Document jmjGXDddxLMDQ1N2ZpVzex2zO

+ toed Gomospondonc am TO. PhooSecanahComemints iembesrs Fluomchemical Steeling Commillee Members FROM: JefMandolMD,33367020.30.05) SUBECT: Papas Gland Jeff MandeL M.D., 333-8670 (220-3W-O5) Papers/Dr. Gilliland ONE: Docenbor?, 1383 December 7, 1~ Thasoato actospapers htsr beng prepare byDr. GR. They These are two additional papers that a~e being prepered by Dr. Gill=land_ They oad ourpraBoe ba sod fo pn. : need ou~ inpul/appmval before being su~itted forpublication. Thepapassr nt forhemos pa,Weswowirh enkregagrd The papers are negative for lhe.mos! part, We're workirg with him regarding So of ot win.WrChoa at pet heit 1 some of the wo~ding. We're operaSng under the pre~nise Ihat these s0Hs of pressedrpy topics need 3M suppod. Plsca sont your comments backtom by he of hemari 1can Please send you~ ~,omments back !o me by the end of Ihe monlh so I can promontory communJc~e with IDr_ Gitlilat~l. smn JHM/vtk "rl exer 25 fr-- 3MA00323875 1409 EExxhhibibiitt 1409 State of Minnesota v, 3M Co,, Court File No, 27-CV-10-28862 CGCIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--,SSUUNOBB.JJEE2CC7TT-CTT-OO10AA.2PP6RR8OO6T2TEECCTTIIVVEE ORDER ORDER ENTERED ENTERED IN IN HENNEPIN HENNEPIN COUNTY COUNTY DISTRICT COURT, NO, 27-CV-10-28862 aM_MNooDS 1484 3M MN00051484 11440099..00000011 PPereiphrerailBBpiloooohddLLeyymmprhpohac~yTlt~ee CCouonuiinonMMetenn OOccccuuppataitioonnaallllyyEEsxppoosseeddttoo Peeluorvoctasoic Ad Perfluomoctanoic Acid PPrraannkk DD..GGliiRlialanndd,,MMD~D,., PPhh.DD.. JJaacckkS.. MMaannddeell PPKRDD.. AfRlinions: DivisionofBavizonmental and Occupational Healtb, School of PuAbflfiilicaHtieoanlst:hD,iUvisnioniovfEenovfrirMoisnnnmieestnottaayl,aMnidnOnecacpuoplaitsio(nFa.lDH.0e)alathn,dSchool of DPubelic pHeaalothfr,IUnntteivrnemars'iMetyedonifcMitnirem,eOscoctuap,aMtiionnnaelapanodlisE(aFv.iDr.oGn)m;eanntdalMedicina DSeectpiaornt,mSenPtaou~lInRtaerrmneanlyMMeeddiiccinale,COoactceurp,atSitoPnaavlla,~dMi]n~pnevsivootnam(eDi~.taCl M ) edic~e Section, St_Paul Ramsey Medica~ Center, SuPaRI0 M~nnesota (F.D.G.) Raprint requastsshouldbe addressed toFraakD. Gilliland, Universiotfy NReewprMiinst irecqnuSecshtososlhoofuMleddbiecianded,rNeseswedMto eF~-nT~xiarmDoi. r(~Raiclg!ii!i~ozdy,,Un9i0v0eCrsa~Wmiofndoe New `Salo dMeN~Ex,icA~lSbculqmuoelroqfuMe,eN~Me,57 New 131. ~ T~or ~, ~ C~mi~ de Telepbone (505) 277-5541, Pax (505) Salud ~, ~buque~ue, ~ 87131. Tetep~ (~5) 277-~41, F~ 271001 277-7041. Thi studywas suppoirntpaerdt byNIOSHGrantT15007098-16 0d3 This study was supported in part by NIOSH Grant T150h07098-16 and 31v MMieddiiccaall DDeeppaarrttammeenn~t RRuunnnaiinngg ttiittlee:LLyymmpphhooccyytteeccoouunntt aanndd PPFFOOAA " Mnsoziers 3MA00323~7~ DCCIOOSNNTFFRIIIDDCEETNNCTTOIIUAARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1A0A-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00000022 33MM_MMNN000000S511448855 AABBSSTTRRAACCTT Studies in Rhwsusmonkeys suggest that perfluscoactazaocicd(PFOA) bas iSmtmuadnieostoinsiRcheefsfuesctmsoonntkheyecs slulggmeesdtiathtaecdipoervfmluuonreosoycstta~eomiicnapcridim(PatFeOsA.)Thhaes immua0toxie predominant heiffsetcotpsaotnhotlhoegiccoail-lmeseidoinaitendPiFmOAm-utnreeastyesdtemmoninkepyxsimwaastedsi.ffTuhsee paretdotmooinfpalnmhtahpyihstnoopdaethsoalnogdiscpallelneisciognerinmiPnFaOl Aca-nttraerast.edAm ltohnokugehysPwFaOsAdiffuse atrophy acount of lymph nodes and forthemajority of splenic laorine gperermseinntial ctehnetseresr. uAmlothfotuhgehgPuFoeOrAal paocpmuluanttisofnoarothdeinmaojocritycouf flpuoraeinxetpopisreesdoewno~nriknaetrhlse,slielryuemionfftohremgaetnieoiransl pavoapiullaabtieocnoanncderianioogcchuupmaatinonraelslypoenxspeostseod PwFoOrkAere~x0polistutlree.inTfoormasastieosns wishether aPvFaOilAaebxlepacsoanrcseirnsiansgshocuimataendrweistphoenfsfeescttosoPnFOthAehexupmoasnucree.llT-omeadsi~astsedwhether iPmFmOuAneexspyosstuarme,wiseasesxoacmiaitneeddwthitehcerfofsesc-tsseocntitohnealhausmsoacniat~iolln-smbeedtiawteeedn piemrimpuhnereaslybslteoomd,lwymepehxoacmytinecedoutnhtescarnosds-PsFecOtAioinnal1a1s5swoocriakteiornssebmeptlwoeyeendat 3 peripheral bk~l lymphocyte PFOA prodoctionplant.Tota lcosuerrtusmanfdluPorFiOneAwainsu1s15ewdaosrk3erssuerm ropglaotyeed at- a PmFOAeprfoaodeuscetsriounmpuPlaFnOhrAlTeoveteallss.erPum efluorrinbeliowoadspyumrph~iiaoescyatesrucroruoasgtatwleas. significantlyassociatedwithtotalserum Quoridelevel: however, the measure for sex~.un PFOA levels. Peripheral blood lymphocyte cotmt was sig~facanrly ass~L~e~_ with total serum JQ~oride level; however, the `mmaagganiittuuddeeaannddddirireecctitioonnoofftthheere~lealattiioonnsshhiippwwaassddeeppeennddeennttoonnssmmookkiinngg., aallccoohhoolluussee,,aanndd obbeseisittyyssttaattuuss.. Forexample, For example, fornon-smaaodkmoederraste for nolI-smokers and moderate ddririnnkkeerrss,,aannin~cnscereaasseeooff 1100ppppmm ns otal in/~! serus serum Boriewes fluoride w~s ssacciwaittoh&d associated with a d decroeasceiinnrllyymmepphhooaccyytts eeccooe uunntt ooff 11~64400cceel)l]ssiinn nnoonn--oobbeessee((BBMMI]==2255klf~gm/m?2)) wowrokrkeerrs~aannddbbyy992255cceellll iinnoobbeesseewworokrkeerrss((BBMMII==3355kkgg//mm)2.). PFOAis ]'I~OA is sss~coicaitaetoddwwitithhaalltteerraatitoinosininsn peripheral peripheral boodlymphocyte blo~ lymphocyte numbersin numbers ha PFOA PFOA pprroo~diuucct~iioonn wwoorrkkeerrss,, suggestithnatgcellmediated suggesting ~hat cel].media~i immanitymay immurd~y may be be affected affected - b~y PPFROOAA.. KEY WWOORRDDSSpopcelrllluuoocrooooccttaanncoiicc aacciidd,, eeppiiddeemmiioollooggyy,, iimmmmuunnee ttooxxiicciittyy,, Iymphocytecount. Mp AD er CCOONNFFIIDDEENNTTIIAALL - SSUUBBIJEECCTT TO A10.4PPRROOTTEECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00000033 33MM_MMNN00000C5S14148866 INTRODUCTION Perfuoroocaitda(nPoFOiAe)i widelyusedinindusprtocerssiesaanld Perfiuorooctanoie acid (PFOA) is widely used in industrial proce~3es and `consumerproducts a aecultofitsuniquechemicalproperticaandpotent. consumer produet~ a~ a reset ofit~ unique chemleal properties and potent uscufrfaacceeacatcitvivitityy((OGtr~fiitfh,i119t98h800),).. BBeeccaauussee PPFFOOAAhhaass salloonnggbbioiollooggiiccaall hhaallffl-iliffee,, `smomaall ~roqquueennttddoos~eessccaann aaccc~ulmmuullaattee ttoo aapppprreecciiaabbllee lleevveellss ((UUbbee)],, 11998800).). AAss aa rreessuultlt,, PPFFOOAA hheas~bbeeeennFfoouuanddiinntthheesseerruummooffaallllhhuummaannppooppuulalattiioonnssttuuddiieedd,, `and acoouats for the majoorf iucrtinye present inthe serumofpopulations. and accounl~ for the majority of fluorine pre~ent in the ~rum ofp~pul~i~n$ in industrialized countries. in industrialized countries1"7. LLititttllee ii~ kknnoowwnn aabboouut~tthheettoixcicppootetentnitaiallooff PPFFOOAAiisnhhuummaanne~;; hboowweevveerr,, `ssttuuddiiees~hhaavveessuuggggeesstteedd tthhaatttthheecceellIommedeidaiatteeddiimmmmuun~eessyysstteemm mmaayybboe aasstites ooffttuxoicxityiiinncpprriiimmatatteeyss.. RRhheessuussmmononkkeeyyss trreeaatteeddwwiitthhoorraall PPFFOOAAddaevveellooppeedd hihsitstoollooggilcecehhaannggees~iinn ~lp~oeoenuaanndd ph lymph nnooddeess.. TThheepprriimmaarryy hhiissttooppaatthhoollooggiicc lleessiioonn wwaassaattrroopphhyy iinn llympy hnnooddmseaanndpd ssppllh eezificcggeerxm~inninaallccaetnetresr"s.1. TThhee iimmmmuunnee ssystyemooaf~rrootddeennttessppeecmciieessbbaese2n0okt beeeennrreepio~rotrteeddttoo uunnddeerrggoosimilar histopatbelogic histvpathologie cchhaannggeessiinnssuubbaaccuutteeaasnddcchhrroonniicclfeeaeddiinnggssttuuddiisess1.!.NNooddaattaa ore `aavvaaiillaabblleeccoonncceerrnniinnggiimmmumnusntootxoixc~ict~yy iinn hhuummaanns~.. BBeeccaautts~ee PPFFOOAAi~sspprreesseenntt iinn theserumofexposedworkersandinthegeneralpopulation 7, itamiattser ofthceo~necreurmn wohfeextphoe~retdhewforakdeir~nganidn minonthkeeygseniendriaclaptoeptuhleatpiootnen~t-7i,alitfiosrahm umaatst.er ofconcern whether the finding~ in monkeys indicate the potential rot human iimmmmunuontootxeixciciittyy.. TToo aasssseessss wwhheetthheerr PPFFOOAA ccoouulldd aaffffecctt tthheecceellll-mmeeddiiaat~eedd - imimmmununee ssyysstteemmiinn hhuummaannss,,wwoessetuuddiieeddtthheeasas~occiiaattiioonnooffPPFFOOAA..aassmmeeaassuurreedd bbyyttoottaall sseerruumm uae, fluorine, wwii~thh ppeerriipphheerraall bblo~ od ylypmhpohcoyctytee ccoouunntt ((PPBBLL)) iinn 111165 ococcucpuaptaitoinoanlalllyyeexxppoosseedd eemmpp]looyeyee~aeastt_aa ppllaanntt lt:hhaatt pprroodduucceess PFOA. BM~ALT-kETRERILA-~LLS~ AAANrDD M~ETTHHOODDSS sunoaszaars ;3MA(}0323878 CDCIOOSNNTFFRIIIDDCEETNNCTTOIIUAARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1A0A-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00000044 33MM_MMNN000000S511448877 AlAlllccuurrrraennttwwoorrkkeerrss eemmppllooyyeedd iinn PPFFOOAAprproodduuccttiioonn oovveerr tthhee 5pprreevviioouussyyeeaarrss aanndd aassaammppllee ooffwwoorkrerksieinnrjjoobsbsswwiitthhnnooaappppaarreenntt PPFFOOAAeex~ppoossuurreeffoortthhee pprreevviioouuss ~yyeeaacrss wweerreeiinnvviitteeddttoopparatrtiicciippaattee.. Participants had vital Participants had via! ppaarxaammeetteerrss mmeeaassuurreedd iinn tthhee.ppllaannttmmedeidcicaallddeeppaartmretnmtbebyynaantn ooccccuuppaattiioonnaall healthnurse,completed a medical history quescionnaire, and underwent. health nurse, veaipuncture. c~mpleted Blood was a medical history questionnaire, and underwent drawaforassaysofperipherallymphocyte count: A venipunc~me. Blood was drawn foz assays ofperipheral lymphocyte count. A uorine-free15mlvacutainerwasusedto collectblondfortoalserum : fluorine-L,-ev 15 ml va~tainer was used to ~Hect uorinedetermination. Totalserum fuorine was blo~i used afotr htoetmael asseruurme o f PfFluOoAriinnetdheites~cr~c_ic~uAptaitoni.oaTlogtraoluspe.rTuomtafllusoerirnuemwflausoruisneedwaasstdheemteearsumreiuonsfiendg. PFOA in this eccupatieual g~oup, Total sexttm fluorine was determined using tthheessooddiiuumm bbiipphheennyyll eexxttrraaccttiioonn aanndd aattoommiicc aabbssoorrppttiioonn ssppeeccttrroommeettryrys., `Pearsoncorrelationcoelficienta were calculated to assessthe usivasiate assaciationsbetween PBL andage,bodymass index (BMD,cigarettewe, and `alkohol use. Linearmultivariateregressionmodels were fit to estimate the `assocofiPBaL.tcoiunotwnitsh PFOA, adjusted fo age, BMI, cigaretza uss, `andalcohol use. Twoway interactionsbetweentotal serum fluorine andtha foarcovariates wereevaluatodusing residual analysis, model it, and tests of significance. Interactiontarswere inchodedinthefinalmodelifbiologically plausibleaodifthe parameter estimateforthe interacttiaron was. significanatt the alp=h1a0 evel. RREESSUULLTTSS PPaaxr~tiicciippaanntt cchhaarraacc~teezriissttiiccss aarree ddiissppllaayyeeddiianTTaabbllee 1L. TToottaall sseerrtutmm fflluuoorriinnee Values ranged from 0 and26 ppm with a mean of33 ppm. Twenty-three values ranged f~m 0 and 26 ppm with a mean of 3.3 ppm. Twenty-three MATS 3MA00323879 CDCIOOSNNTFFRIIIDDCEETNNCTTOIIUAARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1A0A-PP28RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00000055 33MM_MMNNO00000S511448888 ((2200.0.%0%) ppaarrt~cciippaaanttss bbaadd s~eerruumm vvaalluueess less less than than 1 I ppm, ppm. 6 6 (5.2%) (5.2%} bad had values. values between10 and 15pp,and (44%)hadvalues greater than16 ppm. between t0 and 15 ppm, and 5 (4.456) had values greater than 15 ppm_ Table 2presentsthecorrelation coefficientsbetweenPBLandtotal serum TRaaobrlieoe2,pargees,eBnMtsLt,haeloo~bordlautsieo,nancdoceiffgiacriesntztso cboentwsuemepntPiIolnL.anPedrtiopthaelraslerbulmood fluori~e, age, BMI, akohol use, and cigarette co~umption. Peripheral blood Iymphocytecountwassignificantlycorrelated withtotalsecusm uocine lymphocyte count was significantly correlated with total ~erum fluorine (6(2r=.1.199,, pp==0,04)4.). TThhee ffiinna~l] reggrreessssiioonn mmooddeell orPBL,which for PBL, which adjustedfor adjusted for uge. age, BBMMI,I, cciiggaarreetttteeuussee,, aannddaallocoobhoolluussee,.iinncclluuddeeddddaattaaffoorr I11l1lwworokrkererss:; 4 4 ofthe. of the 115workers hadmissingassayvaluesandwereexclidedfromtheanalysis 115 workers had miss~g assay values and were excluded from the analysi~ ((TTaabbllee 33)).. TToottaall sseerruumm fOlvuoorriinneewwaassiinnvvaerrsseellyyaassssoocciiaatteeddwwitithh PPBBLL; hhoowweevveerr,, tthhee rreellaattiioonnsshhiipp wwaass ccoommpplleexx,,wwitithhsisgnii~ ficuanttiinntteerraaccttiioonnssbbeetl~wweeeenntotottaall `serum fluorine andBMI,cigarettause,andakeoboluse. Ta4bllusltratees tsheerruemlatfliuoonrsihniepfanodr BMI0 ~iRarette use, a10ppmchangei mud alcohol totalserum fuesoer. iTnaebfloer4coilmlbuisntraattieosns t~e rela~onship for a 10 ppm chan~e in total s~rum fluor~e for comb~uations of smoking,alohol consumption, and BM status. Inmoderatedrinkers (1- ofsmokingo alcohol consumption, and BMI st~tu~. In moderate ~h~;-ker~ (1o ozaoholparday), PBLdecreasedinthecategoriesofsmokingandof 3oz ~kohol per day), PBL decrea~d in the categar~es of ~moking an~ of obesity;inlight drinkers (<lozper day), PBLdecreased in non-obese smokers obesity; ~n light drinkers (<loz per day), PBL decre~d ~n non-obese smokers oonnllyy.. DDiissccuussssiioonn `Serum PFOAlevelisassociatedwithchangesinthocellmediate immuse Serum PFOA level is asaocia~ed with chan~es in the cell-mediat~ imm~me - s~ys'stteemm,,aasseev~iddeenncceeddbbyycchahnage~si~nPPBBL~h~owweeve~rr,,tth~ ererleatliao6nsohi~pddeeppeennd&s `upon smoking, alcobol use,and obesity. PFOA could modulate cell counts by u~n smok~, alcohol use, ~d ob~i~. PFOA ~d ~ ~B ~ by aalltteer~inngg tthhee k knnow~n eefffec~foofefssmcmokoti~nsgg,, a~lccooh~oll consumption, ~ump~o~ and and adiposity a~si~ on on ppeer~ipphherea~l lleeu~kooc~ytee ~ counts ((r~es)).. NNoo hhuummaann sstcu~dieessooftfht~eeefffefc~t oofEPPFFOOAAoonn the immuse syscew are availablefor comparison; bowever, a studyofthis ~he ~mune sys~m a~ av~ble for ~mpa~n: howe~r, a study of th~ ~rouuppooffwwoorrkkeer~s ss~ugggeessm ts ~thhaatt PPFFOOAA mmaayy m modoif~y ~ the ~heppaaftiicc ~repspoonns~e rtoo wAoas2380 CCDIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1AA0-PP28RR8OO5TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00000066 33MM_MMNN0000005511448899 aallccoohhooll aanndd oobbeessiittyy.. MMoodudlatiuonoloff eeannddtaobbiiioottioccaannndd xenobiotic xenobiotic metabolism metabolism could represent 8 commonmechanismfortheobservedassociationofPFOA ciotuhldsrleeprraetsieonn~sainchoempmatoincmanedchiamnmisumneforre~shpoenosbe.served association o~ PFOA with alterations in hepatic and immune response. Therelationshipbetweonthochanges in PBL in humansaodthe lymphnode `qa'nhdeerpelleantiiocngsehrimpibneatlwcaenetnetrheatcrhoapnhgyoebssinerPvBeodLiianmhounmkaenyssains vdotthcelelyarm.ph node Chanadngspelseniinc PgBerLmmianaylbceenunterrealtartoepdhtyo gobesmeirnvaedlicnemntoenrkaetyrsopishyn.otAclllesanr.atiely, Clothes in PBL may be unrelated to ger_m~al ~nter atrophy. Alterna~icely, `smallchangesin PBI.could relletlargerchangesin Tcllsubsets. In small changes m PBL could reflect larger ~__~n~e~ in T cell subset~ In `aaddddiittiioonn,,tthheemm odoidfii~caattiioonnoofftthherreellaattiioonnsshhiippbbeettwweeeennssmmookkiinnggaannddPPBBLLbbyy PFOAcouldbethe sultofchangesin the nuorfpasrtibculaerTerll `PsFubOeAetsc.ouBlduberthteb~ees~PrltFmoOfAochmraansgyeb,seinathesnusmbwoeirtohcfcphaiarntigcaeusliatrnTiemmudse Esuunbctsieot~n.bFeyuortnhdersmimoprlee, PchI~an)Agemsianyceblelassusombcieart.edCwytitohkiehne~nsgieg~aailning s function beyond simple changes in eell number. Cytokine iimmppoorrttaannttiinniimmmmutnmeeffu~nmct~iioonnaanndd cmouul~ddbbeeaaltlalr~edlbbyyPPFFOOAAexexpposousurree ~2.. TThhee. rFeussppoonosse ttoo ~anut~ii~geennbbiinnddiinnggddeeppeennddss uuppoonn rreaerraanrgermaenntogoffmemememberbnraanntee pprmotteeiinn~s.. CChhaannggeessiinntthheemmeermbrbaranneepphhysyisiccaallcchharaaractceterriissttiiccsspprroodudc~adibbytthhee potentsurfactantactionof PFOAcouldalterimmuneresponses. potent surfactan~ action of PFOA could alter ~rnm~ r~b-pon~eso Interpretation Interpretation oofftthhee ndingsrequirescareful finding~ requires careful consideraotfitohne consideration of the study study limitations. Given the occupasttuidyosenciaogl, the vluntary limitations. Given the occupational study .setting. the voluntary pacticpation,adtharequirementsforbloodsampl collection.theoverall participation, and the requirements foz blood sample collection, the overall ppaasrttiicciippaattiioonn wwaass uunneexxppeecctteeddllyy, hhiigghh,. aanndd nnoonn--rreessppoonnssee biss bias is is likely likely tobe. to be - asrm malall.l WWorokrkeresrsnnoottiinncclluuddeedd mmaayybhaavveehhaadd aa ddiifffeerreennttrreessppoonnsseppaatttteerrntthhaann tthhoossee wwhhoowweerree iinncclluuddeedd.. MMiigrgatrioanootuutriooffotthnheehhiigghh eexpxosuprejo~oobbsss aisuw~nmlril~kkaeellyy ttoobbee tthhee rresueltoosffssuuubbcdlliinniitcc~a!l cchhaannggeess iinn PFBBLcocuonutntss.. TThhee vvaasstt mmaajjoorriittyy ooff `workers who had sigaificant exposureove the previous 3 years would be workers who had sight exposure over the previous 5 years would be iinncclluuddeedd iinntthhee ss~tuuddyy s~aammppllee aass tthhee ~tuurrnn--oovveer rata rate iinn ppllaanntt eemmpplloo.yveeeess wwaass hl)oww {(93%% ppeerr yyeeaarr) aanndd tthhee ssttuuddyy iinncclluuddeedd aalllccrureraentt eemmppllooyyeeeesswwiitthh aapppprroopprriiaattee woerzaest 3MA00323881 CCDIOOSNNTFFRIIIDDCEETNNCTTOIIUAARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1AA0-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00000077 3M_MN000S1490 3M MN00051490 Jjoobb hhiissttoorriieess_. SSeelleeccttiioonn bbiiaass iiss nnoottaa lliikkeellxy explanation explanation oe the for the findiogain this findings in this ssttuuddyy.. Total eranBuorioe wasusedas&surrogatavariable fo PFOAexposure. TheuseoftotalserumOuorinsbasbeenvalidatedinpast biological `monitoring in the plantand otherplants using PFOA. Approximate90l%y. oftotalserum DuoriasinworkorswasreportedtobeinthofrmofPFOA 2.0. Totalserumfucrin islikelytbo highlycorrelatedwith sorumPFOA inthis cohort.Thecosliientofvariation oetotalserum lurewas66%. Atthe Lowendofthespectrum (< 1 pp), wherstheassayi limitedbysensitivity, thetotalserumfuorinevaluesmay oversstimatthetoa value. The measurementervos are likely to leadto an underestimate oftheeffectof PFOAon the physiologic endpoints.Thodurationofexpomsayubreaen importantdeterminantofPFOAlovl and effact; however, infsrmation 0 the duroafetmplioyomenntin exposedjobs asnotavailable, because plast records did potcontain sufSciont informatio0n reconstruct exposures. Inflammatory and infectious processes, which aremajordeterminoafnPBtLs, weInrfleanmomt aatosrysanediinstfehscitsisoeeuusddpyr.oBceecssaeuss, ewthhiecrhsairsepmoeavjoirddenecteermthiantatnhtescoafPBLo were not assessed in ~his study. Because the~e is no evidence that these pPrroecceesdseess aaree rreellaatteedd t0otototatl~sseerruumm vfluionrieneooersseerruumm PPFFOOAA,, tthheeyy aarree uunnlliikkeellyy ttoo ccoonnffoouunndd tthhee eessttiimmaatteedd r~eellaattiioonnsshhiippss.. `Thechangesin PBL countssociatedwith POAexposurepresenta complex The cha,~ges in PBL count~ a~sociar~-d with PFOA expe~ur~ p~.sent a complex ppiiccttuurree.. AAllcooohhooll uussee,, ciiggaarreectttee uussee,, aanndd BBMMII mmooddiiffiieedd tthhee aasssoocoiactiioanotofifccoeelnlll ccoouunntt wwiitthh PPFFOOAA..TThheemmaagganiivtauddeeoofftthheesseeaassssoocciiaattiioonns~ iisnnoott ccllilnnilcea~llllyy sSiigngifniciafntifrcrooammanantn iinnffeeccttiioouuss ddiisseeaassee ppeerrssppeeccttiivvee;: hhoowweevveerr,, ~juudgdmgenmteaanss tttoo tthheecclliiniicc~arlelreovalnceevooaffssuuccheh cchhaanoggeess mmusst~ aavw~aiitt fuertthheerrssctueddyy.. MMoorree wooszseez 3MA00323~82 CCDIOOSNNTFFRIIIDDCEETNNCTTOIIUAARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1AA0-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00000088 3M_MN0DOS 1491 3M MN00051491 researchisneededinthear of PFOAimmunetoxity. The ndinofgthse. prreemsreanrcthstiusdnyenedeeedditnotbheecaornefairozfePdF.OCAhainmgmesuinaotTocxeiclitys.ubTsheetsficnoduinldgbsoofthe cporen~fiernmtesdtubdyyimnmeuesdotpobbeencootnyfpirimnegdl. ymCphhaoncgyteessinuTsicneglwl esulblseeatsccaobulldibseShoewd ecrotoncfairamteeydmbeytihmomdsuno3p.heTnnotaydpdiintgiolny,mtphheosctyar.nedsaursdinigmmwuenlclteaextiacbolil~ohgeidcflow ~;~metry `assess metho~ls defioed 2s. by t~h.eINnataicolndaitlionT,ovthiceolsotagnyPdrarodgrImammunotonxiecootloodgbisec assessment defined by the National Toxicnl~gy Program ~e ne~s to be cconodunctdedufRocsrrtPPRFeOOAAd.. awaos230t3 CCDIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1AA0-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00000099 3M_MN00OS 1482 3M MN00051492 Taba Paricionts searreies Gy BfGorm BMI tk~/mS) s1oScsmoeeopppeeerrrdddeearyy 23aonre onrday ~uces per d~y pe~ day non-re~ aSCeostunemtmieeisweer mre. ursctrioticn e3e aomm 2#5 1mussdeos Rr z6.~ -- zs.s.40.5 oE82a0 me17.4 50 10 sTmrea Sunsuszon 3MA00323~84 DCCIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1A0A-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00001100 33MM_MMNN0000O0S511449833 TABLE? earn cationcofciot bebwee tlse Borde, TABLE2 P~arson orrelztion coeE~ients between to~l serum fluoride, oyae nr(P.alshoboloe, daly mencnsumpion.424 bo~ly ~ass index (HMI). dai~y akoho! use, d~ily tobacco co~suml~tion, and porter bcd mph co peripheral blood lymphocyt~ count me Ap BG Mok Tew Total Age Gre Gun God iw) (stan ~pm) BMI Alcohol Tobacco E EE e EL LYMPHOCYTF.S .19 on ES p=o04 p=.O02 soos 3MA00323885 GCCIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--,SSUUNOBB.JJEE2CC7T-T0TTVO-O1A0A.PP28RR6OO6TT2EECCTTIIVVEE ORDER ORDER ENTERED ENTERED IN IN HENNEPIN HENNEPIN COUNTY COUNTY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00001111 SM_MNGO0S 1494 3M MN00051494 TITAABByLLEESm3LLicpnioneuoanabrtr mamumoulolitnvicvagra1ir1iaya1ttweeort~reekggerrere~ssss.siioonnmmoodde~llooff faacct~orrsspprreddiiccttiongg tthhee lymphocy~ count among 111 workers. EET --=--= a sri Gp) rr 2205.6 nati 6tL1 .0005 Abas Total ~1~or~ (ppm) ~ sar diss oor owcette) ame amr oo oew XPrhit n nn -526,6 -977.1 woemer ro 222.7 35~.7 .07~ .007 RX Pin low X Fl~odae wo sms ows ws 189.0 ms 52.3 om.00~5 CCousitaXsFtelyaciyo SLaao Cilg~u-ettegday 247.9 ""~'~- 34.0 ewse103.9 eo a ~..s .o~ B~ a X~Pi)ne w[s ETae 1.58 19.8 RwRi2r=rev.~ccesctaetressi7ed.t5ickeusews4h.1abcy omdadi1-3eebtaeynb iBaie, [ern sundaszsess 3MA00323886 DCCIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--.SSUUNOBB.JJEE2CC7T-TCTTVO-O1A0A-PP28RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00001122 33MM_MMNN0000O0S511448955 Table Changsin ymphocytecountfor 10ppmincesse in otal serum oe Table 4 Change in lymphocyte count for 10 ppm increase in total serum fluorine <1 oxoz. asliccoohbooll/kddaaNyyonomoker BIZ BM125 mga? mg/Kg2 vio Non-smoker +7~0 BBMMI135mmgg/RKeg2? .+996655 SSmomkero(("224000kc6o.iiggea~d/darary)) -406 ++330086 13 oxofalcoboliday 1-3 oz. ofaIcohoYday Nousmoker BBMMI1Z2S5 mmgp/Kgg?2 Non1-6sm40oker -1~10 BaBmK? a2 BM136 mgiKg~ -924 Smoker (20cigsar) 1585 -2300 Smoker {20 cigs/day} -9.300 - 1585 swacoszsnsr 3MA00323387 CDCIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--.SSUUNOBB.JJEE2CC7T-TCTTVO-O1A0A-PP28RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00001133 M_MNO0OS 1496 3M MN00051496 L. Gh ,LongJ Anica ToetyShBiunrnweitshAmmar perhceoctaauie.A nd HygAsc 190841 75.83. 2elUibmien,aSeRerponrt5..ARmosc0hd.FiHgeAsmcSt19u80o4f1P:l3o04t.w3or9k.erseros mihrmicals: 3T3..oTeTaasrr:ees D.1.0Ev5vi0idd1eo~:ee that that therear t~ere a~e wotwo for of form~ o~ Bide flueri&t banscm. in human set~m. Nature Nature 1968;217: 10S0-51. . . 4T.oriTTsaanr,vess7D.8.5CComompaprairissoionnooft~'eorrtngmaic""Bflouorrdidee iin hs sdochuma sews. human and mmhuman serums. J DesDent Ren Rea 55C .. TTaavressh D7D8,,3GG.auyyWa W.,BBrreeyyBm W ..dOrrBe~amaco cihcFeFumiusoccram brbIoons~sasoiionnHi gHuCumamsraobnPol nPalaassmiaa:n: Pe rrBoeovvlnaleseo.ncceaanndd WCahsahriancgtteorinzaDtiCo:~AImne: rFidclearntC~heed.sBi~l0Scoc~ireat~y trT36/n1e1o7t~ 54.Carbon.Htutr~e Bend~ W~uL,~on, DC: Amer~an ~hemiea[ Society.lS76:llT-lM. 6C6..hGGauuyyrWWs..eFMlrs~owesPocnLcooDmtm.poophuono~ed,tss.oofB fHHuumnac tann PltaNh asYam:sU:an:e iAAvnearaasle iyhtayi~oPf~rRr=ee#sabele, anncr~ee,,,pp1iu9fr7iif.c!~ntii~onn,aandd Characterization. P~.D. the~i~, l~l~sWr, l~; Un~ver~ty ef Rod~tter, 197~ Sa77S..orGmGpauuayyssiW War,,STTaereaTcsDnD,NF.voBBlwrraeayyYRWoW.r.ok.O:OfArtrBegaoarihnceiecmBnfiluCaonuhrsoacomcmlapmeoSm noedcsciianbMIhomuunEmmamTmpr~Fpiplln1o~4-s,o.~:nu-dpperernAvCaelSednvceesannd 8. rViasnkiantcaerwasnteaPo.mpooduindeoiagbBeoclyrmiectehoadstorrdaelterAminn)atCihonomofc19r0l3e5n4lyLbSo21d137 S3~npo~i~n 3er~.~. Hew York:American Chemiud S~:iety.lS76:llT-L~L 8- Venkateswa_-Iu P. ~um b~i~nyl method fe~ deter~;-~t~n of =~alently bmmd R9i.kTeTrohLee3a3b0Mreusomimpo~pmny.E.TTwwooYYoerarOOrraed TesyiCacaSoegduofiC1l6y5. Toxici~ogenicity Study of FC-143. 1906, I986, hR110e0i.k,cegrByKLe,eaaNnbtnoeEerdadytRyoBBr,i,e0isG6:bt7lb3re5or8t~nu71AA5... Incressed Increased cebrepints erythropo~i~ ducedby k~i~ced lq, dee aad~ge~i~ bomen hormone thexapy. ~ 19~7;25~.. 719. i!11.1d. oS S~ritne~.tae~eP.i .SGGocroBrddon opnnABA,i.Cg ChMhaaeirdipps ep1re9rH4H.1.4E8lf1lf6ec3ct.ooffc~rs~arat~taanndds,exx hormooes hormones 0on the the b]~l of rats. Pr~c Soc ]~xp Biot Med 1941;48: 169. er1122y..boSpRiiie~sthbpipononeM-MerpetyeesorssstieniaaaI~m,/, eKKlp~bbiirelddsgneTT,B,lSSoiiomdoo1nn9e8,J50P3F1ir:eie4dd53WW-.4.TT6h0he.eeecffetct of of testcase I;e~to~.er~ne en erythopoiefin le~eb ~n anemic pat.~eur. Blood Lg~;~/: 4,q~f~6~. Bl13e.edN1e9c6a9s3i3an:5R6.E4ctepoitnand ecbepeiotnape menliwiogandreas. 13. Aler.anian R. Erythropoietin and er~hopoiee~in anemic men following ~ 14. Shah.And [~iood 1969;33: 564. res ad erpbpeiessNETH1973289.72 So15d.atPhaaltaeocino Ab.eCaioompopinasL.iMseCrlaleRm,eS.oF e 3,r SadoSi letrRi1l9f8t3.oo4f0s:lt10o0f1t0:1s 14. Shab.kli N. Androgens anal erythropeiesis. NEYM 1973;289: ! 5. Palaeies .et. Campfield L, Mc~lttre R, Steiner ~, Swerdlofl'R Efi~eet of t~stoat~mne enantha~e on hematopoeisis in normal men. Fertility and SI;eri~ty 1983:4~ tO0-104. 1166i..e o GCua,,mni~msgghhanmrGG.J.CSis ltivivneeErrnmedaancVi.p .oTTdoaMo~errtanisbbyy 1JJ,9KvK7o3hol4hl5e. :rP5P.2.0TT.hhee potspotential ranandrogen for an androgen male ~onu~eptive. J CLan Endocrin~ Me~b 1979;49: 1c7.c eMtoatnto,nBtoenrasm,haBter8msc1e4rKr,epRriocher,Leeryiennd.aes.NEcdkeiWn.B(cCopafel)ong. Sunsuszssss 3MA00323888 CDCIOOSNNTFFRIIIDDCEETNNCTTOIIUAARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1A0A-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 2~-CV-10-28862 11440099..00001144 33MM_MMNN00000O5S14149977 PC1a6r. ctusTliLcoon,u1G,0rai5ds72hJa5et71i.5V7o4ll iOa,rThoderoskeineL.TihsAedroellaetisocnsehniptoefOwhlitYnaoultlhcSunyt., E15.xHHosnaste~nI~1,.sGGkrmiemsmnaJJrers.. 1R~5,.4N.Neeoanf~acEnp3Jl.odTToohme9crl9ecl1ai3tioo.nn5as1hii.pp8oof8~ .hwhiitte adblcmd collcoutandsth cell c~u~ ~ ~ 20.tadbeL:ReaydrIlisCkeahmrcpto1ir3nys. e5 rGlbyonmR.heVomkaoias eP. Whsietiebsohaddyc. lCclnEtasompredi1c9to9r0o5f : 2T1.niaGs,ee.cmanc1e.,R.sNdeAwhtovnJi,sLeumpowritsali.tyP,SrAopMtAi1c9L8p5e3c5t:as1c9e3o3f1t9h7e.wieModcout x 2M 222. ZZuE aoslokskiaarrR JJ,,RPi~ec,-h~C as=rrddsJJ,CClIoauudde J.Lesko J. Leu.kocy~ coms, t-otmt smokingond smoking end Myocadilnorco. blyocardial ~ b2~ 3o,lcPrnFrrn1fie9dd8ram 1n;3aon~n01nG:,,K4,K6i5las-Nt4ss6kE8yy.UAA,.S1Si9i7egg0a2es0~s0u;hbA5A7.T5T1hh2ee7l5lse.ukloacxrviteccoouunnt sxpedir s~ a pt~di,~tor of of 20. Pram.Pures 8. ekecotsdcar cay. Eien 24. Fr~Iman G. Fireman B. t.he leuko~ta cuunt and cancer mortality. Am J El~demiet 25. Kamo W,Andason K, WonP. White bodcl oun:and carbons disse. ZS. Kaanei W. Anderson K, Wilson P. White bloo~ cell count Tightsfom the Framing Shed. JAMA 1952267: 136-175. In.gluts from the Fr~m~agham St~t~y. JAM& 1992;267: 125~-1~6, 26. Manta M Masao V.KoshaenP . Lexkocyesa. eons iskfcr. Z6. Mantta~i M, Maunineu V. Koshinen P. et al. Le~ as a cov~ary rk~ ~.or n a uildonimalpopuiaie. AmJar J IS5EAZS $757. d~l~m~ m~l~ pop.fatima. Am Jeart J 1992;12~ 873-7. 21. Youset. ame O.Cunha M.Relationofmaticmil rishasphte 27. Yo~w~t'J, [qwe O. C--r6n~ham ~. Regulation of hepatic in~tol trisphosphate epicsby eros peblrsor.TheTosilogt 191%31 re~pto~ by peroz~some pmliferator~ The Tozi~o|o~sk 1992;1~. 37. 28. Boonen,Pier.NewTechno fru nTeele Sis:Montithe 28. l~bin~on J. l'feifer R. New Teckn~o~es fro- u~e in Tox~mlogy Studies: Monitoring the ico esti a mnfoion.ACro Tokus 1900, 83317 effect~ o1~ genub~otim on immm~e f~uct~n, J Am ~ol Tox~ ~/1990~9: 303-317. 29. Tolls 0, Clark3, Brow Loof.Toeelf ofdartsmcking on Tol sins. 29- Tcller~d D. Clark J, Br~wn L, ~ a!. The effec~ o~cigareey.e s~okingen T cell subsets. AeBenge Ds 1000130: 18-1451. .~x J ]te~pir Dis 1989;139: 1446-145t. 30. Dean J, Corset, Roce] G, Lote M. mse pte: Easton of egy. os 31}. ])ean J, CornacoffJ, P.~en~al G. Ltt~l~" M. Immune sy~m: Evaluation o[injury. In: Hagene.d. PrioandMecthoidsofpTolceoeg,New York:RavenPress965141760 ~ayes A. ed. Prb~p!e~ ~ M~thod.~ of ~o~7. l~/ew York: Raven Press. 1~9"-741-76e. 31. Davi Dai. Aotealfctsofbce Gretesmchin rsh pliale segroacion 31. Davis J, Davis 1t. Acute effects of Wba~o cigarette smokin~ onthe platelet aggre~tlon . Ta Am 3Hed 5 9787. 30145. t~tlo_ Am J Med Sci 1978;278: I39-143. 52. FuserV, Chesebro Pye R, Eraback .Plateletscoa tedevaspme of Fus~er V, Cher,ebro J. Frye R, ~lvel~k L~ Platelet survival an~ the development o~ rary aioe done nh vou dl EsofGarton. 3008 hy scr, artery diae~e in the young adult: Effec~ of cigarette am0king, strong~.~tily hisw~, odanilGory. Coeunion 199163 548.59 medic~tl threapy. Cir~ds~ion 1981;63: 33. Buk 3 Mckee B.Burn.The lfc ofsot shin mnpldt baie. ~3. ~elch J. Met~tle B. B~r~ P- The effects of sc~te smoking on plade~: beb,avior. vasndt hematole ogyinh. abit scrobcs. ThrombHatmarias 043 5. I~br~noiysis, ~ hematology in habiU~l snmker~. Thumb ~tas 1984;51: 34. Mu1b Fyfe Ti .Loveo G Pon sh .Ectof cir smoking osecu lid. 34. Murchlson L. Fyfe T. Lowe G. Forl~ C. Effects ofcipreUe smoking on ~erum-lipid~. Vd ce, ad pate adbsivenes. Lance 19665 142.15 blood ~ucose. and plat~let adhesiveness. Lancet 1966.-i: 182-18~. urgaszass 3MA00323889 CCDIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1AA0-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00001155 33MM_MMNN0000005S14149988 He335Sa.. FF3iitze1~5re0xa8~1Id5G:0,2oO6On7at2ena1,J.NNoowwaak~ .J. Ciarti ~i~,e~e sacking andhemstatic smoking and hemo~t~tic fncion.Am function. Am 3H6e.aarrttaJansa1m9no8kd8i;n11gB5li:an2sr6e7eh-2aD~.iID.sumsonitiD, aTnhdevcaarbo C,mWainses.CoidaPhaagrmeacsTTfo.encPrtinonealtr oseSavane. 3i7.n GrueernnMsLBkeidn.Musasrae 7oGcteadTeiferc3cCesliEnppleaaeeiteco1n9m9t.a4n3:d 150s4.aosin 3e 388.. PPaacckkm mr asnnMS~,eMmMoiutsHar tarorddm3J..iTT1hh9e0~ s o6l3e3oo:ffp5p3ll6st.aeltetss ith in the developement15dcomplications deveb~pment ~d. ~omplka~ of of athep'~!e~sia. Stalin Hematoi 198~;23: 335896._14MM 8a!be3ht5taa6J33,MM 7a.behiteaPP..RRaoJee of o~ odltl hb3od platelet~ iin coc atcy co.rim7 arte~ disese. Ase dlsease. Am J Cordis ~ 1[}61:48: 366-373. P40e.inCcrosnokc,aaMtuer:rAapy,iFlramse,iHuertsMestendmechosfiLoanlTiotcAlppdePnhoacressab0y0s111m5 c00.. R2ueBabbyerra5,sotp.oFsadcotaipoensH.iAeda.s.AmiClallTSeDeZ2n0109.910180:i47n.5s05Leydigxl Masaszae0 CDCIOOSNNTFFRIIIDDCEETNNCTTOIIAUARLLT--,SSUUNOBB.JJEE2CC7T-TCTTVO-O1A0A-PP26RR8OO6TT2EECCTTIIVVEE OORRDDEERR EENNTTEERREEDD IINN HHEENNNNEEPPIINN CCOOUUNNTTYY DISTRICT COURT, NO. 27-CV-10-28862 11440099..00001166 33MM_MMNN00000O5S14149899