Document 37Gpw1gZ9JQMDVdJ5owE20bjn

Corporate OccupationalMedicine 3M Center,Building220-3W-05 St.Paul,MN 55144-1000 651 737 4'@30Telephone 651 733 9066 Fax 7. Serum Perfluorooctanoic Acid and Hepatic Enzymes, Lipoproteins, and Cholesterol: A Study of Occupationally Exposed Men. This isthe published paper (Gillilandand Mandel; Am J Ind Med 1996,29:560-568) from the Gillilandoctoraldissertatio(nseestudy# 5)thatevaluatesthe effectof PFOA on hepaticenzymes and lipoproteinsT.his studyof 115 occupationallyexposed workers examined the cross-sectionalssociationsbetween serum PFOA (measured as serum total organicfluorine)and hepaticenzymes, lipoproteinsa,nd cholesterolT.here was no significanctlinicahlepatictoxicitaytthePFOA (i.e.t,otalorganicfluorinel)evels measured inthisstudy. Based on multivariablmeodels, PFOA may exacerbatethe effect obesityhas on livertransaminasetestsand bluntthe effectthatalcoholhas on HDL levels.[Note:Inthreesubsequenttime periods,the findingsofthisstudycouldnot be replicated.PFOA, assayed by mass spectrometrymethods, did not appear inthis productionworkforce tomodulate hepaticresponsesto eitherobesityor alcohol consumption. See study48 below.] AMERICAN JOURNAL OF INDUSTRIAL MEDICINE 29:560-568 (19961 Serum PerfluorooctanoicAcid and Hepatic Enzymes, Lipoproteins, and Cholesterol:A Study of Occupationally Exposed Men Frank D. Gilliland, MO, PhD and Jack S. Mandel, Pho, mpH Perjliiortp(j(.t-iIci-ii(diPoFiOcA-) preidticn.i-tctsri-heecptaticeffe(.-iIivt.cliitliiit: liepcitfict.i,e.(-.,-.rtfeijtv.i%v'.Polipideistntiittdii,lterati(fi)fhteip(ifilci-l)id,netiihtsiliiisiiii iiiinibieer'aiiiinitivpec/iieirst.)detitPtF.OA ivtipero.Tivt@pnrt(eilifer(ltti(,)ir),idiiit-)e]r' ineinber(.ivfthe c.vio(.-liPr4f5)0mestiperfci,nciili.tovdtherettz.%-mie)sl%-olii-neivleittibi(iii(.- inerabolis)tnj.?ittitc-(@goifploeiridative apidma.vbe (ic-iittcp-retr)tttt)it-r. Aitht)i(PgFhOA isfilemujtjr(@rgan(jflticc)fr)tm'ptti)cii?zdf(ii.i-h(ittiidnctiltist.tlieif(inticitiott isavailablLe:(@iicerihtiiinmgcirtetvp(iiseitt)PFOA erp(icureT.itisvtiidt.jvj'1/5 epccstptitit)ti- all.evrp"sedk@-orkeerxvtimit?tehdecri).T.T-sectaivosrotcailtitiboetnits-eetPiFOA tt?iidtep(itic etj--vinlei.pco.prr)teia@ntd.T(,-IiolesteTri(t.etfli.ndingsindicatethatthereis -irs)ittitifil-atit (.-tinihceaplaticl-epriciant,thePFOA levelotbterveditthisstud,vP.FOA m(l.nvilpdilif(ille pretiousld.exs-cribedhepaticresponsesto obesim,and xetifobioric-vZ./9" KEY WORDS: perfluoroocianoaicid,human, hepaticenzymes,cholesteroHlD,L INTRODUCTION Littliesknown aboutthetoxicpotentiaolf PFOA in humans-.however. studieshave shown that the liveris an Perfluoroocmnoicacid (PFOA) is a potent synthetic importantsiteof toxicityin animals (Griffitahnd Lon&. surfactanthatis used in 2 wide varietyof industriaplro- 1980-,Kennedy. 1985; Kennedy et al.,1986: Pastoor et al.. cessesand products.Organic fluorinehas been found inthe 1987; Van Rafeighem et al.,1987, Justet al..1989). serum of 211human populationsstudied(Ubcl et al..1980; Animals treatedwith PFOA rapidlydevelop hepatome- Tayes. 197 1;Toves et a)..1976-.Guy. 1979. Beiisle,198 1). galy with focalnecrosisand shoa, marked hepaticphysio- Guy and Taves reportedthatPFOA was the principalor- logic responses that include hypolipidemia.peroxisome _eanicfluorinecompound in human serum (Taves. 1971, proliferationi.nductionof xenobiotic inetabolicenzymes. Taves et al..1976:Guy. 1979).PFOA is found in serum increasedhep2tictumor incidence.uncoupling of mitochon- because PFOA has a lone biologicalhalf-lit'acl.lowing ac- drialoxidativephosphorylation.and alterationisn iipidme- cumulationof small doses over time (Ubel et al..1990), tabolism (Grifrtthand Long. 1980: Kennedy. 1985; Kennedy et at..1986. Pastooret al..1987: Van Rafeighem et al..1987.Justctal..1989-.Takagi etal..199 1.Permadi et al..1992: Huughom et al..1992-.Sohleniu.-e;t al..1992- Dmwm OfEftVlrOnMO&MMI 0=03L-CMI he2M.SCHW Of"ic health, LvmnvsrtoyfMinnesotaM,nnotots iF.D.G.J..S.M.). Kelleret al..1992: Handier. 1992).Rat.%treatedwith PFOA Deoamemt c4InternaMledcm. Occupationaalr4 Environmentamlecone and otherperoxisome proliferitor(sPP%).such ar clorthmte. Section.SL PaulAsmsey MedicalCenter.St.Paul,MinnesotaiF.D.G.i. show ;150% reduction of -serumcholesteroland changes in "naen mamt r"um toFMk D.GiPiWndU.rwveMtyofNew MexicoSchool ,ocineE."em*iop and CancerConvoiProgram.goo Camm de smuc _the hepatic production and procc%.,ing of lipt)pmtein,,. JbuwAnwe. NM 87131. tiaughom et al. (1992) showed that the hypt)iipidemic re- AmeWA ftfowcaum April25.1225 %ponse result.f%rom downrevulaiion of HMG-COA reduc- Z 1996 Wiley-Uss.Inc. PFOA, Cholesterol.Lipoprottins,and Hel3aticenzymes 56) TABLE 1.Distnbutionof ExposedWorkers by Tout Strum FluonneCategoryin3M Chemokle Plant.Conagt Grove.MN Age SMI (kgVM2)8 Alcoholuseb <1 oztday 1-3 ovday NontesPonse Tobacco use" Smoker Nonsmoker Nonfesponse Total BMI,bm1y mus "a. $Vaiunam mun (SO). ovaivaaren lpement) <1 39.9(10.2) 27.6(5.3) 17(73.9) 2(8.7) O(D) 4(17.4) 3(13.0) 19(82.7) 1 (4.3) 23(100) 1-3 39.6(8.5) 26.6(2.6) 51(78.5) 13(20-0) 0(0) 1 (1.5) 16(24.6) 49(75,4) O(D) 65(100) Totalserum fluorin(eopm) 1..3-10 @,10-15 36.0(7.5) 26.3(3.3) 39.3(111) 29,4(3@7) 9(56.3) 4(25.0) 0(0) 3 (18@7) 5(83.3) 1 (16.7) 0(0) 0(o) 6(37.5) 9(56.2) 1(6.3) 16(100) 2(33,3) 4(66.7) 0(0) 6(100) >15.-26 41.6110.5) 26-011 4) 51100) 0(0) 0(0) O(D) 1 (20.0) 4(80.0) 0(0) 5 (1DO) Total 39.2 26.9 87(75-6) 20(174) 0(0) 8(7.0) 85(73.9) 28(24,4) 2(1.7) 115 mse. Inaddition.PFOA has been associatedwith hepatocyte TABLE 11.DistributioofnAge,Alcohol.and Tobacco Use inParticipants necrosisand increasedhepaticenzymes, suggestingthatir. by Body Mass IndexinStudy ofWorkers Exposedto PFOA reversiblecelldamage occurs (Kennedy, 1985; Justet al.. 1989).Hepatomegaly and alterationsin lipidmetabolism BMI MgAI2 APPC2r to be rapidly reversible.however. other hepatic changes are not rapidlyreversed (Perkins,1992-.Sohlenius <25 25-30 )130 et al.,1992). Based on findingsfrom the studiesof rodentsand in vitroexperiments.some investigatorhsave suggested that PFOA islikelytopresenta healthrisktohumans (Justetat., 1989;Takagi et al.,1991).If the observationsin rodent speciesare relevantto humans exposed to PFOA, itismasonable to hypothesizethatchanges in human hepatic enzymes and lipidmetabolism am similarto thoseobserved in rodents.Limited data am availableto assessthe hepatic responses to PFOA in humans. Ubel and coworkers (1980) and Griffitahnd Long (1980) mponed thatPFOA-exposed Tout Tobarco use Smoker Nonsmoker Nonresponse Alcoholuse <1 ovday 1-3 ovday Nonmsponse Age workers showed no clinicalevidence of adverse hepatic effects.FunherTnore,a retrospectivceohort mortalitystudy of exposed workers found no excess mortalityfrom liver cancer or liverdisease(Gillilanadnd Mandel. 1993).To assesswhether thechanges incholesterol.lipoproicinsa.nd <40 ysars 240 years Tout serum tiourhm Mean pom (SO) 41 (100-/.) 57(100%) 17 (1ODY.) 11(26.8%) 29(70.7%) 1(2.5%) 15(26.3%) 41 (71.gY,) 1 (1.8%) 2(11.8%) 15(88.2%) 0(0%) 31(75.6%) 6(14.6%) 4(g.8%) 43(75.4%) 11(ig.3%) 3(5.3%) 13(76.4%) 3(17.7%) 1(5.9%) 31(75.6%) 10(24.4%) 2 8(49.1%) 29(50.9%) 6 (35.3%r 11(64.7%) 2.3 (3@7) 4.0(5.5) 2.1(3.5) hepaticenzymes observed in rodents treatedwith PFOA occur in humans, we studied 115 occupationallyexposed employees ata plantthatproduces PFOA. Productionwork- - .DO. amt.boy mm mftz. ers with the highest PFOA exposures had serum PFOA levelssimilarto thosein rodents thatdeveloped hep2iome- MATERIALS AND METHODS S21y when treatedorallywith low doses of PFOA (Ubel et at..1990).We examined the cross..sectionasl%ociationbe- Subject Selection .en serum PFOA. a validatedsurrogatemeasure of total .rum fluorinea.nd cholesteroll.ipoprottins;.t.ndhepatic-- Participantswere recruitedfrom currentemployees ata enzynws inthisgroup of occupationallyexpo!icdmen. PFOA production plant thathas operitetisince 1947. The 562 C;illilanadnd Mandel TABLE Ill.Serum CholesteroLl-.- DensityLiDocroteiann.d Higti DensityUpot)rotaibny TotalSerum FtuoriaienStudyofWorkers Exposed to PFOA TABLE V. Serum Cholesterobly Booy Mass index Age Smoi;in;ano DrinkingStatus 3M CliemolitPelant.CottageGrove Minnesot2 Cholestero(lmvdll Totalfluoride N Mearl SO Median Range Test* k (%) Mean SD Median Range Test' crioiester(omfg/di) <1 PPM 23 zi-3 65 >3-10 is >10--ls 6 >15-26 5 Total il5 LOL (mgvdl) <1 pom 23 al-3 65 )@@10 16 >10-15 6 > 15-26 5 Total 115 HOL (mgvdi) <1 ppm 23 al-3 - 55 >3-1 0 16 >10-15 6 > 15--26 5 Total 115 201 211 206 226 214 210 132 136 134 124 143 135 45.9 46.1 41.8 46.5 45.6 45.4 34.7 40.0 37.7 40.0 27.0 38.1 32-4 34.5 34.5 44.0 20.8 33.8 11.7 10.0 10.2 6.8 10.2 10.2 203 212 198 216 204 210 137 131 133.5 139 144 134 47 44 40 44 49 43 132-268 130-349 150--277 183-298 184-244 130--349 F 066 p :.,62 70-196 7D-264 83-217 36-156 117-t7i 36-264 F - 0.31 p s .87 BMI C25 25-30 >30 Age S30 >30-40 >40-50 >50-60 Alcohol <1 oVd 1-3 oVd Missing Tobacco 41 f35@7) 195 40@l 186 57 (49.6) 219 36.2 220 17(14.8) 214 29.3 216 21 (18.3) 196 37.8 201 48141-7) 2.9 43.8 2D4 27(23.5) 216 30.2 216 19(16.5) 219 29.7 224 87(81.3) 209 38.6 204 20(18.7) 216 33.5 218 a 207 45.5 213 Smoker 26(24-8) 233 41.6 238 1o@-67 F 0.66 Nonsmoker 85(75.2) 203 32.9 203 3(@-79 p .66 29-68 Missing 2 19a 89.1 196 Total 115 40--Sg 29--54 19-79 AAOVL BMI. bodymass index. 130-277 146-349 163-268 130@-254 132-349 163-263 164-268 135-349 130-277 132-261 167-349 13(@-268 135-261 F - 5 10 p - .008 F @ 1,60 0 x .19 F @ .63 p - .43 F . 15.63 p - DO01 'Arca LDL lowdeftsilttyooorattHiOnL: highcenutylipoproten. period were considered highly exposed. This group in. cluded maintenanceand engineeringsupervisorsa.s wellas TABLE iV.PearsoCnorretatCiooenfficieBnathsveenTotaSlerum FluoridAeg.e,Body Mass Index.DailyAlcoholUse.DailyTobacco Consumpbon.and Upoproteins productionworkers.Forty-eigh(t96%) of50 exposed workersagreedtoparticipaitnethestudy.Inaddition.a sample of workersemployed injobs withno apparentPFOA exposurewas askedtoparticipatneo.se withoutdirectcontact CHOLESTEROL LDL HDL Total Age OMI Alcohol Tobacco with PFOA foratleast5 yearswere consideredtohave low fluori(dpepm) (yean) lkVm2)(ovday)(cilsavy)exposure.A randomly selectedlow-exposuregroup of - workers was frequencymatched in5-yearage groupstothe .07 .25 .19 Dg .35 high-exposureworkers.Sixty-rovemployees from jobs p - .0080 - .05 . .000, thoughtto involveno PFOA exposurevolunteeredforthe .02 .13 .06 -.008 .28 study.The toml number of the presumed unexposed em- - .00 ployeesinvitedtoparticipatweas not recorded-h.owever. -,01 .03 -.13 .18 -.09 few individualisn thisgroup declinedto participatWee. DB estimatethatmore than80% of thoseinvitedaemed to participatien the study. LOL.low-dentiltiyvagrottHiOnL:. high-otnsibtpyooroti"BnM:I@bodymass index. Tomi serum fluorinweas used as a surrogatevariable forPFOA exposure.We assayedtotalserum fluorinerather plantproducesa number of specialtcyhemicalsinaddition t.oPFOA. Detailsabouttheplanthave been describedpre- ously(Gillilanadnd Mandel. 1993).All worker,e;m?toyedin PFOA productionduringtheperiod1985-1989were invitedtoparticipaitnethestudy.Workers withjobs involvindgirecctontactwithPFOA duringthe 1985-1989 than measuringPFOA directlbyecausethea-,saywas less expensiveand technicalleyasierto perfonnon the large number of samplescollecteidnthisstudy.Furthermore.the use of totalserum fluorinheas been validatedasa surrogate rnarkerforPFOA inpartbiologicamlonitoringintheplant and otherplantsusingPFOA (UW etul..1980).Approximately90% oftotaslerum fluorinienworkerswas reported PFOA, Cholesterof.Lipaproteins.and HeDatic enzymes SE3 TABLE Vi. Serum Low DensityLiPoproietbny socy mass index Age. Smoiung.and DrinkingStatus3:M ChemolitePiant.Cottage Grove.Minnesota LDLlmg/dl) N (%) Mean SC Median Range T23V smi .c25 25-30 >30 41 (35.7) 130 22.8 133 7D-217 F - .65 57 (49.6) 138 34.2 135 36-264 p a .52 17(14.9) 136 33@O 137 71-196 Age 530 >30--40 21 (18.3) 130 29.6 131 75-177 F - .37 48(41.7) 136 36.2 135 70-264 p - .77 >40-50 27(23.5) 133 34.5 135 36-193 >50-M 19(16.5) 140 32.3 137 20-196 AJeohol <1 ovd 87(81.3) 135 34.5 133 36-264 F x .01 1-33 oztd 20(ig.7) 135 31.4 137 78-217 p a .93 Missing 8 134 35.6 141 70-174 Tobacco Smoker 28(24.8) 152 35.6 146 99--264 F - 9.42 Nonsmoker 85(75.2) 130 31.3 133 78-217 p - DD3 missing 2 115 55.9 115 7D--174 Total 115 aanw& SMI.bodymass vftr.LDL lowdensayhmmtotfi. TABLE Vil.Serum HighDens'rYLipog)rotLb4ynSOCY Mass Inaet Agi Smoking.and DrinkingStatus HOL Imgjdl) (%I Mean SO Median Range smi @C25 41 (35,7) 46.0 10.7 43 25-30 57 (49@6) 45.6 10.5 44 @,30 17 J14.8) 43.6 7.7 43 Age S30 21(18.3) 43.5 14.3 40 >30-40 48141.7) 46@7 9.9 46 >40-50 27(23.5) 46.0 8.3 45 >5D40 19(16.5) 46.6 7.9 43 Alcohol <1 oz/d 87(81.3) 44.3 9.2 43 1-3 oVd 20(ig.7) 49.3 13.5 45 Missing 8 48.3 9.3 53 Tobacco Smoker 28(24.8) 44.3 8.9 43 Nonsmoker 85(75.2) 45.6 10.6 43 Missing 2 54.5 21.2 55 Total 115 1948 22-79 32-55 19-79 22-65 29-61 32-67 19-65 29--79 32-55 29-68 19-79 53-56 Test, F . .38 0 - 69 F . 72 1)- 55 F 3.88 @05 F .35 p .56 $ANWL SIAI.WdY MUS MCer, NDL highdertsihtoyopmton. (LDL). and high-densitlyipoprotein(sHDL). The blood to be inthe form of PFOA (Venkateswariu,1982).Because sample for totalserum fluorine(TSF)was collecteidn a the vastmajorityof totalserum fluorineinplantemployees fluorine-ftr5e-eml Vacutainer. Divided aliquotsof serum isin theform of PFOA. totalserum fluorinecloselyreflects collected fortotaflluorinaessay were frozen at -70*C. serum PFOA inproductionworkers.and itsuse isunlikely After allwtal fluorinesamples had been receivedba.tches to inu-oducesubsmntialerrorinto the study. of 15 samples were assayed on successivework days. Total We expected the group of workers who were selected serum fluorine.reponedasa mean value,was deterrnined for the unexposed group based on job historyto have total using sodium biphenyelxtractioand atomicabsorption serum fluorinleevelssimilarto the generalpopulation.spectroscopy(Venk2teswadu.1992).Each sample was as. However. we found thatthisgroup of workerswas not sayed twice.Each batchincludedhigh-and low-qualitcyon- unexposed.having levels20-50 timeshigherthan levels trolsamples. reportedforthegeneralpopulationW.e concludedthatjob historywas notan accuratemetricforexposure.Because Analysis job historyperformedpoorlyforexposureassessmentw.e used measuredtotalserum fluorinteoclassifiyndividualisn StratifieadnalysisA.nova. Pearsoncorrelatiocnoeffi. the analyses. cientsa.nd linearmultivariatreemssionwere used toeval- Data Collection uateassociationbsetweenPFOA and thebiochemicalend. points.For stratiriaendalysesA.nova procedureswere used to assessdifferenceisnmean values.Totalserum fluorine Panicipantcsompleteda medicalhistoryquestionnaim. was divideda priorintofivecategories--<pIpm. 1-3 were measuredforheightand weight.and donateda blood ppm. >3-10 ppm. >10-15 ppm. and >15 ppni--basedon sample by venipunctumforassaysof totalserum fluorine. the distributiofn previousmonitoringdata.Al.,tb.ody rum plucamytoxaloacetitcransaminas(eSGOT). -,crum-m2ss index(BMI).alcoholuse.and tobaccouse were in,Iummyl pyruvictransaminaseISGPT). gamma glutamyl cluded inregressiomnodel% a.%potentiaclonfounder%.Numtr2nsfemse(GGTI. cholesteroll.ow-dtnsitylipoproteinsber of*cigarette.s,mokedper day was u%cd as a continuou!; 564 Gillilandand Mandel ABLE VIII.Untar MultivanateAegressionmodel of FactorsPredicting theHign I)ensitLyipooroiciinnStudyof WorkersExposedto PFOA Variable 0 SEIP) p volut TABLE X. PearsonCwrelationCoeflicientBsetweer.TotalSerum FluorineA.ge.Body mass index,DailyAlcoricUtse. DailyTobaccc Const)rnt)tiaonnd.HepaticParametersinStudy ofWorkers Exposed to PFOA Intercept Totalfluorine Alcohol' Low (<IOVDSY) Nonresponsive(NR) Low x totalfluorme' NA x totalfluonneb 65.00 -1.61 -9.92 -6.77 1.62 2.05 10.07 77 3.51 5.73 .80 1.63 R2 ,Aeftroxtcategoryisdnf*ecswho consun*d 1-3cz othanovday. bintermiontermstettv"ntotaflluonne&noaiconoctategory. Adpatedforage.bOCyMLU index.SmOluMg.and tESIOSteMfte. DOOI Total Age smi Alcohol Tobacco .04 fluorin(eppm) (vearst (kglmll (ovday) icigvaay) .006 SGOT 01 - 10 .09 12 .24 SGPT oi .01 .20 .03 .04 p - .02 .21 GGT -@04 12 .27 03 p - .004 SGOT.serumglutamiczaicacettircanuminase:SGPT. serum giutanucpyruvicIran. samiriasGeG:I.gamin gila" transocrasBeM:I.bmy mus index. TABLE IX.Serum GlutamicOxaloaceliTcransaminase.Serum Glutamic Pynmc Transminase.and Gamma GiutamylTr2nsteraseby TotalSerum FluorineinStudyofWorkers Exposed toPFOA TABLE Xi.Serum GiutsmicOxaloaceliTcransaminaseby Body mass Index,Age, Smoking.and DrinkingStatusin Studyof Workers Exposed to PFOA Totalfluorine N SGOT ([U/di) <1 ppm 23 ,ti-3 65 3-10 16 >10-15 6 >15-26 5 SGFRT(lwdi) <1 23 ti-3 65 >3-10 16 >10-15 6 )-15-26 5 GGT (ILVdi) @cippm 23 al-3 65 >3--0l 16 >10--15 6 >15-26 5 Total 115 Mean 22.5 24.1 25.8 25.7 22.2 47.7 51.3 53.0 73.2 44.6 37.2 32.4 35.4 38.3 22.2 33.7 $0 4.1 8.6 14@5 11.3 5.1 10.7 30.2 14.0 53.2 8.6 29.4 26.7 35.4 16.7 11.5 27.6 Median 22 23 22.5 22.5 22 46 45 50.5 52.5 42 27 25 26 36.5 20 26 Range Tese $GOT (tutdl) 13-29 10-74 17-77 17-47 14-27 30-69 4-263 29-40 38-177 34-U 6-117 5-174 10-158 19-M 11-37 5--174 F . 0.41 p - @80 F - 1.19 p -.32 F-0 9 p -,Sl smi <25 25--30 >30 Age !;30 >30-40 >40--50 >SO--60 Alcohol <1 ozfd 1-3oVd Missing Tobacco SMaker Nonsmoker Missing Total N 1%) Mean 41 (35.7) 24 57(49.6) 23 17(14.8) 27 21 (18.3) 25 48(41.7) 24 27(23.5) 22 19(16.5) 26 87(81.3) 26 20(18.7) 24 a 23 28(24.8) 24 85(75.2) 24 2 20 115 So Media" Range 12.4 22 5.8 23 8.1 26 12.7 23 9.1 23 5.4 23 7.8 23 13.5 22 9.0 23 4.3 21 8.4 23 11.0 22 3.5 20 13-77 10-42 17-47 17-77 10-74 13-40 14-47 16-77 1 O@-74 19-31 13-77 10-42 17-47 Test, F . .92 p - .40 F -'.78 p . .51 F . .61 p a .44 F - .02 p - .89 SGOT. serumgiutsmiocxiiacetttcransarranneS:GPT.strum giut3mcVMW Irao@- 'Anwa- samirme:GGT. gamma gtutamytiransitran. SGOT. serum Clutamiccxal*mtictrwununast:amt.oocymass index. variableif model fitwas improved compared with the relationshipswere evaluatedby comparing model fitusing model using cateeoficalvariables.BMI was categorized residualanalysisand by comparing parameter estimatesus- intothree cateeories<.25 kipim2.'-)5-30kglm'. and >30 keim-. Alcohol use was divided into threecatcrories:<1 k per day. 1-3 drinks per day. and no rcsFKinseto the ing indicatorvariablesand continuous variables.Interac- tionsbetween tota.lcrunmuorine and the covariateswere evaluated based on biologicplausibilityI,nteractionterms .;estionnairietem.and w2.-e;ntered intothe models as 2 set --were included in the finalmodel ifthe parameter esiimate of indicatorvariables.Signiric2nnotnlineardo%c-response had a p value SO.05.The two nonrespondents to the -;mok. PFOA, CholeSterot.Lipoproteins.and Hepatic enzymes 567 participant4swiilyS.GOT ;jiidSGPT increasedwith incrcus- pit(tilt)xBiencsa.use PFOA hus';ilt)n-h.i-t,)lt)-,hticlal-lilicn ill,P!FOA. The hyruithesitshit PFOA may nicxjulattehe hurtiansi.suhstirbedeasily.;indis hepjttii4)xicn r(xjents. hl:pu(icell-eci%%)I't)hL.Oitsyconsistentwith thesechanges in PFOA productionworker% h;ivt!been under medical %ur-vcil- en/.yiiiperofile.This hy;xilhcsishas hiolo,,,pilcausibilitylance formore than 20 year%. No ad%,ct,-c4linicaloutcomes ht-cau.wobesity h@L,b;een as.-;Lx:i:iwtietdh clcvutit)nof*Iran- relatedto PFOA exposure have been observcd inthese ern- ,-.jminasetshrough fattyinfiltrati(oLnudwig c( al..1990-. ployee.,@. Hodgson %!tal..1989).PFOA may dircctlyor indirectly Insummary. PFOA was not associatedwith the marked potentatethisell'ecitnsusceptibleindividual.%P.FOA alter,. hepaticchanges in humans thathave been observed in to- hepaticlipidmetabolism and may block the metabolism of dents.This rtndingisconsistentwith the resultsof a retro- accumulated fattyacids.resultingin an exacerbationot'the spectivemonality study that found no increasedrnonality pathologicprocess(Haughom et al..1992). from liverdisease(Gillilandand Mandel. 1993) and with PFOA MaV 21SO modulate the effectof alcoholon he- the resultsfrom an earliermorbidity study that found no paticmemboti;m. PFOA isassociatedwith changes in the advem hepaticeffects(Ubel et 21..1980).PFOA may mod- effectof alcoholconsumption on HDL levels.essentially ulatethe effectof alcoholuse and obesityon hepaticlipid blocking the risein HDL associ2tedwith alcoholconsump- and xenobioticmetabolism. Continued epidemiologic sur- tion.GGT was inverselyassociatedwith PFOA indrinkem. veillanceisappropriatein workers exposed to PFOA. Perfluoroocmnoicacid may decrease serum GGT by alter- ing cellmembrane permeability.by reducingthe alcohol- ACKNOWLEDGMENTS mediated inductionof GOT. or by changing alcoholoxida- tion pathways and reducing the productionof such toxic This study was supported in partby NIOSH grant intermediatesas acetildehyde (Bates, 198 1.Schuckit and T 150H07098-16 and ft 3M Medical Department. Griffiths1,982, Orrego et al..1985: Schuckitand Irwin. 1988).These findin-ssupport the hypothesisthat PFOA REFERENCES modulates the effectsof endogenous and exagenous deter- minants of hepaticmetabolism. Interpretationof these findings is limited by a number of factorsO.nly active workers in PFOA production were Abde.llatif A. Pmat V, Vamacq J. t4iLL%on R. Roberf")id M (1990); peroxy$arm proliferatiaonnd modulationof ratlivercamickosenesibsy 2.3. dichlomphenoxyacctic acid. 2.4.5 uichlororphenoxyacelic acid. pedluo- r,,,,,ic acid and na(cn*n. Caminotenesis 11:1999-1902. included in this study. It is unlikely that workers who had significanetxposure during the previous5 years would have Bates H (1981): GGTP 19:1-3. and alcoholism: A sober imk. Lib Managcnwnt been lost to this study because of transfer out of the PFOA Belisle1 (1991): Organic fluoride in human serum: Natural ven.us indus. productiondivision.Transfer as a resultof subclinical i,lsourceSsc.ienc2e12:1509-1510. changes in such biochemicalparameters as SGOT isun- likely.Because of the low tumover rate in plant employees GillilandF. Mandel J (1"3): Moculity among employees in a PFOA productionpiaol J Occup Med. 35:950-954. 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