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Final Report Mortality Study of Workers Employed at the 3M Cottage Grove Facility Submitted by: Bruce H. Alexander, PhD Division of Environmental and Occupational Health School of Public Health University of Minnesota Mayo Mail Code 807 Mayo Building 420 Delaware Street S.E. Minneapolis, MN 55455 April 26, 2001 BACK TO MAIN Summary Objective: To determine whether occupational exposure to perfluorooctanoic acid (PFOA) and other fluorochemicals is related to the mortality experience of employees of the 3M facility in Cottage Grove, Minnesota. Methods All employees who accrued at least one year of employment at Cottage Grove were eligible for inclusion in the study. Cohort members were assigned to one of three exposure groups based on their work history: non-exposed, probable exposure to PFOA, and definite exposure to PFOA. The cohort was followed through December 31, 1997. Death certificates were obtained for all known deaths and coded for analysis. Standardized mortali ty ratios were estimated for all cause and cause specific mortality using mortality rates from the general population of Minnesota as a reference. SMR estimates were made for the sub-cohorts ever exposed to PFOA, by exposure category, and for a minimum of one year of exposure. Results There were 3,992 eligible cohort members who accrued 108,198 person-years of follow-up and 607 deaths. Forty-six of the deaths occurred in the sub-cohort with definite PFOA exposure. The all cause and all cancer mortality rates for the entire study population, and for the exposure sub cohorts were less than expected in the general population, t here was no association between exposure to PFOA or other fluorochemicals and cancer of the liver, kidney, or prostate or cirrhosis o f the liver. A modest increased risk of death from cerebrovascular disease (CVD) was observed in the definite PFOA exposure subcohort the (5 observed, 1.94 expected, SMR=2.58, 95% CI=0.84-6.03). A dose response relationship between PFOA or other fluorochemical exposure and CVD was not apparent. Conclusion Employees of the Cottage Grove facility were not observed to have an excess risk of mortality from cancer in relation to PFOA and other fluorochemical exposure. The association observed between PFOA exposure and CVD was modest, but unexpected. The association may be due to some occupational exposure although there is no biologically plausible mechanism identified at this time. 2 BACK TO MAIN Introduction The Cottage Grove manufacturing facility of the Minnesota Mining and Manufacutring Corporation (3M) has produced perfluoroinated compounds since 1947. A primary product from this plant is ammonium periluorooctanoate (CF3(CF2)6C 02NH4+, APFO), a potent synthetic surfactant used in industrial applications. APFO rapidly dissociates in biologic media to perfluorooctanoate (CF3(CF2)6C02\ PFOA) which is the anion of perfluorooctanoic acid (CF3(CF2)6COOH). In laboratory animals, PFOA and its salts are: 1) absorbed by ingestion, inhalation or dermal contact; 13 2) distributed primarily in the liver and blood;4 3) not biotransformed, conjugated or incorporated into lipids;5,6 and 4) eliminated in the female rat at a greater rate of excretion than the male rat.7In rats, administration of APFO resulted in peroxisome proliferation, uncoupling of mitochondrial oxidative phosphorylation and altered lipid metabolism.8'9In lifetime feeding bioassays of rats, APFO in the diet at 300 ppm (daily dose of 15 mg/kg/day) increased the incidence of liver Leydig cell and pancreas acinar cell adenomas.10The liver tumors most likely occurred via the nongenotoxic mechanisms of oxidative stress and apoptosis. Increased hepatic aromatase activity may have resulted in a hormone-mediated mechanism (increased estradiol) for the formation of the Leydig cell tumors.11,12The pancreas acinar cell adenomas have been hypothesized to be a result of a mild but sustained increase in cholecystokin (CCK) levels secondary to hepatic cholestasis.13In a 90day gavage study of rhesus monkeys, mortality was pronounced prior to end of study in the 100 mg/kg/day and 30 mg/kg/day dose groups.14Histopathologic examination revealed marked diffuse lipid depletion in the adrenals, slight to moderate hypocelluarity of bone marrow and moderate atrophy of lymphoid follicles. No histopathologic changes were reported in the 3 and 10 mg/kg/day dose groups. A recently completed 6-month gavage study of cynomolgus primates demonstrated a steep dose response curve.15Both the low (3 mg/kg/day) and mid (10 mg/kg/day) 3 BACK TO MAIN dose groups resulted solely in increased liver weights. The highest dose group (30/20 kg/mg/day) resulted in severe toxicity, which required the removal of treatment for some of the high dose group animals. The exact mechanism of toxicity in the primate remains to be elucidated. Hepatic toxicity, hypolipidemia and abnormal hormone levels (e.g., estradiol) have not been associated with the PFOA levels measured in male APFO production workers.16'20 However, it should be noted that the serum concentration (50 ppm) associated with liver enlargement in the 3.0 mg/kg/day dose group of the cynomolgus primate study is within the range experienced by workers with higher occupational exposure.1519'20 A retrospective cohort mortality study of workers engaged in APFO production at the Cottage Grove facility found no significantly increased cause-specific standardized mortality ratio although a two-fold nonsignificant increase in prostate cancer mortality, based on 4 observed deaths was reported.21 This report summarizes the results of an update of that cohort mortality study with a specific emphasis on exposure to PFOA. Methods Cohort Enumeration The cohort for this study was enumerated using employment records from the Cottage Grove facility. Workers accruing at least 1 year of cumulative employment at the Cottage Grove facility as of December 31, 1997 were eligible for inclusion in the cohort. A review of employee work history records by 3M personnel identified workers eligible for the cohort. The records of any Cottage Grove employee with at least one year of cumulative employment were abstracted to record the worker's name, Social Security Number, 3M identification number, date of birth, and the dates of any entry on the work history record, including layoffs and leaves of absence. 4 BACK TO MAIN Information about each job was abstracted wherever available, including the department codes, and job classifications. The names, Social Security Numbers, 3M identification numbers, and dates of birth were recorded for workers with less than one year of cumulative employment for comparison with the original cohort. The abstracted data were entered into a computer database and provided to University of Minnesota investigators. The newly enumerated cohort was linked to records from the original cohort to update the employment information and verify names, Social Security Numbers dates of birth and dates of death. Discrepancies identified in the records were resolved using TRW/Experian, a credit reporting agency, and the Social Security Administration service for epidemiologic research studies. The latter reports the most recent account activity of an individual and whether they are recorded as deceased in the Social Security Death Index (SSDI). Duplicate records due to name changes or incorrect data were eliminated. Investigators at the University of Minnesota reviewed the eligibility for inclusion in the cohort. To be eligible for the cohort a worker had to accrue at least 365 days o f cumulative employment at the Cottage Grove site. The eligibility of each cohort member was determined by summing his or her dates of employment, exclusive of periods of absence due to illness, military leave, maternity leave, or layoff. Currently employed workers were assigned December 31, 1997 as their last date of employment. 5 BACK TO MAIN Follow-up and Determination of Vital Status Eligible cohort members were followed from the day they accrued 365 days of cumulative employment till December 31, 1997 or their date of death. Vital records searches were performed for all cohort members not employed by 3M on December 31, 1997, or for whom a death certificate was not obtained in the original study. The National Death Index (NDI) was searched for all workers in the original study and new workers included in the cohort. The Social Security Administration data and/or the SSDI were searched to verify the vital status of workers who terminated employment before 1979. The records of cohort members identified as deceased through the NDI or SSDI were reviewed by hand to ensure a valid match and a copy of the death certificate was requested from the state of record. A licensed nosologist coded the death certificates to the International Classification of Disease Version 8. A second licensed nosologist coded the death certificate using the rules for the ICD version in effect at the time of death. This second coding was used for verification and enabled the use of actual (unadjusted) mortality reference data. Exposure Assessment The goal of this study was to describe mortality experience in relation to fluorochemical exposure. Of particular interest was exposure to PFOA. The areas in the Cottage Grove facility where PFOA and other fluorochemicals were produced changed over the years. Because the department codes used to classify the work areas also changed over years it was not possible to assign the wofkers to exposure categories on work history information alone. To ascertain exposure status the department codes were reviewed to deteirmine the building and division 6 BACK TO MAIN assigned to each code. These lists were then reviewed independently by a panel of veteran workers and plant industrial hygienists to determine where fluorochemical production or the development of fluorochemical products took place throughout the history of the Cottage Grove Facility. The responses of the individual reviews were summarized and the panel was convened as a group to discuss the exposure assignments. The available information limited the panel's ability to classify each department with certainty, thus general classifications of exposure were adopted. The job history information was classified into the three following groups; Definite PFOA exposure (potentially high). These jobs included workers employed in the areas where cell generation, drying, shipping, and packaging of PFOA occurred throughout the history of the plant. Probable PFOA exposure. These jobs include other chemical division jobs where exposure to PFOA was possible, but with lower or transient exposures. Not exposed to fluorochemicals. Primarily non-chemical division jobs. Hereafter these exposure subgroups will be referred to as definite exposure, probable exposure and nonexposed, respectively. ' Potential for exposure to other fluorochemcials was possible in the chemical division. In particular, there has been production of some salts of perfluorooctane sulfonic acid, which may disassociate to perfluoroctanesulfonate (PFOS, CgFnSCV). However, this did not usually occur where definite PFOA exposure in the workplace was likely, as the production areas were in different buildings. It is feasible that employees who had worked in jobs with definite PFOA exposure may have transferred to this other building in the course of their career. 7 BACK TO MAIN Analysis The mortality experience of the Cottage Grove cohort was compared to that of the general population of the state of Minnesota. Mortality reference rates from seven regional counties (Hennepin, Ramsey, Anoka, Carver, Dakota, Scott, and Washington) were also used to rule out large variations based on regional mortality reporting differences. Reference data were obtained from the Mortality Population Data System (MPDS) center at the University of Pittsburgh. These data are derived from National Center for Health Statistics data and provide all cause mortality and malignant neoplasm rates back to 1940, and non-malignant cause specific death rates from 1962 forward. These reference data are age (5 year), gender, race, and calendar period (5 year) specific and are coded using the rules for the ICD version in effect for the calendar period. Standardized mortality ratios (SMR) were computed for all cause and cause specific deaths using the Minnesota reference data. The expected number of deaths for all cause and malignant neoplasm deaths were estimated for all years. The expected number of deaths from non malignant causes was computed for the years 1962-1997. Observed deaths and person-years in the denominator occurring before the reference data were available were excluded from the analysis. The SMRs and appropriate 95% confidence intervals were computed using the PC Life Table Analysis System (PCLTAS) software developed by the National Institutes of Occupational Safety and Health (NIOSH).22This program computes age, gender, and race specific SMR using standard life table methods. The expected number of deaths are estimated by multiplying the age, gender, race, and calendar period tabulated person-years of follow-up to the corresponding cause specific mortality reference rates. No data on race were available for the cohort; therefore, the reference data were limited to the mortality rates for white Minnesotans. 8 BACK TO MAIN The all cause and cause specific SMRs were initially computed for the entire cohort and the subcohorts with definite exposure, probable exposure, and not exposed to fluorochemicals. A more exposure specific analysis stratified workers based on a one-year minimum employment in jobs with definite PFOA exposure and definite or probable exposure. The latter included workers who accrued one year of employment with a combination of definite and probable exposed jobs. Four causes of death potentially related to PFOA exposure based on laboratory animal data and the earlier cohort study, prostate cancer, liver cancer, kidney cancer, and cirrhosis of the liver, were analyzed by duration of exposure in each fluorochemical exposure subgroup. Other causes of death that appeared to be in excess in one or more of the fluorochemical exposed groups were also evaluated by duration of exposure. 9 BACK TO MAIN Results Of the 6678 individual workers identified at the Cottage Grove plant, 3992 employees met the one year inclusion criteria. Of these, 12 percent (492) worked at least one day in areas where definite exposure to PFOA occurred. Forty-two percent (1685) had probable exposure, but not definite PFOA exposure, and the remaining 45% (1815) were not exposed to fluorochemicals (Table 1). The latter are non-chemical division jobs at Cottage Grove. Male workers made up 80% of the cohort, but were 92% of the PFOA exposed cohort. The average age at follow up was slightly less in the PFOA exposed cohort, but the average duration of employment at Cottage Grove was slightly longer. There were 607 deaths identified in the cohort, 46 deaths in the definite PFOA exposure group and 267 in the probable PFOA exposure group. Death certificates were obtained for 590 of the decedents (97%). Six of the missing death certificates were in the probable PFOA exposure group and the rest were in the non-exposed group. More extensive exposure to PFOA, based on a one-year minimum employment in definitely exposed jobs, occurred to 182 workers (17 deaths), and 1673 workers had definite or probable exposure for at least one year (219 deaths) (Table 2). The all cause and cause specific mortality rates for the entire cohort were lower than expected compared to the general population: 607 observed and 715 expected (SMR=0.85, 95% 0=0.780.92) (Table 3). A similar pattern was observed for all deaths from cancer; 172 observed, 204 expected (SMR=0.84, 95% Cl = 0.72-0.98). Deaths from all causes and all cancers were fewer than expected for the exposure subcohorts (Table 4-6), and for the strata limited to workers with a minimum o f one year of definite exposure (Table 7), or a combination of definite or probable exposure (Table 8). 10 BACK TO MAIN There was no association observed between fluorochemical exposure and cancer of the prostate, liver, kidney, or from cirrhosis of the liver (Table 4-8). In the definite PFOA exposure subcohort only one death from prostate cancer was observed (0.77 expected). Five deaths from prostate cancer were observed in the probable PFOA exposure group (5.8 expected), and another 2 observed in the non-exposed sub-cohort (6.8 expected). Only one cancer of the liver was observed and that was in the probable PFOA exposure group. Again, limiting the cohort to a minimum of one year of exposure did not alter the results. Overall, nonmalignant causes of death did not exceed that expected in Minnesota. Deaths from cerebrovascular disease (CVD) did exceed the number of expected in the definite PFOA exposed cohort; 5 observed and 1.94 expected (SMR=2.58, 95% Cl 0.84-6.03). Deaths from CVD were not elevated in the rest of the cohort. Three CVD deaths occurred in the subcohort with definite exposure for at least one year, where 0.89 deaths were expected (SMR=3.36,95% CI=0.69, 9.82). It is plausible that the coding of CVD deaths varies by region, where a CVD death in an older person may be reported as "Natural Causes" on the death certificate, which would receive a different ICD code. To verify these results the CVD deaths were compared to the local county mortality rates. The results were essentially the same. . To further evaluate the distribution of CVD deaths, the SMRs in the definite PFOA exposure sub-cohort were stratified by duration of employment in PFOA exposed jobs (Table 9), and exposure weighted time of employment (Table 10). In the exposure-weighted time of employment weights of 0, 1 and 3 were assigned respectively to the non-exposed, probable 11 BACK TO MAIN PFOA exposed, and definite PFOA exposed jobs in the work histories. The weighted time of exposure was derived by multiplying the duration of employment in the exposed jobs, in days, by the weighting factor. The results for the years of employment in PFOA exposed jobs did not reveal a dose-response relationship between PFOA exposure and the risk of CVD; however, the SMR for high PFOA exposure for five or more years was 6.9 (95% Cl = 1.39-20.24). This, however, was based on only three cases, and no deaths from CVD occurred among workers with ten or more years in high PFOA jobs (Table 9). The weighted exposure analysis, which includes information from the workers with probable exposure to PFOA indicated that the fluorochemical exposed workers with less than 10,000 exposure days experienced fewer than expected deaths from CVD. The SMR for those with 10,000 or more exposure days was 3.32 (95% 0=0.898.49). An exposure days value of 10,000 equates to 27 years of exposure in probable PFOA exposed jobs or 9 years in definite PFOA exposed jobs. The number of deaths from traumatic injuries was less than expected for the entire cohort, however, the frequency of deaths from violence was modestly elevated in the definite exposure cohort. Five o f the six violent deaths were suicides (2.1 expected, SMR 2.33, 95% 0 = 0 .7 6 -5 .4 5 ) (Table 4). 12 BACK TO MAIN Discussion This updated mortality study evaluated the mortality experience of workers with at least one year of employment at the 3M Cottage Grove facility, with specific attention to exposure to PFOA. No excess mortality was observed for malignant neoplasms or for all causes of death. There were modest elevations in the risk of death from cerebrovascular disease and deaths due to violence in the higher PFOA exposed workers, but these results are based on very few cases. Some limitations must be considered when interpreting the results of this mortality analysis. Although several methods of follow-up were employed to ascertain deaths in this cohort, the possibility remains that some deaths were not accounted for in the analysis. A death certificate was not obtained for seventeen known decedents; thus they were not included in the cause specific death analysis. The extent to which these limitations would affect the results is unknown, however most of the missing death certificates were in the nonexposed sub-cohort. Another limitation of this study is the lack of employee specific exposure data for PFOA and other fluorochemicals. The determination of potential exposure to these compounds was made using all available information from work histories and expert input from veteran workers and plant industrial hygienists. Nevertheless, some misclassification of exposure was likely. Maintenance and other mobile workers not specifically identified as definitely PFOA exposed workers may have routinely entered the PFOA exposed sites, and a few workers assigned to the PFOA exposure areas may not have spent much time in those areas. The extent to which this misclassification occurred and the attendant effects on the study results remain unknown. This study differs from the analysis published by Gilliland and Mandel21 by the study inclusion criteria and the exposure definition. The earlier study required six months of cumulative 13 BACK TO MAIN employment for inclusion, while the current study required one year. The change was made primarily to exclude the relatively large number of short-term workers. Workers who left after A only six months on the job were likely to have different underlying risk factors than the long term workers. The Gilliland and Mandel analysis limited the exposure assignment to Chemical Division/Non-Chemical Division and assumed duration of employment in the chemical division equated with exposure to PFOA. The current analysis was driven by more recent toxicological evaluations of the compound, and specifically categorizes PFOA exposure as definite and probable within the Chemical Division as only certain areas and tasks within the Chemical Division would have led to high exposure to PFOA.. Another difference of note between the two analyses is the inclusion of 169 additional cohort members in the current study that, according to available employment data, were eligible for both studies. The two analyses of this cohort differ by the results for prostate cancer and cerebrovascular disease. The previous analysis identified 6 cases of prostate; cancer, four of which were in the Chemical Division. The current analysis identified eight cases of prostate cancer; one in the definite PFOA exposure group and five in the probable PFOA exposure group. In neither of the exposure groups did the number of prostate cancer deaths exceed the expected number. One case of prostate cancer identified in the previous study was not included in the current analysis because the worker did not meet the one-year minimum employment criteria. Although Gilliland and Mandel considered an association between PFOA exposure and prostate cancer as biologically plausible based on the animal and human data,17'21 subsequent research,19 14 BACK TO MAIN as well as the present study findings would argue that, at this time, there is not an association observed in this workforce. The result for cerebrovascular disease is difficult to interpret. There were 13 CVD deaths in the previous analysis and 26 in the current study. There was no excess of CVD deaths in the non exposed group or the probable PFOA exposure group. In fact the SMRs were well below 1.0. There was not an apparent dose-response relationship, however such an analysis was hampered by the relatively few cases available to analyze. The lack of an association in the probable-PFOA exposure group and the absence of a change by using the local counties as a reference suggest that this is not an artifact of death certificate coding. CVD may be related to life style factors including smoking. It is noteworthy that the SMRs for all heart disease (1.08) and lung cancer (1.17) were at or above unity in the PFOA exposed sub-cohort. These diseases may be markers for smoking related illness. Heart disease and CVD are almost always below unity in epidemiologic studies of chemical workers. Therefore, these SMRs reported in the definite PFOA exposure group are unexpected. The observed association may be due to some occupational exposure at the Cottage Grove facility, although there is no biologically plausible mechanism identified. At this time a causal association cannot be drawn between exposure to PFOA and death from cerebrovascular disease. The absence of measurable adverse health effects from PFOA exposure was also reported in earlier studies on this population. PFOA exposure did not alter circulating levels of reproductive hormones 19dnd a study of the effects of PFOA on markers of liver function did not detect frank hepatotoxic effect.18,20 15 BACK TO MAIN Recommendations There does not appear to be a clear association between employment at the Cottage Grove plant and risk of mortality from cancer or other causes. However, due to the previous observation of an association with prostate cancer, the apparent excess occuiTence of death from cerebrovascular disease, and the evolving understanding of the toxicology of PFOA, continued mortality follow up of this cohort is warranted. 16 BACK TO MAIN References 1. Griffith FD, Long JE. Animal toxicity studies with ammonium perfluorooctanoate. Am Ind Hyg Assoc J 1980;41:576-583. 2. Kennedy G. Dermal toxicity of ammonium perfluorooctanoate. Toxicol Appl Pharm 1985;81:348-355. 3. Kennedy G, Hall G, Britteli J, Chen H. Inhalation toxicity of ammonium perfluorooctanoate. Fd CHem Toxicol 1986;24:1325-1329. 4. Vanden Heuvel J, Kuslikis B, Van Refelghem M, Peterson R. Tissue distribution, metabolism and elimination of perfluorooctanoic acid. J Biochem Toxicol 1991;6:83-92. 5. Orphaug R, Singer L. Metabolic handling of perfluorooctanoic acid in rats. Proc Soc Exp Biol Med 1980;163:19-23. . 6. Pastoor T, Lee K, Perri M, Gillies P. Biochemical and morphological studies of ammonium perfluorooctanoate-induced hepatomegaly and peroxisome proliferation. Exp Mol Path 1987;47:98-109. 7. Hanhijarvi H, Phaug R, Singer L. The sex-related difference in perfluorooctanoate excretion in the rat. Proc Soc Exp Biol Med 1982;171:51-55. 8. Keller B, Marsman D, Popp J, Thurman R. Several nongenotoxic carcinogens uncouple mitochondrial phosphorylation. Biochim Biophys Acta 1991;1102:237-244. 9. Haughom B, Spydevold O. The mechanism underlying the hypolipmie effect of perfluorooctanoic acid, perfluorooctane sulphonic acid (PFOSA) and clofibric acid. Biochimica et Biophysicia Acta 1992;1128(l):65-72. 10. Sibinski L. Two-year oral (diet) toxicity/carcinogenicity study of fluorochemical FC-143 in rats. St. Paul; Riker Laboratories, 1987. 11. Cook J, Murray S, Frame S, Hurtt M. Induction of Leydig cell adenomas by ammonium perfluorooctanoate: a possible endocrine-related mechanism. Toxicol Appl Pharm 1992;113:209-217. 12. Biegel L, Liu R, Hurtt M, Cook J. Effects of ammonium perfluorooctanoate on Leydig cell function: in vitro, in vivo, and ex vivo studies. Toxicol Appl Pharm 1995;134:18-25. 13. Oboum J, Frame S, Bell R, Longnecker D, Elliott G, Cook J. Mechanisms for the pancreatic oncogenetic effects of the peroxisome proliferator Wyeth-14,643. Toxicol Appl Pharm 1997;145:425-436. ' 14. Goldenthal E, Jessup D, Geil R, Mehring J. Ninety-day subacute rheus monkey toxicity study. Mattawan, MI: International Research Development Corp, 1987. 17 BACK TO MAIN 15. Butenhoff J, Costa G, Elcombe C, Farrar D, Hansen K, Iwai H, Jung R, Kennedy G, Lieder P, Olsen G, Thomford P. Toxicity of ammonium perfluorooctanoate (APFO) in cynomolgus monkeys after 26 weeks of oral dosing. Toxicol Sci 2001 ;in preparation. 16. Ubel F, Sorenson S, Roach D. Health status of plant workers exposed to fluorochemicals: a preliminary report. Am Ind Hyg Assoc 1980;41: 584-589. 17. Gilliland F. Fluorocarbons and Human Health: Studies in Occupational Cohort [Doctoral Dissertation]. University of Minnesota, 1992. 18. Gilliland F, Mandel J. Serum perfluorooctanoic aciid and hepatic enzymes, lipoproteins and cholesterol: a study of occupationally exposed men. Am J Ind Med 1996;29:560-568. 19. Olsen GW, Gilliland FD, Burlew MM, Burris JM, Mandel JS, Mandel JH. An epidemiologic investigation of reproductive hormones in men with occupational exposure to perfluorooctanoic acid. Journal of Occupational & Environmental Medicine 1998;40(7):614-22. 20. Olsen GW, Burris JM, Burlew MM, Mandel JH. Plasma cholecystokinin and hepatic enzymes, cholesterol and lipoproteins in ammonium perfluorooctanoate production workers. Drug and Chemical Toxicology 2000;23:603-620. 21. Gilliland FD, Mandel JS. Mortality among employees of a perfluorooctanoic acid production plant. Journal of Occupational Medicine 1993;35(9):950-4. 22. National Institutes for Occupational Safety and Health. PC LTAS: Life table analysis system for use on the PC. Cincinnati: U.S. Department of Health and Human Services, 1998. 18 BACK TO MAIN Table 1. Characteristics of 3M employees with one or more years of employment at Cottage Grove. Definite Probable PFOA PFOA Total exposure3 Exposureb 492 1685 Non-exposedc Total 1815 3992 Gender M 452 (92%) 1387 (83%) 1344 (74%) 3183 (80%) F 40 ( 8%) 298 (17%) 471 (26%) 809 (20%) Mean age at follow-up 52.0 57.4 57.0 56.6 Median age at follow-up 50.6 57.8 57.6 57.0 Mean year at birth 1944 1938 1938 1938 Median year at birth 1946 1938 1938 1939 Mean years at CG 16.6 14.5 8.6 12.1 Median years at CG 14.2 10.7 4.5 7.2 Person years of follow-up 10703 44295 49188 108198 Deaths 46 267 294 607 a: Ever employed in job with definite (high) PFOA exposure b: Ever employed in a job with probable to other fluorochemicals including low PFOA exposure, but never in a job with definite exposure, c: Primarily non-Chemical Division. 19 BACK TO MAIN Table 2. Characteristics of Cottage Grove workers with definite PFOA exposure and definite or probable PFOA exposure for a minimum of one year. Definite _________________________________ PFOA exposure3 Total 182 Definite or Probable PFOA exposure13 1673 Deaths 17 219 Person years 3897 41487 Gender M 168 (92%) 1442 (86%) F 14 (8%) 231 (14%) Mean age at follow-up 53 56 Mean year of birth 1943 1940 Mean years at Cottage Grove 17.8 15.7 Mean years of exposure 6.2 9.4_______ a: Definite (high) PFOA exposure for at least one year. b: Definite or Probable PFOA or other fluorochemical ex posure for at least one year. Includes workers who accrued one year of exposure with definite and probable jobs combined 20 BACK TO MAIN Table 3. Cause specific deaths and standardized mortality ratios for selected causes of death for all Cottage Grove employees. Cause All Deaths Cancers All Malignant Neoplasms Buccal Cavity and Pharynx Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas All Other Digestive Respiratory System Larynx Bronchus, Trachea, Lung Breast Female Reproductive Male Reproductive Prostate Testis and Other Male Genital Organs Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin All Lymphatic and Hematopoietic Tissue Observed Expected SMR 95% Cl 607 715.13 0.85 0.78-0.92 172 203.96 0.84 0.72-0.98 2 4.16 0.48 0.06-1.74 42 50.38 0.83 0.60-1.13 3 5.34 0.56 0.12-1.64 4 6.31 0.63 0.17-1.62 19 18.18 1.04 0.63-1.63 2 3.93 0.51 0.06-1.84 1 4.43 0.23 0.01-1.25 12 10.78 1.11 0.57-1.94 1 1.40 0.71 0.02-3.97 56 61.44 0.91 0.69-1.18 2 1.80 1.11 0.13-4.02 53 58.97 0.90 0.67-1.18 6 8.60 0.70 0.25-1.52 ' 3 5.23 0.57 0.12-1.68 9 14.27 0.63 0.29-1.20 8 13.41 0.60 0.26-1.18 1 0.86 1.16 0.03-6.47 8 9.89 0.81 0.35-1.59 3 6.06 0.49 0.10-1.45 5 3.83 1.31 0.42-3.05 4 3.24 1.24 0.34-3.16 18 23.47 0.77 0.45-1.21 Non-malignant causes Cerebrovascular Disease All Heart Disease Nonmalignant Respiratory Disease Cirrhosis of Liver Nephritis and Nephrosis Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides . Homicides'" 26 35.91 0.72 0.47-1.06 195 234.49 0.83 0.72-0.96 29 45.92 0.63 0.42-0.91 11 14.33 0.77 0.38-1.37 2 4.12 0.48 0.06-1.75 32 46.32 0.69 0.47-0.98 19 22.08 0.86 0.52-1.34 13 24.24 0.54 0.29-0.92 17 22.45 0.76 0.44-1.21 13 18.23 0.71 0.38-1.22 4 4.22 0.95 0.26-2.42 21 BACK TO MAIN Table 4. Cause specific deaths and standardized mortality ratios for selected causes of death for Cottage Grove employees ever employed in jobs with definite PFOA exposure. Cause All Deaths Observed Expected SMR 95% Cl 46 50.14 0.92 0.67-1.22 Cancers All Malignant Neoplasms Buccal Cavity and Pharynx Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas All Other Digestive Respiratory System Larynx Bronchus, Trachea, Lung Breast Female Reproductive Male Reproductive Prostate Testis and Other Male Genital Organs Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin All Lymphatic and Hematopoietic Tissue 11 13.79 0.80 0.40-1.43 0 0.31 0.00 0.00-11.81 3 3.44 0.87 0.18-2.55 0 0.42 0.00 0.00-8.86 0 0.42 0.00 0.00-8.85 2 1.20 1.67 0.20-6.02 0 0.26 0.00 0.00-13.97 0 0.30 0.00 0.00-12.12 1 0.75 1.34 0.03-7.42 0 0.09 0.00 0.00-40.54 5 4.45 1.12 0.36-2.63 0 0.13 0.00 0.00-27.97 5 4.26 1.17 0.38-2.74 0 0.18 0.00 0.00-20.31 ` 0 0.09 0.00 0.00-40.65 1 0.85 1.17 0.03-6.51 1 0.77 1.30 0.03-7.20 0 0.08 0.00 0.00-45.03 0 0.71 0.00 0.00-5.22 0 0.47 0.00 0.00-7.82 0 0.23 0.00 0.00-15.72 0 0.30 0.00 0.00-12.27 0 1.70 0.00 0.00-2.17 Non-malignant causes Cerebrovascular Disease All Heart Disease Nonmalignant Respiratory Disease Cirrhosis of Liver Nephritis and Nephrosis Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides'" 5 1.94 2.58 0.84-6.03 17 15.69 1.08 0.63-1.73 1 2.57 0.39 0.01-2.16 0 1.18 0.00 0.00-3.14 0 0.23 0.00 0.00-16.01 5 4.79 1.04 0.34-2.44 2 2.43 0.82 0.10-2.97 3 2.35 1.28 0.26-3.73 6 2.64 2.27 0.83-4.95 5 2.14 2.33 0.76-5.45 1 0.49 2.02 0.05-11.23 22 BACK TO MAIN Table 5. Cause specific deaths and standardized mortality ratios for selected causes of death for Cottage Grove employees ever employed in jobs with probable PFOA exposure, but did not hold jobs with definite PFOA exposure. Cause All Deaths Observed Expected SMR 95% Cl 267 314.73 0.85 0.75-0.96 Cancers All Malignant Neoplasms Buccal Cavity and Pharynx Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas All Other Digestive Respiratory System Larynx Bronchus, Trachea, Lung Breast Female Reproductive Male Reproductive Prostate Testis and Other Male Genital Organs Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin All Lymphatic and Hematopoietic Tissue 80 90.13 0.89 0.70-1.10 1 1.85 0.54 0.01-3.00 19 22.46 0.85 0.51-1.32 1 2.40 0.42 0.01-2.32 1 2.78 0.36 0.01-2.00 8 8.11 0.99 0.43-1.94 2 1.74 1.15 0.14-4.15 1 1.99 0.50 0.01-2.80 6 4.84 1.24 0.45-2.70 0 0.61 0.00 0.00-6.00 26 27.45 0.95 0.62-1.39 1 0.80 1.25 0.03-6.93 25 26.36 0.95 0.61-1.40 * 2 3.58 0.56 0.07-2.02 2 2.22 0.90 0.11-3.26 6 6.15 0.98 0.36-2.12 5 5.78 0.86 0.28-2.02 1 0.36 2.75 0.07-15.30 3 4.38 0.68 0.14-2.00 2 2.70 0.74 0.09-2.67 1 1.68 0.59 0.02-3.30 2 1.41 1.42 0.17-5.11 8 10.34 0.77 0.33-1.52 Non-malienant causes Cerebrovascular Disease All Heart Disease Nonmalignant Respiratory Disease Cirrhosis of Liver Nephritis and Nephrosis Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides ' Homicides 10 15.70 0.64 0.30-1.17 81 104.04 0.78 0.62-0.97 12 20.17 0.60 0.31-1.04 6 6.35 0.95 0.35-2.06 1 1.79 0.56 0.01-3.10 16 19.87 0.81 0.46-1.31 12 9.39 1.28 0.66-2.23 4 10.48 0.38 0.10-0.98 6 9.55 0.63 0.23-1.37 6 7.77 0.77 0.28-1.68 0 1.78 0.00 0.00-2.07 23 BACK TO MAIN Table 6. Cause specific deaths and standardized mortality ratios for selected causes of death for Cottage Grove employees never exposed to PFOA or other fluorochemicals (non-chemical division). Cause All Deaths Observed Expected SMR 95% Cl 294 342.46 0.86 0.76-0.96 Cancers All Malignant Neoplasms Buccal Cavity and Pharynx Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas All Other Digestive Respiratory System Larynx Bronchus, Trachea, Lung Breast Female Reproductive Male Reproductive Prostate Testis and Other Male Genital Organs Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin All Lymphatic and Hematopoietic Tissue 81 1 20 2 3 9 0 0 5 1 25 1 23 *4 1 2 2 0 5 1 4 2 10 98.17 1.96 24.05 2.49 3.04 8.74 1.88 2.11 5.12 0.67 29.18 0.85 28.01 4.70 2.81 7.19 6.82 0.36 4.73 2.84 1.89 1.48 11.10 0.83 0.66-1.03 0.51 0.01-2.83 0.83 0.51-1.28 0.80 0.10-2.90 0.99 0.20-2.88 1.03 0.47-1.96 0.00 0.00-1.96 0.00 0.00-1.75 0.98 0.32-2.28 1.49 0.04-8.26 0.86 0.55-1.27 1.18 0.03-6.53 0.82 0.52-1.23 0.85 0.23-2.18 0.36 0.01-1.98 0.28 0.03-1.00 0.29 0.04-1.06 0.00 0.00-10.12 1.06 0.34-2.47 0.35 0.01-1.96 2.11 0.58-5.40 1.35 0.16-4.89 0.90 0.43-1.66 Non-malienant causes Cerebrovascular Disease All Heart Disease Nonmalignant Respiratory Disease Cirrhosis of Liver Nephritis and Nephrosis Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides 11 18.21 0.60 0.30-1.08 103 114.39 0.90 0.73-1.09 17 23.11 0.74 0.43-1.18 6 6.74 0.89 0.32-1.94 1 2.10 0.48 0.01-2.64 17 20.71 0.82 0.48-1.31 10 9.64 1.04 0.50-1.91 7 11.07 0.63 0.25-1.30 6 9.87 0.61 0.22-1.32 2 8.04 0.25 0.03-0.90 4 1.83 2.19 0.60-5.60 24 BACK TO MAIN Table 7. Cause specific standardized mortality ratios for Cottage Grove employees with a minimum of one year of employment in a job with definite PFOA exposure. Cause Observed Expected SMR 95% Cl All Deaths 17 22.25 0.76 0.44-1.22 Cancers All Malignant Neoplasms Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas All Other Digestive Respiratory System Bronchus, Trachea, Lung All Other Respiratory Breast Prostate Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin Thyroid and Other Endocrine Glands All Lymphatic and Hematopoietic Tissue 4 6.33 0.63 0.17-1.62 1 1.59 0.63 0.02-3.48 0 0.20 0.00 0.00-18.87 0 0.19 0.00 0.00-19.33 1 0.56 1.79 0.05-9.94 0 0.12 0.00 0.00-30.22 0 0.14 0.00 0.00-26.38 0 0.35 0.00 0.00-10.67 0 0.04 0.00 0.00-89.75 1 2.09 0.48 0.01-2.66 1 2.01 0.50 0.01-2.77 0 0.02 0.00 0.00-160.98 0 0.07 0.00 0.00-51.86 1 0.38 2.63 0.07-14.62 0 0.32 0.00 0.00-11.39 ' 0 0.21 0.00 0.00-17.37 0 0.11 0.00 0.00-33.12 0 0.12 0.00 0.00-29.99 0 0.02 0.00 0.00-155.50 0 0.75 0.00 0.00-4.90 Non-malignant causes Cerebrovascular Disease All Heart Disease Other Nonmalignant Respiratory Cirrhosis of Liver Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides 3 0.89 3.36 0.69-9.82 7 7.28 0.96 0.39-1.98 0 0.70 0.00 0.00-5.30 0 0.52 0.00 0.00-7.11 1 1.74 0.58 0.01-3.20 0 0.84 0.00 0.00-4.41 1 0.90 1.11 0.03-6.19 2 0.93 2.15 0.26-7.75 2 0.76 2,62 0.32-9.45 0 0.17 0.00 0.00-22.07 25 BACK TO MAIN Table 8. Cause specific standardized mortality ratios for Cottage Grove employees with a minimum of one year of employment in a job with definite or probable PFOAa. Cause_________________________________ Observed Expected SMR 95% Cl All Deaths 219 274.36 0.80 0.70-0.91 Cancers All Malignant Neoplasms Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas All Other Digestive Respiratory System Bronchus, Trachea, Lung Breast Prostate Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin Thyroid and Other Endocrine Glands All Lymphatic and Hematopoietic Tissue 68 77.33 0.88 0.68-1.11 21 19.40 1.08 0.67-1.65 1 2.16 0.46 0.01-2.57 1 2.42 0.41 0.01-2.29 10 6.91 1.45 0.69-2.66 2 1.51 1.32 0.16-4.78 1 1.70 0.59 0.01-3.27 6 4.17 1.44 0.53-3.13 0 0.52 0.00 0.00-7.06 23 24.20 0.95 0.60-1.43 22 23.22 0.95 0.59-1.43 0 2.09 0.00 0.00-1.77 6 5.19 1.16 0.42-2.52 2 3.88 0.52 0.06-1.86 *1 2.41 0.42 0.01-2.31 1 1.47 0.68 0.02-3.79 2 1.30 1.54 0.19-5.55 0 0.28 0.00 0.00-13.34 4 9.03 0.44 0.12-1.13 Nonmalignant causes Cerebrovascular Disease 11 13.03 0.84 0.42-1.51 All Heart Disease 68 90.90 0.75 0.58-0.95 Nonmalignant Respiratory Disease 6 17.09 0.35 0.13-0.76 Cirrhosis of Liver 4 5.69 0.70 0.19-1.80 Accidents 13 18.75 0.69 0.37-1.19 Motor Vehicle Accidents 10 8.95 1.12 0.53-2.06 All Other Accidents 3 9.80 0.31 0.06-0.90 Violence 7 9.35 0.75 0.30-1.54 Suicides 7 7.62 0.92 0.37-1.89 Homicides 0 1.74 0.00 0.00-2.13 a: Includes workers who accrued one year of exposure with definite and probable jobs combined. 26 BACK TO MAIN Table 9. Observed and expected deaths from cerebrovascular disease with SMRs and 95% Cl by years of employment in jobs with definite PFOA exposure. Years of PFOA ExDosure OBS EXP SMR 95% Cl <1 2 1.05 1.91 0.22-6.91 l-<5 0 0.46 0.00 0.0-8.02 5-<10 3 0.19 15.03 3.02-43.91 10 0 0.23 0.0 0.0-15.17 Total 5 1.94 2.58 0.83-6.03 27 BACK TO MAIN Table 10. Observed and expected deaths from cerebrovascular disease with SMRs and 95% Cl by cumulative exposure. Weighted Exposure3 OBS EXP SMR 95% Cl >0-2499 2500-4999 5000-7499 8 9.67 2 2.80 1 2.32 0.83 0.36-1.63 0.71 0.08-2.58 0.43 0.01-2.40 7500-9999 10000-& Over Total 0 1.76 4 1.21 15 17.75 0.00 0-2.08 3.31 0.89-8.46 . 0.85 0.47-1.39 a: Duration of employment (days)*exposure weighting factor. 28