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June 12, 2000
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TSCA Confidential Business Information Center (7407M)
EPA East - Room 6428, Attn: Section 8(e) & FYI
U.S. Environmental Protection Agency
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Re: Submission To TSCA 8(e)/FY| Database Re: PFOA/PFOS
To TSCA 8(e)/FY| Database:
FYI datWaebaasrees hweirthebryesppreocvtidtiongPtFhOeAfPolFlOowSi:ng information for inclusion in the TSCA 8(e)/
1. Fenton, S.E., et al., "Analysis of PFOA in Dosed CD-1 Mice Part 2: Disposition of PFOA in Tissues and Fluids From Pregnant and Lactating Mice and Their Pups," Reprod. Toxicol. (2009),
doi:10.1016/}.reprotox.2009.02.012;
2.
von Ehrenstein, 0.S., et al., "Polyfluoroalkyl Chemicals in the Serum and
Milk of Breastfeeding Women," Reprod. Toxicol. (2009),
doi:10.1016/j.reprotox.2009.03.001; and
3. EHixnpeoss,urE.eP.,to ePtearlf,luPohroeoncottaynpoiiccADciicdh(otPoFmOyA)FoilnlFoewimnagleDeCvDe-l1opMmiecnet:alLow Doses Induce Elevated Serum Leptin and Insulin, and Overweight in MidLife," 304 Molecular& Cellular Endocrinology 97-105 (2009).
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00i89100-.61203186(]09e)p0r0ol0o4x0.-29009.02.012 RTX 6230
To appear in: Reproductive Toxicology
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4202:.22:0200909 2522009
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1
Analysis of PFOA in Dosed CD-1 Mice Part 2 Disposition of PEOA in tissues and ids from pregaantand actatogmican thetpups.
Suzanne .Feton",Jessica L. Reine, Shi. Nakayama', AmyD.Delos', Jon P.
Stanko", Erin P. Hines", Sally S. White", AndrewB. Lindstrom", Mark J. Suynar', and
Syrago-SylaEi. Peoponiow
*Reprodicive Taxicology Division, National HealthandEnvironmentalEffects Research Laboratory, ORD, US. EPA, MD.7,ResarchTrianglePark,NC27711, USA
* Oakridge InstfiortScuietnceeandEducation (ORISE)Research. Participant, Human
Exposure andAtmospheric SciencesDivision NationalExposure ResearchLaboratory,
ORD, U.S. EPA,ResearchTriangle Park,NC 27711, USA
Human ExposureandAsphericSciencesDivision,NationalExposeResearch Laboratory, ORD, US: EPA, Research Triangle Park, NC2771, USA
* Curriculum in Toxicology, UniversityofNorth Carolina, Chapel Hill, NC 27599, USA
"Current address: DivisionofLaboratorySciences, NationalCenter forEnvironmental
Healt, CentersforDisease onanrdProevenlion, tant, GA 30341, USA
*Conesapuhoonr sdndiaddnregss:
SUu.zS.anEnneviroFnemnetnotna,lPPhroDt.ection Agency Mii Drop 67 RTFeasnae: ao9r11c9h95T54r41i1a:n45g03l21e07Park,NC 27711 USA Emaileonsuzanc@ep go
2202009 Page 132
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LE T RE T T T I T Am R Tee
:
2
Running tite: PFOAdisposiniltacitaotinon
Abbreviations ANOVA analofyvasriaincse
BW bodyweight
a gestational day
Lop liofmdetiecttion
LoQ Vimitofquaniaton
Ms massspectrometer
PEAA perfluoroatiylacid
PFOA perorooctanoaciicd
POS perfivorooctanesulfonate
ND postnatalday
SEM UPLC
uslmupaernrrrdoffatolheirqmrueiddacmhnroamantogcrapehy
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Abstract
Previousstudiesinmice wilhmuliplegestational exposures perflorooctancic acid (PFOA) demansirat numerous dosedependentgrowthand developmental ffocts `which appeared to worsen ifoffspring exposedin utero nursed fromPFOA.exposed dams.Toevaluste thedisposition of PFOAinthepregnantandlactatingdamandher offspring,time-pregoant CD-1micercciveda sin0g,l0.1e, 1,or mg PFOBAW
dose (N=gr2 oup)5 byg/ avagd eono gestas tione day 17. Matemalandpupfluidsand
tieswerecollevcetrteimde. Pupsexhibited signifbiighecrsaounmtPFlOyA concentrations thantheirrespectivedams,andthei bodyburdenincreasedafcbirth oil least 8 days od, regardsofdose. The distributionof milkserum PFOA varied by dose and time, but was typically in excessof020. These data suggest that milk isa substantial PFOA exposure rout in mice and shoukd be considered n risk assessment modeling designs for his compound.
Key words: PFOA; serum; amaiotic fd; wine; milk; mammary glands dosimetry; disposiion
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4 | 1Introduction 2 Pefloarcid(oPFoO)ci umemnbercofitheprforsiysid(PAR) 3 familyofmanmade,Morneorganiccompoundswedin maserofconsumer 4 goad ndindus srfciansdu to tei rss ndwater repelsproper The 5 1s Of AASinmanycommon aplcaons,schassaireelsforclin, 6 cameing, ndphir, and estab ofthe bn: ornbondhav made hem 7 ubaiuthtcoovironnmesnt. The predominantrueofexpos inNorth Arian 8 and Europeanconsumersis iklol ake,nin drinking trwieinlaion 9 andderma sorption compris routes of esr exposure [15] 101 PPARsweprien,readily bird,nokknown obcle,and re 11 poorly clminted,withbelies in nasrnin rom rvghly 8 rs (24. In 12 fctearihmedicad omericmeanbal esoseameliminationrespectively, 13. were 5.4 yer[9574 confidence nev (CT), 3.96n5d4]38 yas (55% C1, 405.5) 14 forPROS;8.5yeas (99% C1, 6.4106) a 3years (95%C1, 92 or PHS, and 1538 yers 95% C3144)00 3.5yours 95% C1, 304.1 or FFOA 4), 16 These characterises od1 crs concer hepototisl es ik of 17. PFAAS in.program oreduceproductsnd cision contentofPFOAad ted 18 chemicalswasrece nid[1 PFAAS ir continuallydetctedworldwide nbs 19. ha adwnide samples 3,6.)A ent analysisofAmericanRedCrossbod 20 donorsindicaeadutcteiodn of60% nbd perlcroctne slant (FOS) and 25% 21 inblood PFOA eves between heyeas 2000 nd 200610) However, wie he 22. prodocion ofand poten for bmn nd wife exposes ces PEARS hs een 23 reduce intheUSin cent ears, pot cles thtperi compounds roced
202009
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s 1 inoberconti ink contin 0 lctherin he USmketplce inh I--
3
Muchoftherecenthealtheffectsresearchon PFOA in mice,commonly
4 associatedwithgestationalexposures of 0.01-5 mg PFOA/kg BW,has focusoedn
5 developmentloicie sua deccreahsed maweighr t ain, aheed ecnatl 6 survival andbodyweigh a well str sft ucha ober delays, mammary 7 gant sbooranmdcasiviwecigsh , gain, 11-16,Batyposadtveraells cbervaions promptedsiscamisin th fect of PFOAo semanand 5 health lftof the singoffiWnhigt,l(14) decribedredued pilin
10 differentiatioonn postndaay(tPNaDl) 10in mamgm lana dsor fCDy-1mousedams.
11 exposed omgPRONEBWfomG11, wellsdelaysin tt vovion 12. and shermicns in milk prongs cxpresion an PNDZD In sion mle offing 13 ofposeddams displayed sumedmammary pte ranching nd grow on PNDIO 14 andPND, cross.foster studyliCnD-1 mie, Wolfetl.(16reportehid 15. although i er xpos 05 PFOA BW rom GDI-17 inthe shen of 16 actatonsl pose vas sffcint doc postal body weight dfs and 17 dexclopmens ea, pp suv rom bith 0 wesin vs foci aly n hose bh 18. in beroan tmtonaly expos. Fuhrer,ren suis 15 ave shown that 19. uncuposcl scones ctrl exposed PFOA quickly desloed mammary gd
20 growth deficits and that control dams nursing in utero-exposed pups (dams exposed via
21 pup grooming) demonstrated slowed differentiation oftheirown mammary glands that 22 was evident in whole mount preparationsof the tissue by the 5dayof lactation. These
220m0 Pagosarsz
vs | ERR RE TERTARR
` 1 els spp oe fo pid action) desclomen ad posi gic 2 ciation anotf PReOA iteahscratyigroowneoffefts 3 Toeotwsem forpotatel prensasnd eon possin Buseshs een 4 red hebthe ctionof PEASin hnbeat ik ndcord bloodandte 5 developmen ltdoutcomesss vith hi ese obserd vations. St. (17) nied 6 arog oF47210 nL. (0.047.021 gf) PFOA in 19 samplesof rest milk on 7 Chics womenPFOAwsdetect anyon f 12 human ilksamples cole 8 from 199.200in Swede at conenoft492ryimo04n92 gs 15), ad 9 mean of 438 pm (0.004 mms repre fo5 US, breast milk samples colloced 10 200419) Twastoi cknlydined negiveassociationbtw PFOAnd 1 grow nics in chide with motion cond ser lel of. gh PFOA in he US. 12 (20130456n/nPFOA inDemat (21) Wie olyonesplwsfound 0consi 15. PFOAintheKron . (8) ny,these recs epored siganmiko
14 serum comelation (r* = 0.7-0.8, p<0.05) for other PFAAs detected. Furthermore, Tao et
15s. (19) vga tht hese mybeprerenial prinof PFOA to milk compared 16. 1 olber PEARS and so indicted tt omenwh wer asin ore frst me 17 exibie 19% ighconcentciofoPnFOsA in rest ikth women wo hd 18. mused previously, atough ine dividual varinin, daily ilk ouput nd ilk pci 19. concntwerranodoakne toconsiders. Toe nlysy htbas cated the 20 issbuioncosfcint of PFCs ewes bad sd mili anil models was 21 harmocokineie soy ofpacts nd actions anspof PoROrA in (2) 22 Although male rts rc Known have sro PFOA Ral. fly fw hos 2), 23 uni mie which have ofshut 15 dys 13 he sty 122) iced
220000
Page 6 of 32
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, 1 emeicromiinpvetpynyfeonesiosteeraies
nepnenan nipt nne ot + Frmsonmt itnmr--t----m----i----n 6? A eosin -------------- supporttheneedforcxaminiagthedispositionofPFAASduringpregnancyacitionin A 2 sumetontrrA i, cat ne 113 mbeytts ,ttftom es4o,lFTdOofe seeteeiet A A A A - "-
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1 2 Materials 300 methods 2 2. Chemicals 3 PFOA (ammoniumsal; >98%pure),usedinanimalexposures,waspurchased 4 from Fluka Chemical (Steinheim, Switzerland). PFOA was completely dissolved by 5 agiationindeionized ap water,inwhich PFOA wasbelowthe levelofdetection (LOD -- 60.5 ng/L.for water),andpreparedfreshjustprior touse. 7 8 22Amimals 9 Alaiastudicswereconductedssapprovedby the National Healthand 10 EnvironmentalEffects ResearchLaboratoryInstitutionalAmalCareandUse 11 Committe. Confirmed timedpregnant femaleCID-1mice (r=100)werepurchasedfrom 12 Charles RiverLaboratories(Raleigh, NC).Pregnantmicewerereceivedatthe US, 13 EPA's Laboratory AnimalCare facilityongestadatyi(GoDn) 14 (dayofsperm pitve 14 designasaGtDeA)d. Uponava,mice (appr12owexeksiolm)waeretweieghledaynd 15 randomlydistriambonugtPFeOdA eatmen groups.Theywere housedindividuallyin 16 polypropylene cages with Alpha-ri (Shepherd Speciahty Papers, Kalamazoo, MI) 17 beadndndesinig manterigal. Theywere providedpectedchow(LabDictS001,PMI 18 Nuiton Interational LLC, Brentwood,MO)andtap wateradlibitum (both contained 19 PFOA at concenuations below the LOD). Anima facies were controlled for 20 temperature (20-24C) and relative humidity (40-60%), an keptunder a 14:10: ight 21 dakcycle. Mice (r-2SHdose group)received theswatervehicleo asingledose(0.1, 22 1.005r.0mg/kg)of PFOA (in water 10 ug) by oral gavage on GDIT. 2
2202009
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t1I 2.3 ttmra---- Animal Asseasnds Sammple eConlletcts ion TA
A1DI gnath,f tn e DYE.m.o .d c1c5.0ndOotke ,eeoite
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1 cololnPeNDsc2,t8,1e1,adnd 18 following a 2b separation of tepups romthedam 2 and an oxytocin simulus. The milk was vacuum aspirated sin low, pulsatile pressure, 3 into 8 pre-weighed microcentrifuge tube. Collocted milk was weighed and frozen uni 4 analyzed. Biologicalsamplesinchingurine,damandpupserum, mao (id, 5 mammary isue, wholepup,andmilkwer analyzedfor PFOAusing themethods 6 described briefly below and in our companion paper [24]
7 & 2.4 PFOA sample analyses Briefly, the analysisofPFOA ws performed usinga Waters AcquityTM Ultra 10 Performance liquid chromlography sysem interfaced with a Waters Quattro Premier XE 11 ipl quadsupole mass specromeer(UPLC-MS/MS)(Waters,Milford, MA). iter 25 12 or50L ofserumandamaiotcfluid (50 kLwedorcon), 20 Laliquots ofwine 13 andmilk,40d300Lofpupormammary tissuehomogenateswer ulizedassiring 14 material for these analyses. Samples were extracted, purified, and concentrated os diluted 15 exactly sdescribbeydReineref al. 24], 10-40 uL. ofthepreparedsample,dependingon 16. the concentrationofthe original exposure, was nected and un on the UPLC-MSIMS 17 (24). Refer toReinertal. [24] for method performance and quality control cps that 18 wereperformed t insur theprecisionandaccuracyofthemethodsused.The limitof 19 quantitation (LOQ)forthese experiments were ng/ml (ser), | ng (smiotc hid, 20 urine,milk),and | ng/g (whole pups, mammary issue).
2
2
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. i1 2.3 am---- Urinary creatinine measures ----------TT--
3 urine. The QuantiChrom creatinine assay (BioAssay Systems, Hayward, CA) exhibited 4 anLODof0.10 ng/mland waslinearup to 300ng/ml.Thirtywlofeachurinesamplewas
5 wemtm------ preapndeavalruae teddat 510nmsingolriyn dup(lfivieducpliacattespeers set of 20 .B#"5+S m OStrr--itt nm--stteS--eefr tsr--ei--os--n--t----T--O--tNea--et----s 7 variation (CV) ranged from 4.0-6.8% and the intra-assay CV ranged from 0.3-16.1%, .-"*"#lseom O e memei--tT rm--15--31-- --t--_-- e -------- ----n---- --e---- 14 (ng/g; mammarytissueandwhole pups).Serum,amniotic fluid, milkandurinary
-- --
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| Res 2 3 Bloc Otome 3 Thisth ftsty oeponsinhe dose isposonof PFOAinprgoan and 4 tainmiceandtherffi Thedoses chen er basedanprevious epsin
:
5 CD-1mice 3, 14, 16]demonstratingdevelopmentalbealthoutcomesfollowingmultiple
6 gearsPFOAexposures.A singePFOAexposeon GDI di no afc he
7 numberoffive ese on GDI), impltaion sics, lvebo pups on PND) ox
5 dam body weight dt ot shown) Unlike dis sing mali gains PFOA
9 exposures (13,25),therewasno changeinpup bodyweight,damliverweight,and dam
10. er BW ros, wl he PFOA dos ans adminis is soy (Fig 1), The
11 risein damliver:BW ratiobetween GD18andPND, whichpersisutnetidlweaning,was
12. due othedmcdecreas inbodyweightot aon, is singletgsaon 15. PFOA expose fied o chang mean vrweight speddame,compared 0 contol 1 vac, ot ny me vated. is 16.3.2 ROA Cocenvatns Piro Birth 17 Themenconcentadon of PFOA inthe mio ida serumof he posed 18. dam 24br er xpos i show (Fie 2 nicTui cols average 3.8 gh 19. The svrae concntion of PFOA detected nda serumwassbowt wie te amitic 20 hid concen t cach dose cvautd amit uid was 6.3, 1.5, an 40% of 21 damm levels 10.1, and mg PFOAg BW,especialy. Acomparisotne 22 amoouf PnFOtA in an cote GDI fetus body idenpupsstadand ror ofhe msn 23 SEM Figure 5 tthe GDIR PFOA concen namie id (sgn suming
nono eo 2022
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n 1 tt volume) eves 2.3.3.1,ad2.700 cress PFOA inthe pupvee uid 2 inhi was contin n ro fo 01,1, 1nd mf os rope,respec. 3 4 3.3 PFOA Corcenvatons inthe Dams s ThescumandwinePFOAconcntionswere vatedindams htwere
6 nursing littersofapproximately 10 pups (PNDI equalized; minimal pup loss over time).
7 hs capeted, da ser coined he ighst PFOA cantons of any mats 5 cvaatd, epicsofdoe Figure 3; serum cons <LOG). The is in ciulting 9 serum PFOA with ceasing dam cxposrs ws proportions ote change nde 10. delivers, eps fsa of action i man 99-0 snd .- odnas 1 betwee0n1-10 mead10-50 mpg expose,epecively). 12 AonPcFOAiexpiosurme ofe0)my produced an vrs damseam PFOA 13. concemiation (Figure 3A) of 44226 nigh a1 24 snd 48 bales xpos, respectively, 4. hich was edd 1 30 vegof4 ng ca th peak f cation (PNDS), and bd 15. iscomcanaf123 g/mlby DIS, ie whe he pp'primarycarenshe 16. cam fom rodechnot nd nt ik The U-shaped seramconceuvneaotbsierovend 17 inthe .1 mg PRONG dose group was alo presen inthe |ad mh xpos 1 gu 19 AsshowninFig (0G;control rin ndmammary god PFOA <10G),
20 although the concentrations of PFOA cannot be compareddirectlybetween serum, urine,
20 ad mammary Guede tthe iffnce nis, i ws det ht aches PFOA 22 was beingexcretedindumwo tha was rstind sum, ndtamammary 25 dome contin considrble suntof PFOA, Whe U-shaped response in dam
270009 Pao 120132
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1 excretionofPFOA (urine) wasnotas pronouncedasthal ofserum, mammarytissue:
2 demonstrated astrong U-shapedresponse,withthelowestconcentrationsmeasurednear
3 thepeakoflactation,anda significantrieinconcentrationsppareotagainat PNDIS.
4 (p<0.05).
+5 rv om----i --or----e --errr--n e--n--r--e o-------- `Whenaspirated milk PFOAvalueswere evaluated(Figure 3D; 1control >LOQ), A 3 siksre---------------------- A BE RTA Aer are? J+ bwee--P1--0)--eg------rTn--c--t r-- = --s--n--i--rai--me------s ----"--i----n--m0 + cmormmee------------------r--s--t----------i + Patterrsamon B sesssnem--m--------------------43--" 70 Fc--n--mo--neao--rn--eo--oar--sSre--petee--te
-- peat
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1s 1 pip erm PFOAcomentionswersignifybigher han hoe eared nds, 2 regal of dose(0.05). houghppspss stil highersumPFOA 3 concnrionthn am he ifieceinppaddamblood ole hsesagsof 4 pop development sr considers, Regsof hose difernces bgt 5 cimalaing PFOA inpups refed increas expos, proportion doe 6 uoughout anionic. ean 10.404 0 43. mrssbene 1-10mp 7 0d 1050 megexpos pete), 8 Unlike heidam,pps did otdemons Ushapedsr PFOA
9
10
cohneceanvterantgieoancmurevers(mFiPguFrOeAc4Bo)c.PeunptsierounmsPaFvOerAicoen,cenntirlatNiIonDscownthineuedhetpoeuxpcaeedd
1 damconcnrionspoche 1:, When he PRO concen (sg)vascai
12. inwholepus upand on: Fg pecs) deinein PFOA concent was
13
14.
odfettehcetepdopvsewratsimseh,eancriostsacloldsolseersm.iHoonwtevoecr,wuhetnteheralpidalymincreaosfinPgbFOoAdyiwheieght
15 coasnshowntin Feie 1), completely dren rendwas med (Fire Sight
16. pach) Regs of pone dos, PFOAbodyburden (cused orweigh rose
17 ough hepeakof tation ddbg 0dein by NDI, desing
08 incre Ustedcurve,Whentheainistred PFOAdos ndmessedoy burden
19. inwholepps (dyweight ake itef)were compared seaiid
20. PRONmeanred PFOAmio was longerproportions sgh con, ad like
21 termi spud oda andpopsam PFOA.Me oyborden ios of 13.2.0
22 11170)a0 43.0 ong 25.1) cessbetween 0.1.1.0 mpgand10
3 5Omghg cpus, pecivly,wee dmind,
u
2200009
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1 | 4 Dicusion 2 Thesdoconim non concen bsdcomparison, gna 3 PRO exposed pups xii significant Lares seam PFOA od than tea, 4 Th bani erm PFOAkdinops was vdt24braf single cone, sd 5 was apparel dos o bod ore (spc) str. Anohermportdiocry
6 istheU-shaped PFOA concentration overtime, regardlessofdose, in the dammammary
7
tissesruuem,,maildk,waansdseevirduemn.tT0hissunirquceiPeFntOAinrheespdoansneswaisnyotdeextcercetteidoinncpuurpvseosrHpuopwer
9 whenROAbodybrn i ol ipws he itofmeasure ves sap
10. curvewas ppt, nd he PFOAbnpusspropos ccs doe tik
1 bome PFOA nak,
12 Thdctieincometcteoninnthemilk,marosyandsen Used
13. curve is ypthesized bed 0 yoGition soc with ces lodsnd
14 milk volumes. Svenpysloiaconditions re changed during tain ahve
15. benwel document int 0 ict etomics ei tion perdi of
16. sameeng. Adecease nolplas roti due to res od vole, cards
17 out, nd bod owtcrti iss chs hemammary gladhsbcrepre
18 int (26,27) Elev od volun be bo cased sma vl 27), Mik
19. itd 9) intsws por 1 echspe by PND 1027)ad he tammy
20
21
gland reaches
sis om PND
its maximum
S.15. Kot m
size (a5
arry
% body weight) by PNDIS 26),
gad od fo nd volume of
with
ilk
prod sc a steep rise in.
22 dicly etd, when mer on PNDLS (26) Tou sna prin re lover in
23 tio shot os msdn ncn is 27), in has, een
2000009
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n 1 bums concentration decreases ding pregnancy and aly ciation (28) Farber, a 14 2d postpartum,thecartaottofactin biswas 30%highstanh in on
3 lactatinganimals,andthemammaryglandwastheonly organshowntoincrease in.
4 weigh live to body weight [29 5 Abough complet ctof dathatcouldadresthe nateonfor he Us 6 shpedcurvesdrogavasnocollectedi thissay, he pried ilkweights 7 deve dramatic crs ilk vom sumed oe to weight hage) om 5 PND?up tbpeakof ction(PDI),Thisdramatic hinge i volume (weigh) 5 may cp he drs in lk PFOA concent se between PND? and PDI 10. PFOA seo spears concn inseruman ilknar heedof tion (PNDIE, 1 for cxampl) when poss cigmorschowsnd scl ssfe. Mammary lad 12. blood howbasbenreportedto dese byhalf 24hperiod,whensuckling 13 offing ar removed fom he dam 26), snd his lin amma lod flow is drcly 14 sso with cs cas ouput 4% lo flow udbytemammary lad 15 Toistudy prciptons drop in weigh of milk lected beente peso cain 16. and PNDIS was nord, dieing apdders nikvolume. Terrhe,U17 Shope aedmPFOAcawvr perosse bedivbeyphysiologicaldionsnd 18 conceniion fhe PFOA lod ver the periodof actin, aching ie reset dition
19 ator nearthe peakoflactation whenthemilkvolumeprod bytuhecdaemad nd
20 consumed by the pups is the rset. need consmpionofmilk up 0 PDI ily 21 diol conned othe sccumlationofbody burdeni the pup over is sng. 2 Aspifan consbofuiikohomne PFOA stern CD-1mic was 23 detect in these dics. Previons epost [2] ad humans (1) hve ested
220m009 Pago 170132
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= TERRE TE
i 1 he dam PFOA milks isbn ti as 0.1 and 001, respectively Tn he 2 prsotsy,the dissbution oange om ilymere han 00. i ice, 3 depeomndode,iwinth ghe owes doses stddemnsiztingtheihe os vr 4 time. milk PFOA concentrations bd ben mesure es he eso tao nly 5 Gy 1, be 0.1 milksers disbuion stmt previously pore for rs nic 6 lctnion 22]may ov so been rsd ein ie However, twopeesig 7 lotion ay and) spikes fcrmil seu tis ppd, regards of doe, with substan ek nikPFOAconcnraoson PND2. Alboughvolumes 5 ofmilecnoughto porto ayiamesses pri 0PND?wer sbi ob 10. ane, we suspect,basednthe sipifcnt PFOA cocenraions he NDI 1 mammary gan, ht substi ilk PFOA cocewnoudaaiv boes ncvisdnt on 12 NDa welIlpm,sl ue to being condensed insllmilkores. 13 InprveoinsboyLna [s13], Wol [16], Whi (14) andcoworkers, ders 14. body weight ain and const marly were cident an sever dy sf ihn 15 CD-1 mse itergesationally posed 103 mg PFOA an higher. Int, n 16. crossfoto say 16) demanirtingdese bodyweigh gai tSmg om in
17 utero exposure only, significant decreases in body weight gain were detected in the 3
18. mhdos rou nly whe nro posedmiceweress lowed ome om 19. PFOAexpos dam. Ev at me, here was no evden ofdeseppbody 20 weoir cgonht morality nthe curen sy, lewin single gestation PFOA 21 expose,Our PFOAmsc inwhospps dicate hathe OAbody ren 22 accumils incl i, nd begin dis pps mare, pe ei yc, and gin 23 oct chow nd ink water, Oedt snd hos demsring deletions ek
2202009
Pog thr 32
v.22
Fs
ETEIE ees eae
1 outcomessuggest thtthe ilkofstrayPFOAexpose micwas mor sores 2 ofconimd expo to his compoundfore developingpps. : Asexpec, arg iffecce indam andpopsumPFOAconcent om 4 hse previously reported (1, 16] wre noted an hos difrencosbog igh te 5 isu fig vs. multiple dos Kiet. A oe fos PFOS, single dose Kins my 6 ifr substantial fom those involving reper oss (30). Connon dependent 7 changesi cernce canes indisraisbeeen silan repeateddose. + kios 9 limi umberofrtemilgil ses hve revealedasocnionsbeween 10 heath ces ithweight,hedicumtrence) cond lodormeatsem
11 PFOA concentrationsinbum [20a ,21)n ,whs ileotherstudiesfailed todetectassociations
12 wil tr developer miso i fs 31), Sve sds hv mow messed 13 PEAASinhuman ik 17-19, 32,3), however oly oesoybas bsnl 0 14. apposite th milks latinsof PFOA wants 18) The report 001
15 (1/100%) relationship was determined from a single voluntarily contributed sample at 3
16. weeks postpartum. Acctheoosueinstu PFOA diibvue imoetnt
17 wereport herein,thevaluesreported inone hum(18a)anndrats (22)maynotbe 18 representativeofthe PFOA distribution to milk throughout lactation in those species.
19 Inconclusitohens,sis confmed and rer ened consider PFOA 20 capone to moe offing ll sine gestions pon. They sho 21 demand he camila hcl ove me in whole pups, ic ily css 22 fommilk home PFOA, 1 xpos ho bd prvisly ben caplet ascii 25 other A singe 0.1 mp PFOA expos bo prean mvss nocd
2202009
Pao 0122
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acterEbmanuscrEipEt
+ST rem------------------ ------ ...3+4+;.: eTrwn reem--r--it----ar--te--------s--T---------------------- 3 accidentally exposed via DuPont production plantemission (34). Becauseofevidence: +14 TvemreamTosCt--G------------------ The authors would like to thank Drs. Barbara Abbott (US EPA, Reproductive Toxicology
16 EPA)fortheirconstructive criticisms ofthismanuscript.Weacknowledgetheexcellent.
17 careofthese animals by New Year Tech, Inc. (Restin, VA).Theresearch in this article.
18 has been reviewed by the Nationa) Health and Environmental Effects Research
19 Laboratory, US Environmental Protection Agency (EPA), and approved for publication.
*-72 --e ive--- ------------ 20 Findingsinthisreportarethoseofthe authorsandapprovaldoesnotsignifythis report
roman
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1 References
423 Sth[1e]waprdsUihSi.p.PErnovgicrrpao.mngmobevynitoAapdlpmtPirinonitiseptcfrtoiaaotlnopruASbgtseelnppchfyeo,snAsLi.enJwoahrnndssoaohnin.p.u(A20con0ef6et)schsAeev2eda0i21lm30a1b/2le10e50aP9nt.FOtA
65 7
L1a2u), GWM.EOAlenn,J.dSceedLLrn.BduKst.eBne.bWoafnltlSa,.cCe.,CPheafnogr,oDsGl.iyFaarcmaird,sGaLn .rKeoeendncehJedrm.yiCi,.cs-
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(B4u)tcnhoGfWfa.ndOLlseRn,ZIoMbe.l,BuHrail,Df.J.oEfbsveersummaenl,imJiWn.tiFon oofpceihoAroMlo.citSaencaecsahu,fJo,Ln.ate,
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221095H2)u5n1g2er6bD.u.blTerr,udEset)iL,m.atHionrgocwiotnzs,uMm.eWoexrpmoustuhr,e1M0.PSFcOhSearnidnPgFO,T.AC,oRuisciknsAantn,d2K8. 2008),
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(Y6a)mashiKtSa., SGpecuis-sPnpMsi.gfMcacneagoe,,nN.cYaemoafnnpaektrsiSv,r.orMoaiaylaytzlacikonit,o.amTinnaannstis yinaanfsadru.m and
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3332118T)anabe,1PTeKorKlaonnva,n,oN.rKajoaiwnadorrae,csMiMtd.fuaCoorosncthaeGc,m.icFsaillsluminaslninba,.ftrToasoksaeshn,aslhetipahncedn5t.
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R11M0.) HGeWr.on2O,l.seMne,dDhCd.izaMadierh,kTaRsh.iC,Bh).uNrochb,ilME.tEi1l.,iRoino,s,W1K1.. BReuagtene,sTahMn.ed1lBo5lyd,
443 45
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&547
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ocLtanasoaJwitLes,RaBenugurlhbToeoxsildcfolna1PnMihda.,rRmogaTecroosl3,oT9,Ae(p2d0p0te4)Pv,h3ce6v3l-mo3a8pc0.lmt1ee9nnc(t3ya0o0lf9,
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11 inthemouse, ToxSci i,9c0(2o006l), 510-518.
1143 1156
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%21 restrictedgestational exposures, ReprodToxicol(2008).
5213 Se
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550 west rom EvoutenChaError36 Teil 30 B06 254392.
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53353%01C1So9mepvoLuTenusnm h,amKaanmmain, CroMm.MWonag,KsF.sAvUoSAa,ndEn1r.oBniSenoboftn,Pter4f3or3000,
25o3120(NeF)uOtSamBmJd.anAdeLpRr.eCsoFbRta.ne,WiCeorr(,Pd1F5Oe.rmHcootnicsmo,ustAiooMwn.eiCogfhapsrotl,wsoRUne.caHonalhen,EoLrnLri.ocr
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z 12 2p1os)luorCFiei,natdchIeKm.icMaclLsa:ugahsltiund,yiRnEt.heTDaraonnicsahnNdatJ.ioOnlacloi,FtehtCaogbroow,thAmindJicEaptiodresmainodl, 3` 1682008), 6672. 5& (Jr2.2P)erfPloMr.ooHciinadnoeartl:ePrlEa,c.eMntayl alndlcacSt.htAi.orGnaalnenaonnes,p1otr.:phBarmuacoekinaenntdicGos.Li.nrKtesn,nedy, 78 Toricology, 211 2005), 139-14. 105 di[s2t3r]ibutJiPo.n,VmaetnadbeolHiesumv,ealn,dBLl.imKiunsahtikiiosn,oMfJp.erVfhaonroRocaifaneoilcaagcnihddiRenEmm.alPeetaenrdsofne,mTailses:oe: 1n1 rat, J BiochemTosico, 6 (1991), 83.92 1143. [L24i]ndJsLatnRrdeioMneJmr., SSFu.ynNaark,aAynaamlyas,isAoDf.PDFiOnAkny,doLsPe.dSCtDanIkmoi,cSe.:E.PFaernt1t.oMne,thA.oB. ds 1156.. tdheevierlpouppmse,nRtepforrotdhTeoainacloylsi(s2o00f8)i.ssues andfluids rompregnantandlactatingmiceand u1n8 [25] BD Abbot,CJ. Wolf, J. Schmid, K.P. Das, RD. Ze,L.Hefan,S. 2109 dNeavkealyoapmmae,ntAa.lBt.oxLiicnidtysitnrotmh,eMm.o.uSsaeyinsadreapnedndCe.ntLaovn,ePxperesshsivonoorfpoeorocxaiicsiaodimnneoduicecd 221 proifeato activatedreceptor alpha, ToxSci,9c8(2o007l), 71-581. 2243 s[u2c6k]lingAo. nHmaamnmawraenybdlJlLolo.dLifnlzoewli,ntThheeerfaft,ectsPohfeysn2ig3,3o(1r973wg)i,te1h1m1mi-l12ke5a,nndotf 226127) K. SuzukiH,. HiroseR,. Hokao,N. Takemura and. Mooyeshi,Changes of 227 plasma osmotic pressureduringlactationin ats,VetMedSc, 55 (1993), 561-564 3209. d(u2r8i)ng aMn.dDaefatner,pBr.egSntaonccky,iRnJ.hPumaarnss,oCnloinnPdhGa.rLmeavcyo,lSTehrro,m 2p8ro1s9e8b0),i2n53-d2o6if1.dnrogs 332 [29] CS. Jones and DS. Parker, Mammary bloodflowand cadin output during 3334 iPnitihatedyi91nvso1l9u8it8i)on,o2o1f-t,2he5m.ammarygland i herabbi, Comp Biochem PhysioAl Comp 33s6 [30] LA. Harisand H.A. Barton,Comparingsingleandrepeateddosimetrydotafor 337 perfluorcoctsne sulfonate i ats, Toicol Let, 181 (2008), 148.156, 3409. (fe3t1a)l grCo.wF:e,asJtKu.dyMwciLthoiungthhelDiRa.nnE,ishTaNraotinoenaalndB)i.rtOhlsCeonr,Pte,rfElnuvcirrnoanteHdeaclhtehmiPcearlsspsenc,d 421 115.007), 1677-1682. 444D3. (T3w2)ardW.elVaoU,l.kReaOla.bGaenndaHe.l-FBroormomvei,caPeenrylH,o.rDoeocrtuamnccslumliphrCo,.naGteeb(oPuFeO,SB). nKodletzko, 4465. pEnevfiuroornoHoecatlatnh,oi2a1c1i(d20(08),P43i0n-F4h4u6mOanbeAastm)ilk: resof upillotstuds, IJnHytg
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