Document O32xLgQx4g2mgOmykbn02KZ1p

Final Report BACK TO MAIN Mortality Study of Workers Employed at the 3M Decatur 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 Obiecti ve To determine whether occupational exposure to fluorochemicalsexposure,particularly to perfluorooctanesulfonyl fluoride (POSF, C8F17S02F) based fluorochemicals, is related to mortality of employees of the 3M facility in Decatur, Alabama. Met hods All workers with at least one year of cumulative employment at the Decatur facility were eligible for inclusion in the cohort. The cohort was followed through December 31, 1998 and death certificates of decedents were obtained and coded for analysis. The jobs held by cohort members were assigned to one of three exposure subgroups: high exposed, low exposed, and nonexposed, based on their exposure to POSF-based fluorochemicals.Standardized mortality ratios (SMR) with 95 percent confidence intervals were calculated to estimate the all cause and cause specific mortalityrisks associated with employment at the Decatur. The association between exposureto POSF-based fluorochemicals was evaluated among all exposed workers and workers with a minimum one year of exposure. Results A total of 145 deaths were identified in the 2083 cohort members. Sixty-five deaths occurred among workers ever employed in high exposed jobs. The overall mortality rates for the cohort and the exposure sub-cohorts were lower than expected in the general population. Two deaths from liver cancer were observed in the workers with at least one year of high or low exposure (SMR= 3.08,95% CI=O.37-11.10). The risk of death from bladder cancer was elevated for the entire cohort (3 observed, SMR=4.81,95% CI=O.99-14.06). All three bladder cancers occurred among workers who held a high exposurejob (SMR=12.77,95% CI=2.63-37.35). The employees who died from bladder cancer were maintenance workers (2) and incinerator and waste water treatment plant operator and process operator (1). Conclusion Workers employedin jobs with high exposure to POSF based fluorochemicals at Decatur have an increased risk of death from bladder cancer, however it is not clear whether these cases can be attributed to fluorochemicalexposure or an unknown bladder carcinogen encountered during the course of maintenance work. 2 BACK TO MAIN Introduction Fluorinated organic compounds have been used for decades in a wide variety of industrial and commercial applications. Perfluorinatedcompounds are used in applicationssuch as specialty lubricants, semiconductormanufacturing, protective barriers or coatings, surfactants, fire retardants, and non-conductive coolants. The 3M Decatur (Alabama) manufacturing site began production in 1961. The site consists of two plants: SpecialtyFilm (film plant) and SpecialtyMaterials (chemical plant). The film plant is located approximately 300 yards west of the chemical plant .The major production buildings in the film plant are polyester and non-polyesterfilms. Logan et a]. provide a detailed description of the chemical plant.' The three major product groups (referred to as focus factories)in the chemical plant are protective chemicals, performance chemicals and fluoroelastomers. There are more than 700 different processes with more than 90 percent being batch processes. Raw materials and intermediates for each product group may flow through many different production buildings before packaging and shipment. Perfluorooctanesulfonylfluoride (POSF, c8F17so2F) is the major sulfonate fluorochemical manufactured at Decatur and is used as the precursor to the production of a variety of perfluorinated amides, alcohols, acrylates and other fluorochemicalpolymers. POSF is produced via an electrochemicalcell process. POSF-based fluorochemicalscan be absorbed into the body and be metabolically transformed, to an undetermined degree, to perfluorooctanesulfonate(PFOS, C8F17So;). Biological monitoring (serum measurement) of PFOS has been used to assess the employees' exposure experience to POSF-based fluorochemidls at this ~ l a n t . ~ . ~ 3 BACK TO MAIN Employees may be exposed by one or all routes (i.e., inhalation, skin contactlabsorption, and ingestion) to these POSF-based fluorochemical materials. The primary route of exposure may be different for each employee and depends on several different factors such as: process conditions,job tasks, work location,personal hygiene, personal habits and general work practices. Although POSF-based chemicals are the primary fluorochemicalsproduced at this plant, exposure to other fluorochemicals,includingperfluorohexanesulfonylfluoride and perfluoroctanoate(PFOA), and exposure to non-fluorochemicals are likely Regarding the toxicology of PFOS, several repeat dose studies have consistently demonstrated that the liver is the primary target organ! Liver tissue response to high doses of PFOS included the enlargementof liver and apparent alterationsin metabolic processes with the reduction in serum cholesterol levels obsereved as the earliest clinical response to PFOS. These effects occurred in cynomolgusprimates at serum PFOS levels at 100ppm. Also at high doses, PFOS adversely affected survuval of rat pups in the neonatal period of life as a result of maternal exposure during fetal development. Reduced weight gain, absorptions and resorptions were observed at the higher doses tested (1.6 mg/kg/day and 3.2 mg/kg/day). There were no effects on post-natal neurological development or on fertility and estrous cycling in offspring in multigeneration studies. Multiple genotoxicity assays suggested PFOS does not present a hazard from interaction with genetic material. Results from a two-year rat bioassay cancer study are scheduled to be reported in 2001. Medical surveillancefindingshave not associated abnormal clinical chemistryresults with Decatur employees' serum PFOS levels.* A previous mortality study of workers employed at the Decatufplant reported an overall lower mortality rate than e ~ p e c t e d .T~his report summarizesthe results of an update of that cohort mortality study with specific emphasison 4 BACK TO MAIN , those jobs which have the potential for fluorochemical exposure in employee that may result in elevated serum PFOS levels. 5 BACK TO MAIN Methods Cohort Enumeration The cohort for this study was enumerated using employmentrecords from the Decatur facility. Workers who accrued at least one year of cumulativeemploymentat Decatur were eligible for inclusion in the cohort. Work history records were obtained from the plant and reviewed and abstracted into an electronic database. This effort was conducted by 3M staff under the supervision of the 3M Medical Department. The records of all employeeswere abstractedto record the workers name, Social SecurityNumber, 3M identification number, date of birth, and the dates of any entry on the work history record, including layoffs and leaves of absence. Information about the particularjobs was abstracted wherever available, includingthe job departmentcodes, and job title. The abstracted data were entered into a computer database and provided to University of Minnesota investigators. To be eligible for the cohort a worker had to accrue at least 365 days of cumulativeemployment at the Decatur site by December 31,1997. The eligibility of each cohort member was determined by summing their dates of employment. Periods of absence due to illness, military leave, maternity leave, or layoff did not contribute to eligibility Currentlyemployedworkers were assigned December 31, 1997 as their last date of employment. The newly enumeratedcohort was linked to records from the original cohort to update employment information, and to verify names, social security numbers, dates of birth, and dates of death for pfeviously identifieddecedents.Discrepanciesidentified in the records were resolved using TRWExperian, a credit reporting agency, and the Social Security Administration 6 BACK TO MAIN service for epidemiologicresearch 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. Follow-up and Determination of Vital Status Eligible cohort members were followed from the day they accrued 365 days of cumulative employmenttill December 31, 1998 or their date of death. Vital records searcheswere performed for all cohort members who were not employed by 3M on December 3 1,1997, or for whom a death certificate was not obtained in the original study. Determination of vital status was made by searching the National Death Index (NDI) for all workers in the original study and new workers included in the cohort. The Social SecurityAdrmnistrationdata and/or the Social SecurityDeath Index (SSDI) was 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. The death certificates were coded by a licensed nosologist 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 to enable the use of actual (unadjusted)mortality reference data. ExDosure Assessment The relativedifferences in serum PFOS by job have been reported elsewhere! In this comprehensive assessment conducted in 1998, a total of 232 Decatur employees were randomly 7 BACK TO MAIN selected for serum sampling with 80% participation (n = 126 chemical plant; 60 = film plant). Sera samples were extracted using an ion-pairingextraction procedure and were quantitatively analyzed for serum PFOS using high-pressure liquid chromatography/electrospray tandem mass spectrometrymethods. The geometric mean serum PFOS level (95%confidence interval) for chemical plant employees was 0.94 ppm (0.79-1.13)and for film plant employeesit was 0.14 ppm (0.11-0.16).The great majority of film plant jobs have no direct workplace exposure to fluorochemicals. Their serum levels are thought to be due, to a large extent, to environmental exposure in proximity to the chemical plant. Chemical plant jobs were categorized into eight categories: cell operators, chemical operators, maintenance workers (primarily mechanics and electricians),mill operators, waste treatment plant operators,engineerdlaboratoryworkers, supervisordmanagersand administrative assistants. The highest geometric mean level of serum PFOS was observed in cell operators (1.97 ppm) followed by the waste operators (1.50), chemical operators (1.48 ppm), and maintenance workers (1.30 ppm). Supervisors/managers (0.89 ppm), mill operators (0.59ppm), engineerllabworkers (0.39 ppm) and administrative assistants (0.40 ppm) had lower geometric mean serum PFOS levels. Mill operators are entry level positions that usually progress to chemical operators within a few years of hire. As mentioned previously, exposureto other fluorochemcials,including PFOA, are possible. Until 1998, PFOA was not manufactured at the Decatur facility. Rather, PFOA exposures were the result of it being produced as a by-producte of the electrolyticcell production or in its use as an elastomerin fluoropolymerproduction. The primary route of PFOA exposurewould be dermal contad: Although observed at slightly lower levels, the Decatur employees' serum PFOA levels correlated with their serum PFOS level^.^ 8 BACK TO MAIN Because production processes have remained constant over time, a straightforward exposure matrix was developed based on the work history records of the study cohort. With the knowledge of the major job-specific serum PFOS levels, a 3M industrial hygienist and epidemiologist assigned each unique job and department combination in the work history records to 1 of the following 3 major exposure categories: 1. no workplace exposure to POSF-basedfluorochemicals(encompassesfilm plant jobs); 2. low potential workplace exposure to POSF-based fluorochemicals(includessuchjobs as engineers, quality control technicians, environmental,health and safety workers, administrative assistants and managers) 3. high potential workplace exposure to POSF-based fluorochemicals(includes cell operators, chemical operators,maintenanceworkers, mill operators,waste operatorsand crew supervisors) Hereafter these three categories will be referred to as the non-exposed, low exposed and high exposed subcohorts. In addition, for the purpose of cumulativeexposurefor this mortality analysis, these three categories were assigned a relative POSF-basedjob exposure value of I, 3 and 10 respectively. All exposure assignmentswere made without knowledge of the mortality outcomes. Analysis The mortalitfexperience of the Decatur cohort was comparedto that of the state of Alabama. An additional reference population using regional counties was also used to check the results and 9 BACK TO MAIN rule out large variations within the state. The twenty three regional counties, Blount, Calhoun, Cherokee, Colbert, Cullman, De Kalb, Etowah, Fayette, Franklin, Jackson, Lamar, Lauderdale, Lawerence, Limestone, Marion, Marshall, Morgan, St. Clair, Shelby, Talladega, Tuscaloosa, Walker, and Winston, were selected for the original study by Mandel and Johnson.' The 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 Statisticsdata and provide rates for all causes of death combined and deaths due to malignant neoplasms 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 ( S M R ) were computedfor all cause and specificcause of death using the Alabama reference data. The SMRs and appropriate 95%confidenceintervals were computed using the PC Life Table Analysis System (PCLTAS) software developed by the National Institutes of OccupationalSafety and Health (NIOSH).7This program computes age, gender, and race specific S M R using standard life table methods. The expected number of deaths are estimatedby 'multiplyingthe age, gender, race, and calendarperiod tabulatedperson-years of follow-up to the correspondingcause specific reference mortality rates. Race of the workers was not available from the company records, but the population of workers is mostly Caucasian. Therefore,the reference rates for Caucasianswere used for this analysis. The all causg'and cause specific S M R s were computed for the entire cohort and the subcohorts of ever high exposure,ever low exposure, and non-exposed. This initial summary analysis was 10 BACK TO MAIN followed by an exposure specific analysisin which the exposed subcohorts were restricted to workers who had at least one year of cumulativeemployment in jobs with high or low exposure. A large number of the workers who ever worked in exposed jobs worked in those jobs for a short period before being permanently transferred to a nonexposedjob. For this analysis the period of follow-up began when the individual reached one year of cumulative exposure, thereby counting person-time that occurred after the minimum exposure was accrued. Causes of death potentially related to Ruorochemical exposure were analyzed by duration of employmentin the three fluorochemical exposure subgroups. The causes of death of a priori interest were cancers of the digestive system, in particular liver cancer, and liver cirrhosis, because, in animals, PFOS circulatesthrough the enterohepaticcirculation and concentrates-in the liver?'* Other causes of death that appearedto be in excess in one or more of the fluorochemicalexposed groups were also evaluated by duration of exposure. 11 BACK TO MAIN Results Of the 35 12 workers identified a total of 2083 workers met the one-year enrollment criteria. Of these, 47 percent (982) worked at some time in jobs where exposure to POSF-based fluorochemicals was considered high (Table 1). Approximately 14%(289) worked in low exposure areas, but never held a job in the high exposure areas, and 8 12 (39%)were considered to have no or minimal workplace exposure to fluorochemicals, i.e. film plant employees. The high exposure group was modestly younger than the other workers, but had a longer average tenure at the plant than the rest of the cohort. Male workers made up 83 percent of the cohort and 84 percent of the high exposed sub-cohort. There were a total of 145 deaths identified in the cohort, 65 deaths in the high exposure group, 27 in the low exposure group, and 53 in the nonexposed group. Death certificates were obtained for 139 (96%)of the decedents. The 6 missing death certificates were in the high exposed group (N=3), the low exposure group (N=2), and the non-exposed group (N=l). A total of 50,970 person-years of follow up was accrued or the entire cohort. There were 782 workers who worked a minimum of 1 year in high exposure jobs and 1065 workers who worked a minimum of 1 year in high or low exposurejobs. The latter subcohort included workers who held high and low exposure jobs for less than one year, but had a combined exposure period of one year (Table 2). Fifty-three deaths were among those working one year or more in high exposurejobs, and additional 29 deaths were in the combined high and low exposure group. /' 12 BACK TO MAIN The all cause and cause specific mortality rates for the entire cohort were lower than expected compared to the general population of Alabama; 145 observed and 230 expected (SMR=0.63, 95%CI=O.53-0.74).(Table 3) A similar pattern was observed for all deaths from cancer; 39 observed, 54 expected (SMR=0.72,95%CI = 0.51-0.98). The all cause and all cancer causes of death were fewer than expected for the high exposure (Table 4), low exposure (Table 5), and nonexposed (Table 6 ) subcohorts. When restricted to workers who accrued at least one year of employment in the high exposure (Table 7), and high or low exposure (Table 8) subgroups, the standardized mortality ratios for all causes of death and all malignant neoplasms were well below unity. Five deaths from cirrhosis of liver were identified in the entire cohort, two of which occurred in the high exposure group; however this did not exceed the number expected. Two deaths from liver cancer were observed in the entire cohort, with 1.24expected (SMR=1.61,95%CI=0.205.82). One liver cancer was observed in the sub-cohort employed in a high exposurejob for at least a year (0.50expected, Table 7), and the other held a low exposurejob for at least one year. The S M R for liver cancer among workers who held high or low exposurejobs for at least one year was 3.08 (95%CI 0.37-11.10) (Table 8). The details of the two liver cancer cases are as follows. Case 1. Died at the age of 85. The cause of death listed on the death certificatewas "respiratory arrest" due to "carcinoma of the liver with metastatic disease". The time from onset of the liver cancer to death was recorded as 4 months. The death certificatewas coded by one nosologist to ICD8 155.0 (primary hepatocellular carcinoma), and to ICD9 155.2 (malignai6 neoplasm of the liver not specified as primary or secondary) by the second nosologist. There were no other contributing causes of death entered on the death certificate. 13 BACK TO MAIN This individual worked as a yard clean-up man and general helper from the mid-1960s through the mid 1970s. Retired at age 65. Case 2: Died at the age of 36. The cause of death listed on the death certificate was "hepatocellularca" and coded to ICD8/9 155.0(primary hepatocellular carcinoma) by both nosologists. The time from disease onset till death was recorded as 2 months. There were no other contributing causes of death listed on the death certificate.This individual worked in the mid-1970's as a general helper for 2.5 months, a process helper for 7 months, and a material handler for 5 months. He terminated employment at age 20. Medical validation by follow-back to the physician of record on the death certificate was conducted for the deaths from liver cancer to verify that liver was the primary cancer. Medical records were obtained for both liver cancers and they were confirmed as primary hepatocellular carcinomas. Three deaths were attributed to malignant neoplasms of the bladder (0.62 expected in the entire cohort, S M R 4.81,95% CI=O.99-14.05). The workers who died from bladder cancer were in the sub-cohort that worked in jobs with high exposure for at least one year (0.19 expected, SMR=16.12,95% CI=3.32-47.41, Table 7). All three cases of bladder cancer were male and each had workedin high exposurejobs for at least 5 years (Table 9); the S M R for five or more years of employment in a high exposurejob was 24.49 (3 observed, 0.12 expected). The results for bladder cancer in relation to fluorochemicalexposure did not change when the reference population was the local counties rather than the entire state of Alabama. The job classkcations of the workers who died from bladder cancer were. 1. Maintenance mechanic, lead man, maintenance foreman, and crew supervisor. Twenty years employment at Decatur 5.3 years in high exposurejobs. First employed in 1960. 14 BACK TO MAIN 2. Maintenance mechanic, general maintenance mechanic; Twenty-three years employment at Decatur, 8.5 years in high exposurejobs, and 1.2 years in low exposurejobs. First employed in 1962. 3. General helper, packer, rewinder, process operator, material handler incinerator and utility operator, and incinerator and waste water operator. Twenty-three years of employment at Decatur. Thirteen years in high exposurejobs, 1.3 years in jobs with low exposure. First employed in 1966. 15 BACK TO MAIN Discussion This study evaluated the mortality experience of workers with at least one year of employment at the 3M facility in Decatur, Alabama. The overall mortality rates were below the expected for most causes. An excess of death from bladder cancer was detected and limited to workers who worked in jobs with high exposureto POSF-based fluorochemicalsfor at least five years. All other causes of death were below the expected or occurred too infrequentlyto evaluate with confidence. Some limitationsmust be considered when interpretingthe results of this mortality analysis. Although several methods of follow-up were employed to identify decedents in this cohort, there is the possibility that some deaths were not ascertained. A death certificate was not obtained for 6 of known decedents, thus they were not included in the cause specific death analysis. The extent to which these limitationswould affect the results is unknown, but they would have their largest effect on the analysis if the unknown and uncoded causes of death were attributedto relatively rare causes of death, including liver, bladder, kidney, and prostate cancer. Another limitation in this study is the lack of employee specific exposure data for PFOS and other fluorochemicals..Theemploymentrecords were used as surrogatesof exposure.The relative exposure estimateswere guided with data from a previous exposure assessment,which reduced misclassification, but did not eliminate it. Finally, the focus of this study was flouorochemical exposure, therefore exposure to other chemicals in the workplace was not assessed. The current s&dy is an update of a cohort mortality study by Mandel and Johnson'. The main difference in the methods used for this study is the more specific exposure assessment. The 16 BACK TO MAIN earlier analysis divided the cohort solely into chemical and film processing workers. In this analysis an effort was made to separate the chemical workers in the high and low fluorochemical exposurejobs; thus the results are more specific to exposures. There are seven more years of follow-up in this study, which added 71 additional deaths to the analysis. Nevertheless, the cohort is relatively young and the low cumulative mortality experience limits the power of this study to evaluate associations between occupational exposures and employment at the Decatur facility. The number of deaths from bladder cancer was more than expected based on the prevailing rates for Alabama and the regional counties. The report by Mandel and Johnson also showed an excess of bladder cancer, but was only based on one case, and therefore could have been a chance finding. In the current analysis only three cases were observed, however the fact that all three cases worked for at least five years in the high exposed jobs warrants further evaluation. There are four possible explanations for this occurrence; 1) the cancers are due to exposure to fluorochemicals, 2) the cancers are attributable to another, undetermined occupational exposure, 3) the cancers are related to non-occupational factors such as smoking or other personal habits, or 4) the finding is due to chance. With only three cases the possibility that the finding is due to chance cannot entirely be ruled out. However, given the magnitude of the risk estimate it would take many years of additional follow-up with no further deaths from bladder cancer for this excess to fully attenuate to null. Preliminary eGamination of a two year feeding bioassay of with either N-ethylperfluorooctane sulfonamide alcohol or PFOS has not shown an increased risk of bladder tumor^..^ The former 17 BACK TO MAIN compound can metabolize to an undetermined, to PFOS. There are no lifetime inhalation bioassay studies for POSF. A known risk factor for bladder cancer is tobacco smoking9However, in this cohort, the rates of other smoking related cancers, including lung cancer, were not elevated, suggesting that the cohort as a whole did not smoke appreciably more than the general population. Although conceivable, it is unlikely that smoking alone could account for a thirteen-fold increase in the rate of bladder cancer among employees who ever held a job with high exposure. In addition to smoking, bladder cancer has been associated with several occupational exposures. Employment in the textile industry in particular has long been associated with risk of bladder cancer due to the use of aniline dyes and other agents. Several chemicals currently or historically used in the textile industry have been classified by the International Agency for Research on Cancer (IARC) as Class 1 (carcinogenic), Class 2A (probably carcinogenic) and Class 2B (possibly carcinogenic). The majority of the chemicals evaluated fall into the 2B category including plasticizers such as acetamide and di(2-ethyl hexyl)-pthalate, flame retardants such as thiourea, tris (2,3;dibromo propyl phosphate), and antimony trioxide.lo Occupational exposure to aromatic amines in the textile and other industries are possibly responsible for up to 25 percent of bladder cancer in some countries. " Exposure to polycyclic aromatic hydrocarbons (PAHs) has also been linked to bladder cancer.I2These associations have been reported in the aluminum industry, and occupations where exposure to coal tar pitch is common. Other occupational .8' exposures possibly related to bladder cancer that are less industry specific, include exposure to 18 BACK TO MAIN metal cutting fluids, diesel exhaust, polybrominated biphenyls, and perchloroethyleneand other solvents. . 13-19 Although the bladder cancer cases in this cohort occurred among workers who held high POSFbased exposedjobs, the specificjobs of the cases suggestthat other exposures could have occurred. The bladder cancer cases worked mostly in maintenance or at the incinerator and waste water treatment plant. The exposuresin thesejobs are not limited to those encounteredin a specificchemical production process. Maintenanceworkers may work in many areas of the plant. The waste water treatment and incinerator workers are on the receiving end of the waste stream, thus they too may have encountered a number of chemical exposures. Mortality from bladder cancer is relatively low with annual incidencerates are five to ten times greater than mortality rates, depending on age and gender. Clearly this mortality study did not ascertain all cases of bladder cancer in this population. Based on rates of bladder cancer in the U.S. from the SurveillanceEpidemiology and End Results (SEER) cancer registry data, 6.9 incident cases of bladder cancer in this population during the follow-up period. Because the population undektudy is not covered by a cancer registry ascertainingthese cases would require direct surveys with living cohort members. Death from liver cancer and cirrhosis of the liver were a priori outcomes of interest for this study because PFOS is concentratedin the liver.' The occurrenceof cirrhosis of the liver did not 1- exceed the expected. There were two deaths from liver cancer in the fluorochemical-exposed subcohorts;approximately three times that expected.Both cases were verified as primary cancers 19 BACK TO MAIN by medical record follow-back.Though more than expected,these results are difficult to interpret because they are based on only two cases. The case with the highest fluorochemcial exposure held a high PFOS exposedjob for only 14 months. The other case occurred in an older man who worked as a general helper in departments with low exposure for eleven years. There were no liver cancer cases among the workers with much longer duration of employment in high exposurejobs, thus a dose response relationship could not be evaluated. Both PFOS and PFOA are hepatic peroxisome proliferators in the rat.'5,20A two-year bioassay of PFOA in the diet caused an increase of hepatic, pancreas, and Leydig cell adenomas.21Two-year bioassays of feeding studies of PFOS in rats are near completion. It is unlikely that peroxisome proliferatorsare carcinogenicto humans under anticipated conditions and levels of human exposure.22 Known causes of primary hepatocelluarcarcinoma include the hepatitis B and C viruses and aflatoxinsproduced by AspergiZZusJlavusand Aspergillus parasiticus primarily in foodstuff^?^ Hepatitis B virus is thought to be responsible for up to 85% of liver cancers in endemic areas, however the prevalence of infection in the U.S. is relatively low. Other contributingcauses may include cirrhosisdue to excessive alcohol consumption.Exposure to high concentrationsof vinyl chloride is associated with angiosarcomaof the liver; a very rare cancer. However, there are no 1 clear occupational causes of primary hepatocellular carcinoma. While the possibility exists that this finding is not due to chance, the results should be interpreted with caution. /' 20 BACK TO MAIN Recommendations Due to the apparent excess risk of bladder cancer in this population a review of potential exposure to known occupational bladder carcinogensat the Decatur site is warranted. The relatively young age and small size of the cohort currentlyprecludes a detailed analysis by exposure, particularly for less common diseases. To further evaluate the health of this cohort in reference to the risk of liver and bladder cancer, and continueto develop the understandingof the toxicology of fluorochemicals,continued follow-up and monitoring of this cohort is recommended. 21 BACK TO MAIN References 1. Logan PW, Johnson TM, Olsen GW, Reagan WK, Mulhausen JR. An industrial hygiene exposure assessment of a fluorochemical manufacturing plant. Am Indust Hyg Assoc J. 2001;Submitted. 2. Olsen GW, Burris JM, Mandel JH, Zobel LR. Serum perfluorooctane sulfonate and hepatic and lipid clinical chemistry tests in fluorochemical production employees. Journal of Occupational & Environmental Medicine 1999;41(9):799-806. 3. Olsen GW, Logan PW, Simpson CA, Hansen KJ, Burris JM, Burlew M, Schumpert JC, Mandel JH. Fluorochemical exposure assessment of Decatur chemical and film plant employees. Am Indust Hyg Assoc J. 2001;Submitted. 4. SIDS. SIDS initial assessment report: perfluorooctane sulfonic acid and its salts. Saint Paul: 3M Company, 2000. 5. Mandel J, Johnson R. Mortality study of employees at 3M plant in Decatur, Alabama. Minneapolis: Division of Environmental and Occupational Health, School of Public Health, University of Minnesota, 1995. 6. Olsen GW, Logan PW, Simpson CA, Hansen KJ, Burris JM, Burlew M, Schumpert JC, Mandel JH. Fluorochemical exposure assessment of Decatur chemical and fillm plant employees. Saint Paul: 3M, 1999. 7. 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. 8. Johnson JD, Gibson SJ, Ober RE. Extent and Route of Excretion and Tissue Distribution of Total Carbon-14 in Rats After a Single i.v. Dose of FC-94-I4-C. Project 8900310200. Saint Paul, MN.: Riker Laboratories Inc., 1979. 9. Silverman DT, Morrison AS, Devesa SS. Bladder Cancer. In: Schottenfeld D, Fraumeni JF,eds. Cancer Epidemiology and Prevention. Seconded. New York: Oxford University Press, 1996;1156-1179. 10. International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans: Some flame retardants and textile chemicals and exposures in the textile manufacturing industry. Vol. 48. Lyon: IARC, 1990. 11. Vineis P, Pirastu R. Aromatic amines and cancer. Cancer Causes & Control 1997;8(3):346-55. 12. 'Boffetta P, Jourenkova N, Gustavsson P. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes & Control 1997;873):444-72. 13. Ward EM, Burnett CA, Ruder A, Davis-King K. Industries and cancer. Cancer Causes & Control 1997;8(3):356-70. 22 BACK TO MAIN 14. Bonassi S , Merlo F, Pearce N, Puntoni R. Bladder cancer and occupational exposure to polycyclic aromatic hydrocarbons. International Journal of Cancer 1989;44(4):648-51. 15. Hours M, Dananche B, Fevotte J, Bergeret A, Ayzac L, Cardis E, Etard JF,Pallen C, Roy P, Fabry J. Bladder cancer and occupational exposures. Scandinavian Journal of Work, Environment & Health 1994;20(5):322-30. 16. Steineck G ,Plato N, Norell SE, Hogstedt C. Urothelial cancer and some industry-related chemicals: an evaluation of the epidemiologic literature. American Journal of Industrial Medicine 1990;17(3):371-91. 17. Anton-Culver H, Lee-Feldstein A, Taylor TH. Occupation and bladder cancer risk. American Journal of Epidemiology 1992;136(1):89-94. 18. Weiss NS. Cancer in relation to occupational exposure to perchloroethylene. Cancer ! Causes & Control 1995;6(3):257-66. 19: Porn S , Aulenti V, Donato F, Boffetta P, Fazioli R, Cosciani Cunico S , Alessio L. Bladder cancer and occupation: a case-control study in northern Italy. Occupational & Environmental Medicine 1996;53(1):6-10. 20. Haughom B, Spydevold 0.The mechanism underlying the hypolipemic effect of perfluorooctanoic acid, perfluorooctane sulphonic acid (PFOSA) and clofibric acid. Biochimica et Biophysicia Acta 1992;1128(1):65-72. 21. Sibinski LJ. Two-year oral (diet) toxicity/c&cinogenicity of fluorochemical FC-143 in rats. Saint Paul: Riker Laboratories, 1987. 22. Cattley RC, DeLuca J, Elcanbe E, Fenner-Crisp P, Lake BG, Marsman DS, Pastoor TA, Popp JA, Robinson DE, Schwetx B, Tugwood J, Wahli W. Do peroxisome proliferating compunds pose a hepatocarciongenic hazard to humans. Regulatory Toxicology & Pharmacology 1998;27:47-60. 23. London WT, McGlynn KA,eds. Liver Cancer. Cancer Epidemiology and Prevention. Second ed. New York: Oxford University Press, 1996. 23 BACK TO MAIN Table 1.Characteristicsof 3M employeeswith a minimum of 1 year of cumulativeemployment at the Decatur facility. Total High exposeda 982 Low exposedb 289 Non-exposed' Total 812 2083 Gender M 826 (84%) 204 (71%) 700 (86%) 1730 (83%) F 156 (16%) 85 (29%) 112 (13%) 353 (17%) Mean age at follow-up 49.9 53.6 51.5 51.1 Median age at follow-up 49.7 52.9 51.4 50.9 Mean year of birth 1948 1944 1946 1947 Median year at birth 1948 1945 1947 1947 Mean years at Decatur 16.4 13.3 13.7 14.9 Median years at Decatur 16.7 10.4 9.9 13.2 Person-years of follow-up 21867 6823 20304 50970 Deaths 65 27 * 53 145 a: Ever employed in high exposurejobs in the chemical plant. b: Ever employed in low exposurejobs, but never a high exposurejob in the chemical plant. c: No or minimal workplace fluorochemical exposure, i.e. film plant employees. BACK TO MAIN Table 2. Characteristicsof Decatur workers with a minimum of one year employment in high exposure and high or low exposurejobs. Total High exposeda 782 High or Low exposedb 1065 Deaths 53 82 Person years 17108 2423 1 Gender M 668 (85%) 867 (81%) F 114 (15%) 198 (19%) Mean age at follow-up 50 51 Mean year of birth 1948 1947 Mean years at Decatur 16.6 15.8 Mean years of exposure 10.5 11.8 a: Employed in high exposurejobs in the chemical plant for at least a year. b: Employed in high or low exposurejobs in the chemical plant for at least a year. 25 BACK TO MAIN Table 3. Cause specific deaths and standardized mortality ratios for selected causes of death for all Decatur employees (chemical and film plants combined). Cause Ail Deaths 0bserved 145 Expected 230.09 SMR 0.63 95%CI 0.53-0.74 Cancers All Malignant Neoplasms 39 54.26 0.72 0.51-0.98 Digestive Organs and Peritoneum 5 9.78 0.51 0.17-1.19 Esophagus 2 1.14 1.76 0.21-6.35 Stomach 0 1.07 0.00 0.00-3.46 Large Intestine 1 3.35 0.30 0.01-1.66 Rectum 0 0.63 0.00 0.00-5.84 Biliary Passages and Liver Primary 2 1.24 1.61 0.20-5.82 Pancreas 0 2.18 0.00 0.00-1.69 Respiratory System 15 21.01 0.7 1 0.40- 1.18 Larynx 0 0.5 1 0.00 0.00-7.25 Bronchus, Trachea, Lung 15 20.33 0.74 0.41-1.22 Breast 2 1.28 1.57 0.19-5.66 Prostate 0 1.44 0.00 0.00-2.57 Testis and Other Male reproductive Organs 0 0.34 0.00 0.00-10.96 Urinary Organs `3 1.89 1.59 0.33-4.65 Kidney 0 1.26 0.00 0.00-2.92 Bladder and Other Urinary 3 0.62 4.81 0.99-14.06 . Malignant Melanoma of Skin 3 1.80 1.67 0.34-4.88 Thyroid and Other Endocrine Glands 0 0.19 0.00 0.00-19.01 All Lymphatic and HematopoieticTissue 4 5.68 0.70 0.19-1.80 Non-malignant causes Cerebrovascular Disease All Heart Disease Nonmalignant RespiratoryDisease Cirrhosis of Liver Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides 5 7.13 0.70 0.23-1.64 35 62.53 0.56 0.39-0.78 1 10.60 0.09 0.00-0.52 5 5.89 0.85 0.27- 1.98 27 36.65 0.74 0.49-1.07 15 22.05 0.68 0.38-1.12 12 14.61 0.82 0.42-1.44 10 19.27 0.52 0.25-0.95 5 11.42 0.44 0.14-1.02 5 7.85 0.64 0.21-1.49 26 BACK TO MAIN Table 4. Cause specificdeaths and standardizedmortality ratios for selected causes of death for Decatur employees ever employed in a high exposurejob. Cause All Deaths Observed ExDected 65 93.56 SMR 0.69 95%CI 0.54-0.89 Cancers All Malignant Neoplasms Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas Respiratory System Larynx Bronchus, Trachea, Lung Breast Prostate Testis and Other Male Reproductive Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin Central Nervous System Thyroid and Other Endocrine Glands All Lymphatic and HematopoieticTissue 18 2 1.54 0.84 0.50- 1.32 2 3.91 0.5 1 0.06-1.85 1 0.46 2.16 0.05-12.02 0 0.42 0.00 0.00-8.75 0 1.33 0.00 0.00-2.77 0 0.26 0.00 0.00- 14.32 1 0.50 2.00 0.05-11.10 0 0.86 0.00 0.00-4.30 7 8.24 0.85 0.34- 1.75 0 0.20 0.00 0.00-18.51 7 7.97 0.88 0.35-1.81 0 0.48 0.00 0.00-7.7 1 0 0.49 0.00 0.00-7.53 0 0.15 0.00 0.00-25.34 3 0.75 4.02 0.83-11.75 0 0.5 1 0.00 0.00-7.2 1 3 0.23 12.77 2.63-37.35 2 0.76 2.62 0.32-9.46 0 0.99 0.00 0.00-3.73 0 0.08 0.00 0.00-46.23 1 2.3 1 0.43 0.01-2.40 Non-malimant causes CerebrovascularDisease All Heart Disease Nonmalignant RespiratoryDisease Cirrhosis of Liver Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides 2 2.76 0.72 0.09-2.62 14 24.78 0.56 0.31-0.95 0 4.00 0.00 0 .OO-0.92 2 2.46 0.81 0.10-2.94 17 15.87 1.07 0.62- 1.72 9 9.60 0.94 0.43-1.78 8 6.26 1.28 0.55-2.52 3 8.38 0.36 0.07- 1.05 1 4.97 0.20 0.01- 1.12 fi L 3.42 0.59 0.07-2.1 1 d' 27 BACK TO MAIN Table 5. Cause specific deaths and standardizedmortality ratios for selectedcauses of death for Decatur employees ever employed in a low exposurejob, but never a high exposurejob. Cause All Deaths Observed 27 ExDected 42.43 SMR 95%CI 0.64 0.42-0.93 Cancers All Malignant Neoplasms Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas Respiratory System Larynx Bronchus, Trachea, Lung Breast Prostate Testis and Other Male Reproductive Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin Thyroid and Other Endocrine Glands All Lymphaticand HematopoieticTissue 6 11.47 0.52 0.19-1.14 2 2.02 0.99 0.12-3.57 0 0.22 0.00 0.00-16.91 0 0.22 0.00 0.00-16.64 1 0.70 1.43 0.04-7.94 0 0.12 0.00 0.00-30.04 1 0.25 3.94 0.10-21.88 0 0.47 0.00 0.00-7.85 4 4.60 0.87 0.24-2.22 0 0.11 0.00 0.00-33.25 4 4.46 0.90 0.24-2.29 0 0.40 0.00 0.00-9.33 0 0.46 0.00 0.00-7.97 0 0.04 0.00 0.00-102.57 '0 0.40 0.00 0.00-9.25 0 0.24 0.00 0.00- 15.13 0 0.16 0.00 0.00-23.78 0 0.27 0.00 0.00-13.7 1 0 0.03 0.00 0.00-109.79 0 1.05 0.00 0.00-3.52 Non-malignant causes Cerebrovascular Disease All Heart Disease Nonmalignant Respiratory Disease Cirrhosis of Liver Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides 2 1.61 1.25 0.15-4.50 7 12.85 0.54 0.22-1.12 0 2.64 0.00 0.00-1.40 1 0.93 1.07 0.03-5.95 1 4.33 0.23 0.01-1.28 0 2.50 0.00 0.00- 1.47 1 1.82 0.55 0.01-3.05 3 2.34 1.28 0.26-3.74 1 1.45 0.69 0.02-3.83 2 0.89 2.24 0.27-8.08 28 BACK TO MAIN Table 6. Cause specific deaths and standardized mortality ratios for selected causes of death for nonexposed Decatur employees,i.e. only worked in film plant. Cause All Deaths Observed 53 Exuected 88.3 1 SMR 0.60 95%CI 0.45-0.79 Cancers All Malignant Neoplasms Digestive Organs and Peritoneum Esophagus Stomach Large Intestine Rectum Biliary Passages and Liver Primary Pancreas Respiratory System Larynx Bronchus, Trachea, Lung Breast Prostate Testis and Other Male Reproductive Urinary Organs Kidney Bladder and Other Urinary Organs Malignant Melanoma of Skin Thyroid and Other Endocrine Glands All Lymphatic and Hematopoietic Tissue 15 20.45 0.73 0.41-1.21 1 3.72 0.27 0.0 1-1.49 1 0.44 2.25 0.06-12.51 0 0.40 0.00 0.00-9.17 0 1.27 0.00 0.00-2.92 0 0.24 0.00 0.00-15.24 0 0.47 0.00 0.00-7.79 0 0.82 0.,oo 0.00-4.50 4 7.90 0.5 1 0.14-1.30 0 0.19 0.00 0.00-19.21 4 7.64 0.52 0.14-1.34 2 0.39 5.11 0.62- 18.45 0 0.48 0.00 0.00-7.74 0 0.14 0.00 0.00-27.23 '0 0.72 0.00 0.00-5.13 0 0.49 0.00 0.00-7.49 0 0.23 0.00 0.00-16.29 1 0.72 1.38 0.03-7.67 0 0.08 0.00 0.00-48.41 3 2.19 1.37 0.28-4.00 Non-malimant causes CerebrovascularDisease All Heart Disease Nonmalignant RespiratoryDisease Ulcer of Stomach and Duodenum Cirrhosis of Liver Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides 1 2.62 0.38 0.01-2.12 14 23.72 0.59 0.32-0.99 1 3.81 0.26 0.01- 1.46 0 0.16 0.00 0.00-22.90 2 2.37 0.84 0.10-3.05 9 14.67 0.61 0.28-1.17 6 8.82 0.68 0.25- 1.48 3 5.84 0.5 1 0.11-1.50 4 7.79 0.51 8.14-1.31 3 4.59 0.65 0.13-1.91 1 3.20 0.31 0.01-1.74 29 , i. * BACK TO MAIN Table 7. Cause specific standardized mortality ratios for workers employed for at least one year in a high exposurejob. Cause All Deaths 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 Observed 53 14 2 1 0 0 0 1 0 0 6 6 0 0 3 0 3' 1 0 I Expected 73.26 16.67 3.05 0.37 0.33 1.03 0.20 0.39 0.67 0.06 6.45 6.24 0.27 0.40 0.59 0.40 0.19 0.60 0.06 1.80 SMR 0.72 0.84 0.66 2.73 0.00 0.00 0.00 2.57 0.00 0.00 0.93 0.96 0.00 0.00 5.11 0.00 16.12 1.67 0.00 0.56 95%CI 0.54-0.95 0.46- 1.4 1 0.08-2.37 0.07-15.16 0.00-11.15 0.00-3.57 0.00-1 8.24 0.06-14.26 0.00-5.52 0.00-66.45 0.34-2.03 0.3 5-2.09 0.00-13.67 0.00-9.26 1.05-14.93 0.00-9.20 3.32-47.14 0.04-9.25 0.00-59.68 0.0 1-3.08 Non-malimant causes CerebrovascularDisease All Heart Disease Nonmalignant Respiratory Disease Cirrhosis of Liver Nephritis and Nephrosis Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides 2 2.14 0.93 0.1 1-3.37 12 19.52 0.61 0.32-1.07 0 3.12 0.00 0.00- 1.18 2 1.93 1.03 0.13-3.73 0 0.39 0.00 0.00-9.38 13 12.46 1.04 0.56-1.78 6 7.53 0.80 0.29- 1.74 7 4.93 1.42 0.57-2.92 3 6.63 0.45 0.09-1.32 1 3.93 0.25 0.01-1.41 9 L 2.7 1 0.74 0.09-2.67 30 BACK TO MAIN Table 8. Cause specific standardized mortality ratios for workers employed for a minimum of one year in high or low exposurejobs, i.e. chemical plant employees. Cause All Deaths 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 HematopoieticTissue Observed 82 19 3 1 0 0 0 2 0 0 10 10 0 0 3 0 3' 1 0 1 ExDected 117.08 28.45 5.13 0.59 0.56 1.75 0.33 0.65 1.15 0.10 11.20 10.84 0.66 0.88 1.oo 0.65 0.35 0.88 0.10 2.88 SMR 0.70 0.67 0.59 1.69 0.00 0.00 0.00 3.08 0.00 0.00 0.89 0.92 0.00 0.00 3.01 0.00 8.68 1.14 0.00 0.35 95% CI 0.56-0.87 0.40-1.04 0.12-1.7 1 0.04-9.41 0.00-6.60 0.00-2.10 0.00-1 1.24 0.37- 11.10 0.00-3.21 0.00-38.8 1 0.43- 1.64 0.44-1.70 0.00-5.63 0.00-4.21 0.62-8.79 0.00-5.66 1.79-25.39 0.03-6.32 0.00-37.95 0.01-1.93 Non-malignant causes CerebrovascularDisease All Heart Disease Nonmalignant Respiratory Disease Cirrhosis of Liver Accidents Motor Vehicle Accidents All Other Accidents Violence Suicides Homicides 4 3.79 1.05 0.29-2.70 19 32.73 0.58 0.35-0.91 0 5.83 0.00 0.00-0.63 3 2.89 1.04 0.2 1-3.03 15 17.07 0.88 0.49-1.45 7 10.20 0.69 0.27- 1.4 1 8 6.87 1.16 0.50-2.29 6 9.09 0.66 0.24- 1.44 2 5.44 0.37 0.04-1.33 4 3.65 1.10 0.30-2.80 31 BACK TO MAIN Table 9. Bladder cancers (observed and expected) with SMRs and 95%CI for Decatur workers ever exposed to PFOS by years of exposure and gender. Years in High PFOS ExDosed jobs c1 1 -<5 5-<10 10 Total Observed 0 0 2 1 3 Expected 0.05 0.06 0.05 0.07 0.23 SMR 0.00 0.00 41.46 13.45 12.77 95% CI 0-75.56 0-58.13 4.66-149.81 0.18-74.88 -2.63-37.35 32