Document KJRgE9b6y9L56qmv5xw3Xm4rX

Lo mp 265 998 AR226-1954 Bladder Cancer inPerfluorooctanesulfonyl Fluoride Manufacturing Workers Final Report 3 Iwa:l Bruce H. Alexander, PhD Division ofEnvironmental Health Sciences School of Public Health University of Minnesota g Ea. 4 November 21,2004 1 NO CBI : . mr 28s 99 Abstract A mortality studyofemployees ofa perfluorooctanesulfonyl fluoride (POSF) manufacturing facility reported a significant excess riskofdeath from bladder cancer in workers who heldjobs with exposure to high levelsof to perfluorooctanesulfonate (PFOS). To further investigate this finding a study to ascertain all cases of bladder cancer was conducted. Membersofthe original cohort were contacted by mail to inform themofthe study and invite them to complete abriefquestionnaire that ascertained any history of bladder cancer. Nonrespondents were contacted by telephone to ensure receiptofthe study material and offered the chance to complete the questionnaire by telephone. Validation of reported cancers was attempted through medical records for those cases consenting to releaseofmedical records. Death cenificates were obtained for all cohort members identified as deceased and coded for * underlying and coniributing causesof death. 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 riskofbladder cancer was compared between workers with varying degrees of exposure. `The questionnaires were returned by 1,400ofthe 1895 cohort members presumed alive during the study period, of which 1,137 were men and 263 were women. The questionnaire respondents contributed 36,982 person-yearsoffollow-up to the analysis. Onc hundred eighty-eight cohort members were identified as deceased. The overall response rate was 74%, with 77% for women and 73% for men. There were 838 respondents and 120 deceased cohort members who held jobs in high or low PFOS exposedjobs, with 624 and 82 of these holding at east one job with high exposure. A totalof eleven casesofprimary 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 SIR for ever working (N=6), and working for more than a year (n=3) in a high 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 No csi . mn 288 9%9 cumulative exposure category the relative riskofbladder cancer was 0.83, (95% C1=0.15-4.65), 1.92 (95% CI=0.30-12.06), and 1.52 (95% C1=0.21-10.99). `Overall the resultsofhis study do not confirm the high excess riskofbladder cancer 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, but the limited sizeofthe population prohibits a conclusive exposure response analysis. 3 NO CBI . mr 28s 77 Background The 3M facility in Decatur Alabama was oneof two major production sites of perfluorooctanesulfonyl fluoride (POSF, CyF17SOF) based specialty chemicals. These specialty chemicals have a wide rangeof applications, including surface treatments, paper and packaging protectants, and performance chemicals.' POSF based chemicals can degrade or be metabolized 0 perfluorooctanesulfonate (PFOS, CgF17505). PFOS is also used as a primary component of limited numberof specialty chemical applications. "The presenceofPFOS in non-occupationally exposed populations and wildlife, particularly marine mammals and piscivorous birds, has raised concerns about the environmental and health effectsof PFOS. PFOS is now recognized as a pervasive compound that wil persist in the environmeantd 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 productionof POSF-based chemicals by the major producer (3M Company). Toxicological studiesofrats and cynomolgus primates have shown that high doses of PFOS induced enlargement of liver 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 maternal dosesof PFOS increased neonatal 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 mechanismoftoxicity in laboratory animals is not fully understood, it may be due to an effect on fatty acidtransportand metabolism, membrane function, peroxisome proliferation, and/or mitochondrial bioenergetics.*!! The potential health effects of PFOS exposure have been studied in occupationally exposed populations. PFOS has not been shownto affect clinical blood and urine chemistry analyses." A study of health insurance claims filed by workers at the Decatur site 1993-1998 evaluated the relative frequencyof episodesofcare for specific conditions between employeesofthe chemical 4 No csi : mp 2esirv plant (fluorochemical exposed) and the film plant (fluorochemical nonexposed)." Workers employed in the area ofthe plant where PFOS exposure may occur had more frequent claims for biliary tract disorders and cystitis recurrence, which were included in the lst ofa priori conditions from the 424 categoriesofconditions identified. Claims for benign colon polyps, malignant colorectal tumors and malignant melanoma were also more frequent in the exposed `population. A cohort mortality studyof current and former employeesofthe 3M Decatur facility `was conducted to evaluate the healthofworkers exposed to POSF based fluorochemicals." The cohort included 2083 workers who were employed foar minimum of 1 year at the Decatur facility, and the mortality experience was ascertained through December, 31, 1998. The main 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% Cl=1.0-14.1), and the SMR for employees who held high exposurejobs was 12.8 (95% CI=2.6-37.4).However,these results were basedononly three cases. The employees who died from bladder cancer all worked for several years in high exposurejobs, howeverjobs were primarily maintenance and waste `water treatment, and not specifically related to fluorochemical production. Twoofthe cases were `maintenance workers and the third worked a majorityofhis career in the wastewater treatment plant and incinerator. Subsequent to the completionof the study an additional death from bladder cancerwas 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 Decatur facility. In response to the elevated riskofbladder cancer in the mortality study," a reviewofthe current and past useofknown or suspected bladder carcinogens at this facility was conducted. Four materials, 4.4 methylene-dianiline, orthotoluidine, benzidine salts, and butyl benzyl phthalate, were formerly used at the plant and the useofthese materials ended in 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 plant in the 1960's and 1970's. Chloroprene is considered a possible human carcinogen, however the evidence fora role in 3 NO CBI : m2 ks 77 bladder cancer is equivocal." This review indicated that the excessofmortality from bladder cancer in the high PFOS exposed sub-cohort couldnotbe clearly attributed to exposure toa known bladder carcinogen. Bladder cancer is a relatively rare malignancy that has been linked to smoking '*and several `occupational exposures. Aromatic amines encountered in the textile and other industriesare 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 di2-ethyl hexy)-pthalate, flame retardants such as thiouree, tris (2,3-dibromo propyl phosphate) and antimony trioxide."" Several other occupational exposures are inconsistently reported to be associated with bladder cancer, including, metal cutting fluids, diesel exhaust, polybromirated biphenyls, and solvents." Bladder cancer occurs more frequently in men than women. The Surveillance Epidemiology and End Results programof the 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."' Due to the large difference between incidence and mortality rates, a mortality study will not fully ascertain the burdenof bladder cancer in a population. The goal ofthe present study was to determine whether the association observed in the mortality is representativeofthe entire bladder cancer experience of the employees at the 3M Decatur facility. This was accomplished through a case finding effort using direct contact with the population. NO CBI . mp 28s 278 Methods Study Population The study site 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 lineofchemicals. The other section is the film plant, where a variety of films are produced, but little or no occupational fluorochemical exposures occur. 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 were not partofthe original cohort, those hired after January 1, 1998, were also included in the case finding exercise, but not a primary focusof the analysis as their exposure had occurred so recently that its contribution to bladder cancer is unlikely. The study required direct contact with theparticipants. A roster of all known addresses and telephone numbers were obtained through 3M persorihel or retiree records. The address information and vital status was `updated through a varietyoftracing resources sources available to the University of Minnesota, including TRW/Experian, Lortan Data, and National Changeof Address.If a cohort member was noted to have died since the `mortality study was completed acopyofthe death certificate was obtained from the state of record. Questionnaires The primary purposeofthe questionnaire was to identify casesofbladder cancer and the year of diagnosis. The questionnaire also recorded historyofsmoking; a known risk factor for bladder cancer. Although bladder cancer was the primary focusof this study, additional questions pertaining to diseases and other conditions were included. These diseases and conditions were selected based on the toxicology studies of PFOS and a study of episodesofcare 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 diagnosesof melanoma, 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 diseases ofthe prostate (men only). Abriefpregnancy outcome history `was askedofthe women. Several other questions were asked related to routine screening procedures that may be related to the diagnosis of prostate disease or colon polyps or cancer. 7 NO CBI mn res 999 Recruitment `The Universityof Minnesota Institutional Review Board approved the study protocol. Prior to recruitmentaseries of meetings were held with currentemployeesand retirees to inform them of the upcoming study and allow them to ask questions about the study. Recruitmentofall presumed living cohort members was initiated with a letter and brochure that outlined the reasons for the study, the scopeofthe study, whati 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 reminder post card was sent to all `non-respondents two weeks after the questionnaire and a second was mailedan additional two weeks after that. Ifmailings were returned with undeliverable addresses, the address information was re-entered into the search engines to identify possible alternate addresses and the maifing was re-sent. Cohort members who did not respond to the second questionnaire mailing after one month were contacted by telephone to verify receiptof the questionnaire and inquire about intent 0 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 conditions were contacted by letter, with telephone follow-up, o request permission to contact their physician to verify the diagnosis. Participants who agreed provided signed consentand medical release forms, and the name and addressof the physician or clinic of reference. Copiesofthe consent and medical release forms were senttothe. physician or clinic along with a request for pathology reports, surgical notes, or any other information pertaining to the diagnosis ofthe reported bladder cancer. Ifno 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 titles, departments, 8 No CBI " mr 2ys79Y and dates ofemployment identified in the participant's individual work histories, and potential for PFOS exposure. The relative differences in serum PFOS. by job 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 sampleof 232 employees. The geometric mean serum PFOS level (95% confidence interval) for chemical plant employees was 0.94 ppm (95% CI=0. 79-113) and for film plant employees it was 0.14 ppm (95% CI=0.11-0.16). The exposure to film plant employees is thoughtto 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 level of serum PFOS was observed in cell operators (2.0 ppm) followed by the 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 work histories 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 knowledge of the major job-specific serum PFOS levels, a company industrial hygienist and epidemiologist assigned each unique job 5 NO CBI ) magi Gv `and department combination in the work history records to oneofthe following three major exposure categories: 1. No direct workplace exposure to POSF-based fluorochemicals (encompasses film plantjobs). 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,dow exposure, and high exposurejobs relative POSE-basedjob exposure value of 1,3 and 10 respectively based on biomonitoring data. The years spent in cachjob were multiplied by the relative weights to develop a cumulative quantitative exposure meric. This exposure metric `assumes a continually increasing accumulation of PFOS exposure. However, the half-life for PFOS is prolonged, thus exposures 10 high concentrations can result in high body burdens foar 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 1 year. Analysis The estimated incidenceofbladder cancer was compared to the expected incidence based on rates derived from the Surveillance Epidemiology and End Results (SEER) at the National Cancer Institute The cohort members contributed person-time to the analysis until the diagnosis ofa bladder cancer, death, or the end of the study (December 31, 2002). All self reported casesof primary 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 NO CBI : mr vs 91 1999. Accordingly, the follow-up period for the incidence analysis began in 1970 and the referent rates for 1999were applied for the years 2000-2002. Standardized incidence ratios (SIR) `were estimated for participants by exposure group and by weighted exposure, Cut-points for the weighted exposure were selected to correspond 10 1, 5, and 10yearsof employment in high exposed jobs. `The expected numberofbladder cancer cases was also determined for the non-respondents to the questionnaire by the above weighted exposure categories. For this analysis, the time at risk was estimated from the beginningofemployment till the endofthe study, which estimated the `maximum number ofexpected cases, (based on prevailing rates). These estimates were used to evaluate potential effectsofselection bias from non-participation. Estimatesofbladder cancer risk by relative cumulative exposure using the study population as an intemal 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 differentlevels over the courseof employment. A summary analysis was conducted using logistic regression to estimate the risk of cumulative exposure at follow-up, `gender and smoking habit. The precision ofthe estimates for all analyses are described with 95% confidence intervals. n No CBI ' ma Les 59 Results Ofthe 2,083 original membersofthe cohort, 188were determined to be deceased at the time the questionnaire was sent and 1,400 responded to the questionnaire. The remaining 495 did not respond either because they declined to participate or were 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 oneyearor `more the response rates were 75.8% (S63 of 741), 81.4% (358of440) and 67.2% (480 of 714) respectively. The response rate for women was slightly higher than men and the respondents were older and less likely 10 have a historyofworking in PFOS exposed areasofthe plant (Table 1-2). Eleven bladder cancer cases were included in the analysis. Fiveofthe cases were identifid 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 sign the consent forms permitting validation. One self-reported case indicated on follow-up that the bladder cancerwas nota primary tumor, but declined to provide access to medical records; this case was not included in the analysis. An additional nine individuals marked the question pertaining to& historyof bladder cancer diagnosis as `unknown'. These respondents marked several types canceras unknown, thus it was assumed that bladder cancer was not diagnosed. Twoofthe bladder cancer cases were women and all were over 50 yearsofage at the time of diagnosis or death. (Table 4) The median ageof the bladder cancer cases was 63. (Table 5) Comparedtothe restof the questionnaire respondents, the bladder cancer cases were more likely to smoke, with 83 percent having ever smoked regularly, compared to 56 percentofthe noncases. Two (18%) of the bladder cancercases never worked in PFOS exposed areas while 9 worked at some time in a lowor high exposed job, and sixofthese worked foar year or more in these jobs. Only three bladder cancer cases worked in a high exposure job for at least one year. These three are the same cases identified in the mortality study. 12 NO CBI m.23 997 For the respondents and decedents, 8.6 cases of bladder 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% CI= 0.78-23.18), butthiswas based on only 2 cases. The women who reported bladder cancer did not work in the exposed jobs. The SIR ranged from 1.1 0 23 for the various exposure groups with the highest being the participants ever employed in low exposedjobs. The highest SIR for the exposure specific strata based on the cumulative exposure score was 2.7 (95% C1=0.55-73.95) corresponding to 5-10 yearsof employment in the higher exposed jobs. The SIR for the workers `who held a high exposure job for at least one year was 1.12 (95% C1 0.23-3.27). `There were 495 eligible cohort members who did not complete a questionnaire. Based on the 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 breakdown ofthe expected number ofcases by cumulative exposure category is also presented in Table 7. The risk of bladder cancer was similar for men and women. (Table 8) Those who had ever smoked regularly had a higher riskofbladder cancer, but fiveofthe eleven cases were identified by death certificate (smoking status coded as missing) so the overall impactofsmokingishard to characterize. There was no clear association between employment in PFOS exposed jobs and bladder cancer. Similar results were observed for the cumulative exposure estimates at the 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 ofbladder cancer. It must be noted in all ofthese. analyses that the `estimates are very unstable as there were only eleven bladder cancer cases. Fluctuations in the point estimates, particularly when the data are adjusted for other covariates, such as smoking, `gender, and age, may be artifactsofthe analysis. " NO CBI  mn ps 79 Discussion The primary objectiveofthis study was to evaluate whether the finding from the mortality study ofa twelve-fold risk ofriskofbladder cancer associated with ever working in a high PFOS exposedjob was representativeofthe overall bladder cancer experienceofthe cohort, The results of this 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 isk of bladder cancer in this analysis does not appear to be significantly influenced by employment injobs where PFOS exposure is more likely. Clearly the greatest uncertainty in these results is the 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 was reasonable for a mailed survey, it is quite possible that some bladder cancer cases were missed. An additional two cases of bladder cancer were expected in the 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 effect of underestimating the true numberofcases. 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 SIRforthe 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 SIRof2.00 (95% CI = 0.75-4.29) would result if the rateof 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 4.91 times the population rates to reach significance at the p<0.1, 0.05, and 0.01 levels. The likelihood that 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 NO CBI mR 2PSTTH substantially higher bladder cancer rates in the nonrespondent group than the reference population. The validity of the cases ascertained by the postal questionnaire is also a potential limitation of this study. Only twoofsix self-reported cases consented to release their medical records pertaining to this diagnosis to confirm this diagnosis. The reasons for declinitnog consent to the validation protocol, be they concerns for personal privacy or the validityofthe self-reported diagnosis, could not be determined. Nevertheless, the other self-reported cases were included in the analysis. Self-reportofbladder cancer has been shown to be quite valid in other populations. A recent study conducted by the Universityof Minnesota and the National Cancer Insitute using the same approach employed for the Decatur study had one-hundred percentofthe 59 bladder cancers for which medical records confirmed.*! ` A significant non-occupational cause of bladder 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 smoking and vital status in the logisti regression models did not change the overall resultsofthe analysis; however the analysis s 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 number of years they smoked, and at what age they stopped ifthey had. Overall, the lifetime prevalenceofregular smoking was 56 percent based on the questionnaire responses. The prevalenceof current smoking was 17 percent (18 percent of men and 16 percentofwomen). Data from the Centers for Discase Control and Prevention indicate that nationally 25 percent of men and 21 percentofwomen were regular smokers in 2001, but the prevalenceof current smoking was as high as 52 and 34 percent for men and women respectively in 1965. While it is possible that smoking was 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. 15 NO CBI 2 28s 39F Toxicological studies on laboratory animals have not shown effects in the urinary bladder due to exposure to PFOS and related compounds Two year feeding bioassays in rats ofNethylperfluorooctane sulfonamide alcohol (N-E(FOSE) and PFOS have not shown an increased iskofbladder tumors.'**** The former compound can metabolize to an undetermined degree 10 PFOS. Most bladder carcinogens are genotoxic and/or precipitate in the urine. POS 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 reviewed by Dr. S. Cohen ** and indicate there isnoevidence that the 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 risk ofbladder cancer that was reported in the mortality study of this population of fluorochemical manufacturing workers." However, the possibility remains foar smaller risk (approximately 1.5 to 2 fold) in the higher exposed workers. Bladder cancer is a relatively rare discase 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. 1s NO CBI PIR 25 TIF References L 3M Company. 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Cincinnati: U.S. Departmentof Health and Human Services, 1998. 31. Sigurdson AJ, Doody MM, Rao RR, Freedman DM, Alexander BH, Hauptmann M, Mohan AK, Yoshinaga , Hill DA, Tarone R, Mabuchi K, Ron E, Linet MS, Cancer Incidence in the U. S. Radiologic Technologists Health Study, 1983-1998. Cancer 2003;97:3080-3089. 32. Seacat AM, Thomford PJ, ButenhoffJL. Terminal observations in Sprague-Dawley rats after lifetime dietary exposure to potassium perfluorooctane sulfonate. Toxicologist 2002;66:185. 33. Thomford PJ, Seacat AM, ButenhoJfLf. Terminal observations in Sprague-Dawley rats afer liftime dietary exposure to N-ethy! perfluorooctanesulfonamide ethanol "Toxicologist 2002;66:185. 34. Seacat AM, Thomford PJ, J HK, W OG, T CM,L BJ. Subchronic toxicity studies on perfluorooctanesulfate potassium salt in cynomolgus monkeys. Toxicological Science 2002;68:249-264. 35. Cohen S. Letter to Dr. John Butenhoff. St. Paul, MN, 2004. 20 No CBI . mn 205978 TDeacbalteu1r. mGoernbdiedri,tyagset,uadnyd exposure characteristics ofparticipants and non-participants in the Total Gender M F Ageatendof <30 study 30-39 4049 50-59 6069 70+ Years worked <5 59 1004 I-19 20+ PFOS Exposure Group* Questionnaire Respondent Yes No N % NN % 1400 95 137 263 812 188 416 79 840 160 5 65 04 46 3 4 0s 83 204 210 144 290 604 431 207 418 32 8 251 57 84 16 170 32 a7 48 312 106 Im 67 M7 135 1179 3% 77 120 86 S847 38 77 180 364 Deceased Total N% 188 2083 177 941 1730 11 59 353 8 4316 2 12 127 40 23 4; 55 293 866 43 27 29 479 12 a7 2 33 277 66 176 248 36 138 175 18 96 17 59 314 83 Non Exposed" 562 40.1 179 362 68 362 809 Low Ever 43295 121 244 67 356 601 Slyer 320 29 78 158 52 277 450 High Ever 624 446 276 558 82 436 om Slyer 480 343 234 423 6 367 8 LoworHigh Ever 838 599 316 638 120 638 1274 yew 689 492 273 552 108 574 1070 "Categories overlap ** Non exposed includes workers from the film plant who never worked in the chemical plant. NO CBI rR es 95 `Table 2. Mean, median, and range of agesanddays in PFOS exposure. groups for participants and non-participants in the Decatur morbidity study TTooww Ageatendof study Mean Median Min Max `Questionnaire Respondent Yes a ha0 e No a4e9s aes Deceased iss Total 55.6 526 289 86.3 52.7 55.4 288 83.0 53.7 54.7 53.7 54.7 18.9 189 85.7 86.3 Years worked Mean Median Min Max 15.5 13.9 133 14.9 152 103 1.0 132 1.0 1.0 1.0 1.0 36.6 36.7 362 36.7 Days in PFOS Exposure groups Non Exposed Mean Median Min Max 3461 1248 0 13051 2818 802 0 12610 2336 1120 0 12637 3234 1053 0 13051 Min 0 Low Mean 833 454 938 774 Median 0 0 0 0 Max 13030 11867 10428 13030 High Mean Median Min Max 1383 172 0 12276 1702 0 0 12302 1279 0 0 10804 1450 0 0 12302 High or low Mean 2216 2246 218 223 Median 77) 552 553 409 Min Max 0 13352 0 0 0 12302 13211 13352 *Never exposed includes workers from the film plant who never worked in the chemical plant. NO CBI Lin es 97F `Table 3. Summaryofbladder cancer cases by sourceofreporting and confirmation status Source of reporting Death certificate Questionnaire confirmed by medical records Questionnaire: Declined consent to medical records N___ Included in analysis 5 Yes 2 Yes 4 Yes Questionnaire: Reported as secondary tumor 1 Questionnaire: Reported as unsureifever had bladder cancer __9 No No 23 No CBI . pon 28597 E Table 4. Demographic and exposure characteristicsof bladder cancer cases and non-cases. Bladder No All Total N %N% N m 1577 T588 Vital status Alive Deceased 6 545 1394 884 1400 5 455183 116 138 Gender M F 9 2 818 1305 828 182 2m 172 1314 2m Ageatendofstudy <30 3039 40-49 50-59 60-69 70+ 0 0 13 08 13 0 0 0 86 55 86 0 34 212 334 4 364 655 als 659 5 ass 30 217 395 2 182 9 63 1014 "Tobacco use" MCiigsasrientgtes. 05 8303 71835 50693" 71930 Smokeless 0 Missing 1 0 2206 148 168 21 Ls 206 2 PFOS Exposure Never 2 182 628 398 630 Low Ever 21 year 7 636 413 300 430 5 455 367 23 372 High Ever 21 year 6 545 700 44s 706 3 273 s46 346 549 Low or High Ever 21 year "Excludes decedents. 9 818 949 602 958 6 S45 791 502 797 2 No CBI | mR 28TITE Table cases 5. Mean, median,and non-cases. range ofage and days in each exposure category for bladder cancer Bladder No All Age Mean Median Min Max Days in PFOS Non-exposed Exposure groups Mean Median Min Max 6238 553 554 633 553 554 505 189 189 72 863 863 4387 3357 3364 4571 1215 1228 0 11286 130051 130051 Low Mean Median 1371 7 841 0 84s 0 ` MMainx 0 0 0 7139 13030 13030 High Mean Median 923 21 13074 13071 Min Max 0 0 0 4963 12276 12276 Lowor High Mean Median Min Max 2203 216 216 606 370 37 0 0 0 7139 13352 13352 25 NO CBI . 2s 978 `Tabl6e. Standardized Incidence Ratios by Exposure Category based on expected bladder cancer rates in U.S. population (SEER) OBS Exp SIR* 95% C1 All n 8.6006 1.28 0.64229 Men 9 8.2891 1.09 0.50-2.06 `Women 2 03115 6.42 0.78-23.18 Never exposed 2 3.2995 0.61 0.07-2.19 Ever high 6 3.4421 1.74 0.64-3.79 Ever low Ever low or high 7 3.0918 226 9 5.3011 1.70 091-4.67 0.77322 4 High >1 year 3 2.6838 112 023-327 Highor low 21 year `Weighted Exposure"* 3653 3654-18263 18264-36525 236526 6 4.5835 131 2 1.8747 1.07 4 4.2209 095 3 1.1019 2712 2 1.4030 1.43 0.48-2.85 0.12-3.85 025-243 0.55-73.95 0.16-5.15 *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 years ofemployment in high PFOSexposed jobs. 26 NO CBI ) . mn ert 5 IF Table 7. Expected bladder cancer cases among 495 eligible non-respondents toquestionnaire 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 * Years in exposure jobs multiplied by exposure >10 yearsofemployment in high PFOS exposed weight. jobs. Cutpoints to represent 1, 1-5, 5-10, and 2 NO CBI : mr 20s 77 `atTatbhlee t8.imReiosfkfeosltliomwa-tueps.for bladder cancer by gender, smoking history, and cumulative exposure Bladder No Tol -- N N OR 95% C1 1 1577 Gender M F 9 2 1305 10 m7 02349 Ever smoked" No Yes Missing 1 5 596 785 10 38 10 044326 5 196 152 176-1309 Cumulative exposure PFOSTM Never Lowor high <Iyear Highfor 1 year 2 6 628 1.0 403 39 + 08202 3 S46 18 03-84 Q`uWaeritgihlteesd exposure "** QI 2914 Q22915-8055 Q3 8056-20525 Q4220526 2 95 10 3 9413 0279 2 95 17 09-53 4 39315 03-84 `Weighted exposure categories" 3653 3634-18263 18264-36525 236526 2 2 10 4 7709 0253 3 12 26 04-102 2 268 14 02-102 *"DAedcjeuassteeddpfeorrsaognes,waenrdegienncdleurded in the missing category for smoking + Exposures are weighted daysof employment. + Cutpoints represent 1, 1-5, 5-10, and >10 years of employment in high PFOS exposed jobs. = No CBI . mR 2PSTIF `Table 9. Estimated population. bladder cancer rates and rate ratios using the cohort as an internal referent Total Cases 0 Person years 3739 Rate 02515 RR 95% CL <W3e6i5g3hted Exposure" 2 15658 01277 10 3654-18263 18264-36525 4 3 18955 4077 02110 083 0.15465 07358 192 030-1206 236526 2 5048 03962 152 021-1099 ***ACdujtupsotiendtfsorreapgree,seanntd gender 1, 1-5, 5-10, and >10 yearsof employment in high PFOS exposed jobs. 2 NO CBI