Document VGL9V8wwjgZGgnV18zxJ9X3V8

Do : AR226- 1088 3CMoCmopmapannyy FINAL REPORT Epidemiology, 220-3W-05 Medical Department 3M Company St. Paul, MN 55144 Date: October 11,2001" TPietrlfel:uoAroLoocntgaintouadtien(alPFAOnaAl)ysLiesveolfs SinerRuelmatPieornfltuoorLoiopcitdaanensduHlefpoanattiec (CPliFnOiSca)laCnhdemistry Test Results from Male Employee Participants of the Fluorochemical Medical Surveillance Program 1994/95, 1997 and 2000 Study Start Date: July 1, 2001 IPrRoBtoAcpoplrNovuamlber (not applicable) : Exempt Expedited x IRB Approval program) Date: (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, MPH. Jeffrey H. Mandel, M.D., MPH.' Jeffrey H. Mandel, M.D., MP.H.' 1. 3M Medical Department, 220-3W-0S5t,.Paul, MN 55144-1000 * (Corrections made from previous version) 2 ER% on o E= = 35 wo 2 000254 Co 3M Company Page 20763 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 of a 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 totalof 41 (24 percent) participated in all three years (Antwerp = 21, Decatu=r 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). 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/dl). high density lipoproteins (HDL, 000255 3PMagCeo3m0p0a6n3y mg/d) and triglycerides (mg/dl); alkaline phosphatase (TU/L), gamma glutamyl transferase (GGT, TUL), aspartate aminotransferase (AST, IU/L), alanine aminotransferase (ALT, IU/L), total and direct bilirubin (mg/dI). Most reference ranges remained relatively 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. Significant coefficients were defined when the p value was < 05. `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 suggested a 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 ths study included the numberof 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 000256 | 3M Company Page 40763 the associated systematic (experimental error) with each fluorochemical assay for the 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. 000257 3PMagCeoSmopfan6y3 INTRODUCTION `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, 1999, 1999b, 2001). Inthe. 1994/1995 medical surveillance program, a total of 178 male employees participated (Antwerp = 88; Decatur = 90) and 149 male employees participated in the 1997 program (Antwerp = 65; Decatur = 84). For these two program years, there were too few female participants to include in the data analysis (Olsen etal 1998). In the 2000 fluorochemical `medical surveillance program. there were considerably more participants: 421 males (Antwerp = 206; Decatu=r 215) and 97 females (Antwerp = 49; Deca=t4u8)r, 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 000258 3PMagCeo6m0p1a6n3y employee population has been significantly younger than Decatur, has had lower Body Mass Indices (BMI) and higher self-reporteddaily 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;Ikedaet al 1987; Pastor etal 1987; Seacat et al 2001; Sohlenius et al 1993) and primates (Seacat etal 2001b). In the 2000 medical surveillance program, statistical analyses also examined the relation between PFOA and acalculated total organic fluorine index (TOF) to clinical chemistries, hematology, thyroid hormones `and urinalyses (Olsen etal 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 et 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 20016). `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 allowedforan opportunity 000259 3PMagCeo7mopfa6n3y to conduct a longitudinal analysis among the male employee population. Altogether, a total of 175 employees (Antwerp = 100; Decat=7u5r) 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 conducta longitudinal assessment of this 6 year time period regarding the relationship of PFOS, PFOA and TOF 10 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. Ofthese 175 employees. a total of41 (24 percent) participated in all three years (Antwerp = 21, Decatur = 20), 65 (37 percent) participated in 1994/95 and 2000 (Antwerp = 45, Decatu=r 20) and 69 (39 percent) participated in 1997 and 2000 (Antwer=p 34, Decatur = 35). For purposes of brevity, these three subpopulations will hereafter be referred to as subeohorts 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 setofclinical chemistries and hematology data was also obtained for each employee. Given results from previous toxicological studies, the longitudinal analyses focused on lipid 000260 3PMagCeo8m.p0a1n6y3 [cholesterol (mg/d), high density lipoproteins (HDL, mg/dl) and triglycerides (mg/d) and hepatic (alkaline phosphatase (IU/L), gamma glutamy 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 IU/L in 1994/95 to 1-40 T/L in 1997 and 2000. Eluorochemical 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 et al 1996). i. `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 1997a; 1997b). In 2000, sera samples were extractedusingan ion-pairing extraction procedure (Hansen et al, 2001). Only in 2000 were the extracts quantitatively analyzed for PFOS and PFOA as well as the other analytes: PFHS, (erfluorohexanesulfonate), PFOSAA (N- ethyl perfluorooctanesulfonamidoacetate), M570 (N-methyl perfluorooctanesulfonamidoacetate), PFOSA (perfluorooctanesulfonateamide) and M556 (perfluorooctanesulfonamidoacetate). High-performance liquid chromatography/electrospray tandem mass spectrometry (HPLC/ESMSMS) was the 000261 3PMagCeomopfan6y3 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,atotal 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 each of these two fluorochemicals and then summed to produce the TOF. Data 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 effecti fixed if the leveilns 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 sampleof a larger set of potential levels. `The focus of the standard linear model is to model the mean ofy by using the fixed-effects parameters 8. Thats, y=Xp+e where y represents a vector of observed data, 8 is an unknown vector of fixed effects parameters with known design matrix X, and e is an unknown random error vector `modeling the statistical `noise around XB. The residual errorse are assumed to be 000262 P3aMgeCo1m0p0a1n6y3 independent and identically distributed Gaussian random variables with mean 0 and variance 0. A generalized standard linear model is amixed model which is: y=Xp+Zy+e where y is an unknown vector of random-<ffects parameters with known design matrix Z. and e is an unknown random error vector whose elements are no longer required to be. independent and homogeneous. Ify + areassumedto be Gaussian random variables "that are uncorrelated and have expectations 0 and variances G and R, respectively, then the variance ofy is: V=2GZ +R "The variance of the data, y, 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 pattern 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 00263 ) P3aMgeCo11mopfa6n3y 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 pairs of observations on the same subject. Autoregressive order 1 (AR(1))covariance structure specifies homogeneous variance but that covariances between observations on the same subject are not equa, 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 only to the common contribution (ot 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 pattems in the covariance matrix and is therefore completely general. The above structures are appropriate if 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 000264 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 valuated as repeated measures incorporating the random subject effect fitted toa mixed modelbythe MIXED procedure in the SAS statistical package (Littell et al 1996). Restricted maximum likelihood estimates (REML) of variance parameters were computed. Adjusted regression models were built by introducing all covariates (see 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 1 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 alsohad consistently lower triglyceride and alkaline phosphatase levels and highet HDL and total bilirubin levels. Decatur employees, on average, had serum PFOS levels 000265 P3aMgeCo1m3p0afn6y3 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 through 30 are the mixed model coefficient estimates, standard errors, p-values and 95% confidence intervals from testing potential determinantsoflipid and hepatic clinical chemistry change. The natural log was used for all dependent variables. . Tables 4 through 6 contain the analyses for 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 significantlypositive 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 time their 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 000266 SM Company Page 140f 63 the Decatur employee population (Table SE) nor were there significant associations between TOF and Antwerp or Decatur but when the two sites were combined there was a significant positive association between TOF and cholesterol (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 overtime when both Antwerp and Decatur populations were examined together (Table 10). However, among the combined Antwerp and Decatur populations, PFOA was positively associated with triglycerides (Table 11) as seen with the significant positive coefficientforthe main effect of PFOA and the nonsignificant positive main coefficient of years and the negative: coefficient for their interaction (PFOA x years). The significant main effect of PFOA was the consequence of the Antwerp population (Table LLA) and primarily subcohort A (table 11B) and, to a lesser extent subcohort B (Table 11C). but not subcohort C (Table 11D). Therefore, the association appeared to be related to the Antwerp workers who were enrolled in this longitudinal cohort beginning in 1995, but not 1997. There was not a significant association between PFOA and triglycerides among Decatur workers (Table 11E). 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 1.32 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). 000267 P3aMgeCo15mp0fan63y 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)ordirect bilirubin (Tables 28-30). Observations apparent in `Tables 2 and 3 can also be seen in these mixed model analyses. For example, the two 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 2001a: 2001b: Sohlenius et al 1993). Our results did suggesta 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 (Butenhofeft al 2001). 000268 P3aMgeCo1m6p0af6n3y Even though we were able to 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 1999a; 1999b; 2001a; 2001b; 20010). 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: systematicerror 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 either 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 0.5 t0 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. 000269 P3aMgeCo1m7p0a1n6y3 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 Tower than those that cause effects in laboratory animals. cne270 3M Company Page 180f63 REFERENCES 3M Company (2000). SIDS Initial assessment report: Perfluorooctane sulfonic acid and its salts. St. Paul (VIN):3M Company, (unpublished repor). Minneapolis (MN):University of Minnesota, (unpublished report). Anderson DJ, Mulvana DE (1997a). 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An epidemiologic investigation of clinical chemistries, hematology and hormanes in perfluorooctane sulfonate in male fluorochemical relation to production serum levels employees. of St. Paul:3M Company (unpublished report). 000271 P3aMgeCo1m9p0a76n3y Olsen GW, Burris JM. MandelJH,Zobel LR (19992). Serum perfluorooctane sulfonate and hepatic and lipid clinical chemistry tests in fluorochemical production employees. JOEM 41(9):799-806. Olsen GW, Logan PW, Simpson CA, Hansen KJ, Burris JM, Burlew MM, Schumpert JC, `Mandel JH (19995). Fluorochemical exposure assessment of Decatur chemical and film plant employees. St. Paul:3M Company (unpublished report). Olsen GW, Burris JM, Burlew MM, Mandel JH (2000). Plasma cholecystokinn and hepatic enzymes, cholesterol and lipoproteins in ammonium perfluorooctancate production workers. Drug Chem Toxicol 23(4):603-620. Olsen GW, Burlew MM,BurrisJM, Mandel JH (2001a). 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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 (20012). Sub-chronic dietary toxicity of potassium perfluorooctanesulfonic acid in rats. Toxicol Sci (submitted 20012). Seacat AM. Thoford PJ. Hansen KJ, Olsen GW, Case MT. ButenhofJLf. Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys. Toxicol Sci (submitted. 20010) Sohlenius AK, Eriksson AM, Hogstrom C, Kimland M, DePierre JW (1993). Perfluorooctane sulfonic acid is a potent inducer of peroxisomal fatty acid B-oxidation and other activities known to be affected by peroxisome proliferators in mouse liver. Pharmacol Toxicol 72:90-93. 000272 | || vos rion on i Cm Neked hWaecendcYon Gps Goes wow | Tigeides Comme a ast aur Telos D:alit WTDahebaolemPo1.urCpirloiscts-CSehcTtaiorwnaclooAtnMaoawdloMyTfoasMilceiiaaalsnShaneed imStraendnarodEfxDAeavnniiatntiwaoinaoonnfSeDcovrcuetmosrPRM9OoS4,e5P5FOpaAld,eT2sO0F0,0 age Motil --T--N)t Ds A) Man SD Mem Sh we 2m Amerie)ow Dene EE Mem SD Men SD Le nus te AMepnowDenNeT, Mem SD Maa SD Le wt 1m Was em as we ww wm aa ar as We am aw maw wx Wee a wo we an mw aa ae am wt om wm ar ow nw we aw ma a me a ww wr a Wow 10 57 mae me a ww 52 wm a me el wwe a1 el mr 8s 47 ws soa sow wm a aw ow wm ew 3 a a0 Wm me mm 5 weom mow wom ow www ow ow oan wom wom won ow uw 6 w nw ox won wx nos 0% 04 02 . 04 0s 2 02 oer of ee of am a6 02 or oo sow sou mw a 2 oe ww ou ow wm ow oe ons osm ow wa os ow wow ow 1m mow aw wow ox 02 ab oss 0o00r2o73 rm Tabke 2s. Cirsotsse-sSedctaionFaloAnntalyMsois oafeMbbeanoaSnd aSetandansd aDevBsiatoifonooAfSchruomMPnRlOS9,B5PFnOAgd, 0TO1F..14) up Hoto5 AcNeIre) ed Mew OEcEe Men Sh ee ANsemeNn mCemOeEs. Mon Men Sh Me eAnNZS)b e MeniBeIssCo oee mestnee wos am om am aw 2m mam am im ow aw un ow on Won am om we we a am eae 2 Im 7 Ls om or am am am ee a a en a an as is 1s aw ne Woe wo aw sma we a 1 ow wi ome wa oa me ow mr ow wa ams wow mew 3 4 me a a we ar aa we a Comey 4 7 48s 1s 1s 4 4 as a vVaal n 99 4 We 6 on 41 53 a0 9 a ue es 4 Cucwm m w m a me mm ow dm oe Dy ow mew ws om so owmoow bs a ou x mom nos on me 8 mms em ame as os ws ss Mme @ mm ow @ we on os now wos on wr om ov ow om om ow om ow om on ow somo J EE E wr om sw o wom wm on om wom now 7 feiss 10 mon 04 mx x ms a 10 mw a wm Damion 02 om 02 oo om ox am a1 om or om oi go DrnegptTiictleC3 CousrSecticonndalCiiAnesolyCsroefMntescsionfdSTchirnedSbgDaeovaipsisoonfoDfeScautumr MPaOlS,ElPoFycOcAsT(O.F,13nd Pe 060 Wi atic in Two. Mie Medical Surveillance Examinations Detween 1994 and 200 pew we AMZ BEE) AMEN) CMR) ANS) BONN) CMa) Men SD Mem SD Men SD Mem SD Mam SD Mem SD Mem SD vos WME AT 6 Am 0 1 UB 24 1M 10 1s 09 roa 0m 2 LL Ue 2 6 LM 26 2m le Li or Ws der 1m am WR 26 26 2% am xn TM @ 1 wos ow 1 ae xs 7 om sows wa Wa a0 ma a mW a me 4s Wm al 3 my us Diddy 01 03 04 0k oo ae 0 or 02 03 ae Cgmetctiy 6 0 was 4 ws om 3s wos wo Whourkceid Yos Bo ke 23 52 We Re W200 06 8 n3 52 m2 wo Coles BE Mm x6 om wm wom wo om a oL sow 9 ws mm 9 a on Ww 6 a9 Tages 0 Wm MW Ns mlz 3 mew us 0s Mme wm ow om om om ow Wm om oun ow dar a 3 sm om ow ow om ow ow Mom mow ast nos 6 0m 6 wm vw 8 3 4 3 7 ar 2 mw om wos ow 6 Wm won mow Twlltis 06 02 0S 02 a6 02 0s 02 08 02 01 oF 08 02 Dialing 02 005 02 08 01 004 01 005 01 008 01 T0M0 01 00aa27s 3P0e4eCBomopan6y Tabrloem4. ToMniixnegdPMootennetliaCloDeeltieiremnintanEsttsiomfaCtheisl,eSsttaenrdaorldCBhoanrgse(ISEn)c,ludPi-nVgalPuFeOsSanndd93th% CIonncfriadcteinocnewLiitmhits NumofeYearrs of Observation of Antwerp and Decatur Male Employees. 95%Confidence Limits _ Costicien: sh phe Lower Upper Inereept ses or <0 618 sus pros aot oo0s mn -0005 0025 ears Observation [re ows " ~0008 [ PROS x Years Obs 00001 oon -0004 0003 Age oon 00 o 0002 oo BMI 0006 oom 0 -00005 003 Drnklday oom oor2 2 -o011 0038 Cigaetesay -00009 [ a 0003 [ Location oom 00 36 -0030 0108 Entry Perio et ozs o 0009 oo Baseline Years -0001 0003 2 -0009 ooo weed o_o ""nAantutrwaelrlpogvs Decatur 10045 vs 1997 000276 TaoMpsC2om4p6an3y Tabrloem5. esMtiixnegdPMoutennet!ialCoDefeiitenetrEsmtoimifaCtnheosa,leSsnttaetnrdosalr'dCrhoanrgss(ISnEc)l,udPi-nVgalPuFeOsaAndan9d5t%heCIonntfeirdsecniocne Lwiitmhits `Number of Years of Observation of Anwerp and Decatur Male Employees. 95% Confidence Limits Intercept ProA Years Observation PFOA Yeu Obs Ase BMI Drinkslday Cigaretesiay Locaion* Entry Period Baseline Years Noted Coston asi oom ons -0005 008 oun vou om oon [a 0004 SE ple oi <n 00 008 ous x 0002 005 000 oo oom on oor2 0 oor = oo zn oom a oon as Lower Upper. ase 5063 oor oust -0004 oor -0009 -0002 000 003 000004 0013 -0010 oon 0003 001 002 ons oois oz 0000 [a A*nAnawtearlpogvs Decatur 410049v5s 1997 000277 pMeCeomrpeandy TableoSAm. TMeisnteidngMPoodteenltiCaoleDfeitieernmtinEasnttismaotfeCs,hoSlteasntdearrodlECrhroarnsg(eSEI)nc,lPu-diVnagluPeFsOaAnda9n5d%thCeonInftiedreanctcieonLimits `wilh Number of YearsofObservation of Antwerp Male Employees 95%Confidence Limits. _ Codie $6 phe Lower Upper. Intercept amo [ <o001 au S005 rroa oo oo on 0006 003 ears Observation ous 006 3% -0006 oon? PFxYOeusAObs 0003 00 2 -0009 0002 Age 0009 0003 08 0003 0016 LY 008 oons a -0003 0019 Drinkslday oon oon 0 -000 oon Cigaetesday 0007 [ n 0003 0001 Eairy Period [a oss 0 0004 0isy Baseline Years "002 0004 Wobed "4n1a9tu9r4a9l5ogv 1997 a -0010 0007 : 000278 "Table 5. Mixed Model Cocficien sina, Standard Fors (SD), P-Valusand 95% Confidence Limits frNomuTesmtiobnfgYePeoatrresntoiaflObDesteerrvmaitniaonntosfoAfnCwhoelrespteSruobl"grCohuapngAe(I9n9cl5u,di1n9g9PaFnOdA20a0n0d)tMhelIenteErmapctliooyneweisth Pcoamspsaendy ee Conticen SE pe Lover Upper teres 5059 oan <a a4 soos pron oom oo ow 000s oom Yous Osersion 0037 outs 0007 0067 PrOAX Verso 0013 os o "oom ~0o2 ee oom oo 95 ~oos oo mi 00s oor mn -000 oos Drinkstay "006 vow i a ~oos4 oom [-- oon ous st -0007 oon BWaosrekliende Years o0is one 36 -o018 0087 natura log 000279 "blfieomSCT,estMiingscPoMtocsnaelCDeotferfmiinnantFsstofiCahcosl,esSttearnodla"rdChranogse I(SnEc)h,iPn-gVaPlFueOsAsnadnd5th%e ICnoenrfaidceinocnewLitih s Namib of YearsofObievai f Ane Subgrou (1995 snd 2000) Mal Employees 95%Confidence Limits MPCounrpearsy Coffe SE pee lower Uppes erent ry 020 <oon 346 sa0 Pros oars oon w ~oo16 0052 YeasObservion 0005 oo ss ~oont oon POAX Verso 002 ooo 5 ~0009 oons Mee oon ons -0006 oois war oon oom n ~0004 oom Dinky oon oo as ~00s 0061 Cipmencuiny on on " 0004 oom Baseline Yes ooo 0006 ~oon oon wotked _____ "natural log. 000280 Table SD. Mixed Model Cosficen Fstimats, Stands ors (SE), P-Valus nd 95% Confidence Lins from NTestoingomPfoYteeneatirasloDfetOehrsmcinravnttosnofofCAholnesteerolS"uCbhgraonugpeCIn(cl1u9d9i7nsgnPdF2O0A00a)nMdlthee EImntpelroacyteieosn with 95%Confidence Limits Pcaorme Co Conticen_ Cs pe Lover bpp rroa ooo ow ss ~ons [ Years Observation -0010 0026 POA Vamos 0010 oon x 0.065 0.044 as -os o0ss ne 0016 00s o oon oos Ba oon oor2 a ~o01s oom Drinksdey oon [2 a -00m 010 Cigaretesiny oot oon on 0007 ous MBaeselkine Yeas ows 00s a. -o02 oon "natural log. idl an ee i Table SE. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Vanad95l%Counfiedensce Limits from Testing Potential Determinants ofCholesterol" Change Including PFOA and the Interaction with ] eo Codffciem SE povalue Lower Upper. ren sz aan Com a0 seo ron aoe - " "oon oo VemOraion 0002 aos 7 "oon ours -- I 2 "oom oon |' oon aves 0 "oom oorz a aos om 5 Er oon J oon ours a "ous "oors -- "oo oon 1s oom aor -- oon I a "oon ons von oo oom @ "oot oom worked ins "natural log. om 000282 P3aMgeC0om0p1a6n3y "Tabflero6.m TMeistxiendgMPootdeenltiaCloeDfefitceiremnitnaFnsttsiomfteCsh,olSetsatnedraorld' ECihraonrsge(SIEn)c,luPd-iVnaglTueOsaFnandd95t%CheoInnftierdaectniconewLiitmhits Numberof Yearsof Observation of Antwerp and Decatur Male Employees 95% Confidence Linits Coefficient Intercept 488 oR 0021 Years Observation 0004 TOFxYeusObs -0003 Age 0007 BMI 0006 Drinkslday oor Cigareteslday. -0001 Location 0042 Entry Periods 0063 Baseline Years 0.004 | Wedked "Annattuwraelrplogvs Decatur 190495 vs 1997 sh pvalue [XE <.0001 0008 07 00s oor: 0 0003 0 0003 05 oor 2 0001 3 0037 26 007 " [5 1 Lower Upper asm 5019 0.006 001s 0005 0014 0005 0.0003 0002 0013 -00001 0013 0012 0036 -0003 0001 -0032 ons 0010 on -0009 0002 000283 Tiero6nA.TeMiixnedPiedneisCDoeimeisnionfCeh,iSlaendno Cihoarngse(n5e,diP ngTOF12l ndd9o5e%ICns roanciioncwiLhis NumerofVewsofOsea ofAwe MleBrployees Pa31gure6) Co Cooficen [-- am or oon YoursObsrtion 0008 TOsYesOls 00008 re ows a ows Dining oon r---- oes En Pens oom eBawien vsous eooeoonn sh pale Lower Upper ors <oon wan soi oon 2 "000s oo oun 5 "0000 oon ow no "ous ao aos on om ais ows 2 02 I) aon ores o0is om "003 oes ous " 00s ous oe ome o ss "F 000 ous | ios "natural log. 7 | 000254 | eCoampsanyy blreo6m.sMiinngedPMotoentliaCl oDeftefriminnanPtisnoftCheo,leSsttaendraorldCEhraonrgseI(nScElu.diPn-gVlTuOeFs aanndd9t5h%CIonnefricdieonncewiLihmits `Number ofYears of Observation ofDecatur MaleEmployees: LoLStCodencelimis Coelicien__ SE pole Lower upper rept sam ome <o00 sn sie Tor oo oon 0 "0007 ooss YeasObservation -0002 ome + oo oon TOFxYersObs 0002 oon 2 ~0006 oon Age oon oo "ooo oor mr oon oo 5s ~0008 oon Dik -00 ous on "0160 -0om Cignenesiny 0002 oun 6 ~0004 0007 BWaoserlkiende Years -0=002 oo.m ~0010 oo "naturallog | 41994195vs 1997 000285 PWoeneg "Tloe7.mMTisecsdiMnodPoetlenCtoiealffDiectieenrtmiEnsatnitmsatoef, DStLandCahrdanrgoersnl(uSdE)i,nPg-PVaFlOuSessannddt9e5I%nCaocntfiiodennwceihLimits Nianbeorf Years ofObservation of Aner adDecal Male Employees | 95%Confidence Limits -- ntereep aan Pros ~oot0 YonOweion ow POSx YanOhs 0001 ne oon oi "oon Drinkliay oot Cigartetiny ooo Locaton ous En Period ous eBasdtineYears ~0007 ""nAatnurearlogvs Decatur 419948v5s 1997 SEs pe om <oo01 oo 2 ous a oon 2 oon 2 ooo <oo0t oon <0 oon 000s oon oon " 000 os Lover Upper 39% 4495 00% 0007 ~0008 oon -000s oon -0002 oon 00s 0010 0037 00% 0007 TM ~oom oon 00% ooss -o013 00005 000286 spo m ||| Table 8. eo er NL! ange dgDe08ls Eoepis o Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits J tw mee ner ur ae a as <aon so en won a - - oom os YemOberaion 0008 ws = oes - Won ot we - one oz a ous om oi - wa von ont <n os ono csi we ans - os ons per om ww om on aoe I. ome wwe oe om J. wz = oan om pair -o00 or - ons oom ee ------------------------eetetteeeeeet f ateec natural log 00287 pt | yo J|. an worked wen om 000288 aSssm | ible 10, Mind el Coin Ftc, Sandor 1, P-Vales 395% Confer Lins | from Testing Potential ra of sro tes Determinants of Triglyceride' Change Including Wl os PFOS and the Interaction with | Guten Cw pais Lower i" 95%Confidence Limits. _-- am ans pr 2008 Je ros wns no ons aves [TN ---- - woo on moss vamon 0006 ams 2 oon ons " ous oom a "oon aos oi I oom com oo oars Duka om am n aon ous Cimetesiy aon ous - 000s oon Locations oone oom "ous oar -- wom was 005s ou punto ons wo 000 ao I ut ansiae e on 000289 pst | one ww com uw ws Turboem1.TeMiinnedPoMteondteiallCDoeetfeircmiiennanFtstoifmaTtgesy,cSetranddea"rdChraonrgse (ISnEc)l,udPi-nVgalPuFeOsAanadn95t%heCIonnfaicdienocnewLiilnhits NumobfYeearrsofObservation of Antwerp and DecaturMaleEmployees | 95% Confidence Limits _Coclricent TR patie Lower Upper Inercent 25% oar <oonn 1883 2196 Pro" oo os oo 00s ou YearsObservation 007 oon 5 -00r oon PROAX YeursObs 0008 ows in 00s 02 ne 0006 0007 009 oot Drinkstday 00 oo "0 00% [ra | Cigarerestny oon oo 002 000s oon Lacaion oo 00% a6 ons 022 Ey Prints ms 000 n -o0n 02% | Baseline Years 0003 0007 @ oon oon Worked "aan fog e A400tvs h 91 000290 ro | | | rept Pron Yes Oberon POA YeusObs I oi Drikattay Cigaenesny Pa Testing Potential Determinants of Tigyceride* Change nungPFOA and he Iitaion wilh NumberofYears of Observation of Antwerp MaleEmployees 95% ConfidenceLimits Cuttcien_ SL pe Lover Upper 2067 om <0 2086 ms oom ao ws oan 01 0024 oars n ~0006 005) 0010 oom is 00s oon om oom -0007 oom oom oo 0 oon oo ~00s oom " 00m 0010 oo 000s 004 0008 os NBaesewlienerYears 00 oon | h9a9n49gSvs1997 Ed "oom 006 000291 pend FleoNm1u1mT.beestrMioinfgsPecoatMenomdieofnlviDCertvoeirmltiiniaonntFsoifosftAiTmnaiesgi, SrtSseunbd'garrCdohuFaponAgres(1I(9nS9cE5l,,u1iPn9-gV9aPlaFuneOdsA2a0na0nd09)t5Mh%aelnCecoEnrfmcipidleoonnyceewsiLtihmits 95% Contitene Linis CC cwmeew se pe Lover Upper trent ion a ww osm sa Pros ois oot on oom 0286 Yes Observation 0167 oom pr oo oa PROAX YeusObs 0061 oon pr oon ~00 ne "own oon 0 ~006 00s at oom 00 oon 0100 Drink oom 00st " 0186 oon Cigseesay oon oon 2 -oon oom DasetioeYeas 00% oon " ~00e 020 Veda att log 000292 3PMeCo0m0pa1n3y Tabflreo1m1T.estMiinxgePdotMenotdieall DCeotcefrimciennanttFstoifmTartigsl,ySctearniddea"rCdhaBnogresI(nScEl)u,di-nVgaPluFeOsAanadnd9t5h% ICnoenrfaicdteinocnewiLtihmits Numbeorf Years ofObservationofAntwerp Subgroup B (1995 und 2000) Male Employees 95% Confidence Limits J Collin SE pale Lower Upper Inercept ams 0s pre 170 as ProA om? oom o oor orn Years Observation ons [ 5 oon oo PFYOea AObs 0.0008 [ 2 -o017 oois Ape oor oon 0 -0004 oon BMI oon oo o 0003 00st Drnkstday 00 0050 as -0062 013 Ciguretesay om [a 03 0008 0036 BaselineYears 0002 oor2 002% oo21 Wodked oo natural log, 000293 , 3PMaCdoimp6an3y "Tabrleom11DT,estMiinxgePdotMeontdieall DCoeeefmfiicniaennttsisofiTmrtiegsl,yeSetraindda!rCd nFgoresI(nScEl)u,diPn-gVPalFeOsAaanndd9t5he%ICnotnerfaicdteinoncewiLtihnits Numbeorf Years ofObservationofAntwerp SubgrouCp (1997 and 200) Male Employees 95%Confidence Limits _ Coticien_____SE________pole Lower Upper Inereept 2285 om 001 1769 sor Pro oon ou " -0280 03s Years Observation 0072 006 2 0203 0058 PROAX Yes Obs 0020 00st -008 ons me ms oie 7 00% [ey BME 0057 000 0 0006 on Drinkslay -oms oust 76 0105 ous Cigaretesdey ooo ous on 0002 00% Baseline Years 0010 [en Norid LE 00 0053 raul log B 000294 "bloem1 _ Lo nterept Pron Years Observation PrOAxYamOw Awe ow Drink Cpe Bey Period eBaecinde Years oIaDrsStosp 1997 ne TestMiinxgePdotMeontdieaNlluDCmobeeefrTtiocfeinvrtersmsotfiioTfnOntynsar,cvnStettiao:snndCofhEaDnregcreat(nuSrEMc)i,tVneaElmPupFelOsoAeaacnnsdd 9h5e% ICnocnrfaicdieonncewiLtihmits 95% Confidence Limits Ceen SE pe Lover Upper as oser <omn L450 am oust oo a 00m oes +0028 2 ~oon ours 0002 oo 5s oo oor oonos oon ss os oo om wn <0 0050 ome oo oom n "ozs oss os ous 6 00 oo 0am oi o ooss 001 oom oon " "oon oo 000295  Pecoeusn (ron TestingNPoutmenbteiralofDeYteearrmsinoafnOtbssoefrvTatiioynoefeiAe"nCheangnedIDnelcaitnurgMTlOeFEamnpdlohyeeeIsniraion with LoLSComdemcelimis -- _Coeffciem SE pvalue Lower Upper. nierept 262 on <o001 195) am Tor oom Ir ns oon oom Years Observation -0.005 oon 0 ~o0 oo TOPxYewsObs -00005 0004 9 ~0008 oon rs oo oor 51 ~o010 oo BM 0066 009 <o001 0089 oom Drinktey ~oon oon EY ~0095 oom Cigaretetiny oon 000s on 000s oon Locaton oon 008 as -on9 0266 Ey Pears ons oon on ~o0ss oa Baseline Years 00s 0007 8 -0010 oors eked n""aAOtnuUriawDleBploAgvv.SssD19a97t 000296 | J or s--o Fle 2 MtMm oSeCohtnht Sninrs6La s35%s nCtonic ins 58ns iis. cee pe toe oe wn wo <a 2am so wer wo - oz wr Ps we oon won - oan wo Jo oan oa po Gp oo wos wos oom om btn on ws ons os eee ee ---------------------------------- "naturallog. 000297 P-- | Te 20 id MeCoenso meSongCroorgs (55igVBiOFd 9m5e%cCoonfenr oiihis | Number af yearsafObeepvaon fo DecaturMaleEmployees | ostConteris eo Codffem SG vile Lover u lw - ano oom are Yer Oberaion 038 wn > "oom om ToFsvemom 0004 ons " wom os we oem - <a oso oe _----_-- - om x wom os ------ oon oom "oo oon Byron os an o ooss a SDoost Yen 00m won - oe n m wae J i 600298 Pceomop fo"TmabTleest13i.ngMPionetdeNMnotudDemleoCbfoteYefeofairrcmsieinooftOfnbEAslsnkieamrtlavitanestesi,oPSnhtooasnfpdAhaanrttdawrseeor"rpCsahna(dnSDgEe)e,cItPnu-clVruadililunsgePaEnFmdOpS9lo5ay%nedeCsotnhfiTdneinrcaectLoinmiwtisth 95% Contdenee Linis _ _ Cocticen se pie Lover Upper Inert am or <o001 saz a | pros oo oom wo 017 0020 Years Observation -051 oom <0 -0062 ~o0i0 PROSxYearsObs oon oo a 0003 0006 re 000s 0004 -0003 ao BM 00007 ooo 8 00 oo Dinky ~0001 oom " 00% 00s Cigmeesiny 0003 000 o oom 0006 Locaion -020 oo <0 EE "ous EyPeriod 00s oom os 00s om BWaosrekliende Years -0006 oon 0 ~0013 oon igheerides" om oon 3 <o001 0067 0160 a"Atnlerlogvs Decatur 01904195 vs 1997 000299 | nes Tle 14. MicNiemstmlraCtYeeeftnAOsivtrmnvtaeeisoPnSroafoapdhteaesBeroCs0had(nSEee,cVMclaoPltsEsEdmpO9s5i7rn%eNCsonfiIderncieoLniwsih cme J aus ror oons VeanOneraion ~~ -0017 POA YeasOb-0001 a ooos TM "oom oy pr Gipsy TM Locaiont "oan ny Pros ooo Vbeeaets coms _ osCofdencelimis si pew om ner ane <oor san um oonz oo oo oo <oon ous oo I aos oo aunt w "oom oon ooo 15 0010 aos aos "oon oon oon ooo oon wo, com 030 "ou aos on os om oor aon oon Triglycerides' ole 0024 <.0001 0.066 0.161 promi Dec 600300 | P3MeCeormpsan)y foTambleTes15t.ingMiPxoteedntMieanldDeletCeoerfmfiicniaennottsf1sAtilmalteisn, SPthaonsdpahradtaEsrer!orCsh(iSnE)g, IPn-cVlaulduiensgaTnOd9F5a%ndChoenfniidrenacceioLinmiwtisth `Number of Years of ObservationofAntwerp and Decatur MaleEmployees 951% Confidence Limits _ Cocllicien SE pe Lower Upper. tere 3m om <001 3am ans Tor 00001 [a ~0019 ors Years Observation oo [a <0001 -0060 pr TOF xYearsObs ~000006 0007 9 -0003 0003 TM 05 ooo mn -0003 oor2 BMI "oon oon -0010 0008 Drinkslay oon ors on 0031 0028 [er 0003 [a 0 00004 0006 Locaion os 004 <0001 -032 01s Entry Perod* 0100 [a 0 00s om Baseline Years ~0006 uot 0 0013 oor Worked Triglycerides" ons [re <.0001 0068 0162 n+Aantawrerlpogvs Decatur tos 1s 1997 000301 TawaeCwuomcnsy "Fable f16r.omMTiessctdinMgoPdoetelntCioaelffDiectieenitnatnitonfeG,GTStaCnhdanrgoerIsncl(uSdE)i,ng-PVaRlOuSeasnadndte5I%ntCroancftiodnewnictehLimits `Number of Years of ObservationofAntwerp snd DecaturMaleEmployees 95% Confidence Linis . Coen SE pe Lover Upper Inereep 1383 on <0 Lite 260 vos "0004 oom " -003 003s Yeas Observion ~~ ~0075 oon <0 00% 0st PROSkYemObs 0004 000s 0005 oor ree "oom 00s ~o019 oo Bt 000s 000 -o013 oo Drinkatny oor oom 1 0020 0104 Cipueesiny ~0000 0003 m 0007 600s Locaion 00% 0104 36 om 010 Entey eros 03 ous <oo01 0204 osi2 WDeosrtkiende Years 000s 007 0 ~0007 oa Trgyerides" ozs 0050 <o001 0 0350 a"Rtoutelogvs Decatur Ses 1907 000302 | pooer "Tle r17.nMTiexsetdinMg PeotlentCioalsDfceetnertmiimanotafeG,nOttTaspCehdanEgxeoInnscl(uSdE)i.ng-PVFaOlAoasnadntdh95In%teCroancftiiodnenwciethLimi Nahe of Yar of ObservationofAnwerp sndDecatur Mle Employees 95%Confidence Lins Co Costien sn pase Lover Upper Inert 16 on oon 18 260 Pron oom ous "oss 0010 Yeas Observation 0077 [a <a "0100 ost | PROAX YesO 0005 ous ~0004 oom ne "oo oons 76 ~o01 oo ma oon oon " ~o0u oom Drinksldey oon oon nw ~o019 0105 Cigatestiny ~00007 oon 2 -0007 oons Locaiont 009 0104 5 -0301 0108 Eny Periods 0355 oom <o001 om os Baseline Years 000 000 0 -0007 oo J Worked | Trghyeerides' 0256 ost <.o001 0156 0356 "nAnatwteropgv.sDecatur 4100v4s109957 000303 eM1Co0mpa3ny "Tlef1r5.omMiTexsetid`nNgMuomdPboeetlrenCotofieafYlfeiDaceritseenonftmOitbnsaienrmtvscaotf,ioGSnGtoaTfndAaCnrhtdawnEergrreporIssnd(SnDE)e,cca-tTVuOarllFMuaaeulnsedatEdnhmdep5liIo%nytecnerCsaocngtfoindewniche Limits 95% Confidence Limits | Coen se pate Lover Upper Inerees 150 om <o001 un 2608 Tor oon [ey 0 0087 out Years Oservaion ~~ -007) [ry < woot 0104 ~00s4 TOR x YearsObs 0004 0003 2s -0003 oon me ~o00 0008 Bi 000s 0009 Drinklday 0013 oon Cigaretestiny 0000 000 Locaion 008s 004 7s -o0i8 oor - -oon 00 Ea -o01 0104 mn -0007 000s " -0204 on BWaosrekliende Years 0008 0008 a -0007 oo Tagheordes" 0209 0050 <o001 ou 03 a"Atntuwerlpogva Decatur "41094195 vs 1997 : 000304 [ 3PMaCeosmiporaen)y Table f19r.amMiTxesetdinMgoPdoetelntCioaelffDiceietnteErsmimiatonefasA,nSSttTasndCahradnEgieroIrnscl(uSdE)i,ngP-PVFaOlSueasnadntdhe9I5n%teCraocntfiiodnewnictehLimits. `NumberofYears of ObservationofAntwerp and Decatur Male Employees 95% Confidence Limits _Costlcient Lose pole. Lower Upper Intercept 2080 0.19% <1 268 am Pros. oot oon -0013 oon Years Observation -0.009 007 a 002 00s PROS x Years Obs 00007 0003 -0005 0006 Ase -0008 0004 05 -0016 -000005 BMI 004 00s " 0007 ool Drinksday [ey omg n 0007 0066 | Cigaretesiay 0003 000 0 0006 00002 Location oo oosy o 0206 0003 Entry Period [ 0s 00% one Baseline Years 000s ooo EY 0003 oor2 Worked Triglycerides' 0063 [ 0 000s 0121 L naturae l log 1"A9nt9we4rp9vv5asD1e9c9a7tur 000305 rom Testing Potential Determinants of AST* Change Including PFOA and the Itersction with wer moa - oo... | Cigarettes/day 0.003 0.002 0 0.006 0.0002 rw Worked wm Triglycerides" 0054 000 0 -0004 ons mem cn 000306 | PWaMsspiony "fable 21f.romMiTxesetdinMgodPeotlenCtoiealfiDieetenrtmiFnsainmtasteosf,ASStTa*ndCahrdanrgoerIsnc(lSuEd)i,ngPT-VOaFluensdantdhe9I5n%erCaocntfoindewnicteh Limits Numberof Years of Observation of Antwerp andDecaturMale Employees | ooSWConfidencelimis -- IT pale Lower, Upper Intercept a0 ows, <o001 2666 2409 | or ors oon 2 -0005 004 Yeus Observation 0.09 oo 2 0024 [a TOFx YersObs -0006 [rs 7 -0005 000 Ase ome 0004 BM 0004 aos Drinks 0029 oo % -0016 00002 "0 -0006 oot n -0007 006s Cigaretestay aoa owe Locations 0095 0053 0 -0006 [re 0 -0199 0010 | Ear Periods [ oom a -0037 ous | WoBarskeleidne Years 0005 0004 EY 0003 oon | Triglycerides" ooss om os 000003 ot "*nAantutrwaelrfpogv.s Decatur 41994195 vs 1997 000307 | cPoopaey Tile 2{2r.onMTiexsetdienMgomPdoetlebnotCfioeaYslefaDcrreisteeonrtfmiFOnbiaenrntveaotfsiAoSnLtoaTfndCAanhrtdawnFeeropIssnncld(uSdED)ie,ncgaPtPuRr-OMSalnVeaEdnmtadphel9o5lny%eeCeuosnificndenswciethLimits 95% ConfidenceLimits ~ Conticen SE pee Lover Upper erent 2501 om <oo0n 1961 00 | eros 000 016 0 -oo oon Years Obervaion 0095 ooo <oom ous ours PROSx Yeas Obs -000003 000s 0008 008 Me 00009 0006 5 -0012 0010 or 000 oon n 0004 oo Drink ~oon2 ous @ -0062 om | Ciprnestiy 000 oon oor -oon2 000 Location 0088 om 5 om 0056 Ey Prod [= oust <0 om os | BWaosrtkiendYeas oon ows " 0010 oor | Triglycer-- ides' -- 0159 0040 0001 0079 0238 a""e1sr00yo4vv8ssDe1c09a7tr 000308 3pMeCaotmpeandy Tule 2r3u.nMTiexseidngMoPdoetelntCioaelffDiectieernmiLntainntssteosf,ASLtTanCdharidnErroIrnscl(uSdEi,ngPP-VFaOlAesaandndth9e5n%crCaocntfiodnenwcitehLimits NuofYmearsbofObeservartion of Antwerp and DecaturMaleEmployees | 95% Confidence Limits _ Cetin SE pe Lower Upp: Inereent 24m om <omnn 1902 2016 proa ons oon a -0ms ots Years Observation 0.107 0010 <ou01 0126 00 PROAXYeusObs 0005 004 1 -0003 oon ne pee aoe " -oon oon Bi oon own n 0003 00s Drinkslay "00m os n oss 000 Cigarettes 0007 oo on -o012 -000y Locaion -00m oom 2 om 0064 Eney Period 030 0051 <o001 os oa Baseline Years 00008 000s -0010 oon Worked Taglpeeides' ost out 003 oon om | ""nAatnurwalerlogvs Decaur ] e1994195 v8 1997 600309 | P3aMesCSo1m0p1a6n)y "Table 2f4.romMiTxeesdinMgodPoetlenCtoieafliDceitenetrmsiniamnsso,f ASLtTan*dCarhdanrgoerIsnc(lSuFd)i,ngPT-VOaFluaensdstnhd 9I5nt%erCaocntfiiondewnicteh Limits `NumofbYeearrs of Observation of Aner andDecaturMale Employees 95% Confidence Limits _ Coffin SE ple Lower Upper Intercept 276 0m <1 19% 3015 Tor oom oot 2 -oon1 ost ews Observation - 0.102 oon <o001 01 oo TOF xYearsObs [a 0003 50 0004 0008 TM ~0m0s 0006 0 -oot ooi0 ] BM oon oom a 000 0026 Drinkslday oon 002s @ -0062 0037 Cigaetestday 008 ou oor 0012 "0003 Locaion 00m oor =n 0217 oon Ear Perioa* os oosy <.0001 020 0430 Baseline Years 0008 000s 58 -0010 oon Worked Tighyoerides" oa 000 0003 0069 0228 n*Aanriwaerlpogvs Decatur 441994195 vs 1997 000310 aPwascosmaposrreys Tafbiloem2s5.tiMnignePdotMenotdieallDCeoteefrfimciineannttsisoftTnotteasl, BSitlairnudbairn'd rCoharnsge(SIEn)c,lPu-dVianlgPucRsOaSnadn9d5%thCoInnfeirdaecniicoenLiwmiitths Numberof Years of ObservoafAtntiwoernp snd Decatur Mle Employees 95%ConfidenceLimits Coefiien st pve Lower Upper Intercept 0am = i ost ote | pros "00s oom = -0046 oon Years Observation ous oom ows 14s wos PROS xYearsObs [I 0004 ot -0007 000 Are oon ons o oot 002 BMI "0003 000 @ -0016 oot0 Drinkshly [ [re -0030 0062 Cigarettstlay 0008 002 <o0o01 -o0r2 -0004 Location ais 0064 <.0001 ois oat Entry Peiod*s ane oor 0206 oon 1 Baseline Years "0002 000s oo 0007 Worked Triglycerides" -0088 00 o -0161 001s |a | "*nAantuirwaelrlpogvs Decatur ++190415 vs 1997 000311 fMoirgd | bl 26. Mixed ide Coffin ines, Standard Eros (5), P-Valocsand95% Confidence init from Testing PoNteantmiableDaerfteYrminaeonftOsonafeTrovtsatloBniloirfuAbinn"eChranagmedDIenccaltuduirngMaPlFeOEAmapnldoyteheesInteraction with | 95%Confidence Limits _ Comin si poke Lover pee nee ois 02 0 om oie Pron "00 oo 1 ons oun Yeu Ocrvaion 002% oun wo oor 006 POA xYaOn 00S oot i" ou oon I oon ons on ower om a ou oun a os 000 Driktey oot oom 55 0mm oso Cipuetesty 000s om <ao0r 003 oon I oats 00st <omi 013 oa | owt on wn wor wos oom | Vaoikems ee uz ows n oan oom Tm riglycee rides"e - 0082 oom 0156 ~0008 Da | "natural log. *Aniwerp vs Decatur G00312 nes | Fle 2T, McieNoelbceCDorfeeoairokofnOciofvoaedonSDoifaaAn"eiCreosunngd5DI,neclcooVinigalTleOoFEmspn9ld5oh%yeeCsnisroe Lwiinhks | 95%Contdene Lis mee si puke Lover re eer "oa aan N ome oi Lor i aon wo "oo ou VersOeraion 0029 ao os I) oom TOR Yeon 0mm oom 3 om oo nee oon ous oot oo a Er own o 0016 oan Dine ois oon 5 oon ou Cipwetesy os own <aoon ~o0n2 "aos Locaions oss one <n oo os || pve Entry Period** Woes om0120 ws0.046 oon Coon-0210 wn-0.029 S ciLo pon 000313 ie 8. Med Moll Coun Ete, So fro 5), Vio nd 95% ConerceLii from Testing Potential DeterminantsofDirect Bilirubin' Change IncludingPFOS and the Interaction with BYomr | ee cattem__m nen 1 aa | - won I - osxYamom -0106 oie J" or ones wo om oo _--_--" os om Cpu ow - | _-- oe i Soyo a om | memven om ame | Worked Tiglyoerdes "00 oom J---- poe = re om a Cas im om comm on om om oo " ot ons * ons ame n om oss wate om 5 worm om pe om on wows os ws ~o1s5 -0026 *Antwepvs Deyc e 000314 "{brloem T2e.stiMnigxPeodNtdconemilleDoCefotseYfmeiianiraennottfsOEobifenrDveiaseit,oniSoiufsndbAanitrnwEeCrrhpoanssgn(deDSEIe)ncc,alPtudui-rngVPalaFeaOlEnAmdupal9eno5dys%eteeCsoInnftirdsecnicoenLiwmiihs I J ose pie Lover Upper ret 115 027 <o001 "2161 "1s Poa oor oon, o 001s oon Yeas Observation 0095 oom <on1 om oom | rroaxvamon 000 oon zn -o0n2 oon nee 0006 oon a ETM oon BM 0003 0006 ~o0m 0009 Drinkstey oom oom EF) -002 00s Cigeesiny ~00008 oom 0004 oon Locaiont oom 00s) 2 -oo2 oss | En Pei os 00s <o001 oan osm WBaosrlkienedYeas ~00008 oon B 008 0007 Tagleerde ~008 oom on 015s 00 n"*AaLntwIuerArlapSolvgsaD9ec9a7tur | 000315 | Te 20. Mc McCoo mse Sud rs GE) Nod35 Cone iis 3a M Company | from Testing PoetmenbtiealrDoefteYremairnsaanftsOofDniresct aBiolfivArunbiaen*rCthsannigdeDeoIcnactlnuudrinMgTleOEFmapnldoyteheesInteraction with 95% Confidence Limits cote sn pak Lover Upper Tor oun Years Oberon -0093 TosYemobs 004 |I oom ma oom Drnkslday oon Cipnenesiy ous | Locsin oom area 030 || WBaseelidne Years 0001 Triglycerides 0081 ng oon -oms oon oon <ont "0 "oom 003 a oon om oom - "ous oo ous ) ~oats oo oo 0mm 00st oo M 000 ous ous 16 om om oo <omn oan oa oo mn -o0s 0006 oom re0 mem0152 rerrs0e02e2ees 000316