Depleted Uranium (DU) and Toxic Embedded Fragments

1. Depleted Uranium (DU) and Toxic Embedded Fragments Melissa A. McDiarmid, MD, MPH Joanna Gaitens, PhD, MSN/MPH Katherine S. Squibb, PhD VA Maryland Health Care System University of Maryland Baltimore, USA

2. Disclaimer The views expressed in this presentation are those of the author and do not necessarily represent the position of the Department of Veterans Affairs or the United States Government I have no known conflicts of interest other than that I work for the Department of Veterans Affairs

3. Topics we will cover: • Environmental exposures of concern to Veterans: Depleted Uranium (DU), Toxic Embedded Fragments • The potential toxicity of DU and retained embedded fragments • Programs available through the VA for Veterans with concerns about these exposures • How Veterans enroll in these programs

4. What is Depleted Uranium? By-product of uranium enrichment process through which 235U is extracted from natural uranium for use as nuclear fuel Leftover is “depleted” with 235U/238U isotopic ratio = 0.245%

5. Isotopic Comparison of Natural and Depleted Uranium Natural Depleted Radioactivity Uranium Uranium Concentration Concentration m Isotope Ci/g of isotopes of isotopes 234 U 6200.0 0.0058% 0.001% * 235 U 2.2 0.72% 0.2% 238 U 0.33 99.28% 99. 8% Relative 1 0.6 Radioactivity

6. Chemical vs Radiological Toxicity • Chemical toxicity U234 = U235 = U238 • Radiological toxicity Specific activity: U234 >>> U235 > U238 so Natural U > DU Primary decay = alpha particles and gamma rays

7. Military Uses of DU • Tank armor for increased resistance to enemy projectiles • Munitions to increase penetrating power • Used in battle for first time in 1991 Gulf War

8. Gulf War I and OEF/OIF Exposures to DU • Friendly-fire incidents exposed US soldiers to: • DU shrapnel • Aerosolized DU oxides • Inhalation, ingestion, wound contamination • Burning of munitions storage facility • Decontamination of military equipment

9. DU Embedded Fragment

10. Potential Toxicity of DU • Systemic effects due to release of U ions to circulation and uptake by organs • Specific target organs of U • Kidney • Bone • Primarily chemical toxicity of U • Local effects on tissue surrounding DU embedded fragments • May be combination of chemical toxicity and radioactivity of U

11. Mission of the DU Follow-Up Program • Since 1993: To provide clinical surveillance for the ‘friendly fire’ DU-exposed GWI Veterans • Since 1998: To provide biologic monitoring by mail for DU for all GWI and OIF Veterans

12. The next several slides will cover: • Depleted Uranium Follow-Up Program • Purpose • Surveillance protocol • Findings • Depleted Uranium Mail-In Surveillance Program • Purpose • Findings

13. Purpose of DU Friendly Fire Victim Surveillance • Determine health effects, if any, in DU exposed populations (GWI, OEF, OIF) • Develop methods to measure DU exposure in this novel exposure mode (embedded fragments) • Examine surgical and medical management of embedded fragments– still an issue!

14. Complete history (medical, social, family, reproductive, occupational exposure, partner) Extensive laboratory studies (hematology, serum chemistry, neuroendocrine, urinalysis, urine, semen and blood uranium, renal markers, semen analysis) Chromosomal analysis (mutations, chromosomal aberrations) Neurocognitive testing Focus group/risk communication Surveillance Protocol during Biennial Inpatient Evaluation

15. Summary of Surveillance through 2009 79 unique cases have been evaluated from Gulf War I 4 Unique cases have been evaluated from OIF

16. Mean Urine Uranium Levels through 2007 for the 2009 Cohort

17. Clinical Findings • No clinically significant differences detected between low and high uranium exposure groups • Hematology • Neuroendocrine • Chemistries • Neurocognitive

18. Second Activity of DU Program: To provide urine uranium surveillance by mail for any Veteran requesting testing

19. Purpose of the DU Urine Biomonitoring Program • Determine urine uranium concentrations in Veterans from GWI and forward • Passively survey for exposure scenarios linked to DU exposure other than friendly fire • Provide assistance to Veterans’ primary care providers in interpreting results and answering Veterans questions

20. Summary of Mail-in Activity through May 31, 2010 TOTAL GWI OIF Sampling kits requested N > 4597 1682 > 2915 Total uranium only 476 Samples tested as of 5/31/10 N = 3136 Total uranium & DU 1847 Total uranium & DU 813 Positive for DU N = 4* 3 1 *All friendly fire

21. Toxic Embedded Fragment Surveillance Center (TEFSC) and Registry

22. Background • Traumatic injuries via contact with improvised explosive devices (IEDs) are a major concern in Iraq, and increasingly in Afghanistan • More than 40,000 soldiers with traumatic injuries may have retained embedded fragments. • IEDs are packed with heterogeneous material that may lead to local and systemic adverse health effects.

23. Presidential Task Force Recommendation P-7 directed the VHA to establish a registry and medical surveillance program for Veterans with embedded fragments VHA directed to address the issue of embedded fragments

24. Health concerns related to embedded fragments • Local effects • Risk of the development of tumors at the fragment sites • Systemic effects • Risk of target organ effects arising from chemicals released from fragments

25. Fate of DU Metal Fragments in Rat Muscle In Situ Correlation of radiographic appearance with histologic appearance. (A) Thick fibrotic capsule with shards of corroded DU in lumen; (B) thick cellular capsule lined by squamous metaplasia, particles, and shards of corroded DU in wall and lumen; (C) particles and shards of disintegrated DU fragment scattered throughout a soft tissue sarcoma (Hahn et al, 2002).

26. Embedded DU Fragment in 1991 Gulf War Veteran 1995 film 2001 film Change in DU fragment appearance over time; suggests oxidation in situ and removal is warranted.

27. New Alloy Used in Munitions: W/Ni/Co • Metastatic tumors caused by implanted tungsten alloy (W/Ni/Co) fragments in rats • Rhabdomyosarcomas rapidly metastasize to lung • Survival time is significantly reduced Kalinich et al. Env. Hlth Perspec. 113: 729-734, 2005

28. Evidence supports development of Toxic Embedded Fragment Surveillance Center (TEFSC) • Local Effects • Evidence from DU Program and medical device and fragment literature • New studies of metal implanted animals with new tungsten alloy (W, Co, Ni) demonstrating rapid carcinogenesis • Systemic Effects • Known renal, reproductive and neurological effects of metals (e.g. Pb, Cd, Ni, Mn, Cu)

29. The next several slides will cover: • Toxic Embedded Fragment Surveillance Center • Mission • Specific functions of TEFSC • VA’s Embedded Fragment Registry • Purpose of the registry • Eligibility criteria • Screening process for identifying eligible veterans • Data captured in the registry

30. VA Toxic Embedded Fragment Surveillance Center • Established at Baltimore VA Medical Center • Mission: To provide care and active medical surveillance for Veterans with retained embedded fragments

31. Functions of TEFSC • Fragment Characterization • Biomonitoring & Medical Surveillance • Registry Development • Case Consultation

32. Analyzing fragment composition is an essential function of TEFSC • Chemical analysis of removed fragments • Surface chemistry • Total fragment composition • Analysis of tissue surrounding fragments • Chemical analysis of tissue • Characterization of tissue morphology • Histology- proliferative cells, neoplastic cells

33. Summary of Composition of Fragments from Military Personnel 2006-2008 (AFIP data)* 407 fragments analyzed 337 Metals 70 Non-Metals 44 Organic materials 10 plastic & polymers 1 fabric and 1 wood 26 Stones 336 non-radioactive alloys (steel & brass) and non-alloyed metals 1 radioactive Fe, Cu, Al, Ni, Pb, Zn with traces of other elements including Cr, Mn, Sn, Sb, Ti, W DU with traces of Al, Cr, Cu, Ti, Zn *Division of Biophysical Toxicology, Armed Forces Institute of Pathology Centeno JA, et al. (2009)

34. Fragment data informs biomonitoring and medical surveillance protocol • Fragment composition data helps: • Identify a list of toxicants to include in biomonitoring panels • Identify outcomes of concern and means of surveillance • Identify potential biomarkers of early effect

35. Fragment Analysis Process 1. TEFSC sends fragment collection kit to requesting VA 2. VA obtains fragment from Veteran and mails completed kit to TEFSC 3. Fragment is analyzed 4. TEFSC sends result letters to Veteran and VA Provider

36. Biological Specimens also provide insight into exposure • Toxicants of interest • Metals: Al, As, Cd, Cr, Co, Cu, Fe, Mn, Ni, Pb, U, W, Zn • Plastics/polymer components: Isocyanate, Acrylics, Diethylhexylphthalates • Others: Based on fragment analysis data • Biological Specimens • Urine, blood, other body fluids when indicated

37. Biological Monitoring Process 1. TEFSC sends kit is sent to requesting VA 2. Veteran provides 24-hour urine sample and completes questionnaire 3. VA mails completed kit to Baltimore VA 4. Specimen and questionnaire are analyzed 5. TEFSC sends result letters to Veteran and VA Provider

38. Surveillance protocol involves periodic follow-up to identify potential health outcomes • Perform baseline urinalysis • based on chemical composition of removed fragment(s) • Perform periodic follow up urinalysis • to identify specific biomarkers of exposure and effects based on baseline results • Conduct periodic radiologic surveillance of embedded fragment location and shape • Consider target organ surveillance for toxicants of concern

39. Purpose of the VA Embedded Fragment Registry To track, monitor and provide appropriate medical care and follow up for Veterans with embedded fragments resulting from injuries sustained during their tour of duty Identify Veterans who served in Iraq and Afghanistan and who have embedded fragments Identify health concerns associated with embedded fragments Develop medical and surgical management guidelines for Veterans with embedded fragments

40. Any Veteran who served in Operation Enduring Freedom or Operation Iraqi Freedom who has or likely has a retained fragment as the result of an injury received while serving in the area of conflict are eligible for inclusion into the registry.

41. Individuals with embedded fragments are identified by both the VA and the DoD The VA has created a process to screen Veterans for embedded fragments at their local VA facility DoD is creating their own “Embedded Metal Fragment Registry” The DoD and VA are collaborating to ensure that all Veterans who have embedded fragments are identified and receive appropriate follow-up care.

42. The VA Screening process for Veterans with fragments uses the “Clinical Reminder” system

43. Screening Questions Do you have or suspect you have a retained fragment as the result of an injury received while serving in the area of conflict? • - Were you injured by a bullet? • - Were you injured as a result of a blast or explosion? • - Were you in or on a vehicle at the time of the blast or explosion? • Was the blast or explosion caused by: IED, RPG, land mine, • grenade, enemy fire, friendly fire, don’t know, or other? • Did you have shrapnel, fragments or bullets removed during • surgery? • - If yes, were they sent to the lab for analysis? • Do you have retained shrapnel, fragments or bullets in your • body? • - If yes, have they been documented by radiograph?

44. Screening information is automatically captured in the VA’s Embedded Fragment Registry Then TEFSC determines if the following services are needed: Fragment analysis Biological monitoring Clinical Consultation The VA’s registry will also identify if the individual is in DoD’s registry AND if the individual had a fragment removed and analyzed by DoD.

45. The Embedded Fragment Registry will capture “basic” data Screening Details Answers to screening question Local VA contact person Referral Status Demographic Information Healthcare Information Contact information for Primary Care Provider VA facility where Veteran receives care

46. …and Exposure/Health Details Injury and exposure information Developed standardized exposure questionnaire Biomonitoring data Tests ordered, analyses methods, results, interpretation of results, tracking information Fragment analysis data Analyses methods, results, interpretation of results, tracking information Health outcomes Results of specific clinical tests ICD-9 codes

47. Much of the registry data will come from existing data sources

48. Conclusion The registry will help the VA and the DoD refine how cases are identified and provide appropriate medical care for individuals with embedded fragments.

49. Toxic Embedded Fragment Surveillance CenterandDepleted Uranium Program1-800-815-7533