Document zQVvx4M9qXZ7a3em9RqDG7N30

- Corporate Occupations Medicine 3pMeCanme,iBiEneg 2TM203005 AR226-0473 651733 5066 Fox 3M 5. Fluorochemicals and Human Health: Studies in an Occupational Cohort "This is a doctoral thesis by Dr. Frank Gilliland (graduate student at the time in the DivisionofEnvironmental and Occupational Health at the University ofMinnesota). The dissertation consists of two studies: 1) an analysis of the 1990 fuorochemical medical surveillance data of employees who voluntarily participated in the program at the Chemolite (Cottage Grove, Minnesota) manufacturing plant; and 2) the second update of the retrospective cohort mortality study at the Chemolite (Cottage Grove, Minnesota) site In 1990, the Cottage Grove fluorochemical medical surveillance program analyzed for serum total organic fluorine. This was considered a proxy for serum perfluorooctanoate (PFOA) levels. Perfluorooctanoate is the anionofperfluorooctanoic acid. Gilliland reported no significant clinical hepatic toxicity associated with PFOA levels. However, the effectof obesity on liver transaminase levels decreased as PFOA increased. Gilliland also reported tha the effectof alcohol on HDL was reduced as serum PFOA levels increased. Serum PFOA (i.e. serum total organic fluorine) was positively associated with estradiol and negatively associated with free testosterone. The negative association between free testosterone and PFOA was stronger in older men, Thyroid Stimulating Hormone (TSH) was positively associated with PFOA. Gilliland concluded that these results suggested that PFOA may affect male reproductive hormones and that the liver is 03173 notasignificant ste of toxicity in humans a the PFOA levels observed in this crosssectional analysis. Note: These observations reported by Gilliland in his dissertation have been examined in three subsequent (biennial) medical surveillance examinations of this workforce. Olsen et al examined 1993 and 1995 fluorochemical medical surveillance data which specifically assayed for perfluorooetanoate in the serum using mass spectrometry methods. The dissertation findings could not be replicated. PFOA was not significantly positively associated with estradiol and TSH, nor was it negatively associated with free testosterone (see stu#d6)y. Olsen et al examined the 1993, 1995 and 1997 fluorochemical medical surveillance data, measuring specifically for perfluorooctanoate, and confirmed the lack of clinical hepatic toxicity in this workforce for the serum PFOA levels measured (see study #8). They were unable to observe, as initially reported by Gilliland, an association of PFOA to modulate the effect of obesity on liver transaminase clinical chemistry tests or blunt the effect that PFOA may have on the effect of alcohol use with HDL. Regarding the second update to the retrospective cohort mortality study, a paper was published in 1993 (see study # 4 ) which described the results from the Gilliland doctoral thesis. 03174 SFTLUUDOIREOSCIANRABNOONCSCUAPNADTHIUOMNAALN CHOEAHLOTRHT: SUBMITTEDOTFOTTHHEEUNFIAVCEUARLSTTIHYTEOYSFIOSFTHMEINGNREASDOUTAATE SCHOOL FRANK DAVIBSY GILLILAND IN PARTIAL FULFFOIRLLTMHEENDTEOGFRTEHEEORFEQUIREMENTS DOCTOR OF PHILOSOPHY/ENVIRONMENTAL HEALTH OCTOBER, 1882 L N 03175 . UNIVERSITY OF MINNESOTA Thisi to certify that I have examined this bound copy of a doctoral thesisby FRANK DAVIS GILLILAND and havaendfotuehnxadtamtahinanytiniatgnisdccoaomllmmpirletvetiteseeioanhnsadvreseaqbtuieisrefenadctmboayrdyteih.ne aflilnarlespects, JACK S. MANDEL PhD. TT Name of Faculty Adviser -- Signature of Facdly Advisor -- Dats ~ GRADUATE SCHOOL A 03176  ACKNOWLEDGEMENTS a! davmiceinwdeerbieeidntvoalDura.blJea.ckNMotanodnel!y dwihdoDsre Mcaonmdpeeltegnutidreesmeeartcohtahinsdrceasreeaerrch hpraosjeecntr;ihceheddirmeyctecldinmicealtometdhiecNinIeOSknHoowclceudpgaetiaonnadlsmuepdpiocritneed fmeyllorwessheiaprtchhat effons deeply over the last appreciated. three years. Dr. Timothy His ganerosity with Church, Dr. William his time and parienca Toscano, Dr. fan are Greaves, and Dr. Thomas Sellers special thanks for their efforts. served on my committee. They desorve a U| nwiivsehrstiotythoafnMkitnhneesDoivtiasiaonndofthEenvOicrcounpmaetnitoanlalaMneddiOccciunpeaSteicotniaolnHaetalStt.h Paatutlhe hReampsaasty tMherdeiecyaelarCsa.ntaDrr. fWoriltiheamsuLpoehrmbatnr,aiDnri.ngSoapmpuoerltuHnailt,esa|ndhaPvaeulhaadGeoivgearr tahteSLa.rdPuaouulsRtaamsskeoyf rMeesdiidcaanlcyCaanntderdopcrtoovraildetdraminuicngh. aSpepvreercaialtmedemsbuepprosrtofdturhieng o Division of Environmental the successful completion and Occupational health staff of this research effort. Sarah wer instrument Wolgamot ang in GMoaeriasslayrn, ZcahpapiradpHroofvfiodaecdk,exacnoldlonttheardmmianimsbtraartsivoefsCuoplpoornt.CanGacveirnCWonattr,olMSitnuddyy + provided outstanding computor and statistical support. DDre.paLratrrmyenZtabperlovainddedDra.dvJeifcieteayndMasnudpepolrto.f tThehe3irMhCeolrppowraastiaonn'sesMseendtiicaall oetlheemren3tMinMetdhiecsaulcDceespsarofmethnits pmreojmobcte.rsStsahnarSeodratnhseoirn,inDvra.luRaobgleerePxeprekriinosn,caend CahnedmikcnoawllCeodrgpeo.ra|twioonulodvearlstohelilkaesttotwaockyneoawrlsaodfgmeythterasiunipnpgo.rt of the Dow lLoavsit,ngbsuutpnpootrtleoafstSutshaisn,womryk wciofuel.d nHoetrhuanvdeerbseteanndaicncgoamnpldiesxhceedllweintthoeuctttihoen comments are greatly appreciated. . 603177 : ABSTRACT Perfluorooctanoic hepatocarcinogen acid and (PFOA) has reproductive been reported to be anongenotoxic hormonal toxin in ats, Although PFOA is thoenemeamjiorngcohmupmoannentotxiocfittioetsa.l fTuhoerihnegalinthheufmfaenctss,olfitPleFiOnAfowrmaartsioansisseasvsaeidlaibnletwo bsteutdwieeesncoPnFdOuActaenddinreopccruopdautcitoinvaelhloyremxopnoesse,dhweoprakteircse.nzTyhmeesas,soicpicaptriooenisns, ehmepmlaotyoeleosg.y pSaerramuemtePrFs,OAanwdaslapuoksoictyitveelcyoausnstoscwiaatreedswtiutdhieesdtrinad1io1l5amnadle ansesgoatciivaetleydawsistohcliuatteeindizwiintgh hroarsmotenset.osTthereonneeg(aTtFi)vebuatswsoacsiantoitonsibgentifwceaenntlTyF and PFOA was strongar in positively associated. older men. PFOA and Thyroid prolactin stimulating hormone and PFOA ware positively associated in wore gmloudtearmayltepydrruinvkiecrts.ranTshaemisfnfaascet odfeaccriepaosseidyaosnPsFeOrAumignclruetaasmeydl.oxTahloeacisntduicctaionndof * gamma glutamyl transferase The effect of alcohol on HDL by alcohol was decreased as PFOA was reduced as PFOA increased.A increased, positive association between hemoglobin, With PFOA was observed. These mean cellular volume, and results suggest that PFOA leukocyte counts affects male hreupmraondusctaitvtehehoPmFaOnAeslevaenlds othbastetrhveediivnetirhsisnosttuadys.igHniofwiacavnetrs,itPe FofOtAoxaipcptyeairns to modify hepatic morality study and immune of 2788 male responses to xenobiotics. and 749 females workers A retrospactive cohort employed between 1847-1884 at a PFOA significantly increased pcraoudsuectsipoencipfliacnSt MwRass.coAnmdoucntgedm.enO,vetreanllyetahresrsofwera no ienmcprleoaysemeinntprionsPtaFtOe Acapnrcoedrucmtoirotnalwtayscaosmspoacrieadtetdowniotheamspilgnoiyfmicnatntitn hproodfuocltdion. (Glisveeanset,hethsemaalslsoncuiamtbieorn obfeptrwoesetnatpercodaunccteirondewaotrhks aannddptrhoestnaatteurcalanhciestromryuosfttbhee viewed as hypothesis generating prostate cancer morality excess and should is related to not be PFOA, over interpreted. the resus of the f the two studies suggest that PFOA endocrine afterations. may increase prostate cancer mortaitythrough ---- 03178  o . HALLQECOTRS 21.: RIENVT2IR0E1OWDIUOOMCFOTCTIUHOCHENO.NL.Iw .TERATURE L s o Ls o .. s s . | 22:3OrPgRaYnSiIcCAFlIPUIOOODCONIONIMEISCAc LS v r o eo sr s 64 222..:675 TTSOO0XuCCrOO0KN8ISNNAGOHMfIICOSCrgSOafnOPficFPOFFIAOUc OAN.C.E .o EXr POr SUIe..so.crrr18 222...777...312 TMFHaoYlmTeaOlIRodOTpROrDNOIIGOGUGHCEUtSCVHc EVTEOTXOIo XCICHHSESSr .w ...r o ....vce ore rrs rn rrr 211066 222..777..854 NIHOMPNMBGUEUNNCOOIITOOOXHXIISGCYHCIo aOSIT1iNO.GNE. SIS. o ro ro r o r . 35330 22..98 EODcIc2Ou.Ep7Ma.It7OiIMoOneQacIlChEFa)lnuiSosIriUmnAseEoSEfxv Apcotsounre.so A.t C.R.Or m.O.i.te e.......s ....0_23836. 3 MET32H.1O10IDOSSMUOw MGMUECHLOYNc v o o o r o o e t s s 239889 3.2 Ret33r.:o22s.p21eScDttGiufvdieyNHCDOoahNtOoarfbtaTMshOeerstCaAOiNfNdyOFSRIW.ISGSYo oe om r. .333010 : 33..22.43 VDa3al.li2ld4a.Et1GiUoAn.s.Os.feTshsemeHnitstOorfiCcaolmCpolheotretneIsnfsorOmfation or. 3812 3.2.5 VAi3St.aC2lO.S4MI.Ba2IMVUNaSMliOAdNSaLCtiOo oMnROINfMCOoNnEor orvIneforrmac tion r cs r o. r 333332 3.3 Cro33s.s22.7S6ecAVtRaiBloiIndYaaSltIiSSot ntuodfyViOtfalPSo FtOatAusEAxSpCor EsMeadinWmoernkr te.r.s.r ....e r ..... .... 3384 96 33..33..12 PD3o2.p13u82la.Ct1OiNoSnCtuHDdeOyfNiLnv iotgisonAAnNdGFRECiTUIlMv Ee NL.s ............333787 333.3..22..323QL.3AU.DE2OS.TH3R.OH1NONHNEeYIiPTgIhOto GaBnAdUTWEeSi.g.hv ..........o..o.o o..o.r..r.rowr. 333777 33.23.32.3B.2030.2..1 Drawing And Handing oo... 3388 RESULTS Bt 33 ANRYSo IS o 33.33.22.33e ..22.23 AQuSaSlBitYys SASoSoUTrANGS , corr 344800 tems40 h 603179 o: o A 41.1 PaDR 4.1 Cross SectionalPerflucrocarbon Physiologic Effects. Study .......... 43 412 TOR SOIIUMCAFAIRUBOCNINESc NCS r or o er r 3 4.1.3 {4.11.54 HCHhooorrlmemsootnneereolRA,astsLiaooyswse Deen--si--ty--L--ip--op--e ro--tei--n,--H--ig--h--s De--n--ssi_tey_s.s,, 5 48 4L.I1D.O6DIHOIeEpIaNt,icANPaDraTmeHtQeIrsY.C..E.R..T.E.S..v ......... st,1 4:1.8 Summary Of Res 41.7 Hematology Parame.. terrTs-- .--..32 ult... 8 4.2 The 1950 Chemolite Retrospective Cohort 4.2.1 Standardized Monality Ratios [2 Morality Study ........... A 58 4.2.1.1 SMRs For Women resistni essssn ainn, 59 $8 4.2.2 4.2.1.2 SMRs For Men Standardized Rate Ratios(SARs). sss sssssssenss erssrssssssssssssasissnssesssnes 59 60 4.2.3 4.2.4 MPraonptoerlt-ioRneallatHiavzeaRridskRseg(rResRsMiHo)n c Modo el Rr elatr iveeo 61 Risk Estimates reassess 4.2.4.1 Proportional Haaezasaers tdtsModsseeslsssnsaFssosrMsssasslaseensenssssssssennes 61 4.2.4.2 Proportional Hazard Models For Female 84:.83 AE FPMIhQyOUsIiLBoSlYot gTicIEEfSfecv ts Tables S t o s ----s ----------s ----------ssssennn1109470 5.DISC5U.S1SPIhyOsNi.olo ogic Effer cts Study...cs TI 110988 5.1.1 fT 5.1.2 Hormones rrr sess 1 sess sssssssssnenn 198. 5.1.4 HEPC 5.1.3 Cholesterol, Triglycerides, and Lipoproteins .................202 PAIBMEIETS cress 208 5.1.5 Hematology Counts and Parameters ...........s08 5.1.6 TotalFILO coves erm 5.1.7 Methodological Considerations. errs sins 209 snesssssessns 210 5.1.7.1 55..11..77..32 CISOneflNoeMrcOmtUaiNtoGinIoBnNBiGaIs@.BSIeoBosSes.ev.er.re.se.se.e.s.ss.ee.sm.e.se.ee.s.n.s.mer.aseosoersmesr222r1111r40 5 5.2 198502C1heL m5o.i1i.t7e.4MAonnaallyittiyc SMtoudT deylsSrpescification--B--i--a--] s--c ------e----n----r----2..12]6T :22 Palticipant ChaIaCISISHS vost 55..22..34 MMoertthaoldiotlyoRgEicSaUlSCOw nSio derr atioe ns w.r.s.s........223108 5.2.4.1 5.2.4.2 CIonfnofromuantdioinngBEaSn.d..SeolercetisonBias...................222201 SUMMARY, CONCLUSIONS 5.2.4.4 Analytic Model Specification Bias. a ---- x: iAND RECOMMENDATIONS 228 6.1 Cross-Sectional Study of the Physiologic Effects of PFOA..........225 03180 o * :2 Retrospeciive Cohort MonalityStudyOfThe Chemolite Workforce, 1947-1930, > APPENDIX 1 r------------------------s--------------5 .= * . 03181 o A LIST OF TABLES TTTaaabbbllleee 444...111...312 TDAihgseetrJiDobiiusntttiroiDnbiusOttifroinAbIuICtnOihoFnoivlOefAYnTegoabTraOAcDcQEoeCAG OndUASO IOr ROP I Us. n e r.rs . . 666845 TTaabbllee 44..11..54 FPDlieusaotrrrisinboeun,tiCAoongrerO.aflBaAotgideoynBMyaCsSoesmfofIikcniiGen6ngxtsA(BnBedtMwD)rei,enn.ki.Tno.gtacSlteatSu.es.vr...ummsrn.. 67 68 TTTaaabbbllleee 444...111...876 TBBhoOedGyDiMMsatarssissbuItIinNodGneExXOfBDIyASgSIemD,UoANklIicOnoNghow AlnAdndDrTiv nokbiancgcSo. tUsaetB. yue... . 6390 TTaabbllee 44..11..910TBoTOtoatYlalSMSeSerSruumImFNFGIlOou.ro.rd.iede eDBIySTs BBoUdLyOs NMaw sss indv exm . Age. e , s ., .7731 TTaabbllee 44..11..1112 ADSigMsetOrKiDIbiuNsttGiroiAnbNuOtGifoDTnoABbyaNcTGoctoaSlUIsSBeaUSnB.uymc TFotIaUloASno eerCuamteFgio ouroyn.dew. s om 7743 Table 4.1.13 DCCiRRsEtIrQQiObONuYYti..onr t Of Alcr ohol Ue se Bt ys Total Ss erume Fis uords e . 75 TTaabbllee 44..11..1154 CBCooRedfIfyQiOcMNiaYens.tsc OifndVearxiDaito sitornibFuotrioSs neBvyenToHtoat lrmSoennesmAe sFslauyosri.nes T7T6 Table 4.1.16 TWhitehOHbosremrvoende VAesrssauyssEOxuptescitdeedTNhuemAbsesrayOfReWfoerrkeanrcse 70 Table 4.1.17 Pearson Correlation Cosficients Between Serum Table 4.1.18 PFleuaorrsioden, CAogrere,laBtoidoyn CMoassflsicIinadnetxs Between Total SerumI (Bmi), Dally Alcohol 7 Use, Daily Tobacco Consumption, And Serum TTaabbllee 44..11..2109 LBSiomnuoeknairdnMTgue,lstDtirovisanrtkieairtnoegnReSet(gaTrtbeu)sssBAiynodBnoTMdooytdaelMlaSsOesfruiFmnadceFtxoI.rOsANgGee, ............ 82 Table 4.1.21 FMPrraeeledeiTcWetOisnRtgoKsTTtShe.erowBnoe.u(vn1do)TcBeysstBeoossdtsyernMonasesrs(nNigcn/dDeeIxe).sAAmsgoes,nsgm1s12snsns8n3 Table 4.1.22 L`iSnmeoakriMnugltAA invadriDartienkRienggrSetsastiuosnAMnoddeTlotOalf SFaecriuomrs 71 TTaabbllee 44..11..2243 LPDPiarrnrietendiakicrciitnMpiguanlnSgttTaEtshtuersaFdArineodle BTToeytsaBtloosdStyeerrMuoamnsesFVIaIOnlduReeEx,.(NAgg./e.D,.I.).S..m..o..k....i..no.g...............88.5. WPOreIdKiOcItSi.ngtc iTvhaeriaEo tsetrRadeigorn lesVsailounes M(Pogd/eDlIe )OAfmFoacn ntgors1.13t Males 67 a . 03182 - o . Table 4.1.25 LSumtoekniiznigngAnHdorDmroinnkein(gLhS)taBtyusB,oAdnydMTaostaslISndeerxu,mAge, `Table 4.1.26 FLiInOeaMrc Muttivao riate Rer gressis on Mode el #1 Ot f Factos rs , 88 Table 4.1.27 FAPorlTelIidciOlceNtiS1ntg1im3TuhlMaeatliLenugtWeOHnMoiKzrEimInoSg.nHsc or(mFohn)r eB*yVaBo loudey(Mr aMsMs)ie ndex, s 8 Table 4.1.28FLIAiUgneOe.aNrNSGmMuoc tkiiivnagriAs atnedRDergit rneksisngiosSntsaMstoumdss,erlAsnOsfdctFTeoatrcatelorSsserutm es, 80 Table 4.1.29 T(PhrMyeUrdoMiicIdt)iSnAtgMiTmOuhNleaGtFio1nl1gl3icHlMoearlSmetoiWnmuOalTaK(tTEisTnhSg).Hc BoyrBmooo dnye MVaae lsuee r, 81 `Table 4.1.30 LSIinOndReeaUxr,MMAFugItetU,iOvMaSNrmGio.aktc sinRgegArnedo ssDiroinnkMiov ndgeSltaOtfue sF,acAtnodrrr seTsotsal s 82 Table 4.1.31 P(PrroMeldUaicMctt)iinnAgBMyTOhBNeoGdTy1hy1Mr3aoMisadslSoItniW dmeuxl,atO Aigneg,R HSomromK koinnegS *, VDaril. nukein. g . 83 Table 4.1.32 LSitnaetaurs,MuAtnidvaTroitaatleSROeMgUreMsFsIiUonOMMNoGdv el Ofo Factr ors es,84 Predicting The Prolactin Value (Ng/M) Among 113 Male Table 4.1.33 PReatairossonAnCdorTroetlaaltiFolnuoCroiedfef,icAigeen,tsBBoedtyweMeanssHIonrdmexo,ne Table 4.1.34 PAecaorhsoolnACnordreTloabtaiconeDCoCefOlNiScUiMenPtHsIBOeNtw ween Pe rojacinerr s96 Table 4.1.35 PIHenoadrerxms,oonnAleCcooRrharoteliloaAstniAdonnTdCOoTbeoEftfCaiClcOiFelCnutOosrNiBSdeeU,tMwAPegIee,nONBT.hoyedryroeiMdramssrrsrsne 87 Table 4.1.36 PBSetoaidrmyusloMantaisCnosgrrIHenoldraetxmi,oonAnleCcooRehafotfliiocAsineAndtnsTdoBTbeoattcawlceoeFnlCuooFnroslilduiemc,pletAog.e.,........ 98 `Table 4.1.37 PBSetoaidmryusloMantaisCnosgrrIHenoldraetxmi,oonAnleCcooRehafotfliiocAsineAndtnsTdoBTbeoattcawlceFoelnuCooPrniistudumeip,ttaAirgoyen,........... 98 Table 4.1.38 LBGilonydecayorpMrMaoultstisievnIanrHdioeaxtr,emARolencgeorheRosalstAiioonsndAMTnooddbsTaloc1tcaoOlfCFolFnuasocurtmiopdrtesi,oAn.g.e.,........ 89 Table 4.1.31g 9 L(Pir1ne2edaiMrc2tMiu0nlgtWiTOvhTarKeiEaBLtoSeu.Rnv edg-rFerseseioTneo sMtoodsteeir2oc nOef RFaatcitooe rAsmong s 100 Table 4.1.40 LP1ir1ne2edaiMrc2tM1iun0lgtWiTOvhaMreKiEaBItoSe.uRnc edg-rFerseso sioTnesMto oodsteelrr OonfeFaRs cattioorsAsmons g n101 APrMeOdiNcGtin1g12ThMealEestWrOaMdKiEoTlS-.Bov und Teo stoster rone r Ratio ei 102 --v . 03183 o Table 4.1.41 LAPirMneOecaiNcrGtMiun1gl1i2TvahMreailaEotsetWaORceKigSorIleS-s.Fsriee oenTMeostdoeslte eOrfoFnaectRoartsir o Table 4.1.42 Linear Muilvarate Regression Model OF Faciors 103 Table 4.1.43 LWPirOneBecaOirIcSMi.unlgc ivTahreiaEiseirRaecge iralsLshisonRaMtot idoeAlmOofnEgac1t i1o2rsMale e104 Table 4.1.44 LTPirnIaecaMircEMiSunlglWiTvOhaRreEiIaBtSoo.uRno edgrTeessstioosnteMrr aodnse]-LOhfe FRaae tiioorsAmong o105 Table 4.1.45 LMPirIneeOdairWcMiOuntgKivSTah.reiaFireeeRoeTgersetesossitoesnroMnoed-aLlheOfRaFtaicos ioArmsongs 112 106 Table 4.1.46 LAPirMnaeOdaiNrcGtMiu1nlg1t1iTvhaMreailaBetoeWuROneKdgErTTeeSss.stioo ostneMroondea-lPr rOoflaFcatciinorRe sio rs rr107 Table 4.1.47 LAPirMneeOdaiNrcGtMiu1nlg1t1iTvhaMreailaFetreeWeROeKTgBersIetSso.ssitcoenroMnroe-dPerloolOaFcstFianciRsoartsioover108 Precicting TheEstradiol Prolactin Ratio Among 111 . Table 4.1.48 LPMirenaecOaircWtMiOunlgKtTvSahr.iaPc irsoRleagcriens-sr Fisohn@MRoadtieole AOmFoFnacgio1t r1s1 Male e108 Tablo 4.1.49 LPWirOneMedKaiErcIiMSnu.glio TvhareiaPirsolp Faocgirna-sLshiTMe onRMaotdioalAr mOfonFgaci1o1o r1sMale n 110 . Table 4.1.50 LPirneediacrtMinugiA vTahreiPirsolRaecgirne-sTsshiso.n MRoatdieolAOmFoFnagcio1r1s1 Male TT WOKEIS. erm Table 4.1.51 L1Pir1na2edaiMrcEtMiOunlgtWiTOvhMaKeriEaBItSoe.uRno edgTreesstsoisotnerMoonde ea.lTsOhfsFaRcattoirosAr mong roe 112 113 TTaabbllee 44..11..5532 LL1Piirn2neeedaaiMrcratMlMiuuonllgttWiiTOvvhaaRrerOiiIaaFttSree.eeRRr eeTggerrseetssosssiitooennroMMnooedd-eer TllshOOeffRFFaaatcciiiosooerArsssmsoor ng sero 114 Predicting The Estraciol-Tehs Ratio Among 112 Male TTaabblleo 44..11..5554 LLTPiir1nne2eedaaiMrcrtEMMiuOnutgiiWvvTOaahRrrKeiiOaaBItiSoee.uFonr sgdgrrTaeessssse tiiooosnntMeMc orododeneell-o OOFffshFFaaRm ccaittooirrossAm mongen116 Table 4.1.56 L1Pir1nd2eiacMrtaMiulnlgtWiTOvhaRreRiaIFtSree.eFv iTgeresstsoiosnte MeordoaFnlsehO+.fRFr aatciioorAsmono g 117 Pracicting Tho Estradiol-Fshs Ratio Among 112 Male vi 03184  Table 4.1.57 Linear Mutivariate Regression Model Of Factors Pradicting The Bound Tsh-Fshe Ratio Among 112 Male Table 4.1.58 Linear Muttivariate Regression Model Of Factors: Predicting The Tsh-Lh+ Ratio Among 112 Male Table 4.1.59 Linear Multivariate Regression Model Of Factors Predicting The Bound Lh-Fsh+ Ratio Among 112 Male Table 4.1.60 PFeluaorrsioden,CAogmee,laBtoidony CMoaesffsicIinednetxs (BBemtiw),eeDnaiTloytAallcSoheorlum Use, Daily Tobacco Consumption, And Lipoproteins................ 122 Table 4.1.81 LPirneedairctMiunlgtiTvhaeriaCtheolReesgtreeroslsiAomnoMnogde1l11OfMaFalcetoWrosrkers. ..........123 Table 4.1.62 LPirneedaicrtMiunlgtiTvhaeriaLtoewReDgenrseistsyioLnipMooprdoetlieOnfAFmaoctnogrs111 Table 4.1.63 Linear Multivariate Regression Model Of Factors Predicting The High Density Lipoprotien (Hdl) Among 111 Malo WOMKEIS. recess125 Table 4.1.64 LPirneedaicrtMiunlgtiTvhaeriTarteigRleycgerreisdseisoAnmMoondgel11O1f FMaaclteorWsorkers. ........ 126 Table 4.1.65 Pearson Correlation Coefficients Between Total Serum Fluoride, Age, Body Mass Index (Bmi), Daily Alcohol Use, Daily Tobacco Consumption, And Hepatic PRIGMGIGIS corer127 Table 4.1.66 PEenazrysmoens,CoSrreerluamtioHnorComeofnfeicsi,enAtnsdBeLItpwOepernOI8HieNpsat.i.c.................128 Table 4.1.67 Pearson Correlation Coefficients Between Hepatic . PBIAMBIBIS cvvvrscrsessrsrssssesssssesssersssnsssesssssssssssssessssssessssassss1ss2s9s Table 4.1.68 Serum Glutamic Oxaloacetic Transaminase (Sot), GGlluuttaammyilc TPryarnuvsifcerTarsaen(sGagmti),naAsned(ASlgkpatl)i,nGeaPmhmosaphatase Table 4.1.69 S(eAkrpuhm)GBlyutTaOmt@ilc SOxMalMoacFsItLiOcMTNrGacn.scvaemevienceaeserese(esSrgeoerte)rsBssycssesesssssan1e3es0s Table 4.1.70 SBeorduymMGalsustaImnidcexP,yAnugvei,cSTmroaknisnagmiAnnadseDr(iSngkpitn)gBSytatBuos.d.y...........131 Mass Index, Age, Smoking AndDrinking Stats ror 132 Table 4.1.71 Gamma Givtamyi Transferase (Got) By Body Mass. Table 4.1.72 AIlnkdaelxi,neAgPeh,osSpmhoaktiansgeA(NAdkpDhA)NBKyINBGoSdIyBMMUaSscsovinedreex,vmAgsee,sveenr13n3s. Table 4.1.73aSLMiOnKeiarngMuAltNiGvaDrAiNatKeINRGegSrIesNsSio.nrMvordcaelr1crOferFaccttrorese. rermnses1n3n4 Predicting The Transaminase Serum (Sgot) Glutamic Oxaloacetic Among 111 Male Workers. ...............135 Table 4.1.73b PLriendeiacrtiMnugltTivhaeriSaeteruRmegGrleustsaimoincMOoxdaelloa2ceOtficFactors Transaminase (Sgot) Among 111 Male WOrKers. .............1.3.6. " GO3185 o: o Table 4.1.73 PLriendeiacrtiMnugltTivhaeriSateeruRemgGrleustsaimoincMOoxdaelloa3ceOtficFactors Table 4.1.74a PTLrirenadeniacsrtaiMmnuiglntTaihvsaeeri(SaSetgeroufR)megAGrlemusotsnaimgoinc11MP1oydrMeualvlice1 OWforFkaecrtso.rs............ Transaminase 137 Table 4.1.74b PL(rSieSndPeiYac)rtiMAnugMltOTiNhvaeGriS1ae1te1ruRMmeaglGreleusWtsaOimoMincKMEPoyTdneuSlv.i3c.OT.rf.aFn.asc.airmori.snoasoerm.. 138 Table 4.1.74c PL(rSiGenPecYai)rciMAnuglMtOTivNhaeGriSa1te1e1ruRMemaglrGeelsuWstiaOmoinTcMPKoydrEeulvIi3cSOTFr.acFno.ascoai.nmori.snsa.seec.c.. 138 Table 4.1.75a P(LrSieGndPeiYac)rtAiMnuMgtOiTNvhaGeri1Ga1ta1emMRmeaglaroeGWslOsuKtiKaoBmnIySMi.oTdv realns1faOrf. aFsasc(iGogrts4 ) 0 Table 4.1.75b PALriMenOdeiNacrGtiMnu1gl1t1TihvMaearilGaetaeWmORmKeaEgrTeGSsl.usr tiaomnyMloTdrasns3fe eOrfaFsaec(toGrgs) o141 Table 4.1.75 LPAirMneOedaNircGiMnu1gl1t1TivhMaearilGaetaeWmROmeKgaEreIGslSsu.it.oanm.yrMlooTdcraoalrns3efreOrfaFo sasc(iGogrr ts) . 142 Table 4.1.76 LPiArneMecOairNctGMiunl1gt1iT1vhaeMriaaAltleekaWRlOeingKerOeIPshSso.isor pnhMaotado seel (1AOks fphF)acAimoc orsng 1o 11 e143 Table 4.1.77 PFMelBuaorErsioWdenO,MCKAoEgrLerSe,.laBw toidoyn CMoassfsicIineo dnetxs (BBerti)w,eeDano llTyotAallcSoheorlums en 144 Table 4.1.78 LPUisAneIe,aBrMDaMEluEllLytiSTvo oarbiaactecoReCgornessusmipotnis oMno,deAlnOdfHFeamcaitoorlsos gy 145 Table 4.1.78 LPPirrneeeddaiirccttMiiunnlggtiTTvhhaereiaMHteeemaRanegglCrooebrspisunisoAcnumloMaonrdgHeel1m1Oo1fblMFaoalbcetionWrsO(Mrckhe)rs.......1.4..6 Table 4.1.80 LPAirMneeOdaiNrcGtMiun1lg1t1iTvhaMerEiaMEteeWaROneRgKCrSoe.rs.p.suise ocnulMaordVeollOufmt eFa(cMtoovr)s Amos ng 147 Table 4.1.81 LPIirTneTedaiMcrtBMiEuntgiWTvOahTreKiBaWIthSei.tReo egBrleososdioCnallMoCdoeuo lntOf(WFbaec)i*orsAmom ng nn148 Table 4.1.82 LP1irn1eedaiMrcRtMiIunSlgtWiTvOhaerKiaPStoe.lyRo meogrrpehsosinounciMv eoadrsL!eOukfoFcaue ctieorCsount r 149 Table 4.1.83 LP(irPneoedlaiyrc)tMAiunMtgOtiTNvhGaeri1aB1ta1enMRdeagClroeeuWsrOstMiK(oOBnIaMSno.dd)aAlmcOofcnFgcac1i1o1rsMale 150 Table 4.1.84 LPirneecairctMiunlgtiTvhaeriaLtyempRehgorceystseioCnouMnotde(lLyOmfphF)acAiomresng 111 vii 03186 o o o `Table 4.1.85 LPirnaecairctMiuntgtiTvhaeriaMtoenoRecgyrteessCioounntMo(dMeolnoO)fAFmacotnogrs111 Table 4.1.86 MJ WOTKETS. cuvvvvvvssvessssesvresressesesasssessssssssssssssssssssssneee Linear Multivariate Regression Model Of Factors. 153 Table 4.1.87 LPirneedairctMiunlgtiTvhareiaEtOeSRIeNgOrPehslsCiOoUnNMto(dEeOlS)O.f.uFvaecrtvovrrsr.rvrvrvrrs nnn 154 Predicting The Platelet Court (Plate) Among 111 Male Table 4.1.88 LiPMnreIeadOriMcWutliOtnigKvTaSrhi.eato BeaRseogprhielssCior ounnMto(dBealsoO)fe AFmacotnorgs.11s 1 156 Table Table 4.2.1 4.2.2 Characteristics Characteristics Of Of 749 Female Employees, 1947-1989........ --r-14 2788 Male Employees, 1947-1990................ 158 Table 4.2.3 Vital Status And Cause Of Death AscenainmentAmong Table 4.2.4 Vit7a4l9StFaetmuaslAenEdmpClaouyseeesO,f 1D9e4a7t-1h:AE scenainmS ent Among---- 1 2788 Male EMPIOY@@S, 1947-1988. ..c.cecerevereeeeresrrrrrseneenn Table 4.2.5 Numbers Of Deaths And Standardized Morality Ratios 159 Table 4.2.6 (Smrs) Numbers Among 748 Female Employees, 1947-1989. senranenenens Of Deaths And Standardized Mortality Ratios 160 E(MSmPrIsO)YOEBSy,Dc uration Ofo Employmer nt Amongm Female s 161 Table 4.2.7 Numbers Of (18S8m9r.s) By Deaths Latency AAnmdonStganFdeamradliezeEdmpMolrotyaelietsy,R1at9i4o7s reese 162 Table 4.2.8 Nu(mSmbresr)s BOyf DAenaytEhsmpAlnodymSetnantdianrdTihzeedChMeomrtiaclailtyDRiavtiisoiosn Among Female EMpIoyees, 1947-1989. w..r...vrreo.....1.6.3 . Table Table 44..22..190NNu(umSmbmbsee)r,rssOBfOafsDDeeeadatOthnhssAUAn.nSd.dSWSthtaiantndedaraMdraidlzieezdeRdaMtoMerostra,nlaiitfytycRaFtaoitoesvs ..1.64 (Smrs), Based On Minnesota White Male Rates, Among 2788 Male Employees, 1947-198. ........................165 Table 4.2.11 N(uSmmrbse)rsByOfLaDteenactyh,s ABnadseSdtaOnndaMridninzeesdoMtoartWahliittye RMaatlieos Table 4.2.12 Rates, Among Male Employees, 1947-1989, evsssssnssssnsnsnnnnns 166 Numbers Of Deaths And Standardized Mortality Ratios (Smrs) By Latency, Based On Minnesota White Male Table 4.2.13 Rates, Among Male Employees, 1947-1988. rn N(uSmmrbse)rsByOfLaDteeanctyh,s ABnadseSdtaOnndaMridninzeesdoMtoartWahliittyeRMaatlioes Table 4.2.14 Rates, Among Male Employees, 1947-1989.srenssnssessrssssssisnenes Numbers Of Deaths And Standardized Mortality Ratios 168 (Smrs) By Minnesota Duration Of White Male Employment, Rates, Among Based Male On Employees, Table 4.2.15 1947-1989. seers N(uSmmrbse)rsByOfDuDreataitohns sss esssrsasssrssess er sssssesssssssassessens OAfndEmSptlaonydmaerndti,zedBaMosretdalOitny Ratios 169 ix 03187 [J . Table 4.2.16 N1Mui9mn4bn7ee1sr9os8t9aO.fWo DhietaethMsas lAendRaStteasn,dAatrmdsoisnzgesdsMMeaorrlaseleiErtmypelFtoaeytsaesass, 170 1M(9iS4nm7rn-se1)s9o8Bt9ya.DWur hriatteioMnalOef ERamtpelr so,ymAemnotn,gBaMasler edEOmnpleoyeets, e 71 Table 4.2.17 N(uSmmsb)e,rsBOafseDedaOtnhsMAinnndeSstoatnadWahridtiezeMdaMleorRaateys,Fatos `Table 4.2.18 NCAuhmmOoMbnIegCras1I3OD3fI9VDIeMSIaaOtlNhe,sE1Am9n4p7dl-oS1yt9ea8en9sd.av ErvdeirzeEdmo pMolrotyaieir dtyInRaTthie oes. s 172 CA(hmSemomsni)gc,a1lB4Da4is9veiMsdiaoOlnen, E1Mm9i4pn7ln-oe1ys9oe8te9as.WvNheivvteverrMEamvlperloRrayteeedsr,ien Tvhse esss17e3 Table 4.2.19 N(uSmmbse)rBsyOfLaDteenactyh,s ABnadseSdtaOnndaMridninzeesdoMtoariWahiiftyeRMaatlieos Table 4.2.20 NTRuhamteebsCe,hrOAsmmiOocfnaDlgeDaIMtVahIlsSIeAONEn,mdp1Sl9to4ay7ne-de1as9r8dN.iezvev edrMEoro mtpalliott yyeadtIe on s r. 174 . CR(aRStEmerMssI,)CaABlmyoDLInaVgItSeInOMcNay,l,e19BE4am7sp-e1ld9o8yO8e.nesMiEnovneeresEostmaplt Wohyiter ed MInale Tehe es 175 Table 4.2.21 N(uSmmrbse)rBsyOfDuDreataitohnsOAfnEdmSptlaonydmaerndti,zedBaMsoretdalOitny Ratios Table 4.2.22 NEMuvimenrbneeEsrmosptlaOofWyhDeiedtaetInhMsTahlAeendCRahStetemasin,cdaAalrmdoDiinzvgeisdiMoMnoa,rlte1a9lEi4tm7yp-1lR9aot6yi8eo.ess........176 : M(iSnmrnse)soBtya DWuhriatteioMnalOef REamtpelso,ymAemnotn,gBaMasleedEOmnployees Table 4.2.23 NEuvmebreErmsplOofyDeedatInhsThAendChSetmaincdaalrdDiizviesdioMno,rt1al8i4t7y-R1a9t8i9o.s.........177 NM(ieSnmvrneser)sEoBmtypalDWouhyriaettdeioIMnnaTlOehfeREamCtphelesom,yiAmceamnlotnD,igviBsMaiaosnle,ed1EO9m4n7p-l1o9y8Se.e.s........178 Table 4.2.24 N(uSmmrbse)rBsyOfDuDreataitohnsOAfndEmSptlaonydmaerndti,zedBaMosretdalOitny Ratios Table 4.2.25NAeMgvienenAredsjEoumtspatleWodhyiSettdeanIMdnaaTlrhedeiRzaCethdeesRm,aitcAeamloRanDtigivoissMiao(nlS,es1E)9m4Fp7ol-ro1yA9l8el9e.s........179 JDCua9ru4ast7ei1,o9nC9aO.nfct Eerm,plAonydmeCnatr,dir AomvaosncgulaMralMoee raElmiptiyoyBoyes, n 180 Table 4.2.26 ACgauesAed,juCsatnecderS,taLnudnagrdCiaznecderR,aiGsI RCaatnicoesr,(SAmns)d ForAll 1TC9har9ed.CiohveamsiccuallarDiMvoirstiaolni,tyABmyonEgveMra/lNeevEemrpElmopyleoesy,ed19In47- 181 03188 ---- -- : " Table 4.2.27 A(gRehS)traFtiofrieAdl,l YCeaaursse,OfCaFnoclelro,w-AUnpdACdajrudsitoevdaRsacutleaRratios Table 4.2.28 MDiovniasilotny, ABymoEnvger/MNaelveeErMEpmIpOiyoeyese,d 1In94T7h-e18C8h8e.m.i.c.a.l...........182 Age Stratified, Years Of Follow-Up Adjusted Rate CRaartidoisov(aRsrcmuhl)arFMoorrAallliCtayuBsye,DCuarnatcieorn, OAfndEmployment In The Chemical Division, Among Mala Employees, 1947. Table 4.2.29 Proportional Hazard Regression ModelAOfA FactoA rs A) Predicting The All Cause Mortality Among 2788 Male Table 4.2.30 PPrroepdoircttiionngaTlhHeazCaarrddioRveagsrceuslsairoMnorMtoadlietly OAfmoFancgto2r7s88 Table 4.2.31 PMroIporWtiOoTnKaAlISH.azc ard r Regrese sions Modelc Of Fe aciorn s ts184 Table 4.2.32 PWrOeIdKiEcItSi.ngr The CancerMortalv ity Among 2788 Ms ale 185 Proportional Hazard Regression Model Of Factors . Predicting The Lung Cancer Mortality Among 2788 Male Table 4.2.33 PPrroepdoircttiionngaTlhHeazGairCdanRceegrreMsosniaolnitMyoAdmelonOgf 2Fa7c8i8orMsale Table 4.2.34 PWrOoKpoErItSi.ono al Hazard v Regressione Model Of Fn actors s 186 Predicting The PA rostate Cancer Mortality Among 2788 Table 4.2.35 PPrroepdoircttiionngaTlhHeazPaanrcdreRaetgirceCsasinocnerMoModretlalOitfyFAamctoonrgs 2788 Table 4.2.36 PMro0portWiOoInKaBlISH.azc ard Rego ressionr Model Or f Factore s s 187 Table 4.2.37 PMraelcoicWtOiTnKgETThSe. Dw iabeteo s Melltr us Mortas lity Ame ong 2n 788 s 187 Proportional Hazard Regression Model Of Factors. Table 4.2.38 PWPrOroeMpdKoiErcIttSii.onngoaTlohHearzAalrlrCdsasuFessgerraMsoisrailotintsyMosAdmseolnnOgrf7Fs4ac9stoFrses.mealsessss18n8 Table 4.2.39 PFPrrOoeMpdoAirIctt0iionWngOaPlTKhHBeaIzSC.aarrv ddioRveagsrceusle sairoMnorMtoadlier tlyOAfmoFancgtv o7r4s9 sse s 188 WPOreTdKiEcItSi.ngc The Canco er Mortalr ity Amonr g 749 Fee male s 188 5 03189  LIST OF TABLES Figure Figure 1. 2. BForeuendTeTsetsotsotsetreornoeneVaVresrussusToTtoatlalSeSreurmumFIFUIOOMFNNGe....c.c................................. 180 191 Figur Figure 3. 4. LEsuttreandiizoilngVeHrosrumsoTnoetaVleSresrusumToFtIaUlOSMIeNrGuw m FIo ONG. ....... ....... ...... 152 183 Figure Figure 5. 6. Folicle Stimulating Hormone Prolactin Versus Total Senum Versus Total Serum FIONG we... Fluorine ......... 194 185 Figure Figure 7. 8. Thyroid Stimulating Hormone Bound Testosterone To Free Versus Total Testosterone Serum Fluorine.......... Ratio Versus 196 TO12l SIUM FIUOMNG worsens 197 [-- 03190 o Laman Fluorine wes first isolated as an element in 1860 by Moisser '. Five years later he synthesized the first fluorocarbons through uncontrolled reactions of carbon with elemental fluorine. It was not until the late 1930s that the controlled synthesis of fluorocarbons became possible. In the 1940s, Frigidaire and DuPont developed chlorofluorocarbons, the first commercially available fluorocarbons, for use in refrigeration '. During the same period perfluorocarbons, a subclass of perfluorinated synthesized to organic fluorocarbons with meet the special needsof uni the que properties, Manhattan pro were ject 2. first The electrochemical flucrination method for perfluorocarbon production made commercial production of perflucrocarbons possible and opened the door to `widespread use of perfluorocarbons 3.4, Fluorocarbons are wide ranging in theirstructures and uses. Many commercial applications have been developed for chiorofluorocarbon compounds including refrigeration, degreasing, aerosol dispensing, polymerization, polymer foam blowing, drugs, and reactive intermediates or catalysts. Perfluorocarbons (PFCs) `have extensive applications because of their unique physical and chemical properties. These applications include use as artificial blood substitutes, computer coolants, polymers such as teflon, surfactants, lubricants, foaming `agents, ski waxes, and in an extensive specialty chemical industry which : produces grease and oil repellent coatings for paperand cloth,polymers, insecticides, and a variety ofconsumer products. Perfluorocarbons are currently being tested as replacements for chlorofluorocarbons in industrial processes and products. For many years fluorocarbons were generally thought to be nontoxic. Perflucrocarbons were considered to be particularly nontoxic because they were chemically and physically inert and showed low acute toxicity in animals 4. Recent epidemiological and experimental studies have associated exposure to chlorofluorocarbons, a subclass of fluorocarbon previously classified as nontoxic, with direct and indirect adverse human health effects. Subsequently, researchers and regulators turned their attention to the study of other fluorocarbons. The discovery that one perfiuorocarbon, perfiucrooctancic acid -1 03191 o (PFOA), was present in #7, the recognition that measurable Quantities some perfiuorocarbons in residents including P of several FOA have U.S.cities long halt lainviemsalins,thienchluudmianng shepaatnodtotxhiecitoyb,seernvdaotciroinnsethtoaxticPitFy,OAimmpurnootdoixciecdittyo,xiacnedffects in pcearrfcliunoorgoecnaersbiosns,, hpaarstilceudlatrolya PrFe-OeAv,aliunathiuomnaonfst.he toxic potential of Despite widespread exposure to perfluorocarbons, little is known about their eefxfpelcotrseotnheihrupmhaynsiohelaolgtihc. efttfewcatssaanpdpaproetnenttitahlataaddvdeirtisoenahleaslttuhdioeustdceosmiegsneadndto conducted in an occupational cohort with high exposure to PFCs, were necessary. The 3M Chemolite Plant located in Cottage Grove, Minnesota is one of a few PFC production facilties in the world. Biological monitoring data from `studiesofthe Chemolite workforce showed and long durations of exposure to PFOA &1 that employees have 0. This occupational had high levels cohort provided the opportunity to study the effects of PFOA on humans. The specific goals and objectives of this study were: GOAL 1) following To quantify the human effects physiologic parameters: of perflucrooctancic acid on the ha)orHmoornmeo,ntehsy:rofirdeesiamnudlabtoiunngdhotersmtoonset,erpornoel,acetsitnr,adainold,lfuotleinciezsitnigmulating `hormone. b) Serum lipids and lipoproteins: cholesterol, low densitylipoprotein, high density lipoprotein, andtriglycerides. ) Hematologic parameters: hemoglobin, mean corpuscularvolume, t`wyhmiptehobclyotoed ccoelulrtc,oumnot,npooclyytmeorcpouhnotn,upcliaetealretlecuokuontc,yteeoscionuonpth,ibl acnodu`rcto,u nt, and `basophil count. -- 2 03192 oe Si) aHempatipcy enzymaesr:sesmeriunmasgl,utgaamimcmoaxaloaacmetticFtraanrsalmein,asea,nsesreuamine phosphatase. QRIECTIV1E: to conduct a cross-sectional study of production workers to estimate the relationships for prefluoroocianoic acid, between total serum fluoride, and physiologic parameters. a sumogate assay GOAL 2)To quantity the mortality in an occupational cohort with long term `exposure to perfiuorooctancic acid production. aOsBsJesEsCtTheImV2orE:taltiotcyoenxdpuecrtieancreetorfoswpoerckteivres cuoshionrgteoxcpceucptateidonmoarltasltiutdyybtaosed . `on Minnesota mortality rates. " : ~3 03193 2BEOV FTHI ELITE ERATW URE 2n1troduction 1T8h5e6pr1.eseMnocree otfhsamnal1l00amyoeuanrstslaotefr,flTuoarviedes in 5 huprmeasnenbtleododevwiadsenrceecotghantizfeludorinine cxosvtalsenitnltywbooumanjdororfgoarnmisc isntahteu.maPnrisora1ndtahinsimraelposr;t,initawfarseeaisosniucmsetdattehaatndfluinoraine existed primarialsy inorganic ionic fluoride in biological systems. Tavs' doibssceorvveartyiotnhsathoarvgeansoifnicueorbieneenccoomnpfoirumnaddsbcyonssetvietruatle otthheemraijnovreisttyiogfatfourosri1n21e6f,ouTnhde in humans identifieda fpoecrufsueodrirneasteeadrccohmopnoucnhadr,acptaerrfiuzoinrgootchtoasneoiucndaecfdin(ePdFcOoAm)p,oausndasm.ajGoury. constituent of (PFOA) is the the serum organic fluorine fraction only organic fluorine compountdo 7-17. Perflucrooctanoic acid be identified in human serum 8. `The recognition of human and animal perfluorochemicals * 1, has renewed toxicities associated with interest in understanding the human health effects of perfluorocarbons (PFC), particularly PFOA. 20min ' cOrogmapnoiscefdluoofrfolcuhoermiinec,alcsa,rbootnhearwnidseotrheefrererleedmteontass sfulcuohroacsarobxoyngse,na,rneitcroomgpenouanndds hsuyldfruro.gePnesrfalrueorexohcaaursbtoinvsehlyavreepsltarcuecdtubryesflaunoarlinoego2u,sAtolihmyidtreodcnaurmbobnesr,oefxocregpatnitche fluorochemicals occur in nature 21-2, however no PFCs occur naturally 24.25, MTohiesfsiarsnt rcelpaoirmteodfttohehasvyentphuersiifsieodfcaarfblounortoectarrafbiounorwiades. pItubisliiskheleyd hine1i8so3l0atwehden fluorographite, however 1. Pure #. Work by Ruff and the Belgia carbon tet n chemist, rafluoride Swarts, in was the not late obtained 16th and until 1930 earty 20th ecexntteunrdieeds lSawiadrtthse' wfoournkdaatnidonreopfoorrtgeadntihceflsuyonrtihdeescihseomfisdtircyh.loMrioddeigfliyuoarnmedthHaennen,e --a 03194  : - L . CizF2, in 1830 27. This chiorofluorocarbon with the trade name Freon 12 is an ine, non-toxic refrigerant which was vastly superio1or other refrigerants available in the 1930s. After commercial production of Freon 12 began in 1836, rapidly became a major industrial chemical 2 2. A numbeorf cholorflucromethanes and chioroflucroethanes have been produced on a `commercial scale in many regions of the wortd. These chiorofluorocarbons have been used in large amounts as aerosol propellants and degreasers, in addition to theiruse as refrigerants. Currently, their production is being reduced as a result of their ozone depleting properties 2.2, In 1937, Simons and Block developed a method to produce laboratory quantities of perflucrocarbons, such as C3Fg, C4F10. CycloCsF10 and cycioCsF12 23, The `analysis of these compounds led10 the understanding that many of the structures of saturated hydrocarbons could be replicated in the form of perfiuorocarbons. Research in the area of perfluorocarbons was stimulated by two developments. First, Plunkett discovered the polymer, polytetrafiuoroethylene, of Teflon . Second, the development of perfluoracarbon chemistry was stimulated by the USS. effort to develop atomic weapons during World War ll under the Manhattan Project. The 235U isotope of uranium was required for the development of atomic bombs. One method of uranium isotope separation was gaseous diffusion. The only volatile uranium compound available for use in this diffusion process was + uranium hexafluoride, UF, an extremely reactive gas. Materials ware needed for use as coolants, lubricants, sealers and buffer gases in equipment exposed to this highly reactive gas *2 25. Perfluorocarbons prepared by Simons wers found 10 be inert to UF. This discovery led to a research effort directed toward understanding the propertiesof a variety of perfluorocarbons and developing commercial mathods for preparation of perfiuorocarbons. The development by Simonsof the electrochemical fluorination (ECF) was a major milestone in the fuorochemical industry. Since World War If there has been much interest and workin this new branch of organic chemistry based on perflucrocarbons. The use of Simons' ECF method has allowed tha production of a wide variety of perfluorocarbons including perfluorinated alkanes, alkenes, ethers, esters, amides, sulfonamides and compounds with cyclic perfluorocarbons are compounds made up of only and ring carbon structures 2. and fluorine. The This nent" class 5 . 03195  [) : L sotfrcucotmupreosunsducshraasngpeesrlflruoormocdeacrabloinn,tePterrafflluucorriidneatteodcsoumrfpalcetxanmtusltiinpclleudreingcarboxylic aacnidesx,tesnuslitovneicfiaucoirdosc,haemnidcatlheiirndduesrtirvya.tiAvevsa.riTehteysoef cpeormfpluoournindastefdopromltyhmeerbsasainsdof sellaassttoommaerrsofexviisnty.lTdhieenemoflsutorwiiddeealyndusheedxaafrleuoproolpyrtoeptyralfainueo.rosthylene and Kel-F, a 2.3 PhysicalProperties Perflucrooctanic acid is a straight chain molecular waight of 414.16. The melting sight point carbon carboxylic acd with a of POFA is 59-60C. hs boiling poirt is 189C at complex mixture softabnrdaanrcdhceodndcihtaiionnsis*o.merPse.rflInuoprroaocctticaen,oiaclaeciigdhtiscparrobdounced as a c(aArPbFoxOyRl)icisactihde icsoommemrosnairnedursetfreiraelldytuosaesdPfFoOrAm.ofTPhFeOAa.mmIonisiaumwhsiatst corfysPtFalOliAne powder that easily becomes airbome and sublimes at 130C. iPmeprofrltuaonrcaceaorfbopnesrflhuaovreinuatniioqnueincphreomdiuccailngantdhepsheyspircoaplerptrioepserctainenso2t0.b2e6. 31.32, The overemphasized. Perfluorocarbons are molecule. Chemically, perfiuorocarbons not just another are remarkably hydrocarbon-iike inert. They are stable to abpoiplriencgiianblsytrwointgh apceirdfsluaonrdocbaarbsoenss..VPeerryfflueowrooxciadribzoinnsg othratrecdounctianignaogtehnetrsorrgeaancitc: - smiotleoefcutlheessseumcohleacsulnietsr.ogFeonr, ionxsytagnecne,apnedrfsluulfourrocwtilalnpoayrltsiuclifpoatneicinacriedacwtililonraetactthaend cfoonrjmutghaetesdulwfiotnhammaidneydoetrhiveartoivreg.anTihcecaommipdoeunpdorst.ioTnhoef tpheirsfimuoolreicnualteedcpaonrttihoennobfe these larger molecules remains non-reactive. wPietrhfoluutorborceaarkbdoonwsna.reAthheiagthsttaebmlpee.raTthureeysc,agnrebaetehreatthaend to 40 greater than 250C 0C, some compounds vainllebxrteraekmdeloywnt.oxFicorgaesxa*m.pBleec,aPuTsFeEm,obsrtepaekrsfdiuoowrnocthoepmiecraflusoraoriesohbeuattyslteanbele(PtFhIeBy), are used in high temperature applications. 6 03196 : o . ! : : aTnhde iinneenritspPeFrfCisu,orsouccahrbaosnspearrfelueoxrcoelhleexnatnei,nsualraetoursse.dPionleylmeectrrsi,casluacphplaiscaPtiToFnEs, pbreocpaerutsieesofmtahkeier spueprefrliuoorrodciaerlebcotnrimcaptreorpiearltsietsh.e Tihnesiurlahteoarst sotfacbihloiitcyean29d, insulation kPenrolwlnuonin2at.edFisuuorrfoaccheesmiarcealthseurmfoacsttanntosn-arweetsaobmlee aofndthneomno-sadthpeostievnet ssuurrffaaccees saucrttivaectaagnetsntesffyeecttidvielsycorveedruecde2t"h.eVesurryflacoew cteonnscieonntraattiinotnesropfhafsieuobrooucnhdeamriiceasl, `MTohsety pfeorrfmlauagrroocuarpboofnsfuaorreopphoiolritcycsoomlpuobluendins,bohthowaeqvueerosuosmaendpeorrugaonrioccasorlbuotinosns. PweitrhflfuuonrcoticoanrablongrloiuqupiscssduicshsoalsvethoexsyagletsnoafviPdFlyO.A,Thairseuhniigqhuley wparotpeerrstoyliusbtlhee3ba3s2i,s forthe use of perfluorocarbons as blood substitutes . Perfluorinated carboxylic and sulfonic acids are some of the strongest organic acids known hey existin 2". The pKa of PFOA is primariy anionic forms. 2.5 The 3. Thus, when in physiologic solutions, anionic forms have a strong propensity 10 form complex ion pairs." pIrnotpheertpiaasst,ofsommaenyinfvueosrtoigcaatrobrosnhsaivsesaysnsounmyemdoutshawtitthhelcachkemoifcaacltiavintdy ipnhybsiioclaolgic systems 35.38, However, abundant evidence exists that their chemical and physical inertness does not implybiologic inertness 19. 30.37.38, 2S.4ynthesis eSlyenctthreoscihseomficfaulcfruoocrairnbaotinosnh(aEsCFb)e,endiraeccctofmlpuolriisnhateidonu,stienlgeofmoeurrimzaajtioorn,meatnhdods; catalyle mathods Simons in 1841 2. using high valence heavy metals. The Simons process is the oldest The ECF was developed by commercial technique and remains a commercial methodto obtain many perflucrocarbans.A solution of S-- r ---- personal communication from James Johnson, 3M Corporation -7 L - - 03197 | | ! | f i noircgkaenliacnsoudbes.trTahtee ipsrsoldsuccttrsloyfzetdheisnaaenlheycdtrrooluyssisHFcealtraealcotwiovnosltaargoe,lahriggehlycurren, perfuorinated. by the starting mTahteerisaple,ctCroummmeofrcmiataelriparlodpurcotdsucferdombtyhitsheprEoCceFssprionccelsusdeis defined ppeerrfflluuoorrotorailaklaknyelsa,mpienrefsu,orpcearlfklyuloreotchaerrbso,rypleircfaicuirdosaaknednspse,rlpueorrfolsuuolrfooanlikcy esters, acids 2, fPrraogdmuecnttsatoifoEnCpFroodfutcetns.inFcolruedxaamspilgen,ifiEcCanFt pprroopdourcttiioonnooffcPoFmOplAexfriosmosmterrasigahtnd cofhapirnodouccttasnofircomaceiadcphroEdCuFcersun30is%uncpormepdliectxabblryanvcarhicabhlaei.nTihseosmeerissom,erTihcemmiixxetsure abr6eedxipfoicsuetdtotosaepcaormaptleeaxnmdixptuurreyt.hat Wcohraknegress pcroomdpuocsiintgioPnFoCvserustiimneg.ECF may sDuirbejcetctfeudortionatthieonimispuanroythperrobmleetmhsodasussoceidattoedprwoitdhuctehepeErCflFuoprrooccaersbso.nsDi.rectis not : fisuoerxitnraatmieolnyrreeaaccttsivfel,uodriirneectgafsuowriitnhathiyodnrioscaartbeochnniscuablsltyradtifef.icBuletcparuosceesfsluaonridnehagsas only recently been pilot tested for commercial production of fluorocarbons. TWhorel3dMprCoodrupcotriaotnioofnfoupoerroactaesrbPoFnsCipsrloidmuicttediotno palahnatsnindMoifnnceosmomtear,cilalilnopilsa,nts. coAnlsaobratmiauamnpdroAdnutcweerspf,imBietlegdiaummo.uAntploafntfuinorHoaclayrobwonnse.dPbeyrfaluJoarpoacnaerbsoenasnadrehaallisaon produced Union. in Germany and have been produced, in the pas, in the former Soviet 2.5 Sources OfOrganic Fluoride Exposure Guy 17 `human prese blood nted possible based on obs candidates for ervation made the dur organic fluorine ing the isolation constitue of PFOA nts fro of m spreortuemi.n oTrhneucolregiacnaiccidf,luboericnaeuwsaesofnoittslsiokleulbyitloitbyeinaomrgaacnriocmoslolevceunltes ssuucchh aass aether rofemcholvoerdofoonrmc/hmaertchoaanlola.t pIHt w3aastnrootocmovtaelmepnetrlaytburoeu.ndTthoeaslobluumbiilntsyicnhcaerafct twearsistics suggested that multiple compounds existed with cifferent polarties. The major 8 03198 I o | ' La . AL lceosmsppooluanrdcwoamspo2upnodlsaaipppiedalriekedmtoolbeecuplreestehnett.waThsiisdecnattiafiseudgagsesPtFsOAth.at Ogher wfelrueornooctomesptoeurnscosf oCt1h3e.r.t1hanfaPttFyOaAciwdseraendbowuenrde tloesaslbpuomlianr.thTahnePseFOcAo,mpouncs dPeesrcfriiupotriooonctaanndy!msauylfboenacmoindsett(uPeFntOsS)ofatnhdeiosrgdaenriicvaftuiovreicnoemfpraocutinodn.s fAitthhoisugh exposure is probably 10 measurable levels. low. the properties of PFOS suggest that t may accumulate efIsunsecerominintaerlaclsoytnttoenitonoifcwfautoerirdaen,dltbelvheraasgbees.enTrheepoflnueodricneonccoemrennintgotfhgeroorugnadniwcatar is caroxylc al in ionic form. acid surtactants Some fluorochemicals, such and their sals, are soluble in as the water. perfuorinated Such water isnodluusbtlreialcopmaprotusntdhastmuasey tlohceaslelyccoomnptoaumnidnast.e Ostuhrefarcpeerafnlduogrrionautneddwcaotmepronuenadrs ch a5 the alkanes, alkenes, and aqueous solutions, Although data ethers on the are oral fluorophilic and organic fluorine ar insoluble in intakeis limited, it is unikely humans. that water and beverages are significant sources of organic fsoring in STuhbjeedcitstofasspaecsuolautrisoonf&t.h&e1%o.r4g,aniNconf-lpuoerrifnueofroiunnadteidn fhuuomraoncosmeprouumnhdasshbaevaenftohuend in biologicalsystems.Marais showed that fluoroacetate was thecompound OrtehsepornisnivbelsetifgoarttoorxsichitayvferfoomutnhdepploaintsosnpoeucsiepslatnhtatDsiycnhtahpeestiazleufmuocryomacoestuamte,41, pfluaonrtosciptrraotdeu,caenfdlumoornooafcieutoartein4a,tedFlfuatotryoaacciedtsa.tePaetnadrfsluroerpoocritteadtethhatavaefbeewtaonxfiocund rinepboeratends tghreoowcncuinrrheingcheflouforfildueorsoociiltr2a,te metabolic activation of fuoroscstate Peters 21 and Lovelace et in a few plants and foods, al. Z have In animals, the Iransport of citrate into the mitochondriitaoa(n)d-ecriyttrahtreo-bfrueoarokcdtorwantebbyleoccoknsitthaese 42. r2"229p.i2dOrtdehesefulrlutooormfiengoaxati-idfoaanttitoyn atchiadtspwriotdhuceevsenflnuucmrobaecrestatoef.caFrlbuoornocaittormatseaarlesohuingdhleyrtgooxiecs low environmental in rat levels, ltihveeriinnfrtehqeupenrtesoecnccureroefncgel,uttahtehitoonxieci(tGy,SHa)nd"t.heGirvapeind the ~ ; 93199 | o . o ! ! `metabolism of these compounds in mammalian species, i is unlikely that these monofiucrinated compounds contribute substantially to the organic fluorine content in humans. Taves measured the organic and inorganic fluorine in 83 food items 45, No. significant organic fluorine was found in the tested foods. Ophaug and Singer tested a market basket of food. They concluded that there was no significant erganic fluorine content in food. Although food and beverages generally do not contain PFCs, itis possible that they may be contaminated by fluorochemical packaging materials. Waterand grease repellent coatings in packaging material could leach into food items in small quantiles. This could occur whan materials thhaavtearnoetnboteednesriegpnoerdtefdorthmaitcqruoawntaivteyuhsuemaarne euxspeodsuinremsicfrroowmafvoeodovpeancsk.agSitnugdies sources. Perfluorocarbons are contained in many consumer products. Fiuorocarbon surfactants such as PFOA, PFOS, and its derivatives are present in window cleaning products, floor waxes and polishes, fabric and leather coatings and carpet and upholstery treatments 2, Additionally `coat food wraps and are incorporated into plastic these compounds are food storage bags. used to TFelfuloornocaanrdboTnefslaornertehleatbeadspirsofdourcatsnaerwe gweindeerlaytuisoneodfacsrolusbsriccoaunntst,ryelsekcitrwiacxales. insulators, heat andchemical stable gaskets and linings and in non-stick rceopolkawcaermee.ntFsi.uoIfropaelrkfainueosroshuecxhanaesopreortfhleurofrlouhoerxoacnarabroensbeairneguesveadluaasted as CFC wrielpliancceremaesnetsdrfaomraCtFicCa'lsl,y.coPnFsCu'msehraevxeposesvuerrealfreoxmpeareirmoesnotlaslamneddioctahlerupsreosducts including use as blood substitutes, x-ray and magnetic resonance imaging contrast agents , vitreous replacement and in liquid ventilation therapeutic methods . Recently, control fire ants 40, a potent fluorocarbon insecticide has beenmarketedto uPsereldlwuohreorcsarhbeoantsshtaabvleeaavnadricehteymiofcailnldyusitnreiratl luisneesrs.,Tgeafslkoentasnadndotlhuebrrpicoalnytmsearrseare necessary. In addition, they are used as electrical insulators both in solid and nT : 03200 | : i : ; A ! ! liquid form and used as inert non-conductive liquid coolants in electrical devices such as Cray supercomputers. Perflucrinated surfactants are important fire suppression materials. Perfluorocarbons have been used to control the metal vapors in electroplating processes and to prevent the release of toxic gases\ trom landfills. Perflucrocarbons are being considerteod replace CFC's in many processes such as refrigeration, polymer foam blowing and building insulation. New applications are being continually developed for these unique compounds, making increased exposure 10 workers probable. {netics of PFO Since Taves and Guy's observations, perfluorocarboxylic acids, pefucrosulfonic acids and their derivatives have been the subject of numerous toxicokinetic and toxicodynamic studies in animals. These studies have focused primarily on two compounds, PFOA, and perfluorodecanoic acd (PFDA). Perfluorooctanoic acid of its salts are well absorbed by ingestion, inhalation or dermal exposure. Absorption has been studied primarily in rats, although a number of other species have been studied. Five male and five female rats were exposed to airbome APFOA for one hour. In this experiment the nominal air concentration of ammonium perflucroociancate was 18.6 mgA-No animals died during the inhalation exposure or the 14 day post exposure observation pariod. Pooled serum samples contained 42 ppm of organic fluorine for males and 2 ppm for females. Inorganic fluoride content was. 0.02 ppm for males and 0.01 ppm for famales %. Kennedy and Hall 3 studied the inhalation toxicity in male rats of ammonium perfiuoroctonate using both single dose and repeated dose schedules. They found a LC50 of 980 mg/m3 fora 4 hour exposure placing PFOA in the moderately toxic by inhalation category. Following ten repeated doses at levels of 1.0, 7.6, and 84 mg/m3 blood `ammonium PFOA levels were obtained. At the 1.0 mg/m3 level PFOA levels were 13 ppm, at the 7.6 mg/m? level PFOA levels were 47 ppm and at 84 mg/m3 foval PFOA levels wera 108 ppm. Thersfore it appears that PFOA is well absorbed by inhalation. It should be noted that the exposures were to APFOA dust, thelikelyform for occupational exposure. - mn . 03201  ! | ! : | | : ! ! Ammonium perfluoroocionoats in food and PFOA administered by gavage in pLrDosp0ylsetnusdygl5y,croaltsofdcisopmlaoyiedveahidcolsees dareepewnadllenatbssoprebcetdruimn roaftst.oxIinciatinesaciuntdiecaotrailng that PFOA was absorbed after ingestion. PFOA levels were not measured in this study. In a subacute oral toxicity study, rats wera fed PFOA for 90 days . Serum concentration of organic fluorine showed a dose response relationship in both sexes. A marked gender difference in organic fluorine levels was observed. Males had organic fluorine 50 times higher than females at each dose level. Studies have since demonstrated excellent oral absorption of PFOA in a variety of Of species including most immediate rats, mice, guinea pigs, dogs, hamsters relevance to humans have been studies and in a monkeys 9. 15, small number of rhesus monkeys . In a 90 ay oral toxicity study, monkeys were given 3, 10, and 30 mg/kg/day doses serum PFOA was 50 of APFOA. In ppm in males monkeys at the 3 mg/kg/day dose, mean and 56 ppm in females. At the same dose, : males had 3 ppm and females 7 ppm in liver samples. At 10 mg/kg/day doses, lmeavleelsmwoenrkee9ysanhdad10a pmpemanfosremraulmesPaFnOdAfoefma6l3esp,prmesapnecdtifveemlayl.eBse7c5aupspem.allLbiuvter1 monkey died at the 30 and 100 mg/kg/day dose levels, only 1 serum sample from a male monkey in the 30 mg/kg/day dose group was available. In this monkey the serum level of PFOAwas 145 ppm. In the 30 and 100 mg/kg/day dose group --`mmeaaynbeliaversilgenviefliscawnetrceongtrreiabtuetrortthoanth1e0b0opdpymb.uTrhduesn,otfhPeForOaAl rIonuetxepoofsaebdsowroprtkieorns. Dermal absorption of PFOA has been studied in rats and rabbits. Ammonium perfluorooctanoate is a fine whitepowder that may come into comact with skin and be absorbed. In rats dermally exposed to ammonium perfluoroctonate a 4 dose levels, PFOA was absorbed in dermal exposure experiments using a dose rabbits, dependent fashion . PFOA appeared to be In single dose absorbed. nLoetveelds.ofIfnluaormiunteiw-edroessnoetxpmeeraismuernet,d,tebnutmadloeseanddepteenndfeenmtatloexircabcbhiatsngweesrewere fionrjtewctoedwdeeerkmsa.llTyotwailthsear1u0m0flmugo/riknge dleovseelsofwePrFsOiAncorneaasfeidveindaaydoaswee-deekpsecnhdeednutle fashion. Dose-dependent changes in weight were noted 4%. From these studies, 12 C0O3202 | oe ! | i ! : L t appears that dermal exposure to the salts of PFOA are absorbed in animals. In the past, Chemolite workers have been exposed to large dermal doses of `ammonium perflucrocionate. i appears that derma exposure may have played a significant role in the absorption of PFOA in these workers. Upon recognition that PFOA could be absorbed dermally, work practices were changed and engineering controls were acopted that reduced dermal exposures. The role that Germal exposures curentlyplay in PFOA absorption at Chemolits has not been wel studied. Ones absorbed, PFOA enters the plasma prabably by diffusing as a neutral ion pair. In plasma, PFOA is strongly bound to proteins in the Serum with mors than 97.5 percent in bound form 52. Itsfikelythat albumin is the major site for high affinity binding 7-34). There does not appear to be a sex difference in protein binding 5% Hanhijarvi et al. have suggested that protein binding is saturable in rats %. Using human serum, Ophaug and Singer found that PFOA was 99% protein bound at PFOA levels up to 16 ppm total fluorine, however. Guy suggested that perfluorocarboxylic acids bind to albumin ina similar fashion to fatty acids 24. This hypothesis is consistent with the results of several studies. Taves obsarved that the organic fraction of serum co-migrated with albumin during electrophoresis . Dialysis and ultrafiltration studies observed the retention of organic fluorine during dialysis and ultrafiltration 7 17.56. Belisle and Hagen reported that PFOA appeared 10 ba strongly protein bound in human serum $1. Extractionof PFOA from acidified water is quantitatively complote using hexane. When PFOA is extracted from plasma, recovery is only 35 percent. Plasma appearad to complex PFOA and PFDA. The partitioningof the bound into organic phase during extraction was more difficult and necessitated the use of mare polar solvents. Kievens = suggested that CF2 and CF3 groups complex with polar groups that are present in the amino acids in proteins such as albumin. In protein precipitation studies using bovine serum albumin, PFOA bound to albumin at an estimated 28 binding sites per molecule 2. Nordby and Luck studied the precipitation of human albumin by PFOA.Under acidic pH conditions, PFOA produced reversible precipitation of albumin 57 by binding to high affinity sites. These studies do not rule out significant binding to other plasma proteins or erythrocyte components. In studies using serum protein electrophoresis, the protein bound organic fluorine was distributed in a diffuse _1 03203 | : i o | | : | pattem & 17 suggesting that PFOA protein binding may be nonspecific. The large amount bound to albumin may reflect the abundance of albumin in plasma and sorum. Inrats, PFOAis distributed to al tissues studied except adipose tissue. The highest concentrations of PFOA ara in the serum, liver, and Kidneys. Yiinen et al. 4 studied the disposition of PFOA in male and female rats after single and 28 ay oral dosing. Aftear single dose of 50 mg/kg, PFOA was concentrated in the serum. Twelve hours after casing 40% of the PFOA dose was found in the serum of males and 10% in females. Males retained 3.5% of the ose in serum after 14 days. PFOA was retained in the liver for muchlonger than in serum. In females, the half-life of PFOA inliver was 60 hours compared to 24 hours in serum. In males the half-life was 210 hours in liver and 105 hours in serum. tis noteworthy that PFOA was not found in adipose tissue in detectable quantities. After 28 days of PFOA treatment, PFOA was distributed to the following sites in decending amounts: serum, live; lung, spleen, brain, and testis. Again, no PFOA was found in adipose tissue. The distribution of PFO from serum to the tissues occurred in a dose dependentmanner for females. In male rats, the concentrations of PFOA in testis and spleen followed a dose dependent trend. The levels in male rat'serum and liverwas the same for the 10 mg/kg and 30 mg/kg dose group. Johnson and Gibson 5% $9 studied the distribution of 14C. labeled ammonium perfiuorooctonoate after a single fv dose in rats. Their findings were similar to thoseof linen et al. The primary sites of distribution were the liver, Kidneys, and plasma. Other sites, including adipose tissue, had less than 1% of the administered dose. The level of PFOA In the testis of male rats was not reported. As discussed previously, the $0 day oral toxicity study In thesus monkeys showed that the relative amounts of PFOA in serum and liver was diferent in monkeys compared to rats. In the low dose group of monkeys (3 nd 10 mg/kg/day) serum had 5 10 10 times the PFOA levels found In liver. However, at higher dose levels, the PFOA levels were equally distributed. `Additionally, no sex differences were noted in the monkeys liver and serum PFOA levels. There is no evidence that perfluorinated compounds including PFOA are biotransformed by living organisms. Several studies have examined whether -- 1a : 03204 | ! i ` oo | : . ! PFOA Is conjugated of Incorporated Into tissue consthuents such as triglycerides or lipids. Yiinen et al. found no evidence in Wistar rats for metabolism or incorporation of PFOA into lipids. Athough the lipid content in PFOA treated rats was cifferent than that in untreated rats, Pastooert al. did not find evidence for PFOA incorporation into pics of of metabolism 80 Vander Heuval et al. showed that PFOA was not incorporated into triacylglycerals, phospholipics, or cholesterol esters in the liver, kidney, hean, fat pat, of testis of male or female rats . No evidence has been found that PFOA is conjugated in phasa Ii metabolism . Kusiikis et al. studied the formation of activated coenzyme A (Co) derivatives of PFOA using rat liver microsomes. They found no evidence forthe formation of a CoA derivative. Sex related differences in the toxicokinetics of PFOA have been reported for rats. The mechanism of PFOA excretion appears to be species-dependent since these gender differences are not seen in mice, monkeys, rabbits, or dogs * 2, The haltiife of PFOA in female rats has been estimated to be less than one day 3, whereas the half-life of PFOA in males is five to seven days 3%. Ht is of note that PFDA does not exhibit this gender difference &. 1 is hypothasized that the sex differences in sensitivi1t0y the toxicities of PFOA are as a result of the slower excretion of PFOA in male rats compared to female rats. Investigators have teported that rats have an estrogen-dependant active renal excration mechanism for PFOA which can be inhibited by probenecid 52:4, As noted previously, . females have a much shorter hall-Ife than male rats. The haltife in males can be reduced by castration or estrogen administration. can be reduced to the female half-fe by a combination of castration and estrogen treatment. Estrogen administration alone is almost as effective as the combination of castration and estradiol treatment in reducing the PFOA half-ife. This treatment increased the renal excretion of PFOA in male rats to those observed in female rats. Other investigators have reported that the gender difference in half-life depends on a testosterone mediated increase in PFOA tissue binding $4. This hypothesis is consistent with the gender difference in tissue half-life discussed previously 3, Johnson has suggested that the primary method of excretion in intact males is via the hepatobiliary route 5% 9. He reported that cholestyramine enhanced the fecal elimination of carbon 14 labeled PFOA in male rats. These data suggest there was biliary excretion with enterohepatic circulation of PFOA, particularly in -- 15 03205 | o @| mals rats. However, in a male worker with high serum PFOA lovals who was. treated with cholestyramine, tle il any change in excretion of PFOA was noted. In this study PFOA was excreted slowly in the urine. In humans, the hall-Ife of PFOA appears to be extremely long and is not sex dependent. Ubel and Gritth # reported kinetic data for one highly exposed worker. At the time he was removed from exposure his serum organic fluorine was 66 ppm, 80 percent of which was PFOA. Over the next 18 months his organic fluorine level decreased 10 39 ppm. Urinary excretion of PFOA fell from 367 micrograms/24 hours to 80 micrograms/24 hours. The decline in organic fluorine levels was consistent with two companment kinetics, with a calculated halife of 2 10 5 years. Adcitional unpublished biological monitoring data from three Chemolite workers is consistent with the 210 5 year halt-ife. In the Chemolite workforce, male and female workers employed in jobs with similar PFOA exposure have increased PFOA levels. Since men and women with similar exposures have similar levels, a large gender difference in PFOA. toxicokinetics is unlikely. Therefore, the relevance of the rat data in assessing the effects of PFOA in humans is questionable. To ics of PFO . Both PFOA and PFDA have been found to produce significant toxicttes in the reproductive systems of male rodents '% 63. 65, The testis has been reported as the target organ of toxicity for both PFOA and PFDA 9. , Additional evidence exists suggesting that these compounds affect the function of the hypothalamic phuitary-gonad axis (HPG) 15-85, Perfluorodecanoic acid, but not PFOA, has been shown to produce degenerative changes in rat seminiferous tubules that could progress to tubular necrosis. Van Raelghem et al. reported that a single ip dose of 50 mg/kg of PFDA, produced degenerative changes in rat seminiferous tubules 8 days ater injection . Similar but lesser changes wers noted in the seminiferous tubules of hamsters and guinea pigs treated in the same manner. They reported no such change in _1 03206 | oo | | | ii *L treated mice. Bookstat! and Moore did not observe similar changes in rats. treated with 20-80 mg/kg of PFDA. They used a differant sirain of rats in their axperiments which is less Susceptible 10 testicular toxicants than those used by Van Rafelghem et al. Thus, the effects of perfluorocarboxylic acids on seminiferous twbules may belimited10 a specific compound, PFDA, in a specific strain of rats. The effects observed by Van Rafelghem at al. in other species ware not consistant and did not demonstrate a dose-response relationship. In monkeys treated orally with PFOA, no compound related histopathologic changes in the seminiferous tubules ware noted . Ina two year rat feeding study, PFOA treated animals wre obsarved to have increased numbers of Leydig cell tumors". Male and female rats ware fod PFOA containing diets resulting in a mean intake of 1.5 and 15 mg/kg/day. A statistically significant increase in Leydig cell adenomas of 0%, 7%, and 14% in the control, low dose, and high ose groups, respectively, was observed at th and of the two year study. The result was statistically significant as a result of the unexpectedly low number of adenomas in control animals. Historically, CD rats `experience a itetime mean Leydig call incidence of 6.3 percent with a range of 2 10 12 percent. The high dose group incidenca is outside the expected range and may represenat compound related effect. Although the evidence was not definitive, t suggested that PFOA may alter the histology as well as the function of Leydig calls in rats. Perfluorooctancic acid was not mutageninc the standard tests including the Ames assay using five species of Salmnella typhimurium and in Saccharomyces cerevisiae S. Mammalian cell transformation assays using C3H 10T 172 cells were also negative &7. These data suggest that PFOA is not a genotoxic xenobiotic. The increase in Leydig cell tumors may be the result of an epigenetic mechanism. `The observation that rats fed PFOA fo2r years had an increased incidence of Leydig cell adenomas prompted researchers to examine the hormonal effects of PFOA in male rats ', Adult male CD rats were treated orally with PFOA in doses. 0 110 50 mg/kg. Serum estradiol levels were elevated in the rats treated with more than 10 mg/kg of PFOA. In the highest dose group estradiol was 2.7 times #2R8ep1oCrRtO:0a1M2,R1i5k8e3r Laboratories. Two Year Oral Toicty/Carcinogenicty Study of FC143 n Rats 7 03207 o| : | PY greater than the estradiol levels in pair fed control group rats. Serum testosterone levels ware significantly decreased in a dose dependent manner when compared with aq libitum feed control animals. No significant differences were observed between the high ose rats and their pair fed controls, however. No significant differences were noted in serum luteinizing hormone (LH) levels. Additionally, the accessory sex organ relative weightsof the highest group were significantly lass than those of their pair-fed controls. In order to clarify the site of PFOA action, Cook ' conducted a set of challenge experiments in PFOA treated rats. The resuls of these experiments demonstrate that the altered testosterone levels wer PFOA related. Human chorionic gonadotropin (NCG) challenge can be used to identify abnormalities in the steriodogenic pathway. Human chorionic gonadotropin binds to the LH receptors on Leycig calls and stimulates sex steroid hormone synthesis . Abnormalities in Leycig cell function can be detected by challenging Leydig cells with hCG and measuring steroid hormone production. Similarly, abnormalies in pituitary secretion of gonadotropin can be identified using a gonadotropin releasing hormone (GnRH) challenge that stimulates LH release . Hypothalamic dysfunction can be identified using a naloxone challenge to stimulate GnRH release 7. In rats treated with PFOA for 14 ays at the same dose level as the inital experiment, the Leydig cell productionoftestosterone was significantly blurted after hCG challenge in the highest dose group compared to ad libtum fed controls. A small, non-significant bluntingof the testosterone production in response to GnRH and naloxone was observed. Following GnRH and naloxone stimulation, LH levels were not significantly diferent in the treatment and control animals. The hCG challenge showed that the decrease in testosterone in PFOA treated rats resulted from altered steroidogenesis in the Leydig call. The results from the GnRH and naloxone stimulation were not definitive. The resutts were `compatible with an effect at the pituitary level as well as at the Leydig call level. Cook et al. examined the site at which testosterone steroidogenesis was affected by PFOA. Progesterone, 17 alpha-hydroxyprogesterone and androstenedione were measured after hCG challenge. Progesterone and 17 alphahydroxyprogesterone were unaffected. Androstenedione levels ware significantly decreased in PFOA treated rats compared to controls. Given that the conversion of 17 alpha-hydroxyprogesterone to androstenedione by C17/20 lyase is -- 1. 03208 oe necessary for testosterone testosterone is the result of synthesis, a block in these results suggest that decreased this conversion'step. In hCG stimulated rat TLaeykdeing tcoeglelst,hetrh,et1h7esaelpdhaatahyadrreocxoynlsaisset/eCn-t1w7i/t2h0tlhyeashsypios tihnehsiibisttehdabt ytheesterladeivoalt,ed aesntdratdhieorlelbeyvedlesparsessoscitaetsteodswtietrhonPeFlOevAeltsr.eCaatmoekntetinahli.bistugthgeesCt-e1d77t2ha0t ltyhaesebleunnzteydme ersetsrpadoinosleloofveLlsH. A1osluobwtlteeshtyopsottehraolnaemmiacyorbpeitmueidtairayteefdf,ecitn mpaaryt,albsyoebleevparteesdent, however. The mechanism for the estradiol elevation was not studied, sPiemrifllaurotrooPdeFcOaAn.cicInacmiadlaeltreartss rreepartoedducwtiitvhedhoosremsoonfePsFinDAmarlaongriatnsgifnraomfa2s0hitoon80 mo/kg, given as cose dependent a single fashion p . dose, Both PFDA decreased plasma androgen plasma testosterone and 5-alpha levels in a cdoinhtyrdorlotraetstvoasltueesr,onmeewaenrplsiagsnmifaictaensttloysrteedruocneedw.aCsodmepcarreeadsetdo badyli8b8itpeurmcafnetdin wPeFrDeArerfaletcetedd ainn iamcaclessasonrdyDsHexTowragsandewecirgehatseadndbyhi6s2topleorgcy.enTth. eThcehsaengcehsaninges taecscteossstoerryonseerxeoprlgaacnemseanttt.erTPheFDPAFDadAmidneicsrtreaatsieoninwaenredrfooguenndstwoabsoftehveerressualdtboyf adheecrreedasmeedtarbeoslpiosnmsiovfetneesstsosotferLoenyed.igAdcdeiltlisontaollLyH,.pTlhaesrmeawLaHs cnoonceevnitdreantcieonfsordid TnhoitsisnucgregaessetsaptphraotpPriFaDteAlymianythaeltfearcteheofnloorwmapllafsemedabtaecsktomsetcehroanneicsomnsceonfttrhateiHonPsG, axis. i {Itiike PofFOinAt,ereisstatononnogteentohtaotx2i,c3r,a7t,8catrectirnaocgheino,roacipbeenrzoox-ips-ocmieoxpirnol(iTfCerDaDt)or,s,whaincdh,an i riantdssuicmeirloafrtPo45th0osseysotbesme,rhvaesd bfoerePnFsOhAowanndtoPpFrDoAd.uceMohoorremoentaall,e7f!fescttusdiinedmatlhee ! reeffseuclttoefd iTnCdDepDreosnssitoenrtoeisdtoogsetneersoinseiannrdat5L-aelpyhac-eDlHsT. cEoxnpcoesnutrraetoifoncse`lwittohTouCtDD ' : i altering LH conceniration or TCD treatment inhitits the testosterone early phase m of etab the olism. synthet Moore concluded that ic pathway and the mabilization of cholesterol to cytochrome P4S0scc. However, Moors ef al, --19 93209 : observed decreased estradiol. TCDD has been shown to increase the estrogen mediated feedback inhibition of LH secretion 72 Accitihally, in studies using MCF-7 breast tumor cells, the antiestrogenic effect of TCDD was mediated by aiterations in the cytochrome P450 metabolism of estradiol TM. The decreased testosterone in rats could be mediatedbythe effectof TCDD on Leydig cells directly, by alterations in testosterone metabolism, or through increased negative feedback at the pituitaryor hypothalamic level. Recently, reports from occupational studies of TCDD exposed workers have associated TCDD exposure `with hormonal alterations in human males. Egeland et al. 7 reported that men with high TCDD levels had significantly depressed serum testosterone levels. The changes in testosterone were not associated with altered LH values. Estradiol values were not reported. They concluded that dioxin has a similar effects in men and male rodents. The obvservations that PFOA, PFDA, and TCDD have overlapping spectrums of rodent toxicities suggests that peroxisome proliferators, inducers of the P-450 system and non-genotoxic carcinogens may also alter the hypothalamic -pituitary-gonad function in male animals. A In the two year rat feeding study, female rats treated with PFOA were observed 10 have an increased number of mammary fibroadenomas compared to control animals. All mammary carcinomas occurred in control animals. Hyperplasiaof the ovarian stroma was observed, but specific histopathological studies were not reported *. No information is available concerning the effect of PFOA and PFDA on HPG axis in women or female animals. 23 Thvoid Toc Altered thyroid hormone dynamics have been observed in rats exposetdo PFDA 787. A'single ip dose of PFDA in rats results in a rapid and persistent decrease in thyroxin (T4) and T3 8. Gutshall reported that the decrease in thyroid hormones occurred as early as eight hoursafter treatment and persistentforat least 80 days 7. These changes were associated with a hypothyroid-like state in spoonh AkerLaororis. Two Year Oral ToxctyCarcogaSnuidcytoyf F140 nRi oF 03210  o : | the treated rats. The alterations in Serum thyroid levels occurred at ose levals that did not produce a hypothyroid syndrome 7. Animals with depressed T4 levels were found to be metabolically euthyroid 7. Replacement of T4 resulted in normal food intake, but did not reverse the hypothyroid-iike syndrome of hypothermia and bradycardia 7%. This suggests that PFDA has a marked effect on cellular metabolism that is independent of ts efect on thyroid homeostasis. The low T4 was thought to be a result of two mechanisms. First, PFDA readily displaces T4 from albumin which results in increased metabolic tum over of the hormone. Second, the response of thehypothalamic pituitary-thyroid (HPT) axis appeared 1o be depressed as assessed by thyrotropin releasing hormone simulation testing 7. In these studies, the animals had increased levels of thyroid responsive hepatic enzyme activities suggesting that the PFDA treated rats wore not functionally hypothyroid. The histological appearance of the thyroid glands were unremarkable, although treated rats had significantly lower thyroid weights. TSH levels were not studied. No similar studies are available for PFOA. PFOA has been noted to produce a transient waight loss in treated rats , The hypothyroid-ike syndrome observed in PFDA treated rats has not been studied in PFOA treated rats, however. Since the thyroid hormone effects of PFDA do not cause the hypothyroid-iike state in rats, PFOA may alter the HPT `axis without producing this syndrome. z ic Toxic `The primary site of PFOA toxicity in rodents is th liver. Peroxisome proliferation (PP), induction of enzymes involved in B-oxidation of fatty acids, and induction of cytochrome P450 occur after a single PFOA dose. Marked hepatomegaly has been noted coincident to the PP and enzyme induction. Increased liver size was the result of a combination of both hypertrophy and hyperplasia. Cell hypertrophy predominated atter an initial burst of cell proliferation. The initial hyperplasia is evidencedby Areas of increased necrosis large in the hepatocytes and markers of DNA synthesis periportal regions have been observed 3". %, `The relationship between hepatic enlargement, peroxisome proliferation, and increased B-oxidation is unclear. Xenobiotic induced changes in one specific peroxisomal enzyme are not necessarily linked to changes in other peroxisomal 2 03211  o | enzymes or hepatic enlargement &2. Studies have suggested that xenobiotic. induced hepatomegaly and PP may be related to the endocrine status of experimental animals or 10 oxidative stress 8346. Adrenal and thyroid hormones may play a role in peroxisomal proliferation. -%. Studies of clofibrate, a PP, have shown that endocrine manipulation can modify its hepatic effects. In adrenalectomized and thryoidectomized rats, clofibrate-induced hepatomegaly was reduced compared to the effect in control rats 5.84, Conversely, in thyroidectomized or hypophysectomized rats, clofibrate induced peroxisomal B-oxidation enzymes were increased compared to normal rats 2, Thonassery et a. compared the PFOAvinduced hepatomegaly in normal rats, adrenalectomized rats and adrenalectomized rats with cortisol replacement 8. They found that hepatomegaly was cortisol dependent and was primarily a resutt of hepatocyte hypertrophy. Hyperplastic responses were also cortisol dependent and were noted in periponial regions of the liver. Peroxisomal proliferation did not ~ depend on cortisol and was observed in centrilobular regions. They concluded processes. that PFOA-induced hepatomegaly and peroxisome proliferation were separate In oral feeding studies, PFOA and other PP were reported to cause increased hepatomegaly in males compared to females. This difference could be reduced by exogenous estradiol administration of castration and eliminated by castration and estradiol administration 4. Theseobservations may beexplainedby an estrogen dependent renal excretion mechanism or a testosterone mediated increase in tissue binding 5:87. 88 Issemann and Green have cloned a mouse PP activated receptor, mPPAR, a member of the nuclear hormonereceptor superfamily of ligand-activated transcription factors that is activated by peroxisome proliferators #9. This. receptor directly mediates the effects of peroxisome proliferators (Ps). Tugwood has shown that PPs activated PPAR recognizes a specific response unit on the Acyl-CoA oxidase gene promoter in a manner similaor the steroid hormone receptor %. The action of PFOA and other PPs may be mediated by a family of cytosolic receptors that regulate gene transcription in a manner similar 10 other nuclear hormone receptors. C= 0321i2 In initiation, selection, and promotion experiments in rats, PFOA produced an increased number of hepatocellular carcinomas "+52 Several mechanisms for PFOA associated nongenotoxic carcinogenesis have been suggested. Perfiuorooctanoic acid is an archetypal member of a nique sub class of PP that are not metabolized. Reddy has argued that the structurally diverse peroxisome prolferators (PP) are a distinct class of nongenotoxic carcinogens , Reddy proposed that PPs induce oxidative stress which results in increased tumor formation. According to this theory, the obsarvad increase in hydrogen peroxide formation associated with increased B-oxidation is not associated with an increase of similar magnitude in detoxifying catalase activity . Oxidative attack by hydrogen peroxide and other reactive oxygen species on cell constituents and membranes leads to DNA damage and increased call proliferation. Increased proliferation in concert with DNA damage produces increased cll transformation and malignancies. Studies testing the theory that PFOA induces HCC by increasing oxidative stress have lead to conflicting results. Takagi at al. observed an increase in 6- hydroxydeoxyguanosine in fiver DNA from rats exposed to PFOA. They `concluded that rat hepatocytes were under increased oxidative stress . Handler et al. found no increase in hydrogen peroxide production in intact vers exposed to PFOA . Lake et al. failed to find an association between hepatic tumor formation and peroxisome proliferation %. Thottassery et al. observed that the PFOA induction of G-oxidation was independent of adrenal hormone status. A PFOA associated increase in catalase activity depended on cortisol 9, Therefore, the hormonal status in animals used in experiments could confound : studies of oxidative stress and account for the conflicting results. 226 - Inthe 30 day monkey feeding study, bone marrow and lymphoid tissue were a site of histopathology . Treated monkeys in the highest two dose groups were. observed to have moderate hypocellularity of the bone marrow. Specific Toa 03243 o : | histopathological findings were not reported. Atrophy of lymphoid follicles in lymph nodes and the spleen were noted in the sam treatment groups. No follow-up studies of these observations have been reported. Studies in PFOA treated rats have not shown histological changes in the immune system . 2M.2.e7 chaniosfAcmtison The mechanism of toxicity of perfiuorinated suractants may be mediated by their effect on cell membranes. Olson and Andersen suggested that PFOA may alter membrane function through changes in fatty acid composttion and oxidation status. Levitt and Liss hypothesized that the effect of perfiucrinated surfactants is `mediated by their alteration of membrane organization or fluidity 5. 7, Shindo 2 reported that miscibility of fluorocarbon and hydrocarbon surfactants depends strongly on carbon chain length. A carbon chain length greater than eight carbons is necessary for immiscibility. Perfluorocarbon surfactants with eight or fewercarbon atoms are miscible with hydrocarbon surfactants with carbon chain lengths up to nine. These observations could have important implications for biological systems that contain fluorocarbon surfactants. Cellular membranes are a phase boundary, usually between a lipid phase and an aqueous phase. Surfactants will segregate to this phase boundary. Two immiscible surfactants may form two coexistent monolayers on the inside and outside of the membrane whereas miscible surfactants will form only one such `monolayer. The presence of two monolayers will maximally reduce the surface tension at the boundary, whereas a single monolayer will affect surface tension to alesser degree. Changes in surface tension may after membrane fluidity and affect ts function in such processes as signal recognition and transduction. It is interesting to note that the change in miscibility in Shindo's experimental system occurred for fluorocarbon surfactants with carbon chain lengths greater than sight. This change in miscibility depended on hydrocarbon surfactant chain length as well. The effects of PFOA and PFDA on experimental membrane systems and cellular membranes have been investigated. Inoue studied the differential effects of octancic acid and perfluorooctancic acid on experimental call membrane --2 03214 1 o pversoipcelretsiedse5c.reTasheedplhianesaerltyraanssiPtiFoOn Ataimnpcerreaatsuerdeionfcdoinpcaelnmtirtaotyiiopnhouspph1a0toidnyeicmhoMline and ihe then reach membrana a plateau. This suggested that PFOA above a crilcal concentration. Such a may form aggregates phase separation is in observed to occur in micelles 22. The partion coefficient between water and the membranes for PFOA, K = 8910, was larger than the coafficiart for ionized obceitawneoeinc ahcyiddr,oKca=rb1o3n5,anpodssfilbuloyrobceacrabounsechoafitnhseidniaffqeureeoncuesisnolhuytdiroonp.hoTbhiecity ifferences between the toxicokinatics and toxicodynamics of PFOA and PFDA may be the result of thei differing miscibilties with call membrane surfactants. Levitt and Liss investigated the effect of PFOA and PFDA on the plasma membranes of calls from F4 human B-lymphoblastoid call line using the dye merocyanine 540 (MC540) 7. The dyebinds to phospholipids that are loosely packed on the outer cell membrane, but dos not bind to highly organized lipids and does not penetrate the MCS40 cell surtace binding membrane of healthy cells *. was observed atter treatment A large decrease with sub-lethal in concentrations of PFOA and PFDA but not other non-perfluorinated fatty acids. Albumin or serum reduced the change in MC540 binding. This effect may be a result of the strong protein binding of PFOA and PFDA by albumin 2. These observations suggest that PFOA and PFDA either interact directly with MC540 lipid binding sites oralterthe structure of the lipids in the membranes. In experiments examining functional changes in the lymphoblastoid cell lines, Levitt and Liss observed that PFOA and PFDA could cause direct damage to cells resulting in the release of membrane bound cell proteins and immunoglobulins in soluble form 96, PFDA was significantly more potent than PFOA in solublizing proteins and king cels. This may be the result of different miscibilies in the cell membrane of these compounds. However, neither PFOA nor PFDA reduces the abilty of surface immunoglobulins to migrate and undergo capping after antigen recognition %7. Inthe PFOA concentration ranges that decreased MC540 binding, PFOA did not affect immunoglobulin migration and capping. Capping involves the cytoskeletal mediated polar migration of immunoglobulins within the plane of the membrane '%. Apparently, the PFOA -- 25 03215 | o o| and PFDA associated membrane changes do not affect membrane characteristics that are important for receptor migration. "The membrane effects of PFDA have been studied in greater detail. Pilcher et al. reported that a single injection of PFDA in rats significantly reduced the apparent numbeorf B adrenergic receptors in cardiac cells '. This change in number of receptors was reflected in the diminished response of adenylyl cyclase (AC) to epinephrine in PFDA treated rat cardiac cells. The intrinsic properties of AC were not altered. The action of PFOA was on the epinephrine receptor. The fatty acid composition of the treated rat cardiac cell membranes was significantly altered 191, palmitic (16:0) acid was elevated 13 percent, eicosotriencic (20:3 we) was elevated 71 percent, and docosahexaenoic acid (22:6 w3) was elevated 18 percent. Arachidonic acid (20:4) was reduced by 18 percent. Several other investigators have reported changes in membrane function following PFDA exposure. Wigler and Shaw 12 demonstrated that PFDA inactivated a membrane transpor channel for 2-aminopurine in L 5178 Y mouse lymphoma cells. In vitro experiments reported by Olson et al. ' showed that erythrocytes `exposed to PFDA exhibited decreased osmotic fragility and increased fluidity. `efTfaekcetns toongectehlelrm,etmhberseansetsu.dieTshiendeifcfaetcetsthaaptppeearrfltuoorbienaltiemditseudr1f0actthaentosuteexrerptortthieoinr of the membranes as the result of differential partitioning within the membrane or binding to specific membrane constituents. Although PFOA and PFDA can be cytotoxic as a result of their detergent action on membranes, their membrane effects at lower doses are not related to their detergent action. From available data, it appears that functional membrane changes may be limitedto specific receptor mediated functions. 2O.8 ccuFpluoraineEtxpoisuro esAntCha emall ite: In workers employed in fluorochemical production plants, blood organic fluorine fhuaosrifanre oiunttwheeisgehgerdoiuopnsichfalsuobriedaen r1ep2o1r4t.e51d.t5o6,bMeoorregatnhiacn f9l8uorpienrec.enTtheorfetfhoeret,ottahle use of total fluoride levels, which consist predominantly of organic fluorine compounds, is a valid surrogate for organic fluorine in occupationally exposed groups. In workers at the Chemolite plant, PFOA has been identified in the serum --~ 2 03216  o : of these workers and was estimatteod account for 80 percent of organic fluorine found in the serum samples . In this cohort of workers, total fluarin is a good surrogate measure for PFOA. Industrial hygiene measurement of fluorachemicals have been conducted at the Chemolits plant since the 1870s . These measurements include arsa samples, personal breathing samples and surface wipe samples. In 1977, a comprehensive for at evaluating fluorochemical exposures was conducted at the Chemiite plant. During cartain operations breathing zone PFOA concentrations wera as high as 165 ppm. After extensive engineering control alterations, the plant was serially re-surveyed. In general, airbome exposures were below the racommanded limit of 0.1mg/m3. However, thers was evidance of surface contamination in production buildings . In 1986, airborne PFOA, as wall as breathing zone samples were less than 0.1 mg/m based on 8 hourtime ~~ * `weighted averages. Levels as high as 1.5 mg/m3 were measured in breathing zone samples during certain clean-up and maintenance zone samples. Perfluorobutyric acid was also found, but in much lower concentrations. Spray dryer operators had consistentlyhigher exposures, even following extensive equipment improvements. Iappears that aitbome exposure to PFOA was low for most workers. Spray dry `operators and workers involved in clean up and maintenance activities have higher intermittent exposures. Although personal protection devices are required in high exposure jobs, workercompliance has not been evaluated. The role that surface contamination plays in worker exposure has not been defined' . The route of PFOA exposure in worker has not been clearly identified. 2.8 Foicemigogizal Se Aretrospective cohort mortality study of employees at the Chemolite Plant in the period of 1948-1978 was conducted by Mandel and Schuman . Of the 3,688 male employees who were employed for at least months, 159 deaths were identified. There was no excess morality in the employees as compared to al ppeerrssoonnaall ccoommmmuunniiccaattiioonn frroomm SSttaann SSoorreennssoonn,, 33MM CCoorrppoorraatte MMeeddiiccaall DDeeppaarrmmeenntt =2 03217 | scuabucsoehoorrtcoafusalel cspheecmiifciaclmodritvailsiitoyn iwnotrhkeerUs.Sd.icwhniottesmhaolweapnoypuallaltciaonu,seTohrecausespecific excess in mortality. eStmaprltoinygeeins1i9n7t6hemCedhiecmailcaslurdvieviilsliaonnce*.eAxpapmrionxaitmiaotneslywe9r0epoefrfceernetd otfo tChheemwoolrikteers fpuarotriocciapratbeodnsinwtehreepreongcroaumn.teNroedheianlptahrtpircoipbalnetms.s Sreerliaatleldy tcoonthdeucetxepdossuurrveetiollance examinations have failed o organic fluorine and clinical reveal any relationship pathology * . between blood levels of 2.10Summary AwintihmPalFOstAudeixepsohsaurvee.sTuhggeessetiendcltuhadte thheepraetoatroxeifciivtey,ariemamsuonfetosxyicsittyemasasfotceriaattieodns, : rheeppraotdouccatricvienohgoernmicotnye. aTlotxeircaittiyonsst,udLieeysdihgavceellpraidmearniolmyauss,edanrdodneonnt-sg.enTohteorxsicis scuoncshiadserLaebyldeivgarcielalbiaidtyenboemtawse.enAdsdtirtaiionnsalolfy,rastsofmoerosfotmhee oeffftehcetstosxeicenenidnproaitnsthsave TohtebleiemintesdedaantainaovtahielarbrloedoenntPsFpOecAieesxspuocshedasrhmeiscues, mhoamnskteeyrssaonrdguoiccnuepaaptiigosn.ally eexxppeorsiemdenwtosrkteorhsusmuagngsesrtesqutihraetsamnayreaxtirnafpoorlmaattiioononfabtohuetrtehseulmtsecfrhoamnirsodmenoft PFOA ttooxxiicciittyy.inFhruommatnhsi.sOdaftgarietadtoeershunomtanappheeaarththcatontcheerfnivaerrsistahempaojtoerntsiiatle effofrePctFsOoAn the immune system and the reproductive hormones. MInatnhye wpoasrtk,erwsorhkaevres lhoavvelasbaebaonvefoounned 1p0pmh.avTehseisgneifbilcoanotdbllaoveoldslaerveel5s0o-f1P0F0O0A. teinmoeusghbatcokpgrrooduuncdelteovxeicsitiinesthien gocecnuepraatlipoonpaulllayteioxnp.osTehdeshusmlaenvsel.s mAacyonbfoidhaingth 9stimato effects of of risk PFOA cannot be exposure made nil in humans further information is obtained. on the adverse heath "personal communication trom Lary Zobel~; 28Corporation Medical Deparimant 03218 o . o AMETHODS " The effects of perfiuorooctancic acid (PFOA) exposure on human health were studied in employaes of the 3M Chemolite plant (hereatter referred to as Chemolite) located in Cottage Grove, Minnesota. Two studies were conducted to investigate of the human health effects associated with PFOA exposure. First, mortality associated with occupational PFOA exposure was studied using a retrospective cohort design. Second, a cross sectional study design was usad to estimate the relationships between PFOA exposure and selected physiologic parameters. A ratrospactive cohort study was designed to examine mortality among workers. All workersever employed at the Chemolits plant for greater than six months were included in the cohort. All causes and cause-specific mortality were compared to expected morality. Expected morality was calculated by applying sex and race specific quinquennial age, calendar period, and cause-specific mortality rates for the United States and Minnesota populations to the distribution of observed person-time 194 195, Age adjusted standardized rate ratios were calculated 106. A relative risk (RR) for PFOA exposed workers compared to unexposed workers * was calculated using proportional hazard regression models 197. The RR were stratified by gender and adjusted for ageatfirst employment, duration of `employment and calendar period of first employment. Any significant differences between observed and expected cause-specific morality were 10 be explored using nested case control studies. Case studies were completed for causes of death with 5 or more Ceaths and standardized mortality rates greater than 1.5. Each deceased individual's record was examined for commonaties in job history information including age at first employment, calendar period of employment, Years in the Chemical Division, and duration of employment. Selected physiologic effects of PFOA exposure were studied using a cross sectional study design. The relationships between total serum fluorine and biochemical parameters including reproductive hormones, hepatic biochemical parameters, lipid and lipoprotein parameters, and hematologic parameters, were ~2 03219 o o | explored. A sample of the work force employed on November 1, 1990 was invited to participate. All employees in high exposure jobs were asked to participate. A sample of workers employed in low exposure jobs was frequency matched to the aagqeueasntdiosnenxaidriestwrhiibucthioinnocflutdheedhmiegdhiecxaplohsiusrteorygraonudp.inEfaocrmhatpiaornticcoinpacnetrncionmgpleted alcohol, tobacco, and medication use. The questionnaire is provided in Appendix 3-1. Blood was drawn for determination of hematologic and biochemical parameters. Total serum fluorine, free (FT) and bound testosterone (BT), e(sFtSrHa)d.ioplro(El)a,cttihnyr(oPi)dasntdimluultaetiinnigzihngorhmoornmeon(eTS(HL)H,)fwolelriceleasstsiamyuleadt.inTghehoPrFmOoAn-e hormone dose-response relationship for each hormone was estimated using linear regression techniques to adjust for the effects of age, sex, body mass, alcohol consumption, tobacco use, andother potential confounders. The PFOA- hormone dose-response relationship was further explored by fitting linear multivariate models to hormone ratios. All unique ratios between the seven hormones were panicipant, The defined . Twenty-one hormone prevalence of hormone values ratios were outside the calculated for each laboratory reference range for men was compared to the expected prevalence assuming a normal distribution for assay values. 2R.2etrosCophoertMcorttaliity Svtuedy 2D.2.e1 finOftThieCoohonrt "The Chemolite facility opened in 1947. Individuals who were employed at the Chemolite plant between January 1, 1947 and December 31, 1983 wers identified from company records. Workers with fewer than six months employment were excluded. In October 1951 large scale commercial PFOA production facilities became operational (Abe 1982). Because large scale PFOA production did not begin until 1951, a second cohort with potentially significant PFOA exposure was defined as those workers employed between Octobor 1, 1951 and Dacember 31, 1983. Subjects with greater than six months employment were included in this second PFOA cohort. oe O3220 o o l "The cohort was initially assembled in 1979. Subsequently, the cohort was updated to include new employees through 1983. Personnel tacords for employees workingpriorto 1879 were coded for demographic items and work history by trained abstractors. Computerized corporate personnel databases were utiized to provide information for workers employed in the 1979 to 1983 period. Abstracted workhistory included year of first employment, year of last smployment, years employed at Chemolits, and months worked in the chemical division. Individual ob histories were not abstracted because job titles were defined by wage gradss and cid not comespond to specific jobs olocations within the plant. 2D .22aStutdyabas Ane dFis les A Chemolite cohort database was created on a VAX computer using Ingres software. Data stored on magnetic tape were transferred to the VAX. Duplicate records were identified and removed. Missing data were identified. The Ingress update function was used for data editing. Final analytic files for the Monson program, SAS programs, and custom programs were constructed using the Ingress report writer. 1.2.3DataEditing The Ingres relational catabase allowed extensive intemal consistency checks to be made. All dates were checked for plausibility. Those records with implausible, inconsistent, of improperly formatted ates were edited and corrected if information was available. Records of workers with fewer than six months `employment were flagged and excluded from the analytic data set. A random check of 50of the 364 workers with fewerthan six month employment found no mors in classification of employment length. Extensive attempts were made to obtain all missing data items. Sources of information Included plant personnel records, corporate personnel databases, benefit records, archived corporate records, plant medical records, and death certificates. No individual employees or next-of-kin were esut of missing contacted. Four employees demographic data ems. were excluded from the cohort as a _ 05221 Jo 2G .24o 1Assmessp mentlOf eten OfAe scens iains ment `The cohort was initially defined from personne records stored at the Chemolite plant. Complete records were maintained on all workers ever employed at the plant. Hourly and salaried workers were included in these files, as were all transferred, terminated and retired former employees. Records for workers first employed in the 1947-1578 period were abstracted from documents, coded and computerized. Acorporate computerized database was used 10 Update the cohort through December 1, 1983. Since insufficient induction time had lapsed between 1983 and 1989, no new employees or work history information was added to the cohort database for the post 1983 periodfor this study. Veritying the ascertainment of all eligible cohort members was problematic. The assumption that the personnel records represented a complete roster was difficult to check because of a lack of independent information. Several sources ware used to exclude major errors in the enumeration of the cohort. The historical plant hiring pattern based on seniority dates was compared with the distribution of dates of first employment. Qualitatively, dates of major plant expansion correspondetdo peaks in the distribution of dates of first employment and to. seniority dates. Large increases in hiring due to new plant openings ware feflected in peaks in the distributionofstarting dates in the cohort. A sample of 25 annuity beneficiaries retired from the Chemolite plant were obtained from the corporate cohort. personnel office. All 25 were found to be included in the enumerated wSeevreermalaipnltaanitnpeadrsfoornnacetlivreecwoorrdkesryss,treemtsirweeesr,etrraannsdfoermrleydsaanmdplteedr.minSaetpeadrawtoerkfeirless, and workers whose employment at Chemolite ended prior to 1960. A sample of records for cumant employees with start datespriorto December 31, 1983 was wceormepafroeudnd1ointthheeccoohohrotr.t dAallta1b2asree.corOdfs3f0rormectohreds19s4a5m-p1l9e6d0fpreormiotdfhoer1s9t6a1r-t1d9a6t9e,s 21857(09-31%5)78weprereioidn.clOudfetdhienstehe52corheocrotr.dsF,ifftoyrttywsoerveecnor(d3s0%h)adwestraertfiongunddatiensthien the 32 L CO3222 o| : | | Ldaasttayb,asien.thIen 1t9h8e11t9h7r5o-u1g9h8019p8e3ripoedri1o8d,of3464of(4317%r)erceorcdosrdwsewreerien itnhethdeadtaatbaabsaese. (67%). The low ascenainment for workers first employed in the 1875-1380 period was further examined. Of the 34 workers not in the cohort database, 16 (47%) were first smployed in the 7/75-1/80 pariod. Thess omissions occurred in the transition period between document abstracting and electronic updating of the cohort. Using seniority lists, 44 workers currently employed were hired btween 1978 and 1980. They represent approximately 1%of the total numbeorf individuals in the worklorce and less than 0.5% of the total person time at risk for the cohort. Records for retired workers were sampled from files containing all workers retired from Chemolite. Forty seven of the 48 (38%) sampled records were present in the database. A sample of the files containing the personnel records of employees completing employment before 1960 was randomly drawn. Of the 67 selected records, 65 (97%) wers in the database. Finally, les `containing records of all transferred, terminated, or disabled employees were : randomly sampled. Of the 120 sampled records, 116 (7%) were present in the cohon database. 242 VaR . Information in the edited database was compared to informationinthe personnel records. A random sample of 25 records was drawn from the personnel fies. Database names, social Security numbers (SSN), dates of birth (DOB), and dates of in employment were verified coding the last digit of one against record information. SSN. All ther information The was sole error occurred correctly entered into the database. The was relabilty of ICD8 coding of death certificates evaluated by resubmiting a sample of death for underlying certificates for cause of death codingby the same nosologist. No change in the The sample consisted of 25 major categories of cause of death death certificates was noted. from 1970 -1989, All cancer deaths were coded concordanily. certificates were discordant. Within cardiovascular causes of death, two 32.5VitalStatusAscenainment --a ' 03223  [) | The vital status was ascenained from the Social Security Administration (SSA) and the National Death Incex (NDI). Allindivicuals with unknown vital status were traced successfully and vital status determined. Vital status determination in the 1875-1989 period was obtained through the NDI. Death certificates were requested ffom the appropriate state health depanments for those individuals identified as, or presumed to be, deceased. A professional nosologist coded the eath cenificates for underlying cause of death according to Intemational Classification of Diseases, 8th revision (ICD). Information concerming the cate and cause of two deaths which occurred outside the United States was obtained from tamily members or other available sources. Date of death and the ICD8 `code for the underlying cause of death were entered into the database. ----_---- , The vital status determination procedures for the cohort was evaluated. Corporate benefit records were utilized as an independent sourcefor vital status among the retirees. Vital status from the database was compared to vital status in corporate records. A list of all retirees in the 1947-1984 cohort was sent to 3M benefits department. These individuals were matched to retirees who had received 3M death benefits. 3M records were nat complete for periodspriorto 1975. Inthe pre-1983 period, 4 deaths in retirees were identified by 3M records. Vitalstatus was correctly ascantained by the SSA matching procadursfor only one of thes retirees. In the 1983-1989 period, 34 deaths in ratirees ware identified in 3M records. The NDI matching procedure ascertained all 34 of these deaths. `The NDI was not available for 1990. 3M records indicate that 8 retirees died during 1990. The incomplete SSA ascortainment in the pariod 1975 to 1983 fesuted in extending the NDI search to include 1979 to 1983. All 3M identified deaths were also identified in the subsequent NDI search covaring the 1979 to 1883 period. 227Analysis Analytic methods employed in this study were appropriate for cohort studies. The relative risk was estimated by calculating an adjusted standardized mortality ratio _a 03224 :| o (coSmMpRa)ri1s%o.nsT.hisMosrttuadliytyusfeordmbaotnhinnatthieonCahleamnodlMtiencnoehsoorttawmaosrtacloimtyparrateeds tfoor eaxnpdercatceed. nTathieonuasleaonfdmMoirnalnietsyotraatmeosrtianltithye,raudrajlusctoeudntfioersagseu,rrcoaulnednidnagr tpheeriopdl,anstex wera not considered to be stable for many causes of death and were not used. Since less than ane percent of plant employees are non-white, white male and female rates wers used for comparison. For women, only U.S. rates were used because cause- and calendar period-specific Minnesota rates were not available. SMPs were calculated for all cause, all cancer, and cause-specific monality. The effects of disease latency, duration of employment, duration of follow-up, and work in the Chemical Division were examined using stratified SMR analyses. Three additional methods of analysis were used to assess the validityof the SMR contrasts. The three methods were: standardized rate ratios (SRR) '%, Mantel Haenszel adjusted relative rates (RRMH) %, and proportional hazard regression . adjusted RR 197, Limited exposure data were availabe from plant records. Exposed workers were defined as all workers who worked for 1 month or more in the chemical division. Exposed and unexposed workers' all cause, al cancer, and cause-specific mortality was compared using stratified SMRs, SRR 1, and stratified Mantel Haenszel analysis 19% 199, Additionally, the same summary measures were calculated contrasting the rates for workers with at least ten years duration of employment and those with less than ten years employment. ~ `The relative risk (RR) and 85% Cl for the RR for deaths from all causes, cancer, cardiovascular diseases, and selected specific causes were estimated using a proportional hazard model (PH) *"- 1%, The time to event or censoring was. defined as me from first employment to event or December 31, 1988. In PH models for specific causes of death, deaths from other causes were censored at the time of death. Exposure was quantified by months of chemical division employment. Covariates included in the models were age at first employment, year of first employment, and duration of employment. The analyses were stratified by gender. The appropriateness of the proportional hazard assumptions. were tested using stratified models with graphical analysis of log (-og(survival)) 3s 03225 o| versus follow-up time relationships and models that tested the significance of a product term between exposure and log(follow-up me) 199: 1, 2.3 CrossSectionalStudyOfPFOAExposed Workers: 2.3.1 Population Definion And Recruitment Medical screening of workers employed at the Chemolite plant occurs every two years. The general medical screening program included a medical questionnaire (Appendix 3-1), measurement of height, weight and vital signs, puimonary function evaluation, urinalysis, serum assays, and hematology indices. This screening program offered an opportunity to assess the physiologic effects of PFOA exposure in workers engaged in commercial production ofa limited spectrum of PFCs. Of particular interest wera the effects of PFOA, the primary fuorochemical found in the serum of Chemolite workers. (Griffith and Ubel, 1980). Participation in the Physiologic Effects Study required the subjects' willingness to undergo hormonal and biochemical testing and to have an addtional 15 mi of blood drawn for total fluorine assay. In the cross-sectional study, exposure classification was based on the potential for PFOA exposure in aworkers job and plant location. All workers engaged in any facet of PFOA production in the `previous five years were considerteod have potentially high PFOA exposure. The jobs Eonisidered to have high exposure potential included all jobs in the production buildings (bldg 6 and 15), all maintenance workers who ware assigned tothe PFOA production areas, and all management jobs requiring physical presence in the production building. Plant records and job history information was used to assign exposure status to individual workers. A random sample of workers in jobs with low exposure potential was frequency matched to the age `and sex distributionofthe high exposure workers. Workers with low exposure potential were defined as those assigned to jobs not involved in the production of PFCsforat least five years.A roster of workers meeting the low exposure potential was defined from plant records and knowledge of plant personnel about the location of high exposure jobs. A gender stratified sample from the group of workers in low exposure jobs with an age (S year strata) distributionsimilarto the exposed group was identified and invited to participate. If a worker in a job with --3 C0O3R26 | o . : | low exposure declined to participate, another worker in the same age and sex stratum was randomly selacted and invited to participate. In all cases informed consent was obtained, Participation in this study was voluntary. 2.3.2DataCollection 2.3.2.1StudyLogsAndFiles A roster of paricipants was maintained by the plant occupational health nurses. A log for biological sample information was completed by the laboratory technician. The date and time of ample coolection was recorded. Quality assurance samples were recorded on a separate log. Results reported on paper records were mairtained as medical records. Results for other tests wers transmitted electronically to a computerized database and coded as SAS datasets. All ' records were stored with employee medical records of in the corporate medical offices for confidentiality purposes. Printed laboratory results and questionnaire data were entered nto a SAS dataset. dasa ema Each participant completed a medical questionnaireprior10 reporting to the plant medical office. (Appendix 3-1) hems included demographic information, `symptoms, lines historyanddiagnoses, and medication usage. Detailed questions concerning tobacco use and alcohol use were included. Workers were not re-contacted to obtain missing informationorto correct inconsistencies. Responses were not validated. Two plant occupational health nurses collected the questionnaires and returned them to the corporate medical depanment. In the corporate mecical office, data were coded and entered into a SAS data base. 1.3.2.3 Laboratory Procedures: 23231HeightandWeight [ --x C0227.  wUepiognhtrdepeotretrimnignteodtbhey aplnanotccmuepdaitciaolnaolfchee,alptharnutriscei.paHehiaghdtthaenidr hweeiigghhttang were measured once on the same calibrated scale. 23232Blood 232321DrawingAnd Handing tFeocuhrnovlaocguitsati.naTrwsoof1b5lmoiodrewderteopcvraacwuntafirnoemrsasoifnbglloeodvewneirpeundcrtauwren abyndaallalboowraetdotroy clot. One 10 mi purple 19p vacutainer was drawn for hematology studies, A sspeercuimallfyluporrienpeadreetderfmluionraitnieonf.reoVe1n5impiunvcaicuurteasinweerrweasschuesdeudlteodcfaolloeccctubrloatodthfeor total sam time of between 6:30 day and and on the 8:00 am. same shift Workers in for each worker. All blood was drawn the Chemical Division of the Chemolite . plant rotate assignedto shifts on a weekly the day shif for at basis. least 3 Blood days. was drawn aftear workerwas o Al specimens wera refrigerated at the plant prior to transport tothe appropriate laboratory. Clotted red top vacutainer specimens were centrifuged for 12 minutes t1o0 rseenpdaerrattehesetortualmsferroummcaflllusorbienfeosrpeetcrianmsepnosrtntoonitnhfeeccotnitoruasc,tslearbourmaftoorryt.otIanl ordar sflaunodriinneg atshseasyasmpwlaessettohetrheex3tMracCtheedmiincathleDciovirspioornataenamleydtiiccallabdoreaptaorrtiemse,ntprior to 232322Assays pSaerraummetsearms,plcehsolewsetreeroal,nalliypozperdotfeoirntso,taalnsdesreuvmefnluhoorrinmeo,nheesp.atiAcssbaioycehdembiicoaclhemical gplatraammaettiecrspyirnucvliucdetdrasnesraummingalsueta(mSiGcPoTx)a,logacaemlmicatgrlauntsaammyilnatrsaens(fSeGrOaTse),(GsGeTr)u,m taensdtoasltkearloinnee,pfhroeseptaetsatsoeste(rAoKnPeH,)e.strTadhiolf,olplroowliancgtihno, rtmeoinniezsiwnegrheoarsmsaaynsd(:LHb),ound pfroleisceervsetdimwuhlaotliengblhooordmosnaem(pFlSeHs)u,nadnerdwetnhytroriodutsitniemuhleamtaitnoglhoogricmoannaely(sTiSsH)i.ndEucDiTnAg _m 03228 o| complete blood count with erythrocyte indices and leukocyte differential cell count (CBC). Analyses wers done without knowledge of te subject status or purpose of the study. Total serum fluorine was determined in 3u's Chemical Division analytic laboratory using the sodium biphenyl extraction method (Venkateswartu, 1962). The `accurate determination of total fluorine in the parts per million (ppm) range required specialized equipment, procedures, and personnel. Assays were completed in a dedicated laboratory following tested protocols. Upon receipt of extracted serum samples divided aliquots wers frozen at -70 degrees centigrade. After all samples had been received, batches of 15 samples were assayed on successive working days. Each batch inciuded high and low quality control samples. Each sample was assayed twice. fi the difference in assayed values was greater than 1 ppm, the sample was re-assayed. The total serum fluorine value was reported as a mean value and a rounded integer value. Serum glutamic oxaloaceti transaminase (SGOT), serum glutamatic pyruvic transaminase (SGPT), gamma glutamyl transferase (GGT), and alkaline phospatase (AKPH) were assayed by the United Health Services Laboratory in Apple Valley, Minnesota using clinical colorimetric assays. CBC were determined using automated Coutter counters. Light microscowpasy utilized for diMferential counts; ~~~ mimes oe Estradiol, prolaciin, thyroid stimulating hormone (TSH), luteinizing hormone (LH), and folicte stimulating hormone (FSH) were assayed by the United Health Services laboratory using radioimmunoassay (RIA) and enzyme linked immunosorbent assay (ELISA). FSH, LH, and prolactin were assayed using Abbott laboratories IMX microparticle enzyme linked immunoassays. TSH was. assayed using London Diagnostics chemiluminescense immunometric assay. Estradiol was determined using Diagnostic Products Corporation's Coat-a-count --3 032z9 | : Testosterone was assayed by the Mayo Clinic dlinical laboratories. Total testosterone was determined by RIA using proprietary immunoglobulins. Free and bound testosterone was determined using equilibrium dialysis. 22.Qu2alit3 y Ass2uran3ce. Two methods were used to assess the accuracy and reliability of the laboratory assays. The laboratories routinely followed quality assurance programs. Three standards were fun with each batch. Ifthe control values were outside two standard deviations of the intra assay mean value for each standard, the assay was repeated. If 10 controls were outside 1 standard deviation of the mean, the assay was flagged for review. The reliability of each of these assays was assessed. For each assay, five specimens were randomly selected and split into two aliquots. The aliquots were labeled with different identifiers ensuring that the assays were carried out in a blinded fashion. Both aliquots were submitted onthe hormone. `same day to the laboratory. The coefficientofvariation was calculated for each There were two analytic strategies. First, assay results were treated as continuous parameters and modeled using regression methods. Models were fit 10-assess the relationship between assay results and total flucrine, body mass. index, alcohol consumption, and smoking. Second, hormonal assay results were dichotomized into those within the reference range and those outside the reference range. The hormone assay categories were based on published sex `specific normal reference values for each assay. The purpose of this dichotomization was to evaluate the possibility that highly susceptible individuals may be affected at lower levels of exposure and not follow the adjusted dose- response curve. The relationships between total serum fluorine and the assayed parameters were estimated by fitting linear multivariate regression models to the data. The clinical parameters and ratios of selected parameters were first modeled as functions of nominally categorized exposure and covariates. Dependent variables that were _4 03230  o | . not normaly distributed were appropriately transformed. Total serum fluorine was categorized into mutually distinct categories. Cutoff values for the categories were chosen to assure adequate numbers in each category while maintaining the fullest range of exposure values possible. Accordingly, total serum fluorine level categories were defined as the following: less than 1 ppm,greaterthan 1 ppm toless than 4 ppm, 4 ppm to 10 ppm, greater than 10 ppm to 15 ppm, and greater than 15 ppm. If insufficient numbers of events occurred within individual categories, the numberof categories was reduced by combining adjacent categories. Additionally, models were fitted with total serum fluorine entered as a continuous variable using linear, square, square root transformations. Age, body mass index (BMI), alcohol use and tobacco use were included in the model as potential confounders. Age was included in the models as both a categorical variable and a continuous variable. Age was grouped intofour ten year age categories. Age was treated as a continuous variable using linear, `square, square root, and log transformations. BMI was entered in the models as. a categorical variable and as a continuous variable. BMI categories were less. than 25 kg/m, 25-30 kg/m?, and greater than 30 kg/m2. Additionally, BMI was dichotomized into obese, greater than 28 kg/m2, and non-obese, less than or `equal to 28 kg/m2. The cofttinuous variable was entered as linear, square, log, and square transformations. Alcohol use was categorized into 3 categories: less than 1 drinkperday, greater than one to 3 drinks per day, and non response to the questionnaire item. Smoking was categorized as current nonsmokers and current smokers. A nonresponse category was not included sinceonly two individuals were in this category. These two individuals were excluded from analyses that required smoking history. Smoking was quantified as cigarettes smokedper day. Linear, square and square root transformations of cigarettes per day were used in regression models. The choiceofthe final model was somewhat subjective. For each dependent variable, other covariates were included in the final model if they were potential confounders. Other potential confounding hormones and biochemical parameters estimates. were included in the models if they produced significant changes in effect -- 41 03231 | Total serum fluorine and confounding covariates were entered into models as continuous variables. Significant nonlinear cose-response relationships were evaluated by comparing model it and parameter estimates using categorical Variables and continuous variables. Square, square root, exponential, and logarithmic transformations were used if the transformed variables produced models of superior predictive power as assessed by model fi. All two way interactions between total serum fluorine and the included covariates were evaluated. Interaction terms were included in the final modelif the parameter estimate for the interaction tarm was significant at the alpha =.10 lev. The potential for suscepibilttoy confound the relationship between PFOA exposure and the assayed parameters was examined by comparing the observed prevalence of assay results outside of the referanca range with the expected prevalence. The prevalence of abnormal assays was based on `published reference values for the adult male US population. Reference ranges for test parameters were defined as being within 2 standard deviations above or below the mean valu for the parameter. The laboratory maintains laboratory and assay specific feferance range for each assay. Given that the distribution of values is approximately normal, about 2.5% of individual values are expected to fall above the upper imit and 2.5% below the lower limit. tt follows that the prevalence for a high testis .025. The prevalence foar low value is .025. Using these prevalences, an expectad number of tests outside of the referance range . can be defined. A priori hypotheses based upon animal and in vitro studies defined the expected direction of the effect. The calculation of an observed to expected ratio allowed the estimation of the relative prevalence faoterst outside of the normal range in the study subjects as compared to the general population. The 85% Ci for the ratio was calculated assuming that the expected numbeirs a constant and the observed number is a random variable with a Poisson distribution. _a C0332 .  : o 4 BESULTS 4P.1CreossrSectlionaul oroc Physa iolot gicEbtecoStnudy In October 1990, at the time of the cross sectional study, the workforce at Chemolite consisted of 880 salaried and hourly employees. There were 50 men `and 2 women in high exposure potential jobs. Since there were only 2 women in this group, the study was restricted to males. Forty-eight (36%) of the 50 male workers in high exposure potential jobs agreed to paricipate. The exact number of low exposure workers invited to participate in the study was not recorded. However, few individuals in this group refused to participate. Thus, it is estimated that over 80% of low exposure workers participated. 4.1.1PanicicanCharacteristics Since frequency matching for age was used to select study participants, the overall age distribution reflected the age distribution of workers in high exposure potential jobs (Table 4.1.1). Ages ranged from 24 to 59 years, with a median age of 37 years and a mean age of 35.2 years. Table 4.1.2 presents the alcohol and tobacco use profile of the study participants. `The light arinkers category included 22 participants who reported no alcohol use. Consumption of one to three ounces of ethanol per day was reported by 20 (18.7%) participants. No panicipants reported drinking greater than three ounces of ethanol per day. Eight workers (7.0%) did not complete this item of the questionnaire. There were 28 (24.8%) smokers who smoked an average of 21.7 cigarettes per day. Smoking status was not availablefortwo workers (1.8%). `The association between smoking and alcohol consumption is presented in Table 4.1.3. Thirteen (15.3%) of 85 nonsmokers and seven (25.0%) of 28 smokers. reported moderate drinking (p=.24). Table 4.1.4 displays the age distribution for alcohol and tobacso use categories. Thers were no significant differences in `mean ages among smoking or drinking categories. --a 03233 o o Total fluorine was not significantly correlated with age, BML, alcohol, of tobacco use (Table 4.1.5). BMI and age were correlated (r:26. p=.005). Alcohol use and tobacco use were not significantly comelated (r=.08: p>.7). BMI ranged from 18.8 10 40.5 kg/m? with a median value of 26.3 kg/m2 and a 3m0eakng/omf22.6.T9hkeg/mme?an(TBabMlIe i4n.s1.m6ok).erHsalwlaosf anllotwosrikgneirfsihcaandtBdMififserbenettwfreoemn t2h5ataonfd nonsmokers (Table 4.17). The mean BMI for moderate drinkers was not significantly diferent from the BMI of light drinkers. Smoking status and BMI were not significantly associated (Table 4.1.6). There was a significant linear relationship between BMI and age (8.10 SE(8)=.035). This relationship was not substantially altered after adjusting for smoking status, alcohol uss, and total `serum fluorine level. 4.1.2TotalSerumFluorine The total serum fluorine values ranged from zero to 26 with a median value of two ppm, a mean of 3.27 ppm and astandard deviation of 4.68 ppm (Table 4.1.9). The inter-assay coefficient of variation was 66% calculated from repeated assays on different days. "Twenty-three (20.0%) of 115 workers had total serum fiuorine values less than one ppri. This group included eight workers values reported as zero ppm (below the mits of detection). Eighty-eight workers (76.5%) had levels less than or equal to three ppm. Six (5.2%) of 115 workers had values between 10 and 15 ppm and five (4.4%) had values greater than 15 ppm. All workers with levels greater than ten had worked in Building 15, the primary PFC production area at the Chemoite Plant. `There were no significant differences in total serum fluoride mean values among the BMI, age, alcohol use and tobacco use categories (Table 4.1.10). No statistically significant differences in mean age between total fluorine categories were observed (Table 4.1.11). oc 03234 | oPfarctiigcairpeatnttesswpietrhdlaesys(tThaabnleon4.e1.p12p)m. tTothaolsfeluowriitnheosnmeopkpedm t1hoetlheraesetp(p16m.3t)otnalumber wflausorsitnaetissmtiockalelydstihgenigfriecaanttes(tp<n.u00m5b)e.rAofsceisgtairemtatteesdpienradraeygr(e2s4.s5i)o.n Tmhoidseld,iftfheerence afinndeaBrMrIe,lawtaiosnsshmiapllbeitn wmeaegnnitottuadl efl(u3o=r0in.e10a,ndSEs(m8o)k=i0.n0g6s2t,atpu=s.,09a)d.jusStmeodkefrosr.age average total serum fluorine was estimated to be 0.1 ppmhigher than nonsmokers. The number of cigarettes with total serum fluorine (Table 4.1.5). smoked per day was weakly correlated eDirgihntki(n7g.0s%ta)tpuasrtwiacsipnaonttsadsisdocnioattreedswpiotnhdtottoalthfilsuqoruienseti(oTna.blFeo4u.r1.h13a)d. Overall, less than one ppm total serum fluorine. dTeafbilneed4.p1r.e1v4iopurselsye.ntBsMtIhemediasntrivbaultuieosn owferBeMInoitn stihgenitfotiaclanftludoirfiineerecnacteesgoarmieosng the ftloutoalrisnee,raudmjuflsutoerdinfeorcaatgeeg,orsimeosk.inTgh,ealnidneaalrcroehloaltiuosnes,hiwpabsetwweeaeknaBnMdInaotnd total significant (Bx-.016 SE(8)=.069, p>.5). 4.1.3HormoneAssavs `esTthreadiinotlr,a-TaSsHs,ayLcHo,efpfriocliaecnttino,f vaanrdiaFtiSoHn (aCsVs)ayfsoratrheepbroouvniddeadnidn Tfraebelete4s.t1o.s1t5e.roTneh,e estradiol assay CVol 3.1%. had the highest CV, 18.3%. The prolactin assay had the lowest oTuatbloef t4h.e1.a1s6psraeysreenftesretnhceeorbasneger,vetdheanobdseexrpveecdtteodenxupmebceterdof(OhoEr)mroantieo,asasnadytshe 95% confidence limits. The estradiol, free testosterone, O/E ratio was significantly greater bound testosterone and prolactin. than The one O/E for ratios for LH. FSH, and TSH wers not significantly different from one. sTthuedyPepaarrtsiocinpacnotmselaartsiopnrecsoeefnftiecdieinntTsaabmloen4g.1t.1h7e.seAvsenexhpoecrtmeodn,eesstarsasdaioylewdaisn = 45 : O323S o Pc=o.m0s0l0a6t)e.d wBiotuhnfdretetsetsotsotsetreornoenwsa(sr=.c4o0m,elpa=t.e0d00w1i)thanfrdeeboteusntdostteesrtoonset(arr=o.n74(r=.32, P=.0001), LH (t=.28, pe.003) significantly comelated (r=.63, and FSH (r=. 16, p=.0001). FSH p=.04). LH and FSH ware and TSH wers significantly comelated (1=.23, pe.01). A(1s2:s19h,opw=n.0in45T)abalned4T.1S.H18,(ro=t.a26l,fpleuo.r0i0n5e).waAsgseigwnaifsicnaentglayticvoerlryelcaotmeedlwaittehdpwriotlhactin e(s1t=r2ad4i,olp=(.10-12),5,anped.p0r1o)l,acftriene t(rees-t.o1s8,tepr=o.n0a1)(.ra-A.g45e, wp=a.s00po0s1i)t,ivbeolyuncdortreelsattoesdtawirtohn BFoSuHnd(1t=e.3s3t,ospt=e.0r0o0n3e)f.oA.2s6,exppme.ct0e0d5,aBnMdIr-w-a.3s6,nepg=a.t0i0v0e1lyrcaosrproecliavtaeldyw)i.thBfMrIeewaansd comelated positively with LH (r=.20, p=.03). Alcohol significantly correlated with FSH (re-.24 pm.01). consumption was aBomuenddiatnesotfo5st6e1rogn/edr!a(nTgaebdlefr4o.1m.1154)1. 1T0h1e15s2tanngd/adrldwditehviaatmieonasnwoefr5e7l2arngge/.dlTahned mean bound testosterone values ware not significantly citferont among the total ssiegrniufmicfalnutolryianes gBrMoIupisn.crAesaseedx.pecTtheed,methaenmbeoaunndbotuenstdotsetsetroosnteevraolneuedsewcerreeased significanty difierant among the age categories (p=.016). `bTohuenred wtaesstoasstiegrnoinfeic(aBnTt)noinnltihneeafirnraellarteigornesshsiiponbmeotdweeeln(tToatballese4.r1u.2m0f)l.uoBrionuenadnd dteesctroesatseerodnaes, wbhoitchhawgaesapnodsiBtMivIeliyncarsesaosceida.tedAlwciothholboatnhdLcHigaarnedtteestursadeiowle,rs weakly associated with BT. total serum fluorine. There There was a significant interaction betwoen was a negative association between bound age and wtoerstkoesrtsergorneeataenrdthtoatnal4s5eyreuamrsflouforaignee,itnotyaolusnegrwuomrkfleurosritnheawnaisnolasdseorcwioartkeedrwsi.thIan ssiegrhutmifnlcuroerainsee sin pBrTe.seTnhteedrefloratfioounrshdiipfebreetnwteseentsboofucnodvatreisattoestvearlounee(aFnidgutroeta2l). Dose-response curvesfor bound individuals aged 30 with BMis of testosterone were plotted for young, 25, young obese individuals aged 30 lean with BMis. of 35, middie aged lean individuals aged 50 with BMI of 25, and middle aged ~ 03236 o obese individuals aged 50 with BMIs of 35. Each of the relationships is for nonsmoking, light drinking men with the sample mean LH value (5.4 mUA) and `mean estradiol value (33.4 pg/mi). In 30 year old workers, bound testosterone decreased s total serum fluorine increased in both BMI groups. The doseresponse relationship for 40 year old workers was approximately flat (not shown). In workers greater than 50 year of age, BT increased as total serum fluorine increased. Total serum fluoride was not significantly associated with free testosterone (FT) (Table 4.1.21). Within BMI categories, ree testosterone was highest in the less than 25 kg/m? group and lowest in the greater than 30 kg/m? category. The ditierence in mean FT among BMI categories was statistically significant (p=.03). `There was a significant nonlinear dose-response relationship between total . serum fluorine and FT in the final regression model (Table 4.1.22). As total serum fluorine increased, free testosterone decreased. There was asignificant interaction between age and total serum fluorine. Figure 4.2 llustrates the modifying effect of age on the total serum fluorine free testosterone relationship. `The covariate vectors (nonsmoker, light drinker, mean LH and estradiol, age=30 and BMI=25or25, age=50 and BMI=25 or 35) were the same as used Figure-1. Lean or obese 50 year old men had low frse testosterone (less than 9 ng/di) for all values of total serum fluorine. In 30 year olds, free testosterone decreased asymptotically toward the 50 year old values. In this model, 50 year old, obese, moderatecrinkerwith any total serum fluorine level (the lower limit of assay sensitivity was approximately 1 ppm total serum fluorine) had free testosterone below nin g/dl. As shown in Table 4.1.23, the estradiol means in the three BMI groups were not significantly differant (p=.88). As the age of participants increased, mean estradiol levels decreased. In the greater than 30 10 40 year age group, mean estradiol was 36.8 pg/ml compared to 25.9 pg/ml in thegreater than 50 to 60 year age group. The age group means were significantly differant (p=.018). There was a nonsignificant positive association between mean estradiol and total serum fluorina. -a 03237  As shown in Table 4.1.24, estradiol andtotal serum fluorine were positively associated in the final regression model. Tetal serum fluorine followed a nonlinear relationship with estradiol. No interaction terms were statistically significant. As expected, free testosterone and estradiol were positively `associated (0.85 p=.0007). The relationship between total serum fluorine and estradiol is lustrated in Figure 3. The plotted curves depict the relationship for lean (25 kg/m?) and obese (35 kg/m?) male workers who were 30 years old with sample mean free testosterone and who were nonsmokers and light drinkers. As total serum fluorine increasedover the observed range, estradiol increased quadratically. In obese men (BMI=35 kg/m? ) aged 30, estradiol exceeded 44 pg/ml when total serum fluorine was between 15 and 20 ppm. The highest estradiol levels were in young, obese smokers who consumed 1 to 3 ounces of ethanol per day. LH was not significantly associated with serum fluorine, but was negatively associated with BMI (p=.003) and positively associated with smoking (pw.025), age, and BT. There was no association between total serum fluorine and FT. (Table 4.1.25, Table 4.1.26, and Figure 4). FSH was not significantly related to total serum fluorine levels but was positively associated with age (p=.014) (Table 4.1.27, Table 4.1.28). The final regression - model for FSH is illustrated in Figure 5. The relationship was essentially fiat over the total fiuorin range. `TSH was positively associated with total serum fluorine in both univariate and multivariate analyses (Table 4.1.29, Table 4.1.30 and Figure 7). TSH was not significantly related 0 age, BMI, alcohol use, smoking, and other hormones. Prolactin was positively associated with total serum fluorine and smoking (Table 4.1.31, Table 4.1.32). Moderate drinkers had a different prolactin-total serum fluorine relationship compared to light drinkers and nonrespondents. Figure 6 ilustrates the relationship of prolactin with total serum fluorine and the modifying effect of alcohol use. Total serum fluorine was weakly associated with prolactin in light and moderate drinkers. However, in moderate drinkers (1-3 oziday), there was a positive association between prolactin and total serum fluorine. & 03238 o 4.1.4Hormone Ratios " The univariate distributions of the 21 ratios are provided in Appendices 4.1 and 42. Atable is presented for eachof the 21 ratios showing the number of paricipants, mean ratio value with the standard deviation, median ratio value, and the range of ratio values in each of the previously defined categories of BMI, age, alcohol use, tobacco use, and total serum fluorine Correlations between total serum fluorine (ppm), age (years), BMI (kg/m2), alconol use (02/day), and cigarente consumption (cigarettes/day) and all possible ratios between E, free testosterone TF, TB, and LH are displayed in Table 4.1.33, `The estradiol to bound testosterone ratio (E/TE) and estradiol o free testosterone ratio (E/TF) were significantly correlated with BMI (=.32, p=.001 and r=.27, p=.004 respectively). The estradiol to Iteinizing hormone ratio (E/LH)was negatively correlated with age (r=-26, p=.005), and positively correlated with BMI (r=:18, p=.06). The bound testosterone to luteinizing hormone ratio (TB/LH) followed a different pattem as compared to ELH. The correlation coefficient between TB/LH and age was -.32 (p=.001) while the coefiicient between TBILH and BMI was -14, (p=.13). The free testosterone to luteinizing hormone ratio (TF/LH) had the strongest correlation with age (fa-.40, p=.0001) but was not significantly correlated with BML. The bound testosterone to trae testosterone. ratio (TB/TF) followed a unique pattem. TB/TF was positively correlated with age (t=.24, p=.01), and negatively correlated with BMI (fa-16,p=.08). Prolactin ratios with bound testosterone (TB/P), free testosterone (TF/P), estradiol (E/P), follicle stimulating hormone (FSH/P), luteinizing hormona (PALH), and thyroid stimulating hormone (P/TSH) are presented in Table 4.1.34, None of the prolactin-hormone ratios were significantly correlated with total serum fluorine orBMI. All except PITSH ware significantly correlated with cigarette consumption. Table 4.1.25 presents the Pearson correlation coefficientsfor the bound testosterone to thyroid stimulating hormone (TB/TSH) ratio, the frea testosterone 10 thyroid stimulating hormone (TF/TSH), and the estradiol to thyroid stimulating _a 03239  homnone (E/TSH). Total serum fluorine and TF/TSH ware negatively comelated (t=-.18,p=.05). All three ratios were significantly and negatively correlated with age. TB/TSH and TF/TSH were negatively correlated with BMI, (fe-.24p=01 and re-23, p=01 respectively). The Pearson correlation coefficients for the bound testosterone to follicle stimulating hormone (TB/FSH) hommons (TF/FSH), and the est ratio, radiol the free testosterone to follicle stimulating to follicle hormone stimulating (E/FSH) are provided in Table 4.1.36. Age was the only covariate that was significantly correlated with the three ratios. The correlation coefficients for selected ratios between pituitary glycoprotein hormones, stimulating TSH, LH, hormone and LH, to follicle are presented in Table 4.1.37. The thyroid stimulating hormone (TSH/FSH), the thyroid . stimulating hormone to luteinizing hormone (TSH/LH), and the folliclestimulating hormone to luteinizing hormone (FSH/LH) are provided. Age wassignificantly correlated with the FSH/LH ratio and the TSH/FSH ratio. Alcoholconsumption was correlated with both TSH/FSH and TSHALH. As shown in the finel regression models, the TE/TF ratio increased as total serum fluorine increased (Tables 4.38 and 4.39). Alcohol consumption,cigarette `consumption, estradiol, prolactin, and TSH were not significantly related to the TB/TF ratio in either model. These covariates do not substantiallyalterthe iensctliumdaetdedinrtehleatrioengsrheispsiboentwmeodeenl.totTalhseeqruuamdrfaltuiocriinnecarnedasTeBo/fTtFheraTtBio/TwFhernatio over the observed range of total serum fluorine is illustrated in Figure 4.8. The covariates used day, 30 years of were: nonsmoker, age, and a BMI of less than one 30 kg/m2. ounce of alcohol consumed per Table 4.1.40 presents the full regression model for the estradiol to bound testosterone ratio (E/TB). Total serum fluorine was not significantly associated with was the E/TB ratio. BMI negatively related to was the a determinant E/TB ratio. of the E/TB ratio. Freetestosterone -% 03240  : dTihseplfaulylerdeignreTsasbiloen4m.o1.d4e1l. fTorheersterawdaioslatosifgrneiefitceasnttopsotseirtoinvee rdaotisoe-(Er/eTsFp)onisse rreelsaptoinonssehirpelbaetitownesehinptfhoer Efr/eTeFtreasttioosatnerdotnoetawlassermuodmiffliueodribnye.agAel,thtohuegdhosthee- doseresponse relationship for the ratio was not modified by age. sAisgnsifhiocawnntlyinaTsasbolceisat4e.d1.w4i2t,h4E.1L.H43aannddT4B./1L.4H4,,btuottawl asserpuosmitfilvueolryinaesswoacsiantoiton wih the TF/LH ratio With the TF/LH (6~-.05, p=.09). Bound testosterone and FSH ratio (B=.003, p=.0001) and (B=-.33, p=.0001). were associated Creilgaatreedrt0e cthoensTuBm/pPtiroatnioa(n0da1f.re4s8,teps=t.o0s2tearnodneBw=e3r.9e3s,tpro=n.g0l0y8arnedspseicgtniivfeiclayn)tl(yTavie 1401t.h4e5)T.F/CPigraarteitot(e8c.o0n4s,umpp=.t0i3onaannddBb=.o0u0n2d, tpe=s.t0o3streersopnecetwivaerlsy)si(gTnaibfilcean4t.l1y.4r5e)l.ated Only cigarette consumption P=.005) (Table 4.1.47). was significantly related to the E/P aio (Ge.10, 1T0abFlSeHs 4(.P4/8FStHh)r,oupgrohla4c.t5i0n ptroeLseHnt(Pf/uLllH)r,egarnedsspiroonlamctoidnetosTfSorHth(eP/raTtSiHo)s.ofInpreoalacchtionf + ahsesotchiraeteedrewgirtehsstihoenpmrooldaecltsint-othaolrsmoenreumratfilou.orMinoedweraastpeosdirtiinvkeelrysahnaddsaignificantly `sicgonmipfaicraendtltyodtihtieerraenltatriaotnioshtioptsalisn elirguhtmdfrliunokreirneadnodsneo-nrreessppoonnsdeenrtelsa.tionship The full regression modes Table 4.1.51 10 4.1.59. As for the shown glycoprotein hormone ratios are presented in table 4.1.52, total serum fluorine was in wsiagrneifsiicganritfliycraenltlayterdeltaotTedF/toTSthHo (TBF--/.T2S8,H pr=a.ti0o3)(Ga=n.d01b,opu=n.d00t6esatnosdteBreo.n6e8,apned.0F&SH respectively). Total serum fluorine glycoprotein hormane ratios. was not significantly associated with the other son Dens . pest Inolvcerides. -- st : 03241 o `Table 4.1.60 provides the correlation coefficients for serum lipids, spacifically cholesterol, low density lipoprotein (LDL), and high density lipoprotein (HDL), with total serum fluorine, age, BMI, alcohol consumption, and cigarette consumption, Total serum fluorine was not significantly correlated with cholesterol, LDL. HDL, or triglycerides. Cholesterol and triglycerides were correlated with age ( re.25, $=.008 and r=.19, p=.04, respectively), and BMI (r=. 19, p=.04 and r=.27, pe.004, respectively). Cigarstte smoking was positively and significantly comelated with cholesterol (r=.35, p=.0001), LDL (r=.28, p=.002), and triglycerides (r=.19, p=.0d). HDL was not significantly correlated with any variable, although the correlation with alcohol consumption was suggestive ( re.18, p=.06). Total fluorine was not significantly associated with cholesterol, LDL or triglycerides (Tables 4.1.61, Table 4.1.62, Table 4.1.64). Smoking, age, and GGT were positively and significantly associated with cholesterol. Smoking and * prolactin were positively and significantly associated with LDL. Smoking and free testosterone were positively associated and bound testosterone was negatively associated with triglycerides. o `The final regression model for HDL, displayed in Table 4.1.63, presents a ditierent picture. HDL decreased as total fluorine increased in moderate drinkers. In ight drinkers, there was a negligible change in HDL as total fluorine increased, Sell-reported moderate alcohol consumption was positively associated with HDL. Additionally, bound testosterone was positively associated with HDL, while free testosterone was negatively associated. 4.1.6HepaticParameters:SerumGlutamicOxaloaceticTransaminase(SGOT), GammaGlutamylTransferase(GGT), Table 4.1.65 presents the comelation coefficients between the hepatic parameters, SGOT, SGPT, GGT, AKPH, and total serum fluorine, age, BMI, alcohol consumption, and cigarette consumption. The hepatic parameters were not significantly correlated with total comelated with any of the pariicipant serum fluorine. characteristics. SGOT SGPT was and not significantly GGT were comelatedsignificantlyonly with BMI (r=.20, p=.02 and r=.27, p=.004 -- 52 03242  @ : cremspmecptiiveolyn). aAnKPaHrweansesicgnoifniscaurtmypco.rrelated with age, BM, alcohol The correlation coefficients between the hepatic parameters and cholesterol, LDL. HDL. triglycerices, estradiol, TF, TB, and prolactin are displayed in Table 4.1.66. SGOT and AKPH were significantly correlated with prolactin. SGPT was corelated with cholesterol and triglycerides. GGT was correlated with cholesterol, triglycerides, and free testosterone. As expected, SGOT, SGPT, and GGT were highly comelated (Table 4.1.67). AKPH was only correlated with GGT. `The SGOT, SGPT, GGT, and AKPH mean values were not significantly diferent `among the five total serum fluorine categories (Table 4.1.68). SGOT and SGPT mean values were not significantly cifferent for BMI, age, alcohol use, and smoking (Tables 4.1.69 10 4.1.72) . Mean GGT was significantly higher in the greater than thirty BMI group (pw=.03). AS shown in Table 4.1.72, mean and median AKPH values were significantly higher in smokers compared to nonsmokers (p=.012). Tables 4.1.73 A, B, and C present three linear multiple regression models for SGOT. In non-obese workers (BMI=25), SGOT decreasedas total fluorine increased. In obese workers (BMiw 35), the association between total serum fuorine and SGOT was in the opposite direction. Model 2 included GGT as a covariate (Table 4.1.73 B). The association between total fluorine and SGOT, as wellas the effect modification by BMI, were present after adjustingfor GGT. When SGPT was included in the regression model (Table 4.1.73 C), the association between total fluorine and SGOT was weak and nonsignificant . The effect modification by BMI was no longer present. AKPH had lite effect on the regression estimates when included in the model. Thro linear multiple regression models for SGPT are provided in Tables 4.1.74 A B,and C. In non-obese workers (BMI=25), SGPT decreased as total fluorine increased. However, in obese workers (BMi= 35), the association between total serum fluorine and SGPTwas in the opposite direction. Little change occurred in the estimates after adjusting for GGT. As seen in Table 4.1.74 C, the association was significant, although weaker in strength, after adjusting for SGOT. The effect _8 03243  `modification by BMI was present. When AKPH was included in the model, effect estimates did not change significantly, - pTrheesefnintalardeigffreersesnitonpimctoudree.lsGfGorTGdGeTc,reparsoeviddaesd tinotTalabfllueosri4n.e7i5nAc.reBa,saenddinC, moderate drinkers. In increased. Controlling light drinkers, GGT decreased for SGOT and SGPT (mods!2 less and steeply as 3) did not total fluorine significantly ater the relationship between total fluorine and GGT. Moderate alcohol consumption was positively associated with GGT. Table serum 4.1.76 presents the final regression fluorine was negatively associated model for AKPH. In nonsmokers, with AKPH, As the number of total cigarettes smoked per as total serum fluorine ay incrsased increased. to more than five per day, AKPH increased 4.1.7HematologyParameters:Hemoglobin,WhiteBloodCount, EamomhanudearLeukooste Count. Band Court,Eosingoni Court, LymohocyteCount,Monocyte Count,PlateletCount,AndBesoohil Court, pTaarbaleme4t.e1r.s77apnrdetsoetnatlsstehreumcofrlrueolraitnieo,n acgoee,ffBiMciIe,ntaslcboehtowleuesne,thaendnicniegahreemtatte ology s`ceornusmumfpltuioorni.ne Twhaes olnylmypphaorcyatmeetceorunthtat(rwe.a1s3,sipg=n.i0f4i)c.antMloyncoocrryetleatceoduwnittwhatostal tchoemeplaartaemdetweirtsh,BeMxIce(pr=t-.t2h2e, bpaes=o.p04h)ilanadndalbcaonhodlccoounnstsu,mpwteiroen,st(rfoan-g.l21y,apses.o0c3i)a.teAdll With cigarette consumption. hemoglobin, (r=-.20, p=.04), Alcohol consumption was correlated and band count (f=.26, pe.00S). with cTohrepufsincaullraerghreemssoigolnobmionde(lMsCfHor) haenmdomgleoabnincoarnpdustchuelaerryvtohlroucmyete(iMnCdVi)ce,s,armeean presenteidn Tables 4.1.78, was significantly associated 4.1.79, and 4.1.80 with hemoglobin... respectively. Total serum fluorine The association hemoglobin and cMiCgaVrewrteersepmeorcdiafyi,edhebymasgmlookbiinng.anIdn MsmCoVkeirnscrwehasoesdmsoigkneifdicsaentvleynaosrtomtoarlefluorine increased. In nonsmokers, hemaglobin and MCVdecreased as total fuorine _ 54 03244  : increased . The association of total fluorine with MCH was modified by smoking ana by alcohol use. The increase in MCH 2s total fluorine increased was ennanced with increased smoking. In light drinkers, total serum fluorine had a weak association with MCH. In moderate drinkers, MCH increased as total fuorine increased. There was a positive association of both MCH and MCV with alcohol consumption. None of the estimated associations are of clinically significant magnitude over the range of total fluorine values. `The white blood cell count (WBC) increased significantly in nonrespondents as total fluorine increased above 2ppm, increased less in moderato drinkers, and increased the least in light drinkers (Table 4.1.81). As expected, cigarette smoking intensity was positively associated with WBC. PMN increased significantly in alcohol use nonrespondents as total fluorine increased and increased less serum fluoride steeply in above 10 moderate drinkers (Table ppm was associated with 4.1.82). In light drinkers, a decreased in PMN. total Cigarette smoking was positively associated with PMN. As shown in Table 4.1.83, the final regression models for band count provides litle evidence that total fluorine was associated with band count. Moderate alcohol use was estimatteod reduce the band count. Smoking was positively associated with band count. +The negative association between total fluorine and lymphocyte count was `modified by adiposity, alcohol consumption, and cigarette smoking (Table 4.1.84). The decrease in lymphocyte count was smalleasr BMI increased. The decrease in lymphocyte count associated with total fluorine above 3 ppm was greater in moderate drinkers compared to nonrespondents. As cigarette consumption increased, the decrease in lymphocyte count increased. mTohdeifpioesditbiyveaadsispoocsiiatyti(oTnabbleetw4.e1e.n85t)o.talAsfluBoMriIneinacnrdeamsoend,octyhteeascsooucnitat(iMonONwiOt)h was MMOONNOO.wAalscowhoelakceornsuCimgpatrieotntewsamsokniegnagtiavnedlyLaHsswoecrieatpeodsiwtiitvhelMy OasNsOo.ciaTtheed with nasosnoscmioakteiorns,bebtutweweanstpootaslitfilvueoraisnemaonrdeetohsainnotpehnilcicgoaurnettt(esEOpSe)r dwaayswneergeatsimveokfeord _ ss 03245  PY (Table 4.1.86). As was smaller (Table smoking 4.1.88). increased, the PFOA associated decrease in BASO The association between total fucrine and platelet count (PLAT) was modified by adiposity and cigarette smoking intensity (Table 4.1.87.). In lean participants (BMI~25), PLAT increased as total fluorine increased. In obese participants (BMI=40), the PLAT decreased as total fluorine increased. As smoking increased, the rate of increase in PLAT associated with total fluorine above 10 ppm decreased. 4.S1.8ummOafRr esuy lts `TehxepesceterduminfwlouorrkienreslenvoetlsdiirnecCthleymionlviotlevewdoirnkPerFsOwAerpero2d0uc-t1i0o0n.tiAmlelswhoirgkheerrstwhiatnh levels above 10 ppm fluorine work in PFOA production areas. Smoking was saessroucmiaftleuodriwniethleaveslmsa.llThinecrtewaosewoinmesenruemmpfllouoyreinde.in Atghee PwFaOsAnoptroadsuscotciioanteadrewaitsh had total serum fluorine levels similar to men. Alcohol use, smoking, age, BMI, and hormones had the expected associations. + with peripheral leukocyte counts, and hepatic enzymes. hematology parameters, cholesterol, HDL, LDL, `The main hormone results are: 1. The number of male workers with hormone values outside of the laboratory reference range was greater than expected for estradiol, free testosterone, bound testosterone, and prolactin. 2. Total serum fluorine was negatively associated with free testosterone and positively associated with estradiol. No association was noted between totalserum fluorine and LH. 3.E/TFand TB/TF, but not E/TB, were positively associated with total serum fluorine. 4. Eth/eLHrelaantdioTnBsh/iLpHbweetrweeennottoatsalsosceirautemdfwliutorhitnoetaalnsdeTrFu/mLfHluwoarisnes.ugHgoewsteivveer., _ 5% 03246  | ? . TSH was positively associated negatively associated with total with total serum serum fluorine; fluorine. TBITSH TF/TSH was and E/TSH were not. 6. Prolactin drinkers, and total serum fluorine but not in light drinkers. were positively associated in moderate 7. PIFSH, PILH, PITSH TB/P, TF/P, and E/P were were positively associated with total not associated with total serum serum fiuorine. fluorine The main hepaticparameter results are: 1. eTnhheanicncerdeabsyetointaSl GseOrTumanfdluoSriGnPe.T levels associated with adiposty was 2. Th induction increased. of GGT by alcohol was decreased as total serum fluorine * 3. The total induction of AKPH serum fluorine. by smoking was increased by increasing levels of `The main cholesterol and lipoprotein results are: 1. Cholesterol fuorine. and triglyceride levels were not associated with total serum 2. LDL was not associated with total serum fluorine. 3. The was positive association between moderate alcohol reduced as total serum fluorine increased. use and HDL levels The main hematology parameter and peripheral leukocyte count results are: 1. The effect of smoking serum fluorine. on hemoglobin and MCV was enhanced by total 2. Tloetuaklocsyetreucmoufnlutosrienxecweapts PneMgNastivaenldy MasOsNocOiSa,tewdhwiicthhwaelrpeerpiopshieirvaally associated. 3. The associations between cell `modified by smoking, drinking, counts and total and adiposity. serum fluorine were 7 03247 o . JAatnoutaalryof31,,8133477iandnidviDdeuaclesmwbheorw3e1,re13e8m3plwoeyreediadtentthiefiCedhefmroomliceomplpaanntybertewcoerecns, (TThaeblceosho4r.t2.c1onasnidst4e.2d.o2)f.2T.7h8e8m(aj7o9r%i)tymoaflewoamnden74(967(.231%%))nfeevmearlweosrekmepdloinyethees cCohecmuirceadlinDitvhiosisoen.whOofwtheere18n.e2v0e8r peemrpsloonyyeedairnst(hPeYC)hoebmsiecravleDdivfiorsiwoon.maTnh,e6m8e.a8n% Cfholelmoiwc-aupl fDoirviwsoiomne(nCDw)asco2h5o.r8,yaenards2i6n.4thyeeoavresrailnltchoehonrotn,-2C4D.6coyheoarrts, inThtehe clstibutonof cohorts. follow-up periods was simiiar in the women's CD and non-CD wTehreewloemssent'hsanm3e0anyeaargse oaltdfartsteemmpplolyomyemnetn;t9w.a7s%2w7.e6ryeoalrdse.r tShiaxny-4s0igahttfipresrcent ceomhporlto.ymTehnet CatDCahnedmanlotne-.CTDhdeisCtOrDibcuothioonrst owfalsatselingchytlfyimoeldserwtehraenntohtsetantoinst-iCcaDlly ainfdleraanntg(e9d-f6r8o)m. sTihxemomnetahnsd1u0r4a1ti.o4nyoefaresm.plTohyemdeinsttrifbourtiwoonmoef nyeawrasso8f.7 years enmopnl-oCyOmweonmtewna,s1s1i.gh8i%fiwcearnteyedmipfelroeynetdfofrorCmDoraendthnaonnt-wCeDntwyoymeaarns.(O5f<.0204051). Of women in the CD cohort. 1(21.1%) were employed for moro than twenty years. #eA5qsuamslohlnoytwdhnisviiandteTdCahbbalemetow4i.ei2et2ne,tcthohenetr2i.b7u8t8edmaantotwalhoofw7a1r,e11e7v.a7rPeYmpwlhoiycehdwfaosr mabroeutthan igsvatriablultmioanloofcoyheoarrtowfafrsst25e.m5pClyDeoayramsne.dntTnhowena-sdCisDtrciobhuotritosn.ofTfhoellomwe-aunp pfeorliloodws-uapnfdor the Jcoo4hrosr,tsc.omTphaeraevde!roagteheaCgeD agtrdouepa,th54w.a2syheairgsshi.emriTlihnarethidneutrmhaaetlimeoanloenC-DCDagnrgnouopn, -5C8.D1 i{spetnib(imieoanno1f3y.e6aryesarofs,emmpelcoiaynme9n.t8 wyeaasrss)igwniafsiclaontnlgyercitfhfearnafnnotorffwoerommCpaDlnoa,ynmgnTehnoetn-fcoro men (p<0001). Of non-CD man, 25.5% wera amploya for longer thantwerty _ : 03248  years. Of men in the CD cohort, 38.0% were employed for longer than twenty years. - Vital status was obtained for 100% of the women's cohort (Table 4.2.3). Among the 749 `cohort. women there were 50 deaths; 11 in Vital status was obtained for 100% the CD cohort and of the men's cohort. 39 in the Among non-CD the 2788 men there were 348 deaths; 148 deaths in the CD group and 200 in the non-CD group. Six individuals who had employment records that were missing information were excluded from the cohort and thirvital status was not aosccceunraeidneodu.tsiDdeeatthhecUer.tSi.fiacnatdescawuersaesoobftadienaetdhfworer9e9.a5sc%eroftadienaetdhsb.y tThweordmeeaatnhss, S21tandiMaortarlitsy Raitiozs (eSMdS) 42SM1 R Fo. rWo1 men The numbers of deaths, the SMRs and 95% confidence intervals (CI) among `women in the 1947-198 follow-up period are shown in Table 4.2.5. The SMRs for all causes of death (SMR=.75, 95% C1 .56-.99), and cancer (SMRw.71, 95% C1.42-1.14) ware significantly lower than expected in comparison to national rates. No association was found with duration of employment orlatencyfor deaths 42.7). from al SMRs l causes, cancer, and cardiovascula for CD women and non-CD woman r diseases (Tabl are displayed in es 4.2.6 and Table 4.2.8. wTohmeeens,titmhaotealdl cSaMuRsfeosrStMheRCwDasco.h4o6rt(9of5%woCmIa.n23,w.e8r6)aalnedsstthheancaenxcpeerctSeMd.R wInasC.D 31 (85% C1.07,1.05). The SMR for the non-CD women were closetro unity. 42.1.2SMBsForMen nTahteionnaulmwbheirteofmmaalleerdateeast,hsa,ndthaegeexapencdtceadlneundmabrepreorfiomdaaldejudsetaetdhsSbMaRssedwiotnh U.S. 9as5s%ocCiIat6e6d,.8851)%. Cflorscaarrediporveassecnutleadr diinsTeaabslees4(.2S.M9R.=.T7h1e,S9M5R% fCo1r6a0ll..c4a8u),sefsor(a.l7l3, dgiassteraosienste(st5i0na.l8(5G%i)CIdi.s2e7a..s8e6s) (w.e5r0e,9s5ig%niCf1ic.a2n6t.l.y87l)esasntdhafonroanlle.resNpoirnaetoofrythe --5 03249  - o cause-specific SMRs were large nor were the `estimates significantly ditferent from one. As shown in Table 4.2.10, the results were similar `when the expected numbers of male deaths was based on Minnesota white male rates. 4216). Table 4.2.11, Table 4.2.12, and Table 4.2.13 present adjusted SMRs and 95% C| for males based on Minnesota mortality rates 2nd 20 years respeciively. The three latency for three intervals latency intervals 10, the all causes SMA 15, ranged from .75 10.7 were nonsignificant. 7. For Among a ll cancers, men there SMRs was no ranged associa from tion 1.06 betw 10 1 een .12 any and cause of death and duration of employment (Table 4.2.14, Table 4.2.15, and Table w(To2ar.bkl1ee.r0s41..)2f.To1hr7etahanleldcC4a.Du2s.g1er8soudSpi.MspRlTsahyewtehSreeMSR.M6R9fso(r.a5p9nr,do.s79t9a)5tf%eorcCatlnhcfeoernr,oCnDbaCasDneddgrnooonunpa-CanDdm.a8l6e . `comparison with Minnesota population rates, were 2.03 (95% CI .55,4.59) in the CD group and .58 (95% CI 07.2.0) in the non-CD cohort. There were 4 observed deaths from prostate cancer `compared to 2 expected in the CD group. 4`2Th.e20l.ateTnhceyraenawlayssinsofoarssnoocni-aCtiDonasndbeCtDwemeennanayrecparuesseenofteddeaitnhTaabnldesla4t.e2n.c1y9inand either group. As shown in Table 4.2.21 and. 4.2.22, male CD cohon members with more than 10or more than 20 years of employment had SMRs that were less than one for all causes of death, all malignancy, cardiovascular diseases and all respiratory diseases. Among male non-CD cohort members with more than ten years of employment or more 20 years of employment, the SMR for allcauses, cardiovascular disease and all respiratory diseases were significantly less than expected (Table 4.2.23 and 4.2.24). There was no association of any cause of death with duration of employment at Chemolite in either CDornon-CD groups. 4S 22tandaRartedRatiioz s(SeARd S) -- 6 cAagneceard,jausntdedcasrtdainodvaarsdciuzleadr draitseearasteisosmo(rStAaRlist)y wceormepacrailncgulmateend f`oermpalllocyaeudsaets,thaell 1 03250  plan for ten years or more to men employed for less than ten years. The SARs are presented in Table 4.2.25. The 95% CIs for all causes, all cancer, and ail cardiovascular diseases were wide and include one. Confounding variables such as year of first employment and length of follow-up were not controlled in this analysis due to small numbers and unstable rates within the large number of strata. Table 4.2.26 presents the age adjusted SRR for all causes, all cancers, lung cancer, GI cancer, and all cardiovascular diseases mortality comparing men ever employed in the CD with men never employed in the CD. All SRRs were slightly greater than one, however, none was statistically significant. 42.3Mantel: RelativeRisks (RRMH) Age stratified RRMH, contrasting the rates in men evar employed in the CD compared to the rates in mennever employed in the CD, ware calculated for all causes, all cancer, and al cardiovascular diseases mortality and are displayed in Table 4.2.27. The estimated RR for CD employment versus non-CD employment did not follow a monotonic pattern and the 85% Cls include one for each of the thre endpoints. + Table 4.2.28 presents the RRMH for man employed for less than ten years to those employed for mora than ten years. The all causes RRMH (2.16, 95% CI 1.52, 2:70) in the 30 10 39 year age at first employmentstratawas reflected in bath the RRMH for all cancars (1.75, 85% CL.95,3.21) and cardiovascular diseases (3.53, 95% Cl 1.68,6.21). The RRMH were not adjusted for important time covariates such as the year of first employment. 2.4 Progen 8 Relative Fisk Est 241 Progerti E Table 4.2.29 to 4.2.36 show the final proportional hazard (PH) model for death from all causes, cardiovascular diseases, all cancers, lung cancer, GI cancer, prostate cancer, pancreatic cancer, and diabetes among the 2788 male workers oe 03251 | feovrevrioelmaptlioonyeofd tahte CPhHemaaslsiutmpftoirognrsaaotefrotr hsaignnisfiixcamroitntnhosn.linTehaerraeswsoacsiantoioenvsidence between the `employment independent variables and mortality. As was positively associated with all causes expected, of death. age The at first RR fora Yoenaer oyefarfirisntcermepasleoyinmeangte aantdfidrsutreatmipolnooyfmeenmtplwoaysme1n.t08w2e(re85n%egCaIti1v.e0l6y9,a1s.s0o8c4i)a.ted with all causes mortality. The risk of death associated with months in the Chemical Division was small and nonsignificant. For first cardiovascular diseases mortality, the RR for employment was 1.126 (95% CI 1.069,1.084). one year increas in age at Year of first employment was negatively associated with cardiovascular diseases mortality. was not associated with death from cardiovascular diseases. Time in the CD Age for at frst employment was positively associated one year increase in age of employment was with 1.08 cancer mortality. The (85% CI 1.06,1.10). RR 8Du7r2at(io8n5o%f Ce1m.p9l6,o.y9m9e)nftorwaaosnneeygeaatrivienlcyreaasssoeciinateemdpwliotyhmecanntc.erT.heTrheewRaRs wnaos association of cancer mortality with employment time in the CD. TmheembfeinralspirsossthaotwencainncTearblmeor4t.a2l.i3t4y.prToipmoretiionntahlehCahzeamridcmaoldDeilvifsoiromnawlaescpoohsoiritvely "oanned syieganriifinccarnetlaysaasisnoCciDateemdpwliotyhmpernostttaitmeecwanacser1.m1o3rt(a9l5tt%y:C--1T1h.e01r,e1l.at4i3v)e.riAsgkefoarta fiornset eyemaprloinycmreenatsewiansapgoesiattivfeirlsyt aesmspolcoiaytmeedntwiwthaspraossstaotceiactaendcweirthmoanaRlRtyofri1s.k0.8A f(o8r5a%oCn1e.8y5e,a1r.1i9n)c.reaTsheeiRn Ragfeoroufnegmpclaonycmeerntm.onaMionttyhwsaisn 1t.h0e7ch(e8m5i%caCl1d.i0v3i,s1i.o1n2) twhaesfinnoatlspirgonpiofritciaonntaylahsaszoacridat(ePdH)wimthodleulngfocraanlcleGrimcoarntcalelry.morTtaalbiltey.4.T2h.3e3 shows Ce1s1t.i0m9a,t1e.d19R)R. fYoeraaroonfofiyrsetaermipnlcoryemaesneti,n adugreataitofnirsotfeemmppllooyymmeennttwaansd t1i.m1e4 (85% eemmppllooyymaednitn twhaesCpDosiwteirveelynoatssaoscsioactieadtewditwhitphaGnIcrceaantciecrcarinsck.erAmgoertaaltiftiyr.st The other covariates were weakly associated with pancreatic cancer risk and ware -- 62 03252  not significantly different from one. A one year increase in age at first employment was positively associated with diabetes morality (RR = 1.10, 95% . Ci1.01,1.19). 4.2.4.2 PropgnionalHazardModelsForFemaleWorkers Table 4.2.37, 4.2.38 and 4.2.39 show the final PH model for death trom all causes, cardiovascular diseases and all cancers among the 749 female cohort members. Age at frst employment was positively associated with all causes monaltty. The RR for all causes of death among women employed for two to ten years (3.72) and among women employed for greater than ten years (2.33) were significantly greater than the all causes mortality in women employed for less than two years. Time in the CD was not elated to mortality. The RR for death from cardiovascular diseases associated with a oneyear increase in age at first employment was 1.13 (1.07,1.18). The year at first employment, duration of employment, and time in the CD wera not significantly associated with female cardiovascular diseases mortality. The RRfordeath from cancer was associated with age at first employment. A one year increasa in age at first employment increase the RRfor death from cancer (1.09 (1.04,1.14). Theyearat first employment, duration of employment, and tim in the chemical division were weakly and non-significantly associated with female cancer mortality. Te . * 03253 -"TA3BMLECH4.E1.M1OALGITEEDIPSLATNRTI,BUCTOITOTNAIGN EFIGVREOYVEEA,RMAIGNENEGSROOTUAPS --_ AGE TE NUMBER eer PERCENT 21.25 3 26 26-30 18 b=i =n rbeod 31.35 26 18.7 226 46-50 9 78 51-55 13 1n3 56-60 6 52 TOTAL 15 100.0 o MEAN 382 SD 891 ov e- MEDIAN RANGE _ 37 2489 - o . 03254  TABLE 4.1.2 DISTRIBUTION OF ALCOHOL AND TOBACCO USE 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA USE STATUS NUMBER PERCENT TOBACCO USE CURRENT SMOKER 28 NONSMOKER 85 MISSING VALUES 2 TOTAL 15 ALCOHOL USE <10z ETHANOL/DAY* 87 1-30z ETHANOUDAY 20 MISSING VALUES 8 TOTAL 15 "Inciudes 22 nondrinkers 243 739 18 100.0 : 756 17.4 7.0 100.0 Te C03255 o "TABLE 4.`13.M3 CTHHEEMJOOLIINTTEDPILSATNRTI,BUCTOITOTNAOGFET`OGBROAVCEC,OMAINNNDEASLOCTOAHOL USE ALCOHOL USE <loz/day 1-3c2/day missing TOTAL som cme TOBACCO 19 (67.9%) 7 (25.0%) 2 (7.1%) TTT 28 (100%) 67 (78.8%) 13 (15.3%) 5 (5.9%) Tew 85(100%) ewe USE ow 1(50.0%) 87 (75.6%) 0 (0%) 1(50.0%) 20 (17.4%) 8(7.0%) romw 2 (100%) wees 115(100%) oe C03256  TABLE 4.1.4 DISTRIBUTION OF AGE BY SMOKING AND DRINKING STATUS. 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA -- -- mE NNN MMEEAANN SSDD MEMEDDAIANN RRAANNGGEE_TeTsEStTs# pSAlrocoehol a n 7vonums sm am oFw% aF s ER Rx nNTToooebaascceo 2&: B w0d E i om xF om uOmSuRE, --To--TAL------------mz------w--w --------z--s-------- "Studentt test, Prob>T, reference groups <1. oz/day, smoker 67 03257 - TABLE 4.1.5 PEARSON CORRELATION COEFFICIENTS BETWEEN TOTAL SERUM FLUORINE, AGE. BODY MASS INDEX (BMI), DAILY ALCOHOL USE, AND DAILY TOBACCO CONSUMPTION. 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA ETITT wm [ree mem TTTTT] -- 68 C0358 8 TABLE 4.1.6 BODY MASS INDEX DISTRIBUTION 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA BMI (kg/m?) sm amas sas aa03s ass ToTaL MEAN 80 ME0DIAN Bl RAGE NUMBER 3 5 1 2 ws 2s 2334 108405 PERCENT os 2s ws no 18 1000 : "e ' | 03259  TABLE 43.M1.7CHBEOMDOYLMITAESSPLIANNDTE,XCBOYTTSAMOGKEIGNRGOAVEN,D MDIRNINNKEISNOGTSATATUS, -- _----------N--=M-- EAN_BM_ i(kSgCDim?0) AMEDNIAN__RARNG-- AE N TET-- EG SSTTE #s A<ltcoozhdol ma1s.s3i02n1g8 2&0 269 - 354 272 a0 22601 2188s1407s pup 253 3s 261 213304 sTmookbearcco nmoanssinmgoker &2 227608 23.389 226683 21184832327 psy 2 22 287 %2 201282 Total -_-- 11s 288 34s 263 188408 "Studentttest, ttest p-value, reference groups <1oz/day, smoker 70 : C02260  TABLE 4.1.8 THE DISTRIBUTION OF AGE, ALCOHOL AND TOBACCO USE BY BODY MASS INDEX 3M CHEMOLITE PLANT, COTTAGE GROVE. MINNESOTA <2 BMI25m.g3/0kg? >30 ECE -- sworeR nese) sas 208%) NONSMOKER MssiNG oo ame 156824) 1 sw Ir 0 on Toma 41 100%) 7000%) 17 00%) ALCOHOL USE <r aartay 13 aattry TMoISrSaING nose) sorasn) 41 1(0908%%)) ams (82%) 7301(0530%)) ns 307m) 171 0(05.%9%)) AGE ip 1 se) 28 401%) asa opus 060 209%) ea Tota a1 100%) 57 (100%) woo) "test p=.005 n 03261 o ' o TABLE 4.1.10 TOTAL SERUM FLUORIDE BY BODY MASS SMOKING AND DRINKING STATUS. INDEX, AGE, 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA -- FLUORINE (ppm) NC) MEAN SD MEDIAN RANGE TEST# 22B3M5I 3% swasowsnn 4220s s3asom 22i ox01na9 FRaSrLa SaAiGdEo as ma20au83yn) 333327 aiisozss 222 o0o2ui0 FFuuisoes 50 ies 30 we i oz oSAlcweohol mating mowrsoee 32a12s 25251557 22i o0oie% pg nmTeoonbsarmcocero masig 8225800250s2)) 33a%2s ao3a8 22 3 o02:60 puss os TOTAL ns 33 . 2 026 hnwanaeAnova "Student t fest, Prob>T ; C0262 o TABLE 4.1.11 AGE DISTRIBUTION BY TOTAL SERUMFLUORINE CATEGORY. 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA T EE e TOTAL SERUM FLUORINE (ppm) w2AGoxE tmnw waenn cmmn oenme eo wbs313ooo85 Jime626.1) enherns 13 (200) Ue4i2m5mR.a0) em22) wn Aciee1200) Tsweuw nemosnm wsdeueemw woviammn oesMmmm o1aSn Im twnm wte ww w o wwn mmmmes e eaomemee eseen "ne 03263  . TABLE 4.1.12 DISTRIBUTION OF TOBACCO USE BY TOTAL SERUM FLUORIDE CATEGORY. 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA == ee reve e en TOTAL SERUM FLUORINE (ppm) oa Smoker Nonsmoker Missing Total 3(13.0) 19(827) 1043) 23(100) 16(24.6) 43(75.4) 0(0) 5(100) 6Q375) 9(562) 1(63) 16(100) 2333) 4(66.7) 00) 6(100) 1(200) 4(80.0) 0(0) 5(100) 28(243) 85(73.8) 2010 115 (100) Clgarettes/day - (among smokers) MEAN 163 245 18.0 20 20 215 m-- e amoe2 e2w m2 R2 = "significantlydifferentfrom <1 ppm mean (p<.005) | or 03264  TABLE 4.1.13 DISTRIBUTION OF FLUORIDE ACALTCEOGHOORLYU.SE BY TOTAL SERUM 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA ALCOHOL USE <evdsy 1Werday MISSING TOTAL SERUM FLUORINE (ppm) <1 13 2310 21015 NUMBER (PERCENT) 17S) 51088) 9(563) s@3) 2 (87) 1300) "@s0) 1067) 4(17.4) 108) 308m 0 215-26 5100) TOTAL -_-- 230100) 65 (100) 16100) (100) 5100) | --7 03265 o. FLUORINE CATEGORY. TABLE 4.1.14 BODY MASS INDEX DISTRIBUTION BY TOTAL SERUM 3M CHEMOLITE PLANT, COTTAGE `GROVE, MINNESOTA o --<t BMIGamd) fe sas "wo Se) s2s30 2303s SEN 00 3540 ots wa Tora OW wens 27s 0 re 5 z BMRAMGE 188405 T1OT1A33L SERUM3F21L2U10O0RINE NoMGER PERCE) I m@y oe sma SEO se san spay om oo) 00 00) woo wi 2s 23 28 23 2s 2507 27 24925 (ip5p1mo0)15s 0 10s aes) o@ 108m spon 24 a7 PY 25955 isssss I) rong mon 00 om 0m som 200 14 26 arr 7 .. ; 03266 ) TABLE 41.15 COEFFICIENT OAFSSVAAYRSI,ATION FOR SEVEN HORMONE 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA ----e HORMONE ov BOUND TESTOSTERONE 108% FREE TESTOSTERONE 121% ESTRADIOL 183% TSH 100% w seu PROLACTIN 31% FFSWH sseewu n . . 03267 o TABWLIETH4.H13.OM1R6CMTHOHEENMEOOBLAISSTESERAVYPSELADONUVTT,ESRCISODUTESTTAEHGXEEPAEGSCRSTOAEVYDE,RNEUMFMIENBRNEEERNSCOOEFTAWROARNKGEERS -_-- OBSERVED EXPECTED OF" ss% cre _--_--mm E>s=tr4adpigo/lml 1" 28 60 (3658) Testboosutnedrone i) 28 4s 268.1) <=300 gic Testorsteerone 1" <=8 g/l 28 3s (207.1) . P>r=o1l5ancgt/imnl 10 28 35 (186.7) 212LmHUmi 3 28 11 3339 11F2SmHimi 1 28 "4 1.20) >4.T6SmHum 1 28 "4 0120 -_-- OIEC-1O5BS%ERCVOENDFITDOEENXCEPEICNTTEEDRVRAALTIO or . 03268 mtrE reSrTR eser om BMsiamaaems---||[||E[ T |E TE| TE T mew we ~ |IT TTT E= E .2 F5m rm HO nol SARABe Or hn 888 o 5 : : i TE STAEBRLUEM4F.1L.U1O8RPIEDEA,RSAOGEN,CBOORDRYELMAATSISONINCDOEEXFF(BIMCI)I,ENDTASILBYEATLWCEOEHN TOTAL DAILY TOBACCO CONSUMPTION, AND SERUM OLUSE, HORMONES. 3M CHEMOLITE PLANT, COTTAGE `GROVE, MINNESOTA emo | a[a = |z =]] oes mou.eme | | a| | on| | [g | =o |=|n| our [T= a ] [a] [= [ez33 =[224 [| ow [me[ww]=] BA Grpgmu/mimmeeT mseion-E oeummS oe C03270  TABLE 4.1.19 BOUND TESTOSTERONE (TE) BY BODY MASS INDEX, AGE, SMOKING, DRINKING STATUS AND TOTAL SERUM FLUORIDE 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA. NOW MEAN SBDl"og/d) MEDIAN RANGE TEsTs 2=2BsM2I0(gm) SoWUssHeo 4esn%s admeee7ss 4ss8ze Zndoueeems bFaesss SiAadgeo as eZZ@on0n ssezee mzdewsrs eae8mn zpieeennse Fpaosee sis Wes a0 zer w8 Hos ppAirlcro)hol mweeesn) issm mesg sw so m2nee2rhS sasa7w dzeoeanemm FoaFx sTomoonbkoaercacro sing 2wW@OemAZY) a$228 2mT3e70 2e6r wdeeaaknosm Feaae o Total saFlep3uhomrine BsTeHosng ssD0mm 21w:8e43s aSsrns zinEoionsne Feoms SSiiosnz SSa6n3) seem mwiess Sdme - sGereeds Total 113(100) 572 2207 561 141-1182 Vov Anoa s ras _ 82 03271 ~ . o | TAPBRLEED4I.C1T.I20NGLITNHEEARBMOUULNTDTIVEASRTIOAVTEIERREGORNEESS(InOgN)MAOMDOENLGO1F12FAMCATLOERS 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA Intercept 1027 190.7 0001 Total Fluorine (ppm)* 148 672 05 Age (years) 9 33 008 `Age X Total Fluoride" 3 16 04 BMI (kgim2) "16 54 003 `Smoker** 7 45.0 28 cohol (<1 oz/day)e 89 415 a Estradiol (pgm) 2 10 02 LH (mum) 116 61 004 Prolactin (ng/m 8 41 04 R"Seqaua3r9e root transfomationoftotal serum fluoride measured in ppm. Treen Hey & moanerswho cons1u:mexetanclay. | 83 . , C0372  ~ TABLE 4.1.21 FREE TESTOSTERONE (TF) BY BODY MASS INDEX. AGE, SMOK3IMNGCHAENMDODLRIITNEKIPNLGANSTT,ACTOUTSTAANGDE TGORTOAVLE,SEMRIUNNMEFSLOUTOARIDE. N(%) MEAN Find) SD MEDIAN RANGE TEST# b=ZyBMoI kg/m? CWsuOsCe IEwvyeA oenz aAgeoe years a3 GmBeaOnnN wwWwye 3iTnme E+ wes Ws am iear riemsps pas 1W16i37 eessanusgss epeane ns sans EScAlEeceoRwhol ssAtmees lSesz E isma E1m5s IsEeEw3s pFes mnmToeobnaawgcrco ms2am0s8a) 1J15e65d8 fdamn w5my3a BMsaeHaS3s fFeassss o Total 2aF1lim0uFmoroine aW2gae0ys 2s8s Stats 653' 8s 3aead5 52 3w15sa Sciaeanss:s Foapm 13 fees ga sa wa 3 ub am Total 113(100) 157 54 1% 32453 Vora Anos _ 84 : C0373  TABLE 4 122 LINEAR PREDICTING MULTIVARIATE REGRESSION MODEL OF FACTORS THE FREE AMONG 111 TESTOSTERONE VALUE MALE WORKERS, (ng/al) -- r EEE e-- 3M CHEMOLITE PLANT, COTTAGE GROVE,MINNESOTA a Intercept 28.72 4.57 0001 Total Fluorine (ppm)* -3.56 1.62 03 Age (years) -34 08 0001 Age X Total Fluoride* 07 04 05 `ABSemMooIhko(elkrg(/<mt2o)ziday)t 11-.426815 11110433 a1Bis6l R Estradiol (pgm) 10 0 003 LH (mU/mi) 18 15 20 #""RRSeeqfufeaerrreeennrccoeoetccatarttaeenggsoofrroyyrimisansmtoionodnsemrofoa: kttoeetradlsr.sinekreurms fluoride measured who consume 1-3 in ppm. ozethanolday. | _es | O3274  TAB`LSEM3OM.K1I:C2NH3GEPMDAORRLITINIKTCIEINPPGALSNANTTTAE,TSUCTSORATADTNIADOGLTEOBGTYRABOLOVSEDE,YRMMUIAMSNFSELSUIGoNHDrEIXR,E.AGE, wNOe Y MEAN e SD MEDIAN _--R--AN--GE----T--ES--TE-- 2BMs5I oom) 5 sCu6s5Ee0 CTmur2 S npem S8a ssss a Fun AcE 4 Sa01540 53 wZf@ImsDo wsMesas Wes xs naesss yes 8o3u% 5eryEs [paass Alconol we mdSaeseisnklg wwsmeio)esn namao wdnammn 8Bx00 2sse%os 7 frTeoeabwran,cccro T43E) sing a9 w28s3 na mae 83om osee apsg o Total 5% i SFlpuomrine mage0n 3saz zw Wea m3 g1reag 3%Hus sa ROuFz SJiaslztes Fge6r3 wRtz is2 ays 2xn%sm "FToamas Arnseed sme nz = on 86 (a 03275 o PTRAEBDLIECT4I.3N1MG24CTHLHEIEMNOEEALSRITRTMAEUDLPITLOIALVNATVR,AILCAUOTETET(RpAEoG/GcElR)EGASRMSOOVINEO,GN M11O3DMELALO%WFOFRAKCETRORSS, pL --E-- T MINNESTGA -- ae intercept 12.89 1213 29 Total Fluorine (ppm)* 03 0 03 Age (years) BMI (kim?) -22 as ae 5 3 14 Cigarettesicay a6 a as AHeohol (<tcziday)w 08 Free Testosterone (ng/ct) 85 a 08 2 .0007 #sRRepeeafer2rs4entcraancsattoegmoartyioins mofodteotraaltseercuimnkfelrusorwidheomceoanssuurreedg i5n poarnr.ethanolcay. "7 | . 03276  TSMEOK2I2MN8GCHLAEUNMTOOENLDIIRZITINENKGPILNHAGONTSR,TMACOTONUTSE,T(AALGiN)EDBGTYROOBTVOAEDL.YSMMEIARNSUNSMESIPONLDTUEAGXG,IANGGE. T NCO MEAN Te SD"m mMEDIA--N --RA--NG-- E --Tes--Ts 3aBM3I mong? sQuEs5e9 Ki ns) 3ssmae 3a%0 $850 276m2107 panog Age yur 1% ECT Vr Ea3E1)040 sie ss2a0@w70s0 ssaxem wie 5:0 2w323o8 o5"s5s a155a05y10 0 rug Alcohol 4% "0 2670 micMstsaoinkg sooer6)nH oasees. 1a5wmm0 a"4250 a1S3e7is8e:0n Fara . mToobaarcco reno 8m474e3) missing wd T5603e08 3a7g1 4$220 2r6a2m1p7 pFuosse Total 5G 4s 570% a=Flpiuomrine musaeas 3 way sgsreo 321s 24 a25m8e3 Fuea s1150125 s6e3q 5534 120337 5$ &5 2330 7777s2 "TotFal onAneomer) sa 30 7 rz -88 | C03277  FATCASTLOERS.P1.R2E6DLIICNTEAIAMNRGOMNTUHGLET1IL1V3UATMREAINLAZTEIEWNROGERHGKORERERMSSSO,INOEN.MVOaDcuEEL a#1cOuFm -- I 3M CHEMOLITE PLANT, C-- OTTAGE GROV-- E, MINNESOTA Intercept Total Fivoine (pom)* 126 001 "0 08 02 FY Age (years) o1 005 0 BMI (md) SmokersTM 02 ot as 2 2 2 Alcohol (ctaa/daye (Sonugn)d Testosterone 0 a0 001 0002 0 008 o #=lR"RgteRaelelfet2eie8rhnemcnieccecvcaianetsegigororyrmysaitsimnooondneosrfmanotekeneidrzrsik,negrhsowrhmoanceon(Lstu),me 1-3 oz atanolcay. a) | : CO3R78 o TAIBNLDEEX4,.1A.G2E7,FSOLMLOIKCILNEGSATINMDUDLRAITNIKNIGNHGOSRTMATOUNSE, (AFNSDH)TBOYTABLODSEYRMUAATSS 3M CHEMOLITE PLANT,FLCUOOTRTIANGEE GROVE, MINNESOTA Tom ---- 22BM%imgag? = Aage urs a31s4o0 sis <Alicaothol miisesisng Twoobarcco marotnisnmgoker FNCT wsesy) wise s20z77 sWaeos ssoeenn a) Z(0@483e)) MEAN s5z3 aan iasses seezs a5n3e7 438 6s418m08 SDeumWEEDDIIAANN 2273 17s 344985 21286 255 4388 6 ar so 21882 143 3498 48 2a04428 44129 RARNANGE_TEES5T7H7 1l8u10s3 kas Fmuag 1e8s10s3 2a pRoanm 27s a20u9s5 Zee pFoosos 2Slehuemess Fpaosm C5pFl8umorine 2e0s0 4544 21878 310 WI) 48 22 4484 43 1eZ8iwe0sr3 Fmuseg feSrisz] ssses) 4s3e 2233 744 32568737 T TE otr al -- no--sa--24-- 0 -- 45 t-- ens -- %0 03279 o EPREiDICsTINGNTEHAERFAOMLMULLOITNCILGVEA1SR1TI3IAMMTAUELLRAEETWGIONRRGEKSFESORIRSOM.NOMNOEDEvLaOlF F(AUGmTiO)RS 12M RR. CHEMOLITE PLANT, COTTAGE S---- GROVE, -- MINNESOTA Intercept 120 Total Fiuorine(ppm)* 004 1.62 4 46 Age (years) El 08 2 0008 BMI (kg/m2) 04 05 a Cigarenesicay 02 Alcohol(<1cz/day)w as TSH (mUm 43 3 20 "8 4 2 05 LH (mumps " 06 0001 o @EJRMnSehegatyarderirosteihndmciSectictmarutalenasgtfoiornrygmiaHstomiroomndoeonfreaf,toelidrcinstkiemruslwathiongchoonrsmuomnee1(3F0SH)e.thanolcay, ##Lutenizing Homans " | 03280  TAIBNDLEEX,1A2GE9,TSHMYORKOIIDNGSTAINMDULDAITUIKNGINHGOSRTMAOTUNSE,(ATNSHD)TBOYTABODY MASS 3M CHEMOLITE PLANT,FLCUOOTRTIAGE GROVE,MINNESOTLASERUM eNOYn -- MEAw N mS0TMw-- MEDI-- AN --mance TESTS 2BMI mong 2fe%y sousae)seesd wise) o1s0s1 172 11008 o0u3sgam pia Age yun on 1S okaz 3S 3<a104s0 si 28202270s0 wes iv1esa 170 ojrss ors 41236 ooorwmeeasms 3p7, Alcohol 074 18 oats <mtimsosainndg OBsrWyePy iO aas ERoorwm 1I48R01 momamss goles rmTooenbeenarccieaor 8m 4743)gsles 081 037222 137 osam o missing Total 08 2 004522 142 oowslss 5p2g R fluorinE e E@4 1s os 0 33 18 5Boa03s83 pBEoy 11502185 s6a3)) 2224 1o0.86m75 Total ney ge oas a 22415 oo1m7e3ss5os 4 oses | _2 03281 o TABLE 4.1.30 LINEAR MULTIVARIATE REGRESSION PREDICTING THETHYROID STIMULATING HORM MODEL oF FACTORS AMONG 113 MALE ONE"VALUE WORKERS. (mUsmi) 3M CHEMOLITE PLANT, COTTAGE GROVE,MINNESOTA Intercept -190 465 68 `Total Fluorine (ppm)* "027 009 .004 Age (years) 006 .005 29 BMI (kg/m?) Cigareties/day -.002 013 89 -.001 004 74 Zm r ee ws Alcohol (<3oz/day)# ~140 194 26 : Free Testosterone** .020 .009 04 FSH 080 019 003 R2e 30 #lRoegfareirtehnmciec ctartaengsofrorymiastmioondeorfatthyerodirdinskteirmsulwahtiongcohnorsmuomnee(3ToSzHe)th.anol/day. - stimulating hormone mU/mi | = . CO3282 o EE TABL3EM4D.CR1HI.-- 3EN1MKIPONRLGOILTSAETCAPTTLIUANSN,TB,AYCNBODOTTDTOYATGMAEALSGSSREOIRVNUDEME,XF,MLIAUNGOENR,EISSNOMETOAKING, NO) MEAN SD 2 B3MI0 Ssegy) aa7) 0 se) 74s 3F501H83 <A0ge a31s4o0 2w202e070s0 8oeoamr 543200 se wes 71 53:327 A"loczohol 1362s r18e06n8 a9ss missing a) =oe 728 23 Tsoobarcco roosmokar 28420493)) 8e1s3r missing 28) ries 531184 odo TFoltuaolrine iS=e)m s1me8ee)sn 4e73ss 101 3 31a3150 1528 sien 8a1 w4o6r Total nao a7 Fora Aor 40 MEDIAN RANGE Tests 3824 22m782y3 OFufge 88825 23ws5wm1ys3 orufg 6 2siss 8778 69 aQ12so2m0sy0 iFegu 18657 S21o2si1me2rs8 oFuorls 8858 2a1d2sie3er rougg 7974 assss:y7 77 12a _ sa 03283  PTRAEBDLIECT4I.31NM.G3C2THLHEIEMNPEOARLROILTMAEUCLPTTLIIANVNATVR,AILCAUOTETET(RnAgE/GGmEiR)EGASRMSOIOVOENN,GMM1IO1N3DNEMELASLOOEFTWAFOARCKTEORRSS F --_-- embe m Sem evveamme Intercept 741 a4 07 Total Fluorine (ppm) 143 36 0002 Age (years) 04 05 a1 BMI (kg/m?) -08 3 5 Cigarettes/days -08 04 08 Estradiol (pg/ml) 06 03 07 Alcohol Uses Light (<102/day) 321 1.65 05 Nonresponse (NR) 214 269 "3 LightX total fuoride 167 mn 03 NR X total fluoride "134 _-- a7 0008 #RR2e.L{tio2genh2rrteeXnscpteoatnacdlaatfrleiugosorri(ydNeiRs)maoldleerdattoecdormipnlkeetrse wthheoacloconhsoulmuese1-q3ueosztieotnhnaaniorle.idamyo.ms. categories and total saenrduNmRflXuotriodtea. fluoride are interaction forms for aiceruny oo" : 03284 HTOARBMLO3ENM4E.C1HR.3EA3AMTLPIOCOELOSIAHTRAEOSNLODPNALTANOCNDTOTAR,TLROCEBOFLLATAUTCTOACIRGOOIEDNCEGOC,RONAOESGVFUEFEM,I,PCBTIOIEDONYNTSMABSESTWNEoEtN, T FLteUamOAE O RGEGmm SwOhh el E RAIMEmIONyRNEOSrOoTToAvRaRSS-- me [eT i ER=Tmw oun EPS [TFeOToEaS I= |a = pwe |T=G mm [) 4$E(E2BS@SF0ETTRUSRRETNAAERDDDATIITDEOOEISLLSOTLTTOT0OTSOSOTPLTERBUEEROTREOUEONTNNNEEZDEIS1TTNT0GEGOLSSLHUTTUOTOETERSRENMTONIEONZZRNIENOENGNGREHHAORTOARIRTOMMIOOONNEEHRAATSIO "BOUND TESTOSTERONE TO FREE TESTOSTERONE RATIO. 9% C3285 o ASHE PR 34 PEARSON CORRELATION COEFFICIENTS BeTween OLACTIN HORMONE RATIOS AND TOTAL FLUORIDE, AGE, BODY MASS ACCO CONSUMP 3M INDEX, ALCOHOL ANDTOB CHEMOLITE PLANT, COTTAGE TION GROVE,MINNESOTA FLiOGEAKE ROE"GoRreTBWWhaogm AALCCOoRrOT ClTguOiaRy)R EC I = a = P en |= rE II ee = I esr see |TG TT pe LI oTai [ I o WS Tay F"+@FPEoFoSrlrtoeaieldsceaicsotsioletnsstmotoiioepiastrareioonrnneognt1enhnotpournrmpleroeornlcmeaciottniorsnperrseoastlsiaoctin aio +<Prolacilo yr simaiaing romana rato | 7 03286  THYTRAOBILDES4T.I1.M3U5LPAETAINRGSOHNORCMORORNEELARATTIIOONSCAONEDFFTIOCTIAELFNLTUS BETWEEN BODY MASS INDEX, ALCOHOL AND TOBACCO ORIDE, CONSUMPTION AGE, 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA FLUORINE OST BM (pm) (ox/day) (clgweay) ne] TET Te remon: IIC I ES parneee ranse okse erin[2T&T = FOLTLAICBLLEE S4.T1I.M36ULPAETAIRNSGOHNOCROMRORNEELARTAITOINOSCOEFFICIENTS BETWEEN BOD3YM MCAHSEMSOILNIDTEEX,PALALNCTO,HCOOLTATNADGETOGBRAAONCVDECT,OMOICTNOANLNFESLUSUMOOPTRTAIIDOENAGE, or ser -- FLUORINE eTSSmreeesnow[ Er|pI Tr7>roTIceEa2eT rI T = T = a - ET 5 Cm) 43 (oxday) (cigwaay) oT . 03287 o PITTUAIBLTEAR4Y.1G.L3Y7CPOEPARROSTOINENCHORORREMLOANTEIORNATCIOOESFFAINCDIETNOTTSALBEFTLWU EEN AGE, BODY MASS INDEX, ALCOHOL AND TOBACCO ORIDE, CONSUMPTION 3M CHEMOLITE PLANT, COTTAGE `GROVE, MINNESOTA RYGHNE anid 3 (oxday) (cigacay) =i:a -- [a rP yme neE n a- we |F |P E w] .| . C0O3288 -- EF wTn Vas-- PTRAEBDLIEC4T.I1N.3G8TLHIENEBAORUMNUDL-TFIRVEAEW RIATO E RE EGRREOSSNIEORNAMTIOODAEML1OONF FACTORS 3M CHEMOLITE WC S. PLANT, COTTAGE GROVE, G 112MALE MINNESOTA Intercept 36.60 6.87 0001 Total Fluorine (ppm)* 02 .008 02 Age (years) BMI (kg/m?) 19 A101 07 -48 244 05 Lhe az 237 7 FsHo $2 440 ou R2e 21 +"lsuqtuiaerniezitnrganhsofrormmoanteiomnUo/fmt|otal serumfluoride @ follicle stimulating hormone mU/mi | 0 CO3289 o PFRAEDDIEC1TI2N9G TLHIENEBAORUMNUDL-TFIRVEAERWIOATREKERREGRETSOSNIEORNAMTOIODEALM2OONFG F1A12CTMOARLSE 3M CHEMOLITE PLANT, CORTKTERASG.E GROVE, MINNESOTA --S-- TD) -- TET Intercept a3 6.97 0001 Total Fluorine (ppm)* 02 008 03 Age (years) 25 097 008 BMI (kg/m?) we 52 250 03 55 271 05 ""Rlseuqtaueai1nri7ezitnrganhsofrormmoanteiomnUojfmtiotal serum fluoride @ follicle stimulating hormone mU/mi --01 * CO3290 PTRAEDBILCET4IS.N1.G40THLIENEESATRRMAUDLITOIMLVA.A8LR0EI0AWNTOSEREAKCEESRRTESO.SSSTIEORNONMEODREATLIOOFAFMaOcNTGoR g2 -- EM ECHEMOLITE PLANT, COTTAGE GROVE,MINNESOTA Intercopt T Evalie 05 027 Total Fluorine (ppm) Age (years) 00001 00001 05 74 BMI (kg/m?) -.0004 0004 29 "002 0007 Cigareties/day Alcohol (<toz/dayp -.00001 -00002 006 6 Free Testosterons 003 -001 007 0006 LHe FsHe 0001 -0008 008 5 TSH ~002 001 az Prolactin" ~003 003 30 0001 -0005 "#Rn2eale2r1ence category is moderate drinkers who consume 1-3 oz 78 et "@p5imozlhiyicrloneidgstsiihmmouulriamatotinnigenghmohurosmrmominaenem(ummi)m) hanolay, rolactin ng/mi 102 03291  TPRAEBDLIEC4T1I.N4G1 TLHINEEESARTRMAUDLITOIMLVAAFLRREIEAWETOERTRKEEESGRTRSOE.SSTSEIROONNMEORDAETLIOOAFMFNACATSOR1SS 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA PR -- E-- Cl -- Bvaie Intercept 131 880 as Total Fluorine (ppm) "002 001 03 Age (years) 012 on a BMI (kgm?) Cigarattes/day 08 028 07 005 008 51 Alcohol (<10z/day)# 080 730 0 Bound Testosterone* ~001 0004 ot LHe 012 03s 7 FsHO -089 046 21 o TSH -204 110 05 Prolactin 027 018 a5 #1 RRteafe2r2ence category is moderate drinkers who consume 1-3 oze.thancliday. +@<luftToihleyinrcitozeiindsgtsihtmioumrluamitoaitnniegnghmohUrommrominoenem(umimmi) * prolactin ng/mi | - 03292 o o TABLE 4.1.42 PREDICTING LINEAR MULTIVARIATE THE ESTRADIOL FI=SRESSION MODEL OF FACTORS arable 3M CHEMOLITEPLANT-,LHC+OTRATTAIGOEGARMOOVNEG,M1I12NMNAELSEOWTOARKERS, Intercept Value Total Fluorine (ppm) 3.07 3.58 39 Age (years) 02 07 80 BMI (kgim2) ~03 05 39 27 Cigarettes/day 10 008 Alcohol(<1oz/day)s 009 03 Bad Free Testosterone" 37 80 68 13 BoundTestosterone* 10 21 FSHe 001 .002 on TSH -75 15 0001 Prolactin -39 42 35 -03 07 2 R2x 34 L#eIRsetrfaedrieonltcoeuctaetnegiozriynighs omordmeorantes.(dmrUi/nmkie)rsrawthioo consume 1.3ozethanolda +@f+olTlhiycrloeids.ti`smtuilmautliantginhgohromrone mU/mi y, ** prolactinng/ml mone(mU/mi) | 104 1. . 03293 . o PPRREEDIDCTINeGSTLHIENEBAORUMNUDLTTIVOARSIATTREORNEEG-RLEHSSIROANTIMOODAEMLONOGF F11A2CTMAOLRES 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA BE . -- --Bvaie tercapt 74.48 4853 3 Total Fluorine (ppm) 27 58 7 Age (years) BMI (kg/m?) 29 2 84 43 135 7s Cigarstiesiday -15 " 78 Alcohol (<1oz/day)# 755 Free Testosterone" 536 121 54 1.01 0001 : esvaciol -28 EY as FsHo 265 203 "0001 TSHe -23 569 87 Prolactin mn 85 s0 2 Te#4hBh eortuenrde entcesetacosatteerognoerityso mIuotdeenrizaitneg dhroirnmkeornsew(hmoUcmo)nsruamtieo 1-3 ozethanolcay. ++@@plrpTooahll/yaimrcciotiiinde snsttgiimmmuuillaattiinngghhoorrmmoonnee (mmiUimmii) 10s : 03294 [J TPARBELDEIC4T1.I4N4GLTIHNEEAFRREMUELTTEISVTAORISATTEERORNEEG-RLEHS-SRIAOTNIMOOADMEOLNOGF1F12ACMTAOLRES 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA 1. E--: )S-- Intercept 300 1.38 03 Total Fluorine (ppm) 05 03 09 Age (years) 01 ot El BMI (kg/m?) 07 Ea 08 Cigarenes/day ~007 0 58 Aeohol (<Toziday 20 36 a Bound Testosterone 003 0007 0001 Estradiol 001 0 81 FsHe -33 06 0001 TSHe a8 ar 30 Prolactin -05 03 08 _-- "#fRrRgeaeele4rt5eesntcoesctaetreognoeroyilsutmeondizeirnagtheodrrmionnkeers(mwUh/omic)ornastiuome 1-3 02 ethanoliday. @7fSaTylhmyirciolied + prolactin ssttiimmuullaattiinngg ngmi hhoorrmmoonnee (mmUuimmi) * I 03295  o TE fi PREDICTIN 45 LINEAR MULTIVARIATE REGRESSION MODEL OF FACTORS G THE BOUNDTESMTAOLSETEWROORNKEER-SP.ROLACTIN RATIO AMONG 111 -- e EE e 13M CHEMOLITE PLANT, COTTAGE GROVE,MINNESOTA Intercept Total Fvorine (ppm) 60.05 68.04 15 138 38 51 Age (years) BM (im?) 84 88 34 1.54 1.82 a Cigaraesitay 1.49 2 0 Alcohol (<1oz/day)# 138 172 42 Estradiol Free Testosterone * -22 ass 53 1.45 68 08 LH" -223 263 40 FSHO 255 aso 7 TSH+ -85 80 24 +R+2peg1m7l f#Rreelterencecategoryis moderate drinkers who consume 1-3 ozethanolday. * lutenizing hormone mU/ml +@Thfoylriiocilde Ssttiimmuullaattiinngg hhoorrmmoonnee mmUU/mmii 07 } 03296 o PPRAESDICCeTINsG TLHIENEFARREMEUTLETSITVOARSITAETREORNeScPeRsOsCiAoRnI,MORDAETLIOOAFMFOANCTORS -- e 2M CHEMOLITE PLAMNATL,ECOWTOTRAKGERESG,ROVE, MINNESOTA G 171 Intercept Total Fluorine (ppm) y value 241 1.76 a7 -03 04 35 Age (years) BMI (kg/mz) Cigarettesicay ~004 02 05 -004 05 83 04 02 0 EsAtlrcoahdoilo(l<+1cz/day)s --000301 o78 E7Y o LBHound Testosterone * -00802 007001 234 FSHO Tse 12 09 21 Ree 15 -18 21 4 soepaoarielnce category is moderate drinkers who consume 1. oz ethanoliay. +@+=Tlhouyltireconliiedzissnttgiimmhuuollraamttiionnnggehhmoorrmmiaonnee mmumm | 108 03297  . o | TRE sanor ier SM CHEMOLITE PLANTCORTASE GROVE, MINNESOTA -- EE intercept 265 01 51 Total Flcrine (ppm) 005 081 85 Age (vears) 0 05 80 BMI (kg/m?) Cigareties/day or 16 53 0 038 005 Alcohol (<toziday)t 8 101 "0 Bound Testosterone" -001 003 95 Free Testosterone * 2 a2 3 Le Fue -13 as 39 22 a7 TSHe -67 47 a6 eR2rxe1n6cecategoryis moderat drinkers who consume 1-3 oz ethanaliay. Ep, + Thyraid stimuiating hormone mUmi | ES) 03298  @ i J SEeS eewort TABLE 4.1.48 LINEAR MULTIVARIATE REGRESSION MODEL OF FACTORS --_-- ry Intercept 256 152 09 ATloctsahloFll#uorine (ppm) 31 1 008 low (<tczday) 8 2 a3 nonresponse (NR) 19 85 82 low X Fluoride -31 12 01 NRX Fluoride -08 29 78 Age (years) ~05 02 01 BMI (kgim2) 01 04 86 Cigarettes/day -03 01 Estradiole+ 03 2 01 06 Bound Testosterone ~001 001 Free Testosterone * 01 04 2 . Ed] LH ~07 05 TSHe 15 TT 31 a7 07 +o ren Lanizing cog hormone mcr mum ar wr rn 1.9. emanccay, Ses imag mes mnt --10 03299  ' FAD tS LINEEArRoMUFLETIAVATRICAToErREiGRESSNIOSN MOMDAELLEOFFOARCTGORSS J-- P-value Intercept 1.07 127 38 Alcohol # Total Fluorine(ppm) 34 09 0003 low (<1,o2/day) 8 nonresponse (NR) 41 low X Fluoride ~35 NR X Fluoride -39 Age (years) 02 BMI (kg/m2) 05 Estadio Cigarettes/day -02 03 Bound Testosterone 001 Free Testosterone * -04 FSH -11 TSHe 15 E TiduE nisina g ho-- rmone ermnectror mosh tars wo corse 43 69 09 20 01 04 01 009 0008 03 05 4 1. eatin. a 55 0004 05 12 a7 708 a7 -30 03 29 "mn } . 03300  o |{[ ! | CRT SATE Aone Hh CES TABLE 4.1.50 LINEAR MULTIVARIATE REGRESSION MODEL OF FACTORS -- Intercept Total Fluorine (ppm) Alcohol # 5.06 1.61 P-value 4.83 30 37 0001 low (<102/day) nonresponse (NR) low X Fluoride NR X Fluoride Age (years) BMI (kg/m2) Cigarettes/day Estradiols+ Bound Testosterona* Free Testosterone * FSHe 4.16 38s "1.76 "2.11 ~19 a -.06 03 008 35 51 1.67 272 38 77 08 14 04 04 003 14 20 01 16 0001 008 003 43 14 45 02 01 01 Eenctr mtnwr 13 rt, H2 03301  PTRAEBDLIECT4I.1N.G51TLHIENBEAORUNMUDLTTIEVSATROISATTEERROENGERTESSHS-IORNATMIOODAEMLOONFGF1A1C2TMOARLSE 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA Intercept 5505 3607 a2 Total Florine (ppm) 377 100.8 7 Age (years) a 62 5 BMi (kg/m?) 28 8s 27 Cigarettes/day -86 29 82 Alcohol (<1eziday)e 749 783 EN Free Testosterone 125 6s 06 Estradiol 1.6 25 5 FsHo Lhe 471 159 004 57 122 4 Prolactin "1 62 5 #3RRAeeoxlse2nrd9entcesetcoastteergoonrsy tios mthoydreoridatsetmduriiantkienrgs hwohromcoonnes(ummeum)3 raetitohanoliday. Eyntae Sstiimmlulaaitinngg hhoormmeonnse (mUuii) | 173 | 03302  PRED TING TEFREETST ONETons RATS mab FATS 3M CHEMOLITEPLANT,COTTAGE GROVE, MINNESOTA Cs wm sw vw -- Intercept 15.65 634 02 Total Fluorine (ppm) -28 a3 03 Age (years) -29 08 .003 BMI (kg/m2) -01 19 84 Cigarettes/day Alcohol (<10z/day -03 06 5 1.50 1.64 36 Bound Testosterone* 01 003 006 Estradiol FH -01 05 80 8 ES 04 LHe -001 25 89 R237 - f+Hreee etesstostceartoengeortoy tishymroodidersatitmeuldartiinnkgerhsowrhmoonceo(nmsUu/mmei)1-ra3tiooz ethanoliday. S * pmroleactein sntgi/mmullating hormone mU/m-+ Thyroid `stimulating hormone (mU/mi) 1 a4 . 03303 o i PTRAEBDLIEC4T.3I1M.N5G3CTHLHEIENMEOEALSRITTMREUALDPTILIAOVNLAT-R,TICSAOHTTERTRAATEGIGEOREAGSRMSOOIVNOEGN, 1MM1OI2NDMNEAELLSEOOFTWAOFRAKCETROSR,S CC Vamble 8 SE vam -- Intercept 3080 16.10 08 Total Fluorine (ppm) -425 31 18 Age (years) -53 20 0 BMI (g/m?) a2 a5 50 Cigarettes/day 06 14 70 Aeohol (<toziday)# 236 400 55 Free Testosterone" -28 45 55 Bound Testosterone" 009 01 a2 FsHe 8 81 a LHe 20 2 75 Pa rofactin 07 EY 8 sReesatr1ad5iol to thyroid stimulating hormone (mUimi) ratio @f"nfgReleicseisttimcualtaetgiongryihosrmmoodneeramtUe/mcriinkers who consume 1-3 oz ethanoliday. *+prtohlyarcotiidnsntgim/umliating hormone (mUjm) 11s 53304 o PTRAEBDLIECT4I1N.G5TLHIENEBAORUNMUDLTTIEVSATROISATTEERRONEEG-RFESSHS*IORNATMIOODAEMLOONFGF1A1C2TMOARLSE 3M CHEMOLITE PLANT,WOCROKTETRASG.E GROVE, MINNESOTA -- Ember vale -- Intercept 101.89 125 10 Total Fluorine (ppm) 6 124 0 Age (years) 13 7s 14 BMI (kg/m?) "1.08 170 53 Cigarettes/cay -a7 55 50 Alcohol (<toz/dayp 2 15.30 98 Free Testosterone" 6.87 128 0001 Hee 761 183 0002 Estadiol@ Ed 7 Ell Tse 830 7.03 21 PE rolactin" 0 -03 11228 00 e87r ";Rebenfoaeul5rnde0ntceastcoastteergoonreytios mfooldietreastteimcuilnaktisnrgshwohromocnoens(ummuem1)-3roatzioethanolicay. @@@luetsetirnaizdiinoglhpogr/mmlone mU/mi +* prTohlyarcotiidn sntgi/mmullating hormone (mum) -- 16 03305  TPRAEBDLIEC4T.I1.N5G5 TLHINEEFARREMEULTTEISVTAORSITAETREORNEEG:RFESSHS+IROANTIMOODAEMLONOGF F11A2CMTAOLRES 3M CHEMOLITE PLANT,WOCROKTETRASG.E GROVE. MINNESOTA B --_-- Verne s SEGn ) ppaanvee -- Intercept an 201 03 Total Fluorine (ppm) -04 04 27 Age (years) -10 02 0001 BMI (kg/m?) 08 08 28 Cigarettes/day 02 02 31 Alcohol (<1oz/day)t 18 52 E2 Bound Testosterone 003 001 02 Hee -25 07 0003 Estadiol Toe 03 " 04 27 2o Pe rolactin 0 05 5 4 04 00 0 2233 00 #sRRreeeefee4rt3eesntcoestceartoengeortoy fioslmicoldeesrtaitmeuldartiinnkgehrsorwmhooneco(nmsUu/mmie)1r-a3tiooz ethanoliday. @*lgu/tdelinizing hormone mU/mi @++@eTshtyrraociidosltipmgu/lmaiting hormone (mUimi) * prolactin ng/mi Tur 03306  PTRAEBDLIEC1T3.IMN5G6CTHLHEIEMNOEEALSRITTMREUALPDTLIIAOVNLAT-R,FICSAOHTTERTRAATEGIGEOREAGSRMSOOIVNOEGN. 1MM1OI2NDMNEAELLSOEOFTWAOFRAKCETROSR.S EEEEE Emm aE -- Intercept 691 569 23 Total iuorine (ppm) 008 006 34 Age (years) -19 07 008 BMI (kgm?) 27 16 a0 Cigarettes/day 03 05 7 Alcohol (ctoziday)# 52 1.42 n . Free Testosterone" 2s 6 nn Bound Testosterone* -002 004 2 we -49 18 009 Toho Peroelacetin 08 85 50 o0e4 0ma o7n0 eRsea ettsrea2tde6inolcetocfaotlleigcalersytiismmuloadteirnagtheorimnokneers(mwUh/omic)ornastiuome 1-3 oz ethanaliday, +4@lupTrtoehliyanrciotziiidnngnstghi/ommurllmaotinneg mhourmmone (mum) Tis 03307  PTRAEBDLIEC4T.I31NM.G5C7THLHEIEMNEOBALORIUTMNEUDLPTTLIASVNHAT.R,FICSAOTHETRTRAAETGIGEOREAGSRMSOOIVNOEGN, M1M1IO2NDMNEAELLSOEOFTWAFOARCKTEORRSS, Venable 5 sem vam-- Intercept Ek] 33 03 Total Florine (ppm) on 006 a4 Age (years) 002 004 58 BMI (km) 00007 01 8 Cigarettes/day -003 003 a7 Alcohol (<1cz/day)# -16 08 05 Estradiol ~001 003 56 Bound Testosterone -0002 0002 28 Free Testosterone* -ot 009 a5 Prolactin" 002 "007 7 = He -0033 o01n 000055 sRepeo2l6 "#Rgeifdorence category is moderate crinkers who consume 1-3 oz ethanolday. @* purtoelnaictziinngnghomrimone mU/mi + (thmyUrioimdistriamtiuolating hormone (mUmi) to folicle stmulating hormone 119 . 03308  TABLPERE4D13.IM5C8CTIHLNEIGMNEOTALHRIETMTEUSLPHTL.IALVNHAT+R,RICAAOTTTIEOTRAAEGMGEOREGNSRGSO1IV1OE2N.MMMAIOLNDENEEWLSOOGRFTK.EFRASC.TORS Em vale -- Intercept a2 25 21 Total Flvorine (ppm) 008 00s 21 Age (years) 008 003 25 BMI (kg/m?) 008 007 27 Cigarettesiday -001 002 5 Alcohol (<1cz/day)e ~07 06 2 Estadiol ~008 002 07 . Bound Testosterone ~0001 001 8 Free Testostarona* "007 007 a2 Prolactin" FSHO 001 005 0 05 01 w Rex 26 T -- 0001 fEsepydaem r category is moderate arnkers who consume 1-3 oz ethanoliay, +@*Tphlroyolrlieacicltdeissnttniigmmuu/llmaaittiinngghHoormmaonnse m(muumm) to ltenizing homens (mum) rato 20 03309 o ee 5 sm paw TABLE 4.1.58 PREDICTING LINEAR MULTIVARIATE REGRESSION MODEL OF FACTORS THE BOUND LH-FSH* RATIO AMONG 112 MALE WORKERS 3M CHEMOLITE PLANT, COTTAGE GROVE,MINNESOTA --_-- SEG pale Intercept 60 43 a7 Total Fluorine (ppm) ~-.0001 008 98 Age (years) 009 005 09 BMI (kg/m2) 01 01 40 Cigareties/day 0001 004 82 Alcohol (<1caiday)t o aM " Estradiol 004 003 18 Bound Testosterone 0001 .0002 18 Free Testosterone" -.004 01 78 Prolactin* TSHHe -.005 008 s -.05 vC0e5s 57 2 29 iR212 spol ____ siete, category is moderate drinkers who consume 1-3 Lo ozethanol/day. (mum ratio * prolactin ng/ml @ thyroid stimulating hormone mU/mi + lutenizing hormone (mU/mi) to follicle stimulating hormone | "121 03310  TABLE `SE 41.60 PEARSON CORRELATION COEFFICIENTS BETWEEN TOTAL RUM FDLAUIOLRYIDTEO,BAAGCEC,OBCOODNYSMUAMSPTSIIONND,EXAN(BDMIL),IPDOAPIRLY ALCOHOL USE, 3M CHEMOLITE PLANT, COTTAGE OTEINS GROVE,MINNESOTA lOigEnbe R CEeOe S RA m AEcoeTor Covmare -- wmoee||Teee[ Te aTe aTTe a=me TTaaa]]2 Sneh eGnersrtyylooprtlocaortnan 122 03311  TOR ATEE necnessiN o wopeLT or pucrons 3M CHEMOLITE PLANT, COTTAGE `GROVE, MINNESOTA Vane Sme P-ve alue -- Intercept 107.30 33.00 .002 Total Fluoride (ppm) 52 7 44 Cigarettes/day 1.12 31 0005 BMI Age (kg/m?) (years) Kesha "1.44 81.01 16 os low (<102/day) -5.50 an 53 nonresponse (NR) -13.53 14.75 35 GGT (urd) 41 a2 001 a BE so ne8 r arin, Bound Testosterone** 03 02 07 o| Tz | ' 03312  ESR RIT peopess oom, or morons 3M CHEMOLITE PLANT, COTTAGE GROVE,MINNESOTA Wemble B-vay lue Intercept 73.83 32.00 03 Total Fluoride (ppm) 22 5 73 Cigarettes/day 8 30 02 BMI (kg/m?) 126 95 19 Age (years) 37 37 32 low(<1oz/day) -3.02 8.33 n nonresponse (NR) -10.85 i Fn cto resem rteam s n wm om BoundTestosterone(ng/d) 04 13.93 02 43 0071 ae 03313 o PRCAEI TeSse ssA ion oomor actors aM CHEMOLITE PLANT CORTAGE GROVE, MINNESOTA C--C_-- Vamabe SSEEB ravawm -- Intercept 65.00 1007 0001 Total Fluoride (ppm) 161 7 04 Alcohol # ow (<toziday) 0.92 ast 008 nonresponse (NR) 6.77 573 24 low X Fluoride 162 80 04 : NR X Fluoride "208 183 21 Age (years) ~008 a2 7 BMI (kg/m?) -31 29 28 o Cigarettes/day -12 0 - ag Bound TestosteroneTM 018 007 009 Ty Free Testosterone" "7m ---- 28 ----=0000--8 -- Be eT Footer. . --zs 02314  TABLE 4.1.6E6NPZEYMAERSS,ONSECROURMREHLOARTMIOONNECSO,EFAFNIDCLIENTS BETWEEN HEPATIC 3M CHEMOLITE PLANT, COTTAGE IPOPROTEINS (GROVE, MINNESOTA = [= T=T+=] oEmereR | T TEeNa EaN] =TTmg/ol moesn or) [ory i i | - 03315 mL TT o TABLE 4.1.67 PEARSOHNEPCAOTRIRCEPLAARTAIOMNETCEORESFFICIENTS BETWEEN 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA wor T Stor eT Sser TemSeGarT T=ARP)-- orm TTTe"e0 [ er 1 TTTE S"SGEERARUMUMAMGGGLLLUUUTTTAAAMMMIIYCCLOPTXYRARALUNOVSAIFCCEETTRRIACASENTSR1AA0MN1SNAAMSIENARSiEd 1d! SSAALINE PHOSPHATASE tad Tz : 03316  | | TTARBALSNEISF4F.AE1.MR6AI8SCSEEP(RYGURGUMT)V,GILCAUNTTDRAAMANILSCKAAOLMXIIANNELAOSPAEHCO(ESSTGPIPHCTA)TTGRAAASNMESMA(AMKIPGNHLA)USTbEAaL(TSEGSTOTL), 2M CHEMOLITE PLA`NSTE,RUCMOFTLTUAOGREINGEROVE. MINNESOTA TS o N__ e MEAN SDb MEDIAN mmai anNcGEe vetessttss F<1LUpGoAmINE 13 s2s 2340 22051 oor P"Y =2 B[CSEC Roa >1>105-.1256 TOTAL 16s n5s 22378 22 "13s 53 22s5 pgoz 2 zr 200 as =n 1077 . Sae13 a2 a saept a 513 a0 we pa 531:01-105 >1T5O.T2A6L 1 5 R0282Ho "s 8s s5s ms 2za0 ag @ 3054 1s 517 2s a an Se<1ip3pm e2s as AlkalinSe Q5Puh5aoysphatas5e as 0s Lim pag . 1203:-1105 T>O1T52A6L 16s 5 @728 m0 a2o3 an ns ssweamy oo 585 eeraass ns 3 29 asus 3<11p3pm &2 372 GuGdT 254 2 224 27 817 Fuog 5>3110105 >T1O5T2A6L 158 38534 5 22 316574 22 %5 oSu74s pg eso 1s 20 nar wa Ayns 27 228 2 S174 30 .- 03317 eee. TABLBEYB4O.31MD.6YC9 HSMEEAMROSULSMIITGNELDEUPXTL,AANAMTGI,EC,COOSXTMAOTLKAOIGANECGEGTARINOCDVTEDR,RAMINNISKNAINMNEIGSNOSATTSAAETU(SSGOT) T NCO MEANseSt Dm aMEDIA--N --R--AN--GE----T--EsT--H 2BM 5#0 swauesssme 5xa 2a24 2x1 oBeT ofds 7 $eAiycde as 2nS@0mo8y nn2 12s5i7 222 lFneA of 5% wes 7s a 7 140 GcAlaacoddhol 2e8eHn ax mating 2 aaIs 22 oBnT offg Tobacco Hi 131 o mnaSasrihanmegcker B2 80El 04 3s 2 20 2 pms a= TOTAL 1s ---------------------------- o 131 03318  TABLEB4O3.DM1Y.C7M0HAESSMESORLIUINMTDEEGXLP,ULATAGNAETM,,ISCCPMOYOTRKTIUANVGGIECAGTNRRDOAVDNERS,IANMMKIIINNNANGSESESTOA(TSTAGUPST) 8Y --nC) NO) 3 B2MsI aSuessy 30 a8 MMEEAANNwSw SDD e MEMEDDIIAANN RRAANNGGEE-- TETESST-- T 6so 6 142 2s s5s 7345a57m pFeaiyz 3A310G4E0 2s0n83 @8 3n38s a 338208 pFaes asiss oimesy a57 21802 prEys 5rsr cAlecaehol Swe 2m087m) s47 imess a a22s60 jFuas]s mesg 8 st 109 2 567 Tmoobaarcco 2828) 48 nmoansaomgoker 285752) 5]3 2215852 aa "035&2078 pFoa7l6a o TOTAL 11s Wnvarate Anoia -- 132 03319 TABLE 4.1.71INGDAEMX,MAAGEG,LUSTMAOMKYILNGTRAANNDSDFREIRNAKSIENG(GSGTTA)TBUYSBODY MASS 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA Nes) GGT (Ud MEAN SD MEDIAN RANGE _ TEST# BMI AGE Alcohol : Bo Tobacco r om oz om es missing. 2 es 02 8s 12158 ------ TOTAL 15 = 03320  i i | ! | . | I I i I | | BEBE torsos or SC FONTH COTASEAO MA MN ORKERE, Intercept Total Fluorine (ppm) BMI (kg/m?) BMIXT. Fiuorine Age (years) `Alcohol # low (<1cz/day) nonresponse (NR) Cigarettes/day Prolactin (ng/mi) 26.7 74 -323 131 ~.0004 23 a2 05 -.003 .08 70 1.85 -1.10 a10 -09 07 a7 a5 rT 0003 02 99 015 87 n 72 16 01 13s i 03321 ee |oo Bl TABLE 4.1.738 LINEAR MULTIVARIATE REGRESSION MODEL 2 OF InerceptP 7. R-- N aTmESERUM sl6u2-- t2--Soni 0001 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA Total Fluorine (ppm) -2.70 BMI (kg/m?) 00 123 02 08 RTI BMIXT. Fluorine* 10 04 02 Age (years) -02 07 74 Acohol# Cigarettes/day =11 06 a1 low (<10z/day) 1.84 161 28 Em `nonresponse (NR) Protactn (gm) zr-1.3 GGT (Iu/dnTM a3 27 64 1 04 02 0001 R aon a i oohean so pan Cor | 0 | Tas . 03322  TRArat DRAnesOoN 0EL2 0 SHCHEMOLTE FLATEOTACEChEMOIS: Yamal 8 Em P-vvaaluse -- Itarcapt 12060 40 002 Total Fivorine (ppm) 8 78 2 BMI (kgm?) -07 a3 58 BMIXT. Fvorine -03 03 En Ago (years) 06 05 2 Cigarettesiday -02 08 as Alcohol # low (<tziday) -65 1.03 5 nonresponse (NR) ~~ -1.40 172 42 Prolactin (ng/ml) -09 08 2 SGPT (Ura) 24 0 0001 = Sarum guia pynv ransamase . wr } 03323 o FACTORSPREDICTTIrNGSETATE BECAESSIoN MoSoAmASE (SGPT) AMONG 111 MALE WORKERS. -- . -- -- 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA inercept se13 2026 o Total Fluorine (ppm) BMI (kg/m?) -15.80 30 4.58 0008 82 7 BMI XT. Flucrine* Age (years) 2 -2 2 a a7 0004 Alcohol # cr low (<10z/day) 554 6.36 39 nonresponse (NR) 1.31 10.63 80 Cigarettes/day Protactin (ngim) -27 23 24 "118 5 02 Fo ET Sirtosome 13 oz manly. o 138 02324 * 3 o nA nr (SGPT) AMONG 111 MALE WORKERS. 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA CT Vermble __----B SEm vane-- Intercept Total Fluoride (ppm) BMI (kg/m?) 62.09 13.70 -70 19.63 3.64 66 002 0003 30 BMI XT. Fluorine Age (years) Cigarettes/day 54 -33 -027 14 0001 22 14 18 4 Alcohol # low (<1c2/day) nonresponse (NR) Prolactin (g/m) GGT (urn) J Ernn 10.02 48 74 56 er 5.09 05 8.44 95 41 07 07 0001 se. 139 03325  FACTTOORRSEPkRi ELD7I4C0(TSILGNIPGNTET)AHRAEMMSUOELNTRGIUV1MA11RGILMAUATTLEAERMWEIOGCRPEYSRSUIVOINCTMROADNESLAM3IONFASE IM CHEMOLITE PLANT, COTTAGE GRORVKEE,RMSI,NNESOTA TEre P-value -- Intercept "1825 14.36 21 Total Fluorine (ppm) "65 261 01 BMI (kg/m?) E 45 51 BMIXT. Fluorine Age (years) 27 10 007 -23 16 4 Cigarenies/day cohol # ~001 13 9 low (<1oz/cay) ass 253 a2 nonresponsa (NR) 430 Prolactin (ng/mi) 1 591 45 SGOT (Iu 29 72 285 19 0001 Sarum glam cxaassate "140 03326 } o FATCATBOLRES4.P1R.E7D5IACLTIINNEGATRHMEULSTaIVARIASTLEURTEAGMRYELSTSRIAONNSFMEORDAESLE1 (OGFGT) --_-- SW va 3M CHEMOLITE PLANT, COTTAGE `GROVE, MINNESOTA Vee Epa Intercept -12.59 22.62 58 Total Fluorine (ppm) -1.83 211 36 Alcohol # low (<10z/day) -12.37 9.50 20 nonresponse (NR) -28.13 15.46 7 low X Fluorine* 1.59 2.18 47 NR X Fluorine* 13.90 448 003 a Age (years) BMI (kg/m?) Cigarettes/day 29 -30 33 171 76 0a 09 24 72 PY --141 : 03327  | TABLE 4.1.758 FACTORS Le INEAs R MULTIVARaIASTLEUTRAEMGYRLESTSRIAONNSMFOEDREALSE2(OGFGT 3M CHEMOLITE PLANT, COTTAGE (GROVE, MINNESOTA EEE P-value Intercept Total Fluoride (ppm) Heahol # -58.78 "1.79 21.55 1.83 .008 233 low (<1oz/day) 9.04 82s nonresponse (NR) -20.08 13.49 low X Fluorine* 1.39 1.90 NRX Fluorine 12.18 ast Age (years) BMI (kg/m2) Cigarettes/day Cholesterol (mgt) seoT(ue) mE pot Smee 15 26 1.30 66 01 23 as 06 11s 24 hs ee1952 Fanaley. 28 14 47 002 57 05 96 02 0001 | er 03328  W suomi E ARAAE BRRssnaE erosor CC Varmble 8 SEB pvame-- Total Fluorine (ppm) Alcohol # low (<10z/day) 1.63 -13.58 1.60 31 797 08 low X Fluorine* 82 1.66 58 NRX Fluorine" 12.04 3.41 0008 Age (years) 25 23 27 BMI (kg/m?) 51 59 38 Cigarettes/day 09 20 65 Cholesterol (mg/d) 12 08 04 SGPT (Iu/d)TM mSHeEsERES 59 07 0001 eerk. o 143 03329 o TAPBRLEEDI4.C1T.7I6NGLITNHEEARALMKUALLTIINVEARPIOATREARTEGARSESES(IAOKNPHM)OADMELON1 GOF111FAMCATLOERS 3M CHEMOLITE PLANT, COTTAGE GROVE,MINNESOTA CC Vamble FF SEB P-vvaalune -- Intercept Total Fluorine (ppm) Cigareties/day Cigarettes/day X Fluorine BMI (kg/m2) Age (years) Alcohol # 24.50 -1.03 -06 2 1.10 54 15.69 43 22 05 55 22 .09 02 79 0001 05 02 low (<10z/day) 578 4.90 24 nonresponse (NR) 8.12 8.13 32 nnctreaeetr ednr wosoreene11m35c.e0aerin a 03330 TTT ---------- STAEDBRALUIELMY4F.1L.U7O7RPIEDEA.RSAOGEN.CBOORDRYELMAATSISONINCDOEEXFF(BIMC)I,ENDTASILBYEATLWCEEN TOTAL 3TMOBCAHCECMOOLCIOTNESUPLMAPNTTI,OCNO,TATNADGEHEGMRAOTVEO,LOMGIYNNPEASROATOMAHEOTLERUSSE, mam aw TrPremes [ T Te E TEe e Tee e E | c |e Tc e e =LT E era n n Tm 3 ~ ws 03331 o TABLPER4E.D1.I7C8TLIINNGEATRHEMUHLETMIAVGALROIABTIEN RAEMGORNEGSS1I11ONMAMLOEDEWLOROKFEFRASC.TORS 3M CHEMOLITE PLANT, COTTAGE GROVE. MINNESOTA CT emme BF Sem vam Imercept 14.51 7 0001 Total Flvorine (ppm)* -002 -0008 02 Neato # low (<taziday) 2 20 27 nonresponse (NR) 56 33 09 Age (years) BMI (kg/m?) 001 009 88 0 02 5 Cigarettes/cay 0 007 20 Cigs/day X Fluorine2" 0003 0001 0005 Estradiol (pgm) 0 008 07 Rceeafemrreentcreancsafoiromgaetrioinos fmotdoetarlafiusodrriid-- nekers who consume 1-3 oz ethanoliday. -- =irtaracion ermbetweenCgaretespar dayand squareSansiormasen ofitalfuoride --6 C0332 . REERREnRemEessoIuioBnsoracrone 3M CHEMOLITE MALE WORKERS, PLANT, COTTAGE GROVE, MINNESOTA --ee or = ey a ter low (<1o2/day) -29 65 5 nonresponse (NR) 03 01 02 lowX Fluorine ~16 09 08 NRX Fluorine ~04 19 80 Age (years) 03 01 02 o BMI (kgm) -07 03 01 Cigarettes/day 02 01 a3 Cigsiday X Fuorine 006 -003 03 i o BR . 03333  AHSTEMEANCORPOgiSo P28 0F FACTORS aM CHEMOLITE PLANT COTTAGE GROVE, MINNESOTA Enable P-vaalmuee-- intercept 874 250 0001 Total Fluorine (ppm) 04 07 52 Aeonol # low (<10z/day) -61 78 4 nonresponse (NR) -95 127 48 Age (years) mn 03 "002 : BMI (kg/m?) -06 08 05 Cigarettesiay 04 03 21 Cigs/day X Flucrine 02 007 004 o TSH (muri) EY 35 2 ninairancteonlcema;uC s mr odpuerse dadybyit ilhnoe scaoonrern 1:30 sparen "us | . 03334  FREEICSHMIECHHEMEOLIRTE PSLAINUT,ACTOTTrAeGcEeGsRsOiVoEn. oMpiNeNEoSOrTA LE mR Intercept 287 132 oa Total Fluorine (ppm) Alcohol # 07 10 49 lylow (<toz/day) " 4s a3 nonresponse (NR) -1.08 74 15 low X Fluorine ~04 -10 68 NR X Fluorine Age (years) 59 21 006 -007 E 84 o CigBaMrIe(tktge/sm/?d)ay 1037 0014 *.005001 we 10 FreeTestosterone(ng/dl) 04 03 13 04 02 innsceasesmocarte cinkars who conus 1:3 x shane, 149 03335  orSS ERE eS 3M CHEMOLITESLANT,COTTAGEGROVE. MINNESOTA CC Varable Intorcapt 8 Em) p p-vvaluee 368 151 5 Total Fluorine (ppm) 165 Alcohol # 88 08 low (<10z/cay) 748 399 0 nonresponse (NR) 651 54 low X Fluoring "161 0 08 NRX Fluorine 370 185 05 Age (vears) 6 1" 56 BMI (kgm?) 4 33 a7 o Cigarettes/day ES 10 0001 LH (mUrmipe+ TM E 0 Bound Testosterone" 1.62 8 04 : Free Testosterone * 8 32 o rs UTES otras dirk wh re 19.6 party, PY -- 150 03336 . TET ee ont Oren 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA ee Em vam Intercept "11.4 129.6 83 Total Fluorine (ppm) -34 32 30 Alcoho#l ow (<toziday) 72 "3 05 nonresponse (NR) 149 67.8 .83 Age (years) 1.0 18 56 BMI (kg/m?) 22 46 3 Cigarettes/day 42 15 005 I, o -151 . Bi | 02337 o aEP SM CHEMOLITE PLANT,COTTAGE GROVE, MINNESOTA CB C Vareble EM) pvawe Intercept 2205 611.1 0005 Total Fluorine (pm) 327 1253 007 Alcohol # low (<10zday) 5266 2227 02 nonresponse (NR) 877.1 385.7 "007 low X Florine 188.0 523 0005 NRX Fluorine 247.9 1039 02 Cigareies/day 40 63 0001 Cigs/day X Fluorine" 23 145 02 BMI (kg/m?) 1.58 19.6 54 BMIX Flvorine 7.15 41 8 Age (years) "16.1 [3 08 Prolactin (n/m) 5 142 008 EnSe TSH (murmiye RE 35 1704 772 03 _ 182 03338  TACiTEMONTECOURT (MONO) AMON1G11MALE aM CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA -- Venable B__SE)_____pvawe Intercept 97.4 198.9 05 Total Fiuorine (ppm) 10.4 386 005 Aeohol # low (<162/cay) 132.1 sas 02 nonresponse (NR) 40.1 89.1 56 Age (years) BMI (kgym3) -a7 24 88 . 266 70 70 ' BMIX Fluorine" "0 1.42 006 Cigarettesiday 70 19 0004 we 139 68 04 EenEcamryRemE a iar who corn 1 abla. Toss : 03339  TABLE 4.1.66 LINEARMULTIVARIATESESRESSoNHOE. OF FACTORS, SUCHEMOLITE PLANT,COTTAGEGROVE MINNESOTA J1 Intercspt 50.45 122.30 8 Total Fluorine (ppm) 731 335 03 Acohol # . low (<1oz/cay) "12.10 3791 5 nonresponse (NR) 21.78 6225 7 Age (years) 156 1.67 35 BMI (gm?) 210 413 Cigarettesicay 304 169 08 Cigs/day X Flucrine 82 35 08 TSH 304 17 08 ed mmo,sm hoconeume 19.2 amano. o Tiss : 02340  TCA S aeARG111 MACE aM CHEMOLITE PLAGONTTA,GE GROVE, MINNESOTA 5 Emme SEB paw Intercept 264.7 54.8 0001 Total Fluorine (ppm) 29.8 Aehal # 85 002 low (<102/day) 82 133 54 nonresponse (NR) 9 25 7 Age (years) "1.3 5 04 BMI (kg/m?) 1.1 1.7 53 . BMIX Fluorine 1.0 "4 004 Cigarettes/day 27 8 0001 Cigs/day X Fluorine" -3 a 04 Prolactin (ng/ml) 28 03 09 Bound Testosterane** -04 03 10 - %________________________ fe oa onespo tybyi Rr. -- 155 03341  FESS eon or iors 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA F me m vame-- Intercept "3s S419 2 Total Fluorine (pom)" -03 06 El Alcohol # low (<tozicay) "473 13.61 0 nonresponse (NR) -.56 254 5 Age (years) -07 58 2 BMI (kgm?) -81 1.58 7 Cigarettesiday -80 52 a2 Cigs/day X Fluorine?" 02 007 007 Y Bound Testostarone## -07 04 06 Free Testosterone 25 16 mn -- we ss 18 002 taeryaame,nCcouL ritsoparE dnay byT toPucre.n 13 2 ari @ anzing homane mui | Tiss 02342 4.4Mortality Tables TABLE 4.2.1 CHARACTERISTICS OF 749 FEMALE EMPLOYEES, 1947-1985. T-- T CDDriivveiissmiioeonn DNe eDinvcin swiomned Tem umber of workers 245 504 748 opbesresrovnatyieoanrs of 6029.0 13280.4 19309.4 (myeeaarns)follow-up 246 264 258 emmepalnoyamgeenatt 288 263 276 (years) emmepalnoyyemaerntof 1965.0 19628 1963.5 (years) o d`emaetahn (yyeeaarrso)f 1981.3 1979.2 1979.6 mean age at death 57 (years) 544 55.4 -_-- 5 03343 TABLE 4.2.2 CHARACTERISTICS OF 2788 MALE EMPLOYEES, 1947-1950. -- TT CDhi_ vimsion feNDiovSiwsiSmone_ a Tew number of workers 1339 1449 2788 opbesresrovnatyieoanrs of 333853 7732.4 nz tmeeaarns)follow-up 248 260 255 memepalnoyamgeenatt 256 289 273 [2 memepalnoyyemaerntof 19638 18623 1963.0 wears) dmeeaatnh y(yeeaarrso)f 19783 1578.1 15782 m(eeaarsn)ageadeah 542 581 S64 eees------------------------------ I o. I 1 158 03344 " TABLE 42.3AVMITOANLGS7T4A9TFUESMAANLDECEAMUPSLEOYOEFESD,EA1T84H7-A1S9C50E.RTAINMENT Visas CheDim visii on cNa onDil cvishioen mi Tem Ia Aive 234 853 485 916 699 gaa Dead" 1M 47 wm ea 0 67 Total 245 1000 504 1000 749 100 "7sIoWuorGceesaiohtsheorctchaunrededaGthucetrteitfhiceaUt.esS..wiltCauseofGealh BSErEnea Tom TABLE 42.4 AVIMTOALNGST2A7T8U8SMAALNED ECMAPULSOEYOEEFSD,E1A9T4H7-A13S8C9E,RTAINMENT o TTVialsas CDrievimsiioend NonDeinviesmioinal Tom We % N --e---- Aive 1191 889 1249 862 2440 g75 Dead" 148 111 200 138 as 125 Total 1339 1000 1449 1000 2788 100.0 "`TswouorcGeesalothhseorctchuarnreddeGatuhtscieretiTfhiceatUe.sS..wi CauseofGoats ESceranea Tom 159 . 03345 TABRLAET4I.O2.S5 (NSUMRMsB)ERASMOONFGDE7A49THFSEMAANLDESETMAPNLDOAYREDEISZ,ED19M47O-R1T98A9L.ITY a All causes HCancer ee BF #3 Respiratory Breast Genital 50 66.74 17 23.04 4 472 3 5.87 2 3.37 75 .56-.99 n 421.14 95 26243 51 .10-1.49 59 .07-2.14 1 BR 8 1 Hear disease 10 12.39 Cerebrovascular 3 3.51 Gastrointestinal 3 3.41 Injuries. 4 6.23 Suicide 1 1.78 81 49-129 86 014.80 88 18-257 64 17-1.64 56 01-313 | - 03346 TARBALTIEO4S.2(.6SMNRUSM)BBEYRSDUORFATDIEEOMANPTLHOOSFYAEENEMSDP,LSOTYANMDEANRTDAIMZEODNGMOFRETMAALLIETY 1847-1989. SaseoTlamebolebenm ObOsbs BoBo SVSMAR msmmC Oi Duration 10 years CaAnl cceaurses Cardiovascular 570 62637044 18 2200 Duration >10 years 775 assi.0e9 2 saz CaAnlcceaurses Cardiovascular 260 8 256.5422 1027 B7s5 2d3e1v3s9 78 aise AEbreviations Used are: OBS, G5s6rved: Exp, expecisd; CT, ConTiaanca aml. o 161 03347 S LLaotmenecyosl10Dyeehars Ob Et e ww mmo o TABLE RATIOS 4(.S2M.R7 sN)UBMYBELARTSEONFCYDEAAMTOHNSGAFNEDMSATLAENEDMAPRLDOIYZEEEDSM,O1R8T4A7-L1I9T8Y9. All causes CCaarndcoevrascuiar 3 ss 41 56.94 16 20.93 8572 76 sigs .52-.98 44-124 Latency15 years Latencys20 years All causes 37 Cancer 14 Cardiovascular 13 49.37 75 531.03 18.25 7 42-129 17.79 73 38-125 All causes Cancer 29 1 39.20 14.47 74 49-1.06 76 .38-1.36 Cardiovascular "AErevatons Used are: 10 14.67 8 Ob, GEsered Ep, swpecied CT 33-125 comioarnca Tama, | --162 | ------- . 03348  SCeE oD OOmk EBnp SWWA--wmoor-- TRAABTLIEOS4.2(.S8MNRAsU)MMOBBNEYRGASNFOYEFMEADMLEPEALETOMHYPSMLEAONNYTDEESISNT,TAHN1E9D4A7CR-H1D9EI8MZ9I.ECDALMODRITVAISLIIOTNY Not employed in co CaAnlcceaurses 1340 Cardiovascular 13 Heart disease 8 All GI 2 All respiratory 2 Injuries 3 4153.0458 s8n aes1i2m6 13.82 7.69 223 223 1.48 84 1.04 80 90 2.02 .50-1.61 45-2.05 -10-323 10-323 .41-5.90 employed in CD - All causes Cancer 13 283.6398 46 23-83 Cardiovascular 5 8.19 36 .07-1.05 81 20-143 Heart disease 2 AGI 1 Al respiratory 4.69 43 05-154 1.18 85 014.73 Injuries 11 11.3288 5718 5011-42.8811 Abbreviations CD, Chemical used are: Division. Obs, Observed; Exp, expecied; TT, confidenceinterval; 163 | 03349  TABLE 4.2.9 NUMBERS OF DEATHS RATIOS (SMRs), BASED ON AND U.S. WSHTIATNEDAMRADLIEZERDATMORTALITY AMONG 2788 MALE EMPLOYEES, 1847-1989, ES, EE CS All causes Cancer Gastrointestinal Colon Pancreas Respiratory Lung Prostate Testis Bladder Lymphopoietic Cardiovascular CHD Cerebrovascular All Gastrointestinal All respiratory IDnijaubrieetses Suicide 347 103 24 9 8 31 29 1 3 13 145 110 10 12 13 388 12 473.56 107.80 25.94 an 5.33 40.53 38.72 5.10 82 2.20 11.42 203.31 147.04 19.92 23.99 25.89 466..5563 17.10 73 95 93 99 1.50 76 75 1.18 12 1.38 1.14 n 75 50 50 50 18223 70 CHD, coronary and atherosclerotic heart disease. .66-.81 T7115 55-1.38 .45-1.88 -65-2.96 .52-1.09 501.08 43-255 026.80 27-3.98 541.84 -60-.84 61-90 24-92 26-87 27-86 5538-12..1422 "32123 ! I 84 03350 o I i c Se e RTAATBILOES4(.2S.M1R0)N.UMB2B7A8ES8REDMSAOOLNFEDMEEIMANPTNLHEOSSYOEATENASD,WSH1TI4A7TN-E1DM9A8AR9LD.EIZREADTEMSO,RATMAOLNIGT.Y a. CameoTDean Ob Ee SR ----smo-- CaAlncceaurses Gastrointestinal 1M037 2 59077.299 2678 7 =69=-86 10505 86127 CPaonlcorneas Respiratory 89 31 5s..582 3042 1946 102 4574-118313 `82283 ProLsutantge Testis 26 268.5047 100 6e7r.1e4s4 99 362.15 1 52 109 LBylmapdhdoeproietic CCarHdiDovascular 133 1221078 145 21219 110387 2o814s0o1s 5718 58 58-80 AClerGeasbtrroovinatsecsutilnaarl 1100 12 i2s498069 21.13 All respiratory. 08 3527--18032 57 25-99 DiInajbureiteses Suicide 183 8 261.7525 47.76 18203 S-322-41.206 80 561.08 2 1508 7 41-139 CHD, coronary and atherosclerotic heart disease. : 65 03351  TARBALTEIO4S2.(1SR1MARNTsEU)SM,BBYAELMRAOSTNEOGNFCYDM,EAALBTEAHESSMEAPDNLODONYSEMTEAISNN,DNAE19RS4DO7IT-1ZA9E8WD5H.MIOTRETAMLAILTEY. eeCawseolDean OeObs LATENCY 2 10 BoEw YEARS SSMWA RoemmTO-- CaAlncceaurses 20E9] Gastrointestinal 2 389887217 2478 1707 86081-8365 87 ees ResPpairnactroerays Lung 28 258.8210 110514 7661340s3 27 27.44 9% E5143 PrSoksintate Bladder 63 3 51.9543 11.0%1 3378.527230 175 172 eso CaLrydmipohvoapsociuleatric 13n0 All Gastrointestinal 8 19150.0913 1858 16160 s5i.g79e Q 19-86 DiAalbreetspeisratory. Injuries 118 250.1376 21 2751 15459 e227-9384 76 47118 Suicide kl 10.13 108 se1s3 "CHDA, cSoroBnarrUysaenedd aavrteh:eriosOdbasi,eroobutsiecrovheeadnr:tExdspis,eeasxep.ecied:Cl, comiaenca Teal: PY -166 : 0Z352  TARABTLIEO4S2.(1SR2AANTSEU)SMB,BYAELMRASOTNEONGFCDYM,EAALBTEAHESSMEAPDNLODONYSEMTEAISNN,DNAE1RS9DO4IT7ZA1E5WD86H.MIOTRETVAALLIETY LemoCElmeeeDmhn OkOh LATEB NCY>e E1e5 YEARSS WSW m--m--moo--r-- CaAnlGcacseavurosiemsesinal 268] 24 Pancreas 5 280366444 472 27 106 geises Bist ResLpiirnagtory SkPrionstate 2257 3 22657415 123 1108 38 E73aam eras 2m asm CartLBylimaopdvhdaoessreolueatric 35 ns5 Tsis7 178s2ess 1158087 lsraeasaoyr AAll rGeasspviroaitmoerysinal Diabetes | s8 7 18185107 454 Injuries 44 s2sgo 225 15 g23as Suicide 52%3 2704217 17215 5s5a2r2iss ECBHSDa,vcioaroonnasryvaensd airtehterosOcbsl.erhoetiacrheeda:rt diEsxpe. aesxep.ected: CT omiaancs Tama; | 187 03353  TRAATRIGOSA(1SR3MANTREU)SM,BBYAELMRASOTNEOGNFCYDM,EAALBTEAHESSMEAPDNLODONYSEMTEIASNNDNAERSDOITZAEWDHIMSOERTWAALLITTY , 1947-189, Seolen OR LATENCYm2e20 YEARsS m --mre-- CAlalnccaeurses `Gastrointestinal 21763 15 Pancreas 6288.6794 19.33 17056 B636t-8a5s 77 32g ResLpuirnagtory Skin 25< 234.0058 2 21.06 1$098 7270.10g% 105 easy PBrloasdtdaetre Lymphopoietic 52 3 59289 175 29052 32032723 172 34s AClarGdaisotvraosicnutelsatrinal E]7 8 Al respiratory 1571.8001 1250 19086 s39a2r0e3 2 27a : DInijaubreiteses Suicide 79 13 136635 1947 15852 T25r1a0s5 67 36114 7 501 140 3520 ECHDD, cToronearUyVSaAndRaartehI:erOobssoclerS noticSheE art5di,ss eSasRep.ec: id;ClSofnideancemint,erval; 168 | 03354 o RATTAIBOLWSEH(I4S.TM2ER.1SM4)ANBLUYEMDBRUAERTRAESTS,IOOFANMDOOEFNAGTEHMSMPALALONYEDMESEMTNPATL,NODYBAEAREDSSIE,ZDE1O9D4N7M-MO1RI08TN5AN.LEMSTOyTA e CeuseolDeah o Obs DURATIBONBpo> 5 YEARS SVswR em--smioor-- CaAnl cceaurses Gastrointestinal 2586 2 732212210 2021 180 87801-.9308 108 estes PCaanlconreas Respiratory 87 25 74.2120 272 111835 64633.2422 108 70153 ProLsutantge BBrlaaicnder 24 2 2a170 1.68 18044 2ge312l155s 119 342g CaLrydmipohvoapscouileatric 63 114 285411 158.50 CHD 1n2n0 2264115550 7 59-86 AClerGeasbtrroovinatsecsutilnaarl 06 7 12108.2404 1520 Allrespiratory a73 260--7912 a 18-95 o DInijaubreiteess' 9 28 1465330 3680 15757 s25a1d0e5 79 53114 Suicide s 8.81 102 artes ECpHmD,ercoaroonnasryuasnedd aatrh:erosOdbsi,ebroetieceheda:rtEi5s7s,aosxsp.eciad; O, confoenca ema; | 189 03355 o RATTAIBOLWSEH(I4S.TM2ER.1sM5)ANBLUYEMDBRUAERTRAESTS,IOOFANMDOOEFNATGEHMSMPALAOLNYEDMEESMNTPTAL,NODYBAERAEDSSIE,ZDE1O9D4N7M-MO19RI8TN9AN.LEISTOYTA SamCaeuseoltDeah oObesDURATIBONeE2xo 10 YEASRWSSRMAA SSRs%OOTI CAalnccaeurses Gastrointestinal 2063 2s57e30 20 675 17139 86781-.9413 119 318s CPoalnocnreas Respiratory 67 355502 2 1938 m1.n18 47323.7414 113 71172 ProLsutantge Bladder 204 184.2407 1 144 1.3058 266214647 `69 `013.85 LByrmapihnopoetic Cardiovascular 53 615889 2 1:21 1758 2202147i7 7 56-85 : CeCrHebDrovascular 75 19594785 Al Gastrointestinal 4 11.96 2n2 1507--7852 = 08-86 DiAalbreetsepisratory 87 133.4890 22591 920314.5015 o SuIinjcuiridees 189 235.8486 1.6386 5394-122628 "AbCbHrDe,vicaotrioonnasryuasnedd aarteh:eOroBsSc,leGrobtsiecvheedan:t diseExp, aesxep.ected; Cl, confidence Tmamval; | | d ro C03356  | : o RATTAIBOLWSEH(I4S2TM.EP1s6M)ANBLUYEMDBRUAERTRAESTS,IOOFANMDOOEFNAGTEHMSMPALALONEYDMEESMNTPTAL,NODYBAEAREDSSIE,ZDE1O4D7NM-M1O9RI8TN8AN,LEISTOYTA CeseolDen OOmmDURATIBONp2Bo 20 YEASRSVSwRR mseewmeor CaAnlcceaurses Gastrointestinal 31054 10 315723.316 1032 S58e 5561-.8330 85 48-175 CPaonlcorneas Respiratory 15 1 23271 1289 14353 4013-.235028 87 43155 ProLstuantge BBrlaaidnder 102 3 122810 54 871 108 0480--215552 01-591 CaLrydmipohvoapsociuleatric CHD 41 @a 318032 806 1.705 58 20816-.50420 18136 6125 AlCeGarsetbrrooivnatessctuilnaarl Al respiratory ~~ 21 5 96.8173 881 a41 0405--5817 3289 031.05 DIinajubreets.es Suicide 25 [1456 23508 1386-.1032 031.08 3 254 118 243.45 o `CHD, cm oronare Uysaand awn trhe:eroscs lOeb. rGoEtsiecrhveeadr;tExdips.eease.xpCel,cCotnTaencsd;mal; i : i | I A Eid 03357  1RT3AA3TB9ILMOEAS4L(.E2S.PE1s7M)NP.ULOMBYBAEESERESSD EOOVNFEDMREIEANMTNPHELSSOOAYTNEADDWSHITNIATTNEHDEMAACRLHDEEIMZRIEACDTAEMLSO,RDITAVAMILSOIINOTNGY, 1947.1585. S mmole OW ES w S0R memo CaAnlcceaurses Gasrointestinal 1s9 1a7g2asr6 577 Colon 4 36 180 1215 772814050 2a RePsapinrcatroeryas Ling 142 o2n0:6 J1s 5S3i8a0r1 Sie 1 W070 103 Steed TPersosttsate LyBmlpanddoeproietic Pii 51 1457 222083 4776 513 gsaassess ora CaCrHdDovasular Carebrovascuar as4i s7enes 85 17005 74 ssaagees Stoo om AAllGraessptioriatnoersyinal Diabetes ~~L7187 3 78m27 255 971 3agis 138 2434s InSjuuirciiedse 1a0 367928 1588 sBse2aess "CHED, rcoroenarvysaeindd aaarteh:etrosOibcsl,eorobosteincrvheesadr:tEdxispea,esxe:pect;GOlriGancoaval, o 72 . 033s8  14RT4AA3TBIMLOAESL4E(.2S.ME1PM8sP)NL.UOMBYBAEESERESSDNOOENFVEDMREIANETNMHEPSSLOAOTNYADEDWSHITINATTNEHDMAEARCLDHEIEZRMEAIDTCEMASOL,RDATIAMVLIOSINITOGYN, 1947-189. AmeoCavseeoiaDean OwObs BoEw SWSMRR SSeHwOeTr-- CAalnccaeurses `Gastrointestinal 26030 15 629715265 16.46 539 75291-.7199 91 51-150 CPoalnocnreas Respiratory 45 353779 1819 232832.0014 19 2558 74 45116 ProLsutantge Tests 182 0 32.44454 7548 4-0 4`0471-21069 `008.45 LBylmapdhdoeproietic Cardiovascular 82 61..8495 9 12977 11.3368 5[106-42.2999 70 56-86 . CeCrHebDrovascular &76 15239834 All Gastrointestinal 4 1456 a71 75-51-0911 27 07-70 o DiAlalbreetspeisratory Injuries 56 Ed 1460757 3828 13264 0 410123.-8788 36-98 Suicide 2 926 5 `02-78 "`CAHD,bcobrornaerUysvaenidd aaarteht:eroisOcslo.erGnobtisscehrevaretdEdx;ips,eease.xpeCl,cGonifaaancsdTa:mval; 1 73 . 03359  RATTAERSBA,TLIEAOMS2O.(N1S9MGPNsMU)AMBLBYEELREASMTPEOLNFCOYDY,EEAEBTSAHNSSEEAVDNEODNSMTIANNNDAERSDOITZAEWDHMIOTRETMAALLIET.Y DIVISION, 1947-R198E9M.PLOYED IN THE CHEMICAL C--a_s--eoDeah Obs LATENCY 2 15 Bo YEARS SWRSVRA sewowre-- CaAlnl cceaurses 161 56 `Gastrointestinal 15 216.10 50.70 1437 75 110 63-87 831.43 PCaonlcorneas Respiratory 5 4 5.13 2.99 1.05 98 581.73 31-228 1.34 -36-3.43 ProLsutantge 11%7 2 1156..9743 1.10002 557811..6637 386 52 061.87 CaLrydmipohvoapsociuelatric 5 7 All Gastrointestinal 4 1135..6400 9.80 83 66 -5320--28.316 All respiratory Diabetes Injuries. 4 5 1214 282 41 33 11-105 05-84 1.77 574.14 7 117 3 25129 "CAHbDb.recvoiraoinaornUyssaenddaarteh:erOossc,lerGoEtSiecnhveeadr;tEdxips.eaSsXep;RCcDe,diChCle,m`iCcoanliGDeinvicaeioinn.erval; 124 -_ : 03350  TABLE 4.2.21 NUMBERS OF DEATHS AND STANDARDIZED MORTALITY RATIOS (SMPs) BY DURATION OF EMPLOYMENT, WHITE MALE RATES, AMONG MALE EMPLOYEES BASED ON MINNESOTA EVER EMPLOYED IN THE CHEMICAL DIVISION, 1947-1989. TLoCsasemoeloDeesnd OOWwDURATIEBONwo2 10YEASSRSVWRAT mwemwor All causes `Gas Cancer 20 108.7 83 -67-1.02 27 244 1.08 7141.58 trCooilnotenstinal 3 26427 1827 22403ks Pancreas Respiratory 2 8 1.46 137 754.86 8.16 98 421.93 Lung 7 7.78 90 .36-1.86 LProstate 3 1.55 1.84 355.66 ymphopoietic 1 284 141 3836 Cardiovascular All respiratory 38 54.60 3 5.42 70 50-97 55 1141.62 Diabetes Injuries 3 1.51 1.99 .40-5.80 7 8.11 86 351.78 "ASbrevions Used are: Ob, OEServad: Exp. expected; CT, Contanca mamal; CHD, coronary and atherosclerotic heart disease; CD, ChemicalDivision. 78 93361  RATTAIBOLSE(4S.2i.s22)NBUYMDBUERRASTIOOFNDOEFATEHMSPLAONYDMSETNATN,DABRADSIEZDEODNMOMRITNANLEISTOYTA WHITE MALE RATES, CAHMEOMNIGCAMLADLIEVIESIMOPNL,O1Y84E7E-S15E85V.ER EMPLOYED IN THE LTaCasuesoelolDDeeaahn CAalnccaeurses GastrCooinltoenstinal RespPiarantcorreya.s ProLsutantge CaLrydmipohvoapsociuleatric DiAalbreetsepisratory Injuries DURATION 2 20YEARS OOpbss EExwo SSMMRA 1%4 16662219 88 33 416813 16864 50 55976 9200 24 153110 17852 138 341.6478 15729 22 38542 25377 2 327 81 SSR5W%COII S501-2910 3173.158348 209-238049 2200615883 33615-8234 2e724552 07-221 "ABCbHrDe,vicaolroonnasryUasnedd aarteh:erosOcbsl,erOobtsiecrhveeadr:t diEsXpe, aesxep;ecCtDe,d;CheClm, iccoanfliDgievnicseioTnm.iamal; --am 03362 TABLE 4.2.23 NUMBERS OF DEATHS AND STANDARDIZED MORTALITY RATIOS (SMRs) BY DURATION OF EMPLOYMENT, BASED ON MINNESOTA TCaEolesn THEOGkHDEUMRIACTAILOEDNIoVIS1IoOvNE,A1Rs6S4w w7-1985. o WHITE MALE RATES, AMONG MALE EMPLOYEES NEVER EMPLOYED IN Al causes 113 Cancer 40 Gastrointestinal 14 Colon 4 Pancreas 4 Respiratory 14 PCryoLmsuptnanotgepoietc 1i3i CaKridrieosvparsactuolnyar s54 Diabetes 5 Injuries. 4 148.60 34.43 9.82 3.45 2.04 11.22 10.69 02S38as8 78.31 1.88 7.96 76 1.16 1.43 1.16 1.96 125 122 237%69 8 252 50 63-91 831.58 782.39 31-297 .53-5.01 .68-2.09 .65-2.08 oGraeso 52-90 gaz .81-3.87 0.14129 "Abbreviations used are: Obs, observed; Exp, expeciad; CI, confidence imerval; `CHD, coronary and atherosclerotic heart disease; CD, Chemical Division. TM . 03363 | RWATHTAIIBTOLESEM(4AS.ML2P.E2s)RNABTUYEMSDB,UERARAMSTOIONOFGNDOEMFAATELHEMSPELAMONPYDLMOSEYTNEATEN,DSABNRAEDSVIEEZDREODENMMPMORLITNOANYLEEISDTOYITNA THE CHEMICAL DIVISION, 1947-1985. moTtaseeoiDean OoObs DURATBIOBNoo2 20YEASRSSVWRRA emoesmTr-- CaAnlccearuses 1599 Gastrointestinal 7 218.60.81 559 880 s5a2t-a88n 17 a7241 PCaonlcorneas Respiratory 21 6 211255 712 880 001343s 8 3113 PrLosutnatge Lymphopoietic 06 1 167739 215 800 3022112s 48 01358 . AClarrdeisopviarsactourlyar Diabetes 34 4651434 55 2447-923 3 110 274 5800 Injuries 0 334 0 00114 "CHAD,bcobrornaeruysvaendid aaarteh:etroisObcsl,oerOonBtiSscEheNaertdEdx:ips,eease;xCDp, CCehle,mciCocnaiTligDieevnicsedioTnr.;isrval; mn . 33364 _--ATLALBCLAEUO4S.FE2,.E2M5CPAALNGOCEEYRAM,DEJNAUTNS,DTAECMDAORSNDTGIAONVMDAAASLRCEDUIELZMAEPRDLOMRYOAERTETESAR,LAI1TT9IY4O7SB-1Y(9SD8R9UR.RsA)TFIOORN --CC auseoo fdeatu h se SsAnRc r lde eosswcs otr h al causes: & 531.03 all cancers 1.08 sen -_ al cardiovascular S213 Albebrsesvitahtainon1s0uyseeadrsaroef:eSmRpRl,oysmteanntdaarsdirzeefderreanttecraattieogo; rCyl, confidence interval, @ "iso . 93365 : TABLE 4.2.26 AGE ADJUSTED STANDARDIZED RATE RATIOS (SARs) FOR ALL CAUSE, CANCER, LUNG CANCER, GI CANCER, AND CARDIOVASCULAR MORTALITY BY EVERNEVER EMPLOYED IN THE ee CHEMIe CAL DIVISION, AMONG MALE--EeMPrLOeYEeESe, 1e84e7-1e98m8. e --C Causea of deatu h se SSRRRRo " lce es95w%a oC!l h all causes 118 (951.47) all cancers 1.10 lung cancer 109 (-74,1.65) (67231) Gl cancer 1.16 (.50,2.69) all cardiovascular = 108 0 (761.48) . Agabsbtrreoviinatetsitoinnsalu.sed are: SRR, standardized rate ratio ;Cl, confidence interval; GI, * Never employed in the Chemical Division as referent category o | "181 23366  TMAORBRALTTEAI4LO.IS2T2(Y7RABAvYyG.E)ESFVTOERRRATNAIELFLVIEECDAR,UESYEME,PALRCOSAYNOECFDERFI,ONLATLHNOEDWCC-HAUERPMDAIIDCOJAVULASSDTICEVUDILSAIRORANT,E --- AMONG MALE EMPLOYEES, 1847-1988. Ageat employment Russ" s5%CH All c1a5u-s1e9syears 20-29 years 13252 ((862.,12..3420)) 4300-4358 yyeeaarrss Al cancers 19052 ((7621-11.4540)) 2105--2199 yyeeaarrss 30-38 years 752 ((32811,3453)4 110 (62.130) Al c4ar0di5ovyaesacruslar 6 (27,1560) 2105--2199 yyeeaarrss 30-39 years 18.40 ((3454,15.6073)) 78 (44,129) 2045 years 111 (73.182) cAvobnrfeivdieantcieoinnsteursvaeld, are: RR, Mantel-Haenszel age adjusted rate ratio; CI, * ANdejuvsetreedmfpolroyyeaerdsinofthfeolClohwe-muipcaalndDistvriastiiofnieadsbryeffoeurrenatgceatceagteogroyries. 182 02367 A e AAllc7cra5ag neu1cs9eerr syso ears s-- to --mR-- 2Rp 17vrl-- oy --me(4s0-- ,e e w11e.6n i1)e -- t . less than 10 years employment as referent category o TABLE 4.2.28 AGE RATIOS (Ruy) FSOTRRAATILFLICEAD,USYEE,ACRASNOCFERF,OALNLDOWC-AURPDAIDOJVUASSTCEUDLARRATE MORTALITY BY DURATION OF EMPLOYMENT IN THE CHEMICAL AMONG MALE EMPLOYEES, 1947-1989. DIVISION, Age at employment RRM" 95%Cl 15-19 years 20-29 years 30-39 years. 40-65 years 1.30 1.16 216 1.69 (.58, 3.28) (.81, 1.65) (1.52, 2.70) (1.07, 2.60) 20-29 years 30-39 years 84 (44, 1.51) 1.75 (.95, 3.21) 40-65 years All cardiovascular 267 (.9985,7.14) 15-19 years .88 (.25,3.33) 3200--3299 yyeeaarrss i 31.5338 ((1..7638,,26..6201)) 40-65 years 1.50 .81, 2.79) Abbreviations used are: RRyw, MantehHaenszel age adjusted rate ratio ; OI, *coAndfjiudsetnecdefionrtyerevaarls. of follow-up and stratified by four age categories. o 183 03358 TABLE 4.2.29 PROPORTIONAL HAZARD REGRESSION MODEL OF FACTORS PREDICTING THE ALL CAUSE MORTALITY AMONG 2788 MALE WORKERS. -- T_ e _Vamab3 l 8e SSEEBW) p FvW alRWi ReLe Year of first employment -55 Age at first employment 079 008 0001 846 006 0001 1.082 Duration of employment" -34 001 0001 967 dMiovnitsihosn in chemical 001 001 24 1.001 "AbbUrsedearev: B,iregaresstioniparoametner;sSE(G),StanendoraoTrTied | slope parameter; RR, relative risk. #"yreealratsive risk for one unit change in independent variable l : `MALE WORKERS. TABLE 4.2.30 PROPORTIONAL HAZARD REGRESSION MODEL OF FACTORS PREDICTING THE CARDIOVASCULAR MORTALITY AMONG 2788 F Vaeriale SF i pP-vval) eue RRRR? Year of first employment -.075 016 001 528 Age at first employment 19 Duration of employment" 230 009 .0001 1.126 294 45 852 Mdoor nths in chemical .0002 001 85 1.00 ADbrevialons Used are: B, regression parameter; SE(B), Standard error oe #slroepleatpivaerarmisekteforr; oRnRe, urneiltatcihvaenrgisek.in independent variable *years " : 02369 FATCATBOLRES42P.R3E1DIPCRTOIPNOGRTTHIEONCWAAOLNRHCKAEEZRRASMR.ODRTRAELGIRTEYSASMIOONNGMO2D78E8LMOAFLE --re vee e 5 8 SWS)E epvvaawmee RRARF Year of frst employment -031 o19 a 69 Age at frst employmert 078 on 0001 1.081 Duration of employment" -.028 EY 002 S72 MGvoinstihosn in chemical 002 001 20 1.002 "obsrieovpsipaauroamnesteurs;eRdRr,er:elBa,tivleegrriseks.sion parameter; SEB), Sanda Gar oTRe #"ryeelaraste risk for one unit change in independent variable o | FATCATBOLRES.2P.R3E2DIPCRTOIPNOGRTTHIEONLAULNHGACZAANRCDERREMGORRETSASLIIOTNY AMMODOENLGO2F788 MALE WORKERS. 8 --_--Vreembel 0 SSEFO)) ppaanlee RWAeV Year of ist employment ~019 042 5 S81 Age atfirst employment" 070 2 001 1072 Duration of employment" -.062 a33 ot 840 GMvoinstihosn in chemical -026 16 mn 75 "Ab#sbrlreolepaevtiipavateriarominseksteUfrosr;eoRdnRwe,eurneia8t.icrihveaagnrrgeisesks.iinoinpndaerpaemnedteenrt;vSaErDia]b,leSandraerror oTTe-- years 185 : 3 : 03370 FACTTAOBRLSE P4.R2E.D33ICPTRIONPGOTRHTEIOGNIWACOLARHNKACEZERARSR.MDORRTEAGLRIETSYSAIOMNONMGOD2E78L8OMFALE -- EF SER()I=pT awsRmR Year of frst employment 015 38 7 1.015 Ago at first employment" 130 021 01 1 Duration of employment 005 20 Fo 1.008 dMiovnitsihosn in chemical 001 002 56 1.001 "#SreulAnatdivaSe errirbsokrUfoosrrfeotdnheeewseul:novipecGl,hpaGaaanrSgatTmeoeitmneoeirsndiAneRnp,alnrsceBel.nttrvedvgaTrneoaskss.lioenParameter,SEO, : years FACTTOARBSLEPR4E.2D3I4CTPIRNOGPTOHRETIPMORANOLASELTWHAOATRZEKACERARDNSC.REERGRMEOSRSTIAOLNITMYOADMEOLNOGF2788 --eame BF SSEGm) ppvaem Ame Year of frst employment. 010 081 0 1011 Age atfist employmert 082 45 0 1.085 Ouraton of employment" 070 052 a8 22 | dMiovnistihosn in chemical o10 008 0 1.010 !| "#$1rA0e9l8aStpiavberarmrisekteeUfrosr:veoAdniRaw,euar:nelitactB,ihovraeenniggsreks.eisnsiindopenapreanmdeatnetr;vaSrEiBab)l,e SEGorRTTE-- "years es 03371 o| ;i | FACTTAOBRLSE P4.R2E3D5ICPTRIONPGORT2TH7IE8O8PNMAAANLCLHREEAWAZOTARIRKCDECRRASEN.GCREERSSMOIROTNAMLOIDTYELAMOFONG --wmaee 55 SESDEm wvwawm ARwe Vewolfistemployment 046 085 a8 1.067 Age atfistemployment 136 034 0001 114s Duatonof employment" -012 035 7 ses dMiovnistihosn in chemical 02 00s ES) ED) TsolborpeevpiaartaomnesteUrs;eAdRa,rer:el8a.tgivreersissk.ion parameter; SEE), SaSnaraSTaE "yreelaartisve risk for one unit change in independent variable FATCATBOLRES4.P2R.E36DIPCRTOIPNOGTR2HT7IE8DO8INMAAALBLEHETAWEZOASRRMKDEELRRLSEI.GTURSESMSOIROTNALMIOTDYEALMOOFNG -- YeTrbSle Yewolfrstemployment Ago atfirst omployment Duration of employment" Mdiovirsiiosn in chemical S BF SEG) T pvawe Rw 408 221 06 567 092 ou 04 1.096 009 030 5 1.008 ~001 004 76 99 "AS#sblroerlpeaevtpiivaaertarominsekstefsorr;eodAnRew,aur:neilta8t,cihvraeengigrsseks.isnioinndpeapreanmdeetnetr;vSaEr(iBab)l,eSERGE or TH "years | 187 C0337 FACTTAOBRLSEP4R.E2.D3I7CPTRIONGPOTRHTEIAOLNLALCAHUASZEARMDORRTAELGIRTEYSSAIMOONNMGO7D4ELFOEFMALE WORKERS. -- CV C ammb 5Bb eSSEEM) PvpaaWlee RRAeF Year of first employment -.02 0 a 77 Age atfirst employmert 08 02 0001 1.08 Duration of employment* 2>1100yeyeaarrss Mdiovnitsihosn in chemical 1531 55 0a14 2a3r3n -003 004 "8 897 "slopFe pabrami eteUrse;eRdRva,rer:eilaBt,ivraeegrirsi eks.siion poaramneters; SE(G), Sanedrroar oiT Fge #"yreealartsive risk for one unit change in independent variable FACTTAOBRLSE P4.R2E.D38ICPTRIONPGOTRHTEIOCNAARLDIHOAVZAASRCDULRAERGRMEOSRSTIAOLNITMYOADMEOLNOGF749 FEMALE WORKERS. --re ate e e 0 5 i Year of first employment -.034 | Age atfirst employment 119 i Duration of employment" ~~ -.011 dMiovnistihosn in chemical -015 SSEBE) Rppvvaalee 048 48 024 0001 025 7 07 a7 RREAF 966 1126 986 85 "RSsblioepveipaatriaomnesteUrs;eRdRw,rer:elGa,tivreegrirseks.sion parameter; SED), Standard error oT He #"yreealartsive risk [or one unit change in independent variable ee 4 03373  FATCATBOLRES4P.R2E.D3IPCRTOIPNGORTTHIEONCAALNCHEARZAMRODRTRAELIGTRYESASMIOONNGM7O4D9EFLEOMFALE WORKERS. --_-- Vee 5 Year of first employment -.043 Age atfirst employment" 085 Duration of employment" -.021 Mdiovnistihosn in chemical 01 EhSEM ppvv e aRRmRAe-- 053 "2 958 025 001 1.089 025 85 80 005 87 1.001 "ASsGlorpeevipaatriaomnesteUrs;eRdRa,rer:elBa.tivreegrriseks.sion parameter; SE(G). SAGES Sor STE-- # relative isk for one unit change in independent variable . "years Treo ' 03374 FIGURE 1. Fr1e9e9t0e3stMosCtheermonleitaendsttoutdayl serum fluorine ---- = ---- u mmm gs ---- 3 g2gegg Of..E.S. iHw 5 AGt-30BMzs AGEe30BM3s AGESOBMMZS ActesOBMa3s To FE 50 TOTAL FLUORINE (ppm) | 190 --- . 03375 | ||: Figure 2 Boun1d9t0es3tMosCtheeromnoellatnedsttoutadlyserum fluorine ao. :2uH3w 00 ---- aceon > -- acess gG8&3 wo. eneSacco"omen -- agEemBas 2 ===rAGE Bus 8 0 10 2 0 TOTAL FLUORINE (ppm) | > 191 03376  | i Figure 3. RSG Estradiol Cremorie sud and total serum fluorine s w :3g2 w Eg2 JE | -- acta BntS : 3 = % TOTAL FLUORINE (ppm) 192 = : 0337?  i| | Figure 4. Lutenizi1n9g90ho3rMmoCnheemaonldltteotsatlusdeyrum fluorine 10 5 . if ' ` sz :3 1 o 0 20 30 TOTAL FLUORINE (ppm) 193 1 . 03378 Figure 5. Follicle stimulating hormone and total serum fluorine 1850 3M Chemolite study . :gE2 E, :, . TOTAL FLUORINE (ppm) | oo TL . 03379 0 1 Z 5 3 g " Figure 6. Prolactin and total serum fluorine 1990 3M Chemolite study Lammers --- Moseratsarn.kers Lo conkers === Nonrspondents 3 0 TOTAL FLUORINE (ppm) | :| 195 03380 iv | | Figure 7. Thyroid s1t9i5m0ul3aMtiCnghehmolrlmtoenestuadnyd total serum fluorine 3 g =7aEg 15 FE) 0 TOTAL FLUORINE (ppm) 198 : 03381 Figure 8. Bound to free 1t9e5s0to3stMerCohneemorlaititoeasntdudtoytal serum fluorine " " w# s 52522 wu 35 2 ow # ------ AGE=30 BMI=30 NS LD % 10 20 30 TOTAL FLUORINE (ppm) .| 187 co 03382 o ! i | I o - prototype peroxisome prolferator, may regulate steroidogenasis by binding to a membar of 2 naw family of cytosolic receptors (PPAR) belonging to the nuclear hormone receptor superfamily and transactivating the transcription of genes. involved in steroid synthesis 115-121, PFOA was positively associated with the TB/TF and E/TF ratios. PFOA binding 10 sex hormone bindint globulin (SHBG) may have produced changes in the bound to free testosterone ratio. However, this would resutt in a change in the TBITF that is in the opposite direction to the observed association between PFOA and TB/TF. The associations of PFOA with these ratios are consistent with a mechanism that involves decreased production of testosterone and increased production of estradiol. The HPG axis of older men appeared to be more susceptible to PFOA compared 10 that of younger men. No animal data hes been reported conceming age related sensitivity 1o the effects of PFOA. However, the onset of Leydig cell tumors has been reported to occurlateintwo year rat feeding studies 12, This finding may represent increased susceptibility for hormonal alterations in aged rats. Further animal research is needed to define any age related susceptibility factors. Prolactin levels were positively associated with total serum fluoride in participants who reported moderate drinking (1-3 crinks/day). Since the function of prolactin in men is uncertain, the ciinical significance of such an association is unclear. Alcohol ingestion is astimulus for prolactin secretion. The mechanismofthis effect appears to be mediated by ahterations in calcium mediated signal transduction pathways 2. This suggests that the elevation of prolactin associated with PFOA and alcohol may be mediated by alterations in calcium mediated events such as transmembrane signal transduction pathways. `Thyroid stimulating hormone was positively associated with total serum fluoride. Animal studies have shown that perfluorodecancic acid depressed peripheral thyroid hormone levels without producing a hypothyroid response 75:73. 101, Jn the present study, peripheral thyroid hormane levels were not assayed. Therefore, it is not possible to assess whether the observed association between 200 03383  | | i ! . | o ePfFfeOctA, oarnadnTeSfHfecctoumieddbioaateddibryeccthhaynpgoetshailnapmeircipohfefracatl,tahyprtouidtahroyrrmeognuelatloorvyes. In summary, this is the first report humans. The present findings in of hormonal changes associated humans are consistant with those with PFOA praviously in treesptoorstteedroinnsa,niimncarlesatsueddieesstr'5a.d.ioTl,heancdonusnisctheanntgfeidndLinHg.s iRnocdleundte laonwdfhreueman reproductive endocrine systems difer greatly, are similar. In ight of the observed similarties yet in the suggested effects effect, ft is tempting to of PFOA ssypesctuelmattehrtohuagthPtFhOeAsammaeymeeffcehcatntihsemh.umAahnyspoatnhdesriosdatnhtats PreFpOroAduacltteirvseaencdaolccriiunme tmreidpihaotsepdhacteelmuleadriastigendalsetrcaonnsddumcetsiosnenpgatehrwareys,psounsceh,amsatyhepAroMviPde oar uinniofsiiteodl . mechanism for the multiple loci of putative effects. No adverse health efects have been observed in exposed . The present study caisdsoncoitaetexdamwiitnhehaodrvmeornsaelhaelatletrhateifofnesctasr,eaplotshsoiubglhe.seTvehrealetaidovloegryseofoautncuommbeesr of cancers including adenocarcinomas of pancreas and breast, have been linked the prostate, endometrium, 10 changes in endogenous colon, rectum, hormones 124. Cancers in this etiologic category include. HPoerwfelvueorr,ooPcFtaOnAoicisaacindoinsgneontctaogxeincortoodxeinctccaarrcciinnooggeenn.in standard assays . In rats exposured to PFOA ovear two year period, there tumors 12, Leydig cell tumors have was associated been observed increase in Leycig in association `with cell other epleervoaxtiesdoLmHe pprrooldfuercaetdortsesitnicrualtasr1n2e.opItlahsamssbe*.en2h.ypHootwheesviezre,ditnhaPtFcOhArontirceaaltleyd dF2i1s5c,uLsHsedwapsrenvcitoueslleyv,atoerdd.ueThtiosimnsaufyfibceienuteextpoereismternotgaelnsinfdeuecdtbioancktiimnehib3i,tion as Atematively, another mecharism may have been operative In producingLeydig Sceeltlratduimoolrlse.veElsxoagreenaosusosceisattreaddiwoilthprLoedyudciegs.ceLleytduimgocresllitn ubmootrhsraintsmaincde 126, High humans I1n27c.r1e24a,seTdheesttriosgsueenssu1r27r.ouHnidgihngestthreadLieoyldmigaycelbleaadestniommualussaflosroLperyoddigucceesll 201 03384 o 1 I d proliferation observation and that tumor estrad ifoolrsmaitmiuolna.teTshiTsGhFy-paotsheecsriestiiosnsiunppLoeyrdtiegdbcyelltshe TGF-a pbrionldfseatotiEonG.FTrheceephtoomrmsoneaxlprcehsasnegdeosnaLsesyocciigatceedllwsi'th2PaFnOdAstmimauylabteesacell mechanism for nongenctoxic nongenotoxic carcinogenesis carcinogenesis. The needs to be clarified role of PFOA in human sApdeerqmuaattoegeannecsriosg,elnibliecvoealsndaremanleecersesparrodyufcotrimveaionrtgeannsa.nceLoowf tpeostteonsctye,rone and fhairgihlteysmtraoygebnes omnaeypdoteecnrteiaalseadlviebirdso,e aonudtcfeormtielitoyfinPFmOaAle.s toxilty of PFOA has not been extensively studiad. 130, The Decreased male reproductive conducted in humans. PFOA was not teratogenic No studies in rats 5. 131. have "32. been No adverse Soetfrufedecitenssoootfnsuhfeduritmialaditn.y wrNeeoprreootdnhuoectrteidrveefporfroudfnucectmitaoilnveearrsaettusndieineesaditneraantiomgaelnseshiasvsetbuedyen5.raMpaolrteadr,ats optrhoecreasnsiamsalarseptehcoiuegsht1%t,o be more sensitive to xeneadbisiontcceihnsuumltasncroemprpoadurcettidove 5.0.3Cholesterol, Triglycerides.and Lipoproteins. TChhoelelsatcekroolf.astsiogcyicaetriiodneso,faPnFOdALwDLiwhecrhaolneosttesriognliofirctarnitglylyacsesriodceisaftsedcownistihstPeFnOtA. ewfiehctobosnerLvDaLtiaornas aivnaeixlapbelreimoerntcaolmpaanriimsaolnm.odTehles.arNeonoansitmuadliesstuidnihesumoafnPgFOA's oncoming the relationship of PFOA with LDL. cholesterol, or tighycoridos, Inlight rinkers, PFOA ha ite increasing PFOA recuced HDL. sTfhieectpuotnatHivDeLeflfeevceltss.ofInPmFoOdAeraantdedarilnokoerfsm,ay fablreusomriiemddieitvaeatdleubdeys,bthyaenasldtmeatrlhaletinoun mobfaorcoofmemxoponsHedDLworrekgeurlsa,totrhye pirmoicteesds,raTngheefoifndtiontgs Suggested mechanism imitations of the study design. must be considered preliminary. The condenand 202 Q2385 | o ' | | i | { o| i . ' | i The mecharism by which mediated by alterations in PFOA modifies the aicohol:HDL relationship fatty acid metabolism or fatty acid binding. could be intake induces specific P4S0. metabolic enzymes including 2E1 Alcohol and afterslipid metabolism 134, PFOA induces a specific P450 At family of metabolicenzymes. and alters lipid P450 mediated metabolism in rodents. lipid metabolism could The alter joint HDL effect of alcohol dynamics. The and PFOA primary on asctirducitnurheepofatPoFcyOtAessaugngdeHstDsLSt.hatThPeFOcoAmpceotuiltdioafnfefcotr tNhEeFAli.gbainnddbiinngdisnitgesofcfoautltdy reduce the effect of alcohol on HDL levels. Studies of the joint effect of PFOA and alcohol on HDL may clarify the regulatory mechanisms for HDL. The decrease significart. In in a HDL associated meta-analysis of with increasing 12 prospective PFOA studies levels may be clinically of therelationship hbeetcwheaenngHeDiLn CleHveDlsriasnk dascsoorcoinaatreydhweiatrhtadiosneeasmeg/(dClHcD)h,anGgoerdinonHDesLtilemvaetleidsthat approximately the same as the change in risk associated with a 2-4 mg/d change in LDL level 1%, The predicted rop in HDL foar moderate drinking participant with may ahatvotealafmlueoarsiuderaobfl2e0 ppm impac is t 30 mg/dl. A chan on the occurence geofthis order ofmagnitude of cardiovascular disease, In the retrospective mortality study, there was no increase in mortality from tcoatraldisoevrauscmulflaurodriinseealseev.elsHoofwe2v0ePr,PMthoefremoarree.a limited number of workers with " cardiovascular diseases among a small group Any increase in risk for of highly `exposed workers be readily apparent in a study of all Chemolite or CD employees. Further may not research is HDL level. needed to confirm and clarify the association Future studies could test the hypothesis that between PFOA and PFOA ang alcohol jointly acallactroedhrioNol.vEaFscAulmaertamobrobliidsimtyraesnudltmionrgtianliatydericsrkesafsoer einxpHoDsLedanwdoraknerisncwrheoasderiinnk 5.1.4 HeoaticParameters Changes in SGOT (AST) and SGPT (ALT) appear to be associated with total serum SGOT falnudorSidGePtThroiungchreaanseidntweirtahctiinocnrewaistihnagdiPpFoOsiAt.y. In obese However, participants, both there tienot "203 . C03386  i 4 o X Tahpepfeinadr0ingbseaar1e ilinmdietpeednbdyenttheefsfmeacltlonfuPmFbOeAr oofneSxpGoOsTeadftweorrkaedrjsu,sttinhge lfiomritSeGdPT. range study of total design. fluoride values, The conclusion and and the previously discussed suggested mechanisms limitations of the must bs considered preliminary. Compared to disruption 12%, STGhOeT,laSckGPofTasissoaciraetliaotinveolfySsGpeOciTfiwcimtharPkFeOr Aforatheerpaatdojcuystteing for aSsGsoPcTiastuegdgecshtasngtehastitnhterlainvesramisintahseepsr.imSairnycesoSuGrPceTifosratheenszmyalmlePaFssOoAciated wih aihsesoEciRatmeedmbErRanpreo.lftehreatiionnc.retasmeaiyn SinGdiPcTatemaaydihsarvupetiboenenn tthhee rienstaugtrtoyf PofFOA ehnepzaytmoecsy.teTmheemtbirssauneesspewchiificch eaflielcotwssuigngcerseatseeddfrorelheeapsaetoofcyctyetomsoelmibc rhaenpaetsiccould be dus to a higher hepatic concentration of PFOA. eLviviedrainncjeurtyhias giannteerraacltliyoncsonbseitdwesreend teonbdeogaenmuolutsifaacntdoreiaxlopgreoncoeusss.faTchtoerrsepias y a 10 in SGPT hepatotoxicity association by observed in workers PFOA suggests that 157. the The modificationof the adipostymachanisms of transaminase terleavnastaimoinnmasaeysbaeslwianlkleda.s Oclbiensiciatlylyhiamspobreteanntashsaopcatiiattsed13w8it1h35e,leTvhateioonbsoefrvation itnhdaitvsidoumales odbeevseleoipndhievpiadtuiaclsfiebvriodsiesncheaslintloetabdaipeonsietxypleafiiencetd.whHilehaosthbeoraonbese sPhuylcpahoaytahsoelscieezrte1ad%i.nthsAaotnlimvmeeatnlatbssotalunidcdiepsolaynmdolripmhiitesdmhsuomraonthdearthaepsautgogteosxtintheaxtpxoesnuobrieomtaicys, Phoetpaanttoitaotxeitnhse1h4e1p.a1t2,otoFxoilcloewffianacgltchooihfoslo,bmeomsdiaetyly.,poPtFenOtAiatmeatyhedierfefcetlcytsoroifndoitrheecrtly qeAspsmpeientitoimacelhrortnodloerfiimanitfsaiottcemoeftaPbFolOiAsma.ctiDoinsrmupatyioonccoufrm.itTohcehomnidtroiaclhofnudnrcitaiopnlcayasnparnoduce oSuttu.diVeeslporfofiacttayciadc,idahnmoenetdiragibhatollcioaxsrimbdoainntiPonFOofAloenxgpocshaeidnhaunmdamnesdhiauvme cnhoatinbefeant.cyaarcriidesd, branched chain faty acid (2 Propy-pentancic 204 603387 | | : | i ! i | ' ; | : | o! oafci2d)hetphaattoitmopxaiicrsxemniotboicohtoincdroifaslimfiulnacrtcioanrbaonnd fatty acid metabolism, structure 10 PFOA 199, is anexample Commercial grade PFOA structure 29. comains isomers with carbon The valproate-like isomers of bPaFcOkbAocnoeusldidpenrtoidcualcetotovxailcpirtoyisciamciildars to that of valproate. The modification of the association between PFOA and the transaminases by adiposity could be mediated by disturbances of mitochondrial fatty acid metabolism in humans. GGT increased as alcohol use increased. The increase in GGT was smaller as PFOA increased. This association was independent of changes in SGOT, SGPT, alcohol. and AKPH. Perflucrooctancic acid may inhibit The GGT-alconol dose respons relationship the hepatotoxic is thought to be effects of secondary fo the induction and increased release of GGT. Increased serum GGT levels. Pin4d5i0casteysptraolmi,felreaatikoangeofftrhoemehnedpoaptloacsytmeisc,roertiicnujluruymtaonodthiendrutcitsisounesofcayrtoec,hrome Perfluorooctanoic acid may decrease permeability, by reducing the alcohol serum GGT by altering call mediated induction of GGT, membrane or by changing aleahol such as oxidation pathways acetaldehyde. and reducing the production of toxic intermediates | o wPoerrkfleurcsrwoohcotasnmciockaecigdrewaatserntehgaantifvievelyCiagsasroactiiaetsepdewridtha A y, KPH in PFOA non-smokers. waspositively In associated with AKPH. The association of AKPH GGT, transaminases, and hormones. Smoking with PFOA was independent of AKPH 4, The mechanism induction by compounds in has been reported coifgtahriestteeffsemctokise.thought to be the result to of elevate AKPH PFOA could increase the induction of AKPH. The joint effect of `smoking and In summary, the associations between PFOA and hepatic enzymes are weakand are not clinically significant. In the increased in monalityassocaited retrospective mortality `study, there was no cafrPcFinOoAgenmsa. yTehleuchiedpaatetipcoessnizbylmewemietrhecshluialvtnesrisdimsseaosfea.ctFiuotnuorfensotnugdeineostoofxtihceehfefpeacttisc extrapolating findings observed in rodent are illustrative animal models of the problem of to otherspecies, including humans 14%. In humans, PFOA does not cause the dramatic hepatic "205 - 003388  PefFfeOcAtsmoobdisfeircvaetdioinn orfotdahretsh.epaItniscteaafde;ctthseoofbosbeersivteyd, aaslscoochioalticoonnssummapytirone,stanfgrom Fsumorkhienrg.stuEdaiecshoofftthheejseeinftafctfoorcstsaroef iPnFdeOpAenadnedntBlMyIa,sasloccoihaotle,dawnidthhsempoaktiotnogxoicnity. hepatic enzymes are needed. H .1.5emat Couo ntsalnd Poarag metey rs. MPFHO.A wTahse awsesaokcliya,tibountssibgentifwiecaanntlPyFaOssAocainadteedrywtihtrhohcyetmeogilnodibciens laepveplesa,rMeCdVto,b. aeng mediated through interactions with smoking, and perhaps alcoholconsumption, pvTroholeduufmcienedaiannndgsianicnlraaernagisemreadlinescctreuelduailseaesrihn e1r5me9odgaclreeolblcionnnusmcibosnetcree.nnttTwoigthetahedre,crtehaesseechinarnegdecsell changes in {otal serum eflruyotrhircoe.cytHeoswienvdeirc,esthaeresenoftinodfincgisiniscuaglgseirsgatntiitfohinac.tanfTcuehrteohveeresrsttitumhcaeiteresadnge of leifmfietcetdobfyPtFhOe Asmoanllrnedumcebllerreogfuleaxtpioosn eadndwofruknecrtsi,onthaerelinmeieteddedr,angTeheofftiontdailnfgolsfuoatrrhieede values, and the previously discussed limitations ofthe study design. Pharmacological doses produce litle change in of androgens MCV or MCH i1n1c.r5e2a,ssThereytmhercohcyatneinsummsbbeyrwahnidchmass but eEannnhidrnroropogopeioneisteitinnncprrreeosadpsuoecnthsieiomvnoeg1nl8e1osbsionf ampupletaiprottoenmteidailastteedmbcyelmlosdaunladtbiyn.gsttihmeutating Cleusntneisntegrhoanme oetnae.ryrtehproorctyetde tihn1ad8ti-ct1ee8s5s,tIoss1ctoenprthorynosevieoirlssoiagasilsc. dPoasleasc,iotsheeteaflf,ecatnodf cinhahnemgoegilnobriend,ceblultnncoiccehsafnogrephiynsMioClVogiocr MCH levels ociated with a small Increase 156. "57. Mauss of testostarone et al. 150, reported no MhprCeeHsr.eandtcsatludiyn.citchees.teEssttorsatdeiroolnwealsevewleawkalsynaostsosctiraotnigolny owritshigHnGifBicabnuttynIrnoettlnMaetCedVtoor System Tihs epoeofrfteyctuonfdeprhsytsoiooldo.gTiecllesettraacl.iorleploavretlesd on the male hematological that the effect of smoking on red cellindices was different hat estrogen levels may in male than play a role in in female the efec aodfoxleensocbeinottsic1s5%o.nTrheigsceslulggests 206 -_-- 0 003389  o cPihnFdaiOncAgese.asniTdnaetkneesinthortsootcgeyerttoheneeri,ndtihceesevwiadsenncoet msuegdgieasttesd tbhyatthtehePaFsOsoAciaatsiosnboectiween estradiol. , bur may have bean mediated in part by changes in aTvhayirloaibidlhtyorofmothnyerowxains (aTs4s)octoiamtyedxewditmhachleavnegles sprinodHuGceBsaandmiMlgCmVa,crAocdeycirceased d'aen%p.eomsTiiStaiHoinnchoinunmfeaoryrutsnh.dreodcTyhtee imnecmrberasaendecseltlhvatolouccmuerissddureintgo ianletfeireacttiiovneseriyntlhirpiogpoiesis, 1c0ouhladveexapnlaiinndseopmenedaofnttthhaeeniadnscsoropcepiaoasstaioinnMbCetVwoaenndPTFSHO.A aHnodweMvoery,. PDFeOcAraepaspeeairneTdg between changes PFOA and changes in thyroid function. in ite efect on red cel incices MCV. Therefore, was probably not theassociation related to mAToshdeiefxiipmeedmctutehndee,asssysmsooctkeimngehffaedctsa asstsroocnigatefefdecwtitohnPlFeuOkAocpyrteesceonutnatsc,omSpmloekxinpgicture, eesostiinmoaptheidlsP,FpOlaAteelefitaasctitaonondnbbeWatBswoCep,heinlsc.allHocwoauvnetra,ndsmPoFkiOnAg fdoirdtnoroatl mloydmipfhyoctyhtees, lmyomdpifhioecdyttehecoausnsto.ciaAtdiiopnosbiattywmaoedniPfPiMeFNdO,tAhbeaannasddsoccecoluilnatct,ioouonnrtmfoonroWcEyGte, cPoMuNn,, aAnldcohol pmrpehliomcinyatrsy dcaotuants,ugmgoensotcsyttheatcoPuFntO,Aanisdapslsaotcelieattecoduwnitt.hbTcehatakwneegnnetsoPgiFentOphAeerrai,pntdhis cvleieltluhkcotochuyenttlesycmopuhnotcs.yteTsheefnfeecgtastiovbessasrsvoecdiaitnipornimwaitthe lstyumdpiheosc,ytPeFcOoAunctouisldcomnoshdiesurtalalanytte on peripherablylaelutkeorcinygtethceouenftfse.cts of smoking, aicohol consumption, and adiposity wfTirhtohemmmaoanrgtrianilftleyucdtieouosf tdhieseWaBseCpearnsdpePctMiNve.assIoncciraetaisoends WweErGe nfeotPocsliitniicvaelllyyassisgonicfiiactaentd cinafuasrectiofo,n o6n1g1o6ti8r.nogmpaailtshuconalcuoglsieecasar,licfatrhdeiaolvtaesrcautlioanr idnisWeBasCes,1s canccoenrseaqnudemnycoecaofr,dioarlthe ofthe PFOA associated changepsroicneWssBeCs.muJsutdgamwaeinttfausrtthoertShteudclyi.nical relevance "207 * 603390 | o AAldeisphooslitaynmdodciigfaireedtttehecoasnssoucmipattiioonn between call-count were independent and PFOA for monocytes. isntduidvyi.duaMlosno1%c.yteThceoubniotlsoghiacvael been basis reported for these to be determinants low in massively in the present obese effects are not len.The anate and hitul area for joint effects of adiposity future research, and PFOA on monocyte coun maya In the present PROA, alcohol ihe ditrential study, the complex use, cigarette use, raenldatbioondsyhimpassbsetmwaeyenhalvyempphaoscsyttehecoruenstu,t of specific subsetsefnfeecetdotnoTbcoelmlesausbusreetds.. in disease endpoints TInheoradsesrotcoiactlioanyofthleysmeapshsooccyitaetsiuobnsse,ts observed association have yet 0 be clarified. requires further research, The interpretation of the o ,! I | iSnmcorkeaisnegd,wathsensemgoaktiivneglyefafsescotcwiaasteddiwmiitnhisbhaesdo.phTialycloourro,f a)A,srePpFoOrtAedleavnelincrease in blood Smokers andloss basophils in smokers and nonsmokers and of basophils. comparetdo nonsmokers found that acute smoking 17. Water et al, stugied causes degranuiation basophil court. prior 1774, However, chronic No attempt was smoking Is associated wy an mace to prohibit subjects from elevated smoking Studytmo athyerteiflmeectofr apparent recuciion blood ecent in the sampling. The smoking by part degranuiatig inceigpaatnitvsepraisosrotcoiabtliooondodbrsaawrivnegd. in this The may interact with the basophil degranulatefifoenctprofocsemsosk,ing suggests that PFOA esEfxaepcnotasiuvcrahenaetsnosgPeoFsf OpienArcomarliadynautbmiecbears.socTihaeteadviwditohxcyhgaenngbeisndiinnigmbmyuPnFeCfsunmctaiyoantbteerytohned a{nmtmguennebfiunndcitnigondeapnedncdosuludpobkneilraitnegtaerbrryeadPnbgMyeNmPe,FntOCAyteoxkpionsgusriegn1a7l5i.ngThiseirmepsoprtoannsteitno citntihoen mofemPbFrOaAnecopuhlydsailctaelicmhamruacnteerirsetsicpsonpsreosc.ioufcomdebmybrthaenpeotPerontteisnusr.facCthaantnges croenafiomfePd.OLAymipmhmoucnoyttoexiccoiuyld. bTehiemfmiundnicnpgsheonfotthMyeoppreredesreanstweSrteusdyisnneeseddteodbien the using well established fiow _ 208 -- 03391  . |; | i | ' . i j | i | cyttohmeetNartyimoenatlhoTdisco17l6o.1g7y7,PrTohgergarman1g78ansyhiomumdunboetocxairrcioeldoguitc afosrspesrssm.ent defines C2Shemaionvkgaieinoagn5ha&asn1d6b5eauegln0roofebghsaeetrofvneedwchttoesninecxrepaosseepdl1oetAeDPnu1m5b1e8r4,. suArcvhievaglh,vaecnhmecssimvaenyess, pSmaokgingseisn,creSauscesh NcoEmFpAetwiiocnhcmoofauslydmocakoiamnpgtehotnwsnimoohneksPitnFegrOiAfiefodrtpaaryceaisem;(eNmEbFrAa)n,e rPoledastekeellenntsghciooupfrtp.latTehliets fhuynpcottihoensiinztehde mpercehsaennciesmofcNouElFdAboantdaessPtsReodcOiXba.yteidnrymspeepenrin anaosnaereinanrefbpraotrsite1no0 fboobcensietsgynaotaitnvcedleiyasa,tsesbloucttimcaoatueyrdtwihtahspnlattebleetecnowunltl1t.ess,p Ev CS2hm5caoekncigineagstaadndwohbeosbietsyitmya.yThhauvs,a rtreesualftfeedctfrmoamcfacbcaetoiemolmnaotonefdtsofefecPchOaonnRgNeasppienssmbaye Sdbisseearsvead1ii8nn1cp7rlaa.taeslDseitirneccdotiusanetnadhsaeivncairbaectanmeacsshoacniiastmeds whiatvheraeorf,orhcayrpdoitohveassiczueldafror the FpularttehleertsctouudnytomfapyobteontiaalmaefrfkeecrtoscfocorufriPanFncrcOeeAa.soeTndhpucaastr,edlPieoFtvOasAcualsasrodmiasreaaysechriasnk.ges in needed. count anc ung are 4.1.6TotalFluorine SsSmtookeridneg esasntdiwmataosttaesl fmsoarelrltuh(em0.df1ilufoerrinaenwcairnemwoeaankdfyucarsisnoecibaettewdeiennpaarmiceipyaenatsn. dThe imeskuinlnigkeilnytetnhsaittyswmoaksinngotatsfipgenocimsf)itchaaenntdplyhapcrromorarbecalobakltiyendneowttiitcohfstboitelsosgiealpsifguonreianneclee,vels. PFOA. tis uniikey that smoking was a primary routs foorfasbsoorpptifounoroifnPgFoOrA, erEmxetpcooasruetrees18r1Me0odPvucaFtlOi1oAn9o8m.easxIpnnotoseturrnvaeenertdeisounltaswiantththererveerssuasl oofftahuermeasrteudshieesp.atInic eedaupcityioenesofweoxuplodsuprreevientesapencyiaploltyenitmipalorratecachnuetrcsseientceheefePPcFFsOOAnAtbhoeday snu.msTenheeoy nag unusually long 209 03392 o | | , | | } f | , rbiilnogeical phaelirfe,. 4 significant recuction in body burden wil require years of 17MethodologicalConsiderations 5.171SelectionBias upGneieqvseupnieetcmhaeendotlcsycufhopigahtb.iloonoadlssatmupclyesectoilnlge,cttihoen vtohleunovtearrayllpaprairctiipcaitpiaotni,onawnagsthe paxrcioceidpaatdio8n0%ra.teGsiovfeP6na0stt%hem1e0hdi7ig0cha%pl.arstcTircheieepanptirinaognsapnrtosgtruadmys'saptaCrhiecmpaotlitoenrhaatge small , non-response bias iy fikely to be iaSncetclilavucedteiCdohnmembaiiyacsahlaisvDaeinvhiiasmidponoarwdtoiarfnektreveransltiwdrietaryssipisonsncuslufdoerdCTin0sthSiss.escttuidoyn.alWsotrudkieerss1n89o,t Only pinaclpudaeds. wIaf scoantsisn0uceidteamdpwliothymtehnetenddeppoeinntdeodfpaiotnnotreramessttp,hoatnnhsetenh1ossseleXopwcothsouwreeraend the iitgvhhsdsouesccccreuapraiesbdo.d 6A0istiasntgosotfohroenepraensdenitnscruacasewdaesstrtahdaitolP,FOIfAwowrakseiraosnwsbhioassmhtaady the dose ilty o the effect response curve could of PFOA be un changed jobs, then the overal slope of JoloosbwsetserseutnsoipskotenelrsyoentceouarsvseocmiaaytebdowiotvherPesFtOdiAmeartceeshdta.inmgaMetidegdrj.aot-bisCoonlnoovssue.trosofeftletyn,,hitfhhiwegonhrktehexerpsoovwseiurtrahlel 1c2um5atnvteCyhoeamrsicwaalrDobisviintschileounrdeeesdmulpitnlootfhyseeubescsalmiwpnhlieocawlocrhkaendgeinshiinghhoerxmpoonsuerleevjeolbss. oAvlelr the employed in participants. the igh exposure The vast majority jobs, but . Many workers who changed jobs of workers who hag signific Who had been were included as CCpurhmeeevmniotoluetsmeipvelemopyyleeoaeryssewewsouwladsbleowin(ctlhurdeeedpienrctheentstpeurg,yYseaarm)plaendaastnhtteehesxtptuoudsmyu-rioenvceoirvuedrraetdtehaleiln explanation for the initchinagpsprionptrhiiastsetjuocby,histories. Selection bias is not a likely -210 gi 03393  o 5.1.22 formation Bias lNoovwaotrekdelrowvaess oulneoxtaplossaedr.umThfeluolroiwnee.stIpnotveinetwiaolfetxhipso,shuerecgbrsoeurpvehdadefsfiagncisfimcaanytly represent an underestimate of the true effect, Tetal sarum fluorine was used usa of total serum fluorine has Chemolte Plant and as a surogate been validated variable in past or PFOA biological exposure, monitoring The in the SUe5riu0mgfuaercihnreoimnatCohgarmoaotpihhtieceptwleoacrnhktreriusqs.uiansg hPaFvOeAbe.anDihriegchtlymceoarsruelraetmeednwtiohftPotEe)O uinsiGnhgamthaiisistuorrwoograktaersmewaassurreepowratsednotot dAbiperpeircnottlxhyiemaasftsoeerlmsysoeSfd0P%FoOftAo.ta1l2,saTrrugmvfalligdriitnyeof {o cost. serum. TShmealhlalatm-iofuonotfsPoFfCPcFoCmsptohuenrdsthiasndiPrFecOtlAy may hian tvhebocuernrapnrtassatndtyndue related to molecular weight, | eCxohmalpaotuionnds1w.itShhsoirxtocrhlaeisnsPcFaCrbsonarbeaucnklbikoenleystoarceonltirkiebluytteo abpaprreacpiiadlbylyextoertaostaelgby serum fluorine. not produced at Longer chain PFC, such Chemolite. The high as perfluorodacanoic acid (PFDA), are sciogmnmifeirccanitalcoamppploinceatnitoonfst&o3t.a7l7.s75e.r1u0m1.f1l8tu2oo,xri|icnigetn.ygoaOfrtPhceFhrDaioArngeaPxncFilCcudfaleruseuornitilnfierkcoeomlmyationibnega mcoomupnotusnadbsseoxribstedinfbrioomlotghiecaelnsvyisrtoenmmsenatnid the the environment. form of drugs However, the sma or lant products are rapidly constituent moefttahbeotloitzaledflaunordineexclerveetlesd. 1S9"e.rIunmorognainiccflfulouroriinneelwevaeslsnionttahela1r.g5e pom TroatnaglesaerreuamsfsloucoiraitneediswiatghodoedatshurirnougnaitnetemnetiaosnuarleocfcorupPaFtiOoAnailn ehxipsoscouhroerst,192, The coefficient of variation for otal ethnedaosfstahye wsapescbtertutmer at total serum serum fucring fluorine lovels was 66%, above five The repeatability PPM. At the low of Serum "vor fluorine values(<ma1 yppomv)e,rewshteirmeattehtehaesrsuaey are likely 10 ead to an underestimate is limited by sensitivity, the total value. These measurement physiologic endpoints. of the effect of PFOA on the Tom 03394  i : d iCosmmceleracritahlaPsFtOruActisuraaclormeptlateexd mcioxmuproeuonfcissosmuecrhs exif for ceniai isomeric forms, aasndvalrperfoaitcedaccoe,mpeoxuondns 39, pihhaatrdmiafceorednytndarmuigcepnraonpteormieesrs*'h.avTbehuudtisnfeodrietfnehtreeprnhstari1ms4ao-cmo1ekr8isno1eftiicwaicnegly recognized eoGstitttieomrtaeatnetsetrouimcifelsu.oriInfecoer toitsaolmPeFrOofAPlFoOveAsicsoauslsdohciaavteedprwoitdhuPcteFodiOcaAtnym,uarnycaenhra.tvneeuse SSauienstucshoiafnigtnhmePiFrxOyeAed,sirtshaoenmgastrpheocfotPrausmsoocfiaotxioini.eHsowisasivmeirl,aritn oantihmaolssotbusdieersuvseding clarify the role of PFOA FOA isomers. 9.30.8. 84 Funtnar research i nosgey PoTdheaenttnsoo.xreEaoxktviranalipadoi.lcaNtoofngPctaFhtOeaAsiun ahudmiastnrsibautrieonifofrPanFtOAfrformotmhaonsimoablssetrovheudmian ns fPxFrOaApldaitsatitbouttihoencoornbcoadrtyrbaeutirosdntesnoantintthhheeumsraietlnoasto.ifonPTsFhhieOpubseotwofeesnersuemrulmovaelnygtio asg minoadpeplrsopirsiaatne.imOpobrttaainitnagrpehaafromrafcuotkuirneertaiscscaartcah ieffohrAutsm,aacntisonormaapyprhoaprvieatbeeannimal GTrheeadtteamnp,oraanld vcairticaabninltuyalofvpahryasbiiotloygoifc tphaerasmuatceresndisporeicnotgsnwiazsedn,otTahseusletsrsareidcian, diSraecmtlys.hiItnsftoreaaldl,pbaritoiocdipsaanmtsp.leOsnweerseamdprlaewwnaasttdhreaswnamfoe oeeeter values. Considerable measu time of day, estimate me on an the Hfoorwheorrm,onsetusdiwietshhsahvoertsphuoiwsantitheaitnotonrevaslrasemmspuelcnehtiaossoasLrHg,iosFoiSdnHha,asroatnnhtrgotieensstthosstperroocneed,ure MHseotinmmaaanltisengltahmeveaoabpnsreovrdauluceesd 1r%a.ndTohmemuesaesoufraemseinngtleersraomrpalnedtwooeusltdimbaeteesmxaepmeapclnteesditno Homanes action. may no ved rolationships. Mean reprsent the biologically simeprourmtavnatluqsusanoif ttehyeaaststahyeesdite of 4Va6lhid2asioenxshtauldeidescaorbsoenlfm-ornepooxritdeed,ssmoekriunmgasntdatuur,inuestihnigocbyiaoncahteem,icaanlasmearrukemrs ~212 03335.  ! atshsiooccyiaantaetde,wihtahvcehasnhgoewsn itnhpathyssmioolkoegriscupnadrearmreetpeorrts tshuecihr samsohkeimnagto1l9o6giScmalokcionugntiss s1t9r7e1n9g9,thchaonldesdtierreoclti2o%n,oflitphoepraostseoicnisa2t-io2n52b,etawnedohnepsaatlilcreepnozrtyemdessm4o8k.inTghe information and these parameters the smoking information 299, can ba used to indirectly assess the validity of | i aInsshoicsiastteuddyw,isthmolkaiuknogcsyttaetcuosunatn,dbiantnadnsciotuyrwt,assosstirnoonpghliylacnodunsti,gnpilfaitcealnettlycoun, | and monocyte court. with basophil count, As expected, smoking intensity was negatively associated o | ; i No participant may reflect the rported drinking mora company's success in than 3 ounces of alcohol per day. This discouraging heavy alcohol consumption in employess, a reporting bias, continue employment due to tohrethdeemfaacntdtshatofhCehaevmyidcrailnkDeirvsismiaonyjnoobst.be able to aAslehoehpoalticconesnuzmypmteison2i%s aesrsyotchiraotceydtewimtehacnhacnogrpeussicnulpahrysvioolluomgei,c ptarirgalmyceetreirdess,suacnhd ahsisgohcdiaatnisoinybieptowpereotnesienl'f4-4r.epAorstewditahlcsomhooklincgo,nstuhmepsttiroenngitnhfaornmdatdiiornecatniodn of the these- - ipnafroarmmaettieorns. cIanncbreeausesdedsetoruimndiHrDecLtlyisaasssseoscsiattheedvwailitdhitmyoodfetrhaetealaclochoohlol intake 144.205.2%, cbserved in The this setxupdeycitneidndrievliatdiuoanlsshwiiptbheltowwePenFOalAcolheovlelis.ntaAkse vas a positive association between alcoho intake and triglyc and HDL was expected, there aspedciirfeicctittyoxoifcMeffVectisup3o0n%eirnytihdernotciyftyeinsgizael,comhaotluircastiforno,masnocdianluemdrrbiidenerkse.2r0sA7.wl2ic0to8hhoalThheas p1 o1s0t3ivderipnrkesdipcetrivdeavyawluaesofas6so%cia2t%e.d Iwnitthheanprienscernetas`estuindyMaGlcVoohfoltchoenssaummpetioornerof d2estercetpionrgteadlcporheovliouusselyva2r%i,esAflrcoomho5l2i%nd0uce9s4%G.GTG.GTTheis aleshol consumption or for hepatic abnormaliies sensitivity of GGT in highly non-specific for 10 fe drinks per day over one week or mare are "4-210, Heavy drinkingof necessary to induce GGT two 146, 2%. GGT may be the only commonly assayed hepatic enzyme to increase with Tas . . 03396  PY Sr 8 vas Share. Toe sesence of cn essonnsn a heavy inking. A significant positive association between GGT andself-reportag emxipslcaliansstihfeicoabtsoenrovfeadicaosnsoocliautsieonwsa.s unlikely to produce a bias large enough to lSAilvGeorPhdTailsaeruaesselee,wssSassGeOwnseiatkilvye iansdsioccaitaotresdofwiatlhcohheoplatuiscettrhaannsaGmGinTa.ses.alScGohOolTianndguced CnoanssibdeeerninsghothwenrteolTadtemicoarnysehaibspeeksinlniogswhotnlmyeelceavsaetsedofaanldcoShGalPiTnrdutcpedchIavnegreddi.seSaGseP2T11, TShGePoTbsietreveadlcwoehaolk aassssoocciiaattieodncihs annotgtosaeinxnisuttnrebaxenptseawcmetieennaaslecsowhoolulusdeb,eSeGxpOeTctaendg. probably does not reflect misciassification of alcohol d finding use, and therefore elNxropenalrtaeeidsnepadosnbadyesnetpsartaottehegraolucpohionltihteeamnwaelyrseisdisfifnerceentthtehadnifrfeesrapnocnedecnotusl.d nTohtebyewere pdoitmeinntiiaslhefdorbbyimatesrzewastauisrngerdaeldccuoocvheaodrli,aitnefso.rmAatfitohnouagshathneompionwaelrcoaftetghoerisctauldyvairsiable, the 5.1.2.3ConfoundingBias. tPIhlnaafnnotrimrvaeetciyooernadrsosndiitndhetnhodturcaotnitoaninofsuefmfipclioenytmiennftorimaetxipoonsteodrejcoobnsstwraucstneoxtpcooslulercetsedm.ore ldeevteelrsmiinncaantPFofOPAFhOaAespetafhsfetec.pto.tTehDneutridaaultriaotnioofn eofmpelxopyosmuernetmmaayybbeearneliamtpedorttoaPntFOA S2uXuPdoy.surInermoadeynthsa,vsatebrecaind haocromnofnoaulnfdaoenrrdbifhooerapcpacetupimtcuildaethioonr,moTnhale ednudrpatoiionntsofin this. mXaPyASrLeIqueitoecclounragfetreerxtpwoosuwreeesks'.ofLeexypdoisgurcael,l twuhmeaorrneszaysmmaPeeypettifadcetshoorfmPoFnaOlAeffects fength of exposure or latency to dovelop 122, require a considerable sTthuedryamaeraesmuarnedy ocnolmypaoufonwdsofinthceomm.plOetxhearndbrioolgoegni-cealsltyriomgpeonrtsaynsttesmt.eroTihda presant = 214 03397 o i ; | o| z 1 (hOetHomtEaaAlnSe)es.streiosngtcernlonuiedn,dceeosxrtirosirooll,e,seatsnrtcorroogsetneincecdaitoanceh,aldsi.hayanrdosdpihiyacnraortossstisonsatdairoannsesu(lOtaHt)e. gilmopboulriannt(StHhBaGn)a.ssaamyasjoofr idnedtievirgdmueiannlaonctotmoefpsotohsuetnaderssotn2re1o2g,reatnSioetox(tEhe/oTs)trommoanye bbginmdairngs ptohteenttiisasluerolloeveolf2t5h,esweahsonromtoansessayaesdc.onMfooruendreersseaorfcthheisonbesoedrevsedtdo1ar0soscnlosacribiataytlitaohnnecse, at dhTeohtreemrromenianetaonbnitnsodtfiitnpgoftgoolrsobbtuoolurionnnd(eSteHsBtGo)s.terSoenxe hmoarymhoanveebbiendainngcognlfoobuuinndefdo abryismtperooritdant rInoeigremertsabaonldisnmeg1a.tivePllyaassmsaaoncSdiHaetGseBtdrwlaiootvhallaslnoadvrreoospgioensnicstiifvaerleynatsissocsiuagtsedaeulwye,ll as fect SHBG 21. may be regulated Tha ratios by SHBG of astral to tstostaro2n,anTdhytreositdoshtoamrmnasnteoleDvHeTls levels 213, The hboorumnodnteescthoasntegreosneinmSaHyBhGavleevbelase.n,Adinulptarra,tasesldsaootcenidoatttioeoxnepsbrtreoastdswieeSlenHanPEgFt#Oh1Ay.roTainhdde ademcoluinnte ionrtboitnalditnegstcohsatreacrtoenraisotbisceorfvSedHBinG.ratTshies noobtsethreverdesduetproefscshiaonngoefsriwn the testosterone probably no siingmniefincainstalynarleloagtoeudstotocchhaannggeessininStoHtaGl tebsitonsgte,rone in rats and is Major affect stresses, such as hormones in me surgical procedures, have been shown to markedly osocated with present study. n PFOA. T2h17e,ref1ojrse,unsltikreelsys that was major nota spihgynsiifciaclansttcroesfsoeuswnederrein the Shiftwork biochemic has been shown al parameters, to a ffe ct a variety of Physiologi c endpoints in cluding paricpants he day shit aroteataesdtwteherkelehydetamhyarstoouplgoohsgtitcshhriiefnetdiscchheiast,nsg.aen.AdlGlhisovaremmnpointeheseswr2eo1tr8a,sStitcnoguldleycted on eSTs=atSniodcmiaaatrtededddd.aoysSehshiirffetiswspraokmnpdslieidngn,ottiasppuenailrketloybtehaa ssihginfitfwiocrakntacnodnfPoFuOngAweerrofosthhifets and relationships. 215 03398 o isSsteuwvdieydr.eallyTdhaiepepteraferfcyeicfatastcetoofrsieatraerydeftaetramnidnacnhtosleosfttehreolsonnapsoeinrtusmcloinpsoiprdoetreeidnsinanthdislipics. hormones 2. Since 2% is d 2. Dietary calories, 2u2n%l.ikDeileytthcaatndaiitsisafafsescot the fat, ang `carbohydrates affect steroig. metabolism of steroid hormones 221. confounding covariate in this study. ciated with PFOA, is probably not a Physical enzymes activity affects many 24, lipoproteins 209, physiologic ang. parameters including hormones 223, pmhayxsiimcaallaectxievrictyi.setpsroudnulciekedlayntheaftfemhcate.nmayNtoopalreotfgifiecccitpiawnndatissceensn.ogtFaeogdrefhdoorirsnmumobanmeasx,imonally HdPeDhtyLesirlcmeaivlenlaasnc,ttivotfyt.heThheorremfoonrae,l ienntdhpiosingtrosuup,ndierissutnuldiyk.elyPhtyhsaicpahlysaictciavlixtayictmmiaavliytyeifsfeact sTthuedrye.fore, phbyustictasl aucntliivkietylywtahsatupnhilykseilcyatoacbteiviatysiwgnaisfiacsasntoccioantfeodunwidtehrPiFn OthAi,s ~ Medication usage and eteminants for some "*%. Questionna diseases such as of the physiologic dpiaarbaemteetsemreslmiteuassuarreeidm1potnhaisntstugy 199. wintchoampnlyemteedaincdaliwreceornatdeinmtoitsovncasolni%dc.aattmedi.ngPmFeOdiAcaetxipoonsuursee haansgn`omtedbiocgatn`haisstsoorcyiawteerde PmeFdOiAcaelxcpoansduirtei,ontthheantcaoffnefcotusnodnionhgoefmtauhyseeopcohcfyusmrie,odliocgaitciaonndoprotihnetdiisagansossoicsioaftead with have been described, Howovar, no such relationships eaIlsnasfteleasdmsmetaodttioonrtyatlhpirsoscteusdsye.s,ThwehrischisanreomeavjiodrednecteetrhmaitniannftlsamomfaWtoBrCy,prwoecreessneost ara leukocyte countsaerreumunlfiukoerliyng10ocrosnefrouumndPtFhOeAe,stTihmeartsefdorree,lattihoenssehidpest,erminants of 4174AnaivicModel Soecification Bias mTohdeealnawliytthicacmtuliivvearoifaftoectaspwparsoaacnh audseeqduainttehimsoSdteuldyitahsswuhmiechdttohastuammlainreiazre the -- 216 . 03399 3 o ["dmaaotvdaea.lbAfeoernnmorewmxaateslnespriarvroetrltiyearlumsdesdwfiainsnetduhsaeepdpa.risotSriambniadlsatrehmeiordaeslssuomfptpihyosnisoltoegsitcedva2r2i5abTlehse pcohwoeirc.eofThaefvianarliamboldeetlrawnassfobramasteidonosnubsieoldogwiecradleoknnnootawbblaieosdlegodegiocpnalluashysbpeposetthperseidsi,ctiTvhee Dlological mechanism, relationships observed bust instead in nature, reflect the basic form of dose cie response 21990 ChemoiiteMortality Study 21Introduction JPTahFniOusaAwraypsr1o,adu1rc9at4tir7oonstoppalcatnitvefocrgorheoarttesrtuthdayn ofsimxormtoalnitthysinduwroirnkgertsheepmeprliooydefdroimn a caoslsleecstseeddfftroommpilanndteDpreeecncoderamdnbsteasronu3dr1vc,eer1si9.89D.eCmoomgprlaeptheinceasnsdowfotrhek chioshtoornwy caasta were ipnofsosribmlaet.ionCoohnorctonmfeoumnbdeirnsg wvaerrieabnloetsfisineuddcivhfirdaousmalsilmynodckeoipnnetgna.dcetnetd fsooruardcdeist.wiohnearl e cceonntfciamteedsffoorr18090.%6%ofofthdeeactohhosrta.ndCoatuhseer soofudrecaetshfwoars0.o4bVi%ttaaoilfnsdetdeaatfturshwo,mdaesath fcdeeercatoitdfhiincwagat.esccoodidnegdwbaysIaCsDs-e8sscaetdegboyrireasnbdyomarneossoulbomgiisssti,onReolfiadbeilaitthy ocferdteifCaiatchuatsees foofr The concordance was 100% forthree digit I0D-8 codes, 22PanticioantCharacteristics eTmhpel7o4y9mewnatmoafn27weyresarosbasnerdvmeedafnor iapected events 19,309 person-years, follow-up of 26 years. had The a mean number age of at first imited power to given detect tmhoedeargaetaenidncsriezaesoefstihneccaouhsoer-tspweacsifsicmamlo,rtaTlhtyy.study had 1fTi0rhsetMe2em7ap8nl8oamygmaeennoftwadwreaeso2b7seyrevaerds.ftohreomveera7n0l,a0n0g0thpeofrsfoonllYoewa-rusp.waTshe25meyaeanrsagaendata ath was 56 years. Non-CD men wore order on average than 217 03400  o CD the men hi and had more person-years in the cer age SroupS where monaity was ghest. Intemal comparisons were confounded by age as well as other time correlated factors such as length of follow-up. 5.2.3Monaliy Rests ' disacvantage. In females, 6.7% were deceased the mean age at first emplo compared to 12.5% in the males. Given that males and females, this yment and mean reflects the expected length of follow-up survival advan was similar for ~ both males and females Employment in th the Proportion of deaths was tage of smaller in the women,For CD cohort, e Chemical Division did not produce a large survival : | The less all causes, all cancer, than expected and all cardiovascular montality ameng womenwas in the overall cohort. The SMRs Were remarkably stable | when stratified on ten Year exposure latency periods. The all Cause groups, and ten, fifteen, and twenty year ! employed for at least ten yearssoSr fMoRr twhaosse.e75mpinlotyheedtoltoalngceorhotrhta,n.t7e5niynetahross,eand 75 in all three latency periods. Cardiovascular diseases and followed a similarpattern. cancermonality rIensmpairlaetso,rythceisalela`sceasusSesM, Rcarwdeiroevassicgunlifaircadnitsleyalseesss, tahllangasatnreo,intTehsetianal,caaunsdesallSMR was .77 using Minnesota mortality SMRs are most likelay resul rates and .73 using national rates, The low Ihe al cancer SMR is less affectteodfbtyhethhaeaHltWhEy.woTrhkeoralelffceacuts(aHsWES)t. eAsw`aerxspe7ct5edf,or dHuWlraEtth.iroeeThleataelnlccyagursoeuspsS.MLRatweanscy8d0idinnotthehgarvaeataorsttrhoanng irveelyaetiaornsheimppwliotyhtmheent n group and .68 in the greater than 20Year employment group. The low foalrl2c0auosresmoSrMeRyeianrtshewagsreaastseorctihaatned20wiytehacrodnutriantuieodn s9erloeucptisoungbgaessetds tohnatwgoorodking amhneeaatllayt-shai.nsaTblhyyesFisaolxlofcaarnuedstreCoosslplSeiecMrtRi2v7ed,eccorheoratsesdtuwdiitehs d2u6ra-tibountionfc`reemapsleodymiennttheinmoentea. "218 . 4 03401 o o The SARS for all causes, coinfeYroenatrsramployment 0 maolrcsantchearn,tnandyaaalrCeaerdmipolvoaysmcuelnatr diseases for lass tha i | ohoet$5no%t cCalolwemualraanetee.wdi.dBeTe.hcoaDuSusse1thtehreastamsawlemraembpaesreodfoVnesnmtaslliwnneturhmeebenfoertmsasloiefgsna,iyfeicsa,nt | employment and greater thAanRstaanrysesairmeimarpltoo ytmheenSthigrnogupfosr, the less than SRR ten year | cTahrediSovAaRsscufloarrCdDisevaesressuswnaroenno.t Working in smiaglniefiWcanet asndfworeralel causes, simila all cancer, ang a mnaukmebe1ruonfliektvehelerytCtshOaotbdimsdoedrnovtedsfuobrsrtaarneticaalusaesrofthdeearatthesofofspdeecaitfihrc.tocTathuheeseSssmmsa, aflolrotwhesuftoflclioawn-tuppopwereirotdotdeherrtaoetucegthimn1oc3dr8asa,sepsoinngafroglslow2-uulpdtbimeedweitlecbteedneinedtheoidfs dtcoaonaorr death. erate increases in rates for specific causes of | cTahueserse,sualtlscfarnocemrt,heanaddjaullstceadrdRiRovyasgcucloanrtrdassting the mortality rates for gf mall Do Detw eWsotrikmeartseswewreorosismtiaatritstoictahlosdeiffoerretnhtefSroomAaosneeas,ndbTeShtMweRe.n e CO and non.cp Non of RRygy eelmepvlaoteeyadmneilnnettshsperteholsadneensttteendyaeadrisfiorfaentmppilcotyurmee,ntAlan2d5gr8eaRteRrMtchHoannwtertaresnetysoeifagnrriasftieocsfa alilisceaansceesrwRaAsMsHignciifsicpairtatwyloeydeaalgeetvragetrneoddupisn,twheh3y9 t1h0e1eRssRMthHanfo4r0cayredairovaagsecuglraorupn,tT, ehmeploolydmesetntt.woTghreoyupms.ayThhaevAe beRenwtseuorbwseatpangnott2asdtjatuisstteicdalfloyrsyieganirfiocfafnitrsyelevation inhe mrSoeXrgtPraOetSsiUstIioEnomvoedretlsi,m yseianrceofyefiarrstoafmipris;oyemmepnl;oyiwmaaellsnyts.ciognnAfsosuenednedinbsyecvehraan)gpesyof Sfoacmtporosaisyse.occAaiftatetegerodawgiethanmodnlaelnigttyh8o%f,foHlelnowc-eu,p,jtciaslkeenldayritfthiiacmaentilsytansesosctiraotnegdeswtittihmtehe ihnoroanttrao,llitewdacsonnfootruifenesdaisonifbglcebayuscealoefnddaeraperniohg,e oldest Given groutptsheweerleeavatreedsuRn goff or the small number of ev employment. to fyrney siratity the data on year of irgy erys 279 03402  o | i hsIiengtnhCifeDicPawHnatlsryeagrsresleoastcseiidaotntatnialmyesiins,thperoCshteatmeiccaalncDeivrismioonn.aiTtyenwayseaprossotfiveemlpylaonygment in Compared omen analysis siratifed ed with 2 3 fold increase never employed in the CD. by CD and non-CD emp in prostate This trend cancermonality was evident in tne SMR eixnpdeecpteendd,enatgeofaturfiartstioenmpolfoeymmpelnotymweanstpaosnildtoiyyvemelaeyrntro,eflfaiTtrhestidsstomaspsioocyiamteino,n wAaes urmobnearlofraftaec.toTrsh.e Tihnteerepsrteitamtaitoensowfetrhsibeasstiemdaotendsirxelpartiovsetarrapetreocsiatsnatcteeemcrpadeneracetehdrby a SiniiifheicCaDntcyohalotretr athned ewsotimianttehse. have been incomplete non-CD cohort. Ascenainment Achange of one case s, could four of all prostate cancer deaths may icmophearri.ectG,imviesncitahsastidfecaa.ttihDocinearogtfniofoisncieasteomrcaamyusheavoef cbeeaetnh minofroarmcaotmipolneitsekinnotwhne 1C0Dbe bmeesntasltuydyasentdhpeoeivnetnbteocaiunsteereosftthfoer eltoinooglroengaitdcuersaattluhdhsiiecsstoouofldproocsctuart,e Tchanecuesreisonfot the cparoussteatdeaactahnc2e4r..22T5h,eFmoarjloorctayliozfeidndciisdent prostate ry and low mortality of cancers do not Progress and patients have werklorce are nbeeeednerdeptoorcteadr2y2.theStsuudgiegeaessseot,feapdrnions8ct0art%eeatscaeannicnyeeprar.roissntucaritvdeievcnacleininutnhtirseated Th findings biologic mec of hormonal alterations in PFOA exposed man ancer risk. suggests a possible studies ofothhaarndiissmeafsoersthtehaitncarreeasheorimnoPnraolsltyatmeedciaantceedr PFOA associated hormonal changes are confirmed, mmoartyalbiotyi2nd,icaItnecdiidf etnhcee 52.4MethodologicalConsiderations 52.43 Information Bias 5T2hc6eaouufssetohoeoffpddoeetaeatntthiaclarbtiiaiscadteepsetnodcsatoengotrhiezecacuasuessofodfedaetaht.h Iinmopenrgfescttud2y2c2a3n8c,erTanse wweerree uunnddaerrmroeppoorrhtteewddasiinnu11n29d%e%rorfepaourttoepdsybcyo1nf3i%rm2e2d,caLseeusk.ormCioalsoraecntgallcyamnpcheormsas ere not severely misclassifioefdc:asAells.carTdhieroevfaosrceu,lairt adpipseeaasressthaast5cagnrcoeurpdmaaayths 220 ---- 03403 o | | i I f i | mhiasvcelsbsaisfhcaitnaecdcuarnatem.ayIndpirvoidcueals death in thecardiovasculargroup, disease with the whole may large such biases. For example, be severely spacitc causes of inaccurately designated on death certificaastecs.erebrovascular disease, arg FTihrsvte,shmeeacsouorreswoafsPdFiOchAoteoxmpiozseudre ose who never worked i the CD. based on job to thos who history were ever worked uinsteheinCpt,ahisntgugy. hCebtuotnall d1u9r8a5tiwonasofuCsheedmo2l5iatocoenmtpilnouSyomeusecnoptnar,waatmsheetuensreufdmobraesPraFoOfcoAmnoterixinptgohossuuwroer,keThdirg,the mpfiorsroctldhauesscie.feiccEataticoohfn.woofCrhaketensgeoarsipuzlamatnoitgoaptroecivuacriinagblPesFOmAayapmroondgucaelaardgiefneruemnbtessrppoafreacmeutoefr he ov OD may na enti PFOA reflec the exposure. biolognicoaflweolrekcetrisveincooseeveorf A number of workers were versus never employedin PeFmOpAl.oyMany Op jobs do Tshhiosncapteergioordiszaintitohne mdiasytamnitspcalsats.sitTyheuinreexxppoosseudrewomrakyernsotashaevxepeobdseeiosnn,tshiegnGifpicoanrt, eCmopnvleoryseeelsy,woPrFkOinAg eixn poobssurweitwhansoweixdpeosspurreeadtoaPmFoOnAg.ChNeomiecxaplosDuirveison(cD) poemnmepealsrousyreewemoseunlhtadsdhhsaiavgveneibfbieceeaenntncbdlaoosnscsifbiiunerdndaoesnn-sCOoDf ePmFpOlAo.yeest.hisHtwisaspotshseibclaeseth,atexnpoons-eCdp bmepeoxypmeecnttetidon tbhieasCtDheweafsfetchteebsetsitmaatveasuitlnobewlxaeproedssettdh.iemnSauul,cofhTPmhFiesOcmiAoasndsotishfeis.caotfNiootn meg TJTohrbeespuhsoaesvoeefdPdWFuCrOaIAtKiEoernxpoaofsseuemrxpep.loosTyehmdeencmtoiuslcdashsaivfecabtiiaosnedprtohecuecsetdimbacytleatsoswiafrydintghe all Gp nul, pPaorsaumerteerinisthleespslsapnechiafsc mfoordPiFatOeAdattdhiaCsnheetaimsmoeeloticnectuahsrerCaeDcn.ocntrIifatnaeunso,tushe.exrpxoesnoubrieotic curation may produce less misciassifiation than uss of the curation in use of the CD. 242Confounding andSelectionBias The healhy worker Sucies 85.23, 1s eaffceoctmpsltreoxngbliyasaftfhaetcsretshueltvsa,liidniptyaro,f many occupational from he selection of E> 03404  | | I pionpduivliadtuiaolns. foTrheemHplWoEymiesnutsuwahlloy asrterohnegaelrthfioerrctahradniotvhaossceulianrtdheicsoemapseasriasnogn respiratory diseases. significant portion of a Because ll causes cardiovascular dis monalty, the HWE eases mortality accounts for a usually reduces the allcauses SMR. The age of employment at first employment, are four time factors age that at risk, length of follow-up, ang duration are associated with changes in the HWE 1%. Generally, the HWE diminishes with age and time. Collection of canfounder informationforincivicuals is cohort mortality studies. The present study included difficut in retrospective than 40 years. It was not feasible to collect individualwoirnkfeorrmsaftioolnloownedsfuocrhmore covariates proportion as smoking, of workers at health status, medical history, or Chemolite who smoke has been dietary habits. The lower than in other faciities owned by the same corporation. In recent health maintenancestudies, the self-rep prevalance. orted The smoking prevalence (25%) is lower than the observation that al respiratory diseases and Statewide smoking lung cancer rates are lower than expected may be the result of historically low smoking prevalence. The and low smoking prevalence may depress t all respiratory disease SMR. The use of he in all causes SMR, all cancerSMR, temal comparison groups may reduce this smoking related bias 27, `Time factors such as age at risk, age at first employment,year of first memapnlyodyimseenats,easn1d%.durTahteiounsoef oefmapnloiynmteemnatlacroemapsasroicsioantegdrowuitphmtaheyorcecduurcreencecretaofin selection comparis effects, on grou bu ps t may not have dife control rent dis confounding if the tributions of thesa `exposure defined internal fime factors, Although the mean age at first employment and mean year of first employment are similar in the CD ofdisease and are ncoonnf-oCuDncdoehdorbtysdoifffmeerenncaensdinwothmeedni,sttrhibeu`ticoonmpoafraigseonast of the risk. rates These time factors are strongly correlated, with some being exactlinearcombinations of others. may be The relationship between measures complex functions of these inter- of exposure and disease occurrence factors 41 may reduce the disease the effects occurrence of confoundrienlagt,edbuttimmeafyacntoortsc.onAtdrjoulsctomnefnotunfdorintgime relationship is defined in terme of cumulative 222 03405 o : | o 6XpOSLIS. he 110 effct uncontrolledconfounding of exposure may bo cus to the complex bidsad toward the time factors 185, nui by xSeonombeiowtoicrsk,erssucwheraas ebxepnozseende taonmdaansyboetshtoesr,podtuernitnigaltlhyeidriesmepasleoycmaeunstinagt Chemie. information wAadjsuasvtamielanbtlef,retxhpeiorsufireecstsarswaosftneonthpiogshlsyibcloerrienltahtiesdstmuadkyi.ngEvtheen if separation of individual effects impossible. vCaolmip,arHioswoanveorf,SfMhRes dainsdtriRbRutMioHn obfetthweepeanresxopnotsiumreeignrtohuepcsommpaayrinostonbegsrtoriucptslyi 1nodt .strtohneglpyedrissocno-rtciamnet,ditshternibsutuicohnsaacroemipfaerriesnotn imnatyhebeexupsoesfeuld.grInoutphse,cuHrorweenvter, the differences SMR possible. appearto be of a magnitude that makes useful comparisons of isAhtteuhdpaiaeusstg,hantdhheaclspirnboicepaoelrnttiisaoulngsa,glefthsahtzaeasdrntdho(attPbHe)emnowdiedlelhyaussbeedeinn uoscecudpartaiqounaarltlsytufdoiresc,onIonrt tohfecmhooidceelbsetcraaiugshtefcoomrpwuatartdi,onaHlocwoesvPtesoriw,sesProeHn lrmeeosgdsreealsnssdiaotrnheweancsoonwctehepaestiaulnayalliuyztnaitcisonraotfegy Sctohaonrdtarsdtucdoimepsuhtaesr fpoastcekraegdetshe1%u.ndTehresitranwdiidnegaopfpltihceatPiHon miondceilnsc.alProiiaslssoawnintdh umnoddeerlsstoaopdp.eaProilsesosnfrreegqrueesnstiloyninanthdePeHramtoudreelsanhdavmeatyhenoortetibcealaslnwkeslland have TCbhoeexenvPsaHhloriewgnroeftsotshgieiovnperwsoaipmsoirlctaihroonrsaeelsnuhlaatzssawtrhhdeesnmausulstsiuevmdaprttioiatoaenamloydzeeltthoe esmapmleoydaIntatsisetwa189y,. HWoowesvtearn,dairndatneaclhynsieqsueisn.volTvhineg aasssumamlpltinounmsbdeird onfotnevsaepwnptases,arethxteoabamesisngeersoesumssleiynngtvoioftlhaeted. vaidity of assumptions may vanables was based on lack be of limited. The use of statistical evidence the for factors as continuous a significant nonlinear the 223 03406 o | effect. Although this strategy has been widely used for control has not been extensively validated in simulation studies. of confounding, it 4 = 03407  PE. .SUMMARY CONCIUSIONSANDRECOMMENDATIONS qTuhainstiwfaisedabycrtoostsa-lsseectriuomnafllusotruidney.ofPasretlieccitpeadntpshywseiroelorgeiccrueiftfeedctfsroofmPwFoOrAke,rass employed during Plant in Cottage November 1890 in Grove, Minnesota. the Chemical Division of the 3M Chemolite: All current workers who were employed in high exposure jobsa any time during the previous five years and an age pmaanticcihpeadtes.ample of workers employed in low exposure jobs were invited to parameters measured by an occupational health nurse. Blood was Grawn for Panicipants completed a corporate medical history questionnaire and hadvital assays of total serum fluorine, seven hormones involved in the hypothalamic. pituftary-gonadal axis, serum lipids, lipoproteins, hepatic function parameters, and hematology indices. Blood was drawn in the moming ater workers were assigned 10 the day shift for at least threedays. In past studies, the majority of total serum fluorine found in Chemolite workers was in the form of PFOA. Thus, total serum fluorine is avalid sumogate measure of PFOA in Chemolite employees. For 93% of workers, total serum fluorine levels were 20 times greater than `community and corporate background levels. mhFaainsydairnelgsousnltginibntihoseliogcgnuiircfraielcnahtnatslbttiuiofdaeyciacnruebmouctlohantsmiieosntnefnartnowdmitwshomamoltelhnef.rredTqauhteaentsluodgnoggsehasastliton-rigfletahroagfte,PPFFOOAA infrequent doses. The hormonal findings from this study are consistent with the hypothesis that PFOA depresses the human hypothalamic-pituitary-gonadal axis. The results show that low levels of serum PFOA (204M) depressed free testosteronae nd elevated estradiol with little observed change in LH levels. In older men, free testosterone was depressed below 9 ng/dl at serum fluorine levels belowone PPM (estimated PFOA levels below 1 HM). 22s 03408  1 i | | | ' Kg : o i 4 cinical significance of this fining is unciear, bMuetannotpirnollaicgthitndrlienvkeelsrsw.erSeinPcoesitthievefluynactsisooncioaftperdolwaictthinPiFnOmAenin Imsoudnecrerattaeind,ritnhkeers, Mean thyroid stimulating hormone was Positively associated with PFOA. Since apsersiepshserwahletthhyerroihdehoorbmsoanreveldevaeslssawceiraeionnotbeatswseaeyendP, FitOwAasanndotTPSoHsswibalse to the result tohfyarodiidrehcotremfofencet omnettahbeohlyipsomt.halamus, pituitary, thyroid gland, orperipheral Cholesterol, triglycerides, and LDL wera nt significantly associated with PFOA. PFOA was negatively associated with HDL in moderate drinkers. PFOA was not associated been observed in rodents. with the marked hepatic changes in humans that have endogenous factors and PFOA appeared xenobiotics. to alter thehepatic response to ePsFtOimAatweadschsiagnngifeiscainntleyraystshroocciyatteesd with hemoglobin are not of clinical levels, MCV, significance and over MCH. The therange of observed total serum fluorine. cTohmeplcehxanpgiecsurisn.laFuokroceyxtaempcloeu,nttsheasnseogcaitaitveedawsistohciPaFtiOoAn beextpwoseuernePpFrOesAenatnedd a lymphocytes was increased by smoking more than 10 cigarettes per day and decreased by al are not clinically cohol use and significant fro adiposity. m an infect The ious magnitude of theseas disease perspective, sociations However, ceilseevaasteesd,WaBndCchaanscebreemonrtaaslsiotcyiaastewdelwlitahs iinnccrreeaasseedd aillncciaduesnecse,ocfamrydoicoavradsicuallar infarction. 1990 This was a retrospective cohort Production plant. All caus study of mortality in workers employed in a PFOA employees were es significantly mloenssaltihtayninexbpoetchtmeadlbeaasnedd female Chemolite on comparisons to the 226 03409 o | fmoorrsaelvietryalexoptehreirenccaeusoefsthoef dMeiantnhesiontcaludainndg UanlitreedspSirtaattoersypdoipsuelaatsieosn.weTreheleSssMRthsan expected. Chemolits Since the haalthy worker effect cohor, intemal comparisons of was apparently strong in the SMRs were made between Chemical Division (CD) comparisons and non-Chermical did not suggest any Division (non-CD) employees. These significant excesses in mortality in CD or non- CD employees. . | ' o CGehnaermalilye, rtehseulftisndiinnegslefvraotmedthmiosrsatludtyyprraotveisdfernomo eavniydcaanucsee.thaHtoewmepvleory,mpernotstaatte D`icvainscieorn.moTnaelnityyeamrasyofbeemapslsoocyimaetnetd iwnitthhelaCnDgthwaofseamspslocoiyamteendtwiinththaesCighneimfiiccaanlt bthertewaefeonldprionsctraetaesecainncperrosmtoartaelciatnycaenrdmoermtaplliotyy.meTnhter(eevwera/snenvoera)sisnoctihaetCiohnemical aDinvdistihoen.naGtiurvaelnhtihsetosrymaofltnheumdbieserasofe,detahtehasssforcoimatpiroonstbaettewceaennceermpinlhoiysmesnttudiyn the CD and prostate cancer must be viewed as hypothesis generating and should not be over interpreted. However, the between CD employment and prostate biological canceris plausibility increased for any association by animal and human toxicological data suggesting hormone changes. an association between PFOA and steroid sex. C.3onclusion ePxerpfolsueodrawoocrtkaenrcsi.c aTchidewclaisnicaaslssoicginaitfeidcawnictehorfetphreodsuecftiinvdeinhgosrmaorenaulnkcnhoawnng,esTihne caassnocceiratmioonnaslotfyPiFn OmAenwiitnhdihcoartmeosntehse,nHeDeLdf,ohrefumrattheorlorgeysepaarrcahm,eters, prostate 8R.e4commendations. Research is needed in five areas. 227 Jd 03410  : i | i i PY s1e.cAtinonaaslssetsusdmyesnhtooufldthbeehcoornmdouncatleedffuescitnogfsPpeFcOifAicIanswsoamysenforisPnFeOedAeda,ngA cross. `accounting for temporal hormonal variations. p2arTahmeetceirniscanleesidgncilfariicfainccateioonf.thSeinacsseomcoirabtiidointsyoffrPomFOdiAsewiatshesthseucphhysaisolporgositcate cancer needed is reflected in in five years. moray, an update ofthe retrospective Morbidity studies should be conducted morality study is of ncipoints that ymoauyngbeanpdroacruecelidmibtyedhionrmnounmbaelrc,htahnegfeeas.sibSlienceendepxopinotssedfowroarksheorrstatreermolmatoirvbailcyty nstuumdbyearrsofleimxiptoeds.edPowoolriknegrsofawnodrkaelrlsowfernodmpaoinnutmsbweitrholfopwlearntisnccioduelndceintcorebaese the studied. The morbidity of endpoints that occur study should be a long term at higher frequency inolder which would age groups. allow the In men, study pernodsptoaitnetscasncheoru.d Tihncelufedaesitbhieliityncoifdiennccleudoifngbeinnifglnampmroasttoartyicbohwypeelrdtirsoepahsyeaanndd seholoourledctianlclcuadnecetrheaasgeendopfomienntsopsahuosueld, atlhseoibneciedveanlcueatofedo.stIenopwoormoesins,aennddproeilnatst.ed afrvaecrttur,ese,nduotemraitnreiaflibcroaindcs,eranadndchionlsfiliatmhimaastiosr.yIbfotwhser!edairseeaasesufsfhiocuielndtbneumber of beveatlwueaetnedP. FIOfAtheancdrohsso-rsmeacntaiosn,althheonrmthoenamlorsbtiuddityyinstwuodmyecnanfibnedslinmoitaesdstoocimaetni,on "* p3o:tSetnucdyi,esanodf rfeerptrioitdyucatrievdeioreucttlcyoamsessociniabtoetdhwmiethnsatenrdoiwdohmoernmoanreesneleevdeelsd.. TLhibeido, feasibly ofa retrospective study of time-to-pregnancy study needs of to reproductive be explored. endpointsor a prospective m4orTbihdeitmye. chMeacrhiasnmisstoifc ascttuodinesofaPreFOneAedneededtotodebfeinsetutdhieedrecloenvcaunrcreaonftyanwiimtahl studies for humans mertality, morbidity, and and provide a firm biological reproduction studies. basis for the findings of the tIhnevpiittouitaanrdy sceelclreltinieonstoufdiLeHs,cFouSlHd,cTlaSrHit,y tahnedmpreoclhacatnini.smPsitouficayctteiocnulotfurPeFsOmAayonbe 228 03411  holphlin PFOA on oevtahleuraatuitnogcrtiheneirorecptareafcfreicneoffaPcFtoOrAs pituitary function. The such as TGF-2, TGF-5, offect FGF, of ang hTeNFefceocutldofalPsFoObAe oevnalauraotmeadt.asHoumacatinvitayd.ipAtdodciyttieoncaulltyu,restsuccoieusldarbee nuseedotosfto.udy cary the hormones. lationship between PFOA and the temporal variabiy of reproducive reo:mupStlteuoodyfiecedsonaattrieCnhuneeemdeadalebtsdeo,totboatatsecrerdteafiinnethtehseoPurFcOeoAfetxhpeoisruPrFeOpArofeixspoofsaalrlswaornkers of PFOA in humans. rption and to clarify the toxicokinetics and toxicodynamics --- 228 . . : 03412 [ i o Bema : 1. IKnitrekr-sOctihemnecre. EPnubclyicslhoepresd,i1a9o6f6.Ch5e0m6i-c8a4l7.Technology. 2 6d. Vol. 3. New York: 2. Abe T, Nagase S.Electrochemical perfluorinated organic eom flucrination (Simons. Process) as a route to Preparation, Properties, pounds of industrial interest. In: Bankes and. Industrial Applications ofOrgan R, eds. Compounds. New York: John Wiley & Sons. 1982. ofiuorine 3. SCihmeomnisstJr,y.BrycNeeTw. YEolrekc:AtrcoacdheemmiciaclPrfleusosr.in1a9t5io4n:.34In0:-S3i7m7.ons J, eds.Fluorine 4. Simons J. Fluorine Chemistry. New York:Academic Press, 1963, 5. Taves D. Evidence that there Nature 1968:217: 1050-51. are two forms of fluoride in human serum. 6. Taves 583. D. Electrophoretic mobility of serum fluoride, Nature 1968:220:582 7. GBuyysvWa,leTnaceveasndD,chBarreayctWe.rizOartgiaonni.cIf:lFuiolroec,ompeocu.ndBsiionchheummiasntypliansvmaa:ng carbon-flucrine bonds. ACS Symposium Series, Chemical Society. 1976:117-134. New York: American 8. UfbleulorFo,cSheomriecnaslso:naS.PrReolaimcihnaDr.yHReeaplotrht.StAamtusInodf HPylagntAsWsoorkce1r9s8e0x;4p1o:se5d84t.o589, 9. GArimffitIhndF,HyLgonAgsJs.oAcn1im9a8l04T1ox:ic5i7t6y-5S8tu3d.ies with Ammonium Pperfluorooctancate, 10. Zobel 1980, L 3M Corporate MedicalDepartment experienca in medicalscreening. -- "230 03413 o o . i- 11. Nicklas M. Presanco cu fluor dans la sang. Compt Rand 1856.43: sss. 12. VB19eo8ur2n;kd5a4f:tlue1o1rsi3nu2e-i1.13oS7r,goanimc cboimghpaonuyn!dmsaatndhbifoorlodgeitcaelrmmiantaetriioanlso,fAcnoav,alOapnetys 13: Ywahmolaemsbtloood,ofYhoushmiaankemaKl.esS.atAonaTl, eBtioalc.hDeimst1t9bu8t9i:o1n82a:nd37f1o.r3m7s6.of faring in 14. Bo1ef8l7iw8shl.oe8l7Je.: bH5l4ao5go.de5,n55sD.e.rMuemtphlaosdmfao,rtahnedeottehremriinoaltogoincoal tuhiedt.otaAlnfaulorBiinoegceorn:tent 15: CSrhpiinenecbatanrKdo, mbTlesoutoanrdnoydsdeawriKtu,hmHbayfrlaaugoluruicmdheiinHu,mFmuownaofKu.orDietdeermmionlaetciuolnarofabfsuoorrpirnieonin electrode. Anal Chem 1980:52: 582.1585, 16. Spilnagsemra.L.COlpinhCauhgemR.1C8o7n9c:e2n5t:r5a2t3i-o5n2s5o.f ionic total, and bound fuorice in 17. GRpuuorcyihfeWisc.atteFiroi,ns,o1ar9n7od2c.oCmhaproaucntdersiozfatHiuonm,aPnh.PDl.astmheas:isA.naRloycshiess,tePrre,vNaYle:nUcen,iversi of 18: TCPeraverevbsaolDne.nucGaeurayinnWde.CbhBoarnredaycst.We.riOzWraagtsiahoninin.cgtIFnoi:nsF,oirloercRarboendss.inBiHoucmheamnisPtlraysImnav:aving 1976:117-134, DO: American Chemica Society . 19: CTaoomxomkAop,npilMuuPmrhpaaeyrmfSu.1o8Fr9or1oa:cm1te1a3nS:c.a2tH0eu8:r-t2A1M3p.,osIsnidbulcetieonndoocfrLienyeeireglcaateldamdoecnhoammaasbm,y = 20. Bryocce.H.FlIunodruistnreiaClhaemnidsUttyi.tarNaonwAsYpoerckt:sAocfadFleumoircinPerCehses.mi1s9t6y4,:2i6nS:7i49m5o.ns v C03414  ! : | 21. P1e8t7e2r:s11R:, 1S3h3o7r-t1h3o3u8s.e M. Fluorocitrate in plants and food, Photochemistry 22. Lovelace J, Miller G, Welkie fuorocitrate in forage crops cGo.llTehceteadcnceuamrulaatpihoonspohf aftleucprloaancte.taAttemaonsg Environ 1968:2: 187-189. 23. Cheng J, fluoride. YU Env M, Miller Sci Tech G. Fiuoro-organic 1868:2: 367, acids in `Soybean leaves exposed to 24. Guy W. T, eds. lonic and organic fiuorine in blood, In: Johansen E. Taves D, Olsen WestvieCwonPtriensusi.ng15E7v9a.luation of the Use of Fluoride. Boulder, CO: : 25. Taves D. Comparison of "organic* J Dent Res 157150: 783, fluoride in human and nonhuman serums. 26. BTaenchkneiscaRl. &FiSvcoirenotciafircb,on1s97a0n,d their Derivatives. London:MacDonald 27. M1i9d3g0l;e2y2:T,54H2e-n5n4e6.A.Organic fluorides as refrigerants. Ind Eng Chem 28. Moore C. 323. Industry response to the Montreal protocol, Ambio 1990;6-7: 320. 29. R1o8w8l0;a6n-d7:R.28S1t-r2a5t2o,spheric ozone depletion bychiorofluorcarbons.Ambio 30. Otson C, Andersen M. The perfluorodecanoic acids acute toxicity of perfluorooctanoic and Appl Pharmacol in male rats 1983;70: 362-372. and their effects on fatty tissue. Toxicol "232 4 03415 o 31. Guenthner R, Vietor M. Surface active materials fromperflucrocarboxylic and perfluorosulfonic acids. I8EC Product Research and Development 19621: 165-168. 5 . | 32. SihnimnidcoelKl,esNaonmdurliaquTi.d Mmiisxctiubrileist.y oBfafsliucosrtoucdairebsonofanoidl rheypderlloecnatrabonnd sfuirrefactants extinguishing agents. J Phys Chem 1980;84: 365-369, 33. Riess J, LeBlanc M. Preparation of perfluorochemical emulsions for biomedical use: principles, materials and methods. In: Lowe K, eds.Blood Suststitutes. London: Ellis Horwood, 1980. 34. Yiinen M, Kojo A, Hanhijarvi H, Peura P. Disposition ofPperfiuorooctancic . acid in the rat atter single and subchronic administration. Bull Environ Contam Toxicol 1990;44: 46-53. 35. Clark L, Becatiini F, Kaplan S, Obrock U, Cohen D, Becker C. Perfluorocarbons 680-682. having a short dwell time in the liver. Science 1973;181: 36. Sargent J, Sef R. Properties of perfiuorinated liquids. Fed Proc 197029: 1699-1703. ns mn ------ se 37. Kennedy G. Dermal toxicity of ammonium Pperfluorooctancate. ToxicolAppl Pharmacol 1985;81: 348-355. 38. Kennedy G, Hall G, Brittelli J, Chen H. Inhalation toxicity of ammonium perfluorooctanoate. Fd Chem Toxic 1986;24: 1325-1329, 39. Ophaug R, Singer L. Metabolic handing of perfluorooctanoic acid in rats. Proc Soc Exp Biol Med 1980;163: 19-23. 40. Belisle J. sources. Organic Science fluoride in 1981212: human serum: 1508-1510, Natural versusindustrial T= 3416  41. Marais J. Monofuoroacetic acid, the toxic principle of "Giblaar Dichapetalum cymosum. Onderstepocn J Vet Sic Anim Ind 1944.20: 67-71 42. Peters R. Lethal synthesis. Proc R Soc London B 1951;139: 143-170. 43. Fanshier D, Gottwald L, Kun E. Studies on specific enzyme inhibitors. VI Characterization and mechanism of actin of the enzyme-inhibitory isomer of monofiucrocitrate. J Biol Chem 1964:239: 425-434. 44. Tecle B, Casida J. Enzymatic deflucrination and metabolism of fluoroacetate, fluoroacetamide, fluorosthanol and (-}-erythro-fluorocitrate in rats and mice examined by F19 and C13 NMR. Chem Res Toxicol 1989:2: 429-435. 45. Taves D. Dietary intake of fluoride ashed (total fluoride) v. unashed (inorganic fluoride) analysis of individual foods. Br J Nutr 1983;49: 295-301. 46. Long D, Higgins C. Is there a time and place for radiopaque fiuorocarbons. In: Bankes R, eds. Preparation, Properties, and Industrial Applications of Organofuorine Compounds. New York: John Wiley & Sons. 1982. 47. Faithtul N. Potential applications of perfluorochemical emulsion in medicine and research. In: Lowe K, eds. Blood Substitutes. Chichester: Ellis Horwood. 1980:130-148. 48. Manning R, Bruckner J, Mispagel M, Bow J. Metabolism and disposition of sulfluramid, a unique poplyfluorinated insecticide, in the rat. Drug Metab Disposition 1981;19: 205-211. 49. McCormick W. Repeat application 28 day dermal absorption study. 1983, Riker Laboratories, 3M: 50. Hanhijarvi H, Ophaug R, Singer L. The sex-related difference in 50-55. perfluorooctancate excretion in the rat. Proc Soc Exp Biol Med 1982;171: Co 03417  o _ | I 61. VdaisntdriebnutiHoenu,vmaeltJa,boKlusilsimk,isanB,d VealinmiRneaftieolngohfepmeMrf.lPucertoeorcstoannaRi.Tciascisdu,eJ i Biochem Toxicol 1991:6: 83-92. 82. Hanhijani H, Yiinen M. A proposed species difference in the renalexcretion of H. perflucrooctancic acid in eds. New Developments the beagle dog and rat. In: Beynen A,Solleveld in Biosciences: their Implications forLaboratory Animal Sciences. Dordrecht: MartinusNijhoff. 1988:408-412. 63. Vanden Heuvel J, Kuslikis B, Peterson R. Disposition ofPperfluorodecanocic acid in male and female rats.Toxicol Appl Pharmacol 19981;107: 450-459, 64. Vanden Heuval J, perfluorooctanoic Davis J, Sommers R, Petersen R. acid in male rats: inhibitory effect Renal excretion of of testosterone, J Biochem Toxicol 1892;7: 31-6. 65. Bookstaff R, Moore R, Ingal G, Petersen R.Androgenicdeficiency in male rats treated with perfluorodecancic acid. Toxicol appl Toxicol 1980;104;322. 333. 66. Van Rafeighem M, Mattie D, Bruner R, Andersen M, Pathological and hepatic ultrastructural effectsof a single dose ofPperfluoro-n-decanocic acid in the rat, hamster, mouse and guinea pig. Fundam Appl Toxicol 1987.9: 522. 540. 67. The 3M Corporation ICPD.ProductToxicitSy ummarySheet 12251, FC-143, 1988, 3m`corporation: 68. O'Dell W, Swerdioff R, Bain J, Wollensen F, Grover P. Theeffect of sexual `maturation on testicular response to LH stimulation of testosterone secretion in the intact rat. Endocrinol 197495: 1380-1384. 69. Glass A, Mellitt R, Vigersky R, Swerdloff RHypoandrogenism and abnormal reguiation of gonadotropin secretion in rats feeda low protein diet. Endocrinol 1979;104: 438-442. = 03418  | | | -- 70. Cicero T, Schainker B, Meyer E. Endogenous opiods participate in the regulation of the of the Hypothalamic-pituitary-lutenizing hormone axis and testosterone's negative feedback control of Iutenizing hormone. Endocrinology 1979;104: 1286-1291. 97. 71. Moore R, Jefcoate C, Peterson R. 2,3,7.8-tetrachlorodibenzo-p-dioxin inhibits steroidogenesis in the rat testis by inhibiting the mobilization of cholesterol to cytochrome p4S0ssc. Toxicol appl Pharmacol 1991 1109: 85- 72. Bookstaff R, Moore R, Petersen R.2.3,7,8-tetrachlorodibenzo-p-dioxin increases luteinizing the potency of androgens and estrogens as feedback inhibitors hormone secretion in male rats. Toxicol Appl Pharmacol of - 1980;104: 212-224. 73. Spink D, Lincoln D, Dickerman H, Gierthy J. 2.3,7,8-tetrachiorodibenzo-pdioxin causes an extensive alteration 0 17 beta-estradiol metabolism in MCF-7 breast tumor cells. Proc Natl Acad Sci 1990:87: 691 7-21. 74. Egeland G. Serum Dioxin 23,7,6,TCDD and total serum test. and `Rgeosneaadracthr,opAinnnsuianlocmceueptaitnigona1l9l9y2.ex1p99o2s.edMimnennea.poinliSso,ciMaNt:y for Epidemiologic 75. Gutshall D, Pilcher G, Langley A. Mechanism of the serum thyroid effect of perfluorodecancic acid (PFDA) in rats. J Toxicol Environ Health 1989:28: 53-65. 76. Gutshall D, Piltcher G,LangleyA. Effects of thyroxin supplementation on the response to perfluoro-n-decancic acid (PFDA) in rats. J ToxicolEnviron Health 1988:24: 491-498. 77. Kelling C, Van Rafelghem M, Menahan L, Petersen R. Effects of pPehrafrlmuaocroolde1ca9n8c7i3c6a:ci1d33o7n-1h3e4pa4t.ic indices of thyroid status of rat. Biochem ~-237 03419 | ! i | o | 78. VoannthRyarfoeidigshtaetmusM,inIrnaths.omToSx,icPoeltearnsdonApRp.lEPffheacrtsm o1f9p8e7r.f8i7u:4or3o0d-e4c3an9c.ic acid 79. GtuhtysrheaildlaxDi.s.Th1e98e5f,feWcrtisgohftpSetraftieuoUrnoi-vner-sdietcya:noic acid on the rat pituitary 80. TpheortftlausosreorocytJa,ncWiicnabceirdg-iL.ndYuocuesdsef J, Cunningham M, Badr M. Regulation of hepatocsliular growth by adrenalPehroorxmiosnoemsa.l eHnepzaytmoeloagctyiv1i9ti9e2s;a15n:d316-322. 81. Just W, Gorgas K, Har F, Heinemann Biochemical effects and zonal P, Salazar M, Schimassek H, induced by perflucrocarboxyiic haectiedrsoginenreatitlyiveorf, pHeerpoaxtiosloomgeyPr1o9l8i9f;e9r:a5t7i0on-81. 82. Lazarow P, Shio H, Leroy-Houyet M. Specificity in the actionof dhiyspsoolciipaitdeedmifcrodmruhgesp:aitnocmreegasaelsyaonfdppereorxoixsiosmoalmeB-porxoildiafetriaotnlioanrgineltyhe rat, J Lipid Res 1982:23: 317.326. 83. ErleigauslsaetnioKno,fOtshmeucnldosfeibnraHt.e-FdaecpteonrdsewnthiicnhdumcatyiobneofshiegpniaftiiccanPterreogxairsdoimnagl 8oxidation and hepatomegaly. Biochem Pharmacol 1984;33: 1023-1031, 84. Best M, Duncan C. Hypolipidemia and hepatomegaly from 642. chlorphenoxyisobutyrate (CPIB) in the rat. J Lab Clin Med 196464: 634- 85. Kawashima Y, Katoh H, Kozuka state on the induction of H. Differential effects of alteredhormonal by colfibric acid. acyl-CoA hydrolases and Peroxisomal Biochim Biophys Acta 1983;750: 365-372. B-oxidation 397-308. 86. RperodldifyerJa,tAorzsafmoortmf aD,noHvieglnictleasCs. oHfypcohleimpiicdaelmiccarhceipnaotgiecnsp.erNoaxtiusroem1e960;283: = 03420 | 1 | - 87. OastulmiiveTr,peHraosxhiismoomteosTb.yEDnih(a2n-cetehmyelnhetxoyf)fpahttthyaalactyel.-CJoABiooxicdhiezmin1g8a7c8t:iv8i3t:y in 1361-1365. 86. Vparontdeeinn aHneduvfeatltyJ,acNiedsbbiitndDi,ngStperroctheeilneinP.raItnhdeucptaitooncyofteAscbyyl-tChoeApbeirnodxiingsome proliferators perfuorodecanoic acid and ciofibrate. Toxicologist 1852:12:8 . 89. Issemann I, Green S. Activation of a member of the steroid hormone receptor 64s. superfamily by peroxisome proliferators. Nature 1990:347: 645- 90. Tugwood J. 1992:12:6. Receptor mediated peroxisome proiferator action. Toxicologist 91. ApbrdoelliifaetriaftiAo,n ParnedatmoV,duVlaatmieocnqofJ,raNtilisvseroncaRr,cRionboegrelnreosiidsMb.yP2e,r3oxisome dichlorophenoxyacetic perflucroociancic acid acid, 2.4.5 trichlororphenoxyacetic acid, and nafenopin. Carcinogenesis 1990;11: 1899-1902. $2. NhiespsaotoncRa,rcBianiolgeeBn,ePcrietyatofVp.eErroixxiosnoKm,eRparomleilferCa.toOrsn. tChheemmecBhioalnIinstmeroafctthe 1991;78: 235-50. 93. Takagi A, Sai K, Xposure 10 the Umemura T, Hasegawa R, Kurokawa Y. Shortterm peroxisome proliferators, perfiuorooctansic acid and perfiuorodecanoic acid, causes significant increases of 8- hydroxydeoxyguanosine in liver DNA of rats. Cancer Left 199157: 55-60, 94. HtarnedaltemernJt, wSietehdpeCr,flBuroardofoocrtdanBc,aTtheudromeasnnRo.t iInncdruecatisoenroaftepserofoxHi2s0o2mes by production in intact fiver. Toxicol Lett 1992:50: 61-68. Tas ' 03421  i o iA #8. Lsatrkaess.B,BGiroacyhTe.mSSmoicthTAr.anHsap1a99t0e;1p8a:ro9x4.i9s7o,me proffaration ang oxidative 96. LceolvlitfiDne,s.LiTsossiAcoTloaxincditAypopflpPehraturomraicnoalte1d9f8a6tt8y6a:ci1c.s11f,or human and murin 8 7- L1e0vpiltaDs,mLaimssemA.brPaonrafsu.orJinTaoxtiecofalttaynadciEdnsviartoenrHmeearlotchy1a9n8i7n-e205:43003d-y3s1b6i,nding 98. IPonhcotauaseneoTa,ttraewnasainntaidognsaodTi,uFmukpeursfhiiumoaroKo,ctSahnicamtoezoanwathRe,gE6Hftcot-lsiqoufisc-ocdriyusmtaling Physics Lipids 19o8f8c4i5pa:i2mi5t.o3y0i,phospaticyicholine vesicly membrane. Chem 99. LmLeoelcmkabotrsiaoPnn.eaMsni.dlesrtr.ucPtourrtalursbeanssiotnisviotfy omfeMmCbrSa4n0ebsoturnucdtutroepbhoysopphtoilciaplipdrobes: 1. J Membr Biol 1980;52: 1.15, 100. dNyineoalmsiacns.G.PrTohgeICmemllunSoulrf1ac7e7:.T3r:a5-n7s,membrane reguiation ofreceptor 101. c(PoiPmlFpcDohsAeir)tGio,onnG.ruatTtoshxheiaaclrotD8,-rLeacnegplteoyrsA,.aTdheenyelfafteectcsyocflapseerfaunogrof-antt-ydaecciadnoic acid l Appl Pharmacol 1987.90: 198.205, 102. TSWomixiginlceoorpluPAr.piSpnlhgaPihnhhYa.erPme5r1f7u8orYodceelclanmoeimcbarcaindeinaanctdivraetcioonveorfyaocfhtahnecnhealnfnoerl2.- ac 1986;85: 456-463, 103. OlosmopnosCt,iGoenoarngdemMe,mAbnrdaenresse,nTMo.xiEcfofleocgtisotf 1p9e8r3f.u3o:ro9gd,ecancic acid on cell 104 B1e9r8r3y:3G8.:T1h7e3-a1n8a4l,ysis of moraity by thesubjectyears method. Biometrics -- 20 C 03422  | | | o 105. BMioonmseodn RRe.sAn1a9l7y4s.i7s:3o2f5r-e3la3t2iv.e survival and proportional mentality. Comput 106. Miettinen O. Standardization of risk ratios. 1972;96: 383-388. 107. Cox D. 220. Regression models and life tables. J R Stat Soc (B) 1972;34: 187. 108. MfeatnrtoeslpNe,ciHvaeesntsuzdeilesWo.f Sdtiasteiastsiec.alIaNsCpIec1t9s5o9f;2t2h:e7a1n8al.y7s4i,s of data from 109. SAS. SAS Users Guide: Statistics. ed. Institute S. Inc., 1990. Cary, NC: SASInstitute 110. Kalbfleisch J, Prentice New York: John Wiley R. The Statistical & Sons. 1980. Analysis of Failure Time Data. 111. pBraemgmnaanncny.BA, mCoJulOabmGCy,nJi1a9n8g0;N1.37T:ot2a9l3a-n2d88f,ree teststerone during 112. RWeeiupltrlhoiedarumacsnt-imAoans.mhmmaanlNseH..wPnYe:orrsKkpn:eocbRitalivv,eensNiPenritelhsles,,mea1d8ls8e.8s:Te7hx2eu7aPlhypshiyoslioolgoygoyfof .752. 113. Juniewicz Effects on P, Oesterfing J, Walters serum LH, serumtes J. Aromatase inhibition in the dog. I. secretion, and spermatogenesist.osJtUerroolne19c8o8n;c1e3n9t:r8a2t7io-n8s3,1t.estosterone 114. Nishihara M, Winters C, Buzko E, Waterman M, Dafau M. Hormonal BriegouplhaytsioRneosf rCaot mLemyudnig1s9e8ll8;c1y5t4o:ch1r5o1m-e15P84,50-17a mRNA. levels. Biochem 115. JrTesBgaiuiol-laMCtoorhrreyismmCe1,c9hK8a6nn:oi2x6s1Gm:,s3Lo4uf71ns.at-e3r,4o7iD4du.ofgaeuneMs.isAciqnuciuslittuiroendoffeetsatlrraadtiLoely-dmiegdicaetllesd. 241 . 03423  16 Cat. Anciogon scion and no se accessouer, Koes 2 L eds. The Physiologyof Reproduction. 1988:1081-1120. New York: Raven Prass, 117. LesetnrgosgeeonpseinC.noKramtaolTa,duHlotrtmoennR.anCdonwvoemresni.onJofCibilnoIondveasntdr18o6g9e:n4s8:to2191. 2201. J | ! 118. MmiaclhenoavnidczfeJm,aFliesshmmoaknerJs..InIcn:reWaasledoNx,idBatairvoenmJe,teadbso.liSsmmookfinoegsatnroggens in Hormone-Felated 207. Disorders. _ Osford; Oxtord University Prass, 1950:197. . 118. sluspseermmtaanmilGbryepeenroS.xiAscotimveatpiroolnlofefraatomres.mbNaetrurofe t1h9e9s0t:e3r4o7i:d 6h4o5r-m6o5n0,e 720. TmouugsweoopdeJm,xsisseormemapnro|l,fAenrdateorrsaocntiRv,atBiunngdreelclepK,toMrcrPehceoagntiWze,sGarereesnpSo,nsTehe element in the EMBO 1992;11: inking 433-439. sequence of the rat acyl CoA oxidase gene, 121. pDerreoyxeirsCo,maKlreBy-oGx,idKatieonlpHal,tGheiwvareyl Fby;HagnioivielebfaemiGinl,yWoafhniulclwe,arCohnotrromlonofe receptor. Cell 1992;58: 875-867, 122. Robers S, Leydig cell NteutmtorT,s HbyaimnacrneasHi,nAgdgaomnasdTt,roStpoi!nsR.inSrDatZs.2J00A-m11C0oilnldTuocxeicsol 19908: 487-505. 123. 2Scnhdukciontt,rolGsoulbdjecEt,sR.iAscmh JC.PsSyecrhiuamtrpyro1l9ac6t7i;n14le4v:el8s54in-8s5o9n,s ofalcoholics 124. Wald N. Baron J. University Press, Smoking and 1850. 275. Hormone Related disorders, Oxford: Oxford = 22 03424 8 | [ | ! | o 125. fRoixkeirclLyacbaorreaitnoongeesn.icRtiyksetru/dayM oEfXFPG.-0124381iCnRra0ts0.1219T8w3,oTyheear3oMralCo(mDipean)ny: 126. AinmdeerrsvtoanltceHl,l SthesitmikciunlarM,tuCmaonrtserinHB.ATLhBe/cgrmoiwcteh. oJfNeastltrCoagnecneirngIuncsted1960:24: 1218-1237. 127. Due W, Dieckmann oestrogen receptor, Kp.roLgoeystVe,rSotneeinreHc.epItmomru,naonhidsitnotleorgmiecdailatdeetlearmmiennattsioinn of Leydig human tceesltlits.umJorPsa,thLoelyc1i9g89c;el1l57h:yp2e2r5p.l2as3i4a,, and normal Leycig cells of the 728. hCyapsetrlpelaWs.iaR:icahcaarsdesoanssJ.ocLieaytseidgwcietlhl tguymnoercsomaansdtimaetaancdhreloenvoautsedLeuyricniagrcyall estrogens. J Urol 1986:136: 1307-1308. 128. TtreaenrsdfsorKm.inRgogmrmoewtnhsfaFc,toDroarlripnhgatoinn JL.eyIdmimguncoalhlissdtuorcihnegmdiecavleldoeptmecetnitoonfotfhe at testis. Mol Cell Endocrinol 199063: R1-R6. 130. Handelsman D, Swerdloft R. Metab 1985;14: 69-124, Male gonadal dysfunction. Clinics Endocrinol 131. SpottaepnlteisalRo,fBaumrgmeosnsiBu,mKpeemrfsluWo.roTochteaneomabtrsyo(-AfePtFaOl)toixnictihteyraatn,dFtuernadtaogmenAipcp.i Toxicol 1984;4: 429-440. 132. Sfteappolre.sPRr.ogImCplrinopBeirolnRteorspr1a9t8at5i;o1n63ofC:da1t6a1c-o1n3c,erning teratogenicity: a case 123. DMi.xDoonulRl. JT,oxaidsc.rCeasspaornestetoafntdheDoruelp'rsodTuocxtiicvoelsogyys.tem.NeInw: KYloraks:seMnacC,miAlmadnur Publishing Co. 1986:432-477. 243 03425 I | ! | | . 134. Koop D. Oxidative and reductive metabolism by. cytochrome P450 2E1 FASEB 1992:6: 724.730, 135. Gordon D. HDL lipoproteins and ang coronary heart Atherosclerosis. disease. In: Amsterdam: Miller N, Elsevier eds. High Science Density Publishers B.V.,.1989:3-10. 136. SBtooylezrAT,, Keadpsl.owHietpz aNt.oBlioogcyhA:emiTceaxltbToeosktosf LfoirvLeirveDrisDeiasseea.se. In: ZakimD, Philadelphia. PA: W.B. Saunders. 1990:637-667. 137. Gitlin N. Clinical Aspects Enviromental Toxins. In: of Liver Diseases Zakim D,Boyer T, Caused by Industrial and ec. HepatologyA: Textbook of . LiverDisease. Philadelphia, PA: W. B. Saunders,.1990:791-821. 138. Hodgson M, Van Theil D, Lauschus K, Karp! M. Liver injury tests in harzardous waste workers:the role of obesity. JOM 1989;31: 238-242. 139. Ludwig J, Viggiano T, McGill D, Ott B. Nonalcoholic Steatohepatitis. Mayo Clin Proc 1980;55: 434-438. 140. DGieeshtlerAo,eGntoeordomloagny Z1,98I8s:h9a5k:K.10A5l6e-o6h2ol.-like liver disease in non-alcoholics, 141. Comish toxicity. H, Adefin J. Am Ind Hyg Ethanol AssoJc potentiationof halogenated 1966:27: 57-61. aliphatic solvent 142. Charbonneau M, Tuchweber B, Plaa G. Acetone potentiation of chronic liver injury induced by repetivie adminstrationofcarbon tetrachloride. Hepatology 1986: 634-700. 143. Rall T, Schleifer Gilman A, ef al, L Drugs Effective eds. The Pharmac in the Therapies of the Epilepsies. In: York: Pergamon. 1990:450-451. ological Basis of Therapeutics. New : 03426 ! 1 o 144. S11c3h3u-5c3k. M, Irwin M. Diagnosisof Aiconalism. Meg Clin of N A 1988;72: 145. dSrcihnukciknigtmMe,n.GriAffmitJhsPJs,yGchaiamtmrya1g9l8u2t:a1m3y9t;i2r2a7n-s2fe2r8a.se values innonalcoholic 146. Orrego H, Blake J, transpeptidase and Israel Y. Relationship mean urinary alcohol between levels in gamma glutamy! alcoholics while drinking and in withdrawal. Alcohol Clin Exp Res 1985;9: 10-13, 147. Bates 13. H. GGTP and alcoholisma: sober look. Lab Management 1981;19: 148. aChnadna-lYcoehuonlgonM,roFuetrirnegirlaabPo,raFrtoolriychteJs,tse.tAalm. TJhCelienffPeactthsoolf 1a9g8e1,`,s7m5o:3k2i1n-g2,6. 149. P1u9r8c0h4a1s:e4I5.4I-n4t6e8r,-species comparisons of carcinogenicity. BrJCancer 150. The 3M company R. Two Year Oral Toxicity/Carcinogenicity Study of FC. 143. 1986, Riker Laboratories: 151. `KheonrnmoendeytBh,eGrialpbye.rNisEoJn MA.1I9n5c7r:e2a5s6e:d7e1n9t.hropoiesis induced by androgenic 152. Steinglass P, Gordon A, Charipper H. Effect of castration and sex hormones on the blood of rats. Proc Soc Exp Biol Med 194148: 169. 153. Rishpon Meyerstein N, Kiticge T, Simone J, Fred W. The effect of testosterone 453-460. on erythopoistin levels in anemic patients. Blood 1968;31: 154. Aalnedxraongieanns.R.BlEoroytdhr1o9p6o9i;e3t3i:n56a4nd. enythopoiesis in anamic men following 245 : 03427 1 | !i | | o i i ! J 155. ShahidiN. Ancrogens and enythropoissis, NEJM 19732280: 72, 86. wPeasltaacsitoesroAnsCanmapnftihlaateL.onMchCelmuarteopRo,eiSstieisnianrn8o,rSmwaelrdmieno.ffRF.erEtfifteyctanofd Sterilty 1983:40: 100-104, 157: aCnudnrnoignegnhamamlGe,cSonitvrearcempainivVe,.TJhCoimnbEynJd,ocKroihnloelrMP.tTahbe1p9o7t9en:t4i9a:l5f2o0r.an 188: MEfafuecstsoJf,lBoongrstcheG,teBsotrosmtaecrhoenre Ke,naRnitchhatteer ,onLmeayleandreapcrkocGi,ciNiovecfkunWct.ion, Acta Endocrinol (Copenh) 197578: 373-384, 188. Tell G, Grimm coun, platlet cJro.unRt,,VaelnldarheO,maTthoecordtotrosceingaLr.eTttheesrmeolkaitinognsihnip of white cell adelescentsihe Oslo Youth Study. Circulation 198572: $71.97, 60: BHaumninsoHn.'AspPprrioncaicphletsootfheinptaetmiaenltMweidtihciannee.miaN.eIwn: YTohrok:mMGc,Geraaw,. acs, Hil1877:1645-1651, 61. HaanndsoetnheL,caGrdriiovmasucr.uaRl.t NriesaktfoanctJo.rsT.hIentrJeloaftiEopnishdiepmof13w9h0i:t19b:i8o8o1d-c0e8ll8,count 162 dveeLcabtioyoLrf Cmaomrpaiyo:n F,esGiuylnsnoRv,erV1o8koyneaasrsPf.rWohmittheebnlooromdacteilvlecoaugnitngas a study. J Clin Epidemiol 1990;43: 153-157, 63. Gb1l9ro3io2md-m1c9oJ3ru7.n.tB,foNrecaotroonnaJr,yL,ucgawnicgerW,.aPnrdoaglnlo-sctaiucseImmpoonratiatnyc,eoJfAtMhAe1w9h8i5t:e254; 164. Zalokar J, Richard J, Claude J. Leukocyte infarction. NEJM 1981;304: 465-468, count, smoking andMyocardial 28 03428 o , o 165. Friedman G, Kiatsky myocardial infarction. A,NESJieMge1l5a7u4b:2A9.0T:h1e2l7e5u-k1o2c7y8t.e count as a predictor of 168. Friedman Epidemiol G, Fireman B. The leukocyte 1991:133: 376.380. count and cancer morality. Am J 167. cKaarndnieolvaWs,cuAlnadredrissoeanseK,. WIinlsisgohntsP.frWohmittehebFlrooadmicenlglhcaomunSttaudnyd. JAMA 1982:267: 1253-1256. 168. fMaanctttoanrriaM,dyMsalinpriicnemeincVm,aKloesphoipnualnatPi,one.tAalm. LJeeuakrotcJyt1e9s92a:s12a3:co8r7o3n.a7r,y risk 169. mKroinsohcmyatnesE,inTrmoosrtbiLd,lAyabreonssaS.indSitvuidduyaolsf.thJeSfuurngctRieonsa1n9d82m:a3t3u:ra8t9i-o6n7,of : 170. TdiafyfleorerntRi,alGrwhoistseEb,loJoodycceellH,coHuonltl,aTnhdoFr,aPxri1d9e85N;.40S:mo1k7i-n22g,, allergy and the 171. Walter S, WaltarA. Smoking and blood basophils. Thorax 198841: 335, 172. Walar , WalterA. Basophil degranulation man. Thorax 1982;37: 756-759. induced by cigarstte smoking in 173. Walter S. Blood Basophil counts Res 1882.76: 317-0. in smokers and nonsmokers. Indian J Med 174. Walter S, Nancy N. Basopenia Res 1980;72: 422.5. following cigarette smoking. Indian J Med 175. iYnoeupshsoesfpJh,atleqwreecOe,ptCournsnbiyngpheraomxMi.soRmeeguplraoitiifornatoofrsh.epTaotxiiccoilnoosgiitsotl 1952:12: a7. = 03429 o | o o: 176. MRoonbiitnosroinngJ,thPeliefffeerctRs. oNfoxwentoabcihontoiclsogoinesifmomruunsee fiunntcotxiiocn.olJogAymstCudoilesT:oxical 1990;9: 303-317. 177. Tollerud D, Clark J, Brown L,etal. The effect of cigarette smoking on T cell subsets. Am J Respir Dis 1989;139: 1446-1451. 178. Dean injury. J, C In: omacotf Hayes A, J, Rosenthal G, eds. Principles Lust and er M. Immune system: Evaluat Methods of Toxicology. New ion of York: Raven Press. 1989:741-760. 179. Davis J, Davis R. Acute effectsof tobacco cigarette smoking ontheplatelet aggregation ratio. Am J Med Sci 1578:278: 138-1.43. 180. dFeusvteelropV,meCnhtesofebcrooroJn,arFryyaertRe,ryEldviseebsaeckinLthPelaytoeluentgsuardvuitv:alEfafnedcttshoef cigarette 198163: amoking, 546-551. strong family history, and medical thraapy. Circulation 181. bBeehlacvhioJ,r,McfiAbrrdinloelyBsi,s,BaunmdshPe.mTathaeleofgfyecitnshoafbiatcuuatlessmmookkeirnsg, on platelet Thiam Haemostas 1984.51: 6-8. 182. Murchison L. Fyfe T, Lows G, Forbes C, Efiecs of Gigaretts smoking on 184.`serum-lipids, blood glucose, and platelet adhesiveness. Lancet 19661: 182- 183. FitzGerald G, Oates J, Nowak J. Cigarette smoking andhemostatic function. Am Heart J 1988;115:267-271. 184. Renaud s, Blanche , Dumont D, Thavenon C, Wissendanger T. Platelet function atter cigarette smoking in relation to nicotine andcarbon monoxide. Clin Pharmacol Ther 1984;36: 389-395, 28 . 03430 o o i 185. EGapsriseodecenimaiMloi.lonP1e9wl9i2et;hg4,i5g;Naa7rj7e-et8in4es.osnmoT.kiGnegnidnear lfaerrgeecnocheosrtininpIlsartaeelle,tJcoGuinnt ang ss 186. PcoamcpklimcaantiMo,nsMoufstaainredroJs.cTihereosoilss. oSfepmliantelHeetmsaitnotlhe19d8e6v:e2l3o:p8m.e2n6t, ang 187. CMaerdtioal.19M8e1n;t4a8:P.36F6-l3e73o.f blood platelets in coronaryater cissase, Am.J 188. PheorrkmionnseR.leIvnevlesstaingdatpieonrcoxfyasmommoenpiruolmifpereartfilounoirnotohcetarnact.atTsexfifceocltoogine 1892:12: 38. 189. COchceucpkaotiwoanyalH,EpPiieemricoelaN,gyC.raNwefworYdo-rBkr:oOwxnfoDr.dRUensievaerrcshtyMPortehsosd,s1i9n8s, 190. `RsieecsosndJ.gReenearsasteisonsmbelnotodofsucbrsitiatiuatefso.r tArhteifsieclOerctgio1n98o4f:p8e:r4f4u.o5r5o,carbons for 191. TGhiemraapneuAt,icRsal.lNTe,wNiYeosrkA:, PTeayrlgoarmPo.n,Th1e95P0h,armacological Basis of 192. sBkuirnkabuWm,. HJoOeMgg18U7.3S;1y5s:ta3m5i-c41f.luorida poisoning resulting from a fuorde 163. Bodass.s HNe,pOactkonleorgRyA.: DTreuxgt-bIonockuocfadLivLeirveDiDsiesaesaes.e. Saunders. 1990:754-790. In: Zain MD,Boyer T, Philadelphia, PA, W.5, 194. KpeursfluiosroBd,ecVaanncdyeln-oHeupveerlfuJ,orPoeotcetrsaennoyRl.-CLoacfkoromfaetviiodneinncmeafloer ats. J Biochem Toxicology 1892.7: 25-36, and female 249 03431  o : : 185. eDpaiidWa,miKoluogry Lo.f pLalPaosrmtaetRe,stGousttaeiroJ,nsFalievveol-sGeinramridccCl,eC-aagggeidumieanA.. AThmeJ Epi 1981;114: 804-816. 196. sKmloeskgiensg La.nKdiecsagrebsoxRy,haCmioggrlaonbgiJn.:DAinscarneapleynsciiseosfbtahtewSaeecnosnadlfN-artaipoonrtaeld Health and Nutrition Survey. Am J Pub Health 1992,82: 1026-1029, 187. Sagone A, Balcerzak S. 1975.82: 512-515. Smoking as a cause of Erythrocytosis. Ann Int Med 198. Schwartz J, Weiss T. Host peripheral blood leukocyte and environmental factors influencing the count. Am J Epidem 1991:134: 1402-1403, 188. Yamell J, Sweetnam P, Rogers on the haemostaic system. Ciin S, eta. Some long term effects of smoking Pathol 1387:40: 808-913, 200. Fraser G. Preventive Cardiology. New York: Oxford University Press, 1986. 201. Hames C, combined Heyden S, Tyroler H, efect of smoking and Heiss G, Cooper G, Manegold C. The coffee drinking on LDL-HDL cholesterol, Am J Cardiol 1978;41: 404-410. 202. cGhaorlreisstieornolR.,AKtahnenreoslcWle,roFseiisrl1a9b78M:,30et:a1l.7-C2i1g.arette smoking and HDL 203. kOlnsoewnnGa,ssKoucsiacthioGn, dSteasfifogrnAd:BAqu,alGiutydmasysnudrsaennceSLm.etChurordiefro,rMoFcc.upTahteiopnoasltive health surveillance data. JOM 1991;33: 988-1000. 204. Lumang L 742.745. New diagnostic markers of alcohol abuse. Hepatology 1986:6: 205. CLaisptoeplrloitWei.n DPohyelneotJ,ypGionrgdoStnudT.y.AlLcaonhcoelta1n9d77b:l2o:od15l3i-pi1d6s0:,The Cooperative ~ 250 | : 03432 oo 206. vBoallutnrtaegeerPs,dBuerirnggBl,oHngagteerrsmtraalcnodhoI.lAienrtaatkei.onE'uorfJliCpiidnmeIntvaebsotl1i9s7m7.i7nh:ea1l2t7.hy 131. 207. Lofinnudterintbiaonuaml dJe,fLieciiebnecrieCs..HNemEantgolJogMiecdef1e9c6t3s:2o8f1i: c33o3n-33in8,man in absence 208. Wmhairtkeerhseaodf aTl.cColhaorlkisntCa,keW.hiLtafniceledtA1.87B8i3o:ch9e7m8i-c9a8l1,and hematological 209. SakbiunsneerusHi,ngHollatboSr,aStcohruyltleesrtsR,anRdoyaJh,isItsorrayelofY.trIdaeunmtai.fiAcantiionofofInatlocronhMo!ed 1984;101: 847-851. 210. tMroaunssspaatviidaanseS,anBdecckherronRi,cPailecophmoelyiesrm.J.DiSgeDriusmsgciam1m9a8-5:g3l0u:ta2m11y,t o 211. MivaetrofdfisDe,asSea.liGnagsetrroMe,nKtaerpollaongyM.19H8e0p:a7t8i:c t13r8a9n-s1a3n9i4m,ase aciiviy in alcoholic 212. ChaonrimkonJ.eTbhieoseyfnftehcetsoifssimnovkitirno.g Ionn: WhaolrdmoNn,eBalreovnelsJ,iendvsi.voSamnodkistnegroaindd * `Hormone-Realted Disorders. 213, Oxtord: Oxford University Press, 1880:208- 213. PEanrddoriRdegevW1.98T1:r2a:ns1p0o3r-t1o2f3.protein bound hormanes into issues in Vivo, 214. Anderson D. Sex-hormone binding globulin. Clin Endocrinol 19743: 65-66, 215. Rosner W, Aden D, Khan M. sSteroid-binding proteins by a Hormonal influences on the secretion of human hepatoma derived cell line. J Clin Endocrinol Metab 1984:53: 806-808, _ 25 l - 03433  od 216. Joseph D, Hail S. androgen binding pYraortbeirno.ugAhnnw,NYCorAtciaMd,SFcire1n9c8h8;F.53S8t:ru3c1t-u3r6e.of the rat 217. `AphlooanrsommoanT,el.KeuvJrelaCslcihonifEtKne.dsoMtciorszitunetoralonniMe,Se,tIoaurtbaeln1.i9z7iI2nng;fl3hu5oe:nr5cme3o5no-fem5,a4j2a,onrdsfuorllgiiclceSatlismturleastsinogn 218. Gidlow in D, Church J, Clayton B. Hematological and biochemicalParameters an industrial workforce. Ann Clin Biochem 1983:20: 341-348, 219. Anderson K, Rosner Protein/carbohydr `W, Khan M, et a.Diet-hormoneinteractions: Stceist1o9s8t7e.r4o0n:e a1n76d1ac-to6er8t.israotlioanadltetrhseirrerceisprpoeccatlilvyetbhiendpilnagsgmlaoblueivienlss oinf man, Life 220. Reed M, Cheng R, add Simmonds M, Richmond W, James V. Dietery lipids: an itional regulator of plasma levels Endocrinol Metab 198764: 723-729. of sexhormone binding globulin, JClin 221. Bishop D, nutritional Meikle factors A, Slattery M, Stringham J, Forg M, West D. The effect of 43-59. on sex hormone levels in male twins. Gen Epid 19885: 222. iMnidcohlneo-3v-iccazriJn,oBlriandhiuomwaHn,s.InJdNucCtIio1n9o9f0e8s2t:ra9di4o7l-m9e4t9a,bolismby dietery 223. eSxuetrtcoinseJ., CBorlMeemdanJ M1,87C3a;1s:ey52J0.-A2.ndrogen responses during physical 224. Nilssen O, Forde . Brenn T. The Tromso Study. Populatio the distribution and 318-326. n determinants of amma-glutamy! transferase. A JE 1990;132: - --252 03434  o . - 225. MKueleiivnabraautmeDTGe,chKnuipqpueers.LLB.elAmpopniti,edCRAe:gLreisestimoen LAenaarlmyisnigs aPnubdliOctahteirons, 1978. 226. GeixlpboesrutrEe.s.SoAmmeJcEopnifdoeumnidoilng19fa8c2t;o1r1s6:in 1t7h7e-s1t8u8d.y mortality ang`occupational 227. Fox A, Collier F. Low mortality rates in industrial cohort studies due to selection for work and survival in industry. BrJ Prev Soc Med 1976:30: 225-230. 228. BinrSeselvoawn Na,reCahs.anIntC,J DChanocmerG.19o7t7a.l.20L:at6e8n0t-c6a88r,cinoma of prostate at autopsy 229. NEpoimduermiaoAl,1K9o9l1o;n1e3l: L20P0r-o2s2t7a.te Cancer: A current perspective. Am J 230. NJaothunraaslshoinstJo,ryAdofalmoicaHl,izAenddperrosstoantiSc,cBaencragrs.trLoamncRe,tK1r9u8s9e:mo79U8,-K8r0a3a,z W. 231. M1e8i9k0l;e17A:,7S0m0i.t7h18J., ___Epidemiology of . prostate cancer. Urol Clin N AM 232. Percy C, Stanek E, Gloeckler L. Accuracy of cancer death certificates and ts effect on cancer montality statistics. Am J Public Health 1981;71:242-50. 233. Rosenberg H. Improving cause-of-death statistics. AJPH 1989;79: 563-4. 234. Kircher T, Nelson J, Burdo H. The autopsyas a measure of accuracy of the death certificate. N Eng J Med 1985313: 1267-73. 235. C1a2r8t6e.r J. The Problematic death centificate. N Eng J Med 1985;313; 1285- = 03435 o - 236. Rothman 1986. K. Modem Epidemiology. Boston: Lite, Brown angCompany, - 237. SoicecmuipaattyicoknialJ,exWpaocshuorled:earrSe,iDnteewmaarl aRn,ealtyaslesSimnockoihnogrtasntduddieegsrleiekeloyfto be confounded by smoking status? Am J Ind Med 188813: 55-68. 238. sRuosbtianisneJ.dAexnpeoswuarpeppreoraicodh.toMactahusMaoldienlfienrgen1c9e8i6n.7m:o1n3a8l3-y1s5t1u2d,ies wih a -- -- 254 03436 APPENDI|X PHYSIOLOGIC EFFECTS STUDY QUESTIONNAIRE -- -- 03437 Medical History Questionnaire a 256 03438 To sim Medical History Questionnaire = . -- = ---- r L Om w G0-- 7 [ T ee Sr rT ew e[mil o , mT re ------ ---- oe E-- r Se--nee OO | [Sae cmeem 0 Oat o 2 oo oo A 5 0 0 0 [sae |xowimann o ooo! S-- S-- " 8 9 o or .o oo TS SE A ---- . o og ooi co oo o 8tere mare -- 0 o [fZmee oo a 1 hone me-- n re ee 0OO0 | [nm2ekman 0 0 [acme 0ooo ! oo i1 roares resme 7 nae e OO OO | [x cxuemms 0 0 [xs---- oo oo o momrmyy EEE OO OO | oma cum o oo co 0t oe menS s Ee 0 0 swam so | gg i : ome ha ey o oo o! "Gmmeimnea OQ 0g or re oo 7 - . 03439  BESTCOPY AVAIIABLE 1 tren Ia -- cj Sf -- SEE mEmmmmae WG a ---a fo---- Tf Ems [I] Hmmee---- Of Jpg amen, SE Et =| ---- ~ gm i gz. of | EEEEE mos moma wo of EEE. BEE, Emm WT Jenin SEE || rEr RE, oLJf ) sens ZC g = Doe Dem Dower (| gFrReReEnEeER.LC|mTr"eel--im----Bo im mne | snmmam-- `grim Gm oe SEREnI |TEn Brmmer FEEEET EE. 3M 258 ~ 03440 APPENDIX 2 TABLES OF HOSRTMAOTNUES,RAANTIDOASLBCYOBHOOLDYCOMNASSUSMIPNTDIEXO,NAGE, SMOKING - oF 03441  Fre 0B 3 om mm ra o TABLE A4.1.1 BOU(NTDB/TTFE)SBTYOSBTOEDRYOMNAESTSoIFNRDEEXE,TAEGSE.TOSTERONE RATIO 3M CH1980PESRMFOLKUIONRGOACNHDEDMRIICNAKLINEGSFFTEACTTUSSSTUDY, EMOLITE PLANT, COTTAGE GROVE, MINNESOTA a mw N MEAN SD MEDIAN RANGE TESTS 5pBMd%I fey 5 7 7as2 [3 503016 bt] II nz emisees pa, srs a3aA1rG4s0E 550 a2P a214 35a3s072 aI3e2 loeermmaess Faag 9s 550 Ws zie p<Atlocorozh)ol missing ias ' 13734 a0 a05n0 sn 2F2z ue mmisue;s roaad Tobaceo ees smoker missing z 2 as 7s 798 5 $2 moms px 7s ems TOTAL. ms Fare pra Ea ~ 280 03442  TABLE 44.1.2 BY BODYMA -ESTRADIOL 10 Fre e TESTOSTERONE RATIO eoSCSERINFDLEUX,AGE, (2/77) SM CHEMOLIT a E P LAGNRTO,CCEOSMTMIrOCaKAgILENEGarmApotNDuaDrMRcIISNNTKNUIEDNYSG,OS TAAT e-- ooMI i" mee N MEAN So MEDIAN RANGE TEST# Zz 7 H Be ow a m3 LoEn ew 8BaAG%eE pi i3= * m BEoooE mm iaomw mwamn has oe ASlicoohaol H" Mm Zoom 3% ommenn missing Tobacco : H= owe Iaa onSHmeEamA rg 0g smmnioosnsksiemnrgoker z4z4 w m A o om m IiEmE og re @oru " open Furvaraie Arov "Student test, Prob>T ) -- i 7 or 9% 5 = _ 261 - . 603443 TABBYLEBAO4D.1Y1.93M9AE0SSPTSERRIANFDDLIEUOXGL.RTAOGOCEBH,EOSMUMINOCDKAITLNEGESFTAFONESDCTTDESRRISONTNKUEIDNYRG,ATSITOA(TEUBS ) 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA ----m -- N -- a MEAN-- _0 _e SD--MME-- EDDIIAANN-- RARANNGG-- EE TET-- ESSTTH# <BM5I 2235030 5 6538 a26n8 5s57 n22e13s6 rpayz " 0 201 7 371es aArGE a31s40 a2 66 217m 5598 B30E9S5 pFoeg0g7 5150 21 e6s4 32758 550 2137111480 <Atloczodhol mi1s-s30i2ng 65s 215908 I57 o12i14s4 pFusgse C s ee 345 se 3813s `Tsmoobkaecrco 7 minsosnismnogker 84 65s9 228m0 6510 n22e13s4 Fpaxo 2 tg 155 br) 37144 TOTAL ns onwardsAreva -------------------- 262 . . 03444 o TBY BE ODY MAESSSTRIANDDEIXO.LATGOE.LUSTMEONKZIINNGGAHNODRDMROINNKEINRGATSIOA(E.11 3M 1980PERFLUOROCHEMICAL CHEMOLITE PLANT, COTTAGE EFFECTS STUDY, GROVE, MINNESOTA ELH N MEAN SD MEDIAN RANGE TEST# %BaBMeI FH7w =270 w aan owaHeaRwnme rreasg SaaiiAdsG5moE =aa poH78 ra mipars 2aas esi anme greasg mT"Aisloscazionhgol HA: "2H2 owaew ss a1B itteEmms Rfaaa msnTimoootrbkeaeanmrcgokceor a8z:4 7a7s0 aammon2 3iRssmed pa ToTAL 1m -- Ponwaae-- Aro ------------ -- _ 263 ' 03445 o T(TAFBALLHE)ABd.Y1.B51O8FD5RY0EPMEEATRSEFSSLTIUNOODSRETXOE,CRHAOEGNEM,EICSTAMOLOLKEUIFTNFEGNEICAZTNISDNSGDTRHUIODNYRK.MIONGNESTRAATTUISO 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA - N__ MEAN mSD nMEDIAN RANGE Testy =B2sM0I 57" akazos Ii752s) BoumX me a res mH aAtGE 3G1400 22a a2as3 25a5 aa3 aFsE Fora 5150 1 25 1h3n0 2257 =27 <$Atl3oc0uoudhdol "Na missing . 3a4 a o15r5d a3z2 o01m4ad rauves 1a as 2182 o sTmoobkaacrco nonsmoker 8z4 a2s2 missing 2 2 513 a22 e1m14s3 Fnaaz 3 23 pe TOTAL i EE -- 284 03446  TABLE A4.1.6 BOUND TESTOSTERONE Jo LUTENIZING HORMONE RATIO BY B3OMDCY1HE9MM0AOSPLSEIRITNFEDLEPUXLG,ARNATOG,CE.HCEOSMTMITOCAKAGILENEGGFRAFONEVDCET,DSRMISINTNKUINDNEYGS,OSTTAATUS - N MEAN _ m SD MEDIAN RANGE TEST aBsMI 255030 56 " h=a a5s79 110275 e38.m258 pFlurs 2 as 121 5199 <AaGE a31450 a2 2 =ur s7to 1116 2B288 pFounn 5160 1 1%01 a8s7 FH 2202808 <Atloczodhol 1-302d o1s9 missing n12e s5a7)1 22 B22a8 ppsu7m s wr a2 "2 En sTmoobkearcco 27 nonsmoker 84 11285 s5a2s4 1n2e1 uama pFaass missing 2 o 43 " EY TOTAL " #univanate Anova TT ------eeetm -- 265 03447 o BY BOTDAYBLMEALASUST.E1IN.N7IDZTEIHXN.YGRAOHGIEOD,RSSMTMOIONMKEUILRNAAGTTIAINONGD(HTDSORHRIAMLNKKO)INNEG TO STAT US 2M C1H9E8M0OPLEIRTFELPULGARNTO,CHCEOMTITCAAGLEEGFRFOEVCET,SMSITNUNDEYS,OTA N MEAN TSHLH x70 SD MEDIAN RANGE JEST# 25BasM3I0 ky 1 7" a3s2 a 2a5730m 33w 20 a o0s83o ruees a3A1rG4E0 5a1s% 22a baaey7 a2Tia6s5 2aFE1I vo10sr8e0 Fur is by 24 EC ver <$At-lo3cz0oiudhdol missing is ' aas a3 2br2 17 F a3s EReoS nsse ram sTmoobkaecrco z mnoonnsamoker 84 3w "0 om 2158 323 o0G4ee7ms rpoapm TOTAL 1" Funvannovaaie -- -- _ 26 03448 Ee -- LUTENIZTINAGBLHEOAR4M.1O.8NEFORLALTIICOLE(FSSTHIIMLUHL)ABTYINBGODHYORMONE TO SMOKING AND DRINKING MASS STATUS INDEX, AGE, 3M C1H9E8M0OPLEIRTEFLPULOARNTO,CHCEOMTITCAAGLEEGFRFOEVCET,SSMTIUNDNYE,SOTA a mmm ------ N MEAN So MEDIAN RANGE TEST# === av8 " omdwooeW vwe naa ouewnes preas BMI a"asArGaxiE 5a HBe swHoooeesods w aw f 0 um un ens rreaee . mT"iArsalsocoiuonhgol n8 V oeCO ose dEoa A aeumm o `rTsamosoebikaenmcrcoo 4z: s0 ofe0sk o8gs eeHesrEs Me TOTAL ms #univanate Anova = 03449 o TABLE 44.1.9 PROLACTIN TO LUTENIZING HORMONE RATIO (PALI) BY BODY18M5A0SPSERINFDLEUXG,RAOGCE,HESMMIOCKAILNGEFAFNEDCTDSRISNTKUIDNYG, STATUS - mm 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA N MEAN So MEDIAN RANGE TEST# a53BsM%I H7"i iiane i1T1i4 111m ooTimseadeenmr pfanp aaA1rG3x0E sis ax= 5s 2brT2o o1173m06 ie as uW Tee eocsas eeesnm Rpaasys oan pi<Alc0ohol ai missing ' 2un5 = 20104 an T1W0 GOosameseasnn Fmoarn Eee snTmooonbksaemcrockeor z!& OE2107 Ovo3rE omgon TM2omeassnen pFaoaws TOTAL m -- Nana-- s AoE-------------- Ce = 03450 o TABLE A4.1.10 BOUND TESTOSTERONE TO THYROID STIMULATING BY BODY19M8A0SPSERINFHDLEOUXRG,MRAOOGNCEEH,ESRMMAITOCIKAOI(LNTGEBF/ATFNSEDHC)TDSRISNTKUIDNYG, STATUS - mm 3M CHEMOLUITE PLANT, COTTAGE GROVE,MINNESOTA N MEAN SD MEDIAN RANGE TEST# 5#=BM0I w" =&20aEw R aa eeatEw rea aSAaGaoE a @g &==) = =m 4Wd an PI mameaadm res BL oom om om ome ore m<Aitlsscoseoainnhgol u5v ==a omm o mS om a mSaERw rRann Tookbaarcco 2 missing : w mn = i @ wens peor oo ah TOTAL "3 #univariate Anova o --- : 269 ) 603451 TBAYBLBEOAD4Y.1.M1A1SFSRIENEHDEOTXER,SMATOGONES.ETSERMAROTOIKNOIEN(TGToFA/TTNSHDHY)DRROIINDKSTIMULATING 3M C1H9E5M0OPLEIRTFELPULOARNTO.CHCEOMTITCAAGLEEGFRFOEVCET,SMSITNUINDNEYGS.OSTTAATUS N MEAN mw SD MEDIAN RANGE Testy aBsMI 3235% 30 6 7" n1ys 7[00 12078 137890578 rag 23 sos 0 20197 ogg aAGE pi3e140 a2" 113548 728027 108 61497 Fagg S160 129 a87 psro naer 7s 317792503 ploy 20213 <Atloczodhol 13024 a" missing 192s4 s1180s 18070 2007 frou s 182 238 23 s17o2w0s7 gly `nsTomonobskamecrokceor 2874 missing 2 1n2s5 a5503 18a g50a27r2 ouRn 17 759 17 e104 TOTAL m3 - ~WunvanateAnova ~ - 270 03452 T(AEB/TLSEH)A4B.Y1.B121O9DE9SY0TPMREAARSDFISLOIULNOTDREOOXT,CHHAYEGREMO,IICSDAMLSOTKEIIFMNFUGELCAATTNSIDNSGDTRUHIDONYRK,IMNOGNSERTAATTUISO 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA -- -- ----N---- MEA--N--E-- SISSDDH--MMEE-- DDIIAANN= RARAN_ NGAGNEEo _ TEu TSE_ sTTn #s aBsMI 5=% 5" 225647 14r0mt 22113 313810580 pFoazze 24 157 15a 77548 aA1GE o31s40 a2 x2758 11824000 2238 s97o50s0 Fpayz 160 %1 21882 11038006 116880 3T3a5s2s2 <Astlocoozzhdol missing *19 . 2214 11533008 210s0 318358402 pFluessy 78 am 25 104081 sTmoobkaecrco 27 mniosnssimnogker 824 2217 11588153 2B0d7 1r0e3r8e0 Fpgasz 1 15.40 71 13.4408 o TOTAL "3 "#univanatAenova -- mn -_-- 03453 EE B -- o HJ=EaA>e, Fo-- E h oE n5eBn eom wEne-- w 8eea TmaoaIO8mew-- mveeme8oeo8rwwwn-- m= eommeeamnmammsemir-- rrnoeeewmomw TABLE A4.1.13 THYROID STIMULATING HORMONE TO FOLLICLE STIMULATING HORMONE RATIO(TSH/FSH) BY BODY MASS INDEX, AGE, SMOKING AND DRINKING STATUS 1990 PERFLUOROCHEMICAL EFFECTS STUDY, 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA BMI N MEAN SD MEDIAN RANGE TEST# AGE TEIToEwboaCeccmo n wo B m&Wwemr smsemeemn rreanm SRToOTA--L --"--3 -------------------- -- 272 03454  TABLE A1.14 FREEHTOERSMTOONSETERRATOINOE(TTOF/FFOSHL)LIC-LE STIMULATING BY BODY19M9A0SPSERINFDLEUXO, RAOGCEH,ESMMIOCKAILNGEFAFNEDCTDSRISNTKUIDNYGS, TATUS 3M CHEMOLITE PLANT, COTTAGE `GROVE, MINNESOTA a ms N MEAN SD MEDIAN RANGE Testy aBsM =530 57 praais 22168 3B8 asoemnpiag 2a a aan 3aA1rG4E0 asi5s P"2y pr528 2a163n2 25a587 s 1o7r8ss e Fasoss kb 22 1a 2 ores <SAl3tcoodzhaol is missing 2238 " 22160 Te 3a7 a odmisae ars omgy me snTmooonbksaemrcokceor 6zE4 Haas BB 218778 1305 og01mn7es Foapn TOTAL " HoAenan ~ 2m 03455 o TABLE A4.1.15 BOUNHDOTREMSOTNOESTREARTIOONE(TTBO/FFSOH)LLICLE STIMULATING BY BODY MASS INDEX, AGE, SMOKING AND DRINKING STATUS 1990 PERFLUOROCHEMICAL EFFECTSSTUDY, 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA ---- N -- MMEEAANN -- mSeSDDw. N MMEEDD--IAANN--R_ R--AANN--GGEE--_ TJe--EsStT-- 2a5mi =0 i7 = wwom awss Wowww omsmamn rae SaA=aGsoE ae =Po 5 iw wow maFsEe]s 7 EA W Wao ma EBlE Saann no BE miA"Tsrlasocimwonshegol iPs: w=rmR ae nwe mmnaamm aes o smTnoooknbesamrcockaor 874 missing : w w = no si w7 o mmeams ohma TOTAL " ~ --#univanate Anova i. 274 ' 03456 T(AEB/LFSEH)A4B.1Y.1B6OEDSYTMRAADSISOILNTDEOXF,OALGLEI,CLSEMOSKTIIMNUGLAATNIDNDGRHIONKRIMNOGNSETARTATUISO 3M C1H9E3M0OPLEIRTFELPULOARNTO,CHCEOMTITCAAGLEEGFRFOEVCET,SMSITNUNDEYS,OTA ----N__ SDmw M MEDIAE N RANA GE TeN s N MEAN SD. MEDIAN RANGE JEST# 52 a5 57 5o7 sT4so &oTe kadiumyme bnEets BMI abAyhG)soE a8 FHiP "W&o isoen Fa8R8 ooua- imme rus =a mppAirlsocsion)hgol iw: wie iTsenm n 68 olaommi ohlo snTmooonkbseamrcokceor 624 missing 2 oosr ice 51 258 oGo amumen oRaRm 51 3289 TOTAL " Fonvanae AoA -- 275 . 03457  T(ATBSHLIEP)A4B.Y1,B17OTDHYYMRAOSISD SITNDIEMXU,LAAGTEI,NGSHMOOKRIMNOGNAENTDODPRRIONLKAINCGTISNTRAATTIISO 3M C1H8E9M0OPLEIRTFELPULOARNTO,CHCEOMTITCAAGLE EGFRFOEVCET.SMSITNUNDEYS,OTA - mw N MEAN So MEDIAN RANGE TEST# p2rBM5yI 3 5kd aaozxx oa0l12s7 0o0l1xs8 coooeoroemmr fy 3Aa1rG40E asis%o0 <Ailoczodhol m3i-s3si0ng 22a a0rxr 02% oaz0 ats is ox a2 ] ' o0z20 on aasazsn o01r5 oz sooeomasteasm rouaa Soom oor1 2 aaomomoeiismz rpiass o Tora smnTooonkbseamrcockeor missing 8224 oo0zi2 a0a2tsss 000112408 oc0mmosioicsz Fpaice `#univanate Anova i -------- -- -- 27 . 03458 o TABBYLEBOA4D.Y1.M18ASFSREIENDTEEXS,TAOGSET,ESRMOONKEINTGO APNRDOLDARCITNIKNINRGATSITOA(TTUFS/P) 1980 PERFLUOROCHEMICAL EFFECTS STUDY. 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA -------- LNH 2BsM3I 5 3% 7 MMEEAANN | SSDD MEMEDDIIAANN RARANNGGEE TETSESTTS# a325 proiaer 2129 ooeeesdness oruas 3aA1G4E0 iass 2a FS b2a2st i1z57 Te ti bl in 2210 20 oowrsesss pran Te ones SpAlrocevoahol missing isv z2o4 oi1r5x4s 22FE07R sso fxs eas snTmooonbksaemcrocksor missing 8z4 ? 22212 bp2xo 22109 urdsas7see oFaesss TOTAL 13 Fonvamae Areva ------ - -- ean . 03459 a tems te  TABBLYEBAOLD1.Y13MABSOSUNINDDETXE.SATGOES,TSEMROOKNIENTGOAPNRDODLRAICNTKIINNRGASTTIAOTU(STa.re) 1990 PERFLUOROCHEMICAL EFFECTSSTUDY, 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA ---- aE=BsMwI pSiiaAedGdoE ae m"SAisloosczioanhgol N MMEEAANN SD TB/P SD MMEEDDIIAANNRARANNGGEE TeTsEStTs# "57 "oo Fwwyos a@2 Ra maE CpEg ax3 5 x=5 waites 5a n78n Emzawas 8rm soa "i: ooa nnaeo w 67 g mmemc rNuEn amnTmiooosnbsksiaemncrogckeor 423 w an aEeaT @"mgmeams rn TOTAL 1" vanes Aoa -- 278 03460 BY B3SOMDLCYH1E9EM5MAA0O4S.PLS1EI:RTI20NFEDLEPEUSLXGT,ARRNAAOGDCEIH,OESLMMTIOCOKAIPLNRGOELFAAFNCEDTCITDNSRIRSNATKTUIIDNOYG,(SERT)ATUS T, COTTAGE GROVE, MINNESOTA N MEAN SD MEDIAN RANGE TEST# a=#Bs3M0I 71 i&o iimu0 aF4ERREuNaSreE pa psiAairttGoE seo =a= H a527 2ii2iz 8 0a@& id1v1a9es0 Fos 2m 2 Wu m<Aiosltscouiodnhgol i"v s"3o &2aan w 3a ainasaes pnegl srTmooonbksaemcrocaor 4z4 missing z aa2 I2e 2 gneass fGeEEn o TOTAL " a a WN Fara Ava 279 = 03461 o TABTLHEY4R4O.I2.D3SHTOIERMSUMTLORANATEDIINRGOALTHPIOROROSMLBOAYNCTETIPONTRAO(LLE/ASPC)ETRIUNM F(LTUSOHR)IDE: FOLL1I9CP5LR0EOPLSEATRCIFTMILUNUL/OALRTUOITNCEGHNEIHZMOIIRNCMGAOLHNOEER/FPMFREOOCNLTESAC(SPTTAIUHND)Y(,FSH/F) 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA N FLUEORmIDE sPetha 2" 21301108 215.26 1s5 5 TOTAL 3 seta 5310 2"a 18 1150-2165 TOTAL 55 na p@ry a" 51301105 1.s >1T5o.T2a6L "5 saeta aa 2103-1105 1.s 2T1O5T.A26L n5z "FunivanaiAenova MEAN ___ SD er asu so raemd as 3ss1s 118008 ar as oz TS4H1R 00224 001281 o02m4 000184 02 oz oosss 0F4u7p 052 00x27 0o3s8s oosms 003582 1usn oPsass 1s aium 30120 1w5r o1u5 - MEDIAN RANGE TEST CICS TESTE Taamimgsmrosez aRew 738 aivdro ao rosa 001217 om ooorteism oorass peaays 0037 oomzooaur oom 008%8 or oowa as oisass oFuyg o004@7 o ooie3misoe 117 145 ooumaammn owas Fpaapm mIZo ie omaann asa 284 03462 o TABELSTEAAD4I2EO4PLFAHODOLIRLOMILOCNLLEULTERAESTNTIIIOMNSUGLBAYLTTIGONRTGAGHLNOSEREM(ROU1NM%LFILUEsO/tRFI)DE. FOLLICLLE S1T9I8M0PUELRAFTLINUGORHOOCRMHOENMEILCUTENIZING HORMONE (FSHAK) 3M CHEMOLITE PLANT, COTTAAGLEGERFOFVEECT,MSSITNUNDEYS,OTA FUomniebe jSiethoasom TNoemaa 3 a TSNooertas N MEAN eSwD--lSMEDDINAN naRAnNeGeE EC aB l:` oEamawem ooiamd"rnmLnA Ha2i wm[o2m eIErWn am wo Go LfC mm dk gaa2mn8 G3 lwk15e1e-9nn0.as01 ew we gGyy mweIn nue EZ mx mTeJErST,# re Fas? ne 3Sahs fers sB a omWo o a Faargwan : we ooodnwe ocoanaealns epaa Toarat m: amwowgn "Forwarate Ava gtpn miciamee - 285 ' 03463 o - TALE hes HORMONE FREE STERONE/THYROID aLoATTIANLGTpHOR PASORIDE: BOUNDFTREESET'TEOSSTTORSOTNEE/RTOHNYERAOUITDESNTIIZMIUNLGATING MON (TF/TSH) HORMONE (TB/TSH) BOUN1D5T5E0SPTEORSFTLEUROORNOECLHUETMEINCIZINGHHOORRMMOONNEE(T(FTALBHH)) 3M CHEMOUITE PLANT, COTTAAGLEEFGFREOVCET,MSISNTNUDEYS,OTA FUToonriabe N MEAN SD MEDIAN TSH RANGE m3o1t0sa s nei Ia2` : uw w1os2o8o onLIX] 3i aw5o 4BSgsapsTE.dy Tori wo i ano en S= s fers aias : m " H a m w m Tm B/TSo HRwm hupeug jTeotra w: oo.5 = > F Gm iWw)ms Jauess Noetas "Ia: a3iz 3 iPiTsFAH 3F8ER mo gn ans auEn ToraL m:o i2B b3r 2Ws 0S 3 "a eSoes "i=: IjiHPe i TaaBH nwoo " wo ammmea Torat m: ow iz ga ymwe mGua roar Rg TEST# ee Feg3 npwg ea epBg 286 pu 03464 -_-- THYROIDTSATBILMEUAL4A.T2.I6NGHOHROMROMONNEERFAOTLILOISCBLYETSOTTIAMLULSAETRIUNGM HFOLUROMROINDEE.:(TSH? THYROID18S9T0IPMEURLFATLIUNOGROHCOHREMMOINCEAALUTEEFNFIEZCITNSGSHTUODRYM,ONE (TSHALH) 3M CHEMOLITE PLANT, COTTAGE GROVE, MINNESOTA LL N MEAN SD MEDIAN RANGE TEST# FLUORIDE . TSHFSH 3Soahlors es ai : oa0G4aeao2 af0ar2zx4y aa ar 0o0o48sn0 0co.a08awm.0rae.8asn9 Fm0m23 os ozam ToTaL "a oe an 0% Gores oy BE OE on on 3mhe Sots 2aW v a0o2a3 oe aaToSzmzHLH o0oan: an sa coaomieirn Rmomm amon JoerTeaL EA2 0r3d aazx ooaot cGoarion S3ah0a a"i iwnw TE22E7SH a37 in a 32 sGoaumrse eFaasm JTeorrea "s = in saa onvanae Anes 287 - 03465___ --_-- me Intercept Total Fluorine(ppm)* Alcohol # 14.51 ~.002 0) 87 0009 P-value 0001 02 . EReR e low (<1oz/day) nonresponse (NR) Age (years) BMI (kg/m?) Cigareties/day Cigs/day X Fluorine2** Estradiol (pg/mi) 22 56 001 01 01 "0003 01 ; of total fluoride 20 33 009 02 007 0001 008 27 09 88 5 : 20 0005 07 -- 03466