Document MGnEEjRaEgR9JB7d3gQMkZZzk

nu ReRseseeaarrcchh A l l EH P c o n t e n t i s a c MR cessibl HTML ern us cl a e to individuals with disabilities version of this article is availabl . A e a f t 13 54 ully accessible (Section 508-compliant) http://dx.doi.org/10.1289/ehp.1206449. UUllcceerraattiivvee CCoolliittiiss aanndd PPeerrfflluuoorrooooccttaannooiicc AAcciidd ((PPFFOOAA)) iinn aa HHiigghhllyy EExxppoosseedd Pooppuullaattiioon ooff Commmmunuintity Reessiidenntts and WWoorrkkeerrss iinn the MMiidd--OOhhiio VVaalllleey Vo Sid ig a! Sto Hmtorre Kyle Steenland,1 Liping Zhao,1 Andrea Winquist,1 and Christine Parks2 mm 1Rollins School of Public Health, Emory University, Atlanta, Georgia, USA; 2National Institute for Environmental Health Sciences, CATT NS Rt National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA mo eB ttR er BACKGROUND: Little is known about environmental determinants of autoimmune diseases. T Ta TETE ET OBJECTIVES: We studied autoimmune diseases in relation to level of exposure to perfluorooctanoic acid (PFOA), which was introduced in the late 1940s and is now ubiquitous in the serum of resi- a HE dents of industrialized countries. i TITER fa e METHODS: In 2008-2011 we interviewed 32,254 U.S. adults with high serum PFOA serum levels ns mame (median, 28 ng/mL) associated with drinking contaminated water near a chemical plant. Disease history was assessed retrospectively from 1952 or birth (if later than 1952) until interview. Self- IE reported history of autoimmune disease was validated via medical records. Cumulative exposure to PFOA was derived from estimates of annual mean serum PFOA levels during follow-up, which were E SFrnm T CLC based on plant emissions, residential and work history, and a fate-transport model. Cox regression en models were used to estimate associations between quartiles of cumulative PFOA serum levels and the incidence of autoimmune diseases with 50 validated cases, including ulcerative colitis (n = 151), aaa TEs SERRE Crohn's disease (n = 96), rheumatoid arthritis (n = 346), insulin-dependent diabetes (presumed to be type 1) (n = 160), lupus (n = 75), and multiple sclerosis (n = 98). EEenES L S ea t S ST e TL RiRsEStULTS:TThheeiinncciiddeenncceeooff ulecrearattiivveeccoollittisswwaassssiiggniifficcaanndtlyyinincrcreeaasseeddiinnaasswocicatiionwawititihhPPoFFOOnAA exposure, with adjusted rate ratios by quartile of exposure of 1.00 (referent), 1.76 (95% CI: rs 1.04, 2.99), 2.63 (95% CI: 1.56, 4.43), and 2.86 (95% CI: 1.65, 4.96) (ptrend < 0.0001). A prospecShaan EEE tive analysis of ulcerative colitis diagnosed after the baseline 2005-2006 survey (n = 29 cases) suggested a positive but non-monotonic trend (ptrend = 0.21). RRNY Sparen DISCUSSION: To our knowledge, this is the first study of associations between this common environSE Armen mental exposure and autoimmune diseases in humans. We found evidence that PFOA is associated with ulcerative colitis. KEY WORDS: autoimmune, inflammatory bowel disease, PFOA, ulcerative colitis. Em an SCeo ) E oo d PEON is no biodegradable adopeseiss Environ Health Perspect 121:900-905 (2013). http://dx.doi.org/10.1289/ehp.1206449 [Online 4 June 2013] odin peng. ER Introduction s Sr Tee erp SR IRSe ERNSy T S ERE ET EE Autoimmune diseases affect about 7% of the er LW CL EE U.S. population (Cooper et al. 2009; Miller and lupus (Delgado-Vega et al. 2010). A number of specific genes have been associated with more than one autoimmune disease. compound introduced into the environment in the 1950s. PFOA (also known as C8) is ubiquitous at low levels (nanograms per milliliter) in the serum of virtually all residents of industrialized countries (Lindstrom et al. 2011). Human exposure to PFOA occurs via many sources, including food, drinking water (Shin et al. 2011a, 2011b), house dust (Strynar and Lindstrom 2008), and air (Fromme et al. 2009). Until recently, PFOA has been used in manufacturing a wide variety of consumer products, such as Gore-texTM, Teflon, and ScotchgardTM (Shin et al. 2011b). The cohort studied here was exposed primarily via drink- i7n8g "waiteerccoonntteammiinnaatteedd wwiith PFOA td hat oxrigi- nated from emissions from a nearby chemical plant that used PFOA in the manufacture of Teflon. Median PFOA serum levels in this population in 2005-2006 were 28 ng/mL, and mean levels were 72 ng/mL, compared with an estimated mean serum concentration of 4 ng/mL for the general U.S. population (Calafat et al. 2007; Steenland et al. 2009). PFOA is not biodegradable and persists indefinitely in the environment. In humans it is thought to be stored in the liver, kidney, and serum, and has an elimination half-life of approximately 3.5 years (Olsen et al. 2007). PFOA is a rodent carcinogen and causes fetal loss in mice at dietary levels et al. 2012). The most common autoimmune diseases include inflammatory bowel disease (consisting of ulcerative colitis and Crohn's E ERe T disease), rheumatoid arthritis, celiac disease, multiple sclerosis, systemic sclerosis, systemic Een lupus, type 1 diabetes, and two types of thyBUTE roid disease (Grave's disease and Hashimoto's EER thyroiditis) (Cooper et al. 2009). In general, SErrTanah these diseases are chronic and incurable. They are thought to occur as a result of an inter- onMtoe oe dhe Sienna, action between genes and the environment. EEE Twin studies on concordance suggest a relaEST tively low genetic contribution for rheuma- To date few environmental risk factors for autoimmune disease have been identified. The principal ones are a) crystalline silica, which ER a has been associated with rheumatoid arthri- tis, systemic sclerosis, and lupus; b) smoking, Tati ERIE positively associated with seropositive rheumaEe RS toid arthritis and negatively associated with EERE ER ee ulcerative colitis; c) solvents, associated with mR EER systemic sclerosis; and d) sunlight, negatively associated with multiple sclerosis (Miller et al. 0D. Abn ratioonn popion013507 Louk termle 2012). Although information on population SRR Rt trends in autoimmune disease rates is limited, SET oe concerns have been raised that autoimmune of approximately 20 ppm (Lau et al. 2007). Rodent studies have reported evidence of immunosuppressant effects including lymphoid organ atrophy and decreased de novo antibody production in certain strains of mice (DeWitt et al. 2008; Yang et al. 2000). To Address correspondence to K. Steenland, Rollins School of Public Health, Emory University, 1518 Clifton Rd., Atlanta, GA 30322 USA. Telephone: (404) 712-8277. E-mail: nsteenl@emory.edu We are grateful to T. Fletcher, D. Savitz, and D. Germolec for comments. This research was funded by the C8 Class Action toid arthritis, ulcerative colitis, and systemic sclerosis; a modest contribution for Crohn's disease and lupus; and a high contribution Erle dhe for type 1 diabetes and autoimmune thyroid Er disease. Data are largely lacking for other autoET eE immune diseases (Baumgart and Carding S SamA ael 2007; Bogdanos et al. 2012). Genetic studies, disease incidence rates may be increasing as a result of increasing exposures to xenobiotics (Miller et al. 2012). One such xenobiotic, BODHERRS which is ubiquitous in the serum of U.S. resi- dents, and which has been shown to affect Sli] immune responses in rodents (DeWitt et al. B Shiee n? 2009), is perfluorooctanoic acid (PFOA). To Settlement Agreement (Circuit Court of Wood County, West Virginia) between DuPont and Plaintiffs, which resulted from releases into drinking Satomi water of the chemical perfluorooctanoic acid (PFOA, or C8). Funds were administered by an agency that reports to the court. The contribution of C.P. to this Sm research was supported by the Intramural Program SERIE of the National Institute of Environmental Health oE t mycommute oE scBe s, including recent genomewide association stud- ies (GWAS), have identified a number of genes that may contribute to autoimmune diseases, particularly genes of the major histocompatibility complex (MHC) that have associated der ma. y our knowledge, there are no prior studies of associations between PFOA and autoimmune disease in humans. In the present study, we focused on a large cohort (n = 32,254) that had been exposed FEnR inccite ereenrmtd Sciences, National Institutes of Health. Our work and conclusions are independent of either party to the lawsuit. The authors declare they have no actual or potential competing financial interests. Received 19 December 2012; accepted 30 May with rheumatoid arthritis, systemic sclerosis, 900 i ans to high levels of PFOA, a perfluorinated 2013. VOLUME 121 | NUMBER 8 | August 2013 t Environmental Health Perspectives EExxhhiibbiitt 33553333 State of Minnesota v. 3M Co., Court File No. 27-CV-10-28862 3553333..0000011 erative cols nd 50 i he Mii Vly a Ulcerative colitis and PFOA in the Mid-Ohio Valley de, formation shout PEO in ion toad pain heCBP bin vy moral (Lond t 2. 208 Scnd sd date, information about PFOA in relation to and participated in the C8HP baseline survey me ton. ea bs 2002000 es co THY Me, We immune function in humans is limited to a in 2005-2006 (Frisbee et al. 2009). The prin- oro eto] la coy mt. rot of pon for the polio mts of sul scrum PFO kl few cross-sectional studies of relatively insensi- cipal route of exposure for this population Fo He ALAA SY WPA oe tive immune markers (reviewed by Steenland was via PFOA-contaminated drinking water. otk eof bmn COI pu3.050p hltb oe SkeFo Voie a S03 et al. 2010). No clear patterns of immune sup- C8HP participants (n = 69,030) had their RO Fs ot ean sd pat kere sh toned ml i pression have been reported based on these PFOA serum levels measured and provided a ae ST A A AA studies. However, a recent study of children medical history. Approximately 80% of the Be er in the Faroe Islands reported a significant current residents who had participated in the ren nb ody ld ol ph 30033006 mcm hee dnpr. Sored shor or ecoonr decrease in childhood antibody levels to diph- 2005-2006 survey in the six districts partici- am 7 sofa. pd CON FeOO We uch coe ln md theria and tetanus at 7 years of age in associa- pated in the C8HP (Frisbee et al. 2009). on ced soo ROR "Mo sil COTE pains 01% of patton br 171 nen hoo tion with elevated serum levels of PFOA and Most adult C8HP participants (74% of Bacon, pont ln pga 3 eso od ths Flo ny BA), mtn another fluorocarbon, perfluoroctane sulfonic participants 20 years of age) consented to aie ee. Bums Tractors loo iy OF hn 5100 ao paca acid (PFOS) (Grandjean et al. 2012). To our participate in a follow-up study. Of these we Erol the sews pabioh dt on cal tional $5 1+ S598) 3005 000 CHI knowledge, there are no published data on subsequently interviewed 82% (n = 32,712). Lr yin autoimmune disease in relation to PFOA in These interviews form the basis for the pres- As SLICER, wt animals or humans. ent study. For further details of the interview he nome dus omit he posetWine Co) eos potato 358 The autoimmune diseases considered here process, see Winquist et al. (2013). se Co dm Fo soun si wit conde, penlo hor we co dy are ulcerative colitis, Crohn's disease, rheuma Two rounds of surveys were conducted, dt ies sro o: undhe oo As30000 AISon ri etn po PFOA sn os ad toid arthritis, multiple sclerosis, lupus, and the first from August 2008 to April 2010 and re ds or and dhe cond ot Mar 307 15 Nay 201: han doc Oot mb aed ome type 1 diabetes. For these six diseases we had the second from May 2010 to May 2011. rir data on self-reported occurrence, for which Surveys were completed over the phone i Sg dion oh eli (35) or ein Cand on Far. BRON ewes ses 3005-3006 we then sought validation through medical (63%) or online (37%), and most partici- Rei hese had pos omori f nc c Bh foo coho y mbes 12 049 records review. Analyses here are limited to pants completed both rounds of surveys. Both ee BL cases validated based on medical records data. surveys included the same questions regarding a Oy Hypnos: For most other autoimmune diseases we did demographic information and medical his- iy wl not have self-reported data, or the numbers of tory, including questions about whether the I lips cases were too small to analyze. Self-reported participants had ever been told by a doctor ts a ad posh ot ds or bo cases of Graves' disease and Hashimoto's that they had specific chronic diseases. For ri ok buddy pn sh d Compt phe ac cue oft een thyroiditis are not included in this analy- participants who died after the completion tt wrt ho igi he CONE sy OOS 0 oh dt po ow gs ond co sis because they were difficult to distinguish of the C8HP survey in 2005-2006 or who ir (oan)fope. oct st plo orien slow eh sv el orweldfr from other (non-autoimmune) forms of hyper were not capable of completing a follow-up tin iin. oe el an Geek Comet cot ne be ie thyroidism and hypothyroidism. survey, we surveyed their next-of-kin (4% of cn Be dan me Th ps pp ot Although it is likely that different auto the cohort had next-of-kin interview). The eas rac og Ey Unb tn hv Bo por as dhe fn 5H immune diseases have separate etiolo gies, the Emory University Institutional Review Board i fact that several genes have been linked to reviewed and approved all aspects of this he more than one autoimmune disease also sug- study, including consent forms and surveys. ms we cord ot Shad Seo dog gests that they may have some aspects in com- To estimate past exposures, we developed En eis a S000) Howe. only PEO cero dev ion fos melons by mon (Delgado-Vega et al. 2010). Here we historical yearly serum PFOA estimates for Be ln Mm iti have analyzed the relationship of each auto community residents based on the estimated mc FOR mois immune disease to PFOA exposure. intake of PFOA-contaminated drinking water, iis fans This study is one of a series of studies assuming low background exposure. The esti- contac bye C8 Sen Fond + ao bigs HOR comcnesions 5 ml ed in (Yc conducted by the C8 Science Panel, a three- mates of drinking-water PFOA concentrations er pd of pdmstaspr. we bad mn of FOR cn 301. Fre reawmh. person panel of epidemiologists set up pur- were based on the amount of PFOA released asm biter te Doo pe ind pore onto sn ny Bw wi suant to a 2004 legal settlement between from the DuPont plant, wind patterns, river snd on C5 Senco Hom, owned od ens ep do FoeCH plaintiffs and DuPont (C8 Science Panel flow, groundwater flow, and the residential 2021031;3;FFrrisbieees ettaalbl..22e 00009e9)).. TThheesesettdtleemmeenntt aaddddreresssshhisisttoorryy pprroovviiddeeddbbyyeeaacchhpapratriticciippaanntt ned bine ey of 9000 pe. Shi a oe 30110, El endl crt wll vo on some mandated a baseline survey of 69,000 per- (Shin et al. 2011a, 2011b). Each estimated smn eT sons who lived or who had lived in six water yearly serum concentration took into account hswae of mt hon oe Bo een smd ch ebmm s n districts where water had been contaminated new exposure during the year and the esti- TOR (lll he C8 ed roar cd moofFuFONnpitng hidm t oe otFo CHP. The elemene slo creed he CB with PFOA (called the C8 Health Project, or C8HP). The settlement also created the C8 bmbooaddtyyedaaflateemer oppuaanrrttkialol feePxxcFcreOetiiAoonnreddmuurraiiinnnggintwghheinpPrtoihorer So ar whch hae neh dc. yr, Th od corm oonSom he efoto hd cr ld em dy Science Panel, which was charged with deter- year. The final community cohort comprised i hr or Me dr oe 50 comm evs wh of a Bd stm dhe wih pe mining whether it is more probable than not 28,541 community residents who had esti- os Se a oe that PFOA is linked to (associated with) any mated historical PFOA serum concentrations a human disease. The C8 Science Panel con- and had never worked at the DuPont plant. ems denotes Vos cho ro ec ls tsoe ducted 11 studies over the course of 5 years to Worker cohort. In addition to the com- Spline ty hon we tle cot of91 moetws popwt hed make this determination. munity cohort, we studied a cohort of 4,391 Methods FdcanowmomoffesiDDaouteunmg,lom inpepc SfeeSdanctt,i wspiegicoonsn Methods past and current workers at the DuPont plant using the same survey completed by the com- Suds population ad spo imation. ysis popoma t los b. LLoLl re obin hl od ody dy Villy community-based population thatcohort of 027workers cmployed a the Study population and exposure estimation. Community cohort. We studied a Mid-Ohio Valley community-based population that munity cohort participants, including a residential history. This group was a subset of a cohort of 6,027 workers employed at the I comprised persons who lived or worked in DuPont chemical plant between 1948 and i ee a tbo ee errl any of six PFOA-contaminated water districts 2002 who were previously studied for mortality (Leonard et al. 2008; Steenland and Woskie 2012). Estimates of annual serum PFOA levels for workers in different jobs were developed by the C8 Science Panel (Woskie et al. 2012) and combined with estimated annual serum levels from residential exposure to contami nated drinking water that were derived as described above for the community cohort. We estimated combined residential and occupational exposure for 3,713 workers who completed a follow-up survey (84%), including 1,890 (51%) who also had participated in the 2005-2006 C8HP. Combined community and worker popu lation. Community residents and workers were combined to form a final population of 32,254 persons for whom we could study the relationship between past PFOA serum levels and subsequent disease. Our model-based exposure predictions were well correlated with serum PFOA measurements obtained in 2005-2006 for community cohort members (r = 0.67) (Shin et al. 2011b). Medical history. All participants were asked about lifetime medical history, focusing on chronic disease. Participants who reported that they had been told they had one of the specific chronic diseases of interest were then asked the age at first diagnosis and for consent to review medical records as well as for consent to contact the relevant health care provider. Approximately 60% of the cohort reported having had a disease of interest; 79% percent of these consented for us to review their medical history. Professional medical abstractors obtained records documenting the disease in question from medical providers by mail or by in-person office visit. Overall, we were able to find a medical record relevant to the reported disease for 92% of those consenting to medical record review (Winquist et al. 2013). For three diseases--multiple sclerosis, rheumatoid arthritis, and lupus--we were also able to use supplemental data from the C8HP (( 2002 5-200060),wwh5hiicch- hccoo2 nndduuc0 ctteedd0 ititss6 oowwnn)mme, eddii-- cal record validation, to confirm some cases that had been self-reported to us but for whom were unable to obtain a medical record. paatneAtsuwwtoeeirrmeemassuhkneeedddwwisheheaesstehheienrr taaheddooccocthtooorrrt.o0Pr aoaretthhiceeirr health professional had ever told them they had an autoimmune disease, with specific categories listed for lupus, multiple sclerosis, myasthenia gravis, Sjgren's syndrome, vasculitis, Addison's disease, or other. If the answer was "other," the participant was asked to specify the disease. In a separate question, participants were asked whether a doctor or inib bowel sye ndrome. Theywee ther health professional had ever told them they had had inflammatory bowel disease, excluding irritable bowel syndrome. They were then asked to specify whether the inflammatory bowel disease was ulcerative colitis or Crohn's im Hlee species + vou 21 man up 207 son Environmental Health Perspectives volume 121 | number 8 | August 2013 901 353333..0002 un StSteeeelnalannddeettalal. dice, In smother gueion paris wee We conducted tn types of ssi dics before paricpation in the CBHP disease. In another question, participants were We conducted two types of sensitivity diseases before participation in the C8HP kd whether doco had evr tld thm analyses Tn oe (quinine analy, (prevalent inc)being cade 10 ric asked whether a doctor had ever told them analyses. In one (qualifying time analysis), (prevalent cases) being excluded to restrict Shy had ari, amd ye, wheter wi th eof flip sarc when the par. he ani0 cen ones gna afr they had arthritis, and if yes, whether it was the time of follow-up started when the par- the analysis to incident cases diagnosed after "hema or aver. nal, pari pane qui or dh CHP (5. tic of 2005-2006. Peon for paicians in rheumatoid or osteoarthritis. Finally, partici- ticipant qualified for the C8HP (i.e., time of 2005-2006. Person-time for participants in pinsweresed ey hd ve ad bts, fin esdence in PFOA comand wt the CSHP said on he doeof hr CBP pants were asked if they had ever had diabetes, first residence in a PFOA-contaminated water the C8HP started on the date of their C8HP ih specific tcgorics of ype or type 3 dirctors cployment a she plan). Thi lod raw snd neni, which varied fom with specific categories of type 1 or type 2 district or first employment at the plant). This blood draw and interview, which varied from {exon pregancyinduced dies). climinaed pio oncsposed prson-me July 2005 ly 200 Fo meresof he (excluding pregnancy-induced diabetes). eliminated prior nonexposed person-time July 2005 to July 2006. For members of the "nabs Msodaions bene PFOA. here cohort citan yru. n 3 os wore chor who dinot parte th Analyses. Associations between PFOA before cohort eligibility, and resulted in a loss worker cohort who did not participate in the cxponare an ach come wre conducted of shou 10-15% of ons, dependinomg che CRAP (3 1829), penna ik began exposure and each outcome were conducted of about 10-15% of cases, depending on the C8HP (n = 1,823), person-time at risk began nig spar svi na (Co ess uicom beng luted, Scawnedci,. an1 July 200, Fo3bttw of the sue using separate survival analyses (Cox regres- outcome being evaluated. Second, we esti- on 1 July 2006. For all but two of the auto Sion) vith se 2 the tm ail. Followy mated socitions with cumulative xpos man discsrheumatod ahr and sion) with age as the time variable. Follow-up mated associations with cumulative exposures immune diseases--rheumatoid arthritis and an in 1952 (the appodsciotf ene ove cground nc nly, ht expo ket cotewer mficincs began in 1952 (the approximate date of first above background levels only, so that expo- ulcerative colitis--there were insufficient cases rcdonosfobfiPr,OwRicfhovmertecDmunorpYlenar,s asmrinbeegdanvactsyeorwoofrAksk hCeluDutfeon1t0pcoen 10cond psp asi i he sy teweetaded in Cove background ait Ths snips ROSUIS emissions of PFOA from the DuPont plant), or date of birth, whichever came later. Years outside the study area were included in fol- sure began at year of first exposure to contaminated water or work in the DuPont plant (above background analysis). These analyses to conduct a prospective analysis. Results Iowa and signed US. background ec, included the same number of parciipans Table | provides dope sis or the low-up and assigned U.S. background levels, included the same number of participants Table 1 provides descriptive statistics for the hough seit ancwre conducted fo cach outcome 5 corroding model coor, Th meta of rhofthe coor although sensitivity analyses were conducted for each outcome as corresponding models cohort. The median year of birth of the cohort cuding pean prior 0 ar n the ofsociaions wih cumin POA spo was 1957, 54% wee ele, 2000 wee cu. excluding person-time prior to arrival in the of associations with cumulative PFOA expo- was 1957, 54% were female, 20% were cur- Nid Ohi Valley andlor excluding buck. sre nding cmt background vlof tne smokes, 279 ves current driers Mid-Ohio Valley and/or excluding back- sure including estimated background levels of rent smokers, 27% were current drinkers, round cl in cling cube ao. pote (p4p gsrm ). 18% hd cole cain or moe, and ground levels in calculating cumulative expo- exposure (approximately 4 ng/mL serum). 18% had a college education or more, and Sr. For cach outcome, olla ended at Othe nlc wre rice 0 enon 36%were bo (9M >30) (WI, ming sure. For each outcome, follow-up ended at Other analyses were restricted to person- 36% were obese (BMI > 30) (BMI, smoking, imeoft ncea ime of discoar. tie sc dhe CBHP wscabo 1 2005 and drinkin sss imofbet cr time of last interview, at time of disease occur- time after the C8HP was established in 2005- and drinking assessed at time of last inter- recs,a imof deeh, icher occur 2006 (prospec asp, ith paricpanes view), PEOA seam lel in 2005-2006 rence, or at time of death, whichever occurred 2006 (prospective analysis), with participants view). PFOA serum levels in 2005-2006 os, Caof ctach outcome wr ited poring ory of sn osfh Aan wet 4 g/m' for omni esdens and earliest. Cases of each outcome were restricted reporting a history of any of the autoimmune were 24 ng/m3 for community residents and to cos valde od on medic record trveoiveicewaw.se.sPPvaraatliicdripattaenditswbwcahhsoieodspseeollanf-fremneppeootrdrttiscecdadlaarnnecooouurttd:am lo le or odd BES : ' a come that was not validated were excluded TTaabblle1e1,.CCoohhoortrt cchhaarraacctetreisrtiicssbtbaiascsesedd 0on tthheemmasotst rsecceenntt ssuurrvveeyy aanndd mmeeaassuureredd sseerurmuPmPFFOOAA levleveelsls iinn 2005-2006 [n (%)]. sheanysforda outcome: TT r owe Gr from the analysis for that outcome. Wecme stawith icumulnive Cosi ems ee "ley We estimated associations with cumulative Characteristic Community cohort (n = 28,541) Worker cohort (n = 3,713) Combined cohorts (n = 32,254) cxponare 10 PFOA, which wa cle by gage exposure to PFOA, which was calculated by ming timate yay rum concen. Songer wr I" wa summing estimated yearly serum concentra- Year of birth 25th percentile 1947 1941 1946 on durllaand ma1d3 idme. iin = is = tions during follow-up and modeled as a time- Median 1958 1951 1957 dependen vale in Co region. Wee Tope k "= = dependent variable in Cox regression. We also 75th percentile 1970 1963 1969 Comidersd cumulative xpos with 3 bof Sex 11co00nycseidamresre(idi..ec.,dudmisuicolautincvteineogxpesxoupspuosrounerrwe iniitnthhthaneelpaprggriiooorfr 10 years). Weconduc nesby qari 2 10 years). We conducted analyses by quartile oF late pore hc pe fe opm ame asm of cumulative exposure, with cut points for oom decrmindfom he comune (7%, i =e jk each outcome determined from the cumulative Sonar of dhecas of tht outcome 3 me 311g) exposure of the cases of that outcome at time [ee Sex Female Race/ethnicity White, non-Hispanic Other Missing BMI (kg/m) 1166,6600225(588) 27,901 (98) 640 (2) 0 7T5588(020)) 3,284 (88) 134 (4) 295 (8) 304 17,360 (54) 31,185 (97) 774 (2) 295 (1) goons, nd separ oe ponsdeed 4165 ww 0 isn of diagnosis, and separate cut points derived < 18.5 414 (2) 38 (1) 452 (1) fo ed and angel ors, Rte ron 60-150 rn om ssw for lagged and unlagged exposures. Rate ratios (RR he roof dia mie)were ord 750-200 mon mw no (ffoRorrRtt;hheteshseeeccrooanntdido,,ottfhhiidrrdids,,eaaasnneddrfafotoeuusrr)tthhwqqeuruaearrtetisiltleiemss rraeetlleaad-tv to dhe foe quar, whichwa the ele "C0, as a0 sem tive to the first quartile, which was the referen group. Tessfor wend werebused on the 7 wma my use ent group. Tests for trend were based on the lu ofte colic of he maluoglof Sty me EE ame p-value of the coefficient of the natural log of Cumlaive expose madd 3 coins Cio cons Em am SE cumulative exposure modeled as a continuous ime-dependem: variable in 4Cox rgrsion Mary 2 pa} a time-dependent variable in a Cox regression 18.5-< 25.0 25.0-< 30.0 -- 30.0 Education < High school High school Some college College diploma Missing 7,693 (27) 110906,,9664899403((33747))) 3,026 (11) 11,706 (41) 9,441 (33) 4,366 (15) 2 (< 1) 972 (26) 111,,.600155877((242849))) 37 (1) 1,265 (34) 1,081 (29) 1,328 (36) 2 (< 1) 8,665 (27) 111110,,737505171 ((733)57)) 3,063 (10) 12,971 (40) 10,522 (33) 5,694 (18) 4 (< 1) od] ncethe sme ovis che San model that included the same covariates as the Cosponding mod of cami FON ert ume me ss kw sidfy 2 sandr corresponding model of cumulative PFOA exposure as a categorical variable. All models were adjusted for a standard set ofcma inclusdxiandg clei "os mew ume nm of covariates including sex and race/ethnicity (ito non-white) and ime-dependens evs stn Sha Seen (white or non-white) and time-dependent varisble for making (curren, forme, Ve bat im mi see variables for smoking (current, former, Smoking Never smoked pide Smoked and quit Smoked, did not quit Regular alcohol consumption Never Yes and quit Yes, did not quit he 13,527 (47) 8,899 (31) 6,115 (21) 17,011 (60) 4,105 (14) 7,360 (26) Ton 1,989 (54) 1,297 (35) 427 (12) 1,683 (45) 535 (14) 1,486 (40) ea 15,516 (48) 10,196 (32) 6,542 (20) 18,694 (58) 4,640 (14) 8,846 (27) neve, BMI (body mas inde) ( 185, ncnrentyeoot asin ses) wei vs. never), BMI (body mass index) (< 18.5, 1857205, 25-299, 2 30.0 kg/m) and Seve OA corti ern fo 18.5-24.9, 25-29.9, 30.0 kg/m2), and alcool consumption (ure, former, vs VeG3P 5s SL) . i. . alcohol consumption (current, former, vs. never) based on the most recent survey. The pormpm op 2 WB = proportional hazard assumption of a constant Ridriofor camcauporbs ovier e meg i 0 5 ee onan of hazard ratio for cumulative exposure over time was verified based on the nonsignificance of am riction frm bec me (1) 300 re hppa GH 68BA G9 4 0 an interaction term between time (age) and In community cohort 28,541 (100) 1,890 (51) 30,431 (94) Serum PFOA concentration measurement from the C8HP (2005-2006) (ng/mL)a Mean 71 325 87 SD 151 921 278 Interquartile range 12-59 56-256 13-68 Sawn OR rt Tr ors oewar oh re tclHwawhoTod or ORmemes Median 24 113 26 aSerum PFOA data for members of the worker cohort are restricted to 1,890 workers who had serum PFOA measure ments because of participation in the C8HP in 2005-2006. All other data for workers are from survey data and refer to all Cami capone Ber cumulative exposure. 3,713 workers. 02 Vo121 nn Aust201 +Enon Heh especies 902 volume 121 | number 8 | August 2013 Environmental Health Perspectives 3533.0003 3533.0003 UUilceerarattiivvee ccoollittiss aanndd PPFFOOAA iinn tthhee MMiidd--OOhhiioo VVaalllleeyy Hu 11 gn fo workers. Th mod eng of ais for whic they wer akin medics Of he 342 selacpored ccs of pe 1 113 ng/m3 for workers. The median length of lopwas 33 vcs (ih tocdo low on (15%of the 1.5% wh repr ling dibec, 69 wee vated 3s cbr re 1 follow up was 53 years (birth to end of followap th md ghof flow. sc the medion). 72paricwiithpapet(0s90 sb or ln dependen bets (ope | up); the median length of follow-up after the Cr yer ing or working in 3 con. of187 cored ct.and 98 ith mul. htiesho know 0 mii dependent earliest year living or working in a contamifroin i4 ipl ros (635 of 150 lfrepre cu). de. nd we fod anor 91 vad nated water district was 29 years. Nuribersofsated cnofccach auto Ther were 151 valde cisof cre cas cher mlindependen or pe 1) Numbers of validated cases of each auto immune doce eh soi mean ac cols (of3 wlfre9 ported cc, nd96. mong ube who epi ht hy bad immune disease are shown along with mean at ings and sn Toe 2. Vad caes valid cass of C's dem (33% of abc bt 4 nt kno what kin, OF he diagnosis and sex in Table 2. Validated cases {bad on medial record review) inchuded lrepored cnc (10coswes vodfor 160 vated acs 35 re voted pci (based on medical record review) included 346 pricipants who poe sheumaond bch ain cond Ctbs di). cl for ep | dibs, whi th remaing 346 participants who reported rheumatoid arthritis for which they were taking medication (25% of the 1,292 who reported taking medication), 72 participants with lupus (39% of 187 self-reported cases), and 98 with multiple sclerosis (65% of 150 self-reported cases). There were 151 validated cases of ulcerative colitis (25% of self-reported cases), and 96 validated cases of Crohn's disease (53% of self-reported cases) (10 cases were validated for both ulcerative colitis and Crohn's disease). Tibi 2 Natsof pri ith std ain ss, me 100GHGS TOSEX" geikesmspoopet on Table 2. Numbers of participants with validated autoimmune diseases, mean age at diagnosis, and sex.a RiormonGoss No Wed Wold? Toon Fer of166valcdesranedadbo for he Autoimmunedisease No. self-reportedb No. validatedb Mean age Percent femalec Testis = w 0 ST group of $5 ces spatial vadned 5 Ulcerative colitis 596 Conran wn % 5 5 lie Crohn's disease 178 Fs = % i 8 "he known higher incidence of hema: Tipe datetes-bs" w Rheumatoid arthritis Type 1 diabetes-broadd i 7 Eman wom compared wil men Type 1 diabetes-narrowe 1,292 342 NA [i 1 2 2 Thien our dus Tile 20 The ae Lupus 187 Multiple sclerosis 150 151 44 59 95 39 59 iw 5 2 346 48 69 160 35 52 85 27 48 72 43 87 99 38 77 Lo TL MUSMUSE WN SUNoy gh pos oh 44 NA,notapplicable. TE ce cot re oon re ctr arg pore KNOW, , moe of hs discs end 0 aCases confirmed through medical records review. bIn the entire cohort, among people reporting diseases for which mn nd pe. a Sr ht bo cea din mid a5. The men 2fo validation was sought, ~ 75% consented to medical record review, and among those who consented, a record was at Sn 4 Ty a Sis Ss 1 dbs Comb i di Bo nt crw.h ha be cof seta rng COP 15 dscos rpc. obtained for 92%; among these the percent validated across all diseases was 77%. For multiple sclerosis, rheumatoid arthritis, and lupus, we included among the validated those cases which had been self-reported and not confirmed by us for lack of a medical record, but which had been confirmed previously during the C8HP (29, 19, and 5 cases respec rn aoe bey mean a5 at anus fo the arr dncacs, tively). For rheumatoid arthritis, numbers are restricted to cases who reported taking medication; these were the only ee Sa Sev ee obewhn emetay reheat oc Fo ho sm of he coe ones for which we sought medical records. c54% of the entire cohort was female. dIncludes cases self-reported as isrerd S| lsoe dash4 4c mong uncle, abough i rece type 1 diabetes and then verified as either type 1 diabetes or insulin-dependent diabetes. eRestricted to the same self- reported cases specifically validated for type 1 diabetes. Tal 3.0 esac srl srs rsdn for or 15 gh20-21 e<uhmanmg atd of 7 so I[TRRaRRb(l(3e9553%%.)O)1].v2aerall retrospective survival anhaleysis results based on follow-u8p from 1952 through 2008-2011 oooat Gad Ghat omen opuiasnhowiendi AagnitlaaFiolieUtsrohde Q2vs.Q1b Q3 vs. Q1 Q4 vs. Q1 ptrend of log cumulative exposure CULL SRS cami POA expose with UUUlnellacrgeagrtaeitdviveeecxcopoollsittuissre 11.7766(110.0042, 29.999)) 22.6633((115.566.,444.433)) 2.28866((11.6655,, 44%.966)) << 000.0000011 [ey TERNS TERE IEERIE OR de maaed and aed pone and si. Crohn's disease 1.25 (0.61, 2.58) 1.15 (0.55, 2.41) 1.00 (0.48, 2.09) 0.73 Prova TMQEIS OKIE 0BORIA DN han nen buon masofbg Rheumatoid arthritis 1.24 (0.85, 1.79) 1.40 (0.96, 2.03) 0.99 (0.68, 1.43) 0.84 Torott OSASIE 090213 OAOZIA IN fumedcamxpoamneiNosiaherend Type 1 diabetes-broadc 0.68 (0.29, 1.58) 0.53 (0.22, 1.30) 0.54 (0.22, 1.33) 0.84 Touldma OBABIM INOGAE OBORIN IB arson br Cons dacstor Bram Type 1 diabetes-narrowd 0.83 (0.25, 2.78) 1.41 (0.40, 4.95) 0.88 (0.25, 3.06) 0.68 Jie TH0RIN DMM OMORIE 0 map orCob deoor Lupus 1.49 (0.68, 3.34) 1.01 (0.44, 2.30) 0.71 (0.31, 1.65) 0.94 \ewpescss masts Bonn imesiie in `a SaemniesridnoscchrtSpoyres Multiplesclerosis 0.85 (0.44, 1.63) 1.56 (0.81, 3.00) 1.26 (0.65, 2.42) 0.22 10-year lagged exposure V--ier nemam amomam dsnssm como beingin hee qul"qualiing a orwithIout Ulcerative colitis 1.71 (0.89, 3.27) 2.05 (1.07, 3.91) 3.05 (1.56, 5.96) < 0.0001 Coren ROTTS WEE OmOmim 0% bacgmundadded inwere mito trhose Crohn'sdisease 0.80 (0.32,1.99) 0.97 (0.36, 2.60) 0.69 (0.26, 1.82) 0.79 Fomsivns ISOSIE IDDM 1SOMIN 0% shown Tabled dark moushown) Fork Rheumatoid arthritis 1.53 (0.61, 2.58) 1.73 (1.10, 2.71) 1.35 (0.87, 2.11) 0.73 Tord okt DGOBAI OROIWOE DBORIT DN uve colt, wih mo background cpr Type 1 diabetes-broadc 0.42 (0.09, 2.00) 0.70 (0.14, 0.35) 0.38 (0.08, 1.93) 0.84 Tondo DHQEAE IOWA OROOIH OB wid th qn NR wee 00 fn Type 1 diabetes-narrowd 0.50 (0.05, 4.90) 1.32 (0.14, 12.40) 0.71 (0.07, 7.14) 0.65 ne Sonim Imomim onOwIm 0m pop | Lupus 0.79 (0.27, 2.34) 1.26 (0.40, 4.03) 0.61 (0.19, 1.91) 0.93 Brecon lneni Ol mE Gn izomGiomam amon Multiplesclerosis 1.16 (0.54, 2.47) 1.62 (0.75, 3.52) 1.32 (0.61, 2.84) 0.59 cots hatt tutny, dctdao rch socom ei as Tae Q,quartile. aFollow up continued until the date of the last survey, the date of diagnosis for each individual outcome being evaluated, oe eho cra tFtd sr Bae ore rdGav roe, gshay or on the date of death, whichever occurred first. bCut points for these quartiles varied by disease analyzed, as they decoy ys ap Se hs ms 5S, apc war dri wer 1.59 (95% CF. were based on dividing the cases equally by quartiles. For example for ulcerative colitis, the cut points were 158, 586, omit mma Pos e ppt5 035, 3.50340 09% Ch Lik, 599 and and 3,500 ng/mL/year, which for a 50-year-old participant would correspond to average exposure of approximately < 3, Sm 2353 G5 1.37 39) ry < 000 3-11, 11-70, and > 70 ng/mL/ year. cIncludes self-reported cases listed as verified as either type 1 diabetes or insulin- dependent diabetes. dRestricted to those self-reported cases specifically validated for type 1 diabetes. Tole ite i rs et, loop0-20 rh 07 or dt. Sgian,ardiePFcOoRl as ce any uc Table 4. Prospective survival analysis results, follow-up 2005-2006 through 2008-2011, for selected out a "Only keratin cols (n+ 30) and comes ( 30 cases) [RR (95%)]. ao " i conti ieee ddareod maesipa(r3i0iondphe aBarotge teGl ed Unlagged exposure [rei IORI 2007558 18205461) on Ulcerative colitis Q2 vs. Q1 1.68 (0.62, 4.66) Q3 vs. Q1 2.10 (0.75, 5.85) Q4 vs. Q1 ptrend of log cumulative exposure 1.62 (0.57, 4.61) 0.21 Fmmiuns OOS 1s 004m 0GGR 08 papenthe OHI. ARforRker Rheumatoid arthritis 0.81 (0.39, 1.68) 2.07 (1.00, 4.27) 0.52 (0.25, 1.09) 0.89 rerlopesenesee Sov cl are lst hie the fi or 10-year lagged exposure Uris 120830 200M ISIGAD 07 Gi bat without a monoernd,obemd Ulcerative colitis 1.21 (0.43, 3.34) 2.16 (0.80, 5.81) 1.51 (0.43, 4.30) 0.12 ois OIDION 0RORI0 OTMILM 0B on this prospec ana (prs + 030 Rheumatoid arthritis 0.31 (0.14, 0.71) 0.90 (0.41, 2.00) 0.32 (0.14, 0.72) 0.89 Toa gdp) (Fe. Q, quartile. Of the 342 self-reported cases of type 1 diabetes, 69 were validated as either type 1 diabetes or insulin-dependent diabetes (type 1 diabetes is also known as insulin-dependent diabetes), and we found another 91 validated cases (as either insulin-dependent or type 1) among subjects who reported that they had diabetes but did not know what kind. Of the 160 validated cases, 85 were validated specifi- cally for type 1 diabetes, while the remaining cases were validated as "insulin-dependent." We conducted analyses for both the group of 160 validated cases and also for the sub- group of 85 cases specifically validated as type 1 diabetes. tooiiddThaacrethhkrnirieotswi,s n , llhuuippguuhs,se,r aainnncddi dmmeunulcledtipoplfleer hssecculleemrrooa- sis among women compared with men is reflected in our data (Table 2). The age at diagnoses also tend to conform to what is known, e.g., most of these diseases tend to occur during middle age. The mean age for 4tayn0pdde ss1ppeedcciiaiffbiieccataellsllyy(ctyoypmpeebi11n))iniisg yyinoosuuunnlgignee-rrd ettphheaannndtethnheet mean age at onset for the other diseases, reflecting the fact that some of these cases occur among juveniles, although in recent years the majority of type 1 diabetes now occurs among adults. TTaabbllee 33 sshhoowwss tthhee rreessuullttss ooff tthhee CCooxx regression for the overall analysis. Ulcerative colitis showed a significant positive associa- tion with cumulative PFOA exposure, with m`onmotoonincalloyinintccrreeoaassiinnnggriraattecrraatatiioosslffoorlrbboyotthh the unlagged and lagged exposures and sig- nificant trends based on models of log-trans- formed cumulative exposure. No such trend was evident for Crohn's disease or for any of the other autoimmune diseases examined. Sensitivity analyses using either exposures beginning in the "qualifying year" or without background added in, were similar to those shown in Table 3 (data not shown). For ulcer- ative colitis, with no background exposures added, the quartile RRs were 1.00 (referent), 1.27 (95% CI: 0.78, 2.08), 2.08 (95% CI: 1((p.2p6c, 3<<.400.4.00)00,001a1)n.)d.TT2hh.e3e0ccoo(rr9rr5ees%sppooCnnddI:iinn1gg.3RR6RR,ssw3wi.9ci1thh) Sesuttrniemnadtateedd ppeersrosn-otinmee bbeeffoorree mmoovviinngg to aann exposed water district were 1.59 (95% CI: 0.95, 2.65), 2.40 (95% CI: 1.44, 3.99), and 2.33 (95% CI: 1.37, 3.97) (ptrend < 0.0001). Again, ulcerative colitis was the only outcome associated with PFOA. Only ulcerative colitis (n = 30) and rheumatoid arthritis (n = 56) had 25 cases emen200t6 osr uly 20or 0hoe diagnosed after participation in the original eCenn8rroHollPlleed(d20iinn0t5th-he2ew0wo06ro)rkkoeerrrc1coJohuholoyrrt2tw0w0hh6oo(dfodiriddthnnooostet participate in the C8HP). All RRs for ulcer- ative colitis were elevated after the first quar- tile, but without a monotonic trend, based on this prospective analysis (ptrend = 0.21, unlagged analysis) (Table 4). coHmuthPespecr tes + me 2 mAvm g 013 03 Environmental Health Perspectives volume 121 | number 8 | August 2013 903 3533.0004 3533.0004 un SStteeeennllaanndd eettaall. 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AiGGnneteiermssrteaimmnlaaalmnntonrdaeccetlttss(a.Bln.au2d2m0011gh22au:r;mtOOaarnnrdddaassCsucaetdrtdsaailnl..gs22u200g101g202)e7.)s;. bTbHoohaotevhcsethydepaeyetnasoosafflsisaoadgdiunheldtiincnnamftclemarmathemtatosattriohayrevnyebpgboroetwvwheaeellelnddGciyseeescaosef AtcphhrnaaeritsmiPPoaFFnloOOmfAAoadttedoolxsaxicaiipntcdy iiihnmnumccmlluuunaddineetssystssuyaydsnstitdeeemsaminsiuccdgbsagoupedp.sy-t phpeearrvieo`odCbusetemundduiilseeldvdige((h2Ct0Pl0y00F44iOn-2A2c0r00ee0a99xs)i)pn. go ove se r the wee sso 6-year ppprrreooas1dd.suuioc2cntt0ii1ooo2nnf,a((adDadeDpWtitivhietetiamcetrmlaslu.on22int00y11o22afn; dGGnraraanantmnidbdajoeida.nny anatcecddCnwwu,imitthhiunluaaotllucivcteesraatiPtuivFvdeOeycAcoopelolixpttpius,bo,tsbbuiuuortents,nnwooUetrkCeCrasrrostshoionvcs'ies- ettPotoFrrayyOl.App2aar0tth1htww2a,adyyassnid((DmDtmeehueWWnaeliittetlreeacttisoaa1ln. m22o00f112ibn2a).fe)l.ammMMeydamasnn.ayy- odcionilslceietaiissceoaa,nnnidnddidCoCorunrosroh,hsntn'wu'sisdtyddhiepsdeomaipsenuelgaaaurtreisoccnhll.iiinnUinicclaaccllelilyryvaitddiciivs,.e- cPaatttFeeoOddrAt-thhs-rrrtoeohuluaaggththedesadcicrmticvvmpaatruoioonnnresoeofff(feppFcertArsooRmxxi)ssaooy,mmbePeeEppmArrooeRldfi,.fi-- octainnmaacttoiemcocincc,aadlni,tiaaoonncnddcsu,hbrwissoiittnolhlooagdgniiiscotaliplnafdrgitunioidnsfihngtignshsg.eCCcglriarnosthiocrnao''l.s, oeonrrroantooo-tbrhro-eeearccrtseeivpecaeoctpretodmonerrsedceiiexpapprttroeeerssdssee(ddcPhPiianAnnRgtthhe)-eescc,mooPalloPoynA,,Rabbs-ouok.t, didinhnisteceessacitsoinendaaocllafnttrahaoccetct,c,ustamrlahtilhonlouuabgnogwhhyelpmm.asorttsUtloccfeaortsheeaseisvgntaaascrtttlroii.n nooneccoctnuu-er r((eDscDeceWptNtvoiVtarto-etmnt leaodlf.uia22t00me11d22a)).c.hAAaPllntPhhgoAoeuusRggmhhhaPPysFFOOaAnlAos.ox- Ulttiihscesirsenireednstocrcifcotttehldestetsofomtdtachhlleebccooohwloeoennml.oaaUnnsddlctettrhhaectirsveeiccutcumolm.li-. brVbeealeeanntdecedexnsataacHbtbielviluasvhteieeodldn (c(otTTfaaahk.kauacmc2ss0aaan0nn0Pdd)PAAAabbcRbbvo-oatttethia22os00n0n07oo7;ft; fUlTiinlfnciiensnrggatoiotvhffeettchwhoheeloitggliusoe)ta).bf,foewwwchethselertrwheeaaelalss.mCCuHrcroooowshheannv('esesrp,dditiihsdeeecalriseaeel lVPPiPgaPaAnnAdRde-Rsn sttHphhprreeoouauurvggsehhl eeetontnddahoola.ggvee2enn0ooa0uun6ssc),iaannnafddcltiecavxamaogmtgieaeontnnooouruosysf uaiissffnenhcootsddbteeehfcifenwiwietneihvnioelehddiiebasogmgwnnooeislnsttwibccaolmmlu.eetHtthho1oow0dde%tvtoeorfdd, iticshtaniesnr:ee- clefifolgfreaocnhtssedrsiinpnaeccpuooptleilitaiscsrsmmptooootddeeehnlcsasivaaaelnndda(niDstiubibnebifinnluaggomeprmxlpoaclottroreaerld.dy {Hg(HuainasSnehmauuboeeekrrti2w2n00e0ge06n6s:;tSShpoaeonnmsddisstii22nv00e0a09lb4)yo.).austs1oc0i%ateodf cases with of22ou00r0r06t)6fh.i)e.nrdTTaiphnhgeeeuossfteeic3ffiipnonoddtsiiennnggetssiasslseco(eeDcmmiuabtttoouioqccnuoononbtytrreaeadtdiciaccltt. rCtrreoh,Shmnsc'usorkddriiienssengacsssiems((oMpkaoiasihnitiddiveecnltaya.lea.s22s0o0g00c6i6)a)a.t.eoIIdncnwccooeintndh.- oPPtuFFrrOOofAAiinndaacnisndiguncolacrfleaaraatptnioevdesitlcciooovcleatitl.iassi.sHmoHocmoiwuawetnvieoeevnercr,,bcpseptewseccteiefioinccf itwiraivhtsht,iuscklucerirrceatntonitvre.smccooAollkittaisins,,gtnhhiosounuygegghhastfoiovrmemflyoeerrasssssmmmooocokkikaiiitnnnegdgg, gPPaFFsOtOrPAAoliniaarrtbeeelsnoteiotntmaddleesasccncrhdribableodndciaifnnl iittmhnhekmilcinutegrnreaPetuFe.frOfee.Ac t s of and aCaisnnudrdaerulnilstckeesrfamatocritvkoeircnc.gooA,llitamsinsedfftooaRuu-Rann.nddaalaynns1RiR7sR6Rfofro= s00m.f.55oo88krmiffneoorgrr uubealrclaeaPtrnilacatveuievsoiebcflceotomslliutseiecshmmamanaayicysrmiionsnpcchllliaunugdkdeeiensgsshhtPiioffFwitsOssriiAdnnsahtnahende Scstwhmhumaearocortskkeiwwniinnetenggsoffm((ouoMueouankandhiddinaidgos.o,etmmataSnelaepd.l.sseRu22uc0p0Rpi0p0p0c6=oo)l)r.r.1tyf.If7otoR6irsRsftshrorhfereeeaoassfsseoruricprpmniraanget..g.r- 1aebaTnnnaclhhtsaieieinllnn(ppcffeeeDllrraaeom((mTfWTmmHtaHiiats))tts2ooua-rtrlHeiylykkmeMM2r0ra2e12c3srp)oopp.ohphnneheEsnneaxogopt0teoteyysrpsspitpeeopmewecaeainnnfacitdrdcdl/aafosoinnrnrsadt.:ina- Wtrfeeeernrnnetsaa0nni6ndd3offoou(rrrm0m5dee%rartssaCm.m0ooSk3kpiie9nncgg,ifaiacnn1addll0yuv,lc1RecrRa-tsriv0feorcc0oocaluil9ntrsids- gi1inengngssrea5(lDpsoreoWssguuriggtagtgemeessmttiaPPnl.PPgA2AR0oR-1f-y2ts).ocasEcctuvxicavpatetmriiiaoomcnnernmmotpaaahlyyafillgneeeaaddsd- w1d1.ie99rl00e.0((9.T965h53%e%(9RCC51RI%11f.C22or9I9c:, 0e22...358n292,t,,1ap.n0=d1;000f.p00o=01r)10m.).,e0rr5ae)osmpoapenkced.- wtttoohowiwracaerhrpddmsrsoaaagynnrcaMMomn22rmbaaiunncttigieinnoftffolaadmtmimesmasrutaeetoordmryyappcchhrieoennnpaeohytapyfgpese,e.s, r0etirvs2se8lffy,oo.rr2T0CCh3rreoo:RhhRnn'sss=fddo0iris.sec3auc9sr)sereawwnnteedraren0d11...9f22o466rm(((99eO5r53%s%9mCCoClIk:I:-: dwciaehccnyiytchooarrmniimacmyymmctuouonnnrtooorissibucpuprTtpeercentosiesidooennrcreiiennsaspddeoidisnevcsaassce(csdindDeeepEpeefWfni-- 030.176: 0.28, 2.03; 0.50, 1.76; p 085),roped. p = 0.35) and 0.94 = 0.85), respectively. (95% CI: 0a1"2012) Other dics suggest PFOA dent on cytotoxic T-cell responses (DeWitt et al. 2012). Other studies suggest PFOA mimnaacyryeaiinsniddnuugcceeprssohhdiifuftscsiiionnnttohhfeeTTTHHH1/TkTHHe2cybbtaaollkaainnncceees,, iiv<nnavcolorelvabe2sdi0n12gi1n).phhryoOpdneyurecsetTnipoHsniytie-voifytypTerrHessyp2p-oolorinksskecesscey((DtonDekeWeinriee.tst elaeetnuudkaklii.cnn2i0((I11LLa2))-)-.113oO3]sl]nitesihTnthoHwoulu2s-ggrthyahpttietvocepypltcalooakylyitna3seun[iniinniqqtgueuoreteammRnoeudcncoiocncsralihltiiic2nna0flfl1aa2rmmo;mmleahaotitwonoerrvyuyelrrtce,eosrpPapotOonivssAee ((cMeoMltaaitnnidnsooinsnncaignnueddt oRoUneibnI1Lis1i-c1h33,2ec0xx1pdp2hrre)ee;sscshiioooownmneehhvsaeavrvo,efPnntFohoOtet Aebme-ereinenlacddteeerdsccoeirfibbbfeeeceldts. 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(scy0yshs.0ttae2mmr%iicdconefreutueotrttraeoolppdeiceneytaitaobkaayinnnwddeeiiringechnertes)caelseeenadodtslpihptaoeorppboaocltyllhps2pa0ooc0pcp9hu)ual,alrits diioeo-nnrsel((auecte.+gd.g,ceymg mntaoaeckctrironopepmhhraeeaglrgeeaecsss)ee) i((inQnQoahutzohiteertscaaeu.ll.l ce2coe0pgp0te9ib)e,ilsi,tuyghgttoeosotinsnfaneodcgtieinnongenrssal((sDiungeDcgWeresWatitstedaecinttaalhhl.oes22t00ss1s1u2o2s)--) Tccinioaittgaiheoetnnhrebobr,ecettwawhe:eeseesenntfuiPPdnyFdFOiinOngAscaasounngnddgseuutslctceewthrraaattiiiv3tvehteacccoaosklhlisotosifsicconlteahathrreaassposroceucsaeiaintaotionsntisusdwwyidit(tiihhnsCcCcroorosnohthcnrna'as'ssnt iwaonritehaa)nna,yylooaacfikgtfhhhoetef ob0betehbecexrxpapalauicitnnoeeiddmibmboyyuneinfefcsedcstiassenooadffseoPPstFEehOxOeaNAmioionnneedrre)e,sspppmoonenigsshesesst otobfoeflbleooawwlcetecerrrigigadaal seibtxrnypociosnsstuyeirsenstsiantalanleodrttomooxxvtiiihhcceicttryyuothnrhagiaqattunmempaaaesyypdennicoottst ibimmemmrueIufnlneiecesteeopfdoffesbcciytbs,l.syesttemhtic nocr rocthsesrdorgguatn-ssbpieocrifpi-c tctiiooonlnIstooiff(siPpPncFoFlsOOusidAAbilnegiinntphssauuotbbiljyneecctrtseasawwsyeiidtthhsgiuucltlceadebrisraotgrinvp:e cnnmooeolsasieestdidusruu(eilkdncrecrsaluaeitdrinviuneemgccPooplFloitssOiss)iA)bclcyloouueellalddr,lyleewasuhtdiilltcohunhhcidioggiuhhalegedrr mcciorenee,aatseuIrfa+emdFfalelsseeearuaamdppppeePavaFrreaaOnnsAcceevlooeefvfeea3lstcc,eawuudhsla(ilc0haspsosrcooeccduiiiladc tcuHiuoorrwnree,envietf r(m(oorrei aeeosvuuenrneddssuilubevsbeewqlsesueewcnte)tir)meuUautlcseekedrdastetiovoceipcctrooielldotitsinic.sst. Hw3wiimotthowhdeccevuuelmmru,tluihanlaatttioivvudeeridPPdaFnFtOoaOtwAAeiexnexcsppotiormopsuoasrrteesdtppearesrmsdoeieccsitaceutdiorbbneyys aP(PbFFmyOOowAAdhceicolocnnhthceeadnnitsctdrcaiuitdsoisosnnmo,si,thgheihenntnccoseirn"prcovearvaseetreeseemmcceaueusasssaaiurliryteey"dd" (by which disease might increase measured d scrum kcnhohl) evntha hserer ls preceding serum levels rather than serum levels preceding dainseyaTTssheh).eeirrseOnaaourrtesrc2aecleonnvhuuaommnrbttbeherwerroseof.flgliimliicytaitoio3nnsssurtovioovuuorrr accaoonhvhaolorybtrs,ti,ns.wwiOittlhhuvreccoocimomnhmm2uo0unr0tni5itwt-yya2s0mm0leea6mmrbg4beeledryrhsseahhsmaauvveriinvnogifvot(4o0r hbbaaausvsoceeliliibmnnemeeeunssnuuarrelvvievedyeys..icnIIff2oc0vom0mem5-mae2nu0in0ti6tiyyatrretelshsi0edihedtyaniemvtssewwosiifutthrha avveuisvtdeodimuulmnyntulitlnh22ea00dn00isa55e--ae2s2e00w00c6e,,reitthhleeedsyys lwwtikoooeuulhlylddvtoehhchavivaevlebblseeuecrdnliHiennosswttelhhivkeeeerlssy,ttuuthwddyayon., opxptocohstsessoriisbbrellaysyidgbbeieinaatsssgiintnoagghnooauuvrertheirrnseerssaouulllltntessd. Heaaxcxtpvipovaerwleanneccavoealieltiiroto,c,insnt.owFfFfooliorrisfstooa,uculItriroftbepprsoecooxsaxiprstpgeieveuchecteeaafnsnaicndcgyydiaiinffnunoog3sgrrstsththffmhoooohsirrsseeevuaeewvlcscirienattr.nhheu<rralacalelrppaoto2ip0pv0ueu9llca.totiilooiStnnciso((inDsDdaaa.bvvoaouiulirtettpharell.o.sas11mp99ce97i7a;e;s WWtahineinnagteheenersroeouftfmuaublll.ecce2rr0e,a0tri3wvs)oe.uccSlooedllcbitotsins,,duaa,lktohhfuooruupcggrhhoslibpimyceciehtteidvsde bbpayyrnoassblmmlyaesalmellssl nan2n1udd)msbsfhoheroroswaw,lssweshorleuevaldartuebepddepueRRrnRRagsfsfue((acrtaraentdngsiibnvyagetfhfrriososmmpthro1e1b..6olewmtt.oo ot qualeofcumive expose, hough 2.1) for all three upper quartiles versus the low- est quartile of cumulative exposure, although 04 ou121 aAn st2013 EnvoHamtheespnecites 904 volume 121 | number 8 | August 2013 Environmental Health Perspectives 3533.0005 3533.0005 UUllcceerraattiivvee ccoollittiss aanndd PPFFOOAA iinn tthhee MMiidd--OOhhiioo VVaalllleeyy BH hes dar are limiby sl mambers, and Co A org 1Kl 2. ey JMem ori 1derrf r these data are limited by small numbers, and ys To Pt ame US poor hot om mes Sn oa there is no significant trend. Other limitations include posible ini es vvconsume ORY Photon Sore ST Other limitations include possible inac- curacies in dices validation nd cern. 1885 ou Fp OBersh Pm Fc.rc curacies in disease validation and ascertainmem, chin ander-aeraiamen ofcoe CorrGSEmer.Som ee ph So 1 uc mt ment, including under-ascertainment of cases tha were noe self-reported by participants, SETSoRTI mes ressencepnescsoan that were not self-reported by participants, ack ofvilidationof dh abwnte ofdncwe Shamans te ro Pp 1m lack of validation of the absence of disease mong hse who dd ox cpr womans Dk ROSABO SiLO. 1 Oe FamhBo. o among those who did not report autoimmune et ome and he i ut Sgrper oe oe BSELuE s disease outcomes, and the possible exclusion of cass hat could oxbeverified bea of ua ep Sos gr Ext gr. Sb ie 1 dr rnogc of cases that could not be verified because of kiof cmomlenwoetrotbd yWE 0 cTbarkospfoo ASo Beanm e 0SCCr G SSnets OA SBPHO y a lack of consent or inability to obtain appro- priate medical records. We also lacked data on other potcnial vironmental OKCANS coi3. Copan CB, Stor Ms, uth UE 100 gtsf Ain ps (PT on other potential environmental toxicants in he sem ofMid Ohi Valley resdems uss set ad nts on a in the serum of Mid-Ohio Valley residents a eo Laob m esm Es So B.SFr Gpsii : de that could have confounded associations with J PFOA, and given the limited information on hecine of atsimn Rec, we can soon oi oops eo Vrs Wa DeeB Sunes, the causes of autoimmune diseases, we canor le ou posible Confounding by orb temperaStne pire. hs Ehime ea not rule out possible confounding by other mesure exposures or chases aa erm eteisomod gm WegoorrTi WesveoEme.r unmAAennaoostuthhreeedrr elliximpmioittsaauttirioeonsnoiirss ctthhhaaatrtaeecxxtepprooisssutuircreess.s wweerree: Clad according ro imacad Boric Ba eee esSs FT Sa ch, Sd at SS classified according to estimated historical serum levels based on predicted Water CON pu07e XPoy Brn men, soenet spein ovt en serum levels based on predicted water con- cceennttrraattiioonnss aanndd pprreeddiicctteedd aaiirr ccoonncceennttrraattiioonnss wing an cironmental fcc and taniport | ochmovsamGToRn5s Fe using an environmental fate and transport model individual residential istorics, and 0 So ies vod model, individual residential histories, and maps of public atc Supply network, Cou: ity 1 ncoi f s Fo TON Sa maps of public water supply networks, couB ldwi ne coE mpar donroda. FTa TeerS41,Wi " eee0.Sest eFre Mahe 1 1 OstcaoVmn, pled with a one-compartment absorption and excretion model (Shin et al. 2011b). Model- eximaced levels were corrated with mer. knee eemy oa Ho pa En Wath Pt estimated levels were correlated with mea- Sard lvlsnin 20n05-2006 (n+ 047), bod C__EovenrteSgm Se 5.20 >SeetreWeiOA31A3Morenpr sry sured levels in 2005-2006 (rS = 0.67), based on 45,000 participants. to go in i et There are also a number of strengths to our ans. We died a well-dined cohort Gngos drs EBs eres Nn, Sed our analysis. We studied a well-defined cohort ES gEinp with documented high exposure to a chem- Tel hn hs ben cpr 0 suppres the SSE TE ical that has been reported to suppress the immune system in animals. Dicis SICOMES ol $0Leu oe da itm Tics m7 immune system in animals. Disease outcomes er mad hough ml Tors SR oa Wot Vode Sn ry 1G were confirmed through medical records a bn ry1EEE eo ies SEAT review, with relatively large numbers for many immune discs. Novels, our Bnd. Fec Sse Oo Hs OGS pan ekco pei5 autoimmune diseases. Nonetheless, our finding of porn anciion reece 4 me core S ADs eso ing of a positive association between cumula- nc erumPFOA concenrti1ond IKKTE 1, ae ee iPchs s SsWoh ona itSoca 0 Gnsent tive serum PFOA concentration and incident leave cols, and 3 ack of ssoctons So Fre Mk ote co hdSh OA e sd ulcerative colitis, and a lack of associations ith ahr ume dc, a bud | ne at Le o e yenme with other autoimmune diseases, are based `onlyonone stuadnyd need replicon. esc ot aySu is. Wir.eT. to WhO,Be 81 only on one study and need replication. Ramones peliaralonro ry een eea pBpe spcLrsopeoapt References ern gene Co e Sno i Co eiteed weCo SonHRn Baumgart DC, Carding SR. 2007. Inflammatory bowel disease: cause and immunobiology. Lancet 369:1627-1640. Tops, WASH MK to CO Gn t nn i Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C, et al. 2012. 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