Squibb, Katherine S. PhD; Gaitens, Joanna M. PhD; Engelhardt, Susan MS; Centeno, Jose A. PhD; Xu, Hanna MSc; Gray, Patrick PhD; McDiarmid, Melissa A. MD
The US Department of Veterans Affairs has established special programs to provide health care to veterans who may have been exposed to hazardous agents during their military service. Predicting the risk of long-term health effects from these exposures is often difficult due to a lack of accurate exposure information or a clear understanding of the routes of exposure. For this reason, medical surveillance of exposed populations is the best means by which to identify and manage potential health effects. The two programs discussed here are the Depleted Uranium (DU) Follow-Up Program, which began in 1993, shortly after the 1991 Gulf War, and the Toxic Embedded Fragment Surveillance Center (TEFSC), which was started in 2008 to observe veterans injured from improvised explosive devices in Iraq and Afghanistan and who possess retained embedded fragments. The purpose of the DU Follow-Up Program is to provide medical surveillance for DU-exposed veterans to identify adverse health effects associated with inhalation and ingestion exposures to DU oxides and also exposures resulting from tissue-embedded DU fragments. In response to lessons learned from the DU program regarding health risks associated with embedded materials, the TEFSC was established to build a registry for and follow the health history of veterans with retained embedded fragments of unknown chemical composition.
Although fragments embedded in soft tissues have long been thought to be relatively inert, recent evidence suggests that both systemic and local tissue effects can result from the release of metals and other compounds from certain types of embedded materials over time.1–5 Of particular relevance to the military are animal studies that have shown that embedded fragments of metals used in military munitions break down in situ, giving rise to systemic circulation and accumulation of metal ions in remote tissues such as kidneys, liver, bone, and brain.6–7 In humans, studies have shown that cobalt (Co) and chromium (Cr) are released from medical implants composed of these metals, giving rise to elevated concentrations of these metals in blood and urine.2,5 Elevated blood lead (Pb) concentrations have also been demonstrated in individuals with retained Pb bullets.3,4 In addition to tissue accumulation of the individual metals in military alloys, sarcomas have been shown to develop in animals in reaction to both DU and tungsten/nickel/cobalt (W/Ni/Co)–embedded fragments.8,9
In light of this evidence and because many US soldiers are returning from recent conflicts with retained embedded fragments, the DU and TEFSC surveillance programs are actively observing veterans to characterize potential long-term health effects of retained fragments. Results of these programs to date, which are summarized here, will be used to inform decisions regarding the removal of fragments for the prevention of future health problems.
Depleted Uranium Follow-Up Program
Natural uranium (U) is composed of three U isotopes, U234, U235, and U238, which differ in their abundance and radioactivity. Of the three isotopes, U234 has the highest specific radioactivity but is present in the lowest amount, whereas U238 is present in highest abundance but has a much lower specific activity. Depleted uranium, a man-made form of U, is created as a by-product of the U-enrichment process, in which U234 and U235 are removed for use as nuclear fuel, leaving U metal that is “depleted” of these two isotopes. The isotopic ratio of U235 to U238 in natural U, calculated on a percent-weight basis, is 0.72%, which is approximately 3.5 times higher than the U235:U238 isotopic ratio of DU, which is 0.20%. On the basis of the loss of U234 and U235 during the enrichment process, the radioactivity of DU is approximately 60% of the radioactivity of natural U.9
The hazardous nature of DU is due to both its radioactive and chemical properties,10–12 depending on routes of exposure and the health effects of interest. Depleted U decays primarily by high-energy, but poorly penetrating, alpha emissions, which therefore primarily affect tissue in close contact with DU-embedded fragments or insoluble DU oxides. Because of the lower radioactivity of DU versus natural U, calculated radiation doses are less than those for equal masses of natural U. Nevertheless, the chemical toxicity of DU and natural U are the same due to the chemical similarity of the different U isotopes. Since the 1940s, considerable research involving both epidemiological studies as well as animal and cell culture research has been conducted on the toxicity of natural and enriched U and, more recently, DU.12,13 One of the most sensitive target organs in humans for soluble forms of U has been shown to be the kidney after both short- and long-term ingestion and inhalation exposures to U, whereas the lung is an important target organ after inhalation of insoluble forms of small U particles.14–16
Depleted U munitions were first used by the United States in combat during the 1991 Gulf War. They were large-caliber anti-armor munitions with DU penetrators designed for tank warfare. The high density of the DU metal increases the effectiveness of the penetrators by increasing their ability to perforate armored vehicles at greater distances than penetrators made of other metals.17 In addition, the pyrophoric properties of DU increase the effectiveness of the DU penetrators by causing the metal to burn and sharpen upon impact, thus increasing its ability to penetrate tanks and cause interior damage. Fine aerosols of soluble and insoluble DU oxides are generated as the penetrators burn. Thus, soldiers in or on tanks struck by DU penetrators, and those who entered the vehicles to rescue their comrades immediately after the vehicles were struck, were exposed to DU by inhalation, ingestion, and wound contamination by the soluble and insoluble DU oxide particles and to larger fragments of DU shrapnel that became embedded in muscle and other soft tissues.
To determine the health impacts of these DU exposures, the Veterans Affairs (VA) DU Follow-Up Program was established in 1993 as a medical surveillance program that follows the health status of the cohort of US soldiers exposed to DU in 1991 Gulf War friendly-fire incidents involving DU munitions. Soldiers involved in DU friendly-fire incidents during the recent Iraq war have also been included in this program. Both exposure assessment and biomonitoring of target organ effects using sensitive biomarkers of organ system damage are important components of this medical surveillance program. Since 1993, members of this cohort have been seen on a biennial basis at the Baltimore VA Medical Center for detailed health assessments. Results from each of these visits have been published.18–25
In 1998, the DU Follow-Up Program mission was expanded to provide biologic monitoring for DU exposure for all Gulf War I and Operation Iraqi Freedom (OIF) veterans with a concern regarding possible exposure to DU. The purpose of this biomonitoring program is to passively survey for elevated urine U (uU) levels and combat exposure scenarios other than the known friendly-fire incidents. Assessment of exposure to low concentrations of DU in urine (as opposed to natural U) was made possible by the development of an inductively coupled plasma mass spectrometry (ICP-MS) analytical method26 capable of quantifying the very low levels of the U235 isotope remaining in the by-product of the U-enrichment process.
Toxic Embedded Fragment Surveillance Center
On the basis of lessons learned from the DU Follow-Up Program regarding the release of DU from embedded fragments in situ and evidence that other embedded materials may behave similarly,1–4,27 the VA established the TEFSC in 2008. The initial goals of the TEFSC were to develop a registry and a urine biomonitoring program for soldiers returning home from Afghanistan and Iraq with any type of soft tissue embedded fragments that could possibly cause long-term health problems, depending on the type and location of the fragments.
The “signature wound” for soldiers in Afghanistan and Iraq has been and continues to be traumatic injuries from blasts or explosions resulting from interactions with improvised explosive devices. Such injuries often involve wound contamination with fragments of the heterogeneous material present in the improvised explosive devices or in vehicles involved in the explosion. Thus, fragments retained in muscle and other soft tissues can vary greatly in composition, size and stability, making estimates of long-term health risks difficult.28
For this reason, urine biomonitoring of veterans with fragments is being conducted to provide important information on whether chemical components of embedded fragments are being released to systemic circulation in sufficient quantities to cause health problems. Local tissue effects of chemicals released from fragments may also lead to neoplastic changes in the vicinity of the fragments. The biomonitoring and health surveillance data captured by the Embedded Fragment Registry will be used to guide future medical management decisions including indications for the surgical removal of fragments in affected veterans.
This article provides an update of the health effects information gathered about the long-term effects of DU exposure in Gulf War veterans and of the progress being made on the development of an active registry and medical surveillance program for veterans with retained embedded fragments of all types, which will aid in managing their care.
Depleted Uranium Follow-Up Program
During the 1991 Gulf War, there were a number of incidents in which US troops fired on US armored vehicles using DU munitions. These “friendly-fire” incidents involved six Abrams tanks, which also contain DU armor for greater protection, and 14 Bradley fighting vehicles. A total of 104 soldiers survived these friendly-fire incidents and were the initial focus of the VA DU Follow-Up Program when it was established in 1993. Of these 104 soldiers, 79 have accepted the VA's invitation to participate in the program (Table 1). An additional four soldiers involved in DU munition friendly-fire incidents that occurred in the war in Iraq have also attended recent surveillance visits.
Biennial Surveillance Visits
Every 2 years, all members of the DU-exposed cohort are invited to attend a 3- to 4-day inpatient clinical assessment at the VA Medical Center in Baltimore, Maryland. Because of military deployments and personal responsibilities, not everyone has been able to attend every 2 years; thus, attendance is generally limited to about half of the cohort at each visit. On average, however, each member of the Gulf War cohort of 79 veterans has attended 3.4 surveillance visits since the first one in 1993–1994.
Elements of the clinical assessment conducted every 2 years include detailed medical and exposure histories, a physical examination, and a battery of laboratory measures selected on the basis of literature data indicating the sensitivity of specific organ systems to U and other similar metals.12,13 Standard clinical parameters and other biomarkers of organ system effects have been measured by methods previously described.25 Blood and semen have also been collected for analysis of U concentrations. Twenty-four–hour and spot urine samples were collected for measurement of renal function and bone metabolism, as well as uU concentrations used for exposure assessment.
Uranium Analysis for Exposure Assessment
Twenty-four–hour urine samples collected at each DU surveillance visit are sent to The Joint Pathology Center, Division of Biophysical Toxicology for analysis of total U and the U235:U238 isotopic ratio to distinguish between natural and depleted U excretion. Total uU has been measured since 2001 by quadrupole ICP-MS with a dynamic reaction cell method developed by Ejnik and coworkers,26 whereas uU isotopic ratio has been determined employing a high-resolution magnetic sector-field ICP-MS instrument.29
Blood and plasma total U concentrations and U235:U238 isotopic ratios have been analyzed using the ICP–dynamic reaction cell–MS method developed by Todorov and coworkers.29
The relationships between DU exposure and health outcomes measured during each surveillance visit have been evaluated using uU concentrations as the measure of DU exposure. Using a cutoff value of 0.1 μg U/g creatinine, members of the cohort were stratified into low versus high uU groups. Statistical significance of differences between mean outcome values in the two groups were determined using the Mann-Whitney U test (Wilcoxon rank sum test). Differences were considered statistically significant when P < 0.05, although differences at the P < 0.2 level are noted because this is a surveillance program and small differences may be indicative of early changes. Regression analysis has also been used to examine continuous relationships between some of the outcome variables and uU concentrations.
Toxic Embedded Fragment Surveillance Center
Embedded Fragment Registry
An Embedded Fragment Registry has been developed for veterans returning with retained embedded fragments from combat service in the wars in Afghanistan and Iraq. As described by Gaitens and coworkers,28 initial information regarding the likelihood that a veteran has one or more embedded fragments is gathered using screening questions in an electronic prompt incorporated into the VA's electronic medical record system. Once a veteran is identified as having a fragment, he/she is automatically added to the registry and additional data elements that are captured for the individual include information about the type, cause, and location of injuries, demographic and health care information, health outcome data, biological monitoring data, and fragment physical and chemical composition data. Additional data will be gathered by patient follow-up through biological monitoring, chemical analysis of any removed fragments, clinical consultation, and medical surveillance, if needed.
Chemical and Physical Characterization of Removed Embedded Fragments
Fragments received from veterans in the Embedded Fragment Registry are sent to The Joint Pathology Center, Division of Biophysical Toxicology, for analysis. Fragments are measured for size and weight, screened for radioactivity (gross alpha and beta activity), and analyzed for metals by energy dispersive x-ray fluorescence spectrometry (Thermo Scientific Fisher Scientific, Waltham, Mass). Energy dispersive x-ray fluorescence spectrometry is a surface technique that allows for the analysis of the outer and inner cores of the fragment. The inner core of the fragment is analyzed by abrasion of the surface to expose the inner layer of the fragment. Metal concentrations in each fragment are reported as percentage levels.
Biological Monitoring for Urinary Excretion of Metals
When veterans likely to have embedded fragments are identified and placed in the Embedded Fragment Registry, the veteran is asked to provide a 24-hour urine sample using a specially designed urine collection kit.28 The urine sample is then mailed to the TEFSC at the VA Medical Center in Baltimore, Maryland. Receipt of the sample is logged into the Embedded Fragment Registry, sent to the Baltimore VA clinical laboratory for creatinine analysis, and then sent to The Joint Pathology Center, Division of Biophysical Toxicology, for analysis by high-resolution magnetic sector-field ICP-MS for the following 13 hazardous metals: Al, As, Cd, Cr, Co, Cu, Fe, Mn, Ni, Pb, U, W, and Zn. Metal urine concentrations reported on a μg/mL basis are corrected for dilution by dividing by the creatinine concentration of the sample to give the microgram of metal per gram creatinine in each urine sample.
Clinical Surveillance Program on DU-Exposed Veterans
Demographic information about the two cohorts of DU-exposed veterans from the 1991 Gulf War and the current war in Iraq is shown in Table 1. The Gulf War I cohort consists of a total of 79 veterans with a mean age of 43 years in 2009. The mean age of the much smaller cohort of DU-exposed veterans from the war in Iraq is 36 years. Because of the difference in their dates of exposure (1991 vs 2003), these individuals have not been combined with the 1991 Gulf War veterans for health outcome data analysis.
Measures of exposure to DU are an important component of this surveillance program to provide information needed to develop an understanding of relationships between exposure doses, routes of exposure, lengths of exposure, and health risks. Whole-body radiation exposure, U body burdens, and ongoing systemic exposures to DU in this cohort have been measured by whole-body counting.19–25 Urine U concentrations determined every 2 years at each surveillance visit serve as the primary measure of U body burden and ongoing systemic exposure to DU at the time of the visit. In addition, cumulative exposure results have also been calculated using uU concentration data from all visits. Comparisons of mean differences in health outcome results calculated using current uU concentrations versus cumulative uU concentrations did not alter the final results, which is consistent with the observation that these two uU exposure metrics are highly correlated.23
The variability of uU excretion over time within individuals is shown in Fig. 1, which was created by plotting, from low to high, the mean uU concentration and standard deviation for each veteran calculated using his uU concentration measurements at each of the biennial visits attended between 1993 and 2007. As seen in this figure, a large number of the Gulf War DU-exposed cohort members have uU concentrations that are at or below the 95th percentile for adults in the US population (0.034 μg/g creatinine).30 These individuals may have received inhalation or ingestion exposures to DU at the time of the friendly-fire incidents but the DU has subsequently been excreted or is currently stored in tissues such as pulmonary lymph nodes, bones, and/or kidneys. Approximately 42% of the veterans in this group, however, continue to excrete U at concentrations above the cutoff level of 0.1 μg U/g creatinine used as an upper limit of normal for U excretion based on literature values.19,30,31 Within the high uU group, 87.5% of the veterans have been demonstrated by radiography to have retained embedded fragments, and isotopic analysis of the urine of these individuals indicates that one or more of the fragments contain DU. The relatively small standard deviations around each mean uU value indicate that uU excretion for each veteran has been relatively stable over the past 18 years, suggesting that DU release from DU-embedded fragments reached a steady state within the first few years after the war. This is consistent with the relatively rapid and sustained release of DU from embedded fragments observed in animal experiments.6
The mean uU concentrations in the Gulf War I–exposed cohort shown in Fig. 1 range from 0.002 to 40.4 μg U/g creatinine. The mean uU concentrations of the two individuals from the Iraq war cohort who attended the 2009 surveillance visit place both individuals in the high uU group. The highest uU concentrations in both cohorts are still less than the mean reported by Thun and coworkers32 (65.1 μg/L) for occupationally exposed U fabrication workers.
Other measures of DU exposure have given results similar to those found for urine. Blood, plasma, and uU concentrations in the 2009 Gulf War cohort were closely correlated with correlation coefficients of 0.907 and 0.963 for blood and plasma to urine, respectively. Blood U concentrations in 2009 ranged from 0.0035 to 1.105 μg/L in the Gulf War cohort and from 0.0146 to 0.0408 μg/L in the two veterans in the Iraq war cohort. Blood and plasma U concentrations have also been steady over time in the Gulf War I cohort. As shown in Fig. 2, mean blood U concentrations for members of the cohort present in the high uU groups at the 2003 and 2007 visits were not significantly different from each other.
Clinical Assessment of DU-related Health Effects
Over the past 18 years of surveillance visits, we have compared health outcome measures between the low versus high uU exposure groups to determine whether elevated U exposure at the level seen in our high DU-exposed cohort is associated with statistically and clinically significant changes in organ system functions. These results have been published for each of the eight surveillance visits conducted to date.18–25 Throughout this work, we have not observed any consistent, clinically significant differences in any of the U-related health parameters measured. Tables 2 through 5 provide summaries of results obtained at each of the eight surveillance visits conducted since 1994. The tables indicate whether there was a significant difference observed between the means of the low versus high uU groups for each clinical parameter. For example, it can be seen in Table 2, that in only a few instances were the concentrations of specific types of blood cells significantly different between the low versus high uU groups. The H > L (high uU more than low uU) and h < 1 (high uU less than low uU) designations indicate that the value for the high uU group was significantly greater than that for the low uU group at P < 0.05 or P < 0.2 levels, respectively. The “ns” designation indicates that there was no significant difference between the low versus high uU groups (P > 0.2). The results presented in Table 2 show no consistent differences between the low versus high uU groups over the years from 1994 to 2009, thus indicating that the long-term elevated U exposure occurring in the veterans in the high uU group is not adversely affecting the hematological system.
A similar lack of DU-related changes has been seen with other clinical parameters (Table 3). Despite known effects of other metals such as Pb on neuroendocrine parameters, there were no significant differences between the means of the low versus high uU exposed groups in the concentrations of the six hormones measured at each surveillance visit, except for two in 2001 (prolactin and free thyroxine) (Table 3). The fact that these differences observed in 2001 were not consistent with those found at other surveillance visits, and the mean values were always within the normal range, suggests that this was an incidental finding not related to DU exposure.
Of particular interest are the measures of renal function and toxicity examined on the basis of literature evidence that the kidney is the most sensitive organ after U exposure.10–12,15 The renal parameters listed in Table 4 for the most part do not show evidence of adverse, clinically important renal effects of DU. Serum creatinine concentrations have been statistically significantly different between the low versus high uU groups in the past two surveillance visits; however, the difference is in the wrong direction from what would be expected to occur if renal filtration were decreased (ie, an adverse effect would be indicated by higher serum creatinine concentrations in the high uU group). There has also been no consistent increase in urine total protein concentrations, which would be indicative of glomerular damage or tubule cell toxicity and sloughing. This finding is consistent with the lack of increased N-acetyl-β-glucosaminidase and intestinal alkaline phosphatase urine concentrations, which would indicate overt proximal tubule cell damage.
Urine concentrations of low molecular weight proteins have also been included in the surveillance protocol because the most sensitive indicator of metal ion effects on renal function is the excretion of low molecular weight proteins in the urine due to the inhibition of the reabsorption of these proteins by proximal tubule cells. Results for beta-2-microglobulin, a low molecular weight protein used to monitor occupational cohorts for early renal effects of Cd exposure, have not shown evidence of an effect of DU on proximal tubule cell function except for the 2007 visit (Table 4). Retinol binding protein urine concentrations, however, have been more consistently elevated in the high uU exposed group. Although this effect has not been statistically significant at the 0.05 level, it suggests that there might be some level of inhibition of retinol binding protein reabsorption in the veterans excreting high concentrations of DU. It does not seem to be increasing over time, however, which may be consistent with the steady-state concentrations of DU in the urine.
All other urine parameters presented in Table 4 have not shown consistent changes over time; however, the recent increases in urine Ca and PO4 concentrations may suggest alterations in bone metabolism that could be starting to occur as this population ages. Bone metabolism parameters measured in 2007 and 2009 (Table 5) show some significant differences; however, these are not consistent between the 2 years. These indices will continue to be monitored in future visits.
Urine DU Biomonitoring Program
Many Gulf War and OIF veterans concerned about possible exposure to DU during their combat service have taken advantage of the opportunity to send a urine sample to the VA Follow-Up Program on DU analysis. As of December (2010), 3246 veterans have submitted 24-hour urine samples for assessment of DU exposure (Fig. 3). Of those submitted by Gulf War I veterans, only one had a DU isotopic signature. Of the 1928 OIF veterans who submitted urine samples, only three tested positive for DU on the basis of the U isotopic signature of their samples. When the four veterans who tested positive were asked about their duties during their Gulf War I or OIF service, it was found that they had been involved in friendly-fire incidents and were subsequently asked to join the medical surveillance program on DU-exposed veterans. An average of 28 urine samples continues to be received per month from Gulf War I and OIF veterans as part of this biomonitoring program.
Toxic Embedded Fragment Surveillance Center
Urine Biomonitoring for Metals
To date, 89 urine samples have been collected from veterans who have or are likely to have retained embedded fragments on the basis of their answers to the VA clinical reminder screening questions. Upon receipt of each individual's metal concentration results for the 13 metals of concern, each metal concentration value was compared with the upper limit of its reference range, which was established on the basis of either the National Health and Nutrition Examination Survey database for urine metal concentrations in the US population30 or from clinical laboratory–reported reference ranges.28
For nine of the metals (As, Cd, Cr, Co, Pb, Mn, Ni, U, and Zn), less than 10% of the 89 urine samples received have metal concentrations that exceed the upper-level reference values established by our program (Table 6). None of the urine samples exceeded the reference values established for Cu and Fe. A larger percentage of urine samples (47.19% and 31.46%) exceeded the reference values established for Al and W, respectively, however. As shown in Fig. 4, most of the urine samples with high Al concentrations were no more than 4-fold higher than the reference range of 10 μg/g creatinine; however, one sample had an Al concentration 10-fold higher than the reference value. Tungsten (W) concentrations in 31.46% of the samples ranged as high as 6 times higher than the reference value of 0.3 μg/g creatinine (Fig. 4). It is interesting to note that the number of individuals with multiple metals exceeding their reference values is not large (Table 7). Although 35.96% of the individuals tested had no urine metal concentration exceeding a reference value, a similar number (34.83%) had only one metal exceeding its reference value and only 1.1% of the samples were above reference values for four metals.
Fragment Composition Results
Fragment composition information is being collected to help to identify the list of toxicants that should be included in the biomonitoring panels recommended for veterans with fragments. Table 8 shows metal composition information for fragments removed from two veterans. Of the six fragments analyzed from veteran number 1, three were primarily (approximately 90%) Cu, with lower amounts of Zn and Pb. Two other fragments were approximately 96% Pb, with small amounts of Cu, and the sixth fragment contained a mix of 56% Cu and 38% Pb. Three fragments from a second veteran (Table 8) were all primarily (99%) Fe, with small amounts of Mn and Zn. None of the fragments from either individual contained DU.
Although results from the DU medical surveillance program to date have not identified the development of clinically significant DU-related health effects in the Gulf War friendly-fire DU-exposed cohort, they have provided evidence that DU fragments embedded in muscle tissue are not inert, but continuously release soluble DU. This DU may affect local muscle tissue or enter the blood stream and accumulate in distant target organs. The potential chemical and radiological toxicities of DU require continued monitoring based on literature evidence of U accumulation over time in two primary tissues: kidneys and bones.33 In addition, radiation effects of DU may become more important over time as the radiation dose to specific cells continues to increase. This may be particularly important for tissue in the vicinity of the embedded DU fragments. For this reason, the availability of sensitive imaging methods for in situ surveillance of fragments and local tissue is currently being explored and will be incorporated into future surveillance visits.
An important shared mission of the DU Follow-Up Program and the TEFSC is the identification of potential health effects related to retained embedded fragments and the development of strategies for medical management of embedded materials. The extent to which an embedded fragment can affect a person's health is dependent on the location of the fragment as well as its chemical and physical characteristics. Local tissue and systemic effects will be determined by whether the fragment is inert in a biological environment or whether it easily breaks down and releases component chemicals. Different metals, for instance, differ significantly in their ability to oxidize, and plastics differ greatly in the extent to which plasticizing compounds diffuse from the basic matrix. Therefore, helpful information will be gained by analyzing all fragments that are removed from individuals to predict which compounds should be incorporated into the TEFSC biomonitoring program.
Data gathered from the TEFSC urine biomonitoring program will be invaluable for understanding potential health risks associated with embedded fragments. Although results obtained to date have focused on metals, the biomonitoring profile will be extended to include other hazardous compounds that may be released from plastics, such as acrylates and phthalates. Continued analysis of fragments removed from veterans will increase our ability to identify other potentially hazardous chemicals for placement in the biomonitoring protocol. Useful information about the bioavailability and tissue distribution of chemicals will also be obtained from studies of animals and humans with medical devices.2,27,34 Thus, though surgical guidelines historically have recommended leaving fragments in place unless there is evidence to the contrary (i.e. if the fragment lies near a vital organ or in a joint space), this guideline may not apply in all cases. Because removal of a fragment may carry risk of surgical morbidity to muscle tissue, depending on how easily accessible it is, careful consideration of the risk versus benefit of removal must be based on knowledge of a fragment's shape, size, composition, and stability in situ.
1. International Agency for Research on Cancer. Surgical Implants and Other Foreign Bodies, Volume 74. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon, France: World Health Organization; 1999.
2. Keegan GM, Learmonth ID, Case CP. Orthopaedic metals and their potential toxicity in the arthroplasty patient: a review of current knowledge and future strategies. J Bone Joint Surg (Br). 2007;89-B:567–573.
3. Machle W. Lead absorption from bullets lodged in tissues: report of two cases. JAMA. 1940;115:1536–1541.
4. Dillman RO, Crumb CK, Lidsky MJ. Lead poisoning from a gunshot wound: report of a case and review of the literature. Am J Med. 1979;66:509–514.
5. Sunderman FW, Hopfer SM, Swift T, et al. Cobalt, chromium, and nickel concentrations in body fluids of patients with porous-coated knee or hip prostheses. J Orthopaedic Res. 1989;7:307–315.
6. Pellmar TC, Fuciarelli AF, Ejnik JW, Edmond C, Mottaz HM, Landauer MR. Distribution of uranium in rats implanted with depleted uranium pellets. Toxicol Sci. 1999;49:29–39.
7. Kalinich JF, Emond CA, Dalton TK, et al. Embedded weapons-grade tungsten alloy shrapnel rapidly induces metastatic high-grade rhabdomyosarcomas in F344 rats. Environ Hlth Perspect. 2005;113:729–734.
8. Hahn FF, Guilmette RA, Hoover MD. Implanted depleted uranium fragments cause soft tissue sarcomas in the muscles of rats. Environ Hlth Perspect. 2002;110:51–59.
9. Army Environmental Policy Institute. Health and Environmental Consequences of Depleted Uranium Use in the US Army. Atlanta, GA: Army Environmental Policy Institute; 1995.
10. The Royal Society. The Health Hazards of Depleted Uranium Munitions Part I. Policy document 6/01. London, UK: Royal Society; 2001.
11. The Royal Society. The Health Effects of Depleted Uranium Munitions. Summary. Policy document 6/02. London, UK, Royal Society; 2002.
12. National Research Council. Review of Toxicologic and Radiologic Risks to Military Personnel From Exposure to Depleted Uranium During and After Combat. Washington, DC: National Academy Press; 2008.
13. McDiarmid MA, Gaitens JM, Squibb KS. Uranium and Thorium. In: Patty's Industrial Hygiene and Toxicology. 6th ed. Bingham E, Cohrssen B, eds. New York, NY: John Wiley and Sons Inc; 2012:769–816.
14. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Uranium (Update). Washington, DC: US Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry; 1999.
15. Roszell LE, Hahn FF, Lee RV, Parkhurst MA. Assessing the renal toxicity of Capstone depleted uranium oxides and other uranium compounds. Health Phys. 2009:96:343–351.
16. Guilmette RA, Parkhurst MA, Miller G, et al. Human Health Risk Assessment of Capstone Depleted Uranium Aerosols. Attachment 3 of Depleted Uranium Aerosol Doses and Risks: Summary of U.S. Assessments. Columbus, OH: Battelle Press; 2005.
17. Parkhurst MA, Daxon EG, Lodde GM, et al. Depleted Uranium Aerosol Doses and Risks. Summary of U.S. Assessments. Columbus, OH: Battelle Press; 2005.
18. Hooper FJ, Squibb KS, Siegel EL, McPhaul K, Keogh JP. Elevated urine uranium excretion by soldiers with retained uranium shrapnel. Health Phys. 1999;77:512–519.
19. McDiarmid MA, Keogh JP, Hooper FJ, et al. Health effects of depleted uranium on exposed Gulf War veterans. Environ Res. 2000;82:168–180.
20. McDiarmid MA, Squibb K, Engelhardt S, et al. Surveillance of depleted uranium exposed Gulf War veterans: health effects observed in an enlarged “friendly fire” cohort. J Occup Environ Med. 2001;43:991–1000.
21. McDiarmid MA, Engelhardt SM, Oliver M, et al. Health effects of depleted uranium on exposed Gulf War veterans: a 10-year follow-up. J Toxicol Environ Hlth Part A. 2004;67:77–296.
22. McDiarmid MA, Engelhardt SM, Oliver M, et al. Biological monitoring and surveillance results of Gulf War I veterans exposed to depleted uranium. Int Arch Occup Environ Health. 2006;79:11–21.
23. McDiarmid MA, Engelhardt SE, Oliver M, et al. Health surveillance of Gulf War I veterans exposed to depleted uranium: updating the cohort. Health Phys. 2007;93:60–73.
24. McDiarmid MA, Engelhardt SM, Dorsey CD, et al. Surveillance results of depleted uranium-exposed Gulf War I veterans: sixteen years of follow-up. J Toxicol Environ Hlth Part A. 2009;72:14–29.
25. McDiarmid M, Engelhardt SM, Dorsey C, et al. Longitudinal health surveillance in a cohort of Gulf War veterans 18 years after first exposure to depleted uranium. J Toxicol Environ Hlth Part A. 2011;74:1–14.
26. Ejnik JW, Todorov T, Mullick FG, Squibb KS, McDiarmid MA, Centeno JA. Uranium analysis in urine by inductively coupled plasma dynamic reaction cell mass spectrometry. Anal Bioanal Chem. 2005;382:73–79.
27. Jacobs JJ, Skipor AK, Patterson LM, et al. J Bone Joint Surg. 1998;80A:1447–1458.
28. Gaitens JM, Dorsey CD, McDiarmid MA. Using a public health registry to conduct medical surveillance: the case of toxic embedded fragments in U.S. military veterans. Eur J Oncol. 2010;15:77–89.
29. Todorov TI, Xu H, Ejnik JW, et al. Depleted uranium analysis in blood by inductively coupled plasma mass spectrometry. J Ann Atom Spectrum. 2009;24:189–193.
30. National Health and Nutrition Examination Survey. Second National Report on Human Exposure to Environmental Chemicals. NCEH Publication No. 02–0716. Atlanta, GA: Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey; 2003.
31. International Commission on Radiologic Protection. Report of the Task Groups on Reference Man. ICRP No. 23. Oxford, England: Pergamon Press; 1975.
32. Thun MJ, Baker DB, Steenland K, Smith AB, Halperin W, Berl T. Renal toxicity in uranium mill workers. Scand J Work Environ Health. 1985;11:83–90.
33. Squibb KS, Leggett RW, McDiarmid MA. Prediction of renal concentrations of depleted uranium and radiation dose in Gulf War veterans with embedded shrapnel. Health Phys. 2005;89:267–273.
34. Brand KG. Do implanted medical devices cause cancer? J Biomater Appl. 1994;8:325–345.
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