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7
Cohort Descriptions

This report builds on the findings reported in Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines (IOM, 2000), hereafter referred to as Volume 1. The present chapter describes the published scientific literature on potential health effects of uranium in humans. Three major categories were constructed to organize the relevant studies: those of workers occupationally exposed to uranium in uranium-processing plants, those focusing on depleted-uranium exposure of deployed populations (some of which were exposed to depleted uranium through friendly-fire incidents), and those assessing exposure to uranium from environmental sources, including drinking water. The studies on the occupationally exposed workers generally had better study design and methods, especially for assessing exposure to uranium and disease outcomes. Studies of deployed populations, in contrast, had limited or no exposure data other than data on deployment itself and on the possibility of exposure to depleted uranium, but the committee chose to include these studies because of their relevance to the Gulf War and Operation Iraqi Freedom veterans. The chapter also includes studies that assessed health outcomes in people who lived near uranium-processing facilities or had high concentrations of uranium in their drinking water; these residents may have exposure conditions similar with veterans who received level III exposures (see Chapter 5).

The chapter first presents an overview of the cohort studies of processing workers examined in Volume 1 and summaries of derivative studies published after that report. A summary of new cohorts introduced into the literature since 2000 follows. The chapter then describes studies that assessed mortality



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7 Cohort Descriptions T his report builds on the findings reported in Gulf war and Health, volume 1: Depleted Uranium, Pyridostigmine Bromide, sarin, vaccines (IOM, 2000), hereafter referred to as volume 1. The present chapter describes the published scientific literature on potential health effects of uranium in humans. Three major categories were constructed to organize the relevant studies: those of workers occupationally exposed to uranium in uranium-processing plants, those focusing on depleted-uranium exposure of deployed populations (some of which were exposed to depleted uranium through friendly-fire incidents), and those assessing exposure to uranium from environmental sources, including drinking water. The studies on the occupationally exposed workers generally had better study design and methods, especially for assessing exposure to uranium and disease outcomes. Studies of deployed populations, in contrast, had limited or no exposure data other than data on deployment itself and on the possibility of exposure to depleted uranium, but the committee chose to include these studies because of their relevance to the Gulf War and Operation Iraqi Freedom veterans. The chapter also includes studies that assessed health outcomes in people who lived near uranium-processing facilities or had high concentrations of uranium in their drinking water; these residents may have exposure conditions similar with veterans who received level III exposures (see Chapter 5). The chapter first presents an overview of the cohort studies of process- ing workers examined in Volume 1 and summaries of derivative studies pub- lished after that report. A summary of new cohorts introduced into the literature since 2000 follows. The chapter then describes studies that assessed mortality 11

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118 UPDateD literatUre review oF DePleteD UraniUm patterns and health outcomes in deployed service personnel. It ends with stud- ies of environmental exposures. In each instance, the study populations and methods—including study design, measures of exposure, and assessment of outcomes—used by the investigators are described. Tables that summarize the studies are included at the end of the chapter. The traditional 5% level of statistical significance is used in reporting findings. Results that did not reach the 5% level of statistical significance are described as nonsignificant. uRANIuM-PROCESSING COHORTS Studies of workers in the uranium-processing and uranium-machining indus- try are essential for understanding the long-term health effects of uranium expo- sure. Cohort studies assessing mortality patterns in processing workers have been conducted for some time. The studies of interest include uranium millers and other processors working in plants that process and refine uranium ore into met- als for commercial and nuclear use. During refinement and enrichment, workers are exposed to a number of hazardous substances, including chemical toxicants and potential carcinogens. Processing workers are exposed primarily to uranium oxides and derivative uranium compounds produced during the refinement pro- cess and other substances that contribute to adverse health outcomes. The studies described present a picture of diverse work histories and varied levels of exposure to enriched uranium, soluble and insoluble uranium compounds, other radioactive elements (such as radium and thorium), and other potentially hazardous industrial chemicals (such as sulfuric acid and fluorocarbons). In occupational settings, exposure is often prolonged, occurring over a period of several months to years in contrast with the shorter periods of expo- sure experienced by Gulf War veterans in friendly-fire incidents. Exposure also was greatest in the early years of the procurement and processing initiative in the United States, when safety measures were not as stringent. In occupational studies, exposure is generally assessed through work histories using cumulative measurement of exposure. Inhalation of dust that contains uranium compounds was the primary route of entry of uranium in processing plants, a route analo- gous to that of many Gulf War veterans exposed to depleted uranium during friendly-fire incidents. This section first details the cohorts reviewed in volume 1, including updates on the cohorts published after the release of the report in 2000. That informa- tion is summarized in Table 7-1. In general, cohorts that did not have updates since that report are not included here, but they are included if there are data on health outcomes in them that were not considered in volume 1. The section then describes new processing cohorts, including studies of uranium processors in the United Kingdom.

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11 CoHort DesCriPtions Colorado Plateau uranium-Mill Workers In assessing long-term health effects of uranium in the processing and machining industry, exposure to uranium and thorium-230 in mill workers is of particular interest (Waxweiler et al., 1983). Before World War II, uranium min- ing in the Colorado Plateau states was on a relatively small scale; efforts were directed primarily to recovery of vanadium contained in the ore. The establish- ment of a domestic uranium-procurement program sparked growth and expan- sion of uranium mining and milling in the United States after the war (Pinkerton et al., 2004). In that effort, uranium mills carried out extraction and purification of uranium ore for commercial use. The enrichment process exposed workers to a number of substances, including dust that contained vanadium, thorium, silica, and radium radionuclides in addition to uranium (IOM, 2000). Concerns about health risks associated with uranium milling were raised as early as 1949, when Colorado health officials submitted a formal request to the US Surgeon General to examine the health of uranium workers (Wagoner et al., 1964). That request, combined with reports from central Europe that documented an increased inci- dence of pulmonary malignancies in miners and millers, prompted the US Public Health Service to initiate a program to monitor health hazards in the uranium- mining and -milling industries (Wagoner et al., 1964; Archer et al., 1973). As radon exposure in the mines emerged as the primary health issue, the mortality experience of mill workers received little attention. As a result, there was little information on hazards in the uranium-milling industry. The studies described below sought to investigate the potential health effects associated with uranium milling in workers in the Colorado Plateau region.1 Wagoner et al., 1964 In the earliest study of the Colorado Plateau mill workers, Wagoner and col- leagues assessed mortality in 5,370 white male uranium miners and mill workers. The study population included three subcohorts, one consisting of 611 millers with no reported mining experience. The workers were prospectively identified and had volunteered for at least one physical examination. Followup of the cohort included triennial physical examinations, an annual uranium-mining industry census, and collection of personal data through mail and other methods. Census takers conducted annual interviews with mine and mill workers, and correspondence was sent to those who could be located. Vital status of 95% of the study group through December 31, 1962, was determined, and mortality was compared with that in the male population of the Colorado Plateau states. Death certificates for 317 workers known to be deceased were obtained 1The Colorado Plateau region includes Arizona, Colorado, New Mexico, and Utah.

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120 UPDateD literatUre review oF DePleteD UraniUm and classified according to the sixth edition of the international Classification of Diseases (ICD-6). The authors examined a number of health outcomes, includ- ing cancers of the digestive, respiratory, and lymphatic systems; nonmalignant respiratory diseases; and cardiovascular-renal disease. Workers were categorized by duration and type of employment (milling or mining) through July 1960 to ascertain exposure. They were initially assigned to three cohorts on the basis of type of work experience. Radiation exposure of a small group of miners was computed on the basis of months of underground experience, estimated dose rate, and cumulative dose. Milling experience of workers with mixed industry experience was discounted, and person-years starting with the date that mining experience began were added. The modified life-table technique was used in the analysis of mortality, and age-, race-, and cause-specific mortality was compared with that in the male population of the Colorado Plateau area by using standard- ized mortality ratios (SMRs). The authors found no significant differences in deaths between the mill subcohort and the general population (56 observed vs 55.8 expected; SMR, 100). Deaths from all forms of cancer were fewer than expected (6 observed vs 8 expected; SMR, 75). However, there was a slight excess of deaths from cardiovascular-renal disease (28 observed vs 25.3 expected). The strengths of this study include a well-defined cohort, inclusion of smok- ing history, and a sound method of followup through annual interviews. In addi- tion, the mortality analysis was conducted by using a local reference population rather than the US population. Despite efforts to measure exposure on an indi- vidual level, biologic monitoring was not carried out; exposure was represented only by work classification. Furthermore, exposure assessment was limited by the lack of specificity of exposure because of the possibility of concomitant exposure, and the cohort was relatively small. Archer et al., 1973 In a second prospective cohort study of Colorado Plateau mill workers, Archer and colleagues extended the followup of mortality in mill workers with a group of 662 white male millers. The men had worked in one of six mills during 1950-1953 and were available for medical examinations (including blood and urine tests, a physical examination, and chest films) in 1950, 1951, and 1953. Occupational and social histories were also documented by the authors. Vital status through December 31, 1967, was ascertained through Social Security Administration (SSA) records and several other sources. Death certificates were collected, and underlying causes of death were coded according to ICD-6. Only 1% of the study population was lost to followup. Person-years by 5-year age group and calendar year were calculated with the modified life-table technique, and cause-specific mortality was compared with that in the white male population in the Colorado Plateau region (Colorado, Utah, New Mexico, and Arizona) by using SMRs.

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121 CoHort DesCriPtions Overall mortality and mortality from major cardiovascular diseases were consistent with the numbers of deaths expected (104 observed vs 105.11 expected and 52 observed vs 47.72 expected, respectively). Mortality from all other causes was significantly less than expected (12 observed vs 22.42 expected; SMR, 54; p < 0.05). However, there was a nonsignificant excess in the number of deaths due to all cancers (20 observed vs 18.11 expected; SMR, 110). A significant excess in deaths from lymphatic and hematopoietic malignancies other than leukemia was also noted (4 observed vs 1.02 expected; SMR, 392; p < 0.05). None of the four people who died had worked in or around the furnace area where exposure to uranium and vanadium was greatest. The study exhibited many of the same strengths as the previous study by Wagoner and colleagues (1964), including the use of a regional comparison group in the mortality analysis and a small sample (662). In contrast with Wagoner et al., Archer and colleagues did not conduct annual followup of the study group. Waxweiler et al., 1983 In this retrospective cohort study, the authors continued through 1977 fol- lowup of the Colorado Plateau mill-worker cohort first studied by Wagoner and colleagues (1964). Microfilmed personnel records of workers in seven uranium mills were used in the selection of 2,002 men who were employed at least 1 day after January 1, 1940; had worked for at least 1 year in uranium mills; and had no work experience in an underground uranium mine. Demographic data and work histories through 1971 were collected and coded for study use. Researchers found that about half the cohort was employed before 1950 and that only a small number had worked longer than 5 years. Vital status was determined through SSA records and other sources for all but 2% of the cohort. Death certificates were obtained for 515 (97%) of the 533 deceased workers. A total of 43,252 person-years were observed for the study group. Mortality was analyzed with the National Institute for Occupational Safety and Health (NIOSH) modified Life Table Analysis System (LTAS), and cause-, age-, race-, sex-, and calendar-period-specific SMRs were calculated. Mortality was compared with national rates. The authors sought to assess the association between mill employ- ment and lymphatic and pulmonary malignancies, toxic effects in the kidneys due to uranium exposure, and all-cause mortality. There were statistically significant deficits in total mortality (533 observed vs 605.2 expected; SMR, 88; 95% CI, 81-96) and mortality from all malignant neoplasms (82 observed vs 109.8 expected; SMR, 75; 95%, CI 59-93). There were also fewer deaths due to lung cancer than expected (26 observed vs 31.4 expected; SMR, 83; 95% CI, 54-121), but this difference did not reach the 5% level of statistical significance. The authors reported a statistically nonsignificant excess in mortality from Hodgkin lymphoma (SMR, 231; 95% CI, 48-675). Of the nonmalignant outcomes, there was a significant excess in deaths due to

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122 UPDateD literatUre review oF DePleteD UraniUm nonmalignant respiratory disease (SMR, 163; 95% CI, 123-212) as a result of increases in the “other nonmalignant respiratory diseases” category. The authors also observed a nonsignificant increase in deaths due to chronic renal disease (SMR, 167; 95% CI, 60-353), but in all cases employment in the mill was rather brief and induction time ranged from 4 to 19 years. Moreover, death certificates in at least half of the six cases also indicated either prostatic obstruction or pros- tatic cancer. Pinkerton et al., 2004 Pinkerton and colleagues examined mortality in 1,484 men who worked in one of the seven uranium mills in the Colorado Plateau area. The cohort was drawn from personnel records of uranium-mill workers previously described by Waxweiler and colleagues (1983) that included 2,002 men employed at least 1 day after January 1, 1940, worked for at least 1 year, and had never worked in an underground uranium mine. The authors reviewed records from the Waxweiler et al. study to ensure the inclusion of workers who met the original criteria but were omitted from the study, and they recoded all work histories to remedy any inaccuracies. The resulting subcohort of 1,485 included men who satisfied the original cohort criteria, had never worked in an aboveground or underground mine, and had worked for at least 1 year in the seven uranium mills at the time of uranium or vanadium concentrate recovery. One person was excluded from analysis because his work history was incomplete. Of the 1,485 men, 97% (1,438) were members of the original Waxweiler et al. cohort. All workers included in the study were followed through the end of 1998. Vital status was determined on the basis of records of SSA, the Inter- nal Revenue Service (IRS), the US Postal Service, and state bureaus of motor vehicles. Death certificates and data from the National Death Index (NDI) were collected to ascertain cause of death of 794 (98%) of the workers known to be deceased and recoded in accord with ICD-9. Less than 2% of the study population had been lost to followup. The End Stage Renal Disease Program Management and Medical Information System (ESRD) was used to assess the risk of death from ESRD and renal disease in the cohort. The NIOSH modified LTAS was used in the analysis of mortality. The num- ber of person-years at risk was calculated and stratified into 5-year intervals by age and calendar time. SMRs were calculated by using US adjusted mortality and observed deaths. In addition, mortality was stratified by duration of employment, time since first employment (latency), and year of first employment. Mortality was also compared with that in the Colorado Plateau states. In general, mortality from all causes and mortality from all malignant neo- plasms were less than expected in comparison with the US population. Cancer mortality was consistent with findings reported in previous studies of this cohort

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12 CoHort DesCriPtions (Archer et al., 1973; Waxweiler et al., 1983). Mortality from tracheal, bronchial, and lung cancer for the first time exhibited a statistically nonsignificant increase (78 observed vs 68.93 expected; SMR, 113; 95% CI, 89-141) that was not found in earlier studies of this cohort. Mortality from tracheal, bronchial, and lung can- cer was higher in those employed before 1955 (SMR, 134; 95% CI, 102-174) than in those hired in 1955 or later (SMR, 79; 95% CI, 49-121), but a reverse associa- tion was observed between tracheal-, bronchial-, and lung-cancer mortality and duration of employment (that is, longer employment was associated with lower mortality). The excess based on regional rates (75 observed vs 49.73 expected; SMR, 151; 95% CI, 119-189) was statistically significant and greater than the excess based on US rates since 1960. Pinkerton and colleagues also reported nonsignificant increases in deaths from lymphatic and hematopoietic cancers other than leukemia (16 observed vs 11.08 expected; SMR, 144; 95% CI, 83-235) and from chronic renal disease (8 observed vs 5.91 expected; SMR, 135; 95% CI, 58-267). The increase in lym- phatic cancers was less than the excess observed by Archer et al. (1973) (SMR, 392; 95% CI, 194-590), which reflected an excess of deaths from Hodgkin lym- phoma and lymphosarcoma and reticulosarcoma, but greater than that found by Waxweiler et al. (1983) (SMR, 119; 95% CI, 21-217). In addition, significantly fewer deaths from all digestive cancers than expected were observed (SMR, 62; 95% CI, 43-87). The authors also observed a significant increase in mortality from non- malignant respiratory disease (SMR, 143; 95% CI, 116-173) that was due to a significant excess in mortality from emphysema (SMR, 196; 95% CI, 121-299) and pneumoconiosis and other respiratory disease (SMR, 168; 95% CI, 126-221). Mortality from emphysema was higher in workers employed before 1955, when exposure to uranium, silica, and vanadium was thought to be highest (17 observed; SMR, 222; 95% CI, 129-356), than in those employed in 1955 or later (4 observed; SMR, 130; 95% CI, 36-333). However, there were no cor- responding differences in mortality from pneumoconiosis and other respiratory diseases. Fewer deaths from nonmalignant digestive disease than expected were observed (SMR, 62; 95% CI, 39-94). The strengths of this study include a long followup period (vital status through 1998 was determined) and the use of ESRD data that provide useful details on mortality from chronic renal disease associated with uranium milling. Like previous studies of the cohort, this one lacked assessment of individual exposure to uranium and other substances in the milling environment. Fernald Feed Materials Production Center Workers From 1951 to 1989, the Fernald Feed Materials Production Center (FFMPC) in Ohio chemically processed uranium-ore concentrate and uranium of low

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12 UPDateD literatUre review oF DePleteD UraniUm enrichment grade into uranium-metal products. The process involved the use of hydrofluoric acid, ammonia, nitric acid, sulfuric acid, tributyl phosphate, trichloro- ethylene (TCE), and cutting fluids through dissolution, evaporation, and denitra- tion to produce pure uranium metal. During operation, the facility monitored internal and external radiation exposure. The Comprehensive Epidemiology Data Resource (CEDR) created by the Department of Energy (DOE) warehoused information regarding workers at multiple nuclear processing facilities, including FFMPC, for 30 years. Boiano et al., 1989 In 1985, NIOSH investigators conducted a cross-sectional medical assess- ment of workers at FFMPC. The study followed requests for investigations due to concerns about potential exposure to reported releases of uranium oxides from dust collectors in November and December 1984. About 850 hourly workers were employed at FFMPC at the time of the evaluation. The study focused on evaluating hazards related to lung and renal toxicity after consultation with plant management and workers. Of the 208 eligible long-term employees (147 hourly and 61 salaried), 146 (70%), identified through employee rosters, participated in the study. The study population consisted of 142 men and four women with mean age and median age of 56 and 58 years, respectively. The employees had worked at the facility for 10-34 years (median, 32 years). Study participants included hourly and salaried employ- ees who had worked at the facility continuously for 10 years, salaried employees who had previously been hourly and who had worked there for at least 10 years, and former hourly employees who had retired within the preceding 2 years after working there continuously for at least 10 years. A medical and occupational questionnaire was carried out with tests that included blood and urine analysis, chest radiography, and pulmonary-function tests (standard screening spirometry). The questionnaire was self-administered and collected details on an employee’s medical history with emphasis on respi- ratory and renal conditions, occupational and job exposure history, cigarette and alcohol use, and basic demographic information. Questions on respiratory conditions were extracted from the American Thoracic Society questionnaire. On the basis of responses to relevant questionnaire items, the investigators cat- egorized breathlessness in five grade levels; 1-second forced expiratory volume (FEV1) and forced vital capacity (FVC) served as indicators of pulmonary func- tion. Blood and urine samples were collected for a number of glomerular and tubular biomarkers.2 Blood and urine tests were used as dichotomous variables in evaluating renal effects. Urinary uranium concentration was also measured. 2The markers included beta-2-microglobulin, retinol-binding protein, albumin, total protein, creatin- ine, n-acetyl glucosaminidase, gamma glutamyl transpeptidase, and alanine aminopeptidase.

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12 CoHort DesCriPtions Personnel records were used to establish work histories, and high-, medium-, low-, and no-exposure groups were created on the basis of job titles. Urinary- uranium data were used to construct exposure histories; the data were used to verify exposure groups and to weight the exposure categories. A cumulative uranium-exposure index was created for each participant by multiplying dura- tion of employment and the potential for uranium exposure in the job held. Radiation measurements (whole-body radiation counts) were used to determine uranium lung burden. Urinary uranium concentrations varied up to 13 µg/L, and 109 (92%) of the participants had concentrations under the detection limit of 5 µg/L. No associations between glomerular and tubular markers and measures of uranium exposure were observed. The ratio of FEV1 to FVC was associated with the job- history–derived uranium-exposure index after adjustment for smoking. Short- ness of breath was significantly associated with self-reported uranium-exposure incidents. Ritz, 1999 A cohort of workers employed at FFMPC during its period of operation (1951-1989) was assembled through CEDR (Ritz, 1999). Some 4,014 white male workers were identified; most of them were employed before 1960. The cohort was followed through 1979 with SSA records and from 1979 to 1989 with the NDI to determine vital status; 1,064 had died, and death certificates were obtained. Internal exposure to uranium was measured through urinalysis and extrapola- tion from environmental sampling, and external exposure was measured with film badges. Internal exposure, measured as annual lung dose, was mostly exposure to various insoluble forms of uranium, from depleted through enriched in 235U. Because urinalysis reflects inhalation and internal transport of soluble uranium, air sampling was incorporated to provide a rough measure of the risk of inhala- tion of insoluble uranium as well. Internal exposure from radionuclides was responsible for the bulk of the radiation doses recorded; most monitored workers (68.9%) received cumulative external radiation doses of less than 10 mSv, only 2.6% had doses of over 100 mSv, and none exceeded 300 mSv. Because CEDR maintained records of exposure to TCE and cutting fluids, these were controlled, as was socioeconomic status (SES). SMRs were calculated by using Monson’s life-table analysis. The numbers were too small to conduct separate dose-response analyses for specific cancers, so only the organ systems with the highest likelihood of exposure—respiratory, transport (blood and lymph), excretory, and upper gastrointestinal—were examined individually. Cumulative dose was lagged by 0, 10, and 15 years to allow for cancer latency. The risk-set approach (similar to the nested case-control approach) of Breslow and Day was used for dose-response comparisons; each cancer death was matched to all cohort

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126 UPDateD literatUre review oF DePleteD UraniUm members who were still alive at the calendar time of the index subject’s death (on average 3,300 survivors per death). All-cause mortality was lower in the workers than in the US white male pop- ulation (SMR, 84; 95% CI, 79-89). Risk of death from all malignant neoplasms was nonsignificantly higher than in the general population (SMR, 109; 95% CI, 98-122) and lung-cancer mortality was similar (SMR, 101; 95% CI, 83-121). External radiation doses in excess of 100 mSv (which occurred in only 2.6% of the cohort) increased mortality from all cancers, all radiosensitive cancers, and lung cancer, but the numbers were too small for precise estimates (all were non- significant). Cumulative external radiation showed a dose-response relationship when lagged by 10 or 15 years and adjusted for chemical exposure and internal dose for all cancers (10-year lag: rate ratio [RR], 1.79; 95% CI, 1.12-2.86; 15- year lag: RR, 1.92; 95% CI, 1.11-3.32), all radiosensitive cancers (10-year lag: RR, 1.88; 95% CI, 1.06-3.32; 15-year lag: RR, 2.0; 95% CI, 1.02-3.94), and lung cancer (10-year lag: RR, 2.13; 95% CI, 1.08-4.18; 15-year lag: RR, 2.77; 95% CI, 1.29-5.95), but not for hematopoietic and lymphopoietic cancers. Cardiovascular mortality was lower in the workers than in the US white male population (SMR, 78; 95% CI, 71-86), as was emphysema mortality (SMR, 21; 95% CI, 4-60). Differences in mortality from all other causes were nonsignificant. The healthy-worker effect probably accounts for those lower SMRs. The SMR for all-cause mortality remained lower when Fernald workers were compared with NIOSH-Computerized Occupational Referent Population System (CORPS) workers (SMR, 81; 95% CI, 76-86); the comparison should have reduced bias caused by the healthy-worker effect. The strengths of this study are that it used one of the largest cohorts with monitored external and internal exposures at the individual level, had a long fol- lowup period, allowed for a lag period for development of radiation-related solid tumors, and adjusted for other exposures, such as to TCE and cutting fluid, and for socioeconomic status. Oak Ridge Nuclear Facilities Workers Oak Ridge, Tennessee, was the home of several nuclear facilities involved in nuclear-weapons production during World War II. Two of the facilities (Y-12 and K-25) were dedicated to uranium enrichment for use in atomic weapons, and a third (X-10, also called Clinton Laboratories) was an experimental laboratory designed to produce plutonium for further research. The Y-12 uranium-processing plant was run by the Tennessee Eastman Corporation TEC) in 1943-1947. With an electromagnetic separation process, uranium was enriched in 235U for use in atomic weapons. In 1947, ownership passed to Union Carbide Corporation, and the plant shifted toward weapons fabrication and research and development for the separation of isotopes. K-25 was a gaseous-diffusion plant for producing enriched uranium.

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12 CoHort DesCriPtions Polednak and Frome, 1981 In the 4 years that TEC operated the Y-12 plant, about 45,000 people worked there; 38,000 left the plant when Union Carbide assumed management. Demographic and payroll data were submitted to SSA in 1974 for validation of decedents. In 1981, a subset of the 38,000 was examined, and mortality assessed (Polednak and Frome, 1981). The researchers excluded women (47%) from the sample because of incomplete recordkeeping at SSA. An additional 307 tempo- rary workers (those who worked less than 2 days) were excluded, as were 543 because of inaccurate or incomplete data at SSA or the plant. Minority-group members were also excluded (no reason given), leaving a total of 18,869 white men for analysis. Death certificates through 1977 were verified, and all underly- ing causes of death recorded on the certificates (according to ICD-8 classification) were recorded for analysis. Electromagnetic separation involved the use of mass spectrograph units in a two-step enrichment process. Both steps exposed workers to uranium dust but little external radiation; the exposure that posed a risk was inhalation of radio- active compounds. Air-sampling records obtained from TEC showed higher than normal readings at concentrations above acceptable limits. In 1945, the first step was eliminated, and this reduced levels of uranium dust, but the enrichment was higher. Company records indicate that particle size varied, some particles being smaller than 1 µm. Film badges were rarely used, because exposure to external radiation was low owing to the nature of the operation; respirators were required but might not have been used with great frequency. Polednak and Frome examined whether mortality was associated with lon- ger periods of employment and exposure to higher levels of airborne uranium. Workers were categorized by stage of enrichment and other job classifications to determine an approximate level of exposure. SMRs were calculated by using both an internal comparison group (workers in buildings where uranium was not being processed) and external comparison group (the US white male population). SMRs were below 100 for all-cause mortality and all-cancer mortality; most of the results were nonsignificant. After correction for incomplete ascertainment of cause of death (access to death records was possible for only 95% of deaths), mor- tality from lung cancer had an SMR of 122 (95% CI, 11-136). Considering type and length of employment resulted in no discernable differences among strata. Checkoway et al., 1988 Researchers examined 6,781 white men who worked at the Y-12 plant for at least 30 days during the period May 31, 1947-December 31, 1974 (Checkoway et al., 1988). They excluded those who had worked at the plant before May 4, 1947 (that is, before it was turned over to Union Carbide), those who had worked at other facilities, and those with unknown employment dates; they also excluded

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182 UPDateD literatUre review oF DePleteD UraniUm TABLE 7-2 Continued Study Design Population Exposure Storm et al., Population- Danish military deployed to Deployment to Balkans 2006 based Balkans (13,552 men, 460 retrospective women); followup from cohort January 2002 to December 2002 Sumanovic- Pre-post All liveborn and stillborn Living in western Herzegovina Glamuzina comparison neonates in Maternity after military activities et al., 2003 Ward of Mostar University Hospital in western Herzegovina, part of Bosnia and Herzegovina, immediately (1995) and 5 years after (2000) 1991- 1995 military activities

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18 CoHort DesCriPtions Outcomes Adjustments Comments Cancer Age-, sex-, period-specific Few cases, wide CIs, young SIRs cohort Major congenital malformations Not known whether DU was used in region

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18 UPDateD literatUre review oF DePleteD UraniUm TABLE 7-3 Studies of Environmental Exposure to Uranium Reference Design Population Exposure residential studies Bithell and Modeling Those living within 6 km of Environmental uranium (for Draper, 1999 Air Force base example, in leaves) Boice et al., Cross-sectional 16,722 people living in Residential proximity to 2003a 8 municipalities in PA; Apollo, Parks nuclear cancer-mortality records facilities in PA from Pennsylvania Cancer Registry for 1993-1997; reference, PA or national SEER registry Boice et al., Ecologic Mortality data from NCI, Residential proximity to 2003c mortality Texas Department of Health uranium-processing site survey for 1950-2001 Cases, Karnes County (site of uranium mining); controls: 4 counties matched on various characteristics; reference, US general population Boice et al., Mortality Cases: 3 comparison Residential proximity to 2003b survey counties matched on Apollo, Parks nuclear demographics; facilities controls, 2 counties in PA from NCHS for 1950-1995; reference, US general population Pinney et al., Cohort 8,464 people from FMMP; Residential proximity (less 2003 comparison rates, NHIS, than 2 miles) to Fernald NHANES uranium-processing plant in direction of groundwater runoff or possible well or cistern contamination in January 1952- December 1984

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18 CoHort DesCriPtions Outcomes Adjustments Comments Childhood leukemia Authors modeled uranium exposure around US Air Force base and compared it with distribution of childhood leukemia in same area; no correlation found between two plots Cancer incidence Age, sex, calendar year No adjustment for diet, smoking, other cancer risk factors; no determination of length of residence (and hence exposure) Cancer mortality Control counties chosen No adjustment for diet, on basis of matched smoking, other cancer risk demographics factors; no determination of length of residence (and hence exposure) Cancer mortality Matched on demographics No adjustment for diet, smoking, other cancer risk factors; no determination of length of residence (and hence exposure) Goiter, other thyroid disease, Age, sex Study questionnaires not chronic bronchitis, asthma, directly comparable; FMMP emphysema, nephritis, other is self-selected volunteer renal disease, diabetes mellitus group Continued

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186 UPDateD literatUre review oF DePleteD UraniUm TABLE 7-3 Continued Reference Design Population Exposure Finland well-water studies Kurttio et al., Cross-sectional 325 people in Finland Median drinking-water 2002 who obtain drinking water uranium concentration, 28 from drilled wells used an µg/L (interquartile average of 13 years range, 6-135 µg/L; maximum, 1,920 µg/L) Median urinary uranium concentration, 13 ng/mmol of creatinine (range, 2-75 ng/mmol) Median daily uranium intake, 39 µg (range, 7-224 µg) Kurttio et al., Cross-sectional 146 men, 142 women in Median drinking-water 2005 southern Finland who obtain uranium concentration, 27 (same drinking water from drilled µg/L (interquartile range, population as wells used an average of 6-116 µg/L) Kurttio et al., 13 years 2002) Median daily uranium intake, 36 µg (range, 7-207 µg) Median cumulative intake, 0.12 g (range, 0.02-0.66 g) Kurttio et al., Cross-sectional 95 men, 98 women in Median drinking-water 2006a Finland who obtain drinking uranium concentration, 25 (same water from drilled wells µg/L (interquartile population as used an average of 16 years range, 5-148 µg/L; Kurttio et al., maximum, 1,500 µg/L) 2002) Auvinen et al., Nested 35 leukemia cases, 274 Well-water samples 2002 case-control stratified randomly sampled collected blind people from subcohort who in July-November 1996 obtained well water before 1981 Median activity uranium concentration for leukemia cases, 0.08 Bq/L; for reference group, 0.06 Bq/L

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18 CoHort DesCriPtions Outcomes Adjustments Comments Renal function (based on urinary, Uranium exposure adjusted Uranium exposure measured serum concentrations of calcium, for age, sex, BMI by daily intake, uranium in phosphate, glucose, albumin, urine, uranium in drinking creatinine, beta-2-microglobulin water, cumulative intake as biomarkers) from drinking water Indicators of bone formation: Age, smoking, estrogen use Used two types of regression serum osteocalcin, amino- (women) analysis (linear regression, terminal of type 1 procollagen weighted robust regression) (P1NP); indicators of bone to account for highly resorption: serum type 1 collagen influential observations carboxy-terminal telopeptide (CTx), urinary calcium, urinary phosphate Renal-cell toxicity, renal Sex, age (linear-quadratic), Reference group is general dysfunction (based on BMI, smoking, use of population concentrations of various analgesics enzymes, creatinine, calcium, phosphate, glucose as indicators) Exposure assessment: uranium concentration in drinking water, hair, nails, urine Association with uranium, radon, Age, sex No dose-response radium assessment; no adjustments for other risk factors Continued

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188 UPDateD literatUre review oF DePleteD UraniUm TABLE 7-3 Continued Reference Design Population Exposure Auvinen et al., Nested 88 stomach-cancer cases, Well-water samples 2005 case-control 274 stratified randomly collected blind sampled people from in July-November 1996 subcohort who obtained water from drilled wells Median activity before 1981 concentration for both cases and reference group, 130 Bq/L Kurttio et al., Nested Cases, 61 bladder-cancer Drilled well water outside 2006b case-control cases, 51 renal-cancer cases municipal water supply diagnosed in 1981-1995; obtained in 1967-1980 controls, 274 randomly sampled people stratified by Uranium concentrations: sex, age bladder cancer, 0.08 Bq/L; renal cancer,0.07 Bq/L; reference, 0.06 Bq/L

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18 CoHort DesCriPtions Outcomes Adjustments Comments Association with uranium, radon, Age, sex No dose-response radium assessment; no adjustments for other risk factors Association with radon, radium, Bladder cancer: age at Exposures measured only up uranium exposure followup, sex, smoking status to 10 years before diagnosis to account for cancer latency Renal cancer: age, sex, smoking, BMI

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