Document 0Lbjov5xjEYDj0LpXn8jVd55V
AR &86- 1351
Page 1
EpidFemIiNoAloLgyR,E2P2O0-R3TW-05 Medical Department 3M Company
St. Paul, MN 55144
Date: June 9, 2003 AssessmentofLipid, Hepatic and Thyroid Function in Relation to an Occupational Biologic Limit Value for Perfluorooctanoate
Principal Investigator:
Co-investigators:
Study Director:
Geary W. Olsen, D.V.M., Ph.D.!
John L. Butenhoff, PhD.?
Jeffrey H. Mandel, M.D.!
Jeffrey H. Mandel, M.D."
1. Corporate Occupational Medicine, 3M Medical Department, St. Paul, MN 55144
2. Corporate MN 55144
Toxicology
and
Regulatory
Services,
3M
Medical
Department,
St.
Paul,
000016
Page2 ABSTRACT
Perfluorooctanoic acid [CF5(CF2)sCOOH] has been used primarialsy a surfaceactive agent in the production of various fluoropolymers, including tetrafluoroethylene. Perfluorooctanoic acid is soluble and readily dissociates to the carboxylate anion, `perfluorooctanoate (PFOA) which has been used in industry primarily as the ammonium salt. In 2000 the 3M Company (3M) established a biological limit value (BLV) of ng/ml (parts per million, ppm) for PFOA. in the serum of ts production workforce. The BLV was considered to represent the best estimate ofa level ofa chemical substance or its metabolite(s) in a biological fluid that ifpresent, even on achronic basis, wouldnot be expectedto pose,orcorrelate with, a significant riskofadverse health effects to the worker(s). 3M Cottage Grove (Minnesota) fluorochemical production employees have voluntarily participated in periodic medical surveillance examinations. Surveillance activities include aselfadministered questionnaire, hematology, standard clinical chemistry tests and serum PFOA determination. In 2000, 131 male and 17 female employees participated in the fluorochemical medical surveillance program (approximately 70 percent participation). Among the men, serum PFOA concentrations were log normally distributed and ranged from 0.007 to 92.03 ppm with a geometric mean of0.85 ppm (95% CI 0.64 - 1.22). The 17 female employees' serum PFOA concentrations ranged from 0.04to4.73 ppm with a geometric meanof0.42 ppm (95% 10.23- 0.79). There were no statistically significa(npt < .05) differences in lipid, `hepatic and thyroid hormonetestresultsamongmale or female employees. There were no statistically significant differences in the percentageoftest results that were above or below the reference rangesofthe clinical chemistryand thyroid parameters. Higher
000017
Page3 serum PFOAconcentrationswereassociatedwiththespecificareawhereAPFOwas produced. Employees' serum PFOA concentrations were not correlated (r = -.02) with thenumbeorf years that they have worked in the Chemical Division at this manufacturing site. These observations firmly support the need to incorporate specific PFOA exposure matrices in epidemiologic assessmentsofthis workforce in order to `minimizethe probability of exposure misclassification. A limitationofthis study was its inability to assess temporal relationships dueto its cross-sectional design.
000018
Page4 INTRODUCTION
Perfluorooctanoic acid [CF5(CF2)COOH] has been used primarily as a surfaceactive agent in the productionofvarious fluoropolymers, including tetrafluoroethylene. Perfluorooctanoic acid is soluble and readily dissociates to the carboxylate anion, `perfluorooctanoate (PFOA), which has been used inindustry primarily as the ammonium salt (APFO). Production may occur by electrochemical fluorination or telomerization. Interest has focused on PFOA and a sulfonate analog, perfluorooctanesulfonate (PFOS), becauseoftheir presence in humans (Hansen et al. 2001; Olsen ef al. 2002; 20020; 2000c) and the environment (Kannan 2002; Hansen et al. 2002), although the properties and toxicologyofthese two compounds are different.
`The potential health hazards of PFOA from experimental studies have been extensively reviewed (USS. E.P.A., 2002; 2003; Buteahofeftal. 2002a). Briefly, PFOA isreadilyabsorbedafter oral dosing and is not metabolized (Vanden Heuvel et al. 1991). `The high rateofabsorption of PFOA from inhalation exposure is comparabletooral exposure with dermal absorption less likely (Kennedy ef al. 1985; 1987; Kennedy ef al. 1986). There are marked species differences in serum eliminationandbetween sexes in some species. Female ras have the highest rateofelimination with half-livesofhours compared to days in the male rats (Johnson and Ober 1980; Hanhijrvi ef al. 1982; Vanden Heuvaletal. 1991). This differencemaybe due to altered expressionoforganic `aniontransporterproteins (Kudo ef al. 2002). Humans appteo haavre a much longer serum elimination half-lifeof several years although the specifics of this assessment are: being determined in acurrent assessment (Burrisefal. 2002). PFOA activates the peroxisome-proliferator-activated receptor alpha (PPAR-c) (Ikeda 1985) although the
000019
Pages
`responsesthat occurinmice andratsmayhaveminimumrelevancetoprimatesand `humans (Cattley ef al. 1998). PFOA did not cause adverse effects in mating or fertility in
`the rat, ormalformations in the developing fetus (York 2002). Delays in sexual
`maturation (both sexes) and an increase in post-weaning mortality (first several days)
`were observed in the first generation offspring in the highest dose group (30 mg/kg/day).
Post-natal developmental effects were not observed in rabbits. Results from sub-chronic
repeated oral dose studies of PFOA in mice, rats and monkeys indicate the liver is the
`primary target organoftoxicity (Griffith and Long 1980; Kennedy 1987; Butenhofeft al.
2002b). Liver weight increase in cynomolgus monkeys wasnotobserved in monkeys for
`which dosingwassuspended or in thosethatwere allowedtorecoverfor 90 days
(Butenhofef al. 2002b). Altered lipid metabolism occurred in rats (Haughom and
`Spydevold 1992). Through nongenotoxic mechanisms, an increase in benign adenomas
of thetestes (Leydig cell), pancreas (acinar cell) and liver in rats was observed at a dietary doseof 300 parts per million (ppm) APFO which approximates 6 mg/kg/day (Biegeletal. 2001). An increase in Leydig cell tumors was observed inanotherlifetime
`bioassay in rats at 300ppm but tumors of the liver andpancreaswerenot observed at 30
or 300 ppm APFO, nor an increaseinLeydig cell tumors at 30 ppm (Riker 1983). In 2000 the 3M Company (3M) established abiological limit value(BLV)of
Sug/m (ppm)for PFOA in the serumofits workforce engagedinthe production of
/APFO via electrochemical fluorination (Roy ef al. 2002). The BLV was considered to repretsheebnestt estimate ofa level ofa chemical substance or its metabolite(s) in a
`biological fluid thatifpresent, even on a chronic basis, would notbeexpectteod pose, or
correlate with, a significant adverse health effect to the worker(s). This BLV was based,
000020
Page inpartontheuseofa 10-foldsafetyfactorappliedtothemeanserumPFOA concentrations associated with liver-to-body weight ratios in the sub-chronic APFO feeding studyofcynomolgus monkeys (Butenheofaflf.2002b). These weight changes were not accompanied by any gossorhistopathological observations or changes in clinical chemistries.
Serum PFOA concentrations greater thanthe BLVdo not necessarily imply a health risk (Roy et al. 2000). Ifemployees' serum PFOA concentrations cither meet or exceedtheBLY,correcatcitivonesmayneedtobeappliedon acase-byba-sicsaatsthee direction ofmedical professionals. This could include temporary removal from the immediate work area. Implementationofthe BLY in 2000 at 3M resulted in the work practice evaluations by industrial hygienists for those employees whose serum PFOA concentrations ranged between 5 and 10 ppm. Employees with serum PFOA concentrations at 10 ppm and higher were restricted from potential workplace exposure to APFO until theirserumconcentrations declined to lessthan10ppm.
The BLV concept is similar to the "Biologische ArbeitstoftoleranzwerteToleranz-Wert" (BAT) (Commission 2002). The BAT is defined as the maximum `permissible quantity ofa chemical compound, ts metabolite, or any deviation from `nomofbiological parameters induced by these substances in exposed humans. The BAT value is established on the basis of currently available scientific data which indicate that the chemical concentration does not generally affect the heaolftthhe employee adversely, even when attained regularly under workplace conditions. BAT values are established for blood and/or urine and take into consideration the effectsofthe substance:
000021
Page? and an appropriate marginofsafety based on occupational, medial and toxicological criteria for the preventionofadverse health effects.
`The purposeofthisstudywas two-fold: 1) examine whether the BLV level of `ppm for PFOA was associated with changes in hepatic, lianpdthiyrodid function obained from employee medical surveillance examinations that were conducted at the 3M Cottage Grove (Minnesota) manufacturing facility in 2000; and 2) assess whether these employees' serum PFOA concentrations were associated with specific fluorochemicalproduction areas andthe numobfyeearrsthey hadworkinethde Chemical Division.
METHODS DescriptionofFacility
APFO was produced by a five-stage process: electrochemical fluorination; isolating and converting the chemical to a salt shury; converting the slurry to a salt cake; dryingthe cake; and packaging. The greatest likelihood for exposure occurred in the drying area. Allofthese APFO-related production activities occurred primarily in one building. Other fluorochemical productionoccurredat this site, including perfluorooctanesulfonyl-fluoride (POSF, CyF17SOSF) related materials that were: `manufactured in adifferent building than APFO. Also,lowerchain perfluorinated `materials have been manufactured at this site. Fluorochemical production has historically beenreferredto as the `Chemical Division at this manufacturing facility(Gillilandand Mandel 1993) although this categorization also includesnonfluorochemical production plants. Aquality control laboratory is also partofthis manufacturing environmert. The
000022
Pages remainderof theCottageGrovemanufacturing sitebelongstoseveraloperationsthat have been referred to as the `non-Chemical Division' (Gilliland and Mandel 1993).
Fluorochemical Medical Surveillance Program 3M Cottage Grove fluorochemical production employees have voluntarily
participated in periodic medical surveillance examinations(Gillilandand Mandel 1996; Olsenetal. 1998; 2000). Surveillance activities include a self-administered questionnaire, measurement of height, weight and pulmonary function, hematology, standard clinical chemistry tests and serum PFOA determination along with an assessment of serum perfluorooctanesulfonate (PFOS, CsF17805). Periodically, non routine tests are offteortheesde fluorochemical production employees. These tests have focused on specific toxicological questions and have included assaysofreproductive hormones (Olsenet al. 19an9dp8las)ma cholecystokinin (Olsen et a. 2000). In order to assess whethertherewas evidence of thyroid toxicity in these workers, assaysforseveral thyroid hormones were included in the 2000 fluorochemical medical surveillance program. Abriefwork history questionnaire was also provided to the participants. Questions involved specific past and present work locations. These questionnaire data were evaluated in context with the measured serum PFOA and PFOS concentrations.
AnalysisofSamples Upon collection and shipmentofspecimens, Allina Laboratory Services (St.
Paul, Minnesota) performed standard hematological and clinical chemistry tests for both `manufacturing sites. These included the following hematological tests: hematocrit
000023
Pages
(percent), hemoglobin (gm/dl), red blood cells (RBC, 1000/mm), whiteblood cells
(WBC, 1000/m)andplatelet count (1000/mm); and the following clinical chemistry tests: alkaline phosphatase (IU/L), gamma glutamy] transferase (GGT, TUL), aspartate aminotransferase (AST, IU/L), alanine aminotransferase (ALT, IU/L), totalanddirect bilirubin (mg/d), cholesterol (mg/dl), highdensity cholesterol (HDL, mg/dl), triglycerides (mg/dl), blood glucose (mg/l), blood urea nitrogen (BUN, mg/dl) and serum creatinine (mg/dl). Sixthyroidtests were conducted byLabCorp(Kansas City, MOY): thyroid stimulating hormone (TSH; wIU/mi); serum thyroxine (T4; pg/dL); free thyroxine (free T4; ng/dL); serum triiodothyronine (T3; pg/mL); thyroid hormone binding ratio (THBR, previouslyreferredto as T3 Uptake) and free thyroxine index (FTI). TSH, free T4andT3 were determined by an immunochemiluminometric assay. T4 and THBR were determinbeyd a cloned enzyme donor immunoassay. FTI was calculated by multiplying T4 and THBR.
`The employees' serum samples were extracted and quantitatively analyzed for PFOA `and PFOS using high-pressure liquid chromatography electrospray tandem mass spectrometry (Hansen etal. 2001). Serum fluorochemical analyses were determined by `Tandem Labs (SaltLake City, UT). For all employee participants, serum PFOA concentrations were above the lower limit of quantitation (LLOQ). There were nine employees whose serum PFOS concentrations were below the LLOQ [ 4.8 ng/mi =4.8 parts per billion (ppb).
000024
Page 10 `Data Analysis
Stratified analyses (c.g., gender), analysisofvariance and multivariable regression techniques were used to evaluate associations between PFOA and the biochemical parameters. PFOAserumconcentrations were categorized in relation totheBLV: 0 - < 1 ppm; 1- 4.9 ppm; an>d S ppm. Besides evaluationofmeasuresofcentral tendency of the various parameters, percentagesofassay values outside their reference ranges were consideredinrelation to PFOA. Potential confounders included age, body mass index, current cigarette smoking status (yes/no) and numberofalcoholic beverages consumed ona daily basis. Analysesofthe PFOS concentrations (independentofthe BLV for PFOA)inrelation to the clinical chemistries were alsoperformedbut are not reported due 0 the lackofassociations. The midpoint value between zero and the LLOQ was used for those individuals whose serum PFOS concentrations were <LLOQ.
RESULTS Atotal of 131 male and 17 female employees participated in the fluorochemical
medical surveillance exams (approximately 70 percentofthose eligible). Among the `men,serum PFOA concentrations were log normally distributed and ranged from 0.007 1092.03ppm(Figure 1). Consequently the median value (0.97 ppm) was comparabtloe thegeometricmean (0.85 ppm, 95% C1 0.64 - 1.22) and not to the arithmetic mean (4.51 ppm, 95% C1242. - 6.61). Twenty (15 percent)ofthe male employees had serum concentrations greater than the BLV.
Serum PFOS concentrations (Figure 2) had a narrower range (0.02 - 4.79 ppm) than PFOA. The PFOS geometric mean was 0.44 ppm (95% C1 0.35- 0.55) and similar to its
000028
Page 11 `median value (0.45 ppm). The arithmetic mean for PFOS was 0.85 ppm (95% C1 0.691.02). There was no association between serum PFOA and PFOS concentrations [Pearson correlation coefficient (t) = .02].
`There was a lackofcorrelation between years worked in the Chemical Division and serum PFOA concentrations measured in 2000 among the 131 male employees(r = -.02, Figure 3). Serum PFOA concentrations, however, were associated with the major `production work areas (Table 1). Those employees who had worked onlyinthe PFOA `production area had a statistically significant (p < .05) higher mean serum PFOA concentration (18.41 ppm) than the other fluorochemical production areas. These workers alsohadthe highest median serum PFOA concentration (5.20 ppm). Likewise, the employees who had worked only in the PFOS-relatedproduction area had a statistically significant greater mean serum PFOS concentration (1.76 ppm) as wellasthe highest median serum PFOS concentration (1.67 ppm) compared to the other fluorochemical production areas. Employees who had worked in the QC lab, but never indicated on their questionnairethatthey had not worked in the PFOAor PFOS-related production areas, had the second highest median serum PFOA concentration (2.62 ppm).
Serumemployee PFOA concentrations were stratified (sce Table 2) into three `groups among the male employees: group 1 (< 1 ppm PFOA, N= 68 employees); group. 2(1-4.9ppm PFOA, N = 43 employees);andgroup 3: (2 5 ppm PFOA, N=20 employes). Group 3 corresponds to those serum values that exceeded the 3M BLY establishedin 2000forPFOA. The median serum PFOA concentrations increased nearly 50foldbetween the lowest (0.30 ppm) and highest (13.57 ppm) groups (Table 2). Medianserum PFOS concentrations were comparableforthe three groups.
000026
Page 12 There were no statistically significant (p < .05) differencesinthe arithmetic mean lipid and hepatic test results between the three PFOA groupsamongmale employees (Table 3) orwiththe thyroid hormone assays (Table 4). Furthermore, there were no statistically significant differences in the mean percentageoftest results that were above. or below the reference rangesofthese various clinical chemainsdtthyrroiyd parameters. Nineemployees (group 1 =4,group 2= 3andgroup 3 =2)indicatedon their questionnaire that they were prescribed cholesterokreducing pharmaceuticals. Because PFOA was associated with hypolipidemia in rats (not primates), inclusionofthese `employees may have masked a negative association. Exclusionofthese nine employees didnotalterthelipidfindings,asshowninthescatterplotsinFigures 4and5. Insimple linear regression models, neither the slopeofthe cholesterol (CHOL = 210+ 0.13 PFOA) or triglyceride (TRIG = 181 + 1.30" PFOA) models were statistically significant (p= 63 anpd = 19, respectively). Figures 6 and 7arescatter plots between ALT and GGT with serum PFOA concentrations, respectively, among all 131 male employees. `The slopeofthe linear models was not statistically significant (AL=T 35 - 0.05 `PFOA, P=.71;GGT =33- 0.11" PFOA, p= 64). Taking log transformationsofthe dependent variables in these three models produced similar statistically nonsignificant results. Figures 8 through 11 are scatter plotsofthe thyroid hormones by serum PFOA concentrations. Using simple linear regression analyses, the slopes for PFOAinthese four models were not statistically significant (p < 05) althoughthenegative slope in the T4 model (Figure 10)approachedsignificance (T4 = 7.93 - 0.02 PFOAp, = .07) but there was minimal variation explained (7 = 03) in the model. Furthermore, all ofthe lowest T4 values, associated with the highest serum PFOA concentrations displayed in
000037
Page13 Figure 10, remainedwell-within the reference range (4.5- 12.0 ug/dL)ofthe T4 assay. `There were no statistically significantlinear associations for TSH (Figure 8: TSH = 2.36
+0003 PFOA, p= 78, * < 01)T,3 (Fig9u:Tr3=e 1+20.308 PFOA, p= 71F,<
01) or free T4 (Figure 11: T4 = 1.11 - 0.0005 *PFOAp, = 64, = 01) in relation to
serum PFOA concentrations. Again, taking log transformations ofthe dependent Variables in these. models produced similar statistically nonsignificant results.
Adjusting for potential confounding factors (age, BMI, cigarette smoker, alcohol drinks) did not result in statistically significant linear associations (p < .05) between PFOA and the lipid, hepatic or thyroid hormone assays (data not shown). Hematology and renal clinical chemistry tests were also not associated with PFOA (data not shown). In addition, PFOS and a calculated total organic fluorine value (determined as the percent `molecular weight of PFOA and PFOS attributed to organic fluorine) were not associated with the lipid, hepatic and thyroid parameters measured in this study (data not shown).
Besides theselfreported prescribed pharmaceuticals, the employees provided information from alist ofmedical conditions which focused on thyroid conditions and. type Il diabetes. There were two self-reported conditionsof hypothyroidism: 1 caseeach in group 1 and group 3. Likewise, there were two self-reported conditionsoftype II diabetes: 1 case each in group 1andgroup 3. Noneoftheseself:reportedconditionswas confirmed via a medical record review.
`The 17femaleemployees' serum PFOA concentrations ranged from 0.04to 4.73 `ppm witah geometric mean concentration of 0.42ppm (95% 1.0.23 - 0.79). The arithmetic mean serum PFOA concentration was 0.85 ppm (95% C1 0.23 - 1.47). No female employee had a serum PFOA concentration that exceeded the BLY.Theirserum
000028
Page 14 'PFOSconcentrranagetdfiroom0n.0s2to2.1ppm with ageommeaenctoncrentiratcion 0.28ppm (95% CI 0.15 - 0.52) and an arithmetic mean serum concentratio0n.o5f3 ppm (95% C1 0.20 - 0.87). There were no statistically significant associations between PFOA and clinical chemistriesorthyroid test resuls for the 17 female workers(datanot shown). Noneofthe female employees reported thyroid conditions or type IT diabetes, or prescribed cholesterol lowering pharmaceuticals.
DISCUSSION There were no statistically significant differences in lipid, hepatic or thyroid
functions in this workforce in relation to the BLV for PFOA. Although the triglyceride concentrations trended higher with serum PFOA concentrations, the response was not statistically significant. A similarpositive association between PFOA and triglycerides `was reported with analyses of medical surveillance dataof 3M's Antwerp (Belgium) and Decatur (Alabama) workforce (Olsen et al. 2003a). PPAR, a nuclearreceptorexpressed `mainlyin adipose tissue, has been shown to be activated by the antidiabetic thiazolidinendinones, which upregulates glycerol kinase activity stimulating increased hepatic enzymes (Guan et al. 2002). Whether this modeofaction is plausible for PFOA in humans is questionable as mouse and human PPAR; were unresponsive to PFOA `when tested atarange of 0.5 t0.40 kM in a cell transfection assay(Maloneyand Waxman 1999).
Therewere no biochemicalindicationsof hepaticinjuryinthepresentstudyatthe serum PFOA concentrations measured. These tests included ALT (a hepatic cytosol enzyme usedas ameasureofincreased cell membrane permeability), GGT (a hepatic
000029
Page 15 `microsomal enzyme indicativeofenzyme induction)andalkaline phosphatase and bilirubin (measuresofcholestasis). These findings support the decision to establish a BLVat 5ppmserum PFOAthatwasbased on a 10-foldmarginof saifn eelattionyto liver-to-body weight changes observed in a sub-chronic APFO primate study where such declines in weight occurred at dosages that were lower than those causing histologic or biochemical indicationsof hepatic injury (Butenhofef al. 20025).
Several thyroid hormones were assayed in these workers with no indication of `hypothyroidism or hyperthyroidism associated with increased serum PFOA concentrations. A weakly negative, marginally nonstatistically significant association `wasobservedbetween T4and serum PFOA. This statistical observation was not considered to represent a biological finding for several reasons. Most importantly,the T4 values associated withthehighest serum PFOA concentrations were well within the reference rangeofthe T4 assay. The statistical association explained minimal variation OfT4 (less than 3 percent). There wasnocorresponding negative association between free T4 and PFOA. There was also no indication ofa compensatory increase in serum TSH. T3 was unaffected as well.
Toxicologically, Butenhoeftf al. (2002) reported no clear changes in thyroid hormonehomeostasisinrelationtoPFOAin asixmonthoraldosingofAPFOinmale cynomolgus monkeys. Steady:state mean serum concentrations ranged between 77 + 39 pmt0158 100ppmforthethreedosegroupsusedinthestudy. Allthyroidhormone values werewithinnormalrangeandtheredidnotappear tobeanyrelevanthistological changes or changes in TSH. Thyroxin values at endoftreatment were statistically significantly (p< .05) lower in the three dose groups compared to the time-related
000030
Page 16 control group butnottoeach dose group's pretreatment values, Three high-dose animals, thatwere removed from dosing due to evidenceoftoxicity, had T3 values that trended `downward compatortheeidr pretreatment values. There was evidenceofa retum to pretreatment T3 values upon dose cessation. Butenheotfal. concluded that these.
changeswerebestexplainedbynormalvariationorstressandnot asadirecteffect of APFOonthyroid hormone homeostasis.
Becauseofthe cross-sectional design, a limitationofthe present study i its inabitolaisstesys temporal relationships. A 6-year longitudinal assessment was conducted of 174 3M employees at its Antwerp and Decatur fluorochemical `manufacturing sites (Olsen et al. 2003a). These employeeshad lowermean PFOA and higher PFOS serum concentrations than the present study population. Adjusting for potential confounding factors, PFOA anda calculated total organic fluorine (determined from the percent molecular weightof PFOA and FOS attributed to organic fluorine) `werereported to be positively associated with cholesterol and triglycerides in a longitudinal analysis. This association was attributed to a subsetof 21 Antwerp workers `whoseserum PFOAconcentirncaretasiedofrnosm 1.3 to2.1 ppminthis 6yeartime period. Again, this association is opposite the hypolipidemnic effects ofPFOA observed in rats. Liver function tests were not associated with PFOA in this longitudinal assessmert.
Higherserum PFOA concentrations were associated with workiinnthge APFO production area. Employees' serum PFOA concentrationswerenot correlated with their years worked in the Chemical Division. These two observations firmly support the necessity to incorporate specific APFO exposure matrices in epidemiologic assessments
000031
|
Page 17 ofthis workforce inorderto minimize the probabilityofexposure misclassification for PFOA. Therefore, the soleuseofthe exposure metric, months employed in the Chemical Division, ian 50-year follow-up assessmentofthe mortality experienceof employees who have worked at this manufacturing site (Gilliland and Mandel 1993) likely introduced considerably more PFOA exposure misclassification than the methods employed by Alexander (2001) who constructed a specific job-, department- and caleyenardexaporsu-re matrixforpotential PFOA exposure in an updated mortality analysis of this workforce. As with any epidemiologic assessment, however, some unknown degreeofexposure misclassification in the Alexander study likely occurred as well
Becauseofthe more specific APFO exposure matrix, the Alexander (2001) findings should be considered the definitive study, to date, regarding the mortality experienceofthis manufacturing workforce in relation to PFOA exposures. Alexander did not observeanexcess riskofmortality from cancer (68 deaths, 77.3 expected, Standardized Mortality Ratio = 0.0, 95% C1 0.7 - 1.1)or ofany specifictypeofcanceirn relation to employees categorized with a minimumofone year employment in a job with definite or probable exposure to PFOA. Alexander did report a modest and unexpected association with cerebrovascular disease among workers identified with definite exposure to PFOA (5 deaths, 2 3 expected, Standardized Mortality Ratio = 2.6, 95% CI 0.8- 6.0). The basis for this observation remains to be understood.
`The average occupational serum PFOA concentrationsofAPFO production: related workers in this study are approximately 3 ordersofmagnitude higherthanthose. repiontrhetgeneerdal population [> 5ng/ml(ppb)) (Hansen efal, 2001;Olsenetal.,
000032
Page18 2002a; 2002b; 2002; 20030). Upper boundsofthe estimated 95th percentile values `approximated 10 ppb in these general population studies and the highest individual value `measured approximated 50 ppb. The levelof PFOA concentrations determined in the serum and the low rateofserum elimination from the body suggestthatthe magnitude of exposure in the general population is quite small. The lack of statistically significant associations for lipid, hepatic and thyroid function in relation to serum PFOA. concentrations among APFO production workers suggestthatthe same would be observed in the general population with its much lower serum PFOA concentrations.
Finally, in May, 2000 3M announced its voluntary decision to phase out ofthe perfluorooctanyl chemistry used to produce certain repellents and surfactant products due to widespread environmental presence of PFOS. This decision included 3M's production ofAPFO at its Cottage Grove manufacturing site. APFO production continues at other companies in the United Statesandelsewhere.
000033
Page 19 REFERENCES
Alexander, BH. 2001. Final report. Mortality studyofworkers employeadt the 3M Cottage Grove facility. Minneapolis (MN):University of Minnesota. U.S. EP.A. docket AR-226-1030-2013.
Biegel, L.B., Hurtt, ME. Frame, SR, O'Connor, J.C., Cook, J.C. 2001. Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats. Toxicol. Sci. Sci. 60:44-55.
`Burris, JM, Lundberg, JX., Olsen, G., Simpson, C., Mandel, J. 2002. Interim report No. 2, Determinationof serum half-livesofseveral fluorochemicals. St. Paul (MN), 3M. Company. US. E.P.A. docket AR-226-1086.
Butenhof, J. L, Kennedy, G. L., Murphy, S. R., O'Connor, J. C., and Olsen, G. W. 20022. Genotoxicity, carcinogenicity, developmental effects, and reproductive effects of perfluorooctanoate: aperspective from available animal and human studies. Association of Plastics ManufacturersofEurope and the Societyofthe Plastics Industry. Submitted 10 US. EP.A. docket AR-226, December 19th, 2002.
000034
Page 20
Butenhoff, J., Costa, G., Elcombe, C., Farrar, D., Hansen, K., Iwai, H, Jung, R., Kennedy, G., Lieder, P., Olsen, G. and Thomford, P. 2002. Toxicityofammonium `perfluorooctanoate (APFO) in male cynomolgus monkeysafteroral dosing for six `months. Toxicol. Sci. 69: 244-257.
Cattley, R.C., DeLuca, I, Elcombe, C., Fenner-Crisp, P., Lake, B.G,, Marsman, DS. Pastoor, T.A., Popp, J.A., Robinson, D.E., Schwetz, B., Tugwood, J, Wahi, W. 1998. Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Reg. Toxicol. Pharmacol. 27:47-60.
Commission (2002). Commissifoonr the InvestigationofHealth HazardsofChemical Compounds in the Work Area. Report No. 38.Wiley-VCH:Weinheim (Federal Republic ofGermany). ISBN 3-527-2275112-6. pp 182-185.
Gilliland, F. D. 1992. Fluorocarbons and human health: studies in an occupational cohort. Ph.D. Dissertation, University ofMinnesota, Minneapolis, MN.
Gilliland, F. D. and Mandel, J. S. 1993. Mortality among employees ofa `perfluorooctancic acid production plant. J. Occup. Med. 35: 950-954.
000035
Page2! Gilliland, F. D. and Mandel, J. S. 1996. Serum perfluorooctanoic acid and hepatic enzymes, lipoproteins, and cholesterol: astudyofoccupationally exposed men. Am. J. Ind. Med. 29: 560-568.
Griffith, F.D., Long, JE. 1980. Animal toxicity studies with ammonium perfluorooctanoate. Am. Ind. Hyg. Assoc. J. 41:576-583.
Guan, HP, Li, Y., Jensen, M.V., Newgard, C.B., Steppan, CM, Lazar, M.A. 2002. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat. Med. 8:1221128,
Hanhijrvi, H., Phaug, R., Singer, L. 1982.Thesex-related difference in `perfluorooctanoate excretion in the rat. Proc. Soc. Exp. Biol. Med. 171:51-55.
Hansen, K.J, Clemen, L.A., Ellefson, M.E., Johnson, H.O. 2001. Compound-specific, `quantitative characterization of organic fluorochemicals in biological matices. Environ. Sci. Technol. 35:766-770.
Hansen, K.J, Johnson, H.O,, Eldridge, 1.5, Butenhoff, J.L., Dick, LA. 2002. Quantitative characterizationoftrace levelsofPFOS and PFOA in the Tennessee river. Environ. Sci. Technol. 36:1681-1685.
000036
Page22 Haughom, B., Spydevold, 0. 1992. The mechanism underlying the hypolipemic effect ofperfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid. Biochim. Biophys. Acta. 1128:65-72.
Johnson, J.D., Ober, RE. 1980. Extent and routeof excretionand tissue distribution of total carbo1n4 in male and female rats aftae singleIVdoseof FC-143-14C. Riker Laboratories, Inc, St. Paul, MN. US. E.P.A. docket AR-226-0457.
Ikeda, T, Aiba, K., Fukuda, K., Tanaka, M. 1985. The inductionof peroxisome proliferationinrat liver by perfluorinated fatty acids, metabolically inert derivatives of fatty acids. J. Biochem. 98:475-482.
Kannan, X., Choi, J.W., Isek, N., Sengthhiljumar, K., Kim., D.H., Masunaga, S., Giesy, JP. 2002. Chemosphere 49:225-231.
Kennedy, G.L. 1985. Dermal toxicity ofammonium perfluorooctanoate. Toxicol. Appl. Pharmacol. 81:348-355.
Kennedy, G., Hall, G., Brittell, J. Chen, H. 1986. Inhalation toxicityofammonium perfluorooctanoate. Fd. Chem. Toxicol. 24:1325-1329.
Kennedy, G.L. 1987. Increase in mouse liver weight following feedingofammonium perfluorooctanoate and related fluorochemicals. Toxicol. Lett. 39:295-300.
000037
Page23
Kudo, N, Katakura, M., Sato, Y., Kawashima, Y. 2002. Sex hormone-regulated renal transportofperfluorooctanoic acid. Chem-Biol. Interact. 139:301-316.
Luebker, D.J, Hansen, K.J., Butenhoff, J.L., Bass, NM, Seacat, AM. 2002. Interactions of fluorochemicals with rat liverfatty acid binding protein. Toxicology 176:175-185.
Maloney, EX., Waxman, D.J. 1999. trans-ActivationofPPAR-t and PPAR-yby structurally diverse environmental chemicals. Toxicol. Appl. Pharmacol. 161:209-218.
Olsen, G. W., Gilliland, F. D., Burlew, M. M, Burris, J. M., Mandel, J. ., and Mandel, J. H. 1998. An epidemiologic investigationofreproductive hormones in men with occupational exposure to perfluorooctanoic acid. J. Occup. Environ. Med. 40: 614-620.
Olsen, G. W., Burris, J. M., Burlew, M. M., and Mandel, J. H. 2000. Plasma. cholecystokinin and hepatic enzymes, cholesterol and lipoproteins in ammonium `perfluorooctanoate production workers. Drug Chem. Toxicol. 23, 603-620.
Olsen, G.W., Burris, JM., Lundberg, JK., Hansen, K.J,, Mandel, J.H., and Zobel, LR. 20022. Identificationoffluorochemicals inhumansera. I. AmericanRed Cross adult blood donors. U.S. EP.A. docket AR-226-1083.
000038
Page24 Olsen, G.W., Burris, JM., Lundberg, J., Hansen, K.J., Mandel, 1H.,andZobel, LR. 2002. Identificationoffluorochemicals in human sera. II. Elderly participants in the adult changes in thought study, Seattle, Washington. U.S. E.P.A. docket AR-226-1084.
Olsen, G:W., Burris, JM, Lundberg, Hansen, K.J,, Mandel, J.H., and Zobel, LR. 2002c. Identification of fluorochemicals in human sera. TIL. Pediatric participantsin a group A Streptococci clinical trial investigation. U.S. E.P.A.docketAR-226-1085.
Olsen, G:W., Burris, JM, Burlew, MM, Mandel, JH. 2003a. Epidemiologic assessmentofworker serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations and medical surveillance examinations. J. Occup. Env. Med 45260270.
Olsen, G.W., Hansen, K.J, Stevenson, L.A., Burris, JM, and Mandel, JH. 2003b. Human donor liver and serum concentrationsofperfluorooctaresulfonate (PFOS) and otherperfluorochemicals. Environ. Sci. Technol. 37:888-891.
Riker. 1983. Twoyearoral (diet) toxicitylcarcinogenicity studyoffluorochemical FC143 in ats. St. Paul (MN): Riker Laboratories. U.S. E.P.A. docket AR-226-0437, 0438, 0439 and 0440.
000039
Page2s Roy, R,, Olsen, G,, Lieder, P., Mandel, J, Butenhoff, J. 2002. A biological limit value (BLY) for occupational exposure to perfluorooctanoate. Toricologist 66:284 (abstract 1392).
Ubel, F.A., Sorenson, $.D., and Roach, D.E. 1980. Health statusofplant workers exposed to fluorochemicals-a preliminary report. 4m. Ind. Hyg. Assoc. J. 41: 584-589.
USS. Environmental Protection Agency 2002. RevisedDraft Hazard Assessment of Perfluorooctanic Acid and Its Salts. OfficeofPollution Prevention and Toxics, Risk Assessment Division, November 4, 2002.
USS. Environmental Protection Agency 2003. Preliminary Risk Assessment ofthe Developmental Toxicity Associated with Exposure to Perfluorooctanoic Acid and lis Salts. OfficeofPollution Prevention and Toxics, Risk Assessment Division, April 10, 2003.
Vanden Huevel, 1, Kuslikis, B., Van Refelghem, M., Peterson, R. 1991. Tissue distribution, metabolism and eliminationofperfluorooctanoic acid. J. Biochem. Toxciol. 683-92.
Yiinen, M., Koho, A., Hanhijrvi, H., Peura, P. Dispositionofperflucrooctanoic acid in the rat aftr single and subchronic administration. Bul. Environ. Contam. Toxicol. 4446-53.
000040
Page 26 York, RG. 2002. Oral (gavage) two-generation (one liter per generation) reproduction study ofammonium perfluorooctancate (APFO) in ats. U.S. E.P.A. docket AR-2261092.
000041
: 3
ddsHe Los s&
ii LIF BI d R af gE d og
HH
: &3
&35 i3 g|f|2 ff: i
gl iL. : 1
dzHe fi5.e1 da di d=
Er els 3 I 3
3
HERE] 3 3
ial
53
:
HE dg
iEsH SHEE3 88g 8E1gg,
dnl. . os lH 1i:
ef
Fld E co Had wd
du 8 7 it
2s
85 HEE EEEEE
qo EA i31
HiAH [= 7=
33:
Ts i
i
i
sze< gl
.
0000s
sl: 108 1
TIE |& 3 8 :
gl:
Mle 3 x 2 08
iofg. zoo Li 2
3S
2
|
[28 BE
ez
28
=F 2%
ss 12
3
3g
2E
iE:fag grsds1 o.1%8
5
i
SEEHuE2 lIE .EE Le
22%513
HiAfRE
25 8
E 2e x E5 x25 3 a3 w3r %W3E 2g8g
ig3
ga:
O2ix2 i i3 os3g= za22g832 g2fs|0|%8B
25 gl:
.
LE
te FE a 2 s 3 23
= S18. 2 og of 3
&2s
Hed
38
of
BE
3d] g
.
:2
g
i
i
5:
3
ys 5 dF ER
000043
1]f
J FL. sss 5
$F 8s
cli
8 OEFEde os 2 oo 2 oo
FE
5 os Lo
2aBE | # 5 a88a5of2$2 4s3ig8 52=82 od20 F 83a a=d8o aF % fg& 22 82
HH iol
EOEz. o: o. z oz o. s os
59 elds 2 ooa2 womoo
$Eg 333EET OC
E g EE2 da8z os8 od28 af5 ad8 gf5 2d
i&
Ey
HE
ih
geg o& l
E32 5
: [JF
5 | Bfz8 of
i
=3
2gs
i3i :
EE
LL...
35 fs 5 72 5 3
=f 2d of ws sd sd 2d
:
:
2PfFogFi igos 5ff=%
000044
B1i E... LL.
g ghli,
g BRE.
0 oe
g135
EERE
a8f
of8
=f3zg
a3g%
gnd3
:igchi
2gEgf. &3 A.
: | 93F
5 Hd
z
oo
as =
82
a2 2
oo
F = 3F 99 28 gE
LlPodit LLL
LY
gE 7
5
g Bad ef of 2% gE al
3
g
Eo
E = e FP EE
000043
28
|
8
Eg
n
8& 8
5g
i
:
o48
52
3
2
51
i : 2i%:
.
gs
2a
{2
i : 2
i : HoE3e
iii
i
r8S-- sete8 -- 83 22 -- 88 38-- 2 -- 88 88 --
(wdd) yO4d wnies
000046
5 i =_
&
23 ig e2s2?
33
g5
i 2 2
3
Zs
Sa
O8e
3=Pa8
3
is
EH 3 as
i2
83
z 3
2IH
3
38
as
e3g3
8g
%
2
35 2
23
"
8
og
&
ce 3Su
5=
8ce 82 88 28 82 88 82 88 88 2
(wdd) S04d wrieg
000047
2
?
53
08
3
2E
2
8<Q
:i
3
53
gL
Tf
EY
=
3 22g
2
g$
2gEe
32
3&
g2&
E
83
2
2
&
0
g 8 8 8 8
8R8
(wdd) void
000048
22
2
2
8 8are83]
52
iz 3<33 a]
aegf
83H>i5
o5t8
2283 22 28 gn
e5s2
88
2<g2
g2
.
..
*
..
.
. CeYSna
0 gp god Siants
8 28 82 8
(Ip/Bw) jo18is8IouD
g
8
8
o
=
8@
o8 g&
82
2
8
o=
s 8- o
000049
r8a
|
--22
3
i 5
i)
3<i%
22
ag2
3228
2%
SE
B<2 3i52 8g
23%
< 3282 .
HH
Ae
62
ge
28 ck
ol.
8
2
og .
. re
| 7g
<
:
re?3
.
*
.
.
.: 8
o. e e Y
.
.
*-
`, 2 at 5
g
8
*
88
8a
8
8
(p/w) sapuoABL
000050
g
g
5
E5H
gi
t3id3t
2358
sBEe:
<
3E8
=
8
*
. }
.
.
:
oo.
.
.
"oe . . $t.
est oo cha
888e
vn) Lv
8
|[ 8
2
2
2
83s 2
|[
Ilg
|le
=
000051
o
re
tg
z
|
&
rs
8
e
EP
s3sg
ule -
E3sw
Eg
a2
85
EH
2
E32h
2?
58 &
.
8 8 E
id
.
~
3 < 2
-
i
.9 -
w_ |2
wh
-.
>,
8g 88 B8 88 88 88 8
(un) 199
000052
8
.
8
38
Eg
eR
g
Sa
<38
-.
.
a2
4z
=
Eg
3g2e8
83Ss
z2e8
ga
EH
.
gg
g
Z 2so
.
5<
3
3
.
[
|
22
. .x <8
-
2gd 25
. 93 2RX
vvoe.
oSo.u. e
ow Tae cl.
98 98 23 9a8 9I 92 93
(w/in) HSL
0000583
5
shg
a5!z2
5%
F$Ls
g 5% @o 2g
g
.
*
88
.
*.
. . .
`ot - .e
*
888
(w/bd) e1.
8
8
ls
|
|s
[
F [| E&
fez
*
8
8
000054
[=8
.
8
8
5
E
8g
3g
gs
..
Ezs
353S
3288
.
LE]
23
=E
.
i:
.
gS
2g
oo. :
|Lo
[T
re
=
|I.r8<&E
S
{
8
[ ]<
L.h .
2
cL EEL
ee aa RAS
oe
a vr
9
86
9
9
@
N
2
9
Ww
2
9
o
9
oa
2
+=
9g
Oo
(p/Bn) pL.
000055
s
[
.
|Lg8
| o8
4 . E
2
3oz s
8
co.
2
asyz
HR
88
8g
2> g
<8
E
a
2sg3eo
og
-
aE5 <
.
8
z23g
.
..
S]
2ge@ e
. vo oh
84 923 8 3
(P/pBLu981)34
8 39 0000S