Document pBdZ5q0GawkVoQoYJXLwOJNwa

3M Company Page 1 of 63 FINAL REPORT Epidemiology, 220-3W-05 Medical Department 3M Company St. Paul. MN 55144 Date: October 11,2001* Title: A Longitudinal Analysis of Serum Perfluorooctanesulfonate (PFS) and Perfluorooctanoate (PFOA) Levels in Relation to Lipid and Hepatic Clinical Chemistry Test Results from Male Employee Participants of the 1994/95,1997 and 2000 Fluorochemical Medical Surveillance Program Study Start Date: July 1, 2001 Protocol Number (not applicable) IRB Approval Exempt E.'.'edited X IRB Approval Date: (not applicable as these data are from a medical surveillance program) Principal Investigator Co-investigators: Study Director Geary W. Olsen, D.V.M., Ph.D.1 Michele M. Burlew, M.S.1 Jean M. Burris, R.N., M.P.H.1 Jeffrey H. Mandel, M D ., M.P.H.1 Jeffrey H. Mandel, M.D., M.P.H.1 1. 3M Medical Department, 220-3W-05, St. Paul, MN 55144-1000 * (Corrections made from previous version) 3M Company Page 2 of 63 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 total of 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). 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, 3M Company Page 3 of 63 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 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 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 3M Company Page 4 of 63 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. INTRODUCTION 3M Company Page 5 of 63 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, 1999b, 2001). In the 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 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 perfluorooctany! 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 3M Company Page 6 of 63 employee population has been significantly younger than Decatur, has had lower Body Mass Indices (BMI) and higher 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; Ikeda 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 (TOF) 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; Pastoor 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 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 3M Company Page 7 of 63 to conduct a longitudinal analysis among the male employee population. Altogether, a total of 175 employees (Antwerp = 100; Decatur = 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 total of 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, BMI, 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 3M Company Page 8 of 63 [cholesterol (mg/dl), high density lipoproteins (HDL, mg/dl) and triglycerides (mg/dl)] 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/dl)] 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 IU/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 PFOS and PFOA in the serum (Johnson et 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 1997a; 1997b). In 2000, sera samples were extracted using an 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^ (perfluorohexanesulfonate), PFOSAA (Nethyl perfluorooctanesulfonamidoacetate), M570 (N-methyl perfluorooctanesulfonamidoacetate), PFOSA (perfluorooctanesulfonateamide) and M556 (perfluorooctanesulfonamidoacetate). High-performance liquid chromatography/electrospray tandem mass spectrometry (HPLC/ESMSMS) was the 3M Company Page 9 of 63 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 attributed 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 measurements of 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 fixed if the levels in the study represent all possible levels of the factor, or at least all levels about which inference is to be made. Factor effects are random if the levels of the factor that are used in the study represent only a random ' sample of a larger set of potential levels. The focus of the standard linear model is to model the mean of y by using the fixed-effects parameters /3. That is, y = X/3 + e where y represents a vector of observed data, /3 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 X/3. The residual errors e are assumed to be 3M Company Page 10 of 63 independent and identically distributed Gaussian random variables with mean 0 and variance a 2. A generalized standard linear model is a mixed model which is: y = X/3 + Z y + 6 where y is an unknown vector of random-effects parameters with known design matrix Z, and 6 is an unknown random error vector whose elements are no longer required to be independent and homogeneous. If y + 6 are assumed to be Gaussian random variables that are uncorrelated and have expectations 0 and variances G and R, respectively, then the variance of y is: V = ZGZ + 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 o f 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. It is usually not realistic for most repeated measures data because it specifies that observations on the same subject are independent. Compound symmetric (CS, otherwise 3M Company Page 11 of 63 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(l))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 only to 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 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 3M Company Page 12 of 63 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 (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 et al 1998; 1999; 2001), Antwerp employees in this longitudinal investigadon 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 3M Company Page 13 of 63 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 determinants of lipid 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 significantly positive but its interaction with time (years variable) was negative (Table 5). Provided in Tables 5A through 5D are separate analyses for Antwerp for all subjects (Table 5A) and by each subcohort. The PFOA and cholesterol association appeared to primarily reside with the 21 Antwerp employees in subcohort A (Table 5B). 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 3M Company Page 14 of 63 the Decatur employee population (Table 5E) 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 over time 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 coefficient for the 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 11A) and primarily subcohort A (table 1IB) and, to a lesser extent subcohort B (Table 11C), but not subcohort C (Table 1ID). 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 1IE). 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 to 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 4 12A) than Decatur employees (Table 12B). 3M Company Page 15 of 63 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 andTOF 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 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 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). 3M Company Page 16 of 63 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; 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 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 to 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. 3M Company Page 17 of 63 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. REFERENCES 3M Company Page 18 of 63 3M Company (2000). SEDS Initial assessment report: Perfluorooctane sulfonic acid and its salts. St. Paul (MN):3M Company, (unpublished report). Minneapolis (MN):University of Minnesota, (unpublished report). Anderson DJ, Mulvana DE (1997a). Analytical Report for the Determination of Perfluorooctanoate and Perfluorooctanesulfonate in Human Serum by LC/MS. Ithaca NY:Advanced Bioanalytical Services Inc; August 1997. Anderson DJ, Mulvana DE (1997b). Analytical Report for the Determination of Perfluorooctanoate and Perfluorooctanesulfonate in Human Serum by LC/MS. Ithaca NY:Advanced Bioanalytical Services Inc; September 1997. Butenhoff JL, Costa G, Elcombe C, Farrar D, Hansen K, Iwai H, Jung R, Kennedy G, Lieder P, Olsen GW, Thomford P. Toxicity of ammonium perfluorooctanoate (APFO) in cynomolgus monkeys after 26 weeks of oral dosing, (unpublished report) Hansen KJ, Clemen LA, Ellefson ME, Johnson JHO (2001). Compound-specific, quantitative characterization of organic fluorochemicals in biological matrices. Environ Sei Technol 35:766-770. Haughom B, Spydevold O (1992). The mechanism underlying the hypolipmie effect of perfluoroctanoic acid (PFOA), perfluoroctanesulphonic acid (PFOSA) and clofibric acid. 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 peroxisome proliferation in rat liver by perfluorinated . octanesulfonic acid. In: Perixosmes in Biology and Medicine. (HD Fahmi and H Sies, eds) New York:Springer Verlag, pp 304-308. Johnson JD, Wolter JT, Colaizy GE, Rethwill PA, Nelson RM. Quantification of Perfluorooctanoate and Perfluorooctanesulfonate in Human Serum Using Ion-Pair Extraction and High Performance Liquid Chromatography-Thermospray Mass Spectrometry with Automated Sample Preparation. St. Paul, MN:3M Env Lab, 1996. Littell RC. Pendergast J, Natarajan R (2000). Modeling covariance structure in the analysis of repeated measures data. Stat Med 19:1793-1819. Littell RC. Milliken GA, Stroup WW, Wolfinger RD. SAS System for Mixed Models. Cary NC:SAS Institute Inc., 1996,633 pp. Olsen GW. Burris JM, Mandel JH, Zobel LR (1998). An epidemiologic investigation of clinical chemistries, hematology and hormones in relation to serum levels of perfluorooctane sulfonate in male fluorochemical production employees. St. Paul:3M Company (unpublished report). 3M Company Page 19 of 63 Olsen GW, Burris JM, Mandel JH, Zobel LR (1999a). 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 (1999b). 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 periluorooctanoate production workers. Drug Chem Toxicol 23(4):603-620. Olsen GW, Burlew MM, Burris JM, Mandel JH (2001a). A cross-sectional analysis of serum perfluorooctansulfonate (PFOS) and perlfuorooctanoate (PFOA) in relation to clinical chemistry, thyroid hormone, hematology and urinalysis results from male and female employee participants of the 2000 Antwerp and Decatur fluorochemical medical surveillance program. St: Paul (MN):3M Company (unpublished report). Olsen GW, Schmickler MN. Tierens JM, Logan PW, Burris JM, Burlew MM, Lundberg JK, Mandel JH (2001b). Descriptive summary of serum fluorochemical levels among employee participants of the year 2000 Antwerp fluorochemical medical surveillance program. St. Paul:3M Company (unpublished report). Olsen GW. Logan PW, Simpson CA, Burris JM, Burlew MM, Lundberg JK, Mandel JH '(2001c). Descriptive summary of serum fluorochemical levels among employee participants of the year 2000 Decatur fluorochemical medical surveillance program. St Paul:3M Company (unpublished report). Pastoor TP, Lee KP, Pern MA, Gillies 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, Butenhoff JL (2001a). Sub-chronic dietary toxicity of potassium perfluorooctanesulfonic acid in rats. Toxicol Sei (submitted 2001a). Seacat AM. Thoford PJ, Hansen KJ, Olsen GW, Case MT. Butenhoff JL. Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys. Toxicol Sei (submitted. 2001b). 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. pros (' Tiihle I. Cross-Sectional Analysis of Mean and St.....mid Deviation of Serum PPOS, IT'OA, TOP, Demographic Characteristics and Clinical Chemistries of Antwerp and Decatur Male Employees Who Participated in Two or More Medical Surveillance Examinations Between 1994/95 and 2(XX) "" ul ____________ 1994/1995______________ ____________ 1997__________;_______ ________________ 2000_______________ Antwerp (N = 06) Decatur (N = 40) Antwerp (N = 55) Decatur (N = 55) Antwerp (N= 100) Decatur (N = 75) Mean 1.87 SI) 1.9b Mean 2.62' SI) 1.78 Mean 1.42 SD 1.26 Mean 1.85 SD 1.64 Mean 1.16 SD 1.07 Mean 1.67" SD 1.39 PPOA 1.08 1.53 1.90" 1.08 1.54 1.61 1.41 1.17 1.4.3 1.21 1.83" 1.53 T()l; 1.9b 1.77 3.00" 1.77 1.98 1.48 2.17 1.76 1.74 1.24 2.34" 1.72 Age lb b.b 43" b.O 32 6.8 43" 7.3 38 7.8 47" 7.0 ItMl 2.1.9 2.4 28.0" 3.7 23.2 2.4 29.1" 4.3 24.7 2.8 29.0" 4.1 Alcohol l.l" l.l 0.3 O.b 0.9" 1.0 0.1 0.1 l.l" 1.0 0.1 0.2 Baseline Years Worked Cigarettes 11.0 4 5.7 7 20.4" 7.1 10" 1.5 7.0 5.2 57 20.0" 5 6.1 10 9.1 6.1 58 20.3e 8.5 5 II Cholesterol 217 4.3 219 38 202 45 214 35 220 41 213 40 IIDL 54" 13 43 n 49c II 4.3 10 53" 12 44 10 Triglycerides III 79 204" 122 108 5.3 181" 112 131 80 178e 115 Aik Phos 72 18 103d 27 68 15 87" 20 58 14 74" 21 (iUT 37 25 47 24 23 II .3.3" 27 ' 25 19 29 18 AST 25 11 31* 11 26 6 26 ' 8 24 7 25 7 ALP 44 17 49 25 30 12 32 15 2.3 11 32" 14 Total Bilirubin 0.9" 0.4 0.5 0.2 0.8" 0.4 0.6 0.2 1.0" 0.3 0.8 0.2 Direct Bilirubin 0.2 0.4 0.2 0.04 0.1" ().()7 0.1 0.04 0.1" 0.05 0.1 0.06 a. p < .05 b. p < .01 c. p c . 001 d. p<.000l compared to year-specific analyses of other manufacturing site. Tabic 2. Cross-Sectional Analysis of Mean anil Standard Deviation of Scrum PROS, PPOA, TOP. I'iij. o f 6.3 pros Who Participated in Two or More Medical Surveillance Examinations Between 1995 and 2(KK) 1995 1997 2000 A (N = 21) B(N = 45) A (N = 21) C (N II wA. A (N = 21) B(N = 45) Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD 2.19 1.27 1.72 2.20 2.24" 1.32 0.91 0.93 1.53. 0.87 1.20 1.31 C(N = 34) Mean SD 0.871' 0.71 proa 1.32 1.28 0.96 1.64 2.37" 2.28 1.04 . 0.61 2.06* 1.04 1.17 1.37 1.38 0.94 TOF 2.33 1.20 1.78 1.98 3.08" 1.59 1.31 0.91 2.41* 0.81 1.58 1.51 1.52 0.89 nOC Age 33 6 37" 7 35" 5 30 7 i 6 42" 7 32" 7 BMI 23.4 2.7 24.1 2.3 23.8 2.8 22.7 2.0 24.3 3.4 25.5` 2.7 23.9 2.4 Drinks/day 1.3 1.4 1.0 0.9 1.2 1.2 0.7 0.8 l.7c 1.3 1.2 l.l 0.8 0.6 Oigaretles/day 4 7 48 57 57 6 84 85 8 Baseline Years 9.9 Worked 4.3 11.6 63 9.9 4.3 5.3 4.9 9.9 4.3 11.6 6.3 5.3 4.9 Cholesterol 208 46 220 41 226' 50 187 34 229 46 233" 38 196 31 HDL 56 II 53 13 51 9 48 II 56 12 52 11 52 13 Triglycerides 85 49 123 88 115 69 104 41 123 65 154 95 105 55 Aik Phns GOT 69 20 30 9 73 16 41 29 67 19 25 10 69 12 22 II 55 17 60 14 58 12 23 13 30` 25 19 11 AST 25 5 25 13 26 5 26 7 22 5 25 9 23 6 ALT 42 8 46 20 31 12 30 13 22 II 25 13 21 7 Total Bilirubin 1.0 0.3 0.8 0.4 0.8 0.3 0.8 0.4 1.0 0.3 1.0 0.3 0.9 0.3 Direct Bilirubin 0.2 (MM 0.2 0.04 0.1 0.05 0.2 0.08 0.1 0.03 0.1 0.06 0.1 0.06 ^ IK >1. I (c\ iii iMnr K r\ s ' l(\tttt <irr\tm A rn \ \v .\n nrnun P PFOS Table .V Cross-Sectional Analysis of Mean and Standard Deviation of Scrum PFOS, I'FOA, TOP, Demographic Characteristics and Clinical Chemistries of Three Subgroups of Decatur Male Employees (A, B and C) Who Participated in Two or More Medical Surveillance Examinations Between 1994 and 2000 i2 of (3 _______ ____I994_____________ ______________\ 1997______________ ____________________ 2000 A (N = 20) B (N = 20) A (N = 20) C(N = 35) A (N = 20) B (N = 20) C (N = 35) Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD 2.07 1.67 3.17* 1.76 1.93 1.76 1.80 1.59 1.78 2.14 1.84 1.03 1.51 0.98 PFOA 1.50 0.87 2.30' 1.14 1.41 1.16 1.41 1.20 1.46 1.34 2.60" 2.02 1.60 1.14 TOP 2.37 1.54 3.64* 1.79 2 22 1.78 2.14 1.78 2.16 2.16 2.98 1.76 2.08 1.32 Age 42 7 44 5 45 7 42 8 48 7 50 5 45 8 HMI 28.2 4.0 27.7 3.3 28.3 4.1 29.6 4.5 28.9 4.1 28.7 3.3 29.3 4.5 Drinks/duy 0.1 0.3 0.4 0.8 0.1 0.1 0.1 0.2 0.0 0.1 0.2 0.3 0.1 0.2 Cigarettcs/day 6 13 14 15 4 10 5 II 3 8 10 15 4 9 Baseline Years 19.6 Worked 8.6 . 21.3 5.2 19.6 8.6 20.2 10.0 19.6 8.6 21.3 5.2 20.2 10.0 Cholesterol 235" 34 204 36 223 31 208 37 228 39 199 33 212 41 1IDL 47" 16 39 9 45 II 41 9 47 12 n90 6 45 9 Triglycerides 180 88 229 148 188 115 178 112 193 124 187 76 165 128 Aik Phos 98 29 107 24 85 22 87 18 70 27 82 17 72 20 CiCiT 41 25 52 22 35 36 31 20 29 16 34 23 27 17 AST 32 15 29 6 25 6 27 8 26 8 25 4 25 7 ALT 52 33 47 11 30 15 34 16 30 18 32 II 33 14 Total Bilirubin 0.6 0.2 0.5 0.2 0.6 0.2 0.6 0.2 0.8 0.2 0.7 0.2C 0.8 0.2 Direct Bilirubin 0.2" 0.05 0.2 0.04 0.1 0.04 0.1 0.05 0.1 0.08 0.1 0.04 0.1 0.06 'i n r * MS f l i ' i n M lltp r r D m i v i i ' i m n / c \ i n v#*r h n s OS l lc m o m i i n A r . n ^ OS llvm o rn n n P I Company l'agc 23 of 63 Table 4. Mixed Model Coefficient Estimates, Standard Errors (SB), P-Values and 95% Confidence Limits from Testing Potential Determinants of Cholesterol* Change Including PFOS and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 4.K68 0.127 <.0001 4.618 5.118 PFOS ' 0.010 0.008 .18 - 0.005 0.025 Years Observation 0.0009 0.005 .84 -0.008 0.010 PFOS x Years Obs - 0.0004 0.002 .83 -0.004 0.Q03 Age 0.007 0.003 .01 0.002 0.013 BMI 0.006 0.003 .07 -0.0005 0.013 Drinks/day 0.014 0.012 .27 -0.011 0.038 Cigareltes/day Location* - 0.0009 0.034 0.001 0.037 i .41 .36 -0.003 -0.039 0.001 0.108 Entry Period** Baseline Years Worked 0.064 -0.004 0.028 0.003 . 02 .20 0.009 -0.009 0.119 0.002 'natural log Antwerp vs Decatur **1994/95 vs 1997 . . Company Page 24 of 63 Table 5. Mixed Model Coefficient listmates, Standard Errors (SE), P-Values and 93% Confidence Limits front 'I'esling Potential Determinants of Cholesterol* Change Including PPOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient Sit " p-value Lower Upper Intercept 4.812 0.127 < .0001 4.561 5.063 PFOA Years Observation ' 0.032 0.005 0.009 0.005 , .0008 .24 0.013 -0.004 0.051 0.014 PPOA x Years Obs - 0.005 0.002 .005 -0.009 -0.002 Age 0.008 0.003 .007 0.002 0.013 BMI 0.007 0.003 .049 0.00004 0.013 Drinks/day Cigarettes/day 0.014 - 0.001 0.012 0.001 .263 -0.010 .32 -0.003 0.037 0.001 Location* 0.041 0.037 .27 - 0.032 0.114 Entry Period** Baseline Years Worked 0.068 -0.004 0.027 0.003 .01 0.015 0.122 .15 -0.009 0.001 *natural log Antwerp vs Decatur 1994/95 vs 1997 Company Page 25 of 63 Table 5A. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Cholesterol* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 4.710 0.149 <.0001 4.414 5.005 PFOA ' 0.029 0.012 .01 0.006 0.053 Years Observation PFOA x Years Obs 0.005 - 0.003 0.006 0.(X)3 .36 -0.006 0.017 .20 -0.009 0.002 Age 0.009 0.003 .008 0.003 0.016 BMI 0.008 0.(X)5 .14 -0.003 0.019 Drinks/duy 0.022 0.013 .09 -0.004 0.047 Cigarcttes/day 0.(XX)7 0.(X)2 .70 -0.003 0.004 Entry Period** 0.079 0.038 .04 0.004 0.153 Baseline Years Worked - 0.002 0.004 .67 - 0.010 0.007 `natural log **1994/95 vs 1997 Table 5B. Mixed Model Coefficient listmates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Cholesterol* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp Subgroup A (1995,1997 and 2000) Male Employees ./ Company Page 26 of 63 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 5.059 0.414 < .0001 4.194 5.925 PFOA ' 0.044 0.020 .03 0.004 0.084 Years Observation PFOA x Years Obs Age 0.037 -0.013 -0.0007 0.015 0.005 0.012 .02 0.007 0.067 .02 - 0.023 -0.002 .95 - 0.025 0.024 BMI Drinks/duy 0.004 -0.016 0.012 0.019 ; .77 .41 - 0.020 - 0.054 0.028 0.023 Cigarettes/day 0.003 0.005 .51 -0.007 0.013 Baseline Years Worked 0.015 0.016 .36 - 0.018 0.047 *natural log . .a Company Puge 27 of 63 Tabic 5C. Mixed Model Coefficient 11stimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Cholesterol* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp Subgroup B (1995 and 2000) Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 4.838 0.244 <0.001 4.346 5.330 PFOA ' 0.018 0.017 .30 -0.016 0.052 Years Observation 0.005 0.008 .55 -0.011 0.021 PFOA x Years Obs - 0.002 0.004 .58 -0.009 0.005 Age 0.004 0.005 .40 -0.006 0.015 BMI 0.014 0.009 .13 -0.004 0.031 Drinks/day 0.017 0.022 .45 - 0.028 0.061 Cigareltcs/day 0.002 0.003 .44 -0.004 0.009 Baseline Years Worked -0.0001 0.(X)6 .99 -0.011 0.011 *natural log -.M Company Page 28 of 63 Table 5D. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from 'I'esting Potential Determinants of Cholesterol* Change Including PPOA and the Interaction with Number of Years of Observation of Antwerp Subgroup C (1997 and 2000) Mule Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 4.528 0.281 <.0001 3.955 5.100 PFOA ' 0.004 0.062 .95 -0.125 0.132 Years Observation -0.010 0.026 .70 -0.065 0.044 PFOA x Years Obs 0.010 0.022 .65 - 0.035 0.055 Age 0.016 0.006 .01 0.004 0.028 BMI Drinks/day 0.009 0.033 0.012 0.032 .43 - 0.015 0.033 .31 - 0.033 0.100 Cigarelles/day Baseline Years Work - 0.0001 - 0.005 0.003 0.008 .97 -0.007 .49 -0.021 0.006 0.011 *natural log Table 5H. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Cholesterol* Change Including PFOA and the Interaction with Number of Years of Observation of Decatur Male Employees _(vl Company Page 29 of 63 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 5.220 0.206 <.0001 4.810 5.630 PFOA Years Observation ' 0.016 -0.002 0.016 0.008 .34 t .77 - 0.017 - 0.017 0.048 0.013 PFOA x Years Obs -0.003 0.003 .22 - 0.009 0.002 Age 0.002 0.005 .70 - 0.008 0.012 BMI 0.003 0.004 .55 - 0.006 0 . 0 1 1 Drinks/day - 0.088 0.035 .01 - 0.158 -0.018 Cigaretles/day -0.002 0.001 .15 - 0.004 0.0007 Entry Period** 0.047 0.040 .24 - 0.032 0.125 Baseline Years Worked - 0.002 0.004 .62 - 0.010 0.006 *natural log **1994/95 ys 1997 . Company Page 30 of 63 Table 6. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Cholesterol* Change Including TOP and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 4.828 0.127 <.0001 4.577 5.079 TOP ' 0.021 0.008 .007 0.006 0.035 Years Observation 0.004 0.005 .37 - 0.005 0.014 TOP x Years Obs ' - 0.003 0.001 : .07 -0.005 0.0003 Age 0.007 0.003 .01 0.002 0.013 BMI 0.006 0.003 .05 -0.0001 0.013 Drinks/day 0.012 0.012 .32 - 0.012 0.036 Cigarettes/day -o.oot 0.001 .37 -0.003 0.001 Location* 0.042 0.037 .26 - 0.032 0.115 Entry Period** 0.063 0.027 .02 0.010 0.117 Baseline Yeurs Worked -0.004 0.003 .17 -0.009 0.002 *natural log Antwerp vs Decatur *1994/95 vs 1997 . c 31 of 63 Table 6A. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from 'festing Potential Determinants of Cholesterol" Change Including TOP and the Interaction with Number of Years of Observation of Antwerp Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 4.721 0.150 <.0001 4.424 5.018 TOF , 0.017 0.011 .12 -0.004 0.038 Years Observation 0.004 0.007 .55 -0.009 0.017 TOF x Years Obs Age -0.0008 0.009 0.002 0.003 .70 -0.005 0.003 .01 0.002 0.016 BMI 0.009 0.006 .12 -0.002 0.020 Drinks/day 0.019 0.013 .14 -0.006 0.045 Cigareties/duy 0.0008 0.002 .69 -0.003 0.005 Entry Period** 0.070 0.038 .07 -0.006 0.145 Baseline Years Worked - 0.0008 0.004 .85 -0.009 0.008 "natural log *1994/95 vs 1997 ,,A Cunipuny Page 32 of 63 Table 6li. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Cholesterol* Change Including TOP and the Interaction with Number of Years of Observation of Decatur Male Employees 95% Confidence Limits Coefficient SE p- value Lower Upper Intercept 5.214 0.202 <.0001 4.811 5.616 TOP 0.014 0.011 .19 - 0.007 0.035 Years Observation -0.002 0.008 . .79 -0.018 0.013 TOP x Years Obs Age -0.002 0.002 0.002 0.005 .22 -0.006 0.001 .69 -0.008 0.012 BM1 0.002 0.004 : .55 -0.006 0.011 Drinks/day Cigarettes/day -0.090 -0.002 0.035 0.001 .012 -0.160 - 0.020 .161 -0.004 0.0007 Baseline Years Worked -0.002 0.004 .60 -0.010 0.006 *natural log **1994/95 vs 1997 a Company Page 33 of 63 Table 7. Mixed Model Coefficient Estimates, Standard Errors (SB), P-Values and 95% Confidence Limits from Testing Potential Determinants of HDL* Change Including PPOS and the Interaction with Numlter of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE : p-value Lower Upper Intercept 4.212 0.144 <.0001 3.930 4.495 PFOS ' - 0.010 0.008 .24 - 0.026 0.007 Years Observation PFOS x Years Obs 0.002 -0.001 0.005 0.002 .71 -0.008 0.012 .52 -0.005 0.002 Age 0.004 0.003 .22 . - 0.002 0.011 BMI -0.017 0.(X)4 <.0001 - 0.025 0.010 Drinks/day 0.064 0.013 <.0001 0.037 0.090 Cigarettes/day - 0.<X)4 0.001 . .0005 - 0.007 - 0.002 Location* 0.006 0.043 .89 - 0.079 0.091 Entry Period** 0.025 0.032 .44 - 0.038 0.088 Baseline Years Worked - 0.007 0.003 .03 -0.013 -0.0005 "natural log Antwerp vs Decatur *1994/95 vs 1997 Company Page 34 of 63 Table 8. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of HDL* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SI? p-value Lower Upper Intercept 4.216 0.145 <.0001 3.929 4.503 PEOA Years Observation ' - 0.006 0.005 0.011 0.005 .56 i .35 - 0.027 - 0.005 0.015 0.014 PFOA x Years Obs - 0.002 0.002 .40 -0.006 0.002 Age 0.004 0.003 .28 ` - 0.003 0.010 BM1 -0.017 0.004 <.0001 - 0.024 -0.010 Drinks/day 0.062 0.013 <.0001 0.036 0.088 Cigarelles/day - 0.004 0.001 > .0004 - 0.007 - 0.002 Location* 0.008 0.043 .85 - 0.076 0.093 Entry Period** 0.020 0.032 .53 -0.042 0.082 Baseline Years Worked -0.007 0.003 .04 - 0.013 - 0.0004 "natural log Antwerp vs Decatur **1994/95 vs 1997 , Company Page 35 of 63 Table 9. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of HDL* Change Including TOP and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees . 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 4.217 0.145 <.0001 3.931 4.502 TOP Years Observation -0.006 0.004 0.008 0.005 : .44 t .47 - 0.023 -0.007 0.010 0.014 TOP x Years Obs - 0.0009 0.001 .57 -0.004 0.002 Age 0.004 0.003 .25 -0.003 0.010 BMI -0.017 0.004 <.0001 - 0.025 -0.010 Drinks/day 0.063 0.013 <.0001 0.037 0.089 Cigarettes/day - 0.004 0.001 .0005 -0.007 -0.002 Location* 0.007 0.043 .88 - 0.078 0.092 Entry Period** 0.021 0.032 .50 . -0.041 0.084 Baseline Years Worked - 0.007 0.003 .04 -0.013 -0.0004 #naturul log Antwerp vs Decatur *1994/95 vs 1997 1Company Page 36 of 63 Table 10. Mixed Model Coefficient (Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Triglyceride* Change Including PFOS and the Interaction with Numltcr of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient Sli p-value Lower Upper Intercept PFOS 2.730 ' 0.025 0.335 0.020 <'.0001 .22 2.068 -0.015 3.392 0.065 Years Observation - 0.004 0.013 .73 - 0.029 0.021 PFOS x Years Obs 0.006 0.005 .22 -0.004 0.015 Age 0.003 0.008 .67 -0.011 0.018 BMI 0.006 0.009 <.0001 0.048 0.083 Drinks/day - 0.029 0.033 .37 - 0.094 0.035 Cigarettes/day 0.011 0.003 .0002 0.005 0.017 Location* Entry Period** 0.052 0.089 0.099 0.073 .60 -0.143 0.247 .22 - 0.055 0.234 Baseline Years Worked 0.005 0.007 ;. .50 -0.010 0.019 *natural log Antwerp vs Decatur *1994/95 vs 1997 I Luiiipany rge 37 of 63 Table 11. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Triglyceride* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 2.539 0.332 < .0001 1.883 3.196 PFOA . 0.094 0.025 .0002 0.045 0.144 Years Observation 0.007 0.012 .57 -0.017 0.031 PFOA x Years Obs -0.008 0.005 .12 -0.018 0.002 Age 0.006 0.007 . .42 -0.009 0.021 BMI 0.066 0.009 <.0001 0.049 0.083 Drinks/day Cigarettes/day - 0.027 0.011 0.032 0.003 .40 .0002 -0.090 0.005 0.037 0.017 Location* 0.072 0.096 .46 -0.118 0.262 Entry Period*41 0.098 0.070 .17 -0.041 0.236 Baseline Years Worked 0.003 0.007 .67 -0.011 0.017 'natural log Aiiim ii V* I M ill vs HMJ1 aM Company Page 38 of 63 Table 11A. Mixed Model Coefficient Estimates,^Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Triglyceride* Change Including PPOA and the Interaction with Number of Years of Observation of Antwerp Male Employees 95% Confidence Limits Coefficient SE p-valuc Lower Upper Intercept PFOA 3.067 ' 0.089 0.394 0.030 <.0001 .005 2.286 0.028 3.848 0.149 Years Observation 0.024 0.015 .12 -0.006 0.053 PFOA x Years Obs Age BMI - 0.010 0.012 0.039 0.007 0.009 0.014 .15 - 0.023 .22 -0.007 .007 0.011 0.004 0.030 0.068 Drinks/day - 0.026 0.033 .44 - 0.092 0.040 Cigaretles/day 0.018 0.005 .0004 0.008 0.028 Entry Period** 0.013 0.100 .90 -0.212 0.186 Baseline Years Worked 0.003 0.011 .76 - 0.019 0.026 *natural log **1994/95 vs 1997 * j M Company Page 39 of 63 Table 11H. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 9 5 % Confidence Limits from Testing Potential Determinants ofTriglyceride* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp Subgroup A (1995, 1997 and 2000) Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 3.104 1.063 .009 0.880 5.328 PFOA ' 0.182 0.051 .001 0.079 0.286 Years Observation 0.167 0.037 <.0001 0.091 0.241 PFOA x Years Obs -0.061 0.011 <.0001 - 0.084 - 0.039 Age - 0.007 0.031 .83 -0.069 0.056 BM1 0.039 0.030 .20 - 0.021 0.100 Drinks/day - 0.082 0.051 .12 -0.186 0.023 Cigareltes/day 0.008 0.012 .52 -0.017 0.033 Baseline Years Worked 0.036 0.041 .40 -0.049 0.120 `natural log 1Company Page 40 of 63 Table 11C. Mixed Model CoelTicienl Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Triglyceride* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp Subgroup B (1995 and 2000) Male Employees . 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 2.775 0.523 <i .0001 1.720 3.830 PFOA ' 0.097 0.038 .02 0.019 0.174 Years Observation 0.005 0.018 .80 - 0.033 0.042 PFOA x Years Obs 0.0008 0.009 .93 -0.017 0.018 Age 0.019 0.011 .10 -0.004 0.041 BMI 0.042 0.019 .04 0.003 0.081 Drinks/duy 0.038 0.050 .45 -0.062 0.138 Cigurclles/day 0.022 0.007 .003 0.008 0.036 Baseline Years Worked - 0.002 0.012 .83 -0.026 0.021 'natural log /vi Company Page 4 1 of 63 Table I ID. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 9 5 % Confidence Limits from Testing Potential Determinants of Triglyceride* Change Including PFOA and the Interaction with Numlier of Years of Observation of Antwerp Subgroup C (1997 and 2000) Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 3.285 0.744 .0001 1.769 4.801 PFOA ' 0.032 0.149 .83 . - 0.280 0.344 Years Observation - 0.072 0.063 .26 - 0.203 0.058 PFOA x Years Obs 0.020 0.051 .70 - 0.087 0.128 Age - 0.005 0.016 .77 - 0.038 0.028 BMI 0.057 0.030 .08 -0.006 0.120 Drinks/day - 0.025 0.081 .76 0.195 0.145 Cigarettes/day 0.019 0.008 .032 0.002 0.036 Baseline Years Worked...... 0.010 0.021 .65 -0.034 0.053 *natural log .vl Company Page 42 of 63 Table I 111. Mixed Model Coefficient listmates, Standard Errors (SE), P-Values and 95% Confidence Limits from 'lesting Potential Determinants of Triglyceride* Change Including PFOA and the Interaction with Number of Years of Observation of Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 2.581 0.567 <.0001 1.450 3.712 PFOA ' 0.054 0.046 .24 - 0.037 0.145 Years Observation - 0.028 0.022 .20 . -0.071 0.015 PFOA x Years Obs Age BM1 Drinks/day Cigarettes/day Entry Period** 0.002 - 0.0008 0.073 - 0.038 0.005 0.274 0.008 0.013 0.012 0.099 0.004 0.109 . .85 .95 <.0001 .70 .16 .01 - 0.014 - 0.028 0.050 -0.235 -0.002 0.058 0.017 0.026 0.096 0.158 0.012 0.491 Baseline Years Worked 0.009 0.011 .44 -0.013 0.030 *natural log **1994/95 vs 1997 A Company Page 43 of 63 Table 12. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from 'I'esling Potential Determinants of Triglyceride* Change Including TOP and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees Coefficient SE i p-value 95% Confidence Limits Lower Upper Intercept 2.612 0.334 <.0001 1.953 3.272 TOP ' 0.053 0.020 .008 0.014 0.093 Yeurs Observation - 0.0005 0.013 .97 - 0.027 0.026 TOP x Years Obs -0.0005 0.004 .91 -0.008 0.007 Age 0.004 . 0.007 .57 -0.010 0.019 BMI 0.066 0.009 <.0001 0.049 0.084 Drinks/day Cigaretles/day -0.031 0.011 0.032 0.003 .34 .0002 - 0.095 0.005 0.033 0.017 Location* Entry Period** 0.074 0.0K5 0.098 0.071 .45 -0.119 0.266 .23 - 0.055 0.226 Baseline Years Worked 0.004 0.007 .58 -0.010 0.018 *na!ural log Antwerp vs Decatur **1994/95 vs 1997 A Company Page 44 of 63 Table 12A. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Triglyceride* Change Including TOP and the Interaction with Number of Years of Observation for Antwerp Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 3.078 0.395 <.0001 2.294 3.862 TOP ' 0.053 0.028 .06 -0.002 0.107 Years Observation 0.016 0.017 .35 -0.018 0.049 TOF x Years Obs -0.0007 0.006 .90 -0.012 0.010 Age 0.009 0.009 .32 -0.009 0.028 BMI Drinks/day 0.042 - 0.032 0.014 0.034 0.004 .34 0.014 - 0.099 0.071 0.035 Cigareltes/day 0.018 0.005 .0005 0.008 0.029 Entry Period** - 0.045 0.101 .66 - 0.245 0.155 Baseline Years Worked 0.007 0.011 . -56 -0.016 0.029 *natuml log **1994/95 vs 1997 A Company Page 45 of 63 Table 12B. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Triglyceride* Change Including TOP and the Interaction with Number of Years,of Observation for Decatur Male Employees 95% Confidence Limits Coefficient SE p-valtie Lower Upper Intercept 2.644 0.563 <.0001 1.521 3.766 TOF ' 0.031 0.030 .29 - 0.028 0.090 Years Observation - 0.035 0.022 .12" - 0.079 0.009 TOF x Years Obs 0.004 0.005 .45 -0.007 0.015 Age -0.002 0.014 ' .90 - 0.029 0.025 BMI Drinks/day 0.073 - 0.030 0.012 0.099 <.0001 .76 0.050 - 0.227 0.010 0.166 Cigarettes/day 0.005 0.004 .20 -0.003 0.012 Entry Period** Busclinc Years Worked 0.275 0.009 0.1 II 0.011 .01 0.055 0.494 .44 -0.013 0.030 *natural log **1994/95 vs 1997 4 Company . age 46 of 63 Table 13. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Alkaline Phosphatase* Change Including PFOS and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 3.789 0.176 <.0001 3.442 4.137 PFOS ' 0.002 0.009 .87 -0.017 0.020 Years Observation -0.051 0.006 < .0001 -0.062 - 0.040 PFOS x Years Obs 0.002 0.002 .47 -0.003 0.006 Age 0.005 0.004 .20 -0.003 0.012 BM1 -0.0007 0.004 .88 -0.009 0.008 Drinks/day -0.001 0.014 .94 - 0.030 0.028 Cigarettes/day 0.003 0.001 .03 0.0004 0.006 Location* - 0.242 0.049 <.0001 -0.338 -0.145 Entry Period** 0.098 0.037 .008 0.025 0.171 Baseline Years Worked -0.006 0.004 .10 -0.013 0.001 Triglycerides* 0.113 0.024 ; <.0001 . 0.067 0.160 "natural log Antwerp vs Decatur **1994/95 vs 1997 , mpany Page 1 of 63 Table 14. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Alkaline Phosphatase* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 3.785 0.176 <.0001 3.437 4.133 PFOA 0.005 0.012 .69 - 0.019 0.028 Years Observation - 0.047 0.06 <.0001 - 0.058 - 0.036 PFOA x Years Obs -0.001 0.002 .62 -0.005 0.003 Age 0.005 0.004 .19 -0.002 0.013 BMI -0.0009 0.004 .85 -0.010 0.008 Drinks/day - 0.002 0.015 .89 -0.031 0.027 Cigarettes/day 0.003 0.001 .03 0.0004 0.006 Location* - 0.243 0.049 , <.0001 -0.340 -0.147 Entry Period** 0.100 0.036 .007 0.028 0.172 Baseline Years Worked -0.006 0.004 .09 - 0.014 0.001 Triglycerides* 0.114 0.024 <.0001 0.066 0.161 *natural log Antwerp vs Decatur *1994/95 vs 1997 "\ 1Company rage 48 of 63 Table 15. Mixed Model Coefficient listimales, Standard Errors (SE), P-Values and 95% Confidence Limits from 'i'esting Potential Determinants of Alkaline Phosphatase* Change Including TOP and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Uppei Intercept 3.780 0.177 <.0001 3.441 4.138 TOP - 0.00004 0.009 .99 -0.019 0.018 Years Observation - 0.049 0.006 <.0001 -0.060 - 0.037 TOF x Years Obs -0.00006 0.0017 .97 -0.003 0.003 Age 0.005 0.004 .19 -0.003 0.012 BMI -o.oot 0.004 .82 - 0.010 0.008 Drinks/day - 0.002 0.015 .91 -0.031 0.028 Cigaretles/day 0.003 0.001 .03 0.0004 0.006 Location* - 0.245 0.049 <.0001 - 0.342 -0.148 Entry Period** 0.100 0.036 .007 0.028 0.172 Baseline Years Worked -0.006 0.004 .10 -0.013 0.001 Triglycerides* 0.115 0.024 <.0001 . 0.068 0.162 *nalura! log Antwerp vs Decatur *1994/95 vs 1997 ( Company rage 49 of 63 Table 16. Mixed Model Coefficient listmates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of GGT* Change Including PFOS and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 1.883 0.373 <.0001 1.146 2.620 PFOS -0.004 0.020 .84 -0.043 0.035 Years Observation - 0.075 0.012 <.0001 -0.098 -0.051 PFOS x Years Obs 0.004 0.004 .42 -0.005 0.012 Age - 0.003 mm .74 -0.019 0.013 BMI 0.005 0.009 .59 -0.013 0.024 Drinks/day 0.042 0.031 .18 - 0.020 0.104 Cigareties/day - 0.0009 0.003 .77 -0.007 0.005 Location* -0.096 0.104 .36 - 0.030 0.110 Entry Period** Baseline Years Worked 0.358 0.008 0.078 0.007 <.0001 .30 0.204 -0.007 0.512 0.024 Triglycerides" 0.251 0.050 <.0001 0.152 0.350 "natural log Antwerp vs Decatur **1994/95 vs 1997 M Company Page SOof 63 Table 17. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of GGT* Change Including PPOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 1.876 0.374 <.0001 1.138 2.613 PFOA Years Observation ' - 0.009 - 0.077 0.025 0.012 .72 <.0001 - 0.058 -0.100 0.040 - 0.054 PFOA x Years Ohs 0.005 0.005 .29 -0.004 0.014 Age - 0.002 0.008 .76 -0.018 0.013 BMI 0.004 0.009 .64 - 0.014 0.023 Drinks/day 0.043 0.031 .17 -0.019 0.105 Cigarefles/day -0.0007 0.003 .82 -0.007 0.005 Location* - 0.097 0.104 .35 -0.301 0.108 Entry Period** 0.355 0.077 <.0001 0.203 0.507 Baseline Years Worked 0.008 0.008 .30 -0.007 0.024 Triglycerides* 0.256 0.051 <.0001 0.156 0.356 `natural log Antwerp vs Decatur **1994/95 vs 1997 M Company Page S1 of 63 Table 18. Mixed Model Coefficient listmates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of GGT* Change Including TOP and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 1.870 0.374 <.0001 1.132 2.608 TOF ' 0.002 0.020 .93 - 0.037 0.041 Years Observation - 0.079 0.013 <.0001 -0.104 - 0.054 TOF x Years Obs 0.004 0.003 .25 -0.003 0.011 Age -0.003 0.008 .75 -0.018 0.013 BMI 0.005 0.009 .57 -0.013 0.024 Drinks/day 0.043 0.031 .17 -0.019 0.104 Cigurcttes/day -0.0009 0.003 .77 -0.007 0.005 Location* -0.088 0.104 .40 -0.294 0.117 Entry Period** 0.352 0.078 < .0001 0.200 0.505 Baseline Years Worked 0.008 0.008 .31 -0.007 0.024 Triglycerides* 0.249 0.050 <.0001 0.149 0.348 'natural log Antwerp vs Decatur **1994/95 vs 1997 t Table 10. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of AST* Change Including PPOS and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees M Company Page 52 of 63 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept 3.080 0.198 <.0001 2.689 3.471 PFOS Years Observation ' 0.010 - 0.009 0.011 0.007 .39 i .19 -0.013 -0.024 0.032 0.005 PFOS x Years Obs 0.0007 0.003 .79 -0.005 0.006 Age -0.008 0.004 .05 - 0.016 -0.00005 BMI 0.004 0.005 47 -0.007 0.014 Drinks/day 0.030 0.018 .11 -0.007 0.066 Cigarettes/day - 0.003 0.002 .07 -0.006 0.0002 Location* Entry Period** 0.102 0.039 0.053 0.039 .06 -0.206 0.003 .32 - 0.038 0.116 Baseline Years Worked 0.005 0.004 .22 -0.003 0.012 Triglycerides* 0.063 0.029 .03 0.005 0.121 *nalural log Antwerp vs Decatur 1994/95 vs 1997 iM Company Page 53 of 63 Table 20. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from rl'esting Potential Determinants of AST* Change Including PPOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Intercept PFOA Coefficient 3.053 ' 0.027 SE 0.199 0.015 p-value < .0001 .06 Lower 2.661 -0.002 Upper 3.445 0.056 Years Observation PFOA x Years Obs Age BMI Drinks/day - 0.008 - 0.002 - 0.007 0.004 0.030 0.007 0.003 0.004 0.005 0.018 .28 - 0.022 0.006 .41 -0.008 0.003 .08 -0.015 0.0008 .39 -0.006 0.015 .10 -0.006 0.066 Cigarcltes/day Location* Entry Period** Baseline Years Worked -0.003 - 0.097 0.044 0.004 0.002 0.053 0.039 0.004 .07 -0.006 0.0002 .07 -0.201 0.008 .26 - 0.032 0.120 .27 -0.003 0.012 Triglycerides* 0.054 0.030 .07 -0.004 0.113 *natural log Antwerp vs Decatur **1994/95 vs 1997 ACompany Page 54 of 63 Table 2 1. Mixed Model Coefficient listimules, Standard lirrors (SE), P-Values and 95% Confidence Limits from 'resting Potential Determinants of AST* Change including TOF and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees ' 95% Confidence Limits Coefficient Sli p-value Lower Upper Intercept 3.058 0.198 , < .0001 2.666 3.449 TOF ' 0.018 0.011 .12 -0.005 0.04 Years Observation - 0.009 0.008 .24 - 0.024 0.006 TOF x Years Obs Age -0.006 - 0.008 0.002 0.004 .79 -0.005 0.004 .06 -0.016 0.0002 BM1 0.004 0.005 .40 -0.006 0.015 Drinks/day 0.029 0.018 .12 -0.007 0.065 Cigarettes/day - 0.003 0.002 .07 -0.006 0.0002 Location* - 0.095 0.053 .08 -0.199 0.010 Entry Period** 0.039 0.039 .31 - 0.037 0.115 Baseline Years Worked 0.005 0.004 .24 -0.003 0.012 Triglycerides* - 0.058 0.029 .05 0.00003 0.116 #natural log Antwerp vs Decatur *1994/95 vs 1997 ' Company . .<e 55 of 63 Tabic 22. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of ALT* Change Including PFOS and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Intercept PFOS Years Observation PFOS x Years Obs Age DM1 Coefficient 2.501 ' 0.010 - 0.095 - 0.00(K)3 0.0009 0.010 SE 0.273 0.016 0.010 0.004 0.006 0.007 p-value <.0001 .54 <.0001 .99 .88 .17 Lower 1.961 -0.021 -0.115 -0.008 -0.012 -0.004 Upper 3.041 0.041 - 0.075 0.008 0.010 0.024 Drinks/day -0.012 0.025 .63 -0.062 0.038 Cigarettes/day - 0.008 0.002 .001 -0.012 -0.003 Location* - 0.088 0.073 .23 -0.233 0.056 Entry Period** 0.329 0.054 <.0001 0.222 0.436 Baseline Years Worked 0.001 0.005 .84 - 0.010 0.012 Triglycerides* 0.159 0.040 .0001 0.079 0.238 *natural log Antwerp vs Decatur **1994/95 vs 1997 . Company Page 56 of 63 Table 23. Mixed Model Coefficient estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of ALT* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits r*3 ( 'oefficiciit p- value Lower Upper Intercept PFOA 2.479 0.015 0.272 0.020 < .0001 .46 1.942 - 0.025 3.016 0.654 Years Observation -0.107 0.010 <.0001 . -0.126 - 0.087 PFOA x Years Ohs Age 0.005 -0.0001 0.t)04 0.006 .19 -0.003 0.013 .98 - 0.011 0.011 BMI 0.011 0.007 ; .13 -0.003 0.025 Drinks/day - 0.009 0.025 .72 - 0.058 0.040 Cigareties/dny -0.007 0.002 .001 -0.012 - 0.003 Location* - 0.079 0.072 .28 - 0.222 0.064 Entry Period** 0.330 0.053 .<.0001 0.225 0.434 Baseline Years Worked 0.0008 0.005 .89 -0.010 0.011 Triglycerides* 0.151 0.041 .0003 0.071 0.231 'natural log Antwerp vs Decatur **1994/95 vs 1997 'C o m p a n y age 57 of 63 Table 24. Mixeil Model Coefficient Intimates, Standard Errors (SE), P-Values and 95% Confidence Limits from 'festing Potential Determinants of ALT* Change Including TOP and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees . . 95% Confidence Limits Coefficient SE : p-value Lower Upper Intercept 2.476 0.273 <.0001 1.936 3.015 TOP Years Observation ' 0.020 -0.102 0.016 0.011 : .21 <.0001 i - 0.011 -0.123 0.051 - 0.082 TOP x Years Obs 0.002 0.003 .50 -0.004 0.008 Age - 0.0005 0.006 .93 -0.011 0.010 BMI 0.011 0.007 .11 -0.003 0.026 Drinks/day -0.013 0.025 .62 -0.062 0.037 Cigarettes/day -0.008 0.002 .001 - 0.012 -0.003 Location* - 0.073 0.073 .32 -0.217 0.072 Entry Period** 0.325 0.053 <.0001 0.220 0.430 Baseline Years Worked 0.0008 0.005 .88 -0.010 0.011 Triglycerides* 0.148 0.040 .0003 0.069 0.228 *natural log Antwerp vs Decatur *1994/95 vs 1997 Company rage 58 of 63 Table 25. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Total Bilirubin* Change Including PFOS and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept -0.334 0.241 .17 -0.811 0.142 PFOS -0.018 0.014 .22 -0.046 0.011 Years Observation 0.033 0.009 - .0005 0.0148 0.052 PFOS x Years Obs - 0.002 - 0.004 .94 -0.007 0.007 Age 0.011 0.005 .02 0.001 0.020 BMI -0.003 0.007 .67 - 0.016 0.010 Drinks/day 0.016 0.024 .50 - 0.030 0.062 Cigarettes/day -0.008 0.002 <.0001 . - 0.012 -0.004 Location* 0.315 0.064 <.0001 0.189 0.441 Entry Period** -0.114 0.047 .02 -0.206 - 0.022 Baseline Years Worked - 0.002 0.005 i .64 -0.011 0.007 Triglycerides* - 0.088 0.037 .02 -0.161 -0.015 *natural log *Antwerp vs Decatur **1994/95 vs 1997 H Company l'ugc 59 of 63 Table 26. Mixed Model Coefficient estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from 'lesting Potential Determinants of Total Bilirubin* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept -0.315 0.242 .19 - 0.793 0.162 PFOA ' - 0.030 0.019 .16 0.066 0.007 Years Observation 0.028 0.009 .003 0.001 0.046 PFOA x Years Obs Age 0.005 0.010 0.004 0.005 t ' .18 .04 -0.002 0.0007 0.013 0.020 BMI -0.003 0.007 .61 - 0.016 0.010 Drinks/day 0.014 0.023 .55 -0.032 0.060 Cigarettes/day - 0.008 0.002 <.0001 - 0.013 -0.004 Location* 0.318 0.064 <.0001 0.193 0.444 Entry Period** Baseline Years Worked -0.124 -0.002 0.046 0.005 .007 -0.215 - 0.034 .71 -0.011 0.007 Triglycerides* - 0.082 0.037 .03 -0.156 -0.008 "natural log Antwerp vs Decatur **1994/95 vs 1997 : Company i'ugc 60 of 63 Table 27. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 9S% Confidence Limits from Testing Potential Determinants of Total Bilirubin* Change Including TOP and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient S'li p-vulue Lower Upper Intercept -0.318 0.242 .19 -0.796 0.160 TOP ' - 0.020 0.014 .16 - 0.049 0.008 Years Observation 0.029 0.010 .005 0.009 0.049 TOF x Years Ohs Age 0.003 0.011 0.003 0.005 .36 - 0.003 0.009 .03 0.001 0.020 BMI - 0.003 0.007 .65 -0.016 0.010 Drinks/day 0.016 0.023 .51 -0.031 0.062 Cigaretlcs/day - 0.008 0.002 <.0001 -0.012 -0.004 Location* 0.316 0.064 <.0001 0.190 0.442 Entry Period** 0.120 0.0-16 .01 -0.210 - 0.029 Baseline Years Worked - 0.002 0.005 .68 - 0.011 0.007 Triglycerides* - 0.085 0.037 .02 -0.158 -0.012 natural log Antwerp vs Decatur **1994/95 vs 1997 i Company Page 61 of 63 'I'uble 28. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Direct Bilirubin* Change Including PFOS and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value . Lower Upper Intercept PFOS - 1.756 ' - 0.013 0.204 0.013 <.0001 .29 -2.160 -0.039 - 1.355 0.012 Years Observation - 0.097 0.009 <.0001 -0.116 - 0.079 PFOS x Years Obs -0.006 0.004 .18 - 0.014 0.003 Age 0.007 0.004 .06 - 0.0003 0.015 BM1 -0.003 0.006 .58 -0.015 0.008 Drinks/day 0.018 0.020 .37 - 0.022 0.058 Ciguretles/day -0.0005 0.002 : .79 -0.004 0.003 Location* 0.076 0.053 .15 -0.028 0.180 Entry Period** 0.353 0.038 . <.0001 0.277 0.428 Baseline Years Worked -0.001 0.004 .74 -0.009 0.006 Triglycerides* -0.090 0.033 .006 -0.155 - 0.026 *natural log Antwerp vs Decatur +*1994/95 vs 1997 Table 29. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Direct Bilirubin* Change Including PFOA and the Interaction with Number of Years of Observation of Antwerp and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept PFOA Years Observation -1.753 -0.012 ' - 0.095 0.207 0.017 0.009 . <.0001 .47 <.0001 -2.161 -0.045 -0.113 - 1.345 0.021 - 0.077 PFOA x Years Obs Age - 0.004 0.006 0.004 0.004 .27 -0.012 0.003 .11 -0.001 0.014 BMI - 0.003 0.006 .66 -0.014 0.009 Drinks/day 0.014 0.020 .50 -0.026 0.053 Cigareltes/day -0.0005 0.002 .80 -0.004 0.003 Locution* 0.083 0.053 .12 -0.022 0.188 Entry Period** 0.345 0.038 <.0001 0.271 0.420 Baseline Years Worked -0.0008 0.004 .83 -0.008 0.007 Triglycerides* - 0.089 0.033 .009 -0.155 - 0.023 *IMlural log Antwerp vs Decatur **1994/95 vs 1997 i A Company Page 63 of 63 Table 30. Mixed Model Coefficient Estimates, Standard Errors (SE), P-Values and 95% Confidence Limits from Testing Potential Determinants of Direct Bilirubin* Change Including TOP and the Interaction with Number of Years of Observation of Antweip and Decatur Male Employees 95% Confidence Limits Coefficient SE p-value Lower Upper Intercept -1.748 0.205 <.0001 -2.154 -1.343 TOF -0.013 0.013 .33 - 0.038 0.013 Years Observation - 0.093 0.010 <.0001 -0.113 - 0.073 TOF x Years Obs -0.004 0.003 .21 -0.011 0.002 Age 0.007 0.004 .08 -0.0008 0.014 BMI -0.003 0.006 .57 - 0.015 0.008 Drinks/day 0.017 0.020 .39 - 0.022 0.057 Cigarettes/day -0.0004 0.002 .84 ' -0.004 0.003 Location* 0.074 0.053 .16 -0.031 0.179 Entry Period** 0.349 0.038 <.0001 0.274 0.424 Baseline Years Worked -0.001 0.004 * .77 -0.008 0.006 Triglycerides* - 0.087 0.033 .009 -0.152 - 0.022 *natural log Antweip vs Decatur *1994/95 vs 1997