Document 2REJVQVN4eMRbM4kRmNqn07Xr

Final Report Mortality of Employees of an Ammonium Perfluorooctanoate Production Facility JessicaI. Lundin, MPH Bruce H Alexander, PhD Associate Professor Principal Investigator Division of Environmental Health Sciences Universityof Minnesota, School of Public Health August 22,2007 Executive Summary Background: This report presents the results ofacohort mortality study ofworkers employed at the 3M Ammonium Perfluorooctanoate (APFO) production facility in Cottage Grove Minnesota. The purposeofthis study was to examine possible associations between working in jobs with varying exposure to APFO and specific causes of death Methods: The study population included all employeesofthe Cottage Grove facility with a `minimumof 365 daysof cumulative employment prior to 1997. The population was followed from the time they entered the workforce through 2002. Underlying and contributing causes of death were obtained from the National Death Index and death certificates. Work history records were used to determine potential APFO exposure. Each job held was assigned to oneof three exposure categories; non-exposed, probable APFO exposure, and definite APFO exposure. Exposure categories were initially established based on duration of employment in cachof these jobs. The cohort members were classified as ever or never having a job with probable exposure, probable or definite exposure or foar minimum period of time in thesejob categories. To estimate cumulative exposure a weighted cumulative exposure model was constructed by multiplying the durationofemployment by an exposure weight of 1 for non exposed, 30 for probable exposure and 100for definite exposure. The weights, though somewhat arbitrary, reflect differences in biological monitoring of the jobs and consider the long half-life ofthe chemical. The cumulative exposures were then categorized as estimates equivalent to less than one, one to five and more than five yearsof employment in high exposurejobs. 2 `Standardized mortality ratios (SMR) were estimated for all cause and cause specific mortality using mortality rates from the general populationof Minnesota as a reference. SMR estimates were made for the sub-cohorts ever exposed to APFO, by exposure category, and for a minimum of one yearofexposure. Time dependent Cox regression models were used to estimate the riskofspecific causesof death using an intemal referent population. Risks were estimated for working in a definite exposure job for a minimum of6months (high exposure) and ever in a job with probable exposure or ajob with definite exposure for less than 6 months (moderate exposure) in comparison to those who never held ajob with definite or probable exposure (low exposure). A similar time dependent analysis for cumulative exposure used weighted estimates equivalentto less than one, one to five. and more than five years in ajob with definite exposure. All models were adjusted for sex, birth year, yearofeligibility, wage type (salary, hourly or both), and an estimate of smoking habit. Causesof death ofa priori interest were liver, pancreatic and testicular cancer and cirthosis of the liver based on animal toxicological data, and prostate cancer and cerebrovascular disease from prior analyses of this cohort. Results: There were 3993 eligible workers, and 807 deaths, in the cohort. The SMR forall causes of death was 0.8 (95% C10.7-0.9) and 0.9 (95% CI=0.8-1.0) for malignant causes of death. No malignant or non-malignant causesofdeath had significantly elevated for any exposure classification, however the members of the non-exposed cohort had significantly reduced mortality due to prostate cancer (SMR=0.4, 95% C1=0.1-0.9), cerebrovascular disease (SMR=0.5, 95% C1=03-0.8), and ischemic heart disease (SMR=0.7, 95% CI=03-0.8). The 3 membersofthe cohort with definite exposure did have lower than expected rateofdeath from ischemic heart disease, but not prostate cancer (SMR=2.1, 95% CI=0.4-6.1), or cerebrovascular disease (SMR=1.6, 95% C1=0.5-3.7) "The time dependent analysis using the intemal referent population produced hazard ratios indicating an association with APFO exposure and prostate cancer and cerebrovascular disease. Those with high or moderate exposure had an elevated risk of dying from cerebrovascular disease (HR=5.1, 95% CI = 1.4-18.6 and HR=2.1, 95% CI = 1.04.6, respectively) and prostate cancer (HR=7.0, 95% CI = 1.2-42.2 and HR=3.0, 95% CI = 0.8-11.0, respectively). The highest cumulative exposure score was associated with an elevated riskof dying from cerebrovascular disease (HR=2.4, 95% CI=1.1-5.5) and prostate cancer (HR=3.8, 95% CI=1.2-13.2). When stratified by wage type similar associations were observed for prostate cancer and cerebrovascular disease. Lagging exposures by 10 years made little or no difference in the hazard ratio estimates. Conclusion: APFO exposed workers did not have an clevated riskofdeath when compared to the populationofthe stateofMinnesota, however within the cohort risk of death from prostate cancer and cerebrovascular disease was elevated for workers with higher estimated exposure. Interpreting the somewhat contradictory results requires caution and considerationofseveral assumptions. A priori causesof death selected based on animal toxicology studies, liver, pancreatic and testicular cancer and cirrhosisofthe liver, were not observed to be associated with APFO exposure. 4 Introduction Ammonium Perfluorooctanoate (APFO, CFs(CF2),COy NH:") is a thermally stable synthetic surfactant which is resistant to a large varietyofchemicals, and resistant to degradation. These unique properties ledto its use in industrial applications, as well as ist use as an ingredient in consumer products such as non-stick coatings for cookware, clothing, automotive products, and paper coatings (sandwich wrappers, popeom bags, etc) for oil and moisture resistance (1). In the presenceof biologic media, APFO dissociates into perfluorooctanoic acid (PFOA, CF5(CF2);COOH;), an anion of APFO. APFO was produced at the 3M facility in Cottage Grove, Minnesota from 1947 until the year 2000. Laboratory studies have shown PFOA to be absorbed through inhalation, ingestion, and dermal contact and is distributed in the liver and in the blood with notable gender differences varying by species (2). PFOA is metabolically inert; it is not biotransformed or conjugated and is climinated primarily through urine and feces (2) Biological monitoring data indicate that occupational exposures to APFO in `manufacturing workers result in median serum PFOA levels in the range of 0.3 to 5.2 parts per `million (ppm), depending on the work area (3). The general population has been shown to have average sera PFOA concentrations of parts per billion (ppb) (4, 5). A comparisonsofbanked Serum from community base samples showed an increase in serum concentrations between 1974 and 1989, but no significant change between 1989 and 2001(6). Preliminary data suggest that the `population exposure has decreased following the phase out of the productionofthese materials . PFOA is a peroxisome proliferator with demonstrated effects in laboratory animals. Animal studies have shown effects on the liver, atrophyof lymphoid tissues (spleen and lymph nodes), benign hepatocellular tumors, , pancreatic acinar cell tumors, and testicular leydig cell 5 tumors (2) A previous mortality study of this cohort have shown an association with working in the chemical divisionof the APFO manufacturing facility and dying from prostate cancer(8), and a updated analysis identified a potential association with high APFO exposure and death from cerebrovascular disease (9). The purposeofthis study with an updated mortality follow-up was to further evaluate potential associations between occupational APFO exposure and specific. causesof death in this cohort. 6 Methods StudyPopulation The protocol for this study was reviewed and approved by the University of Minnesota Institutional Review Board. This occupational cohort of workers at the APFO production plant in Cottage Grove, Minnesota included all workers with one year (365 days) of cumulative employment between the dates of January 1, 1943 and December 31,1997. Cohort members meeting eligibility criteria were followed until either December 31, 2002 or their dateofdeath. The human resource recordsofall eligible employees were abstracted for demographic information, including the worker's name, social security number, employee identification number, date of birth, and details ofwork history. The latter included job specific start and end dates, department codes, and job classifications. Demographic information and vital status was Verified using TRW/Experian (a credit reporting agency) and the Social Security Administration service for epidemiologic research studies. Determination of Vital Status Vital record searches were performed for all cohort members not employed by the company on December 31, 2002 and who had not been identified as deceased in previous studies (8,9). Vital statusof these cohort members was determined through the National Death Index (NDI). All potential matches from the NDI search were reviewed by hand to ensurea valid match. The underlying and contributing causeofdeath was obtained from NDI Plus for deaths after 1979. Death certificates were obtained for decedents who died prior to 1979 and were: coded by a certified nosologist for causesofdeath in the Intemational ClassificationofDisease (ICD) revision in effect at the timeofdeath. Ifa death certificate could not be found for an NDI " identified decedent, the individual causeof death was classified in the `other" cause of death category. ExposureAssessment The goal of this study was to describe mortality experience in relation to fluorachemical `exposure with particular interest in PFOA. Some biological monitoring data are available for more recent years, however they are insufficient to fully characterize exposure to workers over the lifeofthe plant. Therefore, the exposure assessment relied on work history records and expert knowledge of the history of the APFO manufacturing process to first develop a qualitative exposure assessment for each job held by the cohort members. All perfluorochemical development and production occurred in departments affiliated with the chemical division of the plant. The specific areas where APFO and other perfluorochemicals were produced changed over the years, as did the work area department codes, thus exposure levels could not be assigned to workers based on work history alone. To remedy this, the department codes were. reviewed by year to determine the building and division assigned to each code. The resulting lists were reviewed independently by a panelofveteran workers and plant industrial hygienists to determine where the perfluorochemical production, or the developmentofthe perfluorochemical products, took place over the history of the facility. The individual responses were summarized and the panel met as a group to discuss any discrepancies and confirm the exposure assignments. The available information permitted the panel to classify the jobs in the work histories into three general classificationsof exposure. Definite occupational APFO exposure: These jobs were in arcas where electrochemical Auorination, drying, shipping, and packaging of APFO occurred and the worker would be 8 exposed to APFO on a regular basis. These jobs also had the potential for higher exposures. Probable occupational APFO exposure: Thesejobs were in other chemical division areas where exposure to APFO was possible, but the exposures were considered lower or transient. Noor minimal occupational APFO exposure: These jobs were primarily in the nonchemical division of the plant. These workers may have had the opportunity for some exposureifthey passed through an exposed area, but were not exposed specifically as part of theirjob. They likely had higher exposures than the general population due to contamination at the work site. Hereafter thes job exposure subgroups will be referred to as definite APFO exposure, probable APFO exposure, and non-exposed. ExposureClassification for Analysis The employeesofthis plant changed job classifications frequently, thus they could not be Classified into discrete, mutually exclusive exposure groups that mirrored the job exposure subgroups. To accommodate the migration between exposure subgroups we incorporated two approaches for characterizing APFO exposure in the analysis. The primary analysis is based on ever attaining a minimum tenure in jobs with probable or definite exposure. A secondary analysis used a cumulative exposure model developed to explore a weighted exposure distribution based on durationofemployment and an assumed exposure intensity. Exposure by Job Classification. The initial analyses explored the mortality experience of workers compared to thatofthe general population of Minnesota with respect to their entire: 9 work historyof ever working in jobs with definite or probable exposure, a minimumof one year in definite or probable exposurejobs, or only working in the non-exposed jobs. Subsequently a more restrictive classification was developed for an analysis using an internal referent population which classified the cohort members as; 1)those working only in jobs not exposed to fluorochemicals (low exposure), 2) ever working in a probable APFO exposure job or working a definite APFO exposurejob for less than 6 months (moderate exposure), or 3) employment in a definite exposurejob fo6r months or more (high exposure). Entry into the latter two categories could oceur at varying points in the individual's work history. This model assumes that once a person is employed in a high exposurejob fora minimum periodoftime or moderate exposure job they reach a threshold where thei risk is different from individuals working in jobs without direct occupational APFO exposure Cumulative Exposure. A model estimating cumulative APFO exposure requires that both time and intensity be considered. Biological monitoring data indicate a demarcationof exposure by job. Employees in the type ofjobs classified with definite exposure had median serum PFOA levels ranging from 2.6-5.2 ppm, while employees in jobs classified with probable exposure had levels ranging from 0.3-1.5 ppm (3). The biological half-life of PFOA is believed to be 3.8 years (10), thus short-term peak expostres may equate to longer term lower exposures over time. Considering these facts, the initial cumulative exposure assigned exposure weights of 1, 30, and 100 to the time in jobs with no exposure, probable exposure, and definite exposure. These unitless weighting factors, while somewhat arbiteary, were chosen to reflec the relative exposure intensity ofjobs and long biological half-life of PFOA. For each worker the weighted exposure level was multiplied by the total days ofemployment at each level (weighted exposure level*days exposed), which provides a time-dependent exposure metric. The cumulative 10 exposure was categorized at levels representing the equivalentofup to one year (36,499 exposure-days), oneto five years (36,500-182-499 exposure-days) and five or more years (182,500 exposure-days) of employment in ajob with definite exposure. Because these weights are arbitrary we conducted a sensitivity analysis to explore how altemative weighting schemes may affect the results. The altemate weighting schemes were 1,10, 50 and 1, 10, 100, which would minimize migrationof workers in jobs with probable exposure being classified with the higher exposed individuals. DetermoifSnmoakitngiStoatnus `Smoking was apotentially confounding variable for some diseases of interest. To characterize the smoking habitofthe cohort, the occupational medical recordsofthe cohort `members were abstracted for information on smoking status; ever smoked regularly, year started smoking, years they smoked, and cigarettes smoked per day. Cohort members were classified by the smoking history and the availabilityof the records; smoking history available, medical record available but no information about smoking, and medical record not available. Determinationof Salary versus Hourly Wage Type Bascline socio-economic status is a likely determinantof morality from several discascs. As a proxy measureofsocio-economic status, the cohort members were classified by wage type based on the work history records. Workers were classified as hourly, salary, or both. The latter was designatedifthe job history included eaming each typeofwage for at least 365 days. A dichotomous versionofthis covariate was also established in which workers with both hourly and salary experience were classified as hourly or salary based on the predominant wage type. un A priori causes of deathofinterest were selected from toxicological literature and prior studiesof workers exposed to fluorochemicals. Cancerofthe liver, pancreas, and tesicles and cirrhosisofthe liver were selected based on results from toxicological studies (2). Deaths from prostate cancer and cerebrovascular disease (CVD) were previously reported to be associated with potential lurorochemical exposure in this cohort (8,9, 11) and bladder cancer was associated with fluorocheical perflurooctanesulfonate (PFOS) exposure in another occupational cohort (11). Ischemic heart disease was included as an a priori diseaseof interest due fo the effect of PFOA on lipid metabolism. ICD 9" revision codes used to classify the underlying causesof death: prostate cancer, 185; pancreatic cancer, 157; liver cancer, 155; bladder cancer, 188, 189.3-189.9; CVD, 430-435; ischemic heart discase, 410-414; and cirrhosisofthe liver, 571. Congenital cerebral aneurysm (ICD9 747.81) were not identified in this cohort. Analysis The mortality experience of the cohort was initially compared to the mortality rates for the corresponding populationof the state of Minnesota. Reference data were obtained from the Mortality Population Data System (PDS) center at the University of Pittsburgh, which were. derived from National Center for Health Statistics data. The all-cause mortality and malignant neoplasm rates were available from 1940, and the non-malignant cause-specific death rates from 1962. The referent data were available in age (5 year), sex, race, and calendar period (5 year) and were coded using the rules fo the ICD revision in effect for the relevant calendar period. "The Standardized Mortality Ratios (SMR) and 95% confidence intervals were computed using the PC Life Table Analysis System (PCLTAS) software developed by the National Insitute of Occupational Safety and Health (NIOSH) (12). State specif referent data wereonlyavailable 2 through 1999 50 the referent rates for 1999 were applied for the years 2000-2002. The all-cause and cause-specific SMRs were first computed for the full cohort. SMR were then computed separately for the cohort member ever employed in a job with definite APFO exposure, those who worked jobs with definite or probable exposure for at least one year, and for the cohort `members who worked primarily in the non-chemical division. SMRs were also computed for workers by hourly and salary wage type. For this analysis, workers with both hourly and salary jobs were classified by the predominant wage type. To model the risk of the cause-specific mortalitiesofinterest as a functionof PFOA exposure using an internal referent population, hazard ratios and 95% confidence intervals were estimated using in multivariable time-dependent Cox regression models (13). Exposure was characterized byjob classification and then cumulative exposure. The time variable was the numberof days from the first dayof employment at the production facility to an event (death) or the endof the study. In the cause-specific mortality models, all other causesofdeath were: censored at the timeof death. The models were adjusted for sex, age eligibletobe in the study, year ofbirth, and wage type. To explore potential effects of latency the exposure models were. Tagged by 10 years prior to endofstudy or the dateof death. The Cox regression analysis was conducted using SAS 9.1(14) `Smoking is an important potential confounding variable in this study, but smoking habit data were unavailable for maonftyhe cohort members. An initial Cox regression model was fit with smoking coded as ever smoked, never smoked, no information about smoking on medical record, and no medical record available. Ina second approach a multiple imputation model was constructed using individuals with smoking data to predict the smoking statusof those without 3 smoking data (15). The predictors used for the imputation process were sex, yearofbirth, year of first employment at the facility, age eligible to be in the study, and wage type. Eighteen independent, completed data sets were generated and a Cox regression procedure, as described above, was performed on each data set. The results were pooledto give single parameter estimates and 95% confidence intervals. The hazard ratios from the final models are presented to describe the potential efoffceonfcoutndisng by smoking. All imputation procedures were conducted using SAS 9.1(14). 14 Results Ofthe 6678 individual workers identified at the facility, 3993 employees met the inclusion criteria. Of these, 513 workers (12.8%) were ever employed in a job with definite PFOA exposure, 1688 workers (42.3%) were ever employed in ajob with probable exposure: (and never worked ajob with definite exposure), and 1792 workers (44.9%) were employed in jobs where they were never exposed to fluorochemicals (Table 1). The majorityofthe study cohort was male (80%), particularly for the definite exposure subgroup (92%). The average age at the endoffollow-up was slightly younger in the definite exposure subgroup, but the average. number of years of employment was longer. The total numberofdeaths in the cohort was 807, with 68 deaths in the definite, 368 in the probable, and 371 in the non-exposed exposure: subgroups. `Smoking data was found for 1430 (36%) cohort members,of these, 783 (55%) were found to have ever smoked (Table 2). There was a higher prevalenceofsmoking in those who ever worked ajob with definite APFO exposure compared to the non-exposed workers, 65% and 47% respectively. However, smoking data was available for 66%of the definite exposure subgroup (338/513), whereas it was only available for a 20%ofthe non-exposed subgroup (3551792) The all-cause and cause-specific mortality ratios for the entire cohort, and exposure subgroups, were generally lower than expected compared to the Minnesota referent population (Table 3-6). The all-cause standardized mortality ratio (SMR) for the entire cohort was 0.8 (95% C1=0.7-0.9) (Table 3). The results were similar for all deaths from cancer (SMR =0.9, 95% CI = 0.8-1.0). The cause-specific mortalityratios for one or more yearsofdefinite or probable PFOA exposure were lower than expected for cerebrovascular disease (SMR=0.8, 95% CI=0.51.3) and ischemic heart disease (SMR=0.7, 95% CI=0.6-0.9). The SMR for prostate cancer 1s (SMR = 1.4, 95% C1 = 0.7-2.4), pancreatic cancer (SMR = 1.2, 95% CI = 0.5-2.4), bladder cancer (SMR = 1.3, 95% C1 = 0.3-3.9), and diabetes mellitus (SMR=1.7, 95% C1 = 09-28) were modestly, albeit imprecisely, above unity (Table 4). The cause-specific mortality ratios for cohort members ever employed in jobs with definite PFOA exposure were greater than expected for prostate cancer (SMR = 2.1, 95% CI = 0.4-6.1) and cerebrovascular disease (SMR = 1.6, 95% C1 = 0.5-3.7), although the confidence intervals are quite wide and include the null (Table 5). Similar pattems are present when the analysis is restricted to one yearofdefinite exposure (Table 6) though the numobfdeeatrhs is small. The cause specific SMRs for all definite exposure strata all have confidence intervals indicating these elevations are not beyond chance. Cohort members who worked in jobs with probable exposure, but never held a job with definite exposure had an elevated riskofdeath from diabetes mellitus (SMR=2.0, 95% CI =1.2-3.2), but low riskof death from ischemic heart disease (SMR=0.8, 95% C1=0.7-1.0) and cerebrovascular disease (SMR=0.7, 95% C1=0.4-1.1) (Table 7). In contrast, the numberofdeaths from prostate cancer and cerebrovascular disease were significantly lower among the never exposed members ofthe cohort; 0.4 (95% C1 0.1-0.9) and SMR 0.5 (95% C1 0.3-0 8)respectively (Table ). No deaths from testicular cancer were observed and only 3 cases of liver cancer (SMR=0.5, 95% CI=0.1-1.4),ofwhich twoheld jobs with probable exposure. These small numbers precluded further analysis for these causesofdeath. Thirteen deaths from cirrhosis of the liver were identified (SMIR= 0.7, 95% CI=0.4-1.2) with only 4 occurring in workers with at least one year of definite or probable exposure (SMR=0.5, 95% C1-0.2-1.4). 16 The SMR for salaried workers showed a decreased riskofdeath for all cancers (SMR 0.7,95% C1 0.6-0.8), respiratory cancers (SMR 0.6, 95% CI 0.4-0.9), prostate cancer (SMR=0.5, 95% C110.2-1.2), diabetes (SMR= 0.2, 95% CI = 0.02-0.74,), cerebrovascular discasc (SMR=0.6, 95% C1=0.4-1.0) and heart disease (SMR=0.6, 95% C1=0,5-0.7) (Table 9). The results were somewhat different for hourly employees; all cancers (SMR 1.0, 95% C10.9-1.2), respiratory cancers (SMR 1.2, 95% C10.9-1.6), prostate cancer (SMR=0.9, 95% C1 0.4-1.6), cerebrovascular disease (SMR=0.7, 95% CI=0.4-1.0) and heart disease (SMR=0.9, 95% CI=0.8, 1.1) (Table 10). The SMRfordiabetes (2.1, 95% CI = 1.3-3.1) was elevated for the hourly workers. Comparing the mortality experience within the cohort in the time-dependent Cox regression models revealed differences for someof the outcomes of interest. A high or moderate. exposure work history, compared to only working in low exposurejobs, was associated with an increased risk for cerebrovdaisscacseular (HR=5.3, 95% CI= 1.5- 19.6 and HR=2.1, 95% CI = 1.0-4.5, respectively) and prostate cancer (HR=6.9, 95% CI = 1.2-41.8 and HR=3.0, 95% Cl = 0.8-11.0, respectively) (Table 11). A moderate exposure work history was also associated, imprecisely, with an elevated riskofdying from diabetes mellitus; HR=1.9, 95% CI =0.7-5.4, however no deaths from diabetes were reported in cohort members in the high exposure category. Diabetes mellitus was included in these analyses becauseof modestly elevated SMR; specifically in the hourly workers. The inclusion of the imputed values for smoking status derived from the multiple imputation procedure, nor the inclusionofthe actual smoking data, made litle or no difference in the risks estimates (Table 11). The results for prostate cancer, cerebrovascular disease, ischemic heart disease and diabetes were further explored by stratifying by wage type (Table 12). These analyses suffered from small numbers for prostate cancer, 7 cerebrovascular disease, and diabetes. The risk associated with the high exposure category. persisted for cerebrovascular disease. The high exposure prostate cancer deaths were salary workers while mostofthe moderate exposure prostate cancers were hourly employees. Overall, there was not strong evidence that the effects in the models adjusted for wage type were limited to cither hourly or salary workers. Lagging exposures by 10 years also made litle or no difference in the hazard ratio estimates (Table 13). Estimated hazard ratios (HR) comparing the highest to lowest weighted exposure category for cerebrovascular disease and prostate cancer were HR=2.4, 95% CI= 1.1-5.4 and HR=3.6,95% C1 = 1.2-10.6, respectively (Table 14). There was no association between the metrics of weighted exposure and riskof pancreatic or bladder cancer, cirehosisof the liver, disease and diabetes. The risk ofdying from ischemic heart disease was, ifanything, lower among those with increased exposure. As with the results for exposure byjob classification, there was litle evidence that the risks were different between hourly and salary workers (Table 15). The sensitivity analysis using altemate weighting schemes did not change the overall conclusions the analysisofcumulative exposure (Table 16). 13 Discussion "This study evaluated the mortality experience ofa population of workers at an ammonium perfluorooctanoate production facility, with specific attention to exposure to PFOA. No excess mortality was observed for malignant or non-malignant causesofdeath when compared to the corresponding Minnesota mortality rates. The SMRs for prostate cancer and cerebrovasculardisease were slightly elevated for those with a history of working in jobs with definite PFOA exposure, while the SMRs for the members of the cohort never working in a PFOA exposed job were significantly below unity. Analyses using an intemal referent category found increased riskof death from prostate cancer and cerebrovascular disease among workers with a history ofgreater PFOA exposure when compared to those working in jobs with no or minimal exposure. A priori causesofdeath selected based on animal toxicology studies, fiver, pancreatic and testicular cancer and cirthosis of the liver, were not observed to be associated with PFOA exposure. Interpreting these somewhat contradictory results requires caution and considerationof several assumptions. Some elementsof the study design for this study differs from the earlier mortality analysesofths cohort (8, 9). Gilliland and Mandel (8) required six monthsof cumulative employment for inclusion, while the current study required oneyearof employment to exclude short-term workers, often summer interns, who might have different underlying risk factors than the long-term workers. In that analysis, job exposures were assigned as working for a least one month in the chemical division compared to working in the non-chemical division (or chemical division for less than one month). To minimize exposure misclassification the current study focused on PFOA and classified jobs in the chemical division as definite or probable, as only certain areas and tasks within the chemical division likely led to high APFO exposure. Lastly, 19 169 additional cohort members were included in the current study that, according to available employment data, were eligible for both studies. This study also differs from the more recent `mortality analysis of this cohort (9). The population for the current study was followed through 2002, four years longer than the previous study, increasing the numberof deaths from 607 to 807, and included analyses using an intemal referent group. `The association between prostate cancer and work in a APFO exposed job is similar to the resultsofGilliland and Mandel (8) who reported a 3.3-fold increase (95% CI = 1.0-10.6) in prostate cancer mortality associated with working ten years in the chemical division compared to non-chemical division workers; based on 6 cases. In the current study an association was observed between both metrics of PFOA exposure and prostate cancer when compared to the internal referent category. The biological mechanism for an association between PFOA and prostate cancer is not clear. An effect of PFOA on the endocrine system has been described in the rat which involves regulationofestradiol, testosterone, follicle stimulating hormone, luteinizing hormone and thyroid stimulating hormone through action in the liver (16-18). In this occupationally exposed population PFOA exposure was not clearly associated with changes in circulating levelsof reproductive hormones (19), but this cross-sectional assessment was based on single blood samples. The association between APFO exposure and prostate cancer andcerebrovasculardiscasc was most apparent when the intemal referent population was used. An internal referent population from within a cohort may provide a more valid comparison,assuming similar social and demographic characteristics; however the interpretationofthese results should also consider how the strata specific prostate cancer deaths compare to the expected deaths based on 20 Minnesota general population. The SMR for the exposed categories were only modestly above unity, while the non-exposed membersofthe cohort were significantly below. The latter suggests that 3M employees who are not regularly exposed to APFO at work are different from other men in Minnesota with respect to baseline prostate cancer risk; some ofwhich may be related to socioeconomic status (SES). The extent to which this difference may have influenced the internal analysis is unknown. Our analyses adjusted for wage status as a proxy for Socioeconomic status, which may influence several factors associated with prostate cancer death, "The proportional hazards analysis stratified by wage type revealed similar patterns of risk with exposure in the hourly and salary workers, though the numbers were very small. Deaths from heart disease and cerebrovascular disease are almost always below unity in epidemiologic studiesof chemical workers (20) , for this reason the increased risk of cerebrovascular disease death associated with higher exposurewas unexpected. It is possible that the codingof cerebrovascular disease deaths vary by region, however using mortality from local counties rather than the state made no differences in the earlier analysis (9). The risk of stroke is related to hypertension, diabetes, and life style factors including diet and smoking (2123). The SMRs for diabetes mellitus and hypertension in the non-exposed subgroup were 0.52 and 0.98, respectively and 1.73 and 1.84, respectively, in the exposed subgroup. The SMR for lung cancer, a potential indicator of smoking in the cohort was 1.01 in the exposed compared to 0.76 in the non-exposed sub-cohort. Though not directly comparable, these pattems may be related to the cerbreovascular discase finding in that the lifestyle characteristicsof the cohort members with high PFOA exposure were different than the lower exposed persons. Nevertheless, adjusting for smoking habit and wage type did not alter the association, and similar to prostate cancer, the analysis stratified by wage type indicated higherriskof death from cerebral vascular 2 discase associated with exposure in both hourly and salary workers. Diet is a potential factor in the riskofstroke, though it was not measured in this study. In the same working population, however, body mass index (BMI)of almost 50%of the workers ranged from 25-30 (24) , which is considered overweight (25). However, it has also been shown that worker BMIs were similar among varying serum PFOAlevels (26). Any findings in a mortality study related to diabetes should be interpreted with caution as the useofmortality data to evaluate diabetes risk is problematic. Tn a studyof2,766 decedent with a known historyofdiabetes it was shown that diabetes was recorded as the underlying cause of death on approximately 10% of the death certificates, and those recorded were related by age, durationofdiabetes, and co-morbidities (27). The excess in the hourly workers could indicate lifestyle differences, but future research would require a more comprehensive assessment of diabetes morbidity to fully describe any potential relationship with PFOA exposure. `When interpreting this mortality analysis several limitations should be considered. Some exposure misclassification is likely. For example, maintenance and other mobile workers that routinely entered the definite PFOA exposure departments and work arcas, but may have not been classified in the definite exposure subgroup. On the other hand,a few workers assigned to the definite exposure subgroup may not have spent much time in those departments or work areas. The extentof exposure misclassification and the effects on the study results remains unknown, as no additional data are available to verify these assumptions. Although several methodsofapproach were used to find all deaths in this cohort, it is possible that some deaths were not accounted for, which can occur when an individual leaves the country, changes their identity, or due to errors in surveillance systems. Race data were not available for the cohort. n The impact of this is likely to be limited as the populationofMinnesota has been predominately Caucasian over the decades (97% in the 1980 census, 94% in the 1990 census, and 89% in the 2000 census) (28). The analysis was able to account for potential confounding by age, sex, wage Status, and, to some extent, smoking habit. Unfortunately the smoking data were sparse, and though sophisticated methods to impute the missing data were applied, it is debatable whether the assumptions pertainitnog this imputation were upheld. Another noteworthy limitation is the power of the study. The mean age at follow-up was 60 years, thus the relatively small number of deaths from the causes of interest limits the abilityof the study to examine exposure responses, particularly using an intemal reference category. By definition, mortality studies, although cost effective and convenient, miss the cases that do not result in death. Prostate cancer and cerebrovascular disease, the two findings of potential importance, do not always result in death and may not be listed as contributing causes ofdeath on a death certificate unless they had recently been diagnosed or the person was undergoing treatment. While the mortality study does capture the worse case scenario for the diagnosisof these conditions, death from these conditions may be associated with other factors, including access to health care and availability of screening. The potential contributionof these factors are difficult to quantify, however all membersof the cohort were, at least for 1 year, employed by 3M, and would have had access to similar health benefit. There are also notable strengthsofthis study. The cohort was constructed from the production facility employment records, thus allowing for complete enumerationof the cohort. "The availability of the work history information in conjunction with detailed reviewof the zn production historyof PFOA at this plant with veteran workers and industrial hygienists helped reduce exposure uncertainty related to exposure misclassification. A final noteworthy strength to this study is the comprehensive follow-upofthe cohort. An underlying causeof death was found for 99.6% of the known deaths (804/307), all unavailable or unfound death certificates were from cohort members who worked in the non-chemical divisionof the plant. The low SMRs in the non-exposed subgroup are suggestive of a bias contributing to the associations found in the internal analyses. There is also potential bias in the regression models with an intemal referent group in that they were used under the assumption that all individuals in the model were the same by all risk factors except exposure. An attempt was made to account for the differences in lifestyle by the inclusion of wage type and smoking status in the models; however we were not able to fully account for the bias from smoking because the amount of available data was so small and the abilityofthe wage type to fully account for socio-cconomic differences is unknown. Interestingly, the ischemic heart discase mortality risk did not vary by exposure strata, as would be expected ifsignificant differences in risk factors for heart disease existed between the exposure categories. To the extent that the underlying (unmeasured) risk factors for ischemic heart discase are similar to those for CVD and prostate cancer, potential confounding from these factors is of less concern. In summary, ths study evaluated the mortality experience of an occupational cohort exposed to APFO and showed an association within the cohort between both death from cerebrovascular disease and prostate cancer and working in jobs with higher APFO exposure and an estimateof cumulative APFO exposure. No association was observed between APFO exposure and a prior diseasesof interest based on toxicology studies. While findings have been 2 suggested in previous cohort studies; the current study had a longer follow-up period, therefore more deaths, increasing the powerof the study. Additional follow-up of this cohort is recommended to clarify these associations, andifpossible, should account for confounding factors such as BMI, smoking, access to health care, and other lifestyle factors. Studies of disease incidence that capture the cases that do not result in death would be informative, though these typesof studies can be difficult to implement. Assessing the incidenceofprostate cancer through cancer registries would be helpful in clarifying the association with prostate cancer. Future studies should also consider more sophisticated exposure models to properly assign ctiologically relevant estimatesofexposure. 2 References I. PBeergflleuyorToHc,hemWihciatles:K,poHtoennitgiaflorstouPr,cTewsoarfoasnkdi ML, Neches R, migration from Walker RA food packaging. Food Additives & Contaminants 2005;22(10):1023-31. 2 KBieengneeldLyBG,LM,uJrrp.,hByutSeRn,hFoafrfraJLr,DOGl.seTnheGWto,xiOc'oCloongynoofrpIeCr,flSueoarcoaotctAaMn,oatPee.rkCirnistiRcGal, Reviews in Toxicology 2004;34(4):351-84 3. iOnlsreelnatGiWon,toBuatneonchcoufpfaJtLi,onMaalnbdieolloJgiHc. lAismsitesvsamleunetfoofrlpieprifdl,uohreopoacttica,noaanted.thSyarionitdPafuuln:ct3ioMn Company; 2003. Report No.: USEPA Public Docket AR-226-1351 4 OHlesrernonGRWM,,CMheudrhcdhiTzaRd,eMhilklaesrhiJPZ,, BNuorbriliestJtiM,JBH,aOnNseeinlKlJ,EML,unMdabnedreglJJKH,,AZrombietlagLeR.JB, Perfluorooctanesulfonate and other fluorochemicals in the serum of American Red Cross adult blood donors. Environmental Health Perspectives 2003;111(16):1892-901 5. MOlasnednelGWJH,,CZhoubreclhLTR.R,SLearrusmoncoEnBc,envtarnatBieolnlsoefGp,erLfulnudobreoorcgtJaKn,esHualnfsoneanteKJa,ndBuortrhiserIM, fluorochemicals in an elderly population from Seatle, Washington. Chemosphere 2004;54(11):1599-611 6. Olsen GW, Huang HY, Helzlsouer KJ, Hansen KJ, Butenhoff JL, Mandel JH. Historical comparisonofperfluorooctanesulfonate, perfluorooctanoate, and other fluorochemicals in human blood. Environmental Health Perspectives 2005;113(5):539-45. 7. Olsen GW, Mair DC, Reagen WK, Ellefson ME, Ehresman DJ,Butenhoff JL, Zobel LR. Preliminary evidence ofa decline in perfluorooctanesulf(oPFnOaSt)e and perfluorooctanoate (PFOA) concentrations in American Red Cross blood donors. Chemosphere 2007:68(1):105-11 S$. Gilliland FD, Mandel JS. Mortality among employees ofa perfluorooctanoic acid production plant. J Occup Med. 1993:35(9):950-4. 9. Alexander BH. Mortality studyof workers employed at the 3M Cottage Grove Facility. Minneapolis: Universityof Minnesota; 2001. Report No.: U.S. EPA Docket AR-22610303018, 10. Olsen G, Ehresman D, Froehlich J, Burris J, ButenhofJf. Evaluation of the half-life of eliminationofperfluorooctancsulfonate (PFOS), perfluorohexancsulfonate (PFHS) and perfluorooctnaoate (PFOA) from human serum. FLUOROS 2005 [cited 2006 August 3}; Available from: hitp:/chem.utoronto.ca/symposium/fluoros/TpOdXf0s/17Olsen.pdf 11. Alexander BH, Olsen GW, Burris JM, Mandel JH, Mandel JS. Mortality ofemployees of a perfluorooctancsulphonyl fluoride manufacturing facility. Occupational & Environmental Medicine 2003:60(10):722-9. 2 12. National Institute system for use on for the Occupational Safety and PC. In. Cincinnati: U.S. Health. PC LTAS: Life table analysis Departmentof Health and Human Services; 1998. 13. Breslow NE, Day NE. Statistical Methods in Cancer Research. Lyon: International Agency for Research on Cancer; 1987. 14. SAS Institute Inc. SAS 9.1 for Windows. In. Cary, NC USA; 2003, 1s. Allison PD. Missing Data. Thousand Oaks: Sage Publications; 2001 16. Biegel L, Liu cell function: R, in Hurtt vitro, M, Cook J. in vivo, and Eefxfevcitvsoofstaudmiemso. nTiouximcoplerAfplpulorPohoactramno1a9t9c5o;n13L4e:y18d-i2g5. 17. aLimumRoCn,iuHumrtpterMfElu,orCooooctkanJoCa,tBei(eCg8e)l,LoBn. hEefpfaetcitcoafrtohmeatpaesreoxaictsiovmietypirnolaidfuelrtatmoar,le Crl:CD BR (CD) rats. Fund Appl Toxicol. 1996;30(2):220-8. 18. tBiuemgoerl iLnBd,ucHtuirotntbMyEp,erForxaimseomSeR,prOol'iCfoenrantoorrsJiCn,mCaoloekCJDC.raMtes.chTaoxniicsomlsScoif2e0x0t1r;ah6e0p:a4t0i-c55. 19. eOplisdeenmGioWl,ogGiiclliinlvaensdtiFgDat,ioBnuorflerwepMroMd,uctBiurvreihsoJrMm,onMeasndien lmeJSn, Mandel JH. An with occupational exposure to perfluorooctanoic acid. J Occup Environ Med 1998:40(7):614-22. 20. Gworrekeenrbserign RthSe,UM.aS.ndaenldJWS,esPtasetmidEeusrHop,e:BriattmoneNtLa,-RaudneanolkfoycoLsh,ioSrtstarsrtTuBd.iesChdeesmcirciabling mortality and cancer incidence. Epidemiology 2001;12:727-740. 21. GRoarpesliEc,kOPzBe,rSMaNc,coBRraLs,sSLmMit,hMDaBl,onAelbMeErt,sGMo,ldMbuesrtgonSe,-BAoloesxsanJ,deHranLl,eRyaDdFe,r DT,ooRloesJsF,JL, G`mrueletnidgioslcdipNliLn,arRyhceownseDnCs.usPrsetvaetnetmieonnt ofrfaomfitrhste sNtartokieo:naal rSetvrioekweoAfsgsuoicidaetliionne.s Jaanmda.a 1999:281(12):1112-20. 22. Kuller LH. Epidemiology and preventionofstroke, now and in the future. Epidemiol Rev. 200022(1):14-7. 235. Desai J, Devlin H. Diabetes in Minnesota. St Paul: Minnesota Departmentof Health; 2002. 24. lGiiplolpilraontdeiFnsD,anMdanchdoellesJtSe.roSle:rausmtupdeyrfolfuoorcocoucptaatniooincalalcyidexapnodsheedpamteinc.eAnmz.JymIens,d Med 1996:29:560-565. 25. CDC. BML: Body Mass Index. Atlanta: Centers for Disease Control and Prevention; 2006. 7 26. Olsen GW, Burris JM, Burlew MM, Mandel JH. Plasma cholecystokinin and hepatic ewonrzkyemress.,Dcrhoulges&terCohlemaincdallipToopxrioctoelinosgyin20a0m0m;2o3n(i4u):m60p3e-r2f0l.uorooctanoate production 27. aBnialldysDiEs,ofSttehveen1s9o8n6JNMat.ioFnraelquMeonrctyaloiftyreFcoolrldoiwnbgoacfkdiSaubrevteeys. oJnouUr.nSa.lodefaCtlhincierctailficates: Epidemiology 1992:45(3)275-81. 25. US Census Bureau. State and County Quick Facts; 2006. 2 Table 1. CharacteristicsofAPFO Manufacturing Cohort by Job Exposure Subgroups oo _ DefeixnpiotseuAreP'FO ProebxapbolseurAeP'FO Nonexposed" Total "Total S13 1688 1792 3993 Gender Male 473%) 1389(82%) 1323 (74%) 3184 (30%) Female 06%) 298(8%) 4T0Q6%) 509 (20%) Age at follow-up (Mean) 556 60.0 606 596 Person years (Mean) 203 316 316 313 Yeofabirrth (Mean) 1945 1938 1938 1939 Yearsof employment (Mean) 17.8 164 97 138 Age at death (Mean) 60.1 656 649 648 Deaths 68 368 an 507 EveEvrercemppllooyymeendatjionbwjiohb wGiteh perobaPbFleOASPpFOoreexpos, but neve in job with definite exposure Never heldjob with deft or probable exposure primarily non-chemical division 29 585 455% rgifuzgy| 38 3fo 22RY. 353 Rs]_ %%eR deda~cdasy cwziiaaes | *1577 gE 502)] i FOR, e 52 z[it4 2 fz] 7 4ze2ole3a| S [[2g%it BEE e288 d=Ra s82a8e8 BEER A8da 3IR dEaR5c58e83 Zs2 R&EsEfHe EfDE san 285% #m< 8832 cSS88g85as55d% B38% FAEAESefSe gaegveuiegg vwzzoratN gRZigssil d-XdedsSg =23azRecl 3gg3ss2s8ss2gg5ss3ss9yt ~xnsRe-g gEo | Es. T .3 22 :i 2iL 33 s : 3I5,,352: 22 28 =i PofssEiiEtpiaiiydp 3: 2 f122RFAzEEivfSiERViEEiPiFfIPiEEnERiRRRIEgiRcY 83 i% z2 iT SEfssd a EEfEssd 3 "S| meggr=-3% oIlge 2zE3e2i3z2s8s4s | _vvssmosx 2 z Z2Z2ZZ2Zme 7 y "yg RRAELRSE 255. sazsesn-3| if Fl i 5 Ed gq Zia F geld 5585888 Bt MIR TS~3F| 52 BRzasne | fio 3H HH Hi I. sees BeEffiiEtt I Zo23737: (iis : PUTT REE 2 "Table 3. SftoarntdhaerdEintzierdeMAoPrtFaOlitMyanRuaftiaocstu(rSinMgRC)ohfoorrtSelected Cause-Specific Mortalities I "All deaths 807 Cancers All cancers 26 Buccal cavity and pharynx 2 Digestive organs and peritoneum 61 Esophagus 4 Stomach 7 Large Intestine 2 Rectum 4 Biliary passages and liver primary 3 Pancreas 13 Other 2 Respiratory System I Larynx 3 `Trachea, bronchus, and lung, 7 Other 1 Breast" 6 Female genital organs 5 Cervix 2 Other 3 Male genital organs 17 Prostate 16 Other 1 Urinary Organs nu Kidney 4 Bladder and other urinary organs 7 Other and unspecified sites 2 Skin 4 Central nervous system 7 Thyroid gland 1 Lymphatic and hematopoietic tissue 2 Lymphosarcoma and reticulosarcoma 3 Hodgkin's disease 1 Leukemia and aleukemia 2 Other 3 All other cancers 2% Benign neoplasms 3 100018 081 075-08 28628 086 076-097 554 036 004-130 6994 086 067-112 730 055 015-140 849 082 033170 2548 110 073159 523 076 021-19 636 047 010-138 1508 086 0461.47 199 100 0123.63 8642 091 07-Li4 248 121 025354 802 090 071-L13 092 108 003-601 128 053 019116 674 074 024173 090 221 0277.99 370 081 017237 216 073 043-118 220 072 041-L17 096 104 003577 1420 077 039139 853 047 013120 5.67 123 049254 1594 075 039131 418 096 026245 984 O71 029147 099 101 003564 3275 089 059127 250 120 025352 200 050 001278 1246 095 050-168 158 082 044-141 2030 LIS 076176 EAT! 096 02028 2 Table 3. (Continued) Cust Observed Non-malignant causes Tuberculosis 1 Diabetes mellitus 5 Cerebrovascular disease 35 All heart disease 256 Rheumatic heart disease 6 Ischemic heart disease 201 Chronic diseaseofendocardium n Hypertension with heart disease 5 Other 33 Hypertension without heart disease 6 Diseases of respiratory system 50 Influenza and pneumonia 12 Bronchitis 1 Emphysema 3 Asthma 5 Other 3 Ulcerof stomach 1 Cirrhosis of the liver 13 Nephritis and nephrosis 7 Accidents 49 Motor vehicle accidents 27 Other 2 Violence 2 Suicides 1" Homicides and other 5 Allothercauses 95 b: B ReferenE ce rates from sateofMinnesota 5 All breast cancers observed i female employees Expected 049 1997 5439 32961 439 25923 1563 458 4578 420 791 253 149 818 21 3961 3.02 1787 639 5584 2574 3010 2675 200 474 1461 SMR' 95% Cl 205 005-1140 LIS 073173 064 045-090 078 0.68088 137 050297 078 067-089 070 035126 109 035255 072 050-101 145 05231 068 050-089 053 028089 067 002374 037 0081.07 142 029415 078 0s3LII 033 001-184 073 039124 110 044226 088 065-116 105 069-153 073 046LIl 082 052125 077 045124 106 034247 083 -- 067-101 33 Table 4. SMtaannudfaarcdtiuzreidnMgoCrothaloirtty MReatmiboesrfsorwSietlheactMeidnCiaumsuem-oSpfecOinfeicYMeoarrtaolfitEimepslfoorymAePnFtOin Jobs with Definite or Probable APFO Exposure' Cause' "All deaths Cancers. All cancers. Digestive organs and peritoneum Esophagus. Stomach Large Intestine. Rectum Biliary passages and liver Pancreas Respiratory System Larynx "Trachea, bronchus, and lung Female genital organs Male genital organs Prostate Urinary Organs Kidney Bladder and other urinary organs Other and unspecified sites. SCkeintnral nervous system Lymphatic and hematopoietic tissue Lymphosarcoma and reticulosarcoma Leukemia and aleukemia All other cancers Benign neoplasms Non-malignant causes Diabetes mellitus Cerebrovascular disease Observed Expected SMR 309 39802 078 109 112.58 0.97 30 27.81 108 2 3.05 066 4 339 118 12 10.00 120 3 2.09 143 2 2.51 0.80 7 5.99 117 34 35.00 097 2 1.02 1.95 32 3 33.60 0.95 12175 13 933 139 12 8.90 1.35 4 575 070 1 350 029 3 225 1.33 7 6.56 1.07 2 175 11s 5 404 124 1 1312 084 1 0.97 103 6 5.02 119 7 8.08 0.87 2 122 1.64 13 7.87 1.65 17 20.62 0.82 95% Cl 069-087 0.80-1.17 073-154 008-237 0.32-3.02 0.62-2.10 0.30-4.19 0.10-2.88 047-241 0.67-1.36 0.24-7.06 0.65-1.34 036510 074238 0.70-2.35 019-178 001-159 0.28-3.90 043-220 0.14-4.14 040290 042150 003571 0.44-2.60 035-1.78 020-591 0.88-2.82 0.48-1.32 34 Table 4. (Continued) Case" -- Observed Expected SMR___95%Cl "Allheart disease 87 BIST 066 063082 Rheumatic heart disease 1 164 061 002338 Ischemic heart disease 7 10394 071 0560.89 Chronic diseaseofendocardium 3 595 050 010-147 Hypertension with heart disease 3 179 167 034489 Hypertension without heart disease 3 163 184 038538 Diseases of respiratory system 13 2849 046 0240.78 Influenza and pneumonia 4 849 047 013-121 Emphysema 1 319 031 001-174 Asthma 1 080 125 003694 Uleerof stomach 1 117 085 002473 Cirrhosis of the liver 4 735 054 015139 Nephritis and nephrosis 4 244 164 045419 Accidents 19 2420 079 047-123 Motor vehicle accidents n 137097 043173 All other accidents 8 128 062 027123 Violence 8 186 067 029133 Suicides 8 976 082 035161 Al other causes 2 4491 065 043093 T5bn: cCaluusedmeowtsolrikseterdsifWnhoot aobcscerruveeddonc yearofxposwith definite and probable Jobs combined Reference rates from tacof Minnesota 3s Table 5. SAtPanFdOarMdainzuefdaMcotrutrailnigtyCoRhatoirots MfeormbSeelresctEevdeCrauEsmep-lSopeyceidfiIcn Mortalities for Jobs with Definite APFO Exposure "Cause" All deaths Cancers All cancers Digestive organs and peritoneum Esophagus Large Intestine Pancreas Respiratory System Larynx Trachea, bronchus, and lung. Male genital organs Prostate Lymphatic and hematopoietic tissue Leukemia and aleukemia All other cancers Observed 68 19 4 1 2 1 9 1 8 3 3 1 1 2 Expected SMR 7731 088 2195 087 536 075 065 154 187 107 117 085 70127 021 472 681 117 155 193 143 210 268 037 104 096 162 123 95% Cl 068-112 052135 0201.91 004857 013386 002474 058240 0122623 051231 040565 043613 001208 002534 015445 Non-malignant causes Cerebrovascular disease All heart disease Ischemic heart discase: Hypertension with heart disease Other Hypertension without heart disease Diseases of respiratory system Asthma Other Nephitis and nephrosis Accidents Motor vehicle accidents Other Violence Suicides Homicides and other _Alother causes oo b: ReferenceCraotmesmefA rom stateofMinnesota 5 34 159 052372 21 2401 087 054134 16 1903 084 048-136 1 031 327 0081817 4 348 LIS 031294 1 027 37 0092071 3 450 067 014-195 1 014 732 0194068 2 254 079 010284 2 038 522 063-1885 8 691 L1G 050228 4 357 12 031287 4 334 12 033306 6 364 16S 060359 5 296 169 055394 1 067 149 0.04826 3 807 037 008109 36 Table 6. SMtaannudfaarcdtiuzreidnMgoCrothaloirttyMReatmiboesrfsorwSietlheactMeidnCiaumsuem-oSpfecOinfeicYMeoarrtaolfitEimesplfoorymAePnFtOin a Job with Definite APFO Exposure Cause" All deaths Cancers All cancers Digestive organs and peritoneum Esophagus Large Intestine Respiratory System Trachea, bronchus, and lung Male genital organs Prostate All other cancers Observed 25 7 2 1 1 2 2 % 2 1 Expected 3595 1029 254 031 089 336 323 050 075 076 SVR___95%Cl 070 045-103 068 027-140 079 010285 328 0081821 Liz 003-624 059 007215 062 008224 251 030.904 267 032965 132 003732 `Non-malignant causes Cerebrovascular disease 3 155 194 0405.66 All heart disease s WSL 070 030-137 Ischemic heart disease 6 9.16 066 024-143 Other 2 1.64 122 015-440 Diseasesofrespiratory system 2 227 088 011318 Other 2 129 155 019-561 Nephritis and nephrosis 1 019 523 0132908 Accidents 1 2m 036 001201 Other 1 139 072 002399 Violence 2 143 139 017503 Suicides 2 118 170 021613 _Alother causes 1 383 026 001-145 b: CRmesfeenrtelnecdeirmaotteosmfernoemd stateofMinnesota 37 Table 7. SMtaannudfaarcdtiuzreidnMgoCrothaloirttyMReamtiboesrfsorESveelrecEtmepdlCoayuesde-ISnpeJcoibfsiwciMtohrtParloibtaibeslefoArPAFPOFEOxposure, but Did Not Hold Jobs with Definite APFO Exposure Came OwnBoSMw E ewad All deaths 368 W352 083 075092 Cancers Al cancers ny 12663 094 078112 Buccal cavity and pharynx 1 247 040 001225 Digestive organs and peritoneum 27 3119 087 057126 Esophagus 1 326 031 001170 Stomach 4 378 106 029271 Large Intestine 10 13s 088 042162 Rectum 3 233 128 026376 Biliary passages and liver primary 2 288 071 009255 Pancreas 7 674 104 0a2214 Respiratory System 38 3837 099 070136 Larynx 1 110 091 002503 `Trachea, bronchus, and lung 37 3686 100 071-138 Breast" 2 472 042 005153 Female genital organs 4 289 138 038354 Other 3 1.59 189 039552 Male genital organs 10 1002 099 047-182 Prostate 9 969 093 042176 Other 1 043 233 0061296 Urinary Organs 5 630 079 026-185 Kidney 2 38 053 006190 Bladder and other urinary organs 3 250 120 0253.50 Other and unspecified sites 7 701 100 040206 Skin 2 183 109 013395 Central nervous system 5 432 116 0372.70 Lymphatic and hematopoietic tissue 14 1455 096 053161 Lymphosarcoma and reticulosarcoma 2 Ln 180 022651 Leukemia and aleukemia 7 552 127 051261 Other 5 704 071 023166 Allothercancers Benign neoplasms n 901 12 061218 2 139 144 047519 38 Table 7. (Continued) Cause" Observed Fxpected SMR 05% Cl Non-malignant causes Diabetes mellitus 18 887 203 120321 Cerebrovascular discase 1" 2415 070 041-113 All heart disease: no 14686 075 062090 Rheumatic heart disease 2 196 12 012368 Ischemic heart disease 9 1552 081 065099 Chronic diseaseofendocardium 7 7.00 100 040-206 Hypertension with heart disease 2 207 097 012349 Other 6 2031 030 011-064 Hypertension without heart disease: 3 190 158 033462 Diseases of respiratory system 19 3270 058 035091 Influenza and pneumonia 7 982 071 029-147 Bronchitis 1 0.66 153 004847 Emphysema 2 364 055 0071.99 Other 9 1765 OSI 023.097 Ulcerof stomach 1 135 074 0024.13 Cirthosis of the liver 6 794 076 028165 Nephrits and nephrosis 2 28 071 009256 Accidents 2 2456 094 059-141 Motor vehicle accidents 12 N29 106 055186 Other n 1327 083 04l-14s Violence 8 160 069 030-136 BE Suicides 8 956 084 -- 0361.65 b: ARlelferreesncsecraantceesrfsroobmsteraveeodfiMfienmnaelseoteamployees 39 Table 8. Standardized Mortality Ratios for Selected Cause-Specific Mortalities for APFO Manufacturing Cohort Members Never Employed in Jobs with APFO Exposure Case All deaths Cancers All cancers Buccal cavity and pharynx Digestive organs and peritoneum Esophagus Stomach Large Intestine: Rectum Biliary passages and liver Pancreas Respiratory System Larynx "Trachea, bronchus, and lung Other Breast Female genital organs Cervix Male genital organs Prostate Urinary Organs Kidney Bladder and other urinary organs Skin Central nervous system Thyroid gland Lymphatic and hematopoietic tissue Lymphosarcoma and reticulosarcoma. Hodgkin's disease Leukemia and aleukemia All other cancers Benign neoplasms Observed 371 108 1 30 2 3 16 1 1 5 2 1 30 1 4 1 1 4 4 6 2 4 2 2 1 14 1 1 4 n 1 _Bxpeaied SVR 47934 077 13770 078 259 039 3339 090 339 059 408 074 1226 130 250 040 304 033 707070 4094 078 116 086 3935 076 044 230 627 064 370 027 051 196 149 035 108 036 677 089 398 050 278 144 191 105 455 044 046 216 1552 090 120 084 092 109 590 068 967 114 149067 95% 070086 064095 001214 061-128 007213 015215 075212 001222 001-183 023163 053-110 002479 051-.09 0061276 017163 001-150 005-1092 009-089 010092 032.19 006181 039367 013379 005159 0051200 049-151 0.02465 003604 018173 057204 002373 40 Table 8. (Continued) Ge Owed Non-malignant causes Tuberculosis 1 Diabetes mellitus 5 Cerebrovascular disease 13 All heaRrctadmisactaisec heart discase s125 Ischemic heart disease 92 Chronic diseaseofendocardium 4 Hypertension with heart disease 2 Hypertension without heart disease 2 Diseasesofrespiratory system 28 Influenza and pneumonia 5 Emphysema 1 Asthma 2 Cirrhosisof the liver 7 Nephritis and nephrosis 3 Accidents 18 Motor vehicle accidents nu All other accidents 7 Violence: 8 Suicides 4 Homicides and other 4 All other causes. 52 ReforveenceemreesrsfoomvsaetomfeMinnnetsotsampless bpm 023 9.55 27.10 204 158.74 124.58 7.82 221 2.03 36.71 11.50 4.01 1.04 827 3.19 24.38 10.89 13.49 11.52 9.49 2.02 55.57 SMR 4.28 0.52 0.48 01.8769 0.74 051 0.90 0.98 0.76 043 02s 1.93 0.85 0.94 0.74 1.01 0.52 0.69 0.42 1.98 0.94 wa 0.11-23.80 0.17-1.22 0.26-0.82 00.5661-40.7974 0.60-0.91 0.14-1.31 0.11-3.27 0.12-3.55 0.51-1.10 0.14-1.02 0.01-1.38 0.23-6.97 0.34-1.75 0.19-2.75 0.44-1.17 0.50-1.81 0.21-1.07 0.30-1.37 0.11-1.08 0.54-5.05 ia 0.70-1.23 a Table 9. Standardized Mortality Ratios for Selected Cause-Specific Mortalities for Salaried Workersof the APFO Manufacturing Cohort Couse All deaths Cancers All Cancers Buceal cavity and pharynx Digestive organs and peritoneum Esophagus Stomach Large intestine Rectum Bilarypassagesand liver Pancreas Al other digestive Respiratory system Larynx Bronchus, trachea, and lung All other respiratory Breast Female genital organs Al uterine (non-carvix) Cervix Other female genital organs Male genital organs Prostate Testis and other male genital Urinary organs Kidney Bladder and other urinary organs Other and unspecified sites Skin Eye Central nervous system Thyroid gland/other endocrine Bone Deaths Expected SMR __95%Cl 307 48492 06 056071 97 14047 0.69 0.56084 0 268 000 000-138 7 BIT 080 053-116 2 356 056 007203 2 406 049 006-178 1" 1233 138 080221 2 250 080 010289 0 309 000 000-119 4 729 055 015-140 0 095 000 000387 7 255 063 04209 1 120 083 002462 2 4087 061 040-090 1 04s 220 006-1222 2 590 034 004122 3 333 090 019264 0 103 000 000359 2 047 429 0521549 1 18 054 0013.03 6 N47 052 019-114 6 101 054 020-019 0 046 000 0.00804 5 694 072 023-168 2 415 048 006-173 3 276 109 022318 6 792 076 028165 2 210 095 012343 0 009 000 000-4292 3 488 061 013-180 1 048 207 005-1150 0 037 000 000.998 2 Table 9. (Continued) Case Lymphatic and hematopoietic Lymphosarcoma and reticulosarcoma Hodgkin's disease Leukemia and aleukemia Other lymphatic hematologic Allothermalignant neoplasms Benign neoplasm Non-Malignant Causes Diabetes mellitus Cerebrovascular disease All heart disease Rheumatic heart discase Ischemic heart discase Chronic diseaseofendocardium Hypertension with heart disease All other heart disease Hypertension without heart disease Nonmalignant respiratory discase Influenza and pneumonia Bronchitis Emphysema Asthma Other nonmalignant respiratory Cirrhosisof liver Nephritis and nephrosis Nephritis and nephrosis Accidents Motor vehicle accidents All other accidents Violence Suicides Homicides Allother causes 5b: CRaeufesreeonctesraeteds fiommotsdtabtseoerfveMdinnesota Allbreast cancers observed in female crplogees Deas Expected SMR 95%Cl 13 1597 081 043-139 2 16 172 021621 1 097 104 003575 2 610 033 004118 8 774 103 045204 8 996 080 0351.58 2 1S 133 016479 2 975 021 002074 16 2595 062 0351.00 96 15789 061 049-074 2 203 099 012356 7 12383 059 046074 4 752 053 014-136 0 216 000 000-171 1" 235 076 044-122 2 200 100 012361 2 3592 061 038093 5 100 045 015-106 0 071 000 000-521 1 391 026 001-142 2 103 194 0237.00 14 1927 073 040-122 5 868 058 019-135 2 30 064 008232 2 311 064 008232 14 2720 051% 0280.86 8 1259 064 027-125 6 1461 041 0150.89 7 1332 053 021-108 5 1093 046 015-107 2 239 084 010302 2 5560 076 0541.02 a "Table 10. HStoaunrdlayrdWiozrekderMosortfaltihteyARaPtFioOsMfaonruSfealcetcuterdinCgauCsoeh-oSrptecific Mortalities for Came All Deaths Cancers All Cancers Buccal cavity and pharynx Digestive organs and peritoneum Esophagus Stomach Large intestine Rectum Biliary passages and liver Pancreas All other digestive. RespirLaatroyrynxsystem Bronchus, trachea, and lung. All other respiratory Breast Female genital organs All uterine (non-cervix) Cervix Other female genital organs Male genital organs Prostate Testis and other male genital organs Urinary organs, Kidney Bladder and other urinary organs Other and unspecified sites Skin Eye Central nervous system Thyroid/other endocrine gland Bone Lymphatic and hematopoietic Lymphosarcoma and reticulosarcoma Hodgkin's disease. Leukemiaand aleukemia Other lymphatic hematologic Observed 500 149 2 3 2 5 n 2 3 9 2 52 2 50 0 4 2 0 0 2 I 10 1 6 2 4 6 2 0 4 0 0 16 1 0 10 5 Expected SMR 51526 097 14581 102 28 070 3617 094 374 053 443 113 1315s 084 274 073 321 092 779 LI6 104 193 4389 LIS 127 LST 4215 119 047 000 538 074 341 059 110 000 044 000 187 107 1690 | 094 118 089 050 199 727 083 435 046 291 137 802 075 200 097 010 000 496 081 050 000 039 000 1678 095 133 075 103 000 637 157 305 062 95% C1 089-106 086-120 008253 065-131 006-193 037264 042150 009264 019268 053219 023695 088-155 019566 088-156 0007.87 0201.90 007212 000335 000843 013-387 047-168 043-164 0.0511.03 0301.80 006166 037351 027163 012348 00037385 022206 000734 0009.48 0.54155 002407 000359 075289 020145 a4 Table 10. (Continued) Cause Allothermalignant neoplasms Benign neoplasm Non-Malignant Causes Diabetes mellitus Cerebrovascular disease Al heart disease Rheumatic heart disease Ischemic heart disease Chronic diseaseof endocardium Hypertension with heart disease: All other heart disease Hypertension without heart disease Nonmalignant respiratory discase Influcnza and pneumonia Bronchitis Emphysema Asthma Other nonmalignant respiratory Ulcer of stomach and ducodenum Cirthosisofliver Nephritis and nephrosis Accidents Motorvehicleaccidents Allother accidents Violence Suicides Homicides AClaliosthneotrtceadusfesof ome > ARelfebrreancsecraantceserrsobmsesravteodfiMifemmnaclseoieamployees Observed Expected 16 1034 1 160 SMR ___ 95% Cl 155 088251 062 002346 21 1022 206 127304 19 2843 067 040-L.04 160 17172 093 0791.09 4 236 169 046433 128 13540 095 079-112 7 811 086 035-178 5 242 206 067-482 16 243 068 039-11 4 220 182 050465 2 3800 074 049-107 7 S306 024-125 1 078 128 0037.13 z 426 047 006169 1 108 092 0025.14 17 2034 084 049-134 1 159 063 002349 8 919 087 03172 5 328 152 0493.56 35 2864 122 0851.70 19 BIS 14s 087226 16 1549 103 059-168 15 1343 L120 062184 2 109 108 056-189 3 234 128 026374 3 5901 090 067-117 4s "Table 11. Hazard Ratio Estimates and 95% Confidence Intervals from Time-Dependent CFuonxctRieognroefssAioPnFAOnaElxypsoissutroeMCohdaeralcttheeriRziesdkobfyCJaoubseC-lSaspseicfiifcaitcioMnortalties as a ee TA modeG l E Amodd el ee Cause of Death + actual + imputed JCloabssEixfpicoastuiroen' dNeoa.tohfs CrHuRd_e_95%Cl AdjuHsRted _95%Cl `dsmaoakiHnRg 95% Cl samwokHinRg 95%CI PrHositagthe cancer" 16239 07211 69 12418 56 09359 70 12422 Moderate 1023 0775 30 08110 28 08102 30 08110 Low 4 1 1 1 Pancreatic cancer 13 High 0. . Moderate Low 8 so 15 0545 11S 0453 112 0342 115 0452 Bladder cancer 7 High 0 . 5 . Moderate 307 0233 04 0118 03 O17 04 0118 CeLreobrwovascular a 1 1 1 disease 2 High 323 0782 53 15196 66 17245 SI 14186 Moderate 19015 0831 21 1045 22 1048 21 1046 Low Ischemic heart Bo 1 1 1 disease 200 HMiodgehrate 1063 06 0314 LL 0815 08 10 0318 0713 09 10 0421 0714 08 10 0318 0713 Low Cirthosisofthe 21 1 1 1 livHerigh 0. . Moderate 6 08 0326 Ll 0337 LI 0336 11 0337 DiLsboetwes mellitus 237 1 1 1 High Moderate 10 837 1499 19 0754 20 0756 1.9 07-53 Low 57700Clasiication igh-Wa5rked1a Job with GeTit exposu1re for6 mons or grea1ter; Moderawoe1rk-edE3Jv96eitrh nproonb-acbhleemiecaxl dpivoiossirownuoorfrkteheedplajnotb with definite exposure for Iss than 6months Low-Ever worked ob primary in he b: MHeaznarodnlrya,tino-a3d1j8u4stedforsex, ag eligible tbe in th study, bith yes, and wage type Fs "Table 12. HoafzParrodstRaatteiCoaEnscteirmaatnedsCaenrdeb9r5ov%asCcounlfairdeDnisceeasIent,erIvsaclhsetmoicMoHdeearlttDhiescRaissek: and Diabetes by APFO Job Exposure Classification and Wage Type Hourly Wage Type" Sala - "CaJuosbeeoxfpdoseuartehclassification' _ dNeoa.tohfs HRS 95%Cl | dNeoatohfs HR osc Prostate cance High 0- 2 97 137m4 Moderate 9 43 0537 | 1 10 0199 Low 11 31 Cerebrovascular disease High 2 89 1446 | 1 41 0539 Moderate 2 16 0649 | 7 28 1080 Low 51 81 Ischemic heart disease High 5 Lo 0430 | 1 oa 013d Moderate 8 11 0716 | 20 08 051s Low 01 201 Diabetes mellitus High 0- 0- Moderate 719 0659 | 1 17 08339 Low 41 11 WaJogbelatsyipeatfoiropne.rHsiognhw=hWoorwokrekdeadjboobrwiBtohwdle3faiaexrpyosuJroebfoirs 6camsosnitehsdobrygthreatperre,doMmoidnearnatew-aEgveerpweorked a Jporibmwairtihlyprinobtahbelneoenx-pcohseumriecaolrdwiovriskieodnafjotb wlitahntdefinite exposure fo es than 6 monthsLow-Ever worked ajob :a MHeaznarondlyr,atnio-3ad1j8u4sted forse, age eligible 1 be in the study, birth year, snd ifboth wage typejobs were held a Table 13. Hazard Ratio Estimates and 95% Confidence Intervals to Model the Risk of Prostate Cancer andCercbrovascularDisease Mortalities as a Function of APFO Exposure, by Exposure Lag (0 and 10 years) -- CaoufDseaeth JCloabssEixfpiocastuiroen' _ Prostate cancer" High Moderate Low Pancreatic cancer" High Moderate Low Bladder cancer" High Moderate Low Cerebrovascular disease" High Moderate Low Ischemic heart disease" High Moderate Low Cirthofstihse: liver High Moderate Low Diabetes mellitus High Moderate Low Zeroexposure lag dNeoatohfs CrHuRde _95%CI AdjuHsRted" 239 07211 69 1023 0775 30 a 1 0 8 15 0545 15 so 1 0 5 307 0233 04 4 1 323 0782 53 1915 0831 21 Bo 1 6 06 0314 08 1035 LI 0815S 10 21 1 0. . 6 08 0326 LI 7 1 0 18 37 1499 19 5 1 95%Cl 12418 08110) 0453] 0148| 70yearexposure Ia [Ndeoaothfs Crude HR __95%Cl Adjusted" HR _ 2 54 L1280 82 9 33 1199 34 so 1 0 . 7 20 0759 20 61 1 0. 3 13 0358 08 a 1 95%Cl 1115.414067 0662 . 0240 1S196 3 22 0776 44 1215s 1045) 14 14 0729 18 0937 181 1 0318) 6 06 0313 07 0316 0713 [ 59 08 0610 07 0509 1361 1 0 . " 0337] 4 08 0326 10 0334 91 1 0 0754( 12 19 0944 13 0631 TH. 1 a pJroobbCalbalsesiefixcpaotsiounr.e oHriwgohr=kWeoadrkjeoabdwjiotbhwdietfhindietfeineixtpeoseuxrpeosfuorrelfoes t6 moh6ntmhanstohrnsr;esLtorw;-EMvoedrerwsotrek=eBdverjowboprrkimeaadrijloybnwitthhe br Hnaozna-crhdermaitcoaladdjiuvsitseidonfoorftshee,palagnteligible obein the study, birth year, and wage type Menonly, n-3184 a Table 14. CHoaxzaRredgrReastisoioEnstAinmaaltyessisantdo M9o5d%elCotnhfeiRdiesnkcoefICntaeursvea-lSspfercoifmiTciMmoer-tDaeiptieensdeansta Function ofCumulative APFO Exposure Ad`jmuosdteled rmodTel -- CausFeaoufinDselaetnhcyears | Noof Crude Adjusted" s+maakctiunalg +maikmipuntge.d Prostoafteexcpaonscuerre" || d1e6aths HR 95%Cl HR 95%Cl dunHR 95%Cl damHR _95%Cl >5 1-<s 7 38 14135 103 0129 36 05 12106 0136 36 05 10427 0139 38 04 12132 0136 < 51 1 1 1 Pancreatic cancer | 13 >5 1s 2 17 0380 421 0672 1s 22 0375 0681 LI 19 0262 0569 16 23 0378 0682 <1 7 1 1 1 Bl>adsder cancer, 7 113 0119 07 0172 06 0171 07 0173 1-<5 2 19 03103 14 0286 14 0283 15 0389 < a 1 1 1 Cerebrovascular disea>s5e 89 23 1149 24 1154 31 1373 24 LISS 1-<s 305 0116 07 0223 07 0225 07 0224 <1 51 1 1 1 Ischemic heart dise>as5e 20211 10 0615 07 04Ll 08 0514 07 04Ll 1.<s 2 Ll 0816 Ll 0815 LI 08L6 Ll 0816 < B81 1 1 1 tChierrlhiovseirs of 3 2s1-5 311074 00415536 0179 00517538 0178 0159 0571 07 18 0157 0573 <1 91 1 1 1 Diabetes mellitus | 23 >51s 4S1316 00553478 1110 00332374 14 10 0448 0429 LI 10 0435 0328 We <1 iexpgosurheGayt sequuie ovalendtfo 3yeas 1 (182,300weightedexposedays), 1 1-5 1 years(36.500-182.499weighted Vb: Hcaxpsoasnurreadtaoyasd)j.uasntdedIfsosr stehxa.na1geyeealrig(i<bl3e6f,ob50e0 wienitghhetsetdudeyx,pobsiutrheydeaay,s)aonfdwwoargkeiynpein job with definite exposure < Men only, n-3184 4 Table 15. Hazard Ratio Estimates and 95% Confidence Intervals to Model the Risk of Prostate Cancer and Cerebrovascular Disease, Ischemic Heart Disease and Diabetes by Weighted Cumulative APFO Exposure and Wage Type Cause of death ProWsteaitgehtceadnceex Days' 215-<s <1 Cerebrovascular disease. >15 s <1 Hourly Noo deaths. HR 45106319 Wage Type" Woof Salary 95% C1 So deaths HR 1007-51594 | 4 20 03.00 95% CI 05-186 510327 13 1 00.06-25.40 | 42 31s6 10.03-7114.5 10 1 >5 Ischemic heart disease 709 o0sis | 4 04 oLLl 1-<5 31 12 08-1.8 11 1.0 0.5-1.9 Diabet<e1s mellitus 80 1 58 1 25 3 09 03-33 1 33 02-71.7 <11-<5 B5o 11.0 03-28 01- + WWeaeggihgeiheeyddp eexfxpoproopsseuurrrseeondasayyews)h.coqawnudoirv1kaseldntbhtaan0.hy1ehyaoraslry((18a<n23d,65.s05a00l0awrewyiJegoihbgtheeddxsepCxaposoTssiresdda5Gayy)tsh,)1opf.wr5oerdyoekmaiirnnsgan(tm6a,w5ja0og0eb-1yw4pi3et,.h499 dHeafzianritdereaxtpooaset.ed for se, age eligible 1 be nthe study, birth year,an ifbth wage ypejobs wer held & Menonly,ne3154 50 gE 3 5 95 iz i i. 3 i|felg sa2%zCe maz boo}k l i5 - | I fge te:" 53 Ze 53573 2|2 i ol 3 EE = - i 3o% i HE fer 520 Cl i ii P[2I4E4 i 2G05%2 5 |Hi 22%| & iit | 3 of i 5ih %| f : i| 4 aR - Sa oor . 33 8% Bn oo "oS = sze ass i 535 z]l ~~ | a 2| 2% ke| |E8E8 n : o ] : : 233 oi q 52% . "olil Fo i 3 zoelcfii yit 22 }F~ aedE ; . i fiit HEH I EET I : EE i i HE RA g4riv igfaanzic g2FR qllgvlEi i iEsiE3