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TSCA Confidential Business Information Center (7407M) UE.PSA. EEnavsitr-onRmoeontmal64P2r8o,teActttino:nSAegcteinocny8(e) & FYI 1200 Pennsylvania Avenue, NW. Washington, DC 20460-0001
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Re: Submission To TSCA 8(e)/FYI Database Re: PFOAIPFOS
To TSCA 8(e)FYI Database:
We are hereby providing the following information for inclusion in the TSCA 8(e)/ FYI databases with respect to PFOAIPFOS:
1. DFiesnptoosni,tiSo.nEo.fePtFalO,A"iAnnaTliysssiuseosfaPnFdOFAluiindsDoFsreodm PCrDe-g1naMnitceanPdarLta2c:tating dMoiice10a.n10d1T6/hjeirrePpurpotso,x".R2e0p0r9.o0d2..0T1o2x;icol. (2009),
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DTiitslpeo:sAitnionaolfoPyfFsPOFAiOisAnitnisDsuoesseadnCdDf-lu1idMsifcreoPmaprrteg2nant and
lactating mice andtheirpups
SNAuaatlkhlaoyyr.as:mWahS,iutzAea,mnAynneDdE.r.eDFewelniBtn.osnkL,yi,JnedJssastsiroconamPL,..MSRtaearinnkkeorJ.,, SESurhyionnjaiPr.F,.Hines, `SyragoStyliani E. Pesropoulou
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RDPeIfIO;erence "To appear: RReecveiisvededddaatt:e: Accepled date:
RdoISi0X:8916002-,6312003186(f0c9e)p0r0o0t4o0x-29009.02.012
Reproducive Toxicology 240222.0200009 25:2.2000
oIPPlf,eaPHsFienOceAisteiEntPh,iDsoWashretiidtcelCe DSaSs-:,1FLeMinintcdoesntPrSoEam,nReA2i:Bn,DeirSsJtprLoys,niatNriaokMnaJoy,famPPeaFiOrSAoF.,poDuielnloituniss5sk.uySesEA,Dan,AdnSatflayinsckisos df0rio:m10p.r1e0g1n6a/n}treapnrdotolxac2ta0t0i9ng.0m2i.c0e1and their pups, Reproductive Toxicology (2008), "A"TTshhiaesmiasenruavsiPccrDeiFp10tfiwoliuelorlfcuaunsdnteorumgneoecrdosiptyweededimatariennugps.rcoryviippdetisnctghtaittnhighs,ascaanbrdleyernevveaircescwieoopnfteotdhfetfrhoeersupmluatbnilunisgccaprtriiopootnf arbpeopfrloysr10mitatiyhsbepejuodbuilrsincsaohlevdpeeirretadiinws.hfiicnahlcfoourlm.d aPflfeeactstehenotceontthenat,duarnidngaltlhleegparlodduicetliaoinmeprrsoctensts
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CL | ERERA S R EY R ns AT NSECRIST es se
:
1
Analysisof PFOAinDesedCD-1MicePart 2:DispositionofPFOA intissues and olds from pregnant and lactating mice and thelr pups.
`Suzanne E. Feoton", Jessica L. Reine, Shoji F. Nakayama',AmyD. Delinsky', Jason P. Stanko", EriPn. Hines', Sally S. WhiteTM,Andrew B. Lindstron, Mark J. Synar', ad Syrago-Stylani E. Peopoulon
*Reproductive ToxicologyDivision, NationalHealthand EnvironmentalEffects Research Laboratory, ORD, US. EPA, MD-67, Research Triangle Park,NC 27711, USA *Oakridge Institutefor ScienceandEducation (ORISE)Research Participant, Human
Exposure andAtmospheric Sciences Division, National Exposure ResearchLaboratory, ORD, U.S. EPA, ResearchTriangle Park,NC 27711, USA
Human Exposureand AtmosphericSciences Division,NationalExposure Research Laboratory, ORD, USS. EPA, Research Triangle Park, NC 27711, USA Curriculum in Toxicology, UniversityofNorth Carolia, Chapel Hill NC 27599, USA
"Current addres: DivisionofLaboratorySciences, National Cefonr Entviroenmenrtal Health, Centersor Disease ConantdPrreveontilon, Atlanta, GA 30341, USA
*Corresponding author and address:
USuSz.anEnneviEr.oFnemnetnotna,lPPhrDot.ection Agency RMeasielaDrrcohTpr6ia7nglePark,NC27711 USA TFaexl:: 991199.-554411.45202107 E-mail: fentonsuzannc(@epagov
2202009
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ps
! SESE TT TEEE T TTETEe Ae SE
2 Runninige: PFOA dispasiton i lactation
Abbreviations ANOVA saofyvarisance BW bodyweight 3 gestionsdy LOD timitofdetccion
LoQ
limitof quantitation
Ms massspctometes
PFAA
perfluoroalakcyild
PFOA perfluoroocssnicd
PROS perflorooctanesulfonate
PD posalday
SEM sundandnorof heme
UPLC virperformance liquidchromatography
21200009 Page 20122
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ERE
ED
vs
CT mR
3
Abst reinsttcii:with ilegrstionlposes toprercimoie
0 (PFOA) demons mameos osdepengrowth nddelopmenal afc hich apse 0wasn fe xposn intrgsd om PFOA pase damsTo vat he dispoiion ofPOA isprgpanad tating amadhe
`offspring,time-pregnantCD-1micereceasiingv le0e,0.d1,1,or S mgPFOA/BkWg
dose(N=25/dose group)bygaov ngea statg ion e day 17. Matae ndpr upn fluia ds alnd
ites were collected oven. Pops xii sigan ihrsem PFOA constrains han i spedas, hei bodybenersed aferbir oi ast es ck, regan fdose, he ditionofikem PEOA vari by osc aime,butwas icallyinofc0.20. Thdotes gesstehot mili "ubstantit PEexpoOAkeinmieandshox beconsidered nk scent oding dss for is compound.
Keywords PEON sr ari is wi ilk: amaryl: desines doposion
20000 J
nr | ERR EEEET OR Res
` | 1 Intoduction
2
Perfluorooctanoic acid (PFOA) is a membofethre perfluoroalkyl acid (PFAA)
3 amity ofmanmde, crintdrnc compounds ved mame of consumer
4 ood ad ns scansdeo heigras ndwae peltproper. Th
5 weofPPAAS in many common spplications, scha ssn repellant forlobing,
6 cameting, and pbobtry. an he stabil of he cronTurin bod have mde thm
7 ubiquitous nhcvironmen,Th predominant roe of exposure Nor America
and European commer ely orl ak, inching driking water, while lation
9 an denssrpioncomprisruesof sr cpa [1]
10 PEARS weprin, realysete, notknown tbemetic, andsr.
11 pool limited, with bie n hms ranging rom roughly 4. ers 24
12 fot, the arithmetic nd geometric mean les fram ination, spectively,
13 were. yeas 95% confidence ral (C1, 39-69) and 4.8 years O54 CL, 4.05.)
14 for PROS: 5.5 yor (5% C1610)10 3 years 09 CI,5.9f2or FHS: nd
1538 yer O54 C13 1.4) 0d3.5years O54 CL, 30.4.1 for PFOA 4)
16 Theecharctiic oo ceed concen fos he prc bahrisks of
17 PEARS and programt rede product snd isin content of POAsnd reed
18 Chemicals was cen nid 1), PFAAS re could workin bth
19 urn snd wid samples 3, 9). rect nlyof America Red Cros blood
20 donors indicated a reductionof 60% in blood perfluorooctane sulfonate(PFOS) and 25%
21
22.
inblood PFOA levels between
production of nd pci fo
ban and wie xpos the years 2000 and 2006{10).
oti However,
while the
PEAS has
ben
0 reducedinthe US i roc yar i os clahsperhointcd compounds proceed
220009
Porat
ps
s 1 inothe countwiilelosocontinue replace them in heUSmarketpolraincthee 2 conibuion to worldwide expos. 3 MachofthrecentbeskhffctsresearchonPFOA inmice, commonly 4 asociated with gestation) exposes of0.01 mgPRON BW, bas focused on 5 developmental oxcscihastdeesesssedmaeralweight gin,rdheedponatal 6 survivalan bodyweght, swella tieffsschaspba delays,mammary 7 gland sboonmaiies, nd cxcesive weight pain 7, 1-16. Bry posonal adverse bests & bocrvationsprompted tics examiningth effect ofPFOAonmaternallactation and 5 best ffctsofthemarinoffing, White. (14)decrreduicedbcibeelidsl
10 differentiatioonn postndaayt(PaNDl) 10inmammaryglandsofCD-1 mouse dams
11 exposed 05mgPFO BWfomGDI-17, awellsdelaysinpiel involtion 12 and aeration in milk protin gee expression on PND20. In addition, emale offspring 13 ofexposed dam displayed sunted mammary epithelia branching and grow on PNDIO 14 and PND20, I cross.fosterstd liz C1 mi, Wolfe. (16reportehod 15 atough ner posureto 5mgPEOKE BW om GDI-17 ithe baer of 16. actions posure was sufficient nd postal body weight deficits and 17. developmental delays, pup survival rom bith 0 weaning was afte nly nos both 18 interoand cstioalyexposed. Furthermore, ect sudics [15] aveshow that 19 uncaposd nonatscainsly posed 10 PFOA quickly developed mammary gland 20 growth deficits and ths cotrol das sin neroexposd pops (dams exposed via 21 pup grooming) demonstrated slowed diferentinionofhei own mammary glands that 22. wasvide in wholemount preparationsofthetsebythe5day of tation. These
2100009 Pansaaz
RRSS TO RAR
. 1 smth s+2 ttre Peemn--a--ee--e----te--st--m--t lactationaltransfer of PFOA intheobservationofearlygrowtheffects. sA np 0045 FON moift---- 17 CbehtetntItOvtedcmnyra2 iriis + mA etre rte.et et Bee mba ma spon n or
12 [20) and 5.6 ng/ml PFOA in Denmark [21]. While only one sample wasfoundto contain
13 PFOAintheKarmanetal.[18]study,theseresearchersreported asignificantmilkto
S3A A 1E mcetgtr etrto ttortn eotr yh FrON--iht h o--ed 14 serumcorrelation (* = 0.7-0.8,p<0.05)forotherPFAASdetected.Furthermore,Tao et
21 pharmacokineticstudy ofplacentalandlactationaltransportofPFOAinrats{22).
322 itemAlthough cha female rats are oe known tohave aserum 5,PFOA half-lifeofonlay few hours [23), se
Pa6gof3e2
ERTR I TI ER Be
, +`iret----A ---------------------- I omissioneet ST
6 supportstheneedforexaminingthedispositionof PFAAsduringpregnancy/lactationin
1+>0 rn seeF m----nm----t ----e--er--ie----o-t r----e--S--o--re--t 7 anappropriateanimalmodelinordertofullyestablishtheassociationbetween
11 developeandanalyticalmethodfortheanalysisofPFOAinmouseseruriunem ,mi, lk,
-.-B3#%". wvm-- vsiiie--netea--r----e----n--e--e--r--t--s--T------o--_--n--m----s----" 12 mammary tissue, amniotic fluid, and pups [24]. Utilizing these methodwse, report hese oo
ptt
A SREESEs
. 1 2 Marin and methods 2 21 Chemicats 5 PFOA (ammonium sl 98% pe), ved in animal exposures, ws pnchsed 4 from Pika Chica (Ssinbei, Swizeand PFOA was comply ished by
5 agitationin deionized tap water,in which PFOAwasbelowthelevelof detection (LOD ~ 6 0.5ng/Lfor water),andpreparedfreshjustpriortouse.
' b 22mm 9 Aissis werconde sprovedby he NonaHathsnd 10. Environmental Efe Research Laborstory nstuiostAsal Cr nd Use 11 CommiteeConfirmed timedpegrant eal CD-1mic (1100wer purchasedfom 12. Chas RiverLbortorie Raleigh,NC). rgicpeweraresinved he US. 15 EPA's Laboratory Animal Car city onan day (GD) dyof sppe ose 14 despot ss GD). Upon aval, mice apeosimtly 12 weks ad) wre weighed and
15 randomly distributed among PFOA treatment groups. They were housed individually in 16 polypropylene cages with Alpha-di (Shepherd Specialty Papers, Kalamazoo, MI) 17 bedding andnestingmaterials.Theywereprovidedpelleted chow(LabDiet 5001, PMI 18 Nutrition International LLC, Brentwood, MO) and tap wateradlibitum (both contained
19 PFOA st coments blo the LOD). Ania flies were conlled or 20 tmp (20-2 sd relive hamid (40-60%) and kept der 10 gh. 21 dork ye. Mice (o-25os rou) eve sb water vice or single dose (0.1 2 1.00r30 myeof P)FOA Gn tr 10, byonlgavage on G17. n
2n0m009
Poe e32
, 1 sA rm---- ---- PORmp--bi--n--e cpeas--t----i, } wetensp---------------------- 67+ tt evfit n----p S--h--on glandwerecollected.Liver weight,totalnumber offetuses(live,dead,orresorbed),and. 039 eSrmmm--e--n--------------------e-------------- werequickly euthanizedanddiscarded.Thedammammarygland,urine,andamniotic 1n52T keppotfmr--eoatzp-8e0-- enC.er--io--ms----------------r------ h --ra--t--e--r--s--t--sb--rr------------ * iimnwee----s----n--m--irr--e----m----------------_ UA E -- B 3 Mii--A ------------------. 5 Suinentntm----------r
-- pons
PSE REE ITT
p13 se ee
10 1 colted on PND 2,1,ad 18 following 2 brseparion of he pops rom he dom 2 andan onyocinsimu.Themilk vas vaac spirsienghdow, pull presse, 3 ino re weighed microseaifge be. Collected milk ws weighed nd on nl
4
5
maanamlmyzaerd.yBdioulo,giwchaloslaempulepsiandnmiclklvueruirnde,ndilaymnagnfdopuPpFseOrAumus,inagmnihoeticc foluidd,
6 describedbc below and nur companionpaper 24],
'
& 2.4 PFOA sample anaes
5 Briel, the lysis of PFOAwas pero wing Waters AcqiyTM Ul
10. Pertomane liquid chromatography system inesfced with Waters Quo rir XE
11 ile qutpol mas secre UPL MMS) (Waters, Milford, MAY. Ete 25
12 or504.ofscrumandsmite id (50 ul. eforconn)20 L. ligtfun
13. andmilk,snd 300 of pupoxmammary tissu homogenates wer lds ating
14 mari for hese ays Samples vers exacted, pid, and cocotbo
15. exsly ds byReb o a. (24). 1040 of the preparedspl, depen on
16th concenfhteroragintal eixpoosunre was infiendrnon teUPLC-MSMS
17 [24 Reto Rfefoerctr (24)formethodpesformanceand quality conol cps hi
18. were performed to mr the rcs ad syofthe mebods ie.The iit of
19. anion LOG) or es xprimets were gm er), 1 gin amit i,
20 rine,mil),and) ng (whole pops, mammary iso).
2
n
27202009 eae 0a 22
pis ER NT RRE eRe
V 25 vy creatinine mezses 2 Crninine concernswermame
" basistocai PFOAin se
3 urine. TheQuantiChrom creatinineassay (BioAssay Systems, Hayward, CA)exhibited
4 nLODofG10opt ndvas ins p 0300 fi.Tiny wf chinesamplewis: prep andcated 10msingly in plc (iveduplipceraeotfe2s0
6 sample) scot to the mamfacrer's niin. The nraay coeficint of
7 variation (CV)rangedfrom4.0-6.8%and the intra-asCsaVy rangedfrom 0.3-16.1%,
5 with an svragof49%. The say standard scars ranged fom 02-84% Urry 9 PFOA is report once orcrisis concenonions (og PRON restinine). 0 1 26 Computationsand Sats 32 Reported PRON concenirions bv ee addfrditionor concnrion 15. fos,a well as cetnin ves (np rine the eight of he su vane 14 (o/s mammary so nd hole pps) Seam, mii. ud, milk nd winery 15. concenmions we epored sal. Averages, proportions xd acl comparisons
16 were calculated with SAS 9.1 (SAS Institute; Cary, NC). Statistical significance was
17 detcmind ing Fos GLM ANOVA, with Dues stboc comparison, 18 signiwfaissct1a0n.c0e5 n n
anon Page nars2
p15
2
13 Results
2 3.1 Biological Outcomes
3 "This ithefirststudyto report ingledosedispositionof PFOAinpregnantand
4 lacmicteaandttheiriofnfprgin. Thedoseschosenwerebasedonpreviousreportsin
:
5 CD-1mice 3, 14,16]demonstratingdevelopmental bealthovicomesfollowing multiple
6 gestationalPFOAexposures.Asingle PFOAexposusconGDI7didnotaffectthe 7 umboeffirvefetuses (on GDIS), implantationsic,orlive-bompups (onPND),or
8 dambodyweights (daanotshown). Unlike sudics using multiple gestational PFOA 9 exposures(13, 25]therewas nochangeinpupbodyweight,dam liverweigh,anddam 10. liver: BWratios,withinthe PFOAdoserange administered inthisstody(Figur1)e. The 11 riseindam livBeWrratiobetweenGDI8and PNDI,whichpersisieduntilweaning,was 12 due othedramaticdecreaseinbodyweighta parturition,asthissingle at gestation 13 PFOA exposurefiledto changeroanliverweightinexposeddams, compatocronetrodl
14 valucs, a any ime evaluated.
15 163.2 PFOA ConcentrPraiotritooBinrtsh n "Themeanconcentration ofPFOAinthe amiotc ldandscrumoftheexposed
18 dams24hrafte exposureisshown(Figure2 amnioticfluidcontrols average 3.8 ng/m). 19 Theaverageconcentration ofPFOAdetectedindamscrumwasabout twicetheamniotic: 20 fiidconcentrationatcachdoseevaluated (amniotic uid was 68.5, 51a0.d480%,of 21 domserum levels 1 0.1, ,andmg PFOBWA,re/specKtivegly). A compariosfothne 22 amoouf PnFOtAinancnireGDI8fetus(bodyburdenpuptstanderarrodofthe mean
23 (SEM); Figure 5) t the GDI8 PFOA concentration in amniotic (uid (ng/ml; assuming |
2202009
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5 1 mc volume) vel :3,3 1, sd 27-0 ncresed PFOA i the pup vs. he sid 2 in whch itwasconned er for0.,1, 00 mhdose oereset. 5 433 PFOA Concentrations nh Dams s hesna ndwin PFOAconcerns were evshatdindam hat wee 6 nig itesofsproxi1m0autpe(PlNDyequal mini oposaveri). 7 As cet, dm es contin highest PFOA cncentionsofany mai 8 vated, earls fds (Figur 3s seam contol <0). The is crcuaing 5 rum PFOAwith crsin despre vas proprionalohe chang in dose 10. delivered, egressofsageof tation ic. mean 5.910 and 5.1 nrc 1 between 0.110mg 1.050my exposes pein). 12 AanctimePFOA cxpors of 0.1mph produced an averagedamsomPFOA 13 concen (Figur 3A)of 4-22 gna1 24snd 43 afer exposure spectively, 14 which was edocs 30 vemof 4 ng near he ekoftion PND), ad had 15. in 0 camof 123 ni by PNIDIS, a iewhen he paps' clr ne 16. camefom rodent chowand ot milk.The shape semconcen uve observed 17. inh. mgPRONR dose groupwas als present nthe 1and 5mp cose
g 19 Asshowni Figure 3 (A.C control in andmammarygod PFOA <L0G) 20 lbongh te concenaionsof PFOA cnn be compared dey bon serum, ie, 21 and mammary du, doe tthe iffnce nui, as evident ht ch ss PFOA 22 wasbing xt dumwin tanya rst indamser, adtt mary 23 isu comand conse amountof PFOA,Whi shape sponse i dam
220000 [
poi?
E ET EE INERa
" 1 exreion ofPFOA (ric) was ota pronccolth of er,mammaryse 2 demonstrated ston U shod pons, with he lowest oncntrationsmesrder 3th peak of cain,ad ign ieinconcnspars gin 3PNDIS
4 (p=005).
5
`Whenaspirated milk PFOA values were evaluated (Figure 3D; |control>LOQ),
6 +Usbapedcrv verewasgincde. Asdepictedi Table 1, hepecntage of
7 PRON imilkcompartscnun)wassoba Comparing eicomions
tothe closestmachddamerm concntions (oyie),theamosntof PFOA ihe
9 ikcomsiseny nedfom 101 12 tof domsem PFOAacesdosead ine
10. spperd st he dy of tionom which ilkPROAws sre hd3m imporant
1 infec on his lions. The illsscramPFOA towas reset carly and ie:
12 lactation(PND2andPNDI8),ranging from 15-56%(meansof 33% earlyand26% late),
13 whilenearthepeak of lactation(PND8and 11),thePFOAmilk:serumratiorangedfrom
1411790 cn 1175). 1 ws ckposible scumly mes tevolumeof milk 15 obo a pation,botrc weighs vere comparedOnPDS2,8, 11,ad 11, he 16 averageweight ofmilk hindvi pionofconsol micewas 0.073, 0.196, 1702547, 000457 . spel, demonsrin over 3.5 sn weigh rom 18 PND 1 55.dropi6m 0 NDI 01 20 1.4 PEONCocenraitneioins 2 PupscranPFOAconcertovscvalused on PDs 1,4, nd18. In 22. comping he verng PFOAconcernsinPNDIpps viresetiv as 23 (Fire 4;wot contol pupsad amoseam <LOG) speared acelin
2n0n00 Pa wt
p18
CENTER ETRE Rs
15
1 pupserumPFOA concentratiweornes sgaifcanty higherthanthosemeasuinrdaemds, 2 regaorfddosle(pe<0s.05s). Although pupspossessed asubstantially higherserum PFOA. 3 concentrationthandams,th diffrenceinpupanddam bloodvolumes a thosestages of 4 pup development are considerable. Regardlessofthose differences, heighicocd 5 circulating PFOAinpupseareflectedincreasedexposures, proportional todose 6 throughoutlactation i.mean 10.4-foldand 43-fod incbertweeen 0a.1s1.0empsg 7 and 1.0-50 me/kg exposures, respectively). 5 Unliketheirdams,pupsdidpot demonstrateU-shapedserum PFOA 9 concentration curves (Figure 4B). Pup serum PFOA concentrations continued 0 exceed 10. theaveragedamscrumPFOAconcentratioovnesrtime,until PNDI18whenthepupand 11 damconcentration approached 1:. Whenthe PFOAconcentration (nwgas /evaglua)ted 12 inwholepups(pupandblood;Figure 5 Jfpanels), adeclinein PFOAconcentration was 13 dette overtime,acrossalldoses.However, whentherapidlyincrcasingbodyweight 14 ofhe pups was taken ntoconsideration t calculate the taal amountofPFOA in the 15 neon(ssashtoweninFigure1), acompletely different end was noted (Figure 5right 16. panes). Regardlessofexposure dose, PFOA body burden (adjused for weigh) rose 17 throughthepeakoflactationand adbeguntodeclinebyPNDIS,demonstrating an 18 inverse U-shapedcurve.Whentheadministered PFOAdose andmeasuredbodyburden 19. in whole pups (body weight taken ino effect) were compared te administered 20 PFOA measured PFOA ratio was no longer proportional throughout lactation, and unlike: 21 theratiosreportedfordamandpupserumPFOA. Meanbodyburden ratiosof13.2-fold 22 (ange 11.1-a1nd74.3-8fl)d (range 3.25.1) increasesbetween 0.11.0mg/kgaod1.02 5.0 mg/kg exposures, respectively,weredetermined. 2
2002009
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pis
RE EIN EDE ER
It | 4. Dcusion
2
`Thesedataconfirm thaton aconcentratiocnom-pbaraissoend, gestationally
3 PFOA-exposed pups exhibited a significantly larger serum PFOA load than their dam.
4 Tho sbi ermPFOAlod ops was vie 24 be fe singleexpos,sd 5 was sparednu 0 boon (asp)rs. Ano mporant discovery 6 ihe UthapedPFOAconcerto vertie, gales ofdos, nedasmammary 7 ite,mil, ndsce.Tisrigue PFOA response was okdeci opsor ip Tso, as cident a se sn heda"wiry etn curve. Howeve, 9 when PFOA by burden i whol up ws he utofmeasure, vers shaped 10 curve was pr, nd he PFOAbdo up ros 0 cesdefo ilk 11 bome PFOA nak. 12 Tocdetininconcenrton sen nthe milk mammary sdscm U-shaped
13 curvesishypothesized 10beduetohydro-dilutionassociatedwithincreasedblood and
10 lohan. Svea hyslogial conditions ae changed ding cation have 15. bonweldocument isaddirty eet 0 mi 5 hee cation peri i of he 16. same ng.decree iol plas prin do to nrssd bloodvol, cardiac 17 ouput, nd lowto corti ss,sich 5th amar ond bas bon report 18 int 26,27). Eevated bd volumes de fo ese plan volume [27 Milk 19. yield (mts wsreport sh ts pkbyPND 1027) and he rtmammary 20 ghadeches mania sis bd weigbhy PNDIS 26) wil sprien 21 sisfom PNDS.15. Ratmaragadbodfwadvo ofmilkproducedse 22 diay elott, hn meanesd on PADIS 26), To seu rts owe in 23 cing ts thon tos csr i on tating i 27], ad amas, som
2n0n00 Fae thot 32
p20
CE CEE E E E es a
I 1 bun concnriondecrees ding pesdcgyca ation 28), Further, 14 2d oso, ecard ootofting bisws 0 igher han hn
3 lactating animals, and the mammary glandwas the onlyorgan shown toincrease in 4 weight,relative tobodyweight[29).
5 Ahoghcompete tf ia htccd bss he act ssnfor he U6 shapedcurves eignvas ctl in issd,teapined ilk weghs 7 id even dma crs ilk ohm sod ue to weight change) om
8 PND2up tothepeak oflactation (PND11).Thisdramaticchangeinvolume (weight)
9 mycapsinthe decree ilk PFOAconcent between PND? andPDI | 10. PFOA so spears to conc sum sd ilk sr he ndof caion (PDI, 11 orcamp) whe ops re cingmos chowad cle ssfen,Marrygad 12. lodflowbas bnrepo todrs bybln 24 bi period,when suckingrt 13. offspring x rove fom theca 26) adtis llin amaryl s dictly 14. ssidwith ccs cain oot 50%lo lw udby mammary gan 15. Inti dy prcpton dropin weigh of ikcollected been te pes of cation 16. and NDSwas td, cating gtders milk volume Teerhe,U17 Shope ofthe dam PEOA cues proposed 0bedive by physilogidihsiaonnd 18. conenmionof he PFOAload ver he eidof cain,reaching he rsetiio 19. atorcar iepesoctionwhen heik ole:producebyiedmsnd 20 consumedby he pups i egrets.nsconsumption ofmilk up 0 PDI Tikcly 21 diesly conte 0h cumulation of bodybdinthe pup avr his i:sigs. 2 Aspifan conbion of il ome PFOA afr in CD. ice was 25 detinthesesds. Preios eps nr 122] ndamas 1] bve cst
220m009 Page 10132
. 1 entyFA iceinenidy1805 1 iy
3 depeonnddosie,nwigththelowestdosestesteddemonstrthaehtiighnesgtratios over 4 time. Ifthemilk PFOAconcentrationshadbeenmeasurednearthe peakof lactationonly
5 (days 8-11), the 0.1 milksera distribution estimate previously reported for rats in mid-
6 lactation(22)maybavealso been presumedtruein mice.However,attwoperiods during.
7 lactation (carly and late) spoifikncreeassed milk:serum ratios appeared, regardless of 8 dose,with asubstantialpeakinmilk PFOAconcentrationsonPND2. Althoughvolumes
A 9 ofmilklargeenough toperformanalytical measurespriortoPND2werenotabtlobee:
1 mammary gland, that substantial milk PFOA concentrations would have been evident on
b 1 tm y em h teo d gea my, etie1se6m,n oHeOeNibs e nesei, 12 PN aswD ell,I prima, silydue tobeing condensedinsmallmilkvolumes.
16 cross-fosterstudy (16)demonstratingdecreased body weight gain at 5 mg/kg from in 17 uteroexposureonly, significant decreasesinbodyweightgainwere detectiend the 3
12251s ooeeicmmrOubmHtOenNtp iren nOtttieoe raoneergnent FetOrcrroatAre 18 mg/kgdosegrouponlywheninuieroexposedmicewerealsoallotwonuersde from a
wr I
EE ER RRTIE aes
v.22 me
1 outcomessugges hthmilk of stanlyPFOAexpose ic was moross 2 contin exposeto iscomp foredeveloping pops. : As peed, ge diiscces i comndppseu PFOAcocenons 4 thosepreviously ened {14,16 were tc nd os flrnces ing igh he 5 isuofsingle i. mile doseKins. Ascedfo FOS, ingledoseKis ey 6 ifrsusan fom osivohin pet does 30), Concomationdependent 7 changesin clearance can eitindicesbeeensingle nd epee dose + Kincs
9
10
heath oAutlciommietse(d in thu wiogfm hetp,ideb emdioe elotgir ecralesntucdieeas hdavce redveaoledassmocaiactionssbcetween
11 PROA concenaions i bums (20, 21,whicober ses fl to dt sainions
12 wilh er developmen miso nfs 31)Sevensis bvowmn
13 PEAS in man mi (1719, 12, 13,bower nlyan sly osbn be
14 apposite mise lon ofPFOAwas 1], Thereport 0.01
15
16.
1100")relationshipwasdeterminedfrom asingle
wicksposparum.According othemove ils
vohmarilycontributedsamplea
PFOAdisso vr
t3
ht
17 wereponberi, hevaluedin ne man (15ad ts 22)my ctbe
18. reprsemaive of te PFOAdistbution t0milk trvghout tation inthos seis
19 Inconcosion,thes sisconfmed ad rer inedconsider PFOA
20 aposes mov fingllwin sige gesaions xpos.They so
21 dnote he ccuminion ofceilaver iein hol ups,whic cyress
22 from milkbom PFOA, cpr ht adpreviously bee completlyassed
23 otherspecies.A igs 0)my PRON exposure:pregrotmow ioe
2n0n009
ra tht
pas
1 Crean ser PFOAconcntcnions of 4.21 nin damsnd 117326 gin 2 pupsvlcsi 0 owe tansemPFOAconcenof hieth wes 3 scidolly cos vi DuPontrion la cision [4].Becase ofevidence 4 115,35)demorstnin cont nd ketbeste llwindevelop 5 aposurcs 0 PRO imice,tit withihr ccuingPFOA eels hanhse 6 repo bere,contdsods vain spor.fcears ve ward 7 chide . ' 0 u 1 Advovidgements 14 Theatbors would keto hackDr.Bsr Abbot(USEFA,ReprahetieTosco 15. Division nd hetRodigoes (aon Centerfo Compuiost Toicology,US
16
17
EcPaAe)offotrhtehseirncoinmstirubcytNivoecwritYieciusmTseohf,thIiosmRaneusscirnipVtA.)W.eTahceknroewlsesdgienthehiesxciellleent
18. hosbenreviewedby he Nana HehadEnviron! EftResch
19. Laboratory, USEnvirons Prtcion Asay(FA)andproved orpblcion
20 idigs nicpr hos of atorsadprovedos ossity hier
21 rfl EPApoly.Thee fue amesorcommer productsdocs otcsi
2 cotosmen recommendation for
n
u
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roe 0otsz
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REE S EEESoE rerners INETTYTNease e
2
| References
23 (S1t)ewardUs.hSi.pEnPrvoigrroanmmebnytAsdmPirnoitsetcrtaitoonArgSetnecpyh,enALnnoJouhnncseomn.en(2t0o0f6t)hAev2a0i1l0a1b1l5e sPtFOA
45 bapec.pagovioptinpfou/pubspfossicwardsbhuim. Accesed 232009.
67 L1a2u), GWM.E.OlAsnedne,)r.sSeeneL,dLa.nBdueKnBb.oWffa,llS.eC.,CPhanrg, DfG.oFacrmiost,saGr.nL.orKeleanatnededclyh,emIrki, sCt.yics-
&5 toxicoankdmiodnestoficcios, ToSxi1i02(c200o8),3l14.
1110 [P3e]rfivoCr.oLalaiuy,Kc.iAdn:irteeviC,e.wHofomdoneistD,o.rLisng,aAn.dPtaoxbicolloegisca-lHfduaitnngcds,hJ.SeTeonerdcs,o! 51, 99
1n2 (2007). 366394
115814B)utcahoGfWTa.nOdlLsRen.,Z1oMbe.l,BuHraisl,lDi.Je.ofEscesuane,limLiWn.atiFonorfpoeccuArloMo.icStcaenhess,,ifoLn.tc,
1167 pWoerkrerfs,lEnovirroonbHeealxthaPnenrcsdpapeecntr,flh1of1r5oo(oCnc0tt0a7ne,os,1i2i9n8-e13r0e5d. Morochermical prochetion
11s9 (5) D. TrudeL,.Horowitz, M. Wormuth, M. Scheingr, LT. Cousins and K.
2200 H2u9n1ge9r6bubler, Estimatingconsumesexposure 0PROS and PFOA, Risk An, 28 (2008),
x23 (6) KS. Guuge, PM. ManageN,.Yamaks,S.Miyszaki, S. TaiysndsNu.
2245 Ypeasmansihmiatla,sSipneJcaipeasns, Cpheemcospchonecreen,t8ati2o0n0s8o)f,peSr2f1l0u.o2r1o5akyl contaminants in orm and
221 (7) GW. Olen,HY.Huang, KJ. eldsoueKJs.Hansen, LL. ButenhanodfJHT.
2289 oMtahnerdeM,ioHrioscthoerimciaclaclosmipnahriusmoannobflpoeord,orEonorcioanncHuelaflohnaPte,rsppeefcht,ao1r1c3o(c2i0a0n8o,ot3,9-a5n4d5.
331 (8) L Too,K. KanN.Kanvaarsn,M,M. CossG,. Fil5lTakmahaashioannd.
3323 seTaalnsa,bep,enPgeurinf,lainodrpooloarcstuaanscfnrolamnfdotrhneelsSitoeudcthuernoOcreano,EncviihrooanebSacimrToeisceh,nceol,eap8halnt.
334 (006), 627608
3367 (L9i),JP.GLiWes.y,YKeSu.nGg,ugMXe. Saon,d0.PXJ.aLnagm,S,.PTearnfiryoaoscoNa,.ncYsaumafsohniatta,eMa.ndSeonig,dY. Wu,.
338 fToriosch.emicals in human bloodspl from Chin,Enron ci Tech4no(2l00,6,
%4) 42
(R1M0). HeGrrWo.n,O2h.eMne,dhD.dCi.zaadierh,kaTsRh.i,Ch1B.uNrocbhi,lMeE,ElA.ciRoino,s1,W.X.BReuagcenh, TaMn.dBLoRyd,
4443. a5
ZaAosbmme9le,40Dr9ec5RlieindceCrianopsnesraodrulotobcltoaondedsounforosn,s2e0n00d-2o0t0h6e, pEolvyhioSnre aTsecchhe,mi4ca2l(s20in08),
2202009
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eee
2
3 LL10,g JD etn Gor pCt Ci n is5
4:3 1 Cat tet ep, Teper perflvReogur lToo xico olPc hart maca ol,n 39(o200a4)t ,36e 3-3, 80.
11i7;39 L(lL3leCctoohh7tTaeeisknttp itot otpyg nennnn., perfluoroalky)acidsandtheirderivatives,ToxicolApplPharmacol, 198 (2004),231-241
S h1Iks1}i YIhgAonmmA8eoroon KiT eoiCiNmeed 10 l Gvott,
EB 3oa Uo0,Sm n r7Jnftaekn pa lilE1te .
2EEEroem x
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A B I:Ylrepl tTirnsa eres det ere 0oaxnCger an nri
3533B3 0mm U L 0 mrh oLiKa bare ,bOCm r0MeemortoX1rE peoctebmS1i.m lstnetteeonts,tses
2
B3r uSL tm t ConveChl ion 0 Coto0nehveome
--_-- za
T ||:I| OmpOiA u r f S, s u , a Kee- 7 Toxi2c11o(2l005o),g139y-14,8. }3;R OT A 13 [24] JL. Reiner, S.F. Nakayama, A.D. Delinsky, J.P. Stanko, S.E. Fenton, A.B. S 1} oEriT T eA T ss . , 21 proliferatoractivatedreceptor-alpha,ToxicolSci,98 (2007), 571-581. :CEA 24 sucklingonmammary bloodflow intherat, JPhysiol,233 (1973), 111-125. iEE33}2E S :3ES m rTr S oE Cre m eno eee v E me T nt ti r tt 37 perflvorooctanesulfonateinrats, Toxicol Let, 181 (2008), 148-156.
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35 DreantecingWomenReprod vical, TnPros (009).
76& aC[no3dm4)meuxnpioEtsAyeEsxmopmuoenss,r,F0JSO.peoSrhporosEronH,cr.aonZnohMaaeend:g,Di4,s.8t,ro2sn0s0mh6ai)np,,s7bC5e.5Dt.ew7se0ie asnedmLMco.nScheanwr,ions
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| Figurelegends: 2 Figure 1. Dam tissue weights and average pup weights following a singe gavage PFOA
3 exposure on GDI7. PFOA was withouteffecton several biological end points (50.05), 4 suchasdambodyweight measuredonseveralpostaataldays(PND)andongestationday
5 (GD)I8 (not shown). (A) Dam liver weight, (B) liver:body weight ratio, and(C)pup
76 body ty FON opt. one weightovertimeor numbersof ive pupsorBo i Et fetuses(notshown)werealso
BS
--.
10 concentrations. PFOA concentrations were significantly higher in dam serum than
11 amnioticfluid atalldosesevaluated(p<0.05). DataareshownasMean +SEM.
12 Figure 3. PFOA concentrations in exposed dams. PFOA concentrations were measured
13 in dam serum (A; ng/ml), urine (B; ng/g creatinine), and mammary tissue (C; ng/g tissue
14 weight) onpostdmayast(PaNDl) 1, 4,8and 18. PFOAconceatwreraemteaisuorendisn
15 aspirated milk samplescollectedon PNDs 2,8, 11, and 18(D; ng/ml). Althoughpanels
1116 coin A-Cand B-D cane ps cannot be directly piesof oe compared (dve to different units), obthe U-shaped 219 itmtemsemt tiie ot bs rs 18 mammary tissue and aspirated milk. Data are shown as Mean + SEM. "Denotes a single
5 sor m TO ie on n ordeo n Operoarym 21 Figur4e.Neonatal tranosfPfFeOrA 10pups. (A) Asignificantly higherPFOA.
sons --
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+ OndinSe.vonEhrenstein*, Suzanne E. Fenton, Kayoko Kato*,Zsuzsanna Kuklenyike,
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