The management of embedded metal fragment patients and the role of chelation Therapy: A workshop of the Department of Veterans Affairs-Walter Reed National Medical Center.

Exposure to retained metal fragments from war-related injuries can result in increased systemic metal concentrations, thereby posing potential health risks to target organs far from the site of injury. Given the large number of veterans who have retained fragments and the lack of clear guidance on how to medically manage these individuals, the Department of Veterans Affairs (VA) convened a meeting of chelation experts and clinicians who care for embedded fragment patients to discuss current practices and provide medical management guidance. Based on this group's clinical expertise and review of published literature, the evidence presented suggests that, at least in the case of lead fragments, short-term chelation therapy may be beneficial for embedded fragment patients experiencing acute symptoms associated with metal toxicity; however, in the absence of clinical symptoms or significantly elevated blood lead concentrations (greater than 80 µg/dL), chelation therapy may offer little to no benefit for individuals with retained fragments and pose greater risks due to remobilization of metals stored in bone and other soft tissues. The combination of periodic biomonitoring to assess metal body burden, longitudinal fragment imaging, and selective fragment removal when metal concentrations approach critical injury thresholds offers a more conservative management approach to caring for patients with embedded fragments.

Surveillance results and bone effects in the Gulf War depleted uranium-exposed cohort.

A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored in a clinical surveillance program since 1993. During the spring of 2017, 42 members of the cohort were evaluated with a protocol which includes exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes including measures of bone metabolism, and for participants >50 years, bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained DU shrapnel fragments. Only the mean serum estradiol concentration, a marker of bone metabolism, was found to be significantly different for lower-vs- higher urine U (uU) cohort sub-groups. For the first time, a significant deficit in BMD was observed in the over age 50, high uU sub-group. After more than 25 years since first exposure to DU, an aging cohort of military veterans continues to exhibit few U-related adverse health effects in known target organs of U toxicity. The new finding of reduced BMD in older cohort members, while biologically plausible, was not suggested by other measures of bone metabolism in the full (all ages) cohort, as these were predominantly within normal limits over time. Only estradiol was recently found to display a difference as a function of uU grouping. As BMD is further impacted by aging and the U-burden from fragment absorption accrues in this cohort, a U effect may be clarified in future surveillance visits.

Impulse oscillometry measurement of distal airways obstruction in depleted uranium-exposed Gulf War veterans.

INTRODUCTION: A cohort of Gulf War I veterans who sustained exposure to depleted uranium undergoes biennial surveillance for potential uranium-related health effects. We performed impulse oscillometry and hypothesized that veterans with higher uranium body burdens would have more obstructive abnormalities than those with lower burdens. METHODS: We compared pulmonary function of veterans in high versus low urine uranium groups by evaluating spirometry and oscillometry values. RESULTS: Overall mean spirometry and oscillometry resistance values fell within the normal ranges. There were no significant differences between the high and low uranium groups for any parameters. However, more veterans were classified as having obstruction by oscillometry (42%) than spirometry (8%). CONCLUSIONS: While oscillometry identified more veterans as obstructed, obstruction was not uranium-related. However, the added sensitivity of this method implies a benefit in wider surveillance of exposed cohorts and holds promise in identifying abnormalities in areas of the lung historically described as silent.

The U.S. Department of Veterans' Affairs depleted uranium exposed cohort at 25 Years: Longitudinal surveillance results.

BACKGROUND: A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored for health changes in a clinical surveillance program at the Veterans Affairs Medical Center, Baltimore since 1994. METHODS: During the spring of 2015, an in-patient clinical surveillance protocol was performed on 36 members of the cohort, including exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes. RESULTS: On-going mobilization of U from embedded fragments is evidenced by elevated urine U concentrations. The DU isotopic signature is observed principally in participants possessing embedded fragments. Those with only an inhalation exposure have lower urine U concentration and a natural isotopic signature. CONCLUSIONS: At 25 years since first exposure to DU, an aging cohort of military veterans continues to show no U-related health effects in known target organs of U toxicity. As U body burden continues to accrue from in-situ mobilization from metal fragment depots, and increases with exposure duration, critical tissue-specific U concentration thresholds may be reached, thus recommending on-going surveillance of this veteran cohort.

Biologic monitoring and surveillance results for the department of veterans affairs' depleted uranium cohort: Lessons learned from sustained exposure over two decades.

BACKGROUND: A small group of Gulf War I veterans wounded in depleted uranium (DU) friendly fire incidents have been monitored in a clinical surveillance program at the Veterans Affairs Medical Center, Baltimore since 1994. METHODS: An in-patient clinical surveillance protocol was performed on 35 members of the cohort, including exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes. RESULTS: Although urine U concentrations continue to be elevated in this group, illustrating on-going in situ mobilization of U from embedded fragments, no consistent U-related health effects have been observed. CONCLUSIONS: Now more than 20 years since first exposure to DU, an aging cohort of military veterans continues to show no U-related health effects in known target organs of U toxicity. As tissue concentrations continue to accrue with exposure duration, critical tissue-specific U concentration thresholds may be reached, thus recommending on-going surveillance of this veteran cohort.

Chapter 4 embedded metal fragments.

The continued evolution of military munitions and armor on the battlefield, as well as the insurgent use of improvised explosive devices, has led to embedded fragment wounds containing metal and metal mixtures whose long-term toxicologic and carcinogenic properties are not as yet known. Advances in medical care have greatly increased the survival from these types of injuries. Standard surgical guidelines suggest leaving embedded fragments in place, thus individuals may carry these retained metal fragments for the rest of their lives. Nursing professionals will be at the forefront in caring for these wounded individuals, both immediately after the trauma and during the healing and rehabilitation process. Therefore, an understanding of the potential health effects of embedded metal fragment wounds is essential. This review will explore the history of embedded fragment wounds, current research in the field, and Department of Defense and Department of Veterans Affairs guidelines for the identification and long-term monitoring of individuals with embedded fragments.

Respiratory Health Associated with Systemic Metal Exposure in Post 9/11 Veterans in the Department of Veterans Affairs Toxic Embedded Fragment Registry.

OBJECTIVE: Adverse respiratory outcomes in post-9/11 Veterans with elevated urinary metal measures and enrolled in the VA's Toxic Embedded Fragment registry were compared to those without elevated urinary metals. METHODS: Veterans completed questionnaires, pulmonary physiology tests (pulmonary function and oscillometry) and provided urine samples for analysis of 13 metals. Respiratory symptoms, diagnoses and physiology measures were compared in Veterans with ≥1 urine metal elevation to those without metal elevations, adjusted for covariates, including smoking. RESULTS: Among 402 study participants, 24% had elevated urine metals, often just exceeding upper limits of reference values. Compared to Veterans without elevated metals, those with elevated metals had had higher FEV1 values but similar frequencies of respiratory symptoms and diagnoses and abnormalities on pulmonary physiology tests. CONCLUSIONS: Mild systemic metal elevations in post 9/11 Veterans are not associated with adverse respiratory health outcomes.

Cross-Sectional Study of the Frequency and Severity of Traumatic Childbirth Events and How They Affect Maternity Care Clinicians.

OBJECTIVE: To describe the frequency and severity of traumatic childbirth events (TCEs) and how they affected the professional practice and personal lives of maternity care clinicians, including registered nurses (RNs), certified nurse-midwives, attending physicians, and resident physicians. DESIGN: Descriptive cross-sectional study. SETTING: Maternity units across five hospitals in the Baltimore metropolitan area. PARTICIPANTS: Maternity care clinicians (N = 160) including RNs (n = 104), certified nurse-midwives (n = 17), attending physicians (n = 28), and resident physicians (n = 11). METHODS: Participants completed an online survey to measure the frequency and severity of TCEs and how they affect participants' professional practice and personal lives. We used descriptive statistics to characterize maternity care clinicians and bivariate analysis and linear regression to examine relationships. RESULTS: Most participants were women (92.5%), White (62.5%), between the ages of 21 and 54 years (89.4%), RNs (65.0%), and employed full-time (79.2%). Shoulder dystocia was the most frequently observed TCE (90.6%), and maternal death was the most severe TCE (M = 4.82, SD = 0.54). Attending physicians (50.0%) reported a significantly greater frequency of exposure to TCEs than the other participants, χ2(6) = 23.8 (n = 159), p <. 001. The frequency of TCEs had a significant medium correlation with perceived effect on professional practice, r(154) = 0.415, p < .001, and personal life, r(155) = 0.386, p < .001. Perception of severity was strongly associated with professional practice, ß = 0.52, p < .001, and personal life, ß = 0.46, p < .001. CONCLUSION: If severe, TCE exposure can affect the professional practice and personal life of maternity care clinicians.

Succimer chelation does not produce lasting reductions of blood lead levels in a rodent model of retained lead fragments.

Retained lead fragments from nonfatal firearm injuries pose a risk of lead poisoning. While chelation is well-established as a lead poisoning treatment, it remains unclear whether chelation mobilizes lead from embedded lead fragments. Here, we tested whether 1) DMSA/succimer or CaNa2EDTA increases mobilization of lead from fragments in vitro, and 2) succimer is efficacious in chelating fragment lead in vivo, using stable lead isotope tracer methods in a rodent model of embedded fragments. DMSA was > 10-times more effective than CaNa2EDTA in mobilizing fragment lead in vitro. In the rodent model, succimer chelation on day 1 produced the greatest blood lead reductions, and fragment lead was not mobilized into blood. However, with continued chelation and over 3-weeks post-chelation, blood lead levels rebounded with mobilization of lead from the fragments. These findings suggest prolonged chelation will increase fragment lead mobilization post-chelation, supporting the need for long-term surveillance in patients with retained fragments.

Laying the Foundation for a Mesothelioma Patient Registry: Development of Data Collection Tools.

Mesothelioma, a cancer of mesothelial cells that line the chest, lungs, heart, and abdomen, is a relatively rare disease. In the United States, approximately 3000 individuals are diagnosed with mesothelioma annually. The primary risk factor for mesothelioma is occupational asbestos exposure which can occur decades prior to disease development, though in approximately 20% of cases, known asbestos exposure is lacking. While several other countries have developed mesothelioma registries to collect key clinical and exposure data elements to allow better estimation of incidence, prevalence, and risk factors associated with disease development, no national mesothelioma registry exists in the U.S. Therefore, as part of a larger feasibility study, a patient exposure questionnaire and a clinical data collection tool were created using a series of key informant interviews. Findings suggest that risk factor and clinical data collection via an on-line questionnaire is feasible, but specific concerns related to confidentiality, in the context of employer responsibility for exposure in the unique U.S. legal environment, and timing of enrollment must be addressed. Lessons learned from piloting these tools will inform the design and implementation of a mesothelioma registry of national scope.

The Department of Veterans' Affairs Depleted Uranium Cohort in the Time of COVID-19: Translating a Traditional Surveillance Protocol to a Telehealth Platform.

OBJECTIVE: In 2021, 37 members of a cohort of depleted uranium-exposed Gulf War I veterans were evaluated using a protocol tailored to accommodate COVID-19 safety practices on a telehealth platform. METHODS: Individual elements of the legacy protocol were reviewed for urgency and feasibility of inclusion in a modified, telehealth platform. RESULTS: The redesigned protocol included a participant readiness for telehealth assessment, nurse and physician telehealth visits, collection of usual health questionnaires, and urine collections for exposure monitoring for uranium and other fragment-related metal measures. CONCLUSIONS: Despite some limitations in scope, the telehealth platform permitted a visual "visit" with surveillance participants who expressed a high comfort level with the format. The telehealth platform has apparent utility for occupational surveillance and should be explored as a standard approach for surveillance outside of public health emergencies.

Self-reported respiratory outcomes associated with blast exposure in post 9/11 veterans.

BACKGROUND: Blast lung overpressure has received interest as a cause of chronic respiratory disease in Service members who deployed in support of U.S. military operations in Southwest Asia and Afghanistan since 2001. We studied whether veterans who experienced blast exposure report more chronic respiratory symptoms and diagnoses compared to deployed veterans who did not. METHODS: 9,000 veterans included in the Department of Veterans Affairs Toxic Embedded Fragment Registry were invited to complete a survey assessing chronic respiratory symptoms, diagnoses, and exposures. Blast exposure was assessed using the Brief Traumatic Brain Injury Screen and by presence of other symptoms such as blast-induced loss of consciousness. RESULTS: Participants (n = 2147) were predominantly <40 years old, served in the Army, and injured on average 12.8 years previously. 91% reported blast exposure. Blast-exposed veterans were significantly more likely to report cough (OR 1.8), wheeze (OR 2.4), and dyspnea (OR 1.8), even after adjustment for covariates including smoking and occupational exposures to dust, fume, and gas. Veterans reporting higher severity of blast impact, such as traumatic brain injury or loss of consciousness, were more likely to report cough, wheeze, or dyspnea. Veterans with higher severity of blast impact by multiple measures were also more likely to report having COPD. Those reporting a physician-diagnosis of traumatic brain injury were significantly more likely to report having both asthma (OR 1.5) and COPD (OR 1.5). CONCLUSIONS: Blast exposure is associated with respiratory symptoms and COPD. Respiratory system evaluation may warrant inclusion as a standard part of barotrauma health assessment.

The Utility of Spot vs 24-Hour Urine Samples for Metal Determination in Veterans With Retained Fragments.

OBJECTIVES: The objective of this investigation is to explore the utility of using a spot urine sample in lieu of a 24-hour collection in assessing fragment-related metal exposure in war-injured veterans. METHODS: Twenty-four veterans collected each urine void over a 24-hour period in separate containers. Concentrations of 13 metals were measured in each void and in a pooled 24-hour sample using inductively coupled plasma mass spectrometry. To assess the reliability of spot sample measures over time, intraclass correlations (ICCs) were calculated across all spot samples. Lin's concordance correlation coefficient was used to assess agreement between a randomly selected spot urine sample and each corresponding 24-hour sample. RESULTS: In total, 149 spot urine samples were collected. Ten of the 13 metals measured had ICCs more than 0.4, suggesting "fair to good" reliability. Concordance coefficients were more than 0.4 for all metals, suggesting "moderate" agreement between spot and 24-hour concentrations, and more than 0.6 for seven of the 13 metals, suggesting "good" agreement. CONCLUSIONS: Our fair to good reliability findings, for most metals investigated, and moderate to good agreement findings for all metals, across the range of concentrations observed here, suggest the utility of spot urine samples to obtain valid estimates of exposure in the longitudinal surveillance of metal-exposed populations.

Urine miRNAs as potential biomarkers for systemic reactions induced by exposure to embedded metal.

Aim: Explore the potential of urine microRNAs as biomarkers that may reflect the biological responses to pure metals embedded in skeletal muscle over time. Materials & methods: We tested a panel of military-relevant metals embedded in the gastrocnemius muscles of 3-month-old, male, Sprague-Dawley rats (n = 8/group) for a duration of 1, 3, 6 and 12 months, and performed small RNA-sequencing on the urine samples. Results: Results provide potential tissue targets affected by metal exposure and a list of unique or common urine microRNA biomarkers indicative of exposure to various metals, highlighting a complex systemic response. Conclusion: We have identified a panel of miRNAs as potential urine biomarkers to reflect the complex systemic response to embedded metal exposure.

Surveillance of Depleted Uranium-exposed Gulf War Veterans: More Evidence for Bone Effects.

ABSTRACT: Gulf War I veterans who were victims of depleted uranium (DU) "friendly-fire" incidents have undergone longitudinal health surveillance since 1994. During the spring of 2019, 36 members of the cohort were evaluated with a monitoring protocol including exposure assessment for total and isotopic uranium concentrations in urine and a comprehensive review of health outcomes, including measures of bone metabolism and bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained depleted uranium (DU) shrapnel fragments. In addition, a measure of bone resorption, N-telopeptide, showed a statistically significant increase in those in the high DU subgroup, a finding consistent with a statistically significant decrease in bone mass also observed in this high DU subgroup compared to the low DU subgroup. After more than 25 y since first exposure to DU, an aging cohort of military veterans continues to show few U-related health effects in known target organs of U toxicity. The new finding of impaired BMD in the high DU subgroup has now been detected in two consecutive surveillance visits. While this is a biologically plausible uranium effect, it is not reflected in other measures of bone metabolism in the full cohort, which have largely been within normal limits. However, ongoing accrual of the U burden from fragment absorption over time and the effect of aging further impairing BMD suggest the need for future surveillance assessments of this cohort.

Longitudinal Evaluation of Lung Function in Gulf War I Veterans Exposed to Depleted Uranium.

OBJECTIVE: Gulf War I (GWI) Veterans exposed to depleted uranium (DU) have undergone biennial surveillance to assess for DU-related health effects. No DU-specific respiratory effects have been observed cross-sectionally, but longitudinal lung function decline has not been assessed. METHODS: A dynamic cohort of 71 Veterans underwent spirometry testing between 1999 and 2019. Longitudinal rates of decline of spirometry values were compared among Veterans with high versus low uranium levels using a linear mixed model. RESULTS: There was no significant difference in rate of decline of spirometry values between Veterans with high versus low uranium levels. The overall rate of decline was similar to that of the general population. CONCLUSIONS: In 20 years of follow-up, there does not appear to be an accelerated rate of decline of lung function among veterans exposed to depleted uranium.

Determination of Thirteen Trace and Toxic Elements in Urine Using Inductively Coupled Mass Spectrometry.

We developed and validated a method for the assessment of thirteen separate trace and toxic elements using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Included elements were as follows: aluminum, chromium, manganese, iron, cobalt, nickel, copper, zinc, arsenic, molybdenum, cadmium, tungsten, and lead. The measurements of all elements in urine samples were conducted using ICAP-Q ICP-MS in a single method. The performance characteristics of the assay were determined according to clinical laboratory standards. The assay was linear in the concentration range of 1.0 to 1000.0 µg/liter for all elements. The method was precise and accurate with limits of quantitation of 1 µg/liter for chromium, manganese, cobalt, nickel, copper, cadmium, tungsten, and lead; 2 µg/liter for iron and arsenic; 5 µg/liter for aluminum; and 50 µg/liter for zinc. This method has successfully been used for the assessment of all thirteen elements included in urine and has been shown to be effective as a simple, precise, and sensitive analytical technique for biological monitoring of urine samples. © 2018 by John Wiley & Sons, Inc.

Simultaneous Determination of Uranium and Depleted Uranium Isotopic Ratio Using Inductively Coupled Mass Spectrometry.

We have developed and validated a method for the simultaneous quantitative measurement of total uranium (TU) and uranium 235 U/238 U isotopic ratio (UIR) in urine by inductively coupled plasma mass spectrometry (ICP-MS) using a Thermo Scientific iCAP-Q instrument. The performance characteristics of the assay were determined to be in compliance with clinical laboratory standards. The assay was linear in the concentration range of 1.0 to 500.0 ng/liter TU. The method was precise and accurate with limits of detection of 2.5 ng/liter for TU and 9.8 ng/liter for UIR. The accuracy was >93% and the coefficient of variation (% CV) was <5.0% for both TU and UIR. All results were within established guidelines and agreed-upon criteria, and the results fell within the certified range for the reference controls. The method has thus been shown to be effective as a simple, precise, and sensitive analytical technique for testing urine samples. © 2018 by John Wiley & Sons, Inc.

Metal Exposure in Veterans With Embedded Fragments From War-Related Injuries: Early Findings From Surveillance Efforts.

OBJECTIVE: To characterize systemic metal exposures from retained fragments in a cohort of war-injured US Veterans enrolled in the Department of Veterans Affairs' Embedded Fragment Registry. METHODS: Five hundred seventy nine registry-enrolled Veterans submitted an exposure questionnaire and urine sample for analyses of 14 metals often found in fragments. Urine metal results were compared with reference values of unexposed populations to identify elevations. RESULTS: 55% of Veterans had normal urine metal values. When observed, tungsten and zinc were the metals most frequently elevated, followed by cobalt; however, cobalt levels were not associated with a fragment source, but with surgical implants present. CONCLUSIONS: Though most metal elevations observed are not significantly outside the normal range, on-going accrual of metal burdens in these Veterans over time recommends continued surveillance which may inform future medical management.