Document qLDq5Vd15JGbbkdDwN6E5KeM

AR A26 - 1478 A ASimmmpolen,iCuomnsPeerrvfaltuiovreooCcotmapnaoratteme(nAtPaFlOM)oEdxeplostourReeltaote Estimates of Perfluorooctanoate (PFO) Blood Levels in Humans Paul M. Hinderliter, Ph.D. Gary W. Jepson, Ph.D. DuPont Haskell LaborBaitoocrhyefmoircaHleaTlotxhicaonldogEynvironmental Sciences 10 October, 2001 S= 3582 so Es = 5 a DRAFT J Pe tario eoiessss & Gx004797 Abstract DAersfilmupclreonacnidancooantseer(vAaPtiFvOe)ceoxmppoasrutrmeesnttaolesmtoidmeatleswaosf pdeefvleuloorpoeodcttoanroelaattee (aPmFmOo)nium Cionnccleundtermateicohnasniinshiumofanphbylsoioodl.ogiTchael dmeosdcerliptwiaosnsb.asFeudrtohenr,kihneetimcopdreinlciwpaless.nobtutiintdeinddendotto tpehpylsaicoelotghiecanleededscfroirpmtioornse.roTbhuestmmooddeellisntclhutdeidnczleurdoe-omredcehranmiastthiecmiatnidcaaplprdoepsrciriaptteions of horealvaonldumienhsaloaftdiaoinliynwpauttear ncodansfuirmspt toirdoenrealnidmaiinatbiroeanthdeedscwaeprtieoun.sedSttaonrdealradteedstaiimlatienstzokfe oufndAePraFOvalroiectoyncoefnetrxaptoisounrseocfonAdPitFiOonsinaanid aunsdeddr1i0nckrienagtewaatearb.leTrheelamtiondgeAlPwFasOeixnetrackiesveida imondkeilngprowvaitdeer danedc/iosrioain-mtaokPerFsOwibtlhooadnceoancselnytraaptpiloinesd. tToohletsoirmepllaitceitAyPaFnOd uexipotsuorfesthtios estimates of resulting PFO concentrations in human blood. RAFT Page20f10 3 eoressoo ax004798 Introduction pAersfilmupolreocoocmtpaanrctatme(nPtFaOl)miondbellowodasfodlelvoewlionpgeidnahanldatuisoendotroiensgteismtaitoen othfeacmomncoenntiruamtion of Cpoernfsleuqoureonoccteaannoaaltyesi(sAPaFnOd)p.laTnhnienmgoadcteilviptrieesseanntdedisinoitntienntdeenddteod ctoombepalesmuebnsttitvuatreiofuosr a rloibmuistta,timonesochfatnhiesmmobdaesle,ditphsysiimoploorgtiacnatl tmoodcealr.efuIlloyrcdoenrstioderreatlhiezeasbsotuhmptthieosntsraenngdthcsavaenadts relevant to the model development and application. Approach Model Development: Tcohmepmaordtemlendtevdeelfionpeedd afsorthtehibslaopopdliccoamtipoanrwtmaesnattawnod-tchoempotahretrmeasntthoepbeondmyocdoemlpewirtthmeonnte. `toWhoinlleytohneemocdoemlpairstcmoennsttr(ubctleododacsoamtpwaor-tcmoemnpta)ritnmoerndtermo1d0eplr,ovtirdaensafecroonfsePrvFaOtiivse.confined ersetduumcaetseotofaPoFnOe-ccoonmcpenatrrtamteinotnsopinenblmoooddeflolwliotwhitnwgoAzPFroO-oerxdpeors-uirnep.utFpunrcotcieosnsaelslya,ndthoinse. cfiormspt-aorrtdemreneltimainndattihoenPpFroOcecsosn.cenItnroatthieornwionrdblso,oPdFcOaninsoctobnefirneedductoedthbeybtlhoeoddistribution of PbyFOthiisntmoodotehle,rabnoydyAPtiFssOuest.hatInisoridnegresttoedcoonrtriinbhuatleed0isthneotcosnusbejrevcatttoivediefsftuismiaotnaels produced rceosmipsatrantcmeenatn.d SisinacsesuPmFeOditsonboetcmoemtpalbeotleizleyda.nedliimnisntaanttiloynafbrsoomrbtehed ibnltoootdhiesvbilaoroednal esxcchreemtaitoinc. oIfntthheismmooddeellisthseheolwinmiinnatFiiognuries d1e.scribed as a pseudo first-order process. A - Em ' Figure 1.SchematicofPFOComparunerMosdaell. IanndFibgoudrye c1.omKpAarCtCmenisttsh.e dIishtarsibtuhteiounnictosefofficciaenyt,fbourttraasnsdfiesrcoufssPedFeOarbleietrw,eietnitsheetb0lozoedro DRAFT Page 3010 i. W Eisesor GK004799 diensocrrdiebre0PFcrOeaitnepuatcoinnsteortvhaetbilvoeoodnceo-mcpoamrptamretnmten(tugm/oddaeyl). viKaUthPeOoriaslarozuetre.o-oKrUdePrLtiesrm3 to Zero-order term (0 describe PFO input into the blood companment (ug/day) via the idnehsaelnabtieosnrreomutoev.alKoEfLPDFMO ifs raopmsetuhedbolfoiordstc-oormdpearretlmieminntatviioanrceonealffeixccireenttio(nd.ayD)iftfheartential TSaotleveeqduuastiinognsAwdevraencdeedveCloonpteidnuforuosmStihmeuslcahteimoantiLcanignuFaiggeur(eACLSaLn.d tAheegiesquCaotriopn)s.wTehree cmaotmhpeamnatmiecnatl (eqCuBatLiOoOnsD)usaerdetsohdoewscnriibnethtehsecroinecsoenfterqautaiotnioonfsPbFelOowi.n the blood 4 - KPO + KUPL - KELIM * CBLOOD* VOL - RAF w 4AB =(KUP+O KUPI - KELIM * CBLOOD *VOL - RAMFi @ [2 4aB= (KUPO + KUPI ~ KELIM * CBLOOD*VOL - RAiFt @ B=] (KUPO + KUPI ~KELIM * CBL*VOOL-ORAFDYt @ CBLOOD =ABIVOL In the equations above, AB istheamount (ug) of PFO in blood, is time (days). VOL is the volume (ml)ofthe blood compartment andRAF(ug/day) is the rateofPFO `'mAoCvSeLmceondtibnegtowfeethnetahbeobvleooedquaantdiobnosdiys cgiovmepnaritmmmeendtiast(eRlyAFb=el0oiwn atnhidsimnodAeplp)e.ndixTh1e. The corresponding ACSL command fill is provided int Appendix 2. RA=KUPO + KUPI - KELIM*CBLOOD*VOL - RAF ) (CBLOOD=INTEG(RA.0.VVOL @ Model Input Assumptions/Descriptions: Blood Compartment Volume: The blood volume of 3.5 L used in the model was that of 2mFua5ni0cnt-tiaKoignnhotfuhmbaocndoyn(sawevereivrgaahugtvee5h0auplmpaarrgnoearfcebhmodadelyseiwrweeeiidggfhhottr)s.twhiiTlshlmeeoqdfueealmt.aelOteobwvleiaiorgughesrtlybw,laobsoldsoeovldoelcvutoemldeustm.oePisF3O concentrations in blood will therefore decrease for a given APFO exposure as body weighs increase. Elimination Rate Constant: The elimination rae constant, KELIM, was assigned a value of 0.0019/day. This was derived assuming a PFO half-life (ty2) in humans of 365 dpalyacseadnidn tthhaet2f0ir0s-t3o0r0dedrakyinreatnigces,atphpely3.65W-hdialyehcaulrfrleinfte hisuamcaonns`eharlvfa-ltiifveeesvtailmuaetefsorairnetial model conditions. The actual valueforKELIM was derived using the relationship bobeetyweede.n the half-life and the elimination rate constant where first order kinetics are. Keum = 2n2 oRAFT Pagedof 10 eotessoz s aK004800 cInopnuvteorftAetPdo FmiOcrvioagrDarmisnk(uign)goWfaAtPeFr:O Dirnigneksitnegd wpaetredracyonucseinntgrtahteioansssoufmpAtPioFnOthwaetre Sdokprionsigmawtaetleyr2coLntoafitnhienwgat1 epraarrepecrobnislulomned(pppebr)dAayP.FOAnwaesxacmopnlseufmoeldlows where pbp=7plugs, LlBg Bn2LLetJugu ImnipcruotgorfamAsPoFfOAvPiFaOInahbasloartbieodn:inItnohatlheedbcloonocdenutsriantgiothnes aosfsAumPpFuOiownetrheatcoanpvperrotxeimda1t0ely 2'0APmF'Oowfaaisrainrhealebdr.eathed per day. An example follows where air containing | ug/m' Lluugg mw J2do0ammy''__ 22d00auuygg "= 10 `General Assumptions: "2Thsuebsstiimtpultee mfoodarelmodersecrriobbuesdt,hmeerechisandiessimgbnaesdetdo bpehycsoinosleorgviactailvemoadnedl.is nCootnsiinstteenndtedwittohbe the cesign of this model, several general assumptions have been made. "Y(o 2(1) TThherPFiOiisdmisatriabubtedooonlflysFiOnmt.hehumanblood comparment. "ns `ok'(a4(3)) ENloimbiinnadtiinognoorccmuercshabnyisastiincgdleescfriirpstti-oonrsdearrpeaitnhcwlauyd.edIinisthleikmeolydetlha.t eliminat--ion~,Nagy, afcotlulaolwleyddibsypalsalysobwipehoarrsitcecrlmiimnianlapthioansewietlhimainnatiiniotni.al Irnapoirddeelrim0ibneatcioonnspishtaesnet 1. * I (5) weAlililmhAinhPaeFticoonnnsiehrivncactliuovtdeem dnian tthoeg ufmrtodheeilmd n.oidnegl,ownalytetresstlaownl(yeramnidncao)mpphlaestelGyracy "<n rea? (6) aAbPsForObeedxpionstuortehse blood occur ecvoemrpyardtamyetnhtr.ough$oAutvtuhde texoposu*re period modeled. Seda Results "APTEPheOFsOiinmautrhleeasthheudomwPanFnOinbolFedivyge.ulrstehien2.shiuAmmsualwantoibuollnodoibdlleurseetsxrupaltetecistntgehdaftrbaossmteeradedpoy-ensatttahetedeeiPsntgFeiOsmtabitloeondoodhfall6fe-vuleiglf/sedaoarfye rCeiamcihneadtioonnlyofafPeFrOrefpreoamietdheexbploosoudroenfcoerPovFeOr l6eyveealrssa.reFaitgsutreead3yisstaatseimaunldatPiFoOn oefxpthoesure is terminated. DRAFT Pagesof 10 Eress03 ax004801 Fre 1. Sedm PEO Cm earteros awi nFsu Bld Fling aI i Eorssysweat| INET ee ETT { os afcT eTISRa MANE ees is+s | gP e e FE aREINS, | CE Ee E iw: DEm ERE = = = = Fe. Saadn PFOCosEgpraeosr n10HcamgaasyBAlooOdDin ndAer Nr TO a= le WW 1E 7D S A iBee ntpea moeyt sTA gT s g ra, I ar ee RE. . Jeu ee TR at i or ne RECA SUI ih + re em = = =~ ores Pesaro -- 7 Gxo04s02 lAesveerlisersesoufltmiondgeflrosimmdurliantikoinnsg wwaetreerrcuonnttaoiensitnigmaAtPeFtOh,e sbtreeaadtyh-isntgataeifhcuomnatnainPiFnOg AblPoFoOd or CaorembsihnoawtnioinnsToafbtlhee1.twoT.abTlhee 1recsaunltbienguseesdimuantdeesrtohfePcFoOndciotnicoennstrdaetsicornisbeidn ihnutmhae nexbtl,ootod 2c5o5n1tganinainPgF|OpbplbooAdPcFonOcewnatsractoionnsu0meadpaarntdicnuolaAr PexFpOosuwraes. pErxeasmepniltnet1h Ifidnrhianlkedinagi,wattheer Tesulling sicacy-state PFO concentration estimate in human blood would be 0.30 ppm. Ethxeaminphlaele2d: Iafir,notheAPreFsuOltwiangs sptreeasdeyn-tstiantethPeFdOricnoknicnegnwtartateiroanneds0t.im0ateugi/nmh'uAmPanFOblwoaosd in wobeu0.1l5ppdm. Exampl3e: If APEOwas present in the drinkingwaterat ppb and ibnlotohed waiorautld b0.e3 u1g./2m0',pptmh.e resulting steady-state PFO concentration estimate in human Teaxbploseu1r.etEostAiPmaFtOedvhiaumaiarnansdtleaodryd-rsitantkeinPgFwOatberl.ood levels (ppm) following per billion APFO adrinking wate SL 2 5 4 5 6 _1_8 9 To 5 0 _w 53 ou [00s] S0.TT 55% vidoe E oSoEpCEfOoE NmI"TyrsASa.s P1O9RR TREBA"Tt1Eh35or 22485sG3aiRe IssP s SE sEA 112210) = |orofo30 oes. 098 "iz. 25FH07 HD TAD 27030071331 "esl WR 1232 5 ffooumsfhoosuos o0s7e%s 1rd 87Tais"hTnaarnri pFosos2200571 2T55h.2085 331d6 vae6. E4N9E 0 SM 11224672 : 25 J|ooo]ch05i0a- oe120s0)8% eLas pdoyo 20284d proewt2M 202-u300a s23s5a.rsIoka23p91x EEINEI0G2H2 11220:2 : osoff EONSTRLAFS FREI est tow 21 451 BRER 1052 1352 Loo SRR S67 3913 41E " ERREEO 1202 1502 2300008} oof 1202 ios 1232 1262 BENET 1292 (022 1322 1052 1352 1082Fi1112 1382 1412 [ER1C42 1442 1172 TE12T02 1472 102 1103.5522 1633 11580032 2103 2118..0033 2604 FFFOBBlloooodd veespsrhsa orcpotposrnan cal 105m * Udseeosf cthiirsntitabhbleetereexdqtu.ires careful consideration of assumptions and limitations Discussion Arelativelysimple and conservative compartmental model was developed and exercised tocreate an estimate of the PFOconcentratioin human blood followingexposure to ArheePlaFctOoinngsiAtnrPdaFriniOtnskoifnxgptohwseautraeesrssautnmodpe/tsoitroinimsnahtaaenlsdeoddfeaissrct.reiaTpdhtyie-osnmtsaotdpeerPolvFwiOadesbdltoihnoednthcuiossnecrdeepnot0rrtac,trieaoanvtsae.raitetaWybiltoehfin DRAFT PageTo 10 Eo1s6605 8 GK004803 ceoxnpcoesnutrreatcioomnbiinnabtliooonds. cthoeulmdobdeelevcaoluuladteadlsuosibnegutsheedmtoodCerle.ateGiavpelnausisbpleeciefxipcoPsFurOe hSycpeontahneotitchaalt sctoeualddy-psrtaotdeucPeFtOhecoonbcseenrtvreadtiPonFOofb5lopopdbleivnebl.loFood,rethxeamcpolrer,eispfoonndeinhgaAdPaFO exposure estimate using the model would be approximately 16 parts per tilion (pp). "aTnhaelymsoisdeolr palnadnanpipnrgoaacctihviptrieess,enhtoewdevinert,hisitrsehpoourltdmnaoytsbeervvealausabalesufbosrtciotuntseefqouremnocree prorbeussetntmeedchhaenriesitsicb,aspehdysoinolsooguicnadllcyombpaasretdmmeondteallsaanaltyhseiys pbreicncoimpeleasvaainldabilsee.xTchleusmioodvefel cmoencshearnviasttiivcoerapshsyusmipotlioogniscaanlddetshcerriepftoiroensis. lAikseldyistocupsrsoevdideaerlhiiegrh, ethsitsimmaotdeeslofisPbFasOed on `cSoinmcpelnitcritaytiaonnds uitnilbiltoyoodf tfhoilslomwoidneglipnrgoesvtiidoenodreciisnihaolna-tmiaokneorfsPaFnOe.asiNleyvearptphleileedstso,olthteo relate APFO exposures to estimatesofresulting PFO concentrations in human blood. DRAFT sin Pags8of 10 Ei166808 a GK004804 Lo Appendix 1: ACSL Model Code PIRMOODGERLATMO SIMULATE PFO BLOOD LEVELS FOLLOWING ORAL AND. IVANRHIAALBALTEIOTNIMOEF APFO. TIAL {SCYOSNTSETMANOTFSICNATNERBEESTGIVEN VALUES TO SIMULATE EXPOSURE AND CCOONNSSTTAANNTTKKUUPPIO~~ ==00.. CCOONNSSTTAANNTTKKEALCICM ~~ =<00. CCOONNSSTTAANNTTVVFOL ==II. ""ZZEERROO OORRDDEERR OIRNHAALLUAPTTIOANKUEP(TugAdKaEy)(up/day) `{FFIIRRSSTT--OORRDDEERR EDILSITMRIINBAUTTIIOONN(TdaOy)BODY (day) 1!BBLOODOYDVVOLOULMUEME(m(im) ) TIMING COMMANDS CCOONNSSTTAANNTTPTOSITNOTPS +=3366%00.. CONSTANTTOFF 23650. LNOE.NGOTFPHOOIFNETSXPIONSPULROET(day) END OF EXPOTSIMEU(DRAYES) CIENNTD=.TSTOPPOINTS {ECNODMMINUINTIICALATION INTERVAL DYNAMIC ALGORITHM IALG=2 DIFE(RTIIVMAETIGVT.ETOFR) THEN KKUUPPOL==00.. BD FTERMT(TIME GETSTOP) R{AC-OKUNPCOE+NKUTPIR-AKOTEFLIPIOFMNOCBINLTOHOEDB*LVOOOLD-RCAOMFPARTMENT (g/day) CBLOOD=INTEGRA.0 VOL R\ACFON=CKEANCTRCAHTCIBOLNOOOFDP*FVOOILNCTFHVEFB)ODY. CF= INTEGRAFOOWE. EENNDD EENNDD DDEYRNIAVMAITCIVE eo DRAFT - Page90r 10 etsseor 10 GK00480S . Appendix 2: ACSL Command File for Assigning Appropriate Parameter Values TSTOP=10+365: POINTS=50: TVOOFL=F3=5T0S0T:OP+1: KACC=0: KELIM=00019; KUPO=2; KUPI=6: Keyboard figure: lHiInSe(T_AtiRmTe, _cblood, @linestyle="+"); _cblood(POINTS) slabel(Time (Days): {yliatbleel((BCLonOcO.DiCnObNloCoEdN(TugR/AmTL)I)O:N): DRAFT . - Page 10010 , 1 Entessos GK004806