Journal of Occupational & Environmental Medicine:
Pulmonary Health Effects in Gulf War I Service Members Exposed to Depleted Uranium
Hines, Stella E. MD, MSPH; Gucer, Patricia PhD; Kligerman, Seth MD; Breyer, Richard MD; Centeno, Jose PhD; Gaitens, Joanna PhD, MPH/MSN; Oliver, Marc MPH; Engelhardt, Susan MSN; Squibb, Katherine PhD; McDiarmid, Melissa MD, MPH
From the Department of Veterans Affairs Medical Center (Drs Hines, Gucer, Breyer, Gaitens, Squibb, and McDiarmid, Mr Oliver, and Ms Engelhardt), Baltimore, Md; Occupational Health Program (Drs Hines, Gucer, Gaitens, Squibb, and McDiarmid, Mr Oliver, and Ms Engelhardt) and Division of Pulmonary and Critical Care Medicine (Dr Hines), Department of Medicine, and Department of Diagnostic Radiology and Nuclear Medicine (Dr Kligerman), University of Maryland School of Medicine, Baltimore; and Joint Pathology Center (Dr Centeno), Biophysical Toxicology, Silver Spring, Md.
Address correspondence to: Stella E. Hines, MD, MSPH, Occupational Health Program and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, 11 S Paca St, Second Floor, Baltimore, MD 21201 (firstname.lastname@example.org).
This program was funded through the US Department of Veterans Affairs.
The authors report no conflicts of interest.
Objective: In a population of Gulf War I veterans who sustained inhalational exposure to depleted uranium during friendly fire incidents in 1991, we evaluated whether those with high body burdens of uranium were more likely to have pulmonary health abnormalities than those with low body burdens.
Methods: We compared self-reported respiratory symptoms, mean pulmonary function values, and prevalence of low-dose chest computed tomography abnormalities between high and low urine uranium groups.
Results: We found no significant differences in respiratory symptoms, abnormal pulmonary function values, or prevalence of chest computed tomography abnormalities between high and low urine uranium groups. Overall, the cohort's pulmonary function values fell within the expected clinical range.
Conclusions: Our results support previous estimates that the depleted uranium levels inhaled during the 1991 friendly fire incidents likely do not cause long-term adverse pulmonary health effects.
The US Department of Veterans. Affairs Depleted Uranium (DU) Surveillance Program observes service members for health effects derived from exposure to DU as a consequence of friendly fire incidents involving DU-containing munitions and vehicles. Experimental animal and historical human toxicity data have suggested target organs of concern in this cohort who were exposed in 1991 during the first Gulf War (GWI). Although acute pulmonary toxicity of uranium (U) exposure was explored in this cohort during early surveillance visits, less attention has been given to potential long-term effects over a protracted exposure duration and latency. The potential for such toxicity, given the likelihood of absorption both at the time of initial injury and chronically from retained fragments serving as depots in the lung or pulmonary lymph nodes, together with the lengthy clearance time of inhaled DU in the lungs, warrant a systematic evaluation of pulmonary effects in this cohort, who all inhaled insoluble DU oxides.
US MILITARY USE OF DU AND THE DU SURVEILLANCE PROGRAM
The US military first used DU in munitions and armored vehicles during GWI. In February 1991, US forces, using DU penetrators, mistakenly fired on approximately 115 US service members in several different groups of armored tanks and fighting vehicles.1 More than 10 people died and 50 required medical care. Service members involved sustained exposure to DU via inhalation, ingestion, superficial wound contamination, and embedded DU fragments lodged in soft tissue. Since 1993, the DU Surveillance Program has monitored the health of service members involved in these incidents through biennial inpatient evaluations at the Veterans Affairs Medical Center in Baltimore, Maryland. After evaluating renal, hematologic, endocrine, and neurocognitive endpoints,2–8 immunologic function,4,8 and bone metabolism8 as a function of U body burden, we have observed no consistent U-related health effects.
COMPARATIVE TOXICITY OF DU AND NATURAL URANIUM
Uranium is a naturally occurring, radioactive, heavy metal containing three isotopes: 234U, 235U, and 238U. Depleted uranium is created during the U enrichment process in which the more highly radioactive isotopes, 234U and 235U, are removed from natural U. The DU that remains is 40% less radioactive9 but chemically similar to natural U, yielding a diminished radiologic health hazard but an equivalent chemical health hazard.10,11
Alpha radiation causes the principal radiologic hazard associated with U exposure. Radiation-induced lung damage and tumor formation in tissues in proximity to DU particles have been demonstrated in animals in acute and chronic inhalation studies of insoluble U compounds.12–17 Radiation-induced health effects from inhaled U in humans have primarily been explored in U miners with lung cancer. This association is thought, however, to be related to the presence of high levels of radon gas, a well-known carcinogen and decay product of natural U with a 10,000 times greater radiation activity, in underground mines.16–23 In 2008, the Institute of Medicine reported that there does not seem to be an appreciable increased risk for cancer in humans exposed to U, on the basis of human epidemiologic studies.24
The chemical hazards of U exposure are well-described in both animals and humans, with primary effects on the kidneys after oral and inhalation exposures to soluble U compounds.25–32 Pulmonary health effects, including pulmonary edema, hemorrhage, interstitial inflammation and fibrosis, and emphysema, have developed in animal models of acute U hexafluoride inhalation33,34 and in humans involved in occupational accidents involving U hexafluoride. In both the species, these acute effects appear more likely to be related to hydrogen fluoride toxicity than to U.35–38
Chronic inhalation of insoluble U compounds could manifest as nonmalignant respiratory disease, including pneumoconiosis, chronic obstructive pulmonary disease, pulmonary fibrosis, and tuberculosis.22,39 These observations were made, however, in U miners and millers concomitantly exposed to heavy cigarette smoke and silica, both well known to cause nonmalignant respiratory disease.17,23,40 Thus, human studies demonstrate associations between U and nonmalignant respiratory diseases, although contributions from other factors cannot be excluded, and may be causal.
Pulmonary Clearance of Insoluble Uranium Oxides
Five-minute inhalational exposure modeling simulating the brief inhalational exposures incurred in the 1991 fratricide events demonstrates that insoluble DU oxides may persist in the lung after inhalation for more than 8 years and in the thoracic lymph nodes for more than 27 years.38 Consequently, risk from long-term residence of a radioactive heavy metal is plausible both in the lung, but particularly, in the draining lymph nodes.
INHALATION EXPOSURE IN THE DU FOLLOW-UP COHORT
All participants in this surveillance program, whether they were located inside, on, or near a vehicle hit by DU penetrators, sustained inhalational exposure to aerosolized DU present as a mix of soluble and insoluble U oxides.38 The radiation and chemical toxicities from inhaled DU could manifest as respiratory symptoms, abnormal pulmonary function, and abnormal chest imaging. Although DU inhalation doses have been modeled, pulmonary outcomes have not been assessed systematically. On the basis of the known exposure and potential for health effects due to long-term residence of DU particles in the thorax, we searched for DU-specific pulmonary health effects in the DU surveillance cohort during the 2011 assessment.
We propose that service members who have embedded DU fragments were more likely to be in closer proximity to the source of a blast than those who do not have injuries from embedded DU fragments, and thus sustained greater inhalational exposures to DU and blast particulate. Given this assumption, we hypothesized that service members with higher urine U (uU) concentrations will report greater frequencies of chest symptoms, have more abnormal pulmonary function, and have more abnormalities on chest computed tomography (CT) than those with low uU concentrations.
Thirty-seven members of a cohort of 80 GWI veterans participating in the DU Surveillance Program returned for follow-up at the Baltimore Veterans Affairs Medical Center between April and June 2011. Although all the DU Surveillance Program participants are invited to attend the biennial surveillance, attendance is often limited by ongoing military deployments and personal obligations. One new participant joined the group in 2011, while the other participants had all attended at least one prior surveillance visit.
The 3-day, inpatient clinical assessment included a detailed medical and exposure history, physical examination, and laboratory studies. A comprehensive assessment of pulmonary health and function was performed by using a respiratory symptom questionnaire and by obtaining full pulmonary function tests (PFTs) and chest imaging studies.
Respiratory Health History Questionnaire
Participants completed a health history questionnaire, which was then reviewed by a physician. Questionnaire responses pertained to symptoms and diagnoses that have been queried among patients returning from combat in the Middle East and in cohorts exposed to dust inhalation.41–44 We also asked whether the participant had ever been treated with steroids prescribed by a physician and about cigarette smoking status.
Uranium Exposure Assessment
The Joint Pathology Center Biophysical Toxicology Laboratory (Joint Base Andrews Naval Air Facility, MD), previously the Armed Forces Institute of Pathology's Department of Environmental Toxicologic Pathology (Washington, DC), measured total U concentrations and the 235/238U isotopic ratio in 24-hour urine samples collected during the 2011 visits, as previously described.45 Urine U concentrations were standardized to urine creatinine concentrations and reported as microgram per g creatinine (μg U/g Cr), as previously described.2,46
Pulmonary Function Testing
Pulmonary function testing was performed, using a Sensormedics Carefusion Vmax system (Yorba Linda, CA), according to American Thoracic Society guidelines by Registered Respiratory Therapists certified by the National Board for Respiratory Care.47–50 Normal values of Morris et al51 were used for evaluation of the percentage of predicted values for spirometry, while lung volumes and diffusing capacity relied on Crapo reference values.52,53 Prebronchodilator spirometry values were collected, including forced expiratory volume in 1 second, forced vital capacity, and the ratio of forced expiratory volume in 1 second to forced vital capacity. Lung volumes were assessed via the total lung capacity, functional residual capacity, and residual volume. Gas exchange was assessed via diffusing capacity of the lung for carbon monoxide (DLCO).
Computed Tomography. Thin section, noncontrast chest CT was performed on each patient. All patients were scanned at 120kV. The tube current was lowered to between 50 and 100 mAs in an effort to reduce patient dose. Computed tomography dose modulation was also used to further reduce patient dose. Parameters of radiation dose were recorded, including CT dose index volume and dose length product. The effective dose to the patient was calculated as the dose length product times a k-coefficient of 0.14. The average CT dose index and dose length product were 4.93 mGy (range, 3.37 to 5.49 mGy) and 171.39 mGy·cm (range, 112 to 265 mGy·cm), respectively. The average radiation dose was 2.4 mSv (range, 1.58 to 3.71 mSv).
Each scan was reviewed by a fellowship-trained cardiothoracic radiologist who was blinded to the participant DU or smoking exposure status. The presence or absence of several specific findings was noted on the basis of the definitions of the Fleischner Society.54 All scans were assessed for the presence or absence of emphysema. Because of concern for inhaled dust exposure, each patient was assessed for large airway abnormalities, including bronchial wall thickening and bronchiectasis. Similarly, each patient was assessed for mosaicism, an indirect sign of small airway disease. Because of concern for a possible pneumoconiosis from dust or DU metal inhalation, reticulation and honeycombing were evaluated. Each scan was also assessed for the presence or absence of nodules that can be seen in various pathologic conditions, including inhalational injury or pneumonoconiosis, granulomatous disease, or malignancy. Focal solid nodules 3 mm or greater in diameter were classified by location (parenchymal vs fissural or subpleural), while diffuse nodules less than 3 mm in diameter were characterized as micronodularity. Intrathoracic lymph nodes were assessed for enlargement and calcification, given the concern that inhaled insoluble DU particles could be scavenged and take up residence in draining lymph nodes, potentially exposing local tissue to continuous alpha radiation exposure. Because of concerns for dust inhalation exacerbating acid reflux, esophageal abnormalities were evaluated. All radiologic findings were graded on a subjective three-point scale of mild, moderate, and severe.
Positron Emission Tomography/Computed Tomography (PET/CT). The subset of patients who have fragments embedded in their extremities underwent positron emission tomography accompanied by low-dose CT (PET/CT) for attenuation correction and localization for the primary purpose of evaluating the affected extremity and the relevant regional lymph node basins. Results of the extremity fragment evaluation are summarized elsewhere.45 On the basis of models suggesting prolonged residence of DU particles in the thorax and because additional imaging could be accomplished with minimal additional radiation dose, the thorax was also imaged as a separate contemporaneous acquisition.
Patients were imaged, using a Philips Gemini TF PET/CT scanner (Best, the Netherlands), 1 hour after the intravenous administration of approximately 12 mCi of 18-fluorodeoxiglucose. Estimated whole body dose from the radiotracer was 8 mSv, regardless of the extent of imaging. Low-dose (120 kV; 70 mAs) attenuation correction and localization CT of the area evaluated was performed. Using this low-dose technique, the estimated whole body dose was 4 mSv for patients weighing less than 91 kg, and 6 mSv for heavier patients. The CT dose to the patients in this assessment was significantly less than these estimates because the field of view typically did not include the abdomen and the majority of the pelvis.
Acquired images were evaluated by radiologists with additional training in nuclear medicine. Regions of increased radiotracer uptake were identified, localized, and metabolically quantified by using a Philips Extended Brilliance workstation (Best, the Netherlands). Metabolic activity is expressed as standardized uptake value (SUV), a dimensionless measure that expresses the ratio of radiotracer uptake in a specific lesion to the expected activity if the entire dose were distributed uniformly in the body. Nominal SUV for an ideal area of soft tissue would therefore be 1. Although many malignancies are hypermetabolic (typical SUV of 2.5 or greater), increased metabolism is nonspecific and may be seen in various benign pathologic conditions such as infection and inflammation. Similarly, low-grade malignancy may exhibit SUVs significantly lower than 2.5.
Urine U is presented as a binary variable. Comparisons are made between those with low uU (≤0.1 μg U/g Cr) and those with higher uU (>0.1 μg U/g Cr). This cut point of 0.1 μg U/g Cr has been used as a threshold between high and low uU in previous studies of this cohort.7,16,45 The value falls between 0.043 (the 95th percentile reported for creatinine-adjusted uU concentrations in nonexposed populations in the United States55) and 0.35 μg/L reported as a uU upper limit that occurs naturally in areas with elevated U in water and food.7,56 With few exceptions, those with higher uU also have an isotopic signature for DU.16 Over the years, most service members who have embedded fragments excrete U at higher levels than those without embedded fragments, and they fall into the “high” uU group. These service members, therefore, continue to be exposed systemically to DU circulating in the bloodstream because of release of U from the embedded DU fragments. Those in the low uU group do not have embedded DU fragments.
We present means and standard deviations for outcome variables (respiratory symptoms, PFTs, CT scan results) separately for those in the high and low uU groups, and for ever-smokers versus never-smokers. We used the Mann-Whitney U test for determining differences between groups. Analyses were conducted, using the Statistical Package for the Social Sciences version 20 (Statistical Products and Service Solutions, Inc, Chicago, IL).
Demographic characteristics of the cohort are described in Table 1. There were no significant differences between participants with low uU and high uU with respect to age, height, weight, body mass index, race, or smoking status (P values were all greater than 0.05).
Urine Uranium Concentrations
Urinary U concentrations ranged from a low of 0.001 to a high of 39.6 μg/g Cr in 2011, with median concentrations of 0.004 and 1.824 μg/g Cr for the low and high uU groups, respectively. Figure 1 displays the distribution of uU concentrations for the low (uU ≤ 0.1 μg/g Cr) and high (uU > 0.1 μg/g Cr) uU groups. Because the uU values span four orders of magnitude over the two exposure groupings, we display the mean uU values graphically as log-transformed data. We depicted log-transformed uU values as a box plot to display the measures of central tendency and significant differences in the distributions of uU burdens in the two exposure groups. About a third of the total DU cohort are known to have embedded metal fragments, as verified by plain film skeletal surveys during initial evaluations,16,57 and consistently, these individuals, who comprise the high uU group, excrete the highest concentrations of uU, documenting the fragment as a depot of ongoing metal mobilization into the systemic circulation.
All 37 participants completed the respiratory health history questionnaire. No service members reported currently having frequent sore throat or coughing up blood. In addition, no service members reported having the diagnoses of emphysema or tuberculosis. Table 2 shows the frequency of self-reported chest symptoms and diagnoses and prescription use of steroids in the 2011 cohort. We then examined the outcomes by uU categories (high vs low). There were no significant differences in percentage of the high uU group reporting symptoms, diagnoses, or treatment with steroids compared with the low uU group. Because smokers often report respiratory symptoms, we evaluated this same group of symptoms in ever-smokers versus never-smokers. The only symptom more frequently reported in ever-smokers versus never-smokers was frequent cough (P = 0.05).
A total of 36 participants completed PFTs. One person did not complete testing because of concurrent respiratory infection symptoms. In this group of 36, one participant's test did not meet the American Thoracic Society quality criteria for spirometry. We included this individual in the data analysis, however, as exclusion of his data did not modify results significantly. Aside from this individual, all participants who completed lung volumes and DLCO met the American Thoracic Society quality criteria for those tests. Not all participants completed lung volumes or DLCO because of unavailability of equipment on the day of their testing.
Overall, this cohort of service members from GWI had normal pulmonary function (Table 3). Veterans with high uU content did not have significantly different PFT values compared with those with low uU. We analyzed PFT parameters according to smoking status, grouped as ever-smokers versus never-smokers. There were no significant differences in spirometry values between these groups. Ever-smokers tended to have significantly higher functional residual capacity and residual volume than never smokers. Ever-smokers also had lower mean DLCO values than never-smokers, although this difference was not statistically significant.
Low-Dose Chest CT
Low-dose noncontrast chest CT was performed on 36 participants. One individual did not undergo CT because of claustrophobia. Various findings were noted on the chest CT scans of the members of this cohort (Table 4). The most common finding was the presence of one or more parenchymal nodules, which were seen in 61% (22 of 36) of participants. In these 22 participants, there was an average of 3.7 nodules per participant (range, 1 to 11) that ranged in diameter from 2 to 9 mm. At least one nodule was calcified in 13 of these 22 participants (59%). Only 25% (9 of 36) had a noncalcified nodule measuring greater than 4 mm in diameter. Emphysema was seen in 15 of 22 participants (42%), but was mild in most (12 of 15) participants. Bronchial wall thickening and mosaicism were both present in 14 of the 36 participants (39%). Fissural nodules and subpleural nodules, which often represent lymphatic tissue, were present in 9 of 36 participants (25%).58 Three participants had centrilobular nodularity, which was likely secondary to respiratory bronchiolitis in one patient, acute bronchiolitis in another, and suggestive of nontuberculous mycobacterial disease in the last. Although no members of the cohort had findings of honeycombing, two members (6%) demonstrated lower lobe predominant, peripheral reticulation that was concerning for an early fibrotic lung process. Bronchiectasis was present in the one participant who seemed to have nontuberculous myocobacterial disease.
When CT scan findings were evaluated according to high uU status versus low uU status, there were no statistically significant differences between the two groups (Table 4). When CT findings were evaluated according to never-smoking status versus ever-smoking status, ever-smokers were significantly more likely to demonstrate fissural nodules (P = 0.018) and have emphysema (P = 0.001). More smokers also demonstrated large airway thickening, although this was not statistically significant (P = 0.086). Five service members demonstrated calcified intrathoracic lymph nodes, although none were pathologically enlarged.
Thirteen members of the GWI cohort who have embedded fragments underwent PET/CT. There were no findings in the chest CT which were felt to be related to DU exposure. Among the 13 members, 10 had completely unremarkable PET/CT findings of the chest.
Of the remaining three, one participant had increased uptake (SUV 5.4) in the distal esophagus, without a corresponding morphologic abnormality on the CT. This is a nonspecific as well as a relatively common finding, which more likely represents physiologic peristalsis or inflammation. Other entities in the differential diagnosis include infection or neoplasm, but are less likely. Another patient had increased uptake (SUV 4.4) in the lung parenchyma of the posterior left upper lobe. The localizing CT showed ground glass density in the posterior left upper lobe and entire left lower lobe. No enlarged or metabolically active lymph nodes were demonstrated. The findings were felt to represent pneumonia (symptoms of which manifested on the subsequent day). The final patient had increased radiotracer uptake in the bilateral supraclavicular regions (SUV 6.9), as well as the pretracheal and prevascular regions of the superior mediastinum (SUV 5.4). Evaluation of the noncontrast localizing CT demonstrated fat and no soft tissue lesions or lymph nodes in these regions. The pattern of uptake is often seen with brown fat, a normal variant.
In this cohort of GWI veterans who sustained inhalational exposure to DU in 1991, we determined the presence and frequency of chronic chest abnormalities. Overall, service members with high uU values do not have more respiratory symptoms, more abnormal pulmonary function parameters, or more abnormalities on chest CT than service members with low uU. In general, DU-exposed service members seem to have pulmonary function values that fall within the clinically normal range on the basis of age, gender, race, and height. Finally, GWI veterans exposed to inhaled DU particulates do not demonstrate radiographic evidence for chest malignancy, lymphadenopathy, or pulmonary fibrosis 20 years later. Findings of nodularity, emphysema, and airway disease were fairly common in members of this cohort with a high prevalence of cigarette smoking.
The majority of members of this cohort have undergone spirometry at least once as part of a baseline evaluation. On the basis of original screening spirometry, no individuals had significantly abnormal pulmonary function indicative of a DU-specific effect; therefore, PFTs had not been included as a regular part of biennial surveillance. Nevertheless, because of concern about potential ongoing U exposure from depots of U oxide in the chest, it was determined that follow-up spirometry was warranted. Although abnormal spirometry could suggest a progressive parenchymal or airway abnormality, early lung or intrathoracic lymph node abnormalities would not be detected on spirometry. Use of advanced imaging addressed concerns that lymph nodes could be affected.
Correlation to Capstone Modeling
The general population ingests approximately 0.9 to 2.5 μg/day of U from food sources and drinking water and inhales typically 0.001 to 0.01 μg/day.34 The US Army Center for Health Promotion and Preventive Medicine Capstone study simulated the 1991 firing of DU munitions at Abrams tanks and Bradley fighting vehicles and then measured aerosolized DU to understand risks faced by exposed service members.38 In these simulations, median modeled human DU intake ranged from 10 (in DU-armored Abrams tanks with functioning ventilation systems) to 710 mg (in DU-armored Abrams tanks without functioning ventilation systems).
In relation to radiation exposure thresholds, median DU intake estimates in the Capstone assessment translated into median 50-year committed effective doses E(50) ranging from 0.09 to 8.7 rem. These levels fall below the US Nuclear Regulatory Commission's annual dose limit of 10 rem/y for workers with a planned special exposure or a total of 25 rem from planned special exposures in a lifetime.59 In further modeling, 50-year committed equivalent doses (HT(50)) to the lung were higher than doses to other tissues by a factor of 10. Hlung(50) values ranged from a low of 0.7 (in DU-armored Abrams tanks with an operating ventilation system) to 44 rem (DU-armored Abrams tanks with no ventilation).16,38 This exposure level still falls below the US Nuclear Regulatory Commission's recommended annual exposure limit of 50 rem, which is the sum of the deep-dose equivalent and the committed dose equivalent for an individual tissue.58
Because of this potential for prolonged residence of alpha-emitting radioactive particles in the chest, particularly in the draining lymph nodes, we used advanced imaging methods for the first time to help identify lesions in this DU-exposed cohort. Although many nodules were identified on chest CT, most were calcified, implying a benign character, and none demonstrated signs of malignancy, such as irregular margins, spiculation, or internal air bronchograms.60 Although the prevalence of small noncalcified pulmonary nodules in the general population is unknown, a study by Piyavisetpat et al61 demonstrated at least one noncalcified pulmonary nodule in 9.9% of patients undergoing CT scans with a slice thickness of 5 mm. The incidence in our cohort was higher, in part due to much thinner 0.9-mm slice thickness used to evaluate the scans in our study. Although small nodules are of unknown significance, many found in our participants are likely due to prior granulomatous infection, as 59% of those with nodules had at least one calcified nodule.62
In studies that have evaluated the utility of low-dose CT scanning for lung cancer screening in high-risk groups (such as smokers), the prevalence of small noncalcified nodules has varied. In the National Lung Screening Trial, 39.1% of smokers screened via CT (total of 26,722) had at least one positive scan, defined as having at least one noncalcified nodule greater than 4 mm in diameter. This definition of “positive,” however, also included thoracic lymphadenopathy or pleural effusion, thus limiting direct comparison with our population's data.63 In the ITALUNG, German Lung Cancer Screening Intervention trial (LUSI), and Danish lung cancer screening trials, 30%, 26.6%, and 30.9% of patients had at least one noncalcified nodule measuring 5 mm or greater in diameter on initial scan, respectively.64–66 Although direct comparison between our study and these lung cancer screening trials is difficult because of differences in measurement cut points and patient risk factors, the presence of noncalcified nodules greater than 4 mm in diameter in 25% of our patients is not dissimilar. Given the risk factors in this DU-exposed population, including smoking, the finding of small nodules prompts follow-up for stability or progression of nodules. This will be addressed at the 2013 DU follow-up surveillance visits.
Early malignant involvement of lymph nodes, however, is generally occult on CT. Given the exposure models suggesting persistence of DU particles in the intrathoracic draining lymph nodes,38 we used PET/CT scans to look for chest lymph node abnormalities in this at-risk population. We found no abnormal radiolabeled glucose uptake patterns to suggest increased metabolic activity in the intrathoracic lymph nodes. This is particularly reassuring, given that the lymph nodes are likely to continue to contain insoluble DU particles with low-level alpha radiation emission. These radiographic findings support the conclusions reported by the investigators of the Capstone project,38 which state that the predicted range of DU exposures to the lung produced by the fratricide episodes is not expected to cause adverse health effects in the pulmonary system.38
Almost 50% of this cohort has ever smoked cigarettes, with equal frequencies in the high and low U groups. No individuals reported a diagnosis of emphysema on the respiratory health questionnaire, and only 1 person reported a history of bronchitis. Forty-two percent of the cohort, however, had radiographic evidence for emphysema on chest CT, and 39% demonstrated large airway thickening, both findings associated with smoking-related lung disease. We feel that this discrepancy between a high prevalence of radiographic emphysema and the low prevalence of diagnosis of emphysema serves as an opportunity for education of these service members on the importance of tobacco cessation and regular medical follow-up to address emerging respiratory symptoms or functional impairment related to tobacco use.
The pulmonary function values for this population generally fell within normal clinical parameters. From a population-level standpoint, this is helpful in understanding that inhalation of these levels of DU oxide particulates at a finite point in time does not confer a clinically significant risk for below-normal pulmonary function or abnormal chest imaging that would prompt a medical intervention.
It is possible that these service members may have experienced acute or subacute respiratory health effects immediately after exposure in 1991. The DU Surveillance Program came into existence and examined its first cohort of participants in 1993. Thus, it is possible that earlier pulmonary effects may have been missed. Although this cohort's pulmonary function seems to fall within a clinically “normal” range, these veterans could still be experiencing an accelerated decline in lung function. Future efforts will evaluate pulmonary function in this cohort longitudinally. It is encouraging, however, that 20 years postexposure, respiratory health effects have not emerged.
Service members who sustained blast inhalational exposure to DU particulates do not seem to have high reporting of chest symptoms, poorer pulmonary function, or unusual chest imaging 20 years postexposure overall. Patients with high levels of uU, consistent with ongoing systemic exposure to U and possibly a larger blast particulate inhalational exposure, do not have significantly different pulmonary symptoms, function, and imaging than those with low levels of uU. These results further characterize the health status of this DU-exposed cohort, two decades after first exposure.
1. Office of the Special Assistant to the Deputy Secretary of Defense for Gulf War Illnesses. Environmental Exposure Report: Depleted Uranium in the Gulf (II). Washington, DC: US Department of Defense; 2000. Available at: http://www.gulflink.osd.mil/du_ii/
. Accessed April 11, 2013.
2. McDiarmid MA, Keogh JP, Hooper FJ, et al. Health effects of depleted uranium on exposed Gulf War veterans. Environ Res. 2000;82:168–180.
3. 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.
4. 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 Health A. 2004;67:277–296.
5. 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.
6. 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.
7. 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 Health A. 2009;72:14–29.
8. McDiarmid MA, Engelhardt SM, Corsey CD, et al. Longitudinal health surveillance in a cohort of Gulf War veterans 18 years after first exposure to depleted uranium. J Toxicol Environ Health A. 2011;74:678–691.
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, England: The Royal Society; 2001.
11. The Royal Society. The Health Effects of Depleted Uranium Munitions. Summary. Policy Document 6/02. London, England: The Royal Society; 2002.
12. Hueper WC, Zuefle JH, Link AM, Johnson MG. Experimental studies in metal cancerigenesis. II. Experimental uranium cancers in rats. J Natl Cancer Inst (US) 1952;13:291–305.
13. Leach LJ, Yuile CL, Hodge HC, Sylvester GE, Wilson HB. A five-year inhalation study with natural uranium dioxide (UO2) dust. II. Postexposure retention and biologic effects in the monkey, dog and rat. Health Phys. 1973;25:239–258.
14. Cross FT, Palmer RF, Busch RH, Filipy RE, Stuart BO. Development of lesions in Syrian golden hamsters following exposure to radon daughters and uranium ore dust. Health Phys. 1981;41:135–153.
15. Mitchel RE, Jackson JS, Heinmiller B. Inhaled uranium ore dust and lung cancer risk in rats. Health Phys. 1999;76:145–155.
16. Squibb KS, McDiarmid MA. Depleted uranium exposure and health effects in Gulf War veterans. Phil Trans R Soc B. 2006;361:639–648.
17. McDiarmid MA, Gaitens JM, Squibb KS. Uranium and thorium. In: Bingham E, Cohrssen B, eds. Patty's Toxicology. 6th ed. Hoboken, NJ: John Wiley & Sons Inc; 2012:769–816.
18. Kathren RL, Moore RH. Acute accidental inhalation of U: a 38-year follow-up. Health Phys. 1986;51:609–619.
19. Samet JM, Pathak DR, Morgan MV, et al. Radon progeny exposure and lung cancer risk in New Mexico U miners: a case-control study. Health Phys. 1989;56:415–421.
20. Samet JM. Radon and lung cancer. J Natl Cancer Inst. 1989;10:745–757.
21. Kathren RL, McInroy JF, Moore RH, Dietert SE. Uranium in the tissues of an occupationally exposed individual. Health Phys. 1989;57:17–21.
22. Boice JD Jr, Cohen SS, Mumma MT, Chadda B, Blot WJ. A cohort study of uranium millers and miners of Grants, New Mexico, 1979–2005. J Radiol Prot. 2008;28:303–325.
23. Pinkerton LE, Bloom TF, Hein MJ, Ward EM. Mortality among a cohort of uranium mill workers: an update. Occup Environ Med. 2004;61:57–64.
24. Institute of Medicine. Gulf War and Health: Updated Literature Review of Depleted Uranium. Washington, DC: National Academy Press; 2008.
25. Gilman AP, Villeneuve DC, Secours VE, et al. Uranyl nitrate: 28-day and 91-day toxicity studies in the Sprague-Dawley rat. Toxicol Sci. 1998;41:117–128.
26. Gilman AP, Villeneuve DC, Secours VE, et al. Uranyl nitrate: 91-day toxicity studies in the New Zealand white rabbit. Toxicol Sci. 1998;41:129–137.
27. Gilman AP, Moss MA, Villeneuve DC, et al. Uranyl nitrate: 91-day exposure and recovery studies in the male New Zealand white rabbit. Toxicol Sci. 1998;41:138–151.
28. Saccomanno G. The contribution of uranium miners to lung cancer histogenesis. Recent Results Cancer Res. 1982;82:43–52.
29. 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.
30. Zamora ML, Tracy BL, Zielinski JM, Meyerhof DP, Moss MA. Chronic ingestion of uranium in drinking water: a study of kidney bioeffects in humans. Toxicol Sci. 1998;47:68–77.
31. Zamora ML, Zielinski JM, Meyerhof DP, Tracy BL. Gastrointestinal absorption of uranium in humans. Health Phys. 2002;83:35–45.
32. Kurttio P, Auvinen A, Salonen L, et al. Renal effects of uranium in drinking water. Environ Health Perspect. 2002;110:337–342.
33. Spiegl CJ. The chemistry of uranium compounds. In: Voegtlin C, Hodge HC, eds. Pharmacology and Toxicology of Uranium Compounds. New York, NY: McGraw-Hill; 1949:532–548.
34. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Uranium (Update). Atlanta, GA: US Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry; 1999.
35. Howland JW. Comprehensive summary of the pharmacology and toxicology of uranium compounds; studies on human exposures to uranium compounds. At Energy Biophys Biol Med. 1948;1:174.
36. Moore RH, Kathren RL. A World War II uranium hexafluoride inhalation event with pulmonary implications for today. J Occup Med. 1985;27:753–756.
37. Fisher DR, Kathren RL, Swint MJ. Modified biokinetic model for uranium from analysis of acute exposure to UF6. Health Phys. 1991;60:335–342.
38. Parkhurst MA, Daxon EG, Lodde GM, et al. Depleted Uranium Aerosol Doses and Risks: Summary of U.S. Assessments. Columbus, OH: Battelle Press; 2005.
39. Roscoe RJ. An update of mortality from all causes among white uranium miners from the Colorado Plateau Study Group. Am J Ind Med. 1997;31:211–222.
40. Holaday DA, David WD, Doyle HN. An interim report of a health study of the uranium mines and mills by the Federal Security Agency, Public Health Service, Division of Occupational Health and the Colorado State Department of Public Health (May 1952). In: Eischstaedt P, ed. If You Poison Us: Uranium and Native Americans. Santa Fe, NM: Red Crane Books; 1994;203–217.
41. Prezant DJ, Weiden M, Banauch GI, et al. Cough and bronchial responsiveness in firefighters at the World Trade Center site. N Engl J Med. 2002;347:806–815.
42. Landrigan PJ, Lioy PJ, Thurston G, et al. Health and environmental consequences of the World Trade Center disaster. Environ Health Perspect. 2004;112:731–739.
43. Smith B, Wong CA, Smith TC, Boyko EJ, Gackstetter GD. Newly reported respiratory symptoms and conditions among military personnel deployed to Iraq and Afghanistan: a prospective population-based study. Am J Epidemiol. 2009;170:1433–1442.
44. King MS, Eisenberg R, Newman JH, et al. Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan. N Engl J Med. 2011;365:222–230.
45. McDiarmid MA, Gaitens JM, Hines S, et al. The Gulf War depleted uranium cohort at 20: bioassay results and novel approaches to fragment surveillance. Health Phys. In press.
46. Karpas Z, Kirber A, Eliah E, et al. Uranium in urine-normalization to creatinine. Health Phys. 1998;74:86–90.
47. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–338.
48. Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. Eur Respir J. 2005;26:153–161.
49. Macintyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26:720–735.
50. Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26:511–522.
51. Morris JF, Koski A, Johnson LC. Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis. 1971;103:57–67.
52. Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir. 1982;18:419–425.
53. Crapo RO, Morris AH. Standardized single breath normal values for carbon monoxide diffusing capacity. Am Rev Respir Dis. 1981;123:185–189.
54. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Muller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology 2008;246:697–722.
55. 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.
56. International Commission on Radiologic Protection. Report of the Task Groups on Reference Man, Vol. 23. Elmsford, NY: Pergamon Press; 1974.
57. 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.
58. Ahn MI, Gleeson TG, Chan IH, et al. Perifissural nodules seen at CT screening for lung cancer. Radiology. 2010;254:949–956.
60. Erasmus JJ, Connolly JE, McAdams HP, Roggli VL. Solitary pulmonary nodules: part I. Morphologic evaluation for differentiation of benign and malignant lesions. Radiographics. 2000;20:43–58.
61. Piyavisetpat N, Aquino SL, Hahn PF, Halpern EF, Thrall JH. Small incidental pulmonary nodules: how useful is short-term interval CT follow-up? J Thorac Imaging. 2005;20:5–9.
62. Khan AN, Al-Jahdali HH, Allen CM, Irion KL, Al Ghanem S, Koteyar SS. The calcified lung nodule: what does it mean? Ann Thorac Med. 2010;5:67–79.
63. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395–409.
64. Pegna AL, Picozzi G, Mascalchi M, et al. Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. Lung Cancer. 2009;64:34–40.
65. Becker N, Motsch E, Gross ML, et al. Randomized study on early detection of lung cancer with MSCT in Germany: study design and results of the first screening round. J Cancer Res Clin Oncol. 2012;138:1475–1486.
66. Saghir Z, Dirksen A, Ashraf H, et al. CT screening for lung cancer brings forward early disease. The randomized Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT. Thorax. 2012;67:296–301.
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