Document N2V6nK3YnR87nKpnddGYOdL7E

SpecPiraoflH.seiGdlioHnvoaCdnihaoiunCoaoestLaavoro PaCUnnaittveeNrrasstgaaidiMo,agki1Si.3n7o1t3o11lVVLeadrEvooRnraAo cr coAHTAOoEnansari0:r33o8zs AR226-1866 Spett MDiIrTezEioNneS.A. Trissino (VI) Verona, 23.08.2004 Report on the meeting held on Friday 20* and Saturday 21" 2004 at the Inn at Montchanin Village (Wilmington, USA) with 3M and DuPont delegations. 1. Participants: ~~JGoehanryBOultseennhoff P~eLtaemryGZilolbieels -JGoehrnalGdrKeeennnedy ~~ RRoobbeirntLReiocnkaarrdd ~ Giovani Costa 3M, toxicologist 33MM,, oclcicnuipcaatlieopniadlemhieaolltohgipshtysician DDuuPPoonntt,, setxapteirsttiicnialnipid metabolism DDuupPoonntt,, teopxiidceomlioogliosgtist DMiutPeonnit,,otcocxuipcaotlioogniaslt heath physician 2. Background On August 9 I have been invited by G. Olsen (3M) to participate in this meeting, organised jointly with P. Gillies (DuPont), aimed at discussing the results of the analysis of the data collected by me at Miteni plant in Trissino, concerning the workers of the PF department. 1 fo ProfN.aGdilcoovaCnhaiirCoosta PaUnnt iovnedgargsoSitbts6a1 VVeEroRnaO CF PCRaGzShT0a0T n0u23D8eas As it was been agreed last year in the ambit of the APME-APFO ad hoc toxicological working group, I have started a scientific collaboration with them aimed at evaluating the data related to the periodical, biological monitoringofMiteni workers exposed to PFOA. Despite the small number of workers involved (compared to 3M and DuPont workers), such data were considered very helpful in understanding any possible interaction of PFOA with human physiology, as such cohort of workers has been checked regularly since 1979 by annual medical examinations, integrated by several blood and urine analysis. In the case of 3M workers, some workers (on voluntary basis) have been checked occasionaly (1993, 1996, 2000), whereas DuPont did ot carry out regular checksof such kind in the past, but it is now carmying on a general examination of more than 400 workers, the results of which are due by the endofthis year. `Therefore, the statistical analysisofMiteni data was considered very useful for checking whether or not any pre-clinical adverse effect could de detected, in order to better address the checks of larger groups at 3M and DuPont plants, and for further more detailed investigations on some specific biological parameters. So, in December 2003 (after discussion and agreement with Miteni general management in the meeting held in Frankfurt on November 21) I sent G. Olsen the first databaseofthe. biological monitoring of Miteni workers (in anonymous format) and, in February 2004, on occasionofthe SOT Conference held in Baltimore, I had a fist meeting with them and other 3M and DuPont experts (see my report dated 29.03.04 and abstract below) for a preliminary analysisofthe data. Thereafter, we decided to integrate the dataset with some more specific analysis conceming the lipids metabolism, that I collected during the periodical, annual blood check carried out in Spring this year. Consequently, two months ago I sent G. Olsen and P. Gillies two updated datasets (sill in anonymous forma), one concerning the biological data available since 1987ofall exposed workers to PFOA , and the second oneconcerningthe last blood analysis carried out in Spring 2004 2 `SpeciParloifsMt.sedGiniicoMoevdaCinhcininniauCgdooesitLaavoro PU2Cn2iav!etrNtsoiogtaaidrooo.gd1i5cS.i3n7atd15eiu1lVVLodaErvRooiOnrNaoA GF. FCNSxATGiGRhyT0as8us6nzs3o8zs 3. Preliminary resultsofthestatisticalanalysis `The analysis of the first database was aimed at evaluating any possible abnormality of biological parameters, occurred in the last 17 years, in relation to the PFOA blood levels measured in the last 4 years (2000-2003); the second one was aimed at comparing exposed and non-exposed workers to find out any difference that could be statistically associated to PFOA exposure. The statistical analysis, carried out by means of appropriate statistical programs by DuPont expert statisticians, confirmed the negative results for almost all the 37 blood parameters considered: in particular no significant effects were detected as concerns haematology, proteins metabolism, immunology, liver, kidney and prostate function. Only some slight effects on lipids metabolism were detected, which deserve further analysis and proper interpretations. In fact, a slight increaseoftotal cholesterol in workers exposed to PFOA was observed, which also appeared to show an increasing trend associated with the highest blood PFOA levels. Table 1 shows the comparison of exposed and non-exposed workers and the slight significant increase of total cholesterol in exposed workers. There is no increase of other lipids, such as tryglicerides in particular, but the fraction of "Non-HDL Cholesterol" seems that concemed. Figure 1 shows the positive correlation between total cholesterol and PFOA blood levels in the last 4 years (when PFOA was measured): a slight association between PFOA blood level and total cholesterol concentration seems to be consistent over the years. Figure 2 shows the same trend as concerns "Non-HDL Cholesterol". 3 ProMfe.dGiicoovCahninuirgCoosta `S`pCeactoiclrsotadiinMeMdeicciicniensdodlelLaLvaovrooro PaUnailvRorosgiahr (goii1sl5)S.sts3us7de1r5or1fVVEoRroOnNaA GF [ CST Gh in Onzsa Table 1: Comparison of the main lipid components in exposed and non-exposed workers to PFOA Estpons Manutcario Area Perna -_-- Serum Litas Tol oer! HDL Crotstrt LOL Creer Non HDI Chol! Non HOLHOL T--o_lT--righeardes Demographic Charsctrsin Noa-FrOA ness se ma ose 3202 wen Fron mes ous se 0x7 oss a ws on 39203 om 1ese = on we on J-_--r-- msti0 23201 [ET wrsis 27208 036x008 oss os oar 7 aVnadlems=areFxopRrwoeksehse mean SEM oraprosimacly n= 34 on. -PFOA wakes Due rom 200samplecollection 4 SPorotp ff,aGia oovgatnisnic yCeostLe aoov ora ome or heFmaooim Figure 1: Ew Correlations between Total Cholesterol ms (log) and PFOA. (log) levels inthe 4 years Hoo ef wn Lf ei Figure 2: Correlations between non-HDL Cholesterol (log) and PFOA (log) levels in the4 years d Hee r eL|f -- TREO wl eSTT Si we Ea s Prof. Giovani Costa *Speci Hogan se Lavoro GFycFoTAaECunaTaOrnRasos In the light of these findings, G. Olsen (3M epidemiologist) reviewed the 3M datasets elated to thir surveys carried out in 1993, 1996 and 2000, and a preliminary analysis concerning cholesterol levels appears to be in agreement with the Miteni data. In other words, it seems that PFOA (probably only at high blood concentrations) can interfere with metabolism of Cholesterol, in particular by increasing the fraction of "Non. HDL Cholesterol". Such findings need a precise interpretation, also because they are in contrast with the baneimraellaetexdpertoimeinnttearlspdeactiaes(radtisf),fewrhenecreesPiFnOdArucgaumseestaabodleicsrmea,sewohficchholaersetearloslolervaeilss.edThfaort ctahne diffrent findings in carcinogenicity (it is carcinogen in rats, but not in primates and humans). In order to elucidate beter the possible mechanisms underlying such effect P. Gilles, DuPont expert on lipid metabolism, made an updated review of the current knowledge on lipids metabolism, trying to make some hypothesis about possible mechanisms. According to his analysis, such effect cannot be mediated by a PPARalfa mechanism (as suggested for ats), bur it is probably due to an interference with a protein (CEPT) abl to transfer of cholesterol in blood and liver. He is going to have a deeper insight on such matter both by further discussion with the best academy experts on lipids and by a bio-molecular study concerning the nuclear receptors for such protein. 4. Communication and regulatory aspects Robert Rickard (DuPont) sid that is going to have a FYI ("For your information") `meeting with EPA next Wednesday, August 25. According to the TSCA Se rules he has 10 report to EPA any new data concerning possible toxicological characteristicsof PFOA DuPont may know, with particular reference to human health. He exposed his agenda, which includes an updating of the recent toxicological studies carried out at the Haskell Lab concerning the exposure of rats and mice to linea, branched ` poPero.rGciova aae nni nCos sta, A rwr gve iE rosns. vae SRT and mixed (linear/branched) PFOA, as well as the presentation of some ongoing studies, dealing with the health examination of more the 400 workers at DuPont "Washington" plant in West Virginia, and the review of epidemiological data concerning mortality in general population of West Virginia. G. Olsen and L. Zobel (3M) will also communicate their epidemIinolsougcihcaalgednadtaa choenwceorunlidngli3kM womreknetrisoant DlsecastuormeanfdinAdnitnwgserrpellataesto the dat on lid metabolism mentioned above, related to Miteni workers, keeping anonymous the source of data. In particular, he would like to report the positive findingsof a long lasting medical surveillance of workers exposed to PFOA, showing no effects on general health and also on biological parameters, concerning the main target organs and functions, except for a mild possible interference with lipid metabolism, which deserves further analysis. documentSo, he asked me whether he can report such data, in particular he would like to show one or two charts related to the lipid parameters (such as figures 1 and 2) in his presentation, `without mentioning the source and the name of|Miteni, and without giving EPA any written As replied that I could not deal with such request, but he must ask and get the formal spuecrhmirsesqiuoenstfrinomonMdietrenoi gMeatnyaoguermreenstp,ondsuee(twohattheevsehrorit ttiam)se asvoaoinlasblepohsesibalsek,ed me to pass you With kind regards Prof. Giovanni Costa 7 evo Cadi , Prof. Giovanni Costa *USnCivoerasuitctdMoiegdotigcSiiunoadcesolatVLaaarvaoovnraor P2aG1F.NCogTara(Gaiao1r5s.is3s7e1r9r1OnVzEsRaONA FAGTIOR 0s 8 ad hoctAbosxtircaocltogoyfgmryourpeop,orhtedladteindB2a9l.t0i3m.o04recoonncMearrnicnhg2t4h.e03m.e0e4t,ingof the APME-APFO 5.2. Workers. ccuormtemnetnecmTephdleooyCrehewaseirr(emAsaaanbhoinuotGtletadossethmhaabtsarjmukosstotnstoaafrtbtehldeoiotcdaonmldpevaeanlsikemesodnirmteeoprresisnoegmnteperdaodvignircatemhmeceoWnicGnemtihhenaigdr tothrhedeiirpnaadtraetaamtehiteneortushet1cw0oambyeestchfoaoltrlMetichtteeedAniPfraMonEmd g3trhMoeupwh;oardIkegdraosvn)ee. hiHinemthmeenypcaowsiutl,rlaaignnedgdnehaselslafclosoromtpahasatnk.iedesmetotsohcaor.e Solvay, in order IsAusggaelsstoedAstahhait aGlllaEsusroispesaenndsihnogulidtsjosianmpthlies ltaob,thperoGveidremdanthaltabit to limit the factors that can confound the results. already is quite used by reliable, 1Gioltlhieesin(tDAeursPacoctnoitno)nc;ewmistscheoluitrphidedatmeaen,tcIlaobisonelfdoirsmmreepidnortcthoelolgfarbooturhpaettihmoaentewwtieitnahgnaGlheyealsrdiyngOatltshMeaenrmr(iw3oiMtt)th arhneofdteerPleentcoeenr. (wDeudPnoents)d.ay moming with G. Olsen and J. Buthenoff (3M) and P. Gilles and G. Kennedy pinrvoittoecdolfoGhr.eacKidetincnunnleeadrtyebdcytoonLfatirhrreymgeJrdaontushpaetninD(utLPhaeownylteasrti)swsaetenakdr.tRinoOgbneirtWstebdRiinocmekosandriadtyo(rSeicvniegennaiccnecgoDr|idhrieancvgteotrob)otoohnef DuPont for exchanging information about the workers' biomonitoring (see attached repord AMetettaicnhgmewnitth1.G. Olsen and Kennedy (DuPont toxicologists) J. Butenhoff (3M toxicologists), Peter Gillies and J. taonxdiccoolnocgeiOrsnntitnWogeddtinhseecspuodsssasyitbh2le4e"pirnmetloeirrmnfiienrnaegrn,yce1foihfnadPdiFnagOs3A-ohfwoituthrhemldieapetitdaimnceogltlawebicottlheidswmii.tnhM3IMTEaNnTd wDourPkoenrts rLeDlaLtecdhotloGe:syteeOralorsl.e2n00h2avaencdar2r0i0e3d,ouwthaicphreslhimoiwneadryssotamteistpiocaslsiabnlaelyssliisghotftehffeecbtisocohnemHicDaLl daantda lipid compP.onGeilnltisesa(ndDutPheoinrtpoesxspiebrlteoinntleirpaicdtsi)ondewsictrhibPeFdOAth.e meaning of the different blood cbioonmvoennietdoArf(it0negradwadhilofcunhrgtihdseirdsucdeuaststaoio1en0ndatnhbdeyadAatpcarasrieeltf,uIlninatnhpaiaslrytssiiucsruvloaefry ttfhhuerotshpeerrerseaelnnaattleyddsaittsao,otfihtelihpoainsdgsobaiennedgn ptoroctleairnisfy(bLeDttLerCshoulcehstientreorla,ctAioPnO.-A2, APO-B, reactive C-protein) have been added in order decper stSatoi,stIicaalgraeneadlysinissending them such new data by the end of April and then start a endoftheThyeearr.esults are expected to be sent to a toxicology joumal for publication by the 5