Document ZJMxjJogb1gRQaL1w2zgVdN18

ARLZE_--~ 1048 3MMCompany FINAL REPORT Epidemiology, 220-3W-05 Medical Department 3M Company _stPau.MNssM4 Date: October 11, 2001 TPietrlfel:uoAroLoocntgaintouadtien(alPFAOnaAl)ysLiesveolfs SinerRuelmatPieornfltuoorLoiopcitdaannesduHlfeopnaattiec(CPliFnOiSca)laCnhdemistry FTelsutorRoecshuelmtiscfarloMmeMdaiclaelESmuprlvoeiyleleanPcaertPircoipgarnatms of the 1994/95, 1997 and 2000 Study StartDate: July 1, 2001 IPrRoBtoAcpoplrNouvamlber (not applicable) ExeXmpt Expedited IRB Approval Date: program) (not applicable as these data are from a medical surveillance Principal Investigator: Co-investigators: Study Director: Geary W. Olsen, D.V.M., Ph.D.! Michele M. Burlew, M.S. Jean M. Burris, RN. MP.H.' Jeffrey H. Mandel, M.D., M.P.H.' Jeffrey H. Mandel, M.D., MPH." 1. 3M Medical Department, 220-3W-05, St. Paul, MN. 55144-1000 g Ss o 3=s 338 = 33 z= 58 000123 CONTAIN NO CBI 3PMagCeo2mp0a6n3y ABSTRACT `The 3M fluorochemical medical surveillance program was conducted in 1994/95, 1997 and 2000 at the company's Antwerp (Belgium) and Decatur (Alabama) manufacturing plants. Although cross-sectional assessments of the data have been reported, the opportunity to conduct a longitudinal assessment became possible as a result oaf large number of employee participants in the 2000 fluorochemical medical surveillance program. A total of 175 male employees voluntarily participated in the 2000 `program and at least one of the two previous program years. A total of 106 (61 percent) of the 175 employees participated in the 1994/95 program and 110 (63 percent) of the 175 participated in the 1997 program. Of these 175 employees, a totalof41 (24 percent) participated in all three years (Antwerp = 21, Decatur = 20), 65 (37 percent) participated in 1994/95 and 2000 (Antwerp = 45, Decatur = 20) and 69 (39 percent) participated in 1997 and 2000 (Antwerp = 34, Decatu=r 35). There were insufficient number of female employees to conduct any meaningful longitudinal assessment. Only 14 female employees participated in the 2000 fluorochemical medical surveillance program and at least one of the previous program years. Serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) were assayed in each surveillance program year although the method of analysis (high performance liquid chromatography mass spectrometry) differed slightly between years. A different research laboratory was used to assay PFOS and PFOA in each year. `The same hospital laboratory analyzed the clinical chemistries for all three surveillance years. These included: cholesterol (mg/d). high density lipoproteins (HDL. 000124 aFMuCgomepeansy mg/dl) and triglycerides (mg/dl): alkaline phosphatase (IU/L), gamma glutamyl transferase (GGT, IU/L), aspartate aminotransferase (AST, IU/L), alanine aminotransferase (ALT, IU/L), total and direct bilirubin (mg/dl). Most reference ranges remainedrelatively constant over time except for ALT. In each surveillance year, potential confounding factors were also determined. These covariates included age, body `mass index, number of alcoholic drinks per day and cigarettes smoked per day. `The continuous outcomes of lipid and hepatic clinical chemistry tests were evaluated as repeated measures incorporating the random subject effect fitted to a mixed `model by the MIXED procedure in the SAS statistical package. Restricted maximum likelihood estimates of variance parameters were computed. Adjusted regression models `were built by introducing all covariates and testing the covariance structure. There was a positive association between PFOA and serum cholesterol and triglycerides over time but not with PFOS. This was association was limited to the Antwerp employees and, in particular, the 21 Antwerp employees who participated in all three surveillance years. This positive association between PFOA and serum lipids is opposite the inconsistent toxicological evidence that suggesteda possible hypolipidemic effect of PFOA in rodents and no effect in primates. Adjusting for potential confounders, there were no temporal changes associated with the fluorochemical tests, PFOS, PFOA and TOF, and the hepatic clinical chemistry tests. Limitations of this study included the number of employees with three years of surveillance data (only 24% of the 175 subjects), the inability to analyze temporal changes due to small numbers in female employees, the use of different laboratories and the associated systematic (experimental error) with each fluorochemical assay for the 000125 3PMagCeo4m0p1a6n3y three surveillance program years and the lower levels of serum PFOS and PFOA `measured in each program year among these employees compared with those that cause: effects in laboratory animals. 000126 INTRODUCTION 3PMagCeoSmopfa6n3y The 3M fluorochemical medical surveillance program is conducted on a routine basis at the company's Antwerp (Belgium) and Decatur (Alabama) manufacturing plants. Employee participation is voluntary. Prior to 1994, only total organic fluorine was measured and no specific fluorochemical analytes were measured. Serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) have been routinely assayed since 1994/95 rather than total organic fluorine as the analytical capabilities have `improved. Cross-sectional analyses of the 1994/95 and 1997 medical surveillance program data and the 2000 data in relation to Antwerp and Decatur employees' serum PFOS levels have been reported elsewhere (Olsen et al, 1999a, 1999, 2001). In the 1994/1995 medical surveillance program, atotal of 178 male employees participated (Antwerp = 88; Decat=9u0r) and 149 male employees participated in the 1997 program (Antwerp = 65; Decatu=r 84). For these two program years, there were 00 few female participants to include in the data analysis (Olsen et al 1998). In the 2000 fluorochemical `medical surveillance program, there were considerably more participants: 421 males. (Antwerp = 206; Decatur = 215) and 97 females (Antwerp = 49; Decatur = 48). It was suspected that the increased voluntary participation in 2000 was due to increased `employee awareness of the persistence and prevalence of PFOS in human tissue and the environment and the company's May 16, 2000 phase out announcement that it would cease the production of perfluorooctanyl chemistry in certain repellents and surfactants by the end of 2000. Regardless of the surveillance year, there have been several consistent differences between the Antwerp and Decatur male employee populations. The Antwerp male 000127 3PMagCeo6m.p0a1n6y3 employee population has been significantly younger than Decatur, has had lower Body Mass Indices (BMI) andhigher self-reported daily consumption of alcohol. In addition, the Antwerp male employee population clinical chemistry profiles were different for several tests including lower mean alkaline phosphatase and triglyceride values and higher total bilirubin and HDL values than the Decatur male employee population. Analyses of workers'lipid and hepatic clinical chemistry results have not been associated with hypolipidemic effects and PFOS as reported in rodents (3M Company 2000; Haughom and Spydevold 1992; Tkeda et al 1987; Pastoor et al 1987; Seacat et al 2001a; Sohlenius et al 1993) and primates (Seacat et al 2001b). In the 2000 medical surveillance program, statistical analyses also examined the relation between PFOA and a calculated total organic fluorine index (TOP) to clinical chemistries, hematology, thyroid hormones and urinalyses (Olsen et al 2001). A positive association was observed between triglycerides and PFOA; however, this association was opposite the data that have inconsistently reported a hypolipidemia effect of PFOA in rodents (Haughom and Spydevold 1992; Pastor et al 1987) and no effect in primates (Butenhoff ct al 2001) Furthermore, this positive association between PFOA and triglycerides has not been observed at the 3M Cottage Grove manufacturing plant (Olsen et al 2000) where employees' serum levels have, historically, been much higher than those measured among Antwerp and Decatur employees (Olsen et al 1999; 2001a; Olsen et al 2001b). `The inability to assess temporal changes in cross-sectional studies is a wellknown limitation of this design. The large participation of employees in the 2000 fluorochemical medical surveillance who may have participated in the 1994/95 and/or 1997 surveillance programs at these two manufacturing sites allowed for an opportunity 000128 3PMagCeo7m0pfa6n3y to conducta longitudinal analysis among the male employee population. Altogether, a total of 175 employees (Antwer=p 100; Decatu=r 75) who participated in 2000 had also participated in at least one previous fluorochemical medical surveillance exam since 1994/95. Therefore, the purpose of this analysis was to conduct a longitudinal assessment of this 6 year time period regarding the relationship of PFOS, PFOA and TOF to the medical surveillance data collected on these 175 Antwerp and Decatur male employees. METHODS Data Collection Data were compiled from the 1994/95, 1997 and 2000 fluorochemical medical surveillance program databases. A total of 175 male employees participated in the 2000 program and at least one of the two previous program years.A total of 106 (61 percent) of the 175 employees participated in the 1994/95 program and 110 (63 percent) of the 175 participated in the 1997 program. Of these 175 employees, a totalof 41 (24 percent) participated in all three years (Antwerp = 21, Decatur = 20), 65 (37 percent) participated in 1994/95 and 2000 (Antwerp = 45, Decatur = 20) and 69 (39 percent) participated in 1997 and 2000 (Antwerp = 34, Decatur = 35). For purposes of brevity, these three subpopulations will hereafter be referred to as subcohorts A, B and C. Demographic data (age, BML alcoholic drinks per day and cigarettes per day) were recorded for each employee in each surveillance year. A standard set of clinical chemistries and hematology data was also obtained for each employee. Given results from previous toxicological studies, the longitudinal analyses focused on lipid 000129 3PMagCeoSmopfan6y3 [cholesterol (mg/d), high density lipoproteins (HDL, mg/dl) and triglycerides (mg/di)] and hepatic [alkaline phosphatase (IU/L), gamma glutamyl transferase (GGT, IU/L), aspartate aminotransferase (AST, IU/L), alanine aminotransferase (ALT, IU/L), total and direct bilirubin (mg/dD)] clinical chemistries that were measured in each program year by the same laboratory (Allina Laboratories, St. Paul,MN). Reference ranges were relatively constant over time, although for ALT the range declined from 20-65 TU/L in 1994195 10 1-40 U/L in 1997 and 2000. Fluorochemical Analyses PFOS and PFOA were assayed in 1994/95, 1997 and 2000. However, the method of analysis differed slightly for each year. In 1994/95, the method used tetrabutylammonium to ion-pair with POS and PFOA in the serum (Johnson ct al 1996). `The ion-pairs were then extracted with ethyl acetate. The abstraction product was then analyzed using high-performance liquid chromatograph.thermospray mass spectrometry. In 1997, the serum samples were analyzed by liquid chromatography/mass spectrometry, using selected ion monitoring in the negative-ion mode (Anderson and Mulvanna 1997; 1997b). In 2000, sera samples were extracted using an ion-pairing extraction procedure (Hansen et al, 2001). Only in2000were the extracts quantitatively analyzed for PFOS and PFOA as well as the other analytes: PFHS (perfluorohexanesulfonate), PFOSAA (Nethyl perfluorooctanesulfonamidoacetate), M570 (N-methyl perfluorooctanesulfonamidoacetate), PFOSA (perfluorooctanesulfonateamide) and M56 (perfluorooctanesulfonamidoacetate). High-performance liquid chromatographyelectrospray tandem mass spectrometry (HPLC/ESMSMS) was the 000130 3PMagCeo9mopfa6n3y technique used in 2000. The samples were evaluated versus an extracted curve from a human serum matrix. Analyses were conducted at different laboratories in the three surveillance years. For purposes of this longitudinal analysis, a total organic fluorine index (TOF) was determined by calculating the percent of PFOS and PFOA that was auributed to organic fluorine (64.7 and 69.0 percent, respectively) multiplied by the ppm `measured for cach of these two fluorochemicals and then summed to produce the TOF. Statistical Analysis Briefly, mixed models can be used in the analysis of repeated measures data which are simply data sets with multiple measurementsof a response variable on the. same subject over time. Detailed explanation of these models is provided elsewhere (Littell 1996: 2000). Mixed models contain factor effects which are considered both fixed and random. An effect is fixedif the levels in the study represent all possible levels of the factor,orat least all levels about which inference is to be made. Factor effects are randomifthe levels of the factor that are used in the study represent only a random sampleofa larger set of potential levels. `The focus of the standard linear model is to model the mean ofy by using the fixed-effects parameters . That is, y=Xp+e where y represents a vector of observed data, is an unknown vector of fixed effects parameters with known design matrix X, and is an unknown random error vector modeling the statistical noise' around XB. The residual errors are assumed to be 000131 3PaMgeCo1m0p0a16n3y independent and identically distributed Gaussian random variables with mean 0 and variance 0, A generalized standard linear model is a mixed model which is: y=XB+Zy+e wherey is an unknown vector of random-effects parameters with known design matrix Z, and is an unknown random error vector whose elements are no longer required to be: independent and homogeneous. If + are assumed to be Gaussian random variables that are uncorrelated and have expectations 0 and variances G and R, respectively, then the variance ofy is: V=ZGZ +R `The variance of the data, , can be modeled by specifying the structure of Z, G and R. `The model matrix Z is designed in the same fashion as X, the model matrix for the fixedeffects parameters. For the matrices G and R, a covariance structure must be selected in using mixed models. Since observations on different subjects are assumed to be independent, the structure refers to the covariance pattem of repeated measurements on the same subject. For most of these structures, the covariance between two observations on the same subject depends only on the length of the time interval between measurements and the variance is constant over time. Numerous covariance structures exist. Common examples include the following. Simple covariance structure (SIM) specifies that the observations are independent, even on the same subject, and have homogeneous variance. tis usually not realistic for most repeated measures data because it specifies that observations on the same subject are independent. Compound symmetric (CS, otherwise 000132 --- I 3PaMgeCo1m1p01a6n3y known as variance components) structure specifies that observations on the same subject have homogeneous covariance and homogeneous variance. Correlations between two observations are equal for all pairsof observations on the same subject. Autoregressive order | (AR(1))covariance structure specifies homogeneous variance but that covariances between observations on the same subject are not equal, but decrease toward zero with increasing time interval between measurements (lag). Its limitation is that observations `on the same subject far apart in time would be essentially independent. Autoregressive `with random effect for subject (AR +RE) covariance structure specifies homogeneous variance plus the covariance between observations on the same subject arises from two sources: 1) any two observations share a common contribution because they are on the same subject; and 2) the covariance between observations decreases exponentially with lag but onlyto the common contribution (not to independence). Toeplitz (TOEP) structure specifies that covariance depends only on lag but not as a mathematical function with a small number of parameters. The `unstructured structure (UN) specifies no patterns in the covariance matrix and is therefore completely general. The above structures are appropriateif equal spacing (of data) is assumed in a time series analyses. In situations where unequally spaced longitudinal measurements exist, spatial covariance structures can be used. In the present analyses, equal spacing was assumed given there were approximately 3 years between each medical surveillance program examinations. Akaike's information criterion (AIC) and Schwarz's Bayesian criterion (SBC) are indices of relative goodness-of-fit that were used to compare models with the same fixed effects, but different covariance structures. SBC penalizes models more severely for the 000133 - P3aMgeCo1m2p0a16n3y `number of estimated parameters than AIC and thus the two criteria did not always agree on the choice of `best' model. SBC was preferred. In the present study, the continuous outcomes of lipid and hepatic clinical chemistry tests were evaluated as repeated measures incorporating the random subject effect fitted to a mixed model by the MIXED procedure in the SAS statistical package (Litell etal 1996). Restricted maximum likelihood estimates (REML) of variance parameters were computed. Adjusted regression models were built by introducing all covariates (sec below) and testing the covariance structure. Based on goodness-of-fit tests. described above, AR+RE, was routinely considered the best covariance structure chosen for the mixed models. Covariates included PFOS (or PFOA or TOF), years of observation, the interaction term of PFOS and years of observation, age, body mass index (BMI), cigarettes smoked per day, alcohol drinks per day, year at first entry and baseline (at first observation) years worked. For hepatic clinical chemistry tests, serum triglycerides was also considered a covariate (Olsen et al 2001a), RESULTS Provided in Table I are cross-sectional analyses of the study subjects who. participated in each of the three years (1994/95, 1997 and 2000) stratified by location. As reported previously in the complete cross-sectional analyses of these programs (Olsen etal 1998; 1999; 2001), Antwerp employees in this longitudinal investigation were younger, had lower BMIs and drank more alcoholic beverages than Decatur employees. `They also had consistently lower triglyceride and alkaline phosphatase levels and higher HDL and total bilirubin levels. Decatur employees, on average, had serum PFOS levels 000134 P3aMgeCo1m3p0a1n6y3 that were higher by approximately 0.5 ppm in each cross-sectional analysis. Similar findings were observed for PFOA except with the 1997 data where the two populations had comparable mean PFOA levels. Provided in the following two tables are the cross-sectional analyses for the three subcohorts by location. Among Antwerp employees (Table 2), each of the three subcohorts had lower mean serum PFOS levels in 2000 than at their year of entry whereas there were no consistent changes across subcohorts with PFOA. Among the three Decatur subcohorts (Table 3) mean PFOS values declined over time but mean PFOA levels tended to increase. Provided in tables 4 through30are the mixed model coefficient estimates, standard errors, p-values and 95% confidence intervals from testing potential determinants of lipid and hepatic clinical chemistry change. The natural log was used for all dependent variables. `Tables 4 through 6 contain the analysesfor cholesterol. There was no change in cholesterol associated with PFOS (Table 4). Overall, PFOA was positively associated with cholesterol as the main effect coefficient was significantly positive but its interaction with time (years variable) was negative (Table 5). Provided in Tables SA through SD are separate analyses for Antwerp for all subjects (Table SA) and by each subcohort. The PFOA and cholesterol association appeared to primarily reside with the 21 Antwerp `employees in subcohort A (Table SB). This finding can also be observed in Table 2 as the subcohort's mean PFOA levels went from 1.32 ppm, to 2.37 ppm and then declined to 2.06 ppm at the same timetheir cholesterol values rose from 208 mg/dL to 226 mg/dL to 229 mg/dL. There were no associations between cholesterol and PFOA observed among 000135 3PaMgeCo14m.p0a1n6y3 the Decatur employee population (Table SE) nor were there significant associations between TOF and either location (Tables 6, 6A and 6B). There were no significant associations between PFOS, PFOA or TOF with HDL (Tables 7 through 9). BMI, alcoholic drinks per day and cigarettes smoked per day were the most significant associations with HDL. Triglycerides were not significantly associated with PFOS over time (Table 10). Overall, riglycerides were positively associated with PFOA (Table 11) as seen with the significant positive coefficient for the main effect of PFOA and the negative coefficient for its interaction with time (years). Again, this effect was observed among the Antwerp employee population (Table 11A) and in particular, subcohort A (Table 11B), but not subeohorts B (Table 11C) oCr (Table 11D) or Decatur employees in general (Table LIE). Among the Antwerp subcohort A, their mean triglyceride levels rose from 85 mg/dL to 115 mg/dL to 123 mg/dL at the same time their PFOA levels increased from 132 ppm t0 2.37 ppm and then declined to 2.06 ppm. Although the main effect for TOF was significantly positive, the interaction term with time (years) was not significant (Table 12). Again, this association was more consistent for Antwerp employees (Table 12A) than Decatur employees (Table 12B). Among the hepatic clinical chemistry tests that were adjusted for the various changing demographic factors and triglyceride levels, there were no significant associations between PFOS, PFOA and TOF with changes in alkaline phosphatase: (Tables 13 - 15), GGT (Tables 16-18), AST (Tables 19-21), ALT (Tables 22-24), total bilirubin (Tables 25 -- 27) or direct bilirubin (Tables 28-30). Observations apparent in `Tables 2 and 3 can also be seen in these mixed model analyses. For example, the two 000136 P3aMgeCo1m5p0a7n6y3 `most significant predictors of alkaline phosphatase were time (years) and location (as seen with the lower values among Antwerp employees). For ALT, entry period was also significant as it reflected the higher reference range values for ALT that were used in 1994/95 than in subsequent years. DISCUSSION `These analyses were the first longitudinal assessment of the fluorochemical `medical surveillance program at 3M's Antwerp and Decatur manufacturing sites Overall, we observed no associations that were consistent with the toxicological evidence that PFOS produces a hypolipidemic effect at threshold dosages in rats and primates (3M Company 2000; Haughom and Spydevold 1992; Ikeda et al 1987; Pastoor et al 1987: Seacat et al 2001; 2001b; Sohlenius etal 1993). Our results did suggest a positive: association between temporal changes in cholesterol and triglycerides and PFOA; however this is also inconsistent with the toxicological evidence that PFOA may result in a hypolipidemic effect in rats (Haughom and Spydevold 1992; Pastoor et al 1987) but produced no effect on blood lipids in primates (Butenhoff et al 2001). Even though we were able 10 perform a longitudinal assessment, there were several limitations to our analyses. We were limited to 175 employees of which only 41 (24 percent) participated in all three surveillance years. Although a greater absolute number of Decatur employees (but not percent-wise) have participated during each year, for this longitudinal assessment there were more Antwerp (57 percent) than Decatur (43 percent) employees. Antwerp employees have had lower serum PFOS level by approximately 0.5 ppm (Olsen et al 1998; Olsen et al 19992: 1999b; 2001: 2001b; 000137 P3aMgeCo16m0pfa6n3y 2001c). There were insufficient numbers of female employees for any meaningful longitudinal analysis. Given the variability inherent in the analytical method (Hansen et al 2001) and the different laboratories used, serum PFOS and PFOA levels may have systematic error incorporated in each measurement that we were unable to assess as blood samples were analyzed only at the time of the surveillance program. This systematic error may have masked associations with lipid or hepatic clinical chemistries, although the range of PFOS and PFOA measured was relatively consistent throughout the study time period. Because 3M has announced a phase-out of the production of perfluorooctanyl chemistry-related materials, we doubt that there will be many more subjects in the future that can be included in this longitudinal assessment. Also, the findings from this assessment would suggest that serum PFOS levels have cither remained constant or declined slightly over time among these 175 employees. On the other hand, serum PFOA levels appeared to trend upwards, on average, by approximately 0.510 1.0 ppm for these employees. Another limitation is the fact that the serum PFOS and PFOA levels measured in these employees were lower than those that cause effects in laboratory animals. In summary,a longitudinal analysis over a six year time period of 175 Antwerp and Decatur male employees did not show significant changes, consistent with. toxicological data, of lipid or hepatic clinical chemistry values associated with either PFOS or PFOA. The PFOS and PFOA serum levels measured in these employees were lower than those that cause effects in laboratory animals. 000138 P3aMgeCo1m7p0fa6n3y REFERENCES 3itsMsaCltosm. pSatn. yPa(u2l00(0M).N)S:I3DMSCIonimtpiaalnays,se(susnmpeunbtlirsehpoerdt:repPoerrtf).luorooctane sulfonic acid and Minneapolis (MIN):University of Minnesota, (unpublished report). APenrdfelrusoornooDcJt,anMouatlevaannda DPeErf(l1u9o9r7oao)c.tanAensauliytfiocnaalteRienpoHrutmfoarntSheerDuemtebrymiLnCa/tMioSn. ofIthaca NY: Advanced Bioanalytical Services Inc; August 1997. PAenrdfelrusoornooDcJt,anMouatlevaannda DPeErf(l1u9o9r7obo)c.tanAensaullyftoincaatleRienpoHrutmfaorntSheerDuemtebrymiLnCa/tMiSon. ofIthaca NY:Advanced Bioanalytical Services Inc; September 1997. BLiuetdeenrhoPf,fOJlLs,enCoGsWta,G,ThEolmcfoomrbdeP.C,TFoaxrircairtDy,ofHaanmsmeonnKi,uImwapierHf,luJournogocRt,anKoeatnene(dAyPFGO,) in cynomolgus monkeys after 26 weeks of oral dosing. (unpublished report) Hansen KJ, Clemen LA, Ellefson ME, Johnson JHO (2001). Compound-specific, quantitative Sci Technol characterization 35:766-770. of organic fluorochemicals in biological matrices. Environ HpearuflguhooromctBa,noSipcydaecivdol(dPFOOA()19,92p)e.rflTuhoeromcetcanheasnuilsphmounnicdearcliydin(gPFthOeShAy)poalnidpcelmoifciberfifcecatciod.f Biochemica et Biophysica Acta 1128:65-72. Ikeda T, Fukuda K, Mori I, Enomoto M, Komai T, Suga T (1987). Induction of cytochrome P-450 and octanesulfonic acid. In: peroxisome proliferation Perixosmes in Biology in rat liver by and Medicine. perfluorinated (HD Fahmi and H Ses, eds) New York:Springer Verlag, pp 304-308. PJeorhfnlsuoonroJoDc,taWnoolatteeraJnTd, PCeorlfaliuzoyroGoEc,taRneetshuwliflolnaPtAe,inNeHlusmoannRMS.eruQumaUntsiifnigcaltoino-nPaoifr ESxptercatcrtoimoentrayndwiHtihghAuPteormfaotremdanScaemLpilqeuiPdreCpharraotmiaont.ogrSta.pPhayu-lT,hMerNm:o3spMraEynvMiarsonsmental Laboratory, 1996. Littell RC, Pendergast J, Natarajan analofyrespeiatsed measures data. R (2000). Stat Med Modeling covariance 19:1793-1819. structure in the Littell RC, Milliken GA, Stroup WW, Wolfinger RD. Cary NC:SAS Institute Inc., 1996, 633 pp. SAS System for Mixed Models. 000139 -------------------------------------- -------------------------------- 3PaMgeCo1m8p01a6n3y cOllisneicnalGcWh,emiBsutrrriiessJ,Mh,emMaatnodleolgyJHa,ndZohboerlmLonRe(s1i9n98r)e.latAinonetpoidseemriuomlolgevieclsinovfestigation of perfluorooctane sulfonate in male Company (unpublished report). fluorochemical production employees. St. Paul:3M OanldsehnepGaWti,c BaunrdrilsipJiMd,clMinaincadlelchJeHm,isZtorbyetlesLtsRi(n1f9l9u9o3r)o.chSeemriucamlpperrofdluucotrioooncteamnpelsouylefeosn.ate JOEM 41(9):799-806. OMlasnednelGWJH, (L1o9g9a9nb)P.WF,luSoirmopcshoenmiCcAal,eHxapnosseunreKJa,ssBeusrsrmiesnJtMo,fBDuerclaetuwrMcMhe,miSccahlumapnedrftilJmC, plant employees. St. Paul:3M Company (unpublished report). hOelpsaetnicGeWn,zyBmuersri,schJoMl,esBtuerrollewanMdMl,ipoMparnodteeilnsJiHn (2000). Plasma cholecystokinn ammonium perfluorooctanoate and production workers. Drug Chem Toxicol 23(4):603-620. sOlesreunm GpeWr,flBuourroloecwtaMnsMu,lfoBnuartreis(JPMF,OSM)ananddelpeJrHlf(u2o0r0o1o2c)t.anAoactreos(sP-FseOcAti)onianlrealnaatliyosnistoof fcleimnailcaelecmhpelmiosyterey,patrhtyircoiipdanhtosromfotnhee,2h0e0m0atAonltowgeyrapnadnudriDneaclaytsuisr rfelsuuolrtoscfhreommicmaallmeedaincdal surveillance program. St. Paul (MN):3M Company (unpublished report). JOKl,seMnaGndWe,lSJcHhm(i2c0k0l1be)r.MNDe,scTriieprteinvseJsMu,mmLaorgaynofPWse,rBuumrrfilsuoJrMo,chBeumriclaelw lMevMe,lsLaumnodnbgerg `employee program. participants St. Paul:3M of the year 2000 Antwerp fluorochemical Company (unpublished report). medical surveillance O(l20s0e1n6)G.WD,esLcorgiapntiPveWs,uSmimmaprsyonofCsAe,ruBumrrfilsuoJrMo,chBeumirclaelw lMevMe,ls LaumnodnbgeregmpJlK,oyMeaendel JH participants of the year 2000 Decatur fluorochemical Paul:3M Company (unpublished report). medical surveillance program. St Pastoor TP, Lee KP, Perri MA, Gilles PJ (1987). Biochemical and morphological studies of ammonium perfluorooctanoate-induced hepatomegaly and peroxisome proliferation. Exp Mol Pathol 47:98-109. Seacat AM. Thomford PJ, Hansen KJ, Clemen LA, Case MT, ButenhoJfLf (2001a). Sub-chronic dietary toxicity Sci (submitted 20012). of potassium perfluorooctanesulfonic acid in rats. Toxicol Seacat AM, Thoford PJ, Hansen KJ, Olsen GW, Case MT, toxicity studies on perfluorooctanesulfonate potassium salt Butenhoff JL. in cynomolgus Subchronic monkeys. Toxicol Sci (submitted, 2001b). 000140 P3aMgeCo1m9.p0a7n6y3 SPeorhflleunoiruosoActKa,neErsiulkfsosnoincAaMci,d HisoagsptotreonmtCi,ndKuicmelraonfdpMer,oxDiesPoimearlrefaJttWy (a1c9i9d3B)-.oxidation aPhnadromtahceorlacTtoixviitcioels k72n:o9w0-n931.0 be affected by peroxisome proliferators in mouse liver. 000141 Company | WhDeomoTgraaphiictChanraciwrioircMsoenred lMeidiacallCShremvicsofExAamninwaetironnydDDeevcet9Ma9k9e9E4mopldoy0e0s0 w AmwpNeahe ) Des ed) Amwepe Nesh w Decuw(No5S) Amp)a Decsm wovers | wos Mem SD Mam SD Men S$ Was ae mw a Mem SD Men SO ss le ue to Mem er iw ron WS a ese wn wes an aa as or Wem at am am ws a0 am te aa ae am TM woe wm ww mow ow EY Bowe wm a we ww as we ow Aol HOM a ee er ww ow ae oer DWoaedsian 10ST #70 52 me a a er wy ss Coews 47 ws soa sow soos soon Goes 1 www wm as woos mow om ow oi. "5a on wow a 0s on wow - Tighe 0 mem ws wow om ow oe ous MP2 we wm ws wow sw ow ow aor woos wow ow om wow sw wow ast som won x sw x ar " nw os ow on 2s wn wow TeBiatn 0% 0s 0s 02 of 0s ee 02 0 0 os 0 DraBiiobn 0204 02 em oF 00 or oor of oss 01 om SPOS BPO pel pel compared oyearspecifc nalysesofothermamutacrins S0Q0 | b 2 Deeg TalCe.hPCaalrorsaSsdet1rodTnCwAionrsMiosCk MMhesnistocdfSTSavntdmneaSredEgrsxetieisotfoAoofnSsceBnrsetMPsaROtS1,E9P5l1Fo8OiA40T(OF:04. Rei AGI 1s Bess aCe) wr cel amean boovmes coe os Mem Sp wom Men SD maw Men S$ Mem 0 26 me en Mem Sb Mem So Mew sp 1s ow am es on won mom em de 2 a As ee 2 10 7 mm ow wor MW as see 1 en ar om us 1s is ow a Boe wows ow 1 ow oe ow 1 ow wa Bw aww ms aw om a wa ams wows a ay 1314 10 09 22 er esr a2 ou as oe Goi 148s 7s 7 6 a 4 xs a eVoavesen 99 43 We 99 4 sas a9 4 ue a ss a Cunt Ww mw me 0 ww om ow ww we LT TS g Ts 85 mw ws @ ea me ss ws os Mme @ mm ow @ we ons on ow uw os on @ mov ow om x ow om om om on ow ox wou ast xs os omo 0s wm 7 om sow 9 oa are sw om wom on moms ona Tees 1003 05 04 08 03 08 0a 10 en 0 a ar 0s Diabla 02 00 02 om 01 00s 02 os 01 om 01 om oi om .p<.05 than chercomparisoinnyesa)r b. p<03 thangroupA c. p<.05 thangroupC. 000143 pros Pron Tor Ase Ba Dinky Corewsty Wfoarkcedies DemograpThaicbClhe3a.raCcrtoesrsi-sSteicctaionndalCiAianlCahoefmMliesayensanosdfSTitheaesnSdubgDroeupsiotfoDfieSccosrtaunrmMPalOeS.EPrpFlOoAne.eTsO(FA., ndC) M Company Page 22006} `Who Participated in Twoo More Medica Srvilncs Examination: Between 1994 snd 2000 ANS) ew BeeN) Ana em cous we AM=20 BN=20) coved Men SD Mem SD Mem SD Mem SD Men SD Mean SD Mem SD MW MT M6 19 1% 180 1 UT 204 is 10 1S os L008 200 LL Le Le I de 1M 20 20 Le Li WIS 36 1m 22 Um ae Lm 26 206 208 176 208 1m @ 7 ws ws 1 wm sw 1 ss as Jaa W333 Wal me 4s me 41 wr 33 m3 4s 01 03 04 08 01 01 ol 02 00 0 02 03 01 02 6 Bw 1s 4 ws on 3s 0s 4 196 86 23 52 M6 86 2 00 196 86 u3 52 m2 wo Croke 2S 3% Wm 3% ow mM mm wm nm 4 woL os Ws ws ww sw nw 6 aso - Toeorides 180 8 29 Ws WS Us U8 m2 93 mw 6 ls 0s MMos 9% ww os om om ow om wm om ow on ow dar ax mom x ow ow wm 6 ow ow ow on ast Ros 6 3 6 ow 8 ws ox 4 on 1 ar 2 m9 wm ws M6 om oR on on ou Toaimn 06 02 05 02 06 02 06 02 08 02 01 or os 02 Dian 02 005 02 004 01 004 01 005 01 008 01 0 oi 00 3p<.05 than chercomparisoinnysea)r bp<.05 tangrowp Ac. p<th.ang0rou5pC 4 peCotmpaeny om Tsing NPatbeer)ofDYeeaseofGrbsotfvCaohneof rAnCthwaenargpInDcloocinsg PMElOSEamnpdlohyeeersacion wih 95%Confidence Limi Costes si pbc tower per nen san om <a sais sas pros 000 ooos os os YrsOberon 00009 oms se ous oon Pros varon 00008 om 000 oo ae oor oons a oon oon or ows oo " ooo oor Drnktiy one ooiz 2 oon oo Cipnencsiny oon out a 000 oar ; Location oo oo 2 om ous EyPees 0061 oo o os ous Baseline Yes "000s ous n oo oo Worked ---- "natural log. possi Savion -------------------- 000145 RMemues Taolem.ToMinngedFKMtaocmdealrCoDofeYeefacmsioenfstOihomrfsaC,ohnSooufncdAaowCEearnresn5dcDt,elciPng-iPVFeOlAnaEdneld95osh%neCnotnsicdoene wLiihs 95ConteLimsi Contre = pote Lover vp nee asm on <oon asot son ron oon oom as oon oon YorOveraion ms 000s a "000s ois PROAsYasons-oms 002 ws a0 000 ree ooos oon or oon oon i oor om oo ooomns oon ork oo oon ES "aot oon Cipstny "oom oor 2 000 oon EyPea oes oo on aos om WDoeesve 000 oon is 0009 oor "nara tog esis 000145 neCnomopaeny ablrSoA.m TMeisxteidngMPoodteenltiCaolcDfetiecremninEasnttismoatfeCs,hoStlasnedrarodlrChoarnsge(SEI)n,clPu-diVnaglPesFOanAda9n5d%hCeonIfnicdreanccieonLimits with Nomeof Yeasof ObservationofAntwerp Male Employees 95% Confidence Limits oo Content se pac Lower Upper Inereept amo ou <o001 aa soos PFOA 00 oon o 006 0053 YearsObservation 0005 0006 36 -0006 oon? ROA YeusObs 0003 oon x -0009 0002 I 0009 0003 ns 0003 0016 Ba 000s 000s 1" ~0003 oo Drinksday 002 ois ~0004 0047 Cigartesiday ooo oon w -0003 oon ; En Periods 00m 00% o 0001 0153 Basen Years 0002 oon Nees @ ~o0010 oo t19u9r4a05lv5 1997 000147 | Ct ts ot sere Coins sre a popo - I wm. I" . am awe -- -- wn ne, m aee Cgareestny 000 0I00"s sWt em000 oon ] "natural log. 000/14 EO -- from Testing Sone oe Potential Determinantsof Cholesterol' Change Including PFOA tae and the Interaction with omcommetins oo Catton se pune je ee ns ass om <omi ase 530 ron sors oar 0 oone oon YeasOrrin 0005 aos 5 oon oon on Yamon oom oom oon oons I oom ams ome TM I oot oom 5 oom oom | ewe oon oon - oom om -- om oon " om oom . BSeus n 000 oom "oon oon "natural log 000149 PaMaCgoem2p8a0n1y3 "TabflreoSmD.TesMtiixngedPoMteondteilalCDoefefitcieentrEmsotiifmCanhtoeal,esnSttetarnodsla"rCdhBaonrgesI(nScEl)u.dPing-PVFaOaAlnadunde9h5se% ICnotnefraicdteinocnewiLtihmits `NumberofYears ofObservationof Antwerp Subgroup C (1997and2000) Male Employees 95% ConfidenceLimits Coefficient SE pale Lower Upper nterept asm 0281 <.0001 395 5100 PrOA [ey [ 95 ozs on YeasObservation 0010 0026 2] -0065 [x PFx YOeasA Obs 0010 [5 6 -003s o0ss Age 0016 0006 ot 000s [3 BMI 0009 ooiz " -001s 00 Dnkslday oom oon 3 00m 0100 } Cigarettesidny -00001 0003 7 -0007 0006 : BaselineYears -0005 0008 oe a -oo2 [on | 000150 | nMCeommpaany | "TabflreomSET.esMtiinxgedPoMcondteiallDCeotcerfmcienanntsstiofmaCthso,lsSctranodlardChEarngoesI(n5c)lu,diPn-gVPaFlOusAnandd95he% ICnotnrfsicdetnocnewLiitmhits | Numberof ears ofObservation of DecaturMale Employees 958% ConfidenceLimits Co Codfelem SE ple Lover Upper ere sz 0x6 <oo01 as10 sen ! YearsObservation -0002 000s n ~oon7 oo FOAXYesObs 0003 0003 2 -0009 TM Ae 0002 000s 0 ~0008 oon a 0003 000s 55 -0006 oon Drinkatsy ~o0ss 00s o "oss ~o001s Cigaretestay -00 ocr 15 ~0004 00007 Bom EntyPeriod bed 1t9us5lo4gvs919597 mae o0i7 0010 En -00 ous 000151 mcoempnanay || "Tabloem6. TMeisniemdgRMPoomodbeetlrioCofeDfeefaticerirsemnoitnfaEGnthtsieortfCesth,oaSntlaaenfdtaAr"md reChorarnsgaenSdEI)Dn,encPai-tnVugarlTMuciOskFsEnadmnp9l5ho%eyeICeonsnafcitdienocnetLihmits 95% Contdene Limits Co coticen se pe Love Upper nercept Ir om <oon asm som Tor oui ous on oo 00s Years Observation Ir oos x 000s oon TOFxYasOb 0003 oon o 000s oom | 0007 oom o oon oo at 0006 ous os "00001 oon Driksisy oo oorz "002 00% Cipmeesttey "oon oo nn 000 oon . Locations oor oon -00n ons En Periods oon oo " 0010 om WBaosrelkienedYears "000s rang CE oon renree0-- 009 --t-- oo -- 000152 | PCeompeany ablreo6m4,TeMsitixnegdPoMtoednteiNlalCoDeoetfearcfmeiYmnneaanEtrssbtoiomffaOtbCeehssoe,lreSvstatratenirdooanlr"doCfEhaArnongsee(IrSnEc)lM,udlPi-neVgaETlmOupeFlsaoayndedes9h5e%nCeosncfiidoenncweiLhimits 95%ConfidenceLimits Coeticien se pae Lover Upper otrep am 0150 <o001 [ry sons Tor oor oon " oo ons YenObsenaion 0004 oon TOFx Yeo -00008 oon 55 0009 oor? wo ~0005 oo ne oom oon o oon 0016 mr ou oo Driksisy oo oor 2 -00 oo 1 0006 oo | Crue 000s 0002 000 oons : | ay Periods oon oo 0 0006 ous | NBaste in Yee ars d ~00008 000s 5s oon ous | "1na9tu0ra4l l5ogvs 1997 || 000153 PCoemeey | "Tablreo6mB.TeMsitinnegdPMoodne`lNiuCmoDbseefrtocmfeiYnenaEarssttoiosfmfOaCbthseoselreSvstatatenirdooalnr"doCfEhDraenocgsaet(uIr5n)Mc,ahliPe-nVgElTmuOpeFlsosaynnedds9th5e%nCronsfiidoenncweiLtihmits 95%Confidence Limits Co comeem se pose Lover per nee sau om <aont asm sos Tor oo oon 1 0007 ons YeasOberaion ~~ -0002 ous TOF Yeon -0002 oon ne oo oms 00s oon 2 "0006 oot 00s oor mn oon Ir 5s 0006 oon Drnkttay oom ous oz "010 oan Cpeestay 000 oor 10 Er oom . NBeaswteidn Years 0002 oo "000 000s ai35u49gsvs 1997 000154 ] | 3PMeCoampransy "Tabler7.omMTiexseidnMgoPdoetlentCioaelffDiceiteentrmEitnimaantotssf, HStDaLndaCrhdaEnrgosInc(SlEu)d,inPg-PVRaOlSesnadndh9e5I%nCcorncfiiodnenwciehLimits { `Number of YearsofObservationof Antwerp and Decatur Mle Employees 95% Confidence Limits Costicien se plu Lower Upper Intercept am [a <o001 390 05 pros -0010 000s x 002% 0007 | Years Observation ooo 000s n -0008 oon PROS xYearsObs 0001 002 2 -000s 000 Age 0004 0003 Ex -0002 oon BM -00n7 [ey <0001 -0025 0010 Drinksday 0064 oo <o001 0037 0090 Cigaretestday -0004 oot 0s -0007 -0002 : Locaion 006 00 00 0091 Entry Period [3 002 " -0038 [ Baseline Years -000 [= o -o013 -00005 Et cee-------------------------------------------- "*nAnatrwaelrogvs Decatur 1994195vs 1997 000155 Pcoossmepeasr | "Table 8. Mixed Model Coefficient Estimates, Standard Errors (SF), P-Values and 95% Confidence Limits fromTestinNg iPotmentobifalYeeDaerrtseromfinOannstesrvoaftiHonDoLf ACnhtawnegrepaInncdlDudainguPrFOMaAl anEdmtphleoIyneteesraction with | 95%Confidence Limits Coeticient se pac Lover Upper Intercept 216 ous <oom a5 as ron 0006 oon 56 0027 oars Years Observation oons ows 3s ~0005 oon POA VesObs 0002 ou 0006 oon ee oon 000 EY 0003 0010 nar "oon 0004 pr 00s "0010 Drikslday oo oo <onn oo ooss Cipsreetiny "0004 oon Location ows oon 0s ~0007 0002 i ~0076 00% En Period 0020 oon 5 "002 oon BWaosrlkee_dYears 0007 oon o ~o0n 0004 "H naturae l log.t 000156 a Meum Tile. ised Mel Coffin sits, Sn Er (5), PVales nd 95% Confidence iis | from Testienng PeotrenotiaYloDuertserofmiGnaantts ouf nHDoLf"ACrhtaengesInndcluDdeinagTrOFalnedEmtphleoIynteeersaction with 05% Contes ini commen sw pu Lover Gone [-- aan ous om son ws or ooo aos - Er aon VersObraion 0004 aoos a "oom aoe TOF YemOl 0009 aor 5 ooo I ne oon os 2 "os ooo pt "oon I pr "os "0010 Drv oes oors <oon oon ao -- ooo oor wos "0007 "02 Lesions oor aos 5 aos 002 [-- oon oon 0 "aon oss WFeOis os c o o "oo ; oom fo is 000157 nMcsorepy able 10. Mid Mode Cosi sie, Sands Err (SE. Vacs rd 95%Confess from Testing NPootemntoiatl oDeYteermsinoafnthsoifrTaringloyceAridwe' CehangsendIDs ncluding MPFaOeSEamnpdltohyeeIsnteraction with 95% Contr Limi coin sE pote Lover te nee a0 ons <oon 2008 aan ros os ooo 2 001s 006s VenObrsion 000 oon n 009 oon PFOSx Years Obs 0.006 TM oon a 000 Drs "oom Cipmediny oon Locsin oon En Pro aos VBaecst Yer aos 0.005 : 000s 0009 oom om ows om oor 2 0.004 a aon <oon oss n oom 2 os " "ois 2 oss 50 EE 0010 001s ous oom os oon? 027 02 ooo-- + "naturallog. 000158 Roemcys Table 1 Mined Model Coefien Estimaes, Sind Eres 5). Vales and 95% Confidence Lis from Testing PNotenetiaal DetYeermsinoafntisonfTvrigalyceorfidte"oChyanage InDcluedisng PMFeOAEamnpdlothyeeIsnteraction with 958Coen Limits comin spe Lover oer re 25 om <n Lass S150 vor aon oars woz aos Im YenObenaton 0007 oorz 2 "oon oon WOAxYemOt 0008 oats u os oon re a oor o oom oon wt 00s oo <oon oo TM -- "oo ao " om oom Cipreestiny oon oo wo os oon Losin om 00% " "ons 0 -- oms oon n "oon oe Bute Yes aos I a "oon oon TI c "natural log E isto 000159 ncowmp Tale 1. Med Mod Colic Bite, Sandd Err 5, Vland95% Contec Lins | from Testing Somber Yowof Ovation of rr MeEms Potential Determinantsof Triglyceride" Change Including PFOA and the Interaction with | 95%Confidence Limits Co come ow pate . Upper er 2001 om <omt 2m sas vor oon oom ws oon or VersOvrom 0034 ours = ome oon rons amon 0010 oon is "oan oom ae oon oom n "oom oss a oa oo wr oon aes Deku oa TM " om aon Cie oars oo0s aot oom ous . Emree oon oi 0 oan oss Scelse Yes TM oon % "oor TM ferris "natural log 000160 MPcoempoey | "Tfabrloem11T5e.stiMnignePdoMnodtealDCeotecrfmcineanntEssotfiTmartesi, gStalndyarCcdhaEernrgrorsiI(nScdEl)ue,din"gVaPluFeOsAaanndd9t5h%eICnornaficdieonncewiLtihmits Numberof YearofObservoafAtnitwoernp SubgAro(1u96p5,199 nd2000) Ma Employees 95% Confidence Limits Content SE pane Lover ope Inereep 104 1063 0 0380 sas Poa om 00st on oom as YenOberon 0167 00 <1 0091 oan POAYesObs -0061 oon <0 "0084 00% I ~0007 oon 5 -0069 00% a 00% oom x oon 0100 Drinkalday ~0082 00st 2 "ose oo Cigueesiay 000s oon 2 ~oon7 003 } Bastin Years 006 oon ~0089 oo atl log 0001861 cote . pote es sefprn | Tle e HC. i oso Essene SdErr5, nd5%CEomnici | | Numberof Yearsof Observation of Antwerp Subgroup B (1995 and 2000) Male 0Em5p8lCoyoenestinents | Intercept 275 0523 <.0001 1720 3830 Yohei 0008 ous ons Toms on os re - om wo ane - pny os oso Coster om own pit 02 - ran woeked oo ose " oon ons ator - - am oon - ve ors os oms ons ons oan 000162 cpoiotp | "Tabolem11DNT.esMeiixeocmdfYMoleadeeloDCfoeerfnfsmirciiveeannttsiEsootnfimfTatAevsa,nSetragndSareCduhEernrntorCsctd((Si1E)o9,en9P5-nVdaPlEu2Oe0s0oa0nddMl9h5ee%EICmopnnlfoicydeeoensceoiLihmits 056 Contec Limi Cotten pe Lover Une J sass ore pe 1760 aso Fron om ou = "om oss Yous Obraion 0072 oss 2 "0m aos FROAsYamow 00m oost "aos? ons nee os oot n "aos os a aos? ry o as ono Dry "ams aos 6 os ous r---- oo oes w I ans BastinYears oo oon o Er aos Hr -- tee "natural log. 000/63 hos | abloem1.TeMsiedcemelRloCDmoiefTemicooifennYsosusrsoifofTtOavsrgvSaaatondnaoCfhEiDrneesesteo(r 5iM,lPnaBPllFeOoAniadnsd9h5e% ICnocrfacdironewLitihis 958Contes Lins a Coden st pe Loner Upper een 25m ose? <n TM sie Fron oust ovis a 00m os Ves Oberon 0038 oo "oon oois FOAR vamos 002 00s 5 "oo oon ae aos oo 0 0s ons Ba oon oo oon aos aos Dini Er oom n "oa oss Cipeesiny as ous om oor Fay Pero oan om on aoss om f-- oo oon " "oor oon I A p-- is097 natural log 000164 PeCnomipasny "Tabrloe m12.TesitiengdPoMteonteialCoDeefefircmiicnntanEstoifTmr,gycSetarniddaer'dCrhoarnsgSEI),nPc-VladlTeOisF3nanndgd9t5h%e CInotnefriadcteinocnewLitihns NumobfYeearr of ObservoafAtnitwoernp andDecaturMle Employees 95% Conttence Limits Costhicent pum Lover Upper Inept 262 03m <0 195 sam Tor 0053 oom as oon 00m YeasObservation -00005 oon " -00 ous TOFxVeusObs -00005 oon 9 ~0008 oon I oo 0007 5 0010 oo Bi 006s 0009 <oo01 0089 oo Drink ~oon oon ~0095 oom Cigartestiay oon 0003 wo 0005 oon . Location oo oo, as -om9 0266 Enty Periods 008s oon zn 00s ozs Basco Years 000s 0007 ss 0010 oors eed "naturalog. bnSd 000165 3pMeCromspeandy "Tablfero1m2AT.estMiinxgePdotMeondtieall CDoeteefrcmiiennatntEsstoifmTartieg,lySctearniddaer'dCEhrionrgseI(nScEl)udPi-nVgaTluOeFs aanndd9th5e%InCtoenrfaictdieonncweiLtihmits Number ofYearsofObservationfor Antwerp MalcEmployees 95% ConfidenceLimits J Coefficient se palace Lower Upper Intercept 3078 0395 <.0001 2094 3862 Tor. 0083 [= % -0002 0107 Years Observation ooi6 oor Ed -o018 009 TOF xYears Obs -00007 0006 % -0012 0010 Age 0009 0009 n 0009 0028 BMI 0022 0014 0004 oois oon Dankslday 002 00m u 00% oss Cigaeesday oot 000s 00s 0008 00 . Enry PeriodTM "004s oor 5 -0215 0155 Baseline Years 0007 oon Weded "#n1at9u9ra4l9l5ogvs 1997 56 -0016 0029 000166 [ F3aMseCdosmoplasnsy "Tablreo1m2BT.esMtiinngedPotMeondtieall CDoeetfefrimciiennatntEssoifmaTtreig,lySctearniddaer"dCrhoanrgse (ISnEc)l,udPi-nVgalTuOesFaanndd9h5e% ICnoancftiideonncewiLtihmits NumobfYeearrs ofObservation for Decatur Male Employees 95% Confidence Limits Cosficien SE poe Lower Upper Inereept 261 0363 <o001 1521 3766 Tor oon 0030 -00s 0050 Years Observation -0035 002 2 00 0009 TOFxYearsObs 0004 000s as -0007 ois Ase -0002 ois % -0a9 002s BM oom oor <o001 0050 0010 Drinksday -00%0 00% 76 "0 0166 Cigaretestdoy 000s 0004 2 -0003 oon EnryPeriods 0215 ont on 005s os4 Baseline Years 0009 oon J " "0013 00% ""n4a1w9ra9l49l5ogvs 1997 B 000167 [ 3pMCromepadny fr"oTmabTlees1t3i.ngMPioxeendtiMaoldDeelteCromeinfacnitnstofEsAtlikmaaltiense,PShtoasnpdhaartdasEeg'oCsha(nSgE)e,IVncalluudiensg PanFdOS95a%ndCohnefiIdneernsccetLiiomniwtisth `NumofbYeearrs of Observation of Antwerp and Decatur Male Employees 95%Confidence Limits Coelficiem SE ple Lower Upper Intercept 3m ore <0001 342 am pros oo 0009 5 -o017 oom `earsObservation ~0s1 0006 <0001 0062 -00i0 PROS x Years Obs 0002 000 a -0003 0006 Age 00s oon x 0003 ooiz BMI ~00007 oon 58 -0009 0008 Drinksiday ~o001 oot 9 -00%0 oo Cigaretestday 0003 oon 0 [rn 0006 ; Location* "0202 00s <o001 03 "014s Entry Period 0098 0087 008 [3 om BaWsoerlkiendeYears 0006 000 0 0013 oon Trigycerdes" os ozs <0 0067 0160 "Anrtawwerrlpogvs Decatur "1994195 v2 1997 nMoaney Tile 14 Mid al Cosi mats, Sadr Tr (5), Valiesan 95% Contre Lis } from Testing PotentNiealrDeerteorfmiYneantsooffAhlikatlainieoPnhoosfphAatnasoe'sCahanngee tIncsludMianglPEFnOpAalnodetshe Interaction with 05% Contre Lis Cotten se pe om Upper J as ore <oon an am ron owes oonz "ooo oon YoursOnsraion ~~ -0087 TM <oon 00s oe PrOAxYemOb 0001 an 000s oon ne 000s ous 000 oars TM Er aos ss "000 oom Dry Er aos oa oo City 00m aor aon os Locsin "020 aos <oon 030 "on nyPro i oo wr os om BVaancesYes an I oom oon Trae! one os pr I oe --_-- pi -- "RanEn "natural log. car Sp M Cumdpany fr"oTmablTees1t5i.ngMiPxoeednMteldeDeltCeromcifncainetnstoEfsAtilmaltiese, SPthaondsaprhdartosrCsh(n5g)e, IPn-clVuadcinsgnTdO9a5n%dCtoenfIindcernscceiLoinmiwtisth NumobfYeearrsofObservation of AntawndeDecratpur Mil Employees 95%Confidence Limits oo Content se pale Lower Upper nrc 3789 om <oo01 3am ais Tor ~000004 0009 ~oom9 oois Yeu Observation 0049 0006 < oot -0060 "00m TOFxYersObs -000006 ooo? a 0003 000 axe oos oon - -0003 oon Ba ~0001 0004 =" ~0010 oos Drinklday 000 oor 9 -oost 00s [-- 0003 oon ao 000s 0006 ; Locaton 021s oo <0 -032 "os En Perio 0100 ous on 00s om WBaosrckiende Years 0006 0004 1 ~oon oon Tgheeides" ons oo <o001 006s ie || a"Atntuwerlpogvs Deca | "1904S vs 1997 ae ae (1Tr6o. sMiixncdgMoPdetl CeofDfeticnmiEnattscof,GGSTaCdhaangEesIa(SiE,nPP-RaOlSoasndanhde5I%sCoonfnidrwcishLis Nerf ous Ovation of Atwer sndDest Mae Empioyes 95% Confidence Limits Coetisien su puke Lower Upp nent fr om <oo0n Ls 260 wos "001 oom 0 008 ons Yor Obieraion 0075 oon oon oom oost POS Yenow 0008 oom hee ~00m oom ~oms o0r2 E) 001s oon TM aos ous Drnktay aon oot 5 003 002 i oom 0104 Cpenestsy oom oun m 0007 000s . Lacaiont 009% our 6 ~00 ono -- oss ours <omi 0204 osn2 WBourkiend Years ome oun 0 0m 00 retest oxst a0s0 <ao01 012 030 _--------------0--H-- ------ """nAalntoutrwsaelirlpnogv.vseD1e9c9a7tur SPM Caompoany Tabler17o. mMTiexsetidnMg PootlentCioalefDfeiitnterEmtiionmfa,GnGStTsadChranoerIsnclSuEd)i,ng-PVFaOlAcsanadntdh9eI5%naCconifoidnenwcietLhins NumobfYeearrs of Observation of Antwerp ndDecatur Male Employees | 95% Confidence Limits _ Cocticen. se pale_ Lower Upper Inereen 17 om <0 L138 263 Poa ~0009 os n 00s 0010 YeasObservation 0077 oon2 <o001 -0100 00st PROAxYeasObs 0005 000s 0004 oon Are -0002 000 6 0018 0013 Bi oon 0009 001 oo Drnkstay oon oon uw ~o019 010s Cigartesiday ~00007 0003 = ~0007 0005 . Locsin 0097 0104 3 ~0301 0108 Eny Period 035 oom <0 0203 0507 WBaosrekliende Years 000 oous -0007 oo -- 0256 oosi <0 0156 036 a"Atntawerlpogvs Decatur "190485 vs 1997 | sr ule 18, Mised Model Coefin Estimate, Sindrd Eos (SE), Values and 35% Confidence Lis from Nenoef Yeas ofOran Awe Testing Potential DetermionfaGnGtTs* Change IanncdluDdiengcTOFlaendErthpelIontyecrasction with 05 Contre Limi _ Costin se pate Lover Upper ner 1570 oan <a Lis 2008 or oz ooo "00m oon YearsOvanaion 00m oon <n "oto "ast Toxvaso oo fr 2 "oon oon ne Er aos as ons ois sw I ows 2 "aon on | ban oon oon n oo ons ---- "oom os n 0007 ows Loins "00s oro 0am om ---- oss oon oor oo 050s BVouknees Yes aes os a oun os Triglycerides" 0209 0050 <.0001 019 0368 TE "aananvtuirealmrleosgsDoecntr MiCoamnpedy "Table f19r.omMTiexsetdinMgoPdoteenCiaolfDfeticnminEatnitmstocf,ASSdTaCrhdanrgoerIsnc(lSEd)i,nPP-FVaOlSensdantdhe9I5n%rCsonifoindewnictehLimits Number of Yearof Observation ofAntwerp snd Decatur Male Eployees 95% Confidence Limits oo Coctficen. se patie Lower Upper rept S080 0108 <0 269 san pros 0010 oon -o013 00 Years Obseraion 0009 0007 1 00 0005 POS xYemOls 00007 0003 ~0005 0006 I 0008 0004 05 ~o016 000005 Bi oon 000s " 0007 oo Drikslday 00% oo a 0007 006s Cigareestiny 0003 oon Locations 0102 0053 Ey Periods 00% ou o -0006 0002 % -0206 0003 00% one WBaosrekliende Years 000s oon 2 0003 oon Trgyeerde' 0083 ou ows ont "naAtnuirwaelrlpogvs Decatur "419945 vs 1997 Tle 20. Med Mode Confit sie, Spd (5). aloes rd 9% Confidecs Linis from Testing Potential Determinantsof AST' ChangeIncludingPFOA ne and the Interaction with ok Contre Limi L-- o [-- 303 i --CocllicieSmE pprve 20 lower Uspupser | wor oon ors " oom arse Verso 0008 oom oom oom I ---- oon a oom aos a oom oom os oom ow oom oms ome oars Deiat ao os 0 oom oo -- aos I " oon om . Location oon a0ss om ome Srey ou oon 2 "oom or fotinee Yes I I oom oonz "Triglycerides" 0054 0.030 | p"irnamaralogSceaer or 0.004 00071%J3 pcodmp || Tale 21o. mMiTxeNseideModrPelcoCleYleDiasee:ofmhBieianmtaoof,nASSoaTf:nAdCthaaenEgrearnnd(5dD,ePTr-OVFaMsietsdeaEnemdp9nl5oc%yeCosntmdehnc Limits | 95%Contes Lis | Cotten se pate Lover ope | een sos os coon 2666 sa | Tor oo oon 2 ~000s 00s | YasObenaion 0009 000s a 00s ows Toxvamone ous oo 000s oor ne 000s oot - "oot6 oo ma aos ous " "006 aos Dry ons aos "or oes Cipreesiny "aos oo rs "0006 oon: Locsion "os aos "om oo En ore oom oom a "oom ons WBoueesn Yeas oes ooo "os oon -_Triglycerides" 0058 0029 05 0.00003 0116 a"enartuersanleloig. Dse1ca pcrioctrermd Tale 2{2.TMeiidnNMaoPdmeocCotoeDaisfonfiOaaxsr,osf ASLaoTfdCAahanEegeoIsocd(iE5nn.gcPP-FVMOlSlesnEndhle5e%CnsocnidonewinLins 95%Contin Limits Coticin se pe Lover ue J 21 om <omi 150 aon ros oon m st "om oon -- oo <a "ons "om Pros Yeon 000 oom "ome 000s | Me 00009 0006 TM "ooiz ooi0 a oo oor n ome oom Dray aon ons @ ou om Comes 0008 oo oo oon 00m Locsiont aos oom a com TM ny Pri om aoss <oon 0m 0s VotnieYon oon oo0s "000 oo Triglycerides" 0.159 0040 r f"homeer eDecsr eer fe "natural log. 0001 0079 0238 Cnamypy Tule 2f.emMTixeeidNnMmobPdeeolrCoefoYlD eaiscoftEhisrvtaeotfi,AonSLTopfCAhdtawnEgierrlranoSdEDd,eVcPtFaOMAllreudaEnmhedp9el5sIo%yreCisntoindewnicnLis | 95% Confidence Limits } Coefficient se palue Lower Upper | Intercept 247 om <.0001 1942 3006 vron aos ano " "ozs ass YasObsrion ~~ -0.107 oon <n "ons oom POA Yeahs 0005 aos 1 "00 oon ne pr os = "oon oon wa aon aor i Er os Dring Er ons ass ovo Ciesioy 007 om wo oon "0003 Lovin oom oon x om aoe [-- osm aos <a os an Cesa eine Years ooons aos "ao oon Trends ost aon wos oon oa --_-- on ""snaAtiurnaslulosgp. oDenca cnssr Table 2f.omMiTsecndNgeMendPtoeetleoCnftoVceDfresiiocnfmiOEnhxasitrstvsotf,oAnSLToaf:ArCndhtawEnrtopssIndn(DScEe,lcPTt-OVFMaalsnedaEnmhdpe5lIon%yrCeaoscnufiodnenwiceLins 95%Contes Lins | ER se one Lover Upper eens 206 om <oon 19% sos Tor ou sos a "oon aost YousOvrion ~~ -0102 oon <oo01 oi oon ToFxvamo oom 000s "0001 as je ages TM = oon a0 a oon oor u "os ons Drs "oon ons @ 02 oon Cipretetny as ow wo ~oon2 "os . Loaion "oom oom 2 oan oom Eney Po os ooss <a 0x0 I BaVoikensYears ooeos ows - "aso aon Tred ous oo wos oo ozs "n"atoAusrniamlnsogyesDoe1sc | as Tle 2. Med Mode Coffin site, Suda Bros (SE). Vales nd 5% onde Limi fromTesting Potential DeterminofaTnottaslBilirubin' Change Including PFOS and the Interaction with Numberof YeofOabser rvats ionof Antwearnpd Decatur Male Employees 958 Conteris _ Cotten su ewe ime pe __ nen com 02 n "ost on pros "oon oo 2 Ee oon YeObenaten 003 oom as sous oon PFOS xYearsObs 0.002 0.004 94 0007 0007 Je aon aos oon oom a "oom oor @ aoe TM Dry oo fr 5 oom oo -- 000m oo <oot aon "oom Locsin ons aot <omt or oun Byres ona oon EF "oa BVcoisneYen 002 000s o" "oon oom ree HB Triglycerides" 0.088 0037 02 0.161 0015 "e"naAsturnialeslogs.etDoenc Mnu om | Table 26, Mined Model Cosficin Estimate, Sandan Eres (SE). -Valus and 95% Confidence Lis | from Testing PoNteenmtbiaelrDoeftevromuinsanoftsOosfrvToattailoBniloifruAbinw' CehanagnedIDncelusditngrPoFOEAmapnidoteheesInteraction with 1 Cota reps "ois ron i YousObraion 0038 PrOAsYamow ows ne aon a "ows Dinky cons Cope os Locsin os [-- ons Wsoeiense Yeas Er Trends "oon _-- ""anhantnumiramlmrlpeoeg.ss D1eca 95%Confidence Limits se pune Lover Upper 02 0 om oe oon w 006s oor ows w oon ovis aor 8 "0002 aon ows " ooo ano oor a "oot6 aso rs 5 "oon 000 oz <1 "oor "aos . oss <r oi ous ois or "oars aos aves a "oon oon oon o "oss "000s ss p5MeCormpaany "Tafbrloem2T7.estMiinxgePdoMeondieall CDoeetfefrimciineantntEsstoifmTatoetsa, SBitlainrduabridn'rCohrasng(eSEI),nVcalluueTdsOiFanandngd95t%hCoInnfaicdteinocne Lwiimtihts Number of YeofOabserrvatsion of Antwerpand Decatur Male Employees 95% Confidence Limits I se pale Lover Upper Intercept ~0318 022 1. 079 0160 TOF 000 oon 16 -0049 000 Years Observation 00 oo10 00s 0009 [ TOFxYearsObs 0003 0003 3 0003 0009 Age oon 000s o 0001 oom BMI 0003 0007 6 -0016 oo10 Drinks oot6 0023 st oon 0062 Cigaretesday 0008 0002 <.0001 "002 ~0004 ; Locsion 0316 006 <.0001 019 [x EnePerods oi oot6 on -0210 0020 WBaosrekliende Years 0002 000s a -o0n 0007 Tigycerdes" ~008s 0037 ous 002 ""Arnatwuerlpogvs Decatur 4199495 vs 1997 oCrompiany Tfarloem 2T8e.stiMnignPeodeMnotdaellDCeoctfiecmeniEonsftDiaimatrteessc,BSitlainrduabirnd'ECrhransg(e5I)n,clPu-diVnaglPuRsOnSda9n5d%heCoTnrfiadcetnicoenLiwmiihts Nome of Yearsof Observation ofAvanedDecraturMale Employees 95% Confidence Limits _ Coficen se pale Lover Upper rept "1756 om <0 2160 "13s vos ooi3 oos 00 002 Years Observation 0097 0009 <0 oie ~00 PROSxYersOb 0006 0004 1 oom 00s nee oon oon " ~00003 oon Ba 0003 oon 58 ~o01s 000s Drinkalday oo oo wn -002 00s [r---- ~00005 oon ~0004 0003 Locaion oor ooss 15 -00s 0180 Ey Perioass 0353 oo <1 on ous BWaosrekliende Years 0001 000s " 0009 0006 Trgyeendes -00% oon 0s 0155 0026 a+Anttwaerlpogvs Decatur "4199485 vs 1997 P3MiCsocmpeansy "Tfarbolme T20e. nMgixPeodteMnoidaellDCeoetfeciremn:iEnosfaiDnmittrese, BSialinrdubrind'ECoharnsge(SEI)n.clPu-dVianlguPeFsaOnAd a95n%hdeCoInnfirdaecnicoenLiwmiitths `Number of YearofObservation of Anwerp and Decatur Male Employees 95%Confidence Limits _ Costin se pale Lower Upper Intercept 1783 0207 <o001 -2160 1345 Fro -o0r2 oon? a 00s oot YearsObservation -0.095 0009 <o001 -onrs -o0m PROAXYeusObs -0004 000s 2 -o0i2 003 I 0006 0004 mn -0001 oom | BME -0003 0006 -0014 0009 Drinks oon 002 0 -0026 0053 Cigareestday -00005 02 0 -0004 0003 . Lacaion 0083 0053 2 -002 01s Enry Period 034s os <o001 om 0420 BaWsoerlkiende Years ~00008 0004 8 -0008 0007 Toglyerides' -008 003 0 -o1ss 0023 ""Annatwlerlpogvs Decatur "S199495 vs 1997 cHocmy i ------ from Testing Potential DetermionfaDnirtecst ee Bilirubin' Change Including ete TOF and the Interaction with J-- tiem = se gee one erent 1 os <oon is 150 ror oon oons = "oon aos VenOhrain 0038 I <omt "ons oom ToFxYamon 000 oon a "aon aoe I" oor oom - "oows oon wa ows I - "ours aos Dnt oon oom "oon 00s Gpesiey oom oon " "oon oon etn oon 00s 1 "ous am -- ose oo com om on YJ o oom n "oon oom J mgynaet -o08 ours o "os 0188"gon arpoouSmnaoDeecsn