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July30,1998 Faxto:Dr.JackMoore Dr.Joe Rodricks Fax # 202-289-8530 Fax # 703.516.2393 Frorm John L.Butenhoff Fax # 651.733-1773 Tel # 651.733-1962 I have attachedourrationalfeordose settingon thesixmonth chronicoralstudyof PFOS inCynomolgus Monkeys. You willalsofindattachedthereportfmm theenvironmentallaboratoryof serum levels forthefourweek rangefmder ammals. Serum levelsarereportedfor days-7,2,3, 14 and 29. We have done an analysiosf the slopesof the cumulativedose vs.serum concentrationfortheserange finderanimalsatthe low dose of0.02 mg perkg perday. Thisisalsoattached. By theend of theday,we willhave an analysisof the slopesfbrthetwo highdose animst, I willfaxthatto you when available. The interestintghingtoknow from thisanalysiisstheextreme linearitoyf thecumulative dose vs.serum concentratiorl We willneed to produce new chartsbecauseof a slighetrrorinthedataanalysisF.or example: Ifa serum valueisreportedforday two, therehas onlybeen one dose since collectioonf serum isalwayspriorto dosingon the&y of serum collection. The valuethatI stateintherational(e5.8ppm PFOS in senun per I mg perkg ofPFOS dose),has takenthatfactintoconsideration. We lookfbrwardto discussintghisdose-settinegxercisewithyou on August 3,at 5:30 pm (Eeastem)duringour conferencecall(Dial-I#n (303)633-6052). to Dose-SettiRnagtionalfeorSix-MontChhronicOralStudyinCynomolgusMonkeys Preparebdy JohnButenhoff July29,1998 RecommendedDoseGroups:0.00,.02,0.a1n5d0.75mg/kg/day Rationale: ResultosfanalysefsorsenircnoncentratioofPnFsOS fromthefour-weerkangefmder (attacheds)uggesta highlylinearelationshibpetween totalaccumulated dose and serum concentrationA. significanmtale/femaledifferenciesnot apparent.The consistencyof theratiof serum [PFOS] tototalaccumulateddose ateitherdose leveland alltime pointsgivesconfidenceinusing thispreliminarydatato setdose levelsforthesix-month definitivsetudybased on estimatedserum concentrations. The dataprovidedby theEnvirom-nentalLab suggestthatserum PFOS concentration increasesincrementallwyitheach dailydose ofPFOS indirectproportiontothe magnitude of thedose. The datagiveus a good degreeof confidenceinderivinga factor relatinagccumulateddose inmg/kg to ppm PFOS serum. This relationshispuggeststhat I mg/kg resultsina serum PFOS concentratioinncreaseof approximately5.8 0.39 ppm. Assuming thatthiszero-orderaccumulationkineticwillhold atthehigherdose overthecourseof a six-monthstudy,thisallowsus topredictserum concentrationtshat would be attainedwith chronicdosing.The apparentprecisionof thisisinvaluablein settindgose levelsthatwillresultinserum PFOS concentrationwshich can be compared directltyo known human serum PFOS concentrationfsorriskcharacterization. In additionw,e now have thedatatoestimatethesenun concentrationtshatwere associatewdith effectosbserved intheprevious90-dayrhesusstudies.Going back tothe origina9l0-day rhesusstudiest,heLOEL, which we believeto be closeto a NOEL, of 0.5 mg/kg/day would have resultedinan estimatedsenun PFOS concentratioonf 261 ppm. At the1.5mg/kg/day dose,783 ppm would have been attainedafter90 days. Death resultedwithinseven weeks of dosingat4.5mg/kg/day,which isnow estimatedtohave produced senun PFOS concentrationosf approximately1305 ppm. We have thefollowingprimaryobjectivefsorthesix-monthstudy:1)toestablisah NOAEL forchronicexposure;2)todeterminethresholdeffectsforhealthsurveillanc3e); to providea fi-ameworkforinterspeciecsomparison;and,4) toprovidea referencedose forhuman riskcharacterizatioInt.isnotourobjectivteo studyhigherlevelsof exposure which would resultinseriousillnesisnthetestmonkeys. Dose levelsforthesix-month studyshould be setto allow us to achievethestatedobjectives: Low Dose: The low dose needs tobe a confu-medNOEL. Ifwe usethelow dose from therangefinderstudy,we expectto achieveapproximately21 ppm PFOS intheserum of thelow dose animalsattheend of sixmonths. Afterthefirsttwo weeks ofdosing,the animalswillbe atand above theaverageserum concentratioonf our workforce.At study term,theseanimalswillhave serum concentrationtshatareapproximatelyan orderof magnitude above averageworker serum concentrationsW.e are suggestingthatwe keep 0.02mglkg/day dose as our low dose. Mid Dose: The mid-dose isthemost problematicfrom a dose-settinpgerspectiveF.rom therhesusstudy,we know thatminor effect(squestionablseignificanceo)ccurredat0.5 mg/kg/day over90 days. We estimatethatsenim concentrationasttermwere 261 ppm. Ifwe use thisserum concentratioans a referenceforsettingdose on a six-monthstudy, we would assume thatsimilarserum concentrationwsould be reachedwith0.25 mg/kglday. From a riskcharacterizatipoenrspective2,61 ppm senun PFOS istwo orders of magnitude above averageworker serum [PFOS] of 2-3ppm. Achievinga NOAEL at thislevelof exposurewould be desirableh;owever,confidencethat0.25mg&g/day would be a NOAEL isnot as highas confidencethat0.15 mg/kg/day would be a NOAEL. The S.C. Johnson Wax 90-day drinkingwaterstudyinratsyieldedreduced senim triglyceridiensmales at0.3mg/kg/day. Females had increasedliverweightsdown to 0.06mg/kg/day;however, we know thattheratliverespondsmore thanthemonkey to PFOS. Settingthen-iid-dosaet0.15 mg/kg/day would achievean estimatedserum PFOS concentratioonf 156 ppm attheend of sixmonths. This serum levelisstill reasonablyclosetotwo ordersof magnitude above averageemployee serum levelsand closetofourordersof magnitude above currentlyunderstoodgeneralpopulationvalues. Therefore,the0.15 mg/kg/day dose seems to be thebestfitforthemid-dose. High Dose: The highdose shouldbe designedto producethresholdeffectsA.fterone month of dosingat2.0mg/kg/day (resultinign an averageof 306 ppm PFOS inserum), themale and femalerangefindermonkeys (one persex)demonstratedtheexpected reductionin senun cholesteroalnd triglyceridewsh,ich appearsfrom mt and monkey studiestobe an earlymarker of biologiceffect.There were no remarkable histopathologiecffects.Even though therewere no major disturbanceasfterone month at 2.0mg/kg/day,six-monthsof exposureatthisdose isnow predictedtoresultin lethal body burdens.The rangefinderdatatellus thatthresholdeffectbseginto occuratserum levelsapproximating300 ppm. Using theserum concentrationesstimatedtohave been produced inthe90-day rhesusstudyby 1.5mg/kg/day (78)'ppm) as a referencea,0.75 mg/kg/day highdose would seem appropriatetoachievemarginaleffectosn body weight and generalenergylevelof theanimals.Raisingthedose to 1.0mg/kg/day would result in senun levelsof approximately1044 ppm by term,which would approachfatalserum concentrationsT.herefore,0.75mg/kg/day isthesuggestedhigh dose thatwillclearly takeus beyond thresholdeffectsof serum cholesteroalnd triglygeridreeduction. Comment: Itisinterestintgo notethattheconsistenltinearitoyf increasinsgerum [PFOS] and apparentlackof significanetliminatiomnay make itpossibletogivemuch lessfrequentdosesor even to givea singledose atthebeginningof the studyand adjust thatdose periodicalltyomaintaina relativelcyonstantserum level.We willnotreacha steadystatein thestudyas itiscurrentlydesignedand willbe studyingtheeffectof increasinbgody burdenover time. Istherealsovaluein attemptingto hold animalsata relativelcyonstantserum levelovertime? Also,itwould be interestintgo look atserum concentratioantextremelylow levelexposureover time;e.g.,0.1to 1.0ug/kg/day. AMDI'# 041599.1 CovanceN 6329-222 Study-. ProductNumber(Tea Subua=): Matrix: mcow"cvisioa: AnalyticaElquipmentSystemNumber. famument Softwarc/vaam Filenam: R-Squamd Value: s4c: Y-Imercept. Dun ofExb=IWWAiWyst. Datesof Analysis/Awlyst: 4-Wcck Capsok Toxkky StudyvdahPffflucroociam'SulfoAncicd PotassiuSmak inCynmoigus Monkeys T-6295(PFOS) Monkey Scrwn FACT-M-3.0A FACT-M4.0 Amelia062498- MAULYNX 3.1 SeeAtWAummu SeeAitwismou SteAnwhmeab SeeAnwhaKim 7116AS RWW 7117/99 HOJ 7f2219SRWW 7/24/92[IOJ Group I corwoi 0.0IFS&&MAY Sample 0 105349M 1053SOM 105366F 105367F Ilaqw[m Day -7 Day 2 Day 3 Day 7 Day 14 Day 29 Day .7 Day 2 Day 3 Day 7 Day 14 Day 29 Day -7 Day 2 Day 3 Day 7 Day 14 Day 29 Day .7 Day 2 ri4y3 Day 7 Day 14 Day 29 PFOS CWAW. ug!nl 0.0173 0.0223 0.172 0.181 O.IS4 0.160 0.0121 0.0207 0.0202 0.0239 0.017$ 0.0220 O.Otis 0.0214 D.On2 0.0194 0.0183 0.0269 0.0135 0.0213 0.0175 0.0153 0,0333 0.118 Group 2 Low Desc 0.02mg&glday Sample# Timepoint PFOS Conc. ug/=L 105344M Day -7 0.0120 Day 2 0.157 Day 3 0.174 Day 7 0.449 Day 14 1.37 Day 29 2.79 105347M Day -7 0.0140 Day 2 0.147 Day 3 0.297 Day 7 0.776 Day 14 1.36 Day 29 2.56 10534&M Day -7 0.0100 Day 2 Day 3 0.161 0.299 Day 7 0,674 Day 14 1.46 Day 29 3.57 105364F Day -7 0.0161 Day 2 0.131 Day 3 0.292 Day 7 0.736 Day 14 1.59 Day 29 3.76 105363F Day -7 0.0144 rimy2 0.117 Day 3 0.267 Day 7 0.629 Day 14 1.22 thy 29 2.65 105370F Day -7 0.0111 Day 2 0.100 Day 3 0.213 Day 7 0.664 Day 14 1.54 Day 29 3.20 PracticQa"lntitadoiUsmit (PQL): PPOS 2S a&/oL.PFOSA 0.3RWM4 PFOSAA 10 ag/mL PFOS - Peflumooclawsulfonate Sample 0 nmtp Group3 ifigohm 105345M Day Day 2.0mg4olday Day Day Day Day 105369F Day DAY Day Day DAY y AMD'RN 041598.1 CovanceN 6329-222 Method Ddection[Amit(MDL): PFOS - 12.5ng/mL.PFOSA - 0.25ng/mL.PFOSAA - 3 agImL Chartl 6.00- 105344M 5.00-- 4.00-- 0 3.00-LL 9L E 2 2.00-c,oa 1.00-- 0.00- -1.00- 0 0.1 105347M AMDT# 041598.1 105348M - 105364F 0.2 0.3 0.4 Accumlative Dose 105365F 0.6 Page I 105344M Acc Dose mg/kg 0.00 0.04 0.06 0.14 0.28 0.58 [serum] ug/mL o.uizu 0.1570 0.1740 0.4490 1.3700 2.7800 105347M Acc Dose ma/ka 0.00 0.04 0.06 0.14 0.28 0.58 [serum] ua/mL 0.0140 0.1470 0.2870 0.7760 1.3600 2.5600 105348M Acc Dose mg/kg 0.00 0.04 0.06 0.14 0.28 0.58 (serum] ug/mL 0.0100 0.1610 0.2890 0.8740 1.4600 3.5700 105364F Acc Dose [serum) mg/kg ug/mL 0.00- 0.0161 0.04 0.1580 0.06 0.2920 0.14 0.7360 0.28 1.5800 0.58 5.7600 Sheetl Slope se (slope) r-square F-value ss (reg) 4.92 0.21 0.99 540.118 5.749 -0.08 0.06 o.lo .@ 4 0.043 y-Int se (Y-int) se (y-est) df ss (resid) Slope se (slope) r-square F-value ss (reg) 4.43 0.17 0.99 667.749 4.671 0.04 0.05 0.08 4 0.028 y-int se (y-int) se (Y-est) df ss (resid) slope se (slope) r-square F-value ss (reg) 6.13 0.24 0.99 642.745 8.944 -0.06 0.07 0.12 4 0.056 y-int se (y-int) se (y-est) df ss (resid) slope se (slope) r-square F-value ss (reg) 9.85 1.06 0.96 86.129 23.092 -0.38 0.29 0.52 4 1.072 y-int se (y-int) se (Y-eSt) df ss (resid) Page 1 105365F Acc Dose mg/kg 0.00 0.04 0.06 0.14 0.28 0.58 [serum] ug/mL O.Ul 44 0.1170 0.2670 0.6280 1.2200 2.6500 105370F Acc Dose mglkg _ 0.00 0.04 0.06 0.14 0.28 0.58 [serum] ug/mL o.oill 0.1000 0.2130 0.6640 1.5400 3.2000 Shoetl slope se (slope) r-square F-value ss (reg) 4.58 0.08 1.00 3683.682 4.989 ;0.02 0.02 0.04 4 0.005 y-int se (y-int) se Cy-est) df ss (resid) slope se (slope) r-square F-value ss (rog) 5.66 0.13 1.00 1886.988 7.623 -0.08 0.04 0.06 4 0.016 y-int se (y-int) so (y-est) df ss (resid) Page 2 Dose-SettinRgationaleforSix-MonthChronicOral Study inCynomo%w Record ofAugust 3,1998 ConferenceCall Monkeys Pati@ants: Dr.John Butenhoix3m Dr.Marv Case,3M Dr.J@ffMandeL 3M M JohnMoore,EM Dr.Geary Olsen,3M Dr.Joe RodricimM,NMONDr.Andrew Seacat3M Outcome: Datafrom therangefindewras discussedincludintghestrongrelationshibpetween =mdative dose and serumPFOS concentratio(nav* of5.27+/-0.61ppm serum PFOS co on permg/kg PFOS don). DiscussiovnerifieJduly29,1998 writtenrationale fbrsettindgoseswithone chang& Dr.Moore &Wasted thatthelow dosebe raisedfrom 0.02mg&g/day to 0.03mglkg(daytokeep dosesatmultipleosfS. Ile suggestiownas accepted.The studywillproceedon August 12@,1998 withft fouowingdose levels: Control Low-Dose Md-Dose legh-dose 0.00mgwday 0.03mgwday 0.ISmg/Wday 0.75mg&gtday Copies: Par6cipants Dr.Lany Zobel Dr.BillWeppner StudyFile(T-6295.7)