.d tCeosvtaelsoenftrabtisn.dCinhgeomfBpieorlflIunotreirnaactted (72) Getuarlu.gPeerKfSl,uoTriannaityeadsourSg,anYiacmcasohmiptoaunNd,sWiijnehruatmnaanSb,lMooohdostetiruKmMa,ndSesneemviinraaltne HR. Mpolansimta:2a005s;tu7d(y4o)f3u7r1b-a3n77a.nd rural tea worker populations in Si Lanka. JEnviron (73) A3El7tl(mi1os7sD)p:Ah3,e8r1Mi6ac-s3tl8ii2fn0eJ.tiWm,eoMfafbluuroyroStAel,oHmuerrlaelycoMhoDl,s.AEnndveirrsoennSMciP,TeWcahlnloiln2gt0o0n3;TJ. (74) EMplePlrifsleutDoAarl.,inDaMetagerdrtaicdnaarJtbiWoox,nyolDifecfSaliculiovdrsao.AtEeOnl,voimMreaorbnaulSrccoyihoSTlAesc,:hHnauolrlilk2ee0ly0y4Ma;Dtm3,o8s(Sp1uh2le)br:ai3cc3k1s6Ao.nu3dr3ec2re1s.oefn (75) tPrraenvsepdoortuorfospeKr,flCuooursoicnasrbIoTx,ylBautceks.RECn,viKroornzeSneiioTwesckhinoSlH.20S0o6u;rc4e0s(,1)f:a3te2-a4n4d. (76)FBPoeeorgfdlleuAyodrTdoHict,heCWmohinciattleasm:K,2p0oHt0oe5nn;itgi2af2lo(rs1to0u)Pr,:c1Te0ws2oa3rf-oa1s0nk3di1 mMiLg,raNteiconhefsroRm, fWoaoldkeparcRkAag.ing. (77) pcPeoorowtkllweuaoyrrCoeoRuc,tnadMneiorcihcsaialmccuizldyatk(ePMdFJcO,oAKo)akiiesnxtegrrcaMoctnAad,bilteiBoufnxrstobomynthLLeCW/s.uMrSDfe/atcMeeSor.mficAnonaatmlimyoesnrtco2if0a0l5; 13009):1299-1302. (78) (79) FLiitetlldesHSo.fcAwkniwonwtg.hieWrattlfeaershtAo-sfcsokoodciinfaegtawri.oanEtnIevnrci..rooNnrOgHTe/IaNClOtEThIOPCFeErsC%pO2e0Nct0TF2A0%M023I0;NCA1O1TN1IT(AO16MN:I.AN8A7T2.ION uhniet2p0i0/4htm . 2004. 217 Ref Type: Electronic Citation % p.60 (80) MdiasrttriinbuJtiWo,noMfapbeurrfyluSoAri,naStoeldoamcoidnsKiRn,raMiunibrowDCt.rouBtio(cOonncsoernthryantcihounsamnydkitsiss)s.ue Environ Toxicol Chem 2003; 22(1):196-204. ` (81) KReGnneteadl.y GTLh,e Jtro,xiBcuoltoegynohfopJfeLrf,flOulosreooncGtaWn,oaOte'.CoCnrintorReJvC,ToSxeiaccoalt2A0M0,4;P3e4r(k4i)n:s3518. (82) BaumtmeonnhioufmJf,pCerofsltuaorGo,oEctlasnoomabtee iCn,mFaalreracryDn,omHoalngsuesnmKo,nIkweayisH afettearl.orTaolxdiocistiyngoffor 6months. Toxicol Sci 2002; 69(1):244-57. (83) BrTeuoptxreioncdhouolcfotfgiyvJeL2,0t0oK4xe;inc1no9el6od(gy1yo-G2fL)a,9m5J-mr1,o1Fn6r.iaummepSeRr,flOu'oCroooncntoarnoIaCt,eY(oArPkFROG).inThthee rt. ` (84) oPfasatmoomroTnPi,uLmepeeKrfPl,uPoerroroictMaAno,atGei-lliinedsucPeJ.d Bhieopcahteommiecgaallyanadndmopreprhooxliosgoimceal studies proliferation. Exp MolPathol 1987; 47(1):98-109. . (85) SoonhhleepnaituiscApKe,roAxnidseormsespornolKi,feDreatPiioenrraendJWre.laTthedepeaffreacmtestoefrspesrhfoluwornoo-oscetx-arneoliacteadc.id differences in mice. Biochem J 1992; 285 ( Pt3):779-783. (86) iaInkercdataiiTJv,BedAiriobbscayheK.pme,rfF(lTuuokokuryidona)atK1e,9d8Tf5aa;tnta9y8ka(ac2i)Md:.s4,7Tm5he-te4a8ib2no.dluicctailolnyoifneprterdoerxiivsaotmiveepsroolfiffaetrtaytion . (87) BexitergaehlepLaBt,icHtuurmtoMrEi,ndFucrtaimoen SbRy,peOr'oCxoinsnoomreJpCr,olCfoeoraktJorCs. Mechanisms of in male CD rats. Toxicol Sci 2001; 60(1):44-55. ` (88) UR.eSviEenvwiorfonEmPeAn'tsaDlraPfrottReicstkioAnsAsgeesnsmceynStcoifePnocteeAntdivailsoHruymBaonarHdea(lStAhB)E.ffeScAtsB ``AWsassohciinagtteodnwiDtCh.PFOA and Its Salts. EPA-SAB-06-006, 1-34. 1-20-2006. . RefType: Report (89) LacaiudsC,anBduttheeinr hdeorJifLv,fatiRvoegs.erTsoxJiMc.oTlhAeppdlevPehlaorpmmaecnotlal20t0ox4i;ci1t9yo8(f2p):e2r3f1l-u4o1r.oaliyl (90) sYtourdkyoRfG.amOmroaln(iguamvapgeer)fltuwoor-ogoecntearnaotaitoen ((AonPeFOli)teirnpaetrs.gen2e0r0a2t.ioHno)rrsehparmo,duPcAt,ion ` RAerfgTuyspRee:seRaerpcohr.t1926. (91) tU.hSeEdnevvierloonpmmeennttaalltoPxrioctietcytiaosnsoAcgieatnecdywi(Ut.hS.exEpPoAs)u.rePrteolpiemrifnlauroyrorioscktaansosiecssamceidntanodf ` a 7 7'/ ` p61 `itPsresavletnst.iUonSaEnPdAToDxoiccks;etRiOsPkPTA-s2s0e0s3s-m0e0n1t2D-i0v0i0si2o.n.201093.10.OfficeofPollution RefType: Report (92) Lala.uEfCf,ecTthsiobfodpeerafulxuoJrRo,ocHtaannsooicn aRcGi,d NexaproostusrkeydMuGri,ngRopgreergsnaJnMc,yLiinntdhsetmrooumsAe.B et Toxicol Sci 2006; 90):S10-518. (93) HPTieonrxdfielcruololirotoegoryctP2aM0n0o,5a;tMey2:l1cP1hl(ra1ec-ee2ns)tt1aE3l,9a-Gn1ad4n8ln.aoctnatSiAon,alBturtanesnpohrtoJfpLhf,arKmeancnokeidnyetGiLc,sJirn. ats. (94) R20e0n3n;er37R(.1C1)o:n2c0e1mA-s2o0v2eAr. common perfluorinated surfactant, Environ Sci Technol (95) GpirloldiulcatnidoFnDp,laMnat.ndJeOlccJSu.pMMoretdal1i9t9y3a;m3o5n(9g):e9m5p0l-o4y.eesof a perluorooctanoic acid (96) OeepxlipsdoeesnmuGiroWel,toogGipicelrlifinllvuaeonsrdtoiFogcDatt,ainoBnouoircflreacewipdM.roMd/,uOcctBcuiurvrepihsEonJrvMmi,ornoMenasnMdieendlmeJ1S9n,98wM;iat4nh0d(oeTcl)c:uJ6pH1a.4t-iA2on2n.al (97) GliiplolpirloatnediFnsD,,aMnadncdheolleJsSt.erSole:raumstpuedryfolfuoorcocoucptaatniooincaalcliydexapnodsheedpamtiecn.enAzmymJesn,d Med 1996; 29(5):560-8. (98) UEPSA'EsnDvriarfotnmReenptoarltPornottehcetEionnviArgoennmceynt(UT.eS.chEnPiAc)al. DCohcaupmteernt4.-WHausmhainngtHeoanltDhC.: O2f0f0i3c.eof Research and Development and Office ofEnvironmental Information, 2an 72 p62 CHAPTER 3 PERFDLIUSOTRRIINBUATTIEODNCAONMDPDOEUTNEDRSMIINNCANOTRSD OBFLOOD a9 273 . p63 Abstract BACKGROUND: Pefluorinated compounds (PFCs) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are found globally in wildlife and in human blood samples atpartper billion levels. Limited data are available on in utero exposure inthe US. METHODS: We conducted a hospital-based cross-sectional study in Baltimore, MD to examine levels and determinants of PFCsinnewborns. Cord sera were analyzed for 10 PECs by on-line solid-phase extraction, coupled with reversed phase high-performance. liquid ehromatography-tandem mass spectrometry (LODs: PFOS = 0.2 ng/mL; PFOA = 0.1-0.2 ng/mL). Demographic characteristics were abstractedfrom medical records. RESULTS: PFOS and PFOA were detected in 99 and 100 percentof 299 umbilical cord blood samples, respectively, and concentrations were highly correlated (Pearson's 1 = 0.64 after natural log transformation, p<0.01). The geometric mean concentrations of PFOS and PFOA were 5.0ng/mL(range: ND-34.8 ng/mL)and 1.6 ng/mL. (range: 03-7.1 ng/mL), respectively. Other PFCs were detected less frequently and at lower concentrations. Geometric mean concentrationsofPFOS among Asians (6.0 ng/mL) and Blacks (5.1 ng/mL) were higher than among Whites (4.2 ng/mL), while PFOA levels `were more evenly distributed by race. Slightly higher PFOA concentrations were found in babies bor to obese mothers, primiparous mothers, and in female versus male babics. None of the other demographic characteristics, including matemal age, education, and living inth city limits, were associated with PFOS or PFOA cord concentrations CONCLUSION: The identificationofPFOS and PFOA as the predominant compounds. in cord blood is consistent with previous reportsof BFC concentrations in humans. 250 poo Introduction | Perfluorinated compounds (PECs) comprise a class of man-made, fully fluorinated ! organic compounds that have been used in a variety of consumer and industrial applications for more than 50 years. These applications include protective coatings for food-contact packaging, textile, carpets, and leather; production of non-stick cooking. ' `material; commercial and industrial surfactants (e.g, fire-fighting foams, electroplating baths); and insecticides (1;2). Although produced for many years, only recently have } reports documented widespread exposure in wildlife and humans (3-5). The identification of pervasive exposure of the general US. population to one PFC, perfluorooctane sulfonate (PFOS), led its major manufacturer to announce in 2000 the phase-out of perfluorooctanyl-based products. The US. Environmental Protection Agency (EPA) has been evaluating a structurally-related compound, perflucrooctanoate. (PFOA), on the basisofpotential developmental risks (6). ! PECs are highly stable in the environment and biological systems. Based on serum analyses, the halflife in humans has been estimated at 5.4 years for PFOS and 3.8 years for PFOA (7). Many PFCs are surfactants, having both oleophobic and hydrophobic properties which provide utility as repellents of soil, oi, and water. Rather than . accumulating in lipids like traditional persistent organic pollutants, these compounds `partition in humansmainlybetween the liver and serum, where they are bound to proteins (38-12). Some of these compounds have also been shown to undergo enterohipatic t circulation, which may contribute to their long half-life in the body (7). 51 275 p.65 PFOS has been identified es a hepatic peroxisome proliferator that targets the liver and disrupts lipid metabolism in some animal species (13-15). Toxicity studies in animals have shown marked reductions in serum cholesterol and/or triglycerides (16-15), which may be mediated through down-regulation of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, a key enzyme in cholesterol synthesis (18). Recent animal studies have shown that PFOS can affect thyroid hormone levels and other aspectsofthe neuroendocrine system (16;19-22). PFOS has been shown to induce developmental and reproductive effects in rats, such as reduced matemal weight gain, reduced birth weight, decreased gestational length, birth defects, developmental delays, and increased neonatal mortality (1921-25). Among several occupational epidemiology studics, a notable finding was an elevated risk for bladder cancer among workers employed in a high exposure job, although based ononlythree observed cases (26). The primary target of PFOA toxicity is also the liver (27-29). Like PFOS, PFOA has been identified as a peroxisome proliferator (30-32) and has been shown to have hypolipidemic effects in some species (18). PFOA has been shown to cause liver tumors in rats, although it has been suggested that the proposed mechanism of peroxisome proliferation may not be relevant to humans (9,27). Increases in pancreatic and Leydig cell tumors in rats have also been observed, the laterofwhich may be due to increased estradiol levels in male rats (27,33). On the basis of this evidence, a resent draft report from EPA's Science Advisory Board concluded that PFOA should be considered a "likely human carcinogen" (34). In a retrospective cohort mortality study conducted among PFOA production workers, length of employment in the chemical division was are p68 significantly associated with prostate cancer morality, which is plausible given the evidence from animal toxicity data suggesting reproductive hormone changes (33). An update of this study with longer follow-up reportedly showed 10 prostate cancer excess, although eligibility and exposure categories were changed (35). Animal toxicity studies have suggested the potential for developmental toxicity including pregnancy loss, reduced fetal weight, reduced postnatal survival, and delays in postaatal growth and development in ra and mouse pups exposed to high doses (29,35-38). . In human biomonitoring studies, PFOS and PFOA have been the predominant PFCs detected in human blood, although the concentrations observed vary geographically. In the US, mean serum concentrations of PFOS have been reported in the range of 30-40 ng/mL (539-41). Serum PFOA levels are considerably lower, with geometric mean concentrations estimated at around 5 ngfml (539-41). Although no consistent ! association With age or gender has been reported, recent evidence from pooled samples from the 2001-2002 National Health and Nutition Examination Survey (NHANES) . suggests that White males and females have higher serum concentrations of PFCs than Blacks or Merican-Americans (5). PFOS and PFOA have also been detected in the blood of individuals in the general population of many other counties, across several q continents (3:42-50). In some developing counlris (e.g, Per), serum concentrations are considerably lower than in developed countries, suggesting that production and use of products containing these chemicals may contribute to the geographic variations observed ` (50). However, contamination has also been reported in biota from remote regions (5. 5 277 the Arctic) (13;14;41), which would require global transport of these chemicals or their precursors (51-55). Despite the growing body of literature suggesting widespread human exposure, little is known about the presence of PFCs in utero. Such data are necessary to extrapolate developmental toxicity findings from animals to humans. The only previous reports of the presenceof PFCs in the fetal circulation come from two small studiesofcord blood specimens. A study of 15 matemal-fetal pairs in Japan confirmed that PFOS could cross the placental barrier in humans, albeit incompletely (56). Another small study in Northern Canada documented detectable levels of PFOS and PFOA in pooled cord blood samples (48). There is a lack of data on the extent of fetal exposure to PFCs in the United States. To fill in this gap, we measured concentrations of 10 PFCs in umbilical cord blood as part oaf cross-sectional studyof newbomn deliveries at the Johns Hopkins Hospital in Baltimore, MD. We also examined the determinants of cord PFC levels in this population to identify whether demographic and/or socioeconomic factors were Subjects `We conducted a cross-sectional study of newbom deliveries at the JohnsHopkins Hospital in Baltimore, MD. The study received approval from the Johns Hopkins Medicine Institutional Review Board and was determined to be HIPAA `exempt. The study was conducted anonymously and utilized only specimens that otherwisewould arg p.68 have been discarded and medical records that were available to hospital and study personnel. There was no requirement for informed consent due to the anonymization of ! all samples and data. Between November 26, 2004 and March 16, 2005 all singleton, live birth deliveries occurring in the Labor and Delivery Suite at the hospital were eligible for participation in the study. We excluded from the study population babies from multiple births. Over the course of the study period, 609 live births occurred at the Johns Hopkins Hospital, of which 597 were singleton births. We obtained cord blood specimens from 341 of these, of which 42 had insufficient volume for laboratory analyses and were : excluded from this study. Cord blood samples were collected by hospital personnel immediately following delivery (57). Upon delivery, a section of the cord was cleaned with an alcohol wipe and blood was drawn from the umbilical cord vein using 2 sterile 60-mL Becton Dickinson (BD) . syringe with an 18-gauge safety needle. A BD Vacutainer Blood Transfer Device was then attached to the syringe and 10 mL glass BD vacutainers were filled. After collection, cord blood specimens were stored in LaanbdDeolivrery refrigerators. Within . several hours, the specimens were picked up and taken across the street to a laboratory at the Johns Hopkins Bloomberg School of Public Health for processing. Tubes were centrifuged at 2400 rpm for 15 minutes for serum separation. Serum was aliquoted into 2 mL polypropylene prescreened cryovials and stored at -80 C. Frozen specimens were 55 279 . ona transferred on dry ice to the Centers for Disease Control and Prevention (CDC) for Medical Records We abstracted matemal and infant characteristics from clinical databases maintained by the hospital. The data were abstracted by two study investigators concurrently, and a random 10 percent sample was verified by two others. The data collected included demographic information, anthropometric. measures, medical history, and. pregnancy- related characteristics. Age, race, education, marital status, and parity were based on self-report. Insurance type was recoded from the medical record as "Medicaid" or "Private," with "Medicaid" defined to include all forms of public assistance insurance. Body mass index was calculated from reported pre-pregnancy weight and height as the rato of weight (in kilograms) to height (in meters) squared. Gestational age was based on the "best obstetric estimate" and `categorized as term (>37 full weeks)orpreterm (<37 full weeks). Infant gender was abstracted from the mother's medical record and confirmed with the infant record. Smoking status was defined using a combinationofthe matemal medical record and cord serum cotinine concentrations measured at birth. Using cutoffs from Jarvis et al. (1987), samples with cotinine concentrations below 1 ng/mL were included in the categoryofnonsmokers, cotinine concentrations `between 1 and 14 ng/mL were categorized as passive smoking exposure, and samples with concentrations above 14 ng/mL were categorized as active smoking exposure (58). Ifthe clinical record indicated that the mother reported smoking at any time duringpregnancy, she was considered an active smoker regardless of the cotinine concentration in cord .200 p70 blood at birth. The home address recorded in the matemal record was geocoded by a commercial service (Geolytics, Inc). `We used the first five digits of the Census block ! group, referred toa the federal information processing standards (FIPS) code, to deatify the boundaries of Baltimore City. Residence inside the city limits was defined using } FIPS code: 24510. Laboratory Analysis Perfluorinated compounds. Cord serum samples were analyzed for 10 PFCsbyon-line solid-phase extraction (SPE), coupled. with reversed phase high-performance liquid chromatography-tandem mass t spectrometry. The method has been described in detail by Kuklenyik et al. (2005). Excellent recovery, precision, and reliability have been reported using this method for the detection of PFCs in human serum (59). Briefly, without protein precipitation, one. aliquot of 100 kL of serum was injected into a commercial column switching system allowing for concentration of the analytes on a SPE column. This column was placed automatically in fiontofan analytical column for chromatographic separation of the analytes. Detection and quantification were done using negative-ion TurbolonSpray ionization, a variant of electrospray ionization, tandem mass spectrometry. Detection limits were in the low nanogram per milliliter range for the following PFCs: perfluorooctane sulfonamide (PFOSA), 2-(N-cthyl-perfluorooctane sulfonamido) acetate (EtPFOSA-AcOH), 2-(N-methyl-perfluorooctane sulfonamido) acetate (Me-PFOSA- t ACOH), perflucrobutane sulfonate (PFBS), perfluorooctane sulfonate (PFOS), perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perflucrodecanoate (PFDA), Ed 291 nt perfluoroundecanoate (PFUA), and perfluorododecanoate (PFDoA). Although the analytical method allows for the quantificationofperfluorohexane sulfonate (PFHXS) and perfluorononanoate (PFNA), these analytes could not be measured in the cord sera due to the presence of nterferent compounds that eluted at the same retention times and shared ) precursorlproduct ion mass-to-charge ratios (wz) with PFHXS and PFNA. Similarly, the precursorlproduct ion mz transition used for the quantification of PFOS also had an interferent ion. Therefore, PFOS concentrations had to be calculated using another transition, normally used to confirm the presence of BFOS. The nature of these interferences is at present unknown. Quality control (QC) and reagent blank samples were included in cach analytical batch along with the unknown samples. QC samples `were evaluated according to modified Westgard rules.' Cotinine. Serum cotinine was analyzed by CDC using the method described by Bemert et al. (1997). The analytic method uses high-performance liquid chromatography coupled vith atmospheric pressure chemical jonization tandem mass spectrometry to measure serum cotinine concentrations with high accuracy and sensitivity (limit of detection [LOD] = 0.015 ng/mL). This method has been used to measure environmental tobacco smoke dose in large-scale surveys,including NHANES (60). TE ly ee ut ray "32 p.72 Statistical Analysis We used descriptive statistics (geometric mean, median, interquartile range) to describe cord serum PFC concentrations. Because PFC concentrations were skewed to the right, all statistical tests were conducted on natural log-transformed concentrations. Pearson's correlation was used to test for linear relationships between PFCs. We used linear ` regression to describe univariate relationships between continuous predictors and PFC concentrations. The presence of non-linear relationships was explored using restricted cubic spline models. . Linear regression was also used to estimate the ratio of geometric mean concentrations (and 95 percent confidence intervals) among different categories of matemal characteristics. Under the linear regression model, the expectation (or average) of the `natural log PFC concentration is describedasfollows: ! | E(nPfF+Cfx),+=& The regression coefficient, i, is equal to fy = EQnPFO),, ~ E(n PFC),, Aferexponentiating the coeffitcheieqeunattio,n reduces to: FE "GM(In PFC,5) The exponentiated coefficient can be interpreted as the ratio of geometric mean concentrationswhen X,=1versuswhen X,=0. The95percentconfidenceintervalon this ) ratio can be estimated similarly, by exponentiating the confidence intervals of the coefficient, E) 283 . 73 Multivariate linear regression was performed to compare geometric mean concentrations, after adjusting for other covariates. For all models, regression diagnostics were conducted and regression results were reported with and without robust standard errors in the presence of heteroskedssticity. Concentrations below the LOD (<LOD) were imputed a value equal to the LOD divided by the square rootoftwo for all analyses (61). Statistical analyses were performed using STATA version 8.0 (StataCorp, College Station, TX). Results `Table 3-1 summarizes the PFCs detected in umbilical cord serum. PFOA was detected in all samples and PFOS was detectedinallbut two samples, with comresponding geometric means of 1.6 ng/mL for PFOA (range: 0.3-7.1 ng/mL) and 4.9 ng/mL for PFOS (ranges ND-34.8 ng/mL). The 95" percentile concentration was 3.4 ng/mL for PFOA and 12.4 ng/mL for PFOS. These two compounds made up most of the total concentration of the PFCs measured in these specimens (52%, on average). Four other compounds were detested in at least 20 percent of samples (PFOSA, Me-PFOSA-AcOH, PFDeA, PFUA). However, concentrations of these compounds were substantially lower than those of PFOS and PFOA. Becauso only PFOS and PFOA were detected in the majority of samples and the ranges of detections for the other compounds were small, further analyses were conducted only for PFOSand PFOA. 2% i} p74 As expected, concentrations of both PFOS and PFOA were right skewed and became. more Gaussian after natural log-transformation (Figure 3-1). However, both log- ! ransformed distributions still deviated from normality based on the Shapiro-Wilk test (p<0.01). Cord concentrations of PFOS and PFOA were highly correlated with one another (Figure 3-2; Pearson's r= 0.64, p<0.01). ' Figure 3-3 shows the distribution (median and interquartile range) of PFOS and PFOA. y: concentrations by maternal and infant characteristics. In Tables 3-2 and 3-3, the ratios of `geometric means comparing these subgroups are shown for PFOS and PFOA. The geometric mean concentrationsof PFOS for Asians (6.0 ng/mL) and Blacks (5.1 ng/mL) were higher than for Whites (42 ng/ml), while PFOA levels were more evenly distributed by race. There was some evidenceof heteroskedastiity in the comparison of `geometric mean PFOS concentrations by race/ethnicity, so we generated linear regression estimates with robust standard errors as well. Using robust estimates, the difference in geometric mean concentrations between Asians and Whites was no longer statistically sigaificant. Male babies had lower geometric mean concentrations than female babies for ' both compounds (FOS: p=0.10; PFOA: p<0.01). There was 2 trend towards slightly higher average concentrations among obese (BMI 230 kg/m') and underweight (<18.5 ` kg/m?) women, compared with normal weight (18.5 -- 24.9 kg/m') women, although only statistically significant for PFOA concentrations among obese women (p<0.01). Evidence of a non-linear relationship with BMI was confirmed using restricted cubic. spline models (Figures 3-4). Primiparous and term births were associated with slightly higher average cord concentrations of PFOS and BFOA, but the differences were not 61 285 . 5.75 statistically significant in univariate models. There were no other significant predictors of cord concentrations among the remaining covariates, which included age, education, insurance type, marital status, smoking status, and living inside the city limits. Similar relationships were observed when all the variables were included in a multivariate model (Tables 3-2 and 3-3). When examining covariatesasconlinuous measures, no significant linear trends were observed between PFOS or PFOA and matemal age (Figure 3-5), gestational age (Figure 3-6)orcordcotinine concentration (Figures 3-7, 3-8). Discussion "This study confirms earlier findings indicating that the developing fetus is exposed to persistent PFCs in utero. We detected PFOS and PFOA in 99 and 100 percent of 299 umbilical cord blood samples, respectively, at a hospital in Baltimore City. The geometric mean concentrations of PFOS and PFOA were 49 and 16 nim, respectively. Other PFCs were detected less frequently and at lower concentrations. The identification of PFOS and PFOA as the predominant compounds detected in cord blood is consistent with previous reports of PFC concentrations in the blood of individuals in the United States. Cord concentrations of PFOS and PFOA were found to be strongly correlated with one another. Thecorrelationbetween these compounds isofinterest because they arise fom different industrial sources and their presence likely differs in consumer products. Further, there is no evidence that PFOS or PFOA can degrade or metabolize into one another. To date, the pathwaysofhuman exposure to PFOS and PFOA are not well 6` 23 p76 understood. It has been hypothesized that volatile precursor compounds (perfluorinated sulfonamides and fluorotelomer alcohols) may contribute to the widespread ! contamination observed in remote regions (51;53). Recently, residual amounts of these compounds have been identified in commercial and consumer products, including carpet protectors (62) and microwave popcorn bags (63). POS and PFOA have also been ! identified in house dust andlor indoor air (64-67). If exposure through consumer products were occurring and the useof these products were correlated, this could explain , the correlation observedin human serum samples. Altematively, environmental contamination of these compounds has been well- . documented in regions as far away as the Arctic (68:69). PFOS (and PFOA to a lesser extent) has been shown to bioconcentrate in fish (4470-72) and biomagnify in aquatic food chains (470-73), sugsesting tha fish consumption could be a plausible source of ! exposure. In a recent study in Poland, Falandyszetal.(2006) found that individuals with high fish consumption had elevated concentrations of PFOS (and PFOA to a lesser . extent) in their blood relative to other groups (42). The correlation between PFOS and PFOA in blood may reflect the co-occurrence and uptake of these compounds through secondary pathways, such as dietary or drinking water consumption. Alibough the . specific pathwaysofexposure are still uncertain, these data would indicate that PFOS and PFOA share common pathways to the population of women of childbearing age in this region. 6 2497 77 `The analytic method used to measure human serum concentrations of PFCs has been described in detail (59). Excellent precision has been reported using this on-line method. At concentrations in the rangeofwhat we observed in the current study, CVs of 10 percent were reported for both PFOS and PFOA (59). In this study, measurement error for PFOS may be greater, because the precursor/product fon transition nomally used for quantification could not be used due to coelution with another interferent analyte transition fon. In general, measurement emor would be expected to. bias bivariate associations to the nullifthe error is completely random (74). Thus, it may contribute to the lack of differences observed in PFC concentrations between many of the subgroups under study. `Cord PROS and PFOA concentrations in this study were generally within the range of previous reports from Japan and Canada (Figure 3-9). Inoue ct al. (2004) measured. PFOS and PFOA in serum collected in Japan in 2003 from 15 maternalfetal pairs. The authors reported the presence of PFOS in all 15 cord blood samples tested, at concentrations ranging from 1.6 10 5.3 ng/mL (56). In the same study, PFOA was detected in onl3y maternal samples and no fetal samples (LOQ: 0.5 ngimL). In a study of 13 pooled cord plasma samples in northem Canada, collected from 1994-2001, arithmetic mean concentrations of PFOS and PFOA were 16.7 and 3.4 ng/L, respectively, higher than the average concentrations reported here (48). Inoue et al. (2004) reported that concentrations of PFOS in cord blood were approximately one-third those of matemal concentrations (56). If we assume this 6 HH 78 veltionship would be observed in the present study, then this population may have lower exposure than reported for other partsofthe United States. The geomelric mean PFOS. ` serum concentration reported here, 5 ng/mL, would correspond to 15 ng in the mothers. This represents less than half of the average concentrations reported in the United States, which are in the range of 30-40 ng/mL (5539-41). However, in a recent analysis of pooled 2001-2002 NHANES samples, mean concentrations of PFOS among `women of childbearing age were 24 and 18 ng/mL, for Whites and Blacks, respectively . (5). Differences in reported concentrations may result in part, from varied use and exposure to fluorochemically-reated consumer products, different dietary habits, and temporal trends in human exposure. Altematively, th reltionship between mater and ` fetal concentrations may be different in this population than what has been reported by Inoue et al. (2004). Further, tis study was not intended to be representative of the full US. population and regional differences in exposure may exist. The hospital in which ! this study was conducted is located in an urban area on the East Coast of the United States. The patients delivering at this hospital ae likely to represent a diverse mixture of . subjects, including individuals rom the surrounding community, faculty and staff from the adjacent medical institutiasownesl,astransfers from outside ofthe Baltimore area. In this study, very few matemal factors were observed to be predictors of cord PFC concentrations. FOS and PFOA concentrations wee relatively constant across maternal age. This lack ofassociation with age is consistent with reports amongotherpopulations Olsen and colleagues conducted three separate studiesof PFC concentrations in the blood of children, adults, and the elderly, and found similar geometric mean PFOS and PFOA 6 34 5.79 concentrations (39-41). If exposure to these compounds were a functionofthe type of `consumer products and materianlthse home, one might expect to observe adifference in serum concentrations between individuals of different socioeconomic status, However, none of the socioeconomic measures in our study (e.g. education, insurance, marital status, living within the ity limits) were associated with fetal concentrations. It should be noted that a significant amount of data was missing on insurance status and selfreported level of education may not be a precise measure of attained education for the study participants youngerthan age 18 (n= 25). Thus, there may bebettermetrics (c.g. income, wealth) with which to examine the presence of socioeconomic disparities in the distribution of fetal levels of these compounds. Overall, cord concentrations were. relatively low, specifically for PFOA, such that even statistically significant differences estimated by the ratioof geometric means may reflect minor absolute differencesindose. For example, we did find a difference in cord PFOA concentrations by matemal bmi (obese versus normal weight) and infant gender (male versus female), however the absolute difference in geometric means between the groups in cach comparison was only 03 ng/mL. In our study population, babies of Asians and Blacks had somewhat higher PFOS concentrations than those of Whites. `This is in contrast to an analysis of pooled serum samples from 2001-2002 NHANES, in which White females of child-bearing age had higher levels than Black females (5). There are several possible reasons for differences in this relationship, including the use of pooled versus individual serum samples, differences in exposure pattems between the populations under study, or variations in 66 70 p80 placental transfer by race. Interestingly, the three highest PFOS concentrations observed in this study were all among Asians (two from China). Several studies conducted in ` Asian countries have reported concentrations of PFOS in the general population at or above what has been observed in the United States (44-47). In fact,a Chinese study of 85 blood samples collected in 2004 reported a mean PFOS concentration of 52.7 ng/mL. ' (47), substantially higher than what has been typically reported in the United States (40). These data are consistent with regional variability in exposure, for which race/ethnicity . `may represent a surrogate marker. In summary, ourfindingsconfirm the presence of in utero exposure to PFOSand PFOA, and less 50, to other PFCs under study. These data suggest that exposure is occurring among apopulationofwomenofchildbearing ageintheBaltimore rca, at levels that are similar to or slightly below such women across the United States. Concentrations of ' PFOS and PFOA were highly correlated, possibly due to common pathways for exposure. Further, in utero serum concentrations of PFOS appear to be higher in Asian and Black babies, when compared to White babies. Future studies should measure maternal serum concentrations in addition to cord serum concentrations, to describe the extent of placental transfer of these compounds. The next chapter examines the relationship | between cord serum concentrations, birth weight, and birth size in this population. & 9 p81 `rTeapbolret3e-d1.inPuenriftlsuoorfinnga/tmedL.chemicals (PFCs) measured in cord blood serum and Gorapound Tint or Detection %A"bLoopve Geom(eRtarnigceM)ean MToetaanl P%FoCf EPLMFePO-FSPOAFSOASAACAOCHOH 00025 02 Ex1%) 40% 000154((NNDD--0058)) 020(ND- 18) 302080%%% PPEFBOUSS PEHpA 0012 01 93%% 2% 409057((NNDD--30428)) 029(ND 25) 16.20%% 40% PPFFDOeAA PFUA 010022 1200%% 02 us 011577(0N3D-711.1)) 020(ND- 1.9) 2240%% 25% PaulcFfPtoDaEneaOO;tSeAMA;eP-=OPpFSeOrSf=lApu-eoArrfCoiOcriHoneo=c2st-unl(efVo0mn2eualtmfihodyneak;tpe;eBrPfFliuOpoSoAA5o-%ctAaCnOeiHsoorn=oah2me0-pi.(idN1a-o5se)(otahNaytDcee;pt_r1tf.;uForEoBoSca=nspersf2aul0ofcr%aoannboiuunttiiedn)g P++FADsAsum=ipnrgflpuoonr-oddteectasno(aNtDe)PeFaUAls L= eOrDli.roPuFndeca=npoeartf; PFDA = perioPrFoOdAod=ecpaenfoltueoroo 68 9A p82 `cToanbcleen3t-r2a.tiRoantsiions c(oarndd b9l5o%odcsoenrfiudmebncyemiantteerrvnaalls)aonfdgienofmaenttrcihcarmaectaenriPstFicOsS. ` [ome | oo [m eo mms r] `Ag<e1g8ryoeuaprs 1.00(0.76-4.31) 1.02 (0.73-1.43) 1>83:535 yyeeaarsrs 100(0-76.32) 113 (0--841.59) ` R`aWcreite & -- mm ABslaicakn. 2120 112433 ((11,,006211..4985)) 11.4238(1(0..0982:21.0618)) `Ed<ucHaStidoinploma, 8 ~ - H1-S4 dyiepalrosmcaollege 97 6 11.0071((00.8882:413.205)) | 11..0056 ((00.7894-113422)) Tn5su+yraenacres cole 2 1.07 (0.84437) 1.05 (0.70-1.58) PrPiuvblaitceassistance 116 0 1.10 0.--86-1.41) ` WarUtnamlarsrtaiteuds. 198 -- -- Mariod Body mass index 101 095 081-111 090 067-1.19) . UNnodemrawe(i1g8h.t5:(2<41.89.)5) 11365 122087173) -- 122(0851.75) -- OObveersweeig(3h0t+)(25299)|. 65 7 01.9183(008930-11:2307)) | 01.71(10(07.8910-.41379)) PParriitmyiparous. 125 -- -- . SmMouklitnipgarsotuast.us. 174 0920.79.08) 091076108) PaNsosni-vsmeoker 1.07 (0--.79-1.44) 1.05 (0-.76-1.46) TAncfatnitvgee.nder 088 (0731.08) 092 073-1.15) . FMeamlaele 133 166 0.88 (--0761.02) 087 (0--741.02) Tide city mits? NYeos 1.04 (0"881.22) 084 07--51.17) Preterm bith No 20 -- - ` AdYjuessted model cladeals vari3abl9es Ted te0u.8b6e(0.69-1.08) 050070114) `dTahteafwolelrowtirngtdeadaaswaenrienmdiiscsationrgt:e4rombsiertveagtrieossnisofnormeoddueclast.ion, 85forinsurance and 11for BMI Missing 6 `Table 3-3. Ratios (and 95% confidence intervals)of geometric mean PFOA `concentrations in cord blood serum by maternal and infant characteristics. wori osama | osmomzo [Poa Characteristic|vom omer] i2on roso-muasy | mon-i lrynpemnns | 55o || ememmi || sseemm~iis Cer | 2 | meme | reps eis | _ - E i fSnse po | eme_mn | ang_i || iSmrranmnires lne|| 2 2525 ||| iitsmase3moersmn ||| mrsaeoogoersainn iToEgiwcoornn 2us | omem_ion | amo_re _ _ foa nwerd || amreosm i -io se_re | seh_en k=o 2" | o_ni | oe_ m B Prr vewteoerm bir rth |= |ar ason_ia. | se_en Daioh Ll 70 WY p84 2 2 ve2l MH wo pesli 2 )- [r A ` ThFra osihaw m) 3 : nsros 7 7 8 g 8] g --~ : - E 2s A - - B|o - 2 \ = T3_P1ro--n)% % Tonpron 7 7 Figure 3-1. Distributions of PFOS and PFOA concentrations in cord blood serum. 7 295 p65 : TT Tine 2 Ce Trerpneeminte = spseondraiaaBedeisndTe 2g Soa dpDupTiREEEEES . a to. i : PFOA(ngfmL) 3 133 sFeirguurme(3-n2=. 2C9o9r)r.elation between PFOS and PFOA concentrations in cord blood "rest n 27 p86 0, == =m ! BE == SE = Sma] wa = Swaa o --e ,r EarbEre -- =--= re EE- = ee Tirois iom)ww TTronnosto) n F(imgeudriean3-a3.ndDiisnttreirqbuuatritoinloefrPanFgOeS) bayndselPeFctOcAhacraoctnerciestnictsr. atinicoonrsd blood serum . kd 0s sq Td EA een tEieE "_ . Ef Laer Te Te % % 3 % % `Bodymassindex (kg/m2) Lu ef PUL ty % %soy mas %bo) % % . Figure 34. FFOS ap) 0dPFOA (oto) concnitcoardtblooodnsersum vNoetres:usLimnaetererfnlaelctpsrper-edpircetgendav ncyabfordl oymmau asressetirnidcs etexd(uc=ub2i8c8)s.pline model. " Ix of Cod rngth eepiie nTr } 9Z | a REb E Ee E . . i Matema aga @ . - . Scedred, P:aLn . tu * "s cE , 5& p sseait plaitp inT ongnineL hrt e ftye n Matom@alage = vFeirgsuurse 3m.a5t.erFnaOlSag(eto(pa)=2a9n9d).PFOA (bottom) concentrations in cord blood serum (PFOS: = -0.0007p, = 0.90, PFOA: f= -0.0026p, = 0.54) 5 Ix ~ CoE LCoaDetmihnen 8& -- onS d R wyE wl i . . 20 0 220 250 20 a0 Gestational age (days) . 1. . 5 . 2 . soTmenrle te : shot t etwne i t dy fu BE ES 0 240 20 250 at Gestational age (days) Figure versus 3-6. PFOS gestational (top) and PFOA age (n = 299). (bottom) concentrations in cord bloodserum. (PFOS: = 0.00p 4= 06.1,0; PFOA: =0.00p=208.1,7) 7 . comme oe eget to. wT Ee EE pe ad dor WE oh gE Ig mite. Ee . Sl . oe in sv Vales Figure 3-7. PFOS (ng/mL) versus cotinine (ng/mL) concentrations in cord blood ` serum, with(n = 286) and without (n = 211) the inclusionof non-detectable cotinine (With NDs: =-0.0061p, = 0.62; Without NDs: = -0.0131p, = 0.32) " pot Sl ewiEE TLL sliF SmaE d,SeT e 5 Tahmaendth RR lL weet TTTmeTTY TEScrTe TS values, Figure 3-8. PFOA (ng/mL) versus cotinine (ng/mL) concentrations in cord blood `serum, with (n = 286) and without (n = 211) the inclusionof non-detectable cotinine (With NDs: = 0.0095, p = 0.31; Without NDs=: -0.0049p,= 0.63) n kes ze - : go ! 3, . " ------- (n=29) (n=15) (n= 13pools) . 79 5.93 References (1) MKiasrscaelE.DeFklukoerri,naItne,d s2u0r0f1a.ctants and repellents. Second ed. New York, NY: (2) 3DoMcCkoem#tpaOnPyP.T-F2u0o0r2o-c0h0e4m3i.ca1l99u9s.e,5d-i2s6t-r1ib9u9t9i.on, and release overview. EPA RefType: Report (3) Ksale.avnePnrearalfnlcuKoo,urnoCtoorcirtessao.nleEisniuvlSif,roonFanatlSeacniadnyTdserczehJln,aotFleid2l0lfm0la4vno;nr3o8Gc(,h1eK7m)ui:cm4aa4l8rs9-iK4nS4,h9u5L.moagnanbaltohoadnfBrGomet (4) `GEinevsiyroJnP,ScKiaTnencahnnKol.2G0l0o1b;al35d(i7s)t:r1ib3u3t9i-o4n2o.fperfluorooctane sulfonate in wildlife. (5) CPaelrafflautorAoMch,emKiuckallesniynikpoZo,lCeadusdielrlumSPs,aRmepliedsyfJrAo,mNUeneidtheadmStLaLt.s residents in 2001 and 2002. Environ Sci Technol 2006; 40(7)2128-2134. (6) hUsuaSmsaE(nnPvhFieOraAol)nt.mheehnfitftaepcl:t/PsArawoswtsewoc.ctciipaoatn.egdAogwveilntochpype.lxipDnortasrfputfroeiast/okpfpaoesarsrfeilssus.mobernomtooc.ftt2a0hn0eo5.apcoitednatinadlts RefType: Blectronic Citation (7) (EFvOalSu)a,tipoenrofflutohreohhaelxfa-nleifseul(fToyn)atoef(ePlFiHmiSn)aatniodnpoefrfpleurofrlouoocrtoaocntoaantees(ulPfFoOnaAt)e from `ohrugamnaincsseirnumth.eFeLnvUiOrRoOnmSe:ntA;n05inAteumgat1i9o;pa2l00s5y.mposium on fluorinated alkyl (8) `3aMnd Ctooxmipcaonlyo.gyPdeatraf.loErPoAocDtoancekestulOfPonPaTt-e2:0c0u2r-e0n0t43s.um1m9a99r.yo1f-2h1u-1m9a9n9.sera, health RefType: Report (9) KhuudmaonNs,aKnadwaansimhailms.a JY.TTooxxiicciStoyclan2d00t3o;xi2c8o(k2i)n:e4t9i-c5s7o.fperfluorooctanic acid in (10) JfaotnteysaPciDd,sHtousWe,ruDmeprCooteeinnsW.,EnNveiwrsotnedToJxLi,coGlieCshyeJmP.20B0i3n;di2n2g(o1f1)p2e6rf3l9u-o4r9i.nated (11) LfulcubokreorcDhJ,emHiancwsaieltnshKrJa,t lBiavsesr fNaMt,yBauctide-nbhionfdfiJngL,prSoetaeicna.tTAoMxi.coInltoegryac2t0i0o2n;s of 176(3)175-85. (12) VfaatntydeacnidHseutvoeplroJtPe,inKsusilnitkhiespBlIa,sPmetaerlisvoenrRaEn.d tCeosvtaelsoefntrabisn.dCinhgeomfBpeirofllIunotreirnaactted 1992; 82(3)317-28. 50 post (13) SPeorhflleunoiruosoActKa,neErsiuklfsosnoincAaMci,d HisogasptotreonmtCi,ndKuicmelroanfdpMer,oDxeiPsioemrarlefaJtWt.y acid beta- . o`xmioduasteiloinvearn.dPohtahremraaccotilviTtoixeisckonlo1w9n93t;o7b2e(a2f)f9e0c-t3e.dbyperoxisome proliferators in (14) Srpaehnrisfp-llauecoytrIiovMoa,cttiHaounner-sobtfaPCsPeHAd,RcTahaelnmpiahckaaalasSn.SdT,oiDxneidRcuocotloiSsocnFioL2f,0P0BP4uA;teR8na0hl(o1pf)hf:a1J5Lt1,a-r6Sg0ee.tacgaetnAesMbyet al. ` (15) aFnadhmiemdiiHcDin,eS.iBeesrHl,inE;uNroepweaYnorCkel:lSBpiroinlgoegry-OVregralnaigz,a1t9i8o7n.. Peroxisomes in biology (16) SSeuabccahtroAnMic,tTohxoicmiftoyrsdtuPdJi,esHoannspeenrfKluJo,rOolocsteannGesWu,lfoCnaastee MpoTt,asBsuitumensahltoifJnLf. . cynomolgus monkeys. Toxicol Sci 2002; 68(1):249-64. (17) SaleacSautb-AchMr,onTihcodmifeotarrdyPtJo,xiHcaitnysoefnpKoJt,asCslieummepnerLfAl,uoErlodorcitdagneesSuRl,foEnlacteomibneratCs.R et Toxicology 2003; 183(1-3):117-31. (18) H`paeurfglhuoormooBc,taSnpoiycdeavciodld(POF,OTAh)e, mpeercfhlaunoitosomcutnadneersluylipnhgotnhiec hacyipdol(iPpFeOmiScA)efafnecdt of clofibric acid. Biochim Biophys Acta 1992; 1128(1):65-72. (19) TExhpiobsoudreeautxo JpRe,rfHlaunosrooonctRaGn,e sRuolgfeonrastJeMd,urGirnegyprBeEg,nBaanrcbyeienBraDt,anRdicmohuaser.JdHsI: et a. `maternal and prenatal evaluations. Toxicol Sci 2003; 74(2):369-81. (20) PASeuMrs.stpiNenecuMtrE2o,0e0nK3da;osct1ru1ri1in(e1B2Se)f,:fBe1ca4t8rs5bo-ef9r.peMr,flKuaonrnoaonctKa,neMsouhlafonnKatuemianrraPsS.,EMnovhiraonnKHuemaalrth . (21)LEaxupoCs,urTehitboopdeerafluuxorJoRo,cHtaannesosunlfRoGn,atReodguerrisngIMp,reGgrneayncByE,inSrtaatnatnodnMmoEuseet. alI.: postnatal evaluation. Toxicol Sci 2003; 74(2):382-92. (22) Lrfaurteo:bmkdieonsreuDt-Ierr,eosYpeooxnrpskoes,RuGar,nedtHobainpoescrehfnelumKoiJrc,oaoMlcotaoannrdeespuhJlaAfr,oanBmaautcteoek(inPnFheOotSJif)Lcf.ipnaNrSeapomnreatategrausle.-moDratwalleiyty Toxicology 2005; 215(1-2):149-169. (23) GperrafsltuyoRroCo,ctGarneeysBulEf,onLaatue-CiSn,duRcoegdenresonJaMt.alPmreonrattaallitwyiinndtohweoSfprsaugscueep-tDibaiwlliteyytroat. ` Birth Defects Res Part B Dev Reprod Toxicol 2003; 68(6):465-71. (24) L`(guPeeFnbOekrSae)triioDnnJar,tesCp.arTsoodexuiMcctToi,olnoYgaoynr2dk0cR0r5Gos;,s-2Mf1oo5so(t1re-er2)sJt:Au1,d2i6He-as1on4sf8e.pnerKfJl,uBoruotocetnanheosuJflLff.oTnawtoe- 81 (25) Fuentes S, Colomina MT, Rodriguez J, Vicens P, Domingo JL. Interactions in developmental toxicology: Concurrent exposure to perfluorooctane sulfonate (PFOS) and stress in pregnant mice. Toxicol Lett 2006; 164(1):81-89. (26) Alexander BH, Olsen GW, Burris JM, Mandel JH, Mandel JS. Mortality of employeesof a perfluorooctanesulphonyl fluoride manufacturing facility. Occup Environ Med 2003; 60(10):722-9. o (27) Kennedy GL, Jr., Butenhoff JL, Olsen GW, O'Connor JC, Seacat AM, Perkins RG et al. The toxicology ofperfluorooctanoate. Crit Rev Toxicol 2004; 34(4):351- month. Toicl So 2003, 65(1)244.57 (28) ButenhoffJ, Costa G, Elcombe C, Farrar D, Hansen K, Iwai H et al `Toxicity of `ammonium perfluorooctanoate in male cynomolgus monkeys after oral dosing for (29) ButenhoffIL, Kennedy GL, Jr., Frame SR, O'Connor JC, York RG. The reproductive toxicologyofammonium perfluorooctanoate (APFO) in the rat. Toxicology 2004; 196(1-2):95-116. (30) Ikeda T, Aiba K, Fukuda K, Tanaka M. The induction ofperoxisomeproliferation in rat liver by perfluorinated fatty acids, metabolically inert derivativesoffatty acids. J Biochem (Tokyo) 1985; 98(2):475-482. (31) PastoorTP, Lee KP, Perri MA, Gillies PJ. Biochemical and:morphological studies `ofammonium perfluorooctanoate-induced hepatomegaly and peroxisome `proliferation. Exp Mol Pathol 1987; 47(1):98-109. (32) Sohlenius AK, Andersson K, DePierre JW. The effectsofperfluoro-octanoic acid on hepatic peroxisome proliferation and related parameters show no sex-related differences in mice. BiocheJm 1992; 285 ( Pt 3):779-783. (33) Biegel LB, Hurtt ME, Frame extrahepatic tumor induction SR, O'Connor JC, Cook JC. by peroxisome proliferators Mechanisms of in male CD rats. Toxicol Sci 2001; 60(1):44-55. (34) U.S.Environmental Protection Agency Science. Advisory Board (SAB). SAB Reviewof EPA's Draft Risk AssessmentofPotential Human Health Effects Associated with PFOA and Its Salts. EPA-SAB-06-006, 1-34, 1-20-2006. `Washington DC. RefType: Report (35) U.S Environmental Protection Agency. Preliminary risk assessmentofthe developmental toxicity associated with exposure to perfluorooctanoic acid and its salts. USEPA Docket OPPT-2003-0012-0002. 2003. Office of Pollution Prevention and Toxics; Ref Type: Report Risk Assessment Division. 1910. 82 306 5.36 (36) LacaiudsC,anBduttheeinr hdeoriJfvLfa,tRivoegse.rTsoxJMi.colThAeppdlevPehlaorpmmaecnotlal20to0x4i;ci1t9y8o(f2p)e2r3f1l-u4o1r.oalkyl . (37) YstourdkyRofG.amOmraoln(iguamvapgeer)ftlwuoor-ogoecntearnaotaitoen ((AonPeFOli)teirnpreatrs.gen2e0r0a2t.ioHno)rsrehparmo,duPcAt,ion RAerfguTsypRee:seRaerpcohr.t1926. (38) Lala.uEfCf,ecTthsiobfopdeerafuluxoJrRo,ocHtaannsoiocnaRcGi,d eNxaproostusrkeydMuGri,ngRopgreergsnaJnMc,yLiinntdhsetmrooumsAe.B et Toxicol Sci 2006; 902):510-518. (39) `OSlesreunmGcWon,ceCnhturartcihonTsRo,fLpaerrsofnluEBo,rvoaoncBteallneeGs,uLlaufnndodonbteahrtegerJfKu,oHraoncsheemniKcaJlestianl.an ` elderly population from Seale, Washington. Chemosphere 2004; 54(11):1599- 611. (40) OPRleesrdefnClruGooWsrs,ooaCdcuhtluatrnbcelhsoaTolRdf,doMonianalontlrdeesr.oJEtPhne,vriBrluorunroirHsoecJahMlet,mhiHPcaeanrlsssepniencKttJh,2e0Ls0u3en;rdub1m1eo1rf(g1AJ6mK)e:r1eit8a9cl2a.-n901. X (41) OIdlesnetnifGicWat,ioBnourfrfsluJoMr,ochLeumincdalbseinrJKhg,uHmaannsesenraK.J,11.MaPneddeialtJrHic,pZaorbteiclipLaRn.ts in a G1r5-o2u0p02A. SMterdeipctaolcoDceepaclritnmiecanlt,tri3alMinCvoemstpiagnatyi.on. EPA Docket AR226_1085. 3- ` RefType: Report (42) FfiaslhaandmyasjzoJr,sToaunricgeoasfufSl,uoGruilnkatoewdsskuarfAa,ctYaantmsasahnidtraepNe,llSecnhtsulitneh-uOmchalnmsalninviUn.gIosn the Baltic Coast? Environ Sci Technol 2006; 40(3):748-751. ` (43) K`puebrfwlauboroooCc,taVnaeissulNf,onBaetneoaintdFoMt.heAr ppeirlfoltusotruidnyatoend cthoemdpeotuenrdmisniantibolnooodfof Canadians. JEnviron Monit 2004; 6(6):540-545. (44) TpearnfilyuaosruooSc,tKaneasunlfKon,naHatoernainidYr,elHaatneadrpierNf,luYoarmianastheidtoarNg.anAicscuormvepyouonfds in water, . fish, birds, and humans from Japan. Environ Sei Technol 2003; 37(12)2634-9. (45) iHsunalfrflouanedantcaee,oanfSdatipitmoee,N,rseIxfnoaulneduKg,eooYgorrsaihpoinhnihoacugfcmaaacTttn,osrWaesartonuanmnoloaevbaveeelrtsTot,hfeSepaeslraasfktli2u5oryeoetoaacrlst..aTnhJeeOccup Health 2004; 46(2):141-7. (46) M``sOaurslgfuaonnnaaotgheaa(l8Po,gFeKOnaSn)CnoaamnnpdoKou,thnDedorsire2Rl0,a0tN2ea;dkc5a9on:im3sp1ho9iu-3Jn,2d2Gs.ieinsythJeP.blLoeovdeolfsoJfappearnfelsueopreooopcltea.ne 5 ps7 (47) YPeerufnlugorLoWo,ctSanoeMsuKl,foJniaatnegaGn,d Trealnaityeadsfulu5,orYoachmeamischalistNia,n hSuonmganMbletoao.d samples from China. Environ Sci Technol 2006; 40(3):715-720. (48) TsietrtulmemcioelrlSe,ctReydafnroJmJ,nVoarnthOeomsCtadnaaJdmi.aPnrpeospeunlcaetoiofnas.niOrognanoorhgaanliocgecnomCpoomupnodusnidns 2004; 66. (49) Getuarlu.gPeerKfSlu,orTiannaityeadsourSg,anYiacmcaoshmiptoaunNd,sWiijnehruatmnaanSb,lMooohdotsteiruKmMa,ndSesneemviinraaltne HR pMloansimtas20a05s;tu7d(yo4)f37u1r-b3a7n1.and rural tea worker populations in Sri Lanka. J Environ (50) eCCtahalela.mfoaPtserpAfhMleu,roerNie2n0aet0de6hd;ac6mh3e(Lm3Li),c:a4Kl9us0k-li4ne9ns6yeliekctZe,dRreeisdiydeJntAs,oTfutlhley JASm,egruiiclaanr-cVoinltlianleonbto.s M. (51) R3e8(n5n)e:r80RA..Perfluorinated sources outside and inside. Environ Sci Technol 2004; (52) SStcetiloocTmkeecNrhLan,loclLoa2h0oul0Fs4K;a,n3d8E(ls4iu)sl:fD9o9An1,a-m9Mi9ad6re.tsiinnJtWh,e NMouritrhDACm,erMiacbaunrtyroSpAo.spPhoelryef.lEuonrviinraotned (53) MEplePlrifsleutDoaArl,i.nDaMetagerdrtaicdnaartJbiWoox,nyolDifecfSaliculiodvrsa.oAtEeOnl,voimMreaorbnaulSrccoyihoSTlAesc,:hHnauolrlilk2ee0ly0y4Ma;Dtm3,o8s(S1pu2hl)eb:ra3ic3ck16sA-on3ud3r2ec1re.soefn (54) tPrraenvsepdoortuorfospeKr,flCuooursoicnasrbIoTx,ylBautceks.RECn,viKroornzeSnciioTwesckhinoSlH.20S0o6u;rc4e0s(,1)fa3t2e-a4n4d. (55) EA3lt7lm0io1ss7Dp)Ah:,3e8rM1ia6cr3tl8ii2fn0et.JiWm,eoMfafbluuroryoSteAl,oHmeurrlaelycoMhoDl,s.AEnndveirrsoennSMciP,TeWcahlnloiln2g0t0o3n;TJ. (56) sIunlofuoenaKt,eO(kPaFdOaS)F,aIntdorRe,laKtaedtpoe,rfSluaosraikniatS,edNcaokamjpiomuandSseitnalh.uPmerafnlumoartoeorcntaalneand `cdourrdinbglporoedgsnaamnpclye.sE:navsisreosnsHmeeantlothfPPeFrOsSpecetxp2o0s0u4r;e1i1n22(1s)u:s1c2e0p4t.ib7l,e population (57) pWoisttteprarFtRu,mTceonrdBbrloocodc.k JJ,ntFJoxGyHEn.aecAolneOwbsdteevti2c0e0f1o;r s7a2f(e3r):c2o5ll9e-c6t0ion of (58) tJTeaIsr(tv1si1su)sM:e1Jd4,3t5To-ud1ni4sst3ta8il.nlg-uPiesdhosemHo,keFresyefrraobmennodnCs,mVokeesres.y CA,mSaJlPouobjleiscYH.eCaolmthpa1r9i8s7o;n of 8 p.58 (59) KourgkalneincyiackiZd,saNnedeadmhiadmesLLi,nhCaulmaafnatseArMu.mMuesaisnugorne-mleinnteosfol1i8dp-eprhfalsueoerxitnraatcetdion. , Anal Chem 2005; 77(18):6085-6091. (60) B`cDoetemiveneriltnoepJimTne,nsJtmro,aTknuedrrvsnaealrinWddaEtni,oonPnosifmrskoelkneeJsriLst,ibvySeolsminqeoutifhdfoCcdSh,rfoorAmkaditenotsgerrJmaRip,nhayWt/iaaotnmolofspsdMheerKrruiemcetapl. pressure ionization tandem mass spectrometry. Clin Chem 1997; 43(12):2281- 291 (61) H`noomnduentegctRabWl,e Rvaeleueds.LDA.ppElstOicmcautipoEnonfviarvoenraHgyegc1o9n9c0e;nt5r(a1t)i:o4n6-i5n1t.he presence of (62) Dpirnegsleantsainn-PvaanrliioluisofMluJo,riMnaatbeudrmyatSeAr.ialSsi.gnEinfviicarnotnrSecsiidTueaclhfnloulor2i0n0a6te;d4a0l(cSo)h:o1l4s47- ' 1453. (63) FBPoeeorgfdlleuyAodrTdoHict,heCWmohicniattleasm:K,2p0oHt0oe5in;tgif2a2ol(r1sto0u)Pr:,c1Te0ws2oa3r-fo1as0nk3d1i.mMiLg,raNteicohnefsroRm, WfoaoldkepracRkAag.ing. . (64) KotuhbewrapebroflCu,orSotcehweamritcBa,lsZhinudJu,sMtafrrtoomLs.elOeccctuedrrheonmceeosfipnetrhfecluiotryosouflOftotnaawtaes,and Canada. J Environ Monit 2005; 7(11):1074-1078. (65) M(oPrFiOwSa)kainHd,pTerafklautoarhooYc,taAnroiackacaiwdRa.(PCFoOnAce)ntirnavtaiconusuomfcpleerafnleurodruosotctcaonlelescutlefdoniante. Japanese homes. JEnviron Monit 2003; S(3):753-757. (66) SinhionedioboMr,anHdamouetrdoT,orWaiilrfaonrdd BinHd,ooJrondeusstK:Co,ccZurhruenJ.ceP,erpfalrutiotriionnaitnegd, saunldfohnuammaindes exposure. Environ Sci Technol 2005; 39(17):6599-6606. (67) `SchoonecienbtMra,tiHoansmeanrdTp,hIaskeonpoarmtoiutiMo,ninKgaonfnpaernfKl.uoIrnodaolokrylansudlofuotndaomoirdeasirand polybrominated dipheny] ethers. Environ Sci Technol 2004; 38(5):1313-1320. . (68) SCimrictuhmwpioclkarM,stMuadyboufrpyerSfAl,uoSroolaolmkyolncKoRnt,aSmionnannetsC,inMaprotlairnbJeWa,rsB(oUrmsuEsW etal. `maritimus). Environ Sci Technol 2005; 39(15):3517-5523, (69) IMdaernttiinfiJcaWt,ioSnmoiftlhownigc-kchMaMin,pBerrfaluunoreiBnaMt,edHaoceikdsstirnabPiFo,taMfuriormDtCh,e MCaanbaudriyanSA. . Arctic. Environ Sci Technol 2004; 38(2):373-380. (70) SpienrcfllauiorroEa,lkMyalysaucrfkacDtTa,ntRsoibnlweaeteKr,,Yfaismha,sahnidtabiNr,dsKfarnonmanNeK.wOYcocrukrrSetantcee. oAfrch Environ Contam Toxicol 2006; 50(3):398-410. 8s p99 (71) PBaelrtfilcuoSreian.atFeLdUcOheRmOiSca:lsAinn binltoeomdaotfifoinsalhsaynmdpwoastieurmfoownl fflruoomrignateuodfaGllkdyalnofsrkg,anics in the environment ; 05 Aug 19; 2005. (72) `cKhcaaonimnnp.aonAu7nKcd,hsTEiannovaiqLru,oaStniicCncoohnratgraanEmi,sTPmoaxssitacvtoavlaS2rD0i,0o5uJ;sudt4re8o(Dp4hJ)i,:c5G5li9ee-vs5eyl6s6J.iPn. aPeGsrfelautorLiankateesdfood : (73) P`omreagrrafinlniuecosrfooiooncdtthcaehnaeeinns.vuliFfroLonUnamOteeRn(OtPS.F:0O5SA)Anuanigndt1er9re;nla2at0ti0eo5dn.caolmspyomupnodssiuimn aonNofrluwoergiinaatnedAracltkiycl (74) B`mreeansnuerrinHg,eLxopoosmuirse.D.EpViadreimeidolfoorgmyso19f9b4iasS(d5)u:e51t0o-n5o1n7d.ifferential errr in 8 J=,o CHAPTER 4 . AN EPIDEMIOLOGIC INVESTIGATION OF FETAL EXPOSURE TO PFOS AND PFOA AND RELATIONSHIPS `WITH WEIGHT AND SIZE AT BIRTH , o 3 p01 Abstract BACKGROUND: Perfluorinated compounds (PFCs) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are used in a varietyofconsumer and industrial applications. Recent studics have reported developmental toxicity among rodents dosed with PFOS and PFOA, two widely used surfactants. We previously documented in utero exposure to PFCs among newborn deliveriesathospital in Baltimore, MD. METHODS: In this hospital-based cross-sectional study, we examine the relationship between cord concentrations of PFOS or PFOA and birth weight (grams), newbom head circumference (om), length (cm), and ponderal index (g/em'x100). Multiple births and babies with major congenital anomalies were excluded from the study population (n = 293). Cord serum samples were analyzed for PFOS and PFOA by online solid-phase extraction, coupled with reversed phase high-performance liquid chromatography.-tandem `mass spectrometry. Medical record data were obtained from maternal and infant charts. RESULTS: After adjusting for potential confounders, both PFOS and PFOA were `negatively associated with birth weight (per increase from 25 to 75 percentile: f = 58 grams, 95% CI: "125, 9 for PFOS; B = -58 grams, 95% CI -119, 3 for PFOA) and ponderal index (per increase from 25TM to 75 percentile: B = -0.062, 95% CI 0.104, - 0.021 for PFOS; B = 0.039, 95% CI: -0.077, -0.001 for PFOA). A negative association was also observed with head circumference, but only among vaginal deliveries. These assocwieraeitndiepoenndesnt ofcordserum lipid concentrations. . CONCLUSION: Despite relatively low serum concentrations, we detected negative. associations between PFOSandPFOA concentrationsin cordserum and birth weight and size. Future studies should attempttoreplicate these findingsinother populations. 8 317 p.102 Introduction Perfluorinated compounds (PFCs) comprise a class of manmade, filly fluorinated organic compounds that have been used in a variety of consumer and industrial applications for more than 50 years (1:2). Although produced for many years, only recently have reports surfaced suggesting widespread exposure in wildlife and humans (35). Two of the most widely detected and studied compounds in this class are perfluorooctane sulfonate (PFOS) and perflorooctanote (PFOA), PFOS and related . compounds (perfluorinated. sulfonamides) are surfactants used in applications ranging from oil and water repellents for fabrics, apparel, carpets, and paper coatings to specialty chemical applications such as insecticides and fie fighting foams (2). Because of the evidence of human exposure to PFOS, its major U.S. manufacturer announced in 2000 the phase-out of all perfluorooctanyl-based products. PFOA and its salts are used as chemical intermediates and processing aids in the production of fluoropolymers and ! uoroclastomers (6) and ae tll being produced in the United States. Both PFOS and PFOA have shown the potential for developmental toxicity in animal studics. FOS has been shown to induce developmental and reproductive effects in rats and mic, such as reduced birth weight, decreased gestational length, structural defects, ` developmental delays, and increased neonatal mortality (7-12). Recent studies have reported developmental toxicity from PFOA in rodentsa wel, including pregnancy loss, reduced fal weight, reduced postnatal survival, and delays in postnatal growth and development in offspring (13-17). The US. Environmental Protection Agency is currently evaluating PFOA for potential developmental risks to humans (18). PFOS and 3503 PFOA have also been identified as peroxisome proliferators (19-24) and have been shown to have hypolipidemic effects in several animal species. Toxicity studies in animals have shown marked reductions in serum cholesterol and/or triglycerides (7;25- 27), which may be mediated through down-regulation of HMG-CoA (3-hydroxy-3- `methylglutaryl coenzyme A) reductase, a key enzyme in cholesterol synthesis (27). Conversely, a few cross-sectional occupational studies conducted among fluorochemical production employees have reported positive relationships between serum lipids and PFOS and/or PFOA concentrations (28;29). No epidemiologic studies have evaluated the impacts ofPFC exposure on fetal growth and development. 10`The fetus is ce likely to pt, dim, be sensitive to the availability oy wh of cholesterol cmon di and triglycerides, due development (30). Disruptions to normal fetal growth and development have been associated with effects across the lifespan, including adverse neonatal and childhood outcomes (31-36) and metabolic diseases in adulthood (37;38). The most common approaches for identifying potentially growth-restricted newborns are classifying birth weight, length, and head circumference by gestational age. Newboms below the 10 percentile of weight or size are typically classified as small-for-gestational age, even though it is recognized that sucha classification will miss some growth-restricted babies and identify others who are simply constitutionally small (39:40). Body proportionality has been used to define asymmetric growth, which has been associated withincreased severityofgrowth restriction (41) and adverse neonatal outcomes (42-47). Onemeasure = 3 p.108 of disproportionate growth restriction is the ponderal index (weightllength' x 100), a `measureofbody mass atbirth. ` In a previous report, we documented cord blood concentrationsofPFOS and PFOA in a populationofnewbom deliveries occurring in a Baltimore city hospital. In this study, we examine the relationship between these concentrations and measures of birth weight and bith size parameters, including head circumference, length, and ponderal indey. . Material and Methods Subjects ` We conducted a cross-sectional study of newbom deliveries at the Johns Hopkins Hospital in Baltimore, MD. The study received approval from the Johns Hopkins Medicine Institutional Review Board and was determined to be HIPAA exempt. The ! study was conducted anonymously and utilized only specimens that otherwise would have been discarded and medical records that were available to study personel. There } was 10 requirement for informed consent du to the anonymization of all samples and data. Between November 26, 2004and March 16, 2005 all singleton, ive bith deliveries `occurring in the Labor and Delivery Suit at the hospital were eligible for participation in . the study. We excluded from the study population women who gave birth to more than one child or women who delivered a single child but had an inal twin gestation with fetal loss at 20 weeks or greater. Newboms with major congenital anomalies likely to ` impact fetal growth were excluded as wel. 91 JS . 5.105 Over the course of the study period, 609 live births occurred at the Johns Hopkins Hospital,ofwhich 597 were singleton births. We abiained cord blood specimens from 341 of these, of which 42 had insufficient volume for laboratory analyses and were excluded from this study. An additional five singleton births had major congenital anomalies indicated on the birth record and one birth was identified as an initial twin gestation with demise of the fetal twin at 20 weeks. These subjects were excluded, leavaitontagl of293studyparticipants (Figure 4-1) Cord blood samples were collected from the umbilical cord vein by hospital personnel immediately following delivery (48). Upon delivery, a sectionofthe cord was cleaned `with an alcohol wipe and blood was drawn using a sterile 60-mL Becton Dickinson (BD) syringe with an 18-gange safety needle. A BD Vacutainer Blood Transfer Device was then attached to the syringe and 10 mL glass BD vacutsiners were filed. After collection, cord blood specimens were stored in Labor and Delivery refrigerators. Within several hours, the specimens were picked up andtaken across the street to a laboratoarty the Johns Hopkins Bloomberg School of Public Health for processing. Tubes were centrifuged at 2400 rpm for 15 minutes for serum separation. Serum was aliquoted into 2mL polypropylene prescreened cryovials and stored at 80 C. Frozen specimens were transferred on. dry ice to the Centers for Disease Control and Prevention (CDC) for laboratory analyses. Medical Records 32 5.106 We abstracted matemal and infant characteristics from clinical databases maintained by the hospital. Matemal information was abstracted by two study investigators concurrently, anda random 10 percent sample was verified by two others. The data collected included demographic information, anthropometric measures, medical history, and pregnancy-related characteristics. Age, race, education, marital satus, and parity were based on self-report. Body mass index was calculated from reported pre-preguancy weight and height as the ratio of weight (in kilograms) to height (in meters) squared. , Gestational age was based on the "best obstetric estimate." Infant gender was abstracted from the mother's medical record and confirmed with the infant record. Information on `matemal health conditions were abstracted from the medical record. Smoking status was ' defined using a combination of the matemal medical record and cord serum cotinine. concentrations measured at birth. Using cutoffs from Jarvis etal. (1987), samples with a cotinine concentration of1 to 14 ng/mL were categorized as passive smoking exposure : and samples with a concentration above 14 ng/mL were categorized as active smoking exposure (49). Serum samples with cotinine concentrations below 1 ng/ml. were . included in the category of nonsmokers. Ifthe clinical record indicated that the mother reported smoking at any time during pregnancy, she was considered an active smoker regardless of the cotinine concentration in cord blood at birth. Because it was not . possible to measure passive smoking exposure earlier in pregnancy and misclassification is likely to exist between passive and non-smokers, smoking status was dichotomized to active and passive/non-smoker in statistical analyses. t 397 p.107 Infant anthropometric measures were abstracted from the infant medical record. Birth Weight in grams was obtained from the infant record and confirmed with the matemal record. Head circumference and length in centimeters were abstracted fom the infant secord. Ponderal index was calculated as the ratioofbirth weight in grams to length in centimeters cubed, multiplied by 100 (birthweightlenge? x100). We examined the relationships between gestational age, birth weight, length, and head circumference to identify outlying values. Outliers were identified and weight and size measurements were verified using the infant and matemal record. Laboratory Analysis Pefluorinated compounds Cord serum samples were analyzed for PFOS and PFOA by online solid-phase extraction (SPE), coupled with reversed phase high-performance liquid chromatography tandem mass spectrometry.Themethod has been described in detail by Kuklenyik etal. (2005). Excellent precision has been reported using this method for the detection of PECs in human serum (50). Briefly, without protein precipitation, one aliquot of 100 pL. of serum was injected into a commercial column switching system allowing for concentrationofthe analytes on a SPE column. This column was placed automatically in frontofan analytical column for chromatographic separationofthe analytes. Detection and quanification were done using negative-ion TurbolonSpray ionization, a variant of electrospray ionization, tandem mass spectrometry. Detection limits were in the low nanogram per milliliter range for PROS and PFOA. In these cord serum samples, the precursor/product ion m/z wansition used for the quantification of PFOS had an 58 p08 interferent ion. Therefore, PFOS concentrations had to be calculated using another transition, normally used to confirm the presenceofPFOS. The natureofthis interference ` isatpresent unknown. Quality control (QC) and reagent blank samples were included in each analytical batch along with the unknown samples. QC samples were evaluated according to modified Westgard rules All laboratory analyses were conducted by investigators blinded to the characteristicsof study subjects. Cotinine. Serum cotinine was analyzed by CDC using the method described by Bemert ct al. (1997). The analytic method uses high-performance liquid chromatography coupled with ` atmospheric pressure chemical ionizafion tandem mass spectrometry to measure serum cotinine concentrations with high accuracy and sensitivity (limit of detection [LOD] = 0.015 ng/mL). This method has been used to measure environmental tobacco smoke ` dose in large-scale surveys,includingNHANES (51). Statistical Analysis We used descriptive statistics to characterize the study population. We used Fisher's Exact test and Wilcoxon's Raak Sum test to compare subjects with missing data on key . covariate to those with complete data. We used descriptive statistics appropriate. for ight-skewed data o characterize cord PFOS and PFOA concentrations. Spearman rank conelation was used to estimate the comrelation between cord levels of the two compounds. Because PFOS and PFOA concentrations were skewed to the right, all NatiDonaleCtsefseoraErnivilrpomnemteihnotdanlcHeooanltt,feCDC. Antonis Cafe, DivisonofLaborsoySecs, 3 7 p.108 statistical tests were conducted on natural log-transformed concentrations. Natural ogtransformed concentrations were also used as independent variables in regression analysis to minimize the potential influence of outliers on the regression coefficients. Samples. below the detection limit for PFOS, PFOA, and cotinine were assumed tobeequal to the detection limit divided by the square rootoftwo forall analyses (52). We conducted univariate and multivariate linear regression analyses to examine the associations between PFOS or PFOA and birth weight, newbom head circumference, `newborn length, and ponderal index. The inclusionofcovariates in the regression model was based on apriori knowledgeofthekey determinantsofbirth weight and birth size. `The covariates included in the primary adjusted models were: smoking status, matemal age, gestational age, race, matemal pre-pregnancy body mass index (BMI), weight gain during pregnancy, maternal height, parity, gender, diabetes, and hypertension. Diabetes was defined to include subjects with pre-existing or gestational diabetes,assumingboth conditions would result in increased fetal weight for age. Similarly, hypertension was defined to include subjects with pre-eclampsia, pregnancy-induced hypertension, and chronic hypertension, which were expected to result in decreased weight for age. For consistency, the same st of covariates was included intheprimary regression model for each endpoint, with the exception of delivery mode (Vaginal versus Caesarian section), which was included as a predictor of head circumference. The specification of these variables in the model was based on the shapeofthe empirical relationships between the covariates and the different endpoints (Appendix A). Based on the empirical evidence, a quadratic term for materal age was included in regressions of birth weight, head 9% 320 p10 circumference, and ponderal index, but not for length. A quadratic term for gestational age was included in regressions of head circumference only. All other terms were ` included in the models as linear or categorical (indicator) variables. We explored the possible inclusion of other variables (ez. education level, marital status, insurance tas), but were dropped because they had no material effect on the coefficient estimates. A small minority (<4 percent)ofthe study population was missing data on pre-pregnancy \ weigh, height, and/or weight gain during pregnancy, which are important predictors of birth weight and size. Those subjects missing data on at least one ofthese variables were more likely to be smokers and deliver preterm. However, theywere similar with respect 0 other characteristics, including demographics, birth weight, anthropometric measures a birth, and cord levels of PROS and PFOA (Table B-1). We examined two different approaches for handling those missing data: (1) complete case analysis (ic. dropping ! observations for which one of the above measures is missing, also called "lisse" deletion) and (2) imputing the missing data with the median value of height, weight, } andlor weight gain. Both approaches produced similar results (Table B-3), therefore, only the latter approach is presented here. As a sensitivity analysis, we examined the impactofimputing BMI or weight gain with extreme values and found no material effect on the regression coefficientsofPFOS or PFOA. Wie also conducted a series of sensitivity anlyses to examine the impact of modeling . assumptions on the regression estimates. We examined the impact of covariate specification in regression models, including the use ofcotinine concentration instead of 9 32 pm smokingstatus to controlforthe effectof smokianndgw,e exploredthepresenceofnonlincarites among the potential confounders using restricted cubic spline models. We also conducted regressions on untransiommed PFOS and PFOA concentrations to evaluate Whether inferences were consistent withthe primary log-linear models. Regression diagnostics were conducted for all models, including examination of fit, heteroskedasticty, and influence, Statistical analyses were performed using STATA version 8.0 (StataCorp, College Station, TX). Results `Table 4-1 shows the characteristics of the study population. The mean matemal age at delivery was approximately 26 years of age, with a range of 14 to 43. Eight percent of births occurred to mother's less than 18 yearsofage at delivery. The majority of study `participants were Black (71%; n=208), followed by White (21%; n=60) and Asian (9%; 1=25). Over 60 percent of the mothers in our study had a high schooldiplomaor less, while about 14 percent had some amount of post-graduate education. Approximately two-thirds of the study mothers were unmarried. While only 6 percent of the mothers were underweight prior to pregnancy (BMI <I8.5 kg/m'), close to 50 percent were classified as overweightorobese (BMI > 25 kg/m'). The average net weight gain during pregaancy (weight gain minus birth weigh) was 22.7 pounds, with a wide distribution observed (SD = 17.8 Ibs). More than 40 percent of babies were first-bom. Approximately 19 percentofmothers were categorized as smokers on the basisofcord cotinine levels at birth and self-report. Among study subjects, the rates of low birth Fea p12 `weight (<2500 grams) and preterm birth (<37 completed weeks) were 11 and 13 percent, respectively. The distribution of birth weight, newbom length, head circumference, and ~~ `ponderal index is shown in Table 4-2. PFOS was detected in greater than 99 percent of infants" cord blood samples and PFOA was detected in 100 percent of samples. The distribution of PFOS and PFOA concentrations in cord blood is shown in Table 42. The median cord serum concentration of PFOS was 5 ng/mL, with a range from below the limit of detection (<LOD) to 34.8 ng/mL. The median PFOA concentration was 1.6 ng/mL, with a range fiom 0.3 ng/mL to 7.1 ng/mL. Concentrationsof PFOS and PFOA in cord blood were . highly correlated (Speraankrcormrelaatinon coefficient: 0.58; p<.01). `Table 4-3 shows the regression model resultsofbirth weight, length, head circumference, ` and ponderal index on natural log transformed PFOS and PFOA. After adjusting for potential confounders, both PFOS and PFOA were negatively associated with birth weight. For PFOS, an average reduction in birth weight of 58 grams (95% CI -125, 9) was associated with a change in cord concentration from the 25 to 75TM percentile. For PFOA, an increase from the 25 to 75 percentile was associated with an average birth ` `weight decline of $8 grams (95% CI -119, 3). In both models, significant predictors of birth weight included gestational age, smoking status, materal BMI, parity, gender, `matemal height, netweightgainduring pregnancy, and diabetes (Tables C-1, C-2). 323 SE For head circumference, a negative association was observed with In(PFOS) in a concentration from the 25TM to 75% percentile was associated withanaverage decrease in `head circumference of 0.27 centimeters (95% CI: -0.48, -0.06). For PFOA, a negative association was observed in both univariate (p=0.03) and multivariate analyses (p=0.02). sitdeedin me In the multivariate model, an bd mia increase from the of023sie G54 25% to 75% percentile of C16, PFOA was 004). The predicted relationships between PFOS or PFOA and head circumference `based on the unadjusted and adjusted regression models are displayed in Figure 4-2. `Based on the results of multivariate models, significant predictorsofhead circumference were gestational age, smoking status, matemal BMI, parity, race, maternal height, net `weight gain during pregnancy, diabetes, hypertension; and delivery mode (Tables C-3, C4). Delivery mode was highly significant predictor of head circumference, with babies bom by Caesarean section (C-section) having larger head circumferences, on average, compared with vaginal deliveries, after adjusting for potential confounders. Because sion em `babies bom by been FOS a C-section do not FEOA and have head evry molding mode,during ichbirth, wveas ssl included an ven EOS ox PFO sd significant (p<0.05). Among cmt. Amen Csr, re ia0 vaginal births, a large negative association was observed significant positive association between PFOS or PFOA and head circumference. Table 0 324 pote 4-4 shows estimated regression coefficients for PFOS and PFOA under the interaction model. ` Contrary to the associations with birth weight and head circumference, neither PFOS nor PFOA was significantly associated with newbom length in univariate or multivariate ' models (Table 4-3). The following covariates were significant predictors of newbom Iength in multivariate models: gestational age, smoking status, matemal BMI and gender. . Matemal height, net weight gain during pregnancy, and diabetes were marginally significant (Tables C-5, C-6). The association between PFOS and PFOA and ponderal index is shown in Table 4-3. Negative associations were observed for both PFOS and PFOA with ponderal index in univariate and multivariate models. Afer adjustment, an increase in PFOS concentration ! from the 25 to 75" percentile was associated with an average decline in ponderal index of0.062 (95% CI: -0.104, 0.021). An increase in PFOA from the 25 to 75" percentile : was associated with 2 mean decrease in ponderal index of 0.039 (95% Cl: -0.077, - ' 0.001). Figure 4-3 displays the associations between PFOS or PFOA and ponderal index, based on results from the univariate and multivariate regression models. Based on the . results of multivariate models, the only other significant predictors of ponderal index were gestational age, maternal age party, and net weight gain during pregnancy (Tables c7,C8). 101 325 : p.115 We conducted a series of sensitivity analysis to assess the impact of model and variable specification on the results. The associations observed were predominantly insensiitvoe different specifications of potential confounders (e.g. use of cotinine as a continuous measure, non-linear smooth functionsofheight, weight, and weight gain) (Appendices DG). We also examined the consistency of inferences when the multivariate regressions were un on untransformed PFOS and PFOA. Figure 4-4 shows the univariate relationship between PFOSorPFOA and head circumference, comparing the predicted fit from log-linear and linear models. A similar comparison is made for ponderal index in Figure 4-5. As shown in the figures, the choice ofa log-lineoarr linear model had lite impact on the estimates oblained. Similar inferences were obtained in multivariate `models as well when comparing log-linear with linear functions (Figures D-7, E-7, F-7, G9) Discussion In a previous study, we documented the extent and determinants of fetal cord concenteationsof PFOS and PFOA in a hospital in Baltimore. In this study, we examined the relationship betwen these cord concentrations with birth weight and birth size. Our results showed negative associations between PFOS and PFOA with birth weight, ponderal inde, and head circumference, afer adjusting for potential confounders. Gestational age was the strongest confounder in this study and edjustient tended to strengthen the associations observed. No significant associations were observed between cither PFOS or PFOA and newborn length. These associations were relatively consistent, 102 3 p16 after conducting a series of sensitivity analyses examining the impacts of different covariate adjustments, model specifications, and treatmentofmissing data. ` Ponderal index has been used by clinicians and epidemiologists as ameasure of thinness at birth and an indicator of disproportionate or asymmetric growth restriction. Because fetal weightgainand soft tissue mass increases dramatically in the third trimester and the body becomes more proportional, it has been hypothesized that early insults during . `gestation result in symmetric growah restriction and later insults, asymmetric growth : restriction. However, some empirical evidence conflicts with this notion about the timing of fel growth disruption (39;53;54). Kramer et al. (1989) showed that ` disproportionality increased with increasing severity ofgrowth restriction, suggesting the presence ofa continuumoffetal growth restriction, rather than two distinct pattems (41). Regardless, several studies have shown associations between low ponderal index and risk ! ofadverse neonatal outcomes (42-47). It has been reported that other metrics may better predict infant body fat mass, including birth weight alone and birth weightilength ratio } (55-58). We conducted regression analysesofbirthweightlength ratio and birth weight adjusted for length and found similar results to models of ponderal index (Figures G-7 through G-10). These results taken together suggest that at a given length and gestational age, infant body weight is lower among babies with higher cord levels of PFOS and PFOA. The toxicology literature provides evidence of developmental effects among animals dosed with PFOS and PFOA, albeit at substantially higher levels than observed here (7- 103 327 p17 17). Additionally, hypolipidemic effects have been observed in animals in response to PFOS and PFOA exposure (7;25-27). In occupational studies, associations between exposure and cholesterol and triglyceride levels have been observed as wel, although in the opposite direction (2829;59). As a result of their potential effects on lipid `metabolism, our observationsofreduced weight for length would seem plausible. The availability of triglycerides and cholesterol are essential to the developing fetus or the accumulationofbody fat and developmentofcellmembranesand steroid hormones (30). In this study, we had cord serum cholesterol and triglyceride measurements available on the study subjects. However, controlling for otal lipids, total cholesterol,o triglycerides had no impact on the associations between PFOS or PFOA and ponderal index, suggesting that the observed associations were independent of serum lipid levels (Appendix H). We also observed a negative association between PFOS and PFOA concentrations with head circuraference. Head circumference is coelated with brain weight and volume. (60-62) and reduced head circumference has been associated with poor cognitive development in childhood, particularly among growth restricted babies (63-68). However, our findings were somewhat puzzling given tha the associations with POS and PFOA appeared to be completely restricted to vaginal deliveries. It could be expected that if an association existed, it would be more apparent among elective Csections, due to the avoidanceofhead molding that accompanies labor. In our study, there was no evidenceofa negative association when restricting the analysis futher to elective C-sections. However, it should be noted that there were only 24 elective C- 104 323 p.118 sectionsamongthe full study population. Future studies should examine this association further. ` `There are some potential limitations to this cross-sectional study, described below, which should lead to cautious interpretation of the results. In this analysis we used an on-line SPE method for the detection of low-level PFC concentrations in human serum. The precision of the method has described in detail by Kuklenyik et al (2005), with low y coefficientsofvariation (CV) reported for PFOS and PFOA (50). In this study, however, `measurement error for PFOS may be greater, because the precursor/product ion transition normally used for quantification could not be used due to coelution with another ` interferent analyte transition ion. However, measurement error would be expected to bias. `bivariate associations to the nullifthe error is completely random (69). As described above, there was missing data on possible confounders among a small minority (<4 percent)ofstudy subjects. However, when examining different approaches . to handling missing data (i.e. complete case analysis versus median imputation), similar results were found. Similarly, the associations observed were relatively consistent with the inclusion of different sets of covariates in the model and the specification of those `variables (including the use of non-linear smoothing functions for potentialconfounders). The use of medical records as the principle source for data on potential confounders is likely to result in somedegree of misclassification. However, we observed the expected ` relationships between key predictors and birth outcomes, suggesting that the degree of residual confounding is likely to be small. 10s 3X7 pts When comparing the log-linear and linear models, relatively consistent findings were observed. In some cases, the use ofa linear model resulted in PFOA coefficients that did not achieve statistical significance, although the magnitude of the associations was `qualitatively similar to the log-linear model. The associations between PFOS and the endpoints under study were insensitive to the functional form of the model. The log- helinear ost opie and linear models fo ating te provide a similar fit to ap of i lini been cd the data, thus, it is not clear which model concentrations and birth weight and birth size. In this analysis, we adjusted for the major known determinantsofbirth size and weight It remains possible that other unmeasured factors, such as diet, maybeconfounding the relationships observed in this study. The maternal diet would be expected to be related to `weight and sizeofthe fetus, and ponderal index has often been considered a measure of nutritional status (46). Further, it is possible that the consumptionofcontaminated food or water, including the use of fast-food containers, is a pathway of exposure to PFOS and/or PFOA. However, to confound the relationships observed, undemutrition would have to be positively associated with PFOS or PFOA exposure. Our study population represented a group of individuals with more risk factors for adverse birth outcomes than the United States as a whole, Compared to national estimates, the `subjects in our population were more likely to be Black, teenagers, unmarried, and cigarette smokers (Table B-2) (70). This is perhaps not surprising given 350 5.120 the location of the hospital in an urban and disadvantaged community. Although not quantified, these subjects may also have higher rates of other risk factors for poor ! outcomes, such as substance abuse and infections. It i not clear what,ifany, impact the presenceofconcomitant risk factors would have on the results reported here, but future: studies should be conducted in other setings to confirm these findings. It should be noted, however, that we observed relationships between other key determinants and birth weight consistent with the scientific literature, such as mother's age, smoking status, . `mother's weight and height, diabetes, and hypertension (Appendix B), which improves our confidence in the generalizabilityofthese results to other settings. In summary, we observed a negative association between PFOS and PFOA concentrations in cord blood and birth weight, ponderal index, and head circumference Although effects on lipid metabolism have been among the more sensitive effects : observed in animal and human data, the associations observed here were independent of cord lipid levels. We suggest cautious interpretation of this study until findings can be replicated in other populations ` 107 33 : p21 Table 4-1. Study population characteristics. Characteristic Hean(sD) or N (+) Wet<a1r8nayleaargse 79066) 2462) 1283:53y5eyaorasrs 24625(80480)) RaWcheite 60208) ABsliacakn 282751005)) Edu<cHastidopnloma 808) H1-s4 dyiepalrsomcaollege 590222)5) Ma5r+tayesatrastucsollege 2145) MaUnrmiaordied 179876169)) BodUyndmearwsesigihntde(x<16.5) 21760(066)) NOovmemrawlei(g1h8t.5(:22542.88).9) 132466) 6 (226) NetOwbeeisgeht(3g0a%i)n (bs) 277(1127581)) Mpartineirpnaarlohuisght (nches) 644027) YNeos 11212(48148)) SmNookniPnagssstitvuessmoker 238612) AIndfanvt egender 55188) Female 13147) Malo 16253) || PrNetoer2m3b7iwneeks) 2557.0) LoYwebsi(th<7weiwgehetks) 38130) FiYNeos(i2d(2as<,t255ei0x00c0gnirogadrgemadsm)sr)ors cloubion of 23210.610045)) sansand pees "BTMoeIfolfloorwwinegidgahtawgienr, 5i0s44inf:or4mobasterevaetiiognhstf.oreducation, 10 for 108 4 33 p22 `Table 4-2. Distribution ofcord concentrationsof PFOS and PFOA and study endpoints. N_ Mean Min fon 25mPorcSaonntiossth so wax P`FCOonScen(trnagtiimoLn) PFOA(agin) 229 6108 A0O3D 0285 a142 15s 2719 12101 M74s . BHiErentdahodwocieinirtgcshutmi(cgrreanmcse) 293 3200 1145 2495 2777 3200 352 4150 5166 Le(negm)th (em) Ponderslindex 228 B50S0 32600 347 43825s 0N0S w52s0 swss 6950 288 254 179 215 237 285 272 289 341 ' "L=0O2 gDin 109 p123 1 z EE$ | E=R 8 TE 3R% E E85 E3% E Pl He : 32% g [S5gB 3I7I OEE: g | |i .|ec 5 g 8 E| 35 Z| 5 2 3| 5% : 58 33 87 ex 3 ssxs 8288 c3g3 f TTT fz Ecs EL 53% 438 98 = 2 22 2% sg 5?3 8S 58z95g g2if3 3 $| 58 13 33 83 i Tir 9% 9% :5 tH48 2 fPol f8fEs desrg.lia hr fo dp Efi gin 51$82 [8P34x82:5%%8 75%8 2$s59T ::Y93 g2$9%g it i ZB $235|5 |d*853&| 0 ee 55s onng 8599 iI5z5f sh | 8| 32 s% ss 79 iy i9 EZ| ligf IdgToit5oi9g8 n5t 38 TTeEY 5S gy i i 0 k HIRE IRR 33 E5piey suis . "E 3 |? 3 8 g gZ5s | = |g58359ps53ES a" 2 57 2i% S34 f p.126 `Table 4-4. Change in head circumference with a unit change in In(PFOS) or In(PFOA) concentration, among Caesarean section and vaginal deliveries. Delivery moda Coofficlnt (p8r5o%sCI) pvalue Cosffiient (P35F%OACO) pvalue Vaginal Cesecton 046(073,019) POO 062(10,023) pe00t 031(023,086) p025 023(044,091) p=050 o*rRPegFrOesAsiaonndcdoeleilvceiryntmsodaer.e eCsotsifmfaitieefntosmar amaldjvuasrteidaftoermgoesdteatliwoniatlhaaen,imnatterearcntailongtee,mbboedtywmeaesnsPiFdOesS, ace, parity, smoking, baby gender, beigh, etweightgan,diabetes,and ypertcnsion . | m | 335 p.125 HLoisvpelbtiarlthosvaetrJsothudnys pHeorpikoidns. (n=609) Singleton births (1597) 12 win births `cCoolrldecbtleodo(dn=s3a4m1p)les v`oSalmupmlees(nw=i2t9h9s)ufficient o6retxwcilnugdeesdtadtuieontowimtahjfoertaalndoemaatlhies Final study population (n=293) | Figure 4-1. Flow chart of study population. nm SS p.126 S5z g.T 0 T S. r ewweillie e ----E iT d, g$ . o eeTeEF R-- EF T-- ET, T Coo ` 2 : : : . In (PFOS) eq - - . PP lanes, 1g DToLt ElaEgRe. tt 3 S i : In (PFOA) t aFigudre 4j.2. uoHrepasodtecntitricaumlmcfoeenrfeoncunendvetrrsou.s 1a(PFOS) aid In(PFOAY, before and after `dNeontoet:eTsthheedportetdeidcltiendefidtferomntahomeuplrtteidveiacrtiseadtefirtefgrreosmsliionne.arSreeegrTeasbslieon4.-3Tfhoersroelgirdelsisinoen coefficients. . ms 337 . - - - p.127 . _ che i oolp etah. Phi Ei: . ER . tes bo Pa x. | i oo _ Ca SEl MEavei)TS - z 3 : I In (PFOS) --pta Ee | ii. o : - sa teo epptbe, ilgiaLed 3 Crap : coe aie af eo ald TE TT - 3 3 Fon) i 3 aFigure 4-3. Ponderal index versus In(PFOS) and In(PFOA), before and after djuforpsotetntiamlcoenfonundetrs. Note: The dotted line denotesthe predicted fit from linear:regression. The solid line coeticients. denotes the predicted fitfrom a multivariate regression. See Table 4-3 for regression 11s 334 ee p.128 gn ~E, emt, . ETERS 3ig s TaHtea.RE r LC : ; . 3 7 PFS0(]gmt) . PP Lm no 8 hE 3 HH g i3s aR . BhePrNEI, a_ 3I _ 73 _ 73 PFOA (ng/mL) Figure 4-4. Relationship between head circumference and PFOS, using log-linear and linear models. Tegression coefficients Note: PFOS concentrations above 20 ng/mL and PFOA concentrations above 5ng/mL areexcludedfrom figure for display purposes. See Table 4-3 for log-linear model us rr p.120 " oe we _--- SR tae Eamon * iFACT REaNaS amLaTe ] e Tee Jat Lhe : 3 #708To(rgint) b3 - borg St . oea jierod oi ot ateedinggrite 0 LL . -L i13 STEiR eN tated | & etme 0 . af ad oti TTT | . ve .. . | 2 z | 0 1 2 3 4 5 | PFOA (ng/mL) Figure4-5. Relationship between ponderal index and PFOS, using log-linear and | linear models. | || Note: PFOS concentrations above 20 ng/mL and PFOA concentrations above 5 ng/mL arergereesxsciloundceodefffriocmienfitgsu.re fordisplay purposes. See Table 4-3 for log-linear model | | us 5.130 References (1). `KMiasrscaelE.DeFlkukoerri,naIntce.,d2s0u0rf1a.ctants and repellents. Second ed. New York, NY: (2) D3oMckCeotm#paOnPyP.T-F2l0u0o2r-o0c0h4e3m.ica1l99u9s.e,5d-i2s6t-r1i9b9u9ti.on, and release overview. EPA RefType: Report i (3) Kala. nPenraflnu,oroCoocrtsaonlensiulSf,oFnaaltaenadynsdzr.eJl,atFeidllfmlauonrnoGc,heKmuicmaalrs KinS,huLmoagnabnlatohoadnfBrGomet soveral counties. Environ Sci Technol 2004; 38(17):4489-4495. (&) EGinevsiyroJnP,ScKianTencahnnoKl.2G0l0o1b;al35d(i7s)t:r1i3bu3t9i-o4n2o.fperfluorooctane sulfonate in wildife. ` (5) CPaelrafflautorAoMch,emKiuckallesnyinikpoZo,lCeadusdeilrlumSPs,amRpeliedsy fJrAo,mNUeneidtheadmStLaLt.es residents in 2001 and 2002. Environ Sei Technol 2006; 40(7):2128-2134. . (6) SPoelrifcliutoartoioocnotfainnoitceraecsitde(dPpFaOrtAi)e,s Fflouroernifnoartceedabtleelocmoenrsse;nRteaqgureesetmfeonrtcdoemvmeelnotpm,ent, RaenfdTnyotpiec:eoSftaptuubtleic meeting. Federal Register (73). 2003, (7) TEhxipboosdueraeutxo pJRe,rfHlaunorsooonctRaGn,e sRuolgfeornastJeMd,urGirnegyprBeEg,nBaanrcbyeienBraDt,anRidcmhoaursdes.JHI: etal. `maternal and prenatal evaluations.Toxicol Sci 2003; 74(2):369-81. (8) GprerafsltuyoRroCo,ctGarneeysBulEf,onLaatue-CiSn,duRcoegdenresonJaMt.alPrmeonartatlawliinintdthoyewoSfprsaugscueep-tiDbaiwlliteyytroat. Birth Defects Res PartB Dev Reprod Toxicol 2003; 68(6)465-71 (9) ELxapuoCs,urTehitobpoedrefaluuoJrRo,ocHtaannesosunlfRoGn,atReodguerrisngJMp,reGgrneayncByEi,nSrtaatnatnodn mMoEuseet.alI.: postnatal evaluation. Toxicol Sci 2003; 74(2)382:92. . (10) LfureobmkienruDtJe,roYeoxrpkosRuGr,e tHoanpesrefnluKoJr,ooMcotoanreesuJlAf,onBauttee(nPFhOoSJf)Lf.inNeSopnraatgaule-moDratwalleiyty rTaotxs:icdoolsoeg-yre2s0p0o5n;se2,15a(n1d-2b)i:o1c4h9e-m1i6c9a.l and pharamacokinetic parameters. (11) `LguecnbekraetrioDnJ,reCparsodeuMctTi,onYaonrdkcRrGos,s-Mfoosotreer sJtAu,diHeasonsfepnerKfJl,uoBruootcetannhcosuJflLtf.oTnwatoe(FOinSra)ts. Toxicology 2005; 215(1-2):126-148. n7 (12) Fuentes, Colomina MT, Rodriguez J, Vicens P, Domingo JL. Interactions in developmental toxicology: Concurrent exposure to perfluorooctanesulfonate (PFOS) and stress in pregnant mice. Toxicol Lett 2006; 164(1):81-89. (13) Lau C, ButenhoffJL, Rogers. IM. The developmental toxicityofperfluoroalkyl acids and their derivatives. Toxicol Appl `Pharmacol 2004; 198(2):231-41. (14) ButenhoJfLf, Kennedy GL, Jr., Frame SR, O'Connor JC, York RG. The reproductive toxicology ofammonium perfluorooctanoate (APFO) in the rat. Toxicology 2004; 196(1-2):95-116. (15) York RG. Oral (gavage) two-generation (one litter per generation) reproduction `study ofammonium perfluorooctanoate (APFO) in rats. 2002. Horsham, PA, Argus Research. 1926. RefType: Report (16) Ud.eSv.eElnovpimreonntmaelnttoaxlicPirtoytaescstoicoinatAegdenwcityh. ePxrpeloismuirneatroypreirsfklausosreosocstmaennotoicfatchied and its salts. USEPA Docket OPPT-2003-0012-0002. 2003. Officeof Pollution RPerfevTeynpteio:nRaenpdorTtoxics; Risk Assessment Division. 1910. (17) Lal.auEfCf,ecTthsiobfopdeerafulxuoJrRo,ocHtaannsooicn RG, acid Narotsky exposure dMuGri,ngRopgreergsnaJnMc,y Lindstrom AB in the mouse. et Toxicol Sci 2006; 90(2):510-518. (18) U.S.Environmental Protection Agency. Draft risk assessmentofthe potential `human health effects associated with exposure to perfluorooctanoic acid and its. salts (PFOA). http://www.epa.gov/opptintr/pfoa/pfoarisk.htm . 2005. RefType: Electronic Citation (19) oPafsatmomoroTnPi,uLmeepeKrPfl,uPoerroroictMaAn,oaGtiel-liinedsucPJe.d Bhieopcahteommiecgaallyanadndmopreprhooxliosgoimceal studies proliferation. Exp Mol Pathol 1987; 47(1):98-109. (20) Sohlenius AK, Andersson K, DePierre JW. The effectsofperfluoro-octanoic acid. on hepatic peroxisome proliferation and related parameters show no sex-related. differences in mice. Biochem J 1992; 285 ( Pt 3):779-783. (21) TkedaT, Aiba K, Fukuda K, Tanaka M. The inductionofperoxisome proliferation in ratliver by perfluorinated fatty acids, metabolically inert derivativesoffatty acids. JBiochem (Tokyo) 1985; 98(2):475-482. (22) PSeorhflleunoiruosoActKa,neErsiuklfsosnoinc AM, acid Hogstrom is a potent C, Kimland M, inducerof pero xDiesPoimearlrefJatWt.y acid b eta - oxidation and other activities known to be affected by peroxisome proliferators in `mouse liver. Pharmacol Toxicol 1993; 72(2):90-3. Sa p.132 (23) `tSprieaprnlsf-leauycotrIioMvoa,cttiHaounnreos-ftbaCPsPHedA,RcThaaelmnpiahckaaalsaS.nSd,TioDnxediRuccootloisSocnFioL2f,0P0B4Pu;tAeR8na0h(lo1pf)hf:a1J5Lt1,a-r6Sg0ee.atcgaetnAesMbyetal . (24) aFnadhmiemdiHcDin,e.SieBserHl,inE;uNroepweaYnorCke:llSBpiroilngoegry-OVregralnaigz,a1t9i8o7n.. Peroxisomes in biology, (25) SSeuabceahtroAnMi,c tTohxiocmiftoyrsdtuPdJi,esHoannspeenrfKlJu,orOoloscteannGesWu,lfoCnaasteeMpTot,asBsuituemnhsoalftfiJnL. `cynomolgus monkeys. Toxicol Sci 2002; 68(1):249-64. (26) aSTleo.axSciuactbo-lAcoMhgry,o2nT0ih0co3d;mife1ot8ar3rd(y1Pt-Jo3,x)i:Hc1ai1tn7ys-oe3f1np.oKJt,asCslieummepnerLfAl,uoErlodorcitdagneesSuRl,foEnlacteomibneratCs.R et (27) pHearufgluhoormoocBt,anSopiycdeavciodld(PO.FOTAh)e, mpeercfhlaunoirosomctuanndeersluylipnhgontihce hacyipdol(iPpFeOmSiAc)efafnecdt of clofibric acid. Biochim Biophys Acta 1992; 1128(1):65-72. (28) `cOwolonsrcekenenrtGrsWaet,riuoBnmusrpraeinrsfdlTmuMeo,droiBocucartlalnseeuwsruvMelMiflo,lnaaMntcaeen(dePxeFalmOiJSnH)a.taEinopdnispd.eermJfiloOulcoocrgouiopcctEaansnvsoiearstosenm(eMnPetFdOofA) ` 2003; 45(3):260-70. (29) aOnldsehnepGaWti,c BaunrdrilsipJiMd,clMinaincdaleclhJeHm,isZtorbyeltesLtRs.inSeflruuomropcehrefmliucoarloopcrtoadnuectsiuolnfonate . employees. J Occup Environ Med 1999; 41(9):799-806. (30) OWopoilnleLtiptiLdAo.l 2T0h0e1;or1i2g(i3n)s:a30n5d-r1o2l.esofcholesterol and fatty acids in the fetus. Curr (31) KinrtaramuetrerMinSe,gOrloiwvtiherrMet,arMdcatLieonananFdHb,oWdiyllpirsopDoMrt,ioUnsahlietryRoHn.eItmalpaacntdonfeonatal outcome. Pediatrics 1990; 86(5):707-713. (32) MnTeeaomdnai2tm0a0lH4,o;uBt3e2cy(o6md)eo:su5:0n9b-Hi5,r1t3Iht.waeniigMht,,KbhoodgyalmiasMs,iCnhdoekxrorI,pYounndiesraKlAi.ndPerxe?diJcPteinrginat (33) RRoLbeerttasl.onNePoAn,atSanlimdoerrbmiadnitSyH,acLcaorrodsinRgKt,o Jgre,stCatoiwoananlRa,geHeainldbrbiornthD,weGiolgdhenfbreormg. . Gfiyvmeetceorltia1r9y92c;ar1e6c6e(n6tPerts 1i)n:t1h6e29U-n4i1t.ed States, 1983 through 1986. Am J Obstet ; (34) aVinldlamrenJ,taSmledreivgellioopVm,enMtaofirnttraoRutr,eBreirnloewlgnroCwHt,h-KrleetianrdReEd.inHfeatnetsrodguernienogutshegrfiorwstth3 yearsof life. Pediatrics 1984; 74(S):783-791. 9343 (35) Jacobsson B, Hagberg G. Antenatal risk factors for cerebral palsy. Best Pract Res Clin Obstet Gynaecol 2004; 18(3):425-36. (36) Hofman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA et al. Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 1997; 82(2):402-406. (37) Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult disease: strengthofeffects and biological basis. Int JEpidemiol 2002; 3 1(6):1235-9. (38) Barker DJ. The developmental `Suppl):5888-5958.. originsof adult disease. J AmColl Nutr 2004; 23(6 (39) Fetal growth disorders. In: Cunningham FG, Gant NF, Leveno KJ, Gilstrap LCI, Williams JW, Hauth JC et al, editors. Williams Obstetrics. New York: McGrawHill, 2001. (40) Savitz DA, Hertz-Picciotto I, Poole C, Olshan AF. Epidemiologic measuresofthe course and outcomeofpregnancy.Epidemiol Rev 2002; 24(2)91-101. (41) Kramer MS, McLean FH, Olivier M, Willis DM, Usher RH. Body proportionality and head and length 'sparing' in growth-retarded neonates: a criticalreappraisal. Pediatrics 1989; 84(4):717-723. (42) Nieto A, Matorras R, Villar J disproportionate intrauterine , Serra growth M. Neonatal `morbidit retardation at term. J y associated with Obstet Gynaecol 1998; 18(6):540-543. (43) Patterson RM, Pouliot MR. Neonatal morphometrics and perinatal outcome: who. is growth retarded? Am J Obstet Gynecol 1987; 157(3):691-693. (44) Cheung YB, Yip PS, Karlberg `mortality. Acta Paediatr 2002; JP. Size at birth 91(4):447-452. and neonatal andpostneonatal (45) Villar J, de OM, Kestler E, Bolanos F, Cerezo R, Bernedes H.`Thedifferential `neonatal morbidity of the intrauterine growth retardation syndrome. Am J Obstet Gynecol 1990; 163(1 Pt 1):151-157. (46) Walther status at FJ, Ramacke birth and its rs LH. relatio The ponderal index as a measureofthe n to some aspects ofneonatal morbidity. nutritional JPerinat Med 1982; 10(1):42-47. (47) FayRA, Dey PL, Saadie CM, Buhl JA, Gebski VJ. Ponderal index: abetter definitionofthe 'at risk' group with intrauterine growth problems than birth`weightforgestational age in term infants. Aust N Z.J Obstet Gynaecol 1991; 31(1):17-19. 1 344 p13 (48) pWiotstteprarFtRu,mTceonrdBbrlooeocdk.IJn,tFoJxGyHnEa.ecAonleOwbsdteevti2c0e0f1o;r 7sa2f(e3r):c2o5l9l-e6c0t.ion of (49) TtJea(sr1tvs)is:u1sMe4Jd3,5tT-ou1dn4iss3tt8ail.nlg-uPiesdhoscmHo,keFresyefrraobmennodnCs,moVkeesresy. CA,mSaJlPouobjleiecYH.eCaolmthpa1r9i8s7o;n of (50) oKrugkalneincyaickidZs, aNnededamhiadmesLLi,n hCaulmaafantsAeMr.umMuesaisnugroenm-elninteofs1ol8id-ppehrafsleuoerxitnraatcetdion. Anal Cher 2005; T7(18):6085-6091. (51) cDBoeetvmieenlrinotepJmiTne,nsJtmro,aknTedurmvsaelarinddWatEnio,onnsoPimfroskkelenesrJisLt,bivySeolsminqeoutifhdfocCdhS,rfoorAmakdtieontgesrrJamRip,nhayWt/aialotdnmrooesfppshMeerrKuimcet al. pressure 2291 ionization tandem mass spectrometry. Clin Chem 1997; 43(12):2281- (52) nHoonmdeutnegctRabWl,e vRaeleueds.LDA.ppElstOicmcautpioEnonvfiraovnerHaygegc1o9n9c0e;ntSr(a1t)i:o4n6-i5n1the presence of . (53) DKertaemremrinMaSn,tsOolfifveietralMg,roMwctLheaanndFbHo,dyDopurgophoerrttioynGalEi,tyW.ilPleidsiaDtrMi,csU1s9h9e0r;R8E6L(1):182 (54) aVsiykmm,etVraitctesnmaLl,lJ-afocro-bgseesntaGt,ioBnaaklk-eagteeiingfLanSt.s.PEraernaltyalHugrmowDtehvin19s9y7m;me4t8(r1i-c2)a:n1d67- 176. (55) iHnadgegxaritsyaPp,ooCrampprbedeilcltoDroMf,iBneuntdeoromigrroAw,tGhrraeytaErdSa,tiAobnr.aBmJoOviGc2h0D04R;. 1P1o1n(d2e)r:a1l13- . 119. (56) CJRhoMid.lrdSiFkgieuntefazollGNd,mSeeaaomspunerreaEmMdetPn2,t0asO0ll5ait;vba9irr0et(hs3:)JsLFe,2x1Va3e-nnFdt2ua7rn5at.hPr,oMpoormeetnroicLAin,flPueernecez.-GAornczhalDeizs (57) NuWesoeoldnfaemteHeaMs1u,9r9Be0rs;oaf5n7is(n3tY-rW4a),u:t1eG6rr7io-ns1es7g1T.rLo,wBthhatwiitahReKs,tiSmoaktoedl nReIo.nCaotrarleblaotdiyonfoatf.cBoiomlmonly (58) tDeecmhanriiqnuieSt,oDeostninmealtleysMubMc.utNaenaero-uisnfbroadryedfaitntienrnacetwabnocems(.NINRe):onaatnaelwInnotne-nisnivvaesive. ` Care 1994; 7(5)28-30. (59) GliilploiplroatnediFnsD,,aMnadncdheollesJtSe.roSle:ruasmtupedryfloufoorcocoucptaatniooincaalcliydeaxnpdosheedpamtiecn.enAzmymJesI,nd Med 1996; 29(5):560-8. 121 345 - eas (60) iLninndeloenyatAeAs,beBtewneseonncJlEi,niGcralilmyemseaC,suCroeldehTeMa,d IcIiIr,cHuemrfemraenncAeAa.nTdhberarienlavtoilounsmheip estimated from head CT-scans. Early Hum Dev 1999; S6(1):17-29. (61) cLiermcounmfseJrAe,ncSecihnreeianrelryRinLf,anGcrye.sHhiamm EBLi.olRe1l9a8t1i;o5n3s(h3i)po:3f5b1r-a3i54n.weight to head (62) fDeotbalbianngd pJ,osStanantdalsJ.liHfee.aEdarcliyrcHuumfmerDeenvce1,9b7i8p;ar2i(e1t)a:ld81i-a8m7e.terand brain growth in (63) THoawckbiMrt,hBwreeisglhatuaNn,dWseuibsnsormmaanlBh,eAadrasimzeD,onKlceoignniNt,ivBeoarbailwistkieisEa.t Esfcfheocotlofagev.erNy EnglJMed 1991; 325(4)231-237. (64) IHveaandovsiiczeDaMn,d iLnetievlaliBgePn,ceP,erleezamHiTn,g,OnluitvrairteisonMalGs,taDtiusazanNdS,brUarirnutdieaveMlSopmeteanlt.. Head, 131 IQ, learning, nutrition and brain. Neuropsychologia 2004; 42(8):1118- (65) PceitrecrusmofnerJe,nTcaeylionrveHrGy,lMoiwnbiicrhthNw,eKilgehitncNhi,ldHraecn:knMe.onSautablnocrormraellahteeasdand schoolage consequences. Early Hum Dev 2006; 82(5):325-334. (66) tOhuensatgeeodfMs,evMeonaryeVarAs,. ASccottatPAa.edHieaatdr Scciracnudmf1e9r8e8n;cTe7a(n3)d:d3e7v4-e3l7o9p.mental ability at (67) DmeeasscuhreLsWo,fAsncdheorolsopnerSfKo,rmSanncoew.JCHl.inRePleadtiiaotnrsh(iPphoilfa)he1a9d90c;ir2c9u(m7f):e3r8e9n-c3e92to. (68) BinatbeslloenctSuaGl,pHeerfnodremrasnocne.NBP.ediFaettarlicusnd1e9r7g4;ro5w3t(h6:):r8e9l0a-t8io9n4o,f head growth to later (69) `BmreeansnuerrinHg,eLxopoosmuirse.D.EpViadreimeidofloorgmyso19f9b4i;a5s(d5)u:e51to0-n5o1n7d.ifferential error in (70)oHfovyietarlt DstLa,tisMtaictsh:e2w00s4.TJP,eMdieantarcikcser20F0,6S;tr1o1b7i(n1o):D1M68,-1G8u3y.er B. Annual summary 122 36 : p13 CHAPTER } CONCLUSIONS 123 34b7 p.137 This chapter serves as a conclusion to the dissertation titled "Fetal Exposure to Perfluorinated Compounds (PFCs): Distribution and Determinants of Exposure and Relationships with Weight and Size at Birth" Below I reiterate the specific aims of my dissertation and summarize my findings, along with their implications for public health, environmental policy, and future research. * Specific Aim 1: Review the literature on perfluorinated compounds, including production and use, human biomonitoring and exposure pathways, and toxicity and epidemiology (Chapter 2). + Specific Aim 2: Conduct a study to describe the distribution and determinants of PFC cord concentrations among a sample of newbom deliveries occurring at the Johns Hopkins HosinpBalitimtorea, MlD (Chapter 3). * Specific Aim 3: Conduct an epidemiologic investigation into the relationship between PFC cord concentrations and birth weight, newborn head circumference, crown-heel length, and ponderal index (Chapter 4). `SumofmFiandrinygs In Chapter 2, T summarized the litrature on perfluorinated compounds, including human biomonitoring, exposure pathways, animal toxicity, and occupational epidemiology studies. From ths literature review, it is apparent that human exposure to two perfluorinated compounds, PFOS and PFOA, is widespread, as documented by biomonitoring studies conducted in awide rangeofcountries. Its also clear that awide 2% 308 p38 Variation in exposure is occurring, as human blood concentrations in some counties were. considerably lower than others (Figures 2-2 and 2-3). On the basis of environmental c monitoring, it has been established that contamination with PFOSand PFOA. is observed even in remote regions, such as the Arctic (1,2). This provides some insight to possible exposure pathways and suggests that direct contact with consumer products is not the only possible source of exposure. Potential sources of exposure may include industrial releases, consumer product use, dustindoor ai inhalation, drinking water, or dietary . pathways through environmental contamination; however, there are no clear data to suggest the relative contribution, ifany, of these sources to human exposure. Developmental toxicity of PFOS and PFOA has been noted among the effects observed in animal studies. PFOS has been shown to induce developmental and reproductive effects in rats and mice, including reduced birth weight, decreased gestational length, ! structural defects, development delays, and increased neonatal morality (3-8). PFOA has been shown to cause pregnancy loss, reduced fetal weight, reduced postnatal survival, . and delays in postnatal growth and development in offspring of rodents (9-13). PFOS and PFOA have also been shown to have hypolipidemic effects in several animal species (314-16). Characterization of in utero exposure among humans is necessary for extrapolating developmental risk from animal data. Further, the relevance of animal studies conducted at high doses to humans exposed at much lower levels is uncertain. . The direct evaluation of reproductive and developmental endpoints in humans would shed light on the issue ofhealth effects from low dose exposures. 125 3#7 p13 In Chapter 3, I examined the distribution and determinantsofPFC concentrations in cord blood from a sample of newbom infants delivered at the Johns Hopkins Hospital in Baltimore, MD. The resultsofthis analysis confirmed the presenceof in utero exposure to PFOS and PFOA, and less so, to other PFCs under study. Lower concentrations were observed in cord serum when compared with typically reported concentrations in adult `serumintheUnited States. This is consistent with incomplete incomplete transfer across the placenta by simple diffusion becauseofthe relatively large sizeofthese compounds, their affinity for binding to proteins in serum, and other physical characteristics such as their surfactant properties. Differences in protein concentration between matemal and fetal blood may also plaarolye. As expected, the predominant PFCs detected in the cord samples were PFOS and PFOA, `with detection ratesof 99 and 100 percent, respectively. Other PFCs were detected less frequently and, when detected, occurred at much lower levels. Among the demographic characteristics available from the medical record, there were relatively few predictors of cord concentrations. Many persistent pollutants tend to accumulate with age as the opportunity for exposure and accumulationofthe chemical increase with age. However, consistent with previous findings, we observed no such association with these compounds and age. In fact,a predictive model with age, race, education, insurance status, marital staus, body mass index, party, smoking status, infant gender, preterm birth, and an indicator for whether the mother lived inside Baltimore city limits explained only 6 percent of the variation in cord PFOS concentrations and 11 percent of the variation in cord PFOA. concentrations. Whether examined singly or in multivariate models, 126 350 p10 relatively few of the demographic factors measured in this study were predictive of in wero exposure. One notable exception to the above was that Asian babies had the highest average cord serum PFOS concentrations. Most of the mothers were not Asian-American, but instead Werebom in Asian counties. The three highest PFOS concentrations were among babies born to individuals from Asia, two from China. This isofinterest because some of the p `highest levelsof PFOS contamination in humans havebeen reported in China (Figure 2- 2). Although we did not find evidence for significant variability within our region (i.e., within Baltimore vs. outsideofBaltimore city), these data are consistent with variability in exposure over larger geographic regions, for which race/ethnicity may represent a surrogate marker. However, this must be interpreted with caution, given that data on levels of PFCs in human populations are limited. More extensive monitoring is needed ' to understand these exposure pattems. `This study provided an opportunity to examine socioeconomic status as a predictor of cord concentrations. The study population of mothers delivering at Johns Hopkins Hospital represents a diverse mixture of individuals, including those from the . surrounding community, Johns Hopkins faculty and staff, and individualstransported from outside the area. We found no evidence of a socioeconomic or urban environment gradient in cord concentrations of PFOS or PFOA. Because socioeconomic status is ' likely associated withth typesof consumer products and material in the home, lack of gradient in serum concentrations by socioeconomic status may imply that consumer 35) p11 products are not major sources of exposure. Rather, exposure may be occurring from sources that are more ubiquitous and less associated with socioeconomic level, such as `widely consumed foods, drinking water, and/or air. Future studies could include asurvey component to characterize possible sources of exposure in the home environment as predictorsof serum concentrations of PFOS and PFOA. In Chapter 4, I presented the resultsofan epidemiologic investigationoffetal exposure to PFOS and PFOA and associations with birth weight, newbom headcircumference, length, and ponderal index. These birth size parameters have been used as indicators of growth restriction in utero, through the use of classifications such as "small-forgestational age," based on cutoffs at the lower tail of the distributions. In this study, I examined the associations between cord concentrations and these endpoints across the full rangeofthe distribution. We found negative associations between both PFOS and PFOA with birth weight, head circumference, and ponderal index. In contrast, no consistent trend was observed for PFOS or PFOA and newborn length. The associations observed were fairly robust to the inclusion of additional covariates in the model, specification of continuous covariates in the model, and functional formofthe model. Additionally, these associations were independent of cord lipid levels at birth. These findings were consistent with toxicology data that has found decreased weight of `newbom animals when mothers were dosed with PFOS and PFOA. One finding that was not completely intuitive was the interaction between PFOS or PFOA and delivery mode on head circumference. As expected, babies born through 128 359 p42 `Caesarian sections had larger head circumferences, on average, than those born through vaginal delivery, after accounting for other predictorsofhead circumference. Because of ` this phenomenon which is likely due to head molding, one might have expected that any effect of PFOS or PFOA on head circumference would be stronger among Caesarian sections than among vaginal deliveries. However, we observed a strong negative association among vaginal deliveries and a small positive association among Cacsarian sections. The reason for this interaction is unclear at present and future research should `examine this further. A major strengthofthis study was the state-of-the-art analytical method conducted by the t Centers for Discase Control and Prevention for quantifying cord serum PFC concentrations (17). There is some uncertainty as to the extentof measurement error for PFOS because the precursor/product ion transition normally used for quantification could ' not be used due to an interferent ion. However, an increase in random measurement error should make a statistical association more difficult to detect (18). Maternal nutritional status was not measured in this study and could be a potential confounder in the relationship between PFOS or PFOA concentrations and birth `weight or birth size. `However, this would only be the case if poornutrition was correlated with higher levels ` Of PFOS and PFOA, or vice-versa. More research is needed to clucidate the pathways of `human exposure to determine whether these concerns are founded. . `Adding further to our confidence in the validity of these findings was the replication of `previously reported associations between other predictors and birth outcomes: Negative 12935 3 [0 associations were observed between smoking status and birth weigh, head circumference and length; matemal age was associated with birth weight in an inverse U-shape, where both young and older mothers tended to have lighter babies; diabetes was associated with heavier and larger babies and hypertension with lighter and smaller ones; primiparous women had lighter and smaller babies compared with multiparous; matemal anthropometry was a strong predictorofbirth weight and size; males tended to be bigger than female babies; and larger head circumferences were observed among Cacsarian sections versus vaginal deliveries, after adjusting for the key predictors of birth weight and size. There are significant public health implicationsofdisruptions to normal fetal growth and development. Babies bom early or with Iow birth weight (<2,500 grams) are at increased isk ofmortality in the firstyearoflife (19,20). In 2001, the infant morality rate among low birth weight births in the U.S. was more than 25-foldgreater than among babies with birth weights above 2,500 grams (19). In 2002, the combination of preterm birth and unspecified LBW was the second leading cause of infant death (20). Babies born small for gestational age due to fetal growth restriction are at greater risk for perinatal and childhood morbidity, including hypothermia, hypoglycemia, and/or asphyxia (21-27), neonatal intensive care unit admission (28), respiratory distress syndrome (29), reduced mental development in infancy (30), cerebral palsy (31), and reduced insulin sensitivity, a `markeroftypeITdiabetes risk (32). 0300) p14 In addition to the neonatal and childhood impacts associated with fetal growth restriction, a growing bodyofresearch suggests that some metabolic diseases in adulthood may have . their origins in fetal development. Overthe last 15 years, a number of studies conducted in different counties have shown that small size a birth, modified by rapid childhood growth, is associated with risk of coronary heart disease, typeIIdiabetes, and their . metabolic risk factors, including hypertension, hyperlipidemia, and reduced insulin sensitivity (33-38). A number of hypotheses have been suggested to explain this phenomenon, including the `Barker hypothesis', which presumes that birth weight represents a marker of fetal nutrition and that lack of optimal nutrition coupled with catch-up growth predisposes individuals to developing metabolic discases in adulthood. (33;39;40). Barker and colleagues have suggested that the processes of "developmental plasticity" and "compensatory growth" are responsible for the increased discase risk later in life (34,40). The basis for this theory is the presence of "a critical period when a ` system is plastic and sensitive to the environment, followed by loss of plasticity and a fixed functional capacity" (39). It is suggested that the fetus can adapt in wero to undemourishment through metabolic changes in order to improve short-term survival. These metabolic changes may put the individual at greater risk for heart disease and diabetes later in life, specifically, when entering an environment of adequate nutrition ` after birth and excess compensatory growth (29;35;36). Interestingly, the increased risk of adult disease is observed across a range of what could be considered "normal" birth weights. For example, among 10,636 men in a community in England, hazard ratios for ' death from coronary heart disease increased monotonically with decreasing birth weight. Babies bom at weights between 5.5-6.5 Ibs (approximately 2,500-3,000 grams) were 29 131 359 p45 percent more likely to dic from CHD than babies bom at > 10 Ibs (33). These findings suggest thatevensmall decrements in fetal growth can affect long-term disease risk. The major hypotheses regarding the fetal origins of adult disease have been focused on nutrition as the key mechanism underlying this process. However, if exposure to persistent pollutants were causally related to reduced fetal growth, this could be an alterate mechanism. Our study was not intended to examine the riskoffetal growth restriction associated with increased cord blood concentrations of PFOS or PFOA. Instead, we examined the association between exposure and birth size parameters across the full distribution of birth weight, head circumference, length, and ponderal index. We identified an association between increased exposure and reduced birth weight, head circumference, `and ponderal index across the range of these endpoints in our study population. A linear model suggests that a shift in the distribution would occi evenly across the population. Babies with birth size parameters in the middle of this range would not necessarily be classified as growth restrictedifhead circumference or ponderal index were reduced by a small amount. However, one could expect that a similar reduction in birth size among those babies at the lower end of the distribution could result in more of these babies classified as growth restrictedand lead to agreaterriskofadverse outcomes among those. infants. When comparing the 5 to 95 percentile of PFOS cord concentrations, the changes in birth weight, head circumference, and ponderal index were, on average, 134 grams, 0.61 centimeters, and 0.14 g/em*x100 respectively, after adjusting for potential confounders. For a baby bom at 37 completed weeks, this represents a shift from the 16% ce pas 10 10 percentileofbirth weight in the U.S. (41). At term, a change in ponderal index of 0.14 represents a shift from the 25% percentile to the 10% percentile of ponderal index / distribution (42). Thus, changesofthis magnitude would be associated with more babies `being classified as small-for-gestational age. Additionally,ifthe observations made by Barker and others hold, shifts throughout the rangeofthe birth weight distribution may result in increased future morbidity. It is interesting to note that a significant percentage of the mother's in our study were overweight or obese and, subsequently, there were a larger proportion of large-for- gestational age babies than small-for-gestational age babies. For example, based on the . birth weight for gestational age standards used by the hospital, almost 15 percent of babies were classified as large-for-gestational age (LGA), while only 4 percent were classified as SGA. Thus, one could argue that macrosomia may be as important a health ! `problem to the well-beingofour study population as growth restriction. Policy Implications `Comparisons with Animal Toxicity Data In the present study, we observed negative associations between both PFOS and PFOA ` and measuresof weight and size at birth. The doses at which developmental effects were observed in the animal toxicity literature are considerably greater than what was observed in our study. Table 5-1 gives an overview of results from the animal developmental ` toxicity data, by showing the lower confidence limits of the benchmark dose associated with a 5 percent increase in response (BMDLs). Although these estimates are, in part, 133 357 p47 dependent on the model used to fit the observed data, they provide a useful comparison between human exposure levels and animal toxicity studies. Among the most sensitive effects observed in these developmental studies were stemal defects in mice for PFOS `and reduced ossification in mice for POA. The mouse has been suggested as a better model for PFOA human developmental risk because the female rat has the ability to rapidly eliminate the chemical. These estimates are mainly reported in mg/kg/day of external dose. For comparison with human data it is necessary to convert these units to serum concentrations. The corresponding serum levels associated with these BMDL's are not readily available, however,they can be bounded using data from the studies. For PFOS and stemal defects in rats, the BMDLS of 0.122 mg/kg/day would result in fetal serum concentrations between 0.188 and 36 ppm (39). For PFOA and reduced ossification in mice, a BMDL of 0.6 mg/kg/day is equal to less than 20 ppm in matemal serum (13), corresponding to <10 ppm in the fetus assuming one-half is transferred through the placenta (43). Lucbker et al. (2005) report a BMDLsof0.39 mgkg for PFOS and reduced birth weight, which corresponded to a fetal serum level of about 34 ppm in the rat (6). These serum concentrations are ordersofmagnitude greater than what has been observed our study and are higher than the serum concentrations typically reported among occupationally-exposed individuals. It is interesting to note that in severalofthe studies, serum concentrations among the control group are higher than we. report here. For example, Thibodeaux et al. (2003) reports mean fetal serum PFOS concentrations among the control group of 188 ppb at birth (3,9), compared with approximately 5 ppb in our study. ~ Additionally, animal studies are typically conducted with smell numbers of animals and have low statistical power. Thus, as designed, these Be 358 p18 animal studies may not be capable of examining the adverse effects of low-dose exposure. ` Current Regulatory Actions As of 2000, global production of perfluorooctanesulfonyl fluoride-based chemicals was estimated to be 3,665. metric tons, 1,820 of which was either produced in the U.S. or entered the country through importation (44). In 2000, the major manufacturerofPFOS- based materials announced they would end production by 2002 (45). US. EPA subsequently promulgated a Significant New Use Rule tolimitthe production and use of a group of related perfluoroalkyl sulfonated compounds (46). Becauseofthe long half: ` life in humans and the environment, it may take years before concentrations decline noticeably. It is estimated that fewer than 600 metric tons of PFOA are manufactured or imported intothe ULS.peryear (47). In response to concern about the widespread PFOA contamination and potential carcinogenicity and developmental toxicity risk, the USS. EPA issued an enforceable consent agreement, which requires manufacturers to conduct . testing on the fate and transport of fluoropolymers made with PFOA (48). The U.S. EPA has also entered into voluntary agreements with the major manufacturers of PFOA to reduce emissions and residual content in finished products and work towards eliminating ` them completely (49). Despite this progress, the policy options for reducing human exposure to these compounds are tied to improving our understanding of the major sources and pathways of exposure, along with the extent to which precursor compounds contribute to exposure. These and additional future research needs are described below (Table 5-2). 135 359 p14 FutureResearchNeeds. Subsequent studies of fetal exposure and birth outcomes should be conducted to confirm the findings reported here, ideally among a population with a wider range of exposure. These studies should be conducted in settings where subjects have low rates of pregnancy-related complications, including co-morbidities such as diabetes and preeclampsia, intrapartum infection, and substance abuse. Such studies would reduce the chance that findings could result from confounding due to these strong determinants of adverse pregnancy outcomes. Additionally, studies of birth outcomes among women occupationally exposed or among communities exposed at higher levels than the general population would provide insight to the potential for developmental effects. Hospital-based cross-sectional studies are relatively straightforward to conduct and useful for studying the effects of persistent pollutants on birth outcomes. Because these compounds are persistent and matemal levels will not fluctuate over a 9-month time period, cord blood concentrations at birth can be seenas ameasure of exposure actoss the duration of pregnancy. Future studies could improve on this design by measuring matemal concentrations of these compounds as well. This would allow a more direct analysisofthe extent to which these chemicals cross the placenta and an examination of pattems of variation in placental transfer. Additionally, oversampling babies with low birth weight and/or small size for gestational age would improve the statistical power to detect an association between exposure and birth outcomes. 30 5.150 We were able to conduct this study in a relatively short period of time because it was cross-sectional and used pre-existing medical record data. However, there would be ` added advantages to conducting a longitudinal study across the duration of pregnancy. First, serial ultrasounds could be used to examine fetal growth trajectory to distinguish growth restricted from constitutionally small babies. Second, surveys could be ! administered to the mothers to identify dietary, lifestyle, and household determinants that may be predictors of exposure and/or birth outcomes. A biomarker of nutritional status i ould also be used to supplement dietary data obtained from surveys. Animal studies are necessary to further elucidate the mechanisms which have led to observationsofdevelopmental toxicity in rats and mice. Possible mechanisms for these: effects include increased membrane fluidity and permeability (50), disrupted cell communication through gap junctions (51), displacement of endogenous ligands from ` proteins (such as liver fatty acid binding protein) (52), or disrupted thyroid hormone production (3;5;6;14). In addition to the possible human health effects, key data gaps . exist in understanding the pathways of human exposure. Future studies are needed to elucidate these pathways further, so that steps can be taken to minimize human exposure to these compounds. ` In summary, the findings of this research confirm that in utero exposure to PFOS and . PFOA is occurring among babies bom in Baltimore City. Despite the relatively low serum concentrations, we detected negative associations between PFOS and PFOA concentrations in cord serum and birth weight, head circumference, and ponderal index. 137 Jel ' p.151 Future studies are needed to replicate these findings in other settings. Given the widespread human exposure to these compounds documented by biomonitoring studies, impacts on etal growth could have significant public health implications, 18 SEL p12 5 : 2 g 3 fg 85 T24: i[E[5lB8[Ss3.EesScEeEl[fpEeaafBili<yI2a2 f(|SEaEek.ak8s) |L[. E.ER8E8:8fs F825 R3||e5i|l/EPea5|si3EseE8eg8ars%e||8cHd|i5hvanEtiianetlsHsHlsEEH||EHES3eEsiisauSE8nEdnsH|) R11[BsiINi1T31TIIiEEsE% z 0 ziB[3 g5 lg [B[l1z3s3s3n5y3 . BSeErEeEtEEs SSgo ? nLN0zEsEsEy 8 52 . . [sT8S3E37.4 23: ge[MlBs3ZeEizscad,igf, FRR HEE i29 F8882308 323 f5:.ii [c3BeEeEd:3 Sf 3S32%2 |eFi2iEggiiey 2 i : P2E llseo52 gE. ER t3s 5i i-BFs 38 32 Es ' ig zB Je3 5.183 `Table 5-2. Data gaps and future research needs. + Human exposure pathways Roleofprecursor compounds Useofconsumer products versus environmental contamination Mechanismsof developmental toxicity in animals o Denbntes Cell signaling Membrane fluidity Protein binding + Replicationof current epidemiologic study in different settings Occupational or highly-exposed populations Survey component Measurementof maternal and fetal serum concentrations Sey p.154 References (1) IMdaernttiinfiJcaWt,ioSnomiftlhownigc-kchMaMin,peBrrfaluunoreinBaMt,edHaoceikdsstirnabPiFo,taMfuriormDtCh,e CMaanbaudriyanSA. . Asctic. Environ Sci Technol 2004; 38(2):373-380. (2): CSimrictuhmwpioclkaMr,stMuadbyoufrpyeSrfAl,uoSroolaolkmyolncKoRn,taSmoinnannetsC,inMaproltairnbJeWa,rsB(oUrmsuEsW et al. . `maritimus). Environ Sci Technol 2005; 39(15):5517-5523. (3) `TEhxipboosduereautxo JpRe,rfHlaunorsooonctRaGn,e sRuolgfeonrasteJMd,urGirnegypBreEg,nBaanrcbyeienBraDt,aRnidcmhoaursdes.JIH: et al `maternal and prenatal evaluations. Toxicol Sci 2003; 74(2):369-81. (4) `GprearsftlyuoRrCoo,ctGarneeysBulEf,onLaatue-CiSn,duRcoegdenresonJaMt.alPrmeonrattaallitwyiinndtohweoSfprsaugscueep-tDibaiwlliteyytroat. Birth Defects Res Part BDevReprod Toxicol 2003; 68(6):465-71 (5) LEaxpuoCs,urTehitboopdeerafuluxoJrRo,ocHtaannesosunlfRoGn,atReodguerrisngJMp,reGgrneayncByEi,nSrtaatnatnodn mMoEusee.talI.I: . postnatal evaluation. Toxicol Sci 2003; 74(2):382-92. (6) fLruoembkienruDteIr,oYeoxrpkosRuGr,e tHoapnesrefnluKoJr,ooMcotoanreesuJlAf,onBauttee(nPFhOoSfJ)Lf.inNSeopnraatgaule-mDoratwalleiyty rTaotsx:icdoolsoeg-yre2s0p0o5n;se2,15a(n1d-b2i)o:1c4h9e-m1i6c9a.l and pharamacokinetic parameters. ` (7) `LgueenberkaetrioDnJr,eCpraosdeuMctTi,onYaonrdkcRrGos,s-Mfoosotreer JstAu,diHeasnosfepnerKfJl,uoBrouotcteaanhesouJflLff.onTawteo:- (PFOS) in rats. Toxicology 2005; 215(1-2):126-148. . (8) Fdueevnetleospm8e,nCtoallotmoixnicaoMloTg,y:RCoodnrciugrureezntJ,eVxipcoesnusreP,foDopemrifnlguooroJoLc.tIannteersaucltfioonnastein (FOS)andstressin pregnant mice. Toxicol Lett 2006; 164(1):81-89. (9)acLiadusCa,nBduttehenihrodfefriJvLa,tiRvoegse.rTsoJxiMc.olThApepdlevPehlaorpmmaecnotlal20t04;o19xo8(f2ip)e:r2cf3l1u-io4r1o.talkyyl ` (10) TrBeouptxreioncdhouolcfotfgiyJvLe2,0t0oK4xe;inc1no9le6od(gy1yo-G2fL)a:,9mJ5mr-,1o1Fn6r.iaummepSeRr,flOu'oCroonocntoarnoJaCt,eY(oArPkFROG).inThtehe rat. (11) YstourdkyRoGfa.mOmraoln(iguamvapgeer)fltuwoor-ogoecntearnaotaitoen((AoPneFlOit)teirnperarts.gen2e0r0a2t.ioHno)rsrehparmo,duPcAt,ion RAerfgTusypRee:seRaerpcohr.t1926. 141 p.155 (12) dUeSveElnovpimreonntmaelnttoaxlicPirtoytaescstoicoinatAegdenwictyh. ePxrpeolismuirneatroypreirsfklausosreososcmtaennotiocfatchied and its sParletsv.enUtSioEnPaAndDoTcoxkiects;OPRPiTs-k2A0s0s3e-s0s0m1e2n-t00Di0v2i.si2o0n0.3.191O0f,ficeof Pollution RefType: Report (13) aLla.uEfCf,ecTthsoibfopdeerafulxuoJrRo,oHcatnasnooinaRcGi,d eNxaproastusrkeydMuGri,ngRopgreergsnaJnMc,yLiinntdhsetmrooumsAe.B et Toxicol Sci 2006; 90(2):510-513. (14) S`SeuabccahtroAnMi,c tTohxiocmiftoyrsdtudPJi,esHoannspeenrfKlJu,orOoloscteannGesWu,lfoCnaasteeMpTot,asBsuituemnhsoalftfIinL. cynomolgus monkeys. Toxicol Sci 2002; 68(1):249-64. (13) aSle.aScuabt-AchMr,onTihcodmifeotarrdyPtJo,xiHcaitnyosefnpKoJt,asCslieummepnerLfAl,uoErlodorcitdagneesSuRl,foEnlacteominberatCs.R et Toxicology 2003; 183(1-3):117-31. (16) pHearuflguhooromocBt,aSnopiycdeavciodld(POF.OTAh)e, mpeercfhlaunoriosomctuanndeersluylipnhgontihce hacyipdol(iPpFeOmSiAc)efafencdt of clofibric acid. Biochim Biophys Acta 1992; 1128(1):65-72. (17) oKrugkalneincyaickiZd,s NanededamhiadmesLLi,n hCaulmaafantsAeMr.umMuesaisnugroenm-elinnteofs1ol8id-ppehrfalsueoerxitnraatcetdion. Anal Chem 2005; T7(18):6085-6091. (18) BmreeansnuerrinHg,eLxopoosmuirse.D.EpViadreimeidofloorgmyso1f9b94i;a5s(5d)u:51t0o-n5o1n7d.ifferential error in (19) AstraitaisstEi,csM--a20c0D2.orPmedainatMrFic,sS2t0r0o3b;in1o1D2(M6,PtGu1y):e1r21B5.-A30n.nual summary ofvital (20)oHfovyietratl DstLa,tisMtaictsh:e2w0s04T.J,PeMdeiantarcikcser20F0,6S;r1o1b7i(n1o):D1M68,-1G8u3.yeBr. Annual summary (21) DaoncdtnoeronBaAt,alOo'uRtiocrodmaensoMfsAm,aKlilrcfhonregresHtLa,tioSnhaalhaDg,e HinafcakntsM.boPrenriantattaelrmcogrersetlaattieosn. Am JObstet Gynecol 2001; 185(3):652-659. (22) sWtaalttuhseart bFiJr,tRhaamnadciktesrrselLatHi.onTthoespoomnedearsaplecitnsdeoxfnaesonaamteaalsmuorrebiodftithye.nJutPreirtiinoanatl Med 1982; 10(1):42-47. (23) dNiiseptroopAo,rMtiaotnoartreaisnRtr,auVtielrlianreJ,grSoerwrtahMre.taNredoantaitonaal motrerbmi.diJtOybasstseotciGaytneadewciotlh 1998; 18(6):540-543. 142 3c6 p15 (24) iKnrtaramuetrerMinSe,gOrloiwvtiherrMet,arMdcatLieonananFdHb,oWdiyllpirsopDoMrt,ioUnsahlietryRoHn.feItmapaacntdonfeonatal outcome. Pediatrics 1990; 86(5):707-713. . (25) Lubchenco LO, by birth weight Bar and dgeHs.taItniconiadlenacgeeo. fPehdyipaotrgilcysce1m97i1a;i4n7n(e5w):b8o3r1n-8i3n8f.an ts classified (26) ADrcocsusroaucyVo,fDainatmharnotpiomEe,tNroiuctmseiaasHu,reKmonesnttasntiinnpirdeidsiTct,iKnagtssyomupgtioamnantoipcouSlGosAVa.nd LGA neonates. Acta Paediatr 1995; 84(1):1-5. (27) Patterson RM, Pouliot MR. Neonatal morphometrics and perinatal outcome: who is growth retarded? Am J Obstet Gynecol 1987; 157(3):691-693. (28) Tamim H, Beydoun H, Itani M, Khogali M, Chokr I, Yunis KA. Predicting ! `neonatal outcomes: birthweight, body mass index or ponderal index? J Perinat Med 2004; 32(6):509-513. (29) Robertson PA, RLet al. Neona tSanlimdoerrbmiadnitSyH,aLcacroorsdRiKtn,og Jgre.s,tCatoiwoananl R, Heilbron D,Goldenberg age and birth weight from five tertiary care centers in the United States, 1983 through 1986. Am JObstet Gynecol 1992; 166(6 Pt 1):1629-41. (30) VainldlamrenJ,taSmledreivgeliloopVm,enMatortfoirnetlrlaRut,eBrirnoewgnroCwHt,h-KrleetianrdReEd.inHfeatnetsrodguernienogutsgherofiwrstth3 ` yearsoflife. Pediatrics 1984; 74(5):783-791. (31) Jacobsson B, Hagberg G. Antenatal risk factors Clin Obstet Gynaecol 2004; 18(3):425-36. for cercbral palsy. Best Pract Res (32) Hofman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA ` ct al. Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 1997; 82(2):402-406. (33) `BSaurpkpelr):D5J8.8ST-h5e95d8e.velopmental originsofadult disease. J Am Coll Nutr 2004; 23(6 ` (34) Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal originsofadult disease: strengthofeffects and biological basis. Jn J Epidemiol 2002; 31(6):1235-9. (35) Robinson SM, Barker DJ. Coronary heart disease: a disorder`ofgrowth. Proc Nutr Soc 2002; 61(4):537-542. ` (36) iBnasrukleirn-DdJe,peHnadleenst)CNdi,aFbaeltlesCmHe,llOitsums,onhydpeCr,tPehnsiipopns K, Clark PM. Type 2 and hyperlipidaemia (non- (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36(1):62-67. 143 (37) Barker DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol 2006; 49(2):270-283. (38) Jaddoe VW, Witteman JC. Hypotheses on the fetal originsofadult diseases: contributionsofepidemiological studies. Eur J Epidemiol 2006; 21(2):91-102. (39) Barker DJ. A new model for the origins ofchronic disease. Med Health Care Philos 2001; 4(1):31-35. (40) Barker DJ. The developmental originsofadult disease.Eur JEpidemiol 2003; 18(8):733-736. (41) OkenE, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous `measureofbirth weight for gestational age using a United States national reference. BMC Pediatr 2003; 3:6. (42) Lehingue Y, Remontet L, Munoz F, MamellNe. Birth ponderal index and body `mass index reference curves in a large population. Am JHum Biol 1998; 10:327340. A SN (43) Hinderliter PM, Mylchreest E, Gannon SA, ButenhoffJL, Kennedy GL, Jr. Toxicology 2005; 211(1-2):139-148. (44) OECD. Hazard Assessmentof Perfluorooctane Sulfonate (PFOS) and its Salts. ENV/IM/RD(2002)17/FINAL. 2002. Organization for Economic Cooperation and Development; Environment Directorate; Joint Meetingofthe Chemicals `Committee and the Working Party on Chemicals, Pesticides, and Biotechnology. 1921. `Ref Type: Report (45) 3M Company. Letter to EPA re: phase-out plan for POSF-based products. EPA. Docket 2002-0043-0009. 2000. St Paul, MN. 1907. Ref Type: Report (46) U.S Environmental Protection Agency. Perfluoroalkyl Sulfonates; Proposed SignificantNew Use Rule. http://www.cpa gov/fedrgstr/EPATOX/2006/March/Day-10/t3h4t4m4. 3-10-2006. RefType: Electronic Citation (47) Perfluorooctanoic acid (PFOA), Fluorinated telomers; Request for comment, Solicitation of interested parties for enforceable. consent agreement development, and notice of public meeting. Federal Register (73). 2003. Ref Type: Statute. (48) Final enforceable consent agreement and testing consent order for four formulated. `compositesoffluoropolymer chemicals. Federal Register (Volume 70, Number Ze p.158 130), 39630-39637. 7-8-2005. RefType: Statute (49) Uh.SitEpn:v/iAvrwown.meepan.tgaolviPorpoptteicnttiro/npfAogae/npcuyb.s/2p0f1o0a/s1te5wParFdOshAipS.thetwmar. d6-s3h0i-p2P0r0o6g.ram. ! RefType: Electronic Citation (50) cHeullWm,emJbonreasnePDp,roDpeerCtoicesncWau,sKeidnbgyLp,erFfrlaukoerrinPa,tNedewcsotmepdouJendtsa.. CAoltmepraBtiiooncshienm ` Physiol CToxicol Pharmacol 2003; 135(1):77-88. (51) jHuuncWti,onJaolneinstePrDc,elUluplharacmomBmLu,nTircoastkioonJEb,yLpaeurfCl,uoGriienastyeJdP.coImnphiobuintidosnionfrgaatpliver aTnoxdidcoollpShciin2k0i0d2n;ey68e(p2i)t:he4l2i9a-l4c3e6l.l lines in vitro and Sprague-Dawley rats in vivo, . (52) fL1lu7u6eo(br3ko)ec:rh1e7Dm5Ji-,c85aH.lasnsweitnhKrJa, lBiavsesr fNaMtt,y aBcuidt-ebinnhdionJfgLf,prSoetaeicna.tZAoMx.icoInltoegryac2t0i0o2n;s of . 7g APPENDICES 1s 370 5.160 Listof Tables w`Teaibglhet,B-h1e.ighCth,arAanct/eOrTisWtEiIcsgohftsBtAudNy.s.ub.jects missing information on pre-pregnincy 162 . Table study B-2. Comparing the period and with U.S. VsittuadlySptoaptuisltaitcisofnrwoimth20al0l b3i-rt2hs0o0c4cu.r.ri.ng at JHH over the 163 `Table B-3. Comparing regression results using different methods for handling missing `Table C-1. Coefficients from multivariate regressionofbirth weight on In(PFOS)..... 166 `Table C-2. Coefficients from multivariate regressionofbirth weight on In(PFOA).... 167 Table C3. Coefficients from multivariate regressionof head circumference on ITaPbFleOAC-)4.. Coefficies nts from multivas riate regressionos f head circumf. erence on 160 ` Table C-S. Coefficients from multivariate regressionof length on In(PFOS)........... 170 Table C-6. Coefficients from multivariate regressionof length on IN(PFOAY)........... 171 ` Table C7. Coefficients from multivariate regressionofponderal index on In(PFOS). 172 Table C-8. Coefficients from multivariate regressionofponderal index on In(PFOA). 173 147 p61 List of Figures Figure A-1. Key determinantsofbirth weight, Baltimore THREE Study............... 153 Figure A-2. Mean birth weight (grams) by subject characteristics, Baltimore THREE Figure A-3. Key determinants ofnewborn head circumerence, Baltimore THREE Study. Figure A-4. Mean head circumference (cm) by subject characteristics, Baltimore THREE ET Figure A-5. Key determinantsof newborn length, Baltimore THREE Study............ 157 Figure A-6. Mean length (cm) by subject characteristics, Baltimore THREE Study.... 158 Figure A-7. Key determinants ofnewborn ponderal index, Baltimore THREE Study. 159 Figure A-8. Mean ponderal index by subject characteristics, Baltimore THREE Study. EN FGHiEgEuCrTeENDE-S1E.LSCoOeFfCfOiVcAiTeInAtEsSf.rov m linear regressionos fbirth weight ons InPFOS), adjusted b1y76 HFigFureTD-2S.CSCoOeFffCiOcViAeTnAtEsSf.roo m linear regv ressionofbie rth weightn on In(PFOAs ), adjusted1b7y6 FdiifgfuerreenDt-s3p.ecCiofeifcfaitciioennstsoffprootmenltiinaelarCrOeRgFrOeUsNsiGoEnLoSf.b.i.r.t.h.w.e.i.gch.tcocnvvIvnr(rPrFOoSm)s,osweirtnhron 177 FdiifgfuerreenDt-s4p.ecCiofeifcfaitciioennstsoffprootmenltiinaclarCrOeNgrFesOsUioNnoEfSb.ir.t.h.w.eivgchtrornoInnr(rPFoOsA)s,swriothn 177 bFiYgGuHrFeEDr-eSn.t SCeotesffOiFcCiOenVtAsHAfErSo.m lo inear regresv sionof bire th weight on n PFOS, ws ith adjustme1n7t8 FAigdurje uD-s6.btyComdeiffeffiecnrieetnnttsseftrsoOmflCinOeVarRrTeBgrEeSs.si.o.novfvbeiritehewreoigrhntsoennPrFOAo,nwisth en 178 IFiQgRu,rceoDm-p7a.riAndjgulsotge-ldinbieratrhawnediHghAtacroeMfOfiGcEieLnSts.a.s.s.oc.i.atoevdvwvitchraocnhramnegmemerqusanlstoothme 179 SFigUurMeEE-D1.bCyoeIfffTiecrieennttsSeftrsoOmlfiO ncarrV egresA sionR of heI ad ciE rcumfS erenc. e on. In(PF. OS), wi1t8h2 148 372 p12 `FaidgjuursetmEe-n2t. bCyoeiffffiecrieennttsSeftrsoOmflCinOeaVr rAegRrAesEsiSon.o.fh.ea.dvc.irvcurmsfeiresncrerorn eIn(sPFsOnA),, wi1t8h2 dFiifgfuerreenEt-3sp.eCcoiefficfaitciioennstosf pfortoemnltiinaelarCrOeNgfrOeUsNsMiEoTnSo.f.h..e.a.d...c.i.r.ccuvmvfsemrreunvciemsosnmmImnm(sPssFsOrSs)s,icwi1t8h3 FdiifgfuerreenEt-4Sp.CCcoiefficfaitciioennstsOffPrOoLmENliinaelarCrOeMgOrUeDsAsEiLoSn.ofo head c. ircumfeo rence ono In(PFOA), wi1t8h3 , Figure E-5. Coofficients rom linear regressionofhea.dvvcuivrvcrummefrerrseennceenoinesPsOsSmm,mswnitsh. `adjustment by different Sets OfCOVATIAES......... 184 `Figure E-6. adjustment bCyoedfiffifceireennttsSeftrsoOmflCiOnVeAarTArLeEgSre.s.s.i.o.n.o.f..h.eoadrvcrirrrcmusmrfsemrsennecressoinssPsFsOsAsm,nwnist.h 184 ` Figure E- the IQR, 7c.omApdajruisntgedlohge-laidnecairracnumdfHereeanrceMcOoGeeflfSi.ci.e.n.t.s.a.s.s.o.c.i.a.toeodewciotsherarcrhoasnrgeerrerqrural to 185. bFiYgGurTeEFE-D1.tCSo1e5ffOiFciCeOnVtBsIIfArEoSm. vrs, 188 linear regressionof length on In(PFOS), with adjustment bFiYgGuHreFEFT-2C.D CCo1e5ffOifcGieOnVtAsIfBrEoSm r linear regressions of length on Ins (PFOA), with adsjeusssot,men1t88 sFpiegcuirfeicFa-t3.ionCsooefffpioctieennttisalfrCoOmNTlOiUnNeAaErTrSe.gressiv onof length or n In(PFOS), ws ith different 189 | sFpiegcuirfeicFa-t4i.onCsooefffipcoiteennttisaflrCoOmNOliUnNeaArErSe.gressivonofelenrgths on Iin(Po FOA)n , wie th ds iffer:ent 189 . GFiHgEuErTeEFN-5S.ECoOeFffCiOcViAeInItAsESf.roo m linear regrv essionof ler ngth on PFOS, with adjustment by190 GFHiEgTuErTeCFt-6S.E1CSoOefffCiOcViAeInItBsESf.romv linear rege ressionofn length on Po FOA, witm h adjustment by190 . `FiCgOuMrPearFi-n7g.I0Agd-j1uisnetaerdalnedngHtNhEcAorefMfOiGcEiIenSt.s crores associated with a change equal to the IQR, 191 `FaidgjuursetmGe-n1t.byCdoieffffiecrieennttsStfrSoOmf lCiOneVaArTrIeAgrLeEsSsi.on.o..f..p.o..nvdrverrvraslrrivrnedrersxsoosncIens(PsFeOSs), wsietshs 194 ` 2Fig0urse G-t2.bCyoeGffeircieenntsSeftrsoOmlfiCnOeVaAIrIrReEgSr.eso sionv of pornderal index on In(PFOA), with 199 51479 3 Figure G-3. Coefficients from linear `regressionof ponderal index on In(PFOS) using imputation model, with different specificationsof potential confounders. ................. 195 Figure G-4. Cocfficients from linear regressionof ponderal index on In(PFOA) using imputation model, with different specificationos fpotential confounders. .................. 195 FaidgjuursetmGe-n5t.bCyoedfiffifceireennttsSeftrsoOmfClOiVnAeTarIArLeEgSr.esvs.i.on.o.f.p.ovnedevrsalevinsdeerxsosnrPeFsOsSm,swsisthsnn 196. Figure G-6. Coefficients from linear regressionofponderal index on PFOA, with adjustment by different sets OfCOVAFIRLES.........vverrrorrrosn -------- | Figure G-7. Adjusted ponderal index coefficients associated with a change equal to the IQR, comparing log-linear andlinear models.d................, wrrsessamsssssssrssssssssssssessses 197 FaidgjuursetmGe-n8t.fCoorelfefnigctihe,ntwsitfhrosmublsienqeuaren`treagdrejsussitomneofnbtibrytdhifwfeeiregnhttsoentsIonf(cPoFvOaSri)ataefst.e.r..... 198 Figure G-9. adjustment Coefficients from linear `regressionofbirth weight for length, with subsequent adjustment by different on In(PFOA) after setsofcovariates.d..... 198 Figure G-10. Coefficients fromlinear regressionofbirth weight/length ratio on In(PFOS),after adjustment by different setsofcovariates. EE ---------- Figure G-11. Coefficients from linear `regression ofbirth `weight/length ratio on In(PFOA), after adjustment bydifferent sets Of COVATIALES. ....cvvvvrvrerrrosrsns 199 Figure H-1. Association between total serum lipids, total cholesterol, and.triglycerides and PFOS and PFOA. ...ccccccovsvsmsmrsmmsrssrsssssssen ammsmsssssssssssssssssssssssssssasansssssss 201 Figure H-2. Coefficients from linear `regressionofbirth weight on In(PFOS), before and RET BAJUSUNENE FOF PIAS. .vrvevereeereresmeseseneess ------ Figure H-3. Coefficients from linear `regressionofbirth weight on In(PFOA), before and after adjustment for HPIdS. .......vv.ereeroereeensrrrron rrr sss 202 Figure H-4. Coefficients from linear regressionof head circumference on In(PFOS), `before and after adjustment for LL .203 Figure H-S. Coefficients from linear `regressionof head circumference onIn(PFOA), `before and after adjustment for BB. censemmmpusisnssaserammmnssiseron wererne 203 Figure H-6. Coefficients from 20d Aer AUSTEN FOF PIAS. linear regressionofponderal index on In(PFOS), before cvs, 204 150 374 p.164 APPENDIX A CIKRECYUMDFEETREERNMCIEN,ANLTESNGOTFHBAINRTDHPWOENIDGEHRTA,LHIENADDEX 371551 `This appendix presents the univariate relationships between key determinants of low birth `weight and birth size from the epidemiologic literature with these endpoints in our study. Key determinants of birth weight include baby gender, parity, multiple gestation, `matemal age, body composition (height and weight), lifestyle (e.g. smoking, drug abuse, nutrition), and health complications (e.g. hypertension, diabetes) (1). We examined the `associations between the determinants available in this study and birth weight, along with head circumference, length, and ponderal index. This analysis serves two purposes. First, the confirmation of established relationships between these determinants and `endpoints serves to increase our confidence in the validity of the data abstracted for the present study. Second,theobserved dose-response relationships between the continuous predictors and these endpoints were used to inform the specificationofthese variables in the regression modeling conducted and presented in the manuscript. The scatterplots below include a non-parametric smoothing function as well as the predicted fit based on regression with a linear or quadratic term. The need for aquadratic term was based on a significant coefficient (p<.05) when added to a model with only the linear term. Analysis of variance or Student's t-test was used to compare mean values of birth weight, head circumference, length, and ponderal index between levels of categorical variables. Reference (1) United Nations Children's Fund and World Health Organization. Low birthweight: `country, regional and global estimates. Geneva: WHO, 2004. 5% H peor Teens Hpee oT ` CLE aes 5 Lamm CREED : Fg ee oe ee Wer Bo ee ot Hp Hoo H Plae ineDoen Lgo hbiiiinrdies pT pert ` BO go = & w -w = Hp 8 p. e 7. f mA REhe Hope= SHELL P JERR I . TET 8 : 8 : . Figure A-1. Key determinants of birth weight, Baltimore THREE Study. * Solid line based on non-parametric smoothing function. Dashed line denotes predicted linearregressionfit. P-valuesarefrom linearor quadraticterminregression model. & 153 377 p.167 (msemaan iE ; fre t 8 i . fe _ if mp 1} m6 if T E | "im a ain ql tors Nir 80; . ge . g-- ow Bo= - Were geo : [a nf fo el Ll eo Figure A-2. Distribution of birth weight (grams) by subject characteristics, Baltimore THREE Study. + P-values from ANOVA comparing means between groups. 578 notes war 5 os . 8 coafgrs Wl LnnES al ELE es 2 a - @ P32, Bef lie Ll LEE * p02 . RTI NEE TL Cer Tr Co Verano" " ` peor- fa i moe Elena. Lol -. . . Figure A-3. Study. Key determinantsof newborn head circumference, Baltimore THREE Solidline based on linear regression fit. non-parametric smoothing function. P-values are from lionrqeuadaratric Dashed term in line denotes predicted regression model. ( 1535 79 SS Pp.169 paz . Homa0 : CET a |= = 3 + iBioos, ufIo g : hl i I- :. E-L . ee PS --Bl. * "fron m2 RE f L T = Ii 1A-. = WoiL jhy | + E | r . eo : EE by - ray > " oor . Ig} Hom . --: zI : - i: : i : :a -- T: E BaFligtuirmeoAr-e4.THDiRsEtrEiSbtuutidoyn.of head circumference (cm) by subject characteristics, * P-values from ANOVA comparing means between groups. 15S30 p.170 of . pel P50 bea CELoEta ram imry e .= = pull owl . Ts P04 Hort be 3: " pot 3 TL {peor : . # . JERE JETT 3= F| -- 5< . ! Figure + Solid A-5. line Key based odnentoenr-mpianraanmtestorficneswmobootrhninlgenfgutnhc,tiBoan.ltiDmaosrheedTlHiRneEdEenSottuedsyp.redicted linear regression fit. P-valuesarefrom linearor quadraticterminregression model. 0 157 381 ls * pe0s (m= Tr _ =iir smm m} ma J* pTets f p26 . 2 pus? . hI m 8 Ifm ki == Le : - po (-ge Yan [imm mmmn fo Tm LT . `TFiHgRuEreESA-t6u.dyD.istribution oflength (c bysm ubj) ect characteristics, Baltimore * P-values from ANOVA comparing means betweengroups. 0s p72 peo -- "lesa Lov . - |a CCLrUSSEESL ET i ya pLhiedre Hon . Mp Lv P EST iIeIvE e fR l S p SidtiibeT riioe Plssimtaio 0 pte . FT Cetin FF ELT Hopman +t pes . . ` It 1 mdene. o | rpae s en by, ai ARI ETAT en Loo ius Pb i ' Figure A-7. Study. Key determinants of newborn ponderal index,Baltimore THREE * Solid line based on non-parametric smoothing function. Dashed line denotespredicted linear regression fit. P-valuesare from lionrqeuadaratric term in regression model. 159 Hm 7 IT L[ TT RE ~ 7. : .: I L - - . 1 (lm omlm=.L j= fi - ams 4 i i = Hpmss L | : - Figure A-8. Distribution of `ponderal index by subject characteristics, Baltimore Er: NOVA `comparing means betweengroups. "34g p74 APPENDIX B . REPRESENTATIVENESS OF STUDY POPULATION AND SUBJECTS WITH MISSING DATA 161 365 TT p75 `Table `weight, B-1. Characteristicsofstudy height, and/or weight gain. subjects missing information on pre-pregnancy N (%), Mean (SD), or Median (IQR) N Characteristic Nommissing (n=282) Missing (nett) "0 MMaottehrenral age <1t8835 23283(864)) 801793)) p=80 Ra3c5e+ 210) 2(18) AWshiiatne 59205291)) 010609)) p35 Black Education 198(70) 101) <HS degree HS degree 79(28) 94 (34) 72((6184)) p=59 51-4 y1rs5ccoollleeggee 6432((1253)) 2(0108) . Marital status. MaUrnrmiarerdied 1896 ((6364)) 101001)) pe24 PrNimoiparous Yes 1162114(537)) 10619610)) p=t1 SmNookriinpgasssaitvues 2262) 655) p=02 InfAacnttive 50(18) 505) Baby gender MFaelmaele 123 a8) 169 (56) 813) p70 3@) PNreoterm 24788) 8013) peor LYowebsirth weight 35(12) 3en No Yes 253,(90) 29.10) 9662) p13 2(18) `BGiertshtawteiiognahlt a(ggera(mdsa)ys) Length (cm) 272 (13) 3250010(25784)) 261 (20) 3168 (784) p=03 p=62 51.120) p=28 Head circumference (cm) 33417) 338(1.9) p=62 CPoonrddercaolncienndtexra(tgi/oenms") (ngimL) 254 (0.29) 251(0.32) p=97 PFOS PFOA 50(3480) 161221) 423260) 151420) pear =65 CNvoaotrtiiean:bilpne-esvaelxucelsubdeadsefdroomncWoimcpaorxi0os.no1n0Rs(.a<n.kS0aSDmu-p0ml8et4e)ssitzoers dFiifsehrerf'or2El9xe(an0cg.tt0he7s(-t11.2=12Mi7ssvisn9g).dhaeaadon<0ot1her c@i8r9cvusm.fer11e)nce (n=280 vs 9), ponderal index (1=279 vs 9), education (1=278 vs 11) and cotinine 162 #6 [3 `Table B-2. Comparing the study population with all births occurring at Johns Hopkins Hispital over the study period and with U.S. Vital Statistics from 20032004. Charatarisic PopSutluadtion PeABrlicrlettnhvtsea!g_es_ poupulluatsi.on" Viatemal age Met<e2rn0eylrrsoafceage 19.8 126" 103 BWlhaictke 12005 nwaa 789 148 MarAitsailanstatus 65 na 51 UnMamrarriredied 66.9 nla 357 ` Smoking status SNomno-ksemroker 154 na 10.7 Bic2h2w5ei0g0ht (grams) 804 849 19 . <2,500 (LBW) 106 15.1 81 Gestational age (weeks) +Ass<2u33m77in(g(tpeorlretme)lrm)pi Viswerepreterm sd8173.l.o00wbithweig1h88t.200 817255 i2*t*FByreolwomowHnod1y9eyerreetdeea.togaforla,vg2soe0.n0d6,eerxhceelptpfNorartacye bdamta),.whIincchluisdefsromumlCtiDplCe Wbointsd.er for 2002 (See Based onselfreport. Smoking rte athe ndofpregoancy as determinbeyd cotinine level was 15.8% 163 38 7 p77 Table B-3. Comparing missing data. regression results using different methods for handling Model PFOS PFOA Coofficont (95% CI) pvaluo Coefficient (85% Cl) pvaluo Birth weight Complete Case (n=262) Univariate Adjusted 43014459) S4(143,14) p=041 p=OM -106(205,33) 8T(196,23) p=013 p=012 MUendiivaanriiamtpuetation (n=295) (139,64) p=047 97(234,40) p=oi7 HAedajdusted 69 (149, 10) 2009 -104(213,5) p=008 cCiormcpulmefteerCeanscea (n=280) Univariate: Adjusted 020(051.040) 028(052,003) pz019 p=003 045(087,008) 037(072,002) p=003 p=004 MUendiivaanriIamtpeut:ation (n=2505)22(052,007) p=014. 046(087,-005) p=003 Adjusted Tongth 032(056,.007) p=001 _ -041(076.007) _ p=002 `UCnoimpvlaertieatCease (1=279) 029(0.19,076) ' p=023 003(067,06) p=094 MAeddjiuanstiempdutation (n=2860)20(0.19,05) p=032 001(083055 p=097 Univariate: Adjusted 025(021,072) 013(026,052) p=029 p=052 -006(089,057) _ 010(064,044) p=08s p=071 PCoonmdpolraatle iCnadseex(n=270) Univariate Adjusted DOT (0.127,0028) 0082(0.132,0032) p<001 p<001 Median Impuation (n=28) -0081(0.149,-0.013) -0.073(0.143,-0.003) p=002 p=004 Univariate Adjusted 0070(0.119,0021) 0074 (0.123,0025) p<001 _p<0.01 -0074(0.140,-0007) _-0.070(0.138.-0.001) p=003 _p=005 `+ibnRoode(ygrRmeFasOsssSi)oinnodcreoxeI,fnf(riaPcciFeeO,nAtp)sarrcioetnyp,creesnsmteoranktitinhogen,.cbhaaMubnlgyiegveainrbdiiesrrtt,ehemiwogehditeg,lhnneatddwjeubsiitgrethdhtsfgioazriengp,easrtdaaitsmibeoetntaeelsr,saagwn,idmtBhayptueiertesncsghiean.n.g mFoordehleaedxccliucduemsfoebrseernvca,tiaodnjsuswtietdhmmoidseslinigncblmud,eshedieglhitv,eraynmdoordewe(iCg-hstecgtaiino.n/Vagina). "Compecase" 16 368 p.178 APPENDIX C FULL MODEL RESULTS FOR MULTIVARIATE REGRESSION ANALYSES 165 359 Table C-1. Coefficients from multivariate regression of birth weight on In(PFOS).* spree Se memlnma esse immmeentes , cn wR oe wm wm 3ume Magme wwiokmw looms oom ar oa ECE 166 370 Table C-2. Coefficients from multivariate regressionofbirth weight on In(PFOA). wa or ry ` Gestational age (days) `Smoker(Yes/No) 244 -1635 21 0 204 718 0.024 -304.9 285 222 NCNFie oaa neameciy aip elienreg TToaey.ye emN mLaaheo oDoomoawyehe wamm mmhoyswomemmmses }, Asian (vsWhite) 959 107.3 0372 -307.2 115.4 hE PL A constant ee 5716.6 897.4 0 7483.6 -3949.6 ` 167 39 / p.181 TIna(bPlFeOCS-)3.. Coefficients from multivariate regression of head circumference on LnGe(sPtaFtOiSon)al age (days) Gestational age squared 00287060 00144%0 003 0 00532245 00082775 0001 0000 0 0002-0001 `MSamtoerknearl(aYegsei(Nyoe)ars) Maternal age squared 00418184 0012073 0002415 00900868 00031117 0002 0002 0264 0006 0002 NOvoerrmwaeliwgehitg(hvt (UvsndUenrdweeriwgehitg)ht) ~~ 0.585 0831 `Obese (vs Underweighi) 0889 0367 0404 0.413 012 00.146358 11340277 0406 0020 000 1688 ABsliacakn ((vvssWWhhiitte)) Party (1+vsZero) 00253%0 0023022 0080081 10044130 00095074 0569 0183 0003 0.190 0949 BMaatbeyrgnealndheeirgh(tMailnecvhsesF)emale) 0012023 00.01627 00406042 00009%6 00516617 NDieatbweetiegsh(tYgeasi/nNo()os) Hypertension (Yes/No) 00708112 0003005 00001103 00010332 01042320 0860 0275 0002 1401 0319 VDaegivnraly) type (C-section vs constant 1907732 108270965 00010 68o98r1 2916m5 "Resultsfrom "comple caaay 168399 p.182 ITna(bPlFeOCA4).. Coefficients from multivariate regression of head circumference on Independant variable Coot. SW.Em. Pot ss%cl Gne(stPaFtOioAn)al age (days) 0035766 0041707 00% 0 0073106 000812 GSemsotkateiron(aYlesa/gNeo)squared 00040110 0020207 00072-0080072 00000306 MMaatteermnaall aaggee s(yqeuaarrse)d 0001072 00010023 00225574 0-0000858 00030220 ONvoerrmwaeliwgehitg(hvts(UvsndUenrdweeriwgehitg)ht) ~~ 0580 081 0368 0.116 0404 0114 -0.144 0155 1304 1438 Obese (vs Underweight) Asian (vs White) 00911619 00343096 0026 062 005M00 A711 0837 ` PBlaarctky ((v1s+WvhsitZee)ro) Babygender (Malovs Female) 0540 0025025 001232 00002076 0.180 0226 10011660 00088235 0.128 0538 MNaettewreniaglhhtegiagihnt ((ibnsc)hes) Diabetes (YosiNo) 00011013 00003035 00001092 0778 030 0019 000032 00012617 0428 1420 ` DHeylpievretreynstiyopne ((CY-esse/cNtoi)on vs 0847 0275 0002 1388 0307 cVoagnisntaal)nt 500.718534 "Resultsfiom "complete case" analy 108290060 00020 950336707 211.108308 ` 19353 p.183 Table C-5. Coefficients from multivariate regression of length on In(PFOS). GePstraoosn)alage (cays) Smoker(YesiNo) Ootirz 0195 NMoaOrtmevaleweraiggwe(hvts(ey(UevnasirdUsen)grdwerehwlsgtihg)ht~) ~ 00801090 0887 AOsbieasn ((vvs sWhUintdee)rweigh) 213225 PBaBalrebtcyykg(e(v1ns+dWevhsri(ZtMe)arol)ovsFamale) 0023186 0713 MaNteetrwmeiaglhhtegiagihnt ((bnsc)hes) Diabetes (YesiNo) 00001849 087 cHoypnesrttaenntsion(eso) "Tenishom Eamps eS 10025533 o0i0e0 03170 0o18o1 o08i6 00305255 00042s 1040s 00008s 00851668 0015s1 00332180 21490217 m0ss7 0003s5 aomo 2o6ns5 002a0 004537 0A35i5 0o7a8rs 00025600 o00o0r7 0020001 1o2t276 005078 00007589 o000f1 01082%0 0404881 0050804s 0as7t8e t0o0s9e 10347f `Table C-6. Coefficients from multivariate regression of length on In(PFOA). Gestational age (days) 0.112 0.010 0 0.092 0.132 `Baby gender (Male vs Female) 0.685 0.264 0.01 0.165 1.205 k Er Diabetes (Yes/No) Hypertension (Yes/No) 0.848 -0.280 0509 0428 0.097 0.514 0.155 "1.123 1851 0.563 m395 p.185 Table C-7. In(PFOS). Coefficients from multivariate regression of ponderal index on Independant variable Cosf. LnGe(sPtaFtOiSon)al age (days) 00617 00046 Smoker (YesiNo) Maternal age (years) 00109 00371 MNoartmeamlalweaiggehtsq(uvsarUendderweight) ~~ 00008 00311 OOvbeersweei(gvhstUn(vdserUwnediegrhwte)ight) ~~ 00783 00120 ABsliaacnk((vvssWWhhee)) 0000226838 BPaarbiytyg(e1n+dvesrZ(eMraol)o vs Female) 00205 0.0066 MNaettewreniaglhhtegiagihnt ((iionsc)hes) 00017 00020 Diabetes (Yes/No) Hypertension (Yes/No) 00668 0080 "Rceosnusltsanftrom "complete ase" analy. 08081 Std.Er. 00253 00013 00457 00207 00004 00730 00792 00803 0000848815 00381 00335 00084 00010 00652 00551 05745 Pot 95% Cl 0001 0 0.1316 00020 0.0318 00071 00801742 00..100008 0000778708 00687319-0001011257 00..40704080 0324 0872 00777 01452 0.2342 0.71 050573 001.610245 00.40067698 00.081484 00.00175264 00.01569535 0791 0039 00108 0.0001 00143 00040 0306 0107 0.0615 0.1974 0.1951 00194 0.161 03230 1.9393 239 4 `Table C-8. Coefficients from multivariate regression of ponderal index on In(PFOA). Gestational age(days) Smoker(Yes/No) Normalweight (vs. 0.0046 0.0021 0.0013 00461 0 0.964 0.0020 0.0886 0.0072 0.0928 Ee Hypertension(Yes/No) 0.0803 0.0556 0.15 -0.1897 0.0292 377 APPENDIX D BIRTH WEIGHT REGRESSION SENSITIVITY ANALYSES "375 p18 The following sensitivity analyses are provided: . + CCoovvaarriiaattee sapdejcuisftimceanttio(ns(cneonm-oldienelasribteileso)w) * Untransformed PFC independent variable MAo:dUenlisvariate CB:: AAddjjuusstteedd ffoorr ggeessttaattiioonnaall aaggee., maternal age, maternal age squared, body mass index, Dra:ceM,opdaeriltyC, s+mdoikaibnegt,esbaanbdyhgyepnedretre,nhseiiognh.t, and net weight gain. E: Model C + matemal education, insurance status, and marital status. . 175 399 p18 " Fk P7 e | | ! a z . || | awl A 5 < e `aFdijguusrteeDd-1b.y Cdoieffffeirceinetnstestsfroofmcolvianreiaarterse.gressionofbirth weight on In(PFOS), giCh ol TT a0z : - i1.; : - | :|| -l A c e FadijguusrteeDd-b2.yCdoieffffeirceinetnstestsforfocmovlairnieaarterse.gressionofbirth weight on In(PFOA), 16490 w " si o ` 3fw ao I wl eo TE Me ` Figure D-3. Coefficients from linear regression of birth weight on In(PFOS), with different specifications of potential confounders. wy ot ob-- HR 3fw - ! f: -e | a I. ws ---- noa. Figure D-4. Coefficients from linear regressionof birth weight on In(PFOA), with different specifications of potential confounders. 177,Yo/ o . 0 - 8 5s LI 2 | | u | | 1 | Figure D-5. Coefficients from linear regression of birth weight on PFOS, with adjustment by different setsof covariates. " B | ii." i IP "a a Figure D-6. Coefficients from linear regressionofbirth weight on PFOA, with adjustment by different sets of covariates. "02 ps2 " . fu g 0 . | : 0 | 100 20 0 In(PFOS) PFOS In(PFOR) PFOA. ` Figure D-7. Adjusted birth weight coefficients associated with a change equal to the IQR, comparing log-linear and linear models. 179,73 ' p13 APPENDIX E NEWBORN HEAD CIRCUMFERENCE REGRESSION SENSITIVITY ANALYSES 1804 4 p19 `The following sensitivity analyses are provided: + CCoovvaarriiaatteesapdejciufsitcmaetniton(s(eneonm-oldienelasribteileso)w) . + Untransformed PFC independent variable AM:odUenlisvariate . BC:: AAddjjuusstteedd ffoorr ggeessttaattiioonnaall aaggee,, ggeessttaattiioonnaall aaggee ssqquuaarreedd,. maternal age, maternal age asqnudardeedl,ivbeorydymomdaes.s index, race, parity, smoking, baby gender, height, net weight gain, ED:: MMooddeellCC++mdaitaebrenteasl aendudchaytpieornt,einnsisounr.ance status, and marital status. . < "pes o ol o Tio.r fo | g 1 04 - `Figure E-1. Coefficients from linear regressionof head circumference on In(PFOS), with adjustment by different setsofcovariates. | tal [ || iJ: [or $f5 or |al Figure E-2. Coefficients from linear regressionof head circumference on In(PFOA), `with adjustment by different setsof covariates. = 4h onwl J iStorat | fi ool | | os I fa asl orl n ei m --gn SWre ee . or FwiitghurdeifEf-e3r.enCtoesfpfeicciifeinctastifornsoomflpionetaerntrieaglrcesosnifoonunodfehres.ad circumference on In(PFOS), go 1 0 re ---- -------- ail | | Ez He | | fi ol : 084 2 T ost "al por eB EE ` Figure E-4. Coefficients from linear regressionof head circumference onIn(PFOA), with different specificationsof potential confounders. 183 47 past oot i ez i : i HE 3s 1 0! ool f ae! z aos!|| | 1d . . c . Figure E-5. Coefficients from linear `with adjustment by different sets of `regression covariates. of head circumference on PFOS, 0;I ol| || i - : 01 ! - | asl . . c . Figure E-6. Coefficients from linear regressionof head circumference on PFOA, `with adjustment by different setsof covariates. 184 40,8 poss or i: 0 g1ior | : foal | i | 3 04 os 8 orcs eros --_-- ron Figure E-7. Adjusted head circumference coefficients associated with a change equal to the IQR, comparing log-linear and linear models. "07 p19 APPENDIX F NEWBORN LENGTH REGRESSION SENSITIVITY ANALYSES 186 4/0 5.200 `The following sensitivity analyses are provided: + CCoovvaarriiaatteespaedcjiufsitcmaetniton(s(eneomn-oldienleasribteileos)w) Untransformed PFC independent varizble Models MA:odUenlisvariate CB:: AAddjjuusstteedd ffoorr ggeessttaattiioonnaall aaggee., maternal age, body mass index, race, parity, smoking, Db:abMyogdeenldeCr,+hediigahbte,teasndanndethywpeeirgthetnsgiaoinn.. E: Model C + maternal education, insurance status, and marital status. ' wy) pot y o 5o 2 | 2 3 Figure F-1. Coefficients from linear regression oflength on In(PFOS), with adjustment by different sets of covariates. ul oat | $ii a 3 04 ot . Figure F-2. Coefficients from linear regression of length on In(PFOA), with adjustment by different setsofcovariates. 188 4.2 p.202 wr 0 3 . Eo 3 a aul ian onion an wasn vgn oss woos roioese noninar : Figure F-3. Coefficients from linear regressionoflength on In(PFOS), with different specificationsof potential confounders. 0sy [Ibo | wal | ||| . 3 J go l : 02} .! 3 | oat | | 7 . | iwl | : iaotee.n Cane iavner wroosrs oHneeo Figure F-4. Coefficients from linear regression specificationsof potential confounders. of length on In(PFOA), with different 189 413 | iw gon i HwETL | 008 1 00s l A 8 c o E : Figure F-5. cos of coun. Coefficients from linear regression of length on PFOS, with adjustment . " fol | i. i. 1 w | a3 | Figure F-6. Coefficients from linear regression of length on PFOA, with adjustment by different sets of covariates. wo 4/4 p.208 ow : -w 3 02 | -Boo 3 7 -02 : wl wo mm wen : Figure F-7. Adjusted length coefficients associated with a change equal to the IQR, comparing log-linear and linear models. m5 .205 APPENDIX G NEWBORN PONDERAL INDEX REGRESSION SENSITIVITY ANALYSES w24// `The following sensitivity analyses are provided: + Covariate adjustment (see models below) + Covariate specification (non-linearities) + Untransformed PFC independent variable Models A: Univariate i B: Adjusted for gestational age. C: Adjusted for gestational age, maternal age, maternal age squared, body mass index, race, parity, smoking, baby gender, height, and net weight gain. D: Model C + diabetes and hypertension. E: Model C + maternal education, insurance status, and marital status. . 193 47 p.207 ocz o _-- a {5 on oo | H} om 4 | | i: . wl & or al A s c : Figure G-1. Coefficients from linear regression of `ponderal index on In(PFOS), with iIiFoaox" u0mrE| E ! ||-- adjustment by different sets of covariates. pr an | am A . c : Figure G-2. adjustment Coefficients by different from linear regression sets of covariates. of ponderal index on In(PFOA), with 194 wo 5.208 002 I 8freee---------------- oo 32 on ` | : T 0m . 20 012 | "oie Ipuaton Coins a Ws Hein. model ronioear roninesr noninear iFimgpuurteatGi-o3n.mCoodeeflfi,cwieintthsdfirffoemrelnitnesaprecriefgirceastsiioonnsooffppoontednetriaallcionndfeoxunodneIrns.(PFOS) using ` 002 [ o ere ---- fLooon || ` 3 500s | Foot . af an onl Wpruoadteo!n ~~ Cotiine ooamr nwonaionesr nHoeniinnear uFsiignugreimGp-u4t.aCtoieofnfimcoideentls, fwritohm dliifnfeearrenrtegsrpeescsiifoincoatfiopnosnodferpaotleintnidaelx coonnfIonu(nPdFerOsA.) y, q p.209 osI i "000s 58 om 3 aos : e ace ons A . c e Figure G-5. Coefficients from linear regression of ponderal index on PFOS, with adjustment by different sets of covariates. ~oc oor frre -- ful 2 g 002 | fom Taos 1 | 2 008 i | | a8007 | | onl A . c c FaidgjuursetmGe-n6t. Coefficients by different sfertsomoflicnoevaarriraetgerse.ssion of ponderal index on PFOA, with 196 4Z) 0 000 --BE 5 on | 00 3 1 Fon wn wes wen mo Figure G-7. Adjusted ponderal index coefficients associated with a change equal to the IQR, comparing log-linear and linear models. "ly, / p21 Different Birth weight for Length i freer Analyses: ------ " I wl i2] Cl ow * olI 0I ol A c 5 FaidgjuursetmGe-n8t. fCooreflfeincgitehn,twsiftrhosmulbisneeqaurernetgraedsjsuisotnmoefntbibrythdwifefiegrhetntosnetIsn(ofPFcOovSa)riaaftteesr. I=$joa27 of wr | "| Fw ot "0 | -- | 0A . c FaidgjuursetmGe-n9t. fCooreflfeincgitehn,twsiftrhosmulbisneeqaurernetgraedsjsuisotnmoefnbtirbtyhdwifefiegrhetntosnetIsao(fPFcoOvAa)riaaftteesr. p20 Lp 0 o w + | 8 | :fa | . 20 as | " ! Figure G-10. Coefficients from linear regression of birth weight/length ratio on os In(PFOS), after adjustment bydifferent sets of covariates. | 0s]l fool i ifza] EH 1 " 0 Figure G-11. Coefficients from linear regression of birth weight/length ratio on ` In(PFOA), after adjustment by different setsof covariates. 2435 APPENDIX H RELATIONSHIPS BETWEEN PFOS OR PFOA AND SERUM LIPIDS 424 p24 3 . af . i Cle FL ee Il CE ER R TTTrha u s i, - T ER eEg 5 | Le e . i - + . + CpRLr mo od Figure H-1. Association between total serum lipids, total cholesterol, and triglycerides and PFOS and PFOA. * Solid line based on non-parametric smoothing function. Dashed line denotes predicted linearregression fit. 201 4245 = { 3fe i -l mwee g we ee ae Figure H-2. Coefficients from linear regressionofbirth weight on In(PFOS), before wo|ol and after adjustment for lipids. iw i3 || Pal | E-l | | - IE.o J le. Figure H-3. Coefficients from linear regressionof birth weight on In(PFOA), before and after adjustment for lipids. xn 434 p26 = flar | SOU N.SR, :Y Sioar ` f2i oau : asl wl ours roatno oratt Tnoatyee . Figure H4. Coefficients from linear regression of head circumference on In(FOS), before and after adjustment for lipids. or 01} 0fF $1 ipa setts rss | . [foh0r3l+ | . fi awsl] || 1 . $7} | ost | po. psrate Groaima Thyateee F1iag(uPrFeOHA-)5.beCfooerfefiacniedntasftfrroamdjluisntemarenrtegfroerssliipoindos.f head circumference on 203 427 wz . we ifo on 2| : ow mCaEw se ae Figure H-6. Coefficients from linear regression of ponderal index on In(PFOS), sc-- r; - before and after adjustment for lipids. a i= | om | San f2 on om MseE sate Figure before H-7. Coefficients from linear regressionof and after adjustment for lipids. ponderal index on In(PFOA), zr p28 CURRICULUM VITAE 205 #29 BENJAMIN J. APELBERG bapelber@jhsph.edu Birthplace: Baltimore, MD 10/10/1975 [EDUCATION Johns Hopkins Bloomberg Schoolof Public Health, Baltimore, MD Doctor of Philosophy, Epidemiology Dissertation Topic: Fetal exposure to perfluorinated compounds and associations with `weight and size at birth. biownion Johns Hopkins Bloomberg School of PublicHealth,Baltimore, MD Master of Health of Science, Epidemiology `Thesis Topic: Systematic review - Exposure to pets and risk ofasthma and asthma-like Certificate awarded in Risk Sciences and Public Policy. Georgia Instituteof Technology, Atlanta, GA BachelorofScience, Biology RELEVANT EXPERIENCE Institute for Global Tobacco Control Johns Hopkins Bloomberg School ofPublic Health, Baltimore, MD Research Assistant 11/2003-present + Developing amodel to estimate the impacts oftobacco control policies on future `mortality pattems in the U.S. and Japan. * Developing an individual risk prediction tool for smokers to examine the impact of continued smoking and quitting on their mortality risk from lung cancer and cardiovascular disease. * Writing a monograph chapter on the future health implicationsoftobacco control policies in the U.S. Johns Hopkins Bloomberg SchoolofPublic Health, `Baltimore, MD `Teaching Assistant Quantitative Methods in Risk Assessment `Epidemiology and Policy Intermediate Epidemiology Occupational Epidemiology Abt Associates Inc., Bethesda, MD Senior Analyst 1/2005-3/2005 6/2004 10/2003-12/2003 3/2000-5/2000 7/2000-7/2003 43 5.220 Analyzed the potential health impactsofregulations promulgated by the PeErnfvoirromnemednhteaalltPhrortiescktainoanlAysgeesnfcoyr(vEaPrAi)o.us EPA offices. + Created analytical tools to examine the relationships between environmental + pollutants and health risk. Managed clients, assisted in the recruitment of new employees, and participated. in proposal writing RPeesweEanrvcihrAosnsmiesnttaanltHealth Commission, Baltimore, MD 6/1999-5/2000 + * nCoe-eaduftohroarepdubrleipcorhtesalotnhbtirratchkdienfgescytsstaenm.d childhood asthma, which highlighted the \ + 1C0olildeecntteidfydraitsakofnacptorresv,alaenndceevraaltueasotefdbtihrethefdfeefcetcitvse,npeesrsofforsmteadtel-ilteevrealtubriertsheadrecfehcets + tracking systems. Analyzed childhood asthma prevalence rates from national survey data. PROFESSIONAL ACTIVITIES IAnmteerrinactainonPaulbSloicciHeetaylftohrAEsnsvoicrioatnimoenn,taMleEmpbiedremiology, Member AWARDS DSotcutdoernatlTrTahveeslisSuRpepsoeratrcFhuFnudndin,t2h0e0D5epartmentofEpidemiology, 2006 DGeepnaervtimeevnetMo.fMEaptiadneomsikoiloFguyndTuiintiEopnidSeumpipoorlto,gy2,00230-025006 ` PUBLICATIONS rAipseklfbreormgaBi.rJt,oxBiucsckilneMya,rTy.lJa.,ndW.hiEtnevRirHo.n HSeoaclitohePceornsopmeicct a2n0d05raJciuanl;di1s1p3a(r6i)t:i6e9s3-i9n.cancer . `aMncdCpuabrbtciunlaDtRe-.reAlapteeldbheeragltBh.Jb.e,neRfiotes.S.,EnDviivritoan FS.ciJr.TeLcihvneoslt2o0ck02amMmaon1i5a;3m6a(n6a)g:1e1m4e1n-t6 aAsptehlmbaerogr B., Aoki Y., Jaakkola J. Systematic review: Exposure to pets and risk of : asthma-like symptoms. J Allergy Clin Immunol 2001 Mar;07(3):455-60 pGuoblldicmahenalLtRh.,deLfeoncskeesPy.,stAepmeltobebartgtlBe.,enKvoidruornmueSn.taAltttharcekatAs.stPhemaw:EWnvhiyroAnmmeernitacla Hneeaeldtsha Commission, Baltimore, MD, 2000. 207 #31 p.221 GneoelddsmaanbeLttRe.r,syAspteelmbeorgtrBa.c,kKaondduurnudeSr.,stSaonrdiabnirRt.h dHeefaelcttshyanfdrotmhetheenvSitrarotn:mWenhty, APmeewrica Environmental Health Commission, Baltimore, MD, 1999. PRESENTATIONS AHepiedllbeerrJg,BN.Je.e,dChaalamfaLt.LA.,MG,olHdemrabnstLmRa.n JD.iBs.t,rWiibtutteiornF.aRn.d,dHeatledremninRa.nU.t,sofKpuekrlfelnuyoirkinZa.t,ed cInotmepronautnidosnailnCcoonrfderbelnocoed sonerEunmviirnoBnamletnitmoarleE,pMiadreymliaonldo.gyPaosntdeErxpproessuerneta.tiSoenpattetmheb.er 26,2006. AripseklfbreormgaBi.rJt.o,xBiucsckilneMya,rTy.lJa,,ndW.hiPtreesReHnt.atSioonciatoetcheonSoomciiectyafnodrrRaicsiaklAdniaslpyarsiitsie2s0i0n4cancer AnnualMeeting. Decem5,b20e04r. LWiitstJm.aS,n,nTAr.a,nNNa.cLh,mMaanleKc.kiIdKe.n,tNifeyifngfpRr., iRoersintyichkeaBl.tAh.c,oBnudirtkieo,nsT,.Ae.n,vAirpoenlmbeenrtgalB.dJa.t,a, and infrastructure needs: A synopsisofthe Pew environmental health tracking project. Presentation atthe APHA 132 Annual Meeting and Exposition. November 10, 2004 AthpreolubgehragsBt.hJm.,aCmuannnaignegmheanmt Kp.l,anMsudaanrdreinvD.i, roHnemielnMta.l Atisgtghemraavreoliadtaendcec.ostPrseasveinntgastion at IJnudnoeo3r0Ai- rJu2l0y052, -20T02h.e 9" International Conference on Indoor Air Quality and Climate. McCubbin DR, Apelberg B.J., RoeS., Divita F. Jr. Livestock ammonia management aConndfpearretnicceu.latOe-crteolbaeterd1h4e-a1l8t,h2b0e0n1ef.its. Presentation at the 2 InternationalNitrogen 208 #30. r---- | \ p22 \ CONTAINS NO CB! | f 43 '