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Suggested Citation:"8 Conclusions." Institute of Medicine. 2008. Gulf War and Health: Updated Literature Review of Depleted Uranium. Washington, DC: The National Academies Press. doi: 10.17226/12183.
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Suggested Citation:"8 Conclusions." Institute of Medicine. 2008. Gulf War and Health: Updated Literature Review of Depleted Uranium. Washington, DC: The National Academies Press. doi: 10.17226/12183.
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Suggested Citation:"8 Conclusions." Institute of Medicine. 2008. Gulf War and Health: Updated Literature Review of Depleted Uranium. Washington, DC: The National Academies Press. doi: 10.17226/12183.
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Suggested Citation:"8 Conclusions." Institute of Medicine. 2008. Gulf War and Health: Updated Literature Review of Depleted Uranium. Washington, DC: The National Academies Press. doi: 10.17226/12183.
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Suggested Citation:"8 Conclusions." Institute of Medicine. 2008. Gulf War and Health: Updated Literature Review of Depleted Uranium. Washington, DC: The National Academies Press. doi: 10.17226/12183.
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Suggested Citation:"8 Conclusions." Institute of Medicine. 2008. Gulf War and Health: Updated Literature Review of Depleted Uranium. Washington, DC: The National Academies Press. doi: 10.17226/12183.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

8 Conclusions I n this chapter, the committee further evaluates the peer-reviewed published literature to draw conclusions about the long-term human health outcomes as- sociated with exposure to natural uranium (as occurred in uranium-­processing mills and other facilities and in residences) or depleted uranium (as occurred in the Gulf War). The discussion is organized according to cancer (or malignant) and noncancer (or nonmalignant) health outcome. Tables included at the end of this chapter contain results from the studies on which the committee bases its conclusions. The traditional 5% level of statistical significance is used in describing the committee’s conclusions regarding associations. Associations that did not reach the 5% level of statistical significance are described below as nonsignificant. Cancer Outcomes This section presents the strength of associations between exposure to natural or depleted uranium and particular cancer outcomes. It draws on the information from the many studies that were described in Chapter 7 and on Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines (IOM, 2000; hereafter referred to as Volume 1). The committee focused on the following sites: leukemias, lymphomas, and cancers of the lung, bone, kidney, bladder, stomach, central nervous system, prostate, and testis. Most of the studies examined cancer mortality, but several studies of UK Gulf War veterans, Balkans veterans, and the Finnish drinking-water cohort also investigated cancer incidence. Because several cancers of interest are associated 193

194 updated literature review of depleted uranium with a generally good chance of survival, cancer incidence (ascertainable from cancer-registration programs) is a better indicator of cancer risk than cancer- related mortality. Results of cancer studies conducted in animal models are inconsistent (see Chapter 3). Several studies reported positive findings with respect to the devel- opment of a variety of cancers (including lung and renal cancers, leukemia, and sarcoma) in animals exposed by inhalation of uranium-ore dust or uranium dioxide, intratracheal injection of 235U (as tetravalent or hexavalent uranium), or implantation of depleted-uranium pellets (Leach et al., 1973; Filippova et al., 1978; Mitchel et al., 1999; Hahn et al., 2002; Miller et al., 2005). However, other studies reported no increase in tumor development in animals exposed by inha- lation of uranium-ore dust or ingestion of uranium (Maynard and Hodge, 1949; Cross et al., 1981; ATSDR, 1999). Lung Cancer Twenty-three studies of uranium-processing workers examined the associa- tion between exposure to uranium and lung cancer, as did three studies of military populations and three studies of residents (see Table 8-1). Four of the uranium- processing studies reported statistically significantly increased standardized mor- tality ratios (SMR) (that is, above 100). All four of those studies involved the same cohort of Oak Ridge, Tennessee, and all included employees of the Y-12 plant (see Table 8-2). The specific study populations overlapped, but each study took a different approach and examined a different timeframe. The most recent study of the cohort, by Richardson and Wing (2006), did not demonstrate a statis- tically significant increase in lung-cancer mortality in any dose stratum. However, when assessing the dose-response relationship with a 5-year lag assumption, they found a dose-response trend between external exposure and lung-cancer mortality (due largely to a small number of excess deaths among those who accumulated an external dose of 50 mSv or more) but did not find a similar trend for internal exposure. Analyses of the joint effects of external and internal exposures found that compared to the referent group (defined as less than 10 mSv external and internal dose), the rate ratio estimates were increased for each group defined by higher cumulative concentrations of internal and/or external dose; however, the results were not statistically significant and a dose-response trend was not observed. One major limitation of the uranium-processing worker studies is the lack of control for smoking, a major risk factor for lung cancer. Contrary to the Y-12 cohort finding, a UK study of processors found sig- nificant reductions in both mortality from lung cancer (SMR, 85; p < 0.05) and incidence of lung cancer (standardized incidence ratio [SIR], 75; p < 0.001) but is limited by having only external-exposure data (McGeoghegan and Binks, 2000b). Beral et al. (1988) also reported a significant deficit in lung-cancer mortality (SMR, 64; p < 0.01) in employees of UK atomic-weapons research establish-

conclusions 195 ments with radiation records but found a significant positive association between cumulative exposure and lung-cancer mortality in a test for trend. One study of residents living near former nuclear-material processing plants found a significant reduction in risk of lung-cancer death (relative risk [RR], 0.95; 95% confidence interval [CI], 0.93-0.98) (Boice et al., 2003b); this study is limited by imprecise and incomplete data on exposure and information on risk factors. Ritz (1999) found a weak dose-response relationship with a 15-year lag per 100 mSv of external dose in workers in a uranium-processing plant. Cragle et al. (1988) reported a nonsignificant increase in lung cancer mortality (8 deaths) for salaried and hourly nuclear-fuels production-plant workers (SMR 152) but lower SMRs (also nonsignificant) for only hourly or only salaried workers. The study lacks exposure data. Pinkerton et al. (2004) reported a statistically nonsignificant increase in lung cancer mortality among uranium millers (SMR, 113; 95% CI, 89-141, compared to US referent rates) that was not found in earlier studies of this cohort. When compared to regional referent rates, the increase reached statistical significance (SMR, 151; 95% CI, 119-189). This study is limited by lack of assessment of individual exposure to uranium and other substances in the milling environment. In summary, there is no consistent evidence of an effect of exposure to natural or depleted uranium on lung-cancer incidence in the studies reviewed. The finding is unchanged when one considers evidence from the studies with the strongest designs, for example, with measurement of cumulative exposure at the individual level, internal controls, a large study population, long followup, and controlling for confounders. The pattern among studies is varied: some studies show increases in risk of lung cancer, and others show decreases. A major short- coming of the studies is the lack of individual data on smoking, a primary risk factor for lung cancer. The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and lung cancer exists. This conclusion on lung cancer differs from the one in Volume 1. The previous committee concluded that there is limited/suggestive evidence of no association between exposure to uranium and lung cancer at cumulative internal doses lower than 200 mSv and that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and lung cancer exists at higher cumulative exposure (> 200 mSv). The present committee did not place quantitative limits on the dose for the following reasons: • There is substantial uncertainty in the measurement of uranium exposure in the studies reviewed. • The types of quantitative measure vary widely from study to study, from individual biomonitoring data to external or internal exposure measurements

196 updated literature review of depleted uranium (often lacking data on many study subjects) to group estimates based on job title to a general category of years of employment. Furthermore, different dose- r ­ econstruction methods were used to estimate dosage, and different cut-points were often used to categorize the dose in the data analysis, so it was difficult to draw a conclusion. • Some studies of lung cancer that reported dose had small samples and often did not adjust for risk factors, such as smoking. Because inhaled uranium dust remains in lung tissues and hilar lymph-node tissues for several years, they are potential targets for uranium radiation. Fur- thermore, lung cancer is a common malignancy and the leading cause of cancer death; even a modest effect could result in a meaningful increase in the number of cases of lung cancer (that is, an increase in an exposed group compared to an unexposed group might be detectable given the frequency of lung cancer occur- rence). Therefore, the committee assigns high priority to continuing to monitor a possible association between exposure to depleted uranium and lung cancer. Leukemias The results of only one of the 23 studies reviewed by the committee achieved statistical significance: a residential study by Boice et al. (2003b) (see Table 8-3). The authors reported a reduction in mortality from leukemia (RR [computed by comparing SMRs from the study counties with control counties], 0.91; 95% CI, 0.86-0.97). However, that study is limited by a lack of exposure data and infor- mation on other risk factors. The remaining 22 studies showed both increases and decreases in risk associated with exposure to uranium, all of which were nonsignificant. There was no consistent evidence of effect, and the pattern among studies was highly varied. The same pattern was observed after restriction of consideration to the “larger studies” (those with a sample population of about 10,000 or more or with more than 10 cases). The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and leukemias exists. Leukemia is a relatively uncommon malignancy, so large study populations are generally needed to demonstrate any significant moderate effects. The studies reviewed by the committee generally did not have adequate sample size. Earlier studies were complicated by the broad grouping of and changes in classification for leukemia. On the basis of the evidence to date, the committee would assign a low priority to additional study of an association between exposure to depleted uranium and leukemias.

conclusions 197 Lymphomas This section includes discussion of two types of lymphoma: Hodgkin lym- phoma (also known as Hodgkin’s disease) and non-Hodgkin lymphoma (NHL). The risk of lymphatic malignancy is of particular interest because uranium is known to accumulate in lymph-nodel tissues. Study results are summarized in Tables 8-4 and 8-5. Hodgkin Lymphoma The studies considered (see Table 8-4), split virtually evenly between show- ing an increase in risk of Hodgkin lymphoma associated with exposure to natural or depleted uranium and showing no change or a decrease in risk of Hodgkin lymphoma associated with uranium exposure. The same pattern was observed after restriction of consideration to the “larger studies” (those with a sample population of about 10,000 or more or with more than 10 cases). Only the study by Nuccetelli et al. (2005) achieved a statistically significant finding, showing a significant increase in the risk of Hodgkin lymphoma. Most of the smaller studies show nonsignificantly decreased risk of incidence or death. Non-Hodgkin Lymphoma and Other Lymphatic Cancers Table 8-5 presents the results of 24 published studies of a possible relation- ship between exposure to natural or depleted uranium and NHL. Most of them showed that exposed subjects experienced a risk of NHL equal to or lower than that in unexposed subjects. The same is true if one considers only the larger studies. One study indicated a significant increase in risk: the study by Archer et al. (1973), which had a sample size of only 662, including four cases of lymphatic cancer. The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and lymphomas exists. This conclusion applies to both Hodgkin lymphoma and non-Hodgkin lymphoma. On the basis of the available evidence, the committee concludes that there is a lack of strong and consistent evidence of an association between uranium exposure and lymphatic cancers. The finding is unchanged when one considers evidence from the studies with larger samples and stronger designs: there is no consistent evidence of effect. The pattern among studies is highly varied, as one would expect if there truly were no effect in the population. Although the avail- able evidence does not justify further consideration of a possible association

198 updated literature review of depleted uranium between depleted uranium and lymphatic cancers, the committee concludes that further study of this type of cancer may be warranted on biologic grounds, given that uranium is known to accumulate in the lymph nodes. Bone Cancer Twelve studies of uranium-processing workers, one study of a deployed population, and two residential studies assessed bone-cancer outcomes. In most of the studies, the risk of bone cancer was the same or decreased after exposure to natural or depleted uranium (see Table 8-6). Only one study had a significant find- ing: a statistically significant increase in bone-cancer incidence—four cases— in a Danish military population deployed to the Balkans (SIR, 600; 95% CI, 160-1,530) (Storm et al., 2006). However, because three of the four cases occurred within the first year after deployment, it is unlikely that deployment-related expo- sure was a factor, given the latency of cancer. After lagging 1 year after deploy- ment, bone-cancer incidence dropped to one case, with a nonsignificant SIR of 170 (95% CI, 0-1,010). The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and bone cancer exists. Overall, the available studies do not provide clear and consistent evidence of an association between natural or depleted uranium and bone cancer. The estimated effects vary greatly from study to study, showing decreased risk, the same risk, or higher risk after exposure. Given that bone cancer is a relatively uncommon malignancy, relatively large study populations are generally needed to demonstrate any significant moderate effects. The studies reviewed by the com- mittee generally did not have adequate sample size. On the basis of the available evidence, the committee would assign a low priority to additional study of an association between exposure to depleted uranium and bone cancer. Renal Cancer The committee considered 20 studies of an association between natural or depleted uranium and renal cancer. None of the published results demonstrated a significant increase in risk after uranium exposure (see Table 8-7). The reported SMRs, SIRs, and RRs varied above and below unity except for one residential study (Boice et al., 2003c), which indicated a statistically significant decrease in renal-cancer mortality associated with uranium exposure (RR, 0.58; p < 0.05). That study did not include exposure assessment or information on other risk fac- tors. In a more detailed analysis, Dupree-Ellis and colleagues (2000) examined a possible dose-response relationship and found an increasing trend, driven primar-

conclusions 199 ily by four renal-cancer deaths in the highest-dose group (excess risk, 10.5/mSV; 90% CI, 0.6-57.4). That result was not statistically significant. The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and renal cancer exists. None of the 20 studies considered by the committee demonstrated a signifi- cant increase in risk of renal cancer after exposure to uranium. When attention was restricted to the studies with the largest samples, there was no positive evi- dence of an effect at the low exposures observed in the studies. On the basis of the available evidence, the committee would assign a low priority to further study of an association between exposure to depleted uranium and renal cancer. Bladder Cancer The committee evaluated 20 published studies of a potential association between exposure to natural or depleted uranium and bladder cancer: 14 ­uranium- processing studies, two studies of military populations, and four residential studies (see Table 8-8). Most of the studies reported the same or reduced ­bladder-cancer mortality or incidence in exposed subjects. Only one finding achieved statistical significance: a UK processing study found a significant reduction in bladder- cancer incidence (SIR, 76; p < 0.05) but roughly equal mortality (SMR, 92; nonsignificant) (McGeoghegan and Binks, 2000b). That study is limited by a lack of data on internal radiation exposure and other risk factors. Two studies of veterans deployed to the Balkans reported increased but nonsignificant SIRs for bladder cancer, but both studies were based on very small numbers of observed cases (Gustavsson et al., 2004; Storm et al., 2006). The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and bladder cancer exists. Overall, the committee finds little evidence that exposure to natural or depleted uranium increases the risk of bladder cancer. Most of the studies, whether small or large, show the same or reduced risk of bladder cancer in people exposed to uranium. Although the two studies of deployed populations showed nonsignificant increases in risk, the estimates were based on small numbers of cases—two and seven. A small number of cases renders findings less robust in that changes in exposure or outcome status in only one or two people could have altered the findings substantially, so confidence in the findings is reduced. The committee would assign a low priority to further study of an association between exposure to depleted uranium and bladder cancer.

200 updated literature review of depleted uranium Brain and Other Central Nervous System Cancers Findings of 20 published studies of an association between uranium exposure and brain and other central nervous system cancers are described in Table 8-9. Almost all failed to demonstrate statistically significant associations between uranium exposure and brain and other central nervous system cancers, but they are roughly evenly split between those showing increases in and those showing the same or decreases in mortality or incidence. That overall pattern is unchanged if one restricts attention to the larger or better designed studies. Only two studies had significant results: significant decreases in risk after uranium exposure. The study by Cragle et al. (1988) reported a statistically significant decrease in mortal- ity after exposure in hourly workers at a nuclear-fuels production facility (SMR, 23; p < 0.05). However, the SMRs for salaried workers and for combined hourly and salaried workers were not statistically significant. In addition to a possible healthy-worker effect, the study may be limited by a lack of detailed exposure assessment and the use of “hourly” vs “salaried” as a proxy for socioeconomic status. Beral et al. (1988) also reported a significant deficit in mortality from brain and other nervous system cancers in processing workers (SMR, 32; p < 0.05). The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and cancers of the central nervous system, including brain cancer, exists. The published studies show inconsistent results that do not lead to a conclu- sion of an association between natural or depleted uranium and cancers of the central nervous system. Studies of some other cancers (for example, bladder can- cer) showed an equal or reduced risk after exposure, but the distribution of studies of brain and other central nervous system cancers is more balanced: results are roughly equally divided between studies that show increased risk and studies that show the same or decreased risk. Because of that pattern, the committee believes that further study of an association between depleted uranium and central nervous system cancers may be warranted but should not be assigned a high priority. Stomach Cancer The committee considered 21 published studies of a possible association between natural or depleted uranium and stomach cancer, including 16 process- ing studies, one study of military populations, and four residential studies (see Table 8-10). All but three had statistically nonsignificant results, and most dem- onstrated the same or decreased mortality or incidence. The pattern is unchanged if one restricts consideration to the larger or better designed studies. The three studies that had statistically significant results all showed a decrease in mortality or incidence (Beral et al., 1988; Dupree-Ellis et al., 2000; McGeoghegan and

conclusions 201 Binks, 2000b). McGeoghegan and colleagues found a significantly decreased risk of stomach cancer (SIR, 76; p < 0.05) but an approximately equal risk of stomach-cancer death (SMR, 92; nonsignificant) in workers at the Springfields uranium-production facility (McGeoghegan and Binks, 2000b); however, the study is limited by inadequate data on exposure, particularly internal exposure. The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and stomach cancer exists. Overall, the committee finds little evidence to suggest that exposure to natural or depleted uranium increases the risk of stomach cancer. Most of the studies showed similar or reduced risk of stomach-cancer death and incidence in people exposed to uranium. Although four uranium-processing studies showed nonsignificant increase in SMRs, the findings were based on 15 or fewer cases. Similarly, the study of Danish deployed populations that showed a nonsignificant increase in risk was based on two cases. Therefore, confidence in the findings is low. In the view of the committee, further study of an association between depleted uranium and stomach cancer would have a low priority. Male Genital Cancers Prostatic cancer is the most frequently diagnosed cancer in men in the United States, and any increase in risk could result in a large increase in the number of cases or deaths. Testicular cancer, the most common cancer among young men, is of special interest to Gulf War veterans, and some studies of veterans suggested a higher but nonsignificantly increased risk (IOM, 2006). Prostatic Cancer The committee evaluated 19 published studies of a potential association between exposure to natural or depleted uranium and prostatic cancer, including 14 processing studies, two studies of deployed populations, and three residential studies (see Table 8-11). Only one reported a statistically significant finding: McGeoghegan and Binks (2000b) found a significant reduction in prostatic- c ­ ancer incidence (SIR, 77; p < 0.05) but not mortality (SMR, 89; nonsignificant) in workers at the Springfields uranium-processing plant. The study is limited by the lack of data on internal radiation exposure. Three other studies of processing workers reported increased prostatic-cancer mortality, but none of the SMRs was statistically different from the null value indicating no effect (Beral et al., 1988; Loomis and Wolf, 1996; Ritz, 1999). The larger studies (those with samples of about 10,000 or more or with more than 10 affected cases) had more findings of decreased risk than of increased

202 updated literature review of depleted uranium risk in those exposed to uranium. No study showed a statistically significant increase in risk. The only statistically significant finding was a decrease in cancer incidence (SIR, 77; p < 0.05). Overall, there is little evidence of an association between uranium exposure and prostatic cancer. The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and prostatic cancer exists. Of the 19 studies considered, none demonstrated a significantly increased risk of prostatic cancer after exposure to uranium, and one showed a significant decrease in cancer incidence but not mortality. If only the studies with the largest samples are considered, the committee finds that there is no affirmative evidence of effect. On the basis of the available evidence, the committee would assign a low priority to further study of an association between exposure to depleted uranium and prostatic cancer. Testicular Cancer Table 8-12 summarizes the findings of 15 published studies considered by the committee for a possible relationship between exposure to natural or depleted uranium and testicular cancer, including 11 studies of uranium-processing work- ers, three studies of military populations, and one study of residents living near a nuclear facility in Pennsylvania. None of the results achieved statistical signifi- cance. All studies of processing workers showed reduced testicular-cancer mor- tality in people exposed to uranium but did not reach the 5% level of statistical significance. All three studies of deployed veterans found increased incidence rate ratios or SIRs, but they also did not reach statistical significance (Macfarlane et al., 2003; Gustavsson et al., 2004; Storm et al., 2006). The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and testicular cancer exists. The committee finds no consistent evidence that uranium exposure increases the risk of testicular cancer. All occupational cohorts had lower mortality. Tes- ticular cancer, although very rare in the general population, is common in young adults and therefore prevalent in deployed veterans. The nonsignificant excess in incidence observed in the studies of military populations could be due in part to routine medical surveillance of the deployed veterans. Despite the inconsistent evidence, testicular cancer is of special interest to Gulf War veterans. The com- mittee believes that further study of an association between depleted uranium and testicular cancer may be warranted but should not be assigned a high priority.

conclusions 203 Other Cancers A study of health outcomes in 53,462 Gulf War veterans reported only all- cancer incidence, not site-specific incidence (Macfarlane et al., 2005). It did not find a statistically significant increase in cancer incidence (mortality rate ratio, 1.01; 95% CI, 0.79-1.30). However, the 13-year followup period may be too short for most cancers to have developed. Early studies by Archer et al. (1973), Wagoner et al. (1964), and Waxweiler et al. (1983) combined hematopoietic and lymphopoietic cancers, but only one (that by Archer et al.) found a significant increase (SMR, 392; p < 0.05). Beral et al. (1988) also found a significantly lower RR of all lymphopoietic and hemato- poietic cancers (RR, 0.46; 95% CI, 0.23-0.94) in workers with radiation-exposure records than in those without exposure records. Noncancer Outcomes The following subsections present the strength of the evidence of associa- tions between exposure to natural or depleted uranium and specific nonmalignant health outcomes. They draw on the information from the many studies that were described in Chapter 7 and Volume 1. The committee has highlighted the relevant findings on nonmalignant outcomes from the literature, with a focus on outcomes related to the organs and organ systems likely to be affected by natural or depleted uranium, such as the kidneys and the respiratory, central nervous, and reproduc- tive systems. The findings show both positive and negative associations between uranium and nonmalignant health outcomes. Nonmalignant Renal Disease Mortality Fourteen studies assessed the association between occupational exposure and renal-disease mortality. Four reported an excess in mortality that was not statisti- cally significant (see Table 8-13). Two of those followed the mortality experi- ence of uranium millers in the Colorado Plateau region. In 1983, Waxweiler and colleagues reported an excess in deaths from chronic nephritis (SMR, 167; 95% CI, 60-353). However, all deaths in the group occurred in short-term workers, and this lessened the likelihood that the deaths were related to uranium exposure (IOM, 2000). In a followup study of the Colorado group, Pinkerton and col- leagues also observed an increase in mortality due to chronic renal disease (SMR, 135; 95% CI, 58-267) (Pinkerton et al., 2004) that was not statistically significant. Similarly, Dupree-Ellis and colleagues (2000) found an excess in mortality from chronic nephritis (SMR, 188; 95% CI, 75-381) in workers at the Mallinckrodt Chemical works plant that was not statistically significant. The authors noted that

204 updated literature review of depleted uranium prior exposure to silica in previous jobs and misclassification of renal diseases may have limited the interpretability of their results. McGeoghegan and Binks (2001) found a nonsignificant increase in deaths due genitourinary diseases in radiation workers compared with the English and Welsh populations (5 observed vs 4.63 expected; SMR, 108) in a study of processors at the British Nuclear Fuels Chapelcross site. Cragle and colleagues (1988) reported statistically significantly fewer deaths due to genitourinary diseases in hourly employees (SMR, 39; 95% CI, 10-96) in a study of workers at the Savannah River plant. McGeoghegan and Binks (2000b) also reported significantly fewer deaths than expected in radiation workers (SMR, 57; p < 0.01). Frome and colleagues (1997) reported fewer deaths than expected from diseases of the genitourinary system (SMR, 83) in white men in a study of processing workers at the four Federal nuclear plants in Oak Ridge, Tennessee. An earlier study of Oak Ridge workers at the Y-12 and K-25 uranium-enrichment facilities revealed no difference between the numbers of observed and expected deaths from chronic nephritis (SMR, 99; 95% CI, 71-126) (Frome et al., 1990), as reported in Volume 1. The observed findings were probably influenced by a healthy-worker effect. In many of the 14 studies, the computed death rates included all genitouri- nary conditions instead of focusing on renal diseases. Despite reported increases in observed deaths, the SMRs may not have reflected a true response to uranium exposure. In several of the plants, uranium exposure coexisted with other relevant heavy-metal or chemical exposure. Generally, most researchers were unable to isolate the effects of uranium exposure alone. Morbidity Gulf War Veterans Depleted-Uranium Surveillance Study McDiarmid and colleagues conducted a medical investigation of Gulf War veterans who inhaled or ingested airborne depleted-uranium particles or expe- rienced depleted-uranium wound contamination as a result of friendly-fire inci- dents and found renal-function measurements that were generally within normal clinical limits (see Table 8-14) (McDiarmid et al., 2000, 2001, 2004, 2006, 2007). Urinary uranium excretion was used in the exposure assessment, and subjects were separated into high- and low-exposure groups on the basis of a cutpoint of 0.10 μg/g of creatinine. In the first of the Baltimore Veterans Affairs Medi- cal Center (BVAMC) studies, veterans with retained depleted-uranium shrap- nel fragments had higher urinary uranium concentrations than those without 7 years after first exposure. Urinary uranium ranged from 0.01 to 30.74 µg/g of   The confidence interval was calculated by the Committee on Health Effects Associated with Ex- posure During the Gulf War; it was not stated in the original study (IOM, 2000).

conclusions 205 creatinine in veterans with retained fragments and 0.01 to 0.05 µg/g creatinine in veterans without fragments. Despite that finding, renal-function measures (serum creatinine, beta-microglobulin, retinol-binding protein, serum uric acid, urinary creatinine, and urinary protein) were quite similar between the high- and low-exposure groups (McDiarmid et al., 2000). In the 1999 evaluation, urinary uranium ranged from 0.018 to 39.1 µg/g of creatinine in the depleted-uranium– exposed veterans with retained fragments and 0.002 to 0.231 µg/g of creatinine in depleted-uranium–exposed veterans without fragments. Clinical tests revealed renal measures within normal limits with slight differences between high- and low-uranium groups. The authors did not detect any clinically important changes in renal function due to depleted-uranium exposure; urinary creatinine concentra- tion was slightly lower in the high-uranium group, but the difference was only marginally significant (McDiarmid et al., 2001). An increase in urinary uranium (24-hour urinary uranium concentrations higher than 0.05 μg/g of creatinine) was seen in four of the 30 newly enrolled veterans (McDiarmid et al., 2002). The 2001 surveillance reported urinary uranium ranging from 0.001 to 78.125 μg/g of creatinine. The presence of retained depleted-uranium shrapnel appeared to be associated with higher urinary uranium concentration. In addition, most urinary-uranium results were consistent over time. Mean values of all renal- function markers were within normal clinical limits with few statistically signifi- cant differences between high- and low-uranium groups 10 years after first expo- sure. Serum creatinine was higher in the low-uranium group (0.85 vs 0.95 mg/dL; p = 0.03), and urinary retinol-binding protein (65.58 vs 46.13 μg/g of creatinine; p = 0.06) and total urinary protein (78.69 vs 54.63 mg/g of creatinine; p = 0.01) were higher in the high-uranium group (McDiarmid et al., 2004). Those differ- ences were not observed in the previous evaluations of this group. In 2003, all but one of the renal measures were within normal clinical limits. The difference in serum phosphate concentration was the only measurable difference between the high- and low-exposure groups (4.11 vs 3.75 mg/dL; p = 0.03) (McDiarmid et al., 2006), but its clinical importance is unclear. In the most recent evaluation, urinary uranium ranged from 0.002 to 44.1 μg/g of creatinine in total 24-hour urine, and participants with known embedded depleted-uranium shrapnel fragments and specific uranium indicators of depleted uranium had concentrations at or above the cutpoint of 0.10 μg/g of creatinine. The results showed a high correlation between current and cumulative uranium- exposure measures. Of the 34 veterans with depleted-uranium shrapnel, 10 had current urinary uranium concentrations that exceeded the cutpoint of 0.10 μg/g of creatinine. The same number had cumulative urinary uranium concentrations over the cutpoint of 10 μg/g of creatinine. Differences in mean serum uric acid were borderline (p = 0.03) when groups with high and low cumulative uranium exposure were compared. Despite that finding, the values were within the normal clinical range, and the differences were small: 5.22 mg/dL in the high group and 6.19 mg/dL in the low group. Other renal characteristics had no significant dif-

206 updated literature review of depleted uranium ferences whether current or cumulative uranium measures were used (McDiarmid et al., 2007). Drinking Water and Residential Exposure Kurttio and colleagues investigated renal measures related to uranium expo- sure through drinking water in 325 Finnish people who obtained their water from drilled wells (see Table 8-14). The 2002 report on the cohort noted a statisti- cally significant association between uranium exposure and calcium excretion (p = 0.03) in well-water users (Kurttio et al., 2002). The authors documented an association between urinary uranium and fractional excretion of calcium for all exposure metrics. They also observed a statistically significant associa- tion between urinary uranium and fractional phosphate (p = 0.03). There was no association between uranium exposure and measures of glomerular function (Kurttio et al., 2002). In a later study of the cohort, Kurttio and colleagues (2006a) found that uri- nary uranium concentrations were an average of 44% greater than during prior sampling. The study further examined renal toxicity due to uranium exposure through drinking water in 193 of the 325 people included in the 2002 study. In general, markers of renal function were within normal limits. Biomarkers of cyto- toxicity, renal proximal tubular function, glomerular function, and other exposure indicators were not significantly associated with urinary uranium concentration. However, there were statistically significant associations between cumulative uranium intake and glucose excretion (p = 0.02) and between uranium exposure and increased blood pressure (diastolic, p = 0.01; systolic, p = 0.07). In the only study that examined an association between residential exposure and renal effects, researchers observed a statistically significant excess in renal disease (standardized prevalence ratio [SPR], 215; 99% CI, 186-248) and bladder disease (SPR, 132; 99% CI, 111-156) in people who lived near the Fernald Feed Materials Production Center (FFMPC) in Ohio. The outcomes included increases in a few subcategories, such as kidney stones (SPR, 398; 99% CI, 336-468) and chronic nephritis (SPR, 203; 99% CI, 76-435). However, the health outcomes were self-reported, and some were not verified, so the potential for outcome misclassification was increased. Residents who obtained their drinking water from a well or cistern had higher urinary microalbumin concentrations (Pinney et al., 2003). Occupational Uranium Exposure Boiano and colleagues conducted a medical investigation of workers at the FFMPC (see Table 8-14). They observed urinary uranium concentrations up to 13 µg/L, and 109 of the participants had concentrations under the detection limit of 5 µg/L. However, no associations were observed between measures of

conclusions 207 uranium exposure and glomerular filtration or tubular markers (Boiano et al., 1989). A study of processors in Egypt (Shawky et al., 2002) found a mean urinary uranium concentration of 17.8 µg/L. It also reported that urinary uranium was increased in the 13 participants who provided spot urine specimens, ranging from 8 to 29 µg/L. There was a correlation between urinary uranium and serum creatinine in the 13 specimens, and mean uranium excretion was more than 20 times the occupational-exposure decision level of 0.8 µg/L. However, there were no individual exposure data other than data on the 13. That, in addition to the small sample and the absence of more specific markers for evaluating tubular dysfunction, limits the value of the reported results. Conclusion Although high exposure to uranium, a heavy metal, is known to be toxic to the kidneys (see Chapter 3 for a discussion of the toxicity of uranium in ani- mal models), the literature evaluated does not provide substantial evidence of an association between exposure to natural or depleted uranium and important clinical renal effects in humans. Several studies found slight changes in renal markers but no abnormalities in renal function. Gulf War veterans exposed to depleted uranium in embedded shrapnel had minor changes in renal measures and increased urinary uranium concentrations over the course of a 14-year followup, but overall mean values remained within normal clinical ranges. The studies of well-water users in Finland thoroughly characterized the nature of exposure but examined renal effects in a small group and included a relatively short followup. Studies of workers in processing plants at the Fernald Feed Materials Produc- tion Center detected no association between uranium exposure and glomerular or tubular markers. The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and nonmalignant renal disease exists. This conclusion on renal disease differs from the one in Volume 1. The previ- ous committee concluded that there is limited/suggestive evidence of no associa- tion between exposure to uranium and clinically significant renal dysfunction. On the basis of the available evidence, the present committee could not rule out renal effects after exposure of any magnitude (see Chapter 4 for the definition of the category of limited/suggestive evidence of no association). The committee also could not place quantitative limits on the dose, for reasons similar to those detailed above in connection with lung cancer. The published research evidence is inadequate to support a conclusion about depleted uranium as a cause of nonmalignant renal disease. The well-observed

208 updated literature review of depleted uranium renal effects of heavy metals that are excreted in urine make a deleterious effect of depleted-uranium exposure plausible if the exposure is of sufficient magnitude and duration. The kidneys are identified as the most sensitive target of uranium toxicity in the US Army’s “Capstone Report” (USACHPPM, 2004) and in the National Research Council report, Review of Toxicologic and Radiologic Risks to Military Personnel from Exposure to Depleted Uranium During and After Combat (NRC, 2008). However, available modes of uranium exposure—industrial expo- sure, groundwater exposure, and depleted-uranium exposure of a small number of veterans—do not indicate renal toxicity in these settings. Additional studies of larger numbers of exposed people with well-characterized exposure and renal outcomes will be needed before any definitive conclusions can be drawn about a nephrotoxic effect of exposure to depleted uranium in a war theater. On the basis of the available evidence, the committee would assign a high priority to further study of an association between exposure to depleted uranium and nonmalignant renal disease. Nonmalignant Respiratory Disease The committee evaluated 14 mortality and two morbidity studies of exposure to uranium and nonmalignant respiratory disease (see Tables 8-15 and 8-16). In a 2004 study of a cohort of uranium millers in the Colorado Plateau, Pinkerton and colleagues (2004) observed a significant increase in mortality from nonmalignant respiratory disease compared with the US referent population (SMR, 143; 95% CI, 116-173) due to an excess in mortality from emphysema (SMR, 196; 95% CI, 121-299) and pneumoconioses and other respiratory diseases (SMR, 168; 95% CI, 126-221). Those findings were consistent with those of a previous study of the cohort (Waxweiler et al., 1983). However, mortality from emphysema was higher in workers employed before 1955, when exposures to silica and vanadium, in addition to exposure to uranium, were thought to be at their highest (before 1995: 17 observed; SMR, 222; 95% CI, 129-356; 1955 or later: 4 observed; SMR, 130; 95% CI, 36-333) (Pinkerton et al., 2004). Frome and colleagues (1990) also reported a significant excess in deaths from nonmalignant respiratory diseases. However, several studies found decreases in lung-disease mortality. As reported in Volume 1, Ritz (1999) found a significant decrease based on 53 deaths. As with mortality from nonmalignant renal diseases, the respiratory-disease outcomes were grouped, so the ability to observe effects of individual diseases was reduced. In addition, the issue of exposure to multiple respiratory toxicants is important with respect to respiratory disease: many workers were often exposed to other agents (such as silica) known to have effects on the lungs. In a study of lung disease in workers at the FFMPC, investigators found some associations between indicators of uranium exposure and respiratory effects. The ratio of 1-second forced expiratory volume (FEV1) to forced vital capacity was associated with the job-history–derived uranium-exposure index after adjustment

conclusions 209 for smoking. However, the FEV1 alone was not associated with the exposure index. Shortness of breath was significantly associated with self-reported uranium exposure (Boiano et al., 1989). People who lived close to the plant had signifi- cantly fewer cases of asthma (SPR, 85; 99% CI, 73-98), chronic bronchitis (SPR, 19; 99% CI, 14-24), and emphysema (SPR, 61; 99% CI, 41-68) compared with National Health Interview Survey rates (Pinney et al., 2003). The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and nonmalignant respiratory disease exists. Results of several of the studies support an effect of employment in uranium- processing facilities on nonmalignant respiratory disease, but their applicability to military depleted-uranium exposure is limited by the extent of concomitant coexposure of such workers to other respiratory toxicants (such as silica, asbes- tos, and vanadium). Results of inhalation studies of various forms of uranium in several animal species are inconsistent with respect to nonmalignant respiratory effects (see Chapter 3). On the basis of the available evidence, the committee would assign a high priority to further study of an association between exposure to depleted uranium and nonmalignant respiratory disease. Neurologic Effects The studies of uranium-processing workers showed no excess in neurologic- disease mortality (Polednak and Frome, 1981; Cragle and et al., 1988; Frome et al., 1990, 1997; Dupree-Ellis et al., 2000; McGeoghegan and Binks, 2000a,b, 2001; Boice et al., 2006) (see Table 8-17). As part of the Depleted Uranium Follow-up Program at the BVAMC, McDiarmid and colleagues used various traditional and automated test batteries (see Chapter 7) to assess neurocognitive performance in veterans. Results of the evaluation of Gulf War veterans suggested a statistically significant relationship between increased urinary uranium concentrations and poor performance on automated neuropsychologic tests regardless of the models used (24-hour-urine uranium in depleted-uranium–exposed veterans, p = 0.01; spot-urine uranium in all veterans, p = 0.01); traditional test measures showed no statistical differences between exposed and unexposed veterans (McDiarmid et al., 2000). However, the relationship between urinary uranium concentra- tion and performance on automated measures observed in the 1994 and 1997 evaluations appeared to weaken and had only a marginal level of significance (p = 0.098) in high and low urinary-uranium groups in the 1999 surveillance after adjustment for intelligence (WRAT-3) and depression (Beck Depression Inven- tory) (McDiarmid et al., 2001). Later surveillance (2001, 2003, and 2005) found no statistically significant differences between exposure groups in neurocognitive indexes (McDiarmid et al., 2004, 2006, 2007). A modest association was seen

210 updated literature review of depleted uranium between urinary uranium and the accuracy impairment (A-IIac) index in 2001 and 2003 surveillance, but the authors noted that the result was based on test perfor- mance of two veterans whose uranium concentrations were exceedingly high. The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and nonmalignant diseases of the nervous system exists. Overall, published studies of neurologic outcomes are either negative studies that do not find any evidence of health effects of exposure to depleted uranium or relatively small studies, such as the Depleted Uranium Follow-up Program at the BVAMC, that find inconstant associations. As described in Chapter 3, the results of studies in animal models indicate that depleted uranium is a toxicant capable of crossing the blood-brain barrier. Data on effects are inconsistent; some animal studies report behavioral changes, and others do not. Although at high concentra- tions different forms of uranium might be associated with some subtle neurologic dysfunction in animals, the relevance of these observations to humans remains unknown. On the basis of the available evidence, the committee would assign a high priority to further study of an association between exposure to depleted uranium and neurologic effects. Reproductive and Developmental Effects A few studies examined the effects of natural or depleted uranium on human reproduction and development (see Table 8-18). McDiarmid and colleagues evalu- ated endocrinologic function in Gulf War veterans by measuring blood concentra- tions of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone, thyroid-stimulating hormone, and free thyroxine. Study authors also assessed semen for a number of characteristics, including volume, concentration, structure, and motility. A statistically significant difference was observed in mean prolactin concentrations, which were 1.66 and 12.47 µg/g of creatinine (p = 0.04) in low- and high-prolactin groups (McDiarmid et al., 2000). In the 1999 surveillance, there were no statistically significant differences in mean FSH, LH, prolactin, and testosterone concentrations or thyroid measures between low and high groups. Of the 44 sperm samples included in the analysis, three were designated subnormal—possessing below normal values of at least three of the five characteristics as defined by World Health Organization stan- dards. The high-urinary-uranium groups had more abnormal total sperm counts (583.5 ± 106.1 vs 286.6 ± 44.8), total progressive sperm counts (220.9 ± 44.0 vs 108.2 ± 19.2), and total rapid progressive sperm counts (155.5 ± 31.1 vs 81.3 ± 15.4) that were statistically significant (p = 0.02, 0.03, and 0.04, respectively), results not previously seen in this group (McDiarmid et al., 2001). In 2001, over- all neuroendocrine function was normal, but mean free thyroxine was higher in

conclusions 211 the low-uranium group (1.66 vs 1.08 ng/dL), a result not observed in the 1997 and 1999 evaluations. There was no statistically significant difference in semen measures between the high- and low-urinary-uranium groups (McDiarmid et al., 2004); this finding was consistent in successive evaluations. Increased mean values of semen characteristics were seen in the high-urinary-uranium group in the 2003 evaluation, but all were within the normal clinical ranges (McDiarmid et al., 2006). There were no statistically significant differences between high- and low-urinary-uranium groups in neuroendocrine measures, which were generally within normal clinical limits in veterans examined in the following surveillance. Mean values of semen characteristics also showed no statistically significant dif- ferences; however, the percentages of progressive sperm and rapid progressive sperm were lower in the high-uranium group on the basis of the current urinary- uranium metric (McDiarmid et al., 2007). In a study of the prevalence of major malformations in two 1-year cohorts of neonates born in 1995 (immediately after the war in Bosnia) and in 2000 (5 years after military activities), 40 of 1,853 (2.16%) in 1995 had major malformations (95% CI, 1.49-2.82%), and 33 of 1,463 (2.26%) in 2000 had major malforma- tions (95% CI, 1.50-3.01%). In addition, anomalies of the cardiovascular system (0.615% vs 0.162%) and central nervous system (0.273% vs 0%) were more elevated in the 2000 cohort than in the 1995 cohort (Sumanovic-Glamuzina et al., 2003). The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to depleted ura- nium and reproductive and developmental effects exists. Relatively large study populations are generally necessary to demonstrate significant but subtle reproductive or developmental effects. The studies reviewed generally had too few subjects or relied on insufficiently precise exposure assess- ment to support definitive conclusions. Although some toxicology studies have reported that exposure of animals to uranium compounds during development can lead to a variety of adverse effects, others did not find that uranium exposure affected reproduction and development (see Chapter 3). On the basis of the available evidence, the committee would assign a high priority to further study of an association between exposure to depleted uranium and reproductive and developmental effects. Other Health Outcomes The following discussion of additional health outcomes focuses on reported cardiovascular, hematologic, genotoxic, bone, and immunologic effects of expo- sure to natural or depleted uranium. The outcomes have not been studied in detail in humans, so the evidence from which to draw conclusions is sparse. The results

212 updated literature review of depleted uranium presented here come primarily from a case series of Gulf War veterans who par- ticipated in the Depleted Uranium Follow-up Program at the BVAMC and from studies of uranium-processing workers and well-water users in Finland. Cardiovascular Effects Mortality from diseases of the circulatory system was significantly lower in most studies of uranium-processing workers, probably because of the healthy- worker effect. Pinkerton and colleagues reported statistically significantly fewer deaths from heart disease than expected (SMR, 84; 95% CI, 75-94) in a cohort of uranium-mill workers in the Colorado Plateau region (Pinkerton et al., 2004). Similarly, workers employed in the FFMPC had lower cardiovascular mortal- ity than the US white male population (SMR, 78; 95% CI, 71-86) (Ritz, 1999). Mortality from circulatory diseases in workers at the Mallinckrodt processing plant (SMR, 89; 95% CI, 81-97) (Dupree-Ellis et al., 2000) and the Rocketdyne/ Atomics International (SMR, 68; 95% CI, 58-78) (Ritz et al., 2000) was signifi- cantly lower than that in white males in the United States. Results of experimen- tal studies that used exceedingly high doses of uranium in several animal models suggest that the cardiovascular system is not a sensitive target for this metal. Genotoxic Effects McDiarmid and colleagues (2001) found a statistically significant increase in mean sister-chromatid exchanges (SCEs) (6.35 ± 0.267 vs 5.52 ± 0.182; p = 0.03) in cultured peripheral-blood lymphocytes from members of the high- urinary-uranium group in the 1999 medical surveillance of depleted-uranium– exposed Gulf War veterans. The association remained after adjustment for current smoking status. A statistically significant difference between low- and high-exposure groups was also seen in mean SCEs at high doses of bleomycin; the high-exposure group had increased SCEs (6.25 ± 0.338 vs 4.88 ± 0.262; p = 0.01). No differences were observed in tests for chromosomal aberrations. The findings suggest a possible genotoxic effect; however, as the authors sug- gest, additional surveillance was needed to establish a clinical association. In the 10-year postwar followup assessment, the authors reported a statistically significant increase in the mean frequency of chromosomal aberrations in the high-urinary-uranium group (McDiarmid et al., 2004). However, the 12- and 14-year assessments revealed no statistical differences in chromosomal aberra- tions between high- and low-urinary-uranium groups. Hypoxyanthine-guanine phosphoribosyl tranferase mutation frequencies measured at 10, 12, and 14 years were nonsignificantly greater in the high-exposure group than in the low- exposure group.   Human genotoxic effects are covered in greater detail in Chapter 4.

conclusions 213 Hematologic Effects In general, hematologic measures in depleted-uranium–exposed Gulf War veterans were within normal clinical limits. Clinical tests revealed slight differ- ences between high- and low-urinary-uranium groups. In a 1999 surveillance of veterans, hematologic measures exhibited statistically significant differences between high- and low-exposure groups. The high-urinary-uranium group had a lower mean lymphocyte count (32% vs 37%; p = 0.04), a higher mean neutrophil percentage (55% vs 49%; p = 0.03), and a lower mean monocyte percentage (7.6% vs 9.1%; p = 0.01) (McDiarmid et al., 2001). Differences in hematocrit (42.59% in the high-uranium group and 44.60% in the low-uranium group) and hemoglobin (14.79 vs 15.40 g/dL) that were not observed in the 1997 and 1999 surveillance were seen in 2001 (McDiarmid et al., 2004). The most recent evaluation found no statistically significant differences between high- and low- urinary-uranium groups in hematologic and blood-chemistry measures; they were within normal clinical limits (McDiarmid et al., 2007). Overall, increased urinary uranium excretion had little effect on hematologic measures. Immunologic Effects Only one study examined immunologic effects of depleted uranium. Mc­Diarmid and colleagues found a significantly higher proportion of CD4+ T cells in the high- than in the low-uranium group (65.98% vs 60.83%), and CD8+ T cells were significantly lower in the high- than in the low-uranium group (26.55% vs 31.28%) (McDiarmid et al., 2004). Skeletal Effects In studies of the effect of uranium exposure on bone, researchers focused on biochemical markers of bone resorption and formation. In a study of Finnish well- water users, uranium exposure was shown to be associated with increased CTx (a bone-turnover marker) in men (uranium in water, p = 0.05 and 0.01; daily intake, p = 0.16 and 0.02; and cumulative intake, p = 0.16 and 0.03, in the robust and linear-regression analyses, respectively). In addition, uranium concentrations in drinking water appeared to be associated with increased osteocalcin, a biomarker often used for bone formation (p = 0.19; p = 0.04 in linear-regression analysis). Uranium exposure was not related to any biomarkers of bone metabolism in women. Amino-terminal propeptide of type I procollagen was not associated with uranium exposure (Kurttio et al., 2005). In an analysis of tissue collected during an autopsy of a uranium-processing worker, uranium was found to be deposited more in bone than in the liver or kidneys (Kathren et al., 1989).

214 updated literature review of depleted uranium Conclusion The committee concludes that there is inadequate/insufficient evidence to determine whether an association between exposure to uranium and cardiovascular, genotoxic, hemotologic, immunologic, and skeletal effects exists. Summary This chapter summarized the committee’s systematic evaluation of the scien- tific literature about the human health outcomes of exposure to uranium. Overall, the committee concluded that the available data are inadequate and insufficient to support statements that exposure to uranium is associated with the health out- comes or statements that exposure to uranium is not associated with the health outcomes. The inability to reach positive or negative conclusions is due largely to limitations of the available scientific literature. Studies that permit more definitive conclusions might become available in the future. The committee’s review and evaluation of the scientific literature placed particular emphasis on epidemiologic studies. Toxicologic data were considered secondary and were used largely to determine mechanism of action. The commit- tee used direct evidence (that is, from the empirical literature) rather than relying on a theory-driven approach (that is, using mechanistic models) in drawing its conclusions. Most of the evidence on health outcomes of exposure to uranium comes from studies of workers in uranium-processing mills and other facilities, and the committee relied heavily on those studies in developing its conclusions. It also considered studies of Gulf War veterans who were exposed to depleted uranium and studies of residential exposure to uranium. The committee selected studies that it believed to be the most relevant to identifying health outcomes in depleted- uranium–exposed military personnel. Although numerous epidemiologic studies of various forms of radiation exposure have been conducted, the committee limited its review to studies of exposure to uranium (both natural and depleted uranium). The use of the epidemiologic literature in developing conclusions presented several limitations. For example, the number of exposed people in many of the studies was relatively small, and this decreased the statistical power to detect small excesses of disease. The period of followup in several studies might have been too short to detect some diseases that are typically characterized by long latency; this limitation is of particular concern in regard to studies of cancer outcomes. Appropriate classification of study subjects according to exposure status also constituted a limitation. Inaccurate or imprecise characterization of the exposure of each person in a study may reduce the likelihood of detecting a health outcome associated with exposure or, conversely, could lead to the appear-

conclusions 215 ance of an association when none exists. Assessment of exposure to uranium was inadequate in many of the studies reviewed by the committee. The likelihood of detecting an association between exposure and a health outcome depends on several factors (see Chapter 4). For the health outcomes discussed in this chapter, the committee concluded that exposure to uranium is not associated with a large or frequent effect. Nevertheless, it is possible that depleted-uranium–exposed veterans will have a small increase in the likelihood of developing a disease. Typically, extremely large study populations are necessary to demonstrate that a specific exposure is not associated with a health outcome. The committee’s evaluation of the literature supports the conclusion that a large or frequent effect is unlikely, but it is not possible to state conclusively that a particular health outcome cannot occur. In summary, the committee assigned the category inadequate/insufficient evidence to determine whether an association exists to each health outcome described above for one or more of the following reasons: • Well-conducted studies showed equivocal results. • The magnitude or frequency of a health outcome may be so low that it cannot be reliably detected given the sizes of the study populations. • The available studies had limitations (for example, inadequate exposure assessment or followup that was too short) that prevented the committee from reaching clear conclusions about health outcomes. For those reasons, a conclusion of inadequate/insufficient evidence to deter- mine whether an association exists is not synonymous with evidence of no association.

TABLE 8-1  Lung Cancer 216 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Wagoner et al., Uranium mills, Colorado 611 0 1.9 0 NS 1964 Plateau (all respiratory cancers) Archer et al., Uranium mills, Colorado 622 4 4.26 94 NS (–3 to 191, 1973 Plateau (all respiratory from Volume 1) cancers) Waxweiler et al., Uranium mills, Colorado 2,002 26 31.4 83 54-121 1983 Plateau Pinkerton et al., Uranium mills, Colorado 1,485 78 68.93 113 89-141 2004 Plateau (includes bronchi, lungs, trachea) Polednak and Y-12 uranium-processing 18,869 324 296.47 109 97-122 Frome, 1981 plant, Oak Ridge, TN 122 (corrected+) 110-136 (corrected) Checkoway et Y-12 uranium-fabrication 6,781 89 65.4 (calculated) 136 109-167 al., 1988 plant, Oak Ridge, TN (comparison with US WM) Frome et al., Y-12, K-25 uranium- 28,008 850 667.99 127 p < 0.01 1990 enrichment plant, research laboratory, Oak Ridge, TN Loomis and Y-12 uranium-fabrication 10,597 202 172.6 (calculated) 117 (all workers) 101-134 Wolf, 1996 plant, Oak Ridge, TN 194 (WM) 161.7 (calculated) 120 (WM) 104-138

Frome et al., All four plants, Oak Ridge, 106,020 1,849 118 NS (article 1997 TN (wm) states increased because of high value of FTR) Richardson and Y-12 uranium-fabrication 3,864 40 (highest RR, 1.4 0.65-3.01 Wing, 2006 plant, Oak Ridge, TN internal dose, 100+ mSv) Hadjimichael et Nuclear-fuel fabricating 2,613 14 14.7 95 52-160 al., 1983 plant, CT (men) Stayner et al., Phosphate-fertilizer 3,199 10 8.85 113 61-192 1985 production plant, FL Dupree et al., Uranium-processing plant, 995 21 21.7 97 60-148 1987 Buffalo, NY Brown and Uranium-enrichment plant, 5,773 48 54.6 88 65-117 Bloom, 1987 OH Cragle et al., Nuclear-fuels production 9,860 53 (hourly) 62.04 (hourly)   85 (hourly) NS 1988 plant, Savannah, SC 22 (salaried) 33.01 (salaried)   67 (salaried) 8 (both) 5.27 (both) 152 (both) Beral et al., 1988 Atomic Weapons 22,552 85 132.86 64 p < 0.01 Establishment, UK (employees with radiation records) Ritz, 1999 Uranium-processing plant, 4,014 112 111.03 101 83-121 OH Dupree-Ellis et Uranium-processing plant, 2,514 98 96.08 (calculated) 102 83-124 al., 2000 St Louis, MO Continued 217

TABLE 8-1  Continued 218 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Ritz et al., 2000 Rocketdyne/Atomics 2,297 46 56.95 81 59-108 International plant, CA Boice et al., Rocketdyne/Atomics 5,801 151 NR 89 76-105 2006 International plant, CA Dupree et al., Case-control study of lung 787 lung- NA NA (OR, 2.0 for 0.20-20 1995 cancer in four uranium- cancer cases exposed to 25+ processing operations cGy) McGeoghegan Capenhurst uranium- 12,540 67 deaths (50 y) 74.90 deaths 89 NS and Binks, 2000a enrichment plant, 49 cases (20 y) 58.13 cases (SIR, 84) NS Cheshire, UK (radiation workers) McGeoghegan Springfields uranium- 19,454 360 deaths (50 y) 421.93 deaths 85 p < 0.01 and Binks, production plant, 225 cases (20 y) 301.37 cases (SIR, 75) p < 0.001 2000b Lancashire, UK (radiation workers) Studies of Depleted-Uranium–Exposed Persons Macfarlane et al., Gulf War veterans, UK 51,721 14 cases 18 cases (IRR, 0.76) 0.38-1.54 2003 (includes bronchi, (IRR, 0.41 adj++) 0.10-1.73 lungs, trachea) Gustavsson et Swedish UN services 9,188 1 case (male 0.8 (SIR, 125) NS al., 2004 personnel in Balkans military service) Storm et al., Danish veterans deployed 14,012 2 cases (male) NR (SIR, 40) 0-140 2006 to Balkans

Studies of Environmental Exposures to Uranium Boice et al., Residents of municipalities 16,772 74 cases 84.4 cases (SIR, 88) 69-110 2003a near two former nuclear- (includes trachea, material processing plants, bronchi, lungs, PA pleura) Boice et al., County residents near two 443,799 8,064 deaths NR (RR, 0.95) 0.93-0.98 2003b former nuclear-material p < 0.05 processing plants, PA Boice et al., Residents near former 12,455 224 deaths NR (RR, 1.08) 0.90-1.30 2003c uranium milling and mining site, TX NOTE: FTR = Freeman-Tukey residuals, IRR = incidence rate ratio, NR = not reported, NS = not significant, OR = odds ratio, RR = relative risk, SIR = stan- dardized incidence ratio, SMR = standardized mortality ratio, WM = white men, + = corrected for incomplete ascertainment, ++ = adjusted for smoking and alcohol consumption. 219

220 updated literature review of depleted uranium TABLE 8-2  Lung Cancer in the Oak Ridge, Tennessee, Cohort Study SMR or RR 95% CI or P Value Polednak and Frome, 122 110-136 1981 Checkoway et al., 1988 136 109-167 Frome et al., 1990 127 p < 0.05 Loomis and Wolf, 1996 117 101-134 Richardson and Wing, External dose (mSv) External dose (mSv) 2006 <10     Referent <10     Referent   10-49.9  0.92   10-49.9 0.58-1.46   50+     1.33   50+     0.56-3.18 Internal dose (mSv) Internal dose (mSv) <10     Referent <10     Referent   10-49.9  1.52   10-49.9  0.74-3.13   50-99.9  1.20   50-99.9  0.54-2.67   100+    1.40   100+    0.65-3.01 NOTE: CI = confidence interval, RR = rate ratio, SMR = standardized mortality ratio.

TABLE 8-3 Leukemia No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Archer et al., 1973 Uranium mills, Colorado 622 1 0.79 127 NS Plateau Waxweiler et al., 1983 Uranium mills, Colorado 2,002 0 4.5 0 NS Plateau Pinkerton et al., 2004 Uranium mills, Colorado 1,485 5 7.62 66 21-153 Plateau Polednak and Frome, Y-12 uranium-processing 18,869 40 43.57 92 66-125 1981 plant, Oak Ridge, TN 102 (corrected+) 74-137 Checkoway et al., 1988 Y-12 uranium-fabrication 6,781 4 NR 50 14-128 plant, Oak Ridge, TN (comparison with US white men) Frome et al., 1990 Y-12, K-25 uranium- 28,008 92 81.17 113 NS enrichment plant, research laboratory, Oak Ridge, TN Loomis and Wolf, 1996 Y-12 uranium- fabrication 10,597 11 NR 60 3-107 plant, Oak Ridge, TN Frome et al., 1997 All four plants, Oak 106,020 180 NR 98 NS Ridge, TN (white men) Continued 221

TABLE 8-3  Continued 222 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Hadjimichael et al., 1983 Nuclear-fuel fabricating 2,613 2 1.8 113 13-409 plant, CT (men) Beral et al., 1988 Atomic Weapons 22,552 4 9.16 44 NS Establishment, UK (employees with radiation records) Cragle et al., 1988 Nuclear-fuels production 9,860 13 (hourly) 7.95 (hourly) 163 (hourly) NS plant, Savannah, SC 4 (salaried) 3.80 (salaried) 105 (salaried) NS 1 (both) 0.61 (both) 164 (both, calculated) NS Ritz, 1999 Uranium-processing plant, 4,014 13 11.21 116 62-198 OH Dupree-Ellis et al., 2000 Uranium-processing plant, 2,514 11 NR 111 57-189 St Louis, MO Ritz et al., 2000 Rocketdyne/Atomics 2,297 8 5.47 146 63-288 International plant, CA Boice et al., 2006 Rocketdyne/Atomics 5,801 25 leukemia, NR 133 86-197 International plant, CA aleukemia deaths McGeoghegan and Binks, Capenhurst uranium- 12,540 4 deaths (50 y) 5.76 deaths 69 NS 2000a enrichment plant, 4 cases (20 y) 5.41 cases (SIR, 74) NS Cheshire, UK (radiation workers)

McGeoghegan and Binks, Springfields uranium- 19,454 32 deaths (50 y) 32.07 deaths 100 NS 2000b production plant, 22 cases (20 y) 27.75 cases (SIR, 79) NS Lancashire, UK (radiation workers) Studies of Depleted-Uranium–Exposed Persons Gustavsson, 2004 Swedish UN services 9,188 1 chronic myeloid 0.3 case (SIR, 333) NS personnel in Balkans leukemia case Storm et al., 2006 Danish veterans deployed 14,012 4 cases NR (SIR, 140) 40-350 to Balkans Studies of Environmental Exposures to Uranium Boice et al., 2003a Residents of 16,772 18 cases 12.4 cases 145 86-230 municipalities near two former nuclear-material processing plants, PA Boice et al., 2003b County residents near two 443,799 1,529 deaths NR (RR, 0.91) 0.86-0.97 former nuclear-material processing plants, PA Boice et al., 2003c Residents near former 12,455 59 deaths NR (RR, 1.15) 0.9-1.6 uranium milling and mining site, TX Auvinen et al., 2002 Drinking well-water study, 35 leukemia NA NA (HR, 0.89) 0.38-2.11 Finland cases, 274 (HR, 0.91 per Bq/L for 0.73-1.13 controls uranium) NOTE: CI = confidence interval, HR = hazard ratio, NA = not applicable (case-control study), NR = not reported, NS = not significant, RR = relative risk, SIR = standardized incidence ratio, SMR = standardized mortality ratio, + = corrected for incomplete ascertainment. 223

TABLE 8-4  Hodgkin Lymphoma 224 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Waxweiler et al., 1983 Uranium mills, Colorado 2,002 3   1.3 231 48-675 Plateau Pinkerton et al., 2004 Uranium mills, Colorado 1,485 4   1.21 330 90-843 Plateau Polednak and Frome, Y-12 uranium-processing 18,869 9 16.38 55 NS 1981 plant, Oak Ridge, TN Checkoway, 1988 Y-12 uranium-fabrication 6,781 3 NR 87 18-254 plant, Oak Ridge, TN (comparison with US white men) Frome et al., 1990 Y-12, K-25 uranium- 28,008 18 23 78 NS enrichment plant, research labatory, Oak Ridge, TN Loomis and Wolf, 1996 Y-12 uranium-fabrication 10,597 3 NR 62 13-183 plant, Oak Ridge, TN Frome et al., 1997 All four plants, Oak 106,020 40 NR 77 NS Ridge, TN (white men) Beral et al., 1988 Atomic Weapons 22,552 2   3.55 56 NS Establishment, UK (employees with radiation records) Ritz, 1999 Uranium-processing plant, 4,014 6   2.95 204 74-443 OH Dupree-Ellis et al., 2000 Uranium-processing plant, 2,514 2 NR 92 15-283 St Louis, MO

McGeoghegan and Binks, Capenhurst uranium- 12,540 2 deaths (50 y)   1.13 deaths 177 NS 2000a enrichment plant, 1 case (20 y)   1.54 cases (SIR, 65) NS Cheshire, UK (radiation workers) McGeoghegan and Binks, Springfields uranium- 19,454 9 deaths (50 y)   7.23 deaths 124 NS 2000b production plant, 10 cases (20 y)   7.22 cases (SIR, 139) NS Lancashire, UK (radiation workers) Boice et al., 2006 Rocketdyne/Atomics 5,801 5 NR 199 65-463 International plant, CA Studies of Depleted-Uranium–Exposed Persons Gustavsson et al., 2004 Swedish UN services 9,188 2 cases   1.1 cases (SIR, 190) 20-670 personnel in Balkans Nuccetelli et al., 2005 Italian veterans deployed About 40,000 NR NR (SIR, 236) 122-436 to Balkans Storm et al., 2006 Danish veterans deployed 14,012 3 cases NR (SIR, 100) 20-290 to Balkans Studies of Environmental Exposure to Uranium Boice et al., 2003a Residents of 16,772 1 case   2.7 cases (SIR, 37) 0-205 municipalities near two former nuclear-material processing plants, PA Boice et al., 2003b County residents near two 443,799 290 deaths NR (RR, 0.97) 0.85-1.12 former nuclear-material processing plants, PA Boice et al., 2003c Residents near former 12,455 12 deaths NR (RR, 1.79) 0.9-3.6 uranium milling and mining site, TX NOTE: CI = confidence interval, NR = not reported, NS = not significant, RR = relative risk, SIR = standardized incidence ratio, SMR = standardized mortality ratio. 225

TABLE 8-5  Non-Hodgkin Lymphoma and Other Lymphatic Cancers 226 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Archer et al., 1973 Uranium mills, Colorado 662 4 lymphatic,   1.02 392 p < 0.05 Plateau hematopoietic cancers Waxweiler et al., 1983 Uranium mills, Colorado 2,002 4 lymphatic cancers   4.4 91 NS Plateau Pinkerton et al., 2004 Uranium mills, Colorado 1,485 12 lymphatic cancers   9.86 122 NS Plateau Polednak and Frome, Y-12 uranium-processing 18,869 17 lymphosarcoma, 25.39 67 NS 1981 plant, Oak Ridge, TN reticulosarcoma 11 other lymphatic tissue 19.27 57 NS Checkoway et al., 1988 Y-12 uranium-fabrication 6,781 3 lymphosarcoma NR 62 13-181 plant, Oak Ridge, TN 9 other lymphatic cancers NR 186 85-353 Frome et al., 1990 Y-12, K-25 uranium- 28,008 39 lymphosarcoma, 45.80 85 NS enrichment plant, research reticulosarcoma 48.23 83 NS laboratory, Oak Ridge, TN 40 other lymphatic cancers Loomis and Wolf, 1996 Y-12 uranium-fabrication 10,597 4 lymphosarcoma, NR 50 14-129 plant, Oak Ridge, TN reticulosarcoma 22 other lymphatic NR 132 82-199 cancers

Frome et al., 1997 All four plants, Oak 106,020 82 lymphosarcoma, NR 91 NS Ridge, TN (white men) reticulosarcoma 105 other lymphatic NR 84 NS cancers Hadjimichael et al., 1983 Nuclear-fuel fabricating 2,613 2 lymphatic,   3.1 65   7-234 plant, CT (men) hematopoietic cancers Stayner et al., 1985 Phosphate-fertilizer 3,199 2 lymphatic,   3.78 53   9-167 production plant, FL hematopoietic cancers Brown and Bloom et al., Uranium-enrichment 5,773 23 cancer of lymphatic, 15.8 146 NS 1987 plant, OH hematopoietic system (may include leukemia) Cragle et al., 1988 Nuclear-fuels production 9,860 Lymphatic cancers: plant, Savannah, SC 6 (hourly)   9.5 (hourly) 95 (hourly) NS 4 (salaried)   4.73 (salaried) 85 (salaried) NS 4 (both)   0.76 (both) 526 (both) NS Beral et al., 1988 Atomic Weapons 22,552 3 NHL   6.17 49 NS Establishment, UK (employees with radiation 2 multiple myeloma   3.55 56 NS records) Ritz, 1999 Uranium-processing plant, 4,014 8 lymphosarcoma, and   4.79 167 72-329 OH reticulosarcoma 10 lymphatic tissue   9.94 101 48-185 Dupree-Ellis et al., 2000 Uranium-processing plant, 2,514 1 lymphosarcoma NR 28   1-156 St Louis, MO 5 multiple myeloma NR 130 42-303 9 other lymphoid tissue NR 96 43-186 Ritz et al., 2000 Rocketdyne/Atomics 2,297 4 lymphatic cancers 8.98 45 NS International plant, CA Continued 227

TABLE 8-5  Continued 228 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Boice et al., 2006 Rocketdyne/Atomics 5,801 19 NR 98 59-152 International plant, CA McGeoghegan and Binks, Capenhurst uranium 12,540 NHL: 2000a enrichment plant, 5 deaths (50 y) 4.58 deaths 109 NS Cheshire, UK (radiation 3 cases (20 y) 5.21 cases (SIR, 58) NS workers) Multiple myeloma: 2.61 deaths 115 3 deaths (50 y) 2.41 cases (SIR, 83) NS 2 cases (20 y) NS McGeoghegan and Binks, Springfields uranium- 19,454 NHL: 2000b production plant, 15 deaths (50 y) 23.78 deaths 63 NS Lancashire, UK (radiation 20 cases (20 y) 25.39 cases (SIR, 79) NS workers) Multiple myeloma: 11 deaths (50 y) 13.83 deaths 80 NS 10 cases (20 y) 12.36 cases (SIR, 81) NS Studies of Depleted-Uranium–Exposed Persons Gustavsson et al., 2004 Swedish UN services 9,188 1 case NHL   1.2 cases (SIR, 83 NS personnel in Balkans calculated) Storm et al., 2006 Danish veterans deployed 14,012 3 cases NHL NR (SIR, 80) 20-230 to Balkans 1 case myeloma NR (SIR, 190) 0.0-1060

Studies of Environmental Exposures to Uranium Boice et al., 2003a Residents of 16,772 23 cases NHL 20.9 cases (SIR, 110) 70-165 municipalities near two former nuclear-material processing plants, PA 11 cases multiple   5.8 (SIR, 191) 95-342 myeloma Boice et al., 2003b County residents near two 443,799 1,329 deaths NHL NR (RR, 1.06) 0.99-1.13 former nuclear-material processing plants, PA 561 deaths multiple NR (RR, 0.98) 0.89-1.09 myeloma Boice et al., 2003c Residents near former 12,455 38 deaths NHL NR (RR, 1.00) 0.7-1.4 uranium milling and mining site, TX 22 deaths multiple NR (RR, 1.37) 0.8-2.3 myeloma NOTE: CI = confidence interval, NHL = non-Hodgkin lymphoma, NR = not reported, NS = not significant, RR = relative risk (computed as ratio of SMR of study population to that of control population), SIR = standardized incidence ratio, SMR = stanardized mortality ratio. 229

TABLE 8-6  Bone Cancer 230 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Polednak and Frome, Y-12 uranium-processing   18,869 6   6.68 90 33-196 1981 plant, Oak Ridge, TN 100 (corrected+) 40-206 Frome et al., 1990 Y-12, K-25 uranium-   28,008 11 10.35 106 NS enrichment plant, research laboratory, Oak Ridge, TN Loomis and Wolf, 1996 Y-12 uranium-fabrication   10,597 1 NR 62 1-345 plant, Oak Ridge, TN Frome et al., 1997 All four plants, Oak Ridge, 106,020 25 NR 119 NS TN (white men) Hadjimichael et al., 1983 Nuclear-fuel fabricating plant,    2,613 1   0.5 206 3-1140 CT (men) Cragle et al., 1988 Nuclear-fuels production    9,860 0 (hourly) 1.03 (hourly) 0 (hourly) NS plant, Savannah, SC 1 (salaried) 0.48 (salaried) 208 (salaried, NS 0 (both)   0.8 (both) calculated) 0 (both) Beral et al., 1988 Atomic Weapons   22,552 1   1.35 74 NS Establishment, UK (employees with radiation records) Ritz, 1999 Uranium-processing plant,    4,014 0   0.99 0 0-370 OH Dupree-Ellis et al., 2000 Uranium-processing plant, St    2,514 1 NR 120 7-526 Louis, MO

McGeoghegan and Binks, Capenhurst uranium-   12,540 0 deaths (50 y) 0.46 death 0 NS 2000a enrichment plant, Cheshire, 0 cases (20 y) 0.39 case 0 NS UK (radiation workers) McGeoghegan and Binks, Springfields uranium-   19,454 2 deaths (50 y) 2.98 deaths 67 NS 2000b production plant, Lancashire, 0 cases (20 y) 1.92 cases (SIR, 0) UK (radiation workers) Boice et al., 2006 Rocketdyne/Atomics    5,801 0 1 0 0-352 International plant, CA Study of Depleted-Uranium–Exposed Persons Storm et al., 2006 Danish veterans deployed to   14,012 4 casesa NR (SIR, 600) 160-1530 Balkans Studies of Environmental Exposures to Uranium Boice et al., 2003b County residents near two 443,799 168 deaths NR (RR, 1.01) 0.84-1.21 former nuclear-material processing plants, PA Boice et al., 2003c Residents near former   12,455 11 deaths NR (RR, 1.35) 0.7-2.8 uranium milling and mining site, TX NOTE: CI = confidence interval, NR = not reported, NS = not significant, RR = relative risk (computed as ratio of SMR in study population to that in control population), SIR = standardized incidence ratio, SMR = standardized mortality ratio, + = corrected for incomplete ascertainment. aResult is significant. However, three cases occurred in first year after deployment; omitting first year, SIR is 170 (95% CI, 0-1,010). 231

TABLE 8-7  Renal Cancer 232 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Waxweiler et al., 1983 Uranium mills, Colorado 2,002 3   2.7 112 23-325 Plateau Pinkerton et al., 2004 Uranium mills, Colorado 1,485 4   4.96 81 22-206 Plateau Polednak and Frome, Y-12 uranium-processing 18,869 20 26.54 75 NS 1981 plant, Oak Ridge, TN Checkoway et al., 1988 Y-12 uranium-fabrication 6,781 6 NR 122 45-266 plant, Oak Ridge, TN (comparison with US white men) Frome et al., 1990 Y-12, K-25 uranium- 28,008 44 52.63 84 NS enrichment plant, research laboratory, Oak Ridge, TN Loomis and Wolf, 1996 Y-12 uranium-fabrication 10,597 16 NR 130 74-211 plant, Oak Ridge, TN Frome et al., 1997 All four plants, Oak Ridge, 106,020 109 NR 92 NS TN (white men) Cragle et al., 1988 Nuclear-fuels production 9,860 2 (hourly)   5.01 (hourly) 40 (hourly) NS plant, Savannah, SC 1 (salaried)   2.56 (salaried) 39 (salaried) NS 0 (both)   0.41 (both) 0 (both) NS Beral et al., 1988 Atomic Weapons 22,552 11   5.84 188 NS Establishment, UK (employees with radiation records) Ritz, 1999 Uranium-processing plant, 4,014 5   7.89 63 20-146 OH

Dupree-Ellis et al., 2000 Uranium-processing plant, St 2,514 8 NR 117 54-218 Louis, MO Ritz et al., 2000 Rocketdyne/Atomics 2,297 5   3.97 126 41-294 International plant, CA Boice et al., 2006 Rocketdyne/Atomics 5,801 12 NR 94 49-164 International plant, CA McGeoghegan and Binks, Capenhurst uranium- 12,540 2 deaths (50 y)   4.08 deaths 49 NS 2000a enrichment plant, Cheshire, 2 cases (20 y)   4.47 cases (SIR, 45) NS UK (radiation workers) McGeoghegan and Binks, Springfields uranium- 19,454 13 deaths (50 y) 21.65 deaths 60 NS 2000b production plant, Lancashire, 14 cases (20 y) 22.31 cases (SIR, 63) NS UK (radiation workers) Study of Depleted-Uranium–Exposed Persons Storm et al., 2006 Danish veterans deployed to 14,012 2 cases NR (SIR, 110) 10-410 Balkans Studies of Environmental Exposures to Uranium Boice et al., 2003a Residents of municipalities 16,772 14 cases 13.3 cases (SIR, 105) 58-177 near two former nuclear- material processing plants, PA Boice et al., 2003b County residents near two 443,799 784 deaths NR (RR, 1.02) 0.94-1.12 former nuclear-material processing plants, PA Boice et al., 2003c Residents near former 12,455 19 NR (RR, 0.58) 0.4-1.0 uranium milling and mining p < 0.05 site, TX Kurttio et al., 2006b Drinking well-water study, 51 renal-cancer NA NA (HR, 0.74) 0.33-1.66 Finland cases, 274 (HR, 0.92 per 0.36-2.35 controls log [1 Bq/L] for uranium) NOTE: CI = confidence interval, HR = hazard ratio, NA = not applicable (case-control study), NR, = not reported, NS = not significant, RR = relative risk, 233 SIR = standardized incidence ratio, SMR = standardized mortality ratio.

TABLE 8-8  Bladder Cancer 234 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Polednak and Frome, Y-12 uranium-processing 18,869 26 32.32 80 NS 1981 plant, Oak Ridge, TN Checkoway et al., 1988 Y-12 uranium-fabrication 6,781 3 NR 72 15-210 plant, Oak Ridge, TN (comparison with US white men) Frome et al., 1990 Y-12, K-25 uranium- 28,008 54 66.22 82 NS enrichment plant, research laboratory, Oak Ridge, TN Loomis and Wolf, 1996 Y-12 uranium-fabrication 10,597 8 NR 72 31-142 plant, Oak Ridge, TN Frome et al., 1997 All four plants, Oak Ridge, 106,020 105 NR 76 NS TN (white men) Hadjimichael et al., 1983 Nuclear-fuel fabricating plant, 2,613 1 1.9 0.52 1-292 CT (men) Cragle et al., 1988 Nuclear-fuels production 9,860 2 (hourly) 3.34 (hourly) 60 (hourly) NS plant, Savannah, SC 4 (salaried) 2.14 (salaried) 187 (salaried) NS 0 (both) 0.3 (both) 0 (both) NS Beral et al., 1988 Atomic Weapons 22,552 7 13.69 51 NS Establishment, UK (employees with radiation records) Ritz, 1999 Uranium-processing plant, 4,014 8 6.95 115 50-227 OH Dupree-Ellis et al., 2000 Uranium-processing plant, St 2,514 8 NR 116 48-236 Louis, MO (white men)

Ritz et al., 2000 Rocketdyne/Atomics 2,297 3 3.39 89 18-259 International plant, CA Boice et al., 2006 Rocketdyne/Atomics 5,801 8 NR 65 28-129 International plant, CA McGeoghegan and Binks, Capenhurst uranium- 12,540 8 deaths (50 y) 7.69 deaths 104 NS 2000a enrichment plant, Cheshire, 14 cases (20 y) 14.57 cases (SIR, 96) NS UK (radiation workers) McGeoghegan and Binks, Springfields uranium- 19,454 40 deaths (50 y) 43.66 deaths 92 NS 2000b production plant, Lancashire, 57cases (20 y) 75.15 cases (SIR, 76) p < 0.05 UK (radiation workers) Studies of Depleted-Uranium–Exposed Persons Gustavsson et al., 2004 Swedish UN services 9,188 2 cases 0.7 case (SIR, 290) 40-1100 personnel in Balkans Storm et al., 2006 Danish veterans deployed to 14,012 7 cases NR (SIR, 220) 90-450 Balkans Studies of Environmental Exposures to Uranium Boice et al., 2003a Residents of municipalities 16,772 36 cases 30.2 case (SIR, 119) 83-165 near two former nuclear- material processing plants, PA Boice et al., 2003b County residents near two 443,799 1,044 deaths NR (RR, 0.97) 0.9-1.04 former nuclear-material processing plants, PA Boice et al., 2003c Residents near former 12,455 17 deaths NR (RR, 0.64) 0.4-1.1 uranium milling and mining site, TX Kurttio et al., 2006b Drinking well-water study, 61 bladder- NA NA (HR, 0.77 per 0.41-1.98 Finland cancer cases, log [1Bq/L] for 274 controls uranium) NOTE: CI = confidence interval, HR = hazard ratio, NA = not applicable (case-control study), NR = not reported, NS = not significant, RR = relative risk, SIR = standardized incidence ratio, SMR = standardized mortality ratio. 235

TABLE 8-9  Cancers of the Central Nervous System 236 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Polednak and Frome, Y-12 uranium-processing plant, Oak 18,869 32 33.83 95 NS 1981 Ridge, TN Checkoway et al., Y-12 uranium-fabrication plant, Oak 6,781 14 NR 180 98-302 1988 Ridge, TN (comparison with US white men) Frome et al., 1990 Y-12, K-25 uranium-enrichment 28,008 69 59.57 116 NS plant, research laboratory, Oak Ridge, TN Loomis and Wolf, Y-12 uranium-fabrication plant, Oak 10,597 20 NR 129 79-200 1996 Ridge, TN Frome et al., 1997 All four plants, Oak Ridge, TN 106,020 151 (brain only) NR 109 NS (white men) Hadjimichael et al., Nuclear-fuel fabricating plant, CT 2,613 4 1.7 240 65-615 1983 (men) Cragle et al., 1988 Nuclear-fuels production plant, 9,860 2 (hourly) 8.40 (hourly) 23 (hourly) p < 0.05 Savannah, SC 4 (salaried) 3.77 (salaried) 106 (salaried) NS 1 (both) 0.64 (both) 156 (both) NS Beral et al., 1988 Atomic Weapons Establishment, UK 22,552 3 9.36 32 p < 0.05 (employees with radiation records) Ritz, 1999 Uranium-processing plant, OH 4,014 12 9.66 124 64-217 Dupree-Ellis et al., Uranium-processing plant, St Louis, 2,514 12 NR 157 84-264 2000 MO

Ritz et al., 2000 Rocketdyne/Atomics International 2,297 6 4.6 131 48-284 plant, CA Boice et al., 2006 Rocketdyne/Atomics International 5,801 17 NR 115 67-183 plant, CA McGeoghegan and Capenhurst uranium-enrichment 12,540 7 deaths (50 y) 5.04 deaths 139 NS Binks, 2000a plant, Cheshire, UK (radiation 4 cases (20 y) 3.89 cases (SIR, 103) NS workers) McGeoghegan and Springfields uranium-production 19,454 18 deaths (50 y) 27.03 deaths 67 NS Binks, 2000b plant, Lancashire, UK (radiation 12 cases (20 y) 18.76 cases (SIR, 64) NS workers) Studies of Depleted-Uranium–Exposed Persons Macfarlane et al., 2003 Gulf War veterans, UK 51,721 21 cases 25 cases (IRR, 0.83) 0.46-1.48 (IRR, 1.08 adjusted++) 0.44-2.65 Gustavsson et al., Swedish UN services personnel in 9,188 3 cases 2.6 cases (SIR, 120) 20-340 2004 Balkans Storm et al., 2006 Danish veterans deployed to Balkans 14,012 9 cases NR (SIR, 120) 50-220 Studies of Environmental Exposures to Uranium Boice et al., 2003a Residents of municipalities near two 16,772 3 cases 6.7 cases (SIR, 45) 9-130 former nuclear-material processing plants, PA Boice et al., 2003b County residents near two former 443,799 779 deaths NR (RR, 0.96) 0.88-1.04 nuclear-material processing plants, PA Boice et al., 2003c Residents near former uranium milling 12,455 24 deaths NR (RR, 0.92) 0.6-1.4 and mining site, TX NOTE: CI = confidence interval, IRR = incidence rate ratio, NR = not reported, NS = not significant, RR = relative risk, SIR = standardized incidence ratio, SMR = standardized mortality ratio, ++ = adjusted for smoking and alcohol consumption. 237

TABLE 8-10  Stomach Cancer 238 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Waxweiler et al., 1983 Uranium mills, Colorado Plateau 2,002 3 7.5 40 8-117 Polednak and Frome, Y-12 uranium-processing plant, Oak 18,869 53 72.33 73 NS 1981 Ridge, TN Checkoway et al., 1988 Y-12 uranium-fabrication plant, Oak 6,781 5 NR 57 19-133 Ridge, TN (comparison with US white men) Frome et al., 1990 Y-12, K-25 uranium-enrichment 28,008 93 119.92 78 NS plant, research laboratory, Oak Ridge, TN Loomis and Wolf, 1996 Y-12 uranium-fabrication plant, Oak 10,597 12 NR 64 33-112 Ridge, TN Frome et al., 1997 All four plants, Oak Ridge, TN 106,020 176 NR 73 NS (white men) Dupree et al., 1987 Uranium-processing plant, Buffalo, 995 7 4.2 165 66-339 NY Brown and Bloom, 1987 Uranium-enrichment plant, OH 5,773 10 5.9 169 NS Cragle et al., 1988 Nuclear-fuels production plant, 9,860 5 (hourly) 7.38 (hourly) 68 (hourly) NS Savannah, SC 2 (salaried) 4.15 (salaried) 48 (salaried) NS 0 (both) 0.64 (both) 0 (both) NS Beral et al., 1988 Atomic Weapons Establishment, UK 22,552 24 35.78 67 p < 0.05 (employees with radiation records) Ritz, 1999 Uranium-processing plant, OH 4,014 15 11.18 134 75-221 Dupree-Ellis et al., 2000 Uranium-processing plant, St Louis, 2,514 4 NR 38 12-89 MO

Ritz et al., 2000 Rocketdyne/Atomics International 2,297 6 5.07 118 43-257 plant, CA Boice et al., 2006 Rocketdyne/Atomics International 5,801 21 NR 117 73-179 plant, CA McGeoghegan and Binks, Capenhurst uranium-enrichment 12,540 15 deaths (50 y) 16.61 deaths 90 NS 2000a plant, Cheshire, UK (radiation 13 cases (20 y) 13.94 cases (SIR, 93) NS workers) McGeoghegan and Binks, Springfields uranium-production 19,454 92 deaths (50 y) 99.95 deaths 92 NS 2000b plant, Lancashire, UK (radiation 56 cases (20 y) 73.90 cases (SIR, 76) p < 0.05 workers) Study of Depleted-Uranium–Exposed Persons Storm et al., 2006 Danish veterans deployed to Balkans 14,012 2 cases NR (SIR, 160) 20-560 Studies of Environmental Exposures to Uranium Boice et al., 2003a Residents of municipalities near two 16,772 10 cases 9.5 cases (SIR, 105) 50-193 former nuclear-material processing plants, PA Boice et al., 2003b County residents near two former 443,799 2,203 deaths NR (RR, 1.00) 0.95-1.06 nuclear-material processing plants, PA Boice et al., 2003c Residents near former uranium 12,455 72 deaths NR (RR, 1.08) 0.8-1.4 milling and mining site, TX Auvinen et al., 2005 Drinking well-water study, Finland Case- NA NA (HR, 0.69) 0.37-1.27 control (HR, 0.76 0.48-1.21 study: 88 per Bq/L for stomach- uranium) cancer cases, 274 controls NOTE: CI = confidence interval, HR = hazard ratio, NA = not applicable (case-control study), NR = not reported, NS = not significant, RR = relative risk, 239 SIR = standardized incidence ratio, SMR = standardized mortality ratio.

TABLE 8-11 Prostatic Cancer 240 No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Polednak and Frome, Uranium mills, Colorado Plateau 1,485 49 60.71 81 NS 1981 Waxweiler et al., 1983 Uranium mills, Colorado Plateau 2,002 6 8.5 71 26-154 Checkoway et al., 1988 Y-12 uranium-fabrication plant, 6,781 7 NR 92 37-190 Oak Ridge, TN (comparison with US white men) Frome et al., 1990 Y-12, K-25 uranium-enrichment 28,008 150 141.96 106 NS plant, research laboratory, Oak Ridge, TN Loomis and Wolf, 1996 Y-12 uranium-fabrication plant, 10,597 36 NR 131 91-181 Oak Ridge, TN Frome et al., 1997 All four plants, Oak Ridge, TN 106,020 319 NR 101 NS (white men) Cragle et al., 1988 Nuclear-fuels production plant, 9,860 3 (hourly) 5.00 (hourly) 60 (hourly) NS Savannah, SC 5 (salaried) 3.69 (salaried) 135 (salaried) NS 0 (both) 0.47 (both) 0 (both) NS Beral et al., 1988 Atomic Weapons Establishment, 22,552 20 14.36 139 NS UK (employees with radiation records) Ritz, 1999 Uranium-processing plant, OH 4,014 25 17.42 144 93-212 Dupree-Ellis et al., 2000 Uranium-processing plant, St 2,514 23 NR 115 74-170 Louis, MO Ritz et al., 2000 Rocketdyne/Atomics International 2,297 7 9.59 73 29-150 plant, CA

Boice et al., 2006 Rocketdyne/Atomics International 5,801 37 NR 93 66-129 plant, CA McGeoghegan and Binks, Capenhurst uranium-enrichment 12,540 11 deaths (50 y) 13.91 deaths 79 NS 2000a plant, Cheshire, UK (radiation 9 cases (20 y) 16.72 cases (SIR, 54) NS workers) McGeoghegan and Binks, Sprinfields uranium-production 19,454 68 deaths (50 y) 76.71 deaths 89 NS 2000b plant, Lancashire, UK (radiation 69 cases (20 y) 89.79 cases (SIR, 77) p < 0.05 workers) Studies of Depleted-Uranium–Exposed Persons Macfarlane et al., 2003 Swedish UN services personnel 51,721 7 cases 6 cases (IRR, 1.15) 0.39-3.41 in Balkans (IRR, 1.03 adj++) 0.23-4.62 Storm et al., 2006 Danish veterans deployed to 14,012 1 cases NR (SIR, 60) 0-330 Balkans Studies of Environmental Exposures to Uranium Boice et al., 2003a Residents of municipalities near 16,772 81 cases 83.2 cases (SIR, 97) 77-121 two former nuclear-material processing plants, PA Boice et al., 2003b County residents near two former 443,799 2,181 deaths NR (RR, 0.95) 0.9-1.0 nuclear-material processing plants, PA Boice et al., 2003c Residents near former uranium 12,455 76 deaths NR (RR, 0.95) 0.7-1.2 milling and mining site, TX NOTE: CI = confidence interval, IRR = incidence rate ratio, NR = not reported, NS = not significant, RR = relative risk, SIR = standardized incidence ratio, SMR = standardized mortality ratio, ++ = adjusted for smoking and alcohol consumption. 241

242 TABLE 8-12 Testicular Cancer No. Observed No. Expected Study Cohort/Study Site Population Cases/Deaths Cases/Deaths SMR 95% CI Studies of Uranium Processors Dupree-Ellis et al., 2000 Uranium-processing plant, St 2,514 1 NR 93 5-408 Louis, MO Ritz, 1999 Uranium-processing plant, 4,014 1 1.46 67 1-374 OH Frome et al., 1997 All four plants, Oak Ridge, 106,020 18 NR 72 NS TN (white men) Beral et al., 1988 Atomic Weapons 22,552 1 1.72 58 NS Establishment, UK Pinkerton et al., 2004 Uranium mills, Colorado 1,485 15 19.67 76 43-126 Plateau Polednak and Frome, Y-12 uranium-processing 18,869 4 7.29 55 NS 1981 plant, Oak Ridge, TN Frome et al., 1990 Y-12, K-25 uranium- 28,008 7 9.61 73 NS enrichment plant, research laboratory, Oak Ridge, TN Loomis and Wolf, 1996 Y-12 uranium-fabrication 10,597 0 NR 0 0-159 plant, Oak Ridge, TN

McGeoghegan and Binks, Capenhurst uranium- 12,540 0 deaths (50 yrs) 0.54 death 0 NS 2000a enrichment plant, Cheshire, 2 cases (20 yrs) 2.08 cases (SIR, 96) NS UK (radiation workers) McGeoghegan and Binks, Springfields uranium- 19,454 2 deaths (50 yrs) 3.29 deaths 61 NS 2000b production plant, Lancashire, 8 cases (20 yrs) 8.70 cases (SIR, 92) NS UK (radiation workers) Boice et al., 2006 Rocketdyne/Atomics 5,801 1 NR 69 2-382 International plant, CA Studies of Depleted-Uranium–Exposed Persons Macfarlane et al., 2003 Gulf War veterans, UK 51,721 39 cases 46 cases (IRR, 0.83) 0.54-1.28 (IRR, 1.17 adj++) 0.61-2.23 Gustavsson et al., 2004 Swedish UN services 9,188 8 cases 4.3 cases (SIR, 190) 80-370 personnel in Balkans Storm et al., 2006 Danish veterans deployed to 14,012 24 cases NR (SIR, 120) 80-180 Balkans Study of Environmental Exposures to Uranium Boice et al., 2003a Residents of municipalities 16,772 2 cases 2.11 cases (SIR, 95) 11-342 near two former nuclear- material processing plants, PA NOTE: CI = confidence interval, IRR = incidence rate ratio, NR = not reported, NS = not significant, SIR = standardized incidence ratio, SMR = standardized mortality ratio, ++ = adjusted for smoking and alcohol consumption. 243

244 TABLE 8-13 Mortality from Nonmalignant Renal Disease No. No. Observed Expected Study Cohort/Study Site Population Deaths Deaths SMR (95% CI) Disease Classification Waxweiler et al., 1983 Uranium mills, 2,002 6 3.6 167 (60-353) ICD-7 592-594 Colorado Plateau Pinkerton et al., 2004 Uranium mills, 1,484 8 5.91 135 (58-267) ICD-9 582-583, 585-587 Colorado Plateau Ritz, 1999 Uranium-processing plant, 4,014 3 14.25 21 (4-129) ICDA-8 580-629 Fernald, OH Checkoway et al., 1988 Y-12 uranium-materials 6,781 8 11.1 72 (31-142) ICD-8 580-629 fabrication plant, Oak Ridge, TN Frome et al., 1990 Y-12, K-25 uranium-enrichment 28,008 52 52.65 99 (71-126)a ICDA-8 582 facilities, research laboratory, Oak Ridge, TN Polednak and Frome, Y-12 uranium-processing plant, 18,869 30 39.14 77 (45-109)a Chronic nephritis 1981 Oak Ridge, TN Frome et al., 1997 Four uranium-processing plants, 27,982 270 325.3b 83 (NS)c ICDA-8 580-629 Oak Ridge, TN Ritz et al., 2000 Rocketdyne/Atomics International 2,297 5 6.44 78 (25-181) ICD-8 580-629

Boice et al., 2006 Rocketdyne/Atomics International 5,801 12 NR 118 (61-206) Nephritis and nephrosis Dupree-Ellis et al., 2000 Mallinckrodt Chemical works 2,514 6 3.19 188 (75-381) ICD-8 582 plant, St. Louis, MO McGeoghegan and Binks, British Nuclear Fuels plant, 19,454 28 48.94 57 (p < 0.01) Genitourinary diseases 2000b Springfields site McGeoghegan and Binks, British Nuclear Fuels plant, 2,628 5 4.63 108 (NS) Genitourinary diseases 2001 Chapelcross site McGeoghegan and Binks, British Nuclear Fuels plant, 12,543 7 7.13   98 (NS) Genitourinary diseases 2000a Capenhurst Cragle et al., 1988 Nuclear-fuels production facility, 9,860 4 10.27 39 (10-96)d ICDA-8 580-629 Savannah River Plant, SC NOTE: CI = confidence interval, ICD = International Classification of Diseases, ICDA = International Classification of Diseases, Adapted, NR = not reported, SMR = standardized mortality ratio. aCI calculated by Committee on Health Effects Associated with Exposure During the Gulf War; not stated in study (IOM, 2000). bNumber of expected deaths calculated by committee; not stated in study (Frome, 1997). cSMR for white men only. dSMR for hourly workers only. 245

TABLE 8-14  Nonmalignant Renal Disease—Morbidity Risk 246 Health Outcomes or Study Population Exposure Outcome Measures Results Adjustments Gulf War Veterans Depleted-Uranium Surveillance Study McDiarmid et al., 29 exposed Gulf War Exposure to DU by Serum creatinine, No statistically significant Stratification 2000 veterans exposed to friendly fire, may have beta-2-microglobulin, differences in renal at median into DU during friendly-fire inhaled or ingested retinol-binding protein, function between low- and low and high Case series incidents in February airborne DU particles, serum uric acid, urinary high-exposure groups result groups 1991, 38 unexposed experienced wound creatinine, urinary veterans; examined in contamination by DU; protein March-June 1997, 7 years assessed urinary, seminal after first exposure uranium concentration McDiarmid et al., 50 exposed Gulf War Exposure to DU by Same as in McDiarmid No statistically significant 2001 veterans divided into low- friendly fire, may have et al., 2000 differences in renal uranium, high-uranium inhaled or ingested function between low- and Case series groups; examined in airborne DU particles, high-uranium-exposure March-July 1999, 8 years experienced wound groups after first exposure contamination by DU; assessed urinary uranium Mean values in normal concentration range McDiarmid et al., 39 Gulf War veterans Same exposure as in Serum calcium, serum Renal-function measures 2004 exposed to DU during McDiarmid et al., 2001 phosphate, urinary (normal range): friendly-fire incidents in calcium, urinary Serum creatinine (0.5-1.1 Case series February 1991; followup phosphate, measures in mg/dL); low-uranium 1994-2001 McDiarmid et al., 2000 group, 0.95 ± 0.03; high- uranium group, 0.85 ± 0.03; p = 0.03

Urinary retinol-binding protein (3-610 µg/g of creatinine); low-uranium group, 46.13 ± 3.46; high- uranium group, 65.68 ± 11.11; p = 0.06 Urinary total protein (0- 92.8 mg/g of creatinine); low-uranium group, 54.63 ± 4.94; high-uranium group, 78.69 ± 10.52; p = 0.01 McDiarmid et al., 32 Gulf War veterans Same exposure as in Urinary IAP, NAG, Renal-function measures 2006 exposed to DU during McDiarmid et al., 2001 urinary microalbumin, (normal range): friendly-fire incidents; measures in McDiarmid Serum PO4 (2.7-4.5 mg/ Case series examined in April-July et al., 2004 dL); low-uranium group, 2003, 12 years after first 3.75 ± 0.11; high-uranium exposure group, 4.11 ± 0.12; p = 0.03 No statistically significant differences between low- and high-uranium groups for other renal measures Continued 247

TABLE 8-14  Continued 248 Health Outcomes or Study Population Exposure Outcome Measures Results Adjustments McDiarmid et al., 34 Gulf War veterans Exposure to DU by Creatinine clearance, Renal-function measures 2007 exposed to DU during friendly fire, may have urinary glucose, (normal range): friendly-fire incidents in inhaled or ingested measures in McDiarmid Case series 1991; examined in April- airborne DU particles, et al., 2006 Mean serum uric acid June 2005, 14 years after experienced wound (3.4-7 mg/dL); low- first exposure contamination by DU; cumulative-uranium assessed urinary uranium group, 6.19 ± 0.26; concentration, both current high-cumulative-uranium and cumulative exposure group, 5.22 ± 0.46; measures reported p = 0.03 No statistically significant differences between high- and low-urinary-uranium exposure groups for other renal measures Drinking-Water and Residential Exposure Kurttio et al., 2002 325 people in Finland Median drinking-water Urinary, serum calcium, Statistically significant Uranium who obtain drinking water uranium concentration, 28 phosphate, glucose, association between exposure Cross-sectional from drilled wells used an μg/L (interquartile albumin, creatinine, uranium exposure from adjusted for average of 13 years range, 6-135 μg/L; beta-2-microglobulin drinking water and age, sex, and maximum, 1,920 (μg/L) as biomarkers of renal tubular function: calcium body mass function fractional excretion, index Median urinary uranium p < 0.05 for all types concentration, 13 ng/ of exposure; phosphate mmol of creatinine (2-75) fractional excretion, p = 0.03 for urinary uranium

Median daily uranium No association between intake, 39 μg (7-224) uranium exposure and glomerular function markers or remaining tubular markers Kurttio et al., 2006a 95 men, 98 women in Median drinking-water Various enzymes, Indicators of renal Sex, age (same population as Finland who obtain uranium concentration, 25 creatinine, calcium, function within reference (linear/ Kurttio et al., 2002) drinking water from μg/L (interquartile phosphate, glucose as values; uranium in urine, quadratic), drilled wells an average of range, 5-148 μg/L; indicators of renal- hair, nails, drinking body mass Cross-sectional 16 years maximum, 1,500 μg/L) cell toxicity, renal water not statistically index, dysfunction significantly associated smoking, use Median drinking-water with indicators of cell of analgesics uranium concentration, 25 Exposure assessment: toxicity, renal proximal μg/L (interquartile uranium in drinking tubular function, range, 5-148 μg/L; water, hair, nails, urine glomerular function maximum, 1,500 μg/L) Statistically significant association between cumulative uranium intake and glucose excretion (p = 0.02), between uranium exposure and increased blood pressure (diastolic, p = 0.01; systolic, p = 0.07) Continued 249

TABLE 8-14  Continued 250 Health Outcomes or Study Population Exposure Outcome Measures Results Adjustments Pinney et al., 2003 8,496 people in FMMP; Residential proximity (less Renal disease All renal disease: SPR, Age, sex comparison rates NHIS than 2 miles) to Fernald 215 (99% CI, 186-248) Cohort (and NHANES, not listed) uranium-processing plant in direction of All bladder disease: SPR, groundwater runoff or 132 (99% CI, 111-156) possible well or cistern contamination in January Kidney stones: SPR, 398 1952-December 1984 (99% CI, 336-468) Renal infections: SPR, 71 (99% CI, 46-106) Other kidney trouble, NEC: SPR, 111 (99% CI, 68-172) Chronic nephritis: SPR, 203 (99% CI, 76-435) Bladder infections: SPR, 59 (99% CI, 40-84) Other bladder disorders: SPR, 17 (99% CI, 7-33) “Remaining kidney disorders”: SPR, 196 (99% CI, 73-419)

“Remaining bladder disorders”: SPR, 809 (99% CI, 663-977) Occupational Exposure Boiano et al., 1989 NIOSH report on 146 Self-reported exposure Serum: beta-2- No associations between Smoking (70%) of 208 eligible incidents, job history, microglobulin, retinol- glomerular and tubular Cross-sectional long-term employees at assessed urinary-uranium binding protein, markers and measures of FFMPC after releases of data albumin, total protein, uranium exposure uranium oxide from dust creatinine collectors in November- December 1984 Urine: uranium, beta- 2-microglobulin, retinol-binding protein, NAG, gamma-glutamyl transpeptidase, alanine aminopeptidase, creatinine, total protein, albumin Shawky et al., 2002 86 processors at three sites Air uranium Renal-function Mean urinary uranium in Egypt, 13 of whom also concentration, 22.6 × 10–7 indicators: serum concentration, 17.8 μg/L; Cross-sectional participated in urinary- -11.1 × 10–5 Bq/cm3 creatinine, urea, urinary in subgroup from ore- uranium analysis uranium crushing site, 29.2 μg/L Exposure, 1-80 μSv/h Uranium excretion more than 20 times occupational-exposure decision level NOTE: BDI = Beck Depression Inventory, CI = confidence interval, DU = depleted uranium, FFMPC = Fernald Feed Materials Production Center, FMMP = Fernald Medical Monitoring Program, IAP = intestinal alkaline phosphatase, NAG = urinary N-acetyl-beta-glucominidase, NEC = not elsewhere clas- sified, NHANES = National Health and Nutrition Examination Survey, NHIS = National Health Interview Survey, NIOSH = National Institute for Occupational 251 Safety and Health, SPR = standardized prevalence ratio.

252 TABLE 8-15 Mortality from Nonmalignant Respiratory Disease No. No. Observed Expected SMR Study Cohort/Study Site Population Deaths Deaths (95% CI) Disease Classification Waxweiler et al., 1983 Uranium mills, 2,002 55 33.7 163 (123-212) ICD-7 470-527 Colorado Plateau Pinkerton et al., 2004 Uranium mills, 1,484 100 70.16 143 (116-173) ICD-9 460-519 Colorado Plateau State rates 94 79.32 1.9 (0.96-1.45) Ritz, 1999 Uranium-processing plant, OH 4,014 53 79.78 66 (50-87) ICDA-8 460-519 Checkoway et al., 1988 Y-12 uranium-materials 6,781 37 48.9 76 (53-104) ICD-8 460-519 fabrication plant, Oak Ridge, TN Frome et al., 1990 Y-12, K-25 uranium-enrichment 28,008 792 634.11 125 (117-133)a ICDA-8 460-519 facilities, research laboratory, Oak Ridge, TN Polednak and Frome, Y-12 uranium-processing plant, 18,869 340 310.11 122 (110-136)b Diseases of respiratory 1981 Oak Ridge, TN system Frome et al., 1997 Four uranium-processing plants, 27,982 1,568 1,400c 112 (NS) ICDA-8 460-519 Oak Ridge, TN

Ritz et al., 2000 Rocketdyne/Atomics International 2,297 30 40.26 75 (50-106) ICD-8 460-519 Boice et al., 2006 Rocketdyne/Atomics International 5,801 68 NR 67 (52-84) ICD-9 460-479, 488-519 Dupree-Ellis et al., 2000 Mallinckrodt Chemical works 2,514 64 80 80 (62-101) ICD-8 460-519 plant, St. Louis, MO McGeoghegan and Binks, British Nuclear Fuels plant, 2,628 22 45.43 48 (p < 0.01)d Diseases of respiratory 2001 Chapelcross site system McGeoghegan and Binks, British Nuclear Fuels plant, 19,454 379 481.09 79 (p = 0.02) Diseases of respiratory 2000b Springfields site system McGeoghegan and Binks, British Nuclear Fuels plant, 12,543 53 75.62 70 (p = 0.008) Diseases of respiratory 2000a Capenhurst system Cragle et al., 1988 Nuclear-fuels production facility, 9,860 17 41.02 41 (24-66)e ICDA-8 460-519 Savannah River Plant, SC NOTE: CI = confidence interval, ICD = International Classification of Diseases, ICDA = International Classification of Diseases, Adapted, NR = not reported, NS = not significant, SMR = standardized mortality ratio. aConfidence interval calculated by Committee on Health Effects Associated with Exposure During the Gulf War; not stated in study (IOM, 2000). bCorrected for incomplete ascertainment of deaths and for deaths of unknown cause. cNumber of expected deaths calculated by committee; not stated in study. dSMR based on population rates for England and Wales. eListed SMR for hourly workers only. 253

254 TABLE 8-16   Nonmalignant Respiratory Disease—Morbidity Risk Study Population Exposure Outcomes Results Adjustments Comments Boiano et al., 146 (70%) of 208 Self-reported exposure Lung function, Ratio of FEV1 to Smoking Limitations 1989 eligible long-term incidents, job history, symptoms FVC associated with in exposure employees at FFMPC assessed urinary- job-history–derived partly based on Cross-sectional after releases of uranium data uranium-exposure recall; crude, uranium oxide from index; other imprecise dust collectors in spirometry results not exposure November-December associated; shortness categories (low, 1984 of breath significantly medium, high) associated with self- reported uranium- exposure incidents Pinney et al., 8,464 people in Residential proximity Self-reported Asthma: Age, sex Study 2003 FMMP; comparison (less than 2 miles) to symptoms of chronic SPR, 85 (99% CI, questionnaires rates NHIS (and FFMPC in direction bronchitis, asthma, 73-98) not directly Cohort NHANES, not listed) of groundwater runoff emphysema Chronic bronchitis: comparable; or possible well or SPR, 19 (99% CI, FMMP cistern contamination 14-24) self-selected in January 1952- Emphysema: volunteer December 1984 SPR, 61 (99% CI, group 41-86) NOTE: CI = confidence interval, FEV1 = forced expiratory volume in 1 second, FFMPC = Fernald Feed Materials Production Center, FMMP = Fernald Medical Monitoring Program, FVC = forced vital capacity, NHANES = National Health and Nutrition Examination Survey, NHIS = National Health Interview Study, SPR = standardized prevalence ratio.

TABLE 8-17  Mortality from Neurologic Disease No. No. Observed Expected Study Cohort/Study Site Population Deaths Deaths SMR (95% CI) Disease Classification Frome et al., 1990 Y-12, K-25 uranium-enrichment 28,008 76 81.76 93 (71-115)a ICDA-8 320-389 facilities, research laboratory, Oak Ridge, TN Polednak and Frome, Y-12 uranium-processing plant, Oak 18,869 38 49.3 77 (49-105)a Diseases of nervous 1981 Ridge, TN system Dupree-Ellis et al., 2000 Mallinckrodt Chemical works plant, St.   2,514 11 13.41 82 (43-141) ICD-8 320-389 Louis, MO Frome et al., 1997 Four uranium-processing plants, Oak 27,982 148 211.43b 70 (NS) ICDA-8 320-329 Ridge, TN Boice et al., 2006 Rocketdyne/Atomics International   5,801 30 NR 96 (65-137) ICD-9 320-389 McGeoghegan and Binks, British Nuclear Fuels plant, 19,454 40 58.25 69 (p < 0.05) Diseases of nervous, 2000b Springfields site sense organs McGeoghegan and Binks, British Nuclear Fuels plant, 12,543 10 10.25 98 (NS) Diseases of nervous, 2000a Capenhurst sense organs McGeoghegan and Binks, British Nuclear Fuels plant, Chapelcross   2,628 5 7.06 71 (NS) Diseases of nervous, 2001 site sense organs Cragle et al., 1988 Nuclear-fuels production facility,   9,860 8 9.92 81 (NS)c ICDA-8 320-389 Savannah River plant, SC NOTE: CI = confidence interval, ICD = International Classification of Diseases, ICDA = International Classification of Diseases, Adapted, NR = not reported, NS = not significant, SMR = standardized mortality ratio. aConfidence interval calculated by Committee on Health Effects Associated with Exposure During the Gulf War; not stated in study (IOM, 2000). bNumber of expected deaths calculated by committee; not stated in study. cListed SMR for hourly workers only. 255

TABLE 8-18  Reproductive and Developmental Effects 256 Outcomes or Study Population Exposure Outcome Measures Results Adjustments McDiarmid et al., 29 exposed Gulf War Exposure to DU by Neuroendocrine Prolactin, 2.1-17.7 Stratification at median 2000 veterans exposed to friendly fire, may measures: FSH, LH, µg/g of creatinine; low into low-, high-result DU during friendly-fire have inhaled, ingested prolactin, testosterone; urinary uranium, 1.66; groups Case series incidents in February airborne DU particles, semen characteristics high urinary uranium, 1991, 38 unexposed experienced wound 12.47; p = 0.04 veterans, examined in contamination by March-June 1997 DU; assessed urinary and seminal uranium concentration McDiarmid et al., 50 exposed Gulf War Exposure to DU by Neuroendocrine No statistically Prescription 2001 veterans divided into friendly fire, may measures: FSH, LH, significant differences psychotropic-, low-uranium and have inhaled, ingested TSH, free thyroxine, in FSH, LH, prolactin, antidepressant-drug use Case series high-uranium groups, airborne DU particles, prolactin, testosterone; testosterone, thyroid examined in March- experienced wound semen characteristics measures between July 1999 contamination by low- and high-urinary- DU; assessed urinary uranium groups uranium concentration Semen characteristics: Total sperm count [≥40 million] Low urinary uranium, 286.6 ± 44.8 million; high urinary uranium, 583.5 ± 106.1 million; p = 0.02

Total progressive sperm (WHO Class A and B) [≥20 million] Low urinary uranium, 108.2 ± 19.2 million; high urinary uranium, 220.9 ± 44.0 million; p = 0.03 Total rapid progressive sperm (WHO Class A) [≥10 million] Low urinary uranium, 81.3 ± 15.4 million; high urinary uranium, 155.5 ± 31.1 million; p = 0.04 McDiarmid et al., 39 Gulf War veterans Same exposure as in Neuroendocrine No statistically 2004 exposed to DU during McDiarmid et al., 2001 measures: FSH, LH, significant differences friendly-fire incidents prolactin, TSH, free in reproductive-health Case series in February 1991, thyroxine, testosterone; measures examined in April-July semen characteristics 2001, followup 1994- 2001 McDiarmid et al., 32 Gulf War veterans Same exposure as in Neuroendocrine No statistically 2006 exposed to DU during McDiarmid et al., 2001 measures: FSH, LH, significant differences friendly-fire incidents, prolactin, TSH, free in reproductive-health Case series examined in April-July thyroxine, testosterone; measures 2003 semen characteristics Continued 257

TABLE 8-18  Continued 258 Outcomes or Study Population Exposure Outcome Measures Results Adjustments McDiarmid et al., 34 Gulf War veterans Exposure to DU by Neuroendocrine No statistically 2007 exposed to DU during friendly fire, may measures, semen significant differences friendly-fire incidents, have inhaled, ingested characteristics in reproductive-health Case series examined in April-June airborne DU particles, measures 2005 experienced wound contamination by DU; assessed urinary uranium concentration; both current and cumulative exposure measures reported Sumanovic- All liveborn, stillborn Living in western Major congenital 1995 cohort: Glamuzina et al., neonates in Maternity Herzegovina after malformations Major malformations 2003 Ward of Mostar military activities in 40 of 1,853 neonates University Hospital of (2.16%; 95% CI, 1.49- Pre-post western Herzegovina, 2.82%) comparison part of Bosnia and Herzegovina 2000 cohort: immediately (1995) Major malformations and 5 years after (2000) in 33 of 1,463 neonates 1991-1995 military (2.26%; 95% CI, 1.50- activities 3.01%) NOTE: BDI = Beck Depression Inventory, CI = confidence interval, DU = depleted uranium, FSH = follicle-stimulating hormone, LH = luteinizing hormone, TSH = thyroid-stimulating hormone, WHO = World Health Organization.

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conclusions 261 McDiarmid, M. A., F. J. Hooper, K. Squibb, K. McPhaul, S. M. Engelhardt, R. Kane, R. DiPino, and M. Kabat. 2002. Health effects and biological monitoring results of Gulf War veterans exposed to depleted uranium. Military Medicine 167(2 Suppl):123-124. McDiarmid, M. A., S. Engelhardt, M. Oliver, P. Gucer, P. D. Wilson, R. Kane, M. Kabat, B. Kaup, L. Anderson, D. Hoover, L. Brown, B. Handwerger, R. J. Albertini, D. Jacobson-Kram, C. D. Thorne, and K. S. Squibb. 2004. Health effects of depleted uranium on exposed Gulf War veter- ans: A 10-year follow-up. Journal of Toxicology and Environmental Health A 67(4):277-296. McDiarmid, M. A., S. M. Engelhardt, M. Oliver, P. Gucer, P. D. Wilson, R. Kane, M. Kabat, B. Kaup, L. Anderson, D. Hoover, L. Brown, R. J. Albertini, R. Gudi, D. Jacobson-Kram, C. D. Thorne, and K. S. Squibb. 2006. Biological monitoring and surveillance results of Gulf War I veterans exposed to depleted uranium. International Archives of Occupational and Environmental Health 79(1):11-21. McDiarmid, M. A., S. M. Engelhardt, M. Oliver, P. Gucer, P. D. Wilson, R. Kane, A. Cernich, B. Kaup, L. Anderson, D. Hoover, L. Brown, R. Albertini, R. Gudi, D. Jacobson-Kram, and K. S. Squibb. 2007. Health surveillance of Gulf War I veterans exposed to depleted uranium: Updat- ing the cohort. Health Physics 93(1):60-73. McGeoghegan, D., and K. Binks. 2000a. The mortality and cancer morbidity experience of workers at the Capenhurst uranium enrichment facility 1946-95. Journal of Radiological Protection 20(4):381-401. ———. 2000b. The mortality and cancer morbidity experience of workers at the Springfields uranium production facility, 1946-95. Journal of Radiological Protection 20(2):111-137. ———. 2001. The mortality and cancer morbidity experience of employees at the Chapelcross plant of British Nuclear Fuels plc, 1955-95. Journal of Radiological Protection 21(3):221-250. Miller, A. C., C. Bonait-Pellie, R. F. Merlot, J. Michel, M. Stewart, and P. D. Lison. 2005. Leukemic transformation of hematopoietic cells in mice internally exposed to depleted uranium. Molecular and Cellular Biochemistry 279(1-2):97-104. Mitchel, R. E. J., J. S. Jackson, and B. Heinmiller. 1999. Inhaled uranium ore dust and lung cancer risk in rats. Health Physics 76(2):145-155. NRC (National Research Council). 2008. Review of toxicologic and radiologic risks to military personnel from exposure to depleted uranium during and after combat. Washington, DC: The National Academies Press. Nuccetelli, C., M. Grandolfo, and S. Risica. 2005. Depleted uranium: Possible health effects and experimental issues. Microchemical Journal 79(1-2):331-335. Pinkerton, L. E., T. F. Bloom, M. J. Hein, and E. M. Ward. 2004. Mortality among a cohort of uranium mill workers: An update. Occupational and Environmental Medicine 61(1):57-64. Pinney, S. M., R. W. Freyberg, G. E. Levine, D. E. Brannen, L. S. Mark, J. M. Nasuta, C. D. Tebbe, J. M. Buckholz, and R. Wones. 2003. Health effects in community residents near a uranium plant at Fernald, Ohio, USA. International Journal of Occupational Medicine and Environmental Health 16(2):139-153. Polednak, A. P., and E. L. Frome. 1981. Mortality among men employed between 1943 and 1947 at a uranium-processing plant. Journal of Occupational Medicine 23(3):169-178. Richardson, D. B., and S. Wing. 2006. Lung cancer mortality among workers at a nuclear materials fabrication plant. American Journal of Industrial Medicine 49(2):102-111. Ritz, B. 1999. Radiation exposure and cancer mortality in uranium processing workers. Epidemiol- ogy 10(5):531-538. Ritz, B., H. Morgenstern, D. Crawford-Brown, and B. Young. 2000. The effects of internal radiation exposure on cancer mortality in nuclear workers at Rocketdyne/Atomics International. Environ- mental Health Perspectives 108(8):743-751. Shawky, S., H. A. Amer, M. I. Hussein, Z. el-Mahdy, and M. Mustafa. 2002. Uranium bioassay and radioactive dust measurements at some uranium processing sites in Egypt—health effects. Journal of Environmental Monitoring 4(4):588-591.

262 updated literature review of depleted uranium Stayner, L. T., T. Meinhardt, R. Lemen, D. Bayliss, R. Herrick, G. R. Reeve, A. B. Smith, and W. Halperin. 1985. A retrospective cohort mortality study of a phosphate fertilizer production facil- ity. Archives of Environmental Health 40(13):133-138. Storm, H. H., H. O. Jorgensen, A. M. Kejs, and G. Engholm. 2006. Depleted uranium and cancer in Danish Balkan veterans deployed 1992-2001. European Journal of Cancer 42(14):2355-2358. Sumanovic-Glamuzina, D., V. Saraga-Karacic, Z. Roncevic, A. Milanov, T. Bozic, and M. Boranic. 2003. Incidence of major congenital malformations in a region of Bosnia and Herzegovina al- legedly polluted with depleted uranium. Croatian Medical Journal 44(5):579-584. USACHPPM (U.S. Army Center for Health Promotion and Preventive Medicine). 2004. Capstone report: Depleted uranium aerosol doses and risks: Summary of U.S. Assessments. Fort Belvoir, VA: U.S. Army Heavy Metals Office, Chemical and Biological Defense Information Analysis Center. Wagoner, J. K., V. E. Archer, B. E. Carroll, D. A. Holaday, and P. A. Lawrence. 1964. Cancer mortality patterns among U.S. uranium miners and millers, 1950 through 1962. Journal of the National Cancer Institute 32(4):787-801. Waxweiler, R. J., V. E. Archer, R. J. Roscoe, A. Watanabe, and M. J. Thun. 1983. Mortality patterns among a retrospective cohort of uranium mill workers. In Epidemiology Applied to Health Physics, Proceedings of the Sixteenth Midyear Topical Meeting of the Health Physics Society, Albuquerque, New Mexico, January 9-13:428-435.

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The 1991 Persian Gulf War was considered a brief and successful military operation with few injuries and deaths. A large number of returning veterans, however, soon began reporting health problems that they believed to be associated with their service in the gulf. Under a Congressional mandate, the Institute of Medicine (IOM) is reviewing a wide array of biologic, chemical, and physical agents to determine if exposure to these agents may be responsible for the veterans' health problems. In a 2000 report, Gulf War and Health, Volume 1: Depleted Uranium, Sarin, Pyridostigmine Bromide, and Vaccines, the IOM concluded that there was not enough evidence to draw conclusions as to whether long-term health problems are associated with exposure to depleted uranium, a component of some military munitions and armor. In response to veterans' ongoing concerns and recent publications in the literature, IOM updated its 2000 report. In this most recent report, Gulf War and Health: Updated Literature Review of Depleted Uranium, the committee concluded that there is still not enough evidence to determine whether exposure to depleted uranium is associated with long-term health problems. The report was sponsored by the U.S. Department of Veterans Affairs.

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