Document 6RDxR33kQ8LQMpk053MKzznaE

FINAL REPORT Epidemiology, 220-6W-08. Medical Department 3M Company St. Paul, MN 55144 Date: May 2, 2011 Title: Biomonitoring Assessment of the 3M Decatur Buildings2, 48, and 49 Demolition and Disposal Project Study Star Date: Protocol Number N/A IRB Approval N/A Principal Investigator: Co-investigators: Geary W. Olsen, D.V.M., PhD." BeDatvsiydDJ.. BEuhrcehsemra,n,DB0.S,.,MMPTH(.ASCP)* Study Director: Carol A. Ley, MD, MPH. 1. 2. Corporate Occupational Toxicology Laboratory, TMoexdiiccionleo,gyMeAdsisceaslsmDeenptar&tmCeontm,pl2i2a0n-c6eW-A0ss8u,rSatn.cePa,uMl,edMicNal55144 Department, Mail Stop 236-1B-22, St. Paul, MN 55144 SUMMARY 3M ComPpaagney2 `Several cross-sectional epidemiologic studies have reported positive associations between low serum concentration levels of perfluorooctanoate (PFOA) and perfluoroocianesulfonate (PFOS) with increasing non-HDL cholesterol. However, this association is highly inconsistent across different exposure levels found in general and occupational population studies and thereby not supportive oaf dose response. This inconsistent epidemiologic association is also not supported by a large body of toxicological data that indicates, in multiple specics, that PFOA and PFOS are PPAR agonists that result in hypocholesterolemia in rodents (both PFOA and PFOS) and nonhuman primates (PFOS only). The concentrations of PFOA and PFOS measured in these. toxicological studies are several orders of magnitude higher than observed in general human populations. Because most of the epidemiologic studies cited have been cross-sectional investigations, they can not fundamentally address the issue of causality due 10 their inability to assess temporal relationships. Therefore, the purpose of this study was to measure the PFOA and PFOS serum concentrations (ng/mL) at baseline and end-of-project time periods for workers involved with the demolition and disposalofBuildings 2/48/49 at 3M Decatur. The change in PFOA and PFOS concentrations over this time period were then related to the change observed in several serum clinical chemistries including non-HDL cholesterol. The a priori rescarch question was whether he cross-sectional positive associations reported at non-occupational serum levels of PFOA and PFOS with non-HDL can be observed in a longitudinal design of workers whose inital baseline serum concentrations mirrored those of the general population. In 2008-2010, 3M and non-3M employees (referred to as contingent) workers were involved with the demolition and disposal of Buildings 2, 48, and 49 at the company's Decatur 3M ComPapgaeny3 (Alabama) manufacturing plant. A total of 126 workers participated in both baseline and end of project assessments that involved measuring serum perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) concentrations, several lipid, renal, and hepatic clinical chemistries, and inquiring about brief medical history. An additional 48 workers participated only in a baseline assessment because they either did not ultimately work on this project or failed to participate in an end of project examination, OFthe 126 workers who participated in both assessments, 19 were 3M employees (15%) and 155 were contingent workers (85%). Based on their PFOA and PFOS trends, the 126 workers were categorized into4 groups: 1) workers (N = 57) who had their end of project PFOA and PFOS serum concentrations increase (or remain the same) over their baseline measurements; 2) workers (N = 43) who had their end of project PFOA and PFOS serum concentrations decrease over their baseline measurements; 3) workers (N = 16) who had their end of project serum concentrations of PFOA increase and PFOS decrease over their respective baseline. `measurements; and 4) workers (N = 10) who had their end of project PFOA decrease and PFOS increase over their respective baseline measurements. `The 57 workers, whose end of project PFOA and POS concentrations increased (or remained the same) had meanmatched-pair concentration increases of 10.3 ng/mL and 12.0 ng/mL, respectively, from their mean baseline concentrations of 23.7 ng/mL and 24.0 ng/mL, respectively (p < 0.0001). This average increase in PFOA and PFOS is comparable to the `magnitudeof change that has been associated with increasing total cholesterol and non-HDL, levels in cross-sectional studies of the U.S. general population as well as those reported in a `mid-Ohio River valley population whose drinking water was contaminated with PFOA. For these 57 subjects, there were no statistically significant mean changes for total cholesterol (-1.4 3M ComPpaagneys mg/dL,p = 0.70) or non-HDL (4.2 mg/dL, p = 0.22). There was a statistically significant increase in the mean HDL (2.8 mg/dL,p=0.006) and significant decreases in the mean total cholesterol HDL ratio (-0.3, p = 0.02) and triglycerides (-18.7 mg/dL, p = 0.05). However, since fasting was not a requirement, the triglyceride association can not be interpreted. `The 57 subjects were subsequently restricted to those individuals (N = 47) whose change in serum PFOA and PFOS concentrations was within the range (0 to 60 ng/mL) that has been associated with2linear increase in total cholesterol and non-HDL cholesterol levels as reported in the scientific literature for the general population. In addition, none of these 47 individuals Self-reported they were taking cholesterol lowering medications. These 47 individuals had mean baseline concentrations of 7.0 ng/mL and 16.7 ng/mL PFOA and PFOS, respectively. At end of project the 47 workers had a mean matched-pair increase of 10.7 ng/mL for PFOA and 11.6 ng/mL for PFOS, respectively. The mean matched-pair change in clinical chemistries, associated with these 10.7 ng/mL and 11.6 ng/mL increases in PFOA and PFOS, respectfully, included the following: total cholesterol (-0.2 mg/dL,p = 097); non-HDL (-3.5 mg/dL,p = 0.34); HDL (3.4 mg/dL, p= 0.004), and total cholesterolHDL ratio (- 0.4, p = 0.03). Using multiple regression to adjust for potential confounding factors (age, time interval, BMI, and alcohol), there were no statistically significant associations with their increasing PFOA and PFOS levels and the change in total cholesterol, non-HDL, HDL, total cholesterol/HDL ratio, or other clinical chemistries (.g., renal, hepatic) in these analyses. Among the 43 subjects whose PFOA and PFOS concentrations decreased from the baseline measurement, their mean matched-pair changeswere -115.3 ng/mL and -62.0 ng/mL, respectively. These much larger decreases in serum concentrations seen in these 43 workers, compared to the increases discussed above among the 57 (or 47) workers, is the consequence of 3M ComPpaagneys the much higher baseline concentrations that were measured in the 18 3M employees in this `groupof 43 workers. These 3M employees had past work history experience in the production of perfluorochemicals. For these 43 workers with decreasing PFOA and PFOS concentrations, their statistically nonsignificant mean matched-pair changes were: total cholesterol (0.8 mg/dL, p =0.82), non-HDL (0.3 mg/dL, p = 0.92), HDL (0.5 mg/dL,p = 0.72), and total cholesterolHDL (0.02, p=0.80). None of these variables was associated with decreasing PFOA and PFOS concentrations in regression analyses. There was a statistically significant negative association between PFOS and ALT. The biological plausibility of this inverse statistical association must be considered. "The present study's longitudinal assessment did not observe a 10 ng/mL increase in PFOA concentration resulted in an approximate 10 mg/dL increase in non-HDL cholesterol as was reported in an analysis of the Centers for Disease Control and Prevention (CDC) National Health and Nutrition Examination Survey (NHANES) database. This investigation had sufficient statistical power (76%) to detect thos magnitude of change. The lackofan association between PFOA and non-HDL cholesterol in the present study is supported by the recent report from a Phase III clinical trial. In this clinical trial, ammonium salt of PFOA was administered to 37 human patients diagnosed with refractory solid tumors. For some of these individuals, PFOA plasma concentrations increased to approximately 400,000 ng/mL. This PFOA plasma concentration is 3 times higher than any known recorded occupational exposure, let lone 4 `orders of magnitude higher than that reported in the general population. PFOA concentrations in this clinical trial were significantly associated with hypo-, not hyper-, cholesterolemia. This is consistent with the toxicology data. 3M ComPpagaeny6 Collectively, the above results suggest that the positive associations between PFOA and PFOS concentrations with non-HDL cholesterol, as reported from epidemiological crosssectional studies of non-occupationally exposed populations, ae likely non-causal. Whether these positive associations are the consequence of other factors thatjointly influence the absorption, distribution, metabolism, and/or elimination of PFOA and PFOS (or the entire class of perfluoroalkyls) with non-HDL cholesterol, will need to be the focusofother investigations. INTRODUCTION 3M ComPpuagen?y Beginning in 2008, several remediation projects were conducted regarding legacy perfluoroalkyls at the 3M Company. These projects involved either demolition and disposal of manufacturing facilites or remediation of landfills. Specifically, these projects have included the following: 1) the 3M Woodbury landfill remediation projects (main site and the northeast section): 2) the 3M Cottage Grove Building 25 re-roof project; 3) the 3M Cottage Grove D1, D2 and D9 excavation projects; 4) the 3M Cottage Grove Buildings 15 and 73 demolition and disposal project; and the Decatur Buildings 2/48/49 demolition and disposal project. Because of the unique work situations, the magnitude of potential occupational exposure at each of these locations was unknown. Therefore, baseline and end-of-project biomonitoring and medical assessments were required of 3M employees and non-3M employee workers (referred to as contingent workers) who entered specified work zones at eachofthese projects Where potential exposure to two important legacy perfluoroalkyls, perfluorooctanoste (PFOA) and perfluorooctanesulfonate (PFOS), was possible. "The purpose of this report is to provide an analysis of the PFOA and PFOS serum concentrations (ng/mL) measured at baseline and end-of-project time periods for those workers involved with the demolition and disposal of Buildings 2/48/49 at 3M Decatur. As part of this project, trend analyses of the changes in PFOA and POS serum concentrations between baseline and end of project were related to the changes observed in serum clinical chemistries, in particular, non-HDL cholesterol and hepatic enzymes. The magnitude of the changes observed was compared to those reported in the epidemiologic literature. As reviewed by Steenland et al. (2010), positive statistically significant associations have. been reported between PFOA concentrations and non-HDL cholesterol levels in the general 3M ComPpaagneys `population (Nelson et al. 2010), a community population affected with drinking water contaminated with PFOA (Emmet et al. 2006;Frisbeeetal. 2010; Steenland et al. 2009), and in some (Costa et al. 2009; Olsen et al. 2003; Sakr etal. 2007a; 2007b), but not all occupational investigations (Olsen et al. 1999; 2000; 2007). However, as summarized by Steenland et al. (2010) in their review of this literature, "the magnitude of the cholesterol effect is inconsistent across different exposure levels." The strongest positive associations occurred in general populations with the lowest PFOA concentrations. The weakest associations, if present at all, were reported in occupational populations whose serum PFOA (and PFOS) concentrations were 2103 orders of magnitude higher than the general population. And there is some inconsistency even among the general population studies as evidenced by the most recently published study of 723 adult Inuit living in northern Quebec. Chteau-Degat etal. (2010) that did not report any statistically significant association with non-HDL and serum PFOS concentration (geometric mean of 18.6 ng/mL (95% C1 17.8 ~ 19.5)). PFOS was positively associated with HDL and negatively associated with triglycerides and total cholesterolHDL ratio. Because mostofthe epidemiologic studies cited have been cross-sectional investigations, they can not fundamentally address the issue of causality due to their inability to assass temporal relationships. Furthermore, these epidemiologicresultsare contrary to what would be expected based on the toxicological literature. This inconsistent epidemiologic association is also not supported by a large body of toxicological data that indicates, in multiple species, that PFOA and PFOS are PPAR agonists that result in hypocholesterolemia in rodents (both PFOA and PFOS) and nonhuman primates (PEOS only). The concentrations of PFOA and PFOS measured in these toxicological studies are several orders of magnitude higher than those reported in the epidemiologic studies of general (non-occupational) populations discussed below. 3M ComPpaagneys Table 1 outlines the magnitude of the associations reported in the Centers for Disease Control and Prevention (CDC) National Health and Nutition Examination Survey (NHANES) `general population (Nelson et al. 2010) and in a mid-Ohio River community whose drinking water was contaminated with PFOA but not PFOS (Frisbee ct al. 2010; Steenland et al. 2009). In the CDC NHANES study (Nelson et al. 2010), a 4.8 ng/mL increase in the median PFOA concentrations between Quartile 1 and Qurtartle 4 was associated with an 11 mg/dL increase in non-HDL cholesterol (Table 1). Likewise a 27.6 ng/mL increac in median PFOS concentrations was associated with a 13 mg/dL increase in non-HDL. Shallower positive dose response curves were seen with children (Frisbee ct al. 2010) and adults (Steenland ct al. 2009) in the mid-Ohio River studies (Table 1). For example, in children an approximate 20 ng/mL increase in PFOA was associated with a mg/dL increase in LDL. These associations appear linear in the ranges described in Table 1. Associations above serum concentrations of 50 ng/mL PFOA or PFOS appear to be minimum. Steenland et al. (2010) hypothesized that the above positive associations could be the consequence ofa biological pathway with non-HDL cholesterol that may be saturated at relatively low (i.c., general population) PFOA and PFOS levels. Hence, an important research question is whether the cross-sectional associations reported by Nelson et al. (201), Frisbee etal. (2010) and Steenland et al. (2009) can be confirmed in a longitudinal design of workers whose inital baseline serum concentrations PFOA and/or PFOS was comparable 10 these studies. Potential occupational exposure to PFOA and PFOS among workers involved in the demolition and disposal of Decatur Buildings 2/48/49 offered the opportunity to examine this research question. 3M CoPamgpean1y0 METHODS 1. Demolition and disposal process `The demolition and disposal plan for Buildings 2/48/49 addressed several issues related to potential exposures to PFOS, PFOSrelated products, PFOA, and other perfluorocheicals that remained in Buildings 2/48/49. The plan considered potential exposure to workers engaged in the decommissioningofthe buildings involved in the removal ofprocess equipment and piping, the demolitionofthe buildings and their disposal, and the potential exposure to workers atthe recycling and waste disposal facilites where the remains of the facilities would be sent. Priotor the start of decommissioning work, an exclusion zone was established which included decontamination facilities for anyone going into the work zone. All workers entering this zone were required to participate in the blood monitoring program and also have 40 hours of Hazwoper training. "The initial demolition work involved the decommissioning of the process piping and wility services that supported the perfluorochemical-related production operations in these. buildings. All process piping going into and out of the buildings was drained of an free product prior to removal. Any piping that was going to be sentto a recycler was cleaned using a process that utilized high temperature and high pressure washing. All process piping not sent 10 a recycler was disposed at an industrial landfill. Following the severing of outside utilities and process lines, the process equipment inside the buildings was cleaned using the same process and sent toa recycler. All process equipment was destroyed through a smelting process. The same cleaning procedure was used on recycled metals prior to being sent o a smelter. The remainder 3M Company fe cemlion sis tt wes not met, was disposed faa instal anil. Diffen contractors were used throughout his process. 2. Informed consent Workers entering the exclusion zone were required to participate in this biomonitoring project. The purpose of the project was explained in a written informed consent. Subjects read and signed this informed consent at both baseline and end-of-project assessments. Subjects were informed by their employer that they could not work on this specific project without such compliance. 3. Blood collection "The majority of blood collection was performed at the Occupational Health Group Clinic (Decatur, AL). In some instances, blood collection occurred at the 3M nurse's office at the: Decatur manufacturing facility. Upon blood collection, serum was then obained and split into two samples. One sample was shipped to Quest Diagnostics for clinical chemistry analysis. The other sample was shipped to 3M Corporate Occupational Medicine where it was then transferred to the 3M Strategic Toxicology Laboratory for analysis of PFOA and PFOS. 4. Clinical chemistries Clinical chemistries included a lipid panel profile, blood glucose, BUN, creatinine, and liver enzyme tests. Fasting was notarequirement because of the logisticsofcollecting blood `samples during various times of the day when contingent workers would arrive tobe tested. Clinical chemistries were analyzed by Quest Diagnostics. The specific tests measured were: Total Cholesterol (mg/dL) Non-HDL Cholesterol (mg/dL) HDL Cholesterol (mg/dL) LDL Cholesterol (mg/dL. ~ indirect calculation) Triglycerides (mg/dL) Total CholesterolHDL Ratio (calculated) BUN mg/dL) Creatinine (mg/dL) "Total Protein (g/dL) AGllobbuumliinn ((g/dgL)~/caldculLate.d) Albumin/Globulin Ratio (calculated) Total Bilirubin (mg/dL) Alkaline Phosphatase (U/L) AST (UL) ALT (UL) 3M CoPmagpean1y2 The individual's clinical chemistries at baseline and at end of project were medically reviewed by Dr. Buehrer. Values out of reference range were indicated with a notation for the subjects to follow up with their primary care physician if they had abnormal test results. Subjects were informed in writing that this examination program was not a full medical `checkup." However, questions could be directed to Dr. Buehrer regarding their clinical chemistry test results. 5. Brief Medical History Questionnaire At both the baseline and end of project exams, subjects responded to the same health questionnaire that inquired about basic demographic data (age, height, and weight),a brief medical history, and current medication use (blood pressure, lipid lowering, and glucose Towering). 3M CoPmapgean1y3 6. Analysisof PFOA and PFOS `Serum samples were analyzed for POA and PFOS by state-of-the-art high performance liquid chromatography mass spectrometry methods by the 3M Medical Department's Toxicology Laboratory under the direction of Dave Ehresman. These samples were assigned unique identification numbers and randomized priotor the samples being delivered for analysis. The 3M Medical Department's Toxicology Laboratory was "blinded" to the identity of all samples received for analysis. `Sample extractions were performed using solid phase extraction (SPE) technique. The extraction and sample clean-up was based on a 100 uL sample size and utilized Waters (Milford, MA) Oasis hydrophilic-lipophilic balance (HLB) 3.0mL cartridges (Ehresman et al. 2007). The method used two stable labeled intemal standards for quantitation. The internal standards used were a dual labeled PFOS where two '*0 molecules were included in the sulfonate group (internal standard, >99% purity, synthesized by Research Triangle Institute, Research Triangle Park, NC) and a dual labeled PFOA molecule, where the carboxyl and alpha carbons were labeled with C stable isotope (greater than 97%, provided by DuPont, Wilmington, DE). All quantitations were based on matrix matched extracted standard curves. A'S ul injection of the sample eluate was introduced into the High Pressure Liquid Chromatograph (HPLC) which was directly interfaced into the triple quadrupole mass. spectrometer (Applied Biosystems/MDS-Sciex Instrument Corporation, Forest City, CA). Standard curves covered the range from 1.0 - 150 ng/mL. Standard curves were evaluated using a quadratic regression model where the standards were weighted at 1x, and each curve had an *R"" value equaltoor greater than 0.9998. Matrix spiked controls (QC samples) evaluated 3M CoPmapgean1y4 during this study all had acceptable results "with-in" their previously established ranges. Matrix`matched dilutions were used for samples requiring dilution to bring the samples into the linear range of the assay. Extracted serum and aqueous blanks remained below the lower limit of quantitation established at 1.0 ng/mL (lowest standard fitted on the standard curve used for this project). 7. Communication of Results After each blood collection (baseline and end of project), two separate letters were sent to the participant that provided their results. One letter addressed the worker's clinical chemistry results and the other letter provided PFOA and PFOS concentrations. 8. Data analysis Baseline and end of project data were entered into an ExcelTM spread sheet. Quality assurance checks were performed of the data entry process. Upon completion, the data were transferred to IMP-SAS (Cary, NC) for statistical analyses, Because the data were paired samples, a matched-paired statistical analysis was performed where the mean difference was the average of the sum of the individual differences for the N subjects. See Equation I. Equation I. en Die nobis bso Regression analyses were conducted for this study population's baseline and end of project cross-sectionally obtained data. Of much greater importance, however, were regression analyses of the change (ic., difference) in the clinical chemistries between end-of-project and 3M Company baseline compared to the workers' change in PFOA and/or PFOS serum concentrations. for each dependent variable (i.c., change in clinical chemistry), the full hierarchical regression model (Equation 2) considered 7 independent variables that included the change (difference) in PFOA or PROS serum concentrations (or both). The other independent variables were age at baseline, the number of days between baseline and endofproject tests, BMI at end of project, alcohol use: at end ofproject (2 4 drinks per week), and lipid lowering medication use (yes/no). Equation 2. AY = a+ PAPFOA + TX; Where A = difference between end-of-project minus baseline value YX;==tthheedeip=en1dtehnrtu c6licnoivcaarliactheesmidsetsrcyrivbaeridabalbeo:ve a= = intercept regression coefficient of APFOA or APFOS serum concentrations or both variables 1= regression coefficient for covariates Xi Backward regression procedures incorporated removal of any covariate atp > 0.10, except for PFOA or PFOS that remained (forced) in all models. Statistical significance of the regression coefficient () was considered at p < 0.05. 95% confidence intervals of the regression coefficient were calculated. RESULTS 1. Overall Biomonitoring Analysis As shown in Table 2, total of 174 individuals were tested at baseline for serum PFOA and PFOS concentrations and the aforementioned clinical chemistries. The majority (89.1%) were contingent workers. Of the 174 individuals tested at baseline, 126 (72.4%) had end of project assessments. The 48 workers who did not participate at end of project were all contingent workers. Reasons for non-partcipation at the end of project were: 1) tested at baseline but never 3M CoPmapgean1y6 entered the exclusion zone; 2) entered the exclusion zone and completed work assigament but id not return to the occupational medicine clinic for an end of project assessment despite the requirement to dos. The 48 contingent workers with only baseline measurements had lower serum PFOA (Table 3) and PFOS (Table 4) concentrations than the 126 workers with paired measurements. "The latter had significantly higher baseline serum PFOS and PFOA levels because a subset included 3M employees who had past perfluorochemical production experience at Decatur. These differences are scen in Tables 5 and 6 where the baseline geometric mean PFOA (Table 5) and PEOS (Table 6) concentrations for 3M employees were 228.4 ng/mL (95% C197-9 533.2) and 217.1 ng/mL (95% CI 112.2 - 420.2), respectively, compared to 10.0 ng/mL (95% C1 7.6 ~ 13.1) and 25.0 ng/mL, respectively, for the contingent workers. 2. Biomonitoring Employer Categorizations Among the contingent workers, 4 employer categorizations are presented in Tables 5 and 6. CST was the primary demolition contractor and used various subconiractors. All subcontractors were included in the CST definition in Tables 5 and 6. Other major employers of contingent workers were Goss Electric that dealt with the electrical decommissioning of these. buildings and Hubbard and Drake that decommissioned pipe lines as well as performed subcontractor demolition work. `The fourth `Other category listed in Tables 5 and 6 involved a variety of niche applications (c.g., laboratory measurements, environmental monitoring, etc.) The largest increase in serum PFOA concentrations occurred among the 47 CST workers who participated in the baseline and end of project assessments. As seen in Table 5, their `geometric mean PFOA concentrations went from 4.0 ng/mL (95% CI 2.8 - 5.6) at baseline to 3M CoPmapgean1y7 11.6 ng/mL (8.6 - 15.7) at end of project. Smaller increases were observed for Goss Electric and Hubbard & Drake workers for PFOA. For PFOS, CST workers' geometric mean concentration went from a geometric mean of 12.9 ng/mL at baseline to 22.3 ng/ml (95% C1 17.9. 27.8) at end of project (Table 6). Goss Electric workers had a comparable increase in ng/mL concentration of PFOS (approximately 10 ng/mi) although their baseline concentrations were 2 103 times higher than CST workers. Table 7 presents the arithmetic means of the matched-paired differences, 95% confidence intervals (95% CI), and p values from the Student's t tests for these employer categorizations. Statisticallysignificant increases in PFOA and PFOS concentrations were found among the CST workers, especially when compared to the statistically significant decreases in PFOA and PFOS concentrations measuredamongthe 3M employes involved in this project. 3. Biomonitoring Trend Categorizations Figures 1 and 2 are scatter plots of the 126 individuals that participated in baseline and end of project assessments. As shown in both figures,thediagonal identity line displayed represents wherethe x value (baseline) is equal to the y value (end of project). For both PFOA and PFOS, the majority of individuals with concentrations measured at baseline at < 60 ng/mL had higher concentrations measured at end of project. The majorit of workers with PFOA and FPOS measured > 60 ng/mLhad subsequently lower PFOA and PFOS concentrations at end of project. "The above two trends observed in Figures 1 and 2 led o the creation of 4 independent biomonitoring trend categories defined for the 126 workers who had both baseline and end of project assessments. These4 categories were (number of workers in parentheses): 1) both PFOA 3M CoPmapgean1y8 and PFOS concentrations increased (or remained the same) over baseline (N = 57); 2) both PFOA and PFOS concentrations decreased over baseline (N = 43); 3) PFOA concentrations increased and PFOS concentrations decreased over baseline (N = 16); and 4) PFOA concentrations decreased and POS concentrations increased over bascline (N = 10). Stratifying these categories by employer (Table 8) revealed that 78.7% (n= 37) of CST workers had an increase in both PFOA and PFOS concentrations. These 37 CST workers represented 64.9% of this trend category (37 of 57). On the other hand, 94.7% of the 3M employees had lower PFOA and PFOS concentrations at end ofproject that represented 41.8% of this trend category (18 of 43). No 3M employees had PFOA and PFOS concentrations higher at end of project than baseline. Other demographic characteristics of these 4 biomonitoring trend categories are found in Table 9. The 57 workers with an increase in PFOA and PFOS serum concentration from baseline were approximately 7 years younger than the 43 workers who experienced a decrease. This reflects the older 3M employees in the latter category. Very few females were accounted for in any of the 4 biomonitoring trend categorizations. The average BMI approached the level of obesity (BMI 30) levels in all 4 biomonitoring trend categorizations. Tables 10 and 11 provide measures of central tendency of PFOA and PFOS at baseline and end of project for these 4 biomonitoring trend categorizations. Table 12 provides the arithmetic means of the matched-pair differences between baseline and end of project for each of these 4 trend categorizations. For example, the 57 workers with higher concentrations of PFOA and PFOS at end of project had mean increases of 10.3 ng/mL and 12.0 ng/mL, respectively. 3M Company 4. Analysis of the 126 Workers with Baseline and End of Project Measurements rr Demographicsofthe 126 workers that participated in baseline and end of project assessments are provided in Table 13. The average interval of time between assessments was 207 days (range 1 - 477). Table 14 provides the percentage of responses to the medical history questionnaire. Based on self-reporied medication use, high blood pressure and high cholesterol were the highest prevalence. Presented in Appendix A (Tables Al ~ AS) are cross-sectional analyses conducted at baseline and at end of project assessments for these 126 workers. Because the distributions of PFOA and PFOS were log normal, both untransformed and log transformations were performed of these variables in the models. Few statistically significant associations (p < 0.05) were observed in these cross sectional analyses. None were observed for PFOA and/or PFOS with either total cholesterol, non-HDL, or HDL. A positive association was seen with creatinine measured at baseline and at end of project with both PFOA and PFOS. A positive association was also observed for PFOS with AST and ALT at end of project but not baseline. No statistically significant associations were observed with PFOA and AST or ALT for either assessment, As seen in Table 15, the 126 workers had a mean matched-pair decline of 34.6 ng/mL. PFOA and 15.5 ng/mL PFO. The reason for tis decline is autributableto the 19 3M workers. "The unadjusted and adjusted regression analyses between the change in PFOA and PFOS concentrations between baseline and end of project and the respective change in clinical chemistry measurements for the 126 workers are presented in Table 16 for PFOA, Table 17 for PFOS, and Table 18 for including PFOA and PFOS in the model(s). Both unadjusted and adjusted regression coefficients of PFOA and PFOS are provided along with the 95%Cls and p 3M CoPmapgean2y0 values. The change in PFOAor PFOS was normally distributed; thus log transformations were considered not necessary. Few statistically significant associations were observed. None were related to total cholesterol, non-HDL or HDL. There was a statistically significant negative association between ALT and PFOS in the unadjusted model but this was not observed when covariates were considered in the adjusted model. 5. Analysisof57 Workers with Increased PFOA and PFOS Concentrations The PFOA and PFOS geometric means were 10.3 ng/mL and 12.0 ng/mL, respectively, for the 57 subjects whose concentrations increased (or remained the same) between baseline and end ofproject. These increases were statistically significant (p < 0.0001, Table 19). Among these 57 workers, the average increase in PFOA and PFOS was comparable to the magnitude reported to be associated with increased total cholesterol and non-HDL concentrations in the CDC NHANES study (NHANES, Nelson et al. 2010) as outlined in Table 1. The unadjusted `and adjusted regression analyses between the change in PFOA and PFOS concentrations between baseline and end of project and the respective change in clinical chemistry measurements for the 57 workers are presented in Table 21 for PFOA, Table 22 for PFOS, and Table 23 for PFOA and PFOS in the model(s). Both unadjusted and adjusted regression coefficients of PFOA and PFOS are provided along with the 95% Cls and p values. There were no regression coefficients that were statistically significant (p < 0.05) for the mean differences in clinical chemistries and PFOA (Table 20). There was 1statisticallysignificant association (total cholestero/HDL ratio) for PROS (Table 21). Statistical significance was observed for total cholesterol when both PFOA and PFOS were included in the regression model but the coefficient slope was negative for PFOA and positive for PFOS (Table 22) aM CoPmagpean2y1 The 57 subjects were then restricted to the subset of 47 workers whose magnitude of increase was within the range of change associated with increasing cholesterol trends reported in the literature reported in Table 1. None of these 47 individuals self-reported they were taking cholesterol lowering medications either at baseline or at end of project. These 47 individuals had a mean increase of 10.7 ng/mL PFOA and 11.6 mg/dL PFOS. Their mean change in total cholesterol was -0.2 mg/dL (p = 0.97) and for non-HDL cholesterol it was -3.5 mg/dL (p = 0.34). The mean change in HDL (3.4 mg/dL) was significantly (p =0.004) increased over baseline whereas the total cholesterol/HDL ratio was significantly decreased (p = 0.03). Presented in Tables 24 through 28 are the regression analyses for these 47 individuals. `Also, Figures 3 through 12 are scatter plots that show the unadjusted regression trend line results for several of the clinical chemistries examined in Tables 24 and 25. There were no satistically significant associations regarding the change in total cholesterol, non-HDL, HDL, total cholestero/HDL, or liver enzymes in these analyses for PFOA (Tables 24) or PFOS (Table 26). Tables 25 and 27 provide the adjusted PFOA and PFOS regression coefficients, respectively, when the only covariates included in the models were at p < 0.10. These models provide the beter fit of the data. There were no statistically significant coefficients for PFOA or PFOS. In particular, for the change in non-HDL cholesterol, the PFOA coefficient was 0.30620 (p= 0.26) and for PFOS 0.24561 (p = 0.41). No significant coefficients were observed when both PFOA and PFOS were included in the model (Table 28) or when the only covariates included in the model were at p < 0.10 (Table 29). The coefficients when PFOA and PFOS were both in the non-HDL model were -0.39539 (p = 0.20) and 0.36238 (p = 0.28). 6. Analysisof43 Workers with Decreased PFOA and PFOS Concentrations 3M CoPmagpean2y2 Among the 43 subjects whose PFOA and PFOS concentrations decreased, the mean matched-pair decrease in PFOA and PEOS concentrations were -115.3 ng/mL and -62.0 ng/mL, respectively (Table 30). These much larger decline in serum concentrations over baseline reflect the considerably higher baseline concentrations of the 3M employees (18 of 43) included in ths biomonitoring trend category. Of these 43 subjects, their mean matched-paired lipid-related differences were not significantly different (Table 30): total cholesterol 0.8 mg/dL; non-HDL 0.3 mg/dL; and HDL 0.5 mg/dL. There were statistically significant mean decrease with alkaline phosphatase (-5.1 IU/L); and increases in AST (1.8 IU/L) and ALT (3.3 TUL), as well as decreases in total protein and globulin. Unadjusted and adjusted regression coefficients for PFOA and PFOS are presented in Tables 31 and 32, respectively, for these 43 subjects. Neither total cholesterol nor non-HDL was associated with decreasing PFOA and PFOS concentrations, nor when both are included in the regression model (Table 33). The only statistically significant coefficient (negative) was observed with PFOS in the ALT model (Tables 32 and 33) The 43 subjects with decreased PFOA and PFOS concentrations were restricted 0 29 individuals whose decrease was within the approximately 60 ng/mL range (but opposite in direction) reported in the literature (Table 34). These 29 workers had a mean change of -42.5 ng/ml PFOA and -29.6 ng/mL POS. These were not associated with significant lipid changes, including non-HDL (1.6 mg/dL, p = 0.60). Although the regression models are based on few subjects, there were no statistically significant regression coefficients for PFOA or PFOS with total cholesterol, non-HDL, HDL, or any other clinical chemistry (Tables 35 and 36). When PFOA and PFOS were both included in the model, the unadjusted coefficient for PFOS was negative (p = 0.07) whereas it was positive for PFOA (p = 0.12) (Table 37) 3M CoPmapgean2y3 7. Other Analyses Because of the small sample size, regression analyses were not done for the 16 subjects whose PFOA concentrations increased and PFOS concentrations decreased nor for the 10 workers whose PFOA concentrations decreased and PFOS concentrations increased. DISCUSSION "The collectionofbaseline and endof project samples for analysis of serum concentrations of PFOA and PFOS provided an excellent method to assess each worker's exposure experience while involved with the 3M Decatur Building 2/48/49 Demolition and Disposal Project. Specific exposure tasks were not identified for each worker; thus tis not possible to ascertain which tasks yielded the highest potential for exposure. OF the 126 workers who participated in both baseline and end of project assessments, a Subset of 57 non-3M (contingent) workers, had their PFOA and PFOS concentrations increase an average of 10.3 ng/mL (range 0-- 61.1 ng/mL) and 12.0 ng/mL, (range 0 -- S1.5 ng/mL), respectively. This range corresponds to that reported in three cross-sectional studies that associated increasing PFOA and PFOS levels across this range with a linear increase in nonHDL cholesterol (Nelson ct al. 2010; Frisbee et al. 2010; Steenland ct al. 2009). Analyses of these 57 workers, and a subsetof47 that had baseline serum concentrations less than 61 ng/mL. and who did not take cholesterol lowering medications, resulted in no statistically significant associations between the change in PFOAor PFOS and the difference in total cholesterol or nonHDL. 3M CoPmapgean2y4 Among the 47 workers, the mean average change in serum PFOA concentrations was 10.7 ng/mL and for PFOS 11.6 ng/mL. Based on the data presented in Table 1 from the cross- sectional study of Nelson et al. (2010) representing the NHANES population, we might have therefore expected an approximate 10 mg/dL increase in non-HDL for the 10.7 ng/mL increase. in PFOA serum concentration and approximately a mg/dL increase in non-HDL associated with the 11.6 mg/dL increase in PFOS serum concentration. The average non-HDL in these 47 workers decreased 3.5 ng/mL (95% C1 (-10.8) ~ 3.8). Thus, the longitudinal data presented in this report are inconsistent with the cross-sectional associations reported by Nelson etal. The increased trends reported by Steenland (2009) (see Table 1) for non-HDL cholesterol are not as strong as those reported by Nelson et al. (2010). Nevertheless, we still might have expected increases in both total cholesterol and non-HDL cholesterolofat least a few mg/dL that would have been associated with the respective increases in PFOA and PFOS serum concentrations observed in this study. Although our data are not consistent with the trends associated with PFOA in the cross- Sectional studies by Nelson et al. (2010), Frisbee et al. 2010), and Steenland et al. (2009), the precision around our point estimates leads to less firm conclusions for PFOS. We estimate our sample size of 57 individuals would have had 84 percentpowerto detect a 10 mg/dL change in non-HDL but only a 32 percent power to detect a S mg/dL change in non-HDL based ona 1sample t-test. Reducing the sample size to the 47 subjects, the power calculations were 76 percent and 27 percent, respectively. This agrees with our conclusion that the data do not support the hypothesis that PFOA concentrations increase non-HDL cholesterol at the dose: response suggested by Nelson ta (2010). Because of the statistical power of our study, as well 3M CoPmapgean2y5 as the actual study date, we can not rule out a more subtle trend, as suggested by Steenland (2009) et al. for PFOS concentrations, but offer no evidence in support of their trend for PFOA. Increased PFOA exposure, determined by matched-pair biomonitoring analyses, has also been observed at one other 3M remediation site that involved contingent workers during Phase I of the Building 15 Demolition and Disposal project (Olsenet al. 2009). The baseline mean PFOA concentration was 22.6 ng/mL for 45 contingent workers which is approximately 4 times the general population average (Nelson et al. 2010). Serum PFOA concentrations increased an average of 133 ng/mL over a 3+ month time period for these 45 contingent workers involved with the Building 15 project. Their mean PFOA increase was not associated with any statistically significant increase in the workers" mean total cholesterol (-2.5 mg/dL,p = 0.56), non-HDL cholesterol (4.1 mg/dL, p = 0.36), or HDL (2.0 mg/dL, p= 0.34). The present study also did not indicate perturbations in renal function or hepatic clinical chemistries associated with the magnitudes of increased PFOA or PFOS concentrations. Therefore, the present study's longitudinal assessment does not support the findings by Lin et al. (2009) who conducted a cross-sectional analysis of NHANES data and reported a 1.86 unit increase in ALT witha 1 unit increase in log PFOA concentration. This did not occur in the present study. In fact, severalofthe statistical associations were in the negative direction. Nor have there been clinically relevant increases in hepatic clinical chemistries observed in a series of cross-sectionalor longitudinal occupational studiesofammonium perfluorooctanoate production workers (Costa et al. 2009; Olsen et al. 1999; 2000; 2003; 2007; Sakr et al. 20074; 2007b; Steenland et al. 2010). Ina longitudinal assessment of 454 DuPont workers whose medical records were abstracted for many years, Sakr etal. reported a 1,000 ng/mL increase in serum PFOA concentration was statistically significantly associated with a 0.008 mg/dL decline in total 3M CoPmapgean2y6 bilirubin (95% C1-0.014 to 0.002), 2 0.35 U/L increase in AST (95% C1 -10 10 +0.60), and a non-significant 0.54 U/L increase in ALT (95% CI-0.46 to +1.54). These statistical associations do not have clinical relevance at occupational levels of PFOA, let alone extrapolated to the much lower concentrations of PFOA reported in the general population. Besides the limitation of the study sample size, the present study also could not obtain fasting blood samples. This inability to request fasting blood samples was a logistical necessity because the contingent workers workforce had to participate in blood collection throughout the `normal work day. The lack of fasting would bias the serum triglyceride and glucose measurements and could also affect the LDL cholesterol results due to its indirect calculation by the Friedewald formula. Consequently, these specific clinical chemistries can be difficult to interpret in this study. On the other hand, total cholesterol, non-HDL cholesterol, HDL cholesterol, renal function, and the liver enzymes would not be biased by the lack of fasting. Another possible limitation could be the result that the average assessment period of approximately 200 days between baseline and end-of-project may have been too short of fllowup time to observe an altered clinical chemistry profile due to organ pathology. However, increasing serum PFOA concenirations did not result in higher blood lipid values in male cynomolgus monkeys dosed daily for 6 months that resulted in steady serum concentrations ranging between 81,000 ng/mL and 156,000 ng/mL depending upon administered dose (range 3 1020 mg/kg/day via oral capsule) (Butenhoff etal. 2002; 2004). Administered PFOS did result in hypocholesterolemia when serum concentrations approached 100,000 ng/mL. (Seacat et al. 2002). Most recently, a Phase III human clinical trial conducted in Europe, administered the ammonium salt of PFOA to 37 patients (21 males and 16 females) with advanced refractory solid 3M CoFmupgean2y? tumors (16colorectal; 4 pancreatic; 17 "other")]. There were 9 different doses of ammonium PFOA ranging between 50 to 1200 milligrams that were administered once weekly (oral capsule) in group sizesofat least 3 patientsperdose. Median duration of treatment was weeks (range 2-40 weeks). The highest plasma PFOA concentrations reached approximately 1000 micromolar (= 413,000 ng/mL). Toxicites related to the treatment included fatigue, nausea, vomiting, and diarrhea. One of six patients treated at the 600 mg weekly dose level 1 individual experienced grade 5 renal failure and grade 4 elevated transaminases that the study investigators "attributed to progressive disease but contribution of study medication could not be excluded." There was strong association between increasing serum PFOA concentrations and hypocholesterolemia. This should notbe unexpected due to the known PPARa agonist activity of PFOA. Thus, the findings from this Phase II tral donot support the assertion that PFOA would be causally associated with increasing cholesterol levels in the general population. (CONCLUSION Based on two longitudinal assessments of workers involved in the demolition and disposal of legacy production facilities at 3M Cottage Grove (Building 15) and 3M Decatur (Buildings 2/48/49), workers' increased PFOA concentrations have not been associated with non-HDL cholesterol. Although the study samples were relatively small, these investigations had the statisticalpowerto detect the magnitude of change suggested by the Nelson etal. (2010) cross-sectional NHANES data. There was no evidence that a 10 ng/mL increase in PFOA serum concentration resulted in an approximate $ to 10 mg/dL increase in non-HDL cholesterol. This lack of a positive association between PFOA and non-HDL cholesterol in humans is strengthened considerably by data from a Phase II clinical trial of refractory solid tumor patients 3M CoPmagpean2y8 who were administered the ammonium salt of PFOA. Plasma PFOA concentrations that ranged upwards to 400,000 ng/mL resulted in hypocholesterolemia which is not unexpected given the fact that PFOA has been shown to be a PPAR agonist in toxicological studies The present study's data do not suggest a 10 ng/dL increase in PFOS would result ina 10 `mg/dL increase in non-HDL cholesterol (as suggested by the Nelson et al. 2010 data). However, the study's statistical power cannotrule ouatn association ofa lesser magnitude. PFOS is also a PPAR agonist that resulted in hypocholesterolemia in toxicological studies involving rodents and non-human primates. This finding is observed at PFOS serum concentrations several orders of magnitude higher than reported by Steenland et al. (2009) or Frisbee etal. (2010). : Overall, these data argue against a causal association between PFOA and PFOS with non- HDL cholesterol It does suggest that the statistical positive associations reported in the cross- sectional studies might be the consequence ofa third factor that causes their correlation (Steenland et al. 2010). Additional research should focus on the binding, absorption, `metabolism, and/or elimination characteristics of the class of long chain perfluoroalkyls and how this may be correlated with non-HDL cholesterol. ACKNOWLEDGEMENTS "The authors acknowledge the contributions of Kara Andres, Diane Madsen, and Cathy Simpson. 3M CoPmapgaen2y9 REFERENCES ButenhofJf, Costa G, Elcombe C, Farrar D, Hansen K, Iwai H, Jung R, Kennedy G, Lieder P, Olsen G, Thomford P. 2002. Toxicity of ammonium perfluorooctanoate (APFO) in male cynomolgus monkeys after oral dosing for six months. Toxicol Sci 69:244-257. Butenhoff JL, Kennedy GL, Hinderliter PM, Lieder PH, Jung R, Hansen KJ, Gorman GS, Noker PE, Thomford PJ. 2004. Pharmacokinetics of perfluorooctanoate in cynomolgus monkeys. Toxicol Sci 2:394-406. Chiteau-Degat ML, Pereg D, Dallaire R, Ayotte P, Dry S, Dewailly E. 2010. Effects of perfluorooctanesulfonate exposure on plasma lipid levels in the Inuit population of Nunaik (Northern Quebec). Environ Res 110:710-717. Costa G, Sartori S, Consonni D. 2009. Thirty years of medical surveillance in perfluorooctancic acid production workers. J Occup Environ Med 51:364-372. Ehresman DJ, Froehlich JW, Olsen GW, Chang SC, ButenhofJLf. 2007. Comparison of human whole blood, plasma, and serum matrices for the determination of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and other fluorochemicals. Environ Res 103:176-184. 3M CoPmagpean3y0 Emmett EA, Shofer FS, Zhang H, Freeman D, Desai C, Shaw LM. 2006. Community exposure: to perfluorooctanoate: relationships between serum levels and certain health parameters. J Occup Environ Med 48:771-779. Frisbee SJ, Brooks AP, Maher A, Flensborg P, Amold S, Fletcher T, Steenland K, Shankar A, Knox $8, Pollard C, Halverson JA, Viera VM, Jin C, Leyden KM, Ducatman A. 2009. The C8 Health Project: Design, methods, and participants. Environ Health Perspect 117:1873-1882. Frisbee SJ, Shankar A, Knox SS, Steenland K, Fletcher T, Savitz DA. 2010. The C8 Health Project: associations between perfluorooetanoic acid and perfluorooctanesulfonic acid and serum lipids in children. Arch Pediatr Adolesc Med (in press). Lin CY, Lin LY, Chiang CK, Wang WJ, Su YN, Hung KY, Chen PC. 2009. Investigation of the associations between low-dose serum perfluorinated chemicals and liver enzymes in U.S. adults. AmJ Gastroenterol doi:10.1038/2g.2009.707. Nelson JW, Hatch EE, Webster TF. 2010. Exposure to polyfluoroalkyl chemicals and cholesterol, body weight, and insulin resistance in the general U.S. population. Environ Health Perspect 118:197-202. Olsen GW, Burris JM, Mandel JH, Zobel LR. 1999. Serum perfluorooctane sulfonate and hepatic and lipid clinical chemistry tests in luorochemical production employees. J Occup Environ med 41:799-806. 3M CoPmapgean3y1 Olsen GW, Burris JM, Burlew MM, Mande JH. 2000. Plasma cholecystokinin and hepatic enzymes, cholesterol, and lipoproteins in ammonium perfluorooctanoate production workers. Drug Chem Toxicol 23:603-620. Olsen GW, Burris JM, Burlew MM, Mandel JH. 2003. Epidemiologic assessment of worker serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations and medical surveillance examinations. J Occup Environ Med 45:260-270. Olsen GW, Zobel LR. 2007. Assessment of lipid, hepatic, and thyroid parameters with serum perfluorooctanoate (PFOA) concentrations in fluorochemical production workers. Int Arch Occup Environ Health 81:231-246. Olsen GW, Gibson BA, EHresman DJ, Madsen DC. 2009. Biomonitoring Assessment of the 3M Cottage Grove Building 15 Demolition and Disposal Project: Phase I. 3M Final Report. St. Paul, MN. `Sake CJ, Kreckmann KH, Green JW, Gillies PJ, Reynolds JL, Leonard RC. 2007a. Crosssectional study of lipids and liver enzymes related to a serum biomarker of exposure (ammonium `perfluorooctanoate or APFO) as part of a general health survey in a cohort of occupationally exposed workers. J Occup Environ Med 48:1088-1096. 3M CoPmapgean3y2 Sake CJ, Leonard RC, Kreckmann KH, Slade MD, Cullen MR. 2007b. Longitudinal study of Serum lipids and liver enzymes in workers with occupational exposure to ammonium perfluorooctanoate. J Occup Environ Med 49:1086-1096. Steenland K, Tinker S, Frisbee S, Ducatman A, Vacearino A. 2009a. Association of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) with serum lipids among. adults living neara chemical plant. AmJ Epidemiol 170:1268-1278. Steenland K, Tinker S, Frisbee S, Ducatman A, Vaccarino V. 2009b. Association of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) with uric acid among adults with elevated community exposure to PFOA. Environ Health Perspect 11:229-233. Steenland K, Fletcher T, Savitz DA. 2010. Epidemiologic evidence on the health effects of perfluorooctanoic acid (PFOA). Environ Health Perspect 118:1100-1108. i3 : 2 aps rr 3 Poi rk : caxg S93 3 1117 pid $29 ll i i3 : 2 H1 H 3 3 i: 2 2 a8 3 22 59% g3q 32e #5e5s 4 3%$c3 :9 F ef 39 39 == = : 171 i if sBEzE osz s gos 3 of aE af a [1i: Lo. 3. 3x 22 | 35 s foe20s2 0 Ere 2Buu Table 2. Distribution of Workers by Company and Participation for the Buildings 2/48/49 Demolition and Disposal Project Company. Non-3M Baseline 15 csGoTss Electric 6 25 Hubbard & Drake Other 36 31 TaoMul 1 74 E1n0d7o8f4P9ro)ject (%) 70587 14(56.0) 26(122) 20(645) g12e6 asn "PPeerrcceenntt ooff winodrikveirdsuaolfse(anc=h c1o2n6t)rawchtoorpwarhtoicpiaprattiecdipinatbeadseilnibnaesealnidneenadndofenprdojoefctp.rojec. ` zi E E : din. 2g 83 EE &3 533 4 ai8as PEoE g 3IE =iz 23 oe ? 2s 2 oe 8 RE oaan 4nd a8 a a2iE8a 4g 8ig 4J 8a 8 os a3 oc ig 3 2 4 os if 3 == i 3 sz 5A 3I2- os g ss 4: $2 3 gJe 3 Pi E2 LAE Lg E i$58E.5Ri32dad lc8 ald FE 28 FF 383 5idiz iid = ER oz 3 i #3 Z ef RF 8% LL 2z i i 3 if 3< 3 i2s5 iF oasat iJ 3cEgaE 2 g PI is 2 : = 2g IE 2 = 2 ca ge 88 ry 8 pof 2z 3g &3se ~EeH i 38 gz gi iS2 Et f gmzog. SE oF Yo5& 23 2-2 Ja gs 3 E32E C29RE [HgIEE EpdRenEEsI aif EEE 5% i z 8 S&F i188 82 pg Ii fTF igf 8oo8 3i83 4 22 8&2 zm oer .: .. 77 88 82 sz 33 88 =e = 39 m2 os 53 =z ad 21 En 07 gE EE 28 8% 3 3H {24 2828 J] 82 31d 3F 3 EH : 4 53 gE 2 an on an we gos BEE % oo Ln an =z ed 28 3s Ge ad a9 nn. gz 22 48 fg = as as az 2% gq fo 8: er sx wo :ia : IRg L ERR 9.2 gf 14,2 ER 4 BY Jeg 3s ER ERE EE ze ik z $8 zz oz% 8% 8 @ qd de 14 5 23 &8 =2 sa a8 z8a8 gRoY pogo 22 3ee 30on I F gnEE i E 5 %8 gf d&g 8&5 as r3 $2 2ER5 w33e w3n _ 8% aRee o=R 3 ffo: Saeg es% ss s8s 25s d= 5 E8 o3x p $58n Rsfg uEoR a3 28 22 oc oz ET 2 $85 a= =d e3s% 8 ws son i i g% 28 2 3% 33 & g =: ce sp 88 se 3 5: di x18.989%" z i- pt it i d y i3 20 .3B B3a5r3 Eg8d3i3 2323i%: aHild RELA 2 2% GST Table 7. Arithmetic Mean of Matched Paired Differences and 95% Confidence Interval for PFOA and PFOS by Employer Emplover aM PFOA (ng/mL) Mean Difference __95%CI__ pale 2339 (399.8-) (681) 0008 Mean PEOS(ng/ml) Difference 95% CI 01 (172-49) p value 0002 ENmopnl-o3yMee 08 (30)-46 067 13 (27-53 052 oT 104) 60-148 <0.0001 90 5-129 <00001 EGloescstric +100 @n-70 02 12 (27-152 085 &HuDbrbaakred 36 (104-32 028 47 (147-54 035 or 84 CI58-CLO 0 90 L189)-48 007 g 3 32 3sM BELL 2e8 a 2 3g 7 8 = - | 23 _ Fort 2 ~ -8 i &2. - . - == g g ag a8 4q2 5 Bz 5 ~ o 1 :L 3 3 8 8 2 g 25, 5 8 2 2 d % k os fs 2 3E = = = ce oe 2 z :Z Di.:es5.fir0z Bidfle 35s ig E28J ZLi3B3E5 ZBiiBzE2 BF1iid%e = g gg Ade Pzl iEGiEEi 3183:D4 & z go TT 4 2 og sfi EEE $i all 3 oa si3 : FE sd 393 8R/E8 3 1g 32 3% 83 8%2 i 3Po lwo, Pads oa 5 !! 3 3% 23 : Pha i $i 33% E03 % i z 1 2 gii : FT Bx ag FX RY=Z3 52 2% sy go ZJe oi5 ds 37 53 82 3 gFa FI 4 E = 3 3g i q$e3 33 2] 23 =% ce es a 38 2g3g 2=38 " -e 2 38 iia dg 28 ig zz a8 {2 23 o c8o3 8Fg8 4: EI z 33 [RE s:ooeEss.hi $2 33d3 2S51988 J R # CE " ag == sz og (25F3 OuFfBoe.ofse)J B33: Er83z2 2i%iBH sg3s &=28 2i se =o 2 43 33 &y JIT2i 0aRf3 Ei3:2 8E3l%z iBx z g gg us 8 258 ogaz 2#%2 a2n3 8L&E3 3%e 338 eaad g #21 2 Z2 dg 2% 2 32 5E 2 T 88 2on8 i eay8 o 8a3s 8 $22 " z 8% a5 :g gs. :9 zgF E s 4FC2E 543P9IF iE 3 2H 25239 JE e#g383 s3a a#s8 aons Z23a% das2 we om ds 2d ea 2= 223 3g sz ofLgeP.3aiY sft EEIPpTER jLiFBiPEIEBRRE 7% =3 4 asl 84 % oi=q % #o8w 4E3 i o$d9 7 & 3m3d 5 $#99 BI aw gg 3 oo E2 a3 sdf afBi3 EEiR R2 Table 11. MeasuresofCentral Tendency of the Matched Pair Difference of PFOA and PFOS Concentrations (ng/mL) by Trend Categorization CTarteengdorization Minimum. 0 Median. @ 90% Maximum Subjects (N=57) Increase in PFOA 00 23 55 110 32 61.1 PFOS 00 9 77 208 22 sis DSuebcjreecatsse(iNn=43) PFOA PROS. 04 02 a770 115899 10573.00 "31782004 143657000 ISnucbrjeeacstes (inNP=F1O6)A 0.0 Decrease inPFOS 0.1 1000 2200 3585 80 49 80 70 Subjects (N = 10) Decrease nPFOA ~~ -03 Increase nPFOS 0.0 0055 1210 21 3 12784 12837 STtaubdleent1'2s.teArsitthfmoertPicFOMAeaanndofPMFaOtSchbeydtPheirFoDuirffTerreenncdesC,at9e5go%riCzoantfiiondsence Intervals, and p values from Trend AMreiathnmetic Caegorization Difference gsm puilue SIunbcjreecatssei(nN=57) PPFFOOAS 110230 6878--113583 <<00..00000011 SDuebcjreecatsse(iNn=43) PPFFOOSA s203 G(1L9292-)-((23843) 00.000041 ISnucbrjeecatsse(iNnP=F1O6A) 87 Decrease in PROS 24 G1B1-a4-3(14 00.0000021 SDuebcjreecatsse(nN=PF10O)A 3.1 Increase nPFOS 63 203-11-1129 00.0163 aM CoPmapgeandy6 1 2588_ 1 i 2S2 i gs 3 15: 8 gz 1: 4 3 z a oo z 28= i BEE i= 29 5 us i : | i 2353 Table 14. Number of Responses to Self-reported Medical History and Alcohol Usage at Baseline and End of Project (N = 126) Medical History High blood pressure Hepatitis Cirthosis Other liver disease Gall bladder disease Diabetes Medications High blood pressure High cholesterol Diabetes Alcohol Usage <1 drink/wk 1-3drinks/wk 4-7drinks/wk 8-14 drinks/wk > 14 drinks/wk 1. Percent Yes NBaoselineMissing 20 106 0 sous 3 0 24 0 33 sous 3 3 03 EndofProject Yes No Missing 2 104 0 4 mo ois 1 Toe 313 0 3m vo 0 16109 1 2 m3 19107 0 "oom 3 120 3 75 (60)" 73(58) 1703) 2.08) 238) an 86) 1200) 33 40 g 2[Jefsgzzrzscsessass PRlSas8.. a g faze 3388g Eg AIT igiiiiiiigiililcs T E ofdi2 sa aas 8 fsiifzz=ez8igi3 iiisg g& da g 2 :3 $788"s2g930-2235"383:3=25:s85%83%8dzzs3 zi ffgarsanveancgasee y_aaaaosiis g sls sacar elsenzida 2 I l8fs52_o8 28,9888 HE EEEEEREEEEEEEEEEE 33 Cas . cr .sara 228 3gyz2gf8diiie z: 8igEgzasT dg9 ze3s81o0c0n1 ge4i0u0a : J sos gs 2858459383288 i lr 88 230. 78". z Ss a= g= a8 i a 25 3g2 8 284 332 828g3 2g 42 id8 8&83 %=8e74R i fds35:28:282388% iz 3 8 b2i3%c Td PTE2 5Bi E 3, tl5 gsiiig:.2 2E8i3ei5E3g3iT ieEfia3r8azg:i3i:2i8i:i3i5s3 Fi i 1 ao: f:3358252:533s8:8538833838%%38 i :BEA2R2 SEs8Rs8sE38Ri2Ri5 RtiR8iR8 sRg8R8i88 E s I feEiiEiizotiei ! 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See text for definitions. >Su6b1jencgt/smLe.xcluded those taking cholesterol lowering medications and with PFOA concentrations. 1: 3 2: i3sz 2< 2 :3 33[I8 sd 3fc:: LiE I... si 0G BLE8 2g ]5z 32222222 3H:I3 i 33338888 3 23gcisE3g9B8E S 5AEgIs5 L 8E g32 E a2S y3 3 = i: 3 8i: 2 tenzssss 314 2% SEFIEEEER i: $E3l EES :535 59 go:z iEs1o. LEE2 R ERI EREREIE5EH 510 2352 d48 dd S8 g2 aP dEe c2 di x g|z2 2s Sa1Z Fi iFy:Fs4 2 5: 5 S29%8 83% 33%S 2S3S Es 8% = BEE H i 4 EF EE g .. sif e B 58 o2322 gL E L doHF Ei 2 8g ir EI 53 39 9 ee i pq i 2ii% 2 2i% EHLIi. 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Adjusted' PFOA and PFOS Coefficients in Model for All (N = 47) Subjects with CBoaesfefliicnieentasn.d End of Project Measurements" which Included Only Covariates with p < 0.10 Change in Varishle 95% Confidence Interval Coefficient Lower per pyalie Adjusted for in Model T CholHDL PFOA -000437 002930 002057 073 PFOS 002376 0.0038 005138 009 LoL PFOA -03284s -087770 022081 023 PFOS 032280 028463 093041 029 days between tests, BMI days between tests, BMI Triglycerides PFOA -044969 210371 120434 059 age PFOS 153864 030541 338270 0.10 Glucose PFOA 008418 -0.13169 030005 0.44 PFOS -006526 0.30514 017461 059 age, BMI Creatinine PFOA 000156 000058 000370 O15 PFOS 0.00051 000288 00086 0.67 days between tests Globulin PFOA 000176 -0.00366 000718 0s2 PFOS 00009 0.00501 000698 074 days between tests, BMI Alk Phos PFOA -016213 040447 00802 018 BMI PROS 0.18323 008437 045084 017 ALT PFOA 025199 061574 011175 017 Age PFOS 03516 008378 073069 0.1 *nitaly adjusted for age, days between tests, BML, alcohol, and lipid lowering medications. See text for definitions. 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Scatter plot of Matched PFOA Concentrations (ng/mL) at Baseline and End of Project (N = 126), Decatur Buildings 2/48/49 Demolition and Disposal Project og - 3<tw cum of Cdn. < 3L 0 ,: w frwo -- ps Too 3M CoPmagpean9y8 (FiNg=ur1e262).,ScDaetctaetruprloBtuiolfdiMnagtsch2/e4d8/P4F9ODSemCoolnicteinotrnaatnidonDsi(spnogs/amlL)PraotjeBcatseline and End of Project 1000 5 10 &g &2 8 0 1 1 10 100 1000 PFOS Baseline FPeirgfulrueor3.ochEenmdicoaflPCroonjeccetntvsr.atBiaosnel(inneg/Dimf=Lferppebn)c.e in Total Cholesterol (mg/dL) vs. 3MCPoamgpea9n9y PFOA s 5 B= 2 IE TET hrho spkOrkr he PFOS : 3 * o L3ESbonnie 7] Th7h 50Sta8 k rca hw ecooompy Figur4e. Endof Project vs. Baseline DifferenicenNon-HDL (mg/dL) vs. Perfluorochemical Concentration (ng/mL = ppb). PFOA 1:w- i o- 1 . TE5aErET: EE PFOS " : ye Co " hs 0 rar Mf TM 4 NH 0 3M CPoamgpea1n0y1 Figure 5. End of Project vs. Baseline Difference in HDL (mg/dL) vs. Perfluorochemical Concentration (ng/mL = ppb) PFOA = 5IR .FEEL TT wPe FO onk Orene ben PFOS = = 3Zsu gE * I CV oSTdTT s wk he Ew Prossores Morrrary Figure 6. End of Project vs. Baseline Difference in Total Cholestero/HDL Ratio vs. Perfluorochemical Concentration (ng/mL = ppb). PFOA HjiiE: 2g.: Teh EE hh hw bw PFOS BI . 3s 2g. : qa. roomonee 3M CPoamgpea1n0y3 Figure 7. Endof Project vs. Baseline Difference in LDL (mg/dL) vs. Perfluorochemical `Concentration (ng/mL = ppb). PFOA =: Ly . EE i} pe Ps a ER PFonOOE rnAs ] PFOS = = 6 . 5 afodLC 3 al FET o I : #92 TE heerro oomwesnk s Bow 3M CPoamgpea1n0y4 CFoingcuernetr8.atiEonnd(onfgP/rmoLje=ctpvpsb.).Baseline Difference in BUN (mg/dL) vs. Perfluorochemical PFOA i2. a ETRrEnphOneesse PFOS 3 Sho . & oT = BE hh hh how 7705 on tree 3M CPoamgepa1n0y5 CFoingcuernetr9.atEionnd(onfgP/rmoLje=ctppvsb.).Baseline Difference in Creatinine (mg/dL) vs. Perfluorochemical PFOA ors 5 onso ass EhT PhrphpoDrasrncT ehew PFOA or 3 2] ws] Co : h a g EI] IE eres oOrses Figure 10. End of Project vs. Baseline Difference in Alkaline Phosphatase vs. Perfluorochemical Concentration (ng/m=L ppb). i:: EET PFOA i1 Te hh bb Boe PFOS H EoLR E] ETT hk we B comSpoaen)y CFigouren11.cEnod(ognfPmiroj=eopctpnvbs..Baseline Difference in AST (IU/L) vs. Perfluorochemical PFOA 7. BQ olpur l . . TEToEnoERE PFOS 7 BYoe] -no "7 2 o3s4o % ee 7 Comapean0yh Figure 12. 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