Document JNpw9yoqL79eDzpyLrv4Eb0Le

Bladder Cancer inPerfluorooctanesulfonyl Fluoride Manufacturing Workers Final Report Bruce H. Alexander, PhD Divisionof Environmental Health Sciences Schoolof Public Health Universityof Minnesota November 21, 2004 1 Abstract A mortality studyofemployeesof a perfluorooctanesulfonyl fluoride (POSF) manufacturing facility reported asignificant excess riskofdeath from bladder cancer in workers who held jobs with exposure to high levelsofto perfluorooctanesulfonate (PFOS). To further investigate this finding a study to ascertain all casesofbladder cancer was conducted. Membersofthe original cohort were contacted by mail to inform themofthe study and invite them to complete a brief questionnaire that ascertained any historyofbladder cancer. Nonrespondents were contactedbytelephone to ensure receiptofthe study material and offered the chance to complete the questionnaire by telephone. Validationofreported cancers was attempted through medical records for those cases consenting to releaseofmedical records. Death certificates were obtained for all cohort members identifiaesd deceased and coded for underlying and contributing causesofdeath. The ratesofbladder cancer were compared to the expected population based rates from the Surveillance Epidemiology and End Results (SEER) data published by the National Cancer Institute. Analyses were conducted by estimated `cumulative exposure to PFOS. The riskofbladdercancerwas compared between workers with varying degrees ofexposure. The questionnaires were retuned by 1,400ofthe 1895 cohort members presumed alive during the study period, of which 1,137were men and 263 were women. The questionnaire respondents contributed 36,982 person-years of follow-up to the analysis. One hundred eighty-eight cohort members were identified as deceased. The overall response rate was 74%, with 77% for women and 73% for men.Therewere 838 respondents and 120 deceased cohort members who heldjobs in high or low PFOS exposed jobs, with 624 and 82ofthese holding at least one job with high exposure. A totalofeleven cases ofprimary bladder cancer cases were identified from the surveys (N=6) and death certificates (N=5). The age, gender and calendar period adjusted Standardized Incidence Ratio (SIR) for the entire cohort was 1.28 (95% CI=0.64-2.29). The SIRforever `working (N=6), and working for more than a year (n=3) in ahigh exposed job were 1.74 (95% CI=0.64-3.79) and 1.12 (95% C1 = 0.23-3.27) respectively. Compared to employees in the lowest 2 cumulative exposure category the relative riskofbladder cancer was 0. 83, (95% C1=0.15-4.65), 1.92 (95% C1=0.30-12.06), and 1.52 (95% CI=0.21-10.99). Overall, the results ofthis study do not confirm the high excess riskofbladder cancer reported in the mortality study ofthis population of fluorochemical manufacturing workers. However, the possibility remains foar smaller risk (approximately 1.5 to 2 fold)inthe higher exposed workers, but the limited size ofthe population prohibits a conclusive exposure response analysis. 3 Background The 3M facility in Decatur Alabama was oneoftwo major production sites of perfluorooctanesulfonyl fluoride (POS, C4F 17SOF) based specialty chemicals. These specialty chemicals have a wide rangeofapplications, including surface treatments, paper and packaging protectants, and performance chemicals.' POSF based chemicals can degrade or be metabolized to perfluorooctanesulfonate (PFOS, CyF17S05). PFOS is also used as a primary component of limited numberof specialty chemical applications. The presenceof PFOS in non-occupationally exposed populations and wildlife, particularly marine mammals and piscivorous birds, has raised concerns about the environmental and health effects of POS. PFOS is now recognized as a pervasive compound that will persist in the environment and can accumulate in wildlife." Moreover, PFOS has been detected at levelsof 30 10 40 parts per billion in the general population." These facts prompted the phase-outofthe production of POSF-based chemicals by the major producer (3M Company). Toxicological studies of rats and cynomolgus primates have shown that high doses ofPFOS induced enlargementofliver and apparent alterations in metabolic processes, including reduced serum cholesterol levels." PFOS was not found to be a developmental toxicant in rats or rabbits. Higher matemal doses of PFOSincreasedneonatal mortality, absorptions, resorptions, and reduced weight gain in rat pups. There were no effects on post-natal neurological development or on fertility and estrous cycling in offspring in multigeneration studies. Multiple genotoxicity assays indicate PFOS does not present a hazard from interaction with genetic material.' Although the mechanismof toxicity in laboratory animals is not fully understood, it may be dueto an effect on fatty acid transport and metabolism, membrane function, peroxisome proliferation, `and/or mitochondrial bioenergetics.*!! The potential health effectsofPFOS exposure have been studied in occupationally exposed populations. PFOS has not been showton affect clinical blood and urine chemistry analyses." A studyofhealth insurance claims filed by workers at the Decatur site 1993-1998 evaluated the relative frequencyofepisodesofcare for specific conditions between employeesofthe chemical 4 plant (fluorochemical exposed)andthe film plant (fluorochemical nonexposed)." Workers employed in theareaofthe plant where PFOS exposure may occurhadmore frequent claims for `biliary tract disorders and cystitis recurrence, which were included in the listof a;priori `conditions from the 424 categories ofconditions identified. Claims for benign colon polyps, malignant colorectal tumors and malignant melanoma were also more frequent i theexposed population. A cohort mortality studyof current and former employeesofthe 3M Decatur facility `was conducted to evaluatethehealthofworkers exposed to POSF based fluorochemicals.TM The cohort included 2083 workers who were employed for aminimum o1f year at the Decatur facility, and the mortality experience was ascertained through December, 31, 1998.Themain finding from the study was an excessofdeath from bladder cancer. The standardized mortality ratio (SMR) for bladder cancer for the entire workforce was 4.81 (95% CI=1.0-14.1), and the SMR for employees who held highexposure jobs was 12.8 (95% CI=2.6-37.4). However, these results were based on only three cases. Theemployees who died from bladder cancer allworked forseveral years in high exposurejobs, howeverjobs were primarily maintenance and waste `water treatment, and not specificallyrelatedto fluorochemical production. Two ofthe cases were maintenance workers and the third worked a majorityofhis career in the wastewater treatment `plant and incinerator. Subsequentto the completionofthestudy an additional death from bladder cancer was identified outside the study period, and another employee informed the 3M Medical Department that he had been diagnosed with bladder cancer. Neitherofthese cases worked in PFOS exposed jobs, but they were long time employees at the Decaturfacility. In response to the elevated riskof bladder cancer in the mortality study, a reviewofthe current and pst useofknown or suspected bladder carcinogens at this facility was conducted. Four `materials, 4,4 methylene-dianiline, orthotoluidine, benzidine salts, and butyl benzylphthalate, `were formerly used at the plant and theuse ofthese materials endedin the 1960's and 1970's. The chemicals were not widely used in the plant; however the available exposure monitoring and `use information was very limited. Melamine has been used for the last decade in an epoxy capsule (non-fluorochemical) product line. Qualitative exposure assessments indicated exposures to melamine were low based on short exposure task durations. Chloroprene was also used in several manufacturing processes in the chemical plainnthte 1960s and 1970's. Chloroprene is considered a possible human carcinogen, however the evidence fora ole in 5 bladdercanceris equivocal.' This review indicated that the excess ofmortality from bladder cancerin the high PFOS exposed sub-cohort could not be clearly attributed to exposure to a known bladder carcinogen. oBclcaudpdaetriocnaanlceerxpiosasurreelsa.tiAvreolmyartairec maamliingensaennccyotuhnattehraesd bienetnhelitnexkteidletoansdmookthienrgi'nduasntdriseesvearrael classified as known human carcinogens. Other occupational exposures associated with bladder cancer and classified as possible human carcinogens by the International Agency for Research on `Cancer include polycyclic aromatic hydrocarbons (PAHS), plasticizers such as acetamide and di(2-cthyl hexyl)-pthalate, flame retardants such as thiourea, tis (2,3-dibromo propyl phosphate) andantimony trioxide." Several other occupationalexposuresare:inconsistently reported to be associated with bladder cancer, including, metal cutting fluids, diesel exhaust, polybrominated biphenyls, andsolvents. *2 Bladder cancer oceurs more frequently in men than women, The Surveillance Epidemiology and End Results programofthe National Cancer Insitute estimates annual age adjusted incidence rates for 1992-2001of36.1/100,000 and 9.2/100,000 for men and `women respectively. Age adjusted mortality rates for the same period are substantially lower (men =7.7/100,000 and women =2.3/100,000), however survival rates decrease with an increasing age at diagnosis." Duetothe large difference between incidenceand mortality rates, mortality study will not fully ascertain the burden of bladder cancer in a population. The goal ofthe present study was to determine whethteher association observed in the mortality is representativeofthe entire bladder cancer experienceofthe employees at the 3M Decatur facility. This was accomplished througah case finding effort using direct contact with the. `population. 6 Methods StudyPopulation The study ste was the 3M facility in Decatur, Alabama. The plant is divided in two major sections, which are approximately 300 yards apart.The chemical plant produces specialty chemicals, including the POSF lineof chemicals. The other section is the film plant, where a varietyoffilms are produced, but litleornooccupational fluorochemical exposures oceur, The `population of interest included all current, retired, and former Decatur employees who were eligible for the original cohort mortality study. All current employees who werenotpartofthe original cohort, those hiredafter January 1, 1998,werealso included in the case finding exercise, but not a primary focusofthe analysis as their exposure had occurred so recently that its contribution to bladder cancer is unlikely. The study required direct contactwiththe participants. A rosterofall known addresses and telephone numbers were obtained through 3M personnel or retiree records. The address information and vital status was updated through a varietyoftracing resources sources available to the University ofMinnesota, including TRW/Experian, Lortan Data,and National Changeof Address. If acohort member was noted to have died since the mortality study was completed a copyofthe death certificate was obtained from the state of record. Questionnaires `The primary purposeofthe questionnaire was 10 identify casesof bladder cancer and the year of diagnosis. The questionnaire also recorded historyofsmoking; a known risk factor for bladder cancer. Although bladder cancer was the primary focusofthis study, additional questions `pertaining to diseases and other conditions were included. These diseases and conditions were selected based on the toxicology studies ofPFOS and a studyofepisodesof care conducted in the Decatur plant workforce. The results for the non-bladder cancer endpoints will be presented elsewhere. In addition to bladder cancer, the questionnaire ascertained diagnosesofmelanoma, liver, prostate (men only), breast (women only), colon or rectal cancer, non-cancer conditions including liver disease, gall stones, gall bladder infections, stomach ulcers, bladder infections, colon polyps and other diseasesofthe prostate (men only). Abriefpregnancy outcome history was askedofthewomen. Several other questions were asked relatedtoroutine screening procedures that may be related to the diagnosisofprostate disease or colon polyps or cancer. 7 Recruitment `The University ofMinnesota Institutional Review Board approved the study protocol. Prior to recruitmenta the upcoming series study of meetings were held and allow them to ask with current employees and retirees to informthemof questions about the study. Recruitmentofall presumed living cohort members was initiated witha letter and brochure that outlined the reasons for the study, the scopeofthe study, what is requiredofparticipants, and assurances of confidentiality. The study questionnaire, with cover letter and postage paid return.envelope, followed the recruitment letter by approximately one week. A reminderpostcard was sent to all `non-respondents twoweeksafterthe questionnaire and a second `was mailed an additional two `weeks after that.If mailings were returned with undeliverable addresses, the address information was re-entered nto the search engines to identify possible alternate addresses and the mailing wasre-sent. Cohort members who did not respond to the second questionnaire mailing after one `month were contacted by telephone to verify receiptofthe questionnaire and inquire about intent to participate. At that time the respondent was offered the opportunity to complete the questionnaire by telephoneifthey preferred. All questionnaires were reviewed upon receipt and double entered into an electronic database. Validationofthe diagnosisofthe self-reported casesofbladder cancer was attempted through `medical records. Participants reporting these conditionswere contacted by letter, with telephone follow-up, to request permission to contact their physician to `verify the diagnosis. Participants whoagreed provided signed consent and medical release forms, and the name and address of the physician or clinicofreference. Copiesofthe consent and medical release forms were sent to the `physician or clinic along with a request for pathology reports, surgical notes, or any other information pertaining to the diagnosisofthe reported bladder cancer. If no response was received from the clinic or physician they were contacted by telephone to assure receiptofthe material and encourage appropriate response. Exposure Assessment The exposure assessment followed the previously described method used in the`mortality study. This method created job specific exposure categories based on job tiles, departments, 8 and dates of employment identified in the participant's individual work histories, and potential for PROS exposure. The relative differences in serum PFOS byjob were determined by a comprehensive assessment, which is detailed elsewhere?.* Briefly, serum PFOS concentrations `were measured in 186 employees (n = 126 chemical plant; 60 = film plant) from a randomly selected sampleof232 employees. The geometric mean serum PFOS level (95% confidence interval) for chemical plant employeeswas 0.94 ppm (95% CI=0.79-1. 13) and for film plant employeesit was 0.14 ppm (95% CI=0.11-0.16). The exposure to film plant employees is thought to be influenced by environmental exposure from proximity to the chemical plant. Chemical plant jobs were classified into eight categories: cell operators, chemical operators, `maintenance workers (primarily mechanics and electricians), mill operators, waste treatment plant operators, engineers/laboratory workers, supervisors/managers and administrative assistants. The highest geometric mean levelofserum PFOS was observedincell operators (2.0 ppm) followed bythe waste operators (1.5), chemical operators (1.5 ppm), and maintenance `workers (1.3 ppm). Supervisors/managers (0.9 ppm), mill operators (0.6 ppm), engineer/lab `workers (0.4 ppm) and administrative assistants (0.4 ppm) had lower geometric mean serum PFOS levels. Because production processes have remained constant over time, a simple exposure matrix was developed based on the work history records ofthe study cohort. The workhistories used in the exposure analysis covered the period from when the plant opened, 1961, till 1997 when the work histories were collected for the mortality study. With the knowledgeofthe major job-specific `serum PFOS levels, a company industrial hygienist and epidemiologist assigned each unique job. 9 and department combination in the work history records to oneofthe following three major exposure categories: 1. Nodirectworkplace exposure to POSF-based fluorochemicals (encompasses film plant jobs). 2. Low potential workplace exposure to POSF-based fluorochemicals (includes suchjobs as engineers, quality control technicians, environmental, health and safety workers, administrative assistants and managers). 3. High potential workplace exposure to POSF-based fluorochemicals (includes cell operators, chemical operators, maintenance workers, mill operators, waste operators and crew supervisors) Hereafter these three categories will be referred to as the non-exposed, low exposed and high exposure. An additional classification for cumulative exposure assigned the non-exposed, low exposure, and high exposurejobs relative POSF-based job exposure value of 1, 3 and 10 respectively based on biomonitoring data. The years spent in eachjob were multiplied by the relative weights to develop a cumulative quantitative exposure metric. This exposure metric assumes a continually increasing accumulation of PFOS exposure. However, the half-life for PFOS is prolonged, thus exposures to high concentrations can result in high body burdens fora long time after exposure ceases. To account for this possibility the study participants were also classified as being in an exposed job, high or low and high only, for at least | year. Analysis `The estimated incidenceofbladder cancer was compared to the expected incidence based on rates derivedfromthe Surveillance Epidemiology and End Results (SEER) at the National Cancer Institute." The cohort members contributed person-time to the analysis until the diagnosisofa bladder cancer, death, or the endofthe study (December 31, 2002). All self reported casesofprimary bladder cancer from the questionnaire and bladder cancers identified by death certificate were included in the analysis. Ifparticipants checked `Unsure" instead of "Yes' for bladder cancer the case was not included. The age, gender, calendar-year, and exposure-specific person-timeofthe cohort was tabulated using the Life Table Analysis System for the personal computer (PCLTAS) developed by the National Institute for Occupational Safety and Health. SEER referent data were only available for this program from 1970 through 10 1999. Accordingly, the follow-up period for the incidence analysis began in 1970 and the referent rates for 1999 were appliedforthe years 2000-2002. Standardized incidence ratios (SIR) ere estimated for participants by exposure group and by weighted exposure. Cut-points for the weighted exposure were sclected to correspond 0 1, 5, and 10 years of employment in high exposed jobs. The expected number of bladder cancer cases was also determined for the nonrespondents to the questionnaire by the above weighted exposure categories. For this analysis, the time at risk was estimated from the beginningof employment tilltheend of the study, which estimated the emvaaxluiamteumpotneunmtibaelroefffeecxtpseocftseedleccatsieosn, (bibaassefdroomnnporne-vpaairltiincgipraatteiso)n..These estimates were used to Estimatesofbladder cancer risk by relative cumulative exposure using the study population as an internal referent were made using Poisson and logistic regression. Standardized rate ratios, adjusting for age, gender, and calendar period were estimated with Poisson regression. This `analysis accounted for the time-dependent natureofthe PFOS exposure, as participants accrued PFOS exposure at different levels over the course of employment. A summary analysis was conducted using logistic regression to estimate the riskof cumulative exposure a follow-up, `gender and smoking habit. The precisionofthe estimates for all analysesaredescribed with 95% confidence intervals. ji Results Ofthe 2,083 original membersofthe cohort, 188 were determined tobe deceasedatthe time the questionnaire was sent and 1,400 respondteod the questionnaire. The remaining 495 did not respond either because they declined to participateorwere not reachable. Overall 73.9 percent ofthose eligible responded. For eligible cohort members with no occupational PFOS exposure, only low exposure or high exposure for less than one year, and high exposure for one year or moretheresponse rates Were 75.8% (S63 of741), 81.4% (358of440) and 67.2% (480of 714) respectively. The response rate for women was slightlyhigherthan men and the respondents were older and less likely to have ahistoryofworking in PFOS exposed areas ofthe plant. (Table 1-2). Eleven bladder cancer cases were included in the analysis. Five ofthe cases were identified on the death certificates and 6 were reported on the questionnaire. (Table 3) The diagnosisofthe selfreported bladder cancers were confirmed for two cases, but four self-reported cases declined to signtheconsent forms permitting validation. One self-reported case indicated on follow-up that the bladder cancer was noat primary tumor, but declined to provideaccessto medical records; this case was not included in the analysis. An additional nine individuals marked the question pertaining to a historyofbladder cancer diagnosis as `unknown'. These respondents marked several types cancer as unknown, thus it was assumed that bladder cancer was not diagnosed. Twoofthe bladder cancer cases were women and all were over 50 years of age at the time of diagnosis or death. (Table 4) The median ageofthe bladder cancer cases was 63. (Table 5) Compared to the restofthe questionnaire respondents, the bladder cancer cases were more likely to smoke, with 83 percent havingever smoked regularly, compared to 56 percentofthenoncases. Two (18%) of the bladder cancer cases never worked in PFOS exposed areas while 9 worked at some time in a low or high exposed job,and six ofthese worked foar yearor more in these jobs. Only three bladder cancer cases worked in a high exposurejob for at least one year. These three are the same cases identified in the mortality study. 12 For the respondents and decedents, 8.6 casesofbladder cancer were expected in the period of follow-up (SIR=1.28, 95% CI=0.64-2.29).(Table 6) The SIR for women was 6.42 (95% Cl= 0.78-23.18), but this was based on only 2 cases. The women who reported bladder cancer did not work inthe exposedjobs. The SIRs ranged from 1.1 to 2.3 for the various exposure groups with the highest being the participants ever employed in low exposed jobs. The highest SIRs for the exposure specific strata based on the cumulative exposure score was 2.7 (95% CI=0.55-73.95) corresponding to 5-10 yearsofemployment in the higher exposedjobs. The SIR for the workers `whoheld a high exposure job for at least one year was 1.12 (95% C10.23-3.27). There were 495 eligible cohort members who did not complete a questionnaire. Basedonthe U.S. population rates from SEER and the non-respondents age, and gender, an additional 1.93 casesofbladder cancer would be expected to occur in the non-respondent group during the study period (Table 7). The breakdownofthe expected numberof cases by cumulative exposure category is also presented in Table 7. The riskof bladder cancer was similar for men and women. (Table 8) Those who had ever smoked regularly had a higher riskofbladder cancer, but iveofthe eleven cases were identified by death certificate (smoking status coded as missing) so the overall impactof smoking is hard to characterize. There was no clear associationbetweenemployment in PFOS exposedjobs and bladder cancer. Similar results were observed for the cumulative exposure estimates atthe end of follow-up (table 8) and the time dependent exposure analysis (Table 9). Compared to the cohort members who never held a PFOS exposed job, those with moderate PFOS exposure had nominally higher risk of bladder cancer. It must be noted in alofthese analyses that the estimates are very unstable as therewereonly elevenbladdercancer cases. Fluctuationsinthe point estimates, particularly when the data are adjusted for other covariates, such as smoking, gender, and age, may be artifacts ofthe analysis 13 Discussion The primary objectiveofthis study was to evaluate whether the finding from the mortality study ofa twelve-fold riskofrisk of bladder cancer associated with ever working in a high PFOS `exposed job was representativeofthe overall bladder cancer experience ofthe cohort, The resultsofthis study suggest that bladder cancer incidence in this cohort is similar to the incidenceofbladder cancer in the U.S. population with the same age and gender. Moreover, the risk of bladder cancer in this analysis does notappearto be significantly influenced by employment injobs where PFOS exposure is more likely. Clearly the greatest uncertaintyinthese results isthe completenessofcase ascertainment. This study used a postal-questionnaire with telephone follow-up to identify all additional cases of bladder cancer in the population. This approach was taken because there is no population-based cancer registry available for this geographic area or time period. While the overall participation wasreasonable for a mailed survey, it is quite possible that some bladder cancercases were missed. An additional two casesofbladdercancer were expectedinthe non-respondents based on SEER data. The potentially missed cases would only affect the resultsifthe rate in the nonparticipants was higher than the prevailing rates in the population. A sensitivity analysisofthis effect can describe the potential effectofunderestimating the true number ofcases. Ifthe rate in the non-participants were twice the population expected rate, the net effect would produce an overall SIR of 1.41 (95% C1=0.79-2.33). The SIR for the weighted cumulative exposure strata (Table 6) would be 1.27, 1.11, 2.57, and 1.53; all with wide confidence intervals that include the null. To reach nominal statistical significance at the p<0.1, 0.05, and 0.01 levels, the rate of bladder cancer in the non-respondents would need to be 2.07, 2.60, and 3.63 times thatofthe rate ofthe reference population respectively. Ifthe two highest cumulative exposure strata are combined an SIRof 2.00 (95% CI = 0.75-4.29) would result if the rate of bladder cancer in the non-participants was twice the general population. The rates in the non-respondents for this `combined strata would need to be 1.63, 3.27, and 4.91times the populationratesto reach significance at the p<0.1, 0.05, and 0.01 levels. Thelikelihoodthat cohort members who experienced bladder cancer were more or less likely to respond is speculative. However, as described in the sensitivity analysis the overall effect would be marginal, unless there were 14 substantially higher bladdercancerrates in the nonrespondent group than the reference population. The validityofthe cases ascertained by the postal questionnaire is also a potential imitation of this study. Only twoof six self-reported cases consented to release their medical records pertaining to this diagnosis to confirm this diagnosis. Thereasons for declining to consent to the. validation protocol, be they concems for personal privacy or the validity ofthe self-reported diagnosis, could not be determined. Nevertheless, the other self-reportedcaseswere included in the analysis. Self-reportofbladder cancer has beenshownto be quite valid in other populations. A recent study conducted by the Universityof Minnesota andthe National Cancer Institute using the same approach employed for the Decatur study had one-hundred percentofthe 59 bladder cancers for which medical records confirme>d! A significant non-occupational causeofbladder cancer is smoking, which is believed to be due to PAH's in the cigarette smoke. ' Ascertainment of smoking habit in the study population was problematic. The only smoking information available was reported on the questionnaire, thus no smoking information was available for deceased cohort members, which accounted for five of eleven bladder cancer cases. Fiveofthe six cases reported on the questionnaire had a history of `smoking. Adjusting for smokingand vita status in the logistic regression models did not change the overall results ofthe analysis; however the analysis is statistically unstable with so few. subjects in each category. The prevalenceofsmoking in the cohort may also confound the `comparison to the general population. The questionnaire asked whether the participants ever smoked regularly (more than 100 cigarettes), the numberof years they smoked, and at what age they stoppedifthey had. Overall, th lifetime prevalenceofregular smoking was 56 percent based on the questionnaire responses. The prevalenceof current smoking was 17 percent (18 percentofmen and 16 percentofwomen). Data from the Centers for Disease Control and Prevention indicate that nationally 25 percent ofmen and 21 percentof women were regular smokers in 2001, but the prevalenceofcurrent smoking was as high as 52 and 34 percent for `men and women respectively in 1965. While it is possible that smokingwas under-reported by the participants, it does not appear that smoking would account for any excess risk in this population when compared to the national data. 1s Toxicological studies on laboratory animals have not shown effects in the urinary bladder due to exposurteo PFOS and related compounds Two yearfeeding bioassays in rats ofNethylperfluorooctane sulfonamide alcohol (N-EFOSE) and PFOS have not shown an increased riskofbladder tumors.'** The former compound can metabolize to anundetermined degree 10 PFOS. Mostbladdercarcinogens are genotoxic and/or precipitate in the urine. PFOS and related chemistries are neither genotoxic nor insoluble in urine at the levels measured in employees '. A recently completed POSF inhalation studyofrats was conducted in response to the finding of bladder cancer from the mortality study. The resultsofthis study have been reviewedby Dr. S. Cohen ** and indicate there is no evidencethatthe POSF exposure, which results in high PFOS body burdens, leads to treatment related changes in the urinary bladder histology. `Overall, the resultsofthis study do not confirm the twelve-fold excess riskofbladder cancer that `was reported in the mortality studyofthis population of fluorochemical manufacturing `workers.'* However, the possibility remains for a smaller risk (approximately 1.5 to 2 fold) in the higher exposed workers. Bladder canceris a relatively rare disease and the population occupationally exposed to these compounds is limited, thus the power to detect excess risks in this study is inherently low and prohibited a convincing exposure response analysis. Future follow-upofthis cohort may be limited to mortality studies, which will need to consider these: results when interpreting any findings on bladder cancer. 16 References 1. 3M Company. SIDS initial assessment report: perfluorooctane sulfonic acidand is salts: "USEPA Public Docket AR-226. Saint Paul: 3M `Company, 2000. 2. Hansen KI, Clemen LA, Ellefson ME, Johnson HO. Compound-specific, quantitative characterizationoforganic fluorochemicals in biological matrices. Environmental Science and Technology 2001;35:766-770. 3. Giesy JP, Kannan K. Global distributionofperfluoroctane sulfonate and related perfluorinated compounds in wildlife. Environmental Science and Technology 2001;35:1339-1342. 4. Olsen GW, ChurchTR, Larson EB,vanBelle G, LundbergJK, Hansen KJ, Burris IM, Mandel JH, Zobel LR. Serum concentrations ofperfluorooctanesulfonate and other fluorochemicals in an elderly population from Seattle, Washington. Chemosphere. 2004;54(11):1599-611 5. 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St. Paul, MN, 2004, 20 DTeacbalteu1r. mGoernbdiedri,tyagset,uadnyd exposure characteristicsofparticipants and non-participants in the Questionnaire Respondent - N Yes % No NN % Deceased Total N% TW ow 04is5 s mm Gender M F 137 23 812 188 416 79 840 160 177 11 941 1730 59 353 Ageatendof <30 study 30-39 5 65 04 3 06 46 4 83 8 21 4316 12 127 4049 50-59 294 210 14 291 604 431 207 418 40 Ss 213 478 293 866 60-69 0+ 352 8 251 57 8 16 170 32 43 27 29 479 u2 1 Yearsworked <5 59 7132 am M1 48 106 67 135 os 33 217 66 176 248 1014 119 179 120 86 38 38 77 77 36 18 138 175 96 176 20+ S84 47 180 364 59 314 823 PFOS Exposure Group* Non Exposed" 562 401 179 362 68 362 809 Low Ever 413 295 121 244 67 356 601 yer 320 29 8 158 2 277 450 High Ever 64 446 206 558 82 436 982 2lyer 480 343 24 473 69 367 783 LoworHigh Ever 838 599 316 638 120 638 12% Slyear 689 492 273 552 108 57.4 1070 "Categories overlap ** Non exposed includes workers from the film plant who never worked in the chemical plant. 2 `Table 2. Mean, median, and rangeofages and and non-participants in the Decatur morbidity daysin study PFOS exposure groups for participants Questionnaire Respondent Ta ow Yes dNos Decweassed Total Ageatendof Mean 55.6 study Median 526 Min 29 Max 863 527 537 547 554 537 547 2838 8.0 189 189 857 863 Years worked Mean 155 139 133 149 Median 152 103 1.0 132 Min 10 10 1.0 10 Max 366 367 362 367 Days in PFOS Exposure groups NonExposed' Mean 3461 2818 2336 3234 Median 1248 802 1120 1053 Min 0 0 0 0 Max 13081 12610 1267 13051 Low Mean 833 454 938 74 Median 0 0 0 0 Min 0 Max 13030 11867 10428 13030 High Mean 1383 1702 1279 1450 Median 2 0 0 0 Min 0 0 0 0 Max 12276 12302 10804 12302 Highorlow Mean 216 2246 218 223 Median 2 552 553 409 Min 0 0 0 0 Max 13352 12302 13211 1382 Never exposed includes workers from the film plant who never workedinthe chemical plant. 2 Table 3. Summaryofbladder cancer cases by sourceof reportainndg confirmation status Sourceofreporting Death certificate QQuueessttiioonnnnaaiirree:cDoencfliirnmeeddcboynsmeendtictoalmerdeiccoardlsrecords N___ Included in analysis 5 Yes 2 Yes 4 Yes QQuueessttiioonnnnaaiirree:: RReeppoorrtteeddaassusnescuornediafreyvteurmhoardbladdercancer 1 9 No No 23 Table 4. Demographic and exposure chBalraadctdeerristicsofbladderNcaoncer cases and non-cases. All Total N ir %N % 1577 N 1588 Vital status Alive Deceased 6 5 545 139% 884 45518 16 1400 188 Gender M F 9 2 8818 2m 13051s72 1314 274 Ageatendofstudy <30 3039 40-49 50-59 60-69 70+ 0 0 0 13 08 0 86 55 13 86 0 4 0 33 212 364 655 als 334 659 5 2 455 390 217 182 9 63 395 101 `Tobacco use" Cigarettes Missing 5 0 83 785 0 13 563 09 79% 13 Smokeless Missing 0 1 0 206 148 168 21 15 206 2 PFOS Exposure: Never 2 182 628 398 630 Low Ever 21 year 7 5 636 473 300 455 367 233 480 mn High Ever 6 S45 00 444 706 21 year 3 273 546 346 549 Low or High Ever 21 year "Excludes decedents. 9 6 818 949 602 S45 791 502 958 797 2 `cTaasbelsen5o.nM-ecaasne,smedian,andrangeofageanddays ineachexposure category for bladder cancer -_ Blaaddddeerr NNoo AANl Age Mean Median 628 553 633 553 554 554 Min 505 189 189 Max 772 86.3 86.3 Days in PFOS Exposure groups Non-exposed Mean MMeidnian Max Low Mean MMeidnian Max 4387 3357 3364 45701 11286 12015 13051 12028 13051 1371 841 845 70 00 00 7139 13030 13030 High MMeedainan Min Max 29213 0 4963 13074 0 12276 13071 0 12276 Lowor High MMeedainan Min Max 6202693 0 7139 2231706 0 13352 232716 0 13352 25 sTaatbelsein6.US.tSa.npdoaprudliazteidoInnc(iSdEeEnRc)e.Ratios by Exposure Category based on expected bladder cancer OBS Exp SIR* 95% CT Al 1 86006 128 0.64229 Men 9 8291 109 0.50-2.06 Women 2 us 6a 0.782318 Never exposed 2 3295 061 0072.19 Ever high 6 a2 1m 064-379 Ever low 7 30918 226 091-467 Ever low or high 9 sa 170 077322 High21 year 3 2688 112 023-327 High or low 1 year 6 ass 131 0.48285 W3e6i5g3hted Exposure" 3654-18263 18264-36525 236526 2 18M 107 4 420 095 3 L009 27:2 2 14030 143 012385 025243 055-73.95 0165.15 "Standardized by age, calendar year, and gender. ** Years in exposure jobs multiplied by exposure weight. Cutpoints to represent 1, 1-5, 5-10, and >10 yearsofemployment in high PFOS exposed jobs. 2% `Table 7. Expected bladder cancer cases among 495 eligible `non-respondents to questionnaire `based on bladder cancer rates in U.S. population (SEER). "All non respondents Expected Cases 1.9266 Weighted exposure category <3653 3654-18263 18264-36525 236526 0.5198 0.7959 0.2995 03114 >*1Y0eayresarison fexepomspulroeyjmoebnstmuinlthiipglhiePdFbOySeexpxopsousreedwjeoibgs.ht. Cutpoints to represen 1, 1-5, 5-10, and 27 `Table 8. Risk estimates for bladder cancer by gender, smoking history, and cumulative exposure: at the time of follow-up. _ TN Bhd CNNo oR wa Total ir 1577 Gender M F 9 180s 10 2 7 107 023490 Ever smoked" No Yes Missing 1 59 10 10 5 78 38 044326 5 196 152 1761309 eCxupmousluarteive PFOSTM NLeovweror high <Iyear High for 21 year 26 642083 1.0 39 08202 3 sa 18 03-84 `Weighted exposure Quartiles QI 2914 Q22915-8055 Q3 8036-20525 Q4220526 2 95 10 3 9413 0279 2 395 17 09-53 4 931s 03-84 Weighted exposure categories" <3653 3654-18263 18264-36525 : 236526 2 2 10 4 3 B09 12 26 02:53 04-102 2 28 14 02102 "Deceased persons were includedinthe missing category for smoking ++Adjusted for age, and gender ++ CEuxtppoosiunrtessraerperewseeingtht1,ed1-d5,ay5s-o1f0,eamnpdlo>y1m0enyeta.rsofemployment in high PFOS exposedjobs. 2 Tpaobplulea9t.ioEnstimated bladder cancer rates and rate ratios using the cohort as an internal referent Toul Cases 1 Peras7o3ny9eas 0R2a5t1e5 RR_ 95%Cl 3`W6e5ig3hted Exposure" 2 3654-18263 4 1158695585 01277 02110 10 083 0.15465 18264-36525 236526 3 2 4077 5048 07358 03962 192 152 002310-1120.9096 ree eee s--e --eeeeeet seen *Adjusted for age, and +*Cutpoints represent gender 1, 1-5, 5-10, and >10 years of employment in high PFOS exposed jobs. 2