Document RJRLp6R6979Kok24yobMZRObB
pt
MgrianenD0ne8e4 s
To Sn-
"N0SCIoCn5OFPPa1Tra@vEA2Pr"AiTor2E@tAi0Dawk0coCn8a>r
AL226-3pg
Taft/ Deborah McCrea / Legal Assistant a 125 asSr&ehe aotke 1(51050 Cincinnati, Ohio 45202-3957 CAE 355s Fan 10381 coos www.taftiaw.com / mccrea@taftiaw.com
8 :
3
he od3
=
tEroeltsRehoeevterdneueaecSse0ao)roiansemmtoaCintersgcus.olarard2t3o0n.iDfionscloBhbsresurorece:aAmosompmrmooasfvniUidoynedSof(onrhingnoTrgepaaspnEuaarylyCieaeuOulanvtNaoansts,ooaaitcrasln(mdaftasems)or essed rte. ie smmaessssaage geedmaseyorcoeansamniianofscoonmotaatarioannstTonaittrirre.eyGnelaesnstvoopsyeavhedgaedssteoorase3yorfwtTosropk ropomiaacdtasnodaree e FSraonme: ocaonnoniceop3y,202a00@8lf3i.ca5omwPH[malo canonopy20aGactoam] TSourbjceectn0,41a3t/2o00r9 eter To PADckes Center
ES
CONTAINS NO CBI
2 RR,
am 189 8 Shiv nog
ps
25 Wut Set,SeC 1800/Coocinnc a, OHo5Co2ba0ro239n D5oi5n1a3.38p1 2o83l83a51r3.3i8etn0ts20eF5torswo8 naottSemoiUonP
[c A rn--g--sn ----
-
June 12, 2009
FEDERAL EXPRESS
EPA
U.S.
EDnovcikreotnmCeennttearl, PMroCte2ct8i2o2nTAgency
EPA 1301
WCeosntst,itRuotioomn
3334 Avenue,
NW
`Washington, D.C. 20004
Re: Submission to IRIS and AR-226 Database For PFOA/PFOS: 'ORD-2003-0016
EPA-HQ-
To IRIS Database for PFOA/PFOS:
In
USEPA's
response
efforts to
tcoontshiedNeortpiecrefilsusoruoeodctbaynoUiScEaPciAd
o(n"PFFeObAr"u)araynd23p,er2f0l0u6o,roroecgtaarndei:ng
`sulfonate ("PFOS") within the Integrated Risk Information System ("IRIS"), 71 Fed. Reg.
9333-9336 (Feb. 23, 2006), we are submitting the following additional information to
USEPA for inclusion in that review, and for inclusion in the AR-226 database:
i Fenton, S.E.,etal., "Analysis of PFOA in Dosed CD-1 Mice Part 2:
Dispositionof PFOA in Tissues and Fluids From Pregnant and Lactating
dMoii:ce10a.1n0d16T/hje.irrepPruoptsox,."
Reprod. Toxicol. 2009.02.012;
(2009),
2 dvMoioiln:k1Eo0hf.r1Be0rn1es6at/se]it.nfr,eeep0dr.ioSnt.go,xW.eot20ma0le.9,n.,"0P3"o.l0Ry0ef1pi;urooardno.adlTkoyxlicCohle.m(i2c0a0l9s),in the Serum and
3.
xHipnoessu,rEe.P.,oeteralf.l,u"oPrhoeonctoatnyopiicc
Dichotomy Following Developmental
cid PFOA) n emale D-1 ice:
ow
E Doses
tP Induce
Elevated
A( Serum Leptin
and
iF Insulin,
and
OCverweMight
L in Mid-
Life," 304 Molecular& Cellular Endocrinology 97-105 (2009).
CONTAINS NO cB}
nesurazs
JPuangee 122, 2009
Cdl oe in
RAB:mdm Enclosure cc: Gloria Post (NJDEP)w/ encl.) (via U.S. Mail)
Helen Goeden (MDH)(w/ encl.) (via U.S. Mail) Lora Wemer (ATSDR)(w/ encl.) (via U.S. Mail)
sen
ps
Accepted Manuscript
`Title: Anoaf PlFOAyinDsoseidCDs-1MicePart2: DispositionofPFOA intissuesandfluidsfrompregnant and
lactating mice andtheirpups
JLT
L-a
L5
NAauSktahaloylrSays,m:WaSh,uizAtaemn,nyAeDn.Ed.DrFeeewlnntBos.nk,LyiJnJedssostirncoamPL,..MSRtaearinnkkeoJr,,BSSrhuioyjnniaP.rF,H.ines, Syrago Syliani E. Pecropoulon
DoPOl::
Reference:
GS08o90-i62318(00e9)p.0r0o0t14o0x-0290019.6020/12
RTX 6230
Tosppearin: ReproductiveToxicology
.
RReocvesicvdeddadtaee:: 240222.0200909
Accepeddue: 25:2.2009
Pleas cit this atc a: Fenton SE,Reine JL, Nakayama SF, Delinsky AD, Sanko oJfPfr,oRmHiOpnreAesgniEanPn,tDoWashneiddtelCaDcSt-Sa,1tiLnMgiinmcdiesctePraonamtndA2B:t,hDeiSistprpoyosnpiasdr,oMnRJeo,pfroPPdeFutcrOtoAipvoeuinlTootuxiisSce-ocSlsEo,gaynAdn(a2fl0yi0s8d)ie,s 0i10,1016) reprotox200802012 "ATshisa sisearvPiDcFtoofiulrofcausntoumneerdsitweed mraenupsrcorviipdtintghatthihsaseabrelyenvearcscioenpoldftfohr mpuabnluisccartiiopnt. ber`Tfohorersmeamniutaisyscrbpieputdiwbsiclloluvienirdnseeidrhsgwohieciaocdlphycfeodorilmtd.iPnalgfefeaycspteetsnheoettcieontrghi.ntatdn,udrariennvgidetawheeopgraolhdeudcritcieloinlmeiprrspocrheosotf 36ply tothejournal eran.
RSE
CE TIE
ns eee sas
1
AnalysisofPFOA inDose CD MicPart2: Dispsition of PFOAinGusand usfrompregnantand catingmicandthelrpaps.
`Suzanne E. Featon", Jessica L. Reiner", Shoji F. Nakayama, Amy D. Delinsky', Jason P. Stanko", Erin P. Hines", Sally S. White,Andrew B. Lindstrom", Mark J. Stryoar, and `Syrago-Styliani E. PetropoulouTM
* Repodscive TasiclogyDivison NedoralHeathandEviromSemctes Rnesiearlch Laboratory, ORD,US EPA, MD-57, Reseach raParknNC2i711, USA
*Oakridge InstinuteforScienceandEducation (ORISE)Research Pariicipani, Human
~ExpasreandAmosphericSciences Divison, NedoralExposureReseachLabor, ORD, Us EPA. Research TaParkmNC2e7711, USA
manExponentAmospheriSinesDivision,NetnalEpos Research Laborato, ORD, US. EPA, Research TinglePark NC271, USA
Curriculum in Toxicology, Universityof North Carolina, Chapel Hill, NC 27599, USA
"HCeuartrhe,ntmaddrest sf:oDriDviirssieoansoefCLaboorataonnrdyPSrcoieenvceelsn, ,NaAtilonial,CeGnAter3f0o4r1E,nvUiSroAnmental
Comspaoonrddiasnsg:
URVSei5sieuaEDrrvEzT oFiraeanann,PPaPhakg tD,c.NiCo2en77A1gcyUSA FTax aolsess)
`E-mail: fenion.suzanncfiepgoav..
20009 [
EEE TEER
Ese
-
2
Runsogte: PFOAdisoasctatoionn
Avbrovations ANOVA saoftvarisance
BW
`bodyweight
pessoas
Lop lm ofdetcion
Log imitofqunintion
WS ms ectonse
FAA petioroaylacd
PFOA peorocimecidc
PROS peforocme inne
PD pestis
SM sandndocofthomenn
VLC ui petoinidmchroomatocgraephy
20m Pao 20132
ps
-
XoTNE ie
3
Absa Prvions siein icewith liplegaolexpo 0 perros
cid(PFOA)demons mame os depen growthad develope fics
`whichappearedtoworsen if offspringexposedin uteronursedfromPFOA-exposed.
ams.Tocasetsdisosion ofPFOAinthepregaanad cating ama her offen,imepregoanCD.1 ic ceived sige,0.1, ,or mgPRONG BW dose(425d rv)bygavage ongainday17,Mataedpropniaslnd
tissueswere colleovcetrteimde.Pupsexhibited signifbigihecr saernumtPFlOyA
cononrionsthanteresecve dus,ad ibyburden oes fr inh ladat ys,re egiss ofdose.Toediofsilkstna i PFOAvn aried oy osead ie,btwas pial ces of 02,These dtssgotmt ili bsnlPFOAexposurerou in mi andshou beconsidered nikassent [I --
Keywords:PRON: erasmoi us io: ilkmammary gd: doses dposion
2202009 ----
.
re
EON er perio ATA)
+ StS ron-- A --H --
? ----------------------T
6 carpeting,andupholstery,andthestabilityofthecarbon-fluorinebondhavemadethem
7 +
ckpamsmoephyemd asetopeekl g ee ubiquitousinthe environment.Thepredominantrouteof exposureinNorthAmerican
1F0ri
rn A rere PFAASarcpersistent,readily absorbed,notknowntobemetabolized, andare
12 13
fn eon
mt
ome tis
el9e65dint,55)
15rSoeatn 1 or A 4 OL25 0R 41 RY OA HA
16 Toe iri in reterbot
17 ratesortettn AOA
1+ thdt ,A etyy iteri
we----------------------
20 donorsindicated areductionof60%inbloodperfluorooctanesulfonate(PFOS)and 25%
521 yodwimcttyi m ms cr e EAS inblood PFOAlevelsbetween theyears2000and 2006{10). However,whilethe
23 reducedinthe USinrecentyears, it inotclear that perfhorinatedcompoundsproduced
sn rte
p10
:
5
1 ncthorcoun wil nt contin ts her te US kel or oe 2 comtiowboradsiegoosn, 3 Michoftherectbestffsreece onPFOA in ic,commnly 4 ssidvith stim goss of 001.5mg ROAg BY,basoudon 5 devclopmenaloie ch deredmal weigh enced esl 6 aviv aby weight, well ter ft:ft chspcr del,marary 7 ndshore, mdccssiveweightgin 1116,Bay posaladverse beh Observations rompedses arinin effect of PFOA on mane aonsnd 5 both ffs fhe sin fio,Whe tl (14 desribodreed pte 10 ftroiaion on osedy(PND) 10 amy endsof CD msedams 1 exposed 5 mgPOA BWfrmGDI,30 wellasdelaysi piel invlicn 12 snd emis in ilk rotigee crs on PDR0. In dio, omeoffspring 1 of xpos dm ilyedsted marypict rcin ndgh on PDI
14 andPND20. In across-fosterstady utilizingCD-1mice, Wolfetal.[16]reporttehadt
15 althoughin utero exposure to 5mgPFOA/kg BWfrom GD1-17inthe absenceof
16 tocion) poe wes suc postal body weigh ets1nd 17 devlopmenat ays opsri om bit weanwsaftaly inthos oh 18 introsd onlycps, sen se [15] eveshow ha 19. unexposedsonate taal ose10 PFOA qui developedmammary god
20 growthdeficitsandthatcontroldamsnursinginutero-exposedpups (damsexposedvia
21 pupgoamin) demons showedfran oftei ov maar ans
22 was evidentinwholemountpreparationsofthe tissuebytheS*dayoflactation.These
20009 [re
: ++ wa eiri---- ------------------ 6 + sseere--r--rT------------------r--it--n--t--n :o er--m----------------------T------ ? rerie--------p--T-------- n8;C m-- ete-- ---- ----------------T -- from1996-2004inSwedenat 8concentrationof492 pg/ml (0.492ng/m; (18),and 8
11 growthindices in childrenwithmediancordserumlevelsof1.6ng/m)PFOAintheUSS.
12 [20]and 5.6ng/mlPFOAinDenmark(21). Whileonlyonesamplewasfoundtocontain 13 PFOAintheKarman etal. 18]stady, theseresearchersreportad asignificantmilkto 14 serumcorrelation(7 =0.7-0.8, p<0.05)forotherPFAAsdetected. FurthermToaroee,t 15 al. [19)suggestedthattheremaybepreferentialpartitioningofPFOAtomilk compared.
I ete----------r---- ------ 16 tootherPFAAS andalsoindicatedthatwomenwhowerenursingforthefirsttime. =o19 -- e---- ---------- ------ -------- concentrationwere nottakenintoconsideration.Theonlystudythatbasevaluatedthe
22 Althoughfemalerats are knowntohave &serumPFOAhalf-lifeofonly afewhours[23], 23 unlikemicewhichhave a%-lifeofabout 15days (13),thestudy[22)indicated
-- ens
p12
,
1 concentrationsinratmilk approximately 10timeslessthanthatofmaternalplasmaand 2 thatthemilkconcentrationsweregeoerallyofthesamemagnitodeastheconcentrations 3 inpupplasma.
4 Tessas brit
5 PFAAsinanimalstudies,coupledwiththeirdetection inbumancordbloodandmilk, 6 supportstheneedfor examiningthedisposition of PFAAsduring pregnancy/lactationin 7 anappropriateanimalmodelinordertofullyestablishtheassociationbetween
ronson xpos adafro ffs.Whi erstehavecain 5 phumacokineisof PEAS ilindsoins, ledtcentlycis nh
10 disposition ofPFOAinpregnantandlactatingmiceorthei offspring.Werecently
11 developedananalyticalmethodfortheanalysisofPFOAin mouseserum,urine,milk, 12 mammarytissue,amnioticfluid,andpups [24].Utilizingthesemethods,we reporthere.
13. tan nthe inionof PFOA vrsmisopregoant nd acingCD-1. 14 mice awell heserumconcen dolbodyln fhi offiprin,folowing 15a single poeofPEOAonOD17,Thesedeawilllowstorue Wo sin pr spis ed SA w i" w 2 2
2n0m009 Pave 7e32
pis
'
'
| 2Materndimaetlhosds 3 21Chamicts 5 POA (ummaniumsks290% pu),wdinanimalcons, waspurchased 4 fiom Fh Chemical(Scien,Swix. FORwas compel disohvdby 5 anionindno apwt inwhichPFOAwasbelowte eveofdee (LOD 6 050g focwate,snpeered shot rir we ' 22dnime 5 Alon is wee conduct provedby hoNoon Hess nd. 10 EnvironmentBf Reese Laborstoryatta]Asi)CaeadUse: 11 Comite.Confmed medpregrac eseCD mice (100) erepurchasedfom
12 CharlesRiver Laboratories(Raleigh, NC).Pregnant mice werereceived atthe U.S.
13 EPA'sLaboratoryAnimalCarefacilityongestationday (GD) 14(dayofsperm-positive
14
15
designatedasGDO).Uponamival,mice (approximately
radonlydistintedsong PFOAwestmeotgroups.Th
12 weeksold)wereweighed
eywerehosed svat
and
in
16 polypropylenccageswithAlpha-dri(ShepherdSpecialtyPapers, Kalamazoo,MI)
17 beddingandnestingmaterials.Theywereprovidedpelleted chow(LabDiet5001,PMI
18
19.
NPutFrOitAiaotncIntoeronatcioenanlLiLbCeal,otBwrhieenotLwOnoDos)d,,MAOv)ianadftalpiwaetserwadeelicbiotnumt(rbootlhfecodorntained
20 tcmpenture(204C)adreliveBid (40-60%), ndkeptmda 1:10 lig
21 dorkcys.Mic (r-25doegrou)recivedsith wate veilor single oe01,
2 100r50mge) of PFOA mer; 10 byon evagean GDI.
220009
Page8of32
, s r------A t----
3
}
rmoekt.me--t----mt--w ----ri ----d--nt -------- PND (dayafterparturition),andPNDs2,4,8,11, and 18. OnGDS, 24br afterthe
?6+ crmpaein tmose--tom--eor--es--sv--n--m--at--eo glandwerecollected.Liverweight,totalnumberoffetuses(live,dead,orresorbed),and. #5 seeoeerr--et--te--i--bm----s--o i -- " c-- rm ---- F 3 vr wpmn--TP -------------- 4 Te --------rm --------------a --------. 1i eraomems eooenst eeeetm Anr. ovr e--t--ee------------------"h--r--r ---- 2r#1T ns--e------------------"-------- ---- PNDs4,8and 18(n= dams/dosegroup),althesametimeofday.
sod nt
p15
EER EETE IE ie
0
1 collectedonPNDs2,8, 11, a0d 18folowing a 2b separationof tepupsfromthedam 2 endam oxytocinstimulus,ThemillwasvacuumaspiredusingJow,pulsatilepressure, 3 into:pro-weighedmicroccatifig tbe.Collctedmilkwasweighedsodfrozenwil 4 analyzed.Biologicalsamplesiochodingurine,damaodpupsean,amniotic uid, 5 mammarysuc, wholepup,andmilkwereanalyzed orPFOAusingthemethods 6 described briclybelowadinourcorspanonpaper[4].
7 8 24PFOAsampleanalyses 5 Briel,th analysisofPFOAwasperformedusing aWaters AcquityTM Ulra 10 Performanceliquidchromatographysyteminterfacedwith a WatersQuatroPremierXE. 11 plequadrupolemassspectomedsr(UPLC-MSIMS) (Waters,Milford,MA). Eiter 25 12 or SOLofserum ndamaioti fd(50 ul.usedforcontro),20uL.aliquts ofurine 13 andmilk,and300uLofpupormammaryissueboxmogemateswere lizedasstarting 14 mateinfo hes analyses. Sumpleswere extracted,purified,and concentratedordiuied 15 exactlyasdescribedbyReineretal. 24], 10-40uL.oftepreparedsample dependiogon 16 theconcentrationofthe origoalexposure,was injctedaodrunonthe UPLC-MSMS 17 (24).RefertoReestal.[24]formethodperformance ndqualitycontrol sips hat 18 wereperformed fomare theprecisionandaccuracyofthemethodsused.The lit of 19 quantitation (LOQ)for thee experimentswere g/ml (serum), | ng/ml(amniotic uid, 20 urine,milk), and 1ng (whalepups,mammarytse). 2
2
2
2700009
Page 100132
pts
:
n
| 2
25UrCa crnatitne mierens weeemecan onbisn0carb oPOAninusse
3
4
u2r0inLeO.TDh0e0Qu1a0ntiChromndcrewastiniinneasss5a1y0(3Bi0o0AssanyShyTsthemys,Hoayfwaxrcdh,cCAo)sexhpibeitweds
prepared sdcad 510 msi or pl (vepceprof 20
6 samples)accordingtothe manufacturer'sinstructions.Theinter-assaycoefficient of
7 variation (CV)rangedfrom 4.0-6.8%andtheintra-assayCVrangedfrom0.3-16.1%,
5 wilhan avengeof 49%.Thesay stadtsry ranged om 028.4% sory
9 ROA repo as conocercent cocetions (og PRON cet)
W126
ComputatndiSotintess
1 Ror PRO containbvi tedfr dicorcoscnnion
15 ators,awela tine els ngs io) he weight of dime vated
14 15
coognenmaanimomnasryeiosensndswhgehp.opA).vSerrasma,,paniroitadpmsilkirnidiwiannopai,os
16
17
wdeertemcianlceudlatiendgwithrSoASG9L.1(SAANSOIVnsAti,tuiteh;CarDy,iNC)t. Stastitstiocaslsciogmnpifairciasnocne5wads.
18 if vassts005
n
n
20mm [RP
p17
.
2
[ER 2 3.1 Biological Outcomes 3 `This thefirststdytoreport ingle dosedisposition ofPFOA inpregnantand. 4 lactatingmiceandtheioffspring.Thedoseschosenwerebasedonprevious reportsin 5 CP-1mice 3, 14,16] demonstrating developmental beakthoutcomesfollowingmultiple 6 gestationalPFOAexposures. Asingle PFOA exposure on GDI7didnotaffect the: 7 mamberoffivefetuses (an GDI),implantationsites,or live-bompups (on NDI),or 8 dam body weights(daanotshown).Unlikestudi usingmalipl gestational PFOA 9 exposures [13, 25)therewasnochaagein pupbodyweight,dam liverweight, anddam 10. liver:BW ratios,withinthe PFOAdoserange administered in thisstudy(Figure1). The 13 rise indam liver:BWratiobetween GDI endPNDI,whichpersisted until weaning,was: 12. duetothedramaticdecrease in bodyweighta parturition, as tis singlehtegestation 13 PFOA exposurefiled ochangemean iverweight i exposeddams,compared control 14 values,at anytimeevaluated. 15 16 3.2 PFOAConcentrPraitoritooBinrtsh " `Themeanconcentration ofPFOA inthe amiotic fluidandserumoftheexposed 18 dams24hr afrexposure is shown (Figure2;amiotic uidcontrolsaverage3.8ng/mi). 19 Theaverageconoentation ofPFOAdetectedindamserumwasabou twicethe amniotic: 20 fiidconcentrationatcachdose evaluated (amniotic lidwas 68.,51.8,a0d 40% of 21 dam serumlevelsat 0.1,1,and S og PFOA/Kg BW,respectively). Acomparisonofthe 22 amountof PFOA inencotire GIDI fetus (bodyburden/pupstandarderrorofthemean 23 [SEM]; Figure 5)the1GDoIS PFOA concenitnarmnaiottiic oind (ng/ml; assuming 1
2202009
Page 120132
pis
| ove) val 2.3.1, nd 274d ceed PFOAin heppvs. the id.
2 in iciva coi ner fr 01,1, 3mg oegraepee
3 4
3.
PFOAConcerinttheoDonss
s Theera aad inePFOAconecsrions weeeval i umdst wre
6 ning trafpessimaly10pup PNDIcai;minima op osavrie).
7 Aexpected,da senconsindte ighstPFOAconcttons ofanymarx
5 att, egodss (igs; sr cont <Q).Teri in rnin
5 era PROAwitocesingdumexposesvaspropor othe chao in dose:
10 delivered,realsofsage ofhin. en 9-04nd 5.1 ese
1 between01-0 migand 1.050mphexposesrpectivh).
12 AooomePFOA exposof0. mgsproducedsnavngedam scum PFOA
13
14
concentration (Figure
which vas eed 0
3A) of
nave
14
of4-22
6
mgd ng/mlat
24 and 48 hrafter exposure,respectively,
rhekof Rion(PDS), odd
15. risnto mesmo 123ng byPNDIS, imewhentepps prayclrnk
16 came fo edtchowad os ilkThe U-apdseuconcn uve obi
17 inthe.mgPRON dos rovpwsa prescain he | dSmf xpos
3% porn
19
20
bougAhsbsehocwonnicneFnigsuures3of(PA-RCO;cAocntnronlurbienceaonmdpmraemmdairygylabnedePeFnOAser<aLOQ)i,oe,
21 ndmammary sue, dosto he iffrnc ntvas cident ches PFOA
22 wasbeingexcii dum inthanvas presen nda scum,ndth array
25 ieconned consider amon of PFOA.Whi shaped sponse am
220m009 [Rp
pis (oSTE TTTS oHRn |
1 excrionfPROA roe) as ota proouncd1 ifeu, amyGs
2 mons ongUnhped ese, ith lowestoxenmead ar.
3 ep ofcon,and sift e nconscomiaprtasia PRDIS
eons,
5 6a
UshWpheedncaaviero ed milv k PFOAe ats em rAvdaee id (iFnTn gle315,t hecopntcol. LrOe)o,f
7
5
PFOAinmilk (compared toserum)was substantial.Comparing the milk concentrations
toecoset iced dams concen ye), untof PFOA in
5 ik conten nga rom 1101 2 tf der OAsos dose adie
10 esperodyofction onwich ilk PFOAwas rdbd3 port
1 nfo oni esos.The sumPPOA twas rst cayad
12 cain PND? andPDS), agin from 15.56% ns of 396 yd26%1).
15 vhlcsar he ekof ion(NDSsd 11), heFROArill do gedfom
16 10.250on 1779). Twn possibleto smely man vl of ilk
15
16
obtained staspiration,butprecise weights were compared. On PNDs2,8,
avengewiht ikondvi spinofcos miewasO72,
11,and
01906,
18,the
17 0.2547,and0.0457g, respectively, demonstratingover a 3.5-foldincreasein weightfrom
18 FNDZ1a 1and 5.646 dpSomPADI 01,
w 20
3.4PPONConcenrtons
hePgs
3 pen PRO cocinnvas votedonPND 14,6, 18.1
22 compuing heversPFOAconan aPND!pup. irpcivdes
23 (ipa44; wholcool up ndoti rm<LOQ), peedht ccuing
20mm pom thet
p20
R STTT EE Re san
:
15
1 popseramPPOAcocoa erspin igh then hosemessrdi us,
2 regardlessof dose(<0.05).Althoughpupspossessed asubstantiallyhigherserum PFOA.
3 concer thandas, he ifsinp nddam lodvl hose asof 4 updevelaospcommiedrnblte Regofahors ifdieclese,besghesnd 5 clout PFOAinp srsefleced ncn exons,proportional due 6 ought actin (Lc,men104dsd43-dnreses wen 01-0mg
7 and 1.0-5.0mg/kgexposures,respectively).
8
Unliketheir dams, pups did notdemonstrate U-shaped serum PFOA
9 concntaion ives Figur 45. Popsr POA snosatios conned 0send
10 thesvgca semPFOAconestrtion vem,ul NDISwh thpupand
11 damconcentrationsapproached1:1. When the PFOAconcentration(ng/g)wasevaluated
12 in wel ie(upsnd Fire asl) deine in PFOAconnie vas 13 dtctove ime,cos los. However benthe ply increasingbodywight 14. of he opswes ken to consider to alt het atof PFOA inh 15. ectshownin Fir 1), complydiffevendvas nod Fige right
16 pancls). Regardlessofexposuredose,PFOAbodyburden (adjustedforweight)rose
17 throughthe peakoflactation andhadbegun 10declinebyPND18,demonstrating an
18 inverseU-shapedcurve.Whentheadministered PFOAdoseandmeasuredbodyburden
15. imwhoops odywight keto lfc)wrcompared oe distr 20 PROAmesure PFOA io wes 0 ong propor tonghont cain, sod nike 21 temo epor fortmsdpu sn PFOA. Mes byben sof 132-4 Zang 11078) sd 43-00 (age 32.1) ses between 0.110 hgmd L.0-
P)23 5.0mgkgexposures,respecwteriedveteerlmiyne,d. 2202000
[
p21
16
1 4.Discussion 2 "Thesedataconfirm thaton aconcentration-basedcomparison,gestatonally 3 PFOA-exposed pupscibite asigificantylargersemPFOAloadtha thir aan. 4 Thatsubstantial scrumPFOAloadinpupswasevident 24 hrafte asingleexposure,aad 5 wasapparently due oblood-boroe (imasplaccotal)transfer.Anotherimporantdiscovery 6 istheU-shaped PFOAconcentrationove time,regardlessofdoe,iathedammammary 7 tissue,milk, andserum.Thisunique PFOAresponsewasook delctedin pupsof pup 8 serum,andwasevident1a less extca inthedams"urinaryexcretioncurves. However, 9 whenPFOAbodyburden inwhol pupswestheustofmeasure, an inverse U-shaped 10 curvewasapparct, an the PFOAburdenofpupsisproposed increase due 0 ilk 11 bomePFOAintake. 2 "Thedeclineinconccaraionsecainthemilk,mammaryandserum U-shaped 13 curves isbypothesized 1be ue obydro-dilution associated with increased bloodand 14 milkvolumes. Severalphysiologicalconditionsarcchangedduring cation thathave. 15 beenwelldocumentedinrasanddiceyrelae 0mice 8 heirlactationperiodis ofthe 16 same eogth. Adecreas i otal plasmaproteiosdu to increasedblood vohune,cardiac 17 ouput,andbloodflow focetintissues,suchs themammaryglandbasbeen reported 18 inrat 26, 27).Elevatodblood volome idue toincreasedplasmavohume [27].Milk 19 yield(he) in aswasreported 0reachitspeakby PND 10 (27)andtherat mamamary 20 glandreaches itsmaximumsize(ss% bodyweight) byPNDIS(26),withastepis in 21 sizefomPNDS-15. Ratmammary lendbloodflowandvolumeofmilkproduce re 22 dirctyrelated, whenmeasuredonPNDIS [26], Totalserumproteinsaelowerin 23 Ictaing rats thtthosemeasured in on-lciating us (27), andin humans,serum
2202009
Page 160132
p22
Ee eT SECR
:
"
1 albuminconcentrationdecreasesduringpregnancyandcarly lactation 28),Further,at 14 2d postpartum,th cardia outputoflactatingrabbiswas30%higherthanthatin on3 lactatinganimals, andthemammaryglandwastheolyorganshown 0increasein 4 weight,relive obodyweight 29). 5 Although completstofdatathatcouldadressthe cxactrezsonfortheUs 6 shapedcurvesduring acationwasnotcollectedinthisstudy,the aspiredmilkweights 7 didreveal adramaticincroasefomilkvolume (assumedduc tweightchange) rom 8 PND2uptothepeakof action(PND).Thisdramaticchangeinvolume (weigh) 9 mayexplainthedecreaseinmilk PFOAcanceatrationseenbetweenPND?andPNDI | 10 PFOAalsoappears 10conocotrate iserumandmk ne the odof tation(PNDIS, 11 forexample)whenpupsarecatingmorechowandsacle less fin.Mammarygland 12 bloodflowbasbeen reporid deceaseby alin 24hrperiod,whensuckling at 13. offspringar removedfromthedam (26),and hisfllinmammarybloodflowis directly 14 asocisicdwithdecreasedcardiooutputnd94 bloodflowusedbythemammaryglen. 15. nth stdy aprecipitousdropjnweightofmilkcollectedbetweenthepeakoflacaion 16 andPNDISwas noted,indicating arapiddecreaseinmilkvolume.Therefore, theUs 17. shapeofthedam PFOAcurvesarcproposed tbedrivenbyphysiological dilution and 18 conocaiation ofthe PFOAloudover th periodofcation,reachingthegreatestdition 19 atornearthepeakoflacuationwhenthemilk volumeproducedbythedamand 20 consumedbythe upsisth grstst.Increasedconsumptionof milk upto PND! ikl 2) dirtycontributedtothesccumultionofbodyburdeninthepupovertis iestage. 2 Asignificantcontribution ofmilk-bomePFOA ansfe inCD-1micewas 23 detectedinthes suds.Prvious reports rt 22)andhumans(18) ave stimaied
2202009
Page 170132
EE
p28
TCH TCCNs
:
18
1 thatthedamPFOAmilliserum distribution atowas0.1and0.01, respectively. Inthe 2 presentsay,thedisrbutonratorange omslightymor then 0510.0. inmi, 3 dependingondos,with he vestdocetestddemonstratingthe highest tio ver
4 time. IfthemilkPFOAconcentrationshedbeenmeasurednearthepeakoflactationonly.
5 (days8-11),the0.1milkseradistributionestimatepreviouslyreportedforrasinmid-
6 location 22]mayhavealsobeenpresumedtru inmice.However,attwopodsduring 7 lactation (caryandIte)spikes of increasedwillserumratiosappeared,egadiesof
:
8 dose,with asubstantialpeakinmilkPFOAconcentrationsonPND2.Althoughvolumes
9 ofmilklargecaough operformsoa measore prosto PNDZwerenotabletobe:
10 obained,wesuspect,bsedo thesignificantPFOAconccatratons ithePNDI
11 mammarylandthtsubstantialmilk PFOAcopocaraioswouldbavebee evident
12 PND,aswel,prayde obeingcondensedinsllmilkvolumes.
1B
InpreviousreportsbyLau (13), Wolf(16],White [14)andco-workers,decreased
14 bodyweigh gainandaconstamoralitywere evidentonseveraldysjustafterbirth
15 CD-1mouseliters gestational exposed 0 3mpgPFOAaodhigher.Inc,ina
16 cros fosterstudy (16) demonstratingdecreasedbodyweightgana 3mg/gfrom in
17 weroexposure any,significantdecreases inbodyweightganwere detctodinte 3
18 makdosegrouponly when neroexposedmicewer aloallowed 0 urefrom a
19 PFOAexposeddam, Even stmgs,terewaspoevidenceofdecreasedpupbody
20 weightorneonatalmortalityinthecurrentstudy,following asinglegestationalPFOA
21 eaposur.OurPFOAmeasurements inwholepopsindicatethatthePFOAbodyburden 22 accumlates incary Ife,3dbegins adeclinea pups usr,opentei yes,andbegin
23 toeatchowanddrinkwater.Ourdatsandthosedemonstrating deleterious health.
220209
Page 180132
pe
:
1"
1 outssgthemilkofgana PFOA-capose mic ws jorsomes 2 ofconinedexpose otiscompoundfr hedevelopingis. 3 Asexpected,rediffrac indamsndpupsemPFOAconctios om
4 thosepreviously reported [14, 16]werenoticed,andthosedifferencesbringtolightthe
5 issueof singlevs. multipledosekinetics.Asnotedfor PFOS, singledosekineticsmay
6 ifrbanal om hoseinvolving pet does 10), once dependent 7 hingesinclernccaneindiscepaciesbeensigesnd peste dose + Kosi. 9 Alimiedumberofpdemilgial sts ev veldseiadnsbwesn 10 heathote ithweight hdfc)and ond oodorment en 11 PFOAcocentaionin mans[20, 21), whictesis iletodetectsoins
12 with laterdevelopmentalmilestonesininfants [31]. Severalstudieshavenowmeasured
13 PRAASin hnml [17:15, 12, 3,however olyonestd as en beto 14 spasm themilsr relics of PFOApast[1], Thepred 0.01
15 (1/100")relationship was determined from s singlevoluntarily contributed sample at 3
16 weekspopu Acotiog ohmow ilkserumPROAditbutionaveri tat 17 wereportherin,theves porto on human (15 nd i [2] ayn be
18 representativeofthePFOAdistributiontomilkthroughoutlectationinthosespecies.
19 ncooduion,these sisconfmedsodSher definedconsidersPRO
20 exposuresto mouse offspringfollowing asingle gestationalexposure. They also
21 demons tsscum heal avertininwhlepps,which ilyeas 2 rom lorePFOA, xpos hathdpeiuslybn cpl assedin 25 aberspcin.Asale0.1mpg PFOA xpos pga msened
2n0n09 [Tr
p25
1 circulatingserum PFOAconccotaion of44-216 nf indamsand 117-326npnin 2 pups valuessila oorlower hanserumPFOAconcentrationsofchikdcathat were 3 scsidetaly posedvia DuPoutproductionpactemission (34). Becaseofevidence 4 115,35)demonsrtiogneonataland cothealtheffectsfollowingdevelopmental 5 exposure o PFOAjomice,sociatedwithhighercirculatingPFOAlevelsthanthose 6 reportedhere,continuedstoiccvalutin exposure-ffoctetonsipsarcamo in
7 chien.
8
5
10
n
2 13 Adaeidgements 14 Theauthorswould like othakDrs.Barbora Abbott(USEPA,ReproductiveTuxiology 15 Division)andChester Rdigoez(NationalCenterforComputations Toxicology, US 16 EPA)for thei constractive criciamsofthismanuscript. Weacknowledgethexcelent 17 careoftheseamimalsbyNow Year Tech,loc(Rest, VA).The esearchin isaril 16 basboc reviewedbythe NationalHealthandEnvironmentalEffectsResearch 19 Laboratory,USEaviroamentalProtection Agency(EPA), odapproved(orpublication.
20 Finding inthisreportar thoseoftheauthorsndapproval docsnoii isreport
21 22
reeflenctsdEPAopoorlrirceycs.oTmhmeeeunsdmeatoiefonrfnaoderutasem.esorcommercial produc
doesnoconsiaie
zn
2
2102009
Page200132
p26
EE
NIE ee
:
21
1 References
233 SS(b1p)varUtiSi.ppEPnurvoiogoavnmimeoopAtpdiPnreopstocsbibooneAglSeanpocy,sAL noiounnncm.en2At0k0of6r)hceasv2a0l1ib0El1Oe5SP.FOA
75 L(a2 WMiEAnndersn,ad11.BuKtBs.hWoitl,lS.aC,.CPheansgt,Do.nG.Fawrrs, GnLd.Keewvodyh,Jri, C.n
150
onionsand odesofsion, ToeSe. 103 AREY. D1 C.LanKC.Ano,C.Hodes,D.Li, A liteHuchessod.Sd,
11 Peforsallyacids arevi ofmoaiog nd colon dings,To 51,99
1181254
(2007),366-394.
D(8u1chotGfWa.sdOlLen.,Z1ov.eB,aRrisf,D..ofsrsemn,mLVi. FirooeflpircherAeMs.sacnaclefo,1n.tc,
i11s67 Vpeteer,EomirornHeos bPwerdspoefo1ar5sGonOcaNmst1e29a9e1r30ne5dhioroochmnipodtucieon
3F1il0l51H5i)ngrbilTiro,dBl,aL Hiorcoown,mMu.ntWoxrpth,1.0PSHcOhSeiie,PFLOT.AC,oRwik raand2K8. 2008),
2354 V(6amKsSi,SGupmegye,pPaMs.eMacnoanget,aN.iYnosmaonfapiesf,sSroMtiioyt am.aTysossndrmN.and
5%55
pens i uCp romos3GhHOBeSr10.2. (1 GV.Olan, LY. Huang,KJ.HelouK,.. Harn,1. Buienboffa1n1d
23258. SVaensdeDl,riaorcahleSophaumanobflpoec,rrvopwncmHnellloPaeerpeecsf1t3s0s0o0%c,a5m39nv.3,d45
333152 sT[o8ot,s,eP1ngToieon,,KrnKdapinonlsarsnh.seKeofoamvoadrsbl,eiSMenMhd.eDCetonrsontcheGe.ainrF,iBicflloianona,i5Sm.ntrTToaskaaceh,alslthisa0entd.
M 336190 ) LrWe.nYoeun.g MX.So,G, Jang, Tanya,N.Yamshite M.S,.Wo,
33F76 rDDue1o.rycGbieon,sKionbuarsgevmoidPmX.lLasm,oPmeCmhiee,sEsmtraesToaocldato,nd8t2106),
2 [R1A0L] HoGrWo.,O2M lD.Ce.Mai in,TR.Chuh rcbh,tMLE,Ba JlAltioion,Wi X1..BRuenegl,. lTaMo.dLBote,
5453 ZAoembaetlc,saDnecRliendeCinrpeebrufiloeudoornsoo0a0nc0d.3ot0t0hae6r,npEotveyrfshounourSoloalkfTyelcohcnhenetm,isc4a2tls(2ei0n06),
220009
Papo 210152
ET TR Sl es
:
2
, LL ER 2 [11] JL.Butenhoff,D.W.Gaylor, J.A. Moore,G.W. Olsen,J. Rodricks, J.H. Mandel Odopeo.oo 4 perfluReogulrToo xico olPc hart maca ol,n39o (20a 04)t ,36e 3-3, 80.
:i L(S E1) to 11.ti abla 2 epnem e tent e t 9 [13] C.Lau, JR.Thibodeaux,R.G.Hanson, M.G.Narotsky,JM.Rogers,AB. $B SinTen ie ne ry eto nn 11 inthemouse, ToxicolSci,90(2006), 510-518.
i2 if U8M , SSvi,Aae cans2tbioetS nEVliTemnktD.H inotre, 16 andfemaleoffspring,ToxicolSci,96 (2007), 133-144.
3E ziE3xR B2i3I3I:E$28p"URW0lR, lEUre m A UB ge E oC0m,omtmMES I nI 0rh0mnnalbE te iAn rhcKeto,eeemrr aB E a Cini di rs,niCr TmR nnr enbosKKfT ErrT n e r m ena ontrepAr3ae,dmt tCce 0e e hft. eot ilncnte BemeeCtppodernes im1arts5ots 23 [16] C.J. Wolf,SE.Fenton,J.E.Schmid,AM.Calafat,Z.Kukleoyik,X.A. BryantJ,.
sn ron
A NS A is
|||; 0h) CCmrht tain Temes ort eli
h :} oE y D21m evetm , i 1e Cr gn ec Te 5 (22) PM.HindeslitrE,.Mylchreest,S.A. GaJn L.Bn uteno boffn and, G.L..Kennedy,
5y ltl
m E a e moi n1 : E n 8iC S0 e e AL
i %B 31 1S ,mo20maom mepse r sm ope cts
223xEBm Sim m) n me m ott etom i --
3D2EL
I ---- fIy S co emtm mt e rr ce TR
53A 3:3 mI 0 cmreiamaEtRe3re ce h tt
34iB1ot1glr15m2r 00iw7),me16o7e7-s1c 68mo 2. srmo ea n mDn manem rtnarc s r noe
me
-- ers
p20
EEE EEE TT TERCS
x
|
2 [33] O.S. vonEhsenstein,Fenton, Suzanne E.,Kato, Kayoko, Kuklenyik,Zsuzsanna,
3 Calafat,AntoniaM.,Hines,ErinP. , PolyfluoroalkylChemicalsintheSerumandMilkof
45&
BreaWos ment Repf rode Toxie col,d In Pi ressn (20g 09).
(3) EAEmmet, FS,Shot, .Zhang,D.Freeman,C.DisdLM,Sha,
1705
ant corresores eyEviron Me 43000, 755.70 Communityexposure(0perfluorooctanoate:relationshipsbetweenserumconcentrations [35] EP.Hes,Whi,Sal,Sako,Jon P,Gibbs Floumoy,EvgocA,Lo,
111123 CBaexrpvtoaospwoeS1rsr,eaFomecoosp,otScsoasnsdnoeelA.inPk(enFndRarO wDFcehmdaoleaMGy.FAoIllM,oiwciHenogLlDoeCwvDiloE scinaollse
1ii4 TnPress(2009).
uw
pr Page 2sctsz
u
1 Figurelegends:
2 memeeso toeA taosnrescottog0t 1in,s Figur1e.Damtissueweightsandaverage pupweightsfollowing asinglegavagePFOA.
5
7
eecoemat--ys--s rrOTNm--n--t D--o --an rtt--m--rSirn20 (GD)I8 (notshown). (A)Damliverweight,(B)liver:body weightratio,and (C)pup
I 5 moeCompton
pei
GONor i
FEO
eon t ron eet anrnm0o9,ootnete rieo dom5n
I
13 indamserum (A; g/m),urine(B;ng/gcreatinine),and mammary tissue (C; ng/gtissue.
14 wre Sant n reeds weight) onpostataldays (PND)1,4, 8and 18. PFOAconceatrationsweremeasuredin
1716 ten oes tom sori bo i's A-Cand B-D cannotbedirectlycompared(duetodifferentunits), the U-shaped
e o aoreoaannmeroHn asltdtnseftmtTeTooo nnct9stkspttte5yetr1tSeOygr Aoi 18 `mammarytissueandaspiratedmilk.Dataareshownas Mean + SEM. "Denotes asingle.
se rm
EE
p31
FEEDER aE
1 declinedove time,presumablydeto ition ofdosebyincreasedgrowth relied blood 2 volume,Dataaeshown as Mean SEM. 3 Figures. WholepupPFOAconcentrations.PFOAconocommatonsweremeasuredia 8
4 representative wholepup(pupandblood;ng/g;leftpanels)fromeachlitter.Although
5 ther is aconsistentdownwardtrendinPFOAconcentrationove tie, the apy 6 increasing bloodvolume 0dbodyweightchangesmustbetakeninoconsideration when 7 interpreting hes dae.Bodyweightadjusidvahoes(ightpools (oggPFOA 8 measures bodyweight =bodyburden]demonstrate an accumulationofexposureui 9 latinthelacaonalperiod.Daaare shownas Mean +SEM. 10 n2
202009
Popol
p32 EE RE EEEE
Figuress1. 50
S5EHI2lH5 lii7
(A) DLam%Liver Weight
[R 1A7A Tf7TyA A 11 [2a
Comesl | 01
'
s
PFOA Exposure (mglkg)
.
(B)DamLiver:BWRatio
2g, 5
E2R |7
55snA77 om
9os
kii 141>
AAtZM oAi7
or
+
PFOA Exposure (mg/kg)
9
|Z
1AL7Z s
o
(C) PupBodyWeight
.
E
weerAol
7
mdIA
7
lAI
7
{7M
--
`
s
PFOA Exposure (mg/kg)
Faso zrot32
EEE ETE e a ae
Figure 2.
-fmm
= |] BBpis=eoo
=
1
PFOA Exposure (mg/kg)
J
Figure3.
(A)DamSerum PFOA
f | n | | MN | m
igil
} srm---- . "BrounGanePrOA . mrm----
i
po
iEile |=i li
"
I{Mfe
CLINE 88s 00s
]
pmo
il i877 ge
--
:ETM lo. dl |.1. -. lead
| REY Tn IN Ce
me Figure4. (A)Damvs.PupSerumPFOA
HEt 12000 -
i|
=
PFOA Exposure (mg/kg)
(B) Pup Serum PFOAOverTime
i.
3
ho -|-
E 7
w
-
i
-
-
Te aw
TTT ew
TTT awe
PostnDaayt(PaNDl)
ronnor
p36
Figures. a
_
2 oo 3
2 wo
SL~i 1 1f7
I
wd
) a-
eC)
5
i.
il
-
ilvy
b0g |":
fo. ms
IR 1 swwff
c . A Ll)e, LiZW |
-
5."
ailo:
"
7
ITI
y Ri 7 AL LHREVAe
Gestation (6D) and Postnatal (PND) Doaf PFyOA Measurements
Fastorsz
|
2
8
;. .
ii
4P
HHEille is fii
&
3
i
ih) tre il
iI
fi
a ili
i
Ea
i
|
Ei
HBth, $s 1i
bide :8
1 ik HEH]
p38
CU
em
FEEERR
RIT S--e --
rena
J
--------------
=
Pvc
Reproductive Toxicology
Jarl aiepairi e taobe maie tme
+ Polyfluoroalkyl chemicals in the serum and milk of breastfeeding women
+ OnS.d vonEi hrenn steie n*, Suzanne E. Fenton, Kayoko Kato*, Zsuzsanna Kuklenyik,
|1L R pet e s MS TSnegEi,rcmt AntoniaM. Calafat, ErinP. Hines
w LR a E r --ee " am DD okom
ue
F3: sS r Exea
Pa olyfuoroaf tchemicealts (PRCgS)eecromparise 2grloupoyafymBaeno-mmradeWorgo eaniceycOomopT osunds,eoomTemsorrefwtahiycehare lM ori (FS)e werefeud1 ayOaLR tsro acamps, POSanPFOAwereoonostee ER O TdePALStewtrtteeOetT kBsrdaootppaho e 0e0n0 e ee
nse L Hl E or TmCem nntee so te.
ptrnckisogaelnoepidpimremabtiyopnyHToojo neliJ
ro
Erte pg Sr ios 2=
Tepe e ET R E plosa L k 0BL eBeS, m A aT mtp oeh t pSe d alTs r Ug tS lEY
Bh eai npr ep a a im ov a aRaann, E nerTAmeamo TanSeSOSpahrT n boare nnecgyon 421
EnRo t eeee St S, nt RpBhaeocgAh apOemOodeS peocna efrrmsE SLen da bo 22
T R RS E R EE e T TCES e a Ia a rempm eoiism uEiR,rPrA oeneotno acth loym,ou.s x4
wR aL nisEse ony Ree eSe etn SRena ton we rhe 1EPOIEdfor markers af ea cin tehorpostrdeve :
i mtmst
R [Epi E eri : Ee ERR SR
R ERERs i e SRE1Y Oa Teale
p39
R .SER ERchSR rIisTE ----TE --rT------TR R R e aes
oDauon
hbanniikkPIIC cconnncnomronassuaor isOpireeThh:ee
E3D p0 e n iistI ie t n mi i t
E hi eewoimneSl saotiwteorscwnsoorocmhniremtmsmoeovAonee aRsr +A EA a Sr! Ee
= SwB h: y
ST e Imk(3s Tempo omevnt eas eahapnrastsmiscr eksl T me e ae opm e di 5 =8F3 E8 ]i
Tae
e moa nveenan5)Tmce eme5tA)AiwtlT syney nsr:y
omed 74 fo te
seis bt it ens v-
arr -
P Lho aa moeonsha te yAe ciS00e00 inen
S So TENt T E LE E Se E sI aeToli)l SE Sn
2 2=
. n---- I
F R E FCE E l e t IRAaE =2=
I D peep e T , ny - {rotLo nl34bv Eipug are omc
IL ER
SR
IDS D m r rhahmh sam oo k a pmatee nm te m scosdui cCdwi e eagnwormaegdlrn oT n foHn ee FTEtYr),t E
L22
I EE IE R A EEe Ia mEETs Reas 32
IHE E FRi mINIIe e LIILE
I
E
E E e a acre ur tE E oSre neE: so
: EE
F re tICa
D D 3-D D So m oEne mE nmi prtDmARE LIn eLesILeS,e S coSEr I nIEt aS ey Se m ee IenTinn s ne e rnn c 2) 50mm3um:ThermortypersiiKeystone 0ddetection andquanctica:
: 12
7DERE ASS E eetTe e T ees I, . aste E
3 2=
ID -- mTr-- a e eeE y m e h e Selyl S S EA ARE A E = el
= i
RE E
et
EE e er Ia RAIE
JJ I E o i s e . s aa
o=
EE FEP T Ee EE e Ee Er =E oa a Se L Donn :==
tae Ha
bdo
- EERE
ENEIT
esse
The} Gs aetoner tAncei emR . AE 3 ATOR
eem n mr ssn SEES ee
Retoiiacs
fT==e
A= sSnTON
.: A T eer nase e s s rd
arr
=
wo5n3
i
:
:
SP r re et ree ehr z
mei T=
Ed
om
`
:
T3Seeourmkirnsgeeo008,wTo1m3e0n3neiu awye3h13oyrys =
m==
wuwo.
od. SS oi02nHsweFrwrc tc5i ae wenise0(T00e4oweT-s 5vnse) ybo srevinSt t |D6.S =
d=Eerta
tnrm
bi
'
2sy fr
HSoTOmRe si eirmpelsesaontdvWioetT2 OTaeSbslAee2C) NIn0cwoensAnSmirtBsPdpeieds tS poner
= Rva=gone
: :.
# :y
ihne eiaomn(b63i.o0y5csoansrvairpyeTse eaeeode ih redheionC d ernsbe omiar Tes,
2
we --=oer r - .: a Se :. Hn A hrace roenm css mdke orSukatmis OsooSre warini SmeeeCevddnos rreaaoiroln0sS
1 1
S eT e eT eT METI ATI SES
3ovSeridnrhosesenPinONsenveens Creston ts svt
pbsdweosrns rSlop m Soyowosn
J espe per ttsse rea. ShTsToe emcmrys. bSeomeinsion o oeodl onnys =
BIee E SASETI UEIIMiIeME rIa ATSIIITtIElYT e aatome PtE eeceSiRme e Obyoensbrontirrr
T ene. drpti cdprr t3 esre e n R oVe mmeen e oonw i- m o = momea e T=nhs ee n S==eek Wu)Os Wwei omeew wwme == =womow "" == 0=
PvWwsamomnmeeenmm
oh
aamw
os
==
woos
w Boe om
m
2
w2m
=
==
wom om W wome en
= 2=
= k] = S @ uw o2n o=w
= aoe
TRnT e
ep
es)
a ETaEEE TEE RReeeSehe)
p41
DET EG nET N pE EER SSREEsSoi
.
J
BELa'cen
TT
en i ne
TR ee
ireG n esm cte r dKieienipsas
Te aSSaumaeotd. Sarm ai3mm ot ==bi ewnm
=o
a@
m_ Pa t r enT creee w Cm orn . om --T=M,
=xs
om
zi. . `=
I
paurtittieon coeSfofeilcie1nat2fr8reoCmod5s0yetrviuosamwwertaonmeiehlakr,nbsaauttcaernecomnrocleuemdehthhnaotamisk |
M"E YeY8oco,k o=o So"5m
=Drepoa rtedlinvinegn ianNorathnv CccaralieinmE fe oea s10oEifArPTCr eFmOFmmOoprAsescs 3hoo0mepnaa1ri10e0d5d
ZeCrees ic + "
Sy cngaaatins 18weegil
on
a
whe
ao
PT rr AHsS(ngfehmie:m,edioaeno .amIrQRes.vairsOieuthm1ki:in2ogd2(oo1h4ih)ty sovss.i1rw1se(hk0u61nm)-oipIn<o0dAn.e0S01):
h5a08of0a3a3btnsdPeAeSdGloOg00 moescdewnooOnR car moerot wi T ey r showedasignificantcorrelationwiththePFCserumconcentrations
x0
pri
wv
A
TF MRHITwypaoeeoewp t sOoyk e oe a ertaaoS
rcan,
Oe 4 R e= r] m
{r only 3y wommienn--reerpposrtohedathmemsselvwees 3csoBouGoAkCHany-tAmeHE
=
z
, :+
arieasnntaoheiPssorpieEosatcutodamyponoef,nrheotalnkcmhyaloaaicentnegatS FiP nEgSNportphhCt oareold itne ygeewmS Hoesmioeednod.n86. re.
o
SrEal3F8AI VEFORAY
1
FROAVRE
n3et01yto2hsevm8iaPtlRposrraopnooarlkstyisooendtdoffonPmrirlkekaa IvmtpdelerenesshnisnodgdmlG.rsvaea orcuamenetvvlaasawselr0e oo
PRCori
a E y teat v A Sn nwae,n
2 nmeaeNG rs Zo
`hm owei ver,ethaess ehanyalyosesweervewunuoadke ijpurstdsey daaindbSrasoeeddroosnsaocpsmoallldOsson-
=
1
oregon
e=
2ge
!te
E
i
and edeennraruesnan se Sosohesec nd wo dioswmoeme eirne2Sau.y
t5 n
|L
. | inwanesamSavant mmdaaaedromRAtgeteswnha,0 4
i" 10]
ee
T`cEentrratoeieonntsooogfePnsmFHXpSwrearseehsinDgehoerrnp(4ts.o0ang/pmml) aioAn ttheoSewoeAedriseh stt0nued5.y m1v2.
re mscm var verc rveonrm homTsE he ee E orrsGiT ssn le T 000 OS
ino (( go1l5yk.0i)ntchoenDrfaim tnricsa dhfsetotnuldeyre.xcmpn oo noacsyeenitsorr go [a2tri4o3tn0i s]w(GewrTeelloleotw8tee rTUits eonntssPheeersouesommcPtoRnsCd
wr
E En ST NITIES AES 8Ro0 weird epete oro
EVEL]
TEE
RE
Ee
RRR ehShes Be:HS SRT.
ps2
DEEREIYO RR I %
: A RR RE
:
05:vomEte ReproduceToclgyen(2008) n-
5
EBL ReEDcrce nni cr tc T
E . ETReRmiATE ATT,S Rm mEeNmeE E m=e
e : na
: ii
F 7 in)m ESfaitos mnon
va
Gmie> rr
f=ErmReteE,a
REm ET eee mmcms
mo
Bemcine
e ra e
R fo)ET mermamam, RETamIE
ba
fof)
fErRe 3 Te,a e n f;rm e )en
TS RaAAOm Smotar e,|sm R oori) eeT nsmaom: sa. Ey
mmEeni sS eatsRmRs:
:
a m S n Em s E E S mo T etes
So
ttt SP a m =E eam str pn
wa
Sen
ms =mi wt
fees lNaErO s
mT Me Eoesen I nmeho 5
OETT atte
Hm S Ee T mn
mes
ERiEpRsREtTor Me A F TCeRERT r RsR n . anES MtaoIrmnoAine5n. 0)
EE eE R
dbEeETI
ISG eamRimnsTdaopOdENe12 ashnedraoompece,s(oh02i5s14m)deoBnnpcochonoerrnhFterOSWiSAnrsNTaEOfSRr ds(h2u4uitTfbaeSlksncatCD eh cofMoe ConrIehcdn rmeornmdilbd kniaOovdesobTmey AOoeLcoSnorn)k: z
To n Peeo onnosepo ea dpaets l(0sOnueee Ugo svseti2s5r5s4c3o56n0Gcaeyncntr00y20c 350rPdo OOES eonp8pOn eNnne.,
Ti ole
POS rd OAeSn Uhleoopt esevoewon5s5g3 esta tee PROSSER
wPheSieArCneiognrmheiornoeegymias tBoofr0sn0vae6csnoemda3OFtOicNrR Sme EirmoSkrpo(o9)n31
= +
comer weod AEA ps sss Ot cigsofIv eB on 3
EsnTs
Ea EEE
Se
va)
ERRTR pO NS a
p43
.
TEE ES RR
.
8mr 4 coRy B
wv JToseie
sTe i5p1s35rToeepmrbrraiacnlrcdens ncceesuy rtnonicp1o Fbsrioonoolbfsoo(n 2c53l4b3o6s) ta ShAoeppWpoeIrCsin 0al nadikrnecoPtlyC1froo uoi tmhereWnwTdhCo doepcgt otsrdatiroIn)MsE[5o5ay rbreerr
TTTrhL To
Coli mihpeonuanwtnsta5nm0erinsto yciCaaonttSlTOawRmhaPPTOhn AEoCoDeOUmnRaGpaoSpa1a. toAOPehPPHScTondwBPfeOeEruneolodth1ao pAH,RT mdEytaGC sBioCoOP rpRaoRtaREet..e
3
I choeanenssesh oochcE enoenabcieaohrnabnonfesPPofXcPHANsOSH3a1oRReBSOsVEoAeIrkIa.n Cp5o0h er0ed%aacylota oahes aydeer sksfseGraAsr APpSo,OspeIlcy oyOrssUects =z
I I
Ener alINynetirhrgotfSPeoono ennsn533ec4tetespme ioGhatvmsTaogaChhSAeSoaym orhanspI 0grs1e7D0hs5,epPopcrOoyoSppy3r2o0lcTa eHHsESsn.i rfetnsenwin iiAhc.ehlotors tTeFpAGRo OoxoysSnadTepp c0rple0ctseeWo oecomflnler tafpoor.rteess
=
Ieetcta arteeemhwoaontee essda(gpoiysor ncokDotyheraAtEo eNt0 CeTTanEl onaoa ktATVhPDBP EEPIORo OCRREANg aPSOTAr,o PeUESR, aLOtTSNeE. 341
ReerTo eeioadivlLbonou,wabtvoyowahreoriDcPoOeSBenKnPAeR,.of PSPRAmROtENPh,nneMcIttAhoSrTnnoeameCnnpsShaEvstHhotewCnTSOPyPS
5TnEarm snteepeAoliefhsAeCtouwmwhotfTdleoanptisR,ioCpraamesnroenrcaooml flPoCustshCwaotnm1assmSpt maatrooyypieolsne oafmSGerclwrSon ,eepwalsr(e0l1S0y! pdmoaerlPeHapCntdy :
20
icyhee vay e nascienrhaekUomessogsiShnosanFITCoi BRTt.s ied to opi lon oTFmGr.
Wowinongpamraeye,nnhokTfemrchosn bi4s caBae.rt0beiadwisP0C0 ApoEor 0 APRSPOT Es tyvere
<1
TTE LL omcireees y soereeoo u orcilhn see relbtn oiekSen ,seOaieukndue s di gPBiIUaoDcnSt snoEeRefeTd, Ima Bneyy a 3HkmErTcofPoOdo NeFoEC oEkxninpgoorAsovsces ooeornoiRlkrnlScoarlioousn
+2 ot
21 IL
on onodio e we sleedwguaspclihdyeowS deriKco haatoivf noTnEnh.S Soy tescohiaton Ta 6 3,conn 3 pen
hhvnet< WhAoNwAht clFaon1kelnea leOPOleooemtdenwnig. tcpcoeldsoeon G3 3
lorieane rer coin
n
m Te e pFoompvan nrtohnoyce 2oo5nnudtecda oeahstvmihenm ensgkibne aesdedoioend D0ooBsA1scECDotaereWCoE)usSmiknhetdHobyaoPnltPlarRpkiapnepohroaaslreRrrCoskpnmotpiEUGasSoraseOor =r10s
SIS eman Miisa ioomeeswnuaeedetoetaGt eiennsgediosnnmoCaroytmhopCdaaontwirang3 bFeeeEoGcsoporlnemne aasMaAHMbAuaSn1mg7Ph3PbApoeooymmmpvaeyonxowse[uuprmoti.s0 12,
I I
Crmveommooada mnoinmcceepercnseonuaaor fiPpoomnanrpo,feetPnrswSaooena pnrauPRtilOtUSSPnGnuei AtyrgopvolaNuAynirR..rTSTe gancooea0nSDpaESe1rA0S10PtECe Pg1hswe[e rlEc33h4rsHhTedehoestehostoo0fFFOosWrAesAoeos.drey
5
I I
n itenesntoOsSpcaa opCpahierndiis5n8tghsooAwum we nretogaotyvutrogeha sttvsahtCoenaounadcityh.ne
1aSrogiwrPoOCmRoeTnlsePdsaShrilynC[se8nP ixoprtFhCCs apherdvaoamonsd ab5.e oleforher e
.3
Ee Coma: 0)Comparini g ranPRCpi:
I= SaamotnignGeomors aottwhees 6gAmenriccaonnRceednCarotsasnBlfooodIBO ndanklocactioonnsd CoOfitee rest aia snc
-
ITwTomLn
hDigehhmeesnsmtefcaosorionmP2mRe0OnA40r1i8]inwCnhtisareslostpStaeeoi,mNnesoyYrctohkfCiFaroOoeslcNinaFa,RciAnoesae3mp2nleP,sccSomllvehectstesd Da percs fpeone Ie 1h id aeCh
Ahcek4tmhaam enran Theesac nti
unions ofious
ic has bnreviewed he
onl
=
"
I te om hn oudwidto come Hew nd Emme EAR Lorn USEn.
Ee
2
EE ee ein]
pts
.
EEE RE
PRE
EERE NE E T E E
: = ee r OP h et atr To oo 0ti.wrcoyeEhreenp nmefaorAtpres |1TSa( cosoMcR 20S08)mLsr . sEepSt rse mes ton1e-
oa a taeruore sensoomdor vee ESEHBBTC z5
P "constiute etnde eomrsorp reB ecommmendaetion nnore tust e. E SeR e eybrrarnoS rM eca Re 5D
Fs2oE
30dHumanDevelopmen,MalonlIofnHetathhBtetehes,
at cam fingwo pied tugs re.
0 JV,RoAmiRtEcoE metsA nabtsn .m yrt Ut n3i de: m 205
I=D o ommC menedam tiionof: i thehNeatoe mcaorCdWheann'gssStucyocIMCAtRnENY
(SOLIS
SShehSeBp
sPerEtePeseSn-- r sly | 23
Ii foe rd,BanKrasek),ant dtheUr SErnPAnyohrseingrso aele(DebLevninMayry )e zy S 200th, eOeTr eS tm t" pn =
o [--m--
3 mmm
ese
IEP S ARIEER ,t ere r. SEES
i
IERE e eE rin ERS eo E
:IF$ERRY S
E E wmLa IE mPm n U mOD WERASReeERL
v E--ope m re in ree e ha, | DiRToR
3 z2
3II 5
EE M E E a E E S T D a eE RE C eI rCR on SE EeI r e e eE e ere n S n SR
=2
E3g Se
m mm iaE enfSR1 L RS e m mW eC i e weee E
I DSR EC
3DFER
iam in
eenetnies.
iE n ton cre e mtsy SeA rs tuA m ShreS rcrs
=2 85
E
I: E BamRNIE Ef Eorenn t iann
EIR mL mm REESC E wo i oPhm m esn rreame a onses eetee Z
IIvE enmE eEE Tnne| ZEAE
SERSeEREEeERMSaENEe IITy II EEA ey
2
I-DSSE moo VEE ERe ERR Ee T see soeatrme" 1 1E 404)RCSSB OCERahEdTsRaBo tampmratamono metemee sspsvoresg0sEsmteonmntsoohnaIn. 2zz
ZWEBeE n caR er 00 efGE ee 4 tt
En Sr orem 14 RECar repoardt |
NOISIER 8030 GlasAt orgU.K 2 3.Poca chemscl heUS. Saonn ,SDnmncor,y dn. Conee s mieonsaSn, e BeOS
S EEiER nER ER r aE
TEE
Eey NE C leEN SR
wieis
p45
E EERm E RE E S EIR E RE E E
:
2EImo
EEmmeemmnilT EESm Eee 7:iBcrm t mnc mpr a rem0y.5evnomEsbsetsteoaaad,AeeoproduceveHTonokE oolengyoixe (E 3009)mt-bR set OES rmpr dT ArE BeO, iTS
32
E 2Biie mE wiCp AO Ee Irh rce its are nsss ~EEDoHmLRIm rSr NiSrRetT=erDomo nemimtnhpeeeIpnneaobori]s z85
FAI T3a
rmSVEnE ISEtgSc ep RIr Ee Ra meRa doEfn ermmRt EeRnol
WIIB1 S ERNAR SrTan asci oceameynt
2
EEE RT
n.d
Fr
wm
ELSEVIER
temic
Molecular and Cellular Endocrinology
Journal homepsas: wwwslsavior.com/igsateimee
Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin
and insulin, and overweight in mid-life*
Ca E E E EoraEpheE EaiE SEoamEe e &. ioi n, s , Erin P. Hines**,SallyS.WhiteJaso,n P.Stanko? EugeneA. Gibbs-Flournoy<,
E E Ee nn ES==hEo=e =2
C ee er ee se sp TS fE oETn edr de pLEnamSTes Sh ETT ene enkr Tsnr STa S R e EERET ree r eE ertTeeteerSti
F ts T te e ya gLt e v eee T er re ren re terng E EC ERaLS SS TwEm ----
p47
Cm
hcMeerdo tg05075
foPrra e--cifs(FsANSird,b(rFO3oRy),eoon,ocFhaesvag,tpcnearrbooen(nB)lnpeer
oeanstee(Rupddeov3eel0oeKsaivsi,2nh2d0y3;dVaenndtvenaHabeni tgheteLcr.e1ds9e9oef)PpMeiOcne cree La A 2006However,even theremol
coevrinoeussnacafoascnasnftoe,rCbrlepeidnndtugocta[snm0tp[orodwoidnagWrraapmmpedrsrc.keruaesi,eonnc2e0d SpEYraeRdseytwoh3erarseithhekrfcslePnRoOt pnrldeeysecrecHeaid0he0eco5rm4p0o3du.FnAd3A0RS0Ot8Ae
fCroimainanntgtgovaaptnfedrpmaen.rdPisRpkOwhNTiooigthsbhctonrsdrea mycncadtebhooofernSrg muornhnnF)Romo eoan(tda.ie0screses | nCeasrAeyN$ce4Gp2areetdvnaheotdavpleeelenoxdlppoy,kseaenpydecnrgdIyo,nsSGecsphooiewnfgmdaRdlOeefKpcOeabneer1dRymW(O/LEallA.,
Sou0n7dRnT aeprh ohduemui anmcsorfpis.solsewienslsOwahmnoomraeentlaih,eba00gar7nr4sar.
Sopuinion
lemlsofPROAn
P3oR0awO0irnN8cgeWhos horrdceeie rlntSs0u0ik7p ocxWuepdleole sLe,ya,ne2cr o0sl7)PedArmEa pmogsahnpt deaon,tmscrnnee dedwaesasr:
TpoepuilNoaNtmAioNonnEi.tSoTreienNgptoicscaHheomawetdhstssenedcNauoiFreRiOo oExmerieratnibosnSurn.e nimlorr(A(vrHptehgeeale0r01t1s22SwnhdiaFesEh,Oo1r9sn7m)oa.csRdOoAdncerarerLeaetdhJ3cosel.s
5S3nSriaenlg.wiintt2hh0ke0n35o-2wA0np04Go(ipCnauga.tWeaoatlne2P0E0Aa7R,fACornn1bt99ar5m-3e,00h0,a1d0 GrnTihhseehoaakkrfyeocftcsoocnbooow(iinngugmdlevkel1o9p90heBReOgAeexepodmvt2es001f1oFcOseRd
iT<nKpnoonwrnaedpePoROcRcGumpeeaabaosreparruTomcOleeNvsel(psHoinas0re0v8aolr52i0g0e8d]Tvvhi5e.eNrAcengisst T(sti8inswgey1ekssooGfeevgesoopmert1tua4l ()eircotapnhoaalk6o0stPcIo(GrG.e1Osv1a-1r7e)mcvtao-lnsioiafled.t
io(nfB7ho3Uaennfdwe)(oerkaiVmeggt a1hdan3vg0e0a6et7aensdircstFwhOeRrecUSo.redmentcs aicsgsst2wiaecovwiarneiagdnBooimnnaoeunsSe(1coPndOesRyriporck BiLomhidkniedeebsrgeotaek,
VSaeoCuetinljeistdroaeeknnl,ympoaMayeepiseacts)eieioweneAsre(PgpOAAnanCtoPynoROc.HRe2E0rM0pn0Eos.iusn(rosMehiUnpdiectrharHaysonscnkd SSo0Lfe.3cv0ri03nlo)caanpnraieCdrsapeevosierwneip3h0pFet4nOiooNt,yinpdhisecnsfhnosoccrsoesnttociirneekgnsttheeoarssleodl.
ChFnURgaAOLwr2se5rer0u6sdm,lAlostervhealannweheeo n2ncdoomfphn Wearheedet rwtiyvhooodahsracgarpegnPmtRoOi yoNao(rnpo oimTnIetaOd,Nt.bywiesgd,ia SoyeG17035
(mIeneporuiteyc,(2pe 0ol0c8o,drHbekt1nfp c1qu0ea7nm)aotowiifosbnmce LOndoGfcBIPo5RroOd2db(loae tfLproaorAmeriCeio.n smTsippGs5B 1remed aCha mn0siGYtcchSFhPMe tonape
SStliiooonnr1ays0teDo]gu(0OanS2l)0a.gWoi)toahrainndtaahnneoicdrhhFeeErTpCOrKBccWeoompNdnoyucncdAeo.SnpeannrniwuageotoirroonAosG,cgntOhee.e Dani roya oundgantpegaecorel eween
H1oLces8orB 0ennpi8 oem4ooo3tSS3esTBa7sA8,sSr G0C t]dotSS eB waonemd ahkna5hTko8ts
wSirTehhcrorxmaerdpivacoteeobrssycP. RI1pRwoco1nordeti1ptesahPpwRAaiONNogen1ss,FeescterhteahlkH,20ht0eh7l)es.ctdned
ILoki TTtTM hPghdEeoSoSoeeie b et Cr et OC tdi0
Frr2iROghIcheFarOadpRheos(dhOralrvevneybletepe1bnaopow0sep0id7ihi,elcCyhaeamsvspeociegiaantedndweoiatnthPhoOfnRwyCorrp4orniye
Semen
Pe 1 Res ss rls
22 Dmgsen cies
AnnitrherueipgewthcheiessvoebecRrOoKSocneaetgnreigoelrsyh.ye(0d31sy9t09u9m3dpayGs(ass1nndde0Bt0M0O(I)BhOWfZ)Po,wFaO1sA939,5depSv5aio8,)e
5TO 1 rto)nToO!dt ie)rosnspcndooh Ocmicd ei e ebe e bseMk fn oe
Ceornri5edsMinr)gepInoWlsesswBiiam.indhye(i SrreitsnledhseSanRwdOuhKr: timnead rPiOAn
SC meoee rpuAsSe .
ty
(s S arBeaa)r,oOhi2o0,0V6i)rgih r nipah,eeKeSonHtRu,cfkoGWy.eFeIrOe nRdrViaynrasF,ePTernAdnwswoyarlsvae fSnooiUnaS,dATGieTsAnnesvseeen, I2S31 a SOm e AbTTm I ame oypeoe perpvey0
2{0vT0e5h)eUn5ciofeonrarPmRnOaAwninpheenr12nsdwrouresceeRnaorPeOSiAm2ilGar2R(0HOa0cr9ae,doatesal. Loesees ordeBtryosbooder0 rsonig oeBS m brmopn etS.mors:
p.48
.
scrdi Fi 40002-135
-
Ma a Smee
Fe Tm ew
= a Fmaeginom
SN --
i. ctionsem fo ty f opty odskFO apdfe.
e trs ewmvhipd ierrsn1Ke4preopf]ver5ixo o dpfep aeemss iporenlshso
36. Sern m aeSe e 1s)cinn bfypr ditebv3onrcP b3ySt enrgs1Esi E: bReEdUmyoE.
2ne2t3}T DOmoNrmaoei r Scamroa1o p nSopnecfeei mmie1edS(laOogGnsTTt AOEaRgGMOhTNdRNS bL imdSioooemn5o )ST wveeohno e31C 0mTte1Ts to3hTs1eyCmLADe siMryprida ker 8ectot isn
mESEhg,,pTa T im ve vdswnotArreidoaesPhndyaIoridBs ToeeSR enteyo odaen en Os A
3
B 223Acmon
mWtokoermescommeppoesi0s 735i eesndy evrnk.
(Omir nthfieoeNedSMOAsHroRvhs ee dp m 0.otmpet acebdseS3d5t1s 0 pieotSfe ios tnyekh
Pe etcoobCoeestroaeanb ssn emehvfeoiehe0oe meehoobers,n 1eBdiTodOdwOaK 1E . aOEi8e3hP 2tyt ittIso bCeARmhDg1ArB3u 3er .t2k.Okss)eMk ie5a.upyclee ingr)eeddtEeRSnSs0ree0dd
et m monrarey sAhAR8 seIknweitTh53ry o0ei.hr1.mdes35e.dymcepherpoceitnhsdy to eo oest yeyr FOES,
2S01,24.AM R enof t ctme. Senn 35d bi) im 1mt (aded xpoenily
e eyeanmprree aeoeofros c heypki oigidr 1ptd 4omShon ecolpemepbe odsd.,s TTO0e htob.rnpar EesrsirBga tsni,cAWCn aTeaOPRere3e.ne2P0tdcdeUo)ieoheA i rr0tir2h,1edmP )oS rrSsneE dmsi oPCmyTyT
TT ere ey gh.bo pe
A 10
24. Crete i GeFr re ssvneoree8ee(c3nS t grape of0 y ta Sde1p1.
2t8 eohdocesoGmepso nF-paa-R.dd eiragpnmitmclehsye
p en at hee bsrGk pooiegsbea egptodpeertnOtesM5ns Ce3h ilssB1 sia meat Glcp oop ot Ptfh
aT mp eeMnset eoeeg ecShopekorkn hohto ri o's on ek
tfestydToritktA1ddgibe d ndheh
rarmnneemmseesdtreiceaerdT5 ioeee eopp aaert t o wo.es,
2 MemeTOA Tonk bod rnsms (S84) nn fleC1clip
A ilO dP Pr sh meT hame pieetocPecm frrrsoolSer5er5neSirwth cbeoe0B,rsn
2S2 rami10s caotsimvBo encevse sdhrriy
an peter Deme red ing 5) (A
at) yehPs
fr e r sm i: oosS1eeSonsa eseStnCi(Csret (4SSeyeaeeetsspo arnrA tesnpalmmsFoTd ae otdescce5cstsaotmhls
i
n.40
-
maican noms i
SE pmEE msmmT mmm, mee 0
*
SESItSREntE al
J Eo Sr EEe m Re S a t Te nn SitR s
ibr
FE
a para
Er
Serionmnom
SCoZnpstEanptmcEoirnocomtponenht 1ihemosmfnSahinm13rceomiepoenennetweth e35H H] 2no EEwo2,xb 1+S
CpEErcERtrmmmL omottoeneiuriIs 3a" 2
e Er E E R T Ae e R eeTE E L we s
+ee
PiUR
.
221.,eetrmnettS ceneee es pbx i33
SsTyerar hoaetss eh vpeteypeSearryr a re
SnSermons
pT Joe np annyeae rin nT e el L TrOE om
E `coi Tontnrtoles e(r p<e0.05t;Try 1eo6e 4r50C o3).oee e mnO u tg] o {$0O=RE
iHH
ft o t rer he
Ba cm ompardedwithcomntrolv(90.0ese5)E t.rTs hpirsieosstpoece ifniS callwEysy ohoL nwtnsat 5
Bp E Fe S tttrs
SE
horreiBnOomcats ES S Se E Cr
a Tp na redSeeit teCrTeEaytteaeP2CieoyliSSo B C aS S E SEEe
pr rizeennSd Se enTi TSoRgor
-
mensi-- on
.
$B=e
o
ix
5 LEJRC
ie
i
is
- oCmI E
i
o ET e rindr
PO T s CHCSe R OHO ye als.Therewas gran incredecidaX
ha --
SRE TR `bodyfat:bodyweightin PROA-exposedmice(daanotshown).
micewhich weredecrease inBWcomparedtn contol atPADI,
SwMhTrS TR REe. e, `weaning,and 18months, renotshown.
ue ratio acrossdose upshencompared cord(means
a D IC0EE ELL Ei rangedfrom 0.75% incontrols 100.9%in 0.01and0:1mgPROATKE).
D BS E C E TIRLE DTRE OLLEE Ta TiE TL eeerSoe u pnrosesoen re aLea
T a E EE S s E miE a
I tI su emtoat. ge
iI A r e sE inOOr e aRa a LLS L Ao: E aaCia a
uated(Fig. 5).At 51weeksold,whentherewas nomortalityin.
E m A ErS m p R henSm o TR I SS a EhyooT eke LUe Ctuanets
tS LrEreTEE eTD Rr Rmm iE n, C TR EEn ARLe T a n TE Er
pst
PEE ESE to anTE IEEE EE 8 _--
ree mk mtn
Eo Ece tm et 1 t ehmmt A r 1
Ve Gee me wammem
s d STih i SowDl AaAdSO ANn ID .emahaa ow.wream
eDm mis
7 DOeuar
80 3Do
BaHEiEEl Esaeoesme hSeeBARc TmeeimnGeHGsAGSBGLEOEUSOBTuuilR n SENSERtE en-iT ndseNS2 [EDOEH
is eSmeuw
Le pris
mrewaEs hoveceanwfheteeencoconomeipnrnbenrdv esForwROomasvomlSnceoSoohirdnn,of1os8 ipoasipilmenagSgsEnetaravyaseWpAiheetcsGtcorFsRrAehe.ibonhed3y(whCetgocard
E eetos hba oeooseTe e i y htet s Fotop sdovrr demooPwlrss ISSi nooot otdotep vmlesoEo 1seaeio abrofOb2hRn yrFmigwe oacgsrevr ro(coo3nn
e oe wep e ehoeswseiiStptomoeceswesaagoeumrmirortnntsnFSnihah oegp
To ilwer go0 es reeor hi slssSiwedd 8ponhsDepcs
arrohecoA asBoeiaswe eh SheeowOriaANeegeotTnBeomertse isooyyma w5p37 Lw1h4e7:Shome m1enc. nTAGOavNeNGl=1C3e55:
e eoi rT e teens hewt ig mis
Fey 2
wi--
3a 08e. feoe feevrcomywteeoosnmaty stynweitp pn 0Sm0y1
54 5
i f TioopReaasboawmhoh aoa)ptadTbwarsotpoeyekeetbeedSE RCMCIERE
malweightswasappreciableandthereforethedifferences didnot @s
ok bu
sl
i=
R
pwerg e froA S ei3 , e.sSTeorssaI uEScIom,ToOA h rtekm spre
$7
at
1
TE as ve SnREeohamorrseieereeifpTPg~oem emnt y anteete sm
he
p.52
.
1ct ctrde bt 42595110
-
ehpAiocsreewaidthainddtewaetcitgshibntiTnagobslr,eetl1.hievtnesosavbudeodwmeiilnmgahlstw,shnoeiftohnaetrapsambddawoesmiiagarhle, werigificantlyira fomoxorlactconrlevs.Tis
depopsioernreaednisgssetb3aun5croenvmesercw(heaCingoihnstliminn ct<hoe3ns.fe o1a9rn5v6ae)lOrt,wheecgorhnsbgLrsovepnetewcpiietohrue3s ncressd leptinwihdevepolsteo10"poveone)ns
svsilaggrnniiffeiacsnanittgllhyytdJyeefscrseotamhsaenndtanntcsatscitlzic:onngtshr.oolusWghhAe.reiontnsheePwaRhOlikteehxptaotpseegddhoaessd aSbuLerosewo-ghedanotsJsinedcl(1u00d0i1n1cg0rD4eE0aSs.emhdae5wFh1oRkOe)p1deee2va0eln0o7p)bmoesdaylwFeiOghctspio-
`aCAnotintWmreaoiGlohbxEoet(vh43en3steoartscS1ahmpoguwaPrnF)bOsrhNooKwwnep2ds0iw.gen0ii5gf%hitncaoannctdhenecrardevossesesBgroaobwuopnvse npelsyusareelseiisannodceevemvleaoclpuhmeaesnafal21P-pF3aO3Atwchexeypkcosos.urTediainseoesdgaoslevceortttaghht
s(hatoatwcateaodntSisthgaoifawin)cdaawnnadscserielgansiiefe.icTsahpnitlsseonSweiemsllagamrheidntoohsevSeeplalfnecietmnaswleescigawhints og1oucmSoiseye.l.nevaeenlDse(cclienvigatetdsC,baJneosctsenoofsteScpocostaRntae,rneg3ses1o5i.a1ek6wdneieokssil1s
hiPig=gh0ll0yy5v,saireisgapnbelcietafitive1cslt8ayhmnToetbn.1teh2s10,.di1nS1dngsdhPoRmwOgeNdPdReOcdorNseeass(e(ns3o,-ka0Sb0ek6tanyro)dk|1TsaeKspnvoonwseo(rreevwiwesweoedcigtneMhdawTtitRLteh.wCecx1c9eoe9G6ssmiaagbed2ho0mnp0i8n)l(amlafCatttaeerrelmnaeelactyne
W`nWeeriightheeShdsoowpseelsdennioWthEpItiaCccomtpndairifesdatenoschcoeowsnitcrnooglssthFdeaaolsregprsreodlueapctsrvweehalsveeensr sifucdloahbadecoeossse1e0dR0tOmAeGeaeveullapsreycnsadrraaolccoxepioasberoeranannaedmaesddtchistwosnhCwyhiks
compared ov con. 307. Lackofeffec rom dt710Aapa
wecTiitghihesoeavdsenedrwauitmwhedsreuevlldoiprfmefepnuocrltPaFcnOetAr.pnrde.oTvhe laayckroefscdtiiconisl
ionntaAeduxlm1t8iPnmRaoOlbAso-edhxyopoforasogderm,aibcnoewd.eyAaigfdhtst.PuWOheAeeWnexipgchootmsspeawrehbraoednrioeocfoedfrfdaeecdt manoygncfeesccatnoobfrPteFarOkeKpoAlnactievndbdoyeceedxwrpeewgaenignhateheftatilsneamoohafdmyoheeevaoenyvsersee1.d
mraom 1n6t-hmea0p,th1 i0dddu3giPnaRcOtaNndddeaveelgorpomeonptsawlsemxapdoesebdoadi.y Weih,brows(stweght,idWhe3Weigh te1MEPFONE
bTcahesevepldoorpnetnheeanolbisfmeperovcratttiaononcfehPoRafOtLhweia-osrvaaexsrppyleonrectdhebevyeeircaoptrooefsePiaEnOngNwmiacse.
dhe seamevdoseeindelxoploosxepdaopsmedamssoweierltns(i6g3nti3fnictaanstlhylohwig.lhertyan (bKpoedhryowooeitgldhst,c2ui0ns0c3er)edawisenedrh.ibrppoawhpneeartndWeeypoblytpseaclobdersptrateeoddoomoitrnrs(esntmoeomraurseiosn
4. Discussion Thesesudsdemonstratedthe fects ofdevelopmenPtFaOAl
seoirvePiwReOtNgahrfgtfeg(isth.feoOratvyheea)icrloesuarsseytupdbcyramoywanyiaenvabenonytpowesesiioghdteth1e aacctceisoens
sexstrpuoudsimese3pd0iCo3D00-snenlaenlemI-noudcsudhelabbeoordomydopa1nfdpehoheredgnneovtywepledeoispgmwheeatnst5pnawrleePlstFleOn1A in nasfemalemice: ten fectspresentfolowingbig doses
Tewneaicmgkh kmaaimtnoclfhne(dcsalkimFngOesA-.s<tx3pe0o08s0e)Tf3oe0er0a0Ml3smcneeyrPoolReOfoGheBooofvuoarvrsye wasnove3nd gifsth ovarian i33 Pentmetof
AWleatrh:eooluogtwh-ptrdeeosrseeentwFFanOsiNchoeexdpeoetsxeupcrotesasebdl(e0c0l1ho.wn0-g,deooisnebGPo3FdOmyAgwePniFdgOhiNcen)ewoiensde, FPRFOAOnAdoitnhdeeurcepdpoetlmeeecnittnimese.wddtehageoehprtrocinfhnahsntgeoesmseipnaerlienred lsocw-hdeosde
1mp0isicigetafe(lc3epavat0tyi2io0nndconrfesauesreduimmlee3ap7ntwwieenaeikgdshtonfau9dl)a2tv0edoef3wsceoiblgeothcwtiegeeinnnis2n. raePncdepPteorrA(iPPkRARa)AamcuhIastiiPrevsppebehctiyov(el.ydFPrPAvmPegeAataRe(dcPncPshA-arRCo)o)mneds
m0e4toa3bu3olwieTccowkc-ahdio(ns0ee01sh3to2hma4to0nm1eerchgdanPaiFsOtNiIKcnaDdl)kl.aytes6pppoorr ahelTiomdpionrgtsanotf EeLAd.Rb2Cy0s0eH7n:vApobnoRoretnps2c00oe9m)pnoTguhanenesdaesnoPsdEchAhvtRebsseoeblonuwrsymsoieanwe(ioCKObogmoecnrrt1g5
mWoonrcurkseeserduarwne1it4gshhtatsisohtahoelweonxtwteehnrdtdeiodsdeevTegolrooupxpmpse.ontsParleve1ixopuosPsFudOroAespiimree(thrdey 2Pc0Pb0sA6eR:.freaevnlidtewenesddlichiaTnsegAse5suaenint)Wneuegsheetmlporossdsseeiesonhnsv(ihenocchwiietnn,iRe20dn0w8i).tAh
TvhaisllacyoanWtghocnixatoleseuxrpaeom.sua2ry0e0le5ao;Wdftoposlrateaipo,rno2ap0n0rd7anmFemeniytno3gnemiotmntae1ht,sav2pe0bon0ost9tls, htgovernftmetabolismorappeie contolAthoughwewere
dlpoawgerncesgi oarintoyfPcAdRs Synhestse hovebel cnrcoero ryepiesnan ddapnots 2PnFdOsAehaisbtecmaslhoewonftovbreec3iPoAmiRzecsimhiacoer(Kiameelr i51o.e20(0g8)h
ilenupngtaibinlaesnttodiipmneesrpufeloirrnicmosodnoocmefnetgrroaetfaittoehnsestweotitbghhrtiegnnadenp,oofionoutvrsefroiwofedginnhegtsirrnesPbFtOdiAunr.g. do2op0sm0e7es:ntAaalnbdtoxe.ll2cB0y0ni8m,)iacPdeP(ATRabkeaaccteshqa3utniidonABfvioorrP.Ee2Oc00Ni7nrdAboicbentddevabreL.5
tOeprWomseEeddemgniveicnreeotnsemupenpnot1ratdlaucbrihsephshoeengyoel,sAtd)he.yehlaetvnievbbieersoernmosehn(toDawElnSc[)h0e2mi0incWad5lus,c,e 3p8pr0iodmearrcyraedtaseeeddoeccfrrceclsaosiinnnghefeosrPobgAaedRsywsemieagpyhotrpsellalonewsihnlegovwcrihonecgfofnTesOcyAk
b0iinadtoic2o0ng05w:aeditMgiihtythaolwooadskstiaeahoi.gw2h0e0rdd7oo)sseaednsde(arGeulnroevpaiem,wee2dx0npr0to5h:saeNlewwiwbtoheilnd 1oX3fbFieOvoNanntoel vd.micew Howdeevevre,o PlFoOpAsHacpeodsceaornsJobaeoegnfmFenAegRs
dhoSsieerPeRu.OmNepxipnosweadsgrgoupsiThics fclacevacteluditnedm3ihe-sianimtheefFloOewR fdetceAcreterad4ei0ndw3mheaeokrsmaofylipTohosernteaGalersetgo,vCniitsceipseotnssitmotrroeetdsprveiams..
p53
Ce
Cs eedi bs 5
LSJyoooyweheimegfhhetrchoonnrfyaoslro5w0eC,Hd0Oo0VuE4S1Ta3nees.wreeHpessotshmasLe2s000of, 13o3crosgmamNoeengoddoeeuogfhpcchnr,faucheorPloarst,s hgataeasaydnbemorfPogAnRs
opmenntarlPedRroOeNaskopfoePftEsOeNpw(h1a.enatnydoe3vdcmhDPoReOnNryGc) oa6c3bygdvervterly ee napeGo in-gtPRON poet.Thsdeci
Seorcrm.nPeFsOrawAehlddleeceehdettmbeecaockhbsavethsecorosefdc.ioe,hee5a0shhotulaeocysreeleavEainScie .
FFrRdotOynedsaxaptoaCr5iahroeA tTvreOyGNeocryEesrD iidaahiyASeoCR ebG osndyccwA e)igoAhGtyS sIA dOiPewOC riEiNe
pckmetctgements wewottnts ankBs ccs, p for heweofthe
eonwen1s8apoonnrsese S3o
PSREORNENn)dShOBtdoTrEmRsS oo
lowerdosof ROR
rar rry MallKaeiyeoYBf 2o5L4h1n3sd0ELenMocausaeoAnC raaerKitnld0Meraryyilon
sPu2ReOOmtNhewFprOesrNhgatTvenDrW2epdwoearithgem)hdawtdl,eiwohifscctheelwo-sac,swxdhPieeOhldpRotstcsoefxoStpnfoGwpnadhlelieetme0mn0t)b7ts% Joss RAR depenwithBdrm astonOe
{CPoUfRLo3LOpaENbCecoroaoLntrtoDrryLaeSiciioeennnoCcero,posNera1tL rsionamalrCe peeveroeefp sdorervEenlTvt opipeormoendanmteboi anslt,aoDlcDlHn opeeal.elrotdh,.,
`eail.d2002a)y.wInathatsSamcesatundy, ianvesthiegratorstalshoreaporrtedwhit? 13 eIp fforrheeirs statistiacalsupc port:Dn DebeobraprhBiessp .CTTaD.r ffoorcccoont ndtuacctt
spoaoivrbearreoerreco.prVeorndgoPaALwR(e0e0m2t)li shmoisweheo,cdwoPedOhhNgaScerk enredo1keesPnmiwloinsh r0evCnrsecioprrrtater)i8onrCCtoclr)akSiiissto We3U hetoSymooo eEsTYonks
TeTp a c h3wegclaRnl lasoOse4hi e5IWAwphdaRaeo lnaydfeSiTopoOo7sfNdedyeeGsvvSostTpeTe lmweOeedredaNdSp1o SonbeAees
hIc
rb. ed
ndBo
Es ps
a2e
og i
Do
gi.
iofPreRiOett Nosnpooph nlhitnwigehtehGeospseocfPoROsNoHmwoom wecrooonAreDatmRAyEneSnma RarT,21sea ,208oehie d0ecerrtmeS trt e o t
A crteidpoweeittciahldh oseesa(untpnmiooeed,Gwoin9ne8r 3e entd bHmhm eaanst d ASE AoeDSWHeCglXmSJT y0er1r S.2t0 T 15(,RLLm eoa
PFheEnoctoype)shneebrPoeeRtOanNL.2a0i0d3ob),ysigcnmifiimcaianntdgjootvchreaosveasrtayh(sbr.wowdn0a0t "Coa LSi.AodmenSecEmeeV opr esa
ASnowchSeeaTnsammronepnutnnvpees pconhaehatrnoemgeevsstirEpsPeO(AiCkeped. SeTeEteITCtEII T TTE I CS SonLCtnMsiee
Soirna1TecsyeaeTenSoSmseeuoPkeRrOppNmos)rocebisoloepaeoouwnmtcelopeayadFhaatob2e0n3w0nce7aeWkass7 kaedhsr CCUoARSOTN 3WIELLCSeIAAk PoflprSJoT.iPntha1BnLO20Et7rend
GadeivargelgroprpmechaontrntfaiprcmooemudpinronnheenoFsftRdOoofdibhineksy((adockdtss.esedGonovgeohpdmTeeunskl
PBoeista1
ASEraHFeWm
er Tr Mes.
Ser Are cs re
mre CEM A CR
i lLyoeacltocooorytentD)wP-hreLncip ompnarkoedto gaery
ocfhpe
vehichlee,
Au a t m o m irem Cn a eS
cDreCp,ep ehrsee t 0
rmaainseeckataecwniioamenloDtne,hvsePiloipmnTewanthdalAdnUloRoaewsoE-fdeoRMeeOPReTcTOnApconDr1fooedodrc..0
CSP ySp Stea DonEerh |SEgEe SEot I 2
ELRIRE T
SevrerveeiancCcoocleeotnOeMcwEifeongsthodSoUweTSemFta io senprnosLESATrLye C mA.TkgAeA.A SOkeH 2RUEnt
ii5ehvvmgaPgRpOonNiGlTco3o1pvacrySappnlee,msneaddhtoapeyoapPepAorUnorEes311%TBGO5,Ee2,% EC
e -- e
not
.
Cop
rete
ke
Go
SHeraerATmeNIEIRES
etcTtiR t mStme e U,eEEtE et
EEE EEi E SpT m E BEe rtR y mr ca E S f ernTE A E r i nscoT oSI seta so mtReeRS
E E Bp I E E EerA ae CCE E ARAE Au En E yRe
Marichal K.WibeknM. 3008.Bomeaiaragofpecbarinatedcompounds
EE ts. nome,KC.Okada.F. aR_Kat.5. Sasa,5. Naka.S.Uo,A.Su,Y. S38.F.
prog. 4Comp. areper.ckober11.2001. USEPRAdmin "Zobel, L207 keof ser chisasconofprDoceoacasesulonse,
DE onI ir aate N es y Ser iph C mei e ADyit me makinNs
R50e6 r 158
EC t EErEEbEr w errmi ase es rn, N TMe E EE e SR8E t rB e rLE e rmSerEwwhoy rrmems mS eer
ey
er ee, nCAol,.Hodes .LakD.Pesdhchens.A.Sd.J.200.Pron: a PA om Wh.5.CH.AM. kien..Vilar, Zh0.Wel.| Sige. Wr EE SS EERE p ES e a RR r TS E : rLy oo WEI E E BT I e EtsER E E LeEarEneEE R netn wS g T re ETees eeeI er,er ReE ES EREEE SRe SR R ATr E m n Boe ry v mam nnt,t m "ER A En A oeE fe , T
180 ON SNIvINOg
