Radiation emergency medical countermeasures: Current formulary, identified gaps, and future approaches

Abstract

Radiological or nuclear accidents can lead to serious outcomes for individuals exposed to ionizing radiation, with health effects that are either acute or delayed, deterministic or stochastic, depending on the effective dose of exposure. Mechanistically, ionizing radiation can inflict damage either directly on DNA or through oxidative stress, which may trigger a cascade of damages to tissues and organs. The development of effective radiation medical countermeasures is an unmet need and should be a top priority in preparing for radiation emergencies. This paper aims to address the critical questions of whether current countermeasures are available, what additional measures are needed, and what actions can be taken to enhance the development of radiation medical countermeasures from a systematic perspective.

Keywords

acute radiation syndrome / ionizing radiation / radiation injury / radiation medical countermeasures

References

[1] DiCarlo AL, Ramakrishnan N, Hatchett RJ. Radiation combined injury: overview of NIAID research. Health Phys. 2010;98(6):863-867.

[2] Zou Z, Sun H, Su Y, Cheng T, Luo C. Progress in research on radiation combined injury in China. Radiat Res. 2008;169(6):722-729.

[3] Ledney GD, Elliott TB. Combined injury: factors with potential to impact radiation dose assessments. Health Phys. 2010;98(2):145-152.

[4] Singh VK, Seed TM. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures. Int J Radiat Biol. 2017;93(9):851-869.

[5] Wang S, Meyer DH, Schumacher B. Inheritance of paternal DNA damage by histone-mediated repair restriction. Nature. 2023;613(7943):365-374.

[6] Prise KM, Schettino G, Folkard M, Held KD. New insights on cell death from radiation exposure. Lancet Oncol. 2005;6(7):520-528.

[7] Yamaga S, Aziz M, Murao A, Brenner M, Wang P. DAMPs and radiation injury. Front Immunol. 2024;15:1353990.

[8] Rotolo J, Stancevic B, Zhang J, et al. Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice. J Clin Invest. 2012;122(5):1786-1790.

[9] Nagesh PKB, Monette S, Shamu T, et al. Anti-ceramide single-chain variable fragment mitigates gastrointestinal-acute radiation syndrome and improves marrow reconstitution, rendering near-normal 90-day autopsies. Int J Radiat Oncol Biol Phys. 2024;120(2):558-569.

[10] Cheng J, Nagesh PKB, Feldman R, et al. Anti-ceramide scFv prophylaxis for first responders to a limited nuclear attack. Cell Physiol Biochem. 2024;58(4):418-430.

[11] WHO. National stockpiles for radiological and nuclear emergencies: policy advice. Accessed 27 January, 2023. https://www.who.int/publications/i/item/9789240067875.

[12] MacVittie TJ, Monroy RL, Patchen ML, Souza LM. Therapeutic use of recombinant human G-CSF (rhG-CSF) in a canine model of sublethal and lethal whole-body irradiation. Int J Radiat Biol. 1990;57(4):723-736.

[13] Schuening FG, Storb R, Goehle S, et al. Effect of recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoietic recovery after otherwise lethal total body irradiation. Blood. 1989;74(4):1308-1313.

[14] Patchen ML, MacVittie TJ, Solberg BD, Souza LM. Therapeutic administration of recombinant human granulocyte colony-stimulating factor accelerates hemopoietic regeneration and enhances survival in a murine model of radiation-induced myelosuppression. Int J Cell Cloning. 1990;8(2):107-122.

[15] Hosoi Y, Kurishita A, Ono T, Sakamoto K. Effect of recombinant human granulocyte colony-stimulating factor on survival in lethally irradiated mice. Acta Oncol. 1992;31(1):59-63.

[16] Sureda A, Kádár E, Valls A, García-López J. Granulocyte colony-stimulating factor administered as a single intraperitoneal injection modifies the lethal dose95/30 in irradiated B6D2F1 mice. Haematologica. 1998;83(9):863-864.

[17] Patchen ML, MacVittie TJ. Granulocyte colony-stimulating factor and amifostine (Ethyol) synergize to enhance hemopoietic reconstitution and increase survival in irradiated animals. Semin Oncol. 1994;21(5 Suppl 11):26-32.

[18] Tanikawa S, Nose M, Aoki Y, Tsuneoka K, Shikita M, Nara N. Effects of recombinant human granulocyte colony-stimulating factor on the hematologic recovery and survival of irradiated mice. Blood. 1990;76(3):445-449.

[19] Moroni M, Ngudiankama BF, Christensen C, et al. The Gottingen minipig is a model of the hematopoietic acute radiation syndrome: G-colony stimulating factor stimulates hematopoiesis and enhances survival from lethal total-body γ-irradiation. Int J Radiat Oncol Biol Phys. 2013;86(5):986-992.

[20] Farese AM, Cohen MV, Katz BP, et al. Filgrastim improves survival in lethally irradiated nonhuman primates. Radiat Res. 2013;179(1):89-100.

[21] Chua HL, Plett PA, Sampson CH, et al. Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors. Health Phys. 2014;106(1):21-38.

[22] Gasperetti T, Frei A, Prasad Sharma G, et al. Delayed renal injury in survivors of hematologic acute radiation syndrome. Int J Radiat Biol. 2023;99(7):1130-1138.

[23] Hankey KG, Farese AM, Blaauw EC, et al. Pegfilgrastim improves survival of lethally irradiated nonhuman primates. Radiat Res. 2015;183(6):643-655.

[24] Farese AM, Cohen MV, Stead RB, Jackson W 3rd, Macvittie TJ. Pegfilgrastim administered in an abbreviated schedule, significantly improved neutrophil recovery after high-dose radiation-induced myelosuppression in rhesus macaques. Radiat Res. 2012;178(5):403-413.

[25] Legesse B, Kaur A, Kenchegowda D, Hritzo B, Culp WE, Moroni M. Neulasta regimen for the hematopoietic acute radiation syndrome: effects beyond neutrophil recovery. Int J Radiat Oncol Biol Phys. 2019;103(4):935-944.

[26] Nothdurft W, Selig C, Fliedner TM, et al. Haematological effects of rhGM-CSF in dogs exposed to total-body irradiation with a dose of 2.4 Gy. Int J Radiat Biol. 1992;61(4):519-531.

[27] Tanikawa S, Nakao I, Tsuneoka K, Nara N. Effects of recombinant granulocyte colony-stimulating factor (rG-CSF) and recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) on acute radiation hematopoietic injury in mice. Exp Hematol. 1989;17(8):883-888.

[28] Clayton NP, Khan-Malek RC, Dangler CA, et al. Sargramostim (rhu GM-CSF) improves survival of non-human primates with severe bone marrow suppression after acute, high-dose, whole-body irradiation. Radiat Res. 2021;195(2):191-199.

[29] Bunin DI, Bakke J, Green CE, Javitz HS, Fielden M, Chang PY. Romiplostim (Nplate(®)) as an effective radiation countermeasure to improve survival and platelet recovery in mice. Int J Radiat Biol. 2020;96(1):145-154.

[30] Bunin DI, Javitz HS, Gahagen J, et al. Survival and hematologic benefits of romiplostim after acute radiation exposure supported FDA approval under the animal rule. Int J Radiat Oncol Biol Phys. 2023;117(3):705-717.

[31] Sandal N, Mahar R, Sharma P. Optimizing Ca-DTPA/Zn-DTPA therapy for internal decorporation: transitioning from intravenous to oral route with insights on safety and toxicity. J Radiol Prot. 2025;45(1):011002.

[32] Agrawal V, Priyadarshani A, Pathak DP, Sandal N. Enhancing oral bioavailability of Ca-DTPA by self double emulsifying drug delivery system (SDEDDS). Drug Dev Ind Pharm. 2024;50(1):78-88.

[33] Sueda K, Sadgrove MP, Fitzsimmons JM, Jay M. Physicochemical characterization of a prodrug of a radionuclide decorporation agent for oral delivery. J Pharm Sci. 2012;101(8):2844-2853.

[34] Grémy O, Devilliers K, Miccoli L. Chelation therapy with 3,4,3-Li(1,2-HOPO) after pulmonary exposure to plutonium in rats. Chem Biol Interact. 2023;378:110488.

[35] Xue T, Liu F, Lu B, et al. A Prussian blue analog as a decorporation agent for the simultaneous removal of cesium and reactive oxygen species. Nanoscale Adv. 2023;5(20):5661-5670.

[36] Farina R, Brandão-Mello CE, Oliveira AR. Medical aspects of 137Cs decorporation: the Goiânia radiological accident. Health Phys. 1991;60(1):63-66.

[37] Qian J, Xu J, Kuang L, Hua D. Cesium removal from human blood by poly(ethylene glycol)-decorated Prussian blue magnetic nanoparticles. ChemPlusChem. 2017;82(6):888-895.

[38] Carniato F, Gatti G, Vittoni C, et al. More efficient Prussian blue nanoparticles for an improved caesium decontamination from aqueous solutions and biological fluids. Molecules. 2020;25(15):3447.

[39] Lee I, Kim SH, Rethinasabapathy M, et al. Porous 3D Prussian blue/cellulose aerogel as a decorporation agent for removal of ingested cesium from the gastrointestinal tract. Sci Rep. 2018;8(1):4540.

[40] Singh VK, Garcia M, Seed TM. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status. Int J Radiat Biol. 2017;93(9):870-884.

[41] Musa AE, Shabeeb D, Okoro NOE, Agbele AT. Radiation protection by ex-RAD: a systematic review. Environ Sci Pollut Res Int. 2020;27(27):33592-33600.

[42] Singh VK, Seed TM. Development of gamma-tocotrienol as a radiation medical countermeasure for the acute radiation syndrome: current status and future perspectives. Expert Opin Investig Drugs. 2023;32(1):25-35.

[43] Singh VK, Seed TM. The efficacy and safety of amifostine for the acute radiation syndrome. Expert Opin Drug Saf. 2019;18(11):1077-1090.

[44] Singh VK, Seed TM. BIO 300: a promising radiation countermeasure under advanced development for acute radiation syndrome and the delayed effects of acute radiation exposure. Expert Opin Investig Drugs. 2020;29(5):429-441.

[45] Peng R, Zhang W, Zuo Z, et al. Dimethyl sulfoxide, a potent oral radioprotective agent, confers radioprotection of hematopoietic stem and progenitor cells independent of apoptosis. Free Radic Biol Med. 2020;153:1-11.

[46] Shi T, Jiang J, Gao M, et al. Editing flagellin derivatives for exploration of potent radioprotective agents. Eur J Pharmacol. 2021;907:174259.

[47] Liu L, Liang Z, Ma S, Li L, Liu X. Radioprotective countermeasures for radiation injury (review). Mol Med Rep. 2023;27(3):66.

[48] Bai F, Wang L, Li Z, et al. 17α-Ethinyl-androst-5-ene-3β, 17β-diol, a novel potent oral radioprotective agent, confers radioprotection of hematopoietic stem and progenitor cells in a granulocyte colony-stimulating factor-independent manner. Int J Radiat Oncol Biol Phys. 2019;103(1):217-228.

[49] Zuo Z, Wang L, Wang S, et al. Radioprotective effectiveness of a novel delta-tocotrienol prodrug on mouse hematopoietic system against (60)Co gamma-ray irradiation through inducing granulocyte-colony stimulating factor production. Eur J Med Chem. 2024;269:116346.

[50] Cao J, Li X, Wang X, Li K, Liu Y, Tian H. Surface PEGylation of MIL-101(Fe) nanoparticles for co-delivery of radioprotective agents. Chem Eng J. 2020;384:123363.

[51] Andrade ER, Cruz IB, Andrade VV, et al. Evaluation of the potential protective effects of ad libitum black grape juice against liver oxidative damage in whole-body acute X-irradiated rats. Food Chem Toxicol. 2011;49(4):1026-1032.

[52] Saada HN, Said UZ, Meky NH, Abd El Azime AS. Grape seed extract Vitis vinifera protects against radiation-induced oxidative damage and metabolic disorders in rats. Phytother Res. 2009;23(3):434-438.

[53] Yi J, Chen C, Liu X, et al. Radioprotection of EGCG based on immunoregulatory effect and antioxidant activity against (60)Coγ radiation-induced injury in mice. Food Chem Toxicol. 2020;135:111051.

[54] Shi J, Wang L, Lu Y, et al. Protective effects of seabuckthorn pulp and seed oils against radiation-induced acute intestinal injury. J Radiat Res. 2017;58(1):24-32.

[55] Lee TK, Wang W, O'Brien KF, et al. Effect of north American ginseng on 137Cs-induced micronuclei in human lymphocytes: a comparison with WR-1065. Phytother Res. 2008;22(12):1614-1622.

[56] Winters TA, Marzella L, Molinar-Inglis O, et al. Gastrointestinal acute radiation syndrome: mechanisms, models, markers, and medical countermeasures. Radiat Res. 2024;201(6):628-646.

[57] Singh VK, Seed TM. Repurposing pharmaceuticals previously approved by regulatory agencies to medically counter injuries arising either early or late following radiation exposure. Front Pharmacol. 2021;12:624844.

[58] Farese AM, Brown CR, Smith CP, et al. The ability of filgrastim to mitigate mortality following LD50/60 total-body irradiation is administration time-dependent. Health Phys. 2014;106(1):39-47.

[59] Farese AM, MacVittie TJ. Filgrastim for the treatment of hematopoietic acute radiation syndrome. Drugs Today (Barc). 2015;51(9):537-548.

[60] U.S. Centers for Disease Control and Prevention. Acute Radiation Syndrome: Information for Clinicians. Accessed April 23, 2024. https://www.cdc.gov/radiation-emergencies/hcp/clinical-guidance/ars.html.

[61] Christensen DM, Iddins CJ, Parrillo SJ, Glassman ES, Goans RE. Management of ionizing radiation injuries and illnesses, part 4: acute radiation syndrome. J Am Osteopath Assoc. 2014;114(9):702-711.

[62] NIAID. Support for development of promising MCMs for radiation injuries. Accessed December 6, 2023. https://www.niaid.nih.gov/grants-contracts/develop-promising-mcms-radiation-injuries.

[63] McCart EA, Lee YH, Jha J, et al. Delayed captopril administration mitigates hematopoietic injury in a murine model of total body irradiation. Sci Rep. 2019;9(1):2198.

[64] Fu Q, Berbée M, Wang W, et al. Preclinical evaluation of Som230 as a radiation mitigator in a mouse model: postexposure time window and mechanisms of action. Radiat Res. 2011;175(6):728-735.

[65] Zhong Y, Pouliot M, Downey AM, et al. Efficacy of delayed administration of sargramostim up to 120 hours post exposure in a nonhuman primate total body radiation model. Int J Radiat Biol. 2021;97(sup1):S100-s116.

[66] DiCarlo AL, Cassatt DR, Dowling WE, et al. Challenges and benefits of repurposing products for use during a radiation public health emergency: lessons learned from biological threats and other disease treatments. Radiat Res. 2018;190(6):659-676.

[67] Ma S, Jin Z, Liu Y, et al. Furazolidone increases survival of mice exposed to lethal total body irradiation through the antiapoptosis and antiautophagy mechanism. Oxidative Med Cell Longev. 2021;2021:6610726.

[68] Obrador E, Salvador-Palmer R, Villaescusa JI, et al. Nuclear and radiological emergencies: biological effects, countermeasures and biodosimetry. Antioxidants (Basel). 2022;11(6):1098.

[69] Singh VK, Seed TM. Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond. Int J Radiat Biol. 2021;97(11):1526-1547.

[70] Khodamoradi E, Hoseini-Ghahfarokhi M, Amini P, et al. Targets for protection and mitigation of radiation injury. Cell Mol Life Sci. 2020;77(16):3129-3159.

[71] Chmil V, Filipová A, Tichý A. Looking for the phoenix: the current research on radiation countermeasures. Int J Radiat Biol. 2023;99(8):1148-1166.

[72] Burdelya LG, Krivokrysenko VI, Tallant TC, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008;320(5873):226-230.

[73] Singh VK, Seed TM. Entolimod as a radiation countermeasure for acute radiation syndrome. Drug Discov Today. 2021;26(1):17-30.

[74] Ghosh SP, Perkins MW, Hieber K, et al. Radiation protection by a new chemical entity, ex-rad: efficacy and mechanisms. Radiat Res. 2009;171(2):173-179.

[75] Kang AD, Cosenza SC, Bonagura M, Manair M, Reddy MV, Reddy EP. ON01210.Na (ex-RAD®) mitigates radiation damage through activation of the AKT pathway. PLoS One. 2013;8(3):e58355.

[76] Singh VK, Newman VL, Romaine PL, Wise SY, Seed TM. Radiation countermeasure agents: an update (2011-2014). Expert Opin Ther Pat. 2014;24(11):1229-1255.

[77] Kumar VP, Biswas S, Sharma NK, et al. PEGylated IL-11 (BBT-059): a novel radiation countermeasure for hematopoietic acute radiation syndrome. Health Phys. 2018;115(1):65-76.

[78] Serebrenik AA, Verduyn CW, Kaytor MD. Safety, pharmacokinetics, and biomarkers of an amorphous solid dispersion of genistein, a radioprotectant, in healthy volunteers. Clin Pharmacol Drug Dev. 2023;12(2):190-201.

[79] Singh VK, Fatanmi OO, Wise SY, et al. A novel oral formulation of BIO 300 confers prophylactic radioprotection from acute radiation syndrome in mice. Int J Radiat Biol. 2022;98(5):958-967.

[80] Li Y, Girgis M, Jayatilake M, et al. Pharmacokinetic and metabolomic studies with a BIO 300 oral powder formulation in nonhuman primates. Sci Rep. 2022;12(1):13475.

[81] Yang E, Choi H, Park JS, et al. A first-in-human study of KMRC011, a potential treatment for acute radiation syndrome, to explore tolerability, pharmacokinetics, and pharmacodynamics. Clin Transl Sci. 2021;14(6):2161-2170.

[82] Wang S, Han Y, Zhang J, et al. Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation. Theranostics. 2020;10(22):10171-10185.

[83] Song F, Wang S, Pang X, et al. An active fraction of Trillium tschonoskii promotes the regeneration of intestinal epithelial cells after irradiation. Front Cell Dev Biol. 2021;9:745412.

[84] Yang JB, Zhu DQ, Shao M, et al. Effects of Shengmai Jianghuang san on intestinal flora in nude mice with radio resistant cells of nasopharyngeal carcinoma. Zhongguo Zhong Yao Za Zhi. 2019;44(3):553-558.

[85] Rockwell S, Grove TA, Liu Y, Cheng YC, Higgins SA, Booth CJ. Preclinical studies of the Chinese herbal medicine formulation PHY906 (KD018) as a potential adjunct to radiation therapy. Int J Radiat Biol. 2013;89(1):16-25.

[86] Satyamitra M, Cary L, Dunn D, Holmes-Hampton GP, Thomas LJ, Ghosh SP. CDX-301: a novel medical countermeasure for hematopoietic acute radiation syndrome in mice. Sci Rep. 2020;10(1):1757.

[87] Laube M, Kniess T, Pietzsch J. Development of antioxidant COX-2 inhibitors as radioprotective agents for radiation therapy—a hypothesis-driven review. Antioxidants (Basel). 2016;5(2):14.

[88] Singh VK, Seed TM, Olabisi AO. Drug discovery strategies for acute radiation syndrome. Expert Opin Drug Discov. 2019;14(7):701-715.

[89] Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science. 2001;293(5528):293-297.

[90] Yang L, Ran H, Yin Y, et al. Mitochondrial targeted cerium oxide nanoclusters for radiation protection and promoting hematopoiesis. Int J Nanomedicine. 2024;19:6463-6483.

[91] Brand RM, Epperly MW, Stottlemyer JM, et al. A topical mitochondria-targeted redox-cycling nitroxide mitigates oxidative stress-induced skin damage. J Invest Dermatol. 2017;137(3):576-586.

[92] Reis Ferreira M, Andreyev HJN, Mohammed K, et al. Microbiota- and radiotherapy-induced gastrointestinal side-effects (MARS) study: a large pilot study of the microbiome in acute and late-radiation enteropathy. Clin Cancer Res. 2019;25(21):6487-6500.

[93] Li Y, Yan H, Zhang Y, et al. Alterations of the gut microbiome composition and lipid metabolic profile in radiation enteritis. Front Cell Infect Microbiol. 2020;10:541178.

[94] Nam YD, Kim HJ, Seo JG, Kang SW, Bae JW. Impact of pelvic radiotherapy on gut microbiota of gynecological cancer patients revealed by massive pyrosequencing. PLoS One. 2013;8(12):e82659.

[95] Hollingsworth BA, Cassatt DR, DiCarlo AL, et al. Acute radiation syndrome and the microbiome: impact and review. Front Pharmacol. 2021;12:643283.

[96] Guo H, Chou WC, Lai Y, et al. Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites. Science. 2020;370(6516):eaay9097.

[97] The U.S. Department of Health and Human Services. Development of microbiome-related approaches for diagnosis/mitigation/treatment of radiation injuries (U01 Clinical Trial Not Allowed). Accessed September 20, 2021. https://grants.nih.gov/grants/guide/rfa-files/rfa-ai-21-068.html.

[98] Zhidu S, Ying T, Rui J, Chao Z. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Stem Cell Res Ther. 2024;15(1):266.

[99] Han Y, Yang J, Fang J, et al. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther. 2022;7(1):92.

[100] Stavely R, Nurgali K. The emerging antioxidant paradigm of mesenchymal stem cell therapy. Stem Cells Transl Med. 2020;9(9):985-1006.

[101] Kumar VP, Biswas S, Holmes-Hampton GP, et al. Pre-administration of PLX-R18 cells protects mice from radiation-induced hematopoietic failure and lethality. Genes (Basel). 2022;13(10):1756.

[102] Qian L, Cen J. Hematopoietic stem cells and mesenchymal stromal cells in acute radiation syndrome. Oxidative Med Cell Longev. 2020;2020:8340756.

[103] Taliaferro LP, Cassatt DR, Horta ZP, Satyamitra MM. Meeting report: a poly-pharmacy approach to mitigate acute radiation syndrome. Radiat Res. 2021;196(4):436-446.

[104] Chen HX, Xiang H, Xu WH, et al. Manganese superoxide dismutase gene-modified mesenchymal stem cells attenuate acute radiation-induced lung injury. Hum Gene Ther. 2017;28(6):523-532.

[105] Kim BH, Jung HW, Seo SH, Shin H, Kwon J, Suh JM. Synergistic actions of FGF2 and bone marrow transplantation mitigate radiation-induced intestinal injury. Cell Death Dis. 2018;9(3):383.

[106] Zhang L, Sun W, Wang J, et al. Mitigation effect of an FGF-2 peptide on acute gastrointestinal syndrome after high-dose ionizing radiation. Int J Radiat Oncol Biol Phys. 2010;77(1):261-268.

[107] Plett PA, Chua HL, Sampson CH, et al. PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), and IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome. Health Phys. 2014;106(1):7-20.

[108] Kumar VP, Wuddie K, Tsioplaya A, Weaver A, Holmes-Hampton GP, Ghosh SP. Development of a multi-organ radiation injury model with precise dosimetry with focus on GI-ARS. Radiat Res. 2024;201(1):19-34.

[109] Beach T, Bakke J, McDonald JT, et al. Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding. Front Public Health. 2024;12:1349552.

[110] Medhora M, Gao F, Gasperetti T, et al. Delayed effects of acute radiation exposure (Deare) in juvenile and old rats: mitigation by Lisinopril. Health Phys. 2019;116(4):529-545.

[111] Yan S, Brown SL, Kolozsvary A, Freytag SO, Lu M, Kim JH. Mitigation of radiation-induced skin injury by AAV2-mediated MnSOD gene therapy. J Gene Med. 2008;10(9):1012-1018.

[112] Wang L, Zhai M, Lin B, et al. PEG-G-CSF and L-citrulline combination therapy for mitigating skin wound combined radiation injury in a mouse model. Radiat Res. 2021;196(1):113-127.

[113] Li H, Kucharavy HC, Hajj C, et al. Radiation-induced gastrointestinal (GI) syndrome as a function of age. Cell Death Dis. 2023;9(1):31.

[114] Singh VK, Newman VL, Berg AN, MacVittie TJ. Animal models for acute radiation syndrome drug discovery. Expert Opin Drug Discov. 2015;10(5):497-517.

[115] Jackson IL, Gurung G, Poirier Y, et al. A New Zealand white rabbit model of thrombocytopenia and coagulopathy following total body irradiation across the dose range to induce the hematopoietic-subsyndrome of acute radiation syndrome. Int J Radiat Biol. 2021;97(sup1):S19-s31.

[116] Rodgers KE, Tan A, Kim L, et al. Development of a Guinea pig cutaneous radiation injury model using low penetrating X-rays. Int J Radiat Biol. 2016;92(8):434-443.

[117] Burnett LR, Gabard AR, Robinson M, et al. Biomolecular analysis of beta dose-dependent cutaneous radiation injury in a porcine model. Radiat Res. 2019;192(2):145-158.

[118] Rittase WB, McCart EA, Muir JM, et al. Effects of captopril against radiation injuries in the Göttingen minipig model of hematopoietic-acute radiation syndrome. PLoS One. 2021;16(8):e0256208.

[119] Moroni M, Coolbaugh TV, Lombardini E, et al. Hematopoietic radiation syndrome in the Gottingen minipig. Radiat Res. 2011;176(1):89-101.

[120] Doyle-Eisele M, Brower J, Aiello K, et al. Developing and comparing models of hematopoietic-acute radiation syndrome in Göttingen and Sinclair minipigs. Int J Radiat Biol. 2021;97(sup1):S73-s87.

[121] Elliott TB, Deutz NE, Gulani J, et al. Gastrointestinal acute radiation syndrome in Göttingen minipigs (Sus scrofa domestica). Comp Med. 2014;64(6):456-463.

[122] Kaur A, Ten Have GAM, Hritzo B, Deutz NEP, Olsen C, Moroni M. Morphological and functional impairment in the gut in a partial body irradiation minipig model of GI-ARS. Int J Radiat Biol. 2020;96(1):112-128.

[123] Foubert P, Doyle-Eisele M, Gonzalez A, et al. Development of a combined radiation and full thickness burn injury minipig model to study the effects of uncultured adipose-derived regenerative cell therapy in wound healing. Int J Radiat Biol. 2017;93(3):340-350.

[124] Moroni M, Lombardini E, Salber R, et al. Hematological changes as prognostic indicators of survival: similarities between Gottingen minipigs, humans, and other large animal models. PLoS One. 2011;6(9):e25210.

[125] Krigsfeld GS, Shah JB, Sanzari JK, Lin L, Kennedy AR. Evidence of disseminated intravascular coagulation in a porcine model following radiation exposure. Life Sci Space Res (Amst). 2014;3:1-9.

[126] MacVittie TJ, Jackson W 3rd. Acute radiation-induced GI-ARS and H-ARS in a canine model of mixed neutron/gamma relative to reference Co-60 gamma radiation: a retrospective study. Health Phys. 2020;119(3):351-357.

[127] Brooks JW, Evans EI, Ham WT Jr, Reid JD. The influence of external body radiation on mortality from thermal burns. Ann Surg. 1952;136(3):533-545.

[128] Hunter KS, Carnell LS, DiCarlo AL, Hoffman CM, Loelius SG, Homer M. Interagency approaches to animal models for acute radiation exposure. Int J Radiat Biol. 2021;97(sup1):S2-s5.

[129] Bolduc DL, Blakely WF, Olsen CH, et al. Baboon radiation quality (mixed-field neutron and gamma, gamma alone) dose-response model systems: assessment of H-ARS severity using haematological biomarkers. Radiat Prot Dosim. 2019;186(1):15-23.

[130] Carpenter AD, Li Y, Miranda IM, et al. Pharmacokinetic and metabolomic studies with BBT-059 in nonhuman primates exposed to total-body gamma radiation. Radiat Res. 2025;203(2):83-95.

[131] Bertho JM, Demarquay C, Frick J, et al. Level of Flt3-ligand in plasma: a possible new bio-indicator for radiation-induced aplasia. Int J Radiat Biol. 2001;77(6):703-712.

[132] Bertho JM, Frick J, Prat M, et al. Comparison of autologous cell therapy and granulocyte-colony stimulating factor (G-CSF) injection vs. G-CSF injection alone for the treatment of acute radiation syndrome in a non-human primate model. Int J Radiat Oncol Biol Phys. 2005;63(3):911-920.

[133] MacVittie TJ, Farese AM, Bennett A, et al. The acute gastrointestinal subsyndrome of the acute radiation syndrome: a rhesus macaque model. Health Phys. 2012;103(4):411-426.

[134] MacVittie TJ, Bennett A, Booth C, et al. The prolonged gastrointestinal syndrome in rhesus macaques: the relationship between gastrointestinal, hematopoietic, and delayed multi-organ sequelae following acute, potentially lethal, partial-body irradiation. Health Phys. 2012;103(4):427-453.

[135] Accardi MV, Donini O, Rumage A, et al. Characterization of a partial-body irradiation model with oral cavity shielding in nonhuman primates. Int J Radiat Biol. 2020;96(1):100-111.

[136] Cohen EP, Hankey KG, Bennett AW, Farese AM, Parker GA, MacVittie TJ. Acute and chronic kidney injury in a non-human primate model of partial-body irradiation with bone marrow sparing. Radiat Res. 2017;188(6):661-671.

[137] MacVittie TJ. Where are the medical countermeasures against the ARS and DEARE? A current topic relative to an animal model research platform, radiation exposure context, the acute and delayed effects of acute exposure, and the FDA animal rule. Int J Radiat Biol. 2023;99(7):994-1008.

[138] MacVittie TJ, Farese AM. Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule. J Radiol Prot. 2021;41(4):S438-S453.

[139] U.S. Food and Drug Administration. Acute radiation syndrome: developing drugs for prevention and treatment. Accessed April, 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acute-radiation-syndrome-developing-drugs-prevention-and-treatment.

[140] Winters TA, Cassatt DR, Harrison-Peters JR, et al. Considerations of medical preparedness to assess and treat various populations during a radiation public health emergency. Radiat Res. 2023;199(3):301-318.

[141] REMM. Cytokines for treatment of acute eposure to myelosuppressive doses of radiation: hematopoietic subsyndrome of acute radiation syndrome (H-ARS). Accessed July 30, 2025. https://remm.hhs.gov/cytokines.htm.

[142] Singh VK, Carpenter AD, Janocha BL, et al. Radiosensitivity of rhesus nonhuman primates: consideration of sex, supportive care, body weight, and age at time of exposure. Expert Opin Drug Discov. 2023;18(7):797-814.

[143] Patterson AM, Sellamuthu R, Plett PA, et al. Establishing pediatric mouse models of the hematopoietic acute radiation syndrome and the delayed effects of acute radiation exposure. Radiat Res. 2021;195(4):307-323.

[144] Torisawa YS, Spina CS, Mammoto T, et al. Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nat Methods. 2014;11(6):663-669.

[145] Jalili-Firoozinezhad S, Prantil-Baun R, Jiang A, et al. Modeling radiation injury-induced cell death and countermeasure drug responses in a human gut-on-a-chip. Cell Death Dis. 2018;9(2):223.

[146] Dasgupta Q, Jiang A, Wen AM, et al. A human lung alveolus-on-a-chip model of acute radiation-induced lung injury. Nat Commun. 2023;14(1):6506.

[147] U.S. Food and Drug Administration. Human organ chips for radiation countermeasure development. Accessed March 15, 2024. https://www.fda.gov/emergency-preparedness-and-response/preparedness-research/human-organ-chips-radiation-countermeasure-development.

[148] The U.S. Department of Health and Human Services. Development of alternative human models of radiation-induced injuries (extracorporeal systems) (U01 Clinical Trial Not Allowed). Accessed October 04, 2024. https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-24-067.html.

[149] Singh VK, Seed TM. Acute radiation syndrome drug discovery using organ-on-chip platforms. Expert Opin Drug Discov. 2022;17(8):865-878.

[150] Wang S, Zuo Z, Ouyang Z, et al. Sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production. Biochem Biophys Res Commun. 2024;704:149661.

[151] Wang Q, Qu Z, Tu S, Chen X, Hou Z. The whole-of-society approach of mass COVID-19 vaccination in China: a qualitative study. Health Res Policy Syst. 2022;20(1):142.

[152] Fahrni ML, Ismail IAN, Refi DM, et al. Management of COVID-19 vaccines cold chain logistics: a scoping review. J Pharm Policy Pract. 2022;15(1):16.

[153] Gao Y, Han L, Li J, et al. Establishment and verification of the dose-effect curve of dicentric chromosomes by semi-automatic analysis of human peripheral blood irradiated by X-ray in vitro. Int J Radiat Biol. 2025;101(6):590-597.

[154] Yu J, Khan MGM, Mayassi N, Kaushal B, Wang Y. Single-cell sequencing: an emerging tool for biomarker development in nuclear emergencies and radiation oncology. Cancers (Basel). 2025;17(11):1801.

[155] Kim JY, Cho SJ, Choi H, et al. Establishment of a radiation dose-response calibration curve using a rapid cytokinesis-block micronucleus assay for dose assessment of medical radiation equipment. Genome Integr. 2025;16:e20240003.

[156] Oh SJ, Jeong MH, Kang YR, et al. Automated system for establishing standard radiation dose-response curves and dose estimation for the Korean population. Sci Rep. 2025;15(1):10639.

[157] Ma L, Hu Z, Chen Y, Cheng Z, Shi C. Characterization of two stable biodosimeters for absorbed ionizing radiation dose estimation in multiple combined injury models. Radiat Res. 2025;204(1):27-45.

[158] Wei W, Bai H, Chen Y, et al. Circulating tRNA-derived small RNAs as novel radiation biomarkers of heavy ion, proton and X-ray exposure. Int J Mol Sci. 2021;22(24):13476.

[159] Pannkuk EL, Laiakis EC, Garty GY, et al. Sex differences in urinary metabolite profiles between survivors and non-survivors of radiation-induced lung injury in the C57L/J murine model. Radiat Res. 2025;204(1):1-14.

[160] Sproull M, Fan Y, Chen Q, Meerzaman D, Camphausen K. Comparison of novel proteomic expression profiles for radiation exposure in male and female C57BL6 mice. Radiat Res. 2024;201(6):558-566.

[161] Chen Q, Zhao H, Xi C, et al. Targeted lipidomics-based study of radiation-induced metabolite profiles changes in plasma of total body irradiation cases. Int J Radiat Biol. 2024;100(10):1481-1492.

[162] Pannkuk EL, Laiakis EC, Garty G, et al. Impact of partial body shielding from very high dose rates on untargeted metabolomics in biodosimetry. ACS Omega. 2024;9(32):35182-35196.

[163] Shuryak I, Ghandhi SA, Laiakis EC, et al. Biomarker integration for improved biodosimetry of mixed neutron + photon exposures. Sci Rep. 2023;13(1):10936.

[164] Ostheim P, Tichý A, Badie C, et al. Applicability of gene expression in saliva as an alternative to blood for biodosimetry and prediction of radiation-induced health effects. Radiat Res. 2024;201(5):523-534.

[165] Russ E, Fatanmi OO, Wise SY, et al. Serum microRNA profile of rhesus macaques following ionizing radiation exposure and treatment with a medical countermeasure, ex-rad. Sci Rep. 2024;14(1):4518.

[166] Schwanke D, Schüle S, Stewart S, et al. Validating a four-gene set for H-ARS severity prediction in peripheral blood samples of irradiated rhesus macaques. Radiat Res. 2024;201(5):504-513.

[167] Aryankalayil M, Bylicky MA, Chopra S, et al. Biomarkers for biodosimetry and their role in predicting radiation injury. Cytogenet Genome Res. 2023;163(3–4):103-109.

[168] Hecla J, Kambarian E, Tubbs R, et al. Radioactive contamination in feral dogs in the chernobyl exclusion zone: population body-burden survey and implications for human radiation exposure. PLoS One. 2023;18(7):e0283206.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.