Attachment A ATTACHMENT A Excerpts, September 23, 1993 draft of VA Depleted Uranium Follow-up Study Department of Veterans Affairs Program for the Follow-up and Monitoring of Gulf War Veterans with Imbedded Fragments of Depleted Uranium DRAFT 9/23/93 Prepared by the Baltimore Veterans Affair: Medical Center for consideration by the Department of Veteran Affairs, Environmental Agents Service For further Information about this draft contact James P. Keogh, M.D. Director. University of Maryland Occupational Health Project 403 West Redwood Street 2nd Floor Baltimore. Maryland 21201 410-706-7464 Page 1 J. SPECIFIC AIMS The specific aims of the project are: 1. To provide on going clinical surveillance of Gulf War veterans known or suspected imbedded depleted uranium (DU) fragments, DU contaminated wounds or significant amounts of Inhaled DU. This clinical surveillance will provide early detection of health effects related to the presence of DU, and provide recommendations for treatment to participating veterans and the physicians caring for them. 2. To conduct focused research into the toxicological and radiological effects of DU in order to improve medical care for the participating veterans. In particular, research will be directed to improve the scientific basis for advice about fragment removal and other possible techniques to remove uranium from the body. Research will seek to improve currently available techniques for: (1) measuring and documenting uranium levels in affected individuals using in vivo and in vitro measurements techniques, (2) modeling uranium absorption retained fragments, distribution in tissue, and excretion to serve as a basis for estimates of the future health risks from this exposure; (3) comparing the clinical course of the body's response to the DU fragments with that for other non-DU fragments to determine whether clinically significant differences exist due to either the chemical or radiological properties of depleted uranium, (4) characterizing early kidney response to DU and elucidating the relationship between kidney does and the biomarkets of renal toxicity, (5) determining the risk of chronic kidney toxicity due to the long-term chronic exposure to elevated levels of uranium. (6) comparing the morbidity and mortality of individuals with retained DU fragments to other wounded and non wounded controls. 2. SIGNIFICANCE In recent years, the United States Armed Forces have used depleted uranium (DU) in the manufacture of both projectiles and armor. Uranium's high density makes it useful in designing projectiles capable of penetrating armor made with less dense metals, and conversely in armor with a high degree of resistance to penetration. The uranium used is "depleted" in the sense that it is the residue of an extraction process that selectively concentrates U235 and leaves behind U238. Naturally occurring uranium deposits contain over 99 5/8 U238, with small amounts of U235 and U234, U238 has too long a half life to be useful in making nuclear fuel or weapons. To create fissionable materials, the small amount of U235 present in natural uranium must be extracted and concentrated. Depleted uranium is the natural uranium left over from this process which contains even less U235 than naturally occurring ores. In the projectiles and armor, depleted uranium is alloyed with small amounts of molybdenum and titanium. During the Persian Gulf War, 15 Bradley Fighting Vehicles and 9 Abrams tanks were mistakenly fired on and struck by DU munitions. Some crew members who survived were left with imbedded fragments of uranium. Even depleted uranium has some intrinsic radioactivity, and there is uncertainty about the risk that these fragments may pose. Uranium is known from animal and human studies to be nephrotoxic. the rate at which uranium might be absorbed from fragments is unknown, leading to speculation about the possibility of sufficient absorption to present a danger of renal injury. At present only a limited number of U.S. veterans are known to have been wounded with DU weapon. An initial check by the OTSG has revealed that there are approximately 22 soldiers whose records indicate that they have imbedded fragments that might be DU. There are an additional 13 soldiers who were wounded and hospitalized but were not specifically identified as having shrapnel. Other crew members (in addition to the 35 already discussed) were either not wounded during (be incident or had minor wounds that were treated in the field. The latter two sets of soldiers might have inhaled uranium or experienced DU contamination of wounds or minor fragmentation wound: that were either not notIced or did not require extensive treatment. It appears unlikely that.many other U.S. servicemen who were wounded by DU munitions during the Gulf War will be identified. In addition to those individuals currently identified. there may be large numbers of other Individuals for whom information about the possible health effects of DU fragments will be important In the near future. It is possible that some other allied personnel were wounded by DU munitions. An undetermined number of Iraqi soldiers may have survived wounding by DU munitions. U.S. forces continue to use DU munitions, and may use them in future conflicts. DU penetrators are now available In international arm markets, and may become widely available to armies around the globe. In February 1992, OTSG requested that the Armed Forces Radiobiology Research Institute (AFRRI) conduct a review of the potential health hazards (radiological and toxicological) of allowing DU shrapnel to remain imbedded throughout the lifetime of the soldier. Specifically, OTSG wanted to know If there was any reason to change the current surgical practIce for fragment removal. No compelling evidence was found in the literature review to chance current surgical criteria for fragment removal. There were, however, significant uncertainties about the impact of DU fragments on the health of these patients that wanted long- term follow-up. Concern centered principally on the possibility that fragments could serve as a reservoir of absorbable uranium that might cause kidney injury over time.1 {AFFRI Review Document}. OTSG concurred with this finding and initiated action to implement this Follow-up in the Army. The Department of Veterans Affairs (DVA) agreed to perform the follow-up for personnel discharged from the service. Both the DVA and OTSG requested AFRRI's assistance in drafting the protocol to be used in the follow-up effort. A group of DOD physical and scientist: met at AFRRI to draft the protocol. At a subsequent meeting on 10 September 1992, a panel of experts reviewed and revised the draft protocol; representatives of the DVA and OTSG also attended this meeting. The protocol was once again reviewed and approved by the panel of experts.2 {AFFRI Protocol document}. This proposed program incorporates the protocol developed and published as AFRRI's Technical Report 93-2 with some additions and modifications. It benefits from the experience and advice of the authors and reviews involved in the prior DOD effort. Responsibility for the current proposal, including its differences from the prior proposal, rests, however, with the proposed program director and investigators from the Baltimore VA Medical Center. Page 3 Routine clinical measurements made on participants will be compared with laboratory normals and with available clinical measurements will underpin any clinical measurements from prior medical records. Initially, the stability or rate of change in the robust clinical measurements will underpin any clinical recommendations. Since renal toxicity is one of greatest immediate concern, evidence of progressive changes in blood urea nitrogen, serum creatinine and creatinine clearance, and uric acid will be given greatest weight. With time, longitudinal date on these and other measures of renal injury will be available, as well as comparisons between exposed and control subjects. While more sophisticated measures of injury may reveal an ongoing process of renal injury, caution will be used in imputing prognostic value. Few of these measures have been shown to be of prognostic value in any setting and none in the setting of uranium toxicity. Careful follow-up of this cohort may well reveal the prognostic value of some of these measures. In the meantime care will be exercised to weigh the possible harm of any intervention to reduce uranium burden against the likelihood of benefit to be gained. Development of models for the rate of absorption of uranium from fragments: Measurements of urinary excretion of uranium, bone concentration of uranium measured by X-rays fluorescence, and estimate of mass and surface area of fragments will be used to develop model for rate of absorptIon of uranium from fragments. It is hoped that experimental animal data with more direct tissue measurements will be available in the near future with which, these can be compared. Relation of estimated dose with effect: Results of examinations on subjects will be compared with those of controls. Subsequently, indices of dose derived from the measures listed above will be used to assess dose response relationships for the measures of health effects. Indices will be developed that rely on simple (e.g. size measured by plain roentgenogram) as well as more sophisticated measures (MRI dimension, body counting, bone XRF). 4.4 Longitudinal study of health outcomes: Concern over the long term effects or retained DU fragments needs to be resolved through controlled studies. The injuries sustained by participants. the psychological effects of participation in the conflict, the injuries sustained and confounding effects of other exposures during Desert Storm service may all contribute to adverse health outcomes in participating veterans. In order to distinguish those effects caused by absorption of uranium from fragments from those related to other factors, long term follow-up must include control population which make it possible to account for these confounders. 4.41 Methods: Longitudinal study of Death outcomes section under development Data management and data analysis: Longitudinal study Data management: (section under development) Analysis: The small size of the exposed population limits the study's ability to detect differences to only those effects where the differences between DU and non-DU imbedded fragments are large. For example, it is highly unlikely that definitive conclusions concerning cancer induction will be obtained from the study. However, this approach will allow a direct comparison of differences that may exist in deterministic effects. Examples of such effects include differences in the body's propensity to encapsulate a DU fragment, the onset of local or whole-organ tissue necrosis, thorotrastonma-like growth induction, or the Page 12 onset of chronic kidney toxicity. In addition a non exposed group will provide information concerning nominal values for each metabolic value studied in protocol (e.g., normal concentrations of uranium in the body and body fluids as well as kidney function variations with age). Quality assurance: section under development 5. HUMAN SUBJECTS Urgency and timing of the collection of clinical data Human volunteers process at UMBAB BVAMC Human volunteer approval for data sources to identify control groups How and if will consent be obtained from control populations 5.1 Distinction between clinical surveillance activities and the research necessary to support those activities. Participants in the clinical surveillance program will also be asked to volunteer as research subjects. The processes of enrollment in the surveillance program, of obtaining consent for clinical procedures, and of obtaining informed consent for research participation will explicitly distinguish what is clinical care and what is research. Undergoing procedures or tests that are not yet demonstrated to be of established benefit, or providing all or part of urine, blood, or tissue specimens for research activities will be identified to the participants as research, and will proceed only after explicit informed consent. 6. VERTEBRATE ANIMALS: No research on animals planned as a direct part of this program