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4 AFRRI Programs, Research, and Resources This chapter addresses the second element of the committee’s statement of task, assessing how Armed Forces Radiobiology Research Institute (AFRRI) programs are advancing research in radiobiological science related to human health risks from exposures to low-dose ionizing radiation. The chapter presents a brief history of AFRRI and its role within the Military Services. The Institute’s physical plant, staff, budget, current research, collaborations, and educational efforts are also described. Material in this chapter is derived in part from a presentation to the committee by AFRRI Director L. Andrew Huff, Col, USAF, MC, SFS (Huff, 2013a) and on responses that AFRRI provided to questions posed by the committee (AFRRI, 2013a, 2013b; Huff, 2013b, 2014). Citations for these and other sources are made as appropriate. AFRRI HISTORY AND BACKGROUND The Department of Defense (DoD) has been interested in the health effects of exposure to radiological agents since at least the initiation of the Manhattan Project. That interest became operational in 1958 when the U.S. Navy Bureau of Medicine and Surgery proposed that a bionuclear research facility be established to study such issues (DTRA, 2002; Tenforde, 2011). Public Law 86-500 (June 8, 1960) subsequently authorized construction of a laboratory and vivarium under the auspices of the Defense Atomic Support Agency (DASA) and, on December 2, 1960, the Military Services Surgeons General and DASA approved a charter for AFRRI (DTRA, 2002; Solyan, 2004). The Institute was formally established on May 12, 1961 when DoD Directive 5154.16 was issued. Research at AFRRI began in January 1962, although the laboratory was not fully operational until September 1963 (DTRA, 2002; Solyan, 2004). At that time, the research facility included a Training, Research, Isotopes, General Atomics (TRIGA®) Mark F nuclear reactor, laboratory space, and an animal facility. The TRIGA reactor, a unit specifically designed for research, teaching, and commercial applications, allowed studies of radiation characteristics relevant to nuclear weapons that were not available at other DoD or Department of Energy facilities at that time. A high-dose cobalt-60 (60Co) facility, a 54-megaelectron volt (MeV) linear accelerator (LINAC), and a low-level 60Co irradiation facility were subsequently added (Solyan, 2004). The Institute operated as a joint agency of the Army, Navy, and Air Force under the command and administrative control of the Office of the Secretary of Defense. In July 1964, responsibility for AFRRI was assigned to DASA, and the Chief of DASA was designated as the PREPUBLICATION COPY: UNCORRECTED PROOFS 4-1

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4-2 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI chair of its Board of Governors. AFRRI was identified as an operational field element of DASA while essentially functioning as an independent institute (AFRRI, 1968). In the 1960s, the Institute’s research enterprise was partitioned into five departments— Experimental Pathology, Behavioral Sciences, Physical Sciences, Chemistry, and Radiation Biology—and focused on biological responses, with an emphasis on high doses of external radiation. Animal studies were an integral part of this work and were used to establish the effects of radiation on the central nervous and circulatory systems and on other tissues and organs (DTRA, 2002). AFRRI collaborated through Memoranda of Understanding and interagency agreements with universities, government agencies, and corporations (DTRA, 2002). DASA was disestablished in 1971, and its responsibility for AFRRI was assumed by the newly formed Defense Nuclear Agency (DTRA, 2002). At around the same time, concerns were emerging about the possible relationship between exposure to radiation during military service and the occurrence of cancer. AFRRI was involved in the process that resulted in the establishment of the Nuclear Test Personnel Review program in January 1978. This program, which is still in operation, determines or estimates the radiation dose of veterans who participated in U.S. atmospheric nuclear tests or in the occupation forces of Hiroshima and Nagasaki, Japan, immediately after the atomic bombings, information that is used in compensation determinations for long-term radiation-related illnesses (DTRA, 2010). The experience and expertise developed by AFRRI in dealing with accidents, hazardous materials and radiological clean-up issues were used in the international arena when AFRRI staff formed part of the International Chernobyl Site Restoration Assistance Team after the 1986 accident. They also provided assistance to the environmental cleanup efforts at the closed Soviet test site at Semipalatinsk, Kazakhstan (DTRA, 2002). The Defense Nuclear Agency transferred control of AFRRI to the Uniformed Services University of the Health Services (USUHS) in 1993 (DTRA, 2002). As the Cold War wound down, resources shifted to concentrate on peaceful activities, including social and nondefense programs. AFRRI’s funding and personnel levels diminished, and proposals were made to close the facility. However, military leaders indicated that there were no alternative sources for the information that the Institute developed, and these proposals were not acted on (Solyan, 2004). U.S. interest in nuclear preparedness again increased in the late 1990s in response to India’s and Pakistan’s nuclear testing and the suspected development of nuclear weapons by Iraq and North Korea. AFRRI’s mission became more important to DoD in part because private companies lacked the incentive to develop radioprotectants and countermeasures for the military (Solyan, 2004). In response to this renewed interest, funding for AFRRI increased in 2000 (Assistant Secretary of Defense, 2004). Increased awareness of terrorist threats in the wake of the attacks on U.S. sites on September 11, 2001 also stimulated support for the Institute (AFRRI, 2009). These events helped shape a change in AFRRI’s scope of work to include minimizing the effects of radiological dispersal devices (RDDs), terrorist access to radiation sources, and sabotage of nuclear reactors (Solyan, 2004). However, AFRRI’s readiness and capabilities were limited by their facilities and staffing level. At the time, the Institute faced the challenge of deteriorating mechanical and structural systems. Extra support granted in 2003–2004 allowed for infrastructural upgrades and the development of a radioprotective drug (5-androstenediol, HE 2100). PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Programs, Research, and Resources 4-3 Today, AFRRI is DoD’s only medical research and development initiative dedicated to nuclear and radiological defense. It serves the military by performing medical research and development, education, and advisory and consultative functions for the purposes of understanding, preventing, preparing, and responding to releases of ionizing radiation (AFRRI, 2011a). Box 4-1 delineates AFRRI’s mission, responsibilities, and assigned functions. BOX 4-1 AFRRI’s Mission, Responsibilities, and Functions as Delineated in DoD Instruction 5105.33, Issued on March 29, 2006 Mission (§3) The mission of the AFRRI shall be to conduct research in the field of radiobiology and related matters essential to the operational and medical support of the Department of Defense and the Military Services. The AFRRI may provide services and perform cooperative research with other Federal and civilian agencies and institutions with the approval of the Assistant Secretary of Defense for Health Affairs. Responsibilities and Functions (§5.1) • Operate research facilities for the study of radiobiology and ionizing radiation bioeffects and for the development of medical countermeasures against ionizing radiation, and the results shall be disseminated. o The scope of this research shall reflect requirements identified by the DoD Components for support of military operational planning and employment (current and future), and shall put special emphasis on individual and organizational performances under nuclear and radiological combat conditions in realistic operational and force protection scenarios. o The AFRRI program shall consider present and projected threats, Service and joint operational concepts and weapons, and defense systems developments. • Provide analysis, study, and consultation on the impact of the biological effects of ionizing radiation on the organizational efficiency of the Military Services and their members. • Conduct cooperative research with the Military Medical Departments in those aspects of military operational and medical support considerations related to nuclear weapons effects and the radiobiological hazards of space operations. • Conduct advanced training in the field of radiobiology and the biological effects of nuclear and radiological weapons to meet the internal requirements of the AFRRI, the Military Services, and other DoD Components and organizations. • Participate in cooperative research and other enterprises, consistent with the AFRRI mission and applicable authorities, with other Federal agencies involved in homeland security and emergency medical preparedness. • Perform such other functions as may be assigned by the Assistant Secretary of Defense for Health Affairs. SOURCE: DoD, 2006 PREPUBLICATION COPY: UNCORRECTED PROOFS

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4-4 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI Management Structure AFRRI functions as a joint entity of the Military Services under the authority, direction, and control of the president of USUHS, the Assistant Secretary of Defense for Health Affairs, and the Under Secretary of Defense for Personnel and Readiness (DoD, 2006). DoD Initiative 5105.33 (§4.2) specifies that it is to be led by a director who is a military officer with a doctoral degree in one of the life sciences. The Director is nominated by the Surgeons General of the Army, Navy, and Air Force and appointed for a 4-year term. It is the Director’s responsibility (§6.1) to act as liaison to the heads of DoD’s components and other governmental and nongovernmental agencies and to ensure that the DoD components are informed of AFRRI’s activities. No scientific duties are assigned to the post. Scientific leadership is exercised by a Scientific Director, who is tasked with the administration and supervision of the Institute’s research-oriented departments, overall scientific and technical planning of the research program, and service as the scientific liaison with the outside world (AFRRI, 1968). However, this position has not been filled since 2012. There is, at present, a Scientific Advisor who counsels the Director and acts as a liaison with outside agencies but is not a part of the chain of command (Huff, 2013b). Box 4-2 lists AFRRI’s Directors and Scientific Directors since its inception. AFRRI is currently made up of Radiation Sciences, Scientific Research, Military Medical Operations, Veterinary Sciences, Facilities Management, Good Laboratory Practice/Test Facility, and Administration Support departments, which are led by department heads or managers (Figure 4-1). Four primary research areas are identified on the Institute’s website: biodosimetry, combined injury (radiation with other insults), internal contamination and metal toxicity, and countermeasure development (AFRRI, 2014g). PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Programs, Research, and Resources 4-5 BOX 4-2 AFRRI Leadership AFRRI Directors 1961–1966: James T. Brennan, COL, MC, USA 1966–1967: Joseph S. Burkle, CAPT, MC, USN 1967–1971: Hugh B. Mitchell, Col, MC, USAF 1971–1975: Myron I. Varon, CAPT, MC, USN 1975–1977: LaWayne R. Stromberg, Col, MC, USAF 1977–1979: Darrell W. McIndoe, Col, MC, USAF 1979–1982: Paul E. Tyler, CAPT, MC, USN 1982–1985: Bobby R. Adcock, COL, MSC, USA 1985–1986: James J. Conklin, Col, MC, USAF 1986–1987: Richard I. Walker, CAPT, MSC, USN 1987–1991: George W. Irving III, Col, BSC, USAF 1991–1995: Robert L. Bumgarner, CAPT, MC, USN 1995–1997: Eric E. Kearsley, CAPT, MSC, USN 1997–2003: Robert R. Eng, COL, MS, USA 2003–2006: David G. Jarrett, COL, MC, USA 2006–2010: Patricia K. Lillis-Hearne, COL, MC, USA 2010–2012: Mark A. Melanson, COL, MSC, USA 2012–present: L. Andrew Huff, Col, MC, SFS, USAF AFRRI Scientific Directors 1966–1971: Harold O. Wyckoff, Ph.D. 1982–1987: Lawrence S. Myers, Ph.D. 1987–1989: Richard I. Walker, Ph.D., CAPT, MSC, USN 1989–1998: E. John Ainsworth, Ph.D. 2002–2008: Terry C. Pellmar, Ph.D. 2008–2012: Christopher R. Lissner, Ph.D. NOTE: This position was not filled in some periods SOURCE: Solyan, 2004; AFRRI, 2010, 2013b PREPUBLICATION COPY: UNCORRECTED PROOFS

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4-6 Resea arch on Health Effects of Low w-Level Ionizing Radiation Ex g xposure – Opportunities for A AFRRI FIGURE 4-1 AFRRI chain of com mmand and orgganizational s structure. Abbreviat tion: IACUC, Institutional Animal Care and Use Com , e mmittee SOURCE derived from AFRRI, 20 E: m 013c, and Huf 2013b ff, Capability and Infrast tructure AFRRI’s ded A dicated radiat tion sources and speciali ized facilitie are summa es arized in Tab ble 4-1 and are described in the follo a d owing sectionns. TABLE 4-1 AFRRI Radiation Sources I S Source Activi or Energy ity y 1-meggawatt (MW) steady state o 2,500-MW or W TRIGA® Mark F reactor pulse, mixed beam – neutron, ph m hoton 60 Co faci ility (panoram irradiator) mic ) 00-Curie (Ci) 60Co source 450,00 ) Chronic irradiation facility 100-C 60Co source Ci e ndustrial X-ra machine* Philips in ay 40-32 0 peak kilovo oltage (kVp) Cesium (Cs) calibratio facility ( on 100-C 137Cs source Ci e LINA operations up to 15 meg AC gaelectron volt Elekta In nfinity™ linea accelerator (LINAC) wi ar r ith (MeVV) Synergy® image-guide workflow and ed System was acquired in August 2012 but was not m s Philips Brilliance CT Big Bore B operattional as of Ja anuary 2014. SOURCE Huff, 2013 2014; Kan et al., 2011 AFRRI, 20 ES: 3c, ng 1; 011a. * This sour was replac by an Xst rce ced trahl Small Animal Radiat A tion Research Platform in 2 h 2014. TRIGA Reactor R AFRRI’s TRI A IGA reactor is one of 66 worldwide (General At 6 tomics, 2014 These 4). research reactors are used in univversity and government l g laboratories and medica centers for al r applicatio that incl ons lude product isotopes for medicine an treating tu tion of radioi nd umors, nondestruuctive testing, basic scie ence research education, and training. They oper at therm h, , rate mal power lev of <0.1– megawa (MW) an may be p ulsed up to 2 vels –16 atts nd 22,000 MW. PR REPUBLICA ATION COP UNCO RRECTED PROOFS PY: D

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AFRRI Programs, Research, and Resources 4-7 The reactor is licensed by the U.S. Nuclear Regulatory Commission (License R-84). As of 2005, it was one of 18 TRIGA reactors in the United States and the only one dedicated to applied medical radiobiology research (Dix, 2005). It is a medium-sized unit that generates neutrons and gamma rays for radiation experiments. The reactor can produce a controlled, self- sustaining fission chain reaction in the reactor core which, in addition to the fuel elements and control rods (containing boron carbide), includes a neutron start-up source (Americium/Beryllium). It is suspended under 16 feet (~4.9 m) of water within a pool (an effective radiation shield) in a carriage assembly that allows movement of the core between two exposure rooms for experimental work with large-animal or other studies (Dix, 2005). The advantages of such a movable reactor core are that the quantity and character of the radiation that reaches the exposure facilities can be controlled, and more than one exposure facility can be used during reactor operations. The reactor can operate in steady-state as well as pulse mode. The maximum allowed steady-state power level is 1.0 MW. Its pulse mode can produce a short peak (from a prompt critical excursion) of up to 2,500 MW occurring in about 0.1 sec. The neutrons and gamma rays produced in the reactor pass (as a unique mixed field) to exposure facilities, where biological systems are irradiated for studies. The facilities include two large exposure rooms and a core experiment tube, each with a distinctive radiation field and set-up characteristics that allow for studies of a variety of conditions. The gamma:neutron ratio can be varied from 1:20 to 20:1 through the use of shields and absorbers placed in the exposure rooms (AFRRI, 1993). Special set-ups (in-pool portable beam tubes, a pneumatic transfer system, and in-core grid-location tubes) and custom radiation beams are also available. Exposure rates can be varied from about 0.1 rad/min (0.06 gray [Gy]/hr) to 1,000 rad/min/pulse (600 Gy/hr/pulse). Although primarily used for biological studies, the unit may also be used for transient radiation– electronic effects (TREE) studies and the production of isotopes. Cobalt-60 Facility The 60Co facility at AFRRI first opened in 1969. The facility is located below ground in the AFRRI complex, with shielding provided by massive reinforced concrete and earth fill. Its panoramic irradiator is a wet-source storage unit consisting of a 450,000 Ci (at installation) 60Co source, water trench, source and storage racks, elevator mechanism, and associated equipment. The exposure room is 35 ft × 35 ft and 25 ft, 8 in high (10.7 m × 10.7 m × 7.6 m = 870 m3) (AFRRI, 1993). The irradiator produces monoenergetic gamma rays at variable dose rates with flexible configurations in both unilateral and bilateral irradiation modes, and may be used for acute and chronic studies of materials, biologic specimens, and small and large animals (Carter and Verrelli, 1973; Naquin et al., 2001). It has been employed in a variety of applications, including investigations of the effects of ionizing radiation exposure on cells (McKinney et al., 1998), prognostic indicators of survival in a variety of mammals (Moroni, et al. 2011), and the efficacy of radioprotective agents (Landauer et al., 2001; Singh et al., 2010). In 2013, AFRRI contracted to replace the facility’s existing, decaying sources with new 60 Co sources (FedBizOps.gov, 2013). PREPUBLICATION COPY: UNCORRECTED PROOFS

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4-8 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI Chronic-Irradiation Facility AFRRI has a second 60Co radiation source that provides low dose–rate gamma-photon radiation to simulate chronic exposure to low doses and is used to study early and late effects in biological samples. This 100-Ci chronic-irradiation facility (Dix, 2005) is sometimes called the low-level irradiation facility (Solyan, 2004). Earlier AFRRI reports (AFRRI, 1993; Zeman and Dooley, 1984) describe a 4,200-Ci therapeutic irradiator (AECL Theratron-80) capable of providing from 1 to several hundred rad/hr (0.01 to several Gy/hr) over limited field sizes, and a uniform field. It was primarily used to conduct cellular studies. However, this source was decommissioned in the 1990s. Linear Accelerator AFRRI’s first LINAC was designed and assembled between 1965 and 1968; it provided a powerful, flexible source of high-energy electrons, high-energy bremsstrahlung (X-rays), and neutrons (AFRRI, 1993). It was used for a broad range of applications, including radiobiology and radiochemistry studies (AFRRI, 1993). Various machine configurations were used to provide electron energies continuously variable from 10 to 54 MeV (Dix, 2005). This device was retired and, in August 2012, AFRRI acquired a new LINAC and computed tomography (CT) unit: an Elekta Infinity LINAC capable of operations up to 15 MV and a Philips Brilliance CT Big Bore (Huff, 2014). These devices will be used for research purposes only. Neither was operational at the time the committee completed its work in late 2013. Other Radiation Sources AFRRI also has a Philips industrial X-ray machine that is a water-cooled device with peak kilovoltage (kVp) that ranges from 40 to 320 kVp (AFRRI, 2011a).1 This machine is used mainly for cellular work and, depending on the field size, the output can be varied from a few to 7,000 rad/min (4,200 Gy/hr). The machine also serves as a back-up for the 60Co facility (AFRRI, 1993). The Institute also maintains a cesium (Cs) calibration facility that consists of a 100-Ci 137 Cs source and associated equipment. 1 After the report was completed, the committee learned that this source has been replaced by an Xstrahl Small Animal Radiation Research Platform. PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Programs, Research, and Resources 4-9 Usage of Radiation Facilities The committee asked AFRRI to delineate how often its radiation facilities are being used by AFRRI investigators and by any outside investigators or collaborators.2 AFRRI’s response, dated October 15, 2013, is summarized in Table 4-2 (AFRRI, 2013b). TABLE 4-2 Usage and Availability of AFRRI Radiation Sources, January 2012–October 2013 Device Usage Availability* TRIGA reactor 51 days training; 17% of available time 79% unused Accessible 293 days total 10 days in-house use; 3% of available time Cobalt-60 facility 1,058 hr in-house use; 46% of available time 50% unused Accessible 2,300 hr total 82 hr outside use; 4% of available time Chronic-irradiation “Several days” Nearly 100% unused (low-level) facility * These numbers include time when sources were unavailable due to equipment failure or maintenance. SOURCE: (AFRRI, 2013b) Animal Facility An animal-research facility is an important resource for understanding basic radiobiology and for developing medical countermeasures against radiation injuries. AFRRI’s facility is organized within its Veterinary Science Division. The 28,565-ft2 (~2,650-m2) space is designed to support radiation and surgical studies and includes environmental controls and monitoring, histopathology, microbiology, and clinical pathology laboratories. It comprises • Two large-animal surgery suites, • One radiology suite, • One large-animal treatment room, • One large-animal necropsy room, • Ultrasound and electrocautery equipment for diagnostic and surgical purposes, and • Two rodent-procedure rooms. AFRRI is one of the few DoD laboratories capable of housing a variety of animals. In response to an inquiry from the committee, AFRRI indicated that the facility commonly maintains 4,000–5,000 mice and rats, 8–20 minipigs, and 60–80 nonhuman primates (rhesus macaques) (AFRRI, 2013b). In late 2013, the Veterinary Sciences Department comprised 26 staff members: 5 veterinarians (Department Head, Deputy Head, Contract Clinical Veterinarian, Veterinarian, and Veterinary Pathologist), 6 veterinary technicians (5 military and 1 civilian), 11 government animal-husbandry personnel, 3 pathology lab staff (2 military and 1 civilian), and 1 administrative person (military, on loan) (AFRRI, 2013b). 2 Outside investigators may use the facilities for studies performed in collaboration with an AFRRI project or other projects funded by a government agency. PREPUBLICATION COPY: UNCORRECTED PROOFS

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4-10 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI The Veterinary Sciences Department has maintained an American Association for Accreditation of Laboratory Animal Care –accredited animal care and use program since 1984. All research protocols require review and approval from the organization’s Institutional Animal Care and Use Committee. The program supports not only AFRRI research, but also USUHS and Walter Reed National Military Medical Center studies. CURRENT RESEARCH PRIORITIES AND PORTFOLIO AFRRI’s research agenda has evolved over time with U.S. defense needs, changes in funding, and scientific advancements. In the 1960s, the focus was on the effects of high doses of external radiation and the development of causality criteria for radiation illnesses. However, as military and defense priorities changed, it has expanded to include nuclear-weapons effects, trauma, toxicology, nonionizing-radiation effects, cancer markers, and drug toxicity, as well as specific needs for solutions to casualty problems that may be associated multiple insults from exposure to radiation and other battlefield hazards such as biological and chemical agents as well as wounds, infection, and diseases (Solyan, 2004). AFRRI’s current efforts concentrate on minimizing the health effects of exposure to high- dose ionizing radiation in combat and military environments through prevention of hazards, assessment, and medical treatments of injuries relating to radiation both alone and with other chemical or biological hazardous agents. These efforts are summarized in the following sections. Radiobiology Research In accordance with its charter, AFRRI conducts research in the field of radiobiology and related matters essential to the operational and medical support of DoD and the Military Services. This includes evaluation of threats (the threat spectrum, defining the source and risk, operating in a contaminated environment, consequence management, modeling and decision support, and the like); triage (methods, tools, techniques and biodosimetric models); and treatment (both prophylactic and mitigative, as well as evaluating off-label and investigative drug use in DoD). AFRRI research has concentrated on military concerns such as preparation, consequence management, and mitigation, and it extends from acute event–response readiness to actual radiation exposures of DoD personnel. Such work is also relevant to civilian exposures resulting from accidents, terrorist activities, or war. The AFRRI research program is aimed directly at current research gaps in medical preparedness for responding to such events. For example, current countermeasures (amifostine, the only Food and Drug Administration [FDA]-approved radioprotectant) may have effects that make them inappropriate for military use. Available biodosimetric tools for triage are limited in speed and physiological predictive power. There is also a need for mitigation and therapeutic agents approved for radiation-induced hematopoietic or gastrointestinal injury. Therefore, the AFRRI research and development goals concentrate on the following: pursuing new drugs that will prevent the life-threatening and health-degrading effects of ionizing radiation; developing methods for rapidly assessing radiation exposure to ensure appropriate medical treatment; investigating the effects of radiation injury combined with other challenges such as trauma, disease, and chemical exposures; and contributing to the radiobiological knowledge base. PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Pro ograms, Resear and Resou rch, urces 4-11 Biologi Dosime ical etry AFRRI has been engaged in developi rapid, hig A d ing gh-precision analytical m n methods that can t be used to assess radiation-expos t sure doses frrom clinical samples to a in the tria and med aid age dical managem of radio ment ological casuualties. The specific obje s ectives of thi research in is nclude automatin field-dep ng ployable biollogical dosim metry capabi ilities for rap dose asse pid essment on tthe battlefiel establishi reference biological dosimetry fo definitive analysis of biological ld, ing e d or samples from militar theater operations, and identifying and validat f ry d g ting early-ph hase radiatio on- specific biomarkers of late-radiat b o tion effects. AFRRI’s rese A earch in the biological do b osimetry are has cente ena ered on the d development of t integrated biodosime and diag etry gnostic system (Figure 4 ms 4-2). Triage, clinical, an definitive , nd radiation biodosimetr require multiple bioas n ry m ssays and sppecific analyt technolog designe for tic gies ed chemical biological, radiologica nuclear, an explosive (CBRNE) exposures because no si l, , al, nd e ingle assay or technique is sufficient. The aims are to create pr t T e rotocols and analytical systems for h d high- throughp applicatio to identi bio-indic put ons, ify cator assays for rapid ass sessment ove a broad do er ose range, to refine hema atological an molecular protocols a analytica systems, to validate th nd r and al o he systems using in vivo model stud u o dies, and to develop softw d ware for inte egrated biod dosimetry da ata managem ment. FIGURE 4-2 The com mponents of an integrated biodosimetry and diagnost system. a b y tic SOURCE AFRRI, 201 E: 13d The appropria use of medical resou T ate urces for perssonnel expos to ionizing radiation sed n depends on timely, accurate dose information To assist i meeting th specific a often e n. in his and complex need, AFRR developed the Biodos RI d simetry Asseessment Too (BAT) (AF ol FRRI, 2013e a e), computer r-based softw system for use by health care p ware m h providers ressponding to a radiation incident. The BAT as ssists provid in identi ders ifying indivi iduals who h have significant radiation n exposure and then in making ap es n ppropriate tre eatment deci isions using AFRRI-dev veloped, radiation dose–preedicting algo orithms (sing lymphocy count, ly gle yte ymphocyte-d depletion rate and time f e, from exposure to time of onset of emesis). The BA algorithm are also a e o AT ms available at th Radiation he n Event Me edical Manaagement web bsite (www.r remm.nlm.go ov/ars_wbd. .htm), an integrated education and respo nal onse tool suppported by the U.S. Dep partment of HHealth and H Human Servi ices (HHS) an the National Library of Medicine nd o e. PR REPUBLICA ATION COP UNCO RRECTED PROOFS PY: D

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4-22 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI TABLE 4-5 Base and Exercised Options Contract Amounts (in $M) to AFRRI by Contracting Agency and Year Contracting Agency 2006 2007 2008 2009 2010 2011 2012 2013 Total Navy 1.1 0.3 0.8 0.5 1.9 0.0 4.6 Army 20.2 11.6 12.6 0.1 11.2 7.5 63.2 TRICARE 3.9 0.1 4.0 USUHS 0.3 0.4 1.1 0.7 0.5 3.1 Total 20.2 13.0 13.3 1.9 0.8 12.2 13.3 0.1 74.9 SOURCE: USASpending.gov data as of May 15, 2013 It should be noted that the accuracy of these data is subject to timely and accurate reporting by each agency and to the frequency of updates to the online database. Changes may occur as errors are corrected and more information is submitted, and contract amounts may change as modifications are made and other contracting issues occur (USAspending.gov, 2013). STAFF AND CAPABILITIES AFRRI’s current and future research is dependent on its staff and resources. The Institute’s labor force grew from 254 in 1965 to 285 in 1990, followed by budgetary cuts that reduced personnel in the 1990s. In 2004, the staff comprised 154 employees, 97 of whom were civilian (Assistant Secretary of Defense, 2004; Solyan, 2004), and in 2011, there were 183 employees, of whom 130 were civilian (AFRRI, 2011a). As of July 2013, AFRRI’s Scientific Research Department comprised 68 employees: • 19 PIs: 17 civilian federal employees and 2 military personnel, • 14 Research Associates: 13 contractors and 1 military personnel member, and • 35 Technicians: 22 contractors, 9 civilian federal employees, and 4 military personnel. The AFRRI scientific staff is interdisciplinary and diverse. Its PIs come from a range of educational backgrounds. Two have doctoral degrees in the field of Radiation Biology or Radiobiology, a third has a master’s-level degree in the same field, and three others have received specialized training or completed postdoctoral work directly related to the field (radiation countermeasures, radiation biodosimetry, and cell radiobiology). Other fields of doctorate study among the PIs include biodefense, bioinformatics, bio-inorganic chemistry, biology, chemistry, medicinal chemistry and molecular pharmacology, medicine, microbiology, nutritional chemistry, nuclear particle physics, physiology, life space sciences, toxicology, and zoology. Their specialized training includes algorithm development, programming and micro- array, cell and molecular biology, immunology, oxidative stress and cancer research, molecular biology or developmental biology, hematology, B-complex vitamins, neurophysiology or neurophamacology, neuroendocrinology, DNA radiochemistry, neurotechnology, pharmacology, toxicology, transport physiology, and image analysis and microscopy (AFRRI, 2013a). The PIs earned their degrees from both domestic and international institutions. Seven PIs received doctoral degrees in countries other than the United States (India [3]; China, Germany, PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Programs, Research, and Resources 4-23 Italy and Russia [1 each]) (AFRRI, 2013a). The most recent doctorate among the AFRRI PIs was attained in 2011; the range of years when the doctorates were received extends back to 1974, indicating that more than half of the PIs with doctoral degrees have at least 30 years’ experience since completing their degree (median year of attainment, 1983) (AFRRI, 2013a). These PIs participate in AFRRI’s key research areas: six conduct biodosimetry research, eight conduct countermeasures research, four conduct research on combined injuries, two investigate internal contamination and heavy-metal toxicity; some participate in two research areas. However, not everyone fits into these categories. For example, one PI focuses on radiation neutralization to better understand radiation’s effect on microbial infection and the immune system and how radiation can be an effective tool to inactivate microbial threats (sterilization, sanitation, remediation of contaminated sites, and the like) (AFRRI, 2013a). Nine PIs serve as USUHS faculty members in the Departments of Preventive Medicine and Biometrics; Radiation Biology; and Anatomy, Physiology, and Genetics (AFRRI, 2013a). Two PIs list low-dose research topics among their interests (AFRRI, 2013a). One PI conducts work on low dose radiation carcinogenesis models (Miller, 2011), was lead author of a literature review on late and low-level effects of ionizing radiation published in the 2013 Textbook of Military Medicine (Miller et al., 2013), and carries out studies on the effects of DU exposure (for example, Miller, et al., 2010). A second PI notes an interest in the effects of low dose–rate radiation that models the fallout environment (AFRRI, 2014a). In addition—as noted in Chapter 5—some of the other work conducted by investigators has potential low-dose applications. AFRRI posts on its website a list of journal articles produced by its staff (AFRRI, 2014c). Of the 127 articles published or in press from 2010 through May 15, 2014,9 only two explicitly mention doses below 1 Gy. Both of these relate to biodosimetry: one examined the utility of giant magnetoresistive nanosensors for measuring protein concentrations in blood for medical diagnosis (Kim et al., 2013), and the other evaluated the minipig for its potential in γ-H2AX- based biodosimetry after exposure to ionizing radiation from 137Cs and 60Co sources (Moroni et al., 2013). As already noted, the Veterinary Sciences Department, which manages the animal facility, is staffed with specially trained individuals, including veterinarians, veterinary technicians, animal husbandry personnel, pathology staff, and administrators, who are Army, Air Force, federal, and contract employees. COLLABORATIONS AND REPRESENTATION IN SCIENTIFIC GROUPS As of July 2013, AFRRI listed a number of current and recent collaborations on various research projects, listed in Box 4-3. Collaborative projects reflect all of the Institute’s key areas: radiation biology, countermeasures, biodosimetry, combined injury, and heavy-metal toxicity (AFRRI, 2013a). Three of the projects are specified as investigations of low-dose radiation exposure. Two of these three are with USUHS investigators—one on the development of a low-dose radiation- 9 This averages to nearly 2 papers per year per PI over this time period, including papers authored by more than one PI. PREPUBLICATION COPY: UNCORRECTED PROOFS

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4-24 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI induced skin cancer model and the other on low-dose radiation cancer risks; the third is a collaboration with a NASA researcher on low-dose-rate radiation effects. BOX 4-3 Current and Recent AFRRI Research Collaborators as of Mid-2013 Governmental Agencies Army Research Labs, Department of Veterans Affairs, Lawrence Berkeley National Laboratory, NASA, National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Sandia National Laboratory Medical and Academic Institutions Albert Einstein College of Medicine, Columbia University Center for Radiological Research, Indiana School of Medicine, National Space Biomedical Research Institute, New York University Medical School, Roswell Park Cancer Institute, Sloan-Kettering Institute, Southwest Research Institute, Stanford University, Tulane University, USUHS, University of Arkansas, University of California Los Angeles, University of Maryland School of Medicine, University of New Hampshire, University of New Mexico, Wake Forest University, Xavier University Private-Sector Entities Cellerant Therapeutics, Cleveland BioLabs, Eukarion, Hollis-Eden Pharmaceuticals, Humanetics Pharmaceuticals, LaMotte Corporation, Meso Scale Diagnostics, Tech Micro Services International Collaborations Commonwealth Scientific and Industrial Research Organization (Australia), Defence Research and Development Canada, Health Canada, University of Western Ontario (Canada), Commission of Atomic Energy (France), University of Paris (France), Hannover Medical School (Germany), ENEA National Institute of Ionizing Radiation Metrology (Italy), Institute of Nuclear Medicine and Allied Sciences (India), Bhabha Atomic Research Centre (India), Hirosaki University (Japan), National University of Singapore, World Health Organization The Institute indicates that “[a]dditionally, more than 200 companies and researchers have engaged AFRRI in collaborations or discussions regarding novel radiation countermeasure candidates.” SOURCE: AFRRI, 2013a Earlier, AFRRI collaborated with various other academic and governmental organizations for DU research: Columbia University, NIH and NCI, University of Paris, United Kingdom Medical Research Council, French Institute of Nuclear Security, Memorial Sloan Kettering Cancer Center, New York University, University of Maine, Armed Forces Institute of Pathology, and the University of Maryland School of Medicine (Kalinich et al., 2005). AFRRI seeks extramural support for a portion of its research. In July 2013, the Institute reported 21 extramural projects. Sponsors include the Biomedical Advanced Research and Development Authority (BARDA) (three awards), Cleveland BioLabs (to evaluate a countermeasure), the Defense Medical Research and Development Program (DMRDP) (four PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Programs, Research, and Resources 4-25 awards, all for countermeasures research), DTRA (six awards: five for countermeasures research and one for triage biodosimetry), NASA (the previously-mentioned low dose–rate study), NIAID (five awards for countermeasures, one to develop a pediatric radiation injury model), and Xavier University (for a countermeasures study). These extramural awards sponsor the research of ten different AFRRI PIs (AFRRI, 2013a). AFRRI personnel also participate in a number of committees and working groups associated with DoD, the Military Services, other government agencies (including HHS, Department of Homeland Security, Environmental Protections Agency, National Institute of Standards and Technology, and Office of Science and Technology Policy), and national and international organizations (including the National Council on Radiation Protection and Measurements, International Atomic Energy Agency, International Organization for Standardization, North Atlantic Treaty Organization, and World Health Organization) (AFRRI, 2013a). SUMMARY, FINDINGS AND CONCLUSIONS Summary–AFRRI’s Programs, Research, and Resources AFRRI is the only DoD entity dedicated to ionizing-radiation health-effects research. Its unique infrastructure includes a number of radiation sources that may be used to study acute and chronic effects on cells and animals, and it maintains a vivarium that houses mammals, including nonhuman primates, used in studies. The Institute’s research portfolio principally comprises work addressing biodosimetry, combined injury, internal contamination and metal toxicity, and countermeasure development. It disseminates the results of these studies in refereed journal papers, reports, books and book chapters, and other publications. Some projects are supported by and in some cases conducted at the behest of government or private-sector funders, while the remainder are initiated by PIs and supported internally. AFRRI also fulfills its mission by producing manuals and protocols on radiation-exposure response, conducting education and training in these areas, supplying nuclear and radiological emergency response assistance, and providing advice to the federal government. Approximately a third of the Institute’s 19 PIs hold appointments (primarily adjunct) at the USUHS, teaching classes or lecturing there, and mentor students. USUHS and other graduate students can perform research at the Institute. AFRRI hosts participants in fellowship programs and participates in Science, Technology, Engineering, and Mathematics (STEM) outreach. Its budget—~$21M in FY2013—has fluctuated in recent years, including some large infusions to maintain and upgrade the physical plant, but overall it and Institute’s staffing levels are lower than they were in the early 1990s. Findings and Conclusions AFRRI contributes to ionizing-radiation health-effects research by providing specialized expertise and abilities for evaluating, modeling, and countering the consequences of exposure to nuclear and radioactive agents. Assessing risks and creating models to predict casualties from combined injuries and internal contamination (radiation or metal poisoning resulting from embedded shrapnel made of DU or tungsten alloys) permits better military decision making. Developments in biological dosimetry increase the speed and accuracy of radiation-dose assessment; these developments include assays that use blood, urine, or hair for screening, and PREPUBLICATION COPY: UNCORRECTED PROOFS

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4-26 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI improvements in equipment design that aid in the triage, medical management, and treatment of radiation-exposed personnel. Researchers at AFRRI continue to investigate the mechanisms of radiation damage and pursue the development of treatments for persons exposed to harmful doses of ionizing radiation by using molecular and cellular approaches and animal models. These scientific advancements are also applicable to the aerospace industry and flight personnel exposed to cosmic and solar radiation, and to the civilian population in cases of terrorism and industrial accidents that result in radiation exposure. The second element of the statement of task called on the committee to assess how AFRRI programs are advancing research in radiobiological science related to human health risks from exposures to low-dose ionizing radiation. Although AFRRI has conducted a small number of studies at low doses, low-dose radiation exposure was not a specifically-defined research area at the time this report was written. In the dose range 1 Gy and below, studies include the development of models to study carcinogenesis and non-targeted effects at the molecular level. Late effects of radiation (including internal and external contamination from DU), countermeasures to prevent those late effects, and associated biomarkers are also being studied. Areas of research that address both low- and high-level exposure include the tissue and cellular effects of combined injuries on the skeletal system (for example, bone marrow and bone loss), countermeasures to the effects of low dose–rate gamma radiation encountered in nuclear fallout, and some of the Institute’s biodosimetry and exposure characterization work. As noted in this chapter, the Institute’s current portfolio of studies is focused almost exclusively on exposures above 1 Gy—a range that the research community and international organizations classify as moderately high and high dose. This work is consonant with AFRRI’s mission and yields information that is vital to managing the consequences of nuclear and radiological material releases as a result of armed conflicts, terrorist actions, and accidents. It does not, though, generate knowledge that would help answer the questions identified in Chapter 2 as being important to understanding the health risks of low-dose radiation exposure. The committee thus concludes that while AFRRI carries on a robust program of research on the biological and health effects of high dose ionizing radiation exposure, it is not currently substantively advancing low-dose research. Chapter 5 draws on the material presented here to offer findings, conclusions, and recommendations about opportunities for AFRRI to advance its mission for understanding human health risks from exposures to low-level ionizing radiation with special emphasis on DoD military operations and personnel. REFERENCES AFRRI (Armed Forces Radiobiology Research Institute). 1968. Organization. AFRRI Staff Memorandum 10-1. https://www.osti.gov/opennet/servlets/purl/16004533-h9b0K3/16004533.pdf (accessed February 10, 2014). AFRRI. 1993. Annual report on AFRRI research for fiscal year 1992. Bethesda, MD. http://www.dod.mil/pubs/foi/operation_and_plans/NuclearChemicalBiologicalMatters/910.pdf (accessed February 10, 2014). AFRRI. 2009. Former AFRRI Scientific Director was pioneer in radiation research http://www.usuhs.edu/afrri/news/pioneer.htm (accessed December 30, 2013). PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Programs, Research, and Resources 4-27 AFRRI. 2010. Ceremony welcomes new AFRRI director. http://www.usuhs.edu/afrri/news/new_director2010.htm (accessed March 2, 2014). AFRRI. 2011a. AFRRI: A Unique National Resource. Presented at the 2011 Society of American Federal Medical Laboratory Scientists (SAFMLS) annual meeting, New Orleans, LA. March 31. http://www.safmls.org/2011/2011%20Presentations/ST%2014/AFRRI%20- %20A%20Unique%20National%20Resource.pdf (accessed March 2, 2014). AFRRI. 2011b. Emergency Radiation Medicine Response-Pocket Guide. http://www.usuhs.edu/afrri/outreach/pdf/AFRRI-Pocket-Guide.pdf (accessed December 30, 2013). AFRRI. 2013a. Responses to questions provided by the National Academy of Sciences concerning the statement of work for the Committee on Research Direction in Human Biological Effects of Low Level Ionizing Radiation. Bethesda, MD, July 12, 2013. AFRRI. 2013b. Responses to supplementary questions provided by the National Academy of Sciences concerning the statement of work for the Committee on Research Direction in Human Biological Effects of Low Level Ionizing Radiation. Bethesda, MD, October 31, 2013. AFRRI. 2013c. About AFRRI. http://www.usuhs.edu/afrri/organiza/about_afrri.htm (accessed October 8, 2013). AFRRI. 2013d. Biodosimetry. http://www.afrri.usuhs.mil/research/biodos.htm (accessed February 12, 2013). AFRRI. 2013e. Biodosimetry Assessment Tool. http://www.usuhs.edu/afrri/outreach/pdf/BAT_brochure.pdf (accessed December 30, 2013). AFRRI. 2013f. Internal Contamination and Metal Toxicity. http://www.usuhs.edu/afrri/research/metal- tox.htm (accessed December 30, 2013). AFRRI. 2013g. Combined Injury: Radiation with Other Insults. http://www.usuhs.edu/afrri/research/combined-injury.htm (accessed December 30, 2013). AFRRI. 2013h. Medical Effects of Ionizing Radation (course brochure.) November, 2013. http://www.usuhs.edu/afrri/outreach/pdf/MEIR_brochure.pdf (accessed April 12, 2014). AFRRI. 2013i. The Medical Radiobiology Advisory Team. http://www.usuhs.edu/afrri/outreach/pdf/describeMRAT.pdf (accessed February 2, 2014). AFRRI, 2014a. Biography, Dr. Mark H. Whitnall, AFRRI Scientific Advisor. http://www.usuhs.edu/afrri/organiza/Bio-DrWhitnall2014.pdf (accessed May 15, 2014). AFRRI. 2014b. Countermeasures. http://www.usuhs.edu/afrri/research/rcp.htm (accessed February 12, 2014). AFRRI. 2014c. Journal Articles 2010-2019. http://www.usuhs.edu/afrri/outreach/journal2010s.htm (accessed May 15, 2014). AFRRI. 2014d. Medical Effects of Ionizing Radiation (in-person) Course. http://www.usuhs.edu/afrri/outreach/meir/meir.htm (accessed February 5, 2014). AFRRI. 2014e. Medical/Operational Guidance for Managing Radiation Casualties. http://www.usuhs.edu/afrri/outreach/guidance.htm (accessed February 10, 2014). AFRRI. 2014f. Product Quick List. http://www.usuhs.edu/afrri/outreach/infoprod.htm (accessed April 7, 2014). AFRRI. 2014g. Research Programs. http://www.usuhs.edu/afrri/research/research.htm (accessed February 10, 2014). PREPUBLICATION COPY: UNCORRECTED PROOFS

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4-28 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI AMEDD (Army Medical Department). 2013. Medical Consequences of Radiological and Nuclear Warfare. http://www.cs.amedd.army.mil/borden/Portlet.aspx?id=b3cb37ed-08e7-4617-a40c- f148ee3d2303 (accessed December 30, 2013). Assistant Secretary of Defense. 2004. Report to Congress: Armed Forces Radiobiology Research Institute (AFRRI).Washington, DC. September 20, 2004. Cary L.H., D. Noutai, R.E. Salber, M. Williams, B.F. Ngudiankama, and M.H. Whitnall. 2014. Interactions between endothelial cells and T cells modulate responses to mixed neutron/gamma radiation. Radiation Research, in press. Carter R.E. and D.M. Verrelli. 1973. AFRRI Cobalt Whole-body Irradiation, Technical Report 73-3. Bethesda, MD: Armed Forces Radiobiology Research Institute. CDC (Centers for Disease Control and Prevention). 2012. Strategic National Stockpile (SNS). http://www.cdc.gov/phpr/stockpile/stockpile.htm (accessed December 30, 2013). CDMRP (Congressionally Directed Medical Research Programs). 2013. Search Awards. http://cdmrp.army.mil/search.aspx (accessed December 30, 2013). Defense Health Program. 2014. Fiscal Year (FY) 2014 Budget Estimates: Appropriation Highlights. http://comptroller.defense.gov/Portals/45/Documents/defbudget/fy2014/budget_justification/pdf/09_ Defense_Health_Program/VOL_I/VOL_I_Sec_1_PBA-19_Introductory_Statement_DHP_PB14.pdf (accessed May 14, 2014) DoD (Department of Defense). 2006. Instruction: Armed Forces Radiobiology Research Institute. Directive Number 5105.33. http://www.dtic.mil/whs/directives/corres/pdf/510533p.pdf. (accessed December 30, 2013). DoD. 2010a. DoD Response to Nuclear Radiological Incidents. Department of Defense Directive 3150.08. January 20, 2010. DoD. 2010b. Financial Management Regulation, Volume 2b: Budget Formulation and Presentation (Chapters 4-19). Department of Defense Directive 7000.14-R. September 2010. http://comptroller.defense.gov/Portals/45/documents/fmr/current/02b/Volume_02b.pdf (accessed May 14, 2014). DoD. 2013. Nuclear Weapon Accident Response Procedures (NARP). Department of Defense Manual 3150.08. August 22, 2013. www.dtic.mil/whs/directives/corres/pdf/315008m.pdf (accessed February 2, 2014). Dix, M. A. 2005. The Armed Forces Radiobiology Research Institute. Uniformed Services University of the Health Sciences Journal 2004/5 Edition Pp. 461-496. DTRA (Defense Threat Reduction Agency). 2002. Defense's Nuclear Agency 1947–1997. Washington DC: U.S. Department of Defense, DTRA History Series. DTRA. 2010. Nuclear Test Personnel Review (NTPR) Program Fact Sheet http://www.dtra.mil/documents/ntpr/factsheets/NTPR_Program.pdf (accessed February 5, 2014). Dubois, A., N. Fiala, R. H. Weichbrod, G. S. Ward, M. Nix, P. T. Mehlman, D. M. Taub, G. I. Perez- Perez, and M. J. Blaser. 1995. Seroepizootiology of Helicobacter pylori gastric infection in nonhuman primates housed in social environments. Journal of Clinical Microbiology 33(6):1492- 1495. FedBizOpps.Gov. 2013. Cobalt-60, Remove and Replace. Solicitation Number: HT9404-13-Q-0020. https://www.fbo.gov/?s=opportunity&mode=form&tab=core&id=614ea9482f61dd43ae19febece66f2 e1&_cview=1 (accessed February 11, 2014). PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Programs, Research, and Resources 4-29 FEMA (Federal Emergency Management Agency). 2013a. The National Response Framework http://www.fema.gov/media-library/assets/documents/32230?id=7371 (accessed February 2, 2014). FEMA. 2013b. The Nuclear/Radiological Incident Annex. http://www.fema.gov/media- library/assets/documents/25554 (accessed February 2, 2014). Gamble, R. 2013. Personal communication, H. Ray Gamble, Director, Fellowships Office, National Research Council. May 5, 2013. General Atomics. 2014. TRIGA Nuclear Reactors. http://www.ga.com/triga (accessed February 11, 2014). HJF (Henry M. Jackson Foundation). 2013. About HJF. http://www.hjf.org/about (accessed December 30, 2013). Huff, L. A. 2013a. Armed Forces Radiobiology Research Institute: Presentation to the Committee on Research Directions in Human Biological Effects of Low-Level Radiation.Washington, DC, May 3, 2013. Huff, L. A. 2013b. Personal communication, e-mail to the committee, Washington, DC, November 1, 2013. Huff, L. A. 2014. Personal communication, e-mail to the committee, Washington, DC, January 10, 2014. Kalinich, J. F., C. A. Emond, T. K. Dalton, S. R. Mog, G. D. Coleman, J. E. Kordell, A. C. Miller, and D. E. McClain. 2005. Embedded weapons-grade tungsten alloy shrapnel rapidly induces metastatic high- grade rhabdomyosarcomas in F344 rats. Environmental Health Perspectives 113(6):729-734. Kang, A., D. Gibson, and M. Dempsey. 2011. AFRRI: A Unique National Resource. Presented at the 2011 Society of American Federal Medical Laboratory Scientists (SAFMLS), New Orleans, LA, March 31, 2011. Kim, D., F. Marchetti, Z. Chen, S. Zaric, R. J. Wilson, D. A. Hall, R. S. Gaster, J. R. Lee, J. Wang, S. J. Osterfeld, H. Yu, R. M. White, W. F. Blakely, L. E. Peterson, S. Bhatnagar, B. Mannion, S. Tseng, K. Roth, M. Coleman, A. M. Snijders, A. J. Wyrobek, S. X. Wang. 2013. Nanosensor dosimetry of mouse blood proteins after exposure to ionizing radiation. Science Reports 3(2234). Landauer, M. R., D. G. McChesney, and G. D. Ledney. 1997. Synthetic trehalose dicorynomycolate (S- TDCM): Behavioral effects and radioprotection. Journal of Radiation Research 38(1):45-54. Landauer M.R., C. A. Castro, K. A. Benson, J. B. Hogan and J. F. Weiss. 2001. Radioprotective and locomotor responses of mice treated with nimodipine alone and in combination with WR-151327. Journal of Applied Toxicology 21: 25-31. McKinney, L. C., E. M. Aquilla, D. Coffin, D. A. Wink, and Y. Vodovotz. 1998. Ionizing radiation potentiates the induction of nitric oxide synthase by IFN-g and/or LPS in murine macrophage cell lines: role of TNF-α. Journal of Leukocyte Biology 64 (4):459-466. Mele, P. C., C. G. Franz, and J. R. Harrison. 1990. Effects of ionizing radiation on fixed-ratio escape performance in rats. Neurotoxicology and Teratology 12(4):367-373. Miller A. C. 2011. Development of models to study radiation-induced late effects. In RTG 033 Subgroup 1: Radiobiology Mechanisms and Late Effects. HFM Panel-099 RTG-033 Activity: Radiation Bioeffects and Countermeasures. Bethesda, MD. http://ftp.rta.nato.int/public/PubFullText/RTO/TR/RTO-TR-HFM-099/$$TR-HFM-099-Pre-Release- ALL.pdf (accessed May 15, 2014) Miller, A. C., M. Satyamitra, S. Kulkarni, T. Walden. 2013. Late and low- level effects of ionizing radiation. In Medical Consequences of Radiologicial and Nuclear Weapons, edited by A. B. Mickelson. Fort Detrick, MD: Office of the Surgeon General. Pp. 195-215. PREPUBLICATION COPY: UNCORRECTED PROOFS

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4-30 Research on Health Effects of Low-Level Ionizing Radiation Exposure – Opportunities for AFRRI Miller A. C., M. Stewart, R. Rivas. 2010. Preconceptional paternal exposure to depleted uranium: transmission of genetic damage to offspring. Health Physics 99(3):371-379. Moroni, M., E. Lombardini, R. Salber, M. Kazemzedeh, V. Nagy, C. Olsen, M. Whitnall. 2011. Hematological Changes as Prognostic Indicators of Survival: Similarities Between Gottingen Minipigs, Humans, and Other Large Animal Models. PLoS One 6:e25210. Moroni, M., D. Maeda, M. H. Whitnall, W. M. Bonner, C. E. Redon. 2013. Evaluation of the gamma- H2AX assay for radiation biodosimetry in a swine model. International Journal of Molecular Science 14:14119-14135. Naquin, T.D., R.C. Bhatt, G.R. Kahles, and D.M. McKown. 2001. A low gamma dose rate cobalt-60 facility. Radiation Protection Management 18(2):31-36. NAS (National Academy of Sciences). 2014. Associateship Programs at Armed Forces Radiobiology Research Institute. http://nrc58.nas.edu/RAPLab10/Opportunity/Program.aspx?LabCode=15&ReturnURL=%2fRAPLab 10%2fOpportunity%2fPrograms.aspx%3fLabCode%3d15 (accessed February 12, 2014). NRC (National Research Council). 2004. Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident. Washington, DC: National Academies Press. NREIP (Naval Research Enterprise Internship Program). 2014. Participating Labs: Armed Forces Radiobiology Research Institute. https://nreip.asee.org/labs/armed_forces_radiobiology_research_institute__bethesda__md_ (accessed February 12, 2014). Parde, N. 2012. AFRRI: A Global Authority on Ionizing Radiation. The Journal (official newspaper for Walter Reed Army Medical Center). http://www.dcmilitary.com/ARTICLE/20120906/NEWS11/709069953/AFRRI-A (accessed February 6, 2014). SAM (System for Award Management). 2013. System for Awards Management. http://www.sam.gov (accessed December 30, 2013). SEAP (Scientist and Engineering Apprenticeship Program). 2014. Participating Labs: Armed Forces Radiobiology Research Institute. https://seap.asee.org/participating_labs/armed_forces_radiobiology_research_institute_bethesda_md (accessed February 12, 2014). Singh, V. K., D. S. Brown, T-C. Kao. 2010. Alpha-tocopherol succinate protects mice from gamma- radiation by induction of granulocyte-colony stimulating factor. International Journal of Radiobiology 86(1):12-21. Solyan, D. K. 2004. Armed Forces Radiobiology Research Institute. In The Uniformed Services University of the Health Sciences: First Generation Reflections, edited by K. E. Kinnamon. Tenforde, T. S. 2011. Tribute to AFRRI on Its 50th Anniversary and Perspectives on the History and Future of Radiation Biology and Health Protection. Presented at AFRRI Golden Jubilee Banquet, Bethesda, MD, May 12, 2011. Thorp, J. W., and J. E. Germas. 1969. Performance of monkeys after partial body irradiation. AD699127. Bethesda, MD: Armed Forces Radiobiology Research Institute. http://oai.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=AD0699127 (accessed February 10, 2014). USAspending.gov. 2013. USA Spending. http://usaspending.gov (accessed December 30, 2013). PREPUBLICATION COPY: UNCORRECTED PROOFS

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AFRRI Programs, Research, and Resources 4-31 USUHS (Uniformed Services University of the Health Sciences). 2012. Uniformed Services University of the Health Sciences: Learning to Care for Those in Harm’s Way. 2012 Report, 40th Anniversary Edition. Zeman, G. H., and M. A. Dooley. 1984. Performance and Dosimetry of Theratron-80 Cobalt-60 Unit at Armed Forces Radiobiology Research Institute. Technical report. Accession Number: ADA142770. Bethesda, MD: AFRRI. PREPUBLICATION COPY: UNCORRECTED PROOFS

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