Document 3JD1JgYx3e62Y8NwoewXEgqp0

"McCrea, Deborah" < m ccrea@ taftlaw.com > 10/05/2009 01:56 PM To NCIC OPPT@EPA cc "Bilott, Robert A." <bilott@ taftlaw.com> bcc Subject 10/05/2009 Letter To EPA Docket Center AR226 * - ' / T a ft/ Deborah McCrea / Legal Assistant Taft Stettinius & Hollister LLP 425 Walnut Street, Suite 1800 Cincinnati, Ohio 45202-3957 Tel: 513.381.2838 Fax: 513.381.0205 www.taftlaw.com / mccrea@taftlaw.com CD *X> ct o ~ co ^ Internal Revenue Service Circular 230 Disclosure: As provided for in Treasury regulations, advice (if any) relatinq to federal taxes that is contained in this communication (including attachments) is not intended or written to be used, and cannot be used, for the purpose of (1) avoiding penalties under the Internal Revenue Code or (2) promoting, marketing or recommending to another party any transaction or matter addressed herein. This message may contain information that is attorney-client privileged, attorney work product or otherwise confidential. 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B ilott 513-357-9638 bilott@taftlaw.com October 5, 2009 FEDERAL EXPRESS EPA Docket Center, MC 2822T U.S. Environmental Protection Agency EPA West, Room 3334 1301 Constitution Avenue, NW Washington, D.C. 20004 o 03 O c~> --1 t --f - *.73 '1 - H-* '"7> . -- --o 03 ro Re: Submission to IRIS and AR-226 Database For PFOA/PFOS: EPA-HQORD-2003-0016 To IRIS Database for PFOA/PFOS: In response to the Notice issued by USEPA on February 23, 2006, regarding USEPA's efforts to consider perfluorooctanoic acid ("PFOA") and perfluorooctane sulfonate ("PFOS") within the integrated Risk Information System ('`IRIS"), 71 Fed. Reg. 9333-9336 (Feb. 23, 2006), we are submitting the following additional information to USEPA for inclusion in that review, and for inclusion in the AR-226 database: 1. Lundin, J.I., et al, "Ammonium Perfluorooctanoate Production and Occupational Mortality," 20 Epidem. 921-28 (Nov. 2009). RAB:mdm Enclosure cc: Gloria Post (NJDEP)(w/ end.) (via U.S. Mail) Helen Goeden (MDH)(w/ end.) (via U.S. Mail) Lora Werner (ATSDR)(w/ end.) (via U.S. Mail) 11515572.1 P-4 O riginal A rticle Ammonium Perfluorooctanoate Production and Occupational Mortality Jessica /. Lundin* Bruce H. Alexander,a Geary W. Olsen, b and Timothy R. Churcha Background: Perfluorooctanoate (PFOA) is a synthetic chemical widely detectable in blood of nonoccupationally exposed persons. Its human health effects are not well-characterized. Methods: We conducted a mortality study in a cohort of 3993 employees o f an ammonium perfluorooctanoate (APFO) manufac turing facility. APFO rapidly dissociates to PFOA in blood. We estimated standardized mortality ratios (SMRs) compared with the general population, and fit time-dependent Cox regression models to estimate the risks using an internal-cohort referent population. A priori diseases of interest were liver, pancreatic, prostate, and tes ticular cancer; cirrhosis of the liver; and cerebrovascular disease. Results: APFO exposure was not associated with liver, pancreatic or testicular cancer or with cirrhosis of the liver. SMRs (95% CO for prostate cancer with no, probable and definite exposure strata were 0.4(0.1-0.9), 0.9 (0.4-1.8), and 2.1 (0.4-6.1), respectively, and for cerebrovascular disease 0.5 (0.3--0.8), 0.7 (0.4-1.1), and 1.6 (0.5-3.7), respectively. The diabetes SMR for probable exposure was 2.0 (1.0 3.2). Compared with an internal referent population of nonexposed workers, moderate or high exposures to ammonium perfluorooctano ate were positively associated with prostate cancer (HR = 3.0 [0.9-9.7] and 6.6 [1.1-37.7], respectively) and with cerebrovascular disease (1.8 [0.9-3.1] and 4.6 [1.3-17.0], respectively). Diabetes was associated with moderate exposure 3.7 (1.4-10.1); no deaths from diabetes occurred in workers with high exposure. Conclusion: We did not observe ammonium perfluorooctanoate exposure to be associated with liver, pancreatic, and testicular cancer or cirrhosis of the liver. Exposure was associated (albeit inconsistently) with prostate cancer, cerebrovascular disease, and diabetes. [Epidemiology 2009;20: 921-928) Submitted U M arch 2008; accepted 18 December 2008. From the 'Division o f Environmental Health Sciences. University o f Min nesota, School o f Public Health, Minneapolis. MN; and "Medical De partment, 3M Company. St. Paul, MN. Supported by the 3M Company. |s p c j Supplemental digital content is available through direct URL citations in the H TM L and PDF versions o f this article (www.epidem.com). Correspondence: Bruce H. Alexander, Division of Environmental Health Sciences, University o f Minnesota School o f Public Health, MMC 807 Mayo Building. 420 Delaware St S.E. Minneapolis, MN 55455. E-mail: balex@umn.edu. Copyright 0 2009 by Lippincott Williams & Wilkins ISSN: 1044-3983/09/2006-0921 DOI: 10.1097,'EDE.ObOl 3e3l8l b5f395 Epidemiology Volume 20, Number 6, November 2009 Am m onium perfluorooctanoate (CF3(C F2)6C 0 2_ NH4+) is a thermally stable synthetic surfactant manufactured for use as a polymerization aid in fluoropolymers produc tion.1 In the presence o f biologic media, ammonium per fluorooctanoate rapidly dissociates to perfluorooctanoate (PFOA, C F jiC F j^C O O - ) from the perfluorooctanoic acid2,3 and can be absorbed through inhalation, ingestion, and, to a lesser extent, dermal contact. PFOA can be formed from environmental and metabolic degradation o f telomers.3 High human exposure to ammonium perfluorooctano ate occurs in occupational settings, where median serum PFOA levels in the range o f LOO-5000 ng/mL have been reported.4-5 PFOA is also a wide-spread environmental pol lutant, with exposure to the general population arising di rectly through ammonium perfluorooctanoate manufacturing as well as through indirect pathways o f exposure.6 In 1999 2000, the United States general population had an average serum PFOA concentration o f approximately 5 ng/mL (parts per billion); this declined by 25% by 2003-2004.7 The geometric mean serum half-life o f elimination o f PFOA is estimated at 3.5 years (95% confidence interval = 3 .0 -4 .1 ) and may be the consequence o f a saturable renal resorption process in humans. Chronic ammonium perfluorooctanoate feeding studies o f Sprague Dawley rats found an increased incidence o f benign testicular Leydig cell tumors,9-10 and one study re potted an increased incidence o f hepatocellular and pancre atic acinar cell adenomas.9 Ammonium perfluorooctanoate is an agonist for the peroxisome proliferator activated receptor alpha1'~ 13 and a number o f other receptor agonists have been shown to produce liver tumors in rats.14 However, this path way is generally considered o f low relevance to hum ans.14 The Leydig cell and pancreatic acinar cell tumors observed are not common to all peroxisome proliferator activated receptor alpha agonists in the rat, and other modes o f action have been proposed.2-15 Occupational exposure to ammonium perfluorooctano ate at a 3M Company manufacturing facility in Cottage Grove, Minnesota has been previously associated with mor tality from prostate cancer,16 and cerebrovascular disease.17 We present an updated mortality analysis o f this cohort to further evaluate potential associations between occupational exposure to ammonium perfluorooctanoate and specific causes o f death. Updates from the original study16 include a www.epidem.com | 921 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited p. 5 \ Lundin el al Epidemiology Volume 20, Number 6, Novmber 2009 more complete employment roster, additional years o f fol low-up, and a job exposure matrix that is specific for ammo nium perfluorooctanoate exposure. "Definite occupational exposure": Primarily jobs where electrochemical fluorination, drying, shipping, packaging, and quality-control analyses o f ammonium perfluo rooctanoate occurred. Workers were exposed on a regular METHODS The protocol for this study was reviewed and approved by the University o f Minnesota Institutional Review Board. basis with potential for high exposure. "Probable occupational exposure": Jobs in other chemical division areas where ammonium perfluorooctanoate expo sure was possible, but likely lower or transient. Study Population This cohort included employees of a 3M Company plant located in Cottage Grove, Minnesota, where ammonium perfluorooctanoate production began in 1947. This cohort "No or minimal occupational exposure": Jobs primarily in the nonchemical division o f the plant. Opportunity for some exposure (more than the general population) due to contamination at the work site. differs from the previously published analysis16 by a longer Hereafter, these job exposure subgroups will be re period o f enrollment (1997 versus 1983) and later follow-up ferred to as "definite ammonium perfluorooctanoate expo (2002 versus 1989), and by inclusion criteria The current eligi sure," "probable ammonium perfluorooctanoate exposure," bility criterion was a minimum o f 365 days cumulative employ and "nonexposed." ment prior to 31 December 1997, while the earlier study re quired only 6 months o f cumulative employment This change was to exclude the relatively large number o f short-term work ers, many o f whom were summer interns. We also located employment data on an additional 169 employees who were eligible for both studies. The original study identified 398 decedents w hile the updated study identifies 807. Human resource records were abstracted for demo graphic information, including the worker's name. Social Exposure Classification for Analysis We incorporated 2 approaches for characterizing ammo nium perfluorooctanoate exposure in the analysis. The primary analysis is based on ever attaining a minimum time in jobs with probable or definite exposure. A secondary analysis used a cumulative exposure model with a weighted exposure based on duration o f employment and qualitatively-specified expo sure intensity. Security number, employee identification number, date o f birth, and details o f work history. Demographic information and vital status were verified using consumer credit reporting sources and the Social Security Administration service for epidemiologic research studies. Exposure by Job Classification First, we characterized the mortality experience o f workers compared with that o f the general population o f Minnesota with respect to ever working in jobs with definite exposure, ever working in probable exposure jobs but no Mortality Assessment The cohort was followed until 31 December 2002. Vital record searches were performed through the National Death Index for all cohort members not employed by the company on 31 Decem ber 2002 or not previously identified as de ceased.16,17 The underlying cause o f death was coded in the International Classification o f Disease (ICD) revision in ef fect at the tim e o f death. definite exposure jobs, or working only in nonexposed jobs. Subsequently, a more restrictive classification was developed for an analysis using an internal referent population that classified the cohort members as (1) working in a "definite exposure" job for 6 months or more (high exposure), (2) working in a "definite exposure" job for less than 6 months, or never working a "definite exposure" job but ever working in a "probable exposure" job (moderate exposure), or (3) working only in jobs not exposed to fluorochemicals (low Exposure Assessment exposure). Entry into the first 2 categories could occur at t ^ v a ry in g points in the work history. The goal o f the exposure assessment was to classify' jobs by exposure to ammonium perfluorooctanoate. We used Cumulative Exposure work history records and expert historical knowledge o f the Comprehensive biologic monitoring data were not manufacturing process to classify each job held by likelihood available for this cohort. Estimates o f exposure intensity were of exposure. An expert panel o f veteran workers and plant limited to a qualitative assessment in the form o f relative industrial hygienists reviewed job titles and administrative exposure weights assigned to the job exposure matrix. The department codes by year to determine where the perfluoro exposure weights were derived, in part, from serum PFOA chemical production, or the development o f the perfluoro concentrations collected in 2000 from 131 employees in the chemical products, took place over the history of the facility. chemical division of the plant. These data provided relative The available information permitted classification o f jobs in ranges o f serum PFOA for selected areas o f the plant. Areas the work histories into 3 general categories o f ammonium where jobs were classified as having definite exposure had perfluorooctanoate exposure. median serum PFOA levels ranging from 2.6 to 5.2 parts per 922 | www.epidem.com 2009 Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited P-6 Epidemiology Volume 20, Number 6, November 2009 M ortality o f Ammonium Perfluorooctanoate Workers m illion (ppm = /zg/mL), and jobs classified with probable exposure had levels ranging from 0.3 to 1.5 ppm .1* No data were available for jobs in the nonexposed areas o f the plant. Scrum half-life o f PFOA is approximately 3.5 years,8 and thus short-term peak exposures may equate to longer-term low er exposures over time. The initial cumulative exposure assigned w eights o f 1 in jobs with no exposure, 30 in jobs w ith probable exposure, and 100 in jobs with definite expo sure. These weighting factors, while somewhat arbitrary, were chosen to reflect the relative exposure intensity o f jobs and long biologic half-life o f PFOA. We calculated cumula tive exposure for each worker as a sum o f the days of employment at each level, multiplied by the exposure weight ing factor (weighted exposure level X days exposed), which provides a time-dependent exposure metric. The cumulative exposure was categorized into groups selected a priori, rep resenting the equivalent o f up to 1 year (36,499 exposuredays), 1-4.9 years (36,500-182,499 exposure-days) and 5 or more years (182,500 exposure-days) o f employment in a job with definite exposure. Because the hue form of the cumu lative exposure model is unknown, we conducted a sensitivity analysis to explore how alternative weighting schemes may affect the results. The alternate weighting schemes were 1, 10, 50 and 1, 10, 100, which would limit the extent to which workers in jo b s with "probable exposure" for longer periods would be classified with workers who held jobs with "definite exposure." Smoking History Occupational medical records o f die cohort members were abstracted for information on smoking habit: ever smoked regularly, year started smoking, number of years , smoked, and cigarettes smoked per day. We classified cohort members by their smoking history and the availability o f the records as follows: smoking history available, medical record available but no information about smoking, and medical record not available. Wage Type Baseline socioeconomic status is a well-accepted pre dictor o f mortality. In this cohort, there are differences in educational attainment and income between hourly and sal aried workers. To explore potentially confounding effects of these differences, we classified cohort members by wage type: hourly, salaried, or both. The last was designated if the job history included earning each type of wage for at least 365 days. A dichotomization o f this covariate classified workers as hourly or salaried based on the predominant wage type. Causes of Death of Interest A priori causes of death o f interest were cancers o f the liver, pancreas, and testes and cirrhosis o f the liver (selected based on results from toxicological studies2), and prostate cancer and cerebrovascular disease (CVD), (selected from prior analyses o f this cohort16-17). Bladder cancer mortality was associated with perfluorooctancsulfonate (PFOS) in an other occupational cohort,19 although subsequent research o f incident cases offered little support for an association.20 Wc included ischemic heart disease as an a priori disease of interest due to the hypolipidemic effect o f ammonium per fluorooctanoate in laboratory animals and the inconsistently reported and contradictory association o f increased scrum cholesterol levels in relation to PFOA biomonitoring data.4,5 Analysis The mortality experience o f the cohort was initially compared with the mortality rates for the state of Minnesota. We computed age-, sex-, and calendar-period-standardized mortality ratios (SMRs) and 95% confidence intervals (Cls) using the PC Life Table Analysis System.21 The all-cause and cause-specific SMRs were first computed for the full cohort and then for the exposure-specific categories and wage type. To model the risk as a function o f PFOA exposure using an internal referent population, we estimated hazard ratios (HRs) and 95% Cls were estimated with time-depen dent Cox regression models.22 The time covariate was from date o f entry into the cohort until death or end o f follow-up. Exposure was characterized by job classification and cumu lative exposure. We adjusted the models for sex and year o f birth. Age at entry into the cohort, smoking status, and wage type were also examined as potential confounding covariates. To explore potential effects o f latency, the exposure models were lagged by 10 years. Tire Cox regression analysis was conducted using the PHREG procedure in SAS 9 .1.23 Because smoking data were unavailable for many o f the cohort members, a multiple-imputation model was con structed using those with smoking data to predict the smoking status o f those without smoking data.24 The predictors used for the imputation process were sex, year o f birth, year of first employment at the facility, age at entry into the cohort, and wage type. We conducted all imputation procedures using the MI and MIANALYZE procedures in SAS 9.1.23 The imputed models were fit to further explore potential confounding by smoking status. RESULTS The cohort included 3993 employees, o f whom 807 died in the follow-up period. The cohort was mostly male (80%), particularly in the "definite exposure" subgroup (92%) (Table 1). There was a higher prevalence o f smoking in those who ever worked a job with definite ammonium perfluorooctanoate exposure (65%) compared with nonex posed workers (47%). However, smoking data were available for 66% o f tiie definite-exposure subgroup, whereas it w as available for only 20% o f the nonexposed. A majority of the workers holding "definite exposure" jobs were hourly em ployees, while most nonexposed workers were salaried. 7009 L ip p in c o tt W illiam s W ilkins www.epidem.com | 923 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited p .7 . Lundm eI al Epidemiology Volume 20, Number 6, November 2009 TA8LE 1. Characteristics of Ammonium Perfiuorooctanoate Manufacturing Cohort by Job Exposure Subgroups Exposure Definite* (n = 513) Probable* (n = 1688) Nonexposed* (n = 1792) T o ta l (a = 3993) Deaths; no. 68 Sex Men; % 92 Women; % 8 Age at follow-up (years); mean 55.6 Person-years follow-up; mean Year of birth; mean 29.3 1945 Years of employment; mean 17.8 Age at death; mean 60.1 Wage status; % Hourly 77.6 Salaried 5.1 Both" 17.3 Medical record data on cigarette smoking; no. (%) Record found, with smoking data Smoker 220 (42.7) Nonsmoker 118(23.0) Record reviewed; no smoking data 92(17.8) No record found 83 (16.4) 368 82 18 60.0 31.6 1938 16.4 65.6 56.4 31.2 12.4 396 (23.5) 341 (20.2) 414 (24.6) 537(31.7) 371 74 26 60.6 31.6 1938 9.7 64.9 22.0 73.9 4.1 167 (9.3) 188(10.5) 368 (20.5) 1069 (59.6) 807 80 20 59.6 31.3 1939 13.8 64.8 43.7 47.0 9.3 783 (19.6) 647(16.2) 874 (21.9) 1689 (42J ) *Evcr employed in a job with definite ammonium pcrfluoroocianoatc exposure. faEvcr employment in a job with probable ammonium pcrfluorooctanoatc exposure, but never in a job with definite exposure. '''Never held a job with definite or probable exposure. dHcld both hourly and salaried job while employed at facility. The all-cause and cause-specific SMRs were generally lower for the entire cohort and for exposure subgroups than for the general population o f Minnesota (Table 2). (Results for all causes o f death are presented in the online eTable, http://links.lww.com/EDE/A336). The few deaths from tes ticular cancer (0) and liver cancer (3) precluded further analysis for these causes o f death. The number o f deaths due to pancreatic cancer and cirrhosis o f the liver were not more than expected for all exposure subgroups. The SMRs for cohort members ever employed in jobs with definite ammo nium perfiuorooctanoate exposure were elevated for prostate cancer and cerebrovascular disease, although confidence in tervals are wide. By contrast, the number of deaths from prostate cancer and cerebrovascular disease were lower than expected among the never-exposed members o f the cohort. Cohort members who worked in jobs with probable exposure, but who never held a job with definite exposure, had an elevated risk of death from diabetes mellitus. The number o f deaths from ischemic heart disease was lower than expected. The SM Rs for salaried workers (data not shown in tables) indicated a decreased risk o f death for all cancers combined (SM R = 0.7 [95% Cl = 0.6-0.8]), respiratory cancers (0.6 [0.4-0.9]), prostate cancer (0.5 [0.2-1.2]), dia betes (0.2 [0.02-0.7]), cerebrovascular disease (0.6 [0.4 1.0]), and heart disease (0.6 [0.5-0.7]). The results were somewhat different for hourly employees: all cancers com bined (1.0 [0.9--1.2]), respiratory cancers (1.2 [0.9--1.6]), prostate cancer (0.9 [0.4-1.6]), cerebrovascular disease (0.7 [0.4-1.0]), and heart disease (0.9 [0.8, 1.1]). The SMR for diabetes (2.1 [1.3-3.1]) was elevated for the hourly workers. In the time-dependent Cox regression models, moder ate or high exposure work history, compared with working only in low-exposure jobs, was associated w ith an increased risk for prostate cancer and cerebrovascular disease. A work history o f only moderate-exposure was associated with the risk o f dying from diabetes mellitus (Table 3). Due to the rarity of some outcomes, the moderate and high exposure categories were combined; these are presented in Table 3 as well. Including wage type and smoking habit in the models did not alter the results. We further explored the models for prostate cancer, cerebrovascular disease, ischemic heart dis ease and diabetes by stratifying by wage type. There was no evidence that the observed associations were limited to either hourly or salaried workers. Lagging exposures by 10 years made unremarkable differences in the hazard ratio estimates. Hazard ratios comparing the highest with the lowest cumulative exposure category indicated an increased risk for prostate cancer and cerebrovascular disease (Table 4). The 924 | www.epidem.com 2009 Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited p .8 Epidemiology Volume 20, Number 6, November 2009 M ortality o f Ammonium Perfluorooctanoate Workers TABLE 2. Standardized Mortality Ratios for Selected Causes by Ammonium Perfluorooctanoate Exposure Category ___________________________________________________________ _ Employed in Definite or Probable Exposed Job______________ Ever Definite Ever Probable/Never Definite Never Cause* No. Observed SMR (95% Cl) No. Observed SM R (95% Cl) No. Observed SMR (95% C l) All deaths Cancers All cancers Biliary passages and liver primary Pancreas Trachea, bronchus, and lung Prostate Bladder and other urinary organs Nonmalignant causes Diabetes mellitus Cerebrovascular disease All heart disease Ischemic heart disease Cirrhosis o f the liver Nephritis and nephrosis 68 19 0 1 8 3 0 0 5 21 16 0 2 0.9 (0.7-1.1) 0.9 (0.5-1.4) NE (0.0-7.6) 0.9 (0.0-4.7) 1.2 (0.5-2.3) 2.1 (0.4-6.1) NE (0.O-9.6) NE (0.0-2.4) 1.6 (0.5-3.7) 0.7 (0.5-1.3) 0.8 (0.5-1.4) NE (0.0-2.2) 5.2(0.6-18.9) A priori endpoints of interest, and other selected causes. NE indicates not estimable in cells with 0 observed deaths. 368 119 2 7 37 9 3 18 17 110 93 6 2 0.8 (0.8-0.9) 0.9 (0.8-1,1) 0.7 (0.1-2.6) 1.0 (0.4-2.1) 1.0 (0.7-1.4) 0.9 (0.4-1.8) 1.2 (0.3-3.5) 2.0(1.2-3.2) 0.7 (0.4-1.1) 0.8 (0.6-0.9) 0.8 (0.7-1.0) 0.8 (0.3-1.7) 0.7(0.1-2.6) 371 0.8 (0.7-0.9) 108 0.8 (0.6--i -0) 1 0.3 (0.0-1.8) 5 0.7 (0.2-1.6) 30 0.8 (0.5-1.1) 4 0.4(0.1-0.9) 4 1.4 (0.4-3.7) 5 0.5 (0.2-1.2) 13 0.5 (0.3-0.8) 125 0.8 (0.7-0.9) 92 0.7 (0.6-0.9) 7 0.9 (0.3-1.8) 3 0.9 (0.2-2.8) results combining the 2 higher exposure categories are also presented. There was no association between exposure and risk of pancreatic or bladder cancer, cirrhosis of the liver, and diabetes. T he risk o f dying from ischemic heart disease was lower am ong those with increased exposure. The sensitivity analysis using alternate weighting schemes did not change the overall conclusions. DISCUSSION We observed no association between ammonium per fluorooctanoate exposure and liver, pancreatic, and testicular cancer or cirrhosis o f die liver. Exposure was associated with prostate cancer and cerebrovascular disease within the cohort but not when compared with the general population. Diabe tes-related deaths were elevated among workers with moder ate exposure. Interpreting these results requires consideration o f sev eral limitations. Most notably, this is a relatively small cohort with limited power for studying deaths from rare diseases. However, it is one of very few occupational populations exposed to this chemical. The associations o f ammonium perfluorooctanoate exposure with prostate cancer and cere brovascular disease were apparent with the internal referent population. While an internal referent population may pro vide a more valid comparison (assuming similar social and demographic determinants o f disease), the interpretation of this internal analysis should consider the stratum-specific prostate cancer and cerebrovascular disease SMRs. The SMRs for the exposed categories were modestly above unity, while the nonexposed members o f the cohort were markedly below. This difference o f the nonexposed and other men in Minnesota with respect to baseline prostate cancer and cere brovascular disease risk may be related, in part, to socioeco nomic status. Wage status was the only available proxy for socioeconomic status, which does not fully capture the com plexities o f socioeconomic status and its relation to health. Our findings for the association between prostate can cer and work in an exposed job are similar to the results o f Gilliland and M andel,16 who analyzed the same population over a shorter period o f follow-up. They reported (based on 6 cases) a 3.3-fold increase (95% C l = 1.0-10.6) in prostate cancer mortality associated with working 10 years in the chemical division compared with nonchemical division work ers; only one o f these workers was directly involved in the production o f ammonium perfluorooctanoate.25 A cohort mortality study that included about half o f the workers potentially exposed to ammonium perfluorooctanoate during the production o f fluoropolymers did not report an elevated SMR for prostate cancer based on 3 referent populations.26 However, no exposure-specific estimates were provided. A prospective cohort study o f cancer risk in the Danish general population reported no apparent association between prostate cancer risk and plasma levels o f PFOA.27 It is important to note, however, that the mean plasma concentrations in this general population were 0.007 /xg/mL compared mean expo sures ranging from 0.3 to 5.2 p.g/mL in this occupationally exposed population. The biologic mechanism for an associ ation between PFOA and prostate cancer is not clear. There 2009 Lippincott Williams & Wilkins www.epidem.com | 925 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. P-9 Lundin et al Epidemiology Volume 20, Number 6, November 2009 TABLE 3. Hazard Ratios* From Time-dependent Cox Regression Analysis for Cause-specific Mortality as a Function of A m m onium Perfluorooctanoate Exposure Characterized by Job Classification*5 No. Cases HR* (95% Cl) Prostate cancer' Low Moderate High Moderate/high* Pancreatic cancer Low' Moderate High M o d e rate/h ig h '1 Bladder cancer Low Moderate High M o d e ra te /h ig h 11 Cerebrovascular disease Low Moderate High M o d e ra te /h ig h 11 Ischemic heait disease Low Moderate High M o d e rate/h ig h '1 Cirrhosis of the liver Low Moderate High M ode rate/high11 Diabetes mellitus Low Moderate High Moderate/high'1 4 1.0 10 3.0 (0.9-9.7) 2 6.6 (1.1-37.7) 12 3.2 (1.0-10.3) 5 1.0 8 1.7 (O.S-5.2) 0 NE 8 1.6 (0.5-4.8) 4 1.0 3 0.8 (0.2-3.6) 0 NE 3 0.7 (0.2-3.4) 13 1.0 19 1.8 (0.9-3.7) 3 4.6(1.3-17.0) 22 1.7 (0.9-3.5) 92 1.0 103 1.2 (0.9-1.7) 6 0.9 (0.4-2.1) 109 1.2 (0.9-1.6) 7 1.0 6 1.0(0.4-10.1) 0 NE 6 LO (0.3-2.9) 5 1.0 IS 3.7(1.4-10.1) 0 NE IS 3.4(1.3-9.3) "Adjured for sex and birth year. hJob classification: high = worked a job with definite exposure for 6 months or greater, moderate " ever worked a job with probable exposure or worked a job with definite exposure for less than months: low - ever worked a job primarily in the nonchcnucal division of the plant. cMcn only (n 31$4). ^Moderate and high exposure categories combined. NE indicates not estimable in ceils with 0 observed deaths. TABLE 4. Hazard Ratios* From Time-dependent Cox Regression Analysis for Cause-specific Mortalities as a Function of Ammonium Perfluorooctanoate Exposure Characterized by Cumulative Exposure (Years)15 No. Cases HR* (95% Cl) Prostate cancer1 <1 1-4.9 5 S I* Pancreatic cancer <1 1-4.9 2:5 ai Bladder cancer <1 1-4,9 5 a ld Cerebrovascular disease <1 1-4.9 2:5 >r* Ischemic heart disease <1 1-4.9 25 >1 Cirrhosis o f the liver <1 1-4.9 >5 Sri* Diabetes mellitus <1 1-4.9 >5 Srl* 8 l 7 S 7 4 2' 6 4 2 i 3 23 3 9 12 138 42 21 63 9 3 1 4 14 5 4 9 1.0 0.4 (0.1-3.6) 3.7(1.3-10.4) 2.0 (0.7-5.3) 1.0 2.3 (0.7-8.1) 1.3 (0.3--6.4) 1.8 (0.6--5.6) 1.0 2.2 (p.4-8.1) 1.2 (0.1-10.7) 1.7 <0.4--7.8) 1.0 0.6 (0.2-2.2) 2.1 (1.0-4.6) 1.3 (0.7-2.7) 1.0 1.2 (0.9-1.8) 0.8 (0.5-1.2) 1.0 (0.8-I.4) 1.0 1.7 (0.4-6.6) 0.6 (0.1-4.8) 1.2 (0.3-3.9) 1.0 1.3 (0.5-3.7) 1.3 (0.4-4.1) 1.3 (0.6-3.1) *Hazaid ratio adjusted for sex and birth year. '`Weighted exposure days equivalent to S5 years ( a 182.500 weighted exposure days), 1 to 4.9 years (36,500 -182,499), and less than 1 year (<36,500) of working in a job with definite exposure. cMen only (n = 3184). "Two highest exposure categories combined. was no histologic evidence of prostate neoplasia associated with administered ammonium perfluorooctanoate doses o f 0, 30, and 300 pg/kg in a 2-year chronic feeding study of Sprague Dawley rats.2 Doses o f 0, 3, 10, and 30 (reduced to 20) mg/kg/day o f ammonium perfluorooctanoate adminis tered by oral capsule to male cyuomolgus monkeys for 26 weeks resulted in prostate glands that were microscopically normal.28 Nevertheless, nongenotoxic mechanisms o f carci- nogenesis are possible. An effect of PFOA on the endocrine system in the rat has been described, involving the mode o f action of Leydig cell tumors that might involve induction o f CYP19A1 (aromatase), resulting in the conversion o f testoster one to esteadiol. In occupationally exposed populations, PFOA biomonitoring data were not clearly associated with changes in circulating levels o f reproductive hormones.4-25 Inhibition o f gap junction intracellular communication has also been associated with peroxisome proliferators such as PFOA.24 926 | www.epidem.com 2009 Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Epidemiology Volume 20, Number 6, November 2009 M ortality o f Ammonium Perfluorooctanoate Workers Deaths from heart disease and cerebrovascular disease are often below unity in epidemiologic studies o f chemical workers,30 and thus our finding o f an increased risk o f cerebrovascular disease death associated with higher expo sure was unexpected. The risk o f stroke is related to diabetes, hypertension, and life-style factors, including diet and smok ing.3,-33 In this cohort, risks o f death from life-style-associ ated diseases (eg, lung cancer, diabetes and heart disease) w ere not consistent across exposure groups. In the internal analysis, adjusting for smoking status and wage type did not alter die association between working in an ammonium perfluorooctanoate-cxposed job and death from cerebrovascular disease. D iet is also a potential factor in the risk o f stroke. In the same w orking population, body mass index (BMI)34 o f the almost 50% o f the workers for whom these data were available ranged from 25 to 30 kg/m2, which is considered overw eight.35 However, the BMI distribution did not corre late with PFOA levels.3435 Any findings in a mortality study related to diabetes should be interpreted with caution due to poor reporting of prevalent diabetes on death certificates.37 Leonard et al26 reported an elevated SMR for diabetes o f a cohort o f em ployees o f a plant that manufactured ammonium perfluorooctanoate compared with other company workers in re gional plants, but there was no association when compared with the general population. No specific estimates o f PFOA exposure were made. A more comprehensive assessment of diabetes morbidity is required to fully evaluate any potential relationship with PFOA exposure. In addition to the limits o f mortality analyses characteriz ing diseases that do not uniformly cause death, the following limitations are acknowledged. Some exposure misclassification is unavoidable when using work history records. The extent o f exposure misclassification and the effects on the study results remain unknown, as no additional data were available to further verify these assumptions. Although information on race was n o t available for the cohort, the impact is likely to be limited, as most residents o f M innesota over the decades have been w hite (97% in the 1980 census, 94% in 1990, and 89% in 2000).3* O ur analysis considered potential confound ing by age, sex, wage type, and (to some extent) smoking. The smoking data were sparse, and though sophisticated methods to impute the missing data were applied, the validity o f these imputations is not clear. Finally, the mean age at follow-up w as 60 years, and thus the relatively small number o f deaths limits the ability o f the study to examine exposure responses. This study also has several notable strengths, including the complete enumeration o f the cohort from employment records. A detailed review o f the ammonium perfluorooctanoate production history by veteran workers and indus trial hygienists was integrated with the biologic monitoring data, which helped to reduce exposure misclassification. Also, the comprehensive follow-up o f the cohort found an underlying cause o f death for 99.6% o f the known deaths (804/807); all deaths with unknown causes were from cohort members who worked in the nonchcmical division o f the plant In summary, this study did not show ammonium per- fluorooctanoate exposure to be associated with liver, pancre atic, and testicular cancer or cirrhosis o f the liver. Elucidating the observed associations between exposure and prostate cancer, cerebrovascular disease, and diabetes will require study methods that include nonfatal cases. ACKNOWLEDGMENTS We thank Diane Kampa, Nancy Pengra, Allison /wan. and Richard Hoffbeck fo r assistance with data management and analysis, and Harvey Checkoway and Jeffery Monde!fo r constructive comments on earlier versions o f the manuscript. REFERENCES 1. Begley TH, White K, Honigfort P, Twaroski ML, Nechcs R. Walker RA. Perfluorochemicals: potential sources o f and migration from food pack aging. Food Addit Conlam. 2005;22:1023-1031. 2. Kennedy GL, Butenhoff JL, Olsen GW, ct al. The toxicology o f perfluorooctanoate. Crit Rev Toxicol. 2004;34:351-384. 3. Lau C, Anitole K, Hodes C, et al. Perfluoroalkyl acids: 3 review of monitoring and toxicological findings. Toxicol Sci. 2007;99:366-394. 4. Olsen GW, Zobel LR. 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US Census Bureau. 2006. Available at: http://quickfacts.census.gov/qfd/ stales/27000.html. 80 ON SNIV1NOO 928 I www.epidem.com 2009 Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.