Document 1Q1kJQr6g8v9pMvMqJ6pdoG35

FINAL STUDY TITLE Ammonium Perfluorooctanoate: Phase II. Retrospective Cohort Mortality Analyses Related to a Serum Biomarker o f Exposure in a Polymer Production Plant Author: Robin C. Leonard, Ph.D. Study Completed on: September 15, 2006 Performing Laboratory: DuPont Epidemiology Program DuPont Haskell Laboratory for Health and Environmental Sciences 1090 Elkton Road, Newark, DE 19714 Laboratory Project ID: DuPont-14809 (Phase II) Work Request Number: 15259 Service Code Number: 1242 Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. 1 of 73 FINAL Good Epidemiology Practice Compliance Statement............................................................... 5 D uPont A p p ro v al....................................................................................................................................6 Epidemiology Review B o a rd ................................................................................................................ 7 A bbreviations and S ym bols................................................................................................................. 8 Executive S u m m ary ............................................................................................................................... 9 In tro d u ctio n ..........................................................................................................................................11 M ethods................................................................................................................................................... 12 C ohort A scertainm ent................................................................................................................... 13 D uPont M ortality R egistry............................................................................................................13 Exposure C ategorization...............................................................................................................13 Establish Job Exposure Categories.............................................................................................. 14 Exhibit 1. Group changes based on similar job titles................................................................ 15 Application o f Job Exposure Categories to Historical Job Titles.............................................16 Calculation of Individual Exposure M etrics............................................................................... 16 Exhibit 2. Example o f calculation o f average intensity o f exposure*.....................................16 Validate Exposure Classification................................................................................................. 16 Exhibit 3 Etiology of Validation Data S et.................................................................................. 17 Exhibit 4. Results o f mixed model used to validate cumulative exposure to PFOA: serum PFOA as a function o f estimates o f PFOA exposure based on jo b .........................................18 Exhibit 5. Validation of exposure using repeated measurements (mixed model) to predict serum PFOA.................................................................................................................................... 19 M ortality Analyses and Development of O ccupational Reference Files...............................19 Cox Proportional H azards M odeling...........................................................................................20 Description of Methods Specific to Ischemic Heart Disease....................................................21 Categories of exposure for average intensity:.............................................................................21 Exhibit 6. Average intensity o f exposure categories for proportional hazards analyses for ischemic heart disease mortality, stratified by exposure lag period.........................................22 Categories of exposure for cumulative exposure....................................................................... 23 Exhibit 7A. Cumulative exposure categories for proportional hazards analyses for ischemic heart disease mortality, stratified by exposure lag period; quartiles determined by cumulative exposure distribution o f cases among white m ales............................................... 23 Exhibit 7B. Cumulative exposure categories for proportional hazards analyses for ischemic heart disease mortality, stratified by exposure lag period; quartiles determined by cumulative exposure distribution of entire cohort..................................................................... 24 R esu lts.....................................................................................................................................................25 C ohort D escription........................................................................................................................... 25 M ortality Analyses on E ntire C o h o rt...........................................................................................25 All Causes of D eath.......................................................................................................................26 All Malignant N eoplasm s............................................................................................................. 26 Cancer of Biliary Passages and Liver..........................................................................................26 Cancer o f Pancreas.........................................................................................................................26 Urinary Tract Cancers....................................................................................................................27 Cancer of Bronchus, Trachea, L ung............................................................................................27 Cancer of Prostate.......................................................................................................................... 27 Cerebrovascular Disease............................................................................................................... 27 All Heart Disease........................................................................................................................... 28 Ischemic Heart Disease................................................................................................................. 28 FINAL p.3 Diabetes M ellitus............................................................................................................................ 28 Cox Proportional Hazards M odeling........................................................................................... 28 Ischemic Heart Disease.................................................................................................................. 28 D is c u s s io n .................................................................................................................................................29 Conclusions............................................................................................................................................. 32 R e fe r e n c e s ................................................................................................................................................33 T A B L E S ................................................................................................................................................... 36 Table 1 Washington Works mortality study cohort................................................................. 37 Table 2 SMRs for selected causes of death in Washington Works males, females compared to DuPont Region 1 (West Virginia (less Washington Works), Ohio, Virginia, Kentucky, Indiana, Pennsylvania, Tennessee, and North Carolina), U.S.A. national population, West Virginia state population.................................................................................38 Table 3 White male workers included in the risk-sets of the proportional hazard analysis for IHD stratified by case/non-case status...................................................................................39 Table 4 White male workers included in the risk-sets of the proportional hazard analysis stratified by never-APFO-use/ever-APFO-use status............................................................... 40 Table 5 Mortality rate ratios for IHD by exposure category for no-lag analyses using case calendar-year and year of hire (pre-1954) as potential confounders.................................... 41 Table 6 Mortality rate ratios for IHD by average intensity exposure category, including increasing 5-year lags of exposure, using case calendar-year and year of hire (pre-1954) as potential confounders.................................................................................................................. 42 Table 7 Mortality rate ratios for IHD by cumulative exposure category, including increasing 5-year lags of exposure, using case calendar-year and year of hire (pre-1954) as potential confounders; A) exposure categories based on case distribution, B) exposure categories based on cohort distribution........................................................................................43 FIGURES................................................................................................................................................ 44 Figure 1. Time in Job vs Serum PFOA-Cross-Sectional Study-Job Exposure Category 1 ............................................................................................................................................................... 45 Figure 2. Time in Job vs Serum PFOA-Cross-Sectional Study-Job Exposure Category 2 ................................................................................................................................................................46 Figure 3. Time in Job vs Serum PFOA-Cross-Sectional Study-Job Exposure Category 3 ................................................................................................................................................................47 Figure 4. Serum PFOA vs Cumulative Exposure - FLAIR D a ta.................................. 48 Figure 5. Serum PFOA vs Average Intensity of Exposure - FLAIR Data................... 49 Figure 6. Serum PFOA vs Concurrent Job Intensity Factor - FLAIR D ata............... 50 Figure 7. Decreasing IHD mortality rates in the U.S.A........................................................ 51 APPENDICES........................................................................................................................................ 52 Appendix A Washington Works vs Region 1 ........................................................................... 53 All-Cause Mortality Surveillance Report: M ales......................................................................53 All-Cause Mortality Surveillance Report: Females.................................................................. 55 All-Cause Mortality Surveillance Report: Totals (Males and Females).................................. 57 Appendix B Washington Works vs U S A ...................................................................................59 All-Cause Mortality Surveillance Report: M ales......................................................................59 All-Cause Mortality Surveillance Report: Females.................................................................. 61 All-Cause Mortality Surveillance Report: Totals (Males and Females).................................63 Appendix C Washington Works vs West V irginia................................................................. 65 All-Cause Mortality Surveillance Report: M ales..................................................................... 65 All-Cause Mortality Surveillance Report: Females.................................................................. 67 3 of 73 FINAL P-4 All-Cause Mortality Surveillance Report: Totals (Males and Females)............................... 69 Appendix D ...................................................................................................................................... 71 Job Exposure Category Development based on Division and J o b .........................................71 4 of 73 .5 FINAL P-5 Good Epidemiology Practice Compliance Statement This study was conducted according to guidance provided by the American College of Epidemiology Ethics and Standards Practice Committee which can be accessed at http://www.acepidemiology2.org/policystmts/EthicsGuide.asp. Applicant / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. PriBcijwl Instigator: ^ C Rodfclifit C. LUeewtiuitdd, PkX>. PriiKnptl Rocardb Epiderakriogui V -- Dte -- 5 of 73 FINAL P-6 DuPont Approval: We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. { /. ^' ifniirr AflkHaMitCteKvtfmt HMii tMhMHf I.MJUH'btotjr'fet HwMi m l UlIkHUUMMUSlitetMMQM D*. Af^FWMrflQIS Q M W M ltJ& r EJ Aj Port d<KB5sar, Idc. iZ-OAHM 6 of 73 7 FINAL p. 7 Epidemiology Review Board Tke ^pUEOiiit^ rrapwfciBdaa w o in m l jrtviufy Bawd,ikt EpLraHolo R*viwB o ri (EKB). w Ndtii m w M ofsatan o p at iathe w ocia^iwd Meeit^ hiomeiet eiiaL Mdeeeepslieeil m a ta " The nj0aivTM afhE R B t hqotaiiualiir.intt(rity.i c fpltaniotagic n - t ftfi aMMat tpoaaotxdfryt*1D nPft Cranpafly T i t o l i m a ta tBtWtayiaiwad di !!%>ai tadcnnaaanialhtt t a iimn(i i nlcvwt, M al, te^iA ally uad. ad ta l t a wnehnsn ppfoiiiiM tiy fora (te tea toi mndirnt. VrnmM. W*nM.D.. a**,mm CDevSc*w>Jqf1foiaidtaSBWiDeM,UwT,ni*fo*.I*iM) c TteMtsL. W iriw n n MlD. fPoctiikau QKmokma Uriv) / o / / *r/ Q t S \yL L ~ C-JrfrtcklLcQNtotevvMA (O y ipnrtmiripfcyriataa. pW*mkilBgt,YBlUbtT.) . ScJJ. tMi.) te j^ w / . sja-r/ o L -- teMKfcsa Su m , AID, MS. (Otair, 0pt of Epidemiology. Jota* H op Bfaamterg Sctoe aiWbite Hstiih) X 1** S. Sk m , fim ., CXH. C&oterW tatariat, qpt**nfal[>i*t, Univ, orWraJungwiiJ Each ERB member was asked to sign off on this report using their own separate signature page, and then to fax their signature to the DuPont Epidemiology Department. Once received by the DuPont Epidemiology department, each fax was then scanned into the computer system as jpeg files. The jpeg files were then cropped to display only the signature. Each cropped image was then inserted into this page, using Microsoft Word. The original faxes will be retained in the DuPont archives. 7 of 73 g FINAL p .8 Abbreviations and Symbols AIC APFO BMI Cl CPHM CSHS FLAIR GI HDL HWE HWSE IHD LDL MRR NDI OCMAP PFOA PPE PPM PPM-Years SMR VLDL Akaike Information Criterion, a partial likelihood test statistic Ammonium perfluorooctanoate Body mass index Confidence interval Cox proportional hazards model Cross-sectional health survey Fluoropolymers Laboratory Analysis Information Retrieval Gastrointestinal High-density lipoprotein Healthy worker effect Healthy worker survivor effect Ischemic heart disease Low-density lipoprotein Mortality rate ratio National Death Index (USA) Occupational Mortality Analysis Program (University of Pittsburgh) Perfluorooctanoic acid Personal protective equipment Parts per million Parts per million per year, accumulated Standardized mortality ratio Very low-density lipoprotein 8 o f 73 1 FINAL Executive Summary P-9 Ammonium perfluorooctaonate (APFO) is the ammonium salt o f the fully fluorinated, 8-carbon carboxylic acid. APFO is used to aid in the emulsion polymerization o f fluoropolymers. APFO and its salts are soluble in water and readily dissociate to the perfluorooctanoate anion (PFOA). APFO is a surfactant that enables the fluoropolymer components to remain emulsified during polymerization and is not incorporated into the polymer itself. It is the ammonium salt (APFO) to which workers may be exposed; the biomarker measured in serum is the dissociated anion (PFOA). As a result o f the presence and biopersistence o f PFOA in the blood o f humans, the potential health effects o f the chemical have been examined, primarily in occupational cohorts. The plant site where this study was conducted comprises several businesses with a diverse range of polymer manufacturing processes, most o f which do not involve the use o f APFO. Approximately one-half o f the employees at the site have been assigned to APFO areas at some time in their careers. As part of a large project on occupational exposure to PFOA, this study's objective is to determine whether workplace exposure to PFOA is related to increased mortality risk for any cause (Phase II). The overall project comprised two studies: Phase I, a cross-sectional surveillance that analyzed several types o f clinical data (blood chemistries such as lipids, enzymes, and blood counts, among others) and a biomarker o f exposure (serum PFOA) for potential relationships (to be issued in a separate report); and Phase II, a retrospective cohort study that examined site-wide standardized mortality analyses, and also utilized job history information as well as serum PFOA data to classify each member of the historical cohort by level o f potential occupational exposure for a more detailed analysis of ischemic heart disease. Based on the results of the cross-sectional study, we concluded that workers in all areas across the entire plant site show some measurable level o f serum PFOA (range: 0.005 ppm to 9.55 ppm). The cohort for Phase II was defined as all individuals who have ever worked at the Washington Works plant at any time between January 1, 1948 (plant start-up) and December 31, 2002. The cohort (n = 6,027) was ascertained primarily through the DuPont Epidemiology Registries; additional members were identified from plant-based work history records. Standardized mortality ratios were calculated for the study cohort for all causes o f death, death from all cancers combined, and disease-specific causes o f death by comparing the cohort to rates for three reference populations: the general population of the U.S.A., the West Virginia general population, and the population of DuPont workers residing in West Virginia and seven neighboring states in the region (DuPont Region 1). In addition, Cox proportional hazards models provided an internal comparison based on exposure categories o f serum PFOA for mortality due to ischemic heart disease. Mortality rates at this site are generally well within expected values and support the presence of a healthy worker effect. Analyses specific to PFOA categories were conducted for ischemic heart disease mortality. The analyses based on average intensity of exposure showed no relationship to PFOA exposure levels. The analyses based on cumulative exposure indicated an increasing trend for the mortality rate ratio with increasing exposure category if those categories were based 9 of 73 10 FINAL p. 10 on the distribution of case exposures, but not if those categories were based on the distribution of exposures in the entire cohort. In no case were the mortality rate ratio estimates statistically significant. Prostate cancer and cerebrovascular disease, both reported as increased in previous 3M Company occupational epidemiology reports [1,2], were reduced in this cohort against all reference populations, cerebrovascular disease significantly so for the U.S.A. and West Virginia populations. The few cases of each of these causes of death did not allow meaningful internal comparisons. Comparisons using DuPont Region 1 reference rates, but not U.S.A. or West Virginia rates, do indicate statistically non-significant elevations in SMRs for kidney cancer mortality (SMR=185; 95% 0 = 9 5 -- 323, p>0.05), and a statistically significant increase in diabetes mortality (SMR=197; 95% 0 = 1 2 3 -- 298, p<0.05) in males and females combined at this plant site. While few kidney cancer cases had been employed in APFO areas, the data from this study are inadequate for examining in appropriate detail rare outcomes such as kidney cancer. Similarly, the difficulties in examining mortality for diabetes prevent drawing conclusions based on these data. The results reported here show no convincing evidence of increased mortality risk associated with APFO exposure for workers at this plant. These results do show statistically non-significant elevations in relative risk for kidney cancer and a statistically significant increase in diabetes mortality for workers at this site. However, given the size and length o f follow-up of the study population, the evidence to thoroughly examine mortality events like kidney cancer or even diabetes, may not be adequate. Proportional hazards analyses for ischemic heart disease mortality showed an increase in the model based on equal distribution o f cases across cumulative exposure categories in one lagged analysis (the 10-year lag period). Other exposure lags showed no effect, and results for a second set of models using a different set of exposure cutpoints were attenuated toward the null. None of the hazard estimates themselves were statistically significant. Thus the positive finding in the proportional hazard analysis, as well as the increased diabetes mortality, might be due to chance. Because of the complexity of the exposure assessment and limited power for some analyses, additional investigations are needed. 10 of 73 II FINAL p. 11 Ammonium Perfluorooctanoate: Phase II. Retrospective Cohort Mortality Analyses Related to a Serum Biomarker of Exposure in a Polymer Production Plant Introduction Ammonium perfluorooctanoate (APFO) is the ammonium salt o f a fully fluorinated carboxylic acid, perfluorooctanoic acid (PFOA). APFO is used to aid in the emulsion polymerization of fluoropolymers. The salts of PFOA are soluble in water and readily dissociate to the carboxylate anion (PFOA). APFO is a process additive, i.e., it is the surfactant that enables the fluoropolymer components to remain emulsified in order for polymerization to occur. Neither APFO nor PFOA is incorporated into the fluoropolymer. As a result of industrial use o f APFO and biopersistence o f PFOA in the blood o f humans, the potential health effects of APFO have been examined in multiple studies, primarily in occupational cohorts [1-7]. A study o f community exposure to PFOA was conducted to determine the relationships between serum concentrations and exposure sources, and also to examine the relationships between PFOA and hematologic and biochemical clinical markers. This community study indicated that water, not air, was the likely source o f exposure; no associations were seen with adverse health effects [8-9], Some general population samples have been used to examine biomonitoring data that indicated that age, gender, and possible duration o f exposure had little to do with the background levels in the population. [10-12], A retrospective cohort mortality study was conducted at a 3M plant in Cottage Grove, Minnesota, that produced APFO [1], The cohort consisted o f 3,537 workers employed for at least six months between January 1947 and December 1983. Follow-up was nearly complete (99.5%) for the study participants, and 398 deaths were recorded. Since APFO production was limited to the Chemical Division, the two exposure categories were "exposed" (worked at least one month in the Chemical Division) and "not exposed" (worked one month or less in the Chemical Division). Standardized mortality ratios (SMRs) were calculated comparing the Cottage Grove cohort with mortality rates for the populations of the U.S.A. and the state of Minnesota, using stratification for duration of employment and 3 exposure latency periods. When exposure status was taken into account, most SMRs were significantly lower than the expected rate, a not surprising finding, considering the potential for healthy worker bias. The SMR for prostate cancer was elevated in the Chemical Division (area o f APFO production), but this increase was not statistically significant as it was based on only four cases. Internal comparisons were performed using proportional hazards modeling for various categories of causes o f death, including prostate cancer. The only mortality rate ratio that was statistically significantly greater than 1.0 was for the association between prostate cancer and duration of work in the Chemical Division. However, given that there were only four cases in the Chemical Division and an additional two cases in the rest of the cohort, it is difficult to emphasize this finding. This study was updated through 1997; the updated cohort consisted o f 3,992 workers who had worked for at least one year at the Cottage Grove Plant. [2] The exposure categories were changed to comprise three groups: "definite" (based on tasks performed in the Chemical Division); "probable" (tasks involving transient, lower exposures); and "non-exposed" (primarily non-Chemical Division jobs). A few SMRs were elevated: cancer o f the prostate (N =l; 11 o f 73 FINAL SMR=1.30, 95% Cl: 0.03-- 7.20); pancreatic cancer (N =l; SMR=1.34, 95% Cl: 0.03-- 7.42); and cerebrovascular disease (N=5; SMR=2.58, 95% Cl: 0.84-- 6.03); but none were statistically significant, and all elevated SMRs were based on very few cases. The DuPont Epidemiology Program conducted a cross-sectional health survey (Phase I) o f 1,025 employees at the Washington Works, West Virginia polymer production facility. That investigation used epidemiologic and statistical analyses of several types o f clinical data and a biomarker of exposure (serum PFOA) to determine the presence o f any association between occupational exposure to APFO and measurable changes in clinical laboratory measurements or physical examination endpoints. The results of this study indicated a positive association between serum level of PFOA in workers at the polymer production plant and serum cholesterol, triglycerides, and LDL cholesterol. No association was seen with HDL cholesterol [3], These results were similar to those published by Olsen et al. [4] from a cross-sectional study on 3M workers at two plants. After adjustment for potential confounders including body mass index (BMI), current alcohol use, smoking, and age, a statistically significant association between increased serum levels of PFOA and increased levels of both cholesterol and triglycerides were observed in multivariable linear regression analyses. Longitudinal analyses for the 3M workers also showed that PFOA was positively associated with serum cholesterol (log-linear regression coefficient = 1.03; 95% Cl: 1.01-- 1.05) and serum triglycerides (log-linear regression coefficient =1.10; 95% Cl: 1.05-- 1.16). However, as in our own study, the percent o f variation explained by the model, as well as by serum PFOA, was small, and there was no association of serum PFOA with HDL cholesterol. The 3M investigators had concluded that since their results were opposite to those expected based on animal studies, their findings were probably spurious. DuPont conducted a cross-sectional medical surveillance for altered liver function on the workers at the Washington Work plant site in 1979. These results indicated no changes in levels o f liver enzymes associated with work area assignment [5]. Gilliland and Mandel examined clinical chemistries in 3M workers and reported no abnormalities or associations with total organic fluorine levels [6], They did suggest that serum total organic fluorine levels might modulate hepatic responses to obesity and alcohol, but this suggestion was not supported by results of subsequent surveillance examinations among those workers [7]. The current study examines all-causes of death combined and cause-specific mortality rates for the DuPont employees at the Washington Works, West Virginia, polymer manufacturing facility. This facility produces several types of polymers, most of which are made by processes not involving APFO. Approximately one-third of the employees at the plant works in APFO-using areas. SMRs were calculated by using three different reference populations: the general U.S.A. population, the state population of West Virginia, and an eight-state regional DuPont employee population (DuPont Region 1). Because increased lipids levels are a risk factor for cardiovascular diseases, we also used Cox proportional hazards models to estimate mortality rate ratios (MRR) for an internal comparison o f mortality due to ischemic heart disease associated with categories of exposure to APFO. The exposure assessment for PFOA was based on a combination of work history information for each subject and serum PFOA levels obtained from the Phase I cross-sectional survey of the active workers in 2004. Methods FINAL p. 13 Cohort Ascertainment The cohort was defined as all individuals who have ever worked at the Washington Works plant at any time between January 1, 1948 (plant start-up) and December 31, 2002. The cohort was ascertained primarily through the DuPont Epidemiology Registries; additional members were identified from plant-based work history records. DuPont Mortality Registry The DuPont Company has maintained a Mortality Registry for all active and pensioned U.S.A. employees since 1957. This Registry provides the expected numbers o f deaths used in the DuPont Epidemiology Surveillance Program SMR calculations to compare each plant site in the U.S.A. to the rest of the U.S.A. DuPont population. Deaths are reported to the Registry by the corporate Benefits division through death certificates that accompany life insurance claims filed by beneficiaries of deceased employees and pensioners. Until recently, employment duration of at least 15 years was required for pensioning. However, additional changes in vesting strategies and insurance policies created fiduciary responsibility on the part of the Company that requires notification o f death of additional former employees. Deaths are ascribed to the observed numbers for the plant site at which the employee worked at the time of death, or the site at which the pensioner worked at the time o f retirement. For those who left the Company between 1950 and 1979, 91.7% were either pensioned or covered by some other vested benefit. O f the employees leaving the company between 1980 and 2005, only 60% were pensioned or covered by other vested benefits. However, deceased non-pensioned employees terminating after 1979 have been added to the Registry through the use o f the National Death Index database, NDI Plus. In addition, the social security numbers for each cohort member were submitted to the Social Security Administration for confirmation o f vital status. The Employee Registry, which provides the demographic information on all individuals ever employed by DuPont in the United States, is updated from a monthly upload from Corporate Human Resources. The Epidemiology Employee Registry currently includes approximately 265,000 individuals, 6,027 who ever worked at Washington Works, approximately 2000 of whom are presently located at that site. Exposure Categorization While the half-life o f PFOA in humans is estimated to be about 4 years [13], the kinetics of PFOA in humans are not well characterized. APFO can be absorbed via inhalation, as well as orally and dermally. Dermal absorption is very slow, and is an issue only for occupational exposure [14,15], Serum PFOA levels were considered the best measure o f exposure, because serum levels integrate all routes o f exposure and provide an estimate o f the amount o f the compound delivered internally to the organ tissues. Information regarding the relationship between an individual's job and the measured serum PFOA level was based on the Phase I cross sectional health survey conducted in 2004 and incorporated into the exposure assessment for the retrospective cohort mortality study. There were four major steps in determining exposure categories in Phase I. 13 of 73 FINAL p. 14 1) Establish relative exposure categories for current job titles using serum PFOA. a. Link individually measured serum PFOA levels measured with the job title held by the individual at the time of sampling. b. Examine the median, range, and distribution of serum levels for each job to determine the typical exposure for that job title. c. Based on the "typical" exposures, assign each job title to one o f three relative exposure categories (Job Exposure Category: low, medium, high). 2) Apply Job Exposure Categories to historical job titles. a. Link unique job titles from work history files with job titles and assign the historic job titles to the corresponding Job Exposure Category. b. Apply appropriate Job Exposure Category to each record in the cohort work history. 3) Calculate individual exposure metrics a. Multiply the time each individual spent in each Job Exposure Category by the intensity factor associated with that category and sum across all categories to calculate individual Cumulative Exposure. b. Calculate Average Intensity by dividing cumulative exposure by duration of hire. 4) Validate exposure classification by plotting exposure variables (average exposure intensity, cumulative exposure, and concurrent job intensity factor) versus the measured serum PFOA levels collected as part of a plant-site voluntary biomonitoring program Establish Job Exposure Categories Exposure and employment data were collected for 1,025 Washington Works employees as part of the Phase I cross-sectional health survey conducted in 2004. These data were combined to establish exposure categories for job titles. In the cross-sectional study, work divisions at the plant site were designated as "APFO-use" or "no APFO use" based on the potential for exposure to APFO, with the understanding that some individuals within APFO-use divisions may not have had exposure to APFO and some individuals in no APFO-use divisions may have had undocumented exposure to APFO. Median, minimum, and maximum serum PFOA levels were calculated for each no APFO-use division, using only individuals who had never worked in an APFO-use division, to establish the criteria for the low-intensity job exposure category. Next, the median, minimum, and maximum serum PFOA levels were calculated for each job title in the APFO-use divisions. The divisions designated as "APFO-use" Divisions included: TEFLON Maintenance, TEFLON Polymers Production, TEFLON Copolymers Production, Research, and Technical. The distribution of serum PFOA levels within each job title was examined. See Appendix D. APFO-use jobs were then grouped into three job-exposure categories based on job-specific PFOA serum level information: 14 of 73 FINAL Job Exposure Category 1 consisted o f all no APFO-use division jobs, and APFO-use jobs within the same serum level range as those employees who had never had a job assignment in any APFO-use division--median<0.25 ppm. Job Exposure Category 2 consisted of APFO-use jobs with a median serum level >0.25 ppm and <0.75 ppm. Job Exposure Category 3 comprised all APFO-use jobs with a median serum level >0.75 ppm. Some latitude was allowed in the use o f median serum levels as the only criterion in the assignment of a given job title to a job exposure category. In instances where a job title was categorized differently than similar job titles as a result o f a median serum value from a very small sample, the job title was grouped with the similar job titles. (See Exhibit 1.) Exhibit 1. Group changes based on similar job titles Division Job Serum PFOA Median Min Max n APFO-USE@ COPOLYMERS PROD. AREA SPECIALIST 0.255 0.255 0.255 i APFO-USE@ POLYMERS PROD. TECHNICAL APFO-USE@ COPOLYMERS PROD. SR ENGINEER TECH SPEC TECH SPEC 0.765 0.783 1.46 0.412 1.59 4 0.783 0.783 1 1.46 1.46 1 Job Exposure Category From To 21 32 32 32 Reason Moved to be in same category as other "Specialists" (n= l 1) with similar exposure (Range: 0.025 -0.272) M oved to be with other "Sr Engineers" in Job Exposure Category 2 (n= 8; Range: 0.097 - 0.576) Moved to be with other "Specialists" in Job Exposure Category 2 (n= 7; Range: 0.134 - 1.28) The resulting numbers o f cross-sectional study participants with jobs in Job Exposure Categories 1, 2, and 3 were 784, 107, and 134, respectively. The mean serum levels within the respective groups were 0.21, 0.43, and 1.69 ppm. Those mean serum levels served as the intensity factors for the three Job Exposure Categories. Because PFOA is believed to have a half-life o f about 4 years in humans [13], the length o f time spent in the assignments used to define the Job Exposure Categories was examined to ensure that the job titles would not be misclassified as a result o f individuals with either very short or very long stays in the job. Each participant's serum PFOA level was plotted against the time in the concurrent job by Job Exposure Category. The resulting correlation indicated that time in job was not strongly associated with serum PFOA level and should not substantially contribute to misclassification of job titles. FINAL Application of Job Exposure Categories to Historical Job Titles Complete job histories for all Washington Works employees were obtained via electronic files from the Human Resources department at the plant site. In addition, historical work divisions were designated as "APFO-use" or "no APFO-use" based on the potential for occupational exposure to APFO. All historical job titles in the "no APFO-use" work divisions were assigned to Job Exposure Category 1. Approximately 1600 unique "APFO-use" job titles were identified in the work history files. Most of those unique job titles resulted from variations in spelling or abbreviations, or division name changes for common job titles. Historic job titles were matched with similar titles identified in the cross-sectional survey and assigned to the corresponding Job Exposure Category. Calculation of Individual Exposure Metrics Cumulative exposure was calculated for each individual in the full cohort by multiplying time in the various job exposure categories by the intensity factor associated with job exposure categories 1 through 3, either 0.21, 0.43, or 1.69 ppm, respectively. Average intensity was also calculated for each cohort member by dividing the individual's cumulative exposure by their duration o f hire, as shown in Exhibit 2 below. Exhibit 2. Example of calculation o f average intensity o f exposure*. Time in Intensity Exposure Category Factor JobExpCatl 2.50 0.21 0.52 JobExpCat2 12.00 0.43 5.16 JobExpCat3 7.25 1.69 12.25 1 7 .9 4 / 2 1 .7 5 ___________ *Values are at end o f follow-up Validate Exposure Classification To validate the assignment of Job Exposure Categories to historical job titles, relationships were examined between calculated exposure values and measured PFOA serum levels in the Phase III Longitudinal Study dataset [16] (see Figures 4, 5, and 6). The Longitudinal Study dataset was comprised of sampling data for individuals with more than one sample from the Fluoropolymers Laboratory Analysis Information Retrieval (FLAIR) biomonitoring database together with the Phase I study. The FLAIR biomonitoring database archived serum PFOA data collected on a voluntary basis to ensure the effectiveness of workplace controls. Samples had been collected between 1979 and 2002. FINAL Since the assignment o f Job Exposure Categories to historical job titles was based on blood PFOA measurements that were taken in Phase I, those values were removed for the validation analysis. There were also 40 observations from the FLAIR database (corresponding to 23 employees) where the PFOA blood sample was taken after the employee had stopped working at the plant. These 40 observations were also removed from the validation analysis. Our validation was performed on dataset 6 as described in Exhibit 3. Exhibit 3 Etiology o f Validation Data Set Data set 1 FLAIR database 2 Cross-Sectional Study 3 All FLAIR data and Cross sectional data of FLAIR participants 4 FLAIR and Cross-sectional participants with more than 1 measurement each 5 FLAIR and Cross-sectional participants with more than 1 measurement each minus the Cross-sectional samples 6 FLAIR and Cross-sectional participants with more than 1 measurement each minus the Cross-sectional samples and retiree samples Date of Number of Collection Participants 1979-2002 891 2004 1025 1979-2004 891 1979-2004 461 1979-2002 461 1979-2002 451 Number of Observations 1947 1025 2148 1718 1517 1477 Cumulative exposure, average intensity, and concurrent job intensity factor were calculated for each individual up to the time o f the sampling (from hire date to sample date). The relationships between each serum PFOA value and the corresponding average intensity, cumulative exposure, and concurrent job intensity factor were analyzed. There were 21 missing values for job intensity factor and 6 missing observations for average intensity. First, the observations were treated as being independent (although many employees had more than one observation) and examined in a general linear model. Then the associations between serum PFOA and the exposures of interest (average intensity, cumulative exposure, and concurrent job intensity factor) were examined in mixed models. FINAL Exhibit 4. Results o f mixed model used to validate cumulative exposure to PFOA: serum PFOA as a function o f estimates o f PFOA exposure based on job. Correlation P value Coefficient Average Intensity Cumulative Exposure Intensity Factor 0.40 <0.0001 0.36 <0.0001 0.39 <0.0001 Prior to fitting the mixed models, sample variograms were created for the outcome variable (blood PFOA) to evaluate the serial correlation, the measurement error and the random effect for each mixed model. The spatial power covariance structure was found to have the best fit for the data and was therefore used. This structure allows the correlations between errors to be modeled in such a way that two points that are close in time are more correlated than two points that are further apart in time. This covariance structure is appropriate for unequally spaced measurements, which was the case in our dataset since employees were having their blood PFOA checked voluntarily and at different time intervals. Each model included the exposure of interest (average intensity, cumulative exposure, or we calculated the numbers o f years since January 1, 1979 that would correspond to each calendar date (example: (blood sample date-January 1, 1979)/365.25). An interaction term between the exposure variable and the date variable was also added to the model. All exposure variables were positively and significantly associated with the outcome (serum PFOA), suggesting that historical job titles were properly categorized (see Exhibit 5). Time was negatively associated with serum PFOA, supporting the observation that PFOA is reduced over time. The model that gave the best fit was the mixed model that included the exposure variable and the time variable, without the interaction term. The concurrent job intensity factor model had the best fit for the data as suggested by the lowest fit statistic test. Therefore intensity factor explains serum PFOA better than cumulative exposure and average intensity. This suggests that concurrent exposure has greater influence on serum PFOA levels than past exposure and, therefore, the use o f concurrent measured serum levels to characterize job titles into relative exposure categories is a valid approach for this compound despite the concerns around half-life. FINAL Exhibit 5. Validation o f exposure using repeated measurements (mixed model) to predict serum PFOA A. Predictor variable: average intensity Coefficient Average intensity 0.899 Time * -0.036 Fit statistic: AIC = 5445.7** P <0.0001 0.0006 B. Predictor variable: cumulative exposure Coefficient Cumulative exposure 0.0002 Time * -0.034 Fit statistic: AIC = 5477.6 ** P <0.0001 0.0014 C. Predictor variable: intensity factor Coefficient Intensity factor 0.796 Time * -0.036 Fit statistic: AIC = 5407.8 ** P <0.0001 0.0006 * Time is calculated as number o f years since 1979 ** For AIC (Akaike Information Criterion), the smaller value indicates better fit. Mortality Analyses and Development of Occupational Reference Files All SMRs were calculated using OCMAP (Occupational Mortality Analysis Program) developed by the University o f Pittsburgh [17]. This software compares observed numbers of deaths in the study population to expected numbers o f deaths based on rates for chosen reference populations for specific gender, 5-year time, and 5-year age categories by cause of death. State and U.S.A. reference rate files were acquired directly from the University o f Pittsburgh. Estimating relative risks by SMRs is a standard epidemiological approach to adjust for confounding by age and other characteristics that differ between populations. Typically, the general U.S.A. population is used as the reference group; however, it is not an appropriate comparison group for a worker cohort. Because healthier people are selectively hired to work, these populations may not be comparable in terms o f health status. This may introduce a downward bias in estimates o f the SMR due to confounding by the healthy worker effect [18 20]. While the effect is generally stronger for chronic diseases, the downward bias in comparative estimates has also been demonstrated for cancer [21]. One approach for reducing healthy worker bias is to choose a reference population composed of workers unexposed to the particular hazardous agent of interest. Restricting the comparison group to the same geographical region as the exposed cohort also improves comparability by 19 o f 73 c0 FINAL reducing likelihood of unmeasured confounding by commonly shared regional characteristics such as diet and lifestyle. Preliminary results from our work on another large occupational cohort indicated that the most appropriate comparison for occupational cohorts is the working population of the same company drawn from the same region as the study plant site (manuscript in preparation). Potentially biased estimates of reduced SMRs usually seen when comparisons are made to general non-occupational populations are not observed using this comparison, presumably because the healthy worker effect is reduced. Additionally, comparing mortality rates for workers from the same general region adjusts for local socio-cultural factors, although not all local effects are likely to be removed. A second component of healthy worker bias arises from the healthy worker survivor effect (HWSE). This bias is introduced when less healthy workers leave the workforce earlier than healthy workers, thereby having no opportunity to accrue cumulative exposures as large as more healthy workers. One approach that has been proposed to reduce this healthy worker survivor effect, is to assign zero weight to exposures in the 5 to 10 years proximate to the date of death (or diagnosis) in order to discount the effect of exposures during periods of time closer to the event o f interest [22-23]. For the DuPont employee comparisons, we created a DuPont regional reference file (DuPont Region 1) that included all DuPont employees in West Virginia and seven neighboring states: Ohio, Virginia, Kentucky, Indiana, Pennsylvania, Tennessee, and North Carolina (excluding those employees at the Washington Works site). For the DuPont worker mortality rates, race was not an adjustment variable. No follow-up methods or efforts additional to those used in Registry ascertainment were applied to the cohort files. The first level of cohort analysis was the calculation of SMRs for the entire Washington Works cohort, with follow-up from 1948 to 2002, the last year for which the Registry has been updated through NDI Plus. SMRs were calculated based on comparisons to the U.S.A. general population, the state of West Virginia, and the DuPont Region 1 reference file. Cox Proportional Hazards Modeling SMRs are useful for comparing mortality between an exposed to an unexposed reference group. However, in order to take full advantage of the exposure assessment for PFOA and examine exposure-response relationships we turned to Cox models for one outcome-- ischemic heart disease. Cox proportional hazards models (CPHM), with age as the time metameter, were used to estimate adjusted mortality rate ratios (MRRs) for ordinal PFOA exposure categories. These categories were based on the cumulative exposure calculated for each member of the historical cohort based on the categorization of jobs. The cumulative exposure thus calculated was then used to derive the average exposure intensity for each cohort member, based on the job history data. Ischemic heart disease mortality was chosen based on the fact that increased lipids are a risk factor for ischemic heart disease, and there were sufficient cases to enable division into exposure groups. For ischemic heart disease, we estimated mortality rate ratios using lagged exposure (5, 10, 15, and 20 years) to reduce any bias introduced by the healthy worker survivor effect. FINAL p. 21 CPHM is a statistical model used to investigate the relationship between survival time (or time to event) and one or more independent variables [24], An assumption that must be met for these analyses to be meaningful is that the hazard rates are proportional to one another at all ages. This means that at any given age (t), the hazard rate for those exposed to a risk factor [hftf] is a constant multiple o f the underlying hazard [h0(t)] for that age. A significant advantage to the approach is that the baseline hazard function does not have to be explicitly described, since the different risks are relative. The model can be stated as follows: hi(t) = h0(t) x B Estimating the constant multiplication factor for changes in risk (B) is conveniently done using an exponential function, B = cb. Reformulating equation 1 yields h,(t) = h0(t) x Qb. Therefore, if ho(t) represents the hazard in the unexposed group at any given time, the hazard ratio (HR) comparing the exposed and unexposed is HR = [h](t)] / [ h0(t)\ = eb, or taking logarithms, log(HR) = b. All CPHM was conducted using SAS Proc PHREG, version 9.01. Description of Methods Specific to Ischemic Heart Disease There were only three cases of IHD among women and only one non-white male case. Therefore, women and non-whites were excluded from all proportional hazards analysis. Person-time for the risk set of each index case was comprised of people who had started working by the age of the case that defined the risk set (case age at death), and were still alive at that age. In addition to exposure to PFOA, the regression models also included calendar year o f death in order to control for secular trends over the follow-up period. There were 235 cases o f ischemic heart disease available for analysis. Since cases were hired on average 20 years earlier than the non-cases, year o f hire was also included to adjust for confounding. Because half o f the cases were hired before 1954, we created a binary variable for year of hire (before or after 1954) that was included in the model. The correlation between calendar year of death and the binary variable, hired pre- or post-1954, was - 0.44 (pO.OOOl). We chose to use average intensity and cumulative exposure as the exposure metrics for CPHM analysis. Because heart disease mortality is known to be strongly affected by the healthy worker survivor effect, we chose to lag both exposure metrics 5, 10, 15, and 20 years. These lags eliminated the more recent exposures to reduce bias engendered by healthier workers staying in the workplace longer periods of time thus accumulating more exposure. Categories o f exposurefo r average intensity: In each Cox model, workers whose jobs were categorized as having the lowest exposure to PFOA (lowest average intensity) and who also never worked in any APFO-using division were considered the reference group, thus enabling an internal analysis. Both the APFO areas of the plant site and the non-APFO areas comprise a wide diversity ofjobs (mechanics, engineers, supervisors, administrative, etc.) This diversity o f job types in all non-APFO areas o f the plant 21 of 73 22 FINAL should make this group of workers comparable to those workers who ever worked with APFO all characteristics except for exposure to APFO. Five categories of average intensity of exposure to APFO were specified to ensure that an adequate number o f cases would be in each category, thus increasing the stability o f the MRR estimates. The exposure categories are ordinal, with 0 comprising the reference group, 1 being the lowest exposure, and 4 being the highest exposure category, for those analyses that comprised four categories. These exposure category definitions are presented in Exhibit 6. Exhibit 6. Average intensity o f exposure categories for proportional hazards analyses for ischemic heart disease mortality, stratified by exposure lag period. No lag of exposure N = 4,460 o Reference: x = 0.21 ppm and Never APFO-use o Category 1: x = 0.21 ppm and Ever APFO-use o Category 2: 0.21<x<= 0.250 ppm o Category 3: 0.250<x<=0.371 ppm o Category 4: > 0.371 ppm 167 cases 28 cases 12 cases 14 cases 14 cases Exposure lagging 5 years N = 4,440 o Reference: x = 0.21 ppm and Never APFO-use o Category 1: x = 0.21 ppm and Ever APFO-use o Category 2: 0.211 <= x <= 0.254 ppm o Category 3: 0.261 <= x <= 0.551 ppm o Category 4: 0.592 <= x <= 1.524 ppm 162 cases 30 cases 12 cases 13 cases 12 cases Exposure lagging 10 years N = 3,989 o Reference: x = 0.21 ppm and Never APFO-use o Category 1: x = 0.21 ppm and Ever APFO-use o Category 2: 0.211 <= x <= 0.256 ppm o Category 3: 0.261 <= x <= 0.555 ppm o Category 4: 0.565 <= x <= 1.524 ppm 152 cases 30 cases 11 cases 12 cases 12 cases Exposure lagging 15 years N = 3,986 o Reference: x = 0.21 ppm and Never APFO-use o Category 1: x = 0.21 ppm and Ever APFO-use o Category 2: 0.21 < x <= 0.269 ppm o Category 3: 0.269< x <= 0.591 ppm o Category 4: x > 0.591 ppm 142 cases 30 cases 11 cases 12 cases 12 cases 22 of 73 FINAL Exposure lagging 20 years N = 3,440 o Reference: x = 0.21 ppm and Never APFO-use o Category 1: x = 0.21 ppm and Ever APFO-use o Category 2: 0.21< x <= 0.330 ppm o Category 3: x > 0.330 ppm 130 cases 28 cases 16 cases 15 cases Categories o f exposurefo r cumulative exposure Cumulative exposure was estimated as the total attained exposure for each case event at the time o f death. Analytic strata were created for each case event by matching all eligible non-case subjects (workers who had not died by the date of the case event) and assigning cumulative exposure based on total attained exposure for each worker at the same age as the case event. Given that there is debate on the implications of the statistical aspects o f the categorization of cumulative exposure, two different approaches were used to determine four cumulative exposure categories. The two approaches thus provided a form o f sensitivity analysis. In the first analysis (exhibit 7A), quartiles of the cumulative exposure were determined by the distribution of exposures for case subjects. In a second analysis designed to test the model sensitivity to cumulative exposure categorization, quartiles were determined by the distribution of exposures for all workers in the cohort (exhibit 7B). For each lagged analysis, the exposure values for the four categories are shown for both strategies, and the number of cases of IHD mortality are listed. Cox models analyzing the proportional hazards for cumulative exposure categories with the lowest exposure group serving as the referent also included variables adjusting for calendar year of the case event and pre-1954 hire period. Exhibit 7A. Cumulative exposure categories for proportional hazards analyses for ischemic heart disease mortality, stratified by exposure lag period; quartiles determined by cumulative exposure distribution o f cases among white males. No lag of exposure N = 4,460 o Reference: x <= 3.81 ppm years o Category 1: 3.81<x< = 5.45 ppm years o Category 2: 5.45<x<= 6.78 ppm years o Category 3: x>6.78 ppm years Exposure lagging 5 years N = 4,440 o Reference: x: <= 3.42 ppm years o Category 1: 3.42<x< = 5.28 ppm years o Category 2: 5.28<x<= 6.51 ppm years o Category 3: x>6.51 ppm years 58 cases 59 cases 59 cases 59 cases 57 cases 57 cases 57 cases 58 cases 23 of 73 FINAL p. 24 Exposure lagging 10 years N = 3,989 o Reference: x <= 3.12 ppm years o Category 1:3.12<x< = 4.90 ppm years o Category 2: 4.90<x<= 6.40 ppm years o Category 3: x>6.40 ppm years 54 cases 54 cases 54 cases 55 cases Exposure lagging 15 years N = 3,986 o Reference: x <= 2.43 ppm years o Category 1: 2.43<x< = 4.19 ppm years o Category 2: 4 .19<x<= 5.66 ppm years o Category 3: x>5.66 ppm years 51 cases 52 cases 52 cases 52 cases Exposure lagging 20 years N = 3,440 o Reference: x <= 1.66 ppm years o Category 1: 1,66<x< = 3.48 ppm years o Category 2: 3.48<x<= 5.07 ppm years o Category 3: x>5.07 ppm years 47 cases 47 cases 47 cases 48 cases Exhibit 7B. Cumulative exposure categories for proportional hazards analyses for ischemic heart disease mortality, stratified by exposure lag period; quartiles determined by cumulative exposure distribution of entire cohort. No lag of exposure N = 4,460 o Reference: x <= 0.99 ppm years o Category 1: 0.99<x< = 4.29 ppm years o Category 2: 4.29<x<= 6.98 ppm years o Category 3: x>6.98 ppm years 10 cases 61 cases 114 cases 50 cases Exposure lagging 5 years N = 4,440 o Reference: x <= 1.97 ppm years o Category 1: 1.97<x< = 4.42 ppm years o Category 2: 4.42<x<= 6.24 ppm years o Category 3: x>6.24 ppm years 26 cases 61 cases 76 cases 66 cases Exposure lagging 10 years N = 3,989 o Reference: x <= 2.28 ppm years o Category 1: 2.28<x< = 3.85 ppm years o Category 2: 3.85<x<= 5.23 ppm years o Category 3: x>5.23 ppm years 37 cases 46 cases 37 cases 97 cases Exposure lagging 15 years 24 of 73 15 FINAL N = 3,986 o Reference: x <= 1.86 ppm years o Category 1: 1,86<x< = 3.16 ppm years o Category 2: 3.16<x<= 4.27 ppm years o Category 3: x>4.27 ppm years 38 cases 34 cases 33 cases 102 cases Exposure lagging 20 years N = 3,440 o Reference: x <= 1.19 ppm years o Category 1:1.19<x< = 2.38 ppm years o Category 2: 2.38<x<= 3.24 ppm years o Category 3: x>3.24 ppm years 27 cases 34 cases 28 cases 100 cases Results Cohort Description The Washington Works cohort consists o f individuals who worked at the plant at any time between 1948 and 2002. First, 5,476 individuals were originally identified from the Epidemiology Employee Registry. O f these persons, 22 individuals were excluded for the following reasons; 1 had no verifiable birth date, and 21 had transferred to the Washington Works location after December 31, 2002, the end o f the mortality surveillance period. This resulted in 5,454 individuals who were included from the Epidemiology Employee Registry with an additional 573 individuals included based on work history records obtained from the plant site Human Resources Department. The resulting cohort for all analyses included 6,027 individuals. Table 1 shows the descriptive statistics for the historical Washington Works cohort. Total person-years were 127,513.2 for males, and 18,224.5 for females. Person-years ascribed to the three cumulative exposure categories were 74,603.6 for Group 1 (lowest potential exposure to APFO); 52,461.8 for Group 2; and 18,672.3 for Group 3 (highest potential exposure to APFO). Mortality Analyses on Entire Cohort While the DuPont Regional population appears to be the most appropriate reference group for mortality rate comparisons, we also report SMRs based on both the U.S.A. and West Virginia rates. The U.S.A. comparisons provide some context for other studies in the published literature, and the comparisons to the West Virginia state population are presented in response to a request from study participants. As would be expected, almost all SMRs comparing Washington Works mortality rates for defined causes to the U.S.A. and West Virginia population mortality rates were below 100, the standard metric o f the SMR indicating no observed differences in the mortality rates between the compared populations. Further, many SMR estimates were statistically significantly below this estimate of no effect indicating that Washington Works employees had lower mortality rates for many causes o f death compared to the general population. Due to concerns about statistical precision, only those causes o f death for which there were at least five deaths observed were considered relevant for consideration of increased or decreased risk. FINAL p. 26 Table 2 shows selected SMRs for Washington Works males and females when compared to the three reference populations. These causes o f death were selected based on results from animal studies and other occupational studies, and are detailed below. Complete SMR analysis results are presented in Appendices A-C. There were only 33 deaths among females workers; limiting the statistical power to detect significant differences in disease-specific mortality rates among female workers and restricting interpretations o f SMRs to all causes of death combined and all cancers combined. All Causes o f Death For males, the SMR for all causes o f death was 94 (95% Cl: 87-- 100) based on the Region 1 DuPont population. The SMRs for all causes based on comparisons to West Virginia and total U.S.A. were 58 (95% Cl: 54-- 62) and 66 (95% Cl: 62-- 71), respectively. For females, the SMR for all causes of death was 147 (95% Cl: 101-- 207) based on the Region 1 DuPont population. The SMRs for all causes based on comparisons to West Virginia and total U.S.A. were 73 (95% Cl: 51-- 103) and 81 (95% Cl: 56-- 113), respectively. All Malignant Neoplasms For males, the SMR for all malignant neoplasms was 100 (95% Cl: 88-- 114) based on the Region 1 DuPont population. The SMRs for all malignant neoplasms based on comparisons to West Virginia and total U.S.A. were 68 (95% Cl: 60-- 78) (WV) and 74 (95% Cl: 64-- 84) (U.S.A.) For females, the SMRs for all malignant neoplasms were 149 (95% Cl: 77--260); 79 (95% Cl: 41-- 139), and 87 (95% Cl: 45-- 151) when comparing against the Region 1 DuPont Population, West Virginia, and total U.S.A., respectively. Cancer of Biliary Passages and Liver Based on seven deaths, the SMRs in males for cancer o f biliary passages and liver were 133 (95% Cl: 53-- 274), 104 (95% Cl: 42-- 215), and 90 (95% Cl: 36-- 185) when comparing against the Region 1 DuPont Population, West Virginia, and total U.S.A., respectively. There was only one death due to cancer of biliary passages and liver among females. Cancer of Pancreas For males, the SMRs for cancer of the pancreas were 100 (95% Cl: 50-- 180), 83 (95% Cl: 41-- 148), and 71 (95% Cl: 36-- 128) when comparing against the Region 1 DuPont Population, West Virginia, and total U.S.A., respectively. There were no reported cases of cancer of the pancreas in females. 26 of 73 XI FINAL Urinary Tract Cancers There were 12 deaths from kidney cancer in males; the SMRs were 185 (95% Cl: 95-- 323), 155 (95% Cl: 80-- 272), and 156 (95% Cl: 80-- 272) when comparing against the Region 1 DuPont Population, West Virginia, and total U.S.A., respectively. No deaths from kidney cancer were seen in females. There were 7 deaths from cancer of the bladder and other urinary organs in males; the SMRs were 131 (95% Cl: 53-- 269), 105 (95% Cl: 42-- 216), and 101 (95% Cl: 41-- 209) when comparing against the Region 1 DuPont Population, West Virginia, and total U.S.A., respectively. One death from bladder cancer was seen in females. Because there were few deaths from kidney cancer, there was not sufficient statistical power to fit Cox proportional hazard models for assessing the association of this outcome with exposure categories. Examination of job histories showed that only half the cases had ever worked in the APFO-use divisions. Cancer of Bronchus, Trachea. Lung For males, the SMR for cancer o f the bronchus, trachea, and lung was 81 (95% Cl: 63-- 104) based on the Region 1 DuPont population The SMRs for cancer o f the bronchus, trachea, and lung based on comparisons to West Virginia and total U.S.A. were 49 (95% Cl: 38-- 163) (WV) and 61 (95% Cl: 47-- 77) (U.S.A.) Cancer of Prostate The SMR for cancer o f the prostate was 65 (95% Cl: 34-- 114), and 58 (95% Cl: 30-- 100)), based on the Region 1 DuPont population and West Virginia, respectively. The SMR for cancer of the prostate based on comparisons to the total U.S.A. was 52 (95% Cl: 27-- 91). Cerebrovascular Disease For males, the SMR for cerebrovascular disease was 86 (95% Cl: 60-- 120) based on the Region 1 DuPont population. The SMRs for cerebrovascular disease based on comparisons to West Virginia and total U.S.A. were 60 (95% Cl: 42-- 84) (WV) and 61 ((95% Cl: 42-- 85) (U.S.A.). For females, only one death was due to cerebrovascular disease. FINAL All Heart Disease For males, the SMR for all heart disease was 110 (95% Cl: 98-- 123) based on the Region 1 DuPont population. The SMRs for all heart disease based on comparisons to West Virginia and total U.S.A. were 66 (95% Cl: 59-- 74) (WV) and 80 ((95% Cl: 71-- 89) (U.S.A.). For females, the SMRs for all heart disease were 143 (95% Cl: 46-- 333), 51 (95% Cl: 17-- 119), and 64 (95% Cl: 21-- 150) when comparing against the Region 1 DuPont Population, West Virginia, and total U.S.A., respectively. Ischemic Heart Disease In males, the SMRs for ischemic heart disease were 109 (95% Cl: 96-- 124), and 69 (95% Cl: 61-- 78), based on the Region 1 DuPont population and West Virginia, respectively. The SMR for ischemic heart disease based on comparisons to total U.S.A. was 81 (95% Cl: 71-- 93). There were only three deaths due to ischemic heart disease in females. Diabetes Mellitus Mortality from diabetes mellitus among males was significantly elevated based on comparison to the DuPont Region 1 population (SMR= 183; 95% 0 = 1 1 2 --283), but was below 100.0 in comparisons to both the West Virginia (SMR= 67; 95% 0 = 4 1 -- 104) and U.S.A. population (SMR= 81; 95% 0 = 5 0 -- 125). There were only two deaths attributed to diabetes among females. Cox Proportional Hazards Modeling Ischemic Heart Disease Table 3 presents the descriptive statistics for the white males used in the proportional hazards models for IHD, stratified by case/non-case status, and Table 4 shows descriptive statistics for this subset, stratified by never-APFO-use/ever-APFO-use. The first CHPM for ischemic heart disease was fit to data for 4,460 white males using the average intensity as the exposure of interest, with zero lag for exposure. Two models are presented in Table 5: each includes PFOA exposure variables, and one adjusts for calendar year of the event and the other adjusts for hire date (pre or post-1954) in the model (1954 was the median date of hire). Table 5 also shows the mortality rate ratios by exposure category for the no-lag models using case calendar-year or the binary variable for hired before 1954 as a potential confounder. When we looked separately at calendar year of death and date of hire, these two variables were both statistically significant. For calendar year of death, the MRR is less than one, which means that the background death rate for ischemic heart disease is going down over the study period. This is also true for the national mortality rates from ischemic heart disease in the U.S.A. (Figure 7). As for the date of hire, those hired prior to 1954 had higher risk of death from IHD than those hired FINAL p. 29 after 1954. However, when both of these variables (date o f hire and calendar year o f death) were accounted for in the model, only calendar year o f death remained significant which means that the effect of the date o f hire was confounded by the calendar year of death. Table 6 presents a summary o f the CPHM analyses on IHD conducted for all white males in the cohort without lagging average intensity exposures, and those with lags o f different time intervals (5,10, 15, 20 years) to adjust for potential effects of HWSE with the inclusion o f both potential time confounders (case calendar-year and hired before 1954). These results show no significantly increased MRRs for IHD mortality between exposure categories for all analyses, with and without lags. Additionally, no trends o f increasing MRRs are seen across exposure categories with the exception of category 4, the highest exposure group. The increase in MRR with increasing lag provides evidence that analysis using lagged exposures compensates for the healthy worker survivor effect for this cause of death. Details o f these analyses are presented in Table 6. Table 7 displays the results from both analyses o f cumulative exposure categories for Cox proportional hazard models of the association between cumulative exposure and IHD mortality. In the first part of the table (section A), results are reported for categories determined by quartiles of cumulative exposure among case subjects only. This method ensures that each exposure category contains one-fourth o f the cases (see exhibit 7A) for the corresponding lag model. Though no estimates o f the hazard ratio are statistically significant in any model, the results from the 10-year lagged exposure model suggest an increasing trend in the mortality rate ratio for the highest two exposure categories. Due to the lack o f consensus on a universally "best" approach to cumulative exposure categorization, we performed a second set o f analyses using quartiles determined by the entire WW cohort as a form of sensitivity analysis. Table 7B lists the results o f these models corresponding to cutpoints described in exhibit 7B. Although all estimates were still not statistically significant, mortality rate ratio estimates for this analysis attenuated towards the null value o f 1.0 for all lagged exposure models including those for the 10-year lag. Discussion In this retrospective cohort mortality study, we assessed whether workers at a polymer production plant exhibited increased mortality from any specific cause o f death, as well as the more general categories o f all causes and all malignant diseases. SMRs were generated using three different reference populations-- a regional population from the same company, which reduced the bias from both the healthy worker effect and regional socio-cultural attributes; the state population in which the plant was located; and the general U.S.A. population. Although the site o f the study is a manufacturing plant that produces a wide variety o f products from many different chemicals, the only occupational exposure examined was APFO. The areas where this chemical is used employs about one-third o f the site's workers. Exposure to APFO has been shown to cause benign neoplasms in rodent toxicology studies. Liver, Leydig-cell, and pancreatic acinar-cell tumors were observed in rats, but all o f those findings are hypothesized to be mediated via PPARa. Humans have low PPARa receptor expression, and are not as responsive to PPARa agonists [25]. This study had low power to 29 of 73 3 FINAL p. 30 detect excess risk for these rare tumors, and the increased SMR o f 135 for cancer of the biliary passages and liver, based on seven cases in males, was not statistically significant. Prostate cancer and cerebrovascular disease, both reported as increased in previous 3M Company occupational epidemiology reports [1,2], were reduced in this cohort against all reference populations, cerebrovascular disease significantly so for the U.S.A and West Virginia populations. The few cases o f each o f these causes o f death did not allow meaningful internal comparisons. Despite limited statistical power to evaluate mortality rates for specific cancers, some elevated relative risks did emerge that bear further scrutiny by worker surveillance and exposure monitoring. Although animal toxicology data and published occupational studies on workers exposed to PFOA do not provide any a priori reason to suggest a potential effect on risk for kidney cancer, comparisons against DuPont Region 1 returned increased, but non-significant SMRs. However, examination of work histories showed that few cases had spent appreciable time in the APFO areas. We did identify an increased mortality risk for diabetes mellitus in this cohort of workers-- driven largely by 20 cases in males and two in females--when comparisons were made to the regional worker population from the same company (SMR= 183; 95% 0 = 1 1 2 -- 283). However, comparisons to West Virginia (SMR= 67; 95% 0 = 4 1 -- 104) and to the general U.S.A. population (SMR= 81; 95% 0 = 5 0 -- 125) did not indicate an increased risk of mortality due to diabetes. Although Cox proportional hazard modeling could be done, the small number of cases would severely limit the value of the estimates. There is a substantial literature supporting the under-reporting o f diabetes, especially of lateonset or type II diabetes, on death certificates. Differences between countries' mortality reporting for diabetes has been shown to depend, among other factors, on physician differences in reporting this disease in Part I o f the death certificate or as the underlying cause [26]. In the U.S.A., a study o f the frequency of reporting diabetes on death certificates of 540 known diabetics showed that diabetes was recorded on just 39 percent o f the death certificates and as the underlying cause o f death for only 10 percent of decedents with diabetes. In addition, diabetes was significantly less likely to be reported on the death certificates o f decedents dying of cancer [27]. Our SMR analyses are based on the underlying cause o f death, and it is reasonable to assume that the prevalence of diabetes in this cohort has been under-ascertained. We know of no reason why the same under-ascertainment should not apply to the reference populations as well; thus, any bias in ascertainment would be non-differential. Cardiovascular death rates are higher in diabetics than in non-diabetics [28-29]. Although cardiovascular disease and late-onset diabetes share several risk factors (diets high in refined carbohydrates, sedentary lifestyle, age, and body mass index, for example), a study conducted in Iceland identified an independent effect of diabetes on coronary heart disease after adjustment for blood pressure, serum lipids, uric acid, smoking, and height and weight [30], As discussed below, no increase in cardiovascular disease was noted for this cohort. Given the number of endpoints examined in the SMR analyses, it is not surprising to find an isolated increase in one of the causes o f death. The lack of agreement with other studies of PFOA workers, and the lack of any animal toxicology findings to support this association suggest that the finding is due to chance. However, we will follow up on these results in future surveillance. 30 of 73 FINAL Our initial proportional hazards models o f ischemic heart disease, an outcome potentially influenced by increased serum lipids, utilized cumulative exposure. This metric seemed to be the most biologically appropriate. The results of these models, conducted without lagging of exposure, showed significantly reduced rate ratios, which were assumed to be due to confounding by the healthy worker survivor effect (age was controlled for by using it as the time metric in the Cox model). We then turned to average intensity o f exposure. With these analyses, we introduced the five-year lag of exposure, which appeared to mitigate the effects o f the healthy worker survivor effect, prompting the re-analysis o f cumulative exposure with lags. In order to stabilize the estimates of the mortality rate ratio, the exposure cutpoints were determined first by dividing the cases into quartiles, as is commonly done in occupational studies. The multi-dimensionality of occupational exposure metrics contributes to discussion about which metrics are the more robust, least biased, and most biologically meaningful [31]. In light o f this debate, we have presented analyses using both average intensity and cumulative exposure, with lagging and without. In addition, we conducted analyses on cumulative exposure with the cutpoints driven both by case and total cohort distributions o f exposure, which provides a sensitivity analysis for the impact o f cut-point selection on the observed exposure-response relationships. For ischemic heart disease mortality, no increases in mortality rate ratios were seen in the results o f any analyses conducted using average exposure intensity. Many of the MRRs were below 1.0. It is well known, however, that for a chronic disease such as IHD, mortality underestimates morbidity and is therefore not an ideal endpoint for epidemiologic analysis. Furthermore, the rate ratio for IHD may also be biased by the HWSE, even in internal analyses. The use o f lagged exposures by 5 year periods to adjust for the healthy worker survivor effect did not have much effect, as estimates o f the mortality rate ratio were still less than 1.0. There was, however, an increased trend in MRRs as the lag time increased from 0 to 20 years by 5-year intervals for Exposure Category 4 (highest exposure category). While these findings remain statistically non significant, the increase in the MRR as the lag increased for the highest exposure group demonstrated that this approach did indeed compensate for the healthy worker survivor effect among those who worked long enough to achieve exposures in the highest category. For proportional hazards models of cumulative exposure, no significant increase in the MRR was observed with the exception of the 10-year lag model based on the set of exposure categories with an equal distribution of cases assigned to each exposure group. An elevated relative risk of 1.6 was found in the highest exposure category, and there was an increasing trend in MRR with increasing exposure. While neither MRR estimate for the upper two exposure categories in the 10-year lag model was statistically significant, the apparent trend cannot be ignored. In order to investigate the sensitivity of the model to the categorization o f cumulative exposure, we redefined cumulative exposure categories based on quartiles of the entire WW cohort. Effect estimates from this model were attenuated towards a null value. The highest relative risk was again seen in the 10-year lagged model where the MRR was 1.3 for the highest exposure category, but there was no apparent trend. The overall absence of positive effect estimates using either the 5-, 15-, or 20-year exposure lags suggest that the positive exposure-response trend for cumulative exposure lagged by 10 years requires further investigation before firm conclusions can be reached. FINAL When we looked separately at calendar year of death and date o f hire (before or after 1954 for IHD), both time variables were statistically significant. For calendar year o f death, the MRR was less than one, which indicates that the background death rate for ischemic heart disease was going down over the study period. This is also true for the national mortality rates from ischemic heart disease in the U.S.A. As for the date o f hire, those hired prior to 1954 had higher risk of death from IHD than those hired after 1954. However, when both o f these variables (date of hire and calendar year of death) were accounted for in the model, only calendar year of death remained significant, evidence that the effect of the date of hire was confounded by the calendar year o f death. This finding underlines the importance o f exploring in detail all potential timevarying confounders in this type o f analysis. Strengths of this study include the availability of biomonitoring data to support retrospective exposure classification and a large cohort with over fifty years of follow-up. In addition, there were sufficient mortality data to enable several types o f analysis using both external and internal comparisons, including Cox proportional hazards analysis for ischemic heart disease. Limitations of this study include the potential loss to follow-up o f decedents prior to 1979, a period where exposures may have been less well-controlled, causing potential bias towards the null due to the healthy worker survivor effect. Although this loss could have been as high as 10 percent, due to the ascertainment procedures for the DuPont Mortality Registry, it was likely much smaller due to the establishment o f vital status of all cohort members through the Social Security Administration. Moreover, the lagged exposure approach applied to the ischemic heart disease analysis was designed to reduce such bias. A major limitation is likely to be the lack of accounting for confounding by other occupational and non-occupational risk factors. Most importantly, information was not available for members of the cohort about the major risk factors for cardiovascular disease (smoking, diet, and other life-style factors). Additionally, no information was available for cohort members who were being treated with medications such as statins or anti-hypertensive medications. Conclusions The results reported here show no convincing evidence of increased mortality risk associated with APFO exposure for workers at this plant. These results do show statistically non-significant elevations in relative risk for kidney cancer and a statistically significant increase in diabetes mortality for workers at this site. However, given the size and length o f follow-up of the study population, the evidence to thoroughly examine mortality events like kidney cancer or even diabetes, may not be adequate. Proportional hazards analyses for ischemic heart disease mortality showed an increase in the model based on equal distribution of cases across cumulative exposure categories in one lagged analysis (the 10-year lag period). Other exposure lags showed no effect, and results for a second set of models using a different set of exposure cutpoints were attenuated toward the null. None of the hazard estimates themselves were statistically significant. Thus the positive finding in the proportional hazard analysis, as well as the increased diabetes mortality, might be due to chance. Because o f the complexity of the exposure assessment and limited power for some analyses, additional investigations are needed. FINAL References [1] Gilliland, F.D. and Mandel, J.S. (1993). Mortality among employees o f a perfluorooctanoic acid production plant. J. Occup. Med. 35:950-954. [2] Alexander, B.H. (2001). Mortality study o f workers employed at the 3M Cottage Grove Facility. Final Report. 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Med. 45:113-122. FINAL TABLES 36 of 73 37 FINAL Table 1 W ashington W orks m ortality study cohort Washington Works Mortality Study Cohort (as of 12/31/2002) Cohort Age at Hire Year of Hire Age at Termination Year of Termination Duration of Hire (Yrs) Yrs of Follow Up Age at End of Follow _________________ % White Males n 4872 95.40% Mean 29 1974 50 1989 19 26 55 Min 11 1948 19 1955 0 0 20 Max 70 2002 74 2004 49 55 96 Females n 1155 92.29% Mean 27 1986 32 1993 10 16 43 Min 17 1948 18 1967 0 0 21 Max 56 2002 71 2004 44 55 85 #Active Duration of Hire (Yrs) Age at End of Follow Up #Dead #Cancer Deaths AgeAtDeath %White 1650 773 222 99.09% 429 17 0 41 14 0 40 46 23 68 44 22 67 33 12 66 22 96 58 22 85 96.97% FINAL Table 2 SMRs for selected causes of death in Washington Works males, females compared to DuPont Region 1 (W est Virginia (less Washington Works), Ohio, Virginia, Kentucky, Indiana, Pennsylvania, Tennessee, and North Carolina), U.S.A. national population, West Virginia state population Cause of Death All Causes o f Death All Malignant Neoplasms Cancer o f Biliary Passages & Liver Cancer o f Pancreas Cancer o f Bronchus, Trachea, Lung Cancer o f Prostate (Males only) Cancer o f Breast Cancer o f Kidney Diabetes Cerebrovascular Disease All Heart Disease Ischemic Heart Disease MALES N=4872 Total Mortality: 773 Person Years: 127,513.2 West DuPont U.S.A. Virginia Region 1 National State N SMR SMR SMR N (773) 93.6 66.2** 58.1** (33) (222) 100.4 73.7** 68.3** (12) (7) 133.1 (ID 100.5 89.7 74.0 104.2 82.9 (1) 0 (64) 81.3 60.6** 49.0** (2) (12) (0) (12) (20) (34) (309) (236) 65.3 0 184.7 183.1* 86.1 109.9 109.3 51.8** 0 155.7 81.2 60.9** 80.0** 81.4** 57.5 0 155.2 67.0 60.1** 66.3** 69.0 N /A (2) 0 (2) (1) (5) (3) FEMALES N=1155 Total Mortality: 33 Person Years: 18,224.5 West DuPont U.S.A. Virginia Region 1 National State SMR SMR SMR 147.2* 80.7 73.4 149.0 86.6 79.4 384.8# 0 394.5# 0 551.8# 0 132.9A 69.5A 56.6A 0 77.4A N /A 796.1A 90.5# 142.7 135.0 0 6 1 .1A N/A 160.8A 48.7# 64.4 64.0 0 63.5A N/A 121.7A 49.7# 51.1 49.7 (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL; (#) BASED ON 1 CASE; (A) BASED ON 2 CASES N/A Not Applicable FINAL Table 3 White male workers included in the risk-sets of the proportional hazard analysis for IHD stratified by case/non-case status Variable Total Number CASES N(%) or Mean (SD) [Minimu m-Maximu m] 235 (5.27 %) NON-CASES N(%) or Mean (SD) [Minimum-Maximuml 4225 (94.73 %) Males 235(100% ) 4225 (100 %) White Race (v/s non white) 235(100% ) 4225(100 %) Age at hire Year of birth Year o f hire Year o f death Ever-APFO-use 33.72 (9.82) [18.21-65.851 1921 (11.20) [1 892-19581 1955 (8.92) [1948-19951 1987(11.30) [1958-20021 68 (28.94 %) 29.06 (8.77) [11.23-70.171 1945(15.97) [1890-19731 1974(15.71) [1948-20021 NA 2185 (51.72%) 39 of 73 FINAL p. 40 Table 4 White male workers included in the risk-sets of the proportional hazard analysis stratified by never-APFO-use/ever-APFO-use status Variable Total Number Males White Race (v/s non white) Age at hire Year of birth Year o f hire Average intensity (at end of follow-up) Cumulative exposure (at end of follow-up) Time since hire (at end of follow-up) Cases NEVER-APFO-USE N(%) or Mean (SD) [Minimum-Maximum] 2207 (49.48 %) 2207 (100 %) 2207 (100 %) 30.89 (9.42) [14.40-70.17] 1941 (18.37) [1890-1972] 1972 (17.10) [1948-2002] 0.21 (0) [0.21-0.21] 4.06 (2.51) [0.00-9.02] 18.83 (12.20) [0.00-42.27] 167 (7.57 %) EVER-APFO-USE N(%) or Mean (SD) [Minimum-Maximum] 2253 (50.52 %) 2253 (100%) 2253 (100%) 27.74 (8.04) [11.23-64.15] 1947(14.10) [1903-1973] 1974 (14.72) [1948-2002] 0.42 (0.35) [0.21-1.69] 9.10(10.00) [0.01-71.851 21.00 (12.63) [0.05-48.54] 68 (3.02 %) 40 of 73 f/ FINAL p. 41 Table 5 Mortality rate ratios for IHD by exposure category for no-lag analyses using case calendar- year and year of hire (pre-1954) as potential confounders Reference Hired Dre-1954 NO LAG N = 4,460 MRR ( 95 % Cl) 1 Case-calendar year NO LAG N = 4,460 MRR ( 95 % Cl) 1 Category 1 Category 2 Category 3 Category 4 Case CalendarYear Hired before 1954 0.858 (0.569-1.293) 0.575 (0.319-1.035) 0.767 (0.444-1.327) 0.558 (0.323-0.966) -- 1.422 (1.075-1.881) 0.996 (0.657-1.509) 0.715 (0.394-1.298) 0.944 (0.542-1.645) 0.646 (0.372-1.123) 0.965 (0.952-0.978) -- 41 o f 73 FINAL p. 42 Table 6 Mortality rate ratios for IHD by average intensity exposure category, including increasing 5-year lags of exposure, using case calendar-year and year of hire (pre-1954) as potential confounders Reference* NO LAG N = 4,460 MRR ( 95 % Cl) 1 5-YEAR LAG N = 4,440 MRR ( 95 % Cl) 1 10-YEAR LAG N = 3,989 MRR (95 % Cl) 1 15-YEAR LAG N = 3,986 MRR (95 % Cl) 1 20-YEAR LAG N = 3,440 MRR (95 % Cl) 1 Category 1 Category 2 Category 3 Category 4 Case CalendarYear Hired before 1954 0.996 (0.657-1.510) 0.715 (0.394-1.298) 0.944 (0.541-1.646) 0.646 (0.372-1.123) 0.965 (0.951-0.979) 1.001 (0.738-1.360) 1.035 (0.689-1.557) 0.657 (0.361-1.195) 0.738 (0.416-1.310) 0.842 (0.466-1.521) 0.965 (0.950-0.980) 1.042 (0.764-1.421) 1.048 (0.693-1.582) 0.688 (0.369-1.284) 0.802 (0.442-1.457) 0.890 (0.491-1.611) 0.963 (0.947-0.979) 1.089 (0.791-1.501) 0.976 (0.643-1.482) 0.763 (0.409-1.427) 0.943 (0.519-1.715) 0.975 (0.538-1.769) 0.963 (0.946-0.981) 1.087 (0.780-1.513) 0.884 (0.574-1.362) 0.976 (0.573-1.663) 0.828 (0.481-1.424) -- 0.964 (0.944-0.985) 1.053 (0.744-1.492) * Exposure distributions for each category by lag period are listed in exhibit 6. 42 of 73 ^3 FINAL p. 43 Table 7 Mortality rate ratios for IHD by cumulative exposure category, including increasing 5-year lags of exposure, using case calendar-year and year of hire (pre-1954) as potential confounders; A) exposure categories based on case distribution, B) exposure categories based on cohort distribution. NO LAG 5-YEAR LAG 10-YEAR LAG 15-YEAR LAG 20-YEAR LAG A) N = 4,460 N = 4,440 N = 3,989 N = 3,986 N = 3,440 Reference* MRR ( 95 % Cl) 1 MRR ( 95 % Cl) 1 MRR (95 % Cl) 1 MRR (95 % Cl) 1 MRR (95 % Cl) 1 Category 1 Category 2 Category 3 Case CalendarYear Hired before 1954 1.046 (0.711-1.539) 1.156 (0.745-1.793) 1.110 (0.698-1.767) 0.959 (0.942-0.977) 0.946 (0.672-1.333) 0.864 (0.579-1.291) 1.204 (0.757-1.914) 1.077 (0.657-1.764) 0.958 (0.940-0.976) 0.952 (0.671-1.352) 0.996 (0.647-1.531) 1.377 (0.829-2.287) 1.610 (0.942-2.753) 0.948 (0.928-0.968) 0.903 (0.633-1.289) 0.935 (0.598-1.461) 1.102 (0.644-1.887) 1.089 (0.597-1.984) 0.958 (0.935-0.982) 1.032 (0.710-1.501) 0.647 (0.407-1.029) 0.692 (0.388-1.233) 0.764 (0.393-1.489) 0.969 (0.943-0.997) 1.096 (0.733-1.639) B) Reference! 1 1 1 1 1 Category 1 Category 2 Category 3 Case CalendarYear Hired before 1954 1.018 (0.515-2.010) 1.132 (0.573-2.235) 1.027 (0.496-2.127) 0.961 (0.945-0.978) 0.969 (0.692-1.357) 0.980 (0.607-1.582) 1.014 (0.603-1.705) 1.019 (0.571-1.817) 0.961 (0.943-0.980) 1.008 (0.711-1.429) 1.062 (0.662-1.680) 0.825 (0.483-1.409) 1.256 (0.721-2.191) 0.954 (0.934-0.975) 0.974 (0.679-1.398) 0.914 (0.557-1.502) 0.860 (0.494-1.497) 1.069 (0.598-1.910) 0.958 (0.936-0.981) 1.027 (0.710-1.484) 0.967 (0.568-1.647) 0.931 (0.505-1.717) 0.882 (0.461-1.688) 0.967 (0.940-0.994) 1.095 (0.742-1.614) * Exposure distributions for each category by lag period are listed in exhibit 7A. f Exposure distributions for each category by lag period are listed in exhibit 7B. 43 of 73 FINAL FIGURES FINAL Figure 1. Time in Job vs Serum PFOA-Cross-Sectional Study-Job Exposure Category 1 Job Exposure Category 1 APFO-Use Jobs Serum PFOA (ppm) FINAL p. 46 Figure 2. Time in Job vs Serum PFOA-Cross-Sectional Study-Job Exposure Category 2 Job Exposure Category 2 Serum PFOA (ppm) 46 of 73 FINAL p. 47 Figure 3. Time in Job vs Serum PFOA-Cross-Sectional Study-Job Exposure Category 3 Job Exposure Category 3 47 o f 73 48 FINAL Figure 4. Serum PFOA vs Cumulative Exposure - FLAIR Data Serum PFOA vs Cumulative ExposurePotential p. 48 Serum PFOA (ppm) 48 of 73 FINAL p. 49 Figure 5. Serum PFOA vs Average Intensity of Exposure - FLAIR Data Serum PFOA vs Average Intensity Average Intensity (ppm) 49 of 73 50 FINAL p. 50 Figure 6. Serum PFOA vs Concurrent Job Intensity Factor - FLAIR Data Serum PFOA vs Concurrent Job Intensity factor Serum PFOA (ppm) 50 of 73 51 FINAL Figure 7. Decreasing IHD mortality rates in the U.S.A. US rates of death from IHD --20-24 - -2 5 -2 9 30-34 - 35-39 -*-40-44 --45-49 --t-- 50-54 ------55-59 -- 60-64 65-69 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89 1990-94 1995-99 2000-01 51 of 73 FINAL APPENDICES p. 52 52 of 73 os> FINAL Appendix A Washington Works vs Region 1 All-Cause Mortality Surveillance Report: Males Cause of Death Observed Expected All Causes of Death Tuberculosis 773 826.1 0 0.4 All Malignant Neoplasms Cancer of Buccal Cavity & Pharynx Cancer o f Digestive Organs & Peritoneum Cancer of Esophagus Cancer of Stomach Cancer of Large Intestine Cancer of Rectum Cancer of Biliary Passages & Liver Cancer of Pancreas Cancer of All Other Digestive Organs 222 221.2 4 3.2 49 52.6 4 4.8 2 5.7 17 20.9 5 3.7 7 5.3 11 10.9 3 1.3 Cancer o f Respiratory System Cancer of Larynx 70 82.3 3 1.5 Cancer o f Bronchus, Trachea, Lung Cancer o f All Other Respiratory Cancer of Breast Cancer of Prostate (males only) Cancer of Testes and Other male genital Organs Cancer of Kidney Cancer of Bladder and Other Urinary Organs Malignant Melanoma o f Skin Cancer of Eye Cancer of Central Nervous System Cancer of Thyroid & Other Endocrine Glands Cancer of Bone Cancer of All Lymphatic, Haematopoietic Tissue Non-Hodgkins Lymphoma Hodgkins Disease Leukemia & Aleukemia Cancer o f All Other Lymphopoietic Tissue All Other Malignant Neoplasms 64 78.7 3 2.0 0 0.3 12 18.4 1 0.6 12 6.5 7 5.4 2 4.4 0 0.4 9 6.9 3 0.5 2 0.3 29 24.0 9 8.2 2 1.1 12 10.3 6 4.4 22 15.5 SMR 93.6 N/A 100.4 123.5 93.2 83.5 35.0 81.5 135.3 133.1 100.5 232.8 85.1 195.6 81.3 151.0 N/A 65.3 169.7 184.7 130.7 45.5 N/A 130.1 633.2 648.3 * 120.7 109.9 179.8 116.1 136.7 141.9 95% Lower 95% 99% 99% Upper Lower Upper 87.1 100.4 0.0 866.9 85.1 102.6 0.0 1245.0 87.6 114.5 33.6 316.1 69.0 123.2 22.8 213.8 4.2 126.3 47.5 130.4 43.9 315.6 53.5 274.2 50.2 179.8 48.0 680.4 83.8 119.1 20.7 388.7 62.5 133.3 14.0 262.9 1.8 162.1 39.5 147.5 29.2 382.8 38.7 325.7 39.5 208.1 26.2 852.0 66.3 107.5 40.4 571.7 61.2 115.0 22.0 715.8 62.6 31.2 0.0 33.8 4.2 95.4 52.6 5.5 0.0 59.5 130.7 78.4 80.8 50.3 21.8 60.0 50.2 88.9 103.8 441.2 1425.3 114.1 945.7 322.6 269.4 164.4 886.7 246.9 1850.4 2342.1 173.4 208.6 649.5 202.8 297.6 214.8 57.5 111.3 17.0 552.5 0.0 2046.9 26.9 131.5 0.8 1261.1 76.1 371.6 38.0 320.0 2.3 211.0 0.0 1273.5 45.3 289.0 71.3 2316.9 33.4 3006.3 70.8 191.4 38.2 244.2 9.3 833.7 47.8 233.6 35.0 356.9 76.0 240.0 FINAL Appendix A Washington Works vs Region 1 All-Cause Mortality Surveillance Report: Males (Continued) Cause of Death Benign Neoplasms Diabetes Mellitus Observed 1 20 Expected 2,4 10.9 SMR 42.0 183.1 * 95% Lower 1.0 111.8 95% Upper 233.8 282.8 99% Lower 0.2 94.8 99% Upper 311.7 317.4 Cerebrovascular Disease 34 39.5 86.1 59.6 120.3 52.8 132.0 All Heart Disease Rheumatic Heart Disease 309 281.0 5 1.7 109.9 302.5 98.0 122.9 98.2 706.0 94.5 127.1 65.2 856.2 Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. Hypertension with Heart Disease 236 215.9 11 10.3 1 6.2 109.3 106.4 16.2 * 95.8 124.2 53.1 190.3 0.4 90.1 91.8 129.0 41.8 220.2 0.1 120.1 All Other Heart Disease Hypertension w/o Heart Disease 56 46.9 119.4 5 2.3 214.4 90.2 155.0 69.6 500.4 82.3 166.9 46.2 606.8 Non-malignant Respiratory Disease Influenza & Pneumonia 46 50.5 14 15.4 91.1 90.7 66.7 121.6 49.6 152.1 60.2 131.8 40.4 173.8 Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma 11 11.2 98.6 5 3.7 133.8 6 6.7 88.9 0 0.7 N/A 49.2 176.5 43.4 312.1 32.6 193.6 0.0 551.5 38.7 204.2 28.8 378.5 22.8 232.1 0.0 792.0 Other Non-malignant Respiratory Disease Ulcer of Stomach & Duodenum 21 23.9 88.0 0 1.5 N/A 54.4 134.4 0.0 242.9 46.4 150.6 0.0 348.8 Cirrhosis of Liver Nephritis & Nephrosis All External Causes of Death 8 9.2 86.9 8 6.0 132.5 41 65.2 62.9 ** 37.5 171.2 57.2 261.1 45.1 85.3 27.9 201.8 42.6 307.8 40.5 92.9 Accidents 31 40.4 76.7 52.1 108.9 45.9 119.9 Motor Vehicle Accidents 20 22.8 87.6 53.5 135.3 45.3 151.9 All Other Accidents Suicides Homicides & Other External Causes 11 17.6 62.6 8 19.1 41.8 ** 2 5.7 35.3 31.3 112.0 18.1 82.4 4.3 127.4 24.6 129.7 13.4 97.2 1.8 163.5 All Other Causes of Death CERTAIN INFECTIOUS AND PARASITIC DISEASES Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL 78 72.1 108.1 1 1.0 100.1 0 85.5 134.9 2.5 557.9 79.2 143.8 0.5 743.9 FINAL Appendix A Washington Works vs Region 1 All-Cause Mortality Surveillance Report: Females Cause of Death All Causes of Death Tuberculosis All Malignant Neoplasms Cancer of Buccal Cavity & Pharynx Cancer o f Digestive Organs & Peritoneum Cancer of Esophagus Cancer of Stomach Cancer o f Large Intestine Cancer of Rectum Cancer o f Biliary Passages & Liver Cancer o f Pancreas Cancer o f All Other Digestive Organs Cancer o f Respiratory System Cancer o f Larynx Cancer o f Bronchus, Trachea, Lung Cancer o f All Other Respiratory Cancer of Breast All Uterine Cancers (Females only) Cancer of Cervix Uteri (Females only) Cancer of Other Female Genital Organs Cancer of Kidney Cancer o f Bladder and Other Urinary Organs Malignant Melanoma of Skin Cancer of Eye Cancer of Central Nervous System Cancer of Thyroid & Other Endocrine Glands Cancer of Bone Cancer of All Lymphatic, Haematopoietic Tissue Non-Hodgkins Lymphoma Hodgkins Disease Leukemia & Aleukemia Cancer of All Other Lymphopoietic Tissue All Other Malignant Neoplasms Observed 33 0 12 0 2 0 1 0 0 1 0 0 2 0 2 0 2 0 0 0 0 0 1 0 0 0 0 Expected 22.4 0.0 8.1 0.2 1.5 0.0 0.0 0.8 0.1 0.3 0.3 0.0 1.5 0.0 1.5 0.0 2.6 0.0 0.0 0.7 0.1 0.0 0.0 0.0 0.2 0.0 0.0 3 0.8 0 0.1 0 0.2 1 0.3 2 0.1 2 0.3 SMR 147.2 N/A 149.0 N/A 130.2 N/A 2586.7 N/A N/A 384.8 N/A N/A 132.2 N/A 132.9 N/A 77.4 N/A N/A N/A N/A N/A 2138.6 N/A N/A N/A N/A * 395.0 N/A N/A 292.7 1783.8 611.0 * 95% Lower 101.3 0.0 77.0 0.0 15.8 0.0 64.7 0.0 0.0 9.6 0.0 0.0 16.0 0.0 16.1 N/A 9.4 0.0 0.0 0.0 0.0 0.0 53.5 0.0 0.0 0.0 N/A 95% Upper 206.7 491866.7 260.3 2064.0 470.4 14899.0 14412.8 440.6 4151.5 2144.2 1467.2 10537.0 477.5 43969.0 480.2 279.8 17174.1 20449.0 516.9 2793.4 20841.8 11916.2 40988.9 1903.6 105702.0 99% Lower 89.5 0.0 61.4 0.0 6.7 0.0 12.9 0.0 0.0 1.9 0.0 0.0 6.8 0.0 6.8 99% Upper 226.9 706400.0 299.8 2964.2 603.8 21397.4 19218.8 632.7 5962.2 2859.2 2107.1 15132.8 613.0 63146.6 616.4 4.0 359.1 0.0 24664.8 0.0 29368.1 0.0 742.3 0.0 4011.8 0.0 29932.2 10.7 15889.6 0.0 58866.7 0.0 2733.9 0.0 151805.2 81.5 0.0 0.0 7.3 215.8 73.9 1154.4 2890.2 2072.1 1630.9 6444.0 2207.3 44.5 1445.4 0.0 4150.7 0.0 2975.9 1.5 2174.7 91.9 8271.5 31.5 2833.3 55 of 73 FINAL p. 56 Appendix A Washington Works vs Region 1 All-Cause Mortality Surveillance Report: Females (continued) Cause of Death Benign Neoplasms Diabetes Mellitus Cerebrovascular Disease All Heart Disease Rheumatic Heart Disease Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. Hypertension with Heart Disease All Other Heart Disease Hypertension w/o Heart Disease Non-malignant Respiratory Disease Influenza & Pneumonia Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma Other Non-malignant Respiratory Disease Ulcer of Stomach & Duodenum Cirrhosis of Liver Nephritis & Nephrosis All External Causes of Death Accidents Motor Vehicle Accidents All Other Accidents Suicides Homicides & Other External Causes All Other Causes of Death CERTAIN INFECTIOUS AND PARASITIC DISEASES Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL Observed 0 2 1 5 0 3 Expected 0.0 0.3 1.1 3.5 0.1 2.2 SMR N/A 796.1 90.5 142.7 N/A 135.0 0 0.1 N/A 0 0.2 N/A 2 0.9 232.2 0 0.1 N/A 3 1.0 294.6 0 0.3 N/A 2 0.3 679.9 1 0.1 756.4 1 0.1 1411.6 0 0.1 N/A 1 0.4 227.9 0 0.0 N/A 1 0.1 804.8 0 0.1 N/A 4 3.1 130.8 4 1.6 247.3 3 1.4 215.7 1 0.2 441.4 0 0.6 N/A 0 0.9 N/A 5 2.2 223.2 0 0.1 N/A 0 95% Lower 0.0 96.3 2.3 46.3 0.0 27.8 95% Upper 18528.4 2876.1 504.4 333.0 4456.4 394.4 99% Lower 0.0 41.0 0.5 30.8 0.0 15.2 99% Upper 26609.7 3691.7 672.6 403.8 6400.1 493.8 0.0 3005.8 0.0 1724.2 28.1 838.7 0.0 3461.6 60.8 860.8 0.0 1292.5 82.3 2456.1 18.9 4214.8 35.3 7865.6 0.0 4048.1 5.7 1269.6 0.0 8221.5 20.1 4484.5 0.0 2671.3 35.7 335.0 67.4 633.3 44.5 630.4 11.0 2459.5 0.0 660.3 0.0 418.6 72.4 520.7 0.0 4316.8 0.0 2476.3 12.0 1076.5 0.0 4971.4 33.2 1077.8 0.0 1856.3 35.0 3152.6 3.8 5620.3 7.1 10488.4 0.0 5813.7 1.1 1692.9 0.0 11807.4 4.0 5979.9 0.0 3836.4 22.0 412.0 41.6 778.7 24.3 789.3 2.2 3279.6 0.0 948.3 0.0 601.2 48.1 631.5 0.0 6277.0 0.0 9014.8 56 of 73 61 FINAL Appendix A Washington Works vs Region 1 All-Cause Mortality Surveillance Report: Totals (Males and Females) Cause of Death All Causes of Death Tuberculosis All Malignant Neoplasms Cancer of Buccal Cavity & Pharynx Cancer of Digestive Organs & Peritoneum Cancer of Esophagus Cancer of Stomach Cancer o f Large Intestine Cancer of Rectum Cancer o f Biliary Passages & Liver Cancer of Pancreas Cancer o f All Other Digestive Organs Cancer o f Respiratory System Cancer o f Larynx Cancer o f Bronchus, Trachea, Lung Cancer o f All Other Respiratory Cancer of Breast All Uterine Cancers (females only) Cancer o f Cervix Uteri (females only) Cancer o f Other Female genital Organs Cancer o f Prostate (males only) Cancer o f Testes and Other male genital Organs Cancer o f Kidney Cancer of Bladder and Other Urinary Organs Malignant Melanoma of Skin Cancer of Eye Cancer of Central Nervous System Cancer of Thyroid & Other Endocrine Glands Cancer of Bone Cancer o f All Lymphatic, Haematopoietic Tissue Non-Hodgkins Lymphoma Hodgkins Disease Leukemia & Aleukemia Cancer of All Other Lymphopoietic Tissue All Other Malignant Neoplasms Observed Expected 806 848.5 0 0.4 234 229.2 4 3.4 51 54.1 4 4.8 3 5.8 17 21.7 5 3.8 8 5.5 11 11.2 3 1.3 72 83.8 3 1.5 66 80.3 3 2.0 2 2.8 0 0.0 0 0.0 0 0.7 12 18.4 1 0.6 12 6.6 7 5.4 3 4.4 0 0.4 9 7.1 3 0.5 2 0.3 32 24.8 9 8.3 2 1.3 13 10.7 8 4.5 24 15.8 SMR 95.0 N/A 102.1 117.0 94.3 83.1 52.1 78.3 132.1 144.9 98.2 226.7 85.9 194.6 82.2 151.0 70.4 N/A N/A N/A 65.3 169.7 181.0 130.3 67.5 N/A 126.5 628.6 648.3 * 129.1 108.2 155.0 121.8 177.8 151.6 95% Lower 95% 99% 99% Upper Lower Upper 88.5 101.8 0.0 865.4 86.6 104.0 0.0 1242.8 89.4 116.0 31.9 299.6 70.2 123.9 22.6 212.7 10.7 152.2 45.6 125.4 42.9 308.2 62.6 285.6 49.0 175.8 46.8 662.4 85.7 120.6 19.7 368.4 63.7 133.9 14.0 261.5 5.9 190.6 38.0 141.9 28.5 373.8 46.6 336.6 38.6 203.4 25.5 829.4 67.2 108.2 40.1 568.6 62.1 115.6 21.9 711.9 63.6 104.6 31.2 441.2 8.5 254.3 0.0 17174.1 0.0 20449.0 0.0 516.9 33.8 114.1 4.2 93.5 52.4 13.9 0.0 57.8 129.7 78.4 945.7 316.2 268.5 197.4 867.9 240.2 1836.9 2342.1 88.3 182.3 49.5 205.4 18.8 559.9 64.8 208.2 76.8 350.3 97.1 225.5 58.5 112.1 17.0 552.5 3.6 326.4 0.0 24664.8 0.0 29368.1 0.0 742.3 26.9 131.5 0.8 1261.1 74.6 364.2 37.9 318.9 7.6 247.2 0.0 1246.5 44.0 281.1 70.8 2300.0 33.4 3006.3 77.9 200.4 37.7 240.5 8.0 718.7 52.3 238.8 57.1 412.8 83.7 251.0 57 of 73 FINAL Appendix A Washington Works vs Region 1 All-Cause Mortality Surveillance Report: Totals (Males and Females) (continued) Cause of Death Benign Neoplasms Diabetes Mellitus 95% 95% 99% 99% Observed Expected SMR Lower u PPer Lower Upper 1 2.4 41.6 1.0 231.8 0.2 309.2 22 11.2 196.9 ** 123.4 298.1 105.5 333.1 Cerebrovascular Disease 35 40.6 86.2 60.1 119.9 53.3 131.4 All Heart Disease Rheumatic Heart Disease 314 284.5 5 1.7 110.4 288.1 98.5 123.3 93.5 672.3 94.9 127.5 62.1 815.3 Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. Hypertension with Heart Disease 239 218.2 11 10.5 1 6.4 109.5 105.1 15.6 * 96.1 124.4 52.5 188.1 0.4 87.1 92.1 129.2 41.3 217.7 0.1 116.1 All Other Heart Disease Hypertension w/o Heart Disease 58 47.8 121.4 5 2.4 205.1 92.2 156.9 66.6 478.5 84.3 168.8 44.2 580.3 Non-malignant Respiratory Disease Influenza & Pneumonia Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma 49 51.5 95.2 14 15.7 89.0 13 11.4 113.6 6 3.9 155.0 7 6.8 102.7 0 0.8 N/A 70.4 125.8 48.7 149.4 60.5 194.2 56.9 337.4 41.3 211.5 0.0 485.4 63.8 136.1 39.6 170.6 48.7 222.7 39.7 404.6 29.9 251.3 0.0 697.1 Other Non-malignant Respiratory Disease Ulcer o f Stomach & Duodenum 22 24.3 90.5 0 1.6 N/A 56.7 137.0 0.0 235.9 48.5 153.1 0.0 338.8 Cirrhosis of Liver Nephritis & Nephrosis All External Causes of Death 9 9.3 96.5 8 6.2 129.6 45 68.2 65.9 * 44.1 183.1 55.9 255.3 48.1 88.2 33.6 214.3 41.6 300.9 43.4 95.7 Accidents 35 42.0 83.3 58.0 115.9 51.5 126.9 Motor Vehicle Accidents 23 24.2 95.0 60.2 142.5 51.7 158.9 All Other Accidents Suicides 12 17.8 8 19.7 67.4 40.7 ** 34.9 117.8 17.6 80.1 27.8 135.7 13.1 94.4 Homicides & Other External Causes 2 6.6 30.5 3.7 110.3 1.6 141.5 All Other Causes of Death CERTAIN INFECTIOUS AND PARASITIC DISEASES Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL 83 74.4 111.6 1 1.1 94.6 0 88.9 138.3 2.4 526.9 82.6 147.2 0.5 702.6 FINAL Appendix B Washington Works vs USA All-Cause Mortality Surveillance Report: Males Cause of Death All Causes of Death Tuberculosis All Malignant Neoplasms Cancer of Buccal Cavity & Pharynx Cancer of Digestive Organs & Peritoneum Cancer o f Esophagus Cancer of Stomach Cancer o f Large Intestine Cancer of Rectum Cancer o f Biliary Passages & Liver Cancer of Pancreas Cancer of All Other Digestive Organs Cancer of Respiratory System Cancer o f Larynx Cancer of Bronchus, Trachea, Lung Cancer o f All Other Respiratory Cancer of Breast Cancer o f Prostate (males only) Cancer o f Testes and other male Genital Organs Cancer of Kidney Cancer of Bladder and Other Urinary Organs Malignant Melanoma o f Skin Cancer o f Eye Cancer o f Central Nervous System Cancer o f Thyroid & Other Endocrine Glands Cancer o f Bone Cancer o f All Lymphatic, Haematopoietic Tissue Hodgkins Disease Non-Hodgkins Lymphoma Leukemia & Aleukemia Cancer o f All Other Lymphopoietic Tissue All Other Malignant Neoplasms Observed Expected 773 1167.0 0 2.0 222 301.2 4 7.6 49 74.1 4 9.6 2 9.8 17 24.5 5 5.3 7 7.8 11 14.9 3 2.2 70 110.6 3 3.9 64 105.6 3 1.0 0 0.4 12 23.2 1 1.2 12 7.7 7 6.9 2 5.1 0 0.2 9 8.6 3 0.9 2 0.8 29 29.6 2 1.9 9 11.3 12 11.1 6 5,3 22 24.5 SMR 66.2 ** N/A 73.7 52.9 66.2 41.5 20.5 69.4 94.7 89.7 74.0 135.9 ** ** ** 63.3 ** 76.7 60.6 293.1 N/A 51.8 ** * 86.9 155.7 101.4 39.0 N/A 105.0 332.2 251.6 98.0 103.3 80.0 107.8 113.8 89.9 95% Lower 95% 99% 99% Upper Lower Upper 61.6 71.1 0.0 183.7 60.3 72.6 0.0 263.9 64.3 84.1 14.4 135.5 49.0 87.5 11.3 106.4 2.5 74.0 40.4 111.1 30.7 220.9 36.1 184.9 36.9 132.3 28.0 397.2 61.6 87.5 8.9 166.6 44.4 94.6 7.0 130.8 1.1 95.0 33.7 125.7 20.4 267.9 26.1 219.6 29.1 153.2 15.3 497.3 49.3 80.0 15.8 224.0 45.5 85.5 8.6 280.5 46.7 77.4 60.5 856.5 0.0 952.7 26.8 90.5 2.2 484.0 80.4 271.9 40.8 208.9 4.7 140.7 0.0 2299.0 48.0 199.4 68.5 970.7 30.4 909.0 65.6 140.7 12.5 373.0 36.6 151.9 55.7 188.3 41.8 247.8 56.3 136.1 42.9 83.0 33.0 1072.4 0.0 1368.3 21.3 104.2 0.4 645.4 64.1 313.2 29.5 248.1 2.0 180.7 0.0 3301.8 36.5 233.3 37.4 1215.3 13.0 1166.8 57.4 155.3 5.3 478.8 27.8 177.8 44.4 216.9 29.2 297.1 48.2 152.1 FINAL Appendix B Washington Works vs USA All-Cause Mortality Surveillance Report: Males (continued) Cause of Death Benign Neoplasms Diabetes Mellitus Observed 1 20 Expected 2.9 24.6 SMR 35.1 81.2 95% Lower 0.9 49.6 95% u PPer 195.3 125.3 99% Lower 0.2 42.0 99% Upper 260.5 140.7 Cerebrovascular Disease 34 55.8 60.9 ** 42.2 85.1 37.3 93.3 All Heart Disease Rheumatic Heart Disease 309 386.5 5 4.0 80.0 ** 125.7 71.3 89.4 40.8 293.4 68.7 92.5 27.1 355.8 Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. 236 289.8 11 13.1 81.4 ** 83.7 71.4 92.5 41.8 149.7 68.4 96.1 32.9 173.2 Hypertension with Heart Disease 1 11.8 8.5 ** 0.2 47.3 0.0 63.1 All Other Heart Disease Hypertension w/o Heart Disease Non-malignant Respiratory Disease Influenza & Pneumonia Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma Other Non-malignant Respiratory Disease Ulcer o f Stomach & Duodenum Cirrhosis of Liver Nephritis & Nephrosis All External Causes of Death Accidents Motor Vehicle Accidents All Other Accidents Suicides Homicides & Other External Causes All Other Causes of Death Certain Infectious and Parasitic Diseases Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (*) SIGNIFICANT AT 1% LEVEL 56 67.8 82.6 5 4.6 108.3 46 85.4 14 25.8 53.9 ** 54.3 * 11 23.3 47.2 ** 5 11.2 44.7 6 10.3 58.5 0 1.9 N/A 21 36.3 57.9 ** 0 3.5 N/A 8 29.0 8 10.7 27.6 ** 74.7 41 124.4 33.0 ** 31 73.9 42.0 ** 20 36.2 55.2 ** 11 37.7 29.2 ** 8 28.5 28.0 ** 2 22.0 9.1 ** 78 127.4 1 14.3 0 61.2 ** 7.0 ** 62.4 107.3 35.2 252.8 39.4 71.9 29.7 91.1 23.6 84.5 14.5 104.4 21.5 127.3 0.0 197.5 35.8 88.5 0.0 105.7 11.9 54.4 32.3 147.2 23.7 44.7 28.5 59.6 33.7 85.2 14.6 52.3 12.1 55.2 1.1 32.9 48.4 76.4 0.2 38.9 57.0 115.6 23.4 306.6 35.6 77.9 24.2 104.1 18.5 97.7 9.6 126.6 15.0 152.7 0.0 283.7 30.5 99.0 0.0 151.7 8.9 64.1 24.0 173.5 21.2 48.7 25.1 65.6 28.6 95.7 11.5 60.5 9.0 65.1 0.5 42.2 44.9 81.5 0.0 51.9 FINAL Appendix B Washington Works vs USA All-Cause Mortality Surveillance Report: Females Cause of Death All Causes o f Death Tuberculosis All Malignant Neoplasms Cancer o f Buccal Cavity & Pharynx Cancer of Digestive Organs & Peritoneum Cancer of Esophagus Cancer o f Stomach Cancer o f Large Intestine Cancer o f Rectum Cancer o f Biliary Passages & Liver Cancer of Pancreas Cancer o f All Other Digestive Organs Cancer of Respiratory System Cancer o f Larynx Cancer o f Bronchus, Trachea, Lung Cancer o f All Other Respiratory Cancer o f Breast All Uterine Cancers (Females only) Cancer o f Cervix Uteri (Females only) Cancer o f Other Female Genital Organs Cancer o f Kidney Cancer o f Bladder and Other Urinary Organs Malignant Melanoma o f Skin Cancer of Eye Cancer of Central Nervous System Cancer of Thyroid & Other Endocrine Glands Cancer of Bone Cancer o f All Lymphatic, Haematopoietic Tissue Hodgkins Disease Non-Hodgkins Lymphoma Leukemia & Aleukemia Cancer of All Other Lymphopoietic Tissue All Other Malignant Neoplasms Observed 33 0 12 0 2 0 1 0 0 1 0 0 2 0 2 0 2 0 0 0 0 Expected 40,9 0.0 13.8 0.1 2.4 0.1 0.3 0.9 0.2 0.3 0.5 0.1 3.0 0.0 2.9 0.0 3.3 0.9 0.6 0.9 0.2 0 0.1 1 0.2 0 0.0 0 0.4 0 0.1 0 0.0 3 1.2 0 0.1 0 0.5 1 0.5 2 0.2 2 1.0 SMR 80.7 N/A 86.6 N/A 84.0 N/A 397.1 N/A N/A 394.5 N/A N/A 67.7 N/A 69.5 N/A 61.1 N/A N/A N/A N/A N/A 422.2 N/A N/A N/A N/A 245.5 N/A N/A 207.0 1057.3 197.7 * 95% Lower 55.5 0.0 44.8 0.0 10.2 0.0 9.9 0.0 0.0 9.9 0.0 0.0 8.2 0.0 8.4 0.0 7.4 0.0 0.0 0.0 0.0 95% Upper 113.3 8275.0 151.4 2486.0 303.4 3070.1 2212.9 388.6 2150.8 2197.9 698.4 3466.8 244.5 8045.8 251.0 11919.2 220.6 419.5 636.4 416.4 1793.7 99% Lower 49.1 0.0 35.7 0.0 4.3 0.0 2.0 0.0 0.0 2.0 0.0 0.0 3.5 0.0 3.6 0.0 3.1 0.0 0.0 0.0 0.0 99% Upper 124.4 11884.3 174.3 3570.3 389.5 4409.1 2950.8 558.0 3088.9 2930.9 1003.0 4978.9 313.9 11555.1 322.2 17117.9 283.1 602.5 914.0 598.0 2576.0 0.0 3722.5 10.6 2352.3 0.0 52400.6 0.0 834.8 0.0 5346.1 2.1 3136.7 0.0 75255.7 0.0 1199.0 0.0 6334.1 0.0 8833.8 0.0 9096.8 0.0 12686.8 50.6 0.0 0.0 5.2 127.9 23.9 717.4 3891.4 811.3 1153.4 3819.5 714.1 27.7 898.2 0.0 5588.6 0.0 1165.2 1.0 1538.0 54.5 4902.7 10.2 916.6 61 of 73 FINAL Appendix B Washington Works vs USA All-Cause Mortality Surveillance Report: Females (continued) Cause of Death Benign Neoplasms Diabetes Mellitus Cerebrovascular Disease All Heart Disease Rheumatic Heart Disease Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. Hypertension with Heart Disease All Other Heart Disease Hypertension w/o Heart Disease Non-malignant Respiratory Disease Influenza & Pneumonia Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma Other Non-malignant Respiratory Disease Ulcer o f Stomach & Duodenum Cirrhosis of Liver Nephritis & Nephrosis All External Causes of Death Accidents Motor Vehicle Accidents All Other Accidents Suicides Homicides & Other External Causes All Other Causes of Death Certain Infectious and Parasitic Diseases Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL Observed 0 2 1 5 0 3 Expected 0.1 1.2 2.1 7.8 0.2 4.7 SMR N/A 160.8 48.7 64.4 N/A 64.0 0 0.4 N/A 0 0.4 N/A 2 2.1 96.7 0 0.2 N/A 3 2.5 119.6 0 0.7 N/A 2 0.9 228.8 1 0.4 236.2 1 0.2 447.2 0 0.2 N/A 1 0.9 105.7 0 0.1 N/A 1 0.9 105.5 0 0.4 N/A 4 5.3 75.5 4 3.1 129.6 3 1.9 156.4 1 1.2 85.6 0 1.1 N/A 0 1.1 N/A 5 5.8 86.1 0 0.7 N/A 0 95% Lower 0.0 19.5 1.2 20.9 0.0 13.2 95% Upper 2467.4 580.7 271.6 150.2 1694.6 187.1 99% Lower 0.0 8.3 0.2 13.9 0.0 7.2 99% Upper 3543.6 745.4 362.2 182.2 2433.7 234.3 0.0 1017.5 0.0 852.1 11.7 349.4 0.0 2038.1 24.7 349.5 0.0 535.7 27.7 826.4 5.9 1315.9 11.2 2491.9 0.0 1623.5 2.6 589.2 0.0 4846.9 2.6 588.0 0.0 915.7 20.6 193.2 35.3 331.7 32.3 457.0 2.1 476.7 0.0 328.2 0.0 338.6 27.9 200.8 0.0 543.5 0.0 1461.3 0.0 1223.7 5.0 448.5 0.0 2927.1 13.5 437.6 0.0 769.4 11.8 1060.8 1.2 1754.7 2.2 3322.9 0.0 2331.6 0.5 785.6 0.0 6961.0 0.5 784.1 0.0 1315.1 12.7 237.6 21.8 407.9 17.6 572.2 0.4 635.7 0.0 471.3 0.0 486.3 18.6 243.6 0.0 780.6 62 of 73 FINAL Appendix B Washington Works vs USA All-Cause Mortality Surveillance Report: Totals (Males and Females! Cause of Death Observed Expected All Causes of Death Tuberculosis 806 1207.9 0 2.1 All Malignant Neoplasms Cancer o f Buccal Cavity & Pharynx Cancer o f Digestive Organs & Peritoneum Cancer o f Esophagus Cancer of Stomach Cancer o f Large Intestine Cancer of Rectum Cancer o f Biliary Passages & Liver Cancer of Pancreas Cancer o f All Other Digestive Organs 234 315.0 4 7.7 51 76.4 4 9.7 3 10.0 17 25.4 5 5.5 8 8.1 11 15.4 3 2.3 Cancer of Respiratory System Cancer of Larynx 72 113.5 3 4.0 Cancer o f Bronchus, Trachea, Lung Cancer o f All Other Respiratory Cancer of Breast All Uterine Cancers (Females only) Cancer of Cervix Uteri (Females only) Cancer o f Other Female Genital Organs Cancer o f Prostate (Males only) Cancer o f Testes and Other Male Genital Organs Cancer of Kidney Cancer of Bladder and Other Urinary Organs Malignant Melanoma o f Skin Cancer of Eye Cancer of Central Nervous System Cancer of Thyroid & Other Endocrine Glands Cancer of Bone Cancer o f All Lymphatic, Haematopoietic Tissue Flodgkins Disease Non-Hodgkins Lymphoma Leukemia & Aleukemia Cancer o f All Other Lymphopoietic Tissue All Other Malignant Neoplasms 66 108.5 3 1.1 2 3.7 0 0.9 0 0.6 0 0.9 12 23.2 1 1.2 12 7.9 7 7.0 3 5.4 0 0.2 9 9.0 3 1.0 2 0.8 32 30.8 2 2.0 9 11.7 13 11.6 8 5.5 24 25.5 SMR 66.7 ** N/A 74.3 51.9 66.7 41.0 30.0 66.8 91.7 99.3 71.4 129.7 ** ** * 63.4 ** 75.8 60.8 284.5 54.6 N/A N/A N/A 51.8 ** * 86.9 151.6 99.9 55.9 N/A 99.9 312.0 239.1 103.8 98.4 76.9 111.9 146.5 94.2 95% Lower 95% 99% 99% Upper Lower Upper 62.2 71.5 0.0 179.7 60.8 73.0 0.0 258.1 65.1 84.4 14.1 132.9 49.7 87.7 11.2 105.1 6.2 87.6 38.9 107.0 29.8 213.9 42.9 195.7 35.7 127.8 26.8 378.9 62.4 87.8 8.7 163.4 45.1 94.8 6.9 129.2 3.4 109.6 32.4 121.0 19.8 259.5 31.9 230.6 28.1 147.9 14.6 474.5 49.6 79.9 15.6 221.4 45.8 85.3 8.5 277.2 47.0 77.4 58.7 831.4 6.6 197.2 0.0 419.5 0.0 636.4 0.0 416.4 26.8 90.5 2.2 484.0 78.4 264.9 40.2 205.9 11.5 163.2 0.0 2202.4 45.7 189.6 64.4 911.9 28.9 863.6 71.0 146.6 11.9 355.6 35.2 146.0 59.6 191.4 63.3 288.7 60.3 140.1 43.3 82.9 32.1 1041.0 2.8 253.2 0.0 602.5 0.0 914.0 0.0 598.0 21.3 104.2 0.4 645.4 62.5 305.1 29.1 244.6 6.3 204.4 0.0 3163.0 34.8 221.9 35.2 1141.7 12.3 1108.5 62.6 161.1 5.1 456.5 26.8 170.8 48.0 219.5 47.1 340.3 52.0 155.9 63 of 73 FINAL Appendix B Washington Works vs USA All-Cause Mortality Surveillance Report: Totals (Males and Females) (continued) Cause of Death Benign Neoplasms Diabetes Mellitus Cerebrovascular Disease All Heart Disease Rheumatic Heart Disease Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. Hypertension with Heart Disease All Other Heart Disease Hypertension w/o Heart Disease Non-malignant Respiratory Disease Influenza & Pneumonia Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma Other Non-malignant Respiratory Disease Ulcer of Stomach & Duodenum Cirrhosis of Liver Nephritis & Nephrosis All External Causes of Death Accidents Motor Vehicle Accidents All Other Accidents Suicides Homicides & Other External Causes All Other Causes of Death Certain Infectious and Parasitic Diseases Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL Observed 1 22 Expected 3.0 25.9 SMR 33.3 85.0 95% Lower 0.8 53.3 95% Upper 185.6 128.7 99% Lower 0.2 45.5 99% Upper 247.5 143.8 35 57.9 60.4 ** 42.1 84.1 37.4 92.1 314 394.2 5 4.2 79.6 ** 119.2 71.1 89.0 38.7 278.2 68.5 92.0 25.7 337.4 239 294.5 11 13.5 81.2 ** 81.4 71.2 92.1 40.6 145.7 68.3 95.7 32.0 168.6 1 12.2 8.2 ** 0.2 45.6 0.0 60.8 58 69.8 83.1 5 4.8 104.2 49 87.9 14 26.5 13 24.2 55.7 ** 52.9 * 53.8 * 6 11.6 51.7 7 10.5 66.8 0 2.1 N/A 22 37.2 59.1 ** 0 3.6 N/A 9 29.9 8 11.1 30.1 ** 72.0 45 129.7 34.7 ** 35 77.0 45.5 ** 23 38.2 60.3 * 12 38.8 30.9 ** 8 29.7 27.0 ** 2 23.1 8.7 ** 83 133.2 1 15.0 62.3 ** 6.7 ** 0 63.1 107.4 33.8 243.3 41.2 73.7 28.9 88.7 28.6 91.9 19.0 112.5 26.8 137.6 0.0 176.1 37.0 89.4 0.0 103.4 13.8 57.1 31.1 141.9 25.3 46.4 31.7 63.2 38.2 90.5 16.0 54.0 11.6 53.2 1.0 31.3 49.6 77.3 0.2 37.2 57.7 115.5 22.5 295.0 37.4 79.7 23.5 101.4 23.1 105.4 13.2 135.0 19.4 163.5 0.0 252.9 31.7 99.9 0.0 148.5 10.5 66.8 23.1 167.2 22.8 50.4 28.1 69.3 32.8 100.9 12.7 62.2 8.7 62.6 0.4 40.2 46.1 82.2 0.0 49.6 FINAL Appendix C Washington Works vs West Virginia All-Cause Mortality Surveillance Report: Males Cause of Death Observed Expected All Causes of Death Tuberculosis 773 1331.3 0 2.1 All Malignant Neoplasms Cancer o f Buccal Cavity & Pharynx Cancer o f Digestive Organs & Peritoneum Cancer of Esophagus Cancer of Stomach Cancer of Large Intestine Cancer of Rectum Cancer o f Biliary Passages & Liver Cancer of Pancreas Cancer of All Other Digestive Organs 222 325.2 4 6.4 49 68.6 4 8.4 2 8.1 17 23.9 5 5.8 7 6.7 11 13.3 3 2.3 Cancer of Respiratory System Cancer of Larynx 70 136.1 3 4.5 Cancer o f Bronchus, Trachea, Lung Cancer of All Other Respiratory Cancer o f Breast Cancer o f Prostate (Males only) Cancer o f Testes and Other Male Genital Organs Cancer of Kidney Cancer of Bladder and Other Urinary Organs Malignant Melanoma of Skin Cancer o f Eye Cancer o f Central Nervous System Cancer o f Thyroid & Other Endocrine Glands Cancer o f Bone Cancer o f All Lymphatic, Haematopoietic Tissue Hodgkins Disease Non-Hodgkins Lymphoma Leukemia & Aleukemia Cancer o f All Other Lymphopoietic Tissue Ail Other Malignant Neoplasms 64 130.7 3 0.9 0 0.4 12 20.9 1 1.3 12 7.7 7 6.7 2 5.5 0 0.2 9 8.0 3 1.0 2 0.9 29 30.3 2 1.9 9 11.2 12 12.0 6 5.3 22 31.2 SMR 58.1 ** N/A 68.3 62.1 71.5 47.4 24.5 71.1 86.3 104.2 82.9 131.8 ** * * 51.4 ** 67.2 49.0 319.1 N/A 57.5 ** 75.7 155.2 104.7 36.4 N/A 112.0 301.1 230.9 95.8 107.6 80.7 100.2 114.1 70.5 95% Lower 95% 99% 99% Upper Lower Upper 54.0 62.3 0.0 176.8 52.8 63.7 0.0 253.9 59.6 77.9 16.9 159.0 52.9 94.5 12.9 121.4 3.0 88.7 41.4 113.8 28.0 201.4 41.9 214.6 41.4 148.3 27.2 385.2 57.0 81.0 10.4 195.5 47.9 102.2 8.0 149.2 1.3 113.8 34.5 128.7 18.6 244.2 30.3 254.9 32.6 171.6 14.9 482.3 40.1 65.0 13.9 196.3 37.0 69.5 7.6 245.8 37.7 62.5 65.8 932.6 0.0 987.4 29.7 100.4 1.9 421.9 80.2 271.2 42.1 215.6 4.4 131.4 0.0 2230.9 51.2 212.5 62.1 880.0 27.9 833.9 64.2 137.6 13.0 388.6 36.9 153.2 51.8 175.1 41.9 248.3 44.2 106.7 34.6 67.0 36.0 1167.7 0.0 1418.0 23.7 115.6 0.4 562.6 63.9 312.4 30.5 256.2 1.9 168.7 0.0 3203.9 39.0 248.8 33.9 1101.9 11.9 1070.5 56.2 151.9 5.5 498.8 28.1 179.3 41.3 201.6 29.2 297.8 37.8 119.2 65 of 73 FINAL Appendix C Washington Works vs West Virginia All-Cause Mortality Surveillance Report: Males (continued) Cause of Death Benign Neoplasms Diabetes Mellitus Cerebrovascular Disease All Heart Disease Rheumatic Heart Disease Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. Hypertension with Heart Disease All Other Heart Disease Hypertension w/o Heart Disease Non-malignant Respiratory Disease Influenza & Pneumonia Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma Other Non-malignant Respiratory Disease Ulcer of Stomach & Duodenum Cirrhosis o f Liver Nephritis & Nephrosis All External Causes of Death Accidents Motor Vehicle Accidents All Other Accidents Suicides Homicides & Other External Causes All Other Causes of Death Certain Infectious and Parasitic Diseases Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL Observed Expected SMR 95% Lower 95% 99% 99% Upper Lower Upper 1 3.5 20 29.8 28.3 67.0 0.7 157.5 41.0 103.5 0.1 210.1 34.7 116.2 34 56.6 309 465.8 60.1 ** 66.3 ** 41.6 83.9 36.9 92.1 59.1 74.2 57.0 76.7 5 4.3 115.7 37.5 269.9 24.9 327.4 236 342.1 69.0 ** 60.5 78.4 58.0 81.4 11 15.7 70.1 1 9.7 10.3 ** 56 94.0 59.6 ** 5 4.2 117.8 46 116.3 14 27.5 39.6 ** 51.0 ** 11 29.5 5 16.8 37.3 ** 29.8 ** 6 11.1 54.1 0 1.6 N/A 21 59.2 35.4 ** 0 3.5 N/A 8 27.5 29.1 ** 8 13.5 59.2 41 146.0 28.1 ** 31 94.6 20 45.4 32.8 ** 44.0 ** 11 49.1 8 33.1 2 18.3 78 138.1 1 3.2 22.4 ** 24.2 ** 10.9 ** 56.5 ** 30.9 35.0 125.5 0.3 57.5 45.0 77.3 38.2 274.8 29.0 52.8 27.9 85.5 18.6 66.7 9.7 69.5 19.9 117.8 0.0 224.3 21.9 54.2 0.0 106.0 12.6 57.4 25.6 116.7 20.2 38.1 22.3 46.5 26.9 68.0 11.2 40.1 10.4 47.6 1.3 39.4 44.6 70.5 0.8 172.1 27.6 145.2 0.1 76.7 41.1 83.3 25.4 333.3 26.2 57.2 22.7 97.7 14.6 77.1 6.4 84.3 13.9 141.2 0.0 322.1 18.7 60.7 0.0 152.3 9.4 67.6 19.0 137.5 18.1 41.5 19.6 51.2 22.8 76.3 8.8 46.4 7.8 56.1 0.6 50.6 41.4 75.1 0.2 229.5 0 FINAL Appendix C Washington Works vs West Virginia All-Cause Mortality Surveillance Report: Females Cause of Death All Causes of Death Tuberculosis All Malignant Neoplasms Cancer of Buccal Cavity & Pharynx Cancer of Digestive Organs & Peritoneum Cancer of Esophagus Cancer of Stomach Cancer of Large Intestine Cancer of Rectum Cancer o f Biliary Passages & Liver Cancer o f Pancreas Cancer of All Other Digestive Organs Cancer of Respiratory System Cancer o f Larynx Cancer o f Bronchus, Trachea, Lung Cancer of All Other Respiratory Cancer of Breast All Uterine Cancers (Females only) Cancer of Cervix Uteri (Females only) Cancer o f Other Female Genital Organs Cancer of Kidney Cancer of Bladder and Other Urinary Organs Malignant Melanoma of Skin Cancer o f Eye Cancer of Central Nervous System Cancer o f Thyroid & Other Endocrine Glands Cancer of Bone Cancer o f All Lymphatic, Haematopoietic Tissue Hodgkins Disease Non-Hodgkins Lymphoma Leukemia & Aleukemia Cancer o f All Other Lymphopoietic Tissue All Other Malignant Neoplasms Observed 33 0 12 0 2 0 1 0 0 1 0 0 2 0 2 0 2 0 0 0 0 Expected 45.0 0.0 15.1 0.1 2.3 0.1 0.2 1.0 0.2 0.2 0.5 0.1 3.6 0.1 3.5 0.0 3.1 1.2 0.8 0.9 0.2 0 0.1 1 0.3 0 0.0 0 0.5 0 0.1 0 0.0 3 1.3 0 0.1 0 0.5 1 0.5 2 0.2 2 1.3 SMR 73.4 N/A 79.4 N/A 87.0 N/A 551.8 N/A N/A 441.4 N/A N/A 55.2 N/A 56.6 N/A 63.5 N/A N/A N/A N/A N/A 338.9 N/A N/A N/A N/A 235.1 N/A N/A 187.6 1165.6 151.5 * 95% Lower 50.5 0.0 41.0 0.0 10.5 0.0 13.8 0.0 0.0 11.0 0.0 0.0 6.7 0.0 6.8 0.0 7.7 0.0 0.0 0.0 0.0 95% Upper 103.1 9008.5 138.7 3027.2 314.1 4248.5 3074.9 356.1 1992.8 2459.7 778.4 3346.9 199.3 5906.2 204.3 13298.5 229.5 319.3 442.8 397.2 1690.2 99% Lower 44.7 0.0 32.7 0.0 4.5 0.0 2.8 0.0 0.0 2.2 0.0 0.0 2.8 0.0 2.9 0.0 3.3 0.0 0.0 0.0 0.0 99% Upper 113.2 12937.7 159.8 4347.6 403.2 6101.6 4100.2 511.4 2861.9 3279.9 1117.9 4806.8 255.8 8482.2 262.3 19098.8 294.6 458.6 635.9 570.4 2427.4 0.0 2837.0 8.5 1888.5 0.0 48475.7 0.0 764.4 0.0 4074.4 1.7 2518.2 0.0 69618.9 0.0 1097.9 0.0 6825.2 0.0 7639.3 0.0 9802.0 0.0 10971.2 48.5 0.0 0.0 4.7 141.0 18.3 687.2 3287.9 804.2 1045.3 4210.9 547.4 26.5 860.4 0.0 4721.9 0.0 1155.0 0.9 1393.8 60.0 5405.1 7.8 702.6 FINAL Appendix C Washington Works vs West Virginia All-Cause Mortality Surveillance Report: Females (continued) Cause of Death Benign Neoplasms Diabetes Meilitus Cerebrovascular Disease All Heart Disease Rheumatic Heart Disease Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. Hypertension with Heart Disease All Other Heart Disease Hypertension w/o Heart Disease Non-malignant Respiratory Disease Influenza & Pneumonia Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma Other Non-malignant Respiratory Disease Ulcer of Stomach & Duodenum Cirrhosis o f Liver Nephritis & Nephrosis All External Causes of Death Accidents Motor Vehicle Accidents All Other Accidents Suicides Homicides & Other External Causes All Other Causes of Death CERTAIN INFECTIOUS AND PARASITIC DISEASES Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL Observed 0 2 1 5 0 3 Expected 0.2 1.6 2.0 9.8 0.3 6.0 SMR N/A 121.7 49.7 51.1 N/A 49.7 0 0.5 N/A 0 0.3 N/A 2 2.7 74.1 0 0.2 N/A 3 3.1 95.7 0 0.7 N/A 2 1.2 173.9 1 0.7 146.8 1 0.3 383.1 0 0.2 N/A 1 1.3 77.9 0 0.1 N/A 1 0.7 150.1 0 0.5 N/A 4 5.8 69.4 4 3.6 109.9 3 2.5 118.0 1 1.1 91.3 0 1.1 N/A 0 1.0 N/A 5 5.9 85.0 0 0.1 N/A 0 95% Lower 0.0 14.7 1.2 16.6 0.0 10.3 95% Upper 2200.4 439.6 277.2 119.3 1272.7 145.3 99% Lower 0.0 6.3 0.2 11.0 0.0 5.6 99% Upper 3160.2 564.2 369.6 144.6 1827.8 182.0 0.0 792.8 0.0 1239.2 9.0 267.7 0.0 1940.3 19.7 279.7 0.0 526.5 21.0 628.2 3.7 817.7 9.6 2134.5 0.0 1776.0 1.9 434.0 0.0 5737.2 3.8 836.6 0.0 806.0 18.9 177.8 30.0 281.5 24.3 344.7 2.3 508.6 0.0 340.4 0.0 355.2 27.6 198.5 0.0 1138.5 0.0 1779.7 3.8 343.6 0.0 2786.5 10.8 350.2 0.0 756.2 9.0 806.3 0.7 1090.4 1.9 2846.2 0.0 2550.7 0.4 578.7 0.0 8239.5 0.8 1115.5 0.0 1157.5 11.7 218.6 18.5 346.1 13.3 431.7 0.5 678.1 0.0 488.9 0.0 510.1 18.3 240.7 0.0 2506.3 0.0 3599.4 FINAL p. 69 Appendix C Washington Works vs West Virginia All-Cause Mortality Surveillance Report: Totals (Males and Females) Cause of Death Observed Expected All Causes o f Death Tuberculosis 806 1376.3 0 2.1 All Malignant Neoplasms Cancer of Buccal Cavity & Pharynx Cancer of Digestive Organs & Peritoneum Cancer of Esophagus Cancer of Stomach Cancer o f Large Intestine Cancer of Rectum Cancer o f Biliary Passages & Liver Cancer of Pancreas Cancer o f All Other Digestive Organs 234 340.3 4 6.6 51 70.9 4 8.5 3 8.3 17 25.0 5 6.0 8 6.9 11 13.7 3 2.4 Cancer of Respiratory System Cancer o f Larynx 72 139.7 3 4.5 Cancer o f Bronchus, Trachea, Lung Cancer o f All Other Respiratory Cancer of Breast All Uterine Cancers (Females only) Cancer o f Cervix Uteri (Females only) Cancer o f Other Female Genital Organs Cancer o f Prostate (Males only) Cancer o f Testes and Other Male Genital Organs Cancer of Kidney Cancer o f Bladder and Other Urinary Organs Malignant Melanoma of Skin Cancer of Eye Cancer of Central Nervous System Cancer o f Thyroid & Other Endocrine Glands Cancer of Bone Cancer o f All Lymphatic, Haematopoietic Tissue Hodgkins Disease Non-Hodgkins Lymphoma Leukemia & Aleukemia Cancer o f All Other Lymphopoietic Tissue All Other Malignant Neoplasms 66 134.2 3 1.0 2 3.5 0 1.2 0 0.8 0 0.9 12 20.9 1 1.3 12 7.9 7 6.8 3 5.8 0 0.2 9 8.5 3 1.1 2 0.9 32 31.5 2 2.0 9 11.6 13 12.5 8 5.4 24 32.5 SMR 58.6 ** N/A 68.8 ** 60.9 72.0 46.9 36.0 68.1 83.6 115.2 80.0 125.7 * 51.5 ** 66.2 49.2 310.0 56.8 N/A N/A N/A 57.5 ** 75.7 151.0 102.7 51.8 N/A 105.6 285.6 218.7 101.5 101.4 77.5 103.9 147.3 73.8 95% Lower 95% 99% 99% Upper Lower Upper 54.6 62.8 0.0 173.4 53.4 64.1 0.0 249.0 60.2 78.2 16.6 156.0 53.6 94.6 12.8 120.1 7.4 105.3 39.7 109.1 27.1 195.1 49.7 226.9 39.9 143.2 25.9 367.4 57.7 81.2 10.2 191.8 48.7 102.2 7.9 147.7 4.1 131.8 33.1 123.4 18.0 236.7 37.0 267.4 31.4 165.7 14.2 460.0 40.3 64.9 13.7 193.6 37.2 69.3 7.5 242.4 38.0 62.5 64.0 905.9 6.9 205.1 0.0 319.3 0.0 442.8 0.0 397.2 29.7 100.4 1.9 421.9 78.0 263.7 41.3 211.5 10.7 151.4 0.0 2132.7 48.3 200.5 58.9 834.7 26.5 789.9 69.4 143.3 12.3 366.5 35.4 147.1 55.3 177.7 63.6 290.3 47.3 109.8 35.0 67.0 34.9 1134.2 2.9 263.3 0.0 458.6 0.0 635.9 0.0 570.4 23.7 115.6 0.4 562.6 62.2 303.8 29.9 251.3 5.8 189.5 0.0 3063.0 36.8 234.7 32.2 1045.2 11.3 1013.9 61.2 157.5 5.2 470.4 27.0 172.2 44.6 203.9 47.3 342.1 40.7 122.2 69 of 73 10 FINAL Appendix C Washington Works vs West Virginia All-Cause Mortality Surveillance Report: Totals (Males and Females) (continued) Cause of Death Benign Neoplasms Diabetes Mellitus Cerebrovascular Disease All Heart Disease Rheumatic Heart Disease Observed 1 22 Expected 3.7 31.5 SMR 27.0 69.9 95% Lower 0.7 43.8 95% Upper 150.4 105.8 99% Lower 0.1 37.5 99% Upper 200.6 118.2 35 58.6 59.7 ** 41.6 83.1 36.9 91.0 314 475.6 5 4.6 66.0 ** 108.4 58.9 73.7 35.2 253.0 56.8 76.3 23.4 306.8 Ischemic Heart Disease Chronic Endocard. Dis.; Other Myocard. Insuff. Hypertension with Heart Disease 239 348.1 11 16.1 1 10.0 68.7 * * 68.1 10.0 ** 60.2 77.9 34.0 121.9 0.3 55.8 57.7 81.0 26.8 141.1 0.1 74.4 All Other Heart Disease Hypertension w/o Heart Disease Non-malignant Respiratory Disease Influenza & Pneumonia Bronchitis, Emphysema, Asthma Bronchitis Emphysema Asthma Other Non-malignant Respiratory Disease Ulcer of Stomach & Duodenum Cirrhosis of Liver Nephritis & Nephrosis All External Causes of Death Accidents Motor Vehicle Accidents All Other Accidents Suicides Homicides & Other External Causes All Other Causes of Death CERTAIN INFECTIOUS AND PARASITIC DISEASES Unknown Causes (In All Causes Category Only) (*) SIGNIFICANT AT 5% LEVEL; (**) SIGNIFICANT AT 1% LEVEL 58 96.7 60.0 * * 5 4.4 112.7 49 119.4 14 28.2 13 30.7 6 17.5 41.0 ** 49.7 ** 42.4 ** 34.3 ** 7 11.4 61.7 0 1.9 N/A 22 60.5 36.3 ** 0 3.5 N/A 9 28.1 8 14.0 32.0 ** 57.3 45 151.8 29.7 ** 35 98.2 35.6 ** 23 48.0 47.9 ** 12 50.2 23.9 ** 8 34.2 23.4 ** 2 19.4 10.3 ** 83 144.0 1 3.4 0 57.6 ** 29.5 45.5 77.5 36.6 263.0 30.4 54.3 27.2 83.4 22.6 72.5 12.6 74.7 24.8 127.1 0.0 199.1 22.8 55.0 0.0 104.1 14.6 60.7 24.7 112.8 21.6 39.7 24.8 49.6 30.4 71.9 12.3 41.7 10.1 46.1 1.2 37.3 45.9 71.5 0.7 164.6 41.6 24.3 27.5 22.1 18.2 8.8 17.9 0.0 19.5 0.0 11.1 18.4 19.5 22.0 26.1 9.8 7.5 0.5 42.6 0.1 83.4 319.0 58.7 95.2 83.1 89.6 150.9 286.0 61.5 149.5 71.1 133.0 43.1 54.3 80.2 48.1 54.3 47.9 76.0 219.5 FINAL Appendix D Job Exposure Category Development based on Division and Job p. 71 TECHNICAL PROJECT COORD 0.008 0.008 TEFLON POLYMERS PROD. SYSTEMS ANALYST 0.024 0.024 RESEARCH HR SPEC 0.025 0.025 TEFLON POLYMERS PROD. BUSINESS ANALYST 0.034 0.034 M A NUFAC TUR ING 0.037 0.037 RESEARCH DIVISION CHEMIST 0.041 0.04 TEFLON POLYMERS PROD. RES SUPERVISOR 0.056 0.056 POLY ENG DESIGN 0.067 0.012 CONT ADM /BUS SVC/SAFETY 0.072 0.026 RESEARCH 4423 NL ANALYST 0.072 0.036 RESEARCH 4421 LAB ANALYST 0.073 0.073 TEFLON POLYMERS PROD. ENGINEER 0.084 0.037 SPECIALTY COMPOUND PROD 0.084 0.023 TEFLON POLYMERS PROD. ADMIN ASSISTANT 0.089 0.051 BUSINESS SERVICES 0.092 0.007 TEFLON POLYMERS PROD. PROJECT ENGINEER 0.093 0.049 RESEARCH TEFLON@ COPOLYMERS PROD. STAFF ENGINEER PROD'N COORDINATOR 0.095 0.1 0.026 0.1 HUMAN RESOURCES 0.103 0.033 TEFLON POLYMERS PROD. TEFLON@ COPOLYMERS PROD. MASTER SCHEDULER ENGINEER 0.104 0.105 0.104 0.083 TECHNICAL AREA SPECIALIST 0.106 0.106 BUTACITE PRODUCTION 0.107 0.019 RESEARCH RESEARCH SYSTEMS ANALYST TECHNOLOGY MANAGER 0.116 0.118 0.116 0.031 TECHNICAL AREA SUPT TECH 0.119 0.119 RESEARCH ADMIN ASSISTANT 0.119 0.076 TEFLON POLYMERS PROD. SPECIAL ASSIGNMENT 0.12 0.12 E. P. COMPOUNDING PROD. 0.12 0.026 RESEARCH TECHNICAL 4422 LE ANA LY ST PROD'N COORDINATOR 0.127 0.128 0.127 0.128 BUTACITE MAINTENANCE 0.128 0.128 TECHNICAL TEFLON@ COPOLYMERS PROD. DIVISION ENGINEER SPECIAL ASSIGNMENT 0.131 0.131 0.107 0.032 RESEARCH TEFLON COPOLYMERS PROD. SR ENGINEER SENIOR SPECIALIST 0.134 0.136 0.081 0.032 FILAMENT PRODUCTION SHE&EA _________ ______________________ T EFL O N POLYMERS P R O D ....... STA FF B U S ANA LY ST 0.136 0.137 0.138 0.005 0.018 0.138 RESEARCH SPECIALTY COMPOUND MAINT ZYTEL PRODUCTION ACRYLICS SPECIALIST 0.138 0.038 [ 0.139 0.14 0.145 0.067 0.006 0.052 0.008 0.024 0.025 0.034 0.037 0.043 0.056 0.139 0.149 0.605 0.073 0.131 0.377 0.127 1 2 2 8 6 14 2 2 4 4 , ' t' I1 ,1 11 tr 21 11 11 1 11 21 mm 0.183 0.136 0.462 0.1 0.173 0.104 0.118 0.106 0.23 0.116 11 2 23 8 2 21 21 3 i I1 W\ ` ----------------- ---------3-------- l1 44 I t i i I1 0.204 l 0.119 0.171 0.12 0.652 21 0.127 1 0.128 0.128 0.154 2 11 2 ! ~ t ............. 21 11 31 1t *33 . 11 11 21 0.297 2.07 2 1 2 31 41 0.239 0.657 0.279 0.138 0.26) 1 18 _____ 25 __ 1 3 8: 1| 1 2! ; 1 i 21 ________ ; 44 w S U ,1 3 \ :..... 1 0.211 0.746 0481 1 22 6 1I 22 3 4| \ fS R llll 10 i 71 of 73 T<X FINAL p. 72 TECHNICAL TEFLON POLYMERS PROD. TECHNICAL TEFLON POLYMERS PROD. TEFLON POLYMERS PROD. TEFLON@ COPOLYMERS PROD. TEFLON POLYMERS PROD. RESEARCH FILAMENT MAINTENANCE RESEARCH TECHNICAL POLY ENG CONSTRUCTION RESEARCH TEFLON@ COPOLYMERS PROD. RESEARCH TEFLON@ COPOLYMERS PROD. DELRIN MAINTENANCE ZYTEL MAINTENANCE TECHNICAL TEFLON@ COPOLYMERS PROD. RESEARCH DELRIN PRODUCTION B&ES MAINTENANCE TECHNICAL POWER & SERVICES*MAINT. TECHNICAL SR TECH ASSOC MFG SERVICE REP 0.147 .....0 .1 5 SR CHEMIST SPECIALIST PLANT SUPT 0.153 0.153 0.157 STAFF ENGINEER DIVISION ENGINEER TECH ASSOC AREA SUPT SENIOR TECHNICIAN TECHNICIAN 0.159 0.161 0.164 0.167 0.17 0.171 0.172 0.181 AREA SUPT PROD STORES COORDINATOR 0.184 0.184 PROCESS DESIGNER 0.19 0.194 0.194 ADMIN ASSISTANT 0.197 SENIOR TECHNICIAN 4420 LABORATORIAN CERT COORDINATOR 4420 LABORATORIAN 0.198 0.201 0.203 0.209 0.219 0.221 0.225 0.146 0.15 0.153 0.025 0.157 0.017 0.078 0.028 0.104 0.104 0.053 0.172 0.042 0.184 0.184 0.181 0.078 0.069 0.054 0.198 0.055 0.044 0.063 0.185 0.221 0.07 0.148 i 0.15 0.153 0.272 .... 1 0.157 0.35 1 0.242 1 0.426 3 0.213 0.191 0.377 0.172 1 0.275 1 0.184 0.184 0.198 0.43 2 0.43 0.34 0.198 1.38 3 0.457 0.464 0.252 0.221 0.352 3 2; l _ .. _ . _. . i 4 1 2 2 6 4 3 4 l 3 1 1 2 7 3 37 5 31 10 2 2 12 2 ___ 1 1 5 1 3 3 9 ... 3 5 4 1 1 2 4 2 1 47 36 13 2 l 7\ 15 E. P. COMPOUND M A INTE NA NCE TEFLON POLYMERS PROD. SR PROJECT SUPVR EMPLOYEE RELATIONS TEFLON MAINTENANCE AREA SUPT MAINT RESEARCH TECH FELLOW POWER & SERVICES RESEARCH SR CHEMIST ! RESEARCH DIVISION ENGINEER ! TEFLON POLYMERS PROD. DIVISION CHEMIST 1 TECHNICAL j TEFLON@ COPOLYMERS 1 PROD. ............... SPECIAL ASSIGNMENT AREA SPECIALIST i RESEARCH 1 TEFLON@ COPOLYMERS PROD. TEFLON COPOLYMERS ! PROD : TEFLON COPOLYMERS ; PROD. ` '~~ SUPERVISOR SR CHEMIST SPECIALIST AREA SUPT TEFLON POLYMERS PROD. TECH FELLOW : TECHNICAL i TEFLON COPOLYMERS PROD. I SR ENGINEER | i RES ENGINEER TEFLON POLYMERS PROD. TECHNICAL ! RESEARCH 4;. . TE--C--H----A--S--S--O---C----- . . j TECHNICIAN j MFG SUPT 0.234 0.24 0.107 0.24 0.476 0.24 3 0.24 0.242 0.244 0.106 0.242 0.174 0.38 0.242 0.314 3 1 2 0.245 0.045 0.246 0.246 0.247 0.125 0.248 0.248 0.249 ! 0.249 0.963 0.246 0.581 0.248 0.249 6 .... 1 2 't <l 0.255 0.258 ! -255 ! 0.159 0.265 1 0.171 0.255 0.357 0.359 j 1! ;2 ': 0.273 ! 0.134 1.28 14 0.279 : 0.137 ^ 0.369 0.282 0.282 __ 0.282 , 0.097 0.282 0.316 ` 0.286 : 0.133 0.439 ! 0.288 T ; 0.289 ! 0.131 T" : 0.099 0.471 0.562 1 0.292 ! 0.292 0.292 i3 `l !2 |? 6 1i1 ;1 2 l._ . _ ... 1 3 1 3 1 2 IIS sS i _____1 ....... 3 1 1 j! l2 2 1 i5 1 I3 \1 r .......... 3,, !2 !6 1 L - 3 ....... jj__________ 1 72 of 73 FINAL p. 73 TEFLON@ COPOLYMERS PROD. SR TECH ASSOC 0.292 0.197 0.387 2 22 RESEARCH TEFLON@ COPOLYMERS PROD. AREA SUPT TECH SUPERVISOR 0.296 0.307 0.296 0.123 0.296 2.39 1 623 12 11 2 RESEARCH TEFLON@ COPOLYMERS PROD. SENIOR TECHNICIAN DIVISION ENGINEER 0 .3 ! 0.31 0.31 0.33 0.33 0.33 l l 12 I2 TEFLON POLYMERS PROD. ENV1R CONT CONSULT 0.34 0.329 0.35 2 22 RESEARCH TEFLON@ COPOLYMERS PROD. SR TECH ASSOC 6810 OPERATOR I 0.344 0.349 0.058 0.349 0.559 0.349 2 3 3 82 I2 TEFLON MAINTENANCE 6720 STC/SPS MECH 0.35 0.159 0.54 1 22 TEFLON POLYMERS PROD. SR CHEMIST 0.356 0.308 0.405 2 22 TEFLON POLYMERS PROD. TEFLON@ COPOLYMERS PROD. MAINT SUPT SR ENGINEER 0.363 0.363 0.363 0.101 0.363 0.576 4 I2 52 TECHNICAL TEFLON@ COPOLYMERS PROD. TECH ASSOC 4420 LABORATORIAN 0.369 0.382 0.148 0.166 0.589 0.708 72 22 92 TEFLON@ POLYMERS PROD. TEFLON@ COPOLYMERS PROD. AREA SUPT PROCESS ENGINEER 0.39 0.427 0.112 0.837 0.28 0.574 2 52 22 TEFLON POLYMERS PROD. SENIOR TECHNICIAN 0.427 0.244 0.61 22 TEFLON POLYMERS PROD. TEFLON@ COPOLYMERS PROD. TEFLON@ COPOLYMERS PROD. QUALITY COORD TECH ASSOC ADM IN ASSISTANT 0.444 0.459 0.488 0.444 0.196 0.488 0.444 0.715 0.488 2 12 32 12 TEFLON POLYMERS PROD. PRODTM COORDINATOR 0.55 0.528 0.572 2 22 TEFLON POLYMERS PROD. SR TECH ASSOC 0.581 0.17 1.57 42 TECHNICAL TEFLON @ COPOLYMERS PROD. SPECIALIST SPECIALIST 0.635 0.763 0.61 0.134 0.659 2.39 2 42 22 62 TEFLON@ POLYMERS PROD. SR ENGINEER 0.765 0.412 1.59 2 42 TECHNICAL TEFLON POLYMERS PROD. TEFLON POLYMERS PROD. TEFLON@ COPOLYMERS PROD. TEFLON POLYMERS PROD. TEFLON POLYMERS PROD. TEFLON@ COPOLYMERS PROD. TECH SPEC 6 8 1 0 A D V M OPR 11 6810 TRNC OPR II 6810 OPERATORI! SUPERVISOR 6810 STC/SPS OP II TECH SPEC 0.783 0.805 1.07 1.136 1.21 1.3 1.46 0.783 0.299 1.07 0.188 0.233 1.3 1.46 0.783 1.53 1.07 5.015 3.18 1.3 1.46 m m2 17 4 1 l" T ~ m. 1218 19 1 so r r4 ! Hmmi ; . ,! i 2 2 TEFLON MAINTENANCE 6720 MECHANIC 1.726 0.155 6.81 64 7 2 19 TEFLON POLYMERS PROD. 6810 OPERATOR II 3.311 0.199 9.55 2 84 18 32 73 of 73 7Y