Document QXdN61MbqeYrNddykXpOaaaR4

f #R226_27/6 3 | Maas. 2716 AMMONIUM PERFLUOROOCTANOATE: CROSS-SECTIONAL SURVEILLANCE INA COMMUNITY SAMPLE OF CLINICAL MEASURES OF GENERAL HEALTH STATUS RELATED TO A SERUM BIOMARKER OF EXPOSURE A STUDY PROTOCOL Preparedfor DuPont Haskell Laboratory Newark, Delaware Prepared by The Sapphire Group, Inc. Bethesda, Maryland 2 June 2004 -- TAOFBCOL NTEE NTS INTRODUCTION eee BACKGROUND... 1 A AnimalTOXICOIOZY oe vveeeeeieeeieeeiieeieeeieeeeinn 1 B. HumanEpideanmdExiposourleAsosesgsmeynt ...................... 5 OBJECTIVES eee T STUDY OVERSIGHT,SPONSOR,ANDTESTING FACILITIES .................... STUDYDESIGN .........ouiiiiiiieiiaieieaeaieaeeaeeeieaeeeeuenieees A SHAYOVEIVIEW .......eeeieaieeiiseiieieeieieeeeieie B. Community Sample ...............coceiiueiiiiiiiiiiineeinnn. 11 Co SAMISIZE o.oo. 11 D. RandomSelectionofthe CommunitySample ....................... 15 E. RandomDigitDialing Telephone Survey ........................... 16 "~ MATEARNIDMAETLHODSS .............eueiueeeiieaeeeninaenninaenes 18 A Test Substance/OEfIXntperoesst ure .............................. 18 B. ClinicalPathology Evaluation..................cccovieinine..... 18 HUMAN SUBJECTSPROTECTION.............oueieeieieeesineaenn. 21 REAC NDSO AMPR LESD TORS AGE ...........ccuuueiiiiaeieeaienaiinaes 22 PROPOSEDSTUDY DATES ...........ovieiiieiieeeieieaieinas 22 SIGNATURES... eee 28 - --_-- TT zum APPENDIXA ~~ COMPUTER-ASSISTED TELEPHONE INTE (CAR TD.V ..I ...E..WonI nnNG 30 APPENDIX B CONSENT FORM........ooovieiieeiiiiiiiiiiiiinn. 33 APPENDIX C CLINICAL PATHOLOGY COLLECTION PARAMETERS...........oooviiiiiiiiiiiiiiiiiiii3n7. APPENDIXD ~~ ELECTROCA(REKDG).I..O...G...R...A..P...H..3Y8 APPENDIX E AUDIOMETRIC EXAMINATION ...................3.9. APPENDIX F VISUAL ACUITY AND TONOMETRY EXAMINATION......oooiiiiiiieneneeeeeeeeeeeene.. 40 APPENDIX G COMPREHENSIVE MEDICAL AND WORK HISTORY QUESTIONNAIRE........oooon.. 41 APPENDIX H PHYSICALEXAMAI ND EN VALA UATT IONI ...O ....N 42 APPENDIX I EXYGEN STANDARD OPERATING PROCEDURE FORPFOAANALYSES ..........................4..3. HiProjecty6001pool\Community Study\ProtocolCommunity protocol_finalwpd --- TT Zumemm INTRODUCTION - Ammonium perfluorooctanoate (APFO) is a fully fluorinated carboxylic acidused primarily as the ammonium salt to aid in the emulsion polymerization of fluoropolymers. APFO and its salts are soluble in water and readily dissociate to the carboxylate anion, perfluorooctanoate (PFOA). As a result of the presence and biopersistence of PFOA in the blood of humans, the potential health effects of PFOA have been examined in occupational cohorts. Background levels of serum PFOA have also been measured in some general population samples, but no data have been collected in these groups to measure general health status. Epidemiological investigations and medical surveillance of occupationally exposed workers have failed to find any association between PFOA exposure and adverse health effects. However, toxicological findings in animal studies and the slow elimination rate of PFOA observed in humans combine to indicate the desirability of additional surveillance in the general population. "This study is being undertaken to provide additional scientifically-credibledatathat can be used to understand whether or not exposure to PFOA in the community, as measured by serum PFOA levels, is related to adverse health outcomes as measured by standard health screening examinations. DuPont has an external Epidemiology Review Board which will review this protocol, and - DuPont will provide technical be submitted for review and oversight approval for by the the durationofthe University of study. West The protocol will also Virginia Institutional Review Board (IRB). BACKGROUND `The following sections describe studies on PFOA in animals and in humans. A Animal Toxicology `The liver is a primary target organ for both short-term and chronic effects of PFOA in rats (Grif&fLiotngh, 1980; Olson & Anderssen, 1983; Kennedy, 1985;Pastooreral., 1987) and cynomolgus monkeys (Butenhoff ef al., 2002). The increased liver weight in both species does not appeartobe aresultofhepatocellular hyperplasia (no increase in nuclear DNA) and has been variously attributed to increases in peroxisomes, endoplasmic reticulum, and mitochondria (Ikeda ef al., 1985; Pastor ef al., 1987; Butenhoff et al., 2002; Berthiaume andWallace, 2002; Biegelefal., 2001).Higherdoses letoalivder degeneration and necrosis and the appearance in the serumof enzymes reflecting liver damage. - Tamm PFOA and other perfluoroalkanoic acids are part of a widening group of substances -- including plasticizers (phthalate esters), hypolipidemic drugs (clofibrate, nafenopin) and some herbicides (phenoxyacetic acids), solvents (trichloraonedntathuryalllye-onccuerr)in,g compounds such as long-chain fatty acids that are known as peroxisome proliferator- activated receptor alpha (PPAR) agonists (Ikeda et al., 1985; Just ef al., 1989; Pastor ef al., 1987; Cooker al., 1992, 1994; Biegel et al., 1995,2001;Cattleyer al., 1998).PFOAhas been shown to activate the PPAR receptor but not the PPARY receptor (Maloney and Waxman, 1999). As with all peroxisome proliferators (Ps), treatment of rodents with PFOA initiates a characteristic sequence of morphological and biochemical events in the liver and, to a lesser extent, the kidney. These events include: marked hepatocellular hypertrophy duetoan increase in number and size of peroxisomes, and consequently, a large increase in peroxisomal fatty acid b-oxidation, an increased CYP4SO-mediated w- hydroxylation of lauric acid, and a variety of changes in lipid metabolism (Ikeda ef a., 1985; Pastor et al., 1987; Berthiaume & Wallace, 2002). This response is initiated by the activation 1995). ofthe nuclear hormone receptor, PPAR (Green, 1995; Ashby ef al., 1994; Lake, There are, however, differences in the effects exerted by different groups of PPs. For example, PFOA did not cause hepatocellular hyperplasia like most other PPs (Pastooerfal., 1987); although the study design did not include looking at carly time points, such as 3-21 days. In rats, the hepatocellular response is primarily hypertrophic and is caused by an ~~ rientcirceualsuem.inInthaeddnituimobn,ertheorfe pisereovxiidesnocmeesfoarnpdroplriofleirfaetriaotnioonf moiftotchheonsdmroioatthhatemnadyo,plianspmaritc, account for increased liver mass (Butenhoff ef al. 2002; Berthiaume and Wallace, 2002), Peroxisome proliferation induced by PFOA affects fatty acid metabolism and cholesterol synthesis in the liver (Haughom & Spydevold, 1992). Serum cholesterol levels were reduced 50-70% after only 24 hrs inrats fed diets containing 0.02% PFOA, and triglycerols were reduced to about 60% of controls afte7r days. Measurements of selected enzymes in hepatocytes from the PFOA-treated rats showed significant decreases in HMG-CoA reductase, the rate limiting step in cholesterol biosynthesis, and in acyl CoA cholesterol cacoynlctlruadnesdfetrhaastet(hAeChAyTp)o,litpheideenmziycmeeffreecstpoofnsPiFblOeAfoirs tdhuee,eisnteprairfti,ctaotitohne orfedchuocleedstseyrnotlh.esIitswaansd. esterifoifcchoaletstierooln, combinedwith the enhanced oxidation of fatty acids inthe liver (Haughom & Spydevold, 1992). Kudo et al. (1999) confirmed the earlier observation by Pastor etal. (1987) that PFOA treatment increased the leveloftriglycerides intheliverand linked this with increases in two triglyceride synthesizing enzymes, glycerol 3tphheosipnhcorteraasnesfinertarsiegalnycdedriiadcesylignlytcheerloilvearcyalstwrealnslfaersasteh.eirItdaelcsroeasseeemisn ptohsesipbllaes,mhaowfeovlelro,wtihnagt Ctlreeaartlmye,ntPFwiOtAh PhaFsOtAheiasbailsistoycitoatdeidsrwuiptthlaipdidecmreetaasbeolinistmribgylyacenryidoef sseevcerreatliomnefcrhoamnitshmeslitvheart. -- TTT Ziman at the present time are not well understood. The importance of these, if any, in the toxicity ~ of PFOA is not known. A two-year chronic rat bioassay with PFOA indicates a significantly increased incidence of tumors (mainly adenomas)oftheliver,testis (Leydig cell) and pancreas (acinar cell) (Biegel et al., 2001). This is consistent with the fact that PFOA is a PP since, although most attention has been focused on PP-induced liver tumors, bothLeydigcell tumors (Cooket al., 1999), and pancreatic acinar cell tumors (Reddy & Rao, 1977; Svobodaand Azarmoff, 1979) areoftenobservedfollowing chronic expoosfruodrenets to other PPs. Ohmuraet al. (1997) showed that the peroxisome proliferator, d-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(Nbeta-hydroxyethyDacetamide (DR931), a potent hepatocarcinogen in rats, was capable of inducing DNA synthesis in pancreatic acinar cells, yet had no effect on ductal or islet cells. Induction of liver,Leydigcell and pancreatic acinar cell tumors is a common finding for PPs. (Cook et al., 1999). In chronic bioassays in rats, Cook ef al. (1999) reported that 7 out of 11 PPs inducedall threetumor types(Cook ef al.,1999), and 10ofthe 11 PPsproduced liver and Leydig cell tumors (Cook et al., 1999). The presence and established persistence of PFOA in human tissues, combined with the increased incidence of liver, Leydig cell and pancreatic acinar cell tumors in chronic studies with PFOA in rats, raises questions concerning the potential relevance of tumors observed in chronic studies in rats to potential `human health risk. tis generally agreed that liver tumors in rats produced by PPs are unlikely to be relevant to - humans (Bentley ef al., 1993; Ashby ef al., 1994; Cattley et al., 1998; Doull et al., 1999). A large number of humans have been treated for relatively long periods of time with hypolipidemic drugs that are potent PPs in rodents. No significant changes in the peroxisome number or volume ocur in humans taking substantial doses of these drugs for extended periodsoftime (up to 3 years) (Ashby ef al., 1994). Therefore, rodents appear to `bTeheporoerasmoondeflosr ftohrehunmona-nrersispkonassisveesnsemsesntofwihtuhmraensspectto tPoPlsiveirs enfoftectysetobfsuellryveudndweirtshtPoPosd.; although, research shows differences in amount and expression of PPAR: between humans and rodents (Cattley ef al., 1998; Palmer et al., 1998). Experimental evidence for the mechanism of PFOA-induced Leydig cell tumor formation, `while not conclusive, tends to support the hypothesis thata sustained increase in estradiol within the testes may be responsible for the increased incidence of Leydig cell tumors in male Sprague Dawley rats (Cook et al., 1992; Biegel et al, 1995; Liu et al., 1996a, 1996b). It was initially thought that PP-induced Leydig cell tumors arose by a mechanism similar to that suggested for liver (Cook ef al., 1992). Inthe chronic PFOA study, however, there was no evidence that peroxisomes were induced in Leydig cells and no increase in b-oxidation 2ac0t0i1v)i.ty aAbtotveenttihoennhoarsmaslubbasseeqluiennetlleyvefloc(aubsoeudt o2n0 ttihmeersolleessinthLaneytdhiatg icnellilvehr)yp(eBripelgealsiaet aaln.d, --- EE neoplasia of a sustained increase in the level of serum estradiol observed in PFOA treated -- rats (Liu et al., 1996a,b; Biegel et al., 1995, 2001). It has been proposed that PPs, including PFOA, increase serum estradiol levels as well as levels in the testis (interstitial fluid) via induction of the enzyme aromatase, a CYP4S0-mediated enzyme in the liver (Liu ef al., 1996b; Biegel et al., 1995, 2001; Upham ef al., 1998). Itis then proposed that the increase in testicular estradiol will modulate growth factors, specifically TGFa, to stimulate cell proliferation in the Leydig cell as it is known to do in other (e.., mammary) tissues (Liu er al., 1987). The suggested roleofelevated estradiol in Leydig cell neoplasia is still uncertain because estrogenic compounds do not induce Leydig cell tumors in rats. It is possible, however, that the failure of estrogenic compounds to cause Leydig cell tumors results from a depression of luteinizing hormone (LH) which has been demonstrated to be the chief driverofsuch tumors (Biegel etal., 2001). A second mechanism/pathway which has been proposed to be also involved in the formation of PFOA induced Leydig cell tumors is the inhibition of testosterone biosynthesis, which disrupts the hypothalamic-pituitary-thyroid (HPT) axis. In ex vivo studies with PFOA, exposure to PFOA resulted in an inhibition of enzymes critical to the testosterone biosynthetic pathway, which, if occurring in vivo, would subsequently lead to a decrease in circulating testosterone (Biegel et al., 1995). In in vitro studies, 13 PPAR agonists were demonstrated to inhibit testosterone biosynthesis (Liu ef al., 1996a). The decrease in testosterone levels results in compensatory increases in LH, increased binding of LH to the LH receptor on Leydig cells, thus resulting in increases in Leydig cell proliferation (Clegg - et al., 1997). In a two-year mechanistic bioassay with PFOA and another PPAR agonist, LH levels were not consistently increased, yet estradiol levels were increased at several time points (Biegel et al., 2001). This is consistent with PFOA inducing circulating estradiol levels, which would attenuate the elevation of LH caused by the inhibition of testosterone biosynthesis. `There is, however, evidence indicating a substantial difference in the susceptibility of rats and humans to Leydig cell tumorigenesis. There are numerous pharmaceuticals and chemicals that have been documented to produce Leydig cell tumors in rats and other laboratory animals, but not in humans. These include androgen-receptor antagonists, dopamine agonists, estrogen agonists/antagonists, other PPAR agonists (clofibrate, gienmdfiicbartoezditlh)a,t stuhgeraersd(oleasctnosoet,alpapcteiatrol)t,oabned anidcioftfienree(nCceleigngtehfealm.o,r1p9h9o7)l.ogSytuodfieLsehyadvieg acleslol tumors, whether spontaneous or chemically induced. Since PFOA and other PPs do not increase peroxisome levels in the testis, current ideas regarding the mechanism of PP-induced Leydig cell hyperplasia and neoplasia suggest the involvement of hormone-mediated (estradiol) induction of testicular growth factors (Biegel et al., 2001). The increased levels of estradiol are thought to result from the induction ofa -- J RTF} hepatic cytochrome-P450 (CYP450) mediated aromatase. If this is not part of a pleiotropic -- PPAR-mediated response, Leydig cell tumorigenicity could involve a distinct hormone- mediated mechanism that might be of some relevance to humans. There is, however, evidence indicating a substantial difference in the susceptibilityofratsandhumans to Leydig cell tumorigenesis. Thus, while the spontaneous incidence of Leydig cell adenomas in ageing Crl:CD* BR rats ranges from approximately 0-12% and can approach 100% in F344 rats, the rate in humans is reported to be only about 0.4 per million (0.00004%) (Schottenfeld, 1996). It seems highly unlikely that PFOA exposures represent any significant human risk with respect to Leydig cell cancer. There was no evidence of any increase in serum estradiol or testicular cancer in 3M plant workers exposed to PFOA (Olsen, 1998) and in the 6-month PFOA study with cynomolgus monkeys, estradiol levels were not increased (Butenhoeft al., 2002). Furthermore, there was no increased incidence of testicular or other cancers in humans ingesting high daily doses of fibrates and other rodent PPs for hyperlipidemia (Ashby ef al., 1994). `The mechanism by which PFOA and some other PPs induce pancreatic acinar cell tumors is not well understood. It has been hypothesized that it might involve release of cholecystokinin (CCK) in the gut with subsequent stimulation of the acinar cells in the pancreas to secrete pancreatic enzymes into the gut (Biegel ef al., 2001; Herrington & Adrian, 1995). However, it must be concluded that, at the present time, this is a speculative mechanism that is not supported by experimental evidence for PFOA (Biegel ef al., 2001; - aBpuptleicnahboifliftyettoalh.u, m2a0n0s2).is Even if this is found to highly uncertain (Gavin be ef the al., mechanism 1996, 1997; operating Cattley ef in rats, its al., 1998; Pandol, 1998). To assess the hypothesis in production workers at 3M, plasma CCK-33 measurements were made by radioimmunoassay during the 1997 medical surveillanceof75 male production workers (Olsen ef al, 2002). The results showed a weak negative association between serum PFOA and plasma CCK levels and serum liver enzyme tests showed no indication of cholestasis. There was no increased mortality from pancreatic cancer in these workers (Alexander ef al. 2002). B. Human Epidemiology and Exposure Assessment `The presence of organic, covalently bound fluorine in human blood was reported by Taves (1968andaTa,vebse)ta,l. (1976) tentatively identified a componentofthe organic fluorine as PFOA. Following that finding, 3M began monitoring its fluorochemical production workers (Ubel, 1980). Workplace monitoring was originally based on determination of total organofiuorine in serum. Speciation and quantitation of PFOA rather than total organofluorine was introduced in 3M's medical monitoring program in the 1990s. 3Mhas also surveyed sera from the general (non-occupational) population. Using high performance liquid chromatography-electrospray tandem mass spectrometry Hansen et al. (2001), Olsen ef al. (2002a; 2002b; 2002c) have shown in three U.S. general population - Ts rumen studies serum concentrations of PFOA, regardless of age, averaging approximately 5 parts --_ 1pe0r15biplplibo.n (Ipnpabn)owtihtehr satnuduyp,peOrlsbeonuenfdaol.f(t2h0e09358)epxearcmeinntedtoaletroatanlceofli3m0ithuapmparnoxdiomnaotrinlgive1r0s for the presence of PFOA. Almost all donor livers were below the lower limit of aqubaonvteittahteiolnowwehriclhimirtanogfeqduabnettitwaeteinon,5.o4netol3iv5e.r9hnagd/ga.PFOOfAthceontcweontdroantoironloifve2r.s5mnega/sguarnedd the other had a mean analysis of46.9 ng/g. T(hAePFfOir)stppruobdluicsthieodn wreoprokrftorocfes(eUrbueml ecfonacle.n1tr9a8t0i)oinnsdiicnataendaa mtmotoalnoirugmanpiecrfflluuoorrionoecctoanntoeantte MofN.1t0T7h1ephpimgihnest3Mseermupmlocyoenecesnattraatnieolnesctwreorceheombicsaelrvfelduoriinnaetmipolnopyleaents iwniCtohtttahgeelGornogvees,t pparcokdaugcitnigonopweorartkiohniss.toUrsyianngdgaasmocnhrgomaatsuobgsreatphoifcwtoerckhenrisquewsh,oUsbeeljoebfsali.nvroelpvoerdteddrtyhiantg9a0n%d of the organic fluorine was PFOA. cAdodnidtuicotneald sainnacleysUebselofetatlo.talionrgcaoninc jfluuowrniitncehtmoeridisoceanrlumsurPvFeiOllAanmceeaosfutrheemseenCtosttahgaeveGrboeveen production workers (Gilliland, 1992; Gilliland and Mandel 1996; Olsen ef al. 1998; 2000; 2003b) and other production workers (Olsen ef al. 2003c). Serum PFOA concentrations during the 1990's were comparable to those initially estimated by Ubel er al. (1980) with means (range in parentheses) of 5.0 ppm (0-80 ppm), 6.8 ppm (0.0-114) and 6.4 ppm (0.1- ~ 81ppm)in 1993, 1995 and 1997, respectively (Olsen ef al. 2000). Medical surveillance of these questionnaire; measurement of Cottage Grove production workers has height and weight; pulmonary function included a testing; and medical standard b2i0o0c3hbe)m.icaHleapantdihc-eamnadtolliopgiyd-treesltaste(dUbeblloeotdal.te1s9ts80h;aGvielliinlcanlduedtedal.al1a9n9in6e; Oalmsiennotertaanls.f2e0r0a0se; (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma glutamyl transferase (GGT), total and direct bilirubin, total cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL) and triglycerides. Ubel ef al. (1980) initially reported that no health problems were associated with exposure to fluorochemicals in this workforce although aggregate analyses were not presented. Others have subsequently not shown abnormal associations betweenclinical chemistry or hematology findings witheither (toOtlasl eonrgeafnialc. fl2u0o0r0i;ne20le0v3ebl)s (iGniltlhiilsanwdoarnkfdoMrcaen.delAl1t9h9o6u)ghorGsilelriulmanPd FaOndA concentrations Mandel (1996) suggested that serum total organic fluorine levels might modulate hepatic responses to eobxeasmiitnyatainodnsaltchoahtaoln,altyhzeesde sipnetceirfaicctailolnys fwoerrseernuotmPoFbsOeArvceodncienntthrraeteiosnusbs(eOqluseenntesfuarlv.ei2l0l0a0n)c.e -- _ _& 2Jme2ms In response to toxicological findings that suggested PFOA might modulate endocrine --- activity in the rat (Biegel ef al. 1995, 2001), serum levels of several hormones (estradiol, free and bound testosterone, FSH, LH, prolactin and TSH) were incorporated in the medical surveillance program of these Cottage Grove workers starting in 1990. Other hormones (dehydroepiandrosterone sulfate, 17 hydroxyprogesterone and sex hormone binding globulin) were added in 1993 and 1995. Gilliland (1992) reported a positive nonlinear association with estradiol and a negative nonlinear association with free or bound testosterone in relation to serum total organic fluorine concentrations. These associations were not confirmed with analyses specific to serum PFOA concentrations although mean estradiol levels were 10 percent greater among employees with the highest serum PFOA concentrations (30 ppm) (Olsenet al. 1998). Possible explanations for thedisparitybetween findings may involve the use of different biomonitoring and hormonal assay methods and possible misclassification of confounding variables, most importantly, body mass index (Olsen ef al. 1998). Basedontheir data, Olsenaelt. (1998) concluded therewasreasonable assurance of no significant hormonal changes associated with PFOA at the serum levels `measured among these male production employees. Contrary to the relatively rapid rates of elimination reported in laboratoryanimals (DuPont, 1982; Johnson and Ober, 1980; Butenhoff ef al., 2002), PFOA appears to be slowly eliminated in humans (Ubel ef al. 1980; Burris ef al. 2002). In an interim report, Burris ef al. (2002) reported the serum half-life of elimination for PFOA was 4.4 years (S.D. 3.5) in `nine retired fluorochemical production employees who had serum concentrations measured - over an 18 month time period following cessation of exposure. Initial concentrations ranged from 0.1 to 1.8 parts per million (ppm). Although non-occupational sources of PFOA exposure during the follow-up time period were not accountedforand the half-life study is still in progress, the slow elimination rate observed suggests that humans have the least ability to eliminate PFOA of any species studied. This slow elimination does, however, allow the use ofa single measurement to significantly reflect current, recent, past, and chronic/subchronic exposure. `This observation, combined with the effects seen in animal studies, warrant further evaluation of the potential health consequences that might result from exposure to PFOA OBJECTIVES The overall objective of this community study is to generate scientifically sound data to further the understanding by DuPont, regulatory agencies, and others of the nature and potential effect of human exposures resulting from PFOA emissions from Washington Works. - TT umes `The first objective for this study will be to develop a statistical model describing the ~ variation in the exposure biomarker (serum PFOA),if any, in relation to environmental exposure to PFOA considering traditional epidemiology descriptors, such as age, sex, race, Body Mass Index (BMI), alcohol use, prescription medications, and cigarette smoking status. A second objective will be to model health outcome in terms of the adjusted serum PFOA values. For both the first and second objectives, standard regression methodology will be used to determine which of these potential explanatory variables should be included in the final models. `The third objective will be to identify appropriate clinical markers, if any, relatetod changes inPFOA concentrations in serum to allow proper follow-up through continuedsurveillance. STUDY OVERSIGHT, SPONSOR, AND TESTING FACILITIES This community survey will be conducted for DuPont by The Sapphire Group, Inc. The following entities have key roles in this endeavor. Scotourddyinoavteirosni,ghatn,d data TBheetShaespdpah,irMeGDroup.Inc. -- evaluation: Carol Gevecker Graves, Ph.D, Principal Investigator Physical and clinical ~~ Examineties examinations and Kansas City, MO laboratory analyses: Mary H. Dimitri, Senior Sales Executive (Subcontract to Pacific Toxicology, Los Angeles, CA, for standard laboratory analyses) Serum PFOA level analyses: ExygenResearch State College, PA John Flaherty, Vice President of Operations Cohort interviews and enrollment: Aspen Systems Rockville, MD Marie Pogozelski, Manager, Survey Operations - ---__& 2umeam ~~ Random sample selection: GeFonretsWyasshSianmgptloinn,gPA Sponsor: `HEa.Ls.kDelulLPaobnotrDaetoNreyfmoourHresaalntdhCaondmEpnavniyronmental Sciences Newark, DE Robin C. Leonard, Ph.D, MACE. REGULATORY COMPLIANCE `ETphiisdesmtiuodylowgiyll EbtehiccosndauncdteSdtaancdcaorrddsinogftoPrgaucitdiacencCeopmrmoivtitdeede bwyhithcehAcmaenribceanacCcoelslseegde oatf htp://wwwiacepidemiology2. org/policystmis/EthicsGuide.asp. The laboratory `Toxicology, and aEnxaylgyesne,swiplrlobveidceodndbuyctetdheincoanctcroarcdtanlcaebowriattohriUe.sS,. Examinetics, Pacific EPA TSCA (40 CFR pparrotc7ed9u2r)eGsofoodrLsaabmoprlaetsorayndPrraecstulitcsew(iGllLPb)e fSotlalnodwaerdds((E1x9y8g9e)n. RAepsperaorpcrhi,atSetacnhdaairndoOfpceursattoidnyg Procedure). See Appendix 1. Additionally, the final laboratory analyses report will be reviewed and audited by experienced GLP auditors. - STUDY DESIGN `sTehliesctsetdudfyrowimllficveonwsaitsterodfisatriccrtossst-osedcettieornmailnesatmhpelreanogfe coofmvmaulnuiestyforressiedreunmtsPrFaOnAdoamnldy various PFOA. health screening endpoints for people potentially environmentally exposed to 2Eaqcuhessttiuodnynapiarretisciimpialnatrwtiolltchaotmpulseetdeinaasesltfu-daydmoifnwisotrekreerdshaetalDtuhPsotnattuss qWuaesshtiinognntaoinreWoursiknsg bfayciWlaitsyh.inEgatcohnsWtuodrykpsarteimcpilpaonyteewisllwrheocepiavretiacipphaytseicianltehxeawmoinrakteirosntusidmyi.laTrhteo tehxaatmriencaetiivoend will be administered in the principal communityof each water district. A Study Overview `This cross-sectional survey will use standard epidemiologic and statistical analyses of sreelvaetriaolnsthyippesso, fifclainnyi,cabledtawteaenanedxapobsiuormeartokePrFoOfAexapnodsuarney(seaerrluymcPliFnOicAa)l stiogdnsetoefrmaidnveertshee effect in humans. To this end, the study will incorporate data from clinical chemistry and -- Ts TT umm hematology analaswyelslaseclisnic,al parameters customarily utilized in traditional health ~ surveillance examinations, such as chest X-ray, pulmonary function tests, and hearing and vision tests. A broad panel of testing will be conducted that will provide a reasonably extensive snapshot of general health and well-being. These include Chem Screen 25/CBD/Urinalysis, chest Xray, pulmonary function test, EKG, audiometry, and visual acuity tests. Additional specific clinical pathology tests are included that may have more relevance to the overall objectives of the study, based on findings in animal studies and occupational surveillance. These include special tests for lipid profiles, hormone measurements, C-reactive protein, and prostate-specific antigen (Appendix C). Results from the cross-sectional survey will note the prevalence of test values for several health endpoints in community participants. The prevalence of these test values will also be compared across stratification of serum PFOA levels into quartiles. Briefly, the procedures for the community study include these major tasks: Identify service boundariesofthe five water districts with detectable PFOA. Selecta random sample of telephone numbers of the targeted number of community -~ `members in cach water district. Preliminary assessment of the sample size needed suggests that approximately 800 residents exposed through drinking water will be a sample size adequate to make meaningful statistical analyses. Communicate via telephone inform themofthe study and with the randomly selected to invite their participation in community the study. residents to Coordinate between those selecting field team to schedule appointments the for sample and inviting participation and the physical examination for cach participant. Track the review and signing of consent forms and the completion of selfadministered questionnaires. Perform the physical examination, medical tests, and blood drawing for selected community participant at a convenient location in each water district. each sEtaucdhy.paIrntitchiepaenvtenwtilolfbleabeoxraatmoirnyeadccoindceentaanldlohsasovefbslpoeocdimdernas,wnthoenpcaertfiocriptahnits will be notified and asked if he/she is willing to provide an additional specimen. - - wT umes Following the blood draw, a small bagged snack will be provided to each --- participant to mitigate the effects of the fast before the participant leaves the examination site. Transfer data electronically to The Sapphire Group for analysis. Analyze data, prepare reports, and communicate study results to participants. Each study participant will receive a printout of his/her individual results. B. Community Sample `The five water districts in which PFOA has been detected (and hence which are members of the class) are Lubeck, WV Belpre, OH Little Hocking, OH Tupper Plains, OH Village of Pomeroy, OH The sample for the community study will be approximately 800 persons chosen randomly from the five water districts in the class. In addition, the study will include some persons - `who obtain their water from private wells. `Adults, defined as persons 18 yearsofage and older, will be invited to participate. C. SampleSize A power study was conducted to determine the sample sizes needed to have reasonable assurance of finding biologically relevant levels of serum PFOA (J. Green, personal communication). Statistical power considerations are relevant to the proposed statistical analyses since the decision to include or exclude a potential explanatory variable in the proposed regression analyses and the interpretation of the magnitude of a regression coefficient can only be done by taking into account the variance of the estimated coefficient. That variance is in turn related to the power ofthe analysis. The power study consisted of a Monte Carlo computer simulation study and was based on the variance-covariance structure of the 3M study (Olsen et al. 2000, 2003b). While the variability in the community data may differ from that observed in the 3M study, that study constitutes the most reliable information available on variation in serum PFOA levels. - Tw zameas `The following table and figures illustrate the results of the power study. They indicate how --_ `many subjects are required in any given cohort to detect a differenceof a specified percent change based on the population studied by 3M. The sample size required depends on several factors: Size effect one wants to be able to detect Level of confidence one wants to have in detecting that size effect Variability in serum PFOA levels in the population cohort being studied The variability in the proposed study population is presumed to be the same as in the 3M population. Should the variability in the study population be higher, the required sample sizes wil increase. As a rule, the objective is to have high confidence (85-95 %) of detecting the size effect deemed important `The results below are divided into gender and age groups, as statistically significant differences were observed in the variation within these populations. For example, the coefficient of variation (CV) in adult males was 0.40, while in adult females the CV was 0.45. The CV observed among elders of either sex was 0.35. `Table 1 presents the results of the power study. Figure 1 illustrates the sample sizes required for various power levels (0.75, 0.85, and 0.95) for a CV of 0.25. Figure 2 is a similar illustration for a CV of 0.35, and Figure 3 illustrates sample sizes for a CV of 0.45. ~ An example from the table and figures shows that it is possible to have 95% confidence of detecting a 20% change in serum PFOA levels of adult males or females with 66 subjects. `The same size effect can be detected in eldersofeither gender with only 40 subjects. - --_ ___________ zZumezm Tablel. Sample Size (N) Based on Proportion Change To Be Detected, Power - Desired, and Coefficient of Variation in the Cohort Being Sampled Proportion Power change CV=025 ~~ CV=035 N N cv=04s N ol 075 38 73 120 085 50 97 161 095 7s 146 242 02 075 1 20 33 085 14 27 44 095 21 40 66 03 075 5 085 7 10 13 16 2 095 10 20 32 04 075 3 6 10 085 4 8 13 095 6 12 20 0s 0.75 3 5 7 --- 085 3 6 9 095 5 9 14 =. -__________ zun e SD A aTHs AN | - | SL | w ~ : ----| Figure1. Samplesize graph for CV = 0.25 - A ATT Treir Jt ---- --_-- Figure2. Sample size graph for CV =0.35 --_ - wT zumeam SAVPLE SIZE REQUREDTODETECT APERCENTEFFECT INFH \ Figure3. Sample size graph for CV = 0.45 - In setting the sample size for the community study, a percent change of 10% (i.e., a proportion change of 0.1) was selected along with a power of 85% (0.85). From the table, it canbe seen that a sample size of 161 is required to observe this percent change in serum PFOA in adult males or females who exhibit a CV of 0.45. Because there are five water districts (i.e. five sub-cohoarstasmp)l,e size of approximate80l0y is required (i.e., 160 per water district x water districts = 800). D. Random Selection of the Community Sample Two methods were considered as the basis for sampleselection random selection from water district customer lists or random digit dialing based on Census blocks served by a water district. The telephone survey using random digit dialing was deemed preferable to arandom selectionbased on water district customer lists for several reasons. A name onthe utility list may be the owner, but not the occupier, of the residence using the water. The utility lists may not readily identify commercial and other non-residential users. Because negotiations for customer lists may be protracted, obtaining the lists from all five utilities may cause a time burden delaying the initiationofthe study. Finally, since it may not be possible to obtain lists from all water districts, the alternate method would have to be used in some water districts. Less bias would be introducedifthe same selection method were used in all water districts. ~ - _ zim Random digit dialing (RDD) will be used to select study participants from each water ~ district (Waksberg, 1978; Groves and Kahn, 1980). Assumingaparticipationratio of 10-to- 1, RDD will be used to screen an initial list of 8,000 eligible residents aged 18 and older, with a residential listing, and living in the five water districts based on Census blocks. This approach will yield an estimated sample of approximately 800 participants balanced by age `group and gender. An RDD sample of residential phone numbers will be obtained from Genesys Sampling Systems, a product of the Marketing System Group (MSG) of Fort Washington, PA. Genesys is recognized as one of the top ten systems for producing RDD samples. Genesys will be provided with the Census blocks for each water district. They will provide RDD blocks of 100 residential phones excluding all businesses, hospitals, schools, prisons, nursing homes, etc. They will provide blocks totaling 8,000 households distributed among the five water districts. Assuming that only one in every 10 persons contacted will agree to participate in the study, this method will generate the desired sample size of approximately 800. Within each water district, the stratified random sample of approximately 160 will be balanced by gender and age groups. Males and females will be sampled approximately equally reflecting the distribution of genders in the community. Withineach gender, age groups willbe balanced in three broad age categories: 18-44 years, ~ 45-64 years, and 65+ years. The computer-assisted telephone interviewing (CATI) system software will provide daily/weekly counts of sampling quotas incorporating the stratificationcriteriato ensure balancedrecruitmentof all three age groups for eachgender. (See Appendix A.) E. Random Digit Dialing Telephone Survey Recruitment of the community sample will be subcontracted to Aspen System Corporation s Survey Operations Center. They will employ RDD and CATI to accomplish the following tasks: Arecruitment call will establish study enrollment eligibility. The phone call will include a brief introduction about the purpose and value of the study to the community and to the individual (i.e., free health assessments conducted in a location convenient to their home). Questions will be asked concerning place of occupation and source of water (e.g., public water supply or private well, name of water utility). DuPont employees will be excluded from the community study, as will pregnant women and people on chemotherapy. Telephone calls will be placed between 5 and 9 P.M. EST. --_ -__________Z_ um% x= ~ The recruitment screening questionnaire will be programmed for CATI administration offering full telephone interviewing automation and real-time `monitoring of study progress as data are collected. The range of capabilities of the software promote case of telephone interviewing by simplifying questionnaire programming, call management, quota cell control (i.e., grouping of respondents based on demographic characteristics such as gender and age), calling results, interviewer monitoring, and data reports and delivery. The CATI system offers daily electronic reporting of results to monitor total calls made, quota cell reports of completed interviews by gender and age group, and instantaneous quality control. A pilot study of 100 telephone numbers will be conducted to test the telephone screening questions and participation rates. Based on the resultsofthe pilot test, the. recruitment script (introduction and/or questions) may be modified and the recruitment survey retested, as necessary, for clarity. Any persons who agree to participate in the study during this pilot test wil be included in the study. Uadpulttoifnoaurhotuesleehpohlodn.e attempts will be made to reach and recruit a randomly selected Upon reaching an adult and after introductory remarks, the telephone interviewer will determine the number of adults living in the household. If there are more than two adults, an adult respondent will be selected randomly based on the nearest - bwiilrlthbdeaysesltercatteedgyf(oir.es.t,utdhye paadrutlitciwphaotisoen)b.irthday is closest tothe date of the interview If the selected adult is eligible after responding to the screening questions (exclude qinudoitvaisduraelmsawihnoopeevnerfworoernkroeldlfmoerntD)u,Ptohneitrapanrdtivceipraitfiyontihnatt htheeirstguednydweirllanbdeargeequgersotuepd and their home address will be recorded. It is anticipated that for every 10 calls `made one person will agree to participate in the community study on the average. Level one telephone of study participation recruitment interview. will be based on verbal Nightly summaries of agreement attained in the eligible respondents who agree to participate will be calculated by the telephone survey vendor to revise the age and gender enrollment quotas within each of the water districts for the next evening s survey. Physical examination appointments will be made at this time and confirmed in `writing. - wm wean A follow-up letter confirming participation and the date of the examination, the - consent form (Appendix B), the self-administered questionnaire (Appendix G), and a pre-paid return envelope will be distributed to each study participant via Federal Express or USPS priority mail. Respondents who do not return the questionnaire, do not make an appointment, and/or do not showup for their physical exam appointment will be telephoned up 0 three times and urged to participate. A sample in excess of 800 will be recruited to have approximately 800 participants remaining after no-shows are accounted. Level two of assessing the final study participation rates will be calculated weekly, using results from completed self-administered questionnaires and completed physical exams. Study participant rates by age group and gender within each of the water districts will be calculated weekly to adjust subsequent balanced enrollment. MATERIALS AND METHODS A Test Substance/Exposure of Interest Test Substance: Ammonium perfluorooctanoate (APFO), assimilated through environmental exposure --~ Analytical Standard: Exygen (for serum PFOA analyses) and Pacific Toxicology (for all other standard analyses) will provide standard operating procedures that describe their quality control/quality assurance practices. Additional Information: ~~ Community residents may have exposure to chemicals other qtuheasntiPonFnOaAir.e by Tihniqsuiripnogteanbtoiault owciclulpatbieon.addressed in the B. Clinical Pathology Evaluation Approximately 30 mL of blood will be drawn into several vacutainer tubes with the appropriate anticoagulants, barriers, preservatives, and other additives as required for the list of analyses listed in Appendix C. This will require the participants to fast for at least 12 hours before the blood collection. In addition to a standard ChemScreen 25/CBD, other serum markers will be measured. ~ wT mms 1. Collection Sites and Samples Sample Volumes: All sample volumes are approximate. (See Appendix C) Collection Parameters: See Appendix C 2. Electrocardiography (EKG) Evaluation Frequency: Once Scope: See Appendix D 3. Frequency: Scope: 4. Chest X-Ray Evaluation Once 14x 17 PA Chest (full chest x-ray, one view) Audiometric Examination Frequency: - Scope: Once See Appendix E 5. Pulmonary Function Test Evaluation Pulmonary function testing (PFT), or lung function testing, is a method of determining how well the lungs and airways are working. The most common PFT is called spirometry. Each participant will take in as deep a breath as possible, blowing out all of the air as fast and as hard as possible into a tube through which the volume of air is measured. Three attempts are needed, and the best effort is recorded. The results will be recorded as FEV1, FVC, FEV1/FVC%, FEV1% predicted, and FVC%. Frequency: Scope: Once Forced Expiratory Volume 1 (FEV1), Forced Vital Capacity (FVC), FEVIFVC%, Forced Expiratory Flow (FEF25- 75), Peak Expiratory Flow Rate (PEFR) - wT zamas 6. Visual Acuity Frequency: Once Scope: See Appendix F 7. Questionnaire Frequency: Once Scope: See Appendix G 8. Physical Examination Frequency: Once Scope: See Appendix H DATA ANALYSES _ "vTahreiaftiirosnt ionbjtehcetievxepofsourrethibsiosmtaurdkyewril(lsebreumtoPFdeOvAe)l,opifaasntya,tiisnticraellamtioodnelto deensvcirriobnimnegnttahle eBxopdoysuMraestso PInFdOeAx c(oBnMsIi)de,rianlgcothroaldituisoen,alpreepsicdreimptiioolnogmyeddiecsactriipotnosr,s,ansducchigaasreatgtee, ssemxo,kriacneg, status. A second objective is to model health outcome interms of theadjusted serum PFOA values. For both the first and second objectives, standard regression methodology will be used to determine models. which of these potential explanatory variables should be included in the final `Thethirdobjective will beto identify appropriate clinical markers, if any, related to changes in PFOA concentrations in serum to allow proper follow-up through continued surveillance. TInotahveoaindaloyvseers-,paeraacmheteexrpilzaantaitoonr,yavavrairaibalbelewtihlaltbdeoebsronkoetncionnttoriabustmealslignnuimfibcearntolfyctaoteagmoroideesl. will be discarded. * BMIwillbe calculatedas weight! (height'x) 100using metric units. -- mT zuma Missing values for the age, sex, race, relative body weight or height variables will be -- entered into the unknown subgroup for that particular variable rather than excluding the subject from the analysis. Assessments of model assumptions will be conducted to ensure: that the appropriate statistical procedures/models are used. Thedata will be displayed with box plotsofthedistributionsandvariatiforn clinical endpoints. It may be necessary to use normalizing, variance stabilizing transformations for these responses. For continuous variables, such as blood pressure, analyses will be based on group means, adjusted for any potentially confounding variables. For discrete outcome variables, such as the prevalence of liver disease, analyses will bebased on logistic or Poisson regression. In addition, analyses will be performed on the proportion of a group s measurements that fall in the highest or lowest decile. For disease prevalence rates basedon sparse data, exact logistic regression may be used. HUMAN SUBJECTS PROTECTION Specific procedures that will be put in place for human subjects protectionduring this study include, but are not limited to, the following: Detailed consent form from each participant that identifies study purpose, requirements, voluntary nature of participation, right of withdrawal, possible risks, _ and potential benefits (Appendix B). Coded identification to link biological specimens, exam results, and completed questionnaires. Scheduling of exam appointments to ensure that waiting areas are not crowded. Useofmobile office/laborautnoirtys with sufficient capacity to ensure that onlyone participant is occupying atest area. Establishment of coded folders or envelopes that will contain each participant's results for archiving. Analytic data files that identify participants only through study subject identification code. Contact information for study personnel so that any problems or questions that should arise for participants can be addressed as quickly as possible. - 21 2 June 2004 RECORDS AND SAMPLE STORAGE During the executionofthe study and the analysisof data, raw data will be analyzed by The Sapphire Group. These data will be stored in locked file cabinets in a locked office area. Electronic data will be kept on secure servers accessible only by passwords. Access to data with personal identifiers will be limited to select study personnel. Laboratory-specific or site-specificrawdata, suchas personnel filesand equipment records, and specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, DE, or at Iron Mountain Records Management, Wilmington, DE. PROPOSED STUDY DATES Study dates are subject to date of protocol approval and sign-off. ~ 2 2 June 2004 REFERENCES oAflaexnanadmerm,onBiHu,m Oplesrefnl,uoGr.oWoc.t,anBouartiesp,r1odMuc,tiMoanndfaeclil,itJy.H,Ama.ndJ. Mandel, 1.5. (2002). Mortality Ind. Med. (submitted). of employees APusrhchbays,e,1,LFB.rHa.dy(,19A94.).ElMceocmhbanei,stCiRca.llEy-lbiaoste,dBhMu,misahnmhaaezla,rdJ.a,sOsdesusmm,enJt.,ofTpuegrwooxoids,omJe.Dp.r,olKieftetrlaeto,r-Si.n,duacnedd hepatocarcinogenesis. Human Exptl. Toxicol. 13 (Suppl 2): 1-5 117. Bpreonltilfeeyr,atPi.o,nCianldreord,enLt,sEalncdomibtse,siCg.n,ifGiraaasnscoe,fPo.r,hSutmrainngse.r,FoD.o,d.anCdheWmi,egTaonxidc,olH..-J3.1(:1989537)-.90H7e.patic peroxisome Bpeerrtfhliuaourmoeo,ctaJ.nesaunldfoWnaalmliadcoe,etKh.anoBl.; (P2e0r0o2x)isoPmeer.fluPorrooliofcetraantoiaotne,anPderfMliutoorcohoocntdarniealSuBlifoogneanteen,esaisn.d N-ethylToxicol. Let. 120: 23-32. 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St. Paul MN: Riker Laboratories, Inc. US EPA Public Docket AR-226. Just, W.W., Gorgas, K., Hart, F.U, HeinemP.a,Snalnze,r, M. and SchimassekH,. (1989). Biochemical effects and zonal heterogeneity of peroxisome proliferation induced by perfluorocarboxylic acids in rat fiver. Hepatology 9: 570-581. Kennedy, G. L., Jr. (1985). Dermal toxicity of ammonium perfluorooctancate. Toxicol. Appl. Pharmacol. 81: 348.355. oKfudgloy,ceNr.o,liMpiizdugmuecthaib,olHi.s,miYnarmaatmloivteor,, CAh.ema.n-dBiKoal.wasInhtiermaact,. Y1.18(:196999-)8.3.Alterations by perfluorooctanoic acid Lake, B.G. (1995). Mechanisms of hepatocarcinogenicity of peroxisome-proliferating drugs and chemicals. Annu. Rev. Pharmacol. Toxicol. 35: 483-507. Liv, R C. M, Hahn, C., and Hurt, M. E. (1996a).The direct effectofhepatic peroxisome proliferators on rat Leydig cell function in vitro. FJndam. Appl. Toxicol. 30: 102-108. Lis, RC. M, Hurt, M. E., CookJ,. C, and Biegel, L. B. (1996b). 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An epidemiologic investigation of reproductive hormones in perfluorooctanoic acid. J. Occupy. Environ. Med. 40: 614-620. men with occupational exposure to Olsen, G. enzymes, W., Burs, cholesterol J. M. , Bure, M. and lipoproteins in M., and MandelJ,. H. (2000). Plasma cholecystokinin ammonium perfluorooctanoate production workers. and Drug hepatic Chem. Toxicol. 23,603-620. Olsen, G.W., Burris, J.M., Lundberg, Hansen, K.J., Mandel, JH. and Nobel, LB. (20024). Identification offluorochemicals in human sera. |, AmericanRedCross adult blood donors. ISAPI Public Docket AR-226. ~ 2 2 June 2004 Olsen, G.W.,Burris, J.M., Lundberg, Hansen, K.J., Mandel, JH., and Nobel, LB. (20020). Identification -- of fluorochemicals in human sera. II. Elderly participants in the adult changes in thought study, Seattle, `Washington. ISP Public Docket AR-226. Olsen, G.W., Burris, J.M., Lundberg, Hansen, K.J., Mandel, JH., and Nobel, L.B. (2002). Identification of fluorochemicals in human sera. IIL. Pediatric participants in a group A Streptococci clinical trial investigation. ISAPI Public Docket AR-226. Olsen, G.W., Hansen, K.J, Stevenson, L.A., Burris, JM, and Mandel, JH. (20032). Human donorliverand serum concentrations of perfluorooctanesulfonate (PFOS) and other perfluorochemicals. Environ. Sci. Technol. 37:888-891. Olsen, G.W., Butenhof, J.L. Mandel, JH. (2003b) Assessment of lipd, hepatic and thyroid function in relation to an occupational biologic limit value for perfluorooctanoate. US. Environmental Protection Agency docket AR-226, Olsen, G.W., Burris, JM, Burle, MM. Mandel, 1H. (2003c). Epidemiological assessmentofworker serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations and medical surveillance examinations. JOccupy Environ Med 45:260-270. Olson, CT. and Andersen, M.E. (1983). The acute toricityofperfluorooctanoic and perfluorodecanoic acids in male rats andeffectson tissue faty acids. Toxicol. Appl. Pharmacol. 70: 362-372. Palmer, CNA, Hsu, M. H, Griffin, K.J., Raucy, J.L., and Johnson, E.F. (1998). Peroxisome proliferator activated receptor-a expression in human liver. Mol. Pharmacol. 53: 14-22. - Pandol, S. J. (1998). Pancreatic physiology and secretory testing. In Gastrointestinal and Liver Diseases, Vol. 1, Sleisenger, M. and Fordtran, J. ., eds. WB Saunders Co. Philadelphia, pp. 771-782. Pastoor, T. P., Lee, K. P., Perri, M. A., and Gilles, P. J. (1987). Biochemical and morphological studies of a98m-m1o09n.ium perfluorooctanoate-induced hepatomegaly and peroxisome proliferation. Exp. Mol. Pathol. 47: Reddy, 1K. and Rao, MS. (1977). Malignant wmors in rats fed nafenopin, a hepatic peroxisome proliferator. J. Natl. Cancer Inst. $9: 1645-1650. Schottenfeld, D. and Prevention. (1996).Testicularcancer. In New York: Oxford University P(rSecshso.ttpepn.fe1l2d0,7D-.1,21F9r.aumen, LF. eds): Cancer Epidemiology Shyvpoobloidpai,deDm.icJ.draugn.d CAaznacmeorfRfe,s.D.39L:.34(1199-7394)2.8.Tumors in male rats fed ethyl chlorophenoxyisobutyrate, a `Taves, D. (19684). Evidence that there are two forms of fluorine in human serum. Nature 217: 1050-1051. `Taves, D. (19680). Electrophoretic mobilityofserum fluoride. Nature 220: 582-583. Taves, D., Guy, W., and Brey, W. (1976). Organic fluorocarbon in human plasma: Prevalence and AchmaerracitcearnizaCthieomn.icaIln:SocBiieotcyh,empipst1r1y7-1I3n4v.olving Carbon-Fluorine Bonds. Filler, R., ed. Washington DC: - % 2 June 2004 . Ufbleulo,rocFhAem.icaSlosr-eanpsroenl,imiSn.aDr.y, reapnodrt.RAoma.ch,IndD.EH.yg.(1A9s8s0o)c.. JH.e4a1l:th584s-t5a8t9u.s of plant workers exposed to `Ucpohmammu,niBcaLt,ioDneboycapmeprfol,uoNr.iDna.t,edWufraltt,y Ba.c,idasndisTdreopseknod,en1t.on(19t9h8e).chaIinhniblietnigotnhoofftghaep jfulnucotriionnaatledinttaeilr.ceTlnlt.ulaJ.r Cancer 78:491-495. WAsaskoscbieatrigon1.73:(4109-7686).. Sampling methods for random digit dialing. Journal of the American Statistical - _-- 27 2 June 2004 SIGNATURES Approved by: Robert W. Rickard, Ph.D. Scientific Director Carol Gevecker Graves, Ph.D. Principal Investigator FINAL PROTOCOL SUBJECT TO EPIDEMIOLOGY REVIEW BOARD AND INSTITUTIONAL REVIEW BOARD APPROVAL - 28 2 June 2004 DRAFT APPENDIX A _ CCOMPUTER-ASSISTED TELEPHONE INTERVIEWING (CATT) - % TT Zune 2008 Aspen Systems Corporation's Survey Operations Center offers the latest in CATI -- technology. Aspens boutique telephone center consists of 16 interviewer workstations and a supervisor/monitoring station located within Aspens corporate headquarters in Rockville, Maryland. Aspen uses CATI software that offers full telephone interviewing automation and real-time monitoring of studies while the data are being collected. The softwarse range of capabilities promote the ease of telephone interviewing by simplifying questionnaire programming, call management, quota cell (grouping of respondents based on demographic characteristics) control, calling results, interviewer monitoring, and data reports and delivery, including: CATI System. The Survey Operations Center uses the Windows-based CATI software WinCati4.2. The software promotes the efficiency of sample management by controlling the time and day whencallsare made based on time zones and/or the results of the previous call. It also controls the number of times a number is attempted, works available sample evenly, and allows for the adjustment and scheduling ofcallbacks.RapidDial (WinCati s autodialing system) further enhances the automation of the interviewing process by increasing interviewer productivity and lowering dialing errors. Interviewer Training. Telephone interviewers are provided project-specific - instruction and trainingpriorto placing calls. As part of their training, interviewers are given question-by-question instruction manualsas well as background information pertinent to the surveyand must actively participate in scripted telephone role-playing. Additional project-specific job aids (e.g., square footage conversion charts, acronym lists, etc.) for collectingdata are provided as needed. Quality Control and Supervisionof Interviewers. Quality control is an integral part of the data collection process at Aspen. It begins with interviewer training and continues throughout the data collection period until the final data file is delivered. From the supervisor/monitoring station, WinCati allows for instantaneous on-screen monitoring of telephone interviews in progress via SuperView. SuperView, coupled with our audio monitoring capabilites, allows supervisors both to see and hear the interviewers work and spot potential problems more readily. Supervisors can then rate interviewers based on their performance. The Remote Monitoring feature allows our clients to listen to calls fromtheiroffices. CATI Reports. The WinCati software offers built-in reporting capabilities that permit the overall progress of the data collection effort to be monitored on a continual basis. Standard reports showing the current status of the sample - wT zuma database such as the distribution of records by number of call attempts, by time Pa zone, by quota cells, by callback time, and by most recent disposition can be generated at any time. Quota cell reports, which show the number of completed interviews in relation to pre-set goals for respondents withspecified characteristics, can also be run. The reporting system even monitors interviewer productivity by reporting interviewer log-on hours and completed interviews per hour. In addition to printing the reports, they can be downloaded as Excel spreadsheets and sent electronically to the client s desktop for viewing. Data Delivery. At the completion of the telephone data collection period, a clean survey data file in ASCIL, Excel, Access, SPSS, or SAS can be created on a readonly CD and/or delivered via a secured Internet account established for Aspen clients only. Additional features of WinCati allow the coding of answers to openended questions and the automatic generationof documentation for certain types of output files. --- - Tm TTT Zimam DRAFT APPENDIX B _ CONSENT FORM - - __________ zimam CONSENT TO PARTICIPATE IN PFOA EXPOSURE -- AND HEALTH RESEARCH PROGRAM Cross-Sectional Surveillance in a Community Sample of Clinical Measures of General Health Status Related to a Serum Biomarker of Exposure Introduction: You are being asked to participate in a health surveillance and research program. Your participation is voluntary. `This health surveillance is being conducted in community members and parallels a health surveillance questions of being conducted in workers at the site study coordinator if there DuPont s Washington Works. Please is anything you do not understand. ask What is the purposeofthis study? s`Tthaetupsurapnodsethoefbtlhoeosdtuldeyveils tooflPeFaOnAw,heatlhseorkthneorwenisaasnyC-r8e.latGieonnsehriaplbehtewaeltehnsgteanteursalwihlelalbteh measured urinalysis. by a physical examination, These tests are similar to blood work, pulmonary the general health exam function tests, EKG, and that is performed by your personal physician. What does this study involve? - `Your participation in this study requires one physical exam that includes drawing of blood w(ahbiotuetb3lotoadblceelslpocoonusn)tsf,orhesmeorgulmoblienve,laonfdPFtyOpAe,socfliwnhiciatlecbhleomoidstcreyl,lsa).ndWheemwaitlollaolgsyo (prreodvaidned puhryinsailcyaslis,expaumlimnoantiaorny.funIcntioanddtietsitso,n,chyesotu X-wirlaly,baendasEkKeGd.toAcpohmypsliectieanawilcloncfoindednutcitala questionnaire about tobacco and alcohol use and medical and work history. Will the study be affectedifyou do notparticipate? ``Tghoiosdrreesperaerscehntsattuidoyn odfesciogmnmwuansitcyhomseemnbcearrsefaucllryostsotehnesfuirvee gwoaotedrsdtiasttirsitcitcsalmaankailnysgiuspwithteh class in a class action suit against DuPont. Randomsampling of the community is essential sstoutdhyatwiwlel bheavmeuachgosotdrocnrgoesrs-isfetchteiopneoofplpeeospelleecutseidngfotrhesawmaptleirnignbtyhetsheewraatnerdodimstprrioctcse.ssThalel participate. What are the risks involved with being enrolled in this study? `The only risk of participating in this study would be the risk of a bruise (hematoma) where the blood is drawn and possible ordinary discomfort associated with drawing blood. Some. people feel light-headed and dizzy when doing lung function tests. Rarely, a person will --- ww mwa DraFr faint. There will be a chair nearby where you could sit down if necessary, and the Po. technicians are trained to monitor you for any feeling of dizziness. Are there anybenefitsfrom participating in this study? The benefit of participating in this study is that you may gain important knowledge about your general health with regard to, for example, your cholesterol, blood pressure, and the level of important enzymes that assist with digestion and liver and kidney function. We also hope to learn more about how exposure to PFOA may vary depending on where in the community people live. Other important itemsyou should know: Withdrawal from the study: You may choose to stop your participation in this study at any time. New information: To the best of our ability, any significant new findings during this research survey will be made known to you. The clinical services provider for this study, Examinetics, will mail a complete report of your results to your home address, or to any other address that you may provide. Your PFOA blood level will be communicated to you by letter from The Sapphire Group. Confidentiality: Every effort will be taken to protect the names of the participants - ianndthtihsestruedsyu.ltsAlwlilalnableysreespowritleldbeascgornoduupcetdeddaotna.filNeos tihnadtihvaivdeualhsadwinlalmbees irdeemnotivfeide,d as such in any of the published results. All data are retained in locked cabinets in offices of the study overseers, The Sapphire Group, Inc, Bethesda, MD. On completion of the study, data will be transferred to locked cabinets in the Epidemiology Group, DuPont Haskell Laboratory, Newark, DE. Electronic data are kept on secure servers in databases that can only be accessed by The Sapphire Group or DuPont Epidemiology staff. However, you need to know that in litigation pending in the Circuit Court of Wood County, West Virginia, styled Jack W. Leach et al., plaintiffs, vs. EX Du Pont De Nemours Co., defendant, civil action No. 01-C-608, attomeys for the parties will have access to the information generated by this study. However, access to such medical information is governed by the terms. of a protective order entered by the court in the litigation. Funding: Co. Funding for this study has been provided by E.I. Du Pont De Nemours Numberofparticipants: We expect about 800 participants to be enrolled in this community study. - RAFT EJ ~ Zowmay 200 Who shouldyou call with questionsaboutthis study? -- Questions about this study may be directed to the principal investigator, Dr. Carol Graves, at The Sapphire Group (301-657-8008, ext. 205) during normal business hours. Willyou be paid toparticipate in this study? No. We estimate the monetary value of the physical exam and blood work to be about $500. You may find your personal results helpful as you consider your own health promotion activities. CONSENT 1 have read the above information about the comparison of health outcomes in the community potentially exposed to PFOA, and I have been given an opportunity to ask questions. document Iagree to participate for my own records. in this study, andI have been given a copy of this consent Your name: Your signature: Date: `Witness: Date: - wa mwas APPENDIX C CLINICAL PATHOLOGY COLLECTION PARAMETERS `This appendix will be identical to that in the protocol for the worker study. - DRAFT -- a 20 May 2004 APPENDIX D ELECTROCARDIOGRAPHY (EKG) This appendix will be identical to that in the protocol for the worker study. - WE wm avmms APPENDIX E _ AUDIOMETRIC EXAMINATION `This appendix will be identical to that in the protocol for the worker study. - DRAFT EJ 20 May 2004 APPENDIX F VISUAL ACUITY AND TONOMETRY EXAMINATION `This appendix will be identical to thatinthe protocol for the worker study. -- wR wm mvaas APPENDIX G _ COMPREHENSIVE MEDICAL AND WORK HISTORY QUESTIONNAIRE [Examinetics questionnaire in separate files.) - DRAFT 41 20 May 2004 APPENDIX H PHYSICAL EXAMINATION AND EVALUATION (Examinetics physical examination form will be inserted here.] - DRAFT 2 ~ 20 May 2004 APPENDIX I _ EXYGEN STANDARD OPERATING PROCEDURE FOR PFOA ANALYSES [Exygen SOP in separate fle.] - Re zw - --_ HEALTH EXAMINETICS An Exemplar International Company Confei nerd d e ednti sy al INSTRUCTIONS sow to ase 3i0teso i o1 i t ale s laona trae, telesnyouSroan piro.rsyo hve PLEASE READ AND FOLLOW THESE INSTRUCTIONS CAREFULLY BEFORE ARRIVING FOR YOUR APPOINTMENT 2 AeReentryrnommeaaddhr a maton aag2.LU e nlFee mnipheyy ssve onenh untocry. Nakyouane cal oh usr using a ik pn or dark pencil). Completely fill in the appropriate. oval. (see example below). RR --- CECICIECTIII oll @@ A D5 - 4. yout hgtodtrun cosums fd re, ee you will be having blood drawn, consume no foodorliquid (except plain water, blackcoffee,tea [no +. Panealcohol,sof ploy tdrinks, ftr chewing ht rary pa gum, candy and breathiminnts.oD crdI oaoA nrOiMB snIT)TE HorIyiST Ib.NoSI GTRoUC nCTeIS OwhNi.le 6. aotsmokeforaleasthur elsyourira, 7. {HHIfyoowynueewweoearrcpoorenrsctratiptrriosaneseyergalarasrsesssf,fbroifnggattahpepmeerwrimtmehaaytoe)u).lpeanses ilaan onmc hroor loa 9. Donotphotocopy,bend,fold, stapleorotherwise mutilate this questionnaire. 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FR er ee ---- VYoow th tri mesepnr cm re n ne FO ---- Vowbegs snseo os up en? Vow wr or rtett sa? Vow wreyoun edyr he? nu ere 5567 Th Mgpu t112 : nu B n =H DRAFT a : TITLE PAGE - Jack W. Leach, et al. v. E. I. du Pont de Nemours and Company Circuit Court of Wood County, WV, Civil Action No. 01-C-608 Implementation Plan: May 1, 2003 Injunction Order `Appendix No. 2 `Study-Specific Standard Operating Procedure: Documentation, Accountability, and Sample Chain of Custody Requirements for the ShippingofSerum Samples (MPLEMENTATION DIRECTOR Robert L. Grob, Ph.D. Professor Emeritus, Analytical Chemistry ~ Malve1m2,BPirAch1R93o5a5d-1644 (610) 651-0132 ANALYTICAL FACILITY MANAGEMENT Vice PrJesoihdnenFtlaohfeOrpteyrations Exygen Research 3058 Research Drive State College, PA 16801 (814) 272-1039 DRPAagFeT1C0fO8PY i`JmaCpclkimWet.nCLaeotauicrohtnoPfeuWls.a: dEa.CyLo1.u,dnu0t0P3oWsYndn,eciNteimloonuAOrcrstdaieonnrdNCo.om1p.r4y08. Repent. 3 --- I. SCOPEAND APPLICABILITY `This SOP governs the documentation, accountability, and sample chain of custody requirements for the shipment of serum samples to the analytical facility. 2. REPONSIBILITIES 2.1 The Good Laboratory Practices (GLP) Expert and Analytical Facility Management are responsible for conducting the necessary training covering proper documentation, accountability, and sample chain of custody requirements. This training will, at minimum, be given to the Principal Contact from each of the three clinics. 2.2 The phiebotomist who performs the blood collection is responsible for ensuring that the Chain of Custody/Analysis Request Form (COC) (Figure 1) is completely and correctly filled out and signed by staff members who package and ship the serum samples. 2.3 The Principal Investigator at the analytical facility is responsible for ensuring that the chain of custody remains intact after the samples are received by the analytical facility. _ 3. DEFINITIONS GLP Expert: Patricia D. Royal, M.S., President, Quality Systems Consultants, Inc., 80 Main Street, Plympton, MA 02367 (781) 585-9370 Analytical Facility Management: John Flaherty, Vice President of Operations, Exygen Research 3058 Research Drive, State College, PA 16801 (814) 272-1039 Principal Investigator: Emily Decker, Scientist Exygen Research, 3058 Research Drive, State College, PA 16801 (814) 272-1039 Page20f 8 CJoSoecikettLCheoiuarcnthgoPtf lWa.e:ndaCyo1du,u3n0Pt5oWreYd,eCtNleomlnoAuOcrrtsdieonrnd.NCoo.nOg1e.nCy-08 Roped 3 --- 4. MATERIALS AND EQUIPMENT 4.1 Chain of Custody/Analysis Request Forms, triplicate design. 42. A readily `protective eaqvauiilpambelnetsaopuprrcoeproiaftedrfyor ihcaendpleillnegtsd.ry Also, ice. necessary personal 4.3 Coolers for this numbered and coded project. They must with the clinic be purchased sfruonmiquUeliindeenStihfiipcpaitinogn assigned Supplies `Specialists. `part number The Uline part corresponds to naupmabcekragfeorwthhiechreqiunicrleuddecsooolneers19is S788. x 12 x (This 12.5 cooler and one shipping box). These wil be provided to each clinic. 4.4 Plastic bags for use as will also be obtained secondary sample from Uline, part packaging prior to number S-1707 shipping. 3 x 5, These 4 mil reclosable poly bags, 1000 per carton). These will be provided to each clinic. 5. PROCEDURE 5.1.vBeerfiofrieed.collWehcteinng any each blsoaomdp,lteheiscocmopllleectteedd and the signed clinic consent form will assigna must be unique alphanumeric. identification identification code to code and patient code. cach This sample number based will be on the entered clinics into the - aCnldintiicmSeaomfpleeacIhdebnltoifoidcastaimonplceocloulmlenctoifonthweilCl ObCe rsehceoert.dedL,ikaenwdisteh,e tdhaetedaatned {ime that the serum sample preparation is completed will be entered into the appropriate column onthe COC sheet. 52.C"owiolllebres awsislilgnbeedparouvniidqeudetoalepahcahnucmleinriicc(isdeeentsiefcitciaotnio4n.3nuambboevre,).whEiacchhwcilololbeer wSryisttteemn, otnhethoenlcyoolceorn.ditiEoanchbecilnignicthwaitllcadcehrivneumitbserowcnontcaoionlsertnheumcbleirniinscg identification code. 5:3.iBnedfiovrieduaplalcykaignitnogs,matlhle pplarsitmiacrbyagsserausmsescaomnpdlarey containers packaging m(wuhsitchbewilpllaaclesdo bmeusptrohvaivdeedthteouenaicqhuecliCnliicn;icscSeamsepclteioInde4n.t4ifaibcoavtei)o.n sTahmeplseeccoonddearwyritptaecnka0ginngit in permanent black nk. 5.4 Before the `will verify tshaamtptlheessaarmeplpeascdkoecduimnendtreydicoen, a person the COC other form than match the packager exactly with those being packed in the cooler. The verifier then initials and dates the Cooler Contents Verified prompt. Page3of 8 J`oCcrkeunWa.LiCosoaiucrothnoePftWaaos.odeCyo1u1dnu2tyP0o3WnsYIdo,eNcCii oenAmOcoaotnndNuCoo,mr0p1e-srC408 pein 2 ~ 5.5.S`aamwpalyesaasretotobmeidniimsipzeersethdeinpoascsioboilleirtyfulolfofidmrpaycti,ce apneldletssu,cahrrtahnagtedthienysuacrhe. completely covered with dry ice pellets. with the pellets. No more than 20 The cooler samples are must to be be completely filled placed in one cooler. The cooler will be covered promptly after packing with dry ice pellets to `minimize lossofdry ice to sublimation. 5.6.The time shipment between the must be able completion of to be accounted serum for on preparation and packaging the COC page. There must for not be any unexplained gap in the chainof custody for the samples. 57.After the `completed. seSrecutmiosna2mp(lPeesrsaorneneplacIknavgoeldv,edthien Cooler ID# Shipment of prompt will Sample)s of be the CThOeCprfionrtmedanlasomew,ilsligbneatcuorme,plientiteidalsatanthdisdattiemeo,fisiigtnahtausrenonteebdeetno bpererveiocuosrldye.d for each person who entered information anywhere on the form. The page `numberprompts alsoneedtobefilledin. 5.8.The person who Relinquished by speacctkiaong,edantdheversiafmipesletshatthaenny cuonmupsleedtepsrotmhpetsfiasrte line in the lined out. 5.9`.fTahxenCuOCmbfaotretmhriesttohpeonfftahxeedftoormE.xAyfgteenrRietsiesarfcahxedS,atmhpelpeiRnekcceoipvyinigsruesimnogvtehde - aconpdiebseacroemteosbeparptlaocfedtihne acnliennivceslorpeec,orwdhs.ichTihsethwehniptleacoerdigiinntaol tahnedshyieplplionwg carton with the cooler that contains the samples to which the COC form corresponds. 5.10. The serum Receiving at samples are the address required to be given at the shipped top of to Exygen the COC Research form by Sample FedEx overnight delivery. This is the only carrier and method of shipment that is acceptable. 5.11. Upon procedure receipt will of the follow samples Exygen by Exygen Research, the chain of SOP V40l, Contract Rescarch custody Sample Hseacntdiloni,nga.copAyfotefrthEexyCgOenC SwialmlpbleefRaexceedibvaicnkg tcootmhpelcelitnsiec,twhehicRhecweiillvebdebkyept with the clinisc records for this study. 5.12`.ExyAgneny wpilrlobbleemdsocwuimtehntdeedl.iveTrhyeorExcyognednitPiroinncoifpalsaImnpvleestsiguatpoornwialrlrinvoaltifayt the clinic and the Implementation Director of any problems immediately. Page dof 8 `JCioicokWm. CLoeusrhtotfaWaa.s CayoLu1:dne0tP,0rWtYd.enNGceinloAOscnioaenndNCoo.m0p1e-Cr408 open No 3 --- 5.13. Comection and Clarification of Raw Data 5.13.1. Abescsoomoensarsaawndyatian.forAmattihiosn phoaisntb,etehnisenftoerrmed&onnotthteoCbOeCdifsocramr,deidt tfroransacnryiberdeaosnotno. anoItfheitr sbheeceot,mebsut tdhaematrgaends,criipntfioornmpartoicoenssmwaiyll bbee sdhoeceutmmeunsttedbeviaattfaocohtendotteo on the tthreannsecrwibpeadgpea.geT.he original damaged 5.13.2. If be emrraodres,artehemeardreantinihnafnodrwmraittitoennwielnltribees,croorsisfecdlaoruitfiwcaittihonas are to single tlihnee,nsaotuare not of to obscure the error, the an aoprpirgoipnrailaetnetreyr.roTrhceond,edeispecnhdoisnegn upon (see mFiogruerec2o)m,palnedx thtehaenrrowrhactodeis iscoinvietrieadledbayndthdeateedm.orIfctohdeeerlrisotr, is a detailed explanation will be provided by footnote on the COC page. 5.14. See Figure 3 for a properly filled out COC form, and for examples of the use oftheerrorcoding system. 6. REFERENCES - Exygen Research SOP V401, Contract Research Sample Handling 7. FIGURES Figure 1. Chain of Custody/Analysis Request Form Figure 2. Listof Error Codes Figure 3. Example COC Sheet and Use of Error Codes 8. SIGNATURES (SOP becomes effective on the date itis signed by the implementation director) Robert L. Grob, Ph.D. D--ate Implementation Director John M. Flaherty. Date -- `Analytical Facility Management Page Sof 8 e S ==ea ism ClrsuitCourtofWoodCount,WY,CivilActionNo,01-C-608 ~ Figure 1. Chainof Custody/Analysis Request Form Exygena . IAIN OF CUSTODY. Si - .-- --_-- ------ Abn -- -- Fe Ee bTose ety de E FEE EE nem A TT e-- pee --------t-- eeme -- a -- ) Be--r-- eee T-- ereeeereeree-- -- ee -------------------------- --------r------------------ - f--------------------------] [rrr -------------------------- [e--------------------r------------ He ---------- err r-------- 1 f-- e ------------------------ ee--ee E-- e ------ ee -- re-- -- E-- e ------------------------------ tt ----e---------- e--] I------------|----------------------r --------1 geese ef f--------] [------r--------rrr---- e-------------------------- EE e--E ---- (a TT A,S-------- Page 60f 8 JackW.Lach tL. E.Ld PortdeNemours ndCompany NlpoeiniCxoema2lMood CoCno A,mNo.0 ~ Figure 2. List of Error Codes EXPLANATION OF ERROR CODING C`aonrdrleocrtwiroine-oofvrear,w daantdafiilslminagidne btyhedcroarwreicntgdaatsai.nglCearlienmeutshrtobueghtaktheenenrortotnoeooubssdcautrae {thhee coorrirgeicntailone,ntarny.d aTnheexpcloarnraetcitoinonisigsinvietnisfloerdthmedcordraetcetdiobny. the individual making The following error codes shall be used to explain corrections: (wl) ((cwco)) Inadvertently recorded in Wrong Location CWrhiatnegOevdefror(TgercehatneirciCalnariintaydvertently wrote over the error instead of drawing a line throughthe error) (sp) (i) Spelling error Inadvertently not Recorded at time of initial observation ((c9e)) RCaelccourldaitnigonErErrorror - (ne) (ee) NEnutmreyrincoatlintirtainaslcerdiaptnidondaEtxerdorat time of entry (t) (wd) (sm) TWrraonsncgriDpattioeneEnrtrroyr Stray Marks appearing on data with no other feasible explanation (le) Late Entry (1) Technical error Codes, on the other COC than those defined form. Errors that above cannot may be used, be explained if explained or using an error defined by code must footnote be fully detailed at the time of correction. Eferarsoirblceo,dtehse aerrerotrosbheouclidrcbleedfaoontdnowtreidttweintahbaonveasotrercilsoksoertootthheer csoyrmrbeoclti,ona.ndIefxtphliasiinsednoatt the bottom of the page. Page7of 8 SmllmdCseotl EComA 1.CoT ld Figure 3. Example COC Sheet and Use of Error Codes Exyyge:N ! rre coe ! 1 CHAIN OFCUSTODY T8142310002 ww com. FAX: 814.231.1580 A ap rE 3 2. Jobe Dec StaFE Gacrammmanoncose:A LBiliit 7sTints hone: (accCade Lar Si w--_--" i mat: e ---- PR da ogg shah So 1ktvkPa | ET by i Ro hl Re pre1 or Te Apl Tolghs am oul Jara | . AerAni Sack olluln aseem| elk apm | = rr = rr 1] 1 r= ---m--f Ariz 4 --- ll a 1 ~~~: Imm Tr = 1 EZ -- rT r 1 a -- ey KH ec7o ] R ~-- rT 1 ------- Tr ,-- ---- -- TT [eCSet Cc I 1 KEEPTHEPINKCOPY nd ncetheobertwowithsampleshpmert Cos1l0e8r: O EN 07/1) Sia s-- | [Jaden Dns | "Visas[210an) trl oJ he Le Page 80f 8