Document 99dLRpb905Yv61wx9yeJg51DV
Al226- 1734
Study No. T-6295.31; ST77 AN INVESTIGATION OF THE MECHANISM OF TOXICITY IN ADULT RATS EXPOSED TO HIGH LEVELS OF PERFLUOROOCTANESULFONATE
(PFOS).
Study Location: 3M Strategic Toxicology Laboratory
Corporate Toxicology 3M Medical Department
3M Center, Building 270-SB-314
St. Paul, MN 55144
Study Director: DeannJa. Luebker, M.S., Senior Toxicologist 3M Medical Dept.3M/ CCoernptoerra,tBeuTiolxdiincgol2o2g0y-2&E-R0e2gulatory Services
Saint Paul, MN 55144 Ph: 651.737-1374 FAX: 651-733-1773
=
= 88 = S58 NOE j t) o
Laboratory Management: John L. Butenhoff, Ph.D., CTH, DABT, Staff Scientist 3M Medical Dept. / Corporate Toxicology & Regulatory Services 3M Center Building 220-2E-02 Saint Paul, MN 55144 Ph.: 651-733-1962, FAX: 651-733-1773
Sponsored by 3M Specialty Chemicals Division 3M Center Bldg 236 St. Paul, MN 55144
Page Lof 14
Study Objective
T.629F5in.a3l1;Re5p7o7r7t
`(TPhFeOoSb)jeccatuisveesodfathmiasgsetutdoymwuassclteo miintveoscthiognadtreiat,hephoyspsoitbhlyesliesadthiantgPteorfrlhuaobrdooomcytaonleyssuilsfoannadtel.actic pacriedcoispiistoautstdoexcilcienxepsoeseunreinlpevreilosr. roTdheinstmaanyd epxrpilmaaitne tthoexirceiltaytsivteuldyiersapaisdwoenlsleatsopfrtoovxiidceitiynsaingdht in 10 the mechanism by which PFOS decreases viability in the neonatal rat and mouse.
Methods Summary
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LAnaibmGalLPRePvrioegwraCmomPmriotcetdeuere(3(3M).LAAlRl Cin)-laifnedparroecededtuarielsedweinreanaipmparlovuesdagbeyatphpeli3caMtiLoanb2o0ra0t1o-r0y182
(4). 2).
Details
of the
study
methods
can
be
found
in
the
study
protocol
and
protocol
amendment
(1,
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as it was
has been designed
demonstrated to investigate
to cause toxicity in previous the mechanism of toxicity, a
rodent studies and, because toxic dose was required. In
this the
study original
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t(ohuhnucmhainneglayneduetxhtanriezmeealleltahnairgmya)lsanadt 2s4e-vheoruerdsiaprorshte-adoisnetdreuaetetdoasniigmnaslso.f pAaliln aannidmadilsstrweesrse
eInutahdadniitzieond,vuirainCeOs2amapslpheysxifartoimon6.raPtlsapsemra,dolsiveerg,raonudp kwiedrneecyoslwleecrteedcoalplpercotexdimfartoemdc2a4c-hhoaunrismaalf.ter
dosing
`Pmlyaosgmlaoblianc,taptlea/spmyrauvmaytoegrlaotbiiosn w,earned epxlaamsimnaecdreaastainmeakriknearseof(CmiKt)ocwheornedreixaalmidynsefdunacstimoanr.keUrrsionfary cmhuesmcilsetrdyam(acgheo.lestDeuroel,toblloimoidteudresaamniptlreogseizne,(BaUdNe)c,isainond wpaotsamssaiduem)toaneldiPmiFnOatSeatnhaelyclsiinsicfarlom the original study design. No analysisofliver or kidneys was performed.
All results were compared between treated and statistical differences using the students T-test.
control
animals
and
analyzed
to
determine
Results
TArseaetxepdecatneidm,alwse,ighhotwelvosesr,walsostobssiegnrivfeidcainntlayllmaonriemawlse,igrehgatrhdalnescsonotfrotlreaantimmeanlt,s f(oPl<lo0w.i0n1g)daonsidng.
etrxehaitbeidterdatssi(gPns<o0f.d0i1a)r(rTheaabl(eTaIbalend1
and Figure 1). Figure 2). All
Liver values
weight was significantly increased for plasma and urinary myoglobin
in were
below the detection limit of ug/L and 1 as lactic acid) was significantly lower in
mg/L. treated
respectively (Table 1). animals than in control
Plasma lactate (measured animals (P < 0.01)
Page 20f 14
T629F5i.n3al1:Re5p1o7r7t
(Table (Table
1 1
and and
Figure Figure
3), 4).
wDhuieletnoothseigdneicfriceaansteddipflfearsemnacelawcatasteoblesveerlvseodbisnerpvleadsmian
pyruvate levels treated animals,
tahnedpFliagsumrae l5)a.ctPatlea/spmyaruCvaKtelreavteiloswwaesresisginginfiifciacnatnltylyloiwnecrre(aPse<d0i.n0t1r)eaintetdraeantiemdalasniamsalcsom(pTaabrleed1to
control animals (P <0.01) (Table 1 and Figure 6).
Discussion
`inThCeKdiaisgnuossuiaslloyforbhsaebrdvoemdyo2l-y1s2ihsouisrsmaafdteerpmruimsacrlielyinfjruormy wmietahspueraekmecnotncoefntcriartciuloantsiongccCuKrr.inAg rise
within before
1-3 days a rise in
and a decline CK and drops
after more
3-5 daysofinjury. rapidly than does
Serum myoglobin usually increases the concentration of CK. Myoglobinuria
is
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high, the urine may take on a red-brown or cola colored appearance (6).
eIfnfetchte chuarsraelnstosbtuedeyn,osbisgenirfviecdanitneplreevvaitoiuosnlsyinpeprlfaosrmmaedCKPFwOeSreanodbsaemrvmeodniinutmrepaetrefdlaunoirmoaolcs.tanTohaitse
`(mAyPoFgOlo)bipnricmoautledsntoutdibese.obDseesrpvietde tbheicsaeuvsiedaelnlcmeeoafsumruescdlvealduaemsagine,treelaetveadtainondscoofnturroilnaarnyimoarlsserum
wwearsenbotelpoowsstihbeleli0mitacocfurdaetteecltyiomne.asPuorsesimbyloegelxopbliannalteivoenlss aorretthhaatt,adruatc-stpoecliifmiicteadsssaaympislenesciezses,arity.
The assay used `human samples.
in the current In addition,
study was the sample
not specific for collection may
the rat, but developed for use have occurred after an initial
with rise and
fall
ninotciarkcuelaotninagrseedr-ubmromwynogcloloobrinaslwevoeulsl.d bHeoweexvpeerc,tetdhewiutrhiniencorfetarseeadteldevrealtss oinf uthreincaurryremnytogsltoudbyind.id
Blood lactate/pyruvate mitochondrial toxicity
ratios are widely used (7). Despite previous
as a noninvasive observations (see
test for the detection study background in
of the
protocol)
tshuigsgsetsutdiyngdtohantotPFsuOpSpomrtaythcisauhsypeotmhietsoicsh.ondIrniaadldittoixoinc,itty,hetdheeclraecatsaeted/lpaycrtuavtaetelervaetlisosobmseearsvuerdedin in
tthhiiss,sittuidsyobdvoiroiuotsstuhpatpoirrtritthaetihony/psottrehsessioscctuhrast iPnFPOFSOtSretartemaetnetd alenaidmsaltso ltahcatticcaaucsideoseilse.vatDieosnpsitine
fcirracnuklarthianbgdloemvyeollsyosfisC,K.andIttihsatpoisfssiabmlpeltehdatatthae laantiemratlismeinptohiinst,stwuoduylhdahdanvoetsyheotwpnroignrcersesaesdedto
lactate and lactate/pyruvate ratios as expected.
Conclusions
`mTohreibruesnudlittsyo.fTthhiisssstuupdpyorsthsotwhethhaytpPotFhOeSsicsatuhsaetsmaunscilnecrdeaasmeaginepolcacsumras CinKPlFeOveSlstrperaitoerdtroatosv.ert
Bneoccaounscelunseiiotnhsercaurnibnaerdyrnaowrnplaansdmfaurmtyhoerglsotubdiinescoaurledrebqeuidreetdecttoedinivnesctoingtartoel tohrestereeantdedposianmtpsleass,
well as Future
10 explain the studies should,
increased CK levels if possible, utilize a
observed in rat-specific
this and other PFOS and APFO studies assay for urinary and serum myoglobin.
Although expected increases in lactate and lactate/pyruvate ratios were not observed, further
Page 3of 14
T629F5in3a1l:ReSp7or7t
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levels. tis possible that rhabdomyolysis. It may
btehemaonriemaalpsprionprthiiastesttuodiynvheasdtingoatteyetthepsreogernedspsoeidnttso
frank by dosing
at
lower
levels over a toa state of
period of days to reach overt rhabdomyolysis.
the
same
cumulative
dose;
thus
allowing
for
the
progression
Page dof 14
List of Tables and Figures: Table 1: Raw data Figure 1: Body Wight Change (day 0- day 1) Figure 2: Liver Weight Figure 3: Plasma Lactate Figure 4: Plasma Pyruvate Figure 5: Plasma Lactate/Pyruvate: Figure 6: Plasma Creatine Kinase
T629F5in3a1l:ReSpTo7r7t
Page Sof 14
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oo References
7629F5in3a0l:Re5p7o6r9t
1.
3M 7
Medical
Department,
Corporate
Toxicology
Protocol
for
Study
No.
T-6295.31 ST-
2. APenrfilnuvoersotoicgtaatinoensuolffothneatmee(cPhFaOnSi)s,m20o0f1.toxicity in adult rats exposed to high levels of 3. 632M95M.e3d1icSTa-l77D.epAarntmienvnets,tiCgoartpioornaotfetThoexmiceoclhoagnyisAmmeonfdtmoxeincitty#1in faodrulStturdatysNeox.poTs-ed to
high levels of Perfluorooctanesulfonate (PFOS), 2001. 4. S3tManMdeadridcOaplerDaetpianrgtmPernotc,edCuorrepo(rTatOeXTSoOxiPc)olNoo.gy0Str9ate5~gGicL0TPoxPircooglroagmyPLraobcoerdautroer,y1999. 5. 3MEMCLHaAbNAInSiTmaIlCRReEviSeEwACRoCmmHitItNeTeIAMniEmDalPURsEaGgeNAApNpTlicPaRtiEoGn NNoA.N2T00R1A-0T1S82A,ND
MICE - AMENDMENT TO AUA # 2001-0182, 2001. 6. iOnmhiabritMor.sA..,AnWniallssonofJ.PPh.,aramnadcCotohxeTrSa.py(3250,011)09R6h-a11b0d7o.myolysis and HMG-CoA reducatse 7. DanedPGihneireaurxdiG.,R.Ch(1a9r9i6o)t. P.L,iApmidm-il-oSwaeiridngM.d,ruLgosuaanmd Fm.,itLoecjhoonndcrJi.aLl.,fuAnscttiieorn:A.,EfJfaeccottsootfB.,
BHrMJGC-lCinoAPharerdmuacctoalse42i:nh3ib3i3t.o3r3s7o.n serum ubiquinone and blood lactate/pyruvate ratio.
Page 130f 14
!
Signatures:
Prepared By:
rr
Deanna Luebker, M Study Director
Reviewed By:
Glo 2. Cuiloteot
John Butenhoff, Ph.D. DABT, CIH
Laboratory Management
<
Dan Hakes
`Sponsor Representative
T-629F5in.a3l0;ReSpTo6r9t
04Lazfz004
Date
o1/23/200y
Date
9%/393/0
fue
Page ldof 14
